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MANAGEMENT IN EMERGENZA

DEI SANGUINAMENTI DA NAO

11° Meeting CardioLucca

“New Frontiers in Cardiovascular Diseases”

Lucca, 3 Marzo 2017

Giuseppe Di Pasquale

Direttore Dipartimento Medico ASL Bologna

Direttore Unità Operativa Cardiologia

Ospedale Maggiore, Bologna

Giuseppe Di Pasquale Disclosures

• Member of the Steering Committee of the RELY, PALLAS, and

GLORIA AF

• Member of Advisory Board of Dabigatran,

Rivaroxaban, Apixaban, Dronedarone, Edoxaban

• Consulting fees / honoraria

Boehringer Ingelheim, Bayer AG, Sanofi Aventis

BMS / Pfizer, Daiichi Sankyo

Bleeding in NOACs Trials

New Anticoagulant Therapies Compared to

Warfarin: Major Bleeding

0.5 1 1.5

Dabigatran 150 mg BID1

Dabigatran 110 mg BID1

Rivaroxaban 20 mg QD2

Apixaban 5 mg BID3

HR 0.80 (95% CI, 0.70 to 0.93)

HR 1.04 (95% CI, 0.90 to 1.20)

HR 0.69 (95% CI, 0.60 to 0.80)

Edoxaban 60 mg QD4

Edoxaban 30 mg QD4

Hazard Ratio

HR 0.93 (95% CI, 0.81 to 1.07)

Study Drug Better Warfarin Better

4

1.Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.

2.Patel MR et al. N Engl J Med. 2011;365:883-891.

3.Granger CB et al. N Engl J Med. 2011;365:981-992.

4.Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907

HR 0.80 (95% CI, 0.71 to 0.91)

HR 0.47 (95% CI, 0.41 to 0.55)

JAMA Neurol 2013;70(12):1486-90

Blood 2014;124(15):2450-2458

Blood 2014;124:2450-2458

Fatal Bleeding Events

Circulation 2013;128:2325-32

NOACs bleeding management

Medical history : Key points

Huisman M et al, Thromb Haemost 2012;107:838-47

Coagulation tests

Assessment of drug effect

Management of bleeding in patients taking NOACs

Updated EHRA Practical Guide on the use of non-vitamin K antagonist , Europace 2015,

Nuovi Anticoagulanti Orali non VKA Antagonisti

Svantaggi • Aggiustamento empirico del dosaggio

• Necessità di nuovi test laboratoristici da eseguire in caso di eventi emorragici o trombotici

• Difficoltà di valutare l’aderenza del paziente alla terapia

• Mancanza di antidoto

• Inizio e termine d’azione rapidi: potenziale svantaggio nei pazienti con bassa aderenza terapeutica

• Possibile ridotta consapevolezza della terapia da parte del paziente

• Costo elevato

Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65

Reversal of Anticoagulation

Anticoagulant Antidote

Warfarin Vitamin K

Prothrombin Complex Concentrate (PCC)

Heparin Protamine sulphate

LMWH (Enoxaparin) No effective antidote

(only partially reversed by protamine)

Fondaparinux No effective antidote

Bivalirudine No effective antidote

N Eng J Med, June 2015

Idarucizumab Reverses the Anticoagulant Effects of Dabigatran in Patients in an Emergency Setting of Major Bleeding, Urgent Surgery, or Interventions

CV Pollack Jr, MA, MD; PA Reilly, PhD; J van Ryn, PhD; J Eikelboom, MD; S Glund, PhD; RA Bernstein, MD, PhD; R Dubiel, PharmD;

MV Huisman, MD, PhD; EM Hylek, MD; PW Kamphuisen, MD, PhD; J Kreuzer, MD; JH Levy, MD; FW Sellke, MD; J Stangier, PhD;

T Steiner, MD, MEE; B Wang, PhD; C-W Kam, MD; JI Weitz, MD

On behalf of the RE-VERSE AD™ Investigators

Updated Results of the RE-VERSE AD™ Study

RE-VERSE AD™ Study Update

Presentation includes data on 494 patients followed

for 3 months

Data cut-off was July 31, 2016

369 sites were initiated in 39 countries, 173 sites recruited patients

Full trial results will be based on data from 503 patients

22

Group A: Uncontrolled bleeding + dabigatran-treated

Group B: Emergency surgery or procedure + dabigatran-treated

N = 494

0–15 min 90 days follow-up

Hospital arrival

5 g idarucizumab (2 x 2.5 g

intravenously)

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

Blood samples

*Connolly S,et al. N Engl J Med. 2009; 361:1139–51.

Pollack C, et al. Thromb Haemost. 2015;114:198–205. dTT, diluted thrombin time; ECT, ecarin clotting time.

~20 min

Reverses up to the 99th percentile of dabigatran levels

measured in RE-LY®*

Multicenter, Ongoing, Open-label, Single-arm Phase III study

Primary endpoint:

Maximum reversal within 4

h based on dTT, ECT

*Bleeding may occur at more than one site. GI, gastrointestinal; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis.

Type of Bleeding* N

Intracranial 97

Intracerebral 53

Subdural 38

Subarachnoid 25

Gastrointestinal 135

Upper 52

Lower 45

Unknown 42

Non-GI, Non ICH 87

Pericardial 7

Intramuscular 9

Retroperitoneal 10

Intra-articular 5

Other 56

Total 319

Group A: Site of Index Bleed (298 patients)

ISTH Bleeding Severity (n = 298)

(determined locally upon patient entry)

Group B: Indications for Surgery/Procedures

Indication / Procedure Frequency

Acute abdomen (gall bladder, appendix, bowel obstruction) 45

Bone fracture (hip, femur, open extremity, other) 30

Infection (joint, abscess, sepsis) 20

Incarcerated hernia 16

Acute renal failure, obstruction 11

Pacemaker implant 10

Pneumothorax for tube thoracostomy 9

ICH (surgical intervention) 7

Reperfusion for MI 5

Aortic aneurysm repair 5

Pericardiocentesis 4

Emergent spinal surgery 4

Heart transplant 3

Lumbar puncture 2

Other 25

Total 196

ICH, intracranial hemorrhage; MI, myocardial infarction.

10th/90th percentiles 5th/95th percentiles Median and 25th/75th percentiles

RESULTS: Diluted Thrombin Time (dTT) - Assessment of Reversal of Dabigatran Anticoagulation with Idarucizumab

ULN, upper limit of normal

Assay ULN

Similar results were also obtained with Ecarin Clotting Time (ECT)

RESULTS: Unbound Dabigatran Levels Showing Reversal of Dabigatran Anticoagulation with Idarucizumab

10th/90th percentiles 5th/95th percentiles Median and 25th/75th percentiles

Group B: Peri-procedural Hemostasis

191 of 196 (97.4%) patients underwent surgery/procedures

Median time from administration of first vial to procedure was 1.6 hours

Adequacy of hemostasis during surgery determined locally

NOACs Antidotes in Clinical Trials

Connoly SJ et al. N Engl J Med 2016;375:1131-1141


Multicenter, prospective, open-label, single-group study, we evaluated 67 pts

who had acute major bleeding within 18 hours after the administration of a

factor Xa inhibitor.

Anti-Factor Xa Activity and Percent Change from

Baseline in Patients Receiving Rivaroxaban


Anti-Factor Xa Activity and Percent Change from

Baseline in Patients Receiving Apixaban


Documento regionale NAO -Emilia Romagna, Settembre 2016

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