Trials in Progress: The START (STrategies for Anticoagulation in patients with thRombocytopenia and cancer-associated Thrombosis) Pilot Randomized Controlled Trial

Background and Significance

Patients with cancer are at increased risks of both venous thromboembolism (VTE) and bleeding. Anticoagulation management is particularly challenging in those with thrombocytopenia, a frequent complication of chemotherapy or cancer itself. The optimal management in patients with cancer-associated thrombosis and thrombocytopenia is unclear. Common practices include platelet transfusion to a certain threshold (typically platelet count > 50,000/µL) to allow therapeutic anticoagulation, modifying anticoagulation dose by platelet count, or holding anticoagulation completely. Platelet transfusion can be associated with risks including infections, acute lung injury, alloantibodies, and more. We undertake the START (STrategies for Anticoagulation in patients with thRombocytopenia and cancer-associated Thrombosis) pilot trial to evaluate the feasibility of a full randomized controlled trial (RCT) to address this knowledge gap.

Study design and Methods

The START pilot trial (NCT05255003) is an investigator-initiated, prospective, multi-center, open-label RCT funded by The Ottawa Hospital Academic Medical Organization. Adult patients with acute cancer-associated thrombosis (objectively confirmed and diagnosed within 14 days) and thrombocytopenia (platelet count < 50,000/µL) secondary to cancer therapy or cancer itself are randomized 1:1 to modified dose low-molecular-weight heparin (LMWH) vs. higher dose LMWH with platelet transfusion support for 14 days, followed by modified dose LMWH for all patients from days 15 to 30. The study duration is 30 days. Dose of LMWH is adjusted based on a pre-defined regimen according to the first platelet count of the day.

Key exclusion criteria include 1) Management of VTE with platelet count < 50,000/uL for > 72 hours, 2) Life expectancy < 3 months (as judged by the treating physicians), 3) Creatinine clearance < 30 ml/min, 4) Contraindication to LMWH such as a history of heparin induced thrombocytopenia, 5) Thrombocytopenia from other causes, such as thrombotic microangiopathy, immune thrombocytopenia, disseminated intravascular coagulation, 6) History of alloimmune refractoriness to platelet transfusion, 7) Refusal of blood products, 8) Anticoagulation at any dose is deemed unsafe (ie. active bleeding or bleeding disorders).

Study interventions in the two arms include:

1) Modified dose LMWH regimen: 50% dose LMWH when platelet count is 25-50,000/µL and hold anticoagulation when platelet count is < 25,000/µL (based on ISTH guidance).

2) Higher dose LMWH with platelet transfusion support regimen: one adult unit platelet transfusion plus one dose level up of LMWH from the modified dose regimen (ie.100% dose LMWH when pre-transfusion platelet count is 25-50,000/µL) when platelet count is <50,000/µL.

The primary feasibility outcome is the overall average number of patients recruited per month. Multiple secondary feasibility outcomes are obtained including proportion of eligible patients providing consent, reasons for non-participation, adherence to the protocol, rate of withdrawal, protocol deviation, etc. The clinical outcomes include primary safety outcome as the rate of clinically relevant bleeding (composite of major bleeding and clinically relevant non-major bleeding events defined by ISTH). The primary efficacy outcome is the rate of symptomatic or incidentally detected objectively confirmed, recurrent or new VTE and pulmonary embolism related death.

The study is currently actively enrolling at three sites in Canada (Ottawa, Windsor, Edmonton), and three sites in the United Kingdom are in the process of starting the trial. Additional Canadian and European sites have shown interests and are exploring logistics of participation.

Conclusions

Management of patients with cancer, thrombocytopenia, and VTE requiring anticoagulation is challenging and remains a significant knowledge gap. This pilot trial will evaluate the feasibility, identity barriers and mitigation strategies, and improve design and success rate of the future definitive RCT in this population.

Wang:Servier: Honoraria; Valeo: Honoraria; Leo Pharma: Research Funding. Thomas:Bayer: Consultancy, Honoraria, Speakers Bureau; Anthos Therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Leader:Leo Pharma: Honoraria. Wu:Pfizer, Leo Pharma, Servier: Honoraria; BMS-Pfizer: Honoraria, Research Funding; Bayer: Research Funding. Carrier:Leo Pharma: Consultancy, Other: Grants paid to institution; Pfizer: Consultancy, Other: Grants paid to institution; BMS: Consultancy; Bayer: Consultancy; Servier: Consultancy; Anthos: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy.