There is no evidence that treating erectile dysfunction with PDE-5 inhibitors increases cardiac risk. erectile dysfunction and vascular disease share the same risk factors and erectile dysfunction in otherwise asymptomatic men may be a marker of silent vascular disease, especially coronary artery disease. This has now been established to be the case and is discussed extensively in the second Princeton consensus.
Clinical trials and post-marketing data of sildenafil demonstrated no increase in myocardial infarction rates either in patients who received these agents as part of double-blind, placebo-controlled trials or open-label studies, or compared with expected rates in aged-matched populations of men. Analysis of pooled data from more than 120 clinical trials found that sildenafil usage in men with erectile dysfunction did not increase the risk of myocardial infarction or cardiovascular death within 6 or 24 hours after intercourse, or overall. Overall, the rate per 100 patient-years of myocardial infarction or cardiovascular death in men treated with sildenafil was similar to that in men treated with placebo (0.91 vs 0.84) and was slightly lower in open-label and extension studies (0.56).
Sildenafil also has a strong overall safety profile in men with erectile dysfunction and comorbid cardiovascular disease. Pooled data from 37 double-blind, placebo-controlled trials of sildenafil showed similar adverse event profiles for the subset of men with comorbid cardiovascular disease and the overall erectile dysfunction population enrolled in these clinical trials. Except for facial flushing (vasodilatation), each type of treatment-related cardiovascular adverse event (e.g. palpitations, tachycardia) occurred in <1% of men, regardless of treatment assignment or comorbid condition. Similar results have been reported in prospective trials.
Sildenafil does not adversely affect total exercise time or time to ischemia during exercise testing in men with stable angina. In fact it may actually improve exercise tests. While sildenafil causes a modest decrease in blood pressure in both normal and hypertensive patients, it does not result in cardiac strain. Sildenafil does not alter cardiac contractility, cardiac output, or myocardial oxygen consumption, while it improves endothelial function.
In clinical studies of tadalafil, the incidence of myocardial infarction was low and similar to that seen with placebo. Myo-cardial infarction rates in 35 controlled clinical trials were 0.26 per 100 patient-years in tadalafil-treated patients and 0.41 per 100 patient-years in placebo-treated patients. In 8 open-label studies, these rates were 0.36 and 0.33, respectively. These rates were no higher than the myocardial infarction rate of 0.6 per 100 patient-years reported for an age-standardized population (men under 75 years of age). In all trials, the cardiac mortality rate was 0.12 per 100 patient-years compared with 0.26 per 100 patient-years for an age-standardized population.
The incidence of cardiovascular adverse events (including congestive heart failure, cerebrovascular events, hypotension, and arrhythmias) was low and similar to that seen with placebo. Observational studies confirmed this safety profile, reporting similar ischemic heart disease and myocardial infarction rates to those in the general male population. Finally, the incidence rates of myocardial infarction and cardiovascular treatment-emergent adverse events were similar to those with placebo even in cases of once-daily or 3 times per week dosing.
Daily tadalafil administration in healthy men resulted in blood pressure decreases similar to those seen with placebo administration. Single doses of 5mg and 10mg in men with coronary artery disease resulted in small decreases of blood pressure that were not associated with significant hypotensive symptoms. There is no evidence for QT prolongation induced by tadalafil. Tadalafil had no significant effect on global myocardial blood flow at rest, during adenosine infusion, or during dobutamine infusion. Compared with placebo, tadalafil significantly augmented myocardial blood flow during increased workload in normal regions, with a trend toward improving myocardial blood flow in poorly perfused regions. Chronic administration of tadalafil improves endothelial function in men with or without cardiovascular risk factors.
Vardenafil is associated with a very low risk for myocardial infarction, similar to that seen with placebo. In double-blind and open-label clinical trials, myocardial infarction occurred in 0.1 % of 793 placebo-treated patients compared with <1 % of 1812 vardenafil-treated patients, with only 1 patient in each group sustaining a myocardial infarction. In this analysis, 1 placebo-treated patient had a stroke, while no vardenafil-treated patient had a stroke. Similarly, patients reporting angina or chest pain included 2 (0.3 %) in the placebo group and 1 (<0.1 %) in the vardenafil-treated group.
The incidence of cardiovascular adverse events in double-blind, long-term, open label, and real-life studies was very low (≤0.1 % for individual events) and similar to that with placebo. Only a few serious cardiovascular adverse events were reported but none was considered to be due to vardenafil. In a retrospective analysis of 17 clinical studies of vardenafil in men with ED, the incidence rates of drug-related dizziness was slightly higher in vardenafil-treated patients than in placebo-treated patients (1.5 % vs 0.4 %), but without additive effects by antihypertensive or alpha-blocker use.
Vardenafil had only small effects on corrected QT intervals that were not associated with absolute QT prolongation, and they are not considered clinically significant. There was no evidence of long-term cardiovascular safety concerns according to vital sign and electrocardiographic recordings during 2 years of treatment with vardenafil. Compared with placebo, vardenafil had no significant effect on mean total exercise time or time to first awareness of angina. Vardenafil 10mg (but not 20mg) significantly prolonged the time to ischemic threshold (i.e. ST-segment depression ≥1mm compared with baseline). As with the other two PDE-5 inhibitors, vardenafil also improves endothelial function.
Phosphodiesterase type 5 inhibitors and antihypertensive medications
All PDE-5 inhibitors share mild-to-moderate vasodilator effects, resulting in transient decreases in systolic and diastolic blood pressures in healthy volunteers. Since hypertension is a common risk factor in erectile dysfunction patients, it is important to determine if PDE-5 inhibitors potentiate the decreases in blood pressure achieved with different classes of antihypertensive agents.
The incidence of treatment-related adverse events for patients taking sildenafil and antihypertensive medications was similar to that for sildenafil-treated patients not taking any antihypertensive agent (34 % vs 38 %) in 18 double-blind, placebo-controlled studies. The number of antihyperten-sive medications taken from among the five classes (diuretic, beta-blocker, alpha-1-blocker, angiotensin converting enzyme inhibitor, and calcium-channel blocker) had no effect on the adverse event profile of sildenafil even among patients taking more than three different agents. Therefore, sildenafil is a well-tolerated treatment for erectile dysfunction in patients taking concomitant antihypertensive medication, including those on multi-drug regimens.
Tadalafil administration in patients receiving concomitant antihypertensive therapy may result in a reduction in blood pressure, which is, in general, mild and not likely to be of clinical concern. In the phase 3 studies, no statistically significant differences were observed between tadalafil and placebo in the mean changes in blood pressure from baseline in patients taking ≥2 antihypertensive agents. The incidence rates of cardiovascular events in six phase 3 trials were similar in tadalafil-treated patients (3.7 %) and placebo-treated patients (4.8 %). Hypotension or postural hypotension was not reported in any tadalafil-treated patient, compared with one report of each in the placebo-treated patients. Consequently, tadalafil is safe in patients receiving concomitant antihypertensive agents.
Vardenafil is associated with a low incidence of treatment-emergent adverse events (21.2 %) and discontinuation rates (2.1 %) compared with placebo (16.4 % and 1 %, respectively) in erectile dysfunction patients receiving antihypertensive agents. There were no significant changes in systolic and diastolic blood pressure or heart rate between the vardenafil and placebo groups. The average number of antihypertensives used per patient was 1.5 (range 1–4) in the vardenafil group and 1.4 (range 1–5) in the placebo group. Both the incidence of adverse events and the ability to maintain an erection were unaffected by stratification into distinct subsets according to the class of antihypertensive medication being received. Consequently, in hypertensive men treated with concomitant antihypertensive medication, vardenafil is well tolerated, and does not significantly affect blood pressure.
Phosphodiesterase type 5 inhibitors and alpha-adrenergic antagonists
Co-administration of PDE-5 inhibitors and alpha-adrenergic antagonists may result in an additive drop of blood pressure under certain conditions. Sildenafil labeling currently includes a precaution advising that sildenafil 50mg or 100mg should not be taken within a 4-hour window of an alpha-adrenergic antagonist (commonly used for the treatment of lower urinary tract symptoms and benign prostatic hyperplasia). In contrast, sildenafil 25mg may be taken at any time in relationship to alpha-blocker administration. However, this precaution refers mainly to combination treatment with doxazosin. This may not be the case when tamsulosin is used. The concomitant use of tadalafil with doxazosin may result in significant hypotension and is not recommended. This may not be the case for tamsulosin or alfuzosin. Similarly, concomitant use of vardenafil with terazosin resulted in hypotension (especially when given to achieve simultaneous time to peak plasma concentration). However, concomitant use of vardenafil 10mg or 20mg with tamsulosin 0.4mg resulted in small asymptomatic reductions in standing blood pressure.
In all cases, physicians must be cautious when prescribing both PDE-5 inhibitors and alpha-adrenergic antagonists. Patients should be stable on alpha-blocker therapy prior to starting on a PDE-5 inhibitor, which must be initiated at the lowest recommended dose, and dosing should be 3–4 hours apart from alpha-blocker administration.
Selections from the book: “Textbook of Erectile Dysfunction”, 2009