What Do Patients Expect from Erectile Dysfunction Therapy?

European Urology Supplements

European Urology Supplements 1 (2002) 4±11

What Do Patients Expect from Erectile DysfunctionTherapy? Geoffrey I. Hackett* Good Hope Hospital, Sutton Cold®eld, Elford Road, Fisherwick, Lich®eld, Straffordshire WS 149JR, UK

Abstract Erectile insuf®ciency can precipitate emotional distress and a negative spiral of events and feelings. Excessive focus by the patient on the penis as the dysfunctional unit may be associated with physical and psychological problems in the female partner. With the advent of effective, well-tolerated treatments for erectile dysfunction, including the phosphodiesterase type 5 (PDE5) inhibitor sildena®l citrate, the needs and expectations of patients and their partners concerning their medications, their physicians and other factors have come into focus. In addition to the effectiveness or tolerability of a medication, a number of nonmedical outcomes may in¯uence patients and their partners when choosing between therapeutic modalities or pharmacotherapies. These include the spontaneity and naturalness of the sexual encounter, as well as the treatment's acceptability to the sexual partner, onset/duration of action and potential interactions with food or alcohol. Patients of different ages, marital statuses or cultures may assign distinct values to each of these criteria. Couples should therefore be involved in formulating treatment plans and afforded wide latitude when initially selecting therapy and/or deciding how, or whether, to take medications. For the physician, erectile dysfunction represents an opportunity to diagnose and treat other comorbid diseases, including hypertension, ischemic heart disease and diabetes. # 2002 Published by Elsevier Science B.V. Keywords: Apomorphine; Erectile dysfunction; Intracavernosal injection therapy; Male sexuality; Phosphodiesterase type 5 inhibitors; Treatment outcome 1. Introduction In the 1980s, the only available treatment option for the sexually challenged man was sex therapy, a prosthetic implant, a vacuum device or testosterone therapy, which was often inappropriate. The advent of intracavernosal injection therapy (ICIT) enabled stoical couples to resume sexual relationships, but many found such treatment painful and invasive. Despite efforts to re®ne the procedures, more than half of the couples initiated on injection programs dropped out. According to certain literature reviews [1,2], about 15±22% of men in some clinical trials declined more than one trial injection of ICIT, and discontinuation rates with treatment in clinical trials ranged from approximately 40% after 3 months to as high as 70± 80% at 3 years. In 1998, Eardley described the ``ideal'' tablet for erectile dysfunction (ED; Table 1), providing bench* Tel. ‡44-1-543-432-757; Fax: ‡44-1-543-433-303. E-mail address: [email protected] (G.I. Hackett).

marks to assess how expectations are being met [3]. The ideal tablet would be effective; safe; rapidly acting and long-acting; unaffected by food, alcohol and other drugs; and consistent with discreet, on-demand use and a spontaneous sexual encounter. With the advent of effective and well-tolerated oral therapies, a number of ED patients can expect their sex lives to be restored to normal. For many, the concept of a tablet with proven proerectile ef®cacy in response to sexual stimulation in about 70% of intercourse attempts (or patients), usually within 1 hour, would seem ideal. Notwithstanding the widespread use and notoriety of sildena®l, large segments of ED patients either do not come forward for treatment or discontinue therapy prematurely. For instance, in an Australian study [4] involving 62 general medical practices, 88% of men with ED failed to avail themselves of treatment, as did about 75% in a European study [5]. Discontinuation rates range from 36% when ED is managed in a specialist clinic [6] to 78% when care is initiated by a primary-care physician (Data on ®le, Abbott, UK).

1569-9056/02/$ ± see front matter # 2002 Published by Elsevier Science B.V. PII: S 1 5 6 9 - 9 0 5 6 ( 0 2 ) 0 0 1 1 2 - 4

G.I. Hackett / European Urology Supplements 1 (2002) 4±11 Table 1 The ideal tablet for ED Effective Rapid ``On-demand'' Safe Tolerance-free Cheap No effect on desire?

Discreet Spontaneous Long-acting Unaffected by food, drink, other drugs Accepted by partner Curative?

Reproduced from Eardley et al. [3] with permission.

In addition, discontinuation rates for ED treatment with sildena®l range from 29% at 5 months in sildena®l responders to as high as 72% after 1 year [7,8]. These data suggest that currently available therapies do not meet all patient and partner expectations, that insuf®cient advice and follow-up are being furnished by physicians [9] or that some combination of these factors serves to compromise patient compliance and treatment outcomes. 2. Patient expectations Advances in the clinical management of erectile insuf®ciency have been accompanied by a marked evolution of ED treatment objectives and patients' expectations over the past ®ve decades (Fig. 1). Before 1960, when only surgery and natural remedies were available, to the introduction of vacuum devices in the 1960s and penile implantation in the 1960s through 1970s, the modest aim of treatment was any improvement. With the availability of ICIT in the 1980s and 1990s, an erection suf®cient for successful sexual intercourse became a rational treatment goal. Finally, the introduction of oral therapy with the phosphodiesterase type 5 (PDE5) inhibitor sildena®l citrate has completely

Fig. 1. Changing treatment, changing mindset.

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changed the mindsets of many patients and their partners. The availability of effective and well-tolerated oral therapy taken as needed by men with ED enabled many patients and their partners to expect treatment to restore normal sexual functioning. For many patients, the onset of erectile failure can be catastrophic, depending on such factors as culture, levels of physician and partner support, and age. The patient's self-con®dence can also be eroded by ED. Up to 51% of European men reported that erectile dif®culties made them feel generally less con®dent in life, according to a recent survey of 26,000 European and American men aged 40±60 years (Data on ®le, Lilly ICOS LLC). In this survey, the impact of ED on self-con®dence was less marked in UK men than their counterparts in other European countries. Moreover, only 41% of British men considered sex important to their relationships compared with 71% of respondents in Turkey. Sixteen percent of UK respondents admitted concerns over sexual problems, but only 4% remembered ever being asked about sex by their family doctors, a ®nding that ranked the United Kingdom as the lowest of the seven countries studied. Only 36% of Britons felt that their general practitioners should routinely ask about sex compared with 70% of respondents in Turkey. 2.1. What do patients expect of their physicians? When presenting with a health problem, most patients would expect their primary-care physicians to be interested and initiate investigations of the problem and/or specialist referrals. When the problem is ED, however, a number of patients are reluctant to come forward, often for fear of embarrassing themselves and/or their physicians. In a US survey [10], approximately 70% of respondents believed that their physicians would either dismiss, or be uncomfortable discussing, their concerns about sexual dysfunction. In the United Kingdom, men infrequently attend their family physicians, and many patients may be surprised when the physician discusses the associations between ED and important medical conditions. A British survey [11] of 789 men and 979 women demonstrated that sexual problems were associated with a range of social, psychological and physical problems, particularly prostate conditions among men with ED. Erectile insuf®ciency represents an excellent opportunity for health interventions that may result in longterm improvements in cardiovascular and overall health, because ED may be a risk marker for, or the ®rst sign of, occult coronary artery disease (CAD) or cardiovascular disease [12,13]; depression [14,15]; cardiovascular complications [16]; and/or diabetes [17].

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2.2. What do patients expect from their medications? Several studies have looked at patient expectations from ED therapy, and the results obtained have varied according to what questions were asked and how they were phrased. When devising a treatment plan, it is important to leave the patient and partner wide latitude for personal choice. Couples will assess the success of any ED therapy largely on the basis of its ef®cacy and tolerability, but a range of social, cultural, religious and potentially incomprehensible reasons will help to determine how a particular couple will take treatment (e.g. frequency) or whether they will continue with the therapy. Many patients are hoping for a cure, and most expect that treatment will involve a tablet. Among 52 US men of varying demographic and socioeconomic pro®les, including ages ranging from 18 to 70 years [18], outcome variables valued by participants when de®ning the success of ED treatment, in descending order of importance, were (1) cure, which was de®ned by some patients as ``bringing back normal sexual intercourse''; (2) pleasure (e.g. ``sensation,'' ``orgasm is achieved''); (3) partner satisfaction with intercourse; (4) reproduction (e.g. ``ability to ejaculate''); and (5) naturalness with reference to the temperature, size, color and overall appearance of the penis during erection. This study also demonstrated that patients with different demographic and socioeconomic characteristics may attach distinct values to health outcome variables when either deciding whether to use surgery, pharmacotherapy or vacuum devices as a treatment for ED, or choosing between competing pharmacotherapies. For instance, whereas men younger than 40 years were more concerned about the long-term consequences of therapy, those over the age of 60 were more concerned with immediate results [18]. Initially, men often focus on penile rigidity as their main treatment objective. However, recent work by Riley [19] in the United Kingdom demonstrated that ED may be associated with sexual problems (e.g. urogenital atrophy) and relationship con¯ict in the female partner (see below). Treatment outcomes are likely to be enhanced if the objectives of treatment are oriented toward the restoration of a satisfying sexual relationship rather than enhancing penile tumescence per se. 3. What about a cure? Finding a cure for ED was the central hope of many younger men, as it would deliver them from

Table 2 Reasons for sildena®l treatment discontinuation in 53 (30.9%) of 171 patients Reason

n (%)a

Treatment ineffective Partner reluctant Side effects Problem solved Dif®culties with general practitioner Financial No reason given Illness

15 9 7 6 5 5 4 2

(8.7) (5.2) (4.0) (3.5) (2.9) (2.9) (2.3) (1.2)

Data from Hackett and Milledge [6]. a Percent of 171 patients.

a lifetime of medication taking. One recent UK study involving 260 consecutive patients addressed the reasons for discontinuation of oral therapy with sildena®l 12 months after hospital clinic attendance (Table 2) [6]. Of note, six (3.5%) men in the overall study population, or 11% of sildena®l patients who discontinued therapy, stopped treatment because their erections had returned to normal. This study was more likely to re¯ect the true reasons for discontinuation of therapy than clinical trials, in which patients with high motivation may in effect be preselected and administered greater quantities of medications for free. A total of 19% of 791 patients seen in an Argentinean clinic [7] discontinued sildena®l therapy because of recovery of erectile function. Finally, a majority of men in a recent open-label study [20] reported the return of spontaneous erections over 12 months of treatment with self-injected prostaglandin E1 (PGE1). 4. What constitutes success? A reliable and consistent erection for sexual activity was rated as the highest priority in younger patients and the second-most important among older men [18] (Data on ®le, Lilly ICOS LLC). Among patients with severe ED, a PDE5 inhibitor is more likely to be effective than sublingual apomorphine [21,22]. Where proerectile ef®cacy is high, other features of a given medication may be less important for the majority of patients. For patients seeking a therapy that confers reliable, consistent improvements in erectile function, the physician should recommend the drug that will, in his or her opinion, be most effective, because repetitive treatment failures may compromise the patient's outlook and compliance with therapy.

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4.1. Pleasure Clinicians often forget that ED therapy is prescribed to facilitate a pleasurable experience for a patient and his partner. In younger men, pleasure is more likely to revolve around sexual performance and the rigidity of penile erections, whereas, for older couples, vaginal penetration may not be the main goal. The concept of pleasure is in¯uenced by not only age but also by ethnic, cultural, religious and even ®nancial factors. The search for a better sexual experience frequently leads patients to try new therapies, even if the existing one seems to be effective. Such an approach is virtually unique to therapies for sexual dysfunction and may also be in¯uenced by the requirement of the patient to pay for treatment. The assessment of satisfaction with ED therapy is largely based on traditional methods such as the International Index of Erectile Function (IIEF) [23], Global Assessment Question (GAQ), Sexual Encounter Pro®le (SEP) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) [24]. However, more sensitive measures of ejaculation and desire may be required to establish a reliable index or de®nition of satisfaction. 4.2. Partner satisfaction Erectile dysfunction can adversely affect patients' sexual partners. In one study [25], approximately 60% of women whose partners experienced ED reported a diminished interest in sex compared with 29% of those with healthy partners. Many men who are resuming sexual activityÐespecially those in new relationships after bereavement or divorceÐput themselves under extreme pressure to satisfy a new partner. It may be necessary for these men not to inform their new partner that they are taking therapy, at least until the relationship is established. In such cases, a rapidly acting therapy, such as sublingual apomorphine, may be more appropriate than a drug such as sildena®l, as these men are more likely to complain about the need for premeditation associated with taking the therapy 1 hour before planned sexual intercourse. However, a recent study [26] suggested that, among the majority of men in stable relationships, such planning is a minor issue. Further, a randomized, doubleblind, placebo-controlled trial [27] involving 247 ED outpatients showed that men who were treated with sildena®l, as well as their partners, exhibited signi®cantly higher levels of treatment satisfaction (according to the EDITS) compared with their counterparts in a placebo-control group. Agents with the potential for a longer duration of action, such as tadala®l (a PDE5 inhibitor), may also

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have advantages for couples who desire more spontaneous or more frequent sexual activity. As discussed by Prof. Porst elsewhere in this supplement, treatment with tadala®l enabled a majority of ED patients to experience successful intercourse at any time up to 36 h after dosing. Safety concerns may in¯uence partner satisfaction, and these concerns may be greater if a drug remains in the bloodstream for several days. However, the prolonged plasma residence of tadala®l, which has a halflife of 17.5 hours [28], has not been associated with an increase in the frequency or severity of adverse events reported with other (shorter-lived) PDE5 inhibitors, according to large, multicenter, randomized, doubleblind, placebo-controlled clinical trials [29,30]. Invasive therapies, such as ICIT and medicated urethral system for erection (MUSE1), are often less satisfying options for patients' partners. For instance, partners of MUSE patients may experience vaginal burning or itching, although these symptoms may be manifestations of resuming sexual intercourse rather than a direct consequence of transurethral PGE1 per se [31]. The female partner may also resent or feel uninvolved with the ``pharmacologically induced'' erection associated with ICIT [19]. Vacuum constriction is also generally less satisfying to the female partner, although occasionally, her desire for the ED patient to avoid medication use can result in selection of the vacuum device as the preferred treatment option. Apart from psychosexual counseling, vacuum devices represent the least-invasive ED treatment alternative. Sexual satisfaction may be in¯uenced by a disparity in sexual desire between the man and his partner, and health authorities [32,33] have stressed the importance of assessing potential sexual problems in the partner. The sexual history should evaluate the patient's and partner's expectations and motivations concerning ED therapy, and the effectiveness of therapy may be optimized by including both parties in formulating treatment plans [32]. Vaginal dryness is the most common partner problem unmasked when ED therapy is initiated. Fortunately, unlike a disparity in sexual desire, vaginal dryness is readily treatable. 4.3. Reproduction Among younger patients, reproduction is considered an important issue in the treatment of ED [18]; erectile dif®culties, as well as premature ante portas and retrograde ejaculation, are not uncommon causes of infertility. Many patients for whom fertility is an issue expect their physicians to show a high level of interest and offer clinical support, such as prescribing oral therapies for frequent use or medications for ejaculatory disorders

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when indicated, as well as providing other, supportive services as required. 4.4. Naturalness Among men under 40 years of age in the study by Hanson-Divers et al. [18], ``naturalness,'' or the degree to which a treatment had a physiologic effect on the body, was rated as moderately important when choosing between pharmacotherapies for ED, but not more important than the success associated with each drug treatment. Oral therapy with a rapidly acting agent that potentiates the physiologic erectile response to sexual stimulation is more likely to ful®ll the requirement for naturalness than MUSE1 or ICIT. The planning associated with the use of an agent such as sildena®l, which, for optimal effectiveness, must be administered on an empty stomach approximately 1 hour before sexual intercourse, may not satisfy the patient's concept of a natural erection and sexual encounter. In addition, a rapidly acting agent such as sublingual apomorphine, whose pharmacokinetics are not affected by food intake, may also provide a more natural erection and be easier to use, but it must also be effective and reliable. Of note, tadala®l has been administered in clinical trials without any instructions concerning timing of intercourse relative to dosing or any restrictions regarding food or alcohol intake. 4.5. Spontaneity Younger men value spontaneity as a more important issue than men over 40 years of age, for whom sex is more likely to be organized and scheduled into a busy work and family life, particularly when both partners have careers. In some countries in the Middle and Far East, spontaneity and facility for multiple sexual attempts may be important; among 460 Saudi Arabian men with ED seen from 1991 to 1995, a lack of sexual spontaneity and naturalism accounted for 24% of premature discontinuations with ICIT [34]. A recent study of 30,000 men in six countries showed that approximately 50% of European and American men did not want to plan their sexual activities (Fig. 2) (Data on ®le, Lilly ICOS LLC). If approved by regulatory agencies, a longer-acting oral drug such as tadala®l might have practical advantages in this context. 5. Risk A number of studies have clearly demonstrated an association between ischemic heart disease (IHD) and

Fig. 2. Patient expectations. About half of the patients surveyed preferred not to plan their sexual activities. Data on ®le, Lilly ICOS LLC.

ED [13], and the likelihood that a newly presenting ED patient has undiagnosed IHD has been estimated at 40% [35]. Case reports of myocardial infarction (MI) in sildena®l users [36], together with avid coverage in popular media, have prompted concerns among many patients and their partners that resumption of sexual activity while using oral ED therapy may be dangerous. Such concerns need to be discussed openly with the ED patient and his partner so that they understand that the risk usually results from the underlying IHD and not ED therapy per se. Many patients will select sublingual apomorphine or ICIT because of concerns about MI with sildena®l. However, a number of men with severe IHD may be disappointed in the outcomes of therapy with sublingual apomorphine. In a recent randomized, doubleblind, placebo-controlled crossover study [21] of 296 men with ED of various severities and etiologies, 42% of attempts resulted in erections ®rm enough for sexual intercourse among men with CAD who were treated with sublingual apomorphine 3 mg for 4 weeks compared to 28% with placebo; this difference was not statistically signi®cant, although the number of CAD patients was small (n ˆ 14). Consensus recommendations can assist clinicians in risk-stratifying and counseling ED patients with cardiovascular disease who are interested in resuming sexual activity and/or treatment [37]. Administration of PDE5 inhibitors can amplify the hypotensive effects of nitrates or nitric oxide donors, with deleterious outcomes, and sildena®l is hence absolutely contraindicated for concomitant use with these agents [38±40]. However, in many cases where ED therapy is being considered, the prescribing physician

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may stop nitrate therapy and/or change therapy to a drug that in¯uences the prognosis of IHD rather than merely treating its symptoms with nitrates. Analyses of large clinical databases [41,42] suggested that the overall incidences of MI with either sildena®l or tadala®l were low and comparable to placebo. 6. Side effects Compared with the reporting of adverse events in randomized, controlled, clinical trials, side effects tend to be reported less frequently in daily clinical practice. Patients often tolerate side effects, including headache, dyspepsia and ¯ushing with sildena®l, because these effects are far outweighed by the gains in erectile function obtained from effective treatment. In general, ED therapies are well tolerated, with few side effects. Some patients will wish to try other medications to avoid side effects. For instance, the centrally acting dopamine agonist apomorphine has a different mechanism of action and side-effect pro®le than those of PDE5 inhibitors. Nausea, headache and dizziness were among the predominant side effects seen in clinical trials with sublingual apomorphine [43]. In a large, long-term European study [44] involving ICIT, penile pain (occurring in 29% of patients), hematoma (33%), ®brotic changes (12%) and prolonged erection (1.2%) were among adverse events. 7. ``Recreational'' uses Much public concern has been expressed about patients' ordering sildena®l over the Internet or through newspaper advertisements. The common view of such patients is that they are seeking performance enhancement, but it is likely that most of them have mild ED and, like other men, resort to alternative drugseeking behaviors to avoid consultations with their physicians. Obtaining therapy through the Internet or other alternative sources is probably a feature of modern consumerism and may, to some extent, be reinforced by the ED patient's knowledge that he will have to pay privately for his ED treatment irrespective of how it is obtained. Because many of these patients also have undiagnosed CAD, hypertension and/or diabetes, accessing them represents an important challenge. Clinicians should also be vigilant for occult, recreational nitrate use in their patients who are taking PDE5 inhibitors. Amyl nitrate ``poppers'' represent one source

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of nitrates that should not be overlooked in the medical history. 8. What about cost? Compared with men seeking treatment for largely asymptomatic conditions (e.g. hypertension, hypercholesterolemia), some ED patients might be expected to assign a higher priority to therapies that enhance sexual function; such men might even be more willing to pay out of pocket for ED treatment. For other patients who expect their ED therapies to be covered in the same way as interventions for other medical conditions, issues such as private cost and medication rationing may have adverse effects on treatment compliance and outcomes. The common practice of tablet splitting is evidence that cost is a signi®cant issue. Few population studies have surveyed patients about the issue of cost. In a transitional Latin American economy, nearly one of every four sildena®l responders who discontinued did so because of medication costs [7], whereas, in the United Kingdom, ®nancial reasons accounted for about 9% of sildena®l discontinuations [6]. Whether the availability of treatment is regulated or restricted by what the patient can or is willing to afford, costs can ultimately in¯uence patient expectations. Results with oral therapy are improved if the patient is exposed to multiple doses early in the course of therapeutic regimens, but such regimens often prove to be unsuccessful because patients cannot or will not pay for them. Depending on post-registration costs, potentially longer-acting drugs may represent improved values. 9. Conclusions There are fundamental differences between treatments for ED and other chronic diseases. The aim of treating sexual problems in couples is to enable them to enjoy a satisfactory sexual experience. For these reasons, simple or conventional considerations as to whether one medication is more effective than another may be of little relevance to couples when selecting treatment. Many couples will experiment with different therapies to see if the sexual experience is enhanced. They may also decide that they want a variety of experiences and may wish to alternate therapies. The couple will also decide, based on a number of social, cultural, religious and often incomprehensible reasons, how often they take therapy and when to discontinue treatment. Consequently, physicians need a range of therapies to satisfy these diverse patient needs.

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