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Rivaroxaban (Xarelto) Apixaban (Eliquis) Novel Oral An,coagulants: Prac,cal Aspects Caroline Berube, MD Clinical Associate Professor Division of Hematology November 2015 The New Oral An,coagulants (NOACs) The Non VKA Oral An,coagulants (NOACs) Direct Oral An,coagulants (DOACs) Target-Specific Oral An,coagulants (TSOACs) Target-Specific Oral An,coagulants (TSOACs) • Direct Thrombin inhibitors – Dabigatran • Direct Xa inhibitors – Rivaroxaban – Apixaban – Edoxaban Advantages of new oral an,coagulants compared to warfarin Advantage Clinical implicaons Rapid onset of ac,on No need for bridging Predictable an,coagulant effect No need for rou,ne coagulaon monitoring, fixed dose Low poten,al for food interac,ons No dietary restric,on Low poten,al for drug interac,ons Few drug interac,on Betrixaban Argatroban Bivalirudin FDA-approved Betrixaban Argatroban Lepirudin Bivalirudin FDA-approved Betrixaban Argatroban Lepirudin Bivalirudin FDA-approved New Oral An,coagulants large phase III studies Drug Stroke Preven8on VTE treatment Orthopedic Prophylaxis RE-LY RECOVER, RECOVER II RE-MOBILIZE Dabigatran REMEDY-EXT RE-MODEL RESOLVE-EXT RE-NOVATE Rivaroxaban ROCKET AF EINSTEIN PE RECORD 1 EINSTEIN DVT RECORD 2 EINSTEIN-EXT RECORD 3 RECORD 4 Apixaban AVERROES (ASA) AMPLIFY ADVANCE 1 ARISTOTLE (W) AMPLIFY-EXT ADVANCE 2 ADVANCE 3 Edoxaban ENGAGE AF-TIMI HOKUSAI-VTE STARS Current Status on Oral An,coagulant Approval in the United States Dabigatran Rivaroxaban Apixaban Edoxaban (Pradaxa) (Xarelto) (Eliquis) (Savaysa) Atrial Approved Approved Approved Approved Fibrillaon VTE Approved Approved Approved Approved Treatment VTE prevenon Not is US Approved Approved Not is US Ortho surgery Comparison of New Oral An,coagulants Dabigatran Rivaroxaban Apixaban Edoxaban etexilate Target Thrombin FXa FXa FXa Clong ,me PTT, TCT, ECT PT, An,-Xa An,-Xa An,-Xa prolongaon Time to peak (h) 2h 2.5- 4 h 3h 1-2h Half-life (h) 14-17 5-9 healthy 8-15 9-11 9-13 elderly Metabolism/ Renal 80% Renal 35% Renal 25% Renal 35% Eliminaon Bile 20% Bile 75% Bile 65 % An,dote Yes None None None Administraon bid daily bid daily Comparison of New Oral An,coagulants Dabigatran Rivaroxaban Apixaban Edoxaban etexilate Target Thrombin FXa FXa FXa Clong ,me PTT, TCT, ECT PT, An,-Xa An,-Xa An,-Xa prolongaon Time to peak 2h 2-3h 1-2h 1-2h effect (h) Half-life (h) 14-17 5-9 healthy 8-15 9-11 9-13 elderly Metabolism/ Renal 80% Renal 35% Renal 25% Renal 35% Eliminaon Bile 20% Bile 75% Bile 65 % An,dote Yes None None None Administraon bid daily bid daily Comparison of New Oral An,coagulants Dabigatran Rivaroxaban Apixaban Edoxaban etexilate Target Thrombin FXa FXa FXa Clong ,me PTT, TCT, ECT PT, An,-Xa An,-Xa An,-Xa prolongaon Time to peak 2h 2-3h 1-2h 1-2h effect (h) Half-life (h) 14-17 5-9 healthy 8-15 9-11 9-13 elderly Metabolism/ Renal 80% Renal 35% Renal 25% Renal 35% Eliminaon Bile 20% Bile 75% Bile 65 % An,dote Yes None None None Administraon bid daily bid daily Stroke Preven,on in Atrial Fibrillaon Atrial Fibrillaon Studies (> 70,000 pts, median age 70-73) RE-LY ROCKET-AF ARISTOTLE ENGAGE AF- TIMI Design Randomized Randomized Randomized Randomized Blinded for dabi dose Double blind & Open-label for warfarin double dummy N 18,113 14,264 18, 202 21,105 Treatment Dabigatran Rivaroxaban Apixaban Edoxaban 150 mg BID 20 mg daily 5 mg BID 60 mg daily 110 mg BID 30 mg daily in selected pts (25%) Comparator Warfarin 2-3 Warfarin 2-3 Warfarin 2-3 Warfarin 2-3 (67% in-range) (57% in-range) (66% in-range) Mean 2.1 3.5 2.1 2.8 CHADS₂ Connolly, SJ. N Engl J Med 2009; 361:1139-1151 Patel et al. N Engl J Med 2011; 365:883 Granger CB et al. N Engl J Med 2011;365:981-992 Giugliano, RP. N Engl J Med 2013; 369:2093. Efficacity of NOACs with warfarin in paents with AF Meta-analysis Stroke or systemic embolic events Ruff, C. Lancet 2014; 383:955 Safety of NOACs with warfarin in paents with AF Meta-analysis Major Bleeding Ruff, C. Lancet 2014; 383:955 Meta-Analysis of Safety of New Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) Versus Warfarin in Patients With Atrial Fibrillation Major bleeding Intracranial bleed GI bleed NOAC warfarin Corey S. Miller , Am J Cardiol 2012; 110:453 Preven,on of Stroke in Atrial Fibrillaon Summary • The new oral an,coagulants are more effec,ve than vit. K antagonists in the preven,on of stroke • All new an,coagulants result in a 50% decrease in intracranial bleeding complicaons compared with warfarin. • Dabigatran and rivaroxaban are associated with increased extracranial bleeding risk (GI) in the elderly populaon Acute Treatment of Venous Thromboembolism VTE Treatment VKA VTE treatment LMWH * VKA Bridging RE-COVER I and II LMWH * Dabigatran 150 mg BID Switching Day 1 Day 6 -11 At least 6 months Hokusai - VTE LMWH * Edoxaban 60 mg QD Day 1 Switching Day 6 -11 At least 3 months EINSTEIN-DVT/PE Rivaroxaban 15 mg BID X 3 weeks, then 20 mg QD Day 1 Single drug approach At least 3 months AMPLIFY Apixaban 10 mg BID X 7 days; then 5 mg BID Day 1 Single drug approach At least 6 months *Or UFH or fondaparinux Black, Cohen: Tailoring NOAC therapy for VTE 662 period of 15 mg twice daily, against standard therapy with rhage) was reported with any of the NOACs, supporting the safety LMWH followed by dose-adjusted VKAs. The primary efficacy of these drugs. endpoint of symptomatic recurrent VTE was reported in 2.1 % of the rivaroxaban group vs 3.0 % of the warfarin group (HR 0.68, 95 % CI 0.44–1.04) and 2.1 % of the rivaroxaban group and 1.8 % Pulmonary embolism in the warfarin group (HR 1.12, 95 % CI 0.75–1.68), for the DVT and PE trials, respectively. Major or clinically relevant non-major Silent pulmonary embolism (PE) is present in 32 % of patients with bleeding (the principal safety outcome) occurred in 8.1 % of each symptomatic deep-vein thrombosis (DVT) (28). Given that 10 % of group in the EINSTEIN-DVT trial, and a non-significant reduc- patients with acute PE die within 1 hour and 30 % within one week tion in events was observed with rivaroxaban in the EINSTEIN- (29), time is critical to instigate effective treatment. For these rea- PE study (10.3 % vs 11.4 %, HR 0.90, 95 % CI 0.76–1.07). Finally, sons, empirical administration of therapeutic doses of LMWH is in the AMPLIFY study of apixaban monotherapy given at 10 mg indicated prior to CT confirmation where there is a reasonable twice daily for seven days and 5 mg twice daily for six months, clinical suspicion. Of the active control trials reporting on PE sub- the primary efficacy endpoint was recurrent symptomatic VTE groups, the AMPLIFY and Hokusai-VTE trials for apixaban and recurrence or related deaths. Recurrent VTE or related deaths edoxaban, respectively, were unique in reporting a risk reduction, occurred in 2.3 % of the apixaban group compared with 2.7 % in albeit non-significant, with NOAC therapy relative to standard the standard therapy group (relative risk [RR] 0.84, 95 % treatment (▶ Table 3). The EINSTEIN-PE study, which compared 0.60–1.18). The composite safety endpoint of major plus clini- rivaroxaban monotherapy with standard treatment involving initial cally relevant non-major bleeding occurred in 4.3 % of the apixa- heparin therapy demonstrated non-inferiority with respect to the ban group vs 9.7 % of those receiving standard therapy (RR 0.44, primary efficacy endpoint. The safety endpoints were reported 95 % 0.36–0.55). The risk of major bleeding alone was also re- among some subgroups with PE and those available show a reduc- duced in the apixaban group where it occurred in 0.6 % of pa- tion in risk of bleeding associated with NOAC therapy relative to tients compared to 1.8 % in the conventional therapy group (RR active controls. In the AMPLIFY study, the primary safety endpoint 0.31; 95 % CI 0.17–0.55). of major bleeding occurred in 0.4 % of patients with PE assigned to In summary, all NOAC trials in the acute setting met non-in- apixaban and 2.8 % of those on conventional therapy. Similar bene- feriority for the primary efficacy endpoint. Furthermore, there was fits in the primary safety measure for those with PE were observed no clear disparity in efficacy endpoints between trials adopting a in Hokusai-VTE where clinically relevant minor or major bleeding heparin lead in and those with monotherapy of the trial drug. A occurred in 10.1 % and 11.2 % of the edoxaban and conventional comparison of outcomes with differing duration of intensive arms, respectively. In the EINSTEIN-PE study, major or clinically monotherapy in the EINSTEIN (3 weeks) and AMPLIFY (1 week) relevant non-major bleeding occurred in 10.3 and 11.4 % of the studies does not support one approach over the other, particularly rivaroxaban and conventional therapy groups, respectively. with respect to efficacy. All NOACs discussed above appear to be Heparin therapy is thought to have beneficial effects above and at least as efficacious as the conventional regimen of parenteral he- beyond its anticoagulant properties (30), particularly in the pul- parin with bridging to warfarin. In RE-COVER I, RE-COVER II, monary circulation where it exerts pleiotropic effects including Hokusai-VTE,Summary phase III trials of NOACs for the and AMPLIFY trials, significant reductions in the anti-inflammatory and vasodilatory effects. Consistent with the composite safety endpoint of major or clinically relevant non- factor Xa inhibitors, the onset of action of heparin is fast.
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