Management of Novel Oral Anticoagulants in Gastroenterology

Transcription

1 Management of Novel Oral Anticoagulants in Gastroenterology Breakfast with the Experts, CDDW 2018 February 10, 2018 Toronto, ON Brian Yan, MD FRCPC Associate Professor of Medicine Western University Deborah Siegal, MD MSc FRCPC Assistant Professor Department of Medicine McMaster University

2 Name: Dr. Deborah Siegal Conflict of Interest Disclosure (over the past 24 months) Commercial or Non-Profit Interest Servier Inc, Bayer Relationship Advisory board

3 Name: Dr. Brian Yan Conflict of Interest Disclosure (over the past 24 months) No relevant relationships with any commercial or non-profit organizations

4 Objectives At the end of this session participants will be able to: 1. Understand the basic pharmacology of NOACs pertaining to periendoscopic management 2. Evaluate and manage patients taking anticoagulants/noacs in regard to gastrointestinal disease and endoscopy. 3. Manage NOACs in the setting of GI bleeds

5 X X X CanMEDS Roles Covered Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional values in their provision of high-quality and safe patient-centered care. Medical Expert is the central physician Role in the CanMEDS Framework and defines the physician s clinical scope of practice.) Communicator (as Communicators, physicians form relationships with patients and their families that facilitate the gathering and sharing of essential information for effective health care.) Collaborator (as Collaborators, physicians work effectively with other health care professionals to provide safe, high-quality, patient-centred care.) Leader (as Leaders, physicians engage with others to contribute to a vision of a high-quality health care system and take responsibility for the delivery of excellent patient care through their activities as clinicians, administrators, scholars, or teachers.) Health Advocate (as Health Advocates, physicians contribute their expertise and influence as they work with communities or patient populations to improve health. They work with those they serve to determine and understand needs, speak on behalf of others when required, and support the mobilization of resources to effect change.) Scholar (as Scholars, physicians demonstrate a lifelong commitment to excellence in practice through continuous learning and by teaching others, evaluating evidence, and contributing to scholarship.) Professional (as Professionals, physicians are committed to the health and well-being of individual patients and society through ethical practice, high personal standards of behaviour, accountability to the profession and society, physician-led regulation, and maintenance of personal health.)

6 Novel Oral Anticoagulants (NOAC) Contact FXIIa FXIa FIXa TF FVIIa FVIIIa FVa Rivaroxaban Apixaban Edoxaban FXa Dabigatran Prothrombin Thrombin

7 Indications for NOAC Use Novel oral anticoagulant VTE prophylaxis following hip/knee surgery Non-valvular atrial fibrillation Treatment of VTE Secondary prevention of VTE Dabigatran P P P P Rivaroxaban P P P P Apixaban P P P P Edoxaban P P

8 Drugs Time to peak concentration (hrs) Half-life (hrs) Dabigatran Rivaroxaban Population Healthy adults, single dose Healthy adults, multiple doses Healthy adults, single dose Healthy elderly, single dose Healthy adults, multiple doses Renal excretion 80% 85% 36% Apixaban Healthy adults, single dose 25% Edoxaban Siegal and Cuker. Drug Discov Today Sep;19(9): Healthy adults, single dose Healthy adults, multiple doses 36% - 45%

9 Case 1 60y male Rivaroxaban for afib HTN Colonoscopy for new onset diarrhea Direct to procedure? What to do with NOAC? If you stop.when to restart? Acosta RD, et al. For the ASGE Standards of Practice Committee; Gastrointest Endosc 2016; 83: 3-16

10 Periprocedural Management Risk of thrombosis Risk of bleeding - 10

11 Key Questions to Guide OAC Management What is the urgency of the case? What is the procedural bleeding risk? What is the patient s estimated thrombotic risk? Is anticoagulant interruption needed? Is bridging anticoagulation needed? Not for NOACs Minimizing perioperative bleeding is important because it leads to delayed resumption of anticoagulants thereby exposing patients to an increased risk of thromboembolism

12 Risk of Bleeding High (2-day risk of major bleeding 2 to 4%) Neuraxial anesthesia Major surgery (>45 min) Cardiac surgery Neurosurgery Urologic surgery Cancer surgery Polypectomy Renal biopsy Low (2-day risk of major bleeding 0 to 2%) Abdominal hernia repair Abdominal hysterectomy Cholecystectomy GI endoscopy +/- biopsy Cardiac devices Tooth extractions Carpal tunnel repair Bronchoscopy +/- biopsy Ophthalmologic surgery Spyropoulos and Douketis Blood

13 Procedural Bleed Risk Low risk < 1.5% without anticoagulation Acosta RD, et al for ASGE Standards of Practice Committee. Gastrointest Endosc 2016; 83: 3-16.

14 Procedural Bleed Risk on Antithrombotics Acosta RD, et al for ASGE Standards of Practice Committee. Gastrointest Endosc 2016; 83: 3-16.

15 Risk of Thrombosis Atrial fibrillation Mechanical heart valve Venous thrombosis Modified from Douketis J, et al. Chest 2012;141:e326 Very High Risk High Risk Moderate Risk Stroke/TIA <3 mo CHADS CHA 2 DS 2 -Vasc 6 Rheumatic valve disease Caged-ball/tilting disc Mitral valve Stroke/TIA <6 mo VTE <3 mo CHADS CHA 2 DS 2 -Vasc 4-5 Bileaflet AVR + risk factors VTE 3-12 mo Recurrent VTE Active cancer CHADS CHA 2 DS 2 -Vasc 2-3 (no previous stroke) Bileaflet AVR without risk factors VTE >12mo

16 Anticoagulant Interruption Most surgeries/procedures require interruption Limit duration of interruption DOACs do not require bridging due to rapid onset of action and short half-life Continue anticoagulants for selected low bleed risk procedures Consider delaying elective procedures in patients with very high transient risk of thrombosis (e.g. stroke within 1 month, VTE within 3 months)

17 Veitch AM, et al. For BSG/ESGE Guidelines. Gut 2016; 65:

18 Dabigatran Periprocedural Management Before procedure After procedure Renal function (CrCl) Estimated half-life (hrs) 50 ml/min 15 (12-18) Last dose Day to <50 ml/min High bleed risk Low bleed risk High bleed risk (skip 3-4 doses) 18 (28-24) Last dose Day -5 (skip 7-8 doses) Last dose Day -2 (skip 1-2 doses) Last dose Day -3 (skip 3-4 doses) Resume 48 to 72 hours Low bleed risk Resume 24 hours Healey et al. Circulation. 2012;126: ; Spyropoulos A, Douketis J. Blood 2012;120:2954

19 Factor Xa Inhibitor Periprocedural Management Before Procedure After Procedure Drug High bleed risk Low bleed risk High bleed risk Low bleed risk Rivaroxaban Last dose Day -3 Last dose Day -2 (skip 2 doses) (skip 1 dose) Apixaban Last dose Day -3 (skip 4 doses) Last dose Day -2 (skip 2 doses) Resume hrs Resume 24 hrs Edoxaban Last dose Day -3 Last dose Day -2 (skip 2 doses) (skip 1 dose) Spyropoulos A, Douketis J. Blood 2012;120:

20 ASGE Recommendations Acosta RD, et al. For the ASGE Standards of Practice Committee; Gastrointest Endosc 2016; 83: 3-16

21 Case 2 70y female Dabigatran for AF ( (CHADS2=4, CHA 2 DS 2 VASc = 6) HTN, CHF, prior stroke FIT + colonoscopy Direct to procedure? What to do with dabigatran? You remove a 3cm cecal polyp, Paris class 2b requiring submucosal lift and piecemeal resection Close? When to restart dabigatran? Baron T, et al. NEJM 2013; 368:

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24 Post Procedure: When to restart Depends on what you did and the risk of bleed NOACs: Effect in 1h, peak effect within 3h Restart in at least 48h after high risk procedure Clopidogrel: delayed onset of action, therefore can restart in 24h post procedure Depends on risk of thrombosis

25 Case 3 65y male Idiopathic DVT/PE 3 months ago on Rivaroxiban New onset solid food dysphagia with reflux history; no other red flag features Bring patient direct to procedure? When to do procedure? What to do with Rivaroxiban? If stop, when to restart?

26 Bleeding and Reversal

27 Cheung KS and Leung WK. World J Gastroenterol 2017; 23:

28 GI Bleeding VKA vs. NOAC Phase III RCTs Chai-Adisaksopha et al. Blood. 2014;124(15):

29 NOACs: Reduced Risk of Major Bleeding Chai-Adisaksopha et al. Blood. 2014;124(15):

30 NOACs: Reduced Risk of Fatal Bleeding Chai-Adisaksopha et al. Blood. 2014;124(15):

31 Case 4 78M with presyncope to ER by EMS Physical Exam BP 92/56, O2 95% RA, RR 18/min, HR Diaphoretic, drowsy (easily rousable) DRE positive for melena PMHx: AF, ischemic stroke, HTN, OA, macular degeneration, hemorrhoids Meds Dabigatran 150 mg po bid, perindopril 8 mg daily, multivitamin, meloxicam prn 31

32 Case History 2 month history of worsening SOBOE and fatigue Not sure about bleeding (visually impaired) ECG shows AF rate bpm Resuscitation IV fluids Bloodwork sent 32

33 Key Questions Regarding NOAC Bleeding Where is the bleed? How severe is the bleed? Have supportive measures been initiated? Is NOAC present in significant quantities? Is there a role for reversal? Which reversal strategy?

34 Non-Major Bleeding Major Bleeding Examples: subconjunctival hemorrhage, small bruising/lacerations, dental bleeding, self-limited anterior epistaxis, hemorrhoids Not Life, Limb or Organ Threatening Examples: hemodynamically stable GI/GU bleeding, posterior epistaxis Life, Limb or Organ Threatening Examples: ICH, critical site (spine, RP, compartment syndrome), actual or impending hemodynamic compromise, Hb decrease 2 g/l or 2 units RBCs Clinical Reassessment

35 Non-Major Bleeding Major Bleeding Continue NOAC Local measures Monitoring Dose and frequency CBC and creatinine Co-medications (e.g. antiplatelet therapy, NSAIDs) Not Life, Limb or Organ Threatening Interrupt NOAC General measures Compression Volume Replacement Transfusion support Definitive interventions Life, Limb or Organ Threatening Interrupt NOAC General measures Volume/transfusion Hemodynamic support Intensive care unit Definitive interventions Reversal/Hemostatic Idarucizumab (dabi) 4F-PCC *, apcc * Adjunctive therapies DDAVP, antifibrinolytics * Clinical Reassessment *limited/no clinical data; recommended max dose 4F-PCC of 3000 units as per product monograph. Recommend max first dose of FEIBA 2000 units (no data in this setting).

36 Case History 2 month history of worsening SOBOE and fatigue Not sure about bleeding (visually impaired) ECG shows AF rate bpm Resuscitation IV fluids Bloodwork sent When was his last dose of dabigatran? 36

37 Is NOAC present? Drug and dose Timing of last dose Drug half-life Renal function (especially for dabigatran) Concurrent medications that affect drug levels Routine coagulation tests (PT/INR, PTT) Validated NOAC assays

38 Case continued Bloodwork Hb 57 g/l (130 g/l 6 months prior) 258 x10 9 /L INR 1.1, PTT 65 sec Creatinine 165 umol/l (68 umol/l 6 months prior) 38

39 Coagulation Testing is Problematic PT, INR, PTT not accurate or reliable à can be qualitative Alternative assays more reliable but not routinely available Interpretation of tests required: Performance of local assay with drug Dosing interval Drug pharmacokinetics Renal function (especially for dabigatran)

40 Assays to Determine Anticoagulant Activity of NOACs Dabigatran Rivaroxaban Apixaban Edoxaban PT aptt TT dtt ECT Anti-FXa assays û ü û û ü ü ü û û û û û û û û û ü û û û û ü ü ü Time of last NOAC dose should always be considered when interpreting test results Adapted from Heidbuchel H et al. Europace 2015;17: ; Pradaxa EU SmPC, 2014; Eliquis EU SmPC, 2014; Xarelto SmPC, 2014; Savaysa SmPC, 2015

41 Case Supportive care Isotonic IV fluids RBC transfusion Pantoprazole by IV infusion Referral to GI for consideration of urgent endoscopy Should we administer reversal? BP 92/56, O2 95% RA, RR 18/min, HR Hb 56 g/l Last dose dabigatran 4.5 hours prior AKI 41

42 When Should We Consider Reversing Anticoagulation in a Bleeding Patient? Life-threatening (e.g., intracranial, hemodynamically unstable) Critical organ (e.g., pericardial, retroperitoneal) Ongoing (despite measures to control bleeding) Expected long delay in spontaneous restoration of normal hemostasis (over-anticoagulation, renal failure) Eikelboom JW et al. Circulation 2015

43 Idarucizumab: Indications for Use In dabigatran-treated patients: for emergency surgery or urgent intervention in life-threatening or uncontrolled bleeding Contraindications: None to date Idarucizumab can be used in conjunction with standard supportive measures (e.g. plasma, PCC, rfviia) 1. Praxbind EU SmPC, 2015; 2. Praxbind Canadian Product Monograph 2015

44 Case Idarucizumab 5 g IV Urgent EGD Timing?? Forest 1b duodenal ulcer Hemostatic clip placed 24 hours later BP 110/78 HR 87 Hb 94 g/l (after 4 units prbcs) PTT 32 sec Creatinine 109 umol/l Medication management Dabigatran on hold Meloxicam discontinued Pantoprazole infusion x 72h IPC device for VTE prophylaxis 44

45 Case When is it safe to restart anticoagulation??? 45

46 Restarting OAC After GI Bleeding No randomized trials Evidence derived from VKA-related bleeds OAC is permanently discontinued in majority of patients 41% to 51% after GIB Evidence suggests benefit with restarting (with caveats) Timing of resumption unclear

47 Restarting OAC After GI Bleeding THROMBOEMBOLISM RECURRENT GI BLEEDING Chai-Adisaksopha et al. Thromb Haemost 2015; 114:

48 Restarting OAC After GI Bleeding MORTALITY Chai-Adisaksopha et al. Thromb Haemost 2015; 114:

49 Case What if the patient was receiving an oral factor Xa inhibitor? Apixaban Rivaroxaban Edoxaban 49

50 Reversal Strategies Mechanism Non-specific/Hemostatic Prothrombin complex concentrate Activated PCC (FEIBAÒ) Vitamin K dependent factors II, VII, IX, X Activated coagulation factors II, VII, IX, X Recombinant factor VIIa Ciraparantag (PER977) Specific Idarucizumab Andexanet Activated factor VII Small synthetic molecule Monoclonal antibody against dabigatran Recombinant inactive FXa

51 Activate Coagulation to Overcome Drug Effect PCC or apcc FXIIa Contact rviia FXIa FIXa FVIIIa TF FVIIa FVa FXa Rivaroxaban Apixaban Edoxaban Dabigatran Prothrombin Thrombin

52 Evidence for Use of Non-Specific Agents is Limited Derived from in vitro, animal model, volunteer studies, case series No high-quality efficacy and safety data in bleeding patients Evidence for reversal is modest Associated with thrombotic risk Should not be used in lieu of definitive treatments PCC and apcc should be reserved for patients with severe bleeding when specific agents are unavailable

53 Key Messages The best way to manage bleeding is to prevent it NOACs have similar efficacy and improved safety compared to VKA Idarucizmab is the reversal agent of choice for dabigatran Studies are needed to assess the safety and efficacy of non-specific agents (e.g. PCC) for factor Xa-inhibitor reversal Managing bleeding is about more than reversal Address resumption once hemostasis achieved

54 Thank you for your attention!

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