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PDE5 is found in the smooth muscle cells of systemic arteries and veins,
and inhibitors of this isoenzyme act as mild vasodilators. Through relaxation
of vascular smooth muscle, the hemodynamic effects of the PDE5
inhibitors can have major implications for the treatment of ED, especially
in patients with comorbid cardiovascular conditions, such as coronary
artery disease (CAD) and hypertension. Because patients with cardiovascular
disease (CVD) typically receive multiple drug regimens to control
angina, hypertension, and other cardiac conditions, potential drug interactions
between PDE5 inhibitors and agents used for management of these
conditions are particularly important.

Study results consistently show that tadalafil treatment has little effect
on systemic arterial pressure. This is supported by data reported on more
than 5700 subjects treated with tadalafil in more than 22 clinical trials. One study, conducted in 80 healthy subjects, showed that single
doses of 10 or 20 mg of tadalafil have only modest effects on systolic blood
pressure (SBP) or diastolic blood pressure (DBP). Continued dosing once a day for 10 d revealed no clinically significant
changes in standing or supine SBP or DBP or in heart rate. Additionally,
20 mg of tadalafil, administered to healthy male subjects produced no
significant difference compared with placebo in supine SBP and DBP
(difference in the mean maximal decrease of 1.6 and 0.8 mmHg, respectively)
and in standing SBP and DBP (difference in the mean maximal
decrease of 0.2 and 4.6 mmHg, respectively). In addition, there was no
significant effect on heart rate.
The modest hemodynamic effects of tadalafil in healthy subjects are
reflected in the analyses of five placebo-controlled studies in a general
population of men with ED and of one in men with comorbid diabetes.
Men with significant CVD (for example, history of myocardial infarction,
unstable angina, uncontrolled hypertension) were excluded from
these studies. Blood pressure and heart rate were measured at baseline
and at monthly intervals until the end of the 12-wk treatment period. No
clinically or statistically significant effects on SBP or DBP or heart rate
were observed over a range of doses of tadalafil (2.5–20 mg) compared
with placebo.

Patients receiving tadalafil would appear to be at no greater risk for
cardiovascular-related side effects, including flushing, dizziness, hypertension, and syncope, than are patients taking placebo because the incidence
of these adverse events is low (0.1–3.7%) and not statistically significantly
different among the two patient populations. Importantly,
the rate of myocardial infarction among patients taking tadalafil (0.43 per
100 patient-years) was no greater than that among a group of age-standardized
men.
Despite these assurances from the clinical trial database, the potential
cardiac risk of sexual activity in patients with pre-existing CVD should be
considered.

Because ED and CAD may often coexist, a study was conducted in men
with stable CAD who demonstrated ischemia during a screening exercise
test to examine the effects of tadalafil on physical exercise at a workload
similar to that experienced during sexual activity. The study was a
randomized, double-blind, two-way crossover design in which patients
(aged 53–75 yr) received 10 mg of both placebo and tadalafil on separate
occasions approx 2 to 2.5 h before exercise. As assessed by the primary end
point of time to limiting ischemia, tadalafil did not affect the exercise time
or time to ischemia in these men. The mean difference in total exercise time
was 3 s (10 mg of tadalafil minus placebo), which represented no clinically
meaningful difference.

The effect of a single 100-mg dose of tadalafil on QT interval, which
represents ventricular depolarization and repolarization, was evaluated at
the time of peak tadalafil concentration in a randomized, double-blind,
placebo- and active (intravenous ibutilide)-controlled crossover study in
90 healthy males 18 to 53 yr of age. The mean change in QTc (Fridericia
QT correction) for tadalafil, relative to placebo, was 3.5 ms (two-sided
90%, confidence interval = 1.9, 5.1). The mean change in QTc (individual
QT correction) for tadalafil, relative to placebo, was 2.8 ms (two-sided
90%, confidence interval = 1.2, 4.4). A 100-mg dose of tadalafil (five times
the recommended dose) was chosen because this dose yields exposures
covering those observed on coadministration of tadalafil with potent
CYP3A4 inhibitors. In this study, the mean increase in heart rate associated
with a 100-mg dose of tadalafil compared with placebo was 3.1 beats
per min. These changes are not likely to be clinically relevant.