A systematic review and network meta-analysis of existing pharmacologic therapies in patients with idiopathic sudden sensorineural hearing loss

Abstract

Background: Hearing loss is one of the leading causes of disability worldwide. Patients with hearing loss experience impaired quality of life, as well as emotional and financial consequences that affect both themselves and their families. Idiopathic sudden sensorineural hearing loss (ISSNHL) is a common but difficult to treat condition that has a sudden onset of ≤ 72 hour associated with various etiologies, with the majority of cases being idiopathic. There exists a wide range of therapeutic options, however, the uncertainty surrounding their comparative efficacy and safety makes selection of treatment difficult. This systematic review and network meta-analysis (NMA) assessed the relative effects of competing treatments for management of ISSNHL.

Methods: A protocol for this review was registered with PROSPERO (CRD42017073756). A detailed search of MEDLINE, Embase and the Cochrane Library from inception to February 8th, 2018 was carried out by an experienced information specialist. Grey literature was also searched. Screening full-text records, and risk of bias assessment were carried out independently by two reviewers, and disagreements were resolved through consensus or third party adjudication, while data was collected by one reviewer and verified by a second reviewer. Bayesian network meta-analyses (NMA) were performed to inform comparisons between interventions for a priori specified outcomes that included pure tone average (PTA) improvement and hearing recovery.

Results: The search identified a total of 1,138 citations, of which 613 remained for review after removal of duplicates. Of these, 23 publications describing 19 unique studies (total sample size of 1,527) met our a priori eligibility criteria, that were assessed to be at unclear or high risk of bias on several domains. We identified data on several interventions for ISSNHL therapy and were able to construct treatment networks consisting of six intervention groups that included placebo; intratympanic (IT) steroid; IT plus systemic steroid; per oral (PO) steroid; intravenous (IV) steroid; and IV plus PO steroid for our NMAs. IT plus systemic steroids demonstrated the largest difference in PTA improvement compared to placebo (25.85 dB, 95% CrI 7.18-40.58), followed by IV plus PO steroids (22.06 dB, 95% CrI 1.24-39.17), IT steroids (18.24 dB, 95% CrI 3.00-29.81). We observed that the difference of PTA improvement between each intervention and placebo diminished over time, attributed to spontaneous recovery. The binary outcomes of hearing recovery demonstrated similar relative ordering of interventions but were less sensitive than PTA improvement to capture the significant differences between interventions and placebo.

Conclusion: Unclear to high risk of bias trials rated IT plus systemic steroid treatment as the best among the six interventions compared, and all active treatments were better than placebo in improving PTA. However, it should be noted that certain comparisons were based on indirect evidence only or few studies of small sample size, and analyses were unable to control for steroid type and dosage. Given these limitations, further data originating from methodologically sound and rigorous trials with adequate reporting are needed to confirm our findings.

Fig 1. Process of study selection.

The flow diagram shown presents details of the process of study selection toward identification of the evidence base for this systematic review.

Fig 2. Network diagrams of PTA improvement without (left) and with (right) complementary medicine interventions.

The size of treatment nodes was weighted by the number of patients, while the width of the edges each representing a pairwise comparison was weighted by the number of studies.

Fig 3. League table of pairwise difference estimates in PTA improvement.

The league table of posterior median pairwise differences in PTA improvement from the unadjusted (lower triangle) and the time-adjusted models (estimated at the follow-up time of 60 days, upper triangle), with credible intervals (2.5% and 97.5% quantiles). A complete summary of estimates for efficacy from the RE consistency model assuming vague priors is displayed. Statistically significant differences in hearing recovery estimates between regimens are shown in bold, underlined font with shaded background. For each comparison, the lower/right-most treatment is the reference treatment. For example, the largest difference in PTA improvement compared to placebo was associated with IT plus systemic steroids, estimated as 22.29 dB (95% CrI 5.01–38.01) based on the time-adjusted model (at the follow-up time of 60 days).

Fig 4. League tables of odds ratio estimates for responders’ recovery or total recovery.

League tables of posterior median odds ratio in responders’ recovery / total recovery from the unadjusted (lower triangle) and the time-adjusted models (upper triangle), with credible intervals (2.5% and 97.5% quantiles). A complete summary of estimates for efficacy from the RE consistency model assuming vague priors is displayed. Statistically significant odds ratio estimates between regimens are shown in bold, underlined font. For each comparison, the lower/right-most treatment is the reference treatment. Panel A: responders’ recovery, Panel B: total recovery. For example, the largest OR compared to placebo was associated with IT plus systemic steroid, estimated as 16.10 (95% CrI 2.79–118.10) for responders’ recovery and 4.79 (95% CrI 1.01–23.45) for total recovery, based on the time-adjusted model (at the follow-up time of 60 days).