Efficacy of cinnarizine/dimenhydrinate compared to betahistine in the Management of Adults with Peripheral Vestibular Disorder: A Systematic Review of Randomized Controlled Trials

Introduction

Rationale

Vertigo is a frequent symptom self-reported in the general population with a 12-month prevalence of 22.9% and an incidence of 1.8% seeking medical consultation. (1) Its prevalence rises with age and is about two to three times higher in women than in men. (2,3) Vertigo results when there is asymmetric dysfunction of the vestibular system in the inner ear.4 Pathogenesis may involve the peripheral vestibular system comprising of the semicircular canals, otoliths, hair cells and vestibular nerve up to the root entry zone in the brainstem. The Central vestibular system is composed of the vestibular nuclei, oculomotor nuclei, vestibuloocular reflex tracts, cerebellum, brainstem reticular formation, area postrema and other components. (5)

The ability to maintain balance is vital for the activities of daily living and vertigo imposes great limitations on patients’ ability to meet their daily responsibilities. Most patients with vertigo are prone to falls, eventually, this incapacity may lead to immobilization. The clinical impact of vertigo and its consequences sustain the need to develop efficient therapy to resolve the symptoms. (6)

Betahistine has been widely accepted as the standard treatment of peripheral vestibular disorders by increasing capillary blood flow of the labyrinthine vascular system.6 Cinnarizine, a calcium channel antagonist has a fixed combination with dimenhydrinate, an H1 receptor antagonist. Their mechanism of action benefits from a dual mode; cinnarizine, regulating calcium influx into the vestibular cells, in long term improves cerebral circulation and dimenhydrinate, which exerts regulatory effect on the vestibular nuclei. (6,7) Several studies have implicated both as beneficial in the management of vertigo. (6,7,8) However, further analysis is required to assess which drug is more effective in the management of patients with peripheral vestibular disorder. It is the aim of this study to compare the effectiveness of cinnarizine/dimenhydrinate with betahistine in the management of adult patients with peripheral vestibular disorder.

 

Methodology

Eligibility into the study requires a population of adults aged 18 years old and above with peripheral vestibular disorder who were given cinnarizine 20 mg/dimenhydrinate 40 mg per tab or betahistine 12 mg per tab to control their symptoms. Randomized controlled trials (RCTs) comparing the efficacy of administering cinnarizine/dimenhydrinate versus betahistine on patients with peripheral vestibular disorder and their effect on decreasing the intensity of vertigo were included. The side effects of the medications were also monitored. The primary outcome measure was decrease in mean vertigo score (Visual Analog Scale 0-4) comparable to decreasing intensity of vertigo whereas secondary outcome measures were: Mean Concomitant symptom score (Visual Analog Scale 0-4), Angular and lateral deviation values (Unterberger Stepping test) and Frequency of Caloric-induced nystagmus. Publications were limited to English language only. No publication date nor publication status were imposed.

Studies were identified by searching electronic Databases at the University of Santo Tomas (Cochrane, Medline, CINAHL, PubMed, ScienceDirect, DOAJ, Biomed Central), Libraries in Metro Manila, Hard copies of journals, Professional Societies. This search was applied to Medline, Cochrane, CINAHL, PubMed, ScienceDirect, DOAJ and Biomed central. The search was done from May 2012 to July 2012. The following search terms were used to search all trial registers and databases: betahistine*; cinnarizine*; and vertigo* or dizziness*.

assessment was performed independently in an unblinded standardized manner using CASP: Randomized Controlled Trial Appraisal Tool by two (2) reviewers. In case of disagreement, a third reviewer will be asked. criteria for study inclusion were adult participants 18 years and older who were diagnosed with peripheral vestibular disorder. Intervention given was cinnarizine 20mg/dimenhydrinate 40mg per tab and compared with betahistine 12mg per tab. Outcome measures should be decrease in intensity of vertigo and concomitant symptom scores. A data extraction sheet was developed, pilot tested on five randomly selected included studies and refined accordingly. One review author extracted the following data from included studies and the other author checked the extracted data. Disagreements were resolved by discussion between the two authors; if no agreement could be reached, it was planned that a third author would decide. Information was extracted from each included trial on: (1) characteristics of trial participants (including age, Body mass index, Method of diagnosis) and trials inclusion and exclusion criteria, (2) type of intervention (including dose, duration and frequency), (3) type of outcome measure (mean vertigo score for vertigo and concomtiant symptoms). To ascertain the validity of eligible randomized trials, pairs of reviewers working independently and with adequate relaibility determined the adequacy of randomization and concealment of allocation, blinding of patients, health care providers, data collectors, and outcome assessors; and extent of loss to follow up.

Improvement of symptoms by reduction in intensity of vertigo was the primary measure of treatment effect. The meta analyses were performed by computing the weighted mean difference in a fixed effect model using Generic Inverse Variance Method in RevMan. (5) Quantitative analyses were performed on an intent-to-treat basis and were confined to data derived from the period of follow up. The primary outcome measure was the relief of vertigo by a decrease in mean vertigo score via Visual Analog Scale (0-4). These include unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation and blackout. Secondary outcome measures include Mean Concomitant symptom score on Visual Analog Scale (0-4) which includes nausea, vomiting, sweating, tachycardia, tinnitus and impaired hearing. Angular and lateral deviation values (Unterberger Stepping test) and Frequency of Caloric-induced nystagmus were also measured. The questionnaire was developed by the authors and verified by the health authorities. Statistical pooling using Review Manager (5) Java 6 edition will be done. If not possible, narrative synthesis will be done and identifying grades of recommendation using NHMRC grades of recommendation. For each trial, we plotted the effect by the inverse of its standard error. The symmetry of such “funnel plots” was assessed visually. We assessed the possibility of publicaion bias by evaluating a funnel plot of the trial mean differences for asymmetry, which can result from the nonpublication of small trials with negative results. We acknowledge that others factors, such as differences in trial quality or true study heterogeneity could produce asymmetry in funnel plots.

 

Results of Literature Search

Initial search strategy yielded 96 related articles (Fig. 1). After duplicates were removed, 60 articles were screeend on the basis of title and abstract. A total of 10 full-text articles were further examined. Eight (8) of these studies were excluded for the following reasons: did not use combination drug, (1) used different dosage form, (4) different duration of treatment, (1) and different outcome measures. (2) Based on demographic data (table 1), patients were similar in both groups belonging to adults with an age range of 30-84 years old with a Body Mass Index of 23 to 29. Both studies compared the efficacy and tolerability of cinnarizine/dimenhydrinate against betahistine in patients with peripheral vestibular disorder.

 

Critical Appraisal of Articles Included

All articles included in the review met most of the criteria of the Critical Appraisal Skills Programme (CASP) by the International Center for Allied Health Evidence of the University of South Australia. The authors used the recommendtions of the National Health and Medical Research Council of Australia (December 2009) to determine the level of evidence and grade of recommendation.

 

Study Characteristics

The studies selected for review were randomized controlled trials published in English. The duration of the intervention was 4 weeks for both studies of Hahn and Cirek. The included studies involved 127 participants with the trial by Hahn being multicentric while Cirek et al involed only one centre. The main inclusion criteria entails adults (>30 y/o) with at least one vertigo symptom of medium intensity in a 5-point visual analog scale confirmed by Craniocorpography and Electronystagmography with calorics. Patients with confirmed Meniere’s disease, BPPV, Areflexia, Psychogenic Vertigo, with known contraindications to medications, pregnant and breastfeeding women were excluded in the studies. The intervention received was a fixed combination of cinnarizine 20mg/dimenhydrinate 40mg per tab, the comparator was betahistine 12mg per tab. Both medications were given three times a day. The primary outcome measure was decrease in mean vertigo score and secondary outcome measures include decrease in concomitant symptom score, angular and lateral deviation values (Unterberger Stepping test) and frequency of Caloric-induced nystagmus.

 

Assessment of risk of bias within studies

Both studies exhibited blinding of patients, health care providers and data collectors. Randomization was not concealed. We are uncertain whether outcome assessors were blinded. All patients included in the study were accounted for because they used the intent-to-treat principle. Both studies were funded by the pharmaceutical company which may be a source of bias.

 

Results of Individual Studies

The outcome measures were categorized as favors C or favors B when there were evidence of positive discrimination to either cinnarizine/dimenhydrinate or betahistine, respectively.

I. Primary Outcome

The mean vertigo score had improved to a significant degree with the intervention after 1 week of treatment in the trial by Cirek as evidenced by a p-Value of 0.002 (Table 2). The trial by Hahn produced no significant difference between the two treatments as evidenced by a p-Value of 0.85. The evidence is not sufficiently robust to determine comparative effectiveness between the two treatments after 1 week. The mean vertigo score had improved to a significant degree with the intervention after 4 weeks of treatment in both studies. This was evidenced by the p-Value 0.001 and 0.013 for the studies of Cirek and Hahn, respectively (Table 2). Based on the NHMRC guidelines, this systematic review presents level II evidence that the fixed combination of cinnarizine and dimenhydrinate significantly causes improvement in mean vertigo score when compared with betahistine. (Figure 2), shows the forest plot for the decrease in mean vertigo score comparing cinnarizine/dimenhydrinate with betahistine as well as a summary of the mean and standard deviation of the Mean Vertigo Score from the two studies taken after a week and after 4 weeks of treatment. The effect measure is the weighted mean difference for continuous outcome using standard deviation as a measure of variation. The results were analysed using the Generic Inverse Variance Method in Revman. There is moderate heterogeneity between the population in the subgroup after 1 week of treatment whereas there is little heterogeneity between the population in the subgroup after 4 weeks of treatment. In this figure, the 95% confidence intervals of both studies does not overlap 0 except the study of Hahn after 1st week of treatment. The 95% confidence interval of the overall estimate both after 1 week and after 4 weeks of treatment does not overlap 0. Therefore, there is statistical significance at the study level except for the study by Hahn after 1 week of treatment. There is also statistical significance at the meta-analysis level. The intervention group is better than the control group as the overall effect estimate and its 95% confidence interval are to the right of the line of no effect. The results favor the intervention, therefore, the pooled analysis showed that the combination of cinnarizine/dimenhydrinate is better than betahistine in decreasing the symptoms of vertigo in patients with Peripheral Vestibular Disorder.

II. Secondary Outcome

The Mean Concomitant symptom score had decreased to a significant degree with the intervention after 1 week of treatment in the trial by Hahn. This was evidenced by the p-Value 0.004. However, the trial of Cirek did not produce statistically significant results when compared with betahistine (Table 3). The evidence is not sufficiently robust to determine comparative effectiveness between the two treatments after 1 week. The Mean Concomitant symptom score had decreased to a significant degree with the intervention after 4 weeks of treatment in both trials. This was evidenced by the p-Value 0.009 and 0.023 by Cirek and Hahn, respectively (Table 3). This systematic review presents level II evidence that the fixed combination of cinnarizine/dimenhydrinate significantly causes reduction in the mean concomitant symptom score when compared with betahistine based on NHMRC guidelines. (Figure 3), shows the forest plot for the Mean Concomitant Symptom score comparing cinnarizine/dimenhydrinate with betahistine as well as a summary of the data for the mean and standard deviation from the two studies taken after a week and after 4 weeks of treatment. The results were analysed using the Generic Inverse Variance Method in Revman. There is a large heterogeneity between the studies reflected after one week of treatment and no heterogeneity between the two studies after 4 weeks of treatment. The heterogeneity may be due to difference in population, treatment or by chance. In this figure, the 95% confidence interval of both studies does not overlap 0. The 95% confidence interval of the overall effect estimate also does not overlap 0 in both subgroups. Therefore, there is statistical significance in both the study level and meta-analysis level. The intervention group is better than the control group as the overall effect estimate and its 95% confidence interval are to the left of the line of no effect. The results favor cinnarizine/dimenhydrinate, therefore, the pooled analysis showed that the combination of cinnarizine/dimenhydrinate is better than betahistine in decreasing the concomitant symptoms of vertigo in patients with Peripheral Vestibular Disorder.

The results in both studies were confirmed with vestibulospinal tests and vestibulocular tests. In both studies, the mean values of angular deviation, lateral sway and longitudinal deviation decreased during the course of the study, with no significant differences between the two treatments. Moreover, both therapies caused a decrease in frequency of induced nystagmus in caloric test but no statistically significant differences could be detected between the treatment groups. However data was not shown.

 

Risk of Bias Across Studies

For the outcome on decrease in mean vertigo score, evidence of heterogeneity (I2 = 66%) after 1 week and (I2 = 28%) after 4 weeks of treatment were seen. A funnel plot showing symmetry indicates a low risk of publication bias. Similarly, evidence of heterogeneity was seen in the outcome for decrease in mean concomitant symptom score after 1 week (I2 = 92). No evidence of heterogeneity was seen (I2 = 0) after 4 weeks of treatment. The heterogeneity in the subgroup may be influenced by the population involved, how the data were gathered or were there too few included studies to determine the risk of bias. Also, both studies have a high risk of reporting bias as only data with statistical significant difference were presented. No data were shown for the objective tests which are confirmatory outcome measures in the study.

 

Discussion

Overall, there is evidence that shows improvement in the mean vertigo score and decrease in mean concomitant symptom score in the treatment using cinnarizine/dimenhydrinate better than by treatment with betahistine after 4 weeks of treatment. These were shown in both trials with results in favor of cinnarizine/dimenhydrinate in decreasing the mean vertigo score and mean concomitant symptoms score after 4 weeks of treatment. However, there were equivocal results in the vestibulospinal tests and vestibulocular tests. These objective tests showed improvement of symptoms in both medications. The remarkable difference that the study showed was better symptom relief of patients given cinnarizine/dimenhydrinate in terms of the visual analog scale. However, the evidence is not sufficiently robust to determine comparative effectiveness of cinnarizine/dimenhydrinate and betahistine after 1 week of treatment. Only two randomized control trials with 1 month of duration of treatment compared the two medications. It is possible that the trials did not evaluate enough patients to allow definitive conclusions. Moreover, the studies did not explain the inconsistencies regarding the results. There were significant differences in the decrease in mean vertigo score and mean concomitant symptom score but no significant differences between the two treatment groups in the vestibulospinal and vestibulocular tests.

The systematic review shows level II evidence with a moderate risk of bias, with some inconsistency reflecting genuine uncertainty around the clinical question, substantial clinical impact, populations studied in the evidence are similar to the target population in the guideline, and applicable to our healthcare context. The authors give this level of evidence Grade C recommendation. The body of evidence provide some support for recommendation but care should be taken in its application. Therefore, the systematic review shows that the fixed combination of cinnarizine/dimenhydrinate could be used to decrease vertigo and cause improvement of symptoms in patients with peripheral vestibular disorder.

 

Limitations

The meta-analysis reported here combines data across studies in order to estimate treatment effects with more precision than in a single study. Nonetheless, the study possesses inherent weaknesses. The main limitation of this study is the number of studies available for review. The inability to retrieve unpublished studies was also a drawback of this study. We were not able to retrieve some published articles because of the absence of such a searching mechanism. Publication bias might account for some of the effect we observed. Heterogeneity as shown in the asymmetrical funnel plot suggests that selective reporting may have led to an overestimation of an effect. In addition, incomplete reporting of the results particularly the objective tests may hamper the interpretation and synthesis of the included studies.

 

Conclusions 

In summary, this systematic review of Randomized Control Trials until July 2012 suggests that the fixed combination of cinnarizine/dimenhydrinate could decrease the intensity of vertigo and improve the concomitant symptoms better than betahistine after 4 weeks of treatment. However, little data is evident to draw conclusion with the objective tests. A logical next step for future trials would be comparison of this protocol against a fixed combination of the cinnarizine/dimenhydrinate with different dosage, a longer duration of treatment and a bigger population. Several studies have already been identified during the search for literature. To date, we are unaware of additional studies dealing with comparing betahistine with cinnarizine/dimenhydrinate on vertigo outcome.

 

Disclosure

The authors have nothing to disclose.

No funding was received in the conduct of this study.

 

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Figure 1. Flow Diagram

 

Figure 2. Forest plot comparing cinnarizine/dimenhydrinate versus betahistine in decreasing mean vertigo score

 

Figure 3. Forest plot comparing cinnarizine/dimenhydrinate versus betahistine in decreasing concomitant symptom score

 

Table 1. Mean Age and Body Mass Index of Study Population

Parameter

Trials (n=127)

cinnarizine/dimenhydrinate (n=63)

betahistine (n=64)

Mean Age

Hahn et al, 2008

54.3 ± 12.1

53.1 ± 11.0

 

Cirek et al, 2005

49.60 ± 12.31

48.58 ± 11.76

Mean Body Mass Index

Hahn et al, 2008

26.1 ± 3.3

26.0 ± 3.7

 

Cirek et al, 2005

26.99 ± 4.16

26.06 ± 3.34

 

Table 2. Decrease in Mean Vertigo Score

Trials

 

cinnarizine/dimenydrinate

betahistine

p-value

Interpretation

Level of evidence

1 week treatment

4 weeks treatment

1 week treatment

4 weeks treatment

1 week treatment

4 weeks treatment

Cirek

2005

0.65 ± 0.42

1.07 ± 0.58

0.31 ± 0.38

0.51 ± 0.56

0.002

0.001

Favors C

Level II

Hahn

2008

1.30 ± 0.65

0.97 ± 0.62

1.27 ± 0.54

0.64 ± 0.38

0.83

0.013

Equivocal after 1 week; favors C after 4 weeks

 

Table 3. Decrease in Concomitant Symptom Score

Trials

 

cinnarizine/dimenydrinate

betahistine

p-value

Interpretation

Level of evidence

1 week treatment

4 weeks treatment

1 week treatment

4 weeks treatment

1 week treatment

4 weeks treatment

Cirek 2005

-1.50 ± 0.48

0.72 ± 0.49

-0.32 ± 0.39

-0.44 ± 0.50

0.111

0.009

Equivocal after 1 week and Favors C after 4 weeks treatment

Level II

Hahn 2008

-1.02 ± 0.80

-1.15 ± 0.83

-0.56 ± 0.60

-0.73 ± 0.63

0.004

0.023

Favors C

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