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Summary Background Recommendations for management of cancer‐related venous thromboembolism (VTE) in patients already receiving anticoagulant therapy are based on low‐quality evidence. This international registry sought to provide more information on outcomes after a breakthrough VTE in relation to anticoagulation strategies. Methods Patients with cancer and VTE despite anticoagulant therapy were reported to the registry. Data on treatments, VTE events, major bleeding, residual thrombosis symptoms and death were collected for the following 3 months. Breakthrough VTE and subsequent recurrences were objectively verified. Outcomes with different treatment strategies were compared with Cox proportional hazards regression. Results We registered 212 patients with breakthrough VTE. Of those, 59% had adenocarcinoma and 73% had known metastases. At the time of the breakthrough event, 70% were on low‐molecular‐weight heparin (LMWH) and 27% on a vitamin K antagonist (VKA); 70% had a therapeutic or supratherapeutic dose. After breakthrough the regimen was: unchanged therapeutic dose in 33%, dose increased in 31%, switched to another drug in 24%; and other management in 11%. During the following 3 months 11% had another VTE, 8% had major bleeding and 27% died. Of the survivors, 74% had residual thrombosis symptoms. Additional VTE recurrence was less common with LMWH than with a VKA (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.11–0.70) but similar with unchanged or increased anticoagulant intensity (HR, 1.09; 95% CI, 0.45–2.63). The bleeding rate did not increase significantly with dose escalation. Conclusion Morbidity and mortality are high after recurrence of cancer‐related VTE despite anticoagulation. Further treatment appears to be more effective with LMWH than with a VKA.

Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.