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Pragmatic Randomised Trial of the ESC 0/1 Versus 0/3 Hour Troponin Pathway (MACROS2)

Primary Purpose

Acute Coronary Syndrome, Troponin, Chest Pain

Status
Recruiting
Phase
Not Applicable
Locations
United Kingdom
Study Type
Interventional
Intervention
ESC 0/1 hour troponin pathway
Sponsored by
Liverpool University Hospitals NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Acute Coronary Syndrome focused on measuring acs, POC troponin, high sensitivity troponin

Eligibility Criteria

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

Inclusion Criteria:

  • Chest pain with moderate or high suspicion chest pain (see chest pain evaluation chart at end) or any patient the clinician deems suspicious for myocardial ischaemia thus requesting a troponin sample (between daytime hours 0800hrs to 1800hrs)
  • Presentation <12 hours since onset of chest pain (or unknown duration)
  • Age >18 years of age

Exclusion Criteria:

  • ST elevation myocardial infarction (STEMI) infarct on the presenting electrocardiogram (ECG)
  • Symptoms considered definitely non-cardiac
  • Trauma
  • Pregnancy
  • Comorbid conditions requiring hospital admission
  • Coronary artery bypass graft surgery (CABG) <1 month
  • coexistent clinical conditions likely to preclude follow-up.

Sites / Locations

  • liverpool university Hospital nhs foundation trustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

ESC 0/1 pathway

ESC 0/3 hour pathway

Arm Description

A two-arm parallel group, two-centre pragmatic randomised controlled trial of 0-1-hour high sensitivity troponin T (hs cTnT) compared to a 0-3-hour pathway as rules for rapid discharge of suspected ACS. (both incorporating single presentation sample limit of detection (LOD) high sensitive troponin as a rule for discharge, or cut-off selected by manufacturer). The power of the study is on safety rather than percent discharge achieved by 4 hours as this is the primary focus for clinicians and health care institutions. (By virtue of the earlier sampling the 0-1 hour troponin sampling is likely to allow greater discharges by 4 hours and the sample size for safety easily accommodates this aspect).

A two-arm parallel group, two-centre pragmatic randomised controlled trial of 0-1-hour high sensitivity troponin T (hs cTnT) compared to a 0-3-hour pathway as rules for rapid discharge of suspected ACS. (both incorporating single presentation sample limit of detection (LOD) high sensitive troponin as a rule for discharge, or cut-off selected by manufacturer). The power of the study is on safety rather than percent discharge achieved by 4 hours as this is the primary focus for clinicians and health care institutions. (By virtue of the earlier sampling the 0-1 hour troponin sampling is likely to allow greater discharges by 4 hours and the sample size for safety easily accommodates this aspect).

Outcomes

Primary Outcome Measures

percentage safe discharge by 4 hours. safety defined as type 1 MI and CV deah
We will compare safe discharge by each strategy (ie the ESC 0-1 hour pathway versus 0-3 pathway) and the proportion actually discharged by each pathway at 4 hours. The exact definition of safety will be percentage (of cohort randomised to each pathway) safely discharged by 4 hours of presentation to accident and emergency (Safety will be judged by type 1 myocardial infarction, cardiovascular death by 4 weeks with sensitivity >98% - the study will be powered on safety to establish whether 0-1-hour performance is equivalent to 0-3-hour sampling by means of a non-inferiority analysis- see statistics). (Type 1 myocardial infarction is due to acute coronary atherothrombotic myocardial injury with either plaque rupture or erosion and, often, associated thrombosis. A separate analysis will also be undertaken with inclusion of type 2 MI as well as type 1 MI as an endpoint
point of care troponin performance compared to laboratory performance
largely rule-out of Quidel triage true and siemens VTLI

Secondary Outcome Measures

Type 1 myocardial infarction
All cause death, type 1 myocardial infarction and urgent or emergency revascularisation. This analysis will be repeated incorporating both type 1 and 2 MI definition. (prespecified secondary analysis)
Proportion with rule-out or rule-in MI in the 0-1 hour and 0-3 hour
Prediction of MI with myocardial ischemic injury index (MI3) algorithm
HEART ≤3 and a modified HEART score for rule-out MI at 30 days
Proportion with repeat presentations to accident and emergency within 30 days
Proportion undergoing coronary angiography and coronary revascularisation in 0-1 versus 0-3 hour pathway
Performance of point of care troponin samples at time points at 1 to 3 hours (additional samples to 0 hour) with respect to diagnosis of acute or chronic myocardial injury and/or type 1 myocardial infarction
Rule out of MI with GDF-15 (Growth Differentiation Factor 15)

Full Information

First Posted
January 4, 2022
Last Updated
April 7, 2022
Sponsor
Liverpool University Hospitals NHS Foundation Trust
Collaborators
northwest coast academic science network, Quidel Corporation, Siemens Corporation, Corporate Technology, Abbott Diagnostics Division
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1. Study Identification

Unique Protocol Identification Number
NCT05322395
Brief Title
Pragmatic Randomised Trial of the ESC 0/1 Versus 0/3 Hour Troponin Pathway
Acronym
MACROS2
Official Title
Safety and Feasibility of Triage and Rapid Discharge of Patients With Chest Pain From Accident and Emergency: a Pragmatic, Randomised, Multicentre, Non-inferiority Control Trial of the Accelerated European Society of Cardiology (ESC) 0-1 Hour Pathway vs. Conventional 0-3 Hour Accelerated Diagnostic Protocol.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Recruiting
Study Start Date
December 10, 2021 (Actual)
Primary Completion Date
December 10, 2023 (Anticipated)
Study Completion Date
January 10, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Liverpool University Hospitals NHS Foundation Trust
Collaborators
northwest coast academic science network, Quidel Corporation, Siemens Corporation, Corporate Technology, Abbott Diagnostics Division

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
The primary objective of this study is to assess the feasibility and impact of implementing the ESC 0-1 hour high sensitive troponin pathway in clinical practice and with specific reference to the 0-3 hour pathway currently in use. The principal outcome measure will be the safety of the 0-1 hour protocol (which is less established and has limited data on safety when implemented in clinical practice)
Detailed Description
the investigators propose to compare 2 'gold standard' NICE recommended/ESC guideline-backed pathways; the accelerated 0-1 hour troponin clinical pathway versus the conventional 0-3-hour pathway, in a randomised multicentre controlled study. The primary outcome is to compare percentage safe (with the emphasis and sample size calculation on safety) discharge by 4 hours from presentation by means of the 0-3 hours versus the 0-1-hour (with the 0 hour in both pathways incorporating discharge using the limit of detection). the investigators propose to use high sensitivity troponin T (hs cTnT) (ROCHE, Elecsys assay as this is currently in routine clinical use at the site) for this purpose and also perform comparative analyses using a high sensitivity troponin I (hs cTnI) assay (ABBOTT, Architect). Redundant blood sample will also be used to evaluate point of care testing (POCT), with additional blood sample taken for POC. These samples will be undertaken as part of routine clinical care and will not require additional venepuncture (and will only be analysed if consent is gained for tissue use in research) population. A co-primary endpoint will be single sample rule-out by point of care troponin (POCT) (with a value of <4ng/l in those with chest pain onset >3 hours from presentation) as assessed in the recent APACE study of triage true POC.11 A comparison of this rule-out in terms of effectiveness (percentage discharge) and safety (sensitivity) will be made with ROCHE lod (<5ng/l)12 and the optimised rule-out of Abbott architect (HSTNI<5ng/l)13 2.2 Secondary objectives The relative performance of the Abbott Architect high sensitivity troponin I (hs TnI) , Quidel's TriageTrue and Siemens Attellica troponin I assay will also be assessed in terms of the primary and secondary endpoints by reference to high sensitivity troponin T (hs cTnT) with cut-points for Abbott hs-cTn I from the BACC study used for the 0-1-hour pathway.14 The performance of the novel machine learning algorithm, the Myocardial Ischemic Injury Index (MI3, Abbott) will also be assessed retrospectively with regard to safety and efficacy. This sub study using fully anonymized data will be performed in association with coinvestigators from Abbott Diagnostics (appendix 1). To understand if low levels of Growth Differentiation Factor (GDF-15), could expand safe discharge beyond the LOD. This will be tested for retrospectively in stored plasma samples. To assess if point of care troponin samples at time points at 1 to 3 hours (additional samples) mirror gold standard high sensitive troponin analysis with respect to diagnosis of acute or chronic myocardial injury and/or type 1 or type 2 myocardial infarction. 3) Hypothesis That an accelerated 0-1-hour troponin protocol, when implemented into clinical practice as a pragmatic RCT, will effect safe discharge with greater numbers discharged, by 4 hours from presentation, compared to the use of the more conventional 0-3 hour troponin protocol. Means to test hypothesis: A two-arm parallel group, two-centre randomised controlled trial of 0-1-hour high sensitivity troponin T (hs cTnT) compared to a 0-3-hour pathway as rules for rapid discharge of suspected ACS. (both incorporating single presentation sample limit of detection (LOD) high sensitive troponin as a rule for discharge, or cut-off selected by manufacturer). The power of the study is on safety rather than percent discharge achieved by 4 hours as this is the primary focus for clinicians and health care institutions. (By virtue of the earlier sampling the 0-1 hour troponin sampling is likely to allow greater discharges by 4 hours and the sample size for safety easily accommodates this aspect). 4. Outcomes: 4.1 Primary endpoint 1) the investigators will compare safe discharge by each strategy (ie the ESC 0-1 hour pathway versus 0-3 pathway) and the proportion actually discharged by each pathway at 4 hours. The exact definition of safety will be percentage (of cohort randomised to each pathway) safely discharged by 4 hours of presentation to accident and emergency (Safety will be judged by type 1 myocardial infarction, cardiovascular death by 4 weeks with sensitivity >98% - the study will be powered on safety to establish whether 0-1-hour performance is equivalent to 0-3-hour sampling by means of a non-inferiority analysis- see statistics). (Type 1 myocardial infarction is due to acute coronary atherothrombotic myocardial injury with either plaque rupture or erosion and, often, associated thrombosis. A separate analysis will also be undertaken with inclusion of type 2 MI as well as type 1 MI as an endpoint 4.2 Co-primary endpoint: There will be a comparison of the real time performance of point of care troponin (POCT) assay to that of a sample sent for analysis in the laboratory (the current gold standard of central laboratory analysis using HS cTn).The primary interest will be in presentation sample POC rule-out (triage true (quidel) POC <4ng/l with CP onset >3 hours compared to LOD or optimised rule-out of ROCHE (elecsys) assay, siemens attelica and Abbott architect. There will be a similar comparison made with siemens VTLI troponin I POC assay using FDA approved cut-points for MI rule-out 4.3 Secondary Endpoints: Type 1 myocardial infarction (adjudicated with the use of Abbott hs cTnI) and cardiovascular death* at 4 weeks (target for safety negative predictive value (NPV) >99.5% and sensitivity >98%). (co-primary endpoint). This analysis will be repeated incorporating both type 1 and 2 MI definition. (prespecified secondary analysis) All cause death, type 1 myocardial infarction and urgent or emergency revascularisation. This analysis will be repeated incorporating both type 1 and 2 MI definition. (prespecified secondary analysis) Proportion with rule-out or rule-in MI in the 0-1 hour and 0-3 hour Prediction of MI with myocardial ischemic injury index (MI3) algorithm9 HEART ≤3 and a modified HEART score for rule-out MI at 30 days15 Proportion with repeat presentations to accident and emergency within 30 days Proportion undergoing coronary angiography and coronary revascularisation in 0-1 versus 0-3 hour pathway Performance of point of care troponin samples at time points at 1 to 3 hours (additional samples to 0 hour) with respect to diagnosis of acute or chronic myocardial injury and/or type 1 myocardial infarction Rule out of MI with GDF-15 (Growth Differentiation Factor 15) Cardiovascular deaths include deaths that result from an myocardial infarctions (MI), sudden cardiac death, death due to heart failure (HF), death due to stroke, death due to cardiovascular procedures, death due to cardiovascular haemorrhage, and death due to other cardiovascular causes and deaths that do not have a clear non- cardiovascular cause.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Coronary Syndrome, Troponin, Chest Pain, Point-of-care Systems
Keywords
acs, POC troponin, high sensitivity troponin

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
A two-arm parallel group, two-centre randomised controlled trial of 0-1-hour high sensitivity troponin T (hs cTnT) compared to a 0-3-hour pathway as rules for rapid discharge of suspected ACS. (both incorporating single presentation sample limit of detection (LOD) high sensitive troponin as a rule for discharge, or cut-off selected by manufacturer). The power of the study is on safety rather than percent discharge achieved by 4 hours as this is the primary focus for clinicians and health care institutions. (By virtue of the earlier sampling the 0-1 hour troponin sampling is likely to allow greater discharges by 4 hours and the sample size for safety easily accommodates this aspect).
Masking
None (Open Label)
Allocation
Randomized
Enrollment
3536 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ESC 0/1 pathway
Arm Type
Experimental
Arm Description
A two-arm parallel group, two-centre pragmatic randomised controlled trial of 0-1-hour high sensitivity troponin T (hs cTnT) compared to a 0-3-hour pathway as rules for rapid discharge of suspected ACS. (both incorporating single presentation sample limit of detection (LOD) high sensitive troponin as a rule for discharge, or cut-off selected by manufacturer). The power of the study is on safety rather than percent discharge achieved by 4 hours as this is the primary focus for clinicians and health care institutions. (By virtue of the earlier sampling the 0-1 hour troponin sampling is likely to allow greater discharges by 4 hours and the sample size for safety easily accommodates this aspect).
Arm Title
ESC 0/3 hour pathway
Arm Type
Active Comparator
Arm Description
A two-arm parallel group, two-centre pragmatic randomised controlled trial of 0-1-hour high sensitivity troponin T (hs cTnT) compared to a 0-3-hour pathway as rules for rapid discharge of suspected ACS. (both incorporating single presentation sample limit of detection (LOD) high sensitive troponin as a rule for discharge, or cut-off selected by manufacturer). The power of the study is on safety rather than percent discharge achieved by 4 hours as this is the primary focus for clinicians and health care institutions. (By virtue of the earlier sampling the 0-1 hour troponin sampling is likely to allow greater discharges by 4 hours and the sample size for safety easily accommodates this aspect).
Intervention Type
Diagnostic Test
Intervention Name(s)
ESC 0/1 hour troponin pathway
Other Intervention Name(s)
esc 0/3 hour troponin pathway
Intervention Description
randomisation to 0/1 versus 0/3 hour pathway
Primary Outcome Measure Information:
Title
percentage safe discharge by 4 hours. safety defined as type 1 MI and CV deah
Description
We will compare safe discharge by each strategy (ie the ESC 0-1 hour pathway versus 0-3 pathway) and the proportion actually discharged by each pathway at 4 hours. The exact definition of safety will be percentage (of cohort randomised to each pathway) safely discharged by 4 hours of presentation to accident and emergency (Safety will be judged by type 1 myocardial infarction, cardiovascular death by 4 weeks with sensitivity >98% - the study will be powered on safety to establish whether 0-1-hour performance is equivalent to 0-3-hour sampling by means of a non-inferiority analysis- see statistics). (Type 1 myocardial infarction is due to acute coronary atherothrombotic myocardial injury with either plaque rupture or erosion and, often, associated thrombosis. A separate analysis will also be undertaken with inclusion of type 2 MI as well as type 1 MI as an endpoint
Time Frame
4 hours
Title
point of care troponin performance compared to laboratory performance
Description
largely rule-out of Quidel triage true and siemens VTLI
Time Frame
4 hours
Secondary Outcome Measure Information:
Title
Type 1 myocardial infarction
Time Frame
30 days
Title
All cause death, type 1 myocardial infarction and urgent or emergency revascularisation. This analysis will be repeated incorporating both type 1 and 2 MI definition. (prespecified secondary analysis)
Time Frame
30 days
Title
Proportion with rule-out or rule-in MI in the 0-1 hour and 0-3 hour
Time Frame
30 days
Title
Prediction of MI with myocardial ischemic injury index (MI3) algorithm
Time Frame
30 days
Title
HEART ≤3 and a modified HEART score for rule-out MI at 30 days
Time Frame
30 days
Title
Proportion with repeat presentations to accident and emergency within 30 days
Time Frame
30 days
Title
Proportion undergoing coronary angiography and coronary revascularisation in 0-1 versus 0-3 hour pathway
Time Frame
1 year
Title
Performance of point of care troponin samples at time points at 1 to 3 hours (additional samples to 0 hour) with respect to diagnosis of acute or chronic myocardial injury and/or type 1 myocardial infarction
Time Frame
30 days
Title
Rule out of MI with GDF-15 (Growth Differentiation Factor 15)
Time Frame
30 days

10. Eligibility

Sex
All
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Chest pain with moderate or high suspicion chest pain (see chest pain evaluation chart at end) or any patient the clinician deems suspicious for myocardial ischaemia thus requesting a troponin sample (between daytime hours 0800hrs to 1800hrs) Presentation <12 hours since onset of chest pain (or unknown duration) Age >18 years of age Exclusion Criteria: ST elevation myocardial infarction (STEMI) infarct on the presenting electrocardiogram (ECG) Symptoms considered definitely non-cardiac Trauma Pregnancy Comorbid conditions requiring hospital admission Coronary artery bypass graft surgery (CABG) <1 month coexistent clinical conditions likely to preclude follow-up.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Aleem Khand
Phone
+441515292720
Email
aleem.khand@liverpoolft.nhs.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Ahmed Dakshi
Phone
+441515294738
Email
ahmed.dakshi@nhs.net
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Heather Rodgers
Organizational Affiliation
Liverpool University Hospitals NHS Foundation Trust
Official's Role
Study Director
Facility Information:
Facility Name
liverpool university Hospital nhs foundation trust
City
Liverpool
State/Province
GB
ZIP/Postal Code
L186JR
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aleem Khand
Phone
+441512918126
Email
aleem.khand@liverpoolft.nhs.uk
First Name & Middle Initial & Last Name & Degree
Ahmed Dakshi
Phone
+441515294738
Email
ahmed.dakshi@nhs.net

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Pragmatic Randomised Trial of the ESC 0/1 Versus 0/3 Hour Troponin Pathway

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