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2008.02.12    Massie   Hyperlipidemia
 

2008.02.12 Massie Hyperlipidemia

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2008.02.12    Massie   Hyperlipidemia 2008.02.12 Massie Hyperlipidemia Presentation Transcript

  • Stanford Massie M.D. GIM Noon Conference February 12, 2008
  • Objectives By 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 2004
      • Focus 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 Study
      • PROSPER
      • ALLHAT-LLT
      • ASCOT-LLA
      • PROVE IT-TIMI 22
  • JACC 2004;44:720-32
    • Very high risk= established CVD +
    • Major risk factors (especially DM)
    • Severe and poorly controlled risk factors (especially continued smoking)
    • Multiple RFs of the metabolic syndrome
    • Acute coronary syndromes
  • Log-Linear relationship of LDL and CHD risk JACC 2004;44:720-32
  • 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)
      • CHD
      • Stroke
      • ESRD
      • Diabetes
    • 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 Women JAMA. 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 same
      • Apo 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 study
      • Without 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 lipids
      • Chol:HDL vs. ApoB: ApoA-I
    • ApoB:ApoA-I ratio
      • Performed 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 Care The Framingham Heart Study
    • Ralph 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 participants
      • Without 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 HDL
      • Being based on study with more events
      • Estimating 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)
      • CHD
      • Stroke
    • 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 daily
      • Atorvastatin 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/dl
      • Standard 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.
  • Adverse Events in the Trials JACC 2006;48:438–45.
  • 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)
      • CHD
      • Stroke
    • 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 months
      • LDL on entry of 100-190
      • No known CHD
    • Randomly assigned to:
      • Atorvastatin 80mg daily OR
      • Placebo
    • 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/dl
      • Placebo 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.
  • SPARCL: Factors associated with increased hemorrhagic stroke risk Slide from The Heart.org, Data source: Goldstein LB et al. Neurology 2007 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) OR
      • Stopping 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 months
      • Similar 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)
      • CHD
      • Stroke
    • 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
  • ENHANCE: Primary end point Merck/Schering-Plough Pharmaceuticals. ENHANCE trial results. January 14, 2008. 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)
  • Recent statin trials: CHD event rates and LDL Journal of Clinical Lipidology. (2007) 1, 182–190 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 outcomes
      • Designed 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.