The development of positive inotropic agents for chronic heart failure: How have we gone astray?

Because cardiac contractility is impaired in chronic heart failure, many pharmacologic agents have been developed to increase the contractile state of the failing heart. These drugs produce impressive hemodynamic effects, but long-term therapy has to failed to produce clinical benefits and has increased mortality in treated patients. This experience has led many physicians to suggest that positive inotropic therapy be abandoned as a therapeutic approach for heart failure. However, recent studies suggest that the efficacy and safety of many (if not all) positive inotropic drugs can be greatly enhanced by reducing the dose of these drugs. The importance of dose is dramatically illustrated by the results of trials with vesnarinone, which decreases mortality when used in low doses but increases mortality when administered in doses only twice as large. Although low doses of positive inotropic drugs may be clinically superior to high doses, it is not clear that these low doses exert significant inotropic effects. All positive inotropic drugs exert actions on the circulation in addition to stimulating the heart, and these ancillary properties may be particularly important at low doses of these drugs. Low doses of milrinone and pimobendan may act primarily to dilate peripheral blood vessels; low doses of digitalis may exert only neurohormonal effects, and low doses of vesnarinone may act as an antiarrhythmic agent. If the noninotropic actions of low doses account for the therapeutic benefits of these drugs, then the positive inotropic effects seen at high doses may be primarily responsible for their adverse effects. Therefore, hemodynamic activity should not be viewed as a prerequisite for the selection of the dose of a positive inotropic drug. Prior emphasis on the use of high doses with significant cardiostimulatory effects may have derailed the proper development of many positive inotropic agents for the treatment of heart failure.