First‐line drugs inhibiting the renin angiotensin system versus other first‐line antihypertensive drug classes for hypertension
Abstract
Background
Renin‐angiotensin system (RAS) inhibitors are widely prescribed for treatment of hypertension, especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for hypertension in both diabetic and non‐diabetic patients, 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 patients with hypertension.
Search methods
We searched the Cochrane Hypertension Group's Specialised Register, MEDLINE, MEDLINE In‐Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to November 19, 2014 and the Cochrane Central Register of Controlled Trials (CENTRAL) up to October 19, 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Cochrane Hypertension Group's Specialised Register.
Selection criteria
We included randomized, active‐controlled, double‐blinded studies with at least six months follow‐up in people with primary 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. Patients with proven secondary hypertension were excluded.
Data collection and analysis
Two authors independently selected the included trials, evaluated the risk of bias and entered the data for analysis.
Main results
We included 42 studies, involving 65,733 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large studies at a low risk of bias 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 hospitalization, total cardiovascular (CV) events (consisted of fatal and non‐fatal stroke, fatal and non‐fatal MI and fatal and non‐fatal CHF requiring hospitalizations), and 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 quality evidence that first‐line RAS inhibitors decreased heart failure (HF) (35,143 participants in 5 RCTs, RR 0.83, 95% CI 0.77 to 0.90, ARR 1.2%), and moderate quality evidence that they increased stroke (34,673 participants in 4 RCTs, RR 1.19, 95% CI 1.08 to 1.32, ARI 0.7%). They had similar effects on all‐cause death (35,226 participants in 5 RCTs, RR 1.03, 95% CI 0.98 to 1.09; moderate quality evidence), total CV events (35,223 participants in 6 RCTs, RR 0.98, 95% CI 0.93 to 1.02; moderate quality evidence), total MI (35,043 participants in 5 RCTs, RR 1.01, 95% CI 0.93 to 1.09; moderate quality evidence). The results for ESRF do not exclude potentially important differences (19,551 participants in 4 RCTs, RR 0.88, 95% CI 0.74 to 1.05; low quality evidence).
Compared with first‐line thiazides, we found moderate quality 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%). They had similar effects on all‐cause death (24,309 participants in 1 RCT, RR 1.00, 95% CI 0.94 to 1.07; moderate quality evidence), total CV events (24,379 participants in 2 RCTs, RR 1.05, 95% CI 1.00 to 1.11; moderate quality evidence), and total MI (24,379 participants in 2 RCTs, RR 0.93, 95% CI 0.86 to 1.01; moderate quality evidence). Results for ESRF do not exclude potentially important differences (24,309 participants in 1 RCT, RR 1.10, 95% CI 0.88 to 1.37; low quality evidence).
Compared with first‐line beta‐blockers, we found low quality evidence 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 low quality evidence that they decreased stroke (9193 participants in 1 RCT, RR 0.75, 95% CI 0.63 to 0.88, ARR 1.7% ). Our analyses do not exclude potentially important differences between first‐line RAS inhibitors and beta‐blockers on all‐cause death (9193 participants in 1 RCT, RR 0.89, 95% CI 0.78 to 1.01; low quality evidence), HF (9193 participants in 1 RCT, RR 0.95, 95% CI 0.76 to 1.18; low quality evidence), and total MI (9239 participants in 2 RCTs, RR 1.05, 95% CI 0.86 to 1.27; low quality evidence).
Blood pressure comparisons between RAS inhibitors and other classes showed either no differences or small differences that did not necessarily correlate with the differences in the morbidity outcomes.
In the protocol, we identified non‐fatal serious adverse events (SAE) as a primary outcome. However, when we extracted the data from included studies, none of them reported total SAE in a manner that could be used in the review. Therefore, there is no information about SAE in the review.
Authors' conclusions
We found predominantly moderate quality evidence that all‐cause mortality is similar when first‐line RAS inhibitors are compared to other first‐line antihypertensive agents. First‐line thiazides caused less HF and stroke than first‐line RAS inhibitors. The quality of the evidence comparing first‐line beta‐blockers and first‐line RAS inhibitors was low and the lower risk of total CV events and stroke seen with RAS inhibitors may change with the publication of additional trials. Compared with first‐line CCBs, first‐line RAS inhibitors reduced HF but increased stroke. The magnitude of the reduction in HF exceeded the increase in stroke. The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes.
PICOs
Plain language summary
Renin‐angiotensin system inhibitors versus other types of medicine for hypertension
What is hypertension?
Hypertension is a long‐lasting medical condition in which a person's blood pressure is high. Hypertension can contribute to other health problems such as heart disease, stroke, and kidney problems, and so reduces quality of life.
What medicines can be used to treat hypertension?
There are a number of types of medicines that can be used to treat hypertension. These include three types of renin‐angiotensin system (RAS) inhibitors: angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors. Other types of medicine include thiazide diuretics, beta‐blockers, and calcium channel blockers (CCBs).
The first medicine that a person is prescribed for treating hypertension is called the 'first‐line' medicine. Frequently, over time, other medicines are added to this in an attempt to reduce blood pressure in the long‐term.
The purpose of this research
Researchers from the Cochrane Collaboration tried to determine how RAS inhibitors compare 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.
What this research discovered
The researchers searched the medical literature up to November 2014 to identify all the relevant medical research. They identified a total of 42 medical studies that had included a total of 65,733 participants, with an average age of 66 years.
Nine of these studies did not include people who had suffered heart attacks or strokes, but 14 studies did include them if the heart attack or stroke had happened more than three or six months before the study began. Twelve studies included diabetic participants, and seven included people with kidney problems.
Twenty‐six of the 42 studies were sponsored by pharmaceutical companies that manufactured the medicines being studied. The researchers did not investigate how this might have affected the results.
The results of the research showed moderate quality evidence that:
1. thiazides caused less heart failure and stroke than RAS inhibitors;
2. RAS inhibitors caused less heart failure but more stroke than CCBs, however the reduction in heart failure was considerably bigger than the increase in stroke.
Less robust results showed that RAS inhibitors reduced heart attacks and stroke compared to beta‐blockers.
The different medicines produced small differences in effect on blood pressure, but these did not seem to be related to the number of heart attacks, strokes and kidney problems.
More trials are needed to strengthen the findings of this review.
Authors' conclusions
Summary of findings
| RAS inhibitors compared to CCBs for hypertension | |||||||
| Patient or population: people with hypertension | |||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | ||
| Assumed risk | Corresponding risk | ||||||
| CCBs | RAS inhibitors | ||||||
| All‐cause death | 124 per 1000 | 127 per 1000 | RR 1.03 | 35226 | ⊕⊕⊕⊝ | ||
| Total cardiovascular events | 178 per 1000 | 174 per 1000 | RR 0.98 | 35223 | ⊕⊕⊕⊝ | ||
| Total heart failure | 72 per 1000 | 60 per 1000 | RR 0.83 | 35143 | ⊕⊕⊕⊝ | RAS inhibitors decrease death or hospitalization for HF by 1.2% NNTB = 83 | |
| Total myocardial infarction | 68 per 1000 | 69 per 1000 | RR 1.01 | 35043 | ⊕⊕⊕⊝ | ||
| Total stroke | 39 per 1000 | 46 per 1000 | RR 1.19 | 34673 | ⊕⊕⊕⊝ | RAS inhibitors increase stroke by 0.7% NNTH = 143 | |
| End stage renal failure | 25 per 1000 | 22 per 1000 | RR 0.88 | 19551 | ⊕⊕⊝⊝ | ||
| *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). | |||||||
| GRADE Working Group grades of evidence | |||||||
| 1. Some of the included trials were judged to be of high risk of bias. Removing the studies with high risk of bias did not to alter the results (see Discussion) 2. The confidence intervals are wide and include a clinically important benefit | |||||||
| RAS inhibitors compared to thiazides for hypertension | ||||||
| Patient or population: people with hypertension | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Thiazides | RAS inhibitors | |||||
| All‐cause death Follow‐up: mean 4.9 years | 144 per 1000 | 144 per 1000 (135 to 154) | RR 1.00 (0.94 to 1.07) | 24309 (1) | ⊕⊕⊕⊝ | |
| Total cardiovascular events | 194 per 1000 | 204 per 1000 | RR 1.05 | 24379 | ⊕⊕⊕⊝ | |
| Total heart failure Follow‐up: mean 4.9 years | 57 per 1000 | 68 per 1000 (61 to 75) | RR 1.19 (1.07 to 1.31) | 24309 (1) | ⊕⊕⊕⊝ | RAS inhibitors increase death or hospitalization for HF by 1.1% NNTH = 91 |
| Total myocardial infarction | 93 per 1000 | 86 per 1000 | RR 0.93 | 24379 | ⊕⊕⊕⊝ | |
| Total stroke Follow‐up: mean 4.9 years | 44 per 1000 | 50 per 1000 (45 to 56) | RR 1.14 (1.02 to 1.28) | 24309 (1) | ⊕⊕⊕⊝ | RAS inhibitors increase stroke by 0.6% NNTH = 167 |
| End stage renal failure Follow‐up: mean 4.9 years | 13 per 1000 | 14 per 1000 (11 to 18) | RR 1.10 (0.88 to 1.37) | 24309 (1) | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Based on one large trial (ALLHAT 2002) | ||||||
| RAS inhibitors compared to beta‐blockers for hypertension | ||||||
| Patient or population: people with hypertension | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Β‐blockers | RAS inhibitors | |||||
| All cause death Follow‐up mean 4.8 years | 94 per 1000 | 84 per 1000 | RR 0.89 (0.78 to 1.01) | 9193 (1) | ⊕⊕⊝⊝ | |
| Total cardiovascular events | 143 per 1000 | 126 per 1000 | RR 0.88 | 9239 | ⊕⊕⊝⊝ | RAS inhibitors decrease total CV events by 1.7% NNTB = 59 |
| Total heart failure Follow‐up mean 4.8 years | 35 per 1000 | 33 per 1000 (27 to 41) | RR 0.95 (0.76 to 1.18) | 9193 (1) | ⊕⊕⊝⊝ | |
| Total myocardial infarction | 41 per 1000 | 43 per 1000 | RR 1.05 | 9239 | ⊕⊕⊝⊝ | |
| Total stroke Follow‐up mean 4.8 years | 67 per 1000 | 50 per 1000 (42 to 59) | RR 0.75 (0.63 to 0.88) | 9193 (1) | ⊕⊕⊝⊝ | RAS inhibitors decrease total stroke by 1.7% NNTB = 59 |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Based primarily on one moderate to large trial (LIFE 2002) | ||||||
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 patients 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 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 reduced the risk of CV mortality by 14.9% (P value 0.022), myocardial infarction (MI) by 20.8% (P value 0.002) and the need for invasive coronary revascularization by 14% (P value 0.015); but not all‐cause mortality (risk ratio (RR) 0.913, 95% confidence intervals (CI) 0.825 to 1.011; Saha 2008). A Cochrane systematic 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 disease (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 reduced the risk of all‐cause mortality 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 suggested 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 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 patients 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 patients, 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 patients with type 1 or type 2 diabetes or without diabetes. For patients 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 systematic review of RCTs compared any antihypertensive agent with placebo or another agent in hypertensive or normotensive patients 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 patients: 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 mortality. Compared to CCBs, ACE inhibitors significantly reduced progression to microalbuminuria (four trials,1210 patients: 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 anti‐hypertensive treatment in T2DM (three studies, 4423 participants) and examined clinical endpoints (all‐cause mortality, 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 anti‐hypertensive 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 value < 0.001, ARR 0.06 and NNTB 17), CV events (51% reduction, P value < 0.001, ARR 8% and NNTB 13), and all‐cause mortality (62% reduction, P value 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 value < 0.05 versus CCBs; P value < 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 mortality).
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 diabetic patients on the basis of postulated advantages with regard to 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 in terms of clinically relevant outcomes (especially all‐cause mortality and morbidity, renal and CV outcomes) of RAS inhibitors compared to other antihypertensive drugs in patients with elevated blood pressure.
Objectives
To evaluate the benefits and harms of first‐line RAS inhibitors compared to other first‐line antihypertensive drugs in patients with hypertension.
Methods
Criteria for considering studies for this review
Types of studies
Study design must meet the following criteria:
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RCTs with parallel design;
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double‐blind;
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minimum follow‐up of six months.
Types of participants
Patients with primary elevated BP (that equals or exceeds 130/85 mmHg). This BP threshold, lower than the standard 140/90 mmHg, was chosen to include more people and to be consistent with the recommended lower targets for patients with hypertension and diabetes. People with proven secondary hypertension were excluded.
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.
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ARBs include: candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, and KT3‐671.
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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
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All‐cause mortality.
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All‐cause serious morbidity (non‐fatal serious adverse events).
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Total CV events:
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fatal and non‐fatal MI;
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fatal and non‐fatal stroke;
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fatal and non‐fatal CHF requiring hospitalizations.
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Renal outcomes:
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ESRF (defined as a requirement for maintenance dialysis).
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Secondary outcomes
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Change in or end‐point systolic and diastolic BP.
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Change in or end‐point heart rate.
Search methods for identification of studies
Electronic searches
We searched the following databases for primary studies: the Cochrane Hypertension's Group Specialised Register (all years to November 19, 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (all years to October 19, 2014), Ovid MEDLINE (1946 to November 19, 2014), Ovid EMBASE (1974 to November 19, 2014) and ClinicalTrials.gov (all years to November 19, 2014). We searched the Database of Abstracts of Reviews of Effectiveness (DARE) for related reviews (all years to October 19, 2014).
The Hypertension Group Specialised Register includes controlled trials from searches of AGRICOLA, Allied and Complementary Medicine (AMED), BIOSIS, CAB Abstracts, CINAHL, CENTRAL, EMBASE, Food Science and Technology Abstracts (FSTA), Global Health, International Pharmaceutical Abstracts (IPA), LILACS, MEDLINE, ProQuest Dissertations & Theses, PsycINFO, SCIRUS, Web of Science and the World Health Organization's WHO International Clinical Trials Registry Platform (ICTRP).
Electronic databases were searched using a strategy combining a variation of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision; Lefebvre 2011), with selected MeSH terms and free text terms. No language restrictions were used. The MEDLINE search strategy (Appendix 1) was translated into CENTRAL (Appendix 2), EMBASE (Appendix 3) and the Hypertension Group Specialised Register (Appendix 4) using appropriate controlled vocabulary, as applicable.
Searching other resources
Other sources:
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International Clinical Trials Registry Platform (WHO ICTRP);
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reference lists of all papers and relevant reviews identified;
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contact with authors of relevant papers regarding any further published or unpublished work;
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contact with authors of trials reporting incomplete information to request the missing information.
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 pre‐specified inclusion criteria. We searched the bibliographies of pertinent articles, reviews and texts for additional relevant citations. Two independent reviewers assessed the eligibility of the trials using a study selection form. A third reviewer 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 reviewers independently extracted data using a standard form, and then cross‐checked. 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):
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sequence generation;
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allocation concealment;
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blinding or objective assessment of primary outcomes;
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incomplete outcome data;
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selective outcome reporting;
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other biases.
The overall risk of bias was used in the GRADE assessment (Grading of Recommendations Assessment, Development and Evaluation) in the 'Summary of findings' table. GRADE assessment was done 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 risk ratio (RR) with 95% confidence intervals (CI). For combining continuous variables (SBP, DBP and HR), we used weighted mean difference (with 95% CI), whereby the studies are weighted according to the number of subjects in the study and the within‐study variance.
Dealing with missing data
If the included studies had missing information, we contacted investigators (using email, letter and/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:
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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;
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SD at the end of treatment;
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SD at baseline;
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weighted mean SD of change calculated from at least three other trials using the same dose regimen;
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weighted mean SD of change calculated from other trials using any dose.
Assessment of heterogeneity
We tested heterogeneity between studies using the Chi2 test, where P values less than 0.1 indicated significant 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 .
Subgroup analysis and investigation of heterogeneity
Where appropriate, we performed the following subgroup analyses.
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Heterogeneity among participants could be related to:
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gender;
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age;
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presence of diabetes at initiation of antihypertensive treatment (time of trial entry);
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baseline blood pressure;
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previous renal disease;
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previous CV disease.
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Heterogeneity in treatments could be related to:
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dose of drugs;
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duration of therapy.
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Sensitivity analysis
We tested the robustness of the results using several sensitivity analyses, including:
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trials that were industry‐sponsored versus non‐industry sponsored;
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trials with reported standard deviations of effect change versus imputed standard deviations;
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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
The search strategy identified 10,145 citations (Figure 1). We performed full‐text assessment of 87 potentially eligible studies and identified 42 eligible trials (83 citations) that we included in the review.
PRISMA Study flow diagram
Included studies
The 42 included studies involved 65,733 participants with a mean age of 66 years. Participants in eight studies were under 50 years old (Buus 2004; Buus 2007; Dahlöf 1993; Pedersen 1997; Schiffrin 1994; Sørensen 1998; Tarnow 1999; Zeltner 2008); in 21 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; Tedesco 1999; TOHMS 1993); and over 60 years old in the remaining 13 studies (ALLHAT 2002; Devereux 2001; Fogari 2012; Gerritsen 1998; Hajjar 2013; Hayoz 2012; Himmelmann 1996; LIFE 2002; Ostman 1998; Ruggenenti 2004; 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 24,976; while 5472 received beta‐blockers, 18,928 CCBs, 16,034 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 16 for beta‐blockers, 21 for CCBs ‐ within which there were two studies that used non‐dihydropyridine (Gottdiener 1998; Ruggenenti 2004), and nineteen studies that used dihydropyridine, 9 for thiazides, 3 for alpha‐blockers, and 1 for CNS active drugs.
The majority of the included studies were industry‐sponsored (26/42). Diabetic participants were involved in 12 studies; participants with decreased renal function in seven studies; and seven studies contained participants with at least one risk factor for CV diseases. Only male patients were included in three studies (Dahlöf 1993; Gottdiener 1998; Schiffrin 1994). One study included only female participants as it focused on postmenopausal women (Hayoz 2012). All 83 included citations were published in English with publication years ranging from 1993 to 2014.
Most participants (29 studies) were recruited from European countries; seven studies included participants from North America; besides, two studies included participants from North America, Europe, and Asia (Dahlöf 2002 and VALUE 2004); one study included participants from North America, South America, Europe, Asia and Australia (IDNT 2001); one study included participants from North America and Europe (LIFE 2002); the Devereux 2001 trial included participants from Europe and Asia; and the Seedat 1998 included participants from South Africa. Fourteen of the 42 included studies reported ethnicity; the percentages of 'Caucasian', Hispanic, Asian, Black and other race participants were 71.0%, 0.3%, 1.7%, 23.7% and 3.3%, respectively.
In terms of baseline co‐morbidities, 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 they had not occurred within the previous three or six months); the other 19 studies made no clear statement, but in general the proportion of participants without cardiac‐cerebral vascular co‐morbidities was high. Overall, this review represents treatment effects for primary prevention.
A stepwise therapeutic regimen was used in 32 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 ten 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).
With regard to the clinical classification of hypertension (see ESH/ESC 2013), we classified mean blood pressure of participants at the baseline of studies into two groups: 28 studies included Grade 1 hypertensive patients (systolic blood pressure (SBP): 140 mmHg‐159 mmHg); 13 studies included Grade 2 hypertensive patients (SBP: 160 mmHg‐179 mmHg). Baseline untreated mean BP was 156/89 mmHg (SBP/diastolic blood pressure (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 pre‐specified inclusion criteria led to us excluding four of the 87 citations. 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 42 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 34 studies the risk of bias for this domain was unclear. We assessed three of the 42 studies as being at low risk for allocation concealment, one study as being at high risk, and 38 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 alternative 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 42 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 36 studies. We thought that unblinded assessment of outcomes like MI, stroke, heart failure (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 37 of the 42 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 part of all participants) in the analysis. Pedersen 1997 and Tarnow 1999 had many subjects 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 40 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
Six 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.
Effects of interventions
See: 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
Compared with CCBs, RAS inhibitors decreased HF (5 RCTs, RR 0.83, 95% CI 0.77 to 0.90; Analysis 1.3), and increased stroke (4 RCTs, RR 1.19, 95% CI 1.08 to 1.32; Analysis 1.5), but were not significantly different for all‐cause death (5 RCTs, RR 1.03, 95% CI 0.98 to 1.09; Analysis 1.1), total CV events (6 RCTs, RR 0.98, 95% CI 0.93 to 1.02; Analysis 1.2), total MI (5 RCTs, RR 1.01, 95% CI 0.93 to 1.09; Analysis 1.4), and ESRF (4 RCTs, RR 0.88, 95% CI 0.74 to 1.05; Analysis 1.6). CCBs lowered SBP and DBP to a greater degree than RAS inhibitors (SBP: 19 RCTs, WMD 1.20, 95% CI 0.86 to 1.53; Analysis 1.7; DBP: 19 RCTs, WMD 0.97, 95% CI 0.77 to 1.16; Analysis 1.8). There was no difference in the effect of CCBs and RAS inhibitors on HR (5 RCTs, WMD 0.30, 95% CI ‐1.63 to 2.22; Analysis 1.9).
First‐line RAS inhibitors versus first‐line thiazides
Compared with thiazides, RAS inhibitors increased HF (1 RCT, RR 1.19, 95% CI 1.07 to 1.31; Analysis 2.3), and increased stroke (1 RCT, RR 1.14, 95% CI 1.02 to 1.28; Analysis 2.5), but were not significantly different for all‐cause death (1 RCT, RR 1.00, 95% CI 0.94 to 1.07; Analysis 2.1), total CV events (2 RCTs, RR 1.05, 95% CI 1.00 to 1.11; Analysis 2.2), total MI (2 RCTs, RR 0.93, 95% CI 0.86 to 1.01; Analysis 2.4), and ESRF (1 RCT, RR 1.10, 95% CI 0.88 to 1.37; Analysis 2.6). Thiazides lowered SBP to a greater degree than RAS inhibitors (9 RCTs, WMD 1.56, 95% CI 1.16 to 1.96; Analysis 2.7), but had much the same effect as RAS inhibitors on DBP (8 RCTs, WMD ‐0.15, 95% CI ‐0.40 to 0.10; Analysis 2.8). There was also no difference in the effect on HR, but only two small trials reported this outcome (2 RCTs, WMD 0.66, 95% CI ‐2.87 to 4.19; Analysis 2.9).
First‐line RAS inhibitors versus first‐line beta‐blockers
Compared with beta‐blockers, RAS inhibitors decreased total CV events (2 RCTs, RR 0.88, 95% CI 0.80 to 0.98; Analysis 3.2) and decreased stroke (1 RCT, RR 0.75, 95% CI 0.63 to 0.88; Analysis 3.5). Beta‐blockers and RAS inhibitors were not significantly different for all‐cause death (1 RCT, RR 0.89, 95% CI 0.78 to 1.01; Analysis 3.1), HF (1 RCT, RR 0.95, 95% CI 0.76 to 1.18; Analysis 3.3), or MI (2 RCTs, RR 1.05, 95% CI 0.86 to 1.27; Analysis 3.4). The effect on ESRF could not be assessed because there was only one small trial that examined this outcome (1 RCT, RR 0.33, 95% CI 0.01 to 7.78; Analysis 3.6). Beta‐blockers lowered DBP and HR more than RAS inhibitors (DBP: 15 RCTs, WMD 0.52, 95% CI 0.17 to 0.87; Analysis 3.8; HR: 9 RCTs, WMD 6.06, 95% CI 5.60 to 6.51; Analysis 3.9). The effect on SBP did not differ between the two classes of drug (15 RCTs, WMD ‐0.49, 95% CI ‐1.16 to 0.18; Analysis 3.7).
First‐line RAS inhibitors versus first‐line alpha‐blockers
RAS inhibitors lowered SBP more than alpha‐blockers did (3 small RCTs, WMD ‐2.38, 95% CI ‐3.98 to ‐0.78; Analysis 4.1); but did not differ in their effect on DBP and HR (DBP 3 small RCTs, WMD ‐0.12, 95% CI ‐1.09 to 0.85; Analysis 4.2; HR: 1 small RCT, WMD 3.10, 95% CI ‐2.41 to 8.61; Analysis 4.3).
First‐line RAS inhibitors versus first‐line CNS active drugs
When compared with CNS active drugs in one small trial, RAS inhibitors did not differ in their effect on SBP (1 RCT, WMD 1.30, 95% CI ‐6.01 to 8.61; Analysis 5.1), DBP (1 RCT, WMD ‐0.30, 95% CI ‐1.85 to 1.25; Analysis 5.2), or HR (1 RCT, WMD 1.50, 95% CI ‐4.13 to 7.13; Analysis 5.3).
Subgroup analysis and investigation of heterogeneity
In this review, when the result was significant and the value of I² was greater than 50%, we tested whether the result was still significant using the random‐effects model. However, in presenting the data we use the fixed‐effect model, as it weights the contributing trials more appropriately.
In an attempt to explore the heterogeneity of RAS inhibitors versus CCBs on HF (I² of 68%) we analyzed the trials according to whether or not the participants had decreased renal function. In those with decreased renal function the RR was 0.55, 95% CI 0.43 to 0.70 without heterogeneity (Dalla 2004; IDNT 2001); while in those without decreased renal function the RR was 0.87, 95% CI 0.80 to 0.95 without heterogeneity (ALLHAT 2002; Estacio 1998; VALUE 2004). Subgroup analysis has provided a possible explanation for the variation of effect sizes across the studies. The magnitude of the effect of RAS inhibitors for decreasing HF, when compared to CCBs, was greater in hypertensive patients with kidney dysfunction than in those with normal renal function.
The key results on the clinically important outcomes and grading of the evidence quality are presented in the 'Summary of findings tables', which were created by using the software GRADEpro 3.6. (Atkins 2004) (summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3) These tables show the absolute effects as well as the relative effects.
Discussion
Summary of main results
Compared with first‐line CCBs, first‐line RAS inhibitors reduce death or hospitalizations for HF, increase fatal and non‐fatal stroke, and are similar for all‐cause death, total CV events and ESRF events. Compared with first‐line thiazides, first‐line RAS inhibitors increase death or hospitalizations for HF and increase fatal and non‐fatal stroke. RAS inhibitors are similar to thiazides for all‐cause death, total CV events, fatal and non‐fatal MI and ESRF events. Compared with first‐line beta‐blockers, first‐line RAS inhibitors reduce total CV events and fatal and non‐fatal stroke and are similar for all‐cause death, HF, MI and ESRF. There were no RCTs that compared first‐line RAS inhibitors with any other classes of drugs that reported mortality and morbidity outcomes.
These results demonstrate that first‐line RAS inhibitors are inferior to first‐line thiazides, because RAS inhibitors increase both death and hospitalizations for HF and fatal and non‐fatal stroke events compared to thiazides.
The results also make it clear that first‐line RAS inhibitors are a better first‐line choice than first‐line beta‐blockers for hypertension, confirming the conclusions of two Cochrane reviews (Wright 2009; Wiysonge 2012). The results also suggest that first‐line RAS inhibitors are a better choice than first‐line CCBs, because the absolute reduction in death or hospitalizations for HF of 1.2% found with RAS inhibitors is greater than the increase in fatal and non‐fatal stroke of 0.7%. These findings confirm and extend the findings of the Cochrane review of first‐line CCBs versus other classes of drugs (Chen 2010).
For the blood pressure and heart rate outcomes, the small, but statistically significant, greater reduction in SBP of 1.5 mmHg with first‐line thiazides compared to RAS inhibitors could have contributed to the improved outcomes with first‐line thiazides, but is unlikely to be the only explanation. The fact that BP is not the only explanation is demonstrated by the fact that first‐line beta‐blockers, which lowered HR and diastolic BP more than first‐line RAS inhibitors, had worse morbidity outcomes.
Overall completeness and applicability of evidence
The number of trials and participants contributing to the three main comparisons in this review provide sufficient evidence regarding the outcomes that are important to patients to make first‐line thiazides the optimal first‐line drug for hypertension and to make RAS inhibitors the optimal second‐line choice for hypertension. This result is based on moderate quality evidence demonstrating that first‐line thiazides decrease HF and stroke by about 1.7% over 4.9 years when compared to first‐line RAS inhibitors, meaning that for every 59 people treated for five years one event can be prevented. First‐line RAS inhibitors are the best second‐line drug according to moderate quality evidence that first‐line RAS inhibitors reduce stroke by 1.7% compared to beta‐blockers and decrease overall CV events by 0.5% compared to CCBs, due to the reduction in HF events.
The evidence in this review is mostly relevant to primary prevention patients, but also is relevant to patients with hypertension and co‐morbidities such as T2DM, left ventricular hypertrophy, or diabetic nephropathy. It is important to note that for hypertensive patients with diabetes, JNC‐8 2014 has recommended changing the target BP for diabetic patients from 130/80 mmHg to 140/90 mmHg. The recommended target BP for diabetic patients is still 130/80 mmHg according to CPG 2013 and 140/80 mmHg according to ADA 2013.
It is also worth mentioning that the mortality and morbidity comparison involved predominately ACE inhibitors versus thiazides (ALLHAT 2002) and ARBs versus beta‐blockers (LIFE 2002). The comparison with CCBs involved both ACE inhibitors and ARBs. Subgroup comparisons based on either ACE inhibitors or ARBs compared to CCBs showed that the results were similar for HF and stroke. In addition, it is important to note that in 11 of 16 studies using beta‐blockers, atenolol was the study drug, so that it is possible that the worse outcomes seen with beta‐blockers are limited to atenolol.
Sensitivity analysis
In this review, we used several analyses to test the robustness of the results. The specific sensitivity analyses done are described below.
Studies with reported standard deviations (SDs) of effect change versus those with imputed SDs
In this review, three studies did not report a within‐study variance for change of BP and SDs were imputed using the weighted mean SD from other trials (Esnault 2008; Fogari 2012; Roman 1998). When these three trials were excluded from the analysis, the BP estimates were not changed significantly.
Studies that have a high risk of bias versus those with a low risk of bias
We judged four of the included studies that contributed data to the primary outcomes analyses were at a high risk of 'other' bias (Estacio 1998; IDNT 2001; LIFE 2002; VALUE 2004). Three of these four studies compared RAS inhibitors with CCBs; their high risk of bias resulted from an unbalanced proportion of monotherapy and use of higher doses in one of the two treatment groups in the VALUE 2004 study, an unbalanced proportion of monotherapy in the Estacio 1998 study, and many authors receiving research grants form Bristol‐Myers Squibb in the IDNT 2001 study. When these three studies were excluded from the analysis, the results did not change significantly. Another high risk trial was funded and conducted by Merck (LIFE 2002), but because the comparisons related to this trial only included itself, we could not perform a sensitivity analysis. In terms of the secondary outcomes, SBP, DBP and HR, when the studies with a high risk of other bias were excluded from the analysis (Pedersen 1997; Roman 1998), the results did not change significantly.
Potential biases in the review process
One potential bias that deserves attention is combination medication. For most long‐term and large‐scale studies, it is impossible to maintain single first‐line drug treatment, as a single drug frequently does not lower the BP to a level considered to be low enough. In most cases in the included studies, physicians were permitted to add other non‐study drugs to reach the target BP. In these cases, it is hoped that the add‐on drugs were balanced between the different treatment groups and, therefore, that any differences in outcomes were due to the first‐line drugs. The fact that only double‐blinded trials were included in this review decreases this possible bias, however, there was no way of verifying that that was the case in all the trials. A potential limitation of this review is the possibility that there are differences in the effect of ACE inhibitors and ARBs on morbidity and mortality. This would have to be answered by specific head‐to‐head RCTs comparing the subclasses of drugs that inhibit the renin angiotensin system.
Unfortunately, there were not enough trials contributing to the primary outcomes to allow us to assess for publication bias. The BP and HR estimates are not a good reflection of the BP lowering capacity of the first‐line drug, as other drugs could be added. Therefore the small statistically significant differences in BP lowering cannot be entirely attributed to the first‐line drug. They may be representative of real differences in BP‐lowering capacity, but other systematic reviews specifically designed to assess BP will be needed to confirm these results.
Agreements and disagreements with other studies or reviews
The results of comparison between RAS inhibitors and CCBs fully agreed with those in the Chen 2010 Cochrane systematic review for the outcomes of MI, stroke, HF, CV events, and all‐cause death, as well as SBP and DBP. Likewise, the results in this review for RAS inhibitors compared with beta‐blockers are similar to those reported by another review, Wiysonge 2012, for morbidity and mortality outcomes.
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
Comparison 1 RAS inhibitors vs CCBs, Outcome 1 All‐cause death.
Comparison 1 RAS inhibitors vs CCBs, Outcome 2 Total CV events.
Comparison 1 RAS inhibitors vs CCBs, Outcome 3 Total HF.
Comparison 1 RAS inhibitors vs CCBs, Outcome 4 Total MI.
Comparison 1 RAS inhibitors vs CCBs, Outcome 5 Total stroke.
Comparison 1 RAS inhibitors vs CCBs, Outcome 6 ESRF.
Comparison 1 RAS inhibitors vs CCBs, Outcome 7 SBP.
Comparison 1 RAS inhibitors vs CCBs, Outcome 8 DBP.
Comparison 1 RAS inhibitors vs CCBs, Outcome 9 HR.
Comparison 2 RAS inhibitors vs thiazides, Outcome 1 All‐cause death.
Comparison 2 RAS inhibitors vs thiazides, Outcome 2 Total CV events.
Comparison 2 RAS inhibitors vs thiazides, Outcome 3 Total HF.
Comparison 2 RAS inhibitors vs thiazides, Outcome 4 Total MI.
Comparison 2 RAS inhibitors vs thiazides, Outcome 5 Total stroke.
Comparison 2 RAS inhibitors vs thiazides, Outcome 6 ESRF.
Comparison 2 RAS inhibitors vs thiazides, Outcome 7 SBP.
Comparison 2 RAS inhibitors vs thiazides, Outcome 8 DBP.
Comparison 2 RAS inhibitors vs thiazides, Outcome 9 HR.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 1 All‐cause death.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 2 Total CV events.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 3 Total HF.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 4 Total MI.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 5 Total stroke.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 6 ESRF.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 7 SBP.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 8 DBP.
Comparison 3 RAS inhibitors vs beta‐blockers (β‐blockers), Outcome 9 HR.
Comparison 4 RAS inhibitors vs alpha‐blockers (α‐blockers), Outcome 1 SBP.
Comparison 4 RAS inhibitors vs alpha‐blockers (α‐blockers), Outcome 2 DBP.
Comparison 4 RAS inhibitors vs alpha‐blockers (α‐blockers), Outcome 3 HR.
Comparison 5 RAS inhibitors vs CNS active drug, Outcome 1 SBP.
Comparison 5 RAS inhibitors vs CNS active drug, Outcome 2 DBP.
Comparison 5 RAS inhibitors vs CNS active drug, Outcome 3 HR.
| RAS inhibitors compared to CCBs for hypertension | |||||||
| Patient or population: people with hypertension | |||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | ||
| Assumed risk | Corresponding risk | ||||||
| CCBs | RAS inhibitors | ||||||
| All‐cause death | 124 per 1000 | 127 per 1000 | RR 1.03 | 35226 | ⊕⊕⊕⊝ | ||
| Total cardiovascular events | 178 per 1000 | 174 per 1000 | RR 0.98 | 35223 | ⊕⊕⊕⊝ | ||
| Total heart failure | 72 per 1000 | 60 per 1000 | RR 0.83 | 35143 | ⊕⊕⊕⊝ | RAS inhibitors decrease death or hospitalization for HF by 1.2% NNTB = 83 | |
| Total myocardial infarction | 68 per 1000 | 69 per 1000 | RR 1.01 | 35043 | ⊕⊕⊕⊝ | ||
| Total stroke | 39 per 1000 | 46 per 1000 | RR 1.19 | 34673 | ⊕⊕⊕⊝ | RAS inhibitors increase stroke by 0.7% NNTH = 143 | |
| End stage renal failure | 25 per 1000 | 22 per 1000 | RR 0.88 | 19551 | ⊕⊕⊝⊝ | ||
| *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). | |||||||
| GRADE Working Group grades of evidence | |||||||
| 1. Some of the included trials were judged to be of high risk of bias. Removing the studies with high risk of bias did not to alter the results (see Discussion) 2. The confidence intervals are wide and include a clinically important benefit | |||||||
| RAS inhibitors compared to thiazides for hypertension | ||||||
| Patient or population: people with hypertension | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Thiazides | RAS inhibitors | |||||
| All‐cause death Follow‐up: mean 4.9 years | 144 per 1000 | 144 per 1000 (135 to 154) | RR 1.00 (0.94 to 1.07) | 24309 (1) | ⊕⊕⊕⊝ | |
| Total cardiovascular events | 194 per 1000 | 204 per 1000 | RR 1.05 | 24379 | ⊕⊕⊕⊝ | |
| Total heart failure Follow‐up: mean 4.9 years | 57 per 1000 | 68 per 1000 (61 to 75) | RR 1.19 (1.07 to 1.31) | 24309 (1) | ⊕⊕⊕⊝ | RAS inhibitors increase death or hospitalization for HF by 1.1% NNTH = 91 |
| Total myocardial infarction | 93 per 1000 | 86 per 1000 | RR 0.93 | 24379 | ⊕⊕⊕⊝ | |
| Total stroke Follow‐up: mean 4.9 years | 44 per 1000 | 50 per 1000 (45 to 56) | RR 1.14 (1.02 to 1.28) | 24309 (1) | ⊕⊕⊕⊝ | RAS inhibitors increase stroke by 0.6% NNTH = 167 |
| End stage renal failure Follow‐up: mean 4.9 years | 13 per 1000 | 14 per 1000 (11 to 18) | RR 1.10 (0.88 to 1.37) | 24309 (1) | ⊕⊕⊝⊝ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1. Based on one large trial (ALLHAT 2002) | ||||||
| RAS inhibitors compared to beta‐blockers for hypertension | ||||||
| Patient or population: people with hypertension | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Β‐blockers | RAS inhibitors | |||||
| All cause death Follow‐up mean 4.8 years | 94 per 1000 | 84 per 1000 | RR 0.89 (0.78 to 1.01) | 9193 (1) | ⊕⊕⊝⊝ | |
| Total cardiovascular events | 143 per 1000 | 126 per 1000 | RR 0.88 | 9239 | ⊕⊕⊝⊝ | RAS inhibitors decrease total CV events by 1.7% NNTB = 59 |
| Total heart failure Follow‐up mean 4.8 years | 35 per 1000 | 33 per 1000 (27 to 41) | RR 0.95 (0.76 to 1.18) | 9193 (1) | ⊕⊕⊝⊝ | |
| Total myocardial infarction | 41 per 1000 | 43 per 1000 | RR 1.05 | 9239 | ⊕⊕⊝⊝ | |
| Total stroke Follow‐up mean 4.8 years | 67 per 1000 | 50 per 1000 (42 to 59) | RR 0.75 (0.63 to 0.88) | 9193 (1) | ⊕⊕⊝⊝ | RAS inhibitors decrease total stroke by 1.7% NNTB = 59 |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Based primarily on one moderate to large trial (LIFE 2002) | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 All‐cause death Show forest plot | 5 | 35226 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.98, 1.09] |
| 2 Total CV events Show forest plot | 6 | 35223 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.93, 1.02] |
| 3 Total HF Show forest plot | 5 | 35143 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.83 [0.77, 0.90] |
| 4 Total MI Show forest plot | 5 | 35043 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.93, 1.09] |
| 5 Total stroke Show forest plot | 4 | 34673 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [1.08, 1.32] |
| 6 ESRF Show forest plot | 4 | 19551 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.74, 1.05] |
| 7 SBP Show forest plot | 19 | 36210 | Mean Difference (IV, Fixed, 95% CI) | 1.20 [0.86, 1.53] |
| 8 DBP Show forest plot | 19 | 36210 | Mean Difference (IV, Fixed, 95% CI) | 0.97 [0.77, 1.16] |
| 9 HR Show forest plot | 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 Show forest plot | 1 | 24309 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.94, 1.07] |
| 2 Total CV events Show forest plot | 2 | 24379 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [1.00, 1.11] |
| 3 Total HF Show forest plot | 1 | 24309 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.19 [1.07, 1.31] |
| 4 Total MI Show forest plot | 2 | 24379 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.86, 1.01] |
| 5 Total stroke Show forest plot | 1 | 24309 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [1.02, 1.28] |
| 6 ESRF Show forest plot | 1 | 24309 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.88, 1.37] |
| 7 SBP Show forest plot | 9 | 25817 | Mean Difference (IV, Fixed, 95% CI) | 1.56 [1.16, 1.96] |
| 8 DBP Show forest plot | 8 | 25770 | Mean Difference (IV, Fixed, 95% CI) | ‐0.15 [‐0.40, 0.10] |
| 9 HR Show forest plot | 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 Show forest plot | 1 | 9193 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.78, 1.01] |
| 2 Total CV events Show forest plot | 2 | 9239 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.88 [0.80, 0.98] |
| 3 Total HF Show forest plot | 1 | 9193 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.95 [0.76, 1.18] |
| 4 Total MI Show forest plot | 2 | 9239 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.86, 1.27] |
| 5 Total stroke Show forest plot | 1 | 9193 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.75 [0.63, 0.88] |
| 6 ESRF Show forest plot | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.01, 7.78] |
| 7 SBP Show forest plot | 15 | 10805 | Mean Difference (IV, Fixed, 95% CI) | ‐0.49 [‐1.16, 0.18] |
| 8 DBP Show forest plot | 15 | 10805 | Mean Difference (IV, Fixed, 95% CI) | 0.52 [0.17, 0.87] |
| 9 HR Show forest plot | 9 | 9880 | Mean Difference (IV, Fixed, 95% CI) | 6.06 [5.60, 6.51] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 SBP Show forest plot | 3 | 380 | Mean Difference (IV, Fixed, 95% CI) | ‐2.38 [‐3.98, ‐0.78] |
| 2 DBP Show forest plot | 3 | 380 | Mean Difference (IV, Fixed, 95% CI) | ‐0.12 [‐1.09, 0.85] |
| 3 HR Show forest plot | 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 Show forest plot | 1 | 56 | Mean Difference (IV, Fixed, 95% CI) | 1.30 [‐6.01, 8.61] |
| 2 DBP Show forest plot | 1 | 56 | Mean Difference (IV, Fixed, 95% CI) | ‐0.30 [‐1.85, 1.25] |
| 3 HR Show forest plot | 1 | 56 | Mean Difference (IV, Fixed, 95% CI) | 1.5 [‐4.13, 7.13] |
