Combination Therapy With Beta-Adrenergic Receptor Antagonists
Rational use of phosphodiesterase inhibitors represents an ongoing controversy in contemporary pharmacotherapy for heart failure. In randomized clinical trials, phosphodiesterase inhibitors increased cardiac output at the expense of worsening the rates of sudden cardiac death and cardiovascular mortality. Preliminary findings from ongoing clinical and preclinical investigations of phosphodiesterase activity suggest that combined use of phosphodiesterase inhibitors with β-adrenergic antagonists may prevent these adverse outcomes. Compartmentation of cyclic adenosine 3',5'-monophosphate signaling may prove critical in determining myocardial response to combination therapy.

The advent of phosphodiesterase inhibition in heart failure was met with early optimism due to a novel mechanism of inotropic action and symptomatic improvement in patients with heart failure. Subsequent larger clinical trials, however, noted a consistent increase in mortality among patients receiving oral phosphodiesterase inhibitors, primarily due to sudden cardiac death and cardiovascular mortality. These negative findings reduced the clinical role of phosphodiesterase inhibitors to use in patients with acute decompensated heart failure requiring short-term or palliative inotropic support. It is significant to note, however, that early phosphodiesterase inhibitor trials occurred before the benefits of β- adrenergic receptor antagonists in heart failure were widely established. As β-adrenergic receptor antagonists exert a significant protective effect on heart failure mortality, sudden cardiac death, and proarrhythmia (principal adverse events in phosphodiesterase inhibitor trials), the addition of β-adrenergic receptor antagonists to phosphodiesterase inhibitors may constitute a valuable contribution to heart failure pharmacotherapy.

We examine the evidence, both clinical and preclinical, for the combined use of β-adrenergic receptor antagonists and phosphodiesterase inhibitors in patien ts with heart failure.

Although the combined use of an inotropic agent with a β-adrenergic receptor antagonist may seem counterintuitive, we also highlight the distinct, complementary pharmacology of these agents and propose a mechanism by which their combination may produce myocardial responses not attainable with either agent alone.