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Qualitative Synthesis. Vardenafil (any dose, fixed dose, flexible dose) versus placebo






Vardenafil (any dose, fixed dose, flexible dose) versus placebo. This section presents results derived from 21 placebo-controlled trials that compared the efficacy and harms profile of vardenafil (any dose) to that of placebo.180184, 189, 191201, 203206One trial190 that explored a dose-response effect of vardenafil, without using a placebo arm, is reviewed in a later section (vardenafil dose 1 versus vardenafil dose 2).

Harms. Of the 21 trials, harms-related data were reported in all but one.180 Therefore, this section describes harms reported in 20 trials.181184, 189, 191201, 203206

Any all-cause adverse events. This outcome was reported in eight trials, where it was shown that the incidence of any adverse events (number of patients with one or more adverse event), 182184, 189, 191, 193, 200, 203 was higher (either numerically or with statistical significance) in vardenafil groups (regardless of vardenafil dose or dose regimen) than in placebo groups. The proportions of patients with one or more adverse event in vardenafil groups across the trials ranged from about 27 percent (10 mg dose)182 to 74 percent (20 mg dose).189 The corresponding proportion for the placebo groups ranged from about 17 percent200 to 52 percent.189

Specific adverse events. In general, vardenafil was described as well tolerated. Most adverse events were reported as mild or moderate in nature and followed a profile similar to that seen in other medications of the PDE-5 class (e.g. sildenafil, tadalafil). Most commonly, patients in the vardenafil arms experienced headache, flushing, rhinitis, and dyspepsia.

Withdrawals due to adverse events. Two200, 206 of the 20 trials181184, 189, 191201, 203206 did not report the proportion of withdrawals due to adverse events. Overall, the rate of withdrawals due to adverse events (i.e., the proportion of patients) invardenafil and placebo-treated groups of patients were numerically similar. The withdrawal rate in vardenafil groups across the 18 trials181184, 189, 191199, 201, 203205 ranged from 0 percent193, 195, 198 to 5 percent.192 The corresponding rate for the placebo-treated patients ranged from 0 percent193, 195, 203 to 6 percent.189 Some of the reported specific events leading to the withdrawals were myocardial infarction, proctalgia, aortic bifurcation graft, 212 abnormal liver enzyme levels, 182, 192 myalgia, flushing, 181, 182nausea, 192 headache, 181, 191, 192 kidney calculus, 192 abnormal vision, and rhinitis.181

Serious adverse events. The absence or occurrence of serious adverse events could not be ascertained for three trials.189, 199, 206The specific serious adverse events observed across the trials in patients after random assignment to vardenafil therapy were: skin ulcer, 198 reflux disease, 198 unstable angina, 197 myocardial infarction, 198, 201 syncope and encephalitis198 aortic bifurcation, 201facial palsy, and appendicitis.182 Serious adverse events that occurred in 10 trials were not specified.181, 183, 184, 191, 192, 194, 196, 203205 In three trials193, 195, 200 reportedly no serious adverse events occurred. In general, judging from the results of these trials, there were no obvious numerical or statistical differences in the occurrence of serious adverse events between patients randomly assigned to receive vardenafil and those assigned to placebo.

Vardenafil (fixed dose: 5 mg, 10 mg, 20 mg, 40 mg) versus placebo. In 11 trials vardenafil was administered at a fixed dose (5 mg, 10 mg, 20 mg, and/or 40 mg).180183, 189, 192195, 198, 205

The results of all trials demonstrated statistically significant improvements for patients who received vardenafil (5 mg, 10 mg or 20 mg) compared with those treated with placebo after 12 weeks of treatment (or longer followup) with respect to the mean IIEF scores for the “EF domain, ”181183, 189, 192, 194, 198, 205 IIEF-Q3/Q4, 189, 194 SEP-Q2/Q3, 181, 182, 192, 198, 205 GAQ-Q1, 181, 182, 189, 192, 194 and the mean IIEF scores for the domains of “Intercourse Satisfaction, ” “Overall Satisfaction, ” “Sexual Desire, ” and “Orgasmic Function.”183, 194

Results obtained from two trials193, 195 showed a statistically significant increase in the mean duration (in minutes) of penile tip/base rigidity (> 60 percent) in patients randomly assigned to receive vardenafil at a dose of 10 mg, 195 20 mg, 193, 195 or 40 mg, 193 as compared with those randomly assigned to receive placebo.

In one trial, 180 patients treated with vardenafil (20 mg), in comparison with those treated with placebo, experienced a statistically significant improvement in endothelial function measured by the degree of brachial artery flow-mediated dilation (13.0 percent versus 10.7 percent).

The beneficial effects of vardenafil use relative to that of placebo observed in trials of homogeneous clinical groups such as diabetes, 181, 205 nerve-sparing retropubic prostatectomy, 183 and no previous ED treatment180 were consistent with those of other trials conducted in participants with ED and a wide spectrum of diseases.182, 189, 192195, 198

Treatment efficacy subgroup analyses (i.e., stratified efficacy results) were reported for five trials with respect to the origin of ED, 180, 194 baseline severity of ED, 182, 192, 194 age groups, 194 and previous sildenafil use.194, 198 The results of these analyses indicated numerically greater improvements associated with milder forms of ED, 192, 194 no previous use of sildenafil (i.e., sildenafil-naï ve patients), 198 and arteriogenic ED (versus organic nonarterial or psychogenic ED).180 In one of these trials, 194 the degree of improvement in IIEF “EF” domain scores was not modified by age, previous sildenafil use or the origin of ED (organic, mixed, or psychogenic).

Vardenafil (flexible dose: 5 mg- 10 mg- 20 mg) versus placebo. Ten trials administered vardenafil with a flexible daily dose (5 mg, 10 mg, 20 mg).184, 191, 196, 197, 199201, 203, 204, 206 The results of all trials demonstrated statistically significant improvements for patients receiving a flexible dose of vardenafil compared with those treated with placebo after 12 weeks of treatment (or longer followup) with respect to the mean IIEF scores for “EF domain, ”184, 191, 197, 199201, 203, 204, 206 IIEF-Q3/Q4, 200, 206 SEP-Q2/Q3, 184, 191, 196, 197, 199201, 203, 204 and GAQ-Q1.184, 191, 196, 199201, 203 Statistically significant improvements in vardenafil-treated patients, relative to those on placebo, were also observed with respect to mean scores for the following IIEF domains: “Intercourse Satisfaction, ” “Overall Satisfaction, ” “Orgasmic Function”199, 200 and/or “Sexual Desire.”199, 204

In four trials, 184, 201, 203, 204 at followup after 12 weeks of treatment, a statistically significant greater proportion of patients with an IIEF “EF” domain score ≥ 26 was found in groups treated with vardenafil compared with those who received placebo.

The relative beneficial effects of vardenafil use with respect to the above-mentioned outcomes observed in trials of homogeneous clinical groups, such as patients with diabetes, 204 renal transplant, 206 untreated mild major depressive disorder, 199 or arterial hypertension, 196 as well as sildenafil nonresponders184 and sildenafil- naï ve patients201, 204 were consistent with those of other trials conducted in participants with ED and a wide spectrum of diseases.191, 197, 200, 203

Treatment efficacy subgroup analysis (i.e., stratified efficacy results) was reported for only one trial191 with respect to dose-sequence, in which patients who received a stable dose of 10 mg vardenafil over 12 weeks experienced greater improvements on the mean scores for IIEF “EF domain, ” SEP-Q2/Q3, and the proportion for GAQ-Q1 compared with those who gradually increased their vardenafil dose to 20 mg over the followup of 8 weeks.

Vardenafil dose 1 versus vardenafil dose 2. There were 10 trials with two or more dose-specific arms of vardenafil.181, 183, 189, 190, 192195, 198, 205 None of the trials were designed to compare flexible and fixed dosage regimens of vardenafil.

Harms. Any all-cause adverse events.

In seven183, 189, 190, 192, 193, 195, 205 of the 10 dose-response studies, 181, 183, 189, 190, 192195, 198, 205 the incidence of any adverse events was shown to be numerically dose-dependent, increasing with a higher dose. In one multicenter North American study, for example, after 26 weeks of treatment with 5 mg, 10 mg, or 20 mg of vardenafil or placebo 19, 33, 42 and 7 percent of patients, respectively, experienced at least one adverse event.192 In a trial of similar design of 12 weeks' duration, these proportions were 57, 63, 74, and 52 percent, respectively.189 The similar trend was observed in a trial that compared 20 mg and 40 mg doses of vardenafil (47.6 versus 60.9 percent, respectively).193 Statistical test results for these differences were not reported.

Specific adverse events. The most frequently observed adverse events in the 10 trials were headache, flushing, dyspepsia, or rhinitis. In one trial, 190 eight and 13 patients developed visual disturbance(s) in the 10 mg and 20 mg groups, respectively. In another trial, 189 two patients (one patient in each 5 mg and 20 mg groups) were observed to have visual disturbances (sensory, abnormal vision, and brightening).

Withdrawals due to adverse events. In three trials, 193, 195, 198 none of the patients treated with vardenafil withdrew because of adverse events. For the remaining seven trials, 181, 183, 189, 190, 192, 194, 205 the rate of withdrawals was numerically similar between treatment arms using 10 mg versus 20 mg of vardenafil.181, 183, 189, 190, 192, 194, 205

Serious adverse events. There was no apparent numerical or statistically significant difference in the occurrence of serious adverse events across the treatment arms of various doses of vardenafil. For example, one trial reported 4, 1, and 1.4 percent of patients with at least one serious adverse event in 5 mg, 10 mg, and 20 mg vardenafil groups, respectively.194 In another study, the corresponding proportions of patients with at least one serious adverse event were 5, 3, and 4 percent.192 Four deaths were reported during one trial; 190 one death resulted from suicide (10 mg group), while the other three (in the 20 mg group) occurred after myocardial infarction, coronary angioplasty, and ischemic cardiomyopathy. None of the deaths was attributed to the effects of vardenafil.

Efficacy. In three trials, 189, 192, 194 at 12 weeks after randomization, a dose-related effect of vardenafil with respect to the mean IIEF “EF” domain score was observed. Specifically, patients in either 10 mg or 20 mg vardenafil groups had statistically significant higher mean IIEF “EF” domain scores compared with those in the 5 mg vardenafil groups. Although for five trials189, 190, 192, 194, 198the differences in the mean IIEF “EF” domain scores observed between the 10 mg and 20 mg were not statistically significant, patients receiving 20 mg of vardenafil had numerically greater scores than those receiving 10 mg vardenafil.

In two trials, 181, 205 patients treated with 20 mg had statistically significantly higher mean IIEF “EF” domain scores compared with those treated with 10 mg vardenafil: 19.0 versus 17.1181 and 22.9 versus 21.8.205 In another trial, 183 the mean IIEF “EF” domain score was similar for patients receiving 10 mg and 20 mg of vardenafil (7.7 versus 7.2, respectively).

After 12 weeks of treatment, there was a numerical increase (a statistically nonsignificant improvement) in the mean scores of IIEF-Q3/Q4189, 194 and SEP-Q2/Q3181, 190, 192 across the three doses of vardenafil (5 mg versus 10 mg versus 20 mg), the highest being observed in the 20 mg group. For the mean SEP-Q2/Q3, one trial205 demonstrated a statistically significant difference between the two doses of vardenafil (10 mg and 20 mg) in favor of the 20 mg dose.

In one trial, 194 the proportion of participants with improved erections (i.e., who answered “yes” to GAQ-Q1) was shown to be statistically significantly greater in the 20 mg versus 5 mg (80 versus 66 percent, p < 0.01). Results from two other trials189, 192demonstrated trends of a numerical increase in the rate of improved erections across 5 mg, 10 mg, and 20 mg doses of vardenafil. The highest proportion of patients with improved erections was observed in the 20 mg groups (range 80.7–86.4 percent).189, 192 In another trial, 181 the proportion of participants with improved erections was higher in participants who received 20 mg compared with those who received 10 mg of vardenafil (72 versus 57 percent, p < 0.03).

In one trial, 193 the difference in the mean change of the duration of penile rigidity (> 60 percent) between the 20 mg and 40 mg doses of vardenafil was not statistically significant (42.9 versus 49.3).


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