Comparative Effectiveness and Safety of Oral Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction: A Systematic Review and Network Meta-analysis

doi:10.1016/j.eururo.2013.01.012

European Urology

Volume 63, Issue 5, May 2013, Pages 902-912

https://doi.org/10.1016/j.eururo.2013.01.012 Get rights and content

Abstract

Context

Phosphodiesterase type 5 inhibitors (PDE5-Is) are currently the first-line therapy for erectile dysfunction (ED), but available studies investigating the comparative effects of different PDE5-Is are limited.

Objective

To compare the efficacy and safety of different classes of oral PDE5-Is for ED.

Evidence acquisition

A systematic search was performed in PubMed, Cochrane Library, and Embase to identify randomized controlled trials that compared different PDE5-Is or PDE5-Is with a placebo for ED. The methodological quality of included studies was appraised with the Cochrane Collaboration bias appraisal tool, and the quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation system.

Evidence synthesis

A total of 118 trials (31 195 individuals) were included. There was no major difference in the results between the traditional meta-analysis and the network meta-analysis. Network meta-analysis demonstrated that PDE5-Is were superior to placebo to improve erectile function. Compared with tadalafil (relative risk [RR]: 0.61; 95% confidence interval [CI], 0.33–0.90) and vardenafil (RR: 0.63; 95% CI, 0.35–0.92), avanafil was less effective on Global Assessment Questionnaire question 1. Tadalafil was more effective than vardenafil (mean difference [MD]: 1.49; 95% CI, 0.50–2.50) and udenafil (MD: −1.84; 95% CI, −3.31 to −0.33) as measured by the erectile function domain of the International Index of Erectile Function. For all efficacy outcomes, the absolute effects and the rank tests indicated that tadalafil and vardenafil were the most effective agents. After adjusting for dosage, the conclusion remained the same. Safety analysis showed there was no major difference among different agents.

Conclusions

In recommended doses, oral PDE5-Is are more effective than placebo for ED, and tadalafil seems to be the most effective agent, followed by vardenafil. PDE5-Is are generally safe and well tolerated, and there is no major difference on the safety profile.

Introduction

Erectile dysfunction (ED), defined as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse [1], is one of the most common sexual disorders among men. Past surveys indicate that nearly 50% of men reported some degree of ED [2], [3], [4], and about 65% were not satisfied with the hardness of their erection [4]. ED also causes a huge economic burden to society. According to the US National Health and Nutrition Examination Survey, the annual costs of ED treatment in the United States could reach $15 billion if all patients sought medical care [5].

Current therapies for ED include phosphodiesterase type 5 inhibitors (PDE5-Is), hormones, vacuum constriction devices, intraurethral suppositories, intracavernosal injections, and surgery [6], [7]. Oral PDE5-Is including sildenafil, tadalafil, and vardenafil are currently the first-line therapy for ED [6], [7]. Four PDE5-Is (sildenafil, vardenafil, tadalafil, and avanafil) are approved worldwide, and two agents (udenafil and mirodenafil) are approved only in Korea [8]. Lodenafil, a new PDE5-I, is still undergoing clinical trials.

PDE5-Is block the PDE5 enzyme that degrades cyclic guanosine monophosphate and thus results in the relaxation of smooth muscle in the corpus cavernosum, and finally increased blood flow and erection [9], [10], [11]. A large number of studies were conducted after the introduction of PDE5-Is (sildenafil) in 1998. These studies demonstrated that oral PDE5-Is are highly effective and well tolerated for ED patients [9], [12]. However, available studies investigating the comparative effects of different PDE5-Is are limited. Given the variety of PDE5-Is available for prescription to ED patients and the limited evidence regarding the comparative efficacy of different PDE5-Is, it is hard for physicians to prescribe the best medicine.

Network meta-analysis, in the context of a systematic review, is a meta-analysis in which multiple treatments are compared using both direct comparisons of interventions within randomized controlled trials and indirect comparisons across trials based on a common comparator [13], [14]. In this study, we carried out a systematic review and network meta-analysis to compare the efficacy and safety between different PDE5-Is for the treatment of ED in a broad spectrum of the population.

Section snippets

Data sources and searches

We carried out an electronic search of Cochrane Library (Issue 4, 2012), PubMed (1966 to April 2012), and Embase (1984 to April 2012). The search strategy consisted of three parts (strategies for PDE5-Is, ED, and a specific filter for clinical trials) using the following keywords in combination with both Medical Subject Headings terms and text words: phosphodiesterase inhibitor, tadalafil, sildenafil, vardenafil, lodenafil, mirodenafil, udenafil, erectile dysfunction, impotence, and randomized

Search results and study characteristics

The literature search yielded 5938 citations, of which 5709 were excluded after review of titles and abstracts. The full texts of 229 remaining citations were screened, and finally 118 studies including 31 195 patients were included (Fig. 1) (the references of the included studies are provided in Supplement 1). The included studies covered seven different PDE5-Is: sildenafil, tadalafil, vardenafil, udenafil, mirodenafil, avanafil, and lodenafil (Fig. 2). The dosages used in most included trials

Conclusions

This study has important implication for clinical practice and ED research. For practitioners, the findings indicate that, in recommended dosage, oral PDE5-Is are more effective than placebo for ED. Tadalafil is likely to be the most effective PDE5-I for ED, followed by vardenafil. PDE5-Is are generally safe and well tolerated, and there is no major difference among them. Because tadalafil also has many other advantages, such as patient preference, it may be considered the first choice for ED

References (52)

H.A. Feldman et al.
Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study
J Urol
(1994)
J. Mulhall et al.
Importance of and satisfaction with sex among men and women worldwide: results of the global better sex survey
J Sex Med
(2008)
H. Wessells et al.
Erectile dysfunction
J Urol
(2007)
D. Montague et al.
Erectile Dysfunction Guideline Update Panel. Chapter 1: The management of erectile dysfunction: an AUA update
J Urol
(2005)
E. Wespes et al.
EAU guidelines on erectile dysfunction: an update
Eur Urol
(2006)
D.M. Caldwell et al.
Mixed treatment comparison analysis provides internally coherent treatment effect estimates based on overviews of reviews and can reveal inconsistency
J Clin Epidemiol
(2010)
J.S. Paick et al.
Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction
J Sex Med
(2008)
I. Goldstein et al.
A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction
J Sex Med
(2012)
S. Glina et al.
Efficacy and tolerability of lodenafil carbonate for oral therapy in erectile dysfunction: a phase II clinical trial
J Sex Med
(2009)
S. Glina et al.
Efficacy and tolerability of lodenafil carbonate for oral therapy of erectile dysfunction: a phase III clinical trial
J Sex Med
(2010)

M.R. Safarinejad

Oral sildenafil in the treatment of erectile dysfunction in diabetic men: a randomized double-blind and placebo-controlled study

J Diabetes Complications

(2004)

H. van Ahlen et al.

Safety and efficacy of vardenafil, a selective phosphodiesterase 5 inhibitor, in patients with erectile dysfunction and arterial hypertension treated with multiple antihypertensives

J Sex Med

(2005)

M.R. Safarinejad

Evaluation of the safety and efficacy of sildenafil citrate for erectile dysfunction in men with multiple sclerosis: a double-blind, placebo controlled, randomized study

J Urol

(2009)

E.A. Jannini et al.

The ENDOTRIAL study: a spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction

J Sex Med

(2009)

H.M. Conaglen et al.

Investigating women's preference for sildenafil or tadalafil use by their partners with erectile dysfunction: the partners’ preference study

J Sex Med

(2008)

E. Rubio-Aurioles et al.

A randomized open-label trial with a crossover comparison of sexual self-confidence and other treatment outcomes following tadalafil once a day vs. tadalafil or sildenafil on-demand in men with erectile dysfunction

J Sex Med

(2012)

F. Govier et al.

A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction

Clin Ther

(2003)

W.J. Hellstrom et al.

Sustained efficacy and tolerability of vardenafil, a highly potent selective phosphodiesterase type 5 inhibitor, in men with erectile dysfunction: results of a randomized, double-blind, 26-week placebo-controlled pivotal trial

Urology

(2003)

Optimal calcium intake. NIH Consensus Development Panel on Optimal Calcium Intake

JAMA

(1994)

A. Bener et al.

Prevalence of erectile dysfunction in male stroke patients, and associated co-morbidities and risk factors

Int Urol Nephrol

(2008)

A.S. Bell et al.

Novel phosphodiesterase type 5 modulators: a patent survey (2008–2010)

Expert Opin Ther Pat

(2011)

A. Aversa et al.

Phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction

Curr Pharm Des

(2006)

G. Ravipati et al.

Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease

Cardiol Rev

(2007)

M.A. Blount et al.

Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation

Mol Pharmacol

(2004)

A. Tsertsvadze et al.

Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis

Ann Intern Med

(2009)

D.M. Caldwell et al.

Simultaneous comparison of multiple treatments: combining direct and indirect evidence

BMJ

(2005)

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A clear benefit was noted for intracavernosal injection (ICI) of botulinum toxin (BoNT-A) on PSV with a mean difference (MD) of 10.82 [4.99, 16.65] and a heterogeneity of I2=61%. EHS results favored BoNT-A as well over placebo with a MD of 0.7 [0.47, 0.93] and heterogeneity of I2=94%. As for SHIM score, with a heterogeneity of I2=85%, no statistically significant difference was found (MD 0.58 [-0.03, 1.20]).
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Citation Excerpt :
Oral phosphodiesterase type 5 inhibitors (PDE5-Is) are currently the first line therapeutic option for ED treatment [2]. However, it is not effective in up to 30% of ED patients [3]. Moreover, long-term PDE5-Is administration may lead to severe headache and hearing loss [4].
Stem cell-derived exosomes (SC-EXO) was an emerging therapeutic agent in regenerative medicine. Intratunical injection of SC-EXO is considered as a prospective approach for erectile dysfunction (ED) treatment. However, high vascularization of cavernous body makes effective retention a major challenge for SC-EXO intratunical injection. In this study, a Polydopamine nanoparticles (PDNPs) incorporated poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PDNPs-PELA) thermosensitive hydrogels were fabricated by a facile in situ polymerization for intratunical administration of adipose stem cell-derived exosomes (EXO). The hydrogels exhibited sol-gel transition at body temperature. Moreover, the in-situ polymerization of PDNPs using poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PELA) block copolymer as a template was found to be more stable dispersion in the gel system. After being encapsulated into the hydrogel, EXO shows sustained release behavior within two weeks. In vivo animal experiments revealed that exosomes released from hydrogel lead to the healing of endothelial cells and neurons, increase of the cavity's pressure, thereby restoring the erectile function. In particular, since the PDNPs in thermosensitive gels have excellent photoacoustic performance, the hydrogel can be accurately delivered into the tunica albuginea by the guidance of real-time photoacoustic imaging. These results suggest that the as-prepared PDNPs-PELA has a promising future as an injectable exosome carrier for ED treatment.

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Review – Sexual MedicineComparative Effectiveness and Safety of Oral Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction: A Systematic Review and Network Meta-analysis

Abstract

Context

Objective

Evidence acquisition

Evidence synthesis

Conclusions

Introduction

Section snippets

Data sources and searches

Search results and study characteristics

Conclusions

J Urol

J Sex Med

J Urol

J Urol

Eur Urol

J Clin Epidemiol

J Sex Med

J Sex Med

J Sex Med

J Sex Med

J Diabetes Complications

J Sex Med

J Urol

J Sex Med

J Sex Med

J Sex Med

Clin Ther

Urology

Optimal calcium intake. NIH Consensus Development Panel on Optimal Calcium Intake

JAMA

Prevalence of erectile dysfunction in male stroke patients, and associated co-morbidities and risk factors

Int Urol Nephrol

Novel phosphodiesterase type 5 modulators: a patent survey (2008–2010)

Expert Opin Ther Pat

Phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction

Curr Pharm Des

Type 5 phosphodiesterase inhibitors in the treatment of erectile dysfunction and cardiovascular disease

Cardiol Rev

Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation

Mol Pharmacol

Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis

Ann Intern Med

Simultaneous comparison of multiple treatments: combining direct and indirect evidence

BMJ

Review – Sexual Medicine
Comparative Effectiveness and Safety of Oral Phosphodiesterase Type 5 Inhibitors for Erectile Dysfunction: A Systematic Review and Network Meta-analysis