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Optimizing the Diagnosis of Heparin Induced Thrombocytopenia (HIT)

Primary Purpose

Heparin-induced Thrombocytopenia (HIT)

Status
Unknown status
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Diagnostic algorithm
Sponsored by
Ottawa Hospital Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Heparin-induced Thrombocytopenia (HIT)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patient with clinical suspicion of HIT by treating physician

Exclusion Criteria:

  1. Less than 18 years of age;
  2. Prior diagnosis of HIT ever;
  3. Patient enrolled within preceding 100 days;
  4. Functional/ confirmatory platelet activation results available at the time of enrollment;
  5. Requiring cardio-pulmonary bypass or percutaneous cardiac angioplasty or any other cardiac or vascular surgery/procedure requiring intra-operative/procedural heparin administration planned within 30 days;
  6. Unable to complete study follow up;
  7. Unable to obtain consent (or proxy consent from substitute decision maker where applicable);
  8. Life expectancy less than 30 days;
  9. Greater than 72 hours from clinical suspicion of HIT and/or request for HIT anti-PF4 ELISA testing.

Sites / Locations

  • The Ottawa HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

diagnostic algorithm

Arm Description

Optimizing the interpretation of the more readily available anti-PF4 assay would reduce the reliance on functional testing/ confirmatory testing (Serotonin Release Assay, SRA) and the number of patients exposed to unnecessary changes in anticoagulation therapy while awaiting the timely functional test results

Outcomes

Primary Outcome Measures

Recruitment
The pilot will be considered feasible if recruitment of at least 7.5 patients per month (total between the two sites) is achieved.
False negative management failures
The rate of false negative 'management failures' where the study protocol concludes HIT unlikely but SRA (reference standard laboratory test) is positive for HIT (≥50% Serotonin release).

Secondary Outcome Measures

Major arterial and venous thromboembolism events
Events will be ascertained from the date of study consent. However, venous or arterial thrombotic events detected on investigations ordered within 24 hours of study entry will be captured as baseline events and will be counted separately from thrombotic events which occur after the initial 24 hours of study enrolment.
Proximal deep vein thrombosis
Testing performed because of symptoms in a patient with (new) non-compressibility of the common femoral vein, popliteal vein or calf trifurcation vein of the leg on ultrasound; or new non-compressibility or visualization of thrombus in the jugular vein, subclavian vein or axillary vein on ultrasound; or an intraluminal defect seen in one more than one view in proximal leg or arm veins on venography will be diagnostic for deep vein thrombosis.
Pulmonary embolism
Testing performed because of symptoms in a patient with a high probability lung scan (i.e. at least one segmental perfusion mismatch) or CT pulmonary angiography (i.e. intraluminal filling defect in the main, lobar or segmental pulmonary arteries) will be diagnostic for pulmonary embolism.
Stroke
New infarction or hemorrhagic event confirmed on CT or MRI.
Myocardial infarction
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following: Symptoms of ischemia for ≥ 20 minutes ECG changes indicative of new ischemia: new ST-T changes ≥0.1 mV or new left bundle branch block Development of pathological Q waves in the ECG; Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
Systemic arterial embolism
Acute vascular occlusion confirmed on ultrasound or angiography Adrenal hemorrhagic infarction (indicating adrenal vein thrombosis) - radiologic diagnosis on ultrasound or CT.
Death
Due to major arterial or venous thromboembolism within 30days of follow up and major and minor bleeding.

Full Information

First Posted
April 10, 2017
Last Updated
February 22, 2021
Sponsor
Ottawa Hospital Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03148912
Brief Title
Optimizing the Diagnosis of Heparin Induced Thrombocytopenia
Acronym
HIT
Official Title
Optimizing the Diagnosis of Heparin Induced Thrombocytopenia Using Quantified Anti-Platelet Factor 4 Immunological Testing: A Pilot Multicentre Cohort Study
Study Type
Interventional

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Unknown status
Study Start Date
November 23, 2018 (Actual)
Primary Completion Date
December 2021 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ottawa Hospital Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Multicentre (Ottawa and Halifax) prospective cohort study using a diagnostic approach in patients clinically suspected to have HIT that combines pretest probability assessment with quantitative interpretation of anti-PF4 assay.
Detailed Description
The proposed is a prospective cohort study exploring a novel diagnostic approach to Heparin Induced Thrombocytopenia (HIT) using a combination of pretest probability assessment and quantitative interpretation of the anti-platelet factor 4 Immunological assay (anti-PF4). Patient with a clinical suspicion of HIT will follow the study diagnostic algorithm (Figure 1). The study algorithm will be considered a safe approach to move forward into a larger RCT if the upper limit of the 95% confidence interval for 'false negative management failures' is ≤ 4% based on a Serotonin Release Assay (SRA) gold standard. The main objective of the pilot study is to inform feasibility and recruitment barriers for a larger randomized control trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heparin-induced Thrombocytopenia (HIT)

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
180 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
diagnostic algorithm
Arm Type
Experimental
Arm Description
Optimizing the interpretation of the more readily available anti-PF4 assay would reduce the reliance on functional testing/ confirmatory testing (Serotonin Release Assay, SRA) and the number of patients exposed to unnecessary changes in anticoagulation therapy while awaiting the timely functional test results
Intervention Type
Diagnostic Test
Intervention Name(s)
Diagnostic algorithm
Intervention Description
The treating physician will complete an enrollment assessment including the 4T score pretest probability assessment14. All patients will have laboratory testing for HIT anti-PF4 as well as SRA testing. Results of the anti-PF4 assay (OD value) will be available to the treating physician who will be instructed to follow the study diagnostic algorithm
Primary Outcome Measure Information:
Title
Recruitment
Description
The pilot will be considered feasible if recruitment of at least 7.5 patients per month (total between the two sites) is achieved.
Time Frame
2 years
Title
False negative management failures
Description
The rate of false negative 'management failures' where the study protocol concludes HIT unlikely but SRA (reference standard laboratory test) is positive for HIT (≥50% Serotonin release).
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Major arterial and venous thromboembolism events
Description
Events will be ascertained from the date of study consent. However, venous or arterial thrombotic events detected on investigations ordered within 24 hours of study entry will be captured as baseline events and will be counted separately from thrombotic events which occur after the initial 24 hours of study enrolment.
Time Frame
24 hours of baseline and 24 of study enrolment
Title
Proximal deep vein thrombosis
Description
Testing performed because of symptoms in a patient with (new) non-compressibility of the common femoral vein, popliteal vein or calf trifurcation vein of the leg on ultrasound; or new non-compressibility or visualization of thrombus in the jugular vein, subclavian vein or axillary vein on ultrasound; or an intraluminal defect seen in one more than one view in proximal leg or arm veins on venography will be diagnostic for deep vein thrombosis.
Time Frame
2 years
Title
Pulmonary embolism
Description
Testing performed because of symptoms in a patient with a high probability lung scan (i.e. at least one segmental perfusion mismatch) or CT pulmonary angiography (i.e. intraluminal filling defect in the main, lobar or segmental pulmonary arteries) will be diagnostic for pulmonary embolism.
Time Frame
2 years
Title
Stroke
Description
New infarction or hemorrhagic event confirmed on CT or MRI.
Time Frame
2 years
Title
Myocardial infarction
Description
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following: Symptoms of ischemia for ≥ 20 minutes ECG changes indicative of new ischemia: new ST-T changes ≥0.1 mV or new left bundle branch block Development of pathological Q waves in the ECG; Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
Time Frame
2 years
Title
Systemic arterial embolism
Description
Acute vascular occlusion confirmed on ultrasound or angiography Adrenal hemorrhagic infarction (indicating adrenal vein thrombosis) - radiologic diagnosis on ultrasound or CT.
Time Frame
2 years
Title
Death
Description
Due to major arterial or venous thromboembolism within 30days of follow up and major and minor bleeding.
Time Frame
30 days of follow up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patient with clinical suspicion of HIT by treating physician Exclusion Criteria: Less than 18 years of age; Prior diagnosis of HIT ever; Patient enrolled within preceding 100 days; Functional/ confirmatory platelet activation results available at the time of enrollment; Requiring cardio-pulmonary bypass or percutaneous cardiac angioplasty or any other cardiac or vascular surgery/procedure requiring intra-operative/procedural heparin administration planned within 30 days; Unable to complete study follow up; Unable to obtain consent (or proxy consent from substitute decision maker where applicable); Life expectancy less than 30 days; Greater than 72 hours from clinical suspicion of HIT and/or request for HIT anti-PF4 ELISA testing.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Chantal Rockwell, BA
Phone
613-737-8899
Ext
73958
Email
crockwell@ohri.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lisa Duffett, MSc, MD
Organizational Affiliation
Ottawa Hospital Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Ottawa Hospital
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
KIH 8L6
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lisa Duffett, MSc., MD
Phone
613-737-8899
Ext
71069
Email
lduffett@toh.ca
First Name & Middle Initial & Last Name & Degree
Chantal Rockwell, BA
Phone
613-737-8899
Ext
73958
Email
crockwell@ohri.ca

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
22315270
Citation
Linkins LA, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, Crowther M. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e495S-e530S. doi: 10.1378/chest.11-2303. Erratum In: Chest. 2015 Dec;148(6):1529.
Results Reference
background
PubMed Identifier
23703622
Citation
Raschke RA, Curry SC, Warkentin TE, Gerkin RD. Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem. Chest. 2013 Oct;144(4):1269-1275. doi: 10.1378/chest.12-2712.
Results Reference
background
PubMed Identifier
20626620
Citation
Greinacher A, Ittermann T, Bagemuhl J, Althaus K, Furll B, Selleng S, Lubenow N, Schellong S, Sheppard JI, Warkentin TE. Heparin-induced thrombocytopenia: towards standardization of platelet factor 4/heparin antigen tests. J Thromb Haemost. 2010 Sep;8(9):2025-31. doi: 10.1111/j.1538-7836.2010.03974.x.
Results Reference
background
PubMed Identifier
22160026
Citation
Warkentin TE. How I diagnose and manage HIT. Hematology Am Soc Hematol Educ Program. 2011;2011:143-9. doi: 10.1182/asheducation-2011.1.143.
Results Reference
background
PubMed Identifier
15613017
Citation
Zwicker JI, Uhl L, Huang WY, Shaz BH, Bauer KA. Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia. J Thromb Haemost. 2004 Dec;2(12):2133-7. doi: 10.1111/j.1538-7836.2004.01039.x.
Results Reference
background
PubMed Identifier
17722079
Citation
Lo GK, Sigouin CS, Warkentin TE. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol. 2007 Dec;82(12):1037-43. doi: 10.1002/ajh.21032.
Results Reference
background
PubMed Identifier
21781246
Citation
Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011 Jul;9 Suppl 1:105-17. doi: 10.1111/j.1538-7836.2011.04322.x.
Results Reference
background
PubMed Identifier
22947414
Citation
Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH; scientific and standardization committee of the international society on thrombosis and haemostasis. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011 Dec;9(12):2498-500. doi: 10.1111/j.1538-7836.2011.04536.x. No abstract available.
Results Reference
background
PubMed Identifier
18489711
Citation
Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008 Aug;6(8):1304-12. doi: 10.1111/j.1538-7836.2008.03025.x. Epub 2008 May 17.
Results Reference
background
PubMed Identifier
25926600
Citation
Linkins LA, Bates SM, Lee AY, Heddle NM, Wang G, Warkentin TE. Combination of 4Ts score and PF4/H-PaGIA for diagnosis and management of heparin-induced thrombocytopenia: prospective cohort study. Blood. 2015 Jul 30;126(5):597-603. doi: 10.1182/blood-2014-12-618165. Epub 2015 Apr 29.
Results Reference
background
PubMed Identifier
16634744
Citation
Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006 Apr;4(4):759-65. doi: 10.1111/j.1538-7836.2006.01787.x.
Results Reference
background
PubMed Identifier
18036459
Citation
Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007 Nov 27;50(22):2173-95. doi: 10.1016/j.jacc.2007.09.011. No abstract available.
Results Reference
background
PubMed Identifier
15842354
Citation
Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.
Results Reference
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Optimizing the Diagnosis of Heparin Induced Thrombocytopenia

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