Low HDL Cholesterol is Associated with Reduced Bleeding Risk in Patients who Underwent PCI: Findings from the PRACTICE Study

Abstract

Background We sought to examine the dose–response relationship between high-density lipoprotein cholesterol (HDL-C) and bleeds in coronary artery disease (CAD) patients who underwent percutaneous coronary intervention (PCI).

Methods All the 15,250 participants were from the Personalized Antiplatelet Therapy According to CYP2C19 Genotype in Coronary Artery Disease (PRACTICE) study, which is a large, single-center, prospective cohort study based on case records and a follow-up registry performed in the First Affiliated Hospital of Xinjiang Medical University from December 2016 to October 2021. We divided all the patients into five groups according to their HDL-C levels: the ≤35 mg/dL group (n = 4,732), 35 to 45 mg/dL group (n = 6,049), 45 to 55 mg/dL group (n = 2,826), 55 and 65 mg/dL group (n = 1,117), and >65 mg/dL group (n = 526). The incidence of bleeds, mortality, ischemic events, and net adverse clinical events (NACEs) among the five groups was compared.

Results A total of 713 bleeds, 1,180 ischemic events, 456 deaths, and 1,893 NACEs were recorded during the up to 60-month follow-up period. After adjusting for confounders, we observed a nonlinear relation for bleeds, with the highest risk at intermediate HDL-C levels (45–55 mg/dL). We also identified a dose–response relationship for ischemic events. A threshold value of HDL-C ≤35 mg/dL (adjusted hazard ratio = 0.560, 95% confidence interval: 0.360–0.872, p = 0.010) was associated with a decreased risk for bleeds in the multivariable Cox regression model. The results were consistent in multiple sensitivity analyses and propensity score-matching analysis.

Conclusion In the present study, a nonlinear association was identified between HDL-C levels and bleeds in CAD patients who underwent PCI, with a higher risk at intermediate levels. However, further multicenter studies are warranted.

Keywords

high-density lipoprotein cholesterol - bleeds - antiplatelet - coronary artery disease

Data Availability Statement

The data will be available if requested.

Authors' Contribution

X.X. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Y.-Y.Z. and T.-T.W. contributed equally to this work. Concept and design: Y.-Y.Z., T.-T.W., X.-G.H., Y.Y., H.-T.Y., Y.P., W.-J.X., and X.X. Acquisition, analysis, or interpretation of data: Y.-Y.Z., T.-T.W., X.-G.H., X. M., X.-L.Y., Y.-T.M., and X.X. Drafting of the manuscript: Y.-Y.Z., T.-T.W., X.-G.H., Y.Y., H.-T.Y., Y.P., W.-J.X., and X.X. Critical revision of the manuscript for important intellectual content: Y.-Y.Z., T.-T.W., X.M., and X.X. Statistical analysis: Y.-Y.Z., T.-T.W., X.-G.H., Y.Y. Obtained funding: X.X. Administrative, technical, or material support: Y.-Y.Z., T.-T.W., X.-G.H., Y.Y., H.-T.Y., Y.P., W.-J.X., X.-L.Y., X.M., and X.X. Supervision: X.X. and X.M.

^* Contributed to this work equally.

Publication History

Received: 13 December 2022

Accepted: 29 May 2023

Accepted Manuscript online:
01 June 2023

Article published online:
08 July 2023

• References

• 1 Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet 2014; 384 (9943): 618-625
• 2 Toth PP, Barter PJ, Rosenson RS. et al. High-density lipoproteins: a consensus statement from the National Lipid Association. J Clin Lipidol 2013; 7 (05) 484-525
• 3 Bowe B, Xie Y, Xian H, Balasubramanian S, Zayed MA, Al-Aly Z. High density lipoprotein cholesterol and the risk of all-cause mortality among U.S. Veterans. Clin J Am Soc Nephrol 2016; 11 (10) 1784-1793
• 4 Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J 2017; 38 (32) 2478-2486
• 5 Ko DT, Alter DA, Guo H. et al. High-density lipoprotein cholesterol and cause-specifific mortality in individuals without previous cardiovascular conditions: the CANHEART study. J Am Coll Cardiol 2016; 68 (19) 2073-2083
• 6 Yang ZM, Wu MY, Lu JM. et al. HDL-C, longitudinal change and risk of mortality in a Chinese cohort study. Nutr Metab Cardiovasc Dis 2021; 31 (09) 2669-2677
• 7 Liu C, Dhindsa D, Almuwaqqat Z. et al. Association between high-density lipoprotein cholesterol levels and adverse cardiovascular outcomes in high-risk populations. JAMA Cardiol 2022; 7 (07) 672-680
• 8 Trimarco V, Izzo R, Morisco C. et al. High HDL (high-density lipoprotein) cholesterol increases cardiovascular risk in hypertensive patients. Hypertension 2022; 79 (10) 2355-2363
• 9 Zhong G-C, Huang S-Q, Peng Y. et al. HDL-C is associated with mortality from all causes, cardiovascular disease and cancer in a J-shaped dose-response fashion: a pooled analysis of 37 prospective cohort studies. Eur J Prev Cardiol 2020; 27 (11) 1187-1203
• 10 Marquis-Gravel G, Dalgaard F, Jones AD. et al. Post-discharge bleeding and mortality following acute coronary syndromes with or without PCI. J Am Coll Cardiol 2020; 76 (02) 162-171
• 11 Owens III AP, Passam FH, Antoniak S. et al. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest 2012; 122 (02) 558-568
• 12 Wang N, Tall AR. Cholesterol in platelet biogenesis and activation. Blood 2016; 127 (16) 1949-1953
• 13 Yang Q, Sun D, Pei C. et al; CCC-ACS Investigators. LDL cholesterol levels and in-hospital bleeding in patients on high-intensity antithrombotic therapy: findings from the CCC-ACS project. Eur Heart J 2021; 42 (33) 3175-3186
• 14 Song Y, Jiang L, Chen Y. et al. Association between plasma HDL-C levels and coronary artery severity and impact on outcomes of patients underwent percutaneous coronary intervention [in Chinese]. Zhonghua Xin Xue Guan Bing Za Zhi 2020; 48 (02) 123-129
• 15 Wadowski PP, Lee S, Kopp CW, Koppensteiner R, Panzer S, Gremmel T. Low levels of high-density lipoprotein cholesterol are linked to impaired clopidogrel-mediated platelet inhibition. Angiology 2018; 69 (09) 786-794
• 16 Levine GN, Bates ER, Bittl JA. et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68 (10) 1082-1115
• 17 R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. Accessed June 14, 2023 at: https://www.R-project.org/
• 18 Frank E Harrell Jr. (2022). rms: Regression Modeling Strategies. R package version 6.3-0. https://CRAN.R-project.org/package=rms
• 19 Gordon DJ, Rifkind BM. High-density lipoprotein–the clinical implications of recent studies. N Engl J Med 1989; 321 (19) 1311-1316
• 20 Barter P, Gotto AM, LaRosa JC. et al; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357 (13) 1301-1310
• 21 Mahdy Ali K, Wonnerth A, Huber K, Wojta J. Cardiovascular disease risk reduction by raising HDL cholesterol–current therapies and future opportunities. Br J Pharmacol 2012; 167 (06) 1177-1194
• 22 Kjeldsen EW, Thomassen JQ, Frikke-Schmidt R. HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease - Insights from randomized clinical trials and human genetics. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867 (01) 159063
• 23 Chen Y, Yin T, Xi S. et al. A risk score to predict postdischarge bleeding among acute coronary syndrome patients undergoing percutaneous coronary intervention: BRIC-ACS study. Catheter Cardiovasc Interv 2019; 93 (07) 1194-1204
• 24 Ueshima D, Yoshikawa S, Sasaoka T. et al. The hypercholesterolemia paradox in percutaneous coronary intervention: an analysis of a multicenter PCI registry. Intern Med 2019; 58 (03) 345-353
• 25 Ducrocq G, Wallace JS, Baron G. et al; REACH Investigators. Risk score to predict serious bleeding in stable outpatients with or at risk of atherothrombosis. Eur Heart J 2010; 31 (10) 1257-1265
• 26 Hochholzer W, Wiviott SD, Antman EM. et al. Predictors of bleeding and time dependence of association of bleeding with mortality: insights from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Circulation 2011; 123 (23) 2681-2689
• 27 Nofer JR, Walter M, Kehrel B. et al. HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris-phosphate. Arterioscler Thromb Vasc Biol 1998; 18 (06) 861-869
• 28 Barlage S, Boettcher D, Boettcher A, Dada A, Schmitz G. High density lipoprotein modulates platelet function. Cytometry A 2006; 69 (03) 196-199
• 29 Korporaal SJ, Akkerman JW. Platelet activation by low density lipoprotein and high density lipoprotein. Pathophysiol Haemost Thromb 2006; 35 (3-4): 270-280
• 30 Tselepis AD, Tsoumani ME, Kalantzi KI, Dimitriou AA, Tellis CC, Goudevenos IA. Influence of high-density lipoprotein and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy. J Thromb Haemost 2011; 9 (12) 2371-2378
• 31 Weichhart T, Kopecky C, Kubicek M. et al. Serum amyloid A in uremic HDL promotes inflammation. J Am Soc Nephrol 2012; 23 (05) 934-947
• 32 Papageorgiou N, Zacharia E, Androulakis E, Briasoulis A, Charakida M, Tousoulis D. HDL as a prognostic biomarker for coronary atherosclerosis: the role of inflammation. Expert Opin Ther Targets 2016; 20 (08) 907-921
• 33 Baigent C, Keech A, Kearney PM. et al; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366 (9493): 1267-1278
• 34 Singh V, Sharma R, Kumar A, Deedwania P. Low high-density lipoprotein cholesterol: current status and future strategies for management. Vasc Health Risk Manag 2010; 6: 979-996
• 35 Li XX, Zhao Y, Huang LX. et al. Effects of smoking and alcohol consumption on lipid profile in male adults in northwest rural China. Public Health 2018; 157: 7-13
• 36 Szkup M, Jurczak A, Karakiewicz B, Kotwas A, Kopeć J, Grochans E. Influence of cigarette smoking on hormone and lipid metabolism in women in late reproductive stage. Clin Interv Aging 2018; 13: 109-115
• 37 Cho KH, Park HJ, Kim SJ, Kim JR. Decrease in HDL-C is associated with age and household income in adults from the Korean National Health and Nutrition Examination Survey 2017: correlation analysis of low HDL-C and poverty. Int J Environ Res Public Health 2019; 16 (18) 3329