Cardiovascular risk and sildenafil

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Abstract

Sildenafil citrate is the first oral agent approved for the treatment of erectile dysfunction (ED); other oral agents are in the process of development. Because the mechanism of action of many of these agents involves vasodilation, there is a potential for interaction with the cardiovascular system. Sildenafil inhibits phosphodiesterase-5 (PDE-5) which is found in the corpus cavernosum and in the systemic vasculature. Sildenafil causes a mild decrease in systemic arterial pressure (∼−8/−5.5 mm Hg); it causes a synergistic and often major decrease in systemic arterial pressure in the presence of organic nitrates (nitric oxide donors). Sildenafil is therefore contraindicated in patients taking organic nitrates. A review was made of clinical trials in populations of men with (1) erectile dysfunction; (2) chronic stable ischemic heart disease and erectile dysfunction; and (3) hypertension and erectile dysfunction. This review showed that sildenafil was effective and not associated with an increase in serious cardiovascular adverse events, myocardial infarction (MI), or death compared with placebo. Although there have been spontaneous reports of death among men using sildenafil, there are limitations to spontaneous-event reporting. In addition. the numbers of such reports are well below the expected numbers of deaths when considering the number of men who have received prescriptions for sildenafil and their age and cardiovascular risk factor profile. Because there is a small but finite risk of having a cardiac event with sexual activity, physicians should discuss with their cardiac patients the risks of sexual activity before prescribing any treatment for ED. In addition, they should evaluate their patients’ cardiac status when considering the safety of administering any ED treatment that may have systemic vasodilatory properties and can potentially lower blood pressure. In some cases, exercise treadmill testing may be warranted to determine whether ED patients with coronary artery disease can achieve the physiologic workload (4–6 metabolic equivalents) associated with sexual intercourse.

Section snippets

How sildenafil works

Sildenafil is an oral phosphodiesterase inhibitor that enhances erectile function through the same general pathway used by nature.6, 7, 8 Sildenafil requires sexual stimulation to occur in order for it to work. Sexual stimulation results in the release of nitric oxide from nerves and endothelial cells in the corpus cavernosum of the penis. Nitric oxide stimulates guanylate cyclase with the subsequent formation of cyclic guanosine monophosphate. Cyclic guanosine monophosphate is the substance

Efficacy of sildenafil in men with coronary artery disease

Is sildenafil effective in men with ischemic heart disease? Conti et al10 reported the results of a retrospective analysis of 357 men with stable chronic coronary artery disease not taking oral nitrates who were part of randomized, placebo-controlled trials testing the efficacy of sildenafil. Their mean age was 60 (placebo) and 62 (sildenafil) years and the mean duration of ED was about 5.5 years. Approximately half of the patients were on antihypertensives and a third were on antidiabetic

Frequency of cardiovascular events in placebo-controlled sildenafil trials

The issue of whether sildenafil could have an adverse effect on cardiovascular outcomes is best determined by placebo-controlled trials. Morales et al11 reported the incidence of serious cardiovascular events and MI among men who took part in 18 placebo-controlled studies. Serious cardiovascular events were listed as MI, angina, and coronary artery disease. The studies included 1,552 patients on placebo and 2,722 men on sildenafil. The duration of sildenafil use was up to 6 months. Serious

Spontaneous reports of death and cardiac events to the FDA

In November of 1998, the FDA placed information on its website on spontaneous reports of death and serious cardiovascular/cerebrovascular events among men who had used sildenafil.7, 14 Cases of death among men using sildenafil were seized upon by the media. It is worthwhile reviewing the advantages and disadvantages of this spontaneous reporting system and then putting the reports into perspective in relation to known rates of death and MI in a large population of men over a known duration of

Potential causes of death in men on sildenafil

How does one explain the observation that some deaths were temporally coupled to the use of sildenafil? One explanation is that some of these deaths were merely coincidental. A second is that they are the result of “reporting bias” (i.e., a person who takes a drug and experiences an adverse event soon afterward is more likely to associate the event with the drug. Therefore, he is more likely to report it than if he had taken the drug many hours or days before the event; neither situation either

Conclusion

Sildenafil is an effective oral medicine for ED. It improves erectile function in patients with ischemic heart disease and hypertension. In placebo-controlled trials including patients with ischemic heart disease and hypertension, the incidence of adverse cardiovascular events among patients on sildenafil was low and did not differ from placebo. Data from spontaneous reports of death among men using sildenafil have not demonstrated a signal that suggests an increased number of deaths above what

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  • Cited by (0)

    1

    Dr. Kloner is a speaker, consultant and researcher for Pfizer Inc.

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