novel anticoagulants - american college of physicians
TRANSCRIPT
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
Weitz JI et al. Chest 2012
New Oral Anticoagulants Dabigatran – Pradaxa
(Boehringer Ingelheim) Rivaroxaban – Xarelto
(Janssen)
Apixaban – Eliquis (Bristol-Myers Squibb / Pfizer)
Edoxaban – Lixiana (Daiichi Sankyo)
Approved only in Japan, for VTE prophylaxis
New Oral Anticoagulants Approval History
Dabigatran Rivaroxaban Apixaban
VTE prophylaxis (THA, TKA)
Europe – Mar 2008 Canada – Jun 2008
Europe – Sep 2008 Canada – Sep 2008
USA – July 2011
Europe – May 2011 Canada – Mar 2012
Atrial fibrillation
Canada – Oct 2010 USA – Oct 2010
Europe – Aug 2011
USA – Nov 2011 Europe – Dec 2011 Canada – Jan 2012
Europe – Nov 2012 Canada – Dec 2012
USA – Dec 2012
VTE treatment
Europe – Dec 2011 Canada – Feb 2012
USA – Nov 2012
Acute coronary syndromes
Europe – May 2013
Summary of Major Clinical Trials
VTE prophylaxis VTE treatment Atrial
fibrillation Acute coronary
syndromes
REMODEL REMOBILIZE RENOVATE
RENOVATE 2
RECOVER REMEDY
RESONATE RECOVER 2
RELY RELYABLE
REDEEM
RECORD 1 RECORD 2 RECORD 3 RECORD 4
EINSTEIN-DVT EINSTEIN-EXT EINSTEIN-PE
ROCKET-AF
ATLAS (ACS-TIMI 46)
ATLAS (ACS-TIMI 51)
ADVANCE 1 ADVANCE 2 ADVANCE 3
AMPLIFY AMPLIFY-EXT
ARISTOTLE AVERROES
APPRAISE 1 APPRAISE 2
Dabigatran Rivaroxaban Apixaban
FDA Approved Indications As of October 2013
Dabigatran Rivaroxaban Apixaban
VTE prophylaxis (THA, TKA)
x x Atrial fibrillation VTE treatment x x Acute coronary syndromes x x x
Pharmacokinetics Dabigatran Rivaroxaban Apixaban
Target Thrombin Factor Xa Factor Xa
Peak Effect (h) 2 – 3 3 – 4 3 – 4
Half-life (h) 12 – 17 5 – 13 8 – 15
Dosing Frequency Twice daily Daily* Twice daily
Clearance 80% Renal 20% Biliary
66% Renal 33% Biliary
25% Renal 75% Biliary
* Despite short half-life, once daily dosing possible due to persistence of anti-Xa activity
Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33
Drug Interactions • Dabigatran interacts with drugs that affect the
transporter P-glycoprotein (P-gp)
• Rivaroxaban and apixaban also interact with P-gp drugs, as well as those that affect the microsomal enzyme CYP3A4
• Examples Ketoconazole Rifampicin Cyclosporine Itraconazole Clarithromycin Tacrolimus Amiodarone Protease inhibitors Carbamazepine Verapamil St. John’s wort Phenytoin
• Increased risk of major bleeding seen in studies of all 3 drugs when used with anti-platelet agents
Schulman S, Crowther MA. Blood 2012; 119(13):3016-23 Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33
Laboratory Monitoring
Dabigatran Rivaroxaban Apixaban
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
• Thrombotic risk is present • Dabigatran
– aPCC (FEIBA) 50 U/kg • Rivaroxaban and Apixaban
– 4-Factor PCC (Kcentra) 50 U/kg Siegal DM, Crowther MA. Eur Heart J 2013; 34(7):489-498b. Schulman S. HTRS 2013 Annual Meeting, oral presentation.
Khoo TL, et al. Int J Lab Hematol 2013; 35(2):222-4. Eerenberg ES et al. Circulation 2011; 124(14):1573-9.
Perioperative Management
Drug Package Insert Recommendations
Dabigatran
For CrCl >50, stop 1 to 2 days prior For CrCl <50, stop 3 to 5 days prior
Consider longer if major surgery, spinal puncture, spinal or epidural catheter
Rivaroxaban Stop at least 24 hours prior
Apixaban
Stop at least 48 hours prior (moderate or high risk procedures)
Stop at least 24 hours prior (low risk procedures)
• Lab testing – If TT (dabigatran) or anti-Xa (rivaroxaban, apixaban) are normal, drug has cleared
• If not normal, there is still drug on board (but cannot quantitate risk)
Advantages • Direct
anticoagulants
• Predictable pharmacokinetics
• No monitoring needed
• Few diet / drug interactions
Disadvantages • Cannot monitor
• Renal / hepatic excretion
• No antidotes
• Limited experience
• Lack of long-term safety data
• Cost
New Oral Anticoagulants
New Oral Anticoagulants To use or not to use ?
• Those already on warfarin, with good INR control, have little to gain by switching
• New agents slightly preferred over warfarin for those newly initiating treatment
• Some evidence suggests an increased risk of MI or ACS related to dabigatran; use with caution in those with CAD
• Watch renal / liver function
Atrial Fibrillation
New Oral Anticoagulants To use or not to use ?
• Dabigatran and apixaban are not approved in the US for this indication
• Rivaroxaban is a good alternative to LMWH / warfarin in this setting
• Approval currently limited to orthopedic surgery
Prevention of VTE
New Oral Anticoagulants To use or not to use ?
• Dabigatran and apixaban are not approved in the US for this indication
• Rivaroxaban was recently approved in the US for this indication (Nov. 2012)
• Rivaroxaban is a good choice for those who need short term treatment
• Long term concerns: safety, cost (to patient), breakthrough clots (?)
Treatment of VTE
• Malignancy
• Pregnancy
• “Severe” thrombophilia (APS, PC, PS, AT, double heterozygotes or homozygotes for FVL / PGM)
• Extremes of body weight
• Impaired renal / hepatic function
• Mechanical heart valves
• Those with more than “low” bleeding risk
• Real-world compliance (not on studies)
New Oral Anticoagulants To use or not to use ?
We need more experience in patients with:
RE-ALIGN Study (NEJM 2013; 369:1206-14)
• Dabigatran vs. warfarin
• Aortic and mitral valves
• Terminated early due to excess thromboembolic and bleeding events in dabigatran group
Take Home Points
The new oral anticoagulants are not necessarily better than warfarin; they are different, and each has advantages and disadvantages
Careful patient selection is crucial for the safe use of new oral anticoagulants
Management of bleeding complications from the new oral anticoagulants is a major clinical challenge; we lack data and “real world” clinical experience