Combination Therapy Improves ED Outcomes

Combination therapy using a phosphodiesterase type 5 (PDE5) inhibitor and antioxidants outclassed PDE5 monotherapy for managing symptoms of erectile dysfunction (ED), without increasing adverse events rates, according to results from a systematic review and meta-analysis.

What’s more, adding daily tadalafil, low-intensity extracorporeal shockwave therapy (Li-ESWT), or a vacuum erectile device to PDE5 treatment led to additional improvements, though there was less data to back up their use, Ioannis Mykoniatis, MD, MSc, Department of Urology, Faculty of Medicine, Aristotle University of Thessaloniki School of Health Sciences, Thessaloniki, Greece, and colleagues reported in JAMA Network Open.

Based on these results, Mykoniatis and colleagues suggested that “established therapeutic algorithms of ED should be reevaluated to consider combination therapy as the first-line treatment for refractory, complex, or difficult-to-treat cases of ED.”

Due to their convenience, rapid effectiveness, and positive safety profile, PDE5 inhibitors such as sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are considered to be the first-line monotherapy for patients with ED. Other first-line treatment modalities, the study authors explained, include intracavernosal injections, topical or intraurethral alprostadil, vacuum devices, and Li-ESWT.

However, while these treatments can be effective for many patients, other patients experience frustration with the results and end up abandoning therapy.

Here, Mykoniatis and colleagues asked whether combining different ED therapies was more effective in improving outcomes compared with first-line ED monotherapy.

In this systematic review and meta-analysis, the authors identified 44 randomized trials or prospective interventional studies of the outcomes of combination therapy versus recommended monotherapy among men with ED. All of the studies assessed ED at baseline and performed their analyses using the mean International Index of Erectile Function (IIEF) score change from baseline. The IIEF is a questionnaire used as part of the evaluation of erectile dysfunction.

In trials that compared the combination treatment of PDE5 inhibitors — usually sildenafil or tadalafil — and another agent with PDE5 monotherapy, combination therapy was associated with a mean IIEF score improvement of 1.76 points. Adding testosterone to PDE5 inhibitors was associated with a mean IIEF score improvement of 2.27, and the addition of antioxidants was associated with an improvement of 1.99 points.

And, combining PDE5 inhibitor treatment with daily tadalafil, low-intensity shock wave therapy, vacuum erectile device, folic acid, metformin hydrochloride, or angiotensin-converting enzyme inhibitors was also associated with significantly increased mean IIEF scores compared with PDE5 inhibitor monotherapy. The weighted mean difference in IIEF score was:

• 1.70 for the addition of daily tadalafil.
• 8.40 for the addition of a vacuum erectile device.
• 3.46 for the addition of folic acid.
• 4.90 for the addition of metformin hydrochloride.
• 2.07 for the addition of angiotensin-converting enzyme inhibitors.

However, the authors cautioned these measures were based on a single study.

In an invited commentary accompanying the study, John F. Sullivan, MD, Division of Male Reproductive Medicine and Surgery, the Scott Department of Urology, Baylor College of Medicine, Houston, Texas, and colleagues observed that, while these and other add-ons to traditional ED therapy seem promising, more work is needed to establish their efficacy.

“New modalities, including Li-ESWT and plasma-rich platelet and stem cell therapies, are all worthy of evaluation but are still considered to be experimental because further large and well-designed prospective studies are required,” they wrote. “With only a handful of small randomized clinical trials performed to date, Li-ESWT does appear to be associated with greater subjective improvements than other combinations, but the data are preliminary at best.4Intuitively, the proposed mechanism of microtrauma that results in neoangiogenesis of vascular endothelial cells coupled with possible nerve regeneration and remodeling as well as the increase in local neuronal nitric oxide concentration may very well directly potentiate the activity of PDE5 inhibitors.”

As for other therapies, Mykoniatis and colleagues reported that IIEF scores did not improve significantly with the addition of alpha blockers (0.80) or pentoxifylline (0.56) to PDE5 inhibitors. However, there was no statistically significant reported change in erectile function in patients with LUTS (lower urinary tract symptoms), who were all treated with an α-blocker in addition to a PDE5 inhibitor.

There was no difference regarding treatment-related adverse events between combination therapy and monotherapy (odds ratio, 1.10; 95% CI, 0.66-1.85), the authors reported, and, “despite multiple subgroup and sensitivity analyses, the levels of heterogeneity remained high.”

“These findings are not only statistically significant but also clinically important,” the authors wrote. “In particular, the IIEF-ED score displays a minimal clinically important difference (MCID), defined as the smallest difference that patients may actually perceive as beneficial after treatment.” They suggested that the mean IIEF score of 1.76 with combination therapy means it could boost erectile function to an MCID in many patients.

In their commentary, Sullivan and colleagues noted that one of the study’s limitations was the significant heterogenicity of both the populations and the combination therapies in its analysis.

“Therefore, caution must be exercised when considering the clinical efficacy of any combination treatment modality for ED,” wrote Sullivan and his colleagues. Still, they added that they believe that combination therapy “with dual short- and long-acting PDE5 inhibitors may have an additive effect and should be considered, even as a first-line initial strategy in cases of more advanced ED.”

“As the worldwide prevalence of ED continues to increase, it behooves those clinicians who treat men with ED to continue to try new complementary and synergistic treatment options,” they added. “These new options should also be assessed in the appropriate prospective clinical settings.”

1. Combination therapy using a phosphodiesterase type 5 (PDE5) inhibitor and antioxidants outperformed PDE5 monotherapy for managing symptoms of erectile dysfunction (ED), without increasing adverse events rates — and adding daily tadalifil, low-intensity shock therapy, or a vacuum device led to additional improvements, though this result was supported by less data.

2. The study authors concluded that combination therapy is safe and effective and should be considered as a first-line therapy for refractory, complex, or difficult-to-treat ED cases.

Michael Bassett, Contributing Writer, BreakingMED™

Cat ID: 72

Topic ID: 91,72,730,192,72,925