Issue 167 Item 6 Low-Dose Antihypertensive Combinations More Effective Than Stan

Using three antihypertensive drugs in a low-dose combination may reduce the risk of stroke by two thirds and ischemic heart disease (IHD) events by half, according to an estimate by British researchers.

Systolic blood pressure reductions of 10 mm Hg or diastolic blood pressure reductions of 5 mm Hg are known to reduce the risk of stroke by about one third and that of IHD events by about one fourth in persons aged 65 years or older. However, the most appropriate drugs and regimens for achieving this are unclear.

Malcolm R. Law, MSc, from Queen Mary’s School of Medicine and Dentistry, University of London, United Kingdom, and colleagues conducted a meta-analysis of 354 randomized, double-blind, placebo-controlled trials of the five antihypertensive drug classes — thiazides, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers.

They determined the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and IHD events according to dose, both when drugs were used alone and in combination.

A total of 40,000 treated patients and 16,000 patients taking placebo were included in the analysis. The researchers calculated reductions in systolic and diastolic blood pressure and prevalence of adverse effects according to dose.

"All five categories of drug produced similar reductions in blood pressure," the researchers report. 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 at half standard dose (20% lower than at full dose). The drugs reduced blood pressure from all pre-treatment blood pressure levels, but especially in those with higher pre-treatment levels.

The effects of different classes of drugs were additive, and in many cases, symptoms were strongly related to dose. However, the prevalence of adverse events with two drugs in combination was not additive, and adverse metabolic effects were negligible at half standard dose.

"Combinations of two or three drugs at low dose are…preferable to one or two drugs at standard dose," Dr. Law and colleagues note. "Everyone at increased risk would benefit from using three drugs, apart from those with contraindications to a particular drug."

The researchers conclude that based on 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."

Two of the researchers (Drs. Law and Wald) have filed a patent application on the formula of a combined pill to simultaneously reduce four cardiovascular risk factors. BMJ 2003;326:7404:1427.

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