Antidotes to DOACs - what s the status?

Transcription

1 Antidotes to DOACs - what s the status? Charles Marc Samama Professor and Chairman Department of Anaesthesia and Intensive Care Hotel-Dieu and Cochin University Hospitals Paris, France

2 Disclosures Companies and drugs: AstraZeneca (ximelagatran ticagrelor) Bayer (rivaroxaban) BMS (apixaban) Boehringer-Ingelheim (dabigatran-idarucizumab) - CSL Behring (PCC) - Curacyte (antiplasmine) Daichii (edoxaban) -GSK (fondaparinux - nadroparin) - LFB (PCC - fibrinogen) - Leo (tinzaparin) Lilly (prasugrel) - Mitsubishi (argatroban) Octapharma (PCC) Organon (danaparoïd) - Pfizer (dalteparin, apixaban) Portola (betrixaban, andexanet) Roche (Coaguchek XS ) - Stago (anti-xa kits) Sanofi-Aventis (enoxaparin, idraparinux, aspirin, clopidogrel) Agencies, Medical Societies, Publicly Funded Research Organizations: EMA : Efficacy Working Party ACCP : Panelist for the 8th and 9th Guidelines SFAR : Chair of the VTE Prophylaxis Recos INSERM : Head of the Laboratory of Experimental Thrombosis (U1140) Slides: special thanks to: Pierre Sié, Pierre Albaladejo, the GIHP and Meyer Michel Samama

3 Issues with Direct Oral Anticoagulants (DOACs)? Scheduled surgery and invasive procedures Trauma and emergent surgery Bridging with a parenteral anticoagulant agent (ex: unavailability of oral route) Ongoing bleeding Stroke with a proposed thrombolysis Suicides

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6 Non-specific «reversal» agents

7 Am J Cardiovasc Drugs, 2013, Nov (20 mg) When charcoal was administered at 2 and 6 h post-dose: AUC for apixaban without activated charcoal decreased by 50% and 28%, respectively, The mean T1/2 for apixaban alone (13.4 h) decreased to 5 h

8 Rivaroxaban (20 mg bid) Dabigatran (150 mg bid) PCC 50U/kg Circulation 2011; 124:

9 Anesthesiology. 2012;116: rfviia and PCC partially improved laboratory parameters, but did not reverse rivaroxaban induced-bleeding

10 Conclusion: rfviia, PCC, and Fibrinogen failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters.

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13 Thromb Haemost 2012; 108: Ex-vivo study, 10 healthy white male subjects were randomised to receive rivaroxaban (20 mg) or dabigatran (150 mg) in one oral administration thrombin generation tests. dabigatran For both anticoagulants, lower doses of FEIBA, corresponding to a quarter to half the dose usually used, have potential reversal profile of interest rivaroxaban

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15 apcc was more effective than PCC or rfviia in reversing in vitro the effects of apixaban. apcc rapidly triggered the development of an apparently normal fibrin network and corrected latency and quantitative parameters, whereas PCC or rfviia had only a partial effect.

16 1040 patients included by the end of August 2015 Reversal of direct oral anticoagulants in clinical practice: results from the French registry GIHP-NACO Pierre Albaladejo, Pierre Sié, Charles Marc Samama, Gilles Pernod, Jean Luc Bosson

17 Major bleeding (ISTH)= 74.2% GIHP-NACO Observatory % 41 centres (included 1-60 patients) 349 Patients admitted and hospitalised for major bleeding while on DOACs GIHP-NACO (n=349) Rocket AF (n=395) Rely (n=627) EPAHK (AVK) (n=822) GI Intracranial (spont) Intracranial (trauma) Epistaxis Muscular hematoma Multiple Trauma Hemoptysis Intraperitoneal Pericardial Hemarthrosis Hemothorax (unpublished data, March GIHP working group)

18 Clotting factors: 36.9% GIHP-NACO Observatory Coagulation factor concentrate use Dabigatran (n=126) Rivaroxaban (n=223) All (n=349) PCC, n (%) 33 (26.2) 60 (26.9) 93 (26.6) apcc, n (%) 17 (13.5) 19 (8.5) 36 (10.3) Total dose Dabigatran (n=126) Rivaroxaban (n=223) All (n=349) PCC (median, range) Total dose, IU Total dose, IU/kg 2625 [ ] 36 [19 50] 3000 [ ] 45 [25 50] 3000 [ ] 40 [24 50] apcc (median, range) Total dose, IU Total dose, IU/kg 3500 [ ] 46 [40 52] 3000 [ ] 40 [31 47] 3200 [ ] 44 [35 50] apcc, activated prothrombin complex concentrate; PCC; prothrombin complex concentrate; SD, standard deviation; U, unit (unpublished data, March GIHP working group)

19 GIHP-NACO Observatory Did the bleeding stop after administration of these clotting factors? Yes, completely 42.7 % Yes, partially 39.7% No 17.7% (unpublished data, May GIHP working group)

20 Outcome GIHP-NACO (30 days) EHPAK (Crit Care 2014) (7 days Major bleeding in dabigatran studies (Majeed, Circulation 2013) Major bleeding in rivaroxaban studies (Piccini, Eur Heart J 2014) Cardiovascular events 9.1 % Pulmonary oedema 5.0 % Cardiogenic shock 1.8 % Acute coronary syndrome 1.8 % 2.6 Stroke 0.9 % 4.7 VTE 0.9 % Mortality (Hart et al, Stroke 2012) (Majeed et al Circulation 2013) (Hankey, Stroke 2014) (Piccini et al Eur Heart J 2014) All cause 14.6 % 13 % D= 9.1 % W = 13% R = 20.4 % w = 26% Intracranial bleeding (Spont) Intracranial bleeding (Trauma) 31.8 % 33 % D = 37.5 % 12.5 % D = 27.3% R= 49 % (unpublished data, May GIHP working group)

21 Specific antidotes

22 By a tighter network of interactions, the antidote achieves an affinity for dabigatran that is 350 times stronger than its affinity for thrombin. Idarucizumab: a fully humanised monoclonal antibody fragment

23 Lancet. 2015;386: participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1g, 2g, or 4g 5-min infusion, or 5 g plus 2.5 g in two 5-min infusions given 1h apart) was administered about 2 h after the final dabigatran etexilate dose. Primary endpoint: incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate.

24 RE-VERSE AD is a multicentre, open-label, single-arm Phase III trial Group A: Uncontrolled bleeding + dabigatran-treated Group B: Emergency surgery or procedure* + dabigatran-treated 5 g idarucizumab (two separate infusions of 2.5 g) 5 g idarucizumab (two separate infusions of 2.5 g) Reverses up to the 99 th percentile of dabigatran levels measured in RE-LY N= minutes 90 days follow-up 0 24 hours Hospital arrival Pre-1st dose Pre-2nd dose ~20 min 1 h 2 h 4 h 12 h 24 h 30 d 90 d Blood samples Two separate infusions of 2.5 g idarucizumab are administered intravenously <15 minutes apart to allow for blood sampling after the first vial

25 N Eng J Med. 2015;373: Prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who had serious bleeding (group A) or required an urgent procedure Interim analysis: 90 patients (51 patients in group A and 39 in group B).

26 RE-VERSE AD : safety There were no safety concerns in the 90 patients in this study 18 deaths occurred (9 in each Group)/90 patients = 20% mortality! No cases of hypersensitivity were observed Pollack et al. NEJM June 2015

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28 Anti-fXa (ng/ml) Andexanet Alfa: Apixaban Phase 2 Apixaban 5 mg b.i.d. x 6 d prior to andexanet/placebo bolus 420 mg bolus + 4 mg per minute infusion over 2 hours: >90% reversal at 2 minutes >90% reversal at 2 hours Highly statistically significant Reversal sustained throughout andexanet infusion Anti-fXa activity returns to normal decay curve after termination of infusion Well tolerated; no thrombotic events or serious adverse events reported No antibodies to fxa or fx detected End of Bolus 0 Anti-fXa Activity End of Infusion Time after bolus (hr) Placebo (Cohorts 1-3, n=9) 420 mg bolus only (n=6) 420 mg bolus mg infusion (n=6) Crowther, M.A., et al J Thromb Haemost. (abstract); 11: AS

29 ISTH Congress, Toronto, june 2015 Breaking News Session

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31 N Eng J Med Nov 5;371(22): Small, synthetic, water-soluble, cationic molecule that is designed to bind specifically to unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen bonding and charge charge interactions. It binds in a similar way to edoxaban, rivaroxaban, apixaban, and to dabigatran.

32 Take Home Messages Antidotes should have been developed much earlier Activated charcoal could help (and dialysis for dabi, too ) PCC and FEIBA appear to be acceptable solutions, so no hurry for the antidotes. Potential thrombotic risk. Idarucizumab: we cannot accept any approval with less than 100 patients and 20% mortality Andexanet was first presented two years ago: no detailled publication yet... PER977-aripazine: no data yet except a letter.