Periprocedural Management of Direct Oral Anticoagulants (DOACs)

Transcription

1 + Periprocedural Management of Direct Oral Anticoagulants (DOACs) Mary-Margaret Keating MD FRCPC Hematology Assistant Professor, Dalhousie University Halifax, NS Canada

2 + Presenter Disclosures Faculty/Presenter Speakers Bureau/Honoraria Mary-Margaret Keating Bayer

3 + Periprocedural management of DOACs Objectives Describe the pharmacokinetics of DOACs Identify risks of periprocedural bleeding Understand current evidence available for periprocedural management of DOACs Bridging Timing of stop/start Emergent procedures

4 + Periprocedural management of DOACs Introduction Based on 3 major factors Elimination half life of drug Renal function Bleeding risk of surgery

5 + Overview of DOACs History Mechanism Indications Pros/Cons

6 + Overview DOACs History - anticoagulant options

7 + Overview of DOACs Mechanism of action Edoxaban Soff GA. Arterioscler Thromb Vasc Biol 2012

8 + Overview of DOACs Indications Use continues Dabigatran to rise given Rivaroxban multiple studies Apixaban showing Edoxaban they are as efficacious (Pradax and as ) safe (Xarelto as vitamin ) K (Eliquis antagonists ) (Savaysa (VKAs) for ) DVT/PE and non valvular atrial fibrillation A fib VTE treatment VTE prevention (ortho) Douketis J and Liew A. Intern Emerg Med 2013

9 + Overview of DOACs Pros Oral fixed dosing Quick onset No significant drug or food interactions Predictable response No requirement for lab monitoring Cons Not reversible Can t use for CrCl<30cc/min Offset not quick Expensive

10 + Timing of anticoagulant interruption Pharmacokinetic properties Bleeding risk Stop & start recommendations Dabigatran Rivaroxaban & Apixaban

11 + Key pharmacokinetic properties Property DOAC Dabigatran Rivaroxaban Apixaban Peak action (t max ) 1-3 hrs 1-3 hrs 1-3 hrs Elimination half-life (t 1/2 ) hrs 5-9 hrs 9-14hrs Route of clearance 80% renal 35% renal 25% renal Douketis JD. Curr Pharm Des 2010

12 + Perioperative bleeding risk High risk: 2 day risk of major bleed 2-4% Cardiovascular CABG, Valve, AAA Ortho Arthoplasty, laminectomy GI PEG placement, polypectomy, biliary sphincterectomy, endoscopic FNA GU TURP, renal biopsy Other Any major operation >45 minutes Cancer surgeries (neuro,urol,head & neck,abd,breast) Multiple tooth extractions (>3) Spyropoulos AC and Douketis JD. Blood 2012

13 + Perioperative bleeding risk Low risk: 2 day risk of major bleed of <2% CV/Resp Afib ablation/ep testing, Pacemaker insertion Bronchoscopy Ortho GI Arthroscopy, carpel tunnel Abd hernia repair, chole, endoscopy/biopsy, biliary/panc stent, hemorrhoids GU Hysterectomy, D&C Other Simple dental extraction, Skin cancer excision, Cataract and other minor eye surgery Biopsies bladder, prostate, thyroid, breast, LN Spyropoulos AC and Douketis JD. Blood 2012

14 + Timing of anticoagulant interruption Dabigatran CrCl 80 ml/min CrCl ml/min CrCl ml/min Dabigatran timing of withdrawal preop T 1/2 Low bleeding procedure High bleeding procedure ~13 hrs 24 hrs 48 hrs ~15 hrs 36 hrs 72 hrs ~18 hrs 48 hrs 96 hrs Dabigatran Canadian Product Monograph Douketis J and Liew A Intern Emerg Med 2013 Postoperatively resume 24 hrs post if low bleeding risk hrs with high bleeding risk

15 + Timing of anticoagulant interruption Rivaroxaban & Apixaban Direct Xa inhibitors timing of withdrawal preop Low bleeding procedure High bleeding procedure CrCl 80 ml/min 24 hrs 48 hrs CrCl ml/min 24 hrs 48 hrs CrCl ml/min 24 hrs 48 hrs Postoperatively resume 24 hrs post if low bleeding risk hrs with high bleeding risk Rivaroxaban & Apixaban Canadian Product Monograph

16 + Perioperative management DOACs Early evidence - dabigatran Sub-analysis of RE-LY trial of 4591 patients who underwent at least one invasive procedure/surgery Methods Last dose of dabigatran ~49hr pre-procedure 17% with elective surgery received heparin bridging Last dose warfarin ~114hr pre-procedure Results 27% with elective surgery received heparin bridging No difference in rates of periprocedural major bleeding Dabigatran 3.8% vs warfarin 4.6% No difference in bleeding for urgent surgery Dabigatran 17.8% vs warfarin 21.6% Need prospective trial Healey JS et al. Circulation 2012

17 + Canadian multi-center prospective cohort study using pre-specified protocol for perioperative management of dabigatran Study population Age at least 18 and on dabigatran for any indication Elective surgery requiring interruption of dabigatran Schulman S et al. Circulation 2015

18 + Perioperative dabigatran study group Methods Last dose of dabigatran based on CrCl (done at visit 1wk preop) Bleeding risk of procedure Restarting dabigatran Minor procedures Evening of procedure 75mg & increase to full dose next AM Major bleeding risk procedures Delayed 48-72hr post op starting with full dose Neuraxial anesthesia Frist dose dabigatran >4hr after catheter removal Outcome measure (at 30 days) Primary major bleeding Secondary minor bleed, ATE and death Schulman S et al. Circulation 2015

19 + Perioperative dabigatran study group Timing of dabigatran last dose pre-op Schulman S et al. Circulation 2015

20 + Perioperative dabigatran study group Results 541 cases included Compliance 89% compliance with stopping protocol 77% compliance with re-starting protocol Perioperative bleeding rates 1.8% with 1 major bleeding event 5.2% with 35 minor bleeding events 8 patients had neuraxial anesthesia & 5 had epidural injections No bleeding issues with any Perioperative thrombosis rates 1 event (0.2%) a TIA Schulman S et al. Circulation 2015

21 + Perioperative dabigatran study group Conclusion Pros First prospective study using specified protocol for stopping and starting dabigatran preoperatively Results show protocol is feasible and safe No bridging required Cons Only looks at dabigatran Non randomized A little complicated Schulman S et al. Circulation 2015

22 + Perioperative management of DOACs What about the other DOACs? Westendorf JB et al. Eur. Heart J 2014

23 + Perioperative management of DOACs What about the other DOACs? Objective Evaluate peri-interventional DOAC management in unselected patients from daily care Methods Prospective non-interventional registry of 2179 DOAC patients Patients who underwent a procedure were identified Status of DOAC determined periop (held, stopped, bridged) Bleeding & thrombosis outcomes during first 30 days recorded Westendorf JB et al. Eur. Heart J 2014

24 + Perioperative management of DOACs What about other DOACs? Results 863 procedures 74% minor 76% on rivaroxaban, 23% on dabigatran, 0.5% apixaban Major CV events 1% Major bleeding 1.2% Perioprocedural management of DOAC 21% DOAC continued 48% DOAC temporarily stopped without bridging Median time of interruption 2 days pre and 1 day post 7% DOAC temporarily stopped with LMWH bridging 7% prophylactic and 22% therapeutic LMWH dosing Bridging Increased bleeding (2.7% vs 0.5%) No reduction of CV events Westendorf JB et al. Eur. Heart J 2014

25 + Perioperative management of DOACs What about the other DOACs? Conclusion Interventional procedures common in DOAC patients Most are minor Rate of complication is low (bleed and embolic) Bridging did increase bleeding Limitations Registry data Westendorf JB et al. Eur. Heart J 2014

26 + Perioperative management of DOACs What about the other DOACs? Study currently underway PAUSE Perioperative Anticoaulant Use for Surgery Evaluation Canadian multicenter prospective cohort study Uses prespecified stopping rules for all 3 DOACs Results expected ~July 2017 Clinicaltrials.gov

27 + To bridge or not to bridge DOACs Currently no evidence-based practice guidelines No comment in CHEST 2012 No ongoing or planned bridging trials for DOACs Expert opinion Perioperative LMWH bridging is not needed in DOAC treated patients who require elective surgery/procedure Rapid offset and onset Post op may be needed in select patients unable to take pills ie use LMWH until can take/absorb pills again DOAC can be restarted within 12hr of last dose of LMWH Douketis J and Liew A. Intern Emerg Med 2013

28 + What about with emergent procedures? Lab testing that may be helpful Reversal agents

29 + What about with emergent procedures? Lab testing that may be helpful General points Consider lab monitoring for emergent procedures if last dose of DOAC <24hr pre procedure CrCl <50cc/min Be aware of how DOACs may affect routine coag testing Knowledge still evolving in this area Reversal agents Idarucizumab Others Baglin T et al. J Thromb Haemost 2013

30 Douketis JD.Curr Pharm Des 2010 Baglin T et al.j Thromb Haemost 2013 Garcia D et al. J Thromb Haemost What about with emergent procedures? Dabigatran - Lab testing that may be helpful aptt likely best screening test Study looking at aptt 4-8hr post last dose PTT >80s = higher than expected effect (?bioaccumulation) PTT 45-80s = expected effect Normal PTT = likely no significant anticoagulant effect TT is likely too sensitive for screening Normal TT confirms no dabigatran effect High TT may remain for days & doesn t reflect clinically important anticoagulant effect Diluted TT (Hemoclot Thrombin Inhibitory assay) Not widely available Likely most accurate to detect residual effect

31 Douketis JD.Curr Pharm Des 2012 Baglin T et al. J Thromb Haemost 2013 Helin TA et al. Clin Chem Timing of anticoagulant interruption Rivaroxaban & Apixaban PT Rivaroxaban Can be used as qualitative test High PT suggests some drug present Apixaban Limited effect on PT Anti-Xa assay Rivaroxaban & Apixaban If calibrated correctly can be used quantitatively Normal value likely no drug present

32 + What about with emergent procedures? RE-VERSE AD study Pollack CV et al. N Engl J Med 2015

33 + What about with emergent procedures? RE-VERSE AD study - Idarucizumab Methods Prospective cohort to determine safety & efficacy of 5g IV idarucizumab for reversal of dabigatran in patients with serious bleeding or required urgent procedure Primary endpoint % reversal of dabigatran anticoagulant effect within 4 hours Dilute thrombin time or ecarin clotting time (at central lab) Secondary endpoint Restoration of hemostasis Pollack CV et al. N Engl J Med 2015

34 + What about with emergent procedures? Reversal agents - Idarucizumab Results 90 patients (51 bleeding, 39 operative) Median maximum reversal was 100% - effect within minutes 1 thrombotic event within 72hr of idarucizumab Conclusion Idarucizumab seems to work! Pollack CV et al. N Engl J Med 2015

35 + What about with emergent procedures? Rivaroxaban & Apixaban Antidotes under development Andexanet alfa (PRT064445) Recombinant protein binds factor Xa inhibitors Reversed anticoagulant effects of factor XA inhibitors in vitro and in rat model Clinical studies for safety & efficacy underway Perosphere (PER977) Small molecule antidote for all DOACs Binds directly & specifically to all DOACs and LMWH/UFH Lu G et al. Nat Med 2013 Ansell JE et al. N Engl J Med 2014

36 + Perioperative management of DOACs Summary Key elective perioprocedural information Drug half life CrCl Bleeding risk of procedure Bridging is out Resumption of drug postoperatively Don t do do quickly with high risk procedures (48-72hr) Emergent situations should get easier in next few years