A Study of Population and Sex-specific Troponin Cutoffs for Ruling Out Acute Myocardial Infarction

Coronary Artery Disease Clinical Trial

— DANSPOT  

Official title:

A Randomized Clinical Trial (RCT) of Population and Sex-specific Troponin Cutoffs for Ruling Out Acute Myocardial Infarction - The Danish Study of Population and Sex-Specific Cutoffs of Troponin

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05336435
• Other study ID #: FSP 20067240
• Status: Recruiting
• Phase: N/A
• Start date: April 1, 2022
• Est. completion date: February 28, 2025

Study information

• Verified date: October 2023
• Source: Herlev Hospital
• Contact: Kasper K Iversen, MD, DMsc
• Phone: 38686009
• Email: Kasper.Karmark.Iversen[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Acute myocardial infarction (MI) is defined as a rise and/or fall in cardiac troponins (cTn) with at least one value above the 99th percentile upper reference limit (URL) in the context of symptoms or clinical evidence of myocardial ischemia. The URL is based on measurements in a healthy reference population. Currently, a sex-uniform manufacturer provided 99th percentile URL of troponin is utilized at Danish hospitals as a diagnostic cutoff for acute MI for both men and women. Reportedly, healthy men have twofold the troponin level compared to healthy women, suggesting that the use of a uniform URL for troponins may lead to the under-diagnostication of acute MI in women and potentially over-diagnostication in men.

The purpose of the DANSPOT study is to evaluate the clinical effect on diagnosis, treatment and outcomes in men and women presenting with acute MI of implementing international guidelines recommendations of sex-specific 99th percentile URLs for troponin into clinical practice.

First, to determine the sex-specific 99th percentile URLs of troponins based on a healthy Danish reference population, blood samples from Danish blood donors, were analyzed using one troponin T assay and four troponin I assays. Second, the DANSPOT study is a nationwide cluster-randomized trial with "stepped-wedge" design with participation of all 22 Danish hospital laboratories and associated departments of cardiology. With one-month intervals, each of 22 centers are randomized to shift from the presently applied uniform 99th percentile URL of troponin to our newly determined population and sex-specific 99th percentiles URLs. Each patient is followed in Danish registries for 12 months after first admission.

The hypothesis of the DANSPOT study is that implementation of population and sex-specific 99th URLs for troponin, will ensure that the right patients receive the right treatment. The investigators expect to detect significantly more women with acute MI, theoretically resulting in a more accurate diagnosis and treatment of women and men with acute MI.

Description:

The present use of non-sex specific diagnostic cut-off levels of troponins in the diagnosis of acute myocardial infarction (MI) leads to under-diagnostication of acute MI in women and over-diagnostication in men. The purpose of this study is to document this through a randomized nationwide clinical implementation of population and sex-specific cut-off levels.

Coronary artery disease (CAD) is globally the leading cause of mortality for men and women. The latest consensus statement defines myocardial infarction as 1) a rise and/or fall in cardiac troponins with 2) at least one value above the 99th percentile upper reference limit (URL) in the context of 3) symptoms or clinical evidence of myocardial ischemia. Thus, levels of cardiac troponins play a key role in the diagnostic work-up in general. Currently, uniform manufacturer-provided URLs, defined by the 99th percentile of cardiac troponins in a healthy reference population, is applied in Danish hospitals as a diagnostic cut-off for acute MI for both men and women.

Lower levels of cardiac troponins are seen in healthy women as compared to healthy men, i.e. twice as high levels are seen in men. On this basis the clinical use of one uniform 99th percentile URL for cardiac troponins - i.e. applying the same diagnostic levels for men and women - may lead to a systematic under-diagnostication of acute MI in women and potentially an over-diagnostication of acute MI in men. Accordingly, the use of sex-specific 99th percentile URL of cardiac troponins are now recommended in recent guidelines by international cardiological societies, but this remains to be introduced in clinical practice.

The 99th percentile URLs for cardiac troponins currently used in Danish Hospitals are provided by the manufacturer of each specific assay based on blood samples from a healthy reference population collected by the manufacturer. Studies have shown that the 99th percentile value is dependent on patient sex as well as on the reference population selected and the definition for "healthy" used in these studies. It is well known that the 99th percentile URL should stem from a local reference population. This recommendation has never been implemented in Denmark.

The overall purpose of the study is to evaluate the clinical effect of implementing population and sex-specific 99th percentile URL for cardiac troponins in Denmark.

To determine the sex-specific 99th percentile URLs of troponins based on a healthy Danish reference population, blood samples from healthy Danish blood donors, were analyzed using one troponin T assay and four troponin I assays. Second, the DANSPOT study is a nationwide cluster-randomized trial with "stepped-wedge" design with participation of all 22 Danish hospital laboratories and associated departments of cardiology. With one-month intervals, each of 22 centers are randomized to shift from the presently applied uniform 99th percentile URL of troponin to our newly determined population and sex-specific 99th percentiles URLs. Each patient is followed in Danish registries for 12 months after first admission.

The clinical significance of sex-specific 99th percentile URLs of troponin is poorly investigated and for the same reason not yet implemented in Denmark or many other countries. The basic hypothesis of the DANSPOT study is that the implementation of population and sex-specific 99th URLs for troponin, will ensure that the right patients receive the right treatment. The investigators expect to detect significantly more women with acute MI, theoretically resulting in a more accurate diagnosis and treatment of women and men with acute MI. This would be guideline-defining for implementing sex-specific cutoffs for cardiac troponin in Denmark as well as internationally as recommended in guidelines by professional cardiological societies.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 7500
• Est. completion date: February 28, 2025
• Est. primary completion date: February 28, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria for the primary cohort:

The primary cohort will include the women and men who are expected to be most significantly impacted by the intervention, and this group is specifically defined by

1. Presenting complaints suggestive of ACS

2. At least one cTn measurement within 24 hours of admission

3. A peak cTn value between the current sex-uniform manufacturer-derived 99th percentile URL and the novel sex-and population-specific 99th percentile URLs for women and men.

Presenting complaints suggestive of ACS will be identified in hospital records by the following presenting complaints of "chest pain" (DR074), "angina pectoris" (DI20) and "myocardial infarction" (DI21), "abdominal and pelvic pain" (DR10), "pain in the throat and chest" (DR07), "dyspnea" (DR060), "reflux" (DK21) and "observation due to suspicion of another cardiovascular disorder" (DZ035).

Study participants are included at their index admission, and subsequent admissions are evaluated in follow up analyses.

Exclusion criteria:

• Age < 18 years

• Patients with discharge diagnoses with conditions like pericarditis, myocarditis, endocarditis, cardiomyopathy, valve disease, arrhythmia, heart failure, pulmonary embolism, digestive system diseases, diseases of the urinary and reproductive organs, and diseases of bones, muscles, and connective tissue, and no discharge diagnosis of myocardial infarction or angina pectoris

The initial month following the implementation of the new sex-specific 99th percentile URLs will be excluded from consideration, as it will be seen as an adjustment period. Consequently, the intervention period will be extended by one month.

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Coronary Artery Disease
• Coronary Syndrome, Acute
• Infarction
• Myocardial Infarction

Intervention

Diagnostic Test:
• Implementation of the new population and sex-specific 99th percentile URL for cardiac troponin
The new population and sex-specific 99th percentiles URLs will be implemented at all Danish hospitals receiving patients with chest pain for initial diagnostics for possible acute MI. This will take place as a randomized step-by-step introduction of population and sex-specific 99th percentile URLs for troponin in all hospital centers with a monthly start time interval. Each center is randomized to shifting from the sex-uniform manufacturer provided 99th percentile URL of cardiac troponin currently used nationwide to the new population and sex-specific 99th percentiles URLs provided by the DANSPOT study's first phase.

Locations

Country	Name	City	State
Denmark	Hospital of Southern Jutland	Aabenraa
Denmark	Aalborg University Hospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus
Denmark	Bispebjerg & Frederiksberg Hospital	Bispebjerg
Denmark	Rigshospitalet (Blegdamsvej)	Copenhagen Ø
Denmark	Sydvestjysk Sygehus	Esbjerg
Denmark	Glostrup University Hospital	Glostrup
Denmark	Gødstrup Regional Hospital	Gødstrup
Denmark	Herlev & Gentofte Hospital	Herlev
Denmark	C Torp-Pedersen	Hillerød
Denmark	North Denmark Regional Hospital	Hjørring
Denmark	Holbaek Sygehus	Holbæk
Denmark	Horsens Hospital	Horsens
Denmark	Amager & Hvidovre Hospital	Hvidovre
Denmark	Zealand University Hospital	Køge
Denmark	Sygehus Lillebælt (Kolding Sygehus & Vejle Sygehus)	Kolding
Denmark	Nykøbing Falster County Hospital	Nykøbing Falster
Denmark	Odense University Hospital	Odense
Denmark	Randers Regional Hospital	Randers
Denmark	Slagelse Sygehus	Slagelse
Denmark	Svendborg Hospital	Svendborg
Denmark	Central Jutland Regional Hospital (Viborg Hospital & Silkeborg Hospital)	Viborg

Sponsors (25)

Lead Sponsor

Collaborator

Herlev Hospital

Aalborg University Hospital, Aarhus University Hospital, Amager Hospital, Bispebjerg Hospital, Central Jutland Regional Hospital, Glostrup University Hospital, Copenhagen, Gødstrup Hospital, Herlev and Gentofte Hospital, Holbaek Sygehus, Horsens Hospital, Hospital of Southern Jutland, Hvidovre University Hospital, Kolding Sygehus, Nordsjaellands Hospital, North Denmark Regional Hospital, Nykøbing Falster County Hospital, Odense University Hospital, Randers Regional Hospital, Rigshospitalet, Denmark, Slagelse Sygehus, Svendborg Hospital, Sydvestjysk Sygehus, Vejle Hospital, Zealand University Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	A composite of myocardial infarction, unplanned revascularisation (after index admission) or all cause mortality within 1 year of first admission for the primary cohort.	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.; Primary cohort is defined as the cohort of women and men with suspected acute coronary syndrome (ACS) with at least two cTn measurements within 24 hours with a maximal cTn level between the current sex-uniform manufacturer-derived 99th percentiles of cTn and the newly defined sex-specific 99th percentiles for women and men.	12 months after index admission
Secondary	Number of women with coronary events in the primary cohort (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.; Primary cohort is defined as the cohort of women and men with suspected acute coronary syndrome (ACS) with at least two cTn measurements within 24 hours with a maximal cTn level between the current sex-uniform manufacturer-derived 99th percentiles of cTn and the newly defined sex-specific 99th percentiles for women and men.; Coronary events are defined as the prevalence of cardiovascular death, myocardial infarction or unplanned revascularisation (after index admission) within 1 year of first admission.	12 months after index admission
Secondary	Number of men with coronary events in the primary cohort (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.; Primary cohort is defined as the cohort of women and men with suspected acute coronary syndrome (ACS) with at least two cTn measurements within 24 hours with a maximal cTn level between the current sex-uniform manufacturer-derived 99th percentiles of cTn and the newly defined sex-specific 99th percentiles for women and men.; Coronary events are defined as the prevalence of cardiovascular death, myocardial infarction or unplanned revascularisation (after index admission) within 1 year of first admission.	12 months after index admission
Secondary	Number of women and men with coronary events in the primary cohort (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.; Primary cohort is defined as the cohort of women and men with suspected acute coronary syndrome (ACS) with at least two cTn measurements within 24 hours with a maximal cTn level between the current sex-uniform manufacturer-derived 99th percentiles of cTn and the newly defined sex-specific 99th percentiles for women and men.; Coronary events are defined as the prevalence of cardiovascular death, myocardial infarction or unplanned revascularisation (after index admission) within 1 year of first admission.	12 months after index admission
Secondary	Number of women diagnosed with acute MI (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	Number of women diagnosed with acute MI	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	Number of men diagnosed with acute MI (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	Number of men diagnosed with acute MI	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	The overall number of women and men diagnosed with acute MI (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	The overall number of women and men diagnosed with acute MI	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	Number of women receiving unplanned revascularization (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.; Revascularization is defined as Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting.	12 months after index admission
Secondary	Number of women receiving revascularization	Time frame starts from beginning of index admission, defined as first admission in the study period.; Revascularization is defined as Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting.	12 months from index admission
Secondary	Number of men receiving unplanned revascularization (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.; Revascularization is defined as Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting.	12 months after index admission
Secondary	Number of men receiving revascularization	Time frame starts from beginning of index admission, defined as first admission in the study period.; Revascularization is defined as Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting.	12 months from index admission
Secondary	The overall number of women and men receiving unplanned revascularization (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.; Revascularization is defined as Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting.	12 months after index admission
Secondary	The overall number of women and men receiving revascularization	Time frame starts from beginning of index admission, defined as first admission in the study period.; Revascularization is defined as Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting.	12 months from index admission
Secondary	Number of women with all cause death (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	Number of women with all cause death	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	Number of men with over-all death (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	Number of men with over-all death	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	The overall number of women and men with over-all death (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	The overall number of women and men with over-all death	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	Number of women receiving coronary angiographies or heart CT without revascularization	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	Number of men receiving coronary angiographies or heart CT without revascularization	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	The overall number of women and men receiving coronary angiographies or heart CT without revascularization	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	Number of women receiving treatment with aspirin, dual anti-platelet therapy and/or statins	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	Number of men receiving treatment with aspirin, dual anti-platelet therapy and/or statins	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	The overall number of women and men receiving treatment with aspirin, dual anti-platelet therapy and/or statins	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	Number of women re-admitted	Readmission after index admission	12 months after index admission
Secondary	Number of men re-admitted	Readmission after index admission	12 months after index admission
Secondary	The overall number of women and men re-admitted	Readmission after index admission	12 months after index admission
Secondary	Length of hospital stay for women	Calculated as days from date of index admission to date of discharge	30 days
Secondary	Length of hospital stay for men	Calculated as days from date of index admission to date of discharge	30 days
Secondary	Length of hospital stay for women and men	Calculated as days from date of index admission to date of discharge	30 days
Secondary	The number of women diagnosed with myocardial injury and an event in the primary endpoint	Time frame starts from beginning of index admission, defined as first admission in the study period.; The primary endpoint is a composite of myocardial infarction, unplanned revascularisation (after index admission) or all cause mortality within 1 year of index admission.	12 months from index admission
Secondary	The number of men diagnosed with myocardial injury and an event in the primary endpoint	Time frame starts from beginning of index admission, defined as first admission in the study period.; The primary endpoint is a composite of myocardial infarction, unplanned revascularisation (after index admission) or all cause mortality within 1 year of index admission.	12 months from index admission
Secondary	The overall number of men diagnosed with myocardial injury and an event in the primary endpoint	Time frame starts from beginning of index admission, defined as first admission in the study period.; The primary endpoint is a composite of myocardial infarction, unplanned revascularisation (after index admission) or all cause mortality within 1 year of index admission.	12 months from index admission
Secondary	The number of women diagnosed with myocardial injury	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	The number of women diagnosed with myocardial injury (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	The number of men diagnosed with myocardial injury	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	The number of men diagnosed with myocardial injury (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission
Secondary	The overall number of women and men diagnosed with myocardial injury.	Time frame starts from beginning of index admission, defined as first admission in the study period.	12 months from index admission
Secondary	The overall number of women and men diagnosed with myocardial injury (after index admission)	Time frame starts at discharge from the hospital from the index admission, defined as first admission in the study period.	12 months after index admission