Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy

BACKGROUND: Venous thromboembolism (VTE) often complicates the clinical course of
cancer. The risk is further increased by chemotherapy, but the safety and
efficacy of primary thromboprophylaxis in cancer patients treated with
chemotherapy is uncertain. This is an update of a review first published in
February 2012.
OBJECTIVES: To assess the efficacy and safety of primary thromboprophylaxis for
VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or
no thromboprophylaxis.
SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group
Trials Search Co-ordinator searched the Specialised Register (last searched May
2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013).
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any oral or
parenteral anticoagulant or mechanical intervention to no intervention or
placebo, or comparing two different anticoagulants.
DATA COLLECTION AND ANALYSIS: Data were extracted on methodological quality,
patients, interventions, and outcomes including symptomatic VTE and major
bleeding as the primary effectiveness and safety outcomes, respectively.
MAIN RESULTS: We identified 12 additional RCTs (6323 patients) in the updated
search so that this update considered 21 trials with a total of 9861 patients,
all evaluating pharmacological interventions and performed mainly in patients
with advanced cancer. Overall, the risk of bias varied from low to high. One
large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence
interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low
molecular weight heparin (uLMWH) semuloparin relative to placebo, with no
apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when
compared with inactive control, significantly reduced the incidence of
symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%)
with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In
patients with multiple myeloma, LMWH was associated with a significant reduction
in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33,
95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not
statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was
observed in the patients treated with LMWH or warfarin and in less than 1% of
those treated with aspirin. Only one study evaluated unfractionated heparin
against inactive control and found an incidence of major bleeding of 1% in both
study groups while not reporting on VTE. When compared with placebo, warfarin was
associated with a statistically insignificant reduction of symptomatic VTE (RR
0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving
paediatric patients, had no significant effect on VTE nor major bleeding when
compared with inactive control. The new oral factor Xa inhibitor apixaban was
evaluated in a phase-II dose finding study that suggested a promising low rate of
major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in
comparison with placebo.
AUTHORS' CONCLUSIONS: In this update, we confirmed that primary
thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic
VTE in ambulatory cancer patients treated with chemotherapy. In addition, the
uLMWH semuloparin significantly reduced the incidence of symptomatic VTE.
However, the broad confidence intervals around the estimates for major bleeding
suggest caution in the use of anticoagulation and mandate additional studies to
determine the risk to benefit ratio of anticoagulants in this setting. Despite
the encouraging results of this review, routine prophylaxis i