Usage and risk with phosphodiesterase type 5 inhibitors in male patients with chronic ischemic heart disease on oral organic nitrates
Authors: Holt A , Blanche P , Jensen A K G , Nouhravesh N , Rajan D , Jensen M H , El-Sheikh M , Schjerning A M , Schou M , Torp-Pedersen C , Gislason G H , McGettigan P , Lamberts M 
Published: October 2021

Abstract

Background
Combining oral organic nitrates (OON) with phosphodiesterase type 5 (PDE5) inhibitors is contraindicated. Growing and liberal use of PDE5 inhibitors for erectile dysfunction among patients with ischemic heart disease (IHD) could pose serious health consequences especially among patients with IHD on OON.

Purpose
We hypothesize that concomitant prescription of OON and PDE5 inhibitors is prevalent and has increased in recent years, and further that possible co-exposure could be associated with an increased risk of ischemic stroke, myocardial infarction (MI) or acute coronary angiography (CAG).

Methods
During 2000–2018, we included all male patients with history of IHD between 18 and 85 years of age from nationwide Danish health registers. Patients with a history of pulmonary hypertension were excluded and not followed up afterwards if they developed the condition during follow-up. From this cohort, we identified an OON treated subgroup defined by two consecutively redeemed prescriptions of OON within 180 days from each other. Further, to become a case or control, patients had to redeem a prescription of OON within 180 days prior to the event or corresponding date among controls.
Temporal trends during 2001–2018 of PDE5 inhibitor use were calculated among all male patients with IHD and the subgroup on OON. Among OON treated patients, we examined associations between PDE5 inhibitor use and risk of ischemic stroke, MI or CAG using a case-crossover design where each individual serves as his/her own control thereby controlling for time-invariant confounding. The case-crossover design compares an individual's exposure in an index period just before the event occurred to a reference period prior to the index period. We investigated periods of varying length (7, 14, 21 and 28 days). To account for possible temporal trends in the use of PDE5 inhibitors, we also conducted a case-time-control analysis using a control group matched on age and calendar year.

Results
We identified 249,541 male patients with IHD (median age 65 years [IQR 56–73]), and a subgroup of 42,073 (17%) on OON treatment (median age 70 years [IQR 62–77]). From 2001 to 2018, the use of PDE5 inhibitors saw a 6-fold increase among all male IHD patients and a 10-fold rise in the subgroup on OON (Figure 1). The risk of ischemic stroke, MI or CAG following exposure to PDE5 inhibitors was not increased in the OON subgroup in neither the case-crossover nor the case-time-control analyses (Figure 2).

Conclusions
The use of PDE5 inhibitors has increased 6-fold since 2001 among male patients with IHD, and 10-fold among patients on OON–notwithstanding an established absolute contraindication. However, we did not find any evidence of an increased risk of ischemic stroke, MI or acute CAG following exposure to PDE5 inhibitors in the OON subgroup. This suggests that patients on OON are adequately informed and comply with the recommended pause in OON medication prior to PDE5 inhibitor use.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Ib Mogens Kristiansens Almene FondandHelsefonden