CVD Prevention for the Boards Foundation, Leduc Foundation...
Transcript of 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.
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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
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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
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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
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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
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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
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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
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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
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Aspirin RecommendationsAspirin Recommendations
Aspirin (75-162 mg daily) in those at intermediate risk (10 year risk of CHD >10%)
Primary Prevention (Men*)
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CHD=Coronary heart disease
*Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines
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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)
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CHD=Coronary heart disease
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Aspirin RecommendationsAspirin Recommendations
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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
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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
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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
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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
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
Smith SC Jr. et al. JACC 2006;47:2130-9
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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
Goals Recommendations
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
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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
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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
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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.
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III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
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
CHD=Coronary heart disease
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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,
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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
Goals Recommendations
Physical Activity GuidelinesPhysical Activity Guidelines
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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
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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
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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
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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
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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
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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
Number at Risk Follow-up (years)
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
Rosuvastatin 198 / 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
Number at Risk Follow-up (years)
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
Number at Risk Follow-up (years)
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
Rosuvastatin 34 / 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
RosuvastatinSuperior Inferior
0.20 0.5 1.0 2.0
VTE
RosuvastatinSuperior Inferior
0.20 0.5 1.0 2.0
Mortality
RosuvastatinSuperior Inferior
0.20 0.5 1.0 2.0
Diabetes
RosuvastatinSuperior Inferior
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
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?
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
Why do we need data?
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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Photo courtesy of Randal Thomas