ANTICOAGULATION: THE DO'S AND DON'TS OF BRIDGE THERAPY SATURDAY/11:30AM-12:30PM ACPE UAN: 0107-9999-17-236-L01-P 0.1 CEU/1.0 hr Activity Type: Application-Based Learning Objectives for Pharmacists: Upon completion of this CPE activity participants should be able to: 1. Apply recent literature data to guide bridging anticoagulation decision making. 2. Review the pharmacology and kinetic properties of various anticoagulant agents. 3. Describe timing of anticoagulation interruption and resumption around procedural therapies. 4. Summarize current guidelines regarding bridging anticoagulation. 5. Identify appropriate patient populations to receive bridge therapy. Speaker: Tadd Hellwig, PharmD, BCPS Dr. Tadd Hellwig graduated from the Texas Tech University Health Sciences Center School of Pharmacy in 2006 and completed a Pharmacy Practice Residency at Christiana Care Health System in Newark, DE in 2007. He is currently an Associate Professor of Pharmacy Practice at the South Dakota State University College of Pharmacy and Allied Health Professions. Dr. Hellwig holds a clinical practice site in Internal Medicine at the Sanford USD Medical Center in Sioux Falls, SD. Dr. Hellwig is also very active in the South Dakota Society of Health-System Pharmacists (SDSHP) where he has served as a both President and Board Member. Speaker Disclosure: Tadd Hellwig reports no actual or potential conflicts of interest in relation to this CPE activity. Off-label use of medications will not be discussed during this presentation.
Anticoagulation: The Do s and Don'ts of Bridge Therapy Tadd Hellwig, PharmD, BCPS Associate Professor South Dakota State University College of Pharmacy and Allied Health Professions Disclosure I report no actual or potential conflicts of interest associated with this presentation 1
Learning Objectives Upon successful completion of this activity, participants should be able to: - Apply recent literature to guide anticoagulation bridging decision making - Review the pharmacology and kinetic properties of various anticoagulant agents - Describe timing of anticoagulation interruption and resumption around procedures - Summarize current guidelines regarding anticoagulation bridging - Identify appropriate patient populations to receive bridging therapy Peri-operative bridging Patients that are chronically anticoagulated with warfarin who require an invasive procedure may need to have their warfarin interrupted to prevent bleeding Use of heparin or LMWH in the pre/post operative period until an INR becomes therapeutic Bridging therapy relates only to warfarin patients - What to do with patients on DOACs 2
Background Approx 400,000 patients on anticoagulation will require interruption of warfarin for a procedure annually - Up to 20% of patients receiving warfarin Decision to bridge depends on balancing the risk of acute thromboembolic events and bleeding - Grades of bridging recommendations (Level 2C) CHEST 2012; 141(2)(Suppl):e326S e350s What does BRIDGEing look like 3
Perioperative checklist Stopping of an agent before an invasive procedure - Half-life of the agent Renal function, hepatic function, drug interactions What is the thromboembolic risk of the patient What is the bleeding risk of the patient/procedure - DOAC laboratory monitoring When should heparin/lmwh be used When to resume an agent after a procedure How to control a bleeding event Target fixation 4
Comparison of common agents Dabigatran Rivaroxaban Apixaban Edoxaban Warfarin Target Factor IIa Factor Xa Factor Xa Factor Xa Vitamin K epoxidase reductase Tmax (h) 1-3 2-4 3-4 1-2 4 Anticoag effect (72-96 h) Half-life (h) 12-17 5-9 healthy 11-13 elderly Elimination 80% renal 33% unchanged by the kidney 8-15 10-14 40 27% renal 50% renal Hepatic CYP substrate No 3A4 3A4 3A4 2C9, 2C19, 1A2, 3A4 P-gp substrate Yes Yes Yes Yes CHEST Guidelines 2012 Risk Group Atrial Fibrillation VTE Mechanical Heart Valve High CHADS2 score of 5 or 6 CVA/TIA <3 months prior Rheumatic valvular disease VTE <3 months prior Severe thrombophilia Mitral valve prosthesis Cage-ball Tilting disc aortic valve CVA/TIA <6 months prior Moderate CHADS2 score of 3 or 4 VTE 3-12 months prior Recurrent VTE Active cancer Bileaflet aortic valve with risk factors* Low CHADS2 score of 2 or less without prior CVA/TIA VTE >12 months prior with no other risk factors Bileaflet aortic valve without risk factors* *Risk factors: Protein C & S or antithrombin deficiency CHEST 2012; 141(2)(Suppl):e326S e350s 5
Thromboembolic risk in Afib Bleeding risk assessments Pisters et al. Chest 2010;138:1093-1100 6
Risk of bleeding Minimal Low to Moderate High Tooth extraction Peridontology Simple endoscopy, NO biopsy Abscess incision Minor dermatologic procedures Cataract procedure Endoscopy with simple biopsy Prostate/bladder biopsy Coronary angiography Abdominal hernia repair Pace-maker/ICD implant Laparoscopic hysterectomy Neuraxial anesthesia Intracranial surgery Thoracic surgery Cardiac surgery Major orthopedic surgery Liver/Kidney biopsy TURP Robotic surgery Dubois et al. Thrombosis Journal 2017;15:14 Case 1 D.G. is a 75 y.o. M with Afib. He has a planned surgical procedure next week. PMH: Afib, DM, stroke, CAD, HTN. Meds: warfarin 2.5 mg daily, metformin 1000mg BID, atorvastatin 40mg daily, lisinopril 5mg daily. Should D.G. receive bridging therapy prior to his surgical procedure? 7
What is the evidence of bridging Siegal, et al. Circulation. 2012;126:1630-39 ORBIT AF Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry is a prospective, observational registry study of US outpatients with atrial fibrillation Analyzed temporary interruptions for invasive procedures 7372 patients treated with oral anticoagulation - 2803 interruptions in 2200 patients Circulation. 2015;131:488-494 8
ORBIT AF- Baseline Characteristics NO bridging (n= 1608) Bridging (n= 592) Age 75 74 CHADS 2 score 2.34 2.53 Prior stroke (%) 15 22 Significant valve dx (%) 27 34 Prior mechanical valve replacement (%) 2.4 9.6 TTR (%) 67 62 Circulation. 2015;131:488-494 Outcomes Circulation. 2015;131:488-494 9
RE-LY Analysis RE-LY is the trial that led to FDA approval of dabigatran etexilate for NVAF stroke risk reduction - Open label trial Analyzed all the patients in the study who had an interruption of dabigatran or warfarin for an elective surgery/procedure Perioperative management was completely up to the treating physician Outcomes at 30 days Douketis JD, et. al. Thromb Haemost 2015; 113: 625 632 RE-LY Analysis Results Douketis JD, et. al. Thromb Haemost 2015; 113: 625 632 10
Huh.. To BRIDGE or NOT to BRIDGE.?. The BRIDGE Trial Randomized, double blind, placebo controlled trial - Funded by NIH Analyzed atrial fibrillation patients who needed interruptions to warfarin therapy of an elective invasive procedure Patients were randomized to: - LMWH bridging - No bridging with placebo injections Douketis JD, et al. New Engl J Med. 2015; 373:823-833 11
Bridge Trial Inclusion/Exclusion Inclusion - 18 yo with chronic a. fib. (permanent or paroxysmal) or flutter, confirmed by EEG or pacemaker interrogation; valvular a. fib patient were eligible - Warfarin therapy for 3 months with goal INR 2-3 needing a procedure necessitating interruption - CHADS 2 score of at least 1 Exclusion - Mechanical heart valve - Stroke, systemic embolism, TIA in last 12 weeks - Major bleeding in the last 6 weeks - Estimate creatinine clearance of < 30 mls/min - Platelet count < 100K - Planned cardiac, intracranial, or intraspinal surgery Douketis JD, et al. New Engl J Med. 2015; 373:823-833 12
Design Designed as a non-inferiority trial Primary efficacy outcome was arterial thromboembolism at 30 days - Assumed baseline rate for no bridging would be 1% and that absolute non inferiority margin would be an absolute difference of 1% Primary safety outcome was major bleeding - Assumed baseline rate for no bridging would be 1% and 3% in bridging arm Power calculations were done during interim analysis and recruitment was adjusted as needed Douketis JD, et al. New Engl J Med. 2015; 373:823-833 Baseline Characteristics NO Bridging (N= 918) Bridging (N= 895) Age (yr) 71.8 71.6 Male (%) 73.3 73.4 Weight (kg) 96.2 95.4 MI history (%) 14.5 16.6 Previous Stroke 8.3 10.6 CrCl (ml/min) 88.1 87.6 Minor surgical procedure 85.1 84.7 Major surgical procedure 10.2 9.9 Douketis JD, et al. New Engl J Med. 2015; 373:823-833 13
Baseline Characteristics 100 90 80 70 60 50 40 30 20 10 0 CHADS2 Scores NO Bridging Bridging 1 2 3 4 5 6 7 14
The FINAL Bridge Bridge Trial exceptions Few patients with CHADS 2 score of 5 or 6 Few surgical procedures associated with high arterial risk or bleeding - (carotid endarterectomy, major cancer surgery, cardiac surgery, neurosurgery) No mechanical heart valves were in the study Douketis JD, et al. New Engl J Med. 2015; 373:823-833 15
Case 1 D.G. is a 75 y.o. M with Afib. He has a planned surgical procedure next week. PMH: Afib, DM, stroke, CAD, HTN. Meds: warfarin 2.5 mg daily, metformin 1000mg BID, atorvastatin 40mg daily, lisinopril 5mg daily. Should D.G. receive bridging therapy prior to his surgical procedure?? Literature to support Bridging Prior to the BRIDGE trial in 2015 there wasn t a single prospective, randomized trial to support bridging vs. no bridging Accumulating evidence that bridging may not be beneficial prior to the BRIDGE trial - Retrospective or non-randomized Ongoing PERIOP 2 trial - Evaluating LMWH bridging post-operatively in patients with mechanical heart valves or atrial fib/flutter - Study ended Dec 2017 https://clinicaltrials.gov/ct2/show/nct00432796 16
2017 ACC Expert Consensus for Periprocedural Management in Atrial Fibrillation Patients at LOW risk (CHA 2 DS 2 -VASc 4) - Parenteral bridging is not needed Patients at MODERATE risk (CHA 2 DS 2 -VASc of 5-6 or history of TIA/stroke) - Patients with history of TIA/stroke: likely bridge - Patients without history of TIA/stroke: likely do not bridge Patients at HIGH risk (CHA 2 DS 2 -VASc of 7-9) - Parenteral bridging should be considered ACC 2017 Guidelines. J Am Coll Cardiol 2017 Re-initiation of anticoagulation 17
Unanswered Questions What to do with.. - Patients with VTE - Patients receiving DOACs - Neuraxial anesthesia - Pacemaker implantation Case 2 D.G. is a 75 y.o. M with hx of PE. He has a planned surgical procedure next week. PMH: PE (2016), DM, stroke, CAD, HTN. Meds: warfarin 2.5 mg daily, metformin 1000mg BID, atorvastatin 40mg daily, lisinopril 5mg daily. Should D.G. receive bridging therapy prior to his surgical procedure? 18
Clark, et al. Retrospective cohort study at Kaiser Permanente Colorado on patients receiving warfarin for secondary VTE prophylaxis Included patients where warfarin therapy was interrupted for invasive diagnostic or surgical procedures - January 1, 2006-March 31, 2012 1812 procedures in 1178 patients met inclusion criteria JAMA Intern Med. doi:10.1001/jamainternmed.2015.1843 Baseline 19
Outcomes Case 2 D.G. is a 75 y.o. M with hx of PE. He has a planned surgical procedure next week. PMH: PE (2016), DM, stroke, CAD, HTN. Meds: warfarin 2.5 mg daily, metformin 1000mg BID, atorvastatin 40mg daily, lisinopril 5mg daily. Should D.G. receive bridging therapy prior to his surgical procedure?? What if the PE was 2 months ago? 20
What to do with DOACs Pharmacokinetic profile of DOACs differ dramatically compared to warfarin Is bridging necessary with these agents? How to determine when surgery is good to go? What if a patient starts to bleed? When to hold DOACs Low Bleed Risk Mod/High Bleed Risk ACC 2017 Guidelines. J Am Coll Cardiol 2017 21
Clinical Practice Byron, et al. Am J Health-Syst Pharm 2017:74:e96-100 DOACs restart after surgery Should parenteral bridging be used following a surgical procedure prior to reinitiated a DOAC? Low bleed risk procedure - Could consider restarting as soon as 8 hours after Likely better to wait 24 hours before restarting High bleed risk procedure - Likely hold off for 24-72 hours after the procedure - May consider prophylactic dose until full dose resumes 22
Neuraxial anesthesia Neuraxial anesthesia Narouze S. Reg Anesth Pain Med 2015;40:182-212 23
Pacemaker implantation Birnie DH. N Engl J Med 2013;368:2084-93 Take Home Points No good prospective trials to support bridging The majority of bridging is likely unnecessary - Might consider in patients with Atrial fibrillation at high risk of thromboembolic events Recent VTE Mechanical heart valves Be aware of renal function with DOACs 24
Questions? 25