how to handle the bleeding risk related to oral anticoagulants · ammar majeed, hun-gyu hwang,...

Ammar Majeed

Hematology Center, Karolinska University Hospital and Karolinska Institute,

Stocklholm, Sweden;

How to Handle the Bleeding Risk Related

to Oral Anticoagulants

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


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

Dose the fact that having / not

having a reversal agent/antidote

equals good/bad prognosis and

outcome?

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

Development of NOACs focus on two targets in the

coagulation cascade

Fibrin Clot

Intrinsic ExtrinsicXII

VII

IX

XI

Fibrinogen

II

V

Tissue Factor

XDirect Xa Inhibitors

“-xaban”

Direct Thrombin Inhibitors

“-gatran”

warfarin

VIII

New and Emerging Anticoagulants

Anti – Xa : direct

Rivaroxaban (oral) Xarelto®

Apixaban (oral) Eliquis®

Edoxaban (oral) Lixiana®

Betrixiban (oral)

Otamixaban (parenteral)

LY – 517717 (oral)

DU – 176B (oral)

DX – 9065a (parenteral)

PRT054021 (oral)

Anti – IIa

Dabigatran (oral) Pradaxa®

Odiparcil (oral)

Flovagatran (parenteral)

Pegmusirudin (parenteral)

Peg Hirudin

Desiruidin

Status of NOACs

8

Dabigatran

Pradaxa®

Rivaroxaban

Xarelto®

Apixaban

Eliquis®

Edoxaban

Savaysa®

Atrial

FibrillationApproved Approved Approved

Applied for

approval

8/1/2014

VTE

TreatmentApproved Approved

Applied for

approval

19/12/2013

Applied for

approval

8/1/2014

VTE

Prevention

Orth Surgery

Approved Approved Approved No activity

Incidence of Major Bleeding in Phase III studies*

Annual rate of major bleeding≈1-3%

1. N Engl J Med. 2009 Sep 17;361(12):1139-51. 2. N Engl J Med. 2011 Sep 8;365(10):883-91 3. N Engl J Med. 2009 Dec 10;361(24):2342-52. 4. N Engl J Med. 2010 Dec

23;363(26):2499-510 5. N Engl J Med. 2012 Apr 5;366(14):1287-97 6. Thromb Res. 2010 Sep;126(3):175-82 7. Thromb Haemost. 2011 Mar;105(3):444-53. Epub 2010 Dec 6. 8. N

Engl J Med. 2011 Sep 15;365(11):981-92. Epub 2011 Aug 27. 9. N Engl J Med, 2013. 369(9): p. 799-808 . 10. Giuglianpo NEJM 2013. 11. Buller NEJM 2013 12 Kawaji ort res 2012

*Figures in table are unadjusted for treatment duration

Figures in red indicate rates significantly lower than warfarin

Indication AF studies VTE studiesThromboprophylaxis

studies

Dabigatran 5.4-6.2%1 0.9-1.6%3 1.1-1.4%6

Rivaroxaban 5.6%2 0.8-1.1%4,5 0.3%7

Apixaban 3.6%8 0.69 0.6-0.8%

Edoxaban 3.6-6.010 1.411 3.412

Treatment Duration 1.5-2 years 3-12 months 2-5 weeks

Rate of Intracranial Bleeding in AF studies

Rate of Gastrointestinal Bleeding in AF studies

General recommendation for the management of NOAC

bleeding

*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;124:1573–1579; van Ryn J et al. Thromb Haemost 2010;103(6):1116–1127

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

Questions

Introduction



products?

Rationale: Short half life of NOACs – effect diminishes quickly when

discontinued




SchulmanEzekowitz, Lars Wallentin, Martina Brueckmann, Mandy Fraessdorf, Salim Yusuf and Sam

Ammar Majeed, Hun-Gyu Hwang, Stuart J. Connolly, John W. Eikelboom, Michael D.Warfarin

Management and Outcomes of Major Bleeding During Treatment With Dabigatran or

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.113.002332

2013;128:2325-2332; originally published online September 30, 2013;Circulation.

http://circ.ahajournals.org/content/128/21/2325World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circ.ahajournals.org/content/suppl/2013/09/30/CIRCULATIONAHA.113.002332.DC1.htmlData Supplement (unedited) at:

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:

at SWETS BLACKWELL INC on February 19, 2014http://circ.ahajournals.org/Downloaded from at SWETS BLACKWELL INC on February 19, 2014http://circ.ahajournals.org/Downloaded from at SWETS BLACKWELL INC on February 19, 2014http://circ.ahajournals.org/Downloaded from at SWETS BLACKWELL INC on February 19, 2014http://circ.ahajournals.org/Downloaded from at SWETS BLACKWELL INC on February 19, 2014http://circ.ahajournals.org/Downloaded from at SWETS BLACKWELL INC on February 19, 2014http://circ.ahajournals.org/Downloaded from

Patient Population: Phase III Dabigatran Trials

Phase III trial Patients TreatmentsDuration of

treatment

RE-LY118,113 atrial fibrillation

patients

(stroke prevention)

• Dabigatran 110 mg

• Dabigatran 150 mg bid

• Warfarin

Median, 2 years

RE-COVER22539 VTE patients

(treatment)


• Warfarin6 months

RE-COVER II32568 VTE patients

(treatment)


• Warfarin 6 months

RE-MEDY42856 VTE patients

(secondary prevention)


• Warfarin Mean, 15.5 months

RE-SONATE51343 VTE patients

(secondary prevention)


• Placebo 6 months

Number of patients randomized and treated in these 5 trials: 27,419

Dabigatran: 16,755 Warfarin: 10,002

VTE: venous thromboembolism. 1. Connolly SJ et al. N Engl J Med 2009; 361:1139-1151; 2. Schulman S et al. N Engl J Med

2009;361:2342–2352; 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)

Strategies Used for Management of Major Bleeding

Dabigatran* Warfarin P-Value

Blood transfusion, n (%) 439 (59.2) 210 (49.9) 0.002

Fresh frozen plasma, n (%) 147 (19.8) 127 (30.2)

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

Short-term Consequences of Major Bleeding

Length of stay in ICU is shorter with

dabigatran treatment than with comparator

Mortality After a Major Bleed – 5 Phase III Trials

* Data combined from dabigatran 150 and dabigatran 110 mg bid treatment groups. Only first

major bleed included. Analysis not adjusted for covariates.

The Kaplan-Meier analysis indicated a reduced risk for death with dabigatran*

vs. warfarin during 30 days from the bleeding (P=0.057).

Adjusted Analysis of Mortality following a Major Bleed

OR for 30-day mortality adjusted for sex, age, weight, renal function and

additional antithrombotic therapy

CI: confidence interval; OR: odds ratio

Favours dabigatran Favours warfarin10.1 10

0.66 (0.44, 1.00)

0.60 (0.35,1.03)

0.68 (0.42, 1.08)

0.56 (0.36,0.86)

0.53 (0.31,0.88)

0.009

0.015

0.064

0.099

0.051

P-ValueOR (95% CI)Treatment and Database Used

Dabigatran 150 mg + 110 mg, all studies

Dabigatran 150 mg, all studies

Dabigatran 110 mg, RE-LY

Dabigatran 150 mg + 110 mg, RE-LY

Dabigatran 150 mg, RE-LY

Adjusted analysis demonstrates mortality benefit for dabigatran in RE-LY

Prognosis of Intracranial Hemorrhage – RE-LY trial

No significant difference between treatments in modified Rankin

scale score for intracranial hemorrhage since admission

Treatment comparisonP-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

* Data combined from dabigatran 150 and dabigatran 110 mg bid treatment groups

Data on the initial and final Rankin score evaluations were available

for 78 (55%) patients with intracranial hemorrhage.

Rivaroxaban Major Bleeding

Strategies Used for Management of Rivaroxaban Major

Bleeding

Rivaroxaban* Warfarin P-Value

n= 431 409

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

Hospitalization and Mortality after Rivaroxaban MBE

Rivaroxaban* Warfarin P-Value

Hospitalization, n 101 91

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)

Apixaban Major Bleeding

Apixaban Major Bleeding

Apixaban Warfarin P-Value

N= 327 462 0.0052

Led to transfusion 137 188 0.0025

Required surgical or medical intervention 100 136 0.012

Led to hospitalization 162 212

Death within 30 days 36 71

Questions



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

Questions

Introduction



products?


Thrombin Inhibitors

Xa Inhibitors



Thrombin inhibitors

28

Prothrombin Complex Concentrates Octaplex

Animal models showed good effectICeH mouse model

Rabbit kidney injury

Human studies more difficult to evaluateEerenburg study

Case series of 4(2) patients with poor outcome

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

Death

83 Male 57 37 Rectal 1.5 1000 No

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

PCC in Surgery on dabigatran

Tranexamic acid + plasma pre-operatively

Surgeon: Bleeds easily

PCC 1500 IU (70 kg)

Better hemostasis

No reversal of the in vitro anticoagulant effect of

dabigatran by prothrombin complex concentrate

Eerenberg et al, Circulation 2011

PCC for dabigatran bleeding

Age Gender eGFR Bleeding Hours

last

dose

PCC RBC Hours to

bleeding stop

Death

72 Female 14 Intraabdominal 48 40 IU/kg Yes(22) -- Yes

74 Male 14 Gastrointestinal 38 36 IU/kg Yes(12) 10 hrs after

hemodialysis

Yes

Lillo-Le Louet Thromb Haemos 2012

All patients received rVIIa in addition to PCC

Warkentin T E et al. Blood 2012;119:2172-2174

rFVIIa in dabigatran-associated hemorrhage

Experimental evidence: haemodialysis

ESRD = end-stage renal disease

Stangier J et al. Clin Pharmacokinet 2010;49:259–68 Mar 2013

Experimental evidence: haemodialysis

! Dialysis removed 62–68% of dabigatran in patients with ESRD

ESRD = end-stage renal disease

Stangier J et al. Clin Pharmacokinet 2010;49:259–68 Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details

43

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

25

0

20

10

0.5 hrs

Dabig

atr

an c

once

ntr

ation (

ng/m

L)

15

5

Outlet Inlet Outlet Inlet Outlet Inlet

2 hrs 4 hrs

Total dabigatran plasma concentration in dialyser inlet and outlet lines after oral administration of 50 mg dabigatran

Updated slide

36

Dialysis

37

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

Time

Protamine

100 mg

FEIBA

3159 IU

Bleeding slows

and stops

Xa inhibitors

39

Eerenberg E S et al. Circulation 2011;124:1573-1579

PCC for the reversal of Xa inhibitors

PCC in rivaroxaban Bleeding

76 year old male

Atrial fibrillation

Last intake 8 hours

Confusion: ICH

INR 1.3

PCC 1500

Good effect

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.

APCC (FEIBA)

100 IU/kg:

Shortened PT in baboons on rivaroxaban

Corrected PT in rats on edoxaban

No report on blood loss

Questions


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

Questions

Introduction



products?




Anti-dabigatran antibody

46

Anti-dabigatran antibody: rapid neutralization

PRT064445: recombinant FXa

PRT064445 is a recombinant fX a var iant with modifications in

the Gla-domain and active site

PRT064445 (r-Antidote)

S S

EGF1,2

S419A

FXa

S S

S419

EGF1,2 Gla

Light Chain Heavy Chain

Catalytic Domain

Two modifications introduced to human fXa • Removal of the Gla-domain

• Mutation at the active site (S419A)

PRT064445 (r-Antidote) • No pro- or anti-coagulant activity

• Retains binding ability for fXa inhibitors

4

Two modifications introduced to human fXa

•Removal of the Gla-domain

•Mutation at the active site (S419A)

PRT064445 (r-Antidote)

•No pro- or anti-coagulant activity

•Retains binding ability for fXa inhibitors

PRT064445 PRT064445 reversed anti-fX a activity in ASA+r ivaroxaban

treated mice

Vehi ASA Riva ASA+Riva ASA+Riva+PRT0644450

25

50

75

100

125

150P=0.011P=0.431

P=0.001

Anti-f

Xa

(%)

11

Treatment (n=5-8) Riva ASA+Riva ASA+Riva+PRT064445

Total Riva. plasma conc. (µM) 0.20±0.10 0.14±0.06 1.14±0.25

PRT064445 plasma conc. (µM) N/A N/A 2.20±0.47

Small Molecule Reversal

PER977

Heparin

Enoxaparin

Edoxaban

Dabigatran

Effect within 30 min

PER977

Questions

Introduction



products?




N Engl J Med 2012; 366: 864

Choose Wisely

54

Recommendations set by the European Medicine Agency

(EMA) for dabigatran were met in 50%, 90.3 of patients

treated with dabigatran 110mg, 150 mg.

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


PCC (Octaplex) for warfarin reversal


Billie L. Durn and Joshua N. GoldsteinRavi Sarode, Truman J. Milling, Jr, Majed A. Refaai, Antoinette Mangione, Astrid Schneider,

Plasma-Controlled, Phase I I Ib StudyVitamin K Antagonists Presenting With Major Bleeding: A Randomized,

Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.113.002283

2013;128:1234-1243; originally published online August 9, 2013;Circulation.

http://circ.ahajournals.org/content/128/11/1234World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://circ.ahajournals.org/content/suppl/2013/08/09/CIRCULATIONAHA.113.002283.DC1.htmlData Supplement (unedited) at:

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:

at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from


Underused

33% of warfarin bleeds get any reversal

Given too late

Inadequate doses

Poor clinical efficacy

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

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

Warfarin bleeding is poorly managed in many centers resulting in

poor outcome

Thank you

62

how to handle the bleeding risk related to oral anticoagulants · ammar majeed, hun-gyu hwang,...

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