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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
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)
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
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
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
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
Connoly SJ et al. N Engl J Med 2016;375:1131-1141
Anti-Factor Xa Activity and Percent Change from
Baseline in Patients Receiving Apixaban
Connoly SJ et al. N Engl J Med 2016;375:1131-1141