2009, 심장학회
Venous thromboembolism : Evolution of anticoagulation therapy
원주의대 김장영 2009, 심장학회 Venous Thromboembolism (VTE)
• Third most common vascular disease • 600,000 cases of VTE annually in USA • 200,000 cases of pulmonary embolism (PE) annually • PE remains the leading preventable cause of death in hospital
Cause of death # of annual death Pulmonary embolism (PE) 200,000 AIDS 18,017 Breast cancer 40,870
2008, AHA 2009, 심장학회 Treatment guideline Deep Vein Thrombosis (DVT) & pulmonary embolism (PE)
• For objectively confirmed DVT or PE, recommend SC LMWH, IV or SC UFH, SC Fondaparinux [Grade 1] • Overlap a VKA (warfarin) with a parenteral anticoagulant a minimum of 5 days and until the INR is ≥2.0 for at least 24 hours [Grade 1]
ACCP guideline, 2008
LMWH: low molecular weight heparin, UFH: unfractionated heparin, VKA: vitamin K antagonist 2009, 심장학회 Anticoagulants for VTE prophylaxis
Geerts WH. et al. Chest 2001 Turple AGG . et al. Arch Intern Med 2002 2009, 심장학회 Anticoagulants
Venous thrombosis Arterial thrombosis Prevention Prevention – After orthopaedic – Stroke in patients with surgery AF – After general surgery – MI in patients with ACS – In cancer patients – Thrombotic Cx. of prosthetic heart valve treatment 2009, 심장학회 A Brief History of Anticoagulant Therapy
Unfractionated heparins: antithrombin (AT)-dependent inhibition of Parenteral 1930s factor Xa and IIa in a 1:1 ratio Vitamin K antagonists : indirectly affect synthesis of Oral 1940s multiple coagulation factors Low-molecular-weight heparin: Parenteral 1980s AT-dependent inhibition of factor Xa > IIa
Parenteral Direct factor IIa inhibitors (bivalrirudin) 1990s
Parenteral Indirect factor Xa inhibitors (fondaparinux) 2000s Direct factor IIa Oral inhibitors
Direct factor Xa New anticoagulants Parenteral and Oral 2009 inhibitors
Alban s. Eur J Clin Invest 2005;111:2671 2009, 심장학회 Warfain or UFH are problematic
Warfarin – too slow onset of action – variable anticoagulant response ( PT INR) – Numerous food- and drug-drug interaction
UFH - Low bioavailability and short half life - variable anticoagulant response ( aPTT) - Heparin induced thrombocytopenia or osteoporosis 2009, 심장학회 UFH vs. LMWH for acute VTE
Outcomes UFH, No. (%) LMWH, No. (%) Risk Difference (95% CI) Efficacy analysis N=345 N=352
Recurrent VTE 13(3.8) 12 (3.4) 0.4 (-2.6 to 3.3) (3 mo) Type of 2 PE 4 PE recurrence 11 DVT 8 DVT Major bleeding (3 6 (1.7) 12 (3.4) -1.7 (-4.3 to 0.8) mo) Minor bleeding 29 (8.3) 30 (8.5) -0.2 (-4.4 to 4.0) (3 mo) Deaths (3 mo) 18 (5.2) 22 (6.3) -1.1 (-4.6 to 2.5) 2009, 심장학회 Fondaparinux: Treatment of DVT Matisse DVT Study 2009, 심장학회 Anticoagulants that Have Changed Clinical Practice Unfractionated heparin (UFH) Low-molecular-weight heparin Fondaparinux
But…………………………. for oral anticoagulation, Vitamin K antagonists (warfarin) remain the only available option 2009, 심장학회 Anticoagulants in Development
TTP889 TF/VIIa
IX TFPI (tifacogin) X APC (drotrecogin alfa) NAPc2 sTM (ART-123) IXa VIIIa Oral Va Apixaban Xa Rivaroxaban Oral DU-176b Dabigation Betrixaban II YM150 Parenteral IIa Fondaparinux Idraparinux Fibrinogen Fibrin Biotinylated idraparinux 2009, 심장학회 Anticoagulants in Development
TTP889 TF/VIIa
IX TFPI (tifacogin) X APC (drotrecogin alfa) NAPc2 sTM (ART-123) IXa VIIIa Direct thrombin inhibitorsOral Va apixaban Xa Rivaroxaban Oral DU-176b Dabigation Betrixaban II YM150 Parenteral IIa Fondaparinux Idraparinux Fibrinogen Fibrin Biotinylated idraparinux 2009, 심장학회 Dabigatran
• The prodrug dabigatran etexilate is converted completely to active dabigatran
• Terminal elimination t 1/2 of 14 -17 hr • No food interactions
• Mainly by renal excretion (80%) 2009, 심장학회 RE-VOLUTION clinical trial program Secondary prevention of cardiac events in patients with ACS* Primary VTE Prevention
Stroke Prevention in patients with Atrial Fibrillation Acute VTE Treatment Secondary VTE Prevention
Involving >38,000 patients worldwide 2009, 심장학회 Dabigatran Clinical Program: REVOLUTION Phase III Studies in VTE Prophylaxis After THR/TKR Enoxaparin 40mg QD* OR Start evening before surgery* of 30 mg BID* 12-24 hours post-operatively* Dabigatran etexilate 75/ 150 mg QD
R Start 1-4 hours* or 6-12 hours* post-operatively
Dabigatran etexilate 110/ 220 mg QD Venography Follow-up Within 12 hours of last dose 12-14 weeks
*RE-MODEL and RE-NOVATE Therapy Enoxaparin Study Duration Dose (mg) *RE-MOBILIZE RE-MODEL Knee 6-10 days 40 QD
Design: Non-Inferiority RE-NOVATE Hip 28-35 days 40 QD Intention-To-Treat Population RE-MOBILIZE Knee 12-15 days 30 BID
Eriksson et al. Lancet, 2007, J Thromb Haemost 2007 2009, 심장학회 Meta-Analysis Major VTE & VTE-Related Mortality
Dabigatran etexilate Study or 220 mg QD Enoxaparin RR RR [95% CI] sub-category n/N n/N RE-MOBILIZE 21/618 15/658 1.51 [0.79, 2.91]
RE-MODEL 13/506 18/511 0.73 [0.36, 1.47]
RE-NOVATE 28/909 36/917 0.78 [0.48, 1.27]
Total events 62 (dabigatran etexilate), 69 (enoxaparin) Test for
Random Effects Analysis
Total (95% CI) 2033 2096 0.94 [0.61, 1.44]
Test for overall effect: Z = 0.30 ( P=0.76)
0.1 0.2 0.5 1 2 5 10
Favours Favours Dabigatran Etexilate Enoxaparin 2009, 심장학회 Meta-Analysis Major Bleeding Events
Dabigatran etexilate Study or 220 mg QD Enoxaparin RR RR [95% CI] sub-category n/N n/N RE-MOBILIZE 5/857 12/868 0.42 [0.15, 1.19]
RE-MODEL 10/679 9/694 1.14 [0.46, 2.78]
RE-NOVATE 23/1145 18/1154 1.29 [0.70, 2.37]
Total events 62 (datigatran etexilate), 69 (enoxaparin) Test for
Random Effects Analysis
Total (95% CI) 2682 2716 0.94 [0.51, 1.75]
Test for overall effect: Z = 0.30 ( P=0.76)
0.1 0.2 0.5 1 2 5 10
Favours Favours Dabigatran Etexilate Enoxaparin 2009, 심장학회 Anticoagulants in Development
TTP889 TF/VIIa
IX TFPI (tifacogin) X APC (drotrecogin alfa) FactorNAPc2 Xa inhibitorssTM (ART-123) IXa VIIIa Oral Va apixaban Xa Rivaroxaban Oral DU-176b Dabigation Betrixaban II YM150 Parenteral IIa Fondaparinux Idraparinux Fibrinogen Fibrin Biotinylated idraparinux 2009, 심장학회 Apixaban: oral direct Factor Xa inhibitor
• No organ toxicity or LFT abnormalities • Low likelihood of drug interactions or QTc prolongation • Good oral bioavailability • No food effect • Balanced elimination (~25% renal) • Half-life : 9-12 hrs 2009, 심장학회 Apixaban for Prevention of VTE After Major Orthopaedic Surgery • Apixaban od and bid (total daily doses 5-20mg) wre assessed relative to enoxaparin and warfarin, in 1,217 patients
Total VTE and all-cause mortality (%) Major bleeding (%)
Apixaban Apixaban (total Daily Dose) (total Daily Dose) 2009, 심장학회 Apixaban – phase III
• Advance 1 – knee replacement 3000 • Advance 2 – knee replacement 3000 • Advance 3 – hip replacement 4000 • Aristotle – atrial fibrillation (vs warfarin) 15000 • Averroes– atrial fibrillation (vs aspirin) 5600 • Appraise 2 – ACS 1800 • Advocate – VTE in cancer 1600 2009, 심장학회 Primary Efficacy Outcome : Total VTE or All-Cause Mortality
RR = 1.02 (0.78, 1.32) P = 0.064
N Engl J Med 2009;361:594-604 2009, 심장학회 Safety Outcome: Major or Clinically Relevant Bleeding
P = 0.034
N Engl J Med 2009;361:594-604 2009, 심장학회 Rivaroxaban: oral direct Factor Xa inhibitor
• Predictable pharmacology • High bioavailability • Low risk of drug-drug interactions • Fixed dose • No requirement for monitoring 2009, 심장학회 RECORD program Major orthopaedic surgery
• Rivaroxaban 10 mg once-daily investigated • Same study design and efficacy and safety outcomes
REC ORD 1 REC ORD 2 REC ORD 3 REC ORD 4
HIP replacement HIP replacement Knee replacement KNEE replacement
Rivaroxaban 10 mg od Rivaroxaban 10 mg od Rivaroxaban 10 mg od Rivaroxaban 10 mg od for 5 weeks for 5 weeks for 10-14 weeks for 10-14 weeks vs vs vs vs enoxaparin 40 mg od enoxaparin 40 mg od enoxaparin 40 mg od enoxaparin 30 mg bid for 5 weeks for 10-14 days then for 10-14 weeks for 10-14 weeks oral placebo N=4,541 N=2,509 N=2,531 N=3,148 2009, 심장학회 RECORD in VTE Prophylaxis After THR/TKR
F S Rivaroxaban 10 mg QD O U 6-8 hours post-surgery Mandatory L R L R G Bilateral O E W venography R Enoxaparin U Y P Evening before surgery* Last dose day Day 1 Or 12-24 hours post-surgery # before venography
Therapy Duration (weeks) Enoxaparin Study Rivaroxaban Enoxaparin Dose (mg) RECORD1 Hip 5 5 40 QD *RECORD1, 2 and 3 RECORD2 Hip 5 2‡ 40 QD #RECORD4 12-24 hours post-surgery ‡followed by oral placebo for 3 weeks RECORD3 Knee 2 2 40 QD RECORD4 Knee 2 2 30 BID 2009, 심장학회 Primary Efficacy Outcome Total VTE or All-Cause Mortality
Enoxaparin Rivaroxaban RRR=31% RRR=49% ARD = -7.3% (-9.4, -5.2) p<0.0001 ARD = -9.2% (-12.4, -5.9) p<0.001
RRR=31% ARD = -3.19% (-5.67, -0.71) RRR=70% p<0.012 ARD = -2.6% (-3.7, -1.5) p<0.001
RECORD3 RECORD4 RECORD1 RECORD2 (knee) (Hip) 2009, 심장학회 Pooled Analysis of RECORD1-4: Symptomatic VTE & All-Cause Mortality
58% reduction HR=0.42 (95% CI: 0.29-0.63) p<0.001 2009, 심장학회 Major Bleeding Across the RECORD Program
Enoxaparin Rivaroxaban
RECORD1 RECORD2 RECORD3 RECORD4 2009, 심장학회 Summary
Property Rivaroxaban Apixaban Dabigatran
Target Factor Xa Factor Xa Thrombin
Route of administration Oral Oral Oral
Prodrug No No Yes
Bioavailability >80 >50 6
Timetopeakdruglevel,h 3 3 2
Half-life, h 9 9 14-17
Druginteractions Potent CYP3A4 Potent CYP3A4 Proton pump inhibitors
Renalexcretion,% 66 25 80
Antidote No No No 2009, 심장학회 Evolution of Anticoagulant Therapy
Unfractionated heparins Parenteral 1930s
Vitamin K antagonists Oral 1940s
Parenteral Low-molecular-weight heparin 1980s
Parenteral Direct factor IIa inhibitors ( bivalrirudin) 1990s
Parenteral Indirect factor Xa inhibitors 2000s (fondararinux) Direct factor IIa Oral Dabigatran inhibitors
Direct factor Xa Apixaban Parenteral and Oral inhibitors Rivaroxaban
Alban s. Eur J Clin Invest 2005;111:2671 2009, 심장학회 2009, 심장학회
•EXTRA-SLIDE 2009, 심장학회 Oral Factor Xa inhibitors – clinical development
Rivaroxaban (Bayer/J&J) Phase III
Phase III Apixaban (BMS/Pfizer)
Phase IIb YM150 (Astellas)
Edoxaban (Daiichi) Phase IIb
Betrixaban (Portola) Phase II
TAK 442 (Takeda) Phase II
Phase I/II 813893 (GSK) 2009, 심장학회 Targets for ANTITHROMBOTICS
Anticoagulants Antiplatelets
TF/FVIIi Tissue factor collagen
Plasma clotting Aspirin cascade ADP Clopidogrel Thromboxane A 2 LMWH Prothrombin Prasugrel Heparin Ticagrelor Factor Conformational Xa Direct Xa inhib AT-III activation of GPIIb/IIIa GPIIb/IIIa Bivalirudin Thrombin inhibitors Ximelagatran Platelet aggregation dabigatran Fibrinogen Fibrin
Thrombus 2009, 심장학회 Factor X Inhibitors
• Indirect – AT dependent – Fondaparinux, Idraparinux
• Direct – AT Independent 2009, 심장학회 Fondaparinux: synthetic Inhibitor Factor Xa (pentasaccharide)
• Half life of 17-20 h • No monitoring required • Contraindicated if CrCI < 30 mL/min • Prophylaxis dose: 2.5 mg/day/SC • Treatment dose: – 5 mg < 50 kg – 7.5 mg if 50-100 kg – 10 mg if > 100 kg 2009, 심장학회 Fondaparinux for VTE prevention in OS surgery: efficacy versus enoxaparin
Fondaparinux Enoxaparin better better Extra 95% CI
Hip replacement -45.3 (n=3411) [-58.9 to -27.4]
EPHESUS [-72.8 to -37.2] (n=1827)
PENTATHLON 2000 -28.1 (n=1548) [-52.2 to -7.6]
Hip fracture PENTHIFRA -61.6 [-73.4 to -45.0] (n=1250)
Major knee surgery -63.1 PENTAMAKS [-75.5 to -44.8] (n=724)
Overall adds reduction -55.2 (n=5385) p<0.001 [6.31 to -45.8]
-100 -80-60-40-20 0 20 40 60 80 100 % odds reduction 2009, 심장학회 Direct Factor Xa inhibition
XIIa Tissue factor XIa VIIa IXa
Xa Rivaroxaban Apixaban YM150 Edoxaban Betrixaban Factor II TAK442 (prothrombin)
Fibrinogen Fibrin clot