Ischemic and hemorrhagic strokes in the context of the direct acting oral anticoagulants

Transcription

1 Ischemic and hemorrhagic strokes in the context of the direct acting oral anticoagulants Van Hellerslia, PharmD, BCPS, CACP Clinical Assistant Professor Temple University School of Pharmacy

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4 Over 4 million Americans are on oral anticoagulant therapy Treatment of venous thromboembolic events Prevention of stroke in atrial fibrillation(af) patients Number of AF patients expected to rise from million to million by 2050 Mozaffarian D et al Circulation. 2015;131:e29 e322. Heit JA Arterioscler Thromb Vasc Biol 2008;28: Statistical Brief #268: AHRQ, 2007

5 60% 50% 40% 30% 20% 10% 0% Relative Risk Reduction Warfarin vs placebo Antiplatelet vs placebo Warfarin vs antiplatelet Hart RG et al. Ann Intern Med. 2007;146(12):

6 Tissue factor Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Activates Platelets WARFARIN Factor VIIa Factor XIIa Factor VIIIa Factor IXa Factor XIa Factor Xa Factor Va THROMBIN Factor IIa Dabigatran (Pradaxa )

7 Fixed dosing Quick onset/offset Less drug/diet interactions Less lab monitoring At least non-inferior to warfarin in reducing thrombotic outcomes Comparable or less major bleeding relative to warfarin Less intracranial bleeding

8 RE-LY (n=18,113) ROCKET-AF (n=14,264) ARISTOTLE (n=18,201) ENGAGE AF (n=21,108) Design Open label Non-inferiority Double-blind Non-inferiority Double-blind Non-inferiority Double-blind Non-inferiority Population Non valvular afib CHADS 2 > 1 Non valvular afib CHADS 2 > 2 Non valvular afib CHADS 2 > 1 Non valvular afib CHADS 2 > 2 Intervention Dabigatran (dose blinded) 110 mg BID vs 150 mg BID Rivaroxaban (blinded) 20 mg daily Apixaban (blinded) 5 mg BID Edoxaban (blinded) 30 mg daily 60 mg daily Control warfarin (open) warfarin (blinded) warfarin (blinded) warfarin (blinded) Outcomes Stroke/Systemic embolism Major bleeding Major + non-major bleeding Major bleeding Major bleeding Connolly SJ et al. N Engl J Med 2010;363: Patel M et al N Engl J Med 2011;365: Granger CB et al N Engl J Med 2011; 365: Giugliano RP et al N Engl J Med 2013;369:

9 RR (95% CI) RELY (dabigatran) 0.66 ( ) ROCKET-AF (rivaroxaban) 0.88 ( ) ARISTOTLE (apixaban) 0.79 ( ) ENGAGE AF (edoxaban) 0.87 ( )* *97.5% CI Favors DOAC Favors warfarin

10 RELY (dabigatran) 0.93 ( ) ROCKET-AF (rivaroxaban) 1.03 ( ) ARISTOTLE (apixaban) 0.69 ( ) ENGAGE AF (edoxaban) 0.80 ( ) Favors DOAC Favors warfarin

11 Connolly SJ et al. N Engl J Med 2010;363: Patel M et al N Engl J Med 2011;365: Granger CB et al N Engl J Med 2011; 365:

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16 Barreto AD et al Stroke 2012;43:770-5 Tabata E et al Inter Med 2014;53:

17 dabigatran rivaroxaban apixaban Protime Reagent specific aptt Thrombin time Anti-xa level n/a ++ calibrated ++ calibrated Van Ryn J, J Throm Haemost 2010; Rogers R et al. Br J Hemae 2013; Ogata K et a lj Clin Pharmacol 2010; Apixaban-Poster.pdf accessed 9/25/2013

18 Demaerschalk BM et al Stroke 2016;47

19 Gawehn A et al Journal of Medical Case reports 2016;10:269 Berrouschot J et al Stroke 2016;47:1936 Schafter N et al J Stroke Cerebrovas Dis 2016;25: Kafke W and Kraft W Case Rep Neurol 2016;8:

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21 Dabigatran not taken in last 48 hrs and normal renal function? No Check thrombin time. Is TT normal? YES OK to give TPA YES OK to give TPA No Consider ** idarucizumab 5 g then give TPA? ** Risk vs Benefit: BP, size of infarct, stroke severity, age of patient, time of presentation

22 Rivaroxaban not taken in last 48 hrs and normal renal function? No Check Anti-Xa level (preferred) or Prothrombin Time* Result normal? YES OK to give TPA YES OK to give TPA No Avoid TPA * Sensitive Reagent: Neoplastin Plus, HemosIL RecombiPlasTin 2G ** Risk vs Benefit: BP, size of infarct, stroke severity, age of patient, time of presentation Samama MM et al. Thrombosis Journal 2013;11:11

23 Apixaban not taken in last 48 hrs and normal renal function? No Check Anti-Xa level Result normal? YES OK to give TPA YES OK to give TPA No Avoid TPA ** Risk vs Benefit: BP, size of infarct, stroke severity, age of patient, time of presentation Samama MM et al. Thrombosis Journal 2013;11:11

24 Typical Afib Dosing Pearls Dabigatran 150 mg po BID Keep capsules in bottle (close tightly) Expires after 4 months once bottle open CAUTION in Gastric Bypass patients CAUTION with enzyme inducers CANNOT be given via enteral tube Rivaroxaban 20 mg po daily Take with food CAUTION enteral tube administration (must be gastric tube and with enteral feed) Apixaban 5 mg po BID Must be given BID Reduced dose 2.5BID only provides net benefit in specific conditions Edoxaban 60 mg po daily AVOID use in patients with CrCl>80 ml/min

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26 No bridging is necessary Pre-operatively, evaluate renal function and determine number of days to hold anticoagulant Balance bleeding/spinal hematoma risk of procedure with stroke risk of withholding anticoagulation Avoid spinal anesthesia if possible Normal Renal function Impaired Renal function (crcl<50) Standard Risk of Bleeding Dabigatran: hrs Factor Xa: 24hrs Dabigatran: 48 96hrs Factor Xa: 48 hrs High Risk of Bleeding Dabigatran: 48 hrs Factor Xa: 48 hrs Dabigatran: 48 hrs -?days Factor Xa: 48 hrs -?days

27 RELY Dabigatran (Pradaxa ) ROCKET-AF Rivaroxaban (Xarelto ) ARISTOTLE Apixaban (Eliquis ) Ischemic stroke 0.92% per yr 1.37% per yr 0.97% per yr ICH 0.30 % per yr 0.5% per yr 0.33% per yr Connolly SJ et al. N Engl J Med 2010;363: Patel M et al N Engl J Med 2011;365: Granger CB et al N Engl J Med 2011; 365:

28 Kuramatsu JB et al JAMA 2015;313:

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30 Monoclonal antibody fragment with 350x affinity for dabigatran vs thrombin Neutralizes unbound and bound dabigatran Schiele F et al Blood 2013;121: Glund S et al Lancet 2015; 386: Glund S et al Thromb Haemost 2015;113:943-51

31 Description Group A Group B N=51 N=39 Serious Bleeding Indication for surgery ICH n=18(35%) Trauma related n=9 (18%) Gastrointestinal n=20 (39%) Other n= 11 (22%) Bone fractures n= 8 Acute cholecystitis n=5 ARI, cath placement n=4 Acute appendicitis n=3 Joint/wound infection n=3 Abscess n=2 Acute mesenteric ischemia n=2 Pollack CV et al N Engl J Med 2015;373:511-20

32 Pollack CV et al N Engl J Med 2015;373:511-20

33 Pollack CV et al N Engl J Med 2015;373:511-20

34 P kinetics: Onset of activity: within 10 minutes Half-life: 47 minutes, terminal half life: 10.3 hours Elimination: Approximately 30% in urine in 6 hours Metabolism: protein catabolism Dose: 2.5 gm x 2 iv bolus or 1 hour infusion Monitoring: aptt and CBC 4hr, 12hr, 24hr Signs and symptoms of bleeding Schiele F et al Blood 2013;121: Pollack CV et al N Engl J Med 2015;373:511-20

35 In absence of antidote, national guidelines for life threatening bleeding suggest: Supportive care (includes mechanical hemostasis) Dialysis NOT helpful Prohemostatic agents: Prothrombin complex concentrate (PCC) or Factor VII No clinical trials on use of PCC or Factor VIIa for Xa inhibitor reversal Data based on healthy volunteers, animal studies or ex-vivo studies Holbrook A et al. Chest. 2012;141(2_suppl):e152S-e184S Hemphill JC et al. Stroke 2015; 46: EerenbergES et al. Circulation 2011; 124

36 25 Rivaroxaban administration 4F-PCC administration Liver laceration injury PT (seconds ±SD) Time (min) Rivaroxaban vehicle + Saline vehicle Saline vehicle 4F-PCC 25 IU/kg 4F-PCC 50 IU/kg 4F-PCC 100 IU/kg Pine P et al, NCS 14 th Annual Meeting 2016 Poster

37 Lu G et al Nat Med 2013;19: Portola Pharmaceuticals

38 Can be potentially be used to reverse all factor Xa inhibitors (LMWH, fondaparinux, rivaroxabain, apixaban, edoxaban etc) Leeds JM et al, NCS 14 th Annual Meeting 2016 Poster

39 Primary Endpoint: 94±2% vs. 21±9%; P< ±11% vs. 18±15%, P<0.001 Siegal DM et al N Engl J Med 2015;373:

40 Primary Endpoint: 92±3% vs. 33±6%, P< ±2% vs. 45±12%, P<0.001 Siegal DM et al N Engl J Med 2015;373:

41 Siegal DM et al N Engl J Med 2015;373:

42 UFH: unfractionated heparin Aronis KN and Hylek EM J Thromb Thrombolysis 2016;41: LMWH: low molecular weight heparin Ansel J et al N Engl J Med 2014; 371:

43 Supportive care (charcoal, transfusion, mechanical hemostasis) Manage Blood Pressure Dialysis not helpful Prothrombin Complex Concentrate??? Aronis KN and Hylek EM J Thromb Thrombolysis 2016;41:

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45 OK to use X Consider avoiding use # Needs dose adjustment Half-life Normal renal function CrCl CrCl <15 Dialysis Dabigatran hrs # X X Rivaroxaban 5-10 hrs # X X Apixaban 12 hrs # # or X X Edoxaban 5-10 hrs X # X X Severe Hepatic Patients with CrCl <30 ml/min were excluded from clinical trials for dabigatran, rivaroxaban, and edoxaban. Patients with CrCl <25 ml/min or Scr >/=2.5 excluded from apixaban trial

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