Erectile dysfunction and cardiovascular disease.

CLINICAL FOCUS: UROLOGICAL DISORDERS

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Erectile Dysfunction and Cardiovascular Disease

Arthur Menezes, MD 1 Surya Artham, MD, MPH 1 Carl J. Lavie, MD 1 Richard V. Milani, MD 1 James O’Keefe, MD 2 1

Department of Cardiovascular Diseases, John Ochsner Heart and Vascular Institute, Ochsner Clinical School–The University of Queensland School of Medicine, New Orleans, LA; 2 Mid-America Heart Institute, Kansas City, MO

Abstract: Cardiovascular disease (CVD) and erectile dysfunction (ED) are 2 closely intertwined disease processes. Over the past 2 decades, there have been many studies that have linked both conditions and established ED as a risk factor for CVD. In the United States and worldwide, a large population of adult men has ED and/or CVD. Worldwide, approximately 140 million men have ED, and the number is expected to double in the next 15 years. Because ED and CVD share many of the same risk factors, the relationship between CVD and ED is a very valid concern. Our goal is to examine the association and pathophysiological relationship between ED and CVD. We will also review common risk factors, current treatments, and management of the 2 conditions. Finally, we will discuss the risks of sexual activity in patients who have CVD. Keywords: cardiovascular disease; erectile dysfunction; hypertension

Introduction

Correspondence: Carl J. Lavie, MD, Medical Director, Cardiac Rehabilitation and Prevention, Director, Exercise Laboratories, John Ochsner Heart and Vascular Institute, Ochsner Clinical School–The University of Queensland School of Medicine, 1514 Jefferson Highway, New Orleans, LA 70121-2483. Tel: 504-842-5874 Fax: 504-842-5875 E-mail: [email protected]

Erectile dysfunction (ED) is the inability to produce a penile erection, or the inability to produce an erection that is sustained and/or firm enough for completion of sexual intercourse.1 Erectile dysfunction is a highly prevalent and growing problem in the United States and worldwide. It has been estimated that nearly 140 million men worldwide experience ED to a variable degree, and by 2025 ED is predicted to affect ⬎ 300 million men.2 There are many important risk factors that contribute to the development of ED. Age is a very significant ED risk factor, as the prevalence of ED increases with increasing age. A cross-sectional analysis of data from 2126 adult male participants in the 2001–2002 National Health and Nutrition Examination Survey (NHANES) demonstrated that the prevalence of ED in the general US male population aged ⱖ 20 years was approximately 18 million, with a distribution that differed markedly by age, ranging from 5% in men aged 20 to 39 years to 70% in men aged ⱖ 70 years.3 The Massachusetts Male Aging Study identified a prevalence of ED in 52% of men aged 40 to 70 years and 70% in men aged ⱖ 70 years.4 Over the years, many studies have shown a correlation between ED and cardiovascular (CV) risk.5,6 It has also been well documented that ED and CV disease (CVD) share many of the same risk factors (Tables 1, 2), which include: type 2 diabetes mellitus (T2DM), hypertension (HTN), dyslipidemia (DLP), smoking, and obesity.7 The main objective of this article is to systematically approach the connections between these 2 conditions and summarize information regarding the risk factors, treatment, and management of ED.

Mechanism of a Normal Erection Without the presence of sexual stimulation, the penis is normally in a flaccid state. This state is mediated by a baseline sympathetic tone that causes the release of norepinephrine from the penile adrenergic nerves, which results in the contraction of the

© Postgraduate Medicine, Volume 123, Issue 3, May 2011, ISSN – 0032-5481, e-ISSN – 1941-9260

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Table 1. Risk Factors Shared by ED and CVD Common Risk Factors


• • • • • • •

Type 2 diabetes mellitus Cigarette smoking and tobacco use Dyslipidemia Hypertension Obesity Increasing age Sedentary lifestyle

vasculature and the smooth muscles of the corpora cavernosa. In the presence of sexual stimuli, there is an increase in the parasympathetic tone, which causes a decrease in the release of norepinephrine and an increase in acetylcholine. Acetylcholine potentiates the activity of endothelial nitric oxide synthase (eNOS), resulting in an increase in available NO, which stimulates an increase in guanylate cyclase, thus causing increased production of intracellular cyclic guanosine monophosphate (cGMP). This leads to calcium efflux and relaxation of the corporeal smooth muscles. These changes

result in an almost 10-fold increase in the vascular flow. The additional inflow of blood is accommodated by engorgement of the relaxed cavernosal sinusoids, causing compression of the subtunical venules and the obliquely aligned emissary veins. This state of high inflow of blood and restriction of venous outflow due to compression allows blood to enter and remain in the penis, thus generating an erection until either ejaculation or withdrawal of sexual stimulation occurs.8 At the cessation of sexual stimulation, the baseline sympathetic tone becomes dominant once more, the cGMP is broken down by phosphodiesterase type 5 (PDE-5), and the penis returns to its flaccid state (Figure 1).9

Association Between ED and CVD Nearly a decade ago, it was questioned whether ED was a marker for CVD10 and whether ED was a predictor for future CVD events. The First Princeton Consensus Conference in 1999 examined the evidence linking ED and CVD, and used available data to develop guidelines for the management of cardiac patients with respect to ED treatment and

Table 2. Erectile Dysfunction and Baseline Characteristics in Men in the ADVANCE Trial Variable

Age at baseline examination, y Age at completion of education, y Glycated hemoglobin, % Height, cm Body mass index, kg/m2 Total blood cholesterol, mmol/L High-density lipoprotein cholesterol, mmol/L Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Resting heart rate, beats/min Serum creatinine, μmol/L Cognitive function, MMSE score Quality of life, EQ-5D score Diabetes duration, y Number of occasions of exercise ⱖ 15 min/week Number of alcoholic drinks/week Caucasian/European ethnicity, % Current cigarette smokers, % Use of metformin or beta-blockers, % Require assistance with daily activities, % History of major macrovascular disease, % History of major microvascular disease, % History of major diabetic disease, %

Erectile Dysfunction

P Value

No (n = 3146)

Yes (n = 3158)

64.8 ± 6.3 19.8 ± 7.4 7.4 ± 1.5 171.2 ± 7.0 27.8 ± 4.5 5.0 ± 1.1 1.19 ± 0.3

67.0 ± 6.4 19.0 ± 7.2 7.5 ± 1.50 171.2 ± 7.3 28.2 ± 4.9 4.9 ± 1.1 1.19 ± 0.3

0.001 0.001 0.004 0.843 0.005 0.002 0.634

143.8 ± 20.9 81.6 ± 11.0 73.4 ± 12.5 91.9 ± 22.1 28.8 ± 1.7 0.86 ± 0.2 7.5 ± 6.2 4.0 ± 6.3

145.8 ± 21.2 81.0 ± 10.7 73.0 ± 12.4 94.7 ± 26.4 28.5 ± 1.8 0.82 ± 0.2 8.5 ± 6.7 3.3 ± 5.6

0.002 0.026 0.283 0.001 0.001 0.001 0.001 0.001

4.5 ± 9.7 1852 (58.9) 604 (19.2) 2210 (70.2) 67 (2.1)

5.0 ± 9.8 2,037 (64.5) 485 (15.4) 2,227 (70.5) 111 (3.5)

0.057 0.001 0.001 0.814 0.001

1060 (33.7)

1,267 (40.1)

0.001

280 (8.9)

385 (12.2)

0.001

183 (5.8)

267 (8.5)

0.001

Abbreviations: ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation; MMSE, Mini-Mental State Examination. Reproduced with permission from J Am Coll Cardiol.22

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Erectile Dysfunction and Cardiovascular Disease Figure 1. Mechanism of penile erection, detumescence, and the activity of PDE-5 inhibitors. Erection

GTP Guanylyl cyclase

Smooth muscle relaxation cGMP

Nitric oxide PDE-5 Parasympathetic signal to penis

PDE-5 inhibitors (eg, sildenafil)

5’-GMP Arousal

Detumescence


Reproduced with permission from Mayo Clin Proc.9 Abbreviations: cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; PDE-5, phosphodiesterase type 5.

sexual activity.11 Over the years, many studies have shown an association between ED and CVD.11–14 Kaiser et al15 published a study that investigated whether patients with ED and no apparent CVD had any structural and functional abnormalities of their vasculature. The study concluded that patients with ED had defects in the endothelium-dependent and endothelium-independent peripheral vasodilation, even in the absence of any clinical CVD. This endothelial dysfunction is independent of other traditional CV risk factors, and occurs before the development of apparent functional or structural systemic vascular disease.15 The presence of endothelial dysfunction, in turn, affects the production of NO. This disruption in the production of NO leads to impaired relaxation and vasodilation of the arterioles.16,17 Currently, it is widely accepted that most cases of ED are associated with vascular endothelial dysfunction.18 The Second Princeton Consensus on Sexual Dysfunction and Cardiac Risk continued to recognize ED as a significant CV risk factor. According to this consensus statement, a man with ED and no cardiac symptoms or prior CVD should be considered as a cardiac/vascular patient unless proven otherwise.7 Subsequent studies have shown that ED is not only significantly associated with CVD events, but is also a strong predictor of future atherosclerotic CV events.12 It has also been reported that ED has been associated with coronary artery calcification, and that ED might justify consideration as a risk equivalent for coronary heart disease (CHD).19 Furthermore, the presence of ED at a younger age, cigarette smoking, the presence of comorbidities, and socioeconomic disadvantage were all associated with higher hazard ratios (HRs) for subsequent atherosclerotic CV events.20 In The Prostate Cancer Prevention Trial, Thompson et al13 reported that ED conferred a risk for CV events that was equal to or

greater than smoking, DLP, or a family history of premature CHD. In this study, 9457 men aged ⱖ 55 years were evaluated every 3 months for CVD and ED over a 9-year follow-up period. Among the 4247 men without ED at the beginning of the study, 57% reported incident ED after 5 years. After adjusting for the covariates, they demonstrated that incident ED was associated with an HR of 1.25 (95% confidence interval [CI], 1.02–1.53; P = 0.04) for subsequent CV events during study follow-up. The unadjusted risk for incidence of a CV event in men without ED was 0.015 per person-years at study entry, and was 0.024 per person-years for men with ED at study entry.13 It has also been shown that ED is associated with CVD, independent of established cardiac risk factors, age, and Framingham risk score.21 In a prospective, population-based study by Araujo et al,21 of 1709 men between the ages of 40 to 70 years, ED was assessed by self-reported symptoms, and the participants were followed for CVD for an average follow-up period of 11.7 years. In this cohort, 1057 men were free of CVD and diabetes at baseline, and 261 (25%) developed CVD. Of the 261 men who had CVD, 71 had fatal CV events. The study found that ED was associated with CVD incidence after controlling for age (HR, 1.42; 95% CI, 1.05–1.90), age and traditional risk factors (HR, 1.4; 95% CI, 1.05–1.90), and age and Framingham risk score (HR, 1.40; 95% CI, 1.04–1.88). However, they were unable to demonstrate that ED was a predictor of CVD development.21 Another prospective cohort study (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation [ADVANCE; Table 2]) established that baseline ED was associated with an increased risk of all CVD events (HR, 1.19; 95% CI, 1.08–1.32), including CHD events (HR, 1.35; 95% CI, 1.16–1.56) and cerebrovascular disease events (HR, 1.36; 95% CI, 1.11–1.67).22 The onset of sexual dysfunction should be used as a marker of subclinical systemic vascular disease and a predictor for future CVD events. Because ED and CVD share many of the same risk factors, including T2DM, HTN, DLP, smoking, sedentary lifestyle, and obesity (especially abdominal obesity),7,23 it is crucial that patients with ED be evaluated for CHD.24 Early diagnosis and treatment of these risk factors may play a major role in the reduction of CVD events.

Common Risk Factors T2DM It is estimated that approximately 35% to 75% of men with T2DM have ED.25 Furthermore, men with T2DM tend to develop ED 5 to 10 years earlier than men without


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T2DM.25 The following are the contributing factors for ED in patients with T2DM: 1) hyperglycemia causing failed relaxation of the corpora cavernosa and glycation of the elastic fibers; 2) the adverse effects of medications such as beta-adrenergic blocking agents and thiazide diuretics; 3) DLP; 4) a decrease in NO release resulting in impaired vasodilation; 5) decreased arterial and arteriolar inflow due to peripheral vascular disease; 6) diabetic neuropathy resulting in failed neural transmission from the spinal cord; 7) the presence of advanced glycation end products resulting in increased reactive oxidizing substances; and 8) hypogonadotrophic hypogonadism.26 It has been well documented that individuals with T2DM have a higher risk for myocardial infarction (MI), stroke, heart failure (HF), and CHD. In fact, it has been shown that in people with similar demographics, patients with T2DM have a 2 to 4 times higher chance of dying of CHD events than patients without T2DM.27 A meta-regression analysis showed that for every 1% increase in glycated hemoglobin (HbA1c), the risk for CVD increases approximately 18%.28 Furthermore, the UK Prospective Diabetes Study showed that achieving glucose control goals in T2DM could improve clinical outcomes. To explain further, in this 10-year study, the patient group that maintained an HbA1c of 7.0% exhibited a 25% relative risk reduction (RRR) in microvascular outcomes and a 12% RRR in other diabetes-related pathologies when compared with the group that maintained an HbA1c of 7.9%.29 We have recently reviewed the pros and cons of several available therapies for T2DM in the prevention of CVD events.30 It has also been well documented that men with T2DM have a higher prevalence of ED than patients without T2DM.31 A cohort study in 2008 of 2306 subjects showed that in men with T2DM but without any apparent CVD, the presence of symptoms of ED predicts the new onset of CVD.32 Furthermore, it also stated that the presence of ED in T2DM should be used to identify high-risk subjects, and further CV screening should be employed.32 Moreover, in patients with silent coronary ischemia, ED is a strong predictor of CV-related morbidity and mortality.10 In fact, the presence of T2DM has associations not only with ED, but all of the 5 sexual domains (sexual drive, ejaculatory function, sexual problems, sexual satisfaction, and ED).33

Cigarette Smoking Inhaling cigarette smoke, whether as an active or passive smoker, is a well-established risk factor for CVD. The pathophysiology of this can be attributed in part to an increase in

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oxidative stress and a decrease in NO generation and bioavailability. This leads to changes such as the development of atherosclerotic disease, vasomotor dysfunction, an increase in prothrombotic and decrease in fibrinolytic factors, leukocyte and platelet activation, increases in lipid peroxidation, smooth muscle proliferation, and an increase in adhesion and inflammation molecules.34 By the same degree, it could be inferred that vasculogenic ED has a similar causative mechanism. There is also strong indirect evidence that smoking causes ED by affecting NO production due to increased reactive oxygen species generation.35 Over the years, it has been established that there is a correlation between smoking and ED.26 A secondary analysis of a cross-sectional survey of 4462 American Vietnam Veterans between the ages of 31 and 49 years found that the prevalence of impotence was 2.2% among the men who never smoked, and 3.7% among smokers.36 This association remained significant even after the groups were adjusted for confounders such as age, race, mental health, marital status, vascular disease, hormonal status, and psychiatric disease. In addition, a recent study examining 7684 Chinese men suggested that an estimated 22.7% of ED in this cohort may be related to cigarette smoking, and demonstrated an independent and dose-related association between ED and cigarette smoking.37

Dyslipidemia Dyslipidemia is among the strongest independent risk factors for the development of atherosclerotic vascular disease. Subsequently, an increase in the frequency of impotence with age has also been associated with atherosclerotic changes of the arteries of the penis.38 This vasculogenic impotence may, therefore, also be related to DLP. Another mechanism that links hypercholesterolemia with ED may involve the activation of nicotinamide adenine dinucleotide phosphate oxidase in the penis. This would in turn be a source of oxidative stress, which would result in NO synthase uncoupling and endothelial dysfunction.39 Large prospective studies consistently show that a low level of high-density lipoprotein cholesterol (HDL-C) is a stronger risk factor for CHD than a high level of low-density lipoprotein cholesterol (LDL-C).40,41 A study on 250 men aged 26 to 83 years without any preexisting ED concluded that high levels of total cholesterol and a low level of HDL-C were also risk factors for ED.42 The study showed that every 1-mmol/L increase in total cholesterol was associated with a 1.32-fold increased risk of ED, while every 1-mmol/L increase in HDL-C was associated with 0.38 times the risk.42




We have recently reviewed the importance of HDL-C in preventive cardiology.40,43 Statins decrease the amount of circulating LDL-C by decreasing lipoprotein synthesis, as well as by increasing hepatic uptake and catabolism. A small study comprising 18 men showed that treating hypercholesterolemia might improve ED. In this study, increased cholesterol was the only risk factor present for ED. Penile rigidity was measured using RigiScan before and after treatment with atorvastatin. Of the 9 men who participated in the study, 8 men had improved penile rigidity and erection adequate for sexual intercourse.44 Another study assessed a total of 74 patients with a mean age of 44.7 ± 7 years with DLP. Erectile function was measured by using the International Index of Erectile Function (IIEF) questionnaire. Atorvastatin 40 mg daily was started for all of the patients and used for 12 months. The study found that although the lipid profile improved very early during statin treatment, erectile function only improved much later. They concluded that the delayed beneficial effects on ED might have occurred due to restoration of near-normal endothelial function.45 By contrast, some studies have shown that statin therapy may worsen ED.46,47 The use of statins has also been correlated with significantly lower total and calculated free testosterone. These lipid-lowering agents have also been associated with reduced testicular volume, a higher prevalence of hypogonadism-related signs and symptoms, and higher follicle-stimulating hormone levels.48

was published defining HTN as a mean systolic blood pressure of ⬎ 140 mm Hg and a mean diastolic blood pressure of ⬎ 90 mm Hg. This study showed that slightly less than half of the number of individuals with treated HTN (44.1%, 95% CI) had ED, and 19% of males with untreated HTN had ED (95% CI).3 Although not addressed in this study, this discrepancy in ED between treated and untreated HTN may be due to the side effects of antihypertensive medications, which have a propensity to cause ED. In fact, in a study of 5485 patients published in 1985, 8.3% of males with HTN stopped taking their antihypertensive medication due to sexual side effects.51

Management and Treatment In the 1970s, the introduction of the penile prosthesis was a major breakthrough in the treatment of ED. Advances in the treatment of this condition were seen in the next decade with the introduction of intraurethral injections, such as prostaglandins, papavarine, and other vasoactive agents. The discovery and use of sildenafil citrate and other oral systemic medications changed the approach to ED. Currently, oral agents are the mainstay therapy for ED.52 However, 30% to 40% of patients are nonresponders to these oral medications. Furthermore, many men who have successfully used oral medications for ED will most likely eventually need additional therapies (eg, penile prosthesis placement) as the ED progresses.52

Hypertension

Medications Most Commonly Used for ED

It has been estimated that between 38% and 42% of men with ED have HTN.49 Also, nearly 35% of men with HTN have ED.50 In 2007, a cross-sectional analysis of data from 2126 adult males who participated in 2000–2001 NHANES

The introduction of the oral PDE-5 inhibitor, sildenafil citrate, in the late 1990s, changed the approach to ED. Since then, 2 other drugs in this class have been developed and approved for the management of ED (Table 3). The PDE-5 inhibitors

Table 3. Erectile Dysfunction Drug Profiles Viagra (sildenafil)

Levitra (vardenafil)

Cialis (tadalafil)

Pharmaceutical form

25-, 50-, and 100-mg tablets

2.5-, 5-, 10-, and 20-mg tablets

5-, 10-, and 20-mg tablets

Onset of action

30 minutes (effect delayed if taken with food) 50 mg; the physician may adjust this dose to 100 mg or 25 mg, depending on the patient 4–5 hours

25 minutes (effect delayed by fatty meal) 10 mg; the physician may adjust this dose to 20 mg if 10 mg is insufficient 4–5 hours

16–45 minutes (effect not delayed by food) 10 mg; the physician may adjust this dose to 20 mg if 10 mg is insufficient

Facial flushing, headache, indigestion Altered vision, dizziness, nasal congestion

Facial flushing, headache

Headache, indigestion, facial flushing

Indigestion, nausea, dizziness, nasal congestion

Back pain, muscle aches, dizziness, nasal congestion

Recommended dose Duration of action Most common side effects Less common side effects


36 hours

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prevent the degradation of cGMP in the corpus cavernosum. This results in a sustained erection due to continued activation of NO-cGMP. These medications do not precipitate the formation or initiation of an erection in the absence of sexual stimuli.53 Overall, results have shown that the 3 PDE-5 inhibitors improve erectile function in the presence of concomitant HTN.50


Sildenafil Sildenafil was the first of the oral PDE-5 inhibitors. Since its introduction, sildenafil citrate has been shown to be effective for ED in ⬎ 100 clinical trials involving ⬎ 8000 men.54 The effectiveness of sildenafil varies according to the etiology of the ED. In clinical trials, including men with a broad spectrum of ED, approximately 80% noticed improvement in their symptoms with the use of this medication.55 In patients with spinal cord injuries, the response rate to this medication was between 75% and 88%,56–58 and those with depression had a 90% response rate.59,60 Sildenafil is usually started at a dose of 50 mg by mouth 30 minutes to 4 hours prior to sexual activity. According to the results, the medication can be downtitrated to 25 mg/day or increased to 100 mg/day. The maximum approved daily dose is 100 mg/day, and the maximum dosing frequency is once daily. Patients aged ⬎ 65 years or with renal or hepatic dysfunction should be started on a low starting dose of 25 mg/day. The plasma concentration peaks in approximately 1 hour, with a half-life of 4 hours.61,62 Ninetysix percent of the drug is metabolized by the cytochrome P450 3A4 in the liver.61 Patients with ED and CVD can safely take sildenafil as long as nitrates are not being taken concomitantly. A double-blind, placebo-controlled study in 151 men with ED and clinically stable CHD assessed the safety and efficacy of sildenafil. After 12 weeks of randomization, sildenafil-treated patients reported significant improvements in erection and intercourse compared with placebo-treated patients (64% vs 21% and 65% vs 19%, respectively). In these studies, no serious adverse CV events were reported with sildenafil, though occasional side effects occurred, including headache, chest pain, HTN, flushing, dyspepsia, leg cramps, respiratory tract infections, nasal congestion, and abnormal vision.62,63 One common and important drug–drug interaction involves the PDE-5 inhibitors and oral or sublingual nitrates. Many patients with a history of CHD do not use nitrates daily, but carry sublingual nitroglycerine for potential future use during angina pectoris. We believe that it is not necessary for such individuals to completely

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avoid PDE-5 inhibitors. However, it is essential that such individuals understand that they cannot use their sublingual nitrates for at least 24 hours after sildenafil or the other PDE-5 inhibitors (48–72 hours with taldalafil), and patients should also be told to inform their physicians that they are using PDE-5 inhibitors prior to starting any topical, oral, or intravenous nitrates. As stated earlier, approximately 35% of men with HTN have ED.50 Because HTN is a risk factor for the development of both ED and CVD, a high proportion of patients are prescribed both antihypertensive agents and PDE-5 inhibitors, both of which may act as vasodilators. In 2001, a post-hoc analysis published by Kloner et al64 examined the effect of sildenafil in ED patients who were taking antihypertensive medications, and safety was assessed in 3975 men who received sildenafil or placebo in 18 double-blind, placebocontrolled studies. Of the 3975 men, 1094 were taking ⱖ 1 antihypertensive agent, including diuretics, beta-blockers, alpha-1 blockers, angiotensin-converting enzyme inhibitors, or calcium channel blockers. Patients taking sildenafil and an antihypertensive medication had approximately the same incidence of treatment-related side effects (34%) when compared with patients taking sildenafil but no antihypertensive medication (38%), suggesting that sildenafil is a well-tolerated treatment in patients taking antihypertensive medications (which includes a multidrug regimen).64 Sildenafil was also effective in the treatment of ED in patients with T1DM and T2DM,65 even in the setting of poor glycemic control and other diabetic complications.66 However, even though sildenafil was an effective treatment in the setting of T2DM and ED, poorly controlled blood sugars, a longer duration of T2DM, and the presence of ⱖ 1 diabetic complication negatively affected the efficacy of sildenafil.67

Vardenafil Vardenafil was the second oral PDE-5 inhibitor to be approved by the US Food and Drug Administration for the treatment of ED. There have been numerous studies and clinical trials done to determine the efficacy of vardenafil in men with ED, as well as ED with underlying medical conditions.68,69 Vardenafil is usually started at a dose range of 10 mg approximately 1 hour before sexual intercourse. The recommended dose range is between 5 and 20 mg. Like sildenafil, it has a maximum dosing of once daily. Vardenafil is rapidly absorbed and reaches peak serum concentration in approximately 45 minutes when orally dosed in the fasting state. It is metabolized primarily by the cytochrome P450




3A4 enzyme in the liver and is predominantly excreted in the feces. Its half-life is approximately 4 to 5 hours. The most commonly reported adverse events (typical of those seen with PDE-5 inhibitors) in recipients of vardenafil 5 to 20 mg included headache, flushing, rhinitis, dyspepsia, and sinusitis. There were no reports of abnormal color vision in men with ED taking vardenafil at clinically recommended doses (5–20 mg).70 Vardenafil (5, 10, and 20 mg) significantly improved erectile function, penetration, and maintenance rates compared with placebo, irrespective of antihypertensive use (P ⬍ 0.001).70 Vardenafil significantly improved the erectile function in patients with T2DM, irrespective of their glycemic control. With respect to erectile function, the dosedependent final scores for 10 mg and 20 mg were 17.1 and 19.0, respectively (P = 0.003), when compared with 12.6 for the placebo group (P ⬍ 0.0001).71 In the case of T1DM, it has been shown that vardenafil also significantly improves erectile function regardless of glycemic control.72

Tadalafil Tadalafil is usually started at a daily dose of 2.5 mg to 5 mg without regard to the timing of sexual relation. It can also be dosed as needed at 10 mg at least 30 to 45 minutes before sexual activity. The dosing can be reduced to 5 mg or increased to 20 mg depending on patient response to the drug. Unlike sildenafil and vardenafil, this drug reaches peak serum concentration in approximately 2 hours. Furthermore, the half-life of tadalafil is approximately 17.5 hours when compared with the half-life of sildenafil and vardenafil, which is around 4 hours. Like sildenafil and vardenafil, this drug is metabolized by the cytochrome P450 3A4 enzyme. Also, similar to sildenafil and vardenafil, this medication is well tolerated and significantly improves sexual function in men with ED.73–75 We generally avoid this medication, however, in most patients with established CHD due to the fact that nitrates should not be utilized for 48 to 72 hours following the use of tadalafil, compared with only the 24 hours needed with the older 2 agents. However, in men without CVD, especially younger men with ED, the longer half-life provides a significant advantage for many patients, allowing for sexual activity to be less planned in advance, and potentially allowing several sexual encounters with only 1 dose.

Sexual Function and CV Risk Sexual activity appears to have protective effects against fatal CHD.76 A longitudinal study by Hall et al77 demonstrated that a low frequency of sexual activity was associated with an

increased risk of CVD (HR, 1.45; 95% CI, 1.04–2.01). This study also suggested that a low frequency of sexual activity predicted CVD independent of ED. Therefore, screening for sexual activity may be a useful tool in clinical practice.77 However, several studies have suggested that various activities, including sexual activity, may trigger acute CVD events, including acute MI. The study by Muller et al,78 who interviewed 1774 patients with MI in 45 hospitals across the United States, concluded that the relative risk of an MI after sexual activity was low. Outcomes and results were presented for 858 patients who were sexually active in the year prior to the MI. Of these patients, 79 (9%) patients reported having sexual activity within 24 hours of the MI, and 27 (3%) patients reported having sexual activity with the 2 hours preceding the MI. According to this study, the relative risk of an MI in the 2 hours after sexual activity was 2.5 (95 CI%, 1.7–3.7). Furthermore, this study stated that the relative risk of triggering an MI in patients with prior MI or angina was no greater than in those without cardiac disease,78 although the cardiac patients had considerably higher absolute risk of MI. Moreover, this study demonstrated that those who were physically inactive had a nearly 3-fold increased risk of MI during the 2 hours after sexual activity, whereas this risk was not significantly increased in those who performed moderate physical activity (at least 6 metabolic equivalents [METs] of exertion ⱖ 2 times weekly). A crossover analysis in the Stockholm Heart Epidemiology Program study showed similar results.79,80 It established that the relative risk of an MI was 2.1 (95% CI, 0.7–6.5) during the 1 hour after sexual activity, and among patients with sedentary lifestyles, the risk was 4.4 (95% CI, 1.5–12.9). It was concluded that patients should be counseled to maintain healthy, active lifestyle, and to avoid abstaining from sexual activity.79 According to the Second Princeton Consensus Conference, patients with ED should be categorized as low risk, intermediate risk, and high risk. Low-risk patients are those who are asymptomatic and have ⬍ 3 CV risk factors. This places them at a lower risk for manifestation of cardiac symptoms and complications during sexual activity and treatment of ED. Patients with controlled HTN may safely receive medical therapy for ED. It must be noted, however, that certain antihypertensive medications, such as traditional beta-blockers and thiazide diuretics, can frequently precipitate or exacerbate sexual dysfunction. Patients with mild, stable angina pectoris also fall into this category. If a patient with these symptoms is not found to have significant coronary ischemia on noninvasive evaluation, the relative risk of patients with CHD is not greater than in patients without documented CVD. With regards to


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patients who have been revascularized with bypass grafting or percutaneous coronary intervention, the risk of cardiac complications during sexual activity is inversely proportional to the adequacy of revascularization. In patients who have had an MI, those who can be classified as low risk and clinically stable can be cleared to resume sexual activity 4 to 6 weeks following the MI. However, in patients with small MIs and preserved left ventricular function, especially those who have received successful revascularization and/or have no inducible ischemia following MI, sexual activity can be resumed earlier, even within the first 2 to 4 weeks after the event. Patients with mild valvular disease and New York Heart Association (NYHA) class I do not have an increased risk for cardiac complications due to sexual activity. The intermediate-risk patients need further evaluation so that they may be placed in either the low-risk category or the high-risk category before resuming sexual activity. These patients may be asymptomatic but have ⬎ 3 risk factors for CHD. Due to this, these patients must get proper CV testing to assess ischemia during exercise or activity. Likewise, patients with moderate, stable angina pectoris at low-to-moderate workloads that can be reproducible on stress testing fall into this category. Some patients who are early after more complicated MIs, especially without revascularization or with inducible ischemia, may fall into this classification. Patients with NYHA class II HF are also at risk for cardiac complications and symptoms during sexual activity. Finally, patients with a history of stroke, transient ischemic attack, and peripheral artery disease should be evaluated. The high-risk patients comprise those individuals who are moderately to significantly symptomatic, and are at a substantial risk by engaging in sexual activity. In this case, the patient should avoid sexual activity until the patient’s condition is stabilized, and after further consultation with a cardiologist or an internist. Patients with unstable angina fall into this category because they are at a greater risk for an MI during exercise or sex.7 Patients with uncontrolled HTN are also considered high risk due to their increased risk for CV events, including stroke. Patients who are ⬍ 2 weeks post-MI are also typically classified as high risk due to the potential for reinfarction, ventricular rupture, and arrhythmias precipitated by sexual activity. Other conditions that fall into the high-risk umbrella category include (but are not limited to) NYHA class III and IV HF, hypertrophic cardiomyopathy, and moderate-to-severe valvular disease. Patients who can safely perform 5 to 6 METs of physical activity (eg, walking up 2 flights of stairs)

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can generally be cleared for sexual activity. Conversely, patients who cannot safely perform this level of physical activity should not be cleared for sexual activity, should not be prescribed medications or other therapies for ED, and require additional treatment of their CV condition prior to clearance for sexual activity.

Conclusion Cardiovascular disease and ED are 2 highly prevalent conditions worldwide. Many studies have shown that ED is associated with endothelial dysfunction and CVD. Because these conditions tend to share many of the same risk factors, patients with ED and no apparent CVD should be evaluated for CV risk factors as well as CVD. Proper management of risk factors may significantly improve sexual performance and satisfaction as well as CV outcomes in patients with ED.

Conflict of Interest Statement Arthur Menezes, MD, Surya Artham, MD, MPH, Carl J. Lavie, MD, Richard V. Milani, MD, and James O’Keefe, MD disclose no conflicts of interest.

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