Safe Sex for Men With Coronary Artery Disease: Title and subTitle BreakExercise, Sildenafil, and Risk of Cardiac Events

Sildenafil has been in widespread use for 3 years, but concerns persist regarding its safety in patients with a history of cardiac disease. Major adverse effects, including myocardial infarction and death, have been recorded in case reports and postmarketing surveillance.¹ However, questions have been raised regarding the accuracy of these reports, the potential for reporting bias, and whether the number of reported events exceeds that expected in a population of this age.² The central issue is to what extent these adverse events reflect a risk from the drug and to what extent they reflect the risks of physical activity in patients with coronary artery disease.

The study by Arruda-Olson and colleagues³ in this issue of THE JOURNAL suggests that the cardiovascular effects of sildenafil are limited, even in patients with coronary artery disease. In an elegant study using a crossover design, the authors evaluated 105 men with known or suspected coronary disease who underwent exercise echocardiography an hour after receiving placebo or 50 or 100 mg of sildenafil. The hemodynamic effects of the drug included an average systolic blood pressure reduction of 7 mm Hg compared with baseline, with no difference in exercise capacity or hemodynamic response to exercise while patients were receiving sildenafil. These effects are consistent with the reported decrease of less than 10 mm Hg in resting systolic blood pressure in healthy individuals at peak plasma levels, about an hour after sildenafil administration.^{4 - 5} In patients with stable ischemic heart disease, intravenous doses of sildenafil provoked a similar decrease in systolic blood pressure at rest and after exercise.^{4 ,6} Dramatic decreases in blood pressure may occur with administration of nitrates within 24 hours of taking sildenafil, and the combination is therefore contraindicated.⁷

However, the novel findings of Arruda-Olson et al³ relate to the lack of an important influence of sildenafil on the development of ischemia. Exercise echocardiography is a good technique for this analysis, since echocardiographic wall motion abnormalities occur rapidly after the development of ischemia.⁸ Among study participants, the degree of ischemia, presence of ischemia, and heart rate at which ischemia was first manifest were no different in the presence of sildenafil. However, the study was not powered to detect a difference in less than 3 myocardial segments (ie, 1 entire wall) because the wall motion score index, which is calculated by an average of the subjective evaluation of function in each myocardial segment, is neither a reproducible nor a particularly subtle tool, and a truly quantitative approach needs to be developed. Nonetheless, sildenafil exerts a mild vasodilator effect in coronary circulation,⁹ and since neither noninvasive nor invasive studies^{4 ,6 ,10} have demonstrated that the drug influences coronary flow reserve, a reasonable inference is that the drug does not present a clinically important influence on ischemia.

The available evidence suggests that sildenafil does not provoke ischemia and is not associated with adverse hemodynamics. It seems more likely that the ischemia and cardiac events reported with sildenafil are related more to the performance of sexual activity in a patient with coronary disease than the use of the drug. The important clinical issue is how to assess risk when patients with established coronary disease request treatment for erectile dysfunction.

The history should focus on the assessment of functional capacity of the patient. Patients who have coronary artery disease and ischemia provoked by sexual activity also experience ischemia during an exercise electrocardiogram protocol and therefore during daily activity.¹¹ Measurement of exhaled gases during sexual activity has demonstrated relatively low workloads (2-3 metabolic equivalent tasks).¹² However, the cardiac workload has been equated to completion of stage 1 of the Bruce protocol, or a workload of 4 to 6 metabolic equivalent tasks, on the basis of the physiological responses to sexual activity, which include an increase in heart rate of 120/min to 130/min and an increase in systolic blood pressure of 150 to 180 mm Hg.¹³ Cardiac workload varies between individuals and with different sexual activities¹⁰ and especially with the additional cardiac workload related to emotional stress. Thus, the patient's description of his functional capacity may be helpful in assessing whether sexual activity is likely to precipitate clinically important ischemia. The workloads for sexual activity generally are analogous to walking a mile in 20 minutes or climbing 2 flights of stairs (20 steps) in 10 seconds.¹⁴

If the patient's functional or symptom status is ambiguous, or if the patient has diabetes and the clinician has concerns regarding silent ischemia, an exercise test may be informative. An exercise echocardiogram is unnecessary except when the electrocardiogram is uninterpretable (eg, left ventricular hypertrophy). If the patient is unable to exercise because of other comorbidity, such as lower extremity arthritis, a pharmacological stress could be used to identify ischemia. However, if the patient's functional status is so compromised that 3 metabolic equivalent tasks cannot be attained, this limitation may compromise engaging in sexual activity. Patients in this situation generally warrant angiography and may require intervention on symptomatic or prognostic grounds. If the patient is not a candidate for intervention, the maximization of antianginal therapy (not including nitrates in this situation) is appropriate. Patients who demonstrate the resolution of ischemia on repeat functional testing are at lower risk of an ischemic event in follow-up.¹⁵ However, the translation of this response into a lower risk of events with sexual activity might be anticipated but remains to be established.

Physicians should remain cognizant that not all cardiovascular risk pertains to ischemia. The study by Arruda-Olson et al suggests that it is unlikely that hemodynamic changes related to sildenafil account for ischemic events, unless the patient concurrently takes nitrates. Similarly, coronary flow reserve does not appear to be influenced by this drug. The possibility of cyclic adenosine monophosphate–mediated arrhythmogenesis related to sildenafil has been proposed on theoretical grounds¹⁶ but has not been supported by observation.¹⁷ Although the current study cannot address the risk of events when sexual activity is combined with sildenafil therapy, previous studies have suggested that the drug is safe in unselected patients¹⁸ and in patients with a history of cardiac disease.¹⁹ Although the relative risk of myocardial infarction is increased 2.5-fold in the 2 hours after sexual activity in men with and without angina, the absolute risk is still small.²⁰ For clinicians considering prescribing sildenafil for patients with coronary artery disease, careful evaluation of functional capacity and thorough discussion with the patient about the risks of physical and sexual activity are essential.