MATTER: Management and Outcomes of Anti-thrombotic Medication Use in Thrombocytopenia

Sponsor

Maastricht University Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT03288441

Collaborator

(none)

300

Enrollment

Locations

45.4

Anticipated Duration (Months)

14.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hematologic Neoplasms Thrombocytopenia Anticoagulants Platelet Aggregation Inhibitors	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

Detailed Description

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

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

The composite primary outcome
change in the antithrombotic regimen after study index
diagnosis of HIT or TTP
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 Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

300 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Management Patterns of AntiThrombotics and Outcomes in Patients With Hematological Malignancy and ThrombocytopEnia: a Prospective Registry (MATTER Study)

Actual Study Start Date :

Mar 20, 2018

Anticipated Primary Completion Date :

Dec 31, 2020

Anticipated Study Completion Date :

Dec 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
antiplatelet only 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 Hold antithrombotic therapy Drug: Change antithrombotic Drug Change in type of antithrombotic therapy Biological: Change platelet transfusion threshold Increase or reduce platelet transfusion threshold Drug: Full dose antithrombotics Continue full dose antithrombotic therapy
anticoagulant-based 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 Hold antithrombotic therapy Drug: Prophylactic dose antithrombotic Reduction in antithrombotic medication dose to prophylactic dose (without changing type) Drug: Change antithrombotic Drug Change in type of antithrombotic therapy Biological: Change platelet transfusion threshold Increase or reduce platelet transfusion threshold Drug: Full dose antithrombotics Continue full dose antithrombotic therapy Device: Mechanical measures Mechanical measures to reduce thrombotic risk including: IVC filter insertion, Intermittent Pneumatic Compression (IPC), Removal of Central venous catheter Drug: Intermediate dose antithrombotic Reduction in antithrombotic medication dose to prophylactic dose (without changing type). Intermediate dose in between prophylactic and full dose

Arm

Intervention/Treatment

antiplatelet only

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

Hold antithrombotic therapy

Drug: Change antithrombotic Drug

Change in type of antithrombotic therapy

Biological: Change platelet transfusion threshold

Increase or reduce platelet transfusion threshold

Drug: Full dose antithrombotics

Continue full dose antithrombotic therapy

anticoagulant-based

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

Hold antithrombotic therapy

Drug: Prophylactic dose antithrombotic

Reduction in antithrombotic medication dose to prophylactic dose (without changing type)

Drug: Change antithrombotic Drug

Change in type of antithrombotic therapy

Biological: Change platelet transfusion threshold

Increase or reduce platelet transfusion threshold

Drug: Full dose antithrombotics

Continue full dose antithrombotic therapy

Device: Mechanical measures

Mechanical measures to reduce thrombotic risk including: IVC filter insertion, Intermittent Pneumatic Compression (IPC), Removal of Central venous catheter

Drug: Intermediate dose antithrombotic

Reduction in antithrombotic medication dose to prophylactic dose (without changing type). Intermediate dose in between prophylactic and full dose

Outcome Measures

Primary Outcome Measures

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

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
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 platelet tranfusions [30 days (from study index) or until death (whichever first)]
Number of platelet transfusions
Number of RBC tranfusions [30 days (from study index) or until death (whichever first)]
Number of red blood cell transfusions
Death [30 days (from study index)]
death from any cause
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.

Other Outcome Measures

peak anticoagulant intensity [3 days after study index]
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.
Whole blood coagulation [3 days after study index]
Measured by rotational thromboelastometry (ROTEM) drawn at study index

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Oregon Health & Science University Hospital	Portland	Oregon	United States	97239
2	Rambam Health Care Campus	Haifa		Israel
3	Meir Medical Center	Kfar Saba		Israel	4428164
4	Rabin Medical Center	Petaẖ Tiqwa		Israel
5	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	64239
6	Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo di Alessandria	Alessandria		Italy	15121
7	A.O. Papa Giovanni XXIII - S.I.M.T.	Bergamo		Italy	24127
8	ASST degli Spedali Civili di Brescia	Brescia		Italy	25123
9	A.O.U. di Modena	Modena		Italy	41125
10	Ospedale San Gerardo di Monza	Monza		Italy
11	University Hospital Policlinico di Palermo	Palermo		Italy
12	A.O.U Policlinico Umberto I di Roma	Roma		Italy	00161
13	Fondazione Policlinico Universitario A. Gemelli	Roma		Italy	00168
14	Università degli studi di Roma "Tor Vergata"	Roma		Italy
15	A.O.U. CITTA' della SALUTE e della SCIENZA di TORINO	Torino		Italy
16	AZIENDA ULSS N. 8 BERICA di Vicenza	Vicenza		Italy	36100
17	Amsterdam University Medical Centers	Amsterdam		Netherlands
18	University Medical Center Groningen	Groningen		Netherlands
19	Maastricht University Medical Center (MUMC+)	Maastricht		Netherlands	6229 HX
20	Erasmus Medical Center	Rotterdam		Netherlands
21	HagaZiekenhuis	The Hague		Netherlands	2545 AA

Sponsors and Collaborators

Maastricht University Medical Center

Investigators

Principal Investigator: Avi Leader, MD, Rabin Medical Center, Petah Tikva, Israel
Study Chair: Hugo ten Cate, MD, PhD, Maastricht University Medical Center, Maastricht
Study Chair: Anna Falanga, MD, A.O. Papa Giovanni XXIII - S.I.M.T.