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Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis

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A Letter to the Editor to this article was published on 30 May 2020

Abstract

Purpose

To quantitatively assess the benefit–risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction.

Methods

A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included.

Results

Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion.

Conclusion

Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

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References

  1. Eardley I (2013) The incidence, prevalence, and natural history of erectile dysfunction. Sex Med Rev 1(1):3–16. https://doi.org/10.1002/smrj.2

    Article  PubMed  Google Scholar 

  2. Goldstein I, Chambers R, Tang W, Stecher V, Hassan T (2018) Real-world observational results from a database of 48 million men in the United States: relationship of cardiovascular disease, diabetes mellitus and depression with age and erectile dysfunction. Int J Clin Pract 72(4):e13078. https://doi.org/10.1111/ijcp.13078

    Article  PubMed  Google Scholar 

  3. McCabe MP, Sharlip ID, Lewis R, Atalla E, Balon R, Fisher AD, Laumann E, Lee SW, Segraves RT (2016) Incidence and prevalence of sexual dysfunction in women and men: a consensus statement from the fourth international consultation on sexual medicine 2015. J Sex Med 13(2):144–152. https://doi.org/10.1016/j.jsxm.2015.12.034

    Article  PubMed  Google Scholar 

  4. Burnett AL, Nehra A, Breau RH, Culkin DJ, Faraday MM, Hakim LS, Heidelbaugh J, Khera M, McVary KT, Miner MM, Nelson CJ, Sadeghi-Nejad H, Seftel AD, Shindel AW (2018) Erectile dysfunction: AUA guideline. J Urol. https://doi.org/10.1016/j.juro.2018.05.004

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hatzimouratidis K, Salonia A, Adaikan G, Buvat J, Carrier S, El-Meliegy A, McCullough A, Torres LO, Khera M (2016) Pharmacotherapy for erectile dysfunction: recommendations from the fourth international consultation for sexual medicine (ICSM 2015). J Sex Med 13(4):465–488. https://doi.org/10.1016/j.jsxm.2016.01.016

    Article  PubMed  Google Scholar 

  6. Andersson KE (2018) PDE5 inhibitors—pharmacology and clinical applications 20 years after sildenafil discovery. Br J Pharmacol 175(13):2554–2565. https://doi.org/10.1111/bph.14205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Palit V, Eardley I (2010) An update on new oral PDE5 inhibitors for the treatment of erectile dysfunction. Nat Rev Urol 7(11):603–609. https://doi.org/10.1038/nrurol.2010.165

    Article  CAS  PubMed  Google Scholar 

  8. Corona G, Rastrelli G, Burri A, Serra E, Gianfrilli D, Mannucci E, Jannini EA, Maggi M (2016) First-generation phosphodiesterase type 5 inhibitors dropout: a comprehensive review and meta-analysis. Andrology 4(6):1002–1009. https://doi.org/10.1111/andr.12255

    Article  CAS  PubMed  Google Scholar 

  9. Verze P, Cai T, Palmieri A, Mirone V (2015) 17 years of clinical experience with phosphodiesterase type 5 inhibitors: what do we have yet to learn? Eur Urol 68(4):681–682. https://doi.org/10.1016/j.eururo.2015.04.007

    Article  PubMed  Google Scholar 

  10. Yuan J, Zhang R, Yang Z, Lee J, Liu Y, Tian J, Qin X, Ren Z, Ding H, Chen Q, Mao C, Tang J (2013) Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. Eur Urol 63(5):902–912. https://doi.org/10.1016/j.eururo.2013.01.012

    Article  CAS  PubMed  Google Scholar 

  11. Chen L, Staubli SE, Schneider MP, Kessels AG, Ivic S, Bachmann LM, Kessler TM (2015) Phosphodiesterase 5 inhibitors for the treatment of erectile dysfunction: a trade-off network meta-analysis. Eur Urol 68(4):674–680. https://doi.org/10.1016/j.eururo.2015.03.031

    Article  CAS  PubMed  Google Scholar 

  12. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JPA, Straus S (2015) The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162(11):777–784

    Google Scholar 

  13. Moher D, Tetzlaff J, Tricco AC, Sampson M, Altman DG (2007) Epidemiology and reporting characteristics of systematic reviews. PLoS Med 4(3):e78. https://doi.org/10.1371/journal.pmed.0040078

    Article  PubMed  PubMed Central  Google Scholar 

  14. Higgins JPT, Green S (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0. Cochrane, London

    Google Scholar 

  15. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12

    Article  CAS  Google Scholar 

  16. Turner RM, Davey J, Clarke MJ, Thompson SG, Higgins JP (2012) Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews. Int J Epidemiol 41(3):818–827. https://doi.org/10.1093/ije/dys041

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dias S, Welton NJ, Sutton AJ, Caldwell DM, Lu G, Ades AE (2013) Evidence synthesis for decision making 4: inconsistency in networks of evidence based on randomized controlled trials. Med Decis Mak 33(5):641–656. https://doi.org/10.1177/0272989X12455847

    Article  Google Scholar 

  18. Jansen JP, Naci H (2013) Is network meta-analysis as valid as standard pairwise meta-analysis? It all depends on the distribution of effect modifiers. BMC Med 11:159. https://doi.org/10.1186/1741-7015-11-159

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dias S, Welton NJ, Caldwell DM, Ades AE (2010) Checking consistency in mixed treatment comparison meta-analysis. Stat Med 29(7–8):932–944. https://doi.org/10.1002/sim.3767

    Article  CAS  PubMed  Google Scholar 

  20. van Valkenhoef G, Tervonen T, Zwinkels T, de Brock B, Hillege HL (2013) ADDIS: a decision support system for evidence-based medicine. Decis Support Syst 55:459–475

    Article  Google Scholar 

  21. Team RC (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna

    Google Scholar 

  22. Bastian M, Heymann S, Jacomy M (2009) Gephi: an open source software for exploring and manipulating networks. International AAAI Conference on Weblogs and Social Media

  23. van Valkenhoef G, Tervonen T, Zhao J, de Brock B, Hillege HL, Postmus D (2012) Multicriteria benefit–risk assessment using network meta-analysis. J Clin Epidemiol 65(4):394–403. https://doi.org/10.1016/j.jclinepi.2011.09.005

    Article  PubMed  Google Scholar 

  24. Tervonen T, van Valkenhoef G, Buskens E, Hillege HL, Postmus D (2011) A stochastic multicriteria model for evidence-based decision making in drug benefit–risk analysis. Stat Med 30(12):1419–1428. https://doi.org/10.1002/sim.4194

    Article  PubMed  Google Scholar 

  25. Jiann BP (2014) Re: JinQiu Yuan, RenJie Zhang, ZuYao Yang, et al. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. Eur Urol 2013;63:902–12. Eur Urol 65 (3):e40. https://doi.org/10.1016/j.eururo.2013.10.014

  26. Seftel A (2013) Re: Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. J Urol 190(4):1340. https://doi.org/10.1016/j.juro.2013.06.077

    Article  CAS  PubMed  Google Scholar 

  27. Gong B, Ma M, Xie W, Yang X, Huang Y, Sun T, Luo Y, Huang J (2017) Direct comparison of tadalafil with sildenafil for the treatment of erectile dysfunction: a systematic review and meta-analysis. Int Urol Nephrol 49(10):1731–1740. https://doi.org/10.1007/s11255-017-1644-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 TJ (2009) Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann Intern Med 151(9):650–661. https://doi.org/10.7326/0003-4819-151-9-200911030-00150

    Article  PubMed  Google Scholar 

  29. Albersen M, Mwamukonda KB, Shindel AW, Lue TF (2011) Evaluation and treatment of erectile dysfunction. Med Clin N Am 95(1):201–212. https://doi.org/10.1016/j.mcna.2010.08.016

    Article  PubMed  Google Scholar 

  30. Yafi FA, Sharlip ID, Becher EF (2018) Update on the safety of phosphodiesterase type 5 inhibitors for the treatment of erectile dysfunction. Sex Med Rev 6(2):242–252. https://doi.org/10.1016/j.sxmr.2017.08.001

    Article  PubMed  Google Scholar 

  31. McCullough AR, Steidle CP, Klee B, Tseng LJ (2008) 1389-Randomized, double-blind, crossover trial of sildenafil in men with mild to moderate erectile dysfunction: efficacy at 8 and 12 hours postdose. Urology 71(4):686–692. https://doi.org/10.1016/j.urology.2007.12.025

    Article  PubMed  Google Scholar 

  32. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R (2003) 2289-Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology 62(1):121–125 (discussion 125–126)

    Article  Google Scholar 

  33. Zhao C, Kim SW, Yang DY, Kim JJ, Park NC, Lee SW, Paick JS, Ahn TY, Min KS, Park K, Park JK (2011) 905-Efficacy and safety of once-daily dosing of udenafil in the treatment of erectile dysfunction: results of a multicenter, randomized, double-blind, placebo-controlled trial. Eur Urol 60(2):380–387. https://doi.org/10.1016/j.eururo.2011.03.025

    Article  CAS  PubMed  Google Scholar 

  34. Del Popolo G, Li Marzi V, Mondaini N, Lombardi G (2004) 2093-Time/duration effectiveness of sildenafil versus tadalafil in the treatment of erectile dysfunction in male spinal cord-injured patients. Spinal Cord 42(11):643–648. https://doi.org/10.1038/sj.sc.3101617

    Article  PubMed  Google Scholar 

  35. Montorsi F, Padma-Nathan H, Buvat J, Schwaibold H, Beneke M, Ulbrich E, Bandel TJ, Porst H (2004) 1796-Earliest time to onset of action leading to successful intercourse with vardenafil determined in an at-home setting: a randomized, double-blind, placebo-controlled trial. J Sex Med 1(2):168–178. https://doi.org/10.1111/j.1743-6109.2004.04025.x

    Article  CAS  PubMed  Google Scholar 

  36. Hellstrom WJ, Kaminetsky J, Belkoff LH, Goldstein I, Tursi JP, Uy J, Peterson CA, Bowden CH, Day WW (2015) 245-Efficacy of avanafil 15 minutes after dosing in men with erectile dysfunction: a randomized, double-blind. Placebo Controlled Study J Urol 194(2):485–492. https://doi.org/10.1016/j.juro.2014.12.101

    Article  CAS  PubMed  Google Scholar 

  37. Ventimiglia E, Capogrosso P, Montorsi F, Salonia A (2016) The safety of phosphodiesterase type 5 inhibitors for erectile dysfunction. Expert Opin Drug Saf 15(2):141–152. https://doi.org/10.1517/14740338.2016.1131818

    Article  CAS  PubMed  Google Scholar 

  38. Hatzimouratidis K, Buvat J, Buttner H, Vendeira PA, Moncada I, Boehmer M, Henneges C, Boess FG (2014) 345-Psychosocial outcomes after initial treatment of erectile dysfunction with tadalafil once daily, tadalafil on demand or sildenafil citrate on demand: results from a randomized, open-label study. Int J Impot Res 26(6):223–229. https://doi.org/10.1038/ijir.2014.15

    Article  CAS  PubMed  Google Scholar 

  39. Buvat J, Buttner H, Hatzimouratidis K, Vendeira PA, Moncada I, Boehmer M, Henneges C, Boess FG (2013) 559-Adherence to initial PDE-5 inhibitor treatment: randomized open-label study comparing tadalafil once a day, tadalafil on demand, and sildenafil on demand in patients with erectile dysfunction. J Sex Med 10(6):1592–1602. https://doi.org/10.1111/jsm.12130

    Article  CAS  PubMed  Google Scholar 

  40. Mulhall JP, Giraldi A, Hackett G, Hellstrom WJG, Jannini EA, Rubio-Aurioles E, Trost L, Hassan TA (2018) The 2018 revision to the process of care model for management of erectile dysfunction. J Sex Med 15(10):1434–1445. https://doi.org/10.1016/j.jsxm.2018.05.021

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Pedro Duarte for the help in the statistical analyses. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

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Authors and Affiliations

  1. Pharmaceutical Sciences Postgraduate Programme, Federal University of Paraná, Curitiba, Brazil

    Camilla R. Madeira, Fernanda S. Tonin, Mariana M. Fachi, Leticia P. Leonart & Aline F. Bonetti

  2. Department of Pharmacy, Federal University of Paraná, Av. Pref. Lothario Meissner, 632, Curitiba, Paraná, Brazil

    Helena H. Borba, Angela C. L. B. Trindade, Alan G. Gonçalves & Roberto Pontarolo

  3. Division of Urology, School of Medicine, Federal University of Santa Catarina, Florianópolis, Brazil

    Vinicius L. Ferreira & Rogerio P. Moritz

  4. Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal

    Fernando Fernandez-Llimos

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Contributions

CRM: data collection, data analysis, manuscript writing. FST: project development, data analysis, manuscript writing. MMF: data collection, data analysis, manuscript writing. HHB: data collection, data analysis, manuscript editing. VLF: data collection, data analysis, manuscript editing. LPL: data collection, data analysis, manuscript editing. AFB: data collection, data analysis, manuscript editing. RPM: manuscript editing. ACLBT: project development, manuscript editing. AGG: project development, manuscript editing. FF-L: project development, data analysis, manuscript writing. RP: project development, manuscript editing.

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Correspondence to Roberto Pontarolo.

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Madeira, C.R., Tonin, F.S., Fachi, M.M. et al. Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis. World J Urol 39, 953–962 (2021). https://doi.org/10.1007/s00345-020-03233-9

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