Assessment of Combination Therapies vs Monotherapy for Erectile Dysfunction: A Systematic Review and Meta-analysis

Published on Feb 1, 2021
· DOI :10.1001/JAMANETWORKOPEN.2020.36337
Ioannis Mykoniatis6
Estimated H-index: 6
(A.U.Th.: Aristotle University of Thessaloniki),
Nikolaos Pyrgidis3
Estimated H-index: 3
(A.U.Th.: Aristotle University of Thessaloniki)
+ 6 AuthorsDimitrios Hatzichristou51
Estimated H-index: 51
(A.U.Th.: Aristotle University of Thessaloniki)
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 α-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.
#1Paolo Verze (University of Naples Federico II)H-Index: 25
#2Marco Capece (University of Naples Federico II)H-Index: 13
Last. Vincenzo Mirone (University of Naples Federico II)H-Index: 58
view all 8 authors...
: Low-intensity extracorporeal shockwave therapy (LiESWT) represents a promising treatment for patients with erectile dysfunction (ED). We investigated the efficacy of LiESWT combined with tadalafil 5 mg once daily in men with type 2 diabetes mellitus (T2DM) and ED and compared LiESWT protocols administering different number of shockwaves. We performed a retrospective matched-pair comparison using data from a prospectively maintained database. Seventy-eight patients who received tadalafil 5 mg o...
#1Antonio RuffoH-Index: 7
#2N. StanojevicH-Index: 2
Last. Fabrizio Iacono (University of Naples Federico II)H-Index: 13
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#1Luigi GalloH-Index: 1
#2Stefano PecoraroH-Index: 7
Last. Gabriele Antonini (Sapienza University of Rome)H-Index: 17
view all 5 authors...
Abstract Introduction A synergistic effect of the combination therapy tadalafil plus L-Arginine is conceivable in patients affected by erectile dysfunction (ED). Aim To evaluate the effectiveness and tolerability of tadalafil 5 mg and L-Arginine 2.5 grams in monotherapy and combination therapy. Methods Recruited patients completed the International Index of Erectile Function – Erectile Function domain (IIEF-EF) and Sexual Encounter Profile diaries completed at baseline and after treatment. The su...
#1Mohammed Abu El-Hamd (Sohag University)H-Index: 5
#2Eisa M. Hegazy (SVU: South Valley University)H-Index: 5
: This study aimed to evaluate the efficacy of the daily oral administrations of L-arginine, tadalafil and combined L-arginine with tadalafil in treatments of elderly patients with erectile dysfunction (ED). It was designed as a single-blind placebo-controlled clinical trial. It was conducted on 120 male patients aged ≥60 years old with ED. Patients were randomised classified into four groups (n = 30 each). Oral daily use of L-arginine (5 g), tadalafil (5 mg), combined L-arginine (5 g) with tada...
#1Panagiotis Kallidonis (University of Patras)H-Index: 27
#2Constantinos Adamou (University of Patras)H-Index: 3
Last. Anastasios Athanasopoulos (University of Patras)H-Index: 22
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Abstract Context The effects of combination therapy consisted of an α-blocker and a phosphodiesterase-5 inhibitor (PDE5I) for the treatment of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). Objective To systematically investigate the efficacy and safety of combination therapy in comparison with monotherapy. Evidence acquisition The study complied with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement and the recommendations of the Europ...
Abstract Background Erectile dysfunction (ED) after radical prostatectomy (RP) still represents a major issue. Considering the benefits recently described regarding the application of low-intensity extracorporeal shockwave therapy (LiESWT) in vasculogenic ED, questions arise about its role in the scenario of penile rehabilitation. Aim To compare the early introduction of phosphodiesterase-5 inhibitor (PDE5i) with a combination therapy enrolling both early PDE5i use and LiESWT in patients submitt...
#1Alexander Stridh (KI: Karolinska Institutet)H-Index: 1
#2Moa Pontén (KI: Karolinska Institutet)H-Index: 3
Last. Karin B. Jensen (KI: Karolinska Institutet)H-Index: 26
view all 6 authors...
Importance Placebo responses in the treatment of erectile dysfunction (ED) are poorly described in the literature to date. Objective To quantify the association of placebo with ED outcomes among men enrolled in placebo-controlled, phosphodiesterase 5 inhibitor (PDE5I) trials. Data Sources For this systematic review and meta-analysis, a database search was conducted to identify double-blind, placebo-controlled studies using PDE5Is for the treatment of ED published from January 1, 1998, to Decembe...
#1Yu Xi Terence Law (University Health System)H-Index: 2
#2Bee Choo Tai (NUS: National University of Singapore)H-Index: 37
Last. King Chien Joe Lee (University Health System)H-Index: 2
view all 5 authors...
Abstract Introduction Several studies have reaffirmed the use of regular pentoxifylline therapy in increasing the penile brachial pressure index in men affected by erectile dysfunction when compared to placebo. Aim The aim of this study was to evaluate the efficacy of pentoxifylline as an adjunctive treatment for patients with erectile dysfunction. Methods This study was a single center, prospective, randomized, double-blind, placebo-controlled trial. Subjects were recruited between April 2014 a...
#1Maya EpifanovaH-Index: 1
#2Badri R. GvasaliaH-Index: 1
Last. Sergey ArtemenkoH-Index: 1
view all 4 authors...
Abstract Introduction Platelet-rich plasma (PRP) found its use in treating different conditions and diseases, because concentrated plasma PRP consists of many growth factors. Their interaction with surrounding cells, intracellular matrix, and mediators at the site of injection leads to tissue regeneration. Angiogenic, vasculogenic, and regenerative effects of PRP may be used for erectile dysfunction (ED) and Peyronie’s disease (PD) treatment. Aim To present a current data review of preclinical a...
#1L M El-Wakeel (Ain Shams University)H-Index: 1
#2F A Fouad (Ain Shams University)H-Index: 1
Last. M Saber-Khalaf (Sohag University)H-Index: 1
view all 4 authors...
BACKGROUND: Erectile dysfunction is defined as inability to achieve or maintain penile erection sufficient for sexual satisfaction. It is a serious problem that increases by age. The physiology of penile erection depends mainly on nitric oxide release. OBJECTIVES: Compare the efficacy and safety of oral sildenafil 50 mg alone or in combination with l-arginine 3 g/day orally on the treatment of erectile dysfunction. MATERIAL AND METHODS: Randomized controlled study with two parallel groups of ere...
Cited By3
#1Nikolaos Pyrgidis (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 3
#2Ioannis Mykoniatis (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 6
Last. Dimitrios Hatzichristou (A.U.Th.: Aristotle University of Thessaloniki)H-Index: 51
view all 0 authors...
Introduction null Phosphodiesterase-type 5 inhibitors (PDE5i) are the recommended first-line treatment for erectile dysfunction. Previous systematic reviews and meta-analyses suggest that they are a safe and effective option in many patient groups. Similarly, PDE5i may be effective as part of combination therapy in non-responders to PDE5i. We will generate an overview of systematic reviews, meta-analyses and network meta-analyses aiming to summarise the available knowledge regarding the efficacy...
#1John F Sullivan (BCM: Baylor College of Medicine)
#2Kevin J Campbell (BCM: Baylor College of Medicine)
Last. Larry I. Lipshultz (BCM: Baylor College of Medicine)H-Index: 63
view all 3 authors...
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