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.
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.
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.
To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in people with hypertension.
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.
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.
Two authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.
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.