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Original Research |

Evaluation of Newer Risk Markers for Coronary Heart Disease Risk Classification: A Cohort Study

Maryam Kavousi, MD, MSc; Suzette Elias-Smale, MD, PhD; Joost H.W. Rutten, MD, PhD; Maarten J.G. Leening, MD, MSc; Rozemarijn Vliegenthart, MD, PhD; Germaine C. Verwoert, MSc; Gabriel P. Krestin, MD, PhD; Matthijs Oudkerk, MD, PhD; Moniek P.M. de Maat, PhD; Frank W.G. Leebeek, PhD; Francesco U.S. Mattace-Raso, MD, PhD; Jan Lindemans, PhD; Albert Hofman, MD, PhD; Ewout W. Steyerberg, PhD; Aad van der Lugt, MD, PhD; Anton H. van den Meiracker, MD, PhD; and Jacqueline C.M. Witteman, PhD
[+] Article and Author Information

Acknowledgment: The investigators are grateful to the participants and staff from the Rotterdam Study, participating general practitioners, and pharmacists.

Financial Support: The Rotterdam Study is funded by Erasmus University Medical Center and Erasmus University, Rotterdam, the Netherlands; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. This study was supported by grants from the Netherlands Heart Foundation (2003B179 [Dr. Witteman], 2007B159 [Dr. Leebeek]), the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw) (Vici grant 918.76.619), and the Netherlands Consortium for Healthy Ageing. The authors received additional funding from Vereniging Trustfonds Erasmus Universiteit Rotterdam.

Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0450.

Reproducible Research Statement:Study protocol and data set: Not available. Statistical code: Available from Dr. Witteman (e-mail, mailto:j.witteman@erasmusmc.nl).

Requests for Single Reprints: Jacqueline C.M. Witteman, PhD, Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands; e-mail, mailto:j.witteman@erasmusmc.nl.

Current Author Addresses: Drs. Kavousi, Elias-Smale, Leening, Verwoert, Hofman, and Witteman: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands.

Drs. Rutten, Mattace-Raso, and van den Meiracker: Department of Internal Medicine, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands.

Dr. Vliegenthart: Department of Radiology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.

Drs. Krestin and van der Lugt: Department of Radiology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands.

Dr. Oudkerk: Center for Medical Imaging—North East Netherlands, Department of Radiology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.

Drs. de Maat and Leebeek: Department of Hematology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands.

Dr. Lindemans: Department of Clinical Chemistry, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands.

Dr. Steyerberg: Department of Public Health, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, the Netherlands.

Author Contributions: Conception and design: M. Kavousi, M. Oudkerk, M.P.M. de Maat, E.W. Steyerberg, J.C.M. Witteman.

Analysis and interpretation of the data: M. Kavousi, J.H.W. Rutten, R. Vliegenthart, M. Oudkerk, E.W. Steyerberg, A. van der Lugt, A.H. van den Meiracker.

Drafting of the article: M. Kavousi, F.U.S. Mattace-Raso, A. van der Lugt, J.C.M. Witteman.

Critical revision of the article for important intellectual content: M. Kavousi, S. Elias-Smale, J.H.W. Rutten, M.J.G. Leening, R. Vliegenthart, G.P. Krestin, M. Oudkerk, M.P.M. de Maat, F.W.G. Leebeek, F.U.S. Mattace-Raso, E.W. Steyerberg, A. van der Lugt, A.H. van den Meiracker, J.C.M. Witteman.

Final approval of the article: M. Kavousi, S. Elias-Smale, J.H.W. Rutten, R. Vliegenthart, G.C. Verwoert, M. Oudkerk, M.P.M. de Maat, F.W.G. Leebeek, J. Lindemans, A. Hofman, E.W. Steyerberg, A. van der Lugt, J.C.M. Witteman.

Provision of study materials or patients: S. Elias-Smale, J.C.M. Witteman.

Statistical expertise: M. Kavousi, J.H.W. Rutten, E.W. Steyerberg.

Obtaining of funding: A. van der Lugt, J.C.M. Witteman.

Administrative, technical, or logistic support: M.J.G. Leening, M. Oudkerk, F.U.S. Mattace-Raso.

Collection and assembly of data: S. Elias-Smale, M.J.G. Leening, R. Vliegenthart, G.C. Verwoert, M. Oudkerk, M.P.M. de Maat, F.W.G. Leebeek, J. Lindemans, A. van der Lugt.


From Erasmus University Medical Center, Rotterdam, and University Medical Center Groningen, Groningen, the Netherlands.


Ann Intern Med. 2012;156(6):438-444. doi:10.7326/0003-4819-156-6-201203200-00006
Text Size: A A A

Background: Whether newer risk markers for coronary heart disease (CHD) improve CHD risk prediction remains unclear.

Objective: To assess whether newer risk markers for CHD risk prediction and stratification improve Framingham risk score (FRS) predictions.

Design: Prospective population-based study.

Setting: The Rotterdam Study, Rotterdam, the Netherlands.

Participants: 5933 asymptomatic, community-dwelling participants (mean age, 69.1 years [SD, 8.5]).

Measurements: Traditional CHD risk factors used in the FRS (age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and newer CHD risk factors (N-terminal fragment of prohormone B-type natriuretic peptide levels, von Willebrand factor antigen levels, fibrinogen levels, chronic kidney disease, leukocyte count, C-reactive protein levels, homocysteine levels, uric acid levels, coronary artery calcium [CAC] scores, carotid intima–media thickness, peripheral arterial disease, and pulse wave velocity).

Results: Adding CAC scores to the FRS improved the accuracy of risk predictions (c-statistic increase, 0.05 [95% CI, 0.02 to 0.06]; net reclassification index, 19.3% overall [39.3% in those at intermediate risk, by FRS]). Levels of N-terminal fragment of prohormone B-type natriuretic peptide also improved risk predictions but to a lesser extent (c-statistic increase, 0.02 [CI, 0.01 to 0.04]; net reclassification index, 7.6% overall [33.0% in those at intermediate risk, by FRS]). Improvements in predictions with other newer markers were marginal.

Limitation: The findings may not be generalizable to younger or nonwhite populations.

Conclusion: Among 12 CHD risk markers, improvements in FRS predictions were most statistically and clinically significant with the addition of CAC scores. Further investigation is needed to assess whether risk refinements using CAC scores lead to a meaningful change in clinical outcome. Whether to use CAC score screening as a more routine test for risk prediction requires full consideration of the financial and clinical costs of performing versus not performing the test for both persons and health systems.

Primary Funding Source: Netherlands Organization for Health Research and Development (ZonMw)

Figures

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Figure. Multivariable-adjusted HR for incident coronary heart disease.

CAC = coronary artery calcium; cIMT = carotid intima–media thickness; CKD = chronic kidney disease; CRP = C-reactive protein; HR = hazard ratio; NT-proBNP = N-terminal fragment of prohormone B-type natriuretic peptide; PAD = peripheral arterial disease; PWV = pulse wave velocity; vWF = von Willebrand factor.

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Appendix Figure. Multivariable-adjusted HR for incident coronary heart disease in men (top) and women (bottom).

CAC = coronary artery calcium; cIMT = carotid intima–media thickness; CKD = chronic kidney disease; HR = hazard ratio; NT-proBNP = N-terminal fragment of prohormone B-type natriuretic peptide; PAD = peripheral arterial disease; PWV = pulse wave velocity; vWF = von Willebrand factor.

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Evaluation of newer risk markers for CHD
Posted on May 9, 2012
Nicholas JWald, Director
Wolfson Institute of Preventive Medicine, Queen Mary University of London
Conflict of Interest: None Declared

Kavousi et al[1] conclude that 11 of the 12 coronary heart disease (CHD) risk markers they studied (including C-reactive protein and homocysteine levels) did not improve the prediction of who would develop the disease, but they suggest that one marker, coronary artery calcium (CAC) score, did so. The hazards ratio for the CAC score between the highest and lowest quintile groups was 6.2, more than double the ratio for any other risk marker. This converts to a sensitivity (detection rate) of only 16% for a 5% false-positive rate (or 26% for a 10% false-positive rate).[2] This can be seen from the online risk screening converter on http://www.wolfson.qmul.ac.uk/rsc/. It is not a particularly discriminatory screening marker.

There is no good reason, other than custom, to start with the Framingham risk score and then examine the improvement from additional markers. If one started with age alone, risk factors such as blood pressure and cholesterol that are part of the Framingham risk score can be shown to add little to screening performance (discrimination) in spite of their importance in causing coronary heart disease.[3]

Nicholas Wald Wolfson Institute of Preventive Medicine Queen Mary University of London n.j.wald@qmul.ac.uk

References

1. Kavousi M et al. Evaluation of newer risk markers for coronary heart disease risk classification. Ann Intern Med 2012;156:438-444

2. Wald NJ, Morris JK. Assessing risk factors as potential screening tests: A simple assessment tool. Arch Intern Med 2010. 10.1001/archinternmed.2010.378

3. Wald NJ, Simmonds M, Morris JK. Screening for future cardiovascular disease using age alone compared with multiple risk factors and age. PLoS One 2011 May 4;6(5):e18742

Conflict of Interest:

Declaration of interests: Nicholas Wald jointly holds European and Canadian patents (EU1272220 priority date 10 April 2000) for a combination pill for the prevention of cardiovascular disease (pending in USA)

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