Introduction
Arterial hypertension is a major cardiovascular risk factor and represents a significant public health problem that affects more than one billion adults and is presumed responsible for almost 7 million deaths each year worldwide [1]. The advent of antihypertensive therapy rendered more than 100 antihypertensive drugs available on the market for the effective management of arterial hypertension. Each therapeutic class targets a specific mechanism involved in the pathogenesis of hypertension and has its own advantages and disadvantages, indications and contraindications.
Scientific advances in recent decades have resulted in the effective management of many diseases, have significantly prolonged the life expectancy of humankind, and uncovered the importance of quality of life as a significant aspect in the management of any patient. Sexuality is an inherent characteristic of human beings and represents a cardinal component of quality of life. Erectile function is highly appreciated by the majority of males, even at older ages, and erectile dysfunction exerts a major burden on the quality of life not only of patients but also of their sexual partners [2].
Erectile dysfunction is frequently encountered in hypertensive men, and the co-existence of arterial hypertension and erectile dysfunction increases with age. There are several clinically meaningful questions that need to be answered regarding the association between arterial hypertension and erectile dysfunction: a) is hypertension per se related to erectile dysfunction?, b) is blood pressure control beneficial or harmful to erectile function?, c) are antihypertensive drugs associated with the occurrence of erectile dysfunction?, d) are there any differences between antihypertensive drug categories regarding their effects on erectile function?, and e) does switching from one to another class affect erectile function?
This review aims to highlight the importance of recognizing erectile dysfunction in patients with hypertension and cardiovascular disease, to provide practical information about the management of erectile dysfunction in treated and untreated hypertensive patients, and to summarize the efficacy and safety of PDE5 inhibitors in cardiovascular disease.
Searching for erectile dysfunction in hypertension: why?
The importance of searching for and recognizing erectile dysfunction in patients with hypertension lies in four major parameters: a) its frequency, b) the negative impact on quality of life, c) the tendency towards poor adherence to therapy or even treatment withdrawal, and d) its utility as an early diagnostic window for identifying asymptomatic coronary artery disease.
Erectile dysfunction is found almost twice as frequently in hypertensive patients compared to normotensive individuals [3,4]. Moreover, erectile dysfunction is highly prevalent in patients with other concomitant cardiovascular risk factors (diabetes mellitus, obesity, metabolic syndrome, dyslipidemia) or overt cardiovascular disease (coronary artery disease, heart failure). Overall, more than half of patients with hypertension suffer from erectile dysfunction and the prevalence of the latter increases with advancing age, the severity and the duration of hypertension, and the presence of other cardiovascular risk factors.
Erectile dysfunction exerts a major impact on the quality of life of patients and their sexual partners. It has to been seen that hypertension is mainly an asymptomatic disease. It is therefore not surprising that patients experiencing sexual problems induced by antihypertensive drugs are more likely to withdraw or not adhere to antihypertensive therapy than patients free of sexual problems.
Finally, erectile dysfunction is of vasculogenic origin, in the vast majority of cases due to atherosclerotic lesions in the penile arteries. Due to the smaller diameter of penile arteries as compared to coronary arteries, sexual problems tend to appear earlier than symptoms from the heart. Indeed, erectile dysfunction is usually experienced 3 to 5 years before the appearance of symptomatic coronary artery disease. Therefore, erectile dysfunction can be used as an early diagnostic sign of otherwise asymptomatic coronary artery disease.
However, despite the importance of the timely recognition and appropriate management of erectile dysfunction, the latter remains remarkably under-reported, under-recognized, and under-treated [5]. Several patient-related and physician-related factors are responsible for this unpleasant reality. Patients are not keen to discuss sexuality because it still remains a “taboo” issue, mainly for personal, social, cultural, and religious reasons. Physicians are also reluctant to initiate a discussion about sexual problems due to lack of familiarity with this issue, mainly due to lack of appropriate training on this topic.
In order to address this issue, in 2010, the European Society of Hypertension formed a Working Group on arterial hypertension and sexual dysfunction, aiming to sensitize physicians about the magnitude of this problem, and educate cardiologists, internists, primary care physicians, and other doctors regarding how to approach patients about sexuality, how to recognize erectile dysfunction, and how to manage these patients. Along with the position statement of the Working Group published in the Journal of Hypertension [6] and a relevant newsletter [7], several other actions have already taken place: educational lectures at the ESH annual meetings and hypertension congresses in many European countries, regional meetings (Balkan region, Baltic region), and multinational protocols evaluating factors that contribute to erectile dysfunction in hypertensive patients and the impact of combination antihypertensive therapy on erectile function.
Basic principles of the management of erectile dysfunction
The first step in the management of erectile dysfunction is to recognize its existence, and then to identify whether it is vasculogenic or caused by other factors. Penile Doppler and the response to vascular stimulants (the “triple-mix” test) are used in the diagnosis and differential diagnosis of erectile dysfunction; however, these methods are not practical for large populations and everyday practice. Therefore, specifically structured questionnaires are used in everyday clinical practice to identify erectile dysfunction. The International Index of Erectile Function (complete and short version) is widely used and represents a validated, reproducible, easy to perform, and accurate tool for the identification of erectile dysfunction.
Several disease conditions are associated with erectile dysfunction and a detailed medical history combined with a meticulous clinical examination is required to exclude urological, neurological, psychological, endocrine, and iatrogenic causes of erectile dysfunction. Special caution is required in cases of testosterone deficiency (especially in the elderly), the discovery of drug-induced erectile dysfunction, and the recognition that a psychologic component is frequently uncovered in patients with vasculogenic erectile dysfunction, especially in patients with chronic pain, depression, and anxiety.
Management of erectile dysfunction in hypertensive patients
Erectile dysfunction is highly prevalent in hypertensive patients. Several lines of evidence from experimental and clinical studies suggest that blood pressure elevation is associated with structural and functional alterations of the penile arteries which contribute to erectile dysfunction [8]. Despite fears that blood pressure reduction might compromise penile blood supply and worsen erectile function, available data point towards a beneficial effect of blood pressure control on erectile function [3]. Accumulating data indicate that erectile dysfunction is more prevalent in treated than in untreated hypertensive patients and that antihypertensive drugs are associated with the occurrence of erectile dysfunction [9]. However, not all antihypertensive drug classes share the same effects on erectile function. Many experimental and clinical studies (observational, small and large studies) have strongly indicated that older antihypertensive drugs exert detrimental effects on erectile function while newer agents exert either neutral or even beneficial effects [10]. Finally, data from open studies point towards benefits in erectile function when antihypertensive therapy is changed from a drug with detrimental effects to a drug without such effects on erectile function [11].
The management of erectile function in untreated and treated hypertensive patients has some differences [12,13] which are summarized below.
Untreated patients
Once the diagnosis of vasculogenic erectile dysfunction has been established after careful exclusion of other causes (as described above), the first step in the management of erectile dysfunction is to encourage lifestyle modification [14]. Lifestyle modification includes weight reduction, salt restriction, smoking cessation, alcohol moderation, and regular exercise, and is strongly recommended in patients with essential hypertension (Class I, level A recommendation) [15]. Likewise, several studies have shown that lifestyle modification is associated with significant improvements in erectile function [14]. The success rates, however, remain low, especially in the long term, underlining the need for more intense efforts and close follow-up, to avoid a “lip service” (superficial advice) with low adherence, and ensure lifelong changes in lifestyle in more patients.
Antihypertensive drug therapy is required in patients with mild-moderate hypertension and low cardiovascular risk who fail to achieve blood pressure control after a reasonable time period of implementing lifestyle modification or immediately in patients with severe hypertension or high cardiovascular risk [15]. According to the European guidelines, the choice of antihypertensive therapy follows an individualized approach and is mainly based on the presence and type of target organ damage, the presence and type of overt cardiovascular disease, special conditions, comorbidities, and concomitant therapy [15]. Another important factor that enters into the equation concerns patients’ needs and preferences. Therefore, in patients with an active sexual life that is highly appreciated, the choice of antihypertensive therapy has to take into account this important parameter. Older antihypertensive drugs (diuretics and beta-blockers) are not ideal candidates for these patients due to their detrimental effects on erectile function, and should be used only if they are absolutely indicated. In cases where beta-blockers are chosen for an individual patient, the choice of nebivolol should be considered. Moreover, in case more than one class is indicated for an individual patient, the choice of an ARB should be considered.
Treated patients
Four important factors need to be considered in hypertensive patients with erectile dysfunction before any therapeutic changes: a) the time sequence of drug administration and erectile dysfunction, b) exclusion of other conditions or drugs causing erectile dysfunction, c) future consequences on adherence to antihypertensive therapy, and d) implementation of lifestyle modification.
The first question that needs to be answered is whether sexual difficulties appeared or deteriorated after antihypertensive therapy initiation or were pre-existing. Although erectile dysfunction may appear at any time after antihypertensive therapy initiation, it usually appears early, within the first months of therapy. When erectile dysfunction appears years after therapy administration, it is more likely to be the effect of progressive atherosclerosis and less likely to be the effect of antihypertensive therapy. The second question regards the presence of concomitant diseases or drugs (other than antihypertensive agents) that might contribute, at least in part, to erectile dysfunction. The recognition and appropriate management of such comorbidities as well as the replacement of culprit drugs (if possible) need to be addressed before further therapeutic decisions. The third question regards the impact of erectile dysfunction on adherence to drug therapy. It is known that the occurrence of sexual problems is associated with drug discontinuation or poor adherence to drug therapy. Therefore, these problems should be discussed in detail with the patient in order to minimize future poor adherence to therapy or even the discontinuation of antihypertensive drugs. The final question is whether the patient has already implemented lifestyle modification. In case the patient has not followed one or more pieces of advice regarding lifestyle modification, treating physicians need to reinforce relevant advice and persuade the patient about the benefits of lifestyle changes.
After all these factors have been appropriately addressed and erectile dysfunction in the given patient seems to be related to an antihypertensive drug, known to exert negative effects on erectile function, then the therapeutic strategy offers two choices: a) switching to another drug with beneficial effects on erectile function, or b) the addition of PDE5 inhibitors on top of antihypertensive therapy.
Switching antihypertensive therapy
Previous consensus statements negated any benefits from a change in therapeutic class of antihypertensive drugs. However, data from open studies point towards significant benefits when older drugs (diuretics, beta-blockers) are replaced by newer agents (angiotensin receptor blockers, nebivolol) [10,11]. The change of antihypertensive drugs, however, needs to be handled with caution. First, in case a concomitant disease dictates the use of a specific drug category (for example, beta-blockers for coronary artery disease and heart failure, diuretics for heart failure), then drug switching does not seem wise, although potential alternatives might be considered (deltiazem for post-myocardial infarction, nebivolol for heart failure) for patients experiencing a significant impact of erectile dysfunction on their quality of life, because these patients might withdraw from essential therapy. Second, switching to another class does not guarantee either the restoration or the improvement of erectile function. This has to be carefully explained to the patient in advance, in order to avoid unreasonable expectations and future disappointments.
PDE5 inhibitors: efficacy and safety
PDE5 inhibitors represent the cornerstone of the management of erectile dysfunction. PDE5 inhibitors block the breakdown of cGMP and subsequently result in increased nitric oxide bioavailability in the penile tissue and the systemic circulation, thus leading to an adequate erection and, in parallel, systemic vasodilatation. The vasodilatory effect of PDE5 inhibitors is usually modest, resulting in a blood pressure reduction of 2-4 mmHg on average. Of note, the blood pressure reduction is not dose-dependent and usually occurs even at low doses. Moreover, the blood pressure reduction might be significant in a small minority of patients and might result in symptomatic hypotension in a few patients.
Four PDE5 inhibitors are currently available on the market (sildenafil, vardenafil, tadalafil, and avanafil) with different pharmacokinetic and pharmacodynamic characteristics (mainly onset of action and half-life), which allow the tailoring of therapy according to the needs and preferences of the individual patient. PDE5 inhibitors are effective in about 60-70% of hypertensive patients (even if the patient has cardiovascular comorbidities), an efficacy rate that is slightly lower than the one observed in the general population.
The cardiovascular safety of PDE5 inhibitors has been extensively evaluated [16]. Sildenafil was not found to be associated with an increased cardiovascular risk in a large review of clinical trials and post-marketing safety data. Moreover, a recent systematic review and meta-analysis reported similar rates of serious adverse events between sildenafil and placebo. Of note, sildenafil use was found safe not only in men free of cardiovascular disease but also in men with either confirmed cardiovascular disease or in the presence of cardiovascular risk factors. Up to now, an overall good safety profile has been shown with the other members of this drug category as well. It has to be noted, however, that there exist no reliable data regarding the use of PDE5 inhibitors in the immediate post-MI and stroke phase, as well as in patients with hypotension. Therefore, PDE5 inhibitors should not be used in these patient populations unless relevant data become available.
Contraindications and precautions with PDE5 inhibitors
The co-administration of nitrates and PDE5 inhibitors is contraindicated due to the risk of clinically significant hypotension. The time period for the safe use of nitrates following the ingestion of PDE5 inhibitors depends on the half-life of the latter. In general, nitrates can be used with safety 24 hrs after sildenafil or vardenafil intake, and 48 hrs after tadalafil intake. In case of significant hypotension due to concomitant use within this timeframe, general supportive measures should be used to ensure the hemodynamic stability of the patient (intravenous fluids, Trendelenburg position, inotropic agents if necessary and not contraindicated).
Although PDE5 inhibitors can usually be co-administered safely with almost all antihypertensive drugs, some precautions need to be taken when prescribed with alpha-blockers due to the risk of significant hypotension. Several maneuvers used in everyday clinical practice may minimize the hypotensive risk, including the use of uroselective alpha-blockers, a 6-hr dose separation, and the initiation of therapy with low doses and careful up-titration after prior stabilization of therapy [17].
Conclusions
In summary, available data from experimental and clinical studies suggest that blood pressure elevation per se is associated with an increased occurrence of erectile dysfunction, while successful blood pressure control is associated with erectile function benefits. In addition, accumulating data indicate that antihypertensive drug therapy is associated with erectile dysfunction, that antihypertensive drugs have divergent effects on erectile function which is either detrimental (diuretics, beta-blockers, centrally acting agents), neutral (calcium antagonists, ACE inhibitors) or potentially beneficial (angiotensin receptor blockers, nebivolol), and that switching from a drug with negative to a drug with positive effects on erectile function seems to be beneficial in hypertensive patients with erectile dysfunction.
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