Continued Debate About "Benefit Beyond Blood Pressure Control"

Linda Brookes, MSc


June 12, 2007

Any time the results of a trial of cardiovascular disease patients who are enrolled with hypertension are presented, the debate begins as to whether any observed benefit was due to the antihypertensive effect of the therapy or to some "benefit beyond blood pressure control." The debate about the extra benefits purportedly associated with certain class(es) of antihypertensive medications was further elaborated at the 2007 American College of Cardiology (ACC) meeting in a presentation by William J. Elliott, MD, PhD (Rush Medical College, Chicago, Illinois), who reported that the latest results from an ongoing meta-analysis suggest that successful lowering of blood pressure may be more important in preventing myocardial infarction (MI) than the initial drug selected.[1]

Lowering blood pressure with drug therapy has been shown to prevent MI, but it has been suggested that calcium channel blockers (CCBs) or angiotensin receptor blockers (ARBs) are less effective in preventing a first MI (or coronary heart disease) than angiotensin-converting enzyme (ACE) inhibitors. Drs. Elliott and Meyer believe that this question has been incompletely addressed by traditional meta-analyses and they use network meta-analysis, which allows the relative effectiveness of 2 treatments to be assessed when they have not been compared directly in a randomized trial but have each been compared with other treatments.[2] The technique allows estimation of both heterogeneity in the effect of any given treatment and inconsistency (incoherence) in the evidence from different pairs of treatments.

The first network analysis by Psaty and colleagues,[3] involving > 190,000 patients enrolled in 42 clinical trials, suggested that all antihypertensive drugs significantly prevented MI better than placebo, but none were superior to one another. Drs. Elliott and Meyer updated this analysis to compare the relative effectiveness on prevention of a first MI of 5 classes of drugs with placebo or no treatment ("placebo"). The analysis was limited to studies that enrolled > 50% of patients with hypertension (≥ 140/90 mm Hg or taking antihypertensive drugs at baseline) and involved a total of 160 treatment arms and over > 22,000 events in > 400,000 patients ( Table 1 ).

Network meta-analysis showed that every drug class was statistically significantly better than placebo in preventing a first MI, although incoherence (which has no relation to P values) was high ( Table 2 ).

Three of the trials with ARBs in heart failure patients included many patients who did not have hypertension at randomization: the Candesartan in Heart Failure -- Assessment of Mortality and morbidity (CHARM) trial, Valsartan in Acute Myocardial Infarction Trial (VALIANT), and Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) trial. Repeat analysis omitting these 3 trials showed an ARB having a nonsignificant 8% decrease in MI, whereas all the other drug classes remained significantly effective compared with placebo ( Table 3 ). However, there was no significant difference between the ARB and the diuretic. "So the good news is that compared with standard therapy in the United States, the ARB is not significantly worse, but not significantly better than placebo," Dr. Elliott concluded.

The "take-home message" from these data, according to Dr. Elliott, is that successful lowering of blood pressure could be more important to prevent MI than the initial drug selected. "That is the opinion of our European colleagues and their guidelines; it is the opinion of the British and their guidelines, but not the opinion of the US guidelines where we still believe in the primacy of the less expensive diuretic," he said. Asked what was wrong with using a drug that is the least expensive and as effective, Dr. Elliott replied, "I presume that that is the American way and is therefore not wrong."

Dr. Elliott recently reported the results of a similar network analysis suggesting that all antihypertensive drug classes also significantly prevent stroke, and that an initial CCB is slightly, but not significantly, more effective than an initial diuretic.[4]


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