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


METHODS
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.


METHODS
40,000 treated patients and 16,000 patients given placebo.


METHODS
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.
Law
M R
MR
Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London EC1M 6BQ. m.r.law@qmul.ac.uk
Wald
N J
NJ
Morris
J K
JK
Jordan
R E
RE
D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects*; D004311:Double-Blind Method; D004338:Drug Combinations; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000517:prevention & control; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000517:prevention & control; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D004338:Drug Combinations