Clinical trial

Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D)

J Clin Oncol · 2018406 patients (203 in each group)

Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, et al. J Clin Oncol. 2018. 36:2017-2023

Study type: Clinical trial
Study name: SELECT-D
Design: Pilot, multicentre, randomised, open-label trial in the UK
Sample size: 406 patients (203 in each group)
Source: J Clin Oncol · 2018

In plain words

This UK study in 406 patients with cancer and a blood clot compared rivaroxaban tablets with daily injections of dalteparin for 6 months. Clots came back less often with rivaroxaban (4% versus 11%). The difference in serious bleeding between the two groups was not statistically clear (6% versus 4%), but bleeding that was not severe yet still clinically important was more common with rivaroxaban (13% versus 4%). This was a pilot study and fairly small. Your doctor will choose between tablets and injections based on your type of cancer, your bleeding risk and your other medicines.

Key results

4% vs 11%

Venous thromboembolism recurrence at 6 months (cumulative rate; primary outcome)

Rivaroxaban 4% (95% CI 2% to 9%; 8 patients) vs dalteparin 11% (7% to 16%; 18 patients); HR 0.43 (95% CI 0.19 to 0.99)

6% vs 4%

Major bleeding at 6 months (cumulative rate)

Rivaroxaban (95% CI 3% to 11%) vs dalteparin (2% to 8%); HR 1.83 (95% CI 0.68 to 4.96)

13% vs 4%

Clinically relevant non-major bleeding (CRNMB) at 6 months

Rivaroxaban (95% CI 9% to 19%) vs dalteparin (2% to 9%); HR 3.76 (95% CI 1.63 to 8.69)

Dose and schedule cards

Therapeutic rivaroxaban (SELECT-D)

Cancer-associated VTE in a patient without a high risk of GI or genitourinary bleeding (CrCl ≥15)Cycle length: DailyOn the page “Venous thromboembolism in cancer: risk assessment, prevention and treatment” · Treatment of cancer-associated VTE

Cancer-associated VTE in a patient without a high risk of GI or genitourinary bleeding (CrCl ≥15)

Drug	Dose	Route	Schedule
Days 1 to 21
Rivaroxaban	15 mg twice a day with food	Oral	First 21 days
From day 22
Rivaroxaban	20 mg once a day with food	Oral	Continuous, at the same time each day

Cycle length: Daily
Duration: 6 months in total in SELECT-D

Do not use with CrCl below 15, and use with close bleeding monitoring at 15 to below 30; do not use with combined strong P-gp and CYP3A inhibitors or inducers. In SELECT-D, 6-month recurrence was 4% vs 11% with dalteparin, but clinically relevant non-major bleeding was more common (13% vs 4%).

On the page “Venous thromboembolism in cancer: risk assessment, prevention and treatment” · Treatment of cancer-associated VTE

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Rivaroxaban

Oral rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg once daily; total treatment duration 6 months.

FDA label for rivaroxaban (XARELTO), DVT/PE treatment: 15 mg twice daily with food for the first 21 days, then 20 mg once daily with food; avoid use at creatinine clearance below 15 mL/min.

2Dalteparin (comparator)

Dalteparin 200 IU/kg daily for the first month, then 150 IU/kg daily for months 2 to 6.

FDA label for dalteparin (FRAGMIN), venous thromboembolism in patients with cancer: subcutaneous injection once daily; 200 units/kg total body weight for the first 30 days, then about 150 units/kg for months 2 to 6; the total daily dose should not exceed 18,000 units.

Source of the regimen details: Abstract of the paper (J Clin Oncol 2018); intake with food and avoidance at creatinine clearance below 15 mL/min from the FDA label for rivaroxaban (XARELTO, DailyMed); subcutaneous route and daily dose cap from the FDA label for dalteparin (FRAGMIN, DailyMed, section 2.3)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with active cancer who had symptomatic pulmonary embolism (PE), incidental pulmonary embolism, or symptomatic proximal lower-limb deep vein thrombosis (DVT). 58% of patients had metastases. Other eligibility criteria are not stated in the abstract.

Endpoints

Primary outcome: venous thromboembolism recurrence over 6 months.

Safety: major bleeding and clinically relevant non-major bleeding (CRNMB).

A sample size of 400 patients, assuming a 6-month recurrence rate of 10%, would estimate venous thromboembolism recurrence with a precision of ±4.5%.

Safety and side effects

The 6-month cumulative rate of major bleeding was 6% (95% CI 3% to 11%) with rivaroxaban and 4% (2% to 8%) with dalteparin (HR 1.83; 95% CI 0.68 to 4.96). Clinically relevant non-major bleeding was 13% (9% to 19%) with rivaroxaban and 4% (2% to 9%) with dalteparin (HR 3.76; 95% CI 1.63 to 8.69). Other adverse events are not reported in the abstract.

Clinical significance and place in guidelines

In SELECT-D, rivaroxaban compared with dalteparin was associated with fewer venous thromboembolism recurrences but more clinically relevant non-major bleeding. The 2020 ASCO guideline update reported that edoxaban and rivaroxaban carry a higher bleeding risk than low-molecular-weight heparin in gastrointestinal and possibly genitourinary cancers (Key NS et al., J Clin Oncol 2020). The 2022 ITAC international guideline recommends direct oral anticoagulants (rivaroxaban, apixaban, edoxaban) for cancer-associated thrombosis in patients with creatinine clearance ≥30 mL/min who are not at high risk of gastrointestinal or genitourinary bleeding and have no strong drug interactions (grade 1A), and advises caution in gastrointestinal cancers, especially of the upper gastrointestinal tract (Farge D et al., Lancet Oncol 2022). The rivaroxaban regimen of this trial matches the DVT/PE treatment dose in the FDA label (15 mg twice daily with food for the first 21 days, then 20 mg once daily with food).

Limitations

According to the abstract: the trial was a pilot, open-label and relatively small (406 patients) and was conducted only in the UK. The sample size was calculated to estimate the venous thromboembolism recurrence rate with a precision of ±4.5%, and the abstract reports no formal superiority or non-inferiority test. The number of events was small (26 recurrences) and the confidence intervals are wide. Cancer types and other eligibility criteria are not stated in the abstract.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.