Update on Anticoagulants Jay Gaddy, MD, PhD Indiana Hemophilia & Thrombosis Center Indianapolis, Indiana None Disclosures Overview General discussion of anticoagulants New oral anticoagulants (NOACs) and their targets Oral direct thrombin inhibitor - Oral factor Xa Inhibitors, Apixaban Reversal of anticoagulants The Ideal Oral Anticoagulant Good bioavailability No food or drug interactions Rapid onset of action Wide therapeutic window Predictable anticoagulant response Available antidote No unexpected toxicities Reasonable cost Mechanism to ensure compliance with therapy Bauer, KA. Hematology, 2006:1;250 s Therapeutic Window in A-fib When warfarin therapy is started, its anticoagulant effects may not be apparent for several days. The duration of action of a single dose is 2 5 days. The therapeutic effect of warfarin exists within a narrow therapeutic window as dictated by the INR. Considerable inter- and intra-individual dose variability may be affected by a wide range of physiologic (liver and thyroid function), genetic, and environmental (eg, diet, other drugs) factors. Regular monitoring is required to avoid excessive or insufficient anticoagulation. Turpie, A. G.G. Eur Heart J 2008 29:155-165 1
Cumulative Incidence Rates of Bleeding in VTE Patients on Anticoagulation in the Real World Limitations of Therapy Limitations Slow onset of actions Genetic variation in metabolism Multiple food & drug interactions Narrow therapeutic index Consequence Overlap with parenteral anticoagulant Variable dose requirement Frequent INR monitoring Frequent INR monitoring Spencer, F. A. et al. Arch Intern Med 2008;168:425-430. Most Common Currently Available Anticoagulants Sub-class Thrombin inhibitors Xa-inhibitor Vit K antagonists Drugs UFH Bivalirudin, Lepirudin**, Argatroban UFH LMWH Fondaparinux Apixaban (Edoxaban) Generic and Brand Names Pradaxa Xarelto Apixaban Eliquis Use of Newer Oral Anticoagulants Advantages: Fixed oral dosing No need to monitor anticoagulant effect with labs Fewer drug interactions (but there still are some!) No dietary restrictions Use of Newer Oral Anticoagulants Disadvantages: Lack of validated tests of anticoagulant effect No clinically proven antidotes More difficult to assess patient compliance Lack of data on long-term adverse events Absence of head-to-head comparisons between novel oral anticoagulants 2
Targeting Specific Coagulation Factors Newer oral anticoagulants target specific points in the coagulation cascade: Factor Xa inhibitors (eg, rivaroxaban, apixaban) target factor Xa, preventing the conversion of prothrombin to thrombin. Direct thrombin inhibitors (eg, dabigatran, ximelagatran) target thrombin (factor IIa), blocking the conversion of fibrinogen to fibrin. The goal of novel oral anticoagulants is to offer more specific targeting and to afford more predictable responses than current anticoagulant therapies offer. Targets of New Oral Anticoagulants Comparison of New Oral Agents Feature etexilate Apixaban Target Prodrug Dosing Bioavailability (%) Time to onset (hrs) Coagulation monitoring Half-life (h) Renal clearance (%) Interactions USA approved indications Thrombin Factor Xa Factor Xa Yes No No Fixed, 1-2x daily Fixed, once daily Fixed, twice daily 6 80 50 2 2-4 1-3 No No No 12 17 9-13 8-15 80 65 25 P-gp inhibitors* Combined P-gp and Combined P-gp and H2 blockers, PPIs CYP3A4 inhibitors CYP3A4 inhibitors VTE prevention and A-fib A-fib treatment, A-fib Weitz, Thrombosis and Haemostasis, 1/2010 Phase III Randomized Controlled Trials for VTE Prevention Drug Hip Arthroplasty Knee Arthroplasty Medical Surgical RE-NOVATE RE-MODEL...... RE-NOVATEII RE-MOBILIZE RECORD1 RECORD3 MAGELLAN... RECORD2 RECORD4 Apixaban ADVANCE3 ADVANCE1 ADOPT... Phase III Randomized Controlled Trials non-vte prophylaxis Anticoagulant VTE Treatment ACS AF Idrabiotaparinux CASSIOPEA... BOREALIS-AF RE-COVER I RE-LY RE-COVER II RELY-ABLE RE-MEDY RE-SONATE EINSTEIN-DVT ATLAS JapaneseAF EINSTEIN-PE ROCKET-AF EINSTEIN-Extension Apixaban Apixaban VTE APPRAISE2 AVEOES ADVANCE2 Apixaban VTE extension ARISTOTLE Edoxaban Hokusai-DVT... ENGAGEAF TIMI48 Eikelboom et al Circulation 2010 (121(1)) Eikelboom et al Circulation 2010 (121(1)) 3
FDA Approvals CVA and systemic embolism prevention in non-valvular A-fib CVA and systemic embolism prevention in non-valvular A-fib VTE prevention in TKR and THR Treatment of VTE/PE etexilate Oral prodrug, converted to Binds clot-bound and free thrombin with high affinity and specificity Bioavailability: 6.5% Renal excretion: 80% Half-life: 12 17 hours No interaction with food Apixaban CVA and systemic embolism prevention in non-valvular A-fib Pradaxa (dabigatran etexilate). Summary of product characteristics. Apr 2008 Pradaxa (dabigatran etexilate). Summary of product characteristics. Apr 2008 etexilate No participation with CYP450 Predictable anticoagulant effect no need for monitoring No liver toxicity based on available clinical data Dyspepsia is a side effect PPIs and H2 blockers may affect absorption Potential medication interactions with P-gp affecting drugs Amiodarone, Dronedarone, Quinidine, Verapamil, Ketoconazole, Rifampin, St Johns Wort Other considerations Hygroscopic Capsules should not be removed from original container except for immediate use Capsules only approved for 60 days after opening bottle Capsule should not be placed in pill boxes Cannot crush or open pills for use in feeding tubes Pradaxa (dabigatran etexilate). Summary of product characteristics. Apr 2008 : FDA Approval RE-LY (stroke prevention in patients with A-fib) 18,113 patients 110 and 150 mg bid compared with warfarin Treatment duration up to 3 years, median follow-up of 2 yrs 110 mg associated with rates of stroke or systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke or systemic embolism but similar rates of major hemorrhage Major bleeding RE-LY: Major Bleeding & ICH 110 mg 150 mg Rate/ year Rate/ year Rate/ year 2.7 % 3.1 % 3.4 % All ICH 0.2 % 0.3 % 0.7 % 110 mg vs warfarin (95% CI) 0.80 (0.69-0.93) 0.31 (0.20-0.47) P.003 <.001 150 mg vs warfarin (95% CI) 0.93 (0.81-1.07) 0.40 (0.27-0.60) P.31 <.001 150 mg vs 110 mg (95% CI) 1.16 (1.00-1.34) 1.32 (0.82-2.17) P.052.28 Connolly, New England Jl Med, 2009 Connolly SJ. et al. N Engl J Med. 2009 Sep 17;361(12):1139-51. 4
Inhibition of Factor Xa activity (%) RE-LY: Sites of Major Bleeding RE-LY: GI Major Bleeding & MI 110mg Annual rate 150mg Annual rate Annual rate 110mg vs 95% CI P 150mg vs. 95% CI P 110 mg 150 mg Rate/ Year Rate/ Year Rate/ Year 110 mg vs warfarin (95% CI) P 150 mg vs warfarin (95% CI) P 150 mg vs 110 mg (95% CI) P Intracranial 0.23 % 0.30 % 0.74 % Major Bleed 2.71 % 3.11 % 3.36% 0.31 0.20-0.47 0.80 0.69-0.93 <.001.003 0.40 0.27-0.60 0.93 0.81-1.07 <.001.31 GI Major Bleed 1.1 % 1.5 % 1.0 % 1.10 (0.86-1.41).43 1.50 (1.19-1.89) <.001 1.36 (1.09-1.70).007 Gastrointestinal 1.12% 1.51 % 1.02% 1.10 0.86-1.41.43 1.50 1.19-1.89 <.001 MI 0.72% 0.74% 0.53% 1.35 (0.98-1.87).07 1.38 (1.00-1.91).048 1.02 (0.76-1.38).88 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151. Connolly SJ. et al. N Engl J Med. 2009 Sep 17;361(12):1139-51. Variable RE-LY: Drug Discontinuation 110 mg (n = 6015) 150 mg (n = 6076) (n = 6022) P-value a Discontinued at 1 year, % 15% 16% 10% <.001 Discontinued at 2 years, % 21% 21% 17% <.001 : Dosing in US CrCl > 30 150mg bid CrCl 15-30 75mg bid CrCl < 15 not recommended a. Rates of discontinuation at 1 and 2 years were higher with dabigatran than with warfarin (P <.001). Rates are based on Kaplan-Meier estimates CrCl should be assessed yearly in patients > 75 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151. Connolly, New England Jl Med, 2009 Predictable pharmacology High bioavailability Fixed dose No requirement for monitoring Inhibits free and thrombus associated Xa Contraindicated in severe renal insufficiency Drug interactions with meds that affect P-gp and CYP3A4 Ketoconazole, Rifampin, Clarithromycin, St Johns Wort and HIV-protease inhibitors (ritonavir) Specific, competitive, direct FXa inhibitor Inhibits free and clotassociated FXa activity, and prothrombinase activity Inhibits thrombin generation via inhibition of FXa activity Prolongs time to thrombin generation Inhibits peak thrombin generation Reduces the total amount of thrombin generated Does not require a cofactor 100 80 60 40 20 Free FXa Prothrombinase activity Clot-associated FXa 0 0.01 0.1 1 10 100 1000 (nm) Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005 Perzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther 2005; Br J Clin Pharmacol, 2007; Graff et al. Turpie A. Oral Anticoagulation, a look to the future. Presentaiton. Hamilton, CA 5
: FDA Approvals VTE prevention following TKR and THR RECORD studies Stroke prevention in non-valvular A-fib ROCKET-AF studies Treatment of DVT and PE EINSTEIN-DVT and EINSTEIN-PE studies Phase III RECORD - VTE prevention Oral rivaroxaban 10 mg qd compared with subcutaneous enoxaparin Study Duration of rivaroxaban therapy RECORD1 THR 5 weeks 5 weeks Duration of enoxaparin therapy RECORD2 THR 5 weeks 10 14 days, followed by placebo RECORD3 TKR 10 14 days 10 14 days RECORD4 TKR 10 14 days 10 14 days Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005 RECORD - Efficacy endpoints Primary Total venous thromboembolism (VTE): any deep vein thrombosis (DVT, judged by venography), non-fatal pulmonary embolism (PE), and all-cause mortality Secondary Major VTE: proximal DVT, non-fatal PE, and VTE-related death DVT: any, proximal, distal Symptomatic VTE RECORD - Safety endpoints Main Major bleeding starting after the first blinded dose and 2 days after last dose Bleeding that was fatal, into a critical organ or required reoperation Extra-surgical-site bleeding associated with a drop in hemoglobin 2 g/dl or requiring transfusion of 2 units blood Other Any bleeding on treatment* Non-major bleeding* Hemorrhagic wound complications* Cardiovascular adverse events Liver enzyme levels All endpoints were adjudicated centrally by independent, blinded committees All endpoints were adjudicated centrally by independent, blinded committees *Up to 2 days after last dose of study medication Phase III outcomes in VTE prophylaxis RECORD1 (THR) Enoxaparin P-values (10 mg qd) (40mg qd or 30mg bid) % (n/n) % (n/n) 40mg qd Total VTE 1.1 (18/1,595) 3.7 (58/1,558) <0.001 Major VTE 0.2 (4/1,686) 2.0 (33/1,678) <0.001 Major bleeding 0.3 (6/2,209) 0.1 (2/2,224) 0.18 RECORD2 (THR) 40mg qd Total VTE 2.0 (17/864) 9.3 (81/869) <0.0001 Major VTE 0.6 (6/961) 5.1 (49/962) <0.0001 Major bleeding 0.1 (1/1,228) 0.1 (1/1,229) - RECORD3 (TKR) 40mg qd Total VTE 9.6 (79/824) 18.9 (166/878) <0.001 Major VTE 1.0 (9/908) 2.6 (24/925) 0.01 Major bleeding 0.6 (7/1,220) 0.5 (6/1,239) 0.77 RECORD4 (TKR) 30mg bid Total VTE 6.9 (67/965) 10.1 (97/959) 0.012 Major VTE 1.2 (13/1,122) 2.0 (22/1,112) 0.124 Major bleeding 0.7 (10/1,526) 0.3 (4/1,508) 0.11 Conclusions at a dose 10mg po qd shows efficacy and tolerable side effects for VTE prophylaxis Weitz, Thrombosis and Haemostasis, Jan. 2010 6
Cumulative event rate (%) ROCKET AF: Study Design 20 mg daily (15 mg for Cr Cl 30-49 ml/min) Atrial Fibrillation Randomize Double Blind / Double Dummy (N= 14,264) Risk Factors, at least 2 of: CHF Hypertension Age 75 Diabetes OR Stroke, TIA or systemic embolus a INR target: 2.5 (2.0-3.0 inclusive) ROCKET AF: Primary Efficacy Outcome Stroke and non-cns Embolism 6 5 4 3 2 Event Rate 1.71 2.16 Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism a. Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10% Data presented by Mahaffey, KW. AHA Scientific Sessions, Chicago, IL, November 2010 Event Rates are per 100 1 HR (95% CI): 0.79 (0.66, 0.96) patient-years. Based on Protocol Compliant on P-value Non-Inferiority: <.001 Treatment Population 0 0 120 240 360 480 600 720 840 960 No. at risk: Days from Randomization 6958 6211 5786 5468 4406 3407 2472 1496 634 7004 6327 5911 5542 4461 3478 2539 1538 655 Data presented by Mahaffey, KW. AHA Scientific Sessions, Chicago, IL, November 2010 ROCKET AF: Time in Therapeutic Range (TTR): INR Data INR range Median (25 th, 75 th ) < 1.5 2.7 (0.0 9.0) 1.5 to < 1.8 7.9 (3.5 14.0) 1.8 to < 2.0 9.1 (5.3 13.6) 2.0 to 3.0 57.8 (43.0 70.5) > 3.0 to 3.2 4.0 (1.9 6.5) > 3.2 to 5.0 7.9 (3.3 13.8) > 5.0 0.0 (0.0 0.5) ROCKET AF: Primary Safety Outcomes Bleeding: Major and non-major Clinically Relevant HR Event Rate Event Rate 95% CI P-value 14.91 14.52 Major 3.60 3.45 Non-major Clinically Relevant 11.80 11.37 Event Rates are per 100 patient-years Based on Safety on Treatment Population 1.03 0.96, 1.11 1.04 0.90, 1.20 1.04 0.96, 1.13.442.576.345 Data presented by Mahaffey, KW. AHA Scientific Sessions, Chicago, IL, November 2010 Data presented by Mahaffey, KW. AHA Scientific Sessions, Chicago, IL, November 2010 ROCKET AF: Primary Safety Outcomes Event Rate or N (Rate) Event Rate or N (Rate) HR (95% CI) P-value Major 3.60 3.45 1.04 (0.90, 1.20).576 2 g/dl Hgb drop 2.77 2.26 1.22 (1.03, 1.44).019 Transfusion (> 2 units) 1.65 1.32 1.25 (1.01, 1.55).044 Critical organ bleeding 0.82 1.18 0.69 (0.53, 0.91).007 Bleeding causing death 0.24 0.48 0.50 (0.31, 0.79).003 Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94).019 Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02).060 Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00).051 Subarachnoid 4 (0.04) 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population Data presented by Mahaffey, KW. AHA Scientific Sessions, Chicago, IL, November 2010 ROCKET AF: conclusions demonstrated non-inferiority to for primary efficacy and safety outcomes: HR=0.79 (0.66-0.96), p<0.001; HR=1.03, (0.96-1.11), p=0.442, respectively 7
Cumulative event rate (%) : EINSTEIN Studies Phase III Trials Open label, assessor blind, non-inferiority studies comparing standard VKA anticoagulation to for treatment of acute VTE and prevention of recurrent VTE EINSTEIN DVT patients with objectively confirmed proximal DVT EINSTEIN-PE patients with objectively confirmed pulmonary embolus Primary efficacy endpoint Prevention of recurrent symptomatic VTE Primary safety endpoint Combination of major and non-major clinically relevant bleeding : EINSTEIN-DVT and EINSTEIN-PE Phase III Trials EINSTEIN PE: study design Randomized, open-label, event-driven, non-inferiority study Up to 48 hours heparinoid/fondaparinux treatment permitted before study entry 88 primary efficacy outcomes needed Non-inferiority margin: 2.0 Predefined treatment period of 3, 6, or 12 months Objectively confirmed PE ± DVT Day 1 Day 21 N=4833 R 15 mg bid Primary efficacy outcome: first recurrent VTE Enoxaparin bid for at least 5 days, plus VKA INR 2.5 (range 2.0 3.0) 20 mg od Principal safety outcome: first major or nonmajor clinically relevant bleeding 30-day poststudy treatment period : EINSTEIN-DVT results Recurrent symptomatic VTE Major and nonmajor clinically relevant bleeding Composite of primary efficacy outcome and major bleeding Stats 2.1% 3% p < 0.0001 for non-inferiority 8.1% 8.1% 2.9% 4.2% HR 0.67 All cause mortality 2.2 2.9% HR 0.67 Cardiovascular events 0.7% 0.8% HR 0.79 EINSTEIN PE: primary efficacy (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 superior p=0.57 for superiority (two-sided) 0.75 1.12 1.68* 10 (0.4) 6 (0.2) 0 1.00 2.00 non-inferior P=0.0026 for non-inferiority (one-sided) *Potential relative risk increase <68.4%; absolute risk difference 0.24% ( 0.5 to 1.02) HR inferior EINSTEIN PE: principal safety outcome major or non-major clinically relevant bleeding 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Number of patients at risk n/n (%) Enoxaparin/VKA n/n (%) 249/2412 (10.3) 274/2405 (11.4) HR (95% CI) p-value 0.90 (0.76 1.07) p=0.23 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Enoxaparin/VKA N=2405 N=2412 2412 2183 2133 2024 1953 1913 1211 696 671 632 600 588 313 Enoxaparin/VKA 2405 2184 2115 1990 1923 1887 1092 687 660 620 589 574 251 Safety population 8
Cumulative event rate (%) EINSTEIN PE: major bleeding Enoxaparin/VKA HR (95% CI) 3.0 n/n (%) n/n (%) p-value 26/2412 52/2405 0.49 (0.31 0.79) 2.5 (1.1) (2.2) p=0.0032 Enoxaparin/VKA 2.0 N=2405 1.5 1.0 N=2412 0.5 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk 2412 2281 2248 2156 2091 2063 1317 761 735 700 669 659 350 Enoxaparin/VKA 2405 2270 2224 2116 2063 2036 1176 746 719 680 658 642 278 EINSTEIN PE: conclusions In patients with acute symptomatic PE with or without DVT, showed: Non-inferiority to LMWH/VKA for efficacy: HR=1.12 (0.75 1.69); p non-inferiority =0.0026 for non-inferiority margin of 2.0 Similar findings for principal safety outcome: HR=0.90 (0.76 1.07); p=0.23 Superiority for major bleeding: HR=0.49 (0.31 0.79) p=0.0032 Consistent efficacy and safety results irrespective of age, body weight, gender, kidney function and cancer No evidence for liver toxicity Safety population A-fib : Dosing in US 20mg daily with evening meal if CrCl >50 15mg daily with evening meal if CrCl 15-50 DVT/PE 15mg bid with meals x 21 days followed by 20mg daily with meal For patients with CrCl > 30 Joint replacement surgery 10mg daily, 12 days for TKR, 35 days for THR For patients with CrCl > 30 Connolly, New England Jl Med, 2009 Apixaban Predictable pharmacology High bioavailability Fixed dose No requirement for monitoring Inhibits free and thrombus associated Xa Contraindicated in severe renal insufficiency Drug interactions with meds that affect P-gp and CYP3A4 Ketoconazole, Rifampin, Clarithromycin, St Johns Wort and HIV-protease inhibitors (ritonavir) Apixaban: FDA Approval Stoke and thromboembolic prevention in nonvalvular AF ARISTOTLE and AVEOES Studies 9
ARISTOTLE: Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism ARISTOTLE: Efficacy Outcomes P (non-inferiority)<0.001 21% R No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 9081 8620 8301 5972 3405 1768 Granger CB, et al. NEJM 2011;365:981-92 Granger CB, et al. NEJM 2011;365:981-92 ARISTOTLE: Major bleeding 31% R Apixaban 327 patients, 2.13% per year 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60 0.80); P<0.001 No. at Risk Apixaban 9088 8103 7564 5365 3048 1515 9052 7910 7335 5196 2956 1491 Granger CB, et al. NEJM 2011;365:981-92 ARISTOTLE: Bleeding outcomes Primary safety outcome: ISTH major bleeding* Apixaban (N=9088) Event Rate (%/yr) (N=9052) Event Rate (%/yr) HR (95% CI) P Value 2.13 3.09 0.69 (0.60, 0.80) <0.001 Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001 Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37 Major or clinically relevant non-major bleeding 4.07 6.01 0.68 (0.61, 0.75) <0.001 GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001 TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001 Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001 Granger CB, et al. NEJM 2011;365:981-92 ARISTOTLE: Conclusions In patients with non-valvular a-fib, Apixaban showed: Non-inferiority to VKA for efficacy: HR=0.79 (0.66-0.95) Superiority for major bleeding: HR=0.69 (0.60-0.80) p<0.001 Superiority for reduction in all cause mortality: HR=0.89 (0.89-0.998) p=0.046 Assesment of New Oral Anticoagulants In general, they demonstrate equivalent or superior efficacy and major bleeding safety compared to recent standards of care 10
Comparison of New Oral Anticoagulants **There are no head to head trials comparing these agents. Trends that may suggest any comparative superiority are only hypothesis generating and need confirmation in head to head trials Comparable Efficacy of NOACs in A-Fib Copyright The American College of Cardiology. All rights reserved. Comparable Major Bleeding with NOACs in A-Fib Time in Therapeutic Range (TTR) RE-LY (DABIGATRAN) 64% in -experienced, 61% in -naive ROCKET AF (RIVAROXABAN) Mean 55%, Median 58% ARISTOTLE (APIXABAN) Mean 62%, Median 66% Copyright The American College of Cardiology. All rights reserved. Testing of Hemostatic Function Testing of Hemostatic Function DABIGATRAN aptt, thrombin clotting time (TCT) and ecarin cloting time are prolonged TCT has a linear correlation with concentration but prolongs quickly If TCT is not prolonged, level likely is low RIVAROXABAN Prothrombin time (PT) and anti-xa affected Prothrombin time (PT) shows a linear dose response and is prolonged to a similar extent as the degree of inhibition of Xa (assay dependent) APIXABAN Prothrombin time (PT) and anti-xa affected Predictive ability of coag assays has not been clinically proven and target drug levels have not been determined. trough levels may not be detected. Anti-Xa activities can be measured against standard curves for each Xa inhibitor but currently unsure what levels are consistent with clinical efficacy or safety 11
Anticoagulation Interruption Before Surgery Timing of last dose before surgery Moderate or high Half-life (hrs) Low bleeding risk CrCl (ml/min) bleeding risk 13 (11-22) 24 hrs 2 days > 80 15 (12-34) 24 hrs 2 days > 50, < 80 18 (13-23) 2 days 4 days > 30, < 50 27 (22-35) 4 days 6 days < 30 12 (11-13) 24 hrs 2 days > 30 Unknown 2 days 4 days < 30 Apixaban - 24 hrs 2 days > 30 Reversal of NOACs DABIGATRAN Gastric lavage or activated charcoal to reduce absorption Prothrombin complex concentrate (PCC) with efficacy in some animal models, but no effect in reversing coagulation assay abnormalities in human volunteers Recombinant activated factor VII (rfviia) did not reverse coagulation assay abnormalities in human volunteers taking Melagatran Acute hemodialysis (only 35% protein bound) **Antidote being developed a humanized Fab fragment that binds similarly to thrombin. Neutralizes in animal model, does not bind thrombin substrates or cause any coagulopathy or platelet clumping Reversal of NOACs RIVAROXABAN Not dialyzable Four factor prothrombin complex concentrate (PCC) at 50 IU/kg reversed all coagulation assay abnormalities in a human volunteer study Treat with PCC or activated factor VIIa APIXABAN Not dialyzable No data, but would treat as would for Reversal of NOACs ** Anti-Xa antidote being developed. PRT064445 is a catalytically inactive, truncated form of factor Xa. Reverses direct Xa inhibitors as well as LMWH and Fondaparinux **Broad antidote for heparins, DTIs and direct Xa inhibitors is being developed. PER977 is a small molecule that binds to and inhibits.the above anticoagulants. Stable at room temp Reversal of : PCC vs FFP Retrospective cohort study 2006-2008 FFP 2008-2010 PCC (Octaplex, a 4 factor PCC) Adult patients with INR > 1.5 Primary outcome was serious adverse events (death, ischemic stroke, myocardial infarction, heart failure, venous thromboembolism or peripheral arterial thromboembolism) within 7 days Secondary outcomes included time to INR reversal, hospital length of stay and red blood cells transfused within 48 hours Reversal of : PCC vs FFP 148 patients received FFP, 165 patients received Octaplex Serious adverse events 19.5% for FFP 9.7% for Octaplex (p=0.014, Relative Risk () 2.0, 95% CI 1.1 to 3.5) Median INR reversal 11.8 hours for FFP 5.7 hours using Octaplex (p<0. 0001) Mean red cell transfusion 3.2 units for FFP 1.4 for Octaplex (p<0.0001). Hickey, M. et al. Circulation 2013 Hickey, M. et al. Circulation 2013 12
Advantages of New Agents vs. VKAs RAPID ONSET OF ACTION May replace parenteral anticoagulants for selected conditions Eliminates need for two anticoagulant regimen (i.e. heparin and warfarin) PREDICTABLE THERAPEUTIC EFFECT WITH FIXED OR WEIGHT- BASED DOSING No routine coagulation monitoring required LIMITED OR NO FOOD OR DRUG INTERACTIONS SHORT HALF-LIFE Effect wears off more quickly than VKAs NO NEED FOR BRIDGING AC FOR INVASIVE PROCEDURES MORE CONVENIENT FOR PATIENT No routine monitoring, dietary limitations and limited drug interactions MORE CONVENIENT FOR PHYSICIAN No routine coagulation monitoring POTENTIAL FOR GREATER USE Barriers removed that limit more widespread use MORE COST EFFECTIVE? No routine coagulation monitoring Fewer adverse events POSSIBLE SUPERIOR EFFICACY POSSIBLE SUPERIOR SAFETY Disadvantages of New Agents vs. VKAs NO ROUTINE COAGULATION MONITORING Cannot titrate dose Determination of failure of therapy vs. poor compliance SHORT HALF-LIFE Anticoagulation effect declines quickly if compliance poor Poor compliance may affect efficacy more than with VKA NO CLINICALLY PROVEN ANTIDOTES NO MONITORING LAB MARKER AVAILABLE TO RELIABLY MEASURE DRUG ACTIVITY IF NEEDED POTENTIAL DOSE ADJUSTMENT REQUIRED FOR RENAL OR HEPATIC DYSFUNCTION COST? Phillips et al. Jl Thromb Haem. 2010 Phillips et al. Jl Thromb Haem. 2010 Populations That Should be Initially Treated with or Remain on Rather Than be Placed on a Newer Oral Anticoagulant ALREADY TAKING WARFARIN WITH EXCELLENT INR CONTROL RE-LY data demonstrated equivalent efficacy but increased GI bleeding when comparing Dabigatgran 150mg bid to with excellent control RENAL INSUFFICIENCY Consider if CrCl < 30 and definitely if < 15 MECHANICAL HEART VALVES PREDISPOSITION TO GI BLEEDING POOR COMPLIANCE Concern regarding the quick loss of anticoagulant effect (question this) CAN T AFFORD NEWER DRUG Populations That Should Consider Treating With Newer Oral Anticoagulants THOSE WITH UNEXPLAINED POOR INR CONTROL RE-LY data demonstrated equivalent efficacy but increased GI bleeding when comparing 150mg bid to with excellent control POOR INR CONTROL DUE TO UNAVOIDABLE DRUG INTERACTION Recurrent antibiotics, Amiodarone, Chemotherapy, APAP, Azathioprine, polypharmacy NEW PATIENTS ON ANTICOAGULATION WITHOUT SIGNIFICANT RENAL INSUFFICIENCY CAN AFFORD THE NEW DRUGS Acknowledgments Gina Bryant Amy Shapiro, M.D. Chirag Amin, M.D. 13