|Vardenafil (Levitra) for erectile dysfunction: a systematic review and meta-analysis of clinical trial reports
|Markou S, Perimenis P, Gyftopoulos K, Athanasopoulos A, Barbalias G
This review assessed the safety and efficacy of vardenafil, compared with placebo, for erectile dysfunction (ED). The authors concluded that vardenafil is superior to placebo in the treatment of symptoms of ED, although more research is required on its effectiveness and safety in different groups of patients. The authors' conclusions appear to be supported by the evidence presented, but the reliability of them is unclear.
To assess the efficacy and safety of vardenafil in the treatment of male erectile dysfunction (ED).
MEDLINE, EMBASE, CINAHL, Current Contents and the Cochrane Library were searched (from January 2001 to November 2003), as were the proceedings of the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medical Products; the search terms were reported. In addition, the Science Citation Index was used for frequently cited papers, conference proceedings and other relevant publications were searched, the bibliographies of relevant papers were checked and experts were contacted.
Study designs of evaluations included in the review
Randomised controlled trials (RCTs) of at least 12 weeks' duration were eligible for inclusion.
Specific interventions included in the review
Trials comparing vardenafil with placebo were eligible for inclusion. Most of the included trials used a fixed dose, with treatment arms of 5, 10 or 20 mg. Two trials used a flexible dose starting with 10 mg. The duration of treatment was 12 weeks in most studies; two studies had a longer treatment duration (26 weeks).
Participants included in the review
Trials of men with ED were eligible for inclusion. Most of the included trials were of white, general population groups with single trials of diabetic men, men with radical retropubic prostactectomy and men with sildenafil nonresponse histories. The most common co-morbid conditions were hypertension, diabetes mellitus and depression.
Outcomes assessed in the review
Trials were included if they used all of the following outcome assessments: the erectile function domain of the International Index of Erectile Function questionnaire (EF-IIEF), Sexual Encounter Profile-Question (Q2. Were you able to insert your penis in your partner's vagina?), Sexual Encounter Profile (Q3. Did your erection last long enough for you to have successful intercourse?) and the Global Assessment Question (GAQ; Has the treatment you have been taking over the past 4 weeks improved your erections?). The first three outcomes were used as the primary measures of efficacy. Adverse events and withdrawals associated with the treatment were also measured.
How were decisions on the relevance of primary studies made?
Two reviewers independently assessed studies for eligibility, with any disagreements resolved by consensus.
Assessment of study quality
Trials were assessed for appropriateness of randomisation and blinding, description of withdrawals and drop-outs, and the use of intent-to-treat analysis. Two reviewers independently evaluated study quality.
Two reviewers independently extracted the data. For continuous outcomes, the weighted mean difference (WMD) and 95% confidence interval (CI) were estimated for individual studies; the weighted relative risk and 95% CI were calculated for dichotomous outcomes. For adverse events and withdrawals, the percentage of men achieving each outcome according to treatment was calculated, along with the weighted relative risk and 95% CIs.
Methods of synthesis
How were the studies combined?
For each of the outcomes of interest, the trials were pooled in a meta-analysis using a random-effects model.
How were differences between studies investigated?
The trials were pooled according to the dose of vardenafil used (5, 10, 20 mg and flexible dose). Statistical heterogeneity was assessed using a significance level of P less than 0.01.
Results of the review
Nine RCTs (6,809 men in total) were included.
Eight trials reported that they were randomised and double-blind, though only two reported the method of randomisation. None reported whether there was concealment of treatment allocation, and only one provided details of blinding. Six described withdrawals and drop-outs, and eight described results based on an intention-to-treat principle (although the latter was reported to be inadequately described and applied).
All doses of vardenafil led to statistically significant improvements in the EF-IIEF domain score in comparison with placebo. The WMD was 5.06 (95% CI: 3.67, 6.45) for a 5-mg dose, 6.16 (95% CI: 5.25, 7.07) for a 10-mg dose, 6.91 (95% CI: 6.11, 7.70) for a 20-mg dose, and 7.45 (95% CI: 3.97, 10.92) for a flexible dose. There was no evidence of statistically significant heterogeneity (P=0.11). The findings were similar for the other two primary outcomes, with vardenafil showing a significant improvement when compared with placebo: there was a 26% (95% CI: 22.89, 29.11) increase in the success rate for penetration and a 29.8% (95% CI: 26.47, 33.06) increase in the success rate for maintaining erection. The P-values from the tests of heterogeneity (P=0.05 and P=0.06, respectively) were above the cut-off point for significance, as defined by the authors. There was also a significant benefit with vardenafil over placebo for the secondary outcome GAQ. There was evidence of statistical heterogeneity for this outcome.
There was no statistically significant association between vardenafil and serious cardiovascular events or death. Vardenafil was associated with a higher rate of treatment-emergent adverse events, with headache, flushing, rhinitis-sinusitis and dyspepsia occurring at least twice as often. All adverse effects were more frequent at higher doses, compared with placebo, with incidence rates higher in the flexible-dose studies than in the fixed-dose studies. Discontinuations were greater with vardenafil than with placebo.
In the broad population of men with ED, vardenafil safely and consistently improved all aspects of erectile functioning assessed after 12 weeks.
The review addressed a clear research question using defined inclusion criteria. A range of databases was searched and appropriate attempts were made to identify unpublished studies. Appropriate procedures were used to minimise the possibility of error and bias in the review. Study quality was assessed and reported. Relevant participant characteristics were presented, although four of the trials were only available as abstracts and, therefore, relevant details were not available from all of the studies. It was unclear whether the trials only available as abstracts were completed trials. Statistical heterogeneity was assessed, but only for all drug doses combined. Where there was evidence of statistical heterogeneity, possible causes were not investigated or discussed. The authors' conclusions appear to follow from the evidence presented, although the reliability of them is unclear given the concerns about the lack of detail on the participants and the heterogeneity.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors highlighted several important areas for future research. In particular, the efficacy of vardenifil according to the etiology of ED, baseline severity, patient age and prior use of sildenafil; the consistency of efficacy beyond 12 weeks; and its efficacy compared with other active treatments.
Markou S, Perimenis P, Gyftopoulos K, Athanasopoulos A, Barbalias G. Vardenafil (Levitra) for erectile dysfunction: a systematic review and meta-analysis of clinical trial reports International Journal of Impotence Research 2004; 16(6): 470-478
Subject indexing assigned by NLM
3',5'-Cyclic-GMP Phosphodiesterases; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction /drug therapy; Humans; Imidazoles /adverse effects /therapeutic use; MEDLINE; Male; Penile Erection; Phosphodiesterase Inhibitors /therapeutic use; Phosphoric Diester Hydrolases; Piperazines /adverse effects /therapeutic use; Placebos; Randomized Controlled Trials as Topic; Sulfones; Treatment Outcome; Triazines
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.