Washington, DC - Beta blockers, once considered out of the question for patients with heart failure, today are a cornerstone of therapy. Vasodilators that are effectively used in hypertension might also seem risky for a syndrome in which low blood pressure (BP) is a predictor of poor outcome, so they are often avoided in patients with HF whose pressures are already down. But once again, what would seem clear about a drug therapy's risks has turned out quite differently in randomized trials.

A post hoc analysis of the African-American Heart-Failure Trial (A-HeFT) suggests that the significant clinical benefits of the fixed-dose vasodilator combination of isosorbide dinitrate and hydralazine (ISDN-H) (BiDil, NitroMed) weren't related to changes in BP [1]. The drugs lowered pressures that were above the median at baseline—but not those initially lower than the median—in the trial's black patients with chronic HF, and they significantly cut mortality and hospitalization rates for patients with either higher or lower BPs, report Dr Inder S Anand (University of Minnesota, Minneapolis) and associates in the January 2/9, 2007 issue of the Journal of the American College of Cardiology.

The analysis "challenges the belief that vasodilators are deleterious in patients with low systolic blood pressure," the group writes. "In fact, the data suggest that vasodilator therapy can usually be well tolerated by patients with severe HF, and that low blood pressure should not preclude a trial of these agents, which seem to offer a benefit to all patients."

Because patients with HF and low initial BP are more at risk than those with higher BP and show a comparable risk reduction from ISDN-H therapy, they continue, "patients with a low SBP would be expected to derive the greatest absolute benefit from this treatment."

This analysis should allay any concerns about instituting ISDN-H therapy in HF patients with low BP, Anand said to heartwire. "We hope by reading this [report] that physicians will have the confidence to use the drugs in these patients, because the overall benefit is much greater than any deleterious affects they may have."

As previously reported by heartwire, A-HeFT randomized 1050 self-identified African Americans with documented LV systolic dysfunction and predominantly NYHA class 3 HF to receive either ISDN-H or placebo along with state-of-the-art medical therapy [2]. Patients with a systolic BP "persistently" higher than 160 mm Hg or a diastolic pressure greater than 95 mm Hg were excluded, as were any with symptomatic hypotension. Over a mean of 10 months, ISDN-H was associated with a 43% drop in relative mortality risk and a 39% decrease in the relative risk of HF hospitalization. In the current analysis, the hazard ratio for mortality was 2.09 (95% CI 1.02-4.29) for patients with a baseline systolic BP no higher than the median of 126 mm Hg (p<0.05) compared with those with BPs above the median. The corresponding HR for mortality or first HF hospitalization was 1.66 (1.18-2.34) (p<0.01). The HRs were adjusted for demographics, LVEF, other measures of cardiac and renal function, comorbidities, drug therapies, and quality of life.

Mean systolic BP rose over three months among patients who initially had below-median BPs in both the ISDN-H and placebo groups. It fell in both groups among those with baseline BP higher than the median, but significantly more so (p=0.002) for patients who received ISDN-H. Actively treated patients with baseline systolic BP lower or higher than the median received ISDN-H at the same mean daily dosage level.

Regardless of treatment group, patients who started out with above-median systolic pressures had a slightly elevated mortality HR of 1.04 (1.00-1.08) (p<0.05); there was no such HR increase for the composite of death or first HF hospitalization. Systolic BP changes among those with baselines below the median showed no relationships to outcomes. Mortality and morbidity reductions seen with active therapy were independent of the drugs' effects on systolic BP for patients regardless of baseline pressure.

The findings are consistent with V-HeFT observations from the 1980s that ISDN-H, added to digoxin and diuretics in patients with HF, didn't lower BP but improved survival, observes Dr Marc A Pfeffer (Brigham and Women's Hospital, Boston, MA) in an accompanying editorial [3]. The V-HeFT trials provided an early clinical demonstration that treatment with arterial vasodilators to reduce peripheral vascular resistance would unload a poorly functioning left ventricle, "thereby improving stroke volume and cardiac output without necessarily further lowering arterial pressure," he writes; A-HeFT makes a similar statement in an era in which nearly all HF patients receive beta blockers and ACE inhibitors.

Anand said the A-HeFT findings, despite the trial's inclusion of only African Americans, likely apply to HF patients in general. "Most of us believe the data can be generalized."

Race-based labeling for a heart failure drug: "Setback" or "scientifically reasonable"? San Francisco, CA and Washington, DC - The debate over whether the US Food and Drug Administration should have approved BiDil (NitroMed) for the broad HF population instead of restricting its labeling to African Americans played out for a primary-care audience in the January 2, 2007 issue of the Annals of Internal Medicine [4,5]. An opinion-based review called the narrowly defined approval "poor science and poor policymaking," charges answered in a similar article by two prominent FDA administrators, who said it was "a scientifically reasonable, data-based decision, one that provided a major benefit in a group that is particularly burdened by congestive heart failure." The race-based approval was consistent with the recommendation made by the FDA's Cardiovascular and Renal Drugs Advisory Committee, which last year voted unanimously in favor of BiDil's approval. As reported by heartwire at the time, eight of the committee's nine voting members publicly favored the labeling's limitation to blacks. The use of health disparities to justify the 'creation' of an expensive medication is perverse. In their analysis of the medical and social issues surrounding the approval, Drs Kirsten Bibbins-Domingo and Alicia Fernandez (University of California, San Francisco) write that "the FDA decision, although perhaps well-intentioned, may be a setback to scientific discourse on therapeutics and may be specifically deleterious to efforts aimed at addressing disparities in health and healthcare." Drug approvals for specific racial groups, they argue, imply differential drug effects by race that haven't been rigorously tested and send a message to industry that it can gain drug approvals by conducting less-expensive trials in narrowly defined populations. They also "unscientifically endorse a biological model of race" based on a trial, A-HeFT, that didn't actually compare BiDil's effects in blacks vs whites. Moreover, they write, the oft-cited argument that BiDil's approval addresses race-based disparities in public health is counterproductive. "By invoking the rhetoric for health disparities and applying it to the drug-approval process when no direct evidence exists, while ignoring the evidence that health disparities are driven by disparities in healthcare and a wide range of social conditions, the FDA reframes the debate on addressing health disparities without scientific basis." Finally, write Bibbins-Domingo and Fernandez, "The use of health disparities to justify the 'creation' of an expensive medication is perverse. Of the social factors that contribute to disparities in health, poverty and income differentials are among the most important." Given the long history of urgent interest in searching for racial and other demographic differences, which surely accepted the possibility that such differences might be discovered, it seems surprising that there would be so much discomfort when one was found. In an accompanying article, arguments by the FDA's Drs Robert Temple and Norman L Stockbridge supporting the labeling focus largely on the supporting scientific evidence, which they say was "very strong." Although A-HeFT could not compare outcomes by race, "data from three clinical trials showed dramatic effectiveness of [ISDN-H] in black patients and supported a differential effect in black and white patients." And, they ask, why should that be surprising, even if the reason behind the difference is unknown? "Given the long history of urgent interest in searching for racial and other demographic differences, which surely accepted the possibility that such differences might be discovered, it seems surprising that there would be so much discomfort when one was found." Besides, consideration of differences by demographics when weighing the effects of drug therapies isn't new; it has been done frequently and without controversy for sex and age, observe Temple and Stockbridge. "We hope that further research elucidates the genetic or other factors that predict the usefulness of [ISDN-H]," they write. "Until then, we are pleased that one defined group has access to a dramatically life-prolonging therapy."