Making Sense of the Newer Anticoagulants

Transcription

1 Making Sense of the Newer Anticoagulants Brian Tiffany, MD, PhD, FACEP Dept of Emergency Medicine Chandler Regional Medical Center Mercy Gilbert Medical Center

2 I M FROM ARIZONA!

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

4 OBJECTIVES Discuss the new oral anticoagulant drugs that have become available in the last months Discuss advantages and disadvantages of the new drugs relative to Warfarin Discuss PCC (Prothrombin complex concentrate) as a reversal agent in anticoagulated patients

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7 CLINICAL SCENARIO 63 y.o. male with a swollen calf for 3 days U/S reveals a popliteal vein DVT without proximal extension No chest pain or SOB Vitals: /85 97%RA Dispo: You d like to start anticoagulation and send the patient home for follow-up. What agent will you choose?

8 CLINICAL SCENARIO #2 68 yo male with Afib and HTN on rivaroxaban (Xarelto). Last dose of 20 mg was taken 15 hrs ago. Onset of slurred speech, L sided weakness, and L sided neglect 30 minutes ago. BP 164/90, HR 78, T 98.2, 97%RA CT Head: INR: 1.10

9 CLINICAL SCENARIO #2 Neurosurgeon: Xarelto?! What the f$^% is that s%&*!! He needs to go to the OR right now! Do whatever reverses it! What do you do?

10 THE DREADED CLOTTING CASCADE

11 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

12 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 with LMWH Full anticoagulation will not occur for at least 72 hours

13 WHAT S 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 Bleeding: 15-20% per year 1-3% of these are fatal or life-threatening

14 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

15 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 will be prolonged by Dabigatran

16 DABIGATRAN (PRADAXA) Drug interactions Increased risk of bleeding Rifampin Amiodarone and Dronedarone Ketoconazole Verapamil Quinidine Personalized dosing? CES1 gene SNP associated with 15% drop in trough levels and 27% decrease in bleeding Found in ~33% of Europeans

17 DABIGATRAN (PRADAXA) Contraindications Allergy Active bleeding Mechanical heart valve RE-ALIGN trial demonstrated a higher rate of complications among patients taking Pradaxa Pregnancy Category C No human data for Lactation

18 DABIGATRAN (PRADAXA) No specific reversal agent is available Half-life is short (12-17h) Anticoagulation effect wears off in about 24 hours Treatment in overdose Activated charcoal may be effective Dialysis may remove up to 50% of circulating drug

19 DABIGATRAN VS. WARFARIN 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

20 DABIGATRAN (PRADAXA) PCC is not effective for reversal of Dabigatran 12 male subjects were fully anticoagulated PTT and thrombin time (TT) were notably elevated 50 IU/kg PCC was administered PCC had no effect on 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):

21 DABIGATRAN VS.WARFARIN Pros No need for INR monitoring Full anticoag effect occurs within 2 hours of 1 st dose No need for bridging Less variability in anticoagulant effect Fewer drug interactions Fewer dietary restrictions Cons More expensive $4/pill instead of $6/week Less experience with a new drug Not for use in patients with renal failure Increased MI rate? No specific reversal agent

22 OTHER DIRECT THROMBIN INHIBITORS Hirudin (leech spit) Bivalirudin (Angiomax) Lepirudin Argatroban Ximelagatran First oral agent. Development halted due to hepatotoxicity

23 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

24 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

25 RIVAROXABAN (XARELTO) Drug interactions Increased risk of bleeding Ritonavir Clarithromycin and Erythromycin Fluconazole Decreased efficacy Rifampin Phenytoin Carbamazepine

26 RIVAROXABAN (XARELTO) Contraindications Allergy Active bleeding No data available in patients with renal failure (CrCl <15) Pregnancy category C No human data in lactation

27 RIVAROXABAN (XARELTO) No specific reversal agent available Half-life 7-9 hours Anticoagulant effect is gone in hours Overdose treatment activated charcoal may be effective Not effectively dialyzable

28 RIVAROXABAN (XARELTO) 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):

29 RIVAROXABAN (XARELTO) Black box warning:

30 RIVAROXABAN VS. WARFARIN 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)

31 RIVAROXABAN VS. WARFARIN Pros No need for INR monitoring No need for bridging Less variable anticoagulant effect Fewer drug interactions No dietary restrictions Effect gone in h Cons More expensive $6/pill instead of $6/week Not for use in patients with renal impairment (CrCl<15) No specific reversal agent BUT PCC is effective

32 TREATMENT OF DVT AND PE December 2010: NEJM article shows non-inferiority of Rivaroxaban vs Warfarin 2.1% adverse events vs. 3% adverse events November 2012: Rivaroxaban approved for treatment of DVT/ PE An oral option for patients with DVT being discharged from the ED Stable patients with PE or DVT that require admission 15 mg BID for 21 days, then 20mg qday The Einstein Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med 2010; 363:

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

34 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

35 OTHER FACTOR XA INHIBITORS The xabans Betrixaban Edoxaban Otamixaban

36 TREATMENT OPTIONS FOR REVERSAL OF ORAL ANTICOAGULANTS

37 WHY IT S NOT REVERSIBLE IS A STUPID 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 Works for Rivaroxaban also Should work for any factor Xa inhibitor

38 WHY IT S NOT REVERSIBLE IS A STUPID ARGUMENT LMWH isn t reversible either. Protamine is at best 40-60% effective at reversal Anaphylactoid reactions to protamine can occur with rapid infusion We ve been using non-reversible anticoagulants for years. By the time you reverse it, the damage is done.

39 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

40 FRESH FROZEN PLASMA Disadvantages Volume of fluid administered A minimum of 2-4 units required for 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)

41 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

42 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

43 PROTHROMBIN COMPLEX CONCENTRATES Advantages Shortened time to INR normalization Faster than FFP INR normalizes within 15 min of administration Small volume of infusion Easy to reconstitute and administer No need to wait for thawed product Disadvantages Some FFP still required with 3-factor PCC No factor VII in 3-factor concentrate Rare Thrombotic complications occur Relative lack of clinical data

44 ACTIVATED PCC (FEIBA) Similar to PCC products Contains non-activated factors II, IX, and X Also contains activated factor VII Factor VIII inhibitor bypassing activity Indications Control of spontaneous bleeding in hemophilia Control of surgical hemorrhage in hemophilia Off-label use Reversal of Warfarin and Rivaroxaban

45 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:

46 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

47 WARFARIN REVERSAL

48 MY ANSWER SCENARIO #1 Xarelto 15mg BID for 21 days, then 20mg a day

49 MY ANSWER SCENARIO #2 What was done: FFP 2 units PCC 50 U/kg rviia 100 µg/kg What should have been done: Nothing and go to the OR

50 TAKEAWAYS Dabigatran, rivaroxaban, and apixaban are no more 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 drug of choice for crisis reversal of coumadin and the Xa inhibitors Rivaroxaban may be a better choice for outpatient DVT/PE treatment Caution with LPs and non-compressible vessels on these drugs