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

NCT ID: NCT05336435

Last Updated: 2023-10-17

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

NA

Total Enrollment

7500 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-04-01

Study Completion Date

2025-02-28

Brief Summary

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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

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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.

Conditions

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Coronary Syndrome, Acute Coronary Artery Disease Myocardial Infarction

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

SEQUENTIAL

A nationwide cluster-randomized trial with "stepped-wedge" design
Primary Study Purpose

DIAGNOSTIC

Blinding Strategy

SINGLE

Outcome Assessors
A diagnosis of acute MI will be adjudicated for all individuals in the primary cohort by an endpoint committee consisting of three cardiologists from another region in Denmark.

Study Groups

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Control Arm - Current sex-uniform manufacturer provided 99th percentile URL of troponin

Standard use of the current 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

Group Type NO_INTERVENTION

No interventions assigned to this group

Intervention Arm - New population and sex-specific 99th percentile URLs of troponin

Implementation of the new population and sex-specific 99th percentile URLs of troponin for the specific assay utilized at the enrolled centers.

Group Type ACTIVE_COMPARATOR

Implementation of the new population and sex-specific 99th percentile URL for cardiac troponin

Intervention Type DIAGNOSTIC_TEST

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.

Interventions

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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.

Intervention Type DIAGNOSTIC_TEST

Eligibility Criteria

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Inclusion Criteria

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.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Rigshospitalet, Denmark

OTHER

Sponsor Role collaborator

Nordsjaellands Hospital

OTHER

Sponsor Role collaborator

Amager Hospital

OTHER

Sponsor Role collaborator

Bispebjerg Hospital

OTHER

Sponsor Role collaborator

Zealand University Hospital

OTHER

Sponsor Role collaborator

Slagelse Sygehus

OTHER

Sponsor Role collaborator

Nykøbing Falster County Hospital

OTHER

Sponsor Role collaborator

Holbaek Sygehus

OTHER

Sponsor Role collaborator

Odense University Hospital

OTHER

Sponsor Role collaborator

Svendborg Hospital

OTHER

Sponsor Role collaborator

Kolding Sygehus

OTHER

Sponsor Role collaborator

Aarhus University Hospital

OTHER

Sponsor Role collaborator

Gødstrup Hospital

OTHER

Sponsor Role collaborator

Central Jutland Regional Hospital

OTHER

Sponsor Role collaborator

Randers Regional Hospital

OTHER

Sponsor Role collaborator

Glostrup University Hospital, Copenhagen

OTHER

Sponsor Role collaborator

Hvidovre University Hospital

OTHER

Sponsor Role collaborator

Vejle Hospital

OTHER

Sponsor Role collaborator

Hospital of Southern Jutland

OTHER

Sponsor Role collaborator

Horsens Hospital

OTHER

Sponsor Role collaborator

Aalborg University Hospital

OTHER

Sponsor Role collaborator

Regionshospital Nordjylland

OTHER_GOV

Sponsor Role collaborator

Sydvestjysk Sygehus

UNKNOWN

Sponsor Role collaborator

Herlev and Gentofte Hospital

OTHER

Sponsor Role collaborator

Herlev Hospital

OTHER

Sponsor Role lead

Responsible Party

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Kasper Iversen

Professor, Consultant, DMSc

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Kasper K Iversen, MD, DMsc

Role: PRINCIPAL_INVESTIGATOR

Herlev Hospital, University Hospital of Copenhagen

Locations

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Hospital of Southern Jutland

Aabenraa, , Denmark

Site Status RECRUITING

Aalborg University Hospital

Aalborg, , Denmark

Site Status RECRUITING

Aarhus University Hospital

Aarhus, , Denmark

Site Status RECRUITING

Bispebjerg & Frederiksberg Hospital

Bispebjerg, , Denmark

Site Status NOT_YET_RECRUITING

Rigshospitalet (Blegdamsvej)

Copenhagen Ø, , Denmark

Site Status RECRUITING

Sydvestjysk Sygehus

Esbjerg, , Denmark

Site Status NOT_YET_RECRUITING

Glostrup University Hospital

Glostrup Municipality, , Denmark

Site Status RECRUITING

Gødstrup Regional Hospital

Gødstrup, , Denmark

Site Status RECRUITING

Herlev & Gentofte Hospital

Herlev, , Denmark

Site Status RECRUITING

C Torp-Pedersen

Hillerød, , Denmark

Site Status RECRUITING

North Denmark Regional Hospital

Hjørring, , Denmark

Site Status RECRUITING

Holbaek Sygehus

Holbæk, , Denmark

Site Status NOT_YET_RECRUITING

Horsens Hospital

Horsens, , Denmark

Site Status RECRUITING

Amager & Hvidovre Hospital

Hvidovre, , Denmark

Site Status NOT_YET_RECRUITING

Sygehus Lillebælt (Kolding Sygehus & Vejle Sygehus)

Kolding, , Denmark

Site Status NOT_YET_RECRUITING

Zealand University Hospital

Køge, , Denmark

Site Status NOT_YET_RECRUITING

Nykøbing Falster County Hospital

Nykøbing Falster, , Denmark

Site Status RECRUITING

Odense University Hospital

Odense, , Denmark

Site Status RECRUITING

Randers Regional Hospital

Randers, , Denmark

Site Status NOT_YET_RECRUITING

Slagelse Sygehus

Slagelse, , Denmark

Site Status NOT_YET_RECRUITING

Svendborg Hospital

Svendborg, , Denmark

Site Status RECRUITING

Central Jutland Regional Hospital (Viborg Hospital & Silkeborg Hospital)

Viborg, , Denmark

Site Status NOT_YET_RECRUITING

Countries

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Denmark

Central Contacts

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Kasper K Iversen, MD, DMsc

Role: CONTACT

Christian Torp-Pedersen, MD, DMsc

Role: CONTACT

Facility Contacts

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Rasmus Albiniussen, MD

Role: primary

Martin K Christensen, MD

Role: primary

Christian J Terkelsen, MD, DMSc

Role: primary

Ida Gustafsson, MD, PhD

Role: primary

Lene Holmvang, MD, DMSc

Role: primary

Monija M Hansen, MD

Role: primary

Britt Falskov, MD, PhD

Role: primary

Morten Bøttcher, MD, PhD

Role: primary

Kasper K Iversen, MD, DMsc

Role: primary

Nina Strandkjær, MD

Role: backup

+4527207681

C Torp-Pedersen, MD, DMsc

Role: primary

Peter B Stæhr, MD, PhD

Role: primary

Micheael H Olsen, MD,DMSc

Role: primary

Karen K Dodt, MD, PhD

Role: primary

Magnus T Jensen, MD, DMSc

Role: primary

Jonas Sjøland, MD, PhD

Role: primary

Sejr L Horskjær, MD

Role: backup

Niels E Bruun, MD, DMSc

Role: primary

Peer Grande, MD, Dmsc

Role: primary

Gro Egholm, MD

Role: primary

Bo Løfgren, MD, PhD

Role: primary

Henrik Ryde, MD

Role: primary

Jess Lambrechtsen, MD, PhD

Role: primary

Hanne M Søndergaard, MD, PhD

Role: primary

Lene H Madsen, MD, PhD

Role: backup

References

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Hasselbalch RB, Strandkjaer N, Kristensen J, Jorgensen N, Kock TO, Lange T, Ostrowski SR, Nissen J, Larsen MH, Vesterager Pedersen OB, Bor MV, Afzal S, Kamstrup PR, Dahl M, Hilsted L, Rode L, Jorgensen NR, Torp-Pedersen C, Bundgaard H, Iversen KK. Impact of age on cardiac troponin concentration among healthy individuals. Clin Biochem. 2025 Aug;138:110956. doi: 10.1016/j.clinbiochem.2025.110956. Epub 2025 Jun 11.

Reference Type DERIVED
PMID: 40513714 (View on PubMed)

Strandkjaer N, Jorgensen N, Hasselbalch RB, Kristensen J, Knudsen MSS, Kock TO, Lange T, Lindholm MG, Bruun NE, Holmvang L, Terkelsen CJ, Pedersen CK, Christensen MK, Lassen JF, Hilsted L, Ladefoged S, Nybo M, Bor MV, Dahl M, Hansen AB, Kamstrup PR, Bundgaard H, Torp-Pedersen C, Iversen KK. DANSPOT: A Multicenter Stepped-Wedge Cluster-Randomized Trial of the Reclassification of Acute Myocardial Infarction: Rationale and Study Design. J Am Heart Assoc. 2024 May 7;13(9):e033493. doi: 10.1161/JAHA.123.033493. Epub 2024 Apr 19.

Reference Type DERIVED
PMID: 38639348 (View on PubMed)

Other Identifiers

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FSP 20067240

Identifier Type: -

Identifier Source: org_study_id

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