Blood Pressure Lowering Efficacy of Renin Inhibitors for Primary Hypertension: a Cochrane Systematic Review

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Journal of Human Hypertension (2009) 23, 495–502 & 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00 www.nature.com/jhh REVIEW Blood pressure lowering efficacy of renin inhibitors for primary hypertension: a Cochrane systematic review

VM Musini, PM Fortin, K Bassett and JM Wright Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

We conducted a systematic review and meta-analysis of À4.3) and aliskiren 600 mg, À11.4 (À13.5, À9.2)/À6.6 double-blind randomized controlled trials to quantify the (À7.9, À5.2) mm Hg. Aliskiren 300 mg significantly dose-related systolic (SBP) and diastolic blood pressure lowered both SBP À3.0 (À4.0, À2.0) and DBP À1.7 (DBP) lowering efficacy of renin inhibitors vs placebo in (À2.3, À1.0) as compared to aliskiren150 mg. Aliskiren the treatment of adults with primary hypertension. has no effect on blood pressure variability. No data were Databases searched were Medline (1966–March 2008), available to assess the effect of aliskiren on heart rate or EMBASE (1988–March 2008) and Cochrane Central pulse pressure. This review found weak evidence that Register of Controlled Trials (CENTRAL). Six trials in during 4- to 8-week use, aliskiren did not increase 3694 patients met the inclusion criteria. All examined withdrawals due to adverse effects as compared to aliskiren, the only renin inhibitor licensed for marketing placebo. We concluded that aliskiren has a dose-related in Canada and the United States. Aliskiren caused a blood pressure lowering effect better than placebo and dose-related SBP/DBP lowering effect compared to magnitude of effect is similar to that determined for placebo: weighted mean difference with 95% CI: aliski- angiotensin-converting enzyme inhibitors and angioten- ren 75 mg, À2.9 (À4.6, À1.3)/À2.3 (À3.3, À1.3) mm Hg; sin receptor blockers. aliskiren 150 mg, À5.5 (À6.5, À4.4)/À3.0 (À3.7, À2.3) Journal of Human Hypertension (2009) 23, 495–502; mm Hg; aliskiren 300 mg, À8.7 (À9.7,À7.6)/À5.0 (À5.6, doi:10.1038/jhh.2008.162; published online 22 January 2009

Keywords: renin inhibitors; blood pressure; randomized controlled trials; systematic review; meta-analysis; primary hypertension

Introduction Attempts to block renin began in the 1950s with the use of renin antibodies.1 Issues of potency, Hypertension is a chronic condition associated with bioavailability and duration of action and cost of an increased risk of mortality and morbidity from synthesis have marred the drug development. For stroke, coronary heart disease, congestive heart example, potent renin inhibitors such as remikiren failure and renal disease. For patients with estab- and enalkiren had low oral bioavailability.2 Newer lished hypertension, blood pressure (BP) should drugs such as zankiren and terlakiren looked more first be managed with lifestyle/behaviour modifica- promising, but further development was halted in tion. However, if these measures prove inadequate the mid-1990s with the development of ARBs. More then pharmacotherapy is indicated. The renin– recent programmes to develop renin inhibitors have angiotensin–aldosterone system (RAAS) is a major been based on X-ray crystallography of renin’s active regulator of cardiovascular homeostasis. It is influ- site with computational modelling rather than based enced by five distinct anti-hypertensive drug on the structure of angiotensinogen.3 This has led to classes: b-adrenergic blockers, renin inhibitors, aliskiren, a new non-peptide, low-molecular-weight, angiotensin-converting enzyme (ACE) inhibitors, orally active renin inhibitor, which has been angiotensin receptor blockers (ARBs) and aldoster- approved in the United States, Canada and other one inhibitors. countries for the treatment of hypertension. This review was published in the Cochrane database of systematic reviews issue 4, 2008. Correspondence: Dr VM Musini, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Room 317, 2176 Health Science Mall, Vancouver, British Columbia, Canada V6T 1Z3. Objectives E-mail: [email protected] Received 8 October 2008; revised 2 December 2008; accepted 3 The primary objective is to quantify the dose-related December 2008; published online 22 January 2009 systolic (SBP) and/or diastolic blood pressure (DBP) Renin inhibitors for primary hypertension VM Musini et al 496 lowering efficacy of renin inhibitors vs placebo in baseline risk or co-morbid conditions other than the treatment of primary hypertension. Secondary patients must not have creatinine levels greater than objectives are to determine the effects of renin 1.5 times the normal level. inhibitors on variability of BP, pulse pressure, heart rate, withdrawals due to adverse effects and rates of specific adverse effects such as dry cough and angio- Types of interventions oedema. Monotherapy should include different fixed doses of renin inhibitor. However, data from trials or arms of trials with variable doses, based on BP response, Methods were not eligible. Search strategy The following databases were searched: Medline Types of outcome measures (1966–March 2008), EMBASE (1988–March 2008), Primary outcomes: change from baseline of trough Cochrane Central Register of Controlled Trials and/or peak SBP and DBP compared with placebo. (CENTRAL) and bibliographic citations from Secondary outcomes: change in standard devia- retrieved papers. No language restrictions were tion, pulse pressure, heart rate, number of patient applied. The search strategy for identification withdrawals due to adverse effects and number of of studies is summarized in Table 1. patients with dry cough or angio-oedema, compared to placebo. Criteria for considering studies for this review Selection of trials Two reviewers (VM and PF) independently screened Types of studies the titles and the abstracts resulting from the search Study design had to meet the following criteria: strategies. An article was rejected on initial screen- double-blind, random allocation to a specific fixed ing if the title or abstract indicated that the article dose of renin inhibitor or parallel placebo; duration did not report data from a randomized placebo- of treatment of at least 3 weeks; BP measurements at controlled trial. Full texts of the remaining articles baseline (following washout) and at one or more were retrieved. The bibliographies of pertinent time points between 3 and 12 weeks after initiation articles, reviews and texts were searched for addi- of treatment. tional citations. Two independent reviewers assessed the eligibility of the trials using a trial Types of participants selection form. Discrepancies were resolved by Participants must have a baseline BP of at least discussion, and when necessary by a third reviewer 140 mm Hg SBP and/or a DBP of at least 90 mm Hg (JMW or KB). using a standard method of measurement, such as a calibrated standard mercury sphygmomanometer. Data extraction Participants must not be restricted by age, sex, Data were extracted independently by two reviewers VM and PF, and then cross-checked. All numeric calculations and graphic interpolations were con- Table 1 Cochrane search strategy firmed by a second person. Search strategy for identification of studies on aliskiren 1 exp hypertension/ 2 animal/ not human/ Assessment of risk of bias in included studies 3 1 not 2 Two independent reviewers (VM and PF) assessed 4 randomised controlled trial/ the risk of bias of all included trials and prepared a 5 controlled clinical trial/ Risk of Bias Table as described in Chapter 8 of the 6 random allocation/ 7 double-blind method/ Cochrane Handbook. 8 single-blind method/ 9 exp clinical trial/ 10 (clin$ adj25 trial$).ti,ab. Dealing with missing data 11 ((singl$ or doubl$ or trip$) adj25 (blind$ or mask$)).ti,ab. In the case of missing values for standard deviation 12 placebos/ 13 placebo$.ti,ab. of the change in BP, the standard deviation was 14 random$.ti,ab. imputed based on the information in the same trial 15 exp research design/ or from other trials using the same dose. The 16 or/4–15 following hierarchy (listed from high to low pre- 17 renin adj2 inhibit$.mp. ference) was used to impute standard deviation 18 (aliskiren or tekturnas or rasilezs).mp. 19 17 or 18 values: standard deviation of change in BP data from 20 16 and 19 a different position (standing or supine); standard deviation of BP at the end of treatment; standard

Journal of Human Hypertension Renin inhibitors for primary hypertension VM Musini et al 497 deviation of BP at baseline (except if this measure Citations identified in literature was used for entry criteria); mean standard devia- search: n=250 tion of change in BP from other trials using the same Citations excluded and deemed not class of drug. relevant from titles and abstracts: n=235

Assessment of heterogeneity Potentially relevant RCTs Test for heterogeneity of treatment effect between Excluded RCTs: n=9 retrieved for examination n=15 the trials used a w2-statistic. The fixed effects model No placebo control: n=5 Combination therapy: was applied to obtain summary statistics of pooled n=3 Duplicate publication of trials, unless significant between-study heterogene- trial: n=1 ity was present, in which case the random effects model was used. RCTs included in systematic review: n=6

Figure 1 Quorum flow chart for selection of studies for renin Data synthesis inhibitor systematic review. Six double blind randomized con- Data synthesis and analyses used the Cochrane trolled trials met the inclusion criteria and compared aliskiren at Review Manager software, RevMan 5.0. Data for doses ranging from 75 to 600 mg to placebo. changes from baseline in BP were combined using a weighted mean difference method. The withdrawals The manufacturer (Novartis) sponsored all six due to adverse effects were analysed using relative included randomized controlled trials. We con- risk. tacted the manufacturer by email for any additional information on ongoing studies and for missing data Subgroup analysis and investigation on heart rate and pulse pressure from published of heterogeneity trials meeting our inclusion criteria. No response was provided. The following subgroup analyses were planned Following a 1- 2-week washout period from any a priori—race: African-American, white and others; prior anti-hypertensive medications, all trials had a 2- age: adults 18–69 years, more than 70 years old; to 4-week single-blind placebo-controlled run-in peri- baseline severity of hypertension: mild, moderate, od, followed by 8 weeks of randomized treatment. All severe. All trial participants had mild to moderate trials had similar inclusion and exclusion criteria. hypertension. When heterogeneity was significant, Patients were at least 18 years of age with mild to the factors contributing to heterogeneity were moderate essential hypertension defined as mean investigated. sitting diastolic blood pressure (MSDBP) equal to 95 mm Hg and less than 110 mm Hg at baseline. One trial Kushiro 2006 was conducted in Japanese patients Sensitivity analysis between the ages 20 and 80 years.4 Patients were We planned to test the robustness of the results excluded if pregnant or breast feeding; had MSDBP using several sensitivity analyses: trials of high risk equal to or greater than 110 mm Hg and/or mean sitting vs low risk of bias; trials that are drug manufacturer systolic blood pressure (MSSBP) equal to or greater vs non-manufacturer sponsored; trials that assess than 180 mm Hg; had a history or evidence of drug as primary drug of investigation vs trials that secondary hypertension, type I or type II diabetes with assess drug as comparator; trials with BP data poor glycaemic control or any surgical or medical measured in the sitting vs other positions; trials condition that might alter the absorption, distribution, with published standard deviations of BP change vs metabolism or excretion of study drugs. Patients were imputed standard deviations. also excluded if they had a history of severe cardiovascular, cerebrovascular, hepatic or renal disease. Results When BP measurement data were available in more than one position, data were extracted Of the 250 articles identified in the search, six trials in accordance with the following order of prefer- comparing the renin inhibitor, aliskiren (N ¼ 2452), ence: (1) sitting, (2) standing and (3) supine. In all to placebo (N ¼ 1242) met the inclusion criteria trials, MSSBP and MSDBP were available for base- (Figure 1). All included trials were randomized, line measurements, and least-squares mean (LSM) double-blind and parallel group multi-centre stu- change from baseline and standard error (s.e.) of the dies of 8 weeks duration, except for Kushiro 2006, change were available at regular intervals through- which was 13 weeks duration.4 Three trials Pool out trials (usually at weeks 1, 2, 4, 6 and 8). If BP 2007, Villamil 2007 and Oparil 2007 included active measurements were available at more than one time treatment arms in addition to placebo.5–7 Pool 2007 during a 24-h period, the trough measurement was and Oparil 2007 compared aliskiren to valsartan, used. Peak level is defined as within 12 h of the drug and Villamil 2007 compared aliskiren to hydro- ingestion and trough level is defined as between 12 chlorothiazide. and 24 h. The sitting clinic BP was measured using a

Journal of Human Hypertension Renin inhibitors for primary hypertension VM Musini et al 498 calibrated standard mercury sphygmomanometer or sitting position as opposed to only standing or supine an alternative calibrated method, in accordance position. There was no significant difference observed with the 1988 AHA Committee Report on Blood in the effect size of both SBP and DBP using random Pressure Determination. Blood pressure was mea- effects model when sensitivity analyses were con- sured at trough (24±3 h after dose). At the first ducted using standard deviation values of trials study visit, the patient’s arm with the highest sitting reporting them vs imputing standard deviation values DBP became the arm used for all subsequent read- based on information from other trials. ings in the study. At each study visit, BP was measured three times at 1- to 2-min intervals, with the mean of the three measurements used as the BP Risk of bias in included studies for that visit. In addition, one BP measurement was Four trials Pool 2007, Oparil 2007, Gradman 2005 and taken in standing position after the patient stood for Kushiro 2006 report adequate sequence generation 2 min. and allocation concealment.4,5,7,8 In three trials Oparil The mean age of patients across all trials ranged 2007, Gradman 2005 and Kushiro 2006, blinding was from 51 to 57 years, the majority were Caucasians adequately described.4,7,8 Five trials Pool 2007, Villa- (58–95%), except in Kushiro et al. trial (Japanese mil 2007, Oparil 2007, Kushiro 2006 and Oh 2007 patients); the mean baseline SBP ranged from 151 to were free of selective reporting, and it was unclear 155.6 mm Hg and DBP ranged from 99 to whether any trial was free of other bias.4,7,9 Overall the 100.4 mm Hg. In all trials, data comparisons between included trials were of high quality. groups were estimated based on LSMs of change from baseline and the s.e. Baseline and end point BP data were provided by only two trials Gradman 2005 Effects of interventions and Pool 2007.5,8 In three of the trials Kushiro 2006, Pool 2007, and Villamil 2007, patients received once Mean change from baseline of trough SBP compared daily aliskiren 75, 150 and 300 mg.4–6 In two trials with placebo Gradman 2005 and Oh 2007, patients received once Aliskiren monotherapy was superior to placebo in daily aliskiren 150, 300 or 600 mg.8,9 In one trial lowering MSSBP. The additional magnitude of BP Oparil 2007, patients received once daily aliskir- lowering minus the placebo effect: aliskiren 75 mg en150 mg and then increased it to 300 mg in all vs placebo À2.94 (95% CI À4.56, À1.31); aliskiren patients after 4 weeks.7 150 mg vs placebo À5.45 (95% CI À6.46, À4.43); Two trials Oparil 2007 and Villamil 2007 had aliskiren 300 mg vs placebo À8.66 (95% CI À9.68, missing values for s.e.6,7 In the Villamil 2007 trial, À7.64); aliskiren 600 mg vs placebo À11.36 (95% CI the MSDBP standard deviation for the placebo arm À13.53, À9.19) (Figure 2). was imputed from the value of the s.e. given for aliskiren.6 Further, there were no s.e. values for Mean change from baseline of trough DBP compared MSSBP for placebo and aliskiren 75, 150 and with placebo 300 mg. These were imputed from the average of the Aliskiren monotherapy was superior to placebo in s.e. values given for combination therapies. In the lowering MSDBP. The additional magnitude of BP Oparil 2007 trial, MSDBP and MSSBP standard lowering minus the placebo effect: aliskiren 75 mg deviations for both the placebo and aliskiren 300 mg vs placebo À2.29 (95% CI À3.31, À1.26); aliskiren groups were imputed from the values for s.e. given at 150 mg vs placebo À3.00 (95% CI À3.65, À2.34); week 4 for placebo and aliskiren 150 mg, respectively.7 aliskiren 300 mg vs placebo À4.97 (95% CI À5.62, Because significant heterogeneity was present À4.31); aliskiren 600 mg vs placebo À6.57 (95% CI when meta-analysing MSSBP and MSDBP for À7.92, À5.23) (Figure 3). aliskiren 150 and 300 mg as compared to placebo, the random effects model was used. Heterogeneity could not be explained based on the inclusion/ Change in standard deviation compared with placebo exclusion criteria and baseline characteristics be- End of treatment standard deviation of SBP and DBP cause they were similar in all trials. It could be partly was similar in the placebo and aliskiren arms. explained by the large placebo response observed in Standard deviation of SBP ranged from 12.4 the Pool 2007 trial (SBP, À10.0 mm Hg; DBP, to 14.0 in the aliskiren treatment arm as compared À8.6 mm Hg) as compared to placebo response in the to 12.0 to 14.0 in the placebo treatment arm. other four trials. When this trial was removed from the Standard deviation of DBP ranged from 8.0 to 8.6 5 analysis, heterogeneity was no longer significant. in both the aliskiren and placebo treatment arms. This is consistent with aliskiren having no effect on BP variability. Sensitivity analysis No sensitivity analyses occurred because all trials Change in pulse pressure compared with placebo were sponsored by the manufacturer; used aliskiren No trials reported on pulse pressure at baseline or as the primary drug of investigation; measured BP in end point.

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Figure 2 Dose ranging systolic blood pressure lowering effect of aliskiren vs placebo. Systolic blood pressure was significantly reduced by aliskiren 75 mg to 600 mg dose as compared to placebo, a mean reduction ranging from 2.9 to 11.4 mm Hg.

Change in heart rate compared with placebo (1.1%); aliskiren 150 mg, n ¼ 5 (2.8%); aliskiren Two trials recorded baseline heart rate, but no data 300 mg, n ¼ 1 (0.6%). No trials reported angio- were provided at week 8.5,8 oedema.

Number of patient withdrawals due to adverse events Mean change from baseline of trough systolic as well compared with placebo as diastolic blood pressure comparing different doses There were no significant differences in withdra- of aliskiren wals between placebo and aliskiren at any dose. RR The BP lowering efficacy of aliskiren 150 vs 75 mg as with 95% CI for aliskiren 75 mg vs placebo was 0.97 well as aliskiren 600 vs 300 mg was not significantly (0.49, 1.89); for aliskiren 150 mg vs placebo was 1.01 different. However, aliskiren 300 mg significantly (0.61, 1.69); for aliskiren 300 mg vs placebo was 0.91 lowered both systolic and diastolic as compared to (0.57, 1.47) and for aliskiren 600 mg vs placebo was 150 mg (SBP with 95% CI: À2.97 (À3.99, À1.95) and 0.63 (0.21, 1.89). DBP: À1.66 (À2.32, À1.0)) (Figures 4 and 5).

Number of patients with dry cough or angio-oedema as Discussion compared to placebo One trial Pool 2007 reported on incidence of dry The RAAS is a major regulator of cardiovascular cough: placebo, n ¼ 2 (1.1%); aliskiren 75 mg, n ¼ 2 homeostasis, in which the vasoactive peptide,

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Figure 3 Dose ranging diastolic blood pressure lowering effect of aliskiren vs placebo. Diastolic blood pressure was significantly reduced by aliskiren 75 mg to 600 mg dose as compared to placebo, a mean reduction ranging from 2.3 to 6.6 mm Hg.

Figure 4 Systolic blood pressure lowering effect of aliskiren 300 vs 150 mg. Systolic blood pressure was significantly reduced by aliskiren 300 mg as compared to 150 mg, a mean reduction of 3.0 mm Hg.

angiotensin II, has an important function. Renin nogen to angiotensin I, the rate-limiting step in this inhibitors prevent the formation of renin, the cascade. Renin is responsible for all ‘downstream’ enzyme that catalyses the conversion of angiotensi- events leading to production of angiotensin II and

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Figure 5 Diastolic blood pressure lowering effect of aliskiren 300 vs 150 mg. Diastolic blood pressure was significantly reduced by aliskiren 300 mg as compared to 150 mg, a mean reduction of 1.7 mm Hg. subsequent stimulation of its receptors. Because Adverse events renin is the only enzyme that catalyses this conversion, it has been speculated that renin inhibitors The included trials did not detect differences in might provide a more effective means of blockade of adverse events between aliskiren and placebo. Some the RAAS than is possible with ACE inhibitors or trial reports listed only a few events, generally those ARBs.10 ACE inhibitors and ARBs block this system with an incidence greater than 1–2.5% in any group, further downstream by inhibiting the generation and while others reported by broad system affected by action of angiotensin II, respectively. However, they the drugs: cardiac, immune system, respiratory and do not block the RAAS completely. so on. The most common adverse events reported The longest randomized controlled trial of renin were headache, nasopharyngitis, diarrhoea and back inhibitors, Kushiro 2006, is of 13 weeks duration. pain, which were similar in placebo groups and No trials have examined mortality or serious aliskiren groups at all doses. There was no distinc- morbidity of aliskiren as compared to placebo. tion between total adverse events and serious adverse events, with only one trial Oparil 2007 To the best of our knowledge, this is the only 9 systematic review summarizing the dose-related BP reporting ‘any serious adverse event’. Two trials lowering efficacy of the renin inhibitors. Aliskiren is Pool 2007 and Kushiro 2006 reported on death with one death in the aliskiren 150 mg group4 and the only renin inhibitor that has been studied in 5 double-blind randomized controlled trials to date another in the placebo group. and meet the minimum inclusion criteria of this review. Limitations of this systematic review The intervention effect size as reported above and shown in Forrest plots could be an overestimate due Dose-related efficacy to publication bias since the manufacturer spon- Aliskiren at all doses significantly lowered both SBP sored all six published studies. It is likely that and DBP as compared to placebo. Of all aliskiren negative studies have not been published and doses studied in the six included trials, aliskiren therefore not included in this meta-analysis. In 300 mg showed the maximum BP lowering efficacy. addition, the BP lowering efficacy estimate is SBP and DBP lowering with aliskiren 300 mg vs limited to 8–13 weeks. It was not possible to do placebo was significantly greater than with aliskiren any subgroup analyses due to lack of data specific to 150 mg. The magnitude of the BP lowering with race or age. Also the BP data at end point using the aliskiren at the maximum recommended dose of LSM is non-robust to data outliers, particularly if 300 mg daily À8.7/À5.0 mm Hg is similar to ACE outliers have a skewed distribution. This can cause inhibitors À8/À5mmHgandARBsÀ8/À5mmHg.11–13 an increase in type 2 errors, and it is not known if Direct comparison from the three placebo-controlled there were significant outliers in the data. trials included in this systematic review that compared aliskiren 150 mg, aliskiren 300 mg with ARBs Conclusions also supports this finding. Aliskiren 150 mg vs irbesartan 150 mg (SBP, À6.0 vs À7.2 mm Hg and Implications for practice DBP, À2.9 vs À2.5 mm Hg) and comparing aliskiren The renin inhibitor aliskiren (150 and 300 mg) 300 mg to valsartan 320 mg (SBP, À5.1 to À13.0 vs significantly lowered SBP and DBP as compared to À6.5 to À12.8; and DBP, À3.7 to À9.0 vs À2.7 to placebo in a dose-dependent manner (SBP with 95% À9.7 mm Hg). This suggests that inhibiting the renin– CI—150 mg: À5.5 (À6.5, À4.4); 300 mg: À8.7 (À9.7, angiotensin system at different sites does not lead to À7.6) and DBP with 95% CI—150 mg: À3.0 (À3.7, clinically different BP lowering effects. À2.3); 300 mg: À5.0 (À5.6, À4.3)). This systematic

Journal of Human Hypertension Renin inhibitors for primary hypertension VM Musini et al 502 review documents that aliskiren reduces BP by a 3 Krum H, Gilbert RE. Novel therapies blocking the magnitude that is similar to what has been deter- renin–angiotensin–aldosterone system in the manage- mined with ACE inhibitors and ARBs. This review ment of hypertension and related disorders. J Hyper- found weak evidence that in trials of 8 weeks tens 2007; 25: 25–35. duration aliskiren at any dose does not increase 4 Kushiro T, Hiroshige I, Yoshihisa A, Hiromi G, Shinji T, Keefe D. Aliskiren, a novel oral renin inhibitor, withdrawals due to adverse events as compared to provides dose-dependent efficacy and placebo-like placebo. tolerability in Japanese patients with hypertension. Hypertens Res 2006; 29: 997–1005. 5 Pool J, Roland E, Schmieder M, Aldigier JC, Janusze- Implications for research wicz A, Zidek W et al. Aliskiren, an orally effective There is no evidence from randomized control trials renin inhibitor, provides antihypertensive efficacy that renin inhibitors reduce mortality or serious alone and in combination with valsartan. Am J morbidity as compared to placebo or other classes of Hypertens 2007; 20: 11–20. anti-hypertensive drugs. The BP lowering efficacy of 6 Villamil A, Chrysant S, Calhoun D, Schober B, Hsu H, renin inhibitors vs placebo or other classes of anti- Matrisciano-Dimichino L et al. Renin inhibition with hypertensive drugs is not known beyond 8 weeks. aliskiren provides additive antihypertensive efficacy All published randomized controlled trials must when used in combination with hydrochlorothiazide. provide data on all outcomes and all negative trials J Hypertens 2007; 25: 217–226. 7 Oparil S, Yarrows S, Patel S, Fang H, Zhang J, Satlin A. need to be published, for this review to be an Efficacy and safety of combined use of aliskiren and accurate summary of the best available evidence. valsartan in patients with hypertension: a randomised, double-blind trial. Lancet 2007; 370: 221–229. 8 Gradman A, Schmieder R, Lins R, Nussberger J, Chiang Acknowledgements Y, Bedigian M. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive We thank the Cochrane Hypertension Review Group efficacy and placebo-like tolerability in hypertensive for publishing this review in the Cochrane database patients. Circulation 2005; 111: 1012–1018. of systematic review issue 4, 2008. We also acknowl- 9 Oh B, Mitchell J, Herron J, Chung J, Khan ML, Keefe D. edge the contribution of Stephen Adams and Aliskiren, an oral renin inhibitor, provides dose- Ciprian Jauca who assisted in editing of this review. dependent efficacy and sustained 24-h blood pressure control in patients with hypertension. J Am Coll We also thank the Department of Anesthesiology, Cardiol 2007; 49: 1157–1163. Pharmacology and Therapeutics, University of Brit- 10 Duprez D. Role of the renin–angiotensin–aldosterone ish Columbia, Canada, and Canadian Institutes of system in vascular remodeling and inflammation: a Health Research, Canada, for providing financial clinical review. J Hypertens 2006; 24: 983–991. support. 11 Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin converting enzyme (ACE) inhibitors for primary hypertension. Conflict of interest Cochrane Database of Syst Rev 2008; Issue 4. Art. No.: CD003823. doi:10.1002/14651858.CD003823.pub2. The authors declare no conflict of interest. 12 Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efficacy of angiotensin receptor References blockers for primary hypertension. Cochrane Database of Syst Rev 2008; Issue 4. Art. No.: CD003822. 1 Helmer OM. Studies on renin antibodies. Circulation doi:10.1002/14651858.CD003822.pub2. 1958; 17: 648–652. 13 Law MR, Wald NJ, Morris JK, Jordan RE. Value of low 2 Frishman WH, Fozailoff A, Lin C, Dike C. Renin dose combination treatment with blood pressure low- inhibition: a new approach to cardiovascular therapy. ering drugs: analysis of 354 randomised trials. BMJ J Clin Pharmacol 1994; 34: 873–880. 2003; 326: 1427.

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