No association between HDL particle concentration and MACE after ACS

Association of HDL particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial

Literature - - Am Heart J 2019,

Introduction and methods

Concentration of high density lipoprotein cholesterol (HDL-C) is inversely associated with risk of coronary heart disease, epidemiologic studies show. However, it has also been shown that HDL-C concentration is not a reliable predictor of occurrence of major adverse cardiovascular events (MACE) in patients with established coronary heart disease.. Raising HDL-c by medication in clinical trials has not resulted in reduction of MACE, particularly when patients were using statins [1-3]. Data from cohort studies and clinical trials haver suggested that total HDLP is a better indicator of HDL-c function than HDL-c concentration and thus a better predictor of MACE [4-7]. Also, the distribution of HDL particles may contribute to an improved CV risk prediction.

The present study investigated whether total HDL particle (HDLP) concentration, as compared to HDL-C, is a better predictor of MACE in ACS patients.

The present study investigated a nested case-cohort subgroup of patients that participated in the randomized controlled dal-OUTCOMES trial. The trial cohort consisted of 15,871 patients with recent ACS. Patients in the trial cohort, of which 97% used statins, were randomly assigned, between 4 and 12 weeks after ACS, to receive 600 mg of cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib (which raises HDL-C and HDLP levels) orally twice daily or matching placebo. The primary outcome, time to first occurrence of MACE, defined as coronary heart disease death, non-fatal myocardial infarction, ischemic stroke, hospitalization for unstable angina, or resuscitated cardiac arrest. was not decreased with dalcetrapib compared to placebo .

The case-cohort subgroup of the present study included 1378 unique subjects: 476 cases (patients with a primary endpoint event) and 902 controls who were event-free at the time of a case event and had the same type of index ACS as the case. In these patients, total HDLP, small, medium and large HDLP, low-density particles (LDLP) and very low-density particles (VLDLP), HDL-C, LDL-C and triglyceride concentrations were measured by nuclear magnetic resonance (NMR) spectroscopy at baseline (4-12 weeks after ACS) (1378 subjects) and after 3 months (1203 subjects). Median follow-up of cases and controls was 28 months.

This study investigated whether (changes in) HDLP concentration predicted MACE, , as well as association between HDLP subclasses and MACE and including HDL-C. Also, interaction of assigned study treatment with HDLP or HDL-c on MACE was studied.

Main results

  • There were no significant differences between cases and controls in baseline HDL-C, HDLP or HDLP subclasses or triglycerides. However, baseline LDL-C (in mg/dL; cases 80.5 ± 31.0, controls 75.6 ± 25.8, P=0.003) and LDLP (in nmol/L; cases 995.5 ± 332.3, controls 944.4 ± 288.5, P=0.005) were significantly higher in cases (LDL-c: cases 80.5 ± 31.0 mg/dL, controls 75.6 ± 25.8 mg/dL, P=0.003) and LDLP: cases 995.5 ± 332.3 nmol/L, controls 944.4 ± 288.5 nmol/L, P=0.005).
  • There were no associations between HDLP or HDL-C measured at baseline and MACE in either unadjusted or adjusted models. Also, there was no interaction of treatment assignment with baseline HDLP or baseline HDL-C on MACE.
  • Three months after randomization, HDLP, HDL-C, and apolipoprotein A1 increased slightly from baseline in the placebo group, and by a substantially greater amount (P<0.001) with dalcetrapib. Increase in total, large, medium, small HDLP and HDL-c were: +7%, +59%, +6%, and -5%; and +31%, respectively.
  • Changes from baseline to month 3 in HDLP, large and small HDLP, and HDL-C were not associated with the risk of MACE in either unadjusted or adjusted models. After correction, medium HDLP was associated with risk of MACE. Also

there was no interaction of treatment assignment with baseline to month 3 change in HDLP or HDL-C on MACE.


In this study, HDLP and HDL-c were were not associated with MACE in patients after an ACS event in a population well-treated with statins.


1. Barter PJ, Caulfield M, Eriksson M, et al. Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med. 2007;357(21):2109-2122.

2. Schwartz GG, Olsson AG, Abt M, et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med. 2012;367(22):2089-2099.

3. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease. N Engl J Med. 2017;376(20):1933-1942.

4. MacKey RH, Greenland P, Goff DC, Lloyd-Jones D, Sibley CT, Mora S. High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012.

5. Mora S, Glynn RJ, Ridker PM. High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy. Circulation. 2013;128(11):1189-1197.

6. Albers JJ, Slee A, Fleg JL, O’Brien KD, Marcovina SM. Relationship of baseline HDL subclasses, small dense LDL and LDL triglyceride to cardiovascular events in the AIMHIGH clinical trial. Atherosclerosis. 2016;251:454-459.

7. Parish S, Offer A, Clarke R, et al. Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study. Circulation. 2012;125(20):2469-2478.

Find this article online at Am Heart J

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