Commentary based on Kloner RA, Burnett AL, Miner M, et al. Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health. J Sex Med 2024;21:90-116.¹

Background

In 1998, the first oral phosphodiesterase type 5 inhibitor (PDE5i) was approved in the United States for the treatment of erectile dysfunction (ED). The first Princeton guidelines were published in 2000 to help guide the clinical management of sexual dysfunction in men with cardiovascular disease (CVD) risk factors or cardiac disease. Subsequent meetings were convened in 2004 and 2010. Since then, the experience with PDE5i has been more robust and new data have emerged regarding safety and a potential cardioprotective role of these medications. In 2024, the Journal of Sexual Medicine published the Princeton IV Consensus Guidelines.

Commentary

The risk related to cardiac overload during sexual intercourse is low, even in men with stable CVD or risk factors. Typically, sexual intercourse corresponds to a workload of approximately 2-3 METS and would probably not pose a greater risk than climbing two flights of stairs or walking 1.6 km (1 mi) during 20 min without cardiac symptoms. If a patient manifests symptoms at this level of activity, stress tests could help estimate their risk. In patients who undergo 5-6 METs on a treadmill test (i.e., 4 min of the standard Bruce protocol treadmill test) without evidence of ischemia, sexual activity is generally safe.¹

One of the most important messages reinforced by the Princeton IV guidelines is ED as a risk marker for CVD. Data from many epidemiological studies have shown that ED is associated with higher risk of CVD, independently of age, body mass index, previous CVD, and other risk factors, and that ED symptoms may precede clinically evident CVD by several years. The MESA (Multi-Ethnic Study of Atherosclerosis) investigators found that ED was independently associated with a nearly twofold increase in cardiovascular (CV) events (hazard ratio, 1.9; 95% confidence interval, 1.1-3.4).² Evaluating CVD risk in patients with ED seems to be cost-effective regardless of ED severity.³

When estimating CVD risk in men with no cardiac symptoms or established CVD, clinicians should consider ED as a risk-enhancing factor.^1,4 Current prevention guidelines suggest using the American College of Cardiology/American Heart Association (ACC/AHA) tool to stratify 10-year atherosclerotic cardiovascular disease (ASCVD) risk, primarily in people 40-79 years of age.⁵ Many conditions are already recognized as risk-enhancing factors such as family history, chronic kidney disease, and C-reactive protein levels.⁵ The guidelines include specific risk-enhancing factors for women, such as early menopause and pre-eclampsia, but not a specific risk factor for men, such as ED. According to ACC/AHA guidelines, patients at borderline to intermediate risk should be considered for coronary artery calcium (CAC) scoring to better estimate their risk.⁵ The Princeton IV guidelines push for future ACC/AHA guidelines to consider ED as a risk-enhancing factor and recommend that patients at low 10-year ASCVD risk with vasculogenic ED should also be strongly considered for CAC scoring.^1,4

Clinicians should inquire about sexual activity in every man, independently of CVD symptoms or established disease. To better counsel patients on the safety of sexual intercourse and proper use of PDE5i, the Princeton IV guidelines recommend assessing patients' tolerance to exercise, assessing their CV comorbidities, and reviewing current medications, with special attention to nitrate usage. Patients with an active lifestyle who tolerate exercise without symptoms can engage in sexual intercourse safely.¹

Patients at low risk are those who achieve 5 METs without ischemia on a recent exercise test and have controlled hypertension (HTN), minimal heart failure (HF) symptoms (New York Heart Association [NYHA] classes I and II), successful revascularization, or mild valvular disease.

Patients at intermediate (or indeterminate) risk are those with moderate angina, myocardial infarction (MI) within 2-8 weeks without intervention, NYHA class III HF symptoms, other atherosclerotic disease such as previous stroke or transient ischemic attack, or peripheral artery disease. These patients should be better evaluated before resuming sexual activity. Completing 4 min of the standard Bruce protocol treadmill test without symptoms, arrhythmias, or a fall in systolic blood pressure (BP) identifies the safety of sexual activity.¹

Patients at high risk are those who have a cardiac condition severe or unstable enough to pose a significant risk with sexual activity (NYHA class IV HF symptoms, uncontrolled HTN, unstable or refractory angina, recent MI without treatment, or high-risk arrhythmias). In these patients, sexual activity should be deferred until the cardiac condition stabilizes, and referral to a cardiologist is warranted.

PDE5i are widely used for ED treatment and have been considered safe in patients with cardiac conditions. PDE5i may have protective properties in the vasculature and heart because of its abilities to decrease systemic BP and improve endothelial dysfunction. Data from epidemiological studies have shown that PDE5i may potentially reduce major adverse cardiac events and all-cause death in healthy patients and those with type 2 diabetes mellitus or coronary artery disease.⁶

Data from a retrospective study of >70,000 men with ED demonstrated a 13% lower incidence of major CV events over a 15-year period in patients exposed to PDE5i. These data also demonstrated a 25% lower rate of all-cause death and a 39% lower rate of CV death in men exposed to PDE5i.⁷

The results of the studies that suggest a cardioprotective role of PDE5i are retrospective and have some limitations, including indication bias, not providing causality. Prospective studies are needed to definitely demonstrate this cardioprotective role, allowing more confidence in its routine use in the future.

PDE5i should not be used in patients regularly taking nitrates because of the risk of hypotension and increased risk of CV morbidity and mortality.⁸ However, in the modern era, most patients with ASCVD do not require nitrates, or take them exceedingly infrequently. Short-acting PDE5i (sildenafil, vardenafil, avanafil) should be avoided within 24 hours of nitrates, whereas longer-acting PDE5i (tadalafil) should be avoided within 48 hours of nitrate-containing substances. The conversation about nitrate cessation or deprescription should be patient centered. Many patients at low risk could interrupt nitrate use or be offered a substitute, or have the prescription terminated if they never use the medication.¹ If the patient has a true indication of nitrates with no other treatment option, then clinicians must consider other ways to manage ED.

Conclusion

When treating patients with ED, it is important to emphasize the role of lifestyle, obesity, CV risk factors, and mental health in the origin of the disease. Additionally, ED is an important CV risk factor, and CAC may help better estimate the ASCVD risk (Figure 1).

Figure 1: ASCVD Risk Assessment in Men With ED Without Overt Disease or Cardiac Symptoms

References

1. Kloner RA, Burnett AL, Miner M, et al. Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health. J Sex Med 2024;21:90-116.
2. Uddin SMI, Mirbolouk M, Dardari Z, et al. Erectile dysfunction as an independent predictor of future cardiovascular events: the multi-ethnic study of atherosclerosis. Circulation 2018;138:540-42.
3. Kalka C, Keo HH, Ingwersen M, et al. Men with erectile dysfunction (ED) should be screened for cardiovascular risk factors - cost-benefit considerations in Swiss men. Vasa 2024;53:68-76.
4. Rosen RC, Miner M, Burnett AL, et al. Proceedings of PRINCETON IV: PDE5 inhibitors and cardiac health symposium. Sex Med Rev 2024;Jun 27:[ePub ahead of print].
5. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:e177-e232.
6. Andersson DP, Landucci L, Lagerros YT, et al. Association of phosphodiesterase-5 inhibitors versus alprostadil with survival in men with coronary artery disease. J Am Coll Cardiol 2021;77:1535-50.
7. Kloner RA, Stanek E, Crowe CL, et al. Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: a retrospective, observational study based on healthcare claims and national death index data. J Sex Med 2023;20:38-48.
8. Trolle Lagerros Y, Grotta A, Freyland S., et al. Risk of death in patients with coronary artery disease taking nitrates and phosphodiesterase-5 inhibitors. J Am Coll Cardiol 2024;83:417-26.