haematology and oncology
Oral anticoagulants and
cancer-associated thrombosis
Randomised clinical trials comparing prolonged treatment with low molecular weight heparins and
non-vitamin K oral anticaogulants in patients with cancer-associated thrombosis are discussed
Guy Meyer MD
Université Paris Descartes,
Sorbonne Paris Cité;
Assistance Publique
Hôpitaux de Paris, Hôpital
Européen Georges
Pompidou, Paris, France
Venous thromboembolism (VTE) is a frequent
complication in patients with cancer. 1–3 About 8%
of cancer patients will develop VTE during their
disease. 4 VTE is associated with higher risks of
bleeding and recurrence during anticoagulant
treatment in patients with cancer than in other
patients. 5
Low molecular weight heparins
A series of trials have shown that prolonged
treatment with low molecular weight heparin
(LMWH) given for at least three to six months is
associated with a reduction in the risk of
recurrent VTE as compared with the traditional
treatment regimen with LMWH overlapped and
followed by vitamin K antagonists (VKA) in
patients with cancer-associated thrombosis (CAT). 6
Even with LMWH,
about 7% of patients
with CAT experience
recurrent VTE during
the first six months of
treatment. 7 The
prolonged use of
LMWH is associated
with the need of daily
subcutaneous
injections, bruising at
the injection site and
a higher cost than VKA.
In clinical practice,
a significant proportion
of patients with CAT continue receiving VKA. 8
Most of the patients with CAT have a significant
risk of recurrent VTE after the initial six-month
treatment and anticoagulation needs to be
prolonged for more than six months in
a significant number of these patients making
the use of subcutaneous treatment even more
difficult. 9
NOACs
Non-vitamin K oral anticoagulants (NOACs) are
direct inhibitors of factor IIa or factor Xa. These
drugs have a predictable anticoagulant effect and
do not need monitoring; they have an early onset
of action with peak plasma concentrations
obtained about 3–4 hours after ingestion.
Rivaroxaban and apixaban can be administered
in the acute phase of VTE without any preceding
parenteral anticoagulation, whereas dabigatran
and edoxaban have been tested after at least five
days of treatment with LMWH. 10–13 In a series of
17
HHE 2018 | hospitalhealthcare.com
six randomised controlled trials on approximately
26,000 patients with VTE, NOACs were effective
(relative risk (RR) 0.90; 95% CI 0.77–1.06 for first
recurrent VTE or VTE-related death) and safer
than VKA (RR 0.61; 95% CI 0.45–0.83 for major
bleeding) in patients with VTE. 14 A minority of
patients included in these trials had underlying
cancer. Meta-analyses of this subgroup of patients
with CAT show that DOACs are associated with
a non-significant reduction in the risk of recurrent
VTE (RR 0.65, 95% CI 0.38–1.09) and bleeding (RR,
0.67, 95% CI 0.31–1.46) as compared with VKA. 6
Of note, cancer patients in these trials had
less advanced cancer, a smaller proportion
received anticancer treatment and the mortality
was lower than in the trials comparing LMWH
and VKA in patients with CAT. The reference
treatment (VKA) in
these trials was not the
most appropriate for
patients with CAT.
Several
observational cohort
studies have been
published describing
initial experiences with
NOACs in patients with
CAT and have been
summarised in
a systematic review. 15
Most studies used
rivaroxaban and
enoxaparin. The on-treatment duration of
NOACs was longer than that of LMWH. All studies
except one reported lower rates of recurrent
VTE for patients using NOAC as compared
with those on LMWH, but these results may
be attributable to patient selection. Because
of the observational design, patients were not
randomised to receive one of the two treatments
and the treatment groups are not comparable.
In most studies, the outcomes were not
assessed independently. The bleeding outcomes
were heterogeneous across different studies
with two studies that only included
gastrointestinal and gynaecological cancers
reporting higher rates of major bleeds in
patients receiving a NOAC. 16,17
Clinical trials
Two randomised clinical trials comparing
prolonged treatment with LMWH and a NOAC
in patients with CAT have been reported.