Erectile Dysfunction in the Cardiovascular Patient
Erectile Dysfunction in the Cardiovascular Patient
Treatment in the patient with ED and (possible) CVD may have bidirectional benefits. Treating CVD or its risk factors may improve ED and, conversely, treatment of ED may confer an additional benefit in terms of outcome among men with established CVD.
Lifestyle changes, common to those recommended for reduction of CVD risk, are effective in improving sexual function in men. These include physical exercise, improved nutrition with emphasis on the Mediterranean diet, weight control, and smoking cessation.
Treatment of ED which was previously confined to invasive procedures, cavernosal injections or to rather ineffective oral medications was revolutionized in 1999 with the introduction of the orally administered PDE5 inhibitor sildenafil. Phosphodiesterase type 5 inhibitors are the first-line therapy for ED of organic aetiology unless there is a specific contraindication to their use. This class of agents is widely used because of its effectiveness and safety. Interactions with cardiovascular drugs have been minimal with the exception of nitrates and other nitric oxide (NO) donors (such as nicorandil), where co-administration may result in severe vasodilation and hypotension. However, nitrates are often overused in clinical practice; therefore, the option of their discontinuation should be considered. A strong body of clinical data shows that all three agents (sildenafil, tadalafil, and vardenafil) do not increase the risk of non-fatal myocardial infarction, stroke, or cardiovascular deaths. These drugs do not exacerbate ischaemia or worsen exercise tolerance in patients with known CAD who achieve levels of exercise comparable or greater than that achieved during sexual intercourse. Phosphodiesterase type 5 is expressed throughout the human body, including the pulmonary and systemic vasculature and hypertrophied myocardium. While currently their only additional indication, beyond ED, is idiopathic pulmonary hypertension (for sildenafil and tadalafil), they show potential to be of benefit in several other conditions, such as CAD and systolic heart failure. Mechanisms of benefit of PDE5 inhibitors include pulmonary and systemic vasodilation, increased myocardial contractility, reduced large artery stiffness and wave reflections, improved endothelial function, and reduced apoptosis, fibrosis and hypertrophy through mechanisms involving NO, cyclic guanosine monophosphate, protein kinase G and Rho kinase. A very important issue is whether treatment of ED per se (and not of its risk factors and comorbidities) will have an impact on cardiovascular risk. While this applies to all therapeutic modalities of ED, it is particularly pertinent for PDE5 inhibitors, since they represent the mainstay of ED therapy. Data are limited to date. Gazzaruso et al.showed a trend of PDE5 inhibitors to reduce cardiovascular morbidity and mortality in diabetic patients with silent CAD and ED, while Frantzen et al. showed that 2 years after the introduction of sildenafil, the relative risk of the incidence of CVD among men with ED compared with healthy men significantly decreased from 1.7 to 1.1.
Regarding the follow-up of patients, after the initiation of therapy visits are recommended at 2- to 4-week intervals initially and less frequently thereafter in order to assess response to the treatment (including partner satisfaction), consider dosage titration, monitor adverse effects, and assess overall health and psychosocial functioning.
While a widely held perception is that CVD drugs cause ED, data attest towards the contrary and some agents may be even beneficial. Only thiazide diuretics lead clearly to ED, while some older beta-blockers also do so, but the side-effect of ED was very low (~3%) when the patient was blinded for the drug administration. In fact, the vasodilating nebivolol may even improve erectile function. ACE-inhibitors, angiotensin-receptor blockers, and calcium-channel blockers are reported to have neutral or even a positive effect on erectile function but more evidence is needed. Regarding statins, the largest body of evidence point towards a beneficial effect. A negative effect has been reported in high statin doses, possibly related to a potential reduction in serum testosterone levels, but this dose dependency warrants further investigation. In terms of patient management, when ED onset and therapy initiation are linked and a cause-and-effect association is presumed, a short period of drug withdrawal with monitoring for ED resolution for verification may be an option. In patients who developed ED long after the initiation of CV drug treatment, sexual dysfunction is less likely to be drug associated and PDE5 inhibition therapy may be initiated.
Testosterone therapy (TTh) should be reserved for patients who (i) are symptomatic (ED or reduced libido) of testosterone deficiency and (ii) they have biochemical evidence of low testosterone (TT <8 nmol/L or 2.3 ng/mL). In men with borderline TT (8–12 nmol/L or 2.3–3.5 ng/mL), a TTh trial (for 3–6 months and continuation if effective) may be envisaged. While adding a PDE5 inhibitor can be considered in men who have not improved with TTh, the usual clinical scenario is to add TTh in patients who have not responded to PDE5 inhibitors. Improvement is dependent on the testosterone levels with better results being obtained at lower levels of TT. Despite evidence of benefit in patients with pre-existing cardiovascular conditions (angina or heart failure), it should be emphasized that TTh is not a medication with cardiovascular indications.
Testosterone therapy in hypogonadism modulates metabolic components associated with CV risk. The majority of prospective clinical studies indicates that treatment achieving testosterone levels within physiological limits has beneficial or neutral effects on a lipid profile other than HDL-C, beneficial or neutral effects on inflammatory mediators, and generally beneficial effects on glycaemic state. The lean body mass is typically increased in hypogonadal subjects, and visceral adiposity is decreased in several studies and unchanged in the remainder. Such metabolic effects have raised interest on the potential impact on cardiovascular health. Regarding symptoms in patients with pre-existing cardiovascular conditions (angina or heart failure) TTh has been either neutral or beneficial. Regarding CVD risk, available clinical trial data indicate that the use of testosterone in middle-aged to elderly men does not increase cardiovascular risk with the exception of one study in very frail (substantial limitation of mobility and a high rate of comorbidities) elderly subjects that used an off-label high, and rapid escalation, dosing regimen. Prospective data from large, well-designed, long-term trials of TTh are warranted.
After the initiation of TTh patients should be evaluated at 3 and 6 months, and annually thereafter to assess response to treatment and monitor adverse effects. Assessment should include physical examination with particular attention to the prostate. At these intervals testosterone levels should also be monitored, as well as PSA, haematocrit, and HDL.
Contraindications for TTh include (for detailed listing, please refer to Buvat et al.) patients with breast or prostate cancer, while patients with a palpable prostate nodule or induration, or prostate-specific antigen >4 ng/mL (or >3 ng/mL in men at high risk for prostate cancer, such as African-Americans or men with first-degree relatives with prostate cancer), should first undergo urological evaluation. Testosterone therapy is contraindicated also in patients with haematocrit >50% (TTh increases haematocrit) and uncontrolled congestive heart failure (risk of fluid retention). Risk for adverse CVD events may be increased in patients and with the mode of treatment epitomized in the study of Basaria et al. (see earlier).
Lifestyle and Pharmacological Treatment: Common Considerations for Erectile Dysfunction and Cardiovascular Disease
Treatment in the patient with ED and (possible) CVD may have bidirectional benefits. Treating CVD or its risk factors may improve ED and, conversely, treatment of ED may confer an additional benefit in terms of outcome among men with established CVD.
Lifestyle Modification
Lifestyle changes, common to those recommended for reduction of CVD risk, are effective in improving sexual function in men. These include physical exercise, improved nutrition with emphasis on the Mediterranean diet, weight control, and smoking cessation.
Phosphodiesterase Type 5 Inhibitors: Effects on the Cardiovascular System
Treatment of ED which was previously confined to invasive procedures, cavernosal injections or to rather ineffective oral medications was revolutionized in 1999 with the introduction of the orally administered PDE5 inhibitor sildenafil. Phosphodiesterase type 5 inhibitors are the first-line therapy for ED of organic aetiology unless there is a specific contraindication to their use. This class of agents is widely used because of its effectiveness and safety. Interactions with cardiovascular drugs have been minimal with the exception of nitrates and other nitric oxide (NO) donors (such as nicorandil), where co-administration may result in severe vasodilation and hypotension. However, nitrates are often overused in clinical practice; therefore, the option of their discontinuation should be considered. A strong body of clinical data shows that all three agents (sildenafil, tadalafil, and vardenafil) do not increase the risk of non-fatal myocardial infarction, stroke, or cardiovascular deaths. These drugs do not exacerbate ischaemia or worsen exercise tolerance in patients with known CAD who achieve levels of exercise comparable or greater than that achieved during sexual intercourse. Phosphodiesterase type 5 is expressed throughout the human body, including the pulmonary and systemic vasculature and hypertrophied myocardium. While currently their only additional indication, beyond ED, is idiopathic pulmonary hypertension (for sildenafil and tadalafil), they show potential to be of benefit in several other conditions, such as CAD and systolic heart failure. Mechanisms of benefit of PDE5 inhibitors include pulmonary and systemic vasodilation, increased myocardial contractility, reduced large artery stiffness and wave reflections, improved endothelial function, and reduced apoptosis, fibrosis and hypertrophy through mechanisms involving NO, cyclic guanosine monophosphate, protein kinase G and Rho kinase. A very important issue is whether treatment of ED per se (and not of its risk factors and comorbidities) will have an impact on cardiovascular risk. While this applies to all therapeutic modalities of ED, it is particularly pertinent for PDE5 inhibitors, since they represent the mainstay of ED therapy. Data are limited to date. Gazzaruso et al.showed a trend of PDE5 inhibitors to reduce cardiovascular morbidity and mortality in diabetic patients with silent CAD and ED, while Frantzen et al. showed that 2 years after the introduction of sildenafil, the relative risk of the incidence of CVD among men with ED compared with healthy men significantly decreased from 1.7 to 1.1.
Regarding the follow-up of patients, after the initiation of therapy visits are recommended at 2- to 4-week intervals initially and less frequently thereafter in order to assess response to the treatment (including partner satisfaction), consider dosage titration, monitor adverse effects, and assess overall health and psychosocial functioning.
Cardiovascular Drugs: Do They Cause ED?
While a widely held perception is that CVD drugs cause ED, data attest towards the contrary and some agents may be even beneficial. Only thiazide diuretics lead clearly to ED, while some older beta-blockers also do so, but the side-effect of ED was very low (~3%) when the patient was blinded for the drug administration. In fact, the vasodilating nebivolol may even improve erectile function. ACE-inhibitors, angiotensin-receptor blockers, and calcium-channel blockers are reported to have neutral or even a positive effect on erectile function but more evidence is needed. Regarding statins, the largest body of evidence point towards a beneficial effect. A negative effect has been reported in high statin doses, possibly related to a potential reduction in serum testosterone levels, but this dose dependency warrants further investigation. In terms of patient management, when ED onset and therapy initiation are linked and a cause-and-effect association is presumed, a short period of drug withdrawal with monitoring for ED resolution for verification may be an option. In patients who developed ED long after the initiation of CV drug treatment, sexual dysfunction is less likely to be drug associated and PDE5 inhibition therapy may be initiated.
Testosterone Therapy and Cardiovascular Disease
Testosterone therapy (TTh) should be reserved for patients who (i) are symptomatic (ED or reduced libido) of testosterone deficiency and (ii) they have biochemical evidence of low testosterone (TT <8 nmol/L or 2.3 ng/mL). In men with borderline TT (8–12 nmol/L or 2.3–3.5 ng/mL), a TTh trial (for 3–6 months and continuation if effective) may be envisaged. While adding a PDE5 inhibitor can be considered in men who have not improved with TTh, the usual clinical scenario is to add TTh in patients who have not responded to PDE5 inhibitors. Improvement is dependent on the testosterone levels with better results being obtained at lower levels of TT. Despite evidence of benefit in patients with pre-existing cardiovascular conditions (angina or heart failure), it should be emphasized that TTh is not a medication with cardiovascular indications.
Testosterone therapy in hypogonadism modulates metabolic components associated with CV risk. The majority of prospective clinical studies indicates that treatment achieving testosterone levels within physiological limits has beneficial or neutral effects on a lipid profile other than HDL-C, beneficial or neutral effects on inflammatory mediators, and generally beneficial effects on glycaemic state. The lean body mass is typically increased in hypogonadal subjects, and visceral adiposity is decreased in several studies and unchanged in the remainder. Such metabolic effects have raised interest on the potential impact on cardiovascular health. Regarding symptoms in patients with pre-existing cardiovascular conditions (angina or heart failure) TTh has been either neutral or beneficial. Regarding CVD risk, available clinical trial data indicate that the use of testosterone in middle-aged to elderly men does not increase cardiovascular risk with the exception of one study in very frail (substantial limitation of mobility and a high rate of comorbidities) elderly subjects that used an off-label high, and rapid escalation, dosing regimen. Prospective data from large, well-designed, long-term trials of TTh are warranted.
After the initiation of TTh patients should be evaluated at 3 and 6 months, and annually thereafter to assess response to treatment and monitor adverse effects. Assessment should include physical examination with particular attention to the prostate. At these intervals testosterone levels should also be monitored, as well as PSA, haematocrit, and HDL.
Contraindications for TTh include (for detailed listing, please refer to Buvat et al.) patients with breast or prostate cancer, while patients with a palpable prostate nodule or induration, or prostate-specific antigen >4 ng/mL (or >3 ng/mL in men at high risk for prostate cancer, such as African-Americans or men with first-degree relatives with prostate cancer), should first undergo urological evaluation. Testosterone therapy is contraindicated also in patients with haematocrit >50% (TTh increases haematocrit) and uncontrolled congestive heart failure (risk of fluid retention). Risk for adverse CVD events may be increased in patients and with the mode of treatment epitomized in the study of Basaria et al. (see earlier).