The migraine prevention drug erenumab (Aimovig) was associated with elevated blood pressure (BP), an FDA analysis of postmarketing case reports suggested.
Of 61 erenumab-linked hypertension cases submitted to the FDA Adverse Event Reporting System (FAERS), 41 were associated with a serious outcome according to regulatory criteria, including seven cases that specified hospitalization, reported Suprat Saely, PharmD, of the FDA Center for Drug Evaluation and Research in Silver Spring, Maryland, and colleagues.
About half of the 61 cases reported baseline measurements. In those patients, median systolic BP increase was 39 mm Hg and median diastolic BP increase was 28 mm Hg.
"The temporal association observed in our case series suggests that erenumab can cause markedly elevated blood pressure with or without pre-existing hypertension," Saely and colleagues wrote in Headache. "In the patients we studied, this adverse effect can appear shortly after erenumab initiation and can be clinically important as seen in 27 cases that documented either a pharmacological intervention or emergency department visit/hospitalization."
"In light of our findings, the erenumab (Aimovig) prescribing information was amended to include hypertension in the Warnings and Precautions section," they added.
Erenumab, the first in a relatively new class of drugs approved for migraine prevention, is a monoclonal antibody designed to block the calcitonin gene-related peptide (CGRP) receptor. CGRP is a potent vasodilator and vascular dysfunction is believed to play a significant role in migraine. Since erenumab's approval in April 2018, three other anti-CGRP monoclonal antibodies for migraine prevention have come to market: fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti).
Hypertension has not been reported across the monoclonal antibody development programs, noted migraine researcher Peter Goadsby, MBBS, of King's College London in England and the University of California San Francisco. "This new report did not mirror the trials," he told MedPage Today. "Trials have the obvious advantage of closer monitoring; FAERS has the advantage of a broader catchment."
Only 30 of the 61 FAERS cases had a baseline blood pressure measurement, "so it's complex," Goadsby said. "Whether the data were not recorded, or simply not available, is not clear," he said. "A patient with migraine and hypertension would have their blood pressure treated first, as hypertension can aggravate migraine."
Analysis Details
The FAERS analysis evaluated reports of erenumab-associated elevated blood pressure submitted from May 17, 2018 through April 30, 2020. Elevated blood pressure was defined as new medication treatment or emergency department (ED) visit or hospitalization for new or worsening pre-existing hypertension, or as 140 mm Hg or higher systolic or 90 mm Hg or higher diastolic measurements, with or without baseline measurements reported. "Our case definition was designed to identify cases of elevated blood pressure with or without potential end organ dysfunction (i.e., elevated blood pressure associated with symptoms or signs leading to medical attention)," the researchers said.
Thirty cases in the FAERS database reported baseline measurements and 28 reported both baseline and index measurements. Median baseline measurement was 120 mm Hg systolic and 78 mm Hg diastolic; median index measurement was 159 mm Hg systolic and 102 mm Hg diastolic.
Overall, 44% (27/61 cases) reported treatment for elevated blood pressure, either a new prescription or an ED visit or hospitalization. Serious outcomes in 41 cases included seven that specified hospitalization, four that specified disability, two that were reported as life-threatening, and 34 classified as other serious outcomes. Very limited details were provided for these cases. No case reported an outcome of death.
Elevated blood pressure occurred within a week of the first dose of erenumab in 46% of cases. Nearly a third (31%) of all cases reported a history of pre-existing hypertension.
In 2019, a pooled analysis of four placebo-controlled studies of 2,443 migraine patients looked at vascular safety of erenumab and found no differences in blood pressure changes between placebo and erenumab. "It is important to note that these four studies excluded older patients [over age 65], those with poorly controlled hypertension, and those with unstable cardiovascular diseases," Saely and colleagues pointed out.
More recently, a 5‐year, open‐label extension of a randomized trial of erenumab showed no meaningful changes in mean blood pressure or heart rate through the end of study. "Mean systolic blood pressure was 118 mm Hg at baseline and 121 mm Hg at safety follow-up and mean diastolic blood pressure was 75 mm Hg at baseline and 78 mm Hg at safety follow-up," reported Messoud Ashina, MD, PhD, of University of Copenhagen, and colleagues, in European Journal of Neurology. "Similar changes were seen in categorical assessment of blood pressure change from baseline."
'Encourage More Reporting'
FAERS data may vary from these findings because trial participants differ from people who receive erenumab in the real world, said Elizabeth Loder, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School, both in Boston. In the open-label extension, for example, "only about half of participants remained in the study for 5 years," she noted.
"There also may be a difference in the threshold for attributing an event to treatment," Loder told MedPage Today. "In the study, investigators were asked to determine whether adverse events were likely attributable to the study treatment, whereas in real life it would be the patient or their doctor who made that determination." People selected for trials tend to be healthier and have fewer comorbid conditions than those who receive treatments in the real world, she added.
Hypertension may turn out to be a class effect and not a complication specific to erenumab, Loder observed. "Given that the other antibody treatments entered the market after erenumab, the lower number or lack of such reports for them likely reflects the shorter amount of time for adverse event reports to accumulate," she said. "Erenumab was the first of the CGRP monoclonal antibodies to market and thus has accumulated the largest number of FAERS reports."
FAERS is a spontaneous reporting system with inherent limitations, Saely and colleagues noted. "While we performed a detailed case-level analysis, including drug-event causal association, based on information from the narrative of the FAERS cases (not available in the public FAERS database), the reports had variable information quality and quantity limiting the assessment of patient-specific risk factors for elevated blood pressure in some cases," they wrote.
The FAERS study "reminds us migraineurs are allowed to have comorbidity and taking a broader view when we see them is good," Goadsby said. "It will encourage more reporting, so if this is really an issue, it can be tracked better."
Disclosures
Saely and co-authors disclosed no relevant relationships with industry.
