John W. McEvoy

An Analysis of Calibration and Discrimination Among Multiple Cardiovascular Risk Scores in a Modern Multiethnic Cohort

BACKGROUND Accurate risk assessment of atherosclerotic cardiovascular disease (ASCVD) is essential to effectively balance the risks and benefits of therapy for primary prevention. OBJECTIVE To compare the calibration and discrimination of the new American Heart Association (AHA) and American College of Cardiology (ACC) ASCVD risk score with alternative risk scores and to explore preventive therapy as a cause of the reported risk overestimation using the AHA-ACC-ASCVD score. DESIGN Prospective epidemiologic study of ASCVD. SETTING MESA (Multi-Ethnic Study of Atherosclerosis), a community-based, sex-balanced, multiethnic cohort. PATIENTS 4227 MESA participants aged 50 to 74 years and without diabetes at baseline. MEASUREMENTS Observed and expected events for the AHA-ACC-ASCVD score were compared with 4 commonly used risk scores-and their respective end points-in MESA after a 10.2-year follow-up. RESULTS The new AHA-ACC-ASCVD and 3 older Framingham-based risk scores overestimated cardiovascular events by 37% to 154% in men and 8% to 67% in women. Overestimation was noted throughout the continuum of risk. In contrast, the Reynolds Risk Score overestimated risk by 9% in men but underestimated risk by 21% in women. Aspirin, lipid-lowering or antihypertensive therapy, and interim revascularization did not explain the overestimation. LIMITATION Comparability of MESA with target populations for primary prevention and possibility of missed events in MESA. CONCLUSION Of the 5 risk scores, 4, including the new AHA-ACC-ASCVD score, showed overestimation of risk (25% to 115%) in a modern, multiethnic cohort without baseline clinical ASCVD. If validated, overestimation of ASCVD risk may have substantial implications for individual patients and the health care system. PRIMARY FUNDING SOURCE National Heart, Lung, and Blood Institute.

Coronary Artery Calcium Progression: An Important Clinical Measurement?: A Review of Published Reports

Baseline coronary artery calcification (CAC) accurately identifies coronary atherosclerosis and might improve prediction of future cardiac events. Serial assessment of CAC scores has been proposed for monitoring atherosclerosis progression and for assessing the effectiveness of medical therapies aimed at reducing cardiac risk. However, whether knowledge of progression of CAC scores over time further improves risk prediction is unclear. Several trials relating medical therapies to CAC progression have been performed without any formal guidelines on the definition of CAC progression and how it is best quantified. We conducted a comprehensive review of published reports on CAC progression. Increased CAC progression is associated with many known cardiac risk factors. We found that CAC progression correlates with worsening atherosclerosis and may facilitate prediction of future cardiac events. These findings support the notion that slowing CAC progression with therapeutic interventions might provide prognostic benefit. However, despite promising early data, such interventions (most notably with statin therapy) have not been shown to slow the progression of CAC in any randomized controlled trial to date, outside of post hoc subgroup analyses. Thus, routine quantification of CAC progression cannot currently be recommended in clinical practice. First, standards of how CAC progression should be defined and assessed need to be developed. In addition, there remains a need for further studies analyzing the effect of other cardiac therapies on CAC progression and cardiac outcomes.

Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications.

OBJECTIVES The aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values. BACKGROUND LDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients. METHODS We examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥ 400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl. RESULTS Patients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥ 70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl). CONCLUSIONS The Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥ 150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥ 70 mg/dl, and therefore additional evaluation is warranted in high-risk patients.

Coronary artery calcium for the prediction of mortality in young adults 75 years old

AIMS To determine if coronary artery calcium (CAC) scoring is independently predictive of mortality in young adults and in the elderly population and if a young person with high CAC has a higher mortality risk than an older person with less CAC. METHODS AND RESULTS We studied a cohort of 44 052 asymptomatic patients referred for CAC scans for cardiovascular risk stratification. All-cause mortality rates (MRs) were calculated after stratifying by age groups (<45, 45-54, 55-64, 65-74, and ≥75) and CAC score (0, 1-100, 100-400, and >400). Multivariable Cox regression models were constructed to assess the independent value of CAC for predicting all-cause mortality in the <45- and ≥75-year-old age groups. The MR increased in both the <45- and ≥75-year-old age groups with an increasing CAC group. After multivariable adjustment, increasing CAC remained independently predictive of increased mortality compared with CAC = 0 [<45 age group, hazard ratio (95% confidence interval): CAC = 1-100, 2.3 (1.2-4.2); CAC = 100-400, 7.4 (3.3-16.6); CAC > 400, 34.6 (15.5-77.4); ≥75 age group: CAC = 1-100, 7.0 (2.4-20.8); CAC = 100-400, 9.2 (3.2-26.5); CAC > 400, 16.1 (5.8-45.1)]. Persons <45 years old with CAC = 100-400 and CAC > 400 had 2- and 10-fold increased MRs, respectively, compared with persons ≥75 with no CAC. Individuals ≥75 years old with CAC = 0 had a 5.6-year survival rate of 98%, similar to those in other age groups with CAC = 0 (5.6-year survival, 99%). CONCLUSION The value of CAC for predicting mortality extends to both elderly patients and those <45 years old. Elderly persons with no CAC have a lower MR than younger persons with high CAC.

Role of Coronary Artery Calcium Score of Zero and Other Negative Risk Markers for Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis (MESA).

Background— Limited attention has been paid to negative cardiovascular disease (CVD) risk markers despite their potential to improve medical decision making. We compared 13 negative risk markers using diagnostic likelihood ratios (DLRs), which model the change in risk for an individual after the result of an additional test. Methods and Results— We examined 6814 participants from the Multi-Ethnic Study of Atherosclerosis. Coronary artery calcium score of 0, carotid intima-media thickness <25th percentile, absence of carotid plaque, brachial flow-mediated dilation >5% change, ankle-brachial index >0.9 and <1.3, high-sensitivity C-reactive protein <2 mg/L, homocysteine <10 µmol/L, N-terminal pro-brain natriuretic peptide <100 pg/mL, no microalbuminuria, no family history of coronary heart disease (any/premature), absence of metabolic syndrome, and healthy lifestyle were compared for all and hard coronary heart disease and all CVD events over the 10-year follow-up. Models were adjusted for traditional CVD risk factors. Among all negative risk markers, coronary artery calcium score of 0 was the strongest, with an adjusted mean DLR of 0.41 (SD, 0.12) for all coronary heart disease and 0.54 (SD, 0.12) for CVD, followed by carotid intima-media thickness <25th percentile (DLR, 0.65 [SD, 0.04] and 0.75 [SD, 0.04], respectively). High-sensitivity C-reactive protein <2 mg/L and normal ankle-brachial index had DLRs >0.80. Among clinical features, absence of any family history of coronary heart disease was the strongest (DLRs, 0.76 [SD, 0.07] and 0.81 [SD, 0.06], respectively). Net reclassification improvement analyses yielded similar findings, with coronary artery calcium score of 0 resulting in the largest, most accurate downward risk reclassification. Conclusions— Negative results of atherosclerosis-imaging tests, particularly coronary artery calcium score of 0, resulted in the greatest downward shift in estimated CVD risk. These results may help guide discussions on the identification of individuals less likely to receive net benefit from lifelong preventive pharmacotherapy.

Relationship of Cigarette Smoking With Inflammation and Subclinical Vascular Disease: The Multi-Ethnic Study of Atherosclerosis

Objective— We sought to assess the impact of smoking status, cumulative pack-years, and time since cessation (the latter in former smokers only) on 3 important domains of cardiovascular disease: inflammation, vascular dynamics and function, and subclinical atherosclerosis. Approach and Results— The Multi-Ethnic Study of Atherosclerosis (MESA) cohort enrolled 6814 adults without prior cardiovascular disease. Smoking variables were determined by self-report and confirmed with urinary cotinine. We examined cross-sectional associations between smoking parameters and (1) inflammatory biomarkers (high-sensitivity C-reactive protein [hsCRP], interleukin-6, and fibrinogen); (2) vascular dynamics and function (brachial flow-mediated dilation and carotid distensibility by ultrasound, as well as aortic distensibility by MRI); and (3) subclinical atherosclerosis (coronary artery calcification, carotid intima–media thickness, and ankle-brachial index). We identified 3218 never smokers, 2607 former smokers, and 971 current smokers. Mean age was 62 years and 47% were male. There was no consistent association between smoking and vascular distensibility or flow-mediated dilation outcomes. However, compared with never smokers, the adjusted association between current smoking and measures of either inflammation or subclinical atherosclerosis was consistently stronger than for former smoking (eg, odds ratio for hsCRP>2 mg/L of 1.7 [95% confidence interval, 1.5–2.1] versus 1.2 [1.1–1.4], odds ratio for coronary artery calcification>0 of 1.8 [1.5–2.1] versus 1.4 [1.2–1.6], respectively). Similar associations were seen for interleukin-6, fibrinogen, carotid intima–media thickness, and ankle-brachial index. A monotonic association was also found between higher pack-year quartiles and increasing inflammatory markers. Furthermore, current smokers with hsCRP>2 mg/L were more likely to have increased carotid intima–media thickness, abnormal ankle-brachial index, and coronary artery calcification>75th percentile for age, sex, and race (relative to smokers with hsCRP<2 mg/L, interaction P<0.05 for all 3 outcomes). In contrast, time since quitting in former smokers was independently associated with lower inflammation and atherosclerosis (eg, odds ratio for hsCRP>2 mg/L of 0.91 [0.88–0.95] and odds ratio for coronary artery calcification>0 of 0.94 [0.90–0.97] for every 5-year cessation interval). Conclusions— These findings expand our understanding of the harmful effects of smoking and help explain the cardiovascular benefits of smoking cessation.

Diabetes Mellitus, Prediabetes, and Incidence of Subclinical Myocardial Damage

Background— Persons with prediabetes and diabetes mellitus are at high risk for cardiovascular events. However, the relationships of prediabetes and diabetes mellitus to the development of subclinical myocardial damage are unclear. Methods and Results— We measured cardiac troponin T with a highly sensitive assay (hs-cTnT) at 2 time points, 6 years apart, among 9051 participants of the community-based Atherosclerosis Risk in Communities Study with no diabetes mellitus, or prediabetes, and without cardiovascular disease including silent myocardial infarction by ECG. First, we examined the incidence of elevated hs-cTnT (≥14 ng/L) at 6 years of follow-up. Second, we examined clinical outcomes during the subsequent ≈14 years of follow-up among persons with and without incident elevations in hs-cTnT. Cumulative probabilities of elevated hs-cTnT at 6 years among persons with no diabetes mellitus, prediabetes, and diabetes mellitus were 3.7%, 6.4%, and 10.8%, respectively. Compared with normoglycemic persons, the adjusted relative risks for incident elevated hs-cTnT were 1.40 (95% CI, 1.08–1.80) for prediabetes and 2.47 (95% CI, 1.78–3.43) for diabetes mellitus. Persons with diabetes mellitus and incident elevations in hs-cTnT were at a substantially higher risk of heart failure (hazard ratio, 6.37 [95% CI, 4.27–9.51]), death (hazard ratio, 4.36 [95% CI, 3.14–6.07]), and coronary heart disease (hazard ratio, 3.84 [95% CI, 2.52–5.84]) compared with persons without diabetes mellitus and no incident elevation in hs-cTnT. Conclusions— Prediabetes and diabetes mellitus were independently associated with the development of subclinical myocardial damage, as assessed by hs-cTnT, and those persons with evidence of subclinical damage were at highest risk for clinical events. These results support a possible deleterious effect of hyperglycemia on the myocardium, possibly reflecting a microvascular cause.

Impact of Coronary Computed Tomographic Angiography Results on Patient and Physician Behavior in a Low-Risk Population

BACKGROUND The impact of screening coronary computed tomographic angiography (CCTA) on physician and patient behavior is unclear. METHODS We studied asymptomatic patients from a health-screening program. Our study population comprised 1000 patients who underwent CCTA as part of a prior study and a matched control group of 1000 patients who did not. We assessed medication use, secondary test referrals, revascularizations, and cardiovascular events at 90 days and 18 months. RESULTS A total of 215 patients in the CCTA group had coronary atherosclerosis (CCTA positive). Medication use was increased in the CCTA-positive group compared with both the CCTA-negative (no atherosclerosis) and control groups at 90 days (statin use, 34% vs 5% vs 8%, respectively; aspirin use, 40% vs 5% vs 8%, respectively), and 18 months (statin use, 20% vs 3% vs 6%, respectively; aspirin use, 26% vs 3% vs 6%, respectively). After multivariable risk adjustment, the odds ratios for statin and aspirin use in the CCTA-positive group at 18 months were 3.3 (95% confidence interval [CI], 1.3-8.3) and 4.2 (95% CI, 1.8-9.6), respectively. At 90 days, in the total CCTA group vs controls, there were more secondary tests (55 [5%] vs 22 [2%]; P < .001) and revascularizations (13 [1%] vs 1 [0.1%]; P < .001). One cardiovascular event occurred in each group over 18 months. CONCLUSIONS An abnormal screening CCTA result was predictive of increased aspirin and statin use at 90 days and 18 months, although medication use lessened over time. Screening CCTA was associated with increased invasive testing, without any difference in events at 18 months. Screening CCTA should not be considered a justifiable test at this time.

Non-high-density lipoprotein cholesterol, guideline targets, and population percentiles for secondary prevention in 1.3 million adults: The VLDL-2 study (very large database of lipids)

OBJECTIVES This study sought to examine patient-level discordance between population percentiles of non-high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). BACKGROUND Non-HDL-C is an alternative to LDL-C for risk stratification and lipid-lowering therapy. The justification for the present guideline-based non-HDL-C cutpoints of 30 mg/dl higher than the LDL-C cutpoints remains largely untested. METHODS We assigned population percentiles to non-HDL-C and Friedewald-estimated LDL-C values of 1,310,440 U.S. adults with triglyceride levels <400 mg/dl who underwent lipid testing by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. RESULTS LDL-C cutpoints of 70, 100, 130, 160, and 190 mg/dl were in the same population percentiles as non-HDL-C values of 93, 125, 157, 190, and 223 mg/dl, respectively. Non-HDL-C values reclassified a significant proportion of patients within or to a higher treatment category compared with Friedewald LDL-C values, especially at LDL-C levels in the treatment range of high-risk patients and at triglyceride levels ≥150 mg/dl. Of patients with LDL-C levels <70 mg/dl, 15% had a non-HDL-C level ≥ 100 mg/dl (guideline-based cutpoint) and 25% had a non-HDL-C level ≥ 93 mg/dl (percentile-based cutpoint); if triglyceride levels were 150 to 199 mg/dl concurrently, these values were 22% and 50%, respectively. CONCLUSIONS There is significant patient-level discordance between non-HDL-C and LDL-C percentiles at lower LDL-C and higher triglyceride levels, which has implications for the treatment of high-risk patients. Current non-HDL-C cutpoints for high-risk patients may need to be lowered to match percentiles of LDL-C cutpoints. Relatively small absolute reductions in non-HDL-C cutpoints result in substantial reclassification of patients to higher treatment categories with potential implications for risk assessment and treatment.

Risk score overestimation: the impact of individual cardiovascular risk factors and preventive therapies on the performance of the American Heart Association-American College of Cardiology-Atherosclerotic Cardiovascular Disease risk score in a modern multi-ethnic cohort.

Aims To evaluate the 2013 American Heart Association (AHA)-American College of Cardiology (ACC)-Atherosclerotic Cardiovascular Disease (ASCVD) risk score among four different race/ethnic groups and to ascertain which factors are most associated with risk overestimation by the AHA-ACC-ASCVD score. Methods and results The Multi-Ethnic Study of Atherosclerosis (MESA), a prospective community-based cohort, was used to examine calibration and discrimination of the AHA-ACC-ASCVD risk score in 6441 White, Black, Chinese, and Hispanic Americans (aged 45-79 years and free of known ASCVD at baseline). Using univariable and multivariable absolute risk regression, we modelled the impact of individual risk factors on the discordance between observed and predicted 10-year ASCVD risk. Overestimation was observed in all race/ethnic groups in MESA and was highest among Chinese (252% for women and 314% for men) and lowest in White women (72%) and Hispanic men (67%). Higher age, Chinese race/ethnicity (when compared with White), systolic blood pressure (treated and untreated), diabetes, alcohol use, exercise, lipid-lowering medication, and aspirin use were all associated with more risk overestimation, whereas family history was associated with less risk overestimation in a multivariable model (all P < 0.05). Conclusion The AHA-ACC-ASCVD risk score overestimates ASCVD risk among men, women, and all four race/ethnic groups evaluated in a modern American primary prevention cohort. Clinicians treating patients similar to those in MESA, particularly older individuals and those with factors associated with more risk overestimation, may consider interpreting absolute ASCVD risk estimates with caution.