Medical Management of Coronary Artery Disease Focus on Residual Risk - PowerPoint PPT Presentation

Medical Management of Coronary Artery Disease Focus on Residual Risk Duane Pinto, M.D., M.P.H. Interventional Cardiologist Chief, Interventional Section, Beth Israel Deaconess CV Division Associate Professor of Medicine Harvard Medical School Harvard Medical School

Aspirin Evidence: Dose and Efficacy Indirect Comparisons of Aspirin Doses on Vascular Events in High-Risk Patients Odds Ratio for Vascular Events Aspirin Dose No. of Trials (%) 500-1500 mg 34 19 160-325 mg 19 26 75-150 mg 12 32 <75 mg 3 13 Any aspirin 65 23 P<.0001 0 0.5 1.0 1.5 2.0 Antiplatelet Better Antiplatelet Worse Harvard Antithrombotic Trialists Collaboration . BMJ. 2002;324:71-86 Medical School

b -blocker Evidence: Benefit in HF and LVSD HF Patients Follow-up Mean Effects on Outcomes Severity (n) (years) Dosage Study Drug CIBIS Bisoprolol* Moderate- 641 1.9 3.8 All cause mortality  22% (p=NS) Severe mg/day CIBIS-II Bisoprolol* Moderate- 2,647 1.3 7.5 All cause mortality Severe  34% (P<0.0001) mg/day BEST Bucindolol* Moderate- 2,708 2.0 152 All cause mortality  10% (p=NS) Severe mg/day MERIT-HF Metoprolol Mild- 3,991 1.0 159 All cause mortality succinate #  34% (P=0.0062) Moderate mg/day MDC Metprolol Mild- 383 1.0 108 Death or Need for Tx  30% (P=NS) tartrate* Moderate mg/day CAPRICORN Carvedilol Mild 1,989 1.3 40 All cause mortality  23% (P =0.03) mg/day All- cause mortality† US Carvedilol Carvedilol Mild- 1,094 0.5 45  65% ( P =.0001) Moderate mg/day COPERNICUS Carvedilol Severe 2,289 0.9 37 All-cause mortality  35% (P =0.0014) mg/day *Not an approved indication † Not a planned end point. Harvard # Not approved for severe HF or mortality reduction alone Medical School

JNC VII Guidelines for Management and Treatment Initial drug therapy SBP* DBP* Lifestyle BP classification With compelling mmHg mmHg modification indications Normal <120 <80 Encourage Drug(s) for compelling 120 – 139 80 – 89 Pre- Yes indications. ‡ hypertension 140 – 159 90 – 99 Stage 1 Yes Drug(s) for the Hypertension compelling indications. ‡ Other antihypertensive Stage 2 >160 >100 Yes drugs (diuretics, ACEI, Hypertension ARB, BB, CCB) as needed. ACEI=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB= b -blocker, BP=Blood pressure, CCB=Calcium channel blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure *Treatment determined by highest blood pressure category. † Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡Treat patients with chronic kidney disease or diabetes mellitus to blood pressure goal of <130/80 mmHg. Chobanian AV et al. JAMA . 2003;289:2560-2572 Harvard Medical School

Cigarette Smoking Recommendations Goal: Complete Cessation and No Exposure to Environmental Tobacco Smoke • Ask about tobacco use status at every visit. • Advise every tobacco user to quit. •Assess the tobacco user’s willingness to quit. II II II I I I I I I I I a a a a I I I I I I I I b b b b I I I I I I I I I I I I I I I I I I I I I I I a a a a I I I I I I I I b b b b I I I I I I I I I I I I I I I I I I I I a a a a I I I I I I I I b b b b I I I I I I I I I I I I • Assist by counseling and developing a plan for quitting. • Arrange follow-up, referral to special programs, or pharmacotherapy (including nicotine replacement and bupropion. • Urge avoidance of exposure to environmental tobacco smoke at work and home. Harvard Medical School

Lipid Management Goal I I I I I a I I a I I a I I a I I b I I b I I b I I b I I I I I I I I I I I I I I I I I a I I a I I a I I a I I b I I b I I b I I b I I I I I I I I I I I I I I I I I a I I a I I a I I a I I b I I b I I b I I b I I I I I I I I I I I I LDL-C should be less than 100 mg/dL I I I I I I IIa IIb IIa IIb IIa IIb IIa IIb IIa IIa IIa IIa IIb III IIb III IIb III IIb III IIb IIb IIb IIb III III III III III III III III I I I IIa IIa IIa IIa Further reduction to LDL-C to < 70 mg/dL is reasonable If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL* *Non-HDL-C = total cholesterol minus HDL-C Harvard Medical School

HMG-CoA Reductase Inhibitor: Secondary Prevention Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD 30 4S LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Statin 25 Protection Study; CARE=Cholesterol and Placebo Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Event (%) 4S Disease; 4S=Scandinavian Simvastatin 20 Survival Study. LIPID 15 LIPID CARE CARE HPS 10 HPS TNT (atorvastatin 10 mg/d) 5 TNT (atorvastatin 80 mg/d) 0 0 70 90 110 130 150 170 190 210 LDL-C (mg/dL) LaRosa JC et al. NEJM. 2005;352:1425-1435 Harvard Medical School

Components of Secondary Prevention • Cigarette smoking cessation • Physical activity • Weight management to goal • Diabetes management to goal • Influenza vaccination Harvard Medical School

5 Major Trials Addressing Residual Risk • PEGASUS-TIMI 54 • FOURIER • ODYSSEY • CANTOS • COMPASS Harvard Medical School

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) – Chaperones LDL-R to destruction   circulating LDL-C – Loss-of-fxn genetic variants   LDL-R   LDL-C &  risk of MI evolocumab Evolocumab – Fully human anti- PCSK9 mAb – ~60%  LDL-C – Safe & well-tolerated in Ph 2 & 3 studies – Exploratory data suggested  CV events Sever P & Mackay J. Br J Cardiol 2014;21:91- 3 Harvard Giugliano RP, et al. Lancet 2012;380:2007-17 Medical Sabatine MS, et al. NEJM 2015;372:1500-9 School

Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy ( ± ezetimibe) LDL- C ≥70 mg/ dL or non-HDL- C ≥100 mg/ dL RANDOMIZED DOUBLE BLIND Evolocumab SC Placebo SC 140 mg Q2W or 420 mg QM Q2W or QM Follow-up Q 12 weeks Harvard Medical Sabatine MS et al. Am Heart J 2016;173:94-101 School

LDL Cholesterol 100 Placebo 90 80 LDL Cholesterol (mg/dl) 70 Cohort of 11,077 patients who • had all measurements through 120 weeks 60 • did not discontinue study drug • did not D concomitant background lipid-lowering Rx 50 40 30 Evolocumab Similar data out to 4 years 20 in OSLER-1 10 ( JAMA Cardiology online) 0 0 12 24 36 48 60 72 84 96 108 120 Weeks Harvard An Academic Research Organization of Medical Brigham and Women’s Hospital and Harvard Medical School School

Types of CV Outcomes Evolocumab Placebo (N=13,784) (N=13,780) Endpoint HR (95% CI) 3-yr Kaplan-Meier rate CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88) Cardiovascular death 2.5 2.4 1.05 (0.88-1.25) Death due to acute MI 0.26 0.32 0.84 (0.49-1.42) Death due to stroke 0.29 0.30 0.94 (0.58-1.54) Other CV death 1.9 1.8 1.10 (0.90-1.35) MI 4.4 6.3 0.73 (0.65-0.82) Stroke 2.2 2.6 0.79 (0.66-0.95) Harvard Medical School

AC C .18 ALIROCUMAB- ODYSSEY Post-ACS patients (1 to 12months) Run-in period of 2−16 weeks on high-intensity or maximum-tolerated dose of atorvastatin or rosuvastatin At least one lipid entry criterion met R andomization Placebo S CQ2W Alirocumab S CQ2W Patient and investigators remained blinded to treatment and lipid levels for the entire duration of the study Schwartz GG, et al. Am Heart J2014;168:682-689.e1. Harvard Medical 11 School

AC C .18 Primary Efficacy andComponents Alirocumab Placebo Log-rank Endpoint, n (%) HR (95%CI) (N=9462) (N=9462) P-value MACE 903 (9.5) 1052 (11.1) 0.85 (0.78, 0.93) 0.0003 CHDdeath 205 (2.2) 222 (2.3) 0.92 (0.76, 1.11) 0.38 Non-fatal MI 626 (6.6) 722 (7.6) 0.86 (0.77, 0.96) 0.006 Ischemic stroke 111 (1.2) 152 (1.6) 0.73 (0.57, 0.93) 0.01 Unstable angina 37 (0.4) 60 (0.6) 0.61 (0.41, 0.92) 0.02 Harvard Medical 32 School

Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) N = 10,061 Stable CAD (post MI) 39 Countries Residual Inflammatory Risk April 2011 - June 2017 (hsCRP > 2 mg/L) 1490 Primary Events Randomized Randomized Randomized Randomized Canakinumab 150 mg Canakinumab 300 mg Canakinumab 50 mg Placebo SC q 3 months SC q 3 months SC q 3 months SC q 3 months Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Secondary Endpoint: MACE plus Unstable Angina Requiring Urgent Revascularization (MACE+) Harvard Medical Ridker PM et al. N Engl J Med. 2017;377:1119-31 School

CANTOS: Primary Cardiovascular Endpoints Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months MACE MACE - Plus HR 0.85 HR 0.83 Cumulative Incidence (%) Cumulative Incidence (%) 95%CI 0.76-0.96 95%CI 0.74-0.92 P = 0.007 P = 0.0006 0 1 2 3 4 5 Follow-up Years Follow-up Years 35 - 40% reductions in hsCRP and IL-6 No change in LDLC Harvard Medical Ridker PM et al. N Engl J Med. 2017;377:1119-31 School

Thrombus: Made of Both Platelets & Fibrin Harvard Medical Slide by C. Michael Gibson, M.S., M.D. School