Use of a phosphodiesterase type-5 (PDE5) inhibitor was associated with a lower risk for death and cardiovascular events than alprostadil for the treatment of erectile dysfunction in men with stable coronary artery disease in a large Swedish registry study.
“We decided to look at this group because impotence is a huge problem in the male elderly population,” and concerns remain about whether “PDE5 inhibitors can be used in those in this group who also have cardiovascular disease,” lead author Daniel P. Andersson, MD, PhD, Karolinska Institute, Stockholm, Sweden, said in an interview.
The team previously reported a mortality benefit of PDE5 inhibitors in men with a first myocardial infarction (MI), as did a British study in men with type 2 diabetes. However, both compared treatment with men not taking erectile dysfunction (ED) drugs, which may have introduced confounding by indication, he noted.
The present analysis included 18,542 Swedish men with ED who had an MI or underwent coronary bypass surgery or percutaneous coronary intervention, of whom 16,548 were treated with a PDE5 inhibitor (sildenafil, tadalafil, or vardenafil) and 1994 with local alprostadil. The mean follow-up for mortality was 5.8 years.
Alprostadil users were more likely to have a prior stroke, diabetes, active cancer, heart failure, chronic obstructive pulmonary disease, atrial fibrillation, or peripheral artery disease and to use beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, thiazides, opioids, nitrates, or selective serotonin reuptake inhibitors. PDE5 inhibitor users were slightly younger and more likely to have a postgraduate education.
After controlling for these factors, the adjusted risks in the PDE5 inhibitor group were:
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12% lower for all-cause mortality (14% vs 26%; hazard ratio [HR], 0.88)
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19% lower for myocardial infarction (9.4% vs 15%; HR, 0.81)
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25% lower for heart failure hospitalizations (1.0% vs 2.1%; HR, 0.75)
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31% lower for revascularization (13.1% vs 21%; HR, 0.69)
The adjusted risks for stroke and peripheral artery disease were similar between the two treatment groups, according to the study, published March 22 in the Journal of the American College of Cardiology.
Rates of cardiovascular (5.1% vs 10.6%) and noncardiovascular (6.9% vs 12.2%) deaths were roughly halved in the PDE5 inhibitor group, although the association with treatment was significant after adjustment only for cardiovascular death (HR, 0.83) and not for noncardiovascular death.
“Our initial hypothesis was that cardiovascular death would be decreased but, as we see, noncardiovascular mortality was also reduced and we didn’t expect that,” Andersson said. “Both of these drive the decreased mortality, but we still can’t say anything about causality.”
Age-stratified analyses indicated that men ages 60 to 69 years treated with PDE5 inhibition had a lower mortality than their peers treated with alprostadil (adjusted HR, 0.81). This was not seen, however, for men older than 70 years.
When the investigators compared quintiles of filled PDE5 inhibitor prescriptions, men in the third, fourth, and fifth quintiles had a 16%, 25%, and 27% lower adjusted risk for death, respectively, compared with men in the lowest quintile. Men in the highest quintile of alprostadil prescriptions had a lower risk for death vs those in the lowest quintile.
“We need randomized controlled trials, however, if the physician that prescribes this medicine sees that you’re fit enough to get it, then it’s probably good for you and you can take it and feel safe about it,” Andersson said.
Renke Maas, MD, Friedrich Alexander University Erlangen-Nürnberg, Erlangen Germany, and Roman Rodionov, MD, PhD, Dresden University of Technology, Dresden, Germany, write in an accompanying editorial that “the observed association of PDE5i use and survival in men with coronary artery disease is intriguing but still insufficient to support any change in clinical practice.”
They point out that neither PDE5 inhibitors nor alprostadil are typically prescribed or taken for daily use and that only once-daily tadalafil, with a duration of action of 24 to 36 hours, would meet the criteria for continuous exposure. “This makes it difficult to attribute any strong association with mortality to typical dosing patterns of PDE5i in men with ED.”
“In support of a causal relationship, it could be argued that in the Swedish cohort, with a high prevalence of hypertension, PDE5i may have improved survival by augmenting clinical effects of antihypertensive drugs,” they write. “Many may also like the thought that frequent sex qualifies as a physical activity that promotes longevity and that PDE5i may restore this benefit in case of ED. Unfortunately, this interpretation may constitute reverse causality.”
Deteriorating general health is associated with a decrease in sexual desire and activity and, thus, a high cumulative exposure to PDE5 inhibitors may simply have identified healthier and more sexually active patients, Maas and Rodionov suggest.
The editorialists agree that a randomized controlled trial is needed to address issues of confounding and bias by indication but say that before initiating such a trial, “one question should be addressed first: Why has the pharmaceutical industry not already conducted any larger trials in this broad indication in the last 20 years?
“This is puzzling, considering the ample experimental data indicating beneficial effects in the cardiovascular system and that PDE5i were originally developed in the 1990s with the very large potential markets in coronary artery disease and hypertension in mind,” they add. “The answers may offer some important, and possibly sobering, insights.”
The study was conducted in collaboration with the Obesity Centre in Stockholm, Sweden, and the University of Milano-Bicocca in Italy. Andersson was funded by a regional agreement on medical training and clinical research between the Stockholm County Council and the Karolinska Institutet. Maas and Rodionov disclosed no relevant financial relationships.
J Am Coll Cardiol. 2021;77;1535-1550, 1551-1553. Full text, Editorial
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