An observational study in Hematologic Neoplasms, Thrombocytopenia and Anticoagulants, sponsored by Maastricht University Medical Center. Status unknown at 21 sites in 4 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-09-17.
Sponsored by Maastricht University Medical Center · Observational
Background: Antithrombotic therapy in the context of treatment related thrombocytopenia (i.e. low levels of platelets) is not uncommon. Guidelines are based upon a paucity of retrospective data and focus on the scenario of cancer associated venous thrombosis and low molecular weight heparin treatment. Even less is known regarding direct oral anticoagulants, antiplatelet therapy, or anticoagulation prescribed for other indications.
Aims: The study aims are to evaluate how physicians manage anticoagulant and antiplatelet medication in patients with hematological malignancy and thrombocytopenia, and to assess the frequency of bleeding and thrombosis. Additional aims are to assess how management changes affect drug activity and blood clotting (coagulation), and to evaluate the use of platelet transfusions.
Design: The investigators plan a multinational prospective registry of patients admitted to the inpatient hematology department or outpatient clinic at one of the study centers. Patients with hematological malignancies, platelets below 50 X 109/L, and anticoagulant and/or antiplatelet medication will be studied.
Patients will be enrolled when the combination of antiplatelet/anticoagulant medication and thrombocytopenia is first detected. Patients will be followed until 30 days after the baseline study visit (which occurs 30 days after enrollment or when platelets \< 50*109/L, whichever come first) or death. Patients will be indexed at the time of baseline visit.
Patients will be excluded from study analysis if one of the following events occurs before study index: Withdrawal of consent, death, clinically-relevant non-major bleeding or the composite primary outcome.
Risk factors for bleeding and thrombosis will be recorded at baseline. Parameters from routine blood tests will be recorded throughout the study. During the study major bleeding events and thrombosis will be recorded. Investigational blood tests assessing coagulation and drug activity will be drawn at baseline (=study index). Throughout the study all management decisions regarding antithrombotic therapy, including platelet and red blood cell transfusion, will be recorded. This is an observational study and management will be solely at the discretion of the physician.
Analysis: The investigators will first look at the frequency of either bleeding or thrombosis according to the type of management strategy and evaluate the platelet threshold at which a given management strategy is employed.
At the next stage, in selected subgroups, the optimal management strategy with respect to bleeding/thrombotic risk, will be determined.
Thrombocyte-level cohorts Patients will be divided into two groups based on the platelet level at study index .
By definition, there will be an intervention at the time of study index (baseline), meaning that even if no change is made, it will be considered an intervention. Each patient may have multiple exposures/interventions over the study.
Therefore, in a time dependent analysis, each outcome will be linked to the exposure/intervention at study index.
Each exposure/intervention will be linked with the platelet level on the day of the intervention.
#Competing Events:
The following events (in addition to death) will be considered competing events and will be considered as such in the statistical analyses of the outcomes:
a change in the hematological malignancy treatment regimen. Study follow-up will continue after these events, and study data will continue to be recorded until censorship for end of study period or death.
Patients fulfilling the inclusion criteria but not included in the study, will be detected by reviewing the medical records of the hematology institute, weekly. The baseline characteristics and reason for not including these patients will be recorded retrospectively in the "not-included cohort". The baseline characteristics of this cohort will be compared with the study cohort to ascertain whether selection bias exists.
Subjects treated at the inpatient or outpatient hematology departments at the participating centers
"Current" refers to the time when the current thrombocytopenia, or risk thereof (i.e. "predicted"), was first identified (even if the treatment is subsequently stopped)
Exclusion Criteria:
Patients receiving antiplatelet medication, but not anticoagulation. Antiplatelet drugs include any class, dose or duration of any platelet aggregation inhibitor. This refers to the antithrombotic regimen when the current thrombocytopenia, or risk thereof (i.e. "predicted"), was first identified (even if the treatment is subsequently stopped)
Drug: Hold · Drug: Change antithrombotic Drug · Biological: Change platelet transfusion threshold · Drug: Full dose antithrombotics
Patients receiving only anticoagulants or both anticoagulant and antiplatelet medication combined. This includes any class, dose or duration of any antiplatelet or anticoagulant drug. This refers to the antithrombotic regimen when the current thrombocytopenia, or risk thereof (i.e. "predicted"), was first identified (even if the treatment is subsequently stopped)
Drug: Hold · Drug: Prophylactic dose antithrombotic · Drug: Change antithrombotic Drug · Biological: Change platelet transfusion threshold · Drug: Full dose antithrombotics · Device: Mechanical measures · Drug: Intermediate dose antithrombotic
Hold antithrombotic therapy
Reduction in antithrombotic medication dose to prophylactic dose (without changing type)
Change in type of antithrombotic therapy
Increase or reduce platelet transfusion threshold
Continue full dose antithrombotic therapy
Mechanical measures to reduce thrombotic risk including: IVC filter insertion, Intermittent Pneumatic Compression (IPC), Removal of Central venous catheter
Reduction in antithrombotic medication dose to prophylactic dose (without changing type). Intermediate dose in between prophylactic and full dose
Composite of major bleeding or thrombosis
1) ISTH-defined Major bleeding events defined as: Fatal bleeding; bleeding into a critical organ; clinically overt bleeding associated with a decrease in hemoglobin level of more than 2 g/dL or leading to the transfusion of two or more units of blood OR: 2) Thrombosis defined as: Any symptomatic deep or superficial venous or arterial thromboembolism demonstrated on objective imaging/laboratory tests. Ischemic strokes with no immediate imaging signs will also be considered events, provided this was diagnosed by a neurologist and that the patient had objective neurological signs.
Time frame: 30 days (from study index) or until death (whichever first)
Platelet transfusion related adverse effects
Number of adverse effects (all types and individually grouped) related to platelet/plasma transfusion, occurring within 24 hours of transfusion
Time frame: 30 days (from study index) or until death (whichever first)
Clinically Relevant non-Major Bleeding
Defined according to the ISTH criteria published in the journal of thrombosis and Hemostasis by Kaatz et al in 2015
Time frame: 30 days (from study index) or until death (whichever first)
Number of platelet tranfusions
Number of platelet transfusions
Time frame: 30 days (from study index) or until death (whichever first)
Number of RBC tranfusions
Number of red blood cell transfusions
Time frame: 30 days (from study index) or until death (whichever first)
Death
death from any cause
Time frame: 30 days (from study index)
Change in antithrombotic management
Change in dose/type of antiplatelet or anticoagulant medication OR change in platelet threshold, AFTER the initial intervention which was recorded at study index.
Time frame: 30 days (from study index) or until death (whichever first)
peak anticoagulant intensity
anti-Xa, Hemoclot, INR, aPTT will be measured at peak, depending on the anticoagulant drug. Patients will be classified as having sub-therapeutic, therapeutic, supra-therapeutic treatment levels, based upon the reference range at the central laboratory. Only relevant for patients with anticoagulation undergoing dose change.
Time frame: 3 days after study index
Whole blood coagulation
Measured by rotational thromboelastometry (ROTEM) drawn at study index
Time frame: 3 days after study index
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Maastricht University Medical Center