The MD Conference Express ISTH Special Collection - (Page 12)
CLINICAL TrIAL HIGHLIGHTS
ESC 2012, Written by Lori Alexander
Genetic factors may be responsible for some of the interindividual variability in dabigatran exposure, according
to findings from the Randomized Evaluation of Long-Term
Anticoagulation Therapy [RE-LY] Genetics study. The
RE-LY trial demonstrated that dabigatran 150 mg BID was
superior to warfarin, while the 110-mg dose was noninferior
to warfarin in the reduction of stroke in patients with
atrial fibrillation [Connolly SJ et al. N Engl J Med 2009]. The
lower dose was associated with less major bleeding when
compared with warfarin, while the higher dose (150 mg)
had a similar rate of major bleeding.
Dabigatran etexilate is an oral prodrug that is rapidly
converted by esterases (carboxylesterase-1 [CES1]) to the active
agent dabigatran, explained Guillaume Pare, MD, McMaster
University, Hamilton, Ontario, Canada, who presented
the findings of the study. CES1 is a serine esterase that can
activate or deactivate various drugs. Prof. Pare and colleagues
hypothesized that genetic variability in the pathways required
for bioactivation of dabigatran might be responsible for some
of the 30% variability in dabigatran exposure.
In the first phase of the study, a genome-wide analysis
(551,203 markers) was performed on biologic samples
from 1490 patients of European ancestry enrolled in
the RE-LY trial randomized to dabigatran to identify the
genetic determinants of peak and trough concentrations
of dabigatran. Another 807 patients from RE-LY treated
with warfarin also underwent genotyping. Identified
genetic determinants were tested for their association with
efficacy and safety outcomes in an overlapping sample of
1694 patients. The primary efficacy endpoint was stroke or
systemic embolism, and the primary safety endpoint was
any bleeding (minor or major).
Genome-wide analysis demonstrated two variants
associated with peak concentration of dabigatran, one at
the ABCB1 locus (rs4148738) and one at the CES1 locus
(rs8192935). The ABCB1 polymorphism was associated
with a 12% increase in peak concentration per minor allele,
while the CES1 polymorphism was associated with a 12%
decrease in peak concentration per minor allele (p=8.2x10-8
and p=3.2x10-8, respectively). Two variants were associated
with trough concentration: rs4580160 at the CES1P2 locus
and rs2244613 at the CES1 locus. The CES1 polymorphism
had a significant effect, with a 15% decrease in trough
concentration per minor allele (p=1.2x10-8).
None of these genetic determinants had a significant
association with efficacy, but the CES1 rs2244613 variant
did have a significant association with bleeding (Table 1).
A significant interaction by treatment arm was also noted:
12
May 2013
the odds of bleeding with dabigatran decreased 33% for
carriers of the CES1 rs2244613 polymorphism, while there
was no impact of this genetic variant on bleeding for those
receiving warfarin (Figure 1). Approximately one third of
Europeans are carriers of this polymorphism, said Prof. Pare.
Table 1. Association of Significant Genetic Determinants with
Efficacy and Safety.
Peak Concentration
ABCB1 rs4148738
Trough Concentration
CES1 rs8192935
CES1 rs2244613
Odds
Ratio
(95% CI)
p
Value
Odds
Ratio
(95% CI)
p
Value
Odds
Ratio
(95% CI)
p
Value
Ischemic
stroke or
SE
0.88
(0.53-1.46)
0.62
0.76
(0.43-1.34)
0.34
0.70
(0.33-1.47)
0.34
Any
bleeding
0.94
(0.82-1.09)
0.44
0.89
(0.76-1.03)
0.13
0.67
(0.55-0.82)
7x10 -5
Major
bleeding
1.14
(0.85-1.52)
0.40
0.88
(0.64-1.21)
0.44
0.66
(0.43-1.01)
0.06
Minor
bleeding
0.94
(0.81-1.09)
0.38
0.89
(0.76-1.05)
0.17
0.70
(0.57-0.85)
4x10 -4
Event
SE=sytemic embolism.
Figure 1. Freedom from Bleeding According to CES1
rs2244613 Carrier Status in the RE-LY Study.
Carriers/Dabigatran (n events=154)
Noncarriers/Dabigatran (n events=432)
Carriers/Warfarin (n events=110)
1.0
Noncarriers/Warfarin (n events=215)
0.9
Freedom from Bleeding
Genetic Determinants of Variability
in Dabigatran Exposure
0.8
0.7
0.6
Dabigatran only: HR=0.70 (95% CI, 0.58 to 0.84); p=0.00016
Warfarin only: HR=1.13 (95% CI, 0.90 to 1.42); p=0.29
Carrier Status X Treatment Interaction p=0.0015
0.5
0.4
0
200
400
600
Days After Randomization
800
1000
Reproduced with permission from G Pare, MD.
This analysis provides evidence supporting the idea
of dose modification of dabigatran based on genotype but
requires additional study.
Rivaroxaban of Benefit in STEMI:
ATLAS ACS 2-TIMI 51
ESC 2012, Written by Lori Alexander
Treatment with a low dose of rivaroxaban, an oral factor Xa
inhibitor, has been shown to reduce recurrent cardiovascular
(CV) events and offer a survival benefit without a significant
increase in fatal bleeding for patients who have had an
ST-segment elevation myocardial infarction (STEMI).
www.mdconferencexpress.com
http://www.mdconferencexpress.com
Table of Contents for the Digital Edition of The MD Conference Express ISTH Special Collection
The MD Conference Express ISTH Special Collection
Table of Contents
New Oral Anticoagulants and Antiplatelet Drugs
SPS3 Study Does Not Support the Use of Combination Therapy for Stroke Prevention
Apixaban Superior to Warfarin in Patients with Atrial Fibrillation as Well as Prior Stroke or TIA
The HOST-ASSURE Randomized Trial
Oral Rivaroxaban Alone for Symptomatic Pulmonary Embolism
Moderate PE Treated with Thrombolysis (MOPETT Study)
Results of the WOEST Trial
Genetic Determinants of Variability in Dabigatran Exposure
Rivaroxaban of Benefit in STEMI: ATLAS ACS 2-TIMI 51
Hyporesponsiveness to Clopidogrel Does Not Predict 1-Year Mortality
First Large-Scale Platelet Function Evaluation in an Acute Coronary Syndrome Trial: The Trilogy ACS-Platelet Function Substudy
ASPIRE: Using Aspirin to Prevent Recurrence of VTE
ARCTIC: Randomized Trial of Bedside Platelet Function Monitoring
Long-Term Dabigatran Extension Study for Stroke Prevention in Treatment for Atrial Fibrillation
Clopidogrel Plus Aspirin Reduces Risk of Recurrent Stroke: The CHANCE Trial
Anticoagulation and Antithrombotic Therapy in Atrial Fibrillation
Balancing Bleeding and Ischemic Risk in the Acute and Long-Term Setting
Safety and Efficacy of Anticoagulants
The MD Conference Express ISTH Special Collection
https://www.nxtbook.com/nxtbooks/md_conference_express/ISTH
https://www.nxtbookmedia.com