Clinical trial NCT05336435: A Study of Population and Sex-specific Troponin Cutoffs for Ruling Out Acute Myocardial Infarction
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Coronary Syndrome, Acute
Coronary Artery Disease
Myocardial Infarction
Keywords: coronary syndrome
myocardial infarction
clinical assessment
biomarker
troponin
Lead sponsor: Herlev Hospital
Sponsor class: OTHER
Collaborators: name: Rigshospitalet, Denmark
name: Nordsjaellands Hospital
name: Amager Hospital
name: Bispebjerg Hospital
name: Zealand University Hospital
name: Slagelse Sygehus
name: Nykøbing Falster County Hospital
name: Holbaek Sygehus
name: Odense University Hospital
name: Svendborg Hospital
name: Kolding Sygehus
name: Aarhus University Hospital
name: Gødstrup Hospital
name: Central Jutland Regional Hospital
name: Randers Regional Hospital
name: Glostrup University Hospital, Copenhagen
name: Hvidovre University Hospital
name: Vejle Hospital
name: Hospital of Southern Jutland
name: Horsens Hospital
name: Aalborg University Hospital
name: Regionshospital Nordjylland
name: Sydvestjysk Sygehus
name: Herlev and Gentofte Hospital
First posted: 2022-04-20
Enrollment: 7500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: A nationwide cluster-randomized trial with "stepped-wedge" design
Primary purpose: DIAGNOSTIC

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: A composite of myocardial infarction, unplanned revascularisation (after index admission) or all cause mortality within 1 year of first admission for the primary cohort.
timeFrame: 12 months after index admission
Secondary outcomes:
measure: Number of women with coronary events in the primary cohort (after index admission)
timeFrame: 12 months after index admission
measure: Number of men with coronary events in the primary cohort (after index admission)
timeFrame: 12 months after index admission
measure: Number of women and men with coronary events in the primary cohort (after index admission)
timeFrame: 12 months after index admission
measure: Number of women diagnosed with acute MI (after index admission)
timeFrame: 12 months after index admission
measure: Number of women diagnosed with acute MI
timeFrame: 12 months from index admission
measure: Number of men diagnosed with acute MI (after index admission)
timeFrame: 12 months after index admission
measure: Number of men diagnosed with acute MI
timeFrame: 12 months from index admission
measure: The overall number of women and men diagnosed with acute MI (after index admission)
timeFrame: 12 months after index admission
measure: The overall number of women and men diagnosed with acute MI
timeFrame: 12 months from index admission
measure: Number of women receiving unplanned revascularization (after index admission)
timeFrame: 12 months after index admission
measure: Number of women receiving revascularization
timeFrame: 12 months from index admission
measure: Number of men receiving unplanned revascularization (after index admission)
timeFrame: 12 months after index admission
measure: Number of men receiving revascularization
timeFrame: 12 months from index admission
measure: The overall number of women and men receiving unplanned revascularization (after index admission)
timeFrame: 12 months after index admission
measure: The overall number of women and men receiving revascularization
timeFrame: 12 months from index admission
measure: Number of women with all cause death (after index admission)
timeFrame: 12 months after index admission
measure: Number of women with all cause death
timeFrame: 12 months from index admission
measure: Number of men with over-all death (after index admission)
timeFrame: 12 months after index admission
measure: Number of men with over-all death
timeFrame: 12 months from index admission
measure: The overall number of women and men with over-all death (after index admission)
timeFrame: 12 months after index admission
measure: The overall number of women and men with over-all death
timeFrame: 12 months from index admission
measure: Number of women receiving coronary angiographies or heart CT without revascularization
timeFrame: 12 months from index admission
measure: Number of men receiving coronary angiographies or heart CT without revascularization
timeFrame: 12 months from index admission
measure: The overall number of women and men receiving coronary angiographies or heart CT without revascularization
timeFrame: 12 months from index admission
measure: Number of women receiving treatment with aspirin, dual anti-platelet therapy and/or statins
timeFrame: 12 months after index admission
measure: Number of men receiving treatment with aspirin, dual anti-platelet therapy and/or statins
timeFrame: 12 months after index admission
measure: The overall number of women and men receiving treatment with aspirin, dual anti-platelet therapy and/or statins
timeFrame: 12 months after index admission
measure: Number of women re-admitted
timeFrame: 12 months after index admission
measure: Number of men re-admitted
timeFrame: 12 months after index admission
measure: The overall number of women and men re-admitted
timeFrame: 12 months after index admission
measure: Length of hospital stay for women
timeFrame: 30 days
measure: Length of hospital stay for men
timeFrame: 30 days
measure: Length of hospital stay for women and men
timeFrame: 30 days
measure: The number of women diagnosed with myocardial injury and an event in the primary endpoint
timeFrame: 12 months from index admission
measure: The number of men diagnosed with myocardial injury and an event in the primary endpoint
timeFrame: 12 months from index admission
measure: The overall number of men diagnosed with myocardial injury and an event in the primary endpoint
timeFrame: 12 months from index admission
measure: The number of women diagnosed with myocardial injury
timeFrame: 12 months from index admission
measure: The number of women diagnosed with myocardial injury (after index admission)
timeFrame: 12 months after index admission
measure: The number of men diagnosed with myocardial injury
timeFrame: 12 months from index admission
measure: The number of men diagnosed with myocardial injury (after index admission)
timeFrame: 12 months after index admission
measure: The overall number of women and men diagnosed with myocardial injury.
timeFrame: 12 months from index admission
measure: The overall number of women and men diagnosed with myocardial injury (after index admission)
timeFrame: 12 months after index admission
Other outcomes:
Locations:
city: Aabenraa
country: Denmark
facility: Hospital of Southern Jutland
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Bispebjerg
country: Denmark
facility: Bispebjerg & Frederiksberg Hospital
city: Copenhagen Ø
country: Denmark
facility: Rigshospitalet (Blegdamsvej)
city: Esbjerg
country: Denmark
facility: Sydvestjysk Sygehus
city: Glostrup
country: Denmark
facility: Glostrup University Hospital
city: Gødstrup
country: Denmark
facility: Gødstrup Regional Hospital
city: Herlev
country: Denmark
facility: Herlev & Gentofte Hospital
city: Hillerød
country: Denmark
facility: C Torp-Pedersen
city: Hjørring
country: Denmark
facility: North Denmark Regional Hospital
city: Holbæk
country: Denmark
facility: Holbaek Sygehus
city: Horsens
country: Denmark
facility: Horsens Hospital
city: Hvidovre
country: Denmark
facility: Amager & Hvidovre Hospital
city: Kolding
country: Denmark
facility: Sygehus Lillebælt (Kolding Sygehus & Vejle Sygehus)
city: Køge
country: Denmark
facility: Zealand University Hospital
city: Nykøbing Falster
country: Denmark
facility: Nykøbing Falster County Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Randers
country: Denmark
facility: Randers Regional Hospital
city: Slagelse
country: Denmark
facility: Slagelse Sygehus
city: Svendborg
country: Denmark
facility: Svendborg Hospital
city: Viborg
country: Denmark
facility: Central Jutland Regional Hospital (Viborg Hospital & Silkeborg Hospital)
Study officials:
affiliation: Herlev Hospital, University Hospital of Copenhagen
name: Kasper K Iversen, MD, DMsc
role: PRINCIPAL_INVESTIGATOR
References: