Keynote: Inflammation and Cardiovascular Risk: Emerging Complications for Clinical Practice

Keynote: Inflammation and Cardiovascular Risk: Emerging Complications for Clinical Practice Dallas, TX December, 8 7: AM 8: AM

Session 9: Keynote: Inflammation and Cardiovascular Risk: Emerging Implications for Clinical Practice Learning Objectives Discuss the biology of inflammation in atherosclerosis and its complications. Explain how biomarkers of inflammation can add to CV risk prediction. Discuss evidence that preventive therapies can work by lowering inflammation. Evaluate data regarding reducing inflammation as a goal of therapy in secondary prevention of CHD. Recognize the potential role of inflammatory markers in targeting therapy in primary prevention of CHD. Faculty Paul M. Ridker, MD Eugene Braunwald Professor of Medicine Harvard Medical School Director, Center for Cardiovascular Disease Prevention Brigham and Women s Hospital Boston, Massachusetts Dr Ridker is the Eugene Braunwald Professor of Medicine at the Harvard Medical School and directs the Center for Cardiovascular Disease Prevention, a translational research unit at the Brigham and Women s Hospital in Boston which focuses on the molecular and genetic epidemiology of cardiovascular diseases and on novel strategies for cardiovascular disease detection and prevention. As a graduate of Brown University, the Harvard Medical School, and the Harvard School of Public Health, Dr Ridker s primary research brings together classical tools of large-scale, population based epidemiology with emerging genetic and molecular techniques designed to improve our ability to predict and prevent vascular disease. Particular areas of interest involve molecular and genetic determinants of hemostasis, thrombosis, and inflammation with a focus on predictive medicine, early disease diagnosis, and the underlying causes and prevention of acute coronary syndromes. Dr Ridker s research efforts are primarily supported by RO research grants from the National Heart, Lung, and Blood Institute (NHLBI), a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation, and through philanthropic research grants from the Leducq Foundation and the Donald W Reynolds Foundation. Dr Ridker additionally directs an NHLBI-funded institutional National Research Service Award (training grant) in cardiovascular epidemiology at the Brigham and Women s Hospital and Harvard Medical School. Dr Ridker has been the recipient of both a Clinician Scientist Award (99-997) and an Established Investigator Award (997-) from the American Heart Association. A frequent invited lecturer at national and international conferences, Dr Ridker lists among his honors elected membership into the American Society for Clinical Investigation (ASCI), the American Epidemiological Society (AES), and the American Association of Physicians (AAP). Citing his pioneering work on inflammation, C- reactive protein (CRP), and atherothrombosis, Time magazine honored Dr Ridker as one of America s Ten Best Researchers in Science and Medicine in and as one of the Time in. Dr Ridker currently serves on the Board of External Experts for the National Heart, Lung, and Blood Institute. In addition to his work in cardiovascular epidemiology, Dr Ridker has been the principal investigator or study chairman of several multinational clinical trials, including PREVENT, PRINCE, Val-MARC, LANCET, and the ongoing JUPITER trial evaluating the use of statin therapy among 8, apparently healthy individuals with low levels of low-density lipoprotein (LDL-C) and elevated levels of CRP. Dr Ridker is also the principal investigator of the Women s Genome Health Study (WGHS), a comprehensive prospective genome-wide association study being conducted among more than, initially healthy American women. Dr Ridker is the author of over original reports, reviews and book chapters, and textbooks related to cardiovascular medicine. A member of multiple editorial boards, Dr Ridker is a co-inventor on patents filed by the Brigham and Women s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease. Faculty Financial Disclosure Statement The presenting faculty reported the following: Dr Ridker reports research support from AstraZeneca Pharmaceuticals LP, sanofi-aventis U.S., Abbott, and NHLBI. He 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. Session 9

Drug List Generic pravastatin rosuvastatin Trade Pravachol Crestor Suggested Reading List Arima H, Kubo M, Yonemoto K, et al. High-sensitivity C-reactive protein and coronary heart disease in a general population of Japanese: the Hisayama study. Arterioscler Thromb Vasc Biol. 8;8(7):8-9. Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 7;6():-6. Chasman DI, Posada D, Subrahmanyan L, et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. :9():8-87. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 6;():6-7. Crawford DC, Sanders CL, Qin X, et al. Genetic variation is associated with C-reactive protein levels in the Third National Health and Nutrition Examination Survey. Circulation. 6;():8-6. Hochman JS, Lamas GA, Buller CE, et al. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med. 6;():9-7. Ridker PM, Fonseca FA, Genest J, et al. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein. Am J Cardiol. 7;():69-66. Nahrendorf M, Jaffer FA, Kelly KA, et al. Noninvasive vascular cell adhesion molecule- imaging identifies inflammatory activation of cells in atherosclerosis. Circulation. 6;():-. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. ;:9-8. Ridker PM, Pare G, Parker A, et al. Loci related to metabolic-syndrome pathways including LEPR,HNFA, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. Am J Hum Genet. 8;8:8-9. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 7;97:6-69. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. ;:-8. Swirski FK, Libby P, Aikawa E, et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest. 7;7():89-9. Session 9

Notes TM

A 7-year year-old Caucasian woman was evaluated by her primary care physician for routine annual evaluation. The patient was active, living independently, and had no history of diabetes, vascular disease, or cancer. She did have hypertension (treated with ARB SBP ) and consumed a half-pack of cigarettes daily. She was taking no other medications and had stopped HRT several years ago after the WHI results came out. Her current weight is pounds, she is. Screening laboratory evaluation included total cholesterol of 6 mg/dl dl,, LDLC mg/dl dl, and HDLC 8 mg/dl dl.. Glucose is 9 mg/dl dl. Her calculated Framingham -year risk is.9 percent.? Question : Further diagnostic evaluation should include:. homocysteine, Lp(a), fasting triglycerides. hscrp. EBCT, MRI, or Carotid IMT. Exercise stress test. None? Question : In addition to advice to stop smoking, your therapeutic interventions include:. Aspirin 8 mg po qd. Aspirin mg po qd. Statin low dose. Statin high dose. HCTZ. mg po qd 6. None of the above Inflammation and Atherothrombosis: Can Lowering Inflammation Lower Vascular Risk? What Might the JUPITER Trial Tell Us? Paul M. Ridker,, MD Eugene Braunwald Professor of Medicine Harvard Medical School Director, Center for Cardiovascular Disease Prevention Brigham and Women s s Hospital Boston, Massachusetts Can inflammation and hscrp be used to improve risk detection? Can inflammation and hscrp be used to better target and monitor statin therapy? What might the JUPITER trial tell us? Dr Ridker is listed as a coinventor on patents held by the Brigham and Women s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease.

and Risk of Future MI and CVA in Apparently Healthy Men P Trend <. P Trend <. C-Reactive Protein (hscrp) Relative Risk of MI Quartile of Ridker et al N Engl J Med 997;6:97 979. Relative Risk of Stroke Quartile of Risk Factors for Future Cardiovascular Events: WHS A Direct Comparison of LDL-C and CRP in the Prediction of First Ever Cardiovascular Events Among 7,99 Women Lipoprotein(a) Total Cardiovascular Events MI, CABG, PTCA Homocysteine IL-6 TC LDLC sicam- SAA Relative Risk Relative Risk Apo B Ischemic Stroke Cardiovascular Death TC: HDLC + TC: HDLC... 6. Relative Risk of Future Cardiovascular Events Ridker et al N Engl J Med ;:86- Relative Risk Ridker et al N Engl J Med ;7:7-6 Relative Risk hscrp Adds Prognostic Information at all Levels of LDL-C and at all Levels of the Framingham Risk Score Additive Value of hscrp Across All Lipid Ratios Risks Adjusted for Age, Blood Pressure, Smoking Status, Body Mass Index, and Diabetes hscrp < mg/l hscrp to mg/l hscrp > mg/l Probability of Event-free Survival 6 8 Years of Follow-up low hscrp low LDL low hscrp high LDL high hscrp low LDL high hscrp high LDL Relative risk <..-. >. hscrp (mg/l) - - -9 - Framingham estimate of -year risk (%) Fully Adjusted Relative Risk Low Medium High TC : HDLC Ratio Low Medium High Apo B : Apo A-I Ratio Ridker et al N Engl J Med. ;7:7-6. Ridker et al JAMA ;9:6-

Combined Use of CT Calcium Scores and CRP in the Prediction of Cardiovascular Events: South Bay Heart Watch CRP, IL-6 6 and the Risk for Developing Type- Diabetes in the Women s s Health Study Fully adjusted BMI-adjusted Crude Relative Risk 8. 6.... High Medium Low EBCT Calcium Score Park R, Detrano R, Xiang M, et al. Circulation ;6:7-7 <. >., mg/l 6 8 6 Relative Risk IL-6 Quartile of IL-6 Pradhan et al JAMA ; 86:7-6 8 6 Relative Risk Quartile of hscrp adds to the ATP-III Definition of the Metabolic Syndrome (N =,97 with ATP-III Metabolic Syndrome). hscrp Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated CVD Event-Free Survival Probability.99.98.97.96 CRP < mg/l CRP - mg/l Fully Adjusted Relative Risk PHS 997 WHS UK MONICA ARIC Iceland NHS.9 CRP > mg/l CHS PIMA HPFUS EPIC-N Strong Kuopio FHS 6 Ridker et al 6 8 Circulation ;7:9-7 Years of Follow-Up < mg/l to mg/l > mg/l hscrp and Coronary Heart Disease in a General Population of Japanese The Hisayama Study What are the environmental and genetic influences on CRP? Relative Risk of Future CV Events 8 7 6 <..-..-..-..-..-..-..-. > low risk moderate risk high risk Arima H., et al, Arterioscler Thromb Vasc Biol. 8;8:8-9 Ridker et al Circulation ;9:9-9 hscrp (mg/l)

Women s Genome Health Study : GWAS for Plasma CRP Level Women s Genome Health Study : GWAS for Plasma CRP Level (acute phase response) LEPR CRP GCKR HNF APOE CRP p-values IL6R Gene Desert TNF-a IL-6 Ridker et al, Am J Hum Genet 8;8:8-9 Ridker et al, Am J Hum Genet 8;8:8-9 Implication of GWAS Data 6 out of 7 loci are directly linked with the diabesity phenotype or with parameters of hemostasis, thrombosis, and inflammation These genetic GWAS results confirm the importance of low-grade inflammation as a marker of perturbed energy homeostasis CRP/Inflammation Insulin resistance/diabetes Framingham Risk Score Age Blood Pressure Diabetes Smoking Total cholesterol HDL cholesterol Reynolds Risk Score Age Blood Pressure Diabetes Smoking Total cholesterol HDL cholesterol hscrp Parental history of MI < age 6 Risk Reclassification: ATP-III vs Reynolds Risk Score Intermediate Risk Risk Reclassification: ATP-III vs Reynolds Risk Score Intermediate Risk -Year Risk Reynolds Risk Score (%) Intermediate Risk -Year Risk Reynolds Risk Score (%) % 7% % Intermediate Risk -Year Risk ATP-III (%) Ridker et al, JAMA 7;97:6-9 -Year Risk ATP-III (%) Ridker et al, JAMA 7;97:6-9

Risk Reclassification: ATP-III vs Reynolds Risk Score Intermediate Risk Risk Reclassification: ATP-III vs Reynolds Risk Score Intermediate Risk -Year Risk Reynolds Risk Score (%) 7% % 6% % % % Intermediate Risk -Year Risk Reynolds Risk Score (%) % % 7% % % 6% % % Intermediate Risk -Year Risk ATP-III (%) Ridker et al, JAMA 7;97:6-9 -Year Risk ATP-III (%) Ridker et al, JAMA 7;97:6-9 Risk Reclassification: ATP-III vs Reynolds Risk Score Risk Reclassification: ATP-III vs Reynolds Risk Score Intermediate Risk -Year Risk Reynolds Risk Score (%) % 7% % % % 6% % 96% 6% % 7% % -Year Risk ATP-III (%) Ridker et al, JAMA 7;97:6-9 Intermediate Risk -Year Risk Reynolds Risk Score (%) % % 7% % % 6% % 96% 6% % -Year Risk ATP-III (%) Ridker et al, JAMA 7;97:6-9 7% % to percent of those at intermediate risk according to ATP-III were reclassified by the addition of hscrp and family history to clinically relevant higher or lower risk groups. When comparing predicted to observed event rates, reclassification was correct in more than 98 percent of cases Clinical Example: -year risk for a year old non-diabetic female Age Smoker? BP TC HDL hscrp Parental ATP-III RRS History? smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. smoker /8. Clinical Example: -year risk for a year old non-diabetic female Age Smoker? BP TC HDL hscrp Parental ATP-III RRS History? smoker /8. no..9 smoker /8. no. 6. smoker /8. no. 7. smoker /8. no. 8.9 smoker /8. no. 9.7 smoker /8 8. no.. smoker /8. no..9 smoker /8. no.. smoker /8. yes. 7. smoker /8. yes. 9.9 smoker /8. yes.. smoker /8. yes.. smoker /8. yes..6 smoker /8 8. yes..8 smoker /8. yes. 6. smoker /8. yes. 8.

The Reynolds Risk Score Calculating Heart and Stroke Risk for Women www.reynoldsriskscore.org Can inflammation and hscrp be used to improve risk detection? Can inflammation and hscrp be used to better target and monitor statin therapy? What will the JUPITER trial tell us? % JAMA 7;97:6-69 Inflammation, Statin Therapy, and hscrp: Initial Observations hscrp as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS P Trend =.. -.6% (P=.)( Study Group Statin Placebo NNT Relative Risk Pravastatin Placebo Pravastatin Placebo Inflammation Absent Inflammation Present Ridker et al Circulation. 998;98:89 8. Median (mg/dl dl)......9.8 Baseline Placebo Pravastatin Years Ridker et al Circulation. 999;:-. low LDLC / low CRP.. ---- low LDLC / high CRP.9. 8 high LDLC / low CRP.. high LDLC / high CRP.8. 8 Ridker et al N Engl J Med ;:99-6 Median LDLC = 9 mg/dl Median CRP =.6 mg/dl While intriguing and of substantial pathophysiologic as well as public health importance, the observation in AFCAPS/TexCAPS that statin therapy may have utility among patients with low LDL cholesterol but elevated hscrp requires direct testing in prospective randomized trials. JUPITER Randomized Trial of Rosuvastatin in the Primary Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL- C and Elevated Levels of CRP No History of CAD Men >, Women > 6 LDL-C < mg/dl CRP > mg/l Screening Visit LDL CRP FHS week Run-in Randomization Visit Lipids LFTs HbAC Rosuvastatin (N =89) Placebo (N = 89) Safety Visit Lipids LFTs Bi-Annual Follow-Up Visits MI Stroke Unstable Angina CVD Death CABG/PTCA End of Study Visit Lipids HbAC Ridker et al, New Engl J Med ;:99-6 JUPITER Investigators, Circulation 6

Randomizations (% Total.) % % % % % % Randomization into the JUPITER Trial by Country of Origin Uruguay Switzerland 8 8 Romania Chile Estonia 6 Total Randomized = 7,8 97 Israel El Salvador Bulgaria 9 Panama Norway Venezuela 7 Germany Argentina Costa Rica 7 7 6 Russia Brazil Denmark 7 87 8 Colombia Belgium Mexico Poland 987 The Netherlands 87 97 Canada South Africa United Kingdom United States Ridker et al JUPITER Trial Study Group, Am J Cardiol 7 Baseline Clinical Characteristics of the Randomized JUPITER Cohort Age (years) 66. (6.9-7.8) Women (%) 8. Race (%) White 7. Black. Hispanic.7 Other.6 BMI (kg/m) 8. (. -.) SBP (mmg Hg) ( - ) DBP (mm Hg) 8 (7-87) Smoking (%).8 Family History CHD (%). Metabolic syndrome (%). Aspirin Use (%). JUPITER Trial Study Group, Am J Cardiol 7 Baseline Laboratory Data of the Randomized JUPITER Cohort Median (IQR) Total cholesterol (mg/dl) 8 (69-) LDL cholesterol (mg/dl) (9-9) HDL cholesterol (mg/dl) 9 (-6) Non-HDL-cholesterol (mg/dl) (8-7) Triglycerides (mg/dl) 8 (8-69) hscrp (mg/l). (.8-7.) Glucose (mg/dl) 9 (88-) Hemoglobin Ac (%).7 (.-.9) JUPITER Trial Study Group, Am J Cardiol 7 Cumulative Rate of Recurrent Myocardial Infarction or Coronary Death (percent)....6.8. Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy LDLC>7 mg/dl LDLC<7 mg/dl...... Follow-Up (years) Ridker et al NEJM ;:-8. Cumulative Rate of Recurrent Myocardial Infarction or Coronary Death (percent)....6.8. Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy LDLC>7 mg/dl LDLC<7 mg/dl............ Ridker et al NEJM ;:-8. Follow-Up (years)....6.8. hscrp> mg/l hscrp< mg/l Achieved CRP (mg/l) Minimal Relationship Between Achieved LDL and Achieved hscrp After Initiation of Statin Therapy. r =.8 Variance = percent 8 8 Achieved LDLC (mg/dl) Ridker et al NEJM ;:-8. PROVE IT TIMI 7

Recurrent Myocardial Infarction or Coronary Death (percent) Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with Statin Therapy....6.8....... Follow-Up (Years) LDL > 7 mg/dl, CRP > mg/l LDL > 7 mg/dl, CRP < mg/l LDL < 7 mg/dl, CRP > mg/l LDL < 7 mg/dl, CRP < mg/l Ridker et al NEJM ;:-8. REVERSAL: Regression of Atherosclerosis On Statin Therapy Occurs Primarily Among Those with Both LDL and hscrp Reduction Change in Atheroma Volume (mm ) +8mm LDL CRP +mm LDL CRP -mm -mm LDL CRP LDL CRP Progression Regression Nissen et al NEJM ; :9-8 Clinical Importance of Achieving LDL-C < 7 mg/dl and hscrp < mg/l Following Initiation of Statin Therapy Clinical Importance of Achieving LDL-C < 7 mg/dl and hscrp < mg/l Following Initiation of Statin Therapy LDL>7, hscrp> LDL<7, hscrp> LDL>7, hscrp< LDL<7, hscrp< Recurrent Myocardial Infarction or Death (percent) 6 8 8 6 7 9 Follow-up (days) PROVE IT TIMI NEJM ;:-8. LDL>7, hscrp> LDL<7, hscrp> LDL>7, hscrp< LDL<7, hscrp< Recurrent Myocardial Infarction or Death (percent) 6 8 8 6 7 9 Follow-up (days) PROVE IT TIMI NEJM ;:-8. 8 6 6 8 6 Follow-up (days) A to Z Circulation 6;:8-8 Does Achieved LDL or Achieved CRP Predict the Risk of Stroke? PROVE IT TIMI JUPITER Randomized Trial of Rosuvastatin in the Primary Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL- C and Elevated Levels of CRP Achieved LDL Achieved hscrp days days days days Stroke 7. 78..7. No Stroke 7. 8..9.7 No History of CAD Men >, Women > 6 LDL-C < mg/dl CRP > mg/l Screening Visit week Run-in Randomization Visit Rosuvastatin (N =89) Placebo (N = 89) Safety Visit Bi-Annual Follow-Up Visits MI Stroke Unstable Angina CVD Death CABG/PTCA End of Study Visit P.8.8.. In multivariate analysis, age > 6, prior MI, prior CVA, atrial fibrillation, diabetes, and achieved hscrp all predicted stroke events, but not achieved LDL LDL CRP FHS Lipids LFTs HbAC Lipids LFTs Lipids HbAC Mega et al, J Thromb Thrombolysis 6;:7-76 JUPITER Investigators, Circulation 8

ACC Chicago March 9 JUPITER Investigators Meeting What are the implications if JUPITER is a positive trial? If individuals with low levels of LDL-C C but elevated levels of hscrp benefit from aggressive statin therapy, what is the future role of hscrp screening? If in primary prevention the target for LDL-reduction is mg/dl dl,, what becomes the target for secondary prevention or ACS patients? Considerations for Screening and treatment in a Post-JUPITER world? For purposes of initial discussion : assume a % RRR for otherwise healthy individuals with hscrp > mg/l (NNT of to 6, same as AFCAPS/TexCAPS for those with elevated LDL) What, if any, role will there be for global risk prediction scores? What, if any, will be the purpose of imaging tests for CV screening? What if the RRR in JUPITER is smaller than %? What if the RRR in JUPITER is greater than %? What are the implications if JUPITER is a null trial? JUPITER: Final Results to Be Presented At AHA New Orleans November 8 Questions - Part Will rosuvastatin therapy prevent first ever cardiovascular events among those with LDL < mg/dl (.6 mmol/l), but who are nonetheless at increased vascular risk due to elevated levels of hscrp (> mg/l)? If so, is the net benefit of rosuvastatin larger or smaller than that observed in statin trials based on elevated LDL? JUPITER: Final Results to Be Presented At AHA New Orleans November 8 Questions Part If a net benefit of rosuvastatin is observed in the JUPITER trial, is it due to LDL reduction or to CRP reduction, or to both? Is inhibition of inflammation as important, less important, or more important than reduction of LDLC? JUPITER: Final Results to Be Presented At AHA New Orleans November 8 Questions Part Is it safe to reduce LDLC to levels below mg/dl dl? What will be an appropriate target for LDL in primary prevention? In secondary prevention? What will be an appropriate target for hscrp in primary prevention? In secondary prevention? JUPITER: Final Results to Be Presented At AHA New Orleans November 8 Questions Part Is there evidence that rosuvastatin lowers risk in women? In minority patients? In those with metabolic syndrome? In those with low levels of Framingham risk? How will the JUPITER trial data change guidelines for the prevention of heart disease? 9

Prediction : Correct Use of Statin Therapy in the Future Will Require Evaluation for both LDLC and hscrp Prediction : Statin therapy in Primary Prevention. LDL-C C is a strong, independent predictor of future CV events. Statins lower LDL-C. The level of LDL-C achieved after starting statin therapy predicts recurrent event rates (ie( lower is better ). hscrp is a strong, independent predictor of future CV events. Statins lower hscrp. The level of hscrp achieved after starting statin therapy predicts recurrent event rates (ie( lower is better ) If LDL-C C > 6 mg/dl, treat If hscrp > mg/l, treat If diabetic, treat Dual Goals for Statin Therapy : LDL-C < 7 mg/dl and hscrp < mg/l A 7-year year-old Caucasian woman was evaluated by her primary care physician for routine annual evaluation. The patient was active, living independently, and had no history of diabetes, vascular disease, or cancer. She did have hypertension (treated with ARB SBP ) and consumed a half-pack of cigarettes daily. She was taking no other medications and had stopped HRT several years ago after the WHI results came out. Her current weight is pounds, she is. Screening laboratory evaluation included total cholesterol of 6 mg/dl dl,, LDLC mg/dl dl, and HDLC 8 mg/dl dl.. Glucose is 9 mg/dl dl. Her calculated Framingham -year risk is.9 percent.? Question : Further diagnostic evaluation should include:. homocysteine, Lp(a), fasting triglycerides. hscrp. EBCT, MRI, or Carotid IMT. Exercise stress test. None? Question : In addition to advice to stop smoking, your therapeutic interventions include:. Aspirin 8 mg po qd. Aspirin mg po qd. Statin low dose. Statin high dose. HCTZ. mg po qd 6. None of the above

The primary care physician ordered Lp(a), triglycerides, and homocysteine,, all of which were reportedly normal. Basing recommendations for preventive therapy on ATP-III (-year risk by Framingham.9 percent), no further intervention was provided. Seven months later, the patient was admitted to the coronary care with acute chest pain and ruled in for non-fatal MI (CK > ) during which she had significant loss of myocardial function (post-mi LVEF 8 percent with anterior and lateral hypokinesis). Severe coronary obstruction was seen in both the LAD and circumflex arteries, three drug eluting stents were placed, and she was started on aspirin ( mg po qd), plavix (7 mg po qd), and statin therapy ( mg simvastatin po qhs). days later, her LDLC was 8 mg/dl dl.. At the request of her daughter (a BWH nurse), hscrp was sent and found to be. mg/l.? Question : Now that the patient has sustained a myocardial infarction, and has an LDL of 8 mg/dl and hscrp of. mg/l, what would you recommend?. Make no changes. Increase simvastatin from mg to 8mg. Change to a more potent statin. Add ezetimibe mg. Start niacin extended release The patients daughter also reported that, three years earlier, she had taken her mother to a screening fair where her hscrp had been 7.7 mg/l. The daughter, a participant herself in the Women s Health Study, had done this out of frustration with her mother s s primary care physician who had refused at the time to send the test because it wasn t t in the guidelines. 7 year old non-diabetic women ATP-III RRS Smoker Yes.9%.% SBP TC 6 HDL 8 hscrp 7.7 Parental history No Lp(a), homocysteine normal TG normal Myocardial infarction age 7

Risk Factors for Future Cardiovascular Events: WHS Lipoprotein(a) Homocysteine IL-6 TC LDLC sicam- SAA Apo B TC: HDLC + TC: HDLC... 6. Relative Risk of Future Cardiovascular Events N Engl J Med ;:86- Fasting Compared With Non-fasting Triglycerides and Risk of Future Cardiovascular Events: Women s Health Study Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. JAMA 7;98:9-6 Fasting Compared With Non-fasting Triglycerides and Risk of Future Cardiovascular Events: Women s Health Study A Cost-Effective New Approach To To Screening? Cardiovascular Risk Lifestyle + Drug Rx Broad Screening Imaging Broad Screening Blood Pressure, Smoking TC, HDLC, hscrp, HbAc Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. JAMA 7;98:9-6 P.M. Ridker & P. Libby Risk Factors for Atherothrombotic Disease Chapter 9 Braunwald s Heart Disease 8th Edition Slowing of the progression of cardiovascular disease has been conclusively demonstrated with high dose statin therapy (METEOR) Regression of cardiovascular disease may be possible in some, but not all patients (ASTEROID, REVERSAL). The lipid lowering properties and the anti-inflammatory inflammatory properties of high dose statins are important for understanding plaque regression (AFCAPS/TexCAPS TexCAPS, PRINCE, PROVE IT, A to Z) The JUPITER trial (AHA November 8) will help us to understand if these same concepts can be used in primary prevention of heart disease. With thanks National Heart Lung and Blood Institute National Cancer Institute Donald W Reynolds Foundation, NV Doris Duke Charitable Foundation, NY Fondation Leducq,, Paris, FR American Heart Association, TX Pri-Med