Subclinical atherosclerosis in CVD: Risk stratification & management Raul Santos, MD Sao Paulo Medical School Sao Paolo, Brazil
Subclinical atherosclerosis in CVD risk: Stratification & management Prof. Dr. Raul D. Santos Lipid Clinic InCor University of São Paulo Brazil 2
Disclosure Consulting and speakers honoraria : Merck, Astra Zeneca, ISIS-Genzyme, Novo-Nordisk, BMS, Biolab, Pfizer, Boehringer Ingelheim, Lilly, Amgen, Aegerion & Sanofi.
Summary Discuss the role of imaging on: CVD risk stratification How to validate an imaging biomarker Which is the best imaging marker? Imaging vs. CRP Should we treat subclinical disease?
Basis of Atherosclerosis Prevention Seconday Prevention Clinical CHD R I S K Primary Prevention Subclinical Atherosclerosis Risk Factors Adapted from Furberg C.
Subclinical Atherosclerosis Can Be Detected By Different Imaging Modalities
Coronary Calcium by Cardiac CT
Progression of Atherosclerosis : The Remodeling Hypothesis of Glagov Progression The compensatory expansion keeps the lumen constant Expansion supplantantion: The lumen narrows Normal Vessel Minimum CAD Moderate CAD Advanced CAD Adapted form Glagov S, et al. N Engl J Med. 1987;316:1371-1375.
CHD Death Rates and Coronary Artery Calcification (CAC) in 3 asymptomatic cohorts: USA, Brazil, and Portugal (n=17,563) 200 180 160 140 120 100 80 60 40 20 0 CHD Death/100,000 CAC prevalence % 88 12 135 51 P<0.0001 for CAC 189 Portugal Brazil US 61 CAC prevalence adjusted for age, sex, blood pressure, dyslpidemia, DM, smoking Adapted from Santos RD et al Atherosclerosis 2006;187:378-84
Cumulative Survival All Cause Mortality and CAC Scores: Long Term Prognosis in 25, 253 patients 1.00 0.95 0 (n=11,044) 1-10 (n=3,567) 11-100 (n=5,032) 101-299 (n=2,616) 0.90 0.85 300-399 (n=561) 400-699 (n=955) 700-999 (n=514) 0.80 0.75 OR= 10.4 0.70 1,000+ (n=964) 0.0 2.0 4.0 6.0 8.0 10.0 12.0 Time to Follow-up (Years) Budoff, et al. JACC 2007; 49: 1860-70
Carotid Intima Media Thickness By B-Mode Ultrasound
Carotid IMT is an Independent Predictor of Myocardial Infarction and Stroke Hazard Ratio for MI and Stroke per 1 SD difference in IMT measured at the common carotid artery adjusted for age and gender n MI n Stroke ARIC CHS RS MDCS CAPS 13204 4476 2267 5163 5052 14165 4476 5479 5163 5052 TOTAL 30162 34335 0.9 1 1.1 1.2 1.3 1.4 1.5 0.9 1 1.1 1.2 1.3 1.4 1.5 Atherosclerosis Risk in Communities Study (ARIC), Cardiovascular Health Study (CHS), Rotterdam Study (RS), Malmö Diet and Cancer Study, Carotid Atherosclerosis Progression Study (CAPS). Lorenz et al. Circulation 2007;115:459-467
How the detection of subclinical atherosclerosis could change clinical practice? Should we use it? 13
How to validate a new risk marker? Relative risk measurements Calibration Discrimination Reclassification Wilson. JAMA 2009;302:2369-70
Relative risk The intensity of the risk when the biomarker is present vs. absent (multivariate association) 15
Meta-analysis CAC Vs. HNR Study: Major CV Events Greenland et al. JACC 2007;49:378-402 Erbel et al. JACC 201019;56:1397-406 16
Calibration How the predicted risk corresponds to the real risk 17
Risk of hard CV event in 30 years Calibration by deciles 30-year Framingham Risk Score 0,5 0,4 0,3 Adjusted by Kaplan-Meier Based on the model 0,2 0,1 0 1 2 3 4 5 6 7 8 9 10 Decile of risk based on the model Pencina M. et al. Circulation 2009;119-3078-3084
Discrimination How well the model separates those how will from those who won t have the disease: Measured by the ROC curves (C statistics)
sensitivity sensitivity 1.0 0.8 0.6 A B 1.0 0.8 0.6 Thresholder-1 0.4 C 0.4 Thresholder-12 0.2 0.2 0 0 0.2 0.4 0.6 0.8 1.0 1-specificity 0 0 0.2 0.4 0.6 0.8 1.0 1-specificity Zou KH et al. Circulation 2007;115:654-7
ROC curve, its area under the curve (AUC) and corresponding odds ratios True positive rates 1.0 OR=105; AUC=0.95 OR=38; AUC=0.9 0.8 0.6 0.4 0.2 OR=11; AUC=0.8 OR=4; AUC=0.7 OR=2; AUC=0.6 OR=1; AUC=0.5 CRP, LDL, HDL, Smoking HBP, Diabetes etc Biomarkers 0 0 0.2 0.4 0.6 0.8 1.0 False positive rates Based on Pepe et al. Am J Epidemiol 2004; 159:882-890.
ROC curves for major CHD events in 5 years by CAC +FRS: HNR Erbel, R. et al. J Am Coll Cardiol 2010; 56:1397-406
Reclassification How many individuals move from one to other risk categories?
Reclassification NRI: net reclassification improvement IDI: integrated discrimination improvement
Reclassification of ATP III Risk Categories Using CAC 51.5% 28.8% 19.7% CAC Score High risk 14.1 % Intermediate risk 23.1 % Low risk 62.9 % 0 10 20 % 10-year risk ATPIII Score Risk Assessment Scheme according to Wilson PWF et al JACC 41:1889 1906, 2003 with HNR data
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CAC in type 2 diabetes 28
Meta-analyses of association between coronary artery calcium score 10 and outcome in people with type 2 diabetes. Kramer C K et al. BMJ 2013;346:bmj.f1654 2013 by British Medical Journal Publishing Group
Bayes nomogram for coronary artery calcium (CAC) score showing post-test probability of event in people with type 2 diabetes with total coronary artery calcium score 10 and <10 by outcome. Events CAC> 10: 17% CAC< 10 :1.8 % in 5.2 years Kramer C K et al. BMJ 2013;346:bmj.f1654 2013 by British Medical Journal Publishing Group
Cumulative incidence of major cardiovascular events* TNT-time to first major cardiovascular event in patients with diabetes 0.20 HR = 0.75 (95% CI 0.58, 0.97) P = 0.026 0.15 0.10 0.05 Relative risk reduction = 25% 0.00 0 1 2 3 4 5 6 Time (years) Atorvastatin 10mg Atorvastatin 80mg Shepherd et al. Diabetes Care, 2006, 29:1220
CAC and dyslipidemia 33
CAC, LDL-C and CVD: MESA Nasir K et al. Circulation 2013 October 20 34
CT angiography vs. CAC 35
Absence of CAC and CVD events in Asymptomatic Subjects (n=71,595) Sarwar et al. JACC Imaging 2009;2:67-88 No CAC= 0.47% CAC= 4.14% 36
Total Coronary Artery Plaque and EBCT Coronary Calcium 20% Calcified 20% 80% Fibrotic Plaque Detectable by IVUS, Pathology 80% 80% Lipid Rich
CTA does not add risk reclassification power to FRS+ CAC in asymptomatic subjects: CONFIRM Both CACS and ccta significantly improved the performance of standard risk factor prediction models for all-cause mortality and CVD. The net reclassification improvement resulting from the addition of ccta to a model based on standard risk factors and CACS was negligible. N= 7590 follow up : 24 months (short time???) Adapted from Min et al. Circulation. 2012;126: 304-313 38
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IMT and carotid plaque Is it useful? Newer data
Events/1000 IMT/Carotid Plaque Reclassify Predicted CHD ARIC n=13.145 Nambi V et al. JACC 2010;55:1600-07 ROC: 0.743-0.755 NRI= 9.9% NRI intermediate risk o = 21.7% Follow-up 17 years
N = 45,828 Median follow-up of 11 years 4007 first-time MIs and or strokes occurred. JAMA. 2012;308:796-803 42
Which is the best imaging biomarker? Also imaging vs. inflammation
Imaging marker Pairing kappa CAC > 75 th % IMT > 900 (μm) 0.109 CAC > 75 th % PWV > 12 (m/s) 0.004 CAC > 75 th % CRP > 3 (mg/l) 0.16 IMT > 900 (μm) PWV > 12 (m/s) 0.517 IMT > 900 (μm) CRP > 3 (mg/l) 0.064 PWV > 12 (m/s) CRP > 3 (mg/l) 0.031 Martinez LRC et al. Atherosclerosis 2008;200:83-88
FRS + Carotid IMT Events Non Events FRS + CAC Events Non Events FRS +ABI Events Non Events FRS + CRP Events Non Events FRS + Family History Events Non Events % net correct reclassification 3.3 2.7 10.6 36 4.1 2.7 1.6 2.1 0.8 3.2 NRI 0.06 0.466 0.068 0.037 0.040 Adapted from Yeboah et al. JAMA. 2012;308:788-795 45
CAC Events CRP Events CRP +CAC Events
Should we treat subclinical atherosclerosis? 47
Impact of 40 mg/dl reduction on LDL-C upon major cardiovascular events and mortality CTT 2010 Relative Risk (95% CI) All cause mortality CHD mortality Other cardiac deaths Stroke deaths Major vascular events Non-fatal MI Myocardial revascularization Ischemic stroke Cancer incidence Hemorrhagic stroke 0.90 (0.87-0.93), p<0.0001** 0.80 (0.74 0.87); p<0.0001** 0.89 (0.81 0.98); p=0.002** 0.96 (0.84 1.09); p=0.5 0.78 (0 76 0 80); p<0.0001 0.73 (0.70 0.77); p<0.0001 0.75 (0.72 0.78); p<0.0001 0.79 (0.74 0.85); p<0.0001 1.00 (0.96 1.04); p=0.9 1.12 (0.93 1.35); p=0.2 Adapted from The Lancet 2010.; 376:1670-81 **- CI 99%
70 60 Prevalence of Asymptomatic Men Who Would Have Been Qualified for Pharmacological Treatment in Brazil According to ATP III Guidelines or Due to CAC Severity P<0.0001 for trend in groups 55 % 50 40 42 30 20 23 10 0 CACS = 0 CACS = 10-99.9 CACS > 100 Nasir K, Santos RD et al. Int J Cardiol 2006 108:68-75
Conclusions I Detection od subclinical atherosclerosis improves CHD risk stratification Those at intermediate risk benefit the most (>5%/10 years) Diabetics might benefit from CAC imaging Lower LDL +Aspirin??? Can it select dyslipidemic patients for more intensive treatment? 50
Conclusions II CAC is better than IMT and CRP No advantages of CTA over CAC in asymptomatic subjects At the moment High plaque burden = aggressive treatment 51