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

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Blood Pressure Lowering Efficacy of Renin Inhibitors for Primary Hypertension: a Cochrane Systematic Review 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 as- sessed 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.
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