9/14/2015 1 Target Specific Oral Anti-Coagulants: Management in the Peri-Endoscopic Period C. Andrew Kistler, MD, PharmD Daniel M. Quirk, MD, MPH, MBA Division of Gastroenterology and Hepatology Thomas Jefferson University Hospital Disclosures • I have no financial relationships to disclose
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Target Specific Oral Anti-Coagulants: Management in the Peri-Endoscopic PeriodC. Andrew Kistler, MD, PharmDDaniel M. Quirk, MD, MPH, MBADivision of Gastroenterology and HepatologyThomas Jefferson University Hospital
Disclosures
• I have no financial relationships to disclose
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Objectives
• Review the Target Specific Oral Anticoagulants (TSOACs)• Dosing and monitoring• Pharmacodynamics/Pharmacokinetics, Drug-Drug Interactions
(DDIs)• GI adverse events
• Discuss the impact of TSOACs on endoscopic procedures• Pre- and post-procedure management• Acute management of gastrointestinal bleeding• Ongoing and future studies evaluating TSOACs and GI procedures
• Retrospective reviews• Reversal agents
Anticoagulation in Atrial Fibrillation
• Atrial fibrillation is associated with a 5 fold increase in ischemic stroke
• Warfarin reduces the risk of stroke in patients with atrial fibrillation by 2/3
• Warfarin Limitations• Unpredictable pharmacodynamics and pharmacokinetics
• Genetic polymorphisms• Variations in dietary vitamin K intake
• Numerous drug-drug interactions (DDIs)• Need for monitoring (INR)
January CT, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: J Am Coll Cardiol 2014.
CHA2DS2Vasc
Ischemic Stroke Rate/year
0 0.2%
1 0.6%
2 2.2%
3 3.2%
4 4.8%
5 7.2%
6 9.7%
7 11.2%
8 10.8%
9 12.2%
MAX SCORE = 9
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HAS-BLED
HAS-BLED Risk Factor Points
H HTN (SBP >160mmHg) 1
A Abnl renal or liver fx 1 or 2 (each 1)
S Stroke 1
B Bleeding(hx, anemia, predisposition)
1
L Labile INR 1
E Elderly (>65 yrs.) 1
D Drug (antiplatelet,NSAIDs) or ETOH
1 or 2 (each 1)
Total Points Major bleeding risk, %
2 3.3
3 3.9
4 6.1Apolstolakis S. J Am Coll Cardiol. 2013 Jan 22;61(3):386-7.
TSOACs: Target Specific Oral Anticoagulants• Specifically target either factor Xa or IIa (thrombin)• AKA novel oral anticoagulants (NOACs) & direct oral anticoagulants
(DOACs)• Four TSOACs currently FDA approved
• Indications:• DVT/PE post-op prophylaxis and treatment• Prevention of stroke in non-valvular atrial fibrillation
• At least as effective as warfarin for stroke prevention• ½ the rate of intracranial hemorrhage• Fixed dosing without monitoring
Pub date Sept 17, 2009 Sept 8, 2011 Sept 15, 2011 Nov 28, 2013
Trial duration 2 years 2 years 2 years 2 years
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TSOAC & Warfarin Comparison: Major Safety and Efficacy Rates
Risk Dabigatran Rivaroxaban Apixaban Edoxaban
Stroke & SE
Major Bleed*
Maj GI Bleed
Intracranial B
Isch. stroke
All mort.
Desai J et al. Gastrointestinal Endoscopy 2013;78:227-239Giugliano RP et al. N Engl J Med 2013;369:2093-2104
*major bleeding definition: dec in Hgb > 2 gr/dL or transfusion of > 2 U PRBC or bleeding into critical site (ICH, intraspinal, intraocular, pericardial, intra-articular, IM w/ compartment syndrome, RP) or fatal bleeding
TSOAC Risk of Bleeding Per Year vs WarfarinRisk Dabigatran Rivaroxaban Apixaban Edoxaban
Major Bleed 3.32% vs 3.57% (P=0.32)
3.6% vs 3.4%(P=0.58)
2.13% vs 3.09%(P<0.001)
2.75% vs 3.43% (P<0.001)
Major GI Bleed 1.85% vs 1.36%(P=0.002)*esp initialmonths,morelife-threatening (0.76% vs 0.48%)
2.0% vs 1.24% 0.76% vs 0.86% (P=0.37)
Hi dose: 1.51% vs 1.23% (P=0.03)Low dose: 0.82 % vs 1.23% (P<0.001)
Type of GIB UGIB > LGIB N/A UGIB >LGIB UGIB > LGIB
Desai J et al. Gastrointestinal Endoscopy 2013;78:227-239Giugliano RP et al. N Engl J Med 2013;369:2093-2104
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Prevention of TSOAC-related bleeding
• Adhere to administration guidelines and indications• Minimize risk factors• Concomitant ASA only for those with clear indication
• Bleeding risk for dabigatran is 30% - 50% higher with anti-platelet agents
• Consider PPI therapy for those on chronic NSAIDS• Intermittent monitoring of patient’s age, weight, and renal
function
• Utilize bleeding scores to risk-stratify patients• Consultation with cardiology and neurology
ASGE Standards of Practice Committee, Anderson MA, et al. Gastrointest Endosc. 2009 Dec;70(6):1060-70.
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Peri-endoscopic TSOAC management
• Balance the risk of thrombosis and the risk of bleeding• Thrombotic risk of interruption (<1 week) is <0.5%/day in non-
valvular atrial fibrillation• TSOACs are easier to titrate than warfarin
• Rapid return of ability to coagulate: 12-24 hrs.• Near complete coagulation recovery in 5 drug half-lives• Anticoagulation restored within hours of next dose
• Low risk procedures: diagnostic endoscopy or bx• Continue treatment and ideally schedule procedure at trough (~10
hrs) if can be safely done• High risk procedures: polypectomy, PEG, Sphincterotomy, FNA
• Normal renal function: hold 2-3 half-lives (24 -48 hrs.)• Renal insufficiency (GFR 30-50 mL/min): hold 3-5 days• Consider consultation with cardiology +/- neurology in patients at
higher risk that may require bridging therapy
Pre-procedure TSOAC management
Dabigatran Rivaroxaban Apixaban
Procedure risk Hold daysLow risk 2 days 1 day 1 day
High risk 4 days 2 days 2 days
Renal Dysfunction Hold daysLess Severe 1 or 2 days (> 50 mL/min) > 1 day (> 90 mL/min) 1 or 2 days (> 60 mL/min)
3 – 5 days (< 50 mL/min) 2 days (60-90 mL/min) 3 days (50-59 mL/min)
3 days (30-59 mL/min) 4 days (30-49 mL/min)
More Severe 4 days (15-29 mL/min)
Baron et al. NEJM.2013May;368:(22):2113-24.Kozek-Langenecker SA. Seminars in Hematology.2014;51:112-120.Dincq et al. BioMed Research International.2014;1-16.
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Peri-procedural TSOAC management
Dincq et al. BioMed Research International.2014;1-16.
Peri-procedural TSOAC management
Baron et al. NEJM.2013May;368:(22):2113-24.
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Peri-endoscopic TSOAC management
• Resumption of TSOAC• Peak plasma concentrations in 2-3 hrs.• Options
• Immediately• Diagnostic• Cold snare < 5 mm
• > 2-3 days• Large flat polyp >1-2.5 cm with injection and cold snare• ? Benefit of prophylactic clipping
• Reasonable protocol• Resume 24-48 hrs. after hemostasis has been achieved• Warn patient of risk of delayed bleeding particularly for post-cautery (up
to two weeks)• Resume in > 72 hours in patients undergoing sphincterotomy
TSOACs: Management of acute GI bleeding
• ASGE 2009 guidelines: the decision to reverse should be individualized based on the potential risk of thrombosis and continued bleeding
• There are no FDA approved antidotes for TSOACs• Supportive Care
• IVF• PRBCs• Consider platelets for those on anti-platelet therapy
• Early endoscopy vs. supportive care and stabilization for 12 hrs.• Rapid loss of anticoagulation effect in patients with normal renal and liver
function• Laboratory monitoring
• Dabigatran: Prolonged aPTT, ECT, TT (most sensitive)• Rivaroxaban: PT, anti-FXa activity• Apixiban: PT, INR, PTT, anti-FXa acitivity• Edoxaban: PT, PTT• Results of TT and Anti-Factor Xa assay are typically not rapidly available
Unactivated PCCAminocaproic acidTranexamic AcidCharcoal <2-8 hrsPRBC/Plt***NO DIALYSIS 2/2 high protein binding
Unactivated PCCAminocaproic acidTranexamic AcidCharcoal <2-8 hrsPRBC/Plt***NO DIALYSIS 2/2 high protein binding
Unactivated PCCAminocaproic acidTranexamic AcidCharcoal <2-8 hrsPRBC/Plt***NO DIALYSIS 2/2 high protein binding
**Activated PCC (FEIBA): factors II, VII, IX, X (and Protein C/S)4 Factor unactivated PCC: II, VII, IX, X (Kcentra ®) (and Protein C/S)3 factor unactivated PCC: II, IX, X (and Protein C/S)
*DISCLAIMER: There are no FDA approved antidotes for any TSOAC
Endoscopic management
• Consider emergent upper or lower endoscopy: • Acute hemorrhage• Persistent or recurrent hypotension• Signs of end-organ hypoperfusion• Failure to respond to supportive measures
• Delayed endoscopy (12-24 hrs.)• Stable hemodynamics or respond to resuscitation• Theoretical advantages:
• Increased effectiveness of endoscopic therapy• Increased safety in semi-elective setting• Increased time for colon cleansing if needed• Enhanced endoscopic visualization
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TSOAC Antidotes: Future Research
• PER977• Intravenous Cation that binds all TSOACs through hydrogen
bonds (Edoxaban > other TSOACs)• Currently in Phase II clinical trials
• Idarucizumab• Intravenous monoclonal antibody that binds dabigatran• Entering Phase III clinical trials
• Andexanet Alfa• Intravenous Factor Xa decoy that binds FXa inhibitors• Phase III
Conclusions
• TSOACs have their own distinct pharmacokinetic properties that vary considerably from warfarin
• TSOACs are associated with a higher risk of major GI bleeding when compared to warfarin• Apixaban is at least equivalent to warfarin
• There are no formal guidelines on the acute GIB management or peri-procedural endoscopic management of TSOACs• Important factors to consider include renal function, drug-drug
interactions, age and the risk of both procedure and condition
• There are no FDA approved antidotes for TSOACs, however several agents are currently being studied
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Acknowledgements
• Pennsylvania Society of Gastroenterology Board Members• Dr. Manish Thapar• Dr. David Sass• Dr. Dan Quirk• Dr. AJ DiMarino• Dr. Sri Nagalla
References
• Ansell JE , et al. NEJM. 2014 Nov 27;371(22): 2141-2.• Apolstolakis S, et al. J Am Coll Cardiol. 2013 Jan 22;61(3):386-7.• ASGE Standards of Practice Committee, Anderson MA, et al. Gastrointest Endosc. 2009 Dec;70(6):1060-
70.• Baron et al. NEJM.2013 May;368:(22):2113-24.• Desai J et al. Gastrointestinal Endoscopy 2013;78:227-239.• Desai J, et al. Thromb Haemost. 2013 Aug;110(2):205-12.• Dincq et al. BioMed Research International.2014;1-16.• Eliquis ® (Apixiban) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December 2012. • Giugliano RP et al. N Engl J Med 2013;369:2093-2104• January CT, et al. J Am Coll Cardiol 2014.• Kozek-Langenecker SA, et al. Seminars in Hematology.2014;51:112-120.• Pollack CV, et al. NEJM. 2015 Aug 6;373(6):511-20.• Pradaxa ® (Dabigatran Etexilate Mesylate) [package insert]. Ridgefield, CT: Boehringer Ingelheim