A Systematic Review of Sildenafil Mortality Through the Years

Abstract

Sildenafil is a medication used for the treatment of erectile dysfunction. It was approved by the U.S. Food and Drug Administration (FDA) in 1998. Several articles have raised concerns regarding the use of sildenafil and the occurrence of serious adverse events, such as myocardial ischemia, stroke, and even death. Our aim is to systematically review the existing literature on mortality associated with sildenafil use. The method used for this systematic review was completed by searching three databases: PubMed, Scopus, and Web of Science. Articles were screened and assessed for eligibility. This review uses the articles found to address the concerns associated with sildenafil and mortality. A total of 19 reports were used in our systematic review, in which there were 10 case reports, two case series, three systematic reviews, one narrative review, one retrospective study, one article in the British Medical Journal , and one commentary article. One FDA article in particular included case reports and reports to the FDA on the use of sildenafil eight months after its introduction to the market in 1998, with 522 deaths reported. Another retrospective study examined the use of sildenafil on infants below the age of 1 who did not have congenital heart disease but did suffer from severe pulmonary hypertension. The study found a mortality rate of 29%, which increased with sildenafil dosage. A case series examined six deaths related to non-prescription use of sildenafil. All these cases were subjected to autopsies and related to sexual activity. The study suggests that phosphodiesterase 5 inhibitors induced the deaths, and the concentration of sildenafil in the femoral blood was found to be between 0.032and0.087 μg. To conclude, the literature available on this topic is deemed insufficient to provide enough data to establish a direct link of causality between sildenafil and mortality. Although some studies paint sildenafil as the culprit behind these deaths, further studies and research are needed to explain the unexpected deaths following sildenafil use.

Safety profile and signal detection of phosphodiesterase type 5 inhibitors for erectile dysfunction: a Food and Drug Administration Adverse Event Reporting System analysis

“…One claims analysis found that men with ED and PDE5I exposure were associated with 25% lower risk of overall mortality (hazard ratio, 0.51; P < .001) as compared with men with ED and no exposure to PDE5Is, 25 while a systematic review concluded that the existing literature is insufficient to establish causality between sildenafil and mortality. 26 However, a previous study examining CV AEs for PDE5Is in the FAERS database between 2000 and 2010 revealed that deaths represented 12.3% of the total sildenafil AEs while the current study found 9.88%. 27 As sildenafil is the oldest and one of the most used PDE5Is, a larger proportion of patients with comorbidities that have a significantly increased risk of death may be using sildenafil (although this study’s definition of death excluded death directly related to disease).…”

A novel small molecule inhibitor of p38⍺ MAP kinase augments cardiomyocyte cell cycle entry in response to direct cell cycle stimulation

“…Our study showed an off‐target effect of the NDPPC, which augments the 4F‐induced cell cycle through inhibition of p38 MAP kinase. Off‐target effects of small molecules have been identified before in several studies, which might result in toxicity or other side effects (Al Ibrahim et al, 2022; Rudmann, 2013; Salmasi et al, 2016).…”

A Novel Small Molecule Inhibitor of p38⍺ MAP Kinase Augments Cardiomyocyte Cell Cycle Entry in Response to Direct Cell Cycle Stimulation

“…Our study showed an off-target effect of the NDPPC, which augments the 4F-induced cell cycle through inhibition of p38⍺ MAP kinase. Off-target effects of small molecules have been identified before in several studies, which might result in toxicity or other side effects (Al Ibrahim et al, 2022;Rudmann, 2013;Salmasi et al, 2016).…”