James D. Douketis MD, FRCP(C)

St. Joseph’s Healthcare and McMaster University, Hamilton, Canada

Coagulation Control: Anticoagulants and Reversal What do you need to know in 2016?

Lifetime Disclosures for: J. Douketis

Research Support/P.I. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Boehringer-Ingelheim

Employee Up-to-Date, Merck Manual

Consultant Actelion, AGEN Biomedical, Biotie, Boehringer-Ingelheim, Cytori, Ortho-Janssen, Portola

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria/Speaker Fees Funds from these sources deposited into university-based research accounts or SJHH Foundation.

Scientific Advisory Board Astra-Zeneca, Bayer, Bristol-Myers-Squibb, Leo Pharma, Medicines Co., Pfizer, Sanofi

Learning Objectives

• Have an approach to the management of vitamin K antagonist (VKA)-related bleeding.

• Have an approach to the management of direct oral anticoagulant (DOAC)-related bleeding.

• Review emerging data on antidotes to DOACs.

XII

XIa

IXa

Intrinsic Pathway: surface contact

(aPTT)

Xa

Extrinsic Pathway: tissue injury (INR)

VIIa

Thrombin-Fibrin Clot

IX

X

Prothrombin (II)

Primer on Coagulation

VIII

X

VII

XIIa

XI

tissue factor

XIII

warfarin affects II, VII, IX, X DOACs affect II or X

Common Pathway (TCT)

Procoagulant Therapeutic Options

• Clotting factor replacement– frozen or fresh frozen plasma (FFP): 2-8 units

– 4-factor PCC (II, VII, IX, X): 1,000-3,000 IU (INR-dependent for warfarin, ~30 IU/kg)

– activated PCC (FEIBA): II, activated VII, IX, X: 4,000-5,000 IU (~50 IU/kg)

– recombinant factor VII: 90 µg/kg IV bolus

Procoagulant Therapeutic Options

• Other procoagulant options– cryoprecipitate (fVIII, fibrinogen): 6 units

– DDAVP (increases fVIII): 0.3 µg/kg/min IV over 15-30 min

– platelets: 1-2 units

– tranexamic acid (anti-fibrinolytic): 10-15 mg/kg IV over 20 min

Procoagulant Therapeutic Options• Anticoagulant reversal agents

– vitamin K (for VKAs): 2.5-5 mg IV better than 5-10 mg PO but takes 18-36 hours

– protamine sulphate (for heparin, partial effect for LMWHs): 1 mg per 100 units heparin/LMWH (50 mg)

– idarucizumab (for dabigatran)

– andexanet (for apixaban and rivaroxaban)

Case No. 1• 85-year-old hypertensive female with atrial fibrillation

on warfarin (INR = 2.7) presents with severe nausea and ataxia

• BP = 180/90 mmHg, HR = 85/min– Hgb = 125 g/L– CrCl = 45 mL/min

Found to have 4 cm cerebellar hemorrhage…

potentially amenable to surgical intervention

In addition to consulting neurosurgery, what else would you do?

1. FFP……………………………… 4-6 units2. PCC…………………………….. 30 IU/kg over 5-10 min3. activated PCC (FEIBA)…. 50 IU/kg over 5-10 min4. recombinant factor VII… 90 μg/kg5. none of above, continue supportive care

• For patients with VKA-associated major bleeding, we suggest rapid reversal of anticoagulation with 4-factor PCC rather than with plasma (Grade 2C).

• We suggest the additional use of vitamin K, 5-10 mg administered by slow IV infusion, rather than reversal with coagulation factors alone (Grade 2C).

2012 ACCP Guidelines

Holbrook A, et al. Chest 2012;141:e152

How to reverse warfarin?

• Clotting factor replacements– FFP: large volume (4 U = 1L saline), time to thaw, variable

clotting factor levels, need to cross-match blood

– 4-factor PCCs: factors II, VII, IX, X (…easier but expensive!)– activated PCC (FEIBA): factors II, IX, X + activated VII

Liew A, et al. Can J Cardiol 2013;29:S34

Evidence for Anticoagulant Reversal for Urgent Surgery/Procedure

• RCT: 181 patients on warfarin needing urgent surgery/invasive procedure

• Intervention: open-label 4F-PCC or FFP (all receive vitamin K)

• Main outcomes: 1) effective hemostasis2) INR <1.4 at time of PCC infusion end

Goldstein JN, et al. Lancet 2015;385:20

Trial Design

Trial Outcomes

Case No. 2

• 75-yr male with AF + PAD (CHADS2VA2Sc = 7) on rivaroxaban 20 mg daily presents with lower GI bleed and peritoneal signs

• diagnosed with acute ischemic bowel and needs urgent surgery– BP = 88/60 mmHg, HR = 130/min– Hgb = 79 g/L; WBC = 19; platelets = 120 × 109/L– CrCl = 55 mL/min

• Last dose of rivaroxaban in AM (10 hours ago)

In addition to surgical assessment and prepare for OR, what else would you do?

1. supportive (fluids, packed red cells)2. 4 units FFP3. 4-factor PCC4. activated 4-PCC (FEIBA)

How to Reverse NOACs?• Coagulation factors?

– FEIBA for dabigatran– 4-factor PCC for apixaban/rivaroxaban

• Remove drug – dialysis– Yes for dabigatran (not highly protein bound)– No for oral Xa inhibitors (highly protein bound)

• Neutralize drug- specific reversal agents– andexanet-α– idarucizumab

Lauw M, et al. Can J Cardiol 2014; 30: 381

Case No. 3

• 75 yr old female with AF on dabigatran 110 mg BID falls on ice and brought to ER on Friday at 1PM, she is found to have a subdural bleed– BP = 160/100 mmHg, HR = 120/min– Hgb = 119 g/L– PTT = 59, INR = 1.3– TT >150 sec– CrCl = 45 mL/min

• Last dose of dabigatran at 9 AM (4 hours ago)

In addition to surgical assessment and prepare for OR, what else would you do?

1. Supportive (fluids, packed red cells)2. 4-factor PCC3. activated 4-PCC (FEIBA)4. idarucizumab (…what is this?)5. idarucizumab + FEIBA

DOAC Reversal AgentsMolecule Idarucizumab Andexanet Alfa PER977

Molecule type Humanized Antibody Fab Recombinant human FXa variant Small synthetic molecule

Target(s) Dabigatran FXa inhibitors UFH, LMWH, FXa inhibitors

Binding qualities (affinity)

Noncompetitive (350x for dabigatran)

Competitive (equal)

Noncovalent hydrogen bonding (affinity unknown)

Route of administration

Intravenous (5 min infusion)

Intravenous (bolus + infusion) Intravenous

PK/PD Terminal t½:Elimination:

4.5-9h Renal + RES

30-60 minunknown

unknownunknown

Effect Start:Sustained:

<5min 12-14h

<10min during infusion

~10min 12-24h

Safety In volunteers:Clinical settings:

up to 8 g 5g (Phase 3)

up to 800 mg Variable Dosing

up to 300 mgunknown

Off Target Effects None known Competes with Fxa binding to TFPI inducing procoagulant effect

Binds calcium chelators

Availability Approved for clinical use Not approved for clinical use Not approved for clinical use

Schiele et al. Blood 2013;121:3554–62; Lu et al. Nat Med 2013;9:446-53 ; Ansell et al. N Engl J Med, 2014, 371:2141-42; Lauw et al. Can. J. Cardiol 2014;30:381-84e; Portola Pharmaceuticals. Presentatation at Jan 2015 Investigator’s Meeting; Crowther et al. f; Weitz et al. J Thromb Thrombolysis 2015. DOI 10.1007/s11239-015-1194-6

RE-VERSE AD Trial: multicentre, open-label, single-arm Phase III trial

Primary endpoint: reversal of dabigatran activity Multiple safety endpoints

Group A: uncontrolled bleeding + dabigatran-treated

Group B: emergency surgery/procedure + dabigatran-treated

N=300

0 – 15 min 90 days follow-up0 – 24 hrs

Hospital arrival Pre-2nd dose 2 h 4 h 12 h 24 h 30 d 90 dPre-1st dose 1 hBlood

~20 min

Pollack C, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511

5 g idarucizumab(two separate

infusions of 2.5 g)

Dabigatran vs. Idarucizumab

RE-VERSE AD: Patient CharacteristicsGroup A (bleeding)

(n = 51)Group B (surgery)

(n = 39)Total

(N=90)Male, n (%) 32 (63) 18 (46) 50 (56)

Age (yrs), median (min, max) 77.0 (48, 93) 76.0 (56, 93) 76.5 (48, 93)

CrCl , mL/min, Median (range) 54 (16, 187) 60 (11, 171) 58 (11, 187)

Elevated dTT at baseline 40 28 68

Elevated ECT at baseline 47 34 81

Patient-reported time (hrs) since last dabigatran, median (min, max)

15.2 (1.5 - 56.6)

16.6(5 - 93.8)

15.4(1.5 - 93.8)

Dabigatran indication, n (%)AFVTEOther

47 (92.2)1 (2.0)3 (5.9)

39 (100)0 (0)0 (0)

86 (95.6)1 (1.1)3 (3.3)

RE-VERSE AD: patients enrolled due to major bleeding or need for emergency surgery/procedure

Group A (n=51)

Type of bleedingGastrointestinal 20Intracranial 18Trauma 9Other* 11

Group B (n=39)

Reason for surgery†

Bone fractures 8Acute cholecystitis 5Acute renal insufficiency, catheter placement

4

Acute appendicitis 3Joint/wound infection 3Abscess (suprapubic, scrotal) 2Acute mesenteric ischaemia with sepsis

2

Aortic dissection 1Pericardial tamponade 1Peritonitis 1

*’Other’ bleeding types: urogenital, epistaxis, liver, aortic aneurysm and aortic dissection

Primary Endpoint in Group A: Reversal of Dabigatran Anticoagulation with Idarucizumab based on dTT and ECT

Ecarin clotting time (ECT)

Assay upper limit of normal

Diluted thrombin time (dTT)

Idarucizumab 2x 2.5 g

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

EC

T (s

)

325

275

175

150

125

75

50

25

300

250

225

200

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post idarucizumab

100

Primary endpoint in Group B: Reversal of Dabigatran Anticoagulation with Idarucizumab based on dTT and ECT

Ecarin clotting time (ECT)

Assay upper limit of normal

Diluted thrombin time (dTT)

Idarucizumab 2x 2.5 g

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

EC

T (s

)

325

275

175

150

125

75

50

25

300

250

225

200

1h 2h 4h 12h 24hBaseline Betweenvials

10–30min

Time post idarucizumab

100

• maximum % reversal of dabigatran anticoagulation based on dTTor ECT measured within 4 hrs after idarucizumab given

• dTT and ECT show linear correlations with dabigatran levels

Glund S et al, Lancet 2015; 386: 680-690; Pollack C et al. Thromb Haemost. 2015; 114: 198–205.

RE-VERSE AD: Primary endpoint

dTT ECT

Disclaimer: Idarucizumab is not licenced for use in any country.

Re-start of anticoagulant therapy: Time to re-start

+none of these patients were anticoagulated at the time point of event

Antithrombotic therapy restarted after the event

Group A: serious bleeding(38/51)

Group B: urgent procedures

(34/39)

Total(72/90)

Median time (days) to restart antithrombotic therapy (range)

4.1 (0.2 – 77.2)

1.4 (0 – 40.8)

2.4(0 – 77.2)

Median time (days) to re-initiated dabigatran therapy (range)

7.2 (1.3 – 90.6)

8.8(1 – 63.3)

7.8(1 – 90.6)

Restart ofantithrombotic therapywithin 24hrs, n (%)

3 (7.9) 7 (20.6) 10 (13.9)

Clinical Outcomes

• Bleeding Group: time to bleeding stopping = 11.4 hrs

• Surgery Group: Normal intraoperative hemostasis in 33 (92%) of patients.

• 18 deaths: considered related to index event or co-existing conditions

Thromboembolic events within 90 days after idarucizumab treatment

Age/

Gender

Thromboembolic

events

Time after idarucizumab

(days)

Reason for anticoagulation

Treatment group

Index event

75/M DVT and PE 2 atrial fibrillation

A GI bleed

82/F DVT 7 atrial fibrillation

B acute cholecystitis

85/M atrial thrombus, DVT and PE

9 atrial fibrillation

A intracranial hemorrhage

86/F NSTEMI 13 atrial fibrillation

A intracranial hemorrhage

72/F ischemic stroke 24 atrial fibrillation

B infected knee joint

All patients were not receiving any antithrombotic therapyat the time of thromboembolic event

Case No. 4

• 75 year old female with AF on rivaroxaban 20 mg daily comes to ER on Friday at 5PM after several hours of maroon-coloured stools and dizziness– BP = 85/59 mmHg, HR = 120/min– Hgb = 109 g/L– PTT = 35, INR = 1.7– CrCl = 55 mL/min

• Last dose of rivaroxaban at noon (5 hours ago)

In addition to surgical assessment and prepare for OR, what else would you do?

1. Supportive (fluids, packed red cells)2. 4-factor PCC3. activated 4-PCC (FEIBA)4. andexanet-α5. andexanet-α + PCC

Day 1

ANNEXA-4 Study Design

Patient with major bleed, meeting inclusion criteria

Patient ScreeningIV

bolus2-hr IV

infusion

Safety follow-up

Efficacy Outcomes:◆ Change in anti-Xa activity◆ Hemostatic efficacy at 12 hrs

Day 30

Day 3

If last dose of Xa inhib≤18 hrs

Andexanet Bleeding and Laboratory Assessment

Assessments:

Safety Outcomes:◆ Thrombotic events◆ Antibodies to andexanet◆ 30-day mortality

After end of

infusion

1 hr 4 hr 8 hr12 hr

Connolly S, et al. N Engl J Med 2016

Phase 4 Outcomes Study in Bleeding Patients:ANNEXA-4 on apixaban, rivaroxaban and enoxaparin

▸ Open-label, multinational study in patients receiving fXa inhibitors presenting with acute major bleeding▸ Two primary endpoints

▸1) % change from baseline in anti-fXa activity▸2) % patients achieving “effective hemostasis”

(based on Independent Adjudication Committee)▸ Study ongoing in >50 sites in North America and Europe▸ Plan to study edoxaban

ANNEXA-4 Dose SelectionAcute major bleeding ≤18 hrs of last dose of apixaban,

edoxaban, rivaroxaban, or enoxaparin

Andexanet IV bolus and 2 hour infusion

Patients on apixaban or>7 h from last rivaroxaban dose

Bolus 400 mg+

Infusion 480 mg @4 mg/min

Pts on enoxaparin, edoxaban or≤7 h from last rivaroxaban dose

Bolus 800 mg+

Infusion 960 mg @8 mg/min

factor Xa andexanet-a

Gla domain

• Recombinant engineered version of human factor Xa

S S S S

factor Xa inhibitor

• Factor Xa decoy that competes with factor Xa binding site to prevent its activation (and anticoagulant effect)

change of serine to alanine to eliminate catalytic activity and prevent prothrombin cleavage

Gla domain removed to prevent procoagulant effect

Andexanet-a to Reverse Factor Xa Inhibitors

Nature Medicine 2013;19: 446

factor Xa inhibitor

catalytic domain

Site of BleedingSafety

PopulationN=67

Efficacy Population

N=47Gastrointestinal Bleeding, n (%) 33 (49.3) 25 (53.2)

Upper, n (%) 9 (27.3) 7 (28.0)Lower, n (%) 10 (30.3) 8 (32.0)Unknown, n (%) 14 (42.4) 10 (40.0)

Intracranial Bleeding, n (%) 28 (41.8) 20 (42.6)Intracerebral site, n (%) 14 (50.0) 12 (60.0)Sub-dural site, n (%) 11 (39.3) 7 (35.0)Subarachnoid site, n (%) 3 (10.7) 1 (5.0)

Other Bleeding site, n (%) 6 (9.0) 2 (4.3)Nasal, n (%) 1 (16.7) 0 (0.0)Pericardial/pleural/retroperitoneal, n (%) 3 (50.0) 1 (50.0)Genital/urinary, n (%) 1 (16.7) 1 (50.0)Articular, n (%) 1 (16.7) 0 (0.0)

Effect of andexanet on anti-Xa activity of rivaroxaban (n= 26)

Effect of andexanet on anti-Xa activity of apixaban (n=20)

Clinical Hemostatic Efficacy

Safety Assessment

• Anticoagulants re-started in 18 (27%) patients by 30 days

• Thrombosis occurred in 16 (24%) patients by 30 days(anticoagulation re-started in 1 patient before thrombotic event occurred)

• Deaths occurred in 10 (15%) patients by 30 days, of which 6 were CV deaths

…back to the learning objectives

• Have an approach to the management of vitamin K antagonist (VKA)-related bleeding. – 4-factor PCCs + IV vitamin K, 2-3 mg

• Have an approach to the management of direct oral anticoagulant (DOAC)-related bleeding. – idarucizumab for dabigatran, 2.5 g×2 back-to-back– PCC for oral Xa inhibitors pending andexanet approval

• Review emerging data on antidotes to DOACs.– andexanet bolus (400-800 mg) + infusion (480-960 mg)