The Treatment of Venous Thromboembolism (VTE): Has Warfarin Met Its Match? Michael P. Gulseth, Pharm. D., BCPS, FASHP Program Director for

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1 The Treatment of Venous Thromboembolism (VTE): Has Warfarin Met Its Match? Michael P. Gulseth, Pharm. D., BCPS, FASHP Program Director for Anticoagulation Services Sanford USD Medical Center Sioux Falls, SD

2 Objectives Describe the pathophysiology and epidemiology of venous thromboembolism (VTE) Identify how VTE is currently recommended to be medically managed Compare and contrast the novel oral anticoagulants being studied for VTE treatment After reviewing the novel oral anticoagulant studies, identify how you would treat an individual patient through case study examples

3 DVT Pathophysiology Key Points DVT thrombi form in venous valve pockets and other areas of stasis Clots that originate or propagate above the knee are at higher risk of embolizing DVT clots can dislodge and travel through venous vasculature and heart to the lungs Tapson VF. N Engl J Med. 2008; 358:

4 Which of the following diseases kills more Americans than the other 3, combined? 1. Traffic accidents 2. Breast cancer 3. VTE 4. HIV 25% 25% 25% 25%

5 Epidemiology and burden of VTE

6 ACCP 2012: VTE Treatment Acute DVT or Hemodynamically Stable PE Initial parenteral anticoagulant tx or anticoagulation with rivaroxaban (1B) LMWH or fondaparinux > IV UFH (2C) or SC UFH (2B) Thrombolytic therapy for PE with hypotension (2C) Length of Tx for a first proximal DVT or PE Provoked - 3 months (Grade 1B) Unprovoked - extended therapy if bleeding risk is low or moderate (2B) & 3 months if bleeding risk is high (1B); Active cancer» extended therapy (1B) & LMWH > VKA (2B)» VKA or LMWH > dabigatran or rivaroxaban (2B). Chest Feb;141(2 Suppl):e419S-94S.

7 Which of the following novel oral agents was studied separately in DVT vs. PE patients? 1. Dabigatran etexilate 2. Rivaroxaban 3. Apixaban 4. Endoxaban 25% 25% 25% 25%

8 Which of the following novel oral agents was studied as a stand alone initial treatment of VTE? 1. Dabigatran etexilate 2. Rivaroxaban 3. Apixaban 4. 2 and 3 25% 25% 25% 25%

9 Current Treatment Approach for Venous Thromboembolism Heparin LMWH Fondaparinux Thrombolysis Thrombus Removal IVC filter Initial treatment Vitamin K Antagonists LMWH Long term-treatment Vitamin K Antagonists Extended treatment 0 to 7 days 3 to 6 months 6 months to indefinite Dabigatran*, Endoxaban* Rivaroxaban, Apixaban* Chest. 2012;141(2 Suppl):7S-47S; * = Not FDA Approved

10 Novel Oral Anticoagulants X TF VIIa IX VIIIa IXa Dabigatran II Xa Va IIa Rivaroxaban Apixaban Edoxaban Betrixaban Darexaban Fibrinogen Fibrin

11 Novel Oral Agents: Phase III Trials Dabigatran Rivaroxaban Apixaban Total Hip Replacement RE-NOVATE RE-NOVATE II RECORD 1 RECORD 2 ADVANCE-3 Total Knee Replacement RE-MOBILIZE RE-MODEL RECORD 3 RECORD 4 ADVANCE-1 ADVANCE-2 VTE Prophylaxis in Medical Patients MAGELLAN ADOPT VTE Treatment RE-COVER a EINSTEIN-DVT b RE-MEDY c RE-SONATE a EINSTEIN-EXT c EINSTEIN-PE e AMPLIFYa AMPLIFY-EXT c Atrial Fibrillation RE-LY ROCKET-AF AVERROES d ARISTOTLE Acute Coronary Syndrome ATLAS ACS TIMI 51 APPRAISE-2 a DVT & PE treatment b DVT treatment c DVT and PE extended treatment d Apixaban vs. Aspirin e Acute Sx PE + DVT

12 Dabigatran RE-COVER Randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority design of acute VTE treatment 2564 patients Dabigatran 150 mg po bid vs warfarin titrated to INR of x 6 mo after initial parenteral anticoagulation median 9 days Proximal DVT or PE (~30%) Outcomes 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths Major bleeding (fatal, critical organ, fall in Hb 2 g/dl, or 2 units blood) N Engl J Med 2009;361:

13 Dabigatran RE-COVER Recurrent VTE or related death Dabigatran noninferior to warfarin (2.4% vs 2.1%) (p<0.001 for noninferiority) Warfarin time in therapeutic range: 60% N Engl J Med 2009;361: Dabigatran similar to warfarin for major bleeding (1.6% vs 1.9%) and superior for major + clinically relevant nonmajor bleeding (5.6% vs 8.8% (p=0.002) and superior for any bleeding

14 Dabigatran RE-COVER II Limited information since still not in full peer review format Randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority design of acute VTE treatment 2568 patients Dabigatran 150 mg po bid vs warfarin titrated to INR of x 6 mo after initial parenteral anticoagulation of 5-11 days Outcomes 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths Results: Dabigatran noninferior to warfarin (2.4% vs 2.2%) (p<0.001 for noninferiority) Major bleeding (fatal, critical organ, fall in Hb 2 g/dl, or 2 units blood) Results: Dabigatran 15 patients vs warfarin 22 patients (HR 0.67, ) Schulman S, Kakkar AK, Schellong SM, et al. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II). American Society of Hematology 2011 Annual Meeting; December 12, 2011; San Diego, CA. Abstract 205. Available at:

15 Dabigatran RE-MEDY Randomized, multicenter, double-blind, double-dummy, active-controlled, non-inferiority design who had completed at least 3 months of VTE treatment 2866 patients Dabigatran 150 mg po bid vs warfarin titrated to INR of x 6-36 mo Non-inferiority criteria: HR could not exceed 2.85 and absolute increase in VTE recurrence no more than 2.8% Outcomes Incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths Major bleeding (fatal, critical organ, fall in Hb 2 g/dl, or 2 units blood) N Engl J Med 2013;368:709-18

16 Dabigatran RE-MEDY Warfarin time in therapeutic range: 65.3% N Engl J Med 2013;368: Recurrent VTE or related death Dabigatran noninferior to warfarin (1.8% vs 1.3%) (p<0.01 for noninferiority) HR 1.44 ( ) Dabigatran similar to warfarin for major bleeding (0.9% vs 1.8%, p=0.06) and superior for major + clinically relevant nonmajor bleeding (5.6% vs 10.2% (p=<0.001) and superior for any bleeding MI issue? 0.9% vs 0.2%, p=0.02

17 Dabigatran RE-SONATE Randomized, multicenter, double-blind, placebocontrolled, superiority design who had completed at least 3 months of VTE treatment 1353 patients Dabigatran 150 mg po bid vs placebo titrated to INR of x 6-18 mo Proximal DVT or PE (~30%) Outcomes Incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths Major bleeding (fatal, critical organ, fall in Hb 2 g/dl, or 2 units blood)

18 Dabigatran numerically more major bleeding (0.3% vs 0%) and statistically more major + clinically relevant nonmajor bleeding (5.3% vs 1.8% (p=<0.001) and any bleeding when compared to placebo Dabigatran RE-SONATE Recurrent VTE or related death Dabigatran superior to placebo (0.4% vs 5.6%) (p<0.0001)

19 Dabigatran Summary Double blind trials Results encouraging for the acute treatment of VTE, but utility likely hampered by study design Why do we need to treat with initial parenteral therapy? Only new agent to compare themselves to warfarin for extended VTE secondary prevention However, HR a bit worrisome, but bleeding results encouraging Warfarin relatively well controlled MI issue? RE-SONATE proves what we already know Extended secondary prevention anticoagulation treatment in those at risk is better than placebo

20 30-day observation period EINSTEIN DVT: Study Design Randomized, open-label, event-driven, noninferiority study Treatment period of 3, 6 or 12 months* Objectively confirmed proximal DVT without symptomatic PE N=3449 R Rivaroxaban Rivaroxaban 15 mg bid 20 mg od Enoxaparin 1.0 mg/kg bid for 5 days, followed by VKA to start 48 h, target INR 2.5 (INR range 2 3) Day 1 Day 21 Primary efficacy endpoint: symptomatic recurrent VTE Primary safety endpoint: clinically relevant bleeding *Decision to treat for 3, 6, or 12 months made by investigator at randomization; 48-hours pretreatment with LMWH/heparin/fondaparinux permitted before study entry (~70%); Symptomatic recurrent VTE defined as the composite of recurrent DVT, nonfatal PE, or fatal PE. Clinically relevant bleeding defined as composite of major and clinically relevant nonmajor bleeding. Einstein Investigators. N Engl J Med. 2010;363:

21 EINSTEIN DVT: Primary Efficacy Outcome and Individual Components Rivaroxaban (n=1,731) Enoxaparin/VKA (n=1,718) No. % No. % First symptomatic recurrent VTE % % Recurrent DVT % % Recurrent DVT + PE 1 <0.1% 0 0 Nonfatal PE % % Fatal PE/unexplained death (PE cannot be ruled out) 4 0.3% 6 0.3% *HR (95% CI) P-value 0.68 ( ) < Hazard ratio Rivaroxaban superior Rivaroxaban noninferior Rivaroxaban inferior 2.0 ITT analysis; *hazard ratio based on Cox stratified proportional hazard model Einstein Investigators. N Engl J Med. 2010;363:

22 EINSTEIN DVT: Safety Rivaroxaban (n=1718) Enoxaparin/ VKA (n=1711) No. % No. % HR (95% CI) P-value First major or CRNM bleeding occurring during treatment % % 0.97 ( ) Major bleeding % % 0.65 ( ) Contributing to death 1 <0.1% 5 0.3% In a critical site 3 0.2% 3 0.2% Associated with a fall in hemoglobin of 2 g/dl, transfusion of 2 units, or both % % CRNM % % Total deaths through end of tx % % 0.67 ( ) CRNM bleed = Clinically Relevant Non-Major bleed; safety population Einstein Investigators. N Engl J Med. 2010;363: Warfarin time in therapeutic range: 57.7%

23 EINSTEIN PE: Study Design 30-day observation period Randomized, open-label, event-driven, noninferiority study (margin 2.0) Treatment period of 3, 6 or 12 months* Objectively confirmed PE ± DVT N=4833 R Rivaroxaban Rivaroxaban 15 mg bid 20 mg od Enoxaparin 1.0 mg/kg bid for 5 days, followed by VKA to start 48 h, target INR 2.5 (INR range 2 3) Day 1 Day 21 Primary efficacy endpoint: symptomatic recurrent VTE Primary safety endpoint: clinically relevant bleeding *Decision to treat for 3, 6, or 12 months made by investigator at time of randomization; 48-hours pretreatment with LMWH/heparin/fondaparinux permitted before study entry; maximum treatment duration: 6 months for last randomized patients. Symptomatic recurrent VTE defined as the composite of recurrent DVT, nonfatal PE, or fatal PE. Clinically relevant bleeding defined as composite of major and clinically relevant nonmajor bleeding. Einstein Investigators. N Engl J Med. 2010;363:

24 EINSTEIN PE: Primary Efficacy Outcome Analysis Rivaroxaban (n=2419) Enoxaparin/VKA (n=2413) No. (%) No. (%) First symptomatic recurrent VTE 50 (2.1) 44 (1.8) Recurrent DVT 18 (0.7) 17 (0.7) Recurrent DVT + PE 0 2 (<0.1) Nonfatal PE 22 (0.9) 19 (0.8) Fatal PE/unexplained death where PE cannot be ruled out 10 (0.4) 6 (0.2) HR Rivaroxaban superior Rivaroxaban noninferior P= for noninferiority Rivaroxaban inferior Einstein Investigators. N Engl J Med. 2012;366:

25 EINSTEIN PE: Safety Rivaroxaban (n=2412) Enoxaparin/ VKA (n=2405) No. % No. % HR (95% CI) P-value First major or CRNM bleeding occurring during treatment CRNM bleed = component of principal safety outcome; safety population Einstein Investigators. N Engl J Med. 2010;363: % % 0.90 ( ) Major bleeding % % 0.49 ( ) Contributing to death 2 <0.1% 3 0.1% In a critical site 7 0.3% % Associated with a fall in hemoglobin of 2 g/dl, transfusion of 2 units, or both % % CRNM % % Total deaths through end of tx % % 1.13 ( ) Warfarin time in therapeutic range: 62.7%

26 30-day observation period EINSTEIN EXT: Study Design Randomized, double-blind, placebo-controlled, superiority study Treatment period of 6 or 12 months* Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA N=1197 R Placebo Rivaroxaban 20 mg OD Primary efficacy endpoint: symptomatic recurrent VTE Primary safety endpoint: clinically relevant bleeding *Decision to treat for 6 or 12 months made by investigator at time of randomization; 48-hours pretreatment with LMWH/heparin/fondaparinux permitted before study entry. Symptomatic recurrent VTE defined as the composite of recurrent DVT, nonfatal PE, or fatal PE. defined as the composite of recurrent DVT, or unexplained death for which PE cannot be ruled out Clinically relevant bleeding defined as composite of major and clinically relevant nonmajor bleeding. Einstein Investigators. N Engl J Med. 2010;363:

27 EINSTEIN EXT: Primary Efficacy Outcome Symptomatic Nonfatal Recurrent VTE and PE-Related Death (Primary Efficacy Variable) Population: Subjects Valid for Intent to Treat. Placebo (n=594) Rivaroxaban (n=602) HR = 0.18; 95% CI= Number of subjects at risk Placebo n=594 n=582 n=570 n=554 n=521 n=467 n=444 n=164 n=138 n=133 n=110 n=93 n=85 Rivaroxaban n=662 n=590 n=583 n=573 n=552 n=503 n=482 n=171 n=138 n=132 n=114 n=92 n=81 Einstein Investigators. N Engl J Med. 2010;363:

28 EINSTEIN EXT: Safety First major or CRNM bleeding occurring during treatment Rivaroxaban (n=598) Major bleeding 4 0.7% 0 Contributing to death 0 0 In a critical site 0 0 Associated with a fall in hemoglobin of 2 g/dl, transfusion of 2 units, or both Placebo (n=590) HR (95% CI) % 7 1.2% 5.19 ( ) 4 0.7% 0 CRNM % 7 1.2% Total deaths through end of tx 1 0.2% 2 0.3% P-value <0.001 CRNM bleed = component of principal safety outcome; Safety population Einstein Investigators. N Engl J Med. 2010;363:

29 Rivaroxaban Summary Open label trials (extended was double blind) Only agent to be studied separately in DVT and PE PE study included ~24% with extensive PE affecting multiple lobes/>25% of vasculature Bleeding findings in the PE study encouraging Lytic patients excluded EINSTEIN-EXT proves what we already know Extended secondary prevention anticoagulation treatment in those at risk is better than placebo Only agent FDA approved for these indications Einstein Investigators. N Engl J Med. 2012;366:

30 Rivaroxaban Summary Open label trials (extended was double blind) Only agent to be studied separately in DVT and PE PE study included ~24% with extensive PE affecting multiple lobes/>25% of vasculature Bleeding findings in the PE study encouraging Lytic patients excluded EINSTEIN-EXT proves what we already know Extended secondary prevention anticoagulation treatment in those at risk is better than placebo Only agent FDA approved for these indications Einstein Investigators. N Engl J Med. 2012;366:

31 30-day observation period AMPLIFY: Study Design Randomized, double blind, noninferiority study Treatment period of 6 months* Objectively confirmed proximal DVT with or without symptomatic PE N=5400 R Apixaban Apixaban 10 mg bid 5 mg bid Enoxaparin 1.0 mg/kg bid for 5 days + VKA to start concomitantly, target INR 2 3 Day 1 Day 7 Primary efficacy endpoint: symptomatic recurrent VTE Primary safety endpoint: major bleeding *Patients with planned treatment durations less than 6 months excluded; 36-hours pretreatment with LMWH/heparin/fondaparinux permitted before study entry Symptomatic recurrent VTE defined as the composite of recurrent DVT, nonfatal PE, or fatal PE. Major bleeding: fatal, critical organ, fall in Hb 2 g/dl, or 2 units blood AMPLIFY Investigators. N Engl J Med. Epub ahead of print. Available at:

32 AMPLIFY: Primary Efficacy Outcome and Individual Components Apixaban (n=2,609) Enoxaparin/VKA (n=2,635) No. % No. % First symptomatic recurrent VTE % % Recurrent DVT only % % Nonfatal PE with/without DVT 27 1% % Fatal PE 1 <0.1% 2 0.1% Unexplained death where PE cannot be ruled out % % HR (95% CI) P-value 0.84 ( ) <0.001* Hazard ratio Apixaban superior Apixaban noninferior Apixaban inferior 1.8 ITT analysis; *for noninferiority, margin also did not allow absolute difference of more than 3.5% AMPLIFY Investigators. N Engl J Med. Epub ahead of print. Available at:

33 AMPLIFY: Safety Apixaban (n=2676) Enoxaparin/ VKA (n=2689) No. % No. % HR (95% CI) P-value Major bleeding % % 0.31 ( ) Fatal bleeding 1 <0.1% 2 0.1% In a critical site 4 0.1% % Associated with a fall in hemoglobin of 2 g/dl, transfusion of 2 units, or both % % CRNM % % 0.48 ( ) Major bleeding and CRNM % % 0.44 ( ) <0.001 <0.001 CRNM bleed = Clinically Relevant Non-Major bleed; safety population AMPLIFY Investigators. N Engl J Med. Epub ahead of print. Available at: Warfarin time in therapeutic range: 61%

34 30-day observation period AMPLIFY EXT: Study Design Randomized, double-blind, placebo-controlled, superiority study Treatment period of 12 months Confirmed symptomatic DVT or PE completing 6 or 12 months of apixaban or VKA N=2486 R Apixaban 5 mg bid Apixaban 2.5 mg bid Placebo Primary efficacy endpoint: symptomatic recurrent VTE Primary safety endpoint: major bleeding Symptomatic recurrent VTE or death from any cause Major bleeding: fatal, critical organ, fall in Hb 2 g/dl, or 2 units blood N Engl J Med 2013;368:

35 AMPLIFY EXT: Efficacy/Safety N Engl J Med 2013;368:

36 Apixaban Summary Double blind trials Data on bleeding is impressive Lytic patients excluded Consistent with a. fib. trials Data on 1786 patients with acute PE Efficacy consistent with overall trial PE patients included ~37% with extensive PE AMPLIFY-EXT proves what we already know Extended secondary prevention anticoagulation treatment in those at risk is better than placebo Will twice daily dosing hold this agent back? AMPLIFY Investigators. N Engl J Med. Epub ahead of print. Available at:

37 Endoxaban - Hokusai-VTE Randomized, multicenter, double-blind, active-controlled, non-inferiority design of acute VTE treatment 4118 patients Endoxaban 60 mg daily (30 mg daily if estimate CrCl < mls/min or body weight < 60 kg) vs warfarin titrated to INR of x 3-12 mo after initial parenteral anticoagulation median 9 days 938 had PE with RV strain Outcomes 12-month incidence of recurrent symptomatic venous thromboembolism and related deaths Major bleeding (fatal, critical organ, fall in Hb 2 g/dl, or 2 units blood) and clinically relevant nonmajor bleeding N Engl J Med 2013;369:

38 Endoxaban - Hokusai-VTE Recurrent VTE or related death Endoxaban noninferior to warfarin (3.2% vs 3.5%) (p<0.001 for noninferiority) Warfarin time in therapeutic range: 63.5% Endoxaban similar to warfarin for major bleeding (1.4% vs 1.6%) and superior for major + clinically relevant nonmajor bleeding (8.5% vs 10.3% (p=0.004) N Engl J Med 2013;369:

39 Issues to Consider Reversibility Very little known about apixaban, which is slightly less than we know about rivaroxaban and dabigatran Price/affordability/access You cannot prescribe without considering this first Renal function Must be assessed Dosing changes Who writes for what? How does patient know what to do? Patient education Bleeding, dosing, and compliance are key topics

40 Case ER is a 50 kg, yo female who presents with new pain and swelling in her right leg that turns out to be due a DVT that extends from her calf to her popliteal vein PMH: CAD with distant history of drug eluding stent 2 years ago, systolic/diastolic heart failure EF of 35% (recent hospitalization), hypertension, osteoporosis Home medications include aspirin, lisinopril, metoprolol, clopidogrel, digoxin, and furosemide SrCr is 1.2 and this is typical for her

41 Based on what you know, which of the following would be optimal initial VTE treatment? 1. Heparin/warfarin 2. Dabigatran etexilate alone 3. Rivaroxaban alone 4. Apixaban alone 25% 25% 25% 25%

42 Any medications you should likely stop? 1. No 2. Yes, aspirin 3. Yes, clopidogrel 4. Yes, aspirin and clopidogrel 25% 25% 25% 25%

43 You pick rivaroxaban, how would you dose it? mg bid for 21 days, followed by 20 mg daily (PI VTE dose) mg daily (PI a. fib. dosing for this patient) mg bid for 21 days, followed by 15 mg daily (what you made up) 33% 33% 33% 1 2 3

44 Conclusion VTE remains a significant cause of morbidity and mortality in the United States Warfarin is still an excellent, effective option for many, but requires appropriate monitoring Appropriate parenteral overlap can be done at home, and don t forget about fondaparinux! Don t forget about home INR testing! The novel oral anticoagulants, particularly rivaroxaban and apixaban, appear to have encouraging data in this disease state Remember, using any anticoagulant is always going to pose risk to a patient and different agents will have advantages/disadvantages at different times; it will never be easy nor black and white

45 Questions and Discussion Courtesy Steven M. Riddle, Pharm. D.