2008.02.12 Massie Hyperlipidemia


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  • 2008.02.12 Massie Hyperlipidemia

    1. 1. Stanford Massie M.D. GIM Noon Conference February 12, 2008
    2. 2. Objectives By the end of this session, participants should: <ul><li>Recall the recommendations for treatment of cholesterol in the 2004 update to the NCEP/ATP III guidelines </li></ul><ul><li>Recognize and recall the key findings of several important studies since 2004 </li></ul><ul><ul><li>Focus on Lipid measurement, CV risk prediction and Secondary Prevention </li></ul></ul><ul><li>Appreciate emerging trends in “lipidology” </li></ul><ul><li>Apply these insights to the care of patients </li></ul>
    3. 3. The scope of the problem <ul><li>Dyslipidemia affects 1 in 2 Americans </li></ul><ul><li>It is a major RF for CVD, CV death and all cause mortality </li></ul><ul><li>Large observational studies suggest a strong graded relationship between increasing LDL and CAD events. </li></ul><ul><li>Management of dyslipidemia can markedly alter CV morbidity/mortality </li></ul>Ann Intern Med. 2007; ITC-9:1-16.
    4. 4. The scope of the problem-2 <ul><li>Dyslipidemia requiring drug treatment is prevalent in nearly 30% of patients without clinical CV disease </li></ul><ul><li>Of these, only half are taking lipid lowering medication </li></ul><ul><li>Benefits of statins are only realized when pts. take them >80% of time </li></ul><ul><li>6 months after initiation of statin therapy, adherence rates are 40-65% </li></ul>Circulation 2006;113:647-656.
    5. 5. JACC 2004;44:720-32
    6. 6. 2004 Update to NCEP/ATP III <ul><li>Review of 5 major statin trials with implications for therapy: </li></ul><ul><ul><li>Heart Protection Study </li></ul></ul><ul><ul><li>PROSPER </li></ul></ul><ul><ul><li>ALLHAT-LLT </li></ul></ul><ul><ul><li>ASCOT-LLA </li></ul></ul><ul><ul><li>PROVE IT-TIMI 22 </li></ul></ul>
    7. 7. JACC 2004;44:720-32 <ul><li>Very high risk= established CVD + </li></ul><ul><li>Major risk factors (especially DM) </li></ul><ul><li>Severe and poorly controlled risk factors (especially continued smoking) </li></ul><ul><li>Multiple RFs of the metabolic syndrome </li></ul><ul><li>Acute coronary syndromes </li></ul>
    8. 8. Log-Linear relationship of LDL and CHD risk JACC 2004;44:720-32
    9. 9. Ann Intern Med. 2006;145:520-530.
    10. 10. Diminishing returns of the hypothesized log-linear relationship Ann Intern Med. 2006;145:520-530.
    11. 11. Today’s clinic <ul><li>Patient 1: Healthy 40 y.o. male </li></ul><ul><li>Patient 2: 57 y.o. male with stable CAD </li></ul><ul><li>Patient 3: 65 y.o. female with recent stroke here for follow up </li></ul>
    12. 12. Road Map <ul><li>Lipid Measurements </li></ul><ul><li>CVD risk prediction </li></ul><ul><li>Secondary Prevention (select groups) </li></ul><ul><ul><li>CHD </li></ul></ul><ul><ul><li>Stroke </li></ul></ul><ul><ul><li>ESRD </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><li>Future Directions </li></ul>
    13. 13. Patient 1 <ul><li>40 y.o. white male here because </li></ul><ul><li>“ 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.” </li></ul><ul><li>“ My insurance is good, I want the best cholesterol test there is” </li></ul>
    14. 14. Focus Questions for Patient 1 <ul><li>Which lipid test should you order? </li></ul><ul><li>What is the best way to predict his CV risk? </li></ul>
    15. 15. Clinical Utility of Different Lipid Measures for Prediction of Coronary Heart Disease in Men and Women JAMA. 2007;298(7):776-785
    16. 16. Background <ul><li>ApoB 100 is included in all atherogenic particles (VLDL, IDL, LDL, LP(a)) </li></ul><ul><li>Higher ApoB levels and lower Apo A-I levels linked with pathogenesis of CHD </li></ul><ul><li>Some reports suggest these markers may be superior for CHD risk prediction </li></ul><ul><ul><li>LDL not all the same </li></ul></ul><ul><ul><li>Apo B levels may better reflect the number of atherogenic particles in plasma </li></ul></ul>JAMA. 2007;298(7):776-785
    17. 17. Study design <ul><li>Population based, prospective cohort </li></ul><ul><li>3322 middle aged white participants in Framingham offspring study </li></ul><ul><ul><li>Without known CV disease </li></ul></ul><ul><li>Outcome: incidence of first CHD event </li></ul><ul><li>Measure: Complex analyses to compare several different lipid measures for ability to predict CHD events </li></ul>
    18. 18. Results <ul><li>Ratios are superior to individual lipids </li></ul><ul><ul><li>Chol:HDL vs. ApoB: ApoA-I </li></ul></ul><ul><li>ApoB:ApoA-I ratio </li></ul><ul><ul><li>Performed well, but not significantly better than other lipid measures </li></ul></ul><ul><ul><li>“ Did not provide incremental value for CHD risk prediction over established risk factors, including Chol:HDL.” </li></ul></ul>
    19. 19. Implications <ul><li>Head to head, Chol:HDL and ApoB/ApoA-1 ratios are comparable </li></ul><ul><li>Further knowledge of ApoB/ApoA-1 does not seem to improve ability to predict CHD risk </li></ul><ul><li>Suggests routine measurement of apoliproteins in clinical practice is not necessary </li></ul>
    20. 20. General Cardiovascular Risk Profile for Use in Primary Care The Framingham Heart Study <ul><li>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 </li></ul>Circulation. 2008;117:743-753.
    21. 21. Background <ul><li>Framingham risk score effective, but only predicts CHD risk (not stroke etc.) </li></ul><ul><li>CV diseases share common risk factors </li></ul><ul><li>Set out to develop a way to predict risk for all CVD events </li></ul>JAMA. 2007;298(7):776-785
    22. 22. Study design <ul><li>8491Framingham study participants </li></ul><ul><ul><li>Without known CV disease </li></ul></ul><ul><li>Outcome: incidence of first CHD event </li></ul><ul><li>Derived CVD prediction algorithm and compared with disease specific prediction tools </li></ul>Circulation. 2008;117: 743-753.
    23. 23. Results <ul><li>General CV risk prediction algorithm performed as well as individual disease specific multivariable risk predictions </li></ul><ul><li>It builds on prior models by: </li></ul><ul><ul><li>Adding HDL </li></ul></ul><ul><ul><li>Being based on study with more events </li></ul></ul><ul><ul><li>Estimating absolute CV risk </li></ul></ul><ul><li>It is simple to use, will be provided in electronic forms once validated </li></ul>Circulation. 2008;117: 743-753.
    24. 24. Implications <ul><li>A new tool for CVD risk prediction now available </li></ul><ul><li>Allows prediction of all CV events </li></ul><ul><ul><li>Stroke, CAD, PVD, CHF </li></ul></ul><ul><li>Designed for use in primary care </li></ul><ul><li>Needs validation </li></ul>Circulation. 2008;117: 743-753.
    25. 25. Back to Patient 1 <ul><li>Which lipid test should you order? </li></ul><ul><ul><li>Fasting Lipid Profile </li></ul></ul><ul><li>What is the best way to predict his CV risk? </li></ul><ul><ul><li>Framingham Risk score (for CHD), but the new General CV Risk Algorithm may soon take its place </li></ul></ul>
    26. 26. Road Map <ul><li>Lipid Measurements </li></ul><ul><li>CV risk prediction </li></ul><ul><li>Secondary Prevention (select groups) </li></ul><ul><ul><li>CHD </li></ul></ul><ul><ul><li>Stroke </li></ul></ul><ul><li>Future Directions </li></ul>
    27. 27. Patient 2 <ul><li>57 y.o. AA male with stable CAD. He has angina only with strenuous exertion and it is promptly relieved with SL NTG. </li></ul><ul><li>He has HTN and Hyperlipidemia and smoked for many years but quit after his MI in 2003. He does not have Diabetes. </li></ul><ul><li>He takes Simvastatin 10 mg daily for his cholesterol and his LDL is 105. </li></ul><ul><li>He is here for routine f/u. </li></ul>
    28. 28. Focus Questions for Patient 2 <ul><li>Is he on an adequate dose of statin? </li></ul><ul><li>What should his target LDL be? </li></ul>
    29. 29. NEJM 2005;352:1425-35.
    30. 30. Study design <ul><li>Double blind RCT </li></ul><ul><li>10,001 pts. with known CHD, LDL <130 were randomly assigned to: </li></ul><ul><ul><li>Atorvastatin 10 mg daily </li></ul></ul><ul><ul><li>Atorvastatin 80 mg daily </li></ul></ul><ul><li>Washout/run in periods: only those with LDL<130 participated </li></ul><ul><li>Median f/u was 4.9 years </li></ul><ul><li>Outcome: incidence of first CV event </li></ul>NEJM 2005;352:1425-35.
    31. 31. NEJM 2005;352:1425-35.
    32. 32. Results <ul><li>Groups were well matched at baseline </li></ul><ul><li>Concomitant med use was similar </li></ul><ul><li>Mean LDL during the study: </li></ul><ul><ul><li>High dose group: 77 mg/dl </li></ul></ul><ul><ul><li>Standard dose group: 101 mg/dl </li></ul></ul><ul><li>No difference in overall mortality (power) </li></ul><ul><li>Mild increase in adverse events (LFTs) </li></ul>NEJM 2005;352:1425-35.
    33. 33. NEJM 2005;352:1425-35.
    34. 34. TNT Outcomes ACP Journal Club . Sept/Oct 2005;143(2):38.
    35. 35. Implications <ul><li>Reducing LDL to 77 compared with 101 in pts. with stable CHD led to significant improvements in a number of CVD outcomes </li></ul><ul><li>(No difference in overall mortality) </li></ul>NEJM 2005;352:1425-35.
    36. 36. JACC 2006;48:438–45.
    37. 37. JACC 2006;48:438–45.
    38. 38. Risk of coronary death or MI JACC 2006;48:438–45.
    39. 39. Adverse Events in the Trials JACC 2006;48:438–45.
    40. 40. Back to Patient 2 <ul><li>Is he on an adequate dose of statin? </li></ul><ul><ul><li>No, based on recent studies, high dose statin therapy could reduce his chances of further CV events and should be considered. </li></ul></ul><ul><li>What should his target LDL be? </li></ul><ul><ul><li>His optimal LDL may be ~70 or less. </li></ul></ul>
    41. 41. Road Map <ul><li>Lipid Measurements </li></ul><ul><li>CV risk prediction </li></ul><ul><li>Secondary Prevention (select groups) </li></ul><ul><ul><li>CHD </li></ul></ul><ul><ul><li>Stroke </li></ul></ul><ul><li>Future Directions </li></ul>
    42. 42. Patient 3 <ul><li>65 y.o. female who presents to clinic for follow up after recent hospitalization for acute stroke </li></ul><ul><li>She is doing well now, showing some progressive improvement in her deficits </li></ul><ul><li>She wants to know what can be done to prevent future strokes. </li></ul>
    43. 43. Focus Questions for Patient 3 <ul><li>Is treatment with a statin effective for secondary stroke prevention? </li></ul><ul><li>Does the level of her cholesterol matter? </li></ul>
    44. 44. NEJM 2006;355:549-59.
    45. 45. Study design <ul><li>Double blind RCT </li></ul><ul><li>Study group (4731 patients) </li></ul><ul><ul><li>Stroke or TIA in past 1-6 months </li></ul></ul><ul><ul><li>LDL on entry of 100-190 </li></ul></ul><ul><ul><li>No known CHD </li></ul></ul><ul><li>Randomly assigned to: </li></ul><ul><ul><li>Atorvastatin 80mg daily OR </li></ul></ul><ul><ul><li>Placebo </li></ul></ul><ul><li>Outcome: first fatal or nonfatal stroke </li></ul>NEJM 2006;355:549-59.
    46. 46. Screening, Enrollment, and Outcomes NEJM 2006;355:549-59.
    47. 47. NEJM 2006;355:549-59. Baseline Characteristics of the Patients
    48. 48. Results <ul><li>Median f/u was 4.9 years </li></ul><ul><li>Mean cholesterol value during the trial: </li></ul><ul><ul><li>Atorvastatin group: 73 mg/dl </li></ul></ul><ul><ul><li>Placebo group: 129 mg/dl </li></ul></ul><ul><li>Overall mortality was similar </li></ul><ul><li>Elevated LFTs were more common in the statin group, but serious adverse events were similar </li></ul>NEJM 2006;355:549-59.
    49. 49. Kaplan-Meier Curves for Stroke and TIA NEJM 2006;355:549-59.
    50. 50. Kaplan-Meier Curves for Coronary and Cardiovascular Events NEJM 2006;355:549-59.
    51. 51. SPARCL Results ACP Journal Club . Jan/Feb 2007;146(1):7.
    52. 52. 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
    53. 53. Implications <ul><li>In patients with recent stroke or TIA, treatment with 80 mg atorvastatin significantly reduced recurrent strokes and CV events when compared with placebo </li></ul><ul><li>There was a small increase in the incidence of hemorrhagic stroke </li></ul>
    54. 54. Statin treatment withdrawal in ischemic stroke: A controlled randomized study Neurology 2007;69:904–910
    55. 55. Study Design <ul><li>Consecutive pts admitted with acute hemispheric stroke <24 hrs duration </li></ul><ul><li>Randomly assigned to: </li></ul><ul><ul><li>Continuing statin therapy (atorva 20mg/d) OR </li></ul></ul><ul><ul><li>Stopping for 3 days </li></ul></ul><ul><li>Outcome: death, dependency or END </li></ul>Neurology 2007;69:904–910
    56. 56. Results Neurology 2007;69:904–910
    57. 57. Implications <ul><li>Withdrawal of statin therapy immediately after stroke onset is associated with: </li></ul><ul><ul><li>4.7 fold increase in risk of death/dependency at 3 months </li></ul></ul><ul><ul><li>Similar detrimental effect on 2° outcomes </li></ul></ul><ul><li>Stopping statins during hospitalization for stroke can have detrimental effects and should be avoided </li></ul>
    58. 58. Back to Patient 3 <ul><li>Is treatment with a statin effective for secondary stroke prevention? </li></ul><ul><ul><li>High dose statins (started within1-6 months) are proven effective (NNT=51 for stroke, 16 for any CV event) </li></ul></ul><ul><ul><li>Starting statins in first 12 hours may be effective too—studies ongoing </li></ul></ul><ul><ul><li>Avoid stopping statins in pts with acute stroke </li></ul></ul><ul><li>Does the level of her cholesterol matter? </li></ul><ul><ul><li>No. Benefit seen for all levels of cholesterol </li></ul></ul>
    59. 59. Road Map <ul><li>Lipid Measurements </li></ul><ul><li>CV risk prediction </li></ul><ul><li>Secondary Prevention (select groups) </li></ul><ul><ul><li>CHD </li></ul></ul><ul><ul><li>Stroke </li></ul></ul><ul><li>Future Directions </li></ul>
    60. 60. 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.
    61. 61. 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
    62. 62. 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
    63. 63. Future Directions <ul><li>Is there an LDL level threshold? </li></ul><ul><li>LDL level or statin dose? </li></ul><ul><li>Combination therapy effectiveness? </li></ul><ul><li>Design of studies will be more important (decreasing event rate) </li></ul><ul><li>Novel agents and targets (HDL, CRP, Apolipoproteins) </li></ul>
    64. 64. 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.
    65. 65. Take Home Points <ul><li>Recent studies have provided further support for 2004 NCEP/ATP III recs </li></ul><ul><li>Standard lipid profile sufficient for risk assessment and treatment decisions </li></ul><ul><li>New General CV risk prediction tool: </li></ul><ul><ul><li>Allows estimation of all CVD outcomes </li></ul></ul><ul><ul><li>Designed for use in primary care </li></ul></ul><ul><li>Aggressive LDL lowering (<70 or 80) appropriate in CVD (stable CHD/Stroke) </li></ul>
    66. 66. Selected References (in the order they were discussed) <ul><li>Risk Prediction </li></ul><ul><li>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. </li></ul><ul><li>D’Agostino RB et al. General Cardiovascular Risk Profile for Use in Primary Care The Framingham Heart Study. Circulation . 2008;117:743-753. </li></ul><ul><li>CHD </li></ul><ul><li>LaRosa J et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. NEJM 2005;352:1425-35. </li></ul><ul><li>Cannon C et al. Meta-Analysis of Cardiovascular Outcomes Trials Comparing Intensive Versus Moderate Statin Therapy. JACC 2006;48:438–45. </li></ul><ul><li>Stroke </li></ul><ul><li>SPARCL investigators. High dose Atorvastatin after Stroke or Transient Ischemic Attack. NEJM 2006;355:549-59. </li></ul><ul><li>Blanco M et al. Statin treatment withdrawal in ischemic stroke: A controlled randomized study. Neurology 2007;69:904–910. </li></ul>