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Original article
Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes
  1. Ragnhild Røysland1,2,
  2. Marc P Bonaca3,4,
  3. Torbjørn Omland1,2,
  4. Marc Sabatine3,4,
  5. Sabina A Murphy3,
  6. Benjamin M Scirica3,4,
  7. Mette Bjerre5,6,
  8. Allan Flyvbjerg5,6,
  9. Eugene Braunwald3,4,
  10. David A Morrow3,4
  1. 1Divison of Medicine, Akershus University Hospital, Lørenskog, Norway
  2. 2K.G. Jebsen Cardiac Research Centre and Centre for Heart Failure Research, University of Oslo, Oslo, Norway
  3. 3TIMI Study Group, Brigham and Women's Hospital, Boston, Massachusetts, USA
  4. 4Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
  5. 5Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
  6. 6The Medical Research Laboratories, Department of Clinical Medicine, Faculty of Health Sciences, Aarhus University, Aarhus, Denmark
  1. Correspondence to Professor T Omland, Division of Medicine, Akershus University Hospital, Sykehusveien 27, 1478 Lørenskog, Norway; torbjorn.omland{at}medisin.uio.no

Abstract

Objective To assess the relationship between osteoprotegerin (OPG) and cardiovascular death, and the pathobiological mechanisms contributing to the association, in acute coronary syndromes (ACS).

Design Prospective observational.

Setting Biomarker substudy of MERLIN-TIMI 36, a randomised, placebo controlled trial of ranolazine in non-ST elevation (NSTE)-ACS.

Patients 4463 patients with NSTE-ACS.

Interventions Ranolazine or placebo.

Main outcome measures Incidence of cardiovascular death (CV death); additionally, heart failure (HF), cardiac arrhythmias, inhospital ischaemia, severe recurrent ischaemia or recurrent myocardial infarction (MI).

Results During a median follow-up of 341 days, 208 patients died of cardiovascular causes. The OPG baseline concentration was strongly associated with both 30 day and 1 year incidence of CV death. After adjustment for conventional risk markers, OPG concentrations (log transformed) remained a significant predictor of CV death by 30 days (HR (95% CI) 2.32 (1.30 to 4.17); p=0.005) and by 1 year (HR 1.85 (1.33 to 2.59); p<0.001). Baseline levels of OPG were also an independent predictor of new or worsening HF at 30 days (HR 2.25 (1.38 to 3.69); p=0.001) and 1 year (HR 1.81 (1.26 to 2.58) p=0.001). By univariable analysis, higher OPG was associated with both early ischaemic and arrhythmic events. Although OPG levels were associated with recurrent MI within 12 months, this association was attenuated and no longer significant after multivariable adjustment.

Conclusions OPG is independently associated with 30 day and 1 year risk of cardiovascular mortality and HF development after NSTE-ACS. As no independent relationship between OPG levels and recurrent ischaemia or MI was observed, myocardial dysfunction may be a more important stimulus for OPG production than ischaemia in ACS.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

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Footnotes

  • See Editorial, p 762

  • Funding MERLIN-TIMI 36 was supported by CV Therapeutics (now Gilead Science Inc). The company had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

  • Competing interests TO has received speakers' honoraria and research support from Roche Diagnostics and Abbott Laboratories. MS has received grants for clinical research via the TIMI Study Group and Brigham and Women's Hospital from Nanosphere and served as a consultant for Singulex. SAM has received consultant fees from Amarin and Eli Lilly. BMS has received grants for clinical research via the TIMI Study Group and Brigham and Women's Hospital from CV Therapeutics, Novartis Pharmaceuticals Corporation, AstraZeneca Pharmaceuticals LP, Daiichi-Sankyo Inc, Merck & Co Inc, Johnson and Johnson Pharmaceutical Research & Development LLC, Bayer HealthCare Pharmaceuticals and Bristol-Myers-Squibb Company, and has served as a consultant for AstraZeneca Pharmaceuticals LP, Novartis Pharmaceuticals Corporation, CV Therapeutics, Cogentus, Shionogi and Co Ltd, Gilead Sciences Inc, Merck & Co Inc and Schering-Plough Corporation. DAM is an investigator and receives salary from the TIMI Study Group. He has received honoraria for educational presentations from Eli Lilly. He has received remuneration for consulting from Beckman-Coulter, Boehringher Ingelheim, Cardiokinetix, Critical Diagnostics, Gilead, Instrumentation Laboratory, Ikaria, Menarini, Merck, OrthoClinical Diagnostics, Servier, Roche Diagnostics and Siemens, and remuneration from AstraZeneca for adjudication as a member of a Clinical Events Committee. The TIMI Study Group has received research grant support from Accumetrics, Amgen, AstraZeneca, Beckman Coulter, BG Medicine, BRAHMS, Bristol-Myers Squibb, CV Therapeutics, Daiichi Sankyo Co Ltd, Eli Lilly and Co, GlaxoSmithKline, Integrated Therapeutics, Merck and Co, Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Sanofi-Synthelabo, Siemens and Singulex.

  • Ethics approval The protocol was approved by the relevant institutional review boards at all participating centres.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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