Alirocumab reduces LDL C without increasing hemorrhagic stroke risk: ODYSSEY Trial

Delhi: Alirocumab decreased LDL cholesterol and the risk of ischemic stroke without increasing hemorrhagic stroke, suggests a recent study published in the AHA journal Circulation.

According to new data from the ODYSSEY Outcomes trial, PCSK9 inhibitor reduced the risk of ischemic stroke without increasing odds of hemorrhagic stroke, irrespective of baseline LDL-C ( low-density lipoprotein cholesterol) and history of cerebrovascular disease in patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy.

Alirocumab is a human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/Kexin type 9), a circulating protein that modulates the activity of the LDL cholesterol receptor in the liver. It is part of a class of cholesterol-lowering drugs called the PCSK9 inhibitors. The monoclonal antibody lowers serum LDL cholesterol and is used to treat severe hypercholesterolemia. a cholesterol-lowering drug.

Stroke is a leading cause of morbidity and mortality. The majority of strokes are ischemic, caused by thrombotic events arising from atherosclerosis in the aortic arch, carotid arteries, or cerebral arteries, from small vessel occlusions, or cardioembolic sources (ie, atrial fibrillation).

Hemorrhagic stroke, in contrast, is not caused by atherosclerosis but arises from vasculopathy (hypertension, cerebral amyloid, cerebral aneurysms, or other vascular malformations), systemic bleeding disorders, or anticoagulation use.

Lowering of atherogenic lipoproteins including LDL-C reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C and potential risks of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C <15 mg/dL.

This prespecified analysis by J. Wouter Jukema, Leiden University Medical Center, The Netherland, and colleagues was designed to assess the effect of alirocumab on ischemic and hemorrhagic stroke. The researchers hypothesized that for patients treated with alirocumab there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of baseline LDL-C and history of cerebrovascular disease.

Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed. Median follow-up was 2.8 years.

Read Also: Alirocumab has maximum benefit in high risk patients or after CABG: ODYSSEY outcomes

Key findings of the study include:

• In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (HR, 0.72) and ischemic stroke (HR, 0.73) without increasing hemorrhagic stroke (HR, 0.83).


• In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of <80, 80 to 100, and >100 mg/dL, respectively.


• The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity.


• The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and those without a history of cerebrovascular disease.


• There was no apparent adverse relation between lower achieved LDL-C and an incidence of hemorrhagic stroke in the alirocumab group.

"In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, the risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group," wrote the authors.

The study, "Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES," is published in the AHA journal Circulation.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.119.043826