lipid modification in the treatment and prevention of cardiovascular disease: clinical, public...

LIPID MODIFICATION IN THE LIPID MODIFICATION IN THE TREATMENT AND PREVENTION OF TREATMENT AND PREVENTION OF

CARDIOVASCULAR DISEASE:CARDIOVASCULAR DISEASE: Clinical, Public Health and Ethical Clinical, Public Health and Ethical

Challenges Challenges

Charles H Hennekens, MD, DrPHCharles H Hennekens, MD, DrPHSir Richard Doll Research Professor of Medicine Sir Richard Doll Research Professor of Medicine

Charles E. Schmidt College of Medicine Charles E. Schmidt College of Medicine Florida Atlantic UniversityFlorida Atlantic University

Clinical Professor of Preventive MedicineClinical Professor of Preventive MedicineNova Southeastern UniversityNova Southeastern University

Voluntary Professor of Family Medicine and Community HealthVoluntary Professor of Family Medicine and Community HealthUniversity of Miami Miller School of Medicine University of Miami Miller School of Medicine

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

Disclosure

Death is inevitable but Death is inevitable but

premature death is not.premature death is not.

Sir Richard DollSir Richard Doll

Hennekens CH. Epidemiology in Medicine. Boston, Mass: Little, Brown & Co.;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

ADVANTAGES AND DISADVANTAGES

Basic ResearchAdvantage: Precision

Disadvantage: ? Relevance to free living humans

EpidemiologyAdvantage: 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


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


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


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 Hennekens CH, DeMets D: The need for large scale randomized evidence evidence without undue emphasis on small trials, their meta-analyses or without undue emphasis on small trials, their meta-analyses or subgroup analyses JAMA 2009; 302:2361-2362.subgroup analyses JAMA 2009; 302:2361-2362.

CONTRIBUTIONS OF SUBGROUP CONTRIBUTIONS OF SUBGROUP ANALYSES OF RANDOMIZED TRIALSANALYSES OF RANDOMIZED TRIALS

Subgroup analyses of trials are no longer Subgroup analyses of trials are no longer randomized and so have lower sample sizes;randomized and so have lower sample sizes;

They should be viewed, at best, as hypothesis They should be viewed, at best, as hypothesis formulating and, at worst, as rubbish. formulating and, at worst, as rubbish.

The biggest danger in interpretation of subgroups is The biggest danger in interpretation of subgroups is acting as if they provide serious evidence for acting as if they provide serious evidence for clinicians and policymakers.clinicians and policymakers.

Professor Sir Richard PetoProfessor 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

CONFOUNDINGas plausible alternative explanations for any observed findings

Hennekens CH, DeMets D: Statistical association and causation: Contributions of different types of evidenceJAMA 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 PlaqueEvolution 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 Relationship Between Cholesterol and CHD Riskand CHD Risk

MRFIT (Multiple Risk Factor Intervention Trial)MRFIT (Multiple Risk Factor Intervention Trial)

• Each 10% decrease in Each 10% decrease in total cholesterol level is total cholesterol level is associated with a 20-associated with a 20-30% reduction in 30% reduction in coronary eventscoronary events

• In rural China where In rural China where average cholesterol is average cholesterol is about 140mg/dL, those about 140mg/dL, those with cholesterol of 126 with cholesterol of 126 have significantly lower have significantly lower risks of coronary eventsrisks of coronary events

• Epidemological Epidemological evidence suggests no evidence suggests no threshold below which a threshold below which a lower cholesterol is not lower cholesterol is not associated with lower associated with lower risk.risk.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.

Serum TC (mg/dL)

CHD Risk Based on Total Cholesterol (TC) LevelCHD Risk Based on Total Cholesterol (TC) Level

Age

-Adj

uste

d 6-

Year

CH

D

Dea

th R

ate

per 1

000

Men 20

16

12

8

4

0140 160 180 200 220 240 260 280 300

N=361,662

EARLY LANDMARK TRIALS OF STATINSEARLY LANDMARK TRIALS OF STATINS CLINICAL BENEFITS APPEAR @ 2-3 YEARSCLINICAL BENEFITS APPEAR @ 2-3 YEARS

4S(simvastatin)

WOSCOPS(pravastatin)

AFCAPS/TexCAPS(lovastatin)

CARE(pravastatin)

LIPID(pravastatin)

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)

Secondaryprevention

Primaryprevention

Continuumof risk

22.6

12.9

8.44

7.9

2.8Plac

ebo

MI R

ate

per 1

00

Subj

ects

per

5 Y

ears

ATP III GuidelinesATP III Guidelines

Primary target for high risk patients:Primary target for high risk patients:

• LDL-C LDL-C <100 mg/dL<100 mg/dL

Goals for all patientsGoals for all patients

• Total cholesterol Total cholesterol <200 mg/dL<200 mg/dL

• HDL-C HDL-C >40 mg/dL>40 mg/dL

• Triglycerides Triglycerides <150 mg/dL<150 mg/dL

NCEP. NCEP. JAMA.JAMA. 2001;285:2486-2497. 2001;285:2486-2497.

ATP III Guidelines: Increased the numbers of US ATP III Guidelines: Increased the numbers of US patients eligible for statins from 13 to 36 millionpatients eligible for statins from 13 to 36 million

• Prior CVD eventPrior CVD event– CHD CHD – StrokeStroke– Other clinical forms of atherosclerotic disease Other clinical forms of atherosclerotic disease

(peripheral arterial disease, abdominal aortic (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease)aneurysm, and symptomatic carotid artery disease)

• Risk factors that confer a 10-year risk for CHD Risk factors that confer a 10-year risk for CHD ≥20%≥20%– DiabetesDiabetes– ≥≥2 risk factors (metabolic syndrome)2 risk factors (metabolic syndrome)

Metabolic SyndromeMetabolic Syndrome

• Metabolic syndrome is a constellation of obesity, Metabolic syndrome is a constellation of obesity, dyslipidemia, hypertension, and insulin resistance. dyslipidemia, hypertension, and insulin resistance.

• In the U.S. , based on NCHS data, 20% of adults In the U.S. , based on NCHS data, 20% of adults aged 20 and over as well as 40% of adults aged 40 aged 20 and over as well as 40% of adults aged 40 and older have metabolic syndrome.and older have metabolic syndrome.

• Patients with metabolic syndrome have a 10 year risk Patients with metabolic syndrome have a 10 year risk of a first CHD event of 16-18%.of a first CHD event of 16-18%.

Importance of Assessing Multiple Risk Importance of Assessing Multiple Risk Factors for CHDFactors for CHD

LDL cholesterol (mg/dL)

30

25

20

15

10

0<100 100-129 ≥190

CH

D R

isk

per 1

00 (1

0 y)

5

+ Hypertension+ Hyperglycemia+ Smoking

+ Low HDL-CIncreasing LDL

130-159 160-189

There is absolutely no There is absolutely no substitute for good clinical substitute for good clinical judgmentjudgment

This is because:This is because:

Randomized trials are necessary to Randomized trials are necessary to develop guidelinesdevelop guidelines

Guidelines are of crucial importance Guidelines are of crucial importance but are not the sole factor in good but are not the sole factor in good clinical judgment. clinical judgment.

Heart Protection Study: Nonrandomized Subgroup Analyses Heart Protection Study: Nonrandomized Subgroup Analyses Vascular Events by Baseline Lipid LevelsVascular Events by Baseline Lipid Levels

Statin(10269)

Placebo(10267)

Risk ratio and 95% CIStatin better Statin worseBaseline feature

LDL cholesterol (mmol/l)602 761< 3.0 (116 mg/dl)483 655 ≥3.0 < 3.5 957 1190 ≥3.5 (135 mg/dl)

Total cholesterol (mmol/l)361 476< 5.0 (193 mg/dl)746 965 ≥5.0 < 6.0935 1165≥6.0 (232 mg/dl)

24% SE 2.6reduction

(2P<.00001)2042

(19.9%)2606

(25.4%)All patients

0.4 0.6 0.8 1.0 1.2 1.4

HetHet22=0.5=0.5

HetHet22=3.0=3.0

PROVE-ITPROVE-IT

• 4162 post acute coronary syndrome (ACS) 4162 post acute coronary syndrome (ACS) patientspatients

• 80 mg atorvastatin vs 40 mg pravastatin80 mg atorvastatin vs 40 mg pravastatin• Baseline LDL of 106Baseline LDL of 106• Achieved LDL: 44(LDL=62) vs 9(LDL=97)Achieved LDL: 44(LDL=62) vs 9(LDL=97)• 24-month treatment and follow-up24-month treatment and follow-up

Cannon et al. N Engl J Med 2004;350:1495-1504.

00 33 1818 2121 2424 2727 303066 99 1212 1515

% W

ith E

vent

Months of Follow-up

Pravastatin 40 mgPravastatin 40 mg(26.3%)(26.3%)

Atorvastatin 80 mgAtorvastatin 80 mg(22.4%)(22.4%)

16% RR16% RR((PP=.005)=.005)

3030

2525

2020

1515

1010

55

00

Cannon et al. N Engl J Med 2004;350:1495-1504.

PROVE-IT: Primary End point: All-Cause PROVE-IT: Primary End point: All-Cause Death or Major CV EventsDeath or Major CV Events

18% 6.3% 7.7%

End of Follow-up

PROVE-IT: Primary End pointPROVE-IT: Primary End pointOver TimeOver Time

Atorvastatin 80 mg Better 0.5

Pravastatin 40 mg Better

180 Days

90 Days

30 Days

14% 12.2% 14.1%

RR Atorva 80 Prava 40

17% 1.9% 2.2%

16% 22.4%* 26.3%*

Event Rates

0.75 1.51.25 1.0

*2-year event rates.Cannon et al. N Engl J Med 2004;350:1495-1504.

Implications of Recent Clinical TrialsImplications of Recent Clinical Trialsfor NCEP ATP III Guidelinesfor NCEP ATP III Guidelines

• Recent trials of Recent trials of higher versus usual dose higher versus usual dose statinsstatins provide greater rationale for lower target LDL-C provide greater rationale for lower target LDL-C levels and more intensive LDL-lowering therapy levels and more intensive LDL-lowering therapy

• Key modifications to ATP III treatment algorithm for LDL-Key modifications to ATP III treatment algorithm for LDL-C:C:– LDL-C goal <70 mg/dL is therapeutic option for patients LDL-C goal <70 mg/dL is therapeutic option for patients

at very high risk at very high risk – LDL-C goal <100 mg/dL is therapeutic option for moderately high-LDL-C goal <100 mg/dL is therapeutic option for moderately high-

risk patientsrisk patients– At least 30% to 40% reductionAt least 30% to 40% reduction in LDL-C in LDL-C

recommended forrecommended forhigh and moderately high risk patients.high and moderately high risk patients.

Grundy et al. Circulation. 2004;110:227-239.

TNT—Treatment-to-New Targets TrialTNT—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:Primary Efficacy Outcome Measure:First Major Cardiovascular EventFirst Major Cardiovascular Event

LaRosa et al. N Engl J Med 2005;352.

Primary Efficacy Outcome Measure:Primary Efficacy Outcome Measure:First Fatal or Nonfatal StrokeFirst Fatal or Nonfatal Stroke


TNT: Subgroup analyses of primary TNT: Subgroup analyses of primary endpoint and its components by LDL endpoint and its components by LDL

quintiles(<64;64-<77;77-<90;90-<106;quintiles(<64;64-<77;77-<90;90-<106;>> 106) 106)

LaRosa, JC; Grundy, S; et.al. Am J Cardiol 2007;100:747–752

SafetySafety

No. of patients (%)No. of patients (%)

Atorvastatin 10 mgAtorvastatin 10 mg

(n = 5006)(n = 5006)

Atorvastatin 80 mgAtorvastatin 80 mg

(n = 4995)(n = 4995)

Overall treatment-related SAEs Overall treatment-related SAEs Treatment-related myalgiaTreatment-related myalgia

289 (5.8)289 (5.8)

234 (4.7)234 (4.7)

406 (8.1)406 (8.1)

241 (4.8)241 (4.8)

Rhabdomyolysis*Rhabdomyolysis* 3 (0.06)3 (0.06) 2 (0.04)2 (0.04)

AST/ALT elevation >3 x ULNAST/ALT elevation >3 x ULN 9 (0.2)9 (0.2) 60 (1.2)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


Meta-Analysis of CV Outcome Trials Comparing Intensive versus Moderate Meta-Analysis of CV Outcome Trials Comparing Intensive versus Moderate Statin TherapyStatin Therapy

Primary Prespecified Endpoint: Primary Prespecified Endpoint: Death or Myocardial InfarctionDeath or Myocardial Infarction

Cannon et al. J Am Coll Cardiol Aug 2006;48:438-45

Death or Any CV Event: ↓16% RRR, P<0.0001

CV Mortality: ↓12% RRR, P=0.054

Stroke: ↓18% RRR, p=0.012

JUPITERJUPITER

• 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)

((JJustification for the ustification for the UUse of statins in se of statins in PPrimary prevention: rimary prevention: an an IIntervention ntervention TTrial rial EEvaluating valuating RRosuvastatin)osuvastatin)

Ridker PM. Circulation. 2003;108:2292-2297.

EARLY TERMINATION OF JUPITER 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.

0

1.01.25

2

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)

Results (p < 0.00001)

Rosuvastatin(n = 8,901)

Placebo (n = 8,901)

(p = 0.02)

2

0.77

1.36

Even

ts/1

00 P

erso

n-Yr

s

0

Primary outcome All-cause mortality

1

Ridker PM, et al. NEJM 2008;359:2195-207

1

Even

ts/1

00 P

erso

n-Yr

s

LDL levels achieved in three landmark randomized trials of statins in different

populations showing statistically significant and clinically important benefits of achieving

lower LDL levelsNAME OF TRIAL LDL ACHIEVED

HIGH DOSE USUAL DOSE

PROVE-IT 62 97 High risk secondary preventionTNT 77

101 Usual risk secondary preventionJUPITER 55 109

Moderate risk primary prevention

(placebo)

Diabetes and Cardiovascular DiseaseDiabetes and Cardiovascular Disease

• Diabetes is a major risk factor for CVD and can be a Diabetes is a major risk factor for CVD and can be a component to the metabolic syndrome which component to the metabolic syndrome which markedly increases risks of CVDmarkedly increases risks of CVD

• The CARDS trial of diabetics in primary prevention The CARDS trial of diabetics in primary prevention was terminated early due to a statistically extreme was terminated early due to a statistically extreme 37% reduction in the primary pre-specified outcome37% reduction in the primary pre-specified outcome

• The US National Cholesterol Education Program The US National Cholesterol Education Program (NCEP) III has elevated diabetes from a major risk (NCEP) III has elevated diabetes from a major risk factor to a CHD risk equivalent and recommends factor to a CHD risk equivalent and recommends that all patients with diabetes should be treated as that all patients with diabetes should be treated as aggressively as survivors of a CVD event (i.e., MI or aggressively as survivors of a CVD event (i.e., MI or stroke).stroke).

Multiple CV Risk Factor Modification in Multiple CV Risk Factor Modification in Type 2 Diabetes*: UKPDS 23Type 2 Diabetes*: UKPDS 23

PositionPosition VariableVariable PP Value Value††

FirstFirst LDL–CLDL–C <0.0001<0.0001

SecondSecond HDL–CHDL–C 0.00010.0001

ThirdThird AA1c1c 0.00220.0022

FourthFourth Systolic BPSystolic BP 0.00650.0065

FifthFifth SmokingSmoking 0.0560.056

Adapted from Turner RC et al. Adapted from Turner RC et al. BMJBMJ. 1998;316:823–828. . 1998;316:823–828.

*Adjusted for age and gender in 2693 Caucasian patients on time to first event*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.P values are significance of risk factor after controlling for all other risk factors in model.

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 Randomized Comparisons of Different Statins at Different DosesStatins at Different Doses

Change in LDL-C From Baseline (%)0 -10 -20 -30 -40 -50 -60

10mg*

-5 -15 -25 -35 -45 -55

20mg**

40mg†

10mg

20mg

80 mg

10mg

20mg

40mg

80mg

10mg

20mg

40mg

RosuvastatinAtorvastatinSimvastatinPravastatin

40mg

*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 STELLAR Trial

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

STELLAR: Attainment ofSTELLAR: Attainment of Optimal LDL-C < 100mg/dl Optimal LDL-C < 100mg/dl

*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.

Rosuvastatin(n = 473)Atorvastatin(n = 634)

Simvastatin(n = 648)Pravastatin(n = 485)

10 mg 20 mg 40 mg 80 mg

Pati

ents

Rea

chin

gLD

L-C

<10

0 m

g/dL

(%

)

0102030405060708090

53

188

1

**76

44

143

†

80

60

28

8

70

53

100

Treatment

*

Percentage Change From Baseline in Percentage Change From Baseline in TG at Week 6 by Dose (ITT)TG at Week 6 by Dose (ITT)

Simvastatin(mg)

*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.

-20

-22.6

-26.8-28.2

TG R

educ

tion

(%

)

Rosuvastatin(mg)

Atorvastatin(mg)

Pravastatin(mg)

-11.9

-17.6

-14.8

-18.2

10 20 40 80

-23.7**

-26.1†

-19.8*

10 20 40 10 20 40 80

-8.2 -7.7

-13.2

10 20 40

-30

-25

-20

-15

-10

0

-5

Percentage Change From Baseline in Percentage Change From Baseline in HDL-C at Week 6 by Dose (ITT)HDL-C at Week 6 by Dose (ITT)

HD

L-C

Incr

ease

(%

)

Rosuvastatin(mg)

Atorvastatin(mg)

Simvastatin(mg)

Pravastatin(mg)

10 20 40

3.2

4.45.6

10 20 40 80 10 20 40 0

2

4

6

8

10

12

5.74.8

4.4

2.1

*7.7

**9.5

†9.6

10 20 40 80

5.36.0

5.2

6.8

*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.

ITT = intention-to-treat.

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 SafetyCore Components of Statin Safety

• Muscle-related adverse events (AEs)Muscle-related adverse events (AEs)

• Liver-related AEsLiver-related AEs

Incidence of Statin-Associated Incidence of Statin-Associated RhabdomyolysisRhabdomyolysis

• The incidence of statin-associated The incidence of statin-associated rhabdomyolysis across large, randomized, rhabdomyolysis across large, randomized, controlled statin trials is <0.1% controlled statin trials is <0.1%

• The reported incidence of fatal The reported incidence of fatal rhabdomyolysis with statins is extremely rare: rhabdomyolysis with statins is extremely rare: – 0.15 deaths per 1 million prescriptions which is a 0.15 deaths per 1 million prescriptions which is a

weighted average of 0.18 for simvastatin and weighted average of 0.18 for simvastatin and lovastatin; 0.06 for atorvastatin and pravastatin; lovastatin; 0.06 for atorvastatin and pravastatin; and 0.00 for fluvastatin and rosuvastatinand 0.00 for fluvastatin and rosuvastatin

Elevations in CK and LDL-C ReductionElevations in CK and LDL-C Reduction

Brewer B, Am J Cardiol. 2003;92(suppl)23K-29K.

Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)

Rosuvastatin (10, 20, 40 mg)Pravastatin (20, 40 mg)Atorvastatin (10, 20, 40, 80 mg)

Simvastatin (40, 80 mg)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C Reduction (%)

CK

>10

× U

LN (%

)

25 35 45 55 65

Statin-Associated Statin-Associated Transaminase ElevationsTransaminase Elevations

• Progression to liver failure due to statins is Progression to liver failure due to statins is exceedingly rare exceedingly rare

• Reversal of transaminase elevation is frequently Reversal of transaminase elevation is frequently noted with a reduction in statin dosenoted with a reduction in statin dose– Elevations do not often recur with either readministration or Elevations do not often recur with either readministration or

selection of another statinselection of another statin

• Statins have not been shown to worsen the outcome Statins have not been shown to worsen the outcome in persons with chronic transaminase elevations due in persons with chronic transaminase elevations due to hepatitis B or C to hepatitis B or C

• Statin therapy may actually improve transaminase Statin therapy may actually improve transaminase elevations in individuals with fatty livers.elevations in individuals with fatty livers.

Pasternak et al. ACC/AHA/NHLBI Advisory on the Use and Safety of Statins. Circulation. 2002;106:1024-1028.

Pharmacokinetic Profiles of Selected Lipid-Lowering Therapies

CYP450 3A4MetabolismClinically Significant Metabolites

RelativelyHydrophilicHepatoselective

Bioavailability

Plasma Clearance

EliminationHalf-life* (hours)

Rosuvastatin

No

No

Yes

Yes

20%

Dual renal/hepatic

19

Atorvastatin

Yes

Yes

No

Yes

14%

Primarilyhepatic

14

Simvastatin

Yes

Yes

No

Yes

<5%

Dual renal/ hepatic

1.9

Pravastatin

No

No

Yes

Yes

17%

Dual renal/ hepatic

77

*Elimination T1/2 of drug and metabolites, if any.Prescribing Information for CRESTOR® (rosuvastatin calcium). AstraZeneca Pharmaceuticals LP. Wilmington, DE; Lipitor® (atorvastatin calcium) Prescribing Information. Pfizer Inc. New York, NY; Pravachol® (pravastatin sodium) Prescribing Information. Bristol-Myers Squibb Company. Princeton, NJ; Zocor® (simvastatin) Prescribing Information. Merck & Co. Inc. Whitehouse Station, NJ; Livalo(pitavastatin) Prescribing Information. Kowa Pharmaceuticals, Montgomery Ala.

Pitavastatin

No

No

No

Yes

50%

Dual renal/ hepatic

12

Proportional effects on major vascular eventsProportional effects on major vascular events among among 130,000 participants in 21 randomized trials of 130,000 participants in 21 randomized trials of

statins versus controlstatins versus control

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials, Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2010; 376: 1670-1681.

0.85 (0.80-0.91)0.85 (0.80-0.91)0.80.80.70.7Any strokeAny stroke0.77 (0.71-0.83)0.77 (0.71-0.83)0.80.80.60.6•UnspecifiedUnspecified0.76 (0.66-0.87)0.76 (0.66-0.87)0.30.30.20.2•PTCA PTCA 0.71 (0.63-0.80)0.71 (0.63-0.80)0.40.40.30.3•CABGCABG

0.75 (0.72-0.79)0.75 (0.72-0.79)1.61.61.21.2Any coronary Any coronary revascularizationrevascularization

0.78 (0.71-0.86)0.78 (0.71-0.86)0.60.60.50.5•CHD deathCHD death0.71(0.66-0.76)0.71(0.66-0.76)1.21.20.90.9•Nonfatal MINonfatal MI

0.73 (0.70-0.77)0.73 (0.70-0.77)1.71.71.31.3Any major coronary Any major coronary eventevent

0.78 (0.78-0.81)0.78 (0.78-0.81)3.63.62.82.8Any major vascular Any major vascular eventevent

Relative riskRelative risk(95% CI)(95% CI)

Control-arm Control-arm events, % events, % (n=64,782)(n=64,782)

Treatment-arm Treatment-arm events, %events, %(n=64,744)(n=64,744)

End point (events End point (events (%)per annum)(%)per annum)

Proportional effects on major vascular eventsProportional effects on major vascular events among among 40,000 participants in 5 randomized trials of more 40,000 participants in 5 randomized trials of more

versus less statinsversus less statins


0.86 (0.77-0.96)0.86 (0.77-0.96)0.70.70.60.6Any strokeAny stroke0.87 (0.74-1.03)0.87 (0.74-1.03)0.60.60.50.5•UnspecifiedUnspecified0.76 (0.69-0.84)0.76 (0.69-0.84)1.81.81.31.3•PTCA PTCA 0.86 (0.75-0.99)0.86 (0.75-0.99)0.90.90.70.7•CABGCABG

0.81 (0.76-0.85)0.81 (0.76-0.85)3.23.22.62.6Any coronary Any coronary revascularizationrevascularization

0.93 (0.81-1.07)0.93 (0.81-1.07)0.70.70.70.7•CHD deathCHD death0.85 (0.76-0.94)0.85 (0.76-0.94)1.51.51.31.3•Nonfatal MINonfatal MI

0.87 (0.81-0.93)0.87 (0.81-0.93)2.22.21.91.9Any major coronary Any major coronary eventevent

0.85 (0.82-0.89)0.85 (0.82-0.89)5.35.34.54.5Any major vascular Any major vascular eventevent


Statin/lessarm Statin/lessarm events, % events, % (n=19,783)(n=19,783)

Statin/more-arm Statin/more-arm events, %events, %(n=19,829)(n=19,829)

End point (events End point (events (%)per annum)(%)per annum)


Proportional effects on total and cause-specific mortality Proportional effects on total and cause-specific mortality per 1-mmol/L LDL-cholesterol reductionper 1-mmol/L LDL-cholesterol reduction among 170,000 among 170,000

participants in 14 randomized trials of statinsparticipants in 14 randomized trials of statins

0.99 (0.91-1.09)0.99 (0.91-1.09)0.50.50.50.5CancerCancer0.97 (0.92-1.03)0.97 (0.92-1.03)0.80.80.80.8Any nonvascularAny nonvascular0.86 (0.82-0.90)0.86 (0.82-0.90)1.31.31.21.2Any vascularAny vascular0.98 (0.81-1.18)0.98 (0.81-1.18)0.10.10.10.1Other vascularOther vascular0.96 (0.84-1.09)0.96 (0.84-1.09)0.10.10.10.1StrokeStroke

0.89 (0.81-0.98)0.89 (0.81-0.98)0.50.50.40.4Other cardiacOther cardiac

0.80 (0.74-0.87)0.80 (0.74-0.87)0.60.60.50.5Coronary heart Coronary heart diseasedisease

0.90 (0.87-0.93)0.90 (0.87-0.93)2.32.32.12.1All-causeAll-cause


Control/less-Control/less-arm events, arm events, % (n=84,565)% (n=84,565)

Statin/more-arm Statin/more-arm events, % events, % (n=84,573)(n=84,573)

Cause of death Cause of death (Events (%) per (Events (%) per annum)annum)

No significant excess of rhabdomyolysis No significant excess of rhabdomyolysis among 90,056 participants in 14 randomized among 90,056 participants in 14 randomized

trials of statins treated for about 5 yearstrials of statins treated for about 5 years StatinStatin Control Control n(%) n(%) n(%)n(%)

9(0.023) 6(0.015)9(0.023) 6(0.015)

5 year excess risk = 0.01%(p=0.4)5 year excess risk = 0.01%(p=0.4)

Cholesterol Treatment Trialists' (CTT) Collaborators. Lancet 2005; 366: 1267-1278

MAJOR CONCLUSIONS OF CTT MAJOR CONCLUSIONS OF CTT COLLABORATIONCOLLABORATION

•Statin therapy can safely reduce major coronary events, coronary Statin therapy can safely reduce major coronary events, coronary revascularisation and stroke by about one fifth and CHD mortality by about one revascularisation and stroke by about one fifth and CHD mortality by about one fourth per mmol/l (38mg/dl) reduction in LDL cholesterol, largely irrespective of fourth per mmol/l (38mg/dl) reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. the initial lipid profile or other presenting characteristics. •Further reductions in LDL cholesterol safely produce definite further reductions Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke, in the incidence of heart attack, of revascularisation, and of ischaemic stroke, with each 1 mm/l (38mg/dl) reducing the annual rate of these major vascular with each 1 mm/l (38mg/dl) reducing the annual rate of these major vascular events by over a fifth. There is no evidence of any threshold within the events by over a fifth. There is no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 cholesterol range studied, suggesting that reduction of LDL cholesterol by 2-3 mmol/L (76-114 mg/dl) would reduce risk by 40-50%.mmol/L (76-114 mg/dl) would reduce risk by 40-50%.•The absolute benefit relates chiefly to an individual’s absolute risk of such The absolute benefit relates chiefly to an individual’s absolute risk of such events and to the absolute reduction in LDL cholesterol achieved. events and to the absolute reduction in LDL cholesterol achieved. •There was no significant evidence in the meta-analysis of trials of more versus There was no significant evidence in the meta-analysis of trials of more versus less intensive therapy that further lowering of LDL cholesterol (weighted mean of less intensive therapy that further lowering of LDL cholesterol (weighted mean of 2.5 mmol/L (95mg/dl) to 2.0 mmol/L (76mg/dl) produced any adverse effects, 2.5 mmol/L (95mg/dl) to 2.0 mmol/L (76mg/dl) produced any adverse effects, even in participants with baseline LDL cholesterol lower than 2.0 mmol/L even in participants with baseline LDL cholesterol lower than 2.0 mmol/L (76mg/dl).(76mg/dl).•These findings reinforce the need to consider prolonged statin treatment with These findings reinforce the need to consider prolonged statin treatment with substantial LDL cholesterol reductionssubstantial LDL cholesterol reductions in all patients at high in all patients at high risk of any type of major vascular event.risk of any type of major vascular event.

Randomized Patients in Trials of Lipid Randomized Patients in Trials of Lipid Modifying Drugs and Clinical Cardiovascular Modifying Drugs and Clinical Cardiovascular

Disease OutcomesDisease Outcomes• StatinsStatins ~170,000~170,000

• Nicotinic AcidNicotinic Acid 2,835 2,835

• Omega-3-FAOmega-3-FA 11,324 11,324

• FibratesFibrates– GemfibrozilGemfibrozil 2,531 2,531– FenofibrateFenofibrate 15,373(9795+5518) 15,373(9795+5518)

• EzetimibeEzetimibe 0 0

SHARP: Major conclusions

Among 8384 patients with chronic renal disease randomized to simvastatin + ezetimibe or placebo for 4.9 years there were

• No increases in risks of myopathy, liver, biliary disorders, cancer, or nonvascular mortality

• No substantial effects in kidney disease progression

• A significant 17% reduction in major atherosclerotic events with 2/3 compliance to simvastatin +ezetimibe

• Similar proportional reductions in all subgroups (including among dialysis and non-dialysis patients)

• No direct comparisons of whether ezetimibe adds to the benefits of the statin

ETHICAL CONSIDERATIONS

Ethical considerations surrounding statins include whether

To treat or not to treat

Evidence based doses of a statin should be the first choice of drug therapy for virtually all patients who require pharmacologic therapy for the management of their lipids as an adjunct to therapeutic lifestyle changes

French FriesFrench Fries

How to burn* 400 calories: Walk 2 hour 20 minutes

20 years ago20 years ago TodayToday

210 calories2.4 ounces How many calories are

in these fries?610 calories6.9 ounces

Calorie difference: 400 Calories

*Based on 130-pound person.

Darwinism and Risk Darwinism and Risk of Cardiovascular Diseaseof Cardiovascular Disease

Walking the DogWalking the Dog

A bit of cultural news …..

After a 2 year loanto the United States, David returns to Italy

…Proud Sponsors

Trends Among US Adolescents

Smoking (22%-30%)

Obesity

Physical Inactivity

Hennekens CH. Circulation. 1998;97:1095.

Type 2 Diabetes

The United States is the fattest society in the world and likely to be the fattest in the history of the world.

Professor Charles H. Hennekens

New York TimesJanuary 1, 1999

Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996.

Cancer11.9%

CVD28.4%

Communicable,Perinatal, Nutritional

34.2%

All Other25.5%

Cancer18.0%

CVD33.7%

Communicable,Perinatal, Nutritional

15.1%

All Other33.2%

Shifting Worldwide Burden of Disease

19901990 20202020

MalnutritionMalnutrition

InfectionInfection

SmokingSmoking

BMIBMI

Reasons for Worldwide Increase in Cardiovascular Disease

Hennekens CH. Circulation. 1998;97:1095-1102.

2005: Beijing, China vs US

Beijing US

58% Same as 1950

24.8 Same as 1990Body Mass IndexWeight in Kg/Height in m2

Cigarette smokingin men

1990 – 2010: Fast Food restaurants in China

1990 2010

1 800 mainland200 Hong Kong

– 1,900KFC

McDonalds

Increasing Worldwide Burden of Cardiovascular Disease

1st 5th Premature Death and Disability

1st4thYears of Life Lost20201990

Murray CJL, Lopez AD, eds. The Global Burden of Disease. Cambridge, Mass: Harvard University Press; 1996.

PUBLIC HEALTH CONSIDERATIONS

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

CLINICAL CONSIDERATIONSCLINICAL CONSIDERATIONSBlood cholesterolBlood cholesterol

10% 10% = 20%-30% = 20%-30% in CHD in CHDHigh blood pressureHigh blood pressure

5-6 mm Hg 5-6 mm Hg = 42% = 42% in Stroke in Stroke = 16% = 16% in CHD in CHD

Cigarette smokingCigarette smokingCessation = 50%-70% Cessation = 50%-70% in CHD in CHD

Body weightBody weight BMI<25 vs BMI>27 = 35%-55% BMI<25 vs BMI>27 = 35%-55% in CHD in CHD

Physical activityPhysical activity20-minute brisk walk daily = 35%-55% 20-minute brisk walk daily = 35%-55% in CHD in CHD

GOALS OF HEALTH CARE GOALS OF HEALTH CARE PROVIDERS AND ACADEMIC PROVIDERS AND ACADEMIC

RESEARCHERS RESEARCHERS

Health Care Providers:Health Care Providers:Make clinical decisions based on the totality of evidence not dependence on Make clinical decisions based on the totality of evidence not dependence on

particular subgroups of particular studiesparticular subgroups of particular studies..

Academic Researchers:Academic Researchers:Avoid misstatements of benefit to risk ratios which may increase publicity, Avoid misstatements of benefit to risk ratios which may increase publicity, promotions and grant support in the short run but confuse colleagues and promotions and grant support in the short run but confuse colleagues and frighten patients and make it more difficult to conduct high quality research frighten patients and make it more difficult to conduct high quality research

( COX-2 inhibitors and glitazones)( COX-2 inhibitors and glitazones)

Health Care Providers and Academic ResearchersHealth Care Providers and Academic ResearchersMaximize benefit and minimize risk which is not to be confused with avoidance Maximize benefit and minimize risk which is not to be confused with avoidance

of risk.of risk.

When the totality of evidence is incomplete it is appropriate to remain uncertain.

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.

Don’t let the perfect be the enemy Don’t let the perfect be the enemy of the possibleof the possible

““We must all hang together or assuredly we We must all hang together or assuredly we

shall all hang separately.”shall all hang separately.”

Benjamin FranklinBenjamin Franklin

July 4, 1776July 4, 1776

lipid modification in the treatment and prevention of cardiovascular disease: clinical, public...

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