Wat betekent de komst van NOAC antidota voor de klinische praktijk? - - PowerPoint PPT Presentation

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Feb 15, 2023 268 likes •565 views

Wat betekent de komst van NOAC antidota voor de klinische praktijk? Professor Saskia Middeldorp | Department of Vascular Medicine | MiddeldorpS Nationale antistollingsdag 6 november 2018 Disclosures Research Support, Advisory Boards

SLIDE 1

Wat betekent de komst van NOAC antidota voor de klinische praktijk?

Professor Saskia Middeldorp | Department of Vascular Medicine | MiddeldorpS Nationale antistollingsdag 6 november 2018

SLIDE 2

Disclosures

Research Support, Advisory Boards and Lecture Fees Aspen Bayer BMS/Pfizer Boehringer Ingelheim Daiichi Sankyo GSK Portola Sanquin Sanofi

SLIDE 3

Surrogate endpoint

To correct INR

Clinical endpoint

To improve outcome Evidence for antidotes

What we have What we need…

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Hemostatic efficacy – The New Benchmark Effective/Good Ineffective/ Poor

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30 d Thromboembolism 8%

VKA

SLIDE 6

Vitamin K antagonist related bleeding and PCC

Retrospective cohort

study in 5 Dutch hospitals

41% ICH; 36% GI
Hemostatic efficacy:

68%

Thromboembolic

rate 5%

Death 22%, 60%

bleeding-related

Brekelmans, RPTH 2017

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DOAC antidota Dabigatran: Idarucizumab (Praxbind)

Humanized antibody
300x binding to dabigatran than dabigatran with thrombin
single bolus of 2 x 2.5 gram i.v.
Registered in 2015, available in most hospitals now

SPC Praxbind; www.ema.europe.eu

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RE-VERSE-AD

Assay upper limit of normal

Diluted thrombin time

Idarucizumab 2x 2.5 g

dTT (s)

130 110 70 60 50 40 30 20 120 100 90 80

1h 2h 4h 12h 24h Baseline Between vials 10–30 min

Time post idarucizumab

N= 90 Mortality 20% Acute bleeding n=51 11.4 u until cessation of bleeding Acute surgery n=39 92% normalization of coagulation

Pollack, N Eng J Med 2015/ Full cohort analysis NEJM 2017

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DOAC antidota Factor Xa inhibitors: Andexanet alfa Catalytic domain Gla domein

Siegal, N Eng J Med 2015

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Andexanet alfa – not yet on the market

Connolly NEJM 2017

Anti-Xa activity decrease: 89% (58 – 94%)

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Hemostatic Efficacy with Andexanet

Excellent or good in 79% (95%CI 64-89)

Connolly NEJM 2017

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Andexanet alfa – almost on the market in NL?

Siegal NEJM 2015

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PCC in rivaroxaban treated healthy volunteers

50 IU/kg 50 IU/kg

Surrogate endpoint

To correct INR

Clinical endpoint????

SLIDE 14

Factor Xa inhibitor and Prothrombin complex concentrate (PCC)

apixaban

Eerenberg, Circulation 2011 Cheung, J Thromb Haemost 2015

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Recent Regulatory Trials of Reversal Agents

Pivotal Study Reversal agent Anti-coagulant Number Hemostatic Efficacy (95CI) Thrombotic Event Rate (95 CI) Mortality (95CI) Total % ICH Total ICH Total ICH Total ICH ANNEXA-4 Andexanet FXa Inhibitors 227 61 85% (77-90) 83% (72-91) 11% (7-16) 10% (5-18) 11% (7-16) 10% (5-18) REVERSE- AD Idarucizumab Dabigatran 301 33 68% a NR b 5% (3-8) 6% (2-13) 5% (3-8) 6% (2-13) Sarode 2013 4F-PCC Warfarin 98 12 72% (64-81) 42% (15-72) 8% (3-15) NR 8% (3-15) NR Sarode 2013 Plasma Warfarin 104 12 65% (56-75) 58% (28-85) 6% (3-13) NR 6% (3-13) NR 4F-PCC = Four factor prothrombin complex concentrate; ICH = Intracranial hemorrhage; NR = Not reported a 68% had investigator-determined, non-adjudicated time to hemostasis within 24 hours b Time to hemostasis not calculated in ICH patients

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EHRA 2013 practice guidelines

Heidbuchel, Europace 2013

idarucizumab

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Reversal for DOAC in urgent surgery How important is this?

Peri-procedural bleeds in RE-LY (dabigatran) No difference with warfarin despite the absence of a specific antidote

Healey, Circulation 2012

Urgent surgery VKA N=111 Dabigatran 110 mg bid N=107 Dabigatran 150 mg bid N=141 % Major bleeds 21.6 17.8 17.7 RR (95%CI) vs VKA 1 0.82 (0.48-1.41) 0.82 (0.50-1.35)

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Clinical scenario’s

The bleeding patient The patient undergoing urgent surgery The patient on DOAC with ischemic stroke Does having an antidote influence the choice of anticoagulant drug?

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AMC
MUMC+
Erasmus MC
Albert

Schweitzer Ziekenhuis

UMCG.

SLIDE 20

SLIDE 21

Use of idarucizumab

January – August 2016

Kermer, Int J Stroke 2017

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Retrospective cohort study

19 patients with ischemic stroke

18 < 4,5 hrs after onset
1 wake up stroke

R/ idarucizumab + r-tPA 79% benefit of thrombolysis

Kermer, Int J Stroke 2017

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Retrospective cohort study

12 patients with intracranial bleeding

2 patients with hematoma growth

R/ idarucizumab 67% favourable outcome TE events: 1 fatal pulmonary embolism after 5 days

Kermer, Int J Stroke 2017

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Dutch experience

First 2 years after release in January 2016 12 centers 86 patients

51 severe bleeding (20 GI, 18 intracranial)
34 urgent surgery
Mortality in 90 days 20%
? Effective hemostasis in 16 (31%) bleeding patients
? Large proportion of inappropriate use

Van der Wall, Eur Heart J abstract 2018

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What about andexanet?

Full cohort results expected early 2019
Phase 4 RCT with standard of care comparison in

patients with intracranial hemorrhage required by FDA

Surgery intervention not studied
Very high costs…

Andexa FDA approval Letter May 3, 2018

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In a bleeding patient, ask the right questions

1. What anticoagulant is prescribed?
2. Is anticoagulant present at high quantity?
When was last dose taken?
Half-life and renal function, (age, weight)?
3. Site and severity of bleed?
Local measures?
Is reversal necessary?

SLIDE 27

Antidotes….

First, they were not

there

Controversy regarding

the need

Now that we have

them, we need them…

SLIDE 28

Take home messages

The choice of an antidote may drive the choice for an

anticoagulant, particularly in patients at high risk of bleeding

Idarucizumab is easy to administer and widely available
Andexanet is complicated and not yet available
Guidance for stringent use needed