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Men with coronary artery disease who used phosphodiesterase-5 (PDE-5) inhibitors for erectile dysfunction had fewer adverse cardiovascular events than those taking the prostaglandin drug alprostadil (Edex, Caverject, Muse), a large Swedish study showed.

After surviving a myocardial infarction (MI) or cardiac revascularization, those prescribed a PDE-5 inhibitor instead of alprostadil had significantly fewer cardiovascular events during 5-plus years after starting the medication:

• All-cause mortality: 13.7% vs 26.1% (adjusted HR 0.88, 95% CI 0.79-0.98)

• MI: 9.4% vs 14.6% (adjusted HR 0.81, 95% CI 0.70-0.93)

• Heart failure: 5.5% vs 12.2% (adjusted HR 0.75, 95% CI 0.65-0.88)

• Cardiovascular mortality: 5.1% vs 10.6% (adjusted HR 0.83, 95% CI 0.70-0.98)

• Revascularization: 13.1% vs 20.8% (adjusted HR 0.69, 95% CI 0.62-0.78)

Patients with more filled PDE-5 inhibitor prescriptions had a lower mortality risk over follow-up, according to Martin Holzmann, MD, PhD, of Karolinska University Hospital in Stockholm, Sweden, and colleagues. The observational report, including more than 18,000 men, was published online in the .

"Although the decrease in all-cause mortality [with PDE-5 inhibitors was] dose dependent, the data do not permit the inference of causality or any clinical benefits of PDE-5 inhibitors because of the observational study design," the researchers cautioned. They also stopped short of recommending that alprostadil be avoided.

"To our knowledge, this is the largest study investigating the association between the use of erectile dysfunction medication and long-term outcomes," the team noted. "Furthermore, we believe that the external validity of our findings is high and may be generalized to other countries and health care systems similar to the Swedish one."

PDE-5 inhibitors were famously first developed to augment nitric oxide-dependent signaling in heart disease and hypertension. Pfizer turned its attentions to marketing sildenafil (Viagra) for erectile dysfunction after discovering the unexpected effect on men in its cardiovascular trials. Others include tadalafil (Cialis) and vardenafil (Levitra).

A major caveat of the present study, however, is that PDE-5 inhibitors and alprostadil are not prescribed or taken for daily use in most people, said Renke Maas, MD, of Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany, and Roman Rodionov, MD, PhD, of Technische Universität Dresden, Germany, and Flinders University in Adelaide, Australia, in an .

"Therefore, the vast majority of men were most likely exposed to the PDE-5 inhibitor or alprostadil for only a limited fraction of the total observation time," Maas and Rodionov wrote. "This makes it difficult to attribute any strong association with mortality to typical dosing patterns of [PDE-5 inhibitors] in men with ED."

Holzmann's group acknowledged that they did not know the exact amount of erectile dysfunction medication that patients were taking on a weekly basis.

Moreover, confounding by indication could not be excluded, and the investigators said they lacked information about some risk factors that are associated with erectile dysfunction and cardiovascular disease (e.g., body mass index, smoking, physical activity, fitness). Perhaps for those reasons, the authors did not suggest that alprostadil posed a particular danger.

"The observed association of PDE-5 inhibitor use and survival in men with coronary artery disease is intriguing but still insufficient to support any change in clinical practice," Maas and Rodionov concluded.

The study was based on Swedish men who filled at least one PDE-5 inhibitor (n=16,548) or alprostadil (n=1,994) prescription following an MI or a revascularization in 2006-2013. Clinical information and socioeconomic data were collected from national registries.

Holzmann's team reported that the PDE-5 inhibitor users had numerical decreases in peripheral artery disease and stroke; these missed statistical significance upon multivariable adjustment for potential confounders such as marital status and length of education.

The researchers noted that the men in the study constituted a high-risk cohort, so the results are not generalizable to the general population.

"Future studies should aim to differentiate class and substance specific effects of PDE-5 inhibitors," the editorialists wrote. "Considering a possible use in , more efforts are needed to study the effects of PDE-5 inhibitors in women, where the association between the function of female erectile tissues and cardiovascular events is less investigated and understood."

A randomized placebo-controlled trial of these agents in cardiovascular prevention remains to be conducted, which Maas and Rodionov called "puzzling" considering the ample positive data and original intentions for their use.

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