Comparative Efficacy of Oral Calcitonin‑Gene–Related Peptide Antagonists for the Treatment of Acute Migraine: Updated Meta‑analysis

Dong Kyoung Ha1 · Min Ji Kim1 · Nayoung Han2 · Jae‑Hwan Kwak1,3 · In‑hwan Baek1,3

Accepted: 27 December 2020 / Published online: 11 January 2021
The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature 2021

Abstract
Background and Objective The calcitonin gene-related peptide (CGRP) is a new therapeutic target in migraine—a common disorder resulting in reduced quality of life. The aim of this study was to compare the clinical efficacy of five oral CGRP antagonists with that of a placebo and triptans against acute migraine via meta-analysis.
Methods Suitable randomized controlled trials (RCTs) were searched in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) to compare the efficacy of oral CGRP antagonists with that of a placebo and triptans against acute migraine. Review Manager 5.4 was used for data analysis.
Results A total of 17 trials met the eligibility criteria and were studied in detail. The CGRP antagonists were significantly
more effective than the placebo with respect to outcomes such as pain freedom at 2 h post-dose (odds ratio = 2.11; 95% confidence intervals [CIs] = 1.90–2.35) and pain relief at 2 h post-dose (odds ratio = 1.94; 95% CIs = 1.70–2.21). Similar results were found in the subgroup analysis conducted to compare the clinical efficacy of the FDA-approved oral CGRP antagonists (ubrogepant and rimegepant) and placebo. However, the CGRP antagonists were less effective than the triptans with respect to outcomes such as pain freedom at 2 h post-dose (odds ratio = 0.66; 95% CIs = 0.55–0.78) and pain relief at 2 h post-dose (odds ratio = 0.78; 95% CIs = 0.66–0.93).
Conclusion CGRP antagonists are more effective than placebo against acute migraine; however, further studies are required
to consider CGRP antagonists as standard first-line treatment for acute migraine instead of triptans, especially in patients with co-existing cardiovascular diseases.

Jae-Hwan Kwak and In-hwan Baek contributed equally to this study.

Jae-Hwan Kwak [email protected]
In-hwan Baek [email protected]
1 College of Pharmacy, Kyungsung University, 309, Suyeong-ro, Nam-gu, Busan 48434, Republic of Korea
2 College of Pharmacy and Research Institute
of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
3 Functional Food and Drug Convergence Research Center, Industry-Academic Cooperation Foundation, Kyungsung University, 309, Suyeong-ro, Nam-gu, Busan 48434, Republic of Korea

1 Introduction
Migraine is a highly disabling neurological disorder. Its prevalence among adults has been reported in up to 15% of the population, and it is especially more promi- nent in females [1]. It is characterized by episodic and severe headache associated with nausea, photophobia, and/or phonophobia; it may appear with aura (20–30% of cases) or without aura (approximately 70% of cases) [2–4]. Although the pathophysiology of migraine has not yet been fully elucidated, migraine is associated with structural and functional changes in the central nervous system; various parts of the trigeminal system involving somatosensory, autonomic, endocrine, and arousal net- works are necessary for the expression of associated com- plicated symptoms [5].
Over the last decade, several medications have been approved for both acute and prophylactic management of migraine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a convenient first-line treatment for mild-to-moder- ate migraine or historically responsive severe attacks [6]. Triptans, which are 5-hydroxytryptamine (5-HT; serotonin)1B/1D receptor agonists (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan), have been used as the standard first-line treatment for moderate-to-severe migraine, or mild-to- moderate attacks unresponsive to nonspecific analgesics [7]. Triptans can also cause the constriction of coronary arteries, which is mediated mainly through the activation of the 5-HT1B receptor; thus, triptan therapy is contraindi- cated in patients with certain cardiovascular diseases [8]. Because migraine is a risk factor associated with cardio- vascular diseases, this contraindication excludes triptans in a large proportion of migraine patients [7]. Moreover, only 12–40% of patients receiving triptans experience freedom from pain at about 2 h after drug intake [9]; triptan non- responders are still a clinical limitation for the manage- ment of migraine. In addition, ineffective acute treatment of migraine is associated with a two-fold increased risk of new-onset chronic migraine, and current medications have the disadvantage of inducing medication-overuse headache that leads to the intake of more drugs [7, 10, 11]; thus, novel treatments are necessary for the effective manage- ment of acute migraine.
Recently, novel drugs that target the calcitonin gene-
related peptide (CGRP) via the trigeminal sensory neu- rons or its receptor have been developed for the treatment of migraine. Monoclonal antibodies against CGRP or its receptor effectively prevent migraine attacks, whereas small-molecule CGRP receptor antagonists, also called gepants, are effective for acute relief of migraine headache [1, 7]. In contrast to olcegepant, which is administered

intravenously due to its low oral bioavailability, new oral CGRP antagonists (atogepant, BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) have been developed, except zavegepant (formerly known as vazege- pant; BHV-3500), which is an intranasal gepant [7, 12]. Although the development of several oral CGRP antago- nists (BI44370TA, MK-3207, telcagepant) was discontin- ued due to their liver toxicity, ubrogepant (MK-1602) and rimegepant (BMS-927711; BHV-3000) were approved for the treatment of acute migraine by the US Food and Drug Administration (FDA) in December 2019 and Feb- ruary 2020, respectively [13]. Unlike all other oral CGRP antagonists developed for the treatment of acute migraine to date, atogepant has been indicated as an antimigraine prophylactic agent, and is currently under evaluation in Phase III trials [14].
Although individual randomized controlled trials (RCTs) have demonstrated the clinical efficacy of each oral CGRP antagonist, systematic review and meta-analyses are required to verify the comparative efficacy of oral CGRP antagonists and placebo or triptans in acute migraine treatment. To the best of our knowledge, seven meta-analyses have been conducted to determine the efficacy of CGRP antagonists [15–21]. Among them, five of the studies were meta-analy- ses of individual CGRP antagonists consisting of only one or two drugs, while only two studies demonstrated the efficacy of CGRP antagonists for all studied treatments. However, the previous studies did not include RCTs for rimegepant and ubrogepant, which are reported very recently. Moreo- ver, the clinical efficacy of gepants targeting CGRP in the treatment of acute migraine is still controversial compared to that of triptans.
In order to clarify these issues, we performed an updated meta-analysis of all existing RCTs on five oral CGRP antag- onists (BI44370TA, MK-3207, rimegepant, telcagepant and ubrogepant). The clinical efficacy of oral CGRP antagonists versus that of a placebo and triptans was compared.

2 Methods
2.1 Literature Search Strategy

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analy- ses (PRISMA) guidelines [22]. We performed a systematic review of the literature with a meta-analysis of the studies in which the comparison of clinical efficacy between oral CGRP antagonists and placebo or triptans in acute migraine treatment was assessed in the following databases: PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry

Platform (WHO-ICTRP). The literature search was per- formed from the date of establishment to August 28, 2020. Based on our preliminary research, there were five oral CGRP antagonists that have been used in clinical trials to develop treatment for acute migraine [7, 12]. The search query was as follows: “migraine” AND (“calcitonin gene- related peptide antagonist” OR “BI 44370 TA” OR “MK- 3207” OR “Rimegepant” OR “BMS-927711” OR “BHV-
3000” OR “telcagepant” OR “MK-0974” OR “ubrogepant” OR “MK-1602”). These search terms were adapted from dif- ferent bibliographic databases in combination with database- specific filters, if available. The search strategy was used to extract titles and abstracts of relevant studies published in English.
2.2 Eligibility Criteria and Study Selection

Based on the participants, intervention, comparison, out- comes (PICO) strategy, inclusion criteria were as follows:
(a) adult patients aged ≥ 18 years, (b) patients diagnosed with migraine with/without aura as defined by the Inter- national Headache Society (IHS) criteria, (c) treatment intervention for acute migraine, (d) comparisons of efficacy of the treatment intervention to placebo or an active com- parator, and (e) outcomes included pain freedom and pain relief at 2 h post-dose. Duplicate records were removed at the beginning during review of titles or abstracts, and then full texts of the selected articles were retrieved for further study. Study exclusion criterion was (a) irrelevant nonclini- cal studies such as in vitro assays, bioanalytical development and validation studies, animal studies; (b) review papers or expert opinions; (c) long-term safety studies; (d) studies exploring preventive treatment of migraine; (e) Phase I or open-labeled trials, (f) published full texts in languages other than English; and (g) clinical trials with no results.
Identified citations were then tabulated in a Microsoft Excel 2016 spreadsheet and full-text articles were retrieved. These articles were appraised for inclusion according to a pre-specified inclusion criterion. The final set of articles qualified for meta-analysis was then subjected to quality scoring and data extraction by primary investigators.
2.3 Data Extraction and Risk of Bias Assessment

Two investigators independently identified relevant litera- ture. Disagreements were resolved through discussion. All data were extracted independently by two investigators using Microsoft Excel software in accordance with the mentioned inclusion and exclusion criteria. Data based on literal infor- mation, patient demographics, detailed information on the study design, type of oral CGRP antagonists, type of com- parator (placebo and/or triptans), and all clinical efficacy out- come measures were extracted for each study. Raw data were

compared and further cleaned by a third reviewer to avoid any data extraction errors, and then transferred to Review Manager
5.4 for further analysis.
The risk-of-bias (ROB) tool for quality assessment in each study was studied and plotted using Review Manager 5.4 soft- ware. We used the Cochrane Collaboration ROB tool to evalu- ate selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias in each study. Any disa- greements during the bias assessment were resolved through discussion among all authors.
2.4 Outcome Measures

The primary measurable outcomes included pain freedom at 2 h post-dose and pain relief at 2 h post-dose. Pain freedom was defined as the resolution of severe or moderate pain to no pain. Pain relief was defined as a decrease in severity of pain from severe to moderate or moderate to mild or no pain. The newest IHS and FDA guidelines recommended the absence of most bothersome symptoms (MBS) at 2 h post-dose as primary out- come; we included the absence of MBS after treatment with the FDA-approved oral CGRP antagonists (rimegepant and ubrogepant) as the primary endpoint for subgroup analysis. Secondary endpoints included absence of photophobia, pho- nophobia and nausea at 2 h post-dose, sustained pain freedom and sustained pain relief from 2 to 24 h post-dose, sustained pain freedom and sustained pain relief from 2 to 48 h post- dose, and total migraine freedom at 2 h post-dose.
2.5 Statistical Analysis

The clinical efficacy of oral CGRP antagonists was com- pared to that of placebo or triptans. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each study and the study comparisons. A chi-square (Chi2) test was utilized to determine homogeneity and I2. The fixed- effects model was used when heterogeneity was not signifi- cant (I2 < 50%), otherwise a random-effects model was used to calculate the pooled effects values in presence of signifi- cant heterogeneity. The test for measurement of overall effect was also conducted with all the study results combined. A funnel plot was used to identify potential publication bias. All analyses were carried out using Review Manager Rev- Man 5.4 (The Nordic Cochrane Center, The Cochrane Col- laboration, Copenhagen, Denmark).

3 Results
3.1 Selection of Studies

A total of 502 references were identified using the search strategy. After removing 232 duplicate records found

during title and abstract screening, 270 studies were selected. Full texts were retrieved for further evalua- tion. During the pre-screening process, 253 studies were excluded that did not meet inclusion criteria. Finally, 17 studies including 16 full-text publications and one unpub- lished study (ubrogepant, NCT01657370) were selected for the present meta-analysis [23–39]. These 17 clinical trials included 13,995 patients: oral CGRP antagonists included 8923 patients, placebo included 4778 patients, and triptans included 839 patients. One trial compared BI44370TA with placebo or triptan (eletriptan), one trial compared MK-3207 with placebo, four trials compared rimegepant (BMS-927711; BHV-3000) with placebo or triptan (sumatriptan), seven trials compared telcagepant (MK-0974) with placebo or triptans (rizatriptan or zolmi- triptan), and four trials compared ubrogepant (MK-1602) with placebo. These studies were published between 2008 and 2019. The flow diagram of results of the electronic search is shown in Fig. 1, and a summary of trials is pre- sented in Table 1.

3.2 Quality and Risk of Bias Assessment

Results of the ROB assessment of the included trials are shown in Fig. 2. All the trials had a low ROB. However, two trials on rimegepant (NCT01430442 and NCT03235479) were judged as having ‘unclear’ risk of bias because of incomplete data of outcome analysis. In addition, one trial on rimegepant (NCT03235479) did not address the detailed protocol of its multicenter randomized controlled trial and was judged as having ‘unclear’ risk of bias of selective reporting.
3.3 Oral CGRP Antagonists versus Placebo

CGRP antagonists consisting of five oral CGRP antago- nists (BI44370TA, MK-3207, rimegepant, telcagepant and ubrogepant) showed significant efficacy compared to that of placebo with respect to all primary (pain freedom at 2 h post-dose and pain relief at 2 h post-dose) and secondary outcomes (absence of photophobia, phonophobia and nau- sea at 2 h post-dose, sustained pain freedom and sustained

Fig. 1 Flow of the study selec- tion

Table 1 Characteristics of studies included in the meta-analysis of oral CGRP antagonists for treatment of acute migraine

relief at 2 h post-dose/absence of photophobia at 2 h post-dose/ absence of phonophobia at 2 h post-dose/absence of nausea at 2 h post-dose
Connor et al. [27] Telcagepant 50, 140, 150, 280, 300 Placebo 3 Pain freedom at 2 h post-dose/pain
relief at 2 h post-dose/absence of photophobia at 2 h post-dose/ absence of phonophobia at 2 h
post-dose/Absence of nausea at 2 h post-dose
Ho et al. [28] Telcagepant 140, 150, 280, 300 Placebo 3 Pain freedom at 2 h post-dose/
pain relief at 2 h post-dose/ pain freedom consistency at 2 h post-dose/pain relief consist- ency at 2 h post-dose/absence
of photophobia at 2 h post-dose/ absence of phonophobia at 2 h post-dose/absence of nausea at 2 h post-dose

Connor et al. [30] Telcagepant 280, 300 Placebo/rizatriptan
10 mg

3Percentage of patients with ≥ 1 of the following triptan-related adverse events in the 14 days post-dose

Hewitt et al. [26] Telcagepant 280, 300 Placebo 2 Pain freedom at 2 h post-dose
Ho et al. [31] Telcagepant 280, 300 Placebo 3 Pain freedom at 2 h post-dose
Voss et al. [37] Ubrogepant 1, 10, 25, 50, 100 Placebo 2 Pain freedom at 2 h post-dose/
headache response at 2 h post- dose

MBS most bothersome symptom
aUnpublished study

relief at 2 h post-dose

pain relief from 2 to 24 h post-dose, sustained pain freedom and sustained pain relief from 2 to 48 h post-dose, and total migraine freedom at 2 h post-dose).

Primary endpoints were reported in sixteen studies. In our pooled data, 1811 of 8331 patients (21.7%) achieved pain freedom at 2 h post-dose in oral CGRP antagonists

Fig. 2 Risk of bias assessment of included trials

compared with 563 of 4778 patients (11.8%) in placebo. Heterogeneity was low (Chi2 = 20.26; I2 = 26%; p = 0.16), and therefore the fixed-effects model was used. Pooled esti- mates for pain freedom at 2 h post-dose significantly favored oral CGRP antagonists over placebo (OR = 2.11, 95% CI
= 1.90–2.35, p < 0.00001). Further, pain relief at 2 h post- dose was reported in 4548 of 8121 patients (56.0%) in oral CGRP antagonists and in 1957 of 4763 patients (41.1%) in placebo. Comparison of pain relief at 2 h post-dose between oral CGRP antagonists and placebo showed heterogeneity (Chi2 = 39.95, I2 = 62%, p = 0.0005); thus, a random-effects model was used. Pain relief at 2 h post-dose in oral CGRP antagonists was superior (OR = 1.94, 95% CI = 1.70-2.21, p
< 0.00001) to that in placebo (Fig. 3). To assess for publica- tion bias, a funnel plot was generated but no apparent trend was observed.
Similar results were found while comparing secondary endpoints between the oral CGRP antagonists and placebo (Fig. 4). Oral CGRP antagonists showed superior efficacy to placebo with respect to all secondary outcomes as fol- lows: (A) absence of photophobia at 2 h post-dose (16 stud- ies, 12,727 patients; OR = 1.63, 95% CI = 1.43–1.87, p
< 0.00001; I2 = 59%), (B) absence of phonophobia at 2 h

post-dose (16 studies, 11,945 patients; OR = 1.57, 95% CI
= 1.46–1.70, p < 0.00001; I2 = 44%), (C) absence of nausea at 2 h post-dose (16 studies, 11,754 patients; OR = 1.39,
95% CI = 1.28–1.51, p < 0.00001; I2 = 37%), (D) sustained
pain freedom from 2 to 24 h post-dose (15 studies, 11,972
patients; OR = 2.44, 95% CI = 2.16–2.75, p < 0.00001; I2
= 17%), (E) sustained pain relief from 2 to 24 h post-dose (12 studies, 9762 patients; OR = 2.10, 95% CI = 1.91–2.31, p < 0.00001; I2 = 24%) (F) sustained pain freedom from 2 to 48 h post-dose (9 studies, 7743 patients; OR = 2.68, 95% CI = 2.24–3.20, p < 0.00001; I2 = 0%), (G) sustained pain relief from 2 to 48 h post-dose (5 studies, 4625 patients; OR
= 2.07, 95% CI = 1.80–2.39, p < 0.00001; I2 = 0%), and
(H) total migraine freedom at 2 h post-dose (7 studies, 5719 patients; OR = 2.28, 95% CI = 1.89–2.73, p < 0.00001; I2
= 0%).
To investigate the source of heterogeneity for pain relief and absence of photophobia at 2 h post-dose, we performed a sensitivity analysis by sequentially excluding each single study. Study by Ho et al. [32] was reduced heterogeneity for the absence of photophobia at 2 h post-dose (Chi2 = 21.31, I2 = 34%, p = 0.09). However, overall results of pain relief at 2 h post-dose showed that the omission of one study did

Fig. 3 Forest plots for primary outcomes to compare oral CGRP antagonists and placebo. CGRP calcitonin gene-related peptide

not significantly affect heterogeneity. After removing two studies [25, 29], heterogeneity among studies was reduced for pain relief at 2 h post-dose (Chi2 = 18.45, I2 = 30%, p
= 0.14).
3.4 Oral CGRP Antagonists Versus Triptans

Triptans showed superior efficacy compared to CGRP antag- onists (BI44370TA, rimegepant, telcagepant) with respect to all primary outcomes (pain freedom at 2 h post-dose and pain relief at 2 h post-dose). Primary endpoints were reported in five studies. In our pooled data, 611 of 2154 patients (28.4%) achieved pain freedom at 2 h post-dose in oral CGRP antagonists compared with 317 of 839 patients (37.8%) in the triptans. Heterogeneity was low (Chi2 = 2.66;

I2 = 0%; p = 0.62), and hence the fixed-effects model was used. Pooled estimates for pain freedom at 2 h post-dose significantly favored triptans over oral CGRP antagonists (OR = 0.66, 95% CI = 0.55–0.78, p < 0.00001). In addition,
pain relief at 2 h post-dose was reported in 1266 of 2125 patients (59.6%) in oral CGRP antagonists and by 530 of 825 patients (64.2%) in triptans. Comparison of pain relief at 2 h post-dose between oral CGRP antagonists and triptans showed homogeneity (Chi2 = 1.57, I2 = 0%, p =0.81); thus, a fixed-effects model was used. Pain relief at 2 h post-dose for triptans was superior (OR = 0.78, 95% CI = 0.66-0.93, p
= 0.005) to that of oral CGRP antagonists (Fig. 5).
Comparative study on secondary outcomes between oral CGRP antagonists and triptans showed absence of photo- phobia/phonophobia/nausea at 2 h post-dose and sustained

Fig. 4 Forest plots for secondary outcomes to compare oral CGRP antagonists and placebo. CGRP calcitonin gene-related peptide

pain freedom from 2 to 24 h post-dose in five studies, whereas sustained pain relief from 2 to 24 h post-dose and total migraine freedom at 2 h post-dose was reported in three studies. Sustained pain freedom from 2 to 48 h post-dose was reported in two studies. All secondary outcomes such as absence of photophobia at 2 h post-dose (Chi2 = 4.60, I2
= 13%, p = 0.33), absence of phonophobia at 2 h post-dose (Chi2 = 2.23, I2 = 0%, p = 0.69), absence of nausea at 2 h post-dose (Chi2 = 3.83, I2 = 0%, p =0.43), sustained pain freedom from 2 to 24 h post-dose (Chi2 = 3.12, I2 = 0%, p
= 0.54), sustained pain relief from 2 to 24 h post-dose (Chi2
= 1.21, I2 = 0%, p = 0.54), sustained pain freedom from 2 to 48 h post-dose (Chi2 = 0.03, I2 = 0%, p = 0.87), and total migraine freedom at 2 h post-dose (Chi2 = 0.47, I2 = 0%, p = 0.79) showed low heterogeneity; thus, a fixed-effects model was used. The absence of photophobia at 2 h post- dose (OR = 0.82, 95% CI = 0.70.0.97, p = 0.02) and total
migraine freedom at 2 h post-dose (OR = 0.56, 95% CI =

0.44.0.71, p < 0.00001) were significantly better in triptans than in oral CGRP antagonists. In contrast, differences in absence of phonophobia at 2 h post-dose (OR = 0.91, 95% CI = 0.78–1.08, p = 0.29), absence of nausea at 2 h post- dose (OR = 0.88, 95% CI = 0.73–1.05, p = 0.15), sustained
pain freedom from 2 to 24 h post-dose (OR = 0.86, 95% CI
= 0.71–1.04, p = 0.13), sustained pain relief from 2 to 24 h
post-dose (OR = 0.90, 95% CI = 0.65–1.24, p = 0.51), and
sustained pain freedom from 2 to 48 h post-dose (OR = 0.84, 95% CI = 0.56–1.27, p = 0.41) were not significant between oral CGRP antagonists and triptans (Fig. 6).
3.5 Subgroup Analysis of FDA‑Approved Oral CGRP Antagonist (Rimegepant and Ubrogepant) Versus Placebo

Subgroup analyses were conducted using data from eight studies, in order to compare clinical efficacy of the approved

Fig. 5 Forest plots for primary outcomes to compare oral CGRP antagonists and triptans. CGRP calcitonin gene-related peptide

Fig. 6 Forest plots for secondary outcomes to compare oral CGRP antagonists and triptans. CGRP calcitonin gene-related peptide
oral CGRP antagonists (ubrogepant and rimegepant) and placebo. Results of subgroup analyses were similar to those of oral CGRP antagonists versus placebo. The approved oral CGRP antagonists showed superior efficacy to placebo with respect to all primary (pain freedom at 2 h post-dose, I2 = 0%, OR = 1.83, 95% CI = 1.60–2.00, p < 0.00001;
pain relief at 2 h post-dose, I2 = 0%, OR = 1.72, 95% CI =

1.57–1.89, p < 0.00001; absence of MBS at 2 h post-dose,
I2 = 0%, OR = 1.57, 95% CI = 1.41–1.75, p < 0.00001)
and secondary outcomes (absence of photophobia at 2 h post-dose, I2 = 18%, OR = 1.64, 95% CI = 1.48–1.82, p
< 0.00001; absence of phonophobia at 2 h post-dose, I2 = 0%, OR = 1.53, 95% CI = 1.38–1.71, p < 0.00001; absence
of nausea at 2 h post-dose, I2 = 0%, OR = 1.26, 95% CI =

1.13–1.40, p < 0.0001; sustained pain freedom from 2 to 24
h post-dose, I2 = 19%, OR = 2.18, 95% CI = 1.87–2.53, p
< 0.00001; sustained pain relief from 2 to 24 h post-dose, I2
= 8%, OR = 2.02, 95% CI = 1.83–2.25, p < 0.00001; sus-
tained pain freedom from 2 to 48 h post-dose, I2 = 33%, OR
= 2.49, 95% CI = 1.94–3.20, p < 0.00001; sustained pain
relief from 2 to 48 h post-dose, I2 = 0%, OR = 2.00, 95% CI
= 1.70–2.35, p < 0.00001; and total migraine freedom at 2 h post-dose, I2 = 0%, OR = 2.03, 95% CI = 1.37–3.00, p = 0.0004) (Figs, 7, 8).

4 Discussion
The present meta-analysis was conducted to compare the clinical efficacy of oral CGRP antagonists and a placebo or triptans in the treatment of acute migraine. Pooled data were extracted from 17 RCTs that included five oral CGRP antagonists (BI44370TA, MK-3207, rimegepant, telcage- pant and ubrogepant). Our findings showed that oral CGRP antagonists were more efficacious than placebo in treating acute migraine with respect to all primary (pain freedom at 2 h post-dose and pain relief at 2 h post-dose) and second- ary (absence of photophobia, phonophobia and nausea at 2 h post-dose, sustained pain freedom and sustained pain relief from 2 to 24 h post-dose, sustained pain freedom and sustained pain relief from 2 to 48 h post-dose, and total

Fig. 7 Forest plots for primary outcomes to compare FDA-approved oral CGRP antagonists and placebo. CGRP calcitonin gene-related peptide

Fig. 8 Forest plots for secondary outcomes to compare FDA-approved oral CGRP antagonists and triptans. CGRP calcitonin gene-related pep- tide

migraine freedom at 2 h post-dose) outcomes. However, the efficacy of oral CGRP antagonists was inferior to that of triptans with respect to pain freedom and pain relief at 2 h post-dose.
Previous meta-analyses on clinical efficacy and tolerabil- ity of triptans, which were the most frequently used drugs, have provided clinical information to achieve independent treatment guidelines for acute migraine [40, 41]. Likewise, meta-analyses of CGRP antagonists suggest the clinical use of oral CGRP antagonists for acute migraine by comparing their clinical efficacy with that of placebo or triptans. Several meta-analyses published from 2013 to 2020 have compared the clinical efficacy of a single or a class of CGRP antag- onists to that of a placebo or triptans [15–21]. Although the results were similar to our results, we addressed sev- eral limitations of previous studies by using pooled data of a larger sample size and excluding olcegepant, which was administered intravenously. Furthermore, our study reported clinical trials of very recently FDA-approved oral CGRP antagonists—rimegepant and ubrogepant. Our study, which combines all studies on oral CGRP antagonists as a class, will help establish a promising strategy for the treatment of acute migraine.
Owing to the fact that clinical efficacy of drugs in acute
migraine treatment is aimed mainly at short-onset and peak latency, this meta-analysis focused on pain freedom and pain relief at 2 h post-dose as primary outcomes. Measurement of only pain freedom may lead to inappropriate evaluation of clinical efficacy of CGRP antagonists because pain relief is emphasized more than pain freedom in severe migraine as it is more difficult to relieve pain completely in this case than mild or moderate pain [19]. In addition, this meta-analysis also included the absence of MBS at 2 h post-dose as a pri- mary outcome for comparison between the FDA-approved oral CGRP antagonists and placebo. In February 2018, the FDA issued a final guidance document for developing drugs for acute migraine treatment that suggests the absence of

MBS as a co-primary endpoint along with pain freedom at 2 h post-dose [42]. However, the inclusion of the absence of MBS endpoint was not observed in the clinical trials that were performed prior to the guideline publication. There- fore, it was not possible to perform the meta-analysis of the absence of MBS for all oral CGRP antagonists.
CGRP antagonists were significantly more effective than placebo with respect to primary and secondary outcomes. Almost all outcomes showed no significant heterogeneity (I2
< 50%) except pain relief and absence of photophobia at 2 h post-dose. Although sensitivity analysis was performed to investigate the sources of heterogeneity, it was insufficient to explain the cause of heterogeneity for pain relief and the absence of photophobia at 2 h post-dose. We searched for the sources of heterogeneity among treatments, outcomes, meth- odologies, and study population to explore them further. We deemed various doses of telcagepant (2.5–600 mg) used in studies as a source of heterogeneity, but further studies are needed to verify our hypothesis.
Consistently, the FDA-approved CGRP antagonists were significantly more effective than placebo with respect to pri- mary and secondary outcomes. As previously mentioned, the primary outcomes included pain freedom at 2 h post-dose, pain relief at 2 h post-dose, and absence of MBS at 2 h post- dose. The secondary outcomes included rescue medication use and pain relapse, although not included in this study, as these endpoints were not evaluated (apart from 2 studies on rimegepant). A previous study suggests that ubrogepant, a novel acute specific drug, overcomes the vasoconstrictive action of triptans, but its therapeutic benefits might be lower than those of triptans [43]. The investigators emphasize that ubrogepant showed a more favorable safety profile in com- parison with triptans. Rimegepant has been suggested as having an additional benefit in the prophylaxis of migraine and is currently undergoing clinical trials to prove this aspect [44]. Further studies are required to compare the clinical efficacy of FDA-approved CGRP antagonists (rimegepant

and ubrogepant) and another CGRP antagonist (BI44370TA, MK-3207, or telcagepant).
Furthermore, in this study, the clinical efficacy of CGRP antagonists and triptans was compared. Our meta-analysis suggested that CGRP antagonists were less effective than triptans in treating acute migraine and was consistent with previously published data from similar studies [20, 21]. The present study suggests that CGRP antagonists are more effective than placebo, but their use as first-line standard treatment for acute migraine instead of triptans has not been established. The mechanism of action of triptans in the treatment of acute migraine involves vasoconstriction, whereas CGRP antagonists target the key processes involved in the pathophysiology of migraine. Although triptans have been recognized as the current first-line treatment for acute migraine, their contraindication in an increasing number of comorbid patients with existing cardiovascular diseases is a major concern [7, 8]. In addition, the increasing number of triptan non-responders contributes to the limitation of their clinical use [45]. Further studies are needed to better under- stand the mechanisms of migraine and the CGRP pathway; CGRP antagonists may be transitional molecules leading to a completely new therapeutic strategy [46].
Future studies to compare the clinical efficacy of oral
CGRP antagonists with that of triptans, which also focus on adverse effects and long-term safety aspects of both treat- ments, are needed. Previous studies have demonstrated the safety of CGRP antagonists over triptans [14–20]. A study by Hong and Liu [20] found that the incidence of triptan- related adverse events was significantly lower with CGRP antagonists (4.0%) than with triptans (10.8%; p < 0.00001). In addition, the incidence of chest pain was significantly lower with CGRP antagonists (0.5%) than with triptans (3.0%; p < 0.0001), and there was no difference between CGRP antagonists and placebo (0.3%; p = 0.52) [20]. In future, the additional benefits of CGRP antagonists may be proven in comorbid patients with recurrent migraine and cardiovascular diseases, as the use of triptans is further restricted due to the recurrence of the disease.

5 Conclusion
This meta-analysis showed that oral CGRP antagonists (BI44370TA, MK-3207, rimegepant, telcagepant, and ubrogepant) are more effective than placebo in the treat- ment of acute migraine with respect to primary and sec- ondary outcomes. Consistently, the FDA-approved CGRP antagonists (rimegepant and ubrogepant) were significantly more effective than placebo with respect to primary and sec- ondary outcomes. However, CGRP antagonists were less effective than triptans in treating acute migraine. The role of CGRP antagonists as potential first-line treatments for

acute migraine, as alternatives to triptans, needs to be clari- fied. They may prove particularly valuable in patients with recurrent migraine and cardiovascular diseases, in whom the use of triptans is restricted.
Author contributions DKH: methodology, formal analysis, software, writing. MJK: methodology, formal analysis. NH: formal analysis, supervision, writing—review and editing. J-HK: conceptualization, investigation, resources, supervision. IB: conceptualization, method- ology, software, supervision, writing.

Compliance with ethical standards

Conflict of interest The authors declare that there are no conflicts of interest.
Funding This work was supported by the BB21+ Project in 2020. This research was supported by Kyungsung University Research Grants in 2020.
Ethics approval Because this is a secondary literature-based study, ethic approval is not necessary.
Consent to participate Not applicable.
Consent for publication Not applicable.
Availability of data and material Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Code Availability Not applicable.

References
1. Edvinsson L. Role of CGRP in migraine. Handb Exp Pharmacol. 2019;255:121–30. https://doi.org/10.1007/164_2018_201.
2. Viana M, Sances G, Linde M, Ghiotto N, Guaschino E, Allena M, et al. Clinical features of migraine aura: results from a prospective diary-aided study. Cephalalgia. 2017;37(10):979–89. https://doi. org/10.1177/0333102416657147.
3. Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174–82. https
://doi.org/10.1016/s1474-4422(17)30435-0.
4. Rasmussen BK, Olesen J. Migraine with aura and migraine with- out aura: an epidemiological study. Cephalalgia. 1992;12(4):221– 8. https://doi.org/10.1046/j.1468-2982.1992.1204221.x ((discus- sion 186)).
5. Goadsby PJ, Holland PR. An update: pathophysiology of migraine. Neurol Clin. 2019;37(4):651–71. https://doi.org/10.1016/j. ncl.2019.07.008.
6. Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician. 2011;83(3):271–80.
7. de Vries T, Villalón CM, MaassenVanDenBrink A. Pharmacologi- cal treatment of migraine: CGRP and 5-HT beyond the triptans. Pharmacol Ther. 2020;211:107528. https://doi.org/10.1016/j. pharmthera.2020.107528.
8. Papademetriou V. Cardiovascular risk assessment and triptans. Headache. 2004;44(Suppl 1):S31–9. https://doi.org/10.111 1/j.1526-4610.2004.04106.x.
9. Tfelt-Hansen P, Olesen J. Taking the negative view of cur- rent migraine treatments: the unmet needs. CNS Drugs.

2012;26(5):375–82. https://doi.org/10.2165/11630590-00000
0000-00000.
10. van Hoogstraten WS, MaassenVanDenBrink A. The need for new acutely acting antimigraine drugs: moving safely outside acute medication overuse. J Headache Pain. 2019;20(1):54. https://doi. org/10.1186/s10194-019-1007-y.
11. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology. 2015;84(7):688–95. https
://doi.org/10.1212/wnl.0000000000001256.
12. Moreno-Ajona D, Pérez-Rodríguez A, Goadsby PJ. Gepants, calcitonin-gene-related peptide receptor antagonists: what could be their role in migraine treatment? Curr Opin Neurol. 2020;33(3):309–15. https://doi.org/10.1097/wco.0000000000 000806.
13. Agostoni EC, Barbanti P, Calabresi P, Colombo B, Cortelli P, Frediani F, et al. Current and emerging evidence-based treatment options in chronic migraine: a narrative review. J Headache Pain. 2019;20(1):92. https://doi.org/10.1186/s10194-019-1038-4.
14. Negro A, Martelletti P. Gepants for the treatment of migraine. Expert Opin Investig Drugs. 2019;28(6):555–67. https://doi. org/10.1080/13543784.2019.1618830.
15. Diao Y, Yang H, Zhou YC, Du B. The efficacy and tolerability of ubrogepant for episodic migraine: a systematic review and meta- analysis. 2020. https://doi.org/10.21203/rs.2.20666/v2
16. Yang Y, Chen M, Sun Y, Gao B, Chen Z, Wang Z. Safety and effi- cacy of ubrogepant for the acute treatment of episodic migraine: a meta-analysis of randomized clinical trials. CNS Drugs. 2020;34(5):463–71. https://doi.org/10.1007/s40263-020-00715-7.
17. Cui XP, Ye JX, Lin H, Mu JS, Lin M. Efficacy, safety, and toler- ability of telcagepant in the treatment of acute migraine: a meta- analysis. Pain Pract. 2015;15(2):124–31. https://doi.org/10.1111/ papr.12158.
18. Yao G, Yu T, Han X, Mao X, Li B. Therapeutic effects and safety of olcegepant and telcagepant for migraine: a meta-analysis. Neu- ral Regener Res. 2013;8(10):938–47. https://doi.org/10.3969/j. issn.1673-5374.2013.10.009.
19. Gao B, Yang Y, Wang Z, Sun Y, Chen Z, Zhu Y, et al. Efficacy and safety of rimegepant for the acute treatment of migraine: evidence from randomized controlled trials. Front Pharmacol. 2019;10:1577. https://doi.org/10.3389/fphar.2019.01577.
20. Hong P, Liu Y. Calcitonin gene-related peptide antagonism for acute treatment of migraine: a meta-analysis. Int J Neurosci. 2017;127(1):20–7. https://doi.org/10.3109/00207454.2015.11379 15.
21. Canlas KM, Macalintal-Canlas RA, Sakai F. Efficacy of calci- tonin gene-related peptide antagonists in the treatment of acute migraine: a systematic review and meta-analysis. Acta Medica Philippina. 2019;53(1):44–51.
22. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for report- ing of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84. https://doi.org/10.7326/m14-2385.
23. A pharmacokinetic study of MK-1602 in the treatment of acute migraine (MK-1602-007). https://ClinicalTrials.gov/show/NCT01 657370. Accessed 30 July 2020
24. Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna
J. BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study. Cephalalgia. 2011;31(5):573–84. https://doi.org/10.1177/0333102410388435.
25. Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bach- man R, et al. Randomized controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. Cepha- lalgia. 2011;31(6):712–22. https://doi.org/10.1177/0333102411 398399.

26. Hewitt DJ, Martin V, Lipton RB, Brandes J, Ceesay P, Gottwald R, et al. Randomized controlled study of telcagepant plus ibupro- fen or acetaminophen in migraine. Headache. 2011;51(4):533– 43. https://doi.org/10.1111/j.1526-4610.2011.01860.x.
27. Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73(12):970–7. https:// doi.org/10.1212/WNL.0b013e3181b87942.
28. Ho AP, Dahlöf CG, Silberstein SD, Saper JR, Ashina M, Kost JT, et al. Randomized, controlled trial of telcagepant over four migraine attacks. Cephalalgia. 2010;30(12):1443–57. https:// doi.org/10.1177/0333102410370878.
29. Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide recep- tor, compared with zolmitriptan for acute migraine: a ran- domised, placebo-controlled, parallel-treatment trial. Lan- cet. 2008;372(9656):2115–23. https://doi.org/10.1016/s0140
-6736(08)61626-8.
30. Connor KM, Aurora SK, Loeys T, Ashina M, Jones C, Giezek H, et al. Long-term tolerability of telcagepant for acute treatment of migraine in a randomized trial. Headache. 2011;51(1):73–84. https://doi.org/10.1111/j.1526-4610.2010.01799.x.
31. Ho TW, Ho AP, Chaitman BR, Johnson C, Mathew NT, Kost J, et al. Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease. Headache. 2012;52(2):224– 35. https://doi.org/10.1111/j.1526-4610.2011.02052.x.
32. Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, et al. Randomized controlled trial of an oral CGRP receptor antago- nist, MK-0974, in acute treatment of migraine. Neurology. 2008;70(16):1304–12. https://doi.org/10.1212/01.Wnl.00002 86940.29755.61.
33. 60(th) Annual Scientific Meeting American Headache Soci- ety. Headache. 2018;58(S2):61-215. https://doi.org/10.1111/ head.13306.
34. Lipton RB, Croop R, Stock EG, Stock DA, Morris BA, Frost M, et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N Engl J Med. 2019;381(2):142–9. https
://doi.org/10.1056/NEJMoa1811090.
35. Croop R, Goadsby PJ, Stock DA, Conway CM, Forshaw M, Stock EG, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394(10200):737–45. https://doi.org/10.1016/s0140
-6736(19)31606-x.
36. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34(2):114–25. https://doi.org/10.1177/0333102413500727.
37. Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cepha- lalgia. 2016;36(9):887–98. https://doi.org/10.1177/0333102416 653233.
38. Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, et al. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381(23):2230–41. https://doi.org/10.1056/NEJMoa1813049.
39. Lipton RB, Dodick DW, Ailani J, Lu K, Finnegan M, Sze- gedi A, et al. Effect of ubrogepant vs placebo on pain and the most bothersome associated symptom in the acute treatment of migraine: the ACHIEVE II randomized clinical trial. JAMA. 2019;322(19):1887–98. https://doi.org/10.1001/jama.2019.16711.
40. Cameron C, Kelly S, Hsieh SC, Murphy M, Chen L, Kotb A, et al. Triptans in the acute treatment of migraine: a systematic review and network meta-analysis. Headache J Head Face Pain. 2015;55:221–35.

41. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (sero- tonin 5-HT1B/1D agonists) in acute migraine treatment: a meta- analysis of 53 trials. Lancet. 2001;358(9294):1668–75.
42. US Food & Drug Administration. Migraine: developing drugs for acute treatment. Center for Drug Evaluation and Research. 2018. https://www.fda.gov/regulatory-information/search-fda-guidance- documents/migraine-developing-drugs-acute-treatment. Accessed 17 July 2020
43. Curto M, Capi M, Cipolla F, Cisale GY, Martelletti P, Lionetto
L. Ubrogepant for the treatment of migraine. Expert Opin Phar- macother. 2020;21(7):755–9. https://doi.org/10.1080/14656 566.2020.1721462.

44. Do TP, Guo S, Ashina M. Therapeutic novelties in migraine: new drugs, new hope? J Headache Pain. 2019;20(1):37. https://doi. org/10.1186/s10194-019-0974-3.
45. Viana M, Genazzani AA, Terrazzino S, Nappi G, Goadsby PJ. Triptan nonresponders: do they exist and who are they? Cephala- lgia. 2013;33(11):891–6.
46. De Matteis E, Guglielmetti M, Ornello R, Spuntarelli V, Martel- letti P, Sacco S. Targeting CGRP for migraine treatment: mecha- nisms, antibodies, small molecules, perspectives. Expert Rev Neurother. Rimegepant 2020;20(6):627–41. https://doi.org/10.1080/14737 175.2020.1772758.