ORIGINAL INVESTIGATION. Application of the Screening for Heart Attack Prevention and Education Task Force Recommendations to an Urban Population

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1 ORIGINAL INVESTIGATION Application of the Screening for Heart Attack Prevention and Education Task Force Recommendations to an Urban Population Observations From the Dallas Heart Study Raphael See, MD; Jason B. Lindsey, MD; Mahesh J. Patel, MD; Colby R. Ayers, MS; Amit Khera, MD, MSc; Darren K. McGuire, MD, MHSc; Scott M. Grundy, MD, PhD; James A. de Lemos, MD Background: The Screening for Heart Attack Prevention and Education () Task Force recommends noninvasive atherosclerosis imaging of all asymptomatic men (aged years) and women (aged years), except those at very low risk, to augment conventional cardiovascular risk assessment algorithms. Methods: Among 2611 participants in the Dallas Heart Study aged 30 to 65 years who underwent computed tomography to measure coronary artery calcification, lowdensity lipoprotein cholesterol (LDL-C) therapeutic targets were calculated using both National Cholesterol Education Program Adult Treatment Panel III (NCEP- ATP III) and algorithms. The proportion of subjects reclassified as being at goal for LDL-C vs not at goal after implementation of the recommendations was determined. Results: More subjects were identified with LDL-C levels greater than or equal to goal based on than on NCEP-ATP III (27.4% vs 21.6%), with 7.0% of individuals reclassified as having unmet LDL-C goals and 1.1% of individuals reclassified as at goal. When more aggressive optional LDL-C goals were implemented, 31.7% had LDL-C levels greater than or equal to goal using recommendations vs 28.1% using NCEP-ATP III recommendations, with 6.3% of subjects reclassified as being not at goal and 2.7% as being at goal. Conclusions: The recommendations resulted in bidirectional reclassification of eligibility for lipidlowering therapy in subjects aged 30 to 65 years. While broad implementation of these recommendations would modestly increase cholesterol-lowering drug use in this age range, the magnitude of the increase depends on whether standard or optional LDL-C goals are targeted. Arch Intern Med. 2008;168(10): Author Affiliations: Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas. APRINCIPAL RATIONALE FOR accurate coronary heart disease (CHD) risk assessment is to determine which patients may warrant intensification of lipid-modifying therapy, as evidenced by the National Cholesterol Education Program Adult Treatment Panel III For editorial comment see page 1027 (NCEP-ATP III) guidelines that use a CHD risk assessment algorithm to assign lowdensity lipoprotein cholesterol (LDL-C) treatment goals. 1 Computed tomographic assessment of coronary artery calcium (CAC) has emerged as a promising noninvasive atherosclerosis imaging modality that independently adds to CHD risk prediction 2-5 and has been endorsed by several professional organizations for use in selected individuals. 6-8 Recently, the Screening for Heart Attack Prevention and Education () Task Force proposed a broader application of atherosclerosis imaging, in which all asymptomatic men (aged years) and women (aged years), except those already defined as at very high or very low risk, would undergo noninvasive imaging to detect subclinical atherosclerosis. 9 The imaging data would serve as the foundation for CHD risk stratification and assignment of LDL-C goals. It is important to note that the Task Force does not represent an official or professional organization and that the recommendations are based on expert opinion. While the authors predict that implementation of these recommendations would substantially increase the population of individuals receiving cholesterollowering drugs, to our knowledge no formal assessment of the consequences of the algorithm applied to a population has yet been reported. 1055

2 Very low risk (LDL-C <160 No No. of RFs (hypertension, age, smoking, family history, low HDL-C) 1 RF Moderate risk (LDL-C <130 DM, prior CVA or MI, or angina Moderately high risk (LDL-C <130 Optional goal (LDL-C <100 To estimate how implementation of the recommendations would influence the proportion of subjects identified as failing to reach their respective LDL-C goals and therefore deserving consideration for cholesterol-lowering therapy, the NCEP-ATP III and risk assessment algorithms were applied to a representative sample of Dallas County, Texas, residents using data from the Dallas Heart Study (DHS). METHODS STUDY POPULATION 2 RFs Calculate Framingham 10-y risk <10% 10%-20% >20% High risk (LDL-C <100 Optional goal (LDL-C <70 Figure 1. National Cholesterol Education Program Adult Treatment Panel III algorithm for determining cardiovascular risk with corresponding low-density lipoprotein cholesterol (LDL-C) therapeutic targets. Numbers other than risk factors (RFs), cholesterol values (to convert to millimoles per liter, multiply by ), and Framingham 10-year risk scores (%) represent the number of individuals at each division of the algorithm. CVA indicates cerebrovascular accident; DM, diabetes mellitus; HDL-C, high density lipoprotein cholesterol; and MI, myocardial infarction. The DHS is a multiethnic, probability-based, population sample consisting of 6101 adult Dallas County subjects between the ages of 18 and 65 years who were enrolled between July 2000 and January The initial cohort underwent a detailed in-home health survey (visit 1), after which 3398 subjects aged 30 to 65 years returned for blood and urine collection (visit 2). Subsequently, 2971 subjects returned for visit 3, which included a detailed clinical examination and electron beam computed tomography (EBCT) measurements of CAC. No significant differences were noted in demographics, medical history, blood pressure, or body mass index among subjects participating in visits 1 and 2. Moreover, laboratory values were similar among those participating in visits 2 and Details of the study design, including collection of medical history, blood pressure, anthropometric measurements, determination of plasma lipid levels, and EBCT scans for the assessment of CAC, have been described previously. 10 The present analyses include data on 2611 subjects with complete clinical and EBCT data who were fasting at the time of phlebotomy. Because a major objective of the DHS was to produce unbiased population estimates of biologic and social variables, sample weights for each subject were constructed based on 2000 US census estimates from Dallas County to reflect selection probability as well as to adjust for between-visit attrition. The DHS protocol was approved by the institutional review board of the University of Texas Southwestern Medical Center, Dallas, and all participants provided written informed consent. STUDY DEFINITIONS Variable definitions have previously been described. 11 Hypertension was defined as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or the use of an antihypertensive medication. Diabetes mellitus was defined by either self-report accompanied by the use of antihyperglycemic medication, a fasting glucose level of 126 mg/dl or higher (to convert glucose to millimoles per liter, multiply by ), or a nonfasting glucose level of 200 mg/dl or higher. Smoking status was categorized as current smoker or former smoker/never smoker. Angina was defined using the Rose angina questionnaire. 12 Two consecutive coronary EBCT scans were performed (GE Imatron C-150XP; Imatron Inc, San Bruno, California), with mean CAC results expressed in Agatston units. 13 ASSIGNMENT OF LDL-C GOALS The subjects were classified into respective CHD risk categories and assigned corresponding LDL-C goals based on the modification of the NCEP-ATP III criteria published in (Figure 1). Subjects with angina, diabetes mellitus, or history of myocardial infarction (MI) or stroke were assigned a priori to the highest risk status with an LDL-C goal of less than 100 mg/dl (to convert cholesterol to millimoles per liter, multiply by ) and an optional goal of less than 70 mg/dl. Subjects with 2 or more traditional risk factors (smoking, hypertension, high-density lipoprotein cholesterol 40 mg/dl, family history of premature MI, and age 45 years for men and 55 years for women) underwent calculation of the Framingham Risk Score, 6,14 with LDL-C treatment goals assigned based on 10-year estimates of the risk for fatal or nonfatal CHD: an LDL-C level of less than 130 mg/dl for subjects at moderate risk ( 2 risk factors and estimated 10-year CHD event risk 10%); an LDL-C level of less than 130 mg/dl with an optional goal of less than 100 mg/dl for subjects at moderately high risk (10-year risk, 10%-20%); and an LDL-C level of less than 100 mg/dl with an optional goal of less than 70 mg/dl for subjects at high risk (10-year risk, 20%). Individuals with less than 2 risk factors were considered to be at lower risk (10- year risk, 10%) and were assigned an LDL-C goal of less than 160 mg/dl. For subjects taking statins (n=166), statin-naive lipid values were estimated assuming a uniform 40% reduction in LDL-C and a 30% reduction in total cholesterol 15,16 and were used for all assessments. Classification of subjects according to LDL-C treatment goals was also determined using the strategy 9 (Figure 2). Subjects with angina, prior MI, or stroke were assigned a priori to the highest risk status with an LDL-C goal of less than 70 mg/dl. Men younger than 45 years and women younger than 55 years were excluded from further assessment by and therefore maintained the LDL-C goal assignments established by NCEP-ATP III. Individuals at or above these age cutoffs with no -defined risk factors (diabetes, blood pressure 120/80 mm Hg, total cholesterol 200 mg/dl, current smoking, family history of premature MI, and metabolic syndrome) were considered to be at low risk (LDL-C goal 160. For individuals at or above these age cutoffs with 1 risk factor or more, CAC scores were used to assign risk categories with corresponding LDL-C goals as outlined by. Percentile cut points of CAC specific for age and sex were derived from the overall DHS cohort. According to the algorithm, any CAC score of 1 or more Agatston units was considered positive. In contrast to NCEP-ATP III criteria that equate diabetes 1056

3 Prior MI, angina, PVD, CVA, or age >75 y No Age <45 y (men)/<55 y (women) 739 No 1 Risk factors (DM, BP >120/80 mm Hg, TC >200 mg/dl, smoking, family history, metabolic syndrome) 1593 Use NCEP-ATP III guidelines No CAC = 0 EBCT DM CAC 1 No CAC <100 and <75th percentile CAC or >75th percentile CAC >100 and >90th percentile or >400 Very low risk (LDL-C <160 Moderate risk (LDL-C <130 Moderately high risk (LDL-C <130 Optional goal (LDL-C <100 High risk (LDL-C <100 Optional goal (LDL-C <70 Very high risk (LDL-C <70 Figure 2. First Screening for Heart Attack Prevention and Education algorithm for determining cardiovascular risk with corresponding low-density lipoprotein cholesterol (LDL-C) therapeutic targets. Numbers other than coronary artery calcium (CAC) scores and blood pressure (BP) and cholesterol (to convert to millimoles per liter, multiply by ) values represent the number of individuals at each division of the algorithm. CVA indicates cerebrovascular accident; DM, diabetes mellitus; EBCT, electron beam computed tomography; MI, myocardial infarction; NCEP-ATP III, National Cholesterol Education Program Adult Treatment Panel III; PVD, peripheral vascular disease; and TC, total cholesterol. with CHD (and CHD cholesterol targets), the algorithm considers diabetes a CHD equivalent only when atherosclerosis is documented by imaging; otherwise, diabetes is considered similar to the other risk factors. DETERMINATION OF LDL-C AT GOAL STATUS The proportions of subjects in the study cohort with LDL-C goals of less than 160, 130, 100, and 70 mg/dl were determined before and after implementation of the recommendations. The sample weight adjusted proportion of subjects considered at goal or not at goal for LDL-C was determined before and after implementation of the recommendations. Using NCEP-ATP III criteria as the standard determination for LDL-C goals, the proportion of study participants in whom the LDL-C goals would be altered by implementation of the recommendations was calculated. Because both NCEP-ATP III and include optional LDL-C goals in selected subgroups, we performed analyses using both standard LDL-C goals and after applying all optional LDL-C goals. STATISTICAL ANALYSIS To estimate the impact of application of these risk-assessment strategies on the Dallas County population, all proportions and statistical analyses were adjusted for sample weights. 10,11 Results are reported as numerical frequencies and sample weight adjusted population proportions. These proportions are thus reflective of the Dallas County population rather than of the study cohort. To evaluate agreement between the NCEP-ATP III and algorithms in identifying proportions of subjects not at goal for LDL-C, an unweighted McNemar test was used. Sensitivity analyses were performed by restricting the age range of the screened population and by varying the threshold to define a positive CAC scan. Additional sensitivity analyses were performed including and excluding those subjects taking statins at study entry. Statistical analyses were performed using SAS software (Version 9.1; SAS Institute Inc, Cary, North Carolina). RESULTS The study comprised 2611 individuals with a mean (SD) age of 44 (16) years, including 1451 women (55.5%) and 1266 (48.5%) nonwhite participants. Baseline characteristics stratified by sex are presented in Table 1. Ageand sex-specific percentile cut points of CAC scores within the overall DHS cohort are summarized in Table 2.Application of the recommendations identified 685 participants (26.2%) who were eligible for noninvasive atherosclerosis imaging. LDL-C GOAL ASSIGNMENT When standard (nonoptional) LDL-C goals were applied, no patients had an LDL-C goal of less than 70 mg/dl using the NCEP-ATP III guidelines, compared with 12.4% using the strategy. When the optional LDL-C goals were used, application of the algorithm resulted in increases in the proportions of the 3 lowest LDL-C goal categories (15%-17% for LDL-C 70 mg/dl; 6%-10% for LDL-C 100 mg/dl; and 15%-18% for LDL-C 130 mg/ dl) and a concomitant decrease in the proportion of subjects assigned to an LDL-C goal of less than 160 mg/dl (63%-56%) (Figure 3). BIDIRECTIONAL RECLASSIFICATION OF LDL-C GOALS AND ELIGIBILITY FOR LIPID-LOWERING THERAPY Using standard LDL-C goals, 198 participants (7.0%) were reclassified as not at goal and 47 (1.1%) were reclassified as at goal after implementation of the algorithm, resulting in an overall discordance of 8.1 be- 1057

4 Table 1. Baseline Characteristics of the Total Cohort Stratified by Sex a Variable Women (n=1451) Men (n=1160) Total (N=2611) Age, mean (SEM), y 44.7 (0.4) 43.6 (0.5) 44.1 (0.3) Race White Black Hispanic Other Prior MI Prior CVA Diabetes Hypertension Current smoker Metabolic syndrome Total cholesterol, mean (1.7) (1.8) (1.2) (SEM), mg/dl HDL-C, mean (SEM), 53.5 (0.6) 43.4 (0.4) 48.5 (0.4) mg/dl LDL-C, mean (SEM), mg/dl (1.5) (1.6) (1.1) Abbreviations: CVA, cerebrovascular accident; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. SI conversion factor: To convert cholesterol values to millimoles per liter, multiply by a Values are expressed as sample weight adjusted percentages unless otherwise indicated. Table 2. Age- and Sex-Specific Percentile Cut Points for Coronary Artery Calcium Scores Within the Dallas Heart Study Cohort Percentile for Women Age, y 75th 90th 75th 90th NA NA NA NA Abbreviation: NA, not applicable. Percentile for Men tween the 2 strategies. Using optional LDL-C goals, a total of 250 individuals (9.0%) were reclassified with : 162 (6.3%) were reclassified as not at goal and 88 (2.7%) were reclassified as at goal. As a result of the reclassification of LDL-C goals in both directions, application of the recommendations modestly increased the proportion of the population not meeting their individual LDL-C goal and thus potentially eligible for lipid-lowering therapy. Using standard goals, 627 individuals (21.6%) were identified as not meeting their LDL-C goal using the NCEP-ATP III algorithm compared with 778 (27.4%) using the algorithm (absolute difference, 5.9%; relative difference, 27.2%; P.001 by McNemar test). Using optional LDL-C goals, 813 individuals (28.1%) were identified as not at goal using NCEP-ATP III compared with 887 (31.7%) using the algorithm (P.001). This corresponds to a 3.6% absolute (12.8% relative) increase in 15.3% 0% 21.5% % 15.2% 15.3% NCEP-ATP III NCEP-ATP III Standard LDL-C Goals Optional LDL-C Goals 63.2% 4.1% % 17.6% 12.4% 16.5% 56.1% Cholesterol <160 mg/dl <130 mg/dl <100 mg/dl <70 mg/dl 56.1% Figure 3. Low-density lipoprotein cholesterol (LDL-C) goals within the Dallas Heart Study cohort. The figure shows LDL-C therapeutic targets for the entire study cohort (N=2611) using National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines and Screening for Heart Attack Prevention and Education () recommendations. To convert cholesterol to millimoles per liter, multiply by the proportion of subjects not at goal when using optional LDL-C targets (Table 3). When sensitivity analyses excluding subjects taking statins at study entry (n=166) were performed, all results were qualitatively similar (data not shown). Moreover, the results were similar in race-stratified analyses (Table 3). Finally, sensitivity analyses were performed substituting age-, sex-, and race-specific CAC percentile cut points reported from the Multi-Ethnic Study of Atherosclerosis. 17 Using Multi-Ethnic Study of Atherosclerosis cut points, 1.1% of the participants were reclassified to at goal and 8.5% to not at goal with standard LDL-C goals, and 2.7% to at goal and 6.7% to not at goal with optional LDL-C goals. INFLUENCE OF AGE AND DIABETES STATUS When individuals below the recommended age cut points for atherosclerosis imaging ( 45 years for women and 55 years for men) in were excluded, the algorithm had a greater impact on reclassification and eligibility for lipid lowering. The overall discordance in this subgroup between NCEP-ATP III and was 19.0% using nonoptional LDL-C goals (18.3% reclassified as not at goal and 0.6% reclassified as at goal; P.001 by McNemar test); the overall discordance using optional goals was 22.3% (20.0% reclassified as not at goal and 2.3% reclassified as at goal; P.001 by McNemar test) (Table 3). To further examine the effect of age on reclassification of LDL-C goal status, the analyses were stratified by 10-year age groups. The proportion of individuals not meeting LDL-C goals increased in the 55- to 65-yearold stratum with the algorithm, while it decreased or remained qualitatively unchanged in the younger strata whether or not optional LDL-C goals were applied (Table 3). These age-stratified analyses were similar when further stratified by sex (data not shown). 1058

5 Table 3. Age-Stratified Proportions With 95% Confidence Intervals (CIs) of the Cohort Classified as Being at Goal and Not at Goal for Low-Density Lipoprotein Cholesterol (LDL-C) by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and Screening for Heart Attack Prevention and Education () Recommendations a Variable Failure to Meet NCEP-ATP III LDL-C Goal % (95% CI) Net Change in Failure to Meet LDL-C Goal Changed to at Goal With Changed to Not at Goal With Subjects Not Meeting LDL-C Goal With Relative Change in Subjects Not Meeting LDL-C Goal With Standard LDL-C goals Overall (N=2611) 21.6 ( ) 27.4 ( ) 1.1 ( ) 7.0 ( ) Age, y 45 (n=1319) 12.8 ( ) 13.6 ( ) 1.0 ( ) 1.8 ( ) (n=816) 25.8 ( ) 33.4 ( ) 1.8 ( ) 9.4 ( ) (n=476) 42.6 ( ) 61.5 ( ) 0.3 (0-0.5) 19.2 ( ) Men 45, women 55 (n=864) 37.0 ( ) 54.7 ( ) 0.6 ( ) 18.3 ( ) Diabetic subjects (n=277) 60.7 ( ) 64.2 ( ) 12.0 ( ) 15.5 ( ) Black subjects (n=1262) 24.8 ( ) 29.9 ( ) 1.6 ( ) 6.7 ( ) White subjects (n=833) 21.1 ( ) 27.4 ( ) 0.9 ( ) 7.2 ( ) Optional LDL-C goals Overall (N=2611) 28.1 ( ) 31.7 ( ) 2.7 ( ) 6.3 ( ) Age, y 45 (n=1319) 16.9 ( ) 14.2 ( ) 2.7 ( ) 0.0 (0-0) (n=816) 34.7 ( ) 42.0 ( ) 3.9 ( ) 11.2 ( ) (n=476) 53.0 ( ) 70.5 ( ) 0.5 ( ) 18.0 ( ) Men 45, women 55 (n=864) 49.6 ( ) 67.3 ( ) 2.3 ( ) 20.0 ( ) Diabetic subjects (n=277) 90.5 ( ) 64.4 ( ) 26.1 ( ) 0.0 (0-0) Black subjects (n=1262) 31.4 ( ) 33.4 ( ) 2.4 ( ) 4.4 ( ) White subjects (n=833) 26.6 ( ) 33.0 ( ) 2.3 ( ) 8.6 ( ) a All proportions adjusted for sample weights. Table 4. The Impact of Differing Thresholds for Defining Coronary Artery Calcium (CAC) Elevation on Low-Density Lipoprotein Cholesterol (LDL-C) Goal Reclassification Using Screening for Heart Attack Prevention and Education () Recommendations in the Overall Population a CAC Threshold, Agatston Units Failure to Meet NCEP-ATP III LDL-C Goal Failure to Meet LDL-C Goal % (95% CI) Changed to at Goal With Changed to Not at Goal With Net Change in Subjects Not Meeting LDL-C Goal With Relative Change in Subjects Not Meeting LDL-C Goal With ( ) 27.4 ( ) 1.1 ( ) 7.0 ( ) ( ) 26.9 ( ) 1.2 ( ) 6.6 ( ) ( ) 25.8 ( ) 1.5 ( ) 5.7 ( ) Abbreviation: NCEP-ATP III, National Cholesterol Education Program Adult Treatment Panel III. a Standard LDL-C goals were used for both algorithms. The overall population comprised 2611 subjects. Compared with the overall cohort, the participants with diabetes were much more likely to be downgraded to at goal status with (Table 3). Diabetic subjects (n=277) accounted for 87% (41 of 47) of the individuals who were downgraded to at goal status by when standard LDL-C goals were used and for 83% (73 of 88) when optional LDL-C goals were used. CAC THRESHOLDS AND THE EFFICIENCY OF CAC SCANNING To examine the effect of altering the threshold to define a positive EBCT scan, CAC scores of 1 or more, 10 or more, and 100 or more Agatston units were evaluated (Table 4). While the use of higher CAC thresholds led to fewer subjects identified by as not meeting their LDL-C goal, the difference between a threshold of 10 or higher and a threshold of 1 or higher was modest (25.0% [n=763] vs 27.2% [n=778]). Finally, the efficiency of CAC scanning according to the recommendations was assessed by determining the number needed to scan (NNS) to reclassify 1 participant as meeting or not meeting his or her individual LDL-C goal. These analyses were restricted to subjects who were specifically recommended for imaging by (n=685). The NNS ranged from 4.1 to 7.8 and varied modestly depending on age, sex, and threshold used to define a positive scan (Table 5). COMMENT In a probability-based population sample of subjects aged 30 to 65 years, implementation of the Task Force 1059

6 Table 5. The Number Needed to Scan (NNS) Using Screening for Heart Attack Prevention and Education () Recommendations to Reclassify a Single Individual s Low-Density Lipoprotein Cholesterol (LDL-C) Goal Status, Stratified by Age, Sex, and Differing Coronary Artery Calcium (CAC) Thresholds to Identify Atherosclerosis a CAC Threshold, Agatston Units Women, Age Range, y (n=242) Men, Age Range, y (n=295) (n=148) Men and Women Combined, Age, y Men 45, Women 55 (N=685) a Only subjects eligible for imaging (ie, meeting age criteria and not already defined as at very low or very high risk) by were included in this analysis. Standard LDL-C goals are used for both algorithms. All NNS values are adjusted for sample weights. recommendations compared with the updated NCEP- ATP III guidelines resulted in the reclassification of LDL-C goals in 8.1% to 9.0% of subjects. Because subjects were reclassified into both higher- and lower-risk categories, the proportion of participants identified as not meeting their individual LDL-C goal and thus potentially eligible for lipid-lowering intervention increased more modestly than previously predicted. 9 The Task Force recommends the relatively liberal use of noninvasive atherosclerosis imaging for asymptomatic individuals, excluding only those at the very lowest and very highest of risk categories. The authors project that application of this strategy in the entire population would result in as much as a 50% to 65% relative increase in the use of cholesterol-lowering drugs in the United States. 9 In contrast, in our probability-based urban US population sample of 30- to 65-year-old adults, application of the recommendations compared with the NCEP-ATP-III guidelines would result in a 27.2% relative (5.9% absolute) increase in the proportion of subjects with indications for the initiation of lipid-lowering therapy. If optional LDL-C goals are used for both and NCEP-ATP III, the differences would be more modest, with a 12.8% relative (3.6% absolute) increase in subjects eligible for lipid-lowering therapy. Given recent clinical trial evidence to support the optional NCEP-ATP III goals, 18,19 we believe that estimates based on optional LDL-C goals better reflect the future implications of implementation of the recommendations. There are several possible explanations for the discrepancies between the predictions of the Task Force and the findings of the present study. First, the present study used a relatively young population, with a mean age of 44 years, near the earliest age at which men would be considered for imaging by guidelines and well below the age threshold for imaging in women. When the analyses were restricted to the subset of individuals meeting the age criteria specified by the guidelines ( 45 years in men and 55 years in women), a 35.7% to 48.0% relative increase in the proportion of individuals potentially eligible for lipid-lowering drug therapy was noted, nearer to the increase projected by the authors. 9 Analyses stratified by age showed the greatest net increase in potential candidates for drug therapy among individuals 55 to 65 years of age. Inclusion of persons older than 75 years, who are universally classified as very high risk in the recommendations, would substantially increase the number of potential candidates for lipid-lowering therapy. This aspect of the recommendations is not addressed by the present analyses. Another factor contributing to the observed discordance between the projected and the observed influence of the strategy is the different manner in which diabetes is handled in the NCEP-ATP III and the algorithms. While all individuals with diabetes are classified in high-risk categories by the modified NCEP-ATP III guidelines, the Task Force does not consider diabetes to be a high-risk state unless detectable atherosclerosis is documented by imaging. Subjects with diabetes who are either younger than 45 years or 45 years or older but with no detectable CAC are reclassified into a less stringent LDL-C goal category by the algorithm. The presence of diabetes accounts for most of the downward reclassification to at-goal status observed in the present study. Indeed, we observed that 83% to 87% of the individuals who were downgraded to at-goal status by were diabetic subjects. The downgrading of risk in individuals on the basis of atherosclerosis imaging in the present study is of interest as it reflects a possibly unanticipated effect of applying the recommendations, potentially reducing the intensity of CHD risk modification in younger individuals and in individuals with negative atherosclerosis imaging results (including diabetic subjects). Because CAC is a highly specific indicator of coronary atherosclerosis and is associated with increased CHD risk, 3,20 it is reasonable to speculate that subjects reclassified as eligible for drug therapy on the basis of detectable CAC are appropriately reclassified into a higher-risk category. In contrast, fewer data are available regarding the interpretation and therapeutic ramifications of negative atherosclerosis imaging results in subjects who are otherwise perceived to be at an increased CHD risk based on the presence of multiple traditional risk factors or diabetes. Before the full implications of the algorithm can be predicted, it will be necessary to determine rates of adverse CHD events during long-term follow-up among such individuals. The algorithm defines the threshold for a positive EBCT scan as a CAC score of 1 or more Agatston units. However, controversy exists over what CAC threshold should be used to define atherosclerosis. At CAC scores of less than 10 Agatston units, high interscan variability is observed and reduced concordance is seen between multiple scans in the same individual. These problems are magnified in obese subjects. 21 Therefore, the lower threshold recommended by the Task Force may be more likely to result in false-positive assignments of atherosclerosis, resulting in misclassification of individuals as not achieving their LDL-C goal. When we compared a more conservative CAC threshold of 10 or more Agatston units with a threshold of 1 or more 1060

7 Agatston units to define atherosclerosis, the relative increase in individuals potentially eligible for lipidlowering therapy changed only from 27.2% to 25.0%. However, when the CAC threshold was raised to 100 or more Agatston units, the relative increase fell to 19.8%. These findings indicate that the implications of the recommendations are sensitive not only to age but also to the CAC thresholds used to define atherosclerosis. Between CAC thresholds of 1 and 10, however, the influence of the CAC threshold is modest. While cost analyses of as public policy have recently been reported, the cost data were modeled from predicted increases in the proportion of individuals exceeding their LDL-C goal 9,22 rather than from actual patient data. To the best of our knowledge, the present results represent the first application of the screening strategy to a population cohort. Although we did not perform cost analyses in the DHS, we did evaluate the efficiency of CAC scanning as recommended by. The NNS to reclassify 1 individual as newly eligible (or no longer eligible) for lipid-lowering therapy averaged 5.2. Of interest, efficiency was only modestly sensitive to age, sex, and CAC threshold: the NNS ranged from 4.1 to 7.8 as these parameters were varied. The relative efficiency of CAC scanning in suggests that costs of lipid-lowering therapies may be more important than costs of imaging in determining the overall cost implications of the recommendations. Several limitations to the present study should be noted. First, the relatively young age of the study population may be a potential source of bias, as younger populations are less likely to have a high atherosclerosis burden. Therefore, the present findings cannot be generalized to older subjects, and estimates of reclassification apply only to subjects aged 30 to 65 years. In the algorithm, individuals older than 75 years are assigned, regardless of risk factor status, to the very-high-risk category with an LDL-C goal of less than 70 mg/dl; therefore, inclusion of subjects older than 75 years would result in more individuals requiring lipid-lowering therapy. Also, we did not systematically assess peripheral vascular disease, a CHD disease equivalent in both NCEP- ATP III and. Similarly, while the recommendations also consider left ventricular hypertrophy as a high-risk disease state, this was not considered in our analyses. Cardiovascular outcomes were not collected in our cross-sectional study; therefore, no inferences can be made regarding prognostic utility or cost-effectiveness. However, this analysis provides a novel and unbiased evaluation of the magnitude of LDL-C goal reassignment in a specific age range and the potential resource use associated with such reclassification. These data should be useful to researchers and policy makers interested in fully understanding the potential impact of the Task Force recommendations. Finally, the goals for cholesterol-lowering therapy set in this study and in are arbitrary for the purposes of comparison. The NCEP-ATP III guidelines specifically allow clinical judgment to be used both for goal setting and for initiation of drug therapy. Application of recommendations in practice presumably would make the same allowances. In conclusion, in a population-based cohort consisting of subjects aged 30 to 65 years who underwent cardiovascular risk assessment using the NCEP-ATP III guidelines, application of the Task Force recommendations modestly increased the proportion of the population who were not meeting LDL-C goals and who were thus potentially eligible for lipid-lowering therapy. The implications of were magnified in older subjects, particularly in those who met the criteria for noninvasive imaging, and lessened when optional (more aggressive) LDL-C goals were used. The inclusion of older individuals ( 65 years) would result in a substantially larger increase in the proportion of individuals eligible to receive lipid-lowering therapy and should be evaluated in other population-based cohorts. Further investigation of the public health and economic impact of these findings is warranted. Accepted for Publication: November 25, Correspondence: James A. de Lemos, MD, University of Texas Southwestern Medical Center, 5909 Harry Hines Blvd, Ste HA 9.108, Dallas, TX (james.delemos@utsouthwestern.edu). Author Contributions: Drs See and Lindsey contributed equally to the present study. Dr de Lemos had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: See, Lindsey, Patel, Khera, McGuire, Grundy, and de Lemos. Acquisition of data: McGuire, Grundy, and de Lemos. Analysis and interpretation of data: See, Lindsey, Patel, Ayers, Khera, McGuire, Grundy, and de Lemos. Drafting of the manuscript: See, Lindsey, Patel, Ayers, Khera, McGuire, and Grundy. Critical revision of the manuscript for important intellectual content: See, Lindsey, Patel, Ayers, Khera, McGuire, Grundy, and de Lemos. Statistical analysis: Patel, Ayers, Khera, and de Lemos. Obtained funding: de Lemos. Administrative, technical, and material support: Lindsey, McGuire, Grundy, and de Lemos. Study supervision: Khera, McGuire, and de Lemos. Financial Disclosure: Drs Khera and McGuire have received lecture honoraria from Pfizer. Dr Grundy has received consulting fees from Pfizer, Merck/Schering- Plough, and AstraZeneca. Dr de Lemos has received lecture honoraria from Pfizer and Merck/Schering- Plough and consulting fees from Pfizer. Funding/Support: The DHS was funded by the Donald W. Reynolds Foundation and supported in part by US Public Health Service General Clinical Research Center grant M01-RR00633 from National Institutes of Health/ National Center for Research Resources Clinical Research. REFERENCES 1. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2): Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol. 2005;46 (1):

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