Erectile Dysfunction and Cardiovascular Disease

Transcription

1 1 3 4 Erectile Dysfunction and Cardiovascular Disease Sanjay Kaul and James S. Forrester Epidemiology of Erectile Dysfunction Erectile Dysfunction as a Marker or a Harbinger of Coronary Artery Disease Physiology of Erectile Function Pharmacotherapy of Erectile Dysfunction Cardiovascular Safety of Therapy of Erectile Dysfunction Guidelines and Recommendations for the Use of PDE-5 Inhibitors in Patients with Cardiovascular Disease Key Points Cardiovascular risk factors are commonly associated with erectile dysfunction and should be identified and treated. Patients with cardiovascular disease should be assessed and counseled regarding their fitness for sexual activity. Sexual activity is associated with a small risk (0.9% attributable risk) of an adverse cardiovascular event. The PDE-5 inhibitors, the most commonly prescribed treatment for erectile dysfunction, are effective and safe in most patients with stable cardiovascular disease. The PDE-5 inhibitors are absolutely contraindicated in patients receiving nitrates for cardiovascular disease or individuals using recreational amyl nitrite/nitrate ( poppers ). Published recommendations such as the American College of Cardiology/American Heart Association (ACC/ AHA) and Princeton Consensus Guidelines provide a logical approach to the management of patients with cardiovascular disease and erectile dysfunction. Epidemiology of Erectile Dysfunction Erectile dysfunction (ED) is a commonly recognized and treated sexual dysfunction affecting more than 30% of men between 40 and 70 years of age. 1 The prevalence of ED and cardiovascular disease are highly correlated with age, as outlined by the Massachusetts Male Aging Study, which showed that the incidence of both conditions increases by a factor of 3 between the ages of 40 and 70 years. 1 In addition to age and male gender, hypertension, diabetes, dyslipidemia, obesity, and cigarette smoking are shared risk factors for ED and cardiovascular disease. 1,2 The prevalence of ED in patients with cardiovascular disease is higher than that in the general population, ranging from 60% in men with previous myocardial infarctions or who had undergone coronary artery bypass surgery 3 to 75% of men with chronic coronary artery disease. 4 Thus, ED is common in the coronary patient and most likely related to a generalized systemic functional (endothelial dysfunction) and structural (atherosclerosis) vascular abnormalities resulting from smoking, hypertension, lipid abnormalities and diabetes. Erectile Dysfunction as a Marker or a Harbinger of Coronary Artery Disease As ED and cardiovascular disease (CVD) share the same risk factors, ED developing in an asymptomatic male may be a marker for occult vascular or coronary artery disease (CAD) or a harbinger of CAD. Several recent studies have suggested that ED may be an early marker of systemic endothelial dysfunction and CAD. 5 One study found a twofold increase in the risk for acute myocardial infarction (MI) associated with ED. 6 Another study reported impaired endotheliumdependent flow-mediated as well as endothelium-independent nitroglycerin-mediated brachial artery vasodilatation in 30 men with ED compared to 27 age-matched controls. The functional abnormalities preceded any manifest coronary or vascular disease as determined by electron beam tomography and carotid duplex studies. 7 A third study of 50 men with ED between the ages of 40 and 60 and without overt CVD revealed the presence of multiple risk factors for CAD in 80%, an abnormal exercise electrocardiogram (ECG) stress test in >50% and extensive CAD (left main or two- or threevessel CAD) in 65% (13/20) patients. 8 Taken together, these data suggest that ED may provide an early warning of CVD, giving rise to the only partially whimsical idea of a penile stress test. 8 Physiology of Erectile Function Although many organ systems are involved, the process of penile erection begins in the brain, where sexual desire originates During sexual arousal, the parasympathetic nervous 2791

2 2792 chapter 134 system signals the local release of nitric oxide (NO) from the endothelial cells of the corpora cavernosa, the two hollow chambers that run the entire length of the penis. Nitric oxide is a fleeting neurotransmitter that stimulates the production of cyclic guanosine monophosphate (cgmp) via activation of soluble guanylate cyclase. 10,11 Accumulation of cgmp leads to a reduction in intracellular calcium and smooth muscle relaxation resulting in vasodilatation and filling of the spongy tissue of the cavernosal chambers with blood to create an erection. 10,11 The swelling of the penis impedes venous return and helps maintain the erection. After ejaculation or loss of desire, the sympathetic nervous system signals breakdown of cgmp, which restores the penis to its flaccid state The degradation of cgmp into its inactive form, GMP, is catalyzed by cyclic nucleotide phosphodiesterase enzymes. 9,11 The predominant isoform of this enzyme in the corpus cavernosum is phosphodiesterase-5 (PDE-5). 12 Inhibitors of the activity of this enzyme prevent the breakdown of cgmp, resulting in enhanced penile erection. The key steps in penile erection are illustrated in Figure Thus in men with ED, PDE-5 inhibitors do not automatically produce an erection, since they do not stimulate release of NO, which initiates the process. Rather, when cgmp levels increase in the penis during sexual excitation, these drugs amplify vasodilatation and consequent penile tumescence by inhibiting the breakdown of cgmp. Pharmacotherapy of Erectile Dysfunction There are several pharmacotherapeutic options available for ED. The most widely used pharmacotherapeutic agents and their mechanism of action are illustrated in Figure Given the central role of PDE-5 in penile erection, oral PDE-5 inhibitors are considered the first-line treatment. Other drug therapies are also available, but have had mixed results and therefore are considered second-line treatment options. These include α- antagonists such as oral yohimbine (Yocon), which is marginally effective and causes palpitation and elevated blood pressure 11 ; phentolamine (Vasomax), which is quite effective but causes significant hypotension 11 ; apomorphine (Uprima), a compound that stimulates dopamine receptors, which can cause vomiting severe enough to restrict its use 11 ; alprostadil (Caverject, MUSE), a prostaglandin E analogue, which effectively induces an erection, but must be injected directly into the penis or taken in the form of a suppository inserted into the urethra 11 ; and papaverine, a nonspecific PDE inhibitor and a vasodilator that is injected into the corpora cavernosa, which has a high rate of serious side effects, including priapism, fibrosis around the injection site, and hepatotoxicity. 11 Phosphodiesterase-5 Inhibitors There are currently three PDE-5 inhibitors approved in the United States for the treatment of ED (Table 134.1). All are Nitrergic innervation VIPergic innervation NO (nnos) Cavernosal smooth muscle VIP VIP-R Sildenafil Vardenafil Tadalafil Papaverine cgmp GTP Na + pump NO (enos) PDE-5 [Ca 2+ ] camp ATP Hyperpolarization FIGURE Molecular mechanism of penile erection and pharmacotherapeutic targeting. The critical step in penile erection is cavernosal smooth muscle relaxation mediated by intracellular second messengers cyclic adenosine monophosphate (camp) and cyclic guanosine monophosphate (cgmp), which activate specific protein kinases, which in turn phosphorylate certain proteins to cause opening of potassium channels, closing of calcium channels, and sequestration of intracellular calcium by the endoplasmic reticulum. The resultant fall in intracellular calcium leads to smooth muscle relaxation. Sildenafil, vardenafil, and tadalafil inhibit the action of phosphodiesterase (PDE) type 5, thus increasing the intracellular concentration of cgmp. Prostaglandin E (PGE) analogues K + PDE-2 4 K + channel Endothelium b 2 -ADR EP-R Noradrenaline Adrenaline Papaverine PGE Alprostadil such as alprostadil inhibit the action of PDE-2 4, thus increasing the intracellular concentration of camp. Papaverine is a nonspecific phosphodiesterase inhibitor, inhibiting both PDE-5 and PDE-2 4. Vasoactive intestinal peptide (VIP) and α-antagonist phentolamine (both approved in Europe but not in the United States) also act via the camp pathway; by blocking the α-adrenergic receptors, phentolamine allows unopposed activation of β 2 adrenergic receptors (β 2 ADR) by noradrenaline and adrenaline. GTP, guanosine triphosphate; ATP, adenosine triphosphate; enos, endothelial nitric oxide synthase; nnos, neuronal nitric oxide synthase; VIP-R, vasoactive intestinal peptide receptor; EP-R, endoprostanoid receptor.

3 erectile dysfunction and cardiovascular disease 2793 TABLE Phosphodiesterase-5 (PDE-5) inhibitors approved for treatment of erectile dysfunction Drug Sildenafil Vardenafil Tadalafil PDE selectivity PDE-5 vs PDE-6 10 fold 5 fold 700 fold PDE-5 vs PDE fold 1000 fold 10,000 fold Starting dose 50 mg 10 mg 10 mg Onset of action min min 15 min T max (median) 1 h 1 h 2 h Mean terminal half-life 4 h 4 5 h 17.5 h Duration of action 1 h 1 h >24 h Interaction with food High-fat meal High-fat meal Minimum to none Efficacy High High High Adverse effects Headache, flushing, dyspepsia, Headache, flushing, dyspepsia, Headache, myalgia, backache, visual effects increased CK dyspepsia Contraindications Nitrates Nitrates, α-blockers Nitrates, α-blockers other than 0.4 mg tamsulosin effective in patients with organic etiologies of ED, including vascular disease. Sildenafil (Viagra), the first PDE-5 inhibitor approved in 1998, and vardenafil (Levitra), the second PDE-5 inhibitor approved in early 2003, have similar chemical structure and pharmacologic and side-effect profile. Both have relatively short half-lives of 4 hours. Vardenafil is as effective as sildenafil (in about 65 80% of patients), although it may act sooner and be slightly more effective in diabetics. 13 Tadalafil (Cialis), approved in late 2003, has significant differences from the other two PDE-5 inhibitors. Its absorption is not affected by food. More importantly, it reaches maximum serum concentrations in 30 minutes to an hour, has a halflife of about 17.5 hours, and it remains effective for 24 to 36 hours. The longer duration of action allows patients and their partners far more flexibility in scheduling sexual activity. In addition to the side effects that it shares with the other drugs in its class, tadalafil may cause myalgia and back pain. On the other hand, unlike the earlier agents, its higher selectivity for PDE-5 compared to PDE-6 reduces visual side effects. Side effects, however, may last longer or be more pronounced than those of the other PDE-5 inhibitors. The PDE-5 inhibitors are all mild vasodilators and have generally minimal effects on blood pressure (<10 mm Hg drop in systolic or diastolic blood pressure), heart rate, and systemic and pulmonary hemodynamics when taken alone. 14,15 However, they should be used with caution in patients with left ventricle outflow tract obstruction such as hypertrophic cardiomyopathy and moderate-to-severe aortic stenosis, and patients with low blood pressure or blood volume as well as severely impaired autonomic control of blood pressure. 14,15 They do not exacerbate myocardial ischemia and are safe to administer in patients on antihypertensive medicines (except for the α-blockers). Furthermore, sildenafil specifically is well tolerated in patients on multiple antihypertensive agents 16 and in patients with stable congestive heart failure. 17 The most commonly reported side effects of PDE-5 inhibitors are attributed to vasodilatation, including flushing, nasal congestion and headache, dizziness and hypotension, or dyspepsia and reflux-related symptoms due to relaxation of the lower esophageal sphincter. Visual side effects are attributed to inhibition of PDE-6 in the retina. All three PDE-5 inhibitors are contraindicated with nitrate use because the vasodilator actions of nitrates are profoundly amplified with concomitant use of these drugs (Fig ), resulting in major hemodynamic compromise and potentially fatal Sexual stimulation Organic nitrates NO donors FIGURE Mechanism of PDE-5 inhibitor-nitrate hypotensive interaction. Nitric oxide (NO) is released in response to both sexual stimulation and treatment with nitrates or NO donor such as nitroprusside or molsidomine. Nitric oxide in turn increases cgmp, which causes relaxation of cavernosal and vascular smooth muscle cell leading to penile erection and vasodilatation, respectively. PDE- 5 inhibitors (sildenafil, vardenafil, and tadalafil) inhibit the action of phosphodiesterase (PDE) type 5, the enzyme responsible for the breakdown of cgmp, thus increasing the intracellular concentration of cgmp and amplifying the vasodilatory effect of nitrates/no donors, which could potentially result in profound hemodynamic collapse and fatal events. GTP GMP Nitric oxide (NO) Activates Guanylate cyclase PDE-5 Sildenafil Vardenafil Tadalafil Inhibits cgmp Cavernosal smooth muscle relaxation Vascular smooth muscle relaxation Penile erection Vasodilatation

4 2794 chapter 134 events. 14,15 This interaction applies to all nitrates including therapeutic and recreational forms such as amyl nitrate/ nitrite ( poppers ), and NO donors (nitroprusside, molsidomine, morpholinosydnonimine hydrochloride (SIN-1)). Nitrates may be administered under close supervision to patients developing chest pain or acute heart failure at least 24 hours after sildenafil 15 and vardenafil 14 and 48 hours after tadalafil. 14 α-antagonist therapy also is a contraindication by the use of vardenafil and tadalafil except for 0.4 mg tamsulosin, and may be used only with 25-mg dose of sildenafil. 14 Vardenafil should not be administered to patients taking class IA or III antiarrhythmic drugs 14 or to patients with congenital QT prolongation. 14 All three agents require dosage adjustment in the elderly, and in patients with hepatic impairment, severe renal impairment, or concomitant use of cytochrome P-450 3A4 inhibitors such as grape juice, cimetidine, erythromycin, antifungals, fluoxetine, or antiretrovirals. 14,15 The potential for interaction of PDE-5 inhibitors with other frequently used cardiovascular medications such as clopidogrel, dipyridamole, or nesiritide remains unexplored and therefore warrants caution. The interaction with nesiritide warrants special attention because nesiritide (like nitrates) increases cgmp (via activation of membrane-bound guanylate cyclase) and may likely cause profound vasodilatation leading to hypotension and shock when used concomitantly with PDE-5 inhibitors. Thus, the usual nitrate precautions and recommendations for PDE-5 inhibitors should likely be considered for nesiritide as well. The PDE-5 inhibitors are the most commonly prescribed treatment for ED. They are effective and safe in most patients, including patients with chronic coronary artery disease, stable congestive heart failure, and hypertension. However, they have not been studied extensively in patients with baseline severe or unstable cardiac conditions. Cardiovascular Safety of Therapy of Erectile Dysfunction The issue of cardiovascular safety of therapy of ED involves two different issues: the cardiovascular safety of the sexual activity itself, and the safety of current therapies. Cardiovascular Risk Associated with Sexual Activity The physiologic stress of sexual intercourse in men with cardiovascular disease elicits a hemodynamic response similar to moderate exercise, with an energy expenditure of approximately of 5 to 6 metabolic equivalents (METS) Systolic blood pressure (BP) may increase to 150 to 180 mm Hg and heart rate to 120 to 130 beats/min. 17 Environmental factors such as extreme temperatures, anxiety or fear, alcohol intake, heavy meals, or extramarital relations may increase sexual intercourse related energy expenditure. 21 Conversely, exercise training 22 and antianginal therapy with beta-blockers 23 may reduce oxygen consumption and favorably modify metabolic expenditure during sexual activity. Sexual activity induces myocardial ischemia (mostly silent) in one third of patients, 24 provokes ventricular arrhythmia (mostly benign premature ventricular beats), 25 and has a low likelihood of triggering an MI in patients with CAD. 26 Stroke during coital activity is very rare. An old Japanese study reported 0.6% 27 and a recent German study reported 0.19% of all sudden deaths cases attributable to coital activity. 28 Nearly 80% of these deaths occurred during extramarital sexual activity the so-called extramarital coronary. Thus, extramarital sexual activity appears to increase the risk of death, possibly related to enhanced sympathetic activity related to arousal, anxiety, and fear. For example, Cantwell 29 reported a higher heart rate on Holter monitoring in a patient enrolled in a cardiac rehabilitation program during sexual intercourse with an extramarital partner (increase in heart rate from 96 to 150 bpm) than during sexual intercourse with his spouse (increase from 72 to 92 bpm). Put into proper perspective, however, the risk of sexual activity triggered MI is quite low. Muller et al. 26 reported that although the relative risk was increased 2.5-fold over baseline, the absolute (attributable) risk was only 0.9%. In contrast, physical exertion and anger account for as many as 5% and 3% of acute MIs, respectively. 30,31 This increased risk was restricted to the 2-hour time period after sexual intercourse, after which there was no increased risk of MI. The relative risk was not increased in patients with a prior history of cardiac disease or history of angina. Regular exercise appeared to prevent triggering, consistent with the findings of the Caerphilly Cohort Study, which suggested that habitual sexual activity (a surrogate for regular exercise) had a protective effect on men s health. 32 An alternative way to provide perspective is to use the Framingham Heart Study to estimate the annual risk of MI in a 50-year-old healthy, nonsmoking, nondiabetic American male, which is about 1%. 33 This risk increases to 1.01% as a consequence of sexual activity. In a high-risk male with a previous history of MI, the annual risk increases from 10.0% to 10.1% (Table 134.2). From these data we can conclude that sexual activity is associated with a small risk of an adverse cardiovascular event. It is possible that the risk may be greater in patients if they perform at higher cardiac and metabolic expenditures during coitus, such as with an unfamiliar partner or in unfamiliar settings. It is also plausible that the increased physiologic stress during renewed vigorous sexual activity (facilitated by successful treatment for ED) after a long period of sexual and physical inactivity might contribute to enhanced cardiac risk. TABLE Risk of triggering nonfatal myocardial infarction (MI) with sexual activity Probability Incidence (in million/h) (%/year) Risk stratum Baseline Sex Baseline Sex Low-risk 1 2 1% 1.01% High-risk % 10.1% Relative risk = 2.0 (for the first 2 hours postcoitus). Attributable risk = 1%.

5 erectile dysfunction and cardiovascular disease 2795 Cardiovascular Risk Associated with Therapies for Erectile Dysfunction Clinical Trial Data of PDE-5 Inhibitors and Cardiac Risk The cardiovascular safety data for sildenafil pre Food and Drug Administration (FDA) approval was derived mostly from phase II/III double-blind and open-label studies encompassing >3700 patients on active treatment and 2000 patients on placebo. 34 In these trials, serious cardiovascular events (4.1 and 5.7 incidence per 100 patient-years), myocardial infarction (1.7 and 1.4 incidence per 100 patient-years), and death (0.53 and 0.57 incidence per 100 patient-years) occurred with comparable frequency in the sildenafil and placebo treatment groups, respectively. 34 However, only a small number of patients with CAD or risk factors for CAD (25% with hypertension and 17% with diabetes) a relatively common occurrence in patients with ED were enrolled in these studies. 34 Following FDA approval, Mittleman et al. 35 pooled data from 124 clinical trials conducted with sildenafil from 1993 to 2001 involving 5054 placebo-treated and 6896 sildenafiltreated patients in a double-blind design, representing 2593 person-years of observation (949 with placebo and 1644 with sildenafil) (Table 134.3). Although the odds ratio tended to favor placebo [1.14, 95% confidence interval (CI) 0.49 to 2.64], the overall MI incidence rate was similar in placebo-treated (0.95/100 person-years) and sildenafil-treated patients (0.85/100 person-years; p =.801). All-cause mortality showed a similar trend (odds ratio of 1.32, 95% CI 0.44 to 3.94) with no significant difference in the incidence rates. Analysis of the open-label studies also did not show a difference in MI or all cause mortality between the two groups. The overall open-label and double-blind sildenafil mortality rates were 0.37 per 100 patient-years, which compares favorably with 0.66 per 100 patient-years mortality rate reported in agestandardized reference male population in the United States. 36 The authors concluded that rates of MI and cardiovascular death were low and comparable between sildenafil and placebo treatments. 35 Similar results have been observed with tadalafil, with the rate of MI across controlled and openlabel studies reported to be 0.33 per 100 patient-years among 10,460 patients treated with tadalafil versus 0.41 per 100 patient-years among 2118 patients receiving placebo. 37 A preliminary report regarding vardenafil also did not demonstrate an increase in adverse cardiovascular events with this agent compared to placebo. 38 These results suggest that the incidence of serious cardiovascular adverse events including MI and death among patients who received double-blind or open-label treatment with PDE-5 inhibitors is similar to those observed among patients who received placebo or in men in the same age cohort of the general population. Cardiovascular Risk in Patients with Known Coronary Artery Disease The cardiovascular effects of PDE-5 inhibitors, especially sildenafil, have been evaluated in men with concomitant ED and CAD. An analysis of clinical trials with sildenafil indicated no difference in the incidence of serious cardiovascular adverse events or MI in patients with or without CAD for either active or placebo-treated group. 39 This analysis, however, was retrospective, selective (only 11 out of 18 studies considered), and included a small number (<10% of 3700) of patients with stable CAD (off nitrates and anticoagulants). Furthermore, significant heterogeneity in the dose (5 200 mg) and duration (1 6 months) of sildenafil treatment and small sample size (not powered for statistical significance) limit the confidence of this selective, post-hoc subgroup analysis. Two additional small studies have evaluated the efficacy and safety of long-term treatment with sildenafil prospectively in patients with CAD one involving 142 patients with stable CAD 40 and the other in which 20% of 224 patients had stable CAD, and the remaining 80% had hypertension. 41 No treatment-related adverse cardiovascular events were noted in the sildenafil group. The results of these studies suggest that sildenafil is effective in a high percentage (70% success rate) and well tolerated in men with ED and stable CAD. Data specific to the two other approved PDE-5 TABLE Clinical trial update of incidence rates: myocardial infarction (MI) and all-cause mortality* PY of No. of Rate/100 PY Incidence rate Group observation** events (95% CI) ratio (95% CI) p value Incidence of MI Placebo ( ) 0.90 ( ).801 Sildenafil, DB 1, ( ) Sildenafil, OL 10, ( ) Sildenafil, total 12, ( ) Incidence of all-cause mortality Placebo ( ) 1.04 ( ).945 Sildenafil, DB 1, ( ) Sildenafil, OL 10, ( ) Sildenafil, total 12, ( ) CI, confidence interval; DB, double-blind; OL, open label; PY, person-years. * The data are as of September 30, 2001, and are adapted from Mittleman et al. 35 ** Total number of double-blind patients: placebo, 5054; sildenafil, 6896.

6 2796 chapter 134 inhibitors tadalafil and vardenafil have not been reported in detail in CAD patients. A number of studies have also used exercise or stress tests to evaluate the effects of PDE-5 inhibitors in patients with coronary artery disease Most of these studies have enrolled small number of subjects (<110) and focused on the acute (single-dose) administration of these agents during exercise stress tests to determine whether they exacerbate ischemia. The overall results of these investigations suggest that PDE-5 inhibitors do not exacerbate ischemia or worsen exercise tolerance in patients with known CAD who achieve levels of exercise comparable or greater than that achieved during sexual intercourse. However, most of these studies fail to address the risk of serious cardiac events when sexual activity is combined with PDE-5 inhibitor therapy. It is generally accepted that exercise-induced myocardial ischemia may be a useful surrogate for sexual activity induced myocardial ischemia. 15,20,24 However, it has important clinical limitations in predicting serious cardiac events related to sexual activity (with or without PDE-5 inhibitor) because not all cardiovascular risk pertains to ischemia. It fails to replicate the stress associated with sexual arousal, which can be associated with significant sympathetic discharge, and may contribute to the development of ventricular arrhythmias in susceptible individuals. 15 The great majority of serious cardiac events will not occur in patients with inducible ischemia caused by obstructive lesions, but rather in patients who experience rupture of vulnerable but unobstructive lesions. Furthermore, the frequency of serious clinical events related to sexual activity is so low that large numbers of patients would be needed to address any potential impact on clinical events. The studies conducted to date have not been sufficiently powered to address this issue. The enrollment criteria used in these studies excluded many men who regularly receive PDE-5 inhibitor outside the controlled environment of a clinical investigation and may be at an increased risk. Lastly, the risks associated with repeated administration of PDE-5 inhibitor (not an uncommon scenario in the real world) were not assessed in these studies. One particular study that evaluated the effect of a single oral 100-mg dose of sildenafil on coronary, pulmonary and systemic hemodynamics in 14 patients with CAD (>70% stenosis) scheduled for elective percutaneous coronary intervention has garnered a lot of interest. 48 No adverse cardiovascular effects of sildenafil were observed including any evidence of coronary steal phenomenon, thereby leading the authors to conclude that sildenafil was safe from a cardiovascular point of view. However, there are significant limitations of this study that preclude a definitive conclusion of sildenafil s safety: (1) it was a single-dose, open-label study with no controls; (2) the study was conducted following premedications such as diazepam and with no physical or psychological stress mimicking the metabolic expenditure associated with sexual activity; and (3) the study had an insufficient sample size with a type II error (probability of not observing an adverse event) of 20%, which is not reassuring for a drug that is used by millions worldwide. 49 In this regard, the findings of the prospective randomized milrinone survival evaluation (PROMISE) clinical trial, 50 in which treatment with milrinone, a potent PDE-3 inhibitor, was associated with an increased incidence of arrhythmia and death in patients with congestive heart failure (CHF) despite a favorable acute hemodynamic profile, warrant caution. However, the currently approved PDE-5 inhibitors have a to 10,000-fold greater selectivity for PDE-5 over PDE-3, 14 and therefore are less likely to be associated with proarrhythmic effects. A potential mechanism by which PDE-5 inhibitors can exhibit a milrinone-like proarrhythmic effect is via inhibition of cyclic adenosine monophosphate (camp)-hydrolyzing PDE-3 by cgmp. 12,51 Elevation of cgmp by PDE-5 inhibitors, therefore, may mediate elevation of camp via this cross-talk between PDE-5 and PDE-3. This increase in camp levels can potentially augment campmediated effects in various tissues where PDE-3 is localized, for example, Ca 2+ current (I Ca ) in cardiac myocytes leading to lowered threshold for arrhythmia as depicted in Figure The possibility of arrhythmogenesis related to this mechanism has been proposed on theoretical grounds, 15 and has been supported by observation of Stief et al., 52 who demonstrated increasing camp and cgmp concentrations in isolated human auricles in response to sildenafil. Additional observations have suggested both potential protective and detrimental effects of sildenafil on cardiovascular outcomes. The beneficial effects include improvement in flow-mediated brachial artery vasodilatation 53 and exercise capacity 54 in patients with CHF, amelioration of primary or hypoxemia-induced pulmonary hypertension 55,56 and highaltitude pulmonary edema, 57 dilatation of epicardial coronary arteries, improvement in endothelial dysfunction, NO Nitrates NO donors Neuronal release PDE-5 inhibitors GTP cgmp Cardiomyocyte PDE-5 [Ca 2+ ] Arrhythmia ATP PDE-3 camp b 2 -ADR Triggered Automaticity Reentry Electrical Inhomogeneity Noradrenaline adrenaline PDE-3 inhibitors milrinone Vesnarinone Enoximone Dipyridamole Theophylline Pentoxifylline Papaverine FIGURE Potential mechanism of arrhythmogenesis associated with PDE-5 inhibitors via cross-talk between cgmp and camp cell signaling pathways.

7 erectile dysfunction and cardiovascular disease 2797 inhibition of platelet activation in patients with CAD, 58 a favorable effect on aortic stiffness and wave reflection in patients with CAD, 59 inhibition of ischemia-induced endothelial dysfunction through opening of adenosine triphosphate (ATP)-sensitive potassium channels in humans, 60 prevention and reversal of cardiac hypertrophy and adverse remodeling in mice, 61 an ischemic preconditioning effect leading to cardioprotection via opening of mitochondrial ATP-sensitive potassium channels in rabbit hearts, 62 and a direct antinecrotic and antiapoptotic effect on isolated mice ventricular cardiomyocyte, 63 among others. In contrast a potential for harm is suggested by two cases of ventricular tachycardia occurring during sexual intercourse in males with previous MI and using sildenafil, 64 prolongation of cardiac repolarization in isolated guinea pig hearts by high plasma concentration of sildenafil, 65 triggering of ventricular tachyarrhythmia by sildenafil in the presence of a NO donor in isolated swine heart, 66 sympathetic activation by sildenafil in healthy humans, 67 and potentiation of platelet activation in patients. 68 High-risk patients have generally been excluded from PDE-5 inhibitor clinical trials or investigations, such as those with unstable CAD, a recent history of MI and stroke (in the past 6 to 8 weeks or sooner), moderate to severe congestive heart failure/cardiomyopathy, severe valvular heart disease, uncontrolled hypertension, borderline low blood volume and low blood pressure status, and patients taking medications that may affect the metabolic clearance of PDE- 5 inhibitors. 15 From these data, we can reasonably conclude that the risk of an adverse cardiac event associated with PDE-5 inhibitor is low in a low-risk population including patients with risk factors for CAD. Even though the number of patients with stable CAD who have been evaluated prospectively for longterm safety with PDE-5 inhibitors is not large, it appears that these drugs, especially sildenafil, exhibit a favorable cardiovascular profile that permits their safe use in these patients. However, it is difficult to draw firm conclusions about the risk in high-risk patients with unstable cardiovascular disease in whom the drugs could be potentially hazardous. Post-Marketing Surveillance Studies Post-marketing surveillance identifies adverse events as they occur across the range of real-world medical practice in a broader, more susceptible population. Further, it can detect rare events that occur with the frequency of less than 1 in 1000, which most pre-marketing trials do not. For example, patients with ED who were treated with sildenafil in the premarketing trials are not representative of those in the general population with respect to cardiovascular risk factors. 34 Thus, in the absence of controlled data demonstrating the safety of PDE-5 inhibitors across a broad group of patient population at risk, post-marketing analysis of adverse events is a reasonable means for assessing the safety of this medication. One such analysis was published by Wysowski et al. 69 from the FDA, comparing the reported versus the expected deaths in sildenafil users. They found that the number of deaths due to MI in sildenafil users was not greater than the number that would be expected for this age group. 69 The obvious limitation of this analysis is that the number of drug-associated deaths reported to the FDA may represent only a fraction of the true number typically, only 1% to 10% of actual adverse events are reported. Consequently, it is not possible to derive an accurate estimate of the incidence of an adverse event, as neither the true numerator nor the true denominator is known. It is also difficult to ascertain the prevalence of medication use as the number of prescriptions (which can be tracked) does not accurately reflect the number of patients in a given population. Thus, it is difficult to draw firm conclusions from these data, given the lack of case controls. An interesting observation in the FDA report was that most deaths, where the time from ingestion of sildenafil to death or to the onset of symptoms leading to death is available, were clustered around the time of dosing, that is, 66% within 4 to 6 hours and 75% within 24 hours (consistent with the plasma half-life of 6 hours). Although the plasma half-life is only 6 hours, the blood level of sildenafil does remain significant for 24 hours after taking a 100 mg dose, that is, 4 nm, which is within the concentration that inhibits 50% (IC 50 ) for PDE-5 of 3.7 nm. 13 Although the FDA data do not prove that these deaths were caused by sildenafil, a temporal relationship between the time from ingestion of sildenafil to death or to the onset of symptoms leading to death suggests an association. A critical question is whether the risk associated with treatment of erectile dysfunction is unique to one particular treatment or common to all forms of ED therapy. Table summarizes the results of a preliminary analysis of deaths associated with various treatment of ED reported to the FDA adverse event reporting system from April 28, 1998, through July 8, These data reveal a disproportionately higher number of deaths associated with sildenafil as compared with other treatments for ED. If the renewed sexual activity is the cause of the deaths and adverse events, then it would seem logical that all therapies (systemic or local) associated with renewed or continued sexual activity would have similar effects. The differences between the reported event rates with sildenafil and other treatments are so large as to question the validity of the argument that deaths occurring among sildenafil users are simply a reflection of the nonspecific hazards of sexual activity and not attributable to the drug. In fairness, however, one could reasonably argue that the capture of adverse events with sildenafil via spontaneous reports is much greater than any previous therapy given the extent of public awareness and the immense media coverage and publicity. Shakir et al. 71 reported the results of a prescription event monitoring study performed in England. Questionnaires TABLE Deaths of men treated for erectile dysfunction through July 8, 1999 No. of Deaths per No. of prescriptions, million Drug deaths in millions prescriptions Viagra (sildenafil citrate) Yocon (yohimbine) MUSE (transurethral alprostadil) Caverject (injectable alprostadil)

8 2798 chapter 134 were filled out by 5601 sildenafil users with a mean age of 57. The mortality from ischemic heart disease and MI in this cohort was 30% lower than for the general population of English men in 1998 after adjusting for age. The authors concluded that there was no evidence of a higher incidence of death from MI or ischemic heart disease among men taking sildenafil than the general age-adjusted population. This study is limited by small sample size (typical prescription event monitoring study number 10,000 subjects), short follow-up (average length of 4.9 months), fairly low response rate (only 5601 out of 9748 responded), small number of deaths [10, six from MI and four from ischemic heart disease (IHD)], and lack of information about underlying diseases and medications. The data are, however, particularly appropriate for the United Kingdom, where there are governmentmandated contraindications to sildenafil. Post-marketing surveillance data regarding cardiovascular events have yet to be released for tadalafil and vardenafil. From these findings, we can conclude within the limitations of post-marketing surveillance that there is no excess risk of an adverse cardiac event associated with PDE-5 inhibitors (specifically sildenafil) in the general population. To recap, data from controlled clinical trials, open-label long-term extension, small case series, and post-marketing studies suggest that PDE-5 inhibitors (especially sildenafil) are highly effective. A large body of evidence suggests that these drugs are safe when used appropriately in patients at low risk, including patients with risk factors for CAD There are few prospective controlled data evaluating longterm safety of these drugs in patients with stable CAD. The risk in high-risk groups of patients with significant cardiac disease is virtually unknown at the present time since these patients have generally been excluded in the clinical trials of PDE-5 inhibitors. More prospective randomized controlled clinical trial data are needed to assess the specific risks of PDE-5 inhibitors among these cardiovascular patients. Until the real risk in a broad category of at-risk cardiac patients is properly delineated, one should exercise caution in prescribing and using these drugs. The wide availability of this class of drugs through the Internet without proper medical evaluation has raised concern. Self-administration either for medicinal use by patients reluctant to reveal erectile dysfunction to their physicians or for recreational abuse by individuals who coadminister poppers (inhaled amyl nitrate) for enhanced sexual activity remains potentially risky. 75 In some populations, the use of these drugs is associated with increasing risk for sexually transmitted diseases, including HIV infection. 76 Guidelines and Recommendations for the Use of PDE-5 Inhibitors in Patients with Cardiovascular Disease A number of consensus statements and practice guidelines have been published on the management of ED in patients with cardiovascular disease. The American College of Cardiology (ACC) and American Heart Association (AHA) Expert Consensus Document recommendations for the use of sildenafil in cardiac patients with ED are summarized in Table Two other consensus statements, one from the United TABLE Recommendations for use of PDE-5 inhibitors A. Men with cardiac disease 1. PDE-5 inhibitors are absolutely contraindicated in men taking long- or short-acting nitrates, nitric oxide donors and α- adrenergic antagonists (except low-dose sildenafil). 2. If the man has stable coronary disease and does not need nitrates regularly, the risks of PDE-5 inhibitors should be carefully discussed with him. If the man requires nitrates because of mild-to-moderate exercise limitation due to coronary disease, PDE-5 inhibitors should not be given. Alternatively, nonnitrate pharmacologic agents, such as betablockers or calcium channel blockers, should be considered for angina relief. 3. All men taking an organic nitrate (including amyl nitrate) should be informed about the nitrate PDE-5 inhibitor hypotensive interaction. 4. Men must be warned of the danger of taking sildenafil and vardenafil 24 hours or tadalafil 48 hours before or after taking a nitrate preparation. 5. Before PDE-5 inhibitors are prescribed, treadmill testing may be indicated in some men with cardiac disease to assess the risk of cardiac ischemia during sexual intercourse. If the patient can achieve 5 to 6 METS without demonstrating ischemia, the risk of ischemia during coitus with a familiar partner, in familiar settings, without the added stress of a heavy meal or alcohol ingestion, is probably low. 6. PDE-5 inhibitors should not be considered in patients with high cardiovascular risk such as unstable or refractory angina, moderate to severe congestive heart failure, recent MI or stroke (<2 weeks), high-risk arrhythmias, hypertrophic, obstructive, and other cardiomyopathies and moderate to severe valvular disease. B. Management of acute ischemic syndromes in men with PDE-5 inhibitors 1. All men presenting with acute ischemic syndromes should be routinely asked about history of PDE-5 inhibitor administration. 2. Treatment of acute ischemic syndromes including acute MI in a patient who has recently taken PDE-5 inhibitor should be the standard, except for the administration of nitrates. Precordial pain can be treated with narcotic analgesics, beta-blockers, calcium channel blockers, aspirin, thrombolytics, percutaneous coronary intervention, or anticoagulants following the standard treatment. 3. Nitrates may be administered at least 24 hours after sildenafil and vardenafil and at least 48 hours after tadalafil if close monitoring is provided and proper facilities are available for fluid and vasopressor support. 4. In patients in whom the half-life of PDE-5 inhibitors may be prolonged, such as in renal and hepatic dysfunction or patients concurrently taking potent CYP 3A4 inhibitors, a more extended period of time from PDE-5 administration to the time of nitrate administration may be required. C. Treatment of the hypotensive patient with inadvertent PDE-5 inhibitor-nitrate combination effect 1. Immediately stop nitrate (or nitroprusside) treatment. 2. Place the patient in the Trendelenburg position. 3. Provide aggressive fluid resuscitation. 4. Provide judicious use of an intravenous α-adrenergic agonist such as phenylephrine (Neo-Synephrine). 5. Provide an α- and β-adrenergic agonist (norepinephrine) for blood pressure support, with the realization that this could exacerbate or lead to an acute ischemic syndrome. 6. Provide intraaortic balloon counterpulsation. Kingdom 77 and the other from the United States (the Princeton Consensus Panel), 19 provide management recommendations based on the stratification of patients into low-, intermediate-, and high-risk categories (Table 134.6). The

9 erectile dysfunction and cardiovascular disease 2799 TABLE Risk stratification for sexual activity in patients with cardiovascular disease Low risk Asymptomatic, <3 major risk factors for CAD Controlled hypertension Mild, stable angina Successful coronary revascularization Uncomplicated post-mi (>6 8 weeks) Mild valvular disease Modified left ventricular disease/congestive heart failure (NYHA class I) Intermediate risk Three or more major risk factors for CAD, excluding gender Moderate, stable angina Recent MI (>2 weeks, <6 weeks) Left ventricular disease/congestive heart failure (NYHA class II) Noncardiac sequelae of atherosclerotic disease (e.g., stroke syndrome, peripheral vascular disease) High risk Unstable or refractory angina Uncontrolled hypertension Left ventricular disease/congestive heart failure (NYHA class III/IV) Recent MI (<2 weeks), stroke syndrome High-risk arrhythmias Hypertrophic, obstructive, and other cardiomyopathies Moderate/severe valvular disease CAD, coronary artery disease; MI, myocardial infarction; NYHA, New York Heart Association. stepwise risk stratification and management algorithm outlined in the Princeton Consensus Panel recommendations is illustrated in Figure Most patients (nearly 60 70%) with cardiovascular disease are categorized as low risk and can safely initiate or resume sexual activity or receive PDE-5 inhibitor treatment for ED provided there are no contraindications (nitrates or α-blockers). Patients at high risk (10 15%) should be stabilized with treatment before resumption of sexual activity or initiation of any treatment for ED. Patients at intermediate risk (15 30%) should receive further cardiovascular evaluation before restratification into either the lowrisk or high-risk group. There are three additional consensus Low risk Initiate or resume sexual activity Rx for ED Sexual Inquiry Clinical Evaluation Intermediate risk CV assessment and Restratification High risk Sexual activity deferred until cardiac stabilization FIGURE Stepwise risk stratification and management algorithm in patients with erectile dysfunction. documents from Canada, 78 Israel, 79 and Australia, 80 which are generally more stringent in their recommendations for use of sildenafil for treatment of ED in patients at risk compared to the U.K. and the U.S. guidelines. However, the key message common to all published guidelines is that with the exception of patients with ED who are taking nitrates (and α-blockers), most patients can safely take sildenafil (and other PDE-5 inhibitors) for ED if they are deemed to be at low risk after an appropriate cardiovascular risk assessment. References 1. Feldman HA, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151: Kloner RA, Jarow JP. Erectile dysfunction and sildenafil citrate and cardiologists. Am J Cardiol 1999;83: Dhabuwala CB, Kumar A, Pierce JM. Myocardial infarction and its influence on male sexual function. Arch Sexual Behav 1986; 15: Kloner RA, et al. Erectile dysfunction in the cardiac patient: how common and should we treat? J Urol 2003;170:S46 S Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the tip of the iceberg of a systemic vascular disorder? Eur Urol 2003;44: Blumentals WA, Gomez-Caminero A, Joo S, Vannappagari V. Should erectile dysfunction be considered as a marker for acute myocardial infarction? Results from a retrospective cohort study. Int J Impot Res 2004;16: Kaiser DR, et al. Impaired brachial artery endotheliumdependent and -independent vasodilation in men with erectile

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