BEYOND LIFESTYLE CHANGES: THE ROLE OF AGGRESSIVE MEDICAL THERAPY FOR ALL PATIENTS AT INCREASED RISK FOR CARDIOVASCULAR D

1. BEYOND LIFESTYLE CHANGES: THE ROLE OF AGGRESSIVE MEDICAL THERAPY FOR ALL PATIENTS AT INCREASED RISK FOR CARDIOVASCULAR DISEASE Charles H. Hennekens, MD, DrPH Sir Richard Doll Research Professor of Medicine Charles E. Schmidt College of Medicine, Florida Atlantic University (FAU) Clinical Professor of Preventive Medicine, Nova Southeastern University Voluntary Professor of Family Medicine and Community Health University of Miami Miller School of Medicine (UMMSM)

2. Disclosure • I am funded by the Charles E. Schmidt College of Medicine at Florida Atlantic University (FAU). I have served as Principal Investigator on two investigator initiated research grants funded to FAU by Bayer testing the effects of aspirin dose on platelet and inflammatory biomarkers as well as nitric oxide formation. • I serve as an independent scientist in an advisory role to investigators and sponsors as Chair of Data and Safety Monitoring Boards for Actelion, Amgen, Anthera, Bristol-Myers Squibb, and Sunovion and as a Member of Data and Safety Monitoring Boards for AstraZeneca, Bayer , British Heart Foundation, Canadian Institutes of Health Research and Lilly. • I serve as an independent scientist in an advisory role to the U.S. Food and Drug Administration, U.S. National Institutes of Health, Children's Services Council of Palm Beach County and UpToDate. • I serve as an independent scientist in an advisory role to legal counsel for GlaxoSmithKline and Stryker. • I serve as speaker for the Association for Research in Vision and Ophthalmology, Baptist Health South Florida, National Association for Continuing Education, PriMed, and the International Atherosclerosis Society. • I receive royalties for authorship or editorship of three textbooks. • I receive royalties as co-inventor on patents concerning inflammatory markers and cardiovascular disease which are held by Brigham and Women’s Hospital. • I have an investment management relationship with The West-Bacon Group within SunTrust Investment Services who has discretionary investment authority. • I do not own any common or preferred stock in any pharmaceutical or medical device company.

3. Death is inevitable but premature death is not Sir Richard Doll, FRS Regius Professor of Medicine University of Oxford, UK, 1969-1979

4. Advances in Medical Knowledge Proceed on Several Fronts, Optimally Simultaneously • Basic researchers • Health care providers • Clinical investigators • Epidemiologists and biostatisticians Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown and Company; 1987.

5. Totality of Evidence • Basic research (why) • Epidemiology (whether) • Descriptive studies: • Case reports • Case series • Ecological studies • Analytic studies: • Observational • Case-control • Cohort • Randomized trials Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown and Company; 1987.

6. Change In Age-Adjusted Mortality1979 - 1995 Noncardiovascular Disease Coronary Heart Disease % Decline Stroke National Center for Health Statistics.

8. Heart Disease In The United States • Chief cause of death among men age 45 years and older • Chief cause of death among women age 65 years and older • Responsible for 1 in 3 deaths in men and women, or ~750,000 fatalities each year

9. Postulated Reasons for Decreasing CHD Mortality • During acute MI: • Decrease in case fatality rate (20%-30%  5%-10%) for hospitalized MI • Increase in utilization of: • Aspirin • Thrombolytics • -blockers • ACE inhibitors Hennekens CH et al. NEJM 1996;335:1660-1667

10. Postulated Reasons for Decreasing CHD Mortality (cont’d) • Secondary prevention: • Therapeutic lifestyle changes (TLC) • Increase in utilization of: • Aspirin • -blockers • ACE inhibitors • Statins (HMG-CoA reductase inhibitors) Hennekens CH et al. NEJM 1996;335:1660-1667

11. Postulated Reasons for Decreasing CHD Mortality (cont’d) • Primary prevention: • Decrease in smoking • >50%  <25% • Increase in treatment of hypertension: • 16%  55% • Increase in treatment of dyslipidemia: • Cholesterol population target 220 mg/dl  200 mg/dl Manson JE et al. NEJM 1992;326:1406-1416.

12. Smoking (22%-30%) Physical Inactivity Type 2 Diabetes Obesity Trends Among US Adolescents Hennekens CH. Circulation. 1998;97:1095.

13. LIFE EXPECTANCY AT BIRTH • US AND RICH COUNTRIES: 77 YEARS (73 IN MEN AND 81 IN WOMEN • POOR COUNTRIES: 50 YEARS (46 IN MEN AND 54 IN WOMEN)

14. Shifting Worldwide Burden of Disease 1990 2020 Cancer 11.9% Cancer 18.0% All Other 25.5% All Other 33.2% CVD 28.4% CVD 33.7% Communicable,Perinatal, Nutritional 15.1% Communicable,Perinatal, Nutritional 34.2% Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996.

15. Reasons for Worldwide Increase in Cardiovascular Disease Malnutrition Infection Smoking BMI Hennekens CH. Circulation. 1998;97:1095-1102.

16. 1990 2020 Years of Life Lost 4th 1st Premature Death and Disability 5th 1st Increasing Worldwide Burden of Cardiovascular Disease Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996.

17. Conclusion • Based on these considerations, the World Health Organization has projected that, within the next decade, cardiovascular disease will be the leading cause of death and disability in the world

18. Selected Worldwide Death Rates From CHD in Adults Aged 34 to 74 Years* *All values are for 1997.British Heart Foundation. Coronary Heart Disease Statistics: British Heart Foundation Statistics Database. London, England: British Heart Foundation; 2002.

19. CONTRIBUTIONS OF DIFFERENT TYPES OF EVIDENCE(HENNEKENS AND BURING, EPIDEMIOLOGY IN MEDICINE, 1987) For hypotheses testing of large effects (i.e. smoking and lung cancer where RR=20, or even smoking and CHD where RR=2.0) randomized evidence is neither necessary nor desirable For small to moderate effects (i.e.10-50%) the amount of uncontrolled and uncontrollable confounding inherent in all case control and cohort studies is as big as the effect size so randomized evidence is crucial. Subgroup analyses are no longer randomized and have lower sample sizes and should be viewed, at best, as hypothesis formulating and, at worst, as rubbish. The biggest danger in interpretation of subgroups is acting as if they provide serious evidence. (Sir Richard Peto, personal communication)

20. AHA/ACC SECONDARY PREVENTION FOR PATIENTS WITH CORONARY AND OTHER VASCULAR DISEASE-2006 UPDATE • Cigarette Smoking • Blood Pressure Control • Lipid Management • Physical Activity • Weight Management • Diabetes Management • Antiplatelet and/or Anticoagulant therapy • RAAS Blockers • Beta-Blockers Circulation. 2006;113:2363-2372

21. ATP III Guidelines: Definitions of Increased Risk for CVD • Prior CVD event • CHD • Stroke • Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) • Risk factors that confer a 10-year risk for CHD ≥20% • Diabetes • ≥2 risk factors (metabolic syndrome)

23. Diabetes and Cardiovascular Disease • The US National Cholesterol Education Program (NCEP) III has elevated diabetes from a major risk factor to a CHD risk equivalent • Diabetes is a major contributor to the metabolic syndrome of multiple metabolic risk factors (obesity, dyslipidemia, diabetes, hypertension) that markedly increases risks of CVD • In the general US population 25% of adults have metabolic syndrome • All patients with diabetes should be treated as aggressively as survivors of a CVD event (i.e., MI or stroke)(Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.) • In PROVE-IT and TNT there were no modifications of the benefits of higher doses of statins among the diabetics who had higher absolute risks. • The failure to treat diabetics aggressively with higher doses of more potent statins has major deleterious clinical and public health implications.

24. Modifiable CV Risk Factors inPatients with Type 2 Diabetes*: Results from UKPDS 23 CV = cardiovascular. *Adjusted for age and gender in 2693 Caucasian patients with type 2 diabetes, with dependent variable as time to first event. †Significant for coronary artery disease (n = 280). P values are significance of risk factor after controlling for all other risk factors in model. Adapted from Turner RC et al. BMJ. 1998;316:823–828.

25. Metabolic Syndrome • “The U.S. is the fattest society in the world and likely to be the fattest in the history of the world”. (CH Hennekens, NY Times 1/1/99) • Obesity is associated with dyslipidemia, hypertension, and insulin resistance which has been termed metabolic syndrome. • In the U.S. 25% of adults aged 25 and older and 40% of adults aged 40 and older have metabolic syndrome. • Patients with metabolic syndrome have a 10 year risk of a first CHD event of 16-18%.

26. Importance of Assessing Multiple Risk Factors for CHD + Hypertension + Low HDL-C + Hyperglycemia No other RF 30 + Smoking 25 20 15 CHD Risk per 100 (10 y) 10 5 0 <100 100-129 130-159 160-189 ≥190 LDL cholesterol (mg/dL)

27. Randomized Comparisons of Different Statins at Different Doses The STELLAR Trial Change in LDL-C From Baseline (%) 0 -5 -10 -15 -20 -25 -30 -35 -40 -45 -50 -55 -60 10 mg * 20 mg ** 40 mg † 10 mg 20 mg 40 mg 80 mg Rosuvastatin Atorvastatin Simvastatin 10 mg 20 mg 40 mg 80 mg Pravastatin Over 2/3 of the highest risk patients achieved the modified NCEP III goals on 10mg rosuvastatin or 20mg atorvastatin but not 40mg simvastatin or 40 mg pravastatin 40 mg 10 mg 20 mg *P<.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg. **P<.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg. †P<.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg. Adapted from Jones et al. Am J Cardiol 2003;92:152–160.

29. The randomized evidence is necessary but not sufficient for guidelines.The guidelines are necessary but not sufficient for good clinical judgment.There is absolutely no substitute for good clinical judgment

30. Don’t let the perfect be the enemy of the possible

31. EARLY LANDMARK TRIALS OF STATINSCLINICAL BENEFITS APPEAR @ 2-3 YEARS Continuumof risk High-risk CHD patients (high cholesterol) 22.6 4S(simvastatin) Secondaryprevention Majority of CHD patients (broad range of cholesterol levels) CARE(pravastatin) LIPID(pravastatin) 12.9 8.44 Placebo MI Rate per 100 Subjects per 5 Years Patients at high risk of CHD (high cholesterol) WOSCOPS(pravastatin) Primaryprevention 7.9 Patients at low risk of CHD (low HDL-C) AFCAPS/TexCAPS(lovastatin) 2.8

32. PROVE-IT: Primary End point: All-Cause Death or Major CV Events 30 Pravastatin 40 mg (26.3%) 25 20 Atorvastatin 80 mg (22.4%) 15 % With Event 10 16% RR (P=.005) 5 0 0 30 3 6 9 12 15 18 21 24 27 Months of Follow-up Cannon et al. N Engl J Med 2004;350:1495-1504.

33. PROVE-IT: Primary End pointOver Time Event Rates RR Atorva 80 Prava 40 30 Days 17% 1.9% 2.2% 90 Days 18% 6.3% 7.7% 180 Days 14% 12.2% 14.1% End of Follow-up 16% 22.4%* 26.3%* 0.5 0.75 1.0 1.25 1.5 Pravastatin 40 mg Better Atorvastatin 80 mg Better *2-year event rates. Cannon et al. N Engl J Med 2004;350:1495-1504.

34. Primary Efficacy Outcome Measure:First Major Cardiovascular Event LaRosa et al. N Engl J Med 2005;352.

35. Primary Efficacy Outcome Measure:First Fatal or Nonfatal Stroke LaRosa et al. N Engl J Med 2005;352.

36. TNT: Subgroup analyses of primary endpoint and its components by LDL quintiles(<64;64-<77;77-<90;90-<106;> 106) LaRosa, JC; Grundy, S; et.al. Am J Cardiol 2007;100:747–752

37. Safety * No cases were considered by the investigator with direct resposibility for the patient to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria for rhabdomyolysis LaRosa et al. N Engl J Med 2005;352.

38. Elevations in CK and LDL-C Reduction Cerivastatin (0.2, 0.3, 0.4, 0.8 mg) Atorvastatin (10, 20, 40, 80 mg) 3.0 Pravastatin (20, 40 mg) Rosuvastatin (10, 20, 40 mg) 2.5 Simvastatin(40, 80 mg) 2.0 CK >10 × ULN (%) 1.5 1.0 0.5 0.0 20 25 30 35 40 45 50 55 60 65 70 LDL-C Reduction (%) Please note that the data for this analysis were derived from prescribing information, summary basis of approvals, clinical trials, and other sources. Prospectively designed comparative clinical trials were not utilized in this analysis and results should be interpreted with caution. Reprinted with permission from Brewer. Am J Cardiol. 2003;92(suppl)23K-29K.

39. Implications of Recent Clinical Trialsfor NCEP ATP III Guidelines • Recent trials of higher versus usual dose statins provide greater rationale for lower target LDL-C levels and more intensive LDL-lowering therapy • Key modifications to ATP III treatment algorithm for LDL-C: • LDL-C goal <70 mg/dL is therapeutic option for patients at very high risk • LDL-C goal <100 mg/dL is therapeutic option for moderately high-risk patients • At least 30% to 40% reduction in LDL-C recommended forhigh and moderately high risk patients. Grundy et al. Circulation. 2004;110:227-239.

40. Effectiveness of Statin Titration on Low-DensityLipoprotein Cholesterol Goal Attainment in Patients atHigh Risk of Atherogenic Events Less than 50% (48%) achieved an LDL cholesterol < 100 mg/dl with their initial dose of statin Of those who did not achieve goal with their initial dose, less than 50% (45%) had their dosage titrated Among statin-treated patients who did not achieve the LDL cholesterol goal with their initial dose, less than 15% (14%) attained the goal within 6 months of starting treatment. Foley, K.; Simpson, R; et.al. AJC, 2003; 92:79-81

41. Proportional effects on major vascular events per 1-mmol/L LDL-cholesterol reduction among 90,056 participants in 14 randomized trials of statins End point Treatment-arm events, % (n=45 054) Control-arm events, % (n=45 002 Relative risk (95% CI) Any major vascular event 14.1 17.8 0.79 (0.77-0.81) Any major coronary event 7.4 9.8 0.77 (0.74-0.80) • Nonfatal MI 4.4 6.2 0.74 (0.70-0.79) • CHD death 3.4 4.4 0.81 (0.75-0.87) Any coronary revascularization 5.8 7.6 0.76 (0.73-0.80) • CABG 1.6 2.2 0.75 (0.69-0.82) • PTCA 1.1 1.5 0.79 (0.69-0.90) • Unspecified 3.1 3.9 0.76 (0.69-0.84) Any stroke 3.0 3.7 0.83 (0.78-0.88) Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005; 366: 1267-1278

42. Proportional effects on total and cause-specific mortality per 1-mmol/L LDL-cholesterol reduction among 90,056 participants in 14 randomized trials of statins Cause of death Treatment-arm events, % (n=45 054) Control-arm events, % (n=45 002) Relative risk (95% CI) All-cause 8.5 9.7 0.88 (0.84-0.91) Coronary heart disease 3.4 4.4 0.81 (0.76-0.85) Any non-coronary-heart-disease 1.2 1.3 0.93 (0.83-1.03) Stroke 0.6 0.6 0.91 (0.74-1.11) Other vascular 0.6 0.7 0.95 (0.78-1.16) Any vascular 4.7 5.7 0.83 (0.79-0.87) Any nonvascular 3.8 4.0 0.95 (0.90-1.01) Cancer 2.4 2.4 1.01 (0.91-1.12) Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005; 366: 1267-1278

43. No significant excess of rhabdomyolysis among 90,056 participants in 14 randomized trials of statins treated for about 5 years Statin Control n(%) n(%) 9(0.023) 6(0.015) 5 year excess risk = 0.01%(p=0.4) Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005; 366: 1267-1278

44. MAJOR CONCLUSIONS OF CTT COLLABORATION Statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation and stroke by about one fifth per mmol/l (38mg/dl) reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. The absolute benefit relates chiefly to an individual’s absolute risk of such events and to the absolute reduction in LDL cholesterol achieved. These findings reinforce the need to consider prolonged statin treatment with substantial LDL cholesterol reductions in all patients at high risk of any type of major vascular event.

45. Meta-Analysis of CV Outcome Trials Comparing Intensive versus Moderate Statin TherapyPrimary Prespecified Endpoint: Death or Myocardial Infarction Death or Any CV Event: ↓16% RRR, P<0.0001 CV Mortality: ↓12% RRR, P=0.054 Stroke: ↓18% RRR, p=0.012 Cannon et al. J Am Coll Cardiol Aug 2006;48:438-45

46. Randomized Patients in Trials of Lipid Modifying Drugs and Clinical Cardiovascular Disease Outcomes Statins 90,056 Nicotinic Acid 2,835 Omega-3-FA 11,324 Fibrates Gemfibrozil 2,531 Fenofibrate 9,795 Ezetimibe 0

47. ENHANCE AND SEAS: LACK OF CLINICAL OR PUBLIC HEALTH RELEVANCE ENHANCE: In 752 patients ezetimibe added to simvastatin produced beneficial changes in lipids but no significant reduction in CIMT SEAS: Formulated a hypothesis that ezetimibe increased cancer risk that was not supported in either IMPROVE-IT or SHARP. The benefits and risks of ezetimibe are being tested in IMROVE-IT and SHARP.

48. A CLINICIAN’S DILEMMA Unfortunately, most Americans prefer the prescription of pills to the proscription of harmful lifestyles. Charles H. Hennekens, New York Times