Inpatient Constipation Among Migraine Patients Prescribed Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies and Standard of Care Antiepileptic Drugs: A Retrospective Cohort Study in a United States Electronic Health Record Database

In the post-marketing setting, inpatient constipation with serious complications was reported following the use of erenumab. As such, this study assessed the risk of constipation and serious complications among patients with migraine who initiated preventive treatment with erenumab, other CGRP mAbs, or standard of care AEDs in the inpatient setting only; constipation associated with outpatient visits was not assessed. Since antiepileptics are commonly used as migraine preventive agents, they were chosen as the standard of care therapy for the second comparator cohort to avoid drug classes known to be associated with an increased risk of constipation (e.g., antihypertensives, antidepressants).

The risk of inpatient constipation in the 90 days following treatment initiation was similar for the erenumab and other CGRP mAbs cohorts, while a lower risk was observed among erenumab initiators compared to AED initiators. Moreover, inpatient constipation risk was higher among AED initiators than among initiators of erenumab or other CGRP mAbs, even after PS matching. A possible explanation for this finding may be that carbamazepine and valproic acid were among the antiepileptic medications included in the comparator cohort; constipation is a side effect of both treatments [12].

There were few serious complications of constipation observed in this study; the risk of serious complications of constipation was low overall and similar in the erenumab and other CGRP mAb cohorts, but slightly higher in the AED cohort.

The risk of inpatient constipation among all initiators of erenumab in this study was 0.53% within 90 days following treatment initiation. This estimate is similar to the incidence reported in a retrospective cohort study conducted within the MarketScan® Research Databases [13]. Among patients with migraine initiating various acute and preventive migraine treatments, the incidence of serious constipation (i.e., constipation claim in an ED or inpatient setting) was 0.63% [13]. However, the risk observed in this study was lower than that observed among patients in the erenumab clinical studies [3,4,5], where incidence of any constipation during the first 3 months was 1% with placebo, 1% with 70 mg erenumab, and 3% with 140 mg erenumab [6]. Other studies conducted using real-world data have also reported higher incidence of any constipation (13.5–23.9%) among patients treated with erenumab, although most cases were mild, suggesting that constipation may be a frequent but minor effect of erenumab treatment [14,15,16]. As our study assessed inpatient constipation only, it is expected that the risk would be lower than studies that identified any constipation, but may impact the generalizability of the results.

We observed a higher risk of inpatient constipation among erenumab, other CGRP mAb, and AED initiators with constipation risk factors during baseline, including an epilepsy diagnosis and use of medications known to be associated with constipation, such as opioids, anticholinergics, and 5-HT3 receptor antagonists. This suggests that some cases of inpatient constipation may be partially attributable to these factors rather than to use of the CGRP mAbs alone.

In this study, we did not assess gepants which are small molecules that also target the CGRP pathway to treat migraine. Gepants were not approved by the FDA until late in the study period (December 2019 for ubrogepant and February 2020 for rimegepant) or after the study was completed (September 2021 for atogepant). Nonetheless, it is possible that some patients included in this study received a gepant prior to the index date or before the end of the study period.

An advantage of conducting this analysis within an EHR database versus a claims database is that patient assistance programs sponsored by pharmaceutical manufacturers are unlikely to have impacted the identification of treatment initiators in this study. While EHR data are valuable for the examination of clinical outcomes and treatment patterns, EHR databases have certain inherent limitations because the data are collected for the purpose of clinical patient management, not research. The presence of a diagnosis code may not represent the true occurrence of disease, as the diagnosis may be incorrectly coded or included as rule-out criteria rather than actual disease. Furthermore, a diagnosis code for inpatient constipation in this study may have included events for which constipation was the reason for the admission, present on admission, or developed during the hospital stay. Additionally, the prescription data represent the intent of the prescriber through the written prescription for a medication, and do not indicate that a medication was filled, consumed, or taken as prescribed.

It is possible that patients in the AED cohort took their index medication for an indication other than migraine. To ensure these cohort members were patients with migraine, a combination of two migraine diagnosis codes and/or prescriptions for migraine treatments were required in the 12-month baseline period. Analyses stratified by the presence of an epilepsy diagnosis code during the baseline period were also conducted; the OR of inpatient constipation for erenumab relative to AEDs was similar among initiators with a baseline epilepsy diagnosis and initiators without a baseline epilepsy diagnosis.

As is true for most clinical record-keeping systems, it is not possible to directly determine the completeness of data capture during baseline and follow-up periods within Optum’s EHR database as some patients may receive only a portion of their care from a provider included in the database. Furthermore, we cannot confirm when a patient is lost to follow-up. This contrasts with claims databases, where baseline and follow-up are defined on the basis of dates of health plan enrollment, ensuring that capture of clinical encounters in the database during those periods is relatively complete. In this study, visit dates were available in the EHR database to determine when events of interest occurred. A proxy could have been used to define the end of follow-up, such as the date of last encounter, but this approach would enable sicker patients with more frequent medical visits to contribute more follow-up time than healthier patients with fewer medical visits. To avoid this form of selection bias, the risk (incidence proportion), which was calculated using the number of cohort members as the denominator, was estimated rather than the incidence rate, which is calculated using the person-time at risk as the denominator. Given that the primary objective was to identify inpatient constipation events within a relatively short period following drug exposure (i.e., 90 days), the incidence proportion could serve as a proxy of the cumulative incidence.

In this study, multiple risk windows for outcome assessment were evaluated, with the 90-day risk window specified a priori as the primary risk window of interest. When initiators of erenumab were compared to initiators of other CGRP mAbs, the risk of inpatient constipation was similar in the two cohorts for the 30-day, 60-day, and 90-day risk windows. However, for all available follow-up, risk of inpatient constipation was higher among erenumab initiators compared to the other CGRP mAb initiators. In contrast, when the erenumab cohort was compared to the AED cohort, the risk of inpatient constipation was consistently lower in the erenumab cohort across all risk windows. The consistency in the ORs obtained by assessing occurrence of outcomes in risk windows of varying lengths provides assurance on the robustness of the estimates observed in this study.

The start of the study period was 17 May 2018, the date that erenumab was approved in the USA. However, fremanezumab and galcanezumab were not approved until September 2018. Consequently, the follow-up period was longer for erenumab compared to other CGRP mAb initiators, providing greater opportunity for the occurrence of outcomes among erenumab initiators. Indeed, when the main results were compared to those from the sensitivity analysis among the subset of matched initiators whose index date was on or after 1 January 2019, the ORs were attenuated in the sensitivity analysis. This finding suggests that a longer period of available follow-up among the erenumab compared to other CGRP mAb initiators may have contributed to the higher risk of inpatient constipation observed in this cohort, particularly during all available follow-up in the main analysis.

Although adjustment for confounding was implemented through PS modeling and matching, residual confounding is possible. As health plan coverage for erenumab may require prior authorization or a “step-through” therapy (i.e., failure of standard of care medications), the erenumab initiators may have been different from the AED initiators with respect to migraine severity. This difference could have resulted in biased measures of association if migraine severity is associated with constipation [17, 18]. Following PS matching, the study cohorts were found to be comparable with respect to the measured confounders. Nonetheless, migraine severity was not measured directly, although proxies for severity (i.e., use of migraine preventive agents, comorbidities related to migraine) were included in the PS model. Compared to initiators of AEDs, initiators of other CGRP mAbs were likely more comparable to initiators of erenumab with respect to migraine severity, as indicated by the prevalence of proxies for severity pre-matching. The findings observed in this study population, consisting predominantly of women who likely experienced moderate–severe migraine, may not be generalizable to the overall population of patients with migraine, despite the significance of migraine severity as a confounder.

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