cvd prevention for the boards foundation, leduc foundation...

Paul M Ridker, MD, MPHPaul M Ridker, MD, MPHEugene Braunwald Professor of MedicineEugene Braunwald Professor of Medicine

Director, Center for Cardiovascular Disease PreventionDirector, Center for Cardiovascular Disease PreventionBrigham and WomenBrigham and Women’’s Hospitals Hospital

Harvard Medical School, Boston, MA USAHarvard Medical School, Boston, MA USA

Dr Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital

that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes.

Annual Intensive Review of Internal MedicineAnnual Intensive Review of Internal Medicine

CVD Prevention for the BoardsCVD Prevention for the BoardsDr Ridker has received investigatorDr Ridker has received investigator--initiated research support from the initiated research support from the NHLBI, NCI, American Heart Association, Donald W Reynolds NHLBI, NCI, American Heart Association, Donald W Reynolds Foundation, Leduc Foundation, Doris Duke Charitable Foundation, Foundation, Leduc Foundation, Doris Duke Charitable Foundation, AstraZeneca, Novartis, and SanofiAventis.AstraZeneca, Novartis, and SanofiAventis.

Dr Ridker has served as a consultant to Seimens, AstraZeneca, Dr Ridker has served as a consultant to Seimens, AstraZeneca, Vascular Biogenics, Merck Schering Plough, and Novartis.Vascular Biogenics, Merck Schering Plough, and Novartis.

Dr Ridker is listed as a coDr Ridker is listed as a co--inventor on patents held by the Brigham and inventor on patents held by the Brigham and WomenWomen’’s Hospital that relate to the use of inflammatory biomarkers in s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to cardiovascular disease and diabetes that have been licensed to Seimens and AstraZeneca. Seimens and AstraZeneca.

3

Evidence Based Prevention of CV DiseaseEvidence Based Prevention of CV Disease

• Evidence based guidelines are based on rigorous and expert analysis of available data, documenting relative benefits and risks of procedures and therapies

• ACC/AHA practice guidelines reflect a consensus of expert opinion and are intended to assist healthcare providers in decision making by describing a range of approaches for the diagnosis, management, and prevention of CVD

• Intended to help improve the effectiveness of care, optimize patient outcomes, and favorably affect the overall cost of care by focusing resources on the most effective strategies

ACC=American College of Cardiology, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease

4

Evidence Based Prevention of CV DiseaseEvidence Based Prevention of CV Disease

• Implications for taking the boards: The most conservative answer is almost always the correct answer, even if that is not what you would actually do in practice.

ACC=American College of Cardiology, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease

5

Class I

Benefit >>> Risk

Procedure or Rx SHOULD be performed or administered

Class IIa

Benefit >> RiskAdditional studies

needed

REASONABLE to perform procedure or administer Rx

Class IIb

Benefit ≥ RiskAdditional

studies/registry data would be

helpful

Procedure or RxMAY BE

CONSIDERED

Class III

Risk ≥ BenefitNo additional

studies needed

Procedure or Rx should NOT be performed or administered

Applying Classification of Applying Classification of Recommendations and Level of EvidenceRecommendations and Level of Evidence

Rx=Treatment6

Level A

Multiple (3-5) population risk

strata evaluated

General consistency of direction and magnitude of

effect

Class I

Procedure or Rx useful or

effective

Sufficient evidence

from multiple trials or meta-

analyses

Class IIa

In favor of being useful or effective

Some conflicting evidence

Class IIb

Less well established

whether useful or effective

Greater conflicting evidence

Class III

Not useful or effective and

may be harmful

Sufficient evidence

Applying Classification of Applying Classification of Recommendations and Level of EvidenceRecommendations and Level of Evidence

Rx=Treatment

7

Level B

Limited (2-3) population risk

strata evaluated

Class I

Procedure or Rx useful or

effective

Limited evidence

from single trial or non-randomized

studies

Class IIa

In favor of being useful or effective

Some conflicting evidence

Class IIb

Less well established

whether useful or effective

Greater conflicting evidence

Class III

Not useful or effective and

may be harmful

Sufficient evidence

Applying Classification of Applying Classification of Recommendations and Level of Evidence Recommendations and Level of Evidence

Rx=Treatment8

DefinitionDefinition

Primordial Prevention: Prevention of CHD risk factors

Primary Prevention: Modification of risk factors in order to prevent or delay the onset of CHD

Secondary Prevention: Initiation of therapy to reduce recurrent CHD events and decrease cardiac mortality in patients with established CHD

CHD=Coronary heart disease

9

Aspirin Evidence: Primary Prevention in MenAspirin Evidence: Primary Prevention in Men

Physicians’ Health Study (PHS)22,071 men randomized to aspirin (325mg every other day) followed for an

average of 5 years

Aspirin significantly reduces the risk of MI in men

End point Relative Risk (95% CI) P value Myocardial infarction Fatal 0.34 (0.15-0.75) 0.007 Nonfatal 0.59 (0.47-0.74) <0.00001 Total 0.56 (0.45-0.70) <0.00001 Stroke Fatal 1.51 (0.54-4.28) 0.43 Nonfatal 1.20 (0.91-1.59) 0.20 Total 1.22 (0.93-1.60) 0.15

Physicians’ Health Study Research Group. NEJM1989;321:129-35

CI=Confidence interval, MI=Myocardial infarction

10

Aspirin Evidence: Primary Prevention in WomenAspirin Evidence: Primary Prevention in Women

Womens’ Health Study (WHS)

Placebo

Aspirin

Ridker P et al. NEJM 2005;352:1293-304

MI=Myocardial infarction

39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years

Aspirin did not reduce the risk of MI, CVA & CV death

11

Aspirin Evidence: Primary PreventionAspirin Evidence: Primary Prevention

BDT, 1988

Combined

PPP, 2001

HOT, 1998

TPT, 1998

PHS, 1989

RR of MI in Men

1.0 2.0 5.00.50.2

RR = 0.68 (0.54-0.86)P=0.001

1.0 2.0 5.00.50.2

RR = 1.13 (0.96-1.33)P=0.15

HOT, 1998

Combined

WHS, 2005

PPP, 2001

1.0 2.0 5.00.50.2

Aspirin Better Placebo Better

RR = 0.99 (0.83-1.19)P=0.95

1.0 2.0 5.00.50.2

Aspirin Better Placebo Better

RR = 0.81 (0.69-0.96)P=0.01

RR of CVA in Men

RR of MI in Women

RR of CVA in Women

Ridker P et al. NEJM 2005;352:1293-304

CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk

12

Aspirin RecommendationsAspirin Recommendations

Aspirin (75-162 mg daily) in those at intermediate risk (10 year risk of CHD >10%)

Primary Prevention (Men*)

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII


*Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines

13

Aspirin (81 mg daily or 100 mg every other day) in at risk women >65 years of age

Aspirin in at risk women <65 years of age for ischemic stroke prevention

Aspirin in optimal risk women <65 years of age

Primary Prevention (Women)





Aspirin RecommendationsAspirin Recommendations

14

Prospective Studies Collaboration. Lancet2002;360:1903-1913

Usual Diastolic BP (mm Hg)Usual Systolic BP (mm Hg)

Isch

emic

Hea

rt D

isea

se M

orta

lity

(Flo

atin

g ab

solu

te r

isk)

50-59

60-69

70-79

80-89Age at Risk (Y)

40-49

256

128

64

32

16

8

4

2

1

0120 140 160 180

50-59

60-69

70-79

80-89

Age at Risk (Y)

40-49

256

128

64

32

16

8

4

2

1

080 90 100 11070

Blood Pressure: Lower is BetterBlood Pressure: Lower is Better

Isch

emic

Hea

rt D

isea

se M

orta

lity

(Flo

atin

g ab

solu

te r

isk)

Ischemic Heart Disease Mortality and Blood Pressure

BP=Blood pressure

15

Blood Pressure Evidence: Primary PreventionBlood Pressure Evidence: Primary Prevention

0 1 2 3 4 5 6 70

.04

.08

.12

.16

.20

RR (95% CI) P-value

A/C 0.98 (0.90-1.07) 0.65

L/C 0.99 (0.91-1.08) 0.81

Rat

e of

MI o

r fa

tal C

HD

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

ALLHAT Investigators. JAMA 2002;288:2981-97

Years to CHD Event

BP=Blood pressure, CHD=Coronary heart disease, HTN=Hypertension, MI=Myocardial infarction

ChlorthalidoneAmlodipine

Lisinopril

33,357 patients with HTN and >1 CHD risk factor randomized to chlorthalidone, amlodipine, or lisinopril for 5 years

There is similar efficacy among BP lowering agents

16

2-drug combination for most†

(usually thiazide-type diuretic and ACE-I or ARB or BB or CCB).

Yes>100>160Stage 2 Hypertension

Drug(s) for compelling indications.‡

Other antihypertensive drugs (as needed).

Thiazide-type diuretics for most. May consider ACE-I, ARB, BB, CCB, or combination of these.

Yes90–99140–159Stage 1 Hypertension

Drug(s) for compelling indications.‡

No antihypertensive drug indicated.

Yes80–89120–139Prehypertension

Encourage<80<120Normal

With compelling indications

Without compelling indications

Initial drug therapyLifestyle

modificationDBP*

mmHgSBP*

mmHgBP

classification

JNC VII Guidelines for Management and TreatmentJNC VII Guidelines for Management and Treatment

and

or

or

or

Chobanian AV et al. JAMA 2003;289:2560-2572

ACE-I=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB=β-blocker, BP=Blood pressure, CCB=Calcium channel blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure

*Treatment determined by highest blood pressure category†Initial combined therapy should be used cautiously in those

at risk for orthostatic hypotension‡Treat patients with chronic kidney disease or diabetes

mellitus to blood pressure goal of <130/80 mmHg

17

Ask and document tobacco use status

Advise: Provide a strong, personalizedmessage

Assess* readiness to quit in next 30 days

Prevent Relapse• Congratulate successes• Encourage • Discuss benefits experienced by patient• Address weight gain, negative mood, and lack of support

Increase Motivation• Relevance to personal situation• Risks: short and long-term, environmental• Rewards: potential benefits of quitting• Roadblocks: identify barriers and solutions• Repetition: repeat motivational intervention• Reassess readiness to quit

Assist• Negotiate plan • STAR**• Discuss pharmacotherapy• Social support• Provide educational materials

Arrange follow-up to check plan or adjust meds• Call right before and after quit date• Weekly follow-up x 2 weeks, then monthly x 6 months• Ask about difficulties (withdrawal, depressed mood)• Build upon successes• Seek commitment to stay tobacco-free

**STARSet quit dateTell family, friends, and coworkersAnticipate challenges: withdrawal, breaksRemove tobacco from the house, car etc.

Recent Quitter(<6 months)

Current User

Not Ready

Ready

Smoking Cessation AlgorithmSmoking Cessation Algorithm

Complete cessation

No environmental tobacco smoke exposure

Cigarette Smoking Cessation RecommendationsCigarette Smoking Cessation Recommendations

Goals Recommendations

Ask about tobacco use at every visit

In a clear, strong, and personalized manner, advise the patient to stop smoking

Urge avoidance of exposure to second-hand smoke at work and home

Assess patient’s willingness to quit smoking

Develop a plan for smoking cessation and arrange follow-up

Provide counseling, pharmacologic therapy, and referral to a formal cessation program


Smith SC Jr. et al. JACC 2006;47:2130-9

19

160 overweight and obese patients randomized to the Atkins, Zone, Weight Watchers, or Ornish diets for 1 year

Weight loss is similar among diet programs, but hard to sustain because of poor long-term compliance

Dansinger ML et al. JAMA 2005;293:43-53

Diet Evidence: Primary PreventionDiet Evidence: Primary Prevention

20/40*

26/40*

26/40*

21/40*

0 3 6 9

Atkins

Zone

Weight Watchers

Ornish

Wt loss (lbs)

*Ratio of individuals completing the study to those enrolled


Calculate BMI* and measure waist circumference

Monitor response to treatmentBMI 18.5 to 24.9 kg/m2

Women: <35 inchesMen: <40 inches

Weight Management RecommendationsWeight Management Recommendations

Start weight management and physical activity as appropriate

If BMI and/or waist circumference is above goal, initiate caloric restriction and increase caloric expenditure

BMI=Body mass index, Rx=Treatment

*BMI is calculated as the weight in kilograms divided by the body surface area in meters2

10% weight reduction within the 1st yr of Rx


Overweight state is defined by BMI=25-30 kg/m2

Obesity is defined by a BMI >30 kg/m2Smith SC Jr. et al. JACC 2006;47:2130-9

21Joshipura KJ et al. Ann Intern Med 2001;134:1106-14

Diet Evidence: Benefits of Fruits and VegetablesDiet Evidence: Benefits of Fruits and Vegetables

Nurses’ Health Study and Health Professional’s Follow-up Study

*Includes nonfatal MI and fatal coronary heart disease

CV=Cardiovascular, MI=Myocardial infarction

126,399 persons followed for 8-14 years to assess the relationship between fruit and vegetable intake and adverse CV outcomes*

Increased fruit and vegetable intake reduces CV risk

22Pereira MA et al. Arch Int Med 2004;164:370-76

Diet Evidence: Benefits of Whole Grain and FiberDiet Evidence: Benefits of Whole Grain and Fiber

RR=0.73, P<0.001

336,244 persons followed for 6-10 years to assess the relationship between dietary fiber intake and adverse CV outcomes

Increased dietary fiber intake reduces CV risk

CV=Cardiovascular, CHD=Coronary heart disease

AHA Nutrition Committee Dietary RecommendationsAHA Nutrition Committee Dietary Recommendations

• Balance calorie intake and physical activity to achieve or maintain a healthy body weight

• Consume a diet rich in fruits and vegetables

• Consume whole-grain, high-fiber foods

• Consume fish, especially oily fish, at least twice a week

• Limit intake of saturated fat to <7%, trans fat to <1% of energy, and cholesterol <300 mg/day by:

– Choosing lean mean and vegetable alternatives

– Choosing fat free (skim), 1% fat, and low-fat dairy products,

– Minimizing intake of partially hydrogenated fats

• Minimize intake of beverages and foods with added sugar

• Choose and prepare foods with little or no salt

• If alcohol is consumed, do so in moderation

Recommendations for Cardiovascular Disease Risk Reduction

AHA Nutrition Committee. Circulation 2006;114:82-96

AHA=American Heart Association

24

Primary Prevention

Dietary Guidelines Dietary Guidelines

Consume a diet rich in fruits and vegetables; choose whole-grain, high-fiber foods; consume fish, especially oily fish,* at least twice a week; limit intake of saturated fat to <10% of energy, and if possible to <7%, cholesterol to <300 mg/d, alcohol intake to no more than 1 drink per day, and sodium intake to <2.3 g/d(approximately 1 tsp salt). Consumption of trans-fatty acids should be as low as possible (eg, <1% of energy)

*Pregnant and lactating women should avoid eating fish potentially high in methylmercury


25

Secondary Prevention

Dietary GuidelinesDietary Guidelines

Reduce intake of saturated fats (to <7% of total calories), trans-fatty acids, and

cholesterol (to <200 mg/d).

Encouraging consumption of omega-3 fatty acids in the form of fish or in capsule form (1 g per d) for risk reduction may be reasonable for patients with known CAD.



26Yokoyama M et al. Lancet. 2007;369:1090-8

ωω--3 Fatty Acids: Primary and Secondary Prevention3 Fatty Acids: Primary and Secondary Prevention

JELIS Trial18,645 patients with hypercholesterolemia randomized to EPA (1800 mg)

with a statin or a statin alone for 5 years

EPA provides additional cardiovascular benefit to those on statin therapy, particularly in secondary prevention

Composite of cardiac death, myocardial infarction, angina, PCI, or CABG

27Manson JE et al. NEJM 2002;347:716-25

Quintiles of activity (MET-hour/week**)

0.0

0.2

0.4

0.6

0.8

1.0

Walking

Rel

ativ

e R

isk

of C

HD

0.0

0.2

0.4

0.6

0.8

1.0

Vigorous exercise*

Rel

ativ

e R

isk

of C

HD

P=0.004P=0.008

1 2 3 4 5

Exercise Evidence: Effect on CHD RiskExercise Evidence: Effect on CHD Risk

Women’s Health Initiative Observational Study

1 2 3 4 5

**Average active hours per week × energy expenditure per activity

*Includes aerobics, aerobic dancing, jogging, tennis, and swimming laps


28

0.76 0.75

1.15

0

0.5

1

1.5

All Cause Death CV Mortality Nonfatal Recurrence

Poole

d O

dds

Ratio

* *

Exercise Evidence: Secondary PreventionExercise Evidence: Secondary Prevention

Effect of cardiac rehabilitation in randomized controlled trials following a MI

Oldridge NB et al. JAMA 1988;260:945-950

*p<0.0125

CV=Cardiovascular, MI=Myocardial infarction,

29

Assess risk, preferably with an exercise test, to guide prescription (Class I, Level B)

Encourage aerobic activity (e.g., walking, jogging, cycling) supplemented by an increase in daily activities (e.g., walking breaks at work, gardening, household work) (Class I, Level B)

Encourage resistance training (e.g., weight machines, free weights) 2 days a week (Class IIb, Level C)

Encourage cardiac rehabilitation for patients with stable angina, recent MI, LV systolic dysfunction, or recent CABG (Class I, Level B)

Minimum: 30-60 minutes,5 days per week

Optimal: 30-60 minutes,7 days per week


Physical Activity GuidelinesPhysical Activity Guidelines


30Nichol KL et al. NEJM 2003;348:1322-32

Adverse Outcome

Vaccinated

Subjects

(N=77,738)

Unvaccinated

Subjects

(N=62,317)

Adjusted Odds Ratio

P value

Hospitalization for CHD 457 (0.6) 535 (0.9) 0.80 0.001

Hospitalization for HF 466 (0.6) 538 (0.9) 0.81 0.002

Hospitalization for CVD 398 (0.5) 427 (0.7) 0.84 0.018

Death 943 (1.2) 1361 (2.2) 0.52 <0.001

Hospitalization or death 2387 (3.1) 2910 (4.7) 0.65 <0.001

Influenza Vaccination: Primary PreventionInfluenza Vaccination: Primary Prevention

286,383 community-dwelling members aged >65 years of 3 large managed-care organizations evaluated for 1-2 yrs

Influenza vaccination reduces adverse CV events

Patients with cardiovascular disease should receive the influenza vaccination annually

Influenza Vaccination RecommendationInfluenza Vaccination Recommendation


Smith SC Jr. et al. JACC 2006;47:2130-9 32

HMGHMG--CoACoA ReductaseReductase Inhibitor: Primary PreventionInhibitor: Primary Prevention

West of Scotland Coronary Prevention Study (WOSCOPS)

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

Shepherd J et al. NEJM 1995;333:1301-1307

Placebo

7.5

Pravastatin

9

6

3

0

5.3

P<0.001

31% RRR

Rat

e of

MI

or C

HD

de

ath

(%)

6,595 men with moderate hypercholesterolemia randomized to pravastatin (40 mg) or placebo for 5 years

Statins provide significant benefit in those with above average cholesterol levels

33

Rat

e of

MI,

uns

tab

le

angi

na,

or

SC

D (

%)

Placebo

5.5

Lovastatin

6

4

2

0

3.5

HMGHMG--CoA Reductase Inhibitor: Primary PreventionCoA Reductase Inhibitor: Primary PreventionAir Force/Texas Coronary Atherosclerosis Prevention Study

(AFCAPS/TEXCAPS)

P<0.001

37% RRR

MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death

Downs JR et al. JAMA 1998;279:1615–1622

6,605 patients with average LDL-C levels randomized to lovastatin (20-40 mg) or placebo for 5 years

Statins provide benefit in those with average LDL-C levels

34

HMGHMG--CoACoA ReductaseReductase Inhibitor: Primary PreventionInhibitor: Primary PreventionJustification for Use of statins in Prevention: an Intervention

Trial Evaluating Rosuvastatin (JUPITER)

Ridker et al, NEJM 2008

17,802 men and women with mean LDL of 100 mg/dL but

elevated levels of hsCRP > 2 mg/L randomized to rosuvastatin 20 mg or placebo for 5 years

Statins provide benefit in those with low LDL-C but high hsCRP

55 percent reduction in MI48 percent reduction in stroke47 percent reduction in need for CABG/PTCA43 percent reduction in DVT/PE20 percent reduction in all cause mortality

Greatest absolute benefit with the highest CRP levelsNo relationship of benefit to baseline LDLC levels

Sachdeva et al, Am Heart J 2009;157:111-7.e2.

LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006

LDLC (mg/dL) 130-160 > 160< 130

hsCRP and Risk of Future MI and CVA in Apparently Healthy Men

Quartile of Quartile of hshs--CRPCRP

Ridker et al, N Engl J Med 1997;336:973–979.

P P Trend <0.001Trend <0.001

Rel

ativ

e R

isk

of

MI

Rel

ativ

e R

isk

of

MI

0

1

2

3

1 2 3 4

Re

lati

ve R

isk

of

Str

oke

Re

lati

ve R

isk

of

Str

oke

P P Trend <0.01Trend <0.01

0

1

2

1 2 3 4

Quartile of hsQuartile of hs--CRPCRP

37

Coronary Heart Disease

3.0

2.5

2.0

1.5

1.0

hsCRP concentration (mg/L)

Ris

k r

ati

o (

95

% C

I)

All Vascular Deaths

3.0

2.5

2.0

1.5

1.0

0.5 1.0 2.0 4.0 8.0

Meta-analysis of 54 Prospective Cohort StudieshsCRP concentration and risk of cardiovascular events : 2010

Emerging Risk Factor Collaborators, Lancet January 2010

0.5 1.0 2.0 4.0 8.0

38

CR-39Emerging Risk Factor Collaborators, Lancet January 2010

0.5 1.0 1.2 1.4 1.8

hsCRP

Systolic BP

Total cholesterol

Non-HDLC

1.37 (1.27-1.48)

1.35 (1.25-1.45)

1.16 (1.06-1.28)

1.28 (1.16-1.40)

Risk Ratio (95%CI)

Meta-analysis of 54 Prospective Cohort Studies:The magnitude of independent risk associated with inflammation is

at least as large, if not larger, than that of BP and cholesterol

Risk Ratio (95%CI) per 1-SD higher usual values

Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hsCRP

1.00

0.99

0.98

0.97

0.96

0.000 2 4 6 8

Years of Follow-up

Primary Prevention : Whom Should We Treat ?Primary Prevention : Whom Should We Treat ?

Ridker et al N Engl J Med. 2002;347:1157-1165.

Pro

bab

ilit

y o

f E

ven

t-fr

ee S

urv

ival hsCRP < 2, LDL < 130

hsCRP > 2, LDL > 130

hsCRP < 2, LDL > 130

hsCRP > 2, LDL < 130

RosuvastatinRosuvastatin 20 mg (N=8901)20 mg (N=8901) MIMIStrokeStroke

UnstableUnstableAnginaAngina

CVD DeathCVD DeathCABG/PTCACABG/PTCA

JUPITERJUPITERMultiMulti--National Randomized Double Blind Placebo Controlled Trial of National Randomized Double Blind Placebo Controlled Trial of

RosuvastatinRosuvastatin in the Prevention of Cardiovascular Eventsin the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated Among Individuals With Low LDL and Elevated hsCRPhsCRP

44--week week runrun--inin

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060

LDL <130 mg/dLhsCRP >2 mg/L

JUPITERTrial Design

Placebo (N=8901)Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

JUPITERWhy Consider Statins for Low LDL, high hsCRP Patients?

While intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.

New Engl J Med 2001;344:1959-65

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

[A]

[B]

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

AFCAPS/TexCAPS Low LDL Subgroups

RR

JUPITERBaseline Clinical Characteristics

Rosuvastatin Placebo(N = 8901) (n = 8901)

Age, years (IQR) 66.0 (60.0-71.0) 66.0 (60.0-71.0)Female, N (%) 3,426 (38.5) 3,375 (37.9)Ethnicity, N (%)

Caucasian 6,358 (71.4) 6,325 (71.1)Black 1,100 (12.4) 1,124 (12.6)Hispanic 1,121 (12.6) 1,140 (12.8)

Blood pressure, mm (IQR)Systolic 134 (124-145) 134 (124-145)Diastolic 80 (75-87) 80 (75-87)

Smoker, N (%) 1,400 (15.7) 1,420 (16.0)Family History, N (%) 997 (11.2) 1,048 (11.8)Metabolic Syndrome, N (%) 3,652 (41.0) 3,723 (41.8)Aspirin Use, N (%) 1,481 (16.6) 1,477 (16.6)

All values are median (interquartile range) or N (%)

JUPITERBaseline Blood Levels (median, interquartile range)

Rosuvastatin Placebo(N = 8901) (n = 8901)

hsCRP, mg/L 4.2 (2.8 - 7.1) 4.3 (2.8 - 7.2)

LDL, mg/dL 108 (94 - 119) 108 (94 - 119)mmol/L 2.8 (2.43 - 3.08) 2.8 (2.43 - 3.08

HDL, mg/dL 49 (40 – 60) 49 (40 – 60)mmol/L 1.27 (1.03 - 1.55) 1.27 (1.03 - 1.55)

Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169) mmol/L 1.33 (0.96-1.91) 1.33 (0.97-1.91)

Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199)mmol/L 4.82 (4.35-5.18) 4.79 (4.38-5.15)

Glucose, mg/dL 94 (87 – 102) 94 (88 – 102)mmol/L 5.22 (4.83-5.66) 5.22 (4.88-5.66)

HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9)

All values are median (interquartile range) [ Mean LDL = 104 mg/dL (2.69 mmol/L)]

Ridker et al NEJM 2008

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

Number Needed to Treat (NNT5) = 25

- 44 %

0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lati

ve I

nc

ide

nc

e

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

JUPITERFatal or Nonfatal Myocardial Infarction

Rosuvastatin

Placebo

- 55 %

0 1 2 3 4

Follow-up Years

0.0

000

.005

0.0

100

.015

0.0

200

.025

0.0

30

Cu

mu

lati

ve In

cid

en

ce

HR 0.45, 95%CI 0.30-0.70P < 0.0002

JUPITERFatal or Nonfatal Stroke

Rosuvastatin

Placebo

- 48 %

0 1 2 3 4

Follow-up Years

0.0

00

0.0

05

0.0

10

0.0

15

0.0

20

0.0

25

0.0

30

Cu

mu

lati

ve I

nc

ide

nc

e

HR 0.52, 95%CI 0.34-0.79P = 0.002

JUPITERArterial Revascularization

Placebo (N = 143)

Rosuvastatin (N = 76)

HR 0.53, 95%CI 0.40-0.70P < 0.00001

- 47 %

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cu

mu

lati

ve In

cid

ence


Rosuvastatin

Placebo

8,901 8,640 8,426 6,550 3,905 1,966 1,359 989 547 158

8,901 8,641 8,390 6,542 3,895 1,977 1,346 963 538 176

JUPITERPrimary Endpoint – Understudied or “Low Risk” Subgroups

0.25 0.5 1.0 2.0 4.0

Rosuvastatin Superior Rosuvastatin Inferior

Women

Age > 70

Framingham Risk < 10 %

Black, Hispanic, Other

LDLC < 100 mg/dL

No Hypertension

All Participants

N HR (95%CI)

6,801 0.54 (0.37-0.80)

5,695 0.61 (0.46-0.82)

8,882 0.56 (0.38-0.83)

5,117 0.63 (0.41-0.98)

6,269 0.66 (0.47-0.92)

7,586 0.62 (0.44-0.87)

17,802 0.56 (0.46-0.69)

BMI < 25 mg/m2 4,073 0.59 (0.40-0.87)

No metabolic Syndrome 10,296 0.49 (0.37-0.65)

Elevated hsCRP Only 6,375 0.63 (0.44-0.92)

Understudied Subgroups

“Low Risk” Subgroups

JUPITERSecondary Endpoint – All Cause Mortality

Placebo 247 / 8901


HR 0.80, 95%CI 0.67-0.97P= 0.02

- 20 %

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cu

mu

lati

ve In

cid

ence


RosuvastatinPlacebo

8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

0

50

100

150

200

250

300

350

400

450

JUPITER

WOSCOPS

AFCAPS/TexCAPS

HTN - Diuretics

HTN –Beta Blockers

Aspirin - Men

Aspirin - Women

Estimated 5-Year NNT Values for the Primary Prevention of Cardiovascular Disease In Middle-Aged Populations

JH-52

JUPITER:Primary Endpoint by Time Since Randomization

Time since randomization

6 months

12 months

18 months

2 years

2.5 years

3 years

<0.001

<0.001

<0.001

<0.001

<0.001

Hazard ratio (95% CI)

0.029

P value

0.1 1

Am J Cardiol 2010;106:1351-6

JUPITERNo Relationship of Baseline LDLC to Event Reduction

0.20 0.5 1.0 2.0 4.0

Rosuvastatin Better Rosuvastatin Worse

Baseline Levels

LDLC <100 mg/dL

LDLC <90 mg/dL

LDLC <80 mg/dL

LDLC <70 mg/dL

LDLC <60 mg/dL

All Participants

N

6,269

3,687

2,033

1,022

511

17,802

CR-54

JUPITERAbsolute Risk Reduction Increases With Increasing Levels of hsCRP

0.20 0.5 1.0 2.0

Better Worse

Baseline hsCRP

>10 mg/L_

>9 mg/L_

>8 mg/L_

>7 mg/L_

>6 mg/L_

>5 mg/L_

>4 mg/L_

>3 mg/L_

>2 mg/L_

N

2,503

3,071

3,839

4,723

5,897

7,425

9,726

12,939

17,802

1.0 2.0 3.0 4.0 5.0

Placebo Event Rate

Am J Cardiol 2010;106:204-9

JUPITERLDL reduction, hsCRP reduction, or both?

N Rate

Placebo 7832 1.11LDL>70mg/dL,hsCRP>2 mg/L 1384 1.11LDL<70mg/dL,hsCRP>2 mg/L 2921 0.62LDL>70mg/dL,hsCRP<2 mg/L 726 0.54LDL<70mg/dL,hsCRP<2 mg/L 2685 0.38

Placebo 7832 1.11LDL>70mg/dL,hsCRP>1 mg/L 1874 0.95LDL<70mg/dL,hsCRP>1 mg/L 4662 0.56LDL>70mg/dL,hsCRP<1 mg/L 236 0.64LDL<70mg/dL,hsCRP<1 mg/L 944 0.24

1.00.50.25 2.0 4.0

P < 0.001

RosuvastatinBetter

Rosuvastatin Worse

P < 0.001

Full Adjusted Hazard Ratio0.21, 95% CI 0.09-0.52, P < 0.0001

Lancet 2009;373:1175-82 JUPITERNo evidence of increased adverse effects with LDL < 50 mg/dL

LDLC LDLC P>50mg/dL < 50mg/dL

Myalgia 4.0 3.5 0.49Gastrointestinal 14.0 14.4 0.32Respiratory 8.0 8.9 0.18CNS 8.3 8.3 0.60Renal 4.3 4.8 0.30Cancer 1.5 1.4 0.36Diabetes 1.2 1.6 0.70ALT>3x ULN 0.7 0.7 0.78CK>10x ULN 0.01 0.01 0.99Proteinuria 2.5 2.6 0.29

Hsia et al, JACC 2011

Venous Endothelium- transmission electron micrograph

JUPITERTotal Venous Thromboembolism

0 1 2 3 4

0.0

000

.005

0.0

100

.015

0.0

200

.025

Cu

mu

lati

ve I

nci

den

ce


Rosuvastatin

Placebo

8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161

8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

HR 0.57, 95%CI 0.37-0.86P= 0.007

Placebo 60 / 8901


- 43 %

JUPITERStatins and the Development of Diabetes

0.25 0.5 1.0 2 4

WOSCOPS Pravastatin

HPS Simvastatin

ASCOT-LLA Atorvastatin

JUPITER Rosuvastatin

PROVE-IT AtorvastatinVS

Pravastatin

0.70 (0.50–0.98)

1.20 (0.98–1.35)

1.20 (0.91–1.44)

1.11 (0.67–1.83)

1.25 (1.05–1.54)

Statin Better Statin Worse

HR (95% CI)

PROSPER Pravastatin 1.34 (1.06–1.68)

LIPID Pravastatin 0.91 (0.72–1.18)

CORONA Rosuvastatin 1.13 (0.86–1.50)

(Hypothesis Testing Trials) 1.12 (1.04–1.30)

(Hypothesis Generating Trial)

JUPITERIncident Diabetes Limited to Those With Impaired Fasting Glucose

(51) (62) (18)

(43)

(39) (38)

(34)

(53)

(34) (29)

(39)

(45)

Fasting Glucose Level (mg/dL)

0

2

4

6

8

10

12

14

<100 100-104 105-109 110-114 115-119 120-125

Inci

den

ce R

ate

(per

10

0 p

erso

n y

ears

)

Placebo

Rosuvastatin

JUPITERStatin Highly Effective in All Patients – Primary Endpoint

HR 0.51, 95% CI 0.40-0.67

Normal Fasting Glucose

HR 0.69, 95% CI 0.49-0.98

Impaired Fasting Glucose

0 1 2 3 4

Follow-up Years

0.0

00

.02

0.0

40

.06

0.0

80

.10

Cu

mu

lati

ve In

cid

ence

0 1 2 3 4

Follow-up Years

RosuvastatinRosuvastatin

PlaceboPlacebo

JUPITERCardiovascular Benefits of Statin Therapy In All High Risk Groups for Diabetes

0.20 0.5 1.0 2.0

Nonfatal MI+ Stroke

RosuvastatinSuperior Inferior

MetabolicSyndrome

Y

N

FG >100 mg/dL_ Y

N

BMI > 30 kg/m2_ Y

N

HbA1c >6 % Y

N

Any Risk Factor Y

N

N

7,316

10,278

5,504

12,170

6,637

11,042

3,008

14,615

11,508

6,095

0.20 0.5 1.0 2.0

Revascularization +Unstable Angina


0.20 0.5 1.0 2.0

VTE


0.20 0.5 1.0 2.0

Mortality


0.20 0.5 1.0 2.0

Diabetes


Cardiovascular Benefits and Diabetes Risks of Statin Therapy in Primary Prevention: The JUPITER Trial

• In absolute terms for those without a major diabetes risk factor, 65 vascular events or death were avoided by statin therapy with no excess cases of diabetes diagnosed.

• In absolute terms for those with a major diabetes risk factor, 93 vascular events or deaths were avoided by statin therapy for every 54 new cases of diabetes diagnosed.

• Conclusion: In primary prevention, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including among individuals at high risk for developing diabetes. Long-term microvascular effects unknown.

FraminghamRisk Score

AgeBlood PressureDiabetesSmokingTotal cholesterolHDL cholesterol

Reynolds RiskScore

AgeBlood PressureDiabetesSmokingTotal cholesterolHDL cholesterol

hsCRPParental history of MI

JAMA 2007;297:611-9 Circulation 2008

www.reynoldsriskscore.org

AgeSmoking

SBPTC

HDLChsCRPFamilyHistory

ReynoldsRisk

Score

hsCRP (mg/L)is not

CRP (mg/dL)

65

Reynolds Risk Score – Example I

Clinical Example:Clinical Example:

65 year old non65 year old non--smoking man with systolic BP 130 mm smoking man with systolic BP 130 mm Hg, TC 205 mg/dL, HDLC 45 mg/dL, hsCRP 4.0 mg/L, Hg, TC 205 mg/dL, HDLC 45 mg/dL, hsCRP 4.0 mg/L, and a positive family history for MI.and a positive family history for MI.

Predicted 10Predicted 10--year riskyear risk

Framingham Covariates: Framingham Covariates: 11.6 percent11.6 percent

Reynolds Covariates:Reynolds Covariates: 20.4 percent20.4 percent

Cook NR et al, Circulation 2012;125:1748-1756

“The Reynolds Risk Score was better calibrated than the Framingham model in this large external validation cohort. The Reynolds score also showed improved discrimination overall in black and white women. Large differences in risk estimates exist between models, with clinical implications for statin therapy.”

CR-68

Primary Goal : LDLC

High CAD, CVA, PVD <2mmol/L or 50% reduction Class IMost pts with Diabetes Level AFRS > 20 %RRS > 20 %

Moderate FRS 10- 19 % <2mmol/L or 50 % reduction Class IIARRS 10-19 % Level ALDL > 3.5 mmol/LTC/HDLC > 5.0hsCRP > 2 in

men >50 yrwomen > 60 yr

Low FRS < 10 % <5mmol/L Class IIALevel A

Secondary Targets : TC/HDLC < 4, non HDLC < 3.5 mol/L, hsCRP < 2 mg/L, TG < 1.7 mol/L, ApoB/A<0.8

2009 Canadian Cardiovascular Society (CCS)Guidelines for the Diagnosis and Treatment of Dyslipidemia

and Prevention of Cardiovascular Disease in the Adult

567 References - No mention of the JUPITER trial, No Change in Practice at all

Impression: As far as Europe is concerned, the trial did not happen!

CR-70

2010 ACC/AHA Guidelines for Assessment of Cardiovascular Risk in Asymptomatic Adults

JACC November 16, 2010

“The initial step in risk assessment in individual patients involves the ascertainment of a global risk score (Framingham, Reynolds, etc) and the elucidation of a family history of atherosclerotic CVD. These Class I recommendations which are simple and inexpensivedetermine subsequent strategies to be undertaken”

Reynolds = Framingham + hsCRP + HbA1c + family history

CR-71

2010 ACC/AHA Guidelines for Assessment of Cardiovascular Risk in Asymptomatic Adults

Class I Class II Class IIIBenefit >>>Risk Benefit >> Risk No Benefit

Global Screening hsCRP Apo A, apo BFramingham HbA1c Lp(a)Reynolds ABI Advance Lipid Testing

ECG BNP, ANP, NT-BNPcIMT MRICAC ECHO

Stress ECHOBrachial DilatationPulse Wave VelocityArterial StiffnessCT Angiography

JACC November 16, 2010

Two Conflicting World Views Regarding the Role of Screening in Primary Prevention

“If it predicts disease, it must be a good thing

to measure”

Belief Driven Approach

“If I measure it, it will improve outcomes

for my patient”

Evidence Driven Approach

CR-73

Why do we need data?

Isn’t it true that statins are effective in all patients?

Isn’t it true that the higher the absolute risk, the greater the benefit of statin therapy?

CR-74


Isn’t it true that statins are effective in all patients?

Isn’t it true that the higher the absolute risk, the greater the benefit of statin therapy?

Absolutely NOT !

4-D, AURORA, CORONA, GISSI-HF, SEAS are allNULL statin trials in populations that are both at very

high risk and known to have high CAC scores

CR-75

FRS > 20or DM or

Family history

LDLC > 160hsCRP > 2

No EvidenceOf Benefit

High LDL

Low HDLHigh hsCRP

BenefitUnknown

Biomarker Trials Are Routinely Done and Have Changed Medical Practice

WOSCOPS(pravastatin)

AFCAPS/TexCAPS(lovastatin)

JUPITER(rosuvastatin)

Low LDLLow hsCRPHigh HDL

CR-76

Why Are RCTs so Important? Why can’t we just rely on observational data?

The Role of Statins in CAC

Study Year Type SS Change in CAC

Callister 1998 Obs 149 45 % decreaseRaggi 2004 Obs 495 35 % decreaseBudoff 2000 Obs 131 61 % decreaseBudoff 2005 Obs 163 50 % decreaseAchenbach 2002 Obs 66 64 % decrease

CR-77

Why Are RCTs so Important? Why can’t we just rely on observational data?

The Role of Statins in CAC

Study Year Type SS Change in CAC

Callister 1998 Obs 149 45 % decreaseRaggi 2004 Obs 495 35 % decreaseBudoff 2000 Obs 131 61 % decreaseBudoff 2005 Obs 163 50 % decreaseAchenbach 2002 Obs 66 64 % decrease

Housley 2006 RCT 102 44 % increaseTerry 2007 RCT 80 No changeSchmermund 2006 RCT 366 No changeRaggi 2005 RCT 475 No changeArad 2005 RCT 1005 No change

CR-78


Is there randomized trial evidence demonstrating that asymptomatic patients

who do not already have an indication for a statin benefit from statin therapy if they are

identified by an imaging test? NO

Are there patients with a current indication for a statin who you would stop treatment based

on data from an imaging test?NO

EBCT 0.6 – 1.0 mSvMDCT 0.9 – 2.0 mSvCXR 0.01 – 0.02 mSv

Increased Cancer Risk > 2.3 mSv

“The estimated lifetime cancer risk is 42 cases per 100,000 men and 62 per 100,000 women… These radiation risks can be compared withpotential benefits from screening when such estimates are available”.

Arch Int Med 2009;169:1188-1194

What about radiation exposure?

“ > 50% of participants may have at least one non-calcified nodule”“Current limitations thus include the cost and morbidity of follow-up and further testing, the small but difficult to quantify potential risk of cancer associated with multiple follow-up CT scans, and the potential for increased anxiety of both the

patient and the physician about non-significant pathology”

What about incidentalomas?

Be Wary of Expert Opinion

“I know there is no outcome data, but when I tell my patient their CAC score, they improve

their risk factor profiles and have better medication compliance”

Imaging Advocate, ACC 2011

Hackam DG, et al; Arch Intern Med 2011; epublished

“There is little evidence suggesting that non-invasive cardiovascular imagingalters primary prevention efforts”

What About Surrogate Endpoints? Doesn’t CAC at least improve those?

“Compared with no scanning, randomization to CAC was associated with superior coronary artery disease risk factor control”

What About EISNER ? Wasn’t that a positive study” ?No-Scan Scan P

Quit smoking, % 44 49 NSRegular exercise, % 36 37 NSChange in DBP, mm Hg -4 -5 NSChange in TC, mg/dL -16 -21 NSChange in HDLC, mg/dL -1 -1 NSChange in TG, mg/dL -9 -10 NSChange in glucose, mg/dL -2 -0 NSChange in weight, lbs 1 0 NSNew lipid meds,% 25 29 NSNew DM meds, % 3 3 NSNew ASA use, % 7 8 NSAdherence to lipid meds,% 86 86 NSAdherence to BP meds, % 90 94 NSAdherence to DM meds, % 93 88 NSAdherence to ASA, % 31 27 NS

EISNER Trial Results - Rozanski et al, JACC March 28,2100

Death or MI was HIGHER in the scan group than in the no-scan group (2.1 vs 1.0 %, P=0.08)

LDL, HDL,hsCRP

Yes Yes

Yes No

Predict risk ?

Randomized trial evidence ?

Cost-effective or cost-saving ? Yes No

CACLDL, HDL,

hsCRP

No Yes

Yes Yes

Yes No

Predict risk ?

Randomized trial evidence ?

Cost-effective or cost-saving ?

Irradiate my patient ?

Unnecessary downstream testing ?

Major infrastructure investment ?

Anxiety producing incidentalomas ?

Divert time, energy, and resources away from quality patient care ?

Yes No

No Yes

No Yes

No Yes

No Yes

CAC

Two World Views Regarding Screening in Primary Prevention

If you want to practice evidence-free medicine, increase expenses to our health care system, irradiate your patients, and take the medical-legal risk of performing un-indicated down-stream procedures, order imaging tests in the asymptomatic patient.

If you want to practice evidence-based medicine, improve outcomes, and use medical resources wisely, order a simple panel of inexpensive biomarkers in the asymptomatic patient.

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