madman
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Topic dear to our hearts!
Enjoyed this one!
*Based on more than 20 years of unyielding evidence, the P4 panel determined that ED should be considered an independent risk marker and a risk-enhancing factor for CAD. We highly implore future CV guidelines to include ED on the list of established risk-enhancing factors. Thus far, the only cardiac risk tool that incorporates ED is the QRISK calculator.36 In general, CAD risk is enhanced by 25% in this risk score with ED (as binary yes/no, not severity related).
*The PDE5is are ineffective or contraindicated in about one-third of eligible men with ED. No tachyphylaxis occurs with PDE5is, but their efficacy does wane as underlying causes of ED worsen with age
INTRODUCTION AND BACKGROUND
Cardiovascular disease (CVD) is a leading cause of death in which half of all men who die suddenly never have antecedent CVD symptoms.1 Moreover, most men who have a heart attack have normal lipid levels.2 However, between one-third and half of all men younger than 45 years and 90% of men older than 65 years who have a heart attack and survive had at least mild erectile dysfunction (ED) before the event.3-6 Indeed, ED typically predates the first myocardial infarction (MI) by at least 2 to 5 years.7-9
The Princeton III (P3) panel published their findings in Mayo Clinic Proceedings in 2012 to systematically address the evaluation and management of men with ED who may have overlapping atherosclerotic CVD risk factors and thus potentially discoverable occult cardiac disease early in its progression.10 In addition, the P3 panel established an algorithm involving exercise capacity and stress testing to address the safety and risk of sexual activity itself with or without the use of phosphodiesterase type 5 inhibitors (PDE5is).
Princeton IV (P4) was convened by the Huntington Medical Research Institutes, a non profit biomedical research facility in Pasadena, California, on March 10-11,2023. The meeting was funded by an unrestricted educational grant from Sanofi. The sponsor was not involved in the selection of speakers, topics, or any aspect of the content of the meeting. As previously organized, a multispecialty group of US sexual medicine experts was selected by the steering committee to critically evaluate the current evidence for the relationship between ED and cardiovascular (CV) health, to update the CV work-up in the ED patient, to reassess when and how to treat ED patients with known CVD, and to reassess the accuracy and relevance of previous Princeton management algorithms. The role of the now quarter-century-old oral PDE5is in the treatment of men with ED and CVD was explored in depth, with a detailed review of the potential cardioprotective effect of these drugs. The full report of P4 findings is available in the Journal of Sexual Medicine.11 This abridged document targets primary healthcare providers who are uniquely positioned to detect occult CVD before it's often fatal initial manifestation through understanding, treatment, and above all, inquiry about ED.
UNDERSTANDING THE ED AND CORONARY ARTERY DISEASE CONNECTION
Erectile dysfunction is the inability to obtain or to maintain erections for satisfactory sexual intercourse.12 Historically, ED was categorized as psychogenic, organic, or mixed,with an antiquated premise that most cases were psychogenic or “in the man’s head.”In fact, only 1 in every 9 cases of ED can be classified as purely psychogenic, with the rest having definitive organic causes.13 Overall, most ED cases are likely to be mixed, stemming from nearly ubiquitous organic causes related to aging blood vessels or other chronic diseases combined with epinephrine-producing patient anxiety from performance and other causes.
Satisfactory erections require adequate arterial inflow, an intact nervous system to facilitate vasodilation of pudendal penile vasculature, and competent penile veins to adequately occlude and trap blood. The venous trapping system is passive, relying on inside-out compression from penile engorgement to function properly. Venous leak is a common cause of recalcitrant ED and may occur after smooth muscle apoptosis, penile fibrosis, or insufficient arterial pressure. Often stemming from radical prostatectomy for prostate cancer or long standing diabetes, smooth muscle apoptosis often induces a loss of penile elasticity and penile shortening and prevents adequate venous compression, giving rise to the failure of sustained erections. Ample testosterone (T) levels optimize erectile biochemical pathways for vasodilation.Conversely, epinephrine is known to be the most potent anti erectile chemical, with its analogues used to treat priapism. In addition, catecholamines released during performance anxiety increase sympathetic tone, enhance vasoconstriction, and worsen erectile function.
As alluded to before, an important cause of ED is arterial insufficiency (decreased arterial inflow). The size of relevant penile arterial blood vessels is 1 to 2 mm or smaller, compared with 3 to 4 mm in the coronary arteries, 5 to 7 mm in the carotids, and about 6 to 8 mm in the femoral vessels. Systematic progressive luminal obstruction of more than 50% in these vessels typically results in ED, angina, MI, transient ischemic attack and stroke, and intermittent claudication.14 Because of the small diameter of the penile artery lumen, it has been postulated that an equivalent buildup of atherosclerotic plaque in the penile artery vs the coronary artery will compromise blood flow to the penis first and be manifested as symptoms of ED before symptoms of reduced coronary blood flow appear, such as angina.
Yet, progressive, simultaneous narrowing of blood vessels offers a convenient but oversimplified link between ED and coronary artery disease (CAD) and other vascular disorders as half to two-thirds of all young men who have an MI have no reported ED.5 Many men with severe ED will never have an MI. However, several other factors have been reported to link ED to heart disease, including endothelial dysfunction, inflammation, and platelet aggregation.15,16 These factors most often occur subclinically. The Multi-Ethnic Study of Atherosclerosis(MESA) of nearly 2000 men free of CVD at baseline reported much greater odds of future ED and CVD events 9 years after initial testing if coronary artery calcium(CAC) scores or carotid intima-media thickness test results (markers for subclinical CAD) were abnormal.17 From this cohort, ED conferred a 2.5-fold higher risk of CV events even after multiple controls for other potential causes.
Erectile dysfunction should be considered a harbinger of CVD. More severe and longer standing ED yields greater risk. Numerous papers narrate a consistent story of ED predating the first cardiac event, including sudden death, by at least 2 to 5 years.7-9 A large observational trial of men with ED without overt cardiac symptoms revealed that cardiac events occurred in 1 of 9 men at 5 years of incident ED.18 The predictive capacity of the penis for cardiac events is intuitive on the basis of the fact that many of the risk factors for ED overlap with risk factors for CVD, including age, abdominal obesity, dyslipidemia, sedentary lifestyle, smoking, diabetes, hypertension, low T, metabolic syndrome, and any condition that results in endothelial dysfunction (Figure 1). Stratification of ED by severity further amplifies predictive cardiac risk, with several angiographic studies revealing greater degree and number of narrowing cardiac vessels.9,19
A large prospective, population-based Australian cohort examined almost 100,000 men observed for several years and revealed a 1.6-fold risk of ischemic heart disease and a 1.93-fold risk of all-cause mortality in those with ED. Importantly, after accounting for confounding risk, diabetes but not age was associated with a stronger ED-CVD relationship.20 This is in stark contrast to oft-cited yet likely underpowered studies stating that age is the dominant determinate in the ED CVD risk equation. Inman et al21 and Chew et al22 illustrated that younger middle-aged men with ED have a greater CVD risk than older men
Other studies have linked psychogenic ED and its associated distress (depression, anxiety) with higher rates of CVD.23,24 Psychogenic ED leading to CAD is a new concept that warrants further study. A possible mechanism is the increased allostatic load (sympathetic hyperactivity) associated with ED’s increased anxiety and depression.25 Erectile dysfunction and depression share a definitive bidirectional relationship: psychological distress both causes and is a consequence of ED.26-28 Similarly, improvement of either ED or mental health leads to improvement of the other.29-31 Table 1 details important studies linking ED with increased cardiac risk.7-9,17-22,32-34 In general, men with ED have a 1.25- to 2.5-fold higher relative risk for MI. Of note, this cardiac risk is similar to or greater than that of known traditional factors, such as family history, smoking,and hyperlipidemia.35
Based on more than 20 years of unyielding evidence, the P4 panel determined that ED should be considered an independent risk marker and a risk-enhancing factor for CAD. We highly implore future CV guidelines to include ED on the list of established risk-enhancing factors. Thus far, the only cardiac risk tool that incorporates ED is the QRISK calculator.36 In general, CAD risk is enhanced by 25% in this risk score with ED (as binary yes/no, not severity related). Erectile dysfunction confers increased CVD risk at any age but is often underweighted in current models that focus on age. The previous debate of whether ED is a more powerful predictor of future MI in younger vs older men largely misses the point as thousands of men die annually with heart attack being the first “symptom” of their condition. Younger men may have only 1 reliable overt marker of subclinical cardiac disease, and that is ED.
*SEXUAL INQUIRY AND ITS CONCOMITANT BENEFITS
*MANAGING ED OVERLAPS WITH DECREASING CVD RISK
*CARDIOVASCULAR WORK-UP OF MEN WITH ED AND NO PREEXISTING CAD
*EVALUATION OF ED IN MEN WITH PREEXISTING CAD
*UPDATE ON PDE5I USE IN ED
Twenty-five years after their fortuitous discovery, PDE5is remain the best viable first line option for treatment of ED after lifestyle recommendations. Optimization of PDE5is for treatment of ED begins with addressing conditions hampering therapeutic responses (including performance anxiety), basic education of patients (and partners, if available), and promoting practices favoring therapeutic response (including sensate focus therapy).
In general, improving lifestyle conditions that compromise erection responses (eg, glycemic control, hyperlipidemic control, cigarette smoking discontinuation, weight loss) promotes PDE5i efficacy.68 T replacement in the hypogonadal patient improves ED and can enhance PDE5i efficacy by improving nitric oxide regulatory pathways.52,69 The cost of PDE5is was previously prohibitive for many, but the generic status of sildenafil and tadalafil has remedied this. Addressing performance anxiety and preventing sympathetic epinephrine release are essential. Restoring confidence in sexual performance is initially best achieved with allow-pressure, non-partnered masturbatory drug trial. Patients may be encouraged by return of morning erections. Invoking the service of a mental health counselor to reduce anxiety/stressors and to address cognitive dissonance (ED = no interest in sex) is also a valuable tool.68
Patients should be counseled to try PDE5is at least 8 times to enable maximal probability of success.70 Many patients believe PDE5is will cause spontaneous erections, but optimal stimulatory conditions (visual, touch) must be used to facilitate erection responses. In addition, patients may be advised to observe partner interactions and stimulation (eg, sensate focus sextherapy) that may influence medication responsiveness.70 Pharmacokinetic parameters of PDE5is, such as absorption, onset of action, time for maximal effect (Tmax), and time for elimination (T half-life), also influence success. Tadalafil should be taken at least 2 hours before sex, with its effect lasting about 36 hours. Other PDE5is should be taken 30 to 60 minutes before sex on an empty stomach (2-hour absorption delay with fatty meal), with their effect lasting 4 to 8 hours.71 Alternatively, Food and Drug Administration approved daily tadalafil dosing simplifies instructions and is a patient-preferred scheme that allows more spontaneous sexual intercourse.72 Efficacies of PDE5is may differ between patients, and these agents can reasonably be alternated or used in combination (ie, short and long acting).71,73 The combination of PDE5is with penile constriction bands, vacuum erection devices, and vasoactive penile injections can also optimize success.74-76
Behavioral practices (including sensate focus therapy) offer another strategy to improve erection responses to PDE5is. Sensate focus therapy enhances intimacy by shifting focus off of sexual intercourse performance toward sensual touch all over the body. For example, partners with performance anxiety begin twice-weekly 20-minute massages focusing on deep abdominal breaths and avoiding the touching of genitalia and highly arousable body parts(eg, breasts, nipples, clitoris). Couples agree before the exercise not to engage in intercourse. This exercise has the capacity to mitigate anxiety and a predetermined sense of failure that plagues men before they enter therapy. Boddi et al77 compared the efficacy of combined vardenafil and cognitive behavioral sex therapy with vardenafil alone in a pilot study involving 30 participants during 10 weeks. The 15-item IIEF, Female Sexual Function Index, and Index of Sexual Satisfaction were compared throughout the therapy. Whereas both interventions improved erectile function significantly, only the combined therapy improved couplesexual satisfaction and female sexual function. Such simple cognitive-behavioral sex therapy techniques as sensate massage done twice weekly for 20 minutes with both partners focusing on relaxed abdominal breathing can be most helpful and instructed by most practitioners. This outcome may relate to having sufficient opportunities to identify and to employ the best stimulatory conditions to respond to this therapy.Table 4 summarizes tips to optimize sexual function with PDE5i use.54,68-77
*INTERACTIONS OF PDE5I WITH NITRATES AND OTHER CV DRUGS
*PDE5I AND CARDIOPROTECTION
Some preclinical and clinical studies suggest that PDE5is may have cardioprotective properties. Potential mechanisms of PDE5i cardioprotective action include decreased blood pressure and generalized decreases in inflammation, tissue fibrosis, and thrombosis.16 Other mechanisms may include protection against ischemia-reperfusion injury, endothelial activation, regulation of platelet proteins, and oxidative stress reduction.86 Since 2005, numerous studies have signaled potential cardioprotective effects of PDE5is.33,87-95
A large nationwide cohort study in Denmark included 71,710 men receiving their first ED medicines from 2000 to 2012.94 Adjusted risk for overall CVD inthe ED-treated cohort was lower in the first 3 years compared with the general male population (relative risk, 0.92; 95% CI,0.87 to 0.97; P=.003); the benefit was lost after 3 years. There was a persistent lower risk of MI. Most recently, Kloner et al95 retrospectively analyzed a large integrated medical and pharmacy claims database of more than 70,000 men with ED comparing PDE5i exposure while correcting for baseline variables during a 15-year period. The overall incidence of major adverse cardiovascular events was 13% lower in the PDE5i-exposed men (23,816) vs the non exposed men (46,682; hazard ratio, 0.87; 95%CI, 0.79 to 0.95; P= .001). There was a 25% lower incidence of all-cause mortality (P<.001) in the PDE5i-exposed group vs the non exposed group, a 15% lower rate of need for coronary revascularization, a 17% lower rate of heart failure, a 22% lower rate of unstable angina, and a 39% lower rate of CV mortality (all statistically significant). Results were similar for men without CAD but who had CV risk factors at baseline and for those with type 2 diabetes. Quartile stratification of PDE5i exposure showed highest PDE5i use had the lowest risk of both major adverse cardiovascular events (hazard ratio, 0.45; 95%CI, 0.37 to 0.54) and overall mortality (hazard ratio, 0.51; 95% CI, 0.37 to 0.71) compared with those with lowest PDE5i use.
Taken together, these retrospective studies suggest that PDE5is are associated with cardioprotective effects and in the future might play a role in preventive cardiology. Verification of the causal cardioprotective benefit of PDE5is requires a prospective, randomized, controlled study.
*OTHER ED TREATMENTS
The PDE5is are ineffective or contraindicated in about one-third of eligible men with ED. No tachyphylaxis occurs with PDE5is, but their efficacy does wane as underlying causes of ED worsen with age. Recent American Urological Association ED guidelines have shifted away from a rigid stepwise approach to treatment (lifestyle change → PDE5i → vacuum erection device → intracavernosal injection [ICI] → penile implant surgery) toward a shared decision-making model in which all options are reasonable after PDE5i failure.52
CONCLUSION
Erectile dysfunction is an independent marker for future CV risk, including sudden death, and it should be considered a risk enhancing factor in CV risk algorithms. The key to accurately identifying early CV risk is using subclinical markers, and eliciting a history of ED is likely to be the most significant and most easily obtained. Inquiry about sexual function should be systematically employed and brings with it the potential to motivate and adhere to lifestyle change. Lifestyle recommendations emphasizing exercise, healthy diet, and ideal body weight improve both ED and CVD. Healthcare providers performing primary care are uniquely positioned to prevent heart attacks by asking about and treating ED. P4 provides straightforward algorithms to help determine safety of sexual activity and provide guidance for CV work-up. A calculated 10-year ASCVD risk score will often lead to CAC screening in men with borderline to intermediate risk. Management of ED in men with CVD also requires straightforward inquiry with occasional use of stress testing. Both scenarios for management of ED with or without preexisting CAD may lead to cardiology referral. The past 25 years have seen continued accumulation of PDE5i safety data. PDE5i use will continue to evolve, with alternatives to traditional nitrate therapy being considered to facilitate its use alongside its potential cardioprotective benefit.
- Independent Risk Marker: Erectile dysfunction (ED) should be considered an independent risk marker for coronary artery disease (CAD). It predates significant cardiac events, including myocardial infarctions and sudden cardiac deaths, often by several years. Thus, it can serve as an early indicator for potential cardiovascular issues.
- Inclusion in Risk Calculators: The P4 panel advocates for the inclusion of ED as a risk-enhancing factor in cardiovascular risk assessment tools. Currently, only the QRISK calculator incorporates ED, where it increases CAD risk by 25%.
- Link Between ED and Cardiovascular Health: The relationship between ED and cardiovascular health is significant, as ED is often caused by cardiovascular issues like endothelial dysfunction, arterial insufficiency, and inflammation. This relationship is supported by multiple studies linking ED with increased risk of cardiovascular events.
- Management of ED Overlaps with CVD Risk Reduction: Managing ED effectively, such as through the use of PDE5 inhibitors (PDE5is) and lifestyle changes, can also mitigate the risk of cardiovascular diseases. The article discusses the optimization of PDE5i therapy and emphasizes lifestyle modifications as a primary approach.
- PDE5i and Cardioprotection: PDE5is, beyond treating ED, might have cardioprotective effects. Studies suggest they could lower the risk of cardiovascular events and mortality, particularly in men with preexisting cardiovascular risk factors.
- Sexual Inquiry as a Health Tool: Systematic inquiry about sexual function in clinical settings is recommended as it can reveal early signs of cardiovascular disease. This approach not only helps in early identification but also in motivating patients towards healthier lifestyle choices which benefit both ED and cardiovascular health.
- Algorithm for Safe Sexual Activity: The article outlines algorithms to ensure the safety of sexual activity in men with ED, particularly those with overlapping cardiovascular risks. These include evaluations like exercise capacity and stress testing.
- Comprehensive Approach to ED Treatment: Modern guidelines for ED treatment encourage a patient-centered approach rather than a strict stepwise protocol, suggesting a range of therapeutic options after PDE5i failure.
- Future Directions: The article emphasizes the need for future cardiovascular guidelines to incorporate ED as a significant risk factor and calls for further research into the cardioprotective potential of PDE5is through controlled studies.
Topic dear to our hearts!
Enjoyed this one!
*Based on more than 20 years of unyielding evidence, the P4 panel determined that ED should be considered an independent risk marker and a risk-enhancing factor for CAD. We highly implore future CV guidelines to include ED on the list of established risk-enhancing factors. Thus far, the only cardiac risk tool that incorporates ED is the QRISK calculator.36 In general, CAD risk is enhanced by 25% in this risk score with ED (as binary yes/no, not severity related).
*The PDE5is are ineffective or contraindicated in about one-third of eligible men with ED. No tachyphylaxis occurs with PDE5is, but their efficacy does wane as underlying causes of ED worsen with age
INTRODUCTION AND BACKGROUND
Cardiovascular disease (CVD) is a leading cause of death in which half of all men who die suddenly never have antecedent CVD symptoms.1 Moreover, most men who have a heart attack have normal lipid levels.2 However, between one-third and half of all men younger than 45 years and 90% of men older than 65 years who have a heart attack and survive had at least mild erectile dysfunction (ED) before the event.3-6 Indeed, ED typically predates the first myocardial infarction (MI) by at least 2 to 5 years.7-9
The Princeton III (P3) panel published their findings in Mayo Clinic Proceedings in 2012 to systematically address the evaluation and management of men with ED who may have overlapping atherosclerotic CVD risk factors and thus potentially discoverable occult cardiac disease early in its progression.10 In addition, the P3 panel established an algorithm involving exercise capacity and stress testing to address the safety and risk of sexual activity itself with or without the use of phosphodiesterase type 5 inhibitors (PDE5is).
Princeton IV (P4) was convened by the Huntington Medical Research Institutes, a non profit biomedical research facility in Pasadena, California, on March 10-11,2023. The meeting was funded by an unrestricted educational grant from Sanofi. The sponsor was not involved in the selection of speakers, topics, or any aspect of the content of the meeting. As previously organized, a multispecialty group of US sexual medicine experts was selected by the steering committee to critically evaluate the current evidence for the relationship between ED and cardiovascular (CV) health, to update the CV work-up in the ED patient, to reassess when and how to treat ED patients with known CVD, and to reassess the accuracy and relevance of previous Princeton management algorithms. The role of the now quarter-century-old oral PDE5is in the treatment of men with ED and CVD was explored in depth, with a detailed review of the potential cardioprotective effect of these drugs. The full report of P4 findings is available in the Journal of Sexual Medicine.11 This abridged document targets primary healthcare providers who are uniquely positioned to detect occult CVD before it's often fatal initial manifestation through understanding, treatment, and above all, inquiry about ED.
UNDERSTANDING THE ED AND CORONARY ARTERY DISEASE CONNECTION
Erectile dysfunction is the inability to obtain or to maintain erections for satisfactory sexual intercourse.12 Historically, ED was categorized as psychogenic, organic, or mixed,with an antiquated premise that most cases were psychogenic or “in the man’s head.”In fact, only 1 in every 9 cases of ED can be classified as purely psychogenic, with the rest having definitive organic causes.13 Overall, most ED cases are likely to be mixed, stemming from nearly ubiquitous organic causes related to aging blood vessels or other chronic diseases combined with epinephrine-producing patient anxiety from performance and other causes.
Satisfactory erections require adequate arterial inflow, an intact nervous system to facilitate vasodilation of pudendal penile vasculature, and competent penile veins to adequately occlude and trap blood. The venous trapping system is passive, relying on inside-out compression from penile engorgement to function properly. Venous leak is a common cause of recalcitrant ED and may occur after smooth muscle apoptosis, penile fibrosis, or insufficient arterial pressure. Often stemming from radical prostatectomy for prostate cancer or long standing diabetes, smooth muscle apoptosis often induces a loss of penile elasticity and penile shortening and prevents adequate venous compression, giving rise to the failure of sustained erections. Ample testosterone (T) levels optimize erectile biochemical pathways for vasodilation.Conversely, epinephrine is known to be the most potent anti erectile chemical, with its analogues used to treat priapism. In addition, catecholamines released during performance anxiety increase sympathetic tone, enhance vasoconstriction, and worsen erectile function.
As alluded to before, an important cause of ED is arterial insufficiency (decreased arterial inflow). The size of relevant penile arterial blood vessels is 1 to 2 mm or smaller, compared with 3 to 4 mm in the coronary arteries, 5 to 7 mm in the carotids, and about 6 to 8 mm in the femoral vessels. Systematic progressive luminal obstruction of more than 50% in these vessels typically results in ED, angina, MI, transient ischemic attack and stroke, and intermittent claudication.14 Because of the small diameter of the penile artery lumen, it has been postulated that an equivalent buildup of atherosclerotic plaque in the penile artery vs the coronary artery will compromise blood flow to the penis first and be manifested as symptoms of ED before symptoms of reduced coronary blood flow appear, such as angina.
Yet, progressive, simultaneous narrowing of blood vessels offers a convenient but oversimplified link between ED and coronary artery disease (CAD) and other vascular disorders as half to two-thirds of all young men who have an MI have no reported ED.5 Many men with severe ED will never have an MI. However, several other factors have been reported to link ED to heart disease, including endothelial dysfunction, inflammation, and platelet aggregation.15,16 These factors most often occur subclinically. The Multi-Ethnic Study of Atherosclerosis(MESA) of nearly 2000 men free of CVD at baseline reported much greater odds of future ED and CVD events 9 years after initial testing if coronary artery calcium(CAC) scores or carotid intima-media thickness test results (markers for subclinical CAD) were abnormal.17 From this cohort, ED conferred a 2.5-fold higher risk of CV events even after multiple controls for other potential causes.
Erectile dysfunction should be considered a harbinger of CVD. More severe and longer standing ED yields greater risk. Numerous papers narrate a consistent story of ED predating the first cardiac event, including sudden death, by at least 2 to 5 years.7-9 A large observational trial of men with ED without overt cardiac symptoms revealed that cardiac events occurred in 1 of 9 men at 5 years of incident ED.18 The predictive capacity of the penis for cardiac events is intuitive on the basis of the fact that many of the risk factors for ED overlap with risk factors for CVD, including age, abdominal obesity, dyslipidemia, sedentary lifestyle, smoking, diabetes, hypertension, low T, metabolic syndrome, and any condition that results in endothelial dysfunction (Figure 1). Stratification of ED by severity further amplifies predictive cardiac risk, with several angiographic studies revealing greater degree and number of narrowing cardiac vessels.9,19
A large prospective, population-based Australian cohort examined almost 100,000 men observed for several years and revealed a 1.6-fold risk of ischemic heart disease and a 1.93-fold risk of all-cause mortality in those with ED. Importantly, after accounting for confounding risk, diabetes but not age was associated with a stronger ED-CVD relationship.20 This is in stark contrast to oft-cited yet likely underpowered studies stating that age is the dominant determinate in the ED CVD risk equation. Inman et al21 and Chew et al22 illustrated that younger middle-aged men with ED have a greater CVD risk than older men
Other studies have linked psychogenic ED and its associated distress (depression, anxiety) with higher rates of CVD.23,24 Psychogenic ED leading to CAD is a new concept that warrants further study. A possible mechanism is the increased allostatic load (sympathetic hyperactivity) associated with ED’s increased anxiety and depression.25 Erectile dysfunction and depression share a definitive bidirectional relationship: psychological distress both causes and is a consequence of ED.26-28 Similarly, improvement of either ED or mental health leads to improvement of the other.29-31 Table 1 details important studies linking ED with increased cardiac risk.7-9,17-22,32-34 In general, men with ED have a 1.25- to 2.5-fold higher relative risk for MI. Of note, this cardiac risk is similar to or greater than that of known traditional factors, such as family history, smoking,and hyperlipidemia.35
Based on more than 20 years of unyielding evidence, the P4 panel determined that ED should be considered an independent risk marker and a risk-enhancing factor for CAD. We highly implore future CV guidelines to include ED on the list of established risk-enhancing factors. Thus far, the only cardiac risk tool that incorporates ED is the QRISK calculator.36 In general, CAD risk is enhanced by 25% in this risk score with ED (as binary yes/no, not severity related). Erectile dysfunction confers increased CVD risk at any age but is often underweighted in current models that focus on age. The previous debate of whether ED is a more powerful predictor of future MI in younger vs older men largely misses the point as thousands of men die annually with heart attack being the first “symptom” of their condition. Younger men may have only 1 reliable overt marker of subclinical cardiac disease, and that is ED.
*SEXUAL INQUIRY AND ITS CONCOMITANT BENEFITS
*MANAGING ED OVERLAPS WITH DECREASING CVD RISK
*CARDIOVASCULAR WORK-UP OF MEN WITH ED AND NO PREEXISTING CAD
*EVALUATION OF ED IN MEN WITH PREEXISTING CAD
*UPDATE ON PDE5I USE IN ED
Twenty-five years after their fortuitous discovery, PDE5is remain the best viable first line option for treatment of ED after lifestyle recommendations. Optimization of PDE5is for treatment of ED begins with addressing conditions hampering therapeutic responses (including performance anxiety), basic education of patients (and partners, if available), and promoting practices favoring therapeutic response (including sensate focus therapy).
In general, improving lifestyle conditions that compromise erection responses (eg, glycemic control, hyperlipidemic control, cigarette smoking discontinuation, weight loss) promotes PDE5i efficacy.68 T replacement in the hypogonadal patient improves ED and can enhance PDE5i efficacy by improving nitric oxide regulatory pathways.52,69 The cost of PDE5is was previously prohibitive for many, but the generic status of sildenafil and tadalafil has remedied this. Addressing performance anxiety and preventing sympathetic epinephrine release are essential. Restoring confidence in sexual performance is initially best achieved with allow-pressure, non-partnered masturbatory drug trial. Patients may be encouraged by return of morning erections. Invoking the service of a mental health counselor to reduce anxiety/stressors and to address cognitive dissonance (ED = no interest in sex) is also a valuable tool.68
Patients should be counseled to try PDE5is at least 8 times to enable maximal probability of success.70 Many patients believe PDE5is will cause spontaneous erections, but optimal stimulatory conditions (visual, touch) must be used to facilitate erection responses. In addition, patients may be advised to observe partner interactions and stimulation (eg, sensate focus sextherapy) that may influence medication responsiveness.70 Pharmacokinetic parameters of PDE5is, such as absorption, onset of action, time for maximal effect (Tmax), and time for elimination (T half-life), also influence success. Tadalafil should be taken at least 2 hours before sex, with its effect lasting about 36 hours. Other PDE5is should be taken 30 to 60 minutes before sex on an empty stomach (2-hour absorption delay with fatty meal), with their effect lasting 4 to 8 hours.71 Alternatively, Food and Drug Administration approved daily tadalafil dosing simplifies instructions and is a patient-preferred scheme that allows more spontaneous sexual intercourse.72 Efficacies of PDE5is may differ between patients, and these agents can reasonably be alternated or used in combination (ie, short and long acting).71,73 The combination of PDE5is with penile constriction bands, vacuum erection devices, and vasoactive penile injections can also optimize success.74-76
Behavioral practices (including sensate focus therapy) offer another strategy to improve erection responses to PDE5is. Sensate focus therapy enhances intimacy by shifting focus off of sexual intercourse performance toward sensual touch all over the body. For example, partners with performance anxiety begin twice-weekly 20-minute massages focusing on deep abdominal breaths and avoiding the touching of genitalia and highly arousable body parts(eg, breasts, nipples, clitoris). Couples agree before the exercise not to engage in intercourse. This exercise has the capacity to mitigate anxiety and a predetermined sense of failure that plagues men before they enter therapy. Boddi et al77 compared the efficacy of combined vardenafil and cognitive behavioral sex therapy with vardenafil alone in a pilot study involving 30 participants during 10 weeks. The 15-item IIEF, Female Sexual Function Index, and Index of Sexual Satisfaction were compared throughout the therapy. Whereas both interventions improved erectile function significantly, only the combined therapy improved couplesexual satisfaction and female sexual function. Such simple cognitive-behavioral sex therapy techniques as sensate massage done twice weekly for 20 minutes with both partners focusing on relaxed abdominal breathing can be most helpful and instructed by most practitioners. This outcome may relate to having sufficient opportunities to identify and to employ the best stimulatory conditions to respond to this therapy.Table 4 summarizes tips to optimize sexual function with PDE5i use.54,68-77
*INTERACTIONS OF PDE5I WITH NITRATES AND OTHER CV DRUGS
*PDE5I AND CARDIOPROTECTION
Some preclinical and clinical studies suggest that PDE5is may have cardioprotective properties. Potential mechanisms of PDE5i cardioprotective action include decreased blood pressure and generalized decreases in inflammation, tissue fibrosis, and thrombosis.16 Other mechanisms may include protection against ischemia-reperfusion injury, endothelial activation, regulation of platelet proteins, and oxidative stress reduction.86 Since 2005, numerous studies have signaled potential cardioprotective effects of PDE5is.33,87-95
A large nationwide cohort study in Denmark included 71,710 men receiving their first ED medicines from 2000 to 2012.94 Adjusted risk for overall CVD inthe ED-treated cohort was lower in the first 3 years compared with the general male population (relative risk, 0.92; 95% CI,0.87 to 0.97; P=.003); the benefit was lost after 3 years. There was a persistent lower risk of MI. Most recently, Kloner et al95 retrospectively analyzed a large integrated medical and pharmacy claims database of more than 70,000 men with ED comparing PDE5i exposure while correcting for baseline variables during a 15-year period. The overall incidence of major adverse cardiovascular events was 13% lower in the PDE5i-exposed men (23,816) vs the non exposed men (46,682; hazard ratio, 0.87; 95%CI, 0.79 to 0.95; P= .001). There was a 25% lower incidence of all-cause mortality (P<.001) in the PDE5i-exposed group vs the non exposed group, a 15% lower rate of need for coronary revascularization, a 17% lower rate of heart failure, a 22% lower rate of unstable angina, and a 39% lower rate of CV mortality (all statistically significant). Results were similar for men without CAD but who had CV risk factors at baseline and for those with type 2 diabetes. Quartile stratification of PDE5i exposure showed highest PDE5i use had the lowest risk of both major adverse cardiovascular events (hazard ratio, 0.45; 95%CI, 0.37 to 0.54) and overall mortality (hazard ratio, 0.51; 95% CI, 0.37 to 0.71) compared with those with lowest PDE5i use.
Taken together, these retrospective studies suggest that PDE5is are associated with cardioprotective effects and in the future might play a role in preventive cardiology. Verification of the causal cardioprotective benefit of PDE5is requires a prospective, randomized, controlled study.
*OTHER ED TREATMENTS
The PDE5is are ineffective or contraindicated in about one-third of eligible men with ED. No tachyphylaxis occurs with PDE5is, but their efficacy does wane as underlying causes of ED worsen with age. Recent American Urological Association ED guidelines have shifted away from a rigid stepwise approach to treatment (lifestyle change → PDE5i → vacuum erection device → intracavernosal injection [ICI] → penile implant surgery) toward a shared decision-making model in which all options are reasonable after PDE5i failure.52
CONCLUSION
Erectile dysfunction is an independent marker for future CV risk, including sudden death, and it should be considered a risk enhancing factor in CV risk algorithms. The key to accurately identifying early CV risk is using subclinical markers, and eliciting a history of ED is likely to be the most significant and most easily obtained. Inquiry about sexual function should be systematically employed and brings with it the potential to motivate and adhere to lifestyle change. Lifestyle recommendations emphasizing exercise, healthy diet, and ideal body weight improve both ED and CVD. Healthcare providers performing primary care are uniquely positioned to prevent heart attacks by asking about and treating ED. P4 provides straightforward algorithms to help determine safety of sexual activity and provide guidance for CV work-up. A calculated 10-year ASCVD risk score will often lead to CAC screening in men with borderline to intermediate risk. Management of ED in men with CVD also requires straightforward inquiry with occasional use of stress testing. Both scenarios for management of ED with or without preexisting CAD may lead to cardiology referral. The past 25 years have seen continued accumulation of PDE5i safety data. PDE5i use will continue to evolve, with alternatives to traditional nitrate therapy being considered to facilitate its use alongside its potential cardioprotective benefit.
