ANTICOAGULATION USE FOR THE PREVENTION AND TREATMENT OF THROMBOEMBOLIC DISEASE Jamie N. Nadler, M.D. Assistant Professor of Medicine State University of New York at Buffalo Department of medicine Division of Pulmonary, Critical Care and Sleep Medicine
Abbreviations THA TKA HFS LMWH LDUH VKA GCS IPCD VFP IVC Total Hip Arthroplasty Total Knee Arthroplasty Hip Fracture Surgery Low molecular weight heparin Low dose unfractionated heparin Vitamin K Antagonist Graduated compression stockings Intermittent pneumatic compression device Venous foot pump Inferior Vena Cava
VTE PROPHYLAXIS Chest 2012;141;e278S-e325S Chest 2012;141;e195S-e226S
Medical Patients Pharmacologic Prophylaxis 2012 ACCP Acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with (): LMWH LDUH bid or tid fondaparinux For acutely ill hospitalized medical patients who are at low risk of thrombosis bleeding or at high risk for bleeding, we recommend against anticoagulant thromboprophylaxis (1B)
Medical Patients Mechanical Prophylaxis Recommended Risk Factor N (%) OR (CI) Active GD Ulcer 236 (2.2) 4.15 (2.2-7.7) Bleeding 3 months PTA 231 (2.2) 3.64 (2.2 5.9) Platelets < 50 K 170 (1.7) 3.37 (1.8 6.2) Age > 85 yrs (vs 40yrs) 1178 (10.8) 2.96 (1.4 6.2 ) Hepatic Failure (INR> 1.5) 219 (2) 2.18 (1.1 4.3) Renal Failure (GFR < 30ml/min) 1084 (11) 2.14 (1.4 3.2) ICU or CCU admission 923 (8.5) 2.10 (1.4 3.1) CVC 820 (7.5) 1.85 (1.2 2.9) Rheumatic Disease 740 (6.8) 1.78 (1.1 2.8 ) Current Cancer 1166 (10.7) 1.78 (1.2 2.6) Male Gender 5367 (49.4) 1.48 (1.1 1.9) Decousus Chest 2011;139:69-79 2012 ACCP For acutely ill hospitalized medical patients at increased risk of thrombosis Who are bleeding or at high risk for major bleeding, we suggest optimal use of mechanical thromboprophylaxis with GCS or IPC (2C) When bleeding risk decreases, and if VTE risk persists, we suggest pharmacologic thromboprophylaxis be substituted for mechanical thromboprophylaxis (2B)
Medical (Non-surgical)Patients Additional Recommendations Condition 2012 Cancer No specific recommendations for surgical or medical inpatients. High VTE risk outpatients with solid tumors and low bleeding risk suggest prophylactic LMWH or LDUH (2B) Critically Ill Recommendations similar to 2012 general medical patients Compression U/S NOT recommended Chronic Immobility Long Distance Travel Suggest against the routine use of thromboprophylaxis Flight > 6 hours and high risk suggest ambulation, hydration, GCS Pharmacologic therapy is NOT recommended Extended Px Suggest against the routine use of thromboprophylaxis beyond hospitalization (except in certain cancer patients)
Orthopedic Surgery Prophylaxis 2012 ACCP TKA, THA, use one of the following for a min 10 to 14 days: LMWH, Fondaparinux Adjusted-dose VKA LDUH Aspirin Apixaban, Dabigatran, Rivaroxaban (1B) IPCD (1C) Recommended agents for Hip Fracture Surgery LMWH is suggested as the preferred agent (2C) Duration of treatment of 35 days is suggested (2B) Combined Pharmacologic and IPCD is suggested (2C)
Orthopedic Surgery Prophylaxis High Bleeding Risk General Risk Factors for Bleeding Previous major bleeding Includes previous bleeding risk similar to current risk Severe renal failure Concomitant anti-platelet agent Surgical factors: History of difficult to control surgical bleeding Current operative procedure has difficult to control bleeding Extensive surgical dissection Revision surgery 2012 ACCP In patients undergoing major orthopedic surgery and increased risk of bleeding, we suggest: Using an IPCD or no prophylaxis (2C). AGAINST IVC filter placement for primary prevention in patients with an increased bleeding risk or contraindications to both pharmacologic and mechanical thromboprophylaxis (2C)
Orthopedic Surgery Utilization of new anticogulants In patients who decline or are uncooperative with injections or an IPCD, we recommend using oral therapy(1b): apixaban or dabigatran or rivaroxaban or adjusted-dose VKA (if above unavailable) Limitations of alternative agents compared with LMWH Fondaparinux, rivaroxaban, and VKA - Potential increased bleeding LDUH, VKA, aspirin, and IPCD alone - Possible decreased efficacy Apixaban, dabigatran, and rivaroxaban - Lack of long-term safety data
VTE TREATMENT Chest 2012;141;e419S-e494S
Duration of Therapy for Thromboembolic Disease Proximal DVT or Pulmonary Embolism Provoked Unprovoked By Surgery Non Surgical Transient Factor First Episode Second Episode Bleeding Risk 1B 1B 2B 1B 1B Provoked Requiring Treatment High Distal DVT Low/Mod 3 Months 2B Low/Mod 1B High Bleeding Risk Unprovoked High Low/Mod High Mod Low In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals 2B 1B 2B 1B 2B Low/Mod PE / DVT Extended 1B 2B High Bleeding Risk Unprovoked Pulmonary Embolism with Active Cancer
Initial Anticoagulant Treatment Acute DVT and Pulmonary Embolism Acute DVT Suggest LMWH or fondaparinux over IV or SC UFH (2C) Acute PE ACCP 2012 Suggest LMWH or fondaparinux over IV UHF(2C,2B) or SC UFH (2B,2C) IV UFH is preferred if absorption is questionable or if thrombolysis is being considered Recommend early initiation of VKA and continue For a minimum of 5 days and INR is 2.0 for at least 24 h (Grade 1B)
Extended Treatment Special Considerations DVT and Pulmonary Embolism Patients without cancer: ACCP 2012 VKA is suggested over LMWH (2C) If VKA not used LMWH is suggested over rivaroxaban (2C) Patients with cancer: LMWH is suggested over VKA (2B) VKA is suggested over rivaroxaban (2B DVT, 2C PE) Drug choice for extended treatment should be the same as the first 3 months
Extended Treatment Special Considerations DVT and Pulmonary Embolism Rivaroxaban (Xarelto) FDA approved for treatment of thromboembolic disease In studies found to be non-inferior to enoxaparin/warfarin in preventing recurrent DVT/PE Aspirin WARFASA study compared 100mg ASA vs. placebo Approximately 40% relative or 4.5% absolute reduction in recurrent VTE Not compared to standard of care - warfarin NEJM 2010;363;2499-2515 NEJM 2012;366:1287-1297 NEJM 2012;266:1959-1967
Warfarin Therapy ACCP 2012 For patients sufficiently healthy to be treated as outpatients, we suggest initiating VKA therapy with warfarin 10 mg daily for the first 2 days followed by dosing based on INR measurements rather than starting with the estimated maintenance dose (2C) Consider 5mg Load in Inpatients Elderly Impaired nutrition Liver disease CHF High risk of bleeding Careful consideration with use of NSAIDS, Antimicrobials (SMX/TMP and quinolones) Concurrent anti-platelet agents should be reserved for situations where the benefit outweighs the risk of bleeding: ACS, Recent revascularization For patients taking VKA therapy with consistently stable INRs, we suggest an INR testing frequency of up to 12 weeks rather than every 4 weeks (2B)
PERIOPERATIVE MANAGEMENT Chest 2012;141;e326S-e350S
Surgical Procedures: VKA Recommendations High Risk of Bleeding Urologic surgery and procedures such as TURP, bladder resection, or tumor ablation; nephrectomy or kidney biopsy Pacemaker or implantable cardio- defibrillator device implantation Colonic polyp resection, typically of large (ie,1-2 cm long) sessile polyps Surgery and procedures in highly vascular organs, such as the kidney, liver, and spleen Bowel resection Major surgery with extensive tissue injury Cancer surgery, joint arthroplasty, reconstructive plastic surgery Cardiac, intracranial, or spinal surgery 1) Recommend stopping VKAs approximately 5 days before surgery (1C) 2) Recommend resuming VKAs approximately 12 to 24 h after surgery and when there is adequate hemostasis (2C) ACCP 2012 Low Risk Of Bleeding Minor dental procedure Including tooth extractions and endodontic procedures Continuing VKAs with coadministration of an oral prohemostatic agent OR Stop VKAs 2 to 3 days before the procedure Minor dermatologic procedures Including excision of basal and squamous cell skin cancers, actinic keratoses, and premalignant or cancerous skin nevi Cataract surgery Continue VKAs around the time of the procedure and optimizing local hemostasis Continue VKAs around the time of the surgery
Bridging Recommendations ACCP 2012 In patients with a mechanical heart valve, Afib, or VTE High risk for thromboembolism we suggest bridging Low risk for thromboembolism we suggest no-bridging Moderate risk for thromboembolism approach chosen is based on an assessment of individual patientand surgery-related factors
Risk Stratification for Perioperative VTE Risk VTE Mechanical Valves Atrial Fibrillation High Recent VTE (< 3 mo) Severe thrombophilia (eg, deficiency of proteins C or S, Antithrombin or antiphospholipid Abs multiple abnormalities) Any mitral valve Any caged-ball or tilting disc AVR Recent (within 6 mo) stroke or TIA CHADS 2 score 5 or 6 Recent (< 3 mo) stroke or TIA Rheumatic valvular heart disease Moderate VTE > 3 < 12 mo Recurrent VTE Active cancer (treated 6 mo/palliative) Nonsevere thrombophilia Bileaflet AVR and one or more risk factors: Afib, prior stroke or TIA, HTN, DM, CHF, age >75 y CHADS 2 score 3 or 4 (eg, heterozygous factor V Leiden or prothrombin gene mutation) Low VTE > 12 mo and no other risk factors Bileaflet AVR without Afib and no other risk factors for stroke CHADS 2 score 0 to 2 (assuming no prior stroke or TIA High-risk patients may also include those with 1. Prior TE during temporary interruption of VKAs 2. Surgery associated with an increased risk for stroke or other thromboembolism (eg, cardiac valve replacement, carotid endarterectomy, major vascular surgery) 3. Prior stroke or TIA occurring >3 mo before the planned surgery and a CHADS 2 score < 5,
Timing of Bridging Regimens Discontinuation of preoperative therapy Therapeutic-dose IV UFH should stop 4 to 6 h before surgery Therapeutic-dose SC LMWH, the last preoperative dose 24 h before surgery Resumption of postoperative therapy Regardless of bleeding risk the decision to resume therapeutic anticoagulation should be made after hemostasis has been achieved Resumption of bridging anticoagulation in patients undergoing high-bleeding-risk surgery, should be 48 to 72 h after surgery
Recommended Elements for Bridging Protocols 1. Assessing patients at least 7 days before surgery to allow planning of perioperative anticoagulant 2. Providing patients and providers with a calendar outlining: Perioperative timing of warfarin discontinuation and resumption Dose and timing of LMWH bridging INR measurement schedule 3. Ensuring that the perioperative management strategy accounts for the drugs pharmacokinetic profile and patients thromboembolic and bleeding risks 4. Patient/Caregiver education on injection technique 5. INR the day before surgery, where appropriate and feasible Identify patients with elevated INRs Permit timely use of corrective oral vitamin K (1.0-2.5 mg), thereby avoiding blood product administration or surgery deferral 6. Assessing postoperative hemostasis, preferably on the day of surgery and on the first postoperative day Facilitate safe resumption of anticoagulant drugs
BLEEDING MANAGEMENT Chest 2012;141;e152S-e184S
Management of Elevated INRs ACCP 2012 INR 4.5 and 10 with no bleeding We suggest against the routine use of vitamin K (2B) INR> 10.0 with no bleeding We suggest that oral vitamin K be administered (2C). VKA-associated major bleeding We suggest rapid reversal of anticoagulation with four-factor prothrombin complex concentrate rather than with plasma. (2C). We suggest the additional use of vitamin K 5 to 10 mg administered by slow IV injection rather than reversal with coagulation factors alone (2C)
Management of Newer Anticoagulants Reversal Dabigatran Rivaroxaban Apixaban specific antidote None None None Vit K, FFP No No No Protamine No No No apcc, PCC??? Dialysis 60% removed No High protein binding No High protein binding