Download Dabigatran

Presented at
Grand Rounds
Department of Neurology
Loyola University Health System
Maywood, Illinois 60153
September 30, 2011
LOYOLA
UNIVERSITY
HEALTH SYSTEM
Loyola University Chicago
Dabigatran
and other
New Oral Anticoagulants
Jeanine M. Walenga, PhD
Professor, Thoracic-CV Surgery and Pathology
Co-Director, Hemostasis and Thrombosis
Research Laboratories
Loyola University Chicago
Currently Available Anticoagulants
DRUG
• Warfarin
•
•
•
•
•
Heparin
LMW heparins
Lepirudin (DTI)
Bivalirudin (DTI)
Argatroban (DTI)
CLINICAL USE
Long-term AC, stroke
prevention in AF
VTE, ACS, CPB, PCI
VTE prevention
HIT
HIT, PCI
HIT, PCI
Some of the New Anticoagulants
Anti-FXa
–
–
–
–
–
–
–
–
Anti-Flla (anti-thrombin)
Rivaroxaban (o)
Apixaban (o)
Edoxaban (o)
Otamixaban (p)
LY-517717 (o)
DX-9065a (p)
Betrixiban (o)
TK-442 (o)
–
–
–
–
–
–
O:Oral, P:Parenteral
Dabigatran (o)
Odiparcil (o)
Flovagatran (p)
Pegmusirudin (p)
Peg-hirudin (p)
Desirudin (p)
Oral Anticoagulant Target Sites
Factor IX
Factor VII
Factor X
FVIIa
VKA drugs
FIXa
Anti-FXa drugs
•Tecarfarin
•Warfarin
•Apixaban
•Betrixaban
•Edoxaban
•Rivaroxaban
•LY 517717
•TAK 442
•YM 150
Factor Xa
Antithrombin
Anti-FIIa drugs
Factor II
(Prothrombin)
Fibrinogen
•Dabigatran
•Ximelagatran
•AZD 0837
Factor IIa
(Thrombin)
Fibrin
Comparison of
NEW ORAL ANTICOAGULANTS
with WARFARIN
Features
Onset
Dosing
Indications
Food effect
Drug interactions
Monitoring
Half-life
Antidote
Warfarin
Slow
Variable
Same
Yes
Yes
Yes
Long
Yes
New Agents
Rapid
Fixed
Same
No
Yes
No
Short
No
Rivaroxaban
• Direct, specific, competitive
factor Xa inhibitor
Xarelto®
• Rapid onset within 2-4 hours
• High bioavailability of >80%
• Metabolized via the CYP3A4,
CYP211, and P-gp transport
mechanisms
• See interactions with drugs
using the same metabolic
pathways
Perzborn et al., J Thromb Haemost 2005.
• Renal and fecal elimination
Kubitza et al., J Clin Pharmacol 2007.
Rivaroxaban:
Clinical Development
Postsurgical
prophylaxis
of DVT
DVT
Treatment
Stroke
Prevention
in AF
ACS
ODIXa-KNEE
EINSTEIN-DVT
ROCKET-AF
ATLAS
ODIXa-HIP
EINSTEIN-EXT
ROCKET-J
RECORD-1
EINSTEIN-PE
RECORD-2
RECORD-3
RECORD-4
ACS-TIMI 46
ATLAS
ACS-TIMI 51
RECORD 1-4 Summary
Total Treatment Duration Pool
Incidence (%)
2.0
Enoxaparin regimens
ARD=–0.8%
p<0.001
Rivaroxaban regimens
1.5
1.0
Primary population
for analysis
1.3%
0.5
0
ARD=0.2%
p=0.076
0.6%
0.2%
82/6,200 35/6,183
Symptomatic VTE and
all-cause mortality
13/6,200 24/6,183
Major bleeding
p-values analyzed using a Cox regression model; safety population, n=12,383
Turpie AGG, et al. Presented at ASH 2008
0.4%
ROCKET-AF:
Stroke, Non-CNS Embolism
Study Outcome: Rivaroxaban vs Warfarin
On Treatment
N = 14,143
1.70% vs 2.15% stroke rate
21% reduction in stroke rate w/ rivaroxaban
p = 0.015
ITT
N = 14,171
2.12% vs 2.42% stroke rate
12% reduction in stroke rate w/ rivaroxaban
p = 0.117
ROCKET-AF:
Clinical Trial Outcomes
• Efficacy
– Rivaroxaban: non-inferior to warfarin for SPAF
– Rivaroxaban: superior to warfarin while patients were
taking study drug
• Safety
– Similar rates of bleeding and adverse events
– Less ICH and fatal bleeding with rivaroxaban
• Conclusion
– Rivaroxaban is a potential alternative to warfarin for
moderate or high risk AF patients
Rivaroxaban: FDA Status
• Xarelto trade name
• For the prevention of DVT/PE after orthopedic
surgery:
– Rivaroxaban 10 mg OD is FDA approved (July 2011)
– Approved in the EU and Canada
• For the prevention of stroke in patients with atrial
fibrillation:
– FDA advisory committee voted to approve (Sept. 2011)
• Yes=9, No=2, Abstain=1
– Recommended approval in the EU (Sept. 23, 2011)
Apixaban
• Direct, reversible FXa
inhibitor
• Rapid onset, peak within 3
hrs
• Bioavailability of 51-85%
• Long half life, slightly longer
in elderly (15 hrs)
• Multiple elimination pathways
Eliquis
– 25% renal
– 75% biliary
• Metabolism via CYP3A4,
SULT1AA pathways
Perzborn et al., J Thromb Haemost 2005.
Kubitza et al., J Clin Pharmacol 2007.
Apixaban:
Clinical Development
Postsurgical
prophylaxis
of DVT
APROPOS
DVT
Treatment
Stroke
Prevention
in AF
ACS
Botticelli DVT
ARISTOTLE
APPRAISE-1
AVERROES
APPRAISE-2
dose-ranging study
ADVANCE-1
ADVANCE-2
AMPLIFY
(ongoing)
(study terminated
because of bleeding)
AMPLIFY-EXT
APPRAISE
Japan
(ongoing)
(study terminated)
ADVANCE-3
Primary Endpoint* (%)
ADVANCE-2:
Primary Efficacy Results
25%
RR: 0.62; 95% CI: 0.51-0.74
p < 0.0001*
24.4 %
20%
15%
10%
15.1 %
95%CI:
13.0-17.5%
95%CI:
21.8-27.1%
Apixaban 2.5mg BID
(n=976)
Enoxaparin 40mg QD
(n=997)
5%
0%
*Composite of adjudicated asymptomatic DVT by venography; objectively confirmed
symptomatic DVT or PE; or death from any cause. One-sided p-value for superiority.
Lassen MR, et al. Presented at ISTH, Boston, MA. July 2009.
ARISTOTLE: Study Outcomes
• Treatment with apixaban as compared to warfarin
in patients with AF (n>18,000) and at least one
additional risk factor for stroke:
– Reduces stroke and systemic embolism by 21%
(p=0.01)
– Reduces major bleeding by 31% (p<0.001)
– Reduces mortality by 11% (p=0.047)
– Consistent effects across all major subgroups
– Fewer drug discontinuations on apixaban than on
warfarin, consistent with good tolerability
Granger CB, et al. NEJM 2011;365: Aug 28
Apixaban: FDA Status
• Eliquis trade name
• For the prevention of DVT/PE after orthopedic
surgery:
– No FDA approval yet
– Apixaban approved in the EU
• For the prevention of stroke in patients with
atrial fibrillation:
– No approvals yet
Edoxaban: Clinical Development
Postsurgical
prophylaxis of DVT
Oral direct FXa inhibition
with E for thrombophylaxis
after elective THR: a
randomized double-blind
dose-response study
DVT
Treatment
The Edoxaban
Hokusai-VTE
Study
(ongoing)
Stroke Prevention
in AF
Randomized, parallel-group,
multicenter, multinational
Phase II study comparing E,
an oral factor Xa inhibitor,
with warfarin for SPAF
STARS J-1
ENGAGE AF-TIMI 48
STARS J-2
Safety of edoxaban, an oral factor
Xa inhibitor, in Asian patients with
(completed
June 2011; unpublished)
NVAF
STARS E-3
(completed
Feb. 2010; unpublished)
STARS J-4
(completed Feb.
2010; unpublished)
STARS J-5
(completed
March 2010; unpublished)
Edoxaban: FDA Status
• Lixiana trade name
• For the prevention of DVT/PE after orthopedic
surgery:
– No FDA approval yet
– Edoxaban approved in Japan
• For the prevention of stroke in patients with
atrial fibrillation:
– No approvals
Dabigatran Etexilate
• Specific, competitive, reversible univalent
thrombin inhibitor
Pradaxa®
• Pro-drug converted to active form
• Rapid onset within 2 hours
• Low bioavailability, 3.5-5%
• Low protein binding
• Half life 12-17 hours
• Renal clearance as glucuronic acid
conjugate: 85%
• Metabolized by esterase catalyzed
hydrolysis and P-gp transport
mechanisms
Perzborn et al., J Thromb Haemost 2005.
Kubitza et al., J Clin Pharmacol 2007.
Dabigatran:
Clinical Development
Postsurgical
prophylaxis
of DVT
DVT
Treatment
RE-MODEL
RE-COVER
RE-MOBILIZE
RE-MEDY
RE-NOVATE
RE-SONATE
RE-NOVATE 2
(unpublished)
(ongoing)
(unpublished)
Stroke
Prevention in
AF
RE-LY
ACS
RE-DEEM
(unpublished)
RE-LY
A Non-Inferiority Trial
Atrial fibrillation with ≥ 1 Risk Factor
Absence of contraindications
951 centers in 44 countries
Blinded Event Adjudication
R
Open
Warfarin Adjusted
INR 2.0 – 3.0
N=6,000
Blinded
Dabigatran
110 mg BID
N=6,000
Connolly SJ, et al. NEJM 2009; 361:1139-1151
Dabigatran
150 mg BID
N=6,000
RE-LY: Stroke Prevention
150 mg - 34% Fewer Strokes
Non-inferiority Superiority
p-value
p-value
Dabigatran 110
vs. Warfarin
<0.001
0.34
Margin = 1.46
Dabigatran 150
vs. warfarin
<0.001
0.50
0.75
Dabigatran better
Connolly SJ, et al. NEJM 2009;361:1139-51
1.00
1.25
HR (95% CI)
1.50
Warfarin better
<0.001
RE-LY: Study Outcomes
Efficacy
• Both doses of dabigatran were non-inferior to warfarin on the
primary endpoint
– reduction of the incidence of stroke including hemorrhagic and
systemic embolism; p<0.001
• Dabigatran 150 mg BID was superior to warfarin on the primary
endpoint by 34%
– RR 0.66, 95% CI, 0.53-0.82; p<0.001
Safety
• No significant difference in the rate of major bleeding for dabigatran
150 mg BID compared to warfarin
– 3.11 vs 3.36 %/yr; p=0.31
• Rate of major bleeding with dabigatran 110 mg BID (2.71%/yr) was
20% lower compared to warfarin; p=0.003
RE-LY: MORTALITY REDUCTION
DABIGATRAN VS WARFARIN
• Lower death rate with dabigatran:
– Vascular death
2.69% vs 2.43 and 2.28%* (p=0.04 for 150 mg)
– All cause death
4.13% vs 3.75 and 3.64% (p=0.05 for 150 mg)
*Dabigatran 110 mg and 150 mg
Connolly SJ, et al. NEJM 2009;361: 1139-1151
RE-LY: BLEEDING
DABIGATRAN VS WARFARIN
• More bleeding with warfarin:
– Life-threatening bleeding
1.8% vs 1.2 and 1.5%* (p<0.001, 0.04)
– Intracranial bleeding
0.7% vs 0.2 and 0.3% (p<0.001, <0.001)
– Major plus minor bleeding
18.2% vs 14.6 and 16.4% (p<0.001, 0.002)
*Dabigatran 110 mg and 150 mg
Connolly SJ, et al. NEJM 2009; 361:1139-1151
Dabigatran: FDA Status
• Pradaxa trade name
• For the prevention of DVT/PE after orthopedic
surgery:
– FDA approval pending
– Pradaxa approved in EU and Canada
• For the prevention of stroke in patients with
non-valvular atrial fibrillation (SPAF):
– Pradaxa 150 mg BID FDA approved (Oct. 2010)
– Pradaxa approved in EU, Canada and Japan
Dabigatran: FDA Approved Dosing
• 150 mg BID for SPAF
– 150 mg for CrCl >30 mL / min
– 75 mg for CrCl 15-30 mL / min
Stroke from Atrial Fibrillation
• AF is the most preventable cause of
stroke:
– 12-16 million will be on warfarin treatment by
2050 in the US
– Clinical trials have shown stroke can be
reduced:
•
•
•
•
Placebo vs ASA = 19% 
ASA vs warfarin = 30% 
Placebo vs warfarin = 62% 
Dabigatran vs warfarin = 34% 
Dabigatran: Not Without Issues
1.
No anticoagulant effect if missed dose
• 2% discontinuation rate due to GI distress
• Cost of drug ($240/mo vs $4/mo for warfarin)
2.
3.
4.
No test to assess anticoagulation
Difficult to modulate dose
Bleeding in the elderly and renal impaired patients
(5 dabigatran related deaths in Japan)
5. ‘Real world’ untested populations
6. Drug interactions
7. Limited data on bridging between anticoagulants
8. No specific antidote
9. 0.2% increase in myocardial infarction
10. Off-label use
New OACs:
Immediate Practical Issues
• Is there a specific antidote for dabigatran associated
bleeding?
– No, still in development
• How do we manage bleeding complications associated
with dabigatran?
• How can we test a patient for the presence of
dabigatran?
• Are there drug interactions with dabigatran?
– tPA (stroke, AMI)
– Heparins (ACS, stroke)
– Antiplatelet drugs
New OACs: ‘Real Life’ Experience
• Populations not studied in the clinical trials:
– Elderly, pediatrics, pregnant
– Heparin compromised (e.g., HIT)
– Acute vs non-acute VTE
– Chronically ill
• Common patient characteristics that influence the drug
PKs and safety/efficacy of NOACs:
– Co-morbid illnesses
– Reduce renal function
– Reduced hepatic function
– Altered metabolism, gastric pH, intestinal motility,
protein binding
– Extremes in body weight
– Co-administered Rx drugs, dietary supplements, herbs
New OACs: ‘Real Life’ Experience
• Drug interactions with NOACs:
– Potential adverse effects
• Alter the pharmacokinetics of the NOAC
• Increase or decrease exposure to the NOAC
• Increase bleeding risk
– Known ‘cautioned’ drugs
• Proton pump inhibitors
• Inhibitors or inducers of the CYP3A4 or P-gp transport
mechanisms
• NSAIDs, ASA, anti-platelet drugs
– At risk patients
•
•
•
•
•
Cardiovascular disease
Depression
Pain
Epilepsy
Requiring antibiotics, anti-fungals, anti-malaria drugs
Dabigatran: Bleeding Management
• Short half-life
• Maintain adequate diuresis
• Usual supportive measures: compression, surgical
hemostasis
• Dialysis (low protein binding)1
• Activated charcoal w/ subsequent charcoal filtration (in
vitro data)1
• Blood products
– May not be effective: replace factor deficiency (warfarin) vs
overcome an inhibitor (dabigatran)
• PCC not effective (effective against rivaroxaban)2
• rFVIIa
1vanRyn
2
J, et al. Thromb Haemost 2010;103(6):1116-27
Eerenberg ES, et al. Circulation 2011;124:Sept 6
Dabigatran: Laboratory Testing
• Monitoring vs anticoagulant assessment
– PT and aPTT
•
•
•
•
Differing reagent sensitivities
Not a linear association between assay values and drug level
Not validated for association to bleeding
aPTT may be applicable for qualitative assessment
– INR: not sensitive; not validated
– TT: Super-sensitive; can identify if any drug onboard
– Ecarin clotting time: results can vary depending on plasma
factors; research use only (RUO)
– PiCT: RUO
– Chromogenic anti-FIIa
– Hemoclot: quantitative using dabigatran calibrators; FDA
approved yet?
Anticoagulant Effects of Direct Thrombin and Factor Xa Inhibitors in
Retrieved Plasma
(Assay: PT)
140.0
120.0
Time (secs)
100.0
DABIGATRAN
80.0
MELAGATRAN
OTAMIXABAN
60.0
RIVAROXABAN
40.0
20.0
0.0
0
0.5
1
1.5
Conc. (ug/ml)
2
2.5
3
2 case reports of
inaccurate INR values
w/ dabigatran.
Baruch L, Sherman O.
Ann Pharmacother 2011
Jun 28
Anticoagulant Effects of Direct Thrombin and Factor Xa Inhibitors in
Retrieved Plasma (Assay: APTT)
180.0
160.0
140.0
Time (secs)
120.0
DABIGATRAN
100.0
MELAGATRAN
OTAMIXABAN
80.0
RIVAROXABAN
60.0
40.0
20.0
0.0
0
0.5
1
1.5
Conc. (ug/ml)
2
2.5
3
Anticoagulant Effects of Direct Thrombin and Factor Xa Inhibitors in
Human Whole Blood (Assay: TT5UCa++)
350.0
300.0
Time (secs)
250.0
DABIGATRAN
200.0
MELAGATRAN
OTAMIXABAN
150.0
RIVAROXABAN
100.0
50.0
0.0
0
0.5
1
1.5
Conc. (ug/ml)
2
2.5
3
Anticoagulant Effects of Direct Thrombin Inhibitors in Retrieved
Plasma (Assay: Anti-IIa)
90
80
70
% Inhibition
60
50
DABIGATRAN
MELAGATRAN
40
30
20
10
0
0
0.5
1
1.5
Conc. (ug/ml)
2
2.5
3
Anticoagulant Effects of Direct Factor Xa Inhibitors in Retrieved
Plasma (Assay: Anti-Xa)
120.0
100.0
% Inhibtion
80.0
OTAMIXABAN
60.0
RIVAROXABAN
40.0
20.0
0.0
0
0.5
1
1.5
Conc. (ug/ml)
2
2.5
3
Hemoclot Assay for Dabigatran
Dabigatran Calibration Curve
Dabigatran Treated Patients
Dabigatran vs Hemoclot TT (220 mg D)
90
250
200
70
150
Hemoclot TT
Hemoclot thrombin clotting time [s]
80
100
60
50
Linear fit (31.44 +0.1437x)
Linear fit (30.85 +0.04948x)
50
40
95% CI
95% CI
30
95% Prediction interval
95% Prediction interval
0
0
1000
2000
3000
4000
Dabigatran concentration [nM]
(Stangier et al. ISTH 2009, Boston)
20
0
50
100
150
200
Dabigatran [ng/mL]
250
300
The New Oral Anticoagulants:
Similar Yet Different
• Thrombin Inhibitors:
1. Dabigatran: pro-drug, renal clearance - twice daily
• FXa Inhibitors:
1. Rivaroxaban: renal clearance - once daily
2. Apixaban: hepatic clearance - twice daily
3. Edoxaban: hepatic clearance - once daily
Circulation 2010;121:1523-1532
The New Oral Anticoagulants:
Similar Yet Different
Rivaroxaban
Apixaban
Dabigatran
Etexilate
Target
Xa
Xa
IIa
Molecular Weight
436
460
628
Prodrug
No
No
Yes
Bioavailability (%)
80
50
6
Time to peak (h)
3
3
2
Half-life (h)
9
9-14
12-17
Renal excretion (%)
65
25
80
None
None
None
Features
Antidote
• Each drug has its own effect in lab tests.
• The metabolic mechanisms of each drug differ; see drug interactions.
• Each drug has to be managed individually.
The Future of Warfarin
1. Excellent efficacy
2. Low cost ($0.75 per day!)
3. Long track record (since 1954)
4. Centralized Anticoagulation Clinics that maintain TTRs
> 60%
5. PT assay available: fast TAT, inexpensive
6. INR validated for warfarin relation to bleeding risk
7. Point-of-care testing
8. Rapid turnaround genetic testing
Conclusions
1. New anticoagulants are now clinically
available and additional drugs are being
developed.
2. The new oral anticoagulants rivaroxaban,
dabigatran and apixaban, though costly, will
provide more options for the management of
VTE; however, these drugs are not superior to
the standard of care.
3. For VTE prevention, heparins and warfarin will
remain the standard of care for some time,
especially in medical patients.
Conclusions
4. For atrial fibrillation (SPAF) the new oral
anticoagulants appear to have a superior
safety and efficacy profile.
5. Additional clinical trials are needed to
determine the merit of these drugs beyond the
‘clinical trial’ populations, and to address
unanswered questions.
6. Warfarin’s low cost, efficacy, and track record
will prolong its life. Its use may decrease but it
will remain a for years to come.
Regulatory Approvals
• Orthopedic surgery (THR/TKR/Hip fracture):
–
–
–
–
Dabigatran: EU, Canada
Rivaroxaban: EU, Canada, US
Apixaban: EU
Edoxaban: Japan
• Non-ortho surgery, medical patients:
– No approvals
• SPAF:
– Dabigatran: US, EU, Canada, Japan
– Rivaroxaban: US and EU approval recommended