Original Title: Treatment with betahistine or cinnarizine with or without dimenhydrinate for adult patients with Ménière’s disease/syndrome and patients experiencing symptoms of vestibular vertigo and/or tinnitus

Authors' objectives: BACKGROUND Ménière’s disease is a disorder of the inner ear that can cause various symptoms. Patients with Ménière’s disease experience episodes of vertigo, tinnitus, hearing loss and aural fullness. Vertigo refers to the feeling of motion when there is none or the feeling of distorted self-motion during a normal head movement and includes spinning vertigo and non-spinning vertigo. Patients with tin nitus experience a constant or intermittent ringing or other noise in the ear or in the head. Aural fullness is a sensation of pressure deep inside the ear. In Switzerland, betahistine and cinnarizine are reimbursed for patients experiencing symptoms of vertigo, tinnitus and hearing loss caused by Ménière’s disease or other disorders. Furthermore, cinnarizine with dimenhydrinate is reimbursed for the symptomatic treatment of transient vertigo. The evidence for the coverage of these drugs is to be re-evaluated in the context of the Federal Office of Public Health (FOPH) health technology assessment (HTA) program. The presented evidence is intended to inform policy makers in their decision whether these drugs should continue to be reimbursed by the Swiss compulsory health insurance. OBJECTIVE This HTA report assesses the efficacy, effectiveness, safety, cost-effectiveness and budget impact, as well as ethical, legal, social, and organisational benefits and harms of betahistine and cinnariz ine with or without dimenhydrinate for the treatment of vertigo, tinnitus and/or hearing loss caused by Ménière’s disease or for the treatment of vertigo or tinnitus caused by other peripheral or central vestibular disorders.

Authors' results and conclusions: RESULTS In the clinical systematic review 10 RCTs were included on licensed drug use and stratified in 4 groups: betahistine for Ménière’s disease (4 RCTs), betahistine for vertigo (3 RCTs), cinnarizine for tinnitus (1 RCT), and cinnarizine with dimenhydrinate for vertigo (2 RCTs). Some of these RCTs missed relevant outcome data for valid data interpretation; these results are presented in an ap pendix to provide full insight in published RCT evidence. In adult patients with Ménière’s disease treated for 9 months with betahistine versus placebo no statistically significant differences were found in vertigo attack frequency (adjusted rate ratio 1.04 [95% CI 0.94 to 1.14]; 1 RCT; moderate certainty evidence) and tinnitus intensity (adjusted mean difference [aMD] +1.40 dB [95% confidence interval [CI] -5.10 to 7.90]; 1 RCT; low certainty evi dence). Also, no statistically significant difference in hearing loss assessed at 4 different frequen cies was found (range across frequencies evaluated aMD from +0.33 dB [95% CI -3.13 to 3.79] at 250 Hz to +2.83 dB [95% CI -1.93 to 7.59] at 1000 Hz; 1 RCT; low certainty evidence). No statisti cally significant differences were reported for 9-months betahistine versus placebo treatment for disease-specific health-related quality of life (HRQoL) assessed with the dizziness handicap inventory (aMD +0.08 [95% CI -0.17 to 0.33]; mean total score range 0 [best]–4 [worst]; 1 RCT; moderate certainty evidence), vestibular disorders activities of daily living questionnaire (aMD 0.05 [95% CI -0.32 to 0.22]; score range 1 [best]–10 [worst]; 1 RCT; moderate certainty evidence), and mini-tinnitus impairment questionnaire (aMD -0.007 [95% CI -0.14 to 0.13]; score range 0 [best]–24 [worst]; 1 RCT; moderate certainty evidence). A statistically significant improvement in disease-specific HRQoL assessed with the dizziness handicap inventory was reported for 1-month betahistine treatment compared to no treatment (MD -6.1 [95% CI not reported]; score range 0 [best]–100 [worst]; 1 RCT; very low certainty evidence). There was no statistically significant dif ference in the occurrence of serious adverse events for betahistine versus placebo in patients with Ménière’s disease up to 9 months of treatment (risk ratio [RR] 1.12 (95% CI 0.53 to 2.38); 2 RCTs; low certainty evidence). In adult patients with diverse vertigo aetiologies treated up to 3 months with betahistine versus placebo the results for 3 different vertigo outcomes were lacking and seem not consistent. Com pared to baseline, betahistine treatment resulted in a statistically significant decrease in vertigo attack frequency (effect size [95% CI] not reported; 1 RCT; very low certainty evidence) and vertigo attack severity (effect size [95% CI] not reported; 2 RCTs; very low certainty evidence) versus a statistically significant decrease for placebo treatment in vertigo attack duration (effect size [95% CI] not reported; 1 RCT; very low certainty evidence). No statistically significant difference was found in investigator-reported vertigo symptoms for betahistine versus placebo (RR 0.88 [95% CI 0.45 to 1.69]; 1 RCT; very low certainty evidence). No data was reported on HRQoL. No serious adverse events were encountered in the treatment with betahistine or placebo (RR not estimable; 3 RCTs; very low certainty evidence). In adult patients with idiopathic subjective tinnitus treated for 10 weeks with cinnarizine versus placebo no statistically significant differences were found in tinnitus disturbance during activity or rest (MDactivity -0.1 [95% CI not reported]; MDrest -0.15 [95% CI not reported]; score range 0 [best] 4 [worst]; 1 RCT; very low certainty evidence) nor in patient-reported tinnitus symptoms (RR 2.00 [95% CI 0.14 to 28.76]; 1 RCT; very low certainty evidence). No data was reported on HRQoL or serious adverse events. In adult patients with diverse vertigo aetiologies treated for 4 weeks with cinnarizine with dimenhy drinate the vertigo symptoms statistically significantly improved compared to placebo, assessed with the mean vertigo score (aMD -1.3 [95% CI not reported]; score range 0 [best]–3 [worst]; and aMD -0.56 [95% CI -0.38 to -0.75]; score range 0 [best]–4 [worst]; 2 RCTs; moderate certainty evidence). A statistically non-significant improvement of patient and investigator-reported vertigo symptoms was reported (RR 3.44 [95% CI 0.38 to 31.02]; 2 RCTs; very low certainty evidence). No data was reported on HRQoL. No serious adverse events were encountered in the treatment with cinnarizine with dimenhydrinate or placebo (RR not estimable; 2 RCTs; low certainty evi dence). In the economic review. no economic evaluations were included. Only for vertigo caused by other vestibular disorders than Ménière’s disease treated with cinnarizine with dimenhydrinate a positive treatment was found compared to placebo in the clinical review. Evidence for a positive treatment effect was lacking for cinnarizine for Ménière’s disease and tinnitus while for betahistine and cin narizine without dimenhydrinate the evidence was lacking for any of the conditions of interest. Therefore, a cost-effectiveness model was only developed for patients with vestibular vertigo not caused by Ménière’s disease treated with cinnarizine with dimenhydrinate. The cost-effectiveness model for the treatment of vertigo caused by other disorders than Ménière’s disease showed that treatment with cinnarizine with dimenhydrinate was dominant (i.e. lower costs and more effective) compared to no treatment. Scenario analyses and sensitivity analyses showed the robustness of the results. The estimated budget impact of betahistine was CHF 17.2 million over a 5-year period. For cinnarizine without dimenhydrinate, the estimated budget impact was CHF 0.8 million over a 5-year period. The use of cinnarizine with dimenhydrinate resulted in projected cumulative budget savings of CHF 1.2 million over a 5-year period. Note that the extent to which these savings can be expected depends on the accuracy of the estimated distribution between patients using cinna rizine with dimenhydrinate for vertigo caused by Ménière’s disease and patients using it for vertigo caused by other disorders. Twenty-four publications on ELSO issues were included. In the ethical domain, the challenges with diagnosis and treatment were discussed. Several ethical constraints arise from these challenges, including delayed and ineffective treatment of symptoms, reduced quality of life of patients, finan cial burden and strain on the patient-physician relationship. Driving restrictions for patients with Ménière’s disease and vertigo were considered potential legal issues. In Switzerland, drugs can only be placed on the Spezialitätenliste if drugs are licensed by Swissmedic and are effective, appropriate, and economically efficient. Social issues found in the literature considered the impact on a patient's social network and society as a whole. More specifically, patients with Ménière’s disease suffered from reduced quality of life, depressive symptoms, social isolation and participa tion restrictions. Finally, in the organisational domain, the need for a holistic approach was advo cated in the literature, which requires input from various healthcare professionals and thereby po tentially complicating the organisation of treatment pathways. CONCLUSION The evidence base was limited. The clinical evidence in adult patients with Ménière’s disease sug gests little or no difference in the treatment effect of betahistine compared with placebo on vertigo attack frequency (1 RCT; moderate certainty evidence), tinnitus intensity (1 RCT; low certainty evidence), hearing loss (1 RCT; low certainty evidence), and disease-specific HRQoL (1 RCT; moderate certainty evidence). Betahistine may improve disease-specific HRQoL compared with no treatment in patients with Ménière’s disease, but the evidence is very uncertain (1 RCT; very low certainty evidence). Betahistine may be well tolerated in patients with Ménière’s disease, with little or no difference in the occurrence of serious adverse events compared to placebo (2 RCTs; low certainty evidence). In adult patients with diverse vertigo aetiologies the evidence on the effect of betahistine on vertigo compared with placebo is lacking, seems not consistent and is very un certain (3 RCTs; very low certainty evidence). Betahistine may be well tolerated in patients with vertigo, with no serious adverse events encountered with betahistine or placebo treatment, but the evidence is very uncertain (3 RCTs; very low certainty evidence). In adult patients with idiopathic subjective tinnitus cinnarizine may show little or no difference in tinnitus symptoms compared with placebo, but the evidence is very uncertain (1 RCT; very low certainty evidence). No data was reported on serious adverse events. In adult patients with diverse vertigo aetiologies cinnarizine with dimenhydrinate treatment probably results in an improvement of vertigo symptoms compared to placebo (2 RCTs; moderate certainty evidence). Cinnarizine with dimenhydrinate may be well tolerated in patients with vertigo, with no serious adverse events encountered with cinnarizine with dimenhydrinate or placebo treatment (2 RCTs; low certainty evidence). From a health economic perspective, cinnarizine with dimenhydrinate was estimated to dominate no treatment (lower costs, more effects) in the treatment of vertigo caused by other disorders than Ménière’s disease. Over a 5-year period, the budget impact showed that cinnarizine with dimen hydrinate for the treatment of Ménière’s disease and vertigo caused by other disorders than Mé nière’s disease was associated with projected budget savings of CHF 1.2 million. Cost-effective ness was not assessed for betahistine or cinnarizine without dimenhydrinate for the treatment of Ménière’s disease, vertigo or tinnitus, due to a lack of evidence for a positive treatment effect in the clinical review. Despite the lack of evidence for a positive treatment effect of betahistine and cinnarizine, these treatments are currently reimbursed in Switzerland, and hence associated with a budgetary impact. Over a 5-year period, the budget impact of betahistine was projected to be CHF 17.2 million, for cinnarizine without dimenhydrinate projected to be CHF 0.8 million. Finally, the treatment of Ménière’s disease, vertigo and tinnitus was associated with several ethical, legal, social and organisational issues, including issues with diagnosis of disease, effects on patient’s quality of life and social interactions and the organisation of care.

Authors' methods: For the clinical systematic review a primary systematic literature search was conducted in PubMed (MEDLINE), Embase.com and the Cochrane Library to select randomised controlled trials (RCTs) on betahistine or cinnarizine with or without dimenhydrinate for vertigo, tinnitus and hearing loss caused by Ménière’s disease or for vertigo and tinnitus caused by other peripheral or central ves tibular disorders. Based on the output of the primary systematic literature search and expert opinion an additional systematic literature search was performed for RCTs on the most common indications that fall within the scope of the licensed indications for betahistine and cinnarizine with or without dimenhydrinate, i.e. vestibular migraine, vertebrobasilar insufficiency (VBI), transient ischemic attack (TIA), anterior inferior cerebellar artery (AICA) infarct, labyrinthine artery infarct and benign paroxysmal positional vertigo (BPPV). No additional search for comparative non-randomised stud ies was implemented. Studies were selected by applying pre-specified eligibility criteria during the selection process. Included RCTs were critically appraised with the revised Cochrane Risk of Bias tool for randomised trials (RoB 2) and the extracted data was summarised narratively. When event rates and sample sizes were reported, risk ratios and 95% confidence intervals were calculated. Results reported on outcomes with relevant data missing for valid data interpretation were not included in the data synthesis. The overall certainty of the evidence on outcome level was as sessed with GRADE. The economic systematic review followed a procedure similar to the clinical systematic review. The searches were conducted in PubMed (MEDINE), Embase.com, Cochrane Library, as well as the economic databases Tufts Medical Centre Cost-Effectiveness Analysis (CEA) and the international HTA database. A cost-effectiveness model was built to estimate the cost-effectiveness of cinnariz ine with dimenhydrinate for the treatment of vertigo caused by other disorders than Ménière’s dis ease. A decision tree was modelled with a time horizon of 28 days. Due to lack of utility data, outcomes were expressed as cost per one point reduction on the mean vertigo score. A Swiss healthcare payer perspective was used. Based on the findings of the clinical systematic review, no cost-effectiveness models were built for betahistine or cinnarizine without dimenhydrinate for the treatment of Ménière’s disease, vertigo or tinnitus. A budget impact analysis was run for betahis tine, cinnarizine without dimenhydrinate, and cinnarizine with dimenhydrinate, using information from SASIS on volume and the Spezialitätenliste on prices of these treatments. For cinnarizine with dimenhydrinate, costs from the cost-effectiveness model were used to complement the budget impact model. Ethical, legal, social and organisational (ELSO) issues were searched through the systematic literature searches and pragmatic searches and described narratively.

Project Status: Completed

URL for project: https://www.bag.admin.ch/en/use-of-betahistine-or-cinnarizine-in-menieres-disease-vertigo-disorders-or-tinnitus

URL for protocol: https://www.bag.admin.ch/dam/en/sd-web/aDJ7cv1lXia1/h0068bhis-hta-protocol.pdf

Year Published: 2025

URL for published report: https://www.bag.admin.ch/dam/en/sd-web/2poTDtRNlxDo/h0068bhis-hta-report.pdf

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health