Background
Methods
Review of the literature
Development of evidence-based recommendations
Grading of the quality of evidence
| |
High ⨁⨁⨁⨁ | We are very confident that the true effect lies close to that of the estimate of the effect |
Moderate ⨁⨁⨁○ | We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different |
Low ⨁⨁○○ | Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect |
Very low ⨁○○○ | We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect |
Strength of the recommendation
| |
Strong (↑↑) | the panel is confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects |
Weak (↑) | the panel concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but is not confident |
Development of the expert consensus
Drafting of the statements
Final approval of the document
Results
Evidence-based recommendations
Recommendation | Quality of evidencea
| Strength of the recommendation |
---|---|---|
In individuals with episodic migraine we recommend eptinezumab, erenumab, fremanezumab and galcanezumab as preventive treatment | Eptinezumab 100 mg and 300 mg (q): moderate ⨁⨁⨁○ Erenumab 70 mg (m) and 140 mg (m): high ⨁⨁⨁⨁ Fremanezumab 225 (m) and 675 (q): high ⨁⨁⨁⨁ Galcanezumab 120 mg (m) + 240 mg (ld): high ⨁⨁⨁⨁ | Strong ↑↑ |
In individuals with chronic migraine we recommend eptinezumab, erenumab, fremanezumab and galcanezumab as preventive treatment | Eptinezumab 100 mg and 300 mg (q): high ⨁⨁⨁⨁ Erenumab 70 mg (m): high ⨁⨁⨁⨁ Erenumab 140 mg (m): moderate ⨁⨁⨁○ Fremanezumab 225 mg (m): moderate ⨁⨁⨁○ Fremanezumab 675 mg (q): high ⨁⨁⨁⨁ Galcanezumab 120 mg (m) + 240 mg (ld): high ⨁⨁⨁⨁ | Strong ↑↑ |
In individuals with episodic or chronic migraine we recommend erenumab over topiramate as preventive treatment because of better tolerability | Low ⨁⨁○○ | Strong ↑↑ |
Evidence-based recommendation – question 1
In individuals with episodic migraine, is preventive treatment with monoclonal antibodies targeting the CGRP pathway as compared to placebo, effective and safe? |
Drug/Trial | Phase | Dose | Duration | № of participants |
---|---|---|---|---|
Eptinezumab
| ||||
PROMISE-1 NCT02559895 [21] | III | 100 mg (q) 300 mg (q) | 12 weeks | 674 |
Erenumab
| ||||
NCT01952574 [16] | II | 70 mg (m) 140 mg (m) | 12 weeks | 267 |
NCT02630459 [25] | II | 70 mg (m) 140 mg (m) | 12 weeks | 475 |
STRIVE NCT02456740 [24] | III | 70 mg (m) 140 mg (m) | 24 weeks | 955 |
ARISE NCT02483585 [7] | III | 70 mg (m) | 12 weeks | 577 |
EMPOwER NCT03333109 [26] | III | 70 mg (m) 140 mg (m) | 12 weeks | 900 |
NCT03812224 [29] | III | 70 mg (m) | 24 weeks | 261 |
LIBERTY NCT03096834 [15] | IIIb | 140 mg (m) | 12-weeks | 246 |
Fremanezumab
| ||||
NCT02025556 [18] | II | 225 mg (m) 675 mg (m) | 12 weeks | 297 |
HALO EM NCT02629861 [12] | III | 225 mg (m) 675 mg (q) | 12 weeks | 875 |
NCT03303092 [28] | III | 225 mg (m) 675 mg (q) | 12 weeks | 357 |
FOCUS NCT03308968 [11] | IIIb | 225 mg (m) 675 mg (q) | 12 weeks | 329 |
Galcanezumaba
| ||||
EVOLVE-1 NCT02614183 [10] | III | 120 mg (m + 240 mg ld) | 24 weeks | 646 |
EVOLVE-2 NCT02614196 [9] | III | 120 mg (m + 240 mg ld) | 24 weeks | 692 |
CONQUER NCT03559257 [8] | IIIb | 120 mg (m + 240 mg ld) | 12 weeks | 269 |
In individuals with episodic migraine, we recommend eptinezumab, erenumab, fremanezumab and galcanezumab as preventive treatment Quality of evidence: moderate to high Strength of the recommendation: strong |
Outcomes | Anticipated absolute effects (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
---|---|---|---|---|---|---|
Risk with placebo | Risk with active durg | |||||
Eptinezumab 100 mg quarterly | ||||||
Monthly migraine days | The mean monthly migraine days was – 3.2 days | Mean 0.7 days fewer (1.3 fewer to 0.1 fewer) | 443 (1 RCT) | ⨁⨁⨁○ Moderatea
| Eptinezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 37.4 per 100 | 49.8 per 100 (40.9 to 60.0) | 443 (1 RCT) | ⨁⨁⨁○ Moderatea
| Eptinezumab likely results in an increase in > 50% responder rate. | |
Days with acute medication use | n.a | n.a | – | – | – | – |
Eptinezumab 300 mg quarterly | ||||||
Monthly migraine days | The mean monthly migraine days was −3.2 days | Mean 1.1 days fewer (1.7 fewer to 0.5 fewer) | 444 (1 RCT) | ⨁⨁⨁○ Moderatea
| Eptinezumab likely results in a slight reduction in monthly migraine days. | |
> 50% responder rate | 37.4 per 100 | 56.3 per 100 (46.9 to 67.1) | 0.19 (0.10 to 0.28) | 444 (1 RCT) | ⨁⨁⨁○ Moderatea
| Eptinezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | n.a | n.a | – | – | – | – |
Erenumab 70 mg monthly | ||||||
Monthly migraine days | The mean monthly migraine days was −1.5 days | Mean 1.4 days fewer (1.7 fewer to 1.1 fewer) | 2501 (6 RCTs) | ⨁⨁⨁⨁ High | Erenumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 30.5 per 100 | 44.4 per 100 (40.7 to 48.4) | 0.14 (0.10 to 0.18) | 2371 (5 RCTs) | ⨁⨁⨁⨁ High | Erenumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −0.3 | Mean 0.9 fewer (1.1 fewer to 0.7 fewer) | 2128 (4 RCTs) | ⨁⨁⨁⨁ High | Erenumab likely results in a reduction of days with acute medication use | |
Erenumab 140 mg monthly | ||||||
Monthly migraine days | The mean monthly migraine days was −1.1 days | Mean 1.8 days fewer (2.2 fewer to 1.4 fewer) | 1653 (4 RCTs) | ⨁⨁⨁⨁ High | Erenumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 28.6 per 100 | 47.0 per 100 (42.3 to 52.0) | 0.20 (0.16 to 0.25) | 1698 (4 RCTs) | ⨁⨁⨁⨁ High | Erenumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was 0 | Mean 1.6 fewer (1.8 fewer to 1.3 fewer) | 1693 (4 RCTs) | ⨁⨁⨁⨁ High | Erenumab likely results in a reduction of days with acute medication use | |
Fremanezumab 225 mg monthly | ||||||
Monthly migraine days | The mean monthly migraine days was −1.8 days | Mean 2.3 days fewer (2.8 fewer to 1.8 fewer) | 1235 (4 RCTs) | ⨁⨁⨁⨁ High | Fremanezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 25.1 per 100 | 47.6 per 100 (41.8 to 54.0) | 0.23 (0.17 to 0.28) | 999 (3 RCTs) | ⨁⨁⨁⨁ High | Fremanezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −1.6 | Mean 1.7 fewer (2.2 fewer to 1.2 fewer) | 1013 (3 RCTs) | ⨁⨁⨁⨁ High | Fremanezumab likely results in a reduction of days with acute medication use | |
Fremanezumab 675 mg quarterly | ||||||
Monthly migraine days | The mean monthly migraine days was − 1.6 days | Mean 1.9 days fewer (2.4 fewer to 1.4 fewer) | 1030 (3 RCTs) | ⨁⨁⨁⨁ High | Fremanezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 25.1 per 100 | 47.0 per 100 (41.2 to 53.4) | 0.22 (0.16 to 0.28) | 997 (3 RCTs) | ⨁⨁⨁⨁ High | Fremanezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −1.4 | Mean 1.6 fewer (2.1 fewer to 1.1 fewer) | 811 (2 RCTs) | ⨁⨁⨁○ Moderatea
| Fremanezumab likely results in a reduction of days with acute medication use | |
Galcanezumab 120 mg monthly (240 mg loading dose) | ||||||
Monthly migraine days | The mean monthly migraine days was − 1.9 days | Mean 2.1 days fewer (2.5 fewer to 1.7 fewer) | 1596 (3 RCTs) | ⨁⨁⨁⨁ High | Galcanezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 34.7 per 100 | 56.2 per 100 (50.3 to 62.7) | 0.24 (0.19 to 0.29) | 1596 (3 RCTs) | ⨁⨁⨁⨁ High | Galcanezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −1.7 | Mean 1.9 fewer (2.3 fewer to 1.6 fewer) | 1596 (3 RCTs) | ⨁⨁⨁⨁ High | Galcanezumab likely results in a reduction of days with acute medication use |
Evidence-based recommendation – question 2
In individuals with chronic migraine, is preventive treatment with monoclonal antibodies targeting the CGRP pathway as compared to placebo, effective and safe? |
Drug/Trial | Phase | Dose | Duration | № of participants |
---|---|---|---|---|
Eptinezumab
| ||||
NCT02275117 [20] | IIb | 100 mg (q) 300 mg (q) | 12 weeks | 364 |
PROMISE-2 NCT02974153 [22] | III | 100 mg (q) 300 mg (q) | 12 weeks | 1121 |
Erenumab
| ||||
NCT02066415 [19] | II | 70 mg (m) 140 mg (m) | 12 weeks | 667 |
NCT03812224 [29] | III | 70 mg (m) | 24 weeks | 261 |
Fremanezumaba
| ||||
NCT02021773 [17] | II | 225 mg (m + 675 mg ld) | 12 weeks | 177 |
HALO CM NCT02621931 [13] | III | 225 mg (m + 675 mg ld) 675 mg (q) | 12 weeks | 1130 |
NCT03303079 [27] | III | 225 mg (m + 675 mg ld) 675 mg (q) | 12 weeks | 571 |
FOCUS NCT03308968 [11] | IIIb | 225 mg (m + 675 mg ld) 675 mg (q) | 12 weeks | 509 |
Galcanezumab
| ||||
REGAIN NCT02614261 [23] | III | 120 mg (m + 240 mg ld) | 12 weeks | 836 |
CONQUER NCT03559257 [8] | IIIb | 120 mg (m + 240 mg ld) | 12 weeks | 193 |
In individuals with chronic migraine, we recommend eptinezumab, erenumab, fremanezumab and galcanezumab as preventive treatment Quality of evidence: moderate to high Strength of the recommendation: strong |
Outcomes | Anticipated absolute effects (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
---|---|---|---|---|---|---|
Risk with placebo | Risk with active durg | |||||
Eptinezumab 100 mg quarterly | ||||||
Monthly migraine days | The mean monthly migraine days was −5.6 days | Mean 2.1 days fewer (2.9 fewer to 1.3 fewer) | 956 (2 RCTs) | ⨁⨁⨁⨁ High | Eptinezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 39.6 per 100 | 57.0 per 100 (50.4 to 64.2) | 0.17 (0.11 to 0.24) | 956 (2 RCTs) | ⨁⨁⨁⨁ High | Eptinezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −1.9 | Mean 1.2 days fewer (1.7 fewer to 0.6 fewer) | 722 (1 RCT) | ⨁⨁⨁○ Moderatea
| Eptinezumab likely results in a reduction of days with acute medication use | |
Eptinezumab 300 mg quarterly | ||||||
Monthly migraine days | The mean monthly migraine days was – 5.6 days | Mean 2.6 days fewer (3.3 fewer to 1.9 fewer) | 946 (2 RCTs) | ⨁⨁⨁⨁ High | Eptinezumab likely results in a slight reduction in monthly migraine days. | |
> 50% responder rate | 39.6 per 100 | 60.3 per 100 (53.5 to 67.8) | 0.21 (0.15 to 0.27) | 946 (2 RCTs) | ⨁⨁⨁⨁ High | Eptinezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −1.9 | Mean 1.4 days fewer (1.9 fewer to 0.9 fewer) | 716 (1 RCT) | ⨁⨁⨁○ Moderatea
| Eptinezumab likely results in a reduction of days with acute medication use | |
Erenumab 70 mg monthly | ||||||
Monthly migraine days | The mean monthly migraine days was −4.0 days | Mean 2.2 days fewer (3.1 fewer to 1.2 fewer) | 571 (2 RCTs) | ⨁⨁⨁⨁ High | Erenumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 23.0 per 100 | 40.0 per 100 (31.4 to 50.0) | 0.16 (0.08 to 0.25) | 469 (1 RCT) | ⨁⨁⨁○ Moderatea
| Erenumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −1.6 | Mean 1.9 fewer (2.6 fewer to 1.1 fewer) | 469 (1 RCT) | ⨁⨁⨁○ Moderatea
| Erenumab likely results in a reduction of days with acute medication use | |
Erenumab 140 mg monthly | ||||||
Monthly migraine days | The mean monthly migraine days was −4.2 days | Mean 2.5 days fewer (3.5 fewer to 1.4 fewer) | 468 (1 RCT) | ⨁⨁⨁○ Moderatea
| Erenumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 23.0 per 100 | 41.0 per 100 (32.5 to 51.5) | 0.18 (0.09 to 0.26) | 468 (1 RCT) | ⨁⨁⨁○ Moderatea
| Erenumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −1.6 | Mean 2.6 fewer (3.3 fewer to 1.8 fewer) | 468 (1 RCT) | ⨁⨁⨁○ Moderatea
| Erenumab likely results in a reduction of days with acute medication use | |
Fremanezumab 225 mg monthly | ||||||
Monthly migraine days | The mean monthly migraine days was −2.2 days | Mean 2.6 days fewer (3.3 fewer to 2.0 fewer) | 1463 (4 RCTs) | ⨁⨁⨁○ Moderateb
| Fremanezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 18.4 per 100 | 39.0 per 100 (34.4 to 44.2) | 0.20 (0.16 to 0.25) | 1298 (3 RCTs) | ⨁⨁⨁○ Moderateb
| Fremanezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −2.1 | Mean 1.9 fewer (2.6 fewer to 1.3 fewer) | 1123 (2 RCT) | ⨁⨁○○ Lowa,b
| Fremanezumab likely results in a reduction of days with acute medication use | |
Fremanezumab 675 mg quarterly | ||||||
Monthly migraine days | The mean monthly migraine days was −2.2 days | Mean 2.2 days fewer (2.9 fewer to 1.5 fewer) | 1461 (3 RCTs) | ⨁⨁⨁⨁ High | Fremanezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 16.4 per 100 | 34.8 per 100 (30.1 to 40.0) | 0.18 (0.13 to 0.23) | 1125 (2 RCTs) | ⨁⨁⨁○ Moderatea
| Fremanezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −2.1 | Mean 1.7 fewer (2.4 fewer to 1.0 fewer) | 1125 (2 RCT) | ⨁⨁⨁○ Moderatea
| Fremanezumab likely results in a reduction of days with acute medication use | |
Galcanezumab 120 mg monthly (240 mg loading dose) | ||||||
Monthly migraine days | The mean monthly migraine days was −2.5 days | Mean 2.6 days fewer (3.5 fewer to 1.6 fewer) | 1004 (2 RCTs) | ⨁⨁⨁⨁ High | Galcanezumab likely results in a reduction in monthly migraine days. | |
> 50% responder rate | 14.4 per 100 | 28.5 per 100 (23.3 to 34.5) | 0.15 (0.09 to 0.20) | 1004 (2 RCTs) | ⨁⨁⨁⨁ High | Galcanezumab likely results in an increase in > 50% responder rate. |
Days with acute medication use | The mean reduction in days with acute medication use was −2.1 | Mean 2.8 fewer (3.7 fewer to 2.0 fewer) | 1004 (2 RCTs) | ⨁⨁⨁⨁ High | Galcanezumab likely results in a reduction of days with acute medication use |
Evidence-based recommendation – question 3
In individuals with migraine, is preventive treatment with monoclonal antibodies targeting the CGRP pathway, as compared to another migraine preventive treatment, more effective and/or tolerable? |
In individuals with episodic or chronic migraine we recommend erenumab over topiramate as preventive treatment Quality of evidence: low Strength of the recommendation: strong |
Trial | Phase | Monoclonal antiboy/dose | Comparator/dose | Duration | № of participants |
---|---|---|---|---|---|
HER-MES [14] | III | Erenumab 70-140 mg (m) | Topiramate 50-100 mg (d) | 12 weeks | 777 |
Outcomes | Anticipated absolute effects (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
---|---|---|---|---|---|---|
Risk with Topiramate | Risk with Erenumab | |||||
Monthly migraine days | The mean monthly migraine days was −4.02 days | Mean 1.84 days fewer (2.43 fewer to 1.25 fewer) | – | 776 (1 RCT) | ⨁⨁○○ Lowa,b
| Erenumab likely results in a slight reduction in monthly migraine days. |
> 50% reduction in migraine days per month | 31 per 100 | 56 per 100 (48 to 63) | RR 1.78 (1.50 to 2.11) | 776 (1 RCT) | ⨁⨁○○ Lowa,b
| Erenumab likely results in an increase in > 50% reduction in migraine days per month. |
Medication discontinuation | 39 per 100 | 11 per 100 (8 to 15) | RR 0.27 (0.20 to 0.37) | 776 (1 RCT) | ⨁⨁⨁○ Moderatea
| Erenumab likely results in a reduction in medication discontinuation. |
Expert consensus statements
Question | Statement |
---|---|
1. When should treatment with monoclonal antibodies targeting the CGRP pathway be offered to individuals with migraine? | In individuals with migraine who require preventive treatment, we suggest monoclonal antibodies targeting the CGRP pathway to be included as a first line treatment option. |
2. How should other preventive treatments be managed when using monoclonal antibodies targeting the CGRP pathway in individuals with migraine? | In individuals with episodic or chronic migraine there is insufficient evidence to make suggestions regarding the combination of monoclonal antibodies targeting the CGRP with other preventatives to improve migraine clinical outcomes |
3. When should treatment efficacy in individuals with migraine on treatment with anti-CGRP monoclonal antibodies be firstly evaluated? | In individuals with episodic or chronic migraine who start a new treatment with one monoclonal antibody targeting the CGRP pathway we suggest evaluating efficacy after a minimum of 3 consecutive months on treatment |
4. When should treatment with anti-CGRP monoclonal antibodies be paused in individuals with migraine? | In individuals with episodic or chronic migraine we suggest considering a pause in the treatment with monoclonal antibodies targeting the CGRP pathway after 12-18 months of continuous treatment. If deemed necessary, treatment should be continued as long as needed. In individuals with migraine who pause treatment, we suggest restarting the treatment if migraine worsens after treatment withdrawal. |
5. Should individuals with migraine and medication overuse offered treatment with monoclonal antibodies targeting the CGRP pathway? | In individuals with migraine and medication overuse, we suggest offering monoclonal antibodies targeting the CGRP pathway. |
6. In individuals with migraine who are non-responders to one monoclonal antibody targeting the CGRP pathway, is switching to a different antibody an option? | In individuals with migraine with inadequate response to one monoclonal antibody targeting the CGRP pathway, there is insufficient evidence on the potential benefits of antibody switch but switching may be an option. |
7. In which individuals with migraine is caution suggested when considering treatment with monoclonal antibodies targeting the CGRP pathway? | We suggest avoiding monoclonal antibodies targeting the CGRP pathway in pregnant or nursing women. We suggest caution and decision on a case-by-case basis in the presence of vascular disease or risk factors and Raynaud phenomenon. We suggest caution in erenumab use in individuals with migraine with history of severe constipation. |
Expert consensus statement – question 1
When should treatment with monoclonal antibodies targeting the CGRP pathway be offered to individuals with migraine? |
In individuals with migraine who require preventive treatment, we suggest monoclonal antibodies targeting the CGRP pathway to be included as a first line treatment option. |
Expert consensus statement – question 2
How should other preventive treatments be managed when using monoclonal antibodies targeting the CGRP pathway in individuals with migraine? |
In individuals with episodic or chronic migraine there is insufficient evidence to make suggestions regarding the combination of monoclonal antibodies targeting the CGRP with other preventatives to improve migraine clinical outcomes |
Expert consensus statement – question 3
When should treatment efficacy in patients on treatment with anti-CGRP monoclonal antibodies be firstly evaluated? |
In individuals with episodic or chronic migraine who start a new treatment with one monoclonal antibody targeting the CGRP pathway we suggest evaluating efficacy after a minimum of 3 consecutive months on treatment |
Expert consensus statement – question 4
When should treatment with anti-CGRP monoclonal antibodies be paused in individuals with migraine? |
In individuals with episodic or chronic migraine we suggest considering a pause in the treatment with monoclonal antibodies targeting the CGRP pathway after 12-18 months of continuous treatment. If deemed necessary, treatment should be continued as long as needed. In individuals with migraine who pause treatment, we suggest restarting the treatment if migraine worsens after treatment withdrawal. |
Expert consensus statement – question 5
Should individuals with migraine and medication overuse be offered treatment with monoclonal antibodies targeting the CGRP pathway? |
In individuals with migraine and medication overuse, we suggest offering monoclonal antibodies targeting the CGRP pathway. |
Expert consensus statement – question 6
In individuals with migraine who are non-responders to one monoclonal antibody targeting the CGRP pathway, is switching to a different antibody an option? |
In individuals with migraine with inadequate response to one monoclonal antibody targeting the CGRP pathway, there is insufficient evidence on the potential benefits of antibody switch but switching may be an option. |
Expert consensus statement – question 7
In which individuals with migraine is caution suggested when considering treatment with monoclonal antibodies targeting the CGRP pathway? |
We suggest avoiding monoclonal antibodies targeting the CGRP pathway in pregnant or nursing women. We suggest caution and decision on a case-by-case basis in the presence of vascular disease or risk factors and Raynaud phenomenon. We suggest caution in erenumab use in individuals with migraine and history of severe constipation. |