Prevention 2014: Cardiovascular Risk Assessment: Guidelines and Novel Approaches

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Mahesh J. Patel, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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  • Tim russertJOHN CANDY & Michael clarkeduncan
  • Figure 1.The Incidence of Sudden Death in Specific Populations and the Annual Numbers of Sudden Deaths in Those Populations.Most of the deaths occur in the larger, lower-risk subgroups. Modified from Myerburg et al.10with the permission of the publisher.Huikuri nejm2001
  • Figure 1.The Incidence of Sudden Death in Specific Populations and the Annual Numbers of Sudden Deaths in Those Populations.Most of the deaths occur in the larger, lower-risk subgroups. Modified from Myerburg et al.10with the permission of the publisher.Huikuri nejm2001
  • J Am Coll Cardiol. 2004 May 19;43(10):1791-6.The distribution of 10-Year risk for coronary heart disease among US adults: findings from the National Health and Nutrition Examination Survey III.Ford ES, Giles WH, Mokdad AH.SourceDivision of Adult and Community Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA. eford@cdc.govAbstractOBJECTIVES: We sought to establish the distribution of the 10-year risk for coronary heart disease (CHD) among U.S. adults.BACKGROUND: Risk assessment for CHD was developed to provide clinicians with a tool to estimate the absolute risk of developing CHD. More recently, risk assessment is increasingly being incorporated into guidelines for diagnostic testing and treatment. Yet, little is known about the 10-year risk distribution for CHD among adults in the U.S. based on these risk assessment tools.METHODS: We applied the risk prediction algorithm used by the National Cholesterol Education Program Adult Treatment Panel III guidelines to data from 13769 participants (representing 157366716 U.S. adults) age 20 to 79 years in the Third National Health and Nutrition Examination Survey (1988 to 1994).RESULTS: Among participants without self-reported CHD (heart attack and angina pectoris), stroke, peripheral vascular disease, and diabetes, 81.7% (140 million adults) had a 10-year risk for CHD of <10%, 15.5% (23 million adults) of 10% to 20%, and 2.9% (4 million adults) of >20%. The proportion of the participants with a 10-year risk for CHD of >20% increased with advancing age and was higher among men than among women but varied little with race or ethnicity.CONCLUSIONS: Our results help to define the distribution of 10-year risk for CHD among U.S. adults.
  • Ridker Lancet 2013
  • Observed and Predicted Atherosclerotic Cardiovascular Disease Risk Among REGARDS ParticipantsPredicted risk determined using the Pooled Cohort equations. LDL-C indicates low-density lipoprotein cholesterol; REGARDS, Reasons for Geographic and Racial Differences in Stroke.aThe range of predicted risk for each decile is provided in eTable 3 in Supplement.bThe range of predicted risk for each decile in the REGARDS population with Medicare insurance coverage is provided in eTable 6 in Supplement.cMedicare data are not presented due to a small sample size.

    JAMA. 2014 Apr 9;311(14):1406-15. doi: 10.1001/jama.2014.2630.Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations.Muntner P1, Colantonio LD2, Cushman M3, Goff DC Jr4, Howard G5, Howard VJ2, Kissela B6, Levitan EB2, Lloyd-Jones DM7, Safford MM8.Author information AbstractIMPORTANCE: The American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort risk equations were developed to estimate atherosclerotic cardiovascular disease (CVD) risk and guide statin initiation.OBJECTIVE: To assess calibration and discrimination of the Pooled Cohort risk equations in a contemporary US population.DESIGN, SETTING, AND PARTICIPANTS: Adults aged 45 to 79 years enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between January 2003 and October 2007 and followed up through December 2010. We studied participants for whom atherosclerotic CVD risk may trigger a discussion of statin initiation (those without clinical atherosclerotic CVD or diabetes, low-density lipoprotein cholesterol level between 70 and 189 mg/dL, and not taking statins; n = 10,997).MAIN OUTCOMES AND MEASURES: Predicted risk and observed adjudicated atherosclerotic CVD incidence (nonfatal myocardial infarction, coronary heart disease [CHD] death, nonfatal or fatal stroke) at 5 years because REGARDS participants have not been followed up for 10 years. Additional analyses, limited to Medicare beneficiaries (n = 3333), added atherosclerotic CVD events identified in Medicare claims data.RESULTS: There were 338 adjudicated events (192 CHD events, 146 strokes). The observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a 10-year predicted atherosclerotic CVD risk of less than 5% was 1.9 (95% CI, 1.3-2.7) and 1.9, respectively, risk of 5% to less than 7.5% was 4.8 (95% CI, 3.4-6.7) and 4.8, risk of 7.5% to less than 10% was 6.1 (95% CI, 4.4-8.6) and 6.9, and risk of 10% or greater was 12.0 (95% CI, 10.6-13.6) and 15.1 (Hosmer-Lemeshow χ2 = 19.9, P = .01). The C index was 0.72 (95% CI, 0.70-0.75). There were 234 atherosclerotic CVD events (120 CHD events, 114 strokes) among Medicare-linked participants and the observed and predicted 5-year atherosclerotic CVD incidence per 1000 person-years for participants with a predicted risk of less than 7.5% was 5.3 (95% CI, 2.8-10.1) and 4.0, respectively, risk of 7.5% to less than 10% was 7.9 (95% CI, 4.6-13.5) and 6.4, and risk of 10% or greater was 17.4 (95% CI, 15.3-19.8) and 16.4 (Hosmer-Lemeshow χ2 = 5.4, P = .71). The C index was 0.67 (95% CI, 0.64-0.71).CONCLUSIONS AND RELEVANCE: In this cohort of US adults for whom statin initiation is considered based on the ACC/AHA Pooled Cohort risk equations, observed and predicted 5-year atherosclerotic CVD risks were similar, indicating that these risk equations were well calibrated in the population for which they were designed to be used, and demonstrated moderate to good discrimination.
  • Figure 2. Near- and Long-Term Survival From 2 EBT Centers: Nashville, Tennessee, and Los Angeles, CaliforniaComparison of 5-year mortality rates in 2 different cohorts. The results are quite consistent across different study groups (chi-square = 1,503, p < 0.0001, interaction p < 0.0001). CAC = coronary artery calcium; EBT = electron beam tomography.J Am Coll Cardiol. 2007 May 8;49(18):1860-70. Epub 2007 Apr 20.Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.Budoff MJ, Shaw LJ, Liu ST, Weinstein SR, Mosler TP, Tseng PH, Flores FR, Callister TQ, Raggi P, Berman DS.SourceHarbor-UCLA Los Angeles Biomedical Research Institute, Torrance, California 90502, USA. mbudoff@labiomed.orgAbstractOBJECTIVES: The purpose of this study was to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography in asymptomatic patients for the prediction of all-cause mortality.BACKGROUND: Several smaller studies have documented the efficacy of CAC testing for assessment of cardiovascular risk. Larger studies with longer follow-up will lend strength to the hypothesis that CAC testing will improve outcomes, cost-effectiveness, and safety of primary prevention efforts.METHODS: We used an observational outcome study of a cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores.RESULTS: The frequency of CAC scores was 44%, 14%, 20%, 13%, 6%, and 4% for scores of 0, 1 to 10, 11 to 100, 101 to 400, 401 to 1,000, and >1,000, respectively. During a mean follow-up of 6.8 +/- 3 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors (model chi-square = 2,017, p < 0.0001). The addition of CAC to traditional risk factors increased the concordance index significantly (0.61 for risk factors vs. 0.81 for the CAC score, p < 0.0001). Risk-adjusted relative risk ratios for CAC were 2.2-, 4.5-, 6.4-, 9.2-, 10.4-, and 12.5-fold for scores of 11 to 100, 101 to 299, 300 to 399, 400 to 699, 700 to 999, and >1,000, respectively (p < 0.0001), when compared with a score of 0. Ten-year survival (after adjustment for risk factors, including age) was 99.4% for a CAC score of 0 and worsened to 87.8% for a score of >1,000 (p < 0.0001).CONCLUSIONS: This large observational data series shows that CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.
  • JAMA. 2012 Aug 22;308(8):788-95. doi: 10.1001/jama.2012.9624.Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals.Yeboah J1, McClelland RL, Polonsky TS, Burke GL, Sibley CT, O'Leary D, Carr JJ, Goff DC, Greenland P, Herrington DM.Author information AbstractCONTEXT: Risk markers including coronary artery calcium, carotid intima-media thickness, ankle-brachial index, brachial flow-mediated dilation, high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD) have been reported to improve on the Framingham Risk Score (FRS) for prediction of CHD, but there are no direct comparisons of these markers for risk prediction in a single cohort.OBJECTIVE: We compared improvement in prediction of incident CHD/cardiovascular disease (CVD) of these 6 risk markers within intermediate-risk participants (FRS >5%-<20%) in the Multi-Ethnic Study of Atherosclerosis (MESA).DESIGN, SETTING, AND PARTICIPANTS: Of 6814 MESA participants from 6 US field centers, 1330 were intermediate risk, without diabetes mellitus, and had complete data on all 6 markers. Recruitment spanned July 2000 to September 2002, with follow-up through May 2011. Probability-weighted Cox proportional hazard models were used to estimate hazard ratios (HRs). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement were used to compare incremental contributions of each marker when added to the FRS, plus race/ethnicity.MAIN OUTCOME MEASURES: Incident CHD defined as myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, or CHD death. Incident CVD additionally included stroke or CVD death.RESULTS: After 7.6-year median follow-up (IQR, 7.3-7.8), 94 CHD and 123 CVD events occurred. Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independently associated with incident CHD in multivariable analyses (HR, 2.60 [95% CI, 1.94-3.50]; HR, 0.79 [95% CI, 0.66-0.95]; HR, 1.28 [95% CI, 1.00-1.64]; and HR, 2.18 [95% CI, 1.38-3.42], respectively). Carotid intima-media thickness and brachial flow-mediated dilation were not associated with incident CHD in multivariable analyses (HR, 1.17 [95% CI, 0.95-1.45] and HR, 0.95 [95% CI, 0.78-1.14]). Although addition of the markers individually to the FRS plus race/ethnicity improved AUC, coronary artery calcium afforded the highest increment (0.623 vs 0.784), while brachial flow-mediated dilation had the least (0.623 vs 0.639). For incident CHD, the net reclassification improvement with coronary artery calcium was 0.659, brachial flow-mediated dilation was 0.024, ankle-brachial index was 0.036, carotid intima-media thickness was 0.102, family history was 0.160 and high-sensitivity CRP was 0.079. Similar results were obtained for incident CVD.CONCLUSIONS: Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history were independent predictors of incident CHD/CVD in intermediate-risk individuals. Coronary artery calcium provided superior discrimination and risk reclassification compared with other risk markers.
  • Lifetime Risk of Death from Cardiovascular Disease among Black Men and White Men at 55 Years of Age, According to the Aggregate Burden of Risk Factors and Adjusted for Competing Risks of DeathThe risk-factor profile was considered optimal when a participant had a total cholesterol level of less than 180 mg per deciliter (4.7 mmol per liter) and untreated blood pressure of less than 120 mm Hg systolic and less than 80 mm Hg diastolic, was a nonsmoker, and did not have diabetes. It was considered not to be optimal for nonsmokers without diabetes who had a total cholesterol level of 180 to 199 mg per deciliter or untreated systolic blood pressure of 120 to 139 mm Hg or untreated diastolic blood pressure of 80 to 89 mm Hg. Levels of risk factors were viewed as elevated for nonsmokers without diabetes who had a total cholesterol level of 200 to 239 mg per deciliter (5.17 to 6.18 mmol per liter) or untreated systolic blood pressure of 140 to 159 mm Hg or untreated diastolic blood pressure of 90 to 99 mm Hg. Major risk factors were defined as current smoking, diabetes, treatment for hypercholesterolemia, an untreated total cholesterol level of at least 240 mg per deciliter (6.21 mmol per liter), and treatment for hypertension, untreated systolic blood pressure of at least 160 mm Hg, or untreated diastolic blood pressure of at least 100 mm Hg. The data were derived from the 17 studies in the pooled cohort; data from the Multiple Risk Factor Intervention Trial were not included.N Engl J Med. 2012 Jan 26;366(4):321-9. doi: 10.1056/NEJMoa1012848.Lifetime risks of cardiovascular disease.Berry JD, Dyer A, Cai X, Garside DB, Ning H, Thomas A, Greenland P, Van Horn L, Tracy RP, Lloyd-Jones DM.SourceUniversity of Texas Southwestern Medical Center, Department of Medicine, Division of Cardiology, Dallas, USA.AbstractBACKGROUND: The lifetime risks of cardiovascular disease have not been reported across the age spectrum in black adults and white adults.METHODS: We conducted a meta-analysis at the individual level using data from 18 cohort studies involving a total of 257,384 black men and women and white men and women whose risk factors for cardiovascular disease were measured at the ages of 45, 55, 65, and 75 years. Blood pressure, cholesterol level, smoking status, and diabetes status were used to stratify participants according to risk factors into five mutually exclusive categories. The remaining lifetime risks of cardiovascular events were estimated for participants in each category at each age, with death free of cardiovascular disease treated as a competing event.RESULTS: We observed marked differences in the lifetime risks of cardiovascular disease across risk-factor strata. Among participants who were 55 years of age, those with an optimal risk-factor profile (total cholesterol level, <180 mg per deciliter [4.7 mmol per liter]; blood pressure, <120 mm Hg systolic and 80 mm Hg diastolic; nonsmoking status; and nondiabetic status) had substantially lower risks of death from cardiovascular disease through the age of 80 years than participants with two or more major risk factors (4.7% vs. 29.6% among men, 6.4% vs. 20.5% among women). Those with an optimal risk-factor profile also had lower lifetime risks of fatal coronary heart disease or nonfatal myocardial infarction (3.6% vs. 37.5% among men, <1% vs. 18.3% among women) and fatal or nonfatal stroke (2.3% vs. 8.3% among men, 5.3% vs. 10.7% among women). Similar trends within risk-factor strata were observed among blacks and whites and across diverse birth cohorts.CONCLUSIONS: Differences in risk-factor burden translate into marked differences in the lifetime risk of cardiovascular disease, and these differences are consistent across race and birth cohorts. (Funded by the National Heart, Lung, and Blood Institute.).
  • Figure 2. Near- and Long-Term Survival From 2 EBT Centers: Nashville, Tennessee, and Los Angeles, CaliforniaComparison of 5-year mortality rates in 2 different cohorts. The results are quite consistent across different study groups (chi-square = 1,503, p < 0.0001, interaction p < 0.0001). CAC = coronary artery calcium; EBT = electron beam tomography.J Am Coll Cardiol. 2007 May 8;49(18):1860-70. Epub 2007 Apr 20.Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.Budoff MJ, Shaw LJ, Liu ST, Weinstein SR, Mosler TP, Tseng PH, Flores FR, Callister TQ, Raggi P, Berman DS.SourceHarbor-UCLA Los Angeles Biomedical Research Institute, Torrance, California 90502, USA. mbudoff@labiomed.orgAbstractOBJECTIVES: The purpose of this study was to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography in asymptomatic patients for the prediction of all-cause mortality.BACKGROUND: Several smaller studies have documented the efficacy of CAC testing for assessment of cardiovascular risk. Larger studies with longer follow-up will lend strength to the hypothesis that CAC testing will improve outcomes, cost-effectiveness, and safety of primary prevention efforts.METHODS: We used an observational outcome study of a cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores.RESULTS: The frequency of CAC scores was 44%, 14%, 20%, 13%, 6%, and 4% for scores of 0, 1 to 10, 11 to 100, 101 to 400, 401 to 1,000, and >1,000, respectively. During a mean follow-up of 6.8 +/- 3 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors (model chi-square = 2,017, p < 0.0001). The addition of CAC to traditional risk factors increased the concordance index significantly (0.61 for risk factors vs. 0.81 for the CAC score, p < 0.0001). Risk-adjusted relative risk ratios for CAC were 2.2-, 4.5-, 6.4-, 9.2-, 10.4-, and 12.5-fold for scores of 11 to 100, 101 to 299, 300 to 399, 400 to 699, 700 to 999, and >1,000, respectively (p < 0.0001), when compared with a score of 0. Ten-year survival (after adjustment for risk factors, including age) was 99.4% for a CAC score of 0 and worsened to 87.8% for a score of >1,000 (p < 0.0001).CONCLUSIONS: This large observational data series shows that CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.
  • In evolutionary terms, humans are maladapted to handle LDL-C levels in the rangescurrently considered normal in modern industrial culture. Consuming high amountsof fatty foods, the mean LDL-C level in the United States population was 115 mg/dL in2005 to 2006 in The National Health and Nutrition Examination Survey14 comparedwith approximately 50 mg/dL in native hunter-gatherers, healthy human neonates,free-living primates, and other wild mammals (Fig. 1).7 Unlike modern Americans,these groups are notably free of CVD. Therefore, it seems CVD is a direct byproductof our societal structure and lifestyles that promote LDL-C levels 2-fold, ormore, higher than we were intended to have.
  • Second, those with genetically determined low LDL-C are strongly protected from ASCVD.
  • Second, those with genetically determined low LDL-C are strongly protected from ASCVD.N Engl J Med. 2006 Mar 23;354(12):1264-72.Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.Cohen JC1, Boerwinkle E, Mosley TH Jr, Hobbs HH.Author information AbstractBACKGROUND: A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.METHODS: We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proproteinconvertasesubtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.RESULTS: Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).CONCLUSIONS: These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
  • The initial analysis between LDL-C levels and CHD event rates in the major clinical trials seemed to suggest a linear relationship between cholesterol and coronary events. The AVERT trial, however, brings this direct association into question. In this trial, atorvastatin 80 mg reduced LDL-C levels by 46% to a mean LDL-C of 77 mg/dL. Despite this aggressive lipid-lowering in AVERT, the treatment coronary event rate was 13.4%. This rate is greater than that of CARE in which LDL-C was lowered to 98 mg/dL and LIPID in which LDL-C was lowered 25% more than placebo. Therefore, extremely low LDL-C levels may not produce greater clinical benefit.
  • Atherosclerosis progression varies directly with low-densitylipoprotein (LDL) cholesterol. This regression line indicates that atherosclerosisdoes not progress when LDL is 67 mg/dl or below (18–24). Datafrom randomized placebo-controlled trials using statins for preventingatherosclerosis progression (analysis for Fig. 2) or preventing coronaryheart disease events in primary (analysis for Fig. 3) or secondary (analysisfor Fig. 4) prevention were utilized for computation of the univariateregression lines correlating LDL with outcomes. Regression estimates,model R2, and p values for LDL effect were obtained from the unweightedregression lines. AT atorvastatin; CCAIT Canadian CoronaryAtherosclerosis Intervention Trial; LCAS Lipoprotein and CoronaryAtherosclerosis Study; MAAS Multicentre Anti-Atheroma Study;MARS Monitored Atherosclerosis Regression Study; MLD meanluminal diameter; P placebo; PLAC Pravastatin Limitation ofAtherosclerosis in the Coronary Arteries study; PR pravastatin; REGRESS Regression Growth Evaluation Statin Study; REVERSAL Reversal of Atherosclerosis with Aggressive Lipid Lowering; S statin.
  • J Am Coll Cardiol. 2013 Aug 20;62(8):732-9. doi: 10.1016/j.jacc.2013.01.079. Epub 2013 Mar 21.Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications.Martin SS1, Blaha MJ, Elshazly MB, Brinton EA, Toth PP, McEvoy JW, Joshi PH, Kulkarni KR, Mize PD, Kwiterovich PO, Defilippis AP, Blumenthal RS, Jones SR.Author information AbstractOBJECTIVES: 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.Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.KEYWORDS: Friedewald equation, HDL-C, LDL-C, NHANES, National Health and Nutrition Examination Survey, VAP, VLDL-C, Vertical Auto Profile, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low density lipoprotein cholesterol
  • LDL PARTICLE SIZE AND NUMBER — LDL-cholesterol (LDL-C) does not accurately quantify LDL particles no matter how accurately the analytical techniques. This situation is most notable when the LDL particle size is small, since small LDL particles carry less cholesterol than large LDL particles. For the same amount of LDL-C, the patient with smaller LDL particles may require nearly 70 percent more LDL particles to carry the same amount of cholesterol as the patient with larger LDL particles [16]. There are strong associations between LDL particles and cardiovascular disease, which provide a rationale for advanced lipoprotein testing for LDL subclasses and LDL particle numbers in cardiovascular risk assessment and treatment [17].As an example, among patients with insulin resistance disorders (metabolic syndrome, type 2 diabetes), there is discordance between LDL-cholesterol and LDL particle concentration/apolipoprotein B [18]. This discordance results from LDL remodeling in insulin resistance, which results in a smaller, cholesterol depleted LDL particle. Thus, LDL cholesterol levels do not change with insulin resistance or with the number of metabolic risk factors, whereas the concentration of small LDL particles and total LDL particles increases progressively as the severity of insulin resistance increases and the number of metabolic risk factors increases. On statin therapy, nearly two-thirds of type 2 diabetes patients with LDL cholesterol levels less than 100 mg/dL have excess LDL particles. In patients with type 2 diabetes and LDL cholesterol levels less than 70 mg/dL on statin therapy, 41 percent have excess numbers of LDL particles. A 2009 systematic review (of 24 studies) evaluated the association between cardiovascular outcomes and LDL subfractions or distribution (particle size; density) as well as total LDL particle number [19]. Higher LDL particle number was consistently associated with increased cardiovascular risk, independent of lipid markers. LDL subfractions/size did not add incremental risk prediction beyond that achieved with traditional risk factors.Lipoprotein particle sizes can be measured by special laboratories that use three different analytical techniques. These laboratory methods include nuclear magnetic resonance (NMR) spectroscopy (LipoScience, Inc.), gradient gel electrophoresis (GGE) (Berkeley HeartLab, Inc.), and analytical ultracentrifugation (Atherotech). Lipoprotein particle size is most often reported as an average size that takes into account the contribution of the small, intermediate, and large particles. Unlike the other methods, the NMR LipoProfile reports the total concentration or blood levels of the individual LDL subclasses and then derives the average LDL particle size [20]. In high cardiometabolic risk patients, such as those with diabetes, where the disconnect between LDL-C and LDL-P is greatest, the measurement of LDL-P may be of benefit for improved risk stratification and as a guide to titration/adjustment of lipoprotein modifying therapy [21].NCBISkip to main contentSkip to navigationResourcesHow ToAbout NCBI AccesskeysSign in to NCBIPubMedUS National Library of MedicineNational Institutes of HealthSearch databaseSearch termAdvancedHelpResult FiltersDisplay Settings:AbstractSend to:J Clin Lipidol. 2007 Dec;1(6):583-92. doi: 10.1016/j.jacl.2007.10.001.LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study - Implications for LDL Management.Cromwell WC1, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan RS, Wilson PW, D'Agostino RB.Author information AbstractBACKGROUND: The cholesterol content of LDL particles is variable, causing frequent discrepancies between concentrations of LDL cholesterol and LDL particle number. In managing patients at risk for cardiovascular disease (CVD) to LDL target levels, it is unclear whether LDL cholesterol provides the optimum measure of residual risk and adequacy of LDL lowering treatment.OBJECTIVE: To compare the ability of alternative measures of LDL to provide CVD risk discrimination at relatively low levels consistent with current therapeutic targets.METHODS: Concentrations of LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) were measured chemically and LDL particle number (LDL-P) and VLDL particle number (VLDL-P) were measured by nuclear magnetic resonance (NMR) in 3066 middle-aged white participants (53% women) without CVD in the Framingham Offspring cohort. The main outcome measure was incidence of first CVD event.RESULTS: At baseline, the cholesterol content per LDL particle was negatively associated with triglycerides and positively associated with LDL-C. On follow-up (median 14.8 yrs), 265 men and 266 women experienced a CVD event. In multivariable models adjusting for non-lipid CVD risk factors, LDL-P was related more strongly to future CVD in both sexes than LDL-C or non-HDL-C. Subjects with a low level of LDL-P (<25(th) percentile) had a lower CVD event rate (59 events per 1000 person-years) than those with an equivalently low level of LDL-C or non-HDL-C (81 and 74 events per 1000 person-years, respectively).CONCLUSIONS: In a large community-based sample, LDL-P was a more sensitive indicator of low CVD risk than either LDL-C or non-HDL-C, suggesting a potential clinical role for LDL-P as a goal of LDL management.
  • This graph compares the rates at which CVD events accumulate over time in the concordant and 2 discordant subgroups. Compared to the concordant group, patients with discordantly high LDL-P had higher CVD event rates, while patients with discordantly low LDL-P had lower CVD event rates. Risk therefore tracked with LDL-P when there is disagreement between LDL-C and LDL-P.Characteristics of the high risk group included a mean LDL-C 104 mg/dL, LDL-P 1372 nmol/L, and a high prevalence (54%) of ATP-III defined metabolic syndrome. The low risk group had a higher mean LDL-C (130 mg/dL), but lower LDL-P (1117 nmol/L), and a low prevalence (16%) of metabolic syndrome. The importance of this graph is not that the LDL-P > LDL-C subgroup had higher CVD risk, which would have been anticipated based on the high prevalence of metabolic syndrome traits, but that much of this risk might plausibly be attributable to elevated LDL-P (despite low LDL-C) – suggesting these individuals maybenefit from more aggressive LDL-lowering treatment that might not be considered necessary based on their LDL-C levels. MESA: LDL-P and LDL-C Discordance Relations with Incident CVD Events (n=319J Clin Lipidol. 2011 Mar-Apr;5(2):105-13. doi: 10.1016/j.jacl.2011.02.001.Clinical implications of discordance between low-density lipoprotein cholesterol and particle number.Otvos JD1, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr.Author information AbstractBACKGROUND: The amount of cholesterol per low-density lipoprotein (LDL) particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals.METHODS: LDL-P measured by nuclear magnetic resonance spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort of 6814 persons free of clinical cardiovascular disease (CVD) at entry and followed for CVD events (n = 319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by ≥ 12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, gender, and race.RESULTS: LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR 1.20, 95% CI [CI] 1.08-1.34; and 1.32, 95% CI 1.19-1.47, respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR 1.45, 95% CI 1.19-1.78; LDL-C HR 1.07, 95% CI 0.88-1.30). IMT also tracked with LDL-P rather than LDL-C, ie, adjusted mean IMT of 958, 932, and 917 microm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (P = .002) but not LDL-P (P = .60).CONCLUSIONS: For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.
  • Animal and human studies have identified the long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) as the likely active constituents in fish oil.Observational studies in generally healthy adults and randomized trials in patients with established coronary heart disease (CHD) indicate that modest fish oil consumption (approximately 250 mg/day EPA+DHA) reduces the risk of CHD death and sudden cardiac death with little if any risk. This is of particular importance in patients with established CHD or at high risk for CHD.There is limited evidence that long-term consumption of fish oil may reduce the risk of atherosclerosis and cardiovascular events other than CHD death and sudden cardiac death. (See 'Introduction' above and 'Cardiovascular outcomes' above.)Given the effects on CHD death and sudden cardiac death (see 'CHD death and sudden cardiac death' above):We suggest that most adults without known CHD eat a diet containing at least one to two servings per week of oily fish (Grade 2B). We suggest that most adults who do not consume this much fish take a daily fish oil supplement (Grade 2B).We recommend that patients with known CHD or who are at high risk for CHD be urged to consume at least one to two servings per week of oily fish (Grade 1B). In such patients who are unable or unwilling to consume this much fish, we suggest prescribing a daily fish oil supplement (Grade 2B).Fish consumption in women who are pregnant, nursing, or who may become pregnant are discussed separately. (See "Nutrition in pregnancy", section on 'Fish' and "Maternal nutrition during lactation", section on 'Fish intake'.)Average fish consumption to achieve 250 mg/day of EPA+DHA is shown in the table (table 1). When a fish oil supplement is used, it should contain both EPA and DHA; a 1 g daily supplement (containing 200 to 800 mg of EPA and DHA) is a reasonable option. (See 'Dose and form' above.)Fish oil supplements are generally derived from small pelagic fish used for fish feed or from formulations produced by algae. Similar to dietary consumption of the great majority of fish and seafood species, significant exposure to contaminants from fish oil is not a major concern.
  • Prevention 2014: Cardiovascular Risk Assessment: Guidelines and Novel Approaches

    1. 1. Mahesh J. Patel, MD Assistant Professor of Medicine Cardiovascular Risk Assessment: Guidelines & Novel Approaches
    2. 2. Clinical ASCVD Diabetes mellitus (age 40-75) ≥7.5% 10-y risk (age 40-75) LDL-C ≥ 190 High-intensity statin High-intensity statin High-intensity statin Moderate-intensity statin Moderate-to-high intensity statin Benefit Group Statin Dose Moderate-intensity statin
    3. 3. No ASCVD, No Diabetes, & LDL 70-189
    4. 4. Overview • The new ASCVD risk calculator • The role of LDL in the context of the new guidelines • Novel assessment strategies
    5. 5. Importance of Risk Assessment
    6. 6. Challenges in CV Risk Assessment Greatest # of sudden deaths Highest CV risk populations Huikuri NEJM 2001
    7. 7. Challenges in CV Risk Assessment Greatest # of sudden deaths Highest CV risk populations Huikuri NEJM 2001
    8. 8. • Age • Gender • Smoker • Total cholesterol • HDL-C • Systolic BP • HTN Rx Framingham Risk Calculator Calculates 10-year risk for CHD death or nonfatal MI High risk: > 20% Intermediate risk: 10-20% Low risk: < 10%
    9. 9. 82% 15% 3% 10-year Risk of CAD < 10% 10-20% > 20% • Framingham does not fully represent US population • Does not assess risk for related CVD outcomes such as stroke • Does not account for lifetime risk of CAD Limitations of the FRS Ford JACC 2004
    10. 10. • New risk tool was needed with greater emphasis on • African Americans & other races • Women • Stroke as an outcome • Geographic and SES diversity • Pooled Cohort Equation • Atherosclerosis Risk in Communities (ARIC) • Cardiovascular Health Study (CHS) • Coronary Artery Risk Development in Young Adults (CARDIA) • Framingham Original and Offspring studies • ASCVD events • CHD death • Non-fatal MI • Stroke (fatal or non-fatal) • Internal and external validation New ASCVD Risk Calculator
    11. 11. WHITE WOMEN AA WOMEN WHITE MEN AA MEN N 11,240 2641 9098 1647 Ages (years) 40-79 40-79 40-79 40-79 C-statistic 0.81 0.81 0.75 0.71 ASCVD Risk Model Characteristics
    12. 12. External Validation of Risk Calculator Ridker Lancet 2013
    13. 13. Figure Legend: External Validation of Risk Calculator Munter JAMA 2014 Reasons for Geographic and Racial Differences in Stroke (REGARDS) study
    14. 14. Risk Factor Units Value Optimal Values Sex M or F F Age Years 55 Race AA or WH AA TC mg/dL 210 170 HDL mg/dL 56 50 SBP mmHg 145 110 HTN Rx Y or N Y N Diabetes Y or N N N Smoker Y or N N N Patient Example – effect of race
    15. 15. Patient Example – effect of race
    16. 16. Patient Example – effect of race
    17. 17. • Family History of premature ASCVD • High LDL-C 160 – 190 mg/dL • Highly sensitive C – Reactive Protein • > 2.0 mg/L • Coronary artery calcium • Score > 300 Agatston units • Score > 75th percentile for age, sex, &race • Ankle – brachial index • < 0.9 Additional ASCVD Risk Assessment Strategies
    18. 18. Coronary Artery Calcification & All Cause Mortality Budoff JACC 2007 CAC Registry of > 25,000 patients
    19. 19. Comparison of Novel Risk Markers for Improvement in CV Risk Assessment in Intermediate-Risk Individuals Yeboah J, et al. JAMA 2012;308:788-795 0.623 C-statistic 0.784 0.652 0.675 0.640 0.650 Yeboah JAMA 2012 1330 intermediate CV risk individuals from MESA cohort
    20. 20. Improving Risk Perception
    21. 21. Patient Example – compare to optimal risk
    22. 22. Atherosclerosis: A Lifetime in the Making
    23. 23. - Pooled cohort of 18 studies  250,000 patients  Lifetime risk of CV death Lifetime Risk of CV Death Berry NEJM 2012
    24. 24. Subclinical atherosclerosis Coronary artery calcification
    25. 25. LDL ATP III What about LDL ?
    26. 26. The Downsides of LDL Goals • Potential underuse of statins in patients at high CV risk but with low LDL-C • Potential overuse of non-statin agents & combination therapies (strategies which have a less robust evidence base compared to statin monotherapy) • No RCT directly supporting this approach
    27. 27. 27 Evolutionarily Normal LDL-C Levels Martin Med Clinics NA 2012
    28. 28. 28 Genetics of LDL Cohen NEJM 2006 LDL receptor mutations PCSK9 mutations High LDL
    29. 29. 29 Genetics of LDL Cohen NEJM 2006 LDL receptor mutations PCSK9 mutations High LDL Low LDL
    30. 30. 30 Reduction in LDL-C & CHD Risks Opie Lancet 2006 Reducing LDL-C by approx 40 mg/dL reduces CHD risks by 20%
    31. 31. 31 Reduction in LDL-C & Atherosclerosis Progression O’Keefe JACC 2004 Regression line indicates that there is NO atherosclerosis progression at LDL-C < 67 mg/dL
    32. 32. LDL in the New Guidelines • 1) LDL-C > 190 mg/dL – one of 4 statin benefit groups • 2) LDL-C > 160 mg/dL – can consider statin therapy • 3) Measure LDL-C to monitor therapeutic adherence & response
    33. 33. HIGH MODERATE LOW ≥ 50% reduction in LDL 30 – 50% reduction in LDL < 30% reduction in LDL Atorvastatin 40-80 mg Rosuvastatin 20-40mg Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2-4 mg Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg Statin intensity & LDL Reduction
    34. 34. • Expected response • High intensity: ≥ 50% LDL reduction • Moderate intensity: 30-50% LDL reduction • Inadequate response • Focus on medication & lifestyle compliance • Fine tune statin dosing to maximize response/tolerability • Do NOT routinely add 2nd drug • Consider 2nd drug in high risk patients Monitoring Statin Response & Adherence
    35. 35. Estimates of LDL-C • Friedewald equation estimates LDL-C when TG < 400 mg/dL • LDL-C = TC – HDL – TG/5
    36. 36. Martin JACC 2013 LDL cholesterol measurements - 1.3 million US adults in total - 191,000 with est LDL-C < 70 mg/dL LDL-C measurements by vertical spin density gradient ultracentrifugation
    37. 37. LDL particle measurements Cromwell J Clin Lipidology 2007 3066 adults w/o CVD LDL-P measurements by NMR spectroscopy
    38. 38. Follow-up (years) 0 1 2 3 4 5 CumulativeIncidence 0.02 0.04 0.06 LDL-P < LDL-C Concordant LDL-P > LDL-C 0 0.02 0.04 0.06 0.08 0 1 2 3 4 5 60 1 2 3 4 5 0.02 Follow-up (years) CumulativeIncidence 0.04 0.06 LDL-P > LDL-C LDL-P < LDL-C Concordant LDL-P > LDL-C LDL-P < LDL-C Concordant 16% 33% 54% MetSyn LDL-C underestimates LDL-attributable risk LDL-C overestimates LDL-attributable risk LDL-C 104 117 130 mg/dL LDL-P 1372 1249 1117 nmol/L Otvos J Clin Lipidology 2011 LDL-P & LDL-C Discordance and CV Events Discordance defined as > 12 percentile units MESA 6814 patients w/o CVD at entry
    39. 39. • 38 y/o white man p/w atypical chest pain. • PMH – smoking & central obesity (BMI 34 kg/m2) • BP 122/80. PE otherwise unremarkable. • TC 170, TG 104, HDL-C 21, LDL-C 128 • 3 normal stress tests over 2 years Patient KM
    40. 40. • 10-year risk ASCVD: 8.5% • 10-year risk with optimal RF: 0.6% • Lifetime ASCVD risks: 50% • Lifetime risk with optimal RF: 5% • Statin was recommended but he declined Patient KM
    41. 41. Patient KM Coronary CTA: 50% soft plaque in the proximal LAD
    42. 42. • Recommendations arose solely from high quality evidence. • Definitive recommendations were not provided in areas lacking high quality evidence. • Lifestyle modification is the foundation of ASCVD risk reduction. Conclusions
    43. 43. • Rather than LDL-C and nonHDL-C goals, the initiation and intensity of statin therapy is the primary goal of treatment in 4 major risk groups : • ASCVD • LDL > 190 mg/dL • DM • 10 year risk > 7.5% • 10-year ASCVD risk ≥ 7.5% • New Pooled Cohort Equation for ASCVD risk prediction has flaws but is an improvement from FRS Conclusions
    44. 44. • Risk calculator should help initiate conversation on ASCVD risk assessment but should not be used as a strict criterion for or against statin therapy. • Clinical judgment and patient preference should be highly integrated into all treatment decision strategies. Conclusions

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