Erectile dysfunction (ED) is a frequent medical condition affecting millions of men worldwide. Phosphodiesterase 5 inhibitors (PDE5is), which work by enhancing the effects of nitric oxide on erectile function, have revolutionized the treatment of ED [1]. Four PDE5is (sildenafil, tadalafil, vardenafil, and avanafil) have been proved effective and generally safe for treating ED, in both clinical trials and real-world practice [1].

However, head-to-head comparative data are lacking [2]. Real-world patient assessment using patient-reported outcomes (PROs) was deemed to be suitable to fill this knowledge gap. The employment of such PROs is regarded as an essential component of telemedical treatment [3], which facilitates tailoring of management and streamlined gathering of clinical data.

Direct-to-consumer (DTC) online platforms have recently emerged as part of a new asynchronous telemedical ecosystem using these approaches [4]. These platforms have gained significant traction in the treatment of ED, both in the USA and in Europe [5], representing a significant part of the overall PDE5i prescription market [6]. Current application is mostly limited to nonemergency indications that do not require immediate in-person diagnostic workup [7]. These platforms enable longitudinal follow-up across treatments and collect PROs, which offer unique insights into real-world patient preferences and side effects [8,9].

This study aims to carry out a head-to-head comparison of the safety and efficacy profiles of four PDE5is in the treatment of ED, in a single-platform real-world patient cohort. We hypothesize that sildenafil reveals a distinctive efficacy and safety profile, compared with tadalafil and vardenafil, consistent with its pharmacological properties. However, we hypothesize that large-scale real-world data differ in reported adverse events (AEs) from trial data dating back up to 20 yr that are frequently summarized in systematic reviews.