Low Molecular Weight Heparin Thromboprophylaxis in Ambulatory Cancer Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Patients with cancer experience an increased risk of venous thromboembolism (VTE) throughout the course of their illness. The risk of VTE appears to be greatest among hospitalized cancer patients, in the perioperative period of major surgery and in those receiving systemic cancer therapies. While encouraged in hospitalized and surgical patients, routine VTE prophylaxis for cancer patients is not recommended in the ambulatory setting except in very selective high risk circumstances. A number of randomized clinical trials (RCTs) of low molecular weight heparin (LMWH) in ambulatory cancer patients have been reported with inconsistent results. Presented here are the results from our updated meta-analysis of LMWH prophylaxis, including recently presented RCTs.

A systematic review of RCTs of VTE prophylaxis with LMWH in ambulatory cancer patients was conducted including the results of published and recently presented trials. Electronic databases including Medline, EMBASE, and Cochrane Library were searched along with meeting abstracts from ASCO and ASH. Eligibility criteria included RCTs of ambulatory cancer patients randomized to LMWH or not and reporting rates of VTE as a primary outcome (primary VTE prophylaxis studies) or a secondary outcome. Dual blinded data extraction was performed with conflict resolution by a third party. Following assessment of heterogeneity, meta-analyses using the method of Mantel and Haenszel were conducted providing weighted summary estimates of both relative risk (RR) and absolute risk (AR) ± 95% confidence intervals (95% CI). Primary study outcomes consist of all reported VTE events and all major bleeds. Most trials did not require VTE screening by imaging, precluding a separate analysis of asymptomatic VTE events.

A total of 7 RCTs of LMWH in ambulatory patients with cancer were identified with a total of 2,960 patients including 1,685 receiving LMWH and 1,275 controls. These include 3 RCTs with various solid tumors and one RCT each in breast cancer, lung cancer, pancreatic cancer, and glioblastoma. Patients receiving LMWH experienced 47 VTE events compared to 74 control subjects for crude rates of 2.79% and 5.80%, respectively. No significant heterogeneity was observed across trials (Cochran Q=6.19; I²=3.03; P=.40). The RR for VTE across trials was estimated at 0.54 [95% CI: 0.38 – 0.78; P=.001] while the AR decrease was 2.55% [95% CI: 1.06% – 4.05%; P<.001]. The RR for VTE for the 5 primary VTE prophylaxis trials was 0.50 [95% CI: 0.34 – 0.75; P<.001] with an AR decrease estimated at 2.95% [95% CI: 1.26 – 4.63%; P<.001]. Major bleeding events were reported in 30 patients receiving LMWH compared to 15 control subjects for crude rates of 1.78% and 1.18%, respectively. No significant heterogeneity was observed across trials (Cochran Q=5.50; I²=0.0; P=.481). The RR for major bleeding across trials was estimated at 1.74 [95% CI: 0.95 – 3.18; P=.071], while the AR increase was 0.75% [95% CI: 0.17% – 1.33%; P=.011]. The RR for major bleeding in the 5 primary prophylaxis trials was 2.27 [95% CI: 1.12 – 4.59; P=.022] with AR increase estimated at 1.27% [95% CI: 0.27% – 2.27%; P=.013].

LMWH thromboprophylaxis in ambulatory cancer patients is effective and results in a significant 46% relative risk reduction of venous thromboembolism. However, the risk of VTE is low in this setting and the absolute risk reduction with prophylactic anticoagulation is only 2.6%, while concerns remain about the increase in major bleeding events. Additional research is needed to identify ambulatory cancer patients at increased risk for VTE, in whom VTE prophylaxis may have a more favorable risk-benefit ratio.

Ortel:Eisai: Research Funding. Khorana:sanofi-aventis: Consultancy; Eisai: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Francis:Eisai: Consultancy, Honoraria.