Cancer patients are more likely than people without cancer to develop blood clots in their veins (known as venous thromboembolism). Chemotherapy further increases this risk. Yet a number of factors specific to the cancer, such as the bleeding tendency at the site of the cancer, or a relative decrease in the number of platelets in the blood (thrombocytopenia) caused by chemotherapy can increase the likelihood that cancer patients will have bleeding complications with medicines used to prevent and treat blood clots (anticoagulants). This systematic review looked at the effectiveness and safety of anticoagulants when used to prevent blood clots in cancer patients receiving chemotherapy.
We included 26 randomised controlled trials involving a total of 12,352 participants (current until June 2016). Low molecular weight heparin and the ultra-low molecular weight heparin semuloparin were associated with a significant reduction in symptomatic blood clots. We found no evidence that the risk of major bleeding is increased with semuloparin or low molecular weight heparin, but based on the uncertainty around the estimates, we cannot exclude that the risk is doubled. There was no clear survival benefit for semuloparin or low molecular weight heparin. In people with multiple myeloma, low molecular weight heparin significantly reduced the incidence of blood clots when compared with the vitamin K antagonist warfarin, while the difference with aspirin was not significant. There were no major bleeds with low molecular weight heparin or warfarin, and in participants treated with aspirin the rate was below 1%. One study evaluated unfractionated heparin and did not report on venous thromboembolism or major bleeding. There was no mention of blood clots in the two study groups. Data for warfarin in comparison with placebo were too limited to support the use of warfarin in the prevention of blood clots in cancer patients. One study in children evaluated antithrombin, which had no significant effect on blood clots or major bleeding when compared with no antithrombin. A small pilot study evaluated the oral anticoagulant apixaban and found a low rate of bleeding and blood clots compared to placebo.
Quality of the evidence
The quality of the included studies ranged from low to high, such that future studies may change our confidence in the estimates and the size of the estimates, in particular with regard to the safety of anticoagulants. The quality of findings ranged from high to very low across the different outcomes and comparisons. The main limiting factors, which were the reason for a decrease in quality in some outcomes, were imprecision and risk of bias. The relatively low number of studies, participants, and clinical events prevented us from determining the potential influence of age and type or stage of cancer on treatment effects and providing more definitive conclusions about the risk of bleeding in association with anticoagulants. None of the studies tested intermittent pneumatic compression or graduated elastic stockings for the prevention of venous thromboembolism.
In this second 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, which is not commercially available, significantly reduced the incidence of symptomatic VTE. The risk of major bleeding associated with LMWH, while not reaching statistical significance, suggest caution and mandate additional studies to determine the risk-to-benefit ratio of LMWH in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed. We need additional studies investigating targeted primary prophylaxis in people with specific types or stages of cancer associated with a higher risk of VTE.
Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the second update of a review first published in February 2012.
To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis.
For this update the Cochrane Vascular Information Specialist searched the Cochrane Vascular Group Specialised Register (June 2016). In addition, the Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 5). Clinical trials registries were searched up to June 2016.
Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants.
We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively.
We identified five additional randomised controlled trials (2491 participants) in the updated search, considering in this update 26 trials with a total of 12,352 participants, all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The quality of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. One large trial of 3212 participants 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). When compared with no thromboprophylaxis, LMWH significantly reduced the incidence of symptomatic VTE (RR 0.54, 95% CI 0.38 to 0.75; no heterogeneity, Tau2 = 0.00%) with a non-statistically significant 44% higher risk of major bleeding events (RR 1.44, 95% CI 0.98 to 2.11). In participants with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE 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). Major bleeding was observed in none of the participants treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis but did not report on VTE or major bleeding. When compared with placebo, warfarin was associated with a non-statistically significant 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 or on major bleeding when compared with no antithrombin. The direct oral factor Xa inhibitor apixaban was evaluated in a phase II dose-finding study that suggested a low rate of major bleeding (2.1% versus 3.4%) and symptomatic VTE (1.1% versus 13.8%) in comparison with placebo.