Eptinezumab treatment was associated with longer interictal headache/migraine periods which corresponded to greater improvements in patient-reported quality of life measures
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Abstract
Introduction
Longer periods between headache episodes (interictal periods) may provide greater
time for the nervous system to reset from a previous episode, potentially improving
disease status and health-related quality of life. This post hoc analysis evaluated
this hypothesis by associating patients’ longest interictal periods with improvements
in patient-reported outcomes.
Methods
PROMISE-2 (NCT02974153) was a double-blind, placebo-controlled study evaluating eptinezumab
for preventive treatment of chronic migraine (N = 1072). Daily electronic diary data
from Weeks 1–12 and Weeks 1–24 were used to identify interictal periods, defined as
days between headache episodes. For each patient, the longest interictal period within
these intervals was identified and categorized (1–4, 5–9, 10–14, > 14, and > 21 days).
For each category, the following patient-reported outcomes were assessed: 6-item Headache
Impact Test (HIT-6), Patient Global Impression of Change (PGIC), and patient-identified
most bothersome symptom (PI-MBS).
Results
Excluding interictal periods with > 10% missing data (resulting in 1010 patients with
sufficient data), the mean (SD) of longest interictal periods over Weeks 1–12 was
9.4 (11.0) days. A ≥6-point HIT-6 reduction was observed in 78% (56/72) vs 26% (91/351)
of patients with a > 21-day vs 1–4-day longest interictal period, respectively; much
or very much improvement per PGIC was reported in 90% (65/72) vs 25% (87/348), respectively,
and per PI-MBS was reported in 88% (63/72) vs 26% (92/348), respectively. Similar
results were observed for Weeks 1–24.
Conclusion
Longer interictal periods were associated with more patients indicating positive changes
in headache-related life impact, disease status, and symptomology.
Migraine and other severe headaches can cause suffering and reduce functioning and productivity. Patients are the best source of information about such impact. To develop a new short form (HIT-6) for assessing the impact of headaches that has broad content coverage but is brief as well as reliable and valid enough to use in screening and monitoring patients in clinical research and practice. HIT-6 items were selected from an existing item pool of 54 items and from 35 items suggested by clinicians. Items were selected and modified based on content validity, item response theory (IRT) information functions, item internal consistency, distributions of scores, clinical validity, and linguistic analyses. The HIT-6 was evaluated in an Internet-based survey of headache sufferers (n = 1103) who were members of America Online (AOL). After 14 days, 540 participated in a follow-up survey. HIT-6 covers six content categories represented in widely used surveys of headache impact. Internal consistency, alternate forms, and test-retest reliability estimates of HIT-6 were 0.89, 0.90, and 0.80, respectively. Individual patient score confidence intervals (95%) of app. +/-5 were observed for 88% of all respondents. In tests of validity in discriminating across diagnostic and headache severity groups, relative validity (RV) coefficients of 0.82 and 1.00 were observed for HIT-6, in comparison with the Total Score. Patient-level classifications based in HIT-6 were accurate 88.7% of the time at the recommended cut-off score for a probability of migraine diagnosis. HIT-6 was responsive to self-reported changes in headache impact. The IRT model estimated for a 'pool' of items from widely used measures of headache impact was useful in constructing an efficient, reliable, and valid 'static' short form (HIT-6) for use in screening and monitoring patient outcomes.
The capstone papers on the Global Burden of Disease study 2019 (GBD2019), delayed by a diversion of resources to mapping covid-19, appeared in Lancet on October 17th. The accompanying announcement by the Institute for Health Metrics and Evaluation (IHME) described GBD2019 as “the largest and most comprehensive effort to quantify health loss across places and over time”, including “more than 3.5 billion estimates of … 369 diseases and injuries … in 204 countries and territories” [1]. IHME had previously announced its move to a 3-year cycle of major model updates for most non-fatal causes and risk factors (but not causes of death) [2]. Each future GBD round will include a subset of these “in rotation”, while still producing results each year for all causes of death and all non-fatal outcomes. The focus among the capstone papers was therefore on disability-adjusted life years (DALYs) [3], without the usual separately reported estimates of years lived with disability (YLDs). From a policy perspective (GBD’s main purpose is to inform health policy), this makes complete sense: years of healthy life lost to early mortality are clearly no less important than those lost to disability. But the approach takes away the spotlight from disabling diseases that do not cause early death – such as headache disorders. Nevertheless, headache disorders in 2019 ranked 14th among global causes of DALYs (all ages, both genders) [3]. Seven non-communicable disorders were ranked higher: ischaemic heart disease, stroke, chronic obstructive pulmonary disease, diabetes, low back pain, congenital defects and depressive disorders [3]. Among females, headache disorders were tenth, below gynaecological diseases (ninth) but above depressive disorders (11th). Among young adult females (15–49 years), they were second only to gynaecological diseases (note that this was of DALYs, not YLDs). Among young adult men they were tenth, with road injuries, self-harm, interpersonal violence and cirrhosis – all causes of premature mortality – each responsible for more DALYs. What about YLDs? In separate on-line estimates, headache disorders were the cause in 2019 of 46.6 million YLDs globally, 5.4% of total YLDs, with 88.2% of these attributable to migraine [4]. In terms of lost healthy life, that equates to 46.6 million people dying one year early. In the ranked causes of YLDs (all ages, both genders), headache disorders (602.5 per 100,000 person/years) were third, below low back pain (823.0) and, by a tiny margin, depressive orders (605.7) (Table 1). Among females, gynaecological diseases (second: 764.0) overtook both headache (third: 751.0) and depressive disorders (fourth: 743.7) (Table 1) despite their clearly evident association with female gender. Also clearly evident was the association of headache disorders with age – specifically, with young adulthood. Among females aged 15–49 years, headache disorders (1016.1) were second only to gynaecological diseases (1230.5), with depressive disorders third (890.4). But in all young adults, with gynaecological diseases a factor among only half, headache disorders (813.4) were top cause of YLDs (Table 1). Table 1 GBD2019: Top level-3 causes of global disability (expressed as years lived with disability [YLDs]) by gender and age (data from [3, 4]) Gender Age range (years) Rank Cause % of total YLDs [uncertainty interval] Both All 1 Low back pain 7.4 [6.2–8.7] 2 Depressive disorders 5.5 [4.3–6.8] 3 Headache disorders 5.4 [1.1–10.6] 15–49 1 Headache disorders 8.0 [1.6–15.7] 2 Low back pain 7.6 [6.1–9.3] 3 Depressive disorders 7.3 [5.7–9.2] Male All 1 Low back pain 7.0 [5.8–8.2 2 Age-related hearing loss 5.2 [4.3–6.4] 3 Diabetes 4.9 [4.2–5.7] 4 Depressive disorders 4.7 [3.7–5.9] 5 Headache disorders 4.6 [1.0–9.0] 15–49 1 Low back pain 7.8 [6.3–9.6] 2 Headache disorders 7.0 [1.5–13.8] 3 Depressive disorders 6.6 [5.2–8.3] Female All 1 Low back pain 7.7 [6.5–9.2] 2 Gynaecological diseases 6.2 [5.1–7.3] 3 Headache disorders 6.0 [1.2–12.0] 4 Depressive disorders 6.0 [4.8–7.5] 15–49 1 Gynaecological diseases 10.7 [8.7–12.9] 2 Headache disorders 8.7 [1.6–16.2] 3 Depressive disorder 7.8 [6.0–9.9] There were variations according to World Bank region and country income level. Headache disorders were third cause of YLDs in East Asia & Pacific and in Middle East & North Africa, but second in Europe & Central Asia, fourth in South Asia and in sub-Saharan Africa, fifth in Latin America & Caribbean and (surprisingly) sixth in North America. They were third in countries classed by the World Bank as lower- or upper-middle-income, but fourth in low-income countries and fifth in those classed as high income. The association between headache and socioeconomic status has never been clear! GBD is wholly dependent on data. It applies highly sophisticated modelling to fill data gaps, “borrowing strength between locations and over time” [3]. But extrapolations from nearby countries to those where data are sparse or totally lacking is a process that cannot be free from uncertainty (evidenced by the wide uncertainty intervals around estimates for headache disorders [Table 1]). Not too much should be made of these variations. The level-3 grouping of headache disorders in GBD2019 includes only specific diseases: migraine and tension-type headache (TTH), each with medication-overuse headache (MOH) as a sequela factored in according to the proportion of MOH attributed to it [3]. Low back pain, on the contrary, is a symptom. It ought to, and hopefully will in future iterations of GBD, be split according to its diverse aetiologies. Even at level 4 in IHME’s analyses – supposedly of specific disorders – low back pain remains as a listed single cause of YLDs, and inevitably is ranked first among all but young adult women (Table 2). Migraine remains second overall (both genders, all ages) but takes first place in young women as it did in GBD2016 [5] (Table 2). In fact, migraine is top cause of DALYs in young women (Table 3), a finding, surely, of profound significance. No other disease, communicable or non-communicable, is responsible for more years of lost healthy life in young women, notwithstanding that migraine causes no premature mortality. Table 2 GBD2019: Top level-4 causes of global disability (expressed as years lived with disability [YLDs]) by gender and age (data from [3, 4]) Gender Age range (years) Rank Cause % of total YLDs [uncertainty interval] Both All 1 Low back pain 7.4 [6.2–8.7] 2 Migraine 4.9 [0.8–10.1] 3 Age-related hearing loss 4.7 [3.8–5.7] 15–49 1 Low back pain 7.6 [6.1–9.3] 2 Migraine 7.3 [1.1–15.1 3 Major depression 5.8 [4.3–7.5] Male All 1 Low back pain 7.0 [5.8–8.2 2 Age-related hearing loss 5.2 [4.3–6.4] 3 Diabetes type 2 4.7 [4.0–5.4] 4 Migraine 4.1 [0.7–8.3] 15–49 1 Low back pain 7.8 [6.3–9.6] 2 Migraine 6.3 [1.1–12.8] 3 Major depression 5.2 [3.8–6.7] Female All 1 Low back pain 7.7 [6.5–9.2] 2 Migraine 5.5 [0.9–11.6] 3 Other musculoskeletal 5.0 [3.8–6.4] 15–49 1 Migraine 8.0 [1.2–16.7] 2 Low back pain 7.4 [5.9–9.1] 3 Major depression 6.2 [4.6–8.2] Table 3 GBD2019: Top level-4 causes of global lost healthy life (expressed as disability-adjusted life years [DALYs]) among young adult women (data from [3, 4]) Rank Cause % of total DALYs [uncertainty interval] 1 Migraine 4.9 [0.7–10.6] 2 Low back pain 4.5 [3.4–5.6] 3 Major depression 3.8 [2.7–4.9] New to GBD2019 were bias adjustments to make allowance for low-quality sampling and survey methods, and for a range of other methodological deficiencies in data sources [4]. This is an important development, since epidemiological methods in headache have improved over the last decade [6], and case definitions have changed over the last two [7, 8]. These, too, were factors contributing to the wide uncertainty intervals. Also as a methodological innovation, GBD2019 took separate account of definite and probable migraine and of definite and probable TTH [8], using individual participant data from studies in 19 countries on frequency and duration of episodes to estimate proportions of time in ictal state for each [4]. The authors of the GBD2019 report wrote: “The prominent position of headache disorders in the DALY rankings in the 10-24-year and 25-49-year age groups has received little attention in global health policy debates” [3]. A similar message has been our repeated cri de coeur [5, 9–12]. They added: “While there is no cure for these disorders, there are effective symptomatic and preventive treatments available.” This, of course, is not a revelation in headache circles, but outside them it appears still to be so. Remediability is the crucial issue in claims for priority in health care, especially when there is strong evidence of cost-effectiveness [13]. The disability burden of headache disorders – particularly of migraine, by far the principal contributor [3] – is concentrated among those of productive age. It is this factor that keeps headache high among the causes of YLDs (and DALYs) in less wealthy countries, where shorter life expectancies raise the population proportions of young adults. It is this, also, that adds – or should add – a dimension of mind-focusing concern for policy makers everywhere [5, 14].
Calcitonin gene-related peptide (CGRP) is crucial in the pathophysiology of migraine. We assessed the safety, tolerability, and efficacy of ALD403, a genetically engineered humanised anti-CGRP antibody, for migraine prevention.
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