Nontraditional Risk Factors in Cardiovascular Disease Risk Assessment: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

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Incorporating nontraditional risk factors may improve the performance of traditional multivariable risk assessment for cardiovascular disease (CVD).


To systematically review evidence for the US Preventive Services Task Force on the benefits and harms of 3 nontraditional risk factors in cardiovascular risk assessment: the ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP) level, and coronary artery calcium (CAC) score.

Data Sources

MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for studies published through May 22, 2017. Surveillance continued through February 7, 2018.

Study Selection

Studies of asymptomatic adults with no known cardiovascular disease.

Data Extraction and Synthesis

Independent critical appraisal and data abstraction by 2 reviewers.

Main Outcomes and Measures

Cardiovascular events, mortality, risk assessment performance measures (calibration, discrimination, or risk reclassification), and serious adverse events.


Forty-three studies (N = 267 244) were included. No adequately powered trials have evaluated the clinical effect of risk assessment with nontraditional risk factors on patient health outcomes. The addition of the ABI (10 studies), hsCRP level (25 studies), or CAC score (19 studies) can improve both discrimination and reclassification; the magnitude and consistency of improvement varies by nontraditional risk factor. For the ABI, improvements in performance were the greatest for women, in whom traditional risk assessment has poor discrimination (C statistic change of 0.112 and net reclassification index [NRI] of 0.096). Results were inconsistent for hsCRP level, with the largest analysis (n = 166 596) showing a minimal effect on risk prediction (C statistic change of 0.0039, NRI of 0.0152). The largest improvements in discrimination (C statistic change ranging from 0.018 to 0.144) and reclassification (NRI ranging from 0.084 to 0.35) were seen for CAC score, although CAC score may inappropriately reclassify individuals not having cardiovascular events into higher-risk categories, as determined by negative nonevent NRI. Evidence for the harms of nontraditional risk factor assessment was limited to computed tomography imaging for CAC scoring (8 studies) and showed that radiation exposure is low but may result in additional testing.

Conclusions and Relevance

There are insufficient adequately powered clinical trials evaluating the incremental effect of the ABI, hsCRP level, or CAC score in risk assessment and initiation of preventive therapy. Furthermore, the clinical meaning of improvements in measures of calibration, discrimination, and reclassification risk prediction studies is uncertain.

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