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9/24/2017

Disclosures Update on Anticoagulation and Research Support North American Thrombosis Forum, McMaster University Reversals for Direct Oral Employee Presbyterian Healthcare Services Consultant and/or New York Hospital Association, Anticoagulation Honoraria Forum, Pharmacy Times, Point of Care Software Solutions, Janssen, Daiichi Sankyo, Boehringer-Ingelheim, Phizer, Bristol-Myers Charles “Kurt” Mahan, PharmD Squibb, Eisai, Polymedix Inc., Leo Pharm., Clinical Assistant Professor of Pharmacy Travel or Conference McMaster University, Presbyterian Healthcare, Support American Society of Health System University of New Mexico Pharmacists, National Quality Forum Cardiac Critical Care Pharmacist Stockholder None Presbyterian Healthcare Services Speakers Bureau Janssen, Boehringer-Ingelheim, , Albuquerque, NM Bristol-Myers Squibb, Portola Scientific Advisory Board Daiichi-Sankyo, Boehringer-Ingelheim, USA Janssen, Phizer, Leo, Eisai, Portola

Objectives The evolution of . Identify Current Direct Anticoagulants and their drugs pharmacokinetic and pharmacodynamic properties 2004 2008/10 2002 . Discuss new DOAC studies and agents in 1990s 1980s Oral direct Oral direct Indirect Xa inhibitor – Extended medical thromboprophylaxis 1940s Xa inhibitor 1930s Direct inhibitors – Coronary/peripheral artery disease Low-molecular- thrombin weight inhibitors – Non-valvular and PCI (cardiac stents) Heparin antagonists – and extended venous thromboembolism treatment Xa . Recognize current and investigational reversal ATIII + Xa IIa ATIII + Xa + IIa IIa agents for DOACs II, VII, IX, X (Xa > IIa) (Protein ATIII + Xa + IIa C,S) (1:1 ratio)

New anticoagulants DOACs: Approved Indications Agent EU US Canada Japan Pegnivacogin TTP889 - halted TF/VIIa TFPI (tifacogin) NVAF, NVAF, NVAF, NVAF, NAPc2 (Xarelto ®) VTE OrtPX, VTE OrtPX, VTE OrtPX, VTE OrtPX, XIX VTE TX, ACS VTE TX VTE TX VTE TX Direct Xa APC () - Rivaroxaban Andexanet Withdrawn from market Apixaban NVAF, NVAF NVAF, NVAF Apixaban reversal IXa (Eliquis ®) VTE OrtPX VTE OrtPX VTE OrtPX VIIIa Recomodulin TB-402 VTE TX Va Betrixaban Under Review Medical N/A N/A AT independent Indirect Xa TAK 442 (Bevyxxa ®) Thrombo- Xa SR123781A -halted Idrabiotaparinux ? prophylaxis -halted Semuloparin AT Dependent DX-9065a -halted M118 NVAF, NVAF NVAF, NVAF II (Pradaxa ®) VTE OrtPX VTE TX VTE OrtPX Idarucizumab Newer Targets Factor IX - Pegnivacogin VTE TX VTE OrtPX reversal Factor XI - ISIS 416858 antisense Edoxaban NVAF NVAF NVAF NVAF IIa oligonucleotide, antibodies, aptamers (Lixiana ®) VTE TX VTE TX VTE TX VTE TX Factor XII – antisense oligonucleotides, VTE OrtPX antibodies, aptamers Dabigatran Fibrinogen ACS = acute coronary syndrome; NVAF = non‐valvular atrial fibrillation; OrtPX = Ortho prophylaxis; 1. Mahan CE, Fanikos J. Thrombosis Research 2011 127 518–524 TX = treatment; VTE = venous thromboembolism 2. Weitz et al. CHEST 2012 Siegal DM, et al. J Thromb 2013; 35: 391-98.

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US Dabigatran Apixaban Rivaroxaban ** Edoxaban Betrixaban Indications of DOACs and Dosage Non-valvular 150 mg PO BID 5 mg PO 20 mg PO daily 60 mg PO daily N/A Dabigatran Rivaroxaban Apixaban Edoxaban Betrixaban atrial 75 mg PO BID* BID 15 mg PO daily* 30 mg PO daily Direct factor fibrillation CrCl <15 2.5 mg PO inhibition IIa Xa Xa Xa Xa mL/min BID* CrCl <15 mL/min CrCl <15 mL/min Onset of Action, Avoid use Avoid use Avoid use minutes < 30 min < 30 min < 30 min < 30 min < 30 min VTE 110 mg x1, then 2.5 mg PO 10 mg PO daily N / A N/A 6% 80% 80% > 50% 50 % prophylaxis 220 mg daily BID CrCl <30 mL/min (Frel) (orthopedic) Avoid use Peak action (tmax) 1–3 hr 1–3 hr 1–3 hr 1–2 hr 3-4 hr VTE 150 mg PO BID 10 mg po 15 mg PO BID x 60 mg PO BID N/A Protein binding 35% 92 – 95% 84% 55% 60% treatment and after 5-10 days BID x 7days 21 days, then 20 after 5-10 days prevention of of parenteral then mg PO daily of parenteral Renal clearance 80% 36% 27% 35 - 39% 5 – 11% recurrence anticoagulation 5 mg PO Ext: 20 mg or 10 anticoagulation Duration of CrCl <30 BID mg? Ext: not studied Action, hours 24 – 36 24 ≥ 24 ≤ 24 ~ 36-48 hrs mL/min Ext: 2.5 mg CrCl <30 mL/min CrCl <30 mL/min Elimination half Avoid use PO BID Avoid use Avoid use life – varying 13.8 - 27.5 hr 8.3 -9.5 hr 15.1 - 17.3 hr 8.6 - 16.9 hrs 19 – 27 hrs renal function VTE N/A N/A Under N/A 160 mg PO x 1 prophylaxis Investigation then 80 mg PO Effect of Food None Increases None None Decreases In acute Results likely in QDay or 80 mg Absorption Absorption medical Summer 2018 PO x 1 then 40 Drug P-GP and P-GP and illness mg Qday *** Interactions P-GP CYP-3A4 CYP-3A4 P-GP P-GP CrCl <15 mL/min Avoid use Antidote Idarucizumab Andexanet Andexanet Andexanet Andexanet * Adjusted for renal impairment, drug interactions, age, low weight or a combination of these factors ** Treatment doses of rivaroxaban should be taken with largest meal of the day 1. Kaatz S, Mahan CE . 2014 Aug;45(8):2497-2505. Epub 2014 Jun 26. Adapted from. *** For CrCl 15-30 mL/min or with concurrent use of strong P-GP Inhibitors – Duration 35-42 days 2. Kaatz S, Mahan CE, et al. Current Cardiology Reports In PRESS 2017

VTE Prevention Medical Patients – 9th ACCP Recommendations Risk Stratification for and VTE then: At‐risk for VTE, Low Bleed Risk 1 . Low molecular weight heparin (LMWH) (1B) . Low dose unfractionated heparin (LDUH) BID or Venous Thromboembolism TID (1B) . Fondaparinux (1B) Prevention in the Medical Patient At‐risk for VTE, High Bleed Risk or actively bleeding 1 . Optimal use of graduated compression stockings (GCS) or intermittent pneumatic compression (IPC) (2C) . When bleeding risk subsides and if VTE risk persists, pharmacologic TP as above. (2B) We suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (2B) Kahn et al. CHEST 2012;141;e195S-e226S

IMPROVE (IMPACT-ILL) RAM for VTE - evidence based derivation VTE Risk Factor Points For the Risk Score Extended-duration DOACs for IMmobilization ≥7 days 1

Previous VTE 3 VTE Prevention in Hospitalized

Age > 60 years 1 Medical Patients: Current cancer 2 EXCLAIM: enoxaparin Thrombophilia 2 ADOPT: apixaban ICU/CCU stay 1 MAGELLAN: rivaroxaban Lower Limb paralysis 2 APEX: betrixaban Three-Tiered Risk Assessment Model 0-1 Points = Low Risk, 2-3 Points = Moderate Risk, ≥ 4 points = High Risk MARINER: rivaroxaban 1. Spyropoulos AC et al., CHEST 2011 Sep;140(3):706-14 2. Mahan CE et al. Thromb Haemost. 2014 Oct;112(4):692-9. doi: 10.1160/TH14-03-0239. Epub 2014 Jul 3. 3. Rosenberg D et al. J Am Heart Assoc. 2014 Nov 17;3(6):e001152. doi: 10.1161/JAHA.114.001152.

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Summary of Extended Med Prevention Trials Completed Extended TP Studies EXCLAIM ADOPT MAGELLAN APEX Enoxaparin Apixaban Rivaroxaban Betrixaban 8% RRR = 24.0% in Medically Ill p = 0.006 7% RRR = 22.8% Extended Duration VTE Prophylaxis: Medically Ill Patients p = 0.02 6% Study Study Conclusion Net Clinical Benefit RRR = 38.0% 5% EXCLAIM – enoxaparin VTE ↓ No p <0.042 N=5,963 Major Bleeding ↑ 4% RRR = 12.9% p = 0.44 7.03% MAGELLaN – rivaroxaban VTE ↓ No 3% VTE VTE Events 5.7% 5.30% N=8,101 Major Bleeding ↑ 2% 4.0% 4.4% Incidence 3.1% 2.7% 1% 2.5% ADOPT – apixaban VTE ↔ No N=6,528 Major Bleeding ↑

MajorBleeding 0% 0.3% 0.2% 0.5% 0.4% -1% 0.57% 0.67% 0.8% 1.1% APEX – betrixaban VTE ↓ Yes N = 7513 Major Bleeding ↔ -2% p<0.05 p=0.04 p<0.001 p=0.55

Enoxaparin Placebo Enoxaparin Apixaban Enoxaparin Rivaroxaban Enoxaparin Betrixaban (n=2485) (n=2510) (n=2284) (n=2211) (n=2967) (n=3057) (n=3174) (n=3112)

Cohen AT, et al. N Engl J Med. 2016; 375:534-44 Cohen AT, et al. N Engl J Med. 2013;368(6):513-23. Goldhaber SZ, et al. N Engl J Med. 2011;365(23):2167-77. Hull RD, et al. Ann Intern Med. 2010;153(1):8-18.

Failures of Earlier Phase 3 Trials Extended Thromboprophylaxis . Not enough benefit WHY would we need Extended- – How do we select an “at risk” subgroup of heterogeneous medical patients that would duration DOACs for VTE benefit from extended thromboprophylaxis? Prevention in Hospitalized Medical Patients? . Too much harm – How do we minimize harm to key patient subgroups, especially given excellent safety profile of LMWH and Placebo?

Hospital Length of Stay has Decreased Over Time in Baseline Dd ROC (MAGELLAN) Countries Targeted for Participation in the Study

Average length of stay in hospital for all causes, 2000 and 2010 (or nearest year) An important Days finding from the 2000 2010 15 Magellan study was that D-dimer 12

may also be used 9.5

9 8.1 as a biomarker or 7.7 7.1 6.8 6.7 6.0 5.8 risk factor for the 5.7 5.7

(McMaster) 6 5.1 development of future VTE in 3 medical patients 0 Italy Spain Poland France Czech United Belgium Sweden Hungary Republic Kingdom Germany Netherlands • Lengths of hospital stay have SIGNIFICANTLY shortened in the last 15-20 years • US averages 3-4 days where original VTE prophylaxis trials were 6-14 days

Cohen A et al. J Thromb Haemost. 2014 Apr;12(4):479-87. doi: 10.1111/jth.12515. Source: OECD Health Data 2012; Eurostat Statistics Database; WHO European Health For All Database.

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Post-Discharge Thromboprophylaxis Shorter Durations in Medical Patients – US Data of Thromboprophylaxis May be Inadequate . N = 141,628 from US claims analysis . Mean/median LOS days (SD) – 5.9/4.0 days . 3.9% received post- discharge TP (92% ) – Hospital Px use did NOT reduce risk of post- discharge VTE (p = 0.398) . Overall Sx VTE at 90 days – 1.9%

May need 35-45 days of thromboprophylaxis in this population Spyropoulos AC et al. Chest. 2011; 10.1378;10-194 Hull RD, et al. Venous thromboembolism in elderly high-risk medical patients: time course of events and influence of risk factors. Clin Appl Thromb Hemost. 2013 Jul-Aug;19(4):357-62. PubMed PMID: 23610237 Mahan et al. Thromb Res 2013;132(5):520-6 .

APEX Design – Target Patients APEX Study Design

HOSPITALIZED FOR ACUTE MEDICAL ILLNESS FOR 3 DAYS , Respiratory Failure, Infectious Disease, Rheumatic Disease, or Ischemic Stroke EXPECTED MODERATE / SEVERE IMMOBILITY Objective Demonstrate the superiority of extended duration (35‐42 days) anticoagulation with betrixaban Expected severe immobilization for 24h during hospitalization and moderate and/or severe compared to standard of care anticoagulation with enoxaparin (6‐14 days) immobilization ≥3 days after admission with anticipated survival of ≥8 weeks

Enoxaparin AGE AND ADDITIONAL VTE RISK FACTORS Placebo Median length of treatment: 9 days 40 mg SC daily Additional Risk Factors:

BLIND DAY 1

SCREENING ‐ R DUMMY ULTRASOUND Final Safety ≥75 years 60 to 74 years 40 to 59 years • Previous VTE or superficial vein ‐ LOADING DOSE AND VISIT 3 Follow‐Up thrombosis 160 mg betrixaban

• History of NYHA Class III or IV HF DOUBLE 2 Additional Risk Factors DOUBLE • 2 Additional Risk OR Concomitant acute infection Betrixaban 80 mg once daily with food Median length of treatment: 36 days • Obesity (BMI >35) Eligible Factors D‐Dimer >2x ULN • History of cancer EXTENDED OR + 1:1 RANDOMIZATION STANDARD • Inherited or acquired thrombophilia PROPHYLAXIS PROPHYLAXIS D‐Dimer >2x ULN History of VTE OR Up to 96h after • Current use of erythropoiesis hospitalization EVALUATION History of Cancer 6-14 35-42 65-77 stimulating agent DAYS DAYS DAYS • Hormone therapy

▸ Patients with CrCl ≥ 15 and < 30 mL/min were included Dosing adjustments: • In severe renal insufficiency (CrCl 15 to <30 mL/min): Betrixaban 40 mg (80 mg loading dose) and enoxaparin 20 mg SC daily ULN: Upper Limit of Normal • In patients taking concomitant strong P-gp inhibitors: Betrixaban 40 mg (80 mg loading dose), no dose adjustment for Cohen AT et al. N Engl J Med. 2016;375:534-44 enoxaparin

APEX Primary Efficacy Endpoint APEX Safety Results: Major Bleeding

mITT population SAFETY (PRIMARY ENDPOINT) MAJOR BLEEDING1 TYPES OF MAJOR BLEEDS PRIMARY COMPOSITE ENDPOINT: VTE at Day 42 * Enoxaparin/Placebo (median 9 days exposure) Enoxaparin Betrixaban Betrixaban (median 36 days exposure) RRR = 25% 8.0% (N= 3716) (N= 3716) ARR=1.6% n (%) n (%) p=0.003 7.0% 7% Major Bleeding 21 (0.57) 25 (0.67) 6.0% NNT=65 6.0% 6% Gastrointestinal 9 (0.24) 19 (0.51) 5.0% 223 / 3720 RR=1.19 Intracranial 5% 4.0% (95% CI 0.67-2.12) 7 (0.19) 2 (0.05) 4.4% Hemorrhage P=0.55 3.0% 4% Intraocular 1 (0.03) 0 (0) 165 / 3721 2.0% 3% Other 4 (0.11) 4 (0.11)

Event Rate Event (%) 1.0% 0.6% 0.7% 2% 21 / 3716 25 / 3716 Fatal Bleeding * 1 (0.03) 1 (0.03) 0.0% Event Rate Rate (%) Event Major Bleeding Other major bleeding includes , pericardial, 1% rectal, epistaxis * One pericardial fatal bleed in the betrixaban group and 0% one ICH fatal bleed in the enoxaparin group Enoxaparin/Placebo Betrixaban  No significant difference in major bleeding with extended duration betrixaban for a median of 36 days vs. standard duration enoxaparin for a median of 9 days

Composite of asymptomatic proximal DVT between day 32 and day 47, symptomatic proximal  Extended duration betrixaban associated with non-significant reduction in rate of intracranial or distal DVT, symptomatic nonfatal PE, or death from vVTEbetween day 1 and day 42. hemorrhage (ICH) vs. standard duration enoxaparin * Asymptomatic DVT measured up to Day 47 Safety Population includes all patients who received active study drug mITT=modified intent-to-treat; RRR=relative risk reduction. 1- Major bleeding is based on ISTH criteria: Schulman et al. T Thromb Haemost 2005;3:692-4

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APEX Rate of Stroke or Post-Hoc Analysis: Transient Ischemic Attack (TIA) Fatal or Irreversible Outcomes SAFETY (SECONDARY SAFETY ENDPOINT) NON‐HEMORRHAGE CARDIOPULMONARY DEATH + NON‐FATAL PE + MI + ISCHEMIC STROKE + FATAL BLEEDING + ICH ALL STROKE OR TIA ISCHEMIC STROKE a 7.0 THROUGH VISIT 3 THROUGH END OF TRIAL 2.00% Enoxaparin/Placebo Betrixaban HR = 0.71 (95% CI: 0.56, 0.91) HR = 0.70 (95% CI: 0.57, 0.88) ARR = 1.53% 1.80% ARR = 1.18% 6.0 NNT = 65 RR=0.59 RR=0.53 NNT = 85 5.17% 1.60% (95% CI 0.35-0.97) (95% CI 0.30-0.94) 1.40% P=0.03 P=0.03 5.0 4.08% p=0.002 1.20% 1.10% 4.0 p=0.006 1.00% 41/3716 0.91% Enoxaparin/ 3.64% 0.80% 34/3716 3.0 Placebo

Event Rate (%) Rate Event 0.65% 0.60% 0.48% 2.90% 24 / 3716 2.0 0.40% 18 / 3716 Probability of Composite Event (%) Event of Composite Probability VISIT 0.20% Betrixaban 1.0 3 0.00% All Stroke or TIA New Ischemic Stroke 0 01020 30 40 50 60 70 . In safety population, extended duration betrixaban reduced risk of ischemic stroke, all Time (Days) aEnd of trial defined as final follow-up , and all strokes or TIA vs. standard duration enoxaparin visit (30 + 5 days after Visit 3).  . There was 1 hemorrhagic stroke in each group Extended duration betrixaban reduced rate of fatal or irreversible events vs. standard duration enoxaparin at visit 3 and through the end of the trial All stroke includes ischemic and hemorrhagic stroke All Randomized Patients Gibson C et al. Circulation. 2016;134:00-00 Gibson CM et al. J Am Heart Assoc. 2017;6:e006015

APEX Net Clinical Benefit APEX Time to Symptomatic VTE Event (PEOP Population) COMPOSITE OF THE PRIMARY EFFICACY OUTCOME EFFICACY (PRE‐SPECIFIED EXPLORATORY ENDPOINT) COMPOSITE OF SYMPTOMATIC PROXIMAL OR DISTAL DVT, (Symptomatic or Asymptomatic VTE*) AND PRIMARY SAFETY OUTCOME NON‐FATAL PE, OR VTE‐RELATED DEATH RR= 0.78 RR= 0.71 (95% CI 0.57-0.89) 3.0 (95% CI 0.65-0.95) P=0.01 P=0.002 THROUGH END OF TRIAL NNT=67 NNT=48 2.5 HR=0.55 8% 7.3% 7.3% Enoxaparin (95% CI: 0.37-0.83) 7% Betrixaban 2.0 1.89% 233 / 3174 188 / 2562 6% 5.8% 5.2% ENOXAPARIN 1.5 P=0.0038 5% 179 / 3112 131 / 2506 4% 1.0 BETRIXABAN 1.02% 3% Event Rate Event Rate (%) 0.5 2%

1% 0.0 Probability of Composite Endpoint (%) 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 0%  Extended duration betrixaban significantly reduced symptomatic VTE vs. standard OVERALL POPULATION 80 MG DAY 42 DAY 42 duration enoxaparin in the overall study population *VTE defined as asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic non-fatal PE, or VTE- aEnd of trial defined as final follow-up visit (30 + 5 days after Visit 3). related death mITT Population Cohort 1: RRR=18% (95% CI 0.66, 1.01; p=0.07); Cohort 2: RRR=18% (95% CI 0.68, 1.00; p=0.05)

HR=hazard ratio; ARR=absolute risk reduction; NNT=number needed to treat. Cohen AT et al. N Engl J Med. 2016;375:534-44 RR=relative risk.

MARINER Study Design: Post-Discharge Focus MARINER – KEY FEATURES SUMMARY

. Use of a post-discharge design to focus on the key clinical question given that the burden of VTE in the acutely ill hospitalized medical patient population is shifting to the post-discharge setting given shortening hospital LOS Acute medical condition plus total . Use of a validated risk scoring tool and biomarker Dd to identify high risk • IMPROVE VTE Risk Score ≥4 • Or total IMPROVE VTE Risk subgroups that has potential to answer a significant unmet clinical need Score of at least 2 or 3 with Dd . Using a 45 day duration of treatment based on recent epidemiolgic data >2X ULN to suggest the period of greatest VTE risk in this population . Decreasing the bleeding risk by delaying randomization until hospital discharge, excluding patients who have had a bleeding event during hospitalization, excluding active cancer subgroups, and lowering the Primary Efficacy Endpoint: Composite of Symptomatic VTE or VTE‐Related dose in patients with moderate renal impairment, as well and several Death other factors that will improve the bleeding profile Use of Rivaroxaban 10 mg or 7.5 mg with CrCl 30‐50 ml/min . Using symptomatic VTE and VTE-related death as the primary efficacy endpoint heightens the importance of clinically relevant endpoints Estimated Sample Size – Event Driven Study assessed compared to prior studies in the field Sample size Placebo RRR Events Power for 2 sided . Results due in late 2018 superiority αlpha 12,000 2.5% 40% 161 90% 5%

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Venous Thromboembolism Treatment

EINSTEIN CHOICE Rivaroxaban Einstein Choice Study Design . In patients without reversible risk factors, the risk of recurrent venous thromboembolism is up to 10% in . Aim: Compare efficacy and safety of rivaroxaban 20 mg or 10 mg with the first year if anticoagulation therapy is stopped1–5 100mg in patients at equipoise regarding the need for continued anticoagulation . Although extended anticoagulation therapy is . Randomized, double-blind, active-comparator, event-driven, superiority effective for the prevention of recurrent venous study thromboembolism,1–5 concerns about bleeding often Rivaroxaban 20 mg od (n=1107) lead to a reluctance to continue anticoagulant Patients with confirmed N=3396 1 month symptomatic DVT/PE Rivaroxaban 10 mg od (n=1127) treatment beyond 6 to 12 months R observation who completed period 6–12 months of Aspirin 100 mg od (n=1131) . Attempts to reduce the risk of bleeding when anticoagulation treatment is extended include the use of lower dose 12-month treatment duration anticoagulant therapy and the use of aspirin in place of an anticoagulant 2,6–8

1. Prandoni P et al, Ann Intern Med 1996;125:1–7; 2. Ridker PM et al, N Engl J Med 2003;348:1425–1434; 3. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510;4. Schulman S et al, N Engl J Med 2013;368:709–718; 5. Agnelli G et al, N Engl J Med 2013;368:699–708; 6. Brighton TA et al, N Engl J Med 2012;367:1979–1987; 7. Becattini C et al, N Engl J Med 2012;366:1959–1967; 8. Kearon C et al, N Engl J Med Weitz JI et al, Thromb Haemost 2015;114:645–650 2003;349:631–639

Einstein Choice Main Study Outcomes Einstein Choice Patient Flow . Efficacy outcomes: – Primary: Composite of symptomatic recurrent fatal or nonfatal VTE and unexplained death where PE cannot be excluded Randomized N=3396 – Symptomatic recurrent VTE, MI, ischemic stroke or systemic 1121 assigned to 1136 assigned to 1139 assigned to rivaroxaban 20 mg rivaroxaban 10 mg aspirin 100 mg – Death from any cause Included in 14 Did not take 9 Did not take 8 Did not take ITT & study medication study medication study medication – Symptomatic recurrent VTE or death from any cause safety analyses – Symptomatic recurrent VTE or in other locations 1107 1127 1131

– Symptomatic recurrent VTE, MI, ischemic stroke or systemic Included in 1046 1063 1069 per-protocol embolism or venous thrombosis in other locations analyses . Safety outcomes 138 prematurely discontinued 143 prematurely discontinued 182 prematurely discontinued study treatment study treatment study treatment – Prinicipal: Major bleeding (ISTH) 8 died 2 died 7 died 14 withdrew consent 17 withdrew consent 16 withdrew consent – Clinically relevant non-major bleeding 3 were lost to follow-up 3 were lost to follow-up 4 were lost to follow-up – Composite of major bleeding and clinically relevant nonmajor bleeding ITT (Intention to treat) : all randomized patients who received at least one dose of study medication – Non-major bleeding associated with study drug interruption for >14 Weitz, Jl et al. N Engl J Med 2017 days Weitz JI et al, Thromb Haemost 2015;114:645–650

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Einstein Choice Prespecified Einstein Choice Prespecified Efficacy Outcomes Safety Outcome Rivaroxaban Rivaroxaban Aspirin HR (95% CI) 20 mg 10 mg 100 mg Rivaroxaban Rivaroxaban Aspirin HR (95% CI); p-value Rivaroxaban Rivaroxaban Rivaroxaban 20 mg 10 mg 100 mg (n=1107) (n=1127) (n=1131) Rivaroxaban Rivaroxaban Rivaroxaban 20 mg vs aspirin 10 mg vs aspirin 20 mg vs 10 mg (n=1107) (n=1127) (n=1131) 20 mg vs aspirin 10 mg vs aspirin 20 mg vs 10 mg 0.34 (0.20–0.59) 0.26 (0.14–0.47) 1.34 (0.65–2.75) Recurrent VTE 17 (1.5) 13 (1.2) 50 (4.4) P<0.001 P<0.001 P=0.42 Major bleeding 6 (0.5) 5 (0.4) 3 (0.3) 2.01 (0.50–8.04) 1.64 (0.39–6.84) 1.23 (0.37–4.03); DVT 9 (0.8) 7 (0.6) 29 (2.6) Fatal, n (%) 1 (0.1) 0 1 (0.1) PE 6 (0.5) 5 (0.4) 19 (1.7) Non-fatal bleeding in PE+DVT 0 1 (0.1) 0 4 (0.4) 2 (0.2) 1 (0.1) a critical site, n (%) Fatal VTE 2 (0.2) 0 2 (0.2) Intracranial, n (%) 3 (0.3) 1 (0.1) 1 (0.1) Recurrent VTE, MI, 0.34 (0.20–0.57) 0.32 (0.19–0.54) 1.08 (0.57–2.06) 19 (1.7) 18 (1.6) 56 (5.0) ischaemic stroke or SE P<0.001 P<0.001 P=0.80 Major or clinically relevant non-major 36 (3.3) 27 (2.4) 23 (2.0) 1.59 (0.94–2.69) 1.16 (0.67–2.03) 1.37 (0.83–2.26) Recurrent VTE, all-cause 0.42 (0.26–0.68) 0.27 (0.15–0.47) 1.57 (0.82–3.00) 23 (2.1) 15 (1.3) 55 (4.9) bleeding mortality P<0.001 P<0.001 P=0.18 Clinically relevant non- 30 (2.7) 22 (2.0) 20 (1.8) 1.53 (0.87–2.69) 1.09 (0.59–2.00) 1.40 (0.81–2.43) Recurrent VTE, venous 0.35 (0.21–0.58) 0.28 (0.16–0.48 1.28 (0.66–2.46) major bleeding 20 (1.8) 16 (1.4) 57 (5.0) thrombosis in other locations P<0.001 P<0.001 P=0.81 Non-major bleeding with Recurrent VTE, MI, study drug interruption 17 (1.5) 12 (1.1) 12 (1.1) 1.44 (0.69–3.02) 0.99 (0.44–2.20) 1.46 (0.70–3.06) ischaemic stroke, SE, 0.35 (0.22–0.57) 0.33 (0.20–0.54) 1.07 (0.59–1.95) 22 (2.0) 21 (1.9) 63 (5.6) ≥14 days venous thrombosis in other P<0.001 P<0.001 P=0.81 locations All P Values are Not Significant HR, hazard ratio; CI, confidence interval; VTE venous thromboembolism; MI, Weitz JI et al, N Engl J Med 2017 myocardial infarction; SE, systemic embolism

Weitz JI et al, N Engl J Med 2017 Weitz JI et al, N Engl J Med 2017

Einstein Choice Summary . In patients with symptomatic DVT/PE with equipoise for continued anticoagulation, continued treatment with rivaroxaban 20 or 10 mg showed: – Superior reduction vs aspirin for the primary and Atrial Fibrillation and Need for other efficacy outcomes – Number needed to treat (NNT) for rivaroxaban to Percutaneous Coronary prevent one episode of recurrent nonfatal or fatal Intervention VTE without increasing the risk of bleeding is 30 for rivaroxaban 10mg and 33 for rivaroxaban 20 mg* – Rate of bleeding with rivaroxaban similar to aspirin

*NNT compared with aspirin for primary efficacy outcome up to 1 year

Weitz JI et al, N Engl J Med 2017

PIONEER PCI Overview – Atrial PIONEER PCI Stratification, Randomization, and Follow-up. Fibrillation requiring cardiac stents Group 1 - low-dose rivaroxaban (15 mg . This trial compared standard therapy (dual once daily) plus a

antiplatelet therapy plus a ) with P2Y12 inhibitor for 12 two regimens containing rivaroxaban plus antiplatelet months therapy in patients with atrial fibrillation undergoing Group 2 -very-low- percutaneous coronary intervention (PCI) with dose rivaroxaban (2.5 placement of stents mg twice daily) plus DAPT for 1, 6, or 12 months . The rivaroxaban groups had reduced rates of bleeding and similar efficacy in preventing Group 3 - standard therapy with a dose- cardiovascular events. adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months

Gibson CM N Engl J Med Volume 375(25):2423-2434 December 22, 2016 Gibson CM N Engl J Med Volume 375(25):2423-2434 December 22, 2016

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Cumulative Incidence of the Primary Safety End Cumulative Incidence of the Primary Safety End Point and Its Components, Point and a Secondary Efficacy End Point. with Stratification According to Intended Duration of DAPT.

Gibson CM N Engl J Med Volume 375(25):2423-2434 December 22, 2016 Gibson CM N Engl J Med Volume 375(25):2423-2434 December 22, 2016

PIONEER PCI Conclusions

• In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y inhibitor for 12 12 Secondary Prevention of months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate Cardiovascular Events in of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, Coronary or Peripheral Arterial 6, or 12 months. • The three groups had similar efficacy rates, although Disease the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy.

COMPASS Study Design Rationale for Rivaroxaban in CAD/PAD . Phase III, event-driven, blinded, randomized controlled trial with a 3 x 2 partial . Rivaroxaban alone or in combination with aspirin factorial design might be more effective than aspirin alone for vascular . During the 30-day run-in period, potentially eligible subjects (excluding those randomized after CABG surgery) received rivaroxaban placebo twice daily and prevention in patients with stable coronary artery aspirin 100 mg once daily disease (CAD) or peripheral artery disease (PAD) – Pantoprazole/pantoprazole placebo was not administered during run-in . Subjects who successfully completed the run-in period and who consented to . Rivaroxaban has been shown in large RCTs to be continue in the study, as well as those enrolled after CABG were randomized in effective for the prevention and treatment of VTE and a 1:1 ratio to receive pantoprazole or pantoprazole placebo

Rivaroxaban 2.5 mg bid + ASA for prevention of stroke or systemic embolism in ≥1,448 subjects 100 mg od ± pantoprazole‡ 4-14 days post- 30-day 1-4 CABG+ washout patients with atrial fibrillation period* Rivaroxaban 5.0 mg bid 1:1:1 R ‡ . In patients with recent ACS, rivaroxaban at a dose of 27,395 subjects with ± pantoprazole CAD/PAD 2.5 mg or 5 mg twice daily reduced the risk of nonfatal ASA 100 mg 5 1,500 COMPASS- 30-day run-in, od and fatal CV events MIND subjects ASA 100 mg ± Final follow-up Final washout pantoprazole‡ visit** period visit

1. Turpie AG, Lassen MR, Eriksson BI, et al. Thromb Haemost 2011;105:444-53; 2. Buller HR, Prins MH, Lensing AW, et al. N Engl J Med 2012;366:1287-97; 3. Bauersachs R, Berkowitz SD, Brenner B, et al. N Engl J Med 2010;363:2499-510; 4. Patel MR, Mahaffey KW, Garg J, *Patients treated according to local standard of care; **≤30 days of the required prespecified number of events having occurred; ‡Patients et al. N Engl J Med 2011;365:883-91; 5. Mega JL, Braunwald E, Wiviott SD, et al. N Engl J Med 2012;366:9-19; Bosch J, et al. Canadian J who were not receiving a proton pump inhibitor were randomized to pantoprazole or pantoprazole placebo; #defined as at least 80% of Cardiology (2017), doi: 10.1016/j.cjca.2017.06.001. adherence to treatment; + CABG patients underwent same screening, followup, and wash out periods as other COMPASS trial participants except that they did not undergo a run-in Bosch J, et al. Canadian J of Cardiology (2017), doi: 10.1016/j.cjca.2017.06.001.

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Major Bleeding: DOACs vs. Warfarin in NVAF

Reversal of Direct Oral Anticoagulants

Ruff CT, et al. Lancet 2014; 383:955-62

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Intracranial Hemorrhage (ICH): Major Bleeding Case Fatality Rates in NVAF DOACs vs. Warfarin in NVAF Warfarin DOAC n%n% ROCKET AF 55/386 14% 27/395 7% Dabigatran systematic 53/407* 13% 57/627* 9% review ARISTOTLE 55/462 12% 34/327 10%

ENGAGE AF-TIMI 48 59/524 11% 32/418 8% 21/254 8%

Major bleeding with warfarin has a high risk of death that has not diminished over the last several decades 40-70% relative Patel et al. NEJM 2011; Majeed et al. Circ 2013; Granger et al. NEJM 2011; Giugliano et al. reduction in ICH NEJM 2013. *estimated from paper

Idarucizumab: An to Dabigatran REVERSE-AD: DEVELOPMENT Idarucizumab for Dabigatran Reversal Fully humanized • Monoclonal mouse antibody with high Prospective, multicenter cohort study – over 400 international centers dabigatran binding affinity antibody fragment • Humanized & expressed as Fab fragment in (Fab) • Planned recruitment of 300 patients – increased to 503 patients hamster cells Target population: adult patients on dabigatran with one of the following PROPERTIES • Overt, uncontrollable or life-threatening bleeding requiring reversal • Binding affinity ~350 times higher than (group A) binding of dabigatran to thrombin • Need for urgent surgical procedure that could not be delayed ≥ 8 • No procoagulant or anticoagulant effects hours (group B) • Short half life • IV administration, immediate onset of action Intervention: 5 gm idarucizumab given as two 2.5 gm boluses ≤ 15 minutes apart EXPECTED LOW RISK OF ADVERSE REACTIONS • No Fc receptor binding (cellular mediators of Primary objective: max % reversal of dabigatran effect measured by antibody functions) dilute thrombin time (dTT) or ecarin clotting time (ECT) • No endogenous targets Glund S et al. AHA, Dallas, TX, USA, November 2013; Schiele F et al. Blood. 2013;121:3554-62 Pollack CV, et al. N Engl J Med Aug 2015; 373:511-520

REVERSE-AD: Trial Design, REVERSE AD Full cohort Laboratory Monitoring Study Results Overview

Idarucizumab was 100% effective in reversing the anticoagulant effect of dabigatran: . among 300 patients with uncontrolled bleeding (median time to bleeding cessation, 2.5 hours) . and among 200 patients who required an urgent procedure (median time to procedure initiation, 1.6 hours).

Pollack CV N Engl J Med Volume 377(5):431-441 August 3, 2017 Circulation. 2015;132:2412‐2422

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Key Measurements Before and After the Administration of Idarucizumab. REVERSE AD Full Cohort Conclusions

. In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. . Idarucizumab has been available in the US since 2015 and was approved based off of the early interim analysis by the FDA

Pollack CV N Engl J Med Volume 377(5):431-441 August 3, 2017

Andexanet Alfa: Recombinant, Modified Version of Human Factor Xa Produced in CHO Cells

 Andexanet acts as a FXa decoy

Andexanet Phase 3b/4  Andexanet was rationally designed to reverse anticoagulant effects of factor Xa inhibitors Preliminary Study Results AndexanetNative FXa FXa Inhibitor High affinity GLA domain removed to retained

prevent anticoagulant effect Binding A419S419 site

GLA Catalytic Domain Activity eliminated to prevent thrombin S S generation – serine N terminal to alanine residues retained to reduce immunogenicity

CHO=Chinese hamster ovary. GLA=γ-carboxyglutamate. Lu G et al. Nat Med. 2013;19(4):446-451.

Andexanet Mechanism of Action – Direct Factor Xa Inhibitors1,2 ANNEXA—4 Study Design

Bleeding and Laboratory Assessment 3 22 3 Absence of GLA domain 1 Andexanet directly binds and 1 Patient Screening Andexanet Treatment Safety FXa inhibitors block sequesters unbound FXa prevents assembly into follow-up visit enzymatic activity inhibitors with high affinity complex IV 2-hour After end of Patient If last dose of of FXa on surface Bolus IV Infusion infusion presents FXa inhibitor with major was within Without Andexanet With Andexanet bleed 18 hours

Assessments: 1 hr 4 hr 8 hr 12 hr Day 1 Day 3 Day 30

Primary Efficacy Measurements Safety Measurements

. Percent change in anti-FXa activity . Overall safety

. Hemostatic efficacy at 12 hours (assessed by . Thrombotic events independent endpoint adjudication committee as . Antibodies to FX, FXa, andexanet excellent, good, or poor/none) . 30-day all-cause mortality 44 Secondary Efficacy Measurements Restoration of FXa activity and normal thrombin generation . Relationship between decrease in anti-FXa activity and achievement of hemostatic efficacy No lab tests required to enroll patients Portola Data on File. 1. Portola Data on File. 2. Yeh CH et al. Circ Res. 2013;113:954-957.

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ANNEXA-4 Dosing and ANNEXA-4 Preliminary Study Administration Results Andexanet administered as IV bolus, immediately followed by continuous infusion. . ANNEXA-4 is an ongoing study and is expected to be completed by There are two possible dosing regimens: November 2022.

Andexanet Initial Andexanet Follow-on IV Bolus 120-minute Infusion . This preliminary and descriptive report presents the 67 patients for

 Patients on apixaban whom data were complete as of June 17, 2016. 400 mg at a target rate of 480 mg at a target rate of  Patients who received rivaroxaban 30 mg/min 4 mg/min x 2 hrs >7 hours ago – 67 patients were included in the safety analysis and 47 patients

 Patients on enoxaparin or edoxaban were included in the safety analysis

 Patients who received rivaroxaban within 800 mg at a target rate of 960 mg at a target rate of ≤7 hours or at an unknown time* 30 mg/min 8 mg/min x 2 hrs . It cannot be guaranteed that the future results, levels of activity,  Patients who received a Factor Xa performance, or events and circumstances reflected in this inhibitor but it is uncertain which one preliminary analysis will be achieved or occur and therefore the conclusions of this preliminary analysis are limited.

*If there is a delay between medical presentation and start of andexanet of more than 7 hours, the patient should receive the dose for rivaroxaban >7 hours ago.

Portola Data on File.

Hemostatic Efficacy Overall Hemostatic Efficacy by Andexanet and by Bleed Site Dose and by Anticoagulant All Patients Bleed Site Andexanet Dose Anticoagulant 100% 100% 100% 81% 84% 80% 80% 80% 75% 79% 76% 60% 60%

40% 40% 20% Excellent or or Good Excellent or Good Excellent

Hemostatic Efficacy (%) Efficacy Hemostatic 20% (%) Efficacy Hemostatic 0% 0% Andexanet Andexanet Rivaroxaban (n=26) Apixaban (n=20) 0% Low Dose (n=42) High Dose (n=5) All Patients (n=47) Gastrointestinal (n=25) Intracranial (n=20) Other (n=2) 95% CI (61‐88) 95% CI (48‐100) 95% CI (61‐93) 95% CI (51‐91) 95% CI (64‐89) 95% CI (64‐96) 95% CI (56‐94)

Connolly et al. N Engl J Med. 2016; 375(12):1131-42 Connolly et al. N Engl J Med. 2016; 375(12):1131-42

Effect of Andexanet on Rivaroxaban and ANNEXA-4 Safety Outcomes in Bleeding Apixaban Anti-FXa Activity Patients Treated with FXa Inhibitors Rivaroxaban (N=26) Apixaban (N=20) Adverse Events1 . No infusion reactions . 15% (10/67) of patients died within 30 days – Mortality among ICH patients was 21% (6/28) at 30 days – Mortality among non-ICH patients was 10% (4/39) at 30 days . 18% (12/67) of patients experienced a thrombotic event between 1 and 28 days after andexanet treatment – All but 1 patient was not re-started on a therapeutic dose of anticoagulation – Thrombotic events could be attributed to the patient’s underlying medical condition . In an updated cohort of 105 patients receiving andexanet, 12% (13/105) of patients experienced a thrombotic event within 30 days of treatment 2 1 . Andexanet rapidly decreased anti-FXa activity by 89-93% at end of bolus, which was sustained during infusion Immunogenicity . Andexanet also rapidly decreased anti-FXa activity in the 10% of patients with the highest baseline anti-FXa levels by approximately 33% (from 487.1 ng/mL to 327.4 ng/mL) . No antibodies to factors Xa or X – All of these patients were adjudicated as having excellent or good . . No neutralizing antibodies to andexanet Boxplot values represent median, 25th and 75th percentiles; whiskers represent lowest or highest data point within 1.5 times the lower or upper quartile respect Dots represent outliers 1. Connolly et al. N Engl J Med. 2016; 375(12):1131-42 2. Connolly et al. N Engl J Med. 2016; 375(25):2499-500 Connolly et al. N Engl J Med. 2016; 375(12):1131-42

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Single center retrospective analysis of consecutive Summary of ANNEXA-4 patients who received FEIBA in DOAC reversal Preliminary Study Results . UC Davis, acute major bleeding in the presence of DOACs is managed . Andexanet in patients with acute major bleeding associated with activated prothrombin complex concentrate (PCC) FEIBA. with the use of FXa inhibitors:1 . Early experience demonstrated a profound, rapid effect with doses around 8 units/kg, leading to an initial low dose (LD) with the option to – Rapidly reversed anti-FXa activity titrate to effect with additional FEIBA. – Not associated with serious side effects . 54 patients; apixaban (n=18), dabigatran (n=13) and rivaroxaban (n=23) received LD (< 20 units/kg) aPCC (mean 10±3.5 units/kg; n=32) or MD . Effective hemostasis achieved 12 hours after an infusion of (mean 24±2.4units/kg; n=22). CNS bleeds occurred in 20 patients. andexanet in 79% of the patients.1 . 9 patients expired prior to discharge. One TE occurred with MD. Follow- up CT exams did not reveal any clinically concerning active bleeding or . Thrombotic events occurred in 12% of the patients in the safety hematoma expansion except one HD patient where CT showed slight population, and 15% of the patients died during follow-up.1,2 worsening of massive multifocal ICH. . Andexandet has been resubmitted to the FDA on 8/3/2017 with . LD aPCC titration strategy using an option to repeat, and MD aPCC, a likely estimated 200 or more patients depending on the urgency of the situation, may be a management strategy for major DOAC bleeding events.

Dager W Abstract PB 1216 | DOAC Reversal with Low (< 20 Units/kg) or Moderate Dose (≥20 Units/kg) FEIBA in the Urgent 1. Connolly et al. N Engl J Med. 2016; 375(12):1131-42 2. Connolly et al. N Engl J Med. 2016; 375(25):2499-500 Management of Major Bleeding Special Issue: Abstracts of the XXVI Congress of the International Society on Thrombosis and Haemostasis, July 8–13, 2017 Volume 1, Issue S1 July 2017 Pages 1–1451

Conclusions . Five direct oral anticoagulants are now available on the US market for various indications . Betrixaban is a new FXa inhibitor approved for extended thromboprophylaxis in acutely ill medical patients and rivaroxaban is almost complete with the MARINER study in a similar population . Several new DOAC studies have recently been Backup slides published in NVAF and PCI, Secondary Prevention of cardiovascular events in CAD/PAD, and extended treatment of VTE . Idarucizumab is FDA aproved and available for the reversal of dabigatran . Andexanet has been studied for reversal of Factor Xa inhibitors, has recently been resubmitted to the FDA, and may be soon available on the US Market to reverse Factor Xa inhibitors

Disadvantages of Warfarin IMPROVE RAM Validation . Delayed onset/offset

. Unpredictable dose response

. Narrow therapeutic index

. Drug-drug, drug-food interactions VALOURR (McMaster) NS/LIJ Health System . Problematic routine monitoring

. High bleeding rate Low Moderate High TOTAL Population Moderate and (Score 0‐1) (Score 2‐3) (Score ≥ 4) High Risk Population IMPROVE VTE 47 / 10379 49 / 3755 47 / 991 143 / 15125 96 / 4746 Incidence (0.45%) (1.3%) (4.74%) (0.95%) (2 %) . Slow reversibility (6-24 hours) VALOURR VTE 26 /12651 66 / 6307 (1.05%) 47 / 1109 139 / 20067 113 / 7416 Incidence (0.21%) (4.24%) (0.69 %) (1.52 %)

. Complicated peri-operative management 1. Mahan CE et al. Thromb Haemost. 2014 Oct;112(4):692-9. doi: 10.1160/TH14-03-0239. Epub 2014 Jul 3. 2. Rosenberg D et al. J Am Heart Assoc. 2014 Nov 17;3(6):e001152. doi: 10.1161/JAHA.114.001152

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COMPASS Background: CAD/PAD COMPASS Background: Therapeutic Strategies

– Cardiovascular (CV) disease is responsible for . Aspirin, statins, angiotensin modulators, and approximately one-third of deaths in 20131 β-blockers are effective and widely used for CV prevention in patients with CAD, and the . Estimated 17.3 million people worldwide died of CV disease in 2012 first 3 classes of drugs are effective in patients Projected to increase to 23.6 million per year with PAD by 20301 . Despite use of these therapies, as many as 5% of patients experience recurrent vascular . Coronary artery disease (CAD) and peripheral arterial disease (PAD) are 1 strong predictors of risk for future CV events 1,2 events each year

. Long-term aspirin prevents vascular events but is only modestly effective3,4

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 2016;133:e38-360; 2. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. JAMA 2006;295:547-53; 3. CAPRIE Steering Committee. Lancet 1996;348:1329-39; 4. Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006;354:1706-17; Bosch J, et al. Canadian J of Cardiology (2017), doi: 10.1016/j.cjca.2017.06.001.

1. Bhatt DL, Eagle KA, Ohman EM, et al. JAMA 2010;304:1350-7 2. Bosch J, et al. Canadian J of Cardiology (2017), doi: 10.1016/j.cjca.2017.06.001.

COMPASS Evidence for Anti-platelet Efficacy Select APEX Exclusion Criteria Kidney Function . Aspirin reduces the risk of myocardial infarction (MI), stroke, or CV death 1 . End stage renal disease with CrCl <15 mL/min, or requiring dialysis, or severe renal by one-fifth in patients with CAD, cerebrovascular disease, or PAD insufficiency (i.e., CrCl between ≥ 15 mL/min and < 30 mL/min) and requiring concomitant . Aspirin is also effective for prevention of graft failure after coronary use of strong P-gp inhibitor. artery bypass graft (CABG) surgery,1 but despite its use as many as Liver Function 40% of patients have at least 1 obstructed graft within 1 year2 . Known abnormality of liver function tests [ > 3x ULN for serum glutamic-oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST), serum glutamate pyruvate – Graft failure is an independent predictor of MI and death transaminase (SGPT)/alanine transaminase (ALT) or alkaline phosphatase (ALP), or > 2 x ULN for total bilirubin in the absence of Gilbert’s syndrome], active liver disease, or hepatic . Compared with aspirin, produced a reduction in MI, stroke, or dysfunction (e.g., cirrhosis). 3 CV death Bleeding Risk – The combination of aspirin and clopidogrel did not reduce major . History of clinically significant bleeding within 6 months prior to enrollment. 4 adverse CV events compared with aspirin alone, but a benefit was . History of any significant gastrointestinal, pulmonary or urogenital bleeding, ongoing chronic evident in the subgroup of patients with a history of symptomatic peptic ulcer disease or ongoing or acute gastritis within 2 years prior to enrollment. disease5 Anticoagulant Use . Long-term treatment with the combination of aspirin and or . Contraindication to anticoagulant therapy aspirin and compared with aspirin alone, or the combination of . Current intake of dual antiplatelet therapy with standard antiplatelet therapy also yielded benefits without . Anticipated need for prolonged anticoagulation 6-8 significant reductions in mortality . Greater than 96 hours of administration of the following immediately prior to receiving study treatment (enoxaparin or another low molecular weight heparin, fondaparinux, unfractionated 1. Trialists’ Collaboration. [erratum in: 2002;324:141]. BMJ 2002;324:71-86; 2. Alexander JH, Hafley G, Harrington RA, et al. JAMA heparin) 2005;294:2446-54; 3. CAPRIE Steering Committee. Lancet 1996;348:1329-39; 4. Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006;354:1706-17; 5. Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol 2007;49:1982-8; 6. Li X, Zhou G, Zhou X, Zhou S. J Neurol Sci 2013;332:92-6; 7. Bonaca MP, Bhatt DL, Cohen M, et al. N Engl J Med 2015;372:1791-800; 8. Morrow DA, Braunwald E, Bonaca MP, et al. N Engl J Med 2012;366:1404-13; Bosch J, et al. Canadian J of Cardiology (2017), doi: 10.1016/j.cjca.2017.06.001. Cohen AT et al. N Engl J Med. 2016;375:534-44

APEX Efficacy Analyses for FDA Label Were Performed APEX Study Publications Based on the Modified Intent-to-Treat (mITT) Population Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. The mITT population consisted of all patients who had taken at least one Cohen AT, et al. N Engl J Med. 2016;375 dose of study drug and had follow-up assessment of one or more primary or secondary efficacy outcome components. Rationale for pre- The safety and efficacy of full versus reduced-dose betrixaban in the Acute Medically Ill VTE specified mITT analyses: Prevention With Extended-Duration Betrixaban (APEX) trial. . Minimizes the magnitude of any missing data and any bias due to Gibson CM, et al. Am Heart J. 2017.185:93-100 informative censoring in evaluation of study results When academic research organizations and clinical research . A larger sample size provides a more robust estimate of the efficacy organizations disagree: Processes to minimize discrepancies prior to of betrixaban unblinding of randomized trials. The FDA used the mITT analysis as the basis for Betrixaban approval Gibson CM, et al. Am Heart J. 2017. 189:1-8 because: Extended-Duration Betrixaban Reduces the Risk of Stroke Versus . It minimizes the magnitude of any missing data in evaluation of study Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients results Gibson CM, et al. Circulation. 2017;135(7):648-655 . It is based on a larger sample size that provides a better estimate of the efficacy of betrixaban Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus . NOTE: Prior to the completion of the study the FDA requested that Standard Dose Enoxaparin in Acutely Ill Medical Patients: An APEX Trial Substudy the statistical analysis plan (SAP) include and predefine the mITT Gibson CM, et al. J Am Heart Assoc. 2017;6(7) analysis for the assessment of efficacy results

Look for Reduced Rehospitalization Data with betrixaban. Will be Forthcoming

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Pharmacokinetics of Andexanet ANNEXA 4 Preliminary Types of Anticoagulants and Bleeds Drug Properties1 Clearance/Metabolism

 40 KDa protein  Like other large proteins, andexanet is broken down by  Rapid onset of action Type of Anticoagulant Type of Bleed proteolytic cleavage mechanisms  PD/effective half-life ~1 hour into small peptides2 and elimination half-life of ~5-7 hours  Clearance likely occurs via hepatic and renal mechanisms2 6% Other  Anticoagulants don’t affect PK of Rivaroxaban ―Size is within molecular weight 9% 11% andexanet (they clear (n= 32) range for filtration through ICH Subarachnoid separately) Apixaban glomerulus and in 48% Intracerebral (n=31) GI 42% 39%  PK in elderly is same as in urine2 46% Enoxaparin 49% Subdural 50% younger subjects ―In clinical trials, no intact drug (n=4) was detected in urine1

GI: gastrointestinal PD=pharmacodynamics; PK=pharmacokinetics. 1. Portola Data on File. 2. Lu G et al. Nat Med. 2013;19(4):446-451. Connolly et al. N Engl J Med. 2016; 375(12):1131-42 ICH: intracranial hemorrhage

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