Keywords
venous thromboembolism - anticoagulation - extended therapy - rivaroxaban - acetylsalicylic
acid
Introduction
Most patients with venous thromboembolism (VTE), which includes deep vein thrombosis
and pulmonary embolism, are treated with anticoagulant therapy for at least 3 months.
Continuing anticoagulant therapy depends on the balance between the patient's risk
of VTE recurrence if treatment is stopped and the risk of bleeding with continued
treatment. Patient preference also needs to be considered.[1]
Although a 3-month course of anticoagulation therapy is sufficient for patients with
VTE provoked by major transient risk factors such as surgery or trauma, those with
unprovoked VTE or VTE related to active cancer are recommended to receive a longer
course of therapy unless their risk of bleeding is high.[1] Traditionally, VTE is considered unprovoked if it occurs in the absence of major
risk factors such as recent surgery or trauma, active cancer, pregnancy or oestrogen
use.[2] However, in recent years several additional risk factors have been identified, including
long-distance travel,[3] lower limb paresis or paralysis,[4] obesity,[5] inflammatory bowel disease[6]
[7] and renal impairment.[8] Therefore, it is now recommended that provoked VTE be further classified depending
on whether risk factors are major or minor and persistent or transient.[2]
Extended anticoagulation with vitamin K antagonists (VKAs), such as warfarin, is problematic.
Although such therapy reduces the risk of recurrent VTE, it is associated with a nearly
threefold increase in the risk of major bleeding.[9] Furthermore, VKAs are cumbersome to administer because they require frequent coagulation
monitoring and dose adjustments to ensure that the international normalized ratio
(INR) remains within the therapeutic range of 2.0 to 3.0.[1] Such monitoring is inconvenient for patients and physicians and places considerable
burden on health care resources. Consequently, many patients with VTE elect to stop
treatment with VKAs. Acetylsalicylic acid (ASA) is suggested in such patients[1] because, compared with placebo, it was shown to reduce the risk of recurrent VTE
by 32% without significantly increasing the risk of major or clinically relevant non-major
(CRNM) bleeding.[10]
The non-VKA oral anticoagulants (NOACs) were introduced to overcome many of the limitations
of VKAs. Unlike VKAs, the NOACs can be administered in fixed doses without routine
coagulation monitoring. Compared with VKAs for the treatment of VTE, the NOACs had
similar efficacy and were associated with an approximately 40% reduction in major
bleeding.[11] In this review, we will discuss the evidence base for the use of the NOACs for extended
treatment of VTE, focusing on the recent EINSTEIN CHOICE trial, which compared two
doses of rivaroxaban with ASA for extended VTE treatment.[12]
Extended Anticoagulation: The Role of Non-Vitamin K Antagonist Oral Anticoagulants
Extended Anticoagulation: The Role of Non-Vitamin K Antagonist Oral Anticoagulants
To date, randomized clinical trials have investigated the efficacy and safety of extended
anticoagulation with three NOACs (i.e. rivaroxaban, dabigatran and apixaban) in patients
who had already received a period of anticoagulant therapy after a confirmed VTE.[13]
[14]
[15] The results of these studies are summarized in [Table 1].
Table 1
Summary of randomized controlled trials for extended treatment of VTE with NOACs
|
Trial name
|
Study drug
|
Comparator
|
Duration of previous anticoagulation
|
Primary efficacy endpoint (study drug vs. comparator)
|
Primary safety endpoint (study drug vs. comparator)
|
|
EINSTEIN EXT[13]
|
Rivaroxaban 20 mg od
|
Placebo
|
6–12 months
|
Recurrent VTE: 1.3% vs. 7.1%, p < 0.001
|
Major bleeding: 0.7% vs. 0%, p = 0.11
|
|
RE-MEDY[15]
|
Dabigatran 150 mg bid
|
Warfarin
|
≥ 3 months
|
Recurrent or fatal VTE: 1.8% vs. 1.3%, p = 0.01 for non-inferiority
|
Major bleeding: 0.9% vs. 1.8%, p = 0.06
|
|
RE-SONATE[15]
|
Dabigatran 150 mg bid
|
Placebo
|
≥ 3 months
|
Recurrent or fatal VTE: 0.4% vs. 5.6%, p < 0.001
|
Major bleeding: 0.3% vs. 0%, p = 1.0
|
|
AMPLIFY-EXT[14]
|
Apixaban 2.5 mg bid
|
Placebo
|
6–12 months
|
Recurrent VTE or all-cause mortality: 3.8% vs. 11.6%, p < 0.001
|
Major bleeding: 0.2% vs. 0.5% (p-value not reported)
|
|
Apixaban 5 mg bid
|
Recurrent VTE or all-cause mortality: 4.2% vs. 11.6%, p < 0.001
|
Major bleeding: 0.1% vs. 0.5%
(p-value not reported)
|
|
EINSTEIN CHOICE[12]
|
Rivaroxaban 10 mg od
|
ASA
|
6–12 months
|
Recurrent or fatal VTE:
1.2% vs. 4.4%, p < 0.001
|
Major bleeding:
0.4% vs. 0.3%, p = 0.32
|
|
Rivaroxaban 20 mg od
|
ASA
|
6–12 months
|
Recurrent or fatal VTE:
1.5% vs. 4.4% p < 0.001
|
Major bleeding:
0.5% vs. 0.3%, p = 0.50
|
Abbreviations: ASA, acetylsalicylic acid; bid, twice daily; NOAC, non-vitamin K antagonist
oral anticoagulant; od, once daily; VTE, venous thromboembolism.
In the EINSTEIN EXT study, extended treatment with rivaroxaban 20 mg once daily was
compared with placebo in patients who had completed 6 to 12 months of prior anticoagulation
therapy and were in clinical equipoise regarding the need for continued therapy.[13] Rivaroxaban was associated with a significant 82% reduction in the risk of recurrent
VTE (from 7.1 to 3.2%) versus placebo, with no significant increase in the primary
safety outcome of major bleeding (although a significant increase in major or CRNM
bleeding was reported). Two extension studies investigated the efficacy and safety
of dabigatran 150 mg twice daily for the prevention of recurrent VTE in patients who
had completed at least 3 months of anticoagulation therapy for their index event.[15] In the active-controlled RE-MEDY study, dabigatran was non-inferior to warfarin
for efficacy and was associated with a non-significantly lower rate of major bleeding
and a significantly lower rate of major or CRNM bleeding, compared with warfarin.[15] In the placebo-controlled RE-SONATE study, dabigatran was superior to placebo for
efficacy but was associated with a significant increase in major or CRNM bleeding.[15] The AMPLIFY-EXT study compared the treatment dose of apixaban (5 mg twice daily)
and the dose used for thromboprophylaxis (2.5 mg twice daily) with placebo for extended
treatment in patients with VTE who had completed 6 to 12 months of prior anticoagulation
therapy and were in clinical equipoise regarding the need for continued therapy. Compared
with placebo, both doses of apixaban were associated with significant reductions in
the primary outcome of recurrent VTE or all-cause mortality, as well as in recurrent
VTE or VTE-related death.[14] Neither dose of apixaban was associated with a significant increase in major bleeding
or major or CRNM bleeding compared with placebo. A fourth NOAC, edoxaban, has not
been evaluated in a dedicated extension study; however, in the Hokusai-VTE trial,
patients received between 3 and 12 months of anticoagulation with edoxaban 60 mg once
daily (edoxaban 30 mg once daily in patients with reduced renal function or low body
weight) or warfarin after a confirmed venous thromboembolic event.[16] A sub-analysis of this study showed that when therapy was extended beyond 3 months
after the index event, edoxaban was as effective as warfarin and was associated with
a similar risk of clinically relevant bleeding but a lower risk of major bleeding.[17]
Compared with VKAs, the NOACs have several advantages for patients and physicians.
Thus, the NOACs are not influenced by dietary vitamin K intake, have few drug–drug
interactions and can be given in fixed doses without the need for routine coagulation
monitoring. Reflecting these reduced burdens in conjunction with the efficacy and
safety profiles demonstrated in the extension studies, the most recent guidelines
from the American College of Chest Physicians recommend NOAC therapy in preference
to VKAs for VTE treatment in patients without active cancer.[1] In patients with active cancer, guidelines continue to endorse low-molecular-weight
heparin (LMWH) as the standard of care because LMWH has shown superior long-term efficacy
compared with VKAs in patients with cancer-associated thrombosis.[18] Compared with LMWH, NOACs have the advantage of being less expensive and avoiding
the need for daily injections, but until the recent publications of the Hokusai-VTE-Cancer
and select-d studies,[19]
[20] no clinical trial had directly compared their efficacy and safety. The favourable
results with edoxaban and rivaroxaban in cancer-associated thrombosis have prompted
changes to guidelines.[21] Current guidance now suggests the use of edoxaban or rivaroxaban for cancer patients
with an acute diagnosis of VTE, a low risk of bleeding and no relevant drug–drug interactions.
LMWH is an acceptable alternative for such patients and remains the agent of choice
for cancer patients at high risk of bleeding, such as those with luminal gastrointestinal
cancers with an intact primary, cancers of the genitourinary tract at risk of bleeding,
patients with nephrostomy tubes or those with gastrointestinal mucosal abnormalities
such as esophagitis, gastritis, peptic ulcer disease or colitis.
Despite the greater convenience and similar or improved safety of NOACs compared with
VKAs, many patients elect to stop anticoagulation because of the cost of NOACs or
a fear of bleeding. In these cases, guidelines suggest the use of ASA therapy in preference
to no therapy at all.[1] This guidance is based on the outcomes of the WARFASA and ASPIRE trials,[22]
[23] both of which investigated the efficacy and safety of ASA compared with placebo
for extended secondary prevention in patients with unprovoked VTE who had completed
at least a 3-month course of anticoagulation with a VKA. In a pooled analysis of these
two studies (the INSPIRE collaboration), the use of ASA 100 mg once daily reduced
the risk of recurrent VTE by 32% compared with placebo over a median follow-up of
30.4 months with no significant increase in major or CRNM bleeding.[10] This risk reduction is substantially smaller than for anticoagulation, which is
expected to reduce recurrent VTE rates by more than 80%;[24]
[25] therefore, ASA is only recommended for patients at risk of recurrent VTE who have
declined to continue anticoagulation therapy.[1]
Finding the Optimal Benefit–Risk Profile for Extended Anticoagulation Therapy: Reduced
versus Full-Dose Rivaroxaban or Apixaban
Finding the Optimal Benefit–Risk Profile for Extended Anticoagulation Therapy: Reduced
versus Full-Dose Rivaroxaban or Apixaban
In light of the above guideline recommendation, and building on previous successful
extension studies, the recent EINSTEIN CHOICE study investigated the efficacy and
safety of two once daily doses of rivaroxaban versus ASA for extended VTE treatment.[12] Patients who had already received 6 to 12 months of anticoagulation therapy and
were in equipoise regarding the need for continued anticoagulation treatment were
randomized 1:1:1 to receive up to 12 months of therapy with rivaroxaban 20 mg once
daily, rivaroxaban 10 mg once daily or ASA 100 mg once daily. A total of 3,396 patients
underwent randomization, most of whom (59%) had provoked VTE. The patients included
had an index event of confirmed symptomatic proximal deep vein thrombosis (51%), pulmonary
embolism (34%) or both (15%).
Both rivaroxaban 20 mg once daily and rivaroxaban 10 mg once daily were associated
with significant reductions in VTE recurrence versus ASA (rates of recurrence were
4.4% with ASA, 1.5% with rivaroxaban 20 mg once daily and 1.2% with rivaroxaban 10 mg
once daily, equating to a 66% relative risk reduction with the rivaroxaban 20 mg dose
and a 74% relative risk reduction with the rivaroxaban 10 mg dose; p < 0.001 for both comparisons) ([Fig. 1A]). Safety outcomes were similar between the three arms, with no significant increase
in the incidence of major or CRNM bleeding with either dose of rivaroxaban (rates
of major bleeding were 0.3% with ASA, 0.5% with rivaroxaban 20 mg once daily and 0.4%
with rivaroxaban 10 mg once daily) ([Fig. 1B]). The relative risk reductions for VTE recurrence were similar in patients with
a provoked or unprovoked index event, although the rate of recurrence was higher in
patients with unprovoked VTE in all three study arms.[12]
Fig. 1 Key efficacy (A) and safety (B) outcomes in EINSTEIN CHOICE. ASA, acetylsalicylic acid; CRNM, clinically relevant
non-major; od, once daily; VTE, venous thromboembolism.
These results were broadly consistent with those of the earlier AMPLIFY-EXT trial,
which compared apixaban at doses of 5 mg twice daily or 2.5 mg twice daily with placebo.[14] In both trials, both doses of the NOACs were associated with a significant reduction
in recurrent VTE (vs. placebo in the case of AMPLIFY-EXT and ASA in the case of EINSTEIN
CHOICE), with a trend towards lower rates of major or CRNM bleeding in patients receiving
the lower dose.
The benefit–risk profile of reduced doses of rivaroxaban or apixaban was examined
in a recent meta-analysis that included both trials.[26] Compared with full-dose apixaban or rivaroxaban, the reduced dose regimens were
associated with a trend for lower rates of clinically relevant bleeding (2.3% vs.
3.7%; risk ratio [RR] 0.74; 95% confidence interval [CI], 0.52–1.05) and no significant
increase in recurrent VTE (1.6% vs. 1.4%; RR, 1.12; 95% CI, 0.67–1.87).[26] Consequently, these results suggest that reduced doses of either rivaroxaban or
apixaban provide greater safety than full doses without loss of efficacy. Future post-marketing
studies are required to confirm these favourable results.
What Have We Learnt from EINSTEIN CHOICE?
What Have We Learnt from EINSTEIN CHOICE?
The EINSTEIN CHOICE results provided three key lessons for the future treatment and
secondary prevention of VTE. First, rivaroxaban was more effective than ASA without
incurring a significant increase in the risk of bleeding. Second, although both doses
were more effective than ASA, rivaroxaban 10 mg once daily was associated with a trend
for a lower rate of bleeding compared with rivaroxaban 20 mg once daily, suggesting
an improved benefit–risk profile. For every 10,000 patients treated for 1 year with
rivaroxaban instead of ASA, there would be 284 (95% CI, 106–463) fewer episodes of
symptomatic VTE or major bleeding with the rivaroxaban 20 mg dose and 339 (95% CI,
165–512) fewer events with the rivaroxaban 10 mg dose.[27]
This was not the case with low-intensity warfarin: in the ELATE trial, the rate of
recurrent VTE was 2.8-fold higher with low-intensity warfarin (target INR 1.5–1.9)
than with usual-intensity warfarin (target INR 2.0–3.0) without a reduction in overall
bleeding.[28] Finally, rivaroxaban significantly reduced the risk of recurrence in patients with
provoked VTE, as well as unprovoked VTE.[12]
The introduction of the rivaroxaban 10 mg once daily regimen allows for a choice of
doses for extended VTE treatment, providing flexibility for both physicians and patients.
Although patient preference must always be a key consideration, the lower rivaroxaban
dose may reassure patients and physicians that extended secondary prevention can be
achieved with little risk of bleeding. Importantly, the updated European label for
rivaroxaban allows for dose re-escalation from rivaroxaban 10 mg once daily to rivaroxaban
20 mg once daily in the event that the patient's risk profile changes (e.g. because
of VTE recurrence on the lower dose);[29] this should provide further reassurance to patients and physicians.
With the introduction of the lower 10 mg dose of rivaroxaban, the obvious question
that arises is how should physicians select the best dose for each patient? Although
the rivaroxaban 10 mg once daily dose will be suitable for many patients, the higher
20 mg once daily dose of rivaroxaban will continue to be more appropriate for patients
at high risk of VTE recurrence or those who have experienced VTE recurrence on the
lower dose. Similarly, patients with active cancer who elect to switch from LMWH to
rivaroxaban would still be likely to benefit most from the rivaroxaban 20 mg dose.
On the other hand, the rivaroxaban 10 mg dose may provide reassurance for patients
who have experienced a prior bleeding event, those at a high risk of bleeding or those
with lifestyle-based concerns around anticoagulation (e.g. patients who participate
in contact sports).
It should be noted that the EINSTEIN CHOICE study was specifically designed to investigate
how best to treat patients who are at equipoise regarding the need for continued anticoagulation[12] and so its design is likely to have enriched the patient population with certain
patient sub-groups and disfavoured the inclusion of others. Most patients with a major
transient provoking factor for VTE (e.g. orthopaedic surgery) would not have been
included in the trial because they would have no indication for extended therapy beyond
3 months. Similarly, patients with a major persistent provoking factor, such as anti-phospholipid
syndrome or active cancer, have a clear indication for extended therapy, and many
physicians would be unwilling to enrol such patients in a trial in which they would
have a 33% chance of receiving ASA. Consequently, most of the patients with provoked
VTE enrolled in EINSTEIN CHOICE had minor provoking factors, such as a body mass index
greater than 30 kg/m2 or a family history of VTE, which are often overlooked when an event is classified
as provoked or unprovoked. It is, therefore, interesting to note that in the EINSTEIN
CHOICE population, rivaroxaban not only reduced the risk of recurrence compared with
ASA in patients with unprovoked VTE, but also in patients with VTE associated with
minor provoking factors.[12]
A pre-specified analysis combined data from the EINSTEIN CHOICE and EINSTEIN EXT studies
specifically to investigate the effect of minor persistent or minor transient provoking
factors on the risk of VTE recurrence.[30] In this analysis, recurrence rates in patients with VTE provoked by minor persistent
or minor transient risk factors were not significantly lower than in those with unprovoked
VTE, highlighting the importance of extended anticoagulation therapy in these patients.
Perhaps most notably, patients with minor transient risk factors (e.g. a leg injury
with impaired mobility) still had a cumulative annual risk of recurrence of 7.1% in
those who stopped anticoagulation, 3.3% in those who received ASA and 0.4% in those
who received rivaroxaban. It will be interesting to see what impact these data will
have on future trials and clinical practice in the coming years.
Conclusion
The results of the EINSTEIN CHOICE study build on previous extension studies to provide
a new therapeutic option for patients with a continuing risk of VTE recurrence, including
those with unprovoked VTE and those with VTE provoked by minor risk factors. Both
rivaroxaban 20 mg once daily and rivaroxaban 10 mg once daily were found to be superior
to ASA 100 mg once daily without a significant increase in clinically relevant bleeding.
Such results were consistent with those of the earlier AMPLIFY-EXT trial, which compared
apixaban at doses of 5 or 2.5 mg twice daily with placebo. Therefore, like apixaban,
rivaroxaban, particularly the reduced dose, may provide reassurance for patients and
physicians in cases where the decision to extend anticoagulation is less straightforward.
Such reassurance is important because we have learned that VTE is often a chronic
disease associated with a high rate of recurrence in patients if anticoagulation therapy
is stopped.
