The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

Anticoagulant Therapy for Venous Thromboembolism in Cancer

Agnes Y.Y. Lee, M.D.

Direct oral anticoagulants were introduced for
the treatment for acute venous thromboembolism
just over a decade ago. Unlike warfarin, these
drugs are given in fixed doses and do not re-
quire laboratory monitoring of the anticoagulant
effect. Although direct oral anticoagulants are
similar to warfarin in efficacy, they are more
convenient to use and are associated with a lower
risk of major bleeding, particularly intracranial
hemorrhage. These factors prompted a change in
practice guidelines to recommend the use of di-
rect oral anticoagulants as the first-line therapy
over warfarin and transformed outpatient treat-
ment for the majority of patients with acute ve-
nous thromboembolism.1 But for patients with
cancer, who are at increased risk for recurrent
venous thromboembolism, serious bleeding, and
death and in whom low-molecular-weight heparin
is more efficacious than warfarin, more research
was needed to show the efficacy and safety of
direct oral anticoagulants.
In the past few years, investigators in open-
label, randomized, controlled trials have evaluated
the direct factor Xa inhibitors edoxaban (in the
Hokusai VTE Cancer trial), rivaroxaban (SELECT-D
trial), and apixaban (ADAM VTE trial) in this pa-
tient population.2-4 Not surprisingly, these studies
have shown somewhat conflicting results, since
they differed in their primary outcomes, duration
of treatment, and patient selection (cancer type
and prognosis). Nonetheless, guidelines were quick
to recommend the use of edoxaban and rivaroxa-
ban as alternatives to low-molecular-weight hep-
arin in patients with cancer, not only because of
the clinically acceptable results but also because
of the discomfort and cost associated with the
use of low-molecular-weight heparin.5,6 The shift
to using direct oral anticoagulants has been ap-
propriately cautious, largely because of the higher
risk of clinically important bleeding reported with
both edoxaban and rivaroxaban, particularly in
patients with gastrointestinal cancers (including
pancreatic cancer), the uncertainty regarding the
clinical significance of drug–drug interactions
with anticancer therapeutics, and the concern
about adequate absorption in patients with gastro-
intestinal toxicity and in those who have under-
gone surgery involving the upper gastrointestinal
tract.7,8
Agnelli et al. now report in the Journal the
results of the Caravaggio trial, which provides
the latest wave of evidence regarding the efficacy
and safety of apixaban for the treatment of ve-
nous thromboembolism in patients with cancer.9
Similar to previous trials involving this popula-
tion, the Caravaggio trial enrolled patients with
symptomatic or incidental acute proximal deep-
vein thrombosis or pulmonary embolism. The pa-
tients were assigned to receive either subcutane-
ous dalteparin (a low-molecular-weight heparin)
or oral apixaban administered in standard doses
and regimens. The patients were followed for the
primary efficacy outcome of recurrent venous
thromboembolism and the principal safety out-
come of major bleeding. A central adjudication
committee reviewed all suspected outcome events
and deaths in a blinded manner. A modified in-
tention-to-treat analysis, which included patients
who had received at least one dose of the as-
signed anticoagulant, was used for the primary
efficacy comparison in this noninferiority trial,
after adjustment for the competing risk of death.
Over the 6-month treatment period, recurrent
venous thromboembolism occurred in 32 of 576

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 The n e w e ng l a n d j o u r na l
patients (5.6%) in the apixaban group and in 46
of 579 patients (7.9%) in the dalteparin group, a
finding that met the requirement for noninferi-
ority (hazard ratio, 0.63; 95% confidence inter-
val, 0.37 to 1.07; P<0.001 for noninferiority; P = 0.09
for superiority).9 There was also no significant
between-group difference in major bleeding
(3.8% with apixaban and 4.0% with dalteparin,
P = 0.60) or in clinically relevant nonmajor bleed-
ing (9.0% with apixaban and 6.0% with daltepa-
rin). The incidence of death was similar in the
two groups (23.4% in the apixaban group and
26.4% in the dalteparin group), and most deaths
were related to cancer (85.2% with apixaban and
88.2% with dalteparin).
These results compare favorably with those of
prior trials of edoxaban and rivaroxaban in terms
of bleeding relative to low-molecular-weight hep-
arin.2,3 Notably, the Caravaggio trial excluded
patients with primary and metastatic brain le-
sions and included few patients with cancers of
the upper gastrointestinal tract and hematologic
cancers. The ADAM VTE trial,4 in which investi-
gators found no major bleeding events with
apixaban, was a smaller study with an enrollment
of 300 patients. It included patients with other
thrombotic sites (e.g., upper extremity), and the
overall mortality (13.2%) was much lower than
that in other trials, which suggests patient selec-
tion.4 The evidence from these trials makes a
compelling case for adding apixaban as another
anticoagulant option for the treatment of venous
thromboembolism in patients with cancer.10 But
given the heterogeneity of available trials, it is inap-
propriate to conclude that one direct oral antico-
agulant is better than another without a head-to-
head comparison.
So how do we choose which anticoagulant to
use? Carefully! Clinicians need to rely on a detailed
clinical history, ascertaining the cancer type, sta-
tus, and treatment, along with bleeding risk, con-
comitant medications, and the patient’s experi-
ences and values. For example, patients with
primary brain tumors, known intracerebral me-
tastases, or acute leukemia were excluded from
participating in the Caravaggio trial but not
from the Hokusai VTE Cancer trial or SELECT-D
trial. For patients who are treated with edoxa-
ban, an initial week of low-molecular-weight
heparin is required, although fewer drug–drug
interactions are expected than with rivaroxaban
or apixaban. Depending on the specific direct
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of m e dic i n e
oral anticoagulant that was studied in each trial,
patients who were receiving strong inducers or
inhibitors of P-glycoprotein or CYP3A4 were of-
ten excluded, and very few patients were receiv-
ing newer cancer therapies, such as checkpoint
inhibitors. Low-molecular-weight heparin is pre-
ferred in patients in whom drug–drug interac-
tion is a concern and in those who have under-
gone surgery involving the upper gastrointestinal
tract because absorption of all direct oral antico-
agulants occurs in the stomach or proximal small
bowel. Our experience with low-molecular-weight
heparin in patients with bleeding or thrombocy-
topenia, recurrent venous thromboembolism,
central nervous system cancers, or severe renal
impairment and in those in the perioperative
setting will keep this parenteral agent in use.
Last and perhaps least, warfarin may be the only
option when cost is the decision driver in pa-
tients who are facing major financial health care
burdens.
Since the landscape of cancer therapy and
survival is rapidly changing, anticoagulant ther-
apy in patients with cancer needs to keep pace.
Direct oral anticoagulants mark a welcome step
forward in providing effective and safe therapeu-
tic choices for patients with cancer and venous
thromboembolism.
Disclosure forms provided by the author are available with the
full text of this editorial at NEJM.org.
From the University of British Columbia, Vancouver Coastal
Health, and the British Columbia Cancer Agency — all in Van-
couver, Canada.
This editorial was published on March 29, 2020, at NEJM.org.
1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy
for VTE disease: CHEST guideline and expert panel report.
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2. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the
treatment of cancer-associated venous thromboembolism. N Engl
J Med 2018;​378:​615-24.
3. Young AM, Marshall A, Thirlwall J, et al. Comparison of an
oral factor Xa inhibitor with low molecular weight heparin in
patients with cancer with venous thromboembolism: results of
a randomized trial (SELECT-D). J Clin Oncol 2018;​36:​2017-23.
4. McBane RD II, Wysokinski WE, Le-Rademacher JG, et al.
Apixaban and dalteparin in active malignancy-associated venous
thromboembolism: the ADAM VTE trial. J Thromb Haemost
2020;​18:​411-21.
5. Key NS, Khorana AA, Kuderer NM, et al. Venous thrombo-
embolism prophylaxis and treatment in patients with cancer:
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6. Streiff MB, Holmstrom B, Angelini D, et al. NCCN Guide-
lines insights: cancer-associated venous thromboembolic dis-
ease, version 2.2018. J Natl Compr Canc Netw 2018;​16:​1289-303.
7. Carrier M, Blais N, Crowther M, et al. Treatment algorithm
 Editorial

in cancer-associated thrombosis: Canadian expert consensus.
Curr Oncol 2018;​25:​329-37.
8. Suryanarayan D, Lee AYY, Wu C. Direct oral anticoagulants
in cancer patients. Semin Thromb Hemost 2019;​45:​638-47.
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ment of venous thromboembolism associated with cancer.
N Engl J Med. DOI:​10.1056/NEJMoa1915103.
10. Cohen AT, Keshishian A, Lee T et al. Safety and effectiveness
of apixaban, LMWH, and warfarin among venous thromboem-
bolism patients with active cancer: a retrospective analysis using
four US claims databases. Presented at the 61st American Soci-
ety of Hematology Annual Meeting and Exposition, Orlando, FL,
December 7–10, 2019. abstract.
DOI: 10.1056/NEJMe2004220
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