Low-Dose Antihypertensive Combinations
More Effective Than Standard Doses Of Fewer Drugs
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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