Draft Recommendation Statement
Cardiovascular Disease: Risk Assessment With Nontraditional Risk Factors
This opportunity for public comment expired on February 12, 2018 at 8:00 PM EST
Note: This is a Draft Recommendation Statement. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Recommendation Statement will be developed after careful consideration of the feedback received and will include both the Research Plan and Evidence Review as a basis.
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Draft: Recommendation Summary
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of adding the ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP), or coronary artery calcification (CAC) score to traditional risk assessment for cardiovascular disease (CVD) in asymptomatic adults to prevent CVD events.
The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific clinical preventive services for patients without obvious related signs or symptoms.
It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.
The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.
CVD is the most common cause of death in adults in the United States. Treatment to prevent CVD events by modifying risk factors is currently informed by the Framingham Risk Score (FRS), the Pooled Cohort Equations (PCE), or similar CVD risk assessment models. If current CVD risk assessment models could be improved by adding more risk factors, treatment might be better targeted, thereby maximizing benefits and minimizing harms.
The USPSTF found adequate evidence that adding the ABI, hsCRP, and CAC score to existing CVD risk assessment models (i.e., FRS or PCE) may improve calibration, discrimination, and reclassification. The USPSTF chose to review these three nontraditional risk factors because prior evidence reviews identified them as the most promising.
Benefits of Early Detection and Intervention
The USPSTF found inadequate evidence to assess whether treatment decisions guided by ABI, hsCRP, or CAC score test results, in addition to existing CVD risk assessment models, lead to reduced incidence of CVD events or mortality.
Harms of Early Detection and Intervention
The USPSTF found adequate evidence to bound the harms of early detection and intervention as small. Harms can include abnormal results and incidental findings leading to additional testing and possible procedures, as well as anxiety.
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the ABI, hsCRP, or CAC score in risk assessment for CVD in asymptomatic adults to prevent CVD events.
Draft: Clinical Considerations
Patient Population Under Consideration
This recommendation applies to asymptomatic adults without a history of CVD.
Suggestions for Practice Regarding the I Statement
Clinicians should use the PCE to assess CVD risk and to guide risk-based therapy until further evidence shows additional benefit of adding other CVD risk factors.
Potential Preventable Burden
CVD comprises diseases of the heart and vascular system, including atherosclerosis, cerebrovascular disease, and peripheral artery disease. CVD is the most common cause of death in adults in the United States, accounting for 1 in 3 deaths each year.1 Although it remains a significant cause of morbidity and mortality, CVD mortality has been decreasing over time in the United States. Currently, the annual incidence of new cases of myocardial infarction and cerebral vascular accident in the United States is 580,000 and 610,000, respectively.1
The incidence of CVD varies by sex. Men, on average, develop CVD about 10 years earlier than women.2 The burden of CVD increases with age. In 2015, the age-adjusted prevalence of coronary artery disease among Americans ages 45 to 64 years was 6.1%, compared to 16.4% among those ages 65 to 74 years of age and 23.3% among those age 75 years or older.3 In the same year, 2.7%, 5.6%, and 11.2% of Americans in these age groups had a stroke, respectively. Prevalence also varies by race/ethnicity; in 2015, American Indian/Alaskan Native adults had 2 times the prevalence of coronary artery disease than Asian adults (9.3% vs. 3.7%). Prevalence in Hispanic, African American, and white adults was similar at 5.1%, 5.4%, and 5.6%, respectively.3 However, strokes were most common among African American adults, followed by white (2.4%), Hispanic (2.4%), American Indian/Alaska Native (2.2%), and Asian (1.4%) adults.
Testing for hsCRP and the ABI is noninvasive, and there is little direct harm from the tests themselves. Harms of testing for CAC score include exposure to radiation and incidental findings on computed tomography of the chest, such as pulmonary nodules, that may lead to further invasive testing and procedures. Abnormal results may lead to further testing, procedures, and lifelong use of medications without proof of benefit, but with expense and potential side effects for the patient. Psychological harms may result from being reclassified in a higher risk category for CVD events.
Only one of the risk assessment models currently used in the United States, the Reynolds Score, incorporates hsCRP into its basic risk calculation. A number of guidelines, including those from the American College of Cardiology and the American Heart Association, recommend considering hsCRP, ABI, or CAC score to clarify treatment decisions for patients whose risk assessment is borderline or unclear using a traditional risk assessment model.
Assessment of Risk
Accurate identification of persons at high risk for CVD events, particularly nonfatal myocardial infarction or stroke, and CVD death provides the opportunity to intensify risk factor management to reduce the likelihood of one of these events. In addition, identifying persons at low risk may allow for a reduction in interventions with a low benefit-to-risk ratio for those who are not likely to benefit.
Several factors are associated with higher risk for CVD events, including older age, male sex, high blood pressure, current smoking, abnormal cholesterol levels, diabetes, obesity, and physical inactivity. Risk factors can be combined in many ways for classification of a person's risk for a CVD event as low, intermediate, or high. Several calculators and models are available to quantify a person's 10-year CVD event risk. The FRS was one of the first widely used CVD risk assessment tools. Persons with a 10-year CVD event risk greater than 20% on the FRS are generally considered at high risk, those with a 10-year risk less than 10% are considered at low risk, and those in the 10% to 20% range are considered at intermediate risk. The PCE, introduced in 2013, includes the same variables as the FRS plus race/ethnicity and diabetes. Persons with a 10-year CVD event risk less than 7.5% are considered at low risk, and those with a 10-year risk of 7.5% or greater are considered at elevated risk.4
CVD risk assessment in the United States, when performed, has been generally based on the FRS and, more recently, the PCE. However, both have been documented to overestimate and underestimate risk in some persons. Therefore, identification of additional tests that could improve risk prediction, including the ABI, hsCRP, and CAC score, is of interest.
The ABI is the ratio of the systolic blood pressure at the ankle (measuring the pressure proximal to the dorsalis pedis or posterior tibial artery) to the systolic blood pressure at the brachial artery. A value less than 0.9 is indicative of peripheral artery disease.5 hsCRP is a serum protein involved in inflammatory and immune responses. Testing for hsCRP involves taking a single blood sample, and the test is widely available. A threshold of 2 or 3 mg/L is used in clinical practice to signify increased cardiovascular risk..6-8
CAC score is obtained by electron-beam computed tomography, which measures the calcium content in the coronary arteries. Scoring systems and thresholds for an elevated CAC score vary across studies, but the baseline comparison is often a CAC score of 0.9
Treatment and Interventions
Asymptomatic adults at increased risk for CVD are usually treated with a combination of diet and exercise modifications, cholesterol-lowering medications, aspirin, blood pressure management, and smoking cessation interventions.
Additional Approaches to Prevention
The National Heart, Lung, and Blood Institute provides resources on assessing cardiovascular risk, including a link to an online version of the PCE.10 Healthy People 2020 provides a database of evidence-based resources for achieving Healthy People 2020 goals, including interventions to prevent CVD.11
The USPSTF has made recommendations on many factors related to CVD prevention, including screening for high blood pressure,12 statin use,13 counseling on smoking cessation,14 and counseling on healthful diet and physical activity.15 In addition, the USPSTF recommends low-dose aspirin use in persons at increased risk for CVD.16
Draft: Other Considerations
Research Needs and Gaps
A substantial number of studies demonstrate an association between the ABI, hsCRP, and CAC score and cardiovascular outcomes, so additional association studies are unlikely to add more information. Similarly, studies assessing nontraditional risk factors in isolation are of limited value, given that current treatment recommendations are based on risk assessment with either the FRS or PCE. Good-quality studies are needed that measure the effect of adding the ABI, hsCRP, or CAC score to the PCE on clinical decision thresholds and patient outcomes (CVD events and mortality). In addition, studies are especially needed in more diverse populations, in whom nontraditional risk factor assessment may help address the shortcomings of traditional risk models, especially the PCE.
Burden of Disease
CVD is the most common cause of death in adults in the United States, accounting for 1 in 3 deaths each year. Although it remains a major cause of morbidity and mortality, CVD mortality has been decreasing over time in the United States. Currently, the annual incidence of new cases of myocardial infarction and cerebral vascular accident in the United States is 580,000 and 610,000, respectively.1
Scope of Review
The USPSTF commissioned a systematic evidence review to update its 2009 recommendation on using nontraditional risk factors in coronary heart disease risk assessment17 and its 2013 recommendation on screening for peripheral artery disease and CVD risk assessment with the ABI.18 Unlike the 2009 recommendation, the current recommendation focuses on three nontraditional risk factors—the ABI, hsCRP, and CAC score. The USPSTF chose these risk factors because they have the most promising evidence base, are reliably measured, are independently associated with CVD risk or CVD events, and the prevalence and distribution of abnormal and normal values have been described in the target population. The review focused on the health benefits (reduction in CVD events, CVD mortality, and overall mortality) and harms of CVD risk assessment and treatment guided by nontraditional risk factors combined with the PCE or FRS compared to the PCE or FRS alone. The review also evaluated whether the use of nontraditional risk factors, when added to existing CVD risk assessment models, improves measures of calibration, discrimination, and risk reclassification.
Accuracy of Screening Tests
The USPSTF looked for evidence of whether the ABI, hsCRP, or CAC score improves calibration, discrimination, or risk reclassification when added to CVD risk assessment models using traditional risk factors. Calibration measures the agreement between observed and predicted outcomes, discrimination measures the ability to distinguish between persons who will and will not have an event, and reclassification measures the ability to (correctly) reassign persons into clinically meaningful risk strata. The USPSTF found 10 articles representing 22 cohorts for the ABI, 25 articles representing 49 cohorts for hsCRP, and 19 articles representing 10 cohorts for CAC score, although few studies reported all three measures, and most did not use the FRS or the PCE as the base model.
In general, all cohort studies examining calibration (five for the ABI, nine for hsCRP, and eight for CAC score) found that adding one of these three nontraditional risk factors improved calibration, although the preferred measure of calibration was rarely reported, and only one study (of CAC score) used the PCE as a base model. The calibration plots available for hsCRP demonstrate that, although adding hsCRP improved calibration for some groups, it worsened calibration for others.19, 20 An individual patient data meta-analysis of 18 cohorts found that the ABI improved discrimination when added to the FRS, but only for women.21 A separate analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (which was not included in the individual patient data meta-analysis) found no improvement from adding the ABI to the PCE.22 Evidence (25 studies) for adding hsCRP was inconsistent, showing at most a small improvement in discrimination.6 In the only study that added hsCRP to the PCE (MESA), hsCRP did not improve discrimination.22 Adding CAC score (18 studies) to various risk assessment models resulted in at least a small, and often larger, improvement in discrimination.6 However, the magnitude of improvement decreased as the discrimination of the base model improved. The one study22 that added CAC score to the PCE found an improvement of only 0.02 to the area under the curve.
The evidence for risk reclassification was largely similar to the evidence for discrimination. Different studies used different risk strata, but those that used the FRS as the base model generally used less than 10% for low risk, 10% to 20% for intermediate risk, and greater than 20% for high risk, while studies using the PCE as the base model used greater than 7.5% for elevated risk. In general, studies found that the ABI, hsCRP, and CAC score tended to have positive event net reclassification (i.e., more persons who had a CVD event were correctly reclassified to a higher risk category than were incorrectly reclassified to a lower risk category). The ABI (in women) and CAC score tended to have negative event net reclassification (i.e., more persons who did not have a CVD event were incorrectly reclassified to a higher risk category than were correctly reclassified to a lower risk category). Because only a few persons have CVD events (myocardial infarction, stroke, or CVD death) in a given time period compared to the majority of the population, this suggests that on balance, more persons would be inappropriately than appropriately reclassified.6
Effectiveness of Early Detection and Treatment
The USPSTF found only one study that directly assessed the potential benefit on clinical outcomes of adding one of these three nontraditional risk factors to traditional risk assessment models.23 This fair-quality randomized, controlled trial (RCT) assigned asymptomatic volunteers (N=2,137) with no history of CVD to CAC score plus risk factor assessment/counseling versus risk factor assessment/counseling alone. At 4 years there was no difference in CVD outcomes between the two groups; however, the study was not adequately powered to detect a difference in patient health outcomes.23 The USPSTF found no studies that assessed the incremental benefit on health outcomes of adding the ABI or hsCRP to traditional risk factor assessment. The Viborg Vascular (VIVA) screening trial24 recently reported interim results; this trial randomized men ages 65 to 74 years to invitation for a triple screening (screening for high blood pressure, abdominal aortic aneurysm, and peripheral artery disease) or no screening and found a decrease in mortality with screening; however, it was not possible to determine how much of the decrease was due to screening for peripheral artery disease with the ABI and how much was due to screening for abdominal aortic aneurysm and high blood pressure, both of which are already recommended screenings.
The USPSTF found no trials evaluating the additional benefit of adding the ABI, hsCRP, or CAC score to traditional risk assessment models for guiding decisions about specific interventions to prevent CVD. The USPSTF found a few studies evaluating the use of a nontraditional risk factor as a single intervention to guide decisions about specific preventive medications compared to usual care. Two RCTs (total N=4,626) compared clinical outcomes from using the ABI to guide decisions to start aspirin therapy versus usual care, and found no benefit in CVD outcomes at 7 years of followup.25, 26 However, both studies used atypical cutoff points for diagnosing peripheral artery disease, and the results may not be applicable to current practice. One RCT (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin [JUPITER]; n=17,802) compared hsCRP versus usual care to guide high-intensity statin therapy and found benefit at 1.9 years of followup in the reduction of CVD events in the hsCRP group.8 However, because the study only randomized persons with elevated hsCRP levels, it is unknown whether patients with lower hsCRP levels would also have benefited from high-intensity statin therapy. Furthermore, many of these patients met criteria for statin therapy based on traditional risk assessment and would already have been candidates for treatment. Finally, one study (n=1,005) of using CAC score to guide statin therapy found no benefit at 4 years in the reduction of CVD events.27
Potential Harms of Screening and Treatment
The main potential harm of adding nontraditional risk factors to CVD risk assessment is low-dose radiation exposure (≤2.1 mSV) from CAC score measurement. More general potential harms are false-positive test results and subsequent invasive diagnostic procedures (such as coronary angiography). Three studies assessing the effect of CAC score on health care utilization found conflicting results. The Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) study, an RCT of CAC score use in an academic setting, found no statistically significant increase in downstream cardiac testing and procedures.23 In contrast, a retrospective study of Medicare data found that use of CAC score increased downstream cardiac testing and procedures compared to use of hsCRP and lipid screening,28 while a second smaller observational study found no difference.29 A systematic review of seven studies found that 8% to 58% of studies reported incidental findings when using CAC score, including 3% to 42% that were considered serious. The ultimate outcomes of those subsequent diagnostic procedures, whether positive or negative, are not known.30 Two studies found no short-term psychological harms from use of CAC score in CVD risk assessment.31, 32
Treatment with aspirin and statins to prevent CVD events has some potential harms (specifically bleeding and increased incidence of diabetes, respectively), but these harms are generally accepted to be a reasonable tradeoff among persons at higher risk of CVD events.
Estimate of Magnitude of Net Benefit
The USPSTF found adequate evidence that adding the ABI, hsCRP, and CAC score to existing CVD risk assessment models results in small improvements in discrimination and reclassification. However, the clinical meaning of these changes is largely unknown. The sparse evidence on adding the ABI, hsCRP, and CAC score to the PCE makes it also difficult to infer the clinical significance of these findings. The USPSTF found inadequate evidence to assess whether treatment decisions guided by the ABI, hsCRP, or CAC score, in addition to risk factors in existing CVD risk assessment models, leads to reduced incidence of CVD events or mortality. Few studies were available and were either underpowered or used atypical test thresholds for intervention. The USPSTF found adequate evidence to bound the harms of early detection and interventions as small. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the ABI, hsCRP, or CAC score in risk assessment for CVD in asymptomatic adults to prevent CVD events.
Draft: Update of Previous USPSTF Recommendation
This recommendation replaces the 2009 USPSTF recommendation.17 The previous recommendation considered the evidence on several risk factors in addition to the FRS. The major change in the current recommendation is that the PCE was used in addition to the FRS, and the recommendation focused on only three nontraditional risk factors—the ABI, hsCRP, and CAC score.
Draft: Recommendations of Others
The American Association of Clinical Endocrinologists’ 2017 guidelines include hsCRP, as part of the Reynolds Score, as a possible CVD risk evaluation tool and to stratify borderline cases.33 The American College of Cardiology and American Heart Association encourage using the PCE to assess 10-year risk of an initial hard CVD event (defined as stroke, nonfatal myocardial infarction, or CVD death). If risk-based treatment is still uncertain, they recommend using one or more of the nontraditional risk factors (including the ABI, hsCRP, or CAC score) or family history to help clarify treatment decisions.4 The Canadian Cardiovascular Society encourages use of a modified FRS risk assessment tool in asymptomatic persons to assess 10-year risk of any CVD event. It recommends judicious use of secondary testing for those in whom the need for statin therapy is unclear.34 The European Society of Cardiology uses the Systemic Coronary Risk Evaluation (SCORE) risk charts to determine 10-year risk of a fatal CVD event, which do not include the ABI, hsCRP, or CAC score.35 The U.K. National Institute for Health and Care Excellence uses the QRISK3 risk tool to estimate 10-year risk of a CVD event, which does not include the ABI, hsCRP, or CAC score.36 The Scottish Intercollegiate Guidelines Network (SIGN) uses the ASSIGN risk score to determine the 10-year risk of a CVD event, which does not include the ABI, hsCRP, or CAC score.37
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35. Perk J, De Backer G, Gohlke H, et al; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European guidelines on cardiovascular disease prevention in clinical practice (version 2012): the Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2012;33(13):1635-701.
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Internet Citation: Draft Recommendation Statement: Cardiovascular Disease: Risk Assessment With Nontraditional Risk Factors. U.S. Preventive Services Task Force. January 2018.