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Meta-Analysis
. 2017 Apr 5;4(4):CD007066.
doi: 10.1002/14651858.CD007066.pub3.

Blood pressure lowering efficacy of renin inhibitors for primary hypertension

Vijaya M Musini  1 , Kendra Ak Lawrence  2 , Patricia M Fortin  3 , Ken Bassett  1 , James M Wright  1
Affiliations
Meta-Analysis

Blood pressure lowering efficacy of renin inhibitors for primary hypertension

Vijaya M Musini et al. Cochrane Database Syst Rev. .

Abstract

Background: Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II.

Objectives: To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema).

Search methods: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work.

Selection criteria: We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension.

Data collection and analysis: This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs.

Main results: 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue.

Authors' conclusions: Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

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Conflict of interest statement

None known.

Figures

1
1
PRISMA Study flow diagram.
2
2
Methodological quality summary: review authors' judgments about each methodological quality item for each included study.
3
3
Forest plot of comparison: 1 Aliskiren vs. placebo, outcome: 1.1 Systolic BP. Highly significant subgroup differences were observed therefore mean overall effect size across all doses is not shown. The number of placebo group patients are divided equally in dose ranging studies when more than one dose of aliskiren was used. CSPP100A2308 study the SBP reduction in the treatment and placebo group are reported from the CSR page 61. CSPP100A2405 study the SD for all treatment groups are calculated from SEM reported on page 7 in the CSR .
4
4
Forest plot of comparison: 1 Aliskiren vs. placebo, outcome: 1.2 Diastolic BP. Highly significant subgroup differences were observed, therefore mean overall effect size across all doses is not shown. The number of placebo group patients are divided equally in dose ranging studys when more than one dose of aliskiren was used. CSPP100A2308 study the DBP reduction in the treatment and placebo group are reported from the CSR which differ from those reported in the published article. The previous version of this review used data from the published article. CSPP100A2405 study the SD for all treatment groups are calculated from SEM reported from the CSR on page 8.
1.1
1.1. Analysis
Comparison 1 Aliskiren vs. placebo, Outcome 1 Systolic BP.
1.2
1.2. Analysis
Comparison 1 Aliskiren vs. placebo, Outcome 2 Diastolic BP.
1.3
1.3. Analysis
Comparison 1 Aliskiren vs. placebo, Outcome 3 Withdrawals due to adverse event.
1.4
1.4. Analysis
Comparison 1 Aliskiren vs. placebo, Outcome 4 Cough.
1.5
1.5. Analysis
Comparison 1 Aliskiren vs. placebo, Outcome 5 Diarrhoea.
2.1
2.1. Analysis
Comparison 2 Aliskiren150 mg vs. Aliskiren 75 mg, Outcome 1 Systolic BP.
2.2
2.2. Analysis
Comparison 2 Aliskiren150 mg vs. Aliskiren 75 mg, Outcome 2 Diastolic BP.
3.1
3.1. Analysis
Comparison 3 Aliskiren 300 mg Vs. Aliskiren 75 mg, Outcome 1 SBP.
3.2
3.2. Analysis
Comparison 3 Aliskiren 300 mg Vs. Aliskiren 75 mg, Outcome 2 DBP.
4.1
4.1. Analysis
Comparison 4 Aliskiren 300 mg vs. Aliskiren 150 mg, Outcome 1 Systolic BP.
4.2
4.2. Analysis
Comparison 4 Aliskiren 300 mg vs. Aliskiren 150 mg, Outcome 2 Diastolic BP.
5.1
5.1. Analysis
Comparison 5 Aliskiren 600 mg vs. Aliskiren 150 mg, Outcome 1 SBP.
5.2
5.2. Analysis
Comparison 5 Aliskiren 600 mg vs. Aliskiren 150 mg, Outcome 2 DBP.
6.1
6.1. Analysis
Comparison 6 Aliskiren 600 mg vs. Aliskiren 300 mg, Outcome 1 Systolic BP.
6.2
6.2. Analysis
Comparison 6 Aliskiren 600 mg vs. Aliskiren 300 mg, Outcome 2 Diastolic BP.
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