Renin inhibitors versus angiotensin receptor blockers 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 angiotensin receptor blockers 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 2016). 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 receptor blockers (ARBs) are widely prescribed for people with primary hypertension.

How the intervention might work

The renin angiotensin system (RAS) is a neurohumoral regulatory system that is thought to play a role in the pathogenesis of hypertension and its cardiovascular complications.

RIs inhibit the enzymatic action of renin, which controls the first and rate‐limiting step in the RAS. Thus RIs reduce angiotensin Ⅱ production from the very beginning. Although inhibition of renin may cause a compensatory increase in renin production through negative feedback, RIs lower plasma renin activity and decrease angiotensin I and angiotensin Ⅱ (Angeli 2014). Thus RIs are considered to more effectively and thoroughly block the RAS.

ARBs are a class of widely‐prescribed antihypertensive agents which inhibit the RAS by interfering with the binding of angiotensin II with its receptors. Some clinical studies have established ARBs' effect in preventing complications caused by hypertension (LIFE 2002; VALUE 2004). Guidelines such as JNC8 2014 recommend ARBs as first‐line therapy for hypertension. However, the phenomenon called 'aldosterone breakthrough' (Horita 2006), which refers to a rise in the aldosterone level after long‐term use of ARBs, could reduce the antihypertensive effect of ARBs by increasing reabsorption of salt and water. Additionally, ARBs increase plasma renin activity (O' Brien 2007), which is associated with target organ damage.

Why it is important to do this review

RIs may provide more protective effect for people with hypertension than ARBs. However, hypertension guidelines do not make specific recommendations for clinical use of RIs, while they recommend ARBs as first‐line drugs for hypertension (CHEP 2014; JNC8 2014). 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 (Musini 2008) has demonstrated that RIs reduce blood pressure more than placebo, and that the magnitude of this effect is similar to that for ARBs (Heran 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 ARBs, 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) with ACE inhibitors (Li 2014). However, there is currently no Cochrane Review comparing the effectiveness and safety of RIs to ARBs. This review therefore aims to compare RIs and ARBs 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 angiotensin receptor blockers in people with primary hypertension.

Methods

Criteria for considering studies for this review

Types of studies

The studies must be double‐blind randomized controlled trials (DBRCTs), with a parallel design, randomizing participants to the renin inhibitor group or to the ARB group, and must have a minimum follow‐up of four weeks.

Types of participants

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

Hypertension is defined as an office systolic blood pressure (BP) ≥ 140 mmHg or an office diastolic BP ≥ 90 mmHg, or both. If ambulatory BP is measured, diagnostic criteria are as follows: 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

Intervention: renin inhibitors.

Control: angiotensin receptor blockers.

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

Angiotensin receptor blockers include: abitesartan, azilsartan, candesartan, elisartan, embusartan, eprosartan, forasartan, irbesartan, KT3‐671, losartan, milfasartan, olmesartan, saprisartan, tasosartan, telmisartan, valsartan and zolasartan.

Types of outcome measures

Primary outcomes

1. All‐cause mortality.

2. Total cardiovascular events:

   1. fatal and non‐fatal myocardial infarction;

   2. fatal and non‐fatal stroke;

   3. fatal congestive heart failure;

   4. hospitalizations for congestive heart failure.

3. Renal outcomes: 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 blood pressure.

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. (Lefebvre 2011)). Searches for this review have been combined with the related review Renin inhibitors versus angiotensin converting enzyme (ACE) inhibitors 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

We will import references and abstracts of search results into Reference Manager software.

Two review authors will independently perform the initial screening of the results of the searches, to exclude obviously irrelevant citations. We will acquire the full texts of the remaining citations (translated into English if necessary), and will independently screen them for the prespecified inclusion criteria, and record reasons for exclusion. We will check the reference lists of pertinent articles and reviews for additional relevant citations. A third review author will resolve any disagreements or discrepancies.

Data extraction and management

Two review authors will independently extract data from the included studies using a standard data extraction form. The data will include study design, randomization, blinding, drugs, duration of the study, baseline characteristics and outcomes.

A third review author will cross‐check the data, resolve discrepancies, and confirm all numeric calculations and graphic interpolations.

Assessment of risk of bias in included studies

We will assess risks of bias in each included trial, using the 'Risk of bias' methods given in the Cochrane Handbook (Higgins 2011). Two review authors will independently rate the risks of bias in each study as 'low risk', 'high risk ' or 'unclear risk', with a third review author resolving any discrepancy.

We will present the assessment of risk of bias in the following domains:

1. Sequence generation;

2. Allocation concealment;

3. Blinding of participants and personnel;

4. Blinding of outcome assessment;

5. Incomplete outcome data;

6. Selective reporting;

7. Other potential bias.

Measures of treatment effect

We will base data synthesis and quantitative analysis of outcomes upon intention‐to‐treat principles as much as possible, using Review Manager 5 software (RevMan).

For dichotomous variables (all‐cause mortality, total cardiovascular events, renal events, withdrawal due to adverse events and serious adverse events), we will use a risk ratio (RR) with a 95% confidence interval (CI).

For continuous variables (change in systolic and diastolic blood pressure and change in heart rate), weighted mean difference (WMD) with 95% CI are the effect variables. In case of different methods of measurement across the included studies, we will calculate a standardized mean difference (SMD) with a 95% CI.

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

We will contact the investigators to request any missing data.

If the studies did not report a standard deviation (SD) for a continuous outcome, we will impute the SD in 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 the intervention and control 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 assess suspected reporting biases using funnel plots. 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 use RevMan to perform data synthesis and analysis. One review author will input the data and a second will check them. We will pool the data using the Mantel‐Haenszel fixed‐effect model if there is no or low heterogeneity, and a random‐effects model when significant heterogeneity is present.

If there is only one trial on an outcome, or where meta‐analysis is not applicable, we will provide a narrative description of the results.

Subgroup analysis and investigation of heterogeneity

We will perform the following subgroup analyses if possible:

1. Participants:

   1. Gender;

   2. Age;

   3. Race;

   4. Baseline blood pressure level;

   5. Co‐morbid conditions: e.g. diabetes, heart diseases, renal diseases, cardiovascular diseases.

2. Treatments:

   1. Doses of drugs;

   2. Duration of treatment.

Sensitivity analysis

We will perform sensitivity analyses to test the robustness of the results in the following domains:

1. Sponsorship: trials that were industry‐sponsored versus non‐industry sponsored;

2. SD: trials with reported SDs versus those with imputed SDs;

3. Risk of bias: trials that have a high risk of bias versus those having 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 and non‐fatal myocardial infarction;

   2. fatal and non‐fatal stroke;

   3. fatal congestive heart failure;

   4. hospitalizations for congestive heart failure.

3. Renal outcomes: End‐stage renal disease (ESRD).

4. Withdrawal due to adverse effects (WDAE).

5. Fatal or non‐fatal serious adverse events.

6. Adverse events.

Appendices

Appendix 1. MEDLINE search strategy

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$) adj2 (blood pressure or bp)).tw. 19 or/16‐18 20 randomized controlled trial.pt. 21 controlled clinical trial.pt. 22 randomized.ab. 23 placebo.ab. 24 drug therapy.fs. 25 randomly.ab. 26 trial.ab. 27 groups.ab. 28 or/20‐27 29 animals/ not (humans/ and animals/) 30 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ 31 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. 32 28 not (29 or 30 or 31) 33 4 and (10 or 15) and 19 and 32 34 remove duplicates from 33

Appendix 2. Cochrane Hypertension Specialized Register search strategy

#1 ((aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren)) #2 (RAS or renin) near2 inhibit* #3 #1 OR #2 #4 MeSH DESCRIPTOR Angiotensin‐Converting Enzyme Inhibitors EXPLODE ALL #5 ((angiotensin or dipeptidyl or kininase ii) near3 (convert* or enzyme or inhibit* or recept* or block*)) #6 (ace near2 inhibit*) #7 acei #8 ((alacepril or altiopril or benazepril or captopril or ceronapril or cilazapril or delapril or enalapril or fosinopril or idapril or imidapril or lisinopril or moexipril or moveltipril or pentopril or perindopril or quinapril or ramipril or spirapril or temocapril or trandolapril or zofenopril)) #9 #4 OR #5 OR #6 OR #7 OR #8 #10 MeSH DESCRIPTOR Angiotensin Receptor Antagonists EXPLODE ALL #11 angiotensin near3 (receptor antagon* or receptor block*) #12 arb or arbs #13 (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) #14 #10 OR #11 OR #12 OR #13 #15 RCT:DE #16 ((Review OR Meta‐Analysis)):MISC2 #17 #15 OR #16 #18 #3 AND (#9 OR #14) AND #17

Appendix 3. CENTRAL search strategy

#1 ((aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren)) AND CENTRAL:TARGET #2 (RAS or renin) near2 inhibit* AND CENTRAL:TARGET #3 #1 OR #2 #4 MeSH DESCRIPTOR Angiotensin‐Converting Enzyme Inhibitors EXPLODE ALL AND CENTRAL:TARGET #5 ((angiotensin or dipeptidyl or kininase ii) near3 (convert* or enzyme or inhibit* or recept* or block*)) AND CENTRAL:TARGET #6 (ace near2 inhibit*) AND CENTRAL:TARGET #7 acei AND CENTRAL:TARGET #8 ((alacepril or altiopril or benazepril or captopril or ceronapril or cilazapril or delapril or enalapril or fosinopril or idapril or imidapril or lisinopril or moexipril or moveltipril or pentopril or perindopril or quinapril or ramipril or spirapril or temocapril or trandolapril or zofenopril)) AND CENTRAL:TARGET #9 #4 OR #5 OR #6 OR #7 OR #8 #10 MeSH DESCRIPTOR Angiotensin Receptor Antagonists EXPLODE ALL AND CENTRAL:TARGET #11 angiotensin near3 (receptor antagon* or receptor block*) AND CENTRAL:TARGET #12 arb or arbs AND CENTRAL:TARGET #13 (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) AND CENTRAL:TARGET #14 #10 OR #11 OR #12 OR #13 #15 #3 AND (#9 OR #14)

Appendix 4. Embase search strategy

1 exp renin inhibitor/ 2 (aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren).tw. 3 ((RAS or renin) adj2 inhibit$).tw. 4 or/1‐3 5 exp dipeptidyl carboxypeptidase inhibitor/ 6 ((angiotensin$ 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 antagonist/ 12 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw. 13 (arb or arbs).tw. 14 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or forasartan or irbesartan or KT3‐671 or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan).tw. 15 or/11‐14 16 exp hypertension/ 17 (antihypertens$ or hypertens$).tw. 18 ((high or elevat$ or rais$) adj2 blood pressure).tw. 19 or/16‐18 20 randomized controlled trial/ 21 crossover procedure/ 22 double‐blind procedure/ 23 (randomi?ed or randomly).tw. 24 (crossover$ or cross‐over$).tw. 25 placebo.ab. 26 (doubl$ adj blind$).tw. 27 assign$.ab. 28 allocat$.ab. 29 or/20‐28 30 (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) 31 Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ 32 (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. 33 29 not (30 or 31 or 32) 34 4 and (10 or 15) and 19 and 33 35 remove duplicates from 34

Appendix 5. ClinicalTrials.gov search strategy

Search terms: randomized Study type: Interventional Studies Interventions: (renin inhibitor* OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (angiotensin converting enzyme inhibit* OR ace inhibit* OR alacepril OR benazepril OR captopril OR enalapril) (renin inhibitor* OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (perindopril* OR pivopril OR quinapril* OR ramipril* OR rentiapril OR saralasin OR s nitrosocaptopril) (renin inhibitor* OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (spirapril* OR temocapril* OR teprotide OR trandolapril* OR utibapril* OR zabicipril* OR zofenopril* or Aceon) (renin inhibitor* OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (Accupril OR Altace OR Capoten OR Lotensin OR Mavik OR Monopril OR Prinivil OR Univas OR Vasotec OR Zestril) (renin inhibitor* OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (angiotensin receptor antagonist* OR angiotensin receptor blocker* OR arb OR arbs OR bitesartan) (renin inhibitor* OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (azilsartan OR candesartan OR elisartan OR embusartan OR eprosartan OR forasartan OR irbesartan OR KT3‐671) (renin inhibitor* OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan)

Appendix 6. WHO International Clinical Trials Registry Platform search strategy

Condition: hypertens Recruitment status: All Interventions: (renin inhibitor OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (angiotensin converting enzyme inhibit OR ace inhibit OR alacepril OR benazepril OR captopril OR enalapril) (renin inhibitor OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (perindopril OR pivopril OR quinapril OR ramipril OR rentiapril OR saralasin OR s nitrosocaptopril) (renin inhibitor OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (spirapril OR temocapril OR teprotide OR trandolapril OR utibapril OR zabicipril OR zofenopril OR Aceon) (renin inhibitor OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (Accupril OR Altace OR Capoten OR Lotensin OR Mavik OR Monopril OR Prinivil OR Univas OR Vasotec OR Zestril) (renin inhibitor OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (angiotensin receptor antagonist OR angiotensin receptor blocker OR arb OR arbs OR bitesartan) (renin inhibitor OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (azilsartan OR candesartan OR elisartan OR embusartan OR eprosartan OR forasartan OR irbesartan OR KT3‐671) (renin inhibitor OR aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND (losartan OR milfasartan OR olmesartan OR saprisartan OR tasosartan OR telmisartan OR valsartan OR zolasartan)

Contributions of authors

All review authors were involved in drafting the protocol.

Sources of support

Internal sources

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

External sources

• No sources of support supplied

Declarations of interest

Li Liang Jin : None known.

Chen Yu Jie: None known.

Wang Gan Mi: None known.

Tang Wen Lu: : None known.

James M Wright: : None known.

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