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The Efficacy of Tadalafil in Clinical Populations
Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2005 200524517531Original ArticleEfficacy of Tadalafil in Clinical PopulationsLewis et al.
517
The Efficacy of Tadalafil in Clinical Populations Ronald W. Lewis, MD,* Richard Sadovsky, MD,† Ian Eardley, MA, MChir, FRCS, FEBU,‡ Michael O’Leary, MD,§ Allen Seftel, MD,¶ Wei Christine Wang, MS,** Wei Shen, PhD,** Daniel J. Walker, PhD,** David G. Wong, MD,** and Sanjeev Ahuja, MD** *Department of Urology, Medical College of Georgia, Augusta, GA, USA; †Department of Sexual Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA; ‡St. James University Hospital, Leeds, UK; §Division of Urology, Harvard Medical School, Boston, MA, USA; ¶Department of Urology, Case Western Reserve, Cleveland, OH, USA; **Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA DOI: 10.1111/j.1743-6109.2005.00068.x
ABSTRACT
Objectives. To evaluate the efficacy of tadalafil in men with erectile dysfunction (ED) by demographic and ED characteristics, in patients having various comorbid medical conditions, and in patients receiving drug treatment for other medical conditions. Methods. This is an analysis of 11 double-blind, placebo-controlled trials with 2,102 men with a broad spectrum of ED etiology and various comorbid medical conditions as participants. The variables analyzed in this report included race, age, body mass index (BMI), ED etiology, ED severity, ED duration, smoking, prior sildenafil use, presence of comorbid conditions (diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, depression, benign prostatic hyperplasia), and treatment with antihypertensives or antidepressants. Patients were randomly assigned to receive tadalafil 10 mg (N = 321), tadalafil 20 mg (N = 1,143), or placebo (N = 638). The primary efficacy variables included mean changes from baseline in the erectile function (EF) domain score of the International Index of Erectile Function (IIEF) questionnaire, and the mean per-patient percentage of “yes” responses to the Sexual Encounter Profile (SEP) diary question 3 (SEP3––successful intercourse). The Global Assessment Question 1 (GAQ) was evaluated, as was the percentage of men attaining a normal IIEF EF domain score at end point. Results. Patients taking tadalafil 10 mg or 20 mg demonstrated significant improvement (P < 0.005) from baseline to end point on the IIEF EF domain score in all subpopulations analyzed compared with patients receiving placebo. The mean-per-patient percentage of “yes” responses to SEP3 increased significantly in all subpopulations taking tadalafil compared with placebo (P < 0.05). Tadalafil-treated patients had a significantly greater positive response rate on the GAQ in all subpopulations analyzed compared with placebo-treated patients (P < 0.03) except for the tadalafil 10 mg cardiovascular subpopulation (placebo, 46.8%; tadalafil 10 mg, 71.0%; P = 0.127). The percentage of positive responses ranged from 72% to 91% for patients on tadalafil 20 mg and from 52% to 94% for tadalafil 10 mg compared with a range of 20% to 47% for placebo-treated patients. Conclusions. Tadalafil was effective in improving erectile function across a wide spectrum of ED patients including patients with various comorbid conditions. Key Words. Tadalafil; Erectile Dysfunction; Clinical Population
Introduction
E
rectile dysfunction (ED) has become recognized as a significant health issue in a large percentage of men over the age of 40 years [1]. A number of factors can contribute to the development of ED, including aging, cardiovascular disease, diabetes, smoking, anxiety and/or depression, certain drugs including antidepressants and antip-
sychotics [2], and a variety of other organic or psychological factors [3–5]. Awareness of ED increased with the approval in 1998 of sildenafil citrate, an oral treatment that improves erectile function in men having ED of various etiologies [6,7]. Tadalafil and sildenafil are inhibitors of phosphodiesterase type 5. Tadalafil primarily differs from sildenafil by having a duration of efficacy J Sex Med 2005; 2: 517–531
518 lasting up to 36 hours after a single dose compared with about 4 hours for sildenafil [8,9], although a recently published small open-label study in sildenafil responders suggested that sildenafil 100 mg might be effective in some men up to 12 hours after dosing [10]. Tadalafil has been shown to be efficacious and safe in a large number of patients with ED including men with diabetes mellitus [11–14]. Additionally, a recent study demonstrated that tadalafil significantly improved erectile function in men with ED following bilateral nerve-sparing radical retropubic prostatectomy [15]. In this article, 11 double-blind placebo-controlled trials were integrated and analyzed to determine the effectiveness of tadalafil in improving erectile function in more than a dozen clinical subpopulations. Methods
Study Design Data collected from 11 randomized, double-blind, placebo-controlled, parallel trials conducted worldwide at 174 centers in 18 countries from April 1999 to February 2003 were used in all of the analyses (Table 1). Details regarding the general study design, efficacy and safety measures, and statistical analysis were published previously [12,13]. Patients were randomized to 12 weeks of treatment with placebo (N = 638) or tadalafil at fixed doses including 10 mg (N = 321) or 20 mg (N = 1,143) after a 4-week, treatment-free period to determine baseline erectile function. One study had a 24-week duration, but the data presented here are from 12 weeks of this study. Patients were instructed to take one dose of the study drug as needed prior to sexual activity (maximum of once daily) without regard to food intake or timing of sexual activity after dosing. Dosage adjustments were not permitted in these studies. Patient visits occurred at approximately 4-week intervals until study completion or early discontinuation from the study. All studies were conducted according to the Declaration of Helsinki, and ethical review boards approved the study protocols. Patients provided written informed consent for study participation. Patient Population Men (≥18 years old) with a minimum 3-month history (patient reported) of mild to severe ED of organic, psychogenic, or mixed etiology and having a steady, adult female partner were eligible for participation in these studies. To be included, J Sex Med 2005; 2: 517–531
Lewis et al. patients were required to make at least 4 attempts at sexual intercourse during a 4-week, treatmentfree, run-in period. The exclusion criteria, including a history of certain cardiovascular diseases, clinically significant renal or hepatic insufficiency, and treatment with nitrates, have been listed in the five-study and 11-study tadalafil analyses [12,13]. The majority of studies excluded nonresponders to previous sildenafil treatment (nine out of 11). Patients were considered to be sildenafil nonresponders based on the opinion of the investigator.
Measures Measures used to evaluate the efficacy of tadalafil included the International Index of Erectile Function (IIEF) [16], the Sexual Encounter Profile (SEP), and a Global Assessment Question (GAQ). The IIEF was administered after the run-in period (baseline) and at 4-week intervals during treatment (postbaseline). Patients completed the SEP diary after each sexual intercourse attempt throughout the study. The patients’ scores on the erectile function (EF) domain of the IIEF at the end of the 4-week, treatment-free period were used to determine their baseline ED severity (mild, moderate, severe) [17]. Question 1 of the GAQ was asked at study completion or discontinuation. The efficacy variables evaluated in this manuscript included (i) the mean change from baseline to end point in the IIEF EF domain (sum of questions 1–5 and 15); (ii) the percentage of men attaining a normal IIEF EF domain score (≥26) at end point; (iii) the mean changes from baseline to postbaseline in the per-patient percentage of “yes” responses to question 3 of the SEP diary [SEP3––Did your erection last long enough for you to have successful intercourse? (yes/no)]; and (iv) the percentage of men with a “yes” response to Question 1 of the GAQ [“Has the treatment you have been taking over the past study interval improved your erections?” (yes/no)]. The IIEF EF domain score and SEP3 were primary efficacy measures in all 11 studies, whereas the GAQ was a secondary efficacy measure and the percentage of men achieving a normal IIEF EF domain score at end point was a post hoc analysis. Clinical Populations All subgroups analyzed will be referred to as clinical populations. This post hoc analysis includes populations based on ethnic origin, age (£65 years vs. >65 years), body mass index (BMI < 30 kg/m2 or ≥30 kg/m2), ED etiology, ED severity, ED duration, smoking (current), prior sildenafil use,
519
Efficacy of Tadalafil in Clinical Populations Table 1 Study 1 2 3 4 5 6 7 8 9 10 11 Total
Summary of 11 tadalafil studies Number of centers
Placebo
Tadalafil 10 mg
Tadalafil 20 mg
19 18 8 4 25 20 10 17 21 19 13
69 76 66 47 50 49 41 83 48 52 57
74 79 65 — 103 — — — — — —
— — 65 93 100 146 80 159 159 168 173
174
638
321
1,143
Total 143* 155† 196 140 253 195 121 242 207 220 230 2,102
* There were an additional 72 patients randomly assigned to 5 mg of tadalafil. † There were an additional 74 patients and 79 patients randomly assigned to 2.5 mg and 5 mg of tadalafil, respectively. Number (%) of patients from participating countries: Argentina, 54 (3); Australia, 140 (7); Canada, 476 (23); Hong Kong, 38 (2); Indonesia, 21 (1); Israel, 21 (1); Italy, 111 (5), Republic of Korea, 121 (6); Malaysia, 32 (2); Mexico, 21 (1); Philippines, 40 (2); Poland, 104 (5); Puerto Rico, 18 (1); Russia, 105 (5); Singapore, 30 (1); Taiwan, 277 (13); United Kingdom, 109 (5); United States, 384 (18).
presence of comorbid conditions [diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, depression, benign prostatic hyperplasia (BPH)], use of antihypertensives, and use of antidepressants. Comorbid medical conditions were diagnosed on the basis of the patient’s medical history and physical examination.
Statistical Analyses All analyses were conducted on an intent-to-treat basis. Efficacy analyses included all patients with a baseline measurement and at least one postbaseline measurement. The IIEF EF domain scores were analyzed by using the last observation carried forward convention. The study design and patient population were consistent across all 11 studies; therefore, efficacy data could be pooled for these analyses. However, the GAQ analysis included only 10 studies, because in the 24-week study the GAQ was measured at end point and not at week 12. In addition, nine of the 11 trials captured data regarding prior sildenafil use. The IIEF EF domain and SEP3 scores were analyzed by analysis of covariance (ANCOVA) models, including terms for baseline value of the efficacy variable, treatment group, protocol, and baseline-bytreatment group interaction (if P < 0.10). Logistic regression was used to evaluate the GAQ by using the same terms as in the ANCOVA model, except the interaction term (only patients who responded to the GAQ were included in the analysis). For some subgroups of interest, treatment by subgroup interaction test was performed to detect the between-group difference in the overall treatment effect at 0.05 alpha level. Statistical Analysis Software version 8.2 (SAS®, SAS Institute Inc., Cary,
NC) was used to perform statistical analyses. All tests of hypotheses were considered statistically significant if the two-sided P value was less than 0.05. However, because of a lack of statistical power, analysis of statistical significance was not performed in subgroups with fewer than 30 patients in either tadalafil treatment arm. This included the Hispanic 10 mg and 20 mg, African descent 10 mg, psychogenic 10 mg, depression 10 mg, and antidepressant use 10 mg subgroups. Whenever the statement “in all subgroups analyzed,” or a similar statement is made when discussing statistical significance, it is referring to those clinical populations having 30 or more patients in either tadalafil arm. Results
Demographic and Baseline Characteristics Demographic and baseline illness characteristics are shown in Table 2. The mean age was 56 years (range, 22–88 years) with most patients (88%) having ED for at least 1 year. The proportion of patients with mild, moderate, or severe ED was similar in all three treatment groups (P = 0.933). Hypertension (29%), diabetes mellitus (20%), and hyperlipidemia (16%) were common comorbid conditions. The vast majority of patients taking tadalafil (10 mg, 88.5%; 20 mg, 89.7%) and placebo (86.8%) completed 12 weeks of treatment. Lack of efficacy in the placebo group (5.0%), patient decision in the tadalafil 10 mg group (3.7%), and adverse events in the tadalafil 20 mg group (3.2%) were the most common reasons for patient discontinuation (details in Carson et al. [13]). J Sex Med 2005; 2: 517–531
520 Table 2
Lewis et al. Demographic and baseline characteristics of men with erectile dysfunction (ED)
Variable Mean age, year (range) Age > 65, n (%) Ethnicity, n (%) White Asian African descent Hispanic Other BMI, kg/m2 (range) <30, n (%) ≥30, n (%) Duration of ED ≥12 months, n (%) ED etiology, n (%) Organic Psychogenic Mixed ED severity (IIEF EF domain score), n (%)* Normal (26–30) Mild (17–25) Moderate (11–16) Severe (1–10) Comorbid conditions, n (%) Diabetes mellitus Hypertension CVD Hyperlipidemia Depression BPH Concomitant medication, n (%) No antihypertensive 1 antihypertensive ≥2 antihypertensives Antidepressants
Placebo (N = 638)
Tadalafil 10 mg (N = 321)
57 (22–81) 140 (22)
58 (26–81) 96 (30)
Tadalafil 20 mg (N = 1,143) 56 (22–88) 248 (22)
408 (64) 196 (31) 15 (2) 19 (3) 0 27.3 (18.1–53.7) 503 (79) 135 (21) 572 (90)
235 (73) 68 (21) 3 (1) 12 (4) 3 (1) 27.9 (18.2–46.0) 237 (74) 84 (26) 280 (87)
369 (58) 82 (13) 187 (29)
215 (67) 20 (6) 86 (27)
627 (55) 147 (13) 369 (32)
33 (5) 212 (33) 171 (27) 220 (34)
16 (5) 113 (35) 84 (26) 107 (33)
39 (3) 425 (37) 303 (27) 376 (33)
130 (20) 189 (30) 53 (8) 110 (17) 23 (4) 105 (16) 416 (65) 139 (22) 83 (13) 29 (5)
68 90 32 51 15 56
761 (67) 310 (27) 46 (4) 24 (2) 2 (0.2) 27.3 (12.7–52.0) 885 (77) 258 (23) 1,006 (88)
(21) (28) (10) (16) (5) (17)
223 (20) 337 (29) 89 (8) 166 (15) 53 (5) 188 (16)
209 (65) 65 (20) 47 (15) 21 (7)
742 (65) 206 (18) 195 (17) 61 (5)
* Patients were included in the study based on a history of ED. The subsequent assessment of erectile function by the IIEF at baseline indicated that a small percentage of patients had an erectile function domain score in the normal range (26–30). BMI, body mass index; IIEF, International Index of Erectile Function; CVD, cardiovascular disease; BPH, benign prostatic hyperplasia.
Efficacy Results The tadalafil 20 mg group showed a significantly greater mean baseline-to-end-point improvement on the IIEF EF domain score (P < 0.001) than the placebo group in all clinical populations (Table 3). All subgroups treated with tadalafil 20 mg had an end-point score in the range of 19.5–25.7. The tadalafil 10 mg group showed significantly greater improvement vs. placebo (P < 0.005) in all subgroups. The percentage of men attaining a normal IIEF EF domain score at end point was significantly greater (P < 0.001) in the tadalafil 20 mg group (range, 37–68%) compared with the placebo group (range, 3–20%) in all clinical populations (Table 4). Tadalafil 10 mg also had a significantly greater percentage of patients achieving a normal IIEF EF domain score at end point than patients taking placebo (P < 0.001). Significantly greater improvements (P < 0.001) in successful intercourse (SEP3) occurred in all populations taking tadalafil 20 mg than in those J Sex Med 2005; 2: 517–531
taking placebo (Figure 1). Most subgroups taking 20-mg tadalafil had end-point success rates of about 70% compared with about 30% for the placebo group. Patients taking tadalafil 10 mg showed significantly greater improvement (P < 0.05) than placebo on SEP3 in all clinical populations. A significantly greater percentage (P < 0.001) of patients taking tadalafil 20 mg responded “yes” to the GAQ in each subpopulation compared with placebo patients (Figure 2). All but three subgroups had a positive response rate in the 80% range for tadalafil 20 mg (71.6%, 76.4%, and 77.2% in the severe ED, >65 years, and diabetes mellitus subgroups, respectively). All of the tadalafil 10 mg subpopulations demonstrated a significantly greater percentage of patients responding “yes” to the GAQ compared with the placebo group (P < 0.005) except for the tadalafil 10 mg cardiovascular subpopulation (placebo, 46.8%; tadalafil 10 mg, 71.0%; P = 0.127).
14.9 12.8 13.8 15.5 15.4 20.5 13.8 7.4 16.5 14.2 14.9 12.8 14.8 14.4 15.1 14.3 12.8 13.8 13.9 13.7 13.0 14.8 14.7 14.3 13.4 12.8
482 135
356 182 79
205 168 213
45 555
485 132
146 469
199 282
125 182 53 105 23 104
400 135 82 29
15.7 14.9 14.0 14.8
14.1 14.4 15.7 15.1 13.6 15.4
16.8 14.5
16.2 15.1
15.4 15.3
16.4 15.1
19.5 15.5 10.1
14.8 15.8 17.3
15.9 13.0
14.6 11.6 18.7 16.1
End point
0.8 0.7 0.6 1.0
1.2 0.8 1.1 1.0 -0.1 1.1
1.8 0.2
1.3 0.7
0.7 1.6
203 59 47 21
64 85 32 48 14 55
79 83
73 236
230 79
31 268
112 83 100
-1.0 1.9 2.7 0.5 0.8
206 83 20
15.0 14.1 13.1 15.7
13.0 13.8 14.8 15.0 15.4 14.2
14.3 14.8
15.7 14.2
14.5 14.8
15.6 14.3
20.3 13.4 7.3
13.9 15.5 16.9
14.9 13.8
14.2 14.5
10 67 216 93
14.4
Baseline
226
n
0.9 0.5 1.4
0.9 -0.0
0.2 -1.5 4.9 0.9
Change
21.7 20.5 18.4 17.6
19.1 18.7 22.3 22.0 19.3 21.9
22.3 20.6
22.0 20.8
21.4 19.9
23.2 20.7
24.1 22.0 16.3
20.7 22.6 18.9
21.5 19.1
21.3 21.2
20.5
End point
Tadalafil 10 mg
6.8* 6.3* 5.1** 3.9†
6.2* 5.1* 7.7* 7.9* 5.6† 7.6*
7.4* 6.2*
7.1* 6.4*
6.6* 6.1*
7.4* 6.4*
3.6* 8.3* 8.9*
6.8* 7.3* 3.0†
6.6* 6.1*
7.4† 6.0*
6.1*
Change
* P < 0.001; ** P = 0.004; † Statistical significance not analyzed (see Methods). Baselines are raw means; end point and change are least square means. IIEF, International Index of Erectile Function; BMI, body mass index; CVD, cardiovascular disease; BPH, benign prostatic hyperplasia.
14.3 11.9 13.2 15.2
Baseline
395 15 14 193
n
Placebo
Least squares mean IIEF EF domain scores
Ethnicity Caucasian African descent Hispanic Asian Age (year) £65 >65 ED etiology Organic Mixed Psychogenic ED severity Mild Moderate Severe ED duration ≥6 months to <1 year ≥1 year BMI, kg/m2 <30 ≥30 Smoker Yes No Prior sildenafil use No Yes Comorbid conditions Diabetes mellitus Hypertension CVD Hyperlipidemia Depression BPH Concomitant medication No antihypertensive 1 antihypertensive ≥2 antihypertensives Antidepressants
Subgroup
Table 3
719 200 192 61
215 332 85 159 51 184
441 670
251 858
864 247
95 976
410 299 364
606 361 144
871 240
733 46 23 307
n
15.0 14.2 13.4 13.5
12.9 13.6 15.1 14.1 13.6 13.9
15.0 14.3
14.7 14.5
14.8 13.9
15.7 14.3
20.5 13.6 7.4
13.9 15.2 16.0
15.0 13.0
14.4 13.0 14.1 15.4
Baseline
23.4 22.2 22.1 23.7
20.0 22.3 22.7 23.1 22.4 22.6
23.7 22.8
23.2 23.0
23.2 22.7
23.7 22.9
25.7 23.8 19.5
22.5 23.4 24.8
23.6 21.1
22.7 21.9 24.8 22.9
End point
Tadalafil 20 mg
8.4* 8.0* 8.7* 9.9*
7.1* 8.7* 8.0* 9.0* 8.7* 8.4*
8.8* 8.5*
8.3* 8.5*
8.4* 9.0*
7.9* 8.6*
5.2* 10.2* 12.1*
8.7* 8.1* 8.9*
8.6* 8.0*
8.4* 8.9* 10.9† 7.7*
Change
Efficacy of Tadalafil in Clinical Populations 521
J Sex Med 2005; 2: 517–531
522 Table 4
Lewis et al. Percentage of men attaining normal erectile function (EF) domain score (≥26) at end point Placebo
Subgroup Ethnicity Caucasian African descent Hispanic Asian Age, year £65 >65 ED etiology Organic Mixed Psychogenic ED severity Mild Moderate Severe ED duration ≥6 months to <1 year ≥1 year BMI, kg/m2 <30 ≥30 Smoker Yes No Prior sildenafil use No Yes Comorbid conditions Diabetes mellitus Hypertension CVD Hyperlipidemia Depression BPH Concomitant medication No antihypertensive 1 antihypertensive ≥2 antihypertensives Antidepressants
Tadalafil 10 mg
Baseline n
Normal at end point % (n)
372 15 14 185
Tadalafil 20 mg
Baseline n
Normal at end point % (n)
Baseline n
Normal at end point % (n)
11.8 (44) 0 (0) 28.6 (4) 10.8 (20)
216
39.8* (86) 20.0† (2) 41.3* (26)
704 45 22 300
55.3* (389) 51.1* (23) 63.6† (14) 50.7* (152)
10 63
458 128
13.1 (60) 6.3 (8)
206 89
42.7* (88) 32.6* (29)
836 237
56.1* (469) 46.4* (110)
343 169 74
9.3 (32) 14.2 (24) 16.2 (12)
199 78 18
37.2* (74) 50.0* (39) 22.2† (4)
585 349 139
49.9* (292) 58.2* (203) 60.4* (84)
205 168 213
19.5 (40) 12.5 (21) 3.3 (7)
112 83 100
51.8* (58) 41.0* (34) 25.0* (25)
410 299 364
67.8* (278) 52.2* (156) 39.8* (145)
39 531
12.8 (5) 10.4 (55)
30 256
53.3* (16) 37.5* (96)
93 943
53.8* (50) 53.3* (503)
461 125
11.7 (54) 11.2 (14)
222 73
40.5* (90) 37.0* (27)
835 238
55.3* (462) 49.2* (117)
139 445
16.5 (23) 10.1 (45)
67 228
53.7* (36) 35.5* (81)
242 829
55.8* (135) 53.3* (442)
186 270
17.2 (32) 8.9 (24)
73 81
50.7* (37) 40.7* (33)
423 650
57.0* (241) 52.0* (338)
121 174 50 101 22 97
8.3 (10) 9.2 (16) 14.0 (7) 8.9 (9) 9.1 (2) 11.3 (11)
63 83 30 44 13 53
34.9* (22) 31.3* (26) 53.3* (16) 50.0* (22) 38.5† (5) 45.3* (24)
207 325 83 152 51 181
36.7* 51.7* 56.6* 52.6* 59.8* 48.6*
(76) (168) (47) (80) (30) (88)
379 128 79 27
12.9 (49) 9.4 (12) 8.9 (7) 14.8 (4)
192 58 45 19
41.1* (79) 43.1* (25) 28.9* (13) 42.1† (8)
690 194 189 60
55.4* 53.1* 49.7* 53.3*
(382) (103) (94) (32)
* P < 0.001; † Statistical significance not analyzed (see Methods). Baseline N: patients with a baseline EF < 26 and a nonmissing end-point EF score are included. BMI, body mass index; CVD, cardiovascular disease; BPH, benign prostatic hyperplasia.
The safety of tadalafil in these 11 integrated studies was presented previously [13]. Briefly, most adverse events were reported by patients to be mild or moderate, with the most common events being headache, dyspepsia, and back pain. The percentage of patients who discontinued because of adverse events in these studies was 1.3% for placebo, 1.6% for tadalafil 10 mg, and 3.2% for tadalafil 20 mg. Discussion
This analysis of 2,102 men with ED demonstrated that tadalafil 10 mg and 20 mg were effective in all clinical populations analyzed, including in patients with diabetes mellitus, who are considered difficult J Sex Med 2005; 2: 517–531
to treat. Tadalafil 20 mg showed numerically greater improvement than tadalafil 10 mg for each efficacy measure in most of the clinical populations. Tadalafil showed improved efficacy among all racial groups. It would have been more informative if the number of Hispanics and patients of African descent were large enough to address statistical significance vs. placebo at both tadalafil doses. The number of men was low in both subgroups, which may be a reflection of the geographical location of the trial sites (Table 1). However, in trials conducted in the United States and Puerto Rico (N = 402), 14% of men were of African descent and 7% were of Hispanic descent. In the analysis of sildenafil in clinical populations
523
Efficacy of Tadalafil in Clinical Populations a
Placebo Tadalafil 10 mg Tadalafil 20 mg
100
Mean per-patient percent success (SEP3)
90
Baseline * P < 0.001 vs. placebo † significance not analyzed
*
80
76.2
70
† 69.0
* *
*
*
69.6
67.7
*
*
63.7
*
63.1
61.4
59.5
58.4
60
* 51.1
50 † 38.9
40
33.7 30.0
29.7
30 20.8
22.2
21.1
20 10 0 n=
400
227
741
15
46
16
11
23
194
Hispanic
African descent
Caucasian
67
307
486
218
100
Mean per-patient percent success (SEP3)
Figure 1 (a–e) Mean per-patient percentage of successful intercourse (Sexual Encounter Profile question 3) by subgroup. The following tadalafil subgroups had too few patients to analyze for statistical significance: Hispanic 10 mg and 20 mg, African descent 10 mg, psychogenic 10 mg, depression 10 mg, and antidepressant use 10 mg. BMI, body mass index; DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; HPL, hyperlipidemia; DEP, depression; BPH, benign prostatic hyperplasia.
*
80
75.6
70
*
*
64.1
63.8
*
60
93
238
>65
Baseline * P < 0.001 vs. placebo † significance not analyzed
Placebo Tadalafil 10 mg Tadalafil 20 mg
90
139
Age (year)
Ethnicity
b
881
£65
Asian
* *
77.8 78.1
*
*
69.2
69.8
* *
71.1
*
67.9
65.7
†
*
*
59.8
58.8
59.1
57.9
* 50.3
50
46.8
*
40
38.4
36.2 34.1
30
32.7 29.9
28.9
27.5
20 11.3
10 0
n = 360 209 607
Organic
183
82
368
Mixed
82
ED etiology
[7], it was interesting to note that the black subgroup had the best IIEF EF domain score at end point but the lowest percentage of positive responses to the GAQ. This pattern did not occur with the African descent subgroup taking tadalafil. However, in the sildenafil analysis, the Asian subgroup had the lowest IIEF EF score but had a higher GAQ score than the white and black sub-
20 144
Psychogenic
206 112 418
Mild
170
83 299
217 101 363
46
31
96
562
270 983
Moderate Severe ≥ 6 month ≥1 year to <1 year
ED severity
ED duration
groups. The Asian subgroup taking tadalafil had high GAQ scores as well, especially for the 10-mg dose. These findings suggest that racial groups might differ in how they perceive improvements in erections, or have differing expectations of the medical therapy. Further study of this phenomenon could prove interesting both from a scientific and cultural or behavioral perspective. J Sex Med 2005; 2: 517–531
524 c
Lewis et al. 100
Placebo Tadalafil 10 mg Tadalafil 20 mg
Mean per-patient percent success (SEP3)
90
Baseline * P < 0.001 vs. placebo
80 * 67.9
70
*
*
*
63.5
61.4
*
*
66.8
67.2
62.8
*
69.5
66.6
*
*
58.9
*
60
*
* 66.8
58.3
54.9
50 40
36.2
33.6
32.4
30.4
30.2
28.1
30 20 10 0 n=
494
229
869
131
82
250
≥30
<30
147
73
Placebo Tadalafil 10 mg Tadalafil 20 mg
100
Mean per-patient percent success (SEP3)
90
476
238
868
203
Nonsmoker
442
80
No prior use
Smoking
BMI (kg/m2)
d
249
Smoker
282
83
677
Prior use
Sildenafil use
Baseline * P < 0.001 vs. placebo † significance not analyzed
80 *
70
*
* *
71.0
67.5 68.3
*
*
63.6 64.8
64.7
63.2
60
*
*
*
69.9
† 58.6
*
*
54.9
52.8
52.4
50 40 34.3 31.8
30.0
30
30.2
27.5 22.6
20 10 0
n=
125
66
DM
217
183
87
329
HTN
53
32
CVD
87
105
51
159
HPL
Comorbid conditions
It has been shown previously in the Massachusetts Male Aging Study that moderate and severe ED increase from age 40 to 70 years [18]. In our report, younger patients (£65 years) had numerically better scores than older patients on each of the efficacy measures, although the differences were small after accounting for the slightly better J Sex Med 2005; 2: 517–531
23
14
51
DEP
104
55
182
BPH
Figure 1 Continued
baseline scores in younger patients. In addition, the differences in improvement on the primary efficacy measures between younger patients and older patients were not statistically significant (P > 0.700). Although the ≥30 BMI subgroup had slightly lower (worse) scores on each of the efficacy mea-
525
Efficacy of Tadalafil in Clinical Populations e
90 Mean per-patient percent success (SEP3)
Baseline * P < 0.001 vs. placebo ** P < 0.05 vs. placebo † significance not analyzed
Placebo Tadalafil 10 mg Tadalafil 20 mg
100
80 *
70
*
68.8
* 64.2
63.7
*
*
*
63.5
61.3
58.6
60 50
**
†
46.9
47.8
40 32.9 28.4
30
26.7 25.0
20 10 0 n=
406
202
None
Figure 1 Continued
sures after treatment compared with the <30 BMI subgroup, the differences were not statistically significant. A difference would be expected because of the increased risk for diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular problems associated with obesity. Indeed, the percentage of patients with one or more comorbid medical condition (diabetes mellitus, hypertension, BPH, depression, or cardiovascular disease) was higher in the ≥30 BMI subgroup (66%) than in the <30 BMI subgroup (53%, P < 0.001). Patients with an organic ED etiology consistently had lower scores at baseline on the IIEF EF domain and in the SEP3 compared with the mixed and psychogenic subgroups. As expected, the organic subgroup (66%) had more patients with at least one comorbid medical condition compared with patients in the mixed (48%) and psychogenic (32%) subgroups. Moreover, the percentage of patients with severe ED at baseline was much higher in the organic subgroup (67%) compared with the mixed (25%) and psychogenic (8%) subgroups. The psychogenic subgroup had the highest baseline scores. However, the amount of improvement was similar among the three subgroups (IIEF EF, P = 0.280; SEP3, P = 0.745). Both tadalafil doses showed statistically greater improvement than placebo for each ED severity level. Not surprisingly, the improvements were
725
136
62
201
1 class Antihypertensives
83
47
193
28
21
60
_ > 2 classes Antidepressants
more pronounced in the moderate and severe ED patient groups because of the much lower baseline scores. Patients with severe ED treated with tadalafil 20 mg experienced increases from baseline of more than twofold in the IIEF EF domain score and more than 25-fold in SEP3 (baseline, 1.6%; end point, 50.3%). Both sildenafil and vardenafil show similar results in comparable patient groups [7,19]. Patients with ED duration of at least 1 year had lower overall baseline and end-point scores than patients having ED less than 1 year, but the amount of improvement from baseline was similar (IIEF EF, P = 0.189; SEP3, P = 0.138). Similar results were found in the sildenafil integrated analysis inasmuch as patients having ED for a longer period of time had worse baseline scores and showed similar degrees of improvement [7]. Smoking is considered a significant risk factor for vasculogenic ED because of its association with various cardiovascular diseases, atherosclerosis, neuropathy, and endothelial dysfunction [4,20– 22]. Nevertheless, patients treated with tadalafil 20 mg demonstrated significantly greater improvement than placebo-treated patients (P < 0.001) on the primary efficacy measures whether patients smoked or not (no statistical differences between smokers and nonsmokers taking tadalafil 20 mg on the IIEF EF and SEP3, P > 0.500). J Sex Med 2005; 2: 517–531
526 a
Lewis et al. †
100 90
94.0
*
*
*
*
86.0
86.0
83.7
82.6
Percent responding “yes” to GAQ
*
95.2
80
*
*
76.4
73.7
70
*
*
†
64.1
63.0
60.0
60
Placebo Tadalafil 10 mg Tadalafil 20 mg
50 41.7
41.5
40
* P < 0.001 vs. placebo significance not analyzed
35.8
†
30
28.6
28.3
23.1
20 10 0 n = 339
223
628
Caucasian
14
43
African descent
12
10
21
Hispanic
193
67
301
Asian
Ethnicity
441
218
787
£65
117
92
208
>65
Age (year)
Figure 2 (a–e) Percentage of patients reporting improved erections (Global Assessment Question) by subgroup. The following tadalafil subgroups had too few patients to analyze for statistical significance: Hispanic 10 mg and 20 mg, African descent 10 mg, psychogenic 10 mg, depression 10 mg, and antidepressant use 10 mg. BMI, body mass index; DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; HPL, hyperlipidemia; DEP, depression; BPH, benign prostatic hyperplasia. GAQ results for the ten 12-week studies (placebo, N = 591; tadalafil 10 mg, N = 321; tadalafil 20 mg, N = 1,050).
Sildenafil naïve patients had comparable results with previous users of sildenafil on the IIEF EF domain scores (P = 0.157) and SEP3 scores (P = 0.247). Although one could surmise that some of the patients in the sildenafil naïve group would have been sildenafil nonresponders had they used the drug, patients in this group had comparable results with previous users (and responders) of sildenafil. The subgroups of patients with comorbid conditions taking 20-mg tadalafil showed significant improvements from baseline to end point. The subgroup of patients with diabetes mellitus had lower end-point scores than the other subgroups, but the baseline measures were lower as well. The ED in patients with diabetes mellitus is known to be more difficult to treat [23]. The percentage of patients in the diabetes subgroup with severe ED at baseline was 45%. This compares with about 33% in the overall ED population in this analysis. J Sex Med 2005; 2: 517–531
A previously published, placebo-controlled study found that tadalafil significantly improved all efficacy measures compared with placebo in ED patients with either type 1 or type 2 diabetes [14]. A recent analysis of 637 men with ED and diabetes mellitus found that patients taking either tadalafil 10 mg or 20 mg significantly improved all primary efficacy outcomes compared with patients receiving placebo (e.g., mean improvement in IIEF EF domain score: tadalafil 20 mg, 7.4; tadalafil 10 mg, 6.2; placebo, 0.9; P < 0.001) [11]. Patients with hypertension have been shown in several studies to have a higher incidence of severe ED than the general ED population [18,21]. In this analysis, baseline measures of the IIEF EF domain and SEP3 were lower than all other clinical populations except the diabetes mellitus and severe ED subgroups. However, in this group, the degree of improvement in erectile function on
527
Efficacy of Tadalafil in Clinical Populations b
100 * *
90
87.0
*
Percent responding “yes” to GAQ
82.1
** *
88.1
86.7
85.0
*
*
85.6
83.3
*
78.8
80
79.0
*
*
*
74.5
†
70
*
90.9
*
*
71.6
70.0
67.3
68.7
*
60
57.6
50 42.7
42.1
Placebo Tadalafil 10 mg Tadalafil 20 mg
41.5
39.4
40
34.4 31.4
30
28.0
* P < 0.001 vs. placebo ** P = 0.002 vs. placebo † significance not analyzed
22.2
20 10 0
n = 328 205 554
155
Organic
80
308
75
20 133
183 110 363
Psychogenic
Mixed
Mild
81 277
189
99 324
41
500
265 866
≥1 yr
ED duration
100 *
90
*
80
*
**
72.7
72.9
*
84.3
83.0
82.2
*
88.5 87.7
*
*
*
84.5
Percent responding “yes” to GAQ
30 90
Severe ≥6 month to <1 yr
ED severity
ED etiology
c
157
Moderate
81.7
* 74.1
* 69.8
70
** 64.1
60 50
45.6
Placebo Tadalafil 10 mg Tadalafil 20 mg
41.8
40 33.5
31.9
30.3
30
25.0
* P < 0.001 vs. placebo
20
** P = 0.002 vs. placebo
10 0
n= 442
227
776
<30
116
78
≥30
BMI (kg/m2)
219
141
70
235
Smoker
416
235
758
Nonsmoker
Smoking
171
78
389
No prior use
256
81
606
Prior use
Sildenafil use
Figure 2 Continued
J Sex Med 2005; 2: 517–531
528 d
Lewis et al. 100 90
Percent responding “yes” to GAQ
85.6
83.1
*
*
82.1
*
80
*
*
*
82.2
81.4
*
*
77.2
76.4
75.5 71.0
70
*
*
64.6
63.9
†
60
57.1
50
46.8
40
Placebo Tadalafil 10 mg Tadalafil 20 mg
35.0 32.2 28.7
30
23.0
* P < 0.001 vs. placebo
20.0
20
†
significance not analyzed
10 0
n=
115
65
202
164
DM
83
296
47
HTN
31
65
87
49
125
20
43
100
55
174
BPH
DEP
HPL
CVD
14
Comorbid conditions
e
100 90
*
*
Percent responding “yes” to GAQ
84.8
* *
80
*
84.4
80.9
†
76.3
*
81.6
76.2
72.5
70 60
** 54.3
Placebo Tadalafil 10 mg Tadalafil 20 mg
50 40
35.4 30.3
30
29.6
28.0
* P < 0.001 vs. placebo
20
** P < 0.03 vs. placebo †
10 0 n=
364
200
644
None
118
59
76
178
46
173
21
49
≥2 classes
1 class Antihypertensives
Figure 2 Continued
J Sex Med 2005; 2: 517–531
27
Antidepressants
significance not analyzed
Efficacy of Tadalafil in Clinical Populations tadalafil 20 mg was comparable with the overall ED population as reflected in the paper by Carson et al. [13] In the tadalafil 20 mg subgroup, 82.1% of patients with hypertension responded positively to the GAQ. Various cardiovascular diseases, including ischemic heart disease and cerebrovascular disease, may be associated with some degree of ED [18,21]. Hyperlipidemia is a common comorbid condition with ED. Seftel et al. reported that 42.4% of patients with ED from a large managed care claims database had hyperlipidemia [25]. Hyperlipidemia probably contributes significantly to the etiology of ED [21]. The reduction of serum lipids results in the improvement of atherosclerotic plaque formation [21]. Clearly, patients with cardiovascular disease or hyperlipidemia showed significant improvement in erectile function after taking tadalafil as reflected by the IIEF EF domain and SEP3. Importantly, obesity reduction and increased physical activity may improve erectile function [26], or reduce the risk of having ED even if exercise is started during midlife [27]. However, a healthier lifestyle including improved nutrition, cessation of smoking, and reducing alcohol intake if excessive has not yet been proven to decrease the risk of having ED in midlife [27]. Until recently it was believed that BPH and lower urinary tract symptoms (LUTS) occurred in a similar age distribution but were not a risk factor for ED. In a large survey asking German men about ED and urinary voiding problems, it was shown that the risk of developing ED was twice as high in patients with BPH and was independent of other comorbidities such as diabetes mellitus [28]. In a large multinational survey of men between the ages of 50 and 80 years, erection problems were significantly more common in men with LUTS and were strongly related to more severe urinary symptomatology [29]. It appears that treating one condition may improve the other condition. For example, when men were treated for BPH, sexual function scores improved dramatically, especially in men with severe LUTS [30]. Conversely, the symptoms of LUTS improved when men with ED were treated with sildenafil [31]. Data presented here show that tadalafil significantly improved erectile function in men with ED having a comorbid condition of BPH. It would be of interest to determine in a prospective trial if tadalafil would improve not only erectile function but also urinary symptoms associated with BPH or LUTS.
529 Tadalafil 20 mg worked equally well in patients whether they were taking none, one, or multiple antihypertensives (P > 0.500, comparing the IIEF EF domain and SEP3 results in the three subgroups). It appears that ED patients taking antihypertensives should show similar improvement in erectile function to the patients not taking antihypertensives when prescribed tadalafil. It is well known that the use of antidepressants, especially selective serotonin reuptake inhibitors, often causes sexual dysfunction including ED in men [32,33]. Sildenafil previously has been shown to improve erectile function in men with ED taking antidepressants [34,35]. Tadalafil also significantly improved erectile function in the patient subgroup taking antidepressants. We found that 53% of patients on tadalafil 20 mg achieved normal IIEF EF domain scores at end point compared with 15% of patients taking placebo. The percentage of patients responding that they had improved erections (GAQ) was somewhat higher with tadalafil 20 mg (82%) than in the integrated analysis of sildenafil (63%) [7]. A trial including both sildenafil and tadalafil would determine if there are statistically significant differences between these drug therapies in treating men with ED taking antidepressants. Depression by itself can also result in ED [36]. In the present analysis, tadalafil 20 mg significantly improved erectile function in the subgroup of men with a diagnosis of depression. An integrated analysis of patients with depression on sildenafil for ED showed improvement in erectile function as reflected by the IIEF EF domain and GAQ scores [7]. In a prospective, randomized, double-blind, placebo-controlled trial, sildenafil was also shown to be effective in treating ED in men having comorbid depression [37]. A recent open-label trial found that tadalafil 20 mg was efficacious and well tolerated in men with ED (N = 178) and comorbid treated or untreated clinical depression [38]. This was a post hoc analysis, which limits the conclusions for some of the subpopulations, especially the subgroups with comorbid conditions or taking antihypertensives and antidepressants. Prospective trials for some of these conditions, including diabetes [14] and postprostatectomy [15], have been completed. In addition, an open-label study showed that tadalafil 20 mg was effective and well tolerated in a small group of men (N = 49) with ED due to traumatic spinal cord injury [39]. Although retrospective studies have inherent limitations, the results from this 11-study analysis J Sex Med 2005; 2: 517–531
530 strongly support that tadalafil is effective for the treatment of ED in men with various comorbid conditions. Some of the tadalafil 10 mg subgroups contained too few patients to perform statistical significance analyses. Therefore, direct conclusions should not be made for these subgroups, although clear trends were evident. Conclusions
The findings from this 11-study integrated analysis of 2,102 men with ED demonstrate that tadalafil is effective in improving erectile function across a variety of patient demographics and illness characteristics including ED etiology, severity and duration, and comorbid conditions and treatments. Tadalafil also proved to be effective in the subpopulation of men with diabetes mellitus and ED, who are difficult to treat. Corresponding Author: Ronald W. Lewis, MD, Witherington Chair in Urology, Department of Surgery/Chief of Urology, Medical College of Georgia, 1120 15th Street, Room BA-8412, Augusta, GA 30912, USA. Tel: (706) 721-9977; Fax: (706) 721-2548; E-mail: [email protected] Conflict of Interest: Wei Christine Wang, Wei Shen, Daniel J. Walker, David G. Wong, and Sanjeev Ahuja are employees of Eli Lilly and Company. References
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Efficacy of Tadalafil in Clinical Populations 20 Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, McKinlay JB. Erectile dysfunction and coronary risk factors: Prospective results from the Massachusetts Male Aging Study. Prev Med 2000;30:328–38. 21 Sullivan ME, Keoghane SR, Miller MAW. Vascular risk factors and erectile dysfunction. BJU Int 2001;87:838–45. 22 Andersson K.-E. Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol 2003;170:S6–14. 23 Saenz de Tejada I. Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat. Int J Impot Res 2004;16:S40–2. 24 Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil improved erections and increased successful sexual intercourse in diabetic men with erectile dysfunction. Evidence-Based Med 1999;4:111. 25 Seftel AD, Sun P, Swindle R. The prevalence of hypertension, hyperlipidemia, diabetes mellitus and depression in men with erectile dysfunction. J Urol 2004;171:2341–5. 26 Esposito K, Giugliano F, Di Palo C, Giugliano G, Marfella R, D’Andrea F, D’Armiento M, Giugliano D. Effect of lifestyle changes on erectile dysfunction in obese men. JAMA 2004;291:2978–84. 27 Derby CA, Mohr BA, Goldstein I, Feldman HA, Johannes CB, McKinlay JB. Modifiable risk factors and erectile dysfunction: Can lifestyle changes modify risk? Urology 2000;56:302–6. 28 Braun MH, Sommer F, Haupt G, Mathers MJ, Reifenrath B, Engelmann UH. Lower urinary tract symptoms and erectile dysfunction: Co-morbidity or typical “Aging Male” symptoms? Results of the “Cologne Male Survey.” Eur Urol 2003;44:588–94. 29 Rosen R, Altwein J, Boyle P, Kirby RS, Lukacs B, Meuleman E, O’Leary MP, Puppo P, Robertson C, Giuliano F. Lower urinary tract symptoms and male sexual dysfunction: The Multinational Survey of the Aging Male (MSAM-7). Eur Urol 2003;44:637–49. 30 Lukacs B, Grange JC, Comet D. One-year followup of 2829 patients with moderate to severe lower
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J Sex Med 2005; 2: 517–531
517
The Efficacy of Tadalafil in Clinical Populations Ronald W. Lewis, MD,* Richard Sadovsky, MD,† Ian Eardley, MA, MChir, FRCS, FEBU,‡ Michael O’Leary, MD,§ Allen Seftel, MD,¶ Wei Christine Wang, MS,** Wei Shen, PhD,** Daniel J. Walker, PhD,** David G. Wong, MD,** and Sanjeev Ahuja, MD** *Department of Urology, Medical College of Georgia, Augusta, GA, USA; †Department of Sexual Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA; ‡St. James University Hospital, Leeds, UK; §Division of Urology, Harvard Medical School, Boston, MA, USA; ¶Department of Urology, Case Western Reserve, Cleveland, OH, USA; **Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA DOI: 10.1111/j.1743-6109.2005.00068.x
ABSTRACT
Objectives. To evaluate the efficacy of tadalafil in men with erectile dysfunction (ED) by demographic and ED characteristics, in patients having various comorbid medical conditions, and in patients receiving drug treatment for other medical conditions. Methods. This is an analysis of 11 double-blind, placebo-controlled trials with 2,102 men with a broad spectrum of ED etiology and various comorbid medical conditions as participants. The variables analyzed in this report included race, age, body mass index (BMI), ED etiology, ED severity, ED duration, smoking, prior sildenafil use, presence of comorbid conditions (diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, depression, benign prostatic hyperplasia), and treatment with antihypertensives or antidepressants. Patients were randomly assigned to receive tadalafil 10 mg (N = 321), tadalafil 20 mg (N = 1,143), or placebo (N = 638). The primary efficacy variables included mean changes from baseline in the erectile function (EF) domain score of the International Index of Erectile Function (IIEF) questionnaire, and the mean per-patient percentage of “yes” responses to the Sexual Encounter Profile (SEP) diary question 3 (SEP3––successful intercourse). The Global Assessment Question 1 (GAQ) was evaluated, as was the percentage of men attaining a normal IIEF EF domain score at end point. Results. Patients taking tadalafil 10 mg or 20 mg demonstrated significant improvement (P < 0.005) from baseline to end point on the IIEF EF domain score in all subpopulations analyzed compared with patients receiving placebo. The mean-per-patient percentage of “yes” responses to SEP3 increased significantly in all subpopulations taking tadalafil compared with placebo (P < 0.05). Tadalafil-treated patients had a significantly greater positive response rate on the GAQ in all subpopulations analyzed compared with placebo-treated patients (P < 0.03) except for the tadalafil 10 mg cardiovascular subpopulation (placebo, 46.8%; tadalafil 10 mg, 71.0%; P = 0.127). The percentage of positive responses ranged from 72% to 91% for patients on tadalafil 20 mg and from 52% to 94% for tadalafil 10 mg compared with a range of 20% to 47% for placebo-treated patients. Conclusions. Tadalafil was effective in improving erectile function across a wide spectrum of ED patients including patients with various comorbid conditions. Key Words. Tadalafil; Erectile Dysfunction; Clinical Population
Introduction
E
rectile dysfunction (ED) has become recognized as a significant health issue in a large percentage of men over the age of 40 years [1]. A number of factors can contribute to the development of ED, including aging, cardiovascular disease, diabetes, smoking, anxiety and/or depression, certain drugs including antidepressants and antip-
sychotics [2], and a variety of other organic or psychological factors [3–5]. Awareness of ED increased with the approval in 1998 of sildenafil citrate, an oral treatment that improves erectile function in men having ED of various etiologies [6,7]. Tadalafil and sildenafil are inhibitors of phosphodiesterase type 5. Tadalafil primarily differs from sildenafil by having a duration of efficacy J Sex Med 2005; 2: 517–531
518 lasting up to 36 hours after a single dose compared with about 4 hours for sildenafil [8,9], although a recently published small open-label study in sildenafil responders suggested that sildenafil 100 mg might be effective in some men up to 12 hours after dosing [10]. Tadalafil has been shown to be efficacious and safe in a large number of patients with ED including men with diabetes mellitus [11–14]. Additionally, a recent study demonstrated that tadalafil significantly improved erectile function in men with ED following bilateral nerve-sparing radical retropubic prostatectomy [15]. In this article, 11 double-blind placebo-controlled trials were integrated and analyzed to determine the effectiveness of tadalafil in improving erectile function in more than a dozen clinical subpopulations. Methods
Study Design Data collected from 11 randomized, double-blind, placebo-controlled, parallel trials conducted worldwide at 174 centers in 18 countries from April 1999 to February 2003 were used in all of the analyses (Table 1). Details regarding the general study design, efficacy and safety measures, and statistical analysis were published previously [12,13]. Patients were randomized to 12 weeks of treatment with placebo (N = 638) or tadalafil at fixed doses including 10 mg (N = 321) or 20 mg (N = 1,143) after a 4-week, treatment-free period to determine baseline erectile function. One study had a 24-week duration, but the data presented here are from 12 weeks of this study. Patients were instructed to take one dose of the study drug as needed prior to sexual activity (maximum of once daily) without regard to food intake or timing of sexual activity after dosing. Dosage adjustments were not permitted in these studies. Patient visits occurred at approximately 4-week intervals until study completion or early discontinuation from the study. All studies were conducted according to the Declaration of Helsinki, and ethical review boards approved the study protocols. Patients provided written informed consent for study participation. Patient Population Men (≥18 years old) with a minimum 3-month history (patient reported) of mild to severe ED of organic, psychogenic, or mixed etiology and having a steady, adult female partner were eligible for participation in these studies. To be included, J Sex Med 2005; 2: 517–531
Lewis et al. patients were required to make at least 4 attempts at sexual intercourse during a 4-week, treatmentfree, run-in period. The exclusion criteria, including a history of certain cardiovascular diseases, clinically significant renal or hepatic insufficiency, and treatment with nitrates, have been listed in the five-study and 11-study tadalafil analyses [12,13]. The majority of studies excluded nonresponders to previous sildenafil treatment (nine out of 11). Patients were considered to be sildenafil nonresponders based on the opinion of the investigator.
Measures Measures used to evaluate the efficacy of tadalafil included the International Index of Erectile Function (IIEF) [16], the Sexual Encounter Profile (SEP), and a Global Assessment Question (GAQ). The IIEF was administered after the run-in period (baseline) and at 4-week intervals during treatment (postbaseline). Patients completed the SEP diary after each sexual intercourse attempt throughout the study. The patients’ scores on the erectile function (EF) domain of the IIEF at the end of the 4-week, treatment-free period were used to determine their baseline ED severity (mild, moderate, severe) [17]. Question 1 of the GAQ was asked at study completion or discontinuation. The efficacy variables evaluated in this manuscript included (i) the mean change from baseline to end point in the IIEF EF domain (sum of questions 1–5 and 15); (ii) the percentage of men attaining a normal IIEF EF domain score (≥26) at end point; (iii) the mean changes from baseline to postbaseline in the per-patient percentage of “yes” responses to question 3 of the SEP diary [SEP3––Did your erection last long enough for you to have successful intercourse? (yes/no)]; and (iv) the percentage of men with a “yes” response to Question 1 of the GAQ [“Has the treatment you have been taking over the past study interval improved your erections?” (yes/no)]. The IIEF EF domain score and SEP3 were primary efficacy measures in all 11 studies, whereas the GAQ was a secondary efficacy measure and the percentage of men achieving a normal IIEF EF domain score at end point was a post hoc analysis. Clinical Populations All subgroups analyzed will be referred to as clinical populations. This post hoc analysis includes populations based on ethnic origin, age (£65 years vs. >65 years), body mass index (BMI < 30 kg/m2 or ≥30 kg/m2), ED etiology, ED severity, ED duration, smoking (current), prior sildenafil use,
519
Efficacy of Tadalafil in Clinical Populations Table 1 Study 1 2 3 4 5 6 7 8 9 10 11 Total
Summary of 11 tadalafil studies Number of centers
Placebo
Tadalafil 10 mg
Tadalafil 20 mg
19 18 8 4 25 20 10 17 21 19 13
69 76 66 47 50 49 41 83 48 52 57
74 79 65 — 103 — — — — — —
— — 65 93 100 146 80 159 159 168 173
174
638
321
1,143
Total 143* 155† 196 140 253 195 121 242 207 220 230 2,102
* There were an additional 72 patients randomly assigned to 5 mg of tadalafil. † There were an additional 74 patients and 79 patients randomly assigned to 2.5 mg and 5 mg of tadalafil, respectively. Number (%) of patients from participating countries: Argentina, 54 (3); Australia, 140 (7); Canada, 476 (23); Hong Kong, 38 (2); Indonesia, 21 (1); Israel, 21 (1); Italy, 111 (5), Republic of Korea, 121 (6); Malaysia, 32 (2); Mexico, 21 (1); Philippines, 40 (2); Poland, 104 (5); Puerto Rico, 18 (1); Russia, 105 (5); Singapore, 30 (1); Taiwan, 277 (13); United Kingdom, 109 (5); United States, 384 (18).
presence of comorbid conditions [diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, depression, benign prostatic hyperplasia (BPH)], use of antihypertensives, and use of antidepressants. Comorbid medical conditions were diagnosed on the basis of the patient’s medical history and physical examination.
Statistical Analyses All analyses were conducted on an intent-to-treat basis. Efficacy analyses included all patients with a baseline measurement and at least one postbaseline measurement. The IIEF EF domain scores were analyzed by using the last observation carried forward convention. The study design and patient population were consistent across all 11 studies; therefore, efficacy data could be pooled for these analyses. However, the GAQ analysis included only 10 studies, because in the 24-week study the GAQ was measured at end point and not at week 12. In addition, nine of the 11 trials captured data regarding prior sildenafil use. The IIEF EF domain and SEP3 scores were analyzed by analysis of covariance (ANCOVA) models, including terms for baseline value of the efficacy variable, treatment group, protocol, and baseline-bytreatment group interaction (if P < 0.10). Logistic regression was used to evaluate the GAQ by using the same terms as in the ANCOVA model, except the interaction term (only patients who responded to the GAQ were included in the analysis). For some subgroups of interest, treatment by subgroup interaction test was performed to detect the between-group difference in the overall treatment effect at 0.05 alpha level. Statistical Analysis Software version 8.2 (SAS®, SAS Institute Inc., Cary,
NC) was used to perform statistical analyses. All tests of hypotheses were considered statistically significant if the two-sided P value was less than 0.05. However, because of a lack of statistical power, analysis of statistical significance was not performed in subgroups with fewer than 30 patients in either tadalafil treatment arm. This included the Hispanic 10 mg and 20 mg, African descent 10 mg, psychogenic 10 mg, depression 10 mg, and antidepressant use 10 mg subgroups. Whenever the statement “in all subgroups analyzed,” or a similar statement is made when discussing statistical significance, it is referring to those clinical populations having 30 or more patients in either tadalafil arm. Results
Demographic and Baseline Characteristics Demographic and baseline illness characteristics are shown in Table 2. The mean age was 56 years (range, 22–88 years) with most patients (88%) having ED for at least 1 year. The proportion of patients with mild, moderate, or severe ED was similar in all three treatment groups (P = 0.933). Hypertension (29%), diabetes mellitus (20%), and hyperlipidemia (16%) were common comorbid conditions. The vast majority of patients taking tadalafil (10 mg, 88.5%; 20 mg, 89.7%) and placebo (86.8%) completed 12 weeks of treatment. Lack of efficacy in the placebo group (5.0%), patient decision in the tadalafil 10 mg group (3.7%), and adverse events in the tadalafil 20 mg group (3.2%) were the most common reasons for patient discontinuation (details in Carson et al. [13]). J Sex Med 2005; 2: 517–531
520 Table 2
Lewis et al. Demographic and baseline characteristics of men with erectile dysfunction (ED)
Variable Mean age, year (range) Age > 65, n (%) Ethnicity, n (%) White Asian African descent Hispanic Other BMI, kg/m2 (range) <30, n (%) ≥30, n (%) Duration of ED ≥12 months, n (%) ED etiology, n (%) Organic Psychogenic Mixed ED severity (IIEF EF domain score), n (%)* Normal (26–30) Mild (17–25) Moderate (11–16) Severe (1–10) Comorbid conditions, n (%) Diabetes mellitus Hypertension CVD Hyperlipidemia Depression BPH Concomitant medication, n (%) No antihypertensive 1 antihypertensive ≥2 antihypertensives Antidepressants
Placebo (N = 638)
Tadalafil 10 mg (N = 321)
57 (22–81) 140 (22)
58 (26–81) 96 (30)
Tadalafil 20 mg (N = 1,143) 56 (22–88) 248 (22)
408 (64) 196 (31) 15 (2) 19 (3) 0 27.3 (18.1–53.7) 503 (79) 135 (21) 572 (90)
235 (73) 68 (21) 3 (1) 12 (4) 3 (1) 27.9 (18.2–46.0) 237 (74) 84 (26) 280 (87)
369 (58) 82 (13) 187 (29)
215 (67) 20 (6) 86 (27)
627 (55) 147 (13) 369 (32)
33 (5) 212 (33) 171 (27) 220 (34)
16 (5) 113 (35) 84 (26) 107 (33)
39 (3) 425 (37) 303 (27) 376 (33)
130 (20) 189 (30) 53 (8) 110 (17) 23 (4) 105 (16) 416 (65) 139 (22) 83 (13) 29 (5)
68 90 32 51 15 56
761 (67) 310 (27) 46 (4) 24 (2) 2 (0.2) 27.3 (12.7–52.0) 885 (77) 258 (23) 1,006 (88)
(21) (28) (10) (16) (5) (17)
223 (20) 337 (29) 89 (8) 166 (15) 53 (5) 188 (16)
209 (65) 65 (20) 47 (15) 21 (7)
742 (65) 206 (18) 195 (17) 61 (5)
* Patients were included in the study based on a history of ED. The subsequent assessment of erectile function by the IIEF at baseline indicated that a small percentage of patients had an erectile function domain score in the normal range (26–30). BMI, body mass index; IIEF, International Index of Erectile Function; CVD, cardiovascular disease; BPH, benign prostatic hyperplasia.
Efficacy Results The tadalafil 20 mg group showed a significantly greater mean baseline-to-end-point improvement on the IIEF EF domain score (P < 0.001) than the placebo group in all clinical populations (Table 3). All subgroups treated with tadalafil 20 mg had an end-point score in the range of 19.5–25.7. The tadalafil 10 mg group showed significantly greater improvement vs. placebo (P < 0.005) in all subgroups. The percentage of men attaining a normal IIEF EF domain score at end point was significantly greater (P < 0.001) in the tadalafil 20 mg group (range, 37–68%) compared with the placebo group (range, 3–20%) in all clinical populations (Table 4). Tadalafil 10 mg also had a significantly greater percentage of patients achieving a normal IIEF EF domain score at end point than patients taking placebo (P < 0.001). Significantly greater improvements (P < 0.001) in successful intercourse (SEP3) occurred in all populations taking tadalafil 20 mg than in those J Sex Med 2005; 2: 517–531
taking placebo (Figure 1). Most subgroups taking 20-mg tadalafil had end-point success rates of about 70% compared with about 30% for the placebo group. Patients taking tadalafil 10 mg showed significantly greater improvement (P < 0.05) than placebo on SEP3 in all clinical populations. A significantly greater percentage (P < 0.001) of patients taking tadalafil 20 mg responded “yes” to the GAQ in each subpopulation compared with placebo patients (Figure 2). All but three subgroups had a positive response rate in the 80% range for tadalafil 20 mg (71.6%, 76.4%, and 77.2% in the severe ED, >65 years, and diabetes mellitus subgroups, respectively). All of the tadalafil 10 mg subpopulations demonstrated a significantly greater percentage of patients responding “yes” to the GAQ compared with the placebo group (P < 0.005) except for the tadalafil 10 mg cardiovascular subpopulation (placebo, 46.8%; tadalafil 10 mg, 71.0%; P = 0.127).
14.9 12.8 13.8 15.5 15.4 20.5 13.8 7.4 16.5 14.2 14.9 12.8 14.8 14.4 15.1 14.3 12.8 13.8 13.9 13.7 13.0 14.8 14.7 14.3 13.4 12.8
482 135
356 182 79
205 168 213
45 555
485 132
146 469
199 282
125 182 53 105 23 104
400 135 82 29
15.7 14.9 14.0 14.8
14.1 14.4 15.7 15.1 13.6 15.4
16.8 14.5
16.2 15.1
15.4 15.3
16.4 15.1
19.5 15.5 10.1
14.8 15.8 17.3
15.9 13.0
14.6 11.6 18.7 16.1
End point
0.8 0.7 0.6 1.0
1.2 0.8 1.1 1.0 -0.1 1.1
1.8 0.2
1.3 0.7
0.7 1.6
203 59 47 21
64 85 32 48 14 55
79 83
73 236
230 79
31 268
112 83 100
-1.0 1.9 2.7 0.5 0.8
206 83 20
15.0 14.1 13.1 15.7
13.0 13.8 14.8 15.0 15.4 14.2
14.3 14.8
15.7 14.2
14.5 14.8
15.6 14.3
20.3 13.4 7.3
13.9 15.5 16.9
14.9 13.8
14.2 14.5
10 67 216 93
14.4
Baseline
226
n
0.9 0.5 1.4
0.9 -0.0
0.2 -1.5 4.9 0.9
Change
21.7 20.5 18.4 17.6
19.1 18.7 22.3 22.0 19.3 21.9
22.3 20.6
22.0 20.8
21.4 19.9
23.2 20.7
24.1 22.0 16.3
20.7 22.6 18.9
21.5 19.1
21.3 21.2
20.5
End point
Tadalafil 10 mg
6.8* 6.3* 5.1** 3.9†
6.2* 5.1* 7.7* 7.9* 5.6† 7.6*
7.4* 6.2*
7.1* 6.4*
6.6* 6.1*
7.4* 6.4*
3.6* 8.3* 8.9*
6.8* 7.3* 3.0†
6.6* 6.1*
7.4† 6.0*
6.1*
Change
* P < 0.001; ** P = 0.004; † Statistical significance not analyzed (see Methods). Baselines are raw means; end point and change are least square means. IIEF, International Index of Erectile Function; BMI, body mass index; CVD, cardiovascular disease; BPH, benign prostatic hyperplasia.
14.3 11.9 13.2 15.2
Baseline
395 15 14 193
n
Placebo
Least squares mean IIEF EF domain scores
Ethnicity Caucasian African descent Hispanic Asian Age (year) £65 >65 ED etiology Organic Mixed Psychogenic ED severity Mild Moderate Severe ED duration ≥6 months to <1 year ≥1 year BMI, kg/m2 <30 ≥30 Smoker Yes No Prior sildenafil use No Yes Comorbid conditions Diabetes mellitus Hypertension CVD Hyperlipidemia Depression BPH Concomitant medication No antihypertensive 1 antihypertensive ≥2 antihypertensives Antidepressants
Subgroup
Table 3
719 200 192 61
215 332 85 159 51 184
441 670
251 858
864 247
95 976
410 299 364
606 361 144
871 240
733 46 23 307
n
15.0 14.2 13.4 13.5
12.9 13.6 15.1 14.1 13.6 13.9
15.0 14.3
14.7 14.5
14.8 13.9
15.7 14.3
20.5 13.6 7.4
13.9 15.2 16.0
15.0 13.0
14.4 13.0 14.1 15.4
Baseline
23.4 22.2 22.1 23.7
20.0 22.3 22.7 23.1 22.4 22.6
23.7 22.8
23.2 23.0
23.2 22.7
23.7 22.9
25.7 23.8 19.5
22.5 23.4 24.8
23.6 21.1
22.7 21.9 24.8 22.9
End point
Tadalafil 20 mg
8.4* 8.0* 8.7* 9.9*
7.1* 8.7* 8.0* 9.0* 8.7* 8.4*
8.8* 8.5*
8.3* 8.5*
8.4* 9.0*
7.9* 8.6*
5.2* 10.2* 12.1*
8.7* 8.1* 8.9*
8.6* 8.0*
8.4* 8.9* 10.9† 7.7*
Change
Efficacy of Tadalafil in Clinical Populations 521
J Sex Med 2005; 2: 517–531
522 Table 4
Lewis et al. Percentage of men attaining normal erectile function (EF) domain score (≥26) at end point Placebo
Subgroup Ethnicity Caucasian African descent Hispanic Asian Age, year £65 >65 ED etiology Organic Mixed Psychogenic ED severity Mild Moderate Severe ED duration ≥6 months to <1 year ≥1 year BMI, kg/m2 <30 ≥30 Smoker Yes No Prior sildenafil use No Yes Comorbid conditions Diabetes mellitus Hypertension CVD Hyperlipidemia Depression BPH Concomitant medication No antihypertensive 1 antihypertensive ≥2 antihypertensives Antidepressants
Tadalafil 10 mg
Baseline n
Normal at end point % (n)
372 15 14 185
Tadalafil 20 mg
Baseline n
Normal at end point % (n)
Baseline n
Normal at end point % (n)
11.8 (44) 0 (0) 28.6 (4) 10.8 (20)
216
39.8* (86) 20.0† (2) 41.3* (26)
704 45 22 300
55.3* (389) 51.1* (23) 63.6† (14) 50.7* (152)
10 63
458 128
13.1 (60) 6.3 (8)
206 89
42.7* (88) 32.6* (29)
836 237
56.1* (469) 46.4* (110)
343 169 74
9.3 (32) 14.2 (24) 16.2 (12)
199 78 18
37.2* (74) 50.0* (39) 22.2† (4)
585 349 139
49.9* (292) 58.2* (203) 60.4* (84)
205 168 213
19.5 (40) 12.5 (21) 3.3 (7)
112 83 100
51.8* (58) 41.0* (34) 25.0* (25)
410 299 364
67.8* (278) 52.2* (156) 39.8* (145)
39 531
12.8 (5) 10.4 (55)
30 256
53.3* (16) 37.5* (96)
93 943
53.8* (50) 53.3* (503)
461 125
11.7 (54) 11.2 (14)
222 73
40.5* (90) 37.0* (27)
835 238
55.3* (462) 49.2* (117)
139 445
16.5 (23) 10.1 (45)
67 228
53.7* (36) 35.5* (81)
242 829
55.8* (135) 53.3* (442)
186 270
17.2 (32) 8.9 (24)
73 81
50.7* (37) 40.7* (33)
423 650
57.0* (241) 52.0* (338)
121 174 50 101 22 97
8.3 (10) 9.2 (16) 14.0 (7) 8.9 (9) 9.1 (2) 11.3 (11)
63 83 30 44 13 53
34.9* (22) 31.3* (26) 53.3* (16) 50.0* (22) 38.5† (5) 45.3* (24)
207 325 83 152 51 181
36.7* 51.7* 56.6* 52.6* 59.8* 48.6*
(76) (168) (47) (80) (30) (88)
379 128 79 27
12.9 (49) 9.4 (12) 8.9 (7) 14.8 (4)
192 58 45 19
41.1* (79) 43.1* (25) 28.9* (13) 42.1† (8)
690 194 189 60
55.4* 53.1* 49.7* 53.3*
(382) (103) (94) (32)
* P < 0.001; † Statistical significance not analyzed (see Methods). Baseline N: patients with a baseline EF < 26 and a nonmissing end-point EF score are included. BMI, body mass index; CVD, cardiovascular disease; BPH, benign prostatic hyperplasia.
The safety of tadalafil in these 11 integrated studies was presented previously [13]. Briefly, most adverse events were reported by patients to be mild or moderate, with the most common events being headache, dyspepsia, and back pain. The percentage of patients who discontinued because of adverse events in these studies was 1.3% for placebo, 1.6% for tadalafil 10 mg, and 3.2% for tadalafil 20 mg. Discussion
This analysis of 2,102 men with ED demonstrated that tadalafil 10 mg and 20 mg were effective in all clinical populations analyzed, including in patients with diabetes mellitus, who are considered difficult J Sex Med 2005; 2: 517–531
to treat. Tadalafil 20 mg showed numerically greater improvement than tadalafil 10 mg for each efficacy measure in most of the clinical populations. Tadalafil showed improved efficacy among all racial groups. It would have been more informative if the number of Hispanics and patients of African descent were large enough to address statistical significance vs. placebo at both tadalafil doses. The number of men was low in both subgroups, which may be a reflection of the geographical location of the trial sites (Table 1). However, in trials conducted in the United States and Puerto Rico (N = 402), 14% of men were of African descent and 7% were of Hispanic descent. In the analysis of sildenafil in clinical populations
523
Efficacy of Tadalafil in Clinical Populations a
Placebo Tadalafil 10 mg Tadalafil 20 mg
100
Mean per-patient percent success (SEP3)
90
Baseline * P < 0.001 vs. placebo † significance not analyzed
*
80
76.2
70
† 69.0
* *
*
*
69.6
67.7
*
*
63.7
*
63.1
61.4
59.5
58.4
60
* 51.1
50 † 38.9
40
33.7 30.0
29.7
30 20.8
22.2
21.1
20 10 0 n=
400
227
741
15
46
16
11
23
194
Hispanic
African descent
Caucasian
67
307
486
218
100
Mean per-patient percent success (SEP3)
Figure 1 (a–e) Mean per-patient percentage of successful intercourse (Sexual Encounter Profile question 3) by subgroup. The following tadalafil subgroups had too few patients to analyze for statistical significance: Hispanic 10 mg and 20 mg, African descent 10 mg, psychogenic 10 mg, depression 10 mg, and antidepressant use 10 mg. BMI, body mass index; DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; HPL, hyperlipidemia; DEP, depression; BPH, benign prostatic hyperplasia.
*
80
75.6
70
*
*
64.1
63.8
*
60
93
238
>65
Baseline * P < 0.001 vs. placebo † significance not analyzed
Placebo Tadalafil 10 mg Tadalafil 20 mg
90
139
Age (year)
Ethnicity
b
881
£65
Asian
* *
77.8 78.1
*
*
69.2
69.8
* *
71.1
*
67.9
65.7
†
*
*
59.8
58.8
59.1
57.9
* 50.3
50
46.8
*
40
38.4
36.2 34.1
30
32.7 29.9
28.9
27.5
20 11.3
10 0
n = 360 209 607
Organic
183
82
368
Mixed
82
ED etiology
[7], it was interesting to note that the black subgroup had the best IIEF EF domain score at end point but the lowest percentage of positive responses to the GAQ. This pattern did not occur with the African descent subgroup taking tadalafil. However, in the sildenafil analysis, the Asian subgroup had the lowest IIEF EF score but had a higher GAQ score than the white and black sub-
20 144
Psychogenic
206 112 418
Mild
170
83 299
217 101 363
46
31
96
562
270 983
Moderate Severe ≥ 6 month ≥1 year to <1 year
ED severity
ED duration
groups. The Asian subgroup taking tadalafil had high GAQ scores as well, especially for the 10-mg dose. These findings suggest that racial groups might differ in how they perceive improvements in erections, or have differing expectations of the medical therapy. Further study of this phenomenon could prove interesting both from a scientific and cultural or behavioral perspective. J Sex Med 2005; 2: 517–531
524 c
Lewis et al. 100
Placebo Tadalafil 10 mg Tadalafil 20 mg
Mean per-patient percent success (SEP3)
90
Baseline * P < 0.001 vs. placebo
80 * 67.9
70
*
*
*
63.5
61.4
*
*
66.8
67.2
62.8
*
69.5
66.6
*
*
58.9
*
60
*
* 66.8
58.3
54.9
50 40
36.2
33.6
32.4
30.4
30.2
28.1
30 20 10 0 n=
494
229
869
131
82
250
≥30
<30
147
73
Placebo Tadalafil 10 mg Tadalafil 20 mg
100
Mean per-patient percent success (SEP3)
90
476
238
868
203
Nonsmoker
442
80
No prior use
Smoking
BMI (kg/m2)
d
249
Smoker
282
83
677
Prior use
Sildenafil use
Baseline * P < 0.001 vs. placebo † significance not analyzed
80 *
70
*
* *
71.0
67.5 68.3
*
*
63.6 64.8
64.7
63.2
60
*
*
*
69.9
† 58.6
*
*
54.9
52.8
52.4
50 40 34.3 31.8
30.0
30
30.2
27.5 22.6
20 10 0
n=
125
66
DM
217
183
87
329
HTN
53
32
CVD
87
105
51
159
HPL
Comorbid conditions
It has been shown previously in the Massachusetts Male Aging Study that moderate and severe ED increase from age 40 to 70 years [18]. In our report, younger patients (£65 years) had numerically better scores than older patients on each of the efficacy measures, although the differences were small after accounting for the slightly better J Sex Med 2005; 2: 517–531
23
14
51
DEP
104
55
182
BPH
Figure 1 Continued
baseline scores in younger patients. In addition, the differences in improvement on the primary efficacy measures between younger patients and older patients were not statistically significant (P > 0.700). Although the ≥30 BMI subgroup had slightly lower (worse) scores on each of the efficacy mea-
525
Efficacy of Tadalafil in Clinical Populations e
90 Mean per-patient percent success (SEP3)
Baseline * P < 0.001 vs. placebo ** P < 0.05 vs. placebo † significance not analyzed
Placebo Tadalafil 10 mg Tadalafil 20 mg
100
80 *
70
*
68.8
* 64.2
63.7
*
*
*
63.5
61.3
58.6
60 50
**
†
46.9
47.8
40 32.9 28.4
30
26.7 25.0
20 10 0 n=
406
202
None
Figure 1 Continued
sures after treatment compared with the <30 BMI subgroup, the differences were not statistically significant. A difference would be expected because of the increased risk for diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular problems associated with obesity. Indeed, the percentage of patients with one or more comorbid medical condition (diabetes mellitus, hypertension, BPH, depression, or cardiovascular disease) was higher in the ≥30 BMI subgroup (66%) than in the <30 BMI subgroup (53%, P < 0.001). Patients with an organic ED etiology consistently had lower scores at baseline on the IIEF EF domain and in the SEP3 compared with the mixed and psychogenic subgroups. As expected, the organic subgroup (66%) had more patients with at least one comorbid medical condition compared with patients in the mixed (48%) and psychogenic (32%) subgroups. Moreover, the percentage of patients with severe ED at baseline was much higher in the organic subgroup (67%) compared with the mixed (25%) and psychogenic (8%) subgroups. The psychogenic subgroup had the highest baseline scores. However, the amount of improvement was similar among the three subgroups (IIEF EF, P = 0.280; SEP3, P = 0.745). Both tadalafil doses showed statistically greater improvement than placebo for each ED severity level. Not surprisingly, the improvements were
725
136
62
201
1 class Antihypertensives
83
47
193
28
21
60
_ > 2 classes Antidepressants
more pronounced in the moderate and severe ED patient groups because of the much lower baseline scores. Patients with severe ED treated with tadalafil 20 mg experienced increases from baseline of more than twofold in the IIEF EF domain score and more than 25-fold in SEP3 (baseline, 1.6%; end point, 50.3%). Both sildenafil and vardenafil show similar results in comparable patient groups [7,19]. Patients with ED duration of at least 1 year had lower overall baseline and end-point scores than patients having ED less than 1 year, but the amount of improvement from baseline was similar (IIEF EF, P = 0.189; SEP3, P = 0.138). Similar results were found in the sildenafil integrated analysis inasmuch as patients having ED for a longer period of time had worse baseline scores and showed similar degrees of improvement [7]. Smoking is considered a significant risk factor for vasculogenic ED because of its association with various cardiovascular diseases, atherosclerosis, neuropathy, and endothelial dysfunction [4,20– 22]. Nevertheless, patients treated with tadalafil 20 mg demonstrated significantly greater improvement than placebo-treated patients (P < 0.001) on the primary efficacy measures whether patients smoked or not (no statistical differences between smokers and nonsmokers taking tadalafil 20 mg on the IIEF EF and SEP3, P > 0.500). J Sex Med 2005; 2: 517–531
526 a
Lewis et al. †
100 90
94.0
*
*
*
*
86.0
86.0
83.7
82.6
Percent responding “yes” to GAQ
*
95.2
80
*
*
76.4
73.7
70
*
*
†
64.1
63.0
60.0
60
Placebo Tadalafil 10 mg Tadalafil 20 mg
50 41.7
41.5
40
* P < 0.001 vs. placebo significance not analyzed
35.8
†
30
28.6
28.3
23.1
20 10 0 n = 339
223
628
Caucasian
14
43
African descent
12
10
21
Hispanic
193
67
301
Asian
Ethnicity
441
218
787
£65
117
92
208
>65
Age (year)
Figure 2 (a–e) Percentage of patients reporting improved erections (Global Assessment Question) by subgroup. The following tadalafil subgroups had too few patients to analyze for statistical significance: Hispanic 10 mg and 20 mg, African descent 10 mg, psychogenic 10 mg, depression 10 mg, and antidepressant use 10 mg. BMI, body mass index; DM, diabetes mellitus; HTN, hypertension; CVD, cardiovascular disease; HPL, hyperlipidemia; DEP, depression; BPH, benign prostatic hyperplasia. GAQ results for the ten 12-week studies (placebo, N = 591; tadalafil 10 mg, N = 321; tadalafil 20 mg, N = 1,050).
Sildenafil naïve patients had comparable results with previous users of sildenafil on the IIEF EF domain scores (P = 0.157) and SEP3 scores (P = 0.247). Although one could surmise that some of the patients in the sildenafil naïve group would have been sildenafil nonresponders had they used the drug, patients in this group had comparable results with previous users (and responders) of sildenafil. The subgroups of patients with comorbid conditions taking 20-mg tadalafil showed significant improvements from baseline to end point. The subgroup of patients with diabetes mellitus had lower end-point scores than the other subgroups, but the baseline measures were lower as well. The ED in patients with diabetes mellitus is known to be more difficult to treat [23]. The percentage of patients in the diabetes subgroup with severe ED at baseline was 45%. This compares with about 33% in the overall ED population in this analysis. J Sex Med 2005; 2: 517–531
A previously published, placebo-controlled study found that tadalafil significantly improved all efficacy measures compared with placebo in ED patients with either type 1 or type 2 diabetes [14]. A recent analysis of 637 men with ED and diabetes mellitus found that patients taking either tadalafil 10 mg or 20 mg significantly improved all primary efficacy outcomes compared with patients receiving placebo (e.g., mean improvement in IIEF EF domain score: tadalafil 20 mg, 7.4; tadalafil 10 mg, 6.2; placebo, 0.9; P < 0.001) [11]. Patients with hypertension have been shown in several studies to have a higher incidence of severe ED than the general ED population [18,21]. In this analysis, baseline measures of the IIEF EF domain and SEP3 were lower than all other clinical populations except the diabetes mellitus and severe ED subgroups. However, in this group, the degree of improvement in erectile function on
527
Efficacy of Tadalafil in Clinical Populations b
100 * *
90
87.0
*
Percent responding “yes” to GAQ
82.1
** *
88.1
86.7
85.0
*
*
85.6
83.3
*
78.8
80
79.0
*
*
*
74.5
†
70
*
90.9
*
*
71.6
70.0
67.3
68.7
*
60
57.6
50 42.7
42.1
Placebo Tadalafil 10 mg Tadalafil 20 mg
41.5
39.4
40
34.4 31.4
30
28.0
* P < 0.001 vs. placebo ** P = 0.002 vs. placebo † significance not analyzed
22.2
20 10 0
n = 328 205 554
155
Organic
80
308
75
20 133
183 110 363
Psychogenic
Mixed
Mild
81 277
189
99 324
41
500
265 866
≥1 yr
ED duration
100 *
90
*
80
*
**
72.7
72.9
*
84.3
83.0
82.2
*
88.5 87.7
*
*
*
84.5
Percent responding “yes” to GAQ
30 90
Severe ≥6 month to <1 yr
ED severity
ED etiology
c
157
Moderate
81.7
* 74.1
* 69.8
70
** 64.1
60 50
45.6
Placebo Tadalafil 10 mg Tadalafil 20 mg
41.8
40 33.5
31.9
30.3
30
25.0
* P < 0.001 vs. placebo
20
** P = 0.002 vs. placebo
10 0
n= 442
227
776
<30
116
78
≥30
BMI (kg/m2)
219
141
70
235
Smoker
416
235
758
Nonsmoker
Smoking
171
78
389
No prior use
256
81
606
Prior use
Sildenafil use
Figure 2 Continued
J Sex Med 2005; 2: 517–531
528 d
Lewis et al. 100 90
Percent responding “yes” to GAQ
85.6
83.1
*
*
82.1
*
80
*
*
*
82.2
81.4
*
*
77.2
76.4
75.5 71.0
70
*
*
64.6
63.9
†
60
57.1
50
46.8
40
Placebo Tadalafil 10 mg Tadalafil 20 mg
35.0 32.2 28.7
30
23.0
* P < 0.001 vs. placebo
20.0
20
†
significance not analyzed
10 0
n=
115
65
202
164
DM
83
296
47
HTN
31
65
87
49
125
20
43
100
55
174
BPH
DEP
HPL
CVD
14
Comorbid conditions
e
100 90
*
*
Percent responding “yes” to GAQ
84.8
* *
80
*
84.4
80.9
†
76.3
*
81.6
76.2
72.5
70 60
** 54.3
Placebo Tadalafil 10 mg Tadalafil 20 mg
50 40
35.4 30.3
30
29.6
28.0
* P < 0.001 vs. placebo
20
** P < 0.03 vs. placebo †
10 0 n=
364
200
644
None
118
59
76
178
46
173
21
49
≥2 classes
1 class Antihypertensives
Figure 2 Continued
J Sex Med 2005; 2: 517–531
27
Antidepressants
significance not analyzed
Efficacy of Tadalafil in Clinical Populations tadalafil 20 mg was comparable with the overall ED population as reflected in the paper by Carson et al. [13] In the tadalafil 20 mg subgroup, 82.1% of patients with hypertension responded positively to the GAQ. Various cardiovascular diseases, including ischemic heart disease and cerebrovascular disease, may be associated with some degree of ED [18,21]. Hyperlipidemia is a common comorbid condition with ED. Seftel et al. reported that 42.4% of patients with ED from a large managed care claims database had hyperlipidemia [25]. Hyperlipidemia probably contributes significantly to the etiology of ED [21]. The reduction of serum lipids results in the improvement of atherosclerotic plaque formation [21]. Clearly, patients with cardiovascular disease or hyperlipidemia showed significant improvement in erectile function after taking tadalafil as reflected by the IIEF EF domain and SEP3. Importantly, obesity reduction and increased physical activity may improve erectile function [26], or reduce the risk of having ED even if exercise is started during midlife [27]. However, a healthier lifestyle including improved nutrition, cessation of smoking, and reducing alcohol intake if excessive has not yet been proven to decrease the risk of having ED in midlife [27]. Until recently it was believed that BPH and lower urinary tract symptoms (LUTS) occurred in a similar age distribution but were not a risk factor for ED. In a large survey asking German men about ED and urinary voiding problems, it was shown that the risk of developing ED was twice as high in patients with BPH and was independent of other comorbidities such as diabetes mellitus [28]. In a large multinational survey of men between the ages of 50 and 80 years, erection problems were significantly more common in men with LUTS and were strongly related to more severe urinary symptomatology [29]. It appears that treating one condition may improve the other condition. For example, when men were treated for BPH, sexual function scores improved dramatically, especially in men with severe LUTS [30]. Conversely, the symptoms of LUTS improved when men with ED were treated with sildenafil [31]. Data presented here show that tadalafil significantly improved erectile function in men with ED having a comorbid condition of BPH. It would be of interest to determine in a prospective trial if tadalafil would improve not only erectile function but also urinary symptoms associated with BPH or LUTS.
529 Tadalafil 20 mg worked equally well in patients whether they were taking none, one, or multiple antihypertensives (P > 0.500, comparing the IIEF EF domain and SEP3 results in the three subgroups). It appears that ED patients taking antihypertensives should show similar improvement in erectile function to the patients not taking antihypertensives when prescribed tadalafil. It is well known that the use of antidepressants, especially selective serotonin reuptake inhibitors, often causes sexual dysfunction including ED in men [32,33]. Sildenafil previously has been shown to improve erectile function in men with ED taking antidepressants [34,35]. Tadalafil also significantly improved erectile function in the patient subgroup taking antidepressants. We found that 53% of patients on tadalafil 20 mg achieved normal IIEF EF domain scores at end point compared with 15% of patients taking placebo. The percentage of patients responding that they had improved erections (GAQ) was somewhat higher with tadalafil 20 mg (82%) than in the integrated analysis of sildenafil (63%) [7]. A trial including both sildenafil and tadalafil would determine if there are statistically significant differences between these drug therapies in treating men with ED taking antidepressants. Depression by itself can also result in ED [36]. In the present analysis, tadalafil 20 mg significantly improved erectile function in the subgroup of men with a diagnosis of depression. An integrated analysis of patients with depression on sildenafil for ED showed improvement in erectile function as reflected by the IIEF EF domain and GAQ scores [7]. In a prospective, randomized, double-blind, placebo-controlled trial, sildenafil was also shown to be effective in treating ED in men having comorbid depression [37]. A recent open-label trial found that tadalafil 20 mg was efficacious and well tolerated in men with ED (N = 178) and comorbid treated or untreated clinical depression [38]. This was a post hoc analysis, which limits the conclusions for some of the subpopulations, especially the subgroups with comorbid conditions or taking antihypertensives and antidepressants. Prospective trials for some of these conditions, including diabetes [14] and postprostatectomy [15], have been completed. In addition, an open-label study showed that tadalafil 20 mg was effective and well tolerated in a small group of men (N = 49) with ED due to traumatic spinal cord injury [39]. Although retrospective studies have inherent limitations, the results from this 11-study analysis J Sex Med 2005; 2: 517–531
530 strongly support that tadalafil is effective for the treatment of ED in men with various comorbid conditions. Some of the tadalafil 10 mg subgroups contained too few patients to perform statistical significance analyses. Therefore, direct conclusions should not be made for these subgroups, although clear trends were evident. Conclusions
The findings from this 11-study integrated analysis of 2,102 men with ED demonstrate that tadalafil is effective in improving erectile function across a variety of patient demographics and illness characteristics including ED etiology, severity and duration, and comorbid conditions and treatments. Tadalafil also proved to be effective in the subpopulation of men with diabetes mellitus and ED, who are difficult to treat. Corresponding Author: Ronald W. Lewis, MD, Witherington Chair in Urology, Department of Surgery/Chief of Urology, Medical College of Georgia, 1120 15th Street, Room BA-8412, Augusta, GA 30912, USA. Tel: (706) 721-9977; Fax: (706) 721-2548; E-mail: [email protected] Conflict of Interest: Wei Christine Wang, Wei Shen, Daniel J. Walker, David G. Wong, and Sanjeev Ahuja are employees of Eli Lilly and Company. References
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J Sex Med 2005; 2: 517–531