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

BMJ 2003; 326 doi: (Published 26 June 2003) Cite this as: BMJ 2003;326:1427
  1. M R Law ({at}, professor1,
  2. N J Wald, professor1,
  3. J K Morris, senior lecturer1,
  4. R E Jordan, research assistant1
  1. 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
  1. Correspondence to: M R Law
  • Accepted 8 April 2003


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, β 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, β 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.


  • Embedded Image References to studies included and a table appear on

  • Contributors MRL and REJ abstracted the data, and JKM did the statistical analysis. All four authors interpreted the results and wrote the paper. MRL is the guarantor.

  • Funding None.

  • Competing interests NJW and MRL have filed a patent application on the formula of a combined pill to simultaneously reduce four cardiovascular risk factors.

  • Accepted 8 April 2003
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