Xabans Good for What Ails Ya? Brian Tiffany, MD, PhD, FACEP Dept of Emergency Medicine Chandler Regional Medical Center Mercy Gilbert Medical Center

Transcription

1 Xabans Good for What Ails Ya? Brian Tiffany, MD, PhD, FACEP Dept of Emergency Medicine Chandler Regional Medical Center Mercy Gilbert Medical Center

2 DISCLOSURES No relevant financial disclosures I will discuss off-label use of clotting factors

3 OBJECTIVES Discuss the novel oral anticoagulant drugs with emphasis on the xabans Discuss advantages and disadvantages of the xabans relative to Warfarin Discuss reversal options for patients on warfarin, LMWH, and the novel oral anticoagulants.

4 GRATUITOUS CLOTTING CASCADE SLIDE

5 WARFARIN Developed in 1948 as a rodent pesticide Approved as a medication in 1954 Inhibits the vitamin K dependent clotting factors II, VII, IX, and X Protein C

6 WARFARIN Half-life of Warfarin: ~40 hours Elimination half-life of Vitamin-K dependent factors II hours VII 4-6 hours IX hours X hours Protein C 14 hours Patients require bridging Full anticoagulation > 72 hours

7 WHAT WRONG WITH WARFARIN? Highly protein bound (~95%) Interactions occur with a huge list of drugs Up to 740 drugs have known interactions 198 classified as major Antibiotics (Flouroquinolones, Macrolides, sulfa, metronidazole) Antifungals (Fluconazole, Itraconazole) NSAIDS Homeopathic treatments (St. John s wort, ginko) Leading cause of drug-related adverse events Within 30 days of starting warfarin 1 : ICH 0.4% Major GI Bleed 1.9% Minor GI Bleed 3.8% 1 J Managed Care Pharm 2011;17(9):

8 FOCUSED ANTICOAGULATION TARGETS Direct Thrombin Inhibition Ximelgatran Dabigatran Factor Xa Inhibition Rivaroxaban Apixaban Betrixaban Edoxaban

9 DABIGATRAN (PRADAXA) FDA approved in October, 2010 Indications: Stroke prevention in non-valvular Atrial fibrillation Not FDA approved for treatment of DVT or PE A direct inhibitor of thrombin Prevents conversion of fibrinogen to fibrin Inhibits clot-bound thrombin RE-LY Trial NEJM 2009;361:1139 RE-COVER Trial NEJM 2009;361:2342

10 DABIGATRAN (PRADAXA) Half-life of dabigatran is hours Full anticoagulation is achieved within 2 hours of first dose No bridging is required Drug monitoring is not required Drug clearance is mostly renal Dose must be adjusted for patients with CrCl = Not recommended for patients with CrCl < 15 PTT prolonged (but NOT quantitatively)

11 RE-LY TRIAL RE-LY Trial NEJM 2009;361:1139

12 DABIGATRAN SAFETY Dabigatran N (%) Warfarin N (%) Patients Patient-years 12,033 11,794 Intracranial hemorrhage Life-threatening hemorrhage Minor to moderate bleeding Hazard Ratio 38 (0.3%) 90 (0.8%) (1.5%) 218 (1.9%) (3.3%) 412 (3.6%) 0.93 All bleeding 1993 (16.6%) 2166 (18.4%) 0.91

13 RIVAROXABAN (XARELTO) FDA approved in July, 2011 in U.S. Indications: DVT prophylaxis (July, 2011) Non-valvular Atrial fibrillation (November, 2011) Treatment of DVT and PE (November, 2012) The first oral inhibitor of factor Xa Both PT and PTT are prolonged Good negative predictor of effect?

14 RIVAROXABAN (XARELTO) Half-life of Rivaroxaban is 7-9 hours Full anticoagulation is achieved within 2 hours of first dose No bridging is required Drug monitoring is not required Check renal function prior to initiation of therapy Dose must be adjusted for patients with CrCl < 50 Not recommended for patients with CrCl < 15 for a fib Not studied for treatment of DVT in patients with CrCL < 50

15 RIVAROXABAN Non-inferior to enoxaparin-vka in treatment of acute DVT EINSTEIN Trial NEJM 2010;363:

16 RIVAROXABAN SAFETY Rivaroxaban N (%) Event rate (per 100 patient years) Warfarin N (%) Patients All major bleeding Intracranial hemorrhage Life-threatening hemorrhage Bleeding requiring transfusion 395 (5.6%) (5.4) (1.3%) (1.9%) (0.4%) (0.8%) (2.6%) (2.1%) 1.3 Event rate (per 100 patient years)

17 APIXABAN (ELIQUIS) FDA approval December 2012 Indication Non-valvular atrial fibrillation Oral Factor Xa inhibitor

18 APIXABAN (ELIQUIS) ARISTOTLE Trial patients Superior to warfarin for prevention of stroke in non-valvular Afib (1.27% per year vs. 1.60% per year, p=0.01) Fewer bleeds than warfarin (2.13% per year vs. 3.09% per year, p<0.001) AVERROES Trial Non-valvular Afib patients not eligible for warfarin Better than aspirin at stroke prevention (1.6% per year vs. 3.7% per year, p<0.001) No worse than aspirin in bleed rate NEJM 2009; 261:1139 NEJM 2011; 364:806

19 Warfarin/LMWH or Rivaroxaban for outpatient treatment of VTE HOW TO DECIDE?

20 EFFICACY Non-inferior to enoxaparin-vka in treatment of acute DVT EINSTEIN Trial NEJM 2010;363:

21 Major (A) and intracranial (B) bleeding during oral anticoagulant treatment. Dentali F et al. Circulation 2012;126: Copyright American Heart Association, Inc. All rights reserved.

22 XABANS MAYBE (A LITTLE) SAFER No real difference in overall bleeding complications About half as likely to cause ICH Consider the NNH

23 XABANS COST (A LOT) MORE Outpatient DVT in an 80kg patient Xarelto 3 weeks at 15mg BID $ days of 20mg qday $ LMWH/Coumadin 5 days LMWH $ days of 5mg Coumadin $7.23

24 WHY IT S NOT REVERSIBLE IS A BAD ARGUMENT Coumadin takes 6-8 hours for Vit K to work It takes 6-8 hours to clear inhibited factor VII Complete reversal occurs after hours That s not a very good reversal agent! At best, FFP improves INR to about 2 The INR of FFP is about PCC reverses INR more effectively than FFP Should work for any factor Xa inhibitor

25 WHY IT S NOT REVERSIBLE IS A BAD ARGUMENT We ve been using hard to reverse anticoagulants for years. LMWH isn t reversible either. Protamine is at best 40-60% effective at reversal Anaphylactoid reactions to protamine can occur with rapid infusion Coumadin takes hours to reverse (unless you use PCC)

26 FRESH FROZEN PLASMA Advantages: Contains all blood clotting factors INR of stored FFP ~2.0 Available in most centers Still the product of choice in most massive transfusion protocols Disadvantages Volume of fluid administered A minimum of 2-4 units required for meaningful reversal mL / unit mL of additional fluid Delay in treatment due to typing and thawing Typically requires minutes to thaw Transfusion reactions can occur Transfusion Associated Acute Lung Injury (TRALI

27 PROTHROMBIN COMPLEX CONCENTRATES 3 or 4 factor concentrates 3-factor concentrates include II, IX, and X 4-factor concentrates include II, VII, IX, and X Factor concentration is ~25 times that of plasma Available as lyophilised powder Can be reconstituted and administered rapidly

28 PROTHROMBIN COMPLEX CONCENTRATES 46 patients on Vitamin K Antagonists with ICH All patients given reversal therapy PCC dose units/kg Vitamin K 10 mg IV Median INR = 3.5 prior to reversal 30 min after PCC dose administered INR< 1.5 in 89% of patients baseline INR INR<1.5 in 35% of patients with INR>4 required repeat dose required for full reversal Effects of PCC were 96h post infusion Imberti, D. Emergency reversal of anticoagulation with a threefactor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus 2011;9:148-55

29 RIVAROXABAN REVERSAL WITH PCC? Rivaroxaban reversal with PCC 12 male subjects were fully anticoagulated PT/PTT and thrombin time (TT) were elevated 50 IU/kg PCC was administered Complete normalization of PT/PTT and TT Kamphuisen, P.W., et. al. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A randomized placebo-contolled, crossover study in healthy subjects. Circulation. Oct ; 124(14):

30 ACTIVATED PCC 72 patients on warfarin requiring emergent reversal Matched with 69 historical controls receiving FFP Reversal Strategy IV Vitamin K 10mg IV For INR<5.0, 500 units apcc For INR> 5.0, 1000 units apcc Time to INR<1.4 2h in apcc group vs 24h in FFP group No difference in thrombotic complications vs. PCC Wójcik, C., et. al. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarininduced coagulopathy. Int J Emerg Med (2009) 2:

31 BLOOD FACTOR CONCENTRATES rfviia 3-factor PCC 4-factor PCC apcc Brand names Novo-seven Bebulin VH Profilnine SD Available in U.S.A. Beriplex Octoplex FEIBA Yes Yes No yes Factors VIIa II, IX, X II, VII, IX, X II, VIIa, IX, X Activated Yes no no yes Cost $5000- $8500/dose ~$ $2900/dose n/a ~$5000/dose

32 MY OUTPATIENT DVT SPEECH Rivaroxaban vs. enoxparin/warfarin Same efficacy About the same bleeding risks Less likely to cause the already unlikely ICH Drug is about 3x more costly over 3 months No shots No monitoring

33 RIVAROXABAN (XARELTO) Black box warning:

34 PERIOPERATIVE MANAGEMENT Low bleeding risk CrCl >50 ml/min: hold for 24 hours CrCl <50 ml/min: hold for 48 hours High bleeding risk CrCl >50 ml/min: hold for 48 hours CrCl <50 ml/min: hold for 72 hours

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38 TAKEAWAYS Dabigatran, rivaroxaban, and apixaban are (slightly) less likely to cause bleeds than warfarin PT/PTT (for rivaroxaban/apixaban) and PTT (for dabigatran) are sensitive detectors of anticoagulant effect. There is NO reliable way to assess DEGREE of anticoagulation with these agents in the ED Coumadin is actually harder to reverse quickly than the Xa inhibitors, and to some degree, dabigatran. PCC or apcc may be the drugs of choice for crisis reversal of coumadin and the Xa inhibitors Xabans are a viable choice for outpatient DVT/PE treatment Caution with LPs and non-compressible vessels on these drugs