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BackgroundWe conducted a systematic review of evidence from randomized controlled trials to answer the following research question: What are the relative effects of different classes of antihypertensive drugs in reducing the incidence of cardiovascular disease outcomes for healthy people at risk of cardiovascular disease?MethodsWe searched MEDLINE, EMBASE, AMED (up to February 2011) and CENTRAL (up to May 2009), and reference lists in recent systematic reviews. Titles and abstracts were assessed for relevance and those potentially fulfilling our inclusion criteria were then assessed in full text. Two reviewers made independent assessments at each step. We selected the following main outcomes: total mortality, myocardial infarction and stroke. We also report on angina, heart failure and incidence of diabetes. We conducted a multiple treatments meta-analysis using random-effects models. We assessed the quality of the evidence using the GRADE-instrument.ResultsWe included 25 trials. Overall, the results were mixed, with few significant dif-ferences, and with no drug-class standing out as superior across multiple outcomes. The only significant finding for total mortality based on moderate to high quality evidence was that beta-blockers (atenolol) were inferior to angiotensin receptor blockers (ARB) (relative risk (RR) 1.14; 95% credibility interval (CrI) 1.02 to 1.28). Angiotensin converting enzyme (ACE)-inhibitors came out inferior to calcium-channel blockers (CCB) regarding stroke-risk (RR 1.19; 1.03 to 1.38), but superior regarding risk of heart failure (RR 0.82; 0.69 to 0.94), both based on moderate quality evidence. Diuretics reduced the risk of myocardial infarction compared to beta-blockers (RR 0.82; 0.68 to 0.98), and lowered the risk of heart failure compared to CCB (RR 0.73; 0.62 to 0.84), beta-blockers (RR 0.73; 0.54 to 0.96), and alpha-blockers (RR 0.51; 0.40 to 0.64). The risk of diabetes increased with diuretics compared to ACE-inhibitors (RR 1.43; 1.12 to 1.83) and CCB (RR 1.27; 1.05 to 1.57).ConclusionBased on the available evidence, there seems to be little or no difference between commonly used blood pressure lowering medications for primary prevention of cardiovascular disease. Beta-blockers (atenolol) and alpha-blockers may not be first-choice drugs as they were the only drug-classes that were not significantly superior to any other, for any outcomes.Review registration: CRD database ("PROSPERO") CRD42011001066

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From 1977 to 1982 screening for cardiovascular disease was performed in three Norwegian counties. All those aged between 40 and 54 years were invited, of whom 23,690 men and 23,425 women (90%) attended. Smoking habits and previous cardiovascular disease were recorded; total cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), triglycerides and blood pressure were measured. During subsequent follow-up (mean 6.8 years) 422 men and 54 women died from coronary heart disease, 514 and 114 from all cardiovascular diseases and 983 and 404 from all causes, men and women respectively. For men, mortality decreased with increasing HDL cholesterol, to a minimum of around 1.5 mmol.l-1 (58 mg.dl-1), whereafter mortality increased. This applies to coronary, cardiovascular and all causes of death, as well as to men with and without a history of disease. The association between mortality and HDL cholesterol in healthy men disappeared when total cholesterol was below 6.5 mmol.l-1 (251 mg.dl-1). The inverse association between mortality and HDL cholesterol in women was somewhat stronger than in men, both for coronary and cardiovascular diseases. The relative risks of coronary death, associated with an increase in HDL cholesterol of 0.5 mmol.l-1 (19 mg.dl-1), from the Cox proportional hazards regression, with other major cardiovascular risk factors as covariates, were 0.8 (95% confidence interval: 0.6, 1.0) and 0.8 (0.7, 1.0) for men with and without history of disease, respectively. Corresponding figures for women were 0.5 (0.3, 0.9) and 0.7 (0.4, 1.3).

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