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Ditans vs Gepants: A Systematic Review and Indirect Network Meta-Analysis for Comparative Analysis of Efficacy and Safety
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315991
Keywords: 5HT1F, acute migraine, CGRP, lasmiditan, rimegepant, ubrogepant
A chronic paroxysmal disease of neurovascular origin, migraine, has always been one of those diseases which on acute presentation can incapacitate the patient in every aspect. This debilitating disease has a prevalence of around 14%, with an estimated years of life lived with disability (YLDs) as 11.2% among the women of age group 15–49 years.[1],[2] Clinically, the acute attack of migraine is characterized by pulsatile unilateral headache of moderate to severe intensity, lasting for 4–72 h, and accompanied with either of nausea, vomiting, phonophobia or photophobia.[3] And such frequent attacks somehow get translated into emotional as well as socio-economic burden.[4] To neutralize these impacts, drugs with diverse mechanisms of action are accessible, amongst which the most commonly used are triptans and non-steroidal anti-inflammatory drugs.[5] But these routinely used drugs which provide therapeutic benefit of about 21-32% and 8-14%, respectively, have their own detrimental effects owing to which they either appear to be clinically ineffective, or get contraindicated.[6],[7] And after almost three decades of launch of first triptan (sumatriptan), a new drug, lasmiditan, with different mechanism of action, was approved for warding off the symptoms of acute migraine. This was then soon followed by approval of another group of drugs, gepants (ubrogepant and rimegepant), for the same affliction. Lasmiditan, a highly selective 5HT1F receptor agonist, acts more on the neuronal changes produced during an acute attack of migraine, without bringing about any vasoactive effects, unlike triptans, which non-specifically bind to 5HT1B,1D,1F receptors.[8],[9] On the other hand, the gepants, by their antagonistic action on CGRP receptors, alleviate the symptoms of acute migraine attack.[10],[11] There is substantial evidence regarding the efficacy and safety profile of the first line drugs used in management of the acute attack of migraine. But the same, for the newly approved drugs, is quite limited, hence making it crucial to discuss whether these novel drugs could yield a better therapeutic benefit with tolerable safety profile, as compared to their predecessors, as well as, if they could prove to be helpful in those migraineurs in whom the first line drugs are contraindicated or clinically ineffective. Therefore, an umbrella systematic review and meta-analysis has been undertaken, with an objective to comprehend and comment on these queries.
Current systematic review and meta-analysis was performed as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement (PRISMA).[12] As the analysis is based on already published studies ethical approval is not obligatory. Literature search and data extraction Two of the authors systematically searched several databases including Pub Med, Cochrane library, Clinical Trial Registry https://clinicaltrials.gov/from January 2015 to March 2020 using the keywords: lasmiditan and acute migraine; ubrogepant and acute migraine, and rimegepant and acute migraine. Other studies were also hand-searched to improve the validity and discussion. PICOS criteria [Figure 1]
Secondary Outcomes: Proportion of patients:
The data extraction was performed collectively by all the authors. We included all the randomized controlled trials conducted for the newer drugs. Important baseline information was extracted from them, which included name of authors, number of patients enrolled in the intervention and other group, mean age, proportion of females among patients, duration of illness, and methodology in detail. Quality assessment of individual study/studies This was done as per the appraisal criteria mentioned in Jadad scale.[13] The individual clinical trials were scrutinized forrandomization (0–2 points), blinding (0–2 points), and dropouts and withdrawals (0–1 points). A maximum of 05 points can be scored by any trial, while a study with score ≥03 is considered to be of high quality.[14] Quality assessment of individual study along with the risk of bias was performed by as per the risk of bias 2 tool (RoB 2) tool and has been duly demonstrated in the respective forest plots.[15] Statistical analysis Since all the variables under evaluation had dichotomous outcome, the authors assessed their risk ratios (RR) with 95% confidence intervals (CIs). The heterogeneity among these studies was evaluated using the I2 statistics, wherein any study with I2 >50% is considered to be significantly heterogeneous. Along with that the source of heterogeneity was also addressed if any significance was observed, by performing the sensitivity analysis.[16] And for assessing any publication bias funnel plot (for primary outcome) was employed. We utilized software Review Manager Version 5.4 for windows, for conducting this meta-analysis, wherein we had applied random-model effects. Network meta-analysis Owing to the lack of head-on trials of these drugs with an active comparator, an indirect network meta-analysis was done, so as to review about the comparative efficacy amongst these new drugs.[17]
Literature search and study characteristics The initial search yielded around 143 studies that is, 61 of lasmiditan, 47 of ubrogepant, and 35 of rimegepant. On further exploring the Clinical Trial Registry https://clinicaltrials.gov/we found a total of 07, 04 and 07 clinical trials for lasmiditan, ubrogepant, and rimegepant respectively which belonged to phase III. On the other hand, in Pub Med, the published randomized double-blind controlled trials for lasmiditan, ubrogepant, and rimegepant were 02, 02, and 03 respectively.[18],[19],[20],[21],[22],[23],[24] While going through, one study (assessing long-term safety) for each drug was found to be either on-going/completed, but since they were open label, they were not included for analysis.[25],[26],[27] Each drug is also being currently evaluated for its major indication in different settings/patient population. Eventually, we included only 07 RCTs, which were multi-centric and were conducted at United States of America. None of the trials were with active comparator. All the relevant characteristics of RCTs have been mentioned in [Table 1]. The common characteristics of these RCTs were that the diagnosis of migraine in all of them was established with the help of same guideline, and majority of the recruited participants were female.[3] Further all the participants were having at least one year history of migraine while chronic migraine patients were excluded.
Primary outcome The funnel plot indicates publication bias [Figure 2]. As no heterogeneity (I2 = 27%, heterogeneity P = 0.08, [Figure 3]) was observed, sensitivity analysis was not conducted. For primary outcome, all the newer drugs significantly increased the proportion of patients who were headache free at 2 h compared to placebo (RR = 1.73; 95% CI = 1.54–1.94; P = <0.00001).
Secondary outcomes Among the secondary outcomes, again all the newer drugs outdid placebo in terms of efficacy. A significant increase in the proportion of patients MBS free at 2 h was noted (RR = 1.39; 95% CI = 1.30-1.49; P = <0.00001). Similarly, a significant higher proportion of patients who had sustained pain freedom 2–24 h (RR = 1.71; 95% CI = 1.42–2.06; P < 0.00001), were free of any disability at 2 h post-dose (RR = 1.41; 95% CI = 1.32–1.51; P < 0.00001) was observed. Proportion of patients experiencing adverse events was more in treatment group compared to placebo (RR = 1.32; 95% CI = 0.93–1.87; P = 0.12) [Figure 4], [Figure 5], [Figure 6], [Figure 7].
Indirect comparison An indirect comparison for all the outcome criteria was performed among these newly approved drugs. For the primary end-point, the order of effectiveness was found to be lasmiditan >rimegepant >ubrogepant that is, in indirect comparison, more number of patients receiving lasmiditan showed freedom from pain at 2 h by 9.5% and 9.8% compared to rimegepant and ubrogepant respectively. And this similar pattern was observed for proportion of patients MBS free and disability free at 2 h. More number of patients receiving lasmiditan showed freedom from MBS as compared to rimegepant and ubrogepant by 3.4% and 2.1% respectively. In another outcome, more number of patients receiving lasmiditan were disability free at 2 h compared to rimegeapant and ubrogepant by 0.4% and 2.9% respectively. In these three outcome criteria rimegepant showed better efficacy than ubrogepant. But for the effectiveness in providing sustained pain freedom from 2-24 h, the order somehow got reformed as rimegepant >lasmiditan >ubrogepant that is, rimegepant was superior to lasmiditan and ubrogepant by 0.8% and 2.1% respectively. Patients receiving lasmiditan experienced maximum adverse events among three which was more than rimegepant and ubrogepant by 14.5% and 17.3% respectively. The detailed estimates for the same have been elucidated in [Figure 8].
This network meta-analysis of randomized phase III clinical trials for the treatment of acute attack of migraine is based on the well-reported studies, which indicates towards the cogency of conducting an indirect comparison among these new drugs. The usual sexual and epidemiological distribution observed among the migraineurs was reflected in these studies too, as most of the participants enrolled were female, and in their 4th decade of life.[28] Since, the trials compared in this meta-analysis did not exhibit any heterogeneity, as well as contributed equally to the overall effect (similar weight of each study), hence, the result illustrated in this analysis, that is, the newer drugs demonstrated significant improvement as compared to placebo, can be considered as accurate. Lasmiditan, the 5HT1F agonist, proved to be superior in all the outcomes in indirect analysis, except for in providing sustained freedom from pain 2-24 h, wherein rimegepant outdid, probably by virtue of its longer half-life.[29] The reason why ubrogepant appeared to be least effective amongst the three drugs could be the dose (50 mg/d) which was taken in for analysis. The maximum recommended dose is 100 mg/d, but due to non-availability of RCTs with this dose, we could not include this dose for the analysis. The comparison could have been more precise if there would have been RCTs with this maximum recommended dose. The least adverse events were noted in ubrogepant group followed by rimegepant and lasmiditan. In our results, rimegepant was better than ubrogepant in all the efficacy outcomes which is similar to the previous analyses.[30],[31] Before making a final assumption, it is imperative to mention about the adverse drug reactions (ADRs), as acceptability of a drug significantly depends upon them. Despite being more effective than other two drugs, lasmiditan has got unfavorable safety profile. Dizziness, somnolence, paresthesia, were the common ADRs (≥2%) observed, and these ADRs could impair routine activities of a migrainuer. And because of these unwanted effects, this 5HT1F agonist, also becomes a potential target for drug-drug interactions e.g., risk of CNS depression, serotonin syndrome etc.[18],[19] The other two drugs had relatively mild ADRs which may contribute to their patient acceptability. Based on their adverse effect profile these newer drugs may offer an attractive option where triptans are contraindicated due to their cardiac adverse effects or NSAIDs are not useful due to their gastro-intestinal adverse effects. But the appropriate long-term safety and tolerability can only be ascertained when the results of open-label trials are published. Limitations Certain limitations exist in this systematic review and meta-analysis that is,
The results of this network meta-analysis indicate that all the newer drugs are effective in relieving acute attack of migraine and associated symptoms, as compared to placebo. Lasmiditan appears to have an edge over the others in terms of efficacy but it comes with its own burden, that is, unsuitable adverse effect profile. Considering both the efficacy and safety profile of these drugs, rimegepant 75 mg/d emerges to be promising in alleviating the manifestations of acute attack of migraine in real-world. The approved dose of ubrogepant ranges between 50 and 100 mg/d, 50 mg/d ubrogepant seems inferior to rimegepant; however ubrogepant may 100 mg/d may be equivalent to the rimegepant. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1]
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