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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

Rapid Response:

Balancing efficacy and side effects in hypertensive treatment

In their unprecedented study of 354 randomised blood pressure studies
1, Wald and colleagues have highlighted important issues regarding
combination treatment of hypertension that they fail to exploit. This
merits discussion irrespective of the basic integrity of the headline news
generated from their index paper 2.

The British Hypertension Society has published updated guidelines
highlighting combination therapy using the ‘ABCD’ rule to treat young, old
and black hypertensive subjects more effectively 3. But how does the data
from Wald’s study square up against these peer-reviewed guidelines?

The low prevalence of adverse events documented by Wald is not
typical of usual practice and clearly reflects study bias. The majority of
55,695 study subjects would have entered a run-in phase prior to
randomisation to test their tolerance to the therapy under investigation.
Consequently only those who identified side effects later in the study
would be included in the final analysis.

A study by Bloom et al 4 examined prescriptions for sole anti-
hypertensive therapy in 21,723 patients and reported the proportion of
patients who continued their treatment for one year (irrespective of the
reason). 64% and 58 % of patients continued angiotensin II receptor
antagonists (AIIRAs) and ACE inhibitor therapies respectively. Only 50% of
calcium channel blockers (CCBs) and 38% thiazide scripts were continued.
Wald et al’s analysis of adverse events represented as a proportion of
standard dose reinforces this evidence particularly as both ACE inhibitor
and ARIIA therapies are tolerated well irrespective of the dose. CCBs and
thiazides reveal a steep positive relationship between adverse events and

The efficacy of each class of agents in Wald’s paper is population-
based rather than race/age-specific. Standard doses reveal a treated-
placebo systolic blood pressure reduction of 8.5-10.3 mmHg. Half standard
doses for thiazide therapy, b-blockers and AIIRAs were more efficacious
with a mean reduction of 7.4-7.8 mmHg compared to ACE inhibitors and CCBs
(6.9 and 5.9 mmHg respectively).

Wald’s paper of blood pressure studies should not be dismissed
outright. His paper suggests that ACE inhibitors and AIIRAs doses can be
safely increased for their maximum effect while the addition of half-dose
thiazide therapy (ie bendrofluazide 1.25 mg daily) provides efficacious
but almost side effect-free treatment. Physicians will always need to
balance the efficacy of treatment against its side effect profile in
individual patients, but using therapies that patients do not tolerate are
not effective.

1. Wald NJ, Law MR, Morris JK, Jordan RE. Value of low dose
combination treatment with blood pressure lowering drugs: analysis of 354
randomised trials British Medical Journal 2003;326:1427

2. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by
more than 80%. British Medical Journal 2003;326:1419

3. Brown MJ, Cruickshank JK, Dominiczak AF et al. Better blood
pressure control: how to combine drugs. J Hum Hypertens. 2003;17(2):81-6

4. Bloom BS. Continuation of initial antihypertensive medication
after 1 year of therapy. Clin Ther. 1998;20(4):671-81.

Competing interests:  
None declared

Competing interests: No competing interests

04 July 2003
Adrian G Stanley
Clinical Lecturer in Medicine
Philip Swales
Department of Medicine and Therapeutics, University of Leicester. LE2 7LX