Vardenafil rescue rates of sildenafil nonresponders: Objective assessment of 327 patients with erectile dysfunction

ADULT UROLOGY

VARDENAFIL RESCUE RATES OF SILDENAFIL NONRESPONDERS: OBJECTIVE ASSESSMENT OF 327 PATIENTS WITH ERECTILE DYSFUNCTION THEODORE E. BRISSON, GREGORY A. BRODERICK, DAVID D. THIEL, MICHAEL G. HECKMAN, AND DAVID M. PINKSTAFF

ABSTRACT Objectives. To prospectively investigate whether vardenafil can effectively treat patients for whom sildenafil (100 mg) has failed. The introduction of two new oral phosphodiesterase type 5 inhibitors (tadalafil and vardenafil) raises the question of whether the new agents will permit us to treat sildenafil nonresponders with another oral agent. Methods. Patients were seen at one institution during a 5-year period. A total of 327 patients complaining of sildenafil-refractory erectile dysfunction underwent intracavernous pharmacologic injection and color duplex Doppler ultrasonography. Subsequently 59 of these men tried vardenafil home dosing. Results. Of the 327 men in whom sildenafil failed, 16% were younger than 50, 21% were 51 to 60, 34% were 61 to 70, and 28% were older than 70 years. The Doppler diagnoses were arterial insufficiency in 154 (47%), mixed vascular insufficiency in 73 (22%), and cavernous venous occlusive disease in 57 (17%). Forty-three men (13%) had normal erectile responses to prostaglandin E1 (10 to 20 ␮g). Of the 59 men who tried vardenafil, 19% were younger than 50, 17% were 51 to 60, 40% were 61 to 70, and 23% were older than 70 years. The Doppler diagnoses were arterial insufficiency in 28 (42%), mixed vascular insufficiency in 10 (19%), and cavernous venous occlusive disease in 15 (29%). Six men (8%) had normal erectile responses to prostaglandin E1. Only 7 (12%) of the 59 men reported that home vardenafil dosing resulted in successful intercourse. Conclusions. An appropriate diagnostic evaluation and subsequent treatment algorithm have yet to be established for those for whom phosphodiesterase type 5 inhibitors fail. We found that most sildenafil nonresponders had severe arterial insufficiency and were older, with 62% older than 60 years. Our preliminary experience suggests that only a small percentage (12%) of sildenafil nonresponders can be salvaged with vardenafil. UROLOGY 68: 397–401, 2006. © 2006 Elsevier Inc.

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rectile dysfunction (ED) is a common urologic problem affecting as many as 30 million men in the United States.1 Epidemiologic data have suggested that its prevalence will only increase with an aging society. The Massachusetts Male Aging Study showed an increase in the risk of severe ED of 5% to 15% and an increase in the risk of mild ED G. A. Broderick is a study investigator partially funded by Antigenics, GlaxoSmithKline, Lilly/ICOS, and Ortho-Urology/Johnson & Johnson. From the Department of Urology, Mayo Clinic Jacksonville, Jacksonville, Florida Reprint requests: Gregory A. Broderick, M.D., Department of Urology, Mayo Clinic Jacksonville, 3 East Davis Building, 4500 San Pablo Road, Jacksonville, FL 32224. E-mail: broderick. [email protected] Submitted: November 9, 2005, accepted (with revisions): March 7, 2006 © 2006 ELSEVIER INC. ALL RIGHTS RESERVED

of 17% to 34% between 40 and 70 years of age.2 This increased risk is believed to result from normal aging with exacerbation by underlying comorbidities such as cardiovascular disease and diabetes mellitus. The Cologne Male Survey also demonstrated that ED is often associated with chronic diseases and that a steep age-related increase in the prevalence of ED exists.3 The introduction of the first oral phosphodiesterase type 5 inhibitor revolutionized the treatment of ED. No longer were patients limited only to the option of cumbersome and invasive pharmacologic measures or surgery. The early clinical trials with sildenafil showed a remarkably high efficacy rate compared with placebo.4,5 Seven years of postmarket data have confirmed this high efficacy rate.6 Not all men with ED, however, have been effec0090-4295/06/$32.00 doi:10.1016/j.urology.2006.03.005 397

tively treated with sildenafil. Urologists are increasingly confronted with patients who have tried and discontinued use of first-line oral therapy with sildenafil at maximal dosing (100 mg). The reasons for discontinuation are multiple, but the most common is a lack of efficacy.7–9 To date, no consensus opinion has been reached on a diagnostic or treatment algorithm. Recently, several reports have argued that many of the sildenafil nonresponders can be rescued with re-education followed by rechallenge.10 –13 Given the availability of two other oral phosphodiesterase type 5 inhibitors (tadalafil and vardenafil), the urologist must decide whether to treat these patients empirically with a second oral agent. No study has been published comparing vardenafil and sildenafil, but some data have suggested that a significant number of these men can be rescued with vardenafil. The Patient Response with Vardenafil in Sildenafil Non-Responders (PROVEN) study found that nearly 50% of sildenafil nonresponders had significant improvement in their erectile function with vardenafil.14 To evaluate this relationship further, we prospectively evaluated 327 men with color duplex Doppler ultrasonography who presented to our clinic with a complaint of sildenafil-refractory ED. Of the 327 men, 59 subsequently tried vardenafil home dosing. These men were then questioned about the efficacy of vardenafil on subsequent office visits.

TABLE I. Patient characteristics Tried Vardenafil Variable Age (yr) Median Range Diagnosis Arterial insufficiency Mixed disease CVOD Normal Hypertension Diabetes Atherosclerosis Previous smoking Current smoking Cholesterol medication Peyronie’s disease Prior RRP Free testosterone† (⬍9 ng/dL) Total testosterone† (⬍300 ng/dL)

Yes (n ⴝ 59)

No (n ⴝ 268)

P Value*

64 22–80

66 21–89

28 (47) 10 (17) 15 (25) 6 (10) 28 (47) 7 (12) 9 (15) 19 (32) 11 (19) 13 (22)

126 (47) 63 (24) 42 (16) 37 (13) 127 (47) 49 (18) 77 (29) 139 (52) 36 (13) 77 (29)

1.00 0.34 0.034 0.006 0.31 0.34

6 (10) 13 (22) 11 (32)

17 (6) 32 (12) 71 (39)

0.27 0.058 0.57

4 (12)

52 (28)

0.053

0.30

0.90

KEY: CVOD ⫽ cavernous venous occlusive disease; RRP ⫽ radical retropubic prostatectomy. Data in parentheses are percentages. * Characteristics compared between groups with Fisher’s exact test and Wilcoxon’s rank sum test. † Testosterone measurements unavailable for 109 patients.

STATISTICAL ANALYSIS MATERIAL AND METHODS From October 1999 to October 2004, 327 men presented to our clinic with a complaint of sildenafil-refractory ED. A thorough medical and sexual history was obtained. Special attention was paid to potential risk factors for ED. As part of the sexual history, proper use of sildenafil was ascertained. Specifically, patients had to have tried sildenafil at 100-mg dosing on at least four occasions. All of these men underwent penile blood flow study using color duplex Doppler ultrasonography. Patients who went on to try vardenafil were given 10-mg samples and instructed to titrate to 20 mg immediately if unsuccessful. Patients were instructed to try vardenafil on at least four occasions. The following information was collected from the 327 patients in this observational study: patient age, peak systolic velocity (PSV), resistive index, Doppler ultrasound findings, the presence of hypertension, diabetes, or atherosclerosis, history of smoking, current smoking, use of cholesterol medications, Peyronie’s disease, prior radical retropubic prostatectomy, free and total testosterone levels, success of vardenafil, and final disposition. The Doppler ultrasound findings were defined as follows: arterial insufficiency (AI) for a PSV of less than 25 cm/s, mixed vascular insufficiency for a PSV greater than 25 but less than 35 cm/s and a resistive index of less than 0.9, and cavernous venous occlusive disease for a PSV greater than 35 cm/s and an RI of less than 0.9. Special attention was given on Doppler ultrasonography to those men with a history of radical retropubic prostatectomy to look for neurogenic erectile dysfunction. 398

The numeric data are summarized with the sample median and range. Patient characteristics were compared between groups with Wilcoxon’s rank sum test and Fisher’s exact test. An exact binomial confidence interval was used to estimate the proportion of patients in whom sildenafil failed but who were successful with vardenafil. Fisher’s exact test and Wilcoxon’s rank sum test were used to investigate which risk factors might be associated with the response to vardenafil. Logistic regression analysis with forward selection was used to investigate associations between the risk factors and Doppler ultrasound findings. Odds ratios and corresponding 95% confidence intervals were estimated.

RESULTS The patient characteristics for the patients in whom sildenafil failed and did and not try vardenafil are summarized in Table I. The median age between the two groups was not significantly different. In both groups, 60% of the men were older than 60 years. A greater proportion of patients with prior radical retropubic prostatectomy were in the vardenafil group, with a greater proportion of previous smokers, patients with atherosclerosis, and patients with a total testosterone level of less than 300 ng/dL in the group that did not try vardenafil. UROLOGY 68 (2), 2006

TABLE II. Patient characteristics stratified by success with vardenfil Variable Age (yr) Median Range Diagnosis Arterial insufficiency Mixed disease CVOD Normal Hypertension Diabetes Atherosclerosis Previous smoking Current smoking Cholesterol medication Peyronie’s disease Prior RRP Free testosterone† (⬍9 ng/dL) Total testosterone† (⬍300 ng/dL)

Vardenafil Vardenafil Success Failure P (n ⴝ 7) (n ⴝ 52) Value* 61 22–72

64 23–80

2 (29) 0 (0) 1 (14) 4 (57) 2 (29) 2 (29) 0 (0) 4 (57) 3 (43) 4 (57)

26 (50) 10 (19) 14 (27) 2 (4) 26 (52) 5 (10) 9 (17) 15 (29) 8 (15) 9 (17)

0.31

0.023

0.42 0.19 0.58 0.20 0.11 0.036

Tried Vardenafil Disposition

Yes (n ⴝ 59)

No (n ⴝ 268)

34 (58) 1 (2) 7 (12) 0 (0) 6 (10) 11 (18)

141 (53) 25 (9) 24 (9) 40 (15) 8 (3) 30 (11)

Injection therapy MUSE IPP Sildenafil Tadalafil Other

KEY: MUSE ⫽ medicated urethral system for erection; IPP ⫽ inflatable penile prothesis. Data in parentheses are percentages.

TABLE IV. Associations between Doppler result (mixed disease or arterial insufficiency) and ED risk factors Risk Factor

3 (43) 0 (0) 1 (33) 0 (0)

3 (6) 13 (25) 10 (32) 4 (13)

0.018 0.33 1.00 1.00

Abbreviations as in Table I. Data in parentheses are percentages. * Characteristics compared between groups with Fisher’s exact test and Wilcoxon’s rank sum test. † Testosterone measurements unavailable for 25 patients.

Regarding those patients who had a history of radical retropubic prostatectomy, we found that only a small percentage (less than 5%) had a normal response to prostaglandin E, indicating a neurologic basis for their ED. Of the 59 patients who failed sildenafil and then tried vardenafil, only 7 were successful. The patient characteristics according to vardenafil response are summarized in Table II. Patients who were successful with vardenafil had a better Doppler diagnosis than did those who were not (P ⫽ 0.023), took cholesterol medication more often (P ⫽ 0.036), and had a greater incidence of Peyronie’s disease (P ⫽ 0.018). The other patient characteristics showed no evidence of an association with the success of vardenafil. The final disposition of the patients according to vardenafil use is summarized in Table III. The association between the Doppler result and various risk factors of ED is shown in Table IV. The odds ratios corresponded to the increased odds of having a Doppler result of either mixed disease or AI with the presence of the given risk factor. Older patients (P ⬍0.001) and patients with diabetes (P ⫽ 0.020) appeared to have more severe Doppler results. UROLOGY 68 (2), 2006

TABLE III. Final disposition of all patients

Age (10 yr) Hypertension Diabetes Atherosclerosis History of smoking Current smoking Cholesterol medications Peyronie’s disease Prior RRP Free testosterone (⬍9 ng/dL) Total testosterone (⬍300 ng/dL)

Estimated OR* (95% CI)

P Value†

1.76 (1.43–2.17) 1.32 (0.76–2.28) 2.54 (1.17–5.52) 1.27 (0.67–2.40) 1.34 (0.81–2.22) 1.43 (0.69–2.98) 1.56 (0.85–2.84) 0.67 (0.28–1.65) 1.75 (0.79–3.88) 0.82 (0.44–1.56)

⬍0.001 0.32 0.020 0.46 0.26 0.33 0.15 0.39 0.17 0.55

0.84 (0.43–1.67)

0.62

KEY: ED ⫽ erectile dysfunction; OR ⫽ odds ratio; CI ⫽ confidence interval; RRP ⫽ radical retropubic prostatectomy. * Estimated OR for age corresponded to increased risk of mixed disease or arterial insufficiency Doppler result with a 10-year increase in age; all other estimated ORs corresponded to increased risk of mixed disease or arterial insufficiency Doppler result with presence of given characteristic. † From logistic regression models containing age and diabetes.

COMMENT The results of our study have indicated that vardenafil does not have strong efficacy in sildenafil nonresponders. As previously stated, multiple placebo-controlled trials have shown a marked efficacy for sildenafil in men with ED.4 – 6 Multiple placebo-controlled trials have now shown a similar efficacy for vardenafil.15–19 The first at-home study of 580 men with mild to moderate ED showed an overall efficacy of 70% for vardenafil compared with 27% for placebo.15 That study, however, excluded prior sildenafil nonresponders. Subsequent placebo-controlled vardenafil trials included subset analyses of prior sildenafil responders showing similar efficacy to sildenafil-naive patients.17,18 Although multiple studies have demonstrated a greater in vitro potency for vardenafil,20,21 and a molecular basis has explained this increased potency,22,23 no clinical studies have indicated whether this in vitro 399

potency translates to greater clinical efficacy in a head-to-head clinical trial. The PROVEN study was designed to evaluate the efficacy and safety of vardenafil compared with placebo in men with ED previously unresponsive to sildenafil by history. The results showed that vardenafil quadrupled the rate of successful intercourse compared with placebo (46.1% to 10.5%).14 Our experience has not confirmed this high level of efficacy. Only a minority (12%) of our patients found vardenafil effective. It is difficult to explain such a dramatic difference between the efficacy rates, but several points should be made. First, a drug company did not sponsor our study. Most of the published studies involving the use of phosphodiesterase type 5 inhibitors have been sponsored by one of the pharmaceutical companies. This level of involvement raises the potential for conflict of interest in reporting the results. Second, as noted in the editorial comment following the PROVEN study, a third arm of the study using sildenafil would have eliminated the potential bias of simply being enrolled in such a rigorous study. Our experience more likely represents the conditions in a community urologist practice. Third, the patients in our study were older than those included in most published studies, and most had several medical risk factors. Giuliano et al.24 demonstrated in a retrospective pooled analysis that vardenafil efficacy did decrease slightly with increasing age. The investigators believed that this decrease resulted from an increase in comorbidities in the elderly. Our analysis showed that for every 10-year increase in age, the patients had a statistically significant increase in the likelihood of having AI or mixed vascular disease on the penile blood flow study (Table IV). Multiple epidemiologic studies have confirmed the increasing incidence and severity of ED with age.2,3 Finally, the classification of sildenafil nonresponders deserves some attention. A number of studies have suggested that sildenafil nonresponders can be rescued with re-education.10 –13 Undoubtedly, an increase in the response rate can be seen with additional patient counseling. We tried to eliminate this possibility of bias as much as possible by taking a thorough medical and sexual history. If we believed the dosing had been improper, the patient was re-educated and sent for another trial before undergoing additional diagnostic workup. In the PROVEN study, no patients were rechallenged with sildenafil. The strength of our study was that all our patients had undergone penile blood flow studies. Most other studies involving sildenafil nonresponders have relied solely on questionnaires. One half of our patients had AI, with an average PSV of 19.3 cm/s. Murad Basar et al.25 found that patients 400

with severe AI (defined as PSV of less than 20 cm/s) had a significantly lower response rate to sildenafil than did patients with mild AI (PSV 26 to 30 cm/s) or moderate AI (PSV 21 to 25 cm/s). Mulhall et al.26 used Doppler penile blood flow data to correlate the sildenafil response. When patients were stratified as having AI, venous insufficiency, or mixed insufficiency, the sildenafil response rate was 65%, 25%, and 6%, respectively. Finally, Wespes et al.27 demonstrated that most sildenafil nonresponders have vascular abnormalities on penile blood flow study, as well as atrophy of cavernous smooth muscle on penile biopsy. Our study would have been strengthened by randomization with a placebo arm, but when we initially started evaluating patients, no other oral agents were available. The purpose of keeping such detailed records on the first patients was to clarify the diagnostic algorithm for sildenafil nonresponders further. Although some have advocated pharmacologic testing with duplex Doppler ultrasonography for all patients presenting with ED, we believe our results justify the use of this test for sildenafil nonresponders.28 A patient presenting with sildenafil failure should first have a thorough history and physical examination. If evidence is found of improper sildenafil dosing, he should be rechallenged. If no such evidence exists, he should undergo a penile blood flow study. Our series has confirmed that patients with a history of diabetes mellitus or smoking have a greatly increased risk of having abnormal penile blood flow study findings.29 If the blood flow study indicates severe AI or mixed disease, he should be counseled that vardenafil is not likely to help his ED. Most of our patients in this situation ultimately required more invasive surgical or pharmacologic interventions (Table IV). A normal result on the penile blood flow study indicates possible psychogenic ED that may be responsive to a trial of a second oral agent. CONCLUSIONS Most sildenafil nonresponders were older and had multiple medical risk factors for ED. Men for whom sildenafil fails should optimally undergo a diagnostic evaluation before triage to another medical therapy. In this cohort of sildenafil nonresponders, vardenafil was not successful in treating their ED. A placebo-controlled study with vardenafil and sildenafil arms would help to definitively answer the question as to whether sildenafil nonresponders can be rescued by vardenafil. REFERENCES 1. NIH Consensus Development Panel on Impotence: NIH Consensus Conference: impotence. JAMA 270: 83–90, 1993. UROLOGY 68 (2), 2006

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