A comparative evaluation of on-demand phosphodiesterase-5 inhibitor efficacy in erectile dysfunction treatment: a systematic review and network meta-analysis of double-blind, placebo-controlled, randomized trials.

Abstract

Erectile dysfunction (ED) is a multifactorial condition with psychological, vascular, hormonal, neurological, and systemic risk factors. Four phosphodiesterase-5 inhibitors (PDE5is), sildenafil, tadalafil, vardenafil, and avanafil, have been approved by the United States Food and Drug Administration and the European Medicines Agency for the management of ED. While several meta-analyses have assessed the efficacy of PDE5is in the management of ED, none have focused on dose-specific outcomes. Hence, the study was conducted to compare the dose-dependent efficacy and safety of four FDA/EMA-approved PDE5is in the treatment of ED using on-demand dosages. A comprehensive literature search identified randomized, double-blind, placebo-controlled trials. Only on-demand doses of PDE5is were included in the network meta-analysis (NMA), which focused on primary outcomes such as the proportion of participants achieving satisfactory erectile function (EF), defined as an International Index of Erectile Function (IIEF) domain score > 26. A threshold analysis was conducted to evaluate the robustness of treatment recommendations derived from the NMA. A total of 83 studies with 6029 participants (treatment group: 3457 participants; placebo group: 2572 participants) were included. This dose-response network meta-analysis highlighted better efficacy with sildenafil (sildenafil 100 mg: odds ratio [OR] 9.06, sildenafil 50 mg: OR 7.90) in improving EF compared to that with placebo, followed by tadalafil (tadalafil 20 mg: OR 7.13, tadalafil 10 mg: OR 3.14), vardenafil (vardenafil 10 mg: OR 7.78), and avanafil (avanafil 200 mg: OR 3.42, avanafil 100 mg: OR 1.75). Threshold analysis showed a statistically significant improvement in ED with sildenafil 100 mg [OR 2.20; 95% confidence interval (CI) 1.78-2.63] and 50 mg (OR 2.10; 95% CI 1.69-2.50) compared to placebo. This indicated the robustness of the results, with moderate variations unlikely to alter their comparative ranking within the NMA. The odds of treatment-related adverse events were highest for vardenafil, followed by avanafil and sildenafil, and lowest for tadalafil compared to placebo. However, in some instances, the wide CI showed higher variability and potential uncertainty in effect estimates. PDE5is are highly effective, with sildenafil showing a significantly greater efficacy compared with the other PDE5is.