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Latest data on the Management of Bleeding in Patients taking the Direct Oral Anticoagulants Tim Nokes Haematologist Derriford Hospital Plymouth Conflicts of interest Bayer Boerhinger-Ingelheim BMI-Pfizer Daicho-Sanyo Advisory boards, Attendance at meetings, Presentations Overview What is the risk for bleeding from trials ? Non-specific reversal of bleeding Specific reversal agents for DOACs Benefit v Risk of Anticoagulation Risk More bleeding Benefit Less VTE / CVA Warfarin and its challenging therapeutic window Therapeutic range 20 Stroke Odds ratio 15 Intracranial bleed 10 5 1 0 1 2 3 4 5 6 International normalized ratio (INR) 7 8 Comparisons to ideal anticoagulant Type of Drug Oral No interaction Predictable No monitoring Fixed dose Wide Reversible therapeutic window Ideal ✔ ✔ ✔ ✔ ✔ ✔ VKA ✔ LMWH ✔ ✔ ✔ ✔ ✔ Anti Xa ODI ✔ ✔ ✔ ✔ ✔ ✔ Anti thrombi n ODI ✔ ✔ ✔ ✔ ✔ ✔ SPAF trial outcomes for DOACs Primary outcome = CVA or arterial embolism ROCKET-AF RE-LY ARISTOTLE Primary outcome HR 0.79 NS 150: RR 0.65 p=0.03 110: RR 0.90 NS HR 0.79 p=0.01 Haemorrhagic CVA HR 0.67 p=0.02 150: RR 0.31 p<0.001 110: RR 0.26 p<0.001 HR 0.51 p<0.001 Major bleeding HR 1.04 NS 150: RR 0.93 NS 110: RR 0.80 p=0.003 HR 0.69 p<0.001 GI bleeding HR 1.07 NS 150: RR 1.48 p=0.001 110: RR 1.08 NS HR 0.89 NS MI HR 0.81 NS 150: RR 0.85 p=0.04 110: RR 0.90 NS HR 0.88 NS Rivaroxaban, Apixaban & Edoxaban for SPAF Rocket-AF: annual major bleeding risk = 3.6% (warfarin = 3.4%) (Patel 2011) Aristotle: annual major bleeding risk = 2.1% (warfarin = 3.1%) (Granger 2011) Engage AFTIMI 48: Edoxaban superior over Warfarin for major bleeding Dabigatran for SPAF Annual risk for major bleeds = 2.71% (110mg) & 3.11% (150mg), (warfarin = 3.36%) (Connolly et al 2009) Intracranial Haemorrhage Significantly reduced against warfarin in all trials for all DOACs Real life data: About 50% reduction in relative risk of ICH 34% reduction in Haemorrhagic extension (17% v 26%) 60% reduction in Mortality (16% v 35%) Saji et al. Circ J 2015 (5):1018-23 VTE trials with DOACs Rivaroxaban: Pooled data – significantly less major bleeds Apixaban: Significantly less major & CRNM bleeds Edoxaban: Significantly less bleeding Dabigatran: Noninferiority for major bleeding – trend to less Care in interpreting bleeding in trials of anticoagulants Trials are not real-life patients! Selected group and therefore bleeding likely to be higher in real world use. Extremes of body weight not included Renal impairment not accounted for Multiple comorbidities rare in trial patients Guideline on the management of bleeding in patients on antithrombotic agents British Committee for Standards in Haematology. 2012, 160: 35–46 General non-pharmacological measures. Stop the antithrombotic drug Document the timing and amount of the last drug dose and presence of pre-existing renal or hepatic impairment Estimate the half-life and length of functional defect of the drug Assess the source of bleeding Guideline on the management of bleeding in patients on antithrombotic agents British Committee for Standards in Haematology. 2012, 160: 35–46 FBC, PT, APTT, thrombin time, fibrinogen, creatinine If available, request a specific laboratory test to measure the antithrombotic effect of the drug Correct haemodynamic compromise with intravenous fluids and red cell transfusion Apply mechanical pressure, if possible Use endoscopic, radiological or surgical measures Specific measures for bleeding Activated charcoal binds both Dabigatran & Rivaroxaban in water suspension – therefore give if within 2 hours of ingestion (van Ryn, 2010) Only Dabigatran can be dialysed or haemofiltered (van Ryn, 2010) Tranexamic acid (0.5-1 g 3 times daily IV) should be given if not contraindicated (BCSH, 2012) Life threatening Bleeding: BCSH PCC, APCC or rVIIa considered for life- threatening bleeding associated with Dabigatran, Rivaroxaban or Apixaban. After carefully balancing the risks and benefits associated with these products. Risks for thrombosis & DIC with all these drugs and mentioned in SPCs Trial of rVIIa off-license in bleeding patients showed increase in arterial events Studies evaluating bleeding management agents with direct oral anticoagulants Dabigatran Rivaroxaban Apixaban In vitro Rat in vivo Dog in vivo Human in vivo No data No data Haemoperfusion with activated charcoal In vivo No data No data Fresh frozen plasma Mice in vivo No data No data Rodent in vivo Ex vivo; rat, rabbit and baboon in vivo In vitro Non-activated three-factor PCC No data No data No data Non-activated four-factor PCC Ex vivo, rodent and human in vivo Ex vivo; rat, rabbit, baboon and human in vivo In vitro Ex vivo and rodent in vivo Ex vivo and rabbit in vivo In vitro Oral activated charcoal Haemodialysis Recombinant Factor VIIa Activated PCC Kaatz et al, J Thromb Thrombolysis 2013 Derriford NOAC Poster Idarucizumab: Praxabind Idarucizumab (BI655075), a humanized mouse monoclonal antibody fragment directed against Dabigatran. >300-fold higher than the affinity of Dabigatran for Thrombin. In sufficiently high doses, Idarucizumab binds both free & thrombin-bound Dabigatran Rapid reversal of anticoagulant effect in preclinical studies & reduced bleeding in animals, with no thrombogenicity Idarucizumab: mode of action Dabigatran inhibiting thrombin Dabigatran bound to plasma proteins Thrombin Dabigatran molecule Antidote (idarucizumab) Unbound dabigatran Idarucizumab alters the equilibrium – dabigatran dissociates from thrombin Idarucizumab rapidly binds to dabigatran in the plasma Idarucizimab Preclinical studies indicate idarucizumab binds specifically to and inhibits dabigatran. Data from Phase 1 healthy volunteers demonstrating that idarucizumab provided immediate, complete and sustained reversal of the anticoagulant effect of dabigatran. Idarucizumab showed immediate, complete and sustained reversal of dabigatran anticoagulation 70 DE + placebo (n=9) DE + 1 g idarucizumab (day 4) (n=9) DE + 2 g idarucizumab (day 4) (n=9) DE + 4 g idarucizumab (day 4) (n=8) Normal upper reference limit (n=86) Mean baseline (n=86) 65 dTT (sec) 60 55 DE + placebo 50 45 40 35 30 -2 0 2 4 6 8 10 12 Dabigatran DE = dabigatran etexilate 24 36 48 60 72 Time after end of infusion (hr) Antidote Similar effects were seen for 5g + 2.5g dose(data not shown) Normal upper reference limit’ refers to (mean+2SD) of 86 pre-dose measurements from a total of 51 subject Glund S et al. Lancet. Jun 16, 2015. Epub ahead of print. Glund S et al. Presented at AHA, Dallas, TX, USA, 16-20 November 2013, Abstract 17765; Disclaimer: idarucizumab is not currently licensed for use UK/CVS-151023 Date of prep: July 2015 REVERSE-AD Phase 3 global prospective cohort study investigating idarucizumab in clinical settings. Patients treated with Dabigatran who experience an uncontrolled or life-threatening bleeding event or in need of emergency intervention. Idarucizumab for Dabigatran Reversal. Pollack CV et al. NEJM. 2015 Aug 6; 373(6):511-20 Interim analysis from Reverse-AD trial 90 patients - Group A = 51 with serious bleeding & group B = 39 requiring urgent procedures 68 patients with increased dilute Thrombin Time, 81 with elevated Ecrine clotting time, idarucizumab normalised test levels in 88-98% patients 35 group A patients: Haemostasis restored at 11.4 hr 36 group B patients: Median of 1.7 hours between reversal & starting procedure. Haemostasis periprocedure in 33pts (92%) Initial results group A: Primary endpoint Reversal of dabigatran induced anticoagulation with idarucizumab 130 Diluted thrombin time 325 120 300 110 275 250 100 225 Idarucizumab 2x 2.5 g ECT (s) dTT (s) 90 Ecarin clotting time 80 70 200 Idarucizumab 2x 2.5 g 175 150 60 125 50 100 Assay upper limit of normal 40 30 20 75 50 25 Baseline Between 10–30 vials min 1h 2h 4h Time post idarucizumab Pollack C et al. NEJM 2015;377:511-520 12h 24h Baseline Between 10–30 vials min 1h 2h 4h 12h 24h Time post idarucizumab UK/CVS-151023 Date of prep: July 2015 Initial results group B: Primary endpoint Reversal of dabigatran induced anticoagulation with idarucizumab 130 Diluted thrombin time 325 120 300 110 275 250 100 225 Idarucizumab 2x 2.5 g ECT (s) dTT (s) 90 Ecarin clotting time 80 70 200 Idarucizumab 2x 2.5 g 175 150 60 125 50 100 Assay upper limit of normal 40 30 20 75 50 25 Baseline Between 10–30 vials min 1h 2h 4h Time post idarucizumab Pollack C et al. NEJM 2015;377:511-520 12h 24h Baseline Between 10–30 vials min 1h 2h 4h 12h 24h Time post idarucizumab UK/CVS-151023 Date of prep: July 2015 Thrombotic Events Thrombotic events reported in five patients over a period of 90 days of follow up – 1 early event (DVT + PE) 2 days after idarucizumab administration – 4 events 7–26 days after idarucizumab administration • DVT: 7 days • DVT + PE + left atrial thrombus: 9 days • MI: 13 days • Ischaemic stroke: 26 days – None of these 5 patients were receiving any antithrombotic therapy when the events occurred Idarucizumab – FDA approval October 16, 2015, the U. S. Food and Drug Administration granted accelerated approval to idarucizumab (Praxbind Injection, Boehringer Ingelheim Pharmaceuticals, Inc.) for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding. Andexanet alfa by Portola Andexanet alfa is a modified human Factor Xa molecule that acts as a decoy to target and sequester (therefore reverse) with high specificity both oral and injectable Factor Xa inhibitors in the blood. Portola currently evaluating andexanet alfa (AnXa, PRT064445) in Phase 3 trial ANNEXA™ Efficacy initially evaluated using anti-Factor Xa levels as the primary endpoint. Andexanet (ANXa): designed to reverse activity of fXa inhibitors Recombinant engineered version of human factor Xa produced in CHO cells Acts as a FXa decoy and retains high affinity for all FXa inhibitors Change of Serine to Alanine to eliminate catalytic activity and prevent prothrombin cleavage GLA domain removed to prevent anticoagulant effect No known interaction with other coagulation factors except Tissue Factor Pathway Inhibitor (TFPI) No significant antibody signal found in development programme to date Crowther M et al. oral presentation at AHA November 2014; Chicago, Illinois , USA. Part 1: 39 subjects age 50 to 75 randomized to receive either AnXa or placebo in a 2:1 ratio. All subjects received rivaroxaban 20 mg for 4 days. AnXa at a dose of 800 mg IV bolus or placebo was administered on Day 4 andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban and well tolerated Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity Deborah M. Siegal,.N Engl J Med 2015; 373:2413-2424 December 17, 2015DOI: 10.1056/NEJMoa1510991 Part 2 of ANNEXA-R & A studies: 40 healthy volunteers given Rivaroxaban 20 mg or Apixaban 5 mg bd, for four days then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or to placebo. Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. Aripazine (PER977) - universal antidote Small synthetic water soluble molecule, rich in D-Arginine, developed by Perosphere1 Targets: DOACs, fondaparinux, LMWH and UFH Under clinical development as a sterile, intravenous injection In vitro in animal models and ex vivo in human blood: PER977 successfully reverses anticoagulant activity for various anticoagulants1 1. Press release Perosphere: http://decreased after the test persons received aripazinewww.perosphere.com/content/news/httpwww.perosphere.comcontentnewsreleases042513.htm 2. Clinicaltrials.gov NCT 01826266; http://clinicaltrials.gov/ct2/show/NCT01826266?term=per977&rank=1 Aripazine PER977 (Ciraparantag)universal antidote Phase 1 clinical trial showed the ability of PER977 to reverse the anticoagulant activity of Edoxaban Phase 2 single-blind, sequential,PER977 reversal dose study in 80 healthy volunteers, randomized in a 4:1 ratio to receive either PER977 or placebo. All subjects received a single dose of edoxaban 60 mg on Days 14. Aripazine administered 3 hours following edoxaban reduced whole blood clotting time to within 10% above baseline within 10 mins. In all subjects Perosphere in clinical collaboration with Daiichi Sankyo to investigate PER977 in Phase 3 trials with Edoxaban & finally! A specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. Summary Serious bleeding is a challenge with DOACs but probably safer than VKA (ICH) Local and simple measures may be important Tranexamic acid an important adjuvent Evidence for some effectiveness of PCC, aPCC and rVIIa in reversing anticoagulant effect but not always clinical bleeding Reversal agents now available & effective in reversing laboratory tests Idarucizumab: interim-result from phase 3 trial demonstrates clinical effectiveness & FDA approved Other reversal agents for anti-Xa drugs are in trials currently