Xabans—Good for
What Ails Ya?
Brian Tiffany, MD, PhD, FACEP
Dept of Emergency Medicine
Chandler Regional Medical Center
Mercy Gilbert Medical Center
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No relevant financial disclosures
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I will discuss off-label use of clotting factors
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Discuss the novel oral anticoagulant drugs with emphasis on
the “xabans”
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Discuss advantages and disadvantages of the “xabans”
relative to Warfarin
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Discuss reversal options for patients on warfarin, LMWH, and
the novel oral anticoagulants.
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Developed in 1948 as a rodent
pesticide
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Approved as a medication in
1954
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Inhibits the vitamin K dependent
clotting factors
§ II, VII, IX, and X
§ Protein C
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Half-life of Warfarin: ~40 hours
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Elimination half-life of Vitamin-K dependent factors
§ II – 42-70 hours
§ VII – 4-6 hours
§ IX – 21-30 hours
§ X – 27-48 hours
§ Protein C – 14 hours
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Patients require bridging
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Full anticoagulation > 72 hours
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Highly protein bound (~95%)
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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)
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Leading cause of drug-related adverse events
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Within 30 days of starting warfarin
1:
§ ICH 0.4%
§ Major GI Bleed 1.9%
§ Minor GI Bleed 3.8%
WHAT WRONG WITH WARFARIN?
Direct Thrombin
Inhibition
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Ximelgatran
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Dabigatran
Factor Xa Inhibition
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Rivaroxaban
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Apixaban
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Betrixaban
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Edoxaban
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FDA approved in October, 2010
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Indications:
§ Stroke prevention in non-valvular Atrial fibrillation
§ Not FDA approved for treatment of DVT or PE
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A direct inhibitor of thrombin
§ Prevents conversion of fibrinogen to fibrin
§ Inhibits clot-bound thrombin
DABIGATRAN (PRADAXA)
RE-LY Trial NEJM 2009;361:1139
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Half-life of dabigatran is 12-17 hours
§ Full anticoagulation is achieved within 2 hours of first dose
§ No bridging is required
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Drug monitoring is not required
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Drug clearance is mostly renal
§ Dose must be adjusted for patients with CrCl = 15-30
§ Not recommended for patients with CrCl < 15
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PTT prolonged (but NOT quantitatively)
RE-LY TRIAL
Dabigatran
N (%) Warfarin N (%) Hazard Ratio
Patients 6076 6022 Patient-years 12,033 11,794 Intracranial hemorrhage 38 (0.3%) 90 (0.8%) 0.41 Life-threatening hemorrhage 179 (1.5%) 218 (1.9%) 0.80 Minor to moderate bleeding 399 (3.3%) 412 (3.6%) 0.93 All bleeding 1993 (16.6%) 2166 (18.4%) 0.91
DABIGATRAN SAFETY
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FDA approved in July, 2011 in U.S.
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Indications:
§ DVT prophylaxis (July, 2011)
§ Non-valvular Atrial fibrillation (November, 2011)
§ Treatment of DVT and PE (November, 2012)
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The first oral inhibitor of factor Xa
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Both PT and PTT are prolonged
§ Good negative predictor of effect?
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Half-life of Rivaroxaban is 7-9 hours
§ Full anticoagulation is achieved within 2 hours of first dose
§ No bridging is required
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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
RIVAROXABAN
EINSTEIN Trial NEJM 2010;363:2499-2510
Rivaroxaban
N (%) Event rate (per 100 patient years)
Warfarin
N (%) Event rate (per 100 patient years) Patients 7111 7125 All major bleeding 395 (5.6%) 3.6 386 (5.4) 3.5 Intracranial hemorrhage 91 (1.3%) 0.8 133 (1.9%) 1.2 Life-threatening hemorrhage 27 (0.4%) 0.2 55 (0.8%) 0.5 Bleeding requiring transfusion 183 (2.6%) 1.7 149 (2.1%) 1.3
RIVAROXABAN SAFETY
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FDA approval December 2012
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Indication
§ Non-valvular atrial fibrillation
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Oral Factor Xa inhibitor
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ARISTOTLE Trial
§ 18201 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)
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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
APIXABAN (ELIQUIS)
NEJM 2009; 261:1139 NEJM 2011; 364:806
Warfarin/LMWH
or Rivaroxaban
for outpatient
treatment of VTE
EFFICACY
EINSTEIN Trial NEJM 2010;363:2499-2510
Major (A) and intracranial (B) bleeding during oral anticoagulant treatment.
Dentali F et al. Circulation 2012;126:2381-2391
XABANS MAYBE (A LITTLE) SAFER
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No real difference in overall bleeding complications
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About half as likely to cause ICH
Outpatient DVT in an 80kg patient
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Xarelto
§ 3 weeks at 15mg BID $397.41 § 30 days of 20mg qday $285.29
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LMWH/Coumadin
§ 5 days LMWH $245.62 § 30 days of 5mg Coumadin $7.23¡
Coumadin takes 6-8 hours for Vit K to work
§ It takes 6-8 hours to clear inhibited factor VII
§ Complete reversal occurs after 48-72 hours
§ That’s not a very good reversal agent!
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At best, FFP improves INR to about 2
§ The INR of FFP is about 1.8-2.0
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PCC reverses INR more effectively than FFP
§ Should work for any factor Xa inhibitor
WHY “IT’S NOT REVERSIBLE” IS A BAD
ARGUMENT
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We’ve been using hard to reverse anticoagulants for years.
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LMWH isn’t reversible either.
§ Protamine is at best 40-60% effective at reversal
§ Anaphylactoid reactions to protamine can occur with rapid infusion
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Coumadin takes hours to reverse (unless you use PCC)
WHY “IT’S NOT REVERSIBLE” IS A BAD
ARGUMENT
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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
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Disadvantages
§ Volume of fluid administered
§ A minimum of 2-4 units required for meaningful reversal
§ 200-250mL / unit
§ 400-1000mL of additional fluid
§ Delay in treatment due to typing and thawing
§ Typically requires 30-60 minutes to thaw
§ Transfusion reactions can occur
§ Transfusion Associated Acute Lung Injury (TRALI
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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
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Available as lyophilised powder
§ Can be reconstituted and administered rapidly
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46 patients on Vitamin K Antagonists with ICH
§ All patients given reversal therapy
§ PCC dose 25-50 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 2.0-3.9
§ INR<1.5 in 35% of patients with INR>4
§ required repeat dose required for full reversal
§ Effects of PCC were maintained @ 96h post infusion
¡ Imberti, D. Emergency reversal of anticoagulation with a
three-factor prothrombin complex concentrate in patients with intracranial
haemorrhage. Blood Transfus 2011;9:148-55
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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
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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 4 2011; 124(14):1573-1579.
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72 patients on warfarin requiring emergent reversal
§ Matched with 69 historical controls receiving FFP
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Reversal Strategy
§ IV Vitamin K 10mg IV
§ For INR<5.0, 500 units aPCC
§ For INR> 5.0, 1000 units aPCC
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Time to INR<1.4
§ 2h in aPCC group vs 24h in FFP group
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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
warfarin-induced coagulopathy. Int J Emerg Med (2009) 2:217–225.
rFVIIa 3-factor PCC 4-factor PCC aPCC
Brand names Novo-seven Bebulin VH
Profilnine SD Octoplex Beriplex FEIBA
Available in U.S.A.
Yes Yes No yes
Factors VIIa II, IX, X II, VII, IX, X II, VIIa, IX, X
Activated Yes no no yes
Cost
$5000-$8500/dose
~$ 1400 -$2900/dose
n/a ~$5000/dose
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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
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Black box warning:
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Low bleeding risk
§ CrCl >50 ml/min: hold for 24 hours
§ CrCl <50 ml/min: hold for 48 hours
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High bleeding risk
§ CrCl >50 ml/min: hold for 48 hours
§ CrCl <50 ml/min: hold for 72 hours
