Pharmacologic and surgical therapies for patients with Meniere's disease: A systematic review and network meta-analysis

Abstract

Background: Meniere's disease (MD) is a chronic condition of the inner ear consisting of symptoms that include vertigo attacks, fluctuating sensorineural hearing loss, tinnitus and aural fullness. Despite availability of various interventions, there is uncertainty surrounding their relative efficacy, thus making it difficult to select the appropriate treatments for MD. The objective of this systematic review was to assess the relative effects of the available pharmacologic and surgical interventions in patients with MD with regard to vertigo and other key patient outcomes based on data from randomized clinical trials (RCTs).

Methods: Our published protocol registered with PROSPERO (CRD42019119129) provides details on eligibility criteria and methods. We searched various databases including MEDLINE, Embase and the Cochrane Library from inception to December 10th, 2018. Screening at citation and full-text levels and risk of bias assessment were performed by two independent reviewers in duplicate, with discrepancies resolved by consensus or third-party adjudication. Bayesian network meta-analyses (NMA) were performed for hearing change and vertigo control outcomes, along with pairwise meta-analyses for these and additional outcomes.

Results: We identified 2,889 unique citations, that yielded 23 relevant publications describing 18 unique RCTs (n = 1,231 patients). Overall, risk-of bias appraisal suggested the evidence base to be at unclear or high risk of bias. Amongst pharmacologics, we constructed treatment networks of five intervention groups that included placebo, intratympanic (IT) gentamicin, oral high-dose betahistine, IT steroid and IT steroid plus high-dose betahistine for NMAs of hearing change (improvement or deterioration) and complete vertigo control. IT steroid plus high-dose betahistine was associated with the largest difference in hearing improvement compared to placebo, followed by high-dose betahistine and IT steroid (though 95% credible intervals failed to rule out the possibility of no difference), while IT gentamicin was worse than IT steroid. The NMA of complete vertigo control suggested IT gentamicin was associated with the highest probability of achieving better complete vertigo control compared to placebo, followed by IT steroid plus high-dose betahistine. Only two studies related to surgical interventions were found, and data suggested no statistically significant difference in hearing changes between endolymphatic duct blockage (EDB) versus endolymphatic sac decompression (ESD), and ESD with or without steroid injection. One trial reported that 96.5% of patients in EDB group compared to 37.5% of the patients in ESD group achieved complete vertigo control 24 months after surgery (p = 0.002).

Conclusion: To achieve both hearing preservation and vertigo control, the best treatment option among the pharmacologic interventions compared may be IT steroid plus high-dose betahistine, considering that IT gentamicin may have good performance to control vertigo but may be detrimental to hearing preservation with high cumulative dosage and short interval between injections. However, IT steroid plus high-dose betahistine has not been compared in head-to-head trials against other interventions except for IT steroid alone in one trial, thus future trials that compare it with other interventions will help establish comparative effectiveness with direct evidence.

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 diagram of hearing change (left) and complete vertigo control (right).

Each line links interventions and comparators directly compared. 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. Note: IT steroid plus high-dose betahistine has not been compared in head-to-head trials against other interventions except for IT steroid alone.

Fig 3. Findings from risk of bias evaluation.

Findings from risk of bias evaluations using the Cochrane Scale are shown. Green = low risk of bias, red = high risk of bias, yellow = unclear risk of bias.

Fig 4. Difference in hearing change, where positive pure tone average (PTA) change per group indicates hearing deterioration.

*Six studies [38, 40, 42, 44, 50, 51] reported the means and SDs before and after intervention but not the SDs of PTA changes. We calculated the mean PTA changes and the corresponding SDs, assuming the correlation of 0.859 before and after intervention. This correlation had been calculated from individual level data of 22 patients [49].

Fig 5. League table of pairwise difference estimates in hearing change (lower triangle), and the probabilities that a treatment is better than another (upper triangle).

The league table presents pairwise differences in hearing change (PTA) with credible intervals (2.5% and 97.5% quantiles), and the pairwise probabilities that a treatment is better than another based on NMA. A complete summary of estimates for efficacy from the RE consistency model assuming vague priors is displayed. Estimates of difference in PTA change between regimens which ruled out the possibility of no difference are shown in bold, underlined font. 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 steroid + high-dose betahistine, estimated as -3.68 dB (95% CrI -14.10 to 6.98), with a negative sign indicating benefit over comparator in hearing preservation.

Fig 6. Risk ratio of complete vertigo control versus other categories as per the 1995 AAO-HNS definition.

The AAO-HNS classes for vertigo control include complete (class A: numeric value 0) or substantial control (class B: 1–40), limited control (class C: 41–80), insignificant control (class D: 81–120), worse control (class E: >120), and secondary treatment initiated due to disability from vertigo (class F). * In Stokroos and Kingma [50], the number of patients with no complaints of vertigo attacks 6 weeks after the last treatment and during follow-up (6–28 months) had been used. ** In Postema et al [46], the number of patients with no complaints of vertigo (0 of a vertigo score which ranged 0 to 3) 12 months after treatment had been used. # In Morales-Luckie et al [48], maintenance therapy in both groups consisted of diphenidol (25 mg/d) plus acetazolamide (250 mg/48 h) and a low-sodium diet (< 1500 mg/d). Only patients with limited vertigo control (Class C) and severe disability (Scale 3) were included.

Fig 7. SUCRA values of treatments according to hearing change and complete vertigo control.