PDE5i therapy lowers risk of heart failure, death in men with CAD

Treatment with phosphodiesterase 5 inhibitor (PDE5i) appears to reduce the risk of death, myocardial infraction (MI), heart failure, and revascularization in men with stable coronary artery disease (CAD) as compared to alprostadil therapy, a study has found.

“The lower risk of death was dose dependent and stronger among younger than older men,” the researchers said. “PDE5i use is associated with a better prognosis in men with stable CAD.”

Using the Swedish Patient Register and the Swedish Prescribed Drug Register, the researchers included all men with a prior MI or revascularization who received PDE5i or alprostadil during 2006 through 2013 at >6 months after the event.

They used Cox regression to estimate adjusted hazard ratios (HR) with 95 percent confidence intervals (CI) for all-cause mortality, MI, heart failure, cardiovascular mortality, noncardiovascular mortality, cardiac revascularization, peripheral arterial disease, and stroke in men treated with PDE5i compared with alprostadil.

A total of 16,548 men received PDE5i and 1,994 alprostadil. Over a mean follow-up of 5.8 years, 2,261 deaths (14 percent) occurred in the PDE5i group and 521 (26 percent) in the alprostadil group. Compared with alprostadil, treatment with PDE5i resulted in lower mortality (HR, 0.88, 95 percent CI, 0.79–0.98), as well as reduced MI, heart failure, cardiovascular mortality, and revascularization. [J Am Coll Cardiol 2021;77:1535-1550]

Comparing quintiles (q) of filled PDE5i prescriptions with q1 as reference, men in q3, q4, and q5 were found to have lower all-cause mortality. Similarly, those in q5 among alprostadil users also had a lower all-cause mortality when compared to q1.

“Although the decrease in all-cause mortality was PDE5i dose dependent, the data do not permit the inference of causality or any clinical benefits of PDE5i because of the observational study design,” the researchers said.

These findings were consistent with those from two previous studies, one involving men with type 2 diabetes and the other involving men with first MI. Those treated with PDE5i had a lower risk of mortality than untreated patients. The second study also reported a lower risk of heart failure in men who received PDE5i treatment. [Heart 2016;102:1750-1756; Heart 2017;103:1264-1270]

“The main limitation of these studies was that men treated with PDE5i were compared with men who were not treated with ED medication at all,” the researchers said. “This may have introduced confounding by indication, meaning that there may have been reasons unknown to the investigators for not treating the untreated men.”

In addition, several animal and human studies supported the beneficial effects of PDE5i on the cardiovascular system, demonstrating a sustained improvement in haemodynamical parameters including arterial stiffness, flow-mediated dilation, and peak systolic velocity, even after discontinuation. [Am J Physiol Heart Circ Physiol 2002;283:H1263-H1269; Mol Cell Biochem 2013;379:43-49; Int J Impot Res 2007;19:55-61; Cardiovasc Drug Ther 2014;28:493-500]

Other studies also suggested that the effects of PDE5i might be driven by the reduction in arterial stiffness that then results in a decrease in vascular ageing. In addition, diabetic patients on PDE5i had lower mean levels of microalbuminuria. [Eur Heart J 2013;34:2034-2046; J Am Soc Nephrol 2016;27:3459-3468]

“Randomized controlled trials are needed to determine if this is a causal effect because of the pharmacodynamic effects of PDE5i or merely a marker for better socioeconomic status and compliance, younger age, fewer comorbidities, and a healthier lifestyle,” the researchers said.