Managing Bleeding on NOACs

Transcription

1 Managing Bleeding on NOACs and Other Evolving ED Protocols

2 Objectives Understand that NOACs are widely used in clinical practice Discuss the new and evolving protocols for managing bleeding in patients taking NOACs Learn to handle perioperative management with NOACs

3 Disclosure of Commercial Support This program has received financial support from AstraZeneca and Bayer in the form of an educational grant, and has been co developed in conjunction with the Canadian Association of Emergency Physicians (CAEP). Potential for conflict(s) of interest: Dr. Douketis and Dr. Mathieu have all received payment from Bayer. Dr. Eddy Lang has received payment/funding from Bayer being directed to research trainee fund Bayer licenses a product that will be discussed in this program: Xarelto (rivaroxaban)

4 Mitigating Potential Bias Potential Biases are acknowledged and are mitigated by presenting data supported by national and international guidelines, and as follows: Information presented is evidence based Recommendations made are evidence or guidelines based rather than personal recommendations of the presenter Material has been developed and reviewed by an Educational Committee

5 Faculty/Presenter Disclosure Eddy Lang, MD, MDCM CCFP(EM) Relationships with commercial interests: Grants/Research Support: AstraZeneca and Bayer Speakers Bureau/Honoraria: None Consulting Fees: American Heart Association Other: Salary Support, University of Calgary, Alberta Health Services

6 Faculty/Presenter Disclosure James D. Douketis, MD, FRCPC,FACP, FCCP Relationships with commercial interests: Grants/Research Support: N/A Speakers Bureau/Honoraria: AGEN Biomedical, Astra Zeneca, Biotie, Bayer, BMS, Boehringer Ingelheim, Medicines Co., Pfizer, Portola, Sanofi (all funds from these sources are deposited in university based research accounts) Consulting Fees: N/A Other: N/A

7 Faculty/Presenter Disclosure Bernard Mathieu, MD, CCMF Relationships with commercial interests: Grants/Research Support: N/A Speakers Bureau/Honoraria: AstraZeneca, Bayer, Lilly Consulting Fees: N/A Other: N/A

8 Extensive Experience with NOACs NOAC Patients Treated Worldwide Patients in Completed Phase III Trials Patients in On going Trials TOTAL > 10 million 143,000 45,100 Clinicaltrials.gov; Bayer Press Release Sept 5, 2013; BI Press Release March 6, 2014.

9 Case Study

10 Case Study: Mr. Johnson Your Thoughts? 83 year old man Taking NOAC for AF Previous stroke, diabetes Admitted to ER Pale, tired, abdominal cramps, blood in stool

11 Class Direct Thrombin Inhibitor Xa Inhibitor Xa Inhibitor Examples Dabigatran Apixaban Rivaroxaban C max =E max (hrs) Half life 7 9 young adults older adults older % protein binding 35% 87 93% 92 95% % renal excretion 85% 27% 33% active drug 50% metabolized Effect on: PT Minor Elevation No Elevation Moderate Elevation PTT Moderate Elevation No Elevation Minor Elevation Thrombin time Major Elevation No elevation No elevation Anti Xa Normal Major Elevation Major Elevation Cmax = maximum concentration; Emax = maximum effect. Dabigatran Product Monograph; Apixaban Product Monograph; Rivaroxaban Product Monograph.

12 Mr. Johnson Questions and Tests Evaluation similar to patients on warfarin Physical examination: assess bleeding site Differences timing and dose of their last NOAC assess renal function hydration status creatinine clearance

13 Case Study: Mr. Johnson Your Thoughts? 83 year old man Taking NOAC for AF Previous stroke, diabetes Admitted to ER Pale, tired, abdominal cramps, blood in stool How will you manage the bleed? Who will you consult? WHAT IF: he has a minor/selflimiting bleed? WHAT IF: he has a major bleed?

14 Stratify by Severity of Bleed Minor/Self limiting Moderate/Severe Identify source of bleeding Control with local measures If bleeding continues: hold 1 or 2 NOAC doses If bleeding persists or recurs: Assess renal function Stop NSAIDs and ASA (if possible) Yeh, Gross, Weitz, CJIM submitted; ThrombosisCanada Clinical Guide. Evaluate haemodynamic stability Assess renal function Establish time of last NOAC dose Stop NOAC and antiplatelet drugs (if possible) Identify source of bleeding and control with local measures Volume and blood product replacement as required Activated charcoal if last NOAC dose within 2 hrs If bleeding continues Consider: Procoagulants (PCC, apcc or rfviia) Haemodialysis for dabigatran Antifibrinolytics

15 Four Pillars of Bleed Management with NOACs Resuscitate (fluids, oxygen) Identify and control bleeding source (packing, cauterization) Stop anticoagulant 4 Use appropriate blood product: packed red blood cells (prbcs) if low hemoglobin and/or hemodynamic compromise; plasma and/or cryoprecipitate in cases of massive (> 8 10 prbcs) transfusion Activated charcoal can be considered if the offending NOAC was taken within 2 hours. ThrombosisCanada Clinical Guide.

16 Prohemostatic Agents for NOAC Agent Dabigatran Apixaban (based on one study) Rivaroxaban 4 Factor PCC (PCC; Beriplex, Octaplex) Activated 4 Factor PCC (FEIBA) Recombinant activated Factor VII (Novoseven, Niastase) Fresh frozen plasma Cryoprecipitate No study has assessed the clinical effect of these agents in patients with active bleeding events. 2 = Probably beneficial; 1 = Possibly beneficial; 0 = Probably ineffective ThrombosisCanada Clinical Guide.

17 Antidotes for NOACs Specific antidotes to NOACs with rapid reversal are in development expected soon PRT (Andexanet Alfa) phase 2 completed with positive results for apixaban and rivaroxaban phase 3 ongoing adabi Fab for dabigatran phase 1 RCT in healthy subjects successful global phase III study (European sites) ongoing Short half life supportive measures are key Hohnloser SH et al. J Am Coll Cardiol 2007;50(22): doi: /j.jacc

18 NOACs Reduce Mortality vs Warfarin N=71,683 RR (95% CL) P All cause mortality Vascular mortality Bleeding mortality 0.89 ( ) < ( ) < ( ) < Meta analysis incl: RE LY Dabigatran 150 mg BID RE LY Dabigatran 110 mg BID ROCKET AF Rivaroxaban 20 mg OD ARISTOTLE Apixaban 5 mg BID ENGAGE AF TIMI 48 Edoxaban 60 mg OD ENGAGE AF TIMI 48 Edoxaban 30 mg OD Favours NOAC Favours warfarin Liew A et al. J Thromb Haemostasis; first published online: 25 JUL 2014.

19 Case Study: Mr. Johnson Your Thoughts? 83 year old man Taking NOAC for AF Previous stroke, diabetes WHAT IF: he has a lifethreatening ICH after a fall? (normal renal function, taking dabigatran) Admitted to ER Pale, tired, abdominal cramps, blood in stool

20 Role of Hemodialysis POTENTIALLY CAN BE USED TO REMOVE DABIGATRAN because of low protein binding not effective in hypotensive patients NOT EXPECTED TO REMOVE RIVAROXABAN OR APIXABAN because the drugs are highly protein bound 92 95% rivaroxaban 87% apixaban CHALLENGING TO ARRANGE IN A TIMELY MANNER Dager WE. Am J Health Syst Pharm 2013;70(10 Suppl 1):S21 31.

21 Mr. Johnson s Hemodialysis The plasma concentration during the 3 hour hemodialysis session, but after hemodialysis ended Rebound effect probably due to redistribution of the drug from tissues to plasma A longer period of hemodialysis may be needed Chang DN, et al. Am J Kidney Dis 2013;61:487 9.

22 Case Study: Mr. Johnson Your Thoughts? 83 year old man Taking NOAC for AF Previous stroke, diabetes Admitted to ER Pale, tired, abdominal cramps, blood in stool WHAT IF: he needs a surgery? What protocol will you use for stopping the NOAC for his surgery if his condition is stable? What if he needs an urgent surgery?

23 NOAC Must Be Stopped Before a Non Minor Procedure CrCl 30 ml/min Pre Operative Phase Rivaroxaban Minor Procedure Last dose: day 2 before procedure (skip 1 dose) Major Procedure Last dose: day 3 before procedure (skip 2 doses) Post Procedural Period Apixaban & Dabigatran Restart AC Last dose: day 2 before procedure (skip 2 doses) (for dabi and CrCl 30 50, last dose day 3 pre procedure) Restart 24 hrs after surgery Last dose: day 3 before procedure (skip 4 doses) (for dabi and CrCl 30 50, last dose day 6 pre procedure) Restart hrs after surgery ThrombosisCanada Clinical Guide.

24 Correlation between PT and Plasma Rivaroxaban Levels in Healthy Human Subjects Kubitza D, et al. Eur J Clin Pharmacol 2005;61(12):

25 Clotting tests and pharmacodynamic effects of apixaban PT: Prothrombin time INR: International normalized ratio aptt: Activated partial thromboplastin time Change from baseline (%) Eliquis, PM 2012; Frost et al. J Thromb Haemost 2007;5(Suppl 1):P M Apixaban concentration (ng/ml)

26 Laboratory Monitoring of Rivaroxaban and Apixaban around Surgery STEP 1: PROTHROMBIN TIME (PT) if elevated PT, likely some rivaroxaban effect BUT assay dependent if normal PT, no significant rivaroxaban effect may NOT apply to apixaban! STEP 2: ANTI FACTOR XA ASSAY LMWH calibrated anti Xa assay Spyropoulos A, Douketis J. Blood 2012;120: ; Garcia D, et al. J Thromb Haemost 2013;11:

27 Effect of Dabigatran on Coagulation Tests PT (INR) Thrombin time aptt Dilute Thrombin time (Hemoclot)

28 Laboratory Monitoring of Dabigatran around Surgery STEP 1: PARTIAL THROMBOPLASTIN TIME (aptt) if elevated aptt, likely some dabigatran effect if normal aptt, no significant dabigatran effect STEP 2: THROMBIN TIME (TT) OR HEMOCLOT TEST standard TT too sensitive if normal TT (< 30 sec) or if normal Hemoclot, no detectable dabigatran anticoagulant effect Spyropoulos A, Douketis J. Blood 2012;120: ; Garcia D, et al. J Thromb Haemost 2013;11:

29 Bleeding and Urgent NOAC Reversal MINOR MAJOR DELAY NEXT DOSE OR DISCONTINUE TREATMENT (as appropriate) APPROPRIATE SYMPTOMATIC TREATMENT e.g. mechanical compression surgical hemostasis fluid replacement and hemodynamic support blood products (PRBC or FFP) or platelets CONSIDER ADMINISTRATION OF ONE OF THE FOLLOWING PROCOAGULANTS* activated prothrombin complex concentrate (apcc) prothrombin complex concentrate (PCC) recombinant Factor VIIa (rfviia) *There is currently only very limited experience with the use of these products in individuals receiving rivaroxaban. Xarelto Product Monograph; ThrombosisCanada Clinical Guide.

30 QUESTIONS? Enter questions in the text box on Text questions to questions to IMPORTANT: When ing, please enter question in the subject line only

31 Key messages NOACs have a short half life, so bleeding can often be managed with supportive measures Reversal agents and hemodialysis can be used in some cases Despite the lack of antidote, fatality rates with NOACs are lower than with warfarin ER physicians should be involved in creation of hospital wide protocols for managing patients on NOACs

32 Thank You! Content for this program has been developed by the following steering committee: Anil Chopra, Jim Douketis, Indy Ghosh, Lyall Higginson, Eddy Lang, Josée Martineau, Anas Nseir, and Bill Semchuck COMMERCIAL SUPPORT ACKNOWLEDGEMENT: THIS EDUCATIONAL ACTIVITY IS SUPPORTED BY AN INDEPENDENT EDUCATIONAL GRANT FROM ASTRAZENECA and BAYER CANADA