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Unformatted text preview: BEYOND LIFESTYLE CHANGES: THE ROLE OF AGGRESSIVE MEDICAL THERAPY FOR ALL PATIENTS AT INCREASED RISK FOR CARDIOVASCULAR DISEASE CARDIOVASCULAR 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) Disclosure 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. on serve •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. serve •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. Palm serve •I serve as an independent scientist in an advisory role to legal counsel for GlaxoSmithKline and Stryker. serve •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. PriMed, •I receive royalties for authorship or editorship of three textbooks. receive •I receive royalties as co-inventor on patents concerning inflammatory markers and cardiovascular disease which are held by Brigham and Women’s Hospital. and have •I have an investment management relationship with The West-Bacon Group within SunTrust Investment Services who has discretionary investment authority. within do •I do not own any common or preferred stock in any pharmaceutical or medical device company. Death is inevitable but premature death is not death Sir Richard Doll, FRS Sir Regius Professor of Medicine Regius University of Oxford, UK, 1969-1979 Advances in Medical Knowledge Proceed on Several Fronts, Optimally Simultaneously Simultaneously • • • • Basic researchers Basic Health care providers Clinical investigators Epidemiologists and biostatisticians Epidemiologists Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown and Company; 1987. 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. Change In Age-Adjusted Mortality Change 1979 - 1995 10 Noncardiovascular Disease 0 -10 % Decline -20 Coronary Heart Disease -30 Stroke -40 -50 -60 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 National Center for Health Statistics. Heart Disease In The United States Heart • Chief cause of death among men age 45 years Chief and older and • Chief cause of death among women age 65 Chief years and older years • Responsible for 1 in 3 deaths in men and Responsible women, or ~750,000 fatalities each year women, Postulated Reasons for Decreasing CHD Mortality CHD • During acute MI: – Decrease in case fatality rate (20%-30% → 5%-10%) Decrease for hospitalized MI for – Increase in utilization of: • Aspirin • Thrombolytics ∀ β-blockers • ACE inhibitors Hennekens CH et al. NEJM 1996;335:1660-1667 Postulated Reasons for Decreasing CHD Mortality (cont’d) CHD • Secondary prevention: – Therapeutic lifestyle changes (TLC) – Increase in utilization of: • Aspirin ∀ β-blockers • ACE inhibitors • Statins (HMG-CoA reductase inhibitors) Hennekens CH et al. NEJM 1996;335:1660-1667 Postulated Reasons for Decreasing CHD Mortality (cont’d) CHD • Primary prevention: – Decrease in smoking • >50% → <25% >50% – Increase in treatment of hypertension: • 16% → 55% 16% – Increase in treatment of dyslipidemia: • Cholesterol population target 220 mg/dl → 200 mg/dl Cholesterol Manson JE et al. NEJM 1992;326:1406-1416. Trends Among US Adolescents Trends Smoking (22%-30%) Obesity Physical Inactivity Type 2 Diabetes Hennekens CH. Circulation. 1998;97:1095. LIFE EXPECTANCY AT BIRTH LIFE • US AND RICH COUNTRIES: 77 YEARS (73 US IN MEN AND 81 IN WOMEN IN • POOR COUNTRIES: 50 YEARS (46 IN MEN POOR AND 54 IN WOMEN) AND Shifting Worldwide Burden of Disease 1990 All Other 25.5% 2020 Cancer 11.9% All Other 33.2% Cancer 18.0% CVD 28.4% Communicable, Perinatal, Nutritional 34.2% Communicable, Perinatal, Nutritional 15.1% CVD 33.7% Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996. Reasons for Worldwide Increase in Reasons Cardiovascular Disease Cardiovascular Malnutrition Malnutrition Infection Smoking BMI Hennekens CH. Circulation. 1998;97:1095-1102. Increasing Worldwide Burden of Cardiovascular Disease Cardiovascular 1990 Years of Life Lost Premature Death and Disability and 2020 4th 1st 5th 1st Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996. Conclusion Conclusion • Based on these considerations, the World Based Health Organization has projected that, within the next decade, cardiovascular disease will be the leading cause of death and disability in the world the Selected Worldwide Death Rates From CHD in Adults Aged 34 to 74 Years* CHD Death Rate (per 100,000) Country Men Women Total Russian Federation 638 231 869 Bulgaria 353 133 486 United Kingdom 265 97 362 United States 214 87 301 Austria 223 74 297 Germany 206 72 278 France 87 20 107 Japan 57 20 77 *All values are for 1997. British Heart Foundation. Coronary Heart Disease Statistics: British Heart Foundation Statistics Database. London, England: British Heart Foundation; 2002. CONTRIBUTIONS OF DIFFERENT TYPES OF EVIDENCE TYPES (HENNEKENS AND BURING, EPIDEMIOLOGY IN MEDICINE, 1987) For •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 evidence For •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 •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) communication) AHA/ACC SECONDARY PREVENTION FOR PATIENTS WITH CORONARY AND OTHER VASCULAR DISEASE-2006 UPDATE VASCULAR • • • • • • • • • 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 ATP III Guidelines: Definitions of Increased Risk for CVD Risk • Prior CVD event – – – • CHD CHD Stroke Other clinical forms of atherosclerotic disease Other (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease) aneurysm, Risk factors that confer a 10-year risk for CHD Risk ≥20% ≥20% – Diabetes – ≥2 risk factors (metabolic syndrome) Diabetes and Cardiovascular Disease Diabetes • • • • The US National Cholesterol Education Program (NCEP) III has The elevated diabetes from a major risk factor to a CHD risk equivalent Diabetes is a major contributor to the metabolic syndrome of multiple Diabetes metabolic risk factors (obesity, dyslipidemia, diabetes, hypertension) that markedly increases risks of CVD that In the general US population 25% of adults have metabolic syndrome In All patients with diabetes should be treated as aggressively as All survivors of a CVD event (i.e., MI or stroke)(Expert Panel on Detection, survivors Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:24862497.) • • In PROVE-IT and TNT there were no modifications of the benefits of In higher doses of statins among the diabetics who had higher absolute risks. risks. The failure to treat diabetics aggressively with higher doses of more The potent statins has major deleterious clinical and public health implications. implications. Modifiable CV Risk Factors in Modifiable Patients with Type 2 Diabetes*: Patients Results from UKPDS 23 Results Position Variable P Value† First LDL–C <0.0001 Second HDL–C 0.0001 Third A1c 0.0022 Fourth Systolic BP 0.0065 Fifth Smoking 0.056 CV = cardiovascular. CV *Adjusted for age and gender in 2693 Caucasian patients with type 2 diabetes, with dependent variable as time to first *Adjusted event. event. † Significant Turner RC et al. BMJ 1998;316:823–828. are significance of risk factor after controlling for all other risk disease (n = 280). P values ASignificant for coronary artery BMJ. 1998;316:823–828. dapted Adapted from factors in model. factors Metabolic Syndrome Metabolic • • • • “The U.S. is the fattest society in the world and likely The to be the fattest in the history of the world”. (CH Hennekens, NY Times 1/1/99) Hennekens, Obesity is associated with dyslipidemia, Obesity hypertension, and insulin resistance which has been termed metabolic syndrome. termed In the U.S. 25% of adults aged 25 and older and 40% In of adults aged 40 and older have metabolic syndrome. syndrome. Patients with metabolic syndrome have a 10 year risk Patients of a first CHD event of 16-18%. of Importance of Assessing Multiple Risk Factors for CHD Factors + Hypertension + Hyperglycemia CHD Risk per 100 (10 y) 30 + Low HDL-C No other RF + Smoking 25 20 15 10 5 0 <100 100-129 130-159 160-189 LDL cholesterol (mg/dL) ≥190 Randomized Comparisons of Different Statins at Different Doses Statins The STELLAR Trial 0 ­5 ­10 Change in LDL­C From Baseline (%) ­15 ­20 ­25 ­30 ­35 ­40 ­45 10 mg * 20 mg ** 10 mg 20 mg 10 mg 10 mg 20 mg 20 mg ­50 40 mg 40 mg 40 mg 80 mg 80 mg ­55 ­60 40 mg † Rosuvastatin Atorvastatin Simvastatin 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 *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. The randomized evidence is necessary but not sufficient for guidelines. but The guidelines are necessary but not The sufficient for good clinical judgment. sufficient There is absolutely no substitute for There good clinical judgment good Don’t let the perfect be the enemy of the possible of EARLY LANDMARK TRIALS OF STATINS EARLY CLINICAL BENEFITS APPEAR @ 2-3 YEARS CLINICAL Continuum of risk Placebo MI Rate per 100 Subjects per 5 Years 22.6 12.9 Secondary prevention 2.8 CARE (pravastatin) LIPID (pravastatin) 8.44 7.9 4S (simvastatin) Primary prevention WOSCOPS (pravastatin) AFCAPS/TexCAPS (lovastatin) High-risk CHD patients (high cholesterol) Majority of CHD patients (broad range of cholesterol levels) Patients at high risk of CHD (high cholesterol) Patients at low risk of CHD (low HDL-C) PROVE-IT: Primary End point: All-Cause PROVE-IT: Death or Major CV Events Death 30 Pravastatin 40 mg (26.3%) % With Event 25 20 Atorvastatin 80 mg 15 (22.4%) 10 16% RR (P=.005) 5 0 0 3 6 9 12 15 18 21 Months of Follow-up Cannon et al. N Engl J Med 2004;350:1495-1504. 24 27 30 PROVE-IT: Primary End point Over Time Event Rates RR Atorva 80 Prava 40 1.9% 30 Days 17% 90 Days 18% 6.3% 7.7% 180 Days 14% 12.2% 14.1% End of Follow-up 16% 26.3%* 22.4%* 0.5 0.75 1.0 Atorvastatin 80 mg Better 1.25 1.5 Pravastatin 40 mg Better *2-year event rates. Cannon et al. N Engl J Med 2004;350:1495-1504. 2.2% Primary Efficacy Outcome Measure: Primary First Major Cardiovascular Event LaRosa et al. N Engl J Med 2005;352. Primary Efficacy Outcome Measure: Primary First Fatal or Nonfatal Stroke LaRosa et al. N Engl J Med 2005;352. TNT: Subgroup analyses of primary endpoint and its components by LDL quintiles(<64;64-<77;77-<90;90-<106;> 106) quintiles(<64;64-<77;77-<90;90-<106; LaRosa, JC; Grundy, S; et.al. Am J Cardiol 2007;100:747–752 Safety Safety No. of patients (%) Atorvastatin 10 mg Atorvastatin 80 mg (n = 5006) (n = 4995) Overall treatment-related AEs Overall Treatment-related myalgia Treatment-related 289 (5.8) 406 (8.1) 234 (4.7) 241 (4.8) Rhabdomyolysis* 3 (0.06) 2 (0.04) AST/ALT elevation >3 x ULN 9 (0.2) 60 (1.2) * 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. Elevations in CK and LDL-C Reduction Elevations Cerivastatin (0.2, 0.3, 0.4, 0.8 mg) CK >10 × ULN (%) 2.5 Atorvastatin (10, 20, 40, 80 mg) Pravastatin (20, 40 mg) 3.0 Rosuvastatin (10, 20, 40 mg) Simvastatin (40, 80 mg) 2.0 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)23K­29K. Implications of Recent Clinical Trials Implications for NCEP ATP III Guidelines • • Recent trials of higher versus usual dose Recent statins provide greater rationale for lower target LDL-C statins levels and more intensive LDL-lowering therapy Key modifications to ATP III treatment algorithm for LDLC: – LDL-C goal <70 mg/dL is therapeutic option for patients LDL-C at very high risk – LDL-C goal <100 mg/dL is therapeutic option for moderately highrisk patients – At least 30% to 40% reduction in LDL-C recommended for recommended high and moderately high risk patients. Grundy et al. Circulation. 2004;110:227­239. Effectiveness of Statin Titration on Low-Density Effectiveness Lipoprotein Cholesterol Goal Attainment in Patients at High Risk of Atherogenic Events • Less than 50% (48%) achieved an LDL cholesterol < Less 100 mg/dl with their initial dose of statin 100 • Of those who did not achieve goal with their initial Of dose, less than 50% (45%) had their dosage titrated dose, • Among statin-treated patients who did not achieve Among the LDL cholesterol goal with their initial dose, less than 15% (14%) attained the goal within 6 months of starting treatment. starting Foley, K.; Simpson, R; et.al. AJC, 2003; 92:79-81 Proportional effects on major vascular events per 1Proportional mmol/L LDL-cholesterol reduction among 90,056 participants in 14 randomized trials of statins participants End point Any major vascular Any event event Any major coronary Any event event •Nonfatal MI •CHD death Any coronary Any revascularization revascularization •CABG PTCA •PTCA •Unspecified Any stroke Any Treatment-arm Treatment-arm events, % events, (n=45 054) 14.1 Control-arm Control-arm events, % (n=45 002 (n=45 17.8 Relative risk (95% CI) 7.4 9.8 0.77 (0.74-0.80) 4.4 3.4 5.8 6.2 4.4 7.6 0.74 (0.70-0.79) 0.81 (0.75-0.87) 0.76 (0.73-0.80) 1.6 1.1 3.1 3.0 3.0 2.2 1.5 3.9 3.7 0.75 (0.69-0.82) 0.75 0.79 (0.69-0.90) 0.76 (0.69-0.84) 0.83 (0.78-0.88) 0.79 (0.77-0.81) Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005; 366: 1267-1278 Proportional effects on total and cause-specific mortality Proportional per 1-mmol/L LDL-cholesterol reduction among 90,056 per participants in 14 randomized trials of statins participants Cause of death Control-arm Control-arm events, % (n=45 002) (n=45 9.7 Relative risk (95% CI) Coronary heart 3.4 Coronary 3.4 disease disease Any non-coronary- 1.2 heart-disease 4.4 4.4 0.81 (0.76-0.85) 1.3 0.93 (0.83-1.03) Stroke Other vascular Any vascular Any nonvascular Cancer 0.6 0.7 5.7 4.0 2.4 0.91 (0.74-1.11) 0.95 (0.78-1.16) 0.83 (0.79-0.87) 0.95 (0.90-1.01) 1.01 (0.91-1.12) All-cause Treatment-arm Treatment-arm events, % (n=45 054) (n=45 8.5 0.6 0.6 4.7 3.8 2.4 0.88 (0.84-0.91) Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005; 366: 1267-1278 No significant excess of rhabdomyolysis among 90,056 participants in 14 randomized trials of statins treated for about 5 years trials Statin Statin n(%) 9(0.023) 9(0.023) Control n(%) 6(0.015) 5 year excess risk = 0.01%(p=0.4) year Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005; Cholesterol Lancet 366: 1267-1278 366: MAJOR CONCLUSIONS OF CTT COLLABORATION COLLABORATION Statin •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 •The absolute benefit relates chiefly to an individual’s absolute risk of such events and to the absolute reduction in LDL cholesterol achieved. These •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 reductions major vascular event. major Meta-Analysis of CV Outcome Trials Comparing Intensive versus Moderate Statin Therapy Statin Primary Prespecified Endpoint: Death or Myocardial Infarction Death 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 Randomized Patients in Trials of Lipid Modifying Drugs and Clinical Cardiovascular Disease Outcomes Disease • • • • • Statins 90,056 Nicotinic Acid 2,835 Omega-3-FA 11,324 Fibrates – Gemfibrozil – Fenofibrate 2,531 9,795 Ezetimibe 0 ENHANCE AND SEAS: LACK OF CLINICAL OR PUBLIC HEALTH RELEVANCE OR • ENHANCE: In 752 patients ezetimibe added ENHANCE: to simvastatin produced beneficial changes in lipids but no significant reduction in CIMT lipids • SEAS: Formulated a hypothesis that SEAS: ezetimibe increased cancer risk that was not supported in either IMPROVE-IT or SHARP. supported • The benefits and risks of ezetimibe are being The tested in IMROVE-IT and SHARP. tested A CLINICIAN’S DILEMMA Unfortunately, most Americans prefer the prescription of pills to the proscription of harmful lifestyles. harmful Charles H. Hennekens, Charles New York Times New French Fries French 20 years ago 210 calories 2.4 ounces Today 610 calories How manycalories are in6.9 ounces these fries? Calorie difference: 400 Calories How to burn* 400 calories: Walk 2 hour 20 minutes *Based on 130-pound person. Darwinism and Risk of Cardiovascular Disease of Walking the Dog Walking Established Risk Factors for CHD Established Blood cholesterol 10% ↓ = 20%-30% ↓ in CHD 10% High blood pressure 5-6 mm Hg ↓ = 42% ↓ in Stroke 5-6 = 16% ↓ in CHD Cigarette smoking Cessation = 50%-70% ↓ in CHD Cessation Body weight BMI<25 vs BMI>27 = 35%-55% ↓ in CHD Physical activity 20-minute brisk walk daily = 35%-55% ↓ in CHD 20-minute CHIEF AVOIDABLE CAUSES OF PREMATURE DEATH IN THE US PREMATURE • • • • • • CIGARETTES OBESITY PHYSICAL INACTIVITY LIPIDS BLOOD PRESSURE HEAVY ALCOHOL CONSUMPTION Relationship Between Cholesterol and CHD Risk and MRFIT (Multiple Risk Factor Intervention Trial) Age-Adjusted 6-Year CHD Death Rate per 1000 Men CHD Risk Based on Total Cholesterol (TC) Level • 20 16 • 12 8 4 0 N=361,662 140 160 180 200 220 240 260 280 300 Serum TC (mg/dL) CHD - coronary heart disease. Gotto, AM et al. Circulation. 1990;81:1721-1733. Chen, Z; Peto, R ; Collins R et al. BMJ, 1991; 301: 276-282. • Each 10% decrease in Each total cholesterol level is associated with a 20associated 30% reduction in 30% coronary events coronary In rural China where In average cholesterol is about 140mg/dL, those with cholesterol of 126 have significantly lower risks of coronary events risks Epidemological Epidemological evidence suggests no threshold below which a lower cholesterol is not associated with lower risk. lower GOALS OF HEALTH CARE PROVIDERS AND ACADEMIC RESEARCHERS Maximize benefit and minimize risk which is not to be confused with avoidance of risk. of Make clinical decisions based on the totality of evidence not dependence on Make particular subgroups of particular studies. particular Avoid misstatements of benefit to risk ratios which may increase publicity, Avoid promotions and grant support in the short run but confuse colleagues and frighten patients and make it more difficult to conduct high quality research ( COX-2 inhibitors and glitazones) COX-2 “We must all hang together, or assuredly We we shall all hang separately.” we – Benjamin Franklin Benjamin July 4, 1776 ...
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