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MESA Overlooked by USPSTF Guidelines
Submit responseWe 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 “to 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.
References
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.
Conflict of Interest:
None declared
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USPSTF Misses the Mark (or MESA)
Submit responseRecently, 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.
REFERENCES
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, Möhlenkamp S, Moebus S, Schmermund A, Lehmann N, Dragano N, Stang A, Grönemeyer DHW, Seibel R, Kälsch H, Bröcker-Preuss M, Mann K, Siegrist J, Jöckel 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
Conflict of Interest:
None declared
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USPSTF Recommendation Statement...
Submit responseCalonge 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.
References
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.
Conflict of Interest:
None declared
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Randomized evidence on statin therapy guided by high-sensitivity C-reactive protein
Submit responseThe 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).
References
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.
Conflict of Interest:
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.
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Nontraditional Risk Factors in Coronary Heart Disease
Submit responseTo 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.
References
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.
Conflict of Interest:
None declared