Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2020-047396 on 24 August 2021. Downloaded from Effect of phosphodiesterase- type 5 inhibitors on erectile function: an overview of systematic reviews and meta- analyses Nikolaos Pyrgidis ,1,2 Ioannis Mykoniatis,1,2 Anna- Bettina Haidich ,3 Maria Tirta,2 Persefoni Talimtzi,3 Dimitrios Kalyvianakis,1,2 Andreas Ouranidis,4 Dimitrios Hatzichristou1,2 To cite: Pyrgidis N, Mykoniatis I, ABSTRACT Strengths and limitations of this study Haidich A- B, et al. Effect of Introduction Phosphodiesterase- type 5 inhibitors phosphodiesterase- type 5 (PDE5i) are the recommended first- line treatment for ► We will provide the first overview exploring the use inhibitors on erectile function: an erectile dysfunction. Previous systematic reviews and overview of systematic reviews of phosphodiesterase- type 5 inhibitors (PDE5i) for meta- analyses suggest that they are a safe and effective and meta- analyses. BMJ Open the treatment of erectile dysfunction. option in many patient groups. Similarly, PDE5i may be 2021;11:e047396. doi:10.1136/ ► We will assess, in a holistic approach, the safety and effective as part of combination therapy in non- responders bmjopen-2020-047396 efficacy of PDE5i. to PDE5i. We will generate an overview of systematic ► We will evaluate the quality and the strength of ► Prepublication history and reviews, meta- analyses and network meta- analyses evidence deriving from systematic reviews, meta- additional supplemental material aiming to summarise the available knowledge regarding for this paper are available analyses and network meta-analyses in an attempt the efficacy and safety of PDE5i in the general population online. To view these files, to affect clinical and policy decisions. and in multiple subgroups of patients. please visit the journal online ► Due to the excess of available primary studies, we Methods and analysis This overview was designed in (http:// dx. doi. org/ 10. 1136/ will not search for recently published randomised accordance with the PRIO- harms and Preferred Reporting bmjopen- 2020- 047396). controlled trials. Items for Systematic Review and Meta- Analysis Protocols ► We will not extract data from the primary studies Received 26 November 2020 guidelines and its protocol was registered at PROSPERO. but rely on the information provided by the relevant Accepted 05 August 2021 We will systematically search PubMed, Web of Science, systematic reviews and meta-analyses. http://bmjopen.bmj.com/ Cochrane Library and Scopus databases from inception to November 2020 without any language restrictions. We will include systematic reviews or meta- analyses: (1) comparing the efficacy and safety of any dose of PDE5i © Author(s) (or their erectile function has brought on a revolution with each other, with placebo or with other effective employer(s)) 2021. Re- use in the management of erectile dysfunction permitted under CC BY- NC. No treatments for the management of erectile function; (2) (ED).1 Thereafter, other phosphodiesterase- commercial re- use. See rights exploring the use of any PDE5i alone or in combination type 5 inhibitors (PDE5i) have demonstrated and permissions. Published by with other treatment modalities in the general male BMJ. their efficacy and safety for the treatment of population or in specific subgroups and (3) conducted 2 on September 26, 2021 by guest. Protected copyright. 1Institute for the Study with systematic procedures. Our overview will employ ED. Seven PDE5i (avanafil, lodenafil, miro- of Urological Diseases, the AMSTAR 2 tool to evaluate the quality of the included denafil, sildenafil, tadalafil, udenafil and Thessaloniki, Greece studies and the Grading of Recommendations Assessment, vardenafil) at different dosages and formu- 2 Urology Department, School Development and Evaluation approach to assess the lations are currently available and four of of Medicine, Faculty of Health strength of evidence for all outcomes. We will construct them (avanafil, sildenafil, tadalafil and varde- Sciences, Aristotle University forest plots of risk estimates with the corresponding CI for of Thessaloniki, Thessaloniki, nafil) are considered the first-line option all outcomes. 3 Greece for ED. Accumulating evidence suggests 3Department of Hygiene, Social- Ethics and dissemination In this overview, we will that PDE5i may also be safe and effective in Preventive Medicine & Medical undertake an extensive literature search in an attempt to many patient groups such as in individuals evaluate the potential benefits and risks of treatment with Statistics, Aristotle University with diabetes, hypertension, benign prostatic of Thessaloniki, Thessaloniki, one PDE5i versus another or versus placebo and provide hyperplasia, prostatectomy- induced ED or Greece recommendations for clinicians and policy- makers. No 4 5 4Department of Chemical ethical approval is required. end- stage renal disease. Similarly, previous Engineering, Aristotle University PROSPERO registration number CRD42020216754. systematic reviews and meta-analyses indicate of Thessaloniki, Thessaloniki, that PDE5i may be used in combination with Greece other effective treatment modalities such as Correspondence to INTRODUCTION intracavernosal injections or low- intensity Dr Nikolaos Pyrgidis; Sildenafil was initially developed for the extracorporeal shockwave therapy in non- nikospyrgidis@ gmail. com treatment of angina pectoris but its effect on responders to PDE5i.6 Pyrgidis N, et al. BMJ Open 2021;11:e047396. doi:10.1136/bmjopen-2020-047396 1 Open access BMJ Open: first published as 10.1136/bmjopen-2020-047396 on 24 August 2021. Downloaded from Clinicians and policy- makers require a comprehensive sildenafil, tadalafil, vardenafil) alone or in combination overview of the available evidence in order to determine with other treatment modalities both in the general male the potential benefits and harms of PDE5i. Within this population as well as in specific subgroups and (4) were framework, overviews of systematic reviews and meta- conducted in accordance with the Cochrane Handbook analyses are a relatively new approach that provides a for Systematic Reviews of Interventions and the PRISMA holistic approach of a given topic and aids evidence-based statement. On the contrary, we will exclude: (1) system- clinical decision making.7 They aim to summarise and atic reviews or meta-analyses on patients under 18 years of evaluate the strength of scientific evidence as presented age; (2) systematic reviews or meta- analyses assessing the in multiple systematic reviews, meta-analyses or network efficacy and safety of PDE5i for indications not relevant to meta- analyses.8 These studies are becoming increasingly erectile function and (3) narrative reviews, editorials and more common in many healthcare domains and in sexual letters to the editor. medicine as they provide higher level of recommenda- tions and highlight the gaps in the literature.9–11 Outcomes The primary outcome of our overview will be the improve- Aim ment of erectile function in the general population. This In this context, we will generate an overview of systematic will be defined as the mean change in the erectile func- reviews, meta- analyses and network meta-analyses aiming tion after PDE5i administration measured with the Inter- to summarise the available knowledge regarding the effi- national Index of Erectile Function (IIEF). Secondary cacy and safety of PDE5i in the general population and in outcomes will include (1) improvement of erectile func- multiple subgroups of patients. tion based on the IIEF in specific subpopulations such as patients with diabetes, hypertension, end-stage renal disease, adiposity, lower urinary tract symptoms, hypo- METHODS AND ANALYSIS gonadism, radical prostatectomy- induced ED as part of This overview of systematic reviews was designed in accor- a penile rehabilitation strategy or as an adjunct treat- dance with the Preferred Reporting Items for Overviews ment, depression, psychiatric or neurological disorders, of systematic reviews PRIO-harms guidelines.12 13 Our monotherapy- resistant ED as well as elderly and young protocol was drafted based on the Preferred Reporting individuals or other subgroups of patients; (2) severe Items for Systematic Review and Meta-Analysis (PRISMA) adverse events after PDE5i intake both in the general Protocols (online data supplemental file 1).14 population as well as in specific patient subgroups and (3) drop- out rates after treatment with PDE5i. All outcomes Search strategy will be presented as defined in each included systematic Two independent reviewers will conduct a systematic review or meta- analysis. literature search of PubMed, Web of Science, Cochrane http://bmjopen.bmj.com/ Library and Scopus databases from inception to Study selection and data collection November 2020 without any language restrictions. The Two authors will independently search the predeter- search terms will include: (systematic review OR meta- mined electronic databases and the sources of grey liter- analysis) AND (phosphodiesterase-5 OR sildenafil OR ature. After removing duplicate records, the two authors tadalafil OR avanafil OR vardenafil OR mirodenafil will evaluate the relevance of all retrieved records to the OR udenafil OR lodenafil) AND (erectile OR erection prespecified inclusion criteria, based on title and abstract. OR orgasm OR impotence OR IIEF) as well as relevant Subsequently, the potentially eligible systematic reviews synonyms, truncated words and MeSH terms.