PMID- 33599772 OWN - NLM STAT- MEDLINE DCOM- 20210413 LR - 20210413 IS - 2574-3805 (Electronic) IS - 2574-3805 (Linking) VI - 4 IP - 2 DP - 2021 Feb 1 TI - Assessment of Combination Therapies vs Monotherapy for Erectile Dysfunction: A Systematic Review and Meta-analysis. PG - e2036337 LID - 10.1001/jamanetworkopen.2020.36337 [doi] LID - e2036337 AB - IMPORTANCE: Combining 2 first-line treatments for erectile dysfunction (ED) or initiating other modalities in addition to a first-line therapy may produce beneficial outcomes. OBJECTIVE: To assess whether different ED combination therapies were associated with improved outcomes compared with first-line ED monotherapy in various subgroups of patients with ED. DATA SOURCES: Studies were identified through a systematic search in MEDLINE, Cochrane Library, and Scopus from inception of these databases to October 10, 2020. STUDY SELECTION: Randomized clinical trials or prospective interventional studies of the outcomes of combination therapy vs recommended monotherapy in men with ED were identified. Only comparative human studies, which evaluated the change from baseline of self-reported erectile function using validated questionnaires, that were published in any language were included. DATA EXTRACTION AND SYNTHESIS: Data extraction and synthesis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. MAIN OUTCOMES AND MEASURES: A meta-analysis was conducted that included randomized clinical trials that compared outcomes of combination therapy with phosphodiesterase type 5 (PDE5) inhibitors plus another agent vs PDE5 inhibitor monotherapy. Separate analyses were performed for the mean International Index of Erectile Function (IIEF) score change from baseline and the number of adverse events (AEs) by different treatment modalities and subgroups of patients. RESULTS: A total of 44 studies included 3853 men with a mean (SD) age of 55.8 (11.9) years. Combination therapy compared with monotherapy was associated with a mean IIEF score improvement of 1.76 points (95% CI, 1.27-2.24; I2 = 77%; 95% PI, -0.56 to 4.08). Adding daily tadalafil, low-intensity shockwave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was associated with a significant IIEF score improvement, but each measure was based on only 1 study. Specifically, the weighted mean difference (WMD) in IIEF score was 1.70 (95% CI, 0.79-2.61) for the addition of daily tadalafil, 3.50 (95% CI, 0.22-6.78) for the addition of low-intensity shockwave therapy, 8.40 (95% CI, 4.90-11.90) for the addition of a vacuum erectile device, 3.46 (95% CI, 2.16-4.76) for the addition of folic acid, 4.90 (95% CI, 2.82-6.98) for the addition of metformin hydrochloride and 2.07 (95% CI, 1.37-2.77) for the addition of angiotensin-converting enzyme inhibitors. The addition of alpha-blockers to PDE5 inhibitors was not associated with improvement in IIEF score (WMD, 0.80; 95% CI, -0.06 to 1.65; I2 = 72%). Compared with monotherapy, combination therapy was associated with improved IIEF score in patients with hypogonadism (WMD, 1.61; 95% CI, 0.99-2.23; I2 = 0%), monotherapy-resistant ED (WMD, 4.38; 95% CI, 2.37-6.40; I2 = 52%), or prostatectomy-induced ED (WMD, 5.47; 95% CI, 3.11-7.83; I2 = 53%). The treatment-related AEs did not differ between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85; I2 = 78%). Despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high. CONCLUSIONS AND RELEVANCE: This study found that combination therapy of PDE5 inhibitors and antioxidants was associated with improved ED without increasing the AEs. Treatment with PDE5 inhibitors and daily tadalafil, shockwaves, or a vacuum device was associated with additional improvement, but this result was based on limited data. These findings suggest that combination therapy is safe, associated with improved outcomes, and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat cases of ED. FAU - Mykoniatis, Ioannis AU - Mykoniatis I AD - Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece. FAU - Pyrgidis, Nikolaos AU - Pyrgidis N AD - Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece. AD - Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany. FAU - Sokolakis, Ioannis AU - Sokolakis I AD - Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany. FAU - Ouranidis, Andreas AU - Ouranidis A AD - Department of Pharmaceutical Technology, Aristotle University of Thessaloniki, Thessaloniki, Greece. AD - Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece. FAU - Sountoulides, Petros AU - Sountoulides P AD - Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece. FAU - Haidich, Anna-Bettina AU - Haidich AB AD - Department of Hygiene, Social-Preventive Medicine & Medical Statistics, Aristotle University of Thessaloniki Medical School, University Campus, Thessaloniki, Greece. FAU - van Renterghem, Koenraad AU - van Renterghem K AD - Department of Urology, Jessa Hospital, Hasselt University, Hasselt, Belgium. AD - Department of Urology, University Hospitals Leuven, Leuven, Belgium. FAU - Hatzichristodoulou, Georgios AU - Hatzichristodoulou G AD - Department of Urology, Martha-Maria Hospital Nuremberg, Nuremberg, Germany. FAU - Hatzichristou, Dimitrios AU - Hatzichristou D AD - Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20210201 PL - United States TA - JAMA Netw Open JT - JAMA network open JID - 101729235 RN - 0 (Adrenergic alpha-Antagonists) RN - 0 (Angiotensin-Converting Enzyme Inhibitors) RN - 0 (Antioxidants) RN - 0 (Hypoglycemic Agents) RN - 0 (Phosphodiesterase 5 Inhibitors) RN - 12001-76-2 (Vitamin B Complex) RN - 742SXX0ICT (Tadalafil) RN - 9100L32L2N (Metformin) RN - 935E97BOY8 (Folic Acid) RN - BW9B0ZE037 (Sildenafil Citrate) SB - IM CIN - JAMA Netw Open. 2021 Feb 1;4(2):e2037292. PMID: 33599768 MH - Adrenergic alpha-Antagonists/therapeutic use MH - Angiotensin-Converting Enzyme Inhibitors/therapeutic use MH - Antioxidants/*therapeutic use MH - Combined Modality Therapy MH - Drug Therapy, Combination MH - *Equipment and Supplies MH - Erectile Dysfunction/*therapy MH - *Extracorporeal Shockwave Therapy MH - Folic Acid/therapeutic use MH - Humans MH - Hypoglycemic Agents/therapeutic use MH - Male MH - Metformin/therapeutic use MH - Phosphodiesterase 5 Inhibitors/*therapeutic use MH - Sildenafil Citrate/therapeutic use MH - Tadalafil/therapeutic use MH - Treatment Outcome MH - Vitamin B Complex/therapeutic use PMC - PMC7893498 COIS- Conflict of Interest Disclosures: None reported. EDAT- 2021/02/19 06:00 MHDA- 2021/04/14 06:00 PMCR- 2021/02/18 CRDT- 2021/02/18 12:15 PHST- 2021/02/18 12:15 [entrez] PHST- 2021/02/19 06:00 [pubmed] PHST- 2021/04/14 06:00 [medline] PHST- 2021/02/18 00:00 [pmc-release] AID - 2776549 [pii] AID - zoi201088 [pii] AID - 10.1001/jamanetworkopen.2020.36337 [doi] PST - epublish SO - JAMA Netw Open. 2021 Feb 1;4(2):e2036337. doi: 10.1001/jamanetworkopen.2020.36337.