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

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BEYOND LIFESTYLE CHANGES THE ROLE OF AGGRESSIVE
MEDICAL THERAPY FOR ALL PATIENTS AT INCREASED
RISK FOR CARDIOVASCULAR DISEASE
Charles H. Hennekens, MD, DrPH Sir Richard Doll
Research Professor of Medicine Charles E. Schmidt
College of Medicine, Florida Atlantic University
(FAU) Clinical Professor of Preventive Medicine,
Nova Southeastern University Voluntary Professor
of Family Medicine and Community
Health University of Miami Miller School of
Medicine (UMMSM)
2
Disclosure

• I am funded by the Charles E. Schmidt College
  of Medicine at Florida Atlantic University (FAU).
  I have served as Principal Investigator on two
  investigator initiated research grants funded to
  FAU by Bayer testing the effects of aspirin dose
  on platelet and inflammatory biomarkers as well
  as nitric oxide formation.
• I serve as an independent scientist in an
  advisory role to investigators and sponsors as
  Chair of Data and Safety Monitoring Boards for
  Actelion, Amgen, Anthera, Bristol-Myers Squibb,
  and Sunovion and as a Member of Data and Safety
  Monitoring Boards for AstraZeneca, Bayer ,
  British Heart Foundation, Canadian Institutes of
  Health Research and Lilly.
• I serve as an independent scientist in an
  advisory role to the U.S. Food and Drug
  Administration, U.S. National Institutes of
  Health, Children's Services Council of Palm Beach
  County and UpToDate.
• I serve as an independent scientist in an
  advisory role to legal counsel for
  GlaxoSmithKline and Stryker.
• I serve as speaker for the Association for
  Research in Vision and Ophthalmology, Baptist
  Health South Florida, National Association for
  Continuing Education, PriMed, and the
  International Atherosclerosis Society.
• I receive royalties for authorship or editorship
  of three textbooks.
• I receive royalties as co-inventor on patents
  concerning inflammatory markers and
  cardiovascular disease which are held by Brigham
  and Womens 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.

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

4
Advances in Medical Knowledge Proceed on Several
Fronts, Optimally Simultaneously

• Basic researchers
• Health care providers
• Clinical investigators
• Epidemiologists and biostatisticians

Hennekens CH, Buring JE. Epidemiology in
Medicine. Boston, Mass Little, Brown and
Company 1987.
5
Totality of Evidence

• Basic research (why)
• Epidemiology (whether)
• Descriptive studies
• Case reports
• Case series
• Ecological studies
• Analytic studies
• Observational
• Case-control
• Cohort
• Randomized trials

Hennekens CH, Buring JE. Epidemiology in
Medicine. Boston, Mass Little, Brown and
Company 1987.
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Change In Age-Adjusted Mortality1979 - 1995
Noncardiovascular Disease
Coronary Heart Disease
Decline
Stroke
National Center for Health Statistics.
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Heart Disease In The United States

• Chief cause of death among men age 45 years and
  older
• Chief cause of death among women age 65 years and
  older
• Responsible for 1 in 3 deaths in men and women,
  or 750,000 fatalities each year

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Postulated Reasons for Decreasing CHD Mortality

• During acute MI
• Decrease in case fatality rate (20-30 ? 5-10)
  for hospitalized MI
• Increase in utilization of
• Aspirin
• Thrombolytics
• ?-blockers
• ACE inhibitors

Hennekens CH et al. NEJM 19963351660-1667
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Postulated Reasons for Decreasing CHD Mortality
(contd)

• Secondary prevention
• Therapeutic lifestyle changes (TLC)
• Increase in utilization of
• Aspirin
• ?-blockers
• ACE inhibitors
• Statins (HMG-CoA reductase inhibitors)

Hennekens CH et al. NEJM 19963351660-1667
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Postulated Reasons for Decreasing CHD Mortality
(contd)

• Primary prevention
• Decrease in smoking
• gt50 ? lt25
• Increase in treatment of hypertension
• 16 ? 55
• Increase in treatment of dyslipidemia
• Cholesterol population target 220 mg/dl ? 200
  mg/dl

Manson JE et al. NEJM 19923261406-1416.
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Trends Among US Adolescents
Hennekens CH. Circulation. 1998971095.
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LIFE EXPECTANCY AT BIRTH

• US AND RICH COUNTRIES 77 YEARS (73 IN MEN AND
  81 IN WOMEN
• POOR COUNTRIES 50 YEARS (46 IN MEN AND 54 IN
  WOMEN)

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Shifting Worldwide Burden of Disease
1990
2020
Cancer 11.9
Cancer 18.0
All Other 25.5
All Other 33.2
CVD 28.4
CVD 33.7
Communicable,Perinatal, Nutritional 15.1
Communicable,Perinatal, Nutritional 34.2
Murray CJL, Lopez AD, eds. The Global Burden of
Disease. Cambridge, Mass Harvard University
Press 1996.
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Reasons for Worldwide Increase in Cardiovascular
Disease
Malnutrition
Infection
Smoking
BMI
Hennekens CH. Circulation. 1998971095-1102.
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Increasing Worldwide Burden of Cardiovascular
Disease
Murray CJL, Lopez AD, eds. The Global Burden of
Disease. Cambridge, Mass Harvard University
Press 1996.
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Conclusion

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

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Selected Worldwide Death Rates From CHD in Adults
Aged 34 to 74 Years
Death Rate (per 100,000) Death Rate (per 100,000) Death Rate (per 100,000)
Country Men Women Total
Russian Federation 638 231 869
Bulgaria 353 133 486
United Kingdom 265 97 362
United States 214 87 301
Austria 223 74 297
Germany 206 72 278
France 87 20 107
Japan 57 20 77
All values are for 1997.British Heart
Foundation. Coronary Heart Disease Statistics
British Heart Foundation Statistics Database.
London, England British Heart Foundation 2002.
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CONTRIBUTIONS OF DIFFERENT TYPES OF
EVIDENCE(HENNEKENS AND BURING, EPIDEMIOLOGY IN
MEDICINE, 1987)

• For hypotheses testing of large effects (i.e.
  smoking and lung cancer where RR20, or even
  smoking and CHD where RR2.0) randomized evidence
  is neither necessary nor desirable
• For small to moderate effects (i.e.10-50) the
  amount of uncontrolled and uncontrollable
  confounding inherent in all case control and
  cohort studies is as big as the effect size so
  randomized evidence is crucial.
• Subgroup analyses are no longer randomized and
  have lower sample sizes and should be viewed, at
  best, as hypothesis formulating and, at worst, as
  rubbish. The biggest danger in interpretation of
  subgroups is acting as if they provide serious
  evidence. (Sir Richard Peto, personal
  communication)

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AHA/ACC SECONDARY PREVENTION FOR PATIENTS WITH
CORONARY AND OTHER VASCULAR DISEASE-2006 UPDATE

• Cigarette Smoking
• Blood Pressure Control
• Lipid Management
• Physical Activity
• Weight Management
• Diabetes Management
• Antiplatelet and/or Anticoagulant therapy
• RAAS Blockers
• Beta-Blockers

Circulation. 20061132363-2372
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ATP III Guidelines Definitions of Increased Risk
for CVD

• Prior CVD event
• CHD
• Stroke
• Other clinical forms of atherosclerotic disease
  (peripheral arterial disease, abdominal aortic
  aneurysm, and symptomatic carotid artery disease)
• Risk factors that confer a 10-year risk for CHD
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• Diabetes
• 2 risk factors (metabolic syndrome)

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Diabetes and Cardiovascular Disease

• The US National Cholesterol Education Program
  (NCEP) III has elevated diabetes from a major
  risk factor to a CHD risk equivalent
• Diabetes is a major contributor to the metabolic
  syndrome of multiple metabolic risk factors
  (obesity, dyslipidemia, diabetes, hypertension)
  that markedly increases risks of CVD
• In the general US population 25 of adults have
  metabolic syndrome
• All patients with diabetes should be treated as
  aggressively as survivors of a CVD event (i.e.,
  MI or stroke)(Expert Panel on Detection,
  Evaluation, and Treatment of High Blood
  Cholesterol in Adults. JAMA. 20012852486-2497.)
• In PROVE-IT and TNT there were no modifications
  of the benefits of higher doses of statins among
  the diabetics who had higher absolute risks.
• The failure to treat diabetics aggressively with
  higher doses of more potent statins has major
  deleterious clinical and public health
  implications.

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Modifiable CV Risk Factors inPatients with Type
2 Diabetes Results from UKPDS 23
Position Variable P Value
First LDLC lt0.0001
Second HDLC 0.0001
Third A1c 0.0022
Fourth Systolic BP 0.0065
Fifth Smoking 0.056
CV cardiovascular. Adjusted for age and gender
in 2693 Caucasian patients with type 2 diabetes,
with dependent variable as time to first
event. Significant for coronary artery disease
(n 280). P values are significance of risk
factor after controlling for all other risk
factors in model.
Adapted from Turner RC et al. BMJ.
1998316823828.
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Metabolic Syndrome

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

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Importance of Assessing Multiple Risk Factors for
CHD
Hypertension
Low HDL-C
Hyperglycemia
No other RF
30
Smoking
25
20
15
CHD Risk per 100 (10 y)
10
5
0
lt100
100-129
190
130-159
160-189
LDL cholesterol (mg/dL)
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Randomized Comparisons of Different Statins at
Different Doses
The STELLAR Trial
Change in LDL-C From Baseline ()
0
-10
-20
-30
-40
-50
-60
-5
-15
-25
-35
-45
-55
10 mg
20 mg
40 mg
10 mg
20 mg
80 mg
40 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
10 mg
40 mg
20 mg
Plt.002 vs atorvastatin 10 mg simvastatin 10,
20, 40 mg pravastatin 10, 20, 40 mg. Plt.002 vs
atorvastatin 20, 40 mg simvastatin 20, 40, 80
mg pravastatin 20, 40 mg. Plt.002 vs
atorvastatin 40 mg simvastatin 40, 80 mg
pravastatin 40 mg. Adapted from Jones et al. Am J
Cardiol 200392152160.
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The randomized evidence is necessary but not
sufficient for guidelines.The guidelines are
necessary but not sufficient for good clinical
judgment.There is absolutely no substitute for
good clinical judgment
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Dont let the perfect be the enemy of the possible
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EARLY LANDMARK TRIALS OF STATINS CLINICAL
BENEFITS APPEAR _at_ 2-3 YEARS
Continuumof risk
High-risk CHD patients (high cholesterol)
22.6
4S(simvastatin)
Secondaryprevention
CARE(pravastatin) LIPID(pravastatin)
Majority of CHD patients (broad range of
cholesterol levels)
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
AFCAPS/TexCAPS(lovastatin)
Patients at low risk of CHD (low HDL-C)
2.8
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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
3
18
21
24
27
30
6
9
12
15
Months of Follow-up
Cannon et al. N Engl J Med 20043501495-1504.
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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
1.5
1.25
1.0
Pravastatin 40 mg Better
Atorvastatin 80 mg Better
2-year event rates. Cannon et al. N Engl J Med
20043501495-1504.
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Primary Efficacy Outcome MeasureFirst Major
Cardiovascular Event
LaRosa et al. N Engl J Med 2005352.
35
Primary Efficacy Outcome MeasureFirst Fatal or
Nonfatal Stroke
LaRosa et al. N Engl J Med 2005352.
36
TNT Subgroup analyses of primary endpoint and
its components by LDL quintiles(lt6464-lt7777-lt90
90-lt106gt 106)
LaRosa, JC Grundy, S et.al. Am J Cardiol
2007100747752
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Safety
No. of patients () No. of patients ()
Atorvastatin 10 mg (n 5006) Atorvastatin 80 mg (n 4995)
Overall treatment-related AEs Treatment-related myalgia 289 (5.8) 234 (4.7) 406 (8.1) 241 (4.8)
Rhabdomyolysis 3 (0.06) 2 (0.04)
AST/ALT elevation gt3 x ULN 9 (0.2) 60 (1.2)
No cases were considered by the investigator
with direct resposibility for the patient to be
causally related to atorvastatin, and none met
ACC/AHA/NHLBI criteria for rhabdomyolysis
LaRosa et al. N Engl J Med 2005352.
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Elevations in CK and LDL-C Reduction
Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)
Atorvastatin (10, 20, 40, 80 mg)
3.0
Rosuvastatin (10, 20, 40 mg)
Pravastatin (20, 40 mg)
Simvastatin (40, 80 mg)
2.5
2.0
1.5
CK gt10 ULN ()
1.0
0.5
0.0
20
30
40
50
60
70
25
35
45
55
65
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. 200392(suppl)23K-29K.
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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 lt70 mg/dL is therapeutic option for
  patients at very high risk
• LDL-C goal lt100 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. 2004110227-239.
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Effectiveness of Statin Titration on
Low-DensityLipoprotein Cholesterol Goal
Attainment in Patients atHigh Risk of
Atherogenic Events

• Less than 50 (48) achieved an LDL cholesterol lt
  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 9279-81
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Proportional effects on major vascular events per
1-mmol/L LDL-cholesterol reduction among 90,056
participants in 14 randomized trials of statins
Cholesterol Treatment Trialists' (CTT)
Collaborators. Lancet 2005 366 1267-1278
42
Proportional effects on total and cause-specific
mortality per 1-mmol/L LDL-cholesterol reduction
among 90,056 participants in 14 randomized trials
of statins
Cholesterol Treatment Trialists' (CTT)
Collaborators. Lancet 2005 366 1267-1278
43
No significant excess of rhabdomyolysis among
90,056 participants in 14 randomized trials of
statins treated for about 5 years

• Statin Control
  n() n()
• 9(0.023) 6(0.015)
• 5 year excess risk 0.01(p0.4)
• Cholesterol Treatment Trialists' (CTT)
  Collaborators. Lancet 2005 366 1267-1278

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MAJOR CONCLUSIONS OF CTT COLLABORATION

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

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Meta-Analysis of CV Outcome Trials Comparing
Intensive versus Moderate Statin Therapy Primary
Prespecified Endpoint Death or Myocardial
Infarction
Death or Any CV Event ?16 RRR, Plt0.0001
CV Mortality ?12 RRR, P0.054
Stroke ?18 RRR, p0.012
Cannon et al. J Am Coll Cardiol Aug
200648438-45
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Randomized Patients in Trials of Lipid Modifying
Drugs and Clinical Cardiovascular Disease Outcomes

• Statins 90,056
• Nicotinic Acid 2,835
• Omega-3-FA 11,324
• Fibrates
• Gemfibrozil 2,531
• Fenofibrate 9,795
• Ezetimibe 0

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ENHANCE AND SEAS LACK OF CLINICAL OR PUBLIC
HEALTH RELEVANCE

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

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A CLINICIANS DILEMMA

• Unfortunately, most Americans prefer the
  prescription of pills to the proscription of
  harmful lifestyles.
• Charles H. Hennekens,
• New York Times

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French Fries
20 years ago
Today
210 calories 2.4 ounces
610 calories 6.9 ounces
How many calories are in these fries?
Calorie difference 400 Calories
How to burn 400 calories  Walk 2 hour 20 minutes
Based on 130-pound person.
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Darwinism and Risk of Cardiovascular Disease
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Walking the Dog
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Established Risk Factors for CHD

• Blood cholesterol10 ? 20-30 ? in CHD
• High blood pressure5-6 mm Hg ? 42 ? in
  Stroke
• 16 ? in CHD
• Cigarette smokingCessation 50-70 ? in CHD
• Body weight BMIlt25 vs BMIgt27 35-55 ? in CHD
• Physical activity20-minute brisk walk daily
  35-55 ? in CHD

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CHIEF AVOIDABLE CAUSES OF PREMATURE DEATH IN THE
US

• CIGARETTES
• OBESITY
• PHYSICAL INACTIVITY
• LIPIDS
• BLOOD PRESSURE
• HEAVY ALCOHOL CONSUMPTION

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Relationship Between Cholesterol and CHD
RiskMRFIT (Multiple Risk Factor Intervention
Trial)
CHD Risk Based on Total Cholesterol (TC) Level

• 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.

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16
12
Age-Adjusted 6-Year CHD Death Rate per 1000 Men
8
4
N361,662
0
140
160
180
200
220
240
260
280
300
Serum TC (mg/dL)
CHD - coronary heart disease. Gotto, AM et al.
Circulation. 1990811721-1733. Chen, Z Peto, R
Collins R et al. BMJ, 1991 301 276-282.
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GOALS OF HEALTH CARE PROVIDERS AND ACADEMIC
RESEARCHERS

• Maximize benefit and minimize risk which is not
  to be confused with avoidance of risk.
• Make clinical decisions based on the totality of
  evidence not dependence on particular subgroups
  of particular studies.
• Avoid misstatements of benefit to risk ratios
  which may increase publicity, promotions and
  grant support in the short run but confuse
  colleagues and frighten patients and make it
  more difficult to conduct high quality research
• ( COX-2 inhibitors and glitazones)

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• We must all hang together, or assuredly we shall
  all hang separately.
• Benjamin FranklinJuly 4, 1776

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