Why inotropes continue to disappoint in heart failure.

Editorial Why inotropes continue to disappoint in heart failure Despite their low therapeutic index, cardiac glycosides have been used for centuries for the treatment of heart failure. In the past two decades pharmaceutical companies have developed several new orally active drugs, which like the glycosides have positive inotropic activity in vitro. It was hoped that they would replace the glyco-sides and be administered long-term to patients with heart failure but with a lower incidence of adverse effects. Unfortunately the development of these drugs was based on a series of unproven assumptions: that glycosides have an advantageous effect in patients with heart failure, that the benefit is due to the cardiotonic action that can be demonstrated in vitro, and that other drugs with positive inotropic effects in vitro will therefore be beneficial in vivo. Far from assuming that positive inotropic effects are beneficial there should be concern that if glycosides (and other cardiotonic drugs) have genuine inotropic effects in vivo this might worsen prognosis by increasing myocar-dial oxygen consumption, unless there is a concomitant improvement in mechanical efficiency. Glycosides slow atrioventricular conduction and control the ventricular response in patients with atrial fibril-lation.' This improves ventricular filling and cardiac output and allows the heart to operate at a more mechanically efficient rate. Even in sinus rhythm, glycosides slow the heart rate-at least in part by neurally mediated mechanisms.'2 There is little evidence that other effects of glycosides improve the symptoms of patients with heart failure.3 There is certainly no evidence that glyco-sides reduce mortality, though the results of a continuing study of digoxin in patients in sinus rhythm should be available soon. Because there is as yet no proven benefit from the inotropic effects of glycosides, the search for a replacement cardiotonic magic bullet for the treatment of heart failure may have been ill-founded. Further, the positive inotropic effects of the newer cardiotonic agents are inversely related to the severity and duration of heart failure ,4 as indeed are the effects of calcium, the final mediator of electromechanical coupling.5 Other effects of these drugs, such as vasodilatation, become relatively more important, but the arguments about how much of the acute haemodynamic change seen is due to vasodilatation and how much is the result of increased contractility are of academic interest. What concerns patients is whether they improve symptoms and survival. Some drugs (for example, amrinone and prenalterol) were withdrawn early in their …