Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials

Abstract

Objective: To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination.

Design: Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose.

Subjects: 40,000 treated patients and 16,000 patients given placebo.

Main outcome measures: Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs.

Results: All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, beta blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose.

Conclusions: Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.

Fig 1

Average reductions in systolic blood pressure (adjusted for the change in the placebo group; with 95% confidence intervals) according to category of drug and dose as a proportion of standard (designated 1), from the results of 354 randomised trials, with the best fitting line. ACE=angiotensin converting enzyme

Fig 2

Average reduction in blood pressure (adjusted for the change in the placebo group; with 95% confidence intervals) according to the usual pretreatment blood pressure, from the results of 354 randomised trials, with the best fitting line

Fig 3

Trials testing two blood pressure lowering drugs separately and in combination: observed placebo adjusted reduction in systolic blood pressure (treated minus placebo) with two drugs used in combination plotted against the expected reduction in blood pressure from adding the reductions produced by each drug alone. The area of each symbol is inversely proportional to the variance in the trial it represents. Adapted from Law et al

Fig 4

—Proportions of people reporting one or more symptoms attributable to treatment (treated minus placebo; with 95% confidence interval) according to category of drug and dose as a proportion of standard (designated 1). ACE=angiotensin converting enzyme