First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension

Yu Jie Chen; Liang Jin Li; Wen Lu Tang; Jia Yang Song; Ru Qiu; Qian Li; Hao Xue; James M Wright

doi:10.1002/14651858.CD008170.pub3

. 2018 Nov 14;2018(11):CD008170. doi: 10.1002/14651858.CD008170.pub3

First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension

Yu Jie Chen ¹, Liang Jin Li ¹, Wen Lu Tang ^1,^✉, Jia Yang Song ¹, Ru Qiu ¹, Qian Li ¹, Hao Xue ¹, James M Wright ²

Editor: Cochrane Hypertension Group

PMCID: PMC6516995 PMID: 30480768

Abstract

Background

This is the first update of a Cochrane Review first published in 2015. Renin angiotensin system (RAS) inhibitors include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors. They are widely prescribed for treatment of hypertension, especially for people with diabetes because of postulated advantages for reducing diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use for hypertension, the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear.

Objectives

To evaluate the benefits and harms of first‐line RAS inhibitors compared to other first‐line antihypertensive drugs in people with hypertension.

Search methods

The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to November 2017: the Cochrane Hypertension Specialised 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 We also contacted authors of relevant papers regarding further published and unpublished work.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 six months follow‐up in people with elevated blood pressure (≥ 130/85 mmHg), which compared first‐line RAS inhibitors with other first‐line antihypertensive drug classes and reported morbidity and mortality or blood pressure outcomes. We excluded people with proven secondary hypertension.

Data collection and analysis

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

Main results

This update includes three new RCTs, totaling 45 in all, involving 66,625 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large RCTs at low risk for most sources of bias. Imbalances in the added second‐line antihypertensive drugs in some of the studies were important enough for us to downgrade the quality of the evidence.

Primary outcomes were all‐cause death, fatal and non‐fatal stroke, fatal and non‐fatal myocardial infarction (MI), fatal and non‐fatal congestive heart failure (CHF) requiring hospitalizations, total cardiovascular (CV) events (fatal and non‐fatal stroke, fatal and non‐fatal MI and fatal and non‐fatal CHF requiring hospitalization), and end‐stage renal failure (ESRF). Secondary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).

Compared with first‐line calcium channel blockers (CCBs), we found moderate‐certainty evidence that first‐line RAS inhibitors decreased heart failure (HF) (35,143 participants in 5 RCTs, risk ratio (RR) 0.83, 95% confidence interval (CI) 0.77 to 0.90, absolute risk reduction (ARR) 1.2%), and that they increased stroke (34,673 participants in 4 RCTs, RR 1.19, 95% CI 1.08 to 1.32, absolute risk increase (ARI) 0.7%). Moderate‐certainty evidence showed that first‐line RAS inhibitors and first‐line CCBs did not differ for all‐cause death (35,226 participants in 5 RCTs, RR 1.03, 95% CI 0.98 to 1.09); total CV events (35,223 participants in 6 RCTs, RR 0.98, 95% CI 0.93 to 1.02); and total MI (35,043 participants in 5 RCTs, RR 1.01, 95% CI 0.93 to 1.09). Low‐certainty evidence suggests they did not differ for ESRF (19,551 participants in 4 RCTs, RR 0.88, 95% CI 0.74 to 1.05).

Compared with first‐line thiazides, we found moderate‐certainty evidence that first‐line RAS inhibitors increased HF (24,309 participants in 1 RCT, RR 1.19, 95% CI 1.07 to 1.31, ARI 1.0%), and increased stroke (24,309 participants in 1 RCT, RR 1.14, 95% CI 1.02 to 1.28, ARI 0.6%). Moderate‐certainty evidence showed that first‐line RAS inhibitors and first‐line thiazides did not differ for all‐cause death (24,309 participants in 1 RCT, RR 1.00, 95% CI 0.94 to 1.07); total CV events (24,379 participants in 2 RCTs, RR 1.05, 95% CI 1.00 to 1.11); and total MI (24,379 participants in 2 RCTs, RR 0.93, 95% CI 0.86 to 1.01). Low‐certainty evidence suggests they did not differ for ESRF (24,309 participants in 1 RCT, RR 1.10, 95% CI 0.88 to 1.37).

Compared with first‐line beta‐blockers, low‐certainty evidence suggests that first‐line RAS inhibitors decreased total CV events (9239 participants in 2 RCTs, RR 0.88, 95% CI 0.80 to 0.98, ARR 1.7%), and decreased stroke (9193 participants in 1 RCT, RR 0.75, 95% CI 0.63 to 0.88, ARR 1.7% ). Low‐certainty evidence suggests that first‐line RAS inhibitors and first‐line beta‐blockers did not differ for all‐cause death (9193 participants in 1 RCT, RR 0.89, 95% CI 0.78 to 1.01); HF (9193 participants in 1 RCT, RR 0.95, 95% CI 0.76 to 1.18); and total MI (9239 participants in 2 RCTs, RR 1.05, 95% CI 0.86 to 1.27).

Blood pressure comparisons between first‐line RAS inhibitors and other first‐line classes showed either no differences or small differences that did not necessarily correlate with the differences in the morbidity outcomes.

There is no information about non‐fatal serious adverse events, as none of the trials reported this outcome.

Authors' conclusions

All‐cause death is similar for first‐line RAS inhibitors and first‐line CCBs, thiazides and beta‐blockers. There are, however, differences for some morbidity outcomes. First‐line thiazides caused less HF and stroke than first‐line RAS inhibitors. First‐line CCBs increased HF but decreased stroke compared to first‐line RAS inhibitors. The magnitude of the increase in HF exceeded the decrease in stroke. Low‐quality evidence suggests that first‐line RAS inhibitors reduced stroke and total CV events compared to first‐line beta‐blockers. The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the morbidity outcomes.

Plain language summary

Renin angiotensin system inhibitors versus other types of medicine for hypertension

Review question

We determined how RAS (renin angiotensin system) inhibitors compared as first‐line medicines for treating hypertension with other types of first‐line medicines (thiazide diuretics, beta‐blockers, CCBs, alpha‐blockers, or central nervous system (CNS) active drugs) for hypertension.

Background

Hypertension is a long‐lasting medical condition and associated with cardiovascular mortality and morbidity such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease, which will reduce quality of life. RAS inhibitors have become a focus of interventions for hypertension in recent years and have been widely prescribed for treatment of hypertension. However, it remains unclear whether RAS inhibitors are superior to other antihypertensive drugs in terms of clinically relevant outcomes.

Search date

We searched for evidence up to November 2017.

Study characteristics

We included randomized, double‐blind, parallel design RCTs for the present review. 45 trials with 66,625 participants who were followed‐up for between 0.5 year and 5.6 years were included. The participants had an average age of 66 years.

Key results

We found that first‐line RAS inhibitors caused more heart failure and stroke than first‐line thiazides. When compared to first‐line CCBs, first‐line RAS inhibitors showed superiority in preventing heart failure but were inferior in preventing stroke, with greater absolute risk reduction in heart failure than increase in stroke. When compared to first‐line beta‐blockers, RAS inhibitors reduced total cardiovascular events and stroke. Small differences on efficacy for lowering blood pressure were detected, but these did not to seem to be related to the number of heart attacks, strokes or kidney problems.

Certainty of evidence

Overall, certainty of evidence was assessed as low to moderate according to the GRADE assessment. Moderate‐certainty evidence demonstrated superiority of first‐line thiazides to first‐line RAS inhibitors in preventing heart failure and stroke. The certainty of evidence was assessed moderate for comparison between RAS inhibitors and CCBs. The certainty of evidence was low for comparison between RAS inhibitors and beta‐blockers on total cardiovascular events and stroke since the results were based primarily on one large trial with moderate to high risk of bias.

Summary of findings

Background

Description of the condition

Hypertension is a worldwide health problem and has become a heavy burden on healthcare systems. Hypertension is associated with cardiovascular (CV) mortality and morbidity such as coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Blood pressure (BP) is elevated in many people with type 2 diabetes, which is a major health problem worldwide. The increasing prevalence of diabetes mellitus (DM) is primarily due to the increase in type 2 diabetes mellitus (T2DM; Inzucchi 2005). A survey of US adults with diabetes showed that 71.0% had elevated BP, defined as BP that equals or exceeds 130/85 mmHg, or current use of prescription medication for hypertension (Geiss 2002). Elevated BP is associated with a spectrum of later health problems in people with diabetes, notably CV disease and kidney damage (nephropathy). Elevated BP has been identified as a major risk factor in progression of diabetic nephropathy (Aurell 1992). The risk of CV morbidity and mortality is also doubled in hypertensive people when diabetes is present (DeStefano 1993). Review of the evidence base on this topic is covered among guidelines primarily addressing diabetes or hypertension (CPG 2013; JNC‐8 2014, respectively). Antihypertensive agents used as first‐line drugs include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), beta‐blockers and diuretics.

Description of the intervention

In the past 10 years, antagonism of the renin angiotensin system (RAS) has become a focus of therapeutic interventions for hypertension. The guidelines that recommend the use of ACE inhibitors or ARBs in hypertensive people with diabetes or renal disease base their recommendations on the results of placebo‐controlled studies, which have been interpreted to show that ACE inhibitors and ARBs have specific renoprotective effects beyond those resulting from lowering blood pressure (ADA 2013; JNC‐8 2014). Blood pressure‐independent beneficial effects of ACE inhibitors and ARBs on CV outcomes have also been proposed, based on the results of several large, multicenter, placebo‐controlled studies, especially the HOPE 2000, PROGRESS 2001 and RENAAL 2001 studies. A recent meta‐analysis has suggested that in people with DM, treatment with tissue‐specific ACE inhibitors (ramipril 1.25 mg/day or 10 mg/day; perindopril 4 mg/day or 8 mg/day) when compared to placebo significantly reduces the risk of CV mortality by 14.9% (P = 0.022), myocardial infarction (MI) by 20.8% (P = 0.002) and the need for invasive coronary revascularization by 14% (P = 0.015); but not all‐cause death (risk ratio (RR) 0.913, 95% confidence intervals (CI) 0.825 to 1.011; Saha 2008). A Cochrane Review (Strippoli 2006), that included 13 randomized controlled trials (RCTs) with 10,070 participants, showed a significant reduction in the risk of end‐stage renal failure (ESRF) with ACE inhibitors or ARBs compared to placebo or no treatment (RR 0.60, 95% CI 0.39 to 0.93; RR 0.78, 95% CI 0.67 to 0.91, respectively). Furthermore, 10 studies with 2034 participants showed that ACE inhibitors, at the maximum tolerable dose, significantly reduce the risk of all‐cause death in placebo‐controlled studies (RR 0.78, 95% CI 0.61 to 0.98, absolute risk reduction (ARR) 0.04, number needed to treat for an additional beneficial outcome (NNTB) 25).

The evidence of benefit in terms of mortality and morbidity using ACE inhibitors or ARBs versus other antihypertensive agents is not clear. Some studies suggest that RAS inhibitors might prevent or delay CV events in some subgroups, but their role in the broader group of people with hypertension remains unknown (CAPPP 2001; LIFE 2002). Some studies provided evidence of benefit of RAS inhibitors on renal function over other antihypertensive drugs (ABCD‐HT 2000; LIFE 2002; MARVAL 2002), but did not examine clinically relevant outcomes such as combined renal dysfunction or renal failure.

Other systematic reviews related to this review are summarized below in chronological order by date of publication.

A systematic review and Bayesian network meta‐analysis of 63 randomized clinical trials assessed the effects of different classes of antihypertensive treatments (monotherapy and their combinations) on survival and major renal outcomes in people with diabetes (Wu 2013). This review examined clinical endpoints that included all‐cause mortality, requirement for dialysis and doubling of serum creatinine levels. When compared with placebo, ARBs showed no reduction in any of the three outcomes, and ACE inhibitors only reduced the doubling of serum creatinine levels compared with placebo (odds ratio (OR) 0.58, 95% CI 0.32 to 0.90). Although ACE inhibitors did not show other beneficial effects compared with other drugs, the researchers supported the use of ACE inhibitors as the first‐line antihypertensive agent in people with diabetes. However, all the suggestions were based on the results of Bayesian network meta‐analysis, which not only included the results of direct comparisons, but also incorporated indirect comparisons. The review did not report the proportion of hypertensive people, and the indirect comparisons could affect the applicability of this evidence.

A systematic review and meta‐analysis by Casas et al assessed the effect of RAS inhibitors and other antihypertensive drugs on renal outcomes (Casas 2005). In this review, the effects of ACE inhibitors or ARBs in placebo‐controlled studies were indirectly compared to the effects of other antihypertensive drugs in people with type 1 or type 2 diabetes or without diabetes. For those with diabetic nephropathy, comparative studies of ACE inhibitors or ARBs showed no benefit on ESRF, glomerular filtration rate (GFR), or creatinine levels. Placebo‐controlled studies of ACE inhibitors or ARBs decreased all renal outcomes, and also reduced BP.

A Cochrane Review of RCTs compared any antihypertensive agent with placebo or another agent in hypertensive or normotensive people with diabetes and no kidney disease (Strippoli 2005). This review assessed the renal outcomes and all‐cause and CV mortality. It showed that compared to placebo, ACE inhibitors significantly reduced the development of microalbuminuria (six trials, 3840 participants: RR 0.60, 95% CI 0.43 to 0.84, ARR 0.03 and NNTB 33), but not doubling of creatinine or ESRF or all‐cause death. Compared to CCBs, ACE inhibitors significantly reduced progression to microalbuminuria (four trials,1210 participants: RR 0.58, 95% CI 0.40 to 0.84, ARR 0.05 and NNTB 20).

A meta‐analysis of double‐blinded RCTs by Siebenhofer et al compared ARBs to placebo or standard antihypertensive treatment in T2DM (three studies, 4423 participants) and examined clinical endpoints (all‐cause death, CV morbidity and mortality, and ESRF; Siebenhofer 2004). The only statistically significant benefit of ARBs was the reduction of ESRF compared with placebo (OR 0.73, 95% CI 0.60 to 0.89, ARR 0.05 and NNTB 20). ARBs failed to show superiority to standard antihypertensive treatment (CCBs, beta‐blockers) for total mortality and CV morbidity and mortality. However, ACE inhibitors were not included in this meta‐analysis.

A systematic review and meta‐analysis by Pahor et al assessed therapeutic benefits of ACE inhibitors and other antihypertensive drugs in people with T2DM and hypertension (Pahor 2000). This meta‐analysis showed a significant benefit of ACE inhibitors compared with alternative treatments (CCBs, beta‐blockers, diuretics) on acute MI (63% reduction, P < 0.001, ARR 0.06 and NNTB 17), CV events (51% reduction, P < 0.001, ARR 8% and NNTB 13), and all‐cause death (62% reduction, P = 0.010, ARR 0.02 and NNTB 40), but not stroke. However, ARBs were not included in this review. Renal outcomes (ESRF, GFR, serum creatinine or albuminuria) were not reported.

A meta‐analysis of 100 controlled and uncontrolled studies in 2494 participants with diabetes assessed the effect on proteinuria of different classes of antihypertensive agents (ACE inhibitors, CCBs, beta‐blockers and control; Kasiske 1993). This review showed that ACE inhibitors produced the greatest reductions in urine albumin and protein excretion compared with other antihypertensive agents (P < 0.05 versus CCBs; P < 0.05 versus control). ACE inhibitors achieved these beneficial effects on renal function independent of changes in blood pressure. This meta‐analysis examined surrogate markers rather than clinically relevant endpoints (such as ESRF, all‐cause death).

How the intervention might work

The RAS is a potentially pathophysiologic mechanism that causes diabetic heart disease. Angiotensin II (Ang II) is thought to play an important role in the pathogenesis of CV complications (Dzau 2001). RAS inhibitors have been proven to have additional antiproteinuric and renoprotective benefits on diabetic nephropathy (Kocks 2002).

Drugs inhibiting the RAS include: renin inhibitors, ACE inhibitors and ARBs, which inhibit the enzymatic action of renin, the conversion of angiotensin I (Ang I) to Ang II and block the Ang II receptors, respectively.

ACE inhibitors and ARBs block the RAS further downstream than renin inhibitors, which prevent the formation of renin. Renin is the substrate responsible for all downstream events that lead to production of Ang II and subsequent stimulation of its receptors. It has been proposed that renin inhibitors might provide a more effective means of blockade of the RAS than ACE inhibitors or ARBs (Duprez 2006).

Why it is important to do this review

RAS inhibitors are widely prescribed for treatment of hypertension. ACE inhibitors and ARBs are specifically promoted for people with diabetes on the basis of postulated advantages for the reduction of diabetic nephropathy and CV morbidity and mortality. Despite widespread use of ACE inhibitors and ARBs for diabetes, their efficacy compared to other antihypertensive drugs is still unclear. A systematic review is needed in order to establish the benefits and harms of clinically relevant outcomes (especially all‐cause death and morbidity, renal and CV outcomes) of RAS inhibitors compared to other antihypertensive drugs in people with elevated blood pressure.

Objectives

To evaluate the benefits and harms of first‐line RAS inhibitors compared to other first‐line antihypertensive drugs in people with hypertension.

Methods

Criteria for considering studies for this review

Types of studies

Study design must meet the following criteria:

RCTs with parallel design;
double‐blind;
minimum follow‐up of six months.

Types of participants

People with primary elevated BP (that equals or exceeds 130/85 mmHg). We chose this BP threshold, lower than the standard 140/90 mmHg, to include more people and to be consistent with the recommended lower targets for people with hypertension and diabetes. We excluded people with proven secondary hypertension.

Types of interventions

RAS inhibitors including ACE inhibitors, ARBs or renin inhibitors:

ACE inhibitors include: alacepril, altiopril, benazepril, captopril, ceronapril, cilazapril, delapril, derapril, enalapril, enalaprilat, fosinopril, idapril, imidapril, lisinopril, moexipril, moveltipril, pentopril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, and zofenopril.
ARBs include: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, and KT3‐671.
Renin inhibitors include: aliskiren, remikiren.

Comparators

Any other antihypertensive drug class including: thiazides, beta‐blockers, CCBs, alpha‐blockers, or central nervous system (CNS) active drugs.

Types of outcome measures

Primary outcomes

All‐cause death.
All‐cause serious morbidity (non‐fatal serious adverse events).
Total CV events:
1. fatal and non‐fatal MI;
2. fatal and non‐fatal stroke;
3. fatal and non‐fatal congestive heart failure (CHF) requiring hospitalizations.
Renal outcomes:
1. ESRF (defined as a requirement for maintenance dialysis).

Secondary outcomes

Change in or end‐point systolic and diastolic BP.
Change in or end‐point heart rate.

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Group Information Specialist conducted systematic searches in the following databases for randomized controlled trials without language, publication year or publication status restrictions:

the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web) (searched 22 November 2017);
the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 11) via Wiley (searched 22 November 2017);
MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 20 November 2017);
Embase Ovid (searched 20 November 2017);
ClinicalTrials.gov (www.clinicaltrials.gov) (searched 20 November 2017);
World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) (searched 22 November 2017).

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 trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Handbook 2011)). Search strategies are provided in Appendix 1.

Searching other resources

The Cochrane Hypertension Group Information Specialist searched the Hypertension Specialised Register segment (which includes searches of MEDLINE, Embase and Epistemonikos for systematic reviews) to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials. The Specialised Register also includes searches of CAB Abstracts & Global Health, CINAHL, ProQuest Dissertations & Theses and Web of Knowledge.
We checked the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.
Where necessary, we contacted authors of key papers and abstracts to request additional information about their trials.

Data collection and analysis

We performed the initial search of all the databases to identify citations with potential relevance. In our initial screen of these abstracts we excluded articles whose titles or abstracts, or both, were clearly irrelevant. We retrieved the full text of the remaining articles (and translated into English where required) to assess whether the trials met the prespecified inclusion criteria. We searched the bibliographies of pertinent articles, reviews and texts for additional relevant citations. Two independent review authors assessed the eligibility of the trials using a study selection form. A third review author resolved discrepancies.

Selection of studies

We imported references and abstracts of search results into Reference Manager software. We based selection of studies on the criteria listed above.

Data extraction and management

Two review authors independently extracted data using a standard form, and then cross‐checked them. All numeric calculations and graphic interpolations were confirmed by a second person.

Assessment of risk of bias in included studies

We assessed the risk of bias for each trial according to Cochrane 'Risk of bias' guidelines using the following six domains (Higgins 2011):

sequence generation;
allocation concealment;
blinding or objective assessment of primary outcomes;
incomplete outcome data;
selective outcome reporting;
other biases.

We used the overall risk of bias in the GRADE assessment in the 'Summary of findings' table. We conducted GRADE assessment according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Measures of treatment effect

We based quantitative analysis of outcomes on intention‐to‐treat principles as much as possible. For dichotomous outcomes, we expressed results as the risk ratio (RR) with a 95% confidence interval (CI). For combining continuous variables (systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)), we used the mean difference (with 95% CI).

Dealing with missing data

If the included studies had missing information, we contacted investigators (using email, letter or fax or both) 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 dose regimen;
weighted mean SD of change calculated from other trials using any dose.

Assessment of heterogeneity

We used Chi² and I² statistics to test for heterogeneity of treatment effect among trials. We consider a Chi² value P < 0.1 or I² value > 50% indicative of heterogeneity.We used the fixed‐effect model when there was homogeneity and used the random‐effects model to test for statistical significance where there was 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 performed data synthesis and analyses using the Cochrane Review Manager software, RevMan 5.3 (RevMan 2014). We described data results in tables and forest plots according to Cochrane guidelines. In addition we gave full details for all studies we included and excluded. We have included a standard PRISMA flow diagram (Figure 1).

Subgroup analysis and investigation of heterogeneity

Where appropriate, we performed the following subgroup analyses:

Heterogeneity among participants could be related to:
1. gender;
2. age;
3. presence of diabetes at initiation of antihypertensive treatment (time of trial entry);
4. baseline blood pressure;
5. previous renal disease;
6. previous CV disease.
Heterogeneity in treatments could be related to:
1. dose of drugs;
2. duration of therapy.

Sensitivity analysis

We tested 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.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

Up to November 2017, the search strategy identified 15,145 citations (Figure 1). After excluding all the studies that did not meet the inclusion criteria or those we have included before, we performed full‐text assessment of five potentially eligible studies and identified three new trials (NESTOR 2015; SILVHIA 2001; Xiao 2016) (four citations) that we included in the review update. This update includes 45 RCTs with 87 citations, i.e. the three new RCTs and the 42 RCTs (83 citations) in the first publication of this review (Xue 2015).

Included studies

The 45 included studies involved 66,625 participants with a mean age of 66 years. Participants in nine studies were under 50 years old (Buus 2004; Buus 2007; Dahlöf 1993; Pedersen 1997; Schiffrin 1994; Sørensen 1998; Tarnow 1999; Xiao 2016; Zeltner 2008); in 22 studies participants were between 50 and 59 years old (Ariff 2006; Dahlöf 2002; Dalla 2004; Derosa 2004; Derosa 2005; Derosa 2014; Esnault 2008; Estacio 1998; Gottdiener 1998; Hauf‐Zachariou 1993; Hughes 2008; IDNT 2001; Malmqvist 2002; Parrinello 2009; Petersen 2001; Roman 1998; Schmieder 2009; Schneider 2004; Seedat 1998; SILVHIA 2001; Tedesco 1999; TOHMS 1993); and over 60 years old in the remaining 14 studies (ALLHAT 2002; BENEDICT 2004; Devereux 2001; Fogari 2012; Gerritsen 1998; Hajjar 2013; Hayoz 2012; Himmelmann 1996; LIFE 2002; NESTOR 2015; Ostman 1998; Schram 2005; Terpstra 2004; VALUE 2004). The mean duration of therapy was 1.9 years, ranging from 0.5 to 5.6 years. The number of participants who received RAS inhibitors was 25,421, while 5,525 received beta‐blockers, 19,040 CCBs, 16,316 thiazides, 240 alpha‐blockers, and 83 CNS active drugs. Three studies contained multiple different drug groups: Gottdiener 1998 contained six, TOHMS 1993 contained five, and ALLHAT 2002 contained three, so the numbers of studies comparing RAS inhibitors with other drug classes were 17 for beta‐blockers, 22 for CCBs ‐ within which there were two studies that used non‐dihydropyridine (BENEDICT 2004; Gottdiener 1998), and 20 studies that used dihydropyridine, 10 for thiazides, 3 for alpha‐blockers, and 1 for CNS active drugs.

Most of the included studies were industry‐sponsored (28/45). Participants with diabetes were involved in 14 studies, while one study included participants with impaired fasting glucose; participants with decreased renal function in seven studies, and seven studies contained participants with at least one risk factor for CV diseases. Three studies recruited only men (Dahlöf 1993; Gottdiener 1998; Schiffrin 1994). One study included only women, as it focused on postmenopausal women (Hayoz 2012). All 87 included citations were published in English with publication years ranging from 1993 to 2016.

Most participants (30 studies) were recruited from European countries; seven studies included participants from North America; two studies included participants from North America, Europe, and Asia (Dahlöf 2002; VALUE 2004); one study included participants from North America, South America, Europe, Asia and Australia (IDNT 2001); NESTOR 2015 included participants from North America, South America, Europe and Asia; one study included participants from North America and Europe (LIFE 2002); Devereux 2001 included participants from Europe and Asia; Seedat 1998 included participants from South Africa; and Xiao 2016 included participants from Asia. Fifteen of the 45 included studies reported ethnicity; the percentages of white, Hispanic, Asian, Black and other race participants were 71.0%, 0.3%, 1.7%, 23.7% and 3.3%, respectively.

In terms of baseline comorbidities, nine studies stated that they would not include people with a history of prior MI or stroke; 14 studies allowed participants with a history of prior MI or stroke if this had not occurred within the previous three or six months); the other 22 studies made no clear statement, but in general the proportion of participants without cardiac‐cerebral vascular comorbidities was high. Overall, this review represents treatment effects for primary prevention.

A stepwise therapeutic regimen was used in 34 studies, in which add‐on drugs were allowed to achieve BP goals. The second‐line drugs included open‐label, non‐study agents such as CCBs, thiazides, or beta‐blockers. The remaining eleven studies restricted the therapeutic regimens to monotherapy (Dahlöf 1993; Derosa 2004; Derosa 2014; Gottdiener 1998; Himmelmann 1996; Hauf‐Zachariou 1993; Sørensen 1998; Tedesco 1999; Terpstra 2004; TOHMS 1993; Xiao 2016).

With regard to the clinical classification of hypertension (see ESH/ESC 2013), we classified mean blood pressure of participants at baseline into two groups: 30 studies included Grade 1 hypertensive participants (SBP: 140 mmHg to 159 mmHg); 15 studies included Grade 2 hypertensive participants (SBP: 160 mmHg to 179 mmHg). Baseline untreated mean BP was 156/89 mmHg (SBP/DBP) for RAS inhibitors; 151/86 mmHg for CCBs; 172/98 mmHg for beta‐blockers; 146/85 mmHg for thiazides; 150/96 mmHg for alpha‐blockers; 152/99 mmHg for CNS active drugs.

For details, see Characteristics of included studies.

Excluded studies

Full‐text screening according to the prespecified inclusion criteria led to us excluding three of the seven citations during the update, in addition to the four citations excluded in the previous version of the review. In total, we excluded seven citations of six studies in the updated review. The reasons for each study's exclusion are described in Characteristics of excluded studies.

Risk of bias in included studies

The data extraction forms for each included study contained the details of study design, randomization, allocation, blinding, duration of treatment, funding, diagnosis, number of participants, age of participants, gender of participants, history of participants, inclusion and exclusion criteria, outcomes and intervention. We assessed the risk of bias for each included study (Figure 2), and all included studies (Figure 3), in detail (see Characteristics of included studies).

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

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included citations

Allocation

We assessed seven of the 45 studies as being at low risk of bias for reporting the method for generation of random sequence and one study as being at high risk (Roman 1998); in the remaining 37 studies the risk of bias for this domain was unclear. We assessed three of the 45 studies as being at low risk for allocation concealment, one study as being at high risk, and 41 studies as being at unclear risk. The three studies at low risk used either a central office allocation (ALLHAT 2002; VALUE 2004), or were strictly confidential until unblinding time (Schmieder 2009); one study reported using alternate allocation, which is a high risk method (Seedat 1998); two studies at unclear risk of selection bias reported the allocation concealment by using an envelope to maintain the random number (Derosa 2004; Derosa 2005); however, it was not clear whether the envelope was transparent or opaque.

Blinding

All the 45 included studies were at low risk of performance bias as they were all double‐blinded and met the inclusion criteria. In terms of detection bias, we judged only six studies to be at low risk due to the use of blinding for outcome assessment for BP or HR, which was critical for the control of detection bias; the risk of bias for this domain was unclear for the remaining 39 studies. We thought that unblinded assessment of outcomes like MI, stroke, HF, CV events, all‐cause death, and ESRF was not as critical as it would be for BP and HR.

Incomplete outcome data

We judged the risk of attrition bias in 40 of the 45 studies included in the review to be low because missing data were unlikely to have an impact because of low or equal numbers of dropouts between arms. In one study this risk was unclear (Petersen 2001); and in the other four studies we judged it to be high. Among these four studies with a high risk of attrition bias, Gottdiener 1998 only included participants with a left atrial dimension measurement (a small proportion of all participants) in the analysis. Pedersen 1997 and Tarnow 1999 had many participants lost to follow‐up at the end of study and Hayoz 2012 reported inconsistent numbers of participants in Figure 1 and Table 2.

Selective reporting

In this review, we judged 43 included studies to have a low risk of reporting bias; we judged that two studies had a high risk of selective reporting as they did not report HR, which was a prespecified outcome in their 'Methods' sections (Derosa 2004; Terpstra 2004).

Other potential sources of bias

Seven studies had a high risk of other potential sources of bias. Pedersen 1997 and Roman 1998 had unbalanced baseline characteristics. VALUE 2004 had an unbalanced proportion of monotherapy and highest dose between the two groups (including HCTZ and other non‐study add‐on drugs); Estacio 1998 had an unbalanced proportion of monotherapy. LIFE 2002 was evaluated as being at high risk as it was funded and conducted by the pharmaceutical company Merck. Similarly, many of the authors of IDNT 2001 had received research grants from Bristol‐Myers Squibb. Numbers of participants reported for different outcomes were not consistent in SILVHIA 2001.

Effects of interventions

See: Table 1; Table 2; Table 3

Summary of findings for the main comparison. RAS inhibitors compared to CCBs for hypertension.

First‐line RAS inhibitors compared to first‐line CCBs for hypertension
Patient or population: people with hypertension  Settings: outpatients with mean follow‐up of 4.5 years  Intervention: First‐line RAS inhibitors  Comparison: First‐line CCBs
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Certainty of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	CCBs	RAS inhibitors
All‐cause death	124 per 1000	127 per 1000  (121 to 135)	RR 1.03   (0.98 to 1.09)	35,226  (5)	⊕⊕⊕⊝  moderate¹
Total cardiovascular events	178 per 1000	174 per 1000  (166 to 182)	RR 0.98   (0.93 to 1.02)	35,223  (6)	⊕⊕⊕⊝  moderate¹
Death or hospitalization for heart failure	72 per 1000	60 per 1000  (55 to 65)	RR 0.83   (0.77 to 0.90)	35,143  (5)	⊕⊕⊕⊝  moderate¹	ARR = 1.2% NNTB = 83
Total myocardial infarction	68 per 1000	69 per 1000  (63 to 74)	RR 1.01   (0.93 to 1.09)	35,043  (5)	⊕⊕⊕⊝  moderate¹
Total stroke	39 per 1000	46 per 1000  (42 to 51)	RR 1.19   (1.08 to 1.32)	34,673  (4)	⊕⊕⊕⊝  moderate¹	ARI = 0.7% NNTH = 143
End stage renal failure	25 per 1000	22 per 1000  (19 to 26)	RR 0.88   (0.74 to 1.05)	19,551  (4)	⊕⊕⊝⊝  low^{1, 2}
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; RR: risk ratio; ARR: absolute risk reduction; ARI: absolute risk increase; NNTB: number needed to treat to prevent one adverse outcome; NNTH: number needed to treat to cause one adverse outcome
GRADE Working Group grades of evidence  High certainty: further research is very unlikely to change our confidence in the estimate of effect  Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate  Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate  Very low certainty: we are very uncertain about the estimate

Date	Event	Description
15 October 2018	New citation required but conclusions have not changed	This review includes an updated search conducted in November 2017. Three new studies met the inclusion criteria, making the number of included RCTs 45 in total. Three additional authors contributed to the update: Song Jia Yang, Qiu Ru and Li Qian.
15 October 2018	New search has been performed	No data for the primary outcomes were reported in the three new RCTs, so the evidence on all‐cause death, total CV events, total HF, total MI, total stroke and ESRF remain the same. Data on blood pressure were updated in the three main comparisons: RAS inhibitors versus CCBs, thiazides, and beta‐blockers. However, we found little change in blood pressure. In addition, data on heart rate were updated in the comparison of RAS versus beta‐blocker, with no change to that outcome either. The formerly "Ruggenenti 2004" trial was renamed "BENEDICT 2004" in this version, The abbreviation "BENEDICT" stands for "Bergamo Nephrologic Diabetes Complications Trial" and was given by the study group. We regard it necessary to make the change for the readers to identify this trial easier by its official abbreviation.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause death	5	35226	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.98, 1.09]
2 Total CV events	6	35223	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.93, 1.02]
3 Total HF	5	35143	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.77, 0.90]
4 Total MI	5	35043	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.93, 1.09]
5 Total stroke	4	34673	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [1.08, 1.32]
6 ESRF	4	19551	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.74, 1.05]
7 SBP	20	36437	Mean Difference (IV, Fixed, 95% CI)	1.23 [0.90, 1.56]
8 DBP	20	36437	Mean Difference (IV, Fixed, 95% CI)	0.98 [0.79, 1.18]
9 HR	5	540	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐1.63, 2.22]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause death	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.94, 1.07]
2 Total CV events	2	24379	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [1.00, 1.11]
3 Total HF	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [1.07, 1.31]
4 Total MI	2	24379	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.86, 1.01]
5 Total stroke	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [1.02, 1.28]
6 ESRF	1	24309	Risk Ratio (M‐H, Fixed, 95% CI)	1.10 [0.88, 1.37]
7 SBP	10	26382	Mean Difference (IV, Fixed, 95% CI)	1.60 [1.20, 1.99]
8 DBP	9	26335	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.36, 0.13]
9 HR	2	84	Mean Difference (IV, Fixed, 95% CI)	0.66 [‐2.87, 4.19]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause death	1	9193	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.78, 1.01]
2 Total CV events	2	9239	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.80, 0.98]
3 Total HF	1	9193	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.76, 1.18]
4 Total MI	2	9239	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.86, 1.27]
5 Total stroke	1	9193	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.63, 0.88]
6 ESRF	1	46	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.78]
7 SBP	16	10905	Mean Difference (IV, Fixed, 95% CI)	‐0.55 [‐1.22, 0.11]
8 DBP	16	10905	Mean Difference (IV, Fixed, 95% CI)	0.48 [0.14, 0.83]
9 HR	10	9979	Mean Difference (IV, Fixed, 95% CI)	6.05 [5.59, 6.50]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP	3	380	Mean Difference (IV, Fixed, 95% CI)	‐2.38 [‐3.98, ‐0.78]
2 DBP	3	380	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐1.09, 0.85]
3 HR	1	44	Mean Difference (IV, Fixed, 95% CI)	3.1 [‐2.41, 8.61]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 SBP	1	56	Mean Difference (IV, Fixed, 95% CI)	1.30 [‐6.01, 8.61]
2 DBP	1	56	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.85, 1.25]
3 HR	1	56	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐4.13, 7.13]

Methods	Allocation: computer‐generated randomization Blinding: double‐blinded, and blinded assessment Duration: 4.9 ± 1.4 years Funding: National Heart, Lung and Blood Institute and financial support from Pfizer
Participants	Diagnosis: the risk factors included previous (> 6 months) MI or stroke, LVH demonstrated by ECG or echocardiography, history of T2DM, current cigarette smoking, HDL of < 35 mg/dL (< 0.91 mmol/L), or documentation of other atherosclerotic CVD N = 33357 Age: 55 years or older Sex: 47% women, 53% men History: not reported Inclusion criteria: stage 1 or 2 hypertension, 55 years or older, 1 additional risk factor for CHD events Excluded: individual with a history of hospitalized or treated symptomatic HF and/or left ventricular ejection fraction of < 35%
Interventions	RAS inhibitor: lisinopril; CCB: amlodipine; thiazide: chlorthalidone Step 1: 12.5 mg/day, 12.5 mg/day (sham titration), 25 mg/day for chlorthalidone; 2.5 mg/day, 5 mg/day, 10 mg/day for amlodipine; 10 mg/day, 20 mg/day, 40 mg/day for lisinopril Step 2: add‐on, atenolol 25 mg/day‐100 mg/day; 0.05 mg/day‐0.2 mg/day of reserpine; clonidine 0.1 mg‐0.3 mg twice daily Step 3: 25 mg‐100 mg twice daily of hydralazine. Other drugs, including low doses of open‐label step 1 drug classes, were permitted if clinically indicated
Outcomes	Primary outcomes: fatal CHD or non‐fatal MI combined Secondary outcomes: all‐cause mortality; fatal and non‐fatal stroke; combined CHD (the primary outcomes, coronary revascularization, hospitalized angina); combined CVD (combined CHD, stroke, other treated angina, HF (fatal, hospitalized, or treated non‐hospitalized), and peripheral arterial disease) Other secondary outcomes: cancer, incident ECG LVH, ESRF (dialysis, renal transplant, or death), slope of the reciprocal of longitudinal serum creatinine measurements
Notes	Participants assigned to lisinopril were less likely to be black and more likely to be women, had untreated hypertension, evidence of CHD or atherosclerotic CVD, and a lower mean serum glucose
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated
Allocation concealment (selection bias)	Low risk	Clinical trials center was used
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Clinical trials center judged by clinic investigator reports, copies of death certificates, and hospital discharge summaries
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes in the methods were reported
Other bias	Unclear risk	Although the study was supported by the government and industry, insufficient information was found to evaluate the risk as high or low

Methods	Allocation: randomized Blinding: double‐blinded Duration: 52 weeks Funding: this study was supported by a grant from AstraZeneca
Participants	Diagnosis: uncontrolled essential hypertension: 160/100 mmHg in untreated participants or 140/90 mmHg in treated participants plus evidence of target‐organ damage; accelerated hypertension: 220/120 mmHg N = 88 Median age (range): candesartan group 56 (37‐73) years; atenolol group 54 (39‐76) years Sex: 37.5% women, 62.5% men History: median duration of hypertension (range): candesartan 4 (1‐36) years; atenolol 3 (1‐36) years Inclusion criteria: uncontrolled essential hypertension Exclusion criteria: evidence of accelerated hypertension, MI or stroke within previous 6 months, DM, or any other condition that precluded participation
Interventions	RAS inhibitor: candesartan; beta‐blocker: atenolol Candesartan 8 mg or 16 mg daily Atenolol 50 mg or 100 mg daily Add‐ons HCTZ, felodipine doxazosin
Outcomes	SBP and DBP were measured in the right arm with an Omron HEM‐705‐CP
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	There were no patient withdrawals
Selective reporting (reporting bias)	Low risk	All of the study's pre‐specified outcomes that are of interest in the review have been reported in the pre‐specified way
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low

Methods	Allocation: randomization was balanced to ensure an equal gender and age distribution in the 2 groups Blinding: double‐blinded Duration: 1 year Funding: this work was supported in part by grants from Institute de Recherces Internationales Servier and the Danish Heart Foundation
Participants	Diagnosis: not reported N = 31 Age: perindopril group 49 ± 7.7 years, atenolol group 51 ± 7.7 years Sex: 26% women, 74% men History: not reported Inclusion criteria: sitting DBP of 100 mmHg–120 mmHg Exclusion criteria: symptoms or signs of ischemic heart disease or secondary hypertension
Interventions	RAS inhibitor: perindopril; beta‐blocker: atenolol Perindopril 4 mg or 8 mg daily Atenolol 50 mg or 100 mg daily Add‐ons, bendroflumethiazide
Outcomes	BPs measured 3 times with a mercury sphygmomanometer, on 2 or 3 occasions
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes in the methods were reported
Other bias	Low risk	Government funded trial

Methods	Allocation: randomization accomplished by the drawing of envelopes containing randomization codes prepared by a statistician Blinding: double‐blinded. All study staff were blinded to treatment assignment Duration: 12 months Funding: not reported
Participants	Diagnosis: nonsmoking people with T2DM for ≥ 2 years (HbA1c < 7.0%); mild hypertension (DBP 90mmHg‐99 mmHg) N = 116 Age: telmisartan group 52 ± 5 years, nifedipine group 53 ± 4 years Sex: 50% women, 50% men History: known DM for > 2 years Inclusion criteria: mild hypertension with T2DM Exclusion criteria: secondary hypertension; malignant hypertension; unstable angina; MI within the preceding 6 months; abnormalities of liver or renal function; or contraindications to or current use of ARBs or ACE inhibitors
Interventions	RAS inhibitor: telmisartan; CCB: nifedipine Telmisartan 40 mg/day Nifedipine Gastro‐Intestinal Therapeutic System (GITS) 20 mg/day
Outcomes	BP was measured using a standard mercury sphygmomanometer (Korotkoff 1 and 5) in the seated position
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described
Allocation concealment (selection bias)	Unclear risk	Quote: "randomization was accomplished by the drawing of envelopes containing randomization codes prepared by a statistician." Whether the envelopes were opaque was not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "this 12‐months, randomised, double‐blind trial was conducted at the Department of Internal Medicine and Therapeutics of the University of Pavia in Italy." "All study staff were blinded to treatment assignment."
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Quote: "a copy of the code was provided only to the individual responsible for performing the statistical analysis." Reviewer comment: possible high risk of bias because the statistical analysis was not blinded, but it would not result in detection bias; the method of blinding of outcome assessment was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No participants withdrew
Selective reporting (reporting bias)	High risk	Quote: "at each clinical visit, heart rate was measured after the patient had been seated for >=10 minutes." Reviewer comment: high risk due to failure to report HR
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low

Methods	Allocation: randomization performed by the drawing of envelopes containing randomization codes prepared by a statistician Blinding: blinding of the investigators and participants was maintained by using identical numbered bottles prepared by the hospital pharmacy Duration: 12 months Funding: not reported
Participants	Diagnosis: not reported N = 96 Age: doxazosin group 53 ± 9 years, irbesartan group 52 ± 10 years Sex: 51% women, 49% men History: not reported Inclusion criteria: T2DM; mild hypertension (DBP > 90 mmHg and < 105 mmHg) Exclusion criteria: secondary hypertension; malignant hypertension; unstable angina; MI; and/or liver/renal function abnormalities
Interventions	RAS inhibitor: irbesartan; alpha‐blocker: doxazosin Doxazosin 4 mg daily Irbesartan 300 mg daily
Outcomes	SBP (Korotkoff 1) and DBP (Korotkoff 4) measurements were obtained from participants in the seated position using a standard mercury sphygmomanometer (Erkameter 3000, ERKA, Bad Tolz, Germany) with a cuff of appropriate size
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described
Allocation concealment (selection bias)	Unclear risk	Quote: "randomization was performed by the drawing of envelopes containing randomization codes prepared by a statistician." Whether the envelopes were opaque was not mentioned
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "ninety‐six patients with type 2 diabetes … were enrolled in this randomised, double‐blind trial." "Blinding of investigators and patients was maintained using identical numbered bottles prepared by the hospital pharmacy."
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Quote: "… no subject experienced adverse effects serious enough to warrant discontinuing either drug … " Despite the absence of numbers for participants reported in the data tables, the statement above was sufficient
Selective reporting (reporting bias)	Low risk	All of the study's pre‐specified outcomes that are of interest in the review have been reported in the pre‐specified way
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low

Methods	Allocation: randomized Blindness: double blind. Interventions were supplied as identical, opaque, white capsules in coded bottles to ensure the blind status of the study Duration: 24 months Funding: not reported
Participants	Diagnosis: essential hypertension [DBP >90 and <110 mmHg and/or SBP>140 mmHg and <180 mmHg] N= 222 Age: < 65 years old Sex: 51.8% women, 48.2% men History: no reported Inclusion criteria: outpatients of both sex, aged < 65 years, with a first diagnosis of essential hypertension and naïve to antihypertensive treatment Excluded: secondary hypertension, severe hypertension (SBP >180 mmHg or DBP >110 mmHg), hypertrophic cardiomyopathies due to aetiologies other than hypertension, history of heart failure or a left ventricular ejection fraction (LVEF) ≤50%, history of angina, stroke, transient ischaemic cerebral attack, coronary artery bypass surgery or myocardial infarction any time prior to visit 1, concurrent symptomatic arrhythmia, liver dysfunction (AST or ALT values exceeding 2‐fold the upper limit), creatinine >1.5 mg/dL and known hypersensitivity to the study drugs. Pregnant women as well as women of childbearing potential were excluded. Patients with endocrine, infective or inflammatory disorders were excluded, as well as were those taking anti‐inflammatory medications
Interventions	RAS inhibitor: enalapril; CCB: lercanidipine Enalapril 20mg daily Lercanidipine 10mg daily
Outcomes	Blood pressure measurements were obtained from each patient (using the right arm) in the seated position, using a standard mercury sphygmomanometer (Erkameter 3000; ERKA, Bad Tolz, Germany) (Korotkoff I and V) with a cuff of appropriate size. BP was measured by the same investigator at each visit, in the morning before daily drug intake and after the patient had rested for ≥10 min in a quiet room. Three successive BPreadings were obtained at 1‐min intervals, and the mean of the 3 readings was calculated.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described.
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data was unlikely to have an impact on the results of the trial.
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes in the methods were reported.
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low.

Methods	Allocation: the randomization schedule was generated by a statistical analysis system Blinding: double‐blinded Duration: 3 years Funding: Pfizer Inc. The biostatistics department of Pfizer was responsible for entering data, quality controls, and blinded statistical analysis; Pfizer had no other role in the study performance, analysis, and reporting
Participants	Diagnosis: malignant hypertension i.e. DBP > 120 mmHg; congestive heart disease according to New York Heart Association class II–IV N = 263 Age: 18‐80 years Sex: 40.7% women, 59.3% men History: not reported Inclusion criteria: nondiabetic adults, aged 18‐80 years, non‐nephrotic adult hypertensive patients with creatinine clearance of 20 mL‐ 60 mL/min·1.73 m² (Cockcroft‐Gault) Exclusion criteria: nephrotic proteinuria; secondary or malignant hypertension; a major CV event within previous 3 months; angina pectoris; CHD; uncontrolled arrhythmias; II–III degree atrioventricular block; need for steroids, nonsteroidal anti‐inflammatory or cytotoxic drugs; women of childbearing potential not using appropriate contraception; or any disease that could limit the ability of the patient to comply with the protocol requirements
Interventions	RAS inhibitor: enalapril; CCB: amlodipine Amlodipine 5 mg or 10 mg/day Enalapril 5 mg or 10 mg/day Add‐ons: atenolol (50 mg/day‐100 mg/day), loop diuretics (furosemide, 20 mg/day‐500 mg/day or torsemide 5 mg/day‐200 mg/day), alpha‐blockers (prazosin, 2.5 mg/day‐5 mg/day or doxazosin 1 mg/day‐16 mg/day), and centrally acting drugs (rilmenidine, 1 mg/day‐2 mg/day or methyldopa 250 mg/day‐500 mg/day)
Outcomes	All‐cause death, renal failure
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomization schedule was generated by a statistical analysis system
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes in the methods were reported
Other bias	Unclear risk	Although the role of the funding company was unlikely to have an impact on the study, no other information was found to evaluate the risk as either high or low

Methods	Allocation: randomly assigned Blinding: double‐blinded Duration: 67 months Funding: Bayer Pharmaceutical Company, a grant (DK50298‐02) from the National Institute of Diabetes and Digestive and Kidney Diseases; Dr Hiatt was the recipient of an Academic Award in Vascular Disease from the National Institutes of Health
Participants	Diagnosis: NIDDM, mean base‐line DBP ≥ 90 mmHg N = 470 (all in analysis) Age: 40‐74 years Sex: 32.6% women, 67.4% men History: not reported, probably outpatients Inclusion criteria: participants enrolled in the ABCD Trial were between the ages of 40 and 74 years at the time of recruitment and were identified according to diagnosis‐related groups from the pharmacy and billing lists of participating healthcare systems in the Denver metropolitan area. All participants in the ABCD Trial had NIDDM, diagnosed according to criteria based on those of the WHO report of 1985. All enrolled subjects had DBP of 80 mmHg or higher and were receiving no antihypertensive medications at the time of randomization Exclusion criteria: a known allergy to dihydropyridine CCBs or ACE inhibitors; MI or cerebrovascular accident within the previous 6 months; coronary‐artery bypass surgery within the previous 3 months; unstable angina pectoris within the previous 6 months; New York Heart Association class III or IV CHF; an absolute need for therapy with ACE inhibitors or CCBs; were receiving hemodialysis or peritoneal dialysis; or serum creatinine concentration > 3 mg/dL (265 μmol/L)
Interventions	RAS inhibitor: enalapril; CCB: nisoldipine Nisoldipine 10 mg/day, with increases to 20 mg/day, 40 mg/day, and 60 mg/day, plus placebo in place of enalapril (Sular, Zeneca, Wilmington, Del) Enalapril 5 mg/day, with increases to 10 mg/day, 20 mg/day, and 40 mg/day, plus placebo in place of nisoldipine (Vasotec, Merck, Whitehouse Station, NJ) Open‐label, step‐wise, additional medication: metoprolol and HCTZ when participants did not achieve the target BP Notes: 99 participants in the enalapril group took a beta‐blocker, compared with 89 in the nisoldipine group (P value 0.035). 119 participants assigned to enalapril took a diuretic agent, as did 93 assigned to nisoldipine (P value 0.02)
Outcomes	Binary data: fatal MI, non‐fatal MI, cerebrovascular accident, congestive HF, death from CV causes, death from any cause
Notes	Significantly more participants discontinued nisoldipine than enalapril because of headaches (P value 0.009). Significantly more discontinued enalapril because of malaise or fatigue (P value 0.005) or uncontrolled hypertension (P value 0.04)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	The drugs and placebos were administered in a double‐blinded manner
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	All CV events were reviewed by an independent endpoints committee whose members were blinded to the patients' assigned treatment groups
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	Outcomes listed in the methods were all reported
Other bias	High risk	Add‐on medication was not balanced between groups. Quote: "Ninety‐nine patients in the enalapril group took a beta‐blocker, as compared with 89 patients in the nisoldipine group (P=0.035). One hundred nineteen patients assigned to enalapril took a diuretic agent, as compared to 93 assigned to nisoldipine (P=0.02)."

Methods	Allocation: used a computer‐generated allocation schedule Blinding: participants, clinicians, and assessment blinded. "LIFE is an investigator‐initiated, double‐masked, double‐dummy, randomised comparison", "An endpoint classification committee of two masked clinicians reviewed clinical records of all CV events reported by clinical centers to determine whether they met endpoint criteria." Duration: at least 4 years, mean 4.8 ± 0.9 years Funding: study data was in Merck database. Merck provided steering committee for this review free access to all data
Participants	Diagnosis: not reported N = 9193 Age: 55‐80 years Sex: 54.0%, 46.0% men History: Any vascular disease: losartan group1203 (26%); atenolol group1104 (24%); all participants 2307 (25%) Coronary heart disease: losartan group 771 (17%); atenolol group 698 (15%); all participants 1469 (16%) Cerebrovascular disease: losartan group 369 (8%); atenolol group 359 (8%); all participants 728 (8%) Peripheral vascular disease: losartan group 276 (6%); atenolol group 244 (5%); all participants 520 (6%) AF: losartan group 150 (3%); atenolol group 174 (4%); all participants 324 (4%) Isolated systolic hypertension: losartan group 660 (14%); atenolol group 666 (15%); all participants 1326 (14%) DM: losartan group 586 (13%); atenolol group 609 (13%); all participants 1195 (13%) Inclusion criteria: previously treated or untreated hypertension and ECG signs of LVH Trough sitting SBP 160 mmHg–200 mmHg, DBP 95 mmHg‐115 mmHg, or both Exclusion criteria: secondary hypertension; MI or stroke within the previous 6 months; angina pectoris requiring treatment with beta‐blockers or calcium‐antagonists; HF or LV ejection fraction of ≤ 40%; or a disorder that, in the treating physician's opinion, required treatment with losartan or another angiotensin–II type 1‐receptor antagonist, atenolol or another beta‐blocker, HCTZ, or ACE inhibitors
Interventions	RAS inhibitor: losartan; beta‐blocker: atenolol. Losartan: mean 82 ± 24 mg Atenolol: mean 79 ± 26 mg HCTZ added when needed
Outcomes	Change in SBP, change in sitting SBP, sitting DBP, HR. Primary endpoint: CV morbidity, death and a composite endpoint (CV death, MI, stroke) An independent endpoint classification committee reviewed all the events
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Masked endpoint classification committee was responsible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	Outcomes listed in the previous published paper were all reported
Other bias	High risk	Funded and conducted by Merck

Methods	Allocation: double‐blinded randomization using a computer algorithm designed prior to commencement of the study Blinding: each participant was identified with an allocation number that was associated with treatment groups according to a computer‐generated allocation schedule; physicians were blinded to the treatment‐associated allocation number Duration: 12 months Funding: no funding sources reported
Participants	Diagnosis: not reported N = 72 Age: range: 29‐63 years; mean age ± SD: 52 ± 12 years Sex: 44.4% women, 55.6% men History: not reported Inclusion criteria: a diagnosis of essential hypertension (ESH stage 1 or 2 hypertension) established by history and physical examination, together with the absence of clinical findings suggestive of a secondary hypertension, according to ESH guidelines Exclusion criteria: other CV diseases (defined as MI or angina pectoris, heart block, valvular disease, HF and claudication); concomitant LVH (defined according to ECG criteria); other target organ damage (including hypertensive retinopathy); micro‐ or macroalbuminuria or renal diseases; insulin‐dependent or NIDDM; electrolyte imbalances; alcoholism or psychiatric problems, or both; taking antihypertensive drugs; or contraindications to beta‐blockers
Interventions	RAS inhibitor: losartan; beta‐blocker: bisoprolol Bisoprolol 5 mg daily Losartan 50 mg daily HCTZ was added when needed
Outcomes	SBP and DBP measured in triplicate with a mercury sphygmomanometer after 5 min in a supine position. The Korotkoff phase V sound was used to determine DBP
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Double‐blind randomization performed using a computer algorithm designed prior to commencement of the study
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Each participant was identified with an allocation number that was associated with treatment groups according to a computer‐generated allocation schedule; physicians were blinded to the treatment‐associated allocation number
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes in the methods were reported
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low

Methods	Allocation: randomized: "The study was a randomised and double blind comparison" Blinding: double‐blinded Duration: 6 months before randomization, 21 months after randomization or until need of dialysis Funding: isradipine and spirapril were supplied by Novartis and the study was supported by Novartis. Statistical assistance was supported by a grant from the Danish Medical Research Council
Participants	Diagnosis: chronic renal failure (serum creatinine between 150 μmol/L‐600 μmol/L) and hypertension (BP > 140/95 mmHg) N = 36 Age: 18‐75 years Sex: 36% women, 64% men History: previously treated and untreated people with hypertension Inclusion criteria: chronic, inactive renal disease and serum creatinine between 150 μmol/L‐600 μmol/L, (DBP > 95 mmHg, or SBP > 140 mmHg without treatment) Exclusion criteria: renal artery stenosis or severe CHF
Interventions	RAS inhibitor: spirapril; CCB: isradipine Isradipine 5 mg daily Spirapril 6 mg daily Loop diuretics and labetolol were accepted add‐ons when target BP was not sufficient
Outcomes	ESRF SBP, mercury sphygmomanometer and Korotkoff Phase 1, sitting DBP, mercury sphygmomanometer and Korotkoff Phase 5, sitting
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described
Allocation concealment (selection bias)	Unclear risk	Method of concealment was not described
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	The data flow was not mentioned
Selective reporting (reporting bias)	Low risk	All of the study's pre‐specified outcomes that are of interest in the review have been reported in the pre‐specified way
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low

Methods	Allocation: randomized, "Randomization by center was performed by the interactive voice response system provider with the use of a validated system that automates the random assignment of patients to randomization numbers. Randomization data were kept strictly confidential until the time of unblinding." Blinding: double‐blinded Duration: 1 year Funding: Novartis Pharmaceuticals Corporation, East Hanover, NJ
Participants	Diagnosis: hypertension, mean sitting DBP > 90 mmHg and < 110 mmHg at the single‐blind placebo run‐in visit N = 962 Age: Aliskiren group 56.1 ± 10.9 years; HCTZ group 55.7 ± 10.9 years Sex: 36% women; 64% men History: mean duration of hypertension was 7.1 years. 35.2% of participants were classified as obese (body mass index 30 kg/m²), and 10.9% had DM (according to medical history) Inclusion criteria: outpatients aged 18 years or over with essential hypertension Exclusion criteria: not reported
Interventions	RAS inhibitor: aliskiren; thiazide: HCTZ Aliskiren 150 mg 300 mg daily HCTZ 12.5 mg 25 mg daily Amlodipine was added when needed
Outcomes	Mean sitting DBP and SBP were measured by a mercury sphygmomanometer.
Notes
*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 with the use of a validated system that automates the random assignment of patients to randomization numbers."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization data were kept strictly confidential until the time of unblinding."
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	Outcomes listed in the methods were all reported
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low

Methods	Allocation: alternative allocation Blinding: double‐blinded Duration: 1 year Funding: this study was supported by Institut de Recherches Internationales, (IRIS) France
Participants	Diagnosis: DBP 95 mmHg‐115 mmHg. N = 100 Age: Perindopril group 54.3 ± 7.3 years; Atenolol group 56.5 ± 6.9 years Sex: 88% women; 12% men History: duration of hypertension was 8.2 ± 6.2 years and 99% of participants were on previous treatment.Duration of diabetes was 6.6 ± 5.4 years. Proteinuria was present in 40% of participants. Fundal changes consisting of hypertensive and diabetic retinopathy were present in 60% of participants Inclusion criteria: T2DM with hypertension and DBP 95 mmHg‐115 mmHg Exclusion criteria: albuminuria < 200 mg/min (300 mg in 24 hours) or macroalbuminuria > 3.5 g/24 hours; severe complications of hypertension such as stroke, HF, renal failure; severe diabetic retinopathy (neovascularization, vitreous hemorrhages or retinal detachment); contraindications to beta‐blockers or ACE inhibitors; people with poor metabolic control; and women with childbearing potential
Interventions	RAS inhibitor: perindopril; beta‐blocker: atenolol Perindopril 4 mg, 8 mg daily Atenolol 50 mg, 100 mg daily HCTZ, nifedipine were added when needed
Outcomes	Pulse rate and sitting and standing BP evaluated within 12 hours post administration at each review visit. BP determined by taking a mean of 3 readings with the Dinamap (Criticon, Johnson and Johnson) apparatus with the participant seated after 5 min rest
Notes	There were no participants of European origin as the hospital serves only black and Indian people. Black people were excluded because they do not respond well to ACE inhibitors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation was not described
Allocation concealment (selection bias)	High risk	Alternative allocation
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Method of blinding was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	All the pre‐specified outcomes in the methods were reported
Other bias	Unclear risk	Insufficient information was found to evaluate the risk as either high or low

Methods	Allocation: randomized. Computer‐generated random sequence centrally prepared by sponsor Blinding: double‐blinded (patients and clinicians) Duration: 4 ‐ 6 years, 4.2 ± 1.2 years (means ± SD) Funding: Novartis for design (interactively), data management, data analysis
Participants	Diagnosis: hypertension defined as a mean sitting SBP between 160 mmHg ‐ 210 mmHg (inclusive), and a mean sitting DBP of < 115 mmHg N = 15,245: valsartan group 7649; amlodipine group 7596 Age: 50 years or older Sex: 42% women, 58% men Antihypertensive medication taken at time of randomization: Previously treated for hypertension: valsartan group 7088 (92.7%); amlodipine group 6989 (92.0%) ACE inhibitor: valsartan group 3148 (41.3%); amlodipine group 3135 (41.4%) Angiotensin‐receptor blocker: valsartan group 812 (10.7%); amlodipine group 800 (10.6%) Alpha‐blockers: valsartan group 540 (7.1%); amlodipine group 495 (6.5%) Beta‐blockers: valsartan group 2496 (32.7%); amlodipine group 2551 (33.7%) Calcium‐channel antagonist: valsartan group 3181 (41.7%); amlodipine group 3048 (40.2%) Diuretics as monotherapy: valsartan group 2047 (26.9%); amlodipine group 2020 (26.7%) Fixed‐dose diuretic combinations: valsartan group 686 (9.0%); amlodipine group 634 (8.4%) Qualifying disease factors: Coronary heart disease: valsartan group 3490 (45.6%); amlodipine group 3491 (46.0%) Peripheral arterial disease: valsartan group 1052 (13.8%); amlodipine group 1062 (14.0%) Stroke or TIA: valsartan group 1513 (19.8%); amlodipine group 1501 (19.8%) LVH with strain pattern: valsartan group 454 (5.9%); amlodipine group 462 (6.1%) Inclusion criteria: men or women of any racial background, 50 years of age and older, with CV risk factors or disease according to an algorithm based on age and sex Exclusion criteria: renal artery stenosis; pregnancy; acute MI; percutaneous trans luminal coronary angioplasty or coronary artery bypass graft within the past 3 months; clinically relevant valvular disease; cerebrovascular accident in the past 3 months; severe hepatic disease; severe chronic renal failure; CHF requiring ACE inhibitor therapy; monotherapy with beta‐blockers for both coronary artery disease and hypertension
Interventions	RAS inhibitor: valsartan; CCB: amlodipine Valsartan 80 mg, median 151.7 mg, range 83.2 mg‐158.5 mg Amlodipine 5 mg, median 8.5 mg, range 5.0 mg‐9.9 mg
Outcomes	Time to first cardiac event (a composite of sudden cardiac death, fatal MI, death during or after percutaneous coronary intervention or coronary artery bypass graft, death due to HF, and death associated with recent MI on autopsy, HF requiring hospital management, non‐fatal MI, or emergency procedures to prevent MI) Pre‐specified secondary endpoints were fatal and non‐fatal MI, fatal and non‐fatal HF, and fatal and non‐fatal stroke All‐cause mortality and new‐onset DM SBP, DBP
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated
Allocation concealment (selection bias)	Low risk	Computer‐generated random sequence centrally prepared by sponsor
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blinded
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quoted: "A statistician on the executive committee independently analyzed data to validate and further explore the analyses done by statisticians employed by the sponsor." And "An endpoint committee, blinded to therapy allocation, reviewed the clinical records of all CV events reported by clinical centers and adjudicated according to the protocol criteria."
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Missing data were unlikely to have an impact on the results of the trial
Selective reporting (reporting bias)	Low risk	Outcomes listed in the methods were all reported
Other bias	High risk	Quoted: "The proportion of patients receiving valsartan monotherapy as the last recorded study medication was significantly smaller than that of patients receiving amlodipine monotherapy, and a larger proportion of patients in the valsartan group received the highest dose of study drug plus hydrochlorothiazide or plus other antihypertensive drugs than in the amlodipine group." Reviewer comment: the proportion of monotherapy and highest dose (include HCTZ and other non‐study add‐on drugs) was not balanced between the 2 groups

PERMALINK

First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension

Yu Jie Chen

Liang Jin Li

Wen Lu Tang

Jia Yang Song

Ru Qiu

Qian Li

Hao Xue

James M Wright

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Comparators

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

1.

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. RAS inhibitors compared to CCBs for hypertension.

Summary of findings 2. RAS inhibitors compared to thiazides for hypertension.

Summary of findings 3. RAS inhibitors compared to beta‐blockers for hypertension.

First‐line RAS inhibitors versus first‐line CCBs

1.3. Analysis.

1.5. Analysis.

1.1. Analysis.

1.2. Analysis.

1.4. Analysis.

1.6. Analysis.

1.7. Analysis.

1.8. Analysis.

1.9. Analysis.

First‐line RAS inhibitors versus first‐line thiazides

2.3. Analysis.

2.5. Analysis.

Study	Reason for exclusion
AASK 2002	Mortality and morbidity data were not reported in a form that could be extracted and entered
ANBP2 2003	Not double‐blinded trial; study used PROBE (prospective, randomized, open‐label design, with blinded assessments of end points) design
Materson 1993	The outcome of this study was BP control rate, so we could not extract relevant data
Okin 2012	Outcomes were grouped and analyzed according to blood potassium. We have no available data to extract associated with different medications
Peng 2015	This study included participants with high risk of hypertension but excluded people diagnosed as hypertensive
Preston 1998	The study focused on choice of an initial antihypertensive agent by using renin profile methods versus age‐race methods. There were no available data for this review