EDOXABAN VERSUS WARFARIN FOR THE TREATMENT OF

SYMPTOMATIC VENOUS THROMBOEMBOLISM

dr. Hengki Wijaya *
dr. Djoko Heri Hermanto, SpPD-KHOM **
JOURNAL READING
*Resident of Internal Medicine, Faculty of Medicine, Brawijaya University, Saiful Anwar Hospital
**Supervisor of Internal Medicine, Faculty of Medicine, Brawijaya University, Saiful Anwar Hospital
The Hokusai-VTE Investigators

International Journal of Rheumatic Diseases 2012; 15: 6268
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INTRODUCTION
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Venous thromboembolism is the 3rd most common
cardiovascular disease after myocardial infarction and stroke.

The standard treatment consists of LMWH followed by vitamin
K antagonists.

A number of studies have established that new oral
anticoagulants with or without initial heparin therapy are
effective alternatives.

Edoxaban is a direct inhibitor of activated factor X with a rapid
onset of action. It is administered orally once daily and has
proven antithrombotic efficacy.

GOAL
Broadening applicability to real-world practice
and encouraging the enrollment of all
patients, including those with extensive
disease, by specifying that treatment should
be initiated with the proven, global standard
of parenteral heparin.
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MATERIALS AND METHODS (1)
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Study Oversight
Randomized, double-blind trial
Comparation between:
Enoxaparin followed by edoxaban with heparin followed by warfarin
Patients
-Inclusion criteria:
1. 18 years or older
2. Acute, symptomatic DVT involving the popliteal, femoral, or iliac veins or
acute, symptomatic PE (with / without DVT).
-Exclusion criteria:
1. Contraindications to heparin or warfarin
2. Receiving treatment for more than 48 hours of heparin
3. Receiving more than one dose of a vitamin K antagonist
4. Having cancer for which long-term treatment with LMWH
5. Another indication for warfarin therapy, continued to receive treatment
with aspirin at a dose of more than 100 mg daily or dual antiplatelet
6. Cr Cl <30 ml /minute

MATERIALS AND METHODS (2)
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Initial therapy with open-label enoxaparin for at least
5 days.
Edoxaban or warfarin was administered in a double-
blind, double-dummy fashion.
Edoxaban (or placebo)
Started after discontinuation of initial heparin.
60 mg orally once daily, or 30 mg once daily in patients with a Cr Cl of
30 - 50 ml /minute or body weight of 60 kg or less or receiving
concomitant with potent P-glycoprotein inhibitors.
Warfarin (or placebo)
Started concurrently with the study regimen of heparin, with
adjustment of the dose to maintain INR between 2.0 and 3.0.
All measurements were performed by means of a
point-of-care device that provided an actual INR
value for patients receiving warfarin and a sham INR
value for patients receiving edoxaban. INR
measurements were required to be performed at
least monthly.
Edoxaban or warfarin was to be continued for at
least 3 months and for a maximum of 12 months.

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MATERIALS AND METHODS (3)
MATERIALS AND METHODS (4)
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Outcome Measures
The primary efficacy outcome
the incidence of adjudicated symptomatic recurrent VTE, which was defined
as a composite of DVT or nonfatal /fatal PE.
Death was adjudicated as related to VTE, other cardiovascular disease,
bleeding, or other causes.
PE was considered to be the cause of death if there was objective
documentation that a pulmonary embolism caused the death or if the death
could not be attributed to a documented cause and pulmonary embolism
could not be ruled out.
Secondary efficacy outcomes included the primary efficacy outcome
combined with either death from cardiovascular causes or death from any
cause.
The principal safety outcome was the incidence of adjudicated clinically
relevant bleeding, which was defined as a composite of major or clinically
relevant nonmajor bleeding.
MATERIALS AND METHODS (4)
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Surveillance and Follow-up
Patients underwent assessment on days 5 through 12, 30,
and 60 after randomization and monthly or every 3 months
after discontinuing the study drug.
All patients were to be contacted at month 12.
Patients were instructed to report symptoms suggestive of
recurrent VTE or bleeding.

Statistical Analysis
The study was designed as an event-driven trial to test the
hypothesis that edoxaban would be noninferior to warfarin
RANDOMIZATION & FOLLOW UP
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From January 2010 through October 2012, a total of 8292
patients were enrolled at 439 centers in 37 countries
RESULTS(1)

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RESULTS(2)
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RESULTS(3)
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RESULTS (4)
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DISCUSSION(1)
Patients with VTE, treatment with heparin
followed by oral edoxaban once daily, as
compared with standard therapy, was
noninferior with respect to efficacy
superior with respect to bleeding.
fewer fatal and intracranial bleeds in the edoxaban
group
between-group difference with respect to major
bleeding did not reach statistical significance.
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DISCUSSION(2)
The design of the Hokusai-VTE study, as
compared with a design calling for on treatment
analyses only, allowed for a better understanding
of the outcomes that may be expected in clinical
practice.
In the on-treatment analysis, we observed low
rates of recurrence that were similar to those
seen in contemporary studies.
The use of the traditional sequence of a heparin
lead-in followed by an oral agent may be
considered a limitation of the Hokusai-VTE study.
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DISCUSSION(3)
Halving of the daily dose of edoxaban to 30
mg maintained efficacy with significantly less
bleeding than that observed in the warfarin
group.
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CONCLUSIONS
The Hokusai-VTE study showed that in a broad
spectrum of patients with VTE, including those
with severe PE, edoxaban administered once
daily after initial heparin was noninferior to
standard therapy with warfarin after initial
heparin, with significantly less bleeding.
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DOES THIS STUDY ADDRESS A CLEAR QUESTION?
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V
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ARE THE RESULTS OF THIS SINGLE TRIAL VALID?
V
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THIS JOURNAL IS VALID
WHAT WERE THE RESULTS?
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EER= 35%
CER= 65%
ARR= 30%
RRR= 46%
NNT= 3 patient
ARR to population= 29,68% - 30,32%
NNT to population= 3
CAN I APPLY THESE VALID, IMPORTANT RESULTS TO MY PATIENT?
V
V
V
V
THIS JOURNAL IS APPLICABLE
THANK YOU
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