Thromboprophylaxis With Rivaroxaban In Patients With Malignancy and Central Venous Lines

Design:

This is a pilot interventional study to be conducted at 2 Canadian Centres. The Ottawa Hospital and Juravinski Hospital. It is an open label randomized controlled trial.

Consenting participants, meeting eligibility criteria will be randomized at the time of enrollment to one of two groups.

Rivaroxaban 10mg by mouth daily x 90 (+/- 3) days OR Standard of Care

Participants in the treatment arm will have study drug dispensed at Day 1 and take medication for 90 days or until CVC is removed. Follow up visits (in person or phone) will occur at Day 30 (+/- 3 days) and Day 90 (+/- 3 days). Overall, participants will be followed for 3 months. Adverse events will be collected for the first 90 days.

Outcomes The primary feasibility outcome for the pilot study is the number of participants recruited per centre per month. We will obtain baseline details of the patient's type, location and treatment of cancer, comorbidities and medications. Secondary feasibility outcomes of the pilot study will include, consent rates, loss to follow up, adherence to therapy defining 80% or greater medication taken as having good adherence to study drug, proportion of screened patients who meet eligibility criteria.

• Rivaroxaban 10 MG (Drug), also known as Xarelto 10mg tablet po daily: Rivaroxaban 10mg po daily x 90 (+/- 3 days)

Primary outcomes

• Primary Feasibility Outcome - Number of Participants Recruited Per Month [12 months]: A convenience sample size of 100 patients was chosen to allow reporting of the average monthly recruitment.

Secondary outcomes

• Secondary Feasibility Outcomes - Percentage of Participants With Good Adherence to Therapy [90 days]: Good adherence defined as 80% or greater study medication taken in patients randomized to receive Rivaroxaban thromboprophylaxis.

Other outcomes

• Number of Participants With Thrombotic Complication [90 days]: Thrombotic complication was defined as a combination of major venous thromboembolism (VTE); any symptomatic or incidentally detected proximal deep vein thrombosis (DVT) of the lower or upper limbs, any nonfatal symptomatic or incidental pulmonary embolism (PE), and pulmonary embolism-related death) and any other deep (ie, distal, splanchnic, or cerebral) or superficial venous thrombosis.
• Number of Participants With CVC-Related Complication [90 days]: Central venous catheter (CVC) occlusion was defined as an obstruction of the CVC lumen that prevents or limits the ability to flush, withdraw blood, and/or administer solutions or medications
• Number of Participants With Major Bleeding [90 days]: Defined by the International Society on Thrombosis and Haemostasis (ISTH) as overt bleeding associated with a decrease in the hemoglobin level of ≥2 g/dL, which led to transfusion of two or more units of packed red blood cells, occurred in a critical site, or contributed to death.
• Number of Participants With Clinically Relevant Non-Major Bleed [90 days]: Clinically relevant non-major bleeding, as per the standardized definition by the ISTH, is any signs or symptoms of hemorrhage not meeting criteria for major bleeding but associated with medical intervention, unscheduled in-person contact with a healthcare professional or need for hospitalization or increased level of care.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1.Patients 18 years of age or older with a new or existing diagnosis of cancer with a CVC inserted within the last 72 hours.

Exclusion Criteria:

1. CVC in place for >72 hours
2. Patient requires anticoagulation for other indication
3. Concomitant use of dual antiplatelet therapy
4. Prior VTE
5. Major bleeding event in the last 6 weeks
6. Patient on concomitant medication with known interaction with rivaroxaban (eg. CYP3A4 inhibitor)
7. Pregnancy (documentation of use of effective contraception if sexually active or negative B-Hcg required)
8. Known renal failure, based on Creatinine clearance <30 mL/min (Cockcroft-Gault) (in the previous 3 months)
9. Documented severe liver disease (eg. acute clinical hepatitis, chronic active hepatitis, cirrhosis or ALT >3ULN) ( in the previous 3 months)
10. Known thrombocytopenia < 50x 109/L (in the previous 3 months)
11. Allergy to rivaroxaban
12. Life expectancy <6 months
13. History of condition at increased bleeding risk including, but not limited to:

    1. Major surgical procedure or trauma within 30 days before the randomization visit
    2. Clinically significant gastrointestinal bleeding within 6 months before the randomization visit
    3. History of intracranial, intraocular, spinal, or atraumatic intra-articular bleeding
    4. Chronic hemorrhagic disorder
    5. Known intracranial neoplasm, arteriovenous malformation, or aneurysm
    6. Sustained uncontrolled hypertension: systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg
14. Primary malignancy diagnosis of basal cell or squamous cell carcinoma of the skin or acute leukemia or myelodysplastic syndrome
15. Geographic inaccessibility
16. Refused or unable to obtain consent

Participant flow

Outcome results

• Primary Feasibility Outcome - Number of Participants Recruited Per Month (Primary), Number, Average enrolment rate/month/site: Site 1 7.5; Site 2 2.0
• Secondary Feasibility Outcomes - Percentage of Participants With Good Adherence to Therapy (Secondary), Number, percentage of participants: Rivaroxaban Thromboprophylaxis 96.7; Standard of Care
• Number of Participants With Thrombotic Complication (Other pre specified), Count of participants, Participants: Rivaroxaban Thromboprophylaxis 2; Standard of Care 3
• Number of Participants With CVC-Related Complication (Other pre specified), Count of participants, Participants: Rivaroxaban Thromboprophylaxis 0; Standard of Care 2
• Number of Participants With Major Bleeding (Other pre specified), Count of participants, Participants: Rivaroxaban Thromboprophylaxis 1; Standard of Care 0
• Number of Participants With Clinically Relevant Non-Major Bleed (Other pre specified), Count of participants, Participants: Rivaroxaban Thromboprophylaxis 2; Standard of Care 2

Adverse events

Time frame: 3 months

Serious adverse events by term

Other adverse events by term

Limitations and caveats: A PROBE design was chosen in order to be pragmatic and to reflect standard clinical practice, which could make the results more easily applicable to routine medical care. The study was designed to assess feasibility and not to determine differences in the risk of clinical events between treatment groups. As a result, the number of clinical outcome events was relatively small, leading to imprecision and wide confidence intervals.

• Results publication: Ikesaka R, Siegal D, Mallick R, Wang TF, Witham D, Webb C, Carrier M; Canadian Venous Thromboembolism Research Network (CanVECTOR). Thromboprophylaxis with rivaroxaban in patients with malignancy and central venous lines (TRIM-Line): A two-center open-label pilot randomized controlled trial. Res Pract Thromb Haemost. 2021 May 5;5(4):e12517. doi: 10.1002/rth2.12517. eCollection 2021 May. PMID 34027291

• Study Protocol (PDF, 2019-09-18)

• Rick T Ikesaka, MD, Principal investigator, Ottawa Hospital Research Institute / Division of Hematology- The Ottawa Hospital