Abstract
Introduction: Thrombosis is a major concern for patients with cancers. Cancers with the KS ≥ 2 are highly thrombogenic cancers. Outpatient thromboprophylaxis is currently suggested for such patients by recent clinical practice guidelines. Herein, we conducted a meta-analysis to demonstrate the benefit of OTP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in KS ≥ 2 patients receiving chemotherapy.
Methods: Comprehensive literature across MEDLINE and EMBASE databases were searched from inception through July 2025 using search terms ‘thromboprophylaxis’ OR ‘anticoagulation’ OR ‘low-molecular-weight heparin’ OR ‘direct oral anticoagulants’ AND ‘cancer’. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE and major bleeding as a primary or secondary endpoint were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic.
Results: A total of 2,564 patients with cancers with KS ≥ 2 from seven studies (4 studies and a subgroup of 3 RCTs) were included. The prophylactic, intermediate and therapeutics doses of LMWHs (prophylactic doses in PROTECHT and SAVE-ONCO trials, therapeutic/intermediate doses in FRAGEM and CONKO-004 trials), and prophylactic doses of DOAC (rivaroxaban in CASSINI, and apixaban in AVERT trials) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The I2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 46 (3.55%) in the PATP group and 109 (8.60%) in the control group with a RR of 0.36 (95% CI: 0.20 to 0.67, P = 0.001). The absolute RD was -0.06 (95% CI: -0.09 to -0.002, P= 0.002) with an estimate of the number needed to treat (NNT) of 20 to prevent one VTE event. Major bleeding was observed in 23 (2.52%) in the study group and 14 (1.57%) in the control group with a RR of 1.59 (95% CI: 0.82 to 3.07, P = 0.17), based on the 4 studies (n=1,804).
In patients receiving DOAC (n=1,415, 2 studies), the VTE incidence was 37 (5.20%) in PATP arm and 65 (9.23%) in control arm with a RR of 0.56 (95% CI: 0.35 to 0.89, P = 0.01) (NNT = 25). In LMWH subgroup (n=1,149, 5 studies), the VTE incidence was 9 (1.54%) in PATP group and 44 (7.80%) in control arm with a RR of 0.22 (95% CI: 0.09 to 0.51, P = 0.0004) (NNT = 16). In patients receiving prophylactic dose of either LMWH or DOAC (n=2,133, 5 studies), the VTE incidence was 44 (4.09%) in the study group and 84 (7.95%) in control arm with a RR of 0.50 (95% CI: 0.32 to 0.78, P = 0.002) (NNT = 26). The VTE incidence was 2 (0.91%) in the study group and 25 (11.79%) in control arm with a RR of 0.10 (95% CI: 0.03 to 0.38, P = 0.0006) (NNT = 9), in patients with cancer receiving either intermediate or therapeutic dose of LMWH (n=431, 2 studies). Conclusions: OTP in patients with cancers with KS ≥ 2 may statistically significantly decrease venous thromboembolism events, approximately with relative risk reduction of 59% and a NNT of 20 in overall population while relative risk reduction of 80% with a NNT of 16 in patients receiving LMWH. The effect was more pronounced in patients receiving either intermediate or therapeutic dose of LMWH (relative risk reduction of 92% with a NNT of 9). One weakness of our study is that we could not get KS data from the patients in the SAVE-ONCO and PROTECHT trials except those with gastric and pancreas cancers. Although OTP in patients with cancers with KS ≥ 2 is currently suggested by clinical practice guidelines, further studies are required to select high risk subsets among those patients who may benefit from OTP and strategize the proper thromboprophylaxis.
