1. 2012 CHEST Guideline Update VTE prophylaxis, DVT treatment, and Atrial Fibrillation LT Tabatha Welker, PharmD Pharmacy Resident, PHS Claremore Indian Hospital

2. Objectives Explain how to treat a patient with diagnosed DVT of the leg Apply knowledge of VTE prophylaxis to a patient case State the recommended anticoagulation management for patients with Atrial Fibrillation (AF) 2

3. Overview CHEST Grades of Recommendations VTE Prophylaxis – Nonsurgical Patients – Nonorthopedic Surgical Patients DVT Treatment (of the leg) Atrial Fibrillation Management 3

4. INTERPRETATION OF RECOMMENDATIONS Grade Recommend- ation MethodologicalQualityEvidence Benefit vs. Burdens Implication 1A StrongConsistent evidence from RCTs without limitations or very strong evidence from observational studies High Quality “clearly outweighs” Can apply to most patients in most circumstances; further research unlikely to change confidence 1B StrongEvidence from RCT’s with important limitations or very strong evidence from observation studies Moderate Quality “clearly outweighs” Can apply to most patients in most circumstances; higher quality research may well have important impact on confidence in estimate of effect 1C StrongEvidence for at least 1 critical outcome from observational studies, case series or from RCT‘s with serious flaws or indirect evidence Low or very low Quality “clearly outweighs” Can apply to most patients in many circumstances; higher quality research is likely to have an important impact on confidence and may well change estimate 4

5. INTERPRETATION OF RECOMMENDATIONSGrade Recommend- ation MethodologicalQualityEvidence Benefit vs. Burdens Implication 2A WeakConsistent evidence from RCTs without limitations or very strong evidence from observational studies High Quality “closely balanced” The best action may differ depending on circumstances or patient/society values; further research is unlikely to change confidence in estimate of effect 2B WeakEvidence from RCT’s with important limitations or very strong evidence from observation studies Moderate Quality “closely balanced” The best action may differ depending on circumstances or patient/society values; higher quality research may have an important impact on confidence and may change estimate 2C WeakEvidence for at least 1 critical outcome from observational studies, case series or from RCT’s with serious flaws or indirect evidence Low or very low Quality “closely balanced” Other alternatives may be equally reasonable; higher quality research is likely to have an important impact on confidence of effect and may well change estimate 5

6. VTE PROPHYLAXIS

7. PREVENTION OF VTE IN NONSURGICAL PATIENTS 7

8. Hospitalized Acutely Ill Medical Patients Increased risk of thrombosis, recommend anticoagulant thromboprophylaxis with low molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) Low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B) Patients who are bleeding or at high risk of bleeding, we recommend against anticoagulant thromboprophylaxis (Grade 1B) 8

9. Hospitalized Acutely Ill Medical Patients Patients at increased risk of thrombosis who are bleeding or at high risk for major bleeding – Optimal use of mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) – intermittent pneumatic compressions (IPC) (grade 2C) When bleeding risk decreases, and if VTE risk persists – pharmacologic thromboprophylaxis be substituted for mechanical thromboprophylaxis (Grade 2B) 9

10. Hospitalized Acutely Ill Medical Patients In acutely ill hospitalized medical patients who receive an initial course of thromboprophylaxis, we suggest against extending duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B) 10

11. Critically Ill Patients Suggest against routine ultrasound screening for DVT (2C) Suggest using LMWH or LDUH thromboprophylaxis over no prophylaxis (2C) Bleeding or high risk for major bleeding, suggest mechanical thromboprophylaxis with GCS (Grade 2C) or IPC (Grade 2C) until the bleeding risk decreases When bleeding risk decreases, suggest that pharmacologic thromboprophylaxis be substituted for mechanical thromboprophylaxis (Grade 2C) 11

12. Cancer in the Outpatient Setting No additional risk factors for VTE, we suggest against routine prophylaxis with LMWH or LDUH (grade 2B) and recommend against the prophylactic use of VKAs (1B) In outpatients with solid tumors who have additional risk factors for VTE and who are at low risk of bleeding, we suggest prophylactic-dose LMWH or LDUH over no prophylaxis (2B) In outpatient with cancer and indwelling central venous catheters, we suggest against routine prophylaxis with LMWH or LDUH (2B) and suggest against the prophylactic use of VKAs (2C) 12

13. Chronically Immobilized Patients In chronically immobilized persons residing at home or at a nursing home, we suggest against the routine use of thromboprophylaxis (2C) 13

14. Persons Traveling Long-Distance For long-distance travelers at increased risk of VTE (including previous VTE, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder) – frequent ambulation, calf muscle exercise, or sitting in an aisle seat if feasible (2C) – Suggest the use of properly fitted, below-knee GCS providing 15 to 30 mm Hg of pressure at the ankle during travel (2C). For all other long-distance travelers, we suggest against the use of GCS (2C) For long-distance travelers, we suggest against the use of aspirin or anticoagulants to prevent VTE (2C) 14

15. PREVENTION OF VTE IN NONORTHOPEDIC SURGICAL PATIENTS Patient undergoing General, GI, Urological, Gynecologic, Bariatric, Vascular, Plastic, or Reconstructive Surgery 15

16. General and Abdominal-Pelvic Surgery Very low risk of VTE (<0.5%; Rogers score, <7; Caprini score, 0) – No specific pharmacologic (Grade 1B) or mechanical (Grade 2C) prophylaxis be used other than early ambulation Low risk for VTE (~1.5%, Rogers score, 7-10; Caprini score, 1-2) – Mechanical prophylaxis, preferably with intermittent pneumatic compression (IPC), over no prophylaxis (Grade 2C) Moderate risk for VTE (~3.0%; Rogers score, >10; Caprini score 3-4) who are not at high risk for major bleeding complications – LMWH (Grade 2B), LDUH (Grade 2B), or mechanical prophylaxis, preferably with IPC (Grade 2C), over no prophylaxis 16

17. General and Abdominal-Pelvic Surgery Moderate risk for VTE (3.0%; Rogers score, > 10; Caprini score, 3-4) who are at high risk for major bleeding complications or those in whom the consequences of bleeding are thought to be particularly severe – mechanical prophylaxis, preferably with IPC, over no prophylaxis (Grade 2C) High risk for VTE (~6.0%; Caprini score, ≥ 5) who are not at high risk for major bleeding complications – pharmacologic prophylaxis with LMWH (Grade 1B) or LDUH (Grade 1B) over no prophylaxis – Mechanical prophylaxis with elastic stockings or IPC should be added to pharmacologic prophylaxis (Grade 2C) 17

18. General and Abdominal-Pelvic Surgery High-VTE-risk patients undergoing abdominal or pelvic surgery for cancer who are not otherwise at high risk for major bleeding complication, we recommend extended- duration pharmacologic prophylaxis (4 weeks) with LMWH over limited-duration prophylaxis (Grade 1B) High-VTE-risk patients who are at high risk for major bleeding complications or those in whom the consequences or those in whom the consequences of bleeding are thought to be particularly severe, we suggest use of mechanical prophylaxis, preferably with IPC, over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2C). 18

19. General and Abdominal-Pelvic Surgery High risk for VTE (6%; Caprini score, ≥ 5) in whom both LMWH and unfractionated heparin are contraindicated or unavailable and who are not at high risk for major bleeding complications – low-dose aspirin (Grade 2C), fondaparinux (grade 2C), or mechanical prophylaxis, preferably with IPC (Grade 2C), over no prophylaxis. Inferior vena cava (IVC) filter should not be used for primary VTE prevention (Grade 2C) Periodic surveillance with venous compression ultrasound should not be performed (Grade 2C) 19

20. VTE TREATMENT

21. Deep Vein Thrombosis DVT of the leg Acute DVT – Isolated distal – Isolated proximal – Provoked – Non-provoked Recurrent DVT 21

22. Acute Isolated Distal DVT Without severe symptoms or risk factors for extension, suggest serial imaging of the deep veins for 2 weeks over initial anticoagulation (2C) With severe symptoms or risk factors for extension, suggest initial anticoagulation over serial imaging of the deep veins (2C) Patients that are managed with anticoagulation should be managed the same as for patients with acute proximal DVT (1B) 22

23. Acute Isolated Distal DVT Patients managed with serial imaging – No anticoagulation if the thrombus does not extend (1B) – Anticoagulation if the thrombus extends but remains confined to the distal veins (2C) – Anticoagulation if the thrombus extends into the proximal veins (1B) 23

24. Deep Vein Thrombosis In patients with acute DVT of the leg treated with vitamin K antagonist (VKA), suggest initial treatment with parental anticoagulation (1B) Intermediate to high clinical suspicion of acute VTE, treat with parental anticoagulants if the results of diagnostic test are expected to be delayed for more than 4 hours (2C) Low clinical suspicion of an acute VTE, do not treat with parental anticoagulants while awaiting results, provided tests results are expected within 24 hours (2C) 24

25. Parental Anticoagulation In patients with acute DVT of the leg, suggest LMWH or fondaparinux over IV UFH (2C) and over SC UFH (2B for LMWH; 2C for fondaparinux) In patients with acute DVT of the leg treated with LMWH, suggest once- over twice-daily administration (2C) – Only when the approved once daily regimen uses the same daily dose as the twice-daily regimen (i.e. contains double the dose of the twice-daily injection) 25

26. When to initiate VKA? Same day as parental therapy Continue parental anticoagulation for a minimum of 5 days AND until the INR is 2.0 or greater for at least 24 hours (1B) 26

27. INR Range DVT of the leg treated with VKA, therapeutic INR range of 2.0 to 3.0 (1B) is recommended for all treatment durations 27

28. Phases of anticoagulation Initial Long-term Extended (0 to ~7 days) (~7 days to ~3 months) (~3 months to indefinite) *heparin, LMWH, fondaparinux 28 Vitamin K antagonist or other agent (LMWH, dabigatran, rivaroxaban) Vitamin K antagonist or other agent (LMWH, dabigatran, rivaroxaban) Parenteral*

29. DURATION OF THERAPY 29

30. Proximal DVT of the leg Provoked by surgery = 3 months (1B) Provoked by nonsurgical transient factor = 3 months (1B) First unprovoked – Low to moderate bleeding risk = extended therapy over 3 months (2B) – High bleeding risk = 3 months (1B) 30

31. Isolated Distal DVT of the leg Provoked by surgery = 3 months Provoked by nonsurgical transient risk factor = 3 months First unprovoked = 3 months regardless of bleeding risk (2B low or moderate, 1B high) 31

32. Second Unprovoked DVT Low bleeding risk = Extended anticoagulation therapy over 3 months (1B) Moderate bleeding risk = Extended anticoagulation therapy over 3 months (2B) High bleeding risk = 3 months (2B) 32

33. Active Cancer DVT of the leg and active cancer – Extended anticoagulation therapy over 3 months (1B,2B) First line: LMWH (2B) Second line: VKA therapy (2B) 33

34. Inpatient or Outpatient? In patients with acute DVT of the leg and whose home circumstances are adequate, recommend initial treatment at home over treatment in the hospital (1B) 34

35. Early Ambulation In patients with acute DVT of the leg, suggest early ambulation over initial bed rest (2C) 35

36. Compression Stockings Use in patients with acute symptomatic DVT of the leg (2B) – Should be worn for at least 2 years – Wear beyond if patient develops PTS and finds stockings helpful In patients with PTS of the leg, suggest a trial of compression stockings (2C) 36

37. Atrial Fibrillation

38. Atrial Fibrillation: Estimating Risk of Ischemic Stroke CHADS 2 Scoring System C ongestive Heart Failure 1 point H ypertension 1 point A ge ≥ 75 1 point D iabetes 1 point S troke or TIA 2 points (total of 6 points) 38 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

39. Dabigatran Oral anticoagulation Suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy 39 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

40. Dabigatran (Pradaxa®) Approved in October 2010 Indication (U.S.) Prevention of stroke and systemic embolism in patients diagnosed with Atrial Fibrillation Oral capsule, dosed BID and requires no monitoring – 75mg & 150mg capsules 40 PRADAXA® product insert. 2011.

41. Dabigatran (Pradaxa®) Dosing Dosing Renal Function* – Assess prior to initiation – While treated, re-assess when renal decline is suspected – When CrCl 75, re-assess annually 41 CrCl >30ml/min:150mg PO BID (+/- food) CrCl <15-30ml/min:75mg PO BID (+/- food) CrCl <15ml/min:Do not use, no data PRADAXA® product insert. 2011 update.

42. CHADS 2 Score of 0 Low risk of stroke Suggest no therapy rather than antithrombotic therapy Patients that choose antithrombotic therapy – Aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel (2B) Aspirin 75 mg to 325 mg daily 42 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

43. CHADS 2 Score of 1 Intermediate risk of stroke Oral anticoagulation rather than no therapy (1B) Oral anticoagulation (dabigatran) rather than aspirin or combination therapy Patients unsuitable for or choose not to take an oral anticoagulant, suggest combination therapy with aspirin and clopidogrel rather than aspirin alone 43 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

44. CHADS 2 Score of ≥ 2 High risk of stroke Oral anticoagulation rather than no therapy (1B) Oral anticoagulation (dabigatran) rather than aspirin or combination therapy Patients unsuitable for or choose not to take an oral anticoagulant, suggest combination therapy with aspirin and clopidogrel rather than aspirin alone 44 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

45. AF and Mitral Stenosis Recommend adjusted-dose VKA therapy (target INR range 2.0-3.0) Second line: Combination therapy with aspirin and clopidogrel (1B) 45 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

46. AF and Stable Coronary Artery Disease Ex: No acute coronary syndrome within the previous year Adjusted-dose VKA therapy alone – Target INR 2.0-3.0 Grade 2C 46 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

47. Post-Stent Placement and CHADS 2 ≥ 2 Triple Therapy (VKA, ASA, and clopidogrel) – During the first month after placement of a bare-metal stent (2C) – First 3 to 6 months after placement of a drug-eluting stent (2C) After initial period of triple therapy, suggest a VKA (INR 2.0-3.0) plus a single antiplatelet drug rather than VKA alone (2C) At 12 months after intracoronary stent placement, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease. 47 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

48. Post-Stent Placement and CHADS 2 0-1 Dual antiplatelet therapy rather than triple therapy (2C) At 12 months after intracoronary stent placement, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease 48 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

49. AF and Acute Coronary Syndrome CHADS 2 ≥ 1 (intermediate to high risk) Do not undergo intracoronary stent placement First 12 months – Adjusted-dose VKA therapy (INR 2.0-3.0) plus single antiplatelet therapy (eg, aspirin or clopidogrel) (2C) After the first 12 months, see stable coronary artery disease 49 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

50. AF and Acute Coronary Syndrome CHADS 2 = 0 (low risk of stroke) Dual antiplatelet therapy (ex., aspirin and clopidogrel) After the first 12 months, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease 50 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

51. AF being managed with a rhythm control strategy Antithrombotic therapy decisions follow the general risk-based recommendations for patients with AF, regardless of the apparent persistence of normal sinus rhythm (2C) 51 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

52. Cardioversion AF of greater than 48 hours or unknown duration Therapeutic anticoagulation for at least 3 weeks before cardioversion or a transesophageal echocardiography (TEE) (1B) – VKA therapy (target 2.0-3.-0) – LMWH at treatment doses – Dabigatran Therapeutic anticoagulation for at least 4 weeks after successful cardioversion (1B) 52 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

53. Cardioversion AF of documented duration of 48 hours or less Start anticoagulation at presentation and proceeding to cardioversion (2C) After successful cardioversion to sinus rhythm, therapeutic anticoagulation for at least 4 weeks 53 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

54. 2012 ACCP Guidelines Summary - ATRIAL FIBRILLATION - CHADS 2 Score Treatment Recommendation Grade 0 (No Risk Factors)Recommend no therapy, but if choose therapy suggest aspirin 75-325mg daily alone 2B 1Preferred: Oral anticoagulation (1 st :Dabigatran 150mg bid, 2 nd Warfarin; INR 2-3) Alternative: aspirin 75-325mg daily plus clopidogrel 1B 2B >2 or History of ischemic stroke or TIA Preferred: Oral anticoagulation (1 st :Dabigatran 150mg bid, 2 nd Warfarin; INR 2-3) Alternative: aspirin 75-325mg daily plus clopidogrel 1A 1B Mitral stenosisPreferred: Warfarin; INR 2-3 Alternative: aspirin 75-325mg daily plus clopidogrel 1B 54 You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S

55. 2012 ACCP Guidelines Summary - ATRIAL FIBRILLATION & SPECIAL SITUATIONS - CHADS 2 /Risk factor Treatment Recommendation Grade stable CADWarfarin alone (INR 2-3) is preferred over warfarin plus aspirin 2C >2 plus bare metal stent One month of triple therapy (VKA, ASA, clopidogrel), then warfarin; INR 2-3 plus single antiplatelet therapy for 12 months Thereafter refer to stable CAD recommendations 2C >2 plus drug-eluting stent 3 to 6 months of triple therapy (VKA, ASA, clopidogrel), then warfarin; INR 2-3 plus therapy antiplatelet for 12 months Thereafter refer to stable CAD recommendations 2C 0-1 plus any coronary stent First 12 months: dual antiplatelet therapy (ASA and clopidogrel) Thereafter refer to stable CAD recommendations 2C You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S 55

56. 2012 ACCP Guidelines Summary - ATRIAL FIBRILLATION & SPECIAL SITUATIONS - CHADS 2 /Risk factor Treatment Recommendation Grade 0 plus ACS with no stent placement First 12 months: dual antiplatelet therapy (ASA and clopidogrel) Thereafter refer to stable CAD recommendations 2C > 1 plus ACS with no stent placement First 12 months: warfarin; INR 2-3 plus single antiplatelet therapy Thereafter refer to stable CAD recommendations 2C You, JJ et al. Antithrombotic Therapy in Atrial Fibrillation. Chest. 2012; 141 (suppl 2):e531S-e575S 56

57. 2012 CHEST Guideline Update VTE prophylaxis, DVT treatment, and Atrial Fibrillation LT Tabatha Welker, PharmD Pharmacy Resident, PHS Claremore Indian Hospital