Transcript Slide 1

The ADOPT Trial and
Direct Factor Xa Inhibitors
Satyam Sarma, MD
Northwestern University Feinberg School of Medicine,
Chicago, Illinois
A REPORT FROM THE 2011 SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION
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1
New Oral Anticoagulants

Over the past decade, new oral anticoagulants have
been developed to overtake the mantle of heparin
and vitamin K antagonist-based therapies.

Promising convenient fixed dosing, fewer food and
drug interactions, improved side-effect profiles, and
efficacy at least equal to that of warfarin, these
compounds have revolutionized anticoagulant
therapy by overcoming the unpredictability and dose
variability of older treatment options.

Some of these novel agents have been studied
clinically and have been used with varied success
when compared with established therapy.1
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2
Clinically Studied Novel Anticoagulants
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3
Mechanism of Action

Compared with vitamin K antagonists such as
warfarin, direct factor Xa and direct thrombin
inhibitors target specific links in the coagulation
chain to theoretically confer a more predictable
dose-response relationship.

Direct factor Xa inhibitors (eg, rivaroxaban and
apixaban) bind directly to the catalytic site of factor
X in a 1:1 stoichiometric ratio.

Unlike indirect inhibitors, such as enoxaparin and
fondaparinux, direct factor Xa inhibitors do not
require antithrombin III as a mediating factor to
exert their anticoagulant effects.1
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4
Mechanism of Action

Direct thrombin inhibitors (eg, ximelagatran and
dabigatran) block the effects of thrombin and limit
the generation of fibrin from fibrinogen.

These drugs also affect the actions of thrombin on
non-coagulation cascade pathways by inhibiting both
thrombin-mediated platelet activation and activation
of factors V, VIII, XI, and XIII.

Currently, dabigatran is the only oral direct thrombin
inhibitor available for clinical use.1
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5
Mechanism of Action

Considerable variability in the effective
bioavailability of factor X and thrombin exists,
affecting the in vivo actions of these drugs.

Factor Xa complexes with factor Va on the platelet
surface to form the prothrombinase complex,
increasing the catalytic activity of fibrin-bound factor
Xa and allowing for highly efficient thrombin
activation.26

Direct factor Xa and direct thrombin inhibitors can
access the catalytic sites of their respective targets,
whether in the circulation or in spatially confined
locations such as a dense clot.
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6
Measuring Plasma Anticoagulant Activity

Both prothrombin time (PT) and activated partial
thromboplastin time (aPTT) rely on normal plasma
concentrations of coagulation factors.

For direct inhibitors, routine measurement of PT and
aPTT is not recommended, because these drugs may
have unpredictable and unclear effects on assay
results, depending upon their plasma concentration
and dose timing.27

For dabigatran and rivaroxaban, aPTT may offer a
qualitative measure of activity; normal levels suggest
inadequate anticoagulant levels.28,29
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7
Measuring Plasma Anticoagulant Activity

Prothrombin time results are more unreliable than
aPTT measurements due to variability in the
reagents used.

Thrombin time and activated factor Xa level are
more direct measures of plasma anticoagulant
activity for direct thrombin and direct factor Xa
inhibitors, respectively, but their measurement is not
readily available in most clinical laboratories.
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8
Measuring Plasma Anticoagulant Activity

Gray and Fareed30 compared the direct inhibitory
effects of direct factor Xa and direct thrombin
inhibitors on thrombin activation, using an isolated
tissue factor-activated prothrombin assay system.

In this assay, the inhibitory effects of rivaroxaban
were most potent, followed by those of otamixaban,
apixaban, melagatran, and dabigatran.

When assessed using traditional plasma-based assay
systems, direct factor Xa inhibitors were less potent
in altering PT and aPTT than were direct thrombin
inhibitors, suggesting that their actions likely extend
beyond simple inhibition of thrombin and factor Xa.
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9
Anticoagulation Therapy for DVT and PE

Deep venous thrombosis (DVT) and pulmonary
embolism (PE) are significant causes of morbidity
and mortality in nonsurgical hospitalized patients,
and the risk persists after discharge.

Anticoagulant therapy effectively prevents DVT and
PE, has dramatically decreased mortality from PE in
patients hospitalized for hip and knee surgery, and
has become the standard of care.31

In addition, routine DVT prophylaxis during
hospitalization has reduced the rates of DVT and
fatal PE among patients who were hospitalized for
medical illnesses and suffered a loss of mobility.32
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10
Anticoagulation Therapy for DVT and PE

A large number of patients suffer DVT and PE after
hospital discharge, and few studies have assessed the
efficacy of extending antithrombotic therapy into the
postdischarge period in patients who had been
hospitalized for medical illnesses.

A recent study of extended-duration prophylaxis of
DVT in nonsurgical patients given subcutaneous
enoxaparin for 28 days showed no significant net
clinical benefit, due to an increase in bleeding that
counterbalanced the decrease in the incidence of
venous thromboembolism (VTE).33
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11
Anticoagulation Therapy for DVT and PE

Direct factor Xa and direct thrombin inhibitors offer
the opportunity for a better prophylactic agent post
discharge because they are given orally and have a
more predictable dose response when compared
with heparin or exoxaparin and vitamin K
antagonist-based therapies.

Prior studies of novel oral anticoagulants in patients
with atrial fibrillation showed a lower incidence of
bleeding when compared with warfarin, and this
benefit was expected to translate into a net clinical
advantage for direct factor Xa and thrombin
inhibitors in medically ill patients post discharge.
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12
The ADOPT Trial: Background

The MAGELLAN study first examined extendedduration DVT prophylaxis using an oral factor Xa
inhibitor and compared rivaroxaban given for 35
days with enoxaparin administered for 10 days post
discharge.15

Patients treated with rivaroxaban had a decreased
incidence of DVT and PE (4.4%) compared with 5.7%
among patients receiving enoxaparin (relative risk
[RR], 0.771; P = 0.0211).

However, the prophylactic benefits of rivaroxaban
were substantially outweighed by an increase in
bleeding rate (4.1% for rivaroxaban vs 1.7% for
enoxaparin; RR, 2.5; P < 0.0001).
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The ADOPT Trial: Background

Apixaban, a direct factor Xa inhibitor, and
rivaroxaban share a number of similarities.

Apixaban has an oral bioavailability greater than
66%, compared with 80% for rivaroxaban, and a
half-life of 8–13 hours, compared with 7–13 hours
for rivaroxaban.34

In the ROCKET AF trial,12 rivaroxaban therapy was
statistically noninferior to warfarin therapy, with the
two drugs showing similar rates of major bleeding.

Results of selected clinical trials investigating the use
of apixaban and/or rivaroxaban are summarized in
the table on the following slide.12,14,17–19,35,36
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14
Clinical Trials of Rivaroxaban and Apixaban
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15
The ADOPT Trial: Background

The double-blind, double-dummy, placebocontrolled ADOPT trial compared the use of
apixaban with enoxaparin therapy for preventing
acute DVT and PE in medically ill patients following
discharge from the hospital.16

Similar to the group conducting the MAGELLAN
study, the ADOPT investigators hypothesized that
prolonging VTE prophylaxis into the postdischarge
period would prevent the occurrence of DVT or PE in
patients at high risk.
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16
The ADOPT Trial: Patients

For inclusion in this study, patients had to have been
hospitalized for congestive heart failure (CHF) or
acute respiratory failure, with an expected hospital
stay of at least 3 days, or had to have been
hospitalized for an infection, inflammatory bowel
disorder, or acute rheumatic disorder and had a risk
factor for VTE (age  75 years, body mass index
> 30 kg/m², prior history of VTE or estrogen use).

Patients also had to have moderately (walking within
the room) to severely limited (primarily bed-bound)
mobility.
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The ADOPT Trial: Patients

Patients were excluded if they had confirmed VTE;
required anticoagulation for other indications; were
on dual antiplatelet therapy; or had renal
dysfunction, anemia (hemoglobin level < 9 mg/dL),
abnormal liver function tests, or a high risk of
bleeding.

Patients were randomized to receive either 2.5 mg of
apixaban administered orally twice daily for 30 days
or 40 mg of enoxaparin subcutaneously once daily
for 6–14 days. Subjects randomized to the apixaban
arm of the study received placebo injections of
enoxaparin for at least 6 days to preserve blinding.
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The ADOPT Trial: Outcome Measures

The primary efficacy outcome was a 30-day
composite endpoint of:
» Death from VTE
» Fatal or nonfatal PE
» Symptomatic or asymptomatic VTE, as detected by lower
extremity duplex sonography within the 30-day treatment
period

Secondary endpoints included:
» Death from any cause within the 30- or 90-day study period
» A composite of death or the occurrence of VTE within the
6–14 days of enoxaparin therapy
» Symptomatic VTE or nonfatal PE within 60 days
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The ADOPT Trial: Outcome Measures

The primary safety outcome was major bleeding,
clinically relevant nonmajor bleeding, and all
bleeding reported by investigators; MI; stroke;
thrombocytopenia; and death from any cause.

Major bleeding was defined as fatal or overt if at
least one of the following applied:
» A decrease in hemoglobin level of  2 g/dL over 24 hours
» Transfusion of  2 units of packed red cells
» Bleeding that occurred in an operated joint that required
reoperation or intervention; or intramuscular bleeding with
the compartment syndrome; or intracranial, intraspinal,
intraocular, pericardial, or retroperitoneal bleeding
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The ADOPT Trial: Results

In all, 6,528 acutely ill patients were randomized
initially to receive short-term enoxaparin
prophylaxis or extended apixaban prophylaxis.
Approximately 2,000 patients were excluded for
nonevaluable or missing lower extremity venous
ultrasonograms during the 30-day treatment period.

The baseline characteristics of the patients in the two
groups did not differ. The median age was 68 years
in the apixaban arm and 67 years in the enoxaparin
arm. Over 60% were > 65 years of age. About 80%
were hospitalized for CHF or respiratory failure, with
the remainder of patients hospitalized primarily for
infectious causes without septic shock.
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The ADOPT Trial: Results

Data on 4,495 patients were analyzed for efficacy.

At 30 days, there were no significant difference
between apixaban and enoxaparin in the primary
efficacy outcome (2.71% vs 3.06%, respectively; RR,
0.87; 95% CI, 0.62–1.23; P = 0.44).

There was a significant increase in major bleeding in
the apixaban arm compared with the enoxaparin
arm (0.47% vs 0.19%; RR, 2.58; 95% CI, 1.04–7.24;
P = 0.04).

This difference was likely due to the greater number
of patients in the apixaban group who experienced a
decrease in hemoglobin level  2 g/dL.
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The ADOPT Trial: Results

The key secondary outcome of VTE or death during
the 6- to 14-day period prior to discontinuation of
enoxaparin was also similar in both groups (1.73% vs
1.61%; RR, 1.06; 95% CI, 0.69–1.63).

There was a nonsignificant trend toward decreased
symptomatic VTE and VTE-related mortality in
patients treated with apixaban after enoxaparin
therapy was discontinued (0.25% vs 0.58%; RR,
0.44; 95% CI, 0.19–1.00).

The primary driver of the difference was the decrease
in symptomatic VTE among patients given extended
thromboprophylaxis with apixaban when compared
with those given enoxaparin (0.15% vs 0.49%).
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The ADOPT Trial: Results

Mortality in both groups of patients was 4.1%.

Within the early post-discharge period (< 14 days),
when both groups received antithrombotic therapy,
no patients died of VTE-related complications.

During the later follow-up period after enoxaparin
therapy was stopped, there were two and three VTErelated deaths in the apixaban and enoxaparin arms,
respectively.

The most common event over the 30-day treatment
period was development of proximal DVT, which
occurred in 2.4% of patients receiving apixaban and
2.5% receiving enoxaparin.
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The ADOPT Trial: Discussion

Results regarding the primary endpoint of the
ADOPT trial did not show a benefit from extended
apixaban therapy when compared with enoxaparin
use, but it did reveal a trend toward decreased
symptomatic VTE and VTE-related deaths in the
apixaban-treated group after discontinuation of
enoxaparin therapy.

There were no differences in total bleeding events
between the groups, but there was an increase in
major bleeds in patients treated with apixaban.
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The ADOPT Trial: Discussion
Although the overall findings were not statistically
significant, there were many limitations to the final
analysis:

The primary endpoint was underpowered due to the
exclusion of approximately 2,000 patients for
inadequate follow-up ultrasonography.

The comparator arm also was not representative of
real-world practice, as treatment with enoxaparin for
6–14 days is not routine in post-discharge care.

Screening for DVT at 10 days post discharge is not
routine; thus, the natural history and occurrence of
VTE-related events likely were altered.
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The ADOPT Trial: Discussion

The findings from the ADOPT trial do not support a
strategy favoring extended-duration treatment with
apixaban over short-term enoxaparin therapy in
managing nonsurgical patients at high risk for
developing VTE or PE post discharge.

A better understanding of the clinical factors that
identify high-risk patients is necessary to balance the
risk-benefit ratio.

The increased risk of bleeding seen in prior studies
using enoxaparin and rivaroxaban for extended DVT
prophylaxis also was observed in the ADOPT trial.
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27
The ADOPT Trial: Discussion

To date, the use of direct factor Xa inhibitors have
not substantially mitigated the risk for bleeding
when compared with enoxaparin therapy in the
medically ill patient population.

However, with proper identification of patients at
high risk for post-discharge DVT, both apixaban and
rivaroxaban may yet have a role in this undertreated
population.

Further, direct thrombin inhibitors offer the
advantage of oral administration when compared
with injected low-molecular-weight heparins and a
more predictable dose response when compared
with vitamin K antagonists such as warfarin.
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Conclusion

Development of new direct inhibitors has focused
primarily on direct factor Xa inhibitors, such as
rivaroxaban and apixaban.

Whereas their safety profiles with regard to the
occurrence of major bleeding have not been as
robust as hoped, their clinical efficacy when
compared with vitamin K antagonists and lowmolecular-weight heparins has been well validated.

Because of their oral administration and few drug
interactions, these novel anticoagulants may find
new indications for short-term anticoagulant therapy
in patients at high risk for thrombotic complications.
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© 2012 Direct One Communications, Inc. All rights reserved.
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