Διαχείριση ασθενούς με αιμορραγία που λαμβάνει DOACs. Νικόλαος Φραγκάκης

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1 Διαχείριση ασθενούς με αιμορραγία που λαμβάνει DOACs Νικόλαος Φραγκάκης Επίκουρος Καθηγητής Καρδιολογίας ΑΠΘ Γ Πανεπιστημιακή Καρδιολογική Κλινική Γ.Ν. Ιπποκράτειο, Θεσσαλονίκης

2 Δήλωση συμφερόντων Ο ομιλητής έχει λάβει αμοιβές για ομιλίες σε εκπαιδευτικά σεμινάρια από τις κάτωθι φαρμακευτικές εταιρείες: Bayer Healthcare, Menarini, Mylan, St Abbot, Pfizer Jude,

3 DOAC 4-trial Meta-analysis Full Dose Pre-specified meta-analysis of all 71,683 patients Trial Stroke and Systemic Embolism p Major Bleeding p RE-LY ROCKET-AF ARISTOTLE < ENGAGE TIMI Combined Favours DOAC Favours DOAC Ruff C, et al. Lancet 2013

4 Patients with AF on NOACs

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6 a 66-year-old woman with severe sharp chest pain

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9 Idarucizumab led to normal haemostasis during surgery

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11 a 68-year-old man. on dabigatran, 110 mg twice a day, for paroxysmal AF, hypertension and old inferior MI At 7.05 AM, he noticed sudden onset of visual disturbances, dizziness, and slight headache According to his wife, the patient took his last dabigatran dose around 6:00 pm, 1 hour before the start of symptoms

12 Emergency department 50 min later Right sided homonymous hemianopsia and evidence of aphasic disturbances dtt= 218 sec (normal range: sec) APTT= 73 sec (normal range: sec) The remaining routine laboratory values, including creatinine clearance, were normal

13 acute ischemic stroke

14 Considering Need to perform thrombolysis with t-pa 1) hemianopsia as a functionally relevant deficit 2) presence of a diffusion-weighted imaging mismatch 3) early time window

15 NOACS- in acute ischemic stroke Raval AN, et al. Circulation. 2017;135:e604 e633

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19 NOACs Acute ischemic stroke

20 GLOBAL USE OF NOACs

21 Reasons for Underuse of Anticoagulation Novel oral anticoagulants and reversal agents: Considerations for clinical development. White paper cosponsered by the FDA. Sarich TC et al. Am Heart J Jun;169(6): doi: /j.ahj Epub 2015 Mar 26.

22 REAL LIFE RISK OF NOACs COMPLICATIONS

23 Patients on anticoagulants may have to undergo emergency surgery or interventions Emergency surgery may become necessary for a variety of reasons Especially given the high-risk population of patients with AF Bone fractures Thrombolysis for acute stroke Acute abdomen (e.g. appendicitis) Urgent PCI for treatment of ACS Incarcerated hernia Pacemaker implant Infection Acute renal failure Often the need for emergency surgery is not causally associated with the intake of an anticoagulant itself

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26 Rapid reversal of the anticoagulant effects of NOACs may be required in certain emergency situations Emergency surgery Uncontrolled bleeding A specific reversal agent could take the NOAC out of the equation in these situations

27 What are the characteristics of an ideal reversal agent?

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29 What are the key characteristics of idarucizumab? 14

30 Idarucizumab was designed as a specific reversal agent for the anticoagulant activity of dabigatran Humanized antibody fragment (Fab) Ready to use solutions for IV administration Specific to dabigatran Immediate onset of action Binding affinity for dabigatran ~350 higher than dabigatran to thrombin, resulting in essentially irreversible binding Dabigatran No intrinsic procoagulant or anticoagulant activity No endogenous targets Idarucizumab Idarucizumab dabigatran complex is eliminated quickly (within a few hours) Adapted from Schiele et al. Blood 2013; Eikelboom et al. Circulation 2015; Praxbind SPC, 2017; Schmohl et al. Thromb Haemost

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32 Pollack et al. N Engl J Med 2017

33 RE-VERSE AD was a multicentre, open-label, single-arm Phase III trial 503 dabigatran-treated patients at 173 sites in 39 countries Group A: Uncontrolled bleeding Group B: Emergency surgery or procedure 5 g idarucizumab (2 2.5 g intravenously) 0 15 min Primary endpoint Maximum reversal within 4 hrs with dtt and ECT measures Secondary endpoints Determined locally Haemostasis within 24 hours (non-ich) Haemostasis during procedure/surgery Thrombotic events Restart of anticoagulation Mortality aptt / TT Dabigatran plasma levels Immunogenicity Hospital arrival Baseline Between vials ~20 min 1 h 2 h 4 h 12 h 24 h 30 d 90 d follow-up Blood sample time points aptt, activated partial thromboplastin time; dtt, diluted thrombin time; ECT, ecarin clotting time; TT, thrombin time Pollack et al. N Engl J Med 2017; Pollack et al. Thromb Haemost

34 RE-VERSE AD Multicentre, Open-label, Single-arm, Phase III Study Group A: Uncontrolled bleeding N=301 (60%) 45.5% had GI bleeds 32.6% had ICH In 25.9% trauma was cause of bleed i Group B: Emergency surgery or procedure N=202 (40%) Main index events were acute abdomen, bone fractures, and cardiovascular i Pollack et al. N Engl J Med 2017

35 Reversal of Dabigatran Anticoagulation Group A Group B dtt normalized* within 4 hours in 241/244 patients (98.8%) in Group A and 150/152 patients (98.7%) in Group B

36 Group A: bleeding stopped within 2.5 hours in patients with extracranial haemorrhage 301 patients with bleeding type classed as: The 198 assessable non-ich bleeds were: With a median time to bleeding cessation of: 2.5 hrs Assessable non-ich (n=198) ICH (non-assessable)* (n=98) Non-assessable non-ich (n=5) GI (n=120) Non-GI (n-78) *Serial CT scans were not mandated by the protocol; Cessation confirmed within 24 hours in 134/198 bleeding stopped before treatment in two patients and could not be determined in 67 patients; Local investigator-determined time to bleeding cessation.

37 Group B: most patients had normal haemostasis during surgery 197/202 (97.5%) patients underwent surgery/procedure with periprocedural haemostasis classed as: Overall median time from first vial to procedure: 1.6 hrs Normal (93%) Mildly abnormal (5%) Moderately abnormal (1%) Severely abnormal (0%)

38 Post-reversal Thromboembolic Events Thrombotic events (%) Group A (n=301) Group B (n=202) Total (N=503) 30 days days of the 24 patients who experienced a thrombotic event were not anticoagulated at the time of the event No evidence of a prothrombotic effect

39 Mortality Mortality (%) Group A (n=301) Group B (n=202) 30 days days Most of the deaths occurring within 5 days appeared to be related to the severity of the index event or to coexisting conditions, whereas deaths that occurred after 30 days were more likely to be independent events or related to coexisting conditions

40 Re-initiation of Antithrombotic Treatment During the 90-day follow-up, antithrombotic therapy was restarted in 72.8% of the patients in group A and in 90.1% in group B, at a mean of 13.2 days and 3.5 days, respectively, after the administration of idarucizumab. By 72 hours after the administration of idarucizumab, antithrombotic therapy was restarted in 69 of the 301 patients in group A (22.9%), with 10.1% of those patients receiving dabigatran, and in 135 of the 202 patients in group B (66.8%), with 25.9% receiving dabigatran

41 Idarucizumab is Easy to Administer and has no Contraindications Fixed 5 g dose Storage Regardless of the clinical situation \\\\\\ Shelf life: 30 months refrigerated at 2 8 C Infuse or inject intravenously Re-starting anticoagulation Dabigatran can be re-started after 24 hours Heparin can be initiated at any time

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43 Idarucizumab is Widely Available Worldwide

44 Heidbuchel et al. Europace 2015 EHRA guidance on the management of bleeding in patients using NOACs Bleeding while using a NOAC Enquire about last NOAC intake Blood sample to determine CrCl, haemoglobin, white blood cells Enquire with lab about possibility of rapid coagulation assessment Mild bleeding Moderate/severe bleeding Life-threatening bleeding Delay or discontinue next dose Reconsider concomitant medication In patients treated with dabigatran, idarucizumab is the preferred reversal agent when it becomes available + + Supportive measures Mechanical compression Endoscopic haemostasis if GI bleed Surgical haemostasis Fluid replacement (colloids if needed) RBC transfusion if needed FFP (as plasma expander) Platelet transfusion (if platelet count /L) Dabigatran-treated patients Idarucizumab 5 g IV Maintain adequate diuresis Consider haemodialysis Consider For dabigatran-treated patients, idarucizumab 5 g IV PCC 50 U/kg + 25 U/kg if indicated apcc 50 U/kg; max 200 U/kg/day rfviia 90 µg/kg

45 NOAC Reversal Agents Change the Game! The available reversal agent idarucizumab for dabigatran has been shown to be safe. Patients will get a quick and effective bleeding management in case of emergency! Idarucizumab is easy to handle and does not do any harm

46 NOAC Reversal Agents Change the Game! The availability of specific reversal agents provides reassurance, removes one of the perceived barriers to the widespread use of NOACs and gives..

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