Understanding Best Practices in Anticoagulation Therapy in Patients with Venous Thromboembolism. Rajat Deo, MD, MTR

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1 Understanding Best Practices in Anticoagulation Therapy in Patients with Venous Thromboembolism Rajat Deo, MD, MTR Director of Translational Research in Cardiac Arrhythmias Division of Cardiovascular Medicine University of Pennsylvania Disclosures No relevant financial disclosures 1

2 Case of Venous Thromboembolism HPI 63 year old man, quite healthy 4 days h/o moderate CP + SOB; now SOB with 1 flight of stairs. No leg symptoms No preceding trauma, immobility, surgery, long-distance travel PMH Arthroscopic knee surg 2 yrs ago HTN; Obesity (BMI 32.3) No h/o cancer; no h/o bleeding FH Negative for VTE Case Physical Exam BP 135/87; P 92 / min RR at rest 16 min, not SOB when talking; O 2 on RA 93 % BMI 32.3; lungs clear; legs R=L CTA chest RUL segmental PE, L UL and LL subsegmental PE 2

3 Question Outpatient vs. Inpatient? Diagnosis Unprovoked PE. VTE risk factors: (a) obesity. How to manage this patient? A. Outpatient? B. Admit? ACCP Guidelines 2012 Acute Treatment Recommend home treatment for DVT (1B) and early d/c for low-risk PE. (2B). [Kearon C et al. Chest 2012;141(2)(Suppl):e419S-e494S] 3

4 Outpatient vs. Inpatient HESTIA Criteria 1. Hemodynamically unstable? 2. Thrombolysis or embolectomy needed? 3. Active bleeding or high risk of bleeding? 4. Oxygen needed to keep O 2 saturation > 90 % for > 24 hrs? 5. PE dx d during anticoagulant therapy? 6. iv pain meds for > 24 hrs? 7. Medical or social reason for admission? 8. GFR < 30 ml/min? 9. Severe liver impairment? 10. Pregnant? 11. Documented h/o HIT? [Zondag W et al. J Thromb Haemost 2011;9:1500-7] [Zondag W et al. J Thromb Haemost 2013(Jan 6 th )epub] Outpatient vs. Inpatient HESTIA Criteria Outpatient PE management Suitable for nearly 50% of PE patients; HESTIA criteria can be useful for decision making. [Zondag W et al. J Thromb Haemost 2011;9:1500-7] [Zondag W et al. J Thromb Haemost 2013(Jan 6 th )epub] 4

5 PESI = Pulmonary Embolism Severity Index [Aujesky D et al. Am J Respir Crit Care Med 2005;15;172(8):1041-6] Patient Diagnosis few days later 3 mo any time Q1: Outpatient or inpatient? Q2: Thrombolytics? 5

6 Thrombolytics? For PE, with hypotension or high risk for hypotension: suggest thrombolytics, systemically. 2C For DVT, suggest anticoagulant therapy alone over thrombolysis (catheter-directed or systemic). 2C [Kearon C et al. Chest 2012;141(2)(Suppl):e419S-e494S] PE: Indicators of Poor Outcome ESC criteria (based on consensus; lack of validation) High risk Intermediate risk Low risk Criteria Cardiovascular shock or persistent hypotension Lab (troponin, BNP) or RV dysfunction nl labs (troponin, BNP); nl RV function mortality > 30 % 1-30 % < 1 % [Torbicki A et al. Eur Heart J 2008; ] 6

7 PE: Indicators of Poor Outcome PEITHO trial: 1,006 patients with RV stain PLUS pos. troponin: thrombolytics versus placebo [Torbicki A et al. Eur Heart J 2008; ] Efficacy Outcomes. Meyer G et al. N Engl J Med 2014;370:

8 Safety Outcomes in the Intention-to-Treat Meyer G et al. N Engl J Med 2014;370: Patient Diagnosis few days later 3 mo any time Q1: Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or TSOAC? 8

9 Question Anticoagulant Choice Outpatient management is chosen. CBC, PT, aptt normal; Creatinine 0.95; liver enzymes normal. How would you treat? A. LMWH or fondaparinux / warfarin B. Rivaroxaban (Xarelto) C. Dabigatran (Pradaxa) D. Apixaban (Eliquis) Common Pathway Apixaban Rivaroxaban Xa Blocker Xa Dabigatran New Oral Agents Prothrombin Thrombin Clot Fibrinogen Fibrin 9

10 Treatment VTE UFH, LMWH Bridge to Warfarin RE-COVER Study Dabigatran 150 mg, BID for 6 months Double Blind, Double Dummy, Non-Inferiority Schulman S, et al NEJM 2009;361:

11 RE-COVER Study Dabigatran 150 mg, BID VTE Major Bld 2.4% 1.6% VTE Warfarin INR % 1.9% Parenteral Anticoagulant Median 9 days 6 months Warfarin TTR= 60% Schulman S, et al NEJM 2009;361: RE-COVER Study 2.4% Dabigatran = 150mg, BID 2.1% INR = 60% TTR HR = 1.1 ( ) TTR = Therapeutic Time in Range Schulman S, et al NEJM 2009;361:

12 RE-COVER Study Dabigatran Major Bld 1.6% Warfarin Bld 1.9% Major Schulman S, et al NEJM 2009;361: RE-COVER Study Index Events Dabi 1273 Warfarin 1266 Schulman S, et al NEJM 2009;361:

13 RE-COVER Study Major Bleeding Dabi Warfarin Schulman S, et al NEJM 2009;361: RE-COVER A limitation of the study is that the first dose of dabigatran, was given only after initial parenteral anticoagulation therapy had been administered for median of 9 days There is no data to support the use of dabigatran monotherapy for acute venous thromboembolism Schulman S, et al NEJM 2009;361:

14 Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial Einstein Investigators NEJM 2010;363: Einstein DVT DVT Proximal DVT Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday Enoxaparin Warfarin INR 2-3 3, 6, 12 months VTE Major Bld 2.1% 8.1% 3.0% 8.1% Warfarin TTR = 57.7% Einstein Investigators NEJM 2010;363:

15 Acute DVT Study Einstein Acute DVT Study INR = 57.7% TTR 3.0% 2.1% TTR = Therapeutic Time in Range Einstein Investigators NEJM 2010;363: Einstein Acute DVT Study Causes of VTE Riva Standard Einstein Investigators NEJM 2010;363:

16 Einstein Acute DVT Study 8.1% 8.1% HR = 0.97 (95% CI, 0.76 to 1.22, P=0.77) Einstein Investigators NEJM 2010;363: Einstein Acute DVT Study Safety Outcomes Riva Standard Einstein Investigators NEJM 2010;363:

17 Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority Einstein Investigators NEJM 2012;366: Einstein PE PE Rivaroxaban 15 mg, BID x 3 wks 20 mg, Qday Enoxaparin Warfarin INR 2-3 3, 6, 12 months VTE Major Bld 2.1% 1.1% Non-Inferior 1.8% 2.2% Warfarin TTR = 62.7% Einstein-PE Investigators NEJM 2012;366:

18 Einstein PE 2.1% INR = 62.7% TTR 1.8% Einstein Investigators NEJM 2012;366: Einstein PE Causes Riva Standard Einstein Investigators NEJM 2012;366:

19 Einstein PE Anatomical Extent Riva Standard Einstein Investigators NEJM 2012;366: Einstein PE Major Bleeding 2.2% 1.1% Einstein Investigators NEJM 2012;366:

20 Patient Diagnosis few days later 3 mo any time Q1: Outpatient or inpatient? Q2: Thrombolytics? Q4: D/c anticoag or long-term? Q3: LMWH/warfarin or rivaroxaban? How Long To Treat With Anticoagulation? VTE due to transient risk factor 3 months Long-term Woman with DVT or PE, hormones Woman with DVT, not hormones Woman with PE - D-dimer + Strong Thrombophilia Man with DVT Man with PE Other risk factors for recurrence: Obesity?; age? Other considerations: Bleeding, fluctuating INRs, lifestyle impact, pt 20

21 How Long to Treat with Anticoagulation? [Palareti G et al. NEJM 2006;355:1780-9] [Verhovsek M et al. Systematic review on D-dimer to predict recurrent VTE. Ann Int Med 2008;149(7): ] VTE Recurrence Risk Assessment Scores HERDOO-2 score [Rodger M et al; CMAJ 2008;179: ] DASH score [Tosetto A et al. J Thromb Haemost 2012 Jun;10(6): ] 21

22 How Long to Treat With Warfarin? - HERDOO-2 Women HERDOO-2 rule HER = Hyperpigmentation or Edema or Redness D = D-dimer positivity (on warfarin) O= obesity, BMI 30 O = Older age, 65 yrs Conclusion: Women 1 d/c anticoagulation. Men, no matter what the score, need to continue anticoagulation. 2 = score of 2: continue warfarin [Rodger M et al; CMAJ 2008;179: ] How Long to Treat With Warfarin? - DASH DASH score D = D-dimer pos (off warfarin) + 2 A = age < 50 years + 1 S = sex (male) + 1 H = hormone use - 2 Conclusion: Score 1: d/c anticoagulation Annual VTE recurrence rate: 1: 3.1 % 2: 6.4 % 3: 12.3 % [Tosetto A et al. J Thromb Haemost 2012 Jun;10(6): ] 22

23 VTE: Length of Anticoagulation Conglomerate decision of: 1. Risk of recurrent VTE (a)., (b)., (c).. 2. Risk of Bleeding (a)., (b)., (c).. 3. Patient preference Coumadin hate factor ACCP 2012 Guidelines: Highlights Treatment beyond Acute Period Surgery-associated DVT/PE: recommend 3 months. (1B) Non-surgical transient risk factor: recommend 3 months over 6 or more months. (1B) Unprovoked DVT/PE and low/intermediate risk for bleeding: suggest extended anticoagulation (2B). High bleeding risk: 3 months (1B). Cancer patient with DVT/PE: recommend/suggest extended therapy. LMWH rather than VKA (2C). [Kearon C et al. Chest 2012;141(2)(Suppl):e419S-e494S] 23

24 Patient Diagnosis few days later 3 mo any time Q1: Outpatient or inpatient? Q2: Thrombolytics? Q3: LMWH/warfarin or rivaroxaban? Q4: Compression stockings? Q5: D/c anticoag or long-term? Q6: Warfarin or TSOAC? Rivaroxaban 15 mg, PO, BID x 3 weeks then 20mg, Qday Enoxaparin 1mg/kg/Q12hrs bridge to Warfarin INR 2-3 Open Label, Non-Inferiority trial Einstein Investigators NEJM 2010;363:

25 Einstein DVT-Extend Rivaroxaban 20 mg, Qday VTE Major Bld 1.3% 0.7% DVT All Rxed Placebo 7.1% 0% 3, 6, 12 mo 6-12 mo 34 recurrent events were prevented at the cost of 4 MBEs Einstein Investigators NEJM 2010;363: Double Blind, Randomized Trial Schulman S, et al NEJM 2013;368:

26 RE-MEDY Dabigatran 150 mg, BID VTE Major Bld 1.8% 0.9% VTE Patient Rx 3 to 12 months Warfarin INR months 1.3% 1.8% Schulman S, et al NEJM 2013;368: RE-SONATE Dabigatran 150 mg, BID VTE Major Bld 0.4% 0.3% DVT Patient Rx 6 to 18 months Placebo 6-18 months 5.6% 0% Schulman S, et al NEJM 2013;368:

27 RE-MEDY Study 1.8% 1.3% Dabigatran Warfarin Schulman S, et al NEJM 2013;368: RE-SONATE Study Placebo 5.6% Dabigatran 0.4% Schulman S, et al NEJM 2013;368:

28 RE-MEDY Study Any Bleeding 26.2% 19.4% Warfarin Dabigatran Major Bleeding Dabigatran 0.9% Warfarin 1.3% Schulman S, et al NEJM 2013;368: RE-SONATE Study Dabigatran 10.5% Any Bleeding Placebo 5.9% Major or Clinically Relevant Bleeding Dabigatran 5.3% Placebo 1.8% Schulman S, et al NEJM 2013;368:

29 RE-SONATE Study Schulman S, et al NEJM 2013;368: Agnelli G, et al NEJM 2012;

30 AMPLIFY-EXT (n=2486) Apixaban 2.5 mg, BID VTE Major Bld 1.7% 0.2% VTE Rx 6-12 mo Apixaban 5.0 mg, BID Placebo 12 months 1.7% 0.1% 8.8% 0.5% Agnelli G, et al NEJM 2013;368(8): AMPLIFY-EXT Apixaban 2.5 Apixaban 5 Placebo Agnelli G, et al NEJM 2013;368(8):

31 AMPLIFY-EXT Symptomatic Recurrent VTE or VTE Related Death 8.8% 1.7% 1.7% Agnelli G, et al NEJM 2013;368(8): AMPLIFY-EXT Major-Clinical Relevant Non-Major Bleeding 4.3% 3.2% 2.7% Agnelli G, et al NEJM 2013;368(8):

32 ACCP 2012 Guidelines: Highlights Treatment beyond Acute Period Surgery-associated DVT/PE: recommend 3 months. (1B) Non-surgical transient risk factor: recommend 3 months over 6 or more months. (1B) Unprovoked DVT/PE and low/intermediate risk for bleeding: suggest extended anticoagulation (2B). High bleeding risk: 3 months (1B). Cancer patient with DVT/PE: recommend/suggest extended therapy. LMWH rather than VKA (2C). [Kearon C et al. Chest 2012;141(2)(Suppl):e419S-e494S] Major Bleeding Treatment Options 1. Supportive care! 2. Activated charcoal 3. Hemodialysis for Dabigatran, not for Rivaroxaban or Apixaban 4. REVERSAL AGENTS IN DEVELOPMENT 32

33 Major Bleeding Treatment Options 5. Non-activated PCC (prothrombin complex concentrate) 6. Activated PCC 7. Recombinant factor VIIa 8. FFP 9. Anti-fibrinolytic drugs (aminocaproic acid, tranexamic acid) Summary 1. Outpatient VTE management Suitable for approx. 50 % of PE patients; HESTIA criteria for PE risk can be useful for decision making. 2. New oral anticoagulants are an option for acute treatment Starting the drugs; D/c before surgery (24 h for standard risk; 2-4 d for high risk; Major bleeding management. 33

34 Summary 4. How long to treat with anticoagulation? Duration depends on balancing risk factors for VTE and bleeding complications. THANK YOU! 34

35 ED - OBS History & Physical Laboratory Testing Diagnosis DVT Select Treatment Hospital Admission OBS Discharge Plan Secure Rx Communication Follow Up Acquire Med Pt Education Contact PCP D/C Summary Phone call 24 hrs Appointment 3-5 days Discharge OBS Your patient who has been on long term warfarin would like to convert to one of the new oral anticoagulant. 35

36 Warfarin to NOAC Agent Recommendation Rivaroxaban Start when INR < 3.0 (we recommend < 2.0) Apixaban Start when INR < 2.0 Dabigatran Start when INR < 2.0 NOAC= New Oral Anticoagulants 36