Reversal strategies for NOACs - CHU Dinant Godinne | · PDF fileEnd of idarucizumab injection (5-min infusion) Dabigatran etexilate + placebo dTT (s) 70 65 60 55 50 45 40 35 30 Dabigatran

Reversal strategies for NOACs

Namur Thrombosis Haemostasis Center

April 28th

Peter Verhamme

Vascular Medicine and Haemostasis

University of Leuven

Belgium

Honoraria for lectures and advisory boards

• Boehringer Ingelheim• Bayer • Daiichi Sankyo• Pfizer• Sanofi• Ionis Pharmaceuticals• Portola

Research Support • Boehringer Ingelheim• Bayer• Leo Pharma

Disclosures

A real-life patient…

URGENT SURGERY

Needs urgent ERCP

Does your hospital have a

protocol for bleeding and emergencies?

• NOACs provide effective treatment NOACs cause less serious bleeding than warfarin

Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Do we need reversal agents for NOACs ?

• NOACs provide effective treatment NOACs cause less serious bleeding than warfarin

• However:- Emergencies (bleeding, urgent procedures) are not infrequent

- Fear of bleeding and the lack of an antidote are barriers for the use of NOACs

Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Do we need reversal agents for NOACs ?

Meta-analysis: ARISTOTLE, ENGAGE-AF, RE-LY and ROCKET AF

VKAs versus NOACs:

organ-specific patterns of bleeding

Relative risk difference (%) (95% CI)

Intracranial bleeding

Other major bleeding

Gastrointestinal bleeding

Vanassche et al, Thrombosis and Haemostasis, 2014

Favours novel OAC Favours warfarin–100 –50 0 50 100

84,540 patients and 4781 bleeding events

– General measures and supportive care

• Interrupt treatment• Identify and control source of bleeding

• Volume replacement

• Transfusion (packed cells, platelets, FFP)

Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Management of serious bleeding

– General measures and supportive care

• Interrupt treatment• Identify and control source of bleeding

• Volume replacement

• Transfusion (packed cells, platelets, FFP)

– Non-specific measures to support haemostasis

• Factor concentrates (PCCs, aPCCs, FVIIa)

Weitz et al. Circulation (2012); Majeed et al. Circulation (2013); Graham et al. Circulation (2015)

Management of serious bleeding

PCC or aPCC to reverse the anticoagulant effect of NOACs?

Dabigatran 1–14 Rivaroxaban 1-3,15–18 Apixaban 1-3,14,19–21 Edoxaban 1

PCC

Animal models

Preclinical studies

Human volunteers

Case reports

aPCC

Animal models

Preclinical studies

Human volunteers

Case reports �

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� . Siegal DM. J Thromb Thrombolysis 2015;39:395–402; 2. Babilonia K, Trujillo T. Thromb J 2014;12:8; 3. Lazo-Langner A et al. Crit Care 2013;17:230; 4. Honickel M et al. Thromb Haemost 2015;113:728–40; 5. Herzog E et al. Thromb Res 2014;134:729–36; 6. Grottke O et al. Crit Care 2014;18:R27; 7. Masotti L et al. J Thromb Thrombolysis 2015;39:427–33; 8. Plener I et al. Can J Hosp Pharm 2014;67:43–7; 9. Diaz MQ et al. Haematologica 2013;98:e144; 10. Lillo-Le Louet A et al. Thromb Haemost 2012;108:583–5; 11. Dumkow LE et al. Am J Health Syst Pharm 2012;69:1646–50; 12. Wychowski M, Kouides P. Ann Pharmacother 2012;46:e10; 13. Lindahl TL et al. Thromb Res 2015;135:544–7; 14. Dinkelaar J et al. Clin Chem Lab Med 2014;52:1615–2; 15. Herzog E et al. Thromb Res 2015;135:554–60; 16. Zhou W et al. Stroke 2013;44:771–778; 17. Beyer-Westendorf J et al. Blood 2014;124:955–962; 18. Piccini JP et al. Eur Heart J 2014;35:1873–80; 19. Martin AC et al. J Thromb Haemost 2015;13:426–36; 20. Escolar G et al. PLoS One 2013;8:e78696; 21. Perlstein I et al. Presented at ASH 2014; abstr 345

General bleeding management algorithms are available to guide clinical decisions

Consider:

•PCC 50 IU/kg;

•aPCC 50 U/kg; max 200 U/kg/day

• rFVIIa* 90 µg/kg

Supportive measures•Control Source of Bleeding•Fluid replacement •RBC transfusion •FFP (as plasma expander)•Platelet transfusion (if platelet count ≤60×109/L or on long-acting antiplatelet drugs)

Additional options for dabigatran•Consider haemodialysis

+ +

• Delay or discontinue next dose

• Reconsider concomitant medication

Mild bleeding Moderate/severe bleeding Life-threatening bleeding

Heidbuchel H et al. Europace 2013 & 2015;

Bleeding while using a NOAC

NOAC reversal agents in development

Greinacher A et al. Thromb Haemost 2015;113:931–42;

Approved by EMA/FDA

Phase IIIPatients requiring urgent surgery/with major bleeding; started May 20142,3

Phase IIPhase IIdarucizumabTarget: dabigatran

NOAC reversal agents in development

Greinacher A et al. Thromb Haemost 2015;113:931–42;

Approved by EMA/FDA

Phase IIIPatients requiring urgent surgery/with major bleeding; started May 20142,3

Phase IIIPatients with major bleeding; started Jan 20154

Phase II

Phase II

Phase I

Phase I

IdarucizumabTarget: dabigatran

Andexanet alfa (PRT064445)Target: FXa inhibitors

NOAC reversal agents in development

Greinacher A et al. Thromb Haemost 2015;113:931–42;

Approved by EMA/FDA

Phase IIIPatients requiring urgent surgery/with major bleeding; started May 20142,3

Phase IIIPatients with major bleeding; started Jan 20154

Phase II

Phase II

Phase I

Phase I

IdarucizumabTarget: dabigatran

Andexanet alfa (PRT064445)Target: FXa inhibitors

Ciraparantag(PER977)Target: universal?

Phase I

Schiele F et al. Blood 2013;121:3554–62

What is Idarucizumab?

Idarucizumab

Humanized Fab fragmentHumanized Fab fragment

IV administration,immediate onset of action Short half-life

IV administration,immediate onset of action Short half-life

Binding affinity ~350×××× higher than dabigatran to thrombinBinding affinity ~350×××× higher than dabigatran to thrombin

No procoagulant or anticoagulant effects expectedNo procoagulant or anticoagulant effects expected

Supports haemostasis in preclinical studies in pigs and miceSupports haemostasis in preclinical studies in pigs and mice

•Glund et al. Lancet 2015

Immediate and complete reversal of dabigatran in healthy volunteers

16

End of idarucizumab injection (5-min infusion)

Dabigatran etexilate + placebo

dTT

(s)

70

65

60

55

50

45

40

35

30

Dabigatran Idarucizumab

Time after end of infusion (hrs)Minutes

72–2 0 120906030 36241264 8 10 48 60

Dabigatran etexilate plus:

Placebo (n=9)

Internal use only – strictly confidential

2 g idarucizumab (day 4) (n=9)

4 g idarucizumab (day 4) (n=8)

Normal upper reference limit (n=86)Mean baseline (n=86)

•Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education pu rposes only. The information contained herein does not necessarily reflect the content of the approved Can adian product monograph dTT, diluted thrombin time•Glund et al. ASH 2014

Reversal in elderly and volunteers with moderate renal impairment

17

End of bolus

dTT

(s)

90

80

70

55

50

45

40

35

25

Time after end of infusion (hrs)Minutes

30

24–2 0 120906030 20161284

85

75

65

60

Dabigatran Idarucizumab

Mild renal impairment

5-g dose calculated to reverse total body load of dabigatran

associated with 99th percentile in RE-LY®

RE-VERSE AD: multicentre, ongoing, open-label, single-arm Phase III study

dTT, diluted thrombin time; ECT, ecarin clotting time

Pollack CV et al. Thromb Haemost 2015;114:198–205

N=300

0–15 minutes 90 days follow-up

0–24 hours

Hospital arrival

5 g idarucizumab (two infusions of 2.5 g)

Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 dPre-1st vial 1 hBlood

samples10–30 min

Primary endpoint: dabigatran reversal within 4 hours

(dTT or ECT)

7 d

RE-VERSE AD: multicentre, ongoing, open-label, single-arm Phase III study

dTT, diluted thrombin time; ECT, ecarin clotting time

Pollack CV et al. Thromb Haemost 2015;114:198–205

N=300

0–15 minutes 90 days follow-up

0–24 hours

Hospital arrival

5 g idarucizumab (two infusions of 2.5 g)

Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 dPre-1st vial 1 hBlood

samples10–30 min

Primary endpoint: dabigatran reversal within 4 hours

(dTT or ECT)

7 d

Reverses up to the 99th percentile of dabigatran levels

measured in RE-LY

RE-VERSE AD: multicentre, ongoing, open-label, single-arm Phase III study

dTT, diluted thrombin time; ECT, ecarin clotting time

Pollack CV et al. Thromb Haemost 2015;114:198–205

N=300

0–15 minutes 90 days follow-up

0–24 hours

Hospital arrival

5 g idarucizumab (two infusions of 2.5 g)

Pre-2nd vial 2 h 4 h 12 h 24 h 30 d 90 dPre-1st vial 1 hBlood

samples10–30 min

Primary endpoint: dabigatran reversal within 4 hours

(dTT or ECT)

7 d

Reverses up o the 99th percentile of dabigatran levels

measured in RE-LY

Maximum % reversal of the anticoagulation effect of dabigatran based on central laboratory assessment of dTT or ECT within 4 hours after idarucizumab

dTT and ECT show linear correlations with wide range of dabigatran concentrations

Glund S et al, Lancet 2015 June 15 e-pub ahead of print

RE-VERSE AD: Primary endpoint

dTT ECT

RE-VERSE AD: Baseline characteristics

Characteristic Group A Group B Total

Number n=51 n=39 N = 90

Indication for dabigatran

stroke prevention in A Fib47/51 39/39 86/90

Age median,

range (years)

77

(48–93)

76

(56–93)

76.5

(48–93)

Creatinine clearance median,

range (mL/min)

51.5

(15.8–186.8)

60.1

(11.5–171)

57.6

(11.5–186.8)

Patient-reported time since last

dose, median (hours)15.2 16.6 15.4

Elevated dTT or ECT at baseline 47/51 34/39 81/90

Pollack CV, et al. N Engl J Med 2015Pollack CV et al. N Engl J Med 2015:373:511–20

RE-VERSE AD interim results: primary endpoint by dTT reversal

Assay upper limit of normal

Idarucizumab 2x 2.5 g

dTT

(s)

130

110

70

60

50

40

30

20

120

100

90

80

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post idarucizumab

Uncontrolled bleeding

Interim analysis includes data for the first 90 patients.

Pollack CV et al. N Engl J Med 2015:373:511–20

RE-VERSE AD interim results: primary endpoint by dTT reversal

Emergency surgery or procedure

Idarucizumab 2x 2.5 g

dTT

(s)

130

110

70

60

50

40

30

20

120

100

90

80

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post idarucizumab

Assay upper limit of normal

Idarucizumab 2x 2.5 g

dTT

(s)

130

110

70

60

50

40

30

20

120

100

90

80

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post idarucizumab

Uncontrolled bleeding

Interim analysis includes data for the first 90 patients.

Pollack CV et al. N Engl J Med 2015:373:511–20

Short half-life of Idarucizumab Idarucizumab (nmol/L)

50000

40000

20000

15000

10000

5000

0

45000

35000

30000

25000

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post-idarucizumab

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post-idarucizumab

Idarucizumab (nmol/L)

50000

40000

20000

15000

10000

5000

0

45000

35000

30000

25000

Idarucizumab

2x 2.5 g

Idarucizumab

2x 2.5 g

Urgent surgery

Bleeding

Pollack CV et al. N Engl J Med 2015:373:511–20

• Pollack CV et al. N Engl J Med 2015

Reversal was also evident on aPTT results

Patients with bleeding Patients with urgent procedures

Pollack CV et al. N Engl J Med 2015:373:511–20

• dTT normalized in 98% and 93% of Group A (Bleeding) and Group B (urgent surgery) patients, respectively*

• Clinical outcomes– cessation of bleeding: median time was <12 hours*– intraoperative haemostasis: normal in 92% of evaluable patients

Similar results with central laboratory aPTT, ECT an d TT, and unbound dagigatran

Endpoint vs. Outcomes

*calculated for patients with elevated levels at baseline Pollack CV et al. N Engl J Med 2015:373:511–20

• No idarucizumab related safety issues

• Five thrombotic events occurred– 1 early event (DVT + PE) within 72 hours of idarucizumab

administration

– 4 patients had events after 72 hours of idarucizumab administration (DVT, DVT+PE+LA thrombus, MI, ischemic stroke)

– None of these 5 patients was receiving any antithrombotic therapy when the events occurred

• 18 deaths occurred (9 in each Group)– Related to presenting index event and comorbidities

Safety

Pollack CV et al. N Engl J Med 2015:373:511–20

• Open label cohort study– no appropriate comparison

• Fixed dose based on anticipated dabigatran level– What in case of massive overdose?– What if acute renal failure with higher dabigatran

levels?– In this interim analysis, some patients show re-

appearance of low levels of dabigatran at 24 hrs

RE-VERSE AD: Discussion

Pollack CV et al. N Engl J Med 2015:373:511–20

Andexanet: Reversal of Anticoagulation by direct and indirect Factor Xa Inhibitors

Factor Xa andexanet

Catalytic DomainGla

Recombinant engineered version of human factor Xa

S S

S419

S S

A419Factor Xa inhibitor Factor Xa inhibitor

• No catalytic activity

• Binds Xa-inhibitors

Gla

Nature Medicine

(2013),19(4): 446-51

Andexanet in Helathy volunteers: Reversal of Anti-FXa Activity

• Within 2-5 mins, andexanet reversed anti-FXa activity from baseline by 92%-97% (p<0.0001 vs. placebo (21%-45%) for all comparisons)

• Bolus plus infusion of andexanet sustained reversal of anti-FXa activity (Fig.C,D) (Siegal, NEJM 2015)

Ciraparantag

• Binds heparin, rivaroxaban, edoxaban, apixaban, dabigatran (charge-charge and non-covalent hydrogen bonding)

Ansell J, et al. NEJM. 2014; 371: 2141-2142.

What could be the potential impact of the availability of NOAC reversal agents on

clinical practice?

What about the patient…

URGENT SURGERY

Needs urgent ERCP

22 patients / 24 months 8 bleeding / 14 urgent surgery

• ICH (intraparenchymal)• Intoxication• Gangrene Fournier• ICH (subdural 3x)• Cholangitis• Acute mesenteric

ischemia (2x)• Dialysis • Craniofacial trauma• Lower GI bleeding• Abscess drainage

• ‘Fausse route’ after urinary catheter

• Open Tibial Fracture• Visible vessel upper GI-

bleeding• Haematemesis• Hearttransplant (2x)• Colon bleeding • Urgent nephrostomy

Reversal of anticoagulation…

URGENT SURGERY

Heart Transplantation…

Introducing our patients…

MAJOR BLEEDING

• Reversal of anticoagulation ≠ improved clinical outcomes

• Institution wide protocol for emergencies

Implementing reversal agents in clinical practice

Updated bleeding management algorithm

• Idarucizumab 5g for dabigatran

Consider:

• PCC 50 IU/kg;

• aPCC 50 U/kg; max 200 U/kg/day

Supportive measures•Control Source of Bleeding•Fluid replacement •RBC transfusion •FFP (as plasma expander)•Platelet transfusion (if platelet count ≤60×109/L or on long-acting antiplatelet drugs)

Additional options for dabigatran•Consider haemodialysis

+ +

• Delay or discontinue next dose

• Reconsider concomitant medication

Mild bleeding Moderate/severe bleeding Life-threatening bleeding

Heidbuchel H et al. Europace 2013 & 2015;

Bleeding while using a NOAC

Conclusions

2Guidance is available to manage patients on NOACs who are bleeding, or undergoing emergency procedures

3Reversal agents will provide additional treatment options for patients undergoing emergency procedures, or with life-threatening bleeding

1NOACs have favourable safety and efficacy profiles vs warfarin