Therapeutic Response after First Month of Tadalafil Treatment Predicts 12 Months Treatment Continuation in Patients with Erectile Dysfunction: Results from the DETECT Study

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ORIGINAL RESEARCH—ED PHARMACOTHERAPY Therapeutic Response after First Month of Tadalafil Treatment Predicts 12 Months Treatment Continuation in Patients with Erectile Dysfunction: Results from the DETECT Study Thierry Roumeguère, MD,* Benny Verheyden, MD,† Stefan Arver, MD,‡ Alain Bitton, MD,§ Mark Belger,¶ and Henry Schmitt, MD** for the DETECT study investigators *Erasme Hospital, Brussels, Belgium; †University Hospital, Antwerp, Belgium; ‡Karolinska Hospital, Stockholm, Sweden; § Private urological practice, Geneva, Switzerland; ¶Eli Lilly, Erl Wood, United Kingdom; **Eli Lilly, Brussels, Belgium DOI: 10.1111/j.1743-6109.2008.00790.x

ABSTRACT

Introduction. The DETECT study is a prospective, 12-month, European, multicenter, observational study of patients with erectile dysfunction (ED) initiating or changing treatment to tadalafil in routine clinical practice. Aim. To determine the effectiveness of tadalafil and the factors associated with the continuation of treatment for ED at 12 months. Methods. The DETECT study included 1,900 men aged 18 years and older with a history of ED and who were initiating or changing treatment to tadalafil. Main Outcome Measures. Sexual function at baseline, 1, 6, and 12 months was assessed using the International Index of Erectile Function-erectile function (IIEF-EF) domain. Factors associated with treatment continuation at 12 months were evaluated using multivariate regression analysis. Results. At 12 months, 1,319 (84%) of 1,567 patients who completed the questionnaire reported continued use of tadalafil. Among these patients, tadalafil was highly effective: 94%, 95%, and 71% with severe, moderate, and mild ED at baseline, respectively, improved by at least one IIEF-EF category and 65% had normal EF. Five factors were associated with tadalafil continuation at 12 months: (i) ED severity at 1 month (based on IIEF-EF domain score); (ii) tolerance to treatment at 1 month; (iii) age younger than 60 years; (iv) number of sexual attempts in the first month; and (v) no history of pelvic surgery. Patient and partner factors at baseline were not significantly associated with continued tadalafil use. Conclusions. Tadalafil is an effective treatment for ED in routine clinical practice. The therapeutic response and treatment tolerance after 1-month treatment are the most important factors influencing tadalafil continuation. Roumeguère T, Verheyden B, Arver S, Bitton A, Belger M, and Schmitt H for the DETECT study investigators. Therapeutic response after first month of tadalafil treatment predicts 12 months treatment continuation in patients with erectile dysfunction: Results from the DETECT study. J Sex Med 2008; 5:1708–1719. Key Words. Erectile Dysfunction; Phosphodiesterase Type 5 Inhibitors; Tadalafil; Treatment Continuation

Introduction

E

rectile dysfunction (ED) is a common disorder. Various studies have estimated that 19–55% of men aged between 30 and 80 years have some degree of ED, with incidence increasing with age [1–10].

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Oral phosphodiesterase type 5 (PDE5) inhibitors have demonstrated efficacy and safety in clinical trials and are now considered the treatment of choice for most patients with ED [11]. However, despite the availability of efficacious treatments, only a minority of men with ED seek help [5–7,11,12], and about 50% of those who do © 2008 International Society for Sexual Medicine

Tadalafil Treatment Continuation in Erectile Dysfunction seek medical care discontinue their treatment [13–15]. Common reasons for failure with sildenafil include insufficient sexual stimulation before attempting intercourse, intake of drug after a full meal, lack of adjustment of the time of drug administration, and lack of dose titration to maximal tolerated dose with at least four sexual attempts [16,17]. Partner and couple issues are also thought to contribute to treatment discontinuation [18]. Tadalafil is unique among the commercially approved PDE5 inhibitors because it has a long period of responsiveness that lasts up to 36 hours after dosing and can be taken with or without food [11,19–23]. These characteristics of tadalafil may facilitate its correct use in a real-life setting and could increase patient response and satisfaction [24,25]. The DETECT study is a prospective, 12-month, European, multicenter, observational study in patients with ED initiating or changing treatment to tadalafil. We reported here the effectiveness of tadalafil after 12 months of treatment and the factors associated with treatment continuation.

Patients and Methods

Study Design The DETECT study was conducted at 236 centers in eight European countries: Austria, Belgium, Denmark, Greece, Iceland, the Netherlands, Norway, and Sweden. Although Switzerland initially participated in the study, participation was later withheld for regulatory reasons linked to the observational nature of this study. Thus, Swiss patients were excluded from this analysis; they had, however, similar baseline characteristics to the present study cohort. Patients could be enrolled in the study if they were ⱖ18 years of age with a self-reported history of ED, aspired to be sexually active with a female partner, and were initiating or changing treatment to tadalafil. Patients were not allowed to take part in the study if they had used tadalafil in the last 3 months. Treatment with tadalafil 10 or 20 mg was prescribed by physicians according to their usual practice of standard care. Of all patients enrolled, 29% were initially prescribed tadalafil 10 mg and 71% tadalafil 20 mg. There was no significant difference in the proportion of patients initially receiving the 20-mg dose according to the degree of ED severity (normal: 75%, mild: 70%, moder-

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ate and severe: 71%). The study was approved by ethical committees and the patients gave an informed consent. Data were collected at baseline and after approximately 1, 6, and 12 months of treatment. The patients were seen at the doctor’s office for their baseline visit. Follow-up data were collected via a standard questionnaire completed at the doctor’s office or returned by mail, regardless of whether the patient was still taking tadalafil. At baseline, responses to the International Index of Erectile Dysfunction-erectile function (IIEF-EF) domain were collected [26], together with information on previous treatments for ED and reasons for discontinuation, demographics, concomitant diseases, duration and etiology of ED, relationship history, and expectations of treatment. The IIEF-EF domain score was used to categorize the severity of ED: severe (score 1–10), moderate (score 11–16), mild (score 17–25), and normal (score ⱖ 26). At 1, 6, and 12 months, the patients completed the IIEF-EF domain questionnaire, the Erectile Dysfunction Inventory for Treatment Satisfaction questionnaire [27], and the relationship questionnaire, and indicated whether tadalafil was used in the previous 4 weeks. If it was used, the number of tablets, dosage, and tolerance were recorded. If tadalafil was not used, the patients indicated which of the following predefined reasons for discontinuation were applicable: no longer have ED, lack of efficacy–rigidity, duration of action–time constraints, slow onset of action, interference with meals, side effects, lack of confidence that treatment will work each time, request from partner, cost, change in health, loss of partner, and change in ED treatment. If the patient changed their ED treatment, the name of the drug and the reasons for treatment change were also recorded. Treatment satisfaction and effects on relationships are not discussed in this article.

Study Population Overall, 1,900 patients were enrolled in the study: Greece (N = 710), the Netherlands (N = 278), Belgium (N = 276), Austria (N = 225), Sweden (N = 192), Denmark (N = 139), Norway (N = 65), and Iceland (N = 15). Of these patients, 1,719 (90%) returned a completed data collection form (DCF) after 1 month, 1,611 (85%) after 6 months, and 1,537 (81%) after 12 months; the DCF return rates varied across countries. The analysis of tadalafil use was based on a total of 1,567 patients: 1,528 patients with 12-month data plus 39 patients J Sex Med 2008;5:1708–1719

1710 who reported at 6 months that they were no longer using tadalafil but did not report tadalafil usage information at 12 months and were assumed to have stopped treatment. Of the patients enrolled into the study, 65% were treatment naïve, 10% had received ED treatment in the 4 weeks prior to study enrollment, while 25% had previously received treatment but not in the 4 weeks prior to study enrollment. Among the patients who received treatment in the 4 weeks prior to the study, 78% were on sildenafil citrate, 15% on vardenafil HCl, and 7% used both sildenafil and vardenafil. The main reasons for changing PDE5 inhibitor treatment to tadalafil were duration of action (29%), lack of efficacy (25%), unwanted effects (9%), slow onset (9%), lack of confidence in medication working (5%), and cost of medication (5%). Multivariate logistic regression analysis identified the patients with a concomitant disease at baseline as the only patient baseline characteristic that was statistically significantly associated with patients having no tadalafil use information at 12 months. The patients with a concomitant disease (16%) were less likely to have missing information compared with those patients reporting no concomitant disease (21%; P = 0.01). The high return rate of completed DCFs and the lack of difference in baseline characteristics (including ED severity, duration, or etiology) between patients returning or not returning DCFs allow us to conclude that the cohort of patients returning completed questionnaires after 12 months is representative of the whole study population and can be used for this analysis.

Statistical Analysis Descriptive summary statistics (means, standard deviations, frequencies, percentages) were used to describe the study population. Factors associated with treatment continuation at 12 months were investigated using a multivariate logistic regression model. Treatment continuation was defined as a dichotomous outcome measure, based on the patient’s response to the question on tadalafil use in the 4 weeks prior to the 12-month visit. Patients reporting that they had used tadalafil were classified as continuing treatment, while those giving a negative response were classified as discontinuing treatment. Patients who did not answer at 12 months, but had reported stopping tadalafil at 6 months were also classified as discontinuing treatment. Patients who had stopped tadalafil and gave the reason for stopping as no longer having ED were excluded from the analysis of factors influJ Sex Med 2008;5:1708–1719

Roumeguère et al. encing treatment continuation. A multifactorial logistic regression model was used to test the assumption that patients excluded from the analysis were assumed to be missing at random. Factors included in the multivariate regression model were baseline patient characteristics (age, ED severity [based on IIEF-EF domain score], ED etiology, previous ED treatment, number of sexual attempts prior to enrollment, sexual desire); patients’ expectations at baseline; patient relationships; and outcomes after the first 4 weeks of treatment (change in IIEF-EF score, IIEF-EF category of ED severity, change in the number of sexual attempts, tolerance to treatment). As there were differences in baseline patient characteristics between countries, the statistical models did not include country to allow the impact of patient characteristics to be assessed. A sensitivity analysis was performed on all statistical models to determine the impact of the Greek cohort (37% of all patients) on the results. Factors significantly associated with treatment continuation at the 10% level were included in a final model, where a stepwise model reduction approach was used to exclude those factors with a P value of <5%. Odds ratios (ORs) for these factors are reported, together with univariate summary statistics, which help to describe their effect on treatment continuation. Response to treatment was analyzed using the change in IIEF-EF from baseline. A repeated measures analysis of covariance (ANCOVA) model was used to identify baseline factors associated with a change in IIEF-EF score over 12 months. Baseline IIEF-EF score was fitted to the model and other baseline factors were selected using a stepwise approach, based on significance at the 5% level. They included baseline patient characteristics (age, ED severity, ED etiology, previous ED treatment, duration of ED, number of sexual attempts prior to enrollment, sexual desire, concomitant diseases) and patient relationships. Results

Of the 1,567 patients analyzed, 97%, 90%, and 84% reported continued the use of tadalafil at 1, 6, and 12 months, respectively. Table 1 summarizes the baseline characteristics of all patients: the 1,319 patients (84%) reporting tadalafil use at 12 months, the 197 patients (13%) who had stopped tadalafil treatment, and the 51 patients (3%) who reported they no longer had ED.

27% 52% 21% 37% 25% 33% 5% 66% 4.7 (4.3) 13% 66% 23% 43% 10% 14% 17% 5% 24% 3% 51% 11%

28% 51% 21% 37% 24% 33% 5% 67% 4.7 (4.5) 13% 67% 23% 42% 10% 13% 16% 8% 24% 4% 49% 11%

24% 45% 11% 15% 17% 4% 25% 3% 52% 12%

13% 66%

35% 26% 34% 5% 65% 5.0 (4.3)

26% 53% 21%

56.1 (10.7) 27.5 (3.9) 96% 49.5 (11.2)

Patients who used tadalafil at 12 months (N = 1,319) (84%)

20% 42% 9% 13% 19% 8% 23% 7% 42% 6%

12% 69%

52% 18% 26% 4% 76% 3.1 (3.8)

32% 47% 20%

61.0 (11.2) 27.3 (3.7) 96% 56.7 (11.8)

Patients who did not use tadalafil at 12 months (N = 197) (13%)

Data are presented as mean (SD) unless indicated otherwise. Percentages do not always add up to 100% due to rounding. BMI = body mass index; ED = erectile dysfunction; IIEF-EF = International Index of Erectile Dysfunction-erectile function domain; LUTS = lower urinary tract symptoms.

56.5 (11.1) 27.5 (3.9) 96% 50.3 (11.7)

All patients who completed the questionnaire (N = 1,567)

56.7 (11.1) 27.4 (3.9) 96% 50.7 (11.8)

All patients who entered the study (N = 1,900)

Patient demographics and characteristics at baseline

Age (years) (standard deviation [SD]) BMI (kg/m2) (SD) Currently has a partner Partners’ age (years) (SD) ED etiology (investigator judged) Organic Mixed Psychogenic ED severity (IIEF-ED domain) Severe Moderate Mild Normal ED duration >1 year Number of sexual attempts in the last 4 weeks (SD) Duration of relationship <1 year >10 years Comorbidities Diabetes Hypertension Coronary artery disease Depression LUTS Prostatectomy Obesity Pelvic surgery Smoking Alcohol abuse

Table 1

12% 22% 2% 8% 14% 2% 22% 6% 37% 6%

30% 48%

18% 30% 44% 8% 53% 5.1 (4.1)

16% 48% 36%

49.6 (14.1) 27.7 (3.8) 92% 44.9 (13.9)

No longer have ED at 12 months (N = 51) (3%)

Tadalafil Treatment Continuation in Erectile Dysfunction 1711

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Roumeguère et al.

70

65 59

60 50

Patients, %

50 40

40

35

34

Baseline 28

26

30

1 Month

33

6 Months 12 Months

20 10

5

4

3

5

3

Figure 1 Erectile dysfunction (ED) severity (based on the International Index of Erectile Function-erectile function domain scores) at baseline, 1, 6, and 12 months in patients using tadalafil at 12 months (N = 1,319).

5

4

0 Severe

Moderate

Mild

Normal

ED severity

Effectiveness in Patients Continuing Tadalafil at 12 Months Among the patients continuing to take tadalafil at 12 months (N = 1,319; 84%), EF improved with treatment and 65% had normal EF at 12 months (Figure 1). The change in the IIEF-EF domain score from baseline was greater for patients with more severe ED at baseline (Table 2). Figure 2 shows continuous improvement per ED severity group over 12 months relative to the baseline ED severity. At 12 months, 94% with severe ED, 95% with moderate ED, and 71% with mild ED at baseline improved by at least one IIEF-EF category. At baseline, 178 patients reported using another PDE5 inhibitor in the 4 weeks prior to switching to tadalafil. Of these patients, 137 had 12-month follow-up information and 112 (82%) reported they remained on tadalafil. The mean IIEF-EF domain score for these 112 patients increased from 19.2 at baseline to 26.0, 25.9, and 25.8 at 1, 6, and 12 months, respectively. The percentage of Table 2

patients with severe, moderate, and mild ED at baseline decreased from 14%, 17%, and 54%, respectively, to 1%, 4%, and 35% at 12 months, while the percentage of patients with normal EF increased from 14% at baseline to 61% at 12 months.

Tadalafil Discontinuation at 12 Months Of the 1,567 patients analyzed, 248 (16%) indicated that they did not use tadalafil in the previous 4 weeks. Of these 248 patients, 51 (21%) reported they no longer had ED; these patients were removed from the analysis of patients no longer using tadalafil and from the multivariate logistic regression models to identify factors associated with tadalafil use at 12 months. The reasons for not using tadalafil at 12 months (and at 6 months for 30 patients) are presented in Figure 3, expressed as a percentage of the 1,567 patients. When grouped into medication-related reasons (lack of efficacy, duration of action, slow onset of action, interference with meals, unwanted effects

Effectiveness in patients using tadalafil at 12 months (N = 1,319)

IIEF-EF domain score Change in IIEF-EF domain score from baseline All patients Severe ED at baseline (N = 459; 35%) Moderate ED at baseline (N = 340; 26%) Mild ED at baseline (N = 448; 34%) Most frequently used dose (20 mg) Number of tadalafil tablets taken in the previous 4 weeks Number of sexual attempts in the previous 4 weeks Number of sexual attempts per tablet per patient Change from baseline in the number of sexual attempts

Baseline

1 month

6 months

12 months

13.9 (7.3)

24.2 (5.9)

25.1 (5.9)

25.7 (5.6)

10.3 16.1 11.0 5.4 70% 5.9 7.2 1.4 2.2

11.1 17.7 11.9 5.8 73% 5.7 7.4 1.5 2.4

11.8 18.6 12.6 5.9 77% 5.4 7.5 1.6 2.5

5.0 (4.3)

Data are presented as mean (standard deviation) unless indicated otherwise. IIEF-EF = International Index of Erectile Dysfunction-erectile function; ED = erectile dysfunction.

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(7.9) (7.4) (5.0) (4.8) (4.6) (4.3) (0.9) (4.2)

(8.4) (7.5) (4.9) (5.2) (3.3) (4.5) (1.1) (4.7)

(8.5) (7.3) (5.0) (5.4) (3.2) (4.5) (1.1) (4.8)

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Tadalafil Treatment Continuation in Erectile Dysfunction (A) 300

279

Severe Moderate

Number of patients

250

Mild Normal

200

200

164

159

150

149

139

100 50

39

50

48 6

13

7

7

6

0 Severe

Moderate Mild Baseline ED severity

0

9

Normal

(B) 350

Severe

305

Moderate

Number of patients

300

Mild Normal

250

216

200

185

171

150

128

114

100 50

48

32 28

7

11 4

9

5

0 Severe

Moderate Mild Baseline ED severity

0

10

Normal

(C) 350

Severe

317

Moderate

Number of patients

300

Figure 2 Erectile dysfunction (ED) severity (N) per baseline severity category after (a) 1, (b) 6, and (c) 12 months in patients using tadalafil at 12 months (N = 1,319).

Mild 252

Normal

231

250 200 150

150 100 50

111

92 27 29

46 5 11

12 5

1

2

14

0 Severe

Moderate Mild Baseline ED severity

Normal

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Roumeguère et al. Patients (%)

0

0.5

1

1.5

2

2.5

3.5

2.4

Lack of efficacy 1.4

Unwanted effects 0.8

Lack of confidence

2.2

Cost 0.8

Partner request

1.1

Change in health status

1.7

Loss of partner Other specified

3

2.2

Unspecified Not reported

1.9 3.3

No longer have ED

of treatment, lack of confidence in medication) and nonmedication-related reasons (request of partner, cost, change in health status, loss of partner, unspecified), 63 patients (4%) gave medicationrelated reasons, 104 (6.6%) gave nonmedicationrelated reasons, and 30 (1.9%) did not report a reason for discontinuing tadalafil. There was less improvement per ED severity category after 1 month of treatment in patients not using tadalafil at 12 months (Table 3) than in patients continuing tadalafil use (Table 2). The mean IIEF-EF domain score and change from baseline shows that ED severity deteriorated at 12 months following cessation of tadalafil treatment (Table 3). Patients discontinuing tadalafil because of medication-related reasons had a lower IIEF-EF at 1 month (mean 16.6; 95% confidence interval [CI]: 15.8–17.3), compared with that of patients Table 3

Figure 3 Reasons for not using tadalafil at 12 months, all patients (N = 1,567). Other specified includes the duration of action/time constraints, slow onset of action. The patients could provide more than one reason for discontinuing tadalafil.

0.4

who discontinued because of nonmedicationrelated reasons (mean 18.2; 95% CI: 17.5–18.8).

Factors Associated with Tadalafil Continuation at 12 Months Multivariate logistic regression identified the following factors as statistically significantly associated with treatment continuation at 12 months: (i) ED severity at 1 month (based on IIEF-EF domain score); (ii) tolerance to treatment at 1 month; (iii) number of sexual attempts in the first month; (iv) patient age at baseline; and (v) previous history of pelvic surgery. ED severity at 1 month but not at baseline was associated with continued tadalafil use at 12 months (Figure 4). Patients with lower ED severity after 1 month of treatment were more likely to continue using tadalafil at 12 months, compared with

Effectiveness in patients not using tadalafil at 12 months (N = 197)

IIEF-EF domain score Severity of ED (based on IIEF-EF domain score) Severe Moderate Mild Normal Change in IIEF-EF domain score from baseline All patients Severe ED at baseline (N = 99; 52%) Moderate ED at baseline (N = 35; 18%) Mild ED at baseline (N = 50; 26%) Most frequently used dose (20 mg) Number of tadalafil tablets taken in 4 weeks Number of sexual attempts in 4 weeks Number of sexual attempts per tablet per patient Change from baseline in the number of sexual attempts

Baseline

1 month

6 months

12 months

11.7 (7.8)

17.6 (9.4)

14.7 (10.0)

10.6 (9.5)

52% 18% 26% 4%

31% 15% 25% 29%

44% 11% 23% 22%

61% 12% 16% 11%

3.1 (3.8)

5.9 8.5 6.3 2.3 71% 3.3 4.6 1.6 1.3

(9.5) (9.6) (8.1) (7.9) (2.2) (4.8) (1.7) (4.7)

3.1 5.4 3.9 –0.2 76% 2.5 3.4 1.6 0.3

(9.5) (9.0) (9.7) (8.2) (2.4) (3.7) (1.2) (3.4)

Data are presented as mean (standard deviation) unless indicated otherwise. *These patients were not taking tadalafil at 12 months and thus information relating to their tadalafil dose is not applicable at 12 months. IIEF-EF = International Index of Erectile Dysfunction-erectile function; ED = erectile dysfunction; N/A = not available.

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–1.2 (9.8) 1.7 (7.5) –1.7 (10.1) –3.9 (10.6) N/A* N/A* 2.7 (3.7) N/A* –0.6 (4.8)

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Tadalafil Treatment Continuation in Erectile Dysfunction 100 90

89

90

92

91

92

82

Percentage using tadalatil

80

73

70 60

Normal 51

50

Mild Moderate Severe

40 30 20

Figure 4 Tadalafil continuation rates at 12 months by erectile dysfunction (ED) severity categories at baseline and 1 month (based on the International Index of Erectile Functionerectile function domain scores).

10 0

patients with severe ED: normal ED (adjusted OR = 6.88; 95% CI: 3.68–12.86; P < 0.0001); mild ED (adjusted OR = 7.83; 95% CI: 4.25–14.44; P < 0.0001); and moderate ED (adjusted OR = 2.06; 95% CI: 1.01–4.19; P = 0.05). Ninety percent of patients who tolerated their treatment after 1 month (N = 1,350; 98% of total) continued the treatment at 12 months, compared with 39% of patients whose treatment was not well tolerated at 1 month (N = 31; 2% of total): adjusted OR = 9.47; 95% CI: 4.04–22.18; P < 0.0001). Patients with a greater the number of sexual attempts in the first month were significantly more likely to continue the treatment at 12 months (adjusted OR = 1.09; 95% CI: 1.03–1.16; P = 0.003). As compared to 81% of patients aged over 60 years, 89% of patients aged between 51 and 60 years continued the treatment (adjusted OR = 1.88; 95% CI: 1.18–2.99; P = 0.008) as did 92% of those aged 50 years or younger (adjusted OR = 1.43; 95% CI: 0.86–2.38; P = 0.17). The treatment was continued by 71% of the patients with a history of pelvic surgery (N = 48) vs. 88% of those with no history (adjusted OR = 0.40; 95% CI: 0.18–0.93; P = 0.03). In the sensitivity analysis, where the logistic model excluded patients from Greece, ED severity, good tolerance to treatment at 1 month, and patient age were associated with tadalafil continuation at 12 months. However, the number of sexual attempts after 1 month (P = 0.26) and history of pelvic surgery (P = 0.19) were not statistically significant.

Baseline

1 Month ED severity

Factors Associated with a Good Response to Treatment Repeated measures ANCOVA (adjusted for baseline severity) on all patients (N = 1,900) identified the following baseline characteristics were associated with a significantly higher change in IIEF-EF score from baseline: age <60 years (P < 0.0001), psychogenic etiology compared with organic etiology (P = 0.01), ED treatment naïve (P = 0.0001), and ED treatment in the last 4 weeks (P = 0.005) compared with previous treatment, patient in a relationship at enrollment (P = 0.0001), duration of ED <1 year (P = 0.006), history of smoking (P = 0.005), history of alcohol abuse/dependency (P = 0.04), history of spinal cord injury (P = 0.03), no history of pelvic surgery (P = 0.002), and no history of prostatectomy (P < 0.0001). Discussion

Baseline patient characteristics were similar to other large studies of tadalafil treatment in patients with ED in a clinical setting [28] or observational setting [29]. There was a large and rapid improvement in EF among the 84% of patients who continued tadalafil treatment at 12 months: 50% of patients achieved a normal EF after 1 month, increasing to 59% and 65% after 6 and 12 months, respectively. The response was high in all ED categories, with an improvement of at least one IIEF-EF category in more than 90% of the patients with severe and moderate ED and 71% J Sex Med 2008;5:1708–1719

1716 with mild ED at baseline. The absence of tolerance to the therapeutic effect of tadalafil had also been observed in a shorter 6-month controlled clinical study [30]. These findings of the long-term effectiveness of tadalafil under routine clinical practice are consistent with the efficacy observed in clinical trials of shorter duration [28,31,32]. A mean of 7.2 sexual attempts during the first month of treatment indicates that the treating physicians provided good advice for optimal response, which may require multiple attempts in some patients [33]. Too few sexual attempts have been identified as one of the main reasons for failure with sildenafil and are because of inadequate patient education [16]. The patients in this study had a mean of 1.5 sexual attempts per tablet, indicating that they took advantage of the long duration of action of tadalafil. The majority (84%) of the patients continued tadalafil treatment after 12 months. This observation is consistent with the results of another observational study [34] where, after 6 months of treatment, 89% of the patients who started on tadalafil neither made a change nor stopped treatment, while 63% and 64% of those who started on sildenafil and vardenafil, respectively, had switched treatment. Eighty-two percent of the patients who changed treatment from another PDE5 inhibitor reported remaining on tadalafil after 1 year, with improvement in ED severity. This observation is consistent with a similar response to tadalafil observed in naïve patients and sildenafil prior responders [35], and a change in timing of sexual intercourse relative to dose in previous sildenafil users treated with tadalafil [22] that may translate in preference for tadalafil vs. sildenafil as shown in a crossover study [24,36] as well as switch study [37]. Maintenance of other PDE5 inhibitor therapies over time is generally considered to be low, with discontinuation rates ranging from 14% at 3 months to 47% at 1.5 years after initiation of treatment [38]. Observational studies have reported continuation rates with sildenafil of 55% and 49% after 1.5 and 2.5 years, respectively [13,14]. In a postmarketing surveillance study of patients treated with vardenafil, 86% of the patients who returned their questionnaires after a 70-day follow-up indicated that they intended to continue the treatment [39]. Regression analysis indicated that baseline ED severity was not predictive of treatment continuaJ Sex Med 2008;5:1708–1719

Roumeguère et al. tion; rather, it was ED severity and tolerance to tadalafil after the first month that predicted treatment continuation. Our results are supported, to some extent, by the findings of Gonzalgo et al. [14] in a study by telephone interview of 197 men who initiated treatment with sildenafil. These authors found that 49% of the patients continued to use sildenafil at 2.5 years and that the IIEF score at 3 months after starting treatment was strongly predictive of continued sildenafil use at 2.5 years. Among the 47% of men who discontinued sildenafil, lack of efficacy was the predominant reason for discontinuing treatment [14]. Costa et al. also concluded that baseline ED severity explains only about 10% of the variance in end-point scores [40]. Patients younger than 60 years, with an ED of psychogenic etiology or duration of less than 1 year, and with a partner, responded better after 1 month, independent of baseline severity. History of pelvic surgery or prostatectomy diminished the response to treatment. It is unclear why a history of alcohol abuse or smoking improved the response to tadalafil. Conclusions

This study indicates that therapeutic response and tolerance to the first tadalafil prescription after 1 month are the most important factors influencing tadalafil continuation. After 1 month, 90% of the patients continuing treatment had mild or normal IIEF-EF scores compared with only 54% of those not continuing the treatment. EF continued to improve over 1 year in patients who continued tadalafil treatment, while it deteriorated in those who stopped tadalafil. As baseline ED severity was not associated with continued treatment, all patients could benefit from a 1-month trial of tadalafil. A higher response could be expected in patients younger than 60 years, having a partner, a shorter duration of ED, ED of psychogenic etiology, and no history of prostatectomy. Acknowledgments

The authors wish to thank Deirdre Elmhirst, PhD, for her help in preparing the manuscript. The authors thank the investigators who participated in this study from Austria: S. Altziebler, C. Barta, B. Dallinger, K. Diehl, B. Esterbauer, K. Färber, K.H. Grubmüller, H. Heidler, G. Hermandinger, R.M. Holzmann, R. Hude, G. Janetschek, A.E. Jungwirth,

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Tadalafil Treatment Continuation in Erectile Dysfunction H.H. Köck, C. Kratzik, C. Linshalm, C. Lintner, G. Ludvik, G. Lunglmayr, H. Madersbacher, M. Mair, P. Moser, G. Nöst, P. Pleyer, H. Rauschmeier, A. Riedl, G. Roth, G. Schatzl, P. Schön, P. Sternig, D. Strohmeyer, G. Suster, T. Treu, L. Vasold, R. Vincek, A. Zeitelberger; from Belgium: A. Baeyens, P. Beke, H. Biot, P. Boudolf, R. Bourlet, V. Bouts, R. Burssens, H. Cooremans, H. Cuypers, W. Denier, P. De Sutter, C. Evaldre, G. Geeraerts, G. Gorissen, P. Hoet, C. Houthuys, G. Houze, J. Huysmans, P. Jacobs, E. Keutgen, J-M. Lambermont, J. Lambert, F. Le Brun, A. Leva, D. Lievens, C. Lissens, J. Mairiaux, S. Mathay, B. Michaux, D. Pamart, J-L. Parqué, A. Renard, T. Roumeguère, M. Salavacros, B. Schoonvaere, G. Van Damme, M. Vanden Eynde, M. Velghe, B. Verheyden, S. Windmolders, J. Wuyts; from Denmark: F. Andersen, T. Aru, M. Borup, J. Flintholm, J. Heede, U. Heldmann, B. Jacobsen, K. Kakulidis, H. Laursen, A. Luckow, A. Mørch, T. Müller, K. Nissen, A. Nørregaard, B. Nygaard, B. Olesen, J. Otte, G. Petersen, H. Rasmussen, N. Sejr, H. Skibsted, N. Taarnhøj, M. Thomsen, B. Uhrenholt, F. Vogel, O. Wiberg, O. Winkel; from Greece: K. Andrianos, C. Baliakos, S. Boikos, P. Bournelas, E. Chliounakis, M. Chousametin, I. Christodoulou, G. Folas, S. Fotiadis, L. Georgikopoulos, I. Giannakakis, C. Gianoutsos, G. Ioannidis, N. Kaklas, V. Kilintzis, I. Kogias, G. Kordalis, G. Kosteletos, A. Koukios, M. Koutelos, A. Koyrsoumis, V. Laskaris, A. Lepouras, S. Lyberakis, P. Makras, A. Manoudis, I. Massaras, G. Mavrokefalos, N. Mouzakopoulos, G. Papageorgiou, I. Papanikolaou, A. Pappas, G. Pavlidis, P. Perimenis, K. Pitarokoilis, A. Plageras, D. Routsakos, Z. Samis, K. Sergiou, M. Skouloukas, M. Sotiropoulos, V. Stroubos, K. Thanasoulas, S. Theodoridis, A. Thomopoulos, E. Toulis, G. Tsagàris, N. Tsàgaris, P. Vasileiadis, P. Vlachos, S. Voulgaris, N. Xenakis, I. Zafiris; from Iceland: G. Hannesson, A. Hreiðarsson, P. Kolbeinsson, V. Marteinsson, O. Mixa, G. Pálsson, G. Snæbjörnsson; from the Netherlands: Alhakim, H. Bakker, F. Balak, R. Bianchi, W. Blitz, S. Bos, G. Buijs, F. Debruyne, W. Feis, F. Froeling, A. Geboers, W. Heckman, J. Heusdens, J. Hoevenaars, E. Hoogendijk, N. Jahangir, H. Knitel, W. Koch, E. Koldewijn, H. Langelaar, P. Leusink, G. van Loon, B. Meijer, M. Mengerink, H. Mevissen, S. Oerlemans, J. Palmen, P. Passage, J. Pennartz, H. Rol, E. Roos, R. Schaafsma, A. Schellekens, J. Snijders, A. Spreeuw, G. Storms, E. Taubert, H. van Valkenburg, F. Vermetten, R. de Vos, M. Willink, F. Wuister, A. Ypma; from Norway: E. D’Angelo, G. Eilertsen, O. Holmedal, S. Johannesen, K. Lund, G. Råheim, O. Singsaas, M. Ulvan, K. Valnes, S. Vatle; from Sweden: G. Andersson, O. Anker-Hansen, J-O. Berg, G. Bonde, K. Borggren, B. Eliasson, L. Falck, E. Fernquist Forbes, E. Garcia, E-B. Gordon, P. Hellman, I. Högvall, P. Isberg, F. Johansen, P-A. Karlsson, B. Klanger, P-A. Lagerbäck, P. Lorentzon, G. Meden-Britth, S. Nilsson, M. Nyman,

B-O. Persson, L. Särhammar, S. Schyllberg, R. Sicinska, A. Siwek-Runesson, J-O. Skalenius, E. Wahlund. The study was supported by Eli Lilly (Indianapolis, IN, USA). Corresponding Author: Thierry Roumeguère, MD, Urology Department, Erasme Hospital, University Clinics of Brussels, Route de Lennik 808, 1070 Brussels, Belgium. Tel/Fax: 0032 (2) 555-36-14/36-99; E-mail: [email protected] Conflict of Interest: Dr. Belger and Schmitt are employees of Eli Lilly and Co.

Statement of Authorship

Category 1 (a) Conception and Design Thierry Roumeguère; Benny Verheyden; Stefan Arver; Alain Bitton; Mark Belger; Henry Schmitt (b) Acquisition of Data Thierry Roumeguère; Benny Verheyden; Stefan Arver; Alain Bitton; Mark Belger; Henry Schmitt (c) Analysis and Interpretation of Data Thierry Roumeguère; Benny Verheyden; Stefan Arver; Alain Bitton; Mark Belger; Henry Schmitt

Category 2 (a) Drafting the Article Thierry Roumeguère; Benny Verheyden; Stefan Arver; Alain Bitton; Mark Belger; Henry Schmitt (b) Revising It for Intellectual Content Thierry Roumeguère; Benny Verheyden; Stefan Arver; Alain Bitton; Mark Belger; Henry Schmitt

Category 3 (a) Final Approval of the Completed Article Thierry Roumeguère; Benny Verheyden; Stefan Arver; Alain Bitton; Mark Belger; Henry Schmitt

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