Winship Cancer Institute of Emory University New Anticoagulants: When and Why Should I Use Them? Christine L. Kempton, MD, MSc Associate Professor of Pediatrics and Hematology and Medical Oncology Hemophilia of Georgia, Inc, Directors Chair in Hemostasis Disclosures Nothing relevant to disclose. 1
Venous Thromboembolism (VTE) Overall annual incidence 1/1000 persons Increases with age: 5/1000 persons annually in people over 80 years of age Location Pulmonary embolism (PE) 2/3 Deep venous thrombosis (DVT) 2/3 Mortality within one month of diagnosis: DVT 6% PE 12% Long-term complications DVT- post-thrombotic syndrome occurs in 20-50% PE- chronic pulmonary hypertension occurs in 2-4% Yeh et al. Blood 2014 pre-published Old Oral Anticoagulants: Warfarin First approved for medical use in 1954 Inhibits vitamin K reductase (VKOR) Prevents carboxylation of clotting factors II, VII, IX, and X Partially decarboxylated proteins have less clotting activity Metabolised by cytochrome P450 (CYP) particularly CYP2C9 Limitations: Food-drug interactions Drug-drug interactions Delayed onset of action Variability of response monitoring Safety and efficacy dependent on therapeutic INR Hirsh et al. Circulation 2003; 107: 1692-1711 2
Novel Oral Anticoagulants (NOAC) Factor XIa Factor IX Factor VIIIa Factor IXa Factor VIIa Tissue Factor Factor X Factor Va Factor Xa Rivaroxaban Apixiban Edoxaban Prothrombin Thrombin Dabigitran Fibrinogen Fibrin 4 Dabigitran Rivaroxaban Apixiban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa Pro-drug Yes No No No Elimination 14-17 hrs 7-11 hrs 8-14 hrs 5-11 hrs half-life Bioavailability 3-7 80 66 45 % Protein Binding % 35 >90 ~85 40-59 Route of elimination Urine ~80%, feces ~20% Urine ~66%, feces ~30% Urine ~25%, feces ~70% Urine ~35% Feces ~60% Dosing Twice/day Once/day* Twice/day Once/day Substrate of CYP enzymes Substrate of P-glycoprotein No Yes (CYP3A4, CYP2J2) Yes (CYP3A4) Yes Yes Yes Yes Yes (CYP3A4) 3
Indications for Use Nonvalvular A. Fib VTE prevention Initial VTE Treatment Dabigitran + - + (after 5-10 days of parenteral AC) Rivaroxaban + + + + Apixiban + + * * VTE Secondary Prevention + Edoxaban * - *(after 5-10 days of parenteral AC) * *FDA application pending Treatment of Acute VTE: Efficacy Dabigitran- RE-COVER Study 1 ; n=1274 Rivaroxaban-EINSTEIN Study 2 ; n=3449 Rivaroxaban-EINSTEIN PE Study 3 ; n=4832 Apixiban-AMPLIFY Study 4 ; n=5244 Edoxaban-Hokusai-VTE Study 5 ; n=4921 VTE Recurrence NOAC Warfarin HR (95% CI) 2.4% 2.1% 1.10 (0.65-1.84) 2.1% 3.0% 0.68 (0.44-1.04) 2.1% 1.8% 1.12 (0.75-1.68) 2.3% 2.7% 0.84 (0.60-1.18) 3.2% 3.5% 0.89 (0.70-1.13) 1. Schulman et al. NEJM. 2009;361:2342-52 4. Agnelli et al. NEJM 2013; 1369:799-808 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97 4
Treatment of Acute VTE: Safety Major Bleeding Clinically Relevant Non-Major Bleeding Dabigitran- RE-COVER Study 1 ; n=1274 Rivaroxaban-EINSTEIN Study 2 ; n=3449 Rivaroxaban-EINSTEIN PE Study 3 ; n=4832 Apixiban-AMPLIFY study 4 ; n=5244 Edoxaban-Hokusai-VTE study 5 ; n=4921 *p <0.001 NOAC Warfarin HR (95% CI) 1.6% 1.9% 0.82 (0.45-1.48) 1.8% 1.2% 0.65 (0.33-1.30) 1.1% 2.2% 0.49 (0.31-0.79) 0.6% 1.8% 0.31* (0.17-0.55) 1.4% 1.6% 0.84 (0.59-1.21) NOAC Warfarin HR (95% CI) 4.0% 7.8% - 7.3% 7.0% - 9.5% 9.8% - 3.8% 8.0% 0.48 (0.38-0.60) 8.1% 8.6% - 1. Schulman et al. NEJM. 2009;361:2342-52 4. Agnelli et al. NEJM 2013; 1369:799-808 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 5. Houkusai VTE Investigators. NEJM 2013;369:1406-15 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97 Dabigitran Apixiban Rivaroxaban Dabigitran Apixiban Rivaroxaban Dentali F, Circulation 2012;126:2381-2391 5
Secondary Prevention of VTE: Efficacy Dabigitran-RE-MEDY & RE-SONATE 1 ; n=2856 Rivaroxaban-EINSTEIN Study 2 n=1196 VTE Recurrence HR (95% CI) NOAC Placebo 1.8% 5.6%* 0.08 (0.02-0.25) 1.3% 7.1% 0.18 (0.09-0.39) Apixiban-AMPLIFY EXT 3 ; 1.7%^ 8.8% 0.19 (0.11-0.33) 2.5mg n=2482 *Warfarin treated group1.3%, HR 1.44 (95% CI 0.78-2.64) ^Apixiban 2.5 mg and 5.0 mg similar 1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808 Secondary Prevention of VTE: Safety Major Bleeding Clinically Relevant Non-Major Bleeding Dabigitran-RE-MEDY & RE-SONATE 1 ; n=2856 Rivaroxaban- EINSTEIN Study 2 n=1196 Apixiban-AMPLIFY EXT 3 ; 2.5mg n=2482 NOAC Place bo HR (95% CI) NOAC Placebo HR (95% CI) 0.9% 0-5.0% 1.8% 2.92 (1.52-5.60) 0.7% 0-5.4% 1.2% - 0.2% 0.5% 0.49 (0.09-2.64) ^Apixiban 2.5 mg and 5.0 mg similar 3.0% 2.3% 1.29** (0.72-2.33) 1. Schulman et al. 2013;368:709-18 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808 6
Agnelli et al. NEJM 2013; 1369:799-808 Patient Selection Use Avoided: PE with hemodynamic instability Significant risk of bleeding Recent trauma or surgery CrCl < 30 ml/min Hepatic dysfunction (Child- Pugh B) Pregnancy Active cancer High-risk settings such as HIT or antiphospholipid syndrome Concurrent use of : Strong inhibitors/inducers of CYP3A4 and P-glycoprotein Use with Caution: Advanced age > 75 years Extremes of weight < 60 or > 150 kg 7
Patients Currently on Warfarin INR Control Good Poor Lifestyle burden Adherence Low High Good Poor Limited benefit May benefit May benefit No benefit NOAC Selection Preference for once daily vs. twice daily dosing: Favors rivaroxaban and edoxaban Rivaroxaban should be taken with food Ability to use an all oral regimen at diagnosis: Favors rivaroxaban and apixiban Low renal clearance- Avoid dabigitran and favor apixiban History of coronary artery disease Avoid dabigitran Upper GI complaints - Avoid dabigitran Recent GI bleed- Favors apixiban Clinical setting is extended treatment for secondary prevention Favors apixiban CYP3A4 interaction-favors dabigitran 8
Monitoring Acute Treatment: Early follow-up if discharged from the ED Follow-up at times of transition (apixiban: 7 days, rivaroxaban: 21 days) Extended Treatment Follow-up to assess adherence, efficacy, side effects, stability of renal/liver function Every 3-12 months, depending on renal function Laboratory monitoring Approved kits for rivaroxaban (anti-xa assay) and dabigitran (anti-iia assay) Not recommended for routine monitoring Potential uses: Emergent surgery or other invasive procedure Failure of efficacy or safety Anticipated alterations of pharmacokinetics or pharmacodynamics Practical Issues Switching from warfarin to NOAC: Stop warfarin and start NOAC when INR < 2.0 Likely after 2-3 missed doses depending on the INR at cessation of warfarin Encourage use of Medic Alert that identifies NOAC use Discuss importance of adherence: Use of pill box essential Take at similar time each day Missed dose: < 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose, then take dose > 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose skip the dose Do not double up 9
Bleeding Management No reversal agent currently available, but new agents are in development Normalization of hemostasis General measures Factor Xa inhibitors Direct Thrombin Inhibitors 12-24h CrCl > 80 ml/min: 12-24h CrCl 50-80 ml/min: 24-36h CrCl 30-50 ml/min: 36-48h CrCl < 30 ml/min: > 48h Hold medication, local hemostatic measures, transfusion therapy as need for anemia and thrombocytopenia, tranexamic acid Increase clearance -- Hemodialysis Promote hemostasis Prothrombin complex concentrates (PCC) (25 U/kg), activated PCC (apcc) (50 U/kg), or rfviia (90 mcg/kg)-no clinical data Heidbuchel et al. Eur Heart J 2014 pre-published Peri-operative Management Pre-operative: Low vs. high surgical bleeding risk Dabigitran Apixiban Edoxaban Rivaroxaban Low High Low High Low High Low High CrCl > 80 ml/min > 24h > 48h > 24 h > 48h ND ND > 24 h > 48h CrCl 50-80 ml/min > 36h > 72h > 24 h > 48h ND ND > 24 h > 48h CrCl 30-50 ml/min > 72h > 120h > 24 h > 48h ND ND > 24 h > 48h ND=no data Post-operative Restart NOAC once full anticoagulation is allowed likely 48-72 hours after major surgery May need prophylactic anticoagulation with LWMH in the immediate postoperative period until able to resume full dose anticoagulation Heidbuchel et al. Eur Heart J 2014 pre-published Prescribing information 10
Summary New oral anticoagulants offer a real alternative to warfarin therapy for a large number of patients. are efficacious for: Treatment of acute VTE: DVT and hemodynamically stable PE. Secondary prevention of recurrent VTE. are as safe or safer than warfarin. are more convenient and less burdensome than warfarin. Patients not appropriate for NOACs include those with: Severe renal or liver impairment Cancer Extremes of weight Pregnant Significantly advanced age Strong CYP3A4 and P-gp inhibitors 11