Gastroenterology & Hepatology Update 2017 Prevention and Endoscopy: A Balancing Act in Eastern Caribbean CME Cruise Dr.

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1 Kerri Novak MD University of Calgary 1

2 To review and understand the existing bevy of options for anticoagulation and their mechanism of action Familiarize ourselves with options for management of GI bleeding in the setting of DOAC and antiplatelet therapy Become aware of evidenced based RBC transfusion thresholds in the patient with GI bleeding 2

3 Group work DOAC = Direct Oral Anti-Coagulant 3

4 acetylated salicylate (acetylsalicylic acid) irreversibly acetylate serine 530 of cyclooxygenase (COX) 1 inhibits platelet generation of thromboxane A2, resulting in an antithrombotic effect Rate of GI bleeding associated with ASA at < 100 mg to be 1.1% 1 In patients considered low risk of GI complications In patients considered low risk of GI complications on low dose aspirin the Number needed to harm/ NNH= Am J Hematol. 2004;75(1):

5 Principle mechanism of GI toxicity: disruption of mucosal barrier function Ulcers common in H. pylori positive compared with H. pylori negative irrespective of NSAID use (OR 4.03) and in NSAID users compared with nonusers irrespective of H. pylori status (OR 3.10) Chronic NSAID users sould be checked for Hp & cleared Clin Gastro Hep 2006;4(2):

6 Most important risk is duration of therapy short term less risk Greatest risk of bleeding in the first 3mo Other risks include: Increased age Concomittant t steroids/ anticoagulants t Clopidogrel SSRIs Prior PUD 6

7 GI toxicity relative to the dose of the NSAID: Low dose ibuprofen (RR 1.6, 95% CI ) High dose ibuprofen (RR 4.2, 95% CI ) Low dose naproxen (RR 3.7, 95% CI ) High dose naproxen (RR 6.0, 95% CI ) Low dose indomethacin (RR 3.0, 95% CI ) High dose indomethacin (RR 7.0,,95% CI ) Ann Rheum Dis 2004; 63(7);

8 Meta analysis demonstrated rate of GI bleeding while taking thienopyridines to be 1.6% 1 Risk of bleeding is greatest in the first year 1. Bhatt et al. JACC Vol. 52, No. 18,

9 anticoagulants that directly target the enzymatic activity of thrombin and factor Xa Advantages: Monitoring not required Stable anticoagulation levels Disadvantages: Reversal not uniformly possible 9

10 Anticoagulants anticoagulants and and their site site of action. of action 2016 by American Society of Hematology Christine Ribic, and Mark Crowther Hematology 2016;2016:

11 Heparins Heparins act indirectly by binding to antithrombin (AT, formerly called AT III, also known as heparin cofactor I) rather than by binding directly to coagulation factors 11

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13 68 y.o. male referred to clinic FIT positive routine screening Past Medical History: NSTEMI 10 mo prior Drug Eluting Coronary stent inserted Non valvular AFIB Hypertension NIDDM TIA 2 years prior COPD/Chronic Smoker Medications: Dabigitran 110 mg BID Ticagrelor 90 mg BID ASA 81 mg Metformin 500 BID Metoprolol 25 mg BID 13

14 Patient is booked for colonoscopy How would you manage his antithrombotic therapy? Dabigitran You measure his renal function: Serum Creatinine i = 155 umol/l CrCl = 50 ml/min 14

15 Low Procedural Bleeding Risk High Procedural Bleeding Risk Low risk ik of May continue anti Stop anti Thrombosis or thrombotic agents thrombotic agents Embolism High Risk of Thrombosis or Embolism Continue antithrombotic agents Stop antithrombotic agents (consider bridge therapy) 15

16 High risk Procedures Polypectomy Biliary or pancreatic sphincterotomy Pneumatic or bougie dilation PEG placement Therapeutic balloon assisted enteroscopy EUS with FNA Enteral stent deployment Tumor ablation by any technique Low Risk Procedures Diagnostic (EGD, colonoscopy, flexible sigmoidoscopy) including biopsy ERCP without sphincterotomy EUS without FNA Enteroscopy and diagnostic balloon assisted enteroscopy Capsule endoscopy Diagnostic balloon assisted assisted enteroscopy Cystogastrostomy Treatment of varices BSG Guidelines. Gut 2016;65:

17 Low AF with ihchads2 Score 0 3 Bioprosthetic valve or mechanical aortic valve Previous remote DVT (> 3 months) High Recent CVA/TIA ( <3 months) AF with CHADS2 4 6 DVT/PE in last 3 months Mechanical mitral valve Severe/multiple thrombophillic abnormalities Recent placement of coronary stent (<12 months DES, <1 month for bare metal stent) 17

18 ASGE Guidelines. Gastrointestinal Endoscopy 2016;83:

19 Renal and hepatic dependency of drugs discussed. Christine Ribic, and Mark Crowther Hematology 2016;2016: by American Society of Hematology 19

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21 1884 patients NV Afib patients were enrolled 950 assigned to receive no bridging therapy, 934 assigned to receive bridging The incidence of arterial thromboembolism 0.4% in the no bridging group 0.3% in the bridging group The incidence of major bleeding: 1.3% in the no bridging group 3.2% in the bridging group Conclusion: forgoing bridging anticoagulation was non inferior to perioperative bridging for the prevention of arterial thromboembolism and decreased the risk of major bleeding NEJM 2015;373:

22 Patient is booked for gastroscopy/colonoscopy How would you manage his anti platelet l therapy? Ticagrelor ASA 22

23 Low Procedural Bleeding Risk High Procedural Bleeding Risk Low risk ik of May continue anti Stop anti Thrombosis or thrombotic agents thrombotic agents Embolism High Risk of Thrombosis or Embolism Continue antithrombotic agents Stop antithrombotic agents (consider bridge therapy) 23

24 Agent (ADH Inhibitors) Aspirin Clopidogrel (Plavix) Prasugrel (Effient) Ticagrelor (Brilinta) PAR Inhibitors (Vorapaxar) Stop when? Continue for all procedures Restart when? Time to maximal platelet l t inhibition 5 d 1 d 3 5 days 7 d 1 2 d 4 hours 5 d 1 2 d 4 hours 7 d 1 2 d? Adapted from Baron T, NEJM

25 Continued ASA Stopped dabigitran 2 days prior to procedure Discussed ticagrelor issue with his cardiologist. Agreed to hold ldfor 5 days prior to procedure given that his DES stent was inserted 10 months prior 25

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29 How would you manage this patient s postprocedure medications? When should we restart anticoagulants? A) next day B) 1 week C) 2 weeks D) 4 weeks BSG Guidelines. Gut 2016;65:

30 Bleeding from polpectomy p site stopped spontaneously during procedure Remainder of polyps removed (total of 5) Instructed patient to resume both hdb dabigitran and ticagrelor the following day 30

31 5 days post procedure, patient presents to ER with 12 hours of profuse hematochezia BP on arrival 90/50, pulse 80 Hb 71 Creatinine 200. CrCl

32 a) PT/PTT b) Thrombin time c) Ecarin clotting time d) Anti Xa level e) Hemoclot assay f) Don t know any of these test I would ask the patient when they last took their drug 32

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34 A) activated charcoal B) dialysis C) infuse FFP D) give specific antidote E) give IV fluid 34

35 Sites of action for oral anticoagulants approved for stroke prevention in AF. Idarucizumab, andexanet,* and ciraparantag* are specific reversal agents for the NOAC.7,33,66 *Not currently approved for clinical use. Benjamin A. Steinberg Blood 2016;128: by American Society of Hematology 35

36 Multi center, prospective p cohort study 5 g of intravenous idarucizumab, which was administered as two 50 ml bolus infusions, each containing 2.5 g END point: measurement of the dilute thrombin time or ecarin clotting time Clinical outcomes were secondary endpoints 39% patient had GIB 36

37 Primary outcome LABS: The dilute TT was normalized in 98% of the patients in group A who could be evaluated and in 93% of those in group B, and the ecarin clotting time was normalized in 89% and 88% of the patients who could be evaluated, respectively Secondary Outcomes Clinical: i l the median reported time to the cessation of bleeding was 11.4 hours 1% thrombosis rate 37

38 Suggested Management strategy of NOAC-associated for management bleeding of TSOAC-associated bleeding. Deborah M. Siegal et al. Blood 2014;123: by American Society of Hematology 38

39 How would you manage this patient if he was on warfarin instead of a DOAC? INR 2.6 A) Time B) Vitamin K C) 4 factor PCC D) 3 factor PCC E) afiia 39

40 Sabine Eichinger Hematology 2016;2016: by American Society of Hematology 40

41 FFP 4-Factor PCCs * Coagulation factor contained All FII, FVII, FIX, and FX (in all preparations); PC, PS, antithrombin (in some preparations) ABO typing Required Not required Preparation time min (requires thawing) Minutes (reconstitution of lyophilized powder) Administration time Hours 15 min per 2000 IU Initial effective volume 1000 ml 40 ml Duration of action 6 h (dependent on half-life of coagulation factors) 6 h (dependent on half-life of coagulation factors) Virus inactivated No Yes IU, international units; PC, protein C; PS, protein S. * Beriplex N/P/Kcentra (CSL Behring), Cofact (Sanquin), Kaskadil (LFB), Octaplex (Octapharma), and Prothromplex T(otal) (Baxter). Note: PCCs may contain small amounts of Heparin Caution with history of HITT In a meta-analysis of 18 studies, the frequency of thromboembolic events was 1.8% (95% CI, 1.0%-3.0%) in patients treated with 4-factor PCCs ASH Education Book December 2, 2016 vol no

42 1 week admission to hospital 6 units of blood transfused during hospital stay 42

43 How would you manage this patient s anemia? A) fluid resuscitation alone B) O neg blood ASAP plus fluids C) 1 unit cross matched RBC plus fluids D) 2 Units cross matched RBC plus fluids E) 3 units RBCs 43

44 Conservatism regarding RBC transfusion and the use of O neg units Don t use FFP/PCC for non emergent reversal of warfarin or patients with minimal elevation of INR 44

45 RCT 921 adult pts Restrictive <70 g/l vs liberal <90 g/l Survival at 6 weeks 95 vs 91% p= 0.02 Further bleeding 10% vs 16% p= 0.01 Adverse events 40% vs 48% p= Subgroups: survival higher in PUD, cirrhosis with Child Pugh Class A/B but not C NNH 25 Villanueva et al. NEJM

46 Villanueva et al. NEJM

47 Hgb transfusion threshold of for most hospitalized adult patients who are hemodynamically stable versus hemoglobin transfusion threshold h of 80 for patients undergoing orthopedic or cardiac surgery and for those with underlying cardiovascular disease Patients with acute haemorrhage: no recommendations were made 47

48 AABB: no recommendations could be made The 2013 American College of Gastroenterology guidelines as well as international consensus guidelines: patients with hemoglobin levels 70g/L should receive blood transfusions to reach a target hemoglobin level l of 70 90g/L, provided d that t the individual has no coronary artery disease, evidence of tissue hypoperfusion, or acute hemorrhage h N. Barkun et al., International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding, Annals of Internal Medicine, vol. 152, no. 2, pp , L. Laine Management of patients with ulcer bleeding, American Journal of Gastroenterology, vol. 107, no. 3, pp , 2012 ACG practivce guidelines for PUD (2011) and lower GIB (2016) The American J Gastroenterology 48

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50 For anti platelet and anticoagulant management Need to know procedural risk of bleeding and individual patient risk for thrombosis Measure Creatinine Clearance and dose adjust accordingly Continue ASA therapy for all procedures D/C all other antiplatelet agents for 5 days prior to p g 5 y p high risk procedures 50

51 New reversal agents are coming into clinical practice and idarucizumab is currently available in Canada There are dff differences between PCCs and FFP for reversal of warfarin: use clinical judgement Restrictive transfusion strategy is reasonable in the non exsanguinating gpatient 51

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