Author + information
- Received May 15, 2017
- Revision received June 12, 2017
- Accepted June 12, 2017
- Published online August 7, 2017.
- Daniel Lindholm, MD, PhDa,b,∗ (, )
- Johan Lindbäck, MScb,
- Paul W. Armstrong, MDc,
- Andrzej Budaj, MD, PhDd,
- Christopher P. Cannon, MDe,f,
- Christopher B. Granger, MDg,
- Emil Hagström, MD, PhDa,b,
- Claes Held, MD, PhDa,b,
- Wolfgang Koenig, MDh,i,j,
- Ollie Östlund, PhDb,
- Ralph A.H. Stewart, MDk,l,
- Joseph Soffer, MDm,
- Harvey D. White, MB, ChB, DSck,l,
- Robbert J. de Winter, MD, PhDn,
- Philippe Gabriel Steg, MDo,p,q,r,
- Agneta Siegbahn, MD, PhDb,s,
- Marcus E. Kleber, PhDt,u,
- Alexander Dressel, Dr.rer.natv,
- Tanja B. Grammer, MDw,
- Winfried März, MDt,x,y and
- Lars Wallentin, MD, PhDa,b
- aDepartment of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden
- bUppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
- cCanadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada
- dPostgraduate Medical School, Grochowski Hospital, Warsaw, Poland
- eCardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- fBaim Institute of Clinical Research, Boston, Massachusetts
- gDuke Clinical Research Institute, Durham, North Carolina
- hDepartment of Internal Medicine II–Cardiology, University of Ulm Medical Center, Ulm, Germany
- iDeutsches Herzzentrum München, Technische Universität München, Munich, Germany
- jDZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
- kGreen Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
- lUniversity of Auckland, Auckland, New Zealand
- mMetabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania
- nDepartment of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- oDépartement Hospitalo-Universitaire Fibrosis, Inflammation, and Remodeling, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France
- pParis Diderot University, Sorbonne Paris Cité, Paris, France
- qNational Heart and Lung Institute, Imperial College, Institute of Cardiovascular Medicine and Sciences, Royal Brompton Hospital, London, United Kingdom
- rFACT (French Alliance for Cardiovascular Trials), an F-CRIN network, INSERM U1148, Paris, France
- sDepartment of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden
- tMedical Clinic V (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- uInstitute of Nutrition, Friedrich Schiller University, Jena, Germany
- vDACH Society for Prevention of Cardiovascular Disease e.V., Hamburg, Germany
- wMannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- xClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
- ySynlab Academy, Synlab Holding Deutschland GmbH, Mannheim and Augsburg, Germany
- ↵∗Address for correspondence:
Dr. Daniel Lindholm, Uppsala Clinical Research Center, Dag Hammarskjölds väg 14B, SE-752 37 Uppsala, Sweden.
Background Currently, there is no generally accepted model to predict outcomes in stable coronary heart disease (CHD).
Objectives This study evaluated and compared the prognostic value of biomarkers and clinical variables to develop a biomarker-based prediction model in patients with stable CHD.
Methods In a prospective, randomized trial cohort of 13,164 patients with stable CHD, we analyzed several candidate biomarkers and clinical variables and used multivariable Cox regression to develop a clinical prediction model based on the most important markers. The primary outcome was cardiovascular (CV) death, but model performance was also explored for other key outcomes. It was internally bootstrap validated, and externally validated in 1,547 patients in another study.
Results During a median follow-up of 3.7 years, there were 591 cases of CV death. The 3 most important biomarkers were N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and low-density lipoprotein cholesterol, where NT-proBNP and hs-cTnT had greater prognostic value than any other biomarker or clinical variable. The final prediction model included age (A), biomarkers (B) (NT-proBNP, hs-cTnT, and low-density lipoprotein cholesterol), and clinical variables (C) (smoking, diabetes mellitus, and peripheral arterial disease). This “ABC-CHD” model had high discriminatory ability for CV death (c-index 0.81 in derivation cohort, 0.78 in validation cohort), with adequate calibration in both cohorts.
Conclusions This model provided a robust tool for the prediction of CV death in patients with stable CHD. As it is based on a small number of readily available biomarkers and clinical factors, it can be widely employed to complement clinical assessment and guide management based on CV risk. (The Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial [STABILITY]; NCT00799903)
- cardiac troponin
- low-density lipoprotein cholesterol
- N-terminal pro–B-type natriuretic peptide
- risk prediction
The STABILITY trial was funded by GlaxoSmithKline. Roche Diagnostics supported the research by providing the pre-commercial assay of growth differentiation factor-15 (GDF-15) free of charge. Dr. Lindholm has received institutional research grants from AstraZeneca and GlaxoSmithKline; and has received lecture/speaker fees from AstraZeneca. Dr. Lindbäck has received institutional research grants from GlaxoSmithKline. Dr. Armstrong has received grants from Merck, Sanofi, and Bayer; has received lecture fees from AstraZeneca; and has received consulting fees from Merck, Bayer, Axio/Orexigen, Eli Lilly, Bayer, and Mast Therapeutics Inc. Dr. Budaj has received research grants/investigator’s fees, consulting fees, and honoraria for lectures from GlaxoSmithKline, AstraZeneca, Sanofi, Novartis, and Bristol-Myers Squibb/Pfizer; and has received research grants/investigator’s fees from Boehringer Ingelheim, Eisai, and Duke Research Institute. Dr. Cannon has received research grants from Arisaph, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Merck, and Takeda; and has received consulting fees from Alnylam, Amgen, Arisaph, Boehringer Ingelheim, Boehringer Ingelheim/Lilly, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Merck, Takeda, Lipimedix, Pfizer, Regeneron, and Sanofi. Dr. Granger has received grants and consultancy fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Sanofi, Takeda, The Medicines Company, Daiichi-Sankyo, Janssen, and Bayer; has received grants from Medtronic Foundation and Armetheon; has received consultancy fees from Abbvie, Boston Scientific, Eli Lilly, Hoffman-La Roche, Salix Pharmaceuticals, Gilead, Medtronic, Novartis, Sirtex, and Verseon; and has received a research grant from Novartis. Dr. Hagström has served as an expert committee member for Amgen, Sanofi, Ariad, and Merck Sharp & Dohme; has received lecture fees from Amgen and Sanofi; and has received institutional research grants from Amgen AstraZeneca, Sanofi, and GlaxoSmithKline. Dr. Held has served on the speakers bureau of AstraZeneca; has received institutional research grants from AstraZeneca, Bristol-Myers Squibb, Merck, and GlaxoSmithKline; has served on the advisory board for AstraZeneca, Bayer, and Boehringer Ingelheim; and has received lecture fees from AstraZeneca and Bayer. Dr. Koenig has received lecture and consultancy fees from Novartis, Amgen, and AstraZeneca; has received lecture fees from Actavis and Berlin-Chemie; has received consultancy fees from GlaxoSmithKline, The Medicines Company, Pfizer, and Merck Sharpe & Dohme; and has received research grants from Roche Diagnostics, Abbott, Singulex, and Beckmann. Dr. Östlund has received institutional research grants from GlaxoSmithKline. Dr. Stewart has received grants and nonfinancial support from GlaxoSmithKline. Dr. Soffer is an employee of and has stock ownership in GlaxoSmithKline. Dr. White has served on the advisory board of AstraZeneca, Acetelion, Sirtex, and The Medicines Company; and has received research grants from AstraZeneca, Sanofi, Eli Lilly and Company, National Institutes of Health, Merck, Sharp & Dohme, George Institute, GlaxoSmithKline, Omthera Pharmaceuticals, Pfizer New Zealand, Intarcia Therapeutics, Elsai, DalGen Products and Services, and Daiichi-Sankyo Pharma Development. Dr. Steg has received research grants from Merck, Sanofi, and Servier; and has received speaking or consulting fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL-Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Servier, and The Medicines Company. Dr. Siegbahn has received institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline. Dr. März has received grants and personal fees from Siemens Diagnostics, Aegerion Pharmaceuticals, Amgen, AstraZeneca, Danone Research, Sanofi/Genzyme, Sanofi, BASF, and Numares AG; has received personal fees from Alexion, Hoffmann LaRoche Pharma, and MSD; has received grants from Roche Diagnostics and Abbott Diagnostics; and is an employee of Synlab Holding Deutschland. Dr. Wallentin has received institutional research grants, consultancy fees, lecture fees, and travel support from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim; has received institutional research grants from Merck & Co. and Roche; has received consultancy fees from Abbott; and holds 2 patents involving GDF-15. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Iftikhar J. Kullo, MD, served as Guest Editor for this paper.
- Received May 15, 2017.
- Revision received June 12, 2017.
- Accepted June 12, 2017.
- 2017 American College of Cardiology Foundation