BEYOND LIFESTYLE CHANGES: THE BEYOND LIFESTYLE CHANGES: THE ROLE OF AGGRESSIVE MEDICAL ROLE OF AGGRESSIVE MEDICAL THERAPY FOR ALL PATIENTS AT THERAPY FOR ALL PATIENTS AT

INCREASED RISK FOR INCREASED RISK FOR CARDIOVASCULAR DISEASECARDIOVASCULAR DISEASE

Charles H. Hennekens, MD, DrPHSir 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 HealthUniversity of Miami Miller School of Medicine (UMMSM)

• 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 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 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 platelet and inflammatory biomarkers as well as nitric oxide formation.

•I serve as an independent scientist in an advisory role to investigators and 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, 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 Anthera, Bristol-Myers Squibb, and Sunovion and as a Member of Data and Safety Monitoring Boards for AstraZeneca, Bayer , British Heart Foundation, Canadian Monitoring Boards for AstraZeneca, Bayer , British Heart Foundation, Canadian Institutes of Health Research and Lilly. Institutes of Health 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 Administration, U.S. National Institutes of Health, Children's Services Council of Palm Beach County and UpToDate.Palm 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 I have an investment management relationship with The West-Bacon Group within SunTrust Investment Services who has discretionary investment authority.within 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.

DisclosureDisclosure

Death is inevitable but premature death Death is inevitable but premature death is notis not

Sir Richard Doll, FRSSir Richard Doll, FRS

Regius Professor of MedicineRegius Professor of Medicine

University of Oxford, UK, 1969-1979University of Oxford, UK, 1969-1979

Advances in Medical Knowledge Advances in Medical Knowledge Proceed on Several Fronts, Optimally Proceed on Several Fronts, Optimally

SimultaneouslySimultaneously

• Basic researchers Basic researchers

• Health care providersHealth care providers

• Clinical investigatorsClinical investigators

• Epidemiologists and biostatisticians Epidemiologists and biostatisticians

Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown and Company; 1987.

Hennekens CH, Buring JE. Epidemiology in Medicine. Boston, Mass: Little, Brown and Company; 1987.

Totality of EvidenceTotality of Evidence

• Basic research (why)Basic research (why)

• Epidemiology (whether)Epidemiology (whether)– Descriptive studies:Descriptive studies:

• CCase reportsase reports• CCase seriesase series• EEcological studiescological studies

– Analytic studies:Analytic studies:• OObservationalbservational

– CCase-controlase-control– CCohortohort

• RRandomized trialsandomized trials

-60

-50

-40

-30

-20

-10

0

10

79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95

Change In Age-Adjusted MortalityChange In Age-Adjusted Mortality1979 - 19951979 - 1995

%Decline

National Center for Health Statistics.

Noncardiovascular Disease

Coronary Heart Disease

Stroke

Heart Disease In The United StatesHeart Disease In The United States

• Chief cause of death among men age 45 years Chief cause of death among men age 45 years and olderand older

• Chief cause of death among women age 65 Chief cause of death among women age 65 years and olderyears and older

• Responsible for 1 in 3 deaths in men and Responsible for 1 in 3 deaths in men and women, or ~750,000 fatalities each yearwomen, or ~750,000 fatalities each year

Postulated Reasons for Decreasing Postulated Reasons for Decreasing CHD MortalityCHD Mortality

• During acute MI:During acute MI:– Decrease in case fatality rate (20%-30% Decrease in case fatality rate (20%-30% 5%-10%) 5%-10%)

for hospitalized MIfor hospitalized MI– Increase in utilization of:Increase in utilization of:

• AspirinAspirin• ThrombolyticsThrombolytics -blockers-blockers• ACE inhibitorsACE inhibitors

Hennekens CH et al. NEJM 1996;335:1660-1667

Postulated Reasons for Decreasing Postulated Reasons for Decreasing CHD Mortality (cont’d)CHD Mortality (cont’d)

• Secondary prevention:Secondary prevention:– Therapeutic lifestyle changes (TLC)Therapeutic lifestyle changes (TLC)– Increase in utilization of:Increase in utilization of:

• AspirinAspirin -blockers-blockers• ACE inhibitorsACE inhibitors• Statins (HMG-CoA reductase inhibitors)Statins (HMG-CoA reductase inhibitors)

Hennekens CH et al. NEJM 1996;335:1660-1667

Postulated Reasons for Decreasing Postulated Reasons for Decreasing CHD Mortality (cont’d)CHD Mortality (cont’d)

• Primary prevention:Primary prevention:– Decrease in smokingDecrease in smoking

• >50% >50% <25% <25%

– Increase in treatment of hypertension:Increase in treatment of hypertension:• 16% 16% 55% 55%

– Increase in treatment of dyslipidemia:Increase in treatment of dyslipidemia:• Cholesterol population target 220 mg/dl Cholesterol population target 220 mg/dl 200 mg/dl 200 mg/dl

Manson JE et al. NEJM 1992;326:1406-1416.

Trends Among US AdolescentsTrends Among US Adolescents

Smoking (22%-30%)Smoking (22%-30%)

ObesityObesity

Physical InactivityPhysical Inactivity

Hennekens CH. Circulation. 1998;97:1095.

Type 2 DiabetesType 2 Diabetes

LIFE EXPECTANCY AT BIRTHLIFE EXPECTANCY AT BIRTH

• US AND RICH COUNTRIES: 77 YEARS (73 US AND RICH COUNTRIES: 77 YEARS (73 IN MEN AND 81 IN WOMENIN MEN AND 81 IN WOMEN

• POOR COUNTRIES: 50 YEARS (46 IN MEN POOR COUNTRIES: 50 YEARS (46 IN MEN AND 54 IN WOMEN)AND 54 IN WOMEN)

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 DiseaseShifting Worldwide Burden of Disease

1990199019901990 2020202020202020

MalnutritionMalnutritionMalnutritionMalnutrition

InfectionInfectionInfectionInfection

SmokingSmokingSmokingSmoking

BMIBMIBMIBMI

Reasons for Worldwide Increase in Reasons for Worldwide Increase in Cardiovascular DiseaseCardiovascular Disease

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

Increasing Worldwide Burden of Increasing Worldwide Burden of Cardiovascular DiseaseCardiovascular Disease

11stst 55thth Premature Death Premature Death and Disabilityand Disability

11stst44ththYears of Life LostYears of Life Lost

2020202019901990

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

ConclusionConclusion

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

Selected Worldwide Death Rates From Selected Worldwide Death Rates From CHD in Adults Aged 34 to 74 Years*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.

Death Rate (per 100,000)Death Rate (per 100,000)

CountryCountry MenMen WomenWomen TotalTotal

Russian FederationRussian Federation 638638 231231 869869

BulgariaBulgaria 353353 133133 486486

United KingdomUnited Kingdom 265265 9797 362362

United StatesUnited States 214214 8787 301301

AustriaAustria 223223 7474 297297

GermanyGermany 206206 7272 278278

FranceFrance 8787 2020 107107

JapanJapan 5757 2020 7777

CONTRIBUTIONS OF DIFFERENT CONTRIBUTIONS OF DIFFERENT TYPES OF EVIDENCETYPES OF EVIDENCE

((HENNEKENS AND BURING, EPIDEMIOLOGY IN MEDICINE, 1987HENNEKENS AND BURING, EPIDEMIOLOGY IN MEDICINE, 1987))

•For hypotheses testing of large effects (i.e. smoking and lung cancer 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 where RR=20, or even smoking and CHD where RR=2.0) randomized

evidence is neither necessary nor desirableevidence is neither necessary nor desirable

•For small to moderate effects (i.e.10-50%) the amount of uncontrolled For small to moderate effects (i.e.10-50%) the amount of uncontrolled and uncontrollable confounding inherent in all case control and cohort and uncontrollable confounding inherent in all case control and cohort studies is as big as the effect size so randomized evidence is crucial. studies is as big as the effect size so randomized evidence is crucial.

•Subgroup analyses are no longer randomized and have lower sample Subgroup analyses are no longer randomized and have lower sample sizes and should be viewed, at best, as hypothesis formulating and, at sizes and should be viewed, at best, as hypothesis formulating and, at worst, as rubbish. The biggest danger in interpretation of subgroups is worst, as rubbish. The biggest danger in interpretation of subgroups is acting as if they provide serious evidence. (Sir Richard Peto, personal acting as if they provide serious evidence. (Sir Richard Peto, personal

communication)communication)

AHA/ACC SECONDARY PREVENTION FOR AHA/ACC SECONDARY PREVENTION FOR PATIENTS WITH CORONARY AND OTHER PATIENTS WITH CORONARY AND OTHER

VASCULAR DISEASE-2006 UPDATEVASCULAR DISEASE-2006 UPDATE• Cigarette SmokingCigarette Smoking

• Blood Pressure ControlBlood Pressure Control

• Lipid ManagementLipid Management

• Physical ActivityPhysical Activity

• Weight ManagementWeight Management

• Diabetes ManagementDiabetes Management

• Antiplatelet and/or Anticoagulant therapyAntiplatelet and/or Anticoagulant therapy

• RAAS BlockersRAAS Blockers

• Beta-BlockersBeta-Blockers

Circulation. 2006;113:2363-2372

ATP III Guidelines: Definitions of Increased ATP III Guidelines: Definitions of Increased Risk for CVDRisk for CVD

• 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)

Diabetes and Cardiovascular DiseaseDiabetes and Cardiovascular Disease

• The US National Cholesterol Education Program (NCEP) III has The US National Cholesterol Education Program (NCEP) III has elevated diabetes from a major risk factor to a CHD risk equivalent elevated diabetes from a major risk factor to a CHD risk equivalent

• Diabetes is a major contributor to the metabolic syndrome of multiple Diabetes is a major contributor to the metabolic syndrome of multiple metabolic risk factors (obesity, dyslipidemia, diabetes, hypertension) metabolic risk factors (obesity, dyslipidemia, diabetes, hypertension) that markedly increases risks of CVDthat markedly increases risks of CVD

• In the general US population 25% of adults have metabolic syndrome In the general US population 25% of adults have metabolic syndrome

• All patients with diabetes should be treated as aggressively as survivors All patients with diabetes should be treated as aggressively as survivors of a CVD event (i.e., MI or stroke)(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 In PROVE-IT and TNT there were no modifications of the benefits of higher doses of statins among the diabetics who had higher absolute 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 failure to treat diabetics aggressively with higher doses of more potent statins has major deleterious clinical and public health potent statins has major deleterious clinical and public health implications.implications.

Modifiable CV Risk Factors inModifiable CV Risk Factors inPatients with Type 2 Diabetes*: Patients with Type 2 Diabetes*:

Results from UKPDS 23Results from UKPDS 23PositionPosition 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.

CV = cardiovascular.CV = cardiovascular.

*Adjusted for age and gender in 2693 Caucasian patients with type 2 diabetes, with dependent variable as time to first *Adjusted for age and gender in 2693 Caucasian patients with type 2 diabetes, with dependent variable as time to first event.event.

††Significant for coronary artery disease (n = 280). P values are significance of risk factor after controlling for all other risk Significant for coronary artery disease (n = 280). P values are significance of risk factor after controlling for all other risk

factors in model.factors in model.

Metabolic SyndromeMetabolic Syndrome

• ““The U.S. is the fattest society in the world and likely The U.S. is the fattest society in the world and likely to be the fattest in the history of the world”. (CH to be the fattest in the history of the world”. (CH Hennekens, NY Times 1/1/99)Hennekens, NY Times 1/1/99)

• Obesity is associated with dyslipidemia, Obesity is associated with dyslipidemia, hypertension, and insulin resistance which has been hypertension, and insulin resistance which has been termed metabolic syndrome.termed metabolic syndrome.

• In the U.S. 25% of adults aged 25 and older and 40% In the U.S. 25% of adults aged 25 and older and 40% of adults aged 40 and older have metabolic of adults aged 40 and older have metabolic syndrome.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

100

(10

y)

5

+ Hypertension

+ Hyperglycemia

+ Smoking

+ Low HDL-C

No other RF

130-159 160-189

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

The randomized evidence is necessary The randomized evidence is necessary but not sufficient for guidelines.but not sufficient for guidelines.

The guidelines are necessary but not The guidelines are necessary but not sufficient for good clinical judgment.sufficient for good clinical judgment.

There is absolutely no substitute for There is absolutely no substitute for good clinical judgmentgood clinical judgment

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

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

2.8

Pla

ceb

o M

I Rat

e p

er 1

00

Su

bje

cts

per

5 Y

ears

00 33 1818 2121 2424 2727 303066 99 1212 1515

% W

ith

Ev

en

t

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.

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

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

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 AEs Overall treatment-related AEs 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

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

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

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

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.

Effectiveness of Statin Titration on Low-DensityEffectiveness of Statin Titration on Low-DensityLipoprotein Cholesterol Goal Attainment in Patients atLipoprotein Cholesterol Goal Attainment in Patients at

High Risk of Atherogenic EventsHigh Risk of Atherogenic Events

• Less than 50% (48%) achieved an LDL cholesterol < Less than 50% (48%) achieved an LDL cholesterol < 100 mg/dl with their initial dose of statin100 mg/dl with their initial dose of statin

• Of those who did not achieve goal with their initial Of those who did not achieve goal with their initial dose, less than 50% (45%) had their dosage titrateddose, less than 50% (45%) had their dosage titrated

• Among statin-treated patients who did not achieve Among statin-treated patients who did not achieve the LDL cholesterol goal with their initial dose, less the LDL cholesterol goal with their initial dose, less than 15% (14%) attained the goal within 6 months of than 15% (14%) attained the goal within 6 months of starting treatment.starting treatment.

Foley, K.; Simpson, R; et.al. AJC, 2003; 92:79-81

Proportional effects on major vascular events per 1-Proportional effects on major vascular events per 1-mmol/L LDL-cholesterol reductionmmol/L LDL-cholesterol reduction among 90,056 among 90,056 participants in 14 randomized trials of statinsparticipants in 14 randomized trials of statins

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

0.83 (0.78-0.88)0.83 (0.78-0.88)3.73.73.0 3.0 Any strokeAny stroke

0.76 (0.69-0.84)0.76 (0.69-0.84)3.93.93.13.1•UnspecifiedUnspecified

0.79 (0.69-0.90)0.79 (0.69-0.90)1.51.51.11.1•PTCA PTCA

0.75 (0.69-0.82)0.75 (0.69-0.82)2.22.21.61.6•CABGCABG

0.76 (0.73-0.80)0.76 (0.73-0.80)7.67.65.85.8Any coronary Any coronary revascularizationrevascularization

0.81 (0.75-0.87)0.81 (0.75-0.87)4.44.43.43.4•CHD deathCHD death

0.74 (0.70-0.79)0.74 (0.70-0.79)6.26.24.44.4•Nonfatal MINonfatal MI

0.77 (0.74-0.80)0.77 (0.74-0.80)9.89.87.47.4Any major coronary Any major coronary eventevent

0.79 (0.77-0.81)0.79 (0.77-0.81)17.817.814.114.1Any major vascular Any major vascular eventevent

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

Control-arm Control-arm events, % events, % (n=45 002(n=45 002

Treatment-arm Treatment-arm events, %events, %(n=45 054)(n=45 054)

End pointEnd point

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

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 90,056 among 90,056

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

1.01 (0.91-1.12)1.01 (0.91-1.12)2.42.42.42.4CancerCancer0.95 (0.90-1.01)0.95 (0.90-1.01)4.04.03.83.8Any nonvascularAny nonvascular0.83 (0.79-0.87)0.83 (0.79-0.87)5.75.74.74.7Any vascularAny vascular0.95 (0.78-1.16)0.95 (0.78-1.16)0.70.70.60.6Other vascularOther vascular0.91 (0.74-1.11)0.91 (0.74-1.11)0.60.60.60.6StrokeStroke

0.93 (0.83-1.03)0.93 (0.83-1.03)1.31.31.21.2Any non-coronary-Any non-coronary-heart-diseaseheart-disease

0.81 (0.76-0.85)0.81 (0.76-0.85)4.4 4.4 3.43.4Coronary heart Coronary heart diseasedisease

0.88 (0.84-0.91)0.88 (0.84-0.91)9.79.78.58.5All-causeAll-cause

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

Control-arm Control-arm events, % events, % (n=45 002)(n=45 002)

Treatment-arm Treatment-arm events, % events, % (n=45 054)(n=45 054)

Cause of deathCause of death

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. Cholesterol Treatment Trialists' (CTT) Collaborators. LancetLancet 2005; 2005; 366: 1267-1278366: 1267-1278

MAJOR CONCLUSIONS OF CTT MAJOR CONCLUSIONS OF CTT COLLABORATIONCOLLABORATION

•Statin therapy can safely reduce the 5-year incidence of Statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation and major coronary events, coronary revascularisation and stroke by about one fifth per mmol/l (38mg/dl) reduction in stroke by about one fifth per mmol/l (38mg/dl) reduction in LDL cholesterol, largely irrespective of the initial lipid profile LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. or other presenting characteristics.

•The absolute benefit relates chiefly to an individual’s The absolute benefit relates chiefly to an individual’s absolute risk of such events and to the absolute reduction in absolute risk of such events and to the absolute reduction in LDL cholesterol achieved. LDL cholesterol achieved.

•These findings reinforce the need to consider prolonged These findings reinforce the need to consider prolonged statin treatment with statin treatment with substantial LDL cholesterol substantial LDL cholesterol reductionsreductions in all patients at high risk of any type of in all patients at high risk of any type of major vascular event.major vascular event.

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

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 90,056 90,056

• Nicotinic AcidNicotinic Acid 2,835 2,835

• Omega-3-FAOmega-3-FA 11,324 11,324

• FibratesFibrates– GemfibrozilGemfibrozil 2,531 2,531– FenofibrateFenofibrate 9,795 9,795

• EzetimibeEzetimibe 0 0

ENHANCE AND SEAS: LACK OF CLINICAL ENHANCE AND SEAS: LACK OF CLINICAL OR PUBLIC HEALTH RELEVANCEOR PUBLIC HEALTH RELEVANCE

• ENHANCE: In 752 patients ezetimibe added ENHANCE: In 752 patients ezetimibe added to simvastatin produced beneficial changes in to simvastatin produced beneficial changes in lipids but no significant reduction in CIMTlipids but no significant reduction in CIMT

• SEAS: Formulated a hypothesis that SEAS: Formulated a hypothesis that ezetimibe increased cancer risk that was not ezetimibe increased cancer risk that was not supported in either IMPROVE-IT or SHARP.supported in either IMPROVE-IT or SHARP.

• The benefits and risks of ezetimibe are being The benefits and risks of ezetimibe are being tested in IMROVE-IT and SHARP.tested in IMROVE-IT and SHARP.

A CLINICIAN’S DILEMMA A CLINICIAN’S DILEMMA

Unfortunately, most Americans prefer the Unfortunately, most Americans prefer the prescription of pills to the proscription of prescription of pills to the proscription of harmful lifestyles.harmful lifestyles.

Charles H. Hennekens,Charles H. Hennekens,

New York TimesNew York Times

French FriesFrench Fries

How to burn* 400 calories: 

Walk 2 hour 20 minutes

20 years ago20 years ago TodayToday

210 calories

2.4 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

Established Risk Factors for CHDEstablished Risk Factors for CHD

Blood cholesterolBlood cholesterol10% 10% = 20%-30% = 20%-30% in CHD in CHD

High blood pressureHigh blood pressure5-6 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

CHIEF AVOIDABLE CAUSES OF CHIEF AVOIDABLE CAUSES OF PREMATURE DEATH IN THE USPREMATURE DEATH IN THE US

• CIGARETTESCIGARETTES

• OBESITYOBESITY

• PHYSICAL INACTIVITYPHYSICAL INACTIVITY

• LIPIDSLIPIDS

• BLOOD PRESSUREBLOOD PRESSURE

• HEAVY ALCOHOL CONSUMPTIONHEAVY ALCOHOL CONSUMPTION

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

Ag

e-A

dju

sted

6-Y

ear

CH

D

Dea

th R

ate

per

100

0 M

en 20

16

12

8

4

0140 160 180 200 220 240 260 280 300

N=361,662

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

RESEARCHERS RESEARCHERS Maximize 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.

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..

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)

““We must all hang together, or assuredly We must all hang together, or assuredly we shall all hang separately.”we shall all hang separately.”

– – Benjamin FranklinBenjamin FranklinJuly 4, 1776July 4, 1776