Erectile Dysfunction Drugs Don’t Mix Well With Nitrates After MI, PCI

For men with a history of myocardial infarction or PCI, it may be risky to use nitrates for angina and phosphodiesterase-5 (PDE5) inhibitors for erectile dysfunction at the same time, a large Swedish study affirms.

Compared with men taking nitrates alone, those who were also prescribed a PDE5 inhibitor—including sildenafil, tadalafil, and vardenafil—had greater risks of mortality and a range of adverse cardiovascular outcomes, researchers led by Ylva Trolle Lagerros, MD, PhD (Karolinska Institutet, Stockholm, Sweden).

That’s contrary to what they had hypothesized going into the study, Trolle Lagerros told TCTMD, pointing to prior analyses showing possible cardioprotective effects of PDE5 inhibitors compared with either no treatment for erectile dysfunction or use of prostaglandin E1. The current findings also are discordant with recent studies, including one conducted in Denmark, suggesting that concomitant use of nitrates and PDE5 inhibitors does not raise the risk of cardiovascular events.

That last study highlighted the growing number of patients who are using both types of agents, despite the fact that concomitant use is formally contraindicated due to the potential for big drops in blood pressure when they’re combined. That trend is driven by the desire for older men to maintain a high quality of life, including an active sex life, Trolle Lagerros said.

Consideration of a patient’s quality of life is a critical part of treatment decisions, “but for now maybe we should be a little bit cautious” about prescribing nitrates and PDE5 inhibitors together, Trolle Lagerros said, adding that physicians should “have that discussion with the patient so it’s an informed decision.”

It’s important, too, to consider other lifestyle measures—ie, losing weight, exercising more, or stopping smoking—that could help improve patient health, she added.

But with these findings, published online ahead of the January 23, 2024, issue of the Journal of the American College of Cardiology, Trolle Lagerros said, “we’re adding one more brick to this discussion about whether or not we really should co-prescribe those.”

We’re adding one more brick to this discussion about whether or not we really should co-prescribe those. Ylva Trolle Lagerros

Commenting for TCTMD, Glenn Levine, MD (Baylor College of Medicine and Michael E. DeBakey VA Medical Center, Houston, TX), who wrote an accompanying editorial, noted that this study and those preceding it have some limitations in that it’s not clear when patients are taking the two types of medications in relation to each other. Thus, it’s not necessarily surprising that they’ve provided discrepant results.

In that context, physicians must integrate the findings into what’s known about the physiologic effects of the drugs and how they would interact with each other, Levine said. This latest study “confirms our suspicions that it’s probably not a great idea for people who are on these nitrates to also be—at least routinely—taking these erectile dysfunction medicines unless they’re given very careful parameters.”

In general, if a patient is on chronic nitrate therapy, “we should not be co-prescribing the erectile dysfunction agents,” Levine advised, adding, however, that patients can try stopping their nitrates for a couple of weeks to see how they do. If they don’t need them, then a PDE5 inhibitor would likely be okay.

If a patient is prescribed only sublingual nitrates to use on an as-needed basis, Levine said, “in that case it may be okay to give them the erectile dysfunction agents if we give the patient extremely explicit and careful warnings that if they’ve used the erectile dysfunction agent in the past 24 to 48 hours, depending on which agent they used, they absolutely cannot pop one of the sublingual nitros because that can lead to a dangerous drop in blood pressure.”

Possible Hazards of Combined Use

For the study, the investigators examined data from nationwide Swedish registries on men with a history of MI or PCI between June 30, 2005, and December 31, 2013, and a record of at least two dispensed nitrate prescriptions within 6 months of each other. The analysis included 61,487 men, of whom 9% had filled prescriptions for a PDE5 inhibitor. Compared with men treated with nitrates alone, those who had prescriptions for both types of drugs were younger (mean age 61.2 vs 70.3) and generally healthier, despite greater use of platelet inhibitors and statins.

Through a median follow-up of 5.9 years overall (5.7 years for those on nitrates alone and 3.4 years for those on both types of medication), rates of several outcomes—including heart failure and all-cause, cardiovascular, and noncardiovascular death—were lower in men taking both nitrates and a PDE5 inhibitor. After adjustment for potential confounders, however, concomitant use was associated with greater risks of all outcomes examined:

• All-cause mortality (adjusted HR 1.39; 95% CI 1.28-1.51)
• CVD death (adjusted HR 1.34; 95% CI 1.11-1.62)
• Non-CVD death (adjusted HR 1.40; 95% CI 1.27-1.54)
• MI (adjusted HR 1.72; 95% CI 1.55-1.90)
• Heart failure (adjusted HR 1.67; 95% CI 1.48-1.90)
• Coronary revascularization (adjusted HR 1.95; 95% CI 1.78-2.13)
• MACE (adjusted HR 1.70; 95% CI 1.58-1.83)

There were similar results in analyses focused on the different forms of nitrate medication and various PDE5 inhibitors.

Need to Be on a Nitrate?

The issue of concomitant use of nitrates and PDE5 inhibitors in men with coronary disease was recently addressed in Princeton IV consensus guidelines on PDE5 inhibitors and cardiac health, for which Robert Kloner, MD, PhD (Huntington Medical Research Institutes, Pasadena, CA, and University of Southern California, Los Angeles, CA), served as lead author.

The first issue is educating primary care physicians and other physicians that yes, there’s still a contraindication, but there’s probably a lot of people walking around who don’t need to be on nitrates. Robert Kloner

Speaking with TCTMD, Kloner noted that the contraindication to combined use of nitrates and PDE5 inhibitors remains. He speculated that the results of the current study might differ from the prior ones due to the higher risk of the cohort in this study or to differences in how well patients were educated about the potential hazards of combining nitrates and PDE5 inhibitors.

A major issue that was discussed at the Princeton IV meeting, Kloner said, was whether there are a lot of patients who carry around nitroglycerin pills to use on an as-needed basis who don’t need them anymore, perhaps because they’ve already undergone revascularization and no longer experience angina or are being managed using other antianginal medications.

For these types of patients, there should be an assessment of whether they need to continue carrying nitrates. If they do, the contraindication to concomitant use with PDE5 inhibitors persists, Kloner said, but if they don’t, PDE5 inhibitors can be safely used.

“The first issue is educating primary care physicians and other physicians that yes, there’s still a contraindication, but there’s probably a lot of people walking around who don’t need to be on nitrates,” Kloner said, noting, too, that nitrates have never been shown to improve clinical outcomes in men or women with coronary disease.

It’s critical to sort out this issue around concomitant use of nitrates and PDE5 inhibitors, Kloner said, because of the accumulating evidence suggesting that PDE5 inhibitors can be cardioprotective. “If that’s the case, then the time may come when the PDE5 inhibitors . . .  may be important to be administered in people with risk factors for coronary disease,” he said, adding that prospective studies are needed to prove such an impact.