How to Reduce Residual Risk in Primary Prevention

How to Reduce Residual Risk in Primary Prevention Helene Glassberg, MD Assistant Professor of Medicine Section of Cardiology Hospital of the University of Pennsylvania Philadelphia, PA USA

Patients with CHD Event (%) Lower Is Better : Statin Therapy Provides Benefits Even in Patients with Lower LDL-C 30 Secondary prevention Primary prevention 25 20 15 10 4S (1994) WOSCOPS (1995) CARE (1996) AFCAPS (1998) LIPID (1998) HPS (2002) ASCOT-LLA (2003) TNT, 10 (2005) TNT, 80 (2005) 5 0 210 190 170 150 130 110 90 70 Closed symbols = statin group; open symbols = placebo group Mean LDL-C Level at Follow-up (mg/dl) Adapted from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21. Sever PS, et al. Lancet. 2003;361:1149-1158. HPS. Lancet. 2002;360:7-22. LaRosa JC, et al. N Engl J Med. 2005;352:1-11.

LDL cholesterol 3.36mmol/L 4.14mmol/L

30 25 PROVE IT - TIMI 22: All-Cause Death or Major CV Events in All Randomized Subjects Pravastatin 40mg (26.3%) 16% RR (P = 0.005) % with Event 20 15 10 Atorvastatin 80mg (22.4%) Mean LDL 62mg/dL(1.6mmol/L) 5 0 0 3 6 9 12 15 18 21 24 27 30 Ridker PM et al. N Engl J Med 2005;352:20-28. Months of Follow-up

The Need to Go Beyond LDL-cholesterol Reduction Many patients with adequately controlled LDL-C still experience a CVD event. Disorders that contribute to CVD risk other than LDL-C are common among those with CAD, even those with LDL-C<100mg/dL. There are effective therapies to treat other CVD risk factors, and new therapies are under development.

How Can We Improve Our Ability to Predict CHD Risk? Arterial imaging/ function Biomarkers Metabolic syndrome Family history Framingham risk score/score(esc) Adapted from Kullo IJ, et al. Mayo Clin Proc. 2005;80:219-230.

Age-adjusted Prevalence (%) Age- and Sex Adjusted Risk (%) 75 50 Family History: Both Sibling and Parental History Can Affect CV Risk Prevalence of CAC 100 by Family History of Premature CHD No Family History Parental Family History Sibling Family History Both 10 8 6 8-year Risk for CVD in Middle-aged Adults No Sibling CVD Sibling CVD 4 25 2 0 0 No RF 1 RF 2 RF 3 RF Entire Population Cohort with Both Parents in FHS CAC = coronary artery calcification; RF = risk factor Nasir K, et al. Circulation. 2004;110:2150-2156. Murabito MJ, et al. JAMA. 2005;294:3117-3123.

NHANES III Metabolic Syndrome At least 3 metabolic abnormalities: Abdominal obesity (waist): Men >102 cm (>40 in) Women >88 cm (>35 in) FBG 110 mg/dl* TG 150 mg/dl HDL-C NCEP Criteria Men <40 mg/dl Women <50 mg/dl (1.69 mmol/l) BP 130/85 mm Hg or on antihypertensive medication Abdominal Obesity Hypertriglyceridemia Low HDL-C HTN/on Medication High Blood Glucose/on Medication 3 Components US Population (%) 0 10 20 30 40 50 *Fasting plasma glucose; NHLBI/AHA now recommends >100 mg/dl Expert Panel. JAMA. 2001;285:2486-2497. Ford ES, et al. JAMA. 2002;287:356-359. Grundy SM, et al. Circulation. 2004;109:433-438.

Cumulative Incidence (%) Metabolic Syndrome May Increase Risk for MACE Regardless of Framingham Estimated Risk AFCAPS 4S 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.5 0.4 0.3 0.2 0.1 0.00 0.0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Time (months) Time (months) 20%, No Metabolic Syndrome >20%, No Metabolic Syndrome 20%, Metabolic Syndrome >20%, Metabolic Syndrome MACE = major adverse coronary events; AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; 4S = Scandinavian Simvastatin Survival Study Girman CJ, et al. Am J Cardiol. 2004;93:136-141.

hscrp Modified Global CHD Risk Low High Biomarkers May Improve Prediction of CV Events Beyond Framingham Scores 10-20 5-10 <5 Calculated Framingham 10-y Risk (%) <0.5 0.5-1 1-3 3-10 >10 Ridker PM, et al. Circulation. 2004;109:2818-2825.

Ridker P, et al NEJM Nov 2002 27,939 healthy women 1.00 Probability of Event Free Survival.99.98.97 hscrp<2mg/l, LDL<130mg/dL (3.36mmol/L) hscrp<2, LDL>130 hscrp>2, LDL<130.96 hscrp>2, LDL>130 0.0 2 4 6 8 Years of follow up Event free survival according to baseline hs-crp quintile

JUPITER Achieved LDLC, Achieved hscrp, or Both? Objectives: To compare clinical outcomes among JUPITER trial participants according to achieved levels of LDLC and hscrp, after adjustment for all available baseline clinical characteristics, including entry levels of LDLC, HDL-C, and hscrp. To evaluate whether clinical outcomes according to achieved lipid and hscrp levels are altered by substituting ApoB or the ApoB:ApoA ratio for LDLC. Ridker, PM et al. ACC 2009

Ridker P et al. N Eng J Med 2008;359: 2195-2207

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER 5-Year NNT Values for Primary Prevention of CVD Number Needed to Treat (5 years) 450 400 350 300 250 200 150 100 50 0

JUPITER

hscrp: Conclusions LDL-C and hscrp are strong independent predictors of future CVD events. Statins lower LDL-C and hscrp Lower is better for both LDL-C and hscrp Consider Dual Target of LDL-C<70mg/dL and hs CRP<2mg/L.

How has JUPITER affected the guidelines? ATP IV -2011-?hsCRP US FDA has approved the JUPITER indication for rosuvastatin Canadian 2009 Guidelines recommending the use of CRP to determine statin eligibility among patients considered "intermediate risk." (10-year Framingham risk between 10% and 20%). ESC-have not granted the JUPITER indication but endorsed use of rosuvastatin in patients with a Framingham risk score over 20% or a SCORE [risk model used in Europe] over 5%

Clinical Predictors of Plaque Progression Despite Very Low Levels of Low-Density Lipoprotein Cholesterol Pooled Data from 7 prospective atherosclerosis progression/regression IVUS trials. Total of 3437 patient with CAD underwent serial IVUS examinations. Patients who achieved on treatment LDL-C<70mg/dL (n=951) were stratified as progressors -defined as >5% increase in percent atheroma volume (PAV)-(n=200) and nonprogressors (n=751) and compared. Bayturan et al. J Am Coll Cardiol 2010;55:2736-42 Copyright 2008 American College of Cardiology Foundation. Restrictions may apply.

Results Compared to patients with on treatment LDL-C >70mg/dL, those with LDL-C<70mg/dL demonstrated less progression of PAV. Despite achieving LDL-C<70mg/dL, >20% of patients continued to progress. Progressors had higher baseline levels of glucose and triglycerides. Independently associated risk factors of progression in patients with LDL-C<70mg/dL: 1. diabetes mellitus 2. increase in systolic blood pressure 3. less increase in HDL-cholesterol 4. smaller decrease in apob levels (Not changes in c-reactive protein) Bayturan et al. J Am Coll Cardiol 2010;55:2736-42

Coronary Artery Calcium Scoring For image on left (LAD), calcium score is 60. For image on right (RCA), calcium score is 16. For these two slices, score would be 76. Total calcium score is the sum of all individual calcium scores for the entire epicardial coronary artery system.

The St. Francis Heart Study Coronary Artery Calcium Scores Predict CV Events 30 20 Event Rate (%) Relative Risk RR=26.2 10 0 RR=10.2 14% (n=63) RR=1 RR=1.9 5.5% (n=38) 0.54% 1% (n=20) (n=8) 0 1 to 99 100 to 399 400 Coronary Artery Calcium Score Arad Y, et al. J Am Coll Cardiol. 2005;46:158-165.

Imaging to Detect Subclinical Atherosclerosis to Predict Future CVD Events Individualizes risk assessment beyond the use of age. Identifies individuals at risk beyond established risk factors. Offers an integrated assessment of the exposure to risk factors. Detection of subclinical atherosclerosis can guide therapy based on plaque burden. NCEP ATP III and ESC suggest additional tests to better assess intermediate risk for confirmation or reclassification of risk. NCEP ATP III recommends 75 th percentile value based on age and gender, ESC defines high risk as CAC>100 and/or >75 th percentile.

Therapeutic Approaches to Reducing Residual Risk Lifestyle modification Mediterranean diets associated with longevity, low CVD mortality and less diabetes Exercise-physical activity can reduce CVD and type II diabetes by up to 50%. Smoking cessation-return to baseline risk after 5 years Intensify statin monotherapy, consider dual target Combination drug therapy Further reduce LDL-C Reduce non-hdl-c in mixed dyslipidemia

Niacin and Statins: HDL-Atherosclerosis Treatment Study (HATS) 3-year double-blind trial Simvastatin plus niacin and/or antioxidants vs. placebo 160 patients with CAD, low HDL-C, and normal LDL-C levels Simvastatin plus niacin (sustained- or immediate-release) Reduced LDL-C 42%; TG 36% Increased HDL-C 26% Reduced TC:HDL-C ratio from 6.5 to 3.5 (P <0.001) Regression of stenosis by 0.4% (vs. 3.9% progression in placebo group; P <0.001) 90% reduction in composite end point* (P <0.03 vs. placebo) *Death from coronary causes, confirmed MI or stroke, or revascularization for worsening ischemic symptoms Brown et al. N Engl J Med. 2001;345:1583.

Mean Change in Stenosis, % HATS: Angiographic and Clinical Endpoints After 3 Years 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0-0.5 3.9 Placebo S+N S+N+AV -0.4 9 Proximal Lesions * 0.7 23.7 2.6 89% reduction 14.3 Coronary Death, MI, Stroke, or Revascularization HATS = HDL-C-Atherosclerosis Treatment Study; S = simvastatin; N = niacin; AV = antioxidant vitamins. *p<0.001 vs. placebo; p<0.005 vs. placebo; p=0.04 vs. placebo. Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592. 25 20 15 10 5 0 Composite Event Rate, %

mm ARBITER 6-HALTS Trial design: Patients with CHD (or risk equivalent) on statin therapy and with low HDL cholesterol were randomized to extended-release niacin 2000 mg daily (n = 97) versus ezetimibe 10 mg daily (n = 111). Follow-up was 14 months. (p = 0.003) -0.0142 Extended-release niacin -0.0007 Change in mean carotid IMT at 12 months Ezetimibe Results Change in mean carotid intima-media thickness (IMT): -0.0142 mm with niacin vs. - 0.0007 mm with ezetimibe (p = 0.003) Change in LDL cholesterol: -10.0 mg/dl vs. - 17.6 mg/dl (p = 0.01), respectively Change in HDL cholesterol: 7.5 mg/dl vs. -2.8 mg/dl (p < 0.001), respectively MACE: 1% vs. 5% (p = 0.04), respectively Conclusions Among CHD patients on statin therapy, with LDL cholesterol <100 mg/dl and HDL cholesterol <50 mg/dl for men or <55 mg/dl for women, the use of extended-release niacin was beneficial Niacin reduced mean carotid IMT and raised HDL cholesterol Taylor AJ, et al. N Engl J Med 2009;Nov 15:[Epub]

Fibrates (PPAR- Agonists) and Statins Combination may significantly improve TG, LDL-C, and HDL-C levels Fibrates plus statins associated with increased risk for myopathy and rhabdomyolysis Fenofibrate may have relatively less potential for impairment of statin metabolism DATA: VA-HIT 24%RRR, FIELD 11%RRR Ballantyne CM, et al. Arch Intern Med. 2003;163:553-564. Bays H. Am J Cardiol. 2002;90:30K-43K. Bays HE, et al. Expert Opin Pharmacother. 2003;4:1901-1938.

Change from Baseline (%) SAFARI Addition of Fenofibrate to Statin Therapy Benefits Patients with Combined Hyperlipidemia 30 20 10 0-10 -20-30 -40-50 -60 Simvastatin 20 mg Simvastatin 20 mg + Fenofibrate 160 mg -20.1% -43.0% * N=618-24.1% -25.8% -49.1% -31.2% 9.7% TG VLDL-C LDL-C HDL-C SAFARI = Simvastatin Plus Fenofibrate for Combined Hyperlipidemia *P<0.001 vs simvastatin Grundy SM, et al. Am J Cardiol. 2005;95:462-468. 18.6% Baseline: 227-234 mg/dl 50 mg/dl 162-163 mg/dl 43-44 mg/dl * * *

% per year ACCORD Lipid Trial design: Type 2 diabetics treated with a statin were randomized to fenofibrate (n = 2,765) vs. placebo (n = 2,753). Mean follow-up was 4.7 years. (p = 0.32) 2.4 2.2 Fatal or nonfatal CV event Fenofibrate Placebo Results CV mortality, MI, or stroke: 2.2%/year with fenofibrate vs. 2.4%/year with placebo Primary outcome plus revascularization or hospitalization for CHF: 5.4%/year vs. 5.6%/year (p = 0.30), respectively All-cause mortality: 1.5%/year vs. 1.6%/year (p = 0.33), respectively Exploratory analysis: possible benefit in men vs. women (p for interaction = 0.01) Conclusions Among type 2 diabetics treated with a statin, there was no long-term benefit from fenofibrate compared with placebo Composite CV outcomes were similar between the two groups Presented by Dr. Henry Ginsberg at ACC.10/i2 Summit

Clinical Concerns About Combination Drug Therapy Limited data on benefit Potential for increased risk of adverse events (AEs) and reduced tolerability Increased cost, complexity, and reduced tolerability may reduce patient adherence McKenney JM. Am J Ther. 2004;11:54-59.

INTER-HEART: Risk of acute MI associated Risk factor with risk factors in the overall population ApoB/ApoA-1 (fifth quintile compared with first) Odds ratio adjusted for age, sex, and smoking (99% CI) Yusuf S, Hawken S, Ounpuu S, on behalf of the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952. Odds ratio adjusted for all (99% CI) 3.87 (3.39-4.42) 3.25 (2.81-3.76) Current smoking 2.95 (2.72-3.20) 2.87 (2.58-3.19) Diabetes 3.08 (2.77-3.42) 2.37 (2.07-2.71) Hypertension 2.48 (2.30-2.68) 1.91 (1.74-2.10) Abdominal obesity 2.22 (2.03-2.42) 1.62 (1.45-1.80) Psychosocial 2.51 (2.15-2.93) 2.67 (2.21-3.22) Vegetable and fruits daily 0.70 (0.64-0.77) 0.70 (0.62-0.79) Exercise 0.72 (0.65-0.79) 0.86 (0.76-0.97) Alcohol intake 0.79 (0.73-0.86) 0.91 (0.82-1.02) All combined 129.2 (90.2-185.0) 129.2 (90.2-185.0)

Finnish Diabetes Prevention Study Design 522 middle-aged overweight (BMI 31) 172 men and 350 women Mean duration 3.2 years Intervention Group: Individualized counseling Reducing weight, total intake of fat and saturated fat Increasing uptake of fiber, physical activity Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.

Diet and Exercise Intervention Controls Goals Weight reduction >5% Fat intake <30% energy Sat fat <10% energy Fiber >15 g/1000 kcal % of subjects P value 43 13 0.001 47 26 0.001 26 11 0.001 25 12 0.001 Exercise >4 hr/wk 86 71 0.001 Tuomilehto J, et al. N Engl J Med. 2001;344:1343-1350.

Benefit of Lifestyle Changes Risk of 23% (17-29CI) diabetes reduced by 58% 11%( 6-15CI) after 4 years Intervention Control % with Diabetes Tuomilehto J et al. N Engl J Med 2001;344:1343-1350.

Mortality Rate Changes in Physical Fitness and CVD Mortality: ACLS 65.0 87 deaths in 9,777 men 4.9 years between exams 31.4 14.2 Unfit Unfit Unfit Fit Fitness at Two Exams Fit Fit Blair SN et al. JAMA 1995;273:1093-1098.

Conclusions We need to think beyond lower is better LDL goals to adequately address residual risk. Consider additional risk assessors including biomarkers (hscrp, ApoB) and imaging (CAC) to better classify risk category and determine intensity of therapy. Consider a dual target of LDL-C and hs-crp goals.