|
Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis |
Tsertsvadze A, Fink HA, Yazdi F, MacDonald R, Bella AJ, Ansari MT, Garritty C, Soares-Weiser K, Daniel R, Sampson M, Fox S, Moher D, Wilt T |
|
|
CRD summary This generally well-conducted review concluded that oral PDE-5 inhibitors improved erectile function and had similar efficacy and safety profiles; the efficacy and value of hormone treatments remained uncertain. Despite some limitations, the review included a large number of studies and the direction of effect seemed to be consistent across studies and analyses. The conclusions are likely to be reliable. Authors' objectives To evaluate the efficacy and harms of oral phosphodiesterase-5 (PDE-5) inhibitors and hormonal treatments for erectile dysfunction, and assess the effect of measuring serum hormone levels on treatment outcomes for erectile dysfunction. Searching MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, AMED, and SCOPUS were searched for English-language studies; dates of the searches spanned 1966 to April 2009. Search terms were reported. Reference lists of retrieved articles were scanned. Study selection RCTs (randomised controlled trials) of pharmacologic treatments compared to each other or placebo in men aged 18 years or over with erectile dysfunction were eligible for inclusion if they reported prevalence of hypogonadism and/or hyperprolactinaemia. Crossover trials were included if pre-crossover data were available. Any study design was included to assess the risk of non-arteritic anterior ischaemic optic neuropathy in PDE-5 users. Included studies evaluated sildenafil, vardenafil, tadalafil, mirodenafil, udenafil and hormonal treatments (oral, intramuscular, gel, cream or patch testosterone); drug regimens varied across studies. Most studies had a follow-up of 12 weeks or less. The included men were heterosexual. Mean age was 18 to 69 years, where reported. Most trials excluded men with penile/testicular deformity, cardiovascular comorbidity, prostate cancer, HIV/AIDS, hepatic/renal disease, spinal cord injuries and psychiatric disorders. Several vardenafil and tadalafil trials excluded men who were non-responsive to sildenafil treatment. Previous treatment for erectile dysfunction was poorly reported (range 0% to 100%). Two independent reviewers selected studies for the review; differences were resolved by consensus. Assessment of study quality The quality of the RCTs was assessed using the Jadad scale (maximum score 5). Adequacy of allocation concealment was assessed using Schulz and Grimes. Studies of serum hormone levels were assessed using criteria that related to patient spectrum, description of the index test, availability of clinical data and withdrawals from the QUADAS tool (quality assessment of studies of diagnostic accuracy included in systematic reviews). Data extraction Data were extracted on the incidence of successful sexual intercourse attempts and the ability to maintain an erection from patient diaries/event logs or responses to relevant domains on assessment scales. The incidence of adverse events and withdrawals due to adverse events were also extracted. Relative risks (RR) for binary outcomes and mean differences for continuous outcomes, with 95% confidence intervals (CI), were calculated. Two independent reviewers extracted data for the review. Methods of synthesis Pooled relative risks and weighted mean differences (WMD) with 95% CIs were calculated using a DerSimonian and Laird random effects model. Generic inverse variance was used to combine groups from trials with more than one treatment arm to avoid double counting of placebo patients. Statistical heterogeneity was investigated using the X2 and I2 tests. A priori subgroups were defined (severity and cause of disorder, drug choice, dose, duration of treatment and comorbid conditions) and sensitivity analyses conducted. Trials with no events were only included in the assessment of adverse events. Publication bias was assessed using funnel plots and Egger's test. Results of the review One hundred and thirty RCTs evaluated PDE-5 inhibitors (approximately 35,000 men, range 12 to 4,262). Fifteen RCTs evaluated hormonal treatments (1,183 men, range 9 to 406). Ten case reports, two case series (12 men) and one retrospective cohort study (4,157,357 men) reported the incidence of anterior ischaemic optic neuropathy. Forty four trials scored 4 or 5 on the Jadad scale; adequacy of allocation concealment and blinding method was unclear in 85.0% (allocation concealment) and 60.0% (blinding method) of trials. Statistically significant asymmetry was noted in the funnel plots for sildenafil (p<0.001), vardenafil (p=0.003), and tadalafil (p<0.001). Results for the tests for heterogeneity were not reported. All PDE-5 inhibitors consistently improved erectile functioning compared to placebo: 73% to 88% of men who received PDE-5 inhibitors experienced improved erectile function compared with 26% to 32% of men who received placebo. Pooled relative risks for a general population of men with erectile dysfunction were: sildenafil 2.50 (95 % CI 2.27 to 2.76; 19 RCTs; 4,841 men); vardenafil 2.73 (95 % CI 2.46 to 3.04; 11 RCTs; 4,332 men); tadalafil 2.62 (95 % CI 2.15 to 3.18; 13 RCTs; 3,071 men). Further results were reported, including: improvements from baseline in successful intercourse attempts; results for subgroups (men with co-morbidities, different dosing regimens, different severity of baseline erectile dysfunction); mirodenafil (two RCTs); and udenafil (one RCT). Four head-to-head trials of PDE-5 inhibitors were inconsistent in their findings for erectile function. The effectiveness of hormone treatments was inconsistent across trials. The incidence of any adverse event was increased with PDE-5 inhibitors compared to placebo: sildenafil (RR 1.72, 95 % CI 1.53 to 1.93; 25 RCTs); vardenafil (RR 1.64, 95 % CI 1.39 to 1.92; 13 RCTs); tadalafil (RR 1.75, 95 % CI 1.26 to 2.43; three RCTs). There was no statistically significant difference in the incidence of adverse events among men treated with sildenafil, vardenafil, and tadalafil. The incidence of non-arteritic anterior ischaemic optic neuropathy was similar in users and non-users of PDE-5 inhibitors (RR 1.02, 95 % CI 0.92 to 1.12; 4,157,369 men). The incidence of serious and cardiovascular adverse events, headache, flushing, dyspepsia, myalgia and back pain were also reported. The incidence of adverse events did not differ between oral or gel testosterone and placebo; patch testosterone was associated with local irritation and two men developed prostate cancer. Authors' conclusions Oral PDE-5 inhibitors improved erectile function and had similar efficacy and safety profiles. The efficacy and value of hormone treatments remained uncertain. CRD commentary The authors addressed a clear research question with appropriate inclusion criteria. Several sources were search for the original review and two databases and references were searched for the update. Only English-language publications were included. There was no specific search for unpublished studies. Despite the large number of included studies, funnel plots showed some evidence for publication bias. Study selection and data extraction were conducted in duplicate, which reduced the potential for error and bias; it was unclear whether the same precautions were taken during the quality assessment. The quality of included studies were assessed using established and relevant criteria; most of the included studies were of moderate or poor quality. An average treatment versus placebo effect was calculated for trials with more than one treatment arm. Most of the included studies were funded by the pharmaceutical industry, but the review was not. As several major groups of men who may suffer erectile dysfunction were excluded from the trials, the results may not be generalisable to the wider population seen in clinical practice. In addition, most of the trials were short term and, therefore, long-term efficacy and safety remained uncertain. This was a generally well-conducted review as, despite some limitations, the review included a large number of studies and the direction of effect seemed to be consistent across studies and analyses. Implications of the review for practice and research Practice: The authors did not state implications for practice. Research: The authors stated that well-designed long-term studies of PDE-5 inhibitors were required, as were studies that directly compared PDE-5 inhibitors, used standardised hormonal tests and were designed to identify men with erectile dysfunction at risk for hormonal disorders. The authors recommended that future research was reported according to CONSORT guidelines. Funding Agency for Healthcare Research and Quality. One author received honoraria from Pfizer, Lilly and Bayer. Bibliographic details Tsertsvadze A, Fink HA, Yazdi F, MacDonald R, Bella AJ, Ansari MT, Garritty C, Soares-Weiser K, Daniel R, Sampson M, Fox S, Moher D, Wilt T. Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Annals of Internal Medicine 2009; 151(9): 650-661 Other publications of related interest Tsertsvadze A, Yazdi F, Fink HA, MacDonald R, Wilt TJ, Soares-Weiser K, et al. Diagnosis and treatment of erectile dysfunction. AHRQ Evidence Report/Technology Assessment no. 171. Bethesda, MD: Agency for Healthcare Research and Quality. AHRQ publication no.08 (09) E016. 2009 (www.ahrq.gov/downloads/pub/evidence/pdf/erectiledys/erecdys.pdf) Indexing Status Subject indexing assigned by NLM MeSH Cyclic Nucleotide Phosphodiesterases, Type 5 /adverse effects /contraindications /therapeutic use; Erectile Dysfunction /diagnosis /drug therapy /etiology; Hormone Replacement Therapy /adverse effects; Humans; Hyperprolactinemia /complications /diagnosis; Hypogonadism /complications /diagnosis; Male; Penile Erection /drug effects; Prolactin /blood; Testosterone /blood /deficiency /therapeutic use AccessionNumber 12009109148 Date bibliographic record published 28/10/2009 Date abstract record published 04/11/2009 Record Status 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. |
|
|
|