Cardiovascular Safety Update of Tadalafil: Retrospective Analysis of Data From Placebo-controlled and Open-label Clinical Trials of Tadalafil With as Needed, Three Times-per-Week, or Once-a-Day Dosing

Kloner RA, Jackson G, Hutter AM, et al.
Am J Cardiol. 2006;97:1778-1784

Summary and Viewpoint

Erectile dysfunction can affect more than half of men over the age of 40 years, and approximately 10% of these men have lost erectile function entirely.^[1] Because of this wide prevalence and the efficacy of treatment, inhibitors of phosphodiesterase-5 (PDE-5) are now widely used to treat erectile dysfunction. Agents currently available include sildenafil, vardenafil, and tadalafil.

Given that PDE-5 inhibitors increase intravascular concentrations of nitric oxide and promote vasodilation, the question of cardiac safety has been closely examined since their introduction. Early trials demonstrated the danger of the concomitant use of PDE-5 inhibitors with nitrates. Current recommendations call for an interval of 24 hours between the use of nitrates and the last dose of sildenafil or vardenafil, and a period of 48 hours before using nitrates among patients who received tadalafil.^[2] In addition, greater experience from clinical practice as well as from research studies has provided more insight into the cardiac risk associated with PDE-5 inhibitors in general.

Research has demonstrated that PDE-5 inhibitors do not carry increased cardiovascular risk among patients at the highest risk levels. In a study of 142 patients with coronary artery disease and erectile dysfunction along with multiple other chronic illnesses, the use of both sildenafil and placebo was associated with rates of adverse events less than 3%.^[3] Only 1 subject in each treatment group withdrew from the study due to adverse events, and there was no difference in angina status between the sildenafil and placebo groups.

A larger retrospective report summarizing data from 120 trials involving sildenafil also failed to demonstrate a significant cardiovascular risk associated with active therapy.^[4] This study demonstrated that the risk of myocardial infarction or cardiovascular death was 0.91 per 100 person-years of follow-up among sildenafil-treated patients compared with 0.84 per 100 person-years of follow-up among placebo-treated patients. This difference was not statistically significant.

The current study undertakes a similar project with the compendium of data from 36 clinical trials of tadalafil. Of importance, most patients treated with tadalafil in the research scrutinized by the authors had received the maximum dose of 20 mg daily, and the prevalence of significant conditions that are associated with increased cardiovascular risk ranged from 17% to 31% in the trials. Regardless of these concomitant conditions, the duration of use, or the frequency of dosing, active treatment with tadalafil failed to increase the risk of cardiovascular complications compared with placebo. The authors noted that data from 8 other trials involving research of tadalafil for indications other than erectile dysfunction also failed to demonstrate any increased cardiovascular risk with active treatment.

These results echo the opinion of the Second Princeton Consensus Conference, which published recommendations for the management of cardiac risk and sexual dysfunction.^[2] The authors of these guidelines concluded that patients with cardiac risk should be categorized into low-, medium-, and high-risk groups when they are considering sexual activity.

Patients with low cardiac risk include those with controlled hypertension; mild, stable angina pectoris; recent revascularization; myocardial infarction within 6-8 weeks and no evidence of ongoing ischemia; mild valvular disease; and New York Heart Association class I heart failure. These patients may initiate or resume sexual activity and may receive PDE-5 inhibitors.

Patients at high risk of cardiac events with sexual activity include those with unstable angina; uncontrolled hypertension; New York Heart Association class III or IV heart failure; recent myocardial infarction (within the prior 2 weeks); frequent ventricular arrhythmia; obstructive hypertrophic cardiomyopathy; and moderate to severe valve disease, particularly aortic stenosis. These patients should be evaluated and treated by a cardiologist prior to sexual activity or treatment with PDE-5 inhibitors.

Finally, there is an intermediate-risk pool of patients, including asymptomatic patients with 3 or more cardiac risk factors, those with stable angina, those with New York Heart Association class II heart failure, and those with other vascular disease such as stroke or peripheral vascular disease. The goal of management for these patients is to use more testing, especially exercise treadmill testing, plus possible cardiology consultation and treatment in order to stratify these subjects into the low- or high-risk groups for sexual activity.

Risk factors for cardiovascular disease and erectile dysfunction are similar, and physicians should be careful to examine patients for cardiovascular risk factors prior to prescription of PDE-5 inhibitors. However, when used appropriately, it appears that these agents do not significantly contribute to increased cardiovascular risk beyond that associated with sexual activity alone. Primary care physicians are in a unique position to address both the issues of sexual and cardiovascular health and employ effective, safe, and well-tolerated agents such as PDE-5 inhibitors in order to help male patients regain sexual function.