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Home , Aliskiren, Lisinopril, Perindopril, Tolerability

Journal of Human (2007) 21, 780–787 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh ORIGINAL ARTICLE A comparison of the tolerability of the direct inhibitor and in patients with severe hypertension

RH Strasser1, JG Puig2, C Farsang3, M Croket4,JLi5 and H van Ingen4 1Technical University Dresden, Heart Center, University Hospital, Dresden, Germany; 2Department of Internal , La Paz Hospital, Madrid, Spain; 31st Department of , Semmelweis University, Budapest, Hungary; 4Novartis Pharma AG, Basel, Switzerland and 5Novartis Institutes for Biomedical Research, Cambridge, MA, USA

Patients with severe hypertension (4180/110 mm Hg) LIS 3.4%). The most frequently reported AEs in both require large blood pressure (BP) reductions to reach groups were headache, nasopharyngitis and dizziness. recommended treatment goals (o140/90 mm Hg) and At end point, ALI showed similar mean reductions from usually require combination to do so. This baseline to LIS in msDBP (ALI À18.5 mm Hg vs LIS 8-week, multicenter, randomized, double-blind, parallel- À20.1 mm Hg; mean treatment difference 1.7 mm Hg group study compared the tolerability and antihyperten- (95% confidence interval (CI) À1.0, 4.4)) and mean sitting sive of the novel direct aliskiren systolic blood pressure (ALI À20.0 mm Hg vs LIS with the converting À22.3 mm Hg; mean treatment difference 2.8 mm Hg lisinopril in patients with severe hypertension (mean (95% CI À1.7, 7.4)). Responder rates (msDBPo90 mm Hg sitting diastolic blood pressure (msDBP)X105 mm Hg and/or reduction from baselineX10 mm Hg) were 81.5% and o120 mm Hg). In all, 183 patients were randomized with ALI and 87.9% with LIS. Approximately half of (2:1) to aliskiren 150 mg (n ¼ 125) or lisinopril 20 mg patients required the addition of HCTZ to achieve BP (n ¼ 58) with dose titration (to aliskiren 300 mg or control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, lisinopril 40 mg) and subsequent addition of hydrochlor- or in combination with HCTZ, exhibits similar tolerability othiazide (HCTZ) if additional BP control was required. and antihypertensive efficacy to LIS alone, or in Aliskiren-based treatment (ALI) was similar to lisinopril- combination with HCTZ, in patients with severe hyper- based treatment (LIS) with respect to the proportion of tension. patients reporting an adverse event (AE; ALI 32.8%; LIS Journal of Human Hypertension (2007) 21, 780–787; 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; doi:10.1038/sj.jhh.1002220; published online 31 May 2007

Keywords: aliskiren; renin–angiotensin system; angiotensin converting enzyme inhibitor; severe hypertension; ; combination therapy

Introduction 3 hypertension),2,3 with a treatment target of o140/ 90 mm Hg. Due to the large BP reductions required Patients with severe hypertension are at particularly for patients with severe hypertension to reach their high cardiovascular risk due to the direct and treatment goals, combination therapy is almost independent relationship between blood pressure invariably required. (BP) and the risk of mortality due to and 1 Existing antihypertensive are associated ischaemic heart disease. Current treatment guide- with high rates of discontinuation, despite the lines define severe hypertension as BP4160/100 mm proven clinical benefit of reducing BP.4,5 A recent Hg (stage 2 hypertension) or 4180/110 mm Hg (grade population-based study of 4100 000 patients with hypertension found that compliance with older Correspondence: Professor RH Strasser, Technische Universita¨t classes, such as , b-blockers and calcium Dresden, Herzzentrum Dresden, Universita¨tsklinik, Fetscherstr. channel blockers, was as low as 36–59% after 76, 01307 Dresden, Germany. 1year.5 Compliance was better with newer treatments, E-mail: [email protected] such as angiotensin converting enzyme (ACE) Trial registry: This trial is registered at ClinicalTrials.gov with inhibitors (62%) and angiotensin blockers trial identifier NCT00219050. 5 Received 31 October 2006; revised 16 March 2007; accepted 17 (ARBs; 71%). These differences are suspected to be March 2007; published online 31 May 2007 due to the poor tolerability of some of these .5 Tolerability of aliskiren in patients with severe hypertension RH Strasser et al 781 Significant adverse events (AEs) associated with the study drugs; and known or suspected contra- conventional classes include indications to the study . fatigue or dizziness in 16% of patients receiving The study was performed in compliance with the b-blockers,6 Oedema in up to 70% of patients Guidelines for Good Clinical Practice and the receiving calcium channel blockers6,7 and a dry, Declaration of Helsinki of the World Medical non-productive cough in 5–35% of patients receiv- Association, and received approval by the appro- ing treatment with ACE inhibitors.6,8,9 However, this priate independent ethics committees. All partici- does not explain the poor compliance observed with pants gave written informed consent before any diuretics, which have few symptomatic side effects.5 study-related procedure. Inhibitors of the renin system, such as ACE inhibitors and ARBs, do not provide optimal suppression of the renin system as they stimulate a Study design reactive increase in plasma renin activity, which This was an 8-week, randomized, double-blind, may ultimately lead to elevated angiotensin II active-controlled, parallel-group study of aliskiren levels.10 Consequently, direct inhibition of renin compared with lisinopril (both with the optional (that is, targeting the renin system at its point of addition of HCTZ to achieve BP control) in adult activation) has long been proposed as the most patients with uncomplicated severe hypertension. promising means of inhibiting the renin system.11 Owing to the severity of the disease, the use of a Aliskiren will be the first in a new class of oral placebo treatment was not employed. Lisinopril was direct renin inhibitors for the treatment of hyperten- selected as an active control because it is commonly sion. Aliskiren is a highly potent inhibitor of human used to treat patients with severe hypertension. renin in vitro (IC50 ¼ 0.6 nmol/l) and in healthy The primary objective of this study was volunteers.12,13 Studies in patients with mild- to compare the tolerability of aliskiren-based treat- to-moderate hypertension (ESH-ESC grade 1 or 2, ment with treatment based on the ACE inhibitor, or JNC7 stage 1) have shown that aliskiren provides lisinopril. The BP-lowering efficacy of these two similar antihypertensive efficacy and tolerability to treatments was a secondary objective of this study. ARBs,14,15 and that addition of The study consisted of three periods (Figure 1). (HCTZ) to aliskiren produces significant additional Eligibility for study entry was assessed at an initial BP-lowering effects with maintained good tolerabil- study visit and eligible patients then entered a ity.16 Aliskiren alone or in combination with HCTZ washout phase (period 1) of up to 10 days, during has also been shown to provide highly effective BP which all other antihypertensive medications were lowering with excellent tolerability over X1-year withdrawn. However, due to the severity of hyper- period of treatment.17 tension, and the potential increased cardiovascular The aim of the present study was to assess the risk associated with the withdrawal of antihyper- tolerability and antihypertensive efficacy of aliskiren- tensive , the washout period was de- based treatment compared with treatment based on signed to minimize the length of time patients the ACE inhibitor, lisinopril, in patients with severe remained untreated. Consequently, antihypertensive hypertension. medications were withdrawn for a minimum of 3 days and all participants with an msDBPX105 mm Hg and o120 mm Hg at the end of the washout Materials and methods period proceeded immediately to the active treat- ment phase of the study (period 3). Patients with Study population msDBPX85 mm Hg and o105 mm Hg after the This study enrolled 194 patients aged X18 years washout phase entered a single-blind placebo run- with uncomplicated severe hypertension (mean in of 1–3 weeks (period 2). During this period, BP sitting diastolic blood pressure (msDBP)X105 mm Hg was monitored weekly up to a maximum of 3 weeks and o120 mm Hg) from 12 study centres in to assess eligibility for randomization (msDBPX Germany, 9 in Spain and 5 in Hungary. 105 mm Hg and o120 mm Hg). Participants who Exclusion criteria included a history or evidence failed to meet the eligibility criteria after 3 weeks of secondary hypertension; antihypertensive treat- were discontinued from the study. Any patient with ment with more than three classes of antihyperten- an msDBPX120 mm Hg and/or a mean sitting sive medication; mellitus requiring insulin systolic blood pressure (msSBP)X200 mm Hg at treatment; type II diabetes mellitus with poor any time during the washout or single-blind placebo glucose control (HbA1C48% at Visit 1); diagnosed run-in periods was immediately discontinued from ; history of , cor- the study. onary bypass , or any percutaneous coronary In period 3, all patients who met the inclusion intervention; angina pectoris; potentially life- criteria were randomized in a 2:1 ratio to receive threatening arrhythmia or symptomatic arrhythmia aliskiren 150 mg or lisinopril 20 mg once daily. BP or other life-threatening disease; any surgical or was assessed weekly for the first 2 weeks and medical condition that might significantly alter the every 2 weeks thereafter. For patients with msDBPX absorption, distribution, metabolism or of 110 mm Hg or msSBPX180 mm Hg at the end of

Journal of Human Hypertension Tolerability of aliskiren in patients with severe hypertension RH Strasser et al 782

Figure 1 Study design. Dashed arrows represent titration of treatment doses for patients whose BP was not controlled to the appropriate target levels at weeks 1 or 2. Solid arrows indicate titration of drug doses at week 4 for patients who did not undergo early titration, but whose BP was not controlled to target level at week 4. BP, blood pressure.

week 1, or with msDBPX95 mm Hg or accuracy and instructed the site personnel to make msSBPX160 mm Hg at the end of week 2, the any required corrections or additions. Quality treatment dose was doubled (to aliskiren 300 mg or control audits of all key safety and efficacy data in lisinopril 40 mg). Subsequent addition of HCTZ the database were carried out before database lock. 25 mg was permitted for these patients if msDBP X X was 95 mm Hg or msSBP remained 160 mm Hg Tolerability assessments X at weeks 2 or 4, or if msDBP was 90 mm Hg or The safety population was defined as all rando- X msSBP was 140 mm Hg at week 6 (Figure 1). For mized patients who received at least one dose of patients who did not require early titration at weeks study medication. All AEs, serious adverse events 1 or 2, doses were increased to aliskiren 300 mg, or (SAEs) and use of concomitant medications were lisinopril 40 mg at the end of week 4 if BP was not recorded at each study visit. Non-directive ques- controlled to target levels (msDBPo90 mm Hg and tioning was used to elicit information on AEs; for all msSBPo140 mm Hg). AEs, the severity, relationship to study drug and Aliskiren 150 mg and matching placebo were duration were assessed, and any action taken was provided as film-coated tablets. Lisinopril 20 mg, recorded. lisinopril 40 mg and matching placebo were pro- Evaluations of routine blood chemistry, haematol- vided as identically appearing capsules, as were ogy and urine values, as well as a physical HCTZ 25 mg and matching placebo. Patients were examination, vital signs and ECG recordings, were requested to take the study medication orally with performed at screening, randomization (start of water at approximately 0800 hours, except on the period 3) and after the completion of the study. day of a study visit. Randomization was performed by the interactive voice response system provider using a validated Efficacy assessments system that automates the random assignment of BP and pulse rate were measured at follow-up visits treatment groups to randomization numbers. All on weeks 1, 2, 4, 6 and 8 of the double-blind treatment period. Sitting and standing BP was patients, investigator staff, persons performing the 7 assessments and data analysts remained blinded to measured at trough (24 3 h post-dose) from the the identity of the treatment from the time of arm in which the highest sitting DBP was found at randomization until database lock. the first study visit, using a calibrated standard Each investigator site was supplied with a sphygmomanometer. Three measurements were computer loaded with electronic data capture soft- taken at each visit and the average of the three ware and investigator site staff were trained to use measurements was used for analysis. Pulse rate was this system by personnel. All required data measured for 30 s immediately before the first sitting were entered into the electronic case report forms BP measurement. (eCRFs) by designated investigator site personnel before transfer to Novartis via a secure Virtual Statistical analyses Private Network. Novartis staff reviewed the eCRFs Patients were randomized in a 2:1 ratio between entered by investigational staff for completeness and aliskiren and lisinopril treatment groups, respec-

Journal of Human Hypertension Tolerability of aliskiren in patients with severe hypertension RH Strasser et al 783 tively. The lisinopril treatment group contained patients were male (56.8%). The mean age of fewer patients as lisinopril served solely as a patients was 55 years with a mean duration of reference drug for the evaluation of the tolerability hypertension of 9 years. Nearly half of patients were of aliskiren. A sample size of 153 completed patients obese with 46.4% of patients having a body mass (102 patients in the aliskiren-based treatment group index of at least 30 kg/m2. The msDBP and msSBP and 51 patients in the lisinopril-based treatment values at baseline were 108.3 and 162.8 mm Hg, group) was considered sufficient to evaluate the respectively, and these values were similar between overall tolerability profile of the aliskiren- and the two treatment groups. lisinopril-based regimens and to satisfy the regula- Most randomized patients (83.1%) had one or more tory requirement for the assessment of safety. past or continuing medical conditions, the most Assuming a dropout rate of 15%, a total of X180 common of which was hypercholesterolaemia. There patients were to be randomized. No precise power were no notable differences between the two treat- computations were carried out as this was a safety ment groups in the incidence of past or continuing study and was not powered for any specific end medical conditions (Table 1) or in the use of point. There were no pre-set margins for the concomitant medications (55.2% in each group). assessment of safety in terms of AE rates or other Mean exposure to drug treatment was similar for safety parameters. both treatment groups (aliskiren, 52.2 days; lisino- The primary assessment of tolerability was based pril, 53.9 days) and close to the planned duration of on the frequency of AEs, laboratory abnormalities treatment of 56 days. Overall, 165 patients com- and SAEs. The frequency distribution of patients pleted the study and the completion rate was similar who experienced orthostatic BP changes (a decrease in the two treatment groups (aliskiren, 88.8%; of at least 20 mm Hg in SBP or a decrease of at least lisinopril, 93.1%). The main reasons for disconti- 10 mm Hg in DBP when moving from a sitting to a nuation were AEs (n ¼ 6; 3.3%), withdrawal of standing position) was also assessed. consent (n ¼ 5; 2.7%) and unsatisfactory therapeutic All efficacy variables were analysed for the intent- effect (n ¼ 3; 1.6%). At the end of the study, 33 to-treat population, which was defined as all patients (26.4%) were receiving aliskiren 150 mg, 25 randomized patients who had a baseline (start of patients (20.0%) were being treated with aliskiren period 3) measurement and at least one post-base- 300 mg and 67 patients (53.6%) were receiving line efficacy measurement. The key efficacy vari- aliskiren 300 mg plus HCTZ 25 mg. In the lisinopril ables were change from baseline in msDBP and group, 20 patients (34.5%) were being treated with msSBP. The proportion of responders (patients with lisinopril 20 mg, 12 patients (20.7%) were receiving msDBPo90 mm Hg and/or X10 mm Hg reduction lisinopril 40 mg and 26 patients (44.8%) were from baseline in msDBP) was also assessed. receiving lisinopril plus HCTZ 25 mg. Descriptive statistics were provided for each efficacy variable. For each patient, the last post- baseline measurement of a variable during the Tolerability double-blind period was carried forward as the Adverse events. Aliskiren- and lisinopril-based end point measurement for the variable to be treatments were well tolerated. The incidence of analysed. The study was not powered for efficacy AEs was similar in the two treatment groups; 32.8% comparisons. of patients in the aliskiren group and 29.3% of patients in the lisinopril group reported at least one AE during the double-blind treatment period. There Results were no notable differences between treatment groups in the type of AEs observed (Table 2) and Patient characteristics the majority of AEs were mild or moderate in A total of 194 patients were enrolled in the study, of severity. The most frequently reported AEs were whom 183 were randomized to receive active headache (8.7%), nasopharyngitis (2.7%), dizziness treatment (aliskiren, n ¼ 125; lisinopril, n ¼ 58). Of (1.6%) and fatigue (1.6%). Only 3.3% of patients these, 138 patients were randomized directly into withdrew from the study due to AEs with no more the active treatment phase. Fifty-six patients entered than one person reporting the same AE as a reason the optional single-blind run-in period, of whom 45 for discontinuation. were subsequently randomized to receive study The proportion of patients reporting AEs that treatment; the other 11 patients were excluded for were suspected by the investigator to be related to abnormal test procedure results (n ¼ 7; this includes the study drugs was similar in the aliskiren group patients who did not meet BP inclusion criteria), (5.6%) and the lisinopril group (5.2%). The only withdrawal of consent (n ¼ 3) and administrative individual AE suspected to be related to study problems (n ¼ 1). treatment in more than one patient was headache The treatment groups were generally similar with (two patients in the aliskiren group and one in the respect to demographics and baseline characteristics lisinopril group). (Table 1). All but one of the patients in the study was No deaths occurred during the study. Three SAEs Caucasian (99.5%) and a little more than half of the were reported by two patients, both in the lisinopril

Journal of Human Hypertension Tolerability of aliskiren in patients with severe hypertension RH Strasser et al 784 Table 1 Patient baseline characteristics

Parameter Aliskiren (n ¼ 125) Lisinopril (n ¼ 58) Total (n ¼ 183)

Age (years) 55.3712.3 55.6711.1 55.4711.9 X65 years, n (%) 28 (22.4) 12 (20.7) 40 (21.9) X75 years, n (%) 9 (7.2) 3 (5.2) 12 (6.6) Gender Male, n (%) 70 (56.0) 34 (58.6) 104 (56.8) Female, n (%) 55 (44.0) 24 (41.4) 79 (43.2) Race, n(%) Caucasian 124 (99.2) 58 (100) 182 (99.5) Other 1 (0.8) 0 (0) 1 (0.5) Weight (kg) 86.0716.6 84.9720.0 85.6717.7 Height (cm) 168710 16779 16879 BMI (kg/m2) 30.575.3 30.376.3 30.575.6 X30 kg/m2, n (%) 60 (48.0) 25 (43.1) 85 (46.4) Diagnosis of diabetes,a n (%) 15 (12.0) 8 (13.8) 23 (12.6) Diagnosis of metabolic syndrome,b n (%) 66 (52.8) 34 (58.6) 100 (54.6) Duration of hypertension (years) 9.179.3 9.877.4 9.378.7 Medical history and continuing medical conditions, n (%) 103 (82.4) 49 (84.5) 152 (83.1) Hypercholesterolaemia 21 (16.8) 9 (15.5) 30 (16.4) Hyperuricaemia 8 (6.4) 5 (8.6) 13 (7.1) Prior medications, n(%) 111 (88.8) 48 (82.8) 159 (86.9) b-blocking agents 39 (31.2) 21 (36.2) 60 (32.8) Dihydropyridine CCBs 29 (23.2) 18 (31.0) 47 (25.7) ACE inhibitors 33 (26.4) 12 (20.7) 45 (24.6) ARBs 24 (19.2) 13 (22.4) 37 (20.2) ACE inhibitors and diuretic combinations 20 (16.0) 4 (6.9) 24 (13.1) ARBs and diuretic combinations 15 (12.0) 5 (8.6) 20 (10.9) Concomitant medications, n (%) 69 (55.2) 32 (55.2) 101 (55.2) HMG CoA reductase inhibitors 23 (18.4) 12 (20.7) 35 (19.1) Acetylsalicylic acid 15 (12.0) 8 (13.8) 23 (12.6) Topical anti-inflammatory preparations 10 (8.0) 3 (5.2) 13 (7.1) NSAIDs 8 (6.4) 3 (5.2) 11 (6.0) Biguanides 7 (5.6) 4 (6.9) 11 (6.0) ACE inhibitorsc 2 (1.6) 1 (1.7) 3 (1.6) Dihydropyridine derivatives 2 (1.6) 1 (1.7) 3 (1.6) Mean sitting DBP (mm Hg) 108.473.1 108.072.5 108.373.0 Mean sitting SBP (mm Hg) 163.4713.5 161.7712.6 162.8713.2 Mean sitting pulse rate (b.p.m.) 74.9710.8 74.4711.2 74.7710.9

Abbreviations: ACE, angiotensin converting enzyme; ARBs, angiotensin receptor blockers; BMI, body mass index; b.p.m., beats per minute; CCBs, calcium channel blockers; DBP, diastolic blood pressure; HMG CoA, 3-hydroxy-3-methylglutaryl coenzyme A; NSAIDs, non-steroidal anti- inflammatory drugs; SBP, systolic blood pressure. Values are presented as mean7s.d. unless otherwise stated. aFrom medical history. bMetabolic syndrome was defined as any three of the following: waist circumference 4102 cm for men or 488 cm for women; triglycerides X1.69 mmol/l (X150 mg/dl); high-density lipoprotein cholesterol o1.04 mmol/l (o40 mg/dl) for men or o1.29 mmol/l (50 mg/dl) for women; SBPX130 or DBPX85 mm Hg; fasting glucoseX6.1 mmol/l (X110 mg/dl). cOther than lisinopril given as part of this study.

group; one patient suffered severe angina pectoris were no notable differences between treatment and myocardial infarction (leading to hospitaliza- groups. tion and percutaneous coronary intervention with There were no notable changes in haematological stent implantation) and one patient suffered appen- parameters in patients receiving aliskiren-based dicitis. These events were not suspected to be treatment (n ¼ 125) during the course of the study. related to study treatment. In the lisinopril treatment group (n ¼ 58), three patients recorded abnormal haematological values: one patient demonstrated an elevated (475%) Laboratory values and physical signs platelet count, one patient demonstrated an elevated Notable changes in vital signs occurring at single- white blood cell count (450%) and, as is often time points included an increase in mean SBP for observed with ACE inhibitor therapy,18–20 one one patient in the aliskiren group, and decreased patient recorded a 420% decrease in haemoglobin pulse rate for one patient in the lisinopril group; level. The haematological profiles of all other neither of these changes was reported as an AE. The patients in the lisinopril treatment group remained incidence of patients with orthostatic BP changes at normal throughout the course of the study. each visit was low (less than 7% at any visit in any For most parameters, changes from treatment group) and similar to baseline, and there baseline were small and there were no meaningful

Journal of Human Hypertension Tolerability of aliskiren in patients with severe hypertension RH Strasser et al 785 Table 2 Safety and tolerability

Aliskiren (n ¼ 125) Lisinopril (n ¼ 58) Total (n ¼ 183)

Any AE 41 (32.8) 17 (29.3) 58 (31.7) Discontinuations due to AE 4 (3.2) 2 (3.4) 6 (3.3) SAE 0 (0) 2 (3.4) 2 (1.1) Discontinuations due to abnormal lab values 0 (0) 0 (0) 0 (0)

AEs by primary system organ class (X2% of total in any group) Nervous system disorders 13 (10.4) 6 (10.3) 19 (10.4) Infections and infestations 6 (4.8) 3 (5.2) 9 (4.9) Gastrointestinal disorders 5 (4.0) 2 (3.4) 7 (3.8) General disorders and administration site conditions 4 (3.2) 3 (5.2) 7 (3.8) Musculoskeletal and connective tissue disorders 3 (2.4) 4 (6.9) 7 (3.8) Skin and subcutaneous tissue disorders 6 (4.8) 0 (0) 6 (3.3) Respiratory, thoracic and mediastinal disorders 4 (3.2) 1 (1.7) 5 (2.7)

Most common individual AEs (X1% of total in any group) Headache 11 (8.8) 5 (8.6) 16 (8.7) Nasopharyngitis 3 (2.4) 2 (3.4) 5 (2.7) Dizziness 1 (0.8) 2 (3.4) 3 (1.6) Fatigue 1 (0.8) 2 (3.4) 3 (1.6) Peripheral 2 (1.6) 0 (0.0) 2 (1.1) Vertigo 2 (1.6) 0 (0.0) 2 (1.1) Back pain 1 (0.8) 1 (1.7) 2 (1.1) Cough 1 (0.8) 1 (1.7) 2 (1.1) Neck pain 1 (0.8) 1 (1.7) 2 (1.1)

Abbreviations: AEs, adverse events; SAE, serious adverse event. Table shows the number (%) of patients with an AE. differences between treatment groups. Overall, mean uric acid levels increased from baseline in both treatment groups (by 39.2 and 45.7 mmol/l for the aliskiren and lisinopril groups, respectively). There was a slight increase in levels in the aliskiren group (1.5 mmol/l) compared with a slight decrease in the lisinopril group (À0.6 mmol/l). Few individual patients showed notable abnormal laboratory values. Low serum potassium levels (o3.5 mmol/l) occurred in three patients (5.2%) in the lisinopril group and three patients (2.5%) in the aliskiren group. There was only one case each of serum potassium elevation (45.5 mmol/l) and blood nitrogen elevation (414.28 mmol/l), both in the Figure 2 Proportion of patients with severe hypertension receiving monotherapy vs add-on therapy with HCTZ during aliskiren group. None of the abnormal laboratory the active treatment phase of the study. Graph shows proportion values was reported as an AE. of patients who stayed on aliskiren (150 or 300 mg) or lisinopril (20 or 40 mg) monotherapy compared with the proportion who required add-on therapy with HCTZ 25 mg for additional BP Antihypertensive efficacy control. BP, blood pressure; HCTZ, hydrochlorothiazide. Of the 125 patients randomized to receive the aliskiren-based treatment regimen, the majority was titrated from 150 to 300 mg (n ¼ 92; 73.6%), 22.3714.6 mm Hg; mean treatment difference and a little more than half (n ¼ 67; 53.6%) received 2.8 mm Hg (95% CI À1.7, 7.4)). add-on treatment with HCTZ 25 mg. Similar rates of Marked reductions in msDBP and msSBP were titration (n ¼ 38; 65.5%) and add-on therapy (n ¼ 26; observed after 1 week of treatment in both groups, 44.8%) were observed with lisinopril-based treat- and absolute BP values in the aliskiren- and ment (Figure 2). lisinopril-based treatment groups were similar at At the week 8 end point, aliskiren-based treatment all time points during this study (Figure 3). and lisinopril-based treatment provided similar reduc- The majority of patients in both treatment groups tions from baseline (mean7s.d.) in msDBP (aliskiren exhibited a successful response to treatment 18.578.7 mm Hg vs lisinopril 20.177.9 mm Hg; mean (msDBPo90 mm Hg, and/or X10 mm Hg reduction treatment difference 1.7 mm Hg (95% CI À1.0, 4.4)) from baseline) at the week 8 end point. The and msSBP (aliskiren 20.0715.3 mm Hg vs lisinopril proportion of responders for the aliskiren-based

Journal of Human Hypertension Tolerability of aliskiren in patients with severe hypertension RH Strasser et al 786 ability of aliskiren monotherapy or combinations of aliskiren and HCTZ in patients with mild-to- moderate hypertension (JNC7 stage 1, or ESH-ESC grade 1 or 2).14,16 Aliskiren, alone or in combination with HCTZ, also demonstrated excellent long-term tolerability in a 12-month in patients with mild-to-moderate hypertension.17 The design of the present study allowed for the addition of HCTZ 25 mg in patients who did not achieve BP control with aliskiren or lisinopril monotherapy. Although the present study was not designed to have sufficient statistical power for comparisons of antihypertensive efficacy, aliskiren- Figure 3 Effect of study treatment on msDBP and msSBP based therapy provided BP-lowering effects similar throughout the active-treatment phase in patients with severe to those of lisinopril-based treatment in patients hypertension. Graph shows absolute blood pressure values in with severe hypertension. patients receiving aliskiren-based therapy (filled squares) or In conclusion, the results of the present study lisinopril-based therapy (open circles). Blood pressure was measured at weeks 1, 2, 4, 6 and 8. Values are presented as show that aliskiren-based treatment (with the addi- mean7s.d. msDBP, mean sitting diastolic blood pressure; msSBP, tion of HCTZ as needed for BP control) is well mean sitting systolic blood pressure. tolerated and provides highly effective BP lowering similar to that of a lisinopril-based treatment regi- men in patients with severe hypertension. An regimen (81.5%) was similar to that observed with antihypertensive regimen based on the direct renin the lisinopril-based regimen (87.9%). inhibitor aliskiren therefore represents a well-toler- ated and effective option for the treatment of severe hypertension. Discussion What is known about the topic Characteristics that look for when K Patients with severe hypertension (4180/110 mm Hg) require choosing an antihypertensive drug include sus- large reductions in BP to achieve recommended BP levels and tained BP lowering efficacy (both alone and in as a result combination antihypertensive therapy is almost combination with other agents), a good tolerability invariably required. K The renin system is a key regulator of volume and BP profile, and convenient dosing to ensure good homeostasis and inhibitors of the renin system (for example, compliance. This is the first study to investigate ACE inhibitors, angiotensin receptor blockers (ARBs)) are the tolerability and efficacy of the orally effective, widely used in the treatment of hypertension. direct renin inhibitor aliskiren in patients with K The direct renin inhibitor (DRI), aliskiren, will be the first in a new class of antihypertensive therapy. Studies in patients severe hypertension (JNC7 stage 2, or ESH-ESC with mild-to-moderate hypertension have shown that grade 3). The study showed that aliskiren-based aliskiren provides similar antihypertensive efficacy and therapy (with the optional addition of HCTZ to tolerability to ARBs. achieve BP control) was well tolerated by patients with severe hypertension, and provided similar What this study adds K This is the first study to evaluate the tolerability and efficacy BP-lowering effects to therapy based on the ACE of a direct renin inhibitor in patients with severe inhibitor lisinopril. hypertension. The incidence of AEs with aliskiren-based treat- K Aliskiren, with the optional addition of the diuretic, ment was low, and similar to that observed with hydrochlorothiazide, is well tolerated in patients with severe hypertension. lisinopril-based therapy. Moreover, the most fre- K Aliskiren-based treatment provides effective BP reductions in quently reported AEs in both groups were headache, patients with severe hypertension, similar to an equivalent nasopharyngitis and dizziness, events that are regimen based on the ACE inhibitor, lisinopril. commonly observed in studies of antihypertensive drugs in patients with severe hypertension.21–23 Aliskiren-based treatment did not result in any significant changes in laboratory or biochemistry Acknowledgements values. Despite ACE inhibitors being commonly associated with a dry non-productive cough This study was supported by Novartis Pharma AG. (5–35% of patients), the incidence of cough follow- ing lisinopril-based treatment was unusually low in this study (2%). The good tolerability of aliskiren-based therapy References observed in the present study in patients with severe 1 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. hypertension is consistent with previous studies Age-specific relevance of usual blood pressure to that have shown the placebo-like safety and toler- vascular mortality: a meta-analysis of individual data

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