By: Thomas Pickering, MD, DPhil, FRCP, Director of Integrative and Behavioral Cardiology Program
of the Cardiovascular Institute at Mount Sinai School of Medicine, New York.

This article is a follow-up to our report entitled NIH stops part of a study using Cardura (doxazosin).

One of the major issues in the treatment of hypertension is the question whether the different types of blood pressure-lowering medications are equally good at lowering the risks of strokes and heart disease. Some studies have suggested that as long as the blood pressure is brought down, it makes no difference which drugs are used to do it. Others have indicated that there may be good or bad effects that are independent of the drug’s effects on blood pressure. Several large studies are now under way to compare the effects of different classes of blood pressure lowering drugs on the prevention of these complications of hypertension. The biggest is called ALLHAT (for Antihypertensive and Lipid-Lowering Treatment to Prevent Heart attack Trial), which is being conducted in the US by the National Institutes of Health, and is investigating the effects of both blood pressure and lipid-lowering drugs. The four drugs to which the 42,000 participants are randomly allocated are: a diuretic (chlorthalidone - the 'gold standard’ against which the newer drugs are being compared); a calcium channel blocker (amlodipine, or Norvasc); an ACE inhibitor (lisinopril, or Zestril); and an alpha blocker (doxazosin, or Cardura).

Although the study is not yet complete, it was set up so that interim analyses could be made to see how things were going. It has been found that the 9,000 patients allocated to the doxazosin group have not done as well as the 15,000 patients taking the diuretic. After just over three years in the study, the rates of cardiovascular complications (including strokes and heart attacks) was 25% higher in the doxazosin group as in the diuretic group, and the risk of developing heart failure was twice as high in the doxazosin group. The death rates, however, were the same in the two groups. The investigators also looked to see if the difference between the two drugs was the same in different sub-groups of patients- those above versus those below the age of 65, blacks versus non-blacks, and diabetics versus non-diabetics. In each sub-group, the risk was higher for doxazosin than for the diuretic.

The blood pressure was 2-3 mm Hg higher throughout the study in the group given doxazosin than the diuretic group.

As a result of this finding, the NIH decided to stop the doxazosin group from continuing in the trial.

Doctor’s comments

This is the first study to test the effects of an alpha blocker in the prevention of the complications of hypertension. Earlier studies have shown that diuretics and beta blockers are more effective than a placebo (equivalent to no treatment) in this respect, and so the diuretics and beta blockers are the standard treatment against which all the newer classes of drugs are being compared. The main finding of this study was that the alpha blocker doxazosin was not as effective as the diuretic chlorthalidone in preventing the major complications of hypertension. The investigators concluded that the slightly higher blood pressure in the doxazosin group could not by itself account for the difference between the two drugs. Two possible explanations for the relative lack of protection from doxazosin are that it tends to cause fluid retention (one of the features of heart failure), and also causes a reflex activation of the beta-adrenergic component of the sympathetic nervous system (which drives the heart faster and harder). The former can be prevented by combining the alpha blocker with a diuretic, and the latter by combining it with a beta blocker. In the ALLHAT study, however, the doxazosin group were not allowed to be taking a diuretic.

So what are the implications of the study? The main message is that doxazosin is not a good choice for a 'first line' drug to be used to lower blood pressure on its own, and in fact few doctors do this. There is, however, no reason to suggest that the drug should be withdrawn, or that everyone who is taking it in combination with other drugs (particularly diuretics) should stop taking it. It remains a very useful addition to other drugs for getting the blood pressure down to the target level, and the trend is to use combination drugs more and more.

Where it was published