Venous Thromboembolism

Transcription

1 Pennsylvania Academy of Family Physicians November 7, 2015 Allentown, PA Venous Thromboembolism BEAT THE CLOT 1 Faculty and curriculum development team David Garcia, MD Hematology and Internal Medicine Professor of Medicine, Division of Hematology University of Washington School of Medicine Christopher Flores, MD Family Medicine Faculty, Loma Linda University School of Medicine Mark Dressner, MD Family Medicine Long Beach, CA Cheri Olson, MD Family Medicine Faculty, La Crosse Mayor Family Medicine Residency Program 2 Our faculty and planners have completed disclosure of interest statements. Drs. Olson and Dressner, and Mss. Shelly Rodrigues, Jerri Davis and Mary Ales declare that in the past 12 months neither they nor any members of their families have had a financial interest in organizations supporting this activity. Dr. Flores declares that in the past 12 months he has received Advisory Board honoraria from Aerocrine and ResMed. Dr. Garcia declares that in the past 12 months he has served as a consultant for Boehringer Ingelheim, Bristol Myers Squibb, Daiiichi Sankyo and Pfizer and received research support from Daiichi Sankyo and Janssen. CAFP s Committee on Continuing Professional Development reviews and resolves all COI disclosures. Today s faculty 3 William R. Sonnenberg, MD Past President, PAFP Titusville, PA Dr. Sonnenberg declares that in the past 12 months neither he nor his spouse/partner have had any financial relationships commercial entities who might support this project. 1

2 Sponsors and support 4 This activity is sponsored by the California Academy of Family Physicians. It has been developed as part of the work of the TEAM-A Partnership, a 10-organization collaboration seeking to improve the care of patients with AFib and VTE conditions. This initiative is supported by an unrestricted educational grant from Bristol-Meyers- Squibb/Pfizer. VTE: Beat the Clot 5 Online VTE community for you facilitated by us Private! Secure! Interact, share, learn REQUEST an invitation to join via CME-CPD@familydocs.org type yammer in subject line Questions for today 6 1.How do I complete the initial assessment and management? 2.How long do I treat? 3.What about peri-operative and periprocedural care? 2

3 DVT and PE 7 Kills 4-5 times as many as breast cancer 300,000 deaths per year Number one preventable cause of hospital related deaths 10% of hospital deaths #1 killer of pregnant women Initial Assessment and Management 8 Claire 9 49-year-old woman. Unilateral leg pain and swelling 4 days after completing a 10.5 hour air flight.. HR 104, BP normal, po2 91% on room air No history of DVT/PE in primary relatives. Left leg swollen, no circulatory insufficiency. Compression ultrasonography shows acute femoral vein thrombosis (left leg). 3

4 Classic Signs of DVT 10 All have low predictive value Homans sign Edema Tenderness Warmth Redness Differential Diagnosis of DVT 11 75% of suspected DVT will have other cause Ruptured Baker s cyst Cellulitis Muscle tear or cramp Muscle hematoma Superficial phlebitis Wells Criteria for DVT 12 Clinical Feature Points Active Cancer 1 Leg paralysis, immobile 1 Bedridden > 3 days 1 Local vein tenderness 1 Entire leg swollen 1 Unilateral swelling > 3 cm 1 Unilateral pitting edema 1 Superficial veins 1 Likely alternative -2 Pts Risk 3 High 75% 1-2 Mod 17% 0 Low 3% 4

5 D-Dimer Tests 13 Vary widely in sensitivity and specificity Positive test does not raise likelihood of DVT Good sensitivity Wells < 2 and negative D-dimer less than 0.4% likelihood Negative predictive value 94% Doppler Ultrasonography 14 Most widely used Normal study in high risk patient not good enough Repeat in 7 days Old clot, new clot - same on U/S Inaccurate in pelvis or small calf vessels Obesity or edema hurts accuracy False positive in superficial phlebitis, popliteal cysts, or abscess Superficial Femoral Vein 15 DEEP VEIN! 24% of respondents would have anticoagulant (FP, IM, Chairpersons, lab directors) 93% of vascular labs use term 5

6 Assuming Claire s diagnosis is correct: 16 The most important next step in the management of this patient is: A. Measure d-dimer concentration B. Perform CT angiogram (helical/spiral CT) of the chest C. Administer anticoagulation (in therapeutic doses) D. Administer systemic thrombolysis (IV tissue plasminogen activator) E. Perform pharmaco-mechanical thrombolysis (local therapy) You can download medical apps, like the Wells scale, to assist you in your assessment. As you continue to treat Claire: 17 Which of the following would NOT be an indication for treatment over and above anticoagulation? A. Pulmonary embolism with systemic hypotension and tachycardia, but normal arterial oxygen saturation B. Iliac vein thrombosis with phlegmasia cerulea dolens (possibly compromised circulation) C. Common femoral vein thrombosis greater than 6 cm in length D. Pulmonary embolism with biochemical and echocardiographic evidence of right ventricular strain Claire 18 Does this information change your treatment of Claire? She has a diagnosis of VTE Is Claire at risk for complications of pulmonary embolism? Would you assign her high or low risk? 6

7 Low-risk PE may be treated out of hospital 19 Pooled analysis of > 1,200 patients with acute low-risk PE (all treated as outpatients; 11 studies) Outcome 90-day Event Rate (95% CI) Recurrent VTE 1.47% (0.47 to 3.0%) Fatal PE 0.47% (0.16 to 1.0%) Major Bleeding 0.81% (0.37 to 1.42%) Fatal ICH 0.29% (0.06 to 0.68%) Overall Mortality 1.58% (0.71 to 2.80%) Piran et al. Thromb Res Nov;132(5): Multiple screening tools exist to assist you in assigning risk. The Pulmonary Embolism Severity Index (PESI) Score Predictors B Coefficients Points Assigned (95% C1) Demographic characteristics Age, per year 0.03 ( ) Age, in years Male sex 0.17 (( ) + 10 Co morbid conditions Cancer 0.87 ( ) + 30 Heart failure 0.31 ( ) + 10 Chronic lung disease 0.30 ( ) + 10 Clinical findings Pulse > 110/min 0.60 ( ) + 20 Systolic blood pressure < 100mm Hg 0.86 ( ) + 30 Respiratory rate > 30/min 0.41 ( ) + 20 Temperature <36 C 0.42 ( ) + 20 Altered mental status 1.50 ( ) + 60 Arterial oxygen saturation <90% 0.58 ( ) + 20 Point total and risk classes: < 65=Class I, 66 85=Class II, =Class III, Class IV, >125=Class V Aujesky, D. et al J Respir Crit Care Med. 2005;172, What does this mean for Claire? Class 1 Low risk Class 5 Jump on this right now! In a study reported by Jimenez et al Chest 2007 vol. 132(1):P 7-8, of 10,354 patients with 30-day PE risk stratification, 953 died: Class Death PESI I 1.1 ( ) PESI II 3.1 ( ) PESI III 6.5 ( ) PESI IV 10.4 ( ) PESI V 24.5 ( ) Is anticoagulation sufficient? Yes/No, why? Can I treat Claire outside the hospital? If Yes. Why, and how? If No. What are the situations that merit inhospital treatment? Discussion questions 21 7

8 Of the following treatments for acute DVT/PE, which does not require an antecedent course of heparin (i.e. can be given as monotherapy from the outset)? A. Dabigatran 150 PO BID B. Rivaroxaban 15 mg PO BID C. Edoxaban 5 mg PO QD D. Warfarin 5 mg PO QD What medication should I prescribe for Claire? 22 Of the following treatments for acute DVT/PE, which does not require an antecedent course of heparin (i.e. can be given as monotherapy from the outset)? A. Dabigatran 150 PO BID B. Rivaroxaban 15 mg PO BID C. Edoxaban 5 mg PO QD D. Warfarin 5 mg PO QD What medication should I prescribe for Claire? 23 Traditional Preferred Treatment Plan for Most Patients * 24 Prescribe 5-7 days of injectable anticoagulant (e.g. LMWH 1 mg/kg BID) Prescribe 7 days of warfarin (e.g. 5 mg daily) Arrange appropriate follow-up appointments, care and activities *Long-term LMWH preferred for cancer-associated VTE 8

9 Unfractionated Heparin 25 APPT 1.5 to 2.3 control Bleeding, thrombocytopenia Higher in >65, recent surgery, PUD, liver disease, occult cancer, bleeding problems Major complications 2% Can stop when INR exceeds 2.0, 4-5 days Heparin-Induced Thrombocytopenia 26 Develops 5-10 days after start of heparin, surgery resets the clock May happen within 100 days of previous Rx 19 days after stopping heparin Mean platelet count 60,000 Hypercoagulability, thrombosis occurs 1/3 of the time Risk of HIT 27 1/ % in cardiac surgery 10x higher in unfractionated heparin Higher with major surgery Medical therapy Rare in obstetrical patients 9

10 Heparin-Induced Thrombocytopenia 28 Management HIT 29 Platelet factor 4-heparin antibody test if clinical features suggest HIT High negative predictive value Low positive predictive value Stop heparin immediately Use alternative anticoagulants Argatroban, danaparoid, fondaparinux, or bivalirudin Cannot use LMWH or Coumadin Low-Molecular-Weight Heparin 30 Longer ½ life Fixed, weight based dosing Thrombocytopenia less likely Equal to heparin in DVT Out patient therapy safe and cost effective Stable hemodynamically No renal failure Stable home environment 10

11 Nonpharmacologic Measures 31 Limb elevation Local heat Minimal activity Bathroom, kitchen Graded compression stockings 50% reduction in postphlebitic syndrome Challenges with Warfarin 32 Are there similar challenges with the DOACS? Aspirin? Clopidogrel? Delayed onset/offset Unpredictable dose response Narrow therapeutic range Drug-drug, drug-food interactions Problematic monitoring INR should be determined at least weekly during initiation and at least monthly when INR is in range and stable Slow reversibility Ansell J, et al. Chest. 2001;119(1 Suppl):22S-38S. Hirsh J, et al. Chest. 2001;119(1 Suppl):64S-94S. January CT, et al. J Am Coll Cardiol. 2014;64(21):e1-76. doi: /j.jacc Epub 2014 Mar 28. Warfarin Necrosis 33 Typically in first several days Mainly in Protein C deficiency Inhibition of Protein C stronger than K-dependent coagulation factors Protein C is anticoagulant 11

12 Warfarin Herbal Interactions 34 Ginkgo increase bleeding St. John Wort interfere with warfarin Ginseng increase bleeding Garlic not dietary, only supplement; increase bleeding Ginger increase bleeding Inferior Vena Cava Filter 35 Indicated when PE reoccurs on anticoagulation Lower 12 day rate but no difference at two years Not first line therapy AC alone vs. AC + Filter for PE 36 When do you treat more aggressively? A study done by Mismetti et al. JAMA. Clinical Outcomes for Patients with at Least 1 Event in the PREPIC2 Trial 2015;313(16): , showed: Group, No. with Events (%) Clinical Outcomes Filter Group n=200 Control Group n=199 At 3 Months Recurrent pulmonary embolism (primary efficacy outcome) c 6 (3.0) 3 (1.5) Fatal 6 (3.0) 2 (1.0) Nonfatal 0 (0.0) 1 (0.5) Recurrent deep vein thrombosis 1 (0.5) 1 (0.5) Recurrent venous thromboembolism 7 (3.5) 4 (2.0) Major bleeding 8 (4.0) 10 (5.0) Death 15 (7.5) 12 (6.0) At 6 Months Recurrent pulmonary embolism c 7 (3.5) 4 (2.0) Fatal 6 (3.0) 3 (1.5) Nonfatal 1 (0.5) 1 (0.5) Recurrent deep vein thrombosis 1 (0.5) 2 (1.0) Recurrent venous thromboembolism 8 (4.0) 6 (3.0) Major bleeding 13 (6.5) 15 (7.5) Death 21 (10.6) 15 (7.5) 399 Patients randomized 200 Randomized to the retrievable inferior vena cava plus the anticoagulation group (filter group) 199 Randomized to the anticoagulation group alone (control group) 12

13 ACCEPTED indications for? 37 IVC placement? Recent DVT/PE with absolute contraindication to anticoagulants tpa in PE? Hypotension, not corrected with volume resuscitation Deterioration (falling BP, increased HR or O 2 requirement) despite AC therapy? Evidence of RV strain ;? Elevated troponin Meyer et al. N Engl J Med 2014;370: Konstantinides S. N Engl J Med 2008;359: tpa in DVT? Compromise of tissue perfusion (dusky, painful, swollen extremity)?ilio-femoral thrombosis? long term follow-up data suggest reduction of post-thrombotic syndrome) More data to come from the ATTRACT trial Enden et al. Lancet Jan 7;379(9810):31-8. Vedantham et al. Am Heart J Apr;165(4): Catheter-Directed Thrombolysis 38 No mortality improvement (1.2% vs 0.9%) More bleeding and transfusions (11.1% vs 6.5%) Pulmonary embolus (17.9% vs 11.4%) Vena cava filter (34.8% vs 15.6%) Longer LOS and cost JAMA Intern Med. 2014;174(9): DOACs for Venous Thrombosis 39 Rivaroxaban XARELTO Dabigatran PRADAXA Apixaban ELIQUIS Edoxaban SAVAYSA 15 mg b.i.d. for 3 weeks then 20 mg once daily Can be used WITHOUT parenteral heparin treatment first 150 mg b.i.d. 5 days of parenteral treatment needed before dabigatran 10 mg b.i.d. for 7 days then 5 mg b.i.d. Can be used WITHOUT parenteral heparin treatment first Daily (60 mg; or 30 mg for renal impairment or low weight) 5 days parenteral (LMWH) treatment needed before edoxaban FDA Approval Status (for VTE) Approved Nov 2012 Approved Apr 2014 Approved Aug 2014 Approved Jan

14 Novel Anticoagulants 40 Reasons NOT to treat acute PE/DVT with DOACs 41 Severe renal insufficiency (Cr Cl < 30 ml/min) Weight > 120 kg or < 50 kg tpa use contemplated PATIENT CANNOT AFFORD MEDICATION No reversal agent in the case of severe/lifethreatening bleed Known pro-thrombotic state HIT, cancer, antiphospholipid syndrome Clinicians own discomfort using DOACs can also be a barrier to prescribing these agents to patients. Warfarin and DOACs 42 Quick Comparison Warfarin Coumadin Dabigatran 1 Pradaxa Rivaroxaban 2 Xarelto Apixaban 3 Eliquis Edoxaban 4 Savaysa Target VKORC1 Factors II, VII, IX, X Thrombin Factor Xa T (max) hours 2 hours hours 3 hours 2-3 hours Half-life 40 hours hours 5-9 hours healthy, 9-13 hours elderly 8-15 hours 8-10 hours Every 4 weeks Not needed Monitoring or PRN Administration Once daily Twice daily Once daily Twice daily Once daily Cytochrome 80% renal, Metabolism 35% renal 25% renal 35% renal P450 20% fecal Assay PT/INR Ecarin clotting time, thrombin time Anti-Xa activity 1. Connolly SJ, et al. N Engl J Med. 2009;361(12): Patel MR, et al. N Engl J Med. 2011;365(10): Granger CB, et al. N Engl J Med. 2011;365(11): Giugliano RP, et al. N Engl J Med. 2013;369(22):

15 Limitations and Concerns 43 Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Continuous monitoring X Heparin overlap often necessary X Limited experience with reversal X X X X Accumulation in renal dysfunction X X +/- X Lack of experience treating bleeding X X X X Limited experience in elderly, obese X X X X High acquisition cost X X X X Wartak SA, Bartholemew JR. Cleve Clin J Med. 2011;78(10): Gulseth MP, et al. Pharmacotherapy. 2011;31(12): Patel JP, et al. Br J Haematol. 2011;155(2): Connolly SJ, et al. N Engl J Med. 2011;364(9): Granger CB, et al. N Engl J Med. 2011;365(11): Giugliano RP, et al. N Engl J Med. 2013;369(22): DOACs: Comparing risk of bleeding among different anticoagulant medications 44 This is for Afib, but the bottom line is important! 30 day event rates (%) Trial RE LY ROCKET AF ARISTOTLE dabigatran warfarin rivaroxaban warfarin apixaban warfarin Stroke or systemic embolism Major bleed Healey et al. Circulation Sherwood et al. Circulation Garcia et al. Blood Meta-Analysis: NOACS VS Warfarin RELATIVE RISK TO WARFARIN (%) Hemorrhagic Stroke Intracranial Hemorrhage All-Cause Mortality -10 Major GI Hemorrhage Hemorrhage -14 Adapted from Ruff CT, et al. Lancet 2013 Online; S (13)623 15

16 General Comments 46 Reduce hemorrhagic strokes by 50% Tissue factor in CSF?? No dietary interaction All are non-inferior to warfarin Reversal Agents? 47 Aripazone D-arginine compound Apixaban, edoxaban, rivaroxaban, dabigatran, heparin, LMWH Single injection Andexanet modified factor Xa molecule Apixaban, edoxaban, Rivaroxaban Sops up anti-xa anticoagulant Idarucizumab antibody fragment against dabigatran dabigatran Idarucizumab for Dabigatran Reversal 48 Monoclonal antibody fragment binds dabigatran 350x more than thrombin Complete reversal in 88% 98% of patients within minutes 1/90 patients had thrombotic event within 72 hours Approved Oct 2016 $3500 per dose 16

17 Treatment Duration 49 Claire 50 Clot provoked by travel Prescribed rivaroxaban Under your care for 3 months She s asked how long she has to remain on the medication Clots: Provoked or Unprovoked? 51 Provoked blood clot Unprovoked clot Management and workups different 17

18 Provoked Clots Better in near term mortality and in long term limb health Little work up or additional testing is needed Stop anticoagulation after the appropriate duration 52 Claire s clot caused by extended air travel is a provoked clot. Unprovoked Clots Fare poorly / limb threatening Commonly associated with an underlying condition Need work up 53 According to Bagin, Lancet, 2000, unprovoked clots are nearly 2x more likely to recur as provoked clots. According to Kearon et al. Annals of Internal Medicine, males are at higher risk for recurrence than females. 100 Patients with First Unprovoked DVT 54 18

19 One Year off Anticoagulation Medications 55 = recurrent VTE Kearon, et al. NEJM 1999, vol 340. Agnelli, et al. Ann Int Med 2003, vol 139. Ridker, et al. NEJM April, 2003 Two Years off Anticoagulation Medications 56 = recurrent VTE Kearon, et al. NEJM 1999, vol 340. Agnelli, et al. Ann Int Med 2003, vol 139. Ridker, et al. NEJM April, D-dimer for Warfarin Duration? 57 D-dimer abnormal in 223/608 pts one month after stopping warfarin for PE or DVT Resumption of warfarin or placebo in + D- dimer group 15% events in stopped group 2.9% events in treated group Hazard ratio of 4.26 N Engl J Med Dec 28;355(26):

20 DVT/PE Risk Factors 58 Genetic Acquired Circumstantial Genetic Clotting Problems 59 Anticlotting deficiencies far more common than clotting deficiencies Failure to neutralize or control generation of thrombin 50% of DVT or PE s have anticlotting deficiencies Bauer KA et al. Ann Intern Med 2001;135: Age of Onset of Thrombophilia's 60 Mean age As young as second decade with multiple hereditary risk factors Martinelli I et al. Blood 92:

21 Genetic Risk Factors - Common 61 Factor V Leiden (1993) Prothrombin mutation G20210A (1996) Methylenetetrahydrofolate reductase gene mutation 5-15% of white and East Asian Genetic Risk Factors - Rare 62 Protein C deficiency Protein S deficiency Antithrombin III deficiency Hyperhomocystinemia Dysfibrinogenemia Factor V Leiden 63 Identified 1993 Autosomal dominant Variant of Factor V that cannot be inactivated by activated Protein C 5% of North American Caucasians 21

22 Leiden V 64 Suspect with Thrombosis under age 45 Family history 30% of DVT have mutation Doubles lifetime risk of DVT Increased Risk of Miscarriage Clots in pregnancy Clots on BCP s (35x risk) Clots with smokers (30x risk) Leiden V and other Risk Factors 65 Risk Factor Relative Risk Obesity 8 OCP rd Gen OCP 50 HRT 7-16 Air travel Minor injury 50 Cancer 12 Homocysteine 22 Genetics in Medicine (2011) 13, 1 16; doi: /gim.0b013e3181faa0f2 Why so Common? 66 Less blood loss during Menses Childbirth Cardiac surgery No increased risk Arterial thrombosis MI in older pts CVA 22

23 Gene Mutation 20210A % in healthy persons More common in Southern Europeans Rare in Asians and Africans Relative thrombosis risk 2.8% 18% of patients with thrombosis Antithrombin Deficiency 68 Breaks up fibrin and factor X Relatively resistant to heparin Autosomal dominant, 1/2000 Two types Type 1 quantitative Type 2 qualitative Acquired in renal failure lost in urine Timing of Tests 69 Thrombosis antithrombin III, protein C, protein S Heparin antithrombin III 30% Warfarin protein C and S Perform tests 2 weeks after completing warfarin Can check factor V Leiden, hyperhomocysteinemia, and antiphospholipid antibody anytime Ramzi DW and Leeper KV. AFP, June 15,

24 Acquired Risk Factors 70 Antiphospholipid antibodies Renal disease (renal loss of thrombin) Paroxysmal nocturnal hemoglobinuria Antiphospholipid Antibody 71 Primary in 53% Secondary to SLE, RA, TA Consider in thrombosis and recurrent miscarriages May promote placental thrombosis Circumstantial Risk Factors 72 Immobilization after trauma or surgery Medications Oral contraceptives Estrogen Evista Tamoxifen Pregnancy Cancer (Trousseau s Syndrome) 24

25 Hospital Risk Factors 73 Age over 40 Immobility CHF Stroke COPD Anesthesia Obesity Strong Risk Factors (OR > 10) 74 Fracture (hip or leg) Hip or knee replacement Major general surgery Major trauma Spinal cord injury Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1): Intermediate Risk Factors (OR 2-9) 75 Arthroscopic knee surgery Central venous lines Chemotherapy Chronic heart or respiratory failure Hormone therapy Malignancy Oral contraceptive therapy Paralytic stroke Pregnancy/postpartum Previous venous thromboembolism Thrombophilia Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1):

26 Weak Risk Factors (OR <2) 76 Bed rest longer than three days Immobility due to sitting (e.g., car or air travel longer than eight hours) Increasing age Laparoscopic surgery Obesity (BMI > 40 kg per m 2 ) Pregnancy/antepartum Varicose veins Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107(23 suppl 1): Oral Contraceptives 77 4x increase in thromboembolism 3 rd generation progesterones carry twofold greater risk than earlier generations Thrombophilia Summary 78 Antiphospholipid antibody testing is probably appropriate for many patients with spontaneous VTE More comprehensive testing may be indicated with strong family history Testing may be indicated for selected patients with a high risk of recurrence For example, in some patients with prior VTE who are planning pregnancy 26

27 Trousseau s Syndrome 79 8% of idiopathic DVT will found to have cancer within 2 years 60% of occult cancers dx after unprovoked thromboembolism Low grade DIC from a procoagulant tissue factor Armand Trousseau diagnosed own fatal pancreatic carcinoma Cancer Screening after Unprovoked Thromboembolism? pts with unprovoked DVT Labs, CXR, breast, cervical, prostate screen Above and abdominal/pelvic CT 33 occult cancers found (3.9%) 14 occult cancers in limited screen (3.2%) 19 occult cancers in limited screen + CT (4.5%) No mortality benefit Carrier M et al. N Engl J Med DOI: /NEJMoa Pregnancy 81 Relative risk of 4.3 C-section relative risk 13.3 v. vaginal delivery PE more common postpartum D-dimer increases in pregnancy, normal not established Dresang Lee T. et al. AFP, June 15, 2008, p

28 Risk Factors in Pregnancy 82 Hyperemesis dehydration and immobility High BMI Immobility Thrombophilia C-section Greer, IA; N Engl J Med 2015; 373: Differences in Pregnancy 83 Pregnancy Nonpregnant Clinical Suspicion Confirmed 4% 30% Left leg 78-90% 55% Illofemoral vein 72% 9% Treatment in Pregnancy 84 LMWH heparin preferred Coumadin contraindicated in pregnancy, ok in breast feeding No direct thrombin inhibitors cross placenta 28

29 Increased Major Bleeding Risk? 85 Risk Factors Concomitant Antiplatelet and other meds Advanced Age Prior Major Bleeding Anemia Uncontrolled Hypertension INR variability and target range Alcohol Predominantly derived from data in patients with Atrial Fibrillation. Lip et al. Thrombosis and Hemostasis, : Assessing Bleeding Risk: HAS-BLED HAS-BLED Score Bleeds/100 Patients* Any score Score 3 is highly predictive of bleeding events HAS-BLED is recommended by major international guidelines Hypertension Abnormal liver/renal function Stroke history Bleeding predisposition Labile INRs Elderly (>65) Drugs/alcohol use *p=.007 for trend of increasing bleeding risk with increasing score. Lip GY, et al. J Am Coll Cardiol. 2011;57(2): , Omran H, et al. Thromb Haemost. 2012;108(1): Camm AJ, et al. Europace. 2010;12(10): , Caims JA, et al. Can j Cardiol. 2011;27: Treat Proximal DVT or PE (unprovoked) at least 3 months 87 A Suggested Approach Ensure the patient is up-to-date on age-appropriate cancer screening and perform careful physical exam and review of systems. Discuss risks/benefits of extended therapy with all patients Encourage extended therapy for patients who: Male Previous VTE PE (rather than DVT) as their index event Poor cardiopulmonary reserve Low risk of AC-related bleeding Test young patients for antiphospholipid syndrome before permanently discontinuing. Consider d-dimer testing if other factors equivocal. 29

30 Warfarin Duration 88 Event Minimum Duration Strength of Recommendation First with reversible risk factor 3 months A First embolic episode 6 months A Recurrence 12 months B Continuing Risk Factor 12 months B Isolated calf vein thrombosis 6-12 weeks A Long Term Aspirin After Discontinuation of Anticoagulation 89 Meta-analysis of 2 trails, 1225 patients 100 mg aspirin after warfarin Recurrent DVT 1/3 lower in aspirin group 5.1% vs. 7.5% recurrent DVT No difference in bleeding Less MI, CVA or CV death in aspirin group Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014;130(13): Peri-Operative and Peri-Procedural Care 90 30

31 Claire 91 At 2.5 months under your care She is still taking the AC medication as prescribed She recently had a gall bladder attack She is now scheduled to have the gallbladder removed What is Claire s bleed risk? 92 Is Claire at HIGH risk for a bleed during the procedure? Higher Risk Urological Pacemaker Large colonic polyps Bowel Extensive tissue injury Pericardial/intracerbral/ epidural Lower Risk Minor dental Derm Cataract Risk for VTE 93 High Recent VTE Severe thrombophilia Moderate VTE 3-12 mos Nonsevere thrombophilia Recurrent VTE Active cancer Low VTE > 12 mos and no other risk factors 31

32 For patients on Warfarin 94 Most can simply interrupt without bridging Bridging increases the risk of bleeding and likely has no benefit for any patient except those at the highest risk of thrombosis Clark NP. JAMA Intern Med Jul;175(7): Douketis J. NEJM (this is a study of AF pts but shows that bridging clearly increases the risk of post-procedure bleeding) Is bridging necessary? Should I consider alternative anticoagulants during the postoperative period when risk of bleeding is high or if postoperative bleeding occurs? How long do I hold patients on anticoagulation Warfarin medications? Coumadin Dabigatran 1 Pradaxa Rivaroxaban 2 Xarelto Apixaban 3 Eliquis Savaysa Edoxaban 4 95 These questions are important as family physicians complete pre-op physicals. Half-life 40 hours hours 5-9 hours healthy, 9-13 hours elderly 8-15 hours 8-10 hours Many procedures can be performed safely without NOAC interruption Need more data to select patients and procedures Short-term interruption of DOAC (in AF) is associated with low 30-day risk of stroke Bridging likely not needed (except for patients who cannot take oral medication) For patients whose procedure requires interruption hours likely sufficient if renal function normal Longer interruptions if renal impairment and/or high-risk procedure More data anticipated from P.A.U.S.E.* Prospective cohort study with standardized interruption schedule Procedures and interruptions summary 96 * NCT

33 She had an uncomplicated provoked DTV. She was treated with a DOAC for three months. During her treatment she had her gallbladder removed with no issues. Claire is no longer taking AC medications and is flying to Barcelona to meet her family for her 50 th birthday celebration! Claire has ongoing questions about DVTs and is excited to use the EMMI Solutions app recommended by her family physician to learn more about prevention. How is Claire? 97 Flying and Aspirin for DVT Prevention 98 Risk is between 0-40/100,000 29% risk reduction with aspirin NNT 8,600 for high risk NNT 34,000 for low risk Ferrari et al. Chest : Tools and resources are available 99 February 2012; 141(2_suppl) Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

34 VTE: Beat the Clot 100 Online VTE community for you facilitated by us Private! Secure! Interact, share, learn REQUEST an invitation to join via CME type yammer in subject line Thank you