Home treatment of VTE

Home treatment of VTE Prof. Adel El-Etriby Ain-Shams University Venous Thromboembolism (VTE): The DVT and PE Continuum Migration Embolus Thrombus VTE refers to a continuum of disease that begins with DVT and can progress to PE 1 DVT is a condition in which a thrombus typically forms in one or more of the deep veins of the calf or thigh 1,2 PE occurs when all or part of a thrombus originating in the deep veins detaches from the vessel wall and travels in the venous system as an embolus, ultimately obstructing pulmonary arteries 1,2 1. Kroegel C, Reissig A. Respiration. 2003;70(1):7-30. 2. Guyton AC, Hall JE. In: Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Inc.; 2006. 1

Burden of VTE: Put in Perspective VTE kills more people each year than breast cancer, HIV, and traffic accidents combined 1,2 Estimates of >100,000 deaths each year are attributable to DVT/PE 1,3,4 Up to 900,000 people are affected by DVT/PE annually 3 ~550,000 hospitalizations annually in the United States for DVT and/or PE 5 Healthcare costs associated with DVT/PE in 2011 are estimated to be up to $10 billion 1 CDC Reported Causes of Annual Deaths in the United States 120,000 100,000 CDC = Centers for Disease Control *An estimated 100,000 deaths each year are attributable to DVT/PE. 1. Centers for Disease Control and Prevention. http://www.cdc.gov/ncbddd/aboutus/documents/ncbddd_strategicplan_2-10-11.pdf. Accessed September 11, 2012. 2. Centers for Disease Control and Prevention. http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_60_03.pdf. Accessed October 3, 2012. 3. Heit JA. Arterioscler Thromb Vasc Biol. 2008;28:370-372. 4. Heit J et al. Blood. 2005;106:267A. 5. Centers for Disease Control and Prevention. MMWR. 2012;61(22):401-404. 3 80,000 60,000 40,000 20,000 0 41,078 Breast Cancer 2 9406 36,216 100,000* 2 1 HIV Traffic VTE Accidents 2 ACCP Recommended Treatment Approach of VTE 2012 Parenteral anticoagulant and VKA (INR 2.0-3.0) Bridging therapy Initial treatment VKA (INR 2.0-3.0) or parenteral anticoagulation Long-term treatment With these guidelines, Home treatment was not a real option VKA (INR 2.0-3.0) or parenteral anticoagulation Extended treatment 0 to ~7 days ~7 days to ~3 months ~3 months to indefinite ACCP recommends early initiation of VKA and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR i2.0 for at least 24 hours Reprinted with permission from Kearon C et al. Chest. 2012;141(suppl 2):e419Se494s. ACCP = American College of Chest Physicians; INR = international normalized ratio; VKA = vitamin K antagonist. Kearon C et al. Chest. 2012;141(suppl 2):e419S-e494s. 2

The evolution of anticoagulant drugs 1930s Heparin 1940s Vitamin K antagonists 1980s Low-molecularweight heparin 1990s Direct thrombin inhibitors 2002 Indirect Xa inhibitor 2004 Oral direct thrombin inhibitors 2008 Oral direct Xa inhibitor Xa ATIII + Xa + IIa (1:1 ratio) II, VII, IX, X (Protein C,S) ATIII + Xa + IIa (Xa > IIa) IIa ATIII + Xa IIa ORAL TTP889 New anticoagulants TF/VIIa X IX PARENTERAL TFPI (tifacogin) Apixaban Darexaban Edoxaban Betrixaban IXa VIIIa Va Xa II AT APC (drotrecogin alfa) stm (ART-123) Fondaparinux Idrabiotaparinux DX-9065a Otamixaban Dabigatran IIa Fibrinogen Fibrin Adapted from Weitz & Bates, J Thromb Haemost 2005 3

New Anticoagulants Many new anticoagulant drugs are in development New oral anticoagulants have similar or greater efficacy and safety to VKAs, but are easier to administer The new oral anticoagulants offer important advantages for patients (convenience, efficacy, safety) Safe management requires knowledge of drug pharmacology New Oral Anticoagulants All are effective Broad approval worldwide Factor Xa vs Thrombin Inhibitors Widely adopted 4

Novel Oral Anticoagulants Pharmacological Properties Characteristic Dabigatran Apixaban Target Factor Xa Factor IIa Factor Xa Prodrug No Yes No Dosing OD BID BID Bioavailability, % 80-100%* 6.5% 50% Half-life 5-13h 12-14 h 8-15 h Renal clearance (unchanged bioavailable drug) ~33% 85% 27% Cmax 2-4 h 1-2 h 3-4 h Drug interactions Strong inhibitors of CYP3A4 and P-gp P-gp inhibitors Strong inhibitors CYP3A4 and P-gp * When the 15mg and 20mg dose is taken with food ~40-50% of absorbed drug (i.e. 50% of drug is not absorbed and ~27% of the oral administered dose is cleared renally, therefore and 40-50% of bioavailable portion is cleared renally.) 1. Xarelto PM, July 18, 2012 ; 2. Pradaxa PM November 12, 2012; 3. Eliquis PM November 27, 2012; 4. Goette Trends Cardiovasc Med. 2013 [Epub ahead of print] NOACs - Approved indications Dabigatran Apixaban Edoxaban VTE prevention Orthopaedics Stroke Reduction in AF Japan Treatment of DVT after LMWH Treatment of PE after LMWH Prevention of recurrent VTE ACS * Dabigatran is recently approved after acute phase in DVT / PE but not yet in Egyptian Market * Dabigatran approved in SPAF as 150mg BID Reduced dose of 110 BID * Apixaban is recently approved in DVT / PE Treatment but not yet in the Market 5

Risk-adjusted PE management algorithm Yes Diagnostic algorithm as for suspected high-risk PE Clinical suspicion of PE Shock or hypotension? PESI class III VI/sPESI 1 No Diagnostic algorithm as for suspected not high-risk PE PE confirmed Assess clinical risk (PESI or spesi*) PE confirmed High Both + Intermediate risk RV function and laboratory testing Intermediate-high Intermediate-low One positive/both PESI class I II /spesi=0 Low Primary reperfusion Konstantinides et al, 2014 Anticoagulation; monitoring; consider rescue reperfusion Hospitalization; anticoagulation Consider early discharge and home treatment, if feasible *spesi: not validated in a prospective home treatment trial; 2014 ESC update does not give preference to one score over another Early discharge and home treatment of PE Recommendations for early discharge and home treatment Patients with acute low-risk PE should be considered for early discharge and continuation of treatment at home if proper outpatient care and anticoagulant treatment can be provided Class of recommendation IIa Level of evidence B Konstantinides et al, 2014 6

PESI / s PESI PESI / s PESI PESI, Points assignments correspond with the following risk classes: 65: class I, very low risk 66 85: class II, low risk 86 105: class III, intermediate risk 106 125: class IV, high risk > 125: class V, very high risk In Simplified PESI s PESI, Low risk = 0 7

Home treatment of VTE Which Patient? Risk-adjusted PE management algorithm Yes Diagnostic algorithm as for suspected high-risk PE Clinical suspicion of PE Shock or hypotension? PESI class III VI/sPESI 1 No Diagnostic algorithm as for suspected not high-risk PE PE confirmed Assess clinical risk (PESI or spesi*) PE confirmed High Both + Intermediate risk RV function and laboratory testing Intermediate-high Intermediate-low One positive/both PESI class I II /spesi=0 Low Primary reperfusion Konstantinides et al, 2014 Anticoagulation; monitoring; consider rescue reperfusion Hospitalization; anticoagulation Consider early discharge and home treatment, if feasible *spesi: not validated in a prospective home treatment trial; 2014 ESC update does not give preference to one score over another 8

PESI / s PESI PESI, Points assignments correspond with the following risk classes: 65: class I, very low risk 66 85: class II, low risk 86 105: class III, intermediate risk 106 125: class IV, high risk > 125: class V, very high risk In Simplified PESI s PESI, Low risk = 0 Novel OACs: a treatment choice for low- to intermediate-risk PE patients (acute treatment) Recommendations for novel OACs as alternatives to VKA/parenteral anticoagulation Class of recommendation Level of evidence (15 mg bid for 3 weeks, followed by 20 mg od) I B Apixaban (10 mg bid for 7 days, followed by 5 mg bid) I B Dabigatran (150 mg bid, or 110 mg bid for patients 80 years of age or those under concomitant verapamil treatment) following acute-phase parenteral anticoagulation I B Edoxaban* following acute-phase parenteral anticoagulation I B, apixaban, dabigatran and edoxaban are not recommended in patients with severe renal impairment # III A *Edoxaban is in EU regulatory review for VTE treatment; # CrCl <30 ml/min for rivaroxaban, dabigatran and edoxaban, and <25 ml/min for apixaban Konstantinides et al, 2014 9

, dabigatran and apixaban should be considered for extended anticoagulation Recommendations for extended anticoagulation Novel OACs: considered an alternative to VKA (except in patients with severe renal impairment*) : 20 mg od Dabigatran: 150 mg bid (or 110 mg bid for patients >80 years old /those taking verapamil) Apixaban: 2.5 mg bid For patients refusing to take or unable to tolerate OACs, aspirin may be considered Class of recommendation Level of evidence IIa B # IIb B *CrCl <30 ml/min for rivaroxaban and dabigatran, and <25 ml/min for apixaban; # B refers to the level of evidence available for each drug separately Konstantinides et al, 2014 Duration of treatment recommendations Recommendations for duration of oral anticoagulation PE secondary to a transient (reversible) risk factor: 3 months Class of recommendation I Level of evidence B Unprovoked PE: 3 months I A First episode of unprovoked PE and low bleeding risk: consider extended treatment (>3 months) IIa B Second episode of unprovoked PE: indefinite duration I B Risk benefit of continuing anticoagulation should be reassessed at regular intervals I C Currently, no assessment score for risk of VTE recurrence: persistent risk factors (as opposed to major, temporary) may affect decision on duration of anticoagulation after index PE Konstantinides et al, 2014 10

Home treatment of VTE Which Drug? Characteristic of Optimal Drug for Home treatment of VTE Needs No bridging Single daily dose Strongest Level of Evidence Fit for both Acute / Post phase anticoagulation. 11

Dosing regimens of novel OACs for treatment of VTE and prevention of recurrence Single oral drug Switching Bridging 4 15 mg bid (21 days), followed by 20 mg od 1 * Apixaban 10 mg bid (7 days), followed by 5 mg bid (day 8 to month 6), followed by 2.5 mg bid (>6 months) 2 Parenteral agent ( 5 days) Parenteral agent ( 5 days) Dabigatran 150 mg bid 3# VKA (INR adjusted, day 1 onwards) Increasing complexity *In patients with moderate (CrCl 30 49 ml/min) or severe (CrCl 15 29 ml/min) renal impairment, 15 mg od should be considered if patient s assessed risk for bleeding outweighs risk for recurrent DVT/PE; # 110 mg bid for patients 80 years or patients who receive concomitant verapamil 1. Xarelto SPC, 2014; 2. Eliquis SPC, 2014; 3. Pradaxa SPC, 2014; 4. Coumadin (warfarin sodium) Prescribing Information, 2011 EINSTEIN Program 12

30-day observation period 30-day observation period 3/16/2016 EINSTEIN: The Largest DVT and PE Phase 3 Clinical Trial Program Ever Conducted 9477 Patients Randomized DVT Treatment 1 PE Treatment 2 Continued Treatment 1 3449 patients with confirmed DVT (without symptomatic PE) 4832 patients with confirmed PE (±DVT) 1196 patients with confirmed DVT or PE who had already completed 6 to 12 months of anticoagulation* All 3 studies were published in the New England Journal of Medicine *Patients not previously enrolled in EINSTEIN DVT or PE could have received up to 14 months of VKA treatment. 1. EINSTEIN Investigators. N Engl J Med. 2010;363(26):2499-2510. 2. EINSTEIN PE Investigators. N Engl J Med. 2012;366(14):1287-1297. EINSTEIN Phase III: Study Designs EINSTEIN DVT/PE: Pre-defined treatment period of 3, 6, or 12 months Objectively confirmed DVT without symptomatic PE Objectively confirmed PE with or without symptomatic DVT Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA N=3,465 R N=3,300 Day 1 N=1,147 R Day 1 Day 21 15 mg bid Enoxaparin 1.0 mg/kg bid for at least 5 days, plus VKA to start <48 hrs, target INR 2.5 (INR range 2 3) EINSTEIN EXT: Treatment period of 6 or 12 months 20 mg od Placebo 20 mg od EINSTEIN DVT, PE, Extension Evaluation Study Information available at: http://clinicaltrials.gov. Accessed 15 November 2009 26 13

Cumulative Event Rate (%) 3/16/2016 EINSTEIN DVT: Event Rates of Symptomatic Recurrent VTE 4.0 Enoxaparin/VKA (n=1718) 3.5 3.0 2.5 2.0 1.5 XARELTO (n=1731) 1.0 0.5 HR=0.68 (95% CI, 0.44-1.04) 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Days from Randomization No. at risk XARELTO 1731 1668 1648 1635 1424 1412 1369 400 369 364 345 309 266 Enoxaparin/VKA 1718 1616 1581 1565 1368 1358 1301 380 362 342 325 297 264 ITT population. 27 Primary efficacy outcome analysis (n=1,731) Enoxaparin/VKA (n=1,718) n (%) n (%) First symptomatic recurrent VTE 36 (2.1) 51 (3.0) Recurrent DVT 14 (0.8) 28 (1.6) Recurrent DVT + PE 1 (<0.1) 0 (0) Non-fatal PE 20 (1.2) 18 (1.0) Fatal PE/unexplained death where PE cannot be ruled out 0.44 0.68 1.04 4 (0.2) 6 (0.3) 0 1.00 Hazard ratio 2.00 superior p=0.076 for superiority (two-sided) ITT population non-inferior p<0.0001 for non-inferiority (one-sided) inferior 14

30-day poststudy observation period 3/16/2016 Principal safety outcome First major or clinically relevant non-major bleeding (n=1,718) Enox/VKA (n=1,711) HR (95% CI) n (%) n (%) p value 139 (8.1) 138 (8.1) 0.97 (0.76 1.22) p=0.77 Major bleeding 14 (0.8) 20 (1.2) Contributing to death 1 (<0.1) 5 (0.3) In a critical site 3 (0.2) 3 (0.2) Associated with fall in Hb 2 g/dl and/or transfusion of 2 units 10 (0.6) 12 (0.7) Clinically relevant non-major bleeding 129 (7.5) 122 (7.1) EINSTEIN PE: Study Design Treatment period of 3, 6, or 12 months* Day 1 Day 21 XARELTO (rivaroxaban) End of treatment Objectively confirmed PE with or without DVT N=4833 R 15 mg twice daily Enoxaparin, followed by VKA 20 mg once daily 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. 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 PE Investigators. N Engl J Med. 2012;366(14):1287-1297. 15

EINSTEIN PE: Primary Efficacy Outcome Analysis (N=2419) Enoxaparin/VKA (N=2413) n (%) n (%) 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) Non-fatal PE 22 (0.9) 19 (0.8) Fatal PE/unexplained death where PE cannot be ruled out 10 (0.4) 6 (0.2) 0.75 1.12 1.69 p<0.0026 for non-inferiority (one-sided) p=0.57 for superiority (two-sided) 0 1.00 2.00 ITT population superior The EINSTEIN PE Investigators. N Engl J Med 2012; 366:1287-1297 non-inferior inferior 32 16

Patients (%) 3/16/2016 XARELTO (rivaroxaban): Low Rates of Major Bleeding Events Versus Standard of Care (Enoxaparin+VKA) XARELTO (n=4130) Enoxaparin+VKA (n=4116) *Prespecified analysis. Take Home Message VTE is a main Killing disease, kills more people each year than breast cancer, HIV, and traffic accidents combined More than 1/3 of VTE patients are either home treated or not properly managed. Until 2014 LMWH / VKA was the only option in Management in guidelines. NOAC offer the patient a more predictable AC effect with No need for repeated Monitoring 17

Thank You 18