Transcript
Page 1: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Acute management in antithrombotic-related

intracerebral hemorrhage

Stefan Engelter MD, FESOUniversity of Basel, Switzerland

Professor of Neurology

Chair Rehabilitation, University Center for Medicine of Aging & Rehabilitation, Felix-Platter Hospital Basel

Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel

10th International Congress of Internal MedicineAthens, 22nd March 2018

Neurologie und Stroke CenterNeurorehabilitation Unit

Page 2: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Intracerebral hemorrhage related to Antithrombotics

I. Vitamin-K-Antagonists

II. Non-Vitamin K- or Direct orale Anticoagulants (DOAC; NOAC)

III. Antiplatelets

Neurorehabilitation Unit

Page 3: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Different Types

Hemorrhagic Stroke

Intracerebrale Hemorrhage Subarachnoidal Hemorrhage

Subdural Hemorrhage

Epidural Hemorrhage

Traumatic Brain Injury

Page 4: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Frequency of intracerebral bleeds: ⇧

4

Béjot et al, Brain 2013

Page 5: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Causes of der intracerebral hemorrhages

6

▪ Hypertensiv 35%

▪ Cerebrale Amyloidangiopathie (CAA) 20%

▪ Anticoagulation 14%

▪ Aneurysma, AVM, AVF,…. 5%

▪ Systemic diseases (liver failure, thombocytopenia,…) 5%

▪ Other Causes (e.g. Sinus venous thrombosis) 21%

CAA AVM

Stroke. 2012;43:2592-2597

Page 6: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Symposium Hirnschlagzentrum/Stroke Center USB

«Anticoagulant treatment does not cause a bleeding;

they can aggravate it»Kamphuisen; ESOC May 12th 2016, Barcelona

Page 7: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Symposium Hirnschlagzentrum/Stroke Center USB

«Anticoagulant treatment does not cause a bleeding;

it can aggravate it»Kamphuisen; ESOC May 12th 2016, Barcelona

Neurorehabilitation Unit

Page 8: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Anticoagulants and hemorrhagic stroke:The risk in the general poulation

Intracerebrale hemorrhage

❖ OR 2.82 (95% CI 2.26-3.53)

Subarachnoidal hemorrhage

❖ OR 1.67 (95% CI 1.15-2.43)

INR >3.0 ICH

❖ OR 7.01 (95% CI 4.10-11.9)

Neurology 2013;81(6):566-74.

Antithrombotic drugs and risk of hemorrhagic stroke in the general population.

Page 9: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

22. Mai 2014Symposium Hirnschlagzentrum/Stroke Center USB 10

Hämatom Expansion ⇨ Prognosis poor

HE in OAC-ICHs ⇨ 30-50%

Page 10: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Acute management in antithrombotic-related intracerebral hemorrhage

Stroke Unit Blood

pressure↓Antidotes (Surgery?)Hemostatic

Therapy

Page 11: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Death or DisabilityNeurorehabilitation Unit

Page 12: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Stroke Unit Definition

Stroke Unit:

➢ A dedicated geographically clearly defined area or ward in a hospital, where

stroke patients are admitted and

➢ cared for by a multi-professional team

✓medical,

✓nursing,

✓therapy staff

➢ who have specialist knowledge of cerebral function, training and skills in stroke

care with well-defined individual tasks,

➢ regular interaction with other disciplines, and stroke leadership.

➢ This team co-ordinates care through regular (weekly), multidisciplinary meetings.

Neurorehabilitation Unit

Page 13: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Stroke Unit – Treatment of ICH: What matters ?

Evans Lancet 2001

▪ Temperature and glucose management

▪ Systematic screening for dysphagia

▪ Less complications

➢ Pneumonia

➢ Dehydration

▪ Early rehabilitation

Neurorehabilitation Unit

Page 14: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Certification -> clearifies standards , .. less missunderstandings…

This is NOT a STROKE UNIT

We are a JOKE UNIT

Page 15: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

ICH- Guidelines

Steiner et al IJS 2014

Acute stroke unit care reduces both death and dependency for patients

with ICH in comparison with care on a general ward.

Quality of evidence: High

Strength of recommendation: Strong

In acute ICH within 6 h of onset, intensive blood pressure reduction (systolic

target <140 mmHg)

Quality of evidence: Moderate

Strength of recommendation: Weak

Page 16: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

17

Steiner et al, Int J Stroke 2014

Positive

Negative

➢ Further research

required

Page 17: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

(Stroke. 2012;43:2539-2540.)

Page 18: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

VKA-ICH ⇨ INR-Normalisation + RR⇩ in 4h

Kuramatsu et al. JAMA 2015

Neurorehabilitation Unit

Page 19: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

VKA-intracerebral bleed– rapid INR Normalisation

Kuramatsu et al. JAMA 2015

Neurorehabilitation Unit

Page 20: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Intracranial bleed under VKAFresh Frozen Plasma ⇔ Prothrombin Complex?

Neurorehabilitation Unit

Page 21: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Hirnblutung unter VKAFresh Frozen Plasma ⇔ Prothrombin Complex?

Steiner et al Lancet Neurol 2016

Intracranial bleed under VKAFresh Frozen Plasma ⇔ Prothrombin Complex?

Neurorehabilitation Unit

Page 22: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Alberts. Lancet Neurology 2012:1066

Non-VKA oral Anticoagulants (NOAC)

Direct oral Anticoagulants (DOACS)

Page 23: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress
Page 24: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

ICH during Warfarin vs NOAC therapy

Takahashi H et al. Am J Cardiol 2016;118:222-225

Page 25: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

NOAC-associated ICH ↔ VKA-associated ICH

90-day mortality

Wilson D et al. Neurology 2017;88:1-8

Poor outcome

65% (mRS 3-5)

Page 26: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Neurorehabilitation Unit

Page 27: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Neurorehabilitation Unit

Page 28: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Pharmacokinetic and reversal of DOACs

Abo-Salem E, Becker RC. Curr Opin Pharmacol 2016;27:86-91Neurorehabilitation Unit

Page 29: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Specific antidotes for DOACs

Monagle S et al. Future Cardiol 2017;13(2):153-159

Page 30: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

L.C

H.C

OM

.HC

.10.2

015.0

737

-EN

Idarucizumab – Antidote -> Dabigatran

▪ Group A: patients who had serious bleeding (n=51)▪ Hemostasis was restored at a median of 11.4 hours

▪ Group B: patients who required an urgent procedure (n=39)

▪ No control group

▪ Primary endpoint: hemostatic normalization: 100%

▪ Thromboembolic complications: 6.3%; Mortality 18.8%

Pollack CV. N Engl J Med 2015 and 2017

approved 10/2015

(3500 USD)

Neurorehabilitation Unit

Page 31: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Kermer et al Int J Stroke 2017

- Retrospective

- Case series

- 12 Pats with intracranial bleed under Dabigatran treated with Idarucizumab

only 2/12 with Hämatoma Expansion

only 1/12 died

Neurorehabilitation Unit

Page 32: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Connolly et al NEJM 2016

single arm: No control group

Primary endpoint: hemostatic normalization

Thromboembolic complications: 18%

Mortality 15%

Neurorehabilitation Unit

Page 33: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

89%

93%

CAVE: 20/67 Patients excluded due to plasmalevel <75ng/mlNeurorehabilitation Unit

Page 34: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress
Page 35: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress
Page 36: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress
Page 37: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Tranexamic acid for IntraCerebral Haemorrhage

▪ Tranexamic acid for IntraCerebral Haemorrhage 2 – TICH 2

▪ International, RCT

▪ ICB <8h since symptom onset

▪ TXA vs. Placebo

▪ 2325 patients

▪ Subgroup with antiplatelets

▪ RESULTS: May 16th 2018

Page 38: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Tranexamic acid in NOAC –ICH -> TICH-NOAC

▪ Tranexamic acid for IntraCerebral Haemorrhage associated with

NOAC – TICH-NOAC▪ Swiss, randomised, placebo-controlled, proof of concept study

▪ ICB <12h (since onset)

▪ Primary outcome: Hematoma Expansion at 24 hrs

▪ Started 1/2017

▪ N=12 pt (March 13th)

Page 39: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

TICH-NOAC

▪ Design: Randomized, placebo-controlled multi-center trial

▪ Coordinating Center: Basel, Co-PIs Stefan Engelter and Philippe Lyrer

▪ Patients: ICH while under treatment with a NOAC (last intake <48h) within 12

hours of onset

▪ Study treatment: TICH-II regimen

▪ best medical treatment (international guidelines/SOP), may include specific

antidots for NOAC in the future ( study treatment as “add-on”)

▪ Primary Outcome: hematoma expansion on follow-up imaging at 24 hours

▪ Sample size: 109 patients, interims analysis after 70 patients

Page 40: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Intracerebral Hemorrhage associated with Antiplatelets

Page 41: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Intracerebral Hemorrhage associated with Antiplatelets

Page 42: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

68

▪ Supratentorial intracrebral ICH (<6h after symptom onset)

▪ RCT: Platelet transfusion (1-2 platelet concentrats) ⇔ standard care

▪ PROBE

▪ 97 pts with platelet transfusion ⇔ 93 pts with standard care

▪ Primary endpoint: shift in death/dependency (modified Rankin scale score at 3 M)

Platelet transfusion

HARMFUL !

Page 43: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Surgery

Mendelow et al, Lancet 2013

Page 44: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Acute management in antithrombotic-related intracerebral haemorrhage

Take home messages

➢ STROKE UNIT THERAPY: EFFECTIVE

➢ EARLY Blood pressure lowering useful (target?)

➢ Vitamin-K-Antagonists

✓ Vitamine K, PCC, blood pressure↓ (TRAGET 160?); INR-<1.3 in 4h

➢ NOAC

✓ Optimal Management: yet to be determined

PCC: effectiveness not shown

Antidotes

currently only for Dabigatran (“Praxbind”),

clinical effectiveness unclear

Tranexamid Acid: -> “TICH-NOAC”-Study ongoing

Blood pressure lowering: promising

➢Antiplatelet-related ICH❖ NO platelet transfusion (harmful)

❖ Tranexamid Acid?

➢ TICH-2- Results: -> 16th May 2018 (subgroup antiplatelets)

Page 45: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Thank you for your attention

[email protected]; [email protected]

David Seiffge, Christopher Traenka, Alexandros Polymeris, Sebastian Thilemann, Lisa Hert, Mandy Müller, Urs Fisch, Mirjam Rhyner, Marina Maurer, Suzana Eble, Leo Bonati, Gian Marco De Marchis, Henrik Gensicke, Nils PetersPhilippe Lyrer

Page 46: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

Blutungsrisiko unter NOAC verglichen mit VKA

75

Courtesy P. Michel, CHUV

modified from: Connolly et al, NEJM 2009; Granger et al NEJM 2011; Patel et al, NEJM 2011; Giugliano et al NEJM 2013

0%

-50%

-75%

Dabigatran

150mg 110mg

Riva-

roxaban

Apixaban Edoxaban

60mg 30mg

Significant in all NOACs

- 69%- 60% - 58% - 53%- 33% - 70%

-25%

Page 47: Acute management in antithrombotic-related intracerebral ... · Head Stroke Pathway, Department of Neurology and Stroke Center, University Hospital Basel 10th International Congress

What do we know about NOAC-ICH?

76

▪ First data collaborative registry data published/analyzed recently

▪ Purrucker & Veltkamp (JAMA Neurology 2015): prospective registry of 38 german

Stroke Units – 61 NOAC-ICH patients

▪ Duncan Wilson & David Werring (personal communcation): international collaborative

registry based analysis of 13 stroke centers – 97 NOAC-ICH patients

▪ Hematoma volume: 14.4ml – 23.7ml

▪ Hematoma expansion: 38%-40%

▪ Mortality: 28% - 31 %

▪ Unfarorable outcome (mRS 3-6): 65%

No evidence based

treatment option

available


Recommended