LDL cholesterol levels and in-hospital bleeding in patients on high-intensity antithrombotic therapy: findings from the CCC-ACS project

Abstract

Aims Emerging evidence has linked cholesterol metabolism with platelet responsiveness. We sought to examine the dose–response relationship between low-density lipoprotein cholesterol (LDL-C) and major in-hospital bleeds in acute coronary syndrome (ACS) patients. Methods and results Among 42 378 ACS patients treated with percutaneous coronary intervention (PCI) enrolled in 240 hospitals in the Improving Care for Cardiovascular Disease in China-ACS project from 2014 to 2019, a total of 615 major bleeds, 218 ischaemic events, and 337 deaths were recorded. After controlling for baseline variables, a non-linear relationship was observed for major bleeds, with the higher risk at lower LDL-C levels. No dose–response relationship was identified for ischaemic events and mortality. A threshold value of LDL-C <70 mg/dL was associated with an increased risk for major bleeds (adjusted odds ratio: 1.49; 95% confidence interval: 1.21–1.84) in multivariable-adjusted logistic regression models and in propensity score-matched cohorts. The results were consistent in multiple sensitivity analyses. Among ticagrelor-treated patients, the LDL-C threshold for increased bleeding risk was observed at <88 mg/dL, whereas for clopidogrel-treated patients, the threshold was <54 mg/dL. Across a full spectrum of LDL-C levels, the treatment effect size associated with ticagrelor vs. clopidogrel on major bleeds favoured clopidogrel at lower LDL-C levels, but no difference at higher LDL-C levels. Conclusions In a nationwide ACS registry, a non-linear association was identified between LDL-C levels and major in-hospital bleeds following PCI, with the higher risk at lower levels. As the potential for confounding may exist, further studies are warranted. Trial registration ClinicalTrials.gov Identifier: NCT02306616

Antithrombotic therapy and bleeding risk in the era of aggressive lipid-lowering: current evidence, clinical implications, and future perspectives

“…Importantly, these observations could be reversed in HC and against a background of platelet cholesterol efflux defects, in which P2Y12 signaling-mediated platelet hyperreactivity and aggregability are potentiated [59] . Another possible mechanism is that cholesterol is a positive regulator of thrombocytopoiesis in the bone marrow, [60] which is supported by our finding that there is a linear, positive association between LDL-C and platelet counts [7] …”

“…[ 37 ] Moreover, a numerically higher incidence of hemorrhagic stroke was observed in the high-dose statin arm in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial. [ 38 ] Indeed, we also found that in ACS patients treated with PCI, there was a negative linear association between admission LDL-C levels and in-hospital hemorrhagic stroke: the multivariable-adjusted odds ratio (OR) was 0.80 (95% CI: 0.66–0.97) per 30 mg/dL increase of LDL-C. [ 7 ] However, the clinical implications should be interpreted with caution, considering the overwhelmingly high incidence of preventable ischemic strokes vs . the relatively low incidence of hemorrhagic stroke: the cumulative incidence of hemorrhagic stroke reported in long-term cohort studies were 0.80% to 1.60% during 9 to 20 years of follow-up, [ 33 – 35 ] whereas the incidence of ischemic stroke was threefold to fivefold higher than that of hemorrhagic stroke in China.…”

“…[ 49 ] For 42,378 enrolled ACS patients from 240 hospitals, we demonstrated a non-linear negative association between admission LDL-C levels and the risk of in-hospital major bleeds, where a threshold LDL-C <70 mg/dL resulted in a 49% increase in the bleeding risk of patients compared with those with LDL-C ≥70 mg/dL. [ 7 ] We also used a data-driven approach to identify potential markers for an increased bleeding risk: using a forward algorithm for predictor selection, an admission LDL-C < 70 mg/dL was consistently identified as an independent predictor for different criterion-defined major in-hospital bleeds [Figure 2 ]. Interestingly, preadmission statin use was associated with a slight but non-significant increase in the bleeding risk, [ 7 ] whereas major in-hospital bleeds were reduced by combining in-hospital statin use with β-blockers and angiotensin-converting enzyme inhibitors/angio-tensin-receptor blockers, that is, guideline-directed medical therapy for ACS patients, [ 50 ] probably due to the relatively low potency of statin-induced LDL-C-lowering during hospitalization and the pleotropic effects of statin on mortality benefit.…”

“…The advent of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which can lower low-density lipoprotein cholesterol (LDL-C) to levels not previously achievable by statins, has made “the lower the better” the current paradigm in LDL-C reduction for atherosclerotic cardiovascular disease (ASCVD) prevention [6] . However, our recent report based on the Chinese population, [7] as well as previous findings on Western populations [8–10] and East Asian populations, [11,12] demonstrated a close relationship between the serum cholesterol level and bleeding risk in patients on dual antiplatelet therapy (DAPT), that is, the lower the LDL-C levels were, the higher the risk for bleeding complications was. Epidemiological studies have also shown that low LDL-C levels are associated with a higher risk for AF [13,14] .…”

Low-Density Lipoprotein Cholesterol and Mortality Risk in Elderly Patients Undergoing Valve Replacement Surgery: A Propensity Score Matching Analysis

“…The in-hospital mortality was 4.3%. According to previous study ( 18 ), the included patients were classified into two groups: <70 mg/dL ( n = 205) and ≥ 70 mg/dL ( n = 2347). Baseline characteristics for the study population were presented in Table 1 .…”