Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors for primary hypertension

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To evaluate the efficacy and safety of renin inhibitors compared to ACE inhibitors in people with primary hypertension.

Background

Description of the condition

Hypertension is an important worldwide public‐health challenge associated with high frequency and concomitant risks of cardiovascular and kidney disease. An estimated 29.8% of the world's adult population had hypertension in 2010 (Mills 2015). Despite considerable improvement in raising awareness, treatment and control of hypertension, undiagnosed and uncontrolled hypertension among minority groups remains a challenge (Egan 2014).

Description of the intervention

Orally active renin inhibitors (RIs) were developed in the 1980s, and one such drug, aliskiren, was introduced into clinical use for treatment of hypertension in 2007 (Musini 2008). Angiotensin converting enzyme (ACE) inhibitors are widely prescribed for the treatment of primary hypertension (Wang 2014).

How the intervention might work

Excessive activation of the renin‐angiotensin system (RAS) has been known to be associated with the pathophysiology of hypertension for a long time (Ferrario 1990). ACE inhibitors and RIs inhibit the RAS but have different sites of action; ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, while the RIs block enzymatic action of renin, the conversion of angiotensinogen to angiotensin I.

Although pharmacologic manipulation of the RAS with ACE inhibitors has proven effective in the treatment of hypertension and related end‐organ damage, it provides only partial protection from disease progression (Ennezat 2000). This might be attributable to the limitations of ACE inhibitors. Possible mechanisms for the limitations include firstly interruption of negative feedback of renin release and a compensatory increase in renin and angiotensin I levels, which can overcome ACE inhibition; or secondly the production of angiotensin II by non‐ACE pathways (Epstein 2012). Additionally, ACE inhibitors potentiate bradykinin levels, which are associated with cough and angioneurotic edema (Nussberger 1998).

Renin controls the first and rate‐limiting step in the activation of the RAS. By decreasing plasma renin activity and inhibiting the conversion of angiotensinogen to angiotensin I, it has been proposed that RIs might provide a more effective means of blockading of the RAS (Skeggs 1957).

Why it is important to do this review

Guidelines, such as ESH/ESC 2013 and JNC8 2014, have recommended ACE inhibitors as first‐line therapy for hypertension, while the position of RIs in hypertension pharmacotherapy is still unclear. Recent meta‐analyses have shown that RIs have a favourable tolerability profile in people with mild‐to‐moderate hypertension (Weir 2007; White 2010). Moreover, a Cochrane Review has demonstrated that RIs reduce blood pressure (BP) more than placebo, and that the magnitude of this effect is similar to that for ACE inhibitors (Heran 2008; Musini 2008). However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. To investigate the effectiveness and safety of renin inhibitors compared to ACE inhibitors, the most reliable method is head‐to‐head RCTs.

We have written a Cochrane Review evaluating the benefits and harms of first‐line RAS inhibitors as an overall group compared to other first‐line antihypertensive drugs, and have shown that RAS inhibitors reduce adverse cardiovascular events more than calcium channel blockers and beta blockers (Xue 2015). There is a Cochrane Review comparing angiotensin receptor blockers (ARBs) to ACE inhibitors (Li 2014). However, there is currently no Cochrane Review comparing the effectiveness and safety of RIs with ACE inhibitors. This review therefore aims to compare RIs and ACE inhibitors for: 1) their effects on mortality and morbidity, and 2) safety profiles in people with primary hypertension.

Objectives

To evaluate the efficacy and safety of renin inhibitors compared to ACE inhibitors in people with primary hypertension.

Methods

Criteria for considering studies for this review

Types of studies

Studies must be double‐blind randomized controlled trials (DBRCTs) with a parallel design, randomizing participants to the renin inhibitor group or the ACE inhibitor group, and must have a duration of at least four weeks.

Types of participants

We will include people with primary hypertension, and will exclude people with proven secondary hypertension.

Diagnostic criteria for primary hypertension:

1. Office blood pressure (BP): systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg, or both.

2. Ambulatory BP: daytime systolic BP ≥ 135 mmHg or diastolic BP ≥ 85 mmHg, or both; night‐time systolic BP ≥ 120 mmHg or diastolic BP ≥ 70 mmHg, or both; 24‐hour systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg, or both.

Types of interventions

Invervention: any renin inhibitor.

Control: any ACE inhibitor.

Renin inhibitors include: aliskiren, ciprokiren, ditekiren, enalkiren, remikiren, rasilez, tekturna, terlakiren and zankiren.

ACE inhibitors include: alacepril, altiopril, benazepril, captopril, ceranapril, ceronapril, cilazapril, deacetylalacepril, delapril, derapril, enalapril, enalaprilat, epicaptopril, fasidotril, fosinopril, foroxymithine, gemopatrilat, idapril, imidapril, indolapril, libenzapril, lisinopril, moexipril, moveltipril, omapatrilat, pentopril, perindopril, pivopril, quinapril, ramipril, rentiapril, s‐nitrosocaptopril, spirapril, temocapril, teprotide, trandolapril, utibapril, zabicipril, and zofenopril.

Types of outcome measures

Primary outcomes

1. All‐cause mortality

2. Total cardiovascular events:

   1. fatal or non‐fatal myocardial infarction

   2. fatal or non‐fatal stroke

   3. fatal congestive heart failure

   4. hospitalizations for congestive heart failure

3. End‐stage renal disease (ESRD) 

4. Withdrawal due to adverse effects (WDAE)

5. Fatal or non‐fatal serious adverse events

6. Adverse events

Secondary outcomes

1. Individual cardiovascular events

2. Change in systolic and diastolic BP

3. Change in heart rate

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist will search the following databases from date of inception for published, unpublished, and ongoing studies:

• the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web);

• the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web);

• MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations;

• Embase Ovid (from 1974 onwards);

• ClinicalTrials.gov (www.clinicaltrials.gov)

• World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch).

The subject strategies for databases will be modelled on the search strategy designed for MEDLINE in Appendix 1. Where appropriate, these will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)). Searches for this review have been combined with the related review Renin inhibitors versus angiotensin receptor blockers for primary hypertension.

Searching other resources

• The Hypertension Information Specialist will search the Hypertension Specialised Register segment (which includes searches of MEDLINE and Epistemonikos for systematic reviews) to retrieve published systematic reviews related to this review title, so that we can scan their reference lists to identify additional relevant trials.

• We will check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.

• We will contact experts/organisations in the field to obtain additional information on relevant trials.

• We may contact original authors for clarification and further data if trial reports are unclear.

• We will not perform a separate search for adverse effects of interventions used for the treatment of hypertension. We will consider adverse effects described in included studies only.

Data collection and analysis

Selection of studies

Two review authors will independently examine the titles and abstracts of citations identified by the electronic searches for possible inclusion. We will retrieve full‐text publications of potentially relevant studies and two review authors will then independently determine study eligibility. We will resolve any disagreements about study eligibility by discussion and, if necessary, a third review author will arbitrate.

Data extraction and management

Two review authors will independently extract data using a standard form, and then cross‐check. A third person will confirm all numeric calculations and graphic interpolations. We will resolve any discrepancies by consensus.

Assessment of risk of bias in included studies

The review authors will use the Cochrane tool for assessment of risk of bias to categorize studies as having low, unclear, or high risk of bias for sequence generation, allocation sequence concealment, loss of blinding, selective reporting, incomplete reporting of outcomes, and other potential sources of bias (Higgins 2011).

Measures of treatment effect

We will base quantitative analysis of outcomes on intention‐to‐treat principles when possible. For dichotomous outcomes, we will express results as a risk ratio (RR) with a 95% confidence interval (CI). For combining continuous variables, we will use the mean difference (MD) with a 95% CI, whereby the studies are weighted according to the number of participants in the study and the within‐study variance.

Unit of analysis issues

The unit of analysis will be the individual trial. For trials having more than two arms, we will only include arms relevant to this review. Where studies include more than one intervention group with a single comparator arm, we will include both intervention groups.

Dealing with missing data

If the included studies have information missing, we will contact investigators (using email, letter or fax) to obtain the missing information. When studies do not report a within‐study variance for the effect change of continuous data, we will impute the standard deviation (SD) using the following hierarchy:

1. Pooled SD calculated either from the t‐statistic corresponding to an exact P value reported or from the 95% CI of the mean difference between treatment group and comparative group;

2. SD at the end of treatment;

3. SD at baseline;

4. Weighted mean SD of change calculated from at least three other trials using the same class of drug (at any dose).

Assessment of heterogeneity

We will consider a P value of 0.10 or less from the Chi² test as statistically significant for heterogeneity (Deeks 2011). Furthermore, we will use the I² statistic for quantifying inconsistency across studies, following the rough guide to interpretation as described in Deeks 2011:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

We will use funnel plots to investigate publication reporting bias when suspected. As a rule of thumb, tests for funnel plot asymmetry should be used only when there are at least 10 studies included in the meta‐analysis, because when there are fewer studies the power of the tests is too low to distinguish chance from real asymmetry.

Data synthesis

We will conduct data synthesis and analyses using Cochrane Review Manager 5 software (RevMan). We will describe data results in tables and forest plots. In addition we will give full details of all studies we include and exclude.

If we identify statistically significant heterogeneity, we plan to use a random‐effects model for meta‐analysis. Since a random‐effects model can overemphasize smaller studies, we plan a sensitivity analysis to gauge the effects of using a random‐effects model versus a fixed‐effect model on the observed intervention effect.

Subgroup analysis and investigation of heterogeneity

If appropriate, we will perform subgroup analyses.

Heterogeneity among participants could be related to: gender, age, baseline blood pressure, high‐risk participants or participants with comorbid conditions, participants with a previous history of cardiovascular morbidity and renal disease.

Heterogeneity in treatments could be related to: form of drugs, dosage of drugs, duration of therapy.

Sensitivity analysis

We will test the robustness of the results using several sensitivity analyses, including:

1. Trials that were industry‐sponsored versus non‐industry sponsored;

2. Trials with reported standard deviations of effect change versus imputed standard deviations;

3. Trials that have a high risk of bias versus those with a low risk of bias.

Data presentation ‐ 'Summary of findings' tables

We will use the GRADE approach to assess the quality of the supporting evidence behind each estimate of treatment effect (Schünemann 2011a; Schünemann 2011b). We will present key findings of the review, including a summary of the amount of data, the magnitude of the effect size and the overall quality of the evidence, in a 'Summary of findings' table. We have preselected the following outcomes for inclusion in the 'Summary of findings' table:

1. All‐cause mortality

2. Total cardiovascular events:

   1. fatal or non‐fatal myocardial infarction

   2. fatal or non‐fatal stroke

   3. fatal congestive heart failure

   4. hospitalizations for congestive heart failure

3. End‐stage renal disease (ESRD) 

4. Withdrawal due to adverse effects (WDAE)

5. Fatal or non‐fatal serious adverse events

6. Adverse event

Appendices

Appendix 1. MEDLINE Search Strategy

Database: Ovid MEDLINE(R) 1946 to Present with Daily Update ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

1 renin/ai 2 (aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren).mp. 3 ((RAS or renin) adj2 inhibit$).tw. 4 or/1‐3 5 exp Angiotensin‐Converting Enzyme Inhibitors/ 6 ((angiotensin$ or dipeptidyl$ or kininase ii) adj3 (convert$ or enzyme or inhibit$ or recept$ or block$)).tw 7 (ace adj2 inhibit$).tw. 8 acei.tw. 9 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or enalaprilat or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil or Univas or Vasotec or Zestril).tw. 10 or/5‐9 11 exp angiotensin receptor antagonists/ 12 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw. 13 (arb or arbs).tw. 14 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or KT3‐671 or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan).tw. 15 or/11‐14 16 hypertension/ 17 (antihypertens$ or hypertens$).tw. 18 ((elevat$ or high$ rais$) adj2 (blood pressure or bp)).tw. 19 or/16‐18 20 randomized controlled trial.pt. 21 controlled clinical trial.pt. 22 randomized.ab. 23 placebo.ab. 24 drug therapy.fs. 25 randomly.ab. 26 trial.ab. 27 groups.ab. 28 or/20‐27 29 animals/ not (humans/ and animals/) 30 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ (885949) 31 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. 32 28 not (29 or 30 or 31) 33 4 and (10 or 15) and 19 and 32

Contributions of authors

All authors were involved in drafting the protocol.

Sources of support

Internal sources

• University of British Columbia, Department of Anesthesiology, Pharmacology & Therapeutics, Canada.

External sources

• No sources of support supplied

Declarations of interest

Wang Gan Mi: None known.

Li Liang Jin : None known.

Chen Yu Jie: None known.

Tang Wen Lu: : None known.

James M Wright: : None known.

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