Chicago, IL - Results of a prespecified subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial show that in both black and nonblack high-risk hypertensives, patients treated first with an ACE inhibitor or calcium-channel blocker did not have lower rates of coronary heart disease events—or any other prespecified end point—compared with patients treated with the thiazide-type diuretic chlorthalidone and that treatment with the diuretic resulted in the lowest rate of heart failure, the researchers write.

The report appears in the April 6, 2005 issue of the Journal of the American Medical Association.[1]

"While the improved outcomes with chlorthalidone were more pronounced for some outcomes in blacks than in nonblacks, thiazide-type diuretics remain the drugs of choice for initial therapy of hypertension in both black and nonblack hypertensive patients," the ALLHAT investigators, with first author Dr Jackson T Wright Jr (Case Western Reserve University, Cleveland, OH), conclude.

"The bottom line is whether you break it down by race or not, diuretics remain unsurpassed as the agent to initiate antihypertensive therapy," Wright told heartwire. "Certainly in black participants, the benefit of a diuretic as first-line therapy is exaggerated, especially compared with ACE inhibitors."

The ALLHAT trial compared three treatment arms—amlodipine, a calcium-channel blocker; lisinopril, an ACE inhibitor; and doxazosin, an alpha-adrenergic blocker—with chlorthalidone treatment in more than 40 000 high-risk patients with hypertension and at least one other risk factor. The doxazosin arm was discontinued early because of excess events vs the diuretic. The main results of ALLHAT were published in 2002 and showed that on the primary outcome of combined fatal coronary heart disease (CHD) or nonfatal MI, there was no significant difference between the three groups.[2] However, there was an advantage for the diuretic in some outcomes: notably, diuretics were superior to both the ACE inhibitor and calcium-channel blocker in preventing heart failure and more effective than the alpha blocker and the ACE inhibitor in preventing stroke and the composite of cardiovascular disease outcomes.

The researchers concluded that, based on these findings and the lower overall cost, diuretics should be considered the first choice for first-line therapy—a conclusion that has caused and continues to cause some controversy in the hypertension field.

While some results broken down by race were reported in the original ALLHAT publication, Wright said the current paper provides more detail on these analyses in black vs nonblack participants and includes some new analyses.

On the primary outcome, similar to the overall results, they found no difference in either racial group between treatment arms.

For the comparison of amlodipine vs chlorthalidone, heart failure was the only outcome that differed significantly, with no difference in the treatment effects by race.

For lisinopril vs chlorthalidone, the ACE inhibitor was less effective in reducing systolic blood pressure than the diuretic, particularly in black participants, as well as in reducing stroke and combined cardiovascular outcomes. There was also less heart failure with chlorthalidone, although with no significant interaction by race.

Lisinopril was not as well tolerated as chlorthalidone, Wright added, and had a substantially greater risk of angioedema. Even in nonblack subjects where there was no difference in BP lowering between the agents, ACE inhibitors did not prevent cardiovascular or renal outcomes compared with diuretics and were "certainly less effective in preventing heart failure," he added. "This occurs despite modest differences in glucose and lipid parameters," he noted, both of which increased with diuretic treatment.

[The long-term implications of increases particularly of glucose with diuretics have been the subject of debate in the hypertension community, as reported previously by heartwire.]

"Thiazide-type diuretics still represent the optimal first-line therapy for treating the vast majority of hypertensives," Wright concluded. For black patients who cannot take diuretics, probably a calcium-channel blocker should be recommended over the ACE inhibitor, he said. He added, though, that these conclusions relate to the first drug used, "realizing that most patients will require at least three or four medications to control their blood pressure and get to recommended goals."

In an editorial accompanying the publication, Drs James D Neaton (University of Minnesota, Minneapolis) and Lewis H Kuller (University of Pittsburgh, PA) conclude, "After many years of research, the ALLHAT study has shown that diuretic therapy is highly efficacious in reducing the risk of CVD among both blacks and nonblacks."[3] They point out that with respect to the black population, the ALLHAT trial had more events than most trials had participants.

"It is now time to move beyond comparisons of diuretics with other classes of BP-lowering drugs—that issue is settled," Neaton and Kuller write. "Determining how to lower BP to more optimal levels (eg, 120/80 mm Hg) in the most cost-effective manner and in the populations at risk is the new priority."

More research is needed on nutritional hygienic approaches to prevent hypertension and supplement the effects of drugs, they note. It is also important to "continually recognize that reducing the risk of vascular disease (especially CHD) involves control of multiple risk factors to achieve maximum success. The findings of this important study have provided many ideas for the design of the next generation of trials—the children of ALLHAT."