Novel Anticoagulants Mark T. Reding, MD Associate Professor of Medicine Division of Hematology, Oncology, and Transplantation Director, Center for Bleeding and Clotting Disorders University of Minnesota Medical Center American College of Physicians – Minnesota Chapter Annual Scientific Session Minneapolis, MN November 8, 2013
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Novel Anticoagulants - ACP · Novel Anticoagulants . Mark T. Reding, MD . Associate Professor of Medicine . Division of Hematology, Oncology, and Transplantation . Director, Center
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Novel Anticoagulants
Mark T. Reding, MD Associate Professor of Medicine
Division of Hematology, Oncology, and Transplantation Director, Center for Bleeding and Clotting Disorders
University of Minnesota Medical Center
American College of Physicians – Minnesota Chapter Annual Scientific Session
Minneapolis, MN November 8, 2013
Disclosures I have served as an advisory board member, consultant, speaker,
and / or received research funding from:
Baxter Bayer
Biogen Idec Novo Nordisk Octapharma
Pfizer
(All activities related to hemophilia)
Off-label use will be mentioned: dabigatran, rivaroxaban, apixaban
Anticoagulant Therapy What are the options ?
1930s – heparin
1950s – warfarin
1990s – low MW heparins
1990s – direct thrombin inhibitors
2000s – factor Xa inhibitor
2010s – new oral anticoagulants
More new drugs are coming . . .
Partial List of Anticoagulant Drugs Under Development
PT / INR Increases with dose Very insensitive PT / INR and aPTT are both prolonged, but
to a varying degree, and depend upon the reagents used
aPTT Increases with dose Not linear, plateaus
Thrombin Time
Most sensitive Normal TT = no drug
Too sensitive No effect No effect
Other Ecarin clotting time is the best assay, but is not widely
available
Anti-Xa assay can be used, but must be standardized to
the drug
Anti-Xa assay very similar to LMWH,
and may not need to re-calibrate
Baumann-Kreuziger LM, et al. J Trauma Acute Care Surg 2012
Summary of Clinical Trials
Atrial Fibrillation
VTE Prophylaxis
VTE Treatment
Summary of Clinical Trials Atrial Fibrillation
RE-LY (Connolly SJ et al. NEJM 2009; 361:1139-51)
• N = 18,113
• Dabigatran 150 mg bid vs. warfarin Reduced risk of stroke (1.11% / yr vs. 1.69% / yr) Similar major bleed risk
BUT . . . Warfarin TTR averaged 64%
IF . . . Compare to patients with warfarin TTR > 65% Dabigatran not superior to warfarin
Dabigatran associated with less ICH, but double the risk of major GI bleed
Summary of Clinical Trials Atrial Fibrillation
ROCKET AF (Patel MR et al. NEJM 2011; 365:883-91)
• N = 14,264
• Rivaroxaban 20 mg daily vs. warfarin
• Rivaroxaban was non-inferior to warfarin for prevention of stroke
• No overall difference in major bleeding, however…
• Rivaroxaban associated with less ICH and fatal bleeding, but more GI bleeding
Summary of Clinical Trials Atrial Fibrillation
ARISTOTLE (Granger CB et al. NEJM 2011; 365:981-92)
• N = 18,201
• Apixaban 5 mg bid vs. warfarin
• Apixaban was superior in preventing stroke (1.27% / yr vs. 1.6% / yr), with less overall bleeding (7.7% absolute risk reduction) and lower all cause mortality
• Apixaban associated with less ICH (0.8% / yr vs. 0.33% / yr)
• No increase in GI bleeding
Summary of Clinical Trials VTE Prophylaxis (THA, TKA)
Dabigatran
Rivaroxaban
Apixaban
vs. Low Molecular
Weight Heparin
• Equal or better efficacy
• Similar bleeding risk
• Advantage of oral administration
(Dabigatran and apixaban are not approved in the US for this indication)
Summary of Clinical Trials VTE Treatment
Dabigatran
Rivaroxaban
Apixaban
vs. Warfarin
or Placebo
• Non-inferior to warfarin, with same or less overall bleeding risk and less major bleeding
• Need to carefully look at TTR for warfarin patients • Better than placebo (not a surprise)… with
acceptable bleeding risk • Apixaban had same bleeding risk as placebo?!?
(Dabigatran and apixaban are not approved in the US for this indication)
Time in Therapeutic Range (INR 2.0 – 3.0)
RE-MEDY = 65%
EINSTEIN = 58%
EINSTEIN-PE = 63%
AMPLIFY = 61%
Management of Bleeding
Dabigatran Rivaroxaban Apixaban
Antidote None None None
Activated charcoal* Yes Yes Yes
Dialysis
~35% protein bound
~60% removed in 2 -3 h **
Highly protein bound
Dialysis ineffective
Highly protein bound
Dialysis ineffective
* Activated charcoal indicated within 2 – 3 hours of drug ingestion
** Dabigatran has a very large volume of distribution (60 – 70 L); expect multiple dialysis sessions to be required
Hemostatic Agent Options for Management of Bleeding
Name Category Available in US? Aminocaproic acid antifibrinolytic Yes
Tranexamic acid antifibrinolytic Yes
Profilnine, Bebulin 3 factor PCC Yes
Cofact, Kanokad 4 factor PCC No
Octaplex, Kaskadil 4 factor PCC, + PC, PS No
Beriplex / Kcentra 4 factor PCC, + PC, PS, AT Yes
FEIBA Activated PCC Yes
NovoSeven rfVIIa Yes
(None are approved in the US for this indication)
Use of Hemostatic Agents for Management of Bleeding
Summary of Data Dabigatran Rivaroxaban Apixaban
Animal Human Animal Human Animal Human
3 factor PCC
Case rpt +/-
4 factor PCC
Rat +/- Rabbits +
Mice ICH +
In vitro + In vivo -
Case rpt -
Rats + Rabbits -
In vitro +/- In vivo +
In vitro +
aPCC Rats +/- Mice -
In vitro + Rat +
Primate + In vitro + In vitro +
rfVIIa Rats +/- Mice +/-
Mice ICH -
In vitro + Case rpt +/-
Rat + Rabbits +/- Primate +/-
In vitro +/- In vitro +
+ effective, - not effective, +/- mixed results
Bottom Line: very little human, in vivo, real-world, published experience at this time
Use of Factor Concentrates for Management of Bleeding
• Factor Concentrates are NOT antidotes – They create hypercoagulability, not reversal – Specific reversal agents in early phase trials