LIPID MODIFICATION IN THE TREATMENT AND PREVENTION OF CARDIOVASCULAR DISEASE: Clinical, Public Health and Ethical Challenges Charles H Hennekens, MD, DrPH Sir Richard Doll Research Professor of Medicine Charles E. Schmidt College of Medicine Florida Atlantic University Clinical Professor of Preventive Medicine Nova Southeastern University Voluntary Professor of Family Medicine and Community Health University of Miami Miller School of Medicine
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.
Death is inevitable but premature death is not. Sir Richard Doll
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. Epidemiology in Medicine. Boston, Mass: Little, Brown & Co.;1987.
ADVANTAGES AND DISADVANTAGES Basic Research Advantage: Precision Disadvantage: ? Relevance to free living humans Epidemiology Advantage: Relevance to free living humans Disadvantage: Imprecision
QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANS Who would have guessed that Homo sapiens would share with the humble guinea pig the unenviable distinction of being unable to synthesize ascorbic acid or with armadillos a susceptibility to the bacterium that causes leprosy or that intestinal cancer usually occurs in the large intestine of humans and the small intestine of sheep? Professor John Cairns
QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANS In basic research over 750,000 chemicals have a potential to cause human cancer but less than 7500 (1%) have any direct relevance to humans Professor Sir Richard Peto
SACCHARIN AND BLADDER CANCER • Canadian rats fed the daily equivalent of 16 gallons of saccharin containing soft drinks developed bladder cancer • US FDA removed saccharin from diet soft drinks • In a case-control study from Harvard School of Public Health published in the New England Journal of Medicine, Massachusetts humans who drank an average of about one to two 12 ounce cans of saccharin containing soft drinks daily had no increased risk of bladder cancer
QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANS When the Harvard researcher was asked how to explain the apparent discrepancies he replied that there must be systematic differences between the Canadian rats and the Massachusetts humans. Columbus Georgia Ledger
QUESTIONABLE RELEVANCE OF BASIC RESEARCH TO FREE LIVING HUMANS I guess it takes a researcher from Harvard to put 2 and 2 together. The New Yorker Magazine
THE NEED FOR LARGE SCALE RANDOMIZED EVIDENCE 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 the most plausible small to moderate effects (i.e.20%) the amount of uncontrolled and uncontrollable confounding inherent in all case control and cohort studies can be as big as the effect sizes so large scale randomized evidence is crucial. Hennekens CH, DeMets D: The need for large scale randomized evidence without undue emphasis on small trials, their meta-analyses or subgroup analyses JAMA 2009; 302:2361-2362.
CONTRIBUTIONS OF SUBGROUP ANALYSES OF RANDOMIZED TRIALS Subgroup analyses of trials are no longer randomized and so have lower sample sizes; They 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 for clinicians and policymakers. Professor Sir Richard Peto
STATISTICAL ASSOCIATION A valid statistical association can be inferred from an analytic study designed a priori to test a hypothesis after exclusion of CHANCE and/or BIAS and/or CONFOUNDING as plausible alternative explanations for any observed findings Hennekens CH, DeMets D: Statistical association and causation: Contributions of different types of evidence JAMA 2011, 305:1134-1135.
STATISTICAL ASSOCIATION AND CAUSE AND EFFECT RELATIONSHIPS • Statistical Association: A matter of fact like death and taxes • Cause and Effect Relationships: A matter of opinion like truth and beauty Hennekens CH, Buring JE: Epidemiology in Medicine, Little, Brown, and Company, Boston, 1987
Evolution of Atherosclerotic Plaque Libby P. The Vascular Biology of Atherosclerosis. In: Braunwald, Zipes, Libby, eds. Heart Disease. 6th edition. 2001.
1985 Nobel Prize in Physiology or Medicine Professors Michael Brown and Joseph Goldstein of Texas Southwestern Medical School discovered the underlying mechanisms of cholesterol metabolism which led to the development of the statin drugs.
Relationship Between Cholesterol and CHD RiskMRFIT (Multiple Risk Factor Intervention Trial) • Each 10% decrease in total cholesterol level is associated with a 20-30% reduction in coronary events • In rural China where average cholesterol is about 140mg/dL, those with cholesterol of 126 have significantly lower risks of coronary events • Epidemological evidence suggests no threshold below which a lower cholesterol is not associated with lower risk. CHD Risk Based on Total Cholesterol (TC) Level 20 16 12 Age-Adjusted 6-Year CHD Death Rate per 1000 Men 8 4 N=361,662 0 140 160 180 200 220 240 260 280 300 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.
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
ATP III Guidelines Primary target for high risk patients: • LDL-C <100 mg/dL Goals for all patients • Total cholesterol <200 mg/dL • HDL-C >40 mg/dL • Triglycerides <150 mg/dL NCEP. JAMA. 2001;285:2486-2497.
ATP III Guidelines: Increased the numbers of US patients eligible for statins from 13 to 36 million • 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)
Metabolic Syndrome • Metabolic syndrome is a constellation of obesity, dyslipidemia, hypertension, and insulin resistance. • In the U.S. , based on NCHS data, 20% of adults aged 20 and over as well as 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%.
Importance of Assessing Multiple Risk Factors for CHD + Hypertension + Low HDL-C + Hyperglycemia Increasing LDL 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)
There is absolutely no substitute for good clinical judgmentThis is because:Randomized trials are necessary to develop guidelinesGuidelines are of crucial importance but are not the sole factor in good clinical judgment.
Heart Protection Study: Nonrandomized Subgroup Analyses Vascular Events by Baseline Lipid Levels Risk ratio and 95% CI Statin(10269) Placebo(10267) Statin better Statin worse Baseline feature LDL cholesterol (mmol/l) < 3.0 (116 mg/dl) 602 761 Het2=3.0 ≥3.0 < 3.5 483 655 ≥3.5 (135 mg/dl) 957 1190 Total cholesterol (mmol/l) < 5.0 (193 mg/dl) 361 476 Het2=0.5 ≥5.0 < 6.0 746 965 ≥6.0 (232 mg/dl) 935 1165 24% SE 2.6reduction(2P<.00001) All patients 2042(19.9%) 2606(25.4%) 0.4 0.6 0.8 1.0 1.2 1.4
PROVE-IT • 4162 post acute coronary syndrome (ACS) patients • 80 mg atorvastatin vs 40 mg pravastatin • Baseline LDL of 106 • Achieved LDL: 44(LDL=62) vs 9(LDL=97) • 24-month treatment and follow-up Cannon et al. N Engl J Med 2004;350:1495-1504.
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.
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.
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.
TNT—Treatment-to-New Targets Trial • 10,002 chronic stable coronary disease patients • Enrollment in 250 sites from 14 countries • Randomized, double-blind trial of 80mg atorvastatin versus 10 mg atorvastatin • Duration of 5 years or accrual of 750 primary CVD events
Primary Efficacy Outcome Measure:First Major Cardiovascular Event LaRosa et al. N Engl J Med 2005;352.
Primary Efficacy Outcome Measure: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) LaRosa, JC; Grundy, S; et.al. Am J Cardiol 2007;100:747–752
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.
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
JUPITER (Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin) • Objective • To investigate whether long-term treatment with rosuvastatin 20 mg daily decreases the rate of first major cardiovascular events compared with placebo in patients with low LDL-C but with increased risk as identified by elevated hsCRP levels • Primary Endpoint • A 25% reduction in first occurrence of a major cardiovascular event (cardiovascular death, stroke, MI, hospitalization for unstable angina, or arterial revascularization) Ridker PM. Circulation. 2003;108:2292-2297.
EARLY TERMINATION OF JUPITER The 10 year risk of a first CHD event in patients randomized into JUPITER was about 16% (about 50% had metabolic syndrome and about 50% had hypertension). On March 29, 2008 JUPITER was terminated early after a median follow up of 1.9 years based on the unanimous recommendation of the independent Data and Safety Monitoring Board (DSMB) The DSMB recommendation was based on “unequivocal evidence of a reduction in cardiovascular morbidity and mortality among patients assigned at random to rosuvastatin when compared to placebo.” JUPITER achieved an average LDL of 55 in the rosuvastatin group and 109 in placebo which resulted in a 44% reduction in the primary pre-specified endpoint.
JUPITER Rosuvastatin was associated with a statistically extreme 44% reduction in the primary pre-specified combined outcome of MI, stroke, unstable angina, revascularization, or cardiovascular death (HR 0.56, 95% CI 0.46-0.69, p < 0.00001) as well as significant reductions in MI, stroke and revascularization. Rosuvastatin was associated with a significant 20% reduction in all cause mortality (p = 0.02) Serious adverse effects were similar in the rosuvastatin and placebo groups (p = 0.60) (p = 0.02) (p < 0.00001) Rosuvastatin (n = 8,901) Placebo (n = 8,901) Results 2 2 1.36 1.25 Events/100 Person-Yrs Events/100 Person-Yrs 1.0 1 1 0.77 0 0 Primary outcome All-cause mortality Ridker PM, et al. NEJM 2008;359:2195-207
LDL levels achieved in three landmark randomized trials of statins in different populations showing statistically significant and clinically important benefits of achieving lower LDL levels NAME OF TRIALLDL ACHIEVED HIGH DOSE USUAL DOSE PROVE-IT 62 97 High risk secondary prevention TNT 77 101 Usual risk secondary prevention JUPITER 55 109 Moderate risk primary prevention (placebo)
Diabetes and Cardiovascular Disease Diabetes is a major risk factor for CVD and can be a component to the metabolic syndrome which markedly increases risks of CVD The CARDS trial of diabetics in primary prevention was terminated early due to a statistically extreme 37% reduction in the primary pre-specified outcome The US National Cholesterol Education Program (NCEP) III has elevated diabetes from a major risk factor to a CHD risk equivalent and recommends that all patients with diabetes should be treated as aggressively as survivors of a CVD event (i.e., MI or stroke).
Multiple CV Risk Factor Modification in Type 2 Diabetes*: UKPDS 23 *Adjusted for age and gender in 2693 Caucasian patients on time to first event † 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.
STATINS AND DIABETES • In a meta-analysis of 13 statin trials with 91,140 participants 4278 developed diabetes (2226 assigned statins and 2052 assigned control) This increase (OR=1.09, 95%CI 1.02-1.17) in risk, if real, is low both in absolute terms and when compared with the reductions in cardiovascular events • Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change. Lancet, 2010; 375:735-742
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.
STELLAR: Attainment of Optimal LDL-C < 100mg/dl Rosuvastatin(n = 473) Simvastatin(n = 648) Atorvastatin(n = 634) Pravastatin(n = 485) 100 † 80 ** 76 90 80 70 70 * 60 53 53 60 Patients ReachingLDL-C <100 mg/dL (%) 44 50 40 28 30 18 14 20 8 8 3 10 1 0 80 mg 10 mg 20 mg 40 mg Treatment *P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg.**P<.002 vs atorvastatin 20 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg.†P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg. McKenney et al. Curr Med Res Opin. 2003;19:557-566.
Percentage Change From Baseline in TG at Week 6 by Dose (ITT) Rosuvastatin (mg) Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) 10 20 40 10 20 40 80 10 20 40 80 10 20 40 0 -5 -10 -7.7 -8.2 -11.9 TG Reduction (%) -15 -13.2 -14.8 -17.6 -18.2 -20 -19.8 * -20 -22.6 -25 -23.7 ** -26.1 † -26.8 -30 -28.2 *P<.002 vs pravastatin 10 mg, 20 mg. **P<.002 vs simvastatin 40 mg; pravastatin 20 mg, 40 mg. †P<.002 vs simvastatin 40 mg; pravastatin 40 mg. Jones et al. Am J Cardiol. 2003;93:152-160.
12 6.8 10 6.0 5.7 5.6 5.3 5.2 4.8 4.4 4.4 8 3.2 6 2.1 4 2 0 Percentage Change From Baseline in HDL-C at Week 6 by Dose (ITT) ** 9.5 † 9.6 * 7.7 HDL-C Increase (%) 10 20 40 10 20 40 80 10 20 40 80 10 20 40 Atorvastatin (mg) Simvastatin (mg) Pravastatin (mg) Rosuvastatin (mg) ITT = intention-to-treat. *P<.002 vs pravastatin 10 mg. **P<.002 vs atorvastatin 20 mg, 40 mg, 80 mg; simvastatin 40 mg; pravastatin 20 mg, 40 mg. †P<.002 vs atorvastatin 40 mg, 80 mg; simvastatin 40 mg; pravastatin 40 mg. Jones et al. Am J Cardiol. 2003;93:152-160.
Effectiveness of Statin Titration on Low-DensityLipoprotein Cholesterol Goal Attainment • 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
Core Components of Statin Safety • Muscle-related adverse events (AEs) • Liver-related AEs