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.