Changes in High-Density Lipoprotein Cholesterol and Risks of Cardiovascular Events: A Post Hoc Analysis from the PICASSO Trial

Eun-Jae Lee, Sun U Kwon, Jong-Ho Park, Yong-Jae Kim, Keun-Sik Hong, Sungwook Yu, Yang-Ha Hwang, Ji Sung Lee, Juneyoung Lee, Joung-Ho Rha, Sung Hyuk Heo, Sung Hwan Ahn, Woo-Keun Seo, Jong-Moo Park, Ju-Hun Lee, Jee-Hyun Kwon, Sung-Il Sohn, Jin-Man Jung, Hahn Young Kim, Eung-Gyu Kim, Sung Hun Kim, Jae-Kwan Cha, Man-Seok Park, Hyo Suk Nam, Dong-Wha Kang, PICASSO Investigators, Eun-Jae Lee, Sun U Kwon, Jong-Ho Park, Yong-Jae Kim, Keun-Sik Hong, Sungwook Yu, Yang-Ha Hwang, Ji Sung Lee, Juneyoung Lee, Joung-Ho Rha, Sung Hyuk Heo, Sung Hwan Ahn, Woo-Keun Seo, Jong-Moo Park, Ju-Hun Lee, Jee-Hyun Kwon, Sung-Il Sohn, Jin-Man Jung, Hahn Young Kim, Eung-Gyu Kim, Sung Hun Kim, Jae-Kwan Cha, Man-Seok Park, Hyo Suk Nam, Dong-Wha Kang, PICASSO Investigators

Abstract

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.

Keywords: Cholesterol ester transfer proteins; Cholesterol, HDL; Cilostazol; Probucol; Secondary prevention.

Figures

Figure 1.
Figure 1.
Trial profile. Among the intention-to-treat (ITT) population including all randomized patients in the Prevention of Cardiovascular Events in Asian Patients with Ischaemic Stroke at High Risk of Cerebral Haemorrhage study, those who underwent baseline cholesterol evaluation were analyzed in this study.
Figure 2.
Figure 2.
Cholesterol profiles over time. (A) High-density lipoprotein cholesterol (HDL-C), (B) triglyceride, and (C) low-density lipoprotein cholesterol (LDL-C) levels in the antiplatelet study arm, (D) HDL-C, (E) triglyceride, and (F) LDL-C levels in the probucol study arm. The P-values using the generalized estimated equations for probucol-by-visit interaction: cilostazol vs. aspirin, HDL-C (P<0.001), triglycerides (P=0.004), LDL-C (P=0.007); probucol vs. non-probucol, HDL-C (P<0.001), triglycerides (P=0.003), LDL-C (P=0.004). *P<0.05; †P<0.01; ‡P<0.001.
Figure 3.
Figure 3.
The annualized risk of the primary endpoint beginning at 1 month, according to quartiles of change in high-density lipoprotein cholesterol (HDL-C) levels from baseline to 1 month after randomization. (A) Efficacy endpoint (a composite of stroke, myocardial infarction, and cardiovascular death), (B) safety endpoint (cerebral hemorrhage) in the antiplatelet study arm, (C) efficacy endpoint, and (D) safety endpoint in the probucol study arm. The position of each quartile of HDL-C on the x-axis represents the median value of HDL-C changes within that quartile.
Figure 4.
Figure 4.
Hazard ratio for the composite vascular event of the study medication group vs. the control group according to numerical changes in high-density lipoprotein cholesterol (HDL-C) levels from baseline to 1-month post-randomization. (A) Cilostazol vs. aspirin, (B) probucol vs. non-probucol. No significant interactions between the treatment effect and HDL-C alterations were observed in both study arms (Cox proportional hazards regression analysis, P=0.158 for cilostazol in the antiplatelet arm, P=0.532 for probucol in the probucol arm). CI, confidence interval.

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