The Evolving Understanding of Risk With Calcitonin Gene-related Peptide Monoclonal Antibodies Based on Real-world Data

A Focus on Hypertension and Raynaud Phenomenon

Ilana D. Breen BS; Aaron R. Mangold MD; Juliana H. VanderPluym MD


Headache. 2021;61(8):1274-1276. 

Prior to the calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs), preventive treatment of migraine consisted of therapies designed for other purposes and applied to migraine, such as antiseizure, antidepressant, and antihypertensive medications. With the release of the first CGRP mAb on May 17, 2018 (erenumab) and subsequent release of three additional antibodies (fremanezumab, galcanezumab, and eptinezumab), migraine finally had its own disease-specific preventive therapies with demonstrated efficacy and safety in clinical trials.

The package inserts for all four CGRP mAbs only noted serious hypersensitivity to the products as a potential contraindication to receiving these treatments.[1–4] Listed adverse effects for these products are limited and have been amended based on postmarketing surveillance. Table 1 summarizes the warnings and precautions and adverse reactions per the revised package inserts for the CGRP mAbs. The limited adverse effect profiles of the CGRP mAbs are welcomed by patients and clinicians alike but seemed almost unbelievable, especially when considering the multisystem roles of CGRP in the body.

Hypertension was the most recent addition to the warnings and precautions section of the package insert for erenumab.[1] Pooled analysis of vascular adverse events and blood pressure (BP) data from the double-blind, placebo-controlled studies of erenumab and their open-label extensions in patients with chronic or episodic migraine showed that regardless of acute migraine-specific medication use or vascular risk factors at baseline, vascular adverse event incidence was similar across the placebo and erenumab treatment groups. Hypertension adverse events were reported among 0.9% (9/1043) of placebo, 0.8% (7/893) of erenumab 70 mg, and 0.2% (1/507) of erenumab 140 mg recipients.[5] A retrospective analysis of postmarketing case reports of erenumab-associated elevated BP submitted to the FDA Adverse Event Reporting System identified 61 cases of elevated BP prompting amendments to the prescribing information.[6] Of note, the FDA Adverse Event Reporting System is a spontaneous reporting system, which may result in underreporting. Therefore, an incidence rate for elevated BP cannot be calculated from these data. Elevated BP was defined as "initiation of a medication or emergency department visit or hospitalization for emergent de novo or worsening of preexisting hypertension, or BP measurement of ≥140 mm Hg systolic or ≥90 mm Hg diastolic."[6] Elevated BP was most frequent within a week of the first dose of erenumab (28/61, 46.0%). Pooled analysis of vascular adverse events and BP data from clinical trials for fremanezumab and galcanezumab, like with erenumab, showed low vascular adverse event incidence that was similar across the placebo and treatment groups.[7,8] However, unlike erenumab, postmarketing pharmacovigilance for vascular adverse events associated with these other CGRP mAbs is yet to demonstrate a safety signal, although continued surveillance is required. For this reason, hypertension is not a listed warning for these other CGRP mAbs.

Raynaud phenomenon (RP) is another vascular condition that has attracted the attention of CGRP mAb prescribers secondary to concerns about blunting the reflex vasodilatory response. Diminished CGRP activity has been shown to contribute to RP pathophysiology and CGRP infusions have been used to treat RP.[9] Given this, we conducted a retrospective cohort study of 169 adults with RP, both primary and secondary, on CGRP modulators (mAbs and small-molecule receptor antagonists), examining the incidence of microvascular complications as the outcome measure.[10] The median age for the total cohort was 47 years (interquartile range [IQR] 21), 96% (163/169) were female, and 89% (151/169) were non-Hispanic White. Our results indicated that 5.3% (9/169) of patients exhibited microvascular complications, ranging from worsening RP to gangrene and autonecrosis that required distal digit amputation. All nine patients with complications were female with a median age of 45 years (IQR 12.5). Among the patients with complications, five had previously diagnosed RP (three primary and two secondary), whereas four developed the RP de novo after exposure to the CGRP modulator. Most of the patients with complications had chronic migraine (8/9), and four had migraine with aura. All the patients with complications were concurrently on medications considered risk factors for RP such as triptans or beta-blockers. Compared to the elevated BP reports, which were most frequent within a week of CGRP mAb exposure, the microvascular complications in our study were noted after months of exposure. An important point to consider is that the natural history of RP is poorly understood, especially for primary RP. Therefore, it is difficult to determine whether the patients with RP in our study would have experienced worsening microvascular disease irrespective of CGRP antagonist exposure. Comparative analysis of the patients with and without complications did not yield statistically significant differences in demographic characteristics, migraine characteristics, rheumatologic history, RP risk factor history including vascular risk factors such as hypertension, or CGRP antagonist use, limiting our ability to provide guidance on how to prescribe these treatments in potentially at-risk populations.

The real-world data obtained in our cohort study regarding RP or from the FDA Adverse Event Reporting System regarding elevated BP events had several limitations. However, the real-world data also allowed for the evaluation of risk in unselected patients that may not qualify for inclusion in trials but may be more similar to those seen in the clinic.

However, it is important to also consider what clinic your patient is being seen in. The patient with digital gangrenous necrosis in our study presented to the dermatology clinic with their complication symptoms, underscoring the importance of a multidisciplinary understanding of CGRP modulators given the multisystem physiologic role of CGRP. Although CGRP mAbs are most commonly prescribed and monitored by neurologists, all clinicians should be aware of the potential risks to their use. The theoretical vascular risk of CGRP mAbs based on the known pathophysiologic involvement of CGRP in conditions such as RP, in addition to the results of studies outlined above, warrants larger-scale prospective studies to establish the safety of these medications in patients with certain vascular comorbidities and help distinguish who may be at the highest risk for potential adverse events.