New Oral Anticoagulants July 2012
Objectives Review coagulation cascade and previous treatment options for anticoagulation Understand points of interaction within coagulation cascade and new oral agents Understand the basic pharmacologic properties of the new agents Review the recent studies involving oral Direct Thrombin Inhibitors and Xa Inhibitors
A look back 800 BC 400 BC 1300 1980s-90s 1866 1000 1916 1950s 2012
Limitations of Warfarin Slow onset of action Narrow therapeutic window Long ½ life Frequent monitoring Variability Food/drug interactions Inter-patient Inadequate INR in Patients with A-fib 26 41 5 65 No Warfarin Supratherapeutic Therapertic Subtherapeutic
Anticoagulant Wish List Oral administration Rapid on/off Easily reversible Predictable No monitoring needed Renal/Hepatic disease No food/drug interactions Wide therapeutic range $$$
Experimental Designs Treatment of VTE Orthopedic Surgery Atrial Fibrillation Adjucnt for ACS
Clotting Cascade XII XI IX TF VIII X VII V II (thrombin) Intrinsic Pathway Extrinsic Pathway
Basics of Dabigatran MOA Monitoring aptt Ecarin Clotting Time Reversal Considerations Interactions Storage Surgery Cost $8.17/day thrombin fibrinogen fibrin Converts Fibrinogen to Fibrin Amplifies itself Platelet Agonist
Basics of Dabigatran
Basics of Dabigatran MOA Monitoring Reversal Considerations Interactions Storage Surgery Cost thrombin aptt Ecarin Clotting Time $8.17/day fibrinogen fibrin Converts Fibrinogen to Fibrin Amplifies itself Platelet Agonist
Dabigatran vs Enoxaprin in VTE Prevention post Ortho Intervention NonInferiority TKA THA In RE-MOBILIZE, Dabigatran did not reach non-inferiority Ann Rev. Med. 2011.62:41-57
Dabigatran vs Warfarin for Treatment and Prevention of Secondary VTE (RE-COVER) Randomized, Double blind, Non-inferiority Wafarin INR 2-3 N= 1289 Acute, symptomatic LE DVT or PE, 6 mos AC UFH/LMWH Acute VTE R (6 mos) 5-11 days Dabigatran 150 mg bid N= 1279 Primary Outcome: Recurrent, symptomatic VTE or death Primary Safety: Major bleeding Schulman, S. et al, NEJM 2009; 361:2342-52
Dabigatran vs Warfarin in avte (RE-COVER) 21.9% 2.4% 2.1% 16.1% Cumulative risk of rx VTE/death Adverse event: Dyspepsia, 3% Cumulative risk of Bleeding Schulman, S. et al, NEJM 2009; 361:2342-52
Points on Recover II Designed to confirm/extend the original study Low rate of primary outcome Limited study population No difference in Major bleeding events Overall bleeding events were significantly lower, though Confirmed that Dabigatran is non-inferior to warfarin in treatment of acute VTE
Dabigatran vs Warfarin for Afib Randomized Evaluation of Long term Anticoagulant Therapy (RELY) Warfarin INR 2-3 n = 6022 Afib + >1 R Characteristics ~ 71 y/o 63% Men CHADS2 2.1 Dabigatran 110 bid n = 6015 Dabigatran 150 mg bid n = 6076? Primary Outcome: Stroke or Systemic Emboli
Dabigatran vs Warfarin for Afib Randomized Evaluation of Long term Anticoagulant Therapy (RELY) NI SUP MB? GIB? DC?
Clotting Cascade Xa agents XII XI TF IX VIII VII X V II Intrinsic Pathway Extrinsic Pathway
Basics of Rivaroxaban/Apixaban MOA Monitoring Reversal Extrinsic PCC Factor VIIa FFP Activated charcoal Considerations Intrinsic prothrombin Factor Xa Contraindications Surgery timing thrombin Cost Rivaroxaban, $5.80 fibrinogen fibrin
RECORD Trials Rivaroxaban 10mg qd TK/HR R Bilateral Venography Enoxaparin 40mg qd * Primary Outcome: VTE, and all cause mortality Followup
fxai vs Enoxaparin for VTE Prevention post Orthopedic Surgery THA TKA Superiority reached US dose of enoxaparin Enoxaparin for 14 days, then placebo vs Rivaroxaban for ~35 days Ann Rev. Med. 2011.62:41-57
fxai vs Enoxaparin for VTE Prevention post Orthopedic Surgery TKA THA US dose of enoxaparin Did not have needed events in control group, so could not deem Non-inferior Ann Rev. Med. 2011.62:41-57
EINSTEIN Rivaroxaban 15mg bid Symptomatic DVT 21 d Rivaroxaban 20mg qd R Enoxaparin 1mg/kg bid VKA INR 2-3 Primary Outcome: Symptomatic recurrent VTE NEJM. 2010; 363(26):2499-510
EINSTEIN Rivaroxaban non-inferior in terms of primary outcome NEJM. 2010; 363(26):2499-510
EINSTEIN - Extension Rivaroxaban 20mg qd Acute DVT s/p tx x > 6mos N=1197 R Placebo Primary Outcome: Symptomatic, recurrent VTE NEJM. 2010; 363(26):2499-510
EINSTEIN - Extension Rivaroxaban reduced the rate of recurrence by 82% NEJM. 2010; 363(26):2499-510
EINSTEIN - PE Rivaroxaban 15mg bid Symptomatic PE N=4832 21 d Rivaroxaban 20mg qd R Enoxaparin 1mg/kg bid VKA INR 2-3 Primary Outcome: Symptomatic, recurrent VTE NEJM. 2012;336:1287-97.
EINSTEIN PE NEJM. 2012;336:1287-97.
Stroke Prevention in Afib with Rivoxaban Rocket AF Non-inferior, Double-blind study Rivaroxaban 20mg qd AFib + 2 points Characteristics ~ 73 40% Women CHADS2 3.5 R VKA INR 2-3 Primary Outcome: Stroke, TIA or Systemic Emboli NEJM. 2011;365:883-91.
ROCKET AF Results Warfarin, less GIB needing tfn Rivaroxaban, less critical bleeding In patients with a-fib, Rivaroxaban is non-inferior to warfarin for prevention of CVA and systemic embolisms NEJM. 2011;365:883-91.
Stroke Prevention in Afib with Apixaban - Aristotle Apixaban 5mg bid Afib +1 Characteristics ~ 70 y/o 35.3% Women CHADS2 2.1 57% hx of VKA 19% hx CVA/TIA/SE R VKA INR 2-3 Primary Outcome: Stroke, TIA or Systemic Emboli
Aristotle Primary Efficacy Results 8% less Ischemic CVA 49% less Hemorrhagic CVA Other Efficacy Outcomes -Lower rate of death -Lower rate of MI In patients with non-valvular A-fib (+1), Apixaban is superior to Warfarin in preventing strokes and systemic embolisms. NEJM. 2011;365:981-92.
Aristotle Primary Safety Results 3.1% 2.1% No difference in: GIB Drug discontinuation Sub-group analysis For every 1000 pts, treated for ~ 2yrs 15 fewer MBs 8 fewer deaths 6 fewer CVAs NEJM. 2011;365:981-92.
Current Indications - Summary Stroke Prevention in Non-Valvular Afib Dabigatran Rivaroxaban Apixaban (JUNE???) VTE Prophylaxis post Ortho intervention Rivaroxaban Apixaban
DVT/PE Treatment Summary Dabigatran Comparable efficacy & safety vs warfarin Must use UFH/LMWH initially Rivaroxaban Comparable efficacy & safety vs LMWH + warfarin Monotherapy for DVT or PE
Which patients? Trouble checking INR Trouble staying therapeutic No medication interactions Normal CrCl No CA, APS Can afford them
Questions????
Summary