Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D™ Pilot Trial

Introduction: Venous thromboembolism (VTE) in cancer patients is an important and increasingly frequent clinical challenge. In the UK, dalteparin is a licensed low molecular weight heparin (LMWH), administered subcutaneously, for the extended treatment and prevention of recurrence of acute VTE in cancer patients, considered standard treatment prior to the trial starting. Rivaroxaban is a highly selective direct Factor Xa inhibitor with oral bioavailability; a direct oral anticoagulant (DOAC). Data comparing LMWH and DOACs in cancer patients with VTE are limited.

Methods: Select-d is a prospective, randomised, open label, multicentre pilot trial comparing dalteparin (200 IU/kg daily, month 1 and 150 IU/kg, months 2-6); and rivaroxaban (15mg twice daily for 3 weeks then 20mg once daily, for 6 months in total) for cancer patients with VTE [symptomatic or incidental pulmonary embolism (iPE) or symptomatic lower extremity proximal deep vein thrombosis (DVT)]. After 6 months of trial treatment, DVT patients who were residual vein thrombosis (RVT) positive by compression ultrasound and patients with PE at presentation, could be randomised to placebo or rivaroxaban for a further 6 months. The original sample size of 530 patients was large to provide sufficient numbers in the second randomisation (150 in each arm) to assess the duration of anticoagulation. The trial sample size was reduced when the second randomisation closed due to a high attrition rate. The revised sample size of 200 patients in each arm provides estimates of the primary outcome (VTE recurrence) to within +/- 4.5% (i.e. width of 95% confidence interval (CI) of 9%), assuming VTE recurrence rates of 10% at 6 months. Secondary outcomes included major bleeds and clinically relevant non-major bleeds (CRNMB) [including overt bleeds resulting in unscheduled contact with a physician or interruption or discontinuation of study drug], acceptability, survival and health economics.

Results: 406 patients were recruited between October 2013 and December 2016 from 58 sites across the UK; 203 patients randomised to each arm. Patients had a median age of 67 years (range 22-87); 214 (53%) were males; 386 (95%) from white ethnic origin. Patients presented with either early or locally advanced disease (n=156; 38%), metastatic disease (n=240; 59%), or haematological malignancies (n=10; 3%). Over half of the patients had iPE (n=214; 53%); 47% (n=192) had symptomatic PE or DVT. 280 (69%) patients were receiving anticancer treatment at the time of their VTE; the majority receiving chemotherapy (n=232; 83%) or targeted therapy (n=41; 15%).

The VTE recurrence rate at 6 months was 11% (95% CI 7-17%) for patients on dalteparin and 4% (95% CI 2-9%) for patients on rivaroxaban. Major bleeds were similar across trial arms [6 bleeds from 6 patients (3%; 95% CI 1-6%) on the dalteparin arm; 9 bleeds from 8 patients (4%; 95% CI 2-8%) on the rivaroxaban arm]. There were more CRNMBs on the rivaroxaban arm; 5 bleeds from 5 patients (2%; 95% CI 1-6%) on dalteparin compared with 28 bleeds from 27 patients (13%; 95% CI 9-19%) on rivaroxaban. In total, 11 patients (5%; 95% CI 3-9%) on the dalteparin arm had bleeds categorised as either major bleeds or CRNMBs compared to 34 patients (17%; 95% CI 12-22%) on the rivaroxaban arm.

208 (54%) patients completed 6 months of trial treatment [100 (52%) patients on dalteparin; 108 (55%) on rivaroxaban]. Overall survival at 6 months was 70% (95% CI 63-76%) on dalteparin and 74% (95% CI 68-80%) on rivaroxaban. The second randomisation only recruited 92 of the required 300 patients; 82 were PEs (61 iPE and 21 symptomatic) and 10 were DVTs. Patients did not continue to the second randomisation due to: death or withdrawal (50%); being RVT negative (12%); failing the other eligibility criteria (24%) or declining randomisation (14%).

Conclusion: Select-d is a large pilot randomised trial for the treatment of VTE, investigating a DOAC versus a LMWH in patients with cancer. Treating with rivaroxaban resulted in a very low VTE recurrence rate at 6 months with a similar number of major bleeds reported across trial arms but more CRNMBs were seen with rivaroxaban. A large phase III trial will confirm the use of rivaroxaban for the treatment of VTE in cancer patients.