Drugs and Devices for Migraine Prevention: Interactive Evidence Maps

Amy Y. Tsou; Benjamin Rouse; Aaron Bloschichak; Johnathan R. Treadwell

doi:10.25302/EMV1.2021.2

Drugs and Devices for Migraine Prevention: Interactive Evidence Maps

Authors

Amy Y. Tsou,¹ Benjamin Rouse,¹ Aaron Bloschichak,¹ and Johnathan R. Treadwell¹.

Affiliations

¹ ECRI Evidence-based Practice Center, Plymouth Meeting, Pennslyvania

Washington (DC): Patient-Centered Outcomes Research Institute (PCORI); 2021 Feb.

Structured Abstract

Background:

Migraine headache is a common, disabling condition that impacts 1 in 6 Americans. Although many interventions for migraine prevention have been shown to be effective, decision making for patients and physicians can be complex. Although many newer interventions have received United States (US) Food and Drug Administration (FDA) clearance, no systematic reviews have synthesized evidence for efficacy or harms across old and newer interventions.

Purpose:

To summarize evidence from randomized controlled trials (RCTs) for pharmacologic drugs and devices for migraine prevention in visual web-based evidence maps. Specifically, these evidence maps were intended to do the following:

Visualize all existing evidence from randomized clinical trials on drugs and non-invasive devices for migraine prevention.
Assess effectiveness of guideline recommended drugs and noninvasive devices for migraine reduction, tolerability, and reported harms.
Present findings in an easy-to-use interactive visual format.

Methods:

The ECRI Evidence-based Practice Center performed a rapid review of the literature to identify existing RCTs for 44 drugs and 2 devices for migraine prevention. We searched PubMed and EMBASE from inception to June 24, 2020. We included English-language RCTs enrolling adults with episodic or chronic migraine, a study duration ≥ 8 weeks, and >10 patients per arm.

For a subset of interventions (15 drugs, 2 devices) we performed meta-analyses of inactive controlled RCTs to assess efficacy and harms. We used the Cochrane risk of bias tool to assess individual studies and Grading and Recommendations Assessment, Development and Evaluation (GRADE) rating system to assess the quality of evidence.

We summarized findings using 3 web-based evidence maps, accessible here: https://www.pcori.org/research-results/evidence-synthesis/evidence-maps-and-evidence-visualizations/drugs-devices-migraine.

Results:

Overall, 203 RCTs were included: 78 trials in Map 1, 123 trials in Map 2, and 133 trials in Map 3. Two visualizations (Maps 1 and 2) presented findings from placebo-/sham-controlled RCTs, while Map 3 displayed comparisons from head-to-head RCTs.

Key Findings: Placebo-/Sham-Controlled RCTs:

Episodic migraine: Aside from onabotulinumtoxinA (no effect), interventions improved headaches by 0.5 to 2.4 migraine days per month. Efficacy for common first-line interventions (amitriptyline, propranolol, topiramate) was underwhelming (0.73 to 0.95 fewer migraine days per month) and based on low/very-low quality evidence. Calcitonin gene–related peptide (CGRP) antagonists generally provided larger efficacy with fewer side effects and higher quality evidence. Further research is needed to confirm efficacy of devices.
Chronic migraine: Aside from valproate, interventions reduced migraines by 0.9 to 4.2 migraine days per month. Based on 2 small trials, valproate offered a large reduction of 13.2 migraine days per month, although this evidence was rated very low quality.
Sparse evidence for tricyclic antidepressants: Although commonly used as first-line therapy, placebo-controlled RCTs supporting efficacy are sparse (amitriptyline) or nonexistent (nortriptyline).

Key Findings: Head-to-Head RCTs:

Key evidence gaps: No direct comparisons of CGRP antagonists or devices to standard migraine prevention therapies exist.

Conclusions:

Many interventions are effective for reducing migraine, although to what extent these reductions are clinical significant remains unclear. While the largest migraine reduction was seen for valproate (an older drug), most newer therapies appeared to have comparable efficacy and favorable tolerability. Head-to-head comparisons are needed to assess comparative effectiveness to support policy and treatment decisions.

Background

Migraine headache is a common, disabling condition that affected 16% of American adults in 2018; in 2016, migraine accounted for 4 million emergency department visits.¹ Interventions for migraine prevention aim to reduce the number and severity of migraine headaches. Because numerous therapies for migraine prevention therapy exist, selecting a therapy can be challenging. Most pharmacologic therapies commonly used for migraine prevention were originally developed for treatment of other medical conditions, such as hypertension, epilepsy, or depression. Many of these drugs have potential side effects (eg, sedation, hypertension, kidney stones, teratogenicity) that could preclude use in groups of patients, depending on a variety of clinical factors. Thus, choosing a therapy for migraine prevention typically requires careful consideration of patient comorbidities and preferences. Decision making also requires consideration of access: patients are typically required to use older pharmacologic therapies (such as tricyclic antidepressants or beta-blockers) before they are eligible for newer, more costly therapies.

Although many drugs for migraine prevention have been in use for several decades, recently, multiple newer interventions have received FDA clearance, including calcitonin gene–related peptide (CGRP) antagonists and devices (eg, the transcutaneous supraorbital nerve stimulator, noninvasive vagus nerve stimulator). Assessment of the efficacy, tolerability, and side effects of traditional therapies for migraine prevention alongside newer therapies could help inform decisions and identify important evidence gaps.

Scope and Purpose

Migraine prevention therapies encompass a wide range of interventions, including traditional pharmacologic drugs and devices, as well as behavioral therapies, nutritional supplements, and complementary and alternative medicine (CAM) therapies. After considering multiple factors such as existing evidence-based clinical practice guidelines (see Appendix A), anticipated size of evidence base, visual design considerations, and desired timeline, we decided this project would focus on evidence for pharmacologic drugs and devices for migraine prevention.

At the request of the Patient-Centered Outcomes Research Institute (PCORI), ECRI performed a rapid review and conducted meta-analyses to inform creation of 3 web-based interactive evidence maps to present findings using an accessible visual format for clinicians, researchers, and policymakers. In addition, patients may find the maps informative for exploring treatment options. We completed this review on a compressed timeline (in a little more than 6 months) to meet the needs of PCORI stakeholders.

Methods

We performed a rapid review/meta-analysis to address the following 2 key questions for adult patients with episodic or chronic migraine:

Key Question 1: What are the benefits and harms of selected newer drugs and devices (CGRP antagonists and devices) and established pharmacologic therapies (ie, recommended by evidence-based guidelines) for migraine prevention?

Key Question 2: What pharmacologic and noninvasive device interventions for migraine prevention have been assessed using randomized controlled trials (RCTs)?

We designed 3 web-based visual evidence maps to summarize evidence addressing these key questions. Key characteristics of these maps are presented in Table 1.

Table 1

Overview of Map Characteristics.

Table 2 shows included drugs and devices. For Map 1 (assessing effectiveness), we selected 17 interventions of interest. For Maps 2 and 3 (which summarize existing RCTs but do not assess efficacy), we included all interventions included in Map 1, plus 29 additional interventions.

Table 2

Included Interventions by Map.

Stakeholder Input

To inform map content and design, we interviewed key stakeholders including clinicians, patients, policymakers, and primary care physicians (see Acknowledgments). Early input from clinicians and patients informed scope (selection of interventions and outcomes) and map design. Input from policymakers including payers and funders as well as primary care physicians informed data visualization and usability considerations. Our clinician stakeholders were neurologists with expertise in treating migraine headaches and headache research. Our patient stakeholders were women with a personal history of treatment for migraine headaches and experience advocating for and communicating with the migraine community. Finally, the report and evidence maps underwent peer review by our clinician stakeholders and a reviewer with expertise in systematic review and meta-analysis methodology.

Literature Search

A medical information specialist searched PubMed and EMBASE/Medline to identify RCTs for migraine prevention interventions from inception to June 24, 2020. In addition, the specialist searched EMBASE/Medline for relevant systematic reviews through December 16, 2019. Bibliographies from relevant systematic reviews (SRs) were used to identify additional trials. The full search strategy is available in Appendix B.

Inclusion/Exclusion Criteria

We included studies that met the following criteria:

RCT comparing intervention of interest to placebo/sham (for Map 1/Map 2) or active intervention (Map 3)
Full-length, English-language published study
At least one intervention of interest assessed
Study included >80% patients with migraine (or reported data separately for patients with migraine). We included episodic and/or chronic migraine patients; studies were not required to report outcome separately for episodic/chronic.
Age ≥ 16
N ≥ 10 in each study arm at follow-up and reported outcome data for ≥50% of patients enrolled
Trial duration ≥ 8 weeks

Study reported at least 1 of the following 5 outcomes for migraine efficacy: migraine days or migraines per month, number of headache days or headaches per month, or 50% reduction in migraine frequency. Studies that did not report any of these outcomes, but reporting related efficacy outcomes (eg, index based on migraine frequency and severity) were excluded from Map 1 but included in Maps 2 or 3.

In addition, for Map 1, if crossover RCTs reported a washout period, we included data for both study periods. To avoid carryover effects, if studies failed to report a washout period (or its length), we included only period 1 data. If period 1 data were not reported separately, we excluded the study from Map 1 (but included it in Map 2 or 3, as appropriate).

Screening

We performed dual independent screening for abstracts and full-text articles using DistillerSR (Evidence Partners, Ottawa, Ontario, Canada) with disagreements resolved by a third reviewer. See Appendix C for the flow diagram.

Rapid-Review Methodology

To complete this work in a compressed timeline, we used 2 streamlined rapid-review methods: risk of bias and quality-of-evidence assessments performed by a single analyst with a 10% random check by a second analyst for risk of bias only. In addition, this work differs from typical systematic reviews in that results are primarily presented in the data visualizations, along with this report. However, in other respects, our methods were aligned with standard guidance for systematic reviews.²^,³

Data Extraction and Meta-analysis

A single experienced analyst extracted data from full-text articles, with a 10% random validation by another analyst.

We extracted study characteristics including country, year, migraine type, years since onset of migraine, and type of RCT (parallel vs crossover), interventions, comparisons, and number of patients randomized per arm from all included studies. We categorized migraine type as episodic (<15 migraines or headaches per month), chronic (≥15 migraines or headaches per month), episodic plus chronic, and other/not reported. See Appendix D for more details.

Map 1 Outcomes

For studies included in Map 1, we also extracted outcomes for migraine reduction, trial dropout from adverse effects (as a measure of tolerability), and adverse effects. For each outcome, we extracted the data point closest to 8 weeks, 12 weeks, and 6 months, as well as the longest reported timepoint, with data for multiple timepoints extracted if reported.

Specifically, we categorized data from various timepoints as follows:

8 weeks: 8 to <12 weeks
12 weeks: 12 weeks to <6 months
6 months: ≥6 months

Migraine Reduction and Trial Dropout

For migraine reduction, we extracted the following specific outcomes, in descending order of preference:

Migraine days per month
Migraines per month
Headache days per month
Headaches per month

We also extracted 50% reduction in migraine frequency (migraines or migraine days) if reported.

For trial dropout, we extracted the proportion of patients from each arm who dropped out of trials due to adverse effects.

Efficacy Measures and Minimally Important Difference

One accepted threshold for efficacy for migraine prevention is a 50% reduction in number of migraines per month.⁴ However, only roughly half (41 of 78) of studies included in Map 1 reported this outcome, instead reporting results using 1 of the 4 other continuous outcomes of interest (eg, migraine days per month). Ideally, we would have generated a pooled analysis of 50% reduction in migraine/headache frequency by converting these data from continuous outcomes into the dichotomous 50% reduction outcome. However, nearly no studies reported individual before-and-after patient-level data necessary to support meta-analysis of these data across migraine subtypes and multiple end points planned for this map. Thus, we chose to use migraine days per month as the primary outcome measure to display migraine reduction efficacy.

No consensus regarding a minimally important difference (MID) for migraine days per month exists. However, 2 older studies specified a reduction of 1.5 migraines per month as a “clinically important” difference between groups for migraine reduction.⁵^,⁶ Using the median baselines (for migraines per month and migraine days per month), this corresponds to 2.5 migraine days per month reduction, which we used as the MID for quality-of-evidence assessment.

Meta-analysis

To prepare efficacy data for meta-analysis, we calculated or imputed means and standard deviations (SDs) when not reported. We used Hedges’ g as the measure of treatment effect for efficacy and relative risk (RR) for withdrawal due to adverse events. For crossover trials that did not report results accounting for the paired nature of the data, we estimated the standardized mean difference and its standard error using a correlation coefficient of 0.5. If only 50% reduction in migraine frequency was reported, we estimated the Hedges’ g by dividing the log odds ratio by 1.65.7 These statistical approaches supported inclusion of as much data as possible in our meta-analyses. Studies that reported results of interest, but were not suitable for inclusion in the meta-analyses (despite these approaches), are included in the appropriate hover text in the map.

Before combining different doses of the same treatment within or across trials, we considered whether doses assessed in trials were used in current clinical practice. Based on input from our technical expert panel, we excluded data for eptinezumab 1000 mg from the analysis.

We used random-effects meta-analytic models based on the DerSimonian and Laird method to incorporate between-study heterogeneity.⁸ We performed all analyses in Stata 13.⁹ We synthesized evidence for efficacy and trial dropout in 230 analyses, of which 129 were meta-analyses.

Adverse Events

To prioritize adverse events for extraction, our 3 technical expert panel (TEP) members independently listed 5 to 7 key adverse effects for each intervention. These key adverse effects were combined to create a list of adverse events for extraction (see Appendix D). If studies did not report individual side effects (eg, dizziness) by study arm, we extracted information regarding serious adverse events or general adverse events.

For each intervention, we calculated pooled RR and absolute risk difference for each adverse effect. We characterized frequency of adverse effects for each intervention by selecting the adverse effect with the largest absolute risk difference (between intervention and placebo/sham groups). Based on this difference, we categorized frequency of adverse effects for each intervention as the following:

0 to 5%: Rare
≥ 5 to 15%: Infrequent
≥ 15%: More common

This approach flagged an intervention as having “more common” adverse effects if any adverse effect had an absolute risk difference of ≥15% for the intervention arm (compared with placebo/sham). For adverse effects (unlike outcomes for efficacy and dropout), we pooled all available data across all migraine types and study durations for each intervention.

For 2 interventions, we noted substantial differences in risk at higher doses. For these 2 interventions (topiramate ≤200 mg vs topiramate >200 mg) and (onabotulinumtoxinA <225 units vs onabotulinumtoxinA ≥225 units), we calculated pooled RR for all combined doses as well as for each dose separately. However, the overall rating (rare, infrequent, or more common) was determined using the absolute risk difference from combined doses. For example, onabotulinumtoxinA ≥225 units had an absolute risk difference of 19% and onabotulinumtoxinA <225 units had an absolute risk difference of 14%. However, as their combined absolute risk difference was 14.6%, we categorized frequency of adverse effects as infrequent.

Risk of Bias Assessment

We used the Cochrane risk of bias tool³ to assess risk of bias for 5 domains: selection bias (randomization and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessors), attrition bias, and reporting bias. All except performance bias and selective outcome reporting bias were considered key domains for rating the overall risk of bias. We piloted assessment of 2 studies and resolved discrepancies. Remaining studies were rated by a single analyst with a 10% check by a second analyst for agreement.

Quality-of-Evidence Assessment

We used GRADE to rate the quality of evidence for migraine efficacy and trial dropout outcomes as high, moderate, low, or very low for each permutation of filters.¹⁰ We piloted assessment of 5 evidence bases across all analysts and resolved discrepancies. Remaining evidence for each outcome was assessed by a single analyst.

To assess study limitations, we used the Cochrane risk of bias tool.³ To assess indirectness, in addition to typical considerations, we downgraded studies selectively enrolling “enriched” populations (randomizing only patients who had already responded to treatment during a baseline phase). For inconsistency, we examined the forest plot as well as the value of I² to judge whether inconsistency was serious. We did not formally assess publication bias because it was not feasible.

To assess imprecision, given the absence of a clear MID for our primary outcome measure (migraine days per month), we used a between-group difference of 1.5 migraines per month cited by 2 studies (as noted above).⁵^,⁶ Using the typical SD for migraine frequency, this difference was equivalent to Hedges’ g of 0.69. We used this value as an MID to assess the evidence base (summary g’s for each meta-analyses), downgrading for imprecision if the confidence interval crossed +0.69 or –0.69. For trial dropout due to adverse effects, we downgraded for imprecision for RR < 0.8 or > 1.25 based on FDA guidance that 0.8 to 1.25 is an appropriate range for therapeutic equivalence of the ratio of plasma drug levels.¹¹

Data Visualization

Map data from Microsoft Excel was incorporated into Tableau for data visualization by Lovelytics, a data visualization firm. For Map 1, to enhance clinically interpretability in the visualization, we converted results from g to migraine days per month using typical migraine type-specific SDs derived from the data. Similarly, for trial dropout due to adverse effects, we converted RR to risk differences by assuming a 1% rate in the placebo or sham groups. Users can customize the display of data for efficacy and trial dropout using the following filters:

Migraine type (any, episodic, chronic, other/not reported)
Study duration (any, 8-11 weeks only, 12-25 weeks, ≥6 months)
Quality of evidence (high, moderate, low, very low)

We sought and iteratively incorporated feedback on visualization and usability from potential end-users including primary care providers (physicians and nurse practitioner), migraine experts, a payer, guideline developers, and funders (see Acknowledgments).

In addition to efficacy, dropout, and adverse effects, we extracted disease impact outcomes as a measure of quality of life. However, as relatively few RCTs reported this outcome, we chose not to include it in the visualizations.

To ensure accuracy of data translation, we performed a 5% validity check of data points for each outcome (efficacy, dropout, adverse effects) to ensure consistency between visualization and Excel data.

Results

We identified 203 RCTs (published in 254 articles) that met inclusion criteria: 78 trials for Map 1, 123 trials for Map 2, and 133 trials with head-to-head comparisons for Map 3. See Appendix C for a flow diagram. Appendix D provides characteristics of included studies.

Map 1. Benefits and Harms of Selected Interventions for Migraine Prevention: Evidence From Placebo-/Sham-Controlled RCTs

This map summarized 78 placebo or sham-controlled RCTs assessing benefits and harms for 15 drugs and 2 devices. Results and links to individual studies can be viewed using the map, here. Below, we summarize key findings.

Of interventions included in Map 1, we identified the largest number of trials for CGRP antagonists (22 RCTs), followed by antiepileptics (20 trials), and botulinum toxin type A (17 trials). Only 2 trials assessed devices (noninvasive vagal nerve stimulation [1 RCT] and transcutaneous supraorbital nerve stimulation [1 RCT]). Similarly, only a single RCT respectively assessed lisinopril and atogepant. No trials assessed nortriptyline. Most trials (83%) were published after 2000. Older trials (published before 2000) assessed valproate (n = 3), propranolol (n = 9), and metoprolol (n = 2).

Overall, the median baseline number of migraine days per month for study participants across included trials was 9 (any migraine type), 8 (episodic migraine), and 18 (chronic migraine).

Efficacy for All Migraine Types

The efficacy of interventions considering data for all migraine types and follow-up durations ranged from 0.56 to 3.4 fewer migraine days per month (forest plots for each intervention are included in Appendix E). Overall, valproate offered the largest reduction: pooled analysis of 7 trials^12-18 found valproate provided 3.4 fewer migraine days per month, although the quality of evidence was low. Patients receiving valproate were more likely to drop out of trials due to adverse effects (RR 1.7; 95% CI, 0.7-4.2). However, the absolute risk of dropping out remained relatively low (1.9% vs 1% for valproate vs placebo), and adverse effects were rare. Compared with placebo, valproate was slightly more likely to cause weight gain (5% risk difference [RD]), dizziness (4% RD), and fatigue (4% RD).

Only 6 (of 17) interventions represented in Map 1 had high-quality evidence for efficacy: the 5 CGRP antagonists (atogepant, eptinezumab, erenumab, fremanezumab, galcanezumab), and noninvasive vagal nerve stimulation. Efficacy for CGRP antagonists ranged from 1.4 to 1.9 fewer migraine days per month compared with placebo, while noninvasive vagal nerve stimulation had the smallest effect size (only 0.56 fewer migraine days per month compared with sham stimulation). An additional 5 interventions had moderate-quality evidence for efficacy: amitriptyline, candesartan, metoprolol, propranolol, and onabotulinumtoxinA.

Episodic Migraine

Fifty trials specifically assessed efficacy for episodic migraine (select “episodic migraine” filter on the left-hand side of the visual). Topiramate and propranolol each had 8 trials, followed by onabotulinumtoxinA and galcanezumab (6 trials each), erenumab (5 trials), valproate (4 trials), metoprolol, fremanezumab, and amitriptyline (2 trials each), and lisinopril, atogepant, eptinezumab, and venlafaxine, and the 2 devices (1 trial each).

Venlafaxine, transcutaneous supraorbital nerve stimulation (Cefaly), and valproate offered the highest efficacy (2 to 2.4 fewer migraine days per month compared with placebo). While effect sizes were slightly larger for venlafaxine and Cefaly, each was supported by only a single RCT¹⁹^,²⁰ enrolling fewer than 70 patients (compared with 4 trials for valproate). Notably, venlafaxine was not well tolerated: patients randomized to venlafaxine were more likely to drop out due to adverse events (5.6% RD) and reported higher rates of nausea (16% RD), insomnia (9% RD), and fatigue (3% RD) compared with placebo. Cefaly and valproate were better tolerated with rare adverse effects and low trial dropout.

Efficacy for topiramate, propranolol, and amitriptyline (drugs widely used for migraine prevention) ranged from 0.7 to 0.9 fewer migraine days per month (compared with placebo). However, adverse effects were more common in patients using these drugs. For example, compared with placebo, the proportion of patients who reported dry mouth and somnolence was >20% higher for those taking amitriptyline.

High-quality evidence supported 2 treatments (galcanezumab, erenumab) for episodic migraine at all timepoints, including 6 months, although the magnitude of improvement could be considered relatively modest (1.85 fewer migraine days per month or less; see Table 3).

Table 3

Episodic Migraine—High Quality Evidence for Efficacy by Trial Duration.

Chronic Migraine

Fourteen trials specifically assessed efficacy for chronic migraine (select “chronic migraine” filter on the left-hand side of the visual). OnabotulinumtoxinA had the most trials (n = 4), followed by valproate, topiramate, fremanezumab, and galcanezumab (2 trials each). The remaining interventions (amitriptyline, eptinezumab, erenumab) had been assessed with only a single trial.

Valproate offered by far the largest reduction, with 13.2 fewer migraine days per month (pooled data from 2 small trials, very-low-quality evidence),¹²^,¹⁸ followed by onabotulinumtoxinA, with 3 fewer migraine days per month, and 3 CGRP antagonists (eptinezumab, erenumab, galcanezumab), which offered reductions of about 2.6 migraine days per month. Of note, evidence for valproate was based on 2 small, non-US trials performed in Turkey¹⁸ and Iran¹² that randomized only a combined 52 patients to valproate.

Only a single intervention reported outcomes for chronic migraine patients at 6 months: onabotulinumtoxinA improved migraines by 2.3 migraine days per month, although quality of evidence was low.²¹ Only 4 interventions (galcanezumab, fremanezumab, erenumab, eptinezumab) had high-quality evidence supporting efficacy that ranged from 1.7 to 3 fewer migraine days per month (see Table 4).

Table 4

Chronic Migraine—High Quality Evidence for Efficacy by Trial Duration.

Tolerability (Trial Dropout and Adverse Effects)

Interventions with the highest relative risk of trial dropout due to adverse events were venlafaxine and onabotulinumtoxinA. (Of note, data for venlafaxine were drawn from only a single, relatively small study of 60 patients.) Conversely, the 2 devices and atogepant had the lowest relative risks of dropout (RR 0.2 to 1). For noninvasive vagal nerve stimulation (gammaCore), patients receiving sham were more likely to drop out than those receiving gammaCore.

The frequency of adverse effects was categorized as more common for 5 interventions (candesartan, topiramate, propranolol, venlafaxine, amitriptyline), infrequent for 4 interventions (lisinopril, metoprolol, onabotulinumtoxinA, galcanezumab), and rare for 7 interventions (valproate, atogepant, eptinezumab, erenumab, fremanezumab, noninvasive vagal nerve stimulation, transcutaneous supraorbital nerve stimulation).

Map 2. What Types of Drugs and Devices Have Been Studied With RCTs for Migraine Prevention?

This map summarized 123 placebo or sham controlled RCTs assessing 46 interventions (17 of these interventions are also summarized in Map 1; 29 additional interventions are included in Map 2). Interventions with the largest volume of evidence were the following:

Antiepileptics: 26 trials, 2859 patients
Beta-blockers: 25 trials, 1543 patients
CGRP antagonists: 23 trials, 9317 patients
Botulinum toxin type A: 19 trials, 2878 patients

Remaining intervention categories had been studied with only <10 RCTs. Notably, although antiepileptics and beta-blockers had more RCTs, CGRP antagonist trials had more than 3 times as many patients randomized compared with antiepileptics.

Map 3. Head-to-Head Comparisons of Drugs and Devices for Migraine Prevention

This map displays existing head-to-head comparisons from 133 RCTs and highlights potential evidence gaps. Overall, included studies captured 207 head-to-head comparisons, of which 42% (n = 86) compared different doses of the same drug. (Users can hide dose comparison trials by selecting the “Hide Dose Comparison Trials” filter on the bottom left-hand side of the visual.)

Not surprisingly, older interventions widely considered effective for migraine prevention (topiramate, valproate, propranolol, botulinum toxin type A, amitriptyline) were the most frequently assessed in head-to-head comparisons, often compared against each other. Notably, the map demonstrates that several of these interventions have also been compared against nutraceuticals (melatonin, riboflavin) and CAM such as acupressure, acupuncture, exercise, and relaxation. (Users can view these by hovering over dots in the “Other” column.)

Map 3 reveals 2 important evidence gaps. Both CGRP antagonists and transcutaneous supraorbital stimulation performed well for migraine reduction in placebo- or sham-controlled trials (as demonstrated in Map 1) with relatively few side effects. No head-to-head trials comparing these interventions against older, commonly used pharmacologic interventions for migraine prevention exist. In fact, CGRP antagonists have not been compared against any other interventions, and only a single trial²² compared transcutaneous supraorbital stimulation to another type of electrical stimulation (a nonstandard treatment). Direct comparisons of these newer interventions against older therapies to confirm relative efficacy is needed to support decisions by payers, policymakers, and shared decision-making between doctors and patients. Also, comparative effectiveness trials have primarily focused on episodic migraine; only 19 head-to-head comparisons (including 8 dose comparison trials) for chronic migraine exist. However, we note that most of these trials were performed in the past 10 years, which could suggest increased interest in addressing this evidence gap.

Discussion

To our knowledge, this work represents the first rapid review/meta-analysis to assess efficacy for many traditional pharmacologic interventions along with newer drugs and devices. Our analyses confirm that multiple interventions are effective for migraine reduction compared with placebo/sham. As evident in Map 1, older interventions in common use and recommended by guidelines²³^,²⁴ (eg, propranolol, topiramate, valproate, amitriptyline, candesartan) were effective. However, aside from valproate, the size of migraine reduction offered by several newer therapies (CGRP antagonists, transcutaneous supraorbital stimulation) was roughly comparable or slightly larger, but with fewer side effects and dropouts from adverse effects. Of all therapies used for migraine prevention, valproate demonstrated the largest migraine reduction: pooled analysis of 7 trials¹²^-¹⁸ found a reduction of 3.4 migraine days per month, although this evidence was rated low quality. Specifically, valproate provided a large reduction for chronic migraine (13.2 migraine days per month) and smaller effect for episodic migraine (2 migraine days per month).

Important evidence gaps are clear from Map 1. First, few trials reported outcomes beyond 12 weeks, and only 7 interventions had 6-month outcomes. Second, all drugs and devices captured in Map 1 (except for nortriptyline) demonstrated some degree of efficacy for reducing migraines (as anticipated since drugs or devices in common use or recommended in guidelines were intentionally prioritized for inclusion). However, only 6 interventions (of which 5 were CGRP antagonists) were supported by high-quality evidence. For included interventions recommended as first line by an evidence-based practice guideline,²³^,²⁴ overall quality of evidence was only moderate (propranolol, metoprolol), low (valproate), or very low (topiramate). In general, many of these studies were older and had higher risk of bias for many reasons, including poor randomization, unclear blinding procedures, or high attrition. The evidence base for other recommended drugs was quite small: amitriptyline and candesartan were each supported by only 2 trials, and venlafaxine and lisinopril were each supported by only 1.

For most interventions (including CGRP antagonists), the magnitude of improvement was underwhelming. For instance, for included trials of episodic migraine, the baseline median number of migraine days per month was 8. Efficacy for 8 of 9 interventions supported by more than a single RCT ranged from 0.73 to 1.95 fewer migraine days per month (the ninth intervention, onabotulinumtoxinA, is not recommended for episodic migraine). Furthermore, adverse effects were more common for 3 of these interventions (topiramate, amitriptyline, propranolol).

Patients are typically required to start with older drugs (such as propranolol, amitriptyline, or nortriptyline) with failure of several classes of traditional drugs (eg, antihypertensives, antidepressants, antiepileptics) before they are eligible to receive newer, more costly drugs such as CGRP antagonists. Our work highlights the sparse evidence for drugs commonly used first line (particularly amitriptyline and nortriptyline) and suggests patients could experience fewer side effects if CGRP antagonists were considered for initial therapy, although policymakers would also need to consider the uncertainty regarding long-term side effects and substantively higher cost.

Selecting a migraine prevention therapy requires shared decision making that considers multiple factors, including benefits and harms, patient comorbidities, cost/coverage, and (for women) childbearing potential. Patients often inquire at length about potential side effects; investment in visual evidence maps such as these, which display data on adverse effects alongside efficacy, may support realistic expectations for physicians and patients as they weigh potential tradeoffs.

Limitations

We note several important limitations. First, we used migraine days per month, an accepted measure, as the primary efficacy outcome for meta-analyses. We found that most interventions reduced migraine days per month by fewer than 3. However, because this measure averages effects across all patients, some patients may have experienced greater reductions while others had no change. An alternative measure of efficacy, such as 50% reduction in migraine frequency, may reveal which treatments are likely to provide greater reductions for some patients, even if overall average effects are modest.

As previously noted, inconsistencies in reporting did not allow us to calculate 50% reduction in migraine frequency across all studies. However, we extracted these data whenever reported (see Appendix F), also available by selecting a blue bar in Map 1, and the hyperlink “Data on 50% reduction in migraines or migraine days per month” which appears in the hover). We note that these studies generally defined 50% reduction as a truly successful response, not necessarily an MID (the smallest between-group difference needed to be considered important). Furthermore, it is unclear if patients would consider improving from 20 to 10 migraines a month as equally beneficial as improving from 8 to 4 migraines a month. Although quality-of-life measures (eg, disease impact scores) could help address this question, we found that few studies reported disease impact scores. Thus, while potentially informative, we did not incorporate disease impact scores into the evidence map.

For adverse effect frequency (in Map 1), we extracted only selected adverse effects our clinical experts identified as important for clinical decision making (see Appendix G) and compared reported frequency for intervention and placebo arms. However, in some cases, these estimates could fail to capture side effects important to patients (such as teratogenicity). Many migraine prevention therapies are drugs primarily used for other medical conditions, such as hypertension, depression, or epilepsy. For example, valproate and topiramate have known potential teratogenic side effects from the epilepsy literature; however, no migraine trials reported teratogenicity, since studies of valproate or topiramate excluded women of child-bearing age due to this already known side effect. These concerns would also be relevant to other interventions with known teratogenicity, such as candesartan and lisinopril. We also note that, although CGRP antagonists appear to have generally favorable side effect profiles, as new drugs, their long-term safety remains unknown.²⁵

Given variability in study inclusion criteria across studies, it was not feasible to consider all factors that could have impacted efficacy (such as enrolling only patients who had failed a certain number of prior medications). However, this could have led to underestimation of true efficacy in some cases. Similarly, we did not perform subanalyses based on patient clinical characteristics (eg, number of drugs failed, concurrent headache therapies) and demographics (age or gender) to identify particular patient groups more likely to respond.

In some cases, there may appear to be incongruities between reported findings for efficacy from individual studies and those presented in the visualization (eg, a study reporting no statistically significant difference between intervention and control, but the visualization indicating there is). These differences may be due to differences between the analytic approach taken by trial investigators compared with our approach. To facilitate pooling of data across studies, we focused on group-level means and SDs reported by trials; investigators may have used other approaches to derive P values. For example, Schoenen 201319 used the Mann-Whitney U test to assess the distributions of migraine days per month for supraorbital transcutaneous nerve stimulation compared with sham and found no statistically significant difference. On the other hand, when directly comparing the means of each group, there is a significant difference.

We included all RCTs regardless of publication date, recognizing that many migraine prevention trials were published as early as the 1980s. However, as expected for an evidence base spanning nearly 4 decades, findings from older trials could be less generalizable today. Older studies were often assessed as high risk of bias due to failure to report methods for randomization or allocation concealment. In fact, randomization method was unclear for 100% of studies published prior to 2000 (n = 13). However, we acknowledge that reporting standards in the past were different, and, in some cases, authors may simply have failed to report the method due to different expectations for reporting at the time.

Finally, some users may primarily be interested in evaluating how interventions perform relative to each other (instead of efficacy compared with placebo/sham). However, Map 1 provides limited utility to evaluate comparative effectiveness. While users could attempt to extrapolate the relative effects by, for example, subtracting the effect of one intervention from another, this could lead to erroneous conclusions. Strong assumptions regarding the similarity of trials are necessary to ensure these indirect comparisons are valid, and we did not formally assess these assumptions, as would be done in a network meta-analysis.²⁶

Future Directions

Our work suggests CGRP antagonists offer similar efficacy to many commonly used drugs for migraine prevention with higher tolerability, although long-term safety remains unknown. Future studies reporting on long-term side effects will be important to better inform discussions of risk and benefits and support clinical decision making. Although only assessed with a single smaller RCT, transcutaneous supraorbital nerve stimulation also showed promise for episodic migraine, with significant reduction in migraine days per month and high tolerability. Further trials to confirm efficacy are needed.

As noted, patients often begin therapy with older drug therapies. Head-to-head comparisons of both CGRP antagonists and transcutaneous supraorbital nerve stimulation against other traditional migraine prevention drugs could inform policymakers, particularly given the current higher cost of CRGP antagonists.

More research is needed to confirm efficacy for interventions specific for chronic migraine. Also, although not addressed by this project, many patients express preferences for nonpharmacologic drugs (ie, vitamins or supplements), CAM therapies, devices, or behavioral therapies given perceived lower risk of side effects. Although this work did not assess efficacy of these interventions, head-to-head trials with comparisons against standard pharmacologic drugs exist. Future studies assessing effectiveness and comparative effectiveness of these interventions compared with traditional pharmacologic therapies and devices could inform treatment decisions for patients interested in nonpharmacologic treatments.

Conclusion

Multiple drugs and devices successfully reduced migraines, although the magnitude of migraine reduction for many interventions was not large. Valproate offered the largest reduction in migraine days per month, particularly for chronic migraine sufferers, although this evidence was low or very low quality. Compared with older, traditional drug interventions (except valproate), newer therapies (including CGRP antagonists and transcutaneous supraorbital nerve stimulation) had generally comparable or slightly larger effects with fewer side effects. However, only CGRP antagonists and one device were supported by high-quality evidence for efficacy and few studies assessed outcomes beyond 12 weeks.

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Disclaimer

All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors. This publication was developed through a contract to support PCORI’s work. Questions or comments may be sent to PCORI at info@pcori.org or by mail to 1828 L Street NW, Suite 900, Washington, DC 20036.

Acknowledgments

We gratefully acknowledge contributions from the following individuals:

Our TEP members: Christopher H. Gottschalk, MD, FAHS; Katherine Hamilton, MD; and Mia Tova Minen, MD, MPH. In addition, Larry Charleston IV, MD, provided valuable feedback during the scoping and protocol design.

We also interviewed key representatives of potential intended end-users to refine content and usability; their input was invaluable to informing map design. Specifically, the following individuals provided feedback: David T. O’Gurek, MD, FAAFP, Robert Rich, MD, and Christina Worst, CRNP (primary care providers); Desiree Otenti, MSN, MPH (payer); William Lawrence, MD, MS; and Layla Lavasani, PhD, MHS (research funders).

We also thank Nancy Bonk and Angie Glaser, migraine patients and advocates who provided valuable input during protocol development.

We also thank Lovelytics for supporting data visualization.

Finally, we acknowledge contributions from many ECRI colleagues: Helen Dunn and Kitty Donahue (references); Joann Fontanorosa, PhD (data validation checks); Jacquelyn Hostetter (administrative support); Laura Koepfler, MLS (performing literature searches); Jennifer Maslin (formatting); and Michael Phillips (copyediting).

Suggested citation:

Tsou AY, Rouse B, Bloschichak A, et al. Drugs and Devices for Migraine Prevention: Interactive Evidence Maps. Patient-Centered Outcomes Research Institute; February 2021. Prepared by ECRI under Contract No. IDIQ-TO#12-ECRI-SCI-EVIDENCEMAP-2019-07-15. https://doi.org/10.25302/EMV1.2021.2

This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated.

Bookshelf ID: NBK576984PMID: 35099854DOI: 10.25302/EMV1.2021.2

	Key Question 1	Key Question 2
	Map 1. Benefits and Harms of Selected Interventions for Migraine Prevention: Evidence from Placebo/Sham-Controlled RCTs	Map 2. What Types of Drugs and Devices have Been Studied with RCTs for Migraine Prevention?	Map 3. Head-to-Head Comparisons of Drugs and Devices for Prevention
Type of RCTs	Placebo/Sham Controlled	Placebo/Sham Controlled	Head-to-Head Comparisons
Criteria for interventions to be displayed in map	All interventions of interest displayed (including those for which no placebo-/sham-controlled RCTs were identified)	Only interventions assessed with placebo-/sham-controlled RCTs displayed	Only interventions assessed with head-to-head RCTs displayed
Summarizes Efficacy	Yes	No	No
Key Information Reported	For each individual intervention, pooled analysis of the following:: Migraine reduction (migraine days per month) Trial dropout due to adverse events Adverse events	Number of trials and number of patients randomized displayed by the following: Type of intervention (i.e. drug class) Individual drugs or devices Number of existing head-to-head comparisons for individual drugs or devices	Number of head-to-head comparisons (including dose comparisons) for individual drugs and devices Study details for each comparison, including author, migraine type, and comparison arms (intervention and subjects per arm)

	Key Question 1	Key Question 2
Intervention Type	Map 1: Benefits and Harms of Selected Interventions	Map 2: Drugs and Devices That Have Been Studied with RCTs	Map 3: Head-to-Head Comparisons
		Additional Interventions Included
Angiotensin-converting enzyme (ACE) inhibitors/Angiotensin receptor blockers (ARBs)	Lisinopril Candesartan	Captopril Enalapril Telmisartan
Antiepileptics	Topiramate Valproic Acid	Gabapentin Zonisamide Levetiracetam Lamotrigine Oxcarbazepine Carbamazepine
Beta-blockers	Metoprolol Propanolol	Atenolol Nadolol Timolol Nebivolol Bisoprolol Acebutolol
Calcitonin gene-related peptide (CGRP) antagonists	Atopegant Erenumab Fremanezumab Galcanezumab Eptinezumab
Botulinum Toxin Type A	OnabotulinumtoxinA	AbobotulinumtoxinA IncobutulinumtoxinA Unspecified Botulinum Toxin Type A
Tricyclic Antidepressants	Amitriptyline Nortryptiline	Protryptiline Clomipramine
Other anti-depressants	Venlafaxine	Fluoxetine Escitalopram Fluvoxamine Citalopram
Alpha agonists		Clonidine Guanfacine
Calcium channel blockers		Verapamil Nicardipine Nimodipine Nifedipine
Devices	Transcutaneous supraorbital nerve stimulation (Cefaly) Non-invasive vagus nerve stimulator (gammaCore)

Intervention (# of trials)	8 Weeks	12 Weeks	6 Months
Galcanezumab (n=6)	1.44 migraine days/month	1.83 migraine days/month	1.85 migraine days/month
Erenumab (n=5)	1.40 migraine days/month	1.22 migraine days/month	1.84 migraine days/month
Fremanezumab (n=2)	—	1.35 migraine days/month	—
Atopegant (n=1)	—	1.24 migraine days/month	—
Non-invasive vagal nerve stimulation (gammaCore) (n = 1)	—	0.48 migraine days/month	—

Intervention (# of trials)	8 Weeks	12 Weeks	6 Months
Galcanezumab (n = 2)	1.75 migraine days/month	—	—
Fremanezumab (n = 2)	1.66 migraine days/month	1.58 migraine days/month	—
Erenumab (n = 1)	3.03 migraine days/month	2.65 migraine days/month	—
Eptinezumab (n = 1)	—	2.69 migraine days/month	—

Drugs and Devices for Migraine Prevention: Interactive Evidence Maps

Authors

Affiliations

Structured Abstract

Background:

Purpose:

Methods:

Results:

Conclusions:

Background

Scope and Purpose

Methods

Table 1

Table 2

Stakeholder Input

Literature Search

Inclusion/Exclusion Criteria

Screening

Rapid-Review Methodology

Data Extraction and Meta-analysis

Map 1 Outcomes

Migraine Reduction and Trial Dropout

Efficacy Measures and Minimally Important Difference

Meta-analysis

Adverse Events

Risk of Bias Assessment

Quality-of-Evidence Assessment

Data Visualization

Results

Map 1. Benefits and Harms of Selected Interventions for Migraine Prevention: Evidence From Placebo-/Sham-Controlled RCTs

Efficacy for All Migraine Types

Episodic Migraine

Table 3

Chronic Migraine

Table 4

Tolerability (Trial Dropout and Adverse Effects)

Map 2. What Types of Drugs and Devices Have Been Studied With RCTs for Migraine Prevention?

Map 3. Head-to-Head Comparisons of Drugs and Devices for Migraine Prevention

Discussion

Limitations

Future Directions

Conclusion

References

Disclaimer

Acknowledgments

Suggested citation:

Table 1Overview of Map Characteristics

Table 2Included Interventions by Map

Table 3Episodic Migraine—High Quality Evidence for Efficacy by Trial Durationa

Table 4Chronic Migraine—High Quality Evidence for Efficacy by Trial Durationa

Table 3Episodic Migraine—High Quality Evidence for Efficacy by Trial Duration^a

Table 4Chronic Migraine—High Quality Evidence for Efficacy by Trial Duration^a