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As expected, men taking nitrates for stable coronary artery disease (CAD) fared poorly if they added certain erectile dysfunction (ED) drugs to their medicine cabinet, a Swedish population-based study found.

Compared with nitrate users not on phosphodiesterase-5 (PDE5) inhibitor treatment for ED, those who had both types of drugs in their medication history tended to be at higher risk for events over a median follow-up of 5.9 years:

• Mortality: HR 1.39 (95% CI 1.28-1.51)
• Cardiovascular mortality: HR 1.34 (95% CI 1.11-1.62)
• Noncardiovascular mortality: HR 1.40 (95% CI 1.27-1.54)
• Myocardial infarction (MI): HR 1.72 (95% CI 1.55-1.90)
• Heart failure: HR 1.67 (95% CI 1.48-1.90)
• Cardiac revascularization: HR 1.95 (95% CI 1.78-2.13)
• Major cardiovascular events (MACE): HR 1.70 (95% CI 1.58-1.83)

Notably, these risks were not increased within 28 days of dispensing the PDE5 inhibitors, reported Daniel Andersson, MD, PhD, of Karolinska Institutet and Karolinska University Hospital Huddinge in Stockholm, and colleagues in the .

"The use of a PDE5 inhibitor in combination with nitrate medication in men with stable CAD may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5 inhibitors to patients with cardiovascular disease using nitrate medication is warranted," the authors urged, based on their study of over 60,000 individuals.

PDE5 inhibitors on the market include sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra).

For years, FDA labeling and professional guidelines have agreed that these medications should not be prescribed with nitrates due to concerns about a potential significant drop in blood pressure.

"Organic nitrates, such as those used as antianginal therapy, increase the production of cGMP [cyclic guanosine monophosphate], resulting in systemic vasodilation," explained Glenn Levine, MD, of Baylor College of Medicine in Houston, in an .

"Because PDE5 inhibitors reduce cGMP degradation, the combination of these 2 drugs synergistically leads to increased vasodilation and a greater hypotensive response," he continued. "Compared with the decrease in systolic blood pressure with nitrate therapy alone, the decrease in systolic blood pressure with combined nitrate plus PDE5 inhibitor treatment in the 1 to several hours after exposure can be on the order of 20 to 25 mm Hg or more."

Given the limited evidence of such hypotension, however, people are increasingly taking both drugs in the real world, so Andersson and colleagues tried to test whether concomitant use of PDE5 inhibitors with nitrates is as harmful as suggested. To them, it seemed plausible that PDE5 inhibitors might in fact have cardioprotective effects in this population, similar to what was seen in other studies in people with stable CAD not on nitrate therapy, but the study did not support that hypothesis.

These ED drugs remain " in most patients with stable CAD and only mild angina if not on chronic nitrate therapy," Levine wrote, while they are "ill-advised at best and generally contraindicated" for people on chronic oral nitrate therapy.

"In some patients on oral nitrate therapy who desire to use a PDE5 inhibitor, particularly those who have undergone revascularization and have minimal or no angina, it may be reasonable to initiate a several-week trial off the nitrate therapy (or on a different class of antianginal therapy) and assess if the patient remains relatively angina-free," he suggested.

The large population-based cohort study was based on Swedish registry data, and included 55,777 men with previous MI or revascularization in 2006 to 2013 who had two dispensed nitrate prescriptions within 6 months, and another 5,710 peers who also had at least two filled prescriptions for any PDE5 inhibitor.

PDE5 inhibitor users tended to be younger (61.2 vs 70.3 years) and had fewer comorbidities despite a more advanced vascular disease than the nitrate-only cohort.

Andersson and team acknowledged that their observational study could not determine causality and may be subject to confounding. Importantly, they also had no way of knowing patients' real medication habits after receiving their prescribed medications.

"Our data have no information regarding time of intake or usage at the same time. Neither do we know how stable the medication was over time. However, the fact that there were 2 filled prescriptions indicates usage," they wrote.

"Our goal is to underscore the need for careful patient-centered consideration before prescribing PDE5 inhibitor medication to men receiving nitrate treatment," Andersson said in a press release. "Furthermore, it justifies our efforts for continued research into the ambiguous effects of ED drugs on men with cardiovascular disease."

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