International Urology and Nephrology | 2021
Letter to the editor
Abstract
We read with interest the recent paper by Zhongyu Jian et al. [1], which pooled results from 3 Randomized Controlled Trials [2–4] and 1 open-label study [5] and concluded that vibegron 50 mg is the optimal dose for overactive bladder (OAB) management. Here, we question the conclusion due to the insufficiency of evidence and question the validity of the argument. Although the authors concluded that 50 mg is the optimal dose, careful examination of the results from the included studies suggests the otherwise. Among the very limited number of the included studies in the analysis, there is no preponderate evidence for favoring 50 mg over the higher doses. On the contrary, in the 52-week long-term study [5], 51 (30.2%) out of 169 OAB patients had their doses escalated from 50 to 100 mg due to the insufficient efficacy after 8 weeks of treatment, and thereafter, the efficacy in these dose-adjusted patients exceeded the dose-retained ones, indicating that 50 mg is a sub-optimal dose in a third of these patients. Besides, in the head-to-head comparison between vibegron 50 mg and 100 mg [4], 100 mg exhibited longer time-effect relationship than 50 mg, with the decline trend in micturition lasting 8 weeks in the 100 mg group as compared to the 4 weeks in the 50 mg group. Most importantly, based on a recently designed double blinded, active controlled, randomized clinical trial, US FDA just approved vibegron to be used at 75 mg, with no need to adjust dose for age, sex, ethnicity, or renal impairment [6]. In addition to the limited number of the included studies and the opposing results, the robustness of the authors’ conclusion is further undermined by the flaws in the analytical approach. First, the aforementioned 51 patients who underwent dose escalation in the long-term study had more severe OAB symptoms than the dose-retained ones at baseline and at week 8, but the authors did not state how this unbalanced baseline was adjusted or how re-baseline was established in their analysis. Second, the authors did not analyze 75 mg, which has the largest sample size, as a separate dose group. It is inappropriate to claim 50 mg is optimal by adding 75 mg as a subset to the 50 mg vs. 100 mg comparison and shunning direct comparison between 75 mg and others. Moreover, various treatment durations, such as 8, 12 and 52 weeks, were tested in these studies. Considering the varying time-effect relationship across dose levels, the heterogeneity in treatment duration should also be adjusted in the meta-analysis. It is challenging to optimize the dose of a drug with flat dose–response based on few trials with heterogeneous designs, especially for a new drug like vibegron. Any relevant analysis should be meticulously designed to tackle bias, and the results should be interpreted with caution. In summary, the authors’ conclusion that vibegron 50 mg being the optimal algorithm for OAB management is unwarranted.