Osteoprotegerin independently predicts mortality in patients with stable coronary artery disease: The CLARICOR trial

Abstract

Objectives. To elucidate the prognostic power of serum osteoprotegerin (OPG) in patients with stable coronary artery disease (CAD). Methods. Serum OPG levels were measured in the CLARICOR trial cohort of 4063 patients with stable CAD on blood samples drawn at randomization. The follow-up was 2.6 years for detailed cardiovascular events and 6 years for all-cause mortality. Results. OPG levels were significantly increased in non-survivors (21%) compared to survivors (median [quartiles] 2092 ng/L [1636; 2800] compared to 1695 ng/L [1322; 2193, p < 0.0001]). The 2.6-year follow-up showed that OPG adds to the prediction of both cardiovascular and all-cause mortality in combination with clinical risk factors (HR [one log₁₀ unit increase] 6.1 [95% CI 2.4–15.6, p = 0.0001]) and HR 6.5 [95% CI 3.4–12.5, p < 0.0001], respectively). Similar, in the 6-year follow-up, OPG was found to be a strong predictor for all-cause mortality. Importantly, OPG remained an independent predictor of mortality even after adjustment for both clinical and conventional cardiovascular risk markers (HR 2.5 [95% CI 1.6–3.9, p < 0.0001]). Conclusions. Serum OPG has a long-lasting independent predictive power as to all-cause mortality and cardiovascular death in patients with stable CAD.

Trial registration: ClinicalTrials.gov identifier: NCT00121550.

Key Words::

• Biomarker
• osteoprotegerin
• OPG
• cardiovascular disease
• coronary artery disease

Acknowledgements

We thank the Danish Heart Foundation; The Copenhagen Hospital Corporation; The Danish Research Council; The 1991 Pharmacy Foundation; and The Copenhagen Trial Unit for unrestricted grants. Abbott Laboratories, IDC, Queensborough, UK supplied clarithromycin and placebo free of charge. From the Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, we thank Lisa Buus for skilled technical assistance and Karin Ø. Kristensen for linguistic guidance. We thank previous CLARICOR Trial Group collaborators and previous members of the CLARICOR Steering Committee and their hospitals, Inga Lind, Statens Serum Institut, Per Hildebrandt, Frederiksberg Hospital, Henrik Nielsen, Amager Hospital, and Christian M. Jespersen, Bispebjerg Hospital.

Grant support

The CLARICOR Trial is investigator initiated and controlled. We received support from non-profit funds (The Danish Heart Foundation; The Copenhagen Hospital Corporation; The Danish Research Council; The 1991 Pharmacy Foundation) and the Copenhagen Trial Unit. Abbott Laboratories, IDC, Queensborough, UK supplied clarithromycin and placebo free of charge. Supporting parties had no role in design, data collection, data analyses, data interpretation, or writing the reports. The Steering Committee had full access to all the data and had final responsibility for the decision to submit the report for publication.

Contributions

Mette Bjerre and Allan Flyvbjerg had the original idea for this study and conducted the measurement of OPG. The Steering Committee of the CLARICOR trial consisted of Christian Gluud (chair), Jørgen Hilden, Jørgen Fischer Hansen, Gorm Boje Jensen, Jens Kastrup, Hans Jørn Kolmos, Erik Kjøller and Per Winkel. Maria Skoog is academic secretary for the Steering Committee. All authors participated in the development of the statistical analysis plan for this publication. Jørgen Hilden conducted all the statistical analyses. Mette Bjerre and Jørgen Hilden interpreted the data and drafted this report. All authors contributed to intellectual content and the reporting. The authors are solely responsible for the design and conduct of this study, all study analyses, drafting and editing of the paper.

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.