3109/2022 14:50 ‘Sexual activly in patients wih cardiovascular disease - UpToDate UpToDate’ 2ta!reoine rom uptopate® www.uptodate.com © 2022 UpTeDate, Inc. and/or its affiliates, ll Rights Reserved ed Wolters Kluwer Sexual activity in patients with cardiovascular disease Authors: William H Sauer, MD, Stephen E Kimmel, MD, MS Section Editor: Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FAC, FAHA Deputy Editor: Jane Givens, MD, MSCE All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Feb 2022. | This topic last updated: jun 09, 2020. INTRODUCTION Sexual activity is an important component of quality of life and thus is of great concern for both patients with heart disease and their clinicians. Cardiac patients are often fearful of triggering myocardial infarction (MI) during intercourse and may therefore have sex less frequently. Another component of this problem is that patients seeking medical attention for sexual dysfunction often have concomitant cardiovascular disease (CVD). Several aspects of the sexual activity-MI relationship will be discussed here, including the cardiovascular effects of sexual activity, the association between sexual activity and MI, modulating factors that may decrease the risk of MI following sexual activity, and the treatment options for cardiac patients with sexual dysfunction. The risk in patients with other CVDs will also be mentioned. CARDIOVASCULAR EFFECTS OF SEXUAL ACTIVITY Sexual activity, including arousal, erection, ejaculation, orgasm, refractory period, and resolution, is in part dependent upon changes in the autonomic nervous system. * Sexual arousal and penile erection in men results from stimulation of parasympathetic nerves in the penis, reduced activity of sympathetic pathways, and the release of nitric oxide from the endothelium [1]. The importance of nitric oxide constitutes the rationale for the use of sildenafil in men with sexual dysfunction. (See ‘Sildenafil’ below.) * Early sexual arousal in women appears to result from sympathetic nervous system activation [2]. (See "Overview of sexual dysfunction in female: factors, and evaluation".) pidemiology, risk hitps:stwwizuptodate,comloontents/sexual-actvity-n-patien's-with-crdiovascular-diseaselprintsearchexerciclofsico@ impoténcia senual&so.... 1/34arene 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate The main outflow to the cardiovascular system during sexual intercourse is sympathetic and is mediated by outputs from the brain carried by efferent pathways originating from the thoracic spinal cord [1] Hemodynamic stress — Early studies, performed during sexual activity in volunteers who were monitored in the laboratory, found the following changes during orgasm [3,4]: * Peak heart rates were 140 to 180 beats per minute * The mean increase in blood pressure was 80/50 mmHg * Respiratory rates and tidal volumes increased significantly, approaching values seen with moderately severe physical exertion This perception of a high cardiac workload and risk associated with sexual intercourse was reinforced by the observations that patients with stable angina often noted chest discomfort during or immediately after intercourse. However, the results were different in studies performed in “real-life” settings, in which married couples were monitored during sexual intercourse in their own bedrooms [5,6]. The mean heart rate at the time of orgasm was 117 beats per minute, which was lower than the heart rate during normal daily activities (mean 120 beats per minute). Although the blood pressure was not measured in these studies, the mean estimated blood pressure was 162/89 mmbg. This value was based upon the blood pressure achieved during exercise to a heart rate similar to that during orgasm. Although such a calculation might underestimate the peak blood pressure at the time of orgasm, because it does not account for the sympathetic response to arousal and intercourse, similar values were noted in another study in which the blood pressure was measured [6]. The standard clinical measure of exertion is the metabolic equivalent (MET) of oxygen consumption; 1 MET is defined as 3.5 mL O2 uptake/kg per minute, which is the resting oxygen uptake in a sitting position. Sexual activity is often equated with 2 to 3 METS during the preorgasmic phase and 3 to 4 METS during orgasm; this is equivalent to walking at two to four miles per hour on a level surface [7]. Exercise testing is often used to assess both exercise tolerance and tolerance for sex [8]. The clinical implication of these observations is that sexual intercourse is associated with a modest increase in myocardial oxygen demand that lasts only a brief time [9]. This has been confirmed in a number of studies that found that sexual activity contributes to only a small percent of infarctions. Other reports have evaluated the effect of exercise training and sexual position on the cardiovascular response to sexual activity. Exercise training attenuates the heart rate response [10] and reduces the small risk of myocardial infarction (MI) following sex [11,12] hitps:slwwizuptodate,comloontents/sexual-actvity-n-patien's-with-cardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&so... 2/34arene 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate (see ‘Regular exercise’ below). In one report, 16 patients with MI underwent a 16-week exercise training program [10]. The mean peak heart rate during orgasm was significantly lower after exercise training (120 versus 127 beats per minute prior to training) and maximal oxygen consumption increased by 11.5 percent. There was no change in heart rate or oxygen consumption in six control patients. It has been assumed that the man would perform less physical work during sexual intercourse if he were supine. However, this does not appear to be important. In one study of eight normal men who were monitored during sexual intercourse with their wives in their bedrooms, there was no difference in heart rate (114 versus 117 beats per minute) or blood pressure (163/81 versus 161/77 mmHg) between man on top or man on bottom [6]. A second study found a slightly lower minute oxygen consumption for men in the supine position, but this lasted for only a brief period during orgasm [7]. Response in stable angina — During sexual intercourse, the increase in heart rate and blood pressure is the same as any form of exercise. Thus, patients with angina may become symptomatic during intercourse [5,13]. In one series of 35 such patients who were monitored during intercourse in their homes, 65 percent complained of angina on at least some occasions and had to stop activity [13]. Appropriate medical therapy, usually beta blockers and, in some cases, prophylactic sublingual nitrates, can prevent angina in these patients and permit a normal sex life [13]. Patients with chronic coronary disease who undergo revascularization with a percutaneous coronary intervention or bypass surgery and who are asymptomatic do not have an increased risk of symptoms during sexual intercourse. RISK OF MI AFTER SEX In order to determine the relative risk of myocardial infarction (MI) following sex, a case- crossover design has been used. With this method, each patient serves as his or her own control [14]. As a result, the effect of confounding chronic risk factors is virtually eliminated, which is important because people who are sexually active may be different from those who are not sexually active in ways that would be difficult to account for if different individuals were selected for the control group. The case-crossover design was used in the Determinants of Myocardial Infarction Onset Study of 1774 patients who were interviewed within one week of an acute MI; 858 patients were sexually active [11]. The following findings were noted: * The relative risk of MI within two hours after sexual activity was 2.5; there was no increased risk of MI beyond this time period, The risk was reduced in patients who hitps:stwwizuptodate.comloontents/sexual-actvity-in-patien's-withcardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&so... 3/343109/2022 14:50 ‘Sexual activly in patients wih cardiovascular disease - UpToDate underwent regular exercise, * The relative risk of MI after sexual activity was similar in patients with a history of prior angina or MI or no prior cardiac disease. * Only 9 percent of patients had sex in the 24 hours before MI and only 3 percent in the important two-hour time period. As a result, the absolute increase in risk was small, as sexual activity appeared to contribute to the onset of MI in only 0.9 percent of patients. Many other triggers of an MI, such as psychologic stress, anger, or physical activity, may cause a greater increase in absolute risk because they occur more frequently [14]. The results were similar in a second case-crossover study of 699 patients [12]. Only 1.3 percent had sexual intercourse within two hours of an MI; the estimated relative risk of an MI in the hour after sexual intercourse was 2.1 overall and 4.4 in those with a sedentary lifestyle. Although sexual activity can trigger an MI, what is important to the individual is the absolute increase in risk (ie, the risk from sex minus the risk at all other times, referred to as the “attributable risk"), (See "Glossary of common biostatistical and epidemiological terms".) Since sexual activity is a transient trigger that increases risk for only a two-hour period, the absolute increase in risk is very small. Based upon the result from the Determinants of Myocardial Infarction Onset Study [11], a 50-year-old man free of cardiac disease with an annual baseline risk of MI of 1 percent would increase his annual risk of MI to only 1.01 percent from weekly sexual activity [15]. Even a person with a high annual risk for an MI of 10 percent would increase the annual risk to only 10.1 percent from weekly sexual activity. Recognizing the difficulty for studying this phenomenon, investigators communicated a very low incidence (0.7 percent) of recent sexual activity observed in a cohort of 576 patients with coronary heart disease and incident MI. In this same report, there was also no association noted in frequency of sexual activity and MI incidence in this cohort [16]. Modulation of risk — Two factors appear to modulate the risk of MI after intercourse: exercise and medical therapy. Regular exercise — In both of the case-crossover studies described above, the risk of MI following sexual activity was reduced in patients who exercised regularly [11,12]. In an analysis from the Determinants of Myocardial Infarction Onset Study, regular physical exercise at levels of 26 metabolic equivalents (METs) modified the association between sex and MI [14]. The more regularly a person exercised, the lower their relative risk of MI from sexual activity. hitps:twwizuptodate,comloontents/sexual-actvity-n-patien's-with-cardiovascular-diseaselprintsearch=exerciclofsicoe impoténcia senual&so.... 4/342ajoag022 1:80 Sal activi in palais wih caniovascuer disease - UpToDate These findings are consistent with observations that regular exercise reduces the risk of triggering MI and sudden death from heavy physical exertion [17.18] and that exercise training increases the aerobic capacity and decreases the peak heart rate in post-MI subjects engaging in sexual intercourse [10]. In another analysis from the Determinants of Myocardial Infarction Onset Study, 4.4 percent of patients with an acute MI reported heavy physical exertion within one hour of the MI, with symptoms usually beginning during exertion (relative risk 5.9 compared with less strenuous or no physical exercise) [17] Importantly, the relative risk was inversely related to the degree of regular exercise before the MI, ranging from 2.4 to 107 in patients who usually exercised five or more times per week or less than once per week, respectively. Thus, people who have been physically and sexually inactive may require more careful medical advice and monitoring prior to resuming sexual activity. Medical therapy — Other potential modifiers of risk may be hypothesized from studies of patients with an MI and the proposed pathophysiology of triggering factors [19,20]. The increased relative risk of MI from sexual activity makes it similar to other triggers of MI. Among the proposed triggers are enhanced hemodynamic stress, resulting from an increase in heart rate, blood pressure, and myocardial oxygen demand, as well as increased platelet aggregability and coagulation in combination with a coronary artery plaque that is vulnerable to rupture [20]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".) As a result, medications that reduce heart rate or blood pressure or inhibit platelet aggregation may reduce the risk of triggers of MI. * Beta blockers reduce myocardial oxygen demand and can minimize or eliminate angina during sexual intercourse. The Determinants of Myocardial Infarction Onset Study found that beta blockers reduced the risk of MI following anger [21] but not sexual intercourse [11]. * Aspirin lowers the risk of MI following episodes of anger [21] and the morning waking hours [22], both of which are known triggers of MIL. In the Determinants of Myocardial Infarction Onset Study, aspirin therapy was associated with a nonsignificant reduction in the relative risk of MI following sexual activity (11). SEXUAL ACTIVITY RISK ASSIGNMENT Although the risk of a myocardial infarction (MI) or other cardiac event (angina, arrhythmias, exacerbation of heart failure) associated with sexual activity is low, there may be an increased risk in patients with a high-risk cardiovascular profile or those with established disease. hitps:twwizuptodate,comloontents/sexual-actvity-n-patien's-withcardiovascular-diseaselprint?searchexercico fsicoe impoténcia senual&so.... 5/34arene 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate An assessment of sexual function should be performed routinely in the initial evaluation of all patients with cardiovascular disease (CVD). Further clinical evaluation is based upon estimated risk, which must be individualized to any particular patient. In 2005, the Second Princeton Consensus Panel on sexual activity and cardiac risk published recommendations for the initiation or resumption of sexual activity and for the management of sexual dysfunction in patients with CVD [23]. These recommendations were updated by the Third Princeton Consensus in 2012 [24]. The recommended therapeutic approach described below is related to the estimated risk of an acute cardiac event in relation to sexual activity. Low risk — Patients at low risk can be safely encouraged to initiate or resume sexual activity and can be treated for sexual dysfunction. The large majority of patients are at low risk. This includes patients with: * No symptoms and less than three cardiovascular risk factors (excluding gender) Asymptomatic, controlled hypertension Successful coronary revascularization Mild valvular disease Left ventricular dysfunction/heart failure New York Heart Association (NYHA) classes I and II but are able to achieve 5 metabolic equivalents (METS) of the task without ischemia on exercise testing There are limited data on patients with pericarditis, mitral valve prolapse, or atrial fibrillation with a controlled ventricular response, These patients are not at high risk and should be managed on an individualized basis. Intermediate or indeterminate risk — Patients at intermediate or indeterminate risk should receive further evaluation, such as stress testing, particularly in patients with a sedentary lifestyle, which may permit re stratification into the low- or high-risk category. Consultation with a cardiologist may be useful in some cases for assessing risk and management. Intermediate risk includes patients with: * No symptoms and three or more cardiovascular risk factors (excluding gender); a sedentary lifestyle is considered a risk factor. * Mild or moderate stable angina. * Arecent MI (more than two weeks but less than eight weeks) without intervention. In patients who have not undergone revascularization, the risk can be assessed with hitps:twwizuptodate,comloontents/sexual-actvity-n-patien's-withcardiovascular-diseaselprint?searchexercicofsicoe impoténcia senual&so.... 6/343109/2022 14:50 ‘Sexual activly in patients wih cardiovascular disease - UpToDate stress testing, which is often performed during this period. * An MI more than six to eight weeks previously. + Asymptomatic left ventricular dysfunction with left ventricular ejection fraction <40 percent or NYHA class III heart failure (table 1). * Noncardiac manifestations of atherosclerotic disease, such as peripheral vascular disease or prior stroke or transient ischemic attack, As described below, treatment with a phosphodiesterase-5 (PDE-5) inhibitor such as sildenafil is contraindicated in patients taking a nitrate. (See ‘Adverse interaction with nitrates’ below.) High risk — Patients at high risk should be stabilized by appropriate therapy and further risk stratified before resuming sexual activity. High risk includes patients with: * Unstable or refractory angina Uncontrolled hypertension NYHA class IV heart failure( table 1) An MI within the past two weeks High-risk arrhythmias Obstructive hypertrophic cardiomyopathy with severe symptoms Moderate to severe valvular disease, particularly aortic stenosis As described below, treatment with a PDE-S inhibitor such as sildenafil is contraindicated in patients taking a nitrate. (See ‘Adverse interaction with nitrates’ below.) POST-MI SEXUAL DYSFUNCTION Sexual dysfunction is common in patients with cardiovascular disease (CVD) because of concern about risk; side effects of medications (diuretics, beta blockers, lipid-lowering drugs); the coexistence of shared risk factors, such as lipid abnormalities, diabetes, smoking, and hypertension; and the presence of psychologic factors [25-32]. Sexual dysfunction after a myocardial infarction (MI; most often erectile dysfunction in men) is estimated to occur in one-half to three-quarters of patients; although less common, sexual dysfunction is also seen after bypass surgery [33,34]. Both men and women have less sexual activity and less satisfaction with sexual activity after an MI [31,32,35]. In one study, loss of sexual activity in the year following MI was more common in women, and those who did not discuss sex with a clinician in the month after the hitps:stwwizuptodate,comloontents/sexual-actvity-n-patien's-withcardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&so.... 7/342avon022 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate MI were more likely to delay resumption of sexual activity [36]. An inverse relationship has been noted between sexual activity after MI and long-term mortality [37]. Cardiac patients may have psychologic causes for sexual dysfunction, which are often due to perceptions of their illness and should be ascertained in the history [38]. Worries about triggering an MI or sudden death and depression and anxiety about a newly diagnosed illness, especially the occurrence of an MI, can all contribute to sexual dysfunction in patients with heart disease [30,31,39-41]. In a report of 130 women with an MI, for example, 71 percent noted a decrease in or no sexual activity, often due to fear on the part of the patient or spouse [31]. Unfortunately, many clinicians do not discuss this issue of sexual intercourse with post-MI patients or their spouses [31,42]. For these patients, attendance at cardiac rehabilitation, treatment of any psychiatric condition, and reassurance of the low attributable risk of MI may improve sexual function [30,43]. (See "Cardiac rehabilitation programs" and "Psychosocial factors in acute coronary syndrome’, section on ‘Depression after acute coronary syndrome’) Since sexual activity is often equated with physical activity, exercise testing is often used to measure exercise tolerance and tolerance for sex [8]. (See "Exercise ECG testing: Performing the test and interpreting the ECG results") TREATMENT OF SEXUAL DYSFUNCTION Sexual function is an important component of quality of life and subjective wellbeing. The prevalence of sexual dysfunction, especially erectile dysfunction in men, is higher in those with cardiovascular disease (CVD) than in the general population. General issues about the evaluation and management of sexual dysfunction in men and women are discussed more fully elsewhere. (See "Epidemiology and etiologies of male sexual dysfunction" and "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation" and “Treatment of male sexual dysfunction" and "Overview of sexual dysfunction in women: Management") General principles — The management of sexual dysfunction in patients with CVD is based in part upon the estimated risk as described above. (See ‘Sexual activity risk assignment’ above.) The following recommendations from the Second Princeton Consensus Panel (unchanged in the Third Panel) are primarily based upon patients with known coronary heart disease (angina, myocardial infarction [MI], post bypass surgery) but must be individualized to any hitps:lwwizuptodate.comloontents/sexual-actvity-n-patien's-witcardiovascular-diseaselprintsearch=exerciclofsicoe impaténcia sexual&so... 8/34arene 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate particular patient (23). Perhaps the greatest cardiovascular risk is the enabling of moderate exercise (via sexual activity) in previously inactive patients [44]. * Low-risk - Such patients can be safely encouraged to initiate or resume sexual activity or to receive treatment for sexual dysfunction. * Intermediate-risk - Such patients should receive further evaluation in order for restratification into a low- or high-risk category. This is often achieved by stress testing, particularly in patients with a sedentary lifestyle. Consultation with a cardiologist may be useful in some cases for assessing risk and management. * High-risk ~ Such patients should be stabilized by appropriate therapy and further risk stratified before resuming sexual activity or being treated for sexual dysfunction. An important component of the treatment of sexual dysfunction in all patients is correction of reversible causes. In patients with heart disease, this includes reassurance in patients in whom sexual activity is considered to be safe (see 'Sexual activity risk assignment' above) and drug-induced side effects. Among the cardiovascular drugs that may be implicated are thiazide diuretics, beta blockers, and lipid-lowering drugs [45-47]. Consideration should be given to the time sequence of initial symptoms and changes in a patient's medications, and, when possible, alternative prescriptions should be pursued. Another important issue is that phosphodiesterase-5 (PDE-5) inhibitors should not be used with nitrates in any form [23,48]. (See ‘Adverse interaction with nitrates’ below.) PDE-5 inhibitors — The PDE-S inhibitors sildenafil, vardenafil, and tadalafil are widely used in the treatment of erectile dysfunction in men and can have important effects in patients with heart disease. Most of the published data are related to the use of sildenafil. (See ‘Vardenafil and tadalafil’ below.) Sildenafil — Sildenafil can improve erectile function in patients with chronic coronary syndrome, also referred to as stable ischemic heart disease. This was illustrated in a report of 357 men with stable chronic coronary heart disease in whom sildenafil improved erection in 70 percent compared to 20 percent with placebo [49]. Sildenafil is also effective in men with hypertension, diabetes, and nonvascular organic or psychogenic causes for erectile dysfunction [50]. (See "Treatment of male sexual dysfunction", section on 'Sildenafil'.) Sildenafil has two important cardiovascular actions in patients with heart disease: It can lower the blood pressure and it can interact with nitrates [44,48,50]. Sildenafil is a vasodilator that reduces systemic vascular resistance. It lowers the systolic pressure by about 8 mmHg [44,51], an effect that is not more pronounced when given with hitps:stwwizuptodate,comloontents/sexual-actvity-n-patien's-with-cardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&so... 9/342s103/2022 14:80 ‘Sexual activly in patients wih cardiovascular disease - UpToDate antihypertensive drugs that also have vasodilator activity (such as amlodipine) (52). A post hoc analysis of patients taking sildenafil noted a similar incidence of adverse events, including those related to blood pressure (hypotension, dizziness, and syncope) in sildenafil users taking concomitant antihypertensive drugs compared with those who were not [53]. Sildenafil also dilates epicardial coronary arteries and, in patients with coronary heart disease, improves endothelial dysfunction and inhibits platelet activation [54]. Among patients with exercise-induced ischemia, sildenafil has a beneficial effect that is intermediate between that induced by isosorbide dinitrate and placebo. (See ‘Does sildenafil promote MI?’ below.) Vardenafil and tadalafil — Vardenafil and tadalafil are more selective and more potent PDE-S inhibitors than sildenafil. Both drugs appear to be as effective as sildenafil for the treatment of erectile dysfunction. Tadalafil has the advantage of a longer duration of action, thereby allowing more spontaneity in sexual activity. (See “Treatment of male sexual dysfunction".) Data on the cardiovascular effects of vardenafil or tadalafil in men with heart disease are limited. These drugs, like sildenafil, potentiate the hypotensive response to nitrates; this interaction lasts 24 hours with vardenafil and up to 48 hours with tadalafil [55]. Thus, tadalafil and vardenafil are contraindicated with concomitant nitrate use [48]. The concomitant administration of vardenafil or tadalafil and alpha-blocking agents can lead to symptomatic hypotension [48]. As a result, these drugs should not routinely be taken with alpha-blocking agents. Aslight prolongation of the QT interval has been described with vardenafil, but this is not thought to be clinically important [56]. However, vardenafil should not be used in men with congenital long QT syndrome or in those taking drugs that can cause the long QT syndrome (table 2) (48). Adverse interaction with nitrates — An important limitation is the contraindication to the use of PDE-S inhibitors in patients taking nitrates of any form, regularly or intermittently [23,48]. The efficacy of PDE-S inhibitors is based upon the role of nitric oxide-induced vasodilation (which is mediated by cyclic guanosine monophosphate [GMP)) in initiating and maintaining an erection. Detumescence is associated with catabolism of cyclic GMP by type 5 cyclic GMP phosphodiesterase, which is blocked by these drugs. Nitrates also act by a cyclic GMP mechanism and can therefore potentiate the effects of PDE-5 inhibitors. (See "Nitrates in the management of chronic coronary syndrome") Men treated with PDE-S inhibitors and nitrates are at risk for severe hypotension and syncope. Support for this negative interaction comes from a randomized, placebo-controlled hitps:twwizuptodate.comlcontents/sexual-atvity-n-patien's-wit-cardiovascular-diseaselprint?search=exerciclo sic e impaténcia sexual&s.... 10/342avon022 14:50 Sexual actly in paints with cardiovascular dea - UpToDate trial of patients with stable coronary artery disease who were treated with isosorbide mononitrate for five to seven days before a dose of sildenafil and from a second study in which sublingual nitroglycerin was given one hour before sildenafil [57]. Coadministration of sildenafil with either nitrate produced a significantly greater reduction in blood pressure (mean maximum reduction 52/29 mmHg with isosorbide mononitrate and 36/21 mmHg with sublingual nitroglycerin) compared with the nitrate alone (mean maximum reduction 25/15 and 26/12 mmHg, respectively). If a man who has taken a PDE-S inhibitor develops chest pain, nitrates should not be administered within 24 hours (or longer in patients with renal or hepatic dysfunction) of sildenafil, 24 hours of vardenafil, 12 hours of avanafil, or up to 48 hours of tadalafil 123, formulations); erythrityl tetranitrate; and amyl nitrate (which may be abused and known by various names, 48,55,58]. This includes any form of nitroglycerin (eg, sublingual, transdermal, and spray osorbide mononitrate or isosorbide dinitrate; pentaerythritol tetranitrate or including "poppers") Coadministration with antihypertensive drugs — In contrast to the risk associated with nitrates, PDE-S inhibitors are typically well tolerated with only minor reductions in blood pressure in patients taking conventional antihypertensive drugs (eg, angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor blockers, calcium channel blockers, beta blockers, and diuretics), even when used in combination [59,60]. However, they should not routinely be taken with alpha-blocking agents due to concerns of hypotension. Does sildenafil promote MI? — MI and sudden death have been described after sildenafil therapy, but the relation to the drug is uncertain [61,62]. By November 1998, the US Food and Drug Administration (FDA) had received reports of 130 men who died within hours to days after taking sildenafil. MI was confirmed in 77, and 27 deaths were attributed to cardiac arrest. Seventy percent of the men had known CVD and several were using a nitrate concurrently with sildenafil, Among patients taking a nitrate, a large and protracted reduction in systemic blood pressure and in coronary blood flow in arteries with a critical stenosis could lead to coronary ischemia [63]. However, as mentioned previously, sexual activity itself can trigger an MI (see ‘Risk of MI aftter sex’ above). Thus, case reports of MI in association with sildenafil may have been unrelated to the drug. Consistent with this hypothesis are the results of extensive post- marketing surveillance that have failed to demonstrate a significant association between sildenafil and cardiac events [44,49,64-68). * Areview of 4274 patients found that sildenafil did not increase the rate of serious cardiovascular events or MI [65]. hitps:twwizuptodate,comloontents/sexual-actviy-n-patien's-witcardiovascular-diseaselprint?search=exerciclo sic e impaténcia sexualas... 11/34arene 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate * In another review limited to 357 patients with stable coronary disease not taking nitrates, sildenafil did not increase the incidence of serious cardiovascular events or MI [49]. * In data reported to the drug company involving 6527 patients, there was no increase in the incidence of all-cause mortality or MI [44]. * Ina case-crossover study of 69 men with MI, sildenafil was not associated with an increased risk of the event [64]. In addition, sildenafil is generally well tolerated in men with severe coronary disease not using nitrates. This was illustrated in a study of 14 men with stable symptoms, but greater than 70 percent stenosis of at least one coronary artery, who underwent hemodynamic evaluation after a single dose of sildenafil (100 mg) at least 24 hours after the. discontinuation of nitrates [51]. Blood flow velocity and flow reserve were assessed using a Doppler guidewire and intracoronary adenosine administration. Although there were small decreases (<10 percent) in systemic and pulmonary arterial pressures, there was no effect on intracardiac pressures, heart rate, cardiac output, peak coronary flow velocity, coronary artery diameter, or coronary vascular resistance. Coronary flow reserve increased by 13 percent in both stenotic and control arteries. Sildenafil also appears to be safe during exercise in patients with stable coronary disease. This was illustrated in a randomized controlled trial in which sildenafil had no effect on symptoms, exercise duration, or the development or severity of exercise-induced ischemia as detected by exercise echocardiography [69]. Other potential concerns — The vasodilator properties of PDE-5 inhibitors may produce an adverse effect in some patients with a hypertrophic cardiomyopathy. The decrease in preload and afterload can increase the outflow obstruction, culminating in an unstable hemodynamic state [70]. (See "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction") Because of their inhibition of phosphodiesterase, there was initial concern that PDE-5 inhibitors might possess milrinone-like arrhythmogenic properties [71]. However, the specific target of sildenafil is type 5 cyclic GMP phosphodiesterase, which is not expressed in heart muscle [72]. Despite this, class III antiarrhythmic properties (ie, prolongation of cardiac repolarization) have been described with sildenafil [73]. This effect was seen with high doses, which can be achieved in vivo in patients with hepatic or renal impairment, after a drug overdose, or during concurrent therapy with another cytochrome P450 3A (CYP3A) substrate/inhibitor (__ table 3), hitps:twwizuptodate,comloontents/sexual-actvity-in-patien's-withcardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&s... 12/34arene 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate Assmall study of the concomitant administration of sildenafil and doxazosin found that some patients developed symptomatic hypotension [48]. As a result, a labeling precaution advises against taking 50 or 100 mg of sildenafil within four hours of administration of alpha- blocking agents [23,48]. Other therapies — Treatment options for sexual dysfunction other than a PDE-S inhibitor can be pursued in patients with stable cardiac disease. There are no specific cardiovascular effects of androgen replacement therapy, penile prostheses, or vacuum-assisted erection devices. Although there has been one case report of MI temporally associated with alprostadil penile injection, there is no cardiovascular contraindication to its use [74]. However, yohimbine, an alpha-2 receptor blocker, should be used with caution because of its cardiovascular side effects, including tachycardia and the potential for hypertension. (See “Treatment of male sexual dysfunction".) Flibanserin is an approved medication for the treatment of premenopausal women with acquired, generalized, hypoactive sexual desire disorder. (See Overview of sexual dysfunction in women: Management, section on ‘Flibanseri SEXUAL COUNSELING The term "sexual counseling” (SC) describes the interaction between healthcare professionals and cardiovascular disease (CVD) patients that provides information and advice on safe return to sexual activity after a cardiovascular event, as well as assessment, support, and specific advice related to psychological and sexual issues in the context of CVD [75]. Sexual counseling is probably underused in clinical practice at present and/or misapplied in many cases. In 2013, the American Heart Association and the European Society of Cardiology Council on Cardiovascular Nursing and Allied Professions published a comprehensive consensus document on SC for individuals with CVD [76]. The following are important points made in that docume! Health care providers should consider discussing sexual activity with many of their patients. SC should be tailored to the individual needs and concerns of patients and their partners/spouses. Health care professionals may need education and training to properly provide SC. * Assessment tools are available to assess psychosexual concerns and should be used in some patients. hitps:twwizuptodate,comloontents/sexual-actvity-n-patiens-with-cardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&s... 13/34arene 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate * Psychological factors including fear, anxiety, and depression can adversely influence participation in sexual activities. * SC interventions can improve the frequency of sexual intimacy and the quality of sexual functioning and should be offered to all patients as relevant, using a team approach when possible. * SC content includes a review of medications and potential effects on sexual function, risks related to sexual activity, the role of regular exercise in supporting intimacy, use of a comfortable familiar setting to minimize any stress with sexual activity, use of sexual activities that require less energy expenditure as a bridge to sexual intercourse, avoidance of anal sex, and the reporting of warning signs experienced with sexual activity. RECOMMENDATIONS OF OTHERS. A 2012 scientific statement from the American Heart Association addressed the issue of sexual activity in patients with cardiovascular disease (CVD) [77]. We agree with the following general recommendations made in that document: * Sexual activity is reasonable for patients with CVD who, on clinical evaluation, are considered to be at low risk of developing cardiovascular complications. * Sexual activity is reasonable for patients who can exercise 23 to 5 metabolic equivalents (METS) (table 4) without angina, excessive dyspnea, ischemic ST-segment changes, cyanosis, hypotension, or arrhythmia. * Patients with unstable, decompensated, and/or severe symptomatic CVD should defer sexual activity until their condition is stabilized and optimally managed. * Patients with CVD who experience cardiovascular symptoms precipitated by sexual activity should defer sexual activity until their condition is stabilized and optimally managed. We also agree with the following specific recommendations, which allow for sexual activity in the following patients: + Those who are one or more weeks after uncomplicated myocardial infarction, if the patient is without cardiac symptoms during mild to moderate physical activity. * Those who have undergone complete percutaneous coronary revascularization and are several days after the intervention if the vascular access site is without complications. hitps:slwwizuptodate,comloontents/sexual-actviy-in-patien's-with-cardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&s... 14/342s103/2022 14:80 ‘Sexual activly in patients wih cardiovascular disease - UpToDate + Those who have undergone open heart (either coronary or noncoronary) surgery and are six to eight weeks postoperative if the sternotomy is well healed. * Those with mild or moderate valvular heart disease and no or mild symptoms. However, those with severe or significantly symptomatic valvular disease should not participate until their condition is stabilized and optimally managed. * Those with normally functioning prosthetic valves, successfully repaired valves, and successful transcatheter valve intervention. + Those with pacemakers or implantable cardioverter defibrillators (implanted for primary prevention and assuming multiple shocks have not been received). * Those with atrial fibrillation or flutter and well-controlled ventricular rates. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics” and "Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5" to 6!" grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10° to 12% grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles ona variety of subjects by searching on “patient info” and the keyword(s) of interest.) * Basics topics (see "Patient educatior : Heart attack recovery (The Basics)" and "Patient education: Recovery after coronary artery bypass graft surgery (CABG) (The Basics)") * Beyond the Basics topics (see "Patient education: Heart attack recovery (Beyond the Basics)" and "Patient education: Recovery after coronary artery bypass graft surgery (CABG) (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS * Sexual activity is associated with moderate hemodynamic stress and increases the risk of myocardial infarction (MI). However, the absolute increase in risk is very small. In addition, risk modification can be accomplished with regular physical activity and hitps:twwizuptodate,comloontents/sexual-actvity-n-patien's-witcardiovascular-diseaselprint?search=exerciclofsicoe impaténcia sexual... 15/342avon022 14:50 Sexual actly in paints with cardiovascular dea - UpToDate possibly aspirin and beta blocker use. Thus, patients with heart disease who are not deemed to be at high risk should be able to be sexually active after appropriate risk stratification and optimization of therapy and can be safely treated for sexual dysfunction. (See ‘Sexual activity risk assignment! above.) * Both the Princeton Consensus Panel and a consensus statement from the American College of Cardiology/American Heart Association concluded that a phosphodiesterase- 5 (PDE-5) inhibitor is safe for men with stable coronary artery disease who are not taking nitrates. * There are no clinical differences among the PDE-S inhibitors with the exception of a prolonged duration of action with tadalafil. Although vardenafil and tadalafil are not likely to be associated with increased cardiac risk compared with sildenafil, there is less clinical information related to the safety of these drugs in men with heart disease. Until such information is available, and because of its relatively shorter half-life, we recommend sildenafil for men with erectile dysfunction who have heart disease. * The PDE-S inhibitors are contraindicated with any nitrate preparation and should not be routinely used with alpha-blocking agents. Cardiac patients should be counseled about the interaction with nitrates, even if a PDE-S inhibitor is not currently prescribed. If a man who has taken a PDE-5 inhibitor develops chest pain, nitrates should not be administered within 24 hours (or longer in patients with renal or hepatic dysfunction) of sildenafil, 24 hours of vardenafil, or up to 48 hours of tadalafil. * The American College of Cardiology/American Heart Association consensus statement also alerts clinicians to the potentially hazardous cardiovascular effects of PDE-S inhibitors in the following groups of patients: + Patients with active coronary ischemia, even in those who are not taking nitrates (eg, positive exercise stress test for ischemia). + Patients with heart failure and borderline low blood pressure and/or low volume status. (See "Drugs that should be avoided or used with caution in patients with heart failure", section on 'PDE-5 inhibitors',) + Patients on a complicated multidrug antihypertensive drug regimen. + Patients taking drugs that prolong the half-life of PDE-S inhibitors by blocking CYP3A4(__ table 3). On the other hand, drugs that induce cytochrome P450 3A4 (CYP3A4), such as rifampin and phenytoin, can be expected to reduce the effectiveness of these drugs. Use of UpToDate is subject to the Terms of Use, Ipsum uptodate comieontents/sexual ctity-inpaiets-th-cardlovascular-iseaslprn7seareh-exericlo fico e impoténcia sexual6s.. 16042stosi2022 14:50 ‘Sexual activity in patients with cardiovascular disease - UpToDate REFERENCES 1. 12. 13. 14. 15. 16. 17. Rampin O, Giuliano F. Central control of the cardiovascular and erection systems: possible mechanisms and interactions. Am J Cardiol 2000; 86:19F. . 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Men treated with hypolipidaemic drugs complain more frequently of erectile dysfunction. | Clin Pharm Ther 1996; 21:89. 48, Kloner RA, Cardiovascular effects of the 3 phosphodiesterase-5 inhibitors approved for the treatment of erectile dysfunction, Circulation 2004; 110:3149, hitps:twwizuptodate.comlcontents/sexual-atvity-n-patien's-wit-cardiovascular-diseaselprintsearch=exerciclofsicoe impaténcia sexualas... 19/342210312022 14:60 Sexual actly in paints with cardiovascular dea - UpToDate of erectile dysfunction in patients with ischemic heart disease, Am | Cardiol 1999; 83:29C, 50. Goldstein I, Lue TE, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl) Med 1998; 338:1397. 51. Herrmann HC, Chang G,Klugherz BD, Mahoney PD. Hemodynamic effects of sildenafilin men with severe coronary artery disease, N Engl | Med 2000; 342:1622. 52. Webb Dj, Freestone S, Allen Mj, Muirhead G), Sildenafil citrate and blood-pressure- lowering drugs: results of drug interaction studies with an or: nic nitrate and a calcium antagonist. Am J Cardiol 1999; 83:21C, 53. Kloner RA, Jarow JP. Erectile dysfunction and sildenafil citrate and cardiologists. Am) Cardiol 1999; 83:576. 54. Halcox JP, Nour KR, Zalos G, et al, The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. | Am Coll Cardio] 2002; 40:1232. Advisory Committee. Proceedings of the 99th meeting of the Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee. May 29th and 30th, 2003. Circulation 2003; 107:e9052. 57. Webb DJ, Muirhead G), Wulff M, et al, Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. | Am Coll Cardiol 2000; 36:25, 58. STENDRA. US Food and Drug Administration (FDA) approved product information. Revis ed April, 2012. US National Library of Medicine. Available at: https://www.accessdata.fd a.gov/drugsatfda_docs/label/2012/202276s000IbI.pdf (Accessed on May 11, 2020). Kloner RA, risant LM, Collins M. Effect of sildenafil in patients wi dysfunction taking antihypertensive therapy. Sildenafil Study Group, Am J Hypertens 2001; 14:70. 60. Pickering TG, Shepherd AM, Puddey I, et al. Sildenafil citrate for erectile dysfunction in men receiving multiple antihypertensive agents: a randomized controlled trial, Am J Hypertens 2004; 17:1135, erectile 61. Feenstra J, van Drie-Pierik RJ, Laclé CF, Stricker BH. Acute myocardial infarction associated with sildenafil, Lancet 1998; 352:957. 62. Arora RR, Timoney M, Melilli L, Acute myocardial infarction after the use of sildenafil, N Engl | Med 1999; 341:700. hitps:twwizuptodate.comlcontents/sexual-actvity-n-patien's-wit-cardiovascular-diseaselprint?search=exercicofsicoe impaténcia sexual&s.... 20/342stosi2022 14:50 ‘Sexual activity in patients with cardiovascular disease - UpToDate nitrate on the heart. Circulation 2000; 102:2516. 64. Mittleman MA, Maclure M, Glasser DB. Evaluation of acute risk for myocardial infarction in men treated with sildenafil citrate. Am J Cardiol 2005; 96:443. 65, Morales A, Gingell C, Collins M, et al. Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction, Int | Impot Res 1998; 10:69, 66. Shakir SA, Wilton LV, Boshier A, et al. Cardiovascular events in users of sildenafil: results from first phase of prescription event monitoring in England, BM) 2001; 322:651. 67. Bush HS. Safe use of sildenafil in patients with coronary artery disease. Cleve Clin | Med 2001; 68:349, 352. 68. DeBusk RF, Pepine C), Glasser DB, et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction an ronary artery disease, Am | Cardiol 2004; 93:147, 69, Arruda-Olson AM, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized 71. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. | Am Coll Cardiol 1999; 33:273. the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol 1999; 83:3¢. 73. Geelen P, Drolet B, Rail J, et al, Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current, Circulation 74, Vaidyanathan S, Krishnan KR. Myocardial infarction i with intra-cavern: administration of alprostadil in a patient with spinal cord injury and paraplegia. Spinal Cord 1996; 34:754 75. Gamel C, Davis BD, Hengeveld M, Nurses’ provision of teaching and counselling on sexuality: a review of the literature. | Adv Nurs 1993; 18:1219. 76. Steinke EE, Jaarsma T, Barnason SA, et al. Sexual couns: cardiovascular disease and thi artners: a consensus document from the American 7 9 led P (CCNAP). Circulation 2013; 128:2075. hitps:twwizuptodate,comiontents/sexual-actviy-in-patien's-witcardiovascular-diseaselprint?search=exerciclo sic e impaténcia sexualas... 21/342s103/2022 14:80 ‘Sexual activity in patients with cardiovase disease - UpToDate 77. Levine GN, Steinke EE, Bakaeen FG, et al, Sexual activity and cardiovascular disease: a irculation 2012; 125:1058, scientific statement from the American Heart Association, Topic 1541 Version 25.0 hitps:lwwizuptodate.comlcontents/sexual-actvity-n-patien's-wit-cardiovascular-diseaselprint?search=exerciclo sic e impoténcia sexual&s... 22/343109/2022 14:50 ‘Sexual activly in patients wih cardiovascular disease - UpToDate GRAPHICS NYHA and other clas: ications of cardiovascular disability Canadian class NYHA functional Cardiovascular Specific activity classification!) Society functional scalel3) classification!?! 1 Patients with cardiac Ordinary physical Patients can perform to disease but without activity, such as completion any activity resulting limitations of walking and climbing _ requiring >7 metabolic physical activity. stairs, does not cause equivalents (ie, can Ordinary physical angina. Angina with carry 24 Ib up 8 steps; activity does not cause strenuous or rapid do outdoor work undue fatigue, prolonged exertion at __ [shovel snow, spade palpitation, dyspnea, or work or recreation, soill; do recreational anginal pain. activities (skiing, basketball, squash, handball, jog/walk 5 mph). 0 Patients with cardiac Slight limitation of Patients can perform to disease resulting in ordinary activity. completion any activity slight limitation of Walking or climbing requiring 25 metabolic physical activity. They __ stairs rapidly, walking equivalents (eg, have are comfortable at rest. uphill, walking or stair- sexual intercourse Ordinary physical climbing after meals, in without stopping, activity results in cold, inwind, or when garden, rake, weed, fatigue, palpitation, under emotional stress, roller skate, dance dyspnea, or anginal or only during the few foxtrot, walk at 4 mph. pain, hours after awakening. _ on level ground) but Walking more than2 cannot and do not blocks on the level and perform to completion climbing more than 1 activities requiring 27 flight of ordinary stairs metabolic equivalents. at a normal pace and in normal conditions. ml Patients with cardiac Marked limitation of Patients can perform to disease resulting in marked limitation of physical activity. They are comfortable at rest. Less-than-ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain, ordinary physical activity. Walking 1 to 2 blocks on the level and climbing 1 flight in normal conditions. completion any activity requiring 22 metabolic equivalents (eg, shower without stopping, strip and make bed, clean windows, walk 2.5 mph, bowl, play golf, dress without stopping) but cannot and do not perform to completion hitps:twwizuptodate,comloontents/sexual activity n-patiens-with-cardiovascular-diseaselprint?search=exercico fsicoe impoténcia senual&s... 23/34231032022 14:50 ‘Sexual activly in patients wih cardiovascular disease - UpToDate any activities requiring >5 metabolic equivalents. Vv Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased NYHA: New York Heart Association. References: Inability to carry on any physical activity without discomfort. Anginal syndrome may be present at rest. Patients cannot or do not perform to completion activities requiring >2 metabolic equivalents. Cannot carry out activities listed above (specific activity scale M1, 1. The Criteria Committee ofthe New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases ofthe Heart and Great Vessels, ted, Litle, Brown & Co, Boston 1994. p.253. 2. Campeau L. Groding of angina pectoris, Circulation 1976; 54:522. 3. Goldman 1, Hashimoto 8, Cook EF, Loscolzo A. Comparative reproducibility and volidty of systems for assessing cardiovascular functional class: Advantages of a new specific activity scale. Circulation 1981; 64:1227. Graphic 52683 Version 19.0 hitps:slwwizuptodate.comloontents/sexual activity in-patien's-withcardiovascular-diseaselprint?search=exercicofsicoe impoténcia senual&s arse3109/2022 14:50 ‘Sexual activly in patients wih cardiovascular disease - UpToDate Some reported causes and potentiators of the long QT syndrome* Congenital Jervell and Lange-Nielsen syndrome (including "channelopathies") Romano-Ward syndrome Idiopathic Acquired Metabolic disorders Hypokalemia Hypomagnesemia Hypocalcemia Starvation Anorexia nervosa Liquid protein diets Hypothyroidism Bradyarrhythmias Sinus node dysfunction AV block: Second or third degree Analgesic, anesthetic, and sedative drugs Anesthetic/sedative: Propofol (lower risk) Opioids: * Low to moderate risk Buprenorphine’ = High risk: Methadone Androgen deprivation therapy (GnRH agonist/antagonist therapy or bilateral surgical orchiectomy) Antiarrhythmic drugs * High risk: Amiodarone’, disopyramide, dofetilide, dronedarone, ibutilide, procainamide, quinidine, sotalol, vernakalant™ "Moderate risk: Flecainide, pilsicainide™, propafenone Antianginal drugs Low risk: Ivabradine"!, ranolazine (due to Acquired (continued) Antihistamines = High risk: Astemizole®, terfenadine® = Lower risk: Bilastine", hydroxyzine Antineoplastic drugs = High risk: Arsenic trioxide, ivosidenib, lenvatinib, mobocertinib, selpercatinib, vandetanib "Moderate risk: Ceritinib, crizotinib, dasatinib, encorafenib, gilteritinib, inotuzumab ozogamicin, midostaurin, nilotinib, osimertinib, ribociclib, sunitinib, toremifene, vemurafenib = Lower risk: Bosutinib, capecitabine, dabrafenib, eribulin, floxuridine, fluorouracil (systemic), glasdegib, lapatinib, oxaliplatin, panobinostat, pazopanib, romidepsin, sorafenib, tamoxifen, vorinostat Broncho tors (beta-2 agonists) = Moderate risk: Terbutaline ® Lower risk: Albuterol, arformoterol, formoterol, indacaterol, levalbuterol, olodaterol, salmeterol, vilanterol Diuretics Via electrolyte changes (especially hypokalemia or hypomagnesemia) Gastrointestinal drugs Antidiarrheal: Loperamide¥ in overdose (lower risk) Antiemetics: = Moderate risk: Droperidol, ondansetron (risk with IV use greater than oral) = Low to moderate risk: Amisulpride (IV antiemetic dose), dolasetron, granisetron, hydroxyzine, tropisetron™ Promotility: hitps:stwwizuptodate,comloontents/sexual-actvity-n-patien's-withcardiovascular-diseaselprint?search=exercico fsicoe impoténcia senual&s... 25/342aron02e 14:50 bradycardia) Antichol ergic drugs (antimuscai Low risk: Solifenacin Antimicro! Is Antimalarial ® High risk: Delamanid4, quinidine, quinine = Moderate risk: Chloroquine, halofantrine, piperaquine = Lower risk: Artemether- lumefantrine, hydroxychloroquine (rare reports, noted in labeling) Antiparasitic and antiprotozoal: = Moderate risk: Fexinidazole, meglumine antimoniate, sodium stibogluconate Antituberculous: "High risk: Bedaquiline Azole antifungals: "Moderate risk: Fluconazole, voriconazole = Low to moderate risk: Itraconazole, ketoconazole (systemic) Clofazimine (moderate risk) Fluoroquinolones (systemic): "= Moderate risk: Gemifloxacin", levofloxacin, moxifloxacin, sparfloxacin! = Low to moderate risk: Ciprofloxacin, norfloxacin, ofloxacin Foscarnet (low to moderate risk) HIV antiretrovirals: "Moderate risk: Saquinavir = Low to moderate risk: Efavirenz, fostemsavir, lopinavir-ritonavir, rilpivirine Macrolide antibiotics: "Moderate risk: Azithromycin, dlarithromycin, erythromycin ™ Low to moderate risk: Roxithromycin, telithromycin ‘Sexual acivly in patients wih cardiovascular disease - UpToDate = High risk: Cisapride (restricted availability) = Moderate risk: Domperidone™ = Low to moderate risk (rare reports): Metoclopramide Proton pump inhibitors™: Chronic use leading to hypomagnesemia (rare) Neurologic drugs = Low to moderate risk: Apomorphine, deutetrabenazine, donepezil, ezogabine, fingolimod, ozanimod*, pimavanserin, ponesimod, tetrabenazine Psychotropic drugs Antipsychotics: = High risk: Chlorpromazine, IV haloperidol, ziprasidone = Moderate risk: Amisulpride (oral), clozapine, flupentixol, haloperidol (oral), olanzapine, pimozide, quetiapine, risperidone, thioridazine = Low to moderate risk: Asenapine, iloperidone, paliperidone, periciazine®, pimavanserin Tricyclic and tetracyclic antidepressants (TCAs)* = Moderate risk: Clomipramine, doxepin, and imipramine Selective serotonin reuptake inhibitors (SSRIs): = Moderate risk: Citalopram, escitalopram = Low to moderate risk: Fluoxetine, sertraline Others = Low to moderate risk: Atomoxetine, trazodone Vasodilator drugs High risk: Bepridil® Other drugs = High risk: Levoketoconazole, papaverine (intracoronary) hitps:slwwizuptodate,comloontents/sexual-actvity-in-patien's-with-cardiovascular-diseaselprint?search=exercicofsicoe impoténcia senual&s... 26/342210312022 14:60 Sexual actviyn paints with cardiovascular dea - UpToDate Metronidazole (low to moderate risk) = Moderate risk: Gadobenate dimeglumine, lofexidine, probucol® = Low to moderate risk: Alfuzosin, anagrelide, cocaine (topical), eliglustat, Triclabendazole (low to moderate risk) mifepristone, pasireotide, terlipressin', voclosporin Pentamidine (IV) (moderate risk) Telavancin (low to moderate risk) Herbs: Cinchona (contains quinine), licorice extract (glycyrrhizin) in overuse leading to electrolyte abnormalities Other factors Myocardial ischemia or infarction, especially with prominent T-wave inversions Intracranial disease HIV infection Hypothermia Toxic exposure: Organophosphate insecticides This is not a complete list of all corrected QT interval (QTc}-prolonging drugs and does not include drugs with either a minor degree or isolated association(s) with QTc prolongation that appear to be safe in most patients but may need to be avoided in patients with congenital long QT syndrome depending upon clinical circumstances. A more complete list of such drugs is available at the CredibleMeds website. For clinical use and precautions related to medications and drug interactions, refer to the UpToDate topic review of acquired long QT syndrome discussion of medications and the Lexicomp drug interactions tool. AV: atrioventricular; IV: intravenous. * Classifications provided by Lexicomp according to US Food & Drug Administration guidance: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythic Potential for Non-Antiarrhythmic Drugs ~ Questions and Answers; Guidance for Industry US Food and Drug Administration, June 2017 (revision 2) available at: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/UCM 073161.pdf with additional data from CredibleMeds QT drugs list!"-2. The use of other classification criteria may lead to some agents being classified differently by other sources. {Not available in the United States. ‘In contrast with other class III antiarrhythmic drugs, amiodarone is rarely associated with torsades de pointes; refer to accompanying text within UpToDate topic reviews of acquired long QT syndrome. ‘© Withdrawn from market in most countries due to adverse cardiovascular effects. § Rarely associated with significant QTc prolongation at usual doses for treatment of opioid use disorder, making buprenorphine a suitable alternative for patients with methadone-associated QTc prolongation. Refer to UpToDate clinical topic reviews. ¥ Over-the-counter; available without a prescription. hitpsslwwncuptodate.com/contentssexual ivty-in-pation's-with-cardiovascular-diseaselprint?search=exercicio sic e impoténcia sexualas.... 27/342avon022 14:50 Sn actvy in patents wih cardiovascular disease - UpToDate + Not associated with significant QTc prolongation in healthy persons. Refer to UpToDate clinical topic for potential adverse cardiovascular (CV) effects in patients with CV disease. + Other cyclic antidepressants may also prolong the QT interval; refer to UpToDate clinical topic on cyclic antidepressant pharmacology, side effects, and separate UpToDate topic on tricyclic antidepressant poisoning. Data from: 1. Lexicomp Online. Copyright ©1978-2022 Lexicomp, Inc All Rights Reserved. 2. CredibleMeds QT drugs list website sponsored by Science Foundation of the University of Arizona. Available at hetpu/crediblemeds.org/. Graphic 57431 Version 129.0 hitps:lwwizuptodate.comloontents/sexual-actviy-n-patien's-wit-cardiovascular-diseaselprint?search=exerciclo sic e impaténcia sexual&s.... 26/343109/2022 14:50 Cytochrome P450 3A (including 3A4) inhi Strong inhibitors = atazanavir = Ceritinib = Clarithromycin = Cobicistat and cobicistat- containing coformulations = Darunavir = Idelalisib = Indinavir = Itraconazole = Ketoconazole = Levoketoconazole = Lonafarnib = Lopinavir = Mifepristone = Nefazodone = Nelfinavir = Ombitasvir- paritaprevir- ritonavir = Ombitasvir- paritaprevir- ritonavir plus dasabuvir = Posaconazole = Ritonavir and ritonavir-containing coformulations = Saquinavir = Telithromycin = Tucatinib ™ Voriconazole ‘Sexual activly in patients wih cardiovascular disease - UpToDate Moderate inhibitors = Amiodarone* ™ Aprepitant = Berotralstat = Cimetidine* ™ Conivaptan = Crizotinib ™ Cyclosporine = Diltiazem = Duvelisib " Dronedarone = Erythromycin = Fedratinib = Fluconazole = Fosamprenavir = Fosaprepitant* = Fosnetupitant- palonosetron = Grapefruit juice = Imatinib = Isavuconazole (isavuconazonium sulfate) = Lefamulin = Letermovir = Netupitant = Nilotinib = Ribociclib = Schisandra = Verapamil Strong inducers = Apalutamide ™ Carbamazepine = Enzalutamide " Fosphenytoin = Lumacaftor = Lumacaftor- ivacaftor = Mitotane "Phenobarbital = Phenytoin = Primidone = Rifampin (rifampicin) ors and inducers Moderate inducers = Bexarotene = Bosentan = Cenobamate = Dabrafenib = Dexamethasone? = Dipyrone = Efavirenz = Elagolix, estradiol, and norethindrone therapy pack® = Eslicarbazepine = Etravirine = Lorlatinib = Mitapivat = Modafinil = Nafcillin = Pexidartinib = Rifabutin = Rifapentine = Sotorasib = St. John's wort For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. These classifications are based upon US Food and Drug Administration (FDA) guidance.!'.2] other sources may use a different classification system resulting in some agents being classified differently. hitps:stwwizuptodate.comloontents/sexual activity in-patien's-withcardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&s... 28/342210312022 14:60 Sexual actly in patents with carovascular disease - UpToDate = Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. = Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate, = Refer to UpToDate topics on specific agents and indications for further details. * Classified as a weak inhibitor of CYP3A4 according to FDA system.) Classified as a weak inducer of CYP3A4 according to FDA system.{1] A The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, itis a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Dato from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2022 Lexicomp, Inc, All Rights Reserved, References: 1. Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance {for Industry January 2020) available at: https://www fda.gov/regulatory-information/search fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2, US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 86.0 hitps:slwwizuptodate.comloontents/sexual activity in-patien's-withcardiovascular-diseaselprint?search=exercicofsicoe impoténcia senual&s 301343109/2022 14:50 ‘Sexual activly in patients wih cardiovascular disease - UpToDate Leisure activity energy expenditure in metabolic equivalents (METs) Activity Archery Backpacking Badminton Basketball Gameplay Nongame Billiards Bowling Boxing In-ting Sparring Canoeing, rowing, kayaking Conditioning exercise Climbing hills Cricket Croquet cycling Pleasure or to work 10 miles per hour Dancing (social, square, tap) Dancing (aerobic) Fencing Field hockey Fishing From bank Wading in stream Football (touch) Golf Power cart Walking (carrying bag or pulling cart) Handball Mean 39 58 83 13.3 83 72 52 35. 8.0 37 79 54 Range 3to4 Sto11 4to9+ 7 to 12+ 3to09 2to4 3to8 3to 8+ 5 to 10+ 4.6 107.4 3to 8+ 3,707.4 6to9 6 to 10+ 2t04 5t06 6to10 2to3 4to7 8 to 12+ hitps:slwwizuptodate.comloontents/sexual-actviy-n-patien's-withcardiovascular-diseaselprintsearch=exercicofsicoe impoténcia senual&s... 31/342eyos12022 14:50 Hiking (cross country) Horseback riding Galloping Trotting Walking Horseshoe pitching Hunting (bow or gun) ‘Sexual activly in patients wih cardiovascular disease - UpToDate 82 66 2.4 Small game (walking, carrying light load) - Big game (dragging carcass, walking) - Judo Mountain climbing Music playing Paddleball, racquetball Rope jumping 60 to 80 skips/minute 120 to 140 skips/minute Running 12 minutes/mile 11 minutes/mile 10 minutes/mile 9 minutes/mile 8 minutes/mile 7 minutes/mile 6 minutes/mile Sailing Scuba diving Shuffleboard Skating, ice and roller Skiing, snow Downhill Cross-country Skiing, water Sledding, tobogganing Snowshoeing Squash a7 94 10.2 125 141 16.3 99 3to7 2to3 3to7 3to14 5-to 10+ 2to3 8to12 11 t012 2to5 5to10 2to3 5to8 508 6 to 12+ Sto7 4to8 7to14 8 to 12+ hitpsstwwizuptodate,comloontents/sexual-actviy-n-patiens-withcardiovascular-diseaselprint?search=exercicofsicoe impoténcia senual&s... 32/34231032022 14:50 ‘Sexual acivly in patients wih cardiovascular disease - UpToDate Soccer - Sto 12+ Stairclimbing - 4t08 Swimming - 4t0 8+ Table tennis 44 3toS Tennis 65 4t0 9+ Volleyball 3t06 ‘Adapted from: American College of Sports Medicine. Guidelines for Exercise Testing and Prescription, 3rd ed, Lea and Febiger, Philadelphia 1986, p.20. Graphic 66344 Version 7.0, hitps:slwwizuptodate.comloontents/sexual-atvity-in-patien's-withcardiovascular-diseaselprintsearch=exercico fsicoe impoténcia senual&s 331342s103/2022 14:80 ‘Sexual activly in patients wih cardiovascular disease - UpToDate Contributor Disclosures William H Sauer, MD Grant/Research/Clinical Trial Support: Biosense-Webster [Catheter ablation]; Boston Scientific [Catheter ablation]. All of the relevant financial relationships listed have been mitigated. Stephen E Kimmel, MD, MS Consultant/Advisory Boards: GlaxoSmithKline [Birth defects]; GE Healthcare [Contrast MRI]. All of the relevant financial relationships listed have been mitigated. Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA Consultant/Advisory Boards: Servier [Angina]. Speaker’s Bureau: Menarini [Angina pectoris]; Servier [Angina pectoris]. All of the relevant financial relationships listed have been mitigated. Jane Givens, MD, MSCE No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy > hitpsslwwncuptodate.com/contentssexual ivty-n-pations-with-cardiovascular-diseaselprintsearch=exercicio sic e impoténcia sexualas.... 34/34