During Procedures. Neena S. Abraham MD, MSc (EPID), FACG

Transcription

1 Managing Anticoagulants During Procedures Neena S. Abraham MD, MSc (EPID), FACG Professor of Medicine, Mayo Clinic College of Medicine Associate Medical Director, Mayo Clinic i Robert D. and Patricia i E. Kern Center for the Science of Health Care Delivery Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ Division of Health Care Policy & Research, Department of Health Sciences Research, Mayo Clinic, Rochester, MN Learning Objectives 1. Understand GI bleeding risk of anticoagulant regimens Anticoagulants (warfarin, novel oral anticoagulant [NOAC]) Combination anticoagulant and antiplatelet therapy (complex antithrombotic therapy [CAT]) 2. Strategies for common endoscopic situations Stopping and restarting drugs in the elective setting Antithrombotic management in the acute setting Bridge therapy- what is the evidence? 3. Cardiogastroenterology tips Pragmatic and actionable tips for your practice 2013 MFME R 1

2 Complex Antithrombotic Therapy (CAT) in Elderly Patients: Bleeding Outcomes 1-Year NNH for CAT-related Events Upper GI Bleeding NNH (95% CI) Lower GI Bleeding NNH (95% CI) Transfusion NNH (95% CI) Hospitalization* NNH (95% CI) One-Year Number Needed to Harm (NNH) Anticoagulant and Antiplatelet Agent Dual Therapy Aspirin and Anticoagulant Aspirin and Antiplatelet Agent Triple Therapy Aspirin, Antiplatelet and Anticoagulant Agents 65 (24-379) 56 (22-231) 93 (34-544) 52 (20-210) Bleeding NNH 19 (11-37) 15 (9-30) 18 (10-37) 23 (13-49) 43 (21-128) 16 (9-31) 51 (24-182) 25 (14-50) 39 (18-121) 34 (16-89) 67 (30-214) 45 (21-126) Abraham NS et al. Circulation Oral Anticoagulants New Generation Oral Anticoagulants Warfarin Dabigatran Rivaroxaban Apixaban Mechanism of Action Inhibition of Vitamin K-dependent γ- carboxylation Direct thrombin inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor Metabolism Liver Renal Renal Renal/Liver Time to maximum effect Half-life 90 d for circulating drug; ~5-7 d for a therapeutic INR h for circulating drug; ~5 d to normalize INR h 2-4 h 1-3 h h 9-13 h 8-15 h Excretion 92% renal 80% renal 66% renal ~25% renal Other agents: Edoxaban (Factor Xa inhibitor) not yet approved for use in the U.S. (2014) 2

3 CARDIOGASTROENTEROLOGY TIP Classic Supratherapeutic Warfarin Bleed INR at time of endoscopy is not predictive of rebleeding Adjusted OR*: 0.50 ( ) *Controlling for age, comorbidity, antiplatelet use, postprocedure heparin and PPI use, hypotension, ulcer as bleeding source, and active bleeding at endoscopy Normalizing INR does not reduce rebleeding but delays endoscopy N=102 INR >1.3; Mean INR 1.8 ( ) Rebleeding rate similar with and without reversal agent: 24.7% vs. 30.0% (p=0.54) Significant delay in endoscopy with normalization of INR: 20.9 h vs h (p<0.0001) Important stigmata identified in 83% of cases Endoscopic therapy is very effective even in patients with moderately elevated INR. Choudari & Palmer. Gut 1994; Wolf A. Am J Gastroenterol CARDIOGASTROENTEROLOGY TIP Resuming Warfarin After GI Bleeding (GIB) 90-Day Thrombosis 90-Day Recurrent GI Bleeding P=0.002 P=0.10 Warfarin Resumption HR: 0.05 ( ) Warfarin Resumption HR: 1.32 ( ) Analysis Time in Days Analysis Time in Days Patients with warfarin-associated GIB and indications for continued long-term antithrombotic therapy should resume anticoagulation within 4-7 days following hemorrhage. Witt DM et al. Arch Intern Med

4 Warfarin + ASA+ Clopidogrel: Time to Bleeding in Atrial Fibrillation Patients Post-MI/PCI Incidence Rate Ratios (95% CI )* ( ) 2.12 ( ) 1.15 ( ) 0-29 days days days Triple Therapy Treatment Interval *Compared to d treatment interval GI bleeding = 33.8% non-fatal and 45.3% fatal Risk highest after initiation and continually elevated in comparison to other regimens (i.e., dual antiplatelet or monotherapy therapy) Lamberts M et al. Circulation Novel Oral Anticoagulants High GI Bleeding Risk: Meta-Analysis GI Bleeding Risk by Indication GI Bleeding Risk by NOAC Holster L et al. Gastroenterology

5 New Generation Oral Anticoagulants + Antiplatelet Therapy: GI Bleeding in Post-ACS Population Meta-Analysis CV EVENTS ESTEEM (2003) ATLAS ACS-TIMI 46 (2009) APPRAISE (2009) APPRAISE-2 (2011) RUBY-1 (2011) RE-DEEM (2011) ATLAS ACS 2-TIMI 51 (2012) POOLED OR (95% CI) MAJOR BLEEDS 0.76 ( ) 0.78 ( ) 0.76 ( ) 105(056190) 1.05 ( ) 0.95 ( ) 1.30 ( ) 0.84 ( ) 0.86 ( ); NNT= Favors Anticoagulant Favors Placebo ESTEEM (2003) ATLAS ACS-TIMI 46 (2009) APPRAISE (2009) APPRAISE-2 (2011) RUBY-1 (2011) RE-DEEM (2011) ATLAS ACS 2-TIMI 51 (2012) POOLED OR (95% CI) Favors Anticoagulant Favors Placebo Komosci A et al. Arch Intern Med ( ( ) 89) 1.43 ( ) ( ) 2.55 ( ) 2.05 ( ) 1.75 ( ) 3.92 ( ) 3.03 ( ); NNH= 111 CARDIOGASTROENTEROLOGY TIP Management of NOAC Bleeding Initial Assessment and Risk Stratification: The ABC s A= Airway; B= Breathing; C= Circulation Mild Bleeding Moderate-Severe Bleeding Life-Threatening Bleeding Delay next dose Anticoagulant effect dissipates 24 h (with no renal failure) T1/2= h Correct hemodynamics to perfuse kidneys Blood-product transfusion Endoscopic evaluation +/- hemodialysis i with renal failure Oral charcoal (if ingestion <2h)*; PPI probably helpful if recent ingestion (decreases absorption) *Recommendations based on limited nonclinical data ** PCC= prothrombin concentrate complex Consider rfviia or **PCC Charcoal filtration van Ryan et al. Thromb Heamost

6 CARDIOGASTROENTEROLOGY TIP Peri-Procedural Management of NOAC Pre-Procedure - Determine last NOAC dose and creatinine clearance Creatinine Clearance (ml/min) Half-life (h) Timing of Discontinuation Before Procedure Moderate procedural bleeding risk (2-3 half-lives) High procedural bleeding risk (4-5 half-lives) >80 13 (11-22) days 2-3 days >50 to <80 15 (12-34) 1-2 days 2-3 days >30 to <50 18 (13-23) days 3-4 days <30 27 (22-35) 2-3 days 4-6 days Patients at high risk of bleeding: Perform aptt day before procedure. Normal result= no clinically significant dabigatran effect. Post- Procedure - Consider rapid onset of action (1.5 h) when restarting. - Consider prophylaxis (i.e., enoxaparin bridge) until hemostasis established so full dose can be resumed. Weitz et al. Circulation Practical Endoscopic Concerns Synthesis of Current State of Evidence Should I stop cardiac ASA? What is the GI bleeding risk of hemostatic maneuvers? What about prophylactic clip placement? Should I bridge the patient if planning to stop the anticoagulant? When do I restart the drugs? 6

7 ASA for Primary and Secondary Prevention: Meta-Analysis of RCTs Rate Ratio (95% CI) (ASA monotherapy vs. control) Event Primary Prevention Secondary Prevention Vascular 0.88 ( ) 0.81 ( ) events* ARR= 0.06%; NNT= 1667 ARR= 1.5%; NNT= 67 Non-fatal MI CV mortality 0.77 ( ) ARR= 0.05%; NNT= ( ) ARR= 0.01; NNT= 10, ( ) ARI= 0 03%; NNH= ( ) ARR= 0.66%; NNT= ( ) ARR= 0.33%; NNT= ( ) ARI= 0 19%; NNH=526 *MI, stroke or vascular death Major GI Bleeding ARI= 0.03%; NNH= 3333 ARI= 0.19%; NNH=526 Narrow threshold between efficacy and safety with primary prevention (NNT=1667 vs. NNH=3333) 2 vascular events prevented, ~1 GI bleed would occur Antithrombotic Trialists Collaboration. Lancet 2009; Casado-Arroyo et al. Best Pract Res Clin Gastroenterol 2012; De Beradis et al. JAMA 2012; Siller-Matula. JAMA CARDIOGASTROENTEROLOGY TIP Management of ASA Monotherapy Study Yousfi et al Hussain et al Antiplatelet Agent ASA use within 3 days prior ASA or clopidogrel within 10 days prior Procedure Case Control Colonoscopy + polypectomy 40% 33% Sphincterotomy 16% 17% Bleeding Risk OR 1.41 ( ) OR 0.41 ( ) It is reasonable to perform endoscopic procedures in patients taking ASA. Becker et al. Am J Gastroenterol

8 ASA After Endoscopic Control of Peptic Ulcer Bleeding Low-dose ASA (n=78) Placebo (n=78) 20.0% 0% 10.3% ( %) Ev vent Rate (%) 15.0% 10.0% 5.0% 5.4% ARR 4.9% ( %) (NNT= 20) ARI 7.7% (NNH= 13)) 1.3% (0-3.8%) 9.0% ( %) 0.0% 30-day Recurrent Bleeding 30-day All-Cause Mortality Sung et al. Ann Intern Med Endoscopic Risk of Bleeding Endoscopic Procedure Low-Risk Bleeding (<1.5%) High-Risk Bleeding (>1.5%) Diagnostic EGD or X colonoscopy (with or without biopsy) Non thermal removal of X small polyps Coagulation or ablation of X tumors or vascular lesions (includes APC, bi-polar cautery and laser ablation) Large (>1 cm) polypectomy Variceal band ligation X X Hemostatic clip placement Injection therapy X (unknown real life risk) X (unknown real life risk) 8

9 CARDIOGASTROENTEROLOGY TIP Avoiding the Post-Polypectomy Bleed Cold snare technique for small lesions (< 5mm) * Saline/epi lifts to prevent excessive bleeding during hot snare procedures of sessile/flat lesions** Combined loop +clip can be considered for pedunculated lesions >2.0 cm ^^ Prophylactic clip placement following removal of large polyps (>1.0 cm) to close mucosal defects Reduces post-polypectomy bleeds (1.8% vs. 9.7%; p=0.001)^ Cost-effective in patients on antiplatelets and/or anticoagulants** RCTs needed to confirm this finding Avoid cautery alone for immediate post-polypectomy bleeding, due to risk of delayed bleeding with eschar sloughing* **Parikh et al. Clin Gastroenterol Hepatol 2013; ^ Liaquat et al. GIE 2013; * Repici et al. Endoscopy 2012; ^^ Kouklakis et al. Surg Endosc 2009; * anecdotal Bridge Therapy Who? Thromboembolic Risk Category Atrial Fibrillation Annual Risk >10% CHADS2-5 or 6 CVA/TIA w/in 3 mos Rheumatic valvular disease Mechanical Heart Valve Mechanical Mitral Valve Caged-ball or tilting disk aortic valve CVA/TIA w/in 3 mos Venous Thromboembolism (VTE) VTE within 3 mos High-risk thrombophlebitis Annual risk 5-10% CHADS2-3 or 4 Bileaflet Aortic Valveinhighrisk high-risk patient Annual Risk <5% CHADS2-2 No prior CVA/TIA Bileaflet Aortic Valve in low risk patient VTE 3-12 mos ago VTE > 12 mos ago 9

10 Bridge Tx Evidence? Mechanical Heart Valve Studies Douketis 2004 (n=215) Pengo 2009 (n=190) Kovacs 2004 (n=112) Hammerstingl 2007 (n=116) Daniels 2009 (n=556) TOTAL (n=1189) Clot (%) Bleed (%) 1.2 % 2.7% AFIB/VTE/Vascular Bypass Graft Studies Douketis 2004 (n=346) Pengo 2009 (n=663) Kovacs 2004 (n=112) Dunn 2007 (n=76) Wysokinski 2008 (n=345) TOTAL (n=1532) Clot (%) Bleed (%) 09% % 2.0% No thrombotic protection but increased bleeding risk Wysokinski et al. Mayo Clin Proc 2008; Wysokinski & McBane R Circulation 2012 What s the verdict on Bridging? American College of Chest Physicians: Favor no bridging therapy in low to moderate risk patients and possible bridging therapy for moderate to high risk patients * In evolution in the era of NOAC Absence of data BRIDGE trial^ helpful for warfarin; excludes patients on NOAC Most common agents enoxaparin and dalteparin have similar pharmacokinetics to NOAC can NOAC be used in the place of standard bridging therapy? *Guyatt GH, Akl EA, Crowther M, Schunemann HJ, Gutterman DD, Zelman Lewis S. Introduction to the ninth edition: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):48S-52S; ^Investigators TBS. Bridging Anticoagulation: Is it Needed When Warfarin Is Interrupted Around the Time of a Surgery or Procedure? Circulation 2012;125(12):e496-e

11 NOAC temporary interruptions Dabigatran: similar to warfarin with comparable risk of bleeding (HR 0.83; 95% CI, 0.59 to 1.17). Rivaroxaban: similar risk of embolism (HR 0.71; 95% CI ) and bleeding as warfarin (HR 1.17, 95% CI ) Apixaban: for low risk procedures, interruption of apixaban is unnecessary No data showing a rebound hypercoagulability effect exists with cessation of NOACs. FDA issued black box warnings for all three NOAC regarding g increased risk of thrombotic events following discontinuation of use; thus, need to switch to another agent if CHADS2 >5 Restart the drug as soon as hemostasis is assured Healey JS, Eikelboom J, Douketis J, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012;126: ; Sherwood MW, Hellkamp A, Patel M, et al.outcomes of temporary interruptions of rivaroxaban or warfarin in patients with atrial fibrillation in the ROCKET-AF trial. J Am Coll Cardiol 2013;61(10, Supplement):E316.; Lopes RD, Garcia DA, Wojdyla D, et al. Use of Apixaban and Warfarin in Patients Undergoing Invasive Procedures: Insights From Aristotle. Can J Cardiol 2013;29(10, Supplement):S232-S233.; Take-Home Points for Practice 1. It is safe to perform endoscopy on ASA monotherapy. Never stop cardiac aspirin; can dose minimize 2. GIB leading to ACS should be scoped h post- ACS. chance of finding high-risk endoscopic stigmata that are treatable by endoscopy. Leads to faster cardiac catheterization in 43% 3. Endoscopic therapy is effective in patients with moderately elevated INR (< 2.7). No need to normalize INR. 4. Warfarin should be resumed within 4-7 days post-gib 5. Hemostatic manoeuvers are associated with >1.5% risk of GIB in this population. 11

12 6. Some new oral anticoagulants have 3X GIB risk 7. DAPT + new oral anticoagulants (triple antithrombotic therapy) is associated with 3-fold risk of GIB. 8. Consider mechanical hemostasis post-polypectomy to close large mucosal defects (C/E with 1 clip) 9. NOAC-related bleeding Support hemodynamics to promote renal excretion of drug. 10.Elective peri-procedural NOAC management depends on patient s CrCl: With normal CrCl: Cl o High-risk endoscopy Hold 2-3 days prior to case o Low-risk endoscopy Hold 1-2 days prior to case With impaired CrCL: o High-risk endoscopy Hold 4-6 days prior to case o Low-risk endoscopy Hold 2-3 days prior to case 12