Discussion
The results of the present study show that patients with difficult-to-treat episodic or chronic migraine, who previously did not respond to up to three pharmacological classes of migraine preventive medication (being onabotulinumtoxinA one of these options for CM patients), can still achieve a clinically significant improvement with erenumab or galcanezumab.
This observation is supported by the following findings: (i) MHD were significantly reduced after administering 3 or 6 doses of erenumab or galcanezumab, independently if the patients were diagnosed with EM or CM; (ii) AMSMD were also diminished with both CGRP MoAbs after 3 or 6 doses, despite the diagnose; (iii) erenumab and galcanezumab reduced the scores obtained in three different PROMs for migraine and pain assessment: HIT-6, MIDAS and VAS, in all the groups included in the study.
MHD and AMSMD are common objective parameters employed to evaluate CGRP MoAbs efficacy in CTs and effectiveness in real-world studies11-13,22,27. In this regard, a marked significant reduction in MHD was observed, which already implies a marked improvement in patients’ life quality. On top of that, a remarkable effect was also observed on AMSMD, which were reduced by a half in, at least, a 50% of the patients enrolled in each of the groups of the study. This outcome is of great interest since a response rate of ≥ 50% reduction in medication use from baseline is often used as a clinically significant threshold for patients suffering from migraine28 and agrees with previous results obtained from real-world observational studies.
Albeit the authors are aware that PROMs for assessing the impact of headaches and the outcomes of treatment have several limitations, an individual’s self-report of the presence, severity, frequency, and impact of headache is crucial to understanding the effectiveness of therapeutic interventions 29, especially considering that about 45% of the patients with migraine oral preventive therapies discontinue treatment because no improvement is perceived30. Therefore, HIT-6, one of the most reliable and valid tests available for migraine assessment 29, and MIDAS, the most commonly used PROM in phase 3 CTs for both drugs, were employed in the present study 11,16,31.
Both CGRP MoAbs significantly reduced the scores obtained in the HIT-6 tool, meaning that erenumab and galcanezumab successfully diminish the impact of migraine in patients’ quality of life. Interestingly, MIDAS reduction after the administration of 3 doses of either erenumab or galcanezumab observed in this study was substantially greater than the reported in CTs for CM and EM 11,12,16,31,32, fact that supports the need of conducting observational studies in which patients with more complexity (polypharmacy, concomitant preventive treatments, previous treatment failures) are included. Additionally, a significant reduction in VAS was reported for both drugs regardless the diagnose. This result concurs with recent published data for erenumab33, yet, to our knowledge, it is the first time evaluated for galcanezumab (CM and EM). Altogether, these data, though limitedly, may suggest that both CGRP MoAbs are able to not only diminish frequency, but also migraine intensity, yet further studies are required to verify this assumption.
Furthermore, safety profile was also addressed for this work since CTs are typically designed to focus on efficacy endpoints rather than adverse event endpoints. Consequently, these studies are often underpowered to detect adverse events compared to follow-up in clinical practice 34. Here, the most frequent adverse event reported for both CGRP MoAbs was mild-to-moderate constipation (14-18% of the patients), as reported in other real-life studies20,33,35 and higher than registered in CTs11-13, yet no patient had to stop treatment due to this cause. These data are compelling, notably when around 40-70% of patients taking any oral preventive medication for migraine discontinue treatment because of drug-related adverse events30,36,37. However, these safety results should be interpreted with caution because though only 1 (1,2%) patient treated with erenumab and 1 (1,79%) with galcanezumab had to discontinue treatment due to drug related adverse events, these were severe.
Another aspect that needs to be mentioned is that other authors report even higher adverse event frequencies of mild to moderate adverse events (≈70%) in real-world observational studies 20. These findings indicate nothing but the urging need of designing more real-world observational studies in which safety is properly addressed, especially in long-term exposure (more than 12 months), young and elderly populations.
Besides, other questions regarding effectiveness and safety of CGRP MoAbs still require answers, namely, may switching from one to another be useful in non-responders? May this compromise effectiveness by propitiating wearing-off effects? Could this trigger a higher incidence of adverse event? Questions that will require multidisciplinary teams to properly cover healthcare provided for patients with rigor and seek for structured data that could improve the health outcomes pursued.