Perioperative Management of Antithrombotic Therapy

Perioperative Management of Antithrombotic Therapy ----Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Copyright: American College of Chest Physicians 2012©

Chapter 13 Perioperative Management of Antithrombotic Therapy James D. Douketis, MD, FCCP Alex C. Spyropoulos, MD, FCCP Frederick A. Spencer, MD Michael Mayr, MD Amir K. Jaffer, MD Mark Epstein, MD Andrew S. Dunn, MD Regina Kunz, MD (Chapter Editor and Chair)

ACCP Grading System • Reflects system adopted for all ACCP guidelines • The strength of any recommendation depends on two factors: - The trade-off between benefits, risks, burdens, costs, and level of - confidence in estimates of those benefits and risks The quality of the evidence upon which the recommendations are based • If benefits do (or do not) outweigh risks, burdens, and costs, a strong (Grade 1) recommendation is used. • If there is less certainty about magnitude of benefits and risks, burdens, and costs, a weak (Grade 2) recommendation is used. • Support for recommendations may come from high-quality, moderatequality, or low-quality evidence, labeled, respectively, A, B, and C. • The phrase “we recommend” is used for strong recommendations (Grade 1 A, 1 B, 1 C) and “we suggest” for weak recommendations (Grade 2 A, 2 B, 2 C).

Perioperative Bridging Anticoagulation: General Points • To eliminate effect of antithrombotic therapy before surgery, treatment should be stopped before surgery (~5 days for warfarin, 7 -10 days for antiplatelet drug) to minimizing bleeding risk • Giving bridging after surgery increases risk for bleeding; this risk depends on anticoagulant dose (therapeutic-dose > low-dose) and proximity to surgery (higher risk if given closer to surgery) • Delaying resumption of therapeutic-dose bridging (for 48 -72 h after surgery), decreasing the dose or avoiding its use after surgery can mitigate the risk for bleeding • Low-dose LMWH/UFH is effective to prevent postop VTE, but evidence is lacking that such regimens effective to prevent ATE

Hemorrhagic Transformation of Embolic Stroke

Perinephric (Transplant) Hematoma transplanted kidney blood collection

Perioperative Anticoagulation: General Points • In resuming treatment after surgery, it takes: - 2 -3 days for anticoagulant effect to begin after starting warfarin - 3 -5 h for peak anticoagulant effect after starting LMWH minutes for an antiplatelet effect to begin after starting ASA - 3 -7 days for peak inhibition of platelet aggregation after starting a maintenance dose of clopidogrel • Most surgery/procedures done out-of-hospital and potential thromboembolic or bleeding complications occur during the initial 2 wks after surgery while patient is at home - Close patient follow-up during early postop period allows early detection and treatment of complications

Perioperative Anticoagulation: Key Questions Is interruption of antithrombotic therapy in the perioperative period needed? • In patients who are having a major surgical or other major invasive procedure, interruption of antithrombotic therapy is typically required to minimize the risk for perioperative bleeding. Continuation of VKA therapy or aspirin in the perioperative period confers an increased risk for bleeding. • In patients who are undergoing minor surgical or invasive procedure (eg, dental, skin, or cataract), interruption of antithrombotic therapy may not be required.

Perioperative Anticoagulation: Key Questions If antithrombotic therapy is interrupted before surgery, is “bridging Anticoagulation” needed? The need for bridging is driven by patients' estimated risk for thromboembolism (TE): • In high-risk patients, the need to prevent TE will dominate management irrespective of bleeding risk; the potential consequences of TE may justify bridging • In moderate-risk patients, a single perioperative strategy is not dominant and management will depend on individual patient risk assessment • In low-risk patients, the need to prevent TE will be less dominant and bridging may be avoided • In all patients, judicious use of postoperative bridging is needed to minimizing bleeding that would have the undesired effect of delaying resumption of antithrombotic therapy after surgery

Perioperative Anticoagulation: Key Questions What are bridging anticoagulation regimens? – A “high-dose” (therapeutic-dose) regimen involves giving a dose similar to that used to treat acute VTE or ACS (eg, enoxaparin, 1 mg/kg BID or 1. 5 mg/kg QD, dalteparin 100 IU/kg BID or 200 IU/kg QD, tinzaparin 175 IU/kg QD, IV UFH to attain a. PTT 1. 5 - to 2 -times the control a. PTT). – A “low-dose” (prophylactic-dose) regimen involves giving a dose used, typically, to prevent postoperative VTE (eg, enoxaparin 30 mg BID or 40 mg QD, dalteparin 5000 IU QD, UFH 5000 -7500 IU BID) – An “intermediate-dose” regimen has been recently studied for bridging and is intermediate in anticoagulant intensity between a high-dose and low-dose regimen (eg, enoxaparin 40 mg BID). – Recommendations in this chapter, unless otherwise specified, refer to a “therapeutic-dose” regimen because it is most widely studied, it is widely used in clinical practice, and it is the regimen considered most important because of the potential to confer the greatest benefit and harm. – Different bridging regimens may have potential advantages or drawbacks over a “therapeutic-dose” regimen.

Risk Stratification for Thromboembolism • The suggested scheme (Table) is based on indirect evidence from studies outside the perioperative setting involving patients who were not receiving anticoagulation therapy (ie, placebo-treated in AF trials) or received less effective treatment (eg, ASA-treated in MHV trials) • A limitation of this risk stratification scheme is that individual patient factors may trump this classification – eg, high-risk patients may also be those with AF and prior stroke + 1 additional risk factor (CHADS 2 = 3) even though such patients are classified as moderate risk – eg, patients with remote (>1 year ago) but severe VTE may be perceived as high risk even though they would be classified as low risk

Suggested Risk Stratification: Mechanical Heart Valves High Risk • Any mitral valve prosthesis • Older (caged-ball or tilting disc) aortic valve prosthesis • Recent (within 6 months) stroke or TIA Moderate Risk • Bileaflet aortic valve and at least one of: • Atrial fibrillation, prior stroke or transient ischemic attack, hypertension, diabetes, congestive heart failure, age >75 years Low Risk • Bileaflet aortic valve without atrial fibrillation and no other risk factors for stroke

Suggested Risk Stratification: Atrial Fibrillation High Risk • CHADS 2 score = 5 -6 • Recent (within 3 months) stroke or TIA • Rheumatic valvular heart disease Moderate Risk • CHADS 2 score = 3 -4 Low Risk • CHADS 2 score = 0 -2 and no prior stroke or TIA N. B. Individual patient characteristics (eg, prior embolic stroke or perioperative stroke/TIA) may override suggested risk stratification

Suggested Risk Stratification: Venous Thromboembolism High Risk • Recent VTE (<3 months ago) • Severe thrombophilia (eg, antiphospholipid antibodies) Moderate Risk • VTE within the past 3 -12 months • Nonsevere thrombophilia (eg, heterozygous factor V mutation) • Recurrent VTE • Active cancer (treated within 6 months or palliative) Low Risk • Prior VTE >12 months ago and no other risk factors

Risk Stratification for Bleeding High bleeding-risk surgeries/procedures include: • Urologic surgery/procedures: TURP, bladder resection or tumor ablation, nephrectomy or kidney biopsy (untreated tissue damage after TURP and endogenous urokinase release) • Pacemaker or ICD implantation (separation of infraclavicular fascia and no suturing of unopposed tissues may lead to hematoma) • Colonic polyp resection, especially >1 -2 cm sessile polyps (bleeding occurs at transected stalk after hemostatic plug release) • Vascular organ surgery: thyroid, liver, spleen • Bowel resection (bleeding may occur at anastomosis site) • Major surgery involving considerable tissue injury: cancer surgery, joint arthroplasty, reconstructive plastic surgery • Cardiac, intracranial or spinal surgery (small bleeds can have serious clinical consequences)

Case Vignette No. 1 A 68 -year-old woman receiving chronic warfarin for recurrent DVT (most recent was 1 year ago) will undergo two dental extractions that will include local anesthetic injections…

Patient has concerns about dental bleeding…

Case Vignette No. 1: Management Options 1. Stop warfarin at day -5 before procedure, give therapeutic-dose bridging with LMWH (eg, enoxaparin, 1 mg/kg bid) 2. Continue warfarin without dose reduction and give prohemostatic mouthwash (cyclokapron) around procedure 3. Continue warfarin without dose reduction 4. Stop warfarin 2 days before procedure and resume after procedure

Patients Requiring Minor Procedures • Recommendation: In patients who require minor dental surgery and are receiving VKA therapy, we suggest either continuing VKA with co-administration of an oral prohemostatic agent or stopping VKAs 2 -3 days before the procedure instead of alternative strategies (Grade 2 C). • Recommendation: In patients who require minor skin procedures and are receiving VKA therapy, we suggest continuing VKAs around the time of the procedure and optimizing local hemostasis instead of other strategies (Grade 2 C). • Recommendation: In patients who require cataract surgery and are receiving VKA therapy, we suggest continuing VKAs around the time of the surgery instead of other strategies (Grade 2 C).

Case Vignette No. 2 A 54 -year-old man with a mechanical mitral valve replacement on long-term warfarin therapy is scheduled for total hip replacement…

Case Vignette No. 2: Management Options 1. Stop warfarin 5 days preop, administer therapeuticdose bridging with LMWH (eg, enoxaparin, 1 mg/kg bid) preop and postop 2. Stop warfarin 5 days preop, administer low-dose LMWH preop and postop (eg, dalteparin, 5000 IU QD) 1. Continue warfarin but reduce dose by 50% starting 5 days preop 1. Stop warfarin 5 days preop and resume after procedure

Patients at High Risk for TE having Major Surgery • Recommendation: In patients who require temporary interruption of a VKA before surgery, we recommend stopping VKAs approximately 5 days before surgery instead of stopping VKAs a shorter time before surgery (Grade 1 C). • Recommendation: In patients who require temporary interruption of a VKA before surgery, we recommend resuming VKAs approximately 12 -24 hrs after surgery (evening of or next morning) and when there is adequate hemostasis instead of later resumption of VKAs (Grade 2 C). • Recommendation: In patients with a mechanical heart valve, atrial fibrillation or VTE at high risk for TE, we suggest bridging anticoagulation instead of no bridging during interruption of VKA therapy (Grade 2 C).

Concerns About Post-Op Bleeding With Bridging…

Perioperative Administration of Bridging • Recommendation: In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH, we suggest administering the last preoperative dose of LMWH approximately 24 h before surgery instead of 12 h before surgery (Grade 2 C). • Recommendation: In patients who are receiving bridging anticoagulation with therapeutic-dose SC LMWH and are undergoing high bleeding-risk surgery, we suggest resuming therapeutic-dose LMWH 48 -72 h after surgery instead of resuming LMWH within 24 h after surgery (Grade 2 C).

Case Vignette No. 3 A 69 -year-old man with chronic atrial fibrillation and hypertension (CHADS 2 score = 1) is undergoing a abdominal surgery for cancer…

Case Vignette No. 3: Management Options 1. Stop warfarin 5 days preop, administer therapeutic-dose bridging with LMWH (eg, enoxaparin, 1 mg/kg bid) preop and postop 2. Stop warfarin 5 days preop, administer low-dose LMWH preop and postop (eg. , daltearin, 5000 IU qd) 3. Continue warfarin but reduce dose by 50% starting 5 days preop 4. Stop warfarin 5 days preop and resume after procedure

Patients at Low Risk for TE Having Major Surgery • Recommendation: In patients with a mechanical heart valve, atrial fibrillation or VTE at low-risk for TE, we suggest no bridging instead of bridging anticoagulation during interruption of VKA therapy (Grade 2 C). • N. B. In patients at moderate-risk for TE, the bridging or no bridging approach chosen is, as in the higher and lower risk patients, based on an assessment of individual patient- and surgery-related factors.

Case Vignette No. 4 66 -year-old man with a drug-eluting coronary stent inserted 5 months ago following a non-ST-elevation myocardial infarction …now requires surgery for removal of a parotid adenocarcinoma He is receiving ASA 81 mg, and clopidogrel 75 mg daily His other cardiovascular risk factors are the following: CABG 12 years ago, hypertension, and type 2 diabetes

Concerns About Acute Coronary Stent Thrombosis…

Case Vignette No. 4: Management Options 1. Stop ASA and clopidogrel 7 -10 days preop and resume both drugs 1 -2 days postop 2. Stop ASA and clopidogrel 7 -10 days preop and administer bridging with SC LMWH 1. Continue ASA and stop clopidogrel 7 -10 days preop 2. Continue both ASA + clopidogrel perioperatively 3. Stop ASA and clopidogrel 7 -10 days preop and give GP IIb/IIIa inhibitor before/after surgery

Patients With Coronary Stents Having Surgery • Recommendation: In patients with a coronary stent who are receiving dual antiplatelet therapy and require surgery, we recommend deferring surgery for at least 6 weeks after placement of a bare-metal stent and for at least 6 months after placement of a drug-eluting stent instead of undertaking surgery within these time periods (Grade 1 C). • Recommendation: In patients who require surgery within 6 weeks of placement of a bare-metal stent or within 6 months of placement of a drug-eluting stent, we suggest continuing dual antiplatelet therapy around the time of surgery instead of stopping dual antiplatelet therapy 7 -10 days before surgery (Grade 2 C).

Case Vignette No. 5 • 78 -year-old obese woman with a non-ST-elevation myocardial infarction 2 years ago is seen preoperatively prior to inguinal hernia repair – CAD treated medically, no angiography • Receiving ASA, 81 mg • Other cardiovascular risk factors are the following: hypertension, dyslipidemia, glucose intolerance

Case Vignette No. 5: Management Options 1. Stop ASA 7 -10 days preop and resume 1 -2 days postop 2. Stop ASA 4 -5 days preop and resume 1 -2 days postop 3. Continue ASA without interruption before surgery

Patients With Coronary Stents Having Surgery Recommendation: In patients at moderate-to-high risk for cardiovascular events who are receiving ASA therapy and require non-cardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 -10 days before surgery (Grade 2 C). Recommendation: In patients at low risk for cardiovascular events who are receiving ASA therapy, we suggest stopping ASA 7 -10 days before surgery instead of continuation of ASA (Grade 2 C).

Ongoing Studies…Stay Tuned • Randomized controlled trials (RCTs) are ongoing to establish best practices for patients who are receiving antithrombotic therapy and require surgery. • RCTs are assessing the need for LMWH bridging in warfarintreated patients who require surgery: – – PERIOP-2 (clinicaltrials. gov/NCT 00432796) – funded by CIHR BRIDGE (clinicaltrials. gov/NCT 00786474) – funded by NIH PACEBRIDGE BRUISECONTROL (clinicaltrials. gov/NCT 00800137) • RCTs are assessing the need for perioperative ASA: – POISE-2 (clinicaltrials. gov/ NCT 01082874) in patients having noncardiac surgery – ATACAS in patients undergoing CABG surgery

Future Directions… • Observational studies are planned to assess best perioperative practices in patients receiving new oral anticoagulants (dabigatran, rivaroxaban, apixaban) or new antiplatelet drugs (prasugrel, ticagrelor). • Additional research is needed to inform best perioperative practices in patients with coronary stents and in special populations (obese, renal insufficiency).

Endorsing Organizations This guideline has received the endorsement of the following organizations: • • • American Association for Clinical Chemistry American College of Clinical Pharmacy American Society of Health-System Pharmacists American Society of Hematology International Society of Thrombosis and Hemostasis

Acknowledgement of Support The ACCP appreciates the support of the following organizations for some part of the guideline development process: Bayer Schering Pharma AG National Heart, Lung, and Blood Institute (Grant No. R 13 HL 104758) With educational grants from Bristol-Myers Squibb and Pfizer, Inc. Canyon Pharmaceuticals, and sanofi-aventis U. S. Although these organizations supported some portion of the development of the guidelines, they did not participate in any manner with the scope, panel selection, evidence review, development, manuscript writing, recommendation drafting or grading, voting, or review. Supporters did not see the guidelines until they were published.

Perioperative Management of Antithrombotic Therapy —-Antithrombotic Therapy and