Migraine is een aanvalsgewijze hersenziekte die gekenmerkt wordt door hevige, bonzende, eenzijdige hoofdpijn gedurende 4 tot 72 uur, die gepaard gaat met misselijkheid, braken en/of overgevoeligheid voor licht en geluid (migraine zonder aura). Bij één op de drie patiënten is er sprake van auraverschijnselen voorafgaand aan de hoofdpijn (IHS, 2018; Ashina, 2021a; Ashina, 2021b). Deze verschijnselen zijn meestal visueel en kortdurend (5-60 minuten). De hoofdpijn na een aura is vaak milder of kan zelfs geheel afwezig zijn.

Bij de meeste patiënten is er sprake van episodische migraine (<15 hoofdpijndagen per maand). Elk jaar transformeert echter 2,5% van de patiënten naar chronische migraine (≥15 hoofdpijndagen per maand, waarvan ≥8 migraine dagen, > 3 maanden), een proces dat migraine chronificatie wordt genoemd (IHS, 2018). Het onderscheid met episodische migraine wordt gemaakt omdat de behandeling van chronische migraine anders is. In Nederland zijn dit gemiddeld 50.000 patiënten per jaar. Een belangrijke risicofactor is het frequente gebruik van acute hoofdpijnmedicatie, en als zodanig komt medicatieovergebruik bij twee derde van de chronische migraine patiënten voor, maar in de neurologenpraktijk waarschijnlijk nog meer (Pijpers, 2018; Louter, 2013). De diagnose chronische migraine (CM) en medicatieovergebruikshoofdpijn (MOH) kunnen volgens de huidige classificaties dan ook naast elkaar bestaan. MOH is gedefinieerd als een hoofdpijn op ≥15 dagen per maand met overgebruik van acute hoofdpijnmedicatie, (gebruik op ≥10 dagen per maand voor triptanen of combinatie van medicaties, of ≥15 dagen bij alleen gebruik van eenvoudige pijnstillers zoals paracetamol of NSAIDS), gedurende >3 maanden (IHS, 2018).

Volgens de huidige standaard moeten patiënten met CM en MOH eerst het medicatie-overgebruik staken (gedurende 2 maanden bij triptanovergebruik en 3 maanden bij overgebruik andere pijnstillers) alvorens preventieve medicatie gestart kan worden (Pijpers, 2016; Pijpers, 2019; Pijpers, 2022).

De preventieve behandeling van CM bestaat uit dezelfde preventieve middelen als bij episodische migraine (waaronder ook bètablokkers en candesartan), waarbij het bewijs van effectiviteit bij CM met name voor topiramaat, valproaat en onabotulinumtoxine type A onderzocht is (Kennis, 2013; Bendtsen, 2018; Linde, 2013; Herd, 2019) ). Recent is een nieuwe klasse van preventieve middelen op de markt verschenen, de zogenaamde anti-CGRP-(receptor) antilichamen, afgekort CGRP-mAbs. Deze middelen zijn inmiddels goedgekeurd en worden ook vergoed in Nederland voor chronische migraine. Deze module evalueert de effectiviteit en positionering van de CGRP-mAbs in de behandeling voor patiënten met chronische migraine.

reduction in migraine days per month (critical)

2. Monthly migraine days (MMD, important)

3. Quality of Life (QoL, important)

4. 50% reduction in MMD (important)

5. Monthly headache days (MHD, important)

6. Acute medication days per month (MaMD, important)

7. Disability (important)

8. Impact (important)

9. Adverse events (important)

10. Consistency of response (important)

Description of studies

The selection by Lu (2021) was performed in August 2020, and all outcomes were combined in meta-analysis. Six RCTs were included (Bigal, 2015; Detke, 2018, Dodick, 2019; Lipton, 2020a; Silberstein, 2017 and Tepper, 2017). Participants were diagnosed with CM with or without medication overuse headache (MOH) according to the IHS, and only placebo controlled RCTs were included. Furthermore, efficacy and safety of a CGRP monoclonal antibody or botulinum toxin had to be assessed, and at least one of the targeted outcomes had to be assessed (migraine frequency, migraine days, responder rate, headache intensity or adverse events). Case reports/reviews, post hoc analyses, retrospective studies, and cohort studies were excluded, as were studies from which data for meta-analysis could not be extracted.

Silberstein (2020) evaluated efficacy and safety of eptinezumab for CM, based on the RCT from Lipton (2020a) which is included in Lu (2021). The RCT was performed in 13 countries. Patients were 18 to 65 years of age, and with a migraine history of CM for at least 12 months (40% with acute medication overuse). Patients were allowed to use barbiturates or prescription opioids (≤4 days per month) if use was stable for at least two month before screening until study-week 24. Other medications for migraine (e.g. triptans, nonsteroidal anti-inflammatory drugs, simple analgesics) were not restricted. After randomization, 9 participants in the placebo group (2.4%), and 40 participants in the intervention groups (5.4%) did not receive treatment. A total of 693 participants in the intervention groups (92.9%) and 356 in the placebo group (94.9%) completed week 12. This study was sponsored by H. Lundbeck A/S (Copenhagen, Denmark).

Lipton (2019) evaluated patient-reported outcomes of erenumab for CM, based on the RCT from Tepper (2017) which is included in Lu (2021). The RCT was performed in 69 headache/ clinical centres in North America and Europe. Patients were 18 to 65 years of age, and migraine onset had to be before the age of 50 years, 41% of the participants had medication overuse. Preventive drugs for migraine were not allowed from 2 months before baseline during the study period, neither were botulinum toxin injections. After randomization, 4 participants in the placebo group (1.4%) and 3 participants in the intervention groups (0.8%) did not receive treatment. A total of 375 (98%) completed 3 months. This study was sponsored by Amgen.

Lipton (2020b) evaluated the effect of fremanezumab on quality of life and productivity in patients with CM, based on the RCT from Silberstein (2017) which is included in Lu (2021). The RCT was performed at 132 sites in nine countries. Patients were 18 to 70 years of age, and had CM for at least 12 months. The number of participants with medication overuse headache was not stated. Participants were not allowed to use Onabotulinumtoxin type A (up to 4 months before screening) or barbiturates (up to 4 days before treatment). Patients with a lack of efficacy of two or more specific clusters of migraine preventive treatments were excluded. A total of 692 participants in the intervention groups (91.7%) and 342 in the placebo group (91.2%) completed week 12. This study was sponsored by Teva Pharmaceuticals.

Ford (2021) evaluated functioning and disability associated with galcanezumab in patients with CM, based on the RCT from Detke (2018) which is included in Lu (2021). The RCT was performed at 116 headache and clinical research centres in 12 countries. Patients were 16 to 65 years of age, with CM (64% with acute medication overuse), and with migraine onset before the age of 50 years. Patients who previously did not respond to trials of migraine preventives (Level A or level B evidence) from over three different medication classes were not included (based on the list published by the American Academy of Neurology’s evidence-based guidelines). Approximately 15% of the participants continued concurrent preventive medication (propranolol or topiramate).

Patients received monthly injections of galcanezumab or placebo during 3 months of double-blind treatment. A total of 529 (95.3%) participants in the intervention group, and 508 (91%) in the placebo group completed 3 months. The study was sponsored by Eli Lilly and Company.

Sakai (2021) performed an RCT to determine the efficacy and safety of fremanezumab administration in Japanese and Korean patients with CM. Patients were 18 to 70 years of age, had a history of migraine (age at onset ≤50 years), and experienced a headache on ≥15 days or used a triptan or ergot derivative to treat an established headache on ≥8 days. The amount of participants with medication overuse headache was not stated. Patients who failed at least two out of four clusters of preventive medication were not included. A total of 362 (95%) participants in the intervention groups, and 179 (93.7%) in the placebo group completed week 12. The study was sponsored by Otsuka Pharmaceutical.

Mulleners (2020) performed an RCT to assess the safety and efficacy of galcanezumab, at 64 sites (hospitals, clinics, or research centres) in 12 countries. Patients were 18 to 75 years of age, with episodic or CM (64% with acute medication overuse at baseline (CM subgroup)), with migraine onset before the age of 50 years, who had a documented failure of 2-4 standard-of-care migraine preventive medications in the past 10 years owing to lack of efficacy or tolerability, or both. In this module, we specifically focus on patients with CM. This study was sponsored by Eli Lilly.

Takeshima (2021) performed an RCT to evaluate efficacy and safety of erenumab in patients with episodic or CM. Participants were 20 to 65 years of age, had history of episodic or CM of at least 12 months before study-onset, with migraine onset before the age of 50 years. Subgroup analyses were performed for participants with CM. Patients were not eligible when they failed >3 migraine preventive treatment categories. The amount of participants with medication overuse headache was not stated. A total of 127 (97.7%) participants in the intervention group, and 127 (96.9%) in the placebo group completed week 24. This study was sponsored by Amgen.

Table 1 Summary of included studies

Results

1. 30% reduction in MMD (critical)

None of the RCTs assessed the effect of monoclonal antibodies on 30% reduction in MMD or consistency of response in patients with chronic migraine.

1. Level of evidence of the literature (30% reduction in MMD, critical)

The level of evidence regarding the outcome measure 30% reduction in MMD were not graded because of lack of data.

2. Monthly migraine days (MMD, important)

In the systematic review by Lu (2021), five studies measuring MMDs were combined in a meta-analysis (Dodick, 2019; Detke, 2018; Lipton, 2020a; Silberstein, 2017; Tepper, 2017). This meta-analysis was updated using data from two other RCTs (Mulleners, 2020; Sakai, 2021; Takeshima, 2021). The analysis resulted in a mean difference of -2.14 (95%CI -2.53 to -1.76), favouring the intervention group. This difference was not clinically relevant (as defined by our criteria). Results are shown in a forest plot (Figure 1).

2. Level of evidence of the literature (MMD, important)

The level of evidence regarding the outcome measure MMD started as high because it was based on RCTs and was downgraded by one level to moderate because of influence of the industry (Dodick, 2019; Lipton, 2020a; Mulleners, 2020 and Tepper, 2017) (-1, risk of bias).

3. Quality of life (important)

Quality of life was not reported by the systematic review of Lu (2021). This outcome was reported by 5 RCTs (Ford, 2021; Lipton, 2019; Mulleners, 2020; Lipton, 2020b; Silberstein, 2020), using the Patient Global Impression of change (PGIC) (Silberstein, 2020) and with the MSQ- role function-restrictive domain (MSQ-RFR) (Ford, 2021; Lipton, 2019; Mulleners, 2020; Lipton, 2020b). The EQ-5D-5L was not included in analysis.

In the study by Silberstein (2020), 395 (58%) participants in the intervention groups improved much or very much. In the placebo group, 37.9% improved much or very much). Categorized PGIC results by Silberstein (2020) could not be graded.

Outcomes of the MSQ-RFR subscale were reported by three studies (Ford, 2021; Lipton, 2020b and Mulleners, 2020). One study reported mean differences and SEs between the intervention and placebo groups. Differences between the groups were converted to means and SDs using RevMan calculator. The analysis resulted in a mean difference of 7.15 (95%CI 4.62 to 9.68), favouring the intervention group. This difference was clinically relevant. Results are shown in a forest plot (Figure 2).

3. Level of evidence of the literature (Quality of life, important)

The level of evidence regarding the outcome measure quality of life (MSQ-RFR) started as high because it was based on RCTs and was downgraded by one level to moderate because of influence of the industry (Lipton, 2019; Mulleners, 2020) and selective reporting (Lipton, 2020b) (-1, risk of bias). For instance, the sponsor was involved in the study design, data collection, data analysis, data interpretation, and writing of all related reports and publications (Mulleners, 2020).

4. 50% reduction in MMD (important)

In the systematic review by Lu (2021), four studies measuring 50% responder rates were combined in a meta-analysis (Dodick, 2019; Detke, 2018; Lipton, 2020a; Tepper, 2017). This meta-analysis was updated using data from one other RCT (Mulleners, 2020). The analysis resulted in a Risk ratio of 1.63 (95%CI 1.37 to 1.93), favouring the intervention group. This difference was clinically relevant. Results are shown in a forest plot (Figure 3).

4. Level of evidence of the literature (50% reduction in MMD, important)

The level of evidence regarding the outcome measure 50% reduction in MMD started as high because it was based on RCTs and was downgraded by one level to moderate because of influence of the industry (Detke, 2018; Dodick, 2019; Lipton, 2020a; Mulleners, 2020; Tepper, 2017) (-1, risk of bias).

5. Monthly headache days (MHD, important)

In the systematic review by Lu (2021), four studies measuring MHDs with 2794 participants were combined in meta-analysis (Detke, 2018; Dodick, 2019; Lipton, 2020a and Silberstein, 2017). The analysis resulted in a mean difference of -1.94 (95%CI -2.37 to -1.51), favouring the intervention group. This difference was not clinically relevant. Results are shown in a forest plot (Figure 4).

5. Level of evidence of the literature (MHD, important)

The level of evidence regarding the outcome measure MHD started as high because it was based on RCTs and was downgraded by one level to moderate because of influence of the industry (Dodick, 2019; Lipton, 2020a) (-1, risk of bias).

6. Acute medication days per month (MaMD, important)

In the systematic review by Lu (2021), four studies measuring MaMD’s with x participants were combined in meta-analysis (Detke, 2018; Lipton, 2020a, Silberstein, 2017 and Tepper, 2017). This meta-analysis was updated using data from two other RCTs (Mulleners, 2020 and Sakai, 2021). The analysis resulted in a mean difference of -2.01 (95%CI -2.46 to -1.56), favouring the intervention group. This difference was not clinically relevant. Results are shown in a forest plot (Figure 5).

6. Level of evidence of the literature (MaMD, important)

The level of evidence regarding the outcome measure MaMD started as high because it was based on RCTs and was downgraded by one level to moderate because of influence of the industry (Lipton, 2020a; Mulleners, 2020; Tepper, 2017) (-1, risk of bias).

7. Disability (important)

Disability was not reported by the systematic review of Lu (2021). For the outcome disability, three studies measuring disability with 1876 participants were combined in meta-analysis (Lipton, 2019; Ford, 2021; Mulleners, 2020). Disability was measured using the Migraine Disability Assessment total score (MIDAS). All studies reported mean change scores from baseline. The analysis resulted in a mean difference of -11.01 (95%CI -15.93 to -6.09), favouring the intervention group. This difference was clinically relevant. Results are shown in a forest plot (Figure 6).

7. Level of evidence of the literature (disability, important)

The level of evidence regarding the outcome measure disability started as high because it was based on RCTs and was downgraded by one level to moderate because of influence of the industry (Lipton, 2019; Mulleners, 2020) (-1, risk of bias).

8. Impact (important)

In the systematic review by Lu (2021), three studies measuring impact with 3927 participants were combined in meta-analysis (Lipton, 2020a, Silberstein, 2017 and Tepper, 2017). This meta-analysis was updated using data from two other RCTs (Dodick, 2019 and Sakai, 2021).

Impact was measured using the Headache Impact Test-6 (HIT-6). Analysis was performed conform Cochrane Handbook section 10.5.2 (Higgins, 2022). Thus, endpoint values (Dodick, 2019) were extracted and combined with changes from baseline (Lipton, 2020a; Sakai, 2021; Silberstein, 2017). The analysis resulted in a mean difference of -2.01 (95%CI -2.59 to -1.44), favouring the intervention group. This difference was not clinically relevant. Results are shown in a forest plot (Figure 7).

8. Level of evidence of the literature (impact, important)

The level of evidence regarding the outcome measure impact started as high because it was based on RCTs and was downgraded by two levels to low because of influence of the industry (Dodick, 2019; Lipton, 2020a and Tepper, 2017) (-1, risk of bias); and confidence interval overlap with threshold of clinical decision-making (-1, imprecision).

9. Adverse events (important)

In the systematic review by Lu, four studies measuring treatment-related adverse events were combined in a meta-analysis (Bigal, 2015; Dodick, 2019; Lipton, 2020a). This meta-analysis was updated using data from two other RCTs (Mulleners, 2020; Sakai, 2021). The analysis resulted in a risk ratio of 1.29 (95%CI 1.04 to 1.59), favouring the placebo group. This difference was clinically relevant. Results are shown in a forest plot (Figure 8).

Regarding treatment-related serious adverse events, one serious adverse event was treatment related, in a participant who developed a single episode of worsening migrainous visual phenomena (Lipton, 2020a). This participant had a history of migraine with visual aura. This event (lasting 4 days) emerged 126 days after the second dose. Other serious adverse events were not considered to be treatment related (Lu, 2021; Mulleners, 2020).

9. Level of evidence of the literature (adverse events, important)

The level of evidence regarding the outcome measure adverse events started as high because it was based on RCTs and was downgraded by two levels to low because of influence of the industry (Bigal, 2015; Dodick, 2019; Lipton, 2020a; Mulleners, 2020) (-1, risk of bias); and confidence interval overlap with border of no clinical effect (-1, imprecision). The evidence was not downgraded for indirectness, because the group with episodic migraine in the study by Mulleners (2020) was not expected to bias the result.

10. Consistency of response (important)

None of the RCTs assessed the effect of monoclonal antibodies on consistency of response in patients with chronic migraine.

10. Level of evidence of the literature (Constistency of response, important)

The level of evidence regarding consistency of response were not graded because of lack of data.

A systematic review of the literature was performed to answer the following question: What is the effectiveness of monoclonal antibodies compared to placebo or usual care in patients with chronic migraine?

P:           Patients with chronic migraine (≥15 headache days/month, of which at least 8 migraine days/month), possibly in combination with a diagnosis of MOH (medication overuse headache).

I:            Monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab)

C:           Placebo or usual care (e.g. topiramate, valproate)

O:          Number of monthly migraine days (MMD), number of monthly headache days (MHD), number of monthly days with acute headache medication use (MaMD), number of monthly migraine attacks, quality of life (e.g. EQ-5D, SF-36), disability (e.g. MIDAS), impact (e.g. HIT-6), 50% reduction in MMD, 30% reduction in MMD, consistency of response of 30% reduction in MMD for multiple months, adverse events

Relevant outcome measures

The guideline development group considered 30% reduction in MMD as critical outcome measures for decision making; and number of MMD, MHD, quality of life, MaMD, disability, impact, 50% reduction in MMD, consistency of response, and adverse events as important outcome measures for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies. Quality of life (e.g. EQ-5D, SF-36), disability (e.g. MIDAS), impact (e.g. HIT-6) had to be assessed using validated instruments.

Based on expert opinion the working group defined the following minimal clinically (patient) important differences between active treatment and placebo:

Continuous outcomes:

• Number of monthly migraine headache days (MMD): ≥3 dagen
• Number of monthly headache days (MHD): ≥3 dagen
• Number of monthly days with acute headache medication use (MaMD): ≥3 dagen
• Quality of life: ≥10% difference on a scale, or previously defined minimal important differences (e.g. EQ-5D-3L: 0.07, SF-12 physical: 1, SF-12-mental: 4 (Hao, 2019), MSQ-RFR: 3.2, MSQ-RFP: 4.6, MSQ-EF: 7.5 (Lipton, 2019))
• Disability: ≥5 points (MIDAS, Lipton, 2019)
• Impact: ≥2.3 points (HIT, Lipton, 2019)

Dichotomous outcomes (yes/no):           

• 50% reduction in monthly migraine headache days (MMD): ≥30% (ZiN, 2021)
• 30% reduction in monthly migraine headache days (MMD): ≥30%
• Consistency of response (30% reduction in MMD) for all months with treatment/or 3 out of 6 months of treatment: ≥30%
• Adverse events: ≥25% (ZiN, 2021; GRADE-default)

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2000 until 5 October 2021. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 374 hits. Studies were selected based on the following criteria:

• Systematic review (searched in at least two databases, and detailed search strategy, risk of bias assessment and results of individual studies available), randomized controlled trial comparing monoclonal antibodies with placebo or usual care;
• Patients aged ≥ 18 years;
• Minimal follow-up period of ≥ 3 months;
• Full-text English language publication;
• Studies including ≥ 20 (ten in each study arm) patients; and
• Studies according to PICO.

A total of 102 studies were initially selected based on title and abstract screening. After reading the full text, 89 studies were excluded (see the table with reasons for exclusion under the tab Methods), one systematic review and 13 RCTs were included. One systematic review with meta-analysis (Lu, 2021) was found, which included 6 out of 13 studies (Bigal, 2015; Detke, 2018, Dodick, 2019; Lipton, 2020a; Silberstein, 2017 and Tepper, 2017). The meta-analysis by Lu (2021) was used and updated for the outcomes MMD, MHD, MaMD, impact, 50% responder rate, and adverse events. For the outcomes quality of life, disability, 30% responder rate and consistency of response, data from individual trials was used.

Results

A total of 14 studies were included in the analysis of the literature. Important study characteristics and results are summarized in tables (see Table 1). The assessment of the risk of bias is summarized in the risk of bias tables.