ORIGINAL ARTICLE Post-marketing surveillance study of the efficacy and safety of vardenafil among patients with erectile dysfunction in primary care

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1 (2007) 19, & 2007 Nature Publishing Group All rights reserved /07 $ ORIGINAL ARTICLE Post-marketing surveillance study of the efficacy and safety of vardenafil among patients with erectile dysfunction in primary care CM Kim 1, YS Kim 2, S Sunwoo 2, B Cho 3, M Rho 4, YJ Yang 5, CH Kim 6, HC Shin 7, SY Lee 8, DH Kim 9 and Korea Post-Marketing Surveillance Research Group 1 Department of Family Medicine, Catholic University College of Medicine, Uijeongbu, Korea; 2 Department of Family Medicine, University of Ulsan College of Medicine, Seoul, Korea; 3 Department of Family Medicine, Seoul National University College of Medicine, Seoul, Korea; 4 Dr Rho s Family Medicine Clinic, Seoul, Korea; 5 Inje Institute of Advanced Studies, Seoul, Korea; 6 Department of Family Medicine, Medical College of Inje University, Goyang, Korea; 7 Department of Family Medicine, College of Medicine, Sungkyunkwan University, Seoul, Korea; 8 Department of Family Medicine, College of Medicine, Pusan National University, Pusan, Korea and 9 Department of Family Medicine, College of Medicine, Keimyung University, Daegu, Korea To evaluate the safety and efficacy of vardenafil in primary care, we undertook a post-marketing surveillance study in 384 men with erectile dysfunction (ED), enrolled by 22 family physicians in Korea, from July 2004 to August Of the 384 patients enrolled, 343 (89.3%) returned for efficacy assessment and safety evaluation. Among the latter, 279 patients (81.3%) reported that their erectile function improved, 292 (92.1%) showed enhanced IIEF (International Index of Erectile Function)-5 scores and 265 (77.9%) responded that they were very satisfied or satisfied with vardenafil treatment. The most frequent reason for patient satisfaction with vardenafil was erectile potency (62.4%), followed by safety (42.4%), rapid onset (35.3%), adequate duration of efficacy (28.5%) and easy administration (25.9%). A total of 23 adverse events were observed in 18 patients, with the most frequent being hot flushes (3.2%), followed by headache (1.2%), nasal congestion (0.6%), color vision disturbance (0.3%), dizziness (0.3%), dry mouth (0.3%), dyspepsia (0.3%), nausea (0.3%) and diarrhea (0.3%). Only one patient discontinued vardenafil as a direct result of an adverse event. These results suggest that vardenafil prescribed by primary care physicians improved erectile function and was well tolerated by patients with ED. (2007) 19, ; doi: /sj.ijir ; published online 8 February 2007 Keywords: erectile dysfunction; primary care; vardenafil; efficacy; safety Introduction Erectile dysfunction (ED) is a very common health problem, with prevalence rates over 30% among adult men in the community 1,2 and adult male patients in primary care institutions. 3,4 Recently, the International Index of Erectile Function (IIEF), a useful instrument for the detection of ED in Correspondence: Dr YS Kim, Department of Family Medicine, Asan Medical Center, University of Ulsan College of Medicine, Pungnap-2dong, Songpa-gu, Seoul , Korea. youngkim@amc.seoul.kr Received 2 August 2006; revised 2 January 2007; accepted 3 January 2007; published online 8 February 2007 clinical settings, was developed, 5 followed by an abridged, 5-item version of the IIEF (IIEF-5), 6 which may be particularly useful as an initial screening instrument in a primary care setting. In Korea, a version of the IIEF-5 translated into Korean has been used for the diagnosis and severity evaluation of ED since Several phosphodiesterase type 5 (PDE5) inhibitors, including vardenafil, have been developed to treat ED, and most have been prescribed in primary care settings. 8 However, there have been very few studies on the efficacy and safety of vardenafil in the primary care setting. In this post-marketing surveillance study, we investigated the efficacy and safety of vardenafil, and patient satisfaction with its use, using a global assessment questionnaire (GAQ) and the Korean version of the IIEF-5.

2 394 Materials and methods Study subjects A total of 384 consecutive male patients over 20 years old, diagnosed with ED and newly prescribed vardenafil, were enrolled by 22 family physicians in Korea from July 2004 to August Patients with unstable coronary artery disease, those receiving prescribed organic nitrates and those previously treated with vardenafil were excluded. Study design This study was part of a prospective observational study performed after the launch of vardenafil, in which patients were evaluated for efficacy, compliance and occurrence of adverse events 4 and 12 weeks from the start of vardenafil treatment. At each visit, patients were asked about dose, adverse clinical experiences, compliance and reasons for discontinuation, if applicable. For assessment of global efficacy, patients were asked to answer yes or no to the question, Did vardenafil boost your erection capability? We also compared the mean scores on the Korean version of the IIEF-5 at baseline and 12 weeks after treatment. Improvement of erectile function was determined by increases in IIEF-5 scores, which were assorted as 1 3, 4 7 and over 8. For assessment of safety, patients were asked to answer yes or no to the question, Have you experienced any discomfort with vardenafil? In addition, physicians recorded the occurrence of observed and patient-reported adverse events throughout the course of treatment. For assessment of patient satisfaction, patients were asked to answer yes or no to the question, Are you satisfied with vardenafil treatment? If the answer was yes, patients were asked, For what reasons are you satisfied with vardenafil? We suggested five items of reasons for satisfaction without serial numbers in the questionnaire, and informed the patients to select multiple items according to their situation. Basically, each item has equal chance to be selected in the maximum possibility of 100%. Physicians were free to prescribe any dose of vardenafil, in accordance with their customary practice. This reexamination study was approved by the Korea Food and Drug Administration and the Institutional Review Board of the Asan Medical Center, where the coordinating office is located. Questionnaire Using a structured, self-administered questionnaire (I), which included the Korean version of the IIEF-5, patients were asked about their erectile function, demographic characteristics and lifestyles before vardenafil treatment. ED was classified as severe (5 9), moderate (10 13), mild (14 17) and normal (18 25). 6 Demographic characteristics and life style factors evaluated included marital status, educational status, income, alcohol consumption, cigarette smoking and exercise. After vardenafil treatment, patients were again questioned about their erectile function, satisfaction with treatment and reasons for satisfaction using questionnaire (II), which also included the Korean version of the IIEF- 5. There were five items of reasons for satisfaction, which included erectile potency, rapid onset, appropriate duration of sustained effect, safety and easy administration. Data collection and analysis Patients filled out questionnaire (I) at first visit and questionnaire (II) 4 and 12 weeks after starting vardenafil treatment. Patients self-reported compliance and adverse events were reconfirmed by the physician and recorded in the case record form (CRF). Standardized CRFs were completed by the participating physicians, and the completed forms were sent to a coordinating center of the Korea Post- Marketing Surveillance Research Group. Changes in mean scores on the IIEF-5 were analyzed using paired Student s t-tests. Categorical variables were analyzed using w 2 tests. All analyses were carried out on a personal computer using SAS 8e software. Results Patient characteristics The mean age of the 384 patients was 55.1 years, 37.8% were in their 50s, 43.6% were obese (body mass index of 25 kg/m 2 or higher) and 42.3% were current smokers (Table 1). ED was accompanied by hypertension in 45.3%, diabetes in 24.5%, hyperlipidemia in 15.6%, benign prostatic hyperplasia in 9.1%, depression in 3.7% and peripheral artery disease in 3.1% of these patients. Severity of ED was rated as mild in 51.2% of patients, moderate in 31.2% and severe in 17.6%, according to the Korean version of the IIEF-5. A vardenafil dose of 20 mg was used by 65.8% of patients, whereas 32.4% had histories of treatment with other PDE-5 inhibitors (Table 1). Efficacy of vardenafil Of the 384 patients, 41 (10.7%) did not return after their first visit. Of the 343 patients who returned, 279 (81.3%) reported that their erectile function improved after 12 weeks of treatment with vardenafil, including 60.0% of those receiving 5 mg/day, 75.0% of those receiving 10 mg/day and 85.0% of those receiving 20 mg/day (Table 2). Of the 317 patients who answered the IIEF-5 questionnaire, 292 (92.1%) showed increased total scores of IIEF-5, 96 (30.3%) with increases of 1 3, 126 (39.7%) with increases of 4 7 and 70 (22.1%) with increases over 8. The changes in mean IIEF-5 scores from baseline

3 Table 1 Baseline characteristics of 384 male patients with ED Table 2 Efficacy of vardenafil treatment in 343 patients with ED 395 No. % Total 5 mg 10 mg 20 mg Age, years (mean7s.d.) o B X Body mass index (kg/m 2 )(mean7s.d.) p Smoking Nonsmoker Ex-smoker Smoker Medical condition Hypertension Diabetes Hyperlipidemia Prostatic hyperplasia Depression Peripheral artery disease Severity by the Korean version of the IIEF-5 a Mild (X14) Moderate (13 10) Severe (p9) Prior PDE5 b inhibitor use Yes No Abbreviations: ED, erectile dysfunction; IIEF, International Index of erectile function; s.d., standard deviation. a 5-item version of the international index of erectile function. b phosphodiesterase type 5. Note: missing values are excluded. were 3.8, 5.4 and 5.0 for patients taking 5, 10 and 20 mg doses, respectively. The mean scores were significantly increased in the total, 10 and 20 mg groups (Po each). The average number of tablets (mean7s.d.) used in this 12 weeks study was Treatment satisfaction with vardenafil Of the 340 patients who filled out patient satisfaction questionnaires, 265 (77.9%) reported being very satisfied or satisfied with vardenafil treatment. Their satisfaction resulted from erectile potency (62.4%), safety (42.4%), rapid onset (35.3%), appropriate duration of sustained effect (28.5%) and easy administration (25.9%). In addition, physicians reported that they would continue to prescribe vardenafil to about 70% of their patients (Table 3). Adverse events of vardenafil Eighteen patients (5.2%) reported 23 adverse events, none of which was a serious adverse event (Table 3). Most of the reported adverse events were mild and n Improved erectile function by GAQ a, n (%) 279 (81.3) 3 (60.0) 84 (75.0) 192(85.0) Change of IIEF-5 b scores, n (%) c p0 25 (7.9) 1 (20) 11 (11.5) 13 (6.0) (30.3) 2 (40) 24 (25.0) 70 (32.4) (39.7) 1 (20) 34 (35.4) 91 (42.1) X8 70 (22.1) 1 (20) 27 (28.1) 42 (19.5) Mean IIEF-5 scores (mean7s.d.) c Baseline weeks Change from baseline * * * Abbreviations: ED, erectile dysfunction; GAQ, global assessment question; IIEF, International Index of erectile function; s.d., standard deviation. a Global assessment question. b 5-item version of the IIEF. c A total of 26 patients were excluded due to the missing values. *Po by paired t-test. Table 3 ED Outcomes of vardenafil treatment in 343 patients with No. % Patient satisfaction with vardenafil treatment a Yes No Reasons for satisfaction (multiple selection) a Potency Safety Rapid onset Adequate duration of efficacy Easy administration Continuation of vardenafil treatment by physician b Yes No Adverse event Yes No Abbreviations: ED, erectile dysfunction. a Three patients were excluded due to the missing values. b Two physicians did not respond. included facial flushing (3.2%), headache (1.2%), nasal congestion (0.6%), color vision disturbance (0.3%), dizziness (0.3%), dry mouth (0.3%), dyspepsia (0.3%), nausea (0.3%) and diarrhea (0.3%) (Table 4). Only one patient discontinued treatment due to an adverse event (flushing). All adverse events disappeared shortly afterwards, without any additional treatment.

4 396 Table 4 Adverse events reported by 343 patients treated with vardenafil Discussion No. (%) Flushing Headache Nasal congestion Color vision disturbance Dizziness Dry mouth Dyspepsia Nausea Diarrhea Studies of the efficacy of PDE5 inhibitors have generally addressed penetration ability, erectile sustaining capability, erectile stiffness and intercourse satisfaction, as outlined by the IIEF 5 6 and sexual encounter profile questionnaire, 9 and overall erection capacity, using the GAQ. Likewise, in this study, efficacy was evaluated using the GAQ and the Korean version of the IIEF-5. 7 Using the GAQ, we found that the overall efficacy of vardenafil was 81.3%, a result similar to that of the GAQ clinical trial in North America, in which 85% of patients reported positive effects. 10 Our outcome was also similar to that of a clinical trial in Europe, 11 in which 80 86% of men reported overall improvements following vardenafil administration, and to the results of a community practice study, which showed improvements in 92% of men. 12 Our result was also similar to those of sildenafil 8 and tadalafil. 13 The percentages of patients reporting improvements increased relative to the dose of vardenafil, being 60.0, 75.0 and 85.0% in men prescribed 5, 10 and 20 mg/ day vardenafil, respectively. This finding was consistent with earlier studies, in which the percentages of patients showing overall improvement were 65 66, and 80 85% for the 5, 10 and 20 mg/day groups, respectively. 10,14 Of the patients who answered the IIEF-5, 92.1% showed increases in total scores, with 30.3% showing mild increases (1 3), 39.7% showing moderate increases (4 7) and 22.1% showing marked increases (over 8). As the level of severity in the Korean version of IIEF-5 is defined approximately by every score of 4, this score was used to classify increased IIEF-5 scores, thus providing a quantitative evaluation of the efficacy of vardenafil treatment. Total IIEF-5 scores are used not only to determine the severity of ED but also to determine treatment-induced changes. These findings suggest that the IIEF-5 may be a useful tool to compare the efficacy rates among PDE5 inhibitors. 5 In this study, about 32% of subjects were previous PDE5 inhibitor users. PDE5 inhibitors were prescribed before this study by other physicians, who did not participate in this study. In Korea, we do not have a primary care system. Patients are able to visit any physicians or surgeons in private practice and secondary hospitals without any limitations imposed by the government insurance policy. Thus, the majority of prior PDE5 inhibitor users did not have to abandon their previous therapies, but they visited more than one doctor simultaneously under the Korean insurance system. As a result, the efficacy of vardenafil in prior users was not different from that of naive patients in this study. The enrollment of the prior users did not cause any bias results. We also found that 78% of our patients reported being satisfied with vardenafil treatment. The relatively high percentage of satisfaction may be due to a large proportion of the elders in our study subjects whose mean age was 55.1 and about 2/3 of those were 50 years and older. Yoon et al. 15 reported that older men tended to prefer vardenafil and younger men preferred tadalafil. The most frequent reason for satisfaction with vardenafil treatment was erectile potency in present study, followed by safety and rapid onset. These findings were similar to those reported in earlier studies of vardenafil and sildenafil, but they were different from those of tadalafil, in this case the preference was due to a long duration of action The adverse event profile observed in this study reflected the known pharmacologic properties of vardenafil as a selective PDE5 inhibitor and were consistent with previous studies of PDE5 inhibitors. 8,12,13 Our patients reported a lower incidence of adverse events (5.2%) than in other clinical trials of vardenafil in other countries (24 45%). 10,11,18 In these earlier studies, facial flushing and headache were the most commonly reported adverse events, with each having an incidence of 10 22%. 10,11,19 In contrast, we found that only 3.2 and 1.2% of patients experienced flushing and headache, respectively, similar to the results of an earlier trial of vardenafil (1.6 and 3.1%, respectively) 20 and slightly lower than those of sildenafil ( and %, respectively) 8,21 and tadalafil ( and %, respectively). 13,22 The differences in adverse event reporting rates among these trials is largely due to the different methods used for their monitoring. In addition, the majority of patients in our study were suffering from other chronic illnesses or symptoms, which may have masked the adverse effects of vardenafil. Our study had several limitations. First, there was no way to determine accurately how much the placebo effect improved erectile function. Second, because adverse events were measured using a questionnaire administered at a patient s second visit, there was a high likelihood that occurrence of mild adverse events might have been underestimated. Third, some of our patients were

5 lost to follow-up. Despite these limitations, the results of this study provide useful information on the efficacy, safety and patient satisfaction of vardenafil in a primary care setting. In summary, we found that vardenafil was safe, effective and well tolerated in a primary care setting. Patients expressed satisfaction with this agent mainly for the erectile potency, and the incidence of adverse events was quite low, with only one patient discontinuing treatment because of an adverse reaction. Acknowledgments This study is part of a re-examination study of vardenafil, which is supported by a grant from Bayer Korea. References 1 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: Ansong KS, Lewis C, Jenkins P, Bell J. Epidemiology of erectile dysfunction: a community-based study in rural New York State. 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