Reversal of Action: Addressing the Unmet Need for Universal Antidotes to Factor Xa Anticoagulants. Disclosures

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1 Reversal of Action: Addressing the Unmet Need for Universal Antidotes to Factor Xa Anticoagulants Daniel Pallin, MD, MPH Harvard Medical School Brigham and Women s Hospital Boston, Massachusetts Disclosures Daniel Pallin, MD, MPH, has a financial interest/relationship or affiliation in the form of: Other Financial or Material Support from: Chairing a Medical Advisory Board panel for Portola Pharmaceuticals, Inc. Daniel Pallin, MD, MPH, does not intend to discuss any non-fda-approved or investigational use of any products/devices. 1

2 Bleeding Risk Assessment in Patients Receiving DOAC Therapy Case 1: Patient Presents To Emergency Department With a Gastrointestinal Bleed Presentation 67-year-old male presents with ongoing bright red hematemesis He takes apixaban 5 mg BID for atrial fibrillation (time of last dose is unknown) He has melena per rectum There is no history of a prior GI bleed After 1 L saline IV, BP is 93/67 mmhg; blood for transfusion will be available in 15 min How would you manage this patient? 2

3 Oral Anticoagulation Oral anticoagulants are widely used to reduce the risk of thromboembolic events in patients with AF DOACs have gained widespread acceptance due in part to their favorable safety, efficacy, and ease of use compared with warfarin 1 1. Huisman MV et al. Am J Med. 2016;S89-S96; NOAC Meta-Analysis: Major Bleeding RE-Ly a ROCKET Af b ARISTOTLE c ENGAGE AF-TIMI 48 d Combined (random) NOAC (Events) 357/6, /7, /9, /7,012 1,541/29,287 Warfarin (Events) 397/6, /7, /9, /7,012 1,802/29,211 RR (95% CI) 0.94 ( ) 1.03 ( ) 0.71 ( ) 0.80 ( ) 0.86 ( ) P < Favors NOAC Favors Warfarin a Dabigatran. b Rivaroxaban. c Apixaban. d Edoxaban. 3

4 2017 ACC Consensus Recommendations: Assess and Identify the Severity of Bleeding 1 Does 1 of the following factors apply? Bleeding at a critical site Hemodynamic instability Clinically overt bleeding with hemoglobin decrease 2 g/dl or administration of 2 units RBCs Yes No Bleed is considered major Bleed is considered non-major 1. Tomaselli GF et al. J Am Coll Cardiol. 2017;70: ACC Consensus Recommendations: Critical Site Bleeds 1 Type of Bleed Initial Signs and Symptoms Potential Consequences of Bleed Intracranial hemorrhage: Includes intraparenchymal, subdural, epidural, and subarachnoid hemorrhages Other CNS hemorrhage: Includes intraocular, intra- or extra-axial spinal hemorrhages Pericardial tamponade Airway, including posterior epistaxis Hemothorax, intra-abdominal bleeding, and RPH Extremity bleeds: Includes intramuscular and intra-articular bleeding Unusually intense headache, emesis Neurological signs: eg, reduced LOC, vision changes, numbness, weakness, aphasia, ataxia, vertigo, seizures Intraocular: monocular eye pain, vision changes, blindness Spinal: back pain, bilateral extremity weakness or numbness, bowel or bladder dysfunction, respiratory failure Shortness of breath, tachypnea Hypotension, jugular venous distension Tachycardia, muffled heart sounds, rub Airway: hemoptysis, shortness of breath, hypoxia Posterior epistaxis: profuse epistaxis, hemophtysis, hypoxia, SOB Hemothorax: tachypnea, tachycardia, hypotension Intra-abdominal (non-gi): abdominal pain, distension, hypotension, tachycardia RPH: back/flank/hip pain, tachycardia, hypotension Intramuscular: pain, swelling, pallor, paresthesia, weakness, diminished pulse Intra-articular: joint pain, swelling, decreased range of motion Stupor or coma Permanent neurological deficit Death Intraocular: permanent vision loss Spinal: permanent disability, paraplegia, quadriplegia, death Cardiogenic shock Death Hypoxemic respiratory failure, death Hemothorax: respiratory failure RPH: femoral neuropathy All: hypovolemic shock, death Intramuscular: compartment syndrome, paralysis, limb loss Intra-articular: irreversible joint damage 1. Tomaselli GF et al. J Am Coll Cardiol. 2017;70:

5 Case 1 Continued GI bleeds are the most common severe hemorrhagic complications of DOAC treatment GI bleeds are rarely fatal but are associated with substantial morbidity and high resource consumption (blood products, ICU, endoscopy, etc.) Availability of stat GI consult is an important issue in deciding whether or not to reverse Key point in GIB cases: reversal is not hemostasis! Should we order a coagulation test? 2017 ACC Consensus Recommendations: Suggestions for Laboratory Measurement of DOACs When Specialized Assays ARE Available 1 Clinical Objective Exclude Clinically Relevant Drug Levels Measure On-Therapy or Above On-Therapy Drug Levels Drug Suggested Test Interpretation Suggested Test Dabigatran Dilute TT ECT ECA Normal result probably excludes clinically relevant levels a Dilute TT ECT ECA Apixaban, edoxaban, or rivaroxaban Anti-Xa Absent chromogenic anti-xa assay activity probably excludes clinically relevant levels a Anti-Xa b a The term clinically relevant refers to DOAC levels that may contribute to bleeding or surgical bleeding risk. The minimum DOAC level that may contribute to bleeding or surgical bleeding risk is unknown. The International Society on Thrombosis and Hemostasis recommends consideration of anticoagulation reversal for patients with serious bleeding and a DOAC level >50 ng/ml, and for patients requiring an invasive procedure with high bleeding risk and a DOAC level >30 ng/ml. b Useful for quantification of plasma drug levels only when calibrated with the drug of interest. 1. Tomaselli GF et al. J Am Coll Cardiol. 2017;70:

6 2017 ACC Consensus Recommendations: Suggestions for Laboratory Measurement of DOACs When Specialized Assays ARE NOT Available 1 Clinical Objective Exclude Clinically Relevant Drug Levels Measure On-Therapy or Above On-Therapy Drug Levels Drug Suggested Test Interpretation Suggested Test Intepretation Dabigatran TT, aptt Normal TT excludes clinically relevant levels a Prolonged TT does not discriminate between clinically important and insignificant levels Normal aptt usually excludes clinically relevant levels a, if a sensitive reagent is used aptt Prolonged aptt suggests that on-therapy or above on-therapy levels are present Normal aptt may not exclude on-therapy levels, particularly if a relatively insensitive aptt reagent is used Apixaban None Normal aptt usually excludes clinically relevant levels a, if a sensitive reagent is used PT Prolonged aptt suggests that on-therapy or above on-therapy levels are present Normal PT may not exclude on-therapy levels, particularly if a relatively insensitive PT reagent is used Edoxaban or rivaroxaban None Normal PT and aptt do not exclude clinically relevant levels a PT Prolonged PT suggests that on-therapy or above on-therapy levels are present Normal PT may not exclude on-therapy levels, particularly if a relatively insensitive PT reagent is used a The term clinically relevant refers to DOAC levels that may contribute to bleeding or surgical bleeding risk. The minimum DOAC level that may contribute to bleeding or surgical bleeding risk is unknown. The International Society on Thrombosis and Hemostasis recommends consideration of anticoagulation reversal for patients with serious bleeding and a DOAC level >50 ng/ml, and for patients requiring an invasive procedure with high bleeding risk and a DOAC level >30 ng/ml. 1. Tomaselli GF et al. J Am Coll Cardiol. 2017;70: Examining the Current State of Bleeding Management and Reversal of Factor Xa Inhibitors 6

7 Case 1 Continued: Patient Presents to ED With a GI Bleed Presentation 67-year-old male presents with ongoing bright red hematemesis He takes apixaban 5 mg BID for atrial fibrillation (time of last dose is unknown) He has melena per rectum Would you reverse apixaban? If so, how? Anticoagulation Reversal 1 Most bleeding complications associated with oral anticoagulation, especially DOACs, do not warrant emergent reversal 1 Most cases involve only mild-to-moderate bleeding and can be managed with local and supportive measures Supportive care may include transfusion and invasive procedures 1. Huisman MV et al. Am J Med. 2016;S89-S96. 7

8 Why Not Reverse More Often? Reversal immediately removes the protection afforded by anticoagulation against whatever health hazard was being treated (risk of stroke, risk of VTE) Reversal may be complicated by thromboembolism Reversal agents are expensive Reversal agents should not be viewed as a rescue approach that precludes the need for definitive management of bleeding What Are the Characteristics of an Ideal Reversal Agent? 1 An ideal reversal agent would specifically target only the NOAC act immediately provide complete reversal provide a sustained effect have predictable effects have no procoagulant effects be easy to use Take the NOAC out of the equation, helping physicians concentrate on other vital aspects of emergency patient management 1. Pollack C. European Society of Cardiology 365 Congress (ESC 2017). Presentation. 8

9 2017 ACC Expert Consensus Decision Pathway on Bleeding Management 1 If the bleed is at a critical site or life threatening: Stop OAC If patient is on a VKA, give 5-10 mg IV Vit K Provide local therapy / manual compression Provide supportive care If applicable, stop antiplatelet agent(s) Assess for and manage comorbidities that could contribute to bleeding (eg, thrombocytopenia, uremia, liver disease) Consider surgical or procedural management of bleeding site Suggest administering reversal agent 1. Tomaselli GF et al. J Am Coll Cardiol. 2017;70: Case 1 (Cont d) 1 Thinking back to our patient who is taking apixaban, how would you manage the reversal of a factor Xa inhibitor? Consider administering andexanet alfa Recently approved factor Xa inhibitor antidote, specifically to rapidly reverse the effects of apixaban and rivaroxaban 1. Tomaselli GF et al. J Am Coll Cardiol. 2017;70:

10 Andexanet Alfa: Dosing 1,a,b Administer as an IV bolus with a target rate of 30 mg/min, followed by continuous infusion for up to 120 min. There are two dosing regimens Dose Initial IV Bolus Follow-On IV Infusion Low dose High dose 400 mg at a target rate of 30 mg/min 800 mg at a target rate of 30 mg/min 4 mg/min for up to 120 min 8 mg/min for up to 120 min a The safety and effectiveness of more than one dose have not been evaluated. b If andexanet alfa is unavailable, administer 4F-PCC at 50 units/kg IV. If 4F-PCC is unavailable, consider administering apcc at 50 units/kg IV. For known ingestion, consider activated charcoal with 2-4 h after ingestion. 1. Andexxa (coagulation factor Xa [recombinant], inactivated-zhzo) Prescribing Information. Accessed May 16, Andexanet Alfa: Recombinant Modified Human Factor Xa 1 Factor Xa Decoy GLA domain removed to prevent anticoagulant effect S419A S419A High affinity Factor Xa Inhibitor Gla Catalytic Domain N terminal residues retained to reduce immunogenicity S S Activity eliminated to prevent thrombin generation 1. Lu G et al. Nat Med. 2013;19:

11 VG1 ANNEXA-4: Study Design 1 Patient with acute major bleeding Patient Screening Within 18 h of last dose of fxa inhibitor Assessments: IV bolus Andexanet Bleeding and Laboratory Assessment 2-h IV infusion Day 1 After end of infusion 1 h 4 h 8 h 12 h Safety follow-up visit Day 3 Day 30 Efficacy Outcomes Change in anti-fxa activity Clinical hemostatic efficacy through 12 h Safety Measurements Thrombotic events Antibodies to fx, fxa, andexanet 30-day mortality 1. Connolly SJ et al. N Engl J Med. 2016; 375: ANNEXA-4: Dose Selection 1 Acute major bleeding 18 h of last dose of apixaban, edoxaban, rivaroxaban, or enoxaparin Andexanet IV bolus and 2-h infusion Pts on apixaban or >7 h from last rivaroxaban dose Bolus 400 mg + infusion 480 mg at 4 mg/min Pts on enoxaparin, edoxaban or 7 h from last rivaroxaban dose Bolus 800 mg + infusion 960 mg at 8 mg/min 1. Connolly SJ et al. N Engl J Med. 2016; 375:

12 Slide 21 VG1 Please could you provide references for Slides and 39 to 47? Vandana Gupta, 5/4/2018

13 ANNEXA-4: Design and Analysis Plan 1 Analysis populations Safety population includes all patients receiving andexanet Efficacy population excludes patients with baseline anti-fxa activity <75 ng/ml (<0.25 IU/ml for enoxaparin) Interim analysis Includes all patients as of October 20, 2017 ANNEXA-4 study is ongoing 1. Connolly SJ et al. N Engl J Med. 2016; 375: Assessment of Clinical Hemostatic Efficacy 1 All cases assessed by independent committee Independent Core Lab interpreted brain CT and MRI Cases rated as excellent / good vs poor / none based on specific criteria This methodology initially developed for assessment of 4F-PCC in warfarin bleeding, where efficacy reported was 72% 1. Sarode R et al. Circulation. 2013;128:

14 Baseline Characteristics 1 Safety Population (n = 227) Efficacy Population (n = 137) Age (y), mean ± SD 77(±11) 77 (±12) Male, n (%) 117 (52) 70 (51) Time from presentation until Andexanet (h) 4.7 ± ± 3.1 Estimated creatinine clearance <30 ml/min, n (%) 21 (9) 13 (10) Indication for anticoagulation Atrial fibrillation, n (%) 178 (78) 104 (76) Venous thromboembolic disease, n (%) 52 (23) 38 (28) Atrial fibrillation and VTE, n (%) 8 (4) 6 (4) Medical history Myocardial infarction, n (%) 32 (14) 15 (11) Stroke, n (%) 47 (21) 32 (23) Heart failure, n (%) 52 (23) 36 (26) Diabetes, n (%) 67 (30) 42 (31) 1. Connolly SJ et al. American College of Cardiology 2018 Annual Scientific Session (ACC 2018). Abstract Site of Initial Bleeding 1 Safety Population (n = 227) Efficacy Population (n = 137) Intracranial bleeding, n (%) 139 (61) 78 (57) Glasgow Coma Scale, mean ± SD 13.9 ± ± 1.70 Intracerebral site, n (%) 74 (52) 44 (54) Subdural site, n (%) 45 (32) 24 (30) Subarachnoid site, n (%) 23 (16) 13 (16) Gastrointestinal bleeding, n (%) 62 (27) 43 (31) Other bleeding site, n (%) 26 (12) 16 (12) 1. Connolly SJ et al. ACC Abstract

15 Rivaroxaban: Anti Factor Xa Activity (n = 75) 1 Median Change, % % CI -92 to to to to to Connolly SJ et al. ACC Abstract Apixaban: Anti Factor Xa Activity (n = 105) 1 Median Change, % % CI -92 to to to to to Connolly SJ et al. ACC Abstract

16 Enoxaparin: Anti Factor Xa Activity (n = 16) 1 Median Change, % % CI -83 to to to to to Connolly SJ et al. ACC Abstract Effective Hemostasis at 12 Hours Post Andexanet 1 Major Bleeds Adjudicated, n Pts Who Achieved Excellent or Good Hemostasis, n Patients Who Achieved Excellent or Good Hemostasis, % 95% CI % 76% - 89% 1. Connolly SJ et al. ACC Abstract

17 Clinical Hemostatic Efficacy 1 Subgroup No. of Patients Excellent or Good, n (95% CI) Total Efficacy Patients (76-89) Drug Rivaroxaban (73-93) Apixaban (73-91) Enoxaparin (55-100) Sex Male (71-90) Female (76-93) Site of bleeding Gastrointestinal (76-96) Intracranial (72-90) Other (60-100) Age <65 y (66-100) y (76-98) >75 y (71-89) Andexanet dose Low (74-88) High (81-100) Connolly SJ et al. ACC Abstract Safety Assessment 1 Thrombotic events occurred within 3 days of andexanet in 6 (2.6%) patients and by 30 days in 24 (11%) Anticoagulation restarted in 129 patients (57%) by 30 days Therapeutic anticoagulation was restarted in only 9 patients before a thrombotic event occurred 27 deaths occurred by 30 days (12%), of which 11 were cardiovascular 1. Connolly SJ et al. ACC Abstract

18 Thrombotic Events All Events 0.12 Events After Restart of Anticoagulation Data as of: 20OCT2017 # Unrefuted TE after restart of AC among those restarted AC: 7 / 129 Proportion With an Event Days of Follow-Up Days Since Restart Number at Risk: Connolly SJ et al. ACC Abstract Thrombosis/Mortality Rates in Bleeding Patients in Recently Completed Studies 1 Study Reversal Agent Anticoagulant Number Hemostatic Efficiency, % (95% CI) Thrombotic Event Rate, % (95% CI) Mortality, % (95% CI) Total % ICH Total ICH Total ICH Total ICH ANNEXA-4 (2018) Andexanet FXai (76-89) 81 (72-90) 11 (7-16) 12 (7-19) 12 (8-18) 12 (7-20) REVERSE-AD (2017) Idarucizumab Dabigatran a NR b 5 (3-8) 6 (2-13) 14 (10-18) 16 (10-25) Sarode (2013) 4F-PCC Warfarin (64-81) 42 (15-72) 8 (3-15) NR 6 (2-12) NR Sarode (2013) Plasma Warfarin (56-75) 58 (28-85) 6 (3-13) NR 5 (2-10) NR Ezekwudo (2017) None VKA 60% / fxai 35% N/A N/A 15 (9-23) 15 ( (36-54) 45 (36-54) a 68% had investigator-determined, nonadjudicated time to hemostasis within 24 h. b Time to hemostasis not calculated in ICH pts Accessed May 10,

19 Ciraparantag 1 Affinity for heparin, fxa, and thrombin inhibitors Following edoxaban 60 mg, a single IV dose of ciraparantag 100 to 300 mg demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours No evidence of procoagulant activity as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels Safe and well tolerated with minor, non dose limiting adverse events Currently in phase 2 study 1. Ansell JE et al. Thromb Haemost. 2017;117: Conclusions Consider available guidelines for management of DOAC reversal 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants Andexanet alfa rapidly reverses anti-fxa activity, with effective hemostasis achieved in 83% of patients Thrombotic events/mortality rates consistent with the high risk profile of the patients Andexanet reversal of factor Xa inhibitor: bleeding has similar efficacy and safety as reported with other approved reversal agents Based on these data, andexanet alfa was approved for the urgent reversal of both direct and indirect factor Xa inhibitors Ciraparantag shows promise in phase 2 study 18

20 Urgent Reversal of Direct Thrombin Inhibitors But what if our patient with a GIB is on a direct thrombin inhibitor? How would you manage this patient? 19

21 2017 ACC Consensus Recommendations: Guidance for Administering Reversal Agents 1 How would you reverse a direct thrombin inhibitor (dabigatran)? Administer 5 g idarucizumab IV If idarucizumab is not available, administer 4F-PCC or apcc 50 units/kg IV Consider activated charcoal for known ingestion (within 2-4 h) 1. Tomaselli GF et al. J Am Coll Cardiol. 2017;70: Idarucizumab: Designed as a Specific Reversal Agent for the Anticoagulant Activity of Dabigatran 1-3 Humanized Fab: binds free dabigatran and dabigatran bound to thrombin No known off-target effects; does not reverse heparins or any other anticoagulants Dabigatran Binding affinity for dabigatran ~350x higher than dabigatran for thrombin IV administration, immediate onset of action Short half-life Idarucizumab No intrinsic procoagulant or anticoagulant activity 1. Schiele F et al. Blood. 2013;121: Adapted from Eikelboom J et al. Circulation. 2015;132: Schmohl M et al. Thromb Haemost. 2017;117:

22 RE-VERSE AD: A Multicentre Prospective Open-Label Single-Arm Phase 3 Study 1,2 503 dabigatran-treated patients deemed in need of reversal 5 g idarucizumab administered Follow-up Group A: Uncontrolled bleeding Group B: Emergency surgery or procedure Primary endpoint: complete dabigatran reversal within 4 h of idarucizumab administration Secondary endpoints: Hemostasis within 24 h thrombotic events, mortality Secondary endpoints: Hemostasis during procedure, thrombotic events, mortality Hospital arrival 0 15 min Patients treated based only on clinical presentation 4 h 90 days 1. Pollack CV, Jr et al. N Engl J Med. 2017;377: Pollack CV, Jr et al. Thromb Haemost. 2015;114: RE-VERSE AD: Patient Demographics 1 Characteristic Group A (n = 301) Group B (n = 202) Total (N = 503) Age, y a 79 (24-96) 77 (21-96) 78 (21-96) Male sex, n (%) 172 (57.1) 102 (50.5) 274 (54.5) Creatinine clearance, ml/min a 50.8 ( ) 56.0 ( ) 52.6 ( ) Dabigatran, n (%) Atrial fibrillation indication 288 (95.7) 190 (94.1) 478 (95.0) Dabigatran dose 150 mg BID, n (%) 94 (31.2) 57 (28.2) 151 (30.0) Dabigatran dose 110 mg BID, n (%) 185 (61.5) 126 (62.4) 311 (61.8) Dabigatran dose 75 mg BID, n (%) 16 (5.3) 8 (4.0) 24 (4.8) Patient-reported time since last dose, h a 14.6 ( ) 18.0 ( ) 15.6 ( ) Elevated dtt at baseline, n (%) 244 (81.1) 152 (75.2) 396 (78.7) Elevated dtt or ECT at baseline, n (%) 276 (91.7) 185 (91.6) 461 (91.7) a Shown as median (range). 1. Pollack CV, Jr et al. N Engl J Med. 2017;377:

23 RE-VERSE AD: Results 1,a Immediate, complete, and sustained reversal of dabigatran anticoagulation, based on dtt dtt, s Group A: Uncontrolled Bleeding (n = 293) Idarucizumab 5 g Baseline10-30 min 1 h 2 h 4 h 12 h 24 h Time Post Idarucizumab dtt, s Group B: Emergency Surgery or Procedure (n = 195) Idarucizumab 5 g Baseline10-30 min 1 h 2 h 4 h 12 h 24 h Time Post Idarucizumab Median maximum reversal within 4 h was 100% for both dtt and ECT (95% CI: ) a Similar results obtained with other relevant coagulation assays. 1. Pollack CV, Jr et al. N Engl J Med. 2017;377: Group A : Bleeding Cessation in Patients With Extracranial Hemorrhage (n = 301) 1,2 Patients with bleeding type classed as: Assessable Non-ICH (n = 198) ICH (non-assessable) a (n = 98) Non-assessable non-ich (n = 5) a Serial CT scans were not mandated by the protocol. b Cessation confirmed within 24 h in 134/198 patients bleeding stopped before treatment in 2 patients and could not be determined in 67 patients. c Local investigator-determined time to bleeding cessation. 1. Pollack CV, Jr et al. N Engl J Med. 2017;377: Pollack CV, Jr et al. International Society on Thrombosis and Haemostasis 26th Biennial Congress and 63rd Annual Scientific and Standardization Committee (ISTH 2017). Abstract

24 Group B: Patients Requiring Emergency Procedures (n = 202) 1 Acute abdomen (24%) Kidney/urinary (5%) Bone fractures (20%) Sepsis (4%) Cardiovascular (18%) Skin (3%) Central nervous system (8%) Postoperative complications (1.5%) Pancreatic/hepatobiliary (7%) Deliberate dabigatran overdose (0.5%) Respiratory (7%) Uterine (0.5%) 1. Pollack CV, Jr et al. N Engl J Med. 2017;377: Group B: Most Patients Had Normal Hemostasis During Surgery 1,2 197/202 (97.5%) patients underwent surgery/procedure with periprocedural hemostasis classed as a : Normal (93%) Moderately abnormal (2%) Severely abnormal (0%) a Normal hemostasis: as if anticoagulation were absent; abnormal hemostasis: mild (oozing, not requiring intervention), moderate (controlled with local intervention), severe (refractory haemorrhage). Hemostasis was assessed locally by the surgeon. 1. Pollack CV, Jr et al. N Engl J Med. 2017;377: Pollack CV, Jr et al. ISTH Abstract

25 RE-VERSE AD: Low Number of Thrombotic Events 1,2 Thrombotic Events Post Reversal Group A (n = 301) Group B (n = 202) Total (N = 503) Patients, % (4.6%) 10 (5.0%) 24 (4.8%) 19 (6.3%) 15 (7.4%) 30 Days 90 Days 34 (6.8%) Two-thirds of patients received no antithrombotic therapy prior to the event Idarucizumab treatment showed no evidence of a prothrombotic effect 1. Pollack CV, Jr et al. N Engl J Med. 2017;377: Pollack CV, Jr et al. ISTH Abstract RE-VERSE AD: Mortality Reflects Severity of Underlying Diseases 1,2 Within 5 days of idarucizumab treatment, 19 deaths occurred in Group A (6.3%) and 16 deaths occurred in Group B (7.9%) Kaplan Meier Rates 30 days 90 days Group A (n = 301) Group B (n = 202) Patients at risk, n Mortality, % Patients at risk, n Mortality, % Pollack CV, Jr et al. N Engl J Med. 2017;377: Pollack CV, Jr et al. ISTH Abstract

26 Conclusions Idarucizumab approved for dabigatran reversal Prothrombin complex concentrates may be used for factor Xa reversal as a final effort to save patient Audience Q&A 25

27 Please remember to complete and submit your Post-Test and Evaluation for CME credit. Missed anything? Visit us at: Download slides and Practice Aids Watch the online version of this activity Join the conversation on Thank you and have a good day. 26