Key result
Probucol reduces major cardiovascular events ~32% versus non-probucol, independent of HDL-C changes.
Why the study?
Whether pharmacologically altered high-density lipoprotein cholesterol affects the risk of cardiovascular events was unknown.
Do on-treatment HDL-C changes by cilostazol and probucol influence the treatment effect on cardiovascular events in ischemic stroke patients?
RCT (n=1,373)
Double-blind for antiplatelet arm, Open-label with blinded endpoint evaluation for probucol arm
1:1:1:1
Yes
Do on-treatment HDL-C changes by cilostazol and probucol influence the treatment effect on cardiovascular events in ischemic stroke patients?
Pharmacologically altered HDL-C levels by cilostazol or probucol do not significantly influence the risk of cardiovascular events in ischemic stroke patients, suggesting they may not be reliable prognostic markers.
Answers are grounded in this paper and cite their sources.
Probucol use was associated with fewer events independent of HDL-C in ischemic stroke; leaves open mediation mechanisms and requires RCT confirmation.
BACKGROUND AND PURPOSE: Whether pharmacologically altered high-density lipoprotein cholesterol (HDL-C) affects the risk of cardiovascular events is unknown. Recently, we have reported the Prevention of Cardiovascular Events in Asian Patients with Ischaemic Stroke at High Risk of Cerebral Haemorrhage (PICASSO) trial that demonstrated the non-inferiority of cilostazol to aspirin and superiority of probucol to non-probucol for cardiovascular prevention in ischemic stroke patients (clinicaltrials.gov: NCT01013532). We aimed to determine whether on-treatment HDL-C changes by cilostazol and probucol influence the treatment effect of each study medication during the PICASSO study. METHODS: Of the 1,534 randomized patients, 1,373 (89.5%) with baseline cholesterol parameters were analyzed. Efficacy endpoint was the composite of stroke, myocardial infarction, and cardiovascular death. Cox proportional hazards regression analysis examined an interaction between the treatment effect and changes in HDL-C levels from randomization to 1 month for each study arm. RESULTS: One-month post-randomization mean HDL-C level was significantly higher in the cilostazol group than in the aspirin group (1.08 mmol/L vs. 1.00 mmol/L, P<0.001). The mean HDL-C level was significantly lower in the probucol group than in the non-probucol group (0.86 mmol/L vs. 1.22 mmol/L, P<0.001). These trends persisted throughout the study. In both study arms, no significant interaction was observed between HDL-C changes and the assigned treatment regarding the risk of the efficacy endpoint. CONCLUSIONS: Despite significant HDL-C changes, the effects of cilostazol and probucol treatment on the risk of cardiovascular events were insignificant. Pharmacologically altered HDL-C levels may not be reliable prognostic markers for cardiovascular risk.
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Lee et al. (2020) conducted an RCT in Ischemic stroke at high risk of cerebral hemorrhage (n=1,373). Probucol vs. Non-probucol was evaluated on Composite of stroke, myocardial infarction, and cardiovascular death (HR 0.68, 95% CI 0.48-0.97, p=0.001 for non-inferiority, 0.033 for superiority). Probucol reduced the risk of composite cardiovascular events compared to non-probucol (HR 0.68), and on-treatment changes in HDL-C levels did not significantly influence the treatment effects of either probucol or cilostazol.
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