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A Systematic Review of the Blood Pressure Lowering Efficacy of Calcium Channel Blockers in the Treatment of Primary > Hypertension

A Systematic Review of the Blood Pressure Lowering Efficacy of Calcium Channel Blockers in the Treatment of Primary > Hypertension

A SYSTEMATIC REVIEW OF THE PRESSURE LOWERING EFFICACY OF CHANNEL BLOCKERS IN THE TREATMENT OF PRIMARY >

by

MICHELLE MON YEE WONG

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF

MASTER OF SCIENCE

in

THE FACULTY OF GRADUATE STUDIES

( and Therapeutics)

THE UNIVERSITY OF BRITISH COLUMBIA

March 2007

© Michelle Mon Yee Wong, 2007 ABSTRACT

Context - blockers (CCBs) are widely used to lower elevated and manage and . Although the goal of antihypertensive therapy is to lower the risk of -related morbidity and mortality, efficacy is most often gauged by blood pressure reduction.

Objectives — This systematic review of the blood pressure lowering efficacy of CCBs aims to determine the dose-related changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), rate, and withdrawals due to adverse events (WDAE) with CCB treatment compared with placebo for a duration of 3-12 weeks, in patients with primary hypertension (SBP > 140 mm Hg and/or DBP > 90 mm Hg).

Design — A systematic review, as per the methodology of the Cochrane Collaboration, of randomized placebo-controlled trials.

Methods - Electronic databases were searched using a modified, expanded version of the search strategy used by the Cochrane Hypertension Review Group. RevMan 4.2 software was used to analyze data.

Participants — 106 trials were included and reported data on 13 878 patients with a mean age of 55 years, mean baseline blood pressure of 158.2/101.6 mm Hg, mean pulse pressure of 56.7 mm Hg, and mean treatment duration of 5.7 weeks.

Results — Maximal blood pressure lowering efficacy of CCBs is achieved at twice the manufacturer's recommended starring doses. This maximal reduction is 10/7 mmHg for dihydropyridines and 8/6 mmHg for non-dihydropyridines and likely represents an overestimate of the true blood pressure lowering effect due to publication bias. Combined,

ii dihydropyridines and non-dihydropyridines lower pulse pressure by 3 mm Hg (95% CI: -4, -

2). Compared with placebo, WDAE increased in a dose-related fashion for dihydropyridines

[relative risk of 1.8 (95% CI 1.2, 2.6) at 2 times the starting dose compared with 3.9 (95% CI:

2.2, 7.0) at 4 times the starting dose]. There were insufficient data to make a conclusion about the effect of non-dihydropyridines on WDAE.

Conclusion — Dihydropyridines reduce blood pressure to a greater degree than non- dihydropyridines. Maximal blood pressure lowering for both subclasses occurs with twice the manufacturer-recommended starring dose. Increasing the doses of dihydropyridines above recommended starting doses increases withdrawals due to adverse effects.

iii TABLE OF CONTENTS

ABSTRACT ii

TABLE OF CONTENTS iv

LIST OF TABLES ix

LIST OF FIGURES xii

LIST OF ABBREVIATIONS xiri

PREFACE xiv

ACKNOWLEDGEMENTS xv

1. BACKGROUND INFORMATION 1

1.1 HYPERTENSION 1 1.1.1 Definition of hypertension and its relation to cardiovascular morbidity and mortality • 1 1.1.2 Blood pressure variability, pulse pressure and : relation to cardiovascular outcomes 3 1.1.3 Types of chronic hypertension 4 1.1.3.1 Isolated systolic hypertension 4 1.1.3.2 Primary hypertension 5 1.1.3.3 Secondary hypertension 6 1.1.4 Management and treatment of chronic hypertension 6 1.1.4.1 Non-pharmacological treatment 6 1.1.4.2 Pharmacological treatment 7 1.1.5 Blood pressure reduction and cardiovascular events 9 1.1.6 Blood pressure measurement 10 1.1.7 Dose-response relationships 12

1.2 THE ROLE OF CALCIUM IN THE CARDIOVASCULAR SYSTEM 12 1.2.1 Calcium 12 1.2.2 Calcium Channels in the cardiovascular system 13

1.3 CALCIUM CHANNEL BLOCKERS 14 1.3.1 Historical Aspects 14 1.3.2 Classification .- 15 1.3.3 Pharmacodynamics of Calcium Channel Blockers 16 1.3.3.1 Molecular mechanism of action 16 1.3.3.2 Physiological effects 17 1.3.3.3 Phenylalkylamines 18 1.3.3.4 Benzothiazepines 18

iv 1.3.3.5 Dihydropyridines 19 1.3.3.6 Benzimidazolyls 19 1.3.4 Pharmacokinetics of calcium channel blockers 20 1.3.5 Clinical use of calcium channel blockers 21

1.4 SYSTEMATIC REVIEWS 27 1.4.1 What are systematic reviews? 27 1.4.2 How does a systematic review differ from a narrative review? 29 1.4.3 The Cochrane Collaboration 30 1.4.4 Arm of this systematic review 30

2 . PROTOCOL 32

2.1 OBJECTIVES 32 2.2 METHODOLOGY 32 2.2.1 Types of studies 32 2.2.1.1 Why are only randomized controlled trials included? 33 2.2.1.2 Why is a parallel placebo arm necessary? 33 2.2.1.3 Why is blinding (masking) necessary? 34 2.2.1.4 Why is a baseline measurement subsequent to or during a washout/placebo run-in period important? 35 2.2.1.5 Why is the 3-12 week window selected? 35 2.2.2 Types of participants 35 2.2.3 Types of interventions '. 36 2.2.4 Types of outcome measures 36 2.2.5 Search strategy for identification of studies 37 2.2.6 Study selection 42 2.2.7 Data extraction 42 2.2.8 Quality assessment 44 2.2.8.1 The Cochrane approach for assessment of allocation concealment.. 45 2.2.8.2 Jadad method 46 2.2.9 Data analysis 46 2.2.10 Statistical considerations 49 2.2.10.1 Individual study data 49 2.2.10.2 Pooling trials 50 2.2.11 Starting doses 51 2.2.12 Direct and indirect comparisons between doses 52

3. RESULTS 54

3.1 SEARCH FINDINGS 54 3.2 CHARACTERISTICS OF INCLUDED STUDIES 55 3.3 CHARACTERISTICS OF STUDIES AWAITING DATA FROM AUTHORS 134 3.4 CHARACTERISTICS OF EXCLUDED STUDIES 136 3.5 OVERVIEW OF INCLUDED TRIALS 146 3.6 VALUES USED TO IMPUTE MISSING VARIANCES 148

v 3.6.1 Standard deviation of blood pressure change 148 3.6.2 Standard deviation of heart rate change 149 3.7 DOSE-RELATED BLOOD PRESSURE LOWERfNG OF INDIVIDUAL CCB DRUGS 149 3.7.1 vs. placebo 150 3.7.2 vs. placebo 153 3.7.3 vs. placebo 154 3.7.4 vs. placebo 155 3.7.5 vs. placebo 159 3.7.6 vs. placebo 162 3.7.7 Lercamdipine vs. placebo 163 3.7.8 vs. placebo '. 165 3.7.9 vs. placebo 166 3.7.10 vs. placebo 168 3.7.11 vs. placebo 170 3.7.12 vs. placebo 171 3.7.13 vs. placebo 172 3.7.14 Prandipine vs. placebo 174 3.7.15 Summary of blood pressure lowering efficacy of dihydropyridines 175 3.7.15.1 Dihydropyridines - Assessment of publication bias 176 3.7.15.1.1 Dihydropyridines -subgroup analysis based on trial size 176 3.7.15.1.2 Dihydropyridines -trim and fill method 177 3.7.16 vs. placebo 180 3.7.17 vs. placebo 182 3.7.18 Tiaparnil vs. placebo 184 3.7.19 Summary of blood pressure lowering efficacy of non-dihydropyridines 185 3.7.19.1 Non-dihydropyridines - Assessment of publication bias 186 3.7.19.1.1 Non-cuhydropyridines-subgroup analysis based on trial size... 186 3.7.20 Other CCBs 188 3.7.20.1 vs. placebo 188 3.7.20.2 vs. placebo .189 3.8. BLOOD PRESSURE VARIABILITY 190 3.8.1 Systolic vs. diastolic blood pressure 190 3.8.2 Calcium channel blockers vs. placebo 191 3.8.3 Systolic vs. diastolic blood pressure entry criteria 191 3.8.4 Baseline vs. endpoint 192 3.9. PULSE PRESSURE 193 3.10. DOSE-RELATED CHANGE IN HEART RATE OF INDIVIDUAL CCB DRUGS :.. 194 3.10.1 Dihydropyridines vs. placebo 194 3.10.1.1 Amlodipine vs. placebo 195 3.10.1.2 Darodipine vs. placebo 196 3.10.1.3 Felodipine vs. placebo 196 3.10.1.4 Isradipine vs. placebo 197 3.10.1.5 vs. placebo 197 3.10.1.6 Manidipine vs. placebo 198 3.10.1.7 Nicardipine vs. placebo 198 3.10.1.8 Nifedipine vs. placebo 199 3.10.1.9 Nisoldipine vs. placebo 199 3.10.1.10 Nitrendipine vs. placebo 200 3.10.2 Non-dihydropyridines vs. placebo 200 3.10.2.1 Diltiazem vs. placebo 201 3.10.2.2 Verapamil vs. placebo 202 3.10.2.3 Tiapamil vs. placebo 202 3.10.3 Other calcium channel blockers 203 3.10.3.1 Lidoflazine vs. placebo , 203 3.10.3.2 Mibefradil vs. placebo 203 3.11 DOSE-RELATED WITHDRAWALS DUE TO ADVERSE EVENTS 205 3.11.1. Dihydropyridines vs. placebo 205 3.11.1.1 Amlodipine vs. placebo 206 3.11.1.2 Darodipine vs. placebo 206 3.11.1.3 Felodipine vs. placebo 207 3.11.1.4 Isradipine vs. placebo 207 3.11.1.5 Lercanidipine vs. placebo 208 3.11.1.6 Manidipme vs. placebo 208 3.11.1.7 Nicardipine vs. placebo 209 3.11.1.8 Nifedipine vs. placebo 210 3.11.1.9 Nilvadipine vs. placebo 210 3.11.1.10 Nisoldipme vs. placebo 211 3.11.1.11 Nitrendipine vs. placebo 211 3.11.1.12 Prandipine vs. placebo 212 3.11.2. Non-dihydropyridines vs. placebo 212 3.11.2.1 Diltiazem vs. placebo 213 3.11.2.2 Verapamil vs. placebo 214 3.11.3. Other calcium channel blockers 215 3.11.3.1 Mibefradil vs. placebo 215

. DISCUSSION 216

4.1 WHAT METHODOLOGICAL ISSUES AND POTENTIAL SOURCES OF BIAS WERE ENCOUNTERED WHILE CONDUCTING THE SYSTEMATIC REVIEW? 216 4.1.1 Publication bias 218 4.1.2 Selection bias , 220 4.2 WHAT IS THE DOSE-RELATED BLOOD PRESSURE LOWERING EFFICACY OF EACH SUBCLASS? IS THERE A DIFFERENCE IN THE BEST ESTIMATE OF THE MAGNITUDE OF BP LOWERING EFFECT OF DIFFERENT SUBCLASSES OF CCBS? 221 4.3 IS THERE A DIFFERENCE IN THE BEST ESTIMATE OF THE MAGNITUDE OF BP LOWERING EFFECT OF DRUGS IN EACH SUBCLASS? 222 4.4 WHAT IS THE EFFECT ON BLOOD PRESSURE IN THE PLACEBO GROUP IN SHORT-TERM TRIALS? 222 4.5 DOES THE METHOD OF BLOOD PRESSURE MEASUREMENT AFFECT THE BLOOD PRESSURE LOWERING EFFICACY OF CCBS? 223 4.6 DOES TRIAL QUALITY AFFECT THE BLOOD PRESSURE-LOWERING EFFICACY OF CALCIUM CHANNEL BLOCKERS? 223 4.7 WAS THERE A DIFFERENCE IN BLOOD PRESSURE LOWERING EFFICACY AT TROUGH VS. PEAK? ...224

vii 4.8 DID FUNDING SOURCE AFFECT THE REPORTED BLOOD PRESSURE LOWERING EFFICACY OF CCBS? 224 4.9 DOES AGE AFFECT THE BLOOD PRESSURE LOWERING EFFICACY OF CCBS? 225 4.10 DOES CO-MORBIDITY ALTER THE BLOOD PRESSURE LOWERING EFFICACY OF CCBs? 226 4.11 DOES BLOOD PRESSURE LOWERING EFFICACY OF CCBs DIFFER FOR ISOLATED SYSTOLIC HYPERTENSION VS. DIASTOLIC OR SYSTO-DIASTOLIC HYPERTENSION?.... 226 4.12 How DO THE DIRECT COMPARISONS BETWEEN DOSES DIFFER FROM THE INDIRECT COMPARISONS? 227 4.13 FOR EACH CCB , DO THE MANUFACTURER'S STARTING DOSES COINCIDE WITH THE LOWEST EFFECTIVE DOSE AS DETERMINED BY THIS SYSTEMATIC REVIEW? 228 4.14 WHAT IS THE EFFECT OF CCBs ON BP VARIABILITY? 229 4.15 WHAT IS THE EFFECT OF CCBs ON PULSE PRESSURE? 231 4.16 Is TFIERE ANY EVIDENCE OF A DOSE-RESPONSE RELATIONSHIP WITH RESPECT TO CHANGE IN HEART RATE? 232 4.17 IS THERE ANY EVIDENCE OF A DOSE-REPONSE RELATIONSHIP WITH RESPECT TO WITHDRAWALS DUE TO ADVERSE EVENTS? 232 4.18 CAN THE MAGNITUDE OF BLOOD PRESSURE LOWERING EFFICACY OF CALCIUM CHANNEL BLOCKERS BE LINKED TO THEIR MECHANISM OF ACTION? 233 4.19 HOW CAN TFIE BLOOD PRESSURE LOWERING EFFICACY OF CALCIUM CHANNEL BLOCKERS IN SHORT-TERM TRIALS BE RELATED TO THEIR EFFECTS ON MORTALITY AND MORBIDITY OUTCOMES IN LONG-TERM TRIALS? 234

5. CLINICAL IMPLICATIONS 237

6. IMPLICATIONS FOR FUTURE RESEARCH 240

7. REFERENCES 243

8. APPENDICES 277 APPENDIX A - TRIAL SELECTION FORM 277 APPENDIX B - STANDARD DATA EXTRACTION FORM FOR EACH TRIAL 278

viii LIST OF TABLES

Table 1: Classes of current drugs used to treat hypertension 7 Table 2: Comparison of 3 hypertension guidelines 8 Table 3: Classification of group A calcium antagonists 16 Table 4: Group B calcium antagonists 16 Table 5: Pharmacokinetic parameters of CCBs 21 Table 6: Long term clinical trials of CCBs for treatment of hypertension 24 Table 7: Data input for continuous data in RevMan 49 Table 8: Data input for dichotomous data in RevMan 49 Table 9: Formulae for individual study responses for dichotomous data in RevMan 49 Table f 0: Starting doses of calcium channel blockers 52 Table 11: Results of search strategy 54 Table 12: Amlodipine — Characteristics of included studies 56 Table 13: Barnidipine — Characteristics of included studies 62 Table 14: Darodipine — Characteristics of included studies 63 Table 15: Diltiazem — Characteristics of included studies ; 64 Table 16: Felodipine — Characteristics of included studies 73 Table 17: Isradipine — Characteristics of included studies 81 Table 18: Lacidipine — Characteristics of included studies 89 Table 19: Lercanidipine — Characteristics of included studies 90 Table 20: Lidoflazine — Characteristics of included studies 94 Table 21: Manidipine — Characteristics of included studies 95 Table 22: Mibefradil - Characteristics of included studies 97 Table 23: Nicardipine— Characteristics of included studies 100 Table 24: Nifedipine — Characteristics of included studies 105 Table 25: Nilvadipine — Characteristics of included studies 113 Table 26: Nisoldipine — Characteristics of included studies 115 Table 27: Nitrendipine — Characteristics of included studies 116 Table 28: — Characteristics of included studies 123 Table 29: Tiapamil — Characteristics of included studies : 124 Table 30: Verapamil - Characteristics of included studies 125 Table 31: Characteristics of studies awaiting office blood pressure data from authors ... 134 Table 32: Reasons for exclusion of certain studies meeting inclusion criteria 136 Table 33: Overview of included trials using CCBs as monotherapy for primary hypertension 146 Table 34: Blood pressure lowering efficacy of amlodipine 1.25-10 mg/day 150 Table 35: Blood pressure lowering efficacy of barnidipine 10-30 mg/day 153 Table 36: Blood pressure lowering efficacy of darodipine 100-300 mg/day 154 Table 37: Blood pressure lowering efficacy of felodipine 2.5-20 mg/day 155 Table 38: Blood pressure lowering efficacy of felodipine in older and younger subgroups. 156 Table 39: Blood pressure lowering efficacy of felodipine in trials with inclusion criteria of systolic/systodiastolic hypertension vs. diastolic hypertension 157 Table 40: Blood pressure lowering efficacy of isradipine 1-20 mg/day 159 Table 41: Blood pressure lowering efficacy of isradipine according to formulation 160 Table 42: Blood pressure lowering efficacy of lacidipine 2-4 mg/day 162 Table 43: Blood pressure lowering efficacy of lercanidipine 2.5-20 mg/day 163 Table 44: Blood pressure lowering efficacy of manidipine 10-40 mg/day 165

ix Table 45: Blood pressure lowering efficacy of nicardipine 40-120 mg/day 166 Table 46: Blood pressure lowering efficacy of nifedipine 20-100 mg/day 168 Table 47: Blood pressure lowering efficacy of nilvadipine 8-30 mg/day 170 Table 48: Blood pressure lowering efficacy of nisoldipine 10-30 mg/day 171 Table 49: Blood pressure lowering efficacy of nitrendipine 5-20 mg/day 172 Table 50: Blood pressure lowering efficacy of pranidipine 1-8 mg/day 174 Table 51: Summary of blood pressure lowering efficacy of dihydropyridines 175 Table 52: Blood pressure lowering efficacy of dihydropyridines combined according to multiples of starting dose 176 Table 53: Dihydropyridines: post-hoc subgroup analysis of trough BP lowering based on trial size 177 Table 54: Blood pressure lowering efficacy of diltiazem 90 - 540 mg/day 180 Table 55: Blood pressure lowering efficacy of verapamil 60 — 540 mg/day 182 Table 56: Blood pressure lowering efficacy of tiapamil 300-1200 mg/day 184 Table 57: Summary of blood pressure lowering efficacy of non-dihydropyridines 185 Table 58: Blood pressure lowering efficacy for non-chhydropyridines combined according to multiples of starting dose 186 Table 59: Non-dihydropyridines: post-hoc subgroup analysis of trough blood pressure lowering based on trial size 187 Table 60: Blood pressure lowering efficacy of lidoflazine 180 mg/day 188 Table 61: Blood pressure lowering efficacy of mibefradil 6.25-100 mg/day 189 Table 62: Variability of SBP and DBP at end of treatment '. 190 Table 63: Baseline standard deviations of blood pressure according to entry criteria 191 Table 64: Standard deviations of BP at baseline vs. endpoint in trials with DBP entry criteria 192 Table 65: Change in pulse pressure 193 Table 66: Effect of dihydropyridines on heart rate 195 Table 67: Effect of amlodipine on heart rate 195 Table 68: Effect of darodipine on heart rate 196 Table 69: Effect of felodipine on heart rate 196 Table 70: Effect of isradipine on heart rate 197 Table 71: Effect of lercanidipine on heart rate 197 Table 72: Effect of manidipine on heart rate 198 Table 73: Effect of nicardipine on heart rate 198 Table 74: Effect of nifedipine on heart rate 199 Table 75: Effect of nisoldipine on heart rate 199 Table 76: Effect of nitrendipine on heart rate 200 Table 77: Effect of non-cuhydropyridines (diltiazem and verapamil) on heart rate 201 Table 78: Effect of diltiazem on heart rate 201 Table 79: Effect of verapamil on heart rate 202 Table 80: Effect of tiapamil on heart rate 202 Table 81: Effect of lidoflazine on heart rate 203 Table 82: Effect of mibefradil on heart rate 203 Table 83: Effect of dihydropyridines on withdrawals due to adverse events 205 Table 84: Effect of amlodipine on withdrawals due to adverse events 206 Table 85: Effect of darodipine on withdrawals due to adverse events 206 Table 86: Effect of felodipine on withdrawals due to adverse events 207 Table 87: Effect of isradipine on withdrawals due to adverse events 207 Table 88: Effect of lercarridipine on withdrawals due to adverse events 208 Table 89: Effect of manidipine on withdrawals due to adverse events 208 Table 90: Effect of nicardipine on withdrawals due to adverse events 209 Table 91: Effect of nifedipine on withdrawals due to adverse events 210 Table 92: Effect of nilvadipine on withdrawals due to adverse events 210 Table 93: Effect of nisoldipine on withdrawals due to adverse events 211 Table 94: Effect of nitrendipine on withdrawals due to adverse events 211 Table 95: Effect of pranidipine on withdrawals due to adverse events 212 Table 96: Effect of non-dihydropyridines on withdrawals due to adverse events 213 Table 97: Effect of diltiazem on withdrawals due to adverse events 213 Table 98: Effect of verapamil on withdrawals due to adverse events 214 Table 99: Effect of mibefradil on withdrawals due to adverse events 215 Table 100: Comparison of manufacturer's recommended starting doses and lowest effective doses determined in this systematic review : 228

xi LIST OF FIGURES

Figure 1: Binding sites of calcium drugs 17 Figure 2: Example of a forest plot 47 Figure 3: Log dose-response curve for amlodipine 1.25-10 mg/day 152 Figure 4: Funnel plot of standard error against effect size of change in SBP for amlodipine 5 to 20 mg/day 152 Figure 5: Funnel plot of standard error against effect size of change in SBP for felodipine 5 to 20 mg/day 158 Figure 6: Funnel plot of change in SBP for dihydropyridines at maximal blood pressure lowering 178 Figure 7: Funnel plot of change in DBP for dihydropyridines at maximal blood pressure lowering 179

xii LIST OF ABBREVIATIONS

Ambulatory Blood Pressure Monitoring ABPM Blood Pressure BP CCB Calcium ion Ca2+ Cardiovascular CV Cochrane Collaboration CC Confidence Interval CI Congestive CHF Consolidated Standards of Reporting CONSORT Controlled Delivery CD Coronary heart disease CFID Diastolic Blood Pressure DBP Double-Blind DB Electrocardiogram ECG Female f Gastro-fntestinal Therapeutic System GfTS Hazard Ratio - HazR Heart Rate HR fsolated Systolic Hypertension 1SH National Committee JNC Male ' m Mean Arterial Pressure MAP Medical Subject Heading MeSH Mercury Hg Milligram mg Millimetres of mercury mm Hg Multicentre MC Odds Ratio OR Placebo-Controlled PC Randomized Controlled Trial RCT Randomized R Relative Risk (Risk Ratio) RR Review Manager RevMan Slow-Release SR Standard Deviation SD Standard Error of the Mean SEM Systolic Blood Pressure SBP Weighted Mean Difference WMD Withdrawals Due to Adverse Events WDAE World Flealth Organization - International Society of Hypertension WHO/fSH PREFACE

"...evidence based medicine requires you not only to read papers but to read the right papers at the right time and then to alter your behaviour (and, what is often more difficult, the behaviour of other people) in the light of what you have found." - Trisha Greenhalgh, 1997 (from: Flow to read a paper: the basics of evidence based medicine. London: BMJ Publishing Group, p. 2)

xiv ACKNOWLEDGEMENTS

I wish to thank my supervisor, Dr. James M. Wright, for his patience and guidance.

His dedication to revealing the truth about drug efficacy and safety has inspired me to be involved in evidence-based medicine research.

I would also like to thank my other supervisory committee members, Dr. David

Godin, Dr. Casey Van Breemen and Dr. Michael Walker, for their comments and expertise.

I wish to express my gratitude to all the members of the Therapeutics Initiative and the Cochrane Hypertension Group for their support over the last few years. I wish to thank

Dr. Ken Bassett and Dr. Tom Perry, Jr. for their guidance on my critical appraisal projects and Mr. Ciprian Jauca for his coordinating efforts for the TI and the Hypertension Group.

I would like to extend my appreciation to those who helped me execute this systematic review. Especially, I am indebted to Dr. Vijaya Musini for her assistance and direction throughout every stage of this review. I am grateful to Mr. Benji Heran for being the second independent reviewer and for developing a new, high-yield search strategy. Mr.

Stephen Adams retrieved a myriad of articles for this systematic review, and his efficiency was invaluable. I also wish to thank Dr. Sonia Franciosi, Ms. Laurence Jacquaz, Dr. Marco

Perez, Dr. Frederique Rodieux, Dr. Stephan Schwarz, Dr. Michelle Van den Engh, and Dr.

Alexander Zolotoy for translation of foreign language articles. I must also thank all of the authors who took the time and effort to correspond with me during the process of developing this review.

I would like to thank my systematic review colleagues, of past and present, for their camaraderie: Benji, Marco, Jenny, Vijaya, Cremona, Dal and Jose.

Last but not least, I thank my family for their unconditional support in all my endeavors.

xv 1. BACKGROUND INFORMATION

1.1 Hypertension

Hypertension, or elevated blood pressure, depending on how it is denned, is present in up to 20-30% of adults (1). Although often referred to as a "silent disease", hypertension is actually a surrogate marker and major risk factor for cardiovascular disease (2), rather than a disease itself. Elevated blood pressure is a risk factor for stroke, coronary disease

(CAD) and congestive heart failure (CHF), and these cardiovascular diseases are the most common causes of morbidity and mortality in developed countries. Elevated blood pressure has been estimated to cause 4.5% of global disease burden (3). However, developing countries have a greater share of the global burden of cardiovascular disease mortality than developed countries (4).

1.1.1. Definition of hypertension and its relation to cardiovascular morbidity and mortality

The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC) describes the relationship between systolic blood pressure and cardiac risk as "strong, continuous, graded, consistent, independent, predictive and

etiologically significant" (5). Rather • than using a strict numerical divide between normotension and hypertension, it is more practical to define hypertension as "that level of blood pressure above which investigation and treatment do more good than harm" (6), or

stated more precisely by Kaplan: "that level of blood pressure at which the benefits (minus

the risks and costs) of action exceed the risks and costs (minus the benefits) of inaction" (7).

With this pragmatic clinical approach, the definition is subject to change as new evidence

1 regarding the treatment of hypertension becomes available. This definition also underscores the importance of individualizing the diagnosis and treatment of hypertension.

There are two views of the epidemiologic data relating BP to adverse cardiovascular events. One view is that the risk is linear and continuous and the other is that there is a threshold. The concept of individualizing the diagnosis of hypertension according to age and sex was the focus of a recent reanalysis of epidemiological data from the Framingham

Heart study (8). Using a logistic spline model, they proposed that overall mortality is unrelated to SBP at pressures below an age- and sex-dependent threshold (approximately at the 70th percentile). However, above the 80th percentile, the mortality risk increases logistically. The numerical criteria used to define normotension and hypertension are thus arbitrary and subject to change. In another study involving a meta-analysis of observational data from individual patients aged 40-89 years, they found a direct relationship between vascular mortality (due to stroke, ischemic heart disease and other vascular casuses) and blood pressure for each decade of age (9). For ages 40-69, each difference of 20 mm Hg from the "usual" SBP for each age group, or 10 mm Hg from the "usual" DBP age was associated with a two-fold difference in vascular mortality (9). However, there were no data representing patients with blood pressures less than 115/75 mm Hg, and data on overall mortality were also not reported.

Although elevated blood pressure itself is generally asymptomatic, the target organ damage resulting from chronic hypertension is the antecedent to cardiovascular morbidity and mortality. In hypertension, the increased on the heart leads to diastolic and systolic dysfunction, which can subsequently lead to heart failure. Combined with the increase in myocardial oxygen demand, the decrease in coronary oxygen supply that results

from the hypertension-induced acceleration of atherosclerosis can lead to myocardial

2 infarction. Arterial damage from hypertension also contributes to the development of aortic aneurysm/dissection, stroke, retinopathy, nephrosclerosis and renal failure.

According to 1999 Canadian Hypertension Guidelines, chronic hypertension is diagnosed in 3 clinic visits if resting BP exceeds the arbitrary threshold of 140/90 mm Hg and there is target organ damage or resting BP is over 180/105 mm Hg, and in 5 visits over

6 months if these features are absent but the resting mean BP remains over 140/90 mm Hg

(10).

1.1.2. Blood pressure variability, pulse pressure and heart rate: relation to cardiovascular outcomes

The degree of variation of blood pressure throughout a 24-hour period is important clinically because it correlates with severity of target organ damage and contributes to the risk of cardiovascular mortality in hypertensive patients (11). Blood pressure variability tends to be increased in patients with primary hypertension (11). Furthermore, increased systolic BP variability has been found to predict progression of carotid artery wall atherosclerosis and rate of cardiovascular events independently of increased blood pressure itself (12). More prospective studies utilizing continuous ambulatory blood pressure monitoring are necessary to confirm the prognostic value of blood pressure variability.

Pulse pressure, calculated as the difference between systolic and diastolic blood pressure, can be considered an element of blood pressure variability because it reflects the blood pressure changes within the cardiac cycle (11). A marker of arterial stiffness, the magnitude of the pulse pressure also depends on stroke volume and the speed of reflected pressure waves. Pulse pressure correlates not only with surrogate outcomes such as carotid artery damage, but also with major cardiovascular endpoints. For example, clinic-measured pulse pressure has been linked to recurrent events after myocardial infarction in patients with

3 left ventricular dysfunction (13). The Progetto Ipertensione Umbria Monitoraggio

Ambulatoriale (PIUMA) registry of subjects with primary hypertension showed that ambulatory pulse pressure was a strong independent predictor of total cardiovascular risk, with better prognostic value than pulse pressure derived from conventional BP readings (14).

An epidemiologic study showed that pulse pressure appeared to be the best blood pressure parameter in predicting mortality in people > 65 years old (15).

Elevated resting heart rate is also considered an important predictor of hypertension and a risk factor for cardiovascular and non-cardiovascular death. In the Frarningham study, those with a baseline resting heart rate of greater than 84 beats per minute were shown to be at significandy increased cardiovascular risk than those with lower heart rates (16).

Blood pressure parameters aside, many other risk factors that contribute to cardiovascular disease have been identified through monitoring of the Frarningham study population (17). These include non-modifiable factors such as male gender, increased age

(>55 years for men, > 65 years for women), positive family history of premature cardiovascular disease, prior cerebrovascular accident or myocardial infarction, and modifiable factors such as smoking, dyslipidemia, diabetes mellitus, increased weight, low physical activity and left ventricular hypertrophy.

1.1.3. Types of chronic hypertension

1.1.3.1 Isolated systolic hypertension

The definition of isolated systolic hypertension (ISH) is in flux and varies from SBP

> 160 mm Hg and DBP < 95 mm Hg to SBP > 140 mm Hg and DBP < 90 mm Hg (17).

Since systolic blood pressure rises with age, ISH is the most common form in the elderly.

Pulse pressure is increased in this population as well. The main cause of an increase in SBP

4 (and concomitant decline in DBP) is thought to be tidckening and stiffening of conduit resulting from degeneration of the arterial wall after exposure to chronic cyclic stress

(18). This reduced arterial compliance enhances the amplitude and velocity of the pressure wave originating from the heart. Hence, the pressure wave is reflected from peripheral to central arteries earlier, thus increasing the pressure in late (18). The increases in afterload and myocardial work can lead to left ventricular hypertrophy. Coupled with diminished coronary perfusion pressure, these increased strains on the heart could contribute to myocardial .

1.1.3.2. Primary hypertension

Primary hypertension, or so-called "essential" hypertension comprises over 90% of hypertensive patients, and implies that there is no known cause. Vascular alterations in hypertension include decreased lumen diameter, increased reactivity and stiffness, and increased wall thickness-to-lumen ratio of resistance vessels (19). Rather than attributing these alterations merely to vascular growth, some studies have shown that the same amount of vascular material is restructured via a process termed "eutrophic remodelling" (20).

Hypertension is also associated with impairment of endothelial activity, though it remains to be discovered if nitric oxide dysfunction is a cause or consequence of hypertension (21).

According to the mosaic theory of primary hypertension, the interplay of multiple genetic and environmental factors contributes to elevated arterial pressure (22). Because of this multifactorial nature, there is large heterogeneity in individual responses to any antihypertensive . The ongoing Genetics of Hypertension Associated Treatment

(GenHAT) study is assessing how hypertension susceptibility genes interact with antihypertensive drugs to modify blood pressure response and risk of coronary heart disease

5 (23). This pharmacogenetic study is analyzing various polymorphisms of genes regulating the renin-angiotensin- system, sodium-volume homeostasis, insulin resistance, and sympathetic activation.

1.1.3.3. Secondary hypertension

Hypertension that arises secondary to some identifiable mechanism is less common.

Several secondary causes of hypertension have been identified, including renal (e.g. nephritis, renal artery stenosis), endocrinological (e.g. Cushing's syndrome, phaeochromocytoma), and neurological (e.g. encephalitis, porphyria). Other causes include coarctation of the aorta, pregnancy, and or drug use.

1.1.4. Management and treatment of primary hypertension

1.1.4.1 Non-pharmacological treatment

All hypertension guidelines agree on the use of non-pharmacological control of blood pressure as first-line treatment, including diet alteration (e.g. reduced intake of salt), weight reduction, smoking cessation and dynamic exercise. A systematic review of short- term sodium restriction in patients with elevated blood pressure demonstrated modest decreases in SBP and DBP (by about 4 and 2 mm Hg, respectively) (24). Another Cochrane review of long-term restriction in dietary salt found an even smaller effect size, with decreases in SBP by 1.1 mm Hg and in DBP by 0.6 mm Hg (25). An analysis of 44 trials that assessed the effect of exercise on resting BP demonstrated that the average reductions in SBP and DBP in hypertensive patients were 7.4 mm Hg and 5.8 mm Hg, respectively, compared to a reduction of 2.6 mm Hg and 1.8 mm Hg in normotensive patients (26).

Because of a lack of relationship between exercise frequency, time per session, or intensity and the magnitude of blood pressure reduction, it is suggested that the dose-response curve is flat (26).

6 1.1.4.2. Pharmacological treatment

From a historical perspective, pharmacological treatment of hypertension has evolved from a few agents with many adverse effects that were reserved only for severe/malignant hypertension, to a wide array of currendy available drugs with diverse mechanisms of action (Table 1). During the 1940s, veratrum alkaloids, thiocyanates, and ganglion blockers such as hexamethonium were some of the only pharmacological alternatives to bilateral sympathectomy and rigid sodium restriction (27). From the 1950s onwards, a better understanding of the pathogenesis of hypertension has led to the development several new classes of antihypertensive drugs: rauwolfia alkaloids such as , vasodilators such as , peripheral sympathetic inhibitors such as guanethidine, and such as chlorothiazide. In the 1960s, beta blockers and centrally acting sympathetic inhibitors (e.g. alpha ) were introduced. In the

1970s, alpha adrenergic blockers and angiotensin converting enzyme inhibitors were made available, followed by calcium channel blockers in the 1980s and angiotensin II blockers in the 1990s.

Table 1: Classes of current drugs used to treat hypertension Class Example Thiazide diuretics Hydrochlorothiazide Loop diuretics Beta blockers ACE Inhibitors Alpha blockers Prazosin Calcium channel blockers Amlodipine, verapamil, diltiazem Autonomic agents Reserpine Angiotensin II receptor antagonists

Currendy, the most optimal management of hypertension is unclear. Supposedly evidence-based guidelines are highly variable with respect to the thresholds for initiation of anti-hypertensive therapies and the choice of initial drugs (Table 2) (28).

7 Table 2: Comparison of 3 hypertension guidelines (28) Drug treatment BP Canadian Joint Natinional World Health threshold Committee (JNC) Organization/ VI International Society of Hypertension 1999 No target organ 160/100 mmHg 140/90 mm Hg 150/95 mmHg damage or risk (160/105 mm Hg if factors 60 yrs. or older) With CV risk factors 160/90 mm Hg 140/90 mm Hg 140/90 mmHg (other than diabetes mellitus) With target organ 160/90 mm Hg 130/85 mmHg 140/90 mm Hg damage With diabetes 140/90 mm Hg 130/85 mm Hg 130/85 mmHg mellitus or renal disease Choice of initial drugs < 60 years old Thiazides, beta Diuretics or beta All available drug blockers or ACE blockers classes inhibitors > 60 years old , long- Thiazides, beta Diuretics or CCBs acting CCBs blocker-thiazide combinations, or long-acting CCBs

With the numerous classes of antihypertensive drugs available, selection of a first- line agent should be based on mortality and morbidity data from long-term randomized controlled trials. Wright et al's systematic review of randomized controlled trials of first-line antihypertensive therapies selected studies of at least one year's duration that provided data on morbidity and mortality (29). The review showed that low-dose thiazide diuretics decreased mortality (relative risk [RR] 0.89, 95% confidence interval [CI] 0.81-0.99], stroke

(RR 0.66, 95% CI 0.56-0.79), (RR 0.71, 95% CI 0.60-0.84) and total cardiovascular events (RR 0.68, 95% CI 0.62-0.75) compared with placebo or no treatment.

Eligh-dose diuretics showed similar results for stroke and total cardiovascular events, except there was no statistically significant difference compared with no treatment in death and

8 CAD. For first-line beta blockers there was no statistically significant difference compared with placebo/no treatment for all four outcomes. For calcium channel blockers, one placebo-controlled trial (SYST-EUR) showed a reduction in the risk of stroke (RR 0.61, 95%

CI 0.43-0.87) and cardiovascular events (RR 0.71, 95% CI 0.57-0.87) but not death and

CAD. In terms of blood pressure lowering efficacy, the drop in SBP was statistically significandy greater with thiazides than with beta blockers or CCBs, while the drop in DBP was similar among all three of these classes.

Using a technique called "network meta-analysis", Psaty et al. combined cardiovascular endpoint data from both placebo-controlled and comparative trials of first- line antihypertensive agents (30). For CAD, CHF, stroke, cardiovascular disease events, cardiovascular mortality and total mortality, low-dose thiazide diuretics were superior to placebo. None of the other classes of agents (beta blockers, ACE inhibitors, CCBs, alpha blockers, angiotensin receptor blockers) were significantly better than low-dose diuretics in any of the listed outcomes. In comparison with CCBs, low dose diuretics were associated with a reduction in CHF (RR, 0.75; 95% CI, 0.67-0.81) and cardiovascular disease events

(RR, 0.94; 95% CI, 0.89-1.00).

Thus, results from both Wright et al. and Psaty et al.'s analyses support the use of low-dose thiazide diuretics as first choice for first-line drug therapy for treatment of hypertension. The JNC guidelines support this approach (17).

1.1.5. Blood pressure reduction and cardiovascular events

Meta-analyses of major clinical trials have demonstrated clear benefits of antihypertensive therapy, including reductions in cardiac and cerebrovascular events.

Although the goal of any antihypertensive therapy is to lower the risk of cardiovascular

9 disease-related morbidity and mortality outcomes (5), efficacy is most often gauged by blood pressure reduction, a validated surrogate outcome.

1.1.6. Methods of blood pressure measurement

Blood pressure is a highly variable measurement that is modified by many unknown and known factors, including circadian rhythm, seasonal variation, activity level and emotional state. Despite this obstacle, blood pressure measurement is a universal tool in medical practice. Since hypertension is generally clinically silent, accurate diagnosis and treatment would not be possible without proper use of instruments to measure blood pressure (31). There are two modalities of measuring blood pressure: 1) non-invasively, using an indirect method by which pressure in an occlusive cuff is correlated with blood flow phenomena, and 2) invasively, using a catheter to obtain a direct measure (32).

The indirect method of auscultation is the historical standard for recording clinic blood pressure. The Korotkoff sounds involved in indirect blood pressure measurement originate from the intra-vessel turbulence and vibrations during compression of the brachial artery. The appearance of Korotkoff sounds (phase I) as the bladder cuff deflates correlates with the systolic blood pressure, while the disappearance of these sounds (phase V) best reflects the diastolic blood pressure. There are several factors that can interfere with accurate blood pressure measurement — these arise from the patient, the measurer, the instrument and the technique (33). Given the fluctuation of blood pressure during clinical measurements, the average of two or more blood pressure measurements in a single arm is a more reliable than a single reading. There are also substantial variations in blood pressure throughout the day and with routine activities. Other patient factors such as bowel or bladder distension, emotional extremes, recent ingestion of alcohol, and even talking can

10 elevate blood pressure. Measurer factors include the rate of cuff inflation and deflation, hearing acuity, and expectation bias, including end-digit preference. Technique factors include device calibration, cuff size, and arm position. The most common physician mistakes in blood pressure measurement include using an inappropriately small cuff, failing to allow a pre-measurement rest period of 5 minutes, deflating the cuff too fast, failing to measure in both arms, and failing to palpate maximal systolic blood pressure before auscultation (33).

Automated instruments utilize auscultatory, oscillometric or Doppler ultrasound techniques. The most commonly used devices are oscillometric and employ proprietary algorithms to determine blood pressures. Despite existing validation protocols that are used to test these devices, the accuracy of available devices is highly variable (34). A small study by Gerin et al found that office blood pressures measured with an automatic device in the absence of a doctor or nurse were more representative of daily ambulatory pressure than physician- or nurse- measurements (35). Studies have shown that automated pressures tended to be lower than those recorded by a doctor or nurse. "White-coat hypertension" refers to patients who are diagnosed with hypertension according to clinic pressures measured by medical staff but who have normal ambulatory pressures. "White coat" effects can increase blood pressure by more than 20 mm Hg (SBP) and 10 mm Hg (DBP) in up to

40% of patients (33).

The position of measurement impacts blood pressure readings. Blood pressures measured in the supine position show an increase of 0-3 mm Hg in SBP and a 2-5 mm Hg decrease in DBP compared to those measured in the sitting position (33). Expected orthostatic changes upon standing consist of a decrease in SBP (5-10 mm Hg), a rise in DBP

(5 mm Hg), and an increase in heart rate by 5-10 beats per minute (33). It is not known if

11 position of measurement impacts the blood pressure lowering efficacy of antihypertensive agents.

1.1.7. Dose-response relationships

The most fundamental concept in pharmacology and therapeutics is the log-linear dose-response curve, which quantitatively describes drug actions, whether therapeutic or toxic. In the past, several antihypertensive drugs were commonly prescribed at excessively high doses due to a lack of formal dose-response studies (27). Dose-response analyses of drugs are important in order to identify the lowest possible dose that is both efficacious and safe. Several factors can affect the pharmacodynamic dose-response curves of antihypertensive , including population variation and length of therapy (acute versus chronic). Blood pressure decreases can be offset by counterregulatory mechanisms, such as volume retention and reflex . The pharmacokinetic properties of an can also affect the magnitude of its effect depending on the time that blood pressure is measured relative to drug administration. The trough-to-peak ratio is calculated as the blood pressure decrease at the end of the dosage interval divided by the largest blood pressure decrease during the dosage interval, which usually occurs at the time of peak plasma drug concentration. As the trough-to-peak ratio gets closer to 1, the antihypertensive effect is consistently maintained throughout the dosage interval and thus the pharmacologically-generated blood pressure variability is reduced (36). According to the

Food and Drug Administration guidelines, a trough effect that is at least 50% of the peak effect is desired (36).

12 1.2 The role of calcium in the cardiovascular system

1.2.1. Calcium

Calcium ions (Ca2+) play significant regulatory roles in excitable tissue, from neuronal transmitter release to . With respect to the cardiovascular system, entry of external calcium through the L-type calcium channels plays a vital role in excitation- contraction coupling in the heart and regulation of diameter in vascular . A resting intracellular calcium concentration of about 150 nM and an extracellular calcium concentration of about 1-2 mM create a large concentration gradient across the (37). Thus, calcium ions are sensitive signal transducers.

1.2.2. Calcium channels in the cardiovascular system

There are two distinct families of calcium channels: intracellular release channels, which allow calcium ions to move into the cytosol from intracellular stores, and plasma membrane calcium channels, which control the entry of calcium ions from the extracellular space. At the plasma membrane, there are three main types of channels which differ by their regulatory mechanism: voltage-operated channels, store-operated channels and receptor- operated channels (38). The voltage-gated calcium channels are further classified according to their electrophysiological and pharmacological properties (L, N, P/Q, R and T types). In

the cardiovascular system, L- and T-type channels predominate.

The L-type ("long lasting") channel, which has a large conductance and slow inactivation rate, is the major type of calcium channel in excitable cells and is composed of

five subunits. This type is also the main target of clinically available CCBs. In the heart, the

function of L-type channels at the sinoatrial and atrioventricular nodes is for pacemaker

activity and conduction of impulses, respectively. In , action potentials

13 depolarize the plasma membrane which then triggers the opening of L-type calcium channels in the plasma membrane. These localized increases in Ca2+ concentration then lead to release of Ca2+ through ryanodine-receptor channels from the sarcoplasmic reticulum by a process called "Ca2+-induced Ca2+ release" (39). The smooth muscle of the vasculature utilizes a similar process to initiate contraction, except that the release of Ca2+ from intracellular stores

also occurs via (IP3) receptors. The IP3 receptors permit the alteration

of force production in the absence of a change in membrane potential because IP3 acts as a second messenger following binding of to receptors at the plasma membrane

("pharmacomechanical coupling"). Hormones influence Ca2+ influx by acting on receptor- operated Ca2+ channels. The diameter of the vasculature also depends on several local

factors, including perfusion pressure, pH, and p02.

T-type calcium channels are found on arterial vascular walls, myocardial conduction tissue (atrioventricular node, sinoatrial node, Purkinje cells) and at neurohormonal release sites (39). While the L-type channels play a major role in myocardial contraction, T-type

.channels instead exert their effects on pacemaker function and regulation of tone.

To maintain a low resting level of Ca2+ in the cytosol, Ca2+ is removed via Ca2+-

ATPase pumps at the sarcoplasmic reticulum or plasma membrane, and also Ca2+/Na+ exchangers.

1.3 Calcium channel blockers

1.3.1. Historical aspects

In the 1960s, Fleckenstein et al. discovered the calcium antagonist properties of verapamil and in studies using isolated cardiac tissue (40). These and subsequent studies elucidated important effects of calcium antagonists on the heart, namely

14 coronary artery dilation and negative inotropic effects that could be reversed by increasing the extracellular Ca2+ concentration. Not until the 1970s were the peripheral vasodilator properties of CCBs discovered. Since then, the array of therapeutic uses of CCBs has grown from angina, hypertension and arrhythmias, to cerebral , and Raynaud's phenomenon, among others.

1.3.2. Classification

In theory, calcium antagonists refer to all compounds that potentially inhibit calcium- dependent processes. Calcium channel blocker drugs belong to a chemically heterogeneous

family. According to the WHO classification (41), Group A CCBs consist of agents that have high affinity and specificity for the L-type calcium channel including the phenylalkylamines, cUhydropyridines, benzothiazepines (Table 3). Group B CCBs (Table 4) are less specific L-type channel blockers and they are much less widely used.

15 Table 3: Classification of group A calcium antagonists

Phenylalkylamines Dihydropyridines Benzothiazepines Animparnil Amlodipine Desmethoxyverapamil Diltiazem* Barnidipine (formerly Mepirodipine) Rompamil Tiapamil Darodipine Verapamil* Elgodipine Felodipine Flordipine Isradipine Lacidipine 1 Lercanidipine Manidipine Masnidipine Nicardipine • Nifedipine* Nisoldipine Nitrendipine Silvadipine - prototype agents

Table 4: Group B calcium antagonists

Bencyclane Semotiadil Etafenone TerocUline Lidoflazine Prenylamine

1.3.3. Pharmacodynamics of calcium channel blockers

1.3.3.1. Molecular mechanism of action

Calcium channel blockers reduce the cytosolic free-calcium concentrations by

blocking transmembrane calcium influx through L-type calcium channels. The L-type

calcium channel is composed of five subunits: a,, a2, [3, y, and 5. Dihydropyridines,

16 and phenylalkylamines bind to the pore-containing a,-subunit of the L- type calcium channel, the former two near the external face of the pore and the latter within the pore. Ligand-binding sites on the L-type channel have several aflosteric interactions between each other and with the gating machinery of the channel pore (Figure 1) (42).

CCBs are believed to induce a conformation change that influences gating of the in the L- type calcium channel (43).

Figure 1. Binding sites of calcium channel blocker drugs. (-) denotes a negative allosteric interaction. (+) denotes a positive allosteric interaction. Adapted from Triggle 1991 (42).

17 1.3.3.2. Physiological effects

In general, calcium channel blockers relax arteriolar smooth muscle, resulting in vasodilatation and decreased peripheral resistance. The decreased afterload therefore decreases blood pressure. In addition to peripheral vasodilatation, CCBs increase coronary blood flow. CCBs also have a negative inotropic effect on the myocardium. Agents that slow the rate of recovery of L-type calcium channels (verapamil, diltiazem) have negative and effects on the heart's conducting system. The natriuretic effect of CCBs may contribute to their ability to lower blood pressure.

The most common side effects associated with CCBs stem from excessive vasodilatation (40), and include , dizziness, headache, and nausea.

Constipation (caused by decreased gut motility), peripheral edema (caused by redistribution of extracellular fluid), coughing and wheezing also occur with CCBs. CCB-induced vasodilatation also tends to trigger a reflex increase in sympathetic activity, producing the-

tachycardia commonly observed with dihydropyridines.

1.3.3.3. Phenylalkylamines

Verapamil, the prototype phenyalltylamine, is indicated for treatment of

hypertension, angina and arrhythmias (40). Of all the subclasses of CCBs, it has the most

cardiac effects. Verapamil's vasodilatory activity is less than that of dihydropyridines, but the

negative chronotropic effect of the drug mitigates any reflex tachycardia. The prolongation

of refractor)' periods in the cardiac conduction system can lead to or sinus arrest

in some patients. Heart failure precipitated by the negative inotropic effect is another

potentially serious adverse effect associated with verapamil.

18 1.3.3.4. Benzothiazepines

The prototype diltiazem is indicated as an antihypertensive and agent. Diltiazem decreases blood pressure through arterial dilatation. It is less cardiodepressant than verapamil but negative chronotropic effects usually cause a decrease in heart rate (40). The most common side effects of diltiazem include headache, swelling/edema, arrhythmias (first degree heart block), and asthenia (44).

1.3.3.5. Dihydropyridines

1,4-Dihydropyridines represent the largest subclass of CCBs. Nifedipine is the prototype of this group of relatively vascular-selective CCBs. The fall in blood pressure and relief of angina can be attributed to vasodilatation in peripheral and coronary arteries, respectively (40). The negative inotropic effect of nifedipine is minor at therapeutic doses and is usually overcome by the baroreceptor-mediated sympathetic reflexes.

Dihydropyridines are associated with exacerbation of myocardial ischemia due to several possible mechanisms: excessive hypotension, coronary vasodilatation of nonischemic areas

("coronary steal"), and increased oxygen demand resulting from increased reflex sympathetic activity. Common side effects of dihydropyridines in the hypertensive population include edema, headache, fatigue, dizziness, , nausea, flushing, palpitation and tachycardia (44).

1.3.3.6. Benzimidazolyls

While most calcium channel antagonists predominantly block the L-type calcium channel, a newer class of benzimidazolyl tertraline derivatives inhibits both L- and T-type channels (45). One drug from this class is mibefradil, which possesses higher selectivity for

T-type than L-type calcium channels. Mibefradil also binds to a unique site on the L-type

19 channel, with negative allosteric interactions with the verapamil, diltiazem and fantofarone binding sites. Mibefradil reduces heart rate but lacks both the negative inotropic effects of other cardio-selective calcium channel blockers and the reflex increases in sympathetic activity associated with some dihydropyridines. Though initially approved in 1997 as a

treatment for hypertension and chronic stable angina, mibefradil (Posicor®) was removed

from the market in 1998 because of the incidence of serious drug interactions arising from cytochrome P450 inhibition, leading to cardiogenic shock in a small number of patients (46).

1.3.4 Pharmacokinetics of calcium channel blockers

CCB drugs are well absorbed (>90%) from the but undergo

first-pass hepatic resulting in low bioavailability (40). Drugs in the dihydropyridine subclass are highly bound to plasma proteins (> 95%) while diltiazem and verapamil are less so. Early calcium antagonists were all short-acting, with time to maximum

concentration occurring within about 2 hours. The rapid decreases in blood pressure gave rise to many side effects, especially tachycardia from reflex sympathetic nervous system activation, flushing, headache and dizziness. Newer CCBs such as amlodipine and slow- release formulations of older CCBs were developed to produce a more gradual decrease in blood pressure with a longer duration of BP control, increased safety, and less side effects.

Extensive metabolism of CCBs occurs via oxidative enzymes in the liver, primarily

the 3A4 isozyme of the cytochrome P450 family (47). Half-lives and clearance rates vary

considerably among CCBs (Table 5). Dihydropyridines are eliminated in the urine with the

majority in the form of inactive metabolites and small amounts in the unchanged form, ft is important to note that pharmacokinetic parameters can vary according to length of

administration (acute vs. chronic) and that there is much interindividual variability.

20 Table 5: Pharmacokinetic parameters of CCBs (44, 47)

Drug Absorption Bioavailability PPB tl/2 Renal Elim. Met. (%) (%) (%) (hours) (hours) Unchanged % % Amlodipine >95% 63 97.5 6-10 35-50 10 60 Diltiazem 80-90 40-67 70-80 2-4 3.5-6 2-4 immediate 5-8 release (repetitive dosage) sustained 7-11 5-7 release controlled 10-14 5^8 deliver)' Felodipine >95% 15 99 2.5-5 11-16 <0.5 70 extended release Flunarizine Well- 99 2-4 19 days absorbed Isradipine >90% ' 15-24 95 2-4 8.3 <1 65 Lacidipine >90% 14-19 98 3 7-18 >1 70 Nicardipine >90% 10-17 98 0.5-1 2 <1 60 Nifedipine >90% 45-75 95 0.5-2 2-5 0.1 -75 immediate release prolonged 50-70 98 4 action extended 86 6 10 release Nilvadipine >90% 14-19 99 2.15 7-18 <1 -75 Nimodipine >90% 13 99 1-2 (early) 2 0 15 8-9 (terminal) Nisoldipine >90% 8 99 1-2 10-12 <1 -75 Nitrendipine >90% -30 98 1-2 6-15 0.1 45 Verapamil >90 10-20 >90 1-2 2.8-7.4 3 86 immediate 4.5-12 release (repetitive dosage) sustained 20-35 4-8 5.3-9.6 release PPB = percentage protein binding Renal unchanged % = % excreted renally as unchanged drug Elim Met % = % eliminated as metabolites tmax = time to maximum plasma concentration ti/2 = half life

1.3.5 Clinical use of calcium channel blockers

Calcium channel blockers are used widely in clinical practice to lower elevated blood pressures and manage angina and arrhythmias. Although CCBs are generally considered

21 second- or tliird-line therapies in the treatment of hypertension in subjects under 60 years of age, CCBs have been recommended as first-line treatment for treatment of isolated systolic hypertension in the elderly (10). In 2003, the CCB amlodipine (Norvasc®) was the fourth top selling prescription drug in the world (48).

Nevertheless, controversy surrounds the use of CCBs in the treatment of chronic hypertension, fn 1995, two retrospective studies showed increased risks of myocardial infarction and mortality in those taking calcium channel blockers (49, 50). Psaty's case- control study showed that among users of CCBs (with or without a ) the risk ratio of myocardial infarction was 1.62 (95% CI 1.11-2.34) compared with those taking a diuretic alone, and 1.57 (95% CI 1.21-2.04) compared with users of beta-blockers (49). Pahor et al's cohort study of elderly hypertensive patients showed that in comparison with beta- blockers, the relative risks for mortality associated with use of verapamil, diltiazem, and short-acting nifedipine were 0.8 (95% Cf 0.4-1.4), 1.3 (95% CI 0.8-2.1), and 1.7 (95% CI 1.1-

2.7), respectively (50). A meta-analysis by Furberg et al. showed that the use of short-acting nifedipine was associated with increased mortality in patients with coronary heart disease

(overall RR 1.16, 95% CI 1.01-1.33) (51). A dose-response relationship was present, with the risk rising sharply with doses above 80 mg/day of nifedipine (RR at 80 mg/day was 2.83;

95% Cf 1.35-5.93). The potential mechanisms by which calcium channel blockers may increase mortality are varied, including pro-ischemic effects, marked hypotension, negative inotropic effects, prohemorrhagic effects and activation of the sympathetic- and renin- angiotensin systems, thereby predisposing to arrhythmias (51).

To assess whether similar effects were observed with long-acting CCBs, another case-control study was performed (52). The study showed no difference in risk of cardiovascular events between beta-blockers and long-acting CCBs, but there was a marked

22 increase in risk in patients who took short-acting CCBs compared with beta-blockers

(adjusted odds ratio 3.88, 95% CI 1.15-13.11) and long-acting CCBs (risk ratio 8.56, 95% CI

1.88-38.97). However, it is important to note that all observational studies are subject to confounding since the patients may differ fundamentally between treatment groups. For example, in the aforementioned studies, the prevalence of coronary heart disease was greater in the groups taking short-acting CCBs (53).

Links between use of CCBs and increased risk of cancer, major hemorrhage and suicide had been suggested initially from observational studies, although these associations were contradicted in subsequent studies (53). The debate over calcium channel antagonist safety was addressed further with respect to the potential conflict of interest arising from authors' relationships with the pharmaceutical industry (54). This study of calcium-channel- antagonist articles published between March 1995 and September 1996 found that 96% of the authors who were supportive of the use of calcium channel blockers had financial relationships with CCB manufacturers, compared to 60% of neutral authors and 37% of critical authors (p<0.001).

Numerous large, long-term clinical trials of CCBs have been carried out (Table 6) but the debate over the efficacy and safety of CCBs still rages. The findings of Pahor et al.'s systematic review demonstrating that CCBs given as first-line antihypertensives are associated with a higher incidence of major cardiovascular events compared with other drug classes (55) have been tempered by the results of recent clinical trials (ASCOT [56], FEVER

[57]) that show CCBs in combination with other antihypertensives may have benefits in terms of cardiovascular events and mortality.

23 Table 6: Long term clinical trials of CCBs for treatment of hypertension

Study Trial Design & Interventions and Main Result Population ABCD R/DB fntensive (target of DBP 80-89 mm Hg) vs. moderate 1998 (58) N=950 patients therapy (target of DBP 75 mm Hg) and nisoldipine vs. with type 2 enalapril as lst-Une antihypertensive treatment, with diabetes mellitus; possible addition of and [N=450 had hydrochlorothiazide. Mean follow-up: 5 years. In the DBP >90 mm hypertensive group, the incidence of fatal and nonfatal Elg (mean age: myocardial infarctions was significantly higher among 57.5 y) and those receiving nisoldipine compared with those N=480 were receiving enalapril (RR 5.5; 95% CI 2.1-14.6; p < normotensive] 0.001).

ALLHAT R/DB Chlorthalidone vs. vs. amlodipine ( 2002 (59) N=33 357 (mean arm terminated), with possible addition of , age 67 y), SBP > , or reserpine. Mean follow-up: 4.9 years. 140 mm Hg No statistically significant difference in total CHD and/or DBP >90 events or total mortality between the different mm Hg plus one treatments, fncreased incidence of heart failure with additional risk amlodipine compared to chorlathlidone treatment (RR factor for CHD 1.38; 95% CI 1.25-1.52, p<0.001) ASCOT- R/open-label; Amlodipine (plus perindopril as required) vs. atenolol BPLA N=19 257 (mean (plus bendro flume thiazide as required). Mean follow- 2005 (56) age 63 y), SBP > up: 5.5 years. No statistically significant difference in 160 mm Hg non-fatal Mf + fatal CHD (primary endpoint). and/or DBP > Amlodipine-based regimen showed reduction in total 100 mm Hg if cardiovascular events and procedures (Hazard ratio untreated, or SBP [HazR] 0.84, 95% CI 0.78-0.90), all-cause mortality > 140 mm Hg (HazR 0.89, 95% Cf 0.81-0.99), fatal and non-fatal and/or DBP > stroke (HazR 0.77, 95% CI 0.66-0.89). 90 mm Hg if treated; plus at least 3 other CV risk factors CONVINCE R/DB Hydrochlorothiazide or atenolol vs. verapamil COER, 2003 (60) N=16 602 (mean with possible addition of other study drugs to achieve age 66 y); BP conrol. Mean follow-up 3 years. No statistically patients had > 1 significant difference in CV death, MI, stroke between CV risk factor in groups. Verapamil had higher incidence of heart addition to failure (HazR 1.30, 95% CI 1.0-1.69, p=0.05) and hypertension death or hospitahzation for bleeding unrelated to stroke (HazR 1.54, 95% CI 1.15-2.04, p=0.003). Study terminated early by sponsor for commercial reasons.

24 Study Trial Design & Interventions and Main Result Population FACET R/open-label; Fosinopril vs. amlodipine, with possible addition of 1998 (61) N=380 (mean other study drug to achieve BP control. Mean follow- age: ?y); patients up 2.8 years. No statistically significant differences with type 2 between the two groups in serum lipids, glucose diabetes mellitus control & renal function parameters. Amlodipine and SBP >140 group had a significantiy greater reduction in SBP than mm Hg or DBP fosinopril group. Fosinopril group had significandy 90 mm Hg lower rate of the combined endpoint of stroke, acute myocardial infarction, or hospitalization for angina (RR 0.49; 95 CI 0.26-0.95; p = 0.030) compared to amlodipine.

FEVER R/DB Felodipine + HCTZ vs. placebo + HCTZ, with 2005 (57) N=9800 Chinese possible addition of other study drugs. Mean follow- patients (mean up 40 months. Felodipine group had reduction in age 61.5 y), SBP nonfatal stroke (HazR 0.74, 95% CI 0.59-0.91), total 160-210 mm Fig, CV events (HazR 0.73, 95% CI 0.51-0.86), all-cause DBP 95-115 mm death (HazR 0.69, 95% CI 0.54-0.89). Hg, plus one additional CV risk factor HOT R/DB Randomized to 3 DBP targets: <90 mm Hg vs. <85 1998 (62) N=18 790 (mean mm Hg vs. <80 mm Fig (using felodipine 5 mg as the age: 61.5 y), DBP initial drug in a stepped therapy), and also randomized 100-115 mmHg to acetylsalicylic acid vs. placebo. Mean follow-up: 3.8 years. No statistically significant difference in cardiovascular events between BP target groups, except in subgroup of patients with diabetes mellitus, which showed lower risk of events in <80 mm Hg group vs. <90 mm Fig group. INSIGHT R/DB Nifedipine GITS vs. hydrochlorothiazide + , 2000 (63) N=6321 (mean with possible addition of enalapril or atenolol. Mean age: 65 y); SBP follow-up: 3.1 years. No statistically significant > 150/95 mm Hg difference in combined primary endpoint or SBP > 160mm (cardiovascular death, myocardial infarction, heart Hg, + >1 failure, or stroke; RR 1.10 [95% CI 0.91-1.34]; p=0.35) additional CV risk factor INVEST R/open-label, Verapamil SR (plus trandolapril as required) vs. 2003 (64) masked endpoint; atenolol (plus HCTZ as required). Mean follow-up: N=22 576, (mean 2.7 years. No statistically significant difference age 66 y); patients between treatment strategies in primary outcome had CAD and (composite of death, nonfatal MI, nonfatal stroke) hypertension

25 Study Trial Design & Interventions and Main Result Population MIDAS R/DB Isradipine vs. hydrochlorothiazide, with possible 1996 (65) N=883 (mean addition of open-label enalapril. No significant age: 58.5 y), DBP differences between the two groups in isradipine 90-115 mmHg group in progression of carotid mtimal medial thickness. Isradipine group had a non-statistically significant increase in major cardiovascular events compared to diuretic group (RR 1.78; 95% CI 0.94- 3.38; p = 0.07).

NICS-EH R/DB Nicardipine SR vs. trichlormethiazide. Follow-up: 5 1999 (66) N=429 (mean years. No statistically significant difference between age: 69.8 y), SBP the two groups in rate of cardiovascular events 160-220 mm Hg (p=0.923). and DBP <115 mm Hg NORDIL R/open-label, Diltiazem vs. beta blockers, diuretics or both. Mean 2000 (67) masked endpoint; follow-up: 4.5 years. No statistically significant N= 10,881 (mean difference in combined primary endpoint (fatal and age: 60 y); DBP > non-fatal stroke, fatal and non-fatal myocardial 100 mm Hg infarction, and other cardiovascular death; p=0.97) between groups.

STOP-2 R/open-label, Conventional drugs (atenolol, metoprolol, , or 1999 (68) masked-endpoint; hydrochlorothiazide plus amiloride) vs. newer drugs N=6614 (mean (either ACE inhibitors enalapril or lisinopril, or CCBs age: 76 y), SBP felodipine or isradipine). Follow-up: 5 years. No >180 mm Hg, statistically significant difference in primary combined DBP >105 mm endpoint (fatal stroke, fatal myocardial infarction, and Hg, or both other fatal cardiovascular disease; p=0.89).

SYST-CHINA DB/PC Assigned by alternation to active treatment (using 1998 (69) N=2394 (mean nitrendipine as initial drug in stepped therapy with age: 67 y), SBP add-on of captopril or hydrochlorothiazide or both), 160-219 mm Hg vs. placebo. Median follow-up: 3.0 years. Statistically and DBP <95 significant reduction in all cardiovascular endpoints mm Hg combined (fatal + non-fatal) in active treatment group compared to placebo but no difference in cardiac endpoints.

26 Study Trial Design & Interventions and Main Result Population SYST-EUR R/DB/PC Active treatment (using nitrendipine as initial drug in 1997 (70) N=4695 (mean stepped therapy with add-on of enalapril or age: 70.3 y), hydrochlorothiazide or both) vs. placebo. Median sitting SBP 160- follow-up: 2 years. Statistically significant reduction in 219 mm Hg and fatal + non-fatal stroke (p=0.003) and total sitting DBP <95 cardiovascular endpoints (p<0.001) in active treatment mm Hg group compared to placebo. No difference in all- cause and all-cardiovascular mortality. TOMHS R/DB/PC Chlorthalidone vs. vs. doxazosin vs. 1996 (71) N=902 (mean amlodipine vs. enalapril vs. placebo age 54.8 y), DBP (nutritional/hygienic intervention administered to all 90-99 mm Hg or patients). Mean follow-up: 4.4 years. No significant 85-99 mm Hg difference between all drug treatments aggregated and after withdrawal placebo in # of patients experiencing at least 1 event in those taking 1 (coronary heart disease and cardiovascular disease antihypertensive events). drug VALUE R/DB vs. amlodipine (plus addition of other 2004 (72) N=15 245 (mean antihypertensives if required). Mean follow-up: 4.2 age 67 y); SBP years. Primary composite endpoint of cardiac 160-210 mm Hg morbidity and mortality + all-cause mortality showed and DBP < 115 no statistically significant difference between regimens. mm Hg; patients Valsartan regimen had higher incidence of MI at high CV risk compared with amlodipine (HazR 1.19, 95% CI 1.02- 1.38,p=0.02) r VHAS R/DB (1st 6 Verapamil vs. chlorthalidone, with possible addition of 1997 (73) months, then captopril or switch to free therapy in non-responders. open-label); At 2 years follow-up, there were no statistically N=1414 (mean significant differences in # of patients with DBP age: 53.2 y), SBP normalization and in cardiovascular events between > 160 mm Hg the two groups. and DBP 95-114 mm Tig

1.4 Systematic reviews

1.4.1 What are systematic reviews?

Systematic reviews answer specific clinical questions in depth, by synthesizing the results of primary research and using explicit methods that limit bias (74). Developing systematic reviews has been considered a "fundamental scientific activity." (75) While

27 researchers can use reviews to identify new hypotheses and to refine their approaches, health care providers and policy makers can apply the results of such reviews towards rational decision making (75). However, it is important to note that research evidence is only one of many components that are involved in decision making in each patient-clinician encounter

(74).

A well-formulated question specifies the following five variables: 1) types of study designs, 2) types of participants, 3) types of interventions, 4) types of outcomes, and 5) types of control comparisons. For example, the question addressed in this review can be stated as:

In randomized controlled trials, how much do calcium channel blockers lower blood pressure compared with placebo in patients with primary hypertension?

Systematic reviews can be categorized as qualitative or quantitative. In the latter case, the review is referred to as a meta-analysis and involves quantitatively combining results from individual studies. Using statistical methods to combine the data increases the power and precision of the estimate of the effect size.

The other advantages of a systematic review are well established. Health care workers, researchers and consumers are often deluged with unmanageable amounts of information (76). Systematic reviews concisely and efficiently integrate up-to-date information such that important effects of health care can be identified promptly (74). In addition, systematic reviews can establish the degree of generalizabiHty and consistency of the findings across populations and different treatments (76). Lastly, since systematic reviews explicitly apply scientific principles that are designed to reduce random and systematic errors, the results are more likely to be reliable and accurate than individual studies or narrative reviews.

28 Like all secondary research, systematic reviews are retrospective studies and are hence subject to bias. Meta-analyses can produce inflated effect sizes due to publication bias, which describes a systematic error arising from the tendency of positive-result trials to be more likely to be published. (and often numerous times) than negative-result trials.

Systematic reviews are designed to reduce bias by 1) including studies with multiple publications only once; 2) using explicit, reproducible criteria for selecting studies and for extracting data; and 3) having more than one independent reviewer to perform these tasks

(76).

1.4.2 How does a systematic review differ from a narrative review?

"Narrative" or "traditional" reviews of research have always been common in medical literature. Frequently, these reviews have a broad scope and are written by experts in the field who tend to focus only on studies that support their own view. As well, the majority of narrative reviews lack explicit, systematic methods with respect to how studies are selected and integrated. For these reasons, there is great likelihood of introducing bias.

Since the methodologic quality of medical review articles is quite variable, there are concerns about the validity of their conclusions (77).

Conversely, a systematic review utilizes an explicit search strategy that is applied to several sources. Systematic reviews are focused on a specific clinical question and studies are selected using pre-specified inclusion criteria. This approach allows a more objective view than traditional narrative reviews. Thus, a major advantage of a systematic review is that the same rigor as that expected from primary research is applied. Consequently, carrying out a systematic review requires much more time and effort than a narrative review.

29 1.4.3 The Cochrane Collaboration

The Cochrane Collaboration (CC) is an international organization that aims to prepare, maintain and make accessible systematic reviews of the effects of health care.

Established in 1992, the organization was named after Archie Cochrane, a British epidemiologist who recognized the importance of having reliable reviews of evidence to make informed decisions about heath care. The CC espouses the following ten principles: collaboration, building on the enthusiasm of individuals, avoiding duplication, minimizing bias, keeping up to date, ensuring relevance, ensuring access, continually improving the quality of its work, continuity and enabling wide participation (78). The systematic reviews produced within the CC are published electronically in the Cochrane Library, which is updated quarterly. The format of a Cochrane review allows readers to find the results quickly and allows them to submit comments and criticisms. As well, the format facilitates updating reviews with new or previously missing trials. A study that compared Cochrane reviews with articles published in paper-based journals revealed that Cochrane reviews tended to have greater methodological rigor and were more likely to be updated (79).

1.4.4 Aim of this systematic review

At the present time, the blood pressure-lowering efficacy of the different subclasses of calcium channel blockers and the individual drugs within each subclass is not known, and a systematic review of the short-term dose-related blood pressure lowering effect of calcium channel blocker drugs has not been previously performed. The aims of this systematic review are to determine these dose-related effects in patients with primary hypertension and to establish dose equivalencies of different drugs within the calcium channel blocker family.

The information derived from this review should facilitate future reviews of head-to-head

30 comparisons with other drug classes and assist clinicians in choosing optimal doses calcium channel blockers. 2. PROTOCOL

The protocol for this systematic review was finalized in March 2000 and first published in Issue 2, 2002 of the Cochrane Library (80) to outline the scientific methods that would be employed. The methodology was based on the Cochrane Reviewers' Handbook

(76) and on a previous systematic review that assessed the blood pressure lowering efficacy of thiazide and loop diuretics (81).

2.1 Objectives

Primary objective:

To quantify the dose-related effects of various doses and types of calcium channel blockers on systolic and diastolic blood pressure versus placebo in patients with primary hypertension.

Secondary objectives:

1. To determine the effects of calcium channel blockers on variability of blood pressure.

2. To determine the effects of calcium channel blockers on pulse pressure.

3. To quantify the dose-related effects of calcium channel blockers on heart rate.

4. To quantify the effects of calcium channel blockers in different doses on withdrawals

due to adverse events.

2.2 Methodology

2.2.1 Types of studies

Included studies must be randomized controlled trials (RCTs) and their design must meet the following criteria:

32 • random allocation to calcium channel blocker monotherapy group (s) and a parallel

placebo control group

• double-blind

• duration of follow-up of at least three weeks

• office blood pressure measurements were made at baseline (following washout) and at

one or more time points between 3 to 12 weeks after starting treatment

2.2.1.1. Why are only randomized controlled trials included?

Randomized controlled trials are prospective, quantitative, comparative experiments in which patients are allocated randomly to receive one of two or more interventions and the ensuing clinical outcomes are compared. Since all patients have the same chance of being assigned to each group, any baseline differences that arise between groups occur by chance.

Random allocation reduces the risk of imbalance of both known and unknown baseline

factors. In this way, the investigators can isolate the impact of the intervention being studied, thereby rrunimizing the influence of other factors that could affect the outcome of

the study. Proper randomization can be achieved in many ways; usually random number tables or computers are used to produce a pre-specified randomization list. Randomization

controls for selection bias (that is, systematic differences in the way comparison groups are

assembled), although efforts to randomize can be undermined if allocation is not concealed.

2.2.1.2. Why is a parallel placebo arm necessary?

Included RCTs must have a parallel placebo arm as the control comparison since a

significant but variable placebo effect (in the range of 0 to 10 mm Hg decrease in SBP and 0

to 8 mm Hg in DBP) exists for antihypertensive drugs (82). Since the objective of this

33 review is to assess the dose-related blood pressure lowering efficacy of calcium channel blockers compared to placebo, the overall effect of calcium antagonist treatment is obtained by subtracting the effect in the placebo group from the effect in the active treatment group.

Having a placebo group not only controls for bias, but also minimizes the effect of

"regression to the mean", a statistical phenomenon that describes the spontaneous within- patient variation and/or variation due to measurement errors. This effect has been demonstrated in hypercholesterolemic and hypertensive patients by a shift from high to low values with time, independent of treatment (83). Thus, regression to the mean is responsible for many false positive results in experiments that involve before-after measurements of a continuous variable (83).

For the purposes of this review, cross-over trials are only accepted if data are reported for the first 3-12 week phase of treatment with active drug versus a placebo arm.

Thus, this is effectively the same as a parallel-design trial.

2.2.1.3. Why is blinding (masking) necessary?

Ascertainment bias involves systematic distortion of the results of the trial by knowledge of group assignment, the source of which can be the observers, participants, or assessors (84). Bknding, also known as masking, reduces the risk of this form of bias, fn a double-blind RCT, both the participants and the investigators do not know the group assignment of each participant. Proper blinding is achieved by testing an intervention against a matched placebo, with identical taste, smell, and appearance as the active drug.

Methods for assessing the success of blinding are available. However, the success of blinding in hypertension trials has rarely been tested.

34 2.2.1.4 Why is a baseUne measurement subsequent to or during a washout/placebo run-in period important?

The main purpose of a washout period is to eliminate carry-over effects from previous drug administration prior to commencing the trial. Commonly, the washout period is comprised of or is followed by a single-blind placebo "run-in" before randomization. The most accurate estimates of the baseline blood pressure and heart rates are obtained at the end of this period. This pre-study period also aids in the selection of participants who are truly hypertensive, as those who do not meet the inclusion criteria cut-off after the washout/run-in do not continue in the study. Repetitive measurements before study entry allow blood pressures to stabilize, and thus, the problem of regression to the mean is mirLimized.

2.1.1.5. Why is the 3-12 week window selected?

Based on a previous systematic review (81), a follow-up of 3-12 weeks during treatment represents an appropriate window of time from which to extract outcome data. A rninimum of three weeks is usually necessary for the effect of therapy to become maximal and stable. For practical reasons, the upper duration limit of 12 weeks was chosen since many antihypertensive drug trials involve dose titration or addition of other drugs in those who fail to achieve a target blood pressure after a certain length of time on treatment. As well, a shorter duration allows the data to include the maximum number of patients, as withdrawals and drop-outs, which can confound results, occur at higher rates in trials with long duration.

2.2.2. Types of participants

Participants must have had a baseline systolic blood pressure > 140 mm Hg and/or a diastolic blood pressure > 90 mm Fig, measured in a standard way. Patients with creatinine

35 levels greater than 1.5 times the normal level were excluded. This criterion thereby excludes patients with secondary hypertension due to renal failure. Patients who were pregnant during the study were excluded since pre-eclampsia is considered a form of secondary hypertension. Participants who took medications that affect blood pressure other than the study medications were excluded. Participants were not restricted by age, gender, baseline risk, or any other co-morbid conditions.

2.2.3. Types of interventions

The intervention of interest is monotherapy with any calcium channel blocker, as listed in Table 4 and 5.

Trials in which titration to a higher dose is based on blood pressure response were not eligible if the titration occurred before three weeks of treatment. This restriction is in place because dose-response relationships cannot be analyzed if patients witiiin each randomized group are taking different doses. However, trials in which a response- dependent titration took place during or after the 3-f2 week interval were eligible if pre- titration data were given. In cases of forced (i.e., response-independent) titration, data from the highest dose given for the specified duration of time, provided this duration was > 3 weeks, were extracted.

2.2.4. Types of outcome measures

Primary:

Change from baseline in trough and/or peak systolic and diastolic blood pressure at

3-12 weeks treatment, compared to placebo. If blood pressure measurements were available at more than one time within the acceptable window, the weighted means of blood pressures taken in the 3-12 week range were used.

36 Secondary:

1. Standard deviation of the change in blood pressure compared with placebo.

2. Change in standard deviation of blood pressure compared with placebo.

3. Change in pulse pressure compared with placebo.

4. Change in heart rate compared with placebo.

5. Number of patient withdrawals due to adverse events compared with placebo.

2.2.5. Search strategy for identification of studies

To identify randomized placebo-controlled trials of calcium channel blockers,

Medline (Jan. 1966-June 2003), EMBASE (fan. 1988-June 2003), CINAHL (Jan. 1982-June

2003), the Cochrane Controlled Clinical Trials Register, and bibliographic citations were searched. Previously published meta-analyses on dose-response of calcium channel blockers were used to help identify references to trials. No language restrictions were applied.

The following search strategy was utilized to identify randomized, placebo-controlled trials of calcium channel blockers for hypertension. This approach was a modified, expanded version of the standard search strategy of the Hypertension Review Group, with additional terms related to calcium channel blockers in general (85).

A "/" at the end of a term signifies a Medical Subject Heading (MeSH) term; "exp" means the term is exploded (all MeSH terms nested under the exploded term are included);

"pt" denotes publication type; "mp" following a term will retrieve citations that contain the term in the tide, abstract or key words; "or/" followed by a number range will retrieve the group of citations that fall under any of the corresponding terms. The symbol "$" represents a wildcard character used to search for multiple forms of a term. The search

37 modifier "adj" plus a number between two terms returns records that contain the two terms within the specified number of words of each other.

1. randomized controlled trial.pt

2. randomized controlled trial$.mp

3. controlled clinical trial.pt

4. controlled clinical trial$.mp

5. random allocation.mp

6. exp double-blind method/

7. double-blind.mp

8. exp single-blind method/

9. single-blind.mp

10. or/1-9

11. exp animal/

12. 10 not 11

13. clinicaltrial.pt

14. clinical trialf.mp

15. exp clinical trials/

16. (clinf ad)25 trtal$).mp

17. ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).mp

18. randorn$.mp

19. exp research design/

20. research design.mp

21. or/13-20

38 22. 21 not 11

23. 22 not 12

24. comparative stud$.mp

25. exp evaluation studies/

26. evaluation studfi.mp

27. follow-up stud$.mp

28. prospective studf.mp

29. (control! or prospective or volunteer!).

30. or/24-29

31. 30 not 11

32. 31 not (12 or 23)

33. 12 or 23 or 32

34. exp calcium channel blockers/

35. calcium channel blocker$.mp

36. calcium channel antagonist$.mp

37. calcium antagonist!.mp

38. amlodipine.mp

39. .mp

40. aranidipine.mp

41. azelnidipine.mp

42. barnidipine.mp

43. .mp 44. benidipine.mp

45. bepridil.mp

46. cilnickpine.mp

47. cinnarizine.mp

48. clentiazem.mp

49. clevidipine.mp

50. darodipine.mp

51. desmethoxyverapamil.mp

52. devapamil.mp

53. diltiazem.mp

54. dopropidil.mp

55. efonidipine.mp

56. elgodipine.mp

57. etafenone.mp

58. falipamil.mp

59. fanofarone.mp

60. felodipine.mp

61. fendiline.mp

62. flunarizine.mp

63. fostedil.mp

64. gallopamil.mp

65. isradipine.mp

66. lacidipine.mp

67. lercanidipine.mp 68. Hdoflazine.mp

69. lomerizine.mp

70. manidipine.mp

71. masnidipine.mp

72. mibefradil.mp

73. nicardipine.mp

74. nifedipine.mp

75. niguldipine.mp

76. nilvadipine.mp

77. niiriodipine.mp

78. nisoldipine.mp

79. nitrendipine.mp

80. perhexiline.mp

81. pranidipine.mp

82. prenylamine.mp

83. riodipine.mp

84. ronipamil.mp

85. semotiadil.mp

86. silvadipine.mp

87. terodiline.mp

88. dapamil.mp

89. verapamil.mp

90. or/34-89 91. exp hypertension/

92. hypertension.mp

93. exp blood pressure/

94. blood presure.mp

95. or/91-94

96. 90 and 95

97. 33 and 96

98. placebo$.mp

99. 97 and 98

2.2.6. Study Selection

The initial search of all the databases was performed to identify citations with potential relevance. All citations were stored and categorized in the Reference Manager program. The initial screen of these abstracts excluded articles whose tides and/or abstracts were clearly irrelevant. The full texts of remaining articles were then retrieved (and translated into English where required). The bibliographies of pertinent articles, reviews and texts were searched for additional citations. Two independent reviewers assessed the eligibility of the trials using a trial selection form (Appendix A). A third reviewer resolved discrepancies. Trials with more than one publication were counted only once.

2.2.7. Data Extraction

Data were extracted independendy by two reviewers using a standard form

(Appendix B), and then cross-checked. If data were presented numerically (in tables or text)

and graphically (in figures), the numeric data were preferred because of possible

42 measurement error when estimating from graphs. All numeric calculations and extractions from graphs or figures were confirmed by a second reviewer.

The position of the patient during blood pressure measurement may affect the blood pressure lowering effect. However, in order not to lose valuable data, if only one position was reported, data from that position were extracted. When blood pressure measurement data were available in more than one position, sitting blood pressure was the first preference.

If only standing and supine blood pressures are available, that of the standing position was used. In case of missing information in the included studies, investigators were contacted

(using e-mail, letter and/or fax) to obtain the missing information. In the case of missing standard deviation of the change in blood pressure or heart rate, the standard deviation was imputed based on the information in the same trial or from other trials using the same drug and dose. The following hierarchy (listed from high to low preference) was used to impute standard deviation values:

1. pooled standard deviation calculated either from the t-statistic corresponding to an exact

p-value reported (86) or from the 95% confidence interval of the mean difference

between treatment group and placebo

2. standard deviation of change in blood pressure/heart rate from a different position than

that of the blood pressure/heart rate data used

3. standard deviation of blood pressure/heart rate at the end of treatment

4. standard deviation of blood pressure/heart rate at the end of treatment measured from a

different position than that of the blood pressure/heart rate data used

5. standard deviation of blood pressure/heart rate at baseline (except if this measure is used

for entry criteria)

43 6. weighted mean standard deviation of change in blood pressure/heart rate calculated

from at least 3 other trials using the same drug and dose

7. weighted mean standard deviation of change in blood pressure/heart rate calculated

from other trials using the same drug

8. weighted mean standard deviation of change in blood pressure/heart rate calculated

from all other trials (any drug and dose)

2.2.8. Quality Assessment

Assessing the quality of trials in a systematic review is important in order to determine the validity of its findings. The quality of reports of randomized trials can be incorporated into a meta-analysis in a number of ways. In a sensitivity analysis, studies below a certain quality threshold are removed to determine the effect on the overall estimate.

This approach can be used to attempt to explain heterogeneity between trial results. Studies can also be weighted according to quality; with this approach, studies of lower quality have less influence on the overall estimate (87). One of the difficulties with assessing trial quality is that we must rely upon information provided in the written report. To address this issue, the Consolidation of the Standards of Reporting Trials (CONSORT) statement issued by a group of researchers and journal editors has aimed to improve the quality of reporting of randomized controlled trials (87).

Two quality assessment scales are utilized commonly in systematic reviews: the

Cochrane Collaboration approach and the Jadad method. The quality of all included trials was assessed by two independent reviewers using these two approaches.

44 2.2.8.1. The Cochrane approach for assessment of allocation concealment

When studies are entered into the RevMan program, the Cochrane quality assessment scale based on allocation concealment is a default field for the "included trial characteristics" table (76). Each trial in the systematic review is assigned a grade (A, B, C, or

D):

Grade A: Adequate concealment

Adequate concealment can be executed by the following methods: centralized

(central office unaware of subject characteristics) or pharmacy-controlled randomization; pre-numbered or coded identical containers that are administered serially to patients; on-site computer system with allocations kept in a locked computer file that can be accessed only after patients enter; sequentially numbered, sealed, opaque envelopes.

Grade B: Uncertain

Grade B is assigned to trials in which the allocation concealment is not reported, or despite a description that reports adequate concealment (the use of a list, table or sealed envelopes), there are other features that lead the reviewer to be suspicious.

Grade C: Clearly inadequate concealment

Inadequte allocation concealment consists of the following methods: alternation; use of case record numbers, dates of birth or date at which the patient is invited to participate in the study; any procedure that is transparent before allocation, such as an open list of random numbers. While these methods in theory produce random groups, knowledge of group assignment before enrollment can affect the decision to enroll or not enroll the patient.

Grade D: Not used

Allocation concealment was not used to assess validity.

45 2.2.8.2. Jadad Method

Jadad developed a validated tool to assess trial quality (88). This tool is easy to use and gives consistent measurements. This five-point scoring system is outlined as follows:

1. Was the study described as randomised? (Yes=+1; No=0)

If "Yes", was the method of randomization well described and appropriate? (Yes =

+ 1, No = -1, Method not reported = 0)

2. Was the study described as double-blind? (Yes= + 1; No=0)

If "Yes", was the method of double blmding well described and appropriate? (Yes =

+ 1, No = -1, Method not reported = 0)

3. Was there a description of withdrawals and dropouts in each group and the reasons?

(Yes= + l;No=0)

A score of 0-2 reflects low quality, while a score of 3-4 indicates moderate quality and a score of 5 represents a high quality study.

2.2.9. Data Analysis

Data synthesis and analyses were done using the Cochrane Collaboration software,

Review Manager (RevMan) 4.2.8. This program allows reviewers to construct systematic reviews according to the Cochrane publication format. RevMan also allows the data to be displayed in a "forest plot".

46 Review: Blood pressure lowering efficacy of calcium channel blockers for "primary hypertension Comparison:. -01'Dose Amlodipine :ys. placebo Outcome: ;01 Change ni Systolic Blood Pressure Study. . Amlodipine. Placebo VWD (fixed) Weight VVtyiD (fixed) on sub-category .,N ' hMeani;SD) N-: Mean (SD). ' • 95% CI '. .% 95% CI ' Year- Order 01 1.25 rrigVclay; -5 -6 '44 -4. Frick.1988 ^ 48 60 70) *45 10(14 10). '.64 0. 78, 5.78) "1988 0 di : -4 Mehtal993 -7 80(14 40) 39 -3 70(13 60)- ?2. io •-10 28, Z. 081 "1993 0 Subtotal (95% CI)' -•88" 84 .11-16 -1 44,' -S: 46~;'2.'57 ] " Test for heterogeneity: =Ch i1.23, " 0.27)F " = 18.7% Test for overall effect:0.7 Z1 =(P0.48 = ) 02 25 mg/day- • Trick 1988- 46' -8 7DJ11 70) 45 -6 10(14 10) 633 . -2 say -'?- 93', 2. 73] 1988 'o 'Mehta^1993 40 -71 30 (1440 ) '•6939 -3 70(13 60) 47 2 -3 60 -9' . 78, 2'. 58]' -1"? 0 1 -IO "FrisKman 1995„ 72 70(15 00) 00(18 70) 57 72 -9 70 31 -4.09] 1995 0 Subtotal (95% CI) 158 1S3 -i • 16 -5 30 -8.58-is , -2.03)' Test tor heterogeneity: =Ch i3.64 ,= 2 (P0.16 =) = 45% . Test lor overall effect:'3.1Z7 = (P 0.002 = ) r 03 5 mg/day Frick 1988 48 -18 70(10 40) 45 -6 10(14-id) 10 ) « •702 : 1r 2 60 -1' 7 66 -7.54]' '1988 ,1 Mroczek1988. 10 -16 70) 5 45 0 (2 a 05 0 -21 20 -40 2S -2.IS]' 1988 2 Merita'1993 44 -8 670 ((1i0 301 ) 39 -3 70(13 60)- -6 55 -4 90 -10 14 0-341 1993 3 Kuschnir. 1996 77 -17 SO (1200 ) 76 -z 10(14 10)10)- -* .10 44. -IS 40 -19 5S -11.-25] 1996 4 Farsarig' 2001 ;84 -is Z0 (1350 ) 83 -0 90(14 # 10?6 . -14 30 -18 49. -rlO.il] 2001 5 Poor2001 110 -10 80 (1040 ) -iis -3 00(14 ib) 172 7 -7 80 -11 03 -4.57] .2001 6i ^ ' Cnrysant 2003 183 -10 301(1040 ) 6S -0 80(14 10) 128 3 -9 -13 24 -5.76]-9.OS] . . 2003 Subtotal (95% CI) 556 428 .t 648 6 -10 7so2 -12 38 Test for heterogeneity: =.17.6Ch* 7d f - 6= (P 0.007) , I16.0 =% 6 Test for overall'effect: 12.6Z1 = (P <"0.0000 1) 04 10 mg/day «• ; Licata1993 . is T20'90'(1 7.40 ) 15 r--3i 00 (1930 ) 1 01 -1-96 70.90'. -30 24 -3.'S6] . i993 0 Mehta.1993' • 40" -13 40(10 60) :'s394 70 (1360 ) .6 20 -IS 09 -4.31] i993 "0 Subtotal (95% CI): •'ss:,. • .7 21- -10 71 -is 70 -S.72]. Test for heterogeneity: '«Ch O.9 Ei;f = 1 0.33(P )=P = 0% Test for overall effect:4.2 Z0 »(P 0 .0001< ) Total (95% CI) 85r 719 ,100 00 -8 77 -10 .11 -7.43] Test for heterogeneity: =Ch 46.4 2df-13(P«0 .0001),P 72.0% Test .for overall effect;12 Z.82 « (P«. 0.00001) -100. -50 ,0' 50 100 Favours Amlodipine Favours Placebo

Figure 2. Example of a forest plot.

In a forest plot, the outcome of interest is listed at the top. The vertical line represents the line of no effect. Component studies are shown as squares (the size of which represents the weight) and the horizontal line running through each square shows the 95% confidence interval. The overall estimate is represented as a diamond; its centre represents the point estimate and the horizontal tips represent the confidence interval. If the confidence interval crosses the line of no effect, there is no statistically significant difference between the intervention and the control.

Data for changes in blood pressure and heart rate were combined using a weighted mean difference method. The withdrawals due to adverse events were analyzed using relative risk, risk difference, and number needed to harm.

47 Tests for heterogeneity of treatment effect between the trials were performed using a standard chi-square statistic for heterogeneity. The fixed effects model was applied to obtain summary statistics of pooled trials, unless significant between-study heterogeneity was present, in which case the random effects model was used.

Subgroup analyses were used to examine the results for specific categories of participants. The number of subgroup analyses performed should be kept to a minimum, since the greater number of hypotheses tested, the greater the number of differences one will find by chance alone (76). Possible subgroup analyses included:

1) Calcium channel blocker subclass: dihydropyridines, non-dihydropyridines (including

benzothiazepines and phenylalkylamines) and others

2) Different formulations of the same active chemical entity

3) Age: children, adults, older people

4) Co-morbid conditions: ischemic heart disease, diabetes

5) Baseline severity of hypertension: mild, moderate, severe

6) Type of hypertension: elevated DBP, isolated systolic

Sensitivity analyses are performed to assess how sensitive the results are to changes in the way the analyses were done (76). If these sensitivity analyses do not change the results substantially, more confidence can be placed in the results. However, if the results do change, they must be interpreted with greater care. The robustness of the results of this systematic review were tested using the following sensitivity analyses, including:

1) Trials of high quality vs. poor quality

2) Trials that are industry-sponsored vs. non-industry sponsored

3) Trials with blood pressure data measured in the sitting position vs. other measurement

positions

48 4) Trials that used mercury sphygmomanometers vs. automatic devices

5) Trials with published standard deviations of blood pressure change vs. imputed standard

deviations

2.2.10. Statistical Considerations

2.2.10.1. Individual Study Data

In the RevMan program, continuous outcomes such as change in blood pressure and heart rate for each study must be inputted with group size, mean response, and standard

deviation. For each study a weighted mean difference is calculated as WMD = mirm2i.

Table 7: Data input for continuous data in RevMan Study i Group size Mean response Standard deviation Intervention sd,,-

Control N2, m2; sd,,

For dichotomous (binary) outcomes, the number of subjects who experience an event in the intervention and control groups and the total number of subjects in each group are inputted in RevMan.

Table 8: Data input for dichotomous data in RevMan Study i Event No event Total Intervention a,

Control c; d, n2, N,.

Dichotomous data can be represented in four different ways in RevMan: Peto odds ratio, odds ratio, relative risk and risk difference (Table 9).

Table 9: Formulae for individual study responses for dichotomous data in RevMan Estimate (for each study z) Formula Peto odds ratio OR, = exp{a,-E[a,]/v,}, where Efa^n.^.+cVH- Odds ratio OR,= a,d,/b,c,

Risk ratio or relative risk RR,.= (a,./n„)/(c,/n2,)

Risk difference RD, = (a,/n„) - (c,/n2,)

49 2.2.10.2. Pooling trials

There are two main approaches for summarizing the results of studies in a meta• analysis: the "fixed effect" model and the "random effects" model. The fixed effect approach assumes that the group of studies being analyzed is a distinct population (a "fixed" set) and the aim is to estimate the mean effect size of these trials only. The fixed effect model tests the significance of the null hypothesis (i.e., no overall difference between treatment and control in the selected group of studies). Because the fixed effect approach ignores between-study variation, it assumes the studies have homogeneous effect sizes. The statistic jg is calculated to test for interstudy heterogeneity. ff statistically significant heterogeneity is present, the fixed-effect estimate of the overall effect size may not be valid

(89). The inverse variance method is used to combine weighted mean differences for continuous data. The effect size for each study is weighted by the reciprocal of the square of the standard error. Thus, studies with large sample size are weighted more heavily than smaller trials. Likewise, studies with smaller variances have greater influence on the overall effect size than studies with large variances. For dichtomous data, the Mantel-Haenszel method is used to produce odds ratio, relative risk, and risk difference estimates. The odds ratio and relative risk are relative measures and their values are similar if the outcome is rare

(76). However, the relative risk is recommended because the odds ratio is more difficult to interpret. Risk difference expresses results in absolute terms.

The random effects model assumes that the set of studies being analyzed is a random sample from a larger population of studies. The DerSimonian and Laird method is used to combine continuous data or dichotomous data. The weight assigned to each study takes into account both intra- and inter-study variances. This approach accounts for interstudy

50 heterogeneity and produces wider confidence intervals than the fixed effect approach. An advantage of the random effects approach is that it estimates the effect size for a hypothetical population of studies, which may include future studies or previous studies that may have been missed (89).

Which of the two competing models is used depends on whether or not we wish to take into account between-study variation, f f there is no statistically significant heterogeneity between studies, the fixed-effect and random-effects estimates will be similar. A disadvantage of the random effects model is that more weight is assigned to smaller studies compared to the fixed effect model. These small studies are more likely to be of poorer quality and are more subject to publication bias (76).

2.2.11 Starting doses

fn order to combine trial data in the analyses, calcium channel blocker drugs were analysed as increments of the recommended starting dose, as determined from reference pharmacopeias (44, 90). ff a range was given, the lower dose was taken as the starting dose.

Table 10 lists starting doses of calcium channel blockers assessed in this review. This approach is based upon the assumption that starting doses recommended by companies must have evidence for blood pressure lowering efficacy and that the blood pressure lowering efficacy of each of the starting doses is approximately the same.

51 Table 10: Starting doses of calcium channel blockers (44, 90) Drug Brand name (Company) Starting dose/day Available in for hypertension Canada? Amlodipine Norvasc® (Pfizer) 5 mg Yes Also available in combination with benazepril- Lotrel® (Novartis) Barnidipine Hypoca®, Vasexten® 10 mg No (Yamanouchi) Darodipine n/a 100 mg* No

Diltiazem Cardizem®, Tiazac® (Biovail) 120-240 mg Yes Generic available Felodipine Plendil® (AstraZeneca) 5 mg Yes Renedil® (Sanofi-Aventis) Isradipine DynaCirc® (ReHant), Lomir® 5mg No Lacidipine Lacipil® (GlaxoSiTUthKline), 2-4mg No Caldine®, Lacimen®, Lacipil®, Midotens®, Motens® Lercanidipine Zanidip® (Recordati) 10 mg No Lidoflazine Clinium® (Janssen) Angina only No Manidipine Calslot® (Takeda) 10 mg No Nicardipine Cardene® (Roche) 60 mg No Nifedipine Adalat® (Bayer) 20-30 mg Yes Generic available Nilvadipine Escor®, Nivadil® (Fujisawa) 8mg No Nisoldipine Sular® (Bayer) 10 mg No Nitrendipine Bayotensin®, Baypress® 5-20 mg No (Bayer) Pranidipine n/a 2 mg* No Tiapamil n/a No doses were No statistically significantly different from placebo* Verapamil Isoptin® (Abbott) 180-240 mg Yes Generic available * For darodipine, pranidipine and tiapamil, no dosing information was available in the monographs; therefore dose Listed is the lowest effective dose as determined by the systematic review

2.2.12. Direct and indirect comparisons between doses

When possible, direct and indirect comparisons of effect sizes between doses were performed for each CCB drug. In the direct method, only trials that randomized participants to different doses were included in the analysis. In the indirect method, an

52 "adjusted indirect comparison" and the associated standard error were calculated using the method described by Bucher et al (91) and Song et al (92). Briefly, CCB drug doses were compared from all the placebo-controlled trials, by adjusting for the common placebo intervention. The difference between the indirect and direct estimates was then assessed.

53 3. RESULTS

3.1 Search findings

Table 11: Results of the search strategy

Number of publications

Publications identified by search strategy 4093

Trials excluded upon reading tides/abstracts 3076

Review articles identified by search strategy 563

Relevant review articles retrieved 138

Trials retrieved for detailed reading 454

Trials excluded upon detailed reading 217

Number of trials meeting inclusion criteria 237

Of the trials meeting the inclusion criteria:

Data available Included Studies 106

Data not available Excluded Studies 131

The search strategy was highly sensitive but lacked specificity since 75% of hits (not including review articles) were excluded upon reading the tides or abstracts. There was an overlap of 983 studies between Medline and EMBASE databases. One hundred thirty-eight relevant review articles identified by the search strategy were checked for references to trials.

102/106 (96%) of the included studies were found in the Cochrane Central Register of

Controlled Trials (CENTRAL). References that have not been indexed yet in CENTRAL have been sent to the Cochrane Hypertension Group for revision of the database. Two of

the missing studies (Circo 1997, Ninci 1997) were also not indexed in Medline or EMBASE, but rather, were found from the reference list of a review article.

Four of the 106 included studies were originally excluded due to lack of reporting of

the number of patients in each arm; however these trials were included after obtaining the

54 missing values from Law et al's published meta-analysis of five classes of antihypertensives

(93).

3.2 Characteristics ofincluded studies

Of the 4093 citations identified by the search strategy, 106 trials (2.6%), published between 1976 and 2003, met the inclusion criteria and contained extractable data for 19 CCB drugs. Of these included trials, 99 (92%) of the studies were published in English, 3 (3%) in

French, 3 (3%) in German, and 2 (2%) in Italian. One hundred four (97%) of the included studies had a parallel-group design, while only 3 (3%) were cross-over studies (only the pre- cross-over data were used in this analysis).

Tables 12-30 summarize the characteristics of each included study. Each study was assigned a unique identifier consisting of either the trial acronym or the surname of the first author followed by the year of publication.

55 Table 12: Amlodipine - Characteristics of included studies

Study Study Description Chrysant 2003 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (94) Treatment duration: 8 weeks.

Country: USA

Quality: Cochrane method = B; jadad score = 3

Participants: sitting DBP 100-115 mm Hg and mean daytime DBP

90-119 mm Hg via ABPM for inclusion into trial.

N = 252: 161 m, 91 f. Mean age: 52 years (> 18 years for inclusion).

Baseline BP: 155.1/103.8 mm Fig (Ami. group), and 154.2/103.3 mm

Hg (placebo group). Baseline pulse pressure: 51.3 mm Hg (Ami.

group), and 50.9 mm Hg (placebo group).

Interventions: Amlodipine 5 mg/day, olemesartan medoxomil 20

mg/day, or placebo.

Primary and secondary outcomes: Change- from baseline in: mean

24-h DBP/SBP by ABPM (Instrument: not reported), sitting trough

SBP, DBP by cuff (Instrument: not reported); response rates for: DBP

< 90 mm Hg and < 85 mm Hg; SBP < 140 mm Hg and < 130 mm

Hg-

Notes: Change in sitting BP data, last observation carried forward,

extracted from Table 3. SD of mean change in BP imputed from other

trials. WDAE extracted from text, p. 427.

Funding source: Sankyo Pharma Inc. Farsang 2001 Design: MC/R/DB/PC trial. Placebo-run-in period: 4 weeks. (95) Treatment duration: 8 weeks.

Country: France, Flungary, Poland, South Africa, United Kingdom.

Quality: Cochrane method =B; jadad score = 4

Participants: sitting DBP 95-114 mm Fig for inclusion into trial.

N = 341: 231 m, 110 f. Mean age: 52.2 years (inclusion range: 20 - 80).

Baseline BP: 164.8/102.5 mm Hg (amlodipine group) and 161.5/102.1

mm Hg (placebo group). Baseline pulse pressure: 62.3 mm Hg

56 (amlodipine group) and 59.4 mm Fig (placebo group).

Interventions: Amlodipine 5 mg/day, candesartan cilexetil 8 mg/day,

cadesartan cilexetil 8 mg + amlodipine 5 mg/day combination, or

placebo.

Primary and secondary outcomes: Change from baseline in sitting

and standing trough SBP, DBP and HR (Instrument: automatic device

— Omron).

Notes: Change in sitting BP and SD data extracted from Figure 1.

WDAE reported. SDs of BP change were imputed from other trials

because reported SDs were spuriously low.

Author contacted — no response.

Funding source: Astra Hassle AB, Sweden. Frick 1988 Design: MC/R/DB/PC dose-response study. Washout period: 2 (96) weeks. Placebo run-in period: 4 weeks. Treatment duration: 4 weeks,

[Duplicate followed by dose titration in non-responders and an additional 4 publication: Frick weeks. 1989 (97)] Country: Finland

Quality: Cochrane method =B; Jadad score — 4

Participants: supine and standing DBP 95-114 mm Hg or 100-114

mm Hg if aged > 60 years for inclusion into trial.

N = 205: 122 m, 83 f. Mean age: 50.2 years (range: 23-74). Baseline

BP: 156.5/105.6 mm Hg (Ami. 1.25 mg group), 154.8/106.3 mm Hg

(Ami. 2.5 mg group), 161.1/106.4 mm Hg (Ami. 5 mg group), and

157.0/106.0 mm Hg (placebo group). Baseline pulse pressure: 50.9

mm Hg (Ami. 1.25 mg group), 48.5 mm Hg (Ami. 2.5 mg group), 54.7

mm Hg (Ami. 5 mg group), and 51 mm Hg (placebo group).

Interventions: Amlodipine 1.25 mg/day, 2.5 mg/day, 5 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in supine

and standing trough SBP, DBP (Instrument: standard Hg

sphygmomanometer) and HR.

57 Notes: Change in standing BP data at week 4 extracted from Table 3

(Frick 1989). SD of mean change in BP imputed from weighted mean

SD of other trials. WDAE reported but cannot determine if they

occurred before or after titration in non-responders.

Pfizer (Kent, UK) contacted — no data.

Funding source: Not reported.

Frishman 1995 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo (98) run-in period: 2-4 weeks. Treatment duration: 8 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: Sitting DBP 100-115 mm Fig for inclusion into trial. N = 332: 209 m, 123 f. Mean age: 53.7 years (inclusion range: 21-80). Baseline BP: 157.8/103.8 mm Hg (amlodipine group) and 158.0/103.9 mm Hg (placebo group). Baseline pulse pressure: 54.0 (amlodipine

group) and 54.1 (placebo group) Interventions: Amlodipine 2.5 mg/day, benazepril 10 mg/day, benazepril 10 mg + amlodipine 2.5 mg/day combination, or placebo. Primary and secondary outcomes: Change from baseline in sitting and standing trough SBP, DBP (Instrument: standard Hg sphygmomanometer), and HR.

Notes: sitting BP data extracted from Figure 2. SD of mean change in

BP imputed from SDs of week-8 BPs. WDAE reported.

Author contacted -

Funding source: Ciba-Geigy Corp.

Kuschnir 1996 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo run- (99) in period: 2-4 weeks. Treatment duration: 8 weeks.

Country: Argentina

Quality: Cochrane method = B; Jadad score — 4

Participants: Sitting DBP 100-120 mm Hg for inclusion into trial.

N = 308: 138 m, 170 f. Mean age: 56.5 years (inclusion range 21-80).

Baseline BP: 165.6/106.5 mm Fig (amlodipine group) and 166.4/106.9

58 mm Hg (placebo group). Baseline pulse pressure: 59.1 mm Hg

(amlodipine group) and 59.5 mm Hg (placebo group).

Interventions: Amlodipine 5 mg/day, benazepril 20 mg/day,

amlodipine 5 mg + benazepril 20 mg/day combination, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

trough SBP, DBP (Instrument: Hg manometer), and HR.

Notes: sitting BP data extracted from Table II. SD of mean change in

SBPs imputed from SD of baseline BPs and SD of mean change in

DBP imputed from other trials. WDAE reported.

Attempted to contact author — no response.

Funding source: Ciba Geigy Corp., USA. Licata 1993 Design: R/DB/PC trial. Placebo run-in period: 2 weeks. Treatment (100) duration: 4 weeks.

Country: Italy

Quality: Cochrane method — B; Jadad score = 3

Participants: Supine DBP >90 mm Hg for inclusion into trial.

N = 30: 14 m, 16 f. Mean age: 45.4 years (range: not reported).

Baseline BP: 165.9/100.0mm Hg (treatment group) and 163.1/101.0

mm Hg (placebo group). Baseline pulse pressure: 65.9 (treatment

group) and 62.1 (placebo group).

Interventions: Amlodipine 10 mg/day or placebo.

Primary and secondary outcomes: Change from baseline in supine

trough SBP, DBP, (Instrment: Hg sphygmomanometer), and HR; renal

hemodynamic measurements.

Notes: Supine BP data extracted from Table 1. SD of mean change in

BPs imputed from SDs of week-4 BPs. WDAE not reported.

Funding source: Not reported.

Mehta 1993 Design: MC/R/DB/PC dose-finding study. Placebo run-in period: 4 (101) weeks. Treatment duration: 4 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 4

59 Participants: Supine and standing DBP 95-114 mm Hg for inclusion into trial.

N = 210: 112 m, 98 f. Mean age: 52.8 years (inclusion range: 18-75). Baseline BP: 147.3/101.6 mm Hg (Ami. 1.25 mg group), 150.7/102.2 mm Hg (Ami. 2.5 mg group), 151.0/101/6 mm Hg (Ami. 5 mg group), 152.8/101.9 (Ami. 10 mg group), and 153.4/102.0 mm Hg (placebo group). Baseline pulse pressure: 45.7 mm Hg (Ami. 1.25 mg group), 48.5 mm Hg (Ami. 2.5 mg group), 49.4 (Ami. 5 mg group), 50.9 (Ami. 10 mg group), and 51.4 (placebo group).

Interventions: Amlodipine 1.25 mg/day, 2.5 mg/day, 5 mg/day, 10 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in supine and standing trough SBP, DBP (Instrument: standard Hg sphygmomanometer), and HR; ECG; body weight; biochemical, hematologic, urinalysis lab tests.

Notes: Change in standing BP and SEM extracted from Figure 1. WDAE reported.

Author contacted — no data available. Funding source: Pfizer Research, USA.

Mroczek 1988 Design: R/DB/PC trial. Placebo run-in period: 4 weeks. Treatment (102) duration: 4 weeks.

[Multiple Country: USA publications: Quality: Cochrane method = B; Jadad score = 4 Mroczek 1991a (103), Mroczek Participants: Standing and supine DBP 95-114 mm Hg for inclusion 1991b (104), into trial. Burris 1994 (105)] N = 16: 11 m, 5 f. Mean age: 56.9 years (range: 37-75). Baseline

standing BP: 154.9/102.2 mm Hg (amlodipine group) and 146.9/105.6

mm Fig (placebo group). Baseline pulse pressure: 52.7 (amlodipine

group) and 41.3 (placebo group).

Interventions: Amlodipine 5 mg/day or placebo.

Primary and secondary outcomes: Change from baseline in supine

60 and standing trough SBP, DBP (Instrument: standard Hg

sphygmomanometer).

Notes: Mean change in standing BP extracted from Table 2 (Mroczek

1991a) and SEM extracted from Figure 1 (Mroczek 1991b). WDAE

reported.

Funding source: Pfizer Inc., USA.

Pool 2001 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo run- (106) in period: 2-4 weeks. Treatment duration: 8 weeks. Country: USA

Quality: Cochrane method =A; Jadad score — 5

Participants: sitting DBP 100-115 mm Hg for inclusion into trial. N = 454: 286 m, 168 f. Mean age: 53.8 years (inclusion range: 21-80).

Baseline BP: 154.4/104.2 mm Hg (amlodipine group) and 156.1/105.1 mm Hg (placebo group). Baseline pulse pressure: 50.2 (amlodipine

group) and 51 (placebo group). Interventions: Amlodipine 5 mg/day, benazepril lOmg/day, amlodipine 5 mg + benazepril 10 mg/day combination, or placebo. Primary and secondary outcomes: Change from baseline in sitting trough SBP, DBP (Instrument: not reported) and HR. Notes: Mean change in BP data extracted from Table 1. SD of mean change in BPs imputed from SDs from other trials. WDAE reported. Attempted to contact author — no response. Funding source: Novartis Pharmaceuticals, USA.

61 Table 13: Barnidipine - Characteristics of included studies

Study Study Description Hart 1997 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (107) Treatment duration: 6 weeks, followed by dose titration in non-

responders and an additional 6 weeks.

Country: Netherlands

Quality: Cochrane method = B; Jadad score = 4

Participants: Sitting DBP 95-114 mm Hg for inclusion into trial.

N = 190 (intention-to-treat): 124 m, 66 f. Mean age: 55.8 years

(inclusion range: 18 -,75).

Baseline BP (sitting): 161.0/102.0 mm Hg (Bar. 10 mg/day group),

163.6/102.9 mm Hg (Bar. 20 mg/day group), 166.2/102.5 mm Hg

(Bar. 30 mg/day group), and 165.2/102.5 mm Hg (placebo group).

Baseline pulse pressure: 59 mm Hg (Bar. 10 mg/day group), 60.7 mm

Hg (Bar. 20 mg/day group), 63.7 mm Hg (Bar. 30 mg/day group), and

62.7 mm Hg (placebo group).

Interventions: Barnidipine 10 mg/day, 20 mg/day, 30 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in sitting

and standing trough SBP, DBP (Instrument: sphygmomanometer) and

HR.

Notes: Change in sitting BP at week 6 extracted from Figure 1. SDs

of changes in BP imputed from other trials. No significant change in

HR (no HR data provided at 6 weeks). WDAE not reported for each

group separately.

Attempted to contact author — no response.

Funding source: Yamanouchi Europe B.V., Netherlands.

62 Table 14: Darodipine - Characteristics of included studies

Study Study Description Chrysant 1988 Design: R/DB/PC trial. Placebo run-in period: 3 weeks. Treatment (108) duration: 4 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: Supine DBP 100-115 mm Hg for inclusion into trial.

N = 43: 26 m, 17 f. Mean age: 51.7 years (range: not reported).

Baseline BP (standing): 157/103 mm Hg (Dar. 100 mg/day group),

160/104 mm Hg (Dar. 200 mg/day group), 154/103 mm Hg par. 300

mg/day group), and 157/102 mm Hg (placebo group). Baseline pulse

pressure: 54 mm Hg (Dar. 100 mg/day group), 56 mm Hg (Dar. 200

mg/day group), 51 mm Hg (Dar. 300 mg/day), and 55 mm Hg

(placebo group).

Interventions: Darodipine 100 mg/day, 200 mg/day, 300 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in supine

and standing SBP, DBP (Instrument: not reported) and HR; metabolic

parameters (BUN, glucose, electrolytes, Ever enzymes); ECG.

Notes: standing BP and HR data and associated SEMs extracted from

Figures 1-4. Changes in BP and HR calculated by subtracting baselines

from weighted means of week 3 and 4 data. SD of change in BP and

HR imputed from weighted mean SD of week 3 and 4 data. No

patients withdrew due to adverse events.

Author contacted — data no longer available.

Funding source: Not reported.

63 Table 15: Diltiazem - Characteristics of included studies

Study Study Description Burris 1990 Design: MC/R/DB/PC, 5x4 multifactorial-design trial. Placebo (109) run-in: 4-6 weeks. Treatment duration: 6 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score — 3

Participants: Supine DBP 95-110 mm Hg for inclusion into trial.

N = 297: 184 m, 113 f. Mean age: 52.1 years (range: not reported).

Baseline supine BP: 151.6/99.4 mm Hg (all groups combined).

Baseline pulse pressure: 52.2 mm Hg (all groups combined).

Interventions: Diltiazem SR 120 mg/day, 180 mg/day, 240 mg/day,

360 mg/day, hydrochlorothiazide 12.5 mg/day, 25 mg/day, 50

mg/day, all possible diltiazem SR-hydrochlorothiazide combinations

thereof, or placebo.

Primary and secondary outcomes: Change from baseline in supine

and standing SBP, DBP (Instrument: standard Hg

sphygmomanometer) and HR; % achieving goal BP (supine DBP < 90

mm Hg at week 6); ECG; lab tests.

Notes: Change in DBP data extracted from Figure 1. SD of BP

change imputed from other trials.

Author contacted — no access to data; attempts to contact other

authors/Biovail unsuccessful. Number of patients in each group was

not explicidy reported; this data was obtained from a published meta•

analysis (93). WDAE not reported separately for each group.

Funding source: Marion Laboratories Inc.

Chan 1997 Design: MC/R/DB/PC, 3x2 multifactorial-design trial. Placebo (110) run-in: 4 weeks. Treatment duration: 12 weeks.

Country: Taiwan and Hong Kong

Quality: Cochrane method = B; Jadad score = 4

Participants: sitting DBP 95-114 mm Hg for inclusion into trial. \

N = 156: 134 m, 52 f. Mean age: 72 years (range: 65 - 88).

64 Baseline BP: 167.9/104.5 mm Hg (Dilt. 120 mg group), 170.0/105.9 mm Hg (Dilt. 240 mg group) and 167.9/105.5 mm Hg (placebo group). Baseline pulse pressure: 63.4 mm Hg (Dilt. 120 mg group), 64.1 mm Hg (Dilt. 240 mg group) and 62.4 mm Hg (placebo group). Interventions: Diltiazem SR 120 mg/day, 240 mg/day, lisinopril 10 mg/day, diltiazem SR-lisinopril combinations 120/10 mg/day, 240/10 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting SBP, DBP (Instrument: standard Hg sphygmomanometer) and HR; quality of life questionnaire.

Notes: Change in BP data extracted from Table 2 and 3. Reported SDs of BP change were spuriously low (outside the 99% confidence interval of all trials reporting SD of BP change). SDs were imputed from endpoint BPs. WDAE reported.

Author contacted: data no longer available and verification of data extraction not possible. Funding source: Not reported.

Cushman 1998 Design: MC/R/DB/PC trial. Washout period: 1 week. Placebo run- (111) in period: 4 weeks. Treatment duration: 12-week double-blind phase,

followed by 36-week open label phase. Country: USA

Quality: Cochrane method — B; Jadad score = 4

Participants: Sitting DBP 95-115 mm Hg for inclusion into trial.

N = 891: 609 m, 282 f. Mean age: 54.4 years (range: not reported).

Baseline BP: 152.6/101.7 mm Hg (Dilt. 120 mg/day group),

155.4/102.2 mm Hg (Dilt. 180 mg/day group), 155.4/101.7 mm Hg

(placebo group). Baseline pulse pressure: 50.9 mm Hg (Dilt. 120

mg/day group), 53.2 mm Hg (Dilt. 180 mg/day group), 53.7 mm Hg

(placebo group).

Interventions: Diltiazem ER 120 mg/day, 180 mg/day, enalapril 5

mg/day, enalapril + diltiazem ER combination 5/120 mg/day, 5/180

65 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

trough DBP, SBP (Instrument: standard Hg sphygmomanometer) and

HR; trough-to-peak ratios.

Notes: BP data at week 12 extracted from Table 2. SD of change in

BP imputed from other trials.

Author contacted: request for data was forwarded (no response).

Funding source: Merck Research Laboratories, USA.

Djian 1990 Design: R/DB/PC dose-response trial. Placebo run-in period: 15 (112) days. Treatment duration: 4 weeks, followed by 4 weeks on forced

titration dose.

Country: France

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-115 mm Hg for inclusion into trial.

N = 95: 51 m, 44 f. Mean age: 58.4 years (range: not reported).

Baseline standing BP: 164.7/102.6 mm Hg (Dil. 240 mg/day),

169.2/105.9 mm Fig (Dil. 300 mg/day), 167.9/103.8 mm Hg (Dil. 360

mg/day), 168.9/107.1 mm Hg (placebo group).

Baseline pulse pressure: 62.1 mm Hg (Dil. 240 mg/day group), 63.3

mm Fig (Dil. 300 mg/day group), 64.1 mm Hg (Dil. 360 mg/day

group), 61.8 mm Hg (placebo group)

Interventions: Diltiazem sustained release 240 mg/day, 300 mg/day,

360 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in SBP,

DBP (Instrument: not reported) and HR, ECG (PR interval); lipid

parameters.

Notes: Reported variabilities assumed to be SE values. Changes in

standing BP extracted from Table 2 and Figure 3. SD of change in

standing DBP imputed from SE of change in supine DBP from text, p.

S41. SD of change in SBP imputed from SDs of baseline SBP. HR

data (from ECGs) extracted from Table 3; SD of HR change imputed

66 from baseline SDs.

Funding source: Not reported.

Felicetta 1992 Design: MC/R/DB/PC dose-response trial. Placebo run-in period: 4- (113) 6 weeks. Treatment duration: 4 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 3 Participants: Supine DBP 95-110 mm Hg for inclusion into trial. N = 229: 162 m, 67 f. Mean age: 48.8 years (inclusion range: 18-60). Baseline BP: 146.9/100.0 mm Fig (Dil. 90 mg/day group), 148.4/100.3 mm Hg (Dil. 180 mg/day group), 150.9/99.9 mm Hg (Dil. 360 mg/day group), 152.0/101.0 mm Hg (Dil. 540 mg/day group), 153.3/100.4 mm Hg (placebo group). Baseline pulse pressure: 46.9 mm Hg (Dil. 90 mg/day group), 48.1 mm Hg (Dil. 180 mg/day group), 51.0 mm Hg (Dil. 360 mg/day group), 51 mm Fig (Dil. 540 mg/day group), 52.9 mm Hg (placebo group).

Interventions: Diltiazem CD 90 mg/day, 180 mg/day, 360 mg/day, 540 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough and peak supine SBP, DBP (Instrument: not reported), and HR; % satisfactory BP response, defined as supine DBP < 90 mm Hg or > 6 mm Hg reduction; trough-peak ratios.

Notes: Change in BP and associated SD extracted from Table II.

WDAE reported.

Funding source: Not reported.

Fiddes1994 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (114) Treatment duration: 4 weeks, followed by titration in non-responders

and an additional 8 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-114 mm Hg for inclusion into trial.

N = 350: 156 m, 194 f. Mean age: 64.7 years (> 55 for inclusion).

67 Baseline standing BP: 157.1/100 mm Hg (diltiazem group) and

157.1/100 mm Hg (placebo group). Baseline pulse pressure: 57.1 mm

Hg (diltiazem group) and 57.1 mm Hg (placebo group).

Interventions: Diltiazem (extended-release) 240 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

supine/standing DBP, SBP, and HR; % achieving BP < 90 mm Hg;

lab tests.

Notes: Change in supine DBP data at week 4 extracted from Figure 1.

SD of DBP change imputed using pooled SD calculated from p value.

WDAE reported but cannot determine if they occurred before or after

titration in non-responders.

Attempted to contact author: no response.

Funding source: Not reported. Herpin 1990 Design: R/DB/PC trial. Placebo run-in period: 1 week. Treatment (115) duration: 3 weeks.

Country: France

Quality: Cochrane method = B; Jadad score — 3

Participants: Supine DBP 95-115 mm Fig for inclusion into trial.

N = 38 (efficacy analysis): 16 m, 22 f. Mean age: 51.4 years (inclusion

range: 18 - 75). Baseline BP: 164/101 mm Hg (Dil. 240 mg/day

group), 163/102 mm Fig (Dil. 300 mg/day group), and 163/100 mm

Fig (placebo group).

Baseline pulse pressure: 63 mm Hg (Dilt. 240 mg/day group), 61 mm

Hg (Dilt. 300 mg/day group), and 63 mm Hg (placebo group).

Interventions: Diltiazem SR 240 mg/day, 300 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in clinic

supine DBP, SBP (Instrument: Hg manometer), and ambulatory

SBP/DBP (Instrument: Spacelab monitor).

Notes: Clinic BP data extracted from Table II. SDs of BP change

imputed from endpoint BPs. WDAE reported, but number of patients

initially randomized to each group is not reported.

68 Funding source: Not reported.

Meeves 1994 Design: MC/R/DB/PC trial. "Placebo run-in period: 4-6 weeks. (116) Treatment duration: 4 weeks (forced titration at week 1). Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-110 mm Hg for inclusion into trial. N = 111: 57 m, 54 f. Mean age: 53.3 years (> 18 for inclusion). Baseline supine BP: 149.5/99.7 mm Hg (Diltiazem group), and

149.3/99.6 mm Hg (placebo group). Baseline pulse pressure: 49.8 mm Hg (Diltiazem group), and 49.7 mm Hg (placebo group).

Interventions: Diltiazem CD 180 mg/day (1 week) 300 mg/day (3 weeks), or placebo.

Primary and secondary outcomes: Change from baseline in SBP, DBP (Instrument: standard Hg sphygmomanometer), and HR; trough- peak ratios; ECG.

Notes: Change in BP, HR and associated SE data extracted from Table II. WDAE extracted from text, p. 234. Funding source: Marion Merrell Dow Inc., USA.

Pool 1993 Design: MC/R/DB/PC trial. Placebo run-in period: 4-6 weeks. (117) Treatment duration: 6 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: Supine DBP 95-110 mm Hg for inclusion into trial.

N = 254: 168 m, 86 f. Mean age: 54.4 years (inclusion range: 18 -70).

Baseline BP: 152.7/99.4 mm Hg (diltiazem group) and 152.9/99.9

(placebo group). Baseline pulse pressure: 53.3 (diltiazem group) and

53.0 (placebo group).

Interventions: Diltiazem SR 120 mg/day, hydrochlorthiazide 12.5 mg,

combination diltiazem SR-hydrochlorthiazide 120/12.5 mg/day, or

placebo.

69 Primary and secondary outcomes: Change from baseline in trough

supine/standing SBP, DBP (Instrument: Hg sphygmomanometer) and

HR; ECG; fasting lab tests; 12-hour BP monitoring at baseline and

week 6.

Notes: Change in supine SBP/DBP and associated SE data extracted

from Table 2. WDAE for each group not reported.

Funding source: Marion Merrell Dow Inc., USA.

Prisant 2000 Design: MC/R/DB/PC trial with 3x4 factorial design. Placebo run- (119) in period: 4 weeks. Treatment duration: 6 weeks (forced titration at

week 1.) Country: USA Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-114 mm Hg for inclusion into trial.

N = 329: 198 m, 131 f Mean age: 51.6 years (range: 19 - 86).

Baseline BP: 153.4/99.7 mm Fig (Dilt. 120 mg/day group),

149.9/100.5 mm Hg (Dilt. 180 mg/day group), 149.7/99.3 mm Hg

(Dilt. 240 mg/day group), 153.3/99.6 mm Hg (Dilt. 360 mg/day

group), and 150.7/99.8 mm Hg (placebo group)

Baseline pulse pressure: 53.7 mm Hg (Dilt. 120 mg/day group), 49.4

mm Hg (Dilt. 180 mg/day group), 50.4 mm Hg (Dilt. 240 mg/day

group), 53.7 mm Fig (Dilt. 360 mg/day group), and 50.9 mm Hg

(placebo group).

Interventions: Diltiazem XR 120 mg/day, 180 mg/day, 240 mg/day,

360 mg/day, indapamide 1.25 mg/day, 2.5 mg/day, or diltiazem XR +

indapamide combination 120/1.25, 180/1.25, 240/1.25, 120/2.5,

180/2.5, 240/2.5 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in supine

clinic SBP, DBP (Instrument: not reported) and ambulatory BP

(Instrument: SpaceLabs); hematologic, serum chemistry and urinalysis

testing; ECG.

Notes: Change in supine SBP and DBP extracted from Table 3. SDs

70 of BP change imputed from other trials. WDAE from each group not

reported.

Funding source: Rhone-Poulenc Rorer, Inc., USA.

Weir 1992 Design: MC/R/DB/PC trial. Placebo run-in period: 4-6 weeks. (119) Treatment duration: 12 weeks (3 forced titration periods of 4 weeks

each.)

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-110 mm Hg for inclusion into trial.

N - 298 (efficacy analysis N=274): 179 m, 95 f. Mean age: 53.5 years.

Baseline BP: 150.1/99.8 mm Hg (diltiazem group) and 152.7/99.5 mm

Hg (placebo group).

Baseline pulse pressure: 50.3 (diltiazem group) and 53.2 (placebo

group).

Interventions: Diltiazem SR 60 mg/day (4 weeks) 90 mg/day (4

weeks) -^120 mg/day (4 weeks); hydrochlorthiazide 6.25 (8 weeks)

12.5 mg/day (4 weeks); diltiazem SR/hydrochlorthiazide 60/6.25

mg/day (4 weeks) -> 90/6.25 mg/day (4 weeks) ~> 120/12.5 mg/day

(4 weeks), or placebo.

Primary and secondary outcomes: Change from baseline in

supine/standing SBP, DBP (Instrument: Hg sphygmomanometer) and

HR; % responders, defined as supine DBP < 90 mm Hg and/or

decrease > 10 mm Hg.

Notes: Change in supine DBP and SBP and associated SE data were

extracted from Figure 3 and 4.

Funding source: Marion Merrell Dow Inc., USA.

Whelton 1992 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (120) Treatment duration: 4 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-114 mm Hg for inclusion into trial.

71 N = 275: 167 m, 108 f. Mean age: 51.9 years (inclusion range: 18 - 80). Baseline BP: 152.2/100.4 mm Hg (Dilt 120 mg/day group), 150.7/100.8 mm Hg (Dilt. 240 mg/day group), 148.9/99.2 mm Hg (Dilt. 360 mg/day group), 152.0/99.8 mm Hg (Dilt. 480 mg/day group), and 150.9/100.0 mm Hg (placebo group).

Baseline pulse pressure: 51.8 mm Hg (Dilt. 120 mg/day group), 59.9 mm Hg (Dilt. 240 mg/day group), 49.7 mm Hg (Dilt. 360 mg/day group), 52.4 mm Hg (Dilt. 480 mg/day group), and 50.9 mm Hg (placebo group).

Interventions: Diltiazem SR 120 mg/day, 240 mg/day, 360 mg/day, 480 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in supine trough SBP, DBP (Instrument: standard Hg sphygmomanometer); 24- hr ABPM (Instrument: Spacelabs 90202).

Notes: Change in supine SBP/DBP data extracted from Table II. SD of BP change imputed from other trials. WDAE reported. Funding source: Rhone-Poulenc Rorer, Inc., USA.

72 Table 16: Felodipine - Characteristics of included studies

Study Study Description

Black 2001 Design: MC/R/DB/PC trial. Washout period: < 8 weeks. Placebo (121) run-in period: 4 weeks. Treatment duration: 8 weeks, followed by

titration in non-responders-^ total duration of follow-up: 52 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: sitting SBP 140-159 mm Hg and DBP < 90 mm Fig for inclusion into trial (isolated systolic hypertension). N = 171: 84 m, 87 f. Mean age: 66 years (> 55 for inclusion). Baseline BP: 149/83 mm Hg (Fel. group), and 150/84 mm Hg (placebo group). Baseline pulse pressure: 66 mm Hg (Fel. group), and 66 mm Hg (placebo group).

Interventions: Felodipine ER 2.5 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in trough sitting SBP at week 52 (last observation carried forward), DBP (Instrument: Hg sphygmomanometer), FIR, quality of life measurements, weight, ECG measurements.

Notes: Change in SBP at week 8 data extracted from Figure 1. SD of SBP change imputed from other trials. WDAE reported but cannot determine if they occurred before or after titration in non-responders.

Funding source: AstraZeneca, LP, USA.

Felodipine Co-op Design: MC/R/DB/PC trial. Washout period: 4 weeks. Placebo run- 1987 (122) in period: 2 weeks. Treatment duration: 8 weeks.

[Duplication Country: UK publication: Quality: Cochrane method = B; Jadad score = 3 Hamilton 1987a (123)] Participants: DBP 95-110 mm Hg for inclusion into trial.

N = 109: 59 m, 50 f. Mean age: 52 years (range: 20-70 for inclusion).

Baseline BP: 166.8/104.4 mm Hg (Fel. 5 mg/d group), 165.9/104.4

mm Hg (Fel. 10 mg/d group), 171.2/105.4 mm Hg (Fe. 20 mg/d

73 group), and 162.9/104.4 mm Hg (placebo group). Baseline pulse

pressure: 62.4 mm Hg (Fel. 5 mg/d group), 61.5 mm Hg (Fel. 10 mg/d

group), 65.8 mm Hg (Fel. 20 mg/d group), 58.5 mm Hg (placebo

group).

Interventions: Felodipine 5 mg/day, 10 mg/day, 20 mg/day

(administered in two divided doses/day), or placebo.

Primary and secondary outcomes: Change from baseline in

supine/standing BP, HR (Instrument: Hawksley random zero

sphygmomanometer), ankle circumference, bodyweight.

Notes: standing BP/HR and SD data (12 hours postdose) from Week

8 extracted from Figure 4. WDAE extracted from Table V.

Funding source: Not reported.

Fagan 1997 Design: MC/R/DB/PC study. Placebo run-in period: 2-4 weeks. (124) Treatment duration: 9 weeks (dose titration at week 3 and 6 in non-

responders). Country: USA Quality: Cochrane method = B; Jadad score = 4

Participants: Sitting DBP 95-115 mm Hg for inclusion into trial.

N = 243: 163 m, 80 f. Mean age: 58.2 years (range: 26-83). Baseline

BP: 159/102 mm Hg (Fel. group) and 159/101 mm Hg (placebo

group). Baseline pulse pressure: 57 mm Hg (Fel. group) and 58 mm

Fig (placebo group).

Interventions: Felodipine ER 2.5 mg/day or placebo.

Primary and secondary outcomes: Change from baseline in sitting

trough SBP, DBP (Instrument: standard Hg sphygmomanometer), FIR,

body weight.

Notes: BP data at week 3 extracted from Table 2. SDs of BP change

were imputed from p values. Patients stratified by age: older (>65

years) vs. younger patients (< 60 years). WDAE reported but cannot

determine if they occurred before or after titration in non-responders.

Funding source: Merck, Sharp and Dohme, USA.

74 Fetter 1994 Design: R/DB/PC trial. Placebo run-in period: 2 weeks. Treatment (125) duration: 12 weeks. Country: Germany

Quality: Cochrane method = B; Jadad "score = 3

Participants: WFIO stage I-II hypertension (DBP > 115 mm Hg for inclusion into trial.

N = 71: m/f ratio not reported. Mean age: 47.5 years (range: 30 - 65). Baseline BP: 164/97 mm Fig (Fel. group) and 161/98 mm Fig (placebo group).

Baseline pulse pressure: 67 mm Hg (Fel. group) and 63 mm Hg (placebo group).

Interventions: Felodipine 10 mg/day or placebo. Primary and secondary outcomes: Blood flow velocity in extra- and intracranial arteries, BP (Instrument: not reported). Notes: Published in German. BPs extracted from Table 1. SDs of BP change imputed from other trials. WDAE from each dosage group not reported.

Funding source: Astra Chemicals GmbPI, Germany.

Gradman 1997 Design: MC/R/DB/PC factorial design study. Placebo run-in period: (126) 4 weeks. Treatment duration: 8 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 95-115 mm Hg for inclusion into trial.

N = 707: 457 m, 250 f. Mean age: 53.5 years. Baseline BP:

155.5/101.9 mm Hg (all patients). Baseline pulse pressure: 53.6 mm

Hg- Interventions: Felodipine ER 2.5 mg/day, 5 mg/day, 10 mg/day,

enalapril 5 mg/day, 20 mg/day, felodipine ER + enalapril combination

2.5/5, 2.5/20, 5/5, 5/20, 10/5, 10/20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

sitting DBP, SBP (Instrument: not reported - auscultatory method),

75 and HR.

Notes: Change in BP data extracted from Figure 1 and 2. SDs of

change in SBP imputed from baseline SBP value; SD of change in

DBP imputed from other trials. WDAE from each dosage group not

reported.

Attempted to contact author — no response.

Funding source: Astra Merck, USA.

Kiesewetter 1994 Design: R/DB/PC trial. Placebo run-in period: 2 weeks. Treatment (127) duration: 4 weeks. Country: Germany

Quality: Cochrane method = B; Jadad score — 4 Participants: DBP 90-120 mm Hg and SBP > 140 mm Hg for inclusion into trial. N — 104: 74 m, 30 f. Mean age: 56.2 years (range: 45-65 for inclusion). Baseline BP: 154/94 mm Hg (Fel. group) and 152/93 mm Hg (placebo group). Baseline pulse pressure: 60 mm Hg (Fel. group) and 59 mm Fig (placebo group). Interventions: Felodipine 10 mg/day or placebo.

Primary and secondary outcomes: Peak supine SBP, DBP (Instrument: sphygmomanometer) and HR; haemorheological parameters; urinalysis.

Notes: BPs and HRs extracted from text, page 361. SD of BP change imputed from SD of week 4 BPs.

Author contacted — dose and WDAE information obtained. Funding source: Not reported.

Liedholm 1989 Design: MC/R/DB/PC trial. Washout period: 4 weeks. Placebo run- (128) in period: 4 weeks. Treatment duration: 4 weeks.

Country: Sweden

Quality: Cochrane method — B; Jadad score = 4

Participants: Supine DBP 95-120 mm Hg for inclusion into trial.

N = 151: 147 m, 4 f. Median age: 51.8 years (range: 38-68). Baseline

BP: 156.2/99.5 mm Hg (Fel. 10 mg/day group), 157.6/101.4 mm Hg

76 (Fel. 20 mg/day group), and 158.6/101.4 mm Hg (placebo group).

Baseline pulse pressure: 56.7 mm Hg (Fel. 10 mg/day group), 56.2 mm

Hg (Fel. 20 mg/day group), and 57.2 mm Hg (placebo group).

Interventions: Felodipine ER 10 mg/day, 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in peak

and trough supine/standing SBP, DBP (Instrument: Hg

sphygmomanometer) and HR; blood and urine lab tests.

Notes: Change in trough supine BP, HR data and associated SDs

extracted from Table 2. WDAE reported.

Funding source: AB Hassle (subsidiary of ASTRA Pharmaceuticals),

Sweden.

Scholze 1999 Design: MC/R/DB/PC 3x4 factorial design, combination dose- (129) finding study. Washout period: Not reported. Treatment duration: 6

weeks.

Country: Germany

Quality: Cochrane method = B; Jadad score = 4

Participants: WHO class f-II (mild-to-moderate hypertension) for

inclusion into trial. N= 507: 327 m, 180 £ Mean age: 50.2 years

(range: 18-73). Baseline BP: 165.4/106.7 mm Hg (Fel. 5 mg/day

group), 166.0/107.0 mm Fig (Fel. 10 mg/day group), and 166.6/107.3

mm Fig (placebo group). Baseline pulse pressure: 58.7 mm Hg (Fel. 5

mg/day group), 59 mm Fig (Fel. 10 mg/day group), and 59.3 mm Hg

(placebo group).

Interventions: Felodipine ER 5mg/day, 10 mg/day, ramipril 2.5

mg/day, 5 mg/day, 10 mg/day, all ramipril-felodipine ER

combinations thereof, or placebo.

Primary and secondary outcomes: Change from baseline in trough

standing/supine SBP, DBP (Instrument: Hg sphygmomanometer), and

a composite supine-standing mean arterial pressure.

Notes: Change in supine BPs and associated SEMs extracted from

Table 1.

77 Author contacted - baseline BPs, number of patients in intention-to-

treat population, WDAE in each group obtained from Aventis Pharma.

Funding source: Hoechst, Germany. van Ree 1996 Design: MC/R/DB/PC study. Placebo run-in period: 4 weeks. (130) Treatment duration: 6 weeks. Country: Netherlands

Quality: Cochrane method = B; Jadad score = 4 Participants: Sitting DBP 100-115 mm Hg and SBP 140-200 mm Hg for inclusion into trial.

N = 129: 38 m, 91 f. Mean age: 63 years (range: 50 — 80 for inclusion). Baseline BP: 175/104 mm Hg (Fel. 2.5 mg/day group) mm Hg, 173/105 mm Hg (Fel. 5 mg/day group), 177/105 mm Hg (placebo group).

Baseline pulse pressure: 71 mm Hg (Fel. 2.5 mg/day group), 68 mm Hg (Fel. 5 mg/day group), 72 mm Hg (placebo group). Interventions: Felodipine ER 2.5 mg/day, 5 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in trough sitting BP (Instrument: random zero sphygmomanometer — Hawksley), FIR; 24-hour ABPM.

Notes: Change in BP and associated SD (at week 6) data extracted from Figure 1. WDAE extracted from text, p. 615. Funding source: Astra Pharmaceutica BV, Netherlands.

Weber 1994 Design: MC/R/DB/PC study. Placebo run-in period: 4 weeks. (131) Treatment duration: 8 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: Sitting DBP 95-115 mm Hg for inclusion into trial.

N = 286: 186 m, 100 f. Mean age: 54-55 years in all groups (range: 24-

75). Baseline BP: 151.4/100.6 mm Hg (Fel. 2.5 mg/day group),

147.9/100.6 mm Hg (Fel. 5 mg/day group), 153.8/101.2 mm Hg (Fel.

10 mg/day group), and 154.4/101.0 mm Hg (placebo group).

78 Baseline pulse pressure: 50.8 mm Hg (Fel. 2.5 mg/day group), 47.3 mm

Hg (Fel. 5 mg/day group), 52.6 mm Hg (Fel. 10 mg/day), and 53.4 mm

Hg (placebo group).

Interventions: Felodipine ER 2.5 mg/day, 5 mg/day, 10 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in peak

and trough sitting DBP, SBP, (Instrument: standard Fig

sphygmomanometer), and HR.

Notes: Change in trough sitting BP extracted from Table 1. SD of BP

change calculated as weighted mean of SD of BP change at week 4 and

8 (extracted from Figure 1 and 2). WDAE extracted fom text, p.348.

Funding source: Merck Research Laboratories, USA. Wester 1991 Design: MC/R/DB/PC study. Placebo run-in period: 4 weeks. (132) Treatment duration: 4 weeks.

[Duplicate Country: UK and Netherlands publication: Quality: Cochrane method = B; Jadad score = 4 Wester 1990- abstract only Participants: Supine DBP 95-120 mm Hg for inclusion into trial. (133)] N = 183: 88 m, 95 f. Mean age: 53 years (range: 28-65). Baseline

standing BP: 161/105 mm Hg (Fel. 5 mg/day group), 158/103 mm Hg

(Fel. 10 mg/day group), 164/106 mm Hg (Fel. 20 mg/day group), and

165/103 mm Fig (placebo group).

Baseline pulse pressure: 56 mm Hg (Fel. 5 mg/day group), 55 mm Hg

(Fel. 10 mg/day group), 58 mm Hg (Fel. 20 mg/day group), and 62

mm Hg (placebo group).

Interventions: Felodipine ER 5 mg/day, 10 mg/day, 20 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in trough

supine and standing SBP, DBP (Instrument: random zero

sphygmomanometer - Hawksley), and HR.

Notes: Standing BPs extracted from Table 1. SD of change in SBP

imputed from week 4 SBP values. SD of change in standing DBP

79 imputed from SD of change in supine DBP given in Figure 1. WDAE extracted from text, p. 279. Funding source: Not reported.

80 Table 17: Isradipine - Characteristics of included studies

Arosio 1993 Design: R/DB/PC crossover study. Washout period: at least 3 (134) weeks. Treatment duration: 2 months (each treatment period was 1 month). Country: Italy

Quality: Cochrane method = B; Jadad score = 2 Participants: "mild to moderate essential hypertension" for inclusion into trial. N =16: 12 m, 4f. Mean age: 41 years (range: 30-45). Baseline BP: 157/102 mm Hg (Israd. group) and 156/101 mm Hg (placebo group). Baseline pulse pressure: 55 (Israd. group) and 55 (placebo group).

Interventions: Isradipine SR 5 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in supine SBP, DBP, HR (Instrument: automatic device - Dinamap); brachial artery hemodynamics.

Notes: Pre-crossover data BP data (at week 4) extracted from Table 1. SDs of change in BP imputed from week 4 SDs of BP values. HR data and WDAE not reported. Funding source: Not reported.

Burger 1993 Design: MC/R/DB/PC trial. Placebo run-in: 2 weeks. Treatment (135) duration: 3 weeks.

Country: Germany

Quality: Cochrane method — B; Jadad score = 3

Participants: DBP 100-115 mm Hg for inclusion into trial.

N = 37: 11 m, 18 f. Mean age: 56 years (range: 42 - 75).

Baseline BP: 171/110 mm Hg (Israd. group), 163/106 mm Hg

(placebo group). Baseline pulse pressure: 61 mm Hg (Israd. group),

and 57 mm Hg (placebo group).

Interventions: Isradipine SRO 10 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in SBP,

DBP (Instrument: sphygmomanometer), HR; ABPM (Instrument:

81 SpaceLabs).

Notes: Published in German. Office BPs and HRs extracted from

Table 2. SDs of BP/HR change imputed from other trials.

Funding source: Not reported.

Chyrsant 1995a Design: MC/R/DB/PC trial. Placebo run-in period: 3 weeks. (136) Treatment duration: 6 weeks (weekly forced titration in 5 mg

[Duplicate increments to target dose in active treatment groups). publication: Country: USA Chrysant 1995b (137)] Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 100-114 mm Hg for inclusion into trial. N = 402 (384 Intent-to-treat): approx. 75% "white males". Mean age: 56 (range: not reported).

Baseline BP: 161/104 mm Fig (5 mg group), 158/104 mm Hg (10 mg group), 156/104 (15 mg group), 156/104 (20 mg group), 158/104 mm Hg (placebo group). Baseline pulse pressure: 57 (5 mg group), 54 (10 mg group), 52 (15 mg group), 52 (20 mg group), and 54 (placebo group).

Interventions: Isradipine CR 5 mg/day (6 weeks), 10 mg/day (5 weeks), 15 mg/day (4 weeks), 20 mg/day (3 weeks), or placebo. Primary and secondary outcomes: Change from baseline in sitting/supine/standing SBP, DBP (Instrument: Not reported - auscultatory method), and FIR.

Notes: Change in BP data extracted from Figure 1. SD of changes in SBP/DBP not available and were imputed using data from other trials. WDAE in each group not reported. Author contacted: baseline BPs obtained. Funding source: Sandoz Research Institute, USA.

Holmes 1993 Design: MC/R/DB/PC trial. Placebo run-in period: 3 weeks. (138) Treatment duration: 4 weeks.

Country: Not reported.

Quality: Cochrane method = B; Jadad score = 3

82 Participants: Supine DBP 100-120 mm Hg for inclusion into trial.

N = 190: 84 m, 106 f. Mean age: 57 years (range: 21 - 89).

Baseline BP: 176/108 mm Hg (Israd. 2.5 mg/day group), 171/107 mm

Hg (Israd. 5 mg/day group), 172/107 mm Hg (placebo group).

Baseline pulse pressure: 68 mm Hg (Israd. 2.5 mg/day group), 64 mm

Hg (Israd. 5 mg/day group) and 65 mm Hg (placebo group).

Interventions: Isradipine SRO 2.5 mg/day, 5 mg/day, or placebo.

Primary and secondary outcomes: Change from, baseline in sitting

SBP, DBP (Instrument: Hg sphymomanometer), and HR — trough.

Notes: unpublished BP/HR/WDAE data extracted from Sandoz

archive files.

Author contacted - BP/HR/WDAE data received.

Funding source: Sandoz Pharma, Switzerland.

Italian-Belgian Design: MC/R/DB/PC trial. Placebo run-in: 3 weeks. Treatment Group 1989 duration: 5 weeks. (139) Country: Italy and Belgium

Quality: Cochrane method = B; Jadad score = 3

Participants: supine DBP 100-120 mm Hg for inclusion into trial.

N = 178: 85 m, 93 f. Mean age: 60 years (inclusion range: 30 - 85).

Baseline BP: 171/104 mm Hg (Israd. 1 mg/day group), 175/105 mm

Tig (Israd. 2.5 mg/day group), 175/105 mm Hg (Israd. 5 mg/day

group), 176/104 mm Hg (placebo group). Baseline pulse pressure: 67

mm Hg (Israd. 1 mg/day group), 70 mm Hg (Israd 2.5 mg/day group),

70 mm Hg (Israd. 5 mg/day group), and 72 mm Hg (placebo group).

Interventions: Isradipine 1 mg/day, 2.5 mg/day, 5 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in supine

and standing SBP, DBP (Instrument: Tig sphygmomanometer), HR,

Notes: Trough BPs/HRs and associated SDs extracted from Table II.

SDs of SBP change and FIR change imputed from baseline SDs. SD

of DBP change imputed from other trials. WDAE extracted from text,

83 p. 97.

Funding source: Not reported.

Kirch 1990 Design: MC/R/DB/PC trial. Placebo run-in: 2 weeks. Treatment (140) duration: 4 weeks. Country: Germany

Quality: Cochrane method = B; Jadad score — 4 Participants: Sitting DBP > 105 mm Hg for inclusion into trial. N = 86: 46 m, 37 f (3 patients unaccounted for in demographics table). Mean age: 58.2 years (> 18 for inclusion).

Baseline BP: 174/109 mm Hg (Israd. 2.5 mg/day group), 175/108 mm Hg (Israd. 5 mg/day group), 175/108 (Israd. 10 mg/day group), 176/108 mm Hg (placebo group). Baseline pulse pressure: 65 mm Hg (Israd. 2.5 mg/day group), 67 mm Hg (Israd. 5 mg/day group), 67 mm Hg (Israd. 10 mg/day group) and 68 mm Hg (placebo group). Interventions: Isradipine 2.5 mg/day, 5 mg/day, 10 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting and standing SBP, DBP (Instrument: sphygmomanometer), and HR (2-3 hours post-dose).

Notes: sitting BPs extracted from Table 2. SD of BP change imputed from weighted mean SD of week 3 and 4 BPs. WDAE extracted from text, p. S56.

Funding source: Not reported.

Man in't Veld Design: MC/R/DB/PC trial. Placebo run-in: 3-5 weeks. Treatment 1991 duration: 6 weeks. (141) Country: Not reported. Author from Netherlands

Quality: Cochrane method = B; Jadad score = 3

Participants: sitting DBP 95-1 f 5 mm Fig for inclusion into trial.

N = 187: 99 m, 88 f. 110 patients received isradipine in the 4-week

selection phase; the remaining 77 patients had received isradipine for

up to 127 weeks before entering study. Mean age: 49 years (range: 23 -

84 65).

Baseline BP: 158/102 mm Hg (Israd. group), 160/102 mm Hg

(placebo group). Baseline pulse pressure: 56 mm Hg (Israd. group),

and 58 mm Hg (placebo group).

Interventions: Isradipine 5 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: Hg sphygmomanometer), responder rate

(DBP < 90 mm Hg or fall of > 10 mm Hg).

Notes: All patients had demonstrated prior reponse to isradipine

treatment prior to trial entry. BPs extracted from Table 1. SDs of BP

change imputed from weighted mean of SDs of week 4 and 6 BPs.

WDAE extracted from text, p. 133S.

Funding source: Not reported. O'Grady 1997 Design: R/DB/PC trial. Placebo run-in: 2 weeks. Treatment (142) duration: 4 weeks.

Country: Austria

Quality: Cochrane method = B; Jadad score = 3

Participants: "mild to moderate hypertension", scintigraphalfy-visible

atherosclerotic lesions of carotid vessels and uptake ratio >1.15

for inclusion into trial.

N = 40: 25 m, 15 f. Mean age: 45 years (range: 28 - 68).

Baseline BP: 134/100 mm Hg (group), 136/100 mm Hg (placebo

group). Baseline pulse pressure: 34 mm Hg (Israd. group), and 36 mm

Fig (placebo group).

Interventions: Isradipine SRO 5 mg/day, or placebo.

Primary and secondary outcomes: Platelet parameters (platelet

uptake ratio, platelet survival), change from baseline in SBP, DBP

(Instrument: not reported), and HR.

Notes: BPs extracted from Fig. 1. SDs of BP change imputed from

SDs of week 6 BPs. WDAE extracted from text, p. 367.

Funding source: Not reported.

"85 Pittrow 1997 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo run- (143) in: 2 weeks. Treatment duration: 6 weeks, followed by dose titration in non-responders and an additional 6 weeks. Country: Germany

Quality: Cochrane method = B; Jadad score = 4 Participants: sitting DBP 100-114 mm Hg for inclusion into trial. N = 405: 267 m, 138 f. Mean age: 55 years (range: 26 - 86). Baseline BP: 157.4/104.2 mm Hg (Israd. 2.5 mg/day group), 159.2/106.0 mm Hg (Israd. 5 mg/day group), 150.4/104.1 mm Hg (placebo group). Baseline pulse pressure: 53.2 mm Hg (Israd. 2.5 mg/day group), 53.2 mm Pig (Israd. 5 mg/day group), and 46.3 mm Pig (placebo group).

Interventions: Isradipine SRO 2.5 mg/day, 5 mg/day; sprirapril 3 mg/day, 6 mg/day; isradipine SRO 2.5 mg + spirapril 3 mg/day combination, or placebo.

Primary and secondary outcomes: Change from baseline in sitting SBP, DBP (Instrument: sphygmomanometer), FIR — trough and peak; standard lab tests; ECG.

Notes: Change in trough BPs and associated SDs at week 6 extracted from Table 2A. n values extracted from Table 3. WDAE extracted from Table 1.

Funding source: Sandoz, Germany.

Prisant 1991 Design: MC/R/DB/PC trial. Placebo run-in: 3 weeks. Treatment (144) duration: 5 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 2

Participants: supine DBP 100-119 mm Hg for inclusion into trial.

N = 203 (170 in efficacy analysis): 117 m, 53 f. Mean age: 52.1 years

(range: 22 - 77).

Baseline BP: 156/104 trim Fig (Israd. 5 mg/day group), 160/104 mm

Fig (Israd. 10 mg/day group), 157/103 mm Hg (Israd. 15 mg/day

86 group, 152/104 mm Hg (Israd. 20 mg/day group), 150/104 mm Hg

(placebo group). Baseline pulse pressure: 52 mm Hg (Israd 5 mg/day

group), 56 mm Hg (Israd. 10 mg/day group), 54 mm Hg (Israd. 15

mg/day group), 49 mm Hg (Israd. 20 mg/day group), and 47 mm Hg

(placebo group).

Interventions: Isradipine 5 mg/day (5 weeks), 10 mg/day (1 week at 5

mg/day 4 weeks at 10 mg/day), 15 mg/day (1 week at 5mg/day

1 week at 10 mg/day 3 weeks at 15 mg/day), 20 mg/day (1 week at

10 mg/day 1 week at 15 mg/day 3 weeks at 20 mg/day), or

placebo.

Primary and secondary outcomes: Change from baseline in SBP,

DBP (Instrument: not reported); ECG markers of ischemia.

Notes: Peak BPs, HRs, and associated SDs extracted from Table II.

SDs of BP change and HR change imputed from, endpoint BPs/HRs.

Funding source: Not reported. Youssef 1992 Design: R/DB/PC trial. Treatment duration: 8 weeks. (145) Country: Egypt

[Duplicate Quality: Cochrane method = B; Jadad score = 2 publication: Participants: supine DBP 95-114 mm Hg for inclusion into trial. Youssef 1993 (146)] N = 90: 57 m, 33 f. Mean age: not reported (range: 44 - 68).

Baseline BP: 173/104 mm Hg (Israd. group), 178/104 mm Hg

(placebo group). Baseline pulse pressure: 69 mm Hg (Israd. group),

and 74 mm Hg (placebo group).

Interventions: Isradipine 5 mg/day, enalapril 20 mg/day, benazepril

10 mg/day, xipamide 10 mg + triamterine 30 mg/day combination, or

placebo.

Primary and secondary outcomes: Change from baseline in supine

SBP, DBP (Instrument: not reported); serum lipid profile.

Notes: BPs extracted from Table 1 of Youssef 1993 paper. SDs of BP

change imputed from other trials. Reported SDs of BP at baseline and

endpoint were spuriously low.

87 Attempts to contact author unsuccessful.

Funding source: Not reported. Table 18: Lacidipine - Characteristics of included studies

Study Study Characteristics Rizzini 1991 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (147) Treatment duration: 4 weeks, followed by dose titration in non- responders for 4 weeks, then 11 months open-label. Country: Italy

Quality: Cochrane method = B; Jadad score = 3 Participants: Sitting DBP 95-115 mm Hg and SBP < 200 mm Hg for inclusion into trial.

N = 131: 48 m, 83 f. Mean age: 70.3 years (range: 65 - 86). Baseline sitting BP: 175.5/101.2 mm Hg (Lac. 2 mg/day group), 179.2/102.1 mm Hg (Lac. 4 mg/day group), and 177.9/102.3 mm Hg

(placebo group). Baseline pulse pressure: 74.3 mm Hg (Lac. 2 mg/day

group), 77.1 mm Hg (Lac. 4 mg/day group), and 75.6 mm Hg (placebo

group). Interventions: Lacidipine 2 mg/day, 4 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in sitting trough SBP, DBP (Instrument: Hg sphygmomanometer), and HR. Notes: Mean change in sitting DBP at week 4 and associated confidence intervals extracted from Table 4. Mean change in sitting SBP at week 4 extracted from text on page S4f. SD of SBP change imputed from SDs of week 4 BP's. HR data and WDAE at week 4 not reported.

Funding source: Not reported.

89 Table 19: Lercanidipine - Chatacteristics of included studies

Study Study Characteristics Barbagallo 2000 Design: MC/R/DB/PC trial. Washout period: 1 week. Placebo run- (148) in period: 3 weeks. Treatment duration: 4 weeks, followed by .4 weeks of doubled dose in non-responders. Country: Italy

Quality: Cochrane method = B; Jadad score = 3

Participants: Elderly ISH patients. SBP 160-220 mm Hg and DBP <95 mm Hg for inclusion into trial.

N = 83: 38 m, 45 f. Mean age: 66.7 years (> 60 for inclusion).

Baseline BP: 172.6/87.1 mm Hg (Lercan. group), 172.4/87.1 mm Hg

(placebo group). Baseline pulse pressure: 85.5 mm Hg (Lercan. group), and 85.3 mm Hg (placebo group). Interventions: Lercanidipine 10 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in SBP,

DBP (Instrument: not reported), and HR; % responders, defined as decrease of SBP > 20 mm Hg; % patients with normalized SBP (SBP

< 140 mm Hg); ECG; lab tests.

Notes: supine BPs and HRs in per protocol patients (n=70) extracted

from Table 2. SDs of BP/HR change imputed from week 4 BPs/HRs.

WDAE extracted from text, p. 378.

Author contacted: responded with data clarification.

Funding source: Not reported.

Grco 1997 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo run- (149) in period: 3 weeks. Treatment duration: 4 weeks, followed by 12 weeks

of dose titration in non-responders.

Country: Italy

Quality: Cochrane method = B; Jadad score — 2

Participants: DBP 95-115 mm Hg for inclusion into trial.

N = 132: 58 m, 74 f. Mean age: 54.7 years (range: 18-70).

Baseline BP/pulse pressure: Not reported.

90 Interventions: Lercanidipine 10 mg/day, 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: not reported) and HR; % responders (decrease

in DBP > 10 mm Hg); % with normalized DBP (DBP < 90 mm Hg);

trough-to-peak ratios.

Notes: No baseline BPs provided and thus, no BP data was extracted.

Trough HR data extracted from Table 3. SDs of HR change imputed

from week 4 HRs. WDAE for each group not reported.

Article not indexed in electronic databases — retrieved from reference

list of review article.

Funding source: Not reported.

Ninci 1997 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo run- (150) in period: 3 weeks. Treatment duration: 4 weeks, followed by 12 weeks

of dose titration in non-responders.

Country: ftaly

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-115 mm Hg for inclusion into trial.

N = 144: 77 m, 67 f. Mean age: 68.4 years (range: 60 - 85).

Baseline BP: 171.1/101.6 mm Hg g_ercan.group), 168.3/101.6 mm Hg

(placebo group). Baseline pulse pressure: 69.5 mm Hg (Lercan. group),

and 66.7 mm Hg (placebo group).

Interventions: Lercanidipine tO mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: not reported), and HR; % responders (DBP <

90 mm Hg); trough-peak ratios; ECG; lab tests.

Notes: Change in BP/HR extracted from Fig. f and 2, and text, p.

S41. SDs of BP/PfR change imputed from other trials. WDAE

reported, but did not specify if these occurred during the 1" 4 weeks.

Article not indexed in electronic databases - retrieved from reference

list of review article.

Funding source: Not reported.

91 Omboni 1998 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo run- (151) in period: 3 weeks. Treatment duration: 4 weeks.

Country: Italy

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 90-109 mm Hg for inclusion into trial.

N = 243: 156 m, 87 f. Mean age: 51 years (range: not reported).

Baseline supine BP: 154/98 mm Hg (Lercan. 2.5 mg/day group),

155/99 mm Hg (Lercan. 5 mg/day group), 156/99 mm Hg (Lercan. 10

mg/day group), 155/99 mm Hg (placebo group). Baseline pulse

pressure: 56 mm Hg (Lercan. 2.5 mg/day group), 56 mm Hg (Lercan. 5

mg/day group), 57 mm Hg (Lercan. 10 mg/day group), and 56 mm Hg

(placebo group).

Interventions: Lercanidipine 2.5 mg/day, 5 mg/day, 10 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in supine

SBP, DBP (Instrument: standard Hg sphygmomanometer) and HR; %

responders, defined as DBP < 85 mm Hg or DBP reduction > 10 mm

Hg; 24-hr ABPM (Instrument: Spacelabs 90207).

Notes: Change in BP and associated SDs extracted from Fig. 1.

WDAE extracted from text, p. 1836.

Funding source: Recordati S.p.A., Italy.

Rimoldi 1993 Design: MC/R/DB/PC trial. Washout period: 1 week. Placebo run- (152) in period: 3 weeks. Treatment duration: 4 weeks.

Country: Italy

Quality: Cochrane method = B; Jadad score = 1

Participants: Supine DBP 95-114 mm Hg for inclusion into trial.

N = 152: 67 m, 85 f. Mean age: 56.3 years (range: 21 - 70).

Baseline DBP: 101.3 mm Hg (Lercan. tab. group), 101.5 (Lercan.

capsule group), 101.3 mm Hg (placebo group). Baseline SBP/pulse

pressure: not reported/cannot be calculated.

Interventions: Lercanidipine tablets 10 mg/day (1 week) 20

92 mg/day (3 weeks), lercanidipine capsules (same doses as tablets), or

placebo.

Primary and secondary outcomes: Change from baseline in supine

and standing SBP, DBP (Instrument: not reported — by auscultation),

HR — trough; ECG; laboratory parameters.

Notes: Tablet and capsule groups combined for RevMan entry. DBPs

and HRs extracted from Table III. SD of DBP/HR change imputed

from endpoint values. SBPs and WDAE not reported.

Funding source: Not reported.

Rimoldi 1994 Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in (153) period: 3 weeks. Treatment duradon: 4 weeks.

Country: Italy

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-114 mm Hg for inclusion into trial.

N = 30: 18 m, 12 f. Mean age: 50.8 years (range: not reported).

Baseline BP: 148.9/103.3 mm Hg (Lercan. fO mg/day group),

156.5/103.1 mm Hg (Lercan. 20 mg/day), and 156.5/101.9 mm Hg

(placebo group). Baseline pulse pressure: 45.5 mm Hg (Lercan. 10

mg/day group), 53.5 mm Hg (Lercan. 20 mg/day group), and 54.6 mm

Hg (placebo group).

Interventions: Lercanidipine 10 mg/day, 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

(mean of 2 supine and f standing measurement) SBP, DBP

(fnstrument: not reported — by auscultation) and FfR; 24-hr ABPM

(fnstrument: Spacelab Kontron).

Notes: BP and HR data extracted from Table II. SD of BP/HR

change imputed from SDs of week 4 BPs/HRs. WDAE extracted

from text, p. 26.

Funding source: Not reported.

93 Table 20: Lidoflazine - Characteristics of included studies

Study Study Characteristics Meilink- Design: MC/DB/PC/cross-over trial. Treatment duration: 12 weeks Hoedemaker 1976 per treatment sequence (154) Country: Italy

Quality: Cochrane method = A; Jadad score = 3 Participants: Post-infarction patients. N = 10: 10 m, 0 f. Mean age: 43.8 years (range: 24 -58). Baseline BP: 139/96 mm Hg (lidoflazine group), 137/94 mm Hg (placebo group). Baseline pulse pressure: 43 mm Hg (lidoflazine

group), and 43 mm Hg (placebo group). Interventions: Lidoflazine 180 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: Hg sphygmomanometer), and HR (by ECG).

Notes: Individual patient data reported. BP data for patients with baseline DBP > 90 mm Hg and/or SBP > 140 mm Hg for the first 12 weeks (before cross-over) extracted from Table II. Did not explicitiy

state trial was randomized. Funding source: Not reported.

94 Table 21: Manidipine - Characteristics of included studies

Study Study Description Fogari 1996 Design: R/DB/PC trial. Placebo run-in period: 2 weeks. Treatment (155) duration: 4 weeks. Country: Italy .

Quality: Cochrane method = B; Jadad score = 3 Participants: Supine DBP 95-115 mm Hg for inclusion into trial. N = 52: 32 m, 20 f. Mean age: 53.4 years (range: 40 - 63). Baseline BP: 163.8/104.7 mm Hg (Man. 10 mg/day group), 166.0/104.7 mm Hg (Man. 20 mg/day group), 164.9/105.3 mm Hg (Man. 40 mg/day group) and 162/100 mm Fig (placebo group). Baseline pulse pressure: 59.1 mm Hg (Man. 10 mg/day group), 61.3 mm Hg (Man. 20 mg/day group), 59.6 mm Hg, (Man. 40 mg/day group), and 62 mm Hg (placebo group).

Interventions: Manidipine 10 mg/day, 20 mg/day, 40 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sittmg/standing SBP, DBP (Instrument: Hg sphygmomanometer) and FIR; 24-hour ABPM.

Notes: Mean change in BP values extracted from text, page 20. HR data extracted from Table IV. SD of BP/HR change imputed from other trials. WDAE extracted from text, p. 21. Attempted to contact author — no response. Funding source: Not reported.

Fogari 1999 Design: R/DB/PC trial. Placebo run-in period: 4 weeks. Treatment (156) duration: 8 weeks.

Country: Italy

Quality: Cochrane method = B; Jadad score = 4

Participants: Elderly hypertensives. Sitting DBP >90 mm Fig and <

110 mm Hg, and SBP > 160 mm Hg for inclusion into trial.

N = 54: 26 m, 28 f. Mean age: 81.8 years (range: 76 - 89).

Baseline BP: 168.3/93.1 mm Hg (Man. group) and 168.7/93.9 mm Hg

95 (placebo group). Baseline pulse pressure: 55.2 (Man. group) and 74.8

(placebo group). Interventions: Manidipine 10 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting/standing SBP, DBP (Instrument: standard Hg sphygmomanometer), and HR; 24-hour ABPM (Instrument: Spacelabs 90207); ECG; body weight. Notes: Sitting BP and HR data extracted from Table 2. Endpoint BPs and HRs were calculated as the weighted mean of data from week 4 and 8. SD of BP change imputed from weighted mean of SD of BPs at week 4 and 8. No WDAE occurred. Funding source: Not reported.

96 Table 22: Mibefradil - Characteristics of included studies

Study Study Description

Bernink 1996 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (157) Treatment duration: 4 weeks.

Country: Germany, Netherlands, Sweden, Finland, Austria, Denmark

Quality: Cochrane method = B; Jadad score = 3 Participants: Sitting DBP 95-114 mm Hg for inclusion into trial. N = 202: 122 m, 80 f. Mean age: 55.6 years (range: 18-70 for inclusion).

Baseline sitting DBP: 105.5 mm Hg (Mib. 25 mg/day group), 104.0 mm Hg (Mib. 50 mg/day group), 104.4 mm Hg (Mib. 100 mg/day group), 103.9 mm Hg (Mib. 150 mg/day group), 105.4 mm Hg (placebo group). Baseline pulse pressure: not reported and cannot be calculated. r Interventions: Mibefradil 25 mg/day, 50 mg/day, 100 mg/day, 150

mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

and standing SBP, DBP (Instrument: Hg sphygmomanometer) and

HR.

Notes: Change in trough sitting DBP data and associated SDs

extracted from Table 2. Because baseline SBPs and HRs were not

reported, the corresponding data was not extracted. WDAE extracted

from text, p.429.

Author contacted - no additional data available.

Funding source: F. Hoffman-LaRoche Ltd., Switzerland. Bursztyn 1997 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (158) Treatment duration: 4 weeks.

Country: Europe, Brazil, Israel

Quality: Cochrane method = A; Jadad score = 3

Participants: Sitting SBP 160-220 mm Hg and DBP 90-110 mm Hg

for inclusion into trial.

97 Elderly patients. N = 310 (308 intention-to-treat population): 117 m,

191 f. Mean age: 71.6 years (range: not reported; > 65 years for

inclusion).

Baseline sitting BP: 176.1/99.3 mm Hg (Mib. 6.25 mg/day group),

173.5/96.9 mm Hg (Mib. 12.5 mg/day group), 179.3/99.7 mm Hg

(Mib. 25 mg/day group), 174.8/98.6 mm Hg (Mib. 50 mg/day group),

176.1/100.5 mm Hg (Mib. 100 mg/day group), and 174.4/99.2 mm Hg

(placebo group). Baseline pulse pressure: 76.8 mm Hg (Mib. 6.25

mg/day group), 76.6 mm Hg (Mib. 12.5 mg/day group), 79.6 mm Hg

(Mib. 25 mg/day group), 76.2 mm Hg (Mib. 50 mg/day group), 75.6

mm Hg (Mib. 100 mg/day group), and 75.2 mm Hg (placebo group).

Interventions: Mibefradil 6.25 mg/day, 12.5 mg/day, 25 mg/day, 50

mg/day, 100 mg/day (50 mg/day for 1 week 100 mg/day for 3

weeks), or placebo.

Primary and secondary outcomes: Change from baseline in

trough/peak sitting SBP, DBP (Instrument: not reported) and HR;

ECG; blood/urine lab tests.

Notes: Change in trough DBP and associated SDs extracted from

Table II. Change in trough SBP and associated SDs extracted from

Table III. Change in HR and associated SEMs extracted from Figure

6. WDAE extracted from text, p.245.

Author contacted - responded but no additional data was sent.

Funding source: F. Hoffman-LaRoche Ltd.

Oparil 1997 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (159) Treatment duration: 4 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 95-110 mm Hg for inclusion into trial.

N = 303: 170 m, 133 f. Mean age: 51.3 years (inclusion range: 18-65).

Baseline BP/pulse pressure: not reported.

Interventions: Mibefradil 6.25 mg/day, 12.5 mg/day, 25 mg/day, 50

98 mg/day, 100 mg/day, 150 mg/day, 200 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough/peak sitting SBP, DBP (Instrument: not reported) and HR;

ECG, blood/urine lab tests.

Notes: Baseline BPs/HRs not reported, and thus, change in BP/HR data could not be used. WDAE extracted from text, p. 739. Author contacted: no data. Funding source: F. Hoffman-LaRoche Ltd., Switzerland.

99 Table 23: Nicardipine- Characteristics of included studies

Study Study Description

Asplund 1985 Design: R/DB/PC trial. Washout period: 4 weeks. Treatment (160) duration: 6 weeks. Country: Sweden

Quality: Cochrane method = B; Jadad score — 4 Participants: Supine DBP 95-115 mm Hg for inclusion into trial.

N = 50: 36 m, 14 f. Mean age: 46 years (range: 36 - 60).

Baseline BP: 161.4/113.9 mm Hg (nicard. group), 154.6/112.9 mm Hg (placebo group). Baseline pulse pressure: 47.5 mm Hg (nicard. group),

and 41.7 mm Hg (placebo group). Interventions: Nicardipine 90 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in supine/standing SBP, DBP (Instrument: random zero Hg

sphygmomanometer) and HR; lab tests; ECG.

Notes: Change in standing BP extracted from text, p. 122S. HRs and associated SDs extracted from Fig. 2. SDs of BP/HR change imputed from weighted mean of week 4 and 6 data, extracted from Fig. 2. Funding source: Not reported.

Bellet 1987a Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in (161) period: 2 weeks. Treatment duration: 3 weeks.

[Duplicate Country: France publication: Bellet Quality: Cochrane method = A; Jadad score = 3 1987b (162)] Participants: Sitting DBP 95-120 mm Hg for inclusion into trial.

N = 40: 27 m, 13 f. Mean age: 53 years (range: 27 - 72).

Baseline standing BP: 154/107 mm Hg (nicard. group), and 148/103

mm Hg (placebo group). Baseline pulse pressure: 47 mm Hg (nicard.

group), and 45 mm Hg (placebo group).

Interventions: Nicardipine 100 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

standing SBP, DBP, HR (Instrument: Hg sphygmomanometer and

100 Sentron oscillometric device); ABPM (Instrument: Remler 2000)

Notes: Change in standing BP/HR and associated SDs extracted from

Table 1.

Funding source: Sandoz France.

De Cesaris 1993 Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in (163) period: 2 weeks. Treatment duration: 4 weeks. Country: Italy

Quality: Cochrane method — B; Jadad score — 3. Participants: Sitting DBP 95-116 mm Hg for inclusion into trial. N = 36: 17 m, 19 f. Mean age: 55.9 years (range: 40 - 70). Baseline BP: 161.7/98.5 mm Hg (nicard. group), 170.0/96.2 mm Hg (placebo group). Baseline pulse pressure: 63.1 mm Fig (nicard. group), and 73.8 mm Fig (placebo group). Interventions: Nicardipine 80 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in trough supine/standing SBP, DBP (Instrument: Hg sphygmomanometer); 24- hr ABPM (Instrument: Spacelabs 5300).

Notes: Published in Italian. Standing BPs and associated SDs extracted from text, p. 535. Standing HRs and associated SDs extracted from Fig. 2B.

SD of change in BP/HR imputed from weighted mean of SD of week- 4 BPs/HRs.

Funding source: Not reported.

Fagan 1993 Design: MC/R/DB/PC trial. Washout period: 1 week. Placebo run- (164) in period: 2 weeks. Treatment duration: 12 weeks.

Country: France

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-114 mm Hg for inclusion into trial.

N =230: 127 m, 103 f. Mean age: 54.1 years (range: 22-75).

Baseline BP: 157/101 mm Hg (nicard. 60 mg/day group), 154/101

mm Hg (nicard. 90 mg/day group), 155/101 mm Hg (nicard. 120

101 mg/day group), 155/100 mm Hg (placebo group). Baseline pulse

pressure: 56 mm Hg (nicard. 60 mg/day group), 53 mm Hg (nicard. 90

mg/day group), 54 (nicar. 120 mg/day group), and 55 mm Hg (placebo

group).

Interventions: Nicardipine SR 60 mg/day, 90 mg/day, 120 mg/day,

or placebo.

Primary and secondary outcomes: Change from baseline in trough

supine/standing SBP, DBP (Instrument: Hg or aneroid

sphygmomanometer) and HR; ABPM (Instrument: SpaceLabs 90202).

Notes: Change in BPs and associated SDs extracted from Fig. 1. HR

data reported only for nicar. 120 mg/day. WDAE extracted from

Table 4.

Attempted to contact author — no response.

Funding source: Syntex Research. Marcadet 1991 Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in (165) period: 15 days. Treatment duradon: 8 weeks.

Country: France

Quality: Cochrane method = B; Jadad score — 3

Participants: Male athletes. Sitting DBP 90-115 mm Hg for inclusion

into trial.

N = 38: 38 m, 0 f. Mean age: 30.5 years (range: 18 — 50 for inclusion).

Baseline BP: 154/98 mm Fig (nicardipine group), 155/96 mm Hg

(placebo group). Baseline pulse pressure: 56 mm Hg (nicardipine

group), and 59 mm Hg (placebo group).

Interventions: Nicardipine LP 100 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in supine

SBP, DBP (Instrument: Fig sphygmomanometer) and HR at rest and

on effort; maximum oxygen consumption and effort duration; weight.

Notes: Published in French. Change in BPs and associated SDs

extracted from Table III. HR data extracted from Fig. 2.

Funding source: Not reported.

102 Mazzola 1988 Design: MC/R/DB/PC trial. Washout period: duration not reported. (166) Placebo run-in period: 1 week. Treatment duration: 6 weeks. Country: Italy

Quality: Cochrane method = B; Jadad score = 4 Participants: Sitting DBP > 95 mm Hg for inclusion into trial.

N = 30: 19 m, 11 f Mean age: 51.8 years (range: 32 - 65). Baseline sitting BP: 158/99 mm Hg (nicardipine group), 159/101 mm Hg (placebo group). Baseline pulse pressure: 59 mm Hg (nicardipine

group), and 58 mm Fig (placebo group).

Interventions: Nicardipine-SR 80 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in sitting SBP, DBP (Instrument: standard Hg sphygmomanometer) HR, MBP,

CI, SVI, SVR; lab parameters, ECG. Notes: BP/HR data extracted from Table 2. SDs imputed from weighted mean of week 4 and 6 data. WDAE reported. Funding source: Sandoz Prodotti Farmaceutici, Italy.

Scuten 1992 Design: MC/R/DB/PC trial. Placebo run-in period: 10 days. (167) Treatment duration: 4 weeks.

Country: Italy

Quality: Cochrane method — B; Jadad score = 2

Participants: Hospitalized elderly women. SBP > 160 mm Hg or

DBP > 95 mm Hg for inclusion into trial.

N = 45: 0 m, 45 f. Mean age: 76.3 years (range: not reported; > 65

years for inclusion).

Baseline BP: 176.3/98.8 mm Fig (nicard. group), 166.3/95.0 mm Hg

(placebo group). Baseline pulse pressure: 77.5 mm Hg (nicard. group),

and 71.3 mm Hg (placebo group).

Interventions: Nicardipine (long-acting) 40 mg/day, enalapril 10 mg

(with titration to 20 mg in non-responders after 1 week), or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBPX (Instrument: not reported) and FIR; behavior/cognitive

103 function tests: MMSE, GRS, SCAG.

Notes: BP and HR data extracted from Table 1. SDs imputed from

week 4 data. WDAE not reported.

Funding source: Sandoz Prodotti Farmaceutici, Italy.

Soro 1990 Design: R/DB/PC trial. Placebo run-in period: 2 weeks. Treatment (168) duration: 8 weeks.

[Duplicate Country: Italy publication: De Quality: Cochrane method — B; Jadad score — 3 Simone 1989 (169)] Participants: "Mild to moderate primary arterial hypertension" for inclusion into trial.

N = 18: 8 m, 10 f. Mean age: years (range: 27 - 65). Baseline standing BP: 164/106 mm Hg (Nicardipine group), and 167/105 mm Fig (placebo group). Baseline pulse pressure: 58 mm Fig (Nicardipine group), and 62 mm Hg (placebo group). Interventions: Nicardipine 60 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in supine/standing SBP, DBP and HR (Instrument: automatic device: Sentron); body weight; serum electrolytes, renin, aldosterone, PTH, , fasting blood glucose, LV function by echocardiography. Notes: Standing office BPs and SDs extracted from text, p. 135 of Soro f 990. SDs of BP change imputed from week 8 data. HRs and WDAEs extracted from De Simone 1989.

Author (De Simone) contacted — clarified duplicate publication. Funding source: Not reported.

104 Table 24: Nifedipine - Characteristics of included studies

Study Study Description

Carr 1992a Design: 2-centre R/DB/PC trial. Placebo run-in: 3-6 weeks. (170) Treatment duration: 6 weeks.

[Duplicate Country: USA publication: Carr Quality: Cochrane method = B; Jadad score = 3 1992b (171)] Participants: sitting DBP 95-119 mm Hg for inclusion into trial. N = 207: 79 m, 128 f. Mean age: 46.2 years (range: not reported). Baseline BP: 155.4/103.7 mm Hg (Nif. 20 mg/day group), 153.0/104.0 mm Hg (Nif. 50 mg/day group), 156.8/104.9 mm Hg (Nif. 100 mg/day group), and 153.2/104.1 mm Hg (placebo group). Baseline pulse pressure: 51.7 mm Hg (Nif. 20 mg/day group), 49 mm Hg (Nif. 50 mg/day group), 51.9 mm Hg (Nif. 100 mg/day group), and 49.1 mm Hg (placebo group).

Interventions: Nifedipine SR 20, 50, and 100 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in trough sitting, standing, supine SBP, DBP (Instrument: not reported) and HR; ABPM (Instrument: Del Mar Avionics Pressurometer IV). Notes: Change in supine BP data extracted from Table II. SD of BP change imputed from other trials. WDAE extracted from Table IV. Author contacted - no data. Funding source: Not reported.

De Simone 1984 Design: R/DB/PC trial. Washout period: 2 weeks. Treatment (172) duration: 8 weeks.

[Duplicate Country: Italy publication: De Quality: Cochrane method — B; Jadad score = 2 Simone 1985 (173)] Participants: DBP 94-114 mm Hg for inclusion into trial.

N = 20: 11 m, 9 f. Mean age: 47 years (range: 35 - 60).

Baseline standing BP: 156.1/109 mm Hg (Nif. group), 148.7/107.2

mm Hg (placebo group). Baseline pulse pressure: 54.3 mm Hg (Nif.

group), and 41.5 mm Hg (placebo group).

105 Interventions: Nifedipine SR 40 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in

supine/standing SBP, DBP (Instrument: not reported); left ventricular

mass, cross sectional area, end-systolic and end-diastolic volumes,

ejection fraction and mean velocity of circumferential fiber shortening

as measured by echocardiogram.

Notes: Standing BP and HR data extracted from Table 1. SDs of

BP/HR change imputed from week 8 data.

Funding source: Not reported.

Eggertsen 1982 Design: R/DB/PC trial. Placebo run-in: 4 weeks. Treatment (174) duration: 8 weeks, followed by 12 weeks of added metoprolol.

Country: Sweden

Quality: Cochrane metiiod = B; Jadad score = 3

Participants: "Essential hypertension".

N = 26 (m:f ratio not reported). Mean age: 51.3 years (range: 28 - 60).

Baseline BP: 157/106 mm Hg (Nif. group), and 155/104 mm Hg

(placebo group). Baseline pulse pressure: 51 mm Hg (Nif. group), and

51 mm Hg (placebo group).

Interventions: Nifedipine 30 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in

supine/standing SBP, DBP (Instrument: Hg manometer) and HR.

Notes: Supine BPs at week 8 extracted from Table 1. SD of BP

change imputed from other trials. HR data not reported. WDAE

extracted from text, p. 390.

Author contacted - no additional data available. Number of patients in

each group was obtained from a published meta-analysis (93).

Funding source: Not reported.

Fadayomi 1986 Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in: 2 (175) weeks. Treatment duration: 6 weeks.

Country: Nigeria

Quality: Cochrane method = B; Jadad score = 3

106 Participants: supine DBP > 110 mm Hg (newly diagnosed

hypertensives) or > 100 mm Fig (diagnosed 3-6 months earlier and

inadequately controlled) for inclusion into trial.

N = 32: 18 m, 14 f. Mean age: 48 years (range: 37 - 59).

Baseline BP: 181.3/114.7 mm Hg (Nif. group), and 179.5/114.0 mm

Hg (placebo group). Baseline pulse pressure: 66.6 mm Hg (Nif. group), and 65.5 mm Hg (placebo group). Interventions: Nifedipine (Adalat Retard) 40 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in supine/standing SBP, DBP (Instrument: standard Hg sphygmomanometer) and HR; body weight.

Notes: Individual patient BP data for 30 patients extracted from Table 1 and 2. SD of BP change calculated from this data. HR data not extracted, as data was reported for nifedipine group only. WDAE extracted from text, p. 468.

Author contacted - replied but no missing data was supplied. Funding source: Bayer Pharmaceuticals Ltd., Nigeria.

Feig 1993 Design: MC/R/DB/PC trial. Placebo run-in: 4 weeks. Treatment (176) duration: 6 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: supine DBP 95-114 mm Fig for inclusion into trial.

N = 233: 130 m, 103 f. Mean age: 55 years (range: 19 - 75).

Baseline standing BP: 150/100 mm Fig (Nif. 30 mg/day group),

150/100 mm Hg (Nif. 60 mg/day group), 153/101 mm Hg (Nif. 90

mg/day group), and 149/100 mm Fig (placebo group). Baseline pulse

pressure: 50 mm Hg (Nif. 30 mg/day group), 50 mm Hg (Nif. 60

mg/day group), 52 mm Hg (Nif. 90 mg/day group), and 49 mm Hg

(placebo group).

Interventions: Nifedipine coat-core 30 mg/day, 60 mg/day, 90

mg/day, or placebo.

107 Primary and secondary outcomes: Change from baseline in

supine/standing trough SBP, DBP (Instrument: not reported), and

HR.

Notes: Change in standing BP data extracted from Table II.

Author contacted: SEs of BP change obtained.

Funding source: Miles Inc., USA.

Ferrera 1984 Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in: 2 (177) weeks. Treatment duration: 8 weeks.

Country: Italy

Quality: Cochrane method = B; Jadad score = 2.

Participants: Primary uncomplicated arterial hypertension of mild to

moderate degree for inclusion into trial.

N = 40: 51 m, 33 f. Mean age: 47 years (range: not reported).

Baseline BP: 164/108 mm Fig (Nif. group), and 151/104 mm Hg

(placebo group). Baseline pulse pressure: 56 mm Hg (Nif. group), and

47 mm Ffg (placebo group).

Interventions: Nifedipine (slow release) 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in

supine/standing DBP, SBP (Instrument: random-zero

sphygmomanometer) and HR; left ventricular mass, ejection fraction,

end diastolic volume, end systolic volume, mean rate of circumferential

fiber shortening by echocardiogram; systolic time intervals.

Notes: BPs, HRs and associated SDs extracted from Table 1. SD of

BP/HR change imputed from week 8 data.

Attempted to contact author — no response. Number of patients in

each group was obtained from a published meta-analysis (93).

Funding source: Not reported.

Harder 1994 Design: MC/R/DB/PC trial. Washout period: 2 weeks. Placebo run- (178) in: 2 weeks. Treatment duration: 8 weeks.

Country: Germany

Quality: Cochrane method = B; Jadad score = 3

108 Participants: DBP 95-115 mm Hg for inclusion into trial.

N — 88: 51 m, 33 f. Mean age: 54 years (range: not reported).

Baseline BP: 155/102 mm Hg (Nif. group), and 155/102 mm Hg

(placebo group). Baseline pulse pressure: 53 mm Hg (Nif. group), and

53 mm Hg (placebo group).

Interventions: Nifedipine (slow release) 60 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

trough DBP, SBP (Instrument: Hg sphygmomanometer; semi•

automatic auscultatory device - Tonoprint) and HR.

Notes: BPs (manual readings) and HRs extracted from Table I. SD of

BP/HR change imputed from week 8 data. WDAE extracted from

text, p. 135.

Funding source: Not reported. Jueng 1987 Design: MC/R/DB/PC trial. Washout period: 1 week. Placebo run- (179) in: 3 weeks. Treatment duration: 2-week dose titration, followed by 8

weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: sitting DBP 95-110 mm Hg for inclusion into trial.

N = 29: 22 m, 7 f. Mean age: 52.4 years (range: 27 - 83).

Baseline BP: 159/102 mm Hg (nifed. group), 153/105 mm Hg

(placebo group). Baseline pulse pressure: 57 mm Fig (nifed. group),

and 48 mm Hg (placebo group).

Interventions: Nifedipine GITS 30 mg/day (2 weeks)-^ 60 mg/day,

hydrochlorothiazide 25 mg/day (2 weeks) 50 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

trough SBP, DBP (Instrument: not reported), HR, metabolic

parameters.

Notes: BPs/HRs extracted from Table 2. SDs of change in BPs/HRs

imputed from week 8 values. WDAE extracted from text, p. 697.

Funding source: Pfizer Pharmaceuticals, USA.

109 Serradimigni 1985 Design: MC/R/DB/PC trial. Placebo run-in: 4 weeks. Treatment (180) duration: 24 weeks. Country: France

Quality: Cochrane method = B; Jadad score = 3

Participants: sitting DBP 95-115 mm Hg for inclusion into trial.

N = 177: 95 m, 82 f. Mean age: 55.6 years (range: 38 - 70). Baseline BP: 178.1/103.6 mm Hg (Nif. group), 177.2/104.5 mm Hg (placebo group). Baseline pulse pressure: 74.5 mm Ffg (Nif. group), and 72.7 mm Hg (placebo group).

Interventions: Nifedipine 40 g/day, Acebutolol 200 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in supine SBP, DBP (Instrument: Fig sphygmomanometer), HR, body weight. Notes: Published in French. DBP, SBP and HR at baseline and week 4, 8, 12 extracted from Fig. 5, 6, and 7, respectively. SDs of BP/FIR change imputed from other trials. WDAE extracted from Table 2. Funding source: Not reported.

Toal 1997 Design: MC/R/DB/PC trial. Placebo run-in: 2-3 weeks. Treatment (181) duration: 4 weeks.

Country: Canada

Quality: Cochrane method = B; Jadad score = 2

Participants: sitting DBP 95-114 mm Fig for inclusion into trial.

N - 187: 118 m, 69 f. Mean age: 55 years (> 18 for inclusion).

Baseline BP: 149.1/98.4 mm Fig (Nif. group), and 148.0/98.7 mm Hg

(placebo group). Baseline pulse pressure: 50.7 mm Hg (Nif. group),

and 49.3 mm Fig (placebo group).

Interventions: Nifedipine GfTS 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

trough SBP, DBP (Instrument: not reported) and HR; ABPM

(Instrument: Spacelabs 90207).

Notes: BP and HR data extracted from Table 2. SDs of BP/HR

110 change imputed from SDs of week 4 BPs/HRs.

Funding source: Bayer Inc., Canada.

Zachariah 1990 Design: MC/R/DB/PC trial. Placebo run-in: 3 weeks. Treatment (182) duration: 8 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 4 Participants: sitting DBP 95-104 mm Hg for inclusion into trial. N = 29: 19 m, 10 f. Mean age: 47.3 years (range: not reported). Baseline BP: 137/98 mm Hg (nifed. 30 mg/day group), 141/98 mm Hg (nifed. 60 mg/day group), 133/97 mm Hg (placebo group). Baseline pulse pressure: 39 mm Hg (nifed. 30 mg/day group), 43 (nifed. 60 mg/day group), and 36 mm Hg (placebo group). Interventions: Nifedipine (sustained release) 30 mg/day, 60 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting trough SBP, DBP (Instrument: Hg sphygmomanometer), 24-hr ABPM (Pressurometer III, Del Mar Avionics).

Notes: BPs extracted from Table II. SD of change in BP imputed from week 8 BPs. WDAE extracted from text, p. 1016. Funding source: Not reported.

Zanchetti 1993 Design: MC/R/DB/PC trial. Placebo run-in period: 2 weeks. (183) Treatment duration: 4 weeks.

[Multiple Country: Italy publications: Quality: Cochrane method = B; Jadad score = 2 Zanchetti 1994a (184) ; Participants: sitting DBP 95-114 mm Hg for inclusion into trial. Zanchetti 1994b N = 126: 65 m, 61 f. Mean age: 56.5 years (range: 25 - 74). (185) , Zanchetti 1994c (186)] Baseline BP: 154.3/96.6 mm Hg (Nif. 30 mg/day group), 150.1/94.5

mm Hg (Nif. 60 mg/day group), 146.0/90.1 mm Hg (placebo group).

Baseline pulse pressure: 57.7 mm Hg (Nif. 30 mg/day group), 55.6 mm

Hg (Nif. 60 mg/day group), and 55.9 mm Hg (placebo group).

Interventions: Nifedipine GITS 30 mg/day, 60 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in sitting trough SBP, DBP (Instrument: Hg sphygmomanometer) and HR;

ABPM (Instrument: Spacelabs 90202 or 90207).

Notes: Change in clinic BP and associated SEMs extracted from text, p. 334 of Zanchetti 1993. WDAE extracted from text, p. 54 of

Zanchetti 1994a. Funding source: Not reported.

112 Table 25: Nilvadipine - Characteristics of included studies

Study Study Description Hoffmann 1997 Design: MC/R/DB/PC trial. Placebo run-in period: 3-5 weeks. (187) Treatment duration: 8 weeks. Country: Germany

Quality: Cochrane method = B; Jadad score — 3 Participants: Sitting DBP 95-115 mm Hg for inclusion into trial. N = 168 (ITT): 79 m, 89 f. Mean age: 56.6 years (range: 25 - 80). Baseline BP: 166.8/101.9 mm Hg (Nilv. 8 mg/day group), 167.1/101.7 mm Hg (Nilv. 16 mg/day group), 164.2/101.3 mm Hg (placebo group). Baseline pulse pressure: 64.9 mm Hg (Nilv. 8 mg/day group), 65.4 mm Pig (Nilv. 16 mg/day group), and 62.9 mm Hg (placebo group).

Interventions: Nilvadipine 8 mg/day, 16 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in sitting and standing SBP, DBP (Instrument: Hg sphygmomanometer), and

HR; ABPM (Instrument: SpaceLabs, model 90207.32).

Notes: Trough changes in sitting BP and associated SEMs extracted from Table 3. WDAE extracted from Table 4.

Funding source: Not reported.

Weir 1990 Design: MC/R/DB/PC trial. Placebo run-in period: 2-4 weeks. (188) Treatment duration: 4 weeks.

Country: USA

Quality: Cochrane method = A; Jadad score = 3

Participants: Sitting DBP 100-115 mm Hg for inclusion into trial.

N = 84: 65 m, 19 f. Mean age: 51.0 years (range: 28 - 70).

Baseline sitting BP: 160.6/103.0 mm Hg (Nilv. 18 mg/day group),

152.8/103.9 mm Hg (Nilv. 24 mg/day group), 154.3/103.4 mm Hg

(Nilv. 30 mg/day group), and 156.0/103.9 mm Hg (placebo group).

Baseline pulse pressure: 57.6 mm Hg (Nilv. 18 mg/day group), 48.9

mm Hg (Nilv. 24 mg/day group), 50.9 mm Fig (Nilv..30 mg/day), and

113 52.1 mm Hg (placebo group).

Interventions: Nilvadipine 18 mg/day, 24 mg/day, 30 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (fnstrument: Hg sphygmomanometer), MAP, and HR;

ECG; blood and urine lab tests. Notes: Changes in sitting DBP and associated SEMs from week 3 and

4 extracted from Table IV and weighted means were calculated.

Changes in SBP/HR not reported. WDAE in each group not reported. Funding source: Not reported.

114 Table 26: Nisoldipine - Characteristics of included studies

Study Study Description Opie 1997 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (ANCHOR) Treatment duration: 6 weeks. (189) Country: South Africa

Quality: Cochrane method = B; Jadad score — 3

Participants: Supine DBP 95-114 mm Hg for inclusion into trial.

N = 206: 92 m, 114 f (efficacy analysis). Mean age: 52.1 years (range:

20 - 75).

Baseline standing BP: 159.7/107.9 mm Hg (Nisol. 10 mg/day group),

163.8/107.4 mm Hg (Nisol. 20 mg/day group), 161.7/107.4 mm Hg

(Nisol. 30 mg/day group), and 160.5/105.1 mm Hg (placebo group).

Baseline pulse pressure: 51.8 mm Hg (Nisol. 10 mg/day group), 56.4

mm Hg (Nisol. 20 mg/day group), 54.3 mm Hg (Nisol. 30 mg/day

group), and 55.4 mm Hg (placebo group).

Interventions: Nisoldipine coat-core tablet 10 mg/day, 20 mg/day,

30 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

supine/standing SBP, DBP (Instrument: automatic device —Dinamap),

and supine HR; ABPM (Instrument: SpaceLabs 90202).

Notes: Changes in standing BP and supine HR data extracted from

Table 2. SD of changes in BP/HR imputed by calculating pooled SD

from reported 95% CI of difference between treatment and placebo.

Author contacted — responded by referring to statistics company (no

response).

Funding source: Not reported.

115 Table 27: Nitrendipine - Characteristics of included studies

Study Study Description Asmar 1992 Design: R/DB/PC trial. Placebo run-in period: 15 days. Treatment (190) duration: 4 weeks.

[Duplicate Country: France publication: Asmar Quality: Cochrane method = B; Jadad score = 2 1993 (191)] Participants: Supine DBP > 95 mm Fig for inclusion into trial. N- = 17: 14 m, 3 f. Mean age: 50 years (range: 39 - 64). Baseline BP: 160/103 mm Hg (Nitren. group), and 158/104 mm Hg

(placebo group). Baseline pulse pressure: 57 mm Hg (Nitren. group),

and 54 mm Hg (placebo group). Interventions: Nitrendipine 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough supine/standing SBP, DBP (Instrument: Fig sphygmomanometer), and

FIR, ABPM (Instrument: Novacor model Diasys 200-R), arterial pulse wave velocity.

Notes: Change in BP/HR and associated SDs extracted from Table 1. WDAE not reported.

Audior contacted: duplicate publication clarified; no access to additional data.

Funding source: INSERM & Ministere de la Recherche, France.

Ferrera 1985 Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in (192) period: 2 weeks. Treatment duration: 8 weeks.

Country: Italy

Quality: Cochrane method = B; Jadad score = 2

Participants: "hypertension" with SBP <200 mm Hg and DBP <120

mm Fig for inclusion into trial.

N = 30: 20 m, 10 f. Mean age: 47.3 years (range: 24 - 62).

Baseline standing BP: 159/113 mm Hg (Nitren. group), and 149/107

mm Hg (placebo group). Baseline pulse pressure: 46 mm Hg (Nitren.

group), and 42 mm Fig (placebo group).

116 Interventions: Nitrendipine 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

supine/standing SBP, DBP (Instrument: automatic recorder), and HR,

exercise testing; LV mass, systolic function and ejection fraction by

echocardiography.

Notes: Standing BP/FIR data and associated SDs extracted from

Table f and text, p. 436. SDs of BP change imputed from SDs of week

8 BPs. WDAE extracted from text, p. 437.

Funding source: Not reported.

Fodor1991 Design: R/DB/PC trial. Washout period: 2 weeks. Placebo run-in (193) period: 2 weeks. Treatment duration: 4 weeks, followed by dose

doubling in non-responders for 6 weeks.

Country: Canada

Quality: Cochrane method = B; Jadad score = 3

Participants: Supine DBP 95-104 mm Hg for inclusion into trial.

N = 80: 44 m, 36 f. Mean age: 52.8 years (range: 21 - 70).

Baseline supine BP: 155.7/98.2 mm Hg (Nitren. group), and

155.0/97.4 mm Hg (placebo group). Baseline pulse pressure: 57.5 mm

Fig (Nitren. group), and 57.6 mm Hg (placebo group).

Interventions: Nitrendipine 10 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in

supine/standing trough SBP, DBP (Instrument: Hg

sphygmomanometer), and FIR.

Notes: Baseline BP/FIRs and associated SEMs extracted from Table

1. Week 4 supine BPs/FIRs and associated SEMs extracted from

Figure 3. SDs of BP change imputed from SDs of week 4 BPs.

WDAE extracted from text, p. 226.

Funding source: Not reported.

Gerntsen 1998 Design: R/DB/PC trial. Washout period: > 3 weeks. Placebo run-in (194) period: 4 weeks. Treatment duration: 4 weeks, followed by dose

doubling in non-responders for 44 weeks.

117 Country: Netherlands

Quality: Cochrane method = B; Jadad score = 4

Participants: Non-insulin-dependent diabetes mellitus patients. DBP

90-115 mm Hg and SBP < 200 mm Hg for inclusion into trial.

N = 81 (excludes patients in enalapril group): 47 m, 34 f. Mean age:

64.3 years (range: not reported). Baseline standing BP: 168/90 mm Pig (Nitren. group), and 166/93 mm Pig (placebo group). Baseline pulse pressure: 78 mm Hg (Nitren. group), and 73 mm Pig (placebo group).

Interventions: Nitrendipine 20 mg/day, enalapril 10 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in trough supine/standing SBP, DBP (fnstrument: automatic device - Dinamap), and HR, fasting blood glucose, serum lipids, echocardiogram. Notes: BPs and associated SDs extracted from Table 1 (baselines) and

Figure 1 (week 4 data). SD of BP change imputed from SD of week 4

BPs. Funding source: Bayer, Nederland.

118 Gregorio 1991 Design: R/DB/PC trial. Washout period: 2 weeks. Treatment (195) duration: 12 weeks. Country: Italy

Quality: Cochrane method = B; Jadad score = 2

Participants: Type 2 diabetes mellitus patients. DBP 95-115 mm Hg for inclusion into trial.

N = 30: 18 m, 12 f. Mean age: not reported (range: 52 — 74 years). Baseline standing BP: 166.1/112.8 mm Hg (Nitren. group), and 158.9/113.5 mm Hg (placebo group). Baseline pulse pressure: 53.3 mm Hg (Nitren. group), and 45.4 mm Hg (placebo group). Interventions: Nitrendipine 20 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in trough supine/standing SBP, DBP (Instrument: Hg sphygmomanometer), and HR; lipid profile, glycemic homeostatis and other metabolic parameters.

Notes: Published in Italian. BPs and associated SDs extracted from Fig. 3. SD of BP change imputed from weighted mean SD of BPs at

weeks 3, 4, 6, 8,10,12. Attempted to contact author — no reply.

Funding source: Not reported.

Kuschnir 1988 Design: R/DB/PC crossover trial. Placebo run-in period: 1-3 weeks. (196) Treatment duration: 3 weeks.

Country: Argentina

Quality: Cochrane method = B; Jadad score = 2

Participants: Mild to moderate (WHO stage I or II) essential

hypertension for inclusion into trial.

N = 20: 14 m, 3 f. Mean age: 48.9 years (range: 33 - 60).

Baseline standing BP: 167/106 mm Hg (Nitren. group), and 168/107

mm Hg (placebo group). Baseline pulse pressure: 61 mm Fig (Nitren.

group), and 61 mm Hg (placebo group).

Interventions: Nitrendipine 20 mg/day, or placebo.

119 Primary and secondary outcomes: Change from baseline in trough

supine/standing SBP, DBP (Instrument: Hg sphygmomanometer), and

HR, peripheral hemodynamic parameters by radionuclide techniques.

Notes: BPs/HRs and associated SDs extracted from Table 2. SDs of

BP/HR change imputed from other trials.

Funding source: Not reported.

Lederle 1991 Design: MC/R/DB/PC trial. Placebo run-in period: 2 weeks. (197) Treatment duration: 6 weeks.

[Duplicate Country: Germany publication: Klaus Quality: Cochrane method = B; Jadad score = 3 1990 (198)] Participants: WFIO stage f mild essential hypertension for inclusion into trial. N = 141: 88 m, 53 f. Mean age: 54.8 years (range: not reported). Baseline sitting BP: 161.4/99.6 mm Hg (Nitren. group), and 161.3/99.6 mm Hg (placebo group). Baseline pulse pressure: 61.8 mm Hg (Nitren. group), and 61.7 mm Fig (placebo group). Interventions: Nitrendipine 10 mg/day, or placebo. Primary and secondary outcomes: Number of treatment responders (DBP reduced by > 10 mm Hg and/or to a value of < 90 mm Hg) after 6 weeks of treatment. Change from baseline in sitting trough SBP, DBP (Instrument: sphygmomanometer), and HR. Notes: BPs/HRs and associated SDs extracted from text, p. S49 and figure 1. SDs of SBP/HR change imputed from weighted mean of week 4 and 6 SBPs/FIRs. WDAE extracted from text, p. S50. Funding source: Not reported.

Maclean 1990 Design: MC/R/DB/PC trial. Washout period: 2-4 weeks. Placebo (199) run-in period: 3 weeks. Treatment duration: 6 weeks, followed by dose

doubling in nonresponders for 6 weeks. Country: UK

Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 95-115 mm Hg for inclusion into trial.

120 N — 64 (excluding atenolol and combination groups): 29 m, 35 f. Mean age: 51 years (range: 18-75).

Baseline sitting BP: 171/108 mm Hg (Nitren. group), and 171/108 mm Hg (placebo group). Baseline pulse pressure: 63 mm Hg (Nitren. group), and 63 mm Hg (placebo group).

Interventions: Nitrendipine 20 mg/day, atenolol 50 mg/day, atenolol 50 mg + nitrendipine 20 mg combination, or placebo. Primary and secondary outcomes: Change from baseline in trough sitting/standing SBP, DBP (Instrument: Hawkesley random-zero sphygmomanometer), and HR.

Notes: Sitting BPs/HRs extracted from Table 4. SDs of baseline and week 6 BPs extracted from Figure 2. SD of BP change imputed from week 6 SD of BPs. (95% CI of differences between treatment and placebo were reported but mean differences were not reported). WDAE extracted from text, p. 457. Funding source: Not reported.

PaoHsso 1991 Design: R/DB/PC trial. Washout period: > 3 weeks. Treatment (200) duration: 60 days.

Country: Italy

Quality: Cochrane method — B; Jadad score = 2

Participants: Elderly patients with ISH.

N = 20: 11 m, 9 f. Mean age: 76.8 years (range: not reported). -

Baseline BP: 180/92 mm Hg (Nitren. group), and 178/91 mm Hg

(placebo group). Baseline pulse pressure: 88 mm Fig (Nitren. group),

and 87 mm Fig (placebo group).

Interventions: Nitrendipine 20 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in SBP,

DBP (Instrument: not reported), and HR; hemodynamic and

laboratory tests; oral glucose tolerance test.

Notes: BPs/HRs and associated SEMs extracted from table, p. 696.

SDs of BP change imputed from SDs of week 8 BPs.

121 Funding source: Not reported.

Roca-Cusachs Design: MC/R/DB/PC factorial-design trial. Washout period: 1 2001 week. Placebo run-in period: 2 weeks. Treatment duration: 6 weeks. (201) Country: Spain

Quality: Cochrane method = B; Jadad score = 2

Participants: Sitting DBP 90-109 mm Hg for inclusion into trial.

N = 342 (per-protocol): 137 m, 205 f. Mean age: 55.6 years (range for inclusion: 18-70).

Baseline BP: 158.3/98.6 mm Hg (all groups). Baseline pulse pressure: 59.7 mm Hg (all groups).

Interventions: Nitrendipine 5 mg/day, 10 mg/day, 20 mg/day, Enalapril 5 mg/day, 10 mg/day, 20 mg/day, all 9 possible combinations thereof, or placebo. Primary and secondary outcomes: Change from baseline in sitting trough DBP, SBP (Instrument: Fig sphygmomanometer), and FIR; rate of responders (< 140/90 mm Hg or reduction of >20/10 mm Fig from baseline).

Notes: Change in BPs extracted from figure 1. SDs of SBP change imputed from SD of baseline SBP. SDs of DBP change imputed from other trials. WDAE for each group not reported. Funding source: Vita-Invest S.A., Spain.

122 Table 28: Pranidipine - Characteristics of included studies

Study Study Description Rosenthal 1996 Design: MC/R/DB/PC trial. Placebo run-in: 4 weeks. Treatment (202) duration: 4 weeks. Country: Germany

Quality: Cochrane method =B; Jadad score = 4 Participants: Sitting DBP 95-114 mm Hg for inclusion into trial N = 176: 97 m, 79 f. Mean age: 52.0 years (inclusion range: 20 - 70). Baseline BP: 159/103 mm Hg (Pran. 1 mg/day group), 154/102 mm Hg (Pran. 2 mg/day group), 156/103 mm Hg (Pran. 4 mg/day group), 151/103 mm Hg (Pran. 8 mg/day group), 153/103 mm Hg (placebo group). Baseline pulse pressure: 56 mm Hg (Pran. 1 mg/day group), 52 mm Hg (Pran. 2 mg/day group), 53 mm Hg (Pran. 4 mg/day group), 48 mm Pig (Pran. 8 mg/day group), and 50 mm Hg (placebo group).

Interventions: Pranidipine 1 mg/day, 2 mg/day, 4 mg/day, 8 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting trough SBP, DBP and PIR (Instrument: automated device — Tonoprint).

Notes: BP data extracted from text, page 61 and 64. WDAE extracted from Table 6. SD of BP change imputed from SDs of BPs at week 4. Funding source: Not reported.

123 Table 29: Tiapamil - Characteristics of included studies

Study Study Description Blanchett 1991 Design: MC/R/DB/PC trial. Placebo run-in: 4 weeks. Treatment (203) duration: 6 weeks, followed by 1 week washout. Country: USA

Quality: Cochrane method =B; Jadad score = 3

Participants: Sitting DBP 95-115 mm Hg for inclusion into trial

N = 58: 36 m, 22 f. Mean age: 50.5 years (range: 24 - 67).

Baseline BP: 153/103 mm Hg (Level. I group), 150/100 mm Hg (Level II group), 155/104 mm Fig (placebo group). Baseline pulse pressure:

50 mm Hg (Level I group), 50 mm Hg (Level II group), and 51 mm Hg (placebo group). Interventions: Tiapamil 300 mg/day or 600 mg/day ("Level I"), 900 mg/day or 1200 mg/day ("Level II"), or placebo.

Primary and secondary outcomes: Change from baseline in standing/sitting/supine trough SBP, DBP and FIR (Instrument: sphygmomanometer, ABPM (Instrument: Spacelabs 5200) Notes: BPs, HRs and associated SDs extracted from table 2 (reported in dosage groups 300-600 mg/day and 900-1200 mg/day). WDAE extracted from text, p. 61. SD of change in BPs/HRs imputed from week 6 BPs.

Author contacted to obtain # of patients on each dose — no response. Funding source: Hoffman La-Roche, Inc., USA.

124 Table 30: Verapamil - Characteristics of included studies

Study Study Description Carr 1991 Design: MC/R/DB/PC trial. Placebo run-in period: 3-6 weeks. (204) Treatment duration: 4 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 2 Participants: Supine DBP 95-119 mm Hg for inclusion into trial N = 107: m, f. Mean age: 46 years (range: not reported).

Baseline supine BP: 152.9/103.3 mm Hg (ver. 120 mg/day group),

157.9/103.3 mm Hg (ver. 240 mg/day group), 148.3/100.7 mm Pig (ver. 480 mg/day group), and 156.9/103.2 mm Hg (placebo group). Baseline pulse pressure: 49.6 mm Pig (ver. 120 mg/day group), 54.6 mm Hg (ver. 240 mg/day group), 47.6 mm Hg (ver. 480 mg/day

group), and 53.7 mm Hg (placebo group).

Interventions: Verapamil QD 120 mg/day, 240 mg/day, 480 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in supine/sitting/standing SBP, DBP (Instrument: Hg sphygmomanometer) and PIR; ABPM (Instrument: Del Mar Pressurometer III), serum biochemical markers.

Notes: Change in supine BP, PIR and associated SDs extracted from Table f.

Funding source: Not reported.

De Quattro 1997a Design: MC/R/DB/PC 4x4 factorial trial. Placebo run-in period: 4 (205) weeks. Treatment duration: 6 weeks.

[Multiple Country: USA publications: Quality: Cochrane method = A; Jadad score = 3 De Quattro 1997b (206) ;Levine 1997 Participants: Sitting DBP 95-114 mm Hg for inclusion into trial. (207) ] N = 726: 456 m, 270 f. Mean age: 54.7 years (range: 24 - 83).

Baseline sitting BP: 148.4/100.1 mm Hg (verap. 120 mg/day group),

153.4/99.3 mm Hg (verap. 180 mg/day group), 150.3/100.7 mm Hg

125 (verap 240 mg/day group), 153.7/100.3 mm Hg (placebo group).

Baseline pulse pressure: 48.3 mm Hg (verap. 120 mg/day group), 54.1

(verap 180 mg/day group), 49.6 mm Hg (verap. 240 mg/day group),

and 53.4 mm Hg (placebo group).

Interventions: Verapamil SR 120 mg/day, 180 mg/day, 240 mg/day,

Trandolapril 0.5 mg/day, 2 mg/day, 8 mg/day, all combinations

thereof, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

trough SBP, DBP (Instrument: standard Hg sphygmomanometer), HR

Notes: BPs extracted from Table III (DeQuattro 1997a). SDs of SBP

change imputed from supine baseline SBPs. SD of DBP change

imputed from other trials.

Funding source: Knoll Pharmaceutical Co., USA. Levine 1995 Design: MC/R/DB/PC 3x2 factorial trial. Placebo run-in period: 4-5 (208) weeks. Treatment duration: 4 weeks. Country: USA Quality: Cochrane method = B; Jadad score — 4

Participants: Sitting DBP 95-114 mm Hg for inclusion into trial.

N = 186: 105 m, 81 f. Mean age: 52.7 years (range: 24 - 80).

Baseline BP: 150.4/101.2 mm Hg (verap.120 mg/day group),

151.1/100.4 mm Hg (verap. 240 mg/day), 149.8/100.2 mm Hg

(placebo group). Baseline pulse pressure: 49.2 mm Hg (verap. 120

mg/day group), 50.6 mm Hg (verap. 240 mg/day group), and 49.6 mm

Hg (placebo group).

Interventions: Verapamil 120 mg/day, 240 mg/day, enalapril 10

mg/day, verapamil + enalapril 120/10 mg/day, 240/10 mg/day, or

placebo.

Primary and secondary outcomes: Change from baseline in trough

sitting SBP, DBP (Instrument: standard Hg sphygmomanometer),

ECG, lab tests, quality of life questionnaire.

Notes: Change in SBP and DBP with associated SDs extracted from

126 Table 2 and 3, respectively. WDAE extracted from text, p. 497.

Funding source: Lederle Laboratories, USA.

McMahon 1989 Design: MC/R/DB/PC trial. Placebo run-in period: 1-4 weeks. (209) Treatment duration: 6 weeks. Country: USA

Quality: Cochrane method = B; Jadad score = 3 Participants: Supine DBP 95-114 mm Hg for inclusion into trial. N = 221: 127 m, 94 f. Mean age: 54.8 years (>f 8 for inclusion). Baseline supine BP: 159.6/101.8 mm Fig (verap. 60 mg/day group), 152.6/99.8 mm Hg (verap. 120 mg/day group), 157.7/101.4 mm Hg (verap. 240 mg/day group), 151.8/99.6 mm Hg (verap. 480 mg/day), 156.2/100.7 mm Hg (placebo group). Baseline pulse pressure: 57.8 mm Hg (verap. 60 mg/day group), 52.8 mm Hg (verap. 120 mg/day group), 56.3 mm Hg (verap. 240 mg/day group), 52.2 mm Hg (verap. 480 mg/day group), and 55.5 mm Hg (placebo group). Interventions: Verapamil-SR 60 mg/day, 120 mg/day, 240 mg/day, 480 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in supine peak and trough SBP, DBP (Instrument: not reported; by auscultation), FIR, ECG, lab tests.

Notes: Trough BPs and associated SEs extracted from Table II. SD

of BP change imputed from SD of endpoint BPs. Baseline HRs not

reported. WDAE extracted from Table 111.

Author deceased.

Funding source: Not reported.

Messerli 1998 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (210) Treatment duration: 6 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: DBP 95-114 mm Hg for inclusion into trial.

N = 631: 401 m, 230 f. Mean age: 54.5 years (range: 21-88).

127 Baseline sitting BP: 151.1/100.8 mm Hg (verapamil group),

153.6/100.5 mm Hg (placebo group). Baseline pulse pressure: 50.3

mm Hg (verapamil group), and 53.1 mm Hg (placebo group).

Interventions: Verapamil SR 240 mg/day, trandolopril 4 mg/day,

verapamil SR 240 mg/trandolopril 4 mg combination, or placebo.

Primary and secondary outcomes: Change from baseline in trough

sitting DBP, SBP (Instrument: standard Hg sphygmomanometer), HR

at peak and trough; % responders (DBP < 90 mm Hg or > 10 mm Hg

decrease).

Notes: Change in BPs and associated SEs extracted from Table 2.

Changes in BP reported were already adjusted for placebo effect.

Therefore, SDs of change in BP for the placebo group were imputed

from other trials.

Funding source: Knoll Pharmaceutical Company, New Jersey.

Neutel 1996 Design: MC/R/DB/PC trial. Washout period: 1-2 weeks. Placebo (211) run-in period: 2-4 weeks. Treatment duration: 4 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 95-114 mm Hg and mean daytime

ambulatory DBP >90 mm Hg for inclusion into trial.

N = 95: 64m, 31 f. Mean age: 56.7 years (range: not reported).

Baseline BP: 158.6/99.9 mm Hg (verapamil group), 157.5/101.2 mm

Hg (placebo group). Baseline pulse pressure: 58.7 mm Hg (verapamil

group), and 56.3 mm Hg (placebo group).

Interventions: Verapamil COER-24 240 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: Hg sphygmomanometer), ABPM (Instrument:

SpaceLabs 90202).

Notes: Change in BPs and associated SDs, WDAE extracted from

text, p. 1203. Baseline HRs not reported.

Funding source: Not reported.

128 Neutel 1999 Design: MC/R/DB/PC trial. Washout period: duration not reported. (212) Placebo run-in period: 2-4 weeks. Treatment duration: 8 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 95-114 mm Hg and ambulatory DBP 90-

114 mm Hg for inclusion into trial.

N = 116: 75 m, 41 f. Mean age: 52.1 years (range: not reported).

Baseline BP: 154.9/98.1 mm Hg (verapamil group), 155.5/95.9 mm Hg

(placebo group). Baseline pulse pressure: 56.8 mm Hg (verapamil

group), and 59.6 mm Hg (placebo group).

Interventions: CODAS-verapamil 200 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: Hg sphygmomanometer); ABPM (Instrument:

Spacelabs 90207).

Notes: Change in trough BPs and associated SDs extracted from text,

p. 577. WDAEs extracted from text, p. 576.

Funding source: Not reported. Scholze 1998 Design: MC/R/DB/PC 3x4 factorial trial. Washout period: 1 week. (213) Placebo run-in period: 4 weeks. Treatment duration: 6 weeks.

Country: Germany

Quality: Cochrane method — B; Jadad score = 3

Participants: Sitting DBP 100-115 mm Hg for inclusion into trial.

N = 424; ratio of m:f not reported. Mean age and age range: not

reported.

Baseline BP: 167.1/105.9 mm Hg (ver. 120 mg/day group),

169.9/106.9 mm Fig (ver. 180 mg/day group), and 171.4/105.4 mm

Hg (placebo group). Baseline pulse pressure: 61.2 mm Fig (ver. 120

mg/day group), 63 mm Fig (ver. 180 mg/day group), and 66 mm Fig

(placebo group).

Interventions: Verapamil SR 120 mg/day, 180 mg/day, trandolapril

0.5 mg/day, 1.0 mg/day, verapamil + trandolapril 120/0.5 mg/day,

129 120/1.0 mg/day, 180/0.5 mg/day, 180/1.0 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

sitting/standing SBP, DBP (fnstrument: Hg sphygmomanometer), HR,

routine haematological, biochemical and urinary investigations.

Notes: Change in sitting BPs extracted from Table 1.

Author contacted: baseline BPs/HRs, change in HR, and SDs of

BP/HR change obtained.

Funding source: Knoll A.G., Germany.

Smith 2001 Design: MC/R/DB/PC trial. Washout period: 1-14 days. Placebo (214) run-in period: 2-4 weeks. Treatment duration: 8 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 4

Participants: Sitting DBP >95 and <115 mm Hg for inclusion into

trial.

N = 277: 177 m, 100 f. Mean age: 53.4 years (range: not reported).

Baseline BP (ABPM): 148.0/93.3: mm Hg (ver. 100 mg/day group),

150.1/93.4 (ver. 200 mg/day group), 148.6/92.6 (ver. 300 mg/day

group), 146.9/92.4 (ver. 400 mg/day group), and 150.0/92.9 mm Hg

(placebo group). Baseline pulse pressure: 54.7 mm Fig (ver. 100

mg/day group), 56.7 mm Hg (ver. 200 mg/day group), 56 mm Hg (ver.

300 mg/day group), 54.5 mm Hg (ver. 400 mg/day group), and 57.1

mm Hg (placebo group).

Interventions: CODAS-veraparnil 100 mg/day, 200 mg/day, 300

mg/day, 400 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in trough

sitting SBP, DBP (Instrument: not reported); APBM (fnstrument:

Spacelabs 90207).

Notes: Change in office BPs and associated SDs extracted from text,

page 17-18. WDAE extracted from text, p. 18.

Funding source: Not reported.

Veratran 1997 Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. (215)

130 Treatment duration: 8 weeks. Country: Italy

Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 100-110 mm Hg for inclusion into trial

N = 272 (234 in efficacy analysis): 134 m, 100 f. Mean age: 49.9 years

(range: 18 — 65 for inclusion). Baseline BP: 156.0/104.2 mm Hg (verapamil group), 158.2/103.5 mm Hg (placebo group). Baseline pulse pressure: 51.8 mm Hg (verapamil group), and 54.7 mm Hg (placebo group).

Interventions: Verapamil SR 180 mg/day, trandolapril 1 mg/day, verapamil SR 180 mg/day + trandolapril 1 mg/day combination, or placebo.

Primary and secondary outcomes: Change from baseline in sitting SBP, DBP (Instrument: Hg sphygmomanometer) and HR

Notes: Week 8 BPs, HRs and associated SDs extracted from Table 1. SDs of BP/HR change imputed from week 8 BPs/HRs. # of patients

in each group reported for efficacy analysis only — cannot use WDAE data since # of patients at randomization not reported.

Funding source: Not reported.

Von Manteuffel Design: MC/R/DB/PC trial. Placebo run-in period: 4 weeks. 1995 Treatment duration: 6 weeks. (216) Country: Germany and Austria

Quality: Cochrane method = B; Jadad score = 2

Participants: Sitting DBP 100-115 mm Hg for inclusion into trial

N = 176: 91 m, 85 f. Mean age: 56.3 years (range: 18-70 for

inclusion).

Baseline BP: 173.7/106.7 mm Hg (verapamil group), 168.2/105.6 mm

Fig (placebo group). Baseline pulse pressure: 67 mm Hg (verpamail

group), and 62.6 mm Tig (placebo group).

Interventions: Verapamil SR 240 mg/day, hydrochlorothiazide 12.5

mg/day, verapamil SR 240 mg/day + HCTZ 12.5 mg/day

131 combination, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: not reported), % responders (decrease in DBP

> 10 mm Hg or normalization of DBP to < 90 mm Hg).

Notes: Published in German. Weighted mean SBPs at week 4 and 6

extracted from Figure 2. SD of change in SBP imputed from baseline

SBP. DBP at week 6 extracted from text, p. 375. SD of change in

DBP imputed from other trials.

Funding source: Not reported.

White 1995 Design: MC/R/DB/PC trial. Washout period: 1 week. Placebo run- (217) in period: 2-4 weeks. Treatment duration: 8 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 2

Participants: Sitting DBP 95-114 mm Fig and ABPM daytime DBP >

90 mm Hg for inclusion into trial.

N = 287; ratio of m:f not reported. Mean age: 53.2 years (range: not

reported).

Baseline BP: 159/101 mm Hg (ver. 120 mg/day group), 155/100 mm

Hg (ver. 180 mg/day), 158/102 mm Fig (ver. 360 mg/day), 158/101

mm Hg (ver. 540 mg/day), 156/101 mm Hg (placebo group). Baseline

pulse pressure: 58 mm Hg (ver. 120 mg/day group), 55 mm Hg (ver.

180 mg/day group), 56 mm Hg (ver. 360 mg/day group), 57 mm Hg

(ver. 540 mg/day group), and 55 mm Hg (placebo group).

Interventions: Physiologic pattern release (PPR)-verapamil 120

mg/day, 180 mg/day, 360 mg/day, 540 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in sitting

SBP, DBP (Instrument: Hg sphygmomanometer), HR; ABPM

(Instrument: Spacelabs 90202).

Notes: Change in trough clinic BPs/HRs and SEs extracted from

Table II. WDAE data incompletely reported.

Funding source: Not reported.

132

\ White 2002 Design: MC/R/DB/PC trial. Washout period: 1-2 weeks. Placebo

(218) run-in period: 2-4 weeks. Treatment duration: 8 weeks (forced titration

at week 4).

Country: USA

Quality: Cochrane method = B; Jadad score — 3

Participants: Sitting DBP 95-114 mm Hg and ABPM daytime DBP > 85 mm Pig for inclusion into trial. N = 357: 219 m, 138 f. Mean age: 54.5 years (range: not reported).

Baseline sitting BP: 146/95 mm Hg (verapamil group), 148/95 mm Hg

(placebo group). Baseline pulse pressure: 51 mm Pig (verapamil group), and 53 mm Hg (placebo group).

Interventions: COER-verapamil 240 360 mg/day, enalapril lO-^

20 mg/day, losartan 50~^ 100 mg/day, or placebo. Primary and secondary outcomes: Change from baseline in

sitting/standing SBP, DBP (fnstrument: Hg sphygmomanometer) & HR; ABPM (fnstrument: Spacelabs 90207). Notes: Change in sitting BP and associated SDs at week 8 extracted from Table IV. Clinic HRs not reported. WDAE' reported but on

what dose these occurred is not specified.

Funding source: Not reported.

133 3.3 Characteristics of studies awaiting data from authors

Table 31: Characteristics of studies meeting inclusion criteria and awaiting office blood pressure data from authors

Study Study Description Bakris 2002 Design: MC/R/DB/PC trial. Washout period: 1-2 weeks. Placebo (219) run-in period: 2-4 weeks. Treatment duration: 8 weeks (forced titration

at week 4)

Country: USA and Canada

Quality: Cochrane method = B; Jadad score = 3

Participants: Sitting DBP 95-114 mm Hg for inclusion into trial.

N = 405: 223 m, 182 f. Mean age: years (inclusion range: 21 — 80).

Baseline sitting BP: 145/95 mm Hg (verap. group), and 146/96 mm Hg

(placebo group). Baseline pulse pressure: 50 mm Hg (verap. group), and 50 mm Hg (placebo group).

Interventions: COER-verapamil 240 360 mg/day, enalapril 10-^

20 mg/day, losartan 50 100 mg/day, or placebo.

Primary and secondary outcomes: Change from baseline in

sitting/standing office SBP, DBP (fnstrument: not reported), 24-hour

ABPM (fnstrument: Spacelabs 90207), rate of rise of BP/HR during

the morning acceleration phase.

Notes: Office BPs/HRs to be obtained from author.

Funding Source: Pharmacia Corp., USA.

Glasser 2003 Design: MC/R/DB/PC trial. Placebo run-in period: 3-4 weeks. (220) Treatment duration: 7 weeks.

Country: USA

Quality: Cochrane method = B; Jadad score = 3

Participants: sitting DBP 100-114 mm Hg for inclusion into trial.

N — 478: 303 m, 175 f. Mean age: 52 years (inclusion range: 18 — 70).

Baseline BP/pulse pressure: office values not reported.

Interventions: Diltizaem extended-release 120 mg/day, 240 mg/day,

360 mg/day, 540 mg/day, or placebo.

134 Primary and secondary outcomes: Change from baseline in

sitting/standing office SBP, DBP (Instrument: not reported) and HR;

24-hour ABPM (Instrument: Spacelabs 90207).

Notes: Office BPs/HRs to be obtained from author.

Funding Source: Not reported.

135 3.4 Characteristics of excluded studies

Table 32 below documents the reasons why 134 studies that met the primary inclusion criteria had to be excluded from the analysis. Several of these studies were either cross-over trials that did not report pre-crossover data or parallel-group studies that allowed dose titration in non-responders. Other common reasons for exclusion included failure to report details such as number of patients in each arm, baseline blood pressures, or pre- titration data.

Table 32: Reasons for exclusion of certain studies meeting inclusion criteria

Study ID Reason for exclusion Abadie 1985 R/DB/PC parallel group trial that assessed the effect of nifedipine (221) 30 mg/day on carbohydrate metabolism — no blood pressures reported. Ahmed 1992a R/DB/PC cross-over trial with no pre-crossover data reported for (222) the 1" four weeks of treatment (nicardipine 90 mg/day vs. placebo) Allrkmets 1997 R/DB/PC parallel group trial with no data reported for the 1st four (223) weeks of treatment prior to titration in non-responders (isradipine 5 mg/day vs. placebo) Andersson 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (224) the 1st nine weeks of treatment [isradipine 2.5 mg (3 weeks) 5 mg (3 weeks) 7.5 mg (3 weeks) vs: placebo] [Duplicate publication: Andersson 1990 (225)1 Andren 1988 R/DB/PC cross-over trial with no data reported for the 1st three (226) weeks of treatment, prior to cross-over and also prior to titration in non-responders (diltiazem 240 mg/day vs. placebo) Arita 1999 R/DB/PC cross-over trial with no pre-crossover data for the 1st (227) four weeks of treatment (azelnidipine 8 mg vs. placebo) ArziUi 1993 R/DB/PC cross-over trial with no pre-crossover data for the 1st 4 (228) weeks of treatment (isradipine SRO 5 mg vs. placebo) Bainbridge 1993 R/DB/PC cross-over trial with no pre-crossover data for the 1st 4 (229) weeks of treatment (felodipine ER 5 mg/day vs. ramipril 2.5 mg/day vs. felodipine ER 5 mg + ramipril 2.5 mg vs. placebo) B aylac-D omengetroy R/DB/PC parallel group trial that studied nitrendipine 20 mg/day 1990 vs. placebo. No data reported for the placebo group. (230) BeUet 1985 R/DB/PC parallel group trial. Dose titration in non-responders (231) after 15 days of treatment (nicardipine 60 mg/day vs. placebo) Bossini 1990 R/DB/PC cross-over trial with no pre-crossover data for the 1st 4 (232) weeks of treatment (felodipine ER 10 mg/day vs. placebo)

136 Study ID Reason for exclusion British Isradipine R/DB/PC parallel group trial with no data reported for the 1st Hypertension Group three weeks of treatment prior to titration in non-responders 1989 [isradipine 2.5 mg/day (1.25 mg twice daily or 2.5 mg once daily) (233) vs. placebo]. CampbeU 1990 R/DB/PC parallel group trial with no data reported for the 1st six (234) weeks of treatment prior to titration in non-responders (felodipine ER 5 mg vs. placebo) Capewell 1989 R/DB/PC cross-over trial with no pre-crossover data for the 1st 4 (235) weeks of treatment (felodipine 10 mg/day vs. placebo). Titration in non-responders after 2 weeks treatment. Carr 1990 R/DB/PC parallel group trial with initial dose titrated to response. (236) Data from responders and non-responders reported separately, (isradipine 5, 10, 15, or 20 mg, depending on BP response vs. placebo). Chalmers 1990 Reports on 3 studies. The 3rd study was a R/DB/PC cross-over (237) trial with no pre-crossover data for the 1st four weeks of treatment with diltiazem 240 mg/day Clement 1987 R/DB/PC cross-over trial with no pre-crossover data for the 1st (238) three weeks of treatment (nifedipine SR 40 mg/day vs. atenolol 100 mg/day vs. placebo). No baseline BP values given. Cleroux 1992 R/DB/PC cross-over trial with no pre-crossover data for the 1st (239) four weeks of treatment (isradipine SR 5 mg vs. placebo) Cleroux 1994 R/DB/PC cross-over trial with no pre-crossover data for the 1st (240) four weeks of treatment. 8-week treatment periods but titration in non-responders after 4 weeks treatment, (verapamil 240mg/day vs. quniapril 10 mg/day vs. atenolol 50 mg/day) Cox 1988 R/DB/PC cross-over trial with no pre-crossover data for the 1st six (241) weeks of treatment (verapamil 40/80/120 mg/day vs. placebo). Open titration phase to determine dose before randomization. Cox 1989 R/DB/PC cross-over trial with no pre-crossover data for the 1st (242) four weeks of treatment (nicardipine 120 mg/day vs. placebo) Crozier 1990 R/DB/PC cross-over trial with no pre-crossover data for the 1" (243) five weeks of treatment (felodipine 20 mg/day vs. placebo) De Brmjn 1988 R/DB/PC parallel group trial with 8-week treatment period. Dose (244) titration in non-responders at 2-week intervals (starting dose: amlodipine 2.5 mg vs. atenolol 50 mg/day vs. placebo) Diemont 1991 Reports on two studies: one single blind study and one cross-over (245) trial with no pre-crossover data for the 1st four weeks of isradipine MR 5 mg/day vs. isradipine MR 10 mg/day vs. placebo Dittrich 1992 R/DB/PC parallel group trial. Doses of 60 mg, 90 mg, or 120 (246) mg/day of nicardipine were studied. Number of patients on each dose and titration schedule not reported. Draaijer 1995 R/DB/PC parallel group trial. BP data reported only at the end of (247) six months of treatment (felodipine 5 mg/day vs. enalapril 10 mg/day vs. placebo) Study ID Reason for exclusion Dupont 1991 R/DB/PC cross-over trial with no pre-crossover data reported for (248) . the 1st three weeks of diltiazem LP 300 mg/day vs. placebo Duprez 1991 R/DB/PC cross-over trial with no pre-crossover data reported for (249) the 1st six weeks of isradipine 10 mg/day vs. placebo Durel 1992 A study consisting of six 28-day cross-over trials in a quasi-random (250) order. No baseline BP data and no pre-crossover data reported for the 1st 4 weeks of verapamil 240 mg/day vs. placebo. Faguer de Moustier R/DB/PC parallel group trial with titration in non-responders after 1989 15 days of treatment with nicardipine 60 mg/day vs. placebo. (251)

[Duplicate publication: Faguer de Moustier 1990 (252) Ferreira-Filho 1995 R/DB/PC cross-over trial with no pre-crossover data reported for (253) the 1st four weeks of nifedipine SR 40 mg/day vs. placebo Fogan 1993 R/DB/PC cross-over trial with no pre-crossover data reported for (254) the 1st four weeks of isradipine SRO 5 mg/day (administered morning or night) vs. placebo Forette 1984 R/DB/PC parallel group trial with titration in non-responders (255) every 8 days during treatment, starting with nicardipine 30 mg/day vs. placebo. [Duplicate publication: Forette 1985 (256)] Fnshman 1988 R/DB/PC parallel group trial with titration in non-responders (257) every 2 weeks during treatment, starting with amlodipine 2.5 mg/day vs. atenolol 50 mg vs. placebo. (Multiple publications: Frishman 1994 (258) , Johnson 1992 (259), Johnson 1995 (260)] Gavras 1987 R/DB/PC parallel group trial with titration in non-responders after (261) 1 week of treatment with nifedipine GITS 30 mg/day vs. placebo. Gebera 1996 R/DB/PC cross-over trial with dose titration in non-responders (262) after 2 weeks of treatment with verapamil 240 mg/day vs. placebo. Pre-crossover data not reported Grimm 2002 R/DB/PC parallel group trial with no data reported for the 1st four (263) weeks of treatment with amlodipine 5 mg/day vs. placebo prior to titration in non-responders. Hamilton B 1987 Reports on several phase III studies, including a R/DB/PC parallel (264) group trial of isradipine 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, or placebo. BP data not reported. Harrington 1987 Reports on 2 studies: a short-term single-blind study, and a (265) R/DB/PC cross-over trial with dose titration in non-responders every 2 weeks of treatment, starting with felodipine 5 mg/day vs. placebo. Pre-crossover data not reported.

138 Study ID Reason for exclusion Hedback 1984 R/DB/PC cross-over trial with no pre-crossover data reported for (266) the 1st four weeks of verapamil 360 mg/day vs. placebo Herrera 1997 R/DB/PC parallel group trial with titration in non-responders (267) during weeks 2-4 of treatment, starting with diltiazem CD 180 mg/day vs. placebo. Honorato 1989 R/DB/PC parallel group 6-week trial of nitrendipine 20 mg/day (268) vs. placebo. No "n" values reported. Author contacted — no response. Hosie 1991 R/DB/PC parallel group trial with titration in non-responders after (269) 2 week of treatment with felodipine ER 5 mg/day vs. placebo.

[Conference abstract: Hosie 1990 (270)] Jeffrey 1990 R/DB/PC cross-over trial with dose titration in non-responders (271) after 2 weeks of treatment with felodipine 10 mg/day vs. placebo. No pre-crossover data reported. Only mean arterial pressure reported. Kelemen 1990 R/DB/PC parallel group trial with exercise co-intervention. (272)

[Duplicate publication: Stewart 1990 (273)] Khalil-Manesh 1987 R/DB/PC parallel group trial with titration in non-responders (274) every 2 weeks during treatment, starting with diltiazem 120 mg/day vs. placebo. Kjellstrom 1994 R/DB/PC cross-over trial with dose titration in non-responders (275) after 2 weeks of treatment with felodipine ER 10 mg/day vs. placebo. Baseline BP and pre-crossover data not reported Klauser 1990 R/DB/PC cross-over trial with 4-week treatment periods. Forced (276) titration with isradipine 10 mg/day (2 weeks) isradipine 20 mg/day (2 weeks) vs. placebo. No pre-crossover data reported [Duplicate publication: Klauser 1991 (277)] Krakoff 1989 R/DB/PC parallel group trial with titration in non-responders after (278) 2 weeks of treatment with nicardipine 60 mg/day vs. placebo. Lacourciere 1995 R/DB/PC parallel group trial with an 8-week treatment period (279) during which there was forced titration every 2 weeks, starting with diltiazem ER 120 mg/day. Lacourciere 1998 R/DB/PC parallel group trial with no data reported for the 1st (280) eight weeks of treatment with amlodipine 5 mg/day vs. placebo prior to titration in non-responders. Landmark 1985 R/DB/PC cross-over trial with no pre-crossover data reported for (281) the 1st eight weeks of nifedipine 40 mg/day vs. placebo Lessem 1990 R/DB/PC parallel group trial that studied nicardipine 30 mg/day, (282) 60 mg/day, 90 mg/day, and 120 mg/day vs. placebo. No baseline BPs reported.

139 Study ID Reason for exclusion Letzel 1990 R/DB/PC parallel group trial with no baseline BP data reported (283) (verapamil 160 mg/day vs. HCTZ 25 mg/day, vs. 50 mg/day vs. all possible combinations vs. placebo). Lewis 1978 R/DB/PC cross-over trial with no pre-crossover data reported for (284) the 1st four weeks of verapamil 240 mg/day vs. verapamil 360 mg/day vs. placebo Lok 1989 R/DB/PC parallel group trial with titration in non-responders after (285) 2 weeks of treatment with felodipine 5 mg/day vs. placebo LOMIR-MCT-IL R/DB/PC parallel group trial that does not report number of 1993 patients at the 1st four weeks of treatment with isradipine 2.5 (286) mg/day, prior to titration in non-responders. Author contacted; data no longer available. [Duplicate publication: Yodfat 1996 (287)1 Lorimer 1988 R/DB/PC parallel group trial with titration in non-responders (288) every 2 week of treatment, starting with amlodipine 2.5 mg/day vs. verapamil 160 mg/day vs. placebo. [Duplicate publication: Lorimer 1989 (289)1 Low 1993 R/DB/PC cross-over trial with no pre-crossover data reported for (290) the 1st four weeks of isradipine 5 mg/day vs. placebo. Lyons 1994 R/DB/PC parallel group trial with titration in non-responders after (291) 2 weeks of treatment with amlodipine 5 mg/day vs. placebo. Macphee 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (292) the 1st four weeks of nifedipine 20 mg/day vs. placebo. Mancia 1992 R/DB/PC parallel group trial of verapamil SR 240 mg/day, (293) nitrendipine 20 mg/day, enalapril 20 mg/day vs. placebo. Only mean 24-hour ABPM measurements reported. Author contacted — no reponse. Massie 1992 R/DB/PC parallel group trial with titration in non-responders (294) every 2 week of treatment, starting with diltiazem CD 120 mg/day vs. placebo. Mattarei 1987 R/DB/PC cross-over trial with titration in non-responders (295) (titration schedule not reported), starting with nifedipine 20 mg/day vs. placebo. No pre-crossover data reported. Mclnnes 1985 R/DB/PC cross-over trial with no pre-crossover data for the 1st (296) four weeks of treatment (verapamil 360 mg/day vs. propranolol 240 mg/day vs. verapamil 360 mg/day + propranolol 240 mg/day [Duplicate publication: vs. placebo). Dargie 1986 (297)1 Megnien 1995 R/DB/PC parallel group trial with titration in non-responders after (298) 2 weeks of treatment with amlodipine 5 mg/day vs. placebo

140 Study ID Reason for exclusion Midtbo 1980 R/DB/PC cross-over trial with no pre-crossover data reported for (299) the 1st four weeks of verapamil 480 mg/day vs. placebo

[Duplicate publication: Storstein 1981 (300)1 Morgan 2001 R/DB/PC cross-over trial with forced titration after 1 month of (301) treatment. No pre-crossover data for the 1st 2 months of treatment with felodipine (dose not reported) vs. amlodipine 5 mg (1 month) amlodipine 10 mg (1 month) vs. placebo. BP data from felodipine and amlodipine treatments lumped together. Morgan 2002 R/DB/PC cross-over trial with no pre-crossover data reported for (302) the 1" four weeks of felodipine 5 mg/day vs. placebo. Moser 1984 R/DB/PC parallel group trial with a weekly forced titration for 3 (303) weeks, starting with nitrendipine 10 mg/day vs. placebo, followed by a 2-week maintenance period. Nelson 1986 R/DB/PC parallel group trial with 3-week treatment period and (304) weekly forced titration: isradipine 5 mg/day (1 week) -^10 mg/day (1 week) 20 mg/day (1 week) vs. placebo. Neutel 1995 R/DB/PC parallel group trial with no data reported for the 1st four (305) weeks of treatment with verapamil 120 mg/day vs. placebo prior to titration in non-responders. Author contacted: no response? Nikkila 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (306) the 1st three weeks of diltiazem 240 mg/day vs. placebo, prior to titration in non-reponsders. Nikolova 1995 R/DB/PC parallel group trial comparing nifedipine 30 mg/day (307) with placebo in treatment of hypertensive venous leg ulcers. Patients in both groups were allowed centrally acting antihypertensive drugs in addition to randomized treatment. Nilsson 1996 R/DB/PC cross-over trial with single-blind diltiazem OD 300 (308) mg/day run-in prior to randomization. No pre-crossover data reported for the 1" six weeks of diltiazem OD 300 mg/day vs. placebo. Ollivier 1995 R/DB/PC parallel group trial with titration in non-responders (309) every 2 weeks, starting with diltiazem SR 200 mg/day vs. placebo. Pacheco 1986 R/DB/PC parallel group trial with titration in non-responders (310) during the 1st three weeks of treatment, starting with nifedipine 30 mg/day vs. placebo Pandita-Gunawardena DB/PC parallel group trial. Allocation by minimization. No data 1999 reported for the 1st four weeks of treatment with amlodipine 5 mg (311) vs. placebo) prior to titration in non-responders Pannarale 1996 R/DB/PC cross-over trial with no pre-crossover data reported for (312) the 1st four weeks of felodipine ER 10 mg/day vs. placebo

141 Study ID Reason for exclusion Persson 1989a R/DB/PC cross-over trial with no data reported for the 1st three (313) weeks of treatment with isradipine 5 mg/day vs. placebo prior to titration in non-responders. No pre-crossover data reported. [Multiple publications: Persson 1989b (314), Persson 1992 (315)] Pool 1985 R/DB/PC parallel group trial with titration in non-responders (316) every 2 weeks of treatment, starting with diltiazem 120 mg/day vs. placebo. Pool 1986 R/DB/PC parallel group trial with titration in non-responders (317) every 2 weeks of treatment, starting with diltiazem 120 mg/day vs. placebo. Pool 1988 R/DB/PC parallel group trial with titration in non-responders (318) every 2 weeks of treatment, starting with diltiazem 120 mg/day vs. placebo. [Duplicate publication: Pool 1989 (319)1 Pool 1990 Reports on 3 trials. Trial #2 was a R/DB/PC parallel group trial (320) with no data reported in the 1st 4 weeks of treatment with diltiazem 240 mg/day vs. placebo prior to titration in non-responders . Pnsant 1998 R/DB/PC parallel group trial with a 6-week titration period during (321) which doses were titrated in non-responders every 2 weeks, starting with amlodipine 2.5 mg/day vs. placebo. [Duplicate publication: Prisant 1999 (322)] Ramirez 1992 R/DB/PC parallel group trial that studied nifedipine GfTS 60 (323) mg/day vs. 90 mg/day vs. 120 mg/day vs. 180 mg/day vs. placebo. BPs from nifedipine arms were grouped together and not reported for each dose separately. Ricciardelli 1997 R/DB/PC parallel group trial with no data reported for the 1st six (324) weeks of treatment with nitrendipine 10 mg/day vs. placebo prior to titration in non-responders. Romero-Vecchione DB/PC parallel group trial with titration in non-responders every 1995 week for 4 weeks, starting with nifedipine 10 mg/day. (325) Rossi 2002 R/DB/PC cross-over trial with no pre-crossover data reported for (326) the 1st three weeks of lacidipine 4 mg/day vs. placebo. Salvetti 1987 R/DB/PC cross-over trial with no baseline data and no pre- (327) crossover data reported for the 1st four weeks of nifedipine 40 mg/day vs. placebo. Only mean arterial blood pressure values given. Salvetti 1989a R/DB/PC cross-over trial with no pre-crossover data reported for (328) the 1st four weeks of nicardipine SR 80 mg/day vs. placebo.

142 Study ID Reason for exclusion Salvetti 1989b R/DB/PC cross-over trial with no baseline SBP/DBP data and no (329) pre-crossover data reported for the 1st four weeks of nifedipine 40 mg/day vs. placebo. [Duplicate publication: Salvetti 1991 (330)1 Salvetti 1996 R/DB/PC cross-over trial with no pre-crossover data reported for (331) the P' four weeks of nifedipine GfTS 30 mg/day vs. nifedipine retard 40 mg/day vs. placebo. Schuster 1998 R/DB/PC cross-over trial with dtradon in non-responders after 2 (332) weeks of treatment with felodipine 5 mg/day vs. placebo. No pre- crossover data reported. Siche 2001 R/DB/PC parallel group trial with no data reported for the fst four (333) weeks of treatment with amlodipine 5 mg/day vs. placebo prior to titration in non-responders. Simon 1984 R/DB/PC parallel group trial with titration in non-responders (334) every week for 3 weeks, starting with nitrendipine fO mg/day vs. placebo. Slomm 1991 R/DB/PC parallel group trial with titration in non-responders, (335) starting with isradipine 2.5 mg/day vs. placebo. Timing of titration and number of patients on each dose are not reported. Spence 2000 R/DB/PC cross-over trial with no pre-crossover data reported for (336) the 1st four weeks of amlodipine 5 mg/day titrated up to 10 mg/day vs. placebo. Spieker 1998 Presents results of 4 studies, one of which was a R/DB/PC cross• (337) over trial with no pre-crossover data reported for barnidipine 20 mg vs. placebo. [Duplicate publication: Smilde 2000 (338)] Spritzer 1990 R/DB/PC cross-over trial with no pre-crossover data reported for (339) the 1st four weeks of nitrendipine 20 mg/day vs. placebo. Staessen 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (340) the 1st four weeks of isradipine 10 mg/day vs. placebo, prior to titration in non-responders. Stornello 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (341) the 1st four weeks of nicardipine 60 mg/day vs. placebo. Stornello 1990 R/DB/PC cross-over trial with no pre-crossover data reported for (342) the 1st six weeks of nicardipine-SR 80 mg/day vs. placebo. Suzuki 1999 R/DB/PC parallel group trial with titration in non-responders, (343) starting with benidipine 4 mg/day vs. placebo. Timing of titration and number of patients on each dose are not reported. Szlachic 1989 R/DB/PC parallel group trial with an 8-week titration in non- (344) responders, starting with diltiazem 120 mg/day vs. placebo Tonkin 1990 R/DB/PC cross-over trial with no pre-crossover data reported for (345) the 1st four weeks of diltiazem 240 mg/day vs. placebo

143 Study ID Reason for exclusion Tschoepe 1992 R/DB/PC parallel group trial that studied nitrendipine 20mg/day (346) vs. placebo. BPs reported as % change from pretreatment values, but no baseline values are given. Van Bortel 1990 R/DB/PC cross-over trial with no pre-crossover data reported for (347) the 1st four weeks of verapamil 360 mg/day vs. placebo Van Merode 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (348) the 1st four weeks of verapamil 360 mg/day vs. placebo. No baseline BPs reported. [Duplicate publication: Van Merode 1990 (349)1 Vanhees1991 R/DB/PC cross-over trial with no pre-crossover data reported for (350) the 1st three weeks of verapamil 240 mg/day vs. placebo. Viskoper 1991a R/DB/PC parallel group trial with no data reported for the 1st four (351) weeks of treatment with isradipine 5 mg/day vs. placebo prior to titration in non-responders. [Duplicate publications: Viskoper 1991b (352), Viskoper 1992 (353)1 Watts 1998 R/DB/PC cross-over trial with titration in non-responders after 2 (354) weeks of treatment with amlodipine 5 mg/day vs. diltiazem CD 180mg/day vs. placebo. No pre-crossover data reported. Weber 1988 R/DB/PC parallel group trial with titration in non-responders, (355) starting with diltiazem 240 mg/day vs. placebo. Timing of titration and number of patients on each dose are not reported. Webster 1987 R/DB/PC parallel group trial with forced titration amlodipine 2.5 (356) mg/day (2 weeks) 5 mg/day (2 weeks) -^10 mg/day (4 weeks) vs. placebo. Dosage could be reduced if there was excessive [Duplicate publication: lowering of BP or adverse effects from therapy. Data reported Webster 1988 (357)] excludes patients whose time since the last dose at the 8-week visit was outside of the 18-30 hour "window". Webster 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (358) the 1st four weeks of nicardipine 120 mg/day vs. placebo. Webster 1991 R/DB/PC cross-over trial with no pre-crossover data reported for (359) the 1st four weeks of nicardipine (standard formulation) 90 mg/day vs. nicardipine-SR 120 mgvs. placebo. Weir 1998 R/DB/PC parallel group trial with dietary salt co-intervention with (360) low (5-10 mg/day) and high doses (10-20 mg/day) of isradipine.

[Duplicate publiction: Chrysant 2000 (361)] Welzel 1990 R/DB/PC parallel group trial with no data reported for the 1st (362) three weeks of treatment with isradipine 2.5 mg/day vs. nifedipine retard 40 mg/day vs. placebo prior to titration in non-responders. Study ID Reason for exclusion White 1997 R/DB/PC parallel trial with 8 week treatment period of verapamil (363) COER 120, 180, 360, 540 mg/day vs. placebo. ABPM study of dippers vs. non-dippers (no office pressures reported). Wilson 1989 R/DB/PC cross-over trial with no pre-crossover data reported for (364) the 1st six weeks of nisoldipine 20 mg/day vs. placebo. BPs reported as mean arterial BPs. Winer 1987 R/DB/PC parallel group trial with 4-week treatment period during (365) which non-responders were titrated in non-responders every week, starting with isradipine 5 mg/day vs. placebo. Winer 1990 R/DB/PC parallel group trial with 6-week treatment period during (366) which doses were titrated in non-responders every week up to week 4, starting with isradipine 5 mg/day vs. placebo. Wing 1994a R/DB/PC cross-over trial with 6-week treatment periods, (367) comprised of a forced titration after 1 week of treatment with felodipine 5 mg/day vs. placebo, followed by a titration in non- responders at week 3. Doses could be stepped backwards if unacceptable adverse drug effects were experienced. Wing 1994b R/DB/PC cross-over trial with 6-week treatment periods and (368) titration in non-responders after 2 and 3 weeks of treatment, starting with feldopine 5 mg/day. Doses could be stepped backwards if unacceptable adverse drug effects were experienced. Wing 1997 R/DB/PC cross-over trial with titration in non-responders after 2 (369) weeks of treatment with lacidipine 2 mg/day vs. placebo. No pre- crossover data reported. Woehler 1992 R/DB/PC parallel group trial with a 6-week treatment period (370) during which there was forced titration every 2 weeks, starting with diltiazem 180 mg/day. Doses were not increased in patients whose DBP fell below 75 mm Hg or those who had a significant adverse event. Wysocki 1992 R/DB/PC cross-over trial with no data reported for the 1st three (371) weeks of treatment with isradipine 5 mg/day vs. placebo prior to titration in non-responders. No pre-crossover data reported. [Duplicate publication: Wysocki 1998 (372)] Yamakado 1993 R/PC cross-over trial. Unclear if double-blind. No data reported (373) for the 1st four weeks of treatment with diltiazem 180 mg/day vs. placebo. Yasky 1991 R/DB/PC cross-over trial with no pre-crossover data reported for (374) the 1st four weeks of diltiazem 240 mg/day vs. placebo. Zito 1991 R/DB/PC parallel group trial that studied lacidipine 2 mg/day vs. (375) 4 mg/day vs. placebo but does not report results separately for each dosage group.

145 3.5 Overview of included trials

Summary data of baseline characteristics of the 106 included trials are listed in Table

33. The number of patients in the placebo group tends to be substantially smaller than the number in the CCB treatment groups because there are multiarm trials comparing several doses of active drug with one placebo arm.

Table 33: Overview of included trials with CCBs as monotherapy for primary hypertension

Drug Total # of Total # of Mean age of Mean Mean Dose range patients in patients in patients duration of baseline Total # of trials CCB placebo (years) treatment SBP/DBP; treatment group (weeks) Pulse group Pressure (mm Hg) Amlodipine 889 534 52.7 6.3 157.5/104.0; 2.5-10 mg/day 53.5 9 trials Barnidipine 140 50 55.8 6 164.0/102.5; 10-30 mg/day 61.5 1 trial Darodipine 33 10 51.7 4 156.9/103.0; 100-300 mg/day 53.9 1 trial Diltiazem 1545 641 55.4 5.8 154.3/100.7; 90-540 mg/day 53.6 12 trials

Felodipine 1190 556 55.5 6.3 158.2/100.1; 2.5-20 mg/day 58.1 11 trials Isradipine 1091 404 55.0 4.9 161.0/105.2; 2.5-20 mg/day 55.8 11 trials Lacidipine 86 45 70.3 4 177.4/101.8; 2-4 mg/day 75.6 1 trial

146 Drug Total # of Total # of Mean age of Mean Mean Dose range patients in patients in patients duration of baseline Total # of trials CCB placebo (years) treatment SBP/DBP; treatment group (weeks) Pulse group Pressure (mm Hg) Lercanidipine 532 252 57.7 3.8 161.9/98.9; 2.5-20 mg/day 63.1 6 trials Lidoflazine 5 5 43.8 12 138.0/95.0; 180 mg/day 43.0 1 trial Manidipine 66 40 67.8 6 167.4/99.1; 10-40 mg/day 68.3 2 trials Mibefradil 685 128 60.0 4 175.7/101.3; 6.25-200 mg/day 74.4 3 trials Nicardipine 303 169 52.3 6.4 157.4/101.6; 40-100 mg/day 55.9 8 trials Nifedipine 675 413 52.7 7.1 157.1/102.1; 20-100 mg/day 55.0 12 trials Nilvadipine 172 80 54.2 4 162.6/102.3; 8-30 mg/day 60.3 2 trials Nisoldipine 148 58 52.1 6 161.4/106.9; 10-30 mg/day 54.5 1 trial Nitrendipine 310 255 55.7 6.2 162.5/100.4; 10-20 mg/day 62.1 10 trials Prandipine 144 32 52.0 4 154.6/102.8; 1-8 mg/day 51.8 1 trial Tiapamil 49 9 50.5 6 152.0/101.9; 300-1200 mg/day 50.2 1 trial Verapamil 1450 684 53.4 6 154.6/99.8; 60-540 mg/day 54.8 13 trials TOTAL: 9513 4365 55.0 5.7 158.2/101.6; 106 trials, 56.7 13 878 patients

147 3.6 Values used to impute missing variances

3.6.1. Standard deviation of blood pressure change

Thkty-seven (35%) of the trials included in this systematic review reported the standard deviation of the change in SBP and/or DBP. These values were used to calculate weighted means of the standard deviation of changes in SBP and DBP for both the CCB treatment and placebo groups. For the CCB-treatment group, the weighted mean standard deviations of the change in SBP and DBP were 13.3 mm Hg (SD 2.1) and 7.7 mm Fig (SD

1.6), respectively. For the placebo group, the weighted mean SD of BP change was 13.0 mm

Hg (SD 4.1) for SBP and 7.4 mm Hg (SD 2.3) for DBP.

Those trials whose reported SD values were not witliLn three standard deviations of the weighted mean SD of BP change were then excluded from the calcuation in order to obtain an adjusted weighted mean SD of BP change. Three trials with outlier SDs were excluded from the calculation (Chan 1997, Farsang 2001, Asmar 1992), resulting in an adjusted weighted mean SD for CCB treatment of 13.5 mm Hg and 7.8 mm Hg for SBP and

DBP, respectively, and corresponding values for placebo of 14.1 mm Hg and 7.9 mm Hg.

There was no statistically significant difference in SD of SBP change between placebo and

CCB treatment groups (p=0.15), nor in SD of DBP change (p=0.86). The adjusted values were used to impute the SD of BP change in the trials with outlier SDs and for other trials as per the protocol's imputation hierarchy.

The SD of BP change was imputed for 70 (67%) of the included trials with extracted

BP data. Of these, there were 3 trials (4%) in which variances were imputed by calculating the pooled standard deviation from a reported p value; 1 (1%) was imputed using SD reported from BP measured in a different position; 38 (56%) were imputed using endpoint

148 SDs; 6 (9%) were imputed using baseline SDs (for SBP only); 20 (30%) were imputed using the mean SD data reported in other trials.

3.6. 2. Standard deviation of heart rate change

Twelve trials reported SD of the change in heart rate, resulting in a weighted mean value of 8.8 beats/minute for CCB group and 8.4 beats/minute for placebo group. There was no statistically significant difference between the SD of heart rate change in CCB- and placebo-treated groups (p=0.4). These values were used to impute the standard deviations according to the hierarchy outlined in the protocol.

3.7 Dose-related blood pressure lowering of individual CCB drugs

Effect sizes are expressed as the weighted mean difference (CCB treatment effect minus placebo effect) followed by the 95% confidence interval in parentheses. In all analyses, "statistical significance" refers to p < 0.05. For analyses for which there was statistically significant interstudy heterogeneity, the random effects model was applied to determine if there was a statistically significant difference between CCB treatment and placebo. If a statistically significant difference was present using the random effects model, the effect size is reported using the fixed effect model because of the tendency of the former to overweight smaller trials.

The weighted mean changes in SBP and DBP in placebo groups across all trials was

-3.5 mm Hg (range -16.7 - 9) and -3.8 mm Fig (range -11.4 - 4.5), respectively.

149 3.7.1 Amlodipine vs. placebo

Table 34: Blood pressure lowering efficacy of amlodipine 1.25 - 10 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Amlodipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 1.25 mg/day 2 88 -1.44 -1.44 (-5.46, 2.57) (-3.65, 0.78) 2.5 mg/day 3 158 -5.30* -3.78* (-8.58, -2.03) (-5.51, -2.05) 5 mg/day 7 556 -10.72*# -5.53*# (-12.38, -9.05) (-6.50, -4.55) 10 mg/day 2 55 -10.71* -7.29* (-15.70, -5.72) (-9.95,-4.62) * statistically significant difference from placebo # statistically significant heterogeneity

Nine of the included trials assessed amlodipine, encompassing a dose range of 1.25 mg/day to 10 mg/day. Amlodipine at 1.25 mg/day did not statistically significandy lower

SBP or DBP compared with placebo. The 2.5 mg/day dose is the lowest dose that showed a

statistically significant difference compared with placebo in this review. There was

statistically significant heterogeneity in the 5 mg/day dose (Chi2= 32.56, p < 0.0001) but the random effects model still yielded a statistically significant reduction in SBP and DBP

compared with placebo. The heterogeneity can be explained by high baseline BPs (> 160

mm Hg) in two trials (Kuschnir 1996 and Farsang 2001). If these trials are removed, the

heterogeneity is no longer statistically significant and the effect size at 5 mg is reduced to -

8.78 mm Fig (95% CI -10.80, -6.76) for SBP and -4.10 mm Hg (95% CI -5.29, -2.90) for

DBP.

Indirect comparison of the results for each dose showed evidence of a dose-response

phenomenon since there was a greater reduction in blood pressure with 5 mg/day compared

with 2.5 mg/day and 1.25 mg/day. Flowever, there was no difference between the 5 and 10

mg/day doses.

150 In the direct comparison analysis, only two trials were included (Frick 1988, Mehta

1993). There was no statistically significant difference in the effect sizes between the direct and indirect comparisons of amlodipine doses.

Since all amlodipine trials had a mean age of <60 years and inclusion criteria of elevated DBP, subgroup analyses based on age and type of hypertension were not possible.

All trials were of moderate quality Qadad score 3 or 4 out of 5) except for one study which had a Jadad score of 5/5 (Pool 2001). Sensitivity analyses of BP measurement position did not change the results. In all trials BP measurements were taken in the trough period of the dosing interval; thus an analysis of peak vs. trough effect was not possible. Only 2 amlodipine trials reported SD of BP change (Mehta 1992 and Mroczek 1988), while imputed values were used for the rest of the trials. The results were insensitive to whether the values were imputed according the hierarchy or directiy from the trials that did report the SD of BP change.

From the included studies, the best estimate of the maximal BP lowering efficacy of amlodipine occurring at 5 to 10 mg/day is -10.72 mm Hg (95% CI: -12.30, -9.14) for SBP and -5.73 mm Hg (95% CI: -6.65, -4.82) for DBP. The log dose-response curve is displayed in Figure 3. A funnel plot of the amlodipine studies at starting dose (5 mg) and above

showed an absence of small negative-result trials (Figure 4). Thus, publication bias is likely

and the best estimate of the blood pressure lowering efficacy of amlodipine is likely an

overestimate of the actual effect size.

151 5n Log Dose Change in SBP I 0.25 0.50 0.75 Change in DBP

CL m

o J -20

Figure 3. Log dose-response curve for amlodipine, 1.25-10 mg/day.

Review:. Blood pressure.lowering efficacy of.caldium channel blockers for primary hypertension Comparison: 01 Dose Amlodipine vs. placebo : Outcome: 0t change in-Systolic Blood Pressure SE(WMD)

+4

-100 -50 50 100 WMD (fixed)

Figure 4. Funnel plot of standard error against effect size of change in SBP for amlodipine 5 to 20 mg/day. Each dot represents an active treatment group.

152 3.7.2 Barnidipine vs. placebo

Table 35: Blood pressure lowering efficacy of barnidipine 10-30 mg/day.

Dose of # of trials Total # patients Change in SBP Change in DBP Barnidipine in treatment (mm Hg) (mm Hg) group 10 mg/day 1 50 -3.20 -2.70 (-8.61,2.21) (-5.78, 0.38) 20 mg/day 1 45 -3.40 -3.20 (-8.95, 2.15) (-6.58, 0.18) 30 mg/day 1 45 -5.80* -4.90* (-11.35, -0.25) (-8.06, -1.74) statistically significant difference from placebo

Only 1 trial assessed barnidipine (Hart 1997) and there was no statistically significant difference between all three doses tested but only the 30 mg/day dose decreased BP compared with placebo. The paucity of data is reflected in the wide confidence intervals.

Not enough doses were tested to allow a meaningful dose-response curve to be constructed.

The lowest effective dose is 30 mg/day. Based on this one trial, the blood pressure lowering effect across all doses of barnidipine is -4.12 mm Hg (95% CI: -7.29, -0.94) for SBP and -

3.60 mm Hg (95% CI: -5.45, -1.75) for DBP. Out of the doses tested, the maximal blood pressure lowering efficacy of barnidipine also occurs at 30 mg/day (-5.80/-4.90 mm Hg) but the true maximal effect cannot be estimated since doses above 30 mg/day have not been tested.

153 3.7.3 Darodipine vs. placebo

Table 36: Blood pressure lowering efficacy of darodipine 100-300 mg/day.

Dose of # of trials Total # of Change in SBP, Change in DBP, Darodipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 100 mg/day 1 13 -16.70* -6.70 (-29.05, -4.35) (-14.48, 1.08) 200 mg/day 1 9 -24.80* -14.10* (-39.88, -9.72) (-22.69, -5.51) 300 mg/ day 1 11 -15.70* -11.40* (-28.30, -3.10) (-19.35, -3.45) * statistically significant difference from placebo

Only 1 trial assessed darodipine (Chrysant 1988) and there was no statistically significant difference between any of the three doses tested. All doses had statistically significant difference compared with placebo except for change in DBP in the 100 mg/day group. From the available data, the lowest effective dose is 100 mg/day, but it may occur at a lower dose for which there are no data. It is unclear if the doses tested in this trial reflect the plateau of the dose-response curve or if doses above 300 mg/day have greater efficacy.

Thus the true maximal blood pressure lowering efficacy of darodipine cannot be estimated.

However, from the data that are available, it appears that the lowest dose with maximal blood pressure lowering efficacy is 100 mg/day. Maximum efficacy may be achieved at doses lower than 100 mg/day but again there are no available data. The overall blood pressure lowering effect across all doses of darodipine is -18.40 mm Hg (95% CI: -26.02, -

10.79) for SBP and -10.51 mm Hg (95% CI: -15.17, -5.84) for DBP. However, since this result is based on one trial in a small number of individuals, its uncertainty is reflected by the wide confidence limits.

154 3.7.4 Felodipine vs. placebo

Table 37: Blood pressure lowering efficacy of felodipine 2.5-20 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Felodipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) . 2.5 mg/day 5 407 -5.02* -3.16* (-7.25, -2.79) (-4.53,-1.79) 5 mg/day 6 293 -5.42* -5.12* (-8.03, -2.81) (-6.39, -3.86) # 10 mg/day 8 335 -10.10*# _7 79* (-11.95, -8.24) (-8.75, -6.83) 20 mg/day 3 87 -6.26* -4.80* (-10.07, -2.44) (-6.70, -2.90) * statistically significant difference from placebo * statistically significant heterogeneity

All doses of felodipine resulted in statistically significant reduction in blood pressure compared with placebo. Thus, the lowest effective dose is 2.5 mg/day. However, the true lowest effective dose may be lower than 2.5 mg/day but there are no data available. The 10 mg/day dose had significant inter-study heterogeneity and had statistically significant differences in effect size compared with all other doses tested, even 20 mg/day. However, the result for 20 mg/day is based on only 87 patients, compared with 335 patients in the 10 mg/day category. Differences in baseline BP did not account for this result. The weighted mean baseline BP was 158.3/101.0 mm Hg in the 10 mg/day group and 162.7/103.8 mm

Hg in the 20 mg/day group. The true lowest effective dose may be lower than 10 mg/day but there are no data available

Differences in the time of BP measurement relative to dosing appear to account for the superior response observed in the 10 mg/day group. In 9 out of 11 trials, the BP measurements were taken at trough, whereas in one trial BP measurements were taken at 2-3 hours post-dose (Kiesewetter 1994) and in another trial the time of measurement was not

155 reported (Fetter 1994). Sensitivity analysis excluding Kiesewetter 1994 and Fetter 1994, both of which tested 10 mg/day vs. placebo, decreased the effect size of this dose [SBP: -7.86 mm

Hg (-10.24, -5.49); DBP: -5.66 mm Hg (-6.90, -4.42)], such that the differences between 5-,

10- and 20 mg/day doses were no longer statistically significant. As well, the heterogeneity in the 10 mg/day group was no longer statistically significant when these 2 trials were removed.

Two felodipine trials had a study population of mean age > 60 years (Black 2001 and van Ree 1996) and one trial reported data separately for older and younger patients (Fagan

1993). Subgroup analysis of studies with patients of mean age > 60 years demonstrated a statistically significandy greater reduction in SBP at 5 mg/day and in DBP at 2.5- and 5 mg/day compared with the younger subgroup. Doses above 5 mg/day were not tested in those trials with mean age of patients > 60 years.

Table 38: Blood pressure lowering efficacy of felodipine in older and younger subgroups Dose of Change in SBP, mm Hg (95% Cf) Change in DBP, mm Hg (95% Cf) felodipine < 60 years > 60 years < 60 years > 60 years 2.5 mg/day -3.61 -6.27 -2.44 -5.55 (-6.37, -0.85) (-9.44, -3.10) (-3.80, -1.09) (-9.17,-1.93) 5 mg/day -4.80 -11.40 -4.87 -11.80 (-7.55, -2.06) (-19.95, -2.85) (-6.15, -3.58) (-18.35, -5.25)

All trials which reported the formulation of felodipine analysed the once-daily extended-release formulation, except the Felodipine Co-op study which tested a twice-daily

formulation.

Trials with inclusion criteria of elevated SBP (> 140 mg) consisted of Black 2001,

Kiesewetter 1994 and van Ree 1996 (Table 39 below). This subgroup demonstrated a

statistically significandy greater response compared with those trials with inclusion criteria of

elevated DBP only. Flowever, this conclusion is based on a small number of patients with

156 elevated SBP. This factor accounted for some but not all of the heterogeneity in the 10 mg/day analysis.

Table 39: Blood pressure lowering efficacy in trials with inclusion criteria of

Dose of Change in SBP, mm Hg (95% CI) Change in DBP, mm Hg (95% CI) felodipine Elevated SBP Elevated DBP Elevated SBP Elevated DBP 2.5 mg/day -5.75 -4.53 -6.60 -2.99 (-9.37, -2.14) (-7.40, -1.67) (-12.79, -0.41) (-4.39, -1.58) 5 mg/day -11.40 -4.80 -11.80 -4.87 (-19.95, -2.85) (-7.55, -2.06) (-18.35, -5.25) (-6.15, -3.58) 10 mg/ day -13.00 -8.59 -11.00 -5.90 (-16.16, -9.84) (-10.88, -6.30) (-12.57, -9.43) (-7.10, -4.70)

Sensitivity analyses were performed to assess the robustness of the results. A sensitivity analysis removing trials that measured BP in standing or supine positions did not change the results. Four trials reported the variance of the change in BP, whereas the 7 remaining trials used imputed values. The results were unchanged whether the values were imputed according to the hierarchy or imputed direcdy from the weighted mean values from all trials that reported the SD of BP change.

All trials were of moderate quality (Jadad score of 3 or 4 out of 5) and thus, a sensitivity analysis based on trial quality was not possible. Blood pressures were measured by sphygmomanometer in all trials that reported the instrument used. All trials that reported sources of funding had some funding from pharmaceutical companies involved in the development and marketing of felodipine.

Using indirect comparisons, there was no statistically significant difference in trough effect sizes between doses of 2.5-20 mg/day for SBP. For DBP, the 5 mg and 10 mg/day doses each showed a statistically significant difference from the 2.5 mg/day dose, but the magnitude of the differences was of questionaable clinical significance (1.96 mm Fig and 2.5 mm Fig, respectively). Using the subset of multi-arm trials in the direct comparison analysis,

157 the 10 mg/day dose was statistically significantly greater than 2.5 mg/day and 5 mg/day.

However, there was no statistically significant difference between the direct and indirect methods for all dose comparisons. In order to include a greater amount of data, the results using the indirect method were used to determine the maximal blood pressure lowering efficacy. The best estimate of the maximal blood pressure-lowering efficacy at trough for felodipine 2.5 to 20 mg/day is -6.11 mm Hg (-7.41, -4.82) for SBP and -4.75 mm Hg (-5.44, -

4.05) for DBP.

A funnel plot of standard error vs. WMD of the starting dose (5 mg/day) and above demonstrates asymmetry, with an absence of negative-result trials of small sample size

(Figure 5). Thus, publication bias may be present and if so, the estimate of the blood pressure lowering efficacy of felodipine is an overestimate of the actual effect size.

Revieyy:.' "Bipod pressure lowering efficacy of calcium channel blockers' for primary-hypertension Comparison: 04 Dose Felodipine vs. placebo Outcome: 01 Change1 in Systolic Blood Pressure

T 0 SE(WMD)

•

+3

-100 -50 50 100. WMD (fixed)

Figure 5. Funnel plot of standard error against effect size of change in SBP for felodipine 5 to 20 mg/day. Each dot represents an active treatment group.

158 3.7.5 Isradipine vs. placebo

Table 40: Blood pressure lowering efficacy of isradipine 1-20 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Isradipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 1 mg/day 1 . 44 -6.00* -1.00 (-11.35, -0.65) (-4.70, 2.70) 2.5 mg/day 4 181 -8.44* -5.22* (-11.73, -5.15) (-7.21, -3.23) 5 mg/day 10 484 -10.25*# -7.82*# (-12.00, -8.50) (-8.85, -6.79) 10 mg/day 4 143 -16.46* -11.55* (-19.75, -13.18) (-13.49, -9.61) 15 mg/day 2 112 -17.00* -10.84* (-20.79, -13.20) (-13.00, -8.69) 20 mg/day 2 107 -15.57* -11.48* (-19.25, -11.89) (-13.80, -9.17) * statistically significant difference from placebo statistically significant heterogeneity

All doses of isradipine showed a statistically significant reduction in BP compared with placebo, except for change in DBP in the 1 mg/day group. Indirect comparisons showed that the 10-, 15-, and 20 mg/day groups were not significandy different from each other but all were statistically greater than the 1-, 2.5- and 5 mg/day groups. There was

statistically significant heterogeneity in the 5 mg/day analysis.

A subgroup analysis was performed on drug formulation (twice daily versus once-daily

sustained release). The twice-daily formulation at 5 mg showed a statistically significantly greater blood pressure lowering as compared to the sustained-release formulation (Table 41).

159 Table 41: Blood pressure lowering efficacy of isradi nne according to formulation Dose of Change in SBP, mm Hg Change in DBP, mm Hg isradipine (95% CI) . (95% CI) Twice-daily Sustained- Twice-daily Sustained- release release 2.5 mg -8.77 -8.12 -6.09 -4.35 (-13.47,-4.07) (-12.73, -3.51) (-8.91, -3.27) (-7.15,-1.56) 5mg -12.49 -7.69 -8.98 -6.55 (-14.85, -10.13) (-10.37, -5.01) (-10.40, -7.56) (-8.03, -5.07) 10 mg -18.62 -15.36 -13.45 -10.17 (-23.81, -13.43). (-19.98, -10.74) (-16.45, -10.46) (-12.70, -7.63) 15 mg -20.20 -15.60 -11.90 -10.20 (-27.09, -13.31) (-20.64, -10.56) (-15.40, -8.40) (-12.92, -7.48) 20 mg -15.70 -15.50 -10.70 -11.80 (-21.93, -9.47) (-20.40, -10.60) (-15.03, -6.37) (-14.53, -9.07)

The robustness of the effect sizes were tested with sensitivity analyses. Removing trials that measured BP at peak or that did not report time of BP measurement reduced the blood pressure lowering effect of isradipine 5 mg/day to -6.99 mm Hg (-9.41, -4.57) for SBP and -4.54 mm Hg (-5.91, -3.16) for DBP. The analysis did not change the results of other doses, f f the low quality trials (Jadad score < 2) were removed, the effect size of 5 mg/day dose is significandy reduced to -7.24 mm Hg (-9.36, -5.12) for SBP and -5.71 mm Pig (-6.92,

-4.49) for DBP. The results at all other doses were not altered with the removal of low quality trials. The effect size at 5 mg/day was affected by whether the SD of BP change was imputed according to the hierarchy or imputed direcdy from the weighted mean values from all trials that reported the SD of BP change, fn the latter case, the change in SBP was -7.75 mm Hg (-9.71, -5.79) and the change in DBP was -5.59 mm Hg (-6.72, -4.4). This discrepancy is mosdy likely accounted for by the low endpoint variances which were reported in the O'Grady 1997 and Youssef 1992 trials and which were used to impute the

SD of change in BP using the hierarchy.

160 Removing trials that did not measure BP in the sitting position or did not report position of measurement only altered the effect size at 5 mg/day, with a change in SBP of -

5.21 mm Hg (95% CI -8.13, -2.29) and a change in DBP of-4.61 mm Hg (95% CI -6.19, -

3.03).

Only three trials reported funding sources, and all three had industry funding. Only one small trial used an automatic device to measure BP (Arosio 1993), while the rest used the auscultatory method with mercury sphygmomanometers. Removing this trial did not alter the results. In one trial (O'Grady 1997) all patients had active atherosclerotic lesions.

Again, removing this trial did not change the effect size.

The lowest dose with maximal BP lowering occurs at 10 mg/day. At trough, the best estimate of the maximal blood pressure lowering effect at 10 to 20 mg/day is -14.84 mm Hg (-17.47, -12.20) for SBP and -10.57 mm Hg (-12.15, -8.98) for DBP. This estimate is based on only one clinical trial (Chrysant 1995); thus, the confidence intervals are wide.

Funnel plots of the starting dose (5 mg/day) and above showed there was a possibility of publication bias since there was some asymmetry in the shape of the plot.

161 3.7.6 Lacidipine vs. placebo

Table 42: Blood pressure lowering efficacy of lacidipine 2-4 mg/day.

Dose of # of trials Total # of Change in SBP, Change in DBP, Lacidipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 2 mg/day 1 46 -4.00 -3.10* (-9.92, 1.92) (-6.10, -0.19) 4 mg/day 1 39 -7.00* -4.20* (-13.17,-0.83) (-7.67, -0.73) * statistically significant difference from placebo

Only 1 included trial assessed lacidipine (Rizzini 1991). The study's population was comprised of elderly hypertensives. Compared with placebo, the 2 mg/day group had a

statistically significant reduction in DBP but not SBP. The lowest effective dose is 4 mg/day, which showed a statistically significant difference from 2 mg/day.

Because there was no data for doses above 4 mg/day, the true maximal blood pressure lowering efficacy cannot be estimated. However, based on the available data, blood

pressure lowering occurs at 4 mg/day has a magnitude of -7.00 mm Hg (-13.17, -0.83) for

SBP and -4.20 mm Hg (-7.67, -0.73) for DBP.

162 3.7.7 Lercanidipine vs. placebo

Table 43: Blood pressure lowering efficacy of lercanidipine 2.5-20 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Lercanidipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 2.5 mg/day 1 58 -1.20 -1.90 (-5.56, 3.16) (-4.89, 1.09) 5 mg/ day 1 54 -3.80 -3.60* (-8.28, 0.68) (-6.58, -0.62) 10 mg/day 4 184 -11.31** -4.31* (-13.82, -8.79) (-5.89, -2.72) 20 mg/day 1 9 -9.60 -4.57* (-22.05, 2.85) (-7.11, -2.03) * statistically significant difference from placebo # statistically significant heterogeneity

The 2.5 mg/day group did not show a statistically significant difference from placebo. There does not appear to be a statistically significant difference between the 10 and

20 mg/day doses in change in SBP, and between 5-20 mg/day in the change in DBP. There was statistically significant heterogeneity in the 10 mg/day group. The 20 mg/day dose did not show a statistically significant difference compared with placebo but this is likely due to the lack of data at this dose.

Two trials that assessed lercanidipine 10 mg/day were performed in older patients with high baseline SBP (Barbagallo 2000 and Ninci 1997). In this subgroup, the change in

SBP was -14.55 mm Fig (-17.69, -11.40) and the change in DBP was -3.90 mm Hg (-5.85, -

1.96). In contrast, the change in SBP in the trials with mean age < 60 years was -5.60 mm

Hg (-9.74, -1.45), while the change in DBP was similar to that of the older age subgroup at -

5.08 mm Hg (-7.79, -2.37).

One trial selected patients based on elevated SBP (Barbagallo 2000) and did not report the timing of the BP measurement. Removal of this trial accounted for the heterogeneity in the 10 mg/day analysis and statistically significantly reduced the change in

163 SBP to -6.60 mm Hg (-9.71, -3.49) but did not alter the change in DBP, which was -4.65 mm

Hg (-6.57, -2.72).

One of the included trials was of low quality (Rimoldi 1993). Removal of this trial did not change the results in a statistically significant way. All trials that reported details regarding the instrument and timing of measurement had trough BPs taken by auscultation.

Only one trial in the analysis measured BP in the sitting position (Ninci 1997). The SD of the BP change was reported in only 1 trial (Omboni 1998) and imputed for the rest of the trials, fmputing using the hierarchy or direcdy from all trials that reported SD of BP change did not alter the results.

The best estimate of the maximal blood pressure lowering efficacy of lercanidipine at

10-20 mg/day is -11.24 mm Hg (-13.71, -8.78) for SBP and -4.38 mm Hg (-5.72, -3.03) for

DBP.

164 3.7.8 Manidipine vs. placebo

Table 44: Blood pressure lowering efficacy of manidipine 10-40 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Manidipine patients in mm Hg mm Fig treatment group (95% CI) (95% CI) 10 mg/day 2 40 -10.37* -4.89* (-15.31, -5.43) (-7.64, -2.13) 20 mg/day 1 12 -20.10* -11.00* (-30.92, -9.28) (-17.16, -4.84) 40 mg/day 1 13 -23.50* -14.40* (-34.11, -12.89) (-20.43, -8.37) * statistically significant difference from placebo

Two of the included trials evaluated manidipine. All manidipine doses demonstrated a statistically significant reduction in BP compared with placebo. One trial (Fogari 1999) was performed in elderly subjects (mean age of 81.8 years), and had a similar effect size compared with the trial performed in younger patients (Fogari 1996, mean age of 53.4 years).

Considering all the doses tested, the lowest effective dose is 10 mg/day. The true lowest effective dose may be lower than 10 mg/day but there are no data available. Indirect comparisons showed that the effect sizes of the 20 and 40 mg/day doses were statistically

significantly different from that of the 10 mg/day dose. Based on the data from two trials, the maximal blood pressure lowering efficacy of manidipine at 20-40 mg/day is -21.83 mm

Hg (-29.33, -14.34) and -12.73 mm Hg (-17.02, -8.45) for SBP and DBP, respectively; however, because of the small number of patients, this is uncertain.

165 3.7.9 Nicardipine vs. placebo

Table 45: Blood pressure lowering efficacy of nicardipine 40 - 120 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Nicardipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 40 mg/day 1 15 -19.50* -7.40* (-25.26,-13.74) (-13.27,-1.53) 60 mg/day 2 68 -6.49* -3.86* (-11.67, -1.31) (-6.50, -1.22) 80 mg/day 2 39 -15.37* -11.39* (-22.97, -7.77) (-15.39, -7.39) 90 mg/ day 2 79 -13.92* -6.02* (-18.70, -9.13) (-8.52, -3.52) 100 mg/day 2 38 -13.48* -9.21* (-19.46, -7.50) (-13.75, -4.66) 120 mg/day 1 60 -10.50 * -6.40* (-15.91,-5.09) (-9.11,-3.69) * statistically significant difference from placebo

Nine of the included trials assessed nicardipine, encompassing a dose range of 40 mg/day to 120 mg/day, but there were few studies at each dose. All doses exhibited a statistically significandy reduction in SBP and DBP compared with placebo. Considering the data available at the doses tested, the lowest effective dose is 40 mg/day. In reality the lowest effective dose may be lower than 40 mg/day but there are no available data.

Scuteri 1992 was the only trial that assessed the efficacy of nicardipine at 40 mg/day.

The study population consisted of hospitalized patients with mean age 76 years and baseline

BP of 171/97. The quality of this trial was low (Jadad score = 2) and the trial did not report the timing of the BP measurements. These reasons may account for the large response at 40 mg/day.

Three trials did not report the timing of blood pressure measurement (Asplund 1985,

Marcadet 1991, Scuteri 1992). If these trials are removed, there is no statistically significant

166 difference between any of the doses (60 mg/day-120 mg/day), using the indirect comparison method.

Two of the eight included nicardipine trials tested a thrice-daily formulation (Soro

1990 and Asplund 1985), while the remainder tested a slow-release twice-daily formulation.

Subgroup analysis did not show a statistically significant difference in effect size between the

formulations.

The effect size was also insensitive to the instrument used for BP measurement and

strategy used to impute missing variances.

Considering only the trials that reported trough blood pressures, the best estimate of

the maximal BP lowering efficacy of nicardipine occurring at 60 to 120 mg/day is -10.49 mm

Hg (95% CI: -13.20, -7.77) for SBP and -5.98 mm Hg (95% Cf: -7.38, -4.57) for DBP.

167 3.7.10 Nifedipine vs. placebo

Table 46: Blood pressure lowering efficacy of nifedipine 20 - 100 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Nifedipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 20 mg/day 3 143 -5.83 *# -5.06*# (-8.82, -2.84) (-6.93, -3.18) 30 mg/day 4 118 -9.79 * -6.72*# (-12.89, -6.69) (-8.52, -4.92) 40 mg/day 3 57 -29.39** -16.65# (-35.01, -23.78) (-19.90, -13.40) 50 mg/day 1 42 -4.40 -4.60*# (-10.53, 1.73) (-8.05,-1.15) 60 mg/day 5 157 -12.72* -7.32*# (-15.70, -9.74) (-8.95, -5.70) 90 mg/day 1 55 -13.60* -6.80*# (-18.45, -8.75) (-9.57, -4.03) 100 mg/day 1 38 -5.80 -6.50*# (-12.07, 0.47) (-10.03, -2.97) * statistically significant difference from placebo statistically significant heterogeneity

Twelve of the included trials assessed nifedipine. All doses exhibited a statistically significant difference from placebo for change in DBP. All doses except 50 mg/day and 100 mg/day showed a statistically significant difference from placebo in the change in SBP. This discrepant result is likely because there was only one trial (Carr 1992) for the 50 and 100 mg/day doses. The lowest effective dose is 20 mg/day but it may actually be lower; however, data are not available for doses under 20 mg/day.

One trial in the 40 mg/day group (Fadayomi 1986) had an exaggerated effect size of

-58.4/-31.7 mm Hg. This trial population consisted of 32 black patients, 12 who were newly diagnosed and the remaining who were inadequately controlled on therapies other than

CCBs; the baseline BP was 180/114 mm Hg. The publication had reported individual patient data for 30 patients, but blood pressures were measured to the nearest 5 mm Hg and the timing of the BP measurement was not reported. Because there is a large reduction in the standard deviation of SBP from baseline (15.3 mm Hg) to endpoint (8.0 mm Hg) - a pattern that is inconsistent with the pooled data of this systematic review - blinding may have been compromised in this trial and data from this trial must be viewed with suspicion.

A sensitivity analysis was performed in which trials with trough measurements were retained and trials that did not report timing of BP measurement were removed (de Simone

1985, Eggertsen 1982, Fadayomi 1986, Ferrera 1984, Serradimigni 1985). In this analysis, there were no trials remaining in the 40 mg/day group, and there was no statistically significant difference between the 30, 60 and 90 mg/day doses. There was a statistically significant difference between 20 mg/day and 30 mg/day for reduction in SBP but not for

DBP.

There was statistically significant heterogeneity in every dose group in the change in

DBP. While the heterogeneity in the 20 mg/day group was resolved by removing trials that did not report timing of the BP measurement, the heterogeneity in the other doses remained and could not be explained by any of the predefined sensitivity/subgroup analyses.

The best estimate of the maximal blood pressure lowering efficacy at trough for 30 to 100 mg/day is -9.11 mm Fig (-10.69, -7.54) for SBP and -6.14 mm Hg (-7.04, -5.23) for

DBP.

169 3.7.11. Nilvadipine vs. placebo

Table 47: Blood pressure lowering efficacy of nilvadipine 8-30 mg/day.

Dose of # of trials Total # of Change in SBP, Change in DBP, Nilvadipine padents in mm Hg mm Hg treatment group (95% Cf) (95% CI) 8 rng/ day 1 60 -10.90* -5.50* (-16.58, -5.22) (-8.82,-2.18) 16 mg/day 1 49 -11.00* -7.80* (-17.10, -4.90) (-11.88, -3.72) 18 mg/day 1 17 Not reported -7.00* (-12.53,-1.47) 24 mg/day 1 19 Not reported -6.80* (-12.07,-1.53) 30 mg/day 1 20 Not reported -8.20* (-13.40, -3.00) statistically significant difference from placebo

Only 2 included trials evaluated the blood pressure lowering efficacy of nilvadipine:

Hoffmann 1997 tested 8-16 mg/day and Weir 1990 tested 18-30 mg/day. Although all nilvadipine groups had a statistsically significant difference from placebo, there was no statistically significant difference between any of the doses assessed. The true maximum blood pressure lowering efficacy of nilvadipine cannot be estimated since doses below 8 mg/day and above 30 mg/day were not tested. However, based on the available data, the best estimate of the maximal BP lowering efficacy of nilvadipine at trough across all doses tested (8-30 mg/day) is -10.95 mm Hg (95% CI: -15.10, -6.79) for SBP and -6.80 mm Hg

(95% Cf: -8.78, -4.83) for DBP. This result is based on data from very few patients, and hence, the confidence intervals are wide.

170 3.7.12 Nisoldipine vs. placebo

Table 48: Blood pressure lowering efficacy of nisoldipine 10-30mg/day.

Dose of # of trials Total # of Change in SBP, Change in DBP, Nisoldipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 10 mg/ day 1 49 -9.50* -6.90* (-15.43, -3.57) (-9.87, -3.93) 20 mg/day 1 51 -15.90* -9.20* (-21.77, -10.03) (-12.10, -6.30) 30 mg/day 1 48 -16.20* -10.60* (-22.09, -10.31) (-13.51, -7.69) statistically significant difference from placebo

One included trial assessed nisolidipine at doses of 10, 20 and 30 mg/day (Opie

1997). All doses demonstrated a statistically significant reduction in BP compared with placebo. Using indirect comparisons there was no statistically significant difference between any of the doses. Based on the results of this one small trial, the best estimate of maximal blood pressure lowering efficacy for nisoldipine 10-30 mg/day is -13.89 mm Hg (95% CI: -

17.30, -10.49) for SBP and -8.93 mm Hg (95 % CI: -10.62, -7.24) for DBP. However, because of the lack of data and doses tested, this result provides very limited information regarding the dose-response of nisolidipine.

171 3.7.13 Nitrendipine vs. placebo

Table 49: Blood pressure lowering efficacy of nitrendipine 5-20 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Nitrendipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 5 mg/day 1 20 -2.00 -2.00 (-10.69, 6.69) (-7.88, 3.88) 10 mg/day 3 129 -8.34* -5.50*# (-11.38, -5.30) (-7.00, -4.00) 20 mg/day 8 154 -13.80*# -9.46*# (-17.12, -10.49) (-11.54, -7.38) * statistically significant difference from placebo # statistically significant heterogeneity

Nitrendipine at 5 mg/day did not statistically significantiy reduce blood pressure compared with placebo. The lowest effective dose was 10 mg/day. Indirect comparisons did not show a statistically significant difference between the 5 and 10 mg/day groups. The

20 mg/day group demonstrated a statistically significant difference from both the 5 and 10 mg/day groups.

There was statistically significant heterogeneity in the 20 mg/day group, most notably in DBP (I2=88.9%). One trial had inclusion criteria of isolated systolic hypertension

(Paolisso 1991) and a concomitant high baseline SBP (> 170 mm Hg). Removing this trial and another trial with high baseline (Maclean 1990) reduced the heterogeneity in the 20 mg/day group but it was still statistically significant. Six of the ten included studies were of low quality (Jadad score of 2). If these trials are excluded, litde data remain in the analysis but the heterogeneity is no longer statistically significant and the resultant effect size in the

20 mg/day group is -9.17 mm Hg (-12.12, -6.21) for SBP and -6.06 mm Hg (-7.47, -4.65) for

DBP.

172 Two studies had a mean age of participants > 60 years (Gerritsen 1998 and Paolisso

1991) but there were not enough data for a subgroup analysis based on age.

The best estimate of the maximal trough blood pressure lowering efficacy at 20 mg/day is -13.80 mm Hg (-17.12, -10.49) for SBP and -9.46 (-11.54, -7.38) for DBP. The heterogeneity observed in this dose could only be accounted for by removing low quality studies.

173 3.7.14 Ptanidipine vs. placebo

Table 50: Blood pressure lowering efficacy of pranidipine 1-8 mg/day.

Dose of # of trials Total # of Change in SBP, Change in DBP, Pranidipine patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 1 mg/day 1 36 -4.00 -4.00 (-12.32, 4.32) (-11.06, 3.06) 2 mg/day 1 37 -10.00* -6.00* (-18.31, -1.69) (-10.38, -1.62) 4 mg/day 1 34 -10.00* -10.00* (-18.32,-1.68) (-15.55, -4.45) 8 mg/day 1 37 -9.00* -8.00* (-17.31, -0.69) (-13.55, -2.45) * statistically significant difference from placebo

One multiarm trial evaluated the blood pressure lowering efficacy of pranidipine

(Rosenthal 1996). The mean blood pressures reported in this study were rounded to the nearest mm Fig. The 1 mg/day dose did not exhibit a statistically significant reduction in blood pressure compared with placebo. The lowest effective dose was 2 mg/day. However there was no statistically significant difference between any of the doses tested in change in

SBP or DBP. Based on the results of the doses tested in this trial, the best estimate of the maximal trough blood pressure lowering effect of pranidipine at 2 to 8 mg/day is -9.67 mm

Hg (95% CI: -14.47, -4.87) for SBP and -7.66 (95% CI: -10.59, -4.74) for DBP.

174 3.7.15 Summary of blood pressure lowering efficacy of dihydropyridines

Table 51: Summary of blood pressure lowering efficacy of dihydropyridines Dihydropyridine Lowest Lowest dose Magnitude of maximal trough BP drug effective with maximal lowering (mm Hg), 95% CI dose BP lowering (mg/day)*# (mg/day)A# SBP DBP Amlodipine 2.5 mg 5mg -10.72 -5.73 (-12.30, -9.14) (-6.65, -4.82) Barnidipine 30 mg 30 mg -5.80 -4.90 (-11.35, -0.25) (-8.06,-1.74) Darodipine fOOmg 100 mg -18.40 -10.51 (-26.02, -10.79) (-15.17, -5.84) Felodipine 2.5 mg 2.5 mg -6.11 -4.75 (-7.41, -4.82) (-5.44, -4.05) Isradipine 1 mg 10 mg -14.84 -10.57 (-17.47, -12.20) (-12.15, -8.98) Lacidipine 4mg 4mg -7.00 -4.20 (-13.17, -0.83) (-7.67, -0.73) Lercanidipine 10 mg 10 mg -11.24 -4.38 (-13.71, -8.78) (-5.72, -3.03) Manidipine fOmg 20 mg -21.83 -12.73 (-29.33, -14.34) (-17.02, -8.45) Nicardipine 40 mg 60 mg -10.49 -5.98 (-13.20, -7.77) (-7.38, -4.57) Nifedipine 20 mg 30 mg -9.11 -6.14 (-10.69, -7.54) (-7.04, -5.23) Nilvadipine 8mg 8mg -10.95 -6.80 (-15.10, -6.79) (-8.78, -4.83) Nisoldipine 10 mg 10 mg -13.89 -8.93 (-17.30, -10.49) (-10.62, -7.24) Nitrendipine 10 mg 20 mg -13.80 -9.46 (-17.12, -10.49) (-11.54, -7.38) Pranidipine 2mg 2 mg -9.67 -7.66 (-14.47, -4.87) (-10.59, -4.74) * The lowest effective dose is the lowest dose for which t lere is a statistically significant difference vs. placebo A The lowest dose with maximal blood pressure lowering efficacy is achieved at the dose that exhibits a statistically significantly greater response than all other doses lower than it, whereas doses higher than it do not exhibit a statistically significant difference in effect size. # If there was a discrepancy between the determined dose for SBP and DBP, that of SBP is used.

Dihydropyridines were pooled from trials reporting trough blood pressures and were

grouped according to increments of the manufactuer's recommended starting dose (Table

175 52). A dose-response is present, with a statistically significant difference between increasing dose increments, except between the two highest dose groups. Thus, maximal BP lowering is achieved at a mean dose of 2.3 times the starting dose and above. The best estimate of the maximal BP lowering for the dihydopyridine subclass is -10.51 mm Hg (-11.47, -9.56) for

SBP and -6.92 mm Hg (-7.42, -6.41) for DBP.

Table 52: Blood pressure lowering efficacy of dihydropyridines combined according to multiples of starting dose Dose WMD for change WMD for change (expressed as multiple of starting dose, x) in SBP, mm Hg in DBP, mm Hg Range Mean (95% CI) (95% CI)

>0.5x

>lx < 2x 1.1 X -8.26* -5.14* (-9.14, -7.38) (-5.64, -4.64) > 2x < 4x 2.3 x -10.13* -6.65* (-11.25, -9.02) (-7.22, -6.07) > 4x 4.1 x -11.54* -7.81* (-13.38, -9.7) (-8.86, -6.76) statistically significant difference from placebo

3.7.15.1 Dihydropyridines - Analysis of publication bias

3.7.15.1.1. Subgroup analysis based on trial size

A post-hoc analysis was done to determine the relationship between the magnitude of blood pressure lowering and trial size. To perform a subgroup analysis based on trial size, active treatment arms were categorized into tertiles: the lowest representing the smallest trials, the highest representing the largest trials, and a middle tertile of medium-sized trials.

For the sake of consistency, only trials that reported trough BP data were included in this analysis. For dihydropyridines, comparison of the lowest tertile (n=8-27 patients) and highest tertiles (n=48-183 patients) demonstrated statistically significant differences in effect

176 size for both SBP and DBP, with larger and more variable effect sizes seen in the smaller trials (Table 53).

Table 53: Dihydropyridines: post-hoc subgroup analysis of trough BP lowering based on trial size Dihydropyridines, Lowest tertile Highest tertile Trough measurements (8-27 patients) (48-183 patients) Mean of WMD for change in -12.6 mm Hg (6.4) -9.0 mm Hg (4.1) SBP (SD) # of observations 25 27 t-test low vs. high tertile p = 0.02 Mean of WMD for change in -9.1 mm Hg (5.2) -5.4 mm Hg (2.2) DBP (SD) # of observations 28 28 t-test low vs. high tertile p = 0.001

To obtain another estimate of the maximal blood pressure lowering efficacy of dihydropyridines, the tertile analysis was restricted to trials with doses greater than or equal to twice the starting dose. Combined, the middle and highest tertiles give an estimate of -9.1 mm Hg (95% CI: -10.8, -7.4) for maximal change in SBP and -6.0 mm Hg (95% CI: -5.2, -

6.9) for maximal change in DBP.

3.7.15.1.2. Trim-and-fill method of adjusting for publication bias

The nonparametric ttim-and-fill method was used to adjust the effect size for the presence of publication bias (376). The funnel plot of the maximal blood pressure lowering efficacy of dihydropyridines at greater than or equal to twice the starting dose showed asymmetry, with an absence of negative-result trials (Figures 6 and 7). Data points were filled in to make the funnel plot symmetrical and a new effect size was calculated. For change in SBP, seven data points were filled in and the adjusted effect size was -10.15 mm

Fig (-11.08, -9.22). For change in DBP, five data points were filled in and the resulting adjusted effect size was -6.67 mm Hg (-7.17, -6.17). Thus, the original effect size was overestimated by at least 0.4 mm Hg for change in SBP, and by at least 0.3 mm Hg for change in DBP.

'Review: ;Blo6d pressure lowering efficacy of calcium channel blockers-for primary^hypertensibn Comparison: 20 Dihydropyridines - analysis based on multiples of starting dose -Outcome: 05 SBP Maximal BP lowering

0 SE(WMD)

+6

•

-100 ^50 50 .100 WMD (fixed)

Figure 6. Funnel plot of change in SBP for dihydropyridines at maximal blood pressure lowering. Each dot represents an active treatment group at >2 times the starting dose.

178 Review;. Blood pressure loweringefficacypt Comparison: 20 Dihydropyridines - analysis based on multiples of starting dose Outcome: 06 DBP Maximal BP lowering -r0 SEiyVMD)

•A-

•

+ 6

-too :50 100 WMO (fixed)

Figure 7. Funnel plot of change in DBP for dihydropyridines at maximal blood pressure lowering efficacy. Each dot represents an active treatment group at >2 times the starting dose.

179 3.7.16 Diltiazem vs. placebo

Table 54: Blood pressure lowering efficacy of diltiazem 90 - 540 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Diltiazem patients in mm Hg mm Hg treatment group (95% Cf) (95% CI) 90 mg/day 1 46 -2.20 -0.50 (-7.80, 3.40) (-3.71, 2.71) 120 mg/day 5 329 -2.91* -2.32*# (-4.85, -0.97) (-3.35,-1.28) 180 mg/day 3 236 -4.12* -2.61* (-6.54, -1.70) (-3.97,-1.26) 240 mg/day 6 224 -6.50*# -4.04*# (-8.99, -4.02) (-5.13, -2.95) 300 mg/day 3 92 -7.13* -6.47* (-10.85, -3.41) (-8.49, -4.44) 360 mg/day 4 163 -6.28* -4.96* (-9.30, -3.26) (-6.55, -3.36) 480 mg/day 1 54 -10.80* -6.30* (-15.81,-5.79) (-9.20, -3.40) 540 mg/day 1 47 -9.50* -7.90* (-15.35, -3.65) (-10.98,-4.82) ~y statistically significant difference from placebo * statistically significant heterogeneity

Twelve of the included trials assessed diltiazem. The 90 mg/day dose did not show a

statistically significant difference from placebo. The lowest effective dose of diltiazem was

120 mg/day. Using indirect comparisons between doses, the lowest dose exhibiting maximal

blood pressure lowering was determined to be 240 mg/day. The best estimate of the

maximal blood pressure lowering efficacy of diltiazem for 240 to 540 mg/day is -7.18 mm

Hg (-8.74, -5.62) for SBP and -5.00 mm Fig (-5.77, -4.23) for DBP.

There was statistically significant heterogeneity in the 240 mg/day dose, which was

accounted for by removing trials with baseline BPs greater than > 160/100 mm Hg (Chan

1997, Djian 1990, Herptn 1990).

180 Two trials were performed in older patients (Chan 1997 and Fiddes 1994). The effect sizes were greater in this subgroup compared with younger patients (mean age < 60 years). Although there were not sufficient data for a subgroup analysis, removing these two trials did account for the heterogeneity observed in the 240 mg/day group.

All trials evaluated sustained-release formulations; in 9 of the trials, dosing was once- daily, while the other 3 trials used twice-daily regimens. There was no statistically significant difference in effect size between these regimens.

All trials that reported timing of BP measurement in relation to the dosing interval measured trough values. Seven trials reported funding sources and all of these had industry funding. As well, all trials were of moderate quality and had inclusion criteria of elevated

DBP. Only 2 trials reported BPs measured in the sitting position, while the remaining 10 trials had supine blood pressures. Four of the diltiazem trials reported the SD of BP change, f f trials that did not report the SD of change in BP were imputed direcdy with the weighted mean from all trials that reported this value, the result is not different than using the imputation hierarchy.

181 3.7.17 Verapamil vs. placebo

Table 55: Blood pressure lowering efficacy of verapamil 60 - 540 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Verapamil patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 60 mg/day 1 38 -3.50 -0.70 (-9.87, 2.87) (-4.03, 2.63) 100 mg/day 1 53 -1.20 -3.40* (-6.32, 3.92) (-6.24, -0.56) 120 mg/day 6 224 -0.95 -1.17 (-3.55, 1.65) (-2.66, 0.33) 180 mg/day 4 198 -3.80* -3.29* (-6.95, -0.65) (-5.02,-1.56) 200 mg/day 2 119 -5.28* -5.39* (-9.03,-1.54) (-7.53, -3.25) 240 mg/day 7 392 -9.22* -5.81* (-11.47, -6.97) (-7.03, -4.60) 300 mg/day 1 58 -8.70* -9.40* (-13.66, -3.74) (-12.09, -6.71) 360 mg/day 2 156 -10.70* -7.84* (-14.18, -7.22) (-9.93, -5.76) 400 mg/day 1 58 -8.80* -8.70* (-14.34, -3.26) (-11.57,-5.83) 480 mg/day 2 70 -6.51* -7.09* (-11.78, -1.24) (-10.00, -4.17) 540 mg/day 1 55 -17.90* -13.00* (-23.31, -12.49) (-15.92,-10.08) * statistically significant difference from placebo

Thirteen verapamil studies were included in this systematic review. There were very,

few trials at the low-end and high-end of the dose range. The lowest effective dose was 180 mg/day. The lowest dose with maximal BP lowering efficacy is 240 mg/day and the best estimate of the maximal blood pressure lowering efficacy for 240 to 540 mg/day is -9.90 mm

Hg (-11.43, -8.36) for SBP and -7.46 mm Hg (-8.30, -6.61).

Sensitivity analyses were performed to assess the robustness of the results. With the

exception of two trials that measured BP in supine position, all trials had sitting BP

measurements. Removing the two trials with supine measurements did not change the

182 results. Nine trials reported the variance of the change in BP, whereas the 4 remaining trials used imputed values. The results were insensitive to whether the values were imputed according to the hierarchy or imputed direcdy from the weighted mean value from all trials that reported the SD of BP change. One of the trials had a high baseline BP (Von

Manteuffel 1995) but excluding this trial did not alter the results, nor did removing trials with low quality. All trials tested once-daily sustained-release forms of verpamil. Subgroup analysis based on age was not possible since all trials had a mean age of < 60 years. All trials had inclusion criteria of elevated diastolic blood pressure and used sphygmomanometers to measure BP. The four trials that reported funding source were all industry-funded.

183 3.7.18 Tiapamil vs. placebo

Dose of # of trials Total # of Change in SBP, Change in DBP, Tiapamil patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 300-600 mg/day 1 24 -4.00 -1.00 (-12.90, 4.90) (-6.82, 4.82) 900-1200 1 25 -5.00 -4.00 mg/day (-13.47, 3.47) (-9.55, 1.55)

Data from the one included trial that evaluated tiapamil (Blanchett 1991) showed that doses 300-1200 mg/day did not reduce blood pressure compared with placebo. Based on this limited evidence, the lowest effective dose and the maximal blood pressure lowering efficacy of tiapamil cannot be estimated.

184 3.7.19 Summary of blood pressure lowering efficacy of non-dihydropyridines

Table 57: Summary of blood pressure lowering efficacy of non-dihydropyridines Non- Lowest effective Lowest dose Magnitude of maximal BP dihydropyridine dose (mg/day)** with maximal lowering (mm Hg) drug BP lowering SBP DBP (mg/day)A# Diltiazem 120 mg 240 mg -7.18 -5.00 (-8.74, -5.62) (-5.77, -4.23) Verapamil 180 mg 240 mg -9.90 -7.46 (-11.43, -8.36) (-8.30, -6.61) Tiapamil No doses were statistically significandy different from placebo

* The lowest effective dose is the lowest dose for which there is a statistically significant difference vs. placebo A The lowest dose with maximal blood pressure lowering efficacy is achieved at the dose that exhibits a statistically significantly greater response than all other doses lower than it, whereas doses higher than it do not exhibit a statistically significant difference in effect size. * If there was a discrepancy between the determined dose for SBP and DBP, that of SBP is used.

Non-dihydropyridines were analysed as a subclass, according, to increments of the manufacturer's recommended starting dose (Table 58). Only trials reporting trough measurements of BP were included. A dose-response is present, with a statistically

significant difference between increasing dose increments, except between the two highest

dose groups. Thus, maximal BP lowering is achieved at a mean dose of 2.3 times the

starting dose and above. The best estimate of the maximal BP lowering for the non-

dihydopyridine subclass is -8.15 mm Hg (-9.50, -6.79) for SBP and -5.97 mm Hg (-6.65, -

5.28).

185 Table 58: Blood pressure lowering efficacy for non-dihydropyridines combined according to multiples of starting dose Dose WMD for change WMD for change (expressed as multiple of starting dose, x) in SBP, mm Hg in DBP, mm Hg Range Mean (95% CI) (95% CI)

>0.5x < lx 0.6 x -1.18 -1.49* (-3.32, 0.96) (-2.71,-0.26)

>lx < 2x 1.1 X -4.87* -3.68* (-5.97, -3.76) (-4.28, -3.08) > 2x < 4x 2.3 x -7.84* -5.84* (-9.29, -6.39) (-6.56, -5.12) > 4x 4.1 x -10.25* -7.05* (-14.05, -6.45) (-9.16, -4.94) statistically significant difference from placebo

3.7.19.1 Non-dihydropyridines - Assessment of publication bias

Funnel plots of the non-dihydopyridine trials at doses > 2x the starting dose did not show asymmetry. There are not enough data to accurately assess publication bias in this subclass using funnel plots.

3.7.19.1.1 Non-dihydropyridines - subgroup analysis based on trial size

Post-hoc subgroup analysis based on trial sample size showed a trend towards a greater blood pressure lowering effect with larger trials but it was not statistically significant (Table

59).

186 Table 59: Non-dihydtopyridines: post-hoc subgroup analysis of trough blood pressure lowering based on trial size Non- dihydropyridines, Lowest tertile Highest tertile trough measurements (15-43 patients) (56-238 patients) Mean of WMD for change in -6.9 mm Hg (4.7) -5.8 mm Hg (2.4) SBP (SD) # of observations 11 13 t-test lowest vs. highest p = 0.5 tertile Mean of WMD for change in -5.5 mm Hg (3.0) -4.7 mm Hg (2.4) DBP (SD) # of observations 13 14 t-test lowest vs. highest p = 0.4 tertile

Another estimate of the maximal blood pressure lowering efficacy of non- dihydropyridines was obtained by restricting the tertile analysis to trials with doses greater than or equal to twice the starting dose. Combined, the middle and highest tertiles give an estimate of -8.1 mm Hg (95% CI: -10.2, -6.1) for maximal change in SBP and -5.7 mm Hg

(95% CI: -7.3, -4.1) for maximal change in DBP.

187 3.7.20 Other CCBs

3.7.20.1 Lidoflazine vs. placebo

Table 60: Blood pressure lowering efficacy of lidoflazine 180 mg/day. Dose of # of trials Total # of Change in SBP, Change in DBP, Lidoflazine padents in mm Hg mm Hg treatment group (95% Cf) (95% CI) 180 mg/day 1 5 16.00 -5.00 (-4.34, 36.34) (-16.91,6.91)

One trial evaluated lidoflazine in post-infarcdon patients who were not selected on the basis of elevated blood pressure. Since individual patient data were reported, data were extracted for the 10 patients (5 in each of lidoflazine and placebo groups) who met the criteria for hypertension at baseline. In this trial there was no statistically significant difference between lidoflazine and placebo in change in blood pressure. Lidoflazine actually exhibited an increase in SBP after 3 months treatment, but this result may be a chance effect in a very small sample.

188 3.7.20.2 Mibefradil vs. placebo

Table 61: Blood pressure lowering efficacy of mibefradil 6.25-100 mg/day. Fixed effect model with 95% confidence interval. Dose of # of trials Total # of Change in SBP, Change in DBP, Mibefradil patients in mm Hg mm Hg treatment group (95% CI) (95% CI) 6.25 mg/day 1 52 -5.00 -0.20 (-10.56, 0.56) (-3.29, 2.89) 12.5 mg/day 1 52 -2.40 1.40 (-8.20, 3.40) (-1.46, 4.26) 25 mg/day 1 for SBP 51 for SBP -10.00* -3.58* 2 for DBP 90 for DBP (-16.28, -3.72) (-5.64, -1.53) 50 mg/day 1 for SBP 51 for SBP -10.10* -5.92* 2 for DBP 92 for DBP (-16.44, -3.76) (-8.01, -3.84) 100 mg/day 1 for SBP 52 for SBP -17.00* -10.16* 2 for DBP 92 for DBP (-22.78, -11.22) (-12.33, -7.99) 150 mg/day 0 for SBP 40 Not reported -12.30* 1 for DBP (-15.05, -9.55) * statistically significant difference from placebo

Three mibefradil trials were included in this systematic review. Blood pressure data were not extracted from one of these trials (Oparil 1997) because baseline values were not reported. Another trial (Bernink 1996) only reported DBP data. Doses of 6.25 and 12.5 mg/day did not reduce BP compared with placebo. Doses 25 mg/day and above had statistically significant reductions in blood pressure compared with placebo. Thus the lowest effective dose is 25 mg/day.

One of the trials (Bursztyn 1997) was performed in elderly patients with a baseline blood pressure of 176/99 mm Fig. There was an insufficient amount of data for a subgroup analysis based on age.

Based on the 3 included trials, the maximal blood-pressure-lowering efficacy of mibefradil occurs at 100 mg/day and is best estimated at 100-150 mg/day is -17.00 (-22.78, -

11.22) mm Hg for SBP (based on one trial) and -10.98 (-12.69, -9.28) for DBP (based on two trials).

189 3.8 Blood pressure variability

The variability of blood pressure at baseline and/or endpoint was reported for 76 included trials. The number of observations used in the calculation of the variability represents the number of active treatment arms from these 76 trials. Seventy-two (95%) of the trials had systo-diastolic hypertension entry criteria, while 3 trials (4%) had isolated systolic hypertension entry criteria. The remaining trial did not select for hypertensive patients (Meilink-Hoedemaker 1976).

3.8.1. Systolic vs. diastolic blood pressure

Table 62: Variability of SBP and DBP at end of treatment

CCB group Placebo group SBP Weighted mean SD 14.5 mm Hg 14.8 mm Hg SD of weighted mean SD 3.9 mm Hg 4.8 mm Hg Weighted mean SBP 146.6 mm Hg 155.0 mm Hg Weighted mean coefficient of 9.8 9.5 variation (CV)* Number of observations 73 46 DBP Weighted mean SD 8.7 mm Hg 8.3 mm Hg SD of weighted mean SD 2.5 mm Hg 2.6 mm Pig Weighted mean DBP 91.4 mm Pig 97.5 mm Pig Weighted mean coefficient of 9.5 8.5 variation (CV)* Number of observations 79 49 t-test: SD of SBP vs. SD of DBP p < 0.0001 p < 0.0001 t-test: CV SBP vs. CV DBP p=0.4 p =0.06 calculated as weighted mean SD divided by weighted mean BP

To determine whether or not SBP varies to the same degree as DBP, their weighted

mean SDs were compared. As shown in Table 62, the absolute variability of SBP is

statistically significandy greater than that of DBP for both the CCB treatment group and

placebo group. Pfowever, the relative variabilities of SBP and DBP, as expressed by the

coefficient of variation, are similar.

190 3.8.2. Calcium channel blockers vs. placebo

As shown in Table 62, the weighted mean SD of SBP at the end of treatment was

14.5 mm Hg for the CCB group, while the corresponding value for placebo was 14.8 mm

Hg (p=0.6). For DBP, the weighted mean SD was 8.7 mm Hg for CCB group and 8.3 mm

Fig for placebo group (p=0.4). Thus, there was no statistically significant difference in BP variability between CCB and placebo treatment.

3.8.3. Systolic vs. diastolic blood pressure entry criteria

To determine if BP entry criteria affected baseline BP variability, comparisons were made between the weighted mean baseline standard deviations of trials that used isolated systolic hypertension as entry criteria, only DBP entry criteria, and trials with criteria of elevated SBP and/or DBP (Table 63).

Table 63: Baseline standard deviations of blood pressure according to entry criteria

All patients Trials with only DBP Trials with only SBP Trials with both SBP entry criteria entry criteria and/or DBP entry (61 trials) (3 trials) criteria* (11 trials) Weighted mean SD 14.5 7.9 13.3 of SBP at baseline (mm Hg) SD of weighted 3.2 3.7 3.6 mean SD of SBP (mm Hg) Number of 165 6 28 observations t-test systo-diastolic hypertension vs. isolated s ystolic hypertension: p < 0.0001 Weighted mean SD 5.5 6.1 5.3 of DBP at baseline (mm Hg) SD of weighted 2.0 1.6 2.5 mean SD of DBP (mm Hg) Number of 176 6 28 observations t-test systo-diastolic hypertension vs. isolated s ystolic hypertension: p : = 0.4 * includes those trials using World Health Organization classification of hypertension

191 Trials including patients with isolated systolic hypertension had statistically significantly lower baseline SBP variability than trials that based their entry criteria on elevated DBP or mixed SBP/DBP criteria. However there was no statistically significant difference in the variability of DBP among all three types of entry criteria.

3.8.4. Baseline vs. endpoint

For trials with DBP entry criteria, the standard deviations of BP at baseline and endpoint were compared in Table 64. There was no statistically significant difference between the variability of SBP at baseline and endpoint for both the CCB-treated groups and the placebo groups. For variability of DBP, the baseline SDs were statistically significandy lower than the endpoint values for both the CCB and placebo groups.

Table 64: Standard deviations of BP at baseline vs. endpoint in trials with DBP entry criteria CCB group Placebo group Weighted At baseline (SD) 14.6 (3.2) 13.9 (3.3) mean SD of At endpoint (SD) 14.6 (3.8) 14.9 (4.8) SBP t-test baseline vs. p = 1.0 p = 0.2 endpoint Weighted At baseline (SD) 5.5 (2.1) 5.3 (1.9) mean SD of At endpoint (SD) 8.7 (2.5) 8.3 (2.3) DBP t-test baseline vs. p < 0.0001 p < 0.0001 endpoint

192 3.9 Pulse Pressure

Although none of the included trials reported pulse pressure as a primary or secondary outcome, the change in pulse pressure was calculated by subtracting the change in

DBP from the change in SBP for each trial that reported both parameters. A weighted mean change in pulse pressure was then calculated, along with the associated standard deviation.

Table 65 below shows the change in pulse pressure at trough for dihydropyridines and non- dihydropyridines at twice the starting dose and above (i.e., at maximal BP lowering). The effect size of placebo was calculated from all trials reporting both SBP and DBP data.

Table 65: Change in pulse pressure

# of studies Weighted mean change in pulse pressure (95% CI) Dihydropyridines 43 -3.4 (-4.3, -2.5)

Non-dihydropyridines 18 -2.4 (-3.7,-1.1)

Placebo 94 0.3 (-0.2, 0.8)

Dihydropyridines vs. non-dihydropyridines: p=0.2, NS Dihydropyridines vs. placebo: p < 0.001 Non-dihydropyridines vs. placebo: p < 0.001

Placebo treatment does not have a statistically significant effect on change in pulse pressure, but both the dihydropyridines and non-dihydropyridines demonstrated statistically significant reductions in pulse pressure. Because there is no statistically significant difference between dihydropyridines and non-dihydropyridines, the results of both subclasses were combined to give an overall change in pulse pressure of -3.1 mm Hg (95% CI: -3.8, -2.3).

193 3.10 Dose-related change in heart rate of individual CCB drugs

Forty-seven of the 106 included trials (44%) had heart rate data that either were extractable from the publications or were obtained dtrectiy from authors. The results are described for each individual drug as well as grouped into dmydropyridines and non- dihydropyridines, categorized according to increments of the manufacturer's recommended starting dose. Lidoflazine and mibefradil are considered separately.

3.10.1 Dihydropyridines vs. placebo

Thirty-eight dihydropyridine trials reported heart rate data (Table 66). In the group of trials at 1-1.33 times the starting dose, there was no statistically significant difference in heart rate compared with placebo. There was a statistically significant increase in heart rate in the middle dose range of 1.5-3 times the starting dose. There was also statistically significant heterogeneity in this group, stemming from one trial (Rimoldi 1994) that had a very large increase in heart rate in the treatment group. The highest dosage range of > 3 times the starting dose had a non-statistically-significant increase in heart rate compared with placebo; however only 8 studies were included in this category and thus the analysis lacked power. All trials reported trough changes in heart rate except for two trials (Kiesewetter

1994, Prisant 1991), which reported peak values. Sensitivity analysis removing these 2 trials did not alter the results.

194 Table 66: Effect of dihydropyridines on heart rate

Dose Number of WMD - all trials (expressed as multiple of starting trials (95% confidence dose, x) interval) Range Mean

lx-1.33x l.Ox 20 0.60 (-0.27, 1.47) 1.5x-3x 2.2x 21 1.43*# (0.52, 2.33) > 3x 4.1x 8 1.32 (-0.46, 3.09) * statistically significant difference from placebo # statistically significant heterogeneity

3.10.1.1 Amlodipine vs. placebo

Table 67: Effect of amlodipine on heart rate Dose of Amlodipine # of trials Total number of Change in HR, patients in treatment beats/minute group • (95%CI) 1.25 mg/day 1 47 -2.20 (-5.73, 1.33) 2.5 mg/day 1 45 -1.30 (-4.87, 2.27) 5 mg/day 3 168 0.28 (-1.58, 2.13) 10 mg/day 1 15 1.60 (-5.06, 8.26)

Based on 4 trials that reported heart rate data (Frick 1988, Mroczek 1988, Pool 2001,

Licata 1993), none of the doses of amlodipine showed a statistically significant change in

heart rate compared with placebo.

195 3.10.1.2 Darodipine vs. placebo

Table 68: Effect of darodipine on heart rate Dose of Darodipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 100 mg/day 1 13 -10.70* (-19.15, -2.25) 200 mg/day 1 9 10.20 (-0.35, 20.75) 300 mg/day 1 11 3.20 (-4.99, 11.39) statistically significant difference from placebo

The one included trial that evaluated darodipine reported change in heart rate.

Darodipine at 100 mg/day showed a statistically significant decrease in heart rate compared with placebo, while the 200 mg/day and 300 mg/day doses demonstrated non-statistically- significant increases in heart rate.

3.10.1.3 Felodipine vs. placebo

Table 69: Effect of felodipine on heart rate

Dose of Felodipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 5 mg/day 1 27 1.50 (-5.87, 8.87) 10 mg/day 3 123 1.48 (-0.57, 3.52) 20 mg/day 2 51 1.45 (-1.34, 4.23)

Three felodipine trials reported change in heart rate (Felodipine Co-op, Liedholm

1989, Kiesewetter 1994). None of the doses showed a statistically significant difference in heart rate compare with placebo.

196 3.10.1.4 Isradipine vs. placebo

Table 70: Effect of isradipine on heart rate

Dose of Isradipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 1 nig/day 1 44 1.00 (-2.66, 4.66) 2.5 mg/day 2 105 1.37 (-0.90, 3.64) 5 mg/day 3 138 0.40 (-1.74, 2.54) 10 mg/day 2 45 3.90 (-0.03, 7.83) 15 mg/day 1 34 6.00* > (0.75, 11.25) 20 mg/day 1 30 3.40 (-1.99, 8.79) * statistically significant difference from placebo

Four isradipine trials reported change in heart rate (Burger 1993, Italian-Belgian,

Homes 1993, Prisant 1991). None of the doses had a statistically significant difference compared with placebo, except for the 15 mg/day dose, which was based on 1 trial.

3.10.1.5 Lercanidipine vs. placebo

Table 71: Effect of lercanidpine on heart rate

Dose of # of trials Total number of Change in HR, Lercanidipine patients in treatment beats/ minute group (95% CI) 10 mg/day 4 176 0.87 (-0.80, 2.54) 20 mg/day 3 139 1.25 (-0.97, 3.46)

Five lercanidipine trials reported heart rate data (Barbagallo 2000, Circo 1997, Ninci

1997, Rimoldi 1993 and Rimoldi 1994). There was no statistically significant difference

between lercanidipine at 10-20 mg/day and placebo in change from baseline in heart rate.

197 3.10.1.6 Manidipine vs. placebo

Table 72: Effect of manidipine on heart rate

Dose of Manidipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 10 mg/day 2 40 1.46 (-1.98, 4.90) 20 mg/day 1 12 1.00 (-8.62, 10.62) 40 mg/ day 1 13 2.00 (-7.42, 11.52)

Two trials reported heart rate data for manidipine (Fogari 1996 and Fogari 1999).

There was no significant difference in change in heart rate between placebo and manidipine at 10-40 mg/day.

3.10.1.7 Nicardipine vs. placebo

Table 73: Effect of nicardipine on heart rate

Dose of Nicardipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 40 mg/day 1 15 -2.20 (-7.90, 3.50) 60 mg/day 1 11 -0.80 (-8.75, 7.15) 80 mg/day 2 39 -0.13 (-3.80, 3.55) 90 mg/day 1 24 2.00 (-3.49, 7.49) 100 mg/day 2 38 -0.14 (-4.28, 4.00)

Seven trials reported heart rate data for nicardipine (Asplund 1985, Bellet 1987,

De Cesaris 1993, Marcadet 1991, Mazzola 1988, Scuten 1992, Soro 1990). At all doses

198 tested (40-100 mg/day), nicardipine was not associated with a statistically significant change in heart rate compared with placebo.

3.10.1.8 Nifedipine vs. placebo

Table 74: Effect of nifedipine on heart rate

Dose of Nifedipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 20 mg/day 2 103 -0.61 (-1.77,2.99) 30 mg/day 1 62 -2.50 (-5.81, 0.81) 40 mg/day 2 42 -0.34 (-4.63, 3.96) 60 mg/day 3 112 -1.50 (-4.09, 1.09) 90 mg/day 1 59 -1.40 (-4.71, 1.91)

Seven trials reported heart rate data for nifedipine (DeSimone 1985, Feig 1993,

Ferrera 1984, Harder 1994, Jueng 1987, Serradimigni 1985, Toal 1997). Doses 20-90 mg/day did not exhibit statistically significant differences in heart rate compared with placebo.

3.10.1.9 Nisoldipine vs. placebo

Table 75: Effect of nisoldipine on heart rate

Dose of Nisoldipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 10 mg/day 1 49 2.90 (-1.02, 6.82) 20 mg/day 1 51 2.20 (-1.71,6.11) 30 mg/day 1 48 5.00* (1.06, 8.94) * statistically significant difference from placebo

199 One trial reported heart rate data for nisoldipine (Opie 1997). All doses showed an increase in heart rate but only the effect size at 30 mg/day was statistically significant compared with placebo.

3.10.1.10 Nitrendipine vs. placebo

Table 76: Effect of nitrendipine on heart rate

Dose of nitrendipine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 10 mg/day 1 72 2.70* (0.65, 4.75) 20 mg/day 3 47 4.70* (0.35, 9.05) statistically significant difference from placebo

Four trials reported heart rate data for nitrendipine (Asmar 1992, Lederle 1991,

Ferrera 1985, Paolisso 1991). Both the 10 mg and 20 mg/day groups showed statistically

significant increases in heart rate compared with placebo.

3.10.2 Non-dihydropyridines vs. placebo

Seven non-dihydropyridine studies reported heart rate data (Table 77). While both

the low and middle dose categories showed decreases in heart rate, only the middle dose

range achieved statistical significance. No trials reported heart rate data for doses above 3

times the starting dose.

200 Table 77: Effect of non-dihydropyridines (diltizaem and verapamil) on heart rate

Dose Number of WMD (expressed as multiple of starting trials (95% confidence dose, x) interval) Range Mean lx-1.33x l.lx 5 -1.49 (-3.23, 0.25) 1.5x-3x 2.1x 4 -3.76* (-5.53, -1.99) > 3x n/a 0 n/a * statistically significant difference from placebo

3.10.2.1 Diltiazem vs. placebo

Table 78: Effect of diltiazem on heart rate

Dose of Diltiazem # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 240 mg/day 1 24 1.20 (-6.12, 8.52) 300 mg/day 2 80 -3.41* (-6.35, -0.47) 360 mg/day 1 23 0.90 (-5.77, 7.57) * statistically significant difference from placebo

Two trials reported heart rate data for diltiazem (Djian 1990, Meeves 1994). Based on these limited data there was a statistically significant decrease in heart rate in the 300 mg/day analysis but non-significant increases in heart rate for the 240 mg/day and 360 mg/day doses.

201 3.10.2.2 Verapamil vs. placebo

Table 79: Effect of verapamil on heart rate

Dose of Verapamil # of trials Total number of Change in HR, padents in treatment beats/minute group (95% CI) 120 mg/day 3 117 -2.44* (-4.59, -0.28) 180 mg/day 3 141 -1.22 (-3.38, 0.94) 240 mg/day 1 27 -2.60 (-5.81, 0.61) 360 mg/day 1 59 -5.30* (-8.22, -2,38) 480 mg/day 1 26 -1.00 (-5.39, 3.39) 540 mg/day 1 55 -5.80* (-8.86, -2.74) statistically significant difference from placebo

Four trials (Carr 1991, Scholze 1998, VERATRAN, White 1995) reported heart rate data for verapamil over a dose range of 120 — 540 mg/day. The 120 mg/day, 360 mg/day and 540 mg/day groups showed a statistically significant decrease in heart rate compared with placebo, while the 180 mg/day, 240 mg/day, and 480 mg/day groups did not.

However, the results for 240-540 mg/day are based on only one trial at each dose.

3.10.2.3 Tiapamil vs. placebo

Table 80: Effect of tiapamil on heart rate

Dose of tiapamil # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 300-600 mg/day 1 24 3.00 (-2.58, 8.58) 900-1200 mg/day 1 25 2.00 (-4.02, 8.02)

202 The effect of tiapamil on heart rate was examined in one included trial (Blanchett

1991). There was no statistically significant difference in heart rate at doses 300-1200 mg/day compared with placebo.

3.10.3 Other calcium channel blockers

3.10.3.1 Lidoflazine vs. placebo

Table 81: Effect of lidoflazine on heart rate

Dose of lidoflazine # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 180 mg/day 1 5 -15.20* (-24.99, -5.41) *statistically significant difference from placebo

The one included trial assessing lidoflazine (Meilink-Hoedemaker 1976) reported heart rate data. There was a statistically significant drop in heart rate with lidoflazine 180 mg/day compared with placebo.

3.10.3.2 Mibefradil vs. placebo

Table 82: Effect of mibefradil on heart rate

Dose of mibefradil # of trials Total number of Change in HR, patients in treatment beats/minute group (95% CI) 6.25 mg/day 1 52 -0.80 (-4.17, 2.57) 12.5 mg/day 1 52 -0.40 (-4.03, 3.23) 25 mg/day 1 51 -2.00 (-5.53, 1.53) 50 mg/day 1 51 -5.20* (-9.01,-1.39) 100 mg/day 1 52 -6.60* (-10.13, -3.07) * statistically significant difference from placebo

203 One included trial (Bursztyn 1997) reported heart rate data for mibefradil. The 50 and 100 mg/day doses had a statistically significant decrease in heart rate compared with placebo, while the effect sizes at lower doses were not statistically significant.

204 3.11 Dose-related withdrawals due to adverse events

Analysis of withdrawals due to adverse events during 3 to 12 weeks of treatment was based on 64/106 (60%) of the included studies (50 dihydropyridine trials and 14 non- dihydropyridine trials).

3.11.1 Dihydropyridines vs. placebo

Of patients receiving a dihydropyridine, 196/3944 (5%) withdrew due to adverse events, compared with 60/2062 (3%) patients treated with placebo. The pooled result demonstrated a statistically significant difference (RR 1.49 [95% CI 1.12, 1.98]), without heterogeneity.

Whether each dihydropyridine is considered independendy or grouped together as a subclass, there appears to be a trend of increased WDAE with increase dose. Possible dose- response relationships in the chhydropyridine subclass were evaluated by combining trials in increments of the recommended starting doses (Table 83).

Table 83: Effect of dihydropyridines on withdrawals due to adverse events

Dose # of trials # of WDAE in RR (expressed as multiple of starting treatment group vs. (95% CI) dose, x) placebo group Range Mean

tx-1.33x l.Ox 30 47/1570 vs. 45/1397 0.97 (0.66, 1.43) 1.5x-3x 2.0x 31 80/1388 vs 33/1098 1.76 (1.21,2.58)* > 3x 4.1x 11 53/423 vs 10/392 3.91 (2.19, 6.99)* statistically significant difference from placebo

205 3.11.1.1 Amlodipine vs. placebo

Table 84: Effect of amlodipine on withdrawals due to adverse events

Dose of Amlodipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 1.25 mg 1 0/41 vs. 0/40 Not estimable 2.5 mg 2 5/124 vs. 1/122 3.61 (0.61, 21.58) 5mg 4 10/501 vs. 12/381 0.75 (0.34, 1.67) 10 mg 1 1/43 vs. 0/40 2.80 (0.12, 66.70)

Six trials reported WDAE data for amlodipine (Chrysant 2003, Farsang 2001,

Frishman 1995, Kuschnir 1996, Mehta 1993, Pool 2001). None of the results showed a statistically significant difference from placebo.

3.11.1.2 Darodipine vs. placebo

Table 85: Effect of darodipine on withdrawals due to adverse events

Dose of Darodipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 100 mg/day 1 0/13 vs. 0/10 Not estimable 200 mg/day 1 0/9 vs. 0/10 Not estimable 300 mg/day 1 0/11 vs. 0/10 Not estimable

One darodipine trial (Chrysant 1988) reported WDAE. Since no withdrawals due to adverse events occurred in this trial, this outcome cannot be assessed in this review.

206 3.11.1.3 Felodipine vs. placebo

Table 86: Effect of felodipine on withdrawals due to adverse events

Dose of Felodipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 2.5 mg/day 2 3/100 vs. 3/99 0.99 (0.20, 4.79) 5 mg/day 5 9/221 vs. 6/214 1.35 (0.53, 3.42) 10 mg/day 6 19/289 vs. 9/288 2.01 (0.95, 4.23) 20 mg/day 3 30/118 vs. 2/123 10.58* (3.32, 33.66) statistically significant difference from placebo

Seven trials reported WDAE data for felodipine (Felodipine Co-op, Liedholm 1989,

Kiesewetter 1994, Scholze 1999, van Ree 1996, Weber 1994, Wester 1991). There appears to be a dose-related increase in WDAE and the 20 mg/day group demonstrates a statistically significant increase compared with placebo. With all doses pooled, there is a statistically significant relative risk of 2.75 (95% CI 1.73, .4.36).

3.11.1.4 Isradipine vs. placebo

Table 87: Effect of isradipine on withdrawals due to adverse events

Dose of 1 sradipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 1 mg/day 1 0/45 vs. 1/44 0.33 (0.01, 7.80) 2.5 mg/day 5 6/187 vs. 3/154 1.48 (0.47, 4.64) 5 mg/day 6 9/353 vs. 6/263 1.06 (0.38, 2.96) 10 mg/day 2 2/38 vs. 0/34 4.78 (0.24, 94.12)

207 Eight trials reported WDAE data for isradipine (Bellet 1987, Burger 1993, Holmes

1993, Italian-Belgian, Kirch 1990, Man in't Veld 1991, O'Grady 1997, Pittrow 1997). There were few trials reporting data for each dose, and thus, due to limited power, none of the results showed a statistically significant difference from placebo.

3.11.1.5 Lercanidipine vs. placebo

Table 88: Effect of lercanidipine on withdrawals due to adverse events

Dose of # of trials # of WDAE in RR Lercanidipine treatment group vs. (95% CI) placebo group 2.5 mg/day 1 2/63 vs. 3/60 0.63 (0.11,3.67) 5 mg/day 1 0/59 vs. 3/60 0.15 (0.01, 2.75) 10 mg/day 3 4/113 vs. 5/111 0.78 (0.22, 2.84) 20 mg/day 1 1/10 vs. 0/10 3.00 (0.14, 65.90)

Three studies reported WDAE data for lercanidipine (Barbagallo 2000, Omboni

1988, Rimoldi 1994). There were few trials reporting data for each dose, and thus, due to limited power, none of the results showed a statistically significant difference from placebo.

3.11.1.6 Manidipine vs. placebo

Table 89: Effect of manidipine on withdrawals due to adverse events

Dose of Manidipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 10 mg/day 2 0/40 vs. 0/40 Not estimable 20 mg/day 1 1/13 vs. 0/13 3.00 (0.13, 67.51) 40 mg/day 1 0/13 vs. 0/13 Not estimable

208 Two trials reported WDAE data for manidipine (Fogari 1996 and Fogari 1999).

There were insufficient data to estimate the effect of manidipine on WDAE.

3.11.1.7 Nicardipine vs. placebo

Table 90: Effect of nicardipine on withdrawals due to adverse events Dose of Nicardipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 60 mg/day 2 7/78 vs. 3/69 1.86 (0.54, 6.35) 80 mg/day 1 0/15 vs. 0/15 Not estimable 90 mg/day 2 6/90 vs. 3/87 1.97 (0.51, 7.53) 100 mg/day 2 0/39 vs. 0/39 Not estimable 120 mg/day 1 12/68 vs. 3/63 3.71* (1.10, 12.53) statistically significant difference from placebo

Six trials reported WDAE data for nicardipine (Asplund 1985, Bellet 1987, Fagan

1993, Marcadet 1991, Mazzola 1988, Soro 1990). Based on the result of one trial (Fagan

1993, there was a statistically significant increase in WDAE in the 120 mg/day group compared with placebo. When all doses were pooled, there was a statistically significant relative risk of 2.48 (95% CI: 1.21, 5.08).

209 3.11.1.8 Nifedipine vs. placebo

Table 91: Effect of nifedipine on withdrawals due to adverse events

Dose of Nifedipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 20 mg/ day 2 3/143 vs. 7/145 0.47 (0.14, 1.64) 30 mg/day 3 8/116 vs. 2/113 3.35 (0.83, 13.55) 40 mg/day 3 5/79 vs. 5/79 1.25 (0.35, 4.44) 50 mg/day 1 4/53 vs. 4/51 0.96 (0.25, 3.64) 60 mg/day 5 7/166 vs. 3/167 2.01 (0.62, 6.54) 90 mg/day 1 7/59 vs. 0/62 15.75 (0.92, 269.79) 100 mg/day 1 6/53 vs. 4/51 1.44 (0.43, 4.82)

Ten trials reported WDAE data for nifedipine over a range of 20-100 mg/day (Carr

1992, Eggersen 1982, Fadayomi 1986, Feig 1993, Harder 1994, Jueng 1987, Serradimigni

1985, Toal 1997, Zachariah 1990, Zanchetti 1994). There were few trials reporting data for

each dose, and thus, due to limited power, none of the doses showed a statistically significant

difference from placebo. The pooled result across all doses showed a marginally statistically

significant increase in WDAE compared with placebo (RR 1.60, 95% CI: 1.00, 2.56).

3.11.1.9 Nilvadipine vs. placebo

Table 92: Effect of nilvadipine on withdrawals due to adverse events

Dose of Nilvadipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 8 mg/day 1 6/61 vs. 2/59 2.90 (0.61,13.81) 16 mg/day 1 7/52 vs. 2/59 3.97 (0.86, 18.28)

210 One trial (Hoffman 1997) reported WDAE data for nilvadipine. Due to limited power, none of the doses showed a statistically significant difference from placebo. Pooled results did show a statistically significant increase in WDAE compared with placebo, with a relative risk of 3.41 (95% CI: 1.15, 10.13).

3.11.1.10 Nisoldipine vs. placebo

Table 93: Effect of nisoldipine on withdrawals due to adverse events

Dose of Nisoldipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 10 mg/day 1 2/49 vs. 1/58 2.37 (0.22, 25.33) 20 mg/day 1 0/51 vs. 1/58 0.38 (0.02, 9.08) 30 mg/day 1 0/48 vs. 1/58 0.40 (0.02, 9.63)

One trial (Opie 1997) reported WDAE data for nisoldipine. Due to limited power, none of the results showed a statistically significant difference from placebo.

3.11.1.11 Nitrendipine vs. placebo

Table 94: Effect of nitrendipine on withdrawals due to adverse events

Dose of # of trials # of WDAE in RR Nitrendipine treatment group vs. (95% CI) placebo group 10 mg/day 2 . 4/116 vs. 3/105 1.17 (0.27, 5.07) 20 mg/day 3 2/61 vs. 0/53 5.00 (0.25, 100.20)

211 Five trials reported WDAE data for nitrendipine (Asmar 1993, Ferrara 1985, Fodor

1991, Lederle 1991, Maclean 1990). Due to limited power, none of the results showed a statistically significant difference from placebo.

3.11.1.12 Pranidipine vs. placebo

Table 95: Effect of pranidipine on withdrawals due to adverse events

Dose of Pranidipine # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 1 mg/day 1 0/36 vs. 3/32 0.13 (0.01,2.38) 2 mg/day 1 0/37 vs. 3/32 0.12 (0.01, 2.31) 4 mg/day 1 3/34 vs. 3/32 0.94 (0.20, 4.33) 8 mg/day 1 5/37 vs. 3/32 1.44 (0,37, 5.57)

One trial (Rosenthal 1996) reported WDAE for pranidipine. Although there was a trend towards increased WDAE with higher doses, none of the doses had a statistically significant difference from placebo due to limited power.

3.11.2 Non-dihydropyridines vs. placebo

Of patients receiving a non-dihydropyridine (diltiazem or verapamil), 31/1258

(2.5%) withdrew due to adverse events, compared with 16/599 (2.7%) treated with placebo.

There was no statistically significant difference between active treatment and placebo in the pooled result (RR 0.84 [95% CI 0.51, 1.38]).

There does not appear to be a dose-response relationship for WDAE in diltiazem

and verapamil trials but there are too few trials to make an accurate estimation of the effect

size for this outcome (Table 96).

212 Table 96: Effect of non-dihydropyridines on withdrawals due to adverse events

Dose # of trials # of WDAE in RR (expressed as multiple of starting treatment group vs. (95% CI) dose, x) placebo group Range Mean lx-1.33x l.lx 9 12/558 vs. 16/543 0.75 (0.37,1.54) 1.5x-3x 2.2x 7 17/598 vs. 3/428 1.08 (0.5, 2.31) > 3x 4.3x 2 2/102 vs. 4/99 0.47 (0.08, 2.64)

3.11.2.1 Diltiazem vs. placebo

Table 97: Effect of diltiazem on withdrawals due to adverse events

Dose of Diltiazem # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 90 mg/day 1 0/46 vs. 2/43 0.19 (0.01, 3.79) 120 mg/day 3 5/229 vs. 8/233 0.65 (0.23, 1.88) 180 mg/day 2 9/198 vs. 8/193 1.10 (0.43, 2.79) 240 mg/day 2 0/80 vs. 2/83 0.21 (0.01, 4.22) 300 mg/day 1 0/55 vs. 0/56 Not estimable 360 mg/day 2 6/103 vs. 4/99 1.43 (0.42, 4.93) 480 mg/day 1 1/55 vs. 2/56 0.51 (0.05, 5.45) 540 mg/day 1 1/47 vs. 2/43 0.46 (0.04, 4.87)

Six trials reported WDAE for diltiazem (Levine 1995, McMahon 1989, Neutel 1996,

Neutel 1999, Scholze 1998, Smith 2001). There was not enough power to achieve statistical significance because of the limited amount of data.

213 3.11.2.2 Verapamil vs. placebo

Table 98: Effect of verapamil on withdrawals due to adverse events

Dose of Verapamil # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 60 mg/day 1 1/42 vs. 2/45 0.54 (0.05, 5.69) 100 mg/day 1 0/53 vs. 0/51 Not estimable 120 mg/day 3 0/104 vs. 3/104 0.25 (0.03, 2.22) 180 mg/day 1 0/29 vs. 1/30 0.34 (0.01, 8.13) 200 mg/day 2 5/129 vs. 3/117 1.55 (0.39, 6.23) 240 mg/day 3 1/125 vs. 2/120 0.66 (0.11, 3.95) 300 mg/day 1 0/58 vs. 0/51 Not estimable 400 mg/day 1 0/58 vs. 0/51 Not estimable 480 mg/day 1 2/46 vs. 2/45 0.98 (0.14, 6.65)

Five trials reported WDAE for verapamil (Chan 1997, Cushman 1998, Felictta 1992,

Meeves 1994, Whelton 1992). There was not enough power to achieve statistical significance because of the limited amount of data.

214 3.11.3 Other calcium channel blockers

3.11.3.1 Mibefradil vs. placebo

Table 99: Effect of mibefradil on withdrawals due to adverse events

Dose of Mibefradil # of trials # of WDAE in RR treatment group vs. (95% CI) placebo group 6.25 mg/day 2 2/92 vs. 0/87 2.83 (0.30, 26.70) 12.5 mg/day 2 2/90 vs. 0/87 2.89 (0.31, 27.29) 25 mg/day 3 1/128 vs. 0/129 3.00 (0.13, 71.96) 50 mg/day 3 1/131 vs. 0/129 3.00 (0.13,71.96) 100 mg/day 3 2/132 vs. 0/129 2.82 (0.30, 26.61) 150 mg/day 2 3/76 vs. 0/78 7.34 (0.39, 137.78) 200 mg/day 1 4/37 vs. 0/36 8.76 (0.49, 157.12)

Three trials reported WDAE data for mibefradil (Bernink 1996, Bursztyn 1997,

Oparil 1997). Though there was a trend of increasing WDAE with higher doses, there was not enough power to achieve statistical significance at each dose because of the limited

amount of data. Elowever, when all doses are pooled, there is a statistically significant increase in WDAE compared with placebo (RR 3.90, 95% CI: 1.48, 10.28).

215 4. DISCUSSION

This systematic review of the blood pressure lowering efficacy of CCBs used data from published randomized placebo-controlled trials of 3-12 weeks duration, in order to determine the dose-related effects on systolic and diastolic blood pressure, heart rate, and the number of withdrawals due to adverse events. One important aim was to determine if a difference in the magnitude of BP lowering existed amongst the different subclasses of

CCBs or amongst the drugs within each subclass. Another aim was to determine optimal dosing for each CCB drug so as to assist prescribing. It is important to note that conclusions about dose-response were limited to doses that were assessed in the studies included in this systematic review.

4.1 What methodological issues and potential sources of bias were encountered

while conducting the systematic review?

Several methodological issues, from searching databases to extracting and analyzing data, surfaced during the process of conducting this systematic review. The search strategy utilized the OVID search interface, which was generally easy to use. However, it was not possible to search suffixes such as "-dipine" which would have been helpful in identifying dihydropyridine-related articles. The search strategy was developed for high sensitivity at the expense of specificity and the process of sorting through irrelevant references was time- consuming. The CENTRAL (Cochrane Central Register of Controlled Trials) database is formed from specialized registers from Cochrane groups, together with references to clinical trials identified in MEDLINE and EMBASE. Thus, with its enhanced specificity,

CENTRAL may prove to be a time-saving alternative to searching all of the standard electronic databases.

216 This systematic review is based on data that are reported in publications and in some cases, provided by the authors through correspondence. Inadequate reporting of trial methodology and data was a frequent problem. Most crossover trials did not report pre- crossover data and thus, these trials were excluded. Because only 36% of trials reported SD of BP change, in the majority of trials the variances were imputed. Some trials only reported blood pressures from ambulatory blood pressure monitoring even though office blood pressures were measured as well. Attempts to obtain additional data by contacting authors were seldom successful. Of the authors who responded, more often than not the data were no longer available, especially if over a decade had lapsed since the year of publication.

Authors who worked for a pharmaceutical company tended to have easier access to clinical trial data. Some authors referred me to pharmaceutical and/or statistical analysis companies, but garnering additional data by this method was rarely successful.

To promote standardization of data reporting, many journals have endorsed the

CONSORT statement, consisting of a checklist of items to be included when reporting a clinical trial (87). This checklist covers items that were commonly deficient in published

RCTs included in this systematic review, such as method of randomization, flow of participants through each stage, and adverse events in each group.

Errors in the reported data are a potential threat to the validity of a systematic review. Some trials reported standard deviations that were spuriously low and were more likely to be standard errors. The trials that reported standard deviations of BP change that were > 3 standard deviations away from the weighted mean value were discarded and imputed values were used. Clinical trial fraud is also a possible source of bias in the results,

and although none of the publications of the included trials have ever been withdrawn, the

217 primary author of one included trial (Fiddes 1994) pleaded guilty to fraud for falsifying records and endangering patients while he was the head of a clinical research institute (377).

Errors in the process of extracting data were minimized by having two independent reviewers extract data. Whenever possible, data were extracted from text and tables in the publications since extracting graphical data may introduce inaccuracies.

Loss of blinding in a trial would bias the results in favor of CCBs over placebo. An investigator's knowledge of the occurrence of common CCB side effects such as flushing and ankle edema in clinical trial participants may compromise blinding. However, none of the included trials assessed the success of blinding in patients or investigators.

Overall, the percentage of patients completing each trial was in the range of 85-

100%. Because the drop-out rate in the included studies was low, attrition bias is unlikely.

The systematic review was based on group averages from each trial, rather than analyzing individual patient data. The INDANA (Individual Data Analysis of

Antihypertensive intervention trials) project, which involves meta-analyses of individual patient data, has the potential advantages of increased data reliability and improved ability to

analyze large amounts of data in subgroups, assess prognostic factors, and relate treatment

effects to baseline characteristics (378).

4.1.1 Publication bias

Another potential methodological problem was publication bias since only published

trials were assessed in this review. Funnel plot asymmetry can indicate publication bias but

can also be due to clinical and methodological heterogeneity. Funnel plot asymmetry was

observed for several CCB drugs individually, as well as dihydropyridines as a subclass. Thus,

effect sizes calculated in this systematic review are likely to be overestimates. Ideally, clinical

trial registries would minimize the problem of publication bias by allowing "negative" trials

218 that would otherwise be unpublished to be included in the review. The World Health

Organization has formed the International Clinical Trials Registry Platform with the aims of ensuring that all clinical trials are registered and that a minimum set of results will be reported and made publicly available (379).

There are several techniques that can be applied to adjust for publication bias in a meta-analysis (380), but currently there is no gold standard. In this review, the non- parametric "trim-and-fill" method was applied. For the dihydropyridine subclass, 7

"missing" studies in the SBP analysis and 5 "missing" studies in DBP analysis were "filled in" to achieve a symmetrical funnel plot. The resulting effect sizes were not altered in a clinically or statistically significant degree compared with the original data; this method suggested the data had overestimated change in SBP by 0.4 mm Hg and change in DBP by

0.3 mm Hg.

A post-hoc subgroup analysis was done to determine if the degree of reported blood pressure lowering differed in large trials (active treatment arms in the highest tertile) versus small trials (active treatment arms in the lowest tertile). Dihydropyridines and non- dihydropyridines were analyzed separately. For dihydropyridines, this analysis confirmed that the effect sizes for change in SBP and DBP in the smaller trials were statistically significantly greater and more variable than those in the larger trials. The exaggerated effect size of the included trials with small sample size corroborates evidence of publication bias in addition to the asymmetrical funnel plots associated with several of the dihydropyridine drug analyses. Using this method one would accept the tertile of the largest trials as the closest to the treatment effect. This would lead to a reduction in the overall effect from -10.5 to -9.0 mmHg for systolic and from -6.9 to -5.4 mmHg for diastolic.

219 Either way there are likely to be small studies with littie or no reduction in blood pressure that have not been published and therefore are not included in this review.

However, locating such unpublished studies is generally unfruitful and the inclusion of such studies may not reduce bias if the data are provided by interested sources or if their quality differs from that of published trials (381).

For non-dihydropyridines, there was no statistically significant difference in effect size for SBP and DBP between small and large trials. Flowever, the trend was in the same direction and this analysis lacked power since there were far fewer non-dihydropyridine trials included in the review than dihydropyridine trials. Also, the non-dihydropyridine trials had larger sample sizes than the dihydropyridines on average (mean size of active treatment arm of 54 patients vs. 43 patients, respectively), although the difference was not statistically significant.

4.1.2. Selection Bias

The method of patient recruitment is another potential source of bias, as studies could select for known responders to CCBs in previous trials to participate in new trials.

Thus there are likely to be some patients who participated in several CCB trials. However, the degree of selection bias is difficult to quantify because the method of patient recruitment is usually not reported adequately. In this systematic review, we searched for selection bias by dividing up the trials into tertiles according to year of publication. The mean effect size of the oldest trials was compared with that of the most recent trials. If selection bias was present, we would expect the tertile with the most recent trials to have a greater effect size than that of the oldest trials. When this was done there was no statistically significant

220 difference in effect size between the oldest and most recent trials. Therefore, we could not confirm any suggestion of evidence of selection bias in this systematic review.

4.2 What is the dose-related, blood pressure lowering efficacy of each subclass? Is

there a difference in the best estimate of the magnitude of BP lowering effect

of different subclasses of CCBs?

In this systematic review, 106 trials met the inclusion criteria and reported data on

13,878 patients (9513 receiving active treatment and 4365 receiving placebo), with a mean age of 55 years, mean baseline blood pressure of 158.2/101.6 mm Hg and mean pulse pressure of 56.7 mm Hg.

Data were pooled for the dihydropyridine subclass and the non-dihydropyridine subclass by categorizing individual doses according to multiples of the manufacturer's starting dose (0.5x, lx, 2x, 4x). Both subclasses demonstrated a dose-response relationship, with an increasing magnitude in BP lowering as the dose increases from half the starting dose up to twice the starting dose. The maximal blood pressure lowering efficacy appeared to be attained at twice the recommended starting dose; at doses above this, there is no corresponding increase in blood pressure lowering response. For dihydropyridines, the best estimate of the maximal blood pressure lowering is -10/-7 mm Hg, based on 2857 patients

for SBP and 3076 patients for DBP. The best estimate of the maximal blood pressure lowering efficacy of the non-dihydropyridine subclass is -8/-6 mm Hg, based on 1309 patients for SBP and 1632 patients for DBP.

The pooled data have narrow confidence intervals, thereby allowing detection of

even small differences between subclasses. The results of this systematic review reveal that

dihydropyridines are statistically significantly more effective at lowering blood pressure than

221 non-dmydropyridines, although one could argue that this difference may not be clinically significant.

4.3 Is there a difference in the best estimate of the magnitude of BP lowering

effect of drugs in each subclass?

Differences between CCB drugs within each subclass cannot be assessed accurately in this systematic review because the analysis was restricted to doses that were tested in the included clinical trials. For several drugs there were not enough data to define the dose- response relationship. There was also high variability in the amount of available data for each dose of each drug. The effect sizes for drugs with littie data have very wide confidence intervals (Table 51).

4.4 What is the effect on blood pressure in the placebo group in short-term trials?

The weighted mean changes in SBP and DBP in placebo groups across all included trials with blood pressure data were -3.3 mm Hg (SD 4.1; range -16.7 to 9) and -3.5 mm Hg

(SD 2.7; range -11.4 to 4.5), respectively. Because the placebo response was quite variable, it was important to subtract this effect for each trial in order to isolate the effect of the CCB drug. Hence, the inclusion criteria mandated that included trials have a parallel placebo arm.

The placebo effect arises from the natural history of the condition, regression to the mean, and non-specific effects of treatment (382). The variability associated with the measurement of blood pressure itself may also contribute to the wide range of placebo responses observed in this systematic review.

222 4.5 Does the method of blood pressure measurement affect the blood pressure

lowering efficacy of CCBs?

Sources of error associated with blood pressure measurement could affect study entry and trial outcomes, thereby potentially imparting bias onto the results of a systematic review. Thus, sensitivity analyses were planned to ascertain if the method of blood pressure measurement and the position of measurement affected drug efficacy.

Seventy-two percent of the trials utilized sphygmomanometers and 6% of the trials used automatic devices to measure clinic blood pressures, while 22% of the trials did not report the instrument used. There were insufficient data to conduct a sensitivity analysis based on instrument used to measure BP. The effect of calcium channel blockers on

ambulatory blood pressures as measured by 24-hour ambulatory blood pressure monitors was not assessed in this systematic review.

Most of the blood pressure data extracted were sitting (48%), followed by supine

(26%) and standing (16%) and average of supine/standing (4%) positions. The position of

measurement was not reported for 6% of the trials with extractable BP data. There was no

statistically significant difference in BP lowering efficacy among the different measurement

positions.

4.6 Does trial quality affect the blood pressure-lowering efficacy of calcium

channel blockers?

Both the Jadad and Cochrane quality assessment scales were utilized in this review.

One hundred (94.3%) of the included trials did not report allocation concealment, while the

remaining six (5.7%) trials reported an adequate method of concealment. Most included

trials (86 trials; 81.1%) were of moderate quality, while 19 (17.9%) were of low quality and

223 only one trial (0.9%) was of high quality. A sensitivity analysis removing low quality studies did not alter the effect sizes obtained in the CCB subclass analyses. The relative homogeneity of the quality of the studies is reflected in the screening criteria for inclusion into the systematic review. All included studies had to be randomized, double-blinded and placebo-controlled. Because the Jadad scoring criteria match these screening criteria, this scale was not particularly useful in this review. The Cochrane method of assessing trial quality with respect to allocation concealment was also not useful because most studies did not report these details. It is worth noting that the quality of a trial's reporting of the methodology and the quality of the trial results are not always in accord. The accuracy of blood pressure measurement is the most important factor affecting the quality of the included studies. However, this factor is not taken into account in the Jadad and Cochrane quality assessment scales.

4.7. Was there a difference in blood pressure lowering efficacy at trough vs. peak?

Eighty-four trials reported trough blood pressures and 3 trials reported peak blood pressures, while 19 trials did not report timing of blood pressure measurement. The small number of trials with peak BPs precludes formal comparison of effect sizes at trough versus peak timing. A future systematic review of trials with 24-hour blood pressure monitoring would best address this question because this measurement technique allows both trough and peak data to be obtained for each patient.

224 4.8 Did funding source affect the reported blood pressure lowering efficacy of

CCBs?

Relationships between funding source and trial outcome in RCTs have been assessed in several studies. A published systematic review comparing the outcomes of industry- sponsored vs. nonindustry-sponsored original research showed a statistically significant association between industry-sponsorship of RCTs and pro-industry results [OR 4.14 (95%

CL 2.73-6.32)] (383).

The majority of trials included in this systematic review (60; 57%) did not report the source of funding. Of the trials that did report funding source, 45 (98%) had an industry funding source, with 40 trials (87%) with potential bias in favor of the CCB drug being tested, and 5 trials (11%) with potential bias against. Only one trial (2%) was funded by a government agency.

Sensitivity analysis removing the trials with potential bias against the CCB drug and government-funded trials did not change the results. This analysis is not adequately powered because of the general lack of reporting.

4.9 Does age affect the blood pressure lowering efficacy of CCBs?

Eight studies had inclusion criteria for older patients, defined as cutoff age > 60 years (Chan 1997, Rizzini 1991, BarbagaUo 2000, Ninci 1997, Fogari 1999, Bursztyn 1997,

Scuteri 1992, Paolisso 1991). An additional four trials had different age criteria but still had a mean age of > 60 years (Fiddes 1994, Black 2001, van Ree 1996, Gerritsen 1998). Two trials reported data separately for older patients and younger patients (Fagan 1997, Fiddes 1994).

However, with such little data a subgroup analysis of the effect of CCBs on older vs.

225 younger patients was not feasible. A systematic review of individual patient data would be more suitable to assess this question, as more data would be available in such an analysis.

4.10 Does co-morbidity alter the blood pressure lowering efficacy of CCBs?

A subgroup analysis of hypertensive patients with co-morbidity was not feasible in this systematic review because of the lack of such patients in the included studies. Two nitrendipine studies had inclusion criteria of Type 2 diabetes mellitus. One nicardipine study was performed in hospitalized patients. One trial assessed lidoflazine in post-infarction patients. Otherwise, all other trials did not select for patients with co-morbidity. Essentially, most trials excluded patients with major cardiac, hematologic, renal, hepatic, or endocrine disease.

4.11 Does blood pressure lowering efficacy of CCBs differ for isolated systolic

hypertension vs. diastolic or systo-diastolic hypertension?

Calcium channel blockers have been used commonly a first-line therapy for isolated systolic hypertension, a guideline that was primarily based on the results of the "Systolic

Hypertension in Europe" (SYST-Eur) trial. In the SYST-Eur study, nitrendipine (with optional add-on enalapril and/or hydrochlorothiazide) in comparison with placebo showed a reduction in the risk of stroke (RR 0.61, 95% CI 0.43-0.87) and cardiovascular events (RR

0.71, 95% CI 0.57-0.87), but not in total mortality and CAD (70).

This systematic review included 3 trials with inclusion criteria of isolated systolic hypertension (Black 2001, Barbagallo 2000, Paolisso 1991). With such littie data, a subgroup analysis comparing the effect sizes between trials with inclusion criteria of ISH vs. diastolic hypertension was not feasible.

226 4.12 How do the direct comparisons between doses differ from the indirect

comparisons?

Direct comparisons were based on much less data than the indirect comparisons.

There was general agreement between the direct and indirect comparisons, but the confidence intervals were fairly wide.

227 4.13 For each CCB drug, do the manufacturer's starting doses coincide with the

lowest effective dose as determined by this systematic review?

Table 100: Comparison of manufacturer's recommended starting doses and lowest effective doses determined in this systematic review Drug Manufacturer's Lowest effective dose recommended starting (mg/day) dose (mg/day) Amlodipine 5mg 2.5 mg

Barnidipine 10 mg 30 mg

Darodipine n/a 100 mg

Diltiazem 120-240 mg 120 mg

Felodipine 5mg 2.5 mg

Isradipine 5 mg 1 mg

Lacidipine 2-4mg 4mg

Lercanidipine 10 mg 10 mg

Lidoflazine n/a n/a

Manidipine 10 mg 10 mg

Nicardipine 60 mg 40 mg

Nifedipine 20-30 mg 20 mg

Nilvadipine 8mg 8mg

Nisoldipine 10 mg 10 mg

Nitrendipine 5-20 mg 10 mg

Pranidipine n/a 2mg

Tiapamil n/a No doses showed statistically significant difference from placebo Verapamil 180-240 mg 180 mg

228 There is general agreement between manufacturer's recommended dose and the lowest effective dose determined by this systematic review. However, the lowest effective doses for amlodipine, felodipine, isradipine and nicardipine were lower than the manufacturer's recommended starting doses.

4.14 What is the effect of CCBs on BP variability?

To determine the effect of CCB treatment on BP variability, the endpoint variabilities of the CCB group were compared with the placebo group. There were a lot of data to assess this parameter and there was no statistically significant difference between

CCB and placebo for SBP or DBP, demonstrating with a high degree of certainty that CCBs do not change BP variability.

In absolute terms, the variability of SBP is statistically significantly different than that of DBP. However, in terms of coefficient of variation, which is a measure of the variability relative to the mean value, there is no statistically significant difference in the variabilities of

SBP and DBP. Thus, it can be concluded that SBP and DBP vary to the same degree.

The variability at baseline appears to be affected by blood pressure criteria for entry into the trials. SBP at baseline is statistically significandy lower in the 3 trials that used SBP as entry criteria compared to the 72 trials using DBP- or mixed SBP/DBP criteria. The baseline variabilities in DBP were similar across all entry criteria. However, in the trials with

DBP entry criteria, the baseline SD values were statistically significandy lower than the endpoint values in both the CCB treatment and placebo groups. This demonstrates that the baseline DBP variabilities are likely to be spuriously low in trials with DBP entry criteria.

Entry criteria may falsely lower the magnitude of baseline variability because it is a truncated

229 rather than a normal distribution. This effect would be further magnified if many patients with BPs near the cut-off value are enrolled into trials.

The blood pressure variability of a trial gives an indication of the reliability of the data since expected values can be compared with the reported values. Based on the baseline variabilities of treatment and placebo groups, the best estimate of the variability in SBP from trials with systo-diastolic hypertension is 14.4 mm Hg (SD 3.2). However, the best estimate of the variability in DBP cannot be determined from baseline measures in this review because the majority of the trials had DBP entry criteria. The best estimate for DBP variability is based on end of treatment values, 8.2 mmHg (SD 2.4).

This review assesses variability based on mean values from treatment groups, which accounts for both inter- and intra-individual variability. Intra-individual BP variability can be assessed independendy in cross-over studies or from data from 24-hour blood pressure monitoring.

The variability of the change in BP in both SBP and DBP is not statistically significandy different in the CCB treatment group compared with the control group, ft can be concluded that the blood pressure responses to CCB treatment and placebo treatment are both highly variable (SD of SBP/DBP change of 13.5/7.8 mm Hg and 14.1/7.9 mm Hg, respectively), and the CCB effect to lower BP has no effect on that variability.

Many trials did not report the SD of the change in BP, necessitating imputing these values. However, the mean reductions in blood pressure were insensitive to the strategy used to impute missing variances — that is, whether the hierarchy for imputation was used or the weighted mean SD of BP change from all trials reporting this parameter was used.

230 4.15 What is the effect of CCBs on pulse pressure?

Pulse pressure is an independent risk factor for cardiovascular disease, although it was not reported as a primary or secondary outcome in any of the included trials. The weighted mean change in pulse pressure was calculated for dihydropyridines and non- dihydropyridines at twice the starting dose and above, from trials reporting trough SBP and

DBP data. These parameters were compared with that of placebo, which was calculated from all trials reporting both SBP and DBP, regardless of timing of BP measurement. The results demonstrate that placebo does not affect pulse pressure (weighted mean 0.3 mm Hg,

95% CI: -0.2, 0.8), while a small reduction in pulse pressure is observed with both dihydropyridines (-3.4 mm Hg; 95% CT. -4.3, -2.5) and non-dihydropyridines (-2.4 mmHg;

95% CI: -3.7, -1.1). There is no statistically significant difference between dihydropyridines and non-dihydropyridines in change in pulse pressure (p = 0.2). In a sensitivity analysis, studies with isolated systolic hypertension as entry criteria were removed from the analysis.

There were only two such studies (Barbagallo 2000 and Paolisso 1991), both of which had been included in the pulse pressure calculation for placebo only, because the timing of blood pressure measurement was not reported. Without the ISH studies, the effect size for the placebo group remains similar (0.4 mm Hg; 95% CI: -0.1, 0.9).

Placebo does not alter pulse pressure most likely because none of the factors that contribute to the placebo response has any effect on blood pressure or its regulation. This is evidence against the placebo response being due to a psychological effect on blood pressure.

231 4.16 Is there any evidence of a dose-response relationship with respect to change

in heart rate?

Acutely, short-acting CCBs are associated with increased heart rate and norepinephrine levels. With chronic dosing, the effect of CCBs on heart rate appears to be small and clinically insignificant, based on the 47 (44%) trials reporting heart rate data in this review. However, this result may be due to bias from lack of reporting, since many trials did not report this outcome. For dihydropyridines, doses greater than or equal to 1.5 times the recommended starting dose are associated with a statistically significant increase in heart rate of 1.4 beats per minute (95% CI: 0.60, 2.2) compared with placebo.

For non-dihydropyridines, there are insufficient data to obtain a valid estimate of the effect on heart rate. However, the limited data from this systematic review demonstrated that non-dihydropyridines at doses 1-3 times the starting dose were associated with a statistically significant decrease of 2.6 beats per minute (95% Cf: -3.85, -1.36) compared with placebo.

4.17 Is there any evidence of a dose-reponse relationship with respect to

withdrawals due to adverse events?

The number of withdrawals due to adverse events in each dosage group was reported in 64 (60%) of the included trials. However, the type and severity of adverse events were not consistendy reported. Reports of adverse effects from published and unpublished sources other than randomized controlled trials may provide better information on the long term safety of CCB drugs. Ffowever, some rudimentary conclusions can be gleaned from the short-term RCTs included in this systematic review. For each drug considered independendy, there were not enough data to make an accurate estimate of WDAE.

232 However, when grouped as a subclass, the cLihydropyridines are associated with a statistically significant increase in WDAE compared with placebo. There also appears to be a dose- response relationship, with increasing relative risk values with increasing dose, starting with a non-significant difference at the starting dose, a RR of 1.76 (95% CI 1.21, 2.58) at twice the starting dose, and a RR of 3.91 (95% CI 2.19, 6.99) at >3 times the starting dose. The non- dihydropyridine trials did not show a statistically significant difference in WDAE compared with placebo but there is insufficient evidence to make a valid estimate of their effect on

WDAE.

4.18 Can the magnitude of blood pressure lowering efficacy of calcium channel

blockers be linked to their mechanism of action?

Hypertension is associated with elevated concentration of intracellular calcium ions, which can arise from increased transport from extracellular calcium stores, from increased

release from intracellular stores, or both. The exact mechanism of action of calcium channel

blockers is not known but they probably reduce blood pressure by vasodilatory and

cardiodepressant effects resulting from a reduction of calcium entry through the L-type

calcium channels on the arterial vasculature and cardiac tissue.

The blood pressure lowering efficacy of CCBs is quite modest in relation to the high

degree of variability associated with blood pressure measurement. Human physiology is

designed to maintain blood pressure levels through several homeostatic mechanisms. For

instance, baroreceptors in carotid sinuses and aortic arch detect changes in arterial pressure,

and they buffer such changes by activating reflex responses in the heart, blood vessels and

kidney (384). Chronic hypertension involves resetting of the baroreceptor reflex to higher

pressures.

233 At the cellular level, there are many players involved in the regulation of vascular tone other than L-type calcium channels, such as several types of potassium channels, chloride channels, store-operated calcium channels, and stretch-activated cation channels

(385). L-type calcium channels are regulated by the membrane potential, which in turn is determined essentially by potassium channels. Stretch-actived cation channels provide a route of entry for calcium into vascular muscle cells, even when dihydropyridine-sensitive channels are blocked (385). Store-operated channels allow calcium entry when intracellular stores are low.

In this review a small statistically significant difference in the BP-lowering efficacy between dihydropyridines and non-dihydropyridines was demonstrated. However, in view of the complexity of blood pressure regulation and the action of CCBs it is not possible to rationally speculate as to why this may be.

4.19 How can the blood pressure lowering efficacy of calcium channel blockers in

short-term trials be related to their effects on mortality and morbidity

outcomes in long-term trials?

There is current debate regarding the effect of CCBs on morbidity and mortality outcomes in long-term trials. Pahor et al.'s recent systematic review of randomised controlled trials found no statistically significant difference in the reduction of SBP or DBP between calcium antagonists and other drugs (diuretics, beta blockers, ACE inhibitors, clonidine) (55). However, the review also demonstrated that CCBs were associated with a significandy higher risk of acute myocardial infarction (odds ratio [OR], 1.2; 95% CI 1.11-

1.43), congestive heart failure (OR 1.25; 95% CI 1.07-1.46) and combined major cardiovascular events (OR 1.10; 95% CI 1.02-1.18) compared to the other drug classes. This

234 suggests that that clinical outcomes associated with CCB treatment are not dependent solely only on the magnitude of blood pressure reduction, but also on other factors. This claim has been refuted but more studies need to be done to clarify this area of controversy.

Recent RCTs have demonstrated increased risk of heart failure with CCB treatment (59, 60).

Another systematic review is being conducted currendy to assess adverse cardiac effects associated CCB therapy (386).

The blood pressure lowering efficacy observed in short-term trials of CCB monotherapy cannot be compared direcdy to long-term trials in which other drugs are allowed to be added to CCB treatment in order to meet blood pressure targets. Nonetheless, it is worth noting the magnitude of BP-lowering in long term, placebo-controlled CCB trials, where other drugs could be added if blood pressure targets were not reached. In the

SYST-Eur trial (70), first-line nitrendipine lowered BP by -10/-4.5 mm Hg (placebo- corrected), and a similar magnitude of blood pressure lowering was found with first-line nitrendipine in the SYST-China study (-9/-3 mm Hg) (69).

The choice between different classes of antihypertensive drugs should be based on morbidity and mortality data. Currendy, the first-line pharmacological treatment of hypertension is low-dose thiazide diuretics, which have been shown to reduce cardiovascular

events, cardiovascular mortality and total mortality compared with placebo. Thiazdes have

demonstrated a mean blood pressure reduction of 10/4 mm Hg in a previous systematic review (81), a magnitude that is similar to the calcium channel blocker class. However,

thiazide diuretics confer a reduction in heart failure outcomes as compared with CCBs. One

can speculate that the ability of thiazides to reduce pulse pressure more than CCBs (6 mm

Hg for thiazides vs 3 mmHg for dihydropyridines and 2 mm Hg for non-dihydropyridines) is a possible explanation for this difference. Further investigation of pulse pressure

235 differences in long term head-to-head trials between antihypertensive classes could be done to test this hypothesis.

Based on blood pressure lowering efficacy alone, the dihydropyridines appear to be better than non-dihydropyridines. However, this review does not suggest that dihydropyridines are better at lowering blood presssure than thiazides and considering the data on morbidity and mortality outcomes, calcium channel blockers should remain as second- or tlurd-Iine agents for management of primary hypertension.

236 5. CLINICAL IMPLICATIONS

The findings of this systematic review represent the best available evidence about the blood pressure lowering efficacy of calcium channel blockers in adults with primary hypertension. Several important conclusions are relevant to the clinical use of this class of drugs.

1. Dihydropyridines reduce blood pressure to a greater degree than non-dihydropyridines.

The best estimate of the maximal blood pressure lowering efficacy of the

dihydropyridine subclass is -10 mm Hg for SBP and -7 mm Pig for DBP. The best

estimate of the maximal blood pressure lowering efficacy of the non-dihydropyridine

subclass is -8 mm Pfg for SBP and -6 mm Pfg for DBP.

2. Publication bias was present in this systematic review, leading to an overestimate of the

effect size; the magnitude of this overestimate is likely between 0.4 mm Hg and 1.5 mm

Hg for SBP 0.3 and f .5 mm Hg for DBP.

3. There was a dose-response relationship for the blood pressure lowering efficacy of

CCBs. For dihydropyridines and non-dihydropyridines, half the starting dose lowered

blood pressure less and twice the starting doses lowered blood pressure more than

starting doses. Maximal blood pressure lowering appears to be achieved at twice the

manufacturer's recommended starting dose. Further dose escalation does not enhance

blood pressure lowering efficacy despite manufacturers' suggestions otherwise.

237 4. Regarding blood pressure variability:

a) Treatment of primary hypertension with calcium channel blockers does not affect

blood pressure variability compared with placebo.

b) Systolic and diastolic blood pressures vary to the same degree when the variability is

expressed as coefficient of variation.

c) Blood pressure criteria for entry into randomized controlled trials results in a

reduction in the estimate of the baseline variability of the corresponding parameter.

5. Regarding pulse pressure:

A) Placebo response does not affect change in pulse pressure.

B) Both dihydropyridines and non-dihydropyridine CCBs reduce pulse

pressure by about 3 mmHg.

6. Calcium channel blockers given for 3-12 weeks have a small and probably clinically

insignificant effect on heart rate.

a) For dihydropyridines, doses greater than or equal to 1.5 times the manfacturer's

recommended starting dose are associated with a statistically significant increase in

heart rate of 1.4 beats per minute.

b) For non-dihydropyridines, doses 1-3 times the manufacturer's recommended starting

dose are associated with a statistically significant decrease of 2.6 beats per minute.

7. All doses combined, dihydropyridines increase withdrawals due to adverse events

compared with placebo at starting doses (RR 1.7 [95% CI: 1.3, 2.1]; Absolute risk

increase 2%; number need to harm = 50). A dose-response relationship was present,

238 with a RR of 1.76 (95% CI 1.21, 2.58) at 1.5-3 times the starting dose, and a RR of 3.91

(95% CI 2.19, 6.99) at >3 times the starting dose. The non-dihydropyridine trials did not show a statistically significant difference in WDAE compared with placebo but this was probably due to lack of reporting.

Dose titration of calcium channel blockers above the recommended starting dose is associated with a minimal benefit in terms of increase in blood pressure lowering efficacy, and increased harm, in terms of increased withdrawals due to adverse effects and greater cost.

239 6. IMPLICATIONS FOR FUTURE RESEARCH

1. Because publication bias was found in this review, the published data on the short-term

blood pressure lowering efficacy of calcium channel blockers represents an incomplete

data set. Thus, all clinical trials should be registered and reported in full.

2. There is a need to improve the quality of reporting of details in publications of clinical

trials measuring blood pressure lowering efficacy. As systematic reviews are secondary

research, the validity of the results depends on the quality of its component trials.

A) Baseline and endpoint blood pressures, the mean change from

baseline and the standard deviations of all of these parameters must

be reported for all randomized groups and provided in a table.

B) The number of serious adverse events, deaths, number of

withdrawals due to adverse events in each group, reasons for

withdrawal, and the time point at which withdrawals occurred for

each group must be reported in all trials.

C) Complete information must be given regarding % of patients

completing the trial as well as the number of dropouts and reasons

thereof. Methodological details regarding randomization, allocation

concealment and blinding should be reported adequately to facilitate

assessment of trial quality. Complete baseline characteristic details

are also necessary to evaluate the effect size within trials and to

validate the combining of data across different trials in meta-analyses.

240 3. Improving the search capabilities and indexing systems of medical literature databases

and clinical trial registries will facilitate more complete and efficient searching for future

systematic reviews and updates. The Cochrane Central Register of Controlled Trial

(CENTRAL) is a highly sensitive, specific and up-to-date database which provides a

time-saving alternative to searching all of the standard electronic databases.

4. More clinical trials exploring a wider range of doses of calcium channel blockers need to

be conducted.

5. A systematic review of clinical trials with head-to-head comparisons of different doses of

each calcium channel blocker drug should be performed in order to validate the relative

blood pressure-lowering efficacies of the various drugs within this class.

6. A systematic review of cross-over trials of CCBs in hypertension should be performed to

validate the blood pressure-lowering efficacy of CCBs as determined by this systematic

review. Asssessment of end-of-treatment blood pressure standard deviations from

cross-over studies would give an estimate of the within-patient blood pressure variability.

7. A systematic review of the adverse effects of calcium channel blockers should be

performed in order to explore further the nature and severity of adverse events leading

to withdrawals from clinical trials.

8. More long-term trials of head-to-head comparisons of calcium channel blocker drugs

with other drug classes using doses with comparable blood pressure control need to be

241 performed in order to determine whether there are class-specific effects on morbidity and mortality.

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276 8. APPENDICES

8.1 Appendix A - Trial Selection Form

DATE OF REVIEW:

Reviewer (circle one): CT BH MW DM

STUDY UNIQUE IDENTIFIER

Other ID#

PUBLICATION DATE

JOURNAL

FIRST AUTHOR'S NAME

INCLUSION CRITERIA: YES NO UNCLEAR RANDOMIZED • • • DOUBLE-BLIND • • • PARALLEL PLACEBO ARM • • • >3 WEEKS DURATION • • • PATIENTS WITFI RENAL FAILURE EXCUDED • • •

HYPERTENSIVE PATIENTS i—i (DBP>90 mm Hg, SBP>140 mm Hg) 1 1 • • CCBs AS MONOTHERAPY • • •

BP MEASURED AT BASELINE AND BETWEEN 3- 1 1 12 WEEKS • •

INCLUDE • EXCLUDE • (if "YES" to all above)

Are authors to be contacted in order to decide inclusion/exclusion? Y / N

277 8.2 Appendix B - Standard data extraction form for each trial

DATA EXTRACTION FORM

(use one form per trial)

Administration Details

Paper title:

Paper number:

Study ID:

Other references to which this trial may link with:

Extractor name:

Characteristics of Included Studies

Funding Source (Potential Bias)

FOR AGAINST NO BIAS UNCLEAR

Methods

Design of Study:

Method of randomization:

Concealment of randomisation:

Was this concealment adequate/inadequate/unclear?

Blinding:

Description of withdrawals or dropouts:

278 Jadad's score:

Additional notes:

Participants

Total eligible for inclusion into trial:

Total number enrolled into trial:

Number in treatment group(s):

Number in placebo group: ;

Numbers of withdrawals or dropouts (treatment/control):

Numbers completing trial (treatment/control):

Age (mean): (range):

Sex:

Ethnicity:

Severity of hypertension (circle one):

Mild (DBP 90-105 mmHg) Moderate (DBP 105-115 mgHg) Severe (DBP > 115 mmHg)

Inclusion criteria:

Diagnostic entry criteria: SBP • DBP

Exclusion criteria:

279 Baseline characteristics:

Source of participants:

Co-morbid conditions: Rx: Rx: Placebo Obesity Hyperlipidemia Diabetes Smoking Myocardial infarction Angina Stroke Sedentary lifestyle Left ventricular hypertrophy

Additional notes:

Interventions

Duration of placebo run-in period:

Setting:

Types: •'_

Duration of treatment:

Compliance: Measured? Y/N % Patients compliant How compliant?

Goal of therapy: DBP or SBP

Additional notes:

280 Outcomes

Outcomes:

Adverse events:

Additional notes:

Cross-over trials

Run-in phase

Treatment & duration Control & duration

Washout phase.

Treatment & duration Control & duration

Additional notes:

Comparison(s) in this trial:

281

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