Comparative safety and effectiveness of direct oral anticoagulants and low-molecular weight heparin in patients with venous thromboembolism and cancer in europe

Abstract Objectives Cancer associated venous thromboembolism (VTE) poses a dual risk of thrombosis and bleeding, making its management particularly challenging. Randomized controlled trials (RCTs) comparing apixaban, edoxaban, and rivaroxaban with low molecular weight heparins (LMWHs) have demonstrated that direct oral anticoagulants (DOACs) are effective alternatives to LMWH, offering greater convenience in many cases. These findings are reflected in current clinical guidelines, which support the use of DOACs while advising caution in patients at high risk of bleeding. However, despite their growing use in clinical practice, real-world evidence comparing the safety and effectiveness of DOACs versus LMWH in patients with cancer-associated VTE remains limited. This study aimed to address this gap by evaluating the comparative safety and effectiveness of DOACs and LMWH in VTE patients with cancer. Methods This observational study utilized datasets from national patient and prescription registers in Sweden, Finland, and Norway, the Clinical Practice Research Datalink linked to Hospital Episode Statistics in the UK, and two social health insurance datasets in Germany (AOK PLUS and GWQ) from 2013 to 2020. We identified treatment-naive adult patients with VTE and cancer (within 6 months of the index VTE diagnosis) treated with either a DOAC or LMWH. The index date was defined as the first DOAC or LMWH dispensed from a community pharmacy within 30 days of the index VTE. Follow-up continued from the day after index date until the earliest of: 6 months post-index date, patient death, occurrence of the outcome of interest, index treatment discontinuation, emigration, placement of an inferior vena cava (IVC) filter, pregnancy, or March 31, 2020. The primary effectiveness outcome was recurrent VTE (rVTE), defined as an inpatient primary position diagnosis of VTE occurring at least 7 days post-discharge. The primary safety outcome was bleeding, defined as an inpatient hospitalization with at least one overnight stay and a primary or secondary position bleeding diagnosis. Bleeding events were categorized as gastrointestinal (GI), intracranial hemorrhage (ICH), or other, based on diagnosis codes. Analyses were conducted on-treatment, with patients considered to have discontinued treatment when no new index treatment dispensation occurred within a 60-days following end of supply of the prior dispensation. Inverse probability of treatment weighting (IPTW) was used for each DOAC-LMWH comparison to account for potential confounding. Adjusted hazard ratios (HRs) were estimated in each country using Fine-Gray models to assess the risk of rVTE and bleeding (overall and by site) within 6 months of treatment initiation; these models were used to account for competing risk of mortality. Country-specific estimates were meta-analyzed. Results Before IPTW, we identified 34,687 LMWH users, 3,045 apixaban users, 4,537 rivaroxaban users, 145 dabigatran users, and 580 edoxaban users across the five countries. Due to a limited sample size, Finland was excluded from the analysis, as were the edoxaban and dabigatran groups. After IPTW, the LMWH-apixaban comparison included 30,002 LMWH and 2,892 apixaban users, while the LMWH-rivaroxaban comparison included 29,976 LMWH and 4,321 rivaroxaban users. Comparative assessment of rVTE was not possible due to low event numbers. At 6 months, apixaban was associated with a lower risk of overall bleeding and other bleeding compared with LMWH (HR: 0.67 [95% CI, 0.53-0.86]; 0.64 [0.41-0.998]), with similar risks for GI and ICH bleeding (0.89 [0.61-1.29]; 0.67 [0.31-1.44]). For rivaroxaban versus LMWH, the risk of overall, GI, and other bleeding was similar (0.98 [0.83-1.15]; 0.86 [0.47-1.58]; 0.89 [0.74-1.08]), but the risk of ICH was lower (0.32 [0.13-0.82]). Conclusions This multi-country European study, utilizing real-world data on patients with VTE and cancer, found that apixaban was associated with a lower risk of overall bleeding compared with LMWH. The risk of overall bleeding with rivaroxaban was similar to that with LMWH. Comparative assessment of rVTE was not possible due to low event numbers. These findings contribute to the limited body of real-world evidence supporting the use of DOACs over LMWH for treating patients with VTE and cancer.