Cleveland, OH - New findings from ALLHAT fail to support the preference for calcium blockers, alpha blockers, or ACE inhibitors compared with thiazide diuretics in patients with metabolic syndrome, despite their more favorable metabolic profiles [1]. Indeed, the lack of benefit of the agents with the most favorable metabolic profile (ACE inhibitors and alpha blockers) was especially marked in the black participants with metabolic syndrome.

The analysis of ALLHAT patients by metabolic-syndrome status and by race, published in the January 28, 2008 issue of the Archives of Internal Medicine, was conducted by a group led by Dr Jackson Wright (General Clinical Research Center, Cleveland, OH). Results show the same outcome as the main trial—no benefit in terms of cardiovascular-event reduction (and increases in some end points) with the calcium blocker amlodipine, the alpha blocker doxazosin, or the ACE inhibitor lisinopril as compared with the thiazide diuretic chlorthalidone.

Senior author of the paper, Dr Barry Davis (The University of Texas Health Science Center at Houston), commented to heartwire: "Even in patients with metabolic syndrome who have a whole spectrum of metabolic risk factors, these newer antihypertensives, with metabolic benefits compared with thiazide diuretics, were no better at reducing events than the diuretic. Therefore, the metabolic benefits of these newer agents are not being translated into a reduction in clinical outcomes." He added: "The two subgroups in which you might expect the most benefit from these newer agents are diabetics and the patients with metabolic syndrome. We have previously published the results in diabetics from ALLHAT, which also showed no benefit, and now we show the same thing in metabolic-syndrome patients."

The ALLHAT trial enrolled 42 418 men and women 55 years or older with hypertension and at least one additional risk factor for CHD who were randomized to therapy with chlorthalidone, amlodipine, lisinopril, or doxazosin. The doxazosin arm was stopped early because of a higher rate of cardiovascular events. The main results of the trial, reported in 2002, showed very similar rates of fatal CHD/nonfatal MI, the primary end point, with the other three agents, but better results in terms of secondary outcomes with the diuretic. Of note, the ACE inhibitor was significantly less effective in preventing several cardiovascular outcomes, particularly in black participants.

In the current paper, Wright et al note that half the ALLHAT patients met the definition for metabolic syndrome, and the results in this subgroup were very similar results to the main trial. While there were no differences among the four treatment groups for the primary end point, all three of the newer hypertensives showed significantly higher rates of heart failure compared with chlorthalidone in metabolic-syndrome patients, which were particularly marked for black patients.

Higher rates for combined cardiovascular disease (combined CHD, stroke, other treated angina, heart failure, or peripheral arterial disease) were observed with lisinopril and doxazosin as compared with chlorthalidone, which were again more marked in black patients.

Higher rates of stroke were seen with lisinopril and doxazosin vs chlorthalidone only in black participants.

In addition, black patients with metabolic syndrome also had higher rates of end-stage renal disease (ESRD) with lisinopril compared with chlorthalidone—RR 1.70 (95% CI 1.13-2.55).

The authors conclude that the findings by race and metabolic status parallel the findings in the entire cohort and in all other subgroup analyses from the trial. They write: "In no subgroup analysis from ALLHAT has the [calcium-channel blocker], the ACE inhibitor, or the alpha blocker been shown thus far to be more effective than the thiazide-type diuretic in preventing the primary outcome or any other major cardiovascular or renal outcome." While there was a lower rate of stroke in nonblack participants with metabolic syndrome assigned to amlodipine vs chlorthalidone, this was not seen in black patients with metabolic syndrome or in either subgroup without metabolic syndrome and did not translate into a lower rate of the composite CVD; given the number of comparisons and a statistical cutoff of p=0.05, the finding is likely due to chance, they add.

With regard to the particularly disappointing results with lisinopril in black patients with metabolic syndrome, they write: "The magnitude of the excess risk of ESRD (70%), heart failure (49%), and stroke (37%) and the increased risk of combined CVD and combined CHD strongly argue against the preference of ACE inhibitors over diuretics as the initial therapy in black patients with metabolic syndrome."

In a National Heart, Lung, and Blood Institute press release, director Dr Elizabeth Nabel said these new findings were important because "many doctors currently prescribe alpha blockers, calcium-channel blockers, and ACE inhibitors due to their more favorable short-term effects on blood sugar and blood cholesterol levels. However, this new analysis shows that diuretics are better at preventing cardiovascular disease and thus does not support the selection of the newer drugs over diuretics for preventing poor health outcomes related to hypertension or for lowering high blood pressure."