Published: February 2001

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Doxazosin and the ALLHAT study

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Prescriber Update 20: 31-32
February 2001

Medsafe Editorial Team

Medsafe has received notification from the American National Institutes of Health that one arm of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) has been stopped early.  The treatment arm containing the alpha-adrenoceptor blocker doxazosin has been found to be less effective than the diuretic chlorthalidone in reducing hypertensive heart failure.  The MARC advises that until there is better definition of this issue, it may be appropriate to avoid alpha-adrenoceptors in patients with hypertension if an alternative is available.  The situation is unclear in patients with benign prostatic hypertrophy where the use of doxazosin can result in significant improvement in symptoms and quality of life.

Doxazosin and chlorthalidone arm of study stopped early

In February 2000 the doxazosin (Cardoxan, Carduran and Dosan) arm of the ALLHAT trial was stopped early. ALLHAT is a randomised, double blind, active controlled trial in the USA and Canada, which began in February 1994. This trial is comparing treatment of hypertension with a diuretic (chlorthalidone) against newer types of antihypertensives - an alpha-adrenoceptor blocker (doxazosin), an ACE inhibitor, and a calcium antagonist - in a high-risk patient group (all over 55 years with one or more cardiovascular disease (CVD) risk factors). ¹

By January 2000, a total of 9067 subjects had been randomised to the doxazosin treatment arm and another 15268 to receive chlorthalidone. The mean age was 67 years and both groups had similar demographics and CVD baseline characteristics. Median follow up was 3.3 years. At baseline there was no difference in mean blood pressure (BP) between the 2 groups. Doses allowed were doxazosin 2, 4, or 8mg/day or chlorthalidone 12.5, 12.5, or 25 mg/day. Certain other antihypertensives were added if BP wasn't controlled on maximal doses of the study medicines.

No difference in rates of fatal CHD and nonfatal MI

Doxazosin gave similar results to chlorthalidone for the primary endpoint of fatal coronary heart disease (CHD) and nonfatal myocardial infarction (MI), and hence did not show superior efficacy over the diuretic. There was no difference in all-cause mortality.

Higher risk of CHF with doxazosin

However, subjects taking doxazosin had a 25% higher risk of the secondary endpoint of combined CVD events (ie. CHD death, nonfatal MI, stroke, revascularisation procedures, angina, congestive heart failure (CHF), and peripheral arterial disease). This excess in CVD events for doxazosin subjects could predominantly be accounted for by a doubled risk of CHF. The other significant finding was that doxazosin was less effective in controlling systolic BP by an average of 3mmHg. The study authors extrapolated that while this value may explain the increase in risk of angina and stroke of 16% and 19%, respectively, it could not fully account for the doubling of risk for CHF.

It is important to note that the findings may apply only to high-risk patients for CVD when given doxazosin as first-line treatment for hypertension. At year 3, over half of each group who were still taking their blinded medication, were taking the study medicines at maximal doses. Forty percent of the chlorthalidone group and 47% of the doxazosin group were also on second or third line agents to gain BP control. Further analysis of the data will undoubtedly follow.

This trial did not compare efficacy of doxazosin or chlorthalidone with placebo. Hence, as stated by the study authors, "it is difficult to judge whether in ALLHAT the CHF rate with doxazosin is the same as, less than, or more than would be expected without antihypertensive drug treatment."¹

MARC recommends caution with doxazosin in hypertension

The company has provided data that has been reviewed by the Medicines Adverse Reactions Committee (MARC). The MARC advises that until there is better definition of this issue, it may be appropriate to avoid alpha-adrenoceptors in patients with hypertension if an alternative is available. The situation is unclear in patients with benign prostatic hypertrophy where the use of doxazosin can result in significant improvement in symptoms and quality of life.

Reference

1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomised to doxazosin vs chlorthalidone. The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2000;283(15):1967-75.