How to Handle the Bleeding Risk Related to Oral Anticoagulants

Transcription

1 How to Handle the Bleeding Risk Related to Oral Anticoagulants Ammar Majeed Hematology Center, Karolinska University Hospital and Karolinska Institute, Stocklholm, Sweden;

2 Comparing bleeding on NOACs and warfarin Bleeding on NOACs vs bleeding on warfarin The possibility to reverse warfarin with PCC, no antidote for NOACs If you get a head bleeding on warfarin we can treat it with PCC (Octaplex) If you bleed on the new agents, there is no antidote Puts off both patients and doctors from using NOACs

3 Comparing bleeding on NOACs and warfarin Bleeding on NOACs vs bleeding on warfarin The possibility to reverse warfarin with PCC, no antidote for NOACs Dose the fact that having / not If you get a head bleeding on warfarin we can treat it with PCC (Octaplex) having a reversal agent/antidote equals good/bad prognosis and outcome? If you bleed on the new agents, there is no antidote Puts off both patients and doctors from using NOACs

4 Questions Introduction Can the major bleeding evens on the new anticoagulants be managed only by volume substitution and transfusion of blood products? Is there a role for non-specific hemostatic agents? Antidotes under development Prevention of bleeding on NOACs

5 Questions Introduction Can the major bleeding evens on the new anticoagulants be managed only by volume substitution and transfusion of blood products? Is there a role for non-specific hemostatic agents? Antidotes under development Prevention of bleeding on NOACs

6 Development of NOACs focus on two targets in the coagulation cascade Intrinsic XII Extrinsic XI IX VIII X VII Tissue Factor Direct Xa Inhibitors -xaban warfarin V II Fibrinogen Direct Thrombin Inhibitors -gatran Fibrin Clot

7 New and Emerging Anticoagulants Anti Xa : direct Rivaroxaban (oral) Xarelto Apixaban (oral) Eliquis Edoxaban (oral) Lixiana Betrixiban (oral) Otamixaban (parenteral) LY (oral) DU 176B (oral) DX 9065a (parenteral) PRT (oral) Anti IIa Dabigatran (oral) Pradaxa Odiparcil (oral) Flovagatran (parenteral) Pegmusirudin (parenteral) Peg Hirudin Desiruidin

8 Status of NOACs Dabigatran Pradaxa Rivaroxaban Xarelto Apixaban Eliquis Edoxaban Savaysa Atrial Fibrillation VTE Treatment VTE Prevention Orth Surgery Approved Approved Approved Approved Approved Applied for approval 19/12/2013 Applied for approval 8/1/2014 Applied for approval 8/1/2014 Approved Approved Approved No activity 8

9 Incidence of Major Bleeding in Phase III studies* Indication AF studies VTE studies Thromboprophylaxis studies Dabigatran % % % 6 Rivaroxaban 5.6% % 4,5 0.3% 7 Apixaban 3.6% % Edoxaban Treatment Duration years 3-12 months 2-5 weeks Annual rate of major bleeding 1-3% *Figures in table are unadjusted for treatment duration Figures in red indicate rates significantly lower than warfarin 1. N Engl J Med Sep 17;361(12): N Engl J Med Sep 8;365(10): N Engl J Med Dec 10;361(24): N Engl J Med Dec 23;363(26): N Engl J Med Apr 5;366(14): Thromb Res Sep;126(3): Thromb Haemost Mar;105(3): Epub 2010 Dec N Engl J Med Sep 15;365(11): Epub 2011 Aug N Engl J Med, (9): p Giuglianpo NEJM Buller NEJM Kawaji ort res 2012

10 Rate of Intracranial Bleeding in AF studies

11 Rate of Gastrointestinal Bleeding in AF studies

12 General recommendation for the management of NOAC bleeding Patient with bleeding on NOACs Mild bleeding Moderate to severe bleeding Life-threatening bleeding Delay next dose or discontinue treatment as appropriate Symptomatic treatment Mechanical compression Surgical intervention Fluid replacement and hemodynamic support Blood product transfusion Oral charcoal application* (if drug ingested <2 hrs before) Hemodialysis Consideration of rfvlla or PCC* Charcoal filtration* *Recommendation based only on limited non-clinical data; there is almost no experience in volunteers or patients. CFC: coagulation factor concentrate; PCC: prothrombin complex concentrate; rfviia: recombinant activated factor VIIa. Eerenberg ES et al. Circulation 2011;124: ; van Ryn J et al. Thromb Haemost 2010;103(6):

13 Questions Introduction Can the major bleeding evens on the new anticoagulants be managed only by volume substitution and transfusion of blood products? Rationale: Short half life of NOACs effect diminishes quickly when discontinued Is there a role for non-specific hemostatic agents? Antidotes under development Prevention of bleeding on NOACs

14 The online version of this article, along with updated information and services, is located on the M anagement and Outcomes of M ajor Bleeding During Treatment With Dabigatran or Warfarin Ammar Majeed, Hun-Gyu Hwang, Stuart J. Connolly, John W. Eikelboom, Michael D. Ezekowitz, Lars Wallentin, Martina Brueckmann, Mandy Fraessdorf, Salim Yusuf and Sam Schulman Circulation. 2013;128: ; originally published online September 30, 2013; doi: /CIRCULATIONAHA Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2013 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN:

15 Patient Population: Phase III Dabigatran Trials Phase III trial Patients Treatments RE-LY 1 RE-COVER 2 RE-COVER II 3 RE-MEDY 4 RE-SONATE 5 18,113 atrial fibrillation patients (stroke prevention) 2539 VTE patients (treatment) 2568 VTE patients (treatment) 2856 VTE patients (secondary prevention) 1343 VTE patients (secondary prevention) Dabigatran 110 mg Dabigatran 150 mg bid Warfarin Dabigatran 150 mg bid Warfarin Dabigatran 150 mg bid Warfarin Dabigatran 150 mg bid Warfarin Dabigatran 150 mg bid Placebo Number of patients randomized and treated in these 5 trials: 27,419 Dabigatran: 16,755 Warfarin: 10,002 Duration of treatment Median, 2 years 6 months 6 months Mean, 15.5 months 6 months VTE: venous thromboembolism. 1. Connolly SJ et al. N Engl J Med 2009; 361: ; 2. Schulman S et al. N Engl J Med 2009;361: ; 3. Schulman S et al. Proceedings of ASH Conference 2011:Abstr 205; 4. Schulman S et al. J Thromb Haemost 2011;9:22 (Abstr. O-Thu-033); 5. Schulman S et al. J Thromb Haemost 2011;9;22 (Abstr. O-Mo-037)

16 Strategies Used for Management of Major Bleeding Dabigatran* Warfarin P-Value Blood transfusion, n (%) 439 (59.2) 210 (49.9) Fresh frozen plasma, n (%) 147 (19.8) 127 (30.2) <0.001 Vitamin K, n (%) 70 (9.4) 115 (27.3) <0.001 Prothrombin complex concentrate, n (%) 5 (0.7) 5 (1.2) 0.36 Recombinant factor VIIa, n (%) 8 (1.1) 3 (0.7) 0.53 Major bleeds in the dabigatran groups were more frequently treated with blood transfusions than those on warfarin but less frequently with plasma. Data derived based on the randomized set of RE-LY. * Data combined from dabigatran 150 mg and dabigatran 110 mg bid treatment groups

17 Short-term Consequences of Major Bleeding Dabigatran* Warfarin P-Value Patients with hospitalization*, n (%) 456 (61.5) 254 (60.3) 0.68 Length of stay, days, mean (SD) 8.4 (9.1) 8.9 (9.8) 0.48 Nights in ICU/CCU, mean (SD) 1.6 (4.3) 2.7 (6.6) 0.01 Nights in step-down unit, mean (SD) 1.0 (2.5) 1.0 (2.7) 0.84 Patients with major bleed requiring surgery, n (%) 90 (12.1) 63 (15.0) 0.17 Length of stay in ICU is shorter with dabigatran treatment than with comparator

18 Mortality After a Major Bleed 5 Phase III Trials The Kaplan-Meier analysis indicated a reduced risk for death with dabigatran* vs. warfarin during 30 days from the bleeding (P=0.057). * Data combined from dabigatran 150 and dabigatran 110 mg bid treatment groups. Only first major bleed included. Analysis not adjusted for covariates.

19 Adjusted Analysis of Mortality following a Major Bleed OR for 30-day mortality adjusted for sex, age, weight, renal function and additional antithrombotic therapy Treatment and Database Used OR (95% CI) P-Value Dabigatran 150 mg mg, all studies 0.66 (0.44, 1.00) Dabigatran 150 mg, all studies Dabigatran 110 mg, RE-LY Dabigatran 150 mg mg, RE-LY Dabigatran 150 mg, RE-LY 0.68 (0.42, 1.08) 0.60 (0.35,1.03) 0.56 (0.36,0.86) 0.53 (0.31,0.88) Favours dabigatran Favours warfarin Adjusted analysis demonstrates mortality benefit for dabigatran in RE-LY CI: confidence interval; OR: odds ratio

20 Prognosis of Intracranial Hemorrhage RE-LY trial Data on the initial and final Rankin score evaluations were available for 78 (55%) patients with intracranial hemorrhage. Treatment comparison P-Value for comparison of change in modified Rankin score Dabigatran* vs warfarin 0.97 Dabigatran 150 mg bid vs warfarin 0.81 Dabigatran 110 mg bid vs warfarin 0.80 Dabigatran 150 bid mg vs 110 mg bid 0.78 No significant difference between treatments in modified Rankin scale score for intracranial hemorrhage since admission * Data combined from dabigatran 150 and dabigatran 110 mg bid treatment groups

21 Rivaroxaban Major Bleeding

22 Strategies Used for Management of Rivaroxaban Major Bleeding Rivaroxaban* Warfarin P-Value n= Blood transfusion, n (%) 176(40.8) 143(34.9) Plasma transfusion, n (%) 45(10.4) 81(19.8) Vitamin K, n (%) 72 (16.7) 132(32.3) Prothrombin complex concentrate, n (%) 8(1.9) 18(4.4) Recombinant factor VIIa, n (%) 8 (1.9) 2(0.5) Major bleeds in the rivaroxaban group were more frequently treated with blood transfusions than those on warfarin but less frequently with plasma. Most of the bleeds were managed by transfusion of blood products

23 Hospitalization and Mortality after Rivaroxaban MBE Rivaroxaban* Warfarin P-Value Hospitalization, n Hospitalization, duration 5 (4-10) days 6 (4-11) days Death 86 (20.4%) 105 (25.6%) 0.11 Time to death (days) 60 (8 246) 7 (2 88)

24 Apixaban Major Bleeding

25 Apixaban Major Bleeding Apixaban Warfarin P-Value N= Led to transfusion Required surgical or medical intervention Led to hospitalization Death within 30 days <0.001

26 Questions Can the major bleeding evens on the new anticoagulants be managed only by volume substitution and transfusion of blood products? Yes! Without worse outcome Low-therapeutic drug concentration Non-ICH ICH This dose not answer the question of how to deal with NOACs pre-operatively

27 Questions Introduction Can the major bleeding evens on the new anticoagulants be managed only by volume substitution and transfusion of blood products? Is there a role for non-specific hemostatic agents? Thrombin Inhibitors Xa Inhibitors Antidotes under development Prevention of bleeding on NOACs

28 Thrombin inhibitors 28

29 Prothrombin Complex Concentrates Octaplex Animal models showed good effect ICeH mouse model Rabbit kidney injury Human studies more difficult to evaluate Eerenburg study Case series of 4(2) patients with poor outcome

30 Short case-series-pcc for dabigatran bleeding Age Gende r Weigh t egfr Bleedin g Hours from last dose PCC RBC Hours to bleed stop 83 Male Rectal No <6 No 82 Male Melena Yes(2) -- Yes 88 Male Rectal Yes(2) <12 No 76 Male Rectal Yes(1) <12 No 82 Female Rectal No <6 No Death At least 2 of the patients had normal APTT indicating low dabigatran concentration Diaz, haematologica 2013

31 PCC in Surgery on dabigatran 86 year old man Atrial fibrillation: dabigatran 110mg x 2 Acute abdomen: Peritonitis Need surgery urgently Dabigatran intake 8 hours ago egfr 45 ml/min APTT 50 sec

32 PCC in Surgery on dabigatran Tranexamic acid + plasma pre-operatively Surgeon: Bleeds easily PCC 1500 IU (70 kg) Better hemostasis

33 No reversal of the in vitro anticoagulant effect of dabigatran by prothrombin complex concentrate Eerenberg et al, Circulation 2011

34 PCC for dabigatran bleeding Age Gender egfr Bleeding Hours last dose PCC RBC Hours to bleeding stop 72 Female 14 Intraabdominal IU/kg Yes(22) -- Yes Death 74 Male 14 Gastrointestinal IU/kg Yes(12) 10 hrs after hemodialysis Yes All patients received rviia in addition to PCC Lillo-Le Louet Thromb Haemos 2012

35 rfviia in dabigatran-associated hemorrhage Warkentin T E et al. Blood 2012;119:

36 Experimental Experimental evidence: evidence: haemodialysis haemodialysis Updated slide! Dialysis removed 62 68% of dabigatran in patients with ESRD Total dabigatran plasma concentration in dialyser inlet and outlet lines after oral administration of 50 mg dabigatran Dabigatran concentration (ng/ml) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Inlet 0.5 hrs Outlet Inlet Outlet Inlet 2 hrs 4 hrs Outlet ESRD = end-stage renal disease ESRD Stangier = end-stage J et al. renal Clin Pharmacokinet disease 2010;49: Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Stangier Please check J et local al. prescribing Clin Pharmacokinet information for further 2010;49: details Mar

37 Dialysis 37

38 Activated PCC (FEIBA) 67 y.o. male with AF, last dose dabi 7 h preop. Ablation Rx, UFH 5000 u, transseptal perforation, hypotension Pericardiocentesis: 4.5 L blood drained Bleeding slows and stops Protamine 100 mg Time FEIBA 3159 IU

39 Xa inhibitors 39

40 Eerenberg E S et al. Circulation 2011;124: PCC for the reversal of Xa inhibitors

41 PCC in rivaroxaban Bleeding 76 year old male Atrial fibrillation Last intake 8 hours Confusion: ICH INR 1.3 PCC 1500 Good effect

42 rviia (Novoseven) and rivaroxaban Rat model on edoxaban + 3mg/kg rviia: PT, TAT, BT normalized Baboons on rivaroxaban +210 mkg/kg rviia: PT shortened Rats on rivaroxaban or apixaban: rviia shortened PT but did not affect blood loss Rabbits treated with rivaroxaban or apixaban, rfviia reduced the bleeding time and the aptt but did not have any effect on the amount of blood loss.

43 APCC (FEIBA) 100 IU/kg: Shortened PT in baboons on rivaroxaban Corrected PT in rats on edoxaban No report on blood loss

44 Questions Is there a role for non-specific hemostatic agents? No RCT or large cohort studies PCC: Xa inhibitors (laboratory evidence) Dabigatran: probably in patients with low therapeutic concentration Availability Low thrombogenicity compared to APCC and rviia APCC (FEIBA) Especially for dabigatran rviia Inconclusive evidence

45 Questions Introduction Can the major bleeding evens on the new anticoagulants be managed only by volume substitution and transfusion of blood products? Is there a role for non-specific hemostatic agents? Antidotes under development Prevention of bleeding on NOACs

46 Anti-dabigatran antibody 46

47 Anti-dabigatran antibody: rapid neutralization

48 PRT064445: recombinant FXa PRT is a r ecombinant fx a var iant with modification the Gla-dom ain and active site Light Chain Heavy Chain Gla EGF1,2 S S419 S Catalytic Domain EGF1,2 S S419A S FXa PRT (r-antidote) Two modifications introduced to human fxa Two modifications introduced to human fxa Removal of the Gla-domain Mutation at the active site (S419A) PRT (r-antidote) No pro- or anti-coagulant activity Retains binding ability for fxa inhibitors Removal of the Gla-domain Mutation at the active site (S419A) PRT (r-antidote) No pro- or anti-coagulant activity Retains binding ability for fxa inhibitors

49 PRT RT r ever sed anti-fx a activity in ASA+rivar oxaban r eated m ice 150 P=0.431 P=0.001 P= Anti-fXa (%) Vehi ASA Riva ASA+Riva ASA+Riva+PRT Treatment (n=5-8) Riva ASA+Riva ASA+Riva+PRT Total Riva. plasma conc. (µm) 0.20± ± ±0.25 PRT plasma conc. (µm) N/A N/A 2.20±0.47

50 Small Molecule Reversal PER977 Heparin Enoxaparin Edoxaban Dabigatran Effect within 30 min

51 PER977

52 Questions Introduction Can the major bleeding evens on the new anticoagulants be managed only by volume substitution and transfusion of blood products? Is there a role for non-specific hemostatic agents? Antidotes under development Prevention of bleeding on NOACs

53 N Engl J Med 2012; 366: 864

54 Choose Wisely Recommendations set by the European Medicine Agency (EMA) for dabigatran were met in 50%, 90.3 of patients treated with dabigatran 110mg, 150 mg. 54

55 Comparing bleeding on NOACs and warfarin Efficacy of warfarin reversal If you get a head bleeding on warfarin we can reverse it with PCC (Octaplex) If you bleed on the new agents, we cant do anything about it

56 PCC (Octaplex) for warfarin reversal

57 PCC (Octaplex) for warfarin reversal Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding: A Randomized, Plasma-Controlled, Phase I I I b Study Ravi Sarode, Truman J. Milling, Jr, Majed A. Refaai, Antoinette Mangione, Astrid Schneider, Billie L. Durn and Joshua N. Goldstein Circulation. 2013;128: ; originally published online August 9, 2013; doi: /CIRCULATIONAHA Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2013 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at:

58 PCC (Octaplex) for warfarin reversal Underused 33% of warfarin bleeds get any reversal Given too late Inadequate doses Poor clinical efficacy

59 Efficacy of warfarin reversal If you get a head bleeding on warfarin we can reverse it with PCC (Octaplex) If you bleed on the new agents, we cant do anything about it

60 Efficacy of warfarin reversal If you get a head bleeding on warfarin we can reverse it with PCC (Octaplex) If you bleed on the new agents, we cant do anything about it

61 Warfarin bleeding is poorly managed in many centers resulting in poor outcome Conclusions Incidence of major bleeding on NOACs is comparable to or lower than warfarin Most cases can be managed conservatively by transfusion of blood products without resulting in worse outcome No good evidence supporting the use of hemostatic agents (yet) For Xa inhibitorspcc(octaplex) (?) For dabigatran bleeding PCC/FEIBA (?) Specific antidotes are evaluated in clinical trials

62 Thank you 62