BMJ 2003;326:1427 (28 June), doi:10.1136/bmj.326.7404.1427
Paper
Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials
M R Law, professor1,
N J Wald, professor1,
J K Morris, senior lecturer1,
R E Jordan, research assistant1
1 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
Correspondence to: M R Law
m.r.law{at}qmul.ac.uk
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,
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,
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.

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