Estimated benefit of PCSK9 inhibition following ischemic stroke due to severe intracranial atherosclerosis

BackgroundThe risk of recurrent atherosclerotic vascular events in patients with stroke due to intracranial atherosclerotic disease (ICAD) is high. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) can dramatically lower low-density lipoprotein (LDL) levels when added to statins, but are not currently indicated for patients with ICAD. MethodsIn this secondary analysis of the SAMMPRIS trial, we estimated the association between LDL reduction (enrollment to day 30, by quartiles) and recurrent cerebral infarction or myocardial infarction (MI) beyond 30 days (primary outcome). Estimates were assessed using adjusted Cox proportional hazards regression accounting for age, sex, race, Hispanic ethnicity, baseline LDL, vascular comorbidities, and statin use prior to enrollment. We applied relative LDL reduction estimates from PCSK9i trials to project adjusted incidence rate differences of the primary outcome observed in SAMMPRIS with an equivalent LDL reduction. Semiparametric Cox models estimated the annualized relative risk of primary events if PCSK9i were used in the SAMMPRIS population. ResultsOf the 451 patients from SAMMPRIS, 378 met inclusion criteria. By day 30, LDL levels fell significantly (absolute change -19mg/dL, IQR -41 to -2). In unadjusted Cox regression compared to the lowest quartile, patients in the highest quartile of LDL improvement trended toward a lower rate of the primary outcome (Q4 vs. Q1 hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.35-1.26), achieving significance after multivariable adjustment (adjusted HR 0.38, 95% CI, 0.16-0.89). Every 10 mg/dL improvement in 30-day LDL was associated with a 9% lower rate of the primary outcome (adjusted HR 0.91, 95% CI, 0.83-0.997). Assuming an average projected effect of PCSK9i, with half of SAMMPRIS patients having been treated, PCSK9i use could reduce the annualized risk of the primary outcome by 33.2%. ConclusionsMore aggressive LDL lowering in patients with stroke due to ICAD is associated with lower rates of recurrent stroke or MI, and this can be achieved with PCSK9i use.