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

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

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.

Study Overview

• Status: Unknown
• Conditions: Hematologic Neoplasms; Thrombocytopenia; Anticoagulants; Platelet Aggregation Inhibitors
• Intervention / Treatment: Drug: Hold; Drug: Change antithrombotic Drug; Biological: Change platelet transfusion threshold; Drug: Full dose antithrombotics; Drug: Prophylactic dose antithrombotic; 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 .

  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 Type: Observational
• Enrollment (Anticipated): 300

Contacts and Locations

• Study Contact: Name: Avi Leader, MD; Phone Number: +972-3-9377906; Email: avileader@yahoo.com
• Study Contact Backup: Name: Hugo ten Cate, MD, PhD; Email: h.tencate@maastrichtuniversity.nl

Study Locations

• Israel
  • Haifa, Israel
    • Recruiting
    • Rambam Health Care Campus
    • Contact: Yona Nadir, MD, PhD
    • Contact: Debbie Steiner, MHA; Phone Number: +972-4-8543592; Email: d_steiner@rambam.health.gov.il
  • Kfar Saba, Israel, 4428164
    • Recruiting
    • Meir Medical Center
    • Contact: Orly Avnery, MD; Phone Number: +972-9-7471755; Email: avneryho@clalit.org.il
  • Petaẖ Tiqwa, Israel
    • Recruiting
    • Rabin Medical Center
    • Contact: Galia Spectre, MD, PhD; Phone Number: +972-3-9377906; Email: galiasp1@clalit.org.il
  • Tel Aviv, Israel, 64239
    • Recruiting
    • Tel Aviv Sourasky Medical Center
    • Contact: Ron Ram, MD; Phone Number: +972-3-697-3577; Email: ronr@tlvmc.gov.il
• Italy
  • Alessandria, Italy, 15121
    • Recruiting
    • Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo di Alessandria
    • Contact: Dr. Roberto Santi; Phone Number: +39 (0)131 206111; Email: dr.rsanti@gmail.com
  • Bergamo, Italy, 24127
    • Recruiting
    • A.O. Papa Giovanni XXIII - S.I.M.T.
    • Contact: Alessandro Rambaldi, MD; Email: arambaldi@asst-pg23.it
  • Brescia, Italy, 25123
    • Recruiting
    • ASST degli Spedali Civili di Brescia
    • Contact: Dr. Giuseppe Rossi; Phone Number: +39 (0)30 399 8870; Email: giuseppe.rossi@asst-spedalicivili.it
  • Modena, Italy, 41125
    • Not yet recruiting
    • A.O.U. di Modena
    • Contact: Dr. Marco Marietta; Phone Number: +39 (0)59 422 2111; Email: marco.marietta1@gmail.com
  • Monza, Italy
    • Recruiting
    • Ospedale San Gerardo di Monza
    • Contact: Andrea Carrer; Email: mail.carrer@gmail.com
  • Palermo, Italy
    • Recruiting
    • University Hospital Policlinico di Palermo
    • Contact: Mariasanta Napolitano; Phone Number: +39-91 655 1111; Email: mariasanta.napolitano@unipa.it
  • Roma, Italy, 00161
    • Recruiting
    • A.O.U Policlinico Umberto I di Roma
    • Contact: Dr. Antonio Chistolini; Phone Number: +39 06 49971; Email: chistolini@bce.uniroma1.it
  • Roma, Italy, 00168
    • Recruiting
    • Fondazione Policlinico Universitario A. Gemelli
    • Contact: Prof. Valerio De Stefano; Phone Number: +39 06 30151; Email: valerio.destefano@unicatt.it
  • Roma, Italy
    • Recruiting
    • Università degli studi di Roma "Tor Vergata"
    • Contact: Maria Ilaria Del Principe; Email: Del.Principe@Med.uniroma2.it
  • Torino, Italy
    • Recruiting
    • A.O.U. Citta' della Salute e della Scienza di Torino
    • Contact: Eloise Beggiato, MD; Phone Number: +39-11 633 1633; Email: ebeggiato@cittadellasalute.to.it
  • Vicenza, Italy, 36100
    • Not yet recruiting
    • AZIENDA ULSS N. 8 BERICA di Vicenza
    • Contact: Dr. Marco Ruggeri; Phone Number: +39 (0)444 753111; Email: marco.ruggeri@ulssvicenza.it
• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Amsterdam University Medical Centers
    • Contact: Harry R Büller, MD, PhD; Email: h.r.buller@amc.uva.nl
    • Contact: Eva N Hamulyák, MD; Phone Number: +31 20 5667516; Email: e.n.hamulyak@amc.uva.nl
  • Groningen, Netherlands
    • Recruiting
    • University Medical Center Groningen
    • Contact: Karina Meijer, MD, PhD; Email: k.meijer@umcg.nl
    • Contact: Tessa Elling, MD; Phone Number: +31 6 31623491; Email: t.elling@umcg.nl
  • Maastricht, Netherlands, 6229 HX
    • Recruiting
    • Maastricht University Medical Center (MUMC+)
    • Contact: Avi Leader, MD; Phone Number: +31-43-3874780; Email: avileader@yahoo.com
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Center
    • Contact: Mandy Lauw, MD, PhD; Email: m.lauw@erasmusmc.nl
  • The Hague, Netherlands, 2545 AA
    • Withdrawn
    • HagaZiekenhuis
• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Terminated
      • Oregon Health & Science University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects treated at the inpatient or outpatient hematology departments at the participating centers

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	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: 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; Drug: Prophylactic dose antithrombotic; Reduction in antithrombotic medication dose to prophylactic dose (without changing type); 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	30 days (from study index) or until death (whichever first)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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	30 days (from study index) or until death (whichever first)
Number of platelet tranfusions	Number of platelet transfusions	30 days (from study index) or until death (whichever first)
Number of RBC tranfusions	Number of red blood cell transfusions	30 days (from study index) or until death (whichever first)
Death	death from any cause	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.	30 days (from study index) or until death (whichever first)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 days after study index
Whole blood coagulation	Measured by rotational thromboelastometry (ROTEM) drawn at study index	3 days after study index

Collaborators and Investigators

• Sponsor: 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: September 7, 2017
• First Submitted That Met QC Criteria: September 14, 2017
• First Posted (Actual): September 20, 2017

Study Record Updates

• Last Update Posted (Actual): September 17, 2020
• Last Update Submitted That Met QC Criteria: September 16, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Hematologic Neoplasms; Platelet Aggregation Inhibitors; Anticoagulants; Thrombocytopenia
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Blood Platelet Disorders; Hematologic Neoplasms; Thrombocytopenia
• Other Study ID Numbers: METC 17-4-061

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No