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

Abstract

Background

Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.

Objectives

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

Search methods

The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.

Selection criteria

We included randomized, active‐controlled, double‐blinded studies (RCTs) with at least four weeks follow‐up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.

Data collection and analysis

Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.

Main results

We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow‐up duration ranged from four weeks to 36.6 months.

There was no difference between RIs and ACE inhibitors for the outcomes: all‐cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low‐certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low‐certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate‐certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low‐certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low‐certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end‐stage renal disease or change in heart rate. Low‐certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) −1.72, 95% CI −2.47 to −0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD −1.18, 95% CI −1.65 to −0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect. 

Authors' conclusions

For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all‐cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long‐term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure‐lowering effect. 

Plain language summary

How renin inhibitors (RIs) compare with angiotensin converting enzyme (ACE) inhibitors for treating hypertension

Review question

We determined how renin inhibitors (RIs) compared with angiotensin converting enzyme (ACE) inhibitors for treating hypertension.

Background

Hypertension is a worldwide public‐health challenge associated with high levels of occurrence and risks of circulatory and kidney disease. RIs were introduced into clinical use for hypertension in 2007. ACE inhibitors are widely prescribed for hypertension. However, the comparative effectiveness and safety of RIs and ACE inhibitors is not known.

Search date

We searched for evidence up to August 2020.

Study characteristics

We included randomized, active‐controlled, double‐blinded studies (RCTs) for this review. We include 11 RCTs involving 13,627 participants, with an average age from 51 to 74 years. Length of follow‐up ranged from four weeks to 36 months.

Key results and certainty of evidence

Low‐certainty evidence showed no difference between RIs and ACE inhibitors for deaths from any cause, for heart attacks, for serious side effects or for leaving the study because of side effects. Low‐certainty evidence suggested that RIs reduce blood pressure more than ACE inhibitors do, but this could have been due to bias in the design and conduct of the studies. More independent RCTs are needed to assess illnesses and deaths, and to see if the difference in blood pressure‐lowering is real.  

Summary of findings

Summary of findings 1. Renin inhibitors compared to ACE inhibitors for primary hypertension.

Renin inhibitors compared to ACE inhibitors for primary hypertension
Patient or population: people with primary hypertension Setting: ambulatory clinics Intervention: Renin inhibitors Comparison: ACE inhibitors
Outcomes	№ of participants (studies) Follow up	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects* (95% CI)
				Risk with ACE inhibitors	Risk difference with Renin inhibitors
All‐cause mortality follow‐up: range 4 weeks to 36.6 months	5962 (5 RCTs)	⊕⊕⊝⊝ LOWa,b	RR 1.05 (0.93 to 1.18)	Study population
				131 per 1000	7 more per 1,000 (9 fewer to 24 more)
Fatal or non‐fatal myocardial infarction follow‐up: range 8 weeks to 54 weeks	957 (2 RCTs)	⊕⊝⊝⊝ VERY LOWa,c	RR 0.86 (0.22 to 3.39)	Study population
				7 per 1000	1 fewer per 1000 (5 fewer to 16 more)
Adverse events follow‐up: range 4 weeks to 54 weeks	6007 (10 RCTs)	⊕⊕⊕⊝ MODERATEa	RR 0.98 (0.93 to 1.03)	Study population
				489 per 1000	10 fewer per 1000 (34 fewer to 15 more)
Fatal or non‐fatal serious adverse events follow‐up: range 4 weeks to 54 weeks	6007 (10 RCTs)	⊕⊕⊝⊝ LOWa,c	RR 1.21 (0.89 to 1.64)	Study population
				27 per 1000	6 more per 1000 (3 fewer to 17 more)
Withdrawal due to adverse effects (WDAE) follow‐up: range 4 weeks to 54 weeks	6008 (10 RCTs)	⊕⊕⊝⊝ LOWa,c	RR 0.85 (0.68 to 1.06)	Study population
				60 per 1000	9 fewer per 1000 (19 fewer to 4 more)
SBP follow‐up: range 4 weeks to 54 weeks	5001 (9 RCTs)	⊕⊕⊝⊝ LOWa,d	‐	‐	MD 1.72 mm Hg lower (2.47 lower to 0.97 lower)
DBP follow‐up: range 4 weeks to 54 weeks	5001 (9 RCTs)	⊕⊕⊝⊝ LOWa,d	‐	‐	MD 1.18 lower (1.65 lower to 0.72 lower)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; DBP: diastolic blood pressure; RR: Risk ratio; SBP: systolic blood pressure
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

^aDowngraded due to high risk of source of funding bias.
^bResults almost entirely from ATMOSPHERE 2016, 60% hypertensive heart‐failure participants at baseline.
^cDowngraded due to wide confidence interval.
^dDowngraded due to risk of publication bias.

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 2017). 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 long been known to be associated with the pathophysiology of hypertension (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). ACE inhibitors also 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 blocking the RAS (Skeggs 1957).

Why it is important to do this review

Guidelines, such as ESC/ESH 2018 and JNC8 2014, recommend 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 favorable 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 2017). 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 published 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 with ACE inhibitors for their effects on mortality and morbidity, and for their 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 included people with primary hypertension, and excluded people with proven secondary hypertension.

Diagnostic criteria for primary hypertension:

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

• 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. These include: aliskiren, ciprokiren, ditekiren, enalkiren, remikiren, rasilez, tekturna, terlakiren and zankiren.

Control: any ACE inhibitor. These 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

Mortality and morbidity outcomes (see below) are considered most important.  Change in blood pressure is less important.  

Primary outcomes

• All‐cause mortality

• Total cardiovascular events:

  • fatal or non‐fatal myocardial infarction

  • fatal or non‐fatal stroke

  • fatal congestive heart failure

  • hospitalizations for congestive heart failure

• End‐stage renal disease (ESRD) 

• Withdrawal due to adverse effects (WDAE)

• Fatal or non‐fatal serious adverse events (SAEs)

• Adverse events (AEs)

Secondary outcomes

• Individual cardiovascular events

• Change in systolic and diastolic BP

• Change in heart rate

Search methods for identification of studies

Electronic searches

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

• the Cochrane Hypertension Specialized Register via the Cochrane Register of Studies (searched 5 August 2020);

• the Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 7) via the Cochrane Register of Studies (searched 5 August 2020);

• MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 5 August 2020);

• Embase Ovid (from 1974 onwards; searched 4 August 2020);

• ClinicalTrials.gov (www.clinicaltrials.gov; searched 4 August 2020);

• World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch; searched 5 August 2020).

The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomized controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 6.1.0 (Lefebvre 2020)). We present search strategies for major databases in Appendix 1. We have combined searches for this review with the related review Renin inhibitors versus angiotensin receptor blockers for primary hypertension.

Searching other resources

• The Hypertension Information Specialist searched the Hypertension Specialized 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 could scan their reference lists to identify additional relevant trials.

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

• We did 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 (GMW and LJL) independently examined the titles and abstracts of citations identified by the electronic searches for possible inclusion. We retrieved full‐text publications of potentially relevant studies and two review authors (GMW and LJL) then independently determined study eligibility. We resolved disagreements about study eligibility by discussion and, if necessary, a third review author (WLT) would arbitrate.

Data extraction and management

Two review authors (GMW and LJL) independently extracted data using a standard form, and then cross‐checked. A third review author (WLT) confirmed all numeric calculations and graphic interpolations. We resolved any discrepancies by consensus.

Assessment of risk of bias in included studies

The review authors (GMW and LJL) independently used the Cochrane 'Risk of bias' tool 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 based quantitative analysis of outcomes on intention‐to‐treat principles when possible. For dichotomous outcomes, we expressed results as a risk ratio (RR) with a 95% confidence interval (CI). For combining continuous variables, we used 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 was the individual trial. For trials having more than two arms, we only included arms relevant to this review. Where studies included more than one intervention group with a single comparator arm, we included both intervention groups.

Dealing with missing data

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

• 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;

• SD at the end of treatment;

• SD at baseline;

• 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 considered a P value of 0.10 or less from the Chi² test as statistically significant for heterogeneity (Deeks 2020). We also used the I² statistic for quantifying inconsistency across studies, following the rough guide to interpretation as described in Deeks 2020:

• 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 used 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 conducted data synthesis and analyses using Cochrane Review Manager 5 software (Review Manager 2020). We describe data results in tables and forest plots. We also give full details of all studies we include and exclude.

Where we identify statistically significant heterogeneity, we use a random‐effects model for meta‐analysis. Since a random‐effects model can overemphasize smaller studies, we planned 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 would perform subgroup analyses.

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

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

Sensitivity analysis

If appropriate, we would test the robustness of the results using several sensitivity analyses, including:

• Trials that were industry‐sponsored versus non‐industry sponsored;

• Trials with reported standard deviations of effect change versus imputed standard deviations;

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

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach (GRADEpro GDT) to assess the quality of the supporting evidence behind each estimate of treatment effect (Schünemann 2011b; Schünemann 2020). We presented key findings of the review, including a summary of the amount of data, the magnitude of the effect size and the overall certainty of the evidence, in Table 1. We had preselected the following outcomes for inclusion in Table 1:

• All‐cause mortality

• Total cardiovascular events*:

  • fatal or non‐fatal myocardial infarction

  • fatal or non‐fatal stroke*

  • fatal congestive heart failure*

  • hospitalizations for congestive heart failure*

• End‐stage renal disease (ESRD)* 

• Withdrawal due to adverse effects (WDAE)

• Fatal or non‐fatal serious adverse events

• Adverse events

• Systolic blood pressure (SBP)

• Diastolic blood pressure (DBP)

*These outcomes were not shown in the 'Summary of findings' table, due to no data available.

Results

Description of studies

We include 11 studies (15 publications). Nine trials reported BP data; 10 trials reported adverse events (AEs), serious adverse events (SAEs) and withdrawals due to adverse events (WDAEs); five trials reported all‐cause mortality events, and two trials reported fatal or nonfatal myocardial infarction. None of the trials reported total cardiovascular events (myocardial infarction, stroke, congestive heart failure, and hospitalizations for heart failure), hospitalizations for heart failure, stroke, ESRD or change in heart rate.

Results of the search

The results of the search are shown in the PRISMA diagram (Figure 1). Our search revealed 3079 references, which were reduced to 2136 after de‐duplication. After screening titles and abstracts, we obtained 30 full‐text articles. Of these articles, we excluded 14 studies (15 articles) based on them not meeting our inclusion criteria.

1.

Study flow diagram.

Included studies

See Characteristics of included studies for details.

We include 11 RCTs involving 13,627 participants that were randomized (the total number is different from the sum of numbers of participants given in the meta‐analyses form, due to a subtraction of irrelevant groups from trials). Although aimed at people with heart failure, ATMOSPHERE 2016 was included because over 60% of its participants had hypertension at baseline, and it reported all‐cause mortality data for the hypertension subgroup which contributed to our meta‐analysis.

The mean follow‐up of the 11 RCTs ranged from four weeks to 36.6 months. The four trials with the longest duration were: ATMOSPHERE 2016 (36.6 months), NCT00631917 2011 (54 weeks), AGELESS 2010 (36 weeks) and Andersen 2008 (26 weeks). Most of the RCTs were conducted at multiple centers in various geographic locations (North America, Europe, Asia): ATMOSPHERE 2016, 789 centers in 43 countries; NCT00631917 2011, 115 centers in seven countries; Andersen 2008, 80 centers worldwide; Palatini 2010, 97 centers worldwide; Verdecchia 2007, 62 centers worldwide; Uresin 2007, 125 centers worldwide.

The average age of participants ranged from 51.5 years (Jones‐Burton 2010) to 74.2 years (Verdecchia 2007), with an approximately equal number of women in each arm of the various  trials. The mean baseline blood pressure of participants in studies ranged from 146/93 mmHg (Palatini 2010) to 166/91 mmHg (ALIAS 2012). Data obtained were therefore from mild‐to‐moderate hypertension participants. Two RCTs were aimed at hypertensive participants with specific diseases (as inclusion criteria): one targeted chronic heart failure (ATMOSPHERE 2016), and the other type 1 or 2 diabetes mellitus (Uresin 2007). In addition, some of the participants (7% to 58.6%) in several RCTs had co‐morbidities such as diabetes or metabolic syndrome at baseline (AGELESS 2010; Andersen 2008; ATMOSPHERE 2016; NCT00631917 2011; Strasser 2007; Verdecchia 2007; Zhu 2012). See Table 2 for more detail.

1. Main characteristics of included studies.

Study ID	N	Follow‐up (weeks)	Mean Age (years)	Co‐morbidity	Intervention	Add‐on drugs	Baseline SBP/DBP (mm Hg)
AGELESS 2010	901	36	T: 72.0 C: 72.2	Baseline diabetes: aliskiren 21.7%; ramipril 19.6%.	T: Aliskiren 150‐300 mg/day C: Ramipril 5‐10 mg/day	HCTZ 12.5 ‐ 25 mg/day or HCTZ 12.5 ‐ 25 mg/day +amlodipine 5 ‐ 10 mg/day	T: 156.5/85.5 C: 156.6/86.0
ALIAS 2012	506	8	T: 60.1 C: 59.8	NA	T: Aliskiren 150‐300 mg/day C: Ramipril 5‐10 mg/day	None	T: 166.4/89.9 C: 166.3/90.9
Andersen 2008	842	26	T: 53.4 C: 53.1	Baseline diabetes: aliskiren 10%; ramipril 11.6%. Baseline metabolic syndrome: aliskiren 40.7%; ramipril 43.3%.	T: Aliskiren 150 ‐ 300 mg/day C: Ramipril 5 ‐ 10 mg/day	HCTZ 12.5 ‐ 25 mg/day	T: 151.3/98.8 C: 151.4/98.9
ATMOSPHERE 2016	7064	36.6 months	T: 63.3 C1: 63.3 C2: 63.2	Heart failure as inclusion criterion; Baseline diabetes: aliskiren 26.8%; enalapril 27.9%; enalapril + aliskiren 28.4%	T: Aliskiren 150 ‐ 300 mg/day C1: Enalapril 5 ‐ 10 mg/day C2: Enalapril 5 ‐ 10 mg/day + Aliskiren 150 ‐ 300 mg/day	Optimal heart failure therapy, including beta blockers, but with the exception of ACE inhibitors	NA Note: Numbers of hypertensive participants at baseline, n(%): T: 1460 (62.4%) C1: 1425 (61.0%) C2: 1447 (61.8%)
Jones‐Burton 2010	195	4	T1: 52.8 T2: 52.8 C1: 51.5 C2: 53.1	NA	T1:MK‐8141 250 mg/day T2:MK‐8141 500 mg/day C1: Enalapril 20 mg/day C2: Placebo	None	T1: 150.2/93.8 T2: 149.7/94.2 C1: 150.6/95.1 C2: 151.9/93.6
NCT00631917 2011	774	54	T: 59.3 C: 59.3	Baseline diabetes: aliskiren 22.1%; ramipril 25.1%.	T: Aliskiren 150 ‐ 300 mg/day C: Ramipril 5 ‐ 10 mg/day	HCTZ 12.5 ‐ 25 mg/day or HCTZ 12.5 ‐ 25 mg/ay + amlodipine 5 ‐ 10 mg/day	NA
Palatini 2010	654	9	T: 53.5 C1: 53.9 C2: 53.4	NA	T: Aliskiren 150 ‐ 300 mg/day C1: Ramipril 5 ‐ 10 mg/day C2: Irbesartan 150 ‐ 300 mg/day	None	T: 145.5/93 C1:145.8/92.4 C2:145.4/93.0
Strasser 2007	183	8	T: 55.3 C: 55.6	Baseline diabetes: aliskiren 12.0%; lisinopril 13.8%. Baseline metabolic syndrome: aliskiren 52.8%; lisinopril 58.6% Baseline hypercholesterolemia: aliskiren 16.8%; lisinopril 15.5%	T: Aliskiren 150 ‐ 300 mg/day C: Lisinopril 20 ‐ 40 mg/day	HCTZ 25 mg/day	T: 163.4/108.4 C: 161.7/108.0
Uresin 2007	837	8	T: 60.0 C1: 59.9 C2: 59.5	Type 1 or 2 diabetes mellitus as inclusion criteria	T: Aliskiren 150 ‐ 300 mg/day C1: Ramipril 5 ‐ 10 mg/day C2: Aliskiren 150 ‐ 300 mg/day+ Ramipril 5 ‐ 10 mg/day	None	T: 157.4/98.4 C1: 155.9/98.2 C2: 156.5/98.4
Verdecchia 2007	355	8	T1: 73.6 T2: 73.2 T3: 73.0 C: 74.2	Baseline diabetes: aliskiren 75 mg 13.2%; aliskiren 150 mg 11.9%; aliskiren 300 mg 11.7%; lisinopril 7.0% Baseline metabolic syndrome: aliskiren 75 mg 27.5%; aliskiren 150 mg 22.6%; aliskiren 300 mg 24.5%; lisinopril 23.3%	T1: Aliskiren 75 mg/day T2: Aliskiren 150 mg/day T3: Aliskiren 300 mg/day C: Lisinopril 10 mg/day	None	T1: 160.4/88.0 T2: 160.2/89.3 T3: 160.7/90.1 C: 161.4/88.1
Zhu 2012	1316	8	T1: 52.7 T2: 53.3 T3: 53.8 C: 52.9	Baseline diabetes: aliskiren 75 mg 10.5%; aliskiren 150 mg 9.6%; aliskiren 300 mg 10.9%; ramipril 5 mg 15.2%.	T1: Aliskiren 75 mg/day T2: Aliskiren 150 mg/day T3: Aliskiren 300 mg/day C: Ramipril 5 mg/day	None	T1: 147.3/98.9 T2: 146.8/98.5 T3: 148.9/98.9 C1: 148.5/98.8

C: control group; DBP: diastolic blood pressure; HCTZ: hydrochlorothiazide; N: total number of participants randomized in each trial; T: test group; NA: not available; SBP: systolic blood pressure

ACE inhibitors included enalapril (Jones‐Burton 2010; ATMOSPHERE 2016), lisinopril (Verdecchia 2007) and ramipril (AGELESS 2010; ALIAS 2012; Andersen 2008; NCT00631917 2011; Uresin 2007). RIs included MK‐8141 (Jones‐Burton 2010) and aliskiren (all other trials). Four RCTs allowed hydrochlorothiazide or amlodipine or both as add‐on medications to their treatment regimen in order to control BP (AGELESS 2010; Andersen 2008; NCT00631917 2011; Strasser 2007). Three studies had multiple‐dose groups for RIs. Jones‐Burton 2010 had two arms of MK‐8141 at dose 250 mg/day and 500 mg/day respectively. Verdecchia 2007 and Zhu 2012 both had three arms of aliskiren at dose 75, 150 and 300 mg/day respectively. We combined the data from different dose RIs groups from those studies to create a single pair‐wise comparison.

Excluded studies

See Characteristics of excluded studies for details.

We have excluded two potentially eligible studies in the phase of full‐text review, since no information on hypertensive participants was provided (ESCAPE‐SHF 2011; Kiowski 1994). However, we included ATMOSPHERE 2016 in our analyses because it reported all‐cause mortality data on the hypertensive subgroup. Four studies did not report outcomes pertinent to this review (Azizi 1994; Burnier 2011; Fisher 1994; Tsygankova 2012). Three studies were not parallel design (Fisher 1994; Lizakowski 2012; Quinn 2010), and three studies were not blinded (Fogari 2013; Makówka 2012; Virdis 2012). One study (NCT01151410 2015) was aimed at pediatric hypertension, and was excluded because the diagnostic criteria for pediatric hypertension differed from those for adults. In addition, Zeymer 2012 was excluded as a non‐interventional study.

Risk of bias in included studies

See Characteristics of included studies and 'Risk of bias' graph (Figure 2) for more details.

2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

All included studies were double‐blind randomized control trials at low or unclear risk of bias for allocation, blinding, incomplete outcome data and selective reporting, but with high risk of bias for other sources of bias.

Allocation

All included studies reported randomization, but four of them did not mention the sequence generation process (ALIAS 2012; Andersen 2008; NCT00631917 2011; Zhu 2012) and five of them did not provide information about method of allocation concealment (ALIAS 2012; Andersen 2008; Jones‐Burton 2010; NCT00631917 2011; Zhu 2012). In these studies, we deemed selection bias to be unclear. The baseline participant characteristics tables of these studies revealed no significant differences between study arms indicative of inadequate randomization. Seven RCTs (AGELESS 2010; ATMOSPHERE 2016; Jones‐Burton 2010; Palatini 2010; Strasser 2007; Uresin 2007; Verdecchia 2007) are at low risk of bias for the sequence generation process, because they reported adequate sequence generation using computer‐generated random numbers and validated interactive voice response systems that automate random assignment. Six RCTs (AGELESS 2010; ATMOSPHERE 2016; Palatini 2010; Strasser 2007; Uresin 2007; Verdecchia 2007) have low risk of bias for allocation concealment, because they reported the use of a voice‐based computerized randomization system that involved concealed trial‐group assignments.

Blinding

All included studies mentioned blinding, but seven of them (AGELESS 2010; Andersen 2008; ATMOSPHERE 2016; NCT00631917 2011; Palatini 2010; Strasser 2007; Verdecchia 2007) reported using a double‐blind, double‐dummy design, so we deemed them to have a low risk of performance bias. Four studies (ALIAS 2012; Jones‐Burton 2010; Uresin 2007; Zhu 2012) have unclear risk of performance bias as information about blinding of participants and personnel was not provided. Three studies reported using blinding of outcome assessment (ATMOSPHERE 2016; NCT00631917 2011; Strasser 2007). For the remaining eight studies, it was unclear whether outcome assessors were blinded from the time of randomization until release of database lock, so we deemed them to be at unclear risk of detection bias.

Incomplete outcome data

Missing data had been imputed using appropriate methods (intention‐to‐treat analysis), with participant demographics and characteristics at baseline similar between treatment groups in 10 studies, which we judged to be at low risk of attrition bias. One study (Jones‐Burton 2010) accounted for participants lost to follow‐up, and missing data were unlikely to have an impact on the results of the trial.

Selective reporting

Although protocols were not available except for ATMOSPHERE 2016, all studies reported all prespecified outcomes in their Methods, so we judged them as having a low risk of reporting bias.

Other potential sources of bias

Jones‐Burton 2010 was jointly funded by Merck & Co. Inc. and Actelion Pharmaceuticals Ltd. The authors are employees of Merck & Co. Inc. and Actelion Pharmaceuticals Ltd. Novartis, (manufacturer of aliskiren) supported the other 10 trials.

A Cochrane Review (Lundh 2017) has found evidence that industry sponsorship is associated with more favorable results and conclusions, and that this bias is not captured by standard 'Risk of bias' assessments. We therefore rated all the included studies at high risk of bias, with concerns about methodology that might be influenced by vested interests. This is particularly true for the blood pressure outcome.

Effects of interventions

See: Table 1

All‐cause mortality

Five studies (5962 participants) reported all‐cause mortality (AGELESS 2010; Andersen 2008; ATMOSPHERE 2016; NCT00631917 2011; Uresin 2007). There was no difference between RIs and ACE inhibitors (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; Analysis 1.1). There was no evidence of statistical heterogeneity across the trials included for this outcome (P value = 0.79; I² = 0%).

1.1. Analysis.

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 1: All‐cause mortality

Myocardial infarction

Two studies (957 participants) reported total myocardial infarction (NCT00631917 2011; Strasser 2007). There was no difference between RIs and ACE inhibitors (RR 0.86, 95% CI 0.22 to 3.39; Analysis 1.2). There was minimal statistical heterogeneity across the trials included for this outcome (P value = 0.21; I² = 36%).

1.2. Analysis.

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 2: Fatal or non‐fatal myocardial infarction

Adverse events

Pooling of the 10 studies (6007 participants) that reported adverse events showed no difference between RIs and ACE inhibitors (RR 0.98, 95% CI 0.93 to 1.03; Analysis 1.3). There was no significant heterogeneity across trials for this outcome (P value = 0.68, I² = 0%). Specific reasons for adverse events were available for all studies except one (ALIAS 2012).

1.3. Analysis.

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 3: Adverse events

Serious adverse events

Ten studies (6007 participants) reported on serious adverse events. We found no difference between RIs and ACE inhibitors (RR 1.21, 95% CI 0.89 to 1.64; Analysis 1.4). There was no significant heterogeneity across trials for this outcome (P value = 0.84, I² = 0%).
 

1.4. Analysis.

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 4: Fatal or non‐fatal serious adverse events

Withdrawals due to AEs

Ten studies (6008 participants) reported on withdrawals due to adverse events (WDAEs). There was no evidence of a difference between RIs and ACE inhibitors for WDAEs (RR 0.85, 95% CI 0.68 to 1.06; Analysis 1.5) with no significant heterogeneity (P value = 0.44, I² = 0%).
 

1.5. Analysis.

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 5: Withdrawal due to adverse effects (WDAE)

Blood pressure

Nine trials (5001 participants) reported BP data. RIs reduced both systolic blood pressure (SBP) (MD −1.72, 95% CI −2.47 to −0.97; Analysis 1.6) and diastolic blood pressure (DBP) (MD −1.18, 95% CI −1.65 to −0.72; Analysis 1.7) to a greater extent than ACE inhibitors. There was minimal statistical heterogeneity across trials for SBP (P value = 0.14, I² = 34%) or for DBP (P value = 0.13, I² = 36%).

1.6. Analysis.

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 6: SBP

1.7. Analysis.

Comparison 1: Renin inhibitors vs. ACE inhibitors, Outcome 7: DBP

Discussion

Summary of main results

This review demonstrates that RIs compared to ACE inhibitors have not been proven to be significantly different for the outcomes all‐cause mortality and myocardial infarction for people with mild‐to‐moderate hypertension. It should be noted that the data for mortality came almost entirely from a subgroup of the ATMOSPHERE 2016 trial, in which all the participants had heart failure plus hypertension. No data were available for total cardiovascular events, hospitalizations for heart failure, stroke, end‐stage renal disease or change in heart rate. We therefore currently have low‐certainty evidence that RIs and ACE inhibitors do not differ for morbidity and mortality outcomes.

There was no significant difference between RIs and ACE inhibitors for adverse events, serious adverse events or withdrawals due to adverse events. We have low‐to‐moderate certainty that RIs and ACE inhibitors are similar for tolerability outcomes.

RIs appeared to reduce SBP and DBP on average more than ACE inhibitors. However, we have graded this finding as low certainty, as there was a high risk of publication bias and in particular source of funding bias for this outcome.

We conducted subgroup analyses to investigate the effect on blood pressure of RIs versus different ACE inhibitors. The overall reduction in blood pressure with aliskiren was limited to the six RCTs comparing it with ramipril. There was no reduction in blood pressure when aliskiren was compared to lisinopril (one RCT) or to enalapril (two RCTs).

All included studies were industry‐sponsored and had similar high risk of bias. The planned sensitivity analysis for industry sponsorship and risk of bias was therefore not possible. Studies with reported standard deviations of effect change yielded similar results for mean changes in systolic and diastolic BP.

Overall completeness and applicability of evidence

Participants in some of the included studies had no co‐morbidities. The data on all‐cause mortality were mainly derived from ATMOSPHERE 2016, which included participants with chronic heart failure. Diabetes and metabolic syndrome were risk factors for participants in some of the included RCTs. This review therefore provides evidence for hypertensive people with or without co‐morbidities such as heart failure or diabetes and metabolic syndrome.

The baseline blood pressures represented in the pooled population largely ranged from mild to moderate hypertension, with average mean baseline blood pressures ranging from 146/93 (SBP/DBP) mmHg (Palatini 2010) to 166/91 (SBP/DBP) mmHg (ALIAS 2012). Our analyses are therefore confined to people whose hypertension is in the mild‐to‐moderate range. 

In terms of the drugs represented, most of the data are available for aliskiren, the only marketed renin inhibitor. For trials with multiple dose arms (Zhu 2012; Jones‐Burton 2010; Verdecchia 2007), we combined the data for each dose into a single arm. The results represented were therefore all doses taken together for aliskiren (75 mg to 300 mg) and for MK‐8141 (250 mg to 500 mg). For the ACE inhibitors, the analyses of primary and secondary outcomes included ramipril (5 mg to 10 mg), enalapril (2.5 mg to 40 mg) and lisinopril (10 mg to 40 mg). Our analyses were underpowered to differentiate the effects of different drugs and doses using subgroup analysis.

For people using ACE inhibitors, it is known that a refractory dry cough can lead them to stop medication. In our analyses, RIs had no more adverse events, serious adverse events or WDAEs compared to ACE inhibitors. However, we note that several RCTs reported more cough in the ramipril arms than in the aliskiren arms (Andersen 2008; AGELESS 2010; Zhu 2012).

In this systematic review, we did not find any data on change in heart rate, total cardiovascular events (myocardial infarction, heart failure, stroke), stroke, heart failure or end‐stage renal disease. We need more and larger studies comparing RIs with ACE inhibitors for hypertension treatment.

The results of this review are in line with current clinical guidelines for the initial drug treatment of hypertension that recommend agents that have been shown to reduce clinical events, including ACE inhibitors, angiotensin receptor blockers, thiazide diuretics and calcium channel blockers, with renin inhibitors as secondary agents (ACC/AHA 2017; ISH 2020; ESC/ESH 2018).

Quality of the evidence

See Table 1 for details.

The included RCTs were double‐blind, and were at low to high risk of bias. We found no inconsistency across studies in any of the meta‐analyses. The trials contributing to this review were all funded by the manufacturer. Furthermore, we detected possible publication bias in funnel plots (see Figure 3 and Figure 4), although only nine of the 11 RCTs were analyzed. It is therefore possible that the lower blood pressure with the renin inhibitors was achieved by preferentially publishing trials favoring the renin inhibitor. The certainty of evidence for the blood pressure outcomes were therefore downgraded to low, due to the high risk of publication bias and source‐of‐funding bias.

3.

Funnel plot of comparison: 1 Renin inhibitors vs. ACE inhibitors, outcome: 1.6 SBP.

4.

Funnel plot of comparison: 1 Renin inhibitors vs. ACE inhibitors, outcome: 1.7 DBP.

For all‐cause mortality, we downgraded the certainty of evidence to low, because the result was dominated by a hypertensive subgroup of ATMOSPHERE 2016.  For myocardial infarction, fatal or non‐fatal serious adverse events and WDAEs, we downgraded the certainty of evidence to very low to low, due to the wide confidence intervals. For adverse events, the certainty of evidence was graded as moderate.

Potential biases in the review process

We assumed that all doses of all drugs within each class for our outcomes of interest were equally effective. This could have biased the blood pressure results against aliskiren, as aliskiren has been shown to have a dose‐related BP‐lowering effect (Musini 2017). With regard to safety, there was no evidence of an increased incidence of adverse events with increasing aliskiren dose (75 mg to 300 mg) (Verdecchia 2007). However, Musini 2017 found a significant increase in diarrhea in the aliskiren 600 mg group; the U.S. Food and Drug Administration (FDA) have approved a revision of the aliskiren label to warn of this overdose risk (Musini 2017). We did not conduct the subgroup analyses to adequately test this assumption, as it would have been underpowered. In addition, to maximize inclusiveness, we included studies with additional BP‐lowering medications (mainly hydrochlorothiazide, amlodipine, etc.) other than study drugs to control BP. We have assumed that this was balanced in each arm.  However, it is unknown whether the added BP‐lowering regimens would equally affect outcomes. Unfortunately, there were too few trials for the primary outcomes to assess publication bias.

Agreements and disagreements with other studies or reviews

This systematic review suggests that RIs reduce mean SBP and DBP more than ACE inhibitors, but as explained above we have low certainty for this finding.  In contrast, comprehensive Cochrane Reviews of placebo‐controlled data show that the magnitude of the BP‐lowering with RIs is similar to that for ACE inhibitors (Heran 2008; Musini 2017). A non‐Cochrane review  (Chen 2013) suggested that aliskiren reduced SBP  by a similar amount as ACE inhibitors, but reduced DBP more than ACE inhibitors. More independent trials are needed to establish the weight of evidence.

Findings for all‐cause mortality and myocardial infarction show a lack of statistical significance, and are based on very little data. Equivalence between RIs and ACE inhibitors cannot therefore be established based on the results of this review.

Our review indicates that RIs show a similar incidence of adverse events, serious adverse events and WDAEs as ACE inhibitors. Reviews of short‐term placebo‐controlled trials have shown that aliskiren does not increase withdrawals due to adverse effects, compared to placebo (Musini 2017). These findings suggest that aliskiren could be used for the treatment of hypertension. It is important to remember that regulatory agencies have warned that combined use of angiotensin‐converting enzyme inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended, particularly in people with diabetes or renal impairment (EMA 2014; FDA 2012).

Authors' conclusions

Implications for practice.

Head‐to‐head comparisons of renin inhibitors (RIs) and angiotensin converting enzyme (ACE) inhibitors for primary hypertension show no difference for all‐cause mortality or myocardial infarction (low‐certainty evidence).
RIs were similar to ACE inhibitors for adverse events (moderate‐certainty evidence), serious adverse events and withdrawals due to adverse events (low‐certainty evidence).

RIs were found to reduce systolic and diastolic blood pressure by a small amount more compared to ACE inhibitors (low‐certainty evidence), but that may be due to publication and source‐of‐funding bias. 

Implications for research.

Most of the data in this review come from short‐term trials and subgroup data. Many of the included studies aimed at comparing the BP‐lowering effect of interventions within a few weeks are not prolonged enough to observe events such as death or cardiovascular events, etc.

More large long‐term trials are needed to compare renin inhibitors with angiotensin converting enzyme (ACE) inhibitors, particularly for outcomes such as heart rate, cardiovascular events (heart failure, stroke, etc.) and end‐stage renal disease.

Further independent short‐term double‐blinded RCTs are needed to determine whether there are blood pressure‐lowering differences between renin inhibitors and ACE inhibitors. 

History

Protocol first published: Issue 2, 2017
Review first published: Issue 10, 2020

Appendices

Appendix 1. Search Strategies

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions(R) <1946 to August 04, 2020>
Search Date: 5 August 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1     renin/ai (1908)
2     (aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren).mp. (1389)
3     ((RAS or renin) adj2 inhibit$).tw,kf. (6346)
4     or/1‐3 (7314)
5     exp Angiotensin‐Converting Enzyme Inhibitors/ (43645)
6     ((angiotensin$ or dipeptidyl$ or kininase ii) adj3 (convert$ or enzyme or inhibit$ or recept$ or block$)).tw,kf. (66142)
7     (ace adj2 inhibit$).tw,kf. (20010)
8     acei.tw,kf. (3845)
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,kf. (28004)
10     or/5‐9 (94435)
11     exp angiotensin receptor antagonists/ (23724)
12     (angiotensin adj3 receptor antagon$).tw,kf. (3769)
13     (angiotensin adj3 receptor block$).tw,kf. (11375)
14     (arb or arbs).tw,kf. (6968)
15     (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,kf. (18577)
16     or/11‐15 (36462)
17     hypertension/ (234415)
18     essential hypertension/ (2275)
19     (antihypertens$ or hypertens$).tw,kf. (456248)
20     ((elevat$ or high$ or rais$) adj2 (blood pressur$ or bp)).tw,kf. (44859)
21     or/17‐20 (519802)
22     randomized controlled trial.pt. (510765)
23     controlled clinical trial.pt. (93785)
24     randomized.ab. (488319)
25     placebo.ab. (209991)
26     drug therapy.fs. (2224975)
27     randomly.ab. (338381)
28     trial.ab. (515198)
29     groups.ab. (2077452)
30     or/22‐29 (4764174)
31     animals/ not (humans/ and animals/) (4689999)
32     Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ (931377)
33     (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. (18910)
34     30 not (31 or 32 or 33) (3990075)
35     4 and (10 or 16) and 21 and 34 (978)

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Cochrane Hypertension Specialised Register via Cochrane Register of Studies (CRS‐Web)

Search Date: 5 August 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 MESH DESCRIPTOR Renin WITH QUALIFIER AI AND INREGISTER
#2 ((aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren)) AND INREGISTER
#3 (RAS OR renin) NEAR2 inhibit* AND INREGISTER
#4 (#1 OR #2 OR #3) AND INREGISTER
#5 MeSH DESCRIPTOR Angiotensin‐Converting Enzyme Inhibitors EXPLODE ALL AND INREGISTER
#6 ((angiotensin OR dipeptidyl OR kininase ii) NEAR3 (convert* OR enzyme OR inhibit* OR recept* OR block*)) AND INREGISTER
#7 (ace NEAR2 inhibit*) AND INREGISTER
#8 (acei OR aceis) AND INREGISTER
#9 (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 INREGISTER
#10 (#5 OR #6 OR #7 OR #8 OR #9) AND INREGISTER
#11 MeSH DESCRIPTOR Angiotensin Receptor Antagonists EXPLODE ALL AND INREGISTER
#12 (angiotensin NEAR3 receptor antagon*) AND INREGISTER
#13 (angiotensin NEAR3 receptor block*) AND INREGISTER
#14 (arb OR arbs) AND INREGISTER
#15 (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 INREGISTER
#16 (#11 OR #12 OR #13 OR #14 OR #15) AND INREGISTER
#17 RCT:DE AND INREGISTER
#18 Review:ODE AND INREGISTER
#19 (#17 OR #18) AND INREGISTER
#20 #4 AND (#10 OR #16) AND #19 AND INREGISTER

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Cochrane Central Register of Controlled Trials (Issue 7, 2020) via Cochrane Register of Studies (CRS‐Web)

Search Date: 5 August 2020

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

#1 MESH DESCRIPTOR Renin WITH QUALIFIER AI AND CENTRAL:TARGET
#2 (aliskiren OR ciprokiren OR ditekiren OR enalkiren OR remikiren OR rasilez OR tekturna OR terlakiren OR zankiren) AND CENTRAL:TARGET
#3 ((RAS OR renin) NEAR2 inhibit*) AND CENTRAL:TARGET
#4 (#1 OR #2 OR #3) AND CENTRAL:TARGET
#5 MeSH DESCRIPTOR Angiotensin‐Converting Enzyme Inhibitors EXPLODE ALL AND CENTRAL:TARGET
#6 ((angiotensin or dipeptidyl OR kininase ii) NEAR3 (convert* OR enzyme OR inhibit* OR recept* OR block*)) AND CENTRAL:TARGET
#7 (ace NEAR2 inhibit*) AND CENTRAL:TARGET
#8 acei AND CENTRAL:TARGET
#9 (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
#10 (#5 OR #6 OR #7 OR #8 OR #9) AND CENTRAL:TARGET
#11 MeSH DESCRIPTOR Angiotensin Receptor Antagonists EXPLODE ALL AND CENTRAL:TARGET
#12 (angiotensin NEAR3 receptor antagon*) AND CENTRAL:TARGET
#13 (angiotensin NEAR3 receptor block*) AND CENTRAL:TARGET
#14 (arb OR arbs) AND CENTRAL:TARGET
#15 (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
#16 (#11 OR #12 OR #13 OR #14 OR #15) AND CENTRAL:TARGET
#17 MeSH DESCRIPTOR Hypertension AND CENTRAL:TARGET
#18 MeSH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET
#19 (antihypertens* OR hypertens*) AND CENTRAL:TARGET
#20 ((elevat* OR high* OR rais*) NEAR2 (blood pressur*)) AND CENTRAL:TARGET
#21 ((elevat* OR high* OR rais*) NEAR2 (bp)) AND CENTRAL:TARGET
#22 (#17 OR #18 OR #19 OR #20 OR #21) AND CENTRAL:TARGET
#23 (#4 AND (#10 OR #16)) AND #22 AND CENTRAL:TARGET

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: Embase <1974 to 2020 August 03> 
Search Date: 4 August 2020
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
1     exp renin inhibitor/ (5987)
2     (aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren).tw. (2124)
3     ((RAS or renin) adj2 inhibit$).tw. (8510)
4     or/1‐3 (12191)
5     exp dipeptidyl carboxypeptidase inhibitor/ (174444)
6     ((angiotensin$ or dipeptidyl$ or kininase ii) adj3 (convert$ or enzyme or inhibit$ or recept$ or block$)).tw. (85658)
7     (ace adj2 inhibit$).tw. (30263)
8     acei.tw. (8002)
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. (39754)
10     or/5‐9 (223117)
11     exp angiotensin receptor antagonist/ (92132)
12     (angiotensin adj3 receptor antagon$).tw. (4926)
13     (angiotensin adj3 receptor block$).tw. (16676)
14     (arb or arbs).tw. (13848)
15     (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. (28357)
16     or/11‐15 (100033)
17     exp hypertension/ (727096)
18     (antihypertens$ or hypertens$).tw. (665251)
19     ((high or elevat$ or rais$) adj2 blood pressur$).tw. (44183)
20     or/17‐19 (958354)
21     randomized controlled trial/ (614985)
22     crossover procedure/ (63975)
23     double‐blind procedure/ (174879)
24     (randomi?ed or randomly).tw. (1259378)
25     (crossover$ or cross‐over$).tw. (107710)
26     placebo.ab. (300989)
27     (doubl$ adj blind$).tw. (211507)
28     assign$.ab. (392693)
29     allocat$.ab. (152116)
30     or/21‐29 (1826507)
31     (exp animal/ or animal.hw. or nonhuman/) not (exp human/ or human cell/ or (human or humans).ti.) (6443941)
32     Pregnancy/ or Hypertension, Pregnancy‐Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/ (620056)
33     (pregnancy‐induced or ocular hypertens$ or preeclampsia or pre‐eclampsia).ti. (25428)
34     30 not (31 or 32 or 33) (1564685)
35     4 and (10 or 16) and 20 and 34 (675)

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: ClinicalTrials.gov

Search Date: 4 August 2020

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
Condition or disease: Hypertension
Other terms: randomized 
Study type: Interventional Studies (Clinical Trials)

Intervention/treatment:
(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)

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐

Database: WHO International Clinical Trials Registry Platform via Cochrane Register of Studies (CRS‐Web)

Search Date: 5 August 2020

‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
#1 (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) AND CENTRAL:TARGET
#2 (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)  AND CENTRAL:TARGET
#3 (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) AND CENTRAL:TARGET
#4 (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) AND CENTRAL:TARGET
#5 (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) AND CENTRAL:TARGET
#6 (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) AND CENTRAL:TARGET
#7 (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) AND CENTRAL:TARGET
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
#9 MeSH DESCRIPTOR Hypertension  AND CENTRAL:TARGET
#10 MeSH DESCRIPTOR Essential Hypertension AND CENTRAL:TARGET
#11 (antihypertens* OR hypertens*) AND CENTRAL:TARGET
#12 ((elevat* OR high* OR rais*) NEAR2 (blood pressur*)) AND CENTRAL:TARGET
#13 ((elevat* OR high* OR rais*) NEAR2 (bp)) AND CENTRAL:TARGET
#14 (#9 OR #10 OR #11 OR #12 OR #13)
#15 (NCT0* or ACTRN* or ChiCTR* or DRKS* or EUCTR* or eudract* or IRCT* or ISRCTN* or JapicCTI* or JPRN* or NTR0* or NTR1* or NTR2* or NTR3* or NTR4* or NTR5* or NTR6* or NTR7* or NTR8* or NTR9* or SRCTN* or UMIN0*):AU AND CENTRAL:TARGET
#16 http*:SO AND CENTRAL:TARGET
#17 (#15 OR #16)
#18 #8 AND #14 AND #17

Data and analyses

Comparison 1. Renin inhibitors vs. ACE inhibitors.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 All‐cause mortality	5	5962	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.93, 1.18]
1.2 Fatal or non‐fatal myocardial infarction	2	957	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.22, 3.39]
1.3 Adverse events	10	6007	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.93, 1.03]
1.4 Fatal or non‐fatal serious adverse events	10	6007	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.89, 1.64]
1.5 Withdrawal due to adverse effects (WDAE)	10	6008	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.68, 1.06]
1.6 SBP	9	5001	Mean Difference (IV, Fixed, 95% CI)	‐1.72 [‐2.47, ‐0.97]
1.7 DBP	9	5001	Mean Difference (IV, Fixed, 95% CI)	‐1.18 [‐1.65, ‐0.72]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

AGELESS 2010.

Study characteristics
Methods	Allocation: Randomized. Quoted: "The randomization list was generated by the inter‐active voice response system provider with a validated system that automated the random assignment of treatment groups. …producing a separate medication randomization list using a validated system that automates the random assignment of medication numbers to medication packs." Blinding: Double‐blind. Quoted: "Placebo, drug tablets and capsules were matched for size, shape and Colour to maintain blinding. Patients were instructed to take one tablet or capsule per dose from each of three provided bottles." Duration: 36 weeks
Participants	Setting: At 100 centers in the United States Diagnosis: Essential hypertension (msSBP ≥ 140 and < 180 mm Hg and mean sitting diastolic BP (msDBP) < 110 mm Hg) N = 901. Age: Aliskiren 72.0 ± 5.6 yrs; Ramipril 72.2±5.6 yrs Sex: Aliskiren F 235 (51.4%); Ramipril F 237 (53.4%) Co‐morbidity: diabetes, 21.7% in aliskiren group, 19.6% in ramipril group Inclusion criteria: Men and women aged ≥ 65 years with essential hypertension (ms SBP ≥ 140 and < 180 mm Hg and mean sitting diastolic BP (ms DBP) < 110 mm Hg) were eligible Exclusion criteria: People with a history of severe cardiovascular or cerebrovascular disease or other life‐threatening medical conditions were excluded
Interventions	1. Aliskiren 150 mg/day (n = 457) 2. Ramipril 5 mg/day (n = 444) Participants with inadequate mean sitting SBP control (msSBP > 140 mm Hg) at 4 or 8 weeks had their treatments up‐titrated to aliskiren 300 mg/day or ramipril 10 mg/day. If msSBP still remained uncontrolled, hydrochlorothiazide (HCTZ) 12.5 mg/day or HCTZ 25 mg/day or amlodipine 5 mg or amlodipine 10 mg/day will be added to the treatment in sequence
Outcomes	Primary outcomes: Changes in msSBP and msDBP from baseline to week 12 between aliskiren vs ramipril Secondary outcomes: Change from baseline in msSBP at week 36 endpoint with aliskiren‐based therapy vs ramipril‐based therapy; Change from baseline in msDBP at weeks 12 and 36 ( BP was measured 3 times using a standard mercury sphygmomanometer and appropriate cuff size) Safety and tolerability assessments included the recording of all adverse events (AEs) and serious adverse events (SAEs) throughout the study, irrespective of suspected relation to study medication
Notes	Funding: Novartis Pharma AG, Basel, Switzerland. Quote: "Novartis was represented on the trial steering committee in the study design, analysis and interpretation of data. Many authors received support for research studies from the sponsor."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote:"The randomization list was generated by the interactive voice response system provider with a validated system that automated the random assignment of treatment groups."
Allocation concealment (selection bias)	Low risk	Quote:"The randomization list was generated by the interactive voice response system provider with a validated system that automated the random assignment of treatment groups."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Double blind...Novartis supplied the investigators with all study medication. Placebo, drug tablets and capsules were matched for size, shape and color to maintain blinding. Patients were instructed to take one tablet or capsule per dose from each of three provided bottles."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessment was provided. Insufficient information to permit judgement of 'high risk' or 'low risk'.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Discontinuations, n=113 (24.7%) in aliskiren group, lack of efficacy, n=31 (6.8%); while discontinuations, n=108 (24.3%), lack of efficacy, n=24 (5.4%) in ramipril group. Changes from baseline in msSBP and msDBP were analyzed using the intent‐to‐treat populations and these results are reported as the least squares mean (LSM) change from baseline ± standard error (s.e.). Last observation carried forward was used to impute missing values in patients who discontinued." Comment: Missing data has been imputed using appropriate methods (ITT). Patient demographics and characteristics at baseline were similar between treatment groups.
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although protocol was not available
Other bias	High risk	Quote: "This study was funded by Novartis Pharma AG, Basel, Switzerland. Novartis was represented on the trial steering committee in the study design, analysis and interpretation of data. The sponsor provided study drug preparations. Editorial assistance was provided by Complete Healthcare Communications Inc. (Chadds Ford, PA, USA) and supported by Novartis Pharmaceuticals Corporation."

ALIAS 2012.

Study characteristics
Methods	Allocation: Randomized Blinding: Double blind Duration: 8 weeks
Participants	Setting: 124 centers in France (GPs) N = 506 Age: Aliskiren 60.1 ± 11.4 yrs; Ramipril 59.8 ± 11.6 yrs Sex: Aliskiren F = 133; Ramipril F = 142 Co‐morbidity: None Inclusion criteria: Outpatients > 18 years. Male or female patients. Female patients must have been either post‐menopausal for 1 year, surgically sterile, or using effective contraceptive methods. Patients with essential hypertension, previously treated with an antihypertensive single‐drug therapy, either uncontrolled or intolerant. BP thresholds at visit 1: For patients previously treated and uncontrolled: 140 ≤ office SBP < 180 mmHg; For patients previously treated, controlled but intolerant: office SBP ≥ 130 mmHg BP thresholds at visit 2 (for all patients): 160 ≤ office SBP < 180 mmHg; 155 ≤ home SBP < 175 mmHg (3‐day period of home blood pressure monitoring HBPM) Exclusion criteria: Women of child‐bearing potential not using any effective methods of contraception; severe HTN (office BP ≥ 180/110 mmHg); Impossibility to stop abruptly previous antihypertensive treatments at visit 1; Patients previously untreated or patients treated with 2 or 3 antihypertensive medications; history or evidence of a secondary form of hypertension; history of hypersensitivity to ACE or renin inhibitors; heart failure, history of stroke; history of coronary heart disease within 6 months prior to visit 1; Serum potassium ≥ 5.2 mmol/l.
Interventions	1. Aliskiren 150 mg (n = 249) 2. Ramipril 5 mg (n = 257). Medications had to be titrated to aliskiren 300 mg or ramipril 10 mg only if BP remained ≥ 140/90 mmHg
Outcomes	Change in mean sitting SBP and mean sitting DBP Number of participants reported with AEs, SAEs and death (Period II and Period III)
Notes	Study sponsored by Novartis, and no information about conflict of interest statement was provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomized..." Comment: Insufficient information about the sequence generation process to permit judgement of 'Low risk' or 'High risk'.
Allocation concealment (selection bias)	Unclear risk	No information about allocation concealment. Insufficient information to permit judgement of 'Low risk' or 'High risk'.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Double blind." Comment: No information about blinding of participants and personnel was provided. Insufficient information about blinding process to permit judgement of 'Low risk' or 'High risk'.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessor was provided. Insufficient information to permit judgement of 'Low risk' or 'High risk'.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The primary analysis was performed on ITT population and on values at V4 without imputation in case of missing data. The intent‐to‐treat (ITT) population, consisting of all randomized subjects for whom at least one valid post‐baseline efficacy measurement was obtained, was used for efficacy analyses. The main reasons for discontinuation were AEs (aliskiren n=5; ramipril n=6); unsatisfactory therapeutic effect (aliskiren n=0; ramipril n=1) and withdrawal by subjects (aliskiren n=2; ramipril n=1)." Comment: Missing data has been imputed using appropriate methods (ITT). Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although protocol was not available
Other bias	High risk	Study sponsored by Novartis, and no information about conflict of interest statement was provided

Andersen 2008.

Study characteristics
Methods	Allocation: Randomized. Blinding: Double‐blind. Duration: 26 weeks.
Participants	Setting: 92 study centers in 9 countries (Belgium, Canada, Hong Kong, Denmark, Iceland, Slovakia, South Africa, Spain and the USA) N = 842 Age: Aliskiren 53.4 ± 10.8 yrs; Ramipril: 53.1 ± 11.2 yrs Sex: Aliskiren F = 196; Ramipril: F = 166 Co‐morbidity: Diabetes: Aliskiren n = 42; Ramipril n = 49. Metabolic syndrome: Aliskiren n = 171; Ramipril n = 183 Inclusion criteria: Patients aged 18 years or over with hypertension (mean sitting diastolic BP (msDBP) > 90 mmHg and< 110 mmHg) were eligible for inclusion in the study Exclusion criteria: Major exclusion criteria included severe hypertension (msDBP > 110 mmHg or mean sitting systolic BP (msSBP) > 180 mmHg]) history or evidence of secondary hypertension; known Keith–Wagener grade III or IV hypertensive retinopathy; type 1 or type 2 diabetes mellitus with fasting glycosylated hemoglobin in (HbA1c) > 9% at screening; history of severe cerebrovascular or cardiovascular disease; and any condition that may alter the absorption, distribution, metabolism or excretion of study drugs. Pregnant or nursing women were also excluded
Interventions	1. Aliskiren 150 mg (n = 420); 2. Ramipril 5 mg (n = 422) Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control
Outcomes	Change from base‐line in msDBP at week 26 endpoint; change from baseline in msSBP at week 26 endpoint (BP was measured using a standard calibrated sphygmomanometer and appropriate arm cuff size in accordance with the 2005 American Heart Association Committee on Blood Pressure Determination) Serious adverse events or discontinuations due to adverse events
Notes	More participants in the ramipril group (n = 209, 49.5%) required the addition of HCTZ to their therapy than in the aliskiren group (n = 193, 46.1%), although the difference was not statistically significant (P = 0.334). Titration of HCTZ therapy to 25 mg occurred in significantly more ramipril‐treated participants (n = 132, 31.3%) than aliskiren‐treated participants (n = 92, 22.0%; P = 0.0024) Study sponsored by Novartis, and authors received support for research studies, advisory boards or speakers bureau honoraria from several companies. Two authors were employees of Novartis Pharmaceuticals Corporation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Eligible patients were randomized to..." Comment: Insufficient information about the sequence generation process to permit judgement of 'Low risk' or 'High risk'.
Allocation concealment (selection bias)	Unclear risk	No information about allocation concealment. Insufficient information provided to permit judgement of 'Low risk' or 'High risk'
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Blinding was maintained by the use of study drugs that were all identical in packaging, labeling, schedule of administration, appearance, and od or. A double‐dummy design was used to ensure blinding of patients to increases in dosage. from a sub‐analysis by No.259 Karl Andersen etc.doi: 10.1111/j.1755‐5922.2010.00148.x"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessor was provided. Insufficient information provided to permit judgement of 'Low risk' or 'High risk'
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All analyses were performed on the intent‐to‐treat (ITT) population, defined as all randomized patients who had a baseline and at least one post‐baseline efficacy measurement. Last observation carried forward (LOCF) methodology was used for week 6, 12 and 26 endpoint values. The main reasons for discontinuation were withdrawal of consent (n=28, 6.7% in aliskiren group; n=28 6.6% in ramipril group) and AEs (n=24, 5.7% in aliskiren group; n=19, 4.5% in ramipril group). Few patients discontinued due to unsatisfactory therapeutic effect (n=12, 2.9% in aliskiren group; n=14, 3.3% in ramipril group). Patient demographic characteristics were similar between the two treatment groups." Comment: Missing data has been imputed using appropriate methods (ITT). Missing data were unlikely to have an impact on the results of the trial.
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although protocol was not available.
Other bias	High risk	Study sponsored by Novartis, and authors received support for research studies, advisory boards or speakers bureau honoraria from several companies. Two authors were employees of Novartis Pharmaceuticals Corporation

ATMOSPHERE 2016.

Study characteristics
Methods	Allocation: Randomized. Blinding: Double blind. Duration: 36.6 months.
Participants	Setting: Multicenter, 789 centers in 43 countries N=7064 (60% of randomized participants were hypertensive) Age: enalapril + aliskiren 63.2 ± 11.65 yrs; aliskiren 63.3 ± 12.06 yrs; enalapril 63.3 ± 11.71 yrs Sex: enalapril + aliskiren F = 494; aliskiren F = 532; enalapril F = 499 Co‐morbidity: Heart failure Inclusion criteria: Eligible patients had chronic heart failure with New York Heart Association (NYHA) class II to IV symptoms and an ejection fraction of 35% or less. Participants were also required to have a plasma B‐type natriuretic peptide (BNP) concentration of 150 pg or more per milliliter (or an N‐terminal pro‐BNP [NT‐pro BNP] concentration of ≥ 600 pg per milliliter) or, if they had been hospitalized for heart failure within the previous 12 months, a BNP concentration of 100 pg or more per milliliter (or an NT‐pro BNP concentration of ≥ 400 pg per milliliter). Participants must have been receiving stable doses of an ACE inhibitor (equivalent to at least 10 mg of enalapril daily) and of a beta‐blocker at the time of enrolment Exclusion criteria: Included symptomatic hypotension, a systolic blood pressure of < 95 mm Hg at screening (or < 90 mm Hg at randomization), an estimated glomerular filtration rate (GFR) of less than 40 ml per minute per 1.73 m2 of body‐surface area at screening (or < 35 ml per minute per 1.73 m2 at randomization or a decline of > 25% in the estimated GFR between screening and randomization), a serum potassium concentration of 5.0 mmol or more per liter at screening (or ≥ 5.2 mmol per liter at randomization), and a history of inability to take ACE inhibitors
Interventions	1. Aliskiren 150 mg to 300 mg (n = 2340). Hypertensive participants at baseline, n = 1460 (62.4%) 2. Enalapril 5 mg to 10 mg (n = 2336). Hypertensive participants at baseline, n = 1425 (61.0%) 3. Enalapril 5 mg to 10 mg + Aliskiren 150 mg to 300 mg (n = 2340). Hypertensive participants at baseline, n =1447 (61.8%)
Outcomes	Primary outcome: Death from cardiovascular causes or hospitalization for heart failure Secondary outcome: Change in KCCQ clinical summary score at 12 months Exploratory outcome: Death from cardiovascular causes, hospitalization for heart failure, nonfatal myocardial infarction, nonfatal stroke, or resuscitated cardiac arrest; Fatal or nonfatal myocardial infarction; Fatal or nonfatal stroke; First resuscitated cardiac arrest; death from any cause. Safety assessments consisted of monitoring and recording all AEs, AE discontinuations andSAEs
Notes	The number of participants with hypertension history in aliskiren group, enalapril group and enalapril plus aliskiren group was 1447 (61.8%), 1460 (62.4%) and 1425 (61.0%), respectively While the trial was ongoing, the Clinical Trial Facilitation Group of the Heads of Medicines Agencies in Europe mandated that persons with diabetes at baseline and those in whom diabetes developed during the present trial discontinue the treatment and be switched to conventional therapy and that no further patients with diabetes be enrolled. This decision was executed worldwide in a protocol amendment issued in April 2013. This decision led to amendment of the statistical analysis plan. In participants with diabetes, follow‐up for trial outcomes was censored on the date of the enactment of the protocol amendment (or on the date of other country‐specific requests mandating the stopping of the trial treatment). Comparison of the combination therapy with enalapril in patients without diabetes became an additional superiority hypothesis. The change in the NT‐pro BNP concentration was removed as a secondary outcome Funding: Novartis Quote: "Dr. McMurray reports receiving travel support from Cardiorentis and Amgen and serving on advisory boards for Novartis and on steering committees for Cardiorentis and Amgen through a consultancy agreement with his institution; Dr. Dick‐stein, receiving honoraria from Medtronic, Novartis, and Sanofi and grant support from Medtronic, Boston Scientific, St. Jude Medical, Biotronik, Sorin, Amgen, Pfizer, and Abbott Laboratories; Dr. Køber, receiving lecture fees from Novartis and Servier; Dr. Desai, receiving fees for consulting and serving on advisory boards from St. Jude Medical, Relypsa, and Merck; and Dr. Solomon, receiving consulting fees from Novartis, Bayer, Amgen, and Cytokinetics and grant support through his institution from Novartis and Amgen. Mr. Ali, Dr. Chiang, Dr. Shao, and Dr. Tarnesby are employees of Novartis. No other potential conflict of interest relevant to this article was reported."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients who could take both treatments were randomly assigned, in a 1:1:1 ratio, to double‐blind, double‐dummy treatment in one of three groups with the use of a voice‐based computerized randomization system involving concealed trial‐group assignments." Comment:"Done.
Allocation concealment (selection bias)	Low risk	Quote: "Patients who could take both treatments were randomly assigned, in a 1:1:1 ratio, to double‐blind, double‐dummy treatment in one of three groups with the use of a voice‐based computerized randomization system involving concealed trial‐group assignments." Comment: Done.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Patients who could take both treatments were randomly assigned, in a 1:1:1 ratio, to double‐blind, double‐dummy treatment in one of three groups with the use of a voice‐based computerized randomization system involving concealed trial‐group assignments." Comment: Done.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Patients, investigator staff, persons performing the assessments, and data analysts will remain blinded to the identity of the treatment from the time of randomization until database lock (protocol)." Comment: Done.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Analyses included all the patients who underwent randomization validly, according to the intention‐to‐treat principle. The number of patients who were lost to follow‐up for vital status before the completion of the trial (or owing to regulatory censoring with regard to patients with diabetes) was 31 (1.3%) in the combination‐therapy group, 19 (0.8%) in the aliskiren group, and 19 (0.8%) in the enalapril group. The number of patients who had data censored because of diabetes was 665 (28.4%) in the combination‐therapy group, 627 (26.8%) in the aliskiren group, and 652 (27.9%) in the enalapril group. Overall, the treatment groups were balanced with respect to the characteristics at baseline." Comment: Missing data has been imputed using appropriate methods (ITT). Patient demographics and characteristics at baseline were similar between treatment groups.
Selective reporting (reporting bias)	Low risk	All of the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported in the prespecified way according to protocol
Other bias	High risk	Study sponsored by Novartis, and authors received support for research studies, advisory boards or speakers bureau honoraria from several companies. Four authors were employees of Novartis Pharmaceuticals Corporation

Jones‐Burton 2010.

Study characteristics
Methods	Allocation: Randomized. Blinding: Double blind. Duration: 4 weeks
Participants	Setting: Outpatients N = 195 Age: MK‐8141 500mg 52.8 ± 7.7 yrs; Enalapril 51.5 ± 8.5 yrs Sex: A MK‐8141 500 mg F = 25; Enalapril F = 24 Co‐morbidity: None Inclusion criteria: Men and women (non–child‐bearing potential) ages 30 – 65 years with hypertension, with sitting diastolic BP (SiDBP) > 92 to < 105 mmHg if untreated or sitting BP (SiBP) < 160/100 mmHg if previously treated with 2 antihypertensive medications, were eligible for screening Exclusion criteria: Included patients with secondary hypertension, malignant hypertension, or taking any antihypertensive medications or medications that interfere with cytochrome P450 3A
Interventions	1. MK‐8141 250 mg (n = 49) 2. MK‐8141 500 mg (n = 49) 3. Enalapril 20 mg (n = 48) 4. Placebo (n = 49)
Outcomes	Change in mean sitting SBP and mean sitting DBP Number participants reported with AEs SAEs Discontinued from an adverse experience
Notes	Funding: This study was jointly funded by Merck & Co. Inc. and Actelion Pharmaceuticals Ltd Quote: "Jones‐Burton, J. Rubino, S. Roy, Y.Mai, A. Meehan, and P. Feig are employees of Merck, Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., and may hold stock/stock options in the company. M. Bellet is an employee of Actelion Pharmaceuticals Ltd."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "...randomized to treatment once per day with MK‐8141 250 mg, MK‐8141 500 mg, enalapril 20 mg, or placebo in a 1:1:1:1 ratio using a computer‐generated allocation schedule." Comment: Done
Allocation concealment (selection bias)	Unclear risk	No information about allocation concealment was provided. Insufficient information to permit judgement of 'Low risk' or 'High risk'
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blinded. No further detail about blinding of participants and personnel was provided. Insufficient information to permit judgement of 'Low risk' or 'High risk'
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessor was provided. Insufficient information to permit judgement of 'Low risk' or 'High risk'
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The main reason for discontinuation was withdrawal of consent (MK‐8141 250 mg n=1, MK‐8141 500 mg n=1, enalapril 20 mg n=1, placebo n=1). There were no significant differences in demographics or baseline efficacy measures between the placebo, enalapril, and MK‐8141 groups." Comment: Missing data were unlikely to have an impact on the results of the trial.
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although protocol was not available
Other bias	High risk	This study was jointly funded by Merck & Co. Inc. and Actelion Pharmaceuticals Ltd Quote: "Jones‐Burton, J. Rubino, S. Roy, Y.Mai, A. Meehan, and P. Feig are employees of Merck, Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., and may hold stock/stock options in the company. M. Bellet is an employee of Actelion Pharmaceuticals Ltd"

NCT00631917 2011.

Study characteristics
Methods	Allocation: Randomized. Blinding: Double blind. Duration: 54 weeks
Participants	Setting: Multicenter, 115 centers in 7 countries: Argentina (5), Colombia (2), France (3), Germany (8), India (5), Spain (4), USA (88). N = 774 Age: Aliskiren 59.3 ± 7 yrs; Ramipril 59.3 ± 7 yrs Sex: Aliskiren F = 194; Ramipril F = 194 Co‐morbidity: None Inclusion criteria: Patients eligible for inclusion in this study were required to fulfill all of the following criteria: 1. Male or female outpatients, 50 years of age and older 2. Patients with a diagnosis of essential hypertension defined as either: a) Patients who were currently treated with antihypertensive drug(s) at Visit 1 b) Newly‐diagnosed patients who were not treated and who had a mean sitting diastolic blood pressure (msDBP) ≥ 95 mmHg and/or a mean sitting systolic blood pressure (msSBP) ≥ 150 mmHg (msDBP ≥ 85 mmHg and/or msSBP ≥ 140 mmHg for diabetic patients) at Visit 1 c) Newly diagnosed patients who were not treated and who had a msDBP ≥ 90 mmHg and/or a msSBP ≥ 140 mmHg (msDBP ≥ 80 mmHg and/or msSBP ≥ 130 mmHg for diabetic patients) at the randomization visit (Visit 2) 3. Successful high‐quality colonoscopy at baseline including visualization of the entire colon and the cecum as confirmed by a photograph and collection of the rectal and cecal mucosal biopsy samples 4. All rectal, colon or cecal polyps found at baseline colonoscopy must have been completely resected endoscopically at the time of the procedure 5. Patients who were eligible and able to participate in the study, and who consented to do so after the purpose and nature of the investigation had been clearly explained to them (written informed consent) Exclusion criteria: 1. Previously treated in an aliskiren study in this development program and who qualified to be randomized or enrolled into the active drug treatment period 2. Current evidence of inflammatory bowel disease, the presence of colonic ulcerations (or other indices of colitis of any type, e.g., erythema or erosions) or colorectal carcinoma defined as invasive carcinoma into the sub‐mucosa found at baseline colonoscopy 3. History of gastrointestinal carcinoma, Crohn’s disease, ulcerative colitis, microscopic colitis (including lymphocytic colitis and collagenous colitis) 4. History of confirmed diverticulitis within 12 months of Visit 1 5. History of familial polyposis or hereditary nonpolyposis colorectal cancer 6. History of celiac disease (gluten intolerance) 7. History of, or current evidence on the baseline colonoscopy of melanosis coli 8. History of immunodeficiency disorders (e.g., hypogammaglobulinemia, agammaglobulinemia, human immunodeficiency virus (HIV), etc) 9. Chronic use (defined as administration > 1 day per week) of drugs with specific effects on bowel function and motility (e.g., laxatives, enemas, antispasmodics, antidiarrheals, stool softeners, etc). The use of bulking agents (bran, psyllium, etc) > 1 day per week was allowed except in the week prior to both the baseline and end of study colonoscopy procedures. The use of H2‐receptor antagonists or proton pump inhibitors was permitted throughout the trial. 10. Chronic use (defined as administration > 3 days per week) of non‐steroidal anti‐inflammatory drugs or COX‐2 inhibitors. Low dose aspirin (≤ 165 mg/day) for cardiovascular prophylaxis was allowed except in the week prior to both the baseline and end of study colonoscopy procedures. 11. Current or recent (within 12 month prior to Visit 1) treatment with immunosuppressants (e.g. cyclosporine) 12. Long‐term use (defined as administration ≥ 4 weeks) of oral corticosteroids prior to Visit 1
Interventions	1. Aliskiren 150 mg to 300 mg (n = 375) 2. Ramipril 5 mg to 10 mg (n = 399) Starting from Visit 4, hydrochlorothiazide (12.5 mg and 25 mg) could be added in cases where a participant’s blood pressure was not well controlled. If blood pressure was still not well controlled after adding hydrochlorothiazide, amlodipine (5 mg and 10 mg) could be added at any subsequent visit. These add‐on medications were supplied locally to participants
Outcomes	Safety assessments consisted of monitoring and recording all AEs, AE discontinuations and SAEs
Notes	Funding: Novartis The study was sponsored by Novartis, with no information about conflict of interest statement
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information about random sequence generation was provided. Insufficient information to permit judgement of 'High risk' or 'Low risk'
Allocation concealment (selection bias)	Unclear risk	No information about allocation concealment was provided. Insufficient information to permit judgement of 'High risk' or 'Low risk'
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "A 54 week, randomized, double‐blind, parallel‐group, multicenter study evaluating the long‐term gastrointestinal (GI) safety and tolerability of aliskiren (300 mg) compared to ramipril (10 mg) in patients with essential hypertension. Participants also received placebo capsules to the match ramipril or aliskiren..." Comment: Done
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Masking: Double blind( subject, caregiver, investigator, outcome assessors )"." Comment: Done
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Following the intent‐to‐treat principle, patients were analyzed according to the treatment they were assigned to at randomization. The main reasons for discontinuation were adverse events (aliskiren n=34; ramipril n=25), withdrawal by subject (aliskiren n=25; ramipril n=33), unsatisfactory therapeutic effect (aliskiren n=8; ramipril n=14) and lost to follow‐up (aliskiren n=7; ramipril n=7)." Comment: Missing data have been imputed using appropriate methods (ITT). Participant demographics and characteristics at baseline were similar between treatment groups.
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although protocol was not available
Other bias	High risk	The study was sponsored by Novartis, with no information about conflict of interest statement

Palatini 2010.

Study characteristics
Methods	Allocation: Randomized Blinding: Double blind Duration: 9 weeks.
Participants	Setting: 97 centers in Brazil, Canada, Germany, Hungary, Italy, the Netherlands, Norway, Russia, Slovakia and Spain N = 654 Age: Aliskiren 53.5 ± 10.7 yrs; Irbesartan 53.4 ± 9.7 yrs, Ramipril 53.9 ± 9.9 yrs Sex: Aliskiren F = 81; Irbesartan F = 80; Ramipril F = 93 Co‐morbidity: None Inclusion criteria: Patients with hypertension who were 18 years of age or older with an office mean sitting diastolic BP (ms DBP) of ≥ 90 and 110 mm Hg were enrolled in the study. Patients were randomized to active treatment if they exhibited a 24‐hr mean ambulatory diastolic BP (MADBP) ≥ 85 mmHg. Women had to be either post‐menopausal for ≥ 1 year, surgically sterile or using effective contraception Exclusion criteria: Severe hypertension (office systolic BP (SBP)/DBP ≥180/110 mm Hg), secondary hypertension, severe cardiac or cerebrovascular disease, history of type I or type II diabetes with glycosylated hemoglobin (Hb A1C) > 48% at screening or an upper arm circumference 442 cm. Patients were also excluded if they had any condition that might significantly alter the pharmacokinetics or pharmacodynamics of the study drugs
Interventions	1. Aliskiren 150 mg (n = 218) 2. Irbesartan 150 mg (n = 222) 3. Ramipril 5 mg (n = 214) On day 14, active treatments were uptitrated to double the initial dose (aliskiren 300 mg, irbesartan 300 mg and ramipril 10 mg, respectively) for 4 weeks. On day 42, participants were randomized equally within each treatment group to receive 1 day of placebo (simulating a missed dose) on either day 42 or day 49; active treatment was continued on all other days (days 42 – 49)
Outcomes	Number participants reported with AEs, SAEs, discontinuations due to adverse events
Notes	Funding: Novartis Quote: "PP has received honoraria from Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. WJ and ES report no conflicts of interest. JB, CB and DLK are employees of Novartis Pharmaceuticals Corporation and are thus eligible for Novartis stock and stock options."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A separate medication randomization list was produced by Novartis Drug Supply Management using a validated system that automates the random assignment of medication numbers to medication packs containing each of the study drugs." Comment: Done
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was achieved using the interactive voice recording system provider, which automates the random assignment of patient numbers to randomization numbers linked to the different treatment arms, and in turn to medication numbers." Comment: Done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Eligible patients were randomized in a double‐blind　manner to receive once‐daily treatment with aliskiren Comment: Done
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessment was provided. Insufficient information to permit judgement of 'Low risk' or 'High risk'
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The primary efficacy variable (change from baseline in 24‐hMADBP) was analysed for all patients who had a successful 24‐h MABP measurement at baseline and at day 42/49. The safety population comprised all patients who received at least one dose of study drug and had at least one post‐baseline safety assessment. Self‐measured BP was analysed for the intent‐to‐treat (ITT) population. The main reasons for discontinuation were AEs (aliskiren n=2, 0.9%; irbesartan n=4, 1.8%; Ramipril n=5, 2.3%) and withdrawal of consent (aliskiren n=7, 3.2%; irbesartan n=4, 1.8%; Ramipril n=9, 4.2%). Patient demographics and characteristics at baseline were similar between treatment groups, although there was a higher proportion of women in the ramipril group than in the aliskiren or irbesartan groups." Comment: Missing data have been imputed using appropriate methods (ITT). Missing data were unlikely to have an impact on the results of the trial.
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although the protocol was not available
Other bias	High risk	Funding: Novartis Quote: "PP has received honoraria from Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. WJ and ES report no conflicts of interest. JB, CB and DLK are employees of Novartis Pharmaceuticals Corporation and are thus eligible for Novartis stock and stock options."

Strasser 2007.

Study characteristics
Methods	Allocation: Randomized. Quoted: "Randomization was performed by the interactive voice response system provider using a validated system that automates the random assignment of treatment groups to randomization numbers. All patients, investigator staff, persons performing the assessments and data analysts remained blinded to the identity of the treatment from the time of randomization until database lock." Blinding: Double‐blind. Duration: 8 weeks
Participants	Setting: 12 study centers in Germany, 9 in Spain and 5 in Hungary N = 183 Age: Aliskiren 55.3 ± 12.3 yrs; Lisinopril 55.6 ± 11.1 yrs Sex: Aliskiren F = 55; Lisinopril F = 24 Co‐morbidity: Diabetes: Aliskiren n = 15; Lisinopril n = 8. Metabolic syndrome: Aliskiren n = 66; Lisinopril n = 34. Inclusion criteria: Patients aged > 18 years with uncomplicated severe hypertension. Severe hypertension (mean sitting diastolic blood pressure (msDBP) ≥ 105 mm Hg and <120 mm Hg) Exclusion criteria: Included a history or evidence of secondary hypertension; antihypertensive treatment with > 3 classes of antihypertensive medication; diabetes mellitus requiring insulin treatment; type II diabetes mellitus with poor glucose control (HbA1C > 8% at Visit 1); diagnosed heart failure; history of myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention; angina pectoris; potentially life‐threatening arrhythmia or symptomatic arrhythmia or other life‐threatening disease; any surgical or medical condition that might significantly alter the absorption, distribution, metabolism or excretion of the study drugs; and known or suspected contra‐indications to the study medications
Interventions	1. Aliskiren 150 mg (n = 125) 2. Lisinopril 20 mg (n = 58) The treatment dose was doubled (to aliskiren 300 mg or lisinopril 40 mg). Subsequent addition of HCTZ 25 mg was permitted for these participants if msDBP was ≥ 95 mmHg or msSBP remained ≥160 mm Hg at weeks 2 or 4, or if msDBP was ≥ 90 mmHg or msSBP was ≥ 140 mmHg at week 6
Outcomes	Change from baseline in msDBP and msSBP (sitting and standing BP was measured at trough from the arm in which the highest sitting DBP was found at the first study visit, using a calibrated standard sphygmomanometer) Discontinuations due to AEs
Notes	Funding: Novartis Pharma AG The study was sponsored by Novartis, and provided no information about conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed by the interactive voice response system provider using a validated system that automates the random assignment of treatment groups to randomization numbers." Comment: Done
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was performed by the interactive voice response system provider using a validated system that automates the random assignment of treatment groups to randomization numbers." Comment: Done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "All patients, investigator staff, persons performing the assessments and data analysts remained blinded to the identity of the treatment from the time of randomization until database lock." Comment: Done
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "All patients, investigator staff, persons performing the assessments and data analysts remained blinded to the identity of the treatment from the time of randomization until database lock." Comment: Done
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All efficacy variables were analyzed for the intent‐to‐treat population, which was defined as all randomized patients who had a baseline (start of period 3) measurement and at least one post‐base‐line efficacy measurement. 11 patients were excluded for abnormal test procedure results (n= 7; this includes patients who did not meet BP inclusion criteria), withdrawal of consent (n=3) and administrative problems (n=1). The treatment groups were generally similar with respect to demographics and baseline characteristics." Comment: Missing data have been imputed using appropriate methods (ITT). Missing data were unlikely to have an impact on the results of the trial.
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the methods were reported, though the protocol was not available
Other bias	High risk	Funding: Novartis Pharma AG The study was sponsored by Novartis, and provided no information about conflict of interest.

Uresin 2007.

Study characteristics
Methods	Allocation: Randomized. Quoted: "using a validated system that automates the random assignment of treatment groups to randomization numbers in a 1:1:1 ratio. The randomization scheme was reviewed by a Biostatistics Quality Assurance Group and locked by them after approval." Blinding: Double‐blind. Duration: 8 weeks.
Participants	Setting: 125 centers in Canada, Denmark, France, Germany, Italy, Malaysia, the Netherlands, Norway, Spain, Sweden, Taiwan, Turkey and the USA N = 837 Age: Aliskiren 60.0 ± 9.8 yrs; Ramipril 59.9 ± 11.2 yrs Sex: Aliskiren F = 125 (44.3%); Ramipril F = 112 (40.3%) Co‐morbidity: Type 1 or 2 diabetes mellitus Inclusion criteria: Eligible patients were men and women aged > 18 years with type 1 or 2 diabetes mellitus and stage 1‐2 hypertension (mean sitting diastolic BP [msDBP] > 95 mmHg and < 110 mmHg) who had been receiving stable doses of hypoglycemic medication for at least 4 weeks prior to the start of the study Exclusion criteria: Patients whose msDBP was > 110 mmHg were ineligible to participate, as were patients with secondary hypertension, history of severe cardiovascular or cerebrovascular disease, or other severe or life‐threatening disease
Interventions	1. Aliskiren (150 mg titrated to 300 mg after 4 weeks; n = 282) 2. Ramipril (5 mg titrated to 10 mg; n = 278) 3. Aliskiren/ramipril (n = 277)
Outcomes	Change in msDBP from baseline to week 8 endpoint Change from baseline to endpoint in msSBP. (Sitting BP was measured at trough in the arm in which the highest BP measurement was recorded at the first study visit, using a calibrated standard mercury sphygmomanometer in accordance with the 1988 American Heart Association Committee report on BP Determination.) Discontinuation due to AEs SAEs
Notes	Funding: Novartis Pharmaceuticals Corporation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A randomization list was produced by Novartis Drug Supply Management using a validated system that automates the random assignment of treatment groups to randomization numbers in a 1:1:1 ratio." Comment: Done
Allocation concealment (selection bias)	Low risk	Quote: "The randomization scheme was reviewed by a Biostatistics Quality Assurance Group and locked by them after approval. Randomization was performed using a block size of three and by center. Randomization codes were kept strictly confidential until the database was locked." Comment: Done
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Double‐blinded." Comment: Insufficient information about blinding process to permit judgement of 'Low risk' or 'High risk'.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessor provided. Insufficient information to permit judgement of 'High risk' or 'Low risk'.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All efficacy variables were analyzed for the intent‐to‐treat (ITT) population. 95 patients (11.4%) discontinued study treatment before the end of the trial; major reasons were AEs (aliskiren n=11, 3.3%; ramipril n=10, 3.6%; aliskiren/ramipril n=6,2.2%),withdrawal of consent (aliskiren n=6, 2.1%; ramipril n=9, 3.2%; aliskiren/ramipril n=6,2.2%), protocol violation (aliskiren n=6, 2.1%; ramipril n=3, 1.1%; aliskiren/ramipril n=7, 2.5%) and abnormal test procedure results (aliskiren n=6，2.1%; ramipril n=4, 1.4%; aliskiren/ramipril n=3, 1.1%). Rates of and reasons for discontinuation were similar in the three treatment groups. Baseline characteristics showed that the three treatment group were well balanced, although there were fewer obese patients in the ramipril group." Comment: Missing data have been imputed using appropriate methods (ITT). Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although the protocol was not available
Other bias	High risk	The study was sponsored by Novartis, and provided no information about conflict of interest

Verdecchia 2007.

Study characteristics
Methods	Allocation: Randomized. Quoted: "Randomization by center was performed by the interactive voice response system provider using a validated system that automates the random assignment of treatment groups to randomization numbers. Randomization codes were kept strictly confidential until the database was locked." Blinding: Double blind Duration: 8 weeks.
Participants	Setting: Outpatients at 62 centers in Argentina, Austria, France, Italy, Japan, Spain and Sweden Diagnosis: Office msSBP > 140 mmHg and <180 mmHg N = 355 Age: Aliskiren 300 mg 73.0 ± 5.6 yrs; Lisinopril 10 mg 74.2 ± 6.1 yrs Sex: Aliskiren 300 mg F = 59 (62.8%); Lisinopril 10 mg F = 57 (66.3%) Co‐morbidity: Diabetes, Aliskiren 300 mg = 11 (11.7%); Lisinopril 10 mg = 6 (7.0%). Metabolic syndrome, Aliskiren 300 mg = 23 (24.5%); Lisinopril 10 mg = 20 (23.3%) Inclusion criteria: Patients eligible for inclusion were outpatients 65 years or older with essential hypertension, defined as office msSBP > 140 mmHg and < 180 mmHg at the screening and placebo run‐in visits, and msSBP > 145 mmHg and < 180 mmHg at baseline (randomization) Exclusion criteria: Office msDBP < 65 mmHg; severe hypertension (msDBP > 110 mmHg and/or msSBP > 180 mmHg); history or evidence of secondary hypertension; history of severe cardiovascular or cerebrovascular disease; type 1 or type 2 diabetes mellitus with poor glycemic control (HbA1c > 8% at screening); and evidence of renal impairment (defined as any one of the following: serum creatinine > 1.56*the upper limit of normal (male > 172.5 μmol/l; female > 159 μmol /l), a history of dialysis, or a history of nephrotic syndrome). Patients with serum sodium levels less than the lower limit of normal, serum potassium levels < 3.5 mmol/l or ≥ 5.5 mmol/l or dehydration were also excluded. In addition, patients with any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drugs, and patients with known or suspected contraindications to study medications
Interventions	1. aliskiren 75 mg/day (n = 91); 2.aliskiren 150 mg/day (n = 84); 3.aliskiren 300 mg/day (n = 94); 4. lisinopril 10 mg/day (n = 86). Participants randomized to aliskiren 300 mg received the 150‐mg dose for the first 2 weeks of treatment and were then force‐titrated to aliskiren 300 mg
Outcomes	Changes in office mean msSBP and msDBP from baseline to endpoint (sitting and standing office BP were also measured at each visit using a mercury sphygmomanometer) Safety assessments were based on monitoring and recording of adverse events, and evaluation of vital signs, laboratory tests and 12‐lead ECG
Notes	The proportion of participants with diabetes was numerically lower in the lisinopril group (7.0%) compared with the aliskiren groups (11.7 ‐ 13.2%). Funding: Novartis Pharma AG The study was sponsored by Novartis, and provided no information about conflict of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization by center was performed by the interactive voice response system provider using a validated system that automates the random assignment of treatment groups to randomization numbers." Comment: Done
Allocation concealment (selection bias)	Low risk	Quote: "Randomization codes were kept strictly confidential until the database was locked." Comment: Done
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Double blind...A double‐dummy methodology was used to maintain study blinding; patients received an active or placebo tablet for each of the three aliskiren doses, and an active or placebo capsule for lisinopril, as appropriate for their treatment group." Comment: Done
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessment was provided. Insufficient information to permit judgement of 'High risk' or 'Low risk'
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All efficacy variables were analyzed for the intent‐to‐treat (ITT) population. This was defined as all randomized patients with a baseline and at least one post‐baseline efficacy measurement during double‐blind treatment. In all, 25 of the randomized patients (7.0%) discontinued the study early, with similar numbers of patients discontinuing from each treatment group. The main reasons for discontinuation were AEs (aliskiren 75mg n=6, 6.6%; aliskiren 150mg n=2, 2.4%; aliskiren 300mg n=1, 1.1%; lisinopril 10mg n=5, 5.8%) and unsatisfactory therapeutic effect (aliskiren 75mg n=1, 1.1%; aliskiren 150mg n=1, 1.2%; aliskiren 300mg n=2, 2.1%)." Comment: Missing data have been imputed using appropriate methods (ITT). Missing data were unlikely to have an impact on the results of the trial.
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although the protocol was not available
Other bias	High risk	The study was sponsored by Novartis, and provided no information about conflict of interest

Zhu 2012.

Study characteristics
Methods	Allocation: Randomized Blinding: Double‐blind Duration: 8 weeks
Participants	Setting: Multiple centers in China (25), Thailand (4) and India (7) N = 1316 Age: Aliskiren 300 mg mean age 53.8 yrs; Aliskiren 150 mg mean age 53.3 yrs; Aliskiren 75 mg mean age 52.7 yrs; Ramipril 5 mg mean age 52.9 yrs Sex: Aliskiren 300 mg F = 150 (45.3%); Aliskiren 150 mg F = 140 (43.3%); Aliskiren 75 mg F = 144 (43.4%); Ramipril 5 mg F =151 (45.8%) Co‐morbidity: Diabetes; Aliskiren 300 mg n = 35 (10.9%); Aliskiren 150 mg n = 31 (9.6%); Aliskiren 75 mg n = 35 (10.5%); Ramipril 5 mg n = 50 (15.2%) Inclusion criteria: Patients aged > 18 years with uncomplicated essential hypertension who fulfilled the following criteria: (1) mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mm Hg at the visit immediately before randomization; (2) msDBP ≥ 95 and < 110 mm Hg at the time of randomization; and (3) absolute difference of ≤ 10 mm Hg in msDBP after the initial 2 weeks of single‐blind placebo run‐in period to the time of randomization Exclusion criteria: Patients with severe hypertension (msDBP ≥ 110 mm Hg and/or msSBP ≥ 180mmHg), history or evidence of secondary hypertension, known Keith–Wagener grade III or IV hypertensive retinopathy, hypertensive encephalopathy or cerebrovascular accident, transient ischemic cerebral attack within 12 months, severe cardiovascular disease including myocardial infarction, coronary bypass surgery, any percutaneous coronary intervention, Type 1 or Type 2 diabetes mellitus with glycosylated hemoglobin (HbA1c) > 8% at washout period, or any surgical or medical condition that could alter the kinetics and bio‐availability of the study drug were excluded from the study. Pregnant or nursing women were also excluded
Interventions	1. Aliskiren 300 mg (n = 331); 2. Aliskiren 150 mg (n = 323); 3. Aliskiren 75 mg (n = 332); 4. Ramipril 5 mg (n = 330).
Outcomes	Change in msDBP and msSBP from baseline to week 8 endpoint (using a standard sphygmomanometer and appropriate arm cuff size in accordance with the 1988 American Heart Association Committee Report on Blood Pressure Determination) Discontinuation because of AEs (safety assessments consisted of monitoring and recording of all adverse events)
Notes	Patient demographic and baseline characteristics were generally comparable across treatment groups, except for the duration of hypertension that varied from 7.9 to 9.4 years in the aliskiren‐treated groups compared with the ramipril group (8.0 years) Funding: Novartis Pharma AG, Basel, Switzerland Quote: "The content of this paper represents part of a registration study in China. The principal investigator, Professor Jun‐Ren Zhu, was appointed independently by the regulatory authority SFDA, while the funding came from the sponsor, Novartis Pharma AG, Basel, Switzerland. The sponsor was involved in the design, analysis of the data and drafting of the manuscript. Professor Jun‐Ren Zhu has received a research grant from Novartis Pharma AG, Basel, Switzerland. All authors analyzed the data reported here, and all authors contributed to and reviewed the final manuscript. Ruonan Wang and Ying‐Mei Tu are employees of Beijing Novartis Pharma Co Ltd, Beijing, China. Shannon Ritter, and Deborah Keefe are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about the sequence generation process to permit judgement of 'Low risk' or 'High risk.
Allocation concealment (selection bias)	Unclear risk	Insufficient information about the allocation concealment to permit judgement of 'Low risk' or 'High risk'
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Double‐blinded. No information about blinding of outcome assessment was provided.Insufficient information to permit judgement of 'Low risk' or 'High risk'
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information about blinding of outcome assessment was provided. Insufficient information to permit judgement of 'Low risk' or 'High risk'
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "The efficacy analyses were performed on the intent‐to‐treat population. In the case of missing data, the last measurement in the double‐blind period was carried forward. The main reasons for discontinuation were withdrawal of consent (aliskiren 300mg n=16; aliskiren 150mg n=21; aliskiren 75mg n=13; ramipril n=12), AEs (aliskiren 300mg n=9; aliskiren 150mg n=16; aliskiren 75mg n=14; ramipril n=8), unsatisfactory therapeutic effect (aliskiren 300mg n=6; aliskiren 150mg n=2; aliskiren 75mg n=5; ramipril n=4), lost to follow‐up (aliskiren 300mg n=4; aliskiren 150mg n=7; aliskiren 75mg n=4; ramipril n=4), protocol deviation (n=7) and administrative problems (n=4). Patient demographic and baseline characteristics were generally comparable across treatment groups, except for the duration of hypertension that varied from 7.9 to 9.4 years in the aliskiren‐treated groups compared with the ramipril group (8.0 years)" Comment: Missing data have been imputed using appropriate methods (ITT). Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the prespecified outcomes in the Methods were reported, although the protocol was not available
Other bias	High risk	Funding: Novartis Pharma AG, Basel, Switzerland Quote: "The content of this paper represents part of a registration study in China. The principal investigator, Professor Jun‐Ren Zhu, was appointed independently by the regulatory authority SFDA, while the funding came from the sponsor, Novartis Pharma AG, Basel, Switzerland. The sponsor was involved in the design, analysis of the data and drafting of the manuscript. Professor Jun‐Ren Zhu has received a research grant from Novartis Pharma AG, Basel, Switzerland. All authors analyzed the data reported here, and all authors contributed to and reviewed the final manuscript. Ruonan Wang and Ying‐Mei Tu are employees of Beijing Novartis Pharma Co Ltd, Beijing, China. Shannon Ritter, and Deborah Keefe are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA."

AE: adverse event; DBP: diastolic blood pressure: SAE: serious adverse event; SBP: systolic blood pressure

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Azizi 1994	It compares captopril with remikiren in untreated hypertensive patients. It does not report outcomes that are of interest to this review
Burnier 2011	The study aimed to quantify the effects of adherence level and duration of action on estimated mean SBP reduction and CVD risk. It does not report outcomes that are of interest to this review
ESCAPE‐SHF 2011	It included patients with heart failure, and no information about hypertension
Fisher 1994	It is a randomized cross‐over clinical trial. The trial compared the renal vascular responses to enalkiren and captopril to assess the influence of angiotensin II (Ang II), but does not report outcomes that are of interest to this review
Fogari 2013	It is an open study with blind endpoints. It compares the antiproteinuric effect of aliskiren and ramipril in hypertensive participants with type 2 diabetes and microalbuminuria
Kiowski 1994	It included participants with chronic heart failure (New York Heart Association class II or III), and no information about hypertension
Koumaras 2014	The trial is not a double‐blind trial. It compares the effects of 2 renin‐angiotensin‐aldosterone system (RAAS) inhibitors (quinapril and aliskiren) and 2 beta‐blockers (atenolol and nebivolol) on arterial stiffness variables
Lizakowski 2012	It is a cross‐over, randomized, double‐blinded pilot study. Inclusion criterion was BP between 125/75 and 150/95 mmHg
Makówka 2012	It is an open‐label comparative fixed‐order study. It compares aliskiren with ramipril in essential hypertensive participants
NCT01151410 2015	It includes a pediatric hypertensive population; the diagnostic criteria for pediatric hypertension are different from those for adults
Quinn 2010	This is a randomized cross‐over clinical trial
Tsygankova 2012	It compares 3 groups: olmesartan, aliskiren, aliskiren + olmesartan. But it does not report outcomes that are of interest to this review
Virdis 2012	It compares aliskiren with ramipril, but it is an open‐label study with blind endpoints
Zeymer 2012	This is a non‐interventional study. The non‐interventional 3A Registry compares aliskiren with an ACE‐inhibitor or an angiotensin receptor blocker or antihypertensive agents not blocking the renin‐angiotensin system

BP: blood pressure; CVD: cardiovascular disease; DBP: diastolic blood pressure; SBP: systolic blood pressure

Differences between protocol and review

None.

Contributions of authors

Wen Lu Tang formulated the idea for the review, developed the basis for the protocol and was responsible for developing the review.

James M Wright offered expert advice, reviewed the protocol, and contributed to the interpretation of the writing of the review.

Gan Mi Wang took the lead role in searching, identifying and assessing studies, in data extraction and analysis, and in writing up the review.

Liang Jin Li took the executive role in identifying and assessing studies, in data extraction and analysis, and in writing up the review.

Sources of support

Internal sources

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

  infrastructure and salary support

• Fudan University, China

  infrastructure and salary support

External sources

• No sources of support supplied

Declarations of interest

Gan Mi Wang: None known.

Liang Jin Li: None known.

Wen Lu Tang: None known.

James M Wright: None known.

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