Evaluating Treatment Success in CGRP Antibody Prophylaxis: A Retrospective Cohort Study Comparing Monthly Migraine Days, MIDAS Scores, and HIT-6 Scores

Abstract

Introduction

Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) or its receptor represent a major advance in migraine prevention. However, standardized criteria for assessing treatment response are lacking. This study aimed to compare responder rates based on monthly migraine days (MMDs), the Migraine Disability Assessment (MIDAS), and the Headache Impact Test (HIT-6), and to evaluate whether a single outcome measure may be sufficient for therapeutic decision-making.

Methods

In this retrospective, single-center study, 417 patients with episodic or chronic migraine treated with a CGRP or CGRP receptor monoclonal antibody between January 2020 and June 2023 were analyzed. Inclusion required complete documentation of MMDs, MIDAS scores, and HIT-6 scores. Response was defined as a ≥ 50% (episodic) or ≥ 30% (chronic) MMDs reduction, a ≥ 30% MIDAS reduction (baseline > 20), and/or a ≥ 5-point HIT-6 improvement.

Results

In episodic migraine, 50.3% of patients met the MMDs response criterion, while 69.5% and 67.5% responded as per MIDAS and HIT-6, respectively. In chronic migraine, the response rates were 58.2% (MMDs), 48.2% (MIDAS), and 55.0% (HIT-6). Combining all three parameters identified treatment response in 84.8% of episodic and 77.7% of patients with chronic migraine. Only 1.5% of patients with episodic migraine would have been misclassified as non-responders if solely PROMs were used. Treatment discontinuation due to adverse events occurred in 3.3% of patients.

Conclusions

Outcome measures strongly influence responder classification. PROMs such as MIDAS and HIT-6 captured therapeutic benefits not reflected in MMDs reductions, especially in cases of preserved headache frequency but reduced burden. These tools may serve as valid surrogates for diary-based documentation, especially in episodic migraine. PROMs are a practical and patient-centered alternative or complement to headache diaries, particularly under routine care constraints. Regulatory frameworks and clinical guidelines should consider integrating these measures into standard practice.

Key Summary Points

What is already known on this topic:

Monoclonal antibodies targeting CGRP or its receptor are an effective option for migraine prevention.

Regulatory agencies recommend an early assessment of treatment efficacy, typically using a ≥ 50% reduction in monthly migraine days (MMDs) as the primary criterion.

Patient-reported outcome measures (PROMs) such as MIDAS and HIT-6 are recommended in guidelines but lack standardized integration into routine efficacy evaluations.

What this study adds

This study demonstrates that responder rates differ significantly depending on the outcome measure used (MMDs vs. MIDAS vs. HIT-6).

Combining multiple outcome parameters yielded the highest detection rate of treatment benefit, but PROMs alone identified treatment response in > 98% of episodic migraine cases, defined as meeting at least one of the standard efficacy criteria (≥ 50% MMDs reduction, ≥ 30% MIDAS reduction, or ≥ 5-point HIT-6 improvement).

A single PROM (MIDAS or HIT-6) may suffice to confirm efficacy in episodic migraine, potentially reducing the need for diary-based documentation.

How this study might affect research, practice, or policy

These findings support the use of PROMs as valid and practical alternatives to headache diaries in evaluating CGRP antibody efficacy, especially in resource-limited settings.

The results provide an empirical foundation for incorporating functional and subjective measures into routine care and future guideline revisions.

Health policy frameworks could adapt reimbursement and continuation criteria to include PROM-based documentation, improving patient adherence and clinician feasibility.

Introduction

The advent of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) or its receptor has substantially expanded the options for preventive migraine therapy [1–7]. As these targeted therapies become more widely available, new challenges arise in clinical practice regarding the definition and assessment of their therapeutic benefit [1, 3, 6, 8, 9]. In the absence of treatment efficacy, continuation is neither medically warranted nor economically justified. Accordingly, a standardized and transparent evaluation of treatment response is essential for evidence-based and cost-effective prescribing practices [3].

This need for assessment is also reflected in regulatory requirements. The European Medicines Agency (EMA) mandates that the therapeutic benefit of all approved monoclonal antibodies against CGRP or its receptor be evaluated within 3 months of treatment initiation [10]. Continued therapy should be individually considered and reassessed regularly [3]. This implies that efficacy must be demonstrably documented. However, neither product labels nor legal frameworks provide concrete guidance on how such a benefit should be measured. The responsibility for operationalizing success criteria therefore lies with the treating physicians.

In Germany, the German Society of Neurology (DGN) and the German Migraine and Headache Society (DMKG) have defined specific success criteria for the continued use of monoclonal antibodies targeting CGRP or its receptor in their updated 2022 S1 guideline [3]. For episodic migraine, a reduction in mean monthly migraine days (MMDs) by ≥ 50% over at least 3 months is considered a successful treatment response. For chronic migraine, a ≥ 30% reduction is regarded as clinically meaningful. Documentation should preferably be based on a digital or paper-based headache diary. Alternatively, patient-reported outcome measures (PROMs) are also considered valid. These include a reduction in the MIDAS score by ≥ 30% (for baseline scores of > 20) or an improvement in the HIT-6 score by ≥ 5 points. These thresholds are based on expert consensus.

Comparable criteria have also been established internationally. The European Headache Federation defines a “responder” as a patient who achieves a ≥ 50% reduction in MMDs after 3 months of treatment and recommends this threshold as a clinical decision standard [6].

In the United Kingdom, the National Institute for Health and Care Excellence (NICE) has outlined differentiated criteria in its technology appraisals (TA682, TA764) [8, 11]. For episodic migraine, a 50% reduction in MMDs is required to continue treatment, whereas for chronic migraine, a ≥ 30% reduction is considered sufficient. In Italy, the national regulatory agency AIFA directly links continued prescribing to a ≥ 50% improvement in the MIDAS score, thereby placing greater emphasis on functional impairment [9].

Outside Europe, similar response thresholds are applied. The Canadian Agency for Drugs and Technologies in Health (CADTH) recommends a ≥ 50% reduction in monthly migraine days (MMDs) to justify continuation of therapy, with a reassessment typically scheduled after 3 to 6 months [12]. The American Headache Society (AHS) suggests comparable benchmarks [1]: in addition to a ≥ 50% reduction in MMDs, a ≥ 30% improvement in the Migraine Disability Assessment (MIDAS) or a ≥ 5-point improvement in the Headache Impact Test (HIT-6) is considered a valid indicator of treatment success. The reassessment timing generally follows the dosing interval—after 3 months for monthly administrations and after 6 months for quarterly injections such as eptinezumab.

Despite national differences, there is a remarkable international consensus regarding the core outcome measures. A ≥ 50% reduction in monthly migraine days is widely regarded as the gold standard for defining treatment response. In patients with severe disease or chronic migraine, lower thresholds are increasingly accepted as clinically relevant. Additionally, patient-reported outcome measures such as the MIDAS score [13] and HIT-6 [14] are gaining importance, particularly when quantification of headache days is difficult [7, 15, 16].

This study aimed to investigate whether the outcome measures MMDs, MIDAS, and HIT-6 yield comparable response rates, and how the selection of each individual criterion influences continued eligibility for monoclonal antibody therapy targeting CGRP or its receptor. Given the limited time resources in routine care, this study also examined whether a single outcome measure may be sufficient to assess treatment response validly. Furthermore, we analyzed whether omitting any single parameter could alter the threshold for defining treatment failure.

Methods

Study Design and Patient Cohort

This retrospective, single-center data analysis included patients treated at the Kiel Migraine and Headache Center who received preventive treatment with a monoclonal antibody targeting calcitonin gene-related peptide (CGRP) or its receptor between January 1, 2020, and June 30, 2023. Only treatment courses with complete documentation and a confirmed diagnosis of episodic or chronic migraine according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) [17], were eligible for inclusion. Patients were classified as episodic or chronic migraine according to ICHD-3 criteria at the index date (baseline). Transitions between EM and CM during the follow-up interval were not assessed, given the relatively short observation period of 3–6 months.

Treatment was administered according to standardized institutional protocols introduced on January 1, 2020. These guidelines required patients with statutory health insurance to maintain a completed headache diary and provide patient-reported outcome measures using both the Migraine Disability Assessment (MIDAS) [13] and the Headache Impact Test (HIT-6) [14] prior to the initiation of CGRP pathway-targeted therapy. These requirements were based on the updated S1 guideline on acute and preventive migraine treatment issued by the German Society of Neurology (DGN) [3] in autumn 2019.

Patients who received multiple CGRP monoclonal antibodies in sequence due to a lack of efficacy or tolerability were analyzed based only on the initially prescribed agent to avoid bias from multiple counts. Patients whose treatment began prior to 2020 were excluded, as MIDAS and HIT-6 assessments were not yet consistently implemented at that time. The study period, starting January 1, 2020, was therefore chosen to ensure the availability of consistent and quality-assured baseline data.

Ethics and Consent

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Kiel University (Reference: D404/23). Informed consent was obtained from all subjects involved in this study. Only patients who had provided written general consent for the scientific use of routinely collected clinical data were included.

Outcome Measures

The following variables were systematically extracted from the electronic medical records of each included patient: age, sex, diagnostic classification (episodic or chronic migraine), and the average monthly frequencies of migraine and headache days during the 3 months prior to treatment initiation. The specific CGRP pathway-targeting monoclonal antibody prescribed was recorded. The following agents were included:

• Erenumab, 70 mg subcutaneously every 4 weeks;

• Erenumab, 140 mg subcutaneously every 4 weeks;

• Fremanezumab, 225 mg subcutaneously monthly;

• Fremanezumab, 675 mg subcutaneously every 3 months;

• Galcanezumab, 240 mg loading dose followed by 120 mg subcutaneously monthly;

• Eptinezumab, 100 mg intravenously every 3 months.

MIDAS and HIT-6 scores were documented both at baseline and after a predefined follow-up interval. This interval depended on the agent used: for subcutaneous therapies (erenumab, fremanezumab, galcanezumab), the evaluation occurred in the third month of treatment; for eptinezumab, given quarterly, the evaluation was performed in the sixth month. At each follow-up, the average monthly frequencies of migraine and headache days were also reassessed. All data were manually entered into the electronic medical record for quality assurance purposes. MIDAS and HIT-6 questionnaires were archived accordingly.

Headache and migraine frequencies were recorded using standardized headache diaries, either in paper format or as a digital app. The diaries had to distinguish between migraine days and days with other types of headaches on a per-month basis.

The Migraine Disability Assessment (MIDAS) [13] is a validated international questionnaire that quantifies functional impairment due to migraine over a 3-month period. It assesses lost productivity in work, household, and social domains. The maximum score is 270; a score above 20 indicates severe disability (Grade IV).

The Headache Impact Test-6 (HIT-6) [14] consists of six items that assess headache burden over the preceding 4 weeks. Each item is rated on a five-point Likert scale and weighted from 6 to 13 points, yielding a total score between 36 and 78. The HIT-6 questionnaire was administered in paper format using the validated German version, in line with the standardized methodology recommended by the developers. Permission to use the HIT-6 questionnaire was obtained from QualityMetric/IQVIA.

The primary outcome of this study was to determine the treatment response to CGRP monoclonal antibody therapy in patients with migraine, according to established efficacy criteria. In line with current guideline recommendations [3], a treatment response was defined as a ≥ 50% reduction in average monthly migraine days (MMDs) over at least 3 months in patients with episodic migraine, or a ≥ 30% reduction in those with chronic migraine. These response rates were compared to patient-reported outcome measures, defined as a ≥ 30% reduction in the MIDAS score (for baseline scores of > 20) and/or a ≥ 5-point improvement in the HIT-6 score.

For the purpose of this study, the term ‘combining all parameters’ refers to classifying a patient as a responder if any of the three criteria (MMDs, MIDAS, HIT-6) were fulfilled. Conversely, ‘non-responders’ were defined as patients who did not meet any of these predefined response criteria.

Statistical Analysis

Descriptive statistics were used to summarize patient characteristics, treatment parameters, and outcome measures. Continuous variables are reported as means ± standard deviations (SDs). Pre- and post-treatment comparisons for monthly migraine days (MMDs), MIDAS scores, and HIT-6 scores were conducted using paired two-tailed t tests. Data distribution was tested using the Shapiro–Wilk test. Although some variables showed skewness, the large sample size (n = 417) justified the use of paired two-tailed t tests based on the central limit theorem. A p value of < 0.05 was considered statistically significant. For categorical comparisons of responder rates across outcome parameters, Fisher’s exact test was applied. The same test was used to assess the statistical independence of different responder definitions.

Responder rates were calculated based on established thresholds: a ≥ 50% reduction in MMDs for episodic migraine, a ≥ 30% reduction in MMDs for chronic migraine, a ≥ 30% reduction in the MIDAS score (for baseline values of > 20), and a ≥ 5-point improvement in the HIT-6 score.

Subgroup analyses were conducted to identify patients who met response criteria for only one of the three parameters (MMDs, MIDAS, or HIT-6), as well as those who would have been misclassified as non-responders if a single parameter had been used. All statistical analyses were performed using Social Science Statistics, 2023.

Results

Demographics and Clinical Characteristics

A total of 417 patients were included in the analysis. Of these, 374 (89.7%) were female and 43 (10.3%) were male. The mean age was 46.2 ± 12.8 years (range 16–78 years). At treatment initiation, 197 patients (47.2%) met the ICHD-3 diagnostic criteria for episodic migraine (with or without aura), while 220 patients (52.8%) fulfilled the criteria for chronic migraine.

CGRP Monoclonal Antibodies Used

Fremanezumab (53.5%) and erenumab (40.5%) were the most frequently prescribed agents. Most patients received erenumab at a dosage of 140 mg, and fremanezumab was predominantly administered as a monthly 225 mg injection. The detailed absolute and relative frequencies of all CGRP pathway-targeting monoclonal antibodies used in this study are shown in Table 1.

Table 1.

Absolute and relative frequencies of monoclonal antibodies analyzed in this study, targeting CGRP or the CGRP receptor

Substance	Dosage	Frequency	Absolute	Relative
Erenumab	70 mg SC	Once every 4 weeks	6	1.4%
	140 mg SC	Once every 4 weeks	163	39.1%
	Total		169	40.5%
Fremanezumab	225 mg SC	Once per month	220	52.8%
	675 mg SC	Once per quarter	3	0.7%
	Total		223	53.5%
Galcanezumab	240 mg SC (1st month), then 120 mg SC monthly		24	5.8%
Eptinezumab	100 mg IV	Once per quarter	1	0.2%

Effect on Monthly Migraine Days (MMDs)

Across the full cohort (episodic and chronic migraine combined), the mean number of monthly migraine days decreased significantly from 14.4 ± 6.0 to 9.1 ± 6.8 days (p < 0.001). In subgroup analyses, patients with episodic migraine experienced a reduction from 10.3 ± 2.2 to 5.8 ± 3.6 days/month (p < 0.001), while those with chronic migraine showed a decrease from 18.0 ± 5.9 to 12.0 ± 7.6 days/month (p < 0.001). The absolute and relative reductions in MMDs are depicted in Figs. 1A and B. For the total cohort, the relative reduction was 36.5%. In episodic migraine, the mean reduction corresponded to 43.1%, while in chronic migraine it was 33.2%.

Fig. 1.

A Changes in monthly migraine days (MMDs) during treatment for the total population and separately for episodic and chronic migraine. All changes were statistically significant. B Percentage reductions in monthly migraine days during treatment for the total population and separately for episodic and chronic migraine. All changes were statistically significant

Effect on MIDAS Scores

The MIDAS score decreased significantly from 100.5 ± 70.3 to 65.3 ± 65.6 in the total patient cohort (p < 0.001). A subgroup analysis revealed a reduction from 72.4 ± 53.7 to 38.1 ± 45.9 in patients with episodic migraine and from 125.7 ± 73.8 to 89.6 ± 70.9 in those with chronic migraine (p < 0.001 for both). Figure 2A and B illustrate the absolute and relative changes in the MIDAS scores. In the overall cohort, the relative reduction was 36.5%. Subgroup analysis showed a relative reduction of 43.1% in episodic migraine and 33.2% in chronic migraine.

Fig. 2.

A Changes in MIDAS scores during treatment for the total population and separately for episodic and chronic migraine. All changes were statistically significant. B Percentage reductions in MIDAS scores during treatment for the total population and separately for episodic and chronic migraine. All changes were statistically significant

Effect on HIT-6 Scores

The overall HIT-6 score significantly declined from 66.9 ± 5.1 to 59.4 ± 8.5 (p < 0.001). For patients with episodic migraine, the score decreased from 66.1 ± 5.5 to 56.9 ± 8.9, and in those with chronic migraine, it decreased from 67.5 ± 4.5 to 61.6 ± 7.4 (p < 0.001 for both). Figure 3A and B display the changes in the HIT-6 scores. The relative reduction in the total cohort was 7.5%. In episodic migraine, the mean reduction corresponded to 9.3%, while in chronic migraine it was 5.9%.

Fig. 3.

A Changes in HIT-6 scores during treatment for the total population and separately for episodic and chronic migraine. All changes were statistically significant. B Reductions in HIT-6 scores during treatment for the total population and separately for episodic and chronic migraine. All changes were statistically significant

Responder Rates by Efficacy Parameter

Episodic Migraine

A ≥ 50% reduction in MMDs was achieved by 50.3% of patients. The MIDAS responder rate (≥ 30% reduction in patients with a baseline of > 20) was 69.5%, and the HIT-6 responder rate (≥ 5-point improvement) was 67.5%. A response in at least one of the three measures (MMDs, MIDAS, or HIT-6) was observed in 84.8% of patients. The MIDAS and HIT-6 responder rates were both significantly higher than the ≥ 50% MMDs responder rate (p = 0.0001 and p = 0.0007, respectively). The combined responder criterion (response in any of the three parameters) showed a significantly higher rate than each of the single measures (p < 0.00001 vs. MMDs, p = 0.0005 vs. MIDAS, and p = 0.0001 vs. HIT-6). The difference between the HIT-6 and MIDAS responder rates was not statistically significant (p = 0.745). Figure 4A compares the respective responder rates.

Fig. 4.

A Responder rates for the efficacy parameters recommended in the new DGN treatment guideline (as of December 2023) for CGRP antibodies in episodic migraine. The responder rates for MIDAS, HIT-6, and the combined parameter (response in MIDAS or HIT-6 or ≥ 50% reduction in monthly migraine days) were each significantly higher than those for a ≥ 50% reduction in monthly migraine days alone. The combined parameter also showed a significantly higher responder rate compared to MIDAS and HIT-6 alone. The responder rates for MIDAS and HIT-6 did not differ significantly. B Responder rates for the efficacy parameters recommended in the new DGN treatment guideline (as of December 2023) for CGRP antibodies in chronic migraine. The combined parameter (response in MIDAS or HIT-6 or ≥ 30% reduction in monthly migraine days) showed a significantly higher responder rate compared to MIDAS, HIT-6, and a ≥ 30% reduction in monthly migraine days alone. The responder rates for MIDAS and HIT-6 did not differ significantly, nor did those for HIT-6 and a ≥ 30% reduction in monthly migraine days. The responder rate for a ≥ 30% reduction in monthly migraine days was significantly higher than that for the MIDAS score

Chronic Migraine

A ≥ 30% reduction in MMDs was observed in 58.2% of patients. The responder rate was 48.2% for MIDAS and 55.0% for HIT-6. A positive response in at least one of the three parameters was recorded in 77.7% of patients. There was no significant difference between the MIDAS and HIT-6 responder rates (p = 0.182). The ≥ 30% MMDs responder rate was significantly higher than that of MIDAS (p = 0.045) but not significantly different from that of HIT-6 (p = 0.564). The combined responder rate (any of the three parameters) was significantly higher than that of each individual measure (all p < 0.001). Figure 4B presents the comparative responder data.

Combinations of Efficacy Parameters

Episodic Migraine

Beyond individual measures, the responder rates were analyzed for various combinations. Table 2 summarizes all responder rates for episodic migraine. The combination of all three parameters (≥ 50% reduction in MMDs, MIDAS, and HIT-6) yielded higher responder rates than any single parameter or the combination of HIT-6 or MMDs. There were no significant differences between this three-parameter combination and the combination of MIDAS and MMDs (p = 0.1512) or that of MIDAS and HIT-6 (p = 0.7836). Clinically, these findings indicate that in episodic migraine, documentation of PROMs such as MIDAS and HIT-6 can identify the majority of treatment responses and may reduce the need for continuous headache diary documentation in routine practice. However, MMDs remain the gold standard, particularly in chronic migraine and in regulatory frameworks. PROMs should therefore be considered complementary rather than substitutive outcome measures, with their greatest utility in situations where diary compliance is limited.

Table 2.

Responder rates for different efficacy parameters and their combinations in episodic migraine

Efficacy parameter	Responder rate	Significance vs. highest responder rate
Monthly migraine days reduced by ≥ 50%	50.3%	p < 0.00001
HIT-6 score reduced by ≥ 5 points	67.5%	p < 0.00001
MIDAS score reduced by ≥ 30%	69.5%	p < 0.00001
HIT-6 score or monthly migraine days	75.1%	p = 0.0231
MIDAS score or monthly migraine days	78.7%	n.s p = 0.1512
MIDAS score or HIT-6 score	83.3%	n.s p = 0.7836
MIDAS or HIT-6 or monthly migraine days	84.7%	–

Further analyses showed that in only three of 197 patients (1.5%) with episodic migraine, a ≥ 50% MMDS reduction was not accompanied by a MIDAS or HIT-6 response. Table 3 presents these cases along with additional scenarios where only one of the three parameters indicated efficacy.

Table 3.

Responder rates for improvement in only one of three efficacy parameters (episodic migraine)

Efficacy parameter combination	Responder rate	Patients (n)
MIDAS, negative HIT-6, negative Migraine days, positive	1.5%	3
MIDAS, positive HIT-6, negative Migraine days, negative	9.6%	19
MIDAS, negative HIT-6, positive Migraine days, negative	6.1%	12

Chronic Migraine

Table 4 shows the responder rates for chronic migraine, including italicized values for all parameter combinations. The highest responder rate was observed for the combination of a ≥ 30% reduction in MMDs, MIDAS, and HIT-6. Significant differences between this combination and each individual measure, as well as the MIDAS and MMDs combination, are reported, with the three-parameter combination yielding a higher responder rate in each case. No significant difference was found when the three-parameter combination was compared to the HIT-6 and MMDs (p = 0.1876) or MIDAS and HIT-6 (p = 0.1264) combination. Table 5 details all cases in which two of the three parameters did not indicate efficacy but the third did.

Table 4.

Responder rates for different efficacy parameters and their combinations in chronic migraine

Efficacy parameter	Responder rate	Significance vs. highest responder rate
MIDAS score reduced by ≥ 30%	48.2%	p < 0.00001
HIT-6 score reduced by ≥ 5 points	55.0%	p < 0.00001
Monthly migraine days reduced by ≥ 30%	58.2%	p < 0.00001
MIDAS or migraine days	68.2%	p = 0.0316
MIDAS or HIT-6	70.9%	n.s p = 0.1264
HIT-6 or migraine days	71.8%	n.s p = 0.1876
MIDAS or HIT-6 or migraine days	77.7%	–

Table 5.

Responder rates for improvement in only one of three efficacy parameters (chronic migraine)

Efficacy parameter combination	Responder rate	Patients (n)
MIDAS, negative HIT-6, negative Migraine days, positive	6.8%	15
MIDAS, positive HIT-6, negative Migraine days, negative	5.9%	13
MIDAS, negative HIT-6, positive Migraine days, negative	9.6%	21

Treatment Discontinuation Due to Adverse Events

Treatment was discontinued due to adverse events in 14 of 417 patients (3.3%). In ten of these 14 cases, the treatment had been effective according to the predefined responder criteria. Compared with the 79 patients who discontinued due to a lack of efficacy, this indicates that the likelihood of stopping treatment due to inefficacy was 5.6 times higher than that due to adverse events after the standard 3- or 6-month trial period.

Discussion

The continuation of prophylactic migraine treatment with monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) or its receptor beyond the initial treatment period of 3 months (erenumab, fremanezumab, galcanezumab) or 6 months (eptinezumab) requires, according to regulatory guidelines, documented evidence of treatment efficacy [1, 3, 6, 8–11]. From both economic and legal perspectives, it is therefore essential to demonstrate therapeutic benefit on a case-by-case basis when prescribing beyond the initial period. However, regulatory approvals do not provide specific operational criteria for measuring treatment response. The present study aimed to establish an empirical basis for defining such criteria.

This retrospective analysis confirms the high efficacy of CGRP pathway-targeting monoclonal antibodies in the prevention of both episodic and chronic migraine [2, 4, 5, 7, 16]. The findings demonstrate not only a reduction in migraine frequency but also significant improvements in functional and subjective disease burden, as assessed using the MIDAS and HIT-6 scores. These results are consistent with findings from large clinical trials and international registry data [3, 6, 18, 19].

However, a subset of patients did not respond to treatment. Our analysis shows that responder rates vary considerably depending on the outcome measure used. In episodic migraine, a ≥ 50% reduction in monthly migraine days (MMDs) was achieved by 50.3% of patients, while the responder rates based on MIDAS and HIT-6 were notably higher, at 69.5% and 67.5%, respectively. A similar pattern was observed in chronic migraine, where 58.2% of patients achieved a ≥ 30% reduction in MMDs, while the MIDAS and HIT-6 responder rates were 48.2% and 55.0%, respectively.

These discrepancies highlight the risk of underestimating therapeutic benefits when relying on MMDs as the single criterion for treatment success—an issue also noted in previous studies [8, 11, 14]. Importantly, patient-reported outcome measures (PROMs) such as MIDAS and HIT-6 reflect functional impairment and subjective disease burden, which may not directly correlate with headache frequency [13, 20].

Our data show that combining multiple outcome measures (MMDs, MIDAS, and HIT-6) yields the highest responder rates: 84.8% in episodic migraine and 77.7% in chronic migraine. This supports the utility of a multiparametric approach to efficacy assessment, increasingly advocated by scientific societies and regulatory bodies [8, 9, 21].

At the same time, the results indicate that valid treatment evaluations may also be achievable using a single appropriate measure (e.g., MIDAS or HIT-6). Only 1.5% of patients with episodic migraine would have been misclassified as non-responders if response had been assessed exclusively via PROMs. This finding has practical implications, as the regular use of headache diaries in clinical practice is often hampered by compliance issues [13, 14].

The observed responder rates and thresholds are well aligned with international standards. The MMDs reduction thresholds of ≥ 50% (episodic migraine) and ≥ 30% (chronic migraine) are consistent with recommendations from the European Headache Federation [6], NICE [8, 11], and the American Headache Society [1]. The use of MIDAS and HIT-6 as supplemental outcome measures is also supported by international consensus [13], though previously lacking an empirical basis.

Notably, the Italian Medicines Agency (AIFA) accepts the MIDAS score as a sole criterion for determining treatment success [9]. This practice is supported by our data, which shows a strong correlation between MIDAS and HIT-6 responder rates and high diagnostic sensitivity when used in combination with MMDs. These findings underscore the value of functional outcome measures in patient-centered benefit assessment, as emphasized by current health services research [22].

The present study included a predominantly female population (89.7%). Although sex differences in migraine prevalence and treatment response are well documented, subgroup analyses by sex were not performed due to the retrospective design and limited sample size of male participants. Future studies should explicitly investigate sex-specific and gender-related differences in treatment outcomes.

Limitations

This study’s retrospective, single-center design may limit the generalizability of the findings. Potential selection bias may also have arisen from the tertiary care setting. However, the high degree of documentation standardization—including mandatory collection of MMDs, MIDAS scores, and HIT-6 scores—and the large sample size represent methodological strengths. The impact of individual CGRP monoclonal antibodies (e.g., erenumab vs. fremanezumab) on response rates was not analyzed separately.

Further potential confounders were not systematically assessed in this retrospective dataset. These include the concomitant use of acute migraine medications, behavioral or non-pharmacological interventions, as well as herbal or nutritional supplements. Such factors may have influenced treatment outcomes and could not be accounted for in this analysis. In addition, PROMs are inherently subject to patient recollection and perception bias, whereas headache diaries may suffer from compliance issues. Future studies should systematically collect these variables to provide a more comprehensive and controlled assessment of treatment effects.

The 3-month follow-up is relatively short. Recommending PROMs based on short-term data may be premature. Future research should also specifically address the roles of dosages, dosing intervals, and prior preventive treatments.

Conclusions

This study demonstrated that the choice of outcome measure strongly influences treatment evaluations in patients receiving CGRP monoclonal antibodies for migraine prophylaxis. The combined use of MMDs, MIDAS, and HIT-6 allows for a comprehensive and valid assessment of therapeutic benefit. In clinical practice, PROMs represent a feasible and meaningful alternative or supplement to traditional headache diaries. Given the regulatory requirements and constraints in routine care, these findings are of particular relevance.

The simultaneous application of all three recommended instruments—MIDAS, HIT-6, and a headache diary—maximizes the likelihood of demonstrating treatment efficacy. If the documentation burden is to be reduced, the use of at least one validated PROM (MIDAS or HIT-6) is recommended in episodic migraine. In chronic migraine, priority should be given to the headache diary, as it not only captures attack frequency and intensity but also provides important information on possible medication overuse.

Author Contributions

Carl Hartmut Göbel and Axel Heinze contributed to the design and conceptualization of the study, performed the statistical analysis, interpreted the results, and wrote the first draft of the manuscript. Katja Heinze-Kuhn and Anna Cirkel contributed to the interpretation and analysis of the data. Ursula Müller contributed to clinical data collection. Hartmut Göbel contributed to the design and conceptualization of the study, was involved in co-writing the manuscript, and supervised the project. All authors reviewed and approved the final version of the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

The original data presented in this study are openly available on Zenodo https://zenodo.org/records/15722864

Declarations

Conflict of Interest

Carl Hartmut Göbel has nothing to disclose. Axel Heinze has nothing to disclose. Katja Heinze-Kuhn has nothing to disclose. Ursula Müller has nothing to disclose. Anna Cirkel has nothing to disclose. Hartmut Göbel has nothing to disclose.

Ethical Approval

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Kiel University (Reference: D404/23). Informed consent was obtained from all subjects involved in this study. Only patients who had provided written general consent for the scientific use of routinely collected clinical data were included.