Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients

Abstract

We examined the influence of phosphodiesterase inhibitors (PDIs) on mortality in patients with overt chronic heart failure. A total of 13 randomised, placebo-controlled trials of PDIs involving 2808 patients were selected. Meta-analysis, using data for all patients, showed that there was a non-significant (P = 0.16) increase of about 17% in the mortality rate of patients receiving a PDI [odds ratio (OR) 1.17, 95% confidence interval (CI) 0.94-1.46]. However, the observed treatment effects were found to be heterogeneous due to the results from the trials on vesnarinone. The heterogeneity became non-significant (P = 0.77) when these trials were removed, and a significant increase in the mortality rate was observed under treatment with the other PDIs (OR 1.41, 95% CI 1.11-1.79). In the subgroups of patients with or without additional vasodilator (VD) treatment, similar results were observed (PDI with VD: OR 1.3, 95% CI 1.03-1.7; PDI without VD: OR 2.04, 95% CI 1.1-3.8). These results indicate that PDIs (with the exception of vesnarinone) should not be prescribed for long-term use in patients with overt chronic heart failure. Additional vasodilator treatment in patients receiving PDIs for chronic heart failure does not explain the increased mortality seen with PDIs. This toxicity must, therefore, arise by other mechanisms. Further experimental and clinical evaluation is needed to confirm the beneficial influence of vesnarinone on survival in chronic heart failure patients and to identify the mechanism(s) differentiating this agent's therapeutic effect from that of other PDIs.

A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis

“…4). In addition, an increase in mortality after chronic PDE3 inhibitor treatment was also found, primarily because of arrhythmias and sudden death (23,24). Our finding that PDE3 inhibitors induce a autoregulatory positive PDE3A-ICER feedback loop leading to cardiomyocyte apoptosis may provide a molecular mechanism at least for the part of adverse effects of chronic PDE3 inhibitor therapy.…”

“…However, in long-term clinical trials, the hemodynamic improvements seen early in therapy were typically not sustained (23,24). This may be explained by PDE3 inhibitor-induced downregulation of PDE3A expression observed in this study (Fig.…”

Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis

“…However, in long-term clinical trials, the hemodynamic improvements seen early in therapy were typically not sustained, and a 40% increase in mortality was reported after several months of treatment, primarily as a result of arrhythmias and sudden death. 24,25 The mechanisms for loss of therapeutic benefit and increased mortality observed with chronic PDE3 inhibitor treatment are not well understood. Our finding that PDE3 inhibitors induced cardiomyocyte apoptosis may provide an explanation for the increased arrhythmias and sudden death in chronic PDE3 inhibitor therapy.…”

Effect of sildenafil citrate on the cardiovascular system

“…This is important because inhibitors of PDE-3 (the isozyme involved in the regulation of cardiac contractility), such as milrinone, vesnarinone and enoximone, which have been used in patients with heart failure, are generally associated with an increased incidence of cardiac arrhythmias and other serious side effects (20). The cardiotoxic effects of PDE-3 inhibitors are thought to be related to an increase in intracellular cAMP in the myocardium (21,22). However, PDE-5 is not present in cardiac myocytes (19).…”