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Low-molecular-weight Heparins in the Management of Cancer-associated Thrombosis
Table 1: Characteristics of the Four Studies Comparing Low-molecular-weight Heparin and Vitamin K Antagonists for the
Long-term Treatment of Venous Thromboembolism in Patients with Cancer
Trial Patients Number Metastatic Disease (%) Low-molecular-weight Heparin Comparator Design
CANTHANOX
19
VTE, various cancers 146 53 Enoxaparin 150IU/kg OD three months VKA Open
CLOT
20
VTE, solid tumours or 672 68 Dalteparin 200IU/kg OD one month then VKA Open
haematological cancer 150IU/kg OD five months
ONCENOX
21
VTE, various cancers 102 67 Enoxaparin 100IU/kg BID six months VKA Open
Enoxaparin 100IU/kg BID five days
then 150IU/kg OD six months
LITE
22
DVT, solid tumours 200 41 Tinzaparin 175IU/kg OD three months VKA open
CLOT = comparison of low-molecular-weight heparin versus oral anticoagulant therapy (OAC) for the prevention of recurrent VTE in patients with cancer; VTE = venous thromboembolism;
DVT = deep venous thrombosis; OD = once daily; BID = twice daily; IU = international unit; VKA = vitamin K antagonist; LITE = Long-term Innovations in TreatmEnt programme.
Table 2: Four Randomised Controlled Trials Assessing Low-molecular-weight Heparin as Adjuvant Anticancer Treatment
Author Patients Number Metastatic Disease (%) Low-molecular-weight Heparin Comparator Design
Kakkar
34
Solid tumour 383 64 Dalteparin 5,000IU OD one year Placebo DB
Altinbas
33
Small-cell lung cancer 84 43 Dalteparin 5,000IU OD 10 weeks No treatment Open
of chemotherapy
Klerk
35
Solid tumour 302 91 Nadroparin 3,800IU <50kg, Placebo DB
5,700IU 50–70kg, 7,600IU >70kg
BID two weeks then OD for four weeks
Sideras
37
Advanced cancer 141 100 Dalteparin 5,000IU OD Placebo then DB then open
no treatment
OD = once daily; BID = twice daily; DB = double-blind.
Long-term Anticoagulation same period, 22.7% of patients in the warfarin group died compared
According to several cohort studies of patients with VTE, patients with with 11.3% of patients receiving enoxaparin (p=0.07). Importantly, no
cancer have a two to three-fold increase in recurrent VTE and a two to six- fatal bleeding was observed in the enoxaparin group, while six deaths
fold increase in major bleeding during oral anticoagulant treatment (OAC) due to bleeding occurred in the warfarin group (p=0.03).
compared with non-cancer patients.
16,17
In general, vitamin K antagonists
(VKAs) are difficult to use in patients with cancer due to the potential for The comparison of LMWH versus OAC for the prevention of recurrent
interactions of these agents with other medications, especially during VTE in patients with cancer (CLOT) trial was a large, international,
chemotherapy, or problems with anticoagulant control arising from poor open-label randomised study comparing dalteparin and OAC in
intestinal absorption or altered hepatic function, which are common in patients with VTE and cancer.
20
All patients had symptomatic and
patients with cancer. confirmed VTE, and received dalteparin 200IU/kg once daily for one
month, followed by approximately 150IU/kg once daily for five months
In patients with cancer receiving warfarin for VTE, the risk of bleeding (n=336). Patients allocated to OAC (warfarin or acenocoumarol)
and recurrent VTE remains high, even when the international (n=336) initially received dalteparin 200IU/kg for five to seven days. In
normalised ratio (INR) is within the target range. As opposed to this group, OAC was started within 24 hours and adjusted to obtain
patients without malignancy, the bleeding rate is consistently high and an INR of 2.5 and continued for six months. The risk of objectively
is independent of the INR value in patients with cancer.
18
At the time confirmed symptomatic recurrent VTE was significantly reduced in
of recurrence, the INR value is within or above the target range in a patients receiving dalteparin (8.8%) compared with patients receiving
higher proportion of cancer patients than in patients without cancer.
16
OAC (17.4%; p=0.002). The incidences of major bleeding and all
bleeding complications were similar in both groups: 6 and 14%,
In view of the poor results observed with the use of warfarin for the respectively, in the dalteparin group, and 4 and 19%, respectively, in
secondary prevention of VTE in patients with cancer, four randomised, the OAC group (no significant differences).
controlled multicentre studies have compared the effects of LMWH with
warfarin in patients with cancer and VTE (see Table 1). The third study compared three treatments in 122 patients with VTE
and cancer:
The first trial was an open-label, randomised comparison of warfarin
and enoxaparin in which 146 patients with cancer and VTE were • enoxaparin 1mg/kg twice daily for five days, followed by 1mg/kg,
randomised to receive treatment with enoxaparin for three months, once daily for six months;
1.5mg/kg once daily or warfarin, adjusted to achieve an INR of 2–3.
19
• enoxaparin 1mg/kg twice daily for five days, followed by 1.5mg/kg,
In the warfarin group, all patients initially received LMWH at once daily for six months; and
therapeutic dosage until an INR of at least 2 was achieved. During the • enoxaparin 1mg/kg twice daily for five days, followed by oral warfarin
three-month treatment period, 21.1% of patients in the warfarin for six months.
21
group developed objectively confirmed symptomatic VTE and/or major
bleeding compared with 10.5% in the enoxaparin group, although The primary objective of the trial was to evaluate the compliance with
this difference was not statistically significant (p=0.09). During the prolonged subcutaneous LMWH injection. Recurrent VTE was observed
ASIA-PACIFIC ONCOLOGY & HAEMATOLOGY 21
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