Target Specific Oral Anti-Coagulants: Management in the Peri-Endoscopic Period

Transcription

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 1

2 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) 2

3 Thromboembolic and bleeding risk Thrombotic risk CHA 2 DS 2 -Vasc Score (atrial fibrillation) Caprini score (VTE) Bleeding risk HAS-BLED score (atrial fibrillation) RIETE score (VTE) CHA 2 DS 2 -Vasc Score CHA 2 DS 2 Vasc Factor Points C CHF 1 H HTN 1 A 2 Age >75 2 D DM 1 S 2 Stroke, TIA, TE 2 V Vascular disease 1 A Age Sc Sex category: F 1 MAX SCORE = 9 CHA 2 DS 2 Vasc 0 0.2% 1 0.6% 2 2.2% 3 3.2% 4 4.8% 5 7.2% 6 9.7% % % % Ischemic Stroke Rate/year January CT, et al AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: J Am Coll Cardiol

4 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, 1 predisposition) 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, % Apolstolakis S. J Am Coll Cardiol Jan 22;61(3): 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 Factor Xa Inhibitors Direct Thrombin Inhibitors Rivaroxaban (Xarelto ) Apixiban (Eliquis ) Edoxaban (Savaysa ) Dabigatran etexilate (Pradaxa ) 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? Impact on compliance Higher cost No generic formulations available 4

5 Desai J et al. Gastrointestinal Endoscopy 2013;78: TSOACs: Pharmacologic Comparison TSOAC Dabigatran Rivaroxaban Apixaban Edoxaban Brand Name Pradaxa Xarelto Eliquis Savaysa MOA DTI FXa Inhibitor FXa Inhibitor FXa Inhibitor Dosing Renal Dosing 150 mg BID 75 mg BID GFR: = 75 mg bid (*watch DDIs) 10/15/20 mg QD-BID 2.5/5/10 mg bid mg QD *dose dec if <60 kg GFR>50 = 20 mg qpm GFR 15-50: 15 mg qpm N/A* unless: SCr > 1.5 mg/dl and > 80 yo OR wt < 60 kg GFR>95 = don t use (inc risk of stroke) 15-50: 30 mg qd <15: don t use Dose Dec if <60 kg Hepatic Dosing Avoid in severe Avoid in mod-severe Avoid in severe Avoid in mod-severe Half Life hrs 5-9 hrs 8-15 hrs hrs Protein Binding 35% (HD ~50-60%) Monitoring Prolonged aptt ECT, TT** GI Side Effects 25-35% (dyspepsia, gastritis) Misc Open capsules = inc F by 75% 92-95% ~87% 55% PT, anti-fxa activity <3% (N, AP, dyspepsia) PT, INR, PTT, anti- FXa acitivity Nausea: 3% Elev LFTs: < 1% *not studied in SCr >2.5 or CrCl <25 PT, PTT Elev LFTs: 5-8% Not dialyzable 5

6 TSOACs vs Warfarin Desai J et al. Gastrointestinal Endoscopy 2013;78: Drug-Drug Interactions Increase plasma levels of TSOACs (increase bleeding risk) Dabigatran/Edoxaban P-glycoprotein inhibitors: Fluconazole, verapamil, systemic azole antifungals, cyclosporin, dronedarone, tacrolimus, clarithromycin, erythromycin, HIV protease inhibitors Rivaroxaban/Apixaban/ Edoxaban CYP3A4 and/or P- glycoprotein inhibitors: systemic azole antifungals, protease inhibitors, diltiazem, erythromycin, grapefruit juice, quinidine, tacrolimus, verapamil Reduce plasma levels of TSOACs (increase VTE risk) Pharmacodynamic (increased bleeding risk) CYP3A4 and/or P-glycoprotein inducers: carbamazepine, phenobarbital, phenytoin, rifampin, St John s wort Aspirin, NSAIDs, selective COX-2 inhibitors, clopidogrel, prasugrel and ticagrelor, fish oils, Thrombolytics, SSRIs, SNRIs 6

7 Pharmacodynamics Desai J et al. Gastrointestinal Endoscopy 2013;78: Major Clinical Trials RE-LY ROCKET-AF ARISTOTLE ENGAGE NOAC Dabigatran Rivaroxaban Apixaban Edoxaban Comparator Warfarin Warfarin Warfarin Warfarin Design Multicenter/Ran Multicenter/Ran Multicenter/Ran Multicenter/Ran Blinding Open Blinded Blinded Blinded Endpoint Stroke/SEE Stroke/SEE Stroke/SEE Stroke/SEE Safety end. Bleeding Bleeding Bleeding Bleeding Dose 110mg/150mg BID 20mg daily 5mg BID 30mg/60mg No. pts 18,113 14,264 18,201 21,105 No. countries No. sites Pub date Sept 17, 2009 Sept 8, 2011 Sept 15, 2011 Nov 28, 2013 Trial duration 2 years 2 years 2 years 2 years 7

8 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. *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 Desai J et al. Gastrointestinal Endoscopy 2013;78: Giugliano RP et al. N Engl J Med 2013;369: TSOAC Risk of Bleeding Per Year vs Warfarin Risk Dabigatran Rivaroxaban Apixaban Edoxaban Major Bleed 3.32% vs 3.57% (P=0.32) Major GI Bleed 1.85% vs 1.36% (P=0.002) *esp initial months,more life-threatening (0.76% vs 0.48%) 3.6% vs 3.4% (P=0.58) 2.13% vs 3.09%(P<0.001) 2.0% vs 1.24% 0.76% vs 0.86% (P=0.37) 2.75% vs 3.43% (P<0.001) 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: Giugliano RP et al. N Engl J Med 2013;369:

9 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 Dec;70(6):

10 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 nonvalvular atrial fibrillation TSOACs are easier to titrate than warfarin Rapid return of ability to coagulate: 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 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 days Low risk 2 days 1 day 1 day High risk 4 days 2 days 2 days Renal Dysfunction Hold days Less Severe 1 or 2 days (> 50 ml/min) > 1 day (> 90 ml/min) 1 or 2 days (> 60 ml/min) 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): Kozek-Langenecker SA. Seminars in Hematology.2014;51: Dincq et al. BioMed Research International.2014;

11 Peri-procedural TSOAC management Dincq et al. BioMed Research International.2014;1-16. Peri-procedural TSOAC management Baron et al. NEJM.2013May;368:(22):

12 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 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 12

13 TSOAC Acute Bleeding Management Options TSOAC Dabigatran Rivaroxaban Apixaban Edoxaban Brand Name Pradaxa Xarelto Eliquis Savaysa MOA DTI FXa Inhibitor FXa Inhibitor FXa Inhibitor Renal Excretion 80-85% 35% 25% 35% Half Life hrs 5-9 hrs 8-15 hrs hrs Five Half Lives (normal renal fxn) hrs hrs hrs hrs Reversal Management apcc (FEIBA) >PCC Aminocaproic Acid Tranexamic Acid Charcoal (<2 hrs) HD (~50% removal) PRBC/Plt mab (Phase III) Unactivated PCC Aminocaproic acid Tranexamic Acid Charcoal <2-8 hrs PRBC/Plt ***NO DIALYSIS 2/2 high protein binding Unactivated PCC Aminocaproic acid Tranexamic Acid Charcoal <2-8 hrs PRBC/Plt ***NO DIALYSIS 2/2 high protein binding Unactivated PCC Aminocaproic acid Tranexamic Acid Charcoal <2-8 hrs PRBC/Plt ***NO DIALYSIS 2/2 high protein binding *DISCLAIMER: There are no FDA approved antidotes for any TSOAC **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) 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 13

14 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 14

15 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 Nov 27;371(22): Apolstolakis S, et al. J Am Coll Cardiol Jan 22;61(3): ASGE Standards of Practice Committee, Anderson MA, et al. Gastrointest Endosc Dec;70(6): Baron et al. NEJM.2013 May;368:(22): Desai J et al. Gastrointestinal Endoscopy 2013;78: Desai J, et al. Thromb Haemost Aug;110(2): Dincq et al. BioMed Research International.2014;1-16. Eliquis (Apixiban) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; December Giugliano RP et al. N Engl J Med 2013;369: January CT, et al. J Am Coll Cardiol Kozek-Langenecker SA, et al. Seminars in Hematology.2014;51: Pollack CV, et al. NEJM Aug 6;373(6): Pradaxa (Dabigatran Etexilate Mesylate) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.;December Savaysa (Edoxaban) [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.;January Xarelto (Rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; November