PDE5 inhibitors: Two new drugs and cardiovascular uses beyond erectile dysfunction

In 1998, sildenafil (Viagra) was introduced as the first effective oral drug for the treatment of erectile dysfunction (ED). At that time, there was concern that these drugs might place patients with coronary artery and other cardiovascular diseases at risk because the drugs act as mild vasodilators. There was also fear that an excessive drop in blood pressure might precipitate myocardial ischemia, myocardial infarction (MI), fatal arrhythmia, or stroke. This would be of special concern with elderly patients. Organic nitrates increase the production of cyclic guanosine monophosphate (GMP), the second messenger of nitric oxide (NO), resulting in smooth muscle relaxation and vasodilatation. Phosphodiesterase-5 (PDE5) inhibitors can magnify the degree of vasodilatation and cause a marked decrease in blood pressure. For this reason, the concomitant use of nitrates and PDE5 inhibitors is prohibited.1

Since 1998, two new PDE5 inhibitors have been released, vardenafil (Levitra) and tadalafil (Cialis). There is ample evidence from double-blind, placebo-controlled trials and open-label studies that the drugs themselves do not increase the incidence of MI or total death.2-4 More information is available for sildenafil than for the other drugs because it was the first PDE5 inhibitor released. From a pooled study of more than 120 trials between 1993 and 2002, the incidence of acute MI in patients in the placebo-controlled studies was 0.81 per 100 person-years for patients taking sildenafil (n = 7,462 patients) compared with 0.84 per 100 person-years for patients taking placebo (n = 5,753 patients).4 In open-label studies with 11,540 person-years of sildenafil exposure, the incidence of MI was 0.53 per 100 person-years. In an analysis of 29 clinical studies among patients taking tadalafil, the incidence of MI in the double-blind studies was 0.25 per 100 person-years (n = 3,666 patients) for the tadalafil patients and 0.60 per 100 person-years for the placebo patients (n = 1,437).5

Other possible problems noted in the American College of Cardiology/

American Heart Association Consensus document have also been extensively investigated. There is no evidence that a PDE5 inhibitor causes a marked drop in blood pressure in hypertensive patients taking multiple antihypertensive drugs. In large retrospective studies of hypertensive patients taking all classes of antihypertensive drugs, small decreases in systolic pressure occurred when sildenafil was added, with no difference in adverse effects (headache, dizziness, flushing, and esophageal reflux) compared with placebo.6

There was also no difference in adverse effects in those taking one, two, three, or more antihypertensive agents compared with those taking no antihypertensive drugs.6 An analysis of 35 sildenafil double-blind trials (4,819 sildenafil patients and 3,296 placebo patients) showed similar results.7 A study with a sample of hypertensive patients taking multiple antihypertensive drugs who were also taking tadalafil showed a similar lack of increase in side effects compared with placebo.8 These findings might have been anticipated because the PDE5 inhibitors are only weak vasodilators.

There was also a question of whether patients with congestive heart failure might have excessive decreases in blood pressure while taking PDE5 inhibitors. Bocchi and colleagues showed that patients with heart failure who were taking sildenafil had an increase in exercise duration and no change or a beneficial change in central hemodynamics.9 The one question still unanswered is whether patients who have undergone excessive diuresis and who are hypovolemic might have a marked drop in blood pressure if given a PDE5 inhibitor.

The most important problem is treating ED and enabling sexual intercourse in patients with known or latent coronary artery disease (CAD). As already stated, there is no evidence that the PDE5 inhibitor drugs themselves increase the risk in such patients. However, the sudden increase in the physical activity required by sexual intercourse increases oxygen consumption (VO2) and myocardial VO2. There are precious few studies on the increased VO2 that occurs with sexual activity. The best of these studies is one conducted by Bohlen and colleagues, who found that sexual activity involves a modest increase in VO2 of approximately 3 to 5 metabolic equivalents (METs) for just a few minutes, peaking at the time of orgasm.10 In the face of critical obstructive CAD, it is possible that sudden myocardial ischemia and its complications could occur.

The evidence that sexual activity increases the risk of MI was reported by Muller and colleagues, who showed that within 2 hours of sexual activity, there is a slight increase in the risk of acute MI, with the risk being 2.5 times that not related to sex.11 Because the risk of acute MI occurring within a short period of time is very low, even in patients with known CAD, 2.5 times that risk is still very low. Furthermore, if the individual engages in activities equal to or greater than 6 METs three times a week or more, the increased risk associated with sexual activity is eliminated.11

There is an important relationship between ED and CAD. Most ED is caused by endothelial dysfunction. Normal endothelial function depends on the neural stimulation and release of NO by the vascular endothelium and smooth muscle of the lacunae of the corpus cavernosum. This stimulates the formation of cyclic GMP, which ultimately results in smooth muscle relaxation and vascular dilatation. The enzyme PDE5 catalyzes the breakdown of cyclic GMP, thereby allowing vasoconstriction and detumescence. PDE5 inhibitors competitively block the breakdown of cyclic GMP, allowing a given amount of NO to have a greater effect on vasodilatation. The endothelial dysfunction that results in ED limits the release of NO, which has multiple consequences aside from its effect on smooth muscle relaxation and vasodilatation. Endothelial dysfunction is also involved in the initiation of atherosclerosis; therefore, ED and atherosclerosis have a common precursor, and it is not surprising that both have risk factors (hypertension, smoking, dyslipidemia, etc) in common.12 Kaiser and colleagues have shown that ED can be the earliest manifestation of vascular disease, prior to any evidence of CAD or carotid artery disease.13 The message is that the presence of ED should lead the physician to search for evidence of latent coronary or cerebrovascular disease. Further, because ED can be an important factor in the quality of life for some individuals, pa- tients with coronary or other arterial disease who might be reluctant to discuss the subject with their doctors should be questioned about the adequacy of their sexual function.

There have been several studies performed on patients with stable angina who were taking sildenafil, which showed that there was no increase in myocardial ischemia on exercise testing; in fact, there was a slight delay in the onset of ischemia compared with placebo.14,15 Arruda-Olson and coleagues found no increase in ischemia on exercise echocardiography,16 and invasive studies have shown either no change or a slight vasodilatation of atherosclerotic-obstructed coronary arteries when sildenafil was given.17,18

In a prospective, double-blind, placebo-controlled 12-week trial including 151 men with ED and stable CAD, DeBusk and colleagues showed that there was no increase in angina, MI,

or death.19

The approach to the patient with known or suspected cardiovascular disease is addressed in a report from the Princeton Conference by DeBusk and colleagues.20 They presented an algorithm for the classification of pa- tients into low, intermediate, and high risk and recommended a plan to evaluate such patients before treating ED. A report developed at a second Princeton Conference in June 2004 is scheduled for publication in November 2005, in which their recommendations are updated. The suggested approach will be similar, with more emphasis on the history of the patient’s degree of physical activity. Because the danger of sexual activity is a sudden, unaccustomed increase in physical activity, if the patient is performing physical activity without difficulty at the level required for sexual activity, further workup before treating the ED is unnecessary.

Since the approval of sildenafil, vardenafil and tadalafil have been approved by the Food and Drug Administration. The effectiveness of these PDE5 inhibitors appears to be equivalent. Vardenafil and sildenafil have similar molecular structures, which mimic the structure of cyclic GMP. Tadalafil has a markedly different structure, but a portion of the molecule is configured so that it competes for the cyclic GMP receptor. Clinically important differences among the three PDE5 inhibitors exist, probably based on their molecular differences (Table). Vardenafil is the most potent inhibitor, followed by sildenafil and tadalafil. Inhibition of PDE5 reaches a plateau within the therapeutic dose of all three drugs, however, and a further increase in dose does not cause greater PDE5 inhibition. The major difference among the three drugs is the duration of action. The effective half-life of sildenafil and vardenafil is similar, about 4 hours. The effective half-life of tadalafil is 17.5 hours. Tadalafil is therefore effective after a single dose for at least 36 hours, much longer than either of the other two drugs. How important this is clinically depends on how long after a single dose the individual wishes to have effective erectile function. There are also differences in the rate of absorption after a fatty meal, with sildenafil and vardenafil having delayed absorption and therefore delayed onset of activity. Tadalafil is not affected by eating, but because absorption occurs in the small intestine, it has a longer delay in onset of activity compared with the other two drugs, which are taken while fasting.

Recently, there have been reports of nonarteritic ischemic optic neuropathy (NAION) in patients who have taken PDE5 inhibitors,21 both sildenafil and tadalafil. NAION is not an uncommon problem, especially in patients with diabetes and in the elderly. Although there is no evidence that there is a causal relationship, the possibility is taken seriously. NAION, as the name implies, is an ischemic neuropathy, probably caused by hypotension in the ophthalmic artery, resulting in marked visual impairment. Since PDE5 inhibitors are mild vasodilators and cause a minimal drop in systemic pressure, the possibility exists that such a drop in blood pressure in patients at risk might be responsible for the few cases of NAION occurring after PDE5 inhibitors.

Evidence against PDE5 inhibitors as a cause of NAION is the fact that there was not a single report of NAION in all the placebo-controlled trials or open-label follow-up experience. Boshier and colleagues22 reported one patient with NAION identified from a cohort of 8,893 patients from a prescription event-monitoring study prescribed sildenafil in England between April and June 1999; epidemiologic data suggested that was the expected incidence of NAION in that number of patients. Hattenhauer and colleagues23 reported the incidence of NAION in Olmsted County between 1981 and 1990, adjusted to the age and sex distribution of the white US population of 1990 to be 10.2 per 100,000. Extrapolated to the US population, this means that each year there would be 5,700 new cases of NAION. Furthermore, the risk factors for NAION are diabetes, hypertension, advanced age, a small optic-cup-to-disc ratio, and nocturnal hypotension,24 and many of the patients reported with NAION after PDE5 inhibitors had one of these risk factors. Patients with ED have as risk factors diabetes and hy-pertension, so patients taking PDE5 inhibitors are at risk from NAION without there being a causal relationship. Finally, in a small, double-blind, randomized, placebo-controlled crossover trial reported by Grunwald and colleagues,25 100 mg of sildenafil caused no significant change in intraocular choroidal or optic nerve circulatory parameters. However, the possibility of this serious adverse effect is such that caution is advised in using PDE5 inhibitors in patients who have had one eye affected by NAION.

New directions

Finally, there are new possible uses for PDE5 inhibitors beyond that of ED. Most important is the use of PDE5 inhibitors for patients with pulmonary hypertension.26,27 For patients with normal pulmonary artery pressure and vascular resistance, there is little change when they are given PDE5 inhibitors. With pulmonary hypertension, there is an upregulation of PDE5 receptors in the pulmonary vascular bed. Sildenafil has been shown to decrease pulmonary arterial pressure and pulmonary vascular resistance, similar to that obtained by inhalation of NO. Unlike NO, sildenafil increases cardiac output and decreases pulmonary capillary pressure.27 Ghofrani and colleagues28 showed that, for patients who have had inadequate response to prostacyclin therapy, adding sildenafil can further decrease pulmonary artery pressure and pulmonary vascular resistance without significantly affecting systemic vascular resistance. Most of the studies have been done in patients with primary pulmonary hypertension, but there are suggestions that PDE5 inhibitors could be effective in treating patients with pulmonary hypertension secondary to congenital heart disease, connective tissue diseases, and even left ventricular failure.29 With its longer duration of activity, tadalafil might be the best agent for long-term use.

The benefits of PDE5 inhibitors are being investigated for the treatment of other vasospastic diseases, such as Raynaud’s phenomenon. Be- cause endothelial dysfunction is such a basic pathophysiologic mechanism leading to a variety of clinical diseases, the indications for the use of PDE5 inhibitors are likely to increase in the future, for both the elderly and younger age groups. Stay tuned.