TIMI TRIALS. Chairman: Marc S. Sabatine, MD, MPH. Director of Operations: Polly M. Fish. TIMI Study Group 11TH EDITION,

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1 11t hedi t i on THETI MI TRI AL S

2 TIMI Study Group TIMI TRIALS 11TH EDITION, Chairman: Marc S. Sabatine, MD, MPH Director of Operations: Polly M. Fish TIMI Study Group Suite Fenwood Road Boston, MA 2115 T: F:

3 About TIMI Since its inception in 1984, the principal goal of the TIMI Study Group has been to conduct high quality clinical trials that enhance the care of patients suffering from cardiovascular disease and its risk factors. We have studied a broad range of patients, including: patients across the spectrum of acute coronary syndromes; patients with stable coronary disease, stroke, and peripheral artery disease; patients with metabolic cardiovascular risk factors such as dyslipidemia, diabetes, and obesity; and patients with atrial fibrillation. The trials span from phase I to phase IV and from less than 3 to more than 3, subjects. Trials have been conducted in over 5 countries and at more than 5 separate sites. We have studied a wide range of interventions including fibrinolytic, antithrombotic, antiplatelet, anti ischemic, lipid modifying, anti inflammatory, anti diabetes, and anti obesity agents, as well as percutaneous coronary intervention (PCI). By leading large scale, international, randomized controlled trials of novel therapeutics and performing sophisticated analyses, we have been privileged to help shape the very practice of cardiovascular medicine for over a quarter of a century. In addition, the TIMI Study Group has used its growing database of more than 35, subjects and their clinical findings, electrocardiograms, angiograms, biomarkers, and genotypes to enhance the understanding of cardiovascular disease and its risk factors. An important corollary goal has been to train the next generation of clinical investigators. TIMI is especially proud of these trainees who have assumed leadership positions in leading institutions around the world.

4 Marc S. Sabatine, MD, MPH is the Chairman of the TIMI Study Group, and the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women s Hospital, and a Professor of Medicine at Harvard Medical School. He has led multiple large scale, international, randomized controlled trials of novel antithrombotic pharmacotherapies. Dr. Sabatine has also pioneered multimarker approaches to risk stratification and has had several NIH grants supporting the application of proteomics and metabolomics for discovery of novel biomarkers. He has a longstanding interest in pharmacogenetics and has led key studies on the impact of genetic polymorphisms on the pharmacologic and clinical response to antiplatelet therapy. Dr. Sabatine has published extensively in these fields with seminal papers in the New England Journal of Medicine, JAMA, and the Lancet. He has mentored numerous fellows who have gone on to faculty appointments as physician scientists at major academic cardiovascular divisions. Eugene Braunwald, MD, the founding chairman of the TIMI Study Group, is a preeminent researcher, physician, and educator, and has truly improved health care for people around the world. According to Joseph B. Martin, M.D., former Dean of the Faculty of Medicine at Harvard Medical School, Dr. Braunwald s bench to bedside approach to the limitations of myocardial infarct size is perhaps the greatest single example of an individual whose scientific research has led to dramatic translational benefits to improve patient care. Dr. Braunwald s direct contributions as a clinical investigator have improved the prognosis and quality of life for patients with cardiovascular disease. In addition, through his role as the standard bearer for academic excellence, his trainees augment and multiply his positive influence on biomedical research, education, and patient care. He has received many honors, including an honorary Doctorate of Science degree from Oxford University.

5 Table of Contents Listing of TIMI Trials TIMI Lessons Antithrombotic Therapy in Cardiovascular Disease 1.1. Antiplatelet Therapy 1.2. Anticoagulant Therapy 1.3. Thrombolytic Therapy in STEMI 2. Strategies & Therapies for Reducing Ischemic Events 2.1. Beta Blockade in STEMI 2.2. Early Invasive Strategy 2.3. Ranolazine 3. Risk Factor Modification 3.1. Lipid modifying Therapy in Atherosclerotic Vascular Disease 3.2. Glucose Lowering Agents 4. Prevention of Stroke in Atrial Fibrillation 4.1. Edoxaban in patients with atrial fibrillation 5. Personalized Medicine 5.1. Clinical Risk Scores 5.2. Angiographic Scores 5.3. Biomarkers for Risk Stratification & Predicting Treatment Benefit 5.4. Pharmacogenetics Ongoing Trials Recently Completed Trials Completed Trials TIMI Bibliography

6 TIMI TRIALS 217 TRIAL NAME INDICATION COMPARISON TIMI 1 STEMI tpa vs. SK TIMI 2A STEMI Immediate vs. Delayed Angioplasty TIMI 2B STEMI Invasive vs. Conservative Strategy / Immediate vs. Delayed Metoprolol TIMI 3A UA/NSTEMI Thrombolysis vs. Placebo TIMI 3B UA/NSTEMI Thrombolysis vs. Placebo / Invasive vs. Conservative Strategy TIMI 3 Registry UA/NSTEMI Natural History Study TIMI 4 STEMI tpa vs. APSAC vs. Combination TIMI 5 STEMI Hirudin vs. Heparin in conjunction with tpa TIMI 6 STEMI Hirudin vs. Heparin in conjunction with SK TIMI 7 UA Hirulog Dose Ranging TIMI 8 UA/NSTEMI Hirulog vs. Heparin TIMI 9A/B STEMI Hirudin vs. Heparin in conjunction with thrombolytic TIMI 9 Registry STEMI Natural History Study TIMI 1A STEMI TNK Dose ranging TIMI 1B STEMI TNK vs tpa (Angiographic) ASSENT 1 (TIMI 1C) STEMI TNK Dose Ranging TIMI 11A UA/NSTEMI Enoxaparin Dose Ranging TIMI 11B UA/NSTEMI Enoxaparin vs Heparin TIMI 12 Post ACS Oral GP IIb/IIIa inhibitor Dose Ranging TIMI 14 STEMI Abciximab +/ low dose tpa/sk TIMI 15A ACS IV GP IIb/IIIa inhibitor Dose Ranging TIMI 15B ACS IV + oral GP IIb/IIIa inhibitor Dose Ranging OPUS TIMI 16 ACS Oral GP IIb/IIIa inhibitor vs. Placebo InTIME 2 TIMI 17 STEMI npa vs. tpa TACTICS TIMI 18 UA/NSTEMI Invasive vs. Conservative Therapy with Tirofiban ER TIMI 19 STEMI Early rpa vs Standard Therapy INTEGRITI (TIMI 2) STEMI Eptifibatide +/ TNK tpa (Angiographic) A2Z (TIMI 21) ACS Tirofiban + (Enoxaparin vs Heparin) / Simvastatin Early vs. Late PROVE IT TIMI 22 Post ACS Pravastatin vs. Atorvastatin / Gatifloxacin vs. Placebo ENTIRE TIMI 23 STEMI Abciximab +/ TNK / Enoxaparin vs. Heparin (Angiographic) FASTER (TIMI 24) STEMI Tirofiban +/ TNK (Angiographic) ExTRACT TIMI 25 STEMI Enoxaparin vs. Heparin in conjunction with Thrombolytic JUMBO TIMI 26 PCI Prasugrel vs. Clopidogrel Dose Ranging PROXIMATE TIMI 27 Stable CAD Monoclonal Antibody (CH 36 Mab) Against Tissue Factor Dose Ranging CLARITY TIMI 28 STEMI Clopidogrel vs. Placebo with Thrombolytic ADVANCE MI (TIMI 29) STEMI Facilitated PCI (Eptifibatide + TNK) vs. Direct PCI (Eptifibatide + Placebo)/ Enoxaparin vs. Heparin PROTECT TIMI 3 PCI Bivalirudin vs. Heparin + Eptifibatide TIMI 31 STEMI Fibrinolytic (BB 1153) Dose Ranging

7 TRIAL NAME INDICATION COMPARISON ANTHEM TIMI 32 UA/NSTEMI Tissue Factor/fVIIa inhibitor (rnapc2) vs. Placebo DISPERSE2 TIMI 33 UA/NSTEMI Ticagrelor vs. Clopidogrel TITAN TIMI 34 STEMI ED vs. Catheterization Lab initiated Eptifibatide with Primary PCI PROMPT TIMI 35 Stable CAD Novel markers of ischemia during ETT MERLIN TIMI 36 UA/NSTEMI Ranolazine vs. Placebo TIMI 37A STEMI PARP inhibitor in STEMI TRITON TIMI 38 PCI in ACS Prasugrel vs. Clopidogrel in PCI for ACS EARLY ACS (TIMI 39) UA/NSTEMI Early eptifibatide vs. placebo before PCI IMPROVE IT (TIMI 4) Post ACS Simvastatin vs. Ezetimibe + Simvastatin PLATO + ACS Ticagrelor vs. Clopidogrel SEPIA ACS1 TIMI 42 UA/NSTEMI Dose Ranging Study of Otamixaban AVANT GARDE TIMI 43 Post ACS Aliskiren ± Valsartan vs. Placebo to Reduce NT probnp PRINCIPLE TIMI 44 PCI Prasugrel vs. Clopidogrel to Inhibit Platelet Aggregation VERIFY NOW TIMI 45 CABG Degree of Platelet Inhibition and Bleeding in CABG Patients ATLAS ACS TIMI 46 Post ACS Dose Ranging Study of Rivaroxaban vs. Placebo IC TITAN TIMI 47 PCI Intracoronary Eptifibatide vs. Placebo in PCI ENGAGE AF TIMI 48 Atrial Fibrillation Edoxaban (Oral Xa inhibitor) vs. Warfarin ICE T TIMI 49 STEMI Intracoronary Fibrinolytic vs. Placebo TRA 2 P TIMI 5 Stable Atherosclerosis Vorapaxar (Thrombin receptor antagonist) vs. Placebo ATLAS ACS2 TIMI 51 Post ACS Rivaroxaban (Oral Xa inhibitor) vs. Placebo SOLID TIMI 52 Post ACS Darapladib (Selective Lp PLA2 inhibitor) vs. Placebo SAVOR TIMI 53++ Diabetes Saxagliptin (DPP 4 inhibitor) vs. Placebo for CVD Prevention PEGASUS TIMI 54 Stable Post MI Ticagrelor vs. Placebo HPS3/REVEAL (TIMI 55)+++ Stable Atherosclerosis Anacetrapib vs. Placebo ELEVATE TIMI 56 Stable CAD Dose Ranging Study of Clopidogrel in Reduced Function CYP2C19 Carriers LAPLACE TIMI 57 Hypercholesterolemia Dose Ranging Study of AMG145 (PCSK9 inhibitor) vs. Placebo DECLARE TIMI 58++* Diabetes Dapagliflozin (SGLT2 inhibitor) vs. Placebo FOURIER (TIMI 59) Stable Atherosclerosis Evolocumab (PCSK9 inhibitor) vs. Placebo in combination with a statin LATITUDE TIMI 6 ACS Losmapimod (p38 MAPK inhibitor) vs. Placebo CAMELLIA TIMI 61* Obesity Lorcaserin (serotonin receptor agonist 5HT2CR) vs. Placebo PIONEER HF (TIMI 62)* CHF Sacubitril/Valsartan vs. Enalapril on NT probnp in ADHF MEDI612 Multiple Ascending Dose Study (TIMI 63a)* Stable Atherosclerosis Pharmacologic profile of MEDI612 (recombinant LCAT) in subjects with ASCVD * Ongoing In conjunc on with Duke Clinical Research Ins tute + In conjunction with Uppsala Clinical Research Center, Sweden ++ In conjunction with Hadassah Medical Organization, Israel +++ In conjunction with Oxford University,United Kingdom (ACS = Acute Coronary Syndrome; CAD = Coronary Artery Disease; CVD = Cardiovascular Disease; ETT = exercise tolerance test; LMWH = Low Molecular Weight Heparin; NSTEMI = Non ST elevation myocardial infarction; PCI = Percutaneous Coronary Intervention; STEMI = ST elevation myocardial infarction; UA = unstable angina)

8 TIMILESSONS

9 1. ANTITHROMBOTIC THERAPY IN VASCULAR DISEASE ISE 1.1 Antiplatelet Therapy Clopidogrel in Thrombolysis for STEMI - Clopidogrel improves both angiographic and clinical outcomes in patients receiving thrombolytic therapy in STEMI. CLARITY-TIMI 28 enrolled 3491 patients with STEMI receiving aspirin and fibrinolytic therapy and randomized them to adjunctive clopidogrel or placebo. The addition of clopidogrel to fibrinolytic therapy significantly reduced the odds of major cardiovascular events by 2% at 3 days. In CLARITY-TIMI 28, subjects who were pretreated with clopidogrel prior to PCI had a significant 46% reduction in the risk of cardiac events after PCI after adjusting for baseline differences. Of note, the benefit of pre-treatment appeared early and continued to persist over time Prasugrel in ACS - More potent platelet inhibition with prasugrel significantly improves clinical outcomes in patients with ACS undergoing PCI as compared to clopidogrel, but with an increased risk of bleeding and reduces acute limb ischemia in patients with PAD. TRITON-TIMI 38 randomized 13,68 patients with ACS undergoing PCI to prasugrel or clopidogrel. Prasugrel significantly reduced the risk of death, MI or stroke by 19% (Absolute Risk Reduction [ARR] of 2.2%; Number Needed to Treat [NNT] = 46). Although bleeding rates were low, prasugrel significantly increased the risk of TIMI major bleeding by 32% (Absolute Risk Elevation [ARE] =.6%; Number Needed to Harm [NNH] = 167.) In the setting of ACS, prasugrel significantly reduces the risk of stent thrombosis by 52% compared to a 3mg loading dose and 75mg maintenance dose of clopidogrel.

10 In TRITON-TIMI 38, subjects randomized to prasugrel had a significant 52% reduction in the risk of stent thrombosis compared to clopidogrel. This benefit was seen for both drug-eluting and bare-metal stents. Prasugrel reduces major adverse cardiovascular events in STEMI patients. In the 3534 participants presenting with STEMI, the treatment with prasugrel resulted in a 32% reduction in cardiovascular death, non-fatal myocardial infarction or non-fatal stroke at 3 days (HR.68, ; p=.17) compared to placebo, with continued effect to 15 months. Other secondary endpoints, including cardiovascular death, myocardial infarction and stent thrombosis were significant reduced with prasugrel compared to clopidogrel in STEMI patients Routine versus Provisional GP IIb/IIIa Inhibition in NSTE-ACS - A strategy of delayed, provisional eptifibatide yields similar ischemic outcomes and less bleeding compared with early, routine use in patients with NSTE-ACS. 15% 1% 5% OR.92 (.8, 1.6) P =.23 1.% 9.3% EARLY ACS (TIMI 39) Results OR.89 (.79, 1.1) P = % 11.2% Delayed Provisional Early Routine OR 1.75 (1.43, 2.13) P <.1 3.4% 5.7% EARLY ACS (TIMI 39) randomized 9,492 high risk NSTE-ACS patients to early, routine or delayed, provisional administration of eptifibatide. Early use was not associated with improved outcomes as compared with provisional use and led to significantly higher rates of major bleeding. % N = 4684 N = 4722 N = 4684 N = 4722 N = 4643 N = 4686 D/MI/RI UR/TBO D/MI at 3d TIMI Major/Minor at 96h Bleeding at 12h D = Death; MI = Myocardial Infarction; RI UR = Recurrent Ischemia leading to Urgent Revascularization; TBO = Thrombotic Bailout with bolus therapy Opposite to initial study-group assignment Giugliano RP et al. Giugliano NEJMet al. 29;36: NEJM

11 1.1.4 Vorapaxar in Vascular Disease - The addition of vorapaxar, a PAR-1 inhibitor, to standard background anti-thrombotic therapy reduces the risk of cardiovascular death or ischemic events in patients with coronary artery disease, peripheral artery disease, or cerebrovascular disease. Vorapaxar increases bleeding, particularly in patients with prior stroke.. Morrow et al., NEJM 212; 366: Morrow et al., NEJM 212; 366: TRA 2 P-TIMI 5 randomized 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to vorapaxar or placebo. Vorapaxar significantly reduced the risk of death, MI or stroke by 13% (Absolute Risk Reduction [ARR] of 1.2%), but significantly increased the risk of moderate or severe bleeding by 66% (Absolute Risk Elevation [ARE] = 1.7%). The addition of vorapaxar to standard background anti-thrombotic therapy reduces the risk of cardiovascular death or ischemic events in patients with prior MI and reduces acute limb ischemia in patients with PAD. Scirica BM et al., Lancet 212; 38: Among 17,779 patients who had a history of MI, vorapaxar significantly reduced the risk of CV death, MI, or stroke by 2% (Absolute Risk Reduction [ARR] of 1.6%; Number Needed to Treat=62; P<.1). Bonaca MP et al., Circulation 216;133: TRA 2 P-TIMI 5 included 3,767 patients enrolled based on a history of symptomatic peripheral arterial disease (PAD), defined as claudication and an ankle-brachial index <.85 or prior peripheral revascularization. The addition of vorapaxar, as compared to placebo, significantly reduced the risk of the hospitalization for acute limb ischemia by 42% (Absolute risk reduction [ARR] of 1.6%).

12 1.1.5 Ticagrelor in Patients with Prior MI - Among patients with MI more than 1 year earlier, the addition of ticagrelor 9 or 6 mg twice daily to low-dose aspirin reduces the risk of CV death, MI, or stroke, but with an increased risk of bleeding. Bonaca MP et al., N Engl J Med. 215;372: PEGASUS-TIMI 54 randomized 21,162 patients who had a MI 1-3 years earlier to ticagrelor 9 mg BID, ticagrelor 6 mg BID, or placebo. On a background of low-dose aspirin, ticagrelor 9 mg and 6 mg significantly reduced the risk of CV death, MI, or stroke by 15% (Absolute Risk Reduction [ARR] of 1.2%) and 16% (Absolute Risk Reduction [ARR] of 1.7%), respectively. Rates of major bleeding were higher with ticagrelor than with placebo. Bonaca MP et al., N Engl J Med. 215;372:

13 Bonaca MP et al., J Am Coll Cardiol. 216;67: Among patients with PAD who had a history of MI, the combination of ticagrelor and aspirin reduced the risk of CV death, MI, or stroke by 25% (Absolute Risk Reduction [ARR] of 4.1%; Number Needed to Treat=25;) and limb vascular events by 35% (P=.26). Bonaca MP et al., JAMA Cardiol, 216;1: A meta-analysis of trials evaluating prolonged P2Y12 inhibition in patients who had a history of MI showed an 11% reduction in all-cause mortality and 16.5% reduction in CV mortality with prolonged intensive antiplatelet therapy.

14 1.2 Anticoagulant Therapy Enoxaparin in NSTE-ACS - Enoxaparin improves outcomes compared to unfractionated heparin in patients with non-st-elevation ACS. TIMI 11B % Death, MI or Urgent Revascularization at 14 Days UFH ENOX 14.5 % 12.4 % P=.48 RRR 15 % 16.7 % 14.2 % P=.29 RRR 15 % TIMI 11B randomized 3,91 patients with NSTE-ACS to UFH or enoxaparin. Enoxaparin significantly reduced the risk of death, MI or urgent revascularization at both 8 and 14 days Days Antman EM, Circulation 1999; 1: Enoxaparin for Conservative Management of NSTE-ACS - Enoxaparin was superior to unfractionated heparin when evaluated in early conservative management of NSTE-ACS. In A to Z, 3987 patients with NSTE-ACS receiving aspirin and tirofiban were randomized to enoxaparin or unfractionated heparin. The HR for death, myocardial infarction and refractory ischemia was.88 ( ) for enoxaparin vs unfractionated heparin. There was a trend towards greater benefit from enoxaparin in those managed with an early conservative as compared to early invasive strategy. Blazing et al., JAMA 24:292:1;55.

15 1.2.3 Enoxaparin in Thrombolysis for STEMI - A strategy of enoxaparin through index hospitalization is superior to unfractionated heparin for 48 hours in patients receiving thrombolytic therapy for STEMI. ExTRACT-TIMI 25 randomized 2,56 patients with STEMI receiving fibrinolytic therapy to enoxaparin through hospitalization or UFH for 48 hours. Enoxaparin significantly reduced the risk of death or MI by 17% (left panel) and reduced the risk of death, MI or urgent revascularization by 19% (right panel) by 3 days follow-up Bivalirudin Versus Heparin in Patients Undergoing PCI - Bivalirudin use during PCI is associated with higher rates of ischemic events, including myocardial infarctions and stent thrombosis, but lower rates of bleeding compared to heparin-based regimens.

16 A meta-analysis that included data from 16 trials involving patients, of whom 2422 experienced MACE and 146 had a major bleed found an increase in the risk of MACE with bivalirudin as compared to heparin-based regimens (risk ratio 1.9, 95% CI ; p=.24). This was largely driven by increases in myocardial infarction (1.12, ) and by ischemia-driven revascularization (1.16, ) with no effect on mortality (.99, ). Bivalirudin increased the risk of stent thrombosis (risk ratio 1.38, 95% CI ; p=.74), which was primarily due to an increase in acute cases in ST-segment elevation myocardial infarction (4.27, ; p<.1). Overall, bivalirudin-based regimens lowered the risk of major bleeding (risk ratio.62, 95% CI.49.78; p<.1), but the magnitude of this effect varied greatly depending on whether glycoprotein IIb/IIIa inhibitors were used predominantly in the heparin arm only (.53,.47.61; p<.1), provisionally in both arms (.78, ; p=.25), or planned in both arms (1.7, ; p=.53) Rivaroxaban Improves Outcomes in Patients Stabilized Post-ACS - The addition of lowdose rivaroxaban, an oral factor Xa inhibitor, to background antiplatelet therapy reduced the risk of cardiovascular death or ischemic events in patients stabilized after an ACS. Very low-dose rivaroxaban (2.5 mg twice daily) also significantly reduced the risk of cardiovascular and all-cause death. ATLAS-ACS 2 TIMI 51 randomized 15,526 patients with a recent acute coronary syndrome to low dose rivaroxaban (5 mg BID), very low dose rivaroxaban (2.5 mg BID), or placebo. Overall, rivaroxaban significantly reduced the rate of cardiovascular death, MI, or stroke by 16% (Absolute Risk Reduction [ARR] of 1.8%) but significantly increased the risk of major bleeding not related to CABG and intracranial hemorrhage. Very low dose rivaroxaban (2.5 mg BID) significantly reduced the rate of Mega JL et al., N Engl J Med. 212;366:9-19. cardiovascular death and all-cause death.

17 Mega JL et al., NEJM. 212;366:9-19. ATLAS-ACS 2 TIMI 51 randomized 15,526 patients with a recent acute coronary syndrome to low dose rivaroxaban (5 mg BID), very low dose rivaroxaban (2.5 mg BID), or placebo. Overall, rivaroxaban significantly reduced the rate of cardiovascular death, MI, or stroke by 16% (Absolute Risk Reduction [ARR] of 1.8%) but significantly increased the risk of major bleeding not related to CABG and intracranial hemorrhage. Very low dose rivaroxaban (2.5 mg BID) significantly reduced the rate of cardiovascular death and all-cause death as indicated in above and below panels. Mega JL et al. NEJM 212;366:9-19.

18 1.3 Thrombolytic Therapy in STEMI Fibrin-Specific Lytics in STEMI - Tissue plasminogen activator (tpa) improves reperfusion and clinical outcomes when compared to other thrombolytics in STEMI. TIMI 1 % of Patients * * 7 43 t-pa SK *P<.1 Impact of 9 Minute Patency on Mortality Mortality (%) Patent (N=161) 2 Occluded (N=128) Reperfusion of occluded arteries Patency at 9 minutes Weeks from Randomization TIMI Study Group, N Engl J Med 1985; 312: The TIMI 1 trial enrolled 29 patients with acute MI and randomized them to tpa or SK. Patients treated with tpa (yellow bars) had improved reperfusion and vessel patency at 9 minutes. Dalen JE, Am J Cardiol 1988;62: Regardless of treatment arm, a patent infarctrelated artery at 9 minutes was associated with improved long-term survival Pre-Hospital Thrombolytic Therapy in STEMI - A strategy of pre-hospital administration of thrombolytic therapy reduces time to reperfusion. ER-TIMI 19 Data = median times (Q1 - Q3) Ambulance Arrival CONTROL GROUP N = 598 ED Arrival 62 min (47-85) In-hospital Lytic STUDY GROUP N = min (24-37) rpa Bolus TIME SAVED 31 min p <.1* *Adjusted for any effect of site and interaction Morrow DA, J Am Coll Cardiol 22; 4:71-77 ER-TIMI 19 enrolled 315 patients with STEMI. Pre-hospital administration of rpa was found to be feasible and reduced time-to-lytic time by 31 minutes.

19 2. STRATEGIES & THERAPIES FOR REDUCING ISCHEMIC EVENTS 2.1 Beta-Blockade in STEMI - Early administration of intravenous beta-blockers reduces the risk of reinfarction or recurrent ischemia in stable patients with STEMI. 2.2 Early Invasive Strategy - An early invasive strategy reduces death, recurrent MI or rehospitalization with ACS in patients with NSTE-ACS, as compared to a conservative treatment strategy. TACTICS-TIMI TIMI 18 2 Death, MI, Rehosp for ACS at 6 Months 19.4% % Patients O.R.78 95% CI (.62,.97) p=.25 CONS INV Time (months) 15.9% Cannon CP, N Engl J Med 21; 344: TACTICS-TIMI 18 randomized 2,22 patients with UA or NSTEMI to an early invasive strategy (routine cardiac catheterization <48h) or conservative strategy. An early invasive strategy significantly reduced the odds of death, MI or rehospitalization with ACS by 22%.

20 High risk women derive greater benefit from invasive strategy in NSTE-ACS. Early invasive strategy in women: Although some studies suggested that women may not benefit from an invasive strategy, meta-analysis indicated that women with high-risk features, such as elevated biomarkers of necrosis, derive comparable benefit from an invasive strategy in NSTE-ACS as men. In contrast, women without high-risk predictors should undergo further risk stratification before cardiac catheterization in NSTE-ACS. O Donoghue ML et al., JAMA. 28;3: Ranolazine - Ranolazine reduces recurrent ischemia after NSTE-ACS, but does not significantly change the risk of death or recurrent MI. MERLIN-TIMI 36 CV Death, MI, or Recurrent Ischemia (%) Placebo 23.5%* (N=3,281) Ranolazine 21.8%* (N=3,279) HR.92 (95% CI.83 to 1.2) P = Days from Randomization *KM cumulative incidence (%) at 12 months Morrow DA, JAMA 27; 297: MERLIN-TIMI 36 randomized 6,56 patients with NSTE-ACS to the novel anti-ischemic agent ranolazine or placebo. Ranolazine did not significantly reduce the risk of the composite endpoint of CV death, MI or recurrent ischemia. Secondary Endpoint: Recurrent Ischemia (%) In MERLIN-TIMI 36, ranolazine significantly reduced the risk of recurrent ischemia by 13% compared to placebo (P=.3), supporting its use as an antiischemic drug Days from Randomization Placebo 16.1%* (N=3,281) Ranolazine 13.9%* (N=3,279) HR.87 (95% CI.76 to.99) P = Morrow DA, JAMA 27; 297:

21 Ranolazine significantly reduces the risk of arrhythmias after NSTE-ACS. Ventricular ectopy lasting at least 4 beats in patients with NSTE-ACS is independently associated with increased risk of SCD even in the modern era of widespread use of reperfusion, revascularization, and contemporary medical therapy. Scirica BM, Circulation 27; 116: In MERLIN-TIMI 36, ranolazine significantly reduced the incidence of VT by 37%. Scirica BM et al., Circulation. 21;122: In MERLIN-TIMI 36, 4 beats of nonsustained VT following NSTE-ACS was independently associated with risk of SCD.

22 3. RISK FACTOR MODIFICATION 3.1 Lipid-modifying Therapy in Atherosclerotic Vascular Disease 3.1 Lipid-modifying Therapy in Atherosclerotic Vascular Disease Intensive Statin Therapy in ACS - Intensive lipid-lowering therapy with a high-potency statin significantly reduces death or major cardiovascular events among patients who have recently had an ACS. The PROVE-IT TIMI 22 trial randomized 4162 patients to treatment with atorvastatin 8 mg QD or pravastatin 4 mg QD after ACS. Intensive lipidlowering therapy with atorvastatin to a median LDL of 62 mg/dl significantly reduced the risk of the primary endpoint by 16% (P=.5) and death, MI or urgent revascularization by 35% (P=.4, Figure). Achieving very low levels of LDL-C after an ACS is associated with a lower rate of ischemic events and no safety concerns. Wiviott SD, J Am Coll Cardiol 25; 46: In PROVE-IT TIMI 22, patients who achieved very low LDL concentrations appeared to derive as much benefit with intensive lipidlowering therapy after ACS, as patients with higher achieved lipid values.. There were no significant differences in safety parameters, including muscle, liver, or retinal abnormalities, ICH, or death, in the very low LDL group.

23 3.1.2 Ezetimibe Added to Statin Therapy after ACS - The addition of ezetimibe to statin therapy in patients who had an ACS results in further lowering of LDL-C levels and reduces the risk of cardiovascular events. Cannon CP et al., NEJM. 215;372: IMPROVE-IT randomized 18,144 patients to simvastatin 4 mg/ezetimibe 1 mg or simvastatin 4 mg/placebo after ACS. Intensive lipid-lowering therapy with the addition of ezetimibe to simvastatin reduced LDL-C by 16 mg/dl to a mean LDL-C of ~54 mg/dl and significantly reduced the risk of CV death, MI, stroke, unstable angina, or urgent revascularization by 6.4% (P=.16). Cannon CP et al., NEJM. 215;372:

24 Simvastatin/ezetimibe combination significantly reduced the rate of CV death, MI, or stroke by 1% (Absolute Risk Reduction [ARR] of 1.8%; P=.3). Cannon CP et al., NEJM ; Cannon CP et al., NEJM ; Simvastatin/ezetimibe combination significantly reduced the rate of major vascular events as defined by the CTT collaborators (a composite of coronary death, MI, stroke, or coronary revascularization 3 days or more after randomization) by 7.3% (Absolute Risk Reduction [ARR] of 2.2%; P=.7), entirely in keeping with the magnitude of LDL-C lowering as seen in the CTT meta-regression of statin trials.

25 3.1.3 Statin and Nonstatin Therapies to Reduce Vascular Events - Statin and nonstatin therapies that reduce LDL-C are associated with similar benefit in reducing major vascular events per amount of LDL-C lowering. In a meta-regression analysis of 49 clinical trials with participants, each 1-mmol/L (38.7- mg/dl) reduction in LDL-C level was associated with a significant reduction in major vascular events by 23% for statins (relative risk.77, 95% CI ; P <.1) and 25% for nonstatin lipid-lowering therapies (relative risk.75, 95% CI ; P=.2) that act primarily via upregulation of LDL receptor expression. Lower achieved LDL-C levels are associated with lower rates of major coronary events. Lower achieved LDL-C with statins or nonstatin lipid-lowering therapies were associated with a lower incidence of major coronary events.

26 3.1.4 PCSK9 Inhibition in Patients with Atherosclerotic Cardiovascular Disease - Inhibition of PCSK9 with evolocumab safely lowers LDL-C to very low levels and reduces the risk of cardiovascular events. Sabatine MS et al., NEJM ; FOURIER randomized 27,564 patients with atherosclerotic cardiovascular disease and LDL-C of 7 mg/dl or above who were receiving statin therapy to receive evolocumab (either 14 mg every 2 weeks or 42 mg monthly) or placebo. Evolocumab lowered LDL-C by 59% to a median LDL-C of 3 mg/dl (above panel) and significantly reduced the risk of the primary endpoint by 15% (Absolute Risk Reduction [ARR] of 2%; Number Needed to Treat 3 years =5; P<.1) compared to placebo (below panel). Sabatine MS et al., NEJM ;

27 Sabatine MS et al., NEJM ; Evolocumab significantly reduced the risk of CV death, MI, or stroke by 2% (Absolute Risk Reduction [ARR] of 2%; Number Needed to Treat 3 years =5; P<.1) compared to placebo. After 1 year, evolocumab significantly reduced CV death, MI, or stroke by 25% (P<.1) compared to placebo. Sabatine MS et al., NEJM ;

28 The extent of benefit of evolocumab in reducing the risk of cardiovascular events per mmol/l reduction in LDL-C was comparable with the benefit seen with statins. Giugliano RP et al., Lancet. 217,Epub ahead of print. Evolocumab safely reduced LDL-C to unprecedented low levels (<1 mg/dl). There was a strong progressive relationship of achieved LDL-C with cardiovascular events down to LDL less than 1 mg/dl.

29 Sabatine MS et al., NEJM ; There were similar rates of adverse events, including diabetes and neurocognitive events with evolocumab and placebo. PCSK9 inhibition with evolocumab did not increase the risk of new-onset diabetes.

30 The addition of evolocumab to statin therapy in patients with clinically evident cardiovascular disease does not adversely affect cognitive function. Giugliano RP et al., NEJM 217;377: EBBINGHAUS enrolled 1974 patients with known cardiovascular disease randomized to evolocumab or placebo added to statin therapy and prospectively assessed cognitive function. Evolocumab was not associated with any adverse effect on cognitive function compared with placebo. Giugliano RP et al., NEJM 217;377: There was no difference in cognitive function by achieved nadir LDL-C, even less than 25 mg/dl.

31 3.1.5 CETP Inhibition in Patients with Atherosclerotic Vascular Disease - CETP inhibition by anacetrapib reduces risk of major coronary events among patients with atherosclerotic vascular disease on background statin therapy. HPS TIMI REVEAL Collab Group. NEJM 217; 377: REVEAL randomized 3,449 subjects with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy to receive either 1 mg of anacetrapib once daily or placebo. Anacetrapib significantly reduced the risk of coronary death, MI, or coronary revascularization by 9% (P<.4). HPS TIMI REVEAL Collab Group. NEJM 217; 377: HPS TIMI REVEAL Collab Group. NEJM 217; 377:

32 3.2 Glucose-Lowering Agents The DPP4 inhibitor saxagliptin neither increases nor decreases the risk of ischemic complications but increases risk of hospitalization for heart failure in patients at high cardiovascular risk. SAVOR-TIMI 53 randomized 16,492 patients with T2DM and either established cardiovascular disease or multiple cardiovascular risk factors to saxagliptin or placebo, in addition to standard care. The primary safety objective of the trial was met, demonstrating that this novel agent known to effectively lowers A1c is not associated with increased cardiovascular ischemic events. There was, though, an unexpected 27% relative (.8% absolute) increase in the risk of hospitalization for heart failure in patients treated with saxagliptin that was most evident in those patients with impaired renal function, history of prior heart failure, or elevated levels of natriuretic peptides. Scirica BM et al., Circulation. 214;13:

33 4. PREVENTION OF STROKE IN AF 4.1 Edoxaban in patients with atrial fibrillation - Two dose regimens of the once daily oral Factor Xa inhibitor edoxaban were non-inferior to well-managed warfarin while significantly reducing bleeding. The ENGAGE AF-TIMI 48 trial randomized 21,15 patients with AF at moderate to high risk of stroke to one of two dose regimens of once-daily edoxaban vs warfarin. Both dose regimens of edoxaban were non-inferior in the prevention of stroke or systemic embolism, with the higher dose regimen tending to be superior. Both dose regimens of edoxaban significantly reduced a variety of bleeding events, including major, intracranial, and fatal hemorrhage.

34 5. PERSONALIZED MEDICINE 5.1 Clinical Risk Scores TIMI Risk Score for UA/NSTEMI - The TIMI Risk Score for UA/NSTEMI is a simple prognostication scheme that categorizes a patient's risk of death and ischemic events and provides a basis for therapeutic decision making. TIMI 11B TIMI Risk Score for UA/NSTEMI Death, MI, Urgent Revascularization by TRS / /7 One Point for each of: Age > 65 y > 3 CAD Risk Factors Prior Stenosis > 5 % ST deviation > 2 Anginal events < 24 h ASA in last 7 days Elevated Cardiac Markers Antman EM, JAMA 2; 284: The TIMI Risk Score for UA/NSTEMI consists of a 7-point scale. As TIMI Risk Score increases, patients have a steep increase in the risk of adverse outcomes. The score was derived and validated in TIMI 11B and ESSENCE, but has since been validated in several trials including TIMI 3B, TACTICS-TIMI 18, MERLIN-TIMI 36, and CURE TIMI Risk Score for STEMI - The TIMI Risk Score for STEMI is a useful tool for helping to identify those individuals at increased risk of death after STEMI. TIMI TIMI Risk Score for STEMI Mortality at 3 d by STEMI TRS >8 Historical Age pts >75 3pts DM/HTN/Angina 1pt Exam SBP < 1 mmhg 3pts HR > 1 bpm 2pts Killip II IV 2pts Weight < 67 kg 1 pt Presentation Anterior STE or LBBB 1 pt Time to Rx > 4hr 1pt Risk Score = Total (-14) Morrow DA, Circulation 2; 12: The TIMI Risk Score for STEMI consists of a 14-point scale based on history, exam and presentation. A higher TIMI Risk Score is associated with an increased risk of death. The score was derived in InTIME 2 and first validated in TIMI 9. The score has since been validated in several populations including TIMI 17, ExTRACT-TIMI 25, CLARITY- TIMI 28 and NRMI.

35 5.1.3 TIMI Risk Index - A simple risk index based on characteristics that are easily assessed and captures most of the information from more complex tools, and is useful for risk stratification in patients with STEMI. TIMI 17 Mortality (%) Simple Risk Score for STEMI Q1 Q2 Q3 Q4 Q Quartile Q1 Q2 Q3 Q4 Q5 Range < > Hours In-hospital 3 Days 17.4 Simple Risk Score Heart Rate x [Age/1] 2 SBP 3-day mortality by 43% for every 5 point in risk score Morrow DA, Lancet 21; 358: The TIMI risk is calculated using a combination of patient s heart rate, age and SBP at presentation. Every 5-point increase in score is associated with a 43% increase in 3-day mortality. The index was derived in InTIME 2 and validated in TIMI 9, ExTRACT-TIMI 25 and NRMI TIMI Bleeding Classification - The TIMI Bleeding Classifications are widely used across clinical trials to grade severity of bleeding. Bleeding has been shown to be associated with an increased risk of adverse outcomes. The TIMI Bleeding Classifications have been expanded to include new definitions (shown at right). Updated Bleeding Requiring Medical Attention: Any overt sign bleeding that requires intervention (medical or surgical treatment), leads to hospitalization or prompting evaluation (unscheduled contact with a healthcare professional and diagnostic testing) and does not meet criteria for TIMI major or minor bleeding. Instrumented Bleeding: Any hemorrhage that occurs as a result of an invasive procedure. Spontaneous Bleeding: Any hemorrhage that is not the direct result of an invasive procedure (e.g. gingival bleeding, epistaxis, gastrointestinal bleeding).

36 5.1.5 SIHD Risk Score - The TIMI Risk Score for Secondary Prevention (TRS 2 P) is a helpful tool for risk stratification and therapeutic decision making for secondary prevention after ACS. Bohula EA et al., Circulation. 216;134: The TIMI Risk Score for Secondary Prevention (TRS 2 P) is an atherothrombotic risk assessment tool consisting of 9 clinical variables. A higher TRS 2 P is independently associated with an increased risk of cardiovascular events. This score was derived in TRA 2 P-TIMI 5 and first validated in IMPROVE IT. In TRA 2 P-TIMI 5 risk stratification using this tool identified high-risk patients who derive greatest benefit from vorapaxar for secondary prevention after ACS. Bohula EA et al., JACC 217;69: In IMPROVE-IT, patients with high TRS 2 P appeared to derive a greater treatment benefit from the addition of ezetimibe to statin therapy, as compared with statin monotherapy.

37 5.1.6 TIMI-AF Score - The TIMI-AF score assists in the prediction of serious events in VKA naive patients and guides selection of optimal anticoagulant strategy. Fanola CL et al., EHJ. 217;38: TIMI-AF score consists of a 17-point scale that predicts the risk of net clinical outcome in VKA naive patients treated with oral anticoagulation for stroke prevention in AF. The score was derived in the ENGAGE AF-TIMI 48 trial in which edoxaban demonstrated improved outcomes for those with intermediate- or high-risk scores, whereas warfarin performed as well as edoxaban with low-risk scores. In VKA experienced patients, there was no difference in outcomes across risk score categories by treatment arm.

38 5.2 Angiographic Scores TIMI Flow Grade - The TIMI Flow Grade is universally used to assess epicardial perfusion at angiography. A higher TIMI Flow Grade is strongly associated with increased survival. TIMI 1 TIMI TIMI 1 TIMI 2 TIMI 3 TIMI Flow Grade Complete occlusion Penetration of obstruction by contrast but no distal perfusion Perfusion of entire artery but delayed flow Full perfusion, normal flow Mortality at 42 Days 1.6 P < TIMI /1 TIMI 2 TIMI 3 Flygenring BP, J Am Coll Cardiol 1991; 17:275A TIMI Flow Grade is scored from -3 with TIMI Flow Grade representing a complete occlusion and TIMI Flow Grade 3 representing normal perfusion (left). TIMI Flow Grade strongly predicts mortality (right) and has been validated in several trials TIMI Myocardial Perfusion Grade - The TIMI Myocardial Perfusion Grade assesses microvascular perfusion and is also associated with increased survival independent of TIMI Flow Grade. TIMI 1B TIMI Myocardial Perfusion Grade is scored from -3 with TMPG representing no apparent tissue-level perfusion and TMPG 3 indicating that blush begins to fade during washout. Regardless of TIMI Flow Grade, a lower TMPG was associated with an increased risk of death in TIMI 1B. Mortality (%) Epicardial TIMI Grade 3 Flow Overall Mortality: 3.7% 5 way p =.7.7 Myocardial Perfusion Grade Myocardial Perfusion Grade 2 Myocardial Perfusion Grade 5.4 Myocardial Perfusion Grades /1 Epicardial TIMI Grade 2/1/ Overall Mortality: 7% 4.7 Myocardial Perfusion Grade Myocardial Perfusion Grades 2/1/ Gibson CM, Circulation 1999; 99:1945-5

39 5.3 Biomarkers for Risk Stratification & Predicting Treatment Benefit Troponin in ACS - Troponin is a powerful predictor of outcomes and is useful for helping to identify individuals who may benefit more from particular treatment strategies, including GP IIb/IIIa inhibitors and an early invasive strategy in NSTEMI. TIMI IIIB % Mortality at 42 days Troponin I Predicts Mortality in UA/NSTEMI to <.4.4 to <1. 1. to <2. 2. to <5. 5. to <9. > 9. Cardiac Troponin I ng/ml Risk Ratio Antman EM, N Engl J Med 1996; 335: Troponin is the best established marker for diagnosis and risk stratification in NSTEMI. In TIMI 3B, patients with a troponin >9ng/ml had a 7.5-fold higher risk of death than patients with a troponin <.4 ng/ml. TACTICS-TIMI TIMI 18 (%) Death, MI, Rehosp ACS at 6 Months 14.8 CONS p=ns 16.7 INV N= TnT - TnT + TnT cut point =.1 ng/ml (54% of Pts TnT +) * OR=.55 *p<.1 Interaction P=.13 Morrow DA, JAMA 21; 286: In TACTICS-TIMI 18, patients with an elevated troponin T at randomization appeared to derive a greater treatment benefit with an early invasive strategy, as compared to patients with a troponin T<.1 ng/ml High-Sensitivity Troponin in SIHD - In stable patients with ischemic heart disease, elevated troponin is associated with increased risk of cardiovascular events. Bonaca et al., JACC. 216;68: In PROVE IT-TIMI 22, elevated high-sensitivity troponin at 3-days after ACS was independently associated with an increased risk of CV death or heart failure. Patients with high troponin tended to have larger absolute reductions in CV risk with intensive compared with moderate statin therapy.

40 5.3.3 BNP in ACS - B-type natriuretic peptide (BNP) is a powerful predictor of risk of death after ACS. In OPUS-TIMI 16, elevated levels of BNP were associated with an increased risk of death at 1 months. The unadjusted rate of death increased in a stepwise fashion among patients in increasing quartiles of baseline BNP levels (P<.1). In the A2Z trial, patients with a BNP >8 pg/ml measured 4 months after ACS had a 3.4-fold increase in the risk of death or new heart failure through 2 years of follow-up (P<.1) C-Reactive Protein After ACS - When measured 3 days after ACS, high-sensitivity C- reactive protein (hscrp) is a powerful predictor of outcomes, independent of achieved LDL concentration. Intensive statin therapy significantly reduces hscrp and, in part, helps to attenuate the increased risk of death or MI seen with higher levels of hscrp. Median C-reactive protein (hscrp) levels by treatment Risk of Death or MI Ridker P. NEJM 25;352:2-28. In PROVE-IT TIMI 22, patients who have low hscrp levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of achieved LDL cholesterol. Atorvastatin 8mg significantly reduces hscrp more than pravastatin 4mg (left) and may in part attenuate the higher risk of events with elevated hscrp (right).

41 Bohula EA et al., Circ ; In IMPROVE IT, patients who achieved the dual LDL-C (<7 mg/dl) and hscrp (<2mg/L) targets at 1 month had lower rates of primary endpoints than those meeting neither targets. Significantly more patients treated with ezetimibe/simvastatin reached LDL-C and hscrp targets than patients treated with simvastatin alone Multimarker Strategy in Risk Stratification - A multimarker strategy that reflects complementary pathobiological axes of ACS can provide incremental information for risk stratification when compared to a single marker alone. TACTICS-TIMI TIMI RR of D/MI/CHF at 6 months Assign patients 1 point for the presence of each elevated biomarker (TnI >.1 ng/ml, CRP > 1.5 mg/dl, BNP > 8 pg/ml). OR & 95% CI for D/MI/CHF by 6 months Age (per year) Diabetes Prior MI Prior CHF 2 ST deviation 1. Biomarkers 1 Biomarker 1 2 Biomarkers 3 Biomarkers # of Elevated Markers Sabatine MS, Circulation 22; 15: A simple multimarker strategy that categorizes patients based on the number of elevated biomarkers (troponin, BNP and CRP) at presentation. As the number of elevated biomarkers increases, there is a near doubling of mortality risk and cardiac events for each additional biomarker that is elevated. The score was derived in OPUS-TIMI 16 and first validated in TACTICS-TIMI 18.

42 Scirica BM et al., JAMA Cardiol. 216;1: In SAVOR TIMI 53 trial, a multimarker strategy combining biomarkers of myocardial injury (high-sensitive troponin T), hemodynamic stress (NT-proBNP), and inflammation (hscrp) improved risk stratification for the development of first or recurrent cardiovascular events in patients with type 2 diabetes. s. Ruff CT et al., JAMA Cardiol. 216;1: In ENGAGE AF-TIMI 48, a multimarker risk score estimated by analyzing troponin I, NTproBNP, and d-dimer levels at baseline identified a more than 15-fold gradient of risk for stroke, systemic embolic events, or death after adjustment for the CHA2DS2-VASc score.

43 5.4 Pharmacogenetics CYP2C19 Polymorphisms and Outcomes with Clopidogrel and Prasugrel - Among patients on clopidogrel, carriers of a CYP2C19 reduced-function allele have diminished antiplatelet effect and an increased risk of events. These genetic polymorphisms do not affect the antiplatelet effect of prasugrel or result in an increased risk of events, which may explain in part the different pharmacological and clinical responses to the two medications. CYP2C19 is an isoform of cytochrome P45 and is involved in the metabolism of clopidogrel to its active metabolite. In ACS patients within TRITON-TIMI 38, carriers of a reduced-function allele who were treated with clopidogrel had a significant 53% increase in the risk of adverse events despite similar baseline characteristics. Carrier status of the CYP2C19 reduced-function allele had no significant clinical effect in those ACS patients treated with prasugrel Meta Analysis of CYP2C19 Reduced Function Polymorphisms & Outcomes - Among patients on clopidogrel and who have undergone PCI, carriers of 1 or 2 CYP2C19 reduced-function allele(s) have diminished antiplatelet effect and an increased risk of major cardiovascular events. A meta-analysis of 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel and undergoing PCI demonstrates that carriers of reduced function allele(s) have a significantly increased risk of adverse CV events and stent thrombosis. Mega JL et al., JAMA. 21;34:

44 5.4.3 Tailoring Clopidogrel Dosing Based on CYP2C19 Genotype - Tripling the dose of clopidogrel among patients carrying 1 reduced function CYP2C19 allele achieves similar levels of platelet reactivity to that achieved by standard dose clopidogrel in non-carriers. Mega JL et al., JAMA. 211;36: The ELEVATE-TIMI 56 trial genotyped 333 patients with stable cardiovascular disease and randomized carriers of loss-of-function CYP2C19*2 alleles to 75, 15, 225, and 3mg of clopidogrel daily. Tripling the maintenance dose of clopidogrel to 225 mg daily in stable heart disease patients carrying 1 reduced function allele achieved similar levels of platelet reactivity as achieved by standard dose clopidogrel in noncarriers Genetic Risk and Statin Therapy - Genetic risk score (GRS) improves risk stratification for primary and secondary prevention with statin therapy and identifies individuals who derive the greatest benefit from statin therapy. A 27 SNP GRS identified individuals at increased risk of coronary events across primary and secondary prevention populations. A higher GRS was associated with an increased risk of both incident and recurrent CHD events. This GRS was derived and validated in the PROVE IT TIMI 22, CARE, JUPITER and ASCOT trials.

45 Mega JL et al. and Sabatine MS. Lancet 215;385: In trials of primary and secondary prevention with statin therapy, the GRS identified individuals who derive the largest absolute reduction in coronary events Genetics and Outcomes with Warfarin and Edoxaban - Genetic variants identify individuals who are at increased risk of bleeding with warfarin and derive a greater safety benefit with edoxaban compared with warfarin. The ENGAGE AF-TIMI 48 trial genotyped 14,348 patients and found that genetic polymorphisms in CYP2C9 and VKORC1 modify the safety outcomes of warfarin therapy. Compared with normal responders, the risk of overt bleeding with warfarin was increased by 2.7-fold and 1.3-fold in highly sensitive responders and sensitive responders, respectively.

46 Edoxaban compared with warfarin resulted in a greater reduction in bleeding risk in sensitive and highly sensitive responders than in normal responders PCSK9 and HMGCR Variants & Risk of Cardiovascular Disease and Diabetes - Genetic variants in PCSK9 and HMGCR are associated with similar effects on the risk of cardiovascular events and the risk of diabetes. Ference B et al. & Sabatine MS. N Engl J Med. 216;375: In a cohort of 112,772 participants, variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of CV events per decrease in the LDL-C level. Variants in these two genes were also associated with very similar effects on the risk of diabetes. The increased risk of diabetes was limited to individuals with impaired fasting glucose levels for both genes and was lower in magnitude than the protective effect against CV events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both CV events and diabetes.

47 5.4.7 Mendelian Randomization of CETP and HMGCR Genetic Variants and Cardiovascular Risk - The clinical benefit of lowering LDL-C with CETP inhibitors depends on the corresponding reduction in apob-containing lipoprotein particles. Ference B et al. & Sabatine MS, JAMA 217;318: In a Mendelian randomization analysis of 14 population cohorts including 12,837 participants, combined exposure to genetic variants related to the action of CETP inhibitors and statins was significantly associated with discordant reductions in LDL-C and apob levels; the resulting association with CV events was proportional to the attenuated reduction in apob but less than expected per unit change in LDL-C.

48 ONGOINGTRIALS

49 ONGOING CLINICAL TRIALS DECLARE-TIMI 58 is a superiority trial and designed to test the hypothesis that in patients with type 2 diabetes mellitus long-term treatment with dapagliflozin will reduce the incidence of the composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke. CAMELLIA-TIMI 61 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in overweight and obese subjects with CV disease and/or multiple CV risk factors.

50 ONGOING CLINICAL TRIALS PIONEER-HF is a multicenter, randomized, double-blind study evaluating the effect of sacubitril/valsartan versus enalapril on changes in NT-proBNP and safety and tolerability of in-hospital initiation of sacubitril/valsartan compared to enalapril in HFrEF patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF). The Multiple-Ascending-Dose Study (TIMI-63A) is a Phase 2a randomized, blinded, placebocontrolled study designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of MEDI612, a recombinant human lecithin cholesterol acyl transferase in subjects with stable atherosclerotic cardiovascular disease.

51 RECENTLYCOMPLETED TRIALS

52 RECENTLY COMPLETED TRIALS Study Design Patients stabilized post ACS 1 days: LDL-C 5 125*mg/dL (or 5 1**mg/dL if prior lipid-lowering Rx) *3.2mM **2.6mM N=18,144 Standard Medical & Interventional Therapy Simvastatin 4 mg Uptitrated to Simva 8 mg if LDL-C > 79 (adapted per FDA label 211) Ezetimibe / Simvastatin 1 / 4 mg Follow-up Visit Day 3, every 4 months 9% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 525 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization ( 3 days after randomization), or stroke Cannon CP AHJ 28;156:826-32; Califf RM NEJM 29;361:712-7; Blazing MA AHJ 214;168:25-12 IMPROVE-IT randomized 18,144 patients to simvastatin 4 mg/ezetimibe 1 mg or simvastatin 4 mg/placebo after ACS. Intensive lipid-lowering therapy with the addition of ezetimibe to simvastatin resulted in incremental lowering in LDL-C and significantly reduced the primary endpoint by 6.4%. IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit. IMPROVE-IT CTT Collaboration. Lancet 25; 366: ; Lancet 21;376: Using CTT methods: LDL difference between groups using baseline LDL for Pts without blood samples. Endpoint of CV Death, MI, stroke or revasc >3days post Rand. Cox HR reported.

53 RECENTLY COMPLETED TRIALS Primary Endpoint ITT Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization ( 3 days), or stroke HR.936 CI (.887,.988) p=.16 Simva 34.7% 2742 events NNT= 5 EZ/Simva 32.7% 2572 events Cannon CP, Blazing MA, Giugliano RP, et. al. N Engl J Med 215; Epub before print. 7-year event rates

54 RECENTLY COMPLETED TRIALS Trial Design Stable pts with history of MI 1-3 yrs prior + 1 additional atherothrombosis risk factor* RANDOMIZE DOUBLE BLIND * Age >65 yrs, diabetes, 2 nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction Planned treatment with ASA mg & Standard background care Ticagrelor 9 mg bid Ticagrelor 6 mg bid Placebo Follow-up Visits Q4 mos for 1 st yr, then Q6 mos Event-driven trial An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School PEGASUS-TIMI 54 randomized 21,162 patients who had an MI 1-3 years earlier to ticagrelor 9 mg BID, ticagrelor 6 mg BID, or placebo. On a background of low-dose aspirin, ticagrelor 9 mg and 6 mg significantly reduced the risk of CV death, MI, or stroke by 15% and 16%, respectively. Rates of major bleeding were higher with ticagrelor than with placebo. Primary Endpoint 1 9 N = 21,162 Median follow-up 33 months Placebo (9.4%) CV Death, MI, or Stroke (%) Ticagrelor 9 mg vs placebo HR.85 (95% CI.75.96) P=.8 Ticagrelor 6 mg vs placebo HR.84 (95% CI.74.95) P=.43 Ticagrelor 9 (7.85%) Ticagrelor 6 (7.77%) Months from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

55 RECENTLY COMPLETED TRIALS Components of Primary Endpoint Endpoint HR (95% CI) P value.85 ( ).8 CV Death, MI, or Stroke.84 ( ) ( ) ( ).15 CV Death.83 ( ) (.71-1.).57 Myocardial Infarction.81 ( ).1.84 ( ) ( ).55 Stroke.82 ( ) ( ) ( ) Ticagrelor better Placebo better An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Bleeding 3-Year KM Event Rate P< P< TIMI Major TIMI Minor Fatal bleeding or ICH ICH Ticagrelor 9 mg Ticagrelor 6 mg Placebo P=NS P=NS P=NS Fatal Bleeding An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

56 RECENTLY COMPLETED TRIALS REVEAL: Design LDL-C HDL-C 61 mg/dl 4 mg/dl REVEAL randomized 3,449 subjects with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy to receive either 1 mg of anacetrapib once daily or placebo. Anacetrapib significantly reduced the risk of coronary death, MI, or coronary revascularization by 9%. Primary outcome: Major coronary events (Coronary death, myocardial infarction, or coronary revascularization) Participants with Event (%) Anacetrapib Placebo 164 (1.8%) 183 (11.8%) Rate ratio.91 (.85 to.97) P=.4 Placebo Anacetrapib Years offollow up

57 RECENTLY COMPLETED TRIALS Proportional reduction in Coronary death or MI vs. absolute reduction in non HDL cholesterol (derived from published CTT meta analysis) Proportional risk reduction 35% 3% 25% 2% 15% 1% 5% % REVEAL More vs. less 22 mg/dl red n (5 trials) Statin vs. control <5 mg/dl red n (17 trials) Absolute reduction in non HDL cholesterol (mg/dl) Statin vs. control >5 mg/dl red n (4 trials) Major coronary events, by year Year of first event Anacetrapib Placebo (N=15225) (N=15224) no. of participants with events (%) Rate Ratio (95% CI) P Value (3.1) 476 (3.1).98 ( ) (2.7) 414 (2.8).96 ( ) 3 37 (2.6) 427 (3.).86 (.75.99) (3.) 486 (3.7).83 (.73.94) > (8.) 1327 (9.1).88 (.81.95).1 All 164 (1.8) 183 (11.8).91 (.85.97) Anacetrapib Better Placebo Better Test for trend across yearsχ ²=4.87 (p=.3) Test for heterogeneity between 1 year and >1 yearχ ² =. 182 (p=.18)

58 RECENTLY COMPLETED TRIALS 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 7 mg/dl or non-hdl-c 1 mg/dl Evolocumab SC 14 mg Q2W or 42 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J 216;173:94-11 FOURIER randomized 27,564 patients with atherosclerotic cardiovascular disease and LDL-C of 7 mg/dl or above who were receiving statin therapy to receive evolocumab or placebo. Evolocumab lowered LDL-C by 59% to a median LDL-C of 3 mg/dl and significantly reduced the risk of the primary endpoint by 15%.

59 RECENTLY COMPLETED TRIALS LDL Cholesterol 1 9 Placebo , 5., Cohort of 11,77 patients who had all measurements through 12 weeks did not discontinue study drug did not ti concomitant background lipid-lowering Rx Evolocumab Similar data out to 4 years in OSLER-1 (JAMA Cardio/ogyonline) Weeks f Primary Endpoint f ouner ' NJJ r,. WIil 16% 14% - 12% <IJ Ct: % Ul -U o 8% -E <{ ro :::, <IJ... 6% Cl >... u g- 4% Hazard ratio.85 (95% Cl, ) P<.1 Placebo Evolocumab 14.6% 12.6% 2% % Months from Randomization 36

60 RECENTLY COMPLETED TRIALS Key Secondary Endpoint f ouner ' NJJ r,. WIil a, 1% 9% 8% 7% Hazard ratio.8 (95% Cl, ) P<.1 Placebo 9.9% 7.9% a, > u 6% 5% 4% 3% 2% 1% Evolocumab % Months from Randomization Landmark Analysis f ir 8% 6% e ti> 4% 8% 16% RRR 25% RRR HR.84 (95%CI ) P=.8 6% 4% HR.75 (95%CI ) P<.1 a, > U 2% :ZO/o Evolocumab Months from Randomization 36

61 RECENTLY COMPLETED TRIALS Trial Design Placebo SC Q2W or QM RANDOMIZED DOUBLE BLIND Evolocumab SC 14 mg Q2W or 42 mg QM 2442 patients screened for EBBINGHAUS 1974 Enrolled (Full Analysis Pop) Median F/U 19.8 months MAJOR EXCLUSIONS 1. Not enrolled in FOURIER 2. >12 wk FOURIER visit 3. H/O dementia, cognitive impairment or other conditions interfering with participation Primary Analysis Cohort (N=124) Baseline cognitive testing on/before 1 st dose of study drug and had f/u cognitive testing post dosing* Additional 77 pts w/ baseline assessment before week 12 visit *Cognitive tests performed at baseline; at 6, 12, 24 months; and end of study An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Giugliano RP et al. Clin Card 217;4:59 65 EBBINGHAUS enrolled 1974 patients with known cardiovascular disease randomized to evolocumab or placebo added to statin therapy and prospectively assessed cognitive function. Evolocumab was not associated with any adverse effect on cognitive function compared with placebo. Furthermore, there was no difference in cognitive function by achieved nadir LDL-C, even less than 25 mg/dl. Primary Endpoint Spatial Working Memory Strategy Index Mean Number of boxes An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Baseline Placebo Post baseline Raw Scores Evolocumab P non-inferiority <.1 Non-inferiority boundary Change Treatment Difference in Z score (Placebo minus Evolocumab) Favors Evolocumab Favors Placebo P NI is from fixed estimate

62 RECENTLY COMPLETED TRIALS LATITUDE-TIMI 6 trial randomized 3,53 patients hospitalized with an acute MI to losmapimod or placebo. Treatment with losmapimod did not reduce the risk of major ischemic cardiovascular events.

63 COMPLETED TRIALS

64 TIMI 1 Patient with Acute ST Elevation MI < 6 hours Streptokinase 1.5 MU / 6 mins Baseline Angio IV Heparin Protocol Design Double-blindblind t-pa 8 mg / 3 hrs TIMI 1 % of Pa atients Primary Outcome Comparison of t-pa and Streptokinase 8 * t-pa * 6 7 SK *P< Angio 1, 2, 3, 45, 6, 75, 9 Mins Reperfusion of occluded arteries Patency at 9 minutes TIMI Study Group, N Engl J Med 1985; 312: TIMI 1 Impact of 9 Minute Patency on Mortality Patent (N=161) Occluded (N=128) Open Artery Theory Weeks from Randomization Dalen JE, Am J Cardiol 1988; 62: TIMI IIA Immediate Invasive: Cath 2 hrs N=195 Primary Endpoint: Pre-D/C EF Acute MI < 4 hours onset IV t-pa Delayed Invasive: Cath hrs N=194 Pre-D/C Angio and RVG 6 week ETT / RVG Follow-up 1 year Protocol Design Randomize Conservative: Cath if +ETT or ischemia N=197 TIMI IIA Management Strategy Immediate PTCA vs. Delayed Invasive vs. Conservative Strategy post Thrombolysis Patency at Discharge (%) h h Cons. TIMI IIA Investigators, JAMA 1988; 26: Rogers WJ, Circulation 199;81: TIMI IIA Management Strategy Immediate PTCA vs. Delayed Invasive vs. Conservative Strategy post Thrombolysis Death or MI by 6 weeks (%) h h Cons. TIMI IIA Investigators, JAMA 1988; 26: Rogers WJ, Circulation 199; 81:

65 TIMI IIB Invasive: Cath hrs Revasc if feasible Primary Endpoint: Death or MI Acute MI < 4 hours onset IV t-pa Heparin, ASA Pre-D/C ETT / RVG 6 week ETT / RVG Follow-up 1 year Protocol Design Randomize Conservative: Cath if +ETT or ischemia Management Strategy TIMI IIB Conservative vs. Delayed Invasive Death or MI to 1 Year Conservative Invasive P=NS Weeks 15.2% 14.7% PTCA or CABG to 1 Year Invasive Conservative *P< Weeks 72.2% 35.5%* TIMI Study Group, N Engl J Med 1989; 32: Williams DO, Circulation 1992; 85: TIMI IIB 'Death/MI Cost Implications of Invasive Strategy Invasive Conservative PTCA or CABG Cath 1 Pts Management Strategy 37 Caths saved 4 PTCAs saved $3 per Cath $4 per PTCA $3,2, saved With no difference in outcome Williams DO, Circulation 1992; 85: TIMI IIB Adjunctive Therapy IV Beta-Blockade Following Thrombolysis Reinfarction (%) Recurrent Ischemia (%) 4.5 Late Betablocker 3 P = P = IV Beta-blocker 1 5 Late Betablocker Roberts R, Circulation 1991; 83: IV Beta-blocker TIMI IIIA 391 Patients with Unstable Angina / NQWMI t-pa.8 mg/kg over 9 mins Primary Endpoint: Death, MI, Positive ETT 6 weeks IV Heparin, (ASA), Beta-blockers, Nitrates, Ca ++ blockers Baseline Angio Randomize Angio hrs Follow-up 6 weeks Protocol Design Angio Exclusion: no CAD or LMain Placebo TIMI IIIA Investigators, Circulation 1993; 87:38-52 TIMI IIIA BASELINE ANGIORAPHY: Effects of tpa on Coronary Lesions Apparent thrombus 35% ANGIORAPHY AFTER tpa: Possible thrombus 3% Primary Results No thrombus 35% Improvement in Culprit Lesion: 25% t-pa vs. 19% placebo p=ns TIMI IIIA Investigators, Circulation 1993; 87:38-52

66 TIMI IIIA Primary Results Measurable Improvement Substantial Improvement Measurable Worsening tpa Placebo tpa 5 Placebo P =.25 P =.3 P = tpa 1 Placebo TIMI IIIB Early Invasive: Cath h PTCA/CABG prn 1 o Endpoint Inv-Cons: Death, MI, Positive ETT - 6 weeks Circulation 1994;89: Patients with Unstable Angina / NQWMI ASA, IV Heparin, Beta-blockers, Nitrates, Ca ++ blockers Randomize 2x2 Factorial: t-pa vs. Placebo ETT 6 weeks Follow-up 1 year Protocol Design Early Conservative: ST Holter, ETT Thallium Cath/PTCA if +ischemia 1 o Endpoint t-pa: Death, MI, Rec Isch, + ETT, Thallium or ST Holter TIMI IIIA Investigators, Circulation 1993; 87:38-52 TIMI IIIB Primary Results tpa vs. Placebo in Non-ST Elevation ACS Composite Endpoint Death or MI ICH tpa Placebo tpa Placebo P = NS P =.5 P = tpa.4 Placebo TIMI IIIB Primary Results Early Invasive vs. Conservative Strategy Events at 42d Invasive Conservative pvalue No. Pts Death (%) NS MI (%) NS D/MI/+ETT (%) NS Rehosp Angina (%) <.1 D/MI/Rehosp (%) LOS (days) <.1 # Days rehosp <.1 TIMI IIIB Investigators, Circulation 1994; 89: TIMI IIIB Investigators, Circulation 1994; 89: TIMI IIIB % Mortality at 42 days Troponin I Predicts Mortality in UA/NSTEMI to <.4.4 to <1. 1. to <2. 2. to <5. 5. to <9. > 9. Cardiac Troponin I ng/ml Risk Ratio Results 7.5 TIMI III REGISTRY Protocol Design All consecutive patients admitted with unstable angina were screened. Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable pattern: At rest, accelerating, post MI Exclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedure Patients in specific subgroups defined by gender, race and age were randomly selected for detailed evaluation and follow-up at 6 weeks and 1 year. Antman EM, N Engl J Med 1996; 335:

67 TIMI III REGISTRY Risk Stratification Admission ECG as a prognostic indicator ST deviation _ >.1 mv LBBB Tw change No ECG changes TIMI 4 Pt. with AMI < 6 hrs Protocol Design Death or MI In-Hospital 6 Weeks 1 Year Stone PH, JAMA 1996; 275: Cannon CP, J Am Coll Card 1997; 3:133-4 tpa APSAC Heparin, ASA 9 min Angio hr Angio MIBI scan RVG, MIBI scan Follow-up 6 wks, 1 yr Combination TIMI 4 nts % of Patien Benefit of front-loaded tpa Unsatisfactory Outcome One Year Mortality *P =.6 * tpa APSAC Comb. of Pts) Survival (% o *p=.7 t-pa vs. APSAC p=.13 t-pa vs. Comb. Primary Results Days from Randomization Cannon CP, J Am Coll Card 1994; 24:162-1 t-pa Comb. APSAC TIMI 5 Heparin 5 U Bolus, 1 U/h IV APTT 65-9 secs Pt. with AMI < 6 hrs ASA, tpa 9 min angio hr angio MIBI Scan Day 5-6: RVG, MIBI scan F/U 6 Weeks, 1 yr Hirudin Protocol Design 4 Ascending Hirudin Doses:.15 B,.5 IV.1 B,.1 IV.3 B,.1 IV.6 B,.2 IV TIMI Hirudin vs. Heparin: Angiographic Results TIMI 3 Flow at 9 TIMI 3 Flow at 9 Reocclusion and h Primary Results TIMI 6 Heparin 5 U Bolus, 1 U/h IV APTT 65-9 secs Pt. with AMI < 6 hrs ASA, SK Day 5-6: RVG, MIBI scan Protocol Design Hirudin 3 Ascending Hirudin Doses:.15 B,.5 IV.3 B,.1 IV.6 B,.2 IV Heparin N = 84 Hirudin N = 162 Heparin N = 79 Hirudin N = 157 Heparin N = 6 Hirudin N = 123 F/U 6 Weeks Cannon CP, J Am Coll Card 1994; 23:993-3

68 TIMI 6 ith stable APTT % of Patients wi Adjunctive Therapy Heparin vs. Hirudin and stability of aptt APTT range 3 seconds *p <.1 25* Heparin.15/.5.3/.1.6/.2 Hirudin Dose TIMI 7 Hirulog.2 mg/kg/h Patient with Unstable Angina Hirulog.25 mg/kg/h Randomize ASA Hirulog.5 mg/kg/h 3 Day Follow-up Protocol Design Hirulog 1. mg/kg/h Lee VL, Am J Cardiol 1995; 75:7-13 TIMI 7 Death or MI (% Patients) Primary Results Hirulog in Unstable Angina Low Dose (.2 mg/kg/hr) Higher Doses ( P =.9 P = Hospital Discharge Six Weeks Fuchs J, Circulation 1995;92: TIMI 8 UA/NQMI < 24 hrs ASA Heparin (aptt 5-7s) Protocol Design Hirulog Primary Endpoint: Death or MI Follow-up: 3 days TIMI 8 OR (95 CI):.3 (.6,1.53).33 (.8,1.3) P Fisher Exact : % D/MI through day 14 D/MI through day 3 Primary Results UFH Bivalirudin Antman E, Am Heart J 22;143: TIMI 9A Pt. with AMI < 12 hrs Protocol Design ASA Thrombolytic Therapy (accel tpa or SK) HEPARIN Bolus 5 U Inf 1 U/h 13 u/h >8kg Death, MI, CHF/Shock 96 H Rx aptt 6-9 s 3 days F/U HIRUDIN Bolus.6 mg/kg Inf.2 mg/kg/h Major Bleeding

69 TIMI 9A 1% 8% 6% 4% 2% % Results Major Bleeding by Treatment Group p =.6 p =.3 p = NS Non-ICH Major ICH Heparin Hirudin N = 335 N = 335 Antman E, Circulation 1994;9: TIMI 9B Pt. with AMI < 12 hrs Protocol Design Thrombolytic Therapy (accel tpa or SK) HEPARIN Bolus 5 U Inf 1 U/h Death, MI, CHF/Shock 96 H Rx aptt s 3 days HIRUDIN Bolus.1 mg/kg Inf.1 mg/kg/h Major Bleeding Sample Size =3 pts (Power 9%, a.5, 25% Rx effect) TIMI 9B % 8 Pts Hirudin vs. Heparin with tpa for MI UNSATISFACTORY OUTCOME DEATH + REINFARCTION HIRUDIN HEPARIN Primary Results p=ns Days post randomization Antman E, Circulation 1996; 94: TIMI 9 Registry Fibrinolysis n=55 (6%) All Consecutive Patients with Acute STEMI/ LBBB enrolled at 2 Hospitals in US and Canada In 1994 N=84 Primary PCI n=76 (9%) Protocol Design No Reperfusion n=276 (31%) Use of reperfusion Rx in Patients presenting < 12 hours: 65% 1% 25% Cannon CP, Crit Path Cardiol 22; 1:44-52 TIMI 9 Registry In-Hospital Mortality % 3 way p< % Results 18.9 % Fibrinolysis Primary PTCA No reperfusion therapy n=55 n= 79 n=259 TIMI 1A End Points: Pharmacokinetics Coagulation parameters TIMI grade 3 flow at 9' TIMI frame count Major hemorrhage Allergic Events Pt. with Acute MI < 12h TNK- tpa Bolus ASA + IV Heparin (APTT 55-85) Follow-up Hosp. Discharge to 3 days Protocol Design 8 Ascending TNKtPA Doses 5, 7.5, 1, 15, 2, 3, 4, 5 mg Cannon CP, Crit Path Cardiol 22; 1:44-52

70 TIMI 1A (%) Patients TIMI Flow Grade at 9 Minutes TIMI 3 TIMI 2 29 Primary Results mg 7.5 mg 1 mg 15 mg 2 mg 3 mg 4 mg 5 mg TNK-tPA Dose TIMI 1B t-pa 1 mg Patient with Acute ST Elevation MI < 12 hours TNK-tPA 3mg Randomize TNK-tPA 4mg ASA, IV Heparin Angio 6, 75, 9 Mins 3 Day Follow-up Protocol Design TNK-tPA 5mg* *Stopped early Replaced with 4 mg Cannon CP, Circulation 1997; 95: TIMI 1B % TIMI Flow Grade at 9 Minutes 77% 79% TIMI 3 TIMI 2 Primary Results 88% tpa TNK 3 mg TNK 4 mg TNK 5 mg N = ASSENT I (TIMI 1C) Patient with Acute ST Elevation MI < 12 hours Randomize TNK-tPA TNK-tPA TNK-tPA 3mg 4mg 5mg* ASA, IV Heparin 3 Day Follow-up Protocol Design *Stopped early Replaced with 4 mg Cannon CP, Circulation 1998; 98: ASSENT I (TIMI 1C) Primary Results TIMI 1 B /ASSENT I (TIMI 1C) Adjunctive Therapy ents % of Patie Incidence of Stroke at 3 Days 3 mg TNK, n=1,75 4 mg TNK, n=1,457 5 mg TNK, n= % of Pa atients ICH Pre/post Reduction in Heparin 2.8 Pre Post p = p = p =.1.8 Total Stroke ICH Ischemic Stroke. TNK 3 tpa Either Van de Werf F, Am Heart J 1999; 137: Giugliano RP, Am Heart J 21; 141:742-5

71 TIMI 11A Dose 1 N=32 Dose 2 N=39 IV Bolus 3 mg Hospital Phase Wgt Adj 1.25 mg/kg Q 12 h (2-8d) Protocol Design Dose-ranging trial of enoxaparin for patients with UA/NQMI 3 mg Total Rx Period = 14 days 1. mg/kg Q 12 h (2-8d) Home Rx Fixed Dose < 65 kg > 65 kg 4 mg 6 mg Q12 h < 65 kg > 65 kg 4 mg 6 mg Q12 h TIMI 11A 1 % % Spontaneous Instrumented Primary Results Incidence of Major Hemorrhage thru 14 days 1.9% Dose Tier 1 Dose Tier 2 N=321 N= mg/kg 1. mg/kg 3.2% T3B Hep + Plac N=735 TIMI 11A Investigators, J Am Coll Card 1997; 29: TIMI 11B UFH iv > 72 h Placebo sc Death, MI, Severe Rec Isch Requiring Urgent Revasc Pt. with UA/NQMI < 24 h ASA Acute = Day 8 Chronic = Day 43 Major Bleeding Serious AEs Protocol Design ENOX iv-b,sc ENOX sc TIMI 11B % Primary Results Death/MI/Urgent Revascularization at 14 Days UFH ENOX 16.7 % 14.5 % 12.4 % P=.48 RRR 15 % 14.2 % P=.29 RRR 15 % Days Antman E, Circulation 1999; 1: TIMI 11B Primary Results TIMI 12 Protocol Design % Pts Death/MI/Urgent Revascularization at 72 hours UFH ENOX 7.3 % 5.5 % Hours from Randomization RRR 23.8% P=.29 Log rank Sibrafiban 3 mg bid 15 pts/dose 1 o End Point: % Inhibition of ADPinduced Plt aggregation Patients 1-7 days post-acs Sibrafiban 5 mg qd Sibrafiban 5 mg bid Plt. Aggreg. / PK samples, 2, 4, 6, 9, 24 h Follow-up visit Day 7 Phone Contact Day 14, 21 Plt. Aggreg. / PK samples, 2, 4, 6, 9, 24, 36 h Sibrafiban 1 mg qd Additional Doses: 7 mg bid 15 mg qd 1 mg bid Antman E, Circulation 1999; 1: Cannon CP, Circulation 1998; 97:34-49

72 TIMI 12 ibition (ADP) Mean % inh D1 D28 Primary Results Inhibition of Platelet Aggregation by Dose Grp mg bid 5 mg bid 7 mg bid 1 mg bid Hours post-dose Cannon CP, Circulation 1998; 97:34-49 TIMI 14 No Abciximab ST, lytic eligible, < 12 h Protocol Design Abx: bolus.25 mg/kg inf.125 g/kg/min x 12 h Group I Group II Group III Group IV tpa < 1 mg vs dose tpa dose SK No lytic Group V rpa 1+1U STD Heparin (7 U/kg ; 15 U/kg/h) vs Group VI dose rpa Low Dose Heparin (6 U/kg ; 7 U/kg/h) Angio (9 min), In Hospital Events, 3 day F/U TIMI 14 tients % of Pat Min 9 Min 57 Primary Results Speed and Extent of Thrombolysis: TIMI 3 Flow 45 tpa tpa + Abciximab mg bolus bolus + 3 min infusion 2 2 Trend, p < bolus + 6 min infusion Antman E, Circulation 1999; 99: TIMI 14 % Patie ents ctfc TIMI Frame Count at 9 Min Median tpa 5 (15b/35inf) + Abx 28 Normal Flow ctfc < 28 P= Corrected TIMI Frame Count Efficacy Results tpa 1 mg 36 SK + Abx 45 Abx 1 Antman E, Circulation 1999; 99: TIMI 15A ACS within -48h various Doses Protocol Design/Primary Results Safety and pharmacokinetics of various doses of the IV GP IIb/IIIa inhibitor RPR PK/PD at, 2m, 1-4h QD, pre-stop, 2-4h & 8-24h post stop Clinical f/u at 14d % IPA Mean Inhibition of Platelet Aggregation 12.8 ug/kg/min : N=13.6 ug/kg/min : N= ug/kg/min : N=2.4 ug/kg/min : N= ug/kg/min : N= h 24h 48-96h Pre-stop 2-4h post 8-16h post 17-24h post TIMI 15B ACS within -72h IV then oral RPR (3 doses) Safety and pharmacokinetics of the GP IIb/IIIa inhibitor RPR given IV and orally IV then oral placebo Treatment for 4 wks %Inhibibition of Platelet Aggre egation Protocol Design/Primary Results Percent Platelet Inhibition placebo (n=24) 1/.5 (n=52) 1/.4 (n=23) 175 BID (n=14) 2 BID (n=12) 15 TID (n=9) 25 BID (n=9) 3 BID (n=1) 2 TID (n=5) 1-3h end IV 2-4h predose 4h post 7-8h pre- post post dose IV Infusion Day 7, Oral Day 28, Oral Giugliano RP, Am Heart J 2; 14:81-93 Giugliano RP, Am Heart J 2; 14:81-93

73 OPUS - TIMI 16 Protocol Design OPUS - TIMI 16 Results Patient with Unstable Coronary Syndrome <72 hours ASA mg daily Orbofiban Orbo 5 mg BID x 3 days 5 mg BID then Orbo 3 mg BID Primary endpoint to 3 days + follow-up Death, MI Urgent Revasc, Ischemia -> Rehosp, or Stroke IV heparin, other med, Cath, PTCR, and CABG at the discretion of the treating physician Follow-up visits Day 14, Day 3 Follow-up visit every 3 months Randomize 1:1:1 Placebo BID r Percentage Kaplan-Meie Composite Endpoint Time (days) placebo 5-3mg 5-5mg r Percentage Kaplan-Meie Mortality Time (days) placebo 5-3mg 5-5mg Cannon CP, Circulation 2; 12: INTIME 2 - TIMI 17 Protocol Design INTIME 2 - TIMI 17 Primary Results ST Elev MI < 6 h Lanoteplase vs tpa: 3 Day Mortality lanoteplase 12 KU/kg ASA 2 : 1 Heparin (aptt 5-7s) accel tpa < 1 mg/9 min Primary Endpoint: All Cause Mortality (3 days) Follow-up: 3 days, 6 months, 12 months ents % Patie N = 15, 78 24hr Mortality tpa: 2.49% npa: 2.39% 3 Day Mortality tpa: 6.6% npa: 6.77% npa tpa Time (days) InTIME-II Investigators, Eur Heart J 2; 21: TACTICS - TIMI 18 Protocol Design TACTICS - TIMI 18 Primary Results UA/ NQWMI ASA, Hep, TIROFIBAN Early Invasive Early Conservative Angio Medical Rx PTCA/CABG Medical Rx +ischemia ETT Cath/PTCA/CABG Chest pain Randomize -24 hrs Hour 4-48 hrs 18 hrs Cannon CP, Am J Cardiol 1998; 82: Endpoint s 6 mos % Pat tients Death, MI, Rehosp for ACS at 6 Months CONS INV Time (months) 19.4% 15.9% O.R.78 95% CI (.62,.97) p=.25 Cannon CP, N Engl J Med 21; 344:

74 (% %) TACTICS - TIMI 18 Death, MI, Rehosp ACS at 6 Months 14.8 CONS p=ns 16.7 INV 24.2 Troponin T Substudy * 14.8 OR=.55 *p<.1 Interaction P=.13 TACTICS - TIMI 18 Overall sample ST-changes Cost-Effectiveness Based on In-Trial Data CE ratio Costs Death/MI $ per % % (I-C) (C-I) Death/MI Dominant Dominated averted $586 $ $17,758 $12, Results No ST-changes $48.12 $4, N= Troponin T.1 $1,91.42 $24, TnT - TnT + TnT cut point =.1 ng/ml (54% of Pts TnT +) Morrow DA, JAMA 21; 286: Troponin T <.1 $61.16 $3, Mahoney EM, JAMA 22; 288: ER - TIMI 19 Protocol Design ER - TIMI 19 Results Interventional Procedure + Abciximab prn Pre-hospital Administration of rpa in ST Elevation MI Acute MI Suspected 12 lead ECG Lytic Approved ( Medical Control) if transport >3 min, 2nd bolus of Reteplase in ambulance Reteplase 1 U in ambulance Evaluation upon arrival in ED Lysis 2nd bolus of Reteplase 1U Medical Therapy (no further lysis, no PTCA) Ambulance Arrival CONTROL GROUP N = 598 STUDY GROUP N = 39 Data = median times (Q1 - Q3) ED Arrival 62 min (47-85) TIME SAVED In-hospital Lytic 31 min 31 min p <.1* (24-37) rpa *Adjusted for any effect of Bolus site and interaction Morrow DA, J Am Coll Cardiol 22; 4:71-77 INTEGRITI TIMI 2 Protocol Design INTEGRITI TIMI 2 Results 6 Minute Flow Control Full-dose TNK-tPA (.5 mg/kg) No Eptifibatide STEMI within 6 hrs ASA Experimental TNK-tPA: 5-1% std dose Eptifibatide: Bolus #1: 18 mg/kg Bolus #2: 9 mg/kg Infusion: 2. mg/kg/m % Pts Dose Confirmation P=.17 P= Dose Finding + Confirmation 89 TIMI 2 Flow TIMI 3 Flow 62 STD Heparin Low Dose Heparin 6 minutes: TIMI flow ST-resolution, serum markers N= TNK 5% TNK + 5% TNK + ept 18/18 ept 18/18 Giugliano RP, J Am Coll Cardiol 23; 41:1251-6

75 INTEGRITI TIMI 2 Angiographic & ECG Results at 6 Minutes A2Z TIMI 21 Protocol Design 1 Tenecteplase monotherapy High Risk ACS (ST / or + Marker) Receiving Tirofiban A Phase 8 6 % pts Eptifibatide (18/2/18) + 5% TNK (Dose Finding and Dose Confirmation) Enoxaparin Death, MI, refractory ischemia at 7 days If clinically i ll stable and not low-risk Z Phase UF Heparin 2 N: TFG TMPG Complete ST Res Trifecta Giugliano RP, J Am Coll Cardiol 23; 41: Aggressive simvastatin 4 mg/day x 3 d 8 mg day thereafter Standard therapy Placebo and diet x 4 months simvastatin 2 mg/day thereafter 1 year follow-up: CV death, MI, rehospitalization for ACS Blazing JA, Am Heart J 21; 142: A2Z TIMI 21 Results A Phase A2Z TIMI 21 Results Z Phase s (%) Event Rates Primary Endpoint - Death, MI and Refractory Ischemia 9.4% (184 events) UFH Enoxaparin 8.4% %(169 events) HR.89 (.72,1.9) prespecified non-inferiority margin met 7 Day Days From Randomization Blazing JA, JAMA 24; 292:55-64 KM Rate (%) Primary Endpoint Composite of Death, MI and Refractory Ischemia Placebo/Simva 2 Rate = 16.7% Simvastatin 4/8 Rate = 14.4% HR.89, CI p = Month from Randomization De Lemos J, JAMA 24; 292: PROVE IT - TIMI 22 Protocol Design PROVE IT - TIMI 22 Lipid Results Patients stabilized post ACS <1d Total cholesterol <24 mg/dl (N=4) Pravastatin 4 mg qd Gatifoxacin 4 mg qd x 1d/mo ASA & standard medical therapy Placebo 2x2 factorial design Follow-up visit day 15 Placebo Atorvastatin 8 mg qd Follow-up visit day 3 then q4 months (average 2 years, minimum 18 months) Gatifoxacin 4 mg qd x 1d/mo 1 o Endpoint: death, MI, stroke, rehosp for UA, revasc* * Revascularization includes only procedures occurring > 3d post randomization Cannon CP, Am Heart J 22; 89:86-61 DL-C L Changes in LDL 21% 49% Pravastatin 4mg Atorvastatin 8mg P<.1 2 <24h Rand. 3 Days 4 Mos. 8 Mos. 16 Mos. Final Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline Median LDL-C (Q1, Q3) 95 mg/dl (79, 113) 62 mg/dl (5, 79) Cannon CP, N Engl J Med 24; 35:1495-4

76 PROVE IT - TIMI 22 Lipid Results PROVE IT - TIMI 22 Lipid Results with events Percent patients DEATH, NON-FATAL MI, OR URGENT REVASCULARIZATION Pravastatin 4 mg 16.7% RRR 25% P=.4 Atorvastatin 8 mg 12.9% Months of Follow-up Cannon CP, N Engl J Med 24; 35: with events Percent patients DEATH, NON-FATAL MI, OR URGENT REVASCULARIZATION AT 3 DAYS Hazard Ratio =.67 p =.4 Pravastatin 4 mg Atorvastatin 8 mg Days of Follow-up Cannon CP, N Engl J Med 24; 35: PROVE IT - TIMI 22 Lipid Results PROVE IT - TIMI 22 Lipid Results g/l) Median hscrp (mg 1 Median C-reactive protein (hscrp) levels by treatment 1 1 p=.6 Pravastatin 4mg (n=1873) Atorvastatin 8mg (n=1872) p<.1 p<.1 p<.1 Randomization 3 days 12 days Study end Ridker PM, J Am Coll Cardiol 25; 45: tio Odds Rat Risk of Death or MI after Day 3 pravastatin 4mg atorvastatin 8mg Quintiles of hscrp at day 3 P=.5 for prava P=.6 for atorva Ridker PM, J Am Coll Cardiol 25; 45: PROVE IT - TIMI 22 Antibiotic Results ENTIRE TIMI 23 Protocol Design %with Event Death from Any Cause or a Major CV Event Placebo (25.1%) Gatifloxacin (23.7%) TIMI 23 ST Standard Reperfusion: Full Dose TNK MI < 6h ASA Combination Reperfusion: Abx + dose TNK 1 5 5% RR (P =.41) Months of Follow-up Cannon CP, N Engl J Med 25; 352: Group : A B C Low dose DLow dose UFH ENOX ENOX UFH Primary Endpoint: TIMI 3 Flow at 6 min Secondary Endpoints: ST Resolution, Clin. Events, a-xa, IPA

77 ENTIRE TIMI 23 Results ENTIRE TIMI 23 Results % Pts TIMI 2 and 3 Flow at 6 minutes 1 FULL Dose TNK HALF Dose TNK + Abx UFH ENOX TIMI 2 Flow TIMI 3 Flow 2 UFH ENOX UFH ENOX N = Angio Evaluable Patients Antman EM, Circulation 22; 15: ts % P 2 15 FULL Dose TNK 15.9 Death and MI at 3 days P=.5 HALF Dose TNK + Abx P= MI Death UFH ENOX UFH ENOX N = All Treated Population UFH P=.2 P= ENOX Antman EM, Circulation 22; 15: FASTER - TIMI 24 Protocol Design FASTER - TIMI 24 Results ST Elevation MI < 6 h ASA TNK-tPA.53 mg/kg Tirofiban bolus + infusion (1 to 15 µg/kg).15 µg/kg/min STD Heparin TNK-tPA dose Low Dose Heparin Primary Endpoint Part A (Dose Finding): TIMI 3 Flow at 6 min Primary Endpoint Part B (Dose Confirmation): ST segment resolution at 6 min Ohman EM. International Symposium on Thrombolysis and Interventional Therapy in AMI. 22 % Pts TIMI Flow at 6 min TIMI 3 TIMI TNK 5% TNK + Tirof *Corrected for multiple events All TNK +Tirof % Pts 1.4%* 11.9%* 11.9%* 15 N= d Death, MI, Urgent Revasc TNK 5% TNK + Tirof All TNK +Tirof Urgent Revasc MI Death Ohman EM, Am Hear J 25; 15:79-88 EXTRACT TIMI 25 STEMI < 6 h Lytic eligible ASA ENOX < 75 y: 3 mg IV bolus SC 1. mg / kg q 12 h (Hosp DC) 75 y: No bolus SC.75 mg / kg q 12 h (Hosp DC) CrCl < 3: 1. mg / kg q 24 h Lytic choice by MD (TNK, tpa, rpa, SK) Double-blind, double-dummy Day 3 1 Efficacy Endpoint: Death or Nonfatal MI 1 Safety Endpoint: TIMI Major Hemorrhage Protocol Design UFH 6 U / kg bolus (4 U) Inf 12 U / kg / h (1 U / h) Duration: at least 48 h Cont d at MD discretion Antman EM, Am Heart J 25; 149: EXTRACT TIMI 25 Primary Endpoint: Death or non-fatal re-mi by 3 days UFH ENOX % RR =.83 p =.3 Days % Primary Results Main Secondary Endpoint: Death, non-fatal re-mi, urgent revascularization by 3 days Days UFH ENOX RR =.81 p = Antman EM, N Engl J Med 26; 354:

78 SEX Male Female AGE (years) < 75 > 75 INFARCT LOCATIONOther DIABETES PRIOR MI FIBRINOLYTIC TIME TO RX EXTRACT TIMI 25 Anterior No DM DM No Prior MI Prior MI Streptokinase Fibrin-Specific < Median > Median OVERALL 2,479 RRR (%) ARD All Interaction Tests P = NS P < Results ENOX Better Relative Risk UFH Better Antman EM, N Engl J Med 26; 354: % Eve ents EXTRACT TIMI 25 UFH ENOX ARD.7% RR 1.53 Bleeding Endpoints (TIMI) 3 Days ARD.4% RR 1.84 Bleeding Endpoints at 3 Days ARD.4% RR 1.39 ARD.1% RR 1.27 P<.1 P =.1 P =.14 P = Major Bleed (Total).8.4 Fatal Major Bleed Nonfatal Major Bleed.7.8 ICH Antman EM, N Engl J Med 26; 354: EXTRACT TIMI 25 PCI Cohort JUMBO TIMI 26 Protocol Design MI (%) 1 15 Death or 5 Primary Endpoint: Death or Nonfatal MI by 3 days UFH RR.77 p= % ENOX 1.7% Days Gibson CM, J Am Coll Cardiol 27; 49: Parallel Randomization 1 o endpoint: 2 o endpoints: Elective or Urgent PCI with intent to stent ASA 325 mg Major exclusions: Prim PCI for STEMI, L Main > 5%, Target in SVG or Art Conduit, EF < 3% or NYHA CHF II Bleeding Risks, Oral A/C, thienopyridine < 5 d, Rx with PPI Study Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIa Use CS 747 Low dose (Load/ Maintenance) Double-blind CS 747 Intermed dose (Load/ Maintenance) CS 747 Low dose (Load/ Maintenance) Maintenance Rx for 3 days Clopidigrel Loading Dose 3 mg Maint. Dose 75 mg Significant Bleeding (non CABG) bleeding through 3 days Major bleeding (non CABG) through 3 days CV MACE through 3 days Significant bleeding + CV MACE through 3 days JUMBO TIMI 26 Results PROXIMATE -TIMI 27 Protocol Design 1 EP: Significant Non-CABG Bleeding 3 D 5.% 4.% 3.% 2.% 1.%.% R/N Clop. vs Prasugrel 1.2% P =.77 Dose Ranging P= NS 2% 2.% 1.7% 1.5% 1.6% Clop Pras 4/7.5 6/1 6/15 Treatment Group Prasugrel LD/MD 3/254 11/65 3/199 4/2 4/251 Estimate Kaplan-Meier E Time to MACE Death, MI, CTVT, Stroke, and Recurrent Ischemia 1% 8% 6% 4% 2% CLOPIDOGREL PRASUGREL p =.26 % Time since PCI (days) Wiviott SD, Circulation 25;111: Stable CAD Receiving ASA (n = 28) If no safety concerns, proceed to higher dose PROXimal Inhibition of coagulation using a Monclonal Antibody to Tissue factor (Sunol ch36) - TIMI 27 ch36 Bolus Dose # 1 n = 7 ch36 Bolus Dose # 2 n = 7 ch36 Bolus Dose # 3 n = 7 ch36 Bolus Dose # 4 n = 7 Factor VIIa anti-tf Membrane Factor X Measured at multiple time points: ch36 levels Factor Xa activity Hgb/Hct PT/PTT/fibrinogen Platelet count Serum chemistries Human anti-chimeric ab

79 PROXIMATE -TIMI 27 Results CLARITY TIMI 28 Protocol Design Enrolled, N Major bleeding (pts).3 8 Dose Sunol ch Minor bleeding (pts) Spontaneous Provoked Any minor* 1 (13) 2 (25) 2 (25) 2 (5) 1 (25) 3 (75) 2 (5) 2 (5) 6 (86) 1 (14) 6 (86) 3 (1) 1 (33) 3 (1) (Exact CI %) (3, 65%) (19, 99%) (7, 93%) (44,1%) (29,1%) *Provoked bleeds were those that occurred at the site of IV insertion or as the result of minor trauma; all others were classified as spontaneous. Morrow DA, J Am Coll Cardiol 25; 26: Study Drug Open-label clopidogrel per MD in both groups Double-blind, randomized, placebo-controlled trial in 3491 patients, age yrs with STEMI < 12 hours Fibrinolytic, ASA, Heparin randomize Clopidogrel 3 mg + 75 mg qd Coronary Angiogram (2-8 days) Placebo Primary endpoint: Occluded artery (TIMI Flow Grade /1) or D/MI by time of angio 3-day clinical follow-up Sabatine MS, Am Heart J 25; 149: CLARITY TIMI 28 Primary Results CLARITY TIMI 28 Results Occluded Artery or De eath/mi (%) Occluded Artery (or D/MI thru Angio/HD) 36% Odds Reduction 15. Clopidogrel 21.7 n=1752 n=1739 Placebo Odds Ratio.64 (95% CI ) P= Clopidogrel better Placebo better Sabatine MS, N Engl J Med 25; 352: Characteristic Odds Ratio (95% CI) Odds Event Rates (%) Reduction Clopidogrel Placebo OVERALL Age <65 yr yr Gender Male Female Infarct location Anterior Non-anterior Fibrinolytic Fibrin-specific Non-fibrin specific Predominant heparin Low-molecular-weight Unfractionated None Clopidogrel better Placebo better Sabatine MS, N Engl J Med 25; 352: CLARITY TIMI 28 Results CLARITY TIMI 28 Bleeding h endpoint (%) 1 15 Percentage with 5 CV Death, MI, RI Urg Revasc Placebo Odds Ratio.8 (95% CI ) P=.26 Clopidogrel 2% days Sabatine MS, N Engl J Med 25; 352: Outcome Through angiography Clopidogrel (%) Placebo (%) P value TIMI major (Hgb >5 g/dl or ICH) NS TIMI minor (Hgb 3-5 g/dl) NS Intracranial hemorrhage.5.7 NS Through 3 days TIMI major NS In those undergoing CABG NS CABG w/in 5 d of study med NS TIMI minor NS Sabatine MS, N Engl J Med 25; 352:

80 CLARITY TIMI 28 Results PCI Study ADVANCE MI - TIMI 29 Protocol Design 6 8 outcome (%) Percentage with 2 4 CV Death, MI, or Stroke following PCI Placebo N=1739 Clopidogrel N=1752 Adjusted for type of lytic, type of heparin, infarct location, and propensity to undergo PCI. No Pretreatment 6.2% 46% Clopidogrel 3.6% Pretreatment Adj Odds Ratio.54 (95% CI ) P= Days post PCI Sabatine MS, JAMA 25; 294: Combination Rx + Facilitated PCI Eptifibitide + ½ dose TNK Immediate PCI Acute STEMI 3-day Composite Death or CHF GP 2b/3a monotherapy + Direct PCI Eptifibitide + TNK-placebo Immediate PCI Enoxaparin UFH Enoxaparin UFH ADVANCE MI - TIMI 29 Results PROTECT TIMI 3 Protocol Design UA/NSTEMI for PCI of a native coronary artery with either 5 4 1/2 dose TNK Placebo p= Enoxaparin UFH N = 857 1) DM; 2) + Troponin; or 3) ST.5 mm TRANSFER TO CATH LAB, DIAGNOSTIC ANGIOGRAM CONFIRM ELIGIBLE FOR PCI OF CULPRIT IN NATIVE ARTERY % patients p= p= % patients Eptifibatide 18/18 mg/kg + 2 mg/kg/min + UFH 5 U/kg IVB - ACT 2s Eptifibatide 18/18 mg/kg + 2 mg/kg/min + Enoxaparin.5 mg/kg IV Bivalirudin.75 mg/kg IVB mg/kg/h Design Features: Open-label, Randomized (1:1:1), Intention-to-treat Death/CHF TIMI Major bleeding TIMI 3 Flow Death/CHF TIMI Major bleeding TIMI 3 Flow PRIMARY EFFICACY: Coronary Flow Reserve post-pci MAJOR SECONDARY: Duration of Ischemia p-pci to 24h PRIMARY SAFETY: TIMI major bleeding at 48h (or hosp d/c) ADVANCE MI Investigators, Am Heart J 25; 15: PROTECT TIMI 3 Results TIMI 31 Protocol Design eserve Coronary Flow Re Primary Endpoint Post-PCI Coronary Flow Reserve 1.33 EPT (pooled) P= N=516 N=238 BIV inutes) Median Duration (m Secondary Endpoint Duration of Ischemia 36 EPT (pooled) P= N=28 N=15 BIV A Phase II, Open-Label, Multi-Center, Dose Escalation Study to Determine the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BB-1153 in ST Segment Elevation Myocardial Infarction 1mg/kg BB-1153 Patient with Acute ST Elevation MI < 6 hours Randomize (n=21 to 84 depending upon dose finding) 2mg/kg BB mg/kg BB-1153 ASA, IV Heparin Angio 6 Minutes 3 Day Follow-up Death, recurrent MI, recurrent angina 5mg/kg BB o Endpoint: TIMI Grade 3 Flow 2 o Endpoint: ST Resolution (1 & 3 hrs), Pharmacokinetics and Pharmacokinetics Gibson CM, J Am Coll Cardiol 26; 47:

81 TIMI 31 Results ANTHEM TIMI 32 Protocol Design 7% 6% 5% 4% 3% 2% 1% % TFG 3 95% CI TIMI 2 and 3 Flow at 6 Minutes by Dose: ITT Population mg/kg 2 mg/kg 3 mg/kg 5 mg/kg 7.5 mg/kg 1 mg/kg n=7 n=6 n=7 n=15 n=7 n=7 % - 4.2% % - 62.% % - 4.2% 9.5% % % - 62.% 6.2% % TFG 3 TFG 2 Gibson CM, J Thromb Thrombolysis 26; 22:13-21 nste ACS -> Early Catheterization ASA, Glycoprotein IIb/IIIa, clopidogrel Enoxaparin or UFH DOSE RANGING Blinded Randomized 4:1 rnapc2 (n=163) IV bolus q 48h 8 escalating dose groups (1.5, 2, 3, 4, 5, 7.5, 1 mcg/kg) Placebo IV q 48h n = 4 Open Label Heparin De-escalation Phase 2 consecutive panels of 1 mcg/kg rnapc2 1) ½ dose UFH (n=26) 2) No UFH (n=26) Continuous 3-lead ECG for 5-9 days PK and PD : pre-dose, 2-6h, 48h, d7, d42 Hemorrhage, Thrombosis to 7 days Clinical follow-up to 6 months Giugliano RP, Circulation; 112:432 ANTHEM TIMI 32 Results DISPERSE2 DISPERSE 2 TIMI 33 Protocol Design % pts Incidence of Ischemia P =.64 P = P = /34 25/93 9/96 3-way P =.8 placebo rnapc mcg/kg rnapc mcg/kg Giugliano RP, Circulation; 112:432 Onset of chest pain and 48 h maximum to randomization AZD614 9 mg bid AZD mg bid Clopidogrel 75 mg qd Randomization Visit 1 Visit 2 Visit 3 Visit 4 Follow-up Day 1 Week 4 Week 8 Week 12 Final Visit +7 days DISPERSE2 was a double-blind, double-dummy, parallel-group, randomized dose-confirmation and feasibility study of AZD614 in addition to standard therapy with aspirin (75 1 mg qd) compared with clopidogrel combined with aspirin Treatment period was 4 12 weeks, with assessments at Weeks 4, 8, and 12, and a follow-up telephone call 7 days after the last visit 5% of patients in each AZD614 arm received a loading dose of 27 mg In the clopidogrel arm, thienopyridine treatment-naive patients received a 3-mg loading dose DISPERSE2 DISPERSE 2 TIMI 33 Results TITAN TIMI 34 Protocol Design 12 1 Primary Endpoint: Total Bleeding 4 Weeks To Follow-up Minor bleeds 12 Major bleeds 1 EARLY ER EPTIFIBATIDE ASA mg po HEPARIN 6 U/kg bolus (Max 4U) and 7U/kg infusion (Max 8 U/hr) RANDOMIZE Open Label STEMI < 6 HRS Undergoing Primary PCI (n=343) CATH LAB EPTIFIBATIDE g % Bleeding EPTIFIBATIDE 18/2./18 /18 TRANSFER TO CATH LAB DIAGNOSTIC ANGIO TRANSFER TO CATH LAB DIAGNOSTIC ANGIO EPTIFIBATIDE 18/2./ AZD614 9mg AZD614 18mg Clopidogrel AZD614 9mg AZD614 18mg Clopidogrel PRIMARY ENDPOINT: Pre PCI TIMI Frame Count Primary PCI Cannon CP, Circulation 25; 112:615

82 TITAN TIMI 34 Results PROMPT TIMI 35 Protocol Design 155 patients referred for ETT to evaluate for CAD STRESS TEST PROtein Markers of Ischemia Using Proteomic Testing STRESS IMAGING REST IMAGING END OF STUDY PARTICIPATION Baseline post test 3 mins 2 hrs 4 hrs 24 hrs Blood draws Evaluate: cardiac biomarkers novel protein, peptide, and metabolite markers of ischemia Gibson CM, Am Heart J 26; 152: PROMPT TIMI 35 Results MERLIN TIMI 36 Protocol Design schemia Myocardial Is None, but sx/ecg s cath Acute Changes in BNP levels in response to ETT Mild / Moderate None P=.31 (IQR ) Severe P=.47 (IQR ) 14.2 (IQR ) P= (IQR ) P=.17 P=.19 for trend N = 656 Ranolazine IV to PO UA/NSTEMI RANDOMIZE (1:1) Double-blind Holter at enrollment x 7d Follow-up Visits: Day 14, Month 4, Q4 Months ETT Month 8 Follow-up Q4 mo (Avg 8-12 mo) Placebo Matched IV/PO Change in BNP (Immed Post vs Pre Test) Final Visit Primary Endpoint: CV death, MI or Recurrent Ischemia Sabatine MS, J Am Coll Cardiol 24; 44: MERLIN TIMI 36 Primary Results MERLIN TIMI 36 Results Primary Endpoint - CV Death, MI, or Recurrent Ischemia 21.8% for Ranolazine vs. 23.5% for Placebo HR.92 (95% CI.83 to 1.2), P =.11 CV Death or MI (%) Placebo 1.5%* Ranolazine 1.4%* HR.92 (95% CI.83 to 1.2) P= Days from Randomization *KM Cumulative Incidence (%) at 12 months Recurrent Ischemia (%) Placebo 16.1%* (N=3,281) Days from Randomization Ranolazine 13.9%* (N=3,279) 5 HR.87 (95% CI.76 to.99) P = Morrow DA et al, JAMA 27;297(16): Ventricular Arrhythmias Ranolazine Placebo 8% 1% p<.1 p<.1 8.3% 61% 8% 6% p<.1 52% 6% 5.7% 5.3% 4% p<.1 3% 4% 3.5% p<.1 21% 2.5% p=.7 2% 2% 1.3% 1.3%.9% % % > 3 > 4 > 8 > 1 > 15 > 2 Duration (in beats) of Ventricular Tachycardia Scirica BM, Circulation 27; 116:

83 MERLIN TIMI 36 Results TIMI 37A Protocol Design Effect of Ranolazine on HbA1c in Patients with DM 2% % P <.1 % 7% 6% 5% 4% 3% 2% 1% % 51% 41% Ranolazine (N=77) 37% P < Placebo (N=77) 14.2 Failure to Achieve HbA1c <7% Worsening Hyperglycemia* at 4 months *KM Cumulative Inc. of 1% in HbA1c at 12 months Morrow DA, Circulation 27; 116:II_539-II_54 Dose-ranging trial of the PARP inhibitor INO-11 to reperfusion injury STEMI within 12h w/ planned 1 PCI ASA Standard Rx N = 4 INO-11* RANDOMIZE (3:1) CONTROL IVB x 1 Single-blind IVB x 1 *Dose Escalation Dose #1 x 1 (N = 1) Dose #2 x 1 (N = 1) Dose #3 x 1 (N = 1) Primary PCI Samples for PK/PD/Biomarkers F/U at 14 & 3 days Endpoints/Measures Pharmacokinetics Pharmacodynamics CK-MB, ctn, BNP Death/CHF/dysrhythmia TIMI 37A Results TITAN TRITON TIMI 38 Protocol Design 12 PARP ac ctivity (%) ACS (STEMI or UA/NSTEMI) & Planned PCI PRASUGREL ASA Double-blind Median duration of therapy - 12 months N= 13,68 CLOPIDOGREL hr 6 hr 12 hr 24 hr hr 6 hr 12 hr 24 hr hr 6 hr 12 hr 2 mg 4 mg 8 mg Dose INO hr Morrow DA, J Thromb Thrombolysis. 28 Jun 6 Epub 1 o endpoint: 2 o endpoints: CV death, MI, Stroke CV death, MI, Stroke, Re-ischemia CV death, MI, UTVR TITAN TRITON TIMI 38 Results TITAN TRITON TIMI 38 Results Endp point (%) o EP: CV Death / MI / Stroke TIMI Major NonCABG Bleeds Clopidogrel 12.1 Prasugrel Prasugrel Clopidogrel Days HR.81 (.73-.9) P=.4 HR 1.32 ( ) P=.3 Wiviott SD, NEJM 27; 357:21-15 CV Death, MI, Stroke CV Death Nonfatal MI Nonfatal Stroke utvr Stent Thrombosis.5 Clopidogrel Prasugrel Better 1 Clopidogrel Better HR Prasugrel HR All Cause Mortality Wiviott SD, NEJM 27; 357:21-15

84 TITAN TRITON TIMI 38 Results TITAN EARLY ACS (TIMI 39) Protocol Design % of Subjects Definite/Probable Stent Thrombosis (N=12844) CLOPIDOGREL PRASUGREL 2.35% 52% HR.48 [ ].64] P< % n~1, > 2 of the following: 1. MB or Tn 2. New STD > 1mm 3. Age > 6* *Age 5-54 with hx of CAD & either MB or Tn or new STD can be enrolled Eptifibatide tid 18/2/18 Matching Placebo Angiography > 12 Hrs Later Optional Study Drug in Cath Lab Blinded Placebo / Eptifibatide DAYS Primary Endpoint: D/MI/UR/TBO at 96h Secondary Endpoint: D/MI at 3 days Wiviott SD, Lancet 28; 371: EARLY ACS (TIMI 39) Results PLATO A Study of PLATelet inhibition and Patient Outcomes Invasive Results 15% 1% 5% % OR.92 (.8, 1.6) P =.23 1.% 9.3% OR.89 (.79, 1.1) P = % 11.2% Delayed Provisional Early Routine OR 1.75 (1.43, 2.13) P <.1 3.4% 5.7% N = 4684 N = 4722 N = 4684 N = 4722 N = 4643 N = 4686 D/MI/RI->UR/TBO D/MI at 3d TIMI Major/Minor at 96h Bleeding at 12h Giugliano RP et al. Giugliano NEJMet al. 29;36: NEJM ated rate (% per year) K-M estima No. at risk Clopidogrel Ticagrelor ,676 6,732 Time to first 1 endpoint in pts intended to undergo an invasive strategy 6,129 6,236 Days after randomisation 6,34 6,134 5,881 5,972 4,815 4,889 Clopidogrel Ticagrelor HR.84 (95% CI.75.94), p= ,68 3, % 9% 2,965 3,48 Cannon CP et al. Lancet 21;375: PLATO A Study of PLATelet inhibition and Patient Outcomes Ticagrelor (n=4,949) Clopidogrel (n=4,928) Stent Thrombosis HR (95% CI) p value 42 Aspirin + clopidogrel SEPIA-ACS TIMI 42 Protocol Design Dose Ranging Study of Otamixaban - a Novel, Intravenous, Direct Xa Inhibitor Mod-to-High Risk NSTE ACS w/ Planned Early Inv Strategy at randomization R Stent thrombosis, n (%) Definite Probable or definite 62 (1.3) 14 (2.2) 97 (1.9) 142 (3.).64 (.46.88).73 (.57.94).5.1 Bail-out eptifibatide in otamixaban groups if rec. ischemia or thrombotic complic. during PCI Otamix Group 1 (n=45) Otamix Otamix Otamix Otamix UFH + Group 2 Group 3 Group 4 Group 5 Eptifi. (n=45) (n=45) (n=45) (n=45) (n=45) Coronary angiography PCI (Day 1-3) Possible, probable, definite 132 (2.8) 179 (3.8).73 (.59.92) (evaluated in patients with any stent during the study) *Time-at-risk is calculated from first stent insertion in the study or date of randomisation.7 Study drug until end of PCI, as clin. indicated, until Day 4 or hospital d/c, whichever comes first 1 EP: Death, MI, Urgent Revasc, Bail-out IIb/IIIa thru 7 d Day 3 Visit, Day 9 Tel f/up, Day 18 Tel. f/up Cannon CP et al. Lancet 21;375:

85 1 Outcome: Death, MI, Urg Revasc, or Bailout GP IIb/IIIa RR vs UFH (95% CI) thru 7 d (%) Death, MI, Urg Rev, Bailout t SEPIA-ACS TIMI ( ) ( ) ( ).58 ( ) RR.6 (95% CI ) P= OTAM.14 Efficacy Results.69 ( ) 4.3 OTAM n=125 n=676 n=662 n=658 n=671 n=449 mg/kg/hr OTAM.35 OTAM.7 OTAM.15 P=.34 for trend across OTAM UFH + eptifi Sabatine MS et al. Lancet 29;374: RR vs UFH (95% CI) thru 7 d (%) Primary Safety Endpoint mg/kg/hr SEPIA-ACS TIMI 42 TIMI Major or Minor Bleed unrelated to CABG (defined as bleed with in Hgb of 3 g/dl or ICH) ( ) ( ) ( ) ( ).61 ( ) 1.6 OTAM.35 P=.1 for trend across OTAM Dose Arms 1.6 OTAM OTAM OTAM.14 Safety Results 5.4 OTAM n=122 n=669 n=651 n=651 n=664 n=448 UFH + eptifi Sabatine MS et al. Lancet 29;374: AVANT GARDE TIMI 43 Protocol Design AVANT GARDE TIMI 43 Results Blinded Therapy Valsartan Patients post ACS with natriuretic peptides Standard Medical Therapy Aliskiren End of Study Ali/Val Dose up-titration over 2 wks Dose up-titration of 2 nd agent over 2 wks (placebo in 3 arms and active in Combo arm) Placebo Stratified by baseline natriuretic peptide N= 11 NT-proBNP 4 wks NT-proBNP 4 wks p=ns for each Rx compared to placebo at wk 4 and 8 P=NS for all active Rx compared to placebo at wk 4 and 8 ANCOVA with Rx, region, gender, index dx, renal fx, B-blocker b/use, prior ACEI/ARBs and DM as factors and B/L level NP as coviarate Primary Endpoint - NT-proBNP from baseline to week 8 NT-proBNP Scirica B et al. Eur Heart J 21;31(16): n = 21 randomized Clopidogrel 6 mg PRINCIPLE TIMI 44 Phase I: Loading Planned Elective PCI Aggregometry and Biomarkers ASA.5 hour post-ld Aggregometry and biomarkers Diagnostic catheterization anatomy suitable for PCI Post cath aggregometry PCI Post-PCI aggregometry, biomarkers Protocol Design Primary Endpoint: Mean IPA (6h) in all treated subjects Additional Platelet Measures, Myonecrosis, Inflammation Clopidogrel-naive Planned GP IIb/IIIa prohibited Prasugrel 6 mg Prasugrel 1 mg x 14d PRINCIPLE TIMI 44 Clopidogrel 15 mg x 14d Phase II: Maintenance PCI 14 d clinical events, biomarkers, aggregometry, CROSSOVER 3 d clinical events, biomarkers, aggregometry Protocol Design Prasugrel 1 mg x 14d Primary Endpoint: Mean IPA (2&4 wks) in all treated subjects Additional Platelet Measures, Inflammation, Clinical Events Clopidogrel 15 mg x 14d

86 M ADP) IPA (%; 2 PRINCIPLE TIMI 44 Results Loading Phase % Achieving IPA 2uM ADP 1 Mean + SD 9 8 Prasugrel 6 mg P<.1 for each 4 Clopidogrel 6 mg Hours Wiviott SD, Circulation 27; 116: M ADP) IPA (%; 2 PRINCIPLE TIMI 44 Results Maintenance Phase Difference Between Treatments: 14.9 [95% CI ], P<.1* 8 n=4 Prasugrel 1 mg Prasugrel 1 mg Clopidogrel 15 mg Clopidogrel 15 mg 2 n=46 1 Mean + SD Days *ANCOVA factors for treatment, phase, order, site, baseline MPA Wiviott SD, Circulation 27; 116: ATLAS ACS TIMI 46 Protocol Design ATLAS ACS TIMI 46 Primary Safety Results N=3,491 PLACEBO NO Recent ACS Patients Stabilized 1-7 Days Post-Index Event MD Decision to Treat with Clopidogrel Dose Levels Stratum 1 5, 1, & 2 mg STRATUM 1 STRATUM 2 RIVA QD 3 Dose Levels Stratum 2 5, 1, 15, & 2 mg RIVA BID 3 Dose Levels PLACEBO Treat for 6 Months Aspirin 75 1 mg YES RIVA QD 3 Dose Levels Primary Safety Endpoint: TIMI Significant Bleeding Primary Efficacy Endpoint: Death, MI, Stroke, or Ischemia Requiring Revascularization RIVA = Rivaroxaban RIVA BID 3 Dose Levels Clinically significant bleeding (%) P trend < Days after start of treatment KM Rates (%) HR 2 mg ( ) 15 mg 1 mg ( ) 3.35 ( ) 5 mg ( ) Placebo 3.3 Reference ATLAS ACS TIMI 46 Primary Efficacy Results re recurrent ischemia larization (%) Death, MI, stroke, or sever requiring revascul HR.79 (95% CI,.6 1.5) P = Placebo 7.% 5.6% Rivaroxaban (combined) stroke (%) Death, MI, or s Days after randomization HR.69 (95% CI,.5.96) P =.3 3 Placebo 5.5% 3.9% 39% Rivaroxaban (combined)

87 ENGAGE AF-TIMI 48 Protocol Design ENGAGE AF-TIMI 48 Results ENGAGE AF-TIMI 48 Results ENGAGE AF-TIMI 48 Results ICE-T-TIMI 49 Results TRA 2 P-TIMI 5 Protocol Design

88 TRA 2 P-TIMI 5 Results TRA 2 P-TIMI 5 Results Morrow et al. ACC 212, Chicago, March 24, 212 TRA 2 P-TIMI 5 Results TRA 2 P-TIMI 5 Results Morrow et al. ACC 212, Chicago, March 24, 212 Morrow et al. ACC 212, Chicago, March 24, 212 TRA 2 P-TIMI 5 Results TRA 2 P-TIMI 5 Results Morrow et al. ACC 212, Chicago, March 24, 212 Morrow et al. ACC 212, Chicago, March 24, 212

89 ATLAS ACS 2-TIMI 51 Protocol Design ATLAS ACS 2-TIMI 51 Results ATLAS ACS 2-TIMI 51 Results ATLAS ACS 2-TIMI 51 Results SOLID-TIMI 52 Protocol Design SOLID-TIMI 52 Results

90 SAVOR-TIMI 53 Protocol Design SAVOR-TIMI 53 Results SAVOR-TIMI 53 Results ELEVATE-TIMI 56 Protocol Design Mega JL et al. JAMA. 211;36: ELEVATE-TIMI 56 Results ELEVATE-TIMI 56 Results

91 LAPLACE-TIMI 57 Protocol Design LAPLACE-TIMI 57 Results Giugliano RP et al. Lancet. 212;38: LAPLACE-TIMI 57 Results LAPLACE-TIMI 57 Results

92 BIBLIOGRAPHY