Coronary Artery Disease in 2015: Acute Coronary Syndrome and beyond (Primary and Secondary Prevention of CAD)

Coronary Artery Disease in 2015: Acute Coronary Syndrome and beyond (Primary and Secondary Prevention of CAD) Andrew R. Waxler, MD, FACC Berks Cardiologists, Ltd. President Elect, Berks County Medical Society Cardiology Rep. to PAMED (Specialty Leadership Cabinet) Director, Cardiac Rehab., St. Joseph Medical Center (Reading, PA) 1 Disclosure Dr. Waxler has a financial relationship or interest with a commercial entity that may have a direct interest in the subject matter of this session. Dr. Waxler is a consult and part of a speaker s bureau for Sanofi Pasteur. 2 For a cigarette-smoking patient who has an MI, what is the approximate risk reduction of future MI (over the next several years) that he/she will get from smoking cessation? A. There is no significant change in risk of second MI from smoking cessation at time of first MI B. Only about 10% C. About 25% D. About 50% E. Between 75-100% 3 1

Based on the most recent (2013) lipid guidelines, which of the following patients do NOT automatically qualify for statin therapy: A. Healthy 37 y.o. woman with LDL 227, no other medical probs B. 54 y.o. man with recent MI and PCI of LAD; his LDL is 65 C. 44 y.o. man with Diabetes and LDL 90; asymptomatic D. Options A and C E. All of the above qualify 4 Which of the following types of patients should receive dual-antiplatelet therapy for 9-12 months following ACS? (ASA/clopid.) A. Patient with ACS treated with Percutaneous Coronary Intervention(PCI)? B. Patient with ACS treated Coronary Artery Bypass Graft (CABG)? C. Patient with ACS treated medically (no PCI or CABG)? D. What about a High-risk patient who has NOT had ACS (ie, DM)? E. A, B, and C F. All of the above 5 We All Know About the Problem 6 2

7 8 Vascular Disease: A Generalized and Progressive Process Atherosclerosis Thrombosis Unstable angina ACS MI Ischemic stroke/tia Critical leg ischemia Cardiovascular death Stable angina Intermittent claudication Adapted from Stary HC et a l. Circulation.. 1995;92:1355-1374 and Fuster V. Vasc Med.. 1998;3:231-239. 9 3

One Method of Diagnosing CAD 10 Cardiac CT 64 Slice Coronary Artery Disease Congenital abnormalities 45 minutes Correlation needed with other studies (stress test or cardiac cath) 11 Sadly, a Common Method of Diagnosing CAD ACS 12 4

Hospital Discharges for ACS: UA/NSTEMI vs STEMI USA * ACS 1.67 Million Hospital Discharges ACS MI 700,000 973,000 USA/NSTEMI NSTEMI 652,000 Discharges per Year STEMI ** 321,000 Discharges per Year 1.352 Million Discharges per Year * UA=unstable angina. NSTEMI=non ST-segment elevation myocardial infarction (also known as non Q-wave MI). ** STEMI=ST-segment elevation MI (also known as Q-wave MI). American Heart Association. Heart Disease and Stroke Statistics 2005 Update. 2004. 13 A Dangerous Transition Coronary artery with stable atherosclerosis Coronary artery with ruptured unstable atherosclerotic plaque 14 15 5

When there s an elephant on my chest : Don t Do/Watch This Instead, Do This 16 One Often Leads to Another Coronary Atherosclerosis Cardiac catheterization and PCI 17 CAD Starts EARLY 18 6

Vascular Disease: A Generalized and Progressive Process Atherosclerosis Thrombosis Unstable angina ACS MI Ischemic stroke/tia Critical leg ischemia Cardiovascular death Stable angina Intermittent claudication Adapted from Stary HC et a l. Circulation.. 1995;92:1355-1374 and Fuster V. Vasc Med.. 1998;3:231-239. 19 20 Superior doctors prevent the disease. Mediocre doctors treat the disease before evident. Inferior doctors treat the full-blown disease. --Huang Dee: Nai Ching (2600 BC First Chinese Medical Text) 21 7

Framingham, Mass. 22 23 24 8

National ACC speaker for my upcoming conference 5/2/2015 Circulation. 1999; 100: 988-998 25 Circulation. 1998; 97: 1837-1847 26 Framingham Score (CAD event risk) Circulation. 1999; 100: 988-998 27 9

28 Lipoprotein (Sub)Classes 0.95 VLDL Chylomicrons 1.006 IDL Density (g/ml) 1.02 LDL Chylomicron Remnants 1.06 HDL 2 1.10 HDL 3 1.20 Lp(a) 5 10 20 40 60 80 1000 Diameter (nm) 29 10

LDL-C Levels and CAD Risk 30 25 CAD + Revasc + Stroke (HPS = CAD Only) Solid Shapes = Drug Rx Outline Shapes = Placebo 2 Prevention CAD Events, % 20 15 10 5 0 4S CARE HPS LIPID 1 Prevention AFCAPS WOSCOPS 40 60 80 100 120 140 160 180 200 Mean On-Treatment LDL-C Level at Follow-Up, mg/dl Adapted from Am J Cardiol, Vol 82, CM Ballantyne, Low-density lipoproteins and risk for coronary artery disease, pp. 3Q-12Q, Copyright 1998, with permission from Excerpta Medica Inc. Heart Protection Study Collaborative Group. Lancet. 2002;360:7 22. 32 Landmark Statin Trials: LDL-C Levels vs Events (primary prevention) Percentage with CHD event 10 9 8 7 WOSCOPS-S 6 5 4 AFCAPS-S AFCAPS-P 3 2 ASCOT-P 1 ASCOT-S 0 2.3 (90) 2.8 (110) S = statin treated; P = placebo treated 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190) LDL-C, mmol/l (mg/dl) WOSCOPS-P Primary prevention Pravastatin Lovastatin Atorvastatin 5.4 (210) Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21 33 11

1 0 34 Heart Protection Study (HPS) 20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years Baseline LDL-C (mg/dl) Statin (n = 10,269) Placebo (n = 10,267) <100 282 (16.4%) 358 (21.0%) Event Rate Ratio (95% CI) Statin Better Statin Worse 100 129 668 (18.9%) 871 (24.7%) 130 1083 (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) 0.76 (0.72 0.81) P<0.0001 0.4 0.6 0.8 1.0 1.2 1.4 CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus, HPS Collaborative Group. Lancet 2002;360:7-22 35 Heart Protection Study (5-Year Trial) Simvastatin 40 mg Log CHD Risk Simvastatin 40 mg 26% Reduction in CVD 22% Reduction in CVD 60 100 LDL-C (mg/dl) Heart Protection Study Collaborative Group. Lancet 2002;360:7 22. 36 12

What Is Desirable Cholesterol? Cholesterol Levels Among Different Human Populations Hazda Inuit!Kung Pygmy San Adult American Hunter-gatherer humans 50 70 90 110 130 150 170 190 210 Mean total cholesterol, mg/dl Adapted from O Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142 2146. 37 Relationship between LDL-C and Progression Rate Coronary IVUS Progression Trials Median Change In Percent Atheroma Volume (%) 1.8 1.2 0.6 0 REVERSAL atorvastatin A-Plus placebo CAMELOT placebo ACTIVATE placebo REVERSAL pravastatin -0.6 Nissen S. JAMA 2006 ASTEROID rosuvastatin r 2 = 0.95 p<0.001-1.2 50 60 70 80 90 100 110 120 ) Mean Low-Density Lipoprotein Cholesterol (mg/dl) 38 39 13

Intensive LDL-C Goals for High-Risk Patients Recommended LDL-C treatment goals ATP III Update 2004 1 <100 mg/dl: Patients with CHD or CHD risk equivalents (10-year risk >20%) 1 <70 mg/dl: Therapeutic option for very high-risk patients 1 <100 mg/dl <70 mg/dl AHA/ACC guidelines for patients with CHD*,2 <100 mg/dl: Goal for all patients with CHD,2 <70 mg/dl: A reasonable goal for all patients with CHD,2 2006 Update If it is not possible to attain LDL-C <70 mg/dl because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C lowering therapy, including drug combinations. *And other forms of atherosclerotic disease. 2 Factors that place a patient at very high risk: established cardiovascular disesase (CVD) plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic syndrome (triglycerides [TG] 200 mg/dl + non HDL-C 130 mg/dl with HDL-C <40 mg/dl); and acute coronary syndromes. 1 1. Grundy SM et al. Circulation. 2004;110:227 239. 2. Smith SC Jr et al. Circulation, 2006; 113:2363 2372. 40 41 42 14

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52 We ve Come a Long Way Since Back Then But Sadly, Some People Still Haven t Gotten the Message 53 Stopping smoking is easy.i ve done it many times! I don t smoke; the cigarette does! - Said by a patient to Andrew R. Waxler, Internal Medicine intern at UPMC 1992 54 18

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Clinical Diabetes January 2006 vol. 24 no. 1 27-32 61 BMJ 316:823-828, 1998 62 BMJ 316:823-828, 1998 63 21

64 What about meds for Secondary Prevention? 65 ACC/AHA Treatment Recommendations for the Long-term Management of ACS* ACS (UA/NSTEMI* patients) Medical Management Medical Management (no intervention required) PCI (with or without stent) Cath lab CABG Long-term management 1. ASA 2. Clopid.(?Prasug./Ticag.) 3. ß-blocker 4. ACE Inhibitor 5. Statin * UA/NSTEMI=unstable angina/non ST-segment elevation myocardial infarction (also known as non Q-wave MI). If possible, withhold clopidogrel 5 to 7 days prior to the procedure. 66 Braunwald E, et al. Available at: www.acc.org. Accessed February 10, 2005. 22

Mechanisms of Action of Oral Antiplatelet Therapies clopidogrel bisulfate ADP dipyridamole ticlopidine HCl ADP phosphodiesterase ADP GP IIb/IIIa (fibrinogen receptor) COX camp Activation collagen thrombin TXA 2 aspirin TXA 2 ADP=adenosine diphosphate, TXA 2 =thromboxane A 2, COX=cyclooxygenase. Schafer AI. Am J Med. 1996;101:199-209. 67 Antithrombotic Trialists Collaboration Efficacy of Aspirin Doses on Vascular Events in High-Risk Patients Aspirin Dose # Trials OR* (%) Odds Ratio 500 1500 mg 34 19 160 325 mg 19 26 75 150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 0 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse * Odds reduction. Treatment effect P<0.0001. Adapted with permission from the BMJ Publishing Group. Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86. 68 CURE Primary End Point: MI/Stroke/CV Death Cumulative Hazard Rate 0.14 0.12 0.10 0.08 0.06 0.04 0.02 Placebo + ASA* Clopidogrel + ASA* 20% Relative Risk Reduction P=0.00009 N=12,562 The primary outcome occurred in 9.3% of patients in the clopidogrel + ASA group and 11.4% in the placebo + ASA group. 0.00 0 3 6 9 12 Months of Follow-Up * Other standard therapies were used as appropriate. PLAVIX Prescribing Information. Adapted with permission (2002) from the Massachusetts Medical Society. The CURE Trial Investigators. N Engl J Med. 2001;345:494-502. 69 23

CURE Patients Treated with PCI * and/or CABG Cumulative Hazard Rate 0.20 0.15 0.10 0.05 Placebo + ASA (13.8%) Clopidogrel + ASA (11.4%) 18% Relative Risk Reduction (P=0.015 ) 0.00 0 100 200 300 * PCI was also referred to as PTCA. Other standard therapies were used as appropriate. Days of Follow-Up In the combined end point of MI, stroke, or CV death. Only first events after randomization were counted in the composite end point. 70 Data on file, Sanofi-Synthelabo Inc. CURE Patients Treated with Medical Therapy 0.20 Without PCI * and/or CABG Cumulative Hazard Rate 0.15 0.10 0.05 Placebo + ASA (10.0%) Clopidogrel + ASA (8.1%) 20% Relative Risk Reduction (P=0.0025 ) 0.00 0 100 200 300 Days of Follow-Up * PCI was also referred to as PTCA. Other standard therapies were used as appropriate. In the combined end point of MI, stroke, or CV death. Only first events after randomization were counted in the composite end point. 71 Data on file, Sanofi-Synthelabo Inc. CHARISMA: Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death) * 8 Placebo + ASA 7.3% Cumulative event rate (%) 6 4 2 Clopidogrel + ASA 6.8% 1 RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22 2 0 0 6 12 18 24 30 Months since randomization * First occurrence of MI, stroke (of any cause), or cardiovascular death. All patients received ASA 75-162mg/day. The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) 1. Adapted from Bhatt DL et al. 2006, in press. 2. Bhatt DL. Presented at ACC 2006. 72 24

73 CHARISMA: Primary Efficacy Results (MI/Stroke/CV Death)* by Category of Inclusion Criteria Population N RR (95% CI) p value Documented AT 12,153 0.88 (0.77, 0.998) 0.046 Coronary 5,835 0.86 (0.71, 1.05) 0.13 Cerebrovascular 4,320 0.84 (0.69, 1.03) 0.09 PAD 2,838 0.87 (0.67, 1.13) 0.29 Multiple RF 3,284 1.20 (0.91, 1.59) 0.20 Overall Population 15,603 0.93 (0.83, 1.05) 0.22 0.4 0.6 0.8 1.2 1.4 1.6 Clopidogrel Better Placebo Better RF=Risk Factors, AT=Atherothrombosis. * First occurrence of MI, stroke (of any cause), or CV Death. Bhatt DL. Presented at ACC 2006. 74 2002 ACC/AHA UA/NSTEMI* Guideline Update: Recommendations for Long-Term Medical Therapy Class I Aspirin 75 to 325 mg/day (level of evidence: A) Clopidogrel 75 mg daily (in the absence of contraindications) when ASA is not tolerated because of hypersensitivity or gastrointestinal intolerance (level of evidence: A) The combination of ASA and clopidogrel for 9 months after UA/NSTEMI (level of evidence: B) Beta-blockers in the absence of contraindications (level of evidence: B) Lipid-lowering agents and diet in post-acs and post-revascularization patients with LDL cholesterol >130 mg/dl (level of evidence: A) Lipid-lowering agents if LDL cholesterol level after diet is >100 mg/dl (level of evidence: C) ACE inhibitors for patients with CHF, LV dysfunction (EF <0.40), hypertension, or diabetes (level of evidence: A) * Also known as non Q-wave MI. Braunwald E, et al. Available at: www.acc.org. Accessed February 18, 2004. 75 25

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82 CRUSADE Discharge Medication Use Last 12 Months (In patients without contraindications) Utilization of Therapies (%) 100% 80% 60% 40% 20% 93% 89% 64% 86% 69% 0% ASA Beta Blockers ACE- Inhibitors* Any Lipid- Lowering Agent Clopidogrel * LVEF <40%, CHF, DM, HTN. Known hyperlipidemia, TC, LDL. CRUSADE data October 1, 2003-September 30, 2004 (n=40,386) Adapted with permission from CRUSADE Web site. Available at: http://www.crusadeqi.com. Accessed March 11, 2005. 83 CRUSADE Relationship Between Guidelines Adherence and In-Hospital Mortality In-Hospital Mortality (%)* 7 6 5 4 3 2 Improved Hospital Adherence 6.0% 5.2% 5.0% 4.2% 1 0 25% 25 50% 50 75% 75% Hospital Composite Adherence Quartiles * Adjusted figure. Cumulative CRUSADE data (adjusted) through September 2004. Adapted with permission from CRUSADE Web site. Available at: http://www.crusadeqi.com. Accessed February 10, 2005. 84 28

Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven Drug Evaluation - Presented at the ACC meeting, March, 2008, New Orleans, LA - Published NEJM 2007; 356 85 COURAGE: Risk Factor Goals Variable Goal Smoking Cessation Total Dietary Fat / Saturated Fat <30% calories / <7% calories Dietary Cholesterol <200 mg/day LDL cholesterol (primary goal) 60-85 mg/dl HDL cholesterol (secondary goal) >40 mg/dl Triglyceride (secondary goal) <150 mg/dl Physical Activity 30-45 min. moderate intensity 5X/week Body Weight by Body Mass index Initial BMI Weight Loss Goal 25-27.5 BMI <25 >27.5 10% relative weight loss Blood Pressure <130/85 mmhg Diabetes HbAlc <7.0% - Presented at the ACC meeting, March, 2008, New Orleans, LA Published NEJM 2007; 356 86 COURAGE: Overall Survival 1.0 PCI + OMT 0.9 0.8 0.7 0.6 0.5 OMT Hazard ratio: 0.87 95% CI (0.65-1.16) P = 0.38 0.0 0 1 2 3 4 5 6 7 Years Number at Risk Medical Therapy 1138 1073 1029 917 717 468 302 38 PCI 1149 1094 1051 929 733 488 312 44 - Presented at the ACC meeting, March, 2008, New Orleans, LA Published NEJM 2007; 356 87 29

COURAGE: Long-Term Improvement in Treatment Targets (Group Median ± SE Data) Treatment Targets Baseline 60 Months PCI +OMT OMT PCI +OMT OMT SBP 131 ± 0.77 130 ± 0.66 124 ± 0.81 122 ± 0.92 DBP 74 ± 0.33 74 ± 0.33 70 ± 0.81 70 ± 0.65 Total Cholesterol mg/dl 172 ± 1.37 177 ± 1.41 143 ± 1.74 140 ± 1.64 LDL mg/dl 100 ± 1.17 102 ± 1.22 71 ± 1.33 72 ± 1.21 HDL mg/dl 39 ± 0.39 39 ± 0.37 41 ± 0.67 41 ± 0.75 TG mg/dl 143 ± 2.96 149 ± 3.03 123 ± 4.13 131 ± 4.70 BMI Kg/M² 28.7 ± 0.18 28.9 ± 0.17 29.2 ± 0.34 29.5 ± 0.31 Moderate Activity (5x/week) 25% 25% 42% 36% - Presented at the ACC meeting, March, 2008, New Orleans, LA Published NEJM 2007; 356 88 89 90 30

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Keep it Simple; Don t Overthink it 97 Summary CAD remains the number one cause of morbidity and mortality among adults in the USA. There are approximately 1.5-2.0 million episodes of ACS annually. For essentially half a century, we have had data regarding CAD risk factors. We also some very reasonable data demonstrating that interventions do work. Primary and secondary prevention of CAD events can be accomplished but is challenging and may require an astute/aggressive doctor and a motivated patient Keep it simple.remember the basics 98 For a cigarette-smoking patient who has an MI, what is the approximate risk reduction of future MI (over the next several years) that he/she will get from smoking cessation? A. There is no significant change in risk of second MI from smoking cessation at time of first MI B. Only about 10% C. About 25% D. About 50% E. Between 75-100% 99 33

Based on the most recent (2013) lipid guidelines, which of the following patients do NOT automatically qualify for statin therapy: A. Healthy 37 y.o. woman with LDL 227, no other medical probs B. 54 y.o. man with recent MI and PCI of LAD; his LDL is 65 C. 44 y.o. man with Diabetes and LDL 90; asymptomatic D. Options A and C E. All of the above qualify 100 Which of the following types of patients should receive dual-antiplatelet therapy for 9-12 months following ACS? (ASA/clopid.) A. Patient with ACS treated with Percutaneous Coronary Intervention(PCI)? B. Patient with ACS treated Coronary Artery Bypass Graft (CABG)? C. Patient with ACS treated medically (no PCI or CABG)? D. What about a High-risk patient who has NOT had ACS (ie, DM)? E. A, B, and C F. All of the above 101 34