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Journal of Human (2001) 15, 559–565  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Efficacy and safety of a therapeutic interchange from high-dose blockers to a fixed-dose combination of / in patients with moderate-to-severe hypertension

DE Hilleman1, AP Reyes2, RL Wurdeman2 and M Faulkner1 1Creighton University School of Pharmacy and Allied Health Professions, 2500 California Plaza, Omaha, Nebraska 68178, USA; 2Creighton University Cardiac Center, 3006 Webster Street, Omaha, Nebraska 68131, USA

Background: Recent hypertension trials have demon- effects and the cost of the therapeutic interchange were strated the importance of achieving goal blood press- evaluated in the year following the therapeutic interchange. ures to reduce the risk of target organ damage. In Results: Sixty-six of the 75 (88%) patients were success- patients with moderate to severe hypertension, the use fully switched with maintenance of blood pressure con- of high-dose monotherapy and/or combinations of trol and without the development of new dose-limiting drugs are necessary to achieve these goals. Fixed-dose side effects. Reasons for treatment failure after the combination products may be useful in these patients therapeutic interchange included loss of blood pressure by reducing the number of daily doses required to con- control in five patients and the development of new trol blood pressure. dose-limiting side effects in four patients. These side Objective: The objective of the present study was to effects included cough in three patients and rash in one evaluate the efficacy and safety of a therapeutic inter- patient. After accounting for differences in drug acqui- change between high-dose calcium sition cost and costs related to the switch (clinic and therapy and a fixed-dose combination of amlodipine/ emergency room and laboratory tests), a cost savings benazepril (Lotrel; Pharmaceuticals, USA) in of $16030 for all 75 patients was realised in the first patients with moderate to severe hypertension. year. The per patient-per year cost savings was $214. Methods: A total of 75 patients were switched from amlodi- Conclusions: Our data indicate that a therapeutic inter- pine (n = 25), (n = 25), and -GITS (n = change from selected high-dose calcium channel block- 25) to amlodipine/benazepril. Twenty-eight of the 75 ers to a fixed-dose combination of amlodipine/ patients (37%) were taking either a beta-blocker or a benazepril can be successfully accomplished in the diuretic in addition to the high-dose calcium channel majority of patients. blocker prior to the switch. Blood pressure control, side Journal of Human Hypertension (2001) 15, 559–565

Keywords: combination therapy; cost-effectiveness; ACE inhibitor; ; amlodipine; benazepril; felo- dipine; nifedipine

Introduction goal blood pressure reduces target organ damage.1,2 Recent clinical trials such as the Hypertension Opti- In patients with higher elevations of blood pressure, mal Treatment (HOT) trial and the Captopril Preven- achievement of goal blood pressure often requires tion Project (CAPP) indicate that achievement of the use of high dose monotherapy or the combi- nation of two or more antihypertensive agents.1,3 Fixed-dose combination antihypertensive agents Correspondence: Daniel E Hilleman, PharmD, Creighton Univer- represent a therapeutic alternative to high dose sity School of Pharmacy and Allied Health Professions, 2500 Cali- monotherapy or to multiple drug combinations in fornia Plaza, Omaha, Nebraska 68178, USA. Fax: 001 402 280 4 1268 the treatment of hypertension. Received 29 November 2000; revised 16 January and 22 February The fixed-dose combination of amlodipine/  2001; accepted 16 March 2001 benazepril (Lotrel ) was the first calcium channel Interchange from CCBs to amlodipine/benazepril DE Hilleman et al 560 blocker/-converting enzyme inhibitor first or any subsequent follow-up visit, the dose of combination marketed in the United States. This amlodipine/benazepril was increased to the combination has been shown to have a superior 5 mg/10 mg dose and then to the 5 mg/20 mg dose, blood pressure lowering effect compared to its indi- if necessary. Additional physician office visits were vidual drug components with an excellent safety allowed at the discretion of the primary care phys- profile.5 The objective of this study was to evaluate ician. Laboratory tests or other diagnostic tests were the efficacy, safety, and cost of a therapeutic inter- not required by protocol, but were allowed at the change from high dose amlodipine, felodipine, or discretion of the primary care physician. If dose- nifedipine-GITS therapy to a fixed-dose combi- limiting side effects occurred or if the 5 mg/20 mg nation of amlodipine/benazepril in patients with dose of amlodipine/benazepril failed to maintain moderate to severe hypertension. blood pressure, patients were switched back to their original calcium channel blocker. These patients Patients and methods were classified as treatment failures. Patients defined as having a successful switch were required Patients aged 35 to 70 years without restrictions to have three consecutive monthly BP readings on regarding gender or race were eligible to participate amlodipine/benazepril that were within 5 mm Hg of in the trial. Diastolic blood pressure prior to the their last diastolic and systolic BP reading on cal- initiation of any antihypertensive therapy had to be cium channel blocker therapy. Patients successfully between 95 and 115 mm Hg. Pretreatment systolic switched to the fixed-dose combination product blood pressure had to be less than 180 mm Hg. were allowed to continue this therapy as mainte- Patients had to be treated with stable doses of amlo- nance therapy. Patients were followed for one year dipine 10 to 20 mg per day, felodipine 10 to 20 mg after the switch to amlodipine/benazepril. per day, or nifedipine-GITS 60 to 120 mg per day for a minimum of 6 months prior to study entry. Cost analysis Patients who were receiving a maximum of one additional antihypertensive agent (restricted to The cost analysis included direct medical costs either a diuretic or a beta-blocker) prior to incurred by patients who were switched to the initiation of calcium channel blocker therapy amlodipine/benazepril. Direct medical costs of the could continue that therapy as long as the dose of switch included the acquisition cost of the drugs, that drug remained constant throughout the study. costs of all clinic and emergency room visits, and Diastolic blood pressure on antihypertensive ther- laboratory and diagnostic test costs. apy prior to the switch to amlodipine/benazepril Acquisition costs of drugs were based on 2000 PC had to have been reduced to р90 mm Hg or had to Price-Chek (MediSpan Inc; St Louis, MO, USA).6 have decreased by у10 mm Hg from pretreatment Costs for clinic and emergency room visits were $28 values. and $300, respectively. Laboratory test costs were as Patients with renal (serum creatinine Ͼ2.0 mg/dL) follows: electrolytes with renal function, $24; com- or hepatic dysfunction (serum aminotransferase lev- plete blood count, $19; metabolic profile els two times greater than the upper limit of normal) (electrolytes, lipids, renal, hepatic) $38; and 12-lead were excluded. Patients with unstable , myo- electrocardiograms were $12. All health care con- cardial infarction or coronary revascularisation in tacts and laboratory/diagnostic tests that occurred in the 6 months prior to study enrollment were the year following the switch to excluded. Patients with symptomatic , amlodipine/benazepril were included in the cost left ventricular dysfunction defined as an ejection analysis. fraction р40%, cardiac arrhythmias requiring antiarrhythmic therapy or an implantable cardio- Results verter-defibrillator were excluded. Patients judged to be noncompliant with antihypertensive medi- Seventy-five patients stabilised on amlodipine (n = cation (Ͻ80% prescription refill history in the prior 25), felodipine (n = 25), or nifedipine-GITS (n = 25) 6 months) were excluded. for moderate to severe hypertension were switched from their calcium channel blocker to amlodipine/benazepril (Table 1). Baseline clinical Study design characteristics and blood pressures were similar Patients who met eligibility criteria had their cal- among the patients treated with the three different cium channel blocker therapy discontinued without calcium channel blockers. Twenty-eight of the 75 dose tapering. On the day following discontinu- (37%) patients were already taking and continued ation, these patients were started on the amlodipine/ either a diuretic (n = 10) or a beta-blocker (n = 18) benazepril combination at the 2.5 mg/10 mg dose. during calcium channel blocker therapy. Following the switch, patients were seen in the Blood pressure response and adverse effects clinic at monthly intervals. If the patient’s diastolic observed during therapy with calcium channel block- blood pressure was Ͼ5 mm Hg higher or if the sys- ers is summarised in Table 2. Patients switched to the tolic blood pressure was Ͼ10 mm Hg higher at the fixed-dose combination product is summarised in

Journal of Human Hypertension Interchange from CCBs to amlodipine/benazepril DE Hilleman et al 561 Table 1 Clinical characteristics of patients switched to amlodipine/benazepril (n = 75)

Parameter Initial calcium channel blocker therapy

Amlodipine Felodipine Nifedipine-GITS (n = 25) (n = 25) (n = 25)

Age (years) 56 ± 12 59 ± 13 57 ± 14 Gender (men/women) 18/7 17/8 17/8 Past medical history 3 2 3 7 6 6 Coronary revascularisation 1 2 1 Diabetes mellitus 4 4 4 Arthritis 3 2 2 Gastrointestinal disease 2 1 1 Psychiatric illness 0 1 1 Thyroid disease 1 1 0 Blood pressure prior to start of any 156 ± 80 155 ± 10 158 ± 10 antihypertensive therapy 107 ± 4 108 ± 6 106 ± 8 Patients receiving another 9 (36) 13 (52) 6 (24) prior to and during CCB therapy Thiazide diuretic 3 5 2 Beta blocker 6 8 4

CCB, calcium channel blocker.

Table 2 Blood pressure response and adverse effects with calcium channel blocker therapy

Parameter Initial calcium channel blocker therapy

Amlodipine Felodipine Nifedipine-GITS (n = 25) (n = 25) (n = 25)

Blood pressure (mm Hg) prior to start of CCB 148 ± 9 151 ± 11 150 ± 12 therapy 102 ± 5 103 ± 8 101 ± 4 Duration of CCB therapy (mos) 9.7 ± 11.3 12.4 ± 8.3 14.7 ± 11.1 Daily doses of CCB (n) 10 mg (17) 10 mg (16) 60 mg (15) 15 mg (6) 15 mg (5) 90 mg (8) 20 mg (2) 20 mg (4) 120 mg (2) Blood pressure on calcium channel blocker 134 ± 8 135 ± 10 132 ± 11 therapy (mm Hg) 90 ± 788± 12 87 ± 8 Side effects on CCB therapy (n) oedema (10) oedema (12) oedema (15) (2) rash (3) headache (8) headache (2) headache (2) flushing (4) flushing (1) flushing (1) dizziness (2) weakness (1) dyspepsia (1) dizziness (1) weakness (1) diarrhoea (1) dyspepsia (1) Number of patients reporting one or more side 8 (32%) 11 (44%) 14 (56%) effects on CCB (%)

CCB, calcium channel blocker.

Table 3. Mean blood pressure during amlodipine/ patients on nifedipine-GITS were successfully benazepril therapy was not significantly different switched to the amlodipine/benazepril combination. from that observed during baseline calcium channel Thirty-three patients required one dose titration and blocker therapy. A total of 66 of the 75 (88%) patients 12 patients required two dose titrations with were successfully switched to fixed-dose amlodipine/benazepril to maintain BP control similar amlodipine/benazepril combination therapy. Twenty- to that with calcium channel blocker therapy. two of 25 (88%) patients on amlodipine, 23 of 25 Reasons for treatment failure with amlodipine/ (92%) patients on felodipine, and 21 of 25 (84%) benazepril included failure to maintain blood press-

Journal of Human Hypertension Interchange from CCBs to amlodipine/benazepril DE Hilleman et al 562 Table 3 Outcomes of patients converted from calcium channel blocker therapy to a fixed-dose amlodipine/benazepril combination ther- apy

Parameters Initial calcium channel blocker therapy

Amlodipine Felodipine Nifedipine-GITS (n = 25) (n = 25) (n = 25)

Patients with BP control without dose limiting 22 (88%) 23 (92%) 21 (84%) side effects on AML/BZ (%) Reasons for treatment failure Loss of BP control 1 0 4 Side effects 2 2 0 BP on AML/BZ (mm Hg) 132 ± 9 131 ± 8 134 ± 12 89 ± 887± 10 89 ± 14 Final doses of AML/BZ in patients successfully 2.5/10 (7) 2.5/10 (9) 2.5/10 (5) converted 5/10 (13) 5/10 (11) 5/10 (9) 5/20 (2) 5/20 (3) 5/20 (7) Side effects on AML/BZ therapy (n) cough (3) cough (2) cough (3) oedema (1) oedema (1) oedema (3) headache (2) rash (1) dizziness (2) dizziness (1) dyspepsia (1) weakness (1) rash (1) diarrhoea (1) Patients reporting side effects on AML/BZ (%) 4 (16%) 4 (16%) 5 (20%)

AML/BZ, amlodipine/benazepril; BP, blood pressure.

ure control in five patients and the development of Table 4 Cost of therapeutic interchange from calcium channel dose-limiting side effects in four patients. Treatment blocker failure due to loss of blood pressure control Cost parameter Calcium channel Amlodipine/ Difference occurred with four patients previously on nifedip- blocker therapy benazepril ine-GITS and in one patient previously on amlodip- therapy ine. Daily doses of calcium channel blockers prior to switch in patients failing due to loss of blood Acquisition cost pressure control included nifedipine-GITS Total $75300 $48075a $27225 90 mg/day in three patients, nifedipine-GITS Per patient $1004 $641 $363 120 mg/day in one patient, and amlodipine Clinic visit cost 20 mg/day in one patient. Total N/A $8596 −$8596 − The overall frequency of side effects was signifi- Per patient N/A $115 $115 cantly less during amlodipine/benazepril therapy Emergency room (13/75; 17%) compared to calcium channel blocker cost Ͻ Total N/A $300 −$300 therapy (33/75; 44%) (P 0.05) (Tables 1 and 2). Per patient N/A $4 −$4 Side effects resulting in discontinuance of amlodipine/benazepril included cough in three Laboratory/Diagnostic test cost patients and maculopapular rash in one patient. Total N/A $2299 −$2299 Patients failing amlodipine/benazepril therapy were Per patient N/A $31 −$31 switched back to their original calcium channel blocker. All nine treatment failures were success- Total cost for $75300 $59270 $16030 group fully treated to their original blood pressure level Total per patient $1004 $790 $214 after restarting their original calcium channel blocker therapy. aIncludes the acquisition cost of calcium channel blockers in nine The cost of the therapeutic interchange is sum- patients who failed amlodipine/benazepril who were switched marised for all patients in Table 3 and by the orig- back to their original drug. inal individual calcium channel blocker in Table 4. Overall, a $214 per patient per year cost savings was realised. The primary cost advantage of the fixed- tic test costs incurred by patients who were dose combination product was a $363 per patient switched to amlodipine/benazepril (Table 5). The per year lower acquisition cost than high-dose cal- total cost savings for all 75 patients switched to cium channel blocker therapy. This saving was par- amlodipine/benazepril was $16030. The cost sav- tially offset by the increased costs of clinic and ings of the switch based on the original calcium emergency room visits and laboratory and diagnos- channel blocker varied widely. In the first year after

Journal of Human Hypertension Interchange from CCBs to amlodipine/benazepril DE Hilleman et al 563 Table 5 Cost analysis of therapeutic interchange from the individual calcium channel blockers to amlodipine/benazepril

Cost parametera AML AML/BZ ⌬ FEL AML/BZ ⌬ NIF-GITS AML/BZ ⌬

Acquisition cost $967 $637 $330 $725 $600 $125 $1180 $686 $494 Clinic visit cost N/A $113 −$113 N/A $110 −$110 N/A $121 −$121 Emergency room visit cost N/A $0 −$0 N/A $12 −$12 N/A $0 −$0 Laboratory/diagnostic test cost N/A $32 −$32 N/A $29 −$29 N/A $31 −$31 Total $967 $782 $185 $725 $751 −$26 $1180 $838 $342 aCost is reported as cost per patient per year; AML, amlodipine; AML/BZ, amlodipine/benazepril fixed-dose combination; FEL, felodip- ine; NIF-GITS nifedipine-GTS. the switch, cost savings were realised in patients an alternative therapeutic choice in patients requir- switched from amlodipine ($185 per patient per ing a combination of individual drugs or in patients year) and nifedipine-GITS ($342 per patient per requiring high doses of individual drugs. year). However, an excess cost of $26 per patient per In our study, we evaluated the efficacy, safety, and year occurred in patients from felodipine to costs in patients requiring high doses of calcium amlodipine/benazepril. This excess cost resulted channel blockers alone or in combination with one from the higher acquisition cost of amlodipine/ other antihypertensive agent who were switched to benazepril compared to felodipine. The cost savings the fixed-dose combination of amlodipine/ that could be realised in the years after the initial benazepril. We have demonstrated that almost 90% interchange should reflect only differences in acqui- of patients on high dose calcium channel blockers sition cost between the drugs. The additional costs could be successfully switched to amlodipine/ of ensuring continued efficacy and safety reflected benazepril. In addition to the maintenance of blood in laboratory and other diagnostic test costs ordered pressure control, the incidence of side effects was after the switch would not be incurred. lower on the fixed-dose combination. A lower inci- dence of adverse effects may also have potential cost Discussion savings (although this was not specifically evaluated in this study). It is important to note that 19 of the It is well established that lower blood pressure is 75 (25%) patients in this study were taking calcium 7 associated with less target organ damage. The JNC- channel blocker dosages that were higher than rec- VI treatment guideline recommendations and other ommended.7 recent clinical trial data support achievement of goal The total cost savings associated with the thera- blood pressures to reduce the risk of adverse clinical 1,2,7 peutic interchange from calcium channel blockers to events. Achieving an optimal outcome in hyper- amlodipine/benazepril in our 75 patients was tensive patients requires achieving a balance $16030 ($214 per patient) in the first year after the between the favourable effects of treatment that low- switch. The average acquisition cost of ers blood pressure and the adverse consequences of amlodipine/benazepril was $641 per patient per such treatment. Drug therapy is clearly effective in year compared to $1004 for high dose calcium chan- lowering blood pressure and reducing the risk of nel blockers. This $363 difference in acquisition stroke and myocardial infarction.1,2,7 Adverse conse- cost was partially offset by switch-related costs quences that need to be considered with antihyper- including additional clinic visits and tensive drug therapy include the side effects of drugs and the costs of using these drugs. laboratory/diagnostic test. An alternative to using high-dose monotherapy or It is of some interest to note that differences in the combinations of drugs is the fixed-dose single-pill cost of the switch were influenced by the original antihypertensive combinations. A number of fixed- calcium channel blockers used. Costs savings were dose combination antihypertensive therapies are realised in the first year for amlodipine and nifedip- currently available in the United States.7 These com- ine-GITS, but not with felodipine. The reason for binations have traditionally included a diuretic this difference in patients receiving felodipine combined with either a beta-blocker or an angioten- resulted from its lower acquisition cost. The annual sin-converting enzyme inhibitor.8–10 In the early average acquisition cost for felodipine was $725 1990s, the first calcium channel blocker/ compared to $600 for amlodipine/benazepril. This angiotensin-converting enzyme inhibitor combi- difference in acquisition cost ($125) was substan- nation (Lotrel; amlodipine/benazepril, Novartis) tially less than that seen with amlodipine ($330) and was made available in the United States. This com- nifedipine-GITS ($494). It should be pointed out bination provides blood pressure lowering that is that cost savings in the years subsequent to the superior to amlodipine or benazepril alone with a switch would reflect only the differences in acqui- side effect profile that is similar to or better than sition cost between the products. The costs of clinic either agent alone.5 This product can be viewed as visits and laboratory tests to ensure continued safety

Journal of Human Hypertension Interchange from CCBs to amlodipine/benazepril DE Hilleman et al 564 and efficacy would not be incurred in subsequent hypertension: the Captopril Prevention Project (CAPP) years. Randomised Trial. Lancet 1999; 353: 611–616. Therapeutic interchange programmes have prim- 3 Sutton JM, Bagby SP. Non-traditional combination arily been used to evaluate the cost-effectiveness of pharmacotherapy of hypertension. Clev Clin J Med substituting one drug for another in the same thera- 1992; 59: 459–468. 11–17 4 Sakurai Y et al. Management of severe hypertension peutic class. Switching patients from more with nifedipine in combination with clonidine or pro- expensive acquisition cost agents to lower acqui- pranolol. Arzneimittelforschung 1980; 30: 674–678. sition cost drugs is a strategy that may appear to be 5 Frishman WH et al. Comparison of amlodipine and economically sound, but should be confirmed by benazepril monotherapy to amlodipine plus benazep- evaluating not only the differences in acquisition ril in patients with systemic hypertension: a ran- cost of the products that are switched, but also the domized, double-blind, placebo-controlled, parallel- costs involved with switching, which include group study. J Clin Pharmacol 1995; 35: 1060–1066. additional clinic visits and diagnostic or laboratory 6 Price-Chek PT. Version 2.16. St. Louis (MO). Medi- testing to reconfirm efficacy, the need to titrate the Span, Inc. 2000. drugs or add additional therapy, and the occurrence 7 Joint National Committee on Detection P, Evaluation, and Treatment of High Blood Pressure. The Sixth of any new side effects that develop following such Report of the Joint National Committee on the Preven- a product switch. We have established that thera- tion, Detection, Evaluation, and Treatment of High peutic interchange between higher doses of selected Blood Pressure (JNC VI). Arch Intern Med 1997; 157: calcium channel blockers and the fixed-dose combi- 2413–2446. nation product containing amlodipine/benazepril is 8 Frishman WH et al. A multifactorial trial design to not only safe and effective, but also cost-effective. assess combination therapy in hypertension: treatment One other potential advantage involved in our with bisoprolol and . Arch Intern therapeutic interchange is the fact that ACE inhibi- Med 1994; 154: 1461–1468. tors have been recently shown to reduce cardio- 9 Epstein M, Bakris G. Newer approaches to antihyper- vascular events in patients with complicated hyper- tensive therapy: use of fixed-dose combination ther- 18 apy. Arch Intern Med 1996; 156: 1969–1978. tension. In contrast, continued concern exists 10 Gradman AH et al. Combined enalapril and felodipine regarding the use of calcium channel blockers, extended release (ER) for systemic hypertension. Am especially high dose therapy, in hypertensive J Cardiology 1997; 79: 431–435. patients.19 The role of calcium channel blockers in 11 Mohiuddin SM, Hilleman DE. Substituting nifedipine- hypertension remains controversial, with data both GITS for immediate-release calcium channel antagon- supporting and condemning their use.20,21 The ulti- ist in patients with stable angina pectoris. Curr Ther mate benefit of one class of antihypertensive therapy Res 1991; 50: 546–552. over another may not be known until the results of 12 Lorman L, Borysiuk L. Replacing lovastin with pravas- large in-progress mega-trials have been com- tatin: effect on serum lipids and costs. AJHP 1995; 52: pleted.22,23 1078–1082. 13 Nael H. Formulary conversion from to glybu- Our study has a number of limitations, including ride: cost-minimization analysis. Hosp Pharm 1995; a lack of blinding, the retrospective nature of our 30: 467–469, 472–474. data collection for calcium channel blocker therapy, 14 Oh T, Franko T. Comprehensive therapeutic inter- failure to randomise patients to therapy, and the change program in a community hospital. Am J Hosp lack of a placebo baseline period prior to initiation Pharm 1991; 48: 1471–1478. of amlodipine/benazepril. This study was primarily 15 Sotek AJ, Krofeod L. Therapeutic interchange of designed to reflect the practice employed by man- fluoxetine and sertraline: experience in the clinical aged care organisations who institute therapeutic setting. Am J Hosp Pharm 1994; 52: 2279–2281. interchange programmes. Despite these limitations, 16 Lindgren-Furmaga E, Schuna A, Wolf N. Cost of we believe our results represent a fair estimation of switching hypertensive patients from enalapril male- ate to lisinopril. Am J Hosp Pharm 1991; 48: 276–279. the costs and blood pressure outcomes associated 17 Rosen A, Kay B, Halecky D. Implementing a thera- with this type of therapeutic interchange. Our peutic interchange program in an institutional setting. results, however, cannot be extrapolated to other PT 1995; 20: 711–717. calcium channel blockers or to other classes of anti- 18 Yusuf S et al. Effects of angiotensin-converting hypertensive agents. enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; References 342: 145–153. 19 Pahor M et al. Therapeutic effects of calcium antagon- 1 Hansson L et al. Effects of intensive blood-pressure ists and other antihypertensive drugs. Circulation lowering and low-dose in patients with hyper- 2000; 102 (Suppl II): II–519. tension: principal results of the Hypertension Optimal 20 Hansson L et al. Randomized trial of effects of calcium Treatment (HOT) randomized trial. Lancet 1998; 351: antagonists compared with diuretics and beta-blockers 1755–1762. on cardiovascular morbidity and mortality in hyper- 2 Hansson L et al. Effect of angiotensin-converting- tension: the Nordic (NORDIL) Study. Lancet enzyme inhibition compared with conventional ther- 2000; 356: 359–365. apy on cardiovascular morbidity and mortality in 21 Brown MJ et al. Morbidity and mortality in patients

Journal of Human Hypertension Interchange from CCBs to amlodipine/benazepril DE Hilleman et al 565 randomized to double-blind treatment with a long-act- 23 World Health Organisation-International Society of ing calcium channel blocker or diuretic in the Inter- Hypertension Blood Pressure Lowering Treatment Tri- national Nifedipine-GITS Study: Intervention as a alists’ Collaboration. Protocol for prospective collabor- Goal in Hypertension Treatment (INSIGHT). Lancet ative overviews of major randomized trials of blood- 2000; 356: 366–372. pressure lowering treatments. J Hypertens 1998; 16: 22 ALLHAT Collaborative Research Group. Major cardio- 127–137. vascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. JAMA 2000; 283: 1967–1975.

Journal of Human Hypertension