Management and Outcomes of Anti-thrombotic Medication Use in Thrombocytopenia

• Conditions: Thrombocytopenia; Hematologic Neoplasms; Anticoagulants; Platelet Aggregation Inhibitors
• Interventions: Drug: Hold; Drug: Change antithrombotic Drug; Drug: Prophylactic dose antithrombotic; Biological: Change platelet transfusion threshold; Drug: Full dose antithrombotics; Device: Mechanical measures; Drug: Intermediate dose antithrombotic

• Registration Number: NCT03288441
• Lead Sponsor: Maastricht University Medical Center

Brief Summary

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.

Detailed Description

* Thrombocyte-level cohorts Patients will be divided into two groups based on the platelet level at study index .

1. Thrombocytopenic Cohort: Patients with morning platelet count below 50\*109/L at study index. This is the main study cohort for all analyses

2. Non-thrombocytopenic Cohort: Patients whose morning platelet count is ≥ 50\*109/L at study index will be considered as a reference group, and not included in the primary analysis.

* Analysis of outcomes:

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:

1. The composite primary outcome

2. change in the antithrombotic regimen after study index

3. diagnosis of HIT or TTP

4. 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.

* Detecting selection bias:

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.

Study Timeline

• Study First Submitted: 2017-09-07
• Study First Submitted QC: 2017-09-14
• Study First Posted: 2017-09-20
• Study Start: 2018-03-20
• Status Verified: 2020-09
• Last Update Submitted: 2020-09-16
• Last Update Posted: 2020-09-17
• Primary Completion: 2020-12-31
• Study Completion: 2021-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

• Any hematological malignancy with or without active treatment (including autologous or allogeneic stem cell transplantation), irrespective of the treatment line and disease status.
• Disease-related and/or current/predicted treatment-related thrombocytopenia (<50 X 109/L) of any duration.
• Current antiplatelet and/or anticoagulant treatment of any duration and for any indication. This treatment may have been started before or after diagnosis of the hematological malignancy and thrombocytopenia.

"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

• Previous thrombocytopenia (<50 X 109/L) while using the current antithrombotic regimen.
• Current diagnosis of heparin induced thrombocytopenia (HIT) or thrombotic thrombocytopenia purpura (TTP)

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
antiplatelet only	Change antithrombotic Drug	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)
antiplatelet only	Change platelet transfusion threshold	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)
anticoagulant-based	Change platelet transfusion threshold	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)
antiplatelet only	Full dose antithrombotics	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)
anticoagulant-based	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)
antiplatelet only	Hold	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)
anticoagulant-based	Hold	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)
anticoagulant-based	Prophylactic dose antithrombotic	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)
anticoagulant-based	Change antithrombotic Drug	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)
anticoagulant-based	Mechanical measures	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)
anticoagulant-based	Intermediate dose antithrombotic	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)

Primary Outcome Measures

Name	Time	Method
Composite of major bleeding or thrombosis	30 days (from study index) or until death (whichever first)	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.

Secondary Outcome Measures

Name	Time	Method
Death	30 days (from study index)	death from any cause
Number of platelet tranfusions	30 days (from study index) or until death (whichever first)	Number of platelet transfusions
Clinically Relevant non-Major Bleeding	30 days (from study index) or until death (whichever first)	Defined according to the ISTH criteria published in the journal of thrombosis and Hemostasis by Kaatz et al in 2015
Number of RBC tranfusions	30 days (from study index) or until death (whichever first)	Number of red blood cell transfusions
Change in antithrombotic management	30 days (from study index) or until death (whichever first)	Change in dose/type of antiplatelet or anticoagulant medication OR change in platelet threshold, AFTER the initial intervention which was recorded at study index.
Platelet transfusion related adverse effects	30 days (from study index) or until death (whichever first)	Number of adverse effects (all types and individually grouped) related to platelet/plasma transfusion, occurring within 24 hours of transfusion

Trial Locations

Locations (21)

Oregon Health & Science University Hospital; 🇺🇸 Portland, Oregon, United States

Rambam Health Care Campus; 🇮🇱 Haifa, Israel

Meir Medical Center; 🇮🇱 Kfar Saba, Israel

Rabin Medical Center; 🇮🇱 Petaẖ Tiqwa, Israel

A.O.U. CITTA' della SALUTE e della SCIENZA di TORINO; 🇮🇹 Torino, Italy

AZIENDA ULSS N. 8 BERICA di Vicenza; 🇮🇹 Vicenza, Italy

ASST degli Spedali Civili di Brescia; 🇮🇹 Brescia, Italy

Maastricht University Medical Center (MUMC+); 🇳🇱 Maastricht, Netherlands

HagaZiekenhuis; 🇳🇱 The Hague, Netherlands

A.O.U. di Modena; 🇮🇹 Modena, Italy

Università degli studi di Roma "Tor Vergata"; 🇮🇹 Roma, Italy

Tel Aviv Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

A.O. Papa Giovanni XXIII - S.I.M.T.; 🇮🇹 Bergamo, Italy

Ospedale San Gerardo di Monza; 🇮🇹 Monza, Italy

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands

Erasmus Medical Center; 🇳🇱 Rotterdam, Netherlands

Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo di Alessandria; 🇮🇹 Alessandria, Italy

University Hospital Policlinico di Palermo; 🇮🇹 Palermo, Italy

Amsterdam University Medical Centers; 🇳🇱 Amsterdam, Netherlands

A.O.U Policlinico Umberto I di Roma; 🇮🇹 Roma, Italy

Fondazione Policlinico Universitario A. Gemelli; 🇮🇹 Roma, Italy