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Integrated analysis examining first-dose success, success by dose, and maintenance of success among men taking tadalafil for erectile dysfunction
ADULT UROLOGY
INTEGRATED ANALYSIS EXAMINING FIRST-DOSE SUCCESS, SUCCESS BY DOSE, AND MAINTENANCE OF SUCCESS AMONG MEN TAKING TADALAFIL FOR ERECTILE DYSFUNCTION CLAUDE C. SCHULMAN, WEI SHEN, DIANE R. STOTHARD,
AND
HENRY SCHMITT
ABSTRACT Objectives. To examine, in a post-hoc, integrated analysis, the first-dose success, cumulative success by dose, and maintenance of success among men taking tadalafil. Early treatment success is important to men with erectile dysfunction. Methods. In five double-blind, placebo-controlled, 12-week studies, men were randomized to placebo (n ⫽ 308), tadalafil 10 mg (n ⫽ 321), or tadalafil 20 mg (n ⫽ 258) as a fixed dose. The Sexual Encounter Profile (SEP) diary questions assessed success from three perspectives: (a) first-dose success; (b) cumulative proportion of men with first success by dose; and (c) maintenance of success among men with first-dose success. Results. With the first dose, significantly greater proportions of men taking tadalafil 10 and 20 mg versus placebo achieved successful erection (SEP-Q1: 85% and 90% versus 66%, respectively), successful penetration (SEP-Q2: 74% and 79% versus 47%, respectively), successful intercourse (SEP-Q3: 56% and 67% versus 31%, respectively), and were satisfied overall with their sexual experience (SEP-Q5: 36% and 47% versus 15%, respectively; all P ⬍0.001). The proportion of men achieving first success increased with continued dosing, reaching a plateau between doses 4 and 8 at approximately 95% (SEP-Q2), 90% (SEP-Q3), and 81% (SEP-Q5). For men with first-dose success, the subsequent success rate during the 12-week period was significantly greater for men taking tadalafil 10 and 20 mg versus placebo (all P ⬍0.001; SEP-Q2: 85% and 91% versus 75%; and SEP-Q3: 81% and 88% versus 64%, respectively). Conclusions. Most men taking tadalafil achieved successful erection, penetration, and intercourse after one dose and maintained the success over time. Because success increased with continued use, men who do not respond initially should continue treatment to increase the likelihood of treatment success. UROLOGY 64: 783–788, 2004. © 2004 Elsevier Inc.
T
adalafil improves erectile function in men with mild to severe erectile dysfunction (ED)1,2 and exhibits a period of responsiveness for up to 36 hours after taking the dose.2,3 Tadalafil is well tolerated, with the reported adverse events transient and mild or moderate in severity.1,4,5 This study was funded by Lilly ICOS LLC. W. Shen, D. R. Stothard, and H. Schmitt are employees of, and hold stock in, Eli Lilly and Company. From the Department of Urology, University Clinics of Brussels, Brussels, Belgium; Lilly Research Laboratories, Indianapolis, Indiana; and Eli Lilly and Company, Brussels, Belgium Reprint requests: Claude C. Schulman, M.D., Department of Urology, University Clinics of Brussels, Erasmus Hospital, Route de Lennik 808, Brussels B-1070, Belgium Submitted: March 3, 2004, accepted (with revisions): May 24, 2004 © 2004 ELSEVIER INC. ALL RIGHTS RESERVED
Although efficacy and safety are two important characteristics when choosing an ED treatment, the ideal treatment should also be rapidly successful and reliable over time. In addition, improvements in erectile function beyond erection and penetration, such as intercourse success and overall satisfaction with the experience, should be considered when men are treated for ED. Therefore, we performed a post-hoc, integrated analysis of data collected from five randomized, double-blind, placebo-controlled, 12-week studies1 to examine the early treatment success, cumulative success by dose, and maintenance of success over time in men taking tadalafil for ED. MATERIAL AND METHODS STUDY DESIGN An integrated post-hoc analysis was performed on data collected from five randomized, double-blind, placebo-con0090-4295/04/$30.00 doi:10.1016/j.urology.2004.05.046 783
trolled, parallel-group clinical trials with identical designs that were conducted at 74 centers from April 1999 to April 2001. The details of the study design have been previously published.1 In brief, patients were randomly allocated to 12 weeks of treatment with placebo (n ⫽ 308) or tadalafil at fixed doses of 10 mg (n ⫽ 321) or 20 mg (n ⫽ 258). Patients were instructed to self-administer treatment as needed up to once daily before sexual intercourse, with no restrictions on food or alcohol intake or timing of sexual activity.
STUDY POPULATION Men 18 years old or older who had a minimal 3-month history of ED and a steady female partner were eligible to participate. The other details of the inclusion and exclusion criteria have been previously published.1 Prior sildenafil experience was noted for men enrolling in three of the five studies (study codes LVCO, LVDJ, and LVCQ). In these three studies, 320 (54.3%) of the 589 enrolled men had previous experience with sildenafil.
MEASURES The severity of ED was evaluated using the International Index of Erectile Function (IIEF) Erectile Function domain.6,7 The IIEF was self-administered at baseline and at the end of the 12-week period. Patients recorded each sexual attempt and outcome throughout the study in the Sexual Encounter Profile (SEP) diary. The IIEF, SEP-Q2, and SEP-Q3 were coprimary endpoints for the five clinical trials. The post-hoc analyses were based on the responses to SEP-Q1 (“Were you able to achieve at least some erection?”), SEP-Q2 (“Were you able to insert your penis into your partner’s vagina?”), SEP-Q3 (“Did your erection last long enough for you to have successful intercourse?”), and SEP-Q5 (“Were you satisfied overall with the sexual experience?”). Success was analyzed from three perspectives: (a) the proportion of patients achieving success with the first dose for SEP-Q1, SEPQ2, SEP-Q3, and SEP-Q5; (b) the cumulative proportion of patients with first success by dose for SEP-Q2, SEP-Q3, and SEP-Q5; and (c) the subsequent mean proportion of attempts (rate) that were successful in men who had success with the first dose for SEP-Q2 and SEP-Q3. The results were stratified according to age and ED severity (IIEF Erectile Function domain score).
STATISTICAL ANALYSIS For all analyses of SEP data, a hierarchy was established such that if a patient answered “no” to one SEP question, the response to all the following SEP questions related to the same attempt were automatically assigned as “no.” For example, if a patient indicated that he had not been successful for SEP-Q2 (penetration), his answers for SEP-Q3 and SEP-Q5 for that attempt were analyzed as “no,” regardless of how he answered in the diary. Success with the first dose was measured as the proportion of men answering “yes” after the first dose taken after randomization with a valid diary recording. Treatment comparisons were based on Fisher’s exact test. The cumulative proportions of patients with first success by dose were calculated with the Kaplan-Meier method and compared between treatment groups by the log-rank test. Maintenance (reliability) was measured as the rate of successful attempts during the 12 weeks for those patients who achieved success with the first dose and had at least one subsequent attempt. Treatment comparisons were done using the analysis of covariance model. 784
RESULTS PATIENT POPULATION AND DEMOGRAPHICS The demographic and baseline characteristics for the 887 men in the three treatment groups were comparable (Table I). Most men had had ED for more than 1 year, more than one half had organic ED, and the ED was severe in about one third of the men. Hypertension was present in nearly 30% of men, and nearly 20% had diabetes mellitus. Most men (nearly 90%) in the three treatment groups completed the study.1 EFFICACY First Dose. After the first dose, 85% (10 mg) and 90% (20 mg) of all men taking tadalafil achieved a successful erection (SEP-Q1) versus 66% taking placebo (P ⬍0.001, both doses). Successful penetration (SEP-Q2) was achieved by 74% and 79% of those taking 10 mg or 20 mg tadalafil versus 47% taking placebo, successful intercourse (SEP-Q3) by 56% and 67% versus 31%, and overall satisfaction (SEP-Q5) by 36% and 47% versus 15%, respectively (all P ⬍0.001; Fig. 1). In addition, regardless of the severity of ED or age, a significantly greater proportion of men taking 10 and 20 mg tadalafil achieved successful penetration (SEP-Q2) and intercourse (SEP-Q3) compared with those taking placebo (Fig. 2; P ⬍0.001 for all comparisons of tadalafil 10 and 20 mg versus placebo). Men with severe ED were no more or less likely to respond on their first dose. The baseline SEP-Q3 value was 2.2% or 34.5% for men with severe ED or mild-to-moderate ED, respectively. The change from baseline in men with severe ED was 41.8% for men taking 20 mg and 31.8% for men taking 10 mg. The change from baseline in men with mildto-moderate ED was 39.5% for men taking 20 mg and 29.5% for men taking 10 mg. Thus, the magnitude of the change from baseline was similar for both severity groups. Cumulative Success by Dose. Although a significantly greater proportion of men taking tadalafil achieved penetration and intercourse success and were satisfied with their experience on the first dose compared with those taking placebo, we also determined the cumulative proportion of men with first success by dose for SEP-Q2, SEP-Q3, and SEP-Q5 through the first 10 doses (Fig. 3). For all three measures, the cumulative proportion of successful men increased, reaching a plateau between doses 4 and 8 of 95% for SEP-Q2 and 90% for SEP-Q3 and a plateau around dose 8 of 81% for SEP-Q5. Men with mild-to-moderate ED were able to have SEP-Q3 success with fewer doses than men with severe ED. Men with mild-to-moderate ED UROLOGY 64 (4), 2004
TABLE I. Patient demographics and baseline characteristics Tadalafil (mg) Characteristic Age (yr) Mean Range Age ⬎65 yr Duration of ED ⱖ12 mo ED etiology Organic Psychogenic Mixed ED severity* (IIEF EF domain score) Mild (17–25) Moderate (11–16) Severe (1–10) Medical history Hypertension Coronary artery disease Diabetes mellitus Depression
Placebo (n ⴝ 308)
10 (n ⴝ 321)
20 (n ⴝ 258)
59 22–81 84 (27) 276 (90)
58 26–81 96 (30) 280 (87)
59 31–80 84 (33) 239 (93)
185 (60) 29 (9) 94 (31)
215 (67) 20 (6) 86 (27)
136 (53) 27 (11) 95 (37)
98 (32) 74 (24) 114 (37)
113 (35) 84 (26) 107 (33)
122 (47) 51 (20) 72 (28)
93 (30) 24 (8) 70 (23) 15 (5)
90 (28) 18 (6) 69 (22) 15 (5)
72 (28) 24 (9) 47 (18) 16 (6)
KEY: ED ⫽ erectile dysfunction; IIEF ⫽ International Index of Erectile Function; EF ⫽ Erectile Function. Data presented as number of patients, with percentage in parentheses, unless otherwise noted. * Patients were included in study based on history of ED; subsequent assessment of erectile function by IIEF EF domain score at baseline revealed that a small proportion of study participants had a normal EF domain score (26 –30): 20 (6.5%) in placebo, 16 (5.0%) in tadalafil 10 mg, and 13 (5.0%) in tadalafil 20 mg group.
FIGURE 1. SEP diary results after first dose. Results for SEP-Q1, SEP-Q2, SEP-Q3, and SEP-Q5 (erection, penetration, intercourse, and satisfaction, respectively) after first dose of tadalafil 10 mg, tadalafil 20 mg, or placebo.
taking 20 mg had a success rate of 74.4% on their first dose. By dose 4, the cumulative success rate was 92.5%, and by dose 8, the cumulative success rate was only slightly greater at 95.1%, with an overall increase from dose 1 to dose 8 of 20.7%. Men with severe ED taking 20 mg had a success rate of 44.3% on their first dose. By dose 4, the cumulative success rate was 68.4%, and by dose 8, the cumulative success rate was 75.0%, for an overall increase from dose 1 to dose 8 of 30.7%. Thus, the cumulative percentage of successful men with mild-to-moderate ED approached a plateau after four doses, and the cumulative percentage of sucUROLOGY 64 (4), 2004
FIGURE 2. First-dose success by subgroup. Proportion of men achieving (A) successful penetration (SEP-Q2) and (B) successful intercourse (SEP-Q3) on first attempt after first dose of tadalafil determined as stratified by ED severity (IIEF Erectile Function domain score) and age. Numbers below each bar represent number of men in that subgroup (P ⬍0.001 for all comparisons of tadalafil 10 and 20 mg to placebo). 785
FIGURE 3. Cumulative proportion of men achieving first success through the first 10 doses. Cumulative proportions shown for first 10 doses and corresponding 10 attempts. (A) Cumulative proportion of men by dose able to achieve first successful penetration (SEP-Q2); (B) cumulative proportion of men by dose able to achieve first successful intercourse (SEP-Q3); and (C) cumulative proportion of men by dose satisfied with their sexual experience (SEP-Q5).
cessful men with severe ED continued to increase after dose 4, reaching a plateau at dose 8. In addition, a quantitatively larger increase occurred in the cumulative percentage of men with severe ED achieving successful intercourse as they continued to use the drug. However, it should be noted that even after eight doses, the cumulative proportion of men with mild-to-moderate ED who had successful intercourse was 95.1% but the cumulative proportion of men with severe ED who had successful intercourse was 75.0%. Therefore, continued use of tadalafil will increase the likelihood of achieving successful intercourse for all men, but the likelihood of overall success for men with severe ED is less than that for men with mild-tomoderate ED. Maintenance. Among patients who achieved success (SEP-Q2 or SEP-Q3) on their first attempt, the rate of success on subsequent attempts was significantly greater for men taking tadalafil versus men taking placebo (tadalafil 10 and 20 mg versus placebo, P ⬍0.05 for all), regardless of ED severity or patient age (Fig. 4). COMMENT The results of this integrated analysis showed that tadalafil 10 and 20 mg significantly improves erectile function in men after the first dose, regardless of the ED severity or patient age, and that successful treatment with tadalafil is maintained over time. With the first dose, significantly greater proportions of men taking tadalafil 10 and 20 mg versus placebo achieved successful erection, penetration, and intercourse and were satisfied overall with their sexual experience. As the dosing continued, the cumulative proportion of men achieving penetration, intercourse, and satisfaction in786
creased. During the 12-week study, men with success on the first dose were able to maintain that success and the subsequent success rate was significantly greater for men taking tadalafil 10 and 20 mg versus placebo. On the first attempt, up to 67% of men taking tadalafil were able to achieve successful intercourse. These results are similar to those found for the other phosphodiesterase-5 inhibitors, vardenafil and sildenafil.8,9 However, direct comparisons with the studies of men taking sildenafil are limited because the proportion of men reported was a combined value that reflected first-dose success for men taking sildenafil 50 mg and men taking sildenafil 100 mg.9 In the current study, 66% of men taking placebo were able to achieve successful erection on their first dose. However, this compares with 47%, 31%, and 15% of men taking placebo who were able to achieve successful penetration, intercourse, and overall satisfaction, respectively, on their first dose. The apparent effect of placebo on successful erections, perhaps because of optimistic expectations and confidence in the treatment, was not maintained under the more stringent measures of successful penetration, intercourse, and satisfaction. These data also showed that a high success rate for erection, penetration, and intercourse on the first attempt does not necessarily translate into immediate patient satisfaction. The proportion of men satisfied with the sexual experience on the first dose was only 15% for placebo, 36% for tadalafil 10 mg, and 47% for tadalafil 20 mg. As men continued taking tadalafil and making attempts, the cumulative proportion of men who were satisfied with treatment increased from 47% (20 mg) to 74% by dose 4 and 81% by dose UROLOGY 64 (4), 2004
FIGURE 4. Maintenance of success by subgroup. Proportion of subsequent successful attempts made during 12-week study by men who were successful on first attempt stratified by ED severity (IIEF Erectile Function domain score) and age. (A) Successful penetration (SEP-Q2) attempts and (B) successful intercourse (SEPQ3) attempts. Numbers below each bar represent number of men in that group. *P ⱕ0.002. †P ⱕ0.044. P ⬍0.001 for all other comparisons of tadalafil 10 and 20 mg to placebo.
8. Although restoring sexual function is an important first step, it does not immediately restore sexual intimacy.10 Rebuilding a satisfactory relationship after years of failure and sexual avoidance can be difficult.11 However, successful intercourse after a single dose of treatment could positively affect self-confidence, encouraging men to continue treatment, which in turn could help men to rebuild a positive and fulfilling sexual relationship with their partner. Although this analysis did not examine the correlation between improvements in relationship status and improvements in erectile function, future studies on this association will be helpful to understanding the role each plays in overall patient satisfaction with treatment. Previous studies with apomorphine sublingual showed that a “learning curve” of four to six doses was required because of patients’ initial anxiety in resuming sexual relations, as well as the optimal implementation of the therapy.12 Because the proportion of men experiencing success increased as they continued to take tadalafil, especially for men with more severe ED, our results also showed the importance of continuing treatment, even if the UROLOGY 64 (4), 2004
first attempt is not successful. In a study done with sildenafil, the cumulative proportion of successful men increased from 54% on the first dose to 64% on the second, reaching a plateau of 86%.9 Considering that a much greater proportion of men achieve erection compared with the proportion of men who go on to achieve successful intercourse, the increase in the proportion of successful men as they continued to take tadalafil may reflect an increase in the self-confidence obtained from at least achieving a successful erection, a concomitant decrease in anxiety, and the positive emotional effects of that erection on future intercourse attempts. Because sexual function is also related to other parameters, such as the quality of the relationship, spontaneity, and partner satisfaction,11,13,14 the increase in the proportion of men achieving intercourse success after continued dosing may also reflect improvement in the sexual relationship as improvements are made in erection and penetration. Early treatment success may be important in enhancing self-confidence, which in turn will encourage patients to continue treatment and be successful. Because the rate of success was slightly greater for some patients taking tadalafil 20 mg compared with 10 mg, physicians and patients should consider increasing the dose of tadalafil to 20 mg, if preferred, to ensure the greatest likelihood of success. Although the results from this integrated analysis will help patients to realize the full potential of tadalafil, future studies addressing patient satisfaction with ED treatment and quality of life will be meaningful. CONCLUSIONS After taking one dose of tadalafil 10 mg and 20 mg, a large proportion of men achieved successful erection, penetration, and intercourse. Because success increases with continued use, men who do not respond initially should continue treatment to increase the likelihood of treatment success. Among men who had successful penetration and intercourse with their first dose, the maintenance of success over time was high. ACKNOWLEDGMENT. To Christine Wang (Eli Lilly and Company) for her assistance with the statistical analyses. REFERENCES 1. Brock GB, McMahon CG, Chen KK, et al: Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 168: 1332–1336, 2002. 2. Porst H, Padma-Nathan H, Giuliano F, et al: Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 62: 121–126, 2003. 787
3. Eid J-F, Hatzichristou D, Whitaker J, et al: Tadalafil is effective for 36 hours in men with erectile dysfunction—results from an 11 study integrated analysis (abstract). Int J Impot Res 15: S175, 2003. 4. Porst H, Carson C, Kaufman J, et al: Tadalafil is effective in treating mild to severe erectile dysfunction (abstract). Int J Impot Res 15: S49, 2003. 5. Padma-Nathan H, McMurray JG, Pullman WE, et al: On-demand IC351 (Cialis®) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 13: 2–9, 2001. 6. Rosen RC, Riley A, Wagner G, et al: The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 49: 822– 830, 1997. 7. Cappelleri JC, Rosen RC, Smith MD, et al: Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 54: 346 –351, 1999. 8. Montorsi F, Bandel T-J, Eardley I, et al: Vardenafil (Levitra) shows consistent efficacy over time in men with erectile
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dysfunction: a retrospective analysis of two pivotal phase III studies (abstract). Int J Impot Res 15: S21, 2003. 9. McCullough AR, Barada JH, Fawzy A, et al: Achieving treatment optimization with sildenafil citrate (Viagra®) in patients with erectile dysfunction. Urology 60: 28 –38, 2002. 10. Heaton JPW, Hackett G, Savage D, et al: Patient choice is critical in managing erectile dysfunction. Eur Urol Suppl 1: 33–37, 2002. 11. Leiblum SR: After sildenafil: bridging the gap between pharmacologic treatment and satisfying sexual relationships. J Clin Psychiatry 63: 17–22, 2002. 12. Heaton JP, Dean J, and Sleep DJ: Sequential administration enhances the effect of apomorphine SL in men with erectile dysfunction. Int J Impot Res 14: 61– 64, 2002. 13. Hanson-Divers C, Jackson SE, Lue TF, et al: Health outcomes variables important to patients in the treatment of erectile dysfunction. J Urol 159: 1541–1547, 1998. 14. Seftel AD: Challenges in oral therapy for erectile dysfunction. J Androl 23: 729 –736, 2002.
UROLOGY 64 (4), 2004
INTEGRATED ANALYSIS EXAMINING FIRST-DOSE SUCCESS, SUCCESS BY DOSE, AND MAINTENANCE OF SUCCESS AMONG MEN TAKING TADALAFIL FOR ERECTILE DYSFUNCTION CLAUDE C. SCHULMAN, WEI SHEN, DIANE R. STOTHARD,
AND
HENRY SCHMITT
ABSTRACT Objectives. To examine, in a post-hoc, integrated analysis, the first-dose success, cumulative success by dose, and maintenance of success among men taking tadalafil. Early treatment success is important to men with erectile dysfunction. Methods. In five double-blind, placebo-controlled, 12-week studies, men were randomized to placebo (n ⫽ 308), tadalafil 10 mg (n ⫽ 321), or tadalafil 20 mg (n ⫽ 258) as a fixed dose. The Sexual Encounter Profile (SEP) diary questions assessed success from three perspectives: (a) first-dose success; (b) cumulative proportion of men with first success by dose; and (c) maintenance of success among men with first-dose success. Results. With the first dose, significantly greater proportions of men taking tadalafil 10 and 20 mg versus placebo achieved successful erection (SEP-Q1: 85% and 90% versus 66%, respectively), successful penetration (SEP-Q2: 74% and 79% versus 47%, respectively), successful intercourse (SEP-Q3: 56% and 67% versus 31%, respectively), and were satisfied overall with their sexual experience (SEP-Q5: 36% and 47% versus 15%, respectively; all P ⬍0.001). The proportion of men achieving first success increased with continued dosing, reaching a plateau between doses 4 and 8 at approximately 95% (SEP-Q2), 90% (SEP-Q3), and 81% (SEP-Q5). For men with first-dose success, the subsequent success rate during the 12-week period was significantly greater for men taking tadalafil 10 and 20 mg versus placebo (all P ⬍0.001; SEP-Q2: 85% and 91% versus 75%; and SEP-Q3: 81% and 88% versus 64%, respectively). Conclusions. Most men taking tadalafil achieved successful erection, penetration, and intercourse after one dose and maintained the success over time. Because success increased with continued use, men who do not respond initially should continue treatment to increase the likelihood of treatment success. UROLOGY 64: 783–788, 2004. © 2004 Elsevier Inc.
T
adalafil improves erectile function in men with mild to severe erectile dysfunction (ED)1,2 and exhibits a period of responsiveness for up to 36 hours after taking the dose.2,3 Tadalafil is well tolerated, with the reported adverse events transient and mild or moderate in severity.1,4,5 This study was funded by Lilly ICOS LLC. W. Shen, D. R. Stothard, and H. Schmitt are employees of, and hold stock in, Eli Lilly and Company. From the Department of Urology, University Clinics of Brussels, Brussels, Belgium; Lilly Research Laboratories, Indianapolis, Indiana; and Eli Lilly and Company, Brussels, Belgium Reprint requests: Claude C. Schulman, M.D., Department of Urology, University Clinics of Brussels, Erasmus Hospital, Route de Lennik 808, Brussels B-1070, Belgium Submitted: March 3, 2004, accepted (with revisions): May 24, 2004 © 2004 ELSEVIER INC. ALL RIGHTS RESERVED
Although efficacy and safety are two important characteristics when choosing an ED treatment, the ideal treatment should also be rapidly successful and reliable over time. In addition, improvements in erectile function beyond erection and penetration, such as intercourse success and overall satisfaction with the experience, should be considered when men are treated for ED. Therefore, we performed a post-hoc, integrated analysis of data collected from five randomized, double-blind, placebo-controlled, 12-week studies1 to examine the early treatment success, cumulative success by dose, and maintenance of success over time in men taking tadalafil for ED. MATERIAL AND METHODS STUDY DESIGN An integrated post-hoc analysis was performed on data collected from five randomized, double-blind, placebo-con0090-4295/04/$30.00 doi:10.1016/j.urology.2004.05.046 783
trolled, parallel-group clinical trials with identical designs that were conducted at 74 centers from April 1999 to April 2001. The details of the study design have been previously published.1 In brief, patients were randomly allocated to 12 weeks of treatment with placebo (n ⫽ 308) or tadalafil at fixed doses of 10 mg (n ⫽ 321) or 20 mg (n ⫽ 258). Patients were instructed to self-administer treatment as needed up to once daily before sexual intercourse, with no restrictions on food or alcohol intake or timing of sexual activity.
STUDY POPULATION Men 18 years old or older who had a minimal 3-month history of ED and a steady female partner were eligible to participate. The other details of the inclusion and exclusion criteria have been previously published.1 Prior sildenafil experience was noted for men enrolling in three of the five studies (study codes LVCO, LVDJ, and LVCQ). In these three studies, 320 (54.3%) of the 589 enrolled men had previous experience with sildenafil.
MEASURES The severity of ED was evaluated using the International Index of Erectile Function (IIEF) Erectile Function domain.6,7 The IIEF was self-administered at baseline and at the end of the 12-week period. Patients recorded each sexual attempt and outcome throughout the study in the Sexual Encounter Profile (SEP) diary. The IIEF, SEP-Q2, and SEP-Q3 were coprimary endpoints for the five clinical trials. The post-hoc analyses were based on the responses to SEP-Q1 (“Were you able to achieve at least some erection?”), SEP-Q2 (“Were you able to insert your penis into your partner’s vagina?”), SEP-Q3 (“Did your erection last long enough for you to have successful intercourse?”), and SEP-Q5 (“Were you satisfied overall with the sexual experience?”). Success was analyzed from three perspectives: (a) the proportion of patients achieving success with the first dose for SEP-Q1, SEPQ2, SEP-Q3, and SEP-Q5; (b) the cumulative proportion of patients with first success by dose for SEP-Q2, SEP-Q3, and SEP-Q5; and (c) the subsequent mean proportion of attempts (rate) that were successful in men who had success with the first dose for SEP-Q2 and SEP-Q3. The results were stratified according to age and ED severity (IIEF Erectile Function domain score).
STATISTICAL ANALYSIS For all analyses of SEP data, a hierarchy was established such that if a patient answered “no” to one SEP question, the response to all the following SEP questions related to the same attempt were automatically assigned as “no.” For example, if a patient indicated that he had not been successful for SEP-Q2 (penetration), his answers for SEP-Q3 and SEP-Q5 for that attempt were analyzed as “no,” regardless of how he answered in the diary. Success with the first dose was measured as the proportion of men answering “yes” after the first dose taken after randomization with a valid diary recording. Treatment comparisons were based on Fisher’s exact test. The cumulative proportions of patients with first success by dose were calculated with the Kaplan-Meier method and compared between treatment groups by the log-rank test. Maintenance (reliability) was measured as the rate of successful attempts during the 12 weeks for those patients who achieved success with the first dose and had at least one subsequent attempt. Treatment comparisons were done using the analysis of covariance model. 784
RESULTS PATIENT POPULATION AND DEMOGRAPHICS The demographic and baseline characteristics for the 887 men in the three treatment groups were comparable (Table I). Most men had had ED for more than 1 year, more than one half had organic ED, and the ED was severe in about one third of the men. Hypertension was present in nearly 30% of men, and nearly 20% had diabetes mellitus. Most men (nearly 90%) in the three treatment groups completed the study.1 EFFICACY First Dose. After the first dose, 85% (10 mg) and 90% (20 mg) of all men taking tadalafil achieved a successful erection (SEP-Q1) versus 66% taking placebo (P ⬍0.001, both doses). Successful penetration (SEP-Q2) was achieved by 74% and 79% of those taking 10 mg or 20 mg tadalafil versus 47% taking placebo, successful intercourse (SEP-Q3) by 56% and 67% versus 31%, and overall satisfaction (SEP-Q5) by 36% and 47% versus 15%, respectively (all P ⬍0.001; Fig. 1). In addition, regardless of the severity of ED or age, a significantly greater proportion of men taking 10 and 20 mg tadalafil achieved successful penetration (SEP-Q2) and intercourse (SEP-Q3) compared with those taking placebo (Fig. 2; P ⬍0.001 for all comparisons of tadalafil 10 and 20 mg versus placebo). Men with severe ED were no more or less likely to respond on their first dose. The baseline SEP-Q3 value was 2.2% or 34.5% for men with severe ED or mild-to-moderate ED, respectively. The change from baseline in men with severe ED was 41.8% for men taking 20 mg and 31.8% for men taking 10 mg. The change from baseline in men with mildto-moderate ED was 39.5% for men taking 20 mg and 29.5% for men taking 10 mg. Thus, the magnitude of the change from baseline was similar for both severity groups. Cumulative Success by Dose. Although a significantly greater proportion of men taking tadalafil achieved penetration and intercourse success and were satisfied with their experience on the first dose compared with those taking placebo, we also determined the cumulative proportion of men with first success by dose for SEP-Q2, SEP-Q3, and SEP-Q5 through the first 10 doses (Fig. 3). For all three measures, the cumulative proportion of successful men increased, reaching a plateau between doses 4 and 8 of 95% for SEP-Q2 and 90% for SEP-Q3 and a plateau around dose 8 of 81% for SEP-Q5. Men with mild-to-moderate ED were able to have SEP-Q3 success with fewer doses than men with severe ED. Men with mild-to-moderate ED UROLOGY 64 (4), 2004
TABLE I. Patient demographics and baseline characteristics Tadalafil (mg) Characteristic Age (yr) Mean Range Age ⬎65 yr Duration of ED ⱖ12 mo ED etiology Organic Psychogenic Mixed ED severity* (IIEF EF domain score) Mild (17–25) Moderate (11–16) Severe (1–10) Medical history Hypertension Coronary artery disease Diabetes mellitus Depression
Placebo (n ⴝ 308)
10 (n ⴝ 321)
20 (n ⴝ 258)
59 22–81 84 (27) 276 (90)
58 26–81 96 (30) 280 (87)
59 31–80 84 (33) 239 (93)
185 (60) 29 (9) 94 (31)
215 (67) 20 (6) 86 (27)
136 (53) 27 (11) 95 (37)
98 (32) 74 (24) 114 (37)
113 (35) 84 (26) 107 (33)
122 (47) 51 (20) 72 (28)
93 (30) 24 (8) 70 (23) 15 (5)
90 (28) 18 (6) 69 (22) 15 (5)
72 (28) 24 (9) 47 (18) 16 (6)
KEY: ED ⫽ erectile dysfunction; IIEF ⫽ International Index of Erectile Function; EF ⫽ Erectile Function. Data presented as number of patients, with percentage in parentheses, unless otherwise noted. * Patients were included in study based on history of ED; subsequent assessment of erectile function by IIEF EF domain score at baseline revealed that a small proportion of study participants had a normal EF domain score (26 –30): 20 (6.5%) in placebo, 16 (5.0%) in tadalafil 10 mg, and 13 (5.0%) in tadalafil 20 mg group.
FIGURE 1. SEP diary results after first dose. Results for SEP-Q1, SEP-Q2, SEP-Q3, and SEP-Q5 (erection, penetration, intercourse, and satisfaction, respectively) after first dose of tadalafil 10 mg, tadalafil 20 mg, or placebo.
taking 20 mg had a success rate of 74.4% on their first dose. By dose 4, the cumulative success rate was 92.5%, and by dose 8, the cumulative success rate was only slightly greater at 95.1%, with an overall increase from dose 1 to dose 8 of 20.7%. Men with severe ED taking 20 mg had a success rate of 44.3% on their first dose. By dose 4, the cumulative success rate was 68.4%, and by dose 8, the cumulative success rate was 75.0%, for an overall increase from dose 1 to dose 8 of 30.7%. Thus, the cumulative percentage of successful men with mild-to-moderate ED approached a plateau after four doses, and the cumulative percentage of sucUROLOGY 64 (4), 2004
FIGURE 2. First-dose success by subgroup. Proportion of men achieving (A) successful penetration (SEP-Q2) and (B) successful intercourse (SEP-Q3) on first attempt after first dose of tadalafil determined as stratified by ED severity (IIEF Erectile Function domain score) and age. Numbers below each bar represent number of men in that subgroup (P ⬍0.001 for all comparisons of tadalafil 10 and 20 mg to placebo). 785
FIGURE 3. Cumulative proportion of men achieving first success through the first 10 doses. Cumulative proportions shown for first 10 doses and corresponding 10 attempts. (A) Cumulative proportion of men by dose able to achieve first successful penetration (SEP-Q2); (B) cumulative proportion of men by dose able to achieve first successful intercourse (SEP-Q3); and (C) cumulative proportion of men by dose satisfied with their sexual experience (SEP-Q5).
cessful men with severe ED continued to increase after dose 4, reaching a plateau at dose 8. In addition, a quantitatively larger increase occurred in the cumulative percentage of men with severe ED achieving successful intercourse as they continued to use the drug. However, it should be noted that even after eight doses, the cumulative proportion of men with mild-to-moderate ED who had successful intercourse was 95.1% but the cumulative proportion of men with severe ED who had successful intercourse was 75.0%. Therefore, continued use of tadalafil will increase the likelihood of achieving successful intercourse for all men, but the likelihood of overall success for men with severe ED is less than that for men with mild-tomoderate ED. Maintenance. Among patients who achieved success (SEP-Q2 or SEP-Q3) on their first attempt, the rate of success on subsequent attempts was significantly greater for men taking tadalafil versus men taking placebo (tadalafil 10 and 20 mg versus placebo, P ⬍0.05 for all), regardless of ED severity or patient age (Fig. 4). COMMENT The results of this integrated analysis showed that tadalafil 10 and 20 mg significantly improves erectile function in men after the first dose, regardless of the ED severity or patient age, and that successful treatment with tadalafil is maintained over time. With the first dose, significantly greater proportions of men taking tadalafil 10 and 20 mg versus placebo achieved successful erection, penetration, and intercourse and were satisfied overall with their sexual experience. As the dosing continued, the cumulative proportion of men achieving penetration, intercourse, and satisfaction in786
creased. During the 12-week study, men with success on the first dose were able to maintain that success and the subsequent success rate was significantly greater for men taking tadalafil 10 and 20 mg versus placebo. On the first attempt, up to 67% of men taking tadalafil were able to achieve successful intercourse. These results are similar to those found for the other phosphodiesterase-5 inhibitors, vardenafil and sildenafil.8,9 However, direct comparisons with the studies of men taking sildenafil are limited because the proportion of men reported was a combined value that reflected first-dose success for men taking sildenafil 50 mg and men taking sildenafil 100 mg.9 In the current study, 66% of men taking placebo were able to achieve successful erection on their first dose. However, this compares with 47%, 31%, and 15% of men taking placebo who were able to achieve successful penetration, intercourse, and overall satisfaction, respectively, on their first dose. The apparent effect of placebo on successful erections, perhaps because of optimistic expectations and confidence in the treatment, was not maintained under the more stringent measures of successful penetration, intercourse, and satisfaction. These data also showed that a high success rate for erection, penetration, and intercourse on the first attempt does not necessarily translate into immediate patient satisfaction. The proportion of men satisfied with the sexual experience on the first dose was only 15% for placebo, 36% for tadalafil 10 mg, and 47% for tadalafil 20 mg. As men continued taking tadalafil and making attempts, the cumulative proportion of men who were satisfied with treatment increased from 47% (20 mg) to 74% by dose 4 and 81% by dose UROLOGY 64 (4), 2004
FIGURE 4. Maintenance of success by subgroup. Proportion of subsequent successful attempts made during 12-week study by men who were successful on first attempt stratified by ED severity (IIEF Erectile Function domain score) and age. (A) Successful penetration (SEP-Q2) attempts and (B) successful intercourse (SEPQ3) attempts. Numbers below each bar represent number of men in that group. *P ⱕ0.002. †P ⱕ0.044. P ⬍0.001 for all other comparisons of tadalafil 10 and 20 mg to placebo.
8. Although restoring sexual function is an important first step, it does not immediately restore sexual intimacy.10 Rebuilding a satisfactory relationship after years of failure and sexual avoidance can be difficult.11 However, successful intercourse after a single dose of treatment could positively affect self-confidence, encouraging men to continue treatment, which in turn could help men to rebuild a positive and fulfilling sexual relationship with their partner. Although this analysis did not examine the correlation between improvements in relationship status and improvements in erectile function, future studies on this association will be helpful to understanding the role each plays in overall patient satisfaction with treatment. Previous studies with apomorphine sublingual showed that a “learning curve” of four to six doses was required because of patients’ initial anxiety in resuming sexual relations, as well as the optimal implementation of the therapy.12 Because the proportion of men experiencing success increased as they continued to take tadalafil, especially for men with more severe ED, our results also showed the importance of continuing treatment, even if the UROLOGY 64 (4), 2004
first attempt is not successful. In a study done with sildenafil, the cumulative proportion of successful men increased from 54% on the first dose to 64% on the second, reaching a plateau of 86%.9 Considering that a much greater proportion of men achieve erection compared with the proportion of men who go on to achieve successful intercourse, the increase in the proportion of successful men as they continued to take tadalafil may reflect an increase in the self-confidence obtained from at least achieving a successful erection, a concomitant decrease in anxiety, and the positive emotional effects of that erection on future intercourse attempts. Because sexual function is also related to other parameters, such as the quality of the relationship, spontaneity, and partner satisfaction,11,13,14 the increase in the proportion of men achieving intercourse success after continued dosing may also reflect improvement in the sexual relationship as improvements are made in erection and penetration. Early treatment success may be important in enhancing self-confidence, which in turn will encourage patients to continue treatment and be successful. Because the rate of success was slightly greater for some patients taking tadalafil 20 mg compared with 10 mg, physicians and patients should consider increasing the dose of tadalafil to 20 mg, if preferred, to ensure the greatest likelihood of success. Although the results from this integrated analysis will help patients to realize the full potential of tadalafil, future studies addressing patient satisfaction with ED treatment and quality of life will be meaningful. CONCLUSIONS After taking one dose of tadalafil 10 mg and 20 mg, a large proportion of men achieved successful erection, penetration, and intercourse. Because success increases with continued use, men who do not respond initially should continue treatment to increase the likelihood of treatment success. Among men who had successful penetration and intercourse with their first dose, the maintenance of success over time was high. ACKNOWLEDGMENT. To Christine Wang (Eli Lilly and Company) for her assistance with the statistical analyses. REFERENCES 1. Brock GB, McMahon CG, Chen KK, et al: Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol 168: 1332–1336, 2002. 2. Porst H, Padma-Nathan H, Giuliano F, et al: Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 62: 121–126, 2003. 787
3. Eid J-F, Hatzichristou D, Whitaker J, et al: Tadalafil is effective for 36 hours in men with erectile dysfunction—results from an 11 study integrated analysis (abstract). Int J Impot Res 15: S175, 2003. 4. Porst H, Carson C, Kaufman J, et al: Tadalafil is effective in treating mild to severe erectile dysfunction (abstract). Int J Impot Res 15: S49, 2003. 5. Padma-Nathan H, McMurray JG, Pullman WE, et al: On-demand IC351 (Cialis®) enhances erectile function in patients with erectile dysfunction. Int J Impot Res 13: 2–9, 2001. 6. Rosen RC, Riley A, Wagner G, et al: The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 49: 822– 830, 1997. 7. Cappelleri JC, Rosen RC, Smith MD, et al: Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Urology 54: 346 –351, 1999. 8. Montorsi F, Bandel T-J, Eardley I, et al: Vardenafil (Levitra) shows consistent efficacy over time in men with erectile
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dysfunction: a retrospective analysis of two pivotal phase III studies (abstract). Int J Impot Res 15: S21, 2003. 9. McCullough AR, Barada JH, Fawzy A, et al: Achieving treatment optimization with sildenafil citrate (Viagra®) in patients with erectile dysfunction. Urology 60: 28 –38, 2002. 10. Heaton JPW, Hackett G, Savage D, et al: Patient choice is critical in managing erectile dysfunction. Eur Urol Suppl 1: 33–37, 2002. 11. Leiblum SR: After sildenafil: bridging the gap between pharmacologic treatment and satisfying sexual relationships. J Clin Psychiatry 63: 17–22, 2002. 12. Heaton JP, Dean J, and Sleep DJ: Sequential administration enhances the effect of apomorphine SL in men with erectile dysfunction. Int J Impot Res 14: 61– 64, 2002. 13. Hanson-Divers C, Jackson SE, Lue TF, et al: Health outcomes variables important to patients in the treatment of erectile dysfunction. J Urol 159: 1541–1547, 1998. 14. Seftel AD: Challenges in oral therapy for erectile dysfunction. J Androl 23: 729 –736, 2002.
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