Management of invasive procedures and bleeding compica5ons in pa5ents on NOACs

Management of invasive procedures and bleeding compica5ons in pa5ents on NOACs Michiel Coppens MD PhD Internist- Vascular Medicine Academic Medical Center, Amsterdam, The Netherlands McMaster University, Hamilton, Ontario, Canada

Research grant Conflicts of interest Michiel Coppens Sanquin Blood supply (manufacturer of a 4 factor PCC) Boehringer Ingelheim (dabigatran) Consulta5on fees Boehringer Ingelheim Bayer (rivaroxaban)

Two clinical seqngs Non- emergency Interrup5on for invasive procedures Elec5ve, semi- elec5ve procedures Emergency Major bleeding Emergency/immediate surgery

Non- emergency interrup5ons 1. How long un5l the an5coagulant ac5vity wears off? 2. What is the acceptable residual ac5vity to proceed with the invasive procedure? 3. Should we bridge with (LMW) Heparins?

How long un5l the effect wears off? Elimina'on half- life (T 1/2 ) egfr (ml/min) Dabigatran > 80 51-80 30-50 15-30 Rivaroxaban > 30 15-30 T 1/2 (h + 95%CI) 13 15 18 27* 9 ~ 10* Apixaban > 25 12 * Based on popula5on PK modeling and/or very limted number of pa5ents

Acceptable residual ac5vity Ideally: threshhold blood level per drug Currently unavailable Real world data may eventually provide answers (similar to VKA) Un5l that 5me: a pragma5c approach Very low risk of bleeding Don t stop; perform at trough blood level Standard bleeding risk 2-3 elimina5on half- lives: 12.5-25% residual ac5vity High bleeding risk 4-5 elimina5on half- lives: 3.125-6.25% residual ac5vity

Risk of bleeding per type of procedure

A prac5cal scheme European Heart Rhythm Associa5on (EHRA) Prac5cal Guide Europace 2013;15:625-51

Bridging with LMWH? Is there a ra5onale? Hardly... T 1/2 NOACs shorter than VKA T 1/2 NOACs only modestly longer than LMWH Lessons from bridging VKA therapy Observa5onal data, subject to bias * Increased risk of bleeding (OR 3-6) Uncertain protec5on from thrombosis (OR 0.8 N.S.) Randomized studies ongoing * Siegal, Circula5on 2012

Management of urgent surgery Management of bleeding

No An5dote for NOACs! The No. 1 concern! Desirable to get rid of ac5vity at 5me of emergency Goal of using an5dote To improve outcome, not to normalize a blood test How important is a reversal agent? How ooen do we need it? Does it improve outcome?

How important is an an5dote? Phase 3 trials provide insight Comparisons of outcome of bleeding VKA (specific an5dote available) NOAC (no specific an5dote available) Hypothesis: outcome beqer for VKA than for NOACs by virtue of the an5dote

RE- LY trial dabigatran vs. VKA in AF (N=18,113) Management of Major Bleeding Dabigatran Warfarin P Pts with major bleeding 741 6.1% 421 7.0% RBC transfusion 59.2% 3.6% 49.9% 3.5% 0.002 FFP transfusion 19.8% 1.2% 30.2% 2.1% <0.001 Vitamin K used 9.4% 0.6% 27.3% 1.9% <0.001 Factor concentrates (PCC, rviia, others) 2.2% 0.1% 2.9% 0.2% 0.38 Majeed, Circula5on 2013

RE- LY trial Dabigatran vs. VKA: AF (N=18,113) Outcome of Major Bleeding Dabigatran Warfarin P OR (95%CI) Pts with major bleeding 741 421 Length of stay (days) 8.4 8.9 0.48 Nights in ICU/CCU (days) 1.6 2.7 0.01 Requiring surgery 12.1% 15.0% 0.17 30 day mortality 9.1% 13.0% 0.06 0.56 (0.36-0.86) Adjusted for age, sex, weight, renal func5on and concomitant use of an5platelet drugs Majeed, Circula5on 2013

EINSTEIN DVT/PE/Ext Rivaroxaban vs. VKA: VTE treatment (N=8,246) Rivaroxaban VKA/LMWH Major bleeding episodes 40 1.0% 72 1.7% Life threatening requiring immediate and 11.1% 0.1% 21.5% 0.4% elaborate measures to avoid death, incl - surgical/endoscopic/radiological - factor concentrates (PCC, rviia) Mortality 7.5% 0.07% 11.1% 0.2% Eerenberg, Abstract OC 02.2, ISTH Amsterdam 2013

Emergency surgery RE- LY Dabigatran VKA Emergency surgery 248 111 Major bleeding 17.7% 21.6% N.S. Surgery <24 h aoer discon5nua5on Major bleeding 4.8% 15.4% 0.01 Healey, Circula5on 2012

NOACs vs. VKA Lessons from the phase 3 trials 1. Factor concentrates rarely necessary/used Max 2% of pa5ents with major bleeding <1% of pa5ents using dabigatran/rivaroxaban 2. Compared with VKA bleeds No increased mortality More RBC use, less FFP use No addi5onal surgery necessary

Lessons from phase 3 trials Drawbacks Trial pa5ents are healthier Will this apply to daily prac5se? Were warfarin bleeds op5mally managed? Vitamin K use 27%, PCC use 1.2% Does not seem to match European prac5se Prospec7vely collected (phase 4) data necessary to verify trial results

Immediate reversal of NOACs Non- specific prohaemosta5c agents Prothrombin complex concentrate 4 factor or 3 factor (II, IX, X only) Recombinant ac5vated factor VII Ac5vated PCC (FEIBA)

Non- specific prohaemosta5c agents Evidence from humans with bleeding complica5ons Non- existent thus far Placebo controlled RCT considered unethical Case series awaited Alterna5ves Poten5al to normalize coagula5on tests in non- bleeding volunteers Poten5al to reduce bleeding in animal models

Poten5al to normalize coagula5on tests Eerenberg, Circula5on 2011

Animal studies Mice, intracranial bleeding Zhou, Stroke 2011

Summary non- specific prohaemosta5c agents Healthy human volunteers PCC 50 U/kg may work for rivaroxaban Similar results for 3 factor PCC* 25 U/kg, 37.5 U/kg: analyses underway No effect in dabigatran treated pa5ents Apixaban: analyses underway APCC, rviia not tested Animal models Somewhat conflic5ng studies 4 factor PCC may be effec5ve at 25-100 U/kg dose * Levi, Abstract OC 36.5, ISTH 2013 Amsterdam

The Future: specific an5dotes Dabigatran Humanized an5body fragment directed at dabigatran Phase 2 (145 healthy male volunteers treated with dabigatran): immediate and sustained full reversal Phase 3 (bleeding pa5ents) to start in 2014 Schiele, Blood 2013; Glund, AHA Dallas 2013

Specific an5dote Factor Xa inhibitors Andexanet alfa Recombinant factor Xa GLA domain deleted; ac5ve site modifica5on Compe55ve inhibi5on of all Xa inhibitors apixaban, rivaroxaban, betrixaban, LMWH Ongoing phase 2 apixaban (abstract of first few pa5ents) Dose dependent reversal of apixaban Lu, Nat Medicine 2013; Crowther, ISTH Amsterdam 2013

How to manage NOAC bleeding in 2013? 1. Have a protocol in your hospital 2. Time is your best friend Every 12 h wait: 50% decrease in blood levels 3. Suppor5ve measures will likely be sufficient in the vast majority of pa5ents 4. Source control: endoscopy, radiological interven5ons, surgery

How to manage NOAC bleeding in 2013? 5. Consider: Platelet transfusion in case of an5platelet drugs Tranexamic acid? FFP for replacement of blood/plasma loss Dialysis for dabigatran? 6. For the most severe cases / life- threatening bleeding PCC 25-50 U/kg Recombinant VIIa? APCC?

Conclusions 1. NOACs if we want the phase 3 trial results to apply to our pa5ents: use NOACs properly! Check renal func5on Check potent interac5ons (strong CYP3A4, P- gp inhibitors) Who provides follow- up 2. Non- emergency interrup5ons Timing of cessa5on based on T1/2 and type of procedure LMWH bridging not advised

Conclusions 3. Major bleeding Specific an5dotes are only needed in a minority of pa5ents Suppor5ve measures usually sufficient Most severe cases: consider non- specific agents Specific an5dotes are coming