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Stanford Massie M.D.
GIM Noon Conference
February 12, 2008
ObjectivesBy the end of this session, participants should: Recall the recommendations for treatment
of cholesterol in the 2004 update to the NCEP/ATP III guidelines
Recognize and recall the key findings of several important studies since 2004Focus on Lipid measurement, CV risk prediction
and Secondary Prevention
Appreciate emerging trends in “lipidology” Apply these insights to the care of patients
The scope of the problem Dyslipidemia affects 1 in 2 Americans It is a major RF for CVD, CV death and
all cause mortality Large observational studies suggest a
strong graded relationship between increasing LDL and CAD events.
Management of dyslipidemia can markedly alter CV morbidity/mortality
Ann Intern Med. 2007; ITC-9:1-16.
The scope of the problem-2 Dyslipidemia requiring drug treatment is
prevalent in nearly 30% of patients without clinical CV disease
Of these, only half are taking lipid lowering medication
Benefits of statins are only realized when pts. take them >80% of time
6 months after initiation of statin therapy, adherence rates are 40-65%
Circulation 2006;113:647-656.
JACC 2004;44:720-32
2004 Update to NCEP/ATP III Review of 5 major statin trials with
implications for therapy:Heart Protection StudyPROSPERALLHAT-LLTASCOT-LLAPROVE IT-TIMI 22
JACC 2004;44:720-32
Very high risk= established CVD + 1)Major risk factors (especially DM)2)Severe and poorly controlled risk factors (especially continued smoking)3)Multiple RFs of the metabolic syndrome 4)Acute coronary syndromes
JACC 2004;44:720-32
Log-Linear relationship of LDL and CHD risk
Ann Intern Med. 2006;145:520-530.
Diminishing returns of the hypothesized
log-linear relationship
Ann Intern Med. 2006;145:520-530.
Today’s clinic
Patient 1: Healthy 40 y.o. male Patient 2: 57 y.o. male with stable CAD Patient 3: 65 y.o. female with recent
stroke here for follow up
Road Map
Lipid Measurements CVD risk prediction Secondary Prevention (select groups)
CHDStrokeESRDDiabetes
Future Directions
Patient 1
40 y.o. white male here because “One of my coworkers who is my age
just dropped dead from a heart attack. I want you to check me and make sure I’m not going to do the same thing.”
“My insurance is good, I want the best cholesterol test there is”
Focus Questions for Patient 1 Which lipid test should you order? What is the best way to predict his CV
risk?
Clinical Utility of Different Lipid Measures
for Prediction of Coronary Heart Disease
in Men and WomenJAMA. 2007;298(7):776-785
Background
ApoB 100 is included in all atherogenic particles (VLDL, IDL, LDL, LP(a))
Higher ApoB levels and lower Apo A-I levels linked with pathogenesis of CHD
Some reports suggest these markers may be superior for CHD risk prediction LDL not all the sameApo B levels may better reflect the number
of atherogenic particles in plasma
JAMA. 2007;298(7):776-785
Study design
Population based, prospective cohort 3322 middle aged white participants in
Framingham offspring studyWithout known CV disease
Outcome: incidence of first CHD event Measure: Complex analyses to
compare several different lipid measures for ability to predict CHD events
Results
Ratios are superior to individual lipidsChol:HDL vs. ApoB: ApoA-I
ApoB:ApoA-I ratioPerformed well, but not significantly better
than other lipid measures“Did not provide incremental value for CHD
risk prediction over established risk factors, including Chol:HDL.”
Implications
Head to head, Chol:HDL and ApoB/ApoA-1 ratios are comparable
Further knowledge of ApoB/ApoA-1 does not seem to improve ability to predict CHD risk
Suggests routine measurement of apoliproteins in clinical practice is not necessary
General Cardiovascular Risk Profile for Use in
Primary CareThe Framingham Heart
StudyRalph B. D’Agostino, Sr, PhD; Ramachandran S. Vasan, MD; Michael J. Pencina, PhD; Philip A. Wolf, MD; Mark Cobain, PhD; Joseph M. Massaro, PhD; William B. Kannel, MD
Circulation. 2008;117:743-753.
Background
Framingham risk score effective, but only predicts CHD risk (not stroke etc.)
CV diseases share common risk factors Set out to develop a way to predict risk
for all CVD events
JAMA. 2007;298(7):776-785
Study design
8491Framingham study participantsWithout known CV disease
Outcome: incidence of first CHD event Derived CVD prediction algorithm and
compared with disease specific prediction tools
Circulation. 2008;117:743-753.
Results
General CV risk prediction algorithm performed as well as individual disease specific multivariable risk predictions
It builds on prior models by:Adding HDLBeing based on study with more eventsEstimating absolute CV risk
It is simple to use, will be provided in electronic forms once validated
Circulation. 2008;117:743-753.
Implications
A new tool for CVD risk prediction now available
Allows prediction of all CV events Stroke, CAD, PVD, CHF
Designed for use in primary care Needs validation
Circulation. 2008;117:743-753.
Back to Patient 1
Which lipid test should you order?Fasting Lipid Profile
What is the best way to predict his CV risk?Framingham Risk score (for CHD), but the
new General CV Risk Algorithm may soon take its place
Road Map
Lipid Measurements CV risk prediction Secondary Prevention (select groups)
CHDStroke
Future Directions
Patient 2
57 y.o. AA male with stable CAD. He has angina only with strenuous exertion and it is promptly relieved with SL NTG.
He has HTN and Hyperlipidemia and smoked for many years but quit after his MI in 2003. He does not have Diabetes.
He takes Simvastatin 10 mg daily for his cholesterol and his LDL is 105.
He is here for routine f/u.
Focus Questions for Patient 2 Is he on an adequate dose of statin? What should his target LDL be?
NEJM 2005;352:1425-35.
Study design
Double blind RCT 10,001 pts. with known CHD, LDL <130
were randomly assigned to:Atorvastatin 10 mg dailyAtorvastatin 80 mg daily
Washout/run in periods: only those with LDL<130 participated
Median f/u was 4.9 years Outcome: incidence of first CV event
NEJM 2005;352:1425-35.
NEJM 2005;352:1425-35.
Results
Groups were well matched at baseline Concomitant med use was similar Mean LDL during the study:
High dose group: 77 mg/dlStandard dose group: 101 mg/dl
No difference in overall mortality (power) Mild increase in adverse events (LFTs)
NEJM 2005;352:1425-35.
NEJM 2005;352:1425-35.
TNT Outcomes
ACP Journal Club. Sept/Oct 2005;143(2):38.
Implications
Reducing LDL to 77 compared with 101 in pts. with stable CHD led to significant improvements in a number of CVD outcomes
(No difference in overall mortality)
NEJM 2005;352:1425-35.
JACC 2006;48:438–45.
JACC 2006;48:438–45.
Risk of coronary death or MI
JACC 2006;48:438–45.
JACC 2006;48:438–45.
Adverse Events in the Trials
Back to Patient 2
Is he on an adequate dose of statin?No, based on recent studies, high dose
statin therapy could reduce his chances of further CV events and should be considered.
What should his target LDL be?His optimal LDL may be ~70 or less.
Road Map
Lipid Measurements CV risk prediction Secondary Prevention (select groups)
CHDStroke
Future Directions
Patient 3
65 y.o. female who presents to clinic for follow up after recent hospitalization for acute stroke
She is doing well now, showing some progressive improvement in her deficits
She wants to know what can be done to prevent future strokes.
Focus Questions for Patient 3 Is treatment with a statin effective for
secondary stroke prevention? Does the level of her cholesterol matter?
NEJM 2006;355:549-59.
Study design
Double blind RCT Study group (4731 patients)
Stroke or TIA in past 1-6 monthsLDL on entry of 100-190No known CHD
Randomly assigned to:Atorvastatin 80mg daily ORPlacebo
Outcome: first fatal or nonfatal stroke
NEJM 2006;355:549-59.
Screening, Enrollment, and Outcomes
NEJM 2006;355:549-59.
NEJM 2006;355:549-59.
Baseline Characteristics of the Patients
Results
Median f/u was 4.9 years Mean cholesterol value during the trial:
Atorvastatin group: 73 mg/dlPlacebo group: 129 mg/dl
Overall mortality was similar Elevated LFTs were more common in
the statin group, but serious adverse events were similar
NEJM 2006;355:549-59.
Kaplan-Meier Curves for Stroke and TIA
NEJM 2006;355:549-59.
Kaplan-Meier Curves for Coronary and Cardiovascular Events
NEJM 2006;355:549-59.
SPARCL Results
ACP Journal Club. Jan/Feb 2007;146(1):7.
Slide from The Heart.org, Data source: Goldstein LB et al. Neurology 2007
SPARCL: Factors associated with increased
hemorrhagic stroke risk
Factor Hazard ratio
95% CI p
Atorvastatin treatment 1.68 1.09–2.59 0.02
Hemorrhagic stroke as entry event
5.65 2.82–11.30 0.001
Male sex 1.79 1.13–2.84 0.01
Increasing age (per 10-y increment)
1.42 1.16–1.74 0.001
Implications
In patients with recent stroke or TIA, treatment with 80 mg atorvastatin significantly reduced recurrent strokes and CV events when compared with placebo
There was a small increase in the incidence of hemorrhagic stroke
Statin treatment withdrawal in
ischemic stroke: A controlled randomized study
Neurology 2007;69:904–910
Study Design Consecutive pts
admitted with acute hemispheric stroke <24 hrs duration
Randomly assigned to: Continuing statin therapy
(atorva 20mg/d) ORStopping for 3 days
Outcome: death, dependency or END
Neurology 2007;69:904–910
Results
Neurology 2007;69:904–910
Implications
Withdrawal of statin therapy immediately after stroke onset is associated with:4.7 fold increase in risk of
death/dependency at 3 monthsSimilar detrimental effect on 2° outcomes
Stopping statins during hospitalization for stroke can have detrimental effects and should be avoided
Back to Patient 3 Is treatment with a statin effective for
secondary stroke prevention? High dose statins (started within1-6 months)
are proven effective (NNT=51 for stroke, 16 for any CV event)
Starting statins in first 12 hours may be effective too—studies ongoing
Avoid stopping statins in pts with acute stroke
Does the level of her cholesterol matter?No. Benefit seen for all levels of cholesterol
Road Map
Lipid Measurements CV risk prediction Secondary Prevention (select groups)
CHDStroke
Future Directions
ENHANCE Study : Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis
Regression
Double blind RCT in 720 patients designed to assess changes in Carotid IMT by imaging.
Study not yet published.
ENHANCE: LDL values at baseline and % reduction
after treatment
Merck/Schering-Plough Pharmaceuticals. ENHANCE trial results. January 14, 2008.
Ezetimibe plus simvastatin
Simvastatin alone
p
Baseline LDL (mg/dL)
319 318 NS
Reduction after 2-y treatment (%)
58 41 <0.01
Merck/Schering-Plough Pharmaceuticals. ENHANCE trial results. January 14, 2008.
ENHANCE: Primary end point
End point Ezetimibe plus simvastatin
Simvastatin alone
p
Change in mean carotid IMT after 2-y treatment (mm)
0.0111 0.0058 0.29
Future Directions
Is there an LDL level threshold? LDL level or statin dose? Combination therapy effectiveness? Design of studies will be more important
(decreasing event rate) Novel agents and targets (HDL, CRP,
Apolipoproteins)
Journal of Clinical Lipidology. (2007) 1, 182–190
Recent statin trials: CHD event rates and LDL
TNT: If results extrapolated to clinical practice, use of 80 mg atorvastatin to reduce LDL from 101 to 77 in 1000 pts with stable CAD would prevent 34 CV events over a period of 5 years. NNT to prevent one event~30.
Take Home Points
Recent studies have provided further support for 2004 NCEP/ATP III recs
Standard lipid profile sufficient for risk assessment and treatment decisions
New General CV risk prediction tool:Allows estimation of all CVD outcomesDesigned for use in primary care
Aggressive LDL lowering (<70 or 80) appropriate in CVD (stable CHD/Stroke)
Selected References(in the order they were discussed)
Risk Prediction Ingelsson E et al. Clinical Utility of Different Lipid Measures for Prediction of
Coronary Heart Disease in Men and Women. JAMA. 2007;298(7):776-785. D’Agostino RB et al. General Cardiovascular Risk Profile for Use in Primary Care
The Framingham Heart Study. Circulation. 2008;117:743-753.
CHD LaRosa J et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable
Coronary Disease. NEJM 2005;352:1425-35. Cannon C et al. Meta-Analysis of Cardiovascular Outcomes Trials Comparing
Intensive Versus Moderate Statin Therapy. JACC 2006;48:438–45.
Stroke SPARCL investigators. High dose Atorvastatin after Stroke or Transient
Ischemic Attack. NEJM 2006;355:549-59. Blanco M et al. Statin treatment withdrawal in ischemic stroke: A controlled
randomized study. Neurology 2007;69:904–910.
Recommended