Elsevier

The Lancet

Volume 353, Issue 9169, 12 June 1999, Pages 2008-2013
The Lancet

Articles
Optimisation of antihypertensive treatment by crossover rotation of four major classes

https://doi.org/10.1016/S0140-6736(98)07614-4Get rights and content

Summary

Background

Most comparisons of antihypertensive drugs aee undertaken in parallel groups. We undertook a crossover rotation of the four main classes of antihypertensive drugs, in untreated young hypertensive patients, to assess the response rate with monotherapy achieved by a systematic rotation.

Methods

56 patients, mean blood pressure 161/98 mm Hg, entered the rotation, of whom 36 received all four monthly cycles of treatment with an angiotensin-converting-enzyme (ACE) inhibitor (A), β-blocker (B), calcium-channel blocker (C), and diuretic (D). Each patient's best drug was then repeated to assess repeatability. Two measures of individual variability in response were used. First, the value of rotation was measured by the increased proportion of patients reaching target blood pressure on their best drug versus their first drug. Second, we assessed whether the responses to each drug were correlated with each other.

Findings

Significant variability in response was found. 20 of the 41 patients reaching target blood pressure (<140/90 mm Hg) failed to achieve this target on their first drug. Rotation increased from 22/56 (39%) to 41/56 (73%) the success of monotherapy (p=0·0001); in half the patients, blood-pressure on the best treatment was 135/85 mm Hg or less. There were significant correlations between the blood pressure responses to A and B (r=0·5, p<0·01), and C and D (r=0·6, p<0·001), but not between the other four pairings of treatments. The responses to the AB pair were, on average, at least 50% higher than those to the CD pair; this difference was highly significant by multivariate repeated-measures ANOVA.

Interpretation

There is a marked variability in hypertensive patients' response to different antihypertensive drugs. The basis may be underlying variability in types of essential hypertension. Optimisation of treatment requires systematic rotation through several therapies; however, an “AB/CD” rule is proposed in which one of each of the two pairs of treatments is initially selected to abbreviate the rotation in routine practice.

Introduction

Most studies of antihypertensive agents in unselected patients with essential hypertension have emphasised the similarity of the average response to the different drug groups,1 despite the widely differing mechanisms of action. However, essential hypertension is a heterogeneous disorder, and it would be surprising if the variable pathogenesis did not cause detectable variability in individual responses to the different agents. A few investigators have observed such variability during crossover studies,2, 3, 4, 5, 6, 7 and systematic rotation through each class has been suggested as the most logical, if laborious, approach to treatment.8, 9 However, to our knowledge no prospective rotation study of the four main classes of antihypertensive drugs has previously been done.

Our study was of young hypertensive patients, in whom it was safe to have a wash-out period between each drug. Our main question was whether, and by how much, a systematic rotation of patients through the four drug classes would increase the proportion of patients reaching target and normal blood pressure. Changes in response rate were measured by comparing response to first and response to best drug for each patient. Our secondary aims were to find out whether a patient's best drug could be predicted by a range of baseline measurements and whether inter-individual variability in response was itself quantifiable.

A logistic obstacle to a four-way crossover study is that of masking. However, in a study concerned solely with individual responses to each drug, there is no systematic bias to be avoided and an open-label study has the advantage of testing a scheme for treatment initiation that could be readily adapted for routine practice.

Section snippets

Study design and participants

A four-way, open-label, crossover study, approved by the local research ethics committee, was done in 56 white patients from the East Anglia region of the UK, aged 22–51 years, with previously untreated essential hypertension. All patients gave written informed consent. Routine screening was followed by a 7-month rotation phase in which patients received sequentially each of the four main drug groups, angiotensin-converting-enzyme (ACE) inhibition (A), β-blockade (B), diuretic (D), and

Patients

36 men and 20 women were recruited. Their mean supine blood pressure, at the start of treatment, was 161/98 mm Hg (SD 12/8).

Calcium-channel blockade and ACE inhibition were not contraindicated for any patients; 13 patients were excluded from receiving β-blockade and three from receiving diuretic therapy. 40 patients were eligible for, and 36 completed, all four cycles.

Mean blood pressure for all patients at the first visit and the three subsequent wash-out phases are shown in table 2. The

Discussion

We found significant variability in the response of most patients to the four main classes of antihypertensive agent. This variability was such that only a minority of patients were likely to receive their best drug first, or to reach a conventional target for blood-pressure treatment, without the process of systematic rotation. By contrast, such a target or better was reproducibly achieved in most patients on at least one treatment during rotation. With our predefined assessment of good

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