Article In Brief
Four separate double-blind, placebo-controlled prevention studies and up to a year of results from open-label trials studying adverse events in almost 2,500 migraine patients showed erenumab, a monoclonal antibody, does not increase the risk for vascular events.
Erenumab (Aimovig), a monoclonal antibody approved to prevent migraine, does not increase the risk for vascular events, a research team reported in a safety study published in the online December 18, 2019, edition of Neurology.
Erenumab, which blocks calcitonin gene-related peptide (CGRP) receptors, is known to play an important role in preventing migraine. But CGRP is a potent vasodilator, which concerned scientists and researchers about the risk of adverse vascular events.
However, four separate double-blind, placebo-controlled prevention studies and up to a year of results from open-label trials studying adverse events in almost 2,500 migraine patients showed the monoclonal antibody does not increase the risk for vascular events.
“That is great news for the field,” said the lead study author, David B. Kudrow, MD, medical director of the California Medical Clinic for Headache, who in addition to his clinical practice managing headache patients, has been an investigator in pharmaceutical studies developing therapies for migraine.
“Migraine patients have a slightly higher incidence of cardiovascular events, and we are not sure why,” Dr. Kudrow said. “Many of the acute migraine medicines also have effects on vasoconstriction and we wanted to know whether we were compromising a patient's ability to vasodilate in the throes of a stroke or heart attack.”
Dr. Kudrow cautioned that the patients enrolled in the trials were not at high risk of having vascular events—those with events in the past six to 12 months were excluded from enrolling, “so we did not expect to see strokes and heart attacks in this population.
“However, if the use of a medication to block CGRP activity contributed to vascular events by attenuating compensatory vasodilation and in particular, in patients also using triptans, we might see an increased incidence of these events during the trial. We did not.”
The US Food and Drug Administration approved erenumab in 2018 as a preventive therapy for migraine. It was the first in a new class of migraine medicines, and two similar monoclonal antibodies have also been federally approved in the past year. The other two medications target the CGRP ligand, not the receptor itself.
Study Design, Findings
To conduct the analysis, the scientists collaborated with many other migraine and cardiovascular and cerebrovascular specialists to collect and analyze vascular adverse events and blood pressure data from four double-blind clinical studies testing erenumab for the prevention of chronic or episodic migraine.
They also included data from an ongoing open-label extension that began after the completion of three of these studies. They had information on the use of acute migraine medicines, which were allowed with some limitations, and the patient's vascular risk factors at the start of the studies. They identified all vascular events and sent the data to an independent committee of cardiovascular specialists to see whether the events were vascular or not and whether or not they were to the medications the patient was taking when the event was reported.
A total of 2,443 patients were included in the studies: 1,043 in the placebo arm; 893 on 70 mg of erenumab; and 500 on 140 mg of erenumab, all delivered subcutaneously once a month for three months, and one study extended to six months.
The incidence of vascular adverse events were similar across all groups, including the placebo group, and were not associated with the acute medications or the vascular risk factors at baseline. Hypertension adverse events were also low in all groups—0.9 percent in the placebo arm, 0.8 percent in the 70 mg erenumab arm, and 0.2 percent in the 140 mg arm.
Eighteen patients with questionable adverse events were reviewed by the independent committee, and four were cardiovascular in origin. Two deaths and two vascular events occurred during the open-label study. One patient had a subdural hematoma and cerebral venous thrombosis following a closed head injury during a biking accident. He was found unconscious and under the influence of the drug, 3-4, methylenedioxymethamphetamine (Ecstasy). Two other patients had myocardial ischemia. One of these patients had demand, and the other had exercise-induced ischemia and had taken sumatriptan four hours before the exercise test. This patient received two doses of erenumab 70 mg, with the second dose 36 days before the event.
Another patient had pneumococcal infection, acute respiratory distress syndrome, atrial fibrillation, myocardial (demand) ischemia, and elevated troponin levels. She became sick around day 135 of the open-label treatment with erenumab 70 mg. Finally, another patient with a history of hypertensive cardiovascular disease died of arteriosclerosis and hypertensive heart disease on day 650 of the open-label treatment with erenumab 70 mg.
Another death in one of the studies was attributed to heart failure. The patient had cardiomyopathy/dysplasia, and an autopsy found hyperplastic sclerosis of coronary arteries, fat infiltration of the right heart chamber musculature, hypertrophy of the left cardiac musculature, and dilation of both cardiac chambers.
The committee found no evidence that the events were caused by the preventive medication. The independent team also analyzed data from patients taking acute migraine medicines and also found no link to increased cardiovascular or cerebrovascular events related to these medications. Blood pressure changes were also not associated with the use of either preventive or acute medications.
Traditional migraine medicines were not designed to target headache pathways, Dr. Kudrow said. “It's been challenging to get patients to take migraine prevention medications. About 40 percent of migraine sufferers might benefit from preventive medicines but only one in three have tried them. Most, around 80 percent, stopped within the first year, either because it wasn't working or the side effects made it too difficult.”
(Dr. Kudrow noted that methysergide was introduced more than 50 years ago to treat migraine based on the prevailing understanding of migraine pathophysiology at the time but it is no longer available in the US due to safety concerns.)
“While these findings are encouraging,” said Dr. Kudrow, “longer term studies are needed to further establish vascular safety with erenumab in this population.”
“The study is very important because one of the things that has concerned us about blocking the vasodilatory effects of CGRP is whether it would increase the risk to patients about to have a cardiovascular or cerebrovascular event,” said Alan M. Rapoport, MD, clinical professor of neurology at the David Geffen School of Medicine at UCLA and past president of the International Headache Society.
“CGRP increases pain but is a vasodilator in humans. This study, which analyzed events during both double-blind studies and the open-label safety continuations, demonstrates that the cardiovascular adverse events were no different whether patients were on erenumab at either dose or placebo, at the same time they were using vasoconstrictive ergots or triptans acutely. Erenumab also did not alter blood pressure versus placebo.
Dr. Rapoport added: “Although these findings make us less worried about blocking the vasodilatory effects of CGRP, we would like to see the long-term effects in a million or more people to be sure there is no deleterious signal before we feel entirely comfortable that we are not putting people at risk by blocking the effects of CGRP.”
“This analysis adds some data in a low-risk population,” said Andrew M. Blumenfeld, MD, FAAN, director of the Headache Center of Southern California. (People with a recent history of stroke or heart attack were excluded from the study.)
“It helps us feel a little more secure when we use these medicines.” But, he added, “the study has a lot of limitations. It is only looking at adverse events over a 12-week period and it doesn't tell us anything about the long-term cardiovascular effects in patients taking these medicines. What if the patient had an event at week 13? Also, what happens when someone who is at high-risk is prescribed these medications? We have no idea. I recommend that physicians don't prescribe these medicines if a patient has had a recent stroke or heart attack until we know more about these high-risk patients.”
Dr. Kudrow has participated in advisory boards for Amgen, Novartis, Alder, Eli Lilly, Biohaven, and Promius; and has received research support from Amgen-Novartis, Alder, Teva, Eli Lilly, Biohaven, Zosano, Allergan, Roche-Genentech, Dr. Reddy's Laboratories, Novartis, and UCB. Dr. Rapoport serves as an advisor for Allergan, Amgen, Amneal, Assertio, Autonomic Technologies, Biohaven, Cala Health, Neurolief, Novartis, Promius, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano; he is on the speakers' bureau of Amgen and Teva Pharmaceutical Industries.
Studies in the Current Analysis
- NCT02066415 was a phase 2 study that enrolled 667 patients with chronic migraine and tested two doses (70 mg and 140 mg) for 12 weeks in the placebo-controlled period. Patients taking lower doses in all of the studies were not included in the analysis. The study was followed by an open-label erenumab treatment arm.
- NCT02456740 (STRIVE) enrolled 955 patients with episodic migraine and two doses (70 mg and 140 mg) for 24 weeks in the placebo-controlled period. There was also an active dose-blinded treatment period.
- NCT02483585 (ARISE) enrolled 577 patients with episodic migraine, 70 mg was the highest dose tested in the 24-week placebo-controlled period. Patients assigned to an erenumab arm received the same dose (70 mg or 140 mg) throughout double-blind treatment. The study was followed by an open-label erenumab treatment arm.
- NCT01952574 included 483 patients, and the double-arm placebo-controlled extended for 12 weeks, followed by an open-label erenumab treatment arm that was maintained monthly for up to five years.