Background
Cancer patients are more likely than people without cancer to develop venous thromboembolism (blood clots in the veins). Chemotherapy may activate blood coagulation (clotting) and further increase this risk. Anticoagulants are medicines which are used to prevent and treat blood clots. They are sometimes known as blood thinners. This systematic review aimed to look at the effectiveness and safety of anticoagulants and mechanical interventions when used to prevent blood clots in cancer patients receiving chemotherapy.
Key results
We included 32 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) involving 15,678 participants (current search to August 2020). All studies evaluated anticoagulants and were performed mainly in people with locally advanced (unlikely to be cured) or metastatic (where the cancer has spread from the part of the body where it started) cancer. Direct oral anticoagulants (anticoagulants that act by directly binding to and inhibiting specific coagulation factors – thrombin or activated factor X) may reduce the occurrence of blood clots and probably increase the risk of major bleeding in people with cancer. Low-molecular-weight heparins (anticoagulants that increase the activity of the natural anticoagulant antithrombin) were associated with a reduction in symptomatic blood clots, but increased the risk of major bleeding. In people with the blood-related cancer, multiple myeloma, low-molecular-weight heparin reduced the number of symptomatic blood clots when compared with the vitamin K antagonist warfarin, while the difference with aspirin was not clear; 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 blood clots or major bleeding. Data for warfarin in comparison with placebo (pretend treatment) were too limited to support the use of warfarin in the prevention of symptomatic blood clots in cancer patients. One study in children evaluated antithrombin, which had no significant effect on any type of blood clots or major bleeding when compared with no antithrombin.
Quality of the evidence
The methodological quality of the included studies ranged from low to high, such that future studies may change our confidence in the results, in particular with regard to the safety of anticoagulants. The reliability of the 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 reliability in some outcomes, were imprecision and risk of bias. The relatively low number of studies, participants, and clinical events prevented us from providing more definitive conclusions about the risk of bleeding in association with anticoagulants. None of the studies tested intermittent pneumatic compression (a mechanical device using an air pump and inflatable leggings to provide pulsing pressure that pushes blood through the veins) or graduated elastic stockings (special socks that improve blood flow in the leg veins and prevent blood from pooling in the legs) for the prevention of venous thromboembolism.
In ambulatory cancer patients, primary thromboprophylaxis with direct factor Xa inhibitors may reduce the incidence of symptomatic VTE (low-certainty evidence) and probably increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo. LMWH decreases the incidence of symptomatic VTE (high-certainty evidence), but increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo or no thromboprophylaxis. Evidence for the use of thromboprophylaxis with anticoagulants other than direct factor Xa inhibitors and LMWH is limited. More studies are warranted to evaluate the efficacy and safety of primary prophylaxis in specific types of chemotherapeutic agents and types of cancer, such as gastrointestinal or genitourinary cancer.
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 third 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, or an active control intervention.
For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 3 August 2020. We also searched the reference lists of identified studies and contacted content experts and trialists for relevant references.
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 risk of bias, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We applied GRADE to assess the certainty of evidence.
We identified six additional randomised controlled trials (3326 participants) for this update, bringing the included study total to 32 (15,678 participants), all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The certainty 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.
Thromboprophylaxis with direct oral anticoagulants (direct factor Xa inhibitors apixaban and rivaroxaban) may decrease the incidence of symptomatic VTE (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.18 to 1.06; 3 studies, 1526 participants; low-certainty evidence); and probably increases the risk of major bleeding compared with placebo (RR 1.74, 95% CI 0.82 to 3.68; 3 studies, 1494 participants; moderate-certainty evidence).
When compared with no thromboprophylaxis, low-molecular-weight heparin (LMWH) reduced the incidence of symptomatic VTE (RR 0.62, 95% CI 0.46 to 0.83; 11 studies, 3931 participants; high-certainty evidence); and probably increased the risk of major bleeding events (RR 1.63, 95% CI 1.12 to 2.35; 15 studies, 7282 participants; moderate-certainty evidence).
In participants with multiple myeloma, LMWH resulted in lower symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83; 1 study, 439 participants; high-certainty evidence), while LMWH probably lowers symptomatic VTE more than aspirin (RR 0.51, 95% CI 0.22 to 1.17; 2 studies, 781 participants; moderate-certainty evidence). Major bleeding was observed in none of the participants with multiple myeloma 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 or no thromboprophylaxis, warfarin may importantly reduce symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20; 1 study, 311 participants; low-certainty evidence) and may result in a large increase in major bleeding (RR 3.82, 95% CI 0.97 to 15.04; 4 studies, 994 participants; low-certainty evidence).
One study evaluated antithrombin versus no antithrombin in children. This study did not report on symptomatic VTE but did report any VTE (symptomatic and incidental VTE). The effect of antithrombin on any VTE and major bleeding is uncertain (any VTE: RR 0.84, 95% CI 0.41 to 1.73; major bleeding: RR 0.78, 95% CI 0.03 to 18.57; 1 study, 85 participants; very low-certainty evidence).