Erectile Dysfunction (ED) European Urology - Extended Duration of Efficacy of Vardenafil When Taken 8 Hours Before Intercourse: A Randomized, Double-Blind, Placebo-Controlled Study | European Urology - Extended Duration of Efficacy of Vardenafil When Taken 8 Hours Before Intercourse: A Randomized, Double-Blind, Placebo-Controlled Study |
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Volume 50, Issue 5, Pages 1086-1095 (November 2006) 1. Introduction - It has been estimated that >150 million men worldwide experience erectile dysfunction (ED) and that its prevalence is likely to rise with the ageing population [1], [2]. ED has a detrimental impact on quality of life, self-esteem and personal relationships [3], [4], [5], [6]. Oral phosphodiesterase type 5 (PDE5) inhibitors increase levels of cyclic guanosine monophosphate, thereby increasing cavernosal tumescence and rigidity, and are considered first-line treatments for ED [7], [8], [9]. Vardenafil has demonstrated efficacy and tolerability in a broad population of men with ED and in those with traditionally difficult-to-treat ED in both fixed and flexibly dosed studies [10], [11], [12], [13], [14], [15], [16]; a recent review confirms that the trial results are consistent with clinical experience [17]. In the multinational Men's Attitudes to Life Events and Sexuality (MALES) study, 69% of men could not predict sexual activity >30min in advance [18]. Similar findings (71%) were reported by partners of men with ED in the Female Experience of Men's Attitudes to Life Events and Sexuality (FEMALES) study [19]. However, analysis of pooled clinical trial data found that even when instructed to take vardenafil 1hour before intercourse, some patients attempted sex several hours later [20]. For many couples, even after manifestation of ED, timing of sexual activities remains flexible and unplanned rather than a scheduled event. Any PDE5 inhibitor that could provide a wide time frame for achieving successful sexual intercourse, within 1hour and lasting many hours after taking the medication, would be likely to meet more couples’ expectations and needs, thereby increasing acceptance and treatment continuation. The duration of such a time frame would need to extend for a period that has practical meaning and to reflect the fact that 90% of couples engage in sexual activity over the period of one night. Vardenafil has previously demonstrated a rapid onset of action, within 10minutes postdose in some men [21]. A pooled retrospective analysis provided evidence of efficacy up to 8–12hours postdose [20]. Our study investigated prospectively whether vardenafil had an extended duration of action, at least for 8hours after dosing. 2. Methods 2.1. Study design This international, multicentre, randomized, double-blind, placebo-controlled, parallel-group study was conducted at 31 centres in the United States, Germany, Canada, Australia, Austria, Brazil, Greece, South Korea, Mexico, Sweden, Singapore and Turkey. During a 4-week, treatment-free, run-in period, patients had to have experienced unsuccessful sexual intercourse on ≥50% of attempts to qualify for study entry. Patients were randomized to 10 weeks of treatment with flexible-dose vardenafil or placebo. The starting dose was 10mg; thereafter, the dose could be titrated to 5 or 20mg, on the basis of response and tolerability at weeks 2 and 6. Patients were instructed to take study medication, without regard to food, 8hours before attempting intercourse. One tablet was to be taken as needed with no more than one dose per day. Patients were advised to attempt sexual intercourse at least once between each study visit (weeks 2, 6 and 10). Patients recorded in diaries the date and time that (1) study medication was taken and (2) sexual activity was attempted, and answered questions about erections and attempts at sexual activity. Study medication compliance was monitored by noting discrepancies between diary entries and the number of unused tablets returned at each study visit. 2.2. Patients Eligible patients were men with ED for >6 months according to the National Institutes of Health Consensus Statement (the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance); in a heterosexual relationship; and aged ≥18 years. Patients had a score of ≥5 and <26 on the International Index of Erectile Function-Erectile Function (IIEF-EF) domain at randomization. Exclusion criteria included presence of penile anatomic abnormalities that could significantly impair erectile function; primary hypoactive sexual desire; spinal cord injury; history of surgical prostatectomy (excluding transurethral resection of the prostate); retinitis pigmentosa; history of positive test for hepatitis B surface antigen or hepatitis C; history of moderate/severe hepatic impairment; clinically significant chronic haematological disease that could lead to priapism; bleeding disorder; unstable angina pectoris; history of myocardial infarction, stroke or life-threatening arrhythmia within previous 6 months; uncontrolled atrial fibrillation/flutter at screening; resting hypo- (<90mmHg) or hypertension (>170mmHg); New York Heart Association class III or IV heart failure; symptomatic postural hypotension within 6 months of screening; use of nitrates or nitric oxide donors, antiandrogens, androgens, α-blockers and anticoagulants (other than antiplatelet agents); use of vardenafil within 30 days of screening or any treatment for ED within 7 days of screening or during the study; use of potent inhibitors of cytochrome P-450 3A4; presence of abnormal laboratory values (low serum total testosterone level; elevated serum creatinine or aminotransferases); poorly controlled diabetes (HbA1c >12%); history of unresponsiveness to other PDE5 inhibitor treatments or known hypersensitivity to vardenafil. 2.3. Treatment outcomes and their analysis The primary measurement of efficacy was patient diary responses to Sexual Encounter Profile Question 3 (SEP3). Secondary efficacy measurements were SEP2, IIEF-EF domain score (sum of scores from questions 1–5 and 15), Global Assessment Question (GAQ), Global Confidence Question (GCQ) and Erection Quality Scale (EQS) [22] total score. Patients were instructed to take medication 8hours before attempting intercourse; attempts that fell into an assigned-time window of 6–10hours postdose were included in the 8-hour efficacy analyses. This ±2-hour window was built into the statistical analyses to ensure that sufficient data were available for meaningful analysis. Information from previous patient diary studies indicated that patients often deviated from specific instructions, and the ±2-hour window thus represents a realistic expectation of patients’ behaviour. The main focus of the SEP data was during weeks 2–10, which represented the period of treatment once patients had the opportunity to titrate their dose if necessary. Success (defined as a positive answer to SEP) rates were calculated first at the per-patient level and then averaged across each treatment group. A ≥18% difference in SEP3 was defined as clinically meaningful, in line with accepted practice and values used in previous studies [23], [24]. This magnitude of contrast represented a difference in treatment response that provided patients with an appreciable relative improvement in ED symptoms. Last observation carried forward (LOCF) was used to account for missing SEP data and was compared with the use of analysis of covariance (ANCOVA) with adjustment for centre and baseline response. IIEF-EF domain score, GAQ, GCQ and EQS were assessed at weeks 6 and 10 or on premature discontinuation (as observed and LOCF for week 10 only). IIEF-EF was compared with the use of ANCOVA with adjustment for centre and baseline IIEF-EF domain score. A 5-point increase on the EF domain was considered a clinically meaningful response [25]. GAQ was analyzed with the use of logistic regression on the basis of responses from week 10 using LOCF data. Adverse-event (AE) and safety monitoring including clinical laboratory tests, vital signs, 12-lead electrocardiograms (ECGs) and physical examinations were undertaken throughout the study. AEs that had been identified in the study protocol as being of particular clinical interest in patients with ED were defined a priori to include angina pectoris, myocardial infarction, stroke, atrial tachycardia, ventricular arrhythmia, syncope, hypotension and visual AEs. 2.4. Statistical considerations The safety population included all patients receiving one or more doses of study drug and who had any postrandomization safety data. The intent-to-treat population included patients within the safety population who had baseline and any postbaseline efficacy data. With a projected screening failure rate of 20% and a postrandomization dropout rate of 25%, 478 patients needed to be screened and 382 randomized to obtain 286 completers. In total, 143 patients per study arm were required to detect a statistically meaningful treatment difference in SEP3 of 18.0 (standard deviation [SD]=40.0) in a mean proportion of successes at 10 weeks with an alpha level of 0.0125 and 90% power. A Bonferroni approach was used to control the overall type I error rate associated with testing multiple hypotheses: SEP3 (primary), SEP2, IIEF-EF domain and GAQ. Demonstration of superiority depended on achieving both a clinically meaningful difference and statistical significance between treatments. Each of the primary comparisons of interest was assessed on its own clinical and statistical merits. 2.5. Ethics Ethics committees or institutional review boards approved the study protocol and subsequent protocol amendment. All patients provided signed written, informed consent. The study was conducted in accordance with regulatory standards of Good Clinical Practice and the Declaration of Helsinki (1996). 3. Results 3.1. Patients Of the 483 patients screened, 383 were randomized to treatment with vardenafil (n=194) or placebo (n=189). Fig. 1 shows the disposition of patients at study entry. A higher proportion of patients in the placebo group discontinued from the study, compared with the vardenafil group (16% vs 9%), primarily because of insufficient efficacy and withdrawal of consent. Baseline patient characteristics were similar between treatment groups (Table 1). Most patients (75%) were Caucasian and diagnosed with moderate or severe ED (66%).
Fig. 1. Patient disposition and reasons for withdrawal.
3.2. DosingTotal exposure to study drug was greater in the vardenafil group, compared with the placebo group. The mean (SD) number of doses in the placebo group was 22.5 (14.91) taken over 59.5 (16.2) days; 28.3 (14.81) doses in the vardenafil group were taken over 63.6 (13.2) days. At week 2, 94% of patients receiving placebo and 75% receiving vardenafil had their initial dose of study medication increased from 10 to 20mg. At week 6, most patients in each treatment group remained on the same dose as the previous 4 weeks (placebo, 96%; vardenafil, 89%). 3.3. EfficacyPatients treated with vardenafil achieved a clinically meaningful (≥18%) and statistically significant greater least-squares (LS) mean per-patient SEP3 success rate over weeks 2–10 compared with patients receiving placebo: 69% vs 34%; p<0.001 (Fig. 2). SEP3 success rate was maintained across the 6–10-hour postdose time interval over weeks 2–10 (Fig. 3A). Further data analysis (including the initial 2-week titration phase) showed that the superiority of vardenafil over placebo was evident from the week 2 assessment (weeks 0–2: 52% vs 27%; p<0.001) and was maintained over the entire treatment phase (Table 2). ;)
Fig. 3. Overall mean success rates during weeks 2–10 (the period after the initial titration phase) for (1) maintaining an erection that led to successful sexual intercourse (SEP3) and (2) inserting the penis into the partner's vagina (SEP2) at hourly intervals 6–10hours postdose. SEP=Sexual Encounter Profile Question.
Patients treated with vardenafil achieved a clinically meaningful (≥18%) and statistically significant greater LS mean per-patient SEP2 success rate over weeks 2–10 compared with patients receiving placebo: 81% vs 51%; p<0.001 (Fig. 2). SEP2 success rate was maintained across the 6–10-hour postdose time interval (Fig. 3B). Further data analysis (including the initial 2-week titration phase) showed that the superiority of vardenafil over placebo was evident from week 2 (weeks 0–2, 74% vs 48%; p<0.001) and was maintained over the 10-week treatment phase (Table 2). At week 10 (LOCF), vardenafil-treated patients achieved clinically meaningful (≥5 points) and statistically significant greater LS mean IIEF-EF domain scores compared with placebo-treated patients (22.8 vs 14.9; p<0.001) (Fig. 4). Superiority of vardenafil over placebo was evident at the weeks 2–6 assessment (p<0.001) and was maintained over the 10-week treatment phase. A significantly higher proportion of patients in the vardenafil group returned to normal erectile function (defined as IIEF-EF ≥26), compared with placebo (50% vs 11%; p<0.001; LOCF).
In response to the GAQ, a higher proportion of patients on vardenafil compared with placebo stated at week 10 (LOCF) that treatment over the previous 4 weeks had improved their erections (77% vs 27%; p<0.001) (Fig. 5). Superiority of vardenafil over placebo was evident by week 6 (weeks 2–6, 75% vs 28%; p<0.001) and was maintained over the 10-week treatment phase. Vardenafil-treated patients achieved a greater improvement in self-confidence (based on GCQ scores) by week 6 (weeks 2–6, 3.50 vs 2.54; p<0.001) that was sustained until week 10 (Table 3). Moreover, EQS total scores demonstrated superior erection quality with vardenafil, compared with placebo by week 6 (weeks 2–6, 35.40 vs 19.57; p<0.001), which was sustained until week 10 (Table 3).
Fig. 5. Percentage of patients with a positive response to the GAQ (“Has the treatment you have been taking over the last 4 weeks improved your erections? (Y/N)”) after the initial titration phase at weeks 2–6, 6–10 and week 10 LOCF (intent-to-treat population). GAQ=Global Assessment Question; LOCF=last observation carried forward.
3.4. SafetyVardenafil was generally well tolerated. Fewer than half of the patients in each treatment group had any treatment-emergent AEs during the study (placebo, 22%; vardenafil, 39%). Most treatment-emergent AEs were of mild or moderate intensity: Only eight patients in the vardenafil group (4%) and none in the placebo group experienced serious AEs. These AEs included flushing, headache, hypoaesthesia, hypotension, muscle cramp (all were considered related to study medication and resolved); and arthralgia, back pain, diarrhoea, intervertebral disc protrusion and lethargy (none was related to study medication). The incidence of drug-related, treatment-emergent AEs was 26% in the vardenafil group and 5% in the placebo group (Table 4). This finding was primarily due to the higher incidence among vardenafil-treated patients of drug-related headache, flushing and nasal congestion, commonly reported AEs with PDE5 inhibitors.
No deaths or nonfatal serious AEs occurred during the study. Two patients (one in each treatment group) had an AE that led to discontinuation. The patient who discontinued from the placebo group reported headache, fatigue, pain and pyrexia but had not taken the study drug before these AEs occurred. The patient who discontinued from vardenafil 10mg experienced hypotension, which was considered severe and treatment related, and resolved on discontinuation of treatment. There were no clinically relevant findings in laboratory evaluations, vital signs or ECG assessments in either treatment group. 4. DiscussionThis study provides the first prospectively generated evidence for the extended duration of action of flexibly dosed vardenafil in men with ED when taken 8hours before intercourse and supports previous findings from retrospective studies. Vardenafil-treated patients achieved statistically significant improvements in all primary (SEP3) and secondary efficacy end points (SEP2, GAQ, IIEF-EF domain score, GCQ and EQS), compared with placebo.In this study, patients were instructed to initiate sexual intercourse 8hours after taking vardenafil or placebo. This time frame was selected to better quantify the effectiveness of vardenafil at extended time intervals postadministration. Previous studies have examined the efficacy rates of vardenafil at extended time intervals in which to achieve successful sexual intercourse. For example, a retrospective analysis of two randomized, double-blind, fixed-dose studies of vardenafil (5, 10 or 20mg/d) in men with ED demonstrated that vardenafil was statistically superior to placebo irrespective of when couples choose to initiate sexual activity after dosing, from ≤15minutes up to 8–12hours postdose [20]. Furthermore, a 12-week, open-label study of fixed-dose vardenafil (10mg) in men with ED for >6 months found that SEP3 success rates improved from within 30minutes of taking vardenafil up to 12hours postmedication [26]. In a recent open-label study, vardenafil was effective (SEP3 success rate, 77%) when taken 15minutes to 4hours before intercourse [27]. The findings of the current study add to our knowledge of the extended time frame in which vardenafil would prove to be efficacious. Previously shown to have a rapid onset of action as early as 10minutes postdose [21], our prospective, controlled trial showed that the efficacy of vardenafil extends up to at least 8hours postdose, which allows couples the freedom to engage in sexual activities within this extended time frame. It should be noted that confining our study design and analysis to patients starting sexual intercourse 8hours postdose precludes determination of the full extent of the duration of action of vardenafil and highlights the need for further studies to investigate longer time intervals. As with all duration of action studies, determination of patients’ compliance with starting intercourse at the times reported is wholly dependent on their diary entries. Molecular pharmacology studies have shown that vardenafil has greater in vitro potency for PDE5 enzyme inhibition, compared with other PDE5 inhibitors [28]. Furthermore, vardenafil was found to bind more rapidly to PDE5 and dissociate more slowly than sildenafil or tadalafil [29]. These binding characteristics may explain the rapid onset and extended duration of action of vardenafil. A preclinical study of vardenafil in conscious rabbits found significant erectile effects after 7hours (four times the half-life in rabbits) [30]. If these preclinical findings can be extrapolated to humans (half-life, 4–5hours), then improvements in erectile function may be achievable beyond the 8-hour postdose observed here. In this study, vardenafil was generally well tolerated: The most common AEs related to treatment were headache, flushing and nasal congestion. These AEs are consistent with previous vardenafil studies and are commonly reported among the PDE5 inhibitor class [10], [11], [12], [13], [14], [15]. 5. Conclusion This prospective study confirms the efficacy and tolerability of vardenafil found in previous retrospective studies. The new data in this study showing efficacy of vardenafil at least 8hours after dosing, which covers approximately the course of a whole night, may provide couples with considerably more flexibility in their sexual activities. Conflicts of interest This research was supported by the Bayer HealthCare Corporation Pharmaceutical Division, West Haven, CT, and GlaxoSmithKline, Research Triangle Park, NC, USA. Editorial CommentKnowledge of the efficacy, duration of action and side effects of a medication plays an important role in the patient–physician discussions on medical treatment options. It also guides health professionals in assessing the achievement of therapeutic goals which, in turn, will determine the level of patient satisfaction with a given treatment. Several studies have discussed the duration of efficacy of the three existing PDE5 inhibitors for the treatment of erectile dysfunction since their introduction. This issue takes on special importance, especially in an era when patients seek medications that do not interfere with spontaneity and afford flexibility in the timing of their sexual activity. This well-designed prospective, double blind, placebo-controlled study demonstrates for the first time the efficacy of vardenafil at eight hours after ingestion of the medication. Although the pharmacokinetic data indicate that the T 1/2 is 2.6–3.7hours for sildenafil, 17.5hours for tadalafil and 3.9hours for vardenafil, and that the respective duration of efficacy is up to 12, 36, and 14hours [1], knowing the exact duration of efficacy for each medication would be important information for the physician and patient during the decision-making process. Several independent studies have shown that the duration of action of various drugs has no major impact upon the final decision on drug preference [2], [3]. It is entirely understandable, however, that pharmaceutical companies will emphasize the extended action of their own product since this characteristics translates into its affording more “flexibility” of timing of the patient's sexual activity [1], [2], [3]. This study was entirely supported by the pharmaceutical company that produces vardenafil, and the statistical analysis of the data was performed by the company as well. These facts inevitably raise some questions about non-medical vested interests. Having said that, the authors are to be congratulated for gathering, interpreting and presenting this useful information. No doubt there will be more studies, hopefully independent ones, which will shed more light on this important subject. References31. [1]. EAU guidelines on erectile dysfunction: an update. Eur Urol. 2006;49:806–815.32. [2]. Prescribing all phosphodiesterase 5 inhibitors to a patient with erectile dysfunction – a realistic and feasible option in everyday clinical practice – outcomes of a simple treatment regime. Eur Urol. 2006;49:900–907. 33. [3]. Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int. 2005;96:257–280. Editorial CommentKonstantinos HatzimouratidisPhosphodiesterase type 5 inhibitors (PDE5i) are today the first treatment option for erectile dysfunction (ED) of both physicians and patients. The selection of the appropriate drug for each patient remains a dilemma, as all PDE5i have proven efficacy and excellent safety profile [1]. Therefore, pharmacokinetic differences may play a key role in patients’ selection, based on their specific needs and sexual life profile [2]. Applying such patient-centered approach, physicians have to inform patients on specific characteristics of each PDE5i. Initial reports, based on PDE5i plasma half-life, characterized sildenafil and vardenafil as short acting drugs, with duration of action lasting about 4hours; tadalafil on the other hand, was considered as long acting and efficacious for up to 24hours. On the contrary to those initial reports, clinical trials have demonstrated that tadalafil is efficacious for up to 36hours [3]. Despite the clinical experience, which suggested that the so called short acting PDE5i are efficacious for a much longer period of time, no methodologically sound studies have been published to support such clinical observations [4]. This paper is the first publication that assesses the efficacy of vardenafil 6–10hours after dosing; In a well designed, randomized, double-blind, placebo-controlled, flexible-dose study, the authors found that vardenafil-treated patients achieved statistically significant improvements in all primary (SEP3) and secondary efficacy end points (SEP2, GAQ, IIEF-EF domain score, GCQ and EQS) compared with placebo. Safety profile, as expected, was consistent with previous vardenafil studies. What is the meaning of such data in everyday clinical practice? The up to 10hours duration of vardenafil's action offers to the patients a wider therapeutic window with sufficient time after dosing to attempt sexual intercourse, that may decrease considerably sexual encounter-related anxiety, both for the patient and his partner. Such characteristics may increase treatment satisfaction, improving acceptance and adherence to treatment. Physicians must be aware of these data and properly inform their patients. References 34. [1]. EAU guidelines on erectile dysfunction: an update. Eur Urol. 2006;49:806–815. 35. [2]. A comparative review of the options for treatment of erectile dysfunction: which treatment for which patient?. Drugs. 2005;65:1621–1650.36. [3]. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003;62:121–125. 37. [4]. Efficacy of sildenafil citrate at 12 hours after dosing: re-exploring the therapeutic window. Eur Urol. 2004;46:357–360. 1. McKinlay JB. The worldwide prevalence and epidemiology of erectile dysfunction. Int J Impot Res. 2000;12:S6–S11. 15. Stief C, Porst H, Sáenz de Tejada I, Ulbrich E, Beneke Mfor the Vardenafil Study Group. Sustained efficacy and tolerability with vardenafil over 2 years of treatment in men with erectile dysfunction. Int J Clin Pract. 2004;58:230–239. 30. Bischoff E. Vardenafil preclinical trial data: potency, pharmacodynamics, pharmacokinetics, and adverse events. Int J Impot Res. 2004;16:S34–S37.
Accepted 18 May 2006 published online 6 June 2006.
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