Reverse the New Anticoagulants?

Reverse the New Anticoagulants?

Mitchell J Daley, PharmD, BCPS Clinical Pharmacy Specialist, Critical Care

University Medical Center Brackenridge / Dell Seton Medical Center at the University of Texas

Seton Healthcare Family

Clinical Adjunct Faculty

University of Texas College of Pharmacy

Disclosure

• No financial conflicts of interest to disclose

related to this subject manner

• Discuss off-label uses of laboratory and

medication therapy

Learning Objectives

• Describe how to assess for the

presence of TSOA

• Discuss available options for TSOA

reversal

VIIa VII

Target Specific Oral Anticoagulants (TSOA)

Direct Thrombin Inhibitor

• Dabigatran (Pradaxa®- 2010)

Factor Xa Inhibitor

• Rivaroxaban (Xarelto® - 2011)

• Apixaban (Eliquis® - 2012)

• Edoxaban (Savaysa® - 2015)

• Betrixaban (Portola® - in development)

XII XIIa

Damaged Surface

XI XIa

IX IXa VIIIa

X Xa

Tissue Factor

Va

Fibrinogen Fibrin

(I) (Ia)

Prothrombin Thrombin

(II) (IIa)

Intrinsic Pathway

Extrinsic

Pathway

Approach to Reversal

1. Recognize TSOA coagulopathy

2. Determine if drug present / assess urgency

3. Pharmacologic reversal

Recognizing Dabigatran Coagulopathy

Van Ryn, et al. J Thromb Haemost 2010;103:1116.

Assay Relationship Pearl

Diluted thrombin time (Hemoclot®) Diluted plasma, constant thrombin concentration

Quantitative, direct, linear Not routinely available

Use in clinical trials

Ecarin clotting time (ECT) Ecarin converts prothrombin to meizothrombin

Quantitative, direct, linear

Thrombin clotting time (TT) Directly assess the activity of thrombin

Qualitative, direct, linear Lacks standardization in

reagents; very sensitive

Activated partial thromboplastin time

(aPTT) Measures intrinsic pathway

Qualitative, indirect,

curvilinear

Normal suggests little to no

dabigatran acitivity

Recognizing Factor Xa Inhibitor Coagulopathy

Garcia D, et al. J Thromb Haemost 2013;11:245.

Cuker A, et al. J Thromb Thrombolysis 2015;39:288.

Assay Relationship Pearl

Chromogenic anti-FXa assay Factor Xa cleaves chromogenic substrate

directly proportional to activity

Quantitative, direct, linear No data on threshold values

Requires local calibration

and validation

Prothrombin time Clotting time triggered with tissue factor

Rivaroxaban: qualitative

Apixaban: insensitive

Edoxaban: qualitative, can’t rule

out

Dependent on reagent

May see modest elevations

Recognizing TSOA Coagulopathy Is Difficult…

• Lack of optimal and readily available assay

• Limited medical history

• Example: RCT of idarucizumab for dabigatran reversal

– Efficacy outcome: ECT & dTT reversal at central laboratory

– Patients given study drug & excluded from efficacy analysis

• ~25% normal dTT

• ~11% normal ECT

• Pharmacologic reversal should be guided by bleeding

Pollack CV, et al. N Eng J Med 2015;373:511.





Applying Pharmacokinetics Characteristic Dabigatran Rivaroxaban Apixaban Edoxaban

Half-life by renal function, hrs

Clcr: > 80 mL/min

Clcr: 50-79 mL/min

Clcr: 30-49 mL/min

Clcr: < 30 mL/min

12-14

17

19

28

5-9

9

9

10

8-15

15

18

17

8.5

9

9

9.5

Renal elimination, % 80 36 27 50

Protein binding, % 35 92-95 87 55

Typical duration of

anticoagulation, days

1-3

AKI >3-5 d

1-2

> in AKI?

1-2

> AKI?

1-2

> AKI?

Drug – drug interactions

examples

P-glycoprotein

inhibitors

P-glycoprotein inhibitors

Cytochrome 3A4 inhibitors

P-glycoprotein

inhibitors

Nutescu EA, et al. Am J Health Syst Pharm 2013;70:1914.





• Coagulation factor replacement / hemostatic agents

• Antidotes

PCC Considerations

Nutescu EA, et al. Am J Health Syst Pharm 2013;70:82.

Enriquez A, et al. Eurospace 2015; doi:10.1093/eurospace/euv030.

Frontera JA, et al. Neurocrit Care 2016:24:6-46.

• PCC recommended for TSOA reversal from multiple guidelines → if antidotes not available

– Dabigatran: activated or 4 factor PCC 50 unit/kg

– Anti-factor Xa: activated or 4 factor PCC 50 unit/kg

• Not considered standard of care in RCT

“Do what you can, with what you have, where you are”

-Theodore Roosevelt




3. Pharmacologic reversal • Coagulation factor replacement / hemostatic agents

• Antidotes

Hopeful Future: TSOA Antidotes Drug Mechanism Which TSOA Early Results Current Status

Idarucizumab

(Praxbind®)

From

Boehringer

Monoclonal

antibody;

binds dabigatran

(>350 affinity)

Dabigatran

Reversed coagulation markers

within 5 minutes

Sustained for >12 hours in

• Phase III study

ongoing

• FDA approved

Andexanet

From Portola

Modified factor Xa;

binds anti-Xa

(similar affinity)

Xa inhibitors

(direct and

indirect)

Plasma anti-Xa reduced >90%

within 2 minutes

Dose dependent response

• Phase III study

ongoing

Ciraparantag /

Aripazine

From

Perosphere

Synthetic

molecule; direct

binding

Universal Baseline hemostasis achieved

in 10-30 minutes

• Phase II study

ongoing

Mo Y, et al. Pharmacotherapy 2015;35:198.

Ansell JE, et al. N Eng J Med 2014;371:2141.

Idarucizumab: RE-VERSE AD Study Population Intervention Endpoints

Pollack

Phase 3

Multicenter

Single arm

Patients on dabigatran

A: life threatening hemorrhage

B: urgent (<8 hr) surgical or

invasive procedure

Goal = 300 pt; interim = 90 pt

5 g

intravenous

idarucizumab

(2.5 g / 50 mL x 2)

10 endpoint:

- Maximum percent dabigatran reversal (dTT or ECT)

2o endpoint:

- Proportion of patients with normalization by 4 hours

- Reduction in concentration of unbound dabigatran

- Clinical outcomes


• Demographics – Group A = 51 patients; Group B = 39

– Age 76.5 y, eCrCl 58 mL/min; time from dabigatran 15.4 hr

– Type of bleeding: ICH (20%), trauma (10%), GI (22%)


Unbound Dabigatran Levels


ECT Reversal

Idarucizumab Reverses Dabigatran…

• 100% maximum percentage reversal & normalized labs in 88-98%

• Unbound dabigatran levels <20 ng/mL: – 93% of pts at 12 hours

– 79% at 24 hours

• Clinical outcomes – Investigator-reported time to hemostasis: 11.4 hours

– Urgent procedures: 92% normal intraoperative hemostasis

– Mortality: 20% (5 fatal bleeding events)

– Thrombotic events: 5 patients; only 1 within 72 hours

• Remains to be defined – Repeat dosing?

– Overdose?


Does Idarucizumab Improve Outcomes?

• Considerations – Lack of control group

– Broad inclusion (mortality: 20% vs. 10-20% previously)

• How important is neutralizing the anticoagulant effect? – Warfarin vs. dabigatran in intracranial hemorrhage

• In-hospital mortality dabigatran 20% (n=101) vs. warfarin 22% (n=2,290)

• Propensity score adjustment 0.93 (0.62-1.37)

Bauer K. N Eng J Med 2015;373:569.

et al. Circulation 2013;128:2325.

Alonso A, et al. Stroke 2014;45:2286.

Granger, et al. Circulation 2012;125:159.

Majeed,

Hopeful Future: TSOA Antidotes Drug Mechanism Which TSOA Early Results Current Status

Idarucizumab

(Praxbind®)

From

Boehringer

Monoclonal

antibody;

binds dabigatran

(>350 affinity)

Dabigatran

Reversed coagulation markers

within 5 minutes

Sustained for >12 hours in

• Phase III study

ongoing

• FDA approved

Andexanet

From Portola

Modified factor Xa;

binds anti-Xa

(similar affinity)

Xa inhibitors

(direct and

indirect)

Plasma anti-Xa reduced >90%

within 2 minutes

Dose dependent response

• Phase III study

ongoing

Ciraparantag /

Aripazine

From

Perosphere

Synthetic

molecule; direct

binding

Universal Baseline hemostasis achieved

in 10-30 minutes

• Phase II study

ongoing

Mo Y, et al. Pharmacotherapy 2015;35:198.

Ansell JE, et al. N Eng J Med 2014;371:2141.

Andexanet Study Population Intervention Endpoints

Siegal

Phase 2

Placebo

controlled

Elderly (50-75), healthy

volunteers

Received rivaroxaban and

apixaban for ~4 days

Andexanet: 400-800 mg bolus

-or-

Andexanet: 400-800 mg bolus & 4-8 mg/min for 2 hr

-or-

Placebo

10 endpoint:

- % change in anti-factor

Xa activity

Siegal DM, N Eng J Med 2015. epub

ahead of print

Phase 3 trial primary outcome good or excellent clinical

hemostasis

Conclusions • Identify TSOA coagulopathy:

– Dabigatran: TT, aPTT, and maybe rapid TEG

– Factor Xa inhibitors: protime and chromogenic anti-Xa

• Establish time from last dose (3-5 half-lives)

– Prolonged with end-organ dysfunction?

– Drug-drug interactions?

• Reversal options in a transition period – Dabigatran: ? dialysis and / or aPCC ? → idarucizumab

– Xa inhibitors: 4 factor or activated PCC → andexanet

• This transition will:

– Challenge our approach to reversal

– Improve outcomes?

Reverse the New Anticoagulants?

Mitchell J Daley, PharmD, BCPS Clinical Pharmacy Specialist, Critical Care

University Medical Center Brackenridge / Dell Seton Medical Center at the University of Texas

Seton Healthcare Family

Clinical Adjunct Faculty

University of Texas College of Pharmacy

Documents

Reverse the New Anticoagulants?