Commentary

The A-HeFT trial convincingly shows that ID+H reduces mortality, morbidity, and symptoms in self identified African Americans with low ejection fraction HF but raises several questions. Why was the trial restricted to black patients? The investigators rationalise this approach based on post hoc analyses of the V-HeFT I and II trials,¹ which showed significant differences between black and white HF patients and substantial evidence of efficacy with ID+H only in blacks. It has also been speculated that this population was selected because it might facilitate more rapid approval and longer patent protection. Whether these points are true is arguable, but previous data¹ indicate that this was a reasonable hypothesis to test, despite the politically and scientifically charged atmosphere surrounding race based therapeutics.

What is the mechanism of benefit with ID+H? Limited data show that it may prolong the activity of nitric oxide and prevent the generation of reactive oxygen species. Alternative explanations include the known haemodynamic effects of this combination and the potential to reverse left ventricular dilatation and to mitigate secondary mitral regurgitation, which is more prevalent in non-ischaemic cardiomyopathy.

How should clinicians use ID+H in light of the A-HeFT results? The race based design and lack of efficacy data in whites leaves no alternative to making race based recommendations. ID+H should become standard care in black patients with systolic HF who fulfill the A-HeFT entry criteria and arguably in patients with milder symptoms. For whites, ID+H might be used empirically, but primarily only in patients who continue to have symptoms or evidence of progression despite regimens that include β blockers, angiotensin converting enzyme inhibitors (or angiotensin receptor blockers if intolerant), and aldosterone blockers, plus diuretics and possibly digoxin. With this degree of polypharmacy and limited data in whites, physicians and patients may be reluctant to add a thrice-daily drug.