U.S. Preventive Services Task Force
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For a list of the members of the USPSTF, see the Appendix.
. Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2009;151:474-482. doi: 10.7326/0003-4819-151-7-200910060-00008
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Published: Ann Intern Med. 2009;151(7):474-482.
Appendix: U.S. Preventive Services Task Force
New recommendation from the U.S. Preventive Services Task Force (USPSTF) on the use of nontraditional, or novel, risk factors in assessing the coronary heart disease (CHD) risk of asymptomatic persons.
Systematic reviews were conducted of literature since 1996 on 9 proposed nontraditional markers of CHD risk: high-sensitivity C-reactive protein, ankleâ€“brachial index, leukocyte count, fasting blood glucose, periodontal disease, carotid intimaâ€“media thickness, coronary artery calcification score on electron-beam computed tomography, homocysteine, and lipoprotein(a). The reviews followed a hierarchical approach aimed at determining which factors could practically and definitively reassign persons assessed as intermediate-risk according to their Framingham score to either a high-risk or low-risk strata, and thereby improve outcomes by means of aggressive risk-factor modification in those newly assigned to the high-risk stratum.
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the nontraditional risk factors studied to screen asymptomatic men and women with no history of CHD to prevent CHD events. (I statement).
The U.S. Preventive Services Task Force (USPSTF) makes recommendations about preventive care services for patients without recognized signs or symptoms of the target condition.
It bases its recommendations on a systematic review of the evidence of the benefits and harms and an assessment of the net benefit of the service.
The USPSTF recognizes that clinical or policy decisions involve more considerations than this body of evidence alone. Clinicians and policymakers should understand the evidence but individualize decision making to the specific patient or situation.
The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of using the nontraditional risk factors discussed in this statement to screen asymptomatic men and women with no history of coronary heart disease (CHD) to prevent CHD events. This is an I statement.
The nontraditional risk factors included in this recommendation are high-sensitivity C-reactive protein (hs-CRP), ankle–brachial index (ABI), leukocyte count, fasting blood glucose level, periodontal disease, carotid intima–media thickness (carotid IMT), coronary artery calcification (CAC) score on electron-beam computed tomography (EBCT), homocysteine level, and lipoprotein(a) level.
See the Clinical Considerations section for suggestions for practice concerning the Insufficient Evidence statement.
See the Figure for a summary of the recommendation and suggestions for clinical practice.
For a summary of the evidence systematically reviewed in making these recommendations, the full recommendation statement, and supporting documents, please go to www.preventiveservices.ahrq.gov.
See Table 1 for a description of the USPSTF grades and Table 2 for a description of the USPSTF classification of levels of certainty about net benefit.
Coronary heart disease is the most common cause of mortality in adults in the United States. Treatment to prevent CHD events by modifying risk factors is currently based on the Framingham risk model, which sorts individuals into low-, intermediate-, or high-risk groups. If the risk model could be improved, treatment might be better targeted, thereby maximizing screening benefits and minimizing harms. The most likely opportunity to improve the model is use of additional risk factors to reclassify those in the intermediate-risk group to either high- or low-risk.
There is insufficient evidence to determine the percentage of persons with an intermediate CHD risk who would be reclassified by screening with nontraditional risk factors other than hs-CRP and ABI.
About 11% of men with an intermediate CHD risk would be reclassified into the high-risk category by hs-CRP screening, and about 12% of men would be reclassified into the low-risk category. National estimates of the number of women who would be reclassified by hs-CRP screening are not reliable because of small study samples. The available meta-analysis of individual data on ABI does not yield a clear picture on the proportion of intermediate-risk men who would be reclassified but does suggest that approximately 10% of women would be reclassified from intermediate to high risk for CHD.
The evidence is insufficient to determine the magnitude of any reduction in CHD events and CHD-related deaths obtained by using nontraditional risk factors in CHD screening. This constitutes a critical gap in the evidence for benefit from screening.
Little evidence is available to determine the harms of using nontraditional risk factors in CHD screening. Harms include lifelong use of medications without proof of benefit but with expense and potential side effects. Statins are the class of medication most commonly used; these medications have been demonstrated to be safe but are associated with the rare but serious side effect of rhabdomyolysis (1). Psychological and other harms may result from being put into a higher risk category for CHD events.
The USPSTF concludes that the evidence is insufficient to determine the balance between benefits and harms of using nontraditional risk factors in screening for CHD risk.
Although using hs-CRP and ABI to screen men and women with intermediate Framingham CHD risk would reclassify some into the low-risk group and others into the high-risk group, the evidence is insufficient to determine the ultimate effect on the occurrence of CHD events and CHD-related deaths.
The USPSTF intends this recommendation for asymptomatic men and women with no history of CHD, diabetes, or any CHD risk equivalent.
Clinicians should use the Framingham model to assess CHD risk and to guide risk-based therapy until further evidence is obtained. (See the Other Considerations section for a discussion of risk calculators.)
Because adding nontraditional risk factors to CHD assessment requires additional patient and clinical staff time and effort, routinely screening with nontraditional risk factors could result in lost opportunities for provision of other important health services of proven benefit.
This recommendation is to be used for those who fall into a 10% to 20% (intermediate) 10-year risk category after being screened for CHD risk by using traditional CHD risk factors. Using a risk assessment tool is a key step in managing CHD risk in patients. One validated method of assessing CHD risk is the Framingham model. Persons with low (<10%) Framingham risk scores do not benefit from aggressive risk factor modification, whereas those with high (>20%) Framingham risk scores do benefit. Examples of persons who fall into the intermediate-risk category include a 60-year-old male smoker with untreated hypertension or a 60-year-old female with untreated hypertension and hyperlipidemia. The current recommendation used the Adult Treatment Panel III (ATP III) Framingham risk calculator (available at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof) and does not include diabetic populations.
About 31% of asymptomatic U.S. men and 7% of asymptomatic U.S. women age 40 to 79 years without diabetes will fall into the intermediate-risk category. No evidence or consensus is available regarding how to treat and counsel these persons.
Other USPSTF recommendations (1–5) provide guidance for preventing CHD events.
Because of limitations in the evidence of effectiveness, little information is available on the cost-effectiveness of using nontraditional risk factors in CHD screening. When the evidence for effectiveness is clearer, evaluating cost-effectiveness will be a research priority.
For hs-CRP, ABI, and EBCT, high priority should be given to determining the benefits and harms of aggressive treatment of persons reclassified from intermediate to high risk on the basis of additional information obtained from these tests.
For hs-CRP and ABI, future priority should be given to studies that assess the health effect of reclassifying those at high and intermediate risk for CHD events into lower-risk categories on the basis of this assessment. Similar studies for EBCT would be useful.
The predictive value and prevalence of periodontal disease, carotid IMT, and lipoprotein(a) should be examined in conjunction with traditional Framingham risk factors for predicting CHD events and death.
Various risk models for CHD are available. Some consider diabetes as a CHD equivalent and others use it as a risk factor for CHD. The predictive value and prevalence of nontraditional risk factors for predicting CHD events and death should be examined specifically in diabetic populations.
Several risk calculators are available that use data from the Framingham studies; 2 of the most commonly used are the ATP III and the traditional Framingham risk calculator (available at www.intmed.mcw.edu/clincalc/heartrisk.html). Evidence for this recommendation relied on the risk estimation from the ATP III calculator.
In the United States, CHD is the leading cause of death, accounting for 27% of all deaths in 2004 (6). The decision to adopt preventive interventions as well as the intensity of these interventions are guided by a person's 10-year risk for myocardial infarction (MI) or death from CHD. Several risk calculators are available for this purpose, including the ATP III and traditional Framingham calculators (7, 8). The ATP III of the National Cholesterol Education Program algorithm categorizes adults without CHD, diabetes, or noncardiac vascular disease into 3 risk categories, low (<10% risk over 10 years), intermediate (10% to 20% risk over 10 years), and high (>20% risk over 10 years), on the basis of age, sex, systolic blood pressure, serum total cholesterol level, high-density lipoprotein cholesterol level, and cigarette smoking. The traditional Framingham risk calculator uses these risk factors plus diastolic blood pressure and diabetes. Neither risk calculator takes hs-CRP, ABI, leukocyte count, fasting blood glucose, periodontal disease, carotid intimal thickness, EBCT, homocysteine, or lipoprotein(a) into account.
In the United States, approximately 31% of asymptomatic men and 7% of asymptomatic women fall into the intermediate-risk category. It would be useful if those in the intermediate category could be recategorized into the low-risk category to be reassured or into the high-risk category to be prescribed more aggressive medical management (such as treatment to lower low-density lipoprotein level or blood pressure or chemoprophylactic aspirin administration) or possibly invasive interventions (such as coronary catheterization or bypass) if such management were judged beneficial for reclassified persons.
For this review, the USPSTF addressed the health benefits, including reduction in CHD events, CHD mortality, and overall mortality, of applying nontraditional risk factors to those identified as intermediate-risk by the Framingham CHD risk algorithm. The nontraditional risk factors addressed in this recommendation include ABI, leukocyte count, fasting glucose level, periodontal disease, carotid IMT, EBCT, homocysteine level, lipoprotein(a) level, and hs-CRP level. In addition to direct evidence for benefit, the USPSTF evaluated indirect evidence for the independent predictive value of these risk factors for MI and death from cardiovascular disease (CVD), the prevalence of such risk factors in intermediate- and low-risk persons, the frequency with which those in the low- and intermediate-risk groups would be restratified into high-risk groups, the benefit of aggressive medical management or other treatments of groups identified as high-risk by using these risk factors, and the harms and burdens of risk restratification resulting from use of these risk factors (9).
The USPSTF found no evidence that risk stratification with any of these risk factors, either independently or in addition to Framingham risk scoring, reduces MI or CVD mortality compared with risk stratification and treatment on the basis of Framingham scoring alone. Therefore, the USPSTF examined the evidence for the independent and additive predictive value of each nontraditional risk factor in assessing 10-year risk for MI and CHD mortality. For those risk factors for which evidence for independent or additive predictive value is available, the USPSTF evaluated the evidence for the effect such factors may have on recategorizing intermediate-risk persons into low- or high-risk groups.
A recent well-conducted meta-analysis of 16 population-based cohort studies concluded that lower ABI is associated with an increased risk for CVD events and mortality, independent of Framingham risk score (10). However, because of particular aspects of the meta-analysis, this evidence cannot provide an unbiased determination of how many asymptomatic men without known vascular disease would be reclassified from the intermediate classification obtained by using Framingham factors alone to a higher cardiac risk stratum. This analysis did provide an unbiased estimate that approximately 10% of women would be reclassified from intermediate to high CHD risk.
Three good- and 3 fair-quality cohort studies and 1 meta-analysis examined the value of leukocyte count in predicting CHD risk, independent of Framingham risk factors, in participants without known coronary disease (9). The results of these studies are conflicting: 4 of the studies found an independent predictive value for leukocyte count, whereas the others did not. The USPSTF concluded that there is at least fair evidence of no association between leukocyte count and the risk for coronary events.
Fair-quality evidence indicates that impaired fasting serum glucose (defined as levels of 5.55 and 6.94 mmol/L [100 and 125 mg/dL]) is a weak predictor of CHD, independent of Framingham risk factors, in persons without diabetes. Two good- and 5 fair-quality studies had conflicting results. One good-quality study showed a weak association between fasting glucose level and CHD after 4 years of follow-up (hazard ratio, 1.09 [95% CI, 1.02 to 1.16] per 0.72-mmol/L [13-mg/dL] increase in fasting glucose level), after adjusting for Framingham risk score without diabetes (11), and the other good-quality study found no association after 8 years of follow-up (adjusted hazard ratio, 1.05 [CI, 0.94 to 1.17]) (12). The remaining fair-quality cohort studies compared patients with elevated fasting glucose level with those with normal fasting glucose level and found no significant increased risk for CHD (13).
Fair-quality evidence indicates that periodontal disease can predict CHD risk independent of Framingham risk factors. A meta-analysis performed by Humphrey and colleagues (14) examined the results from 3 good and 4 fair-quality cohort studies in North America and Finland, which included from 175 to more than 100 000 men and women and had follow-up that ranged from 5 to 21 years; pooled data from 6 of these studies showed a risk ratio of 1.24 (CI, 1.01 to 1.51) for any CHD or CVD event. Of note, these studies did not consistently define periodontal disease or CHD outcomes.
Periodontal bone loss was an important risk factor for subsequent CHD, with 2 studies showing statistically significant relative risks that ranged from 1.36 to 1.90. A meta-analysis of 4 cohort studies showed that tooth loss, a component of periodontal disease, predicts CVD events independent of Framingham risk factors. Investigators observed a 41% increased risk for CHD or CVD events among those with 0 to 10 teeth at baseline, compared with those who had 25 to 32 teeth (combined risk estimate, 1.41 [CI, 1.22 to 1.63]) (14). No information was available about prevalence or applicability in populations at intermediate risk for CHD events.
Fair-quality evidence indicates, on the basis of 1 fair- and 2 good-quality population-based longitudinal studies in the United States and the Netherlands, that carotid IMT predicts CHD independent of Framingham risk factors in asymptomatic persons (1300 to 16 000 men and women who showed a relative risk of 1.19 to 3.80) (15–17). Adding carotid IMT scores to a risk prediction equation based on traditional risk factors modestly improved the prediction of subsequent CHD among healthy adults, particularly for men (18). However, the studies that show an association of carotid IMT with CHD outcome have all been done in research settings, and the ability to conduct carotid IMT with precision in nonresearch settings has not been established. No information is available about the prevalence or applicability of carotid IMT to populations at intermediate risk for CHD events.
Poor- to fair-quality evidence indicates that higher CAC scores on EBCT predict CHD events independent of Framingham risk factors, on the basis of a systematic review of 8 cohort studies. Three good-quality population cohort studies and 5 fair-quality studies reported that the highest CAC score groups had significantly greater relative risk estimates than the lowest score groups (19–26). Although 3 of the studies met the technical requirements for a good-quality rating, none of them make a convincing case that CAC adds information about intermediate-risk persons. One of the 3 included only low-risk persons. Another study, from the Rotterdam Coronary Calcification Study, used self-selected participants who were classified into 2 categories (10-year Framingham risk of >20% or <20%), and results for the intermediate-risk group (10% to 20%) were therefore not reported separately. Several features of the third study, from the South Bay Heart Watch, limit its applicability to an intermediate risk group. The predictive value of a high CAC score was inconsistent; for example, participants with a Framingham risk score of 11% to 15% and participants with a risk score of 16% to 20% had the same baseline risk (7%). The CAC score also seemed to be imprecise; among participants who had a high CAC score, those with a pretest Framingham risk score of 10% to 15% had a higher posttest risk (19%) than those with a pretest score of 16% to 20%. Finally, participants were potentially self-selected.
The 5 studies rated as fair quality were primarily limited by their use of proxy measures to control for Framingham risk factors or their recruitment of self-selected participants.
In summary, although the 8 included studies consistently reported statistically significant relative risks for coronary events with increasing CAC scores, no study uniformly met all 3 of the following conditions: addressed an intermediate-risk cohort, was population-based or free of selection bias, and appropriately measured or controlled for traditional risk factors (13).
Fair-quality evidence indicates that elevated homocysteine levels predict CHD events after adjustment for some Framingham risk factors; however, no studies calculated a Framingham risk score, assessed predictive value beyond Framingham risk scoring, or assessed whether homocysteine levels contribute to reclassification from intermediate to another risk category (27). Results from 21 studies in 20 cohorts were conflicting; 16 found a positive association and 5 found no association or a negative association. When all good- or fair-quality studies in participants without previous coronary disease were pooled, each 5-μmol/L increase in homocysteine level was associated with an 18% increase in the risk for coronary events (1.21 [CI, 1.10 to 1.32]) (27). However, none of the studies addressed the prevalence and applicability of homocysteine level in intermediate-risk participants.
Fair-quality evidence indicates that lipoprotein(a) level predicts CHD events after adjustment for some Framingham risk factors, but no studies calculated a Framingham risk score, assessed predictive value beyond Framingham risk scoring, or assessed whether lipoprotein(a) contributes to reclassification from intermediate to another risk category. In a systematic review and meta-analysis of 4 good- and 11 fair-quality studies, 12 of the 15 found a positive association (13). A meta-analysis of the 15 fair- and good-quality studies that excluded baseline CHD and CVD showed an increased relative risk of 1.59 (CI, 1.29 to 1.97) when comparing lipoprotein(a) levels of 300 mg/L or greater with levels less than 300 mg/L (13). The pooled estimate was similar among men and women, and the association between lipoprotein(a) level and CHD was greater in studies with follow-up times of more than 10 years. No studies attempted to evaluate the prevalence and applicability of lipoprotein(a) level in intermediate-risk participants.
Ten good-quality studies, 13 fair-quality studies, and 2 meta-analyses provide fair-to-good evidence that an elevated hs-CRP level predicts a higher risk for CHD events independent of Framingham risk factors (28). For studies that adjusted for all Framingham risk variables (including diabetes), the summary estimate of relative risk for incident CHD was 1.58 (CI, 1.37 to 1.83) for an hs-CRP level greater than 3.0 mg/L, compared with a level of less than 1.0 mg/L. No trials directly addressed application of hs-CRP in the intermediate-risk population.
The USPSTF found no evidence that using ABI in addition to Framingham-based risk assessment to guide risk factor treatment reduces CVD events more than using Framingham risk assessment alone to guide treatment.
The USPSTF found no evidence that treating persons with a high homocysteine level improves outcomes. In several well-conducted trials (29, 30), homocysteine therapy did not prevent CHD events in persons with known heart disease. Trials are currently under way to evaluate the strategy of treating elevated homocysteine levels for primary prevention of CHD (31, 32).
The USPSTF found no evidence regarding the efficacy of preventive dental care or treatment for periodontal disease in reducing CHD events.
Lipid-lowering therapy has been shown to be associated with slowing of carotid IMT.
Statins have not been shown to decrease mortality in patients screened and found to have elevated CAC scores, and evidence conflicts about whether statins produce the intermediate outcome of reduction in CAC scores (33, 34).
JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) (35) did not address the issue of whether using hs-CRP in addition to Framingham risk assessment would reduce CVD events beyond the use of Framingham risk assessment alone, and no other treatment studies answer this question. However, there are observational studies or small controlled trials showing that weight loss, exercise training, or both have been associated with reductions in hs-CRP level (36). Intervention trials in those with MI have shown that statins decrease hs-CRP level (as well as low-density lipoprotein cholesterol level), and that this reduction is independently associated with slower atherosclerotic progression (37).
The USPSTF found no studies that addressed the harms of assessing nontraditional risk factors and using this information for risk assessment. Electron-beam computed tomography uses the equivalent radiation of 10 chest x-rays. Potential adverse effects of using these risk factors include false-positive test results and labeling, resulting in unnecessary invasive diagnostic procedures (such as coronary angiography), and side effects of aggressive risk factor management (such as the adverse effects of antihypertensive and lipid-lowering drugs). In particular, the potential harm associated with the long-term decrease of low-density lipoprotein cholesterol to very low levels is cause for concern.
C-reactive protein is the only risk marker for which magnitude of benefit could be estimated by modeling based on sufficient information about predictive value and prevalence among persons at intermediate risk. Buckley and colleagues include analyses in their review (28) that model the additive benefit of hs-CRP to traditional Framingham risk factors in those at intermediate risk. The model predicts that 11% of men in the intermediate group would be reclassified as high-risk; if those reclassified men are provided intensive risk-reduction therapy, it could avert 47.8 CHD events over 10 years per 1000 among men age 40 to 79 years. The net benefit of hs-CRP testing was felt to be of uncertain magnitude because of the lack of information on harms of testing and the unknown effect of intensive therapy on those who are defined as high-risk by virtue of hs-CRP testing.
The American Heart Association encourages Framingham risk assessment in asymptomatic persons, advises against CAC assessment by EBCT in asymptomatic persons at low and high risk (those at <10% and >20% 10-year risk, respectively), and states that “it may be reasonable to consider use of CAC measurement in such patients based on available evidence that demonstrates incremental risk prediction information in this selected (intermediate-risk) patient group. This conclusion is based on the possibility that such patients might be reclassified to a higher-risk status based on high CAC score, and that subsequent patient management may be modified” (38).
A joint statement by the American Heart Association and the Centers for Disease Control and Prevention recommends against the use of hs-CRP as a risk marker in the general population and against the use of other inflammatory markers or acute-phase reactants for CHD risk prediction (Class III, Level of Evidence C). The recommendation states that “measurement of hs-CRP is an independent marker of risk and, in those judged at intermediate risk by global risk assessment (10 to 20% risk of CHD per 10 years), at the discretion of the physician, may help direct further evaluation and therapy in the primary prevention of CVD. The benefits of such therapy based on this strategy remain uncertain. (Class IIa, Level of Evidence B)” (39).
The ATP III states that homocysteine level, hs-CRP level, carotid IMT, and CAC score on EBCT may be useful in certain circumstances but does not recommend incorporating any emerging risk factors into risk assessment for all persons receiving primary prevention risk assessment (40).
Members of the U.S. Preventive Services Task Force at the time this recommendation was finalized† were Ned Calonge, MD, MPH, Chair (Colorado Department of Public Health and Environment, Denver, Colorado); Diana B. Petitti, MD, MPH, Vice Chair (Arizona State University, Phoenix, Arizona); Thomas G. DeWitt, MD (Children's Hospital Medical Center, Cincinnati, Ohio); Kimberly D. Gregory, MD, MPH (Cedars-Sinai Medical Center, Los Angeles, California); Russell Harris, MD, MPH (University of North Carolina School of Medicine, Chapel Hill, North Carolina); George Isham, MD, MS (HealthPartners, Minneapolis, Minnesota); Michael L. LeFevre, MD, MSPH (University of Missouri School of Medicine, Columbia, Missouri); Carol Loveland-Cherry, PhD, RN (University of Michigan School of Nursing, Ann Arbor, Michigan); Lucy N. Marion, PhD, RN (Medical College of Georgia, Augusta, Georgia); Virginia A. Moyer, MD, MPH (Baylor College of Medicine, Houston, Texas); Judith K. Ockene, PhD (University of Massachusetts Medical School, Worcester, Massachusetts); George F. Sawaya, MD (University of California, San Francisco, San Francisco, California); Albert L. Siu, MD, MSPH (Mount Sinai Medical Center, New York, New York); Steven M. Teutsch, MD, MPH (Merck & Company, West Point, Pennsylvania); and Barbara P. Yawn, MD, MSc (Olmsted Medical Center, Rochester, Minnesota).
† For a list of current Task Force members, go to www.ahrq.gov/clinic/uspstfab.htm.
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Eric L. Matteson
Division of Rheumatology and Department of Health Sciences Research, Mayo Clinic College of Medicine
October 14, 2009
Nontraditional Risk Factors in Coronary Heart Disease
To the Editor:
The recently published U.S. Preventive Services Task Force statement and systematic review summary of emerging risk factors for coronary heart disease (CHD) highlight important recognized risk factors, but neglect an important and emerging aspect of CHD (1,2).
In the past decade, it has become increasing clear that accelerated atherosclerosis and CHD are more common among patients with systemic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Women with SLE have a more than two-fold increased risk of cardiovascular disease including myocardial infarction (MI) compared to women without SLE, and indeed the incidence of CHD in women with lupus aged 35"“44 years has been estimated to be 50-fold greater than in control populations (3) Patients with RA have a more than 2-fold increased risk of CHD including heart failure compared to patients without RA (4). This increased risk is not fully explained by traditional risk factors nor treatment with corticosteroids, although it may be related to the cumulative burden of inflammatory disease (3,4).
The population burden of these and related inflammatory diseases is significant. SLE affects between 161,000 to 322,000 adults, and RA affects 1.3 million adults in the United States (5). Patients with SLE and RA have a range of detectable coronary risk factors that are not fully reflected in the Framingham risk model, nor are they reflected in the nontraditional risk factors summarized in these reports of the Task Force and Helfland et al (1,2). The nontraditional risk factors assessed by the Task Force did include C- reactive protein (CRP), a marker of inflammation. However, the inclusion of CRP as a risk factor for CHD does not adequately address this issue, as a single CRP measure cannot fully explain the increased risk of CHD in persons with systemic inflammatory diseases.
We suggest that systemic inflammatory diseases should be identified as risk factors for CHD to better and fully reflect their impact on CHD related morbidity and mortality, and raise awareness for the need for screening of these patients, who often have premature cardiovascular disease unexplained by traditional risk factors or treatment of the underlying inflammatory disease.
1. U.S. Preventative Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;151:474 -482.
2. Helfland M, Buckley DI, Freeman M, Fu R, Rogers K, Flemming C, Humphrey LL. Emerging risk factors for coronary heart disease: A summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151:496-507.
3. Bruce IN, Urowitz MB, Gladman DD, Ibanez D, Steiner G. Risk factors for coronary heart disease in women with systemic lupus erythematosus: the Toronto Risk Factor Study, Arthritis Rheum 2003;48:3159"“3167.
4. Crowson CS, Nicola PJ, Kremers HM, O'Fallon WM, Therneau TM, Jacobsen SJ, Roger VL, Ballman KV, Gabriel SE. How much of the increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease? Arthritis Rheum 2005; 52:3039-3044.
5. Helmick CG, Felson DT, Lawrence RC, Gabriel SE, Hirsch R, Kwoh CK, Liang MH, Maradit Kremers H, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part I Arthritis Rheum 2008; 58:15-25.
Robert J Glynn
JUPITER trial statistician, Brigham & Women's Hospital, Harvard Medical School
October 16, 2009
Randomized evidence on statin therapy guided by high-sensitivity C-reactive protein
The JUPITER trial of apparently healthy men and women with hsCRP levels >= 2 mg/L included almost exclusively persons with Framingham Risk Scores in the "intermediate" and "low" range who, under current guidelines, would not qualify for statin therapy because they additionally had LDL-C levels <130 mg/dL. Nonetheless, compared to placebo, allocation to rosuvastatin 20 mg/day resulted in a 44 percent reduction in the primary trial endpoint of major vascular events (P<0.0001), a 54 percent reduction in myocardial infarction (P=0.0002), a 48 percent reduction in stroke (P=0.002), a 46 percent reduction in the need for angioplasty or bypass surgery (P<0.0001), and a 20 percent reduction in all-cause mortality (P=0.02) (1). As reported in 2008, these risk reductions were observed at all levels of Framingham Risk (1). To provide more detail, among 6,091 persons in JUPITER with elevated hsCRP but Framingham Risk Scores of 5 to 10%, a 45 percent reduction in major vascular events was observed (HR=0.55, 95%CI 0.36-0.84, P=0.005), whereas among 7,340 persons with elevated hsCRP but Framingham Risk Scores of 11 to 20%, a 49 percent reduction in major vascular events was observed (HR=0.51, 95%CI 0.39-0.68, P<0.0001). Absolute risk reductions were large in JUPITER, so that estimated numbers needed to treat were smaller than those estimated from primary prevention trials of antihypertensive agents, aspirin, and statin regimens directed by other indications (2).
The statement from the United States Preventive Services Task Force (USPSTF) (3) that "persons with low (<10%) Framingham risk scores do not benefit from aggressive risk factor modification" and the conclusion for patients that hsCRP does not improve a doctor's ability to guide treatment, fail to reflect current randomized trial data. The USPSTF conclusions should be of particular concern for women, almost all of whom have Framingham Risk Scores below 10%.
Clinicians interested in alternative evidence-based recommendations for the use of novel biomarkers in cardiovascular disease are referred to the 2009 Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease in the Adult (4) and the 2009 National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines (5).
1. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gottto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.
2. Ridker PM, MacFadyen JG, Fonseca FAH, Genest J, Gottto AM, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C- reactive protein. Circ Cardiovasc Qual Outcomes 2009; e-pub ahead of print.
3. U.S. Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2009; 151: 474-482.
4. Genest J, McPherson R, Frohlich J, Anderson T, Campbell N, Carpentier A, Couture P, Dufour R, Fodor G, Francis GA, Grover S, Gupta M, Hegele RA, Lau DC, Leiter L, Lewis GF, Lonn E, Mancini GBJ, Ng D, Pearson GJ, Sniderman A, Stone JA, Ur E. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult "“ 2009 recommendations. Can J Cardiol 2009;25:567-579.
5. NACB LMPG Committee Members, Myers GL, Christenson RH, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, Grundy SM, Labarthe DR, Levy D, Rifai N, Wilson PW. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem 2009;55:378-84.
The author has received research support from AstraZeneca. The Brigham & Women's Hospital holds patents that relate to the use of inflammatory biomarkers in cardiovascular disease.
University of Southern California
October 19, 2009
USPSTF Recommendation Statement...
Calonge et al presented the U.S. Preventive Services Task Force Recommendation Statement on the use of nontraditional, or novel, risk factors in assessing the coronary heart disease risk of asymptomatic persons in the October 6, 2009 issue of Annals of Internal Medicine. Review was conducted on nine nontraditional markers: highsensitivity C- reactive protein, ankle"“brachial index, leukocyte count, fasting blood glucose, periodontal disease, carotid intima"“media thickness, coronary artery calcification score on electron-beam computed tomography, homocysteine, and lipoprotein (a). These do not include uric acid. Currently available research studies show conflicting data regarding the role of uric acid as a risk factor for coronary heart disease. Several studies (1, 2) reported relationship between serum uric acid levels and coronary artery disease. There is also report (3) of cardiovascular benefits from lowering uric acid levels. Uric acid can function as an antioxidant (4), as well as a pro-oxidant (5). Therefore, it is expected for the task force to address utility of uric acid, if any, in management of coronary heart disease.
1. Tuttle KR, Short RA, Johnson RJ. Sex differences in uric acid and risk factors for coronary artery disease. Am J Cardiol 2001;87:1411-4.
2. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality: the NHANES I epidemiologic follow-up study, 1971-1992. JAMA 2000;283:2404- 10.
3. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on the blood pressure of adolescents with newly diagnosed essential hypertension. JAMA 2008;300:924-32.
4. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant-and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A 1981;78:6858-62.
5. Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classical antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol 2007;293:C584- C596.
Matthew J. Budoff
Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor-UCLA
USPSTF Misses the Mark (or MESA)
Recently, the USPSTF updated their statement on non-traditional risk factors and cardiovascular risk assessment. It is not surprising that their opinion did not change as to the clinical utility of tests such as coronary artery calcium since 2004, as they did not consider any of the new and available evidence on the topic. Their "˜comprehensive review of the literature' failed to uncover 19 reports on CAC outcomes that have been published, contributing 103,124 additional subjects and 2883 events. How the USPSTF makes recommendations on the utility of CAC testing for risk stratification and only identifying 8 studies is disturbing. Most worrisome is the obvious failure to include the Multi-Ethnic Study of Atherosclerosis (MESA), which has been described as one of the best epidemiologic studies ever done.
This prospective, population-based study included 6,814 asymptomatic persons, demonstrating that those patients with high coronary artery calcium (CAC) scores were 10-fold more likely to suffer cardiac events, and reclassifying a majority of intermediate risk patients. The primary outcome paper was published in the New England Journal of Medicine in March 2008. To date, there are over 200 published manuscripts (dating back to 2002) reporting design and results of the MESA study, including CAC reclassification of risk, independent and incremental ability of CAC to predict events in intermediate risk cohorts, and the ability of this measure to outperform both traditional risk factors and other subclinical markers such as carotid intimal media thickness.
This NHLBI funded study is clearly an exceptional epidemiologic study that meets all the USPSTF criteria of a good study, which proved that CAC scanning provides both robust incremental and independent prediction of future coronary events, reclassifies a large number of intermediate risk patients and raises the area under the curve for prediction of events.
Had the USPSTF just failed to include one major CAC study, even of the magnitude of MESA, one could argue that mistakes of omission occur. However, the paper only cited that 8 outcome studies were included in their "˜systemic review'. To date, there are at least 20 such prospective outcome studies, including multiple large prospective, population based studies. The Saint Francis Heart Study is a prospective, population-based study of 4,903 asymptomatic persons age 50 to 70 years, who underwent CAC scanning and were followed for 4.3 years, demonstrating robust prediction of events using CAC over Framingham models. Most of the patients were intermediate risk, and over 70% were "˜reclassified' to either high or low- risk with use of CAC scanning. USPSTF also failed to include the recently completed RECALL study, a prospective, population-based study of 5000 persons with 5.0 years of follow up, demonstrating reclassification of 76% intermediate risk patients based on CAC testing. Of the intermediate risk patients, 14% were classified to higher risk, and 63% to lower risk. This robust reclassification is much greater than either reported for ABI or CRP.
Even the Rotterdam Study, which was referenced, described the reclassification of their cohort, yet the USPSTF did not acknowledge this. In that study, 64% of intermediate risk men were reclassified, 38% moved to the low-risk (<10% risk) and 26% to the high-risk category (>20% risk). In women at intermediate risk, 58% were reclassified of which 38% moved downward and 20% upward in risk. All subjects were reclassified into more accurate risk categories, and this was much more robust than CRP reclassification in that particular study.
Each of the 20 CAC outcomes studies have similar conclusions, with an approximate 10-fold increase in risk among asymptomatic persons with high score, and each providing evidence of incremental risk prediction and ability to reclassify significant portions of the population. The USPSTF conclusions that not enough data exists for the validation of CAC testing is not due to lack of existing published data, but the failure of the task force to evaluate available studies. The disparity between recommendations of other organizations, such as the National Cholesterol Education Panel, American Heart Association and American College of Cardiology as compared to the USPSTF has nothing to do with different analysis of data, but entirely on analyzing all the available data when making conclusions.
It is imperative that the USPSTF immediately revisit this topic, with analysis of all available literature, to make more cogent and complete recommendations.
1. U.S. Preventive Services Task Force. Using Nontraditional Risk Factors in Coronary Heart Disease Risk Assessment: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2009;151:474-482.
2. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, O'Leary DH, Tracy R, Watson K, Wong ND, Kronmal RA. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358(13):1336-1345.
3. Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2008; 168:1333-9.
4. Arad Y, Spadaro LA, Roth M, Newstein D, Guerci AD. Treatment of Asymptomatic Adults with Elevated Coronary Calcium Scores with Atorvastatin, Vitamin C, and Vitamin E: The St. Francis Heart Study Randomized Clinical Trial. J Am Coll Cardiol 2005: 46: 166-172.
5. Erbel R, MÃ¶hlenkamp S, Moebus S, Schmermund A, Lehmann N, Dragano N, Stang A, GrÃ¶nemeyer DHW, Seibel R, KÃ¤lsch H, BrÃ¶cker-Preuss M, Mann K, Siegrist J, JÃ¶ckel KH on behalf of the Heinz Nixydorf Recall Investigators. Signs of Subclinical Coronary Atherosclerosis Measured as Coronary Artery Calcification Improve Risk Prediction of Hard Events Beyond Traditional Risk Factors in an Unselected General Population - The Heinz Nixdorf Recall Study Five-Year Outcome Data. J Am Coll Cardiol 2009.
6. van der Meer IM, Bots ML, Hofman A, del Sol AI, van der Kuip DA, Witteman JC. Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction: the Rotterdam Study. Circulation. 2004;109: 1089-94. [PMID: 14993130
Michael J. Blaha
The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease
November 2, 2009
MESA Overlooked by USPSTF Guidelines
We read with interest the statement from the USPSTF on emerging risk factors for CHD. Specifically, the authors suggest that the current evidence does not support the use of coronary artery calcium (CAC) scoring "for further risk stratification of intermediate-risk persons." The authors identify a 2004 study by Greenland et al. as the "best-quality" study, and suggest "flaws in the other studies." This overall conclusion from the USPSTF is at odds with current recommendations from the American Heart Association (AHA) and American College of Cardiology (ACC)(1).
We are perplexed as to why the Multi-Ethnic Study of Atherosclerosis (MESA) was not considered a high quality study. The primary objective of the NIH/NHLBI funded MESA study was Ã¢"Âœto determine characteristics related to progression of subclinical to clinical cardiovascular disease (2)." MESA enrolled an ethnically-diverse population-based sample of 6,814 asymptomatic men and women aged 45-84 from 6 field centers across the United States. All patients received a common scanning protocol. During 3.8 year follow-up, doubling of CAC increased the risk of any coronary event by 18 to 39%, and CAC increased the area under the receiver-operating-characteristic curves (ROCs) for the prediction of coronary events when added to standard risk factors (3).
The influence of CAC on the ROC is of great significance, and the USPSTF authors rightly point out how difficult it is for a risk factor to increase the area under the ROC. While we await the presentation of the MESA reclassification analysis at AHA Scientific Sessions 2009, there are existing publications that suggest a reclassification benefit with CAC. For example, women in MESA characterized as low-risk by Framingham Risk Score (FRS) but with CAC>300 had a 6.7% and 8.6% risk of coronary heart disease (CHD) and cardiovascular (CVD) events, respectively, during 3.75 year follow-up (4). These women with advanced CAC were indeed at elevated risk, despite low calculated risk by FRS.
MESA is one of 10 NIH/NHLBI-funded population based studies of CVD risk, and its goal was to assess the question posed by the USPSTF authors -the predictive value of subclinical atherosclerosis in predicting coronary events. If the MESA study is not considered high-quality, we question what type of study will be sufficient to demonstrate the importance of selective CAC testing in persons with risk factors who do not yet qualify for treatment with statin and aspirin therapy.
In the future the USPSTF should include an experienced preventive cardiologist to avoid these major oversights.
1. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography). Circulation. 2007;115:402-26.
2. Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol. 2002;156(9):871- 81.
3. Detrano R, Guerci AD, Carr JJ, et al. Coronary Calcium as a Predictor of Coronary Events in Four Racial or Ethnic Groups. N Engl J Med. 2008;358:1336-1345.
4. Lakoski SG, Greenland P, Wong ND, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as "low risk" based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med. 2007;167(22):2437-42.
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