Associations of Lisinopril/Candesartan, Anti-CGRP Treatments vs. Topiramate on Cardiovascular Outcomes in Patients with Migraine

BackgroundMigraine is a prevalent neurological condition associated with increased cardiovascular risk; however, the pathophysiologic mechanisms underlying this association remains poorly understood, and the long-term cardiovascular effects of migraine preventive medications have yet to be determined. MethodsWe emulated two separate two-arm target trials comparing patients who initiated lisinopril/candesartan or anti-calcitonin gene-related peptide (aCGRP) treatments versus those receiving topiramate for migraine prevention within the U.S. Department of Veterans Affairs between June 1, 2018 and September 30, 2024. The outcome was major adverse cardiovascular event (MACE) including myocardial infarction (MI), ischemic stroke, intracerebral and subarachnoid hemorrhage (ICH/SAH) and all-cause mortality. Five-year cumulative incidences, risk differences, risk ratios and overall hazard ratios (HRs) were estimated. ResultsAmong 48,610 patients initiating lisinopril/candesartan (mean [SD] age, 52.3 [12.3] years; 18.9% women) and 25,635 initiating aCGRP treatment (mean [SD] age, 47.2 [12.2] years; 39.4% women), lisinopril/candesartan was associated with a higher risk of MACE (HR 1.21; 95%CI, 1.10-1.34), particularly MI (HR 1.28; 95%CI, 1.03-1.59). The MI risk was greater in patients without documented cardiovascular indications (HR 2.75; 95%CI, 2.01-3.77), patients aged <40 years (HR 3.18; 95%CI, 1.63-6.20), or with baseline systolic blood pressure <130 mm Hg (HR 1.86; 95%CI, 1.44-2.39). aCGRP use was associated with a reduced risk of MI (HR 0.80; 95% CI, 0.62-1.02) and was not associated with ischemic stroke (HR 1.11; 95% CI, 0.84-1.49) or ICH/SAH (HR 0.95; 95% CI, 0.65-1.38). ConclusionsIn this retrospective cohort study, lisinopril/candesartan may increase cardiovascular risk among migraine patients, particularly those at low risk of atherosclerosis, while aCGRP treatment appears safe and potentially protective against MI. These findings suggest a role for neurogenic inflammation-mediated by CGRP and substance P-in migraine-associated, non-atherosclerotic cardiovascular risk. Future research is warranted.