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

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

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 up for 12 months after their first troponin measurement during the index 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.

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Coronary Artery Disease; Coronary Syndrome, Acute
• Intervention / Treatment: Diagnostic test: Implementation of the new population and sex-specific 99th percentile URL for cardiac troponin

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 up for 12 months after their first troponin measurement during the index admission.

The clinical significance of sex-specific 99th percentile URLs for troponin remains 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 and internationally, as recommended by professional cardiological societies.

• Study Type: Interventional
• Enrollment (Actual): 4865
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Aabenraa, Denmark, 6200
    • Hospital of Southern Jutland
  • Aalborg, Denmark, 9000
    • Aalborg University Hospital
  • Aarhus, Denmark, 8000
    • Aarhus University Hospital
  • Bispebjerg, Denmark, 2400
    • Bispebjerg & Frederiksberg Hospital
  • Copenhagen Ø, Denmark, 2100
    • Rigshospitalet (Blegdamsvej)
  • Esbjerg, Denmark, 6700
    • Sydvestjysk Sygehus
  • Glostrup Municipality, Denmark, 2600
    • Glostrup University Hospital
  • Gødstrup, Denmark, 7400
    • Gødstrup Regional Hospital
  • Herlev, Denmark, 2730
    • Herlev & Gentofte Hospital
  • Hillerød, Denmark, 3400
    • C Torp-Pedersen
  • Hjørring, Denmark, 9800
    • North Denmark Regional Hospital
  • Holbæk, Denmark, 4300
    • Holbaek Sygehus
  • Horsens, Denmark, 8700
    • Horsens Hospital
  • Hvidovre, Denmark, 2650
    • Amager & Hvidovre Hospital
  • Kolding, Denmark, 6000
    • Sygehus Lillebælt (Kolding Sygehus & Vejle Sygehus)
  • Køge, Denmark, 4600
    • Zealand University Hospital
  • Nykøbing Falster, Denmark, 4800
    • Nykøbing Falster County Hospital
  • Odense, Denmark, 5000
    • Odense University Hospital
  • Randers, Denmark, 8930
    • Randers Regional Hospital
  • Slagelse, Denmark, 4200
    • Slagelse Sygehus
  • Svendborg, Denmark, 5700
    • Svendborg Hospital
  • Viborg, Denmark, 8800
    • Central Jutland Regional Hospital (Viborg Hospital & Silkeborg Hospital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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), "observation due to suspicion of myocardial infarction" (Z034), "myocardial infarction" (DI21), "abdominal and pelvic pain" (DR10), "pain in the throat and chest" (DR07), "dyspnea" (DR060), "reflux" (DK21), "ischemic heart disease" (DI22-DI25) 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, respiratory diseases, infectious diseases, digestive system diseases excluding reflux, digestive system diseases, diseases of the urinary and reproductive organs, and diseases of bones, muscles, and connective tissue, and do not have a 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: 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
Active Comparator: 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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A composite endpoint of: 1) readmission for myocardial infarction 2) readmission for unplanned revascularisation (PCI or CABG) 3) all cause mortality All events must occur within 12 months of the first troponin measurement during the index admission	We will compare the occurrence of the primary outcome separately in men and women within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. For individuals included in the primary cohort, all readmissions within the 12-month follow-up period will be adjudicated by an endpoint committee to identify type 1, type 2, and type 4b myocardial infarction, as well as unplanned coronary revascularization. All-cause mortality will be ascertained from national patient data extracts. For the diagnosis of type 2 infarctions, we will utilize the criteria established by Saaby et al. Unplanned coronary revascularization is defined as any percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) performed after discharge from the index admission, in patients without coronary angiography or cardiac CT performed or planned during the index admission, leading to planned revascularization.	The 12-month period starting from the first troponin measurement during the index admission.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality within 12 months	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. All-cause mortality within follow-up will be identified through patient data extracts. Follow-up is defined as the 12-month period starting from the first troponin measurement during the index admission.	Within 12 months from the first troponin measurement during the index admission
Non-fatal myocardial infarction (MI) occurring during any readmission within 12 months	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. Non-fatal MI during readmissions within follow-up will be identified through endpoint adjudication. Follow-up is defined as the 12-month period starting from the first troponin measurement during the index admission.	Within 12 months from the first troponin measurement during the index admission
Unplanned coronary revascularization (PCI or CABG) performed during any readmission within 12 months	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. Unplanned coronary revascularization during readmissions within follow-up will be identified through endpoint adjudication. Follow-up is defined as the 12-month period starting from the first troponin measurement during the index admission.	Within 12 months from the first troponin measurement during the index admission
Non-fatal myocardial infarction (MI) occurring during the index admission	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. Non-fatal MI during the index admission will be identified from patient data extracts.	During index admission
Myocardial injury occurring during the index admission	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. Myocardial injury during the index admission will be identified through patient data extracts.	During index admission
Coronary angiography or coronary computed tomography performed during the index admission	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. Coronary angiography and coronary computed tomography performed during the index admission will be identified through patient data extracts.	During index admission
Coronary revascularization (PCI or CABG) performed during the index admission or planned during the index admission and subsequently performed within 3 months	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. Coronary revascularization performed during the index admission, or planned during the index admission and subsequently performed within 3 months, will be identified using patient data extracts. Follow-up is defined as the 12-month period starting from the first troponin measurement during the index admission.	During the index admission or within 3 months of discharge
Coronary angiography or coronary computed tomography performed during the index admission without subsequent planned coronary revascularization within 3 months	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. Coronary angiography and coronary computed tomography performed during the index admission without subsequent planned coronary revascularization within 2 months will be identified through patient data extracts. Follow-up is defined as the 12-month period starting from the first troponin measurement during the index admission.	During the index admission or within 3 months of discharge
Length of stay during the index admission in the primary cohort	Secondary endpoints will be evaluated separately in women and men within the primary cohort before and after implementation of the new sex-specific diagnostic thresholds. The length of stay during the index admission will be identified from patient data extracts.	During index admission

Collaborators and Investigators

• Sponsor: Herlev Hospital
• Collaborators: Odense University Hospital; Zealand University Hospital; Aarhus University Hospital; Rigshospitalet, Denmark; Hvidovre University Hospital; Bispebjerg Hospital; Glostrup University Hospital, Copenhagen; Vejle Hospital; Amager Hospital; Aalborg University Hospital; Holbaek Sygehus; Herlev and Gentofte Hospital; Gødstrup Hospital; Svendborg Hospital; Nykøbing Falster County Hospital; Sydvestjysk Sygehus; Horsens Hospital; Kolding Sygehus; Nordsjaellands Hospital; Randers Regional Hospital; Central Jutland Regional Hospital; Hospital of Southern Jutland; Slagelse Sygehus; Regionshospital Nordjylland
• Investigators: Principal Investigator: Kasper K Iversen, MD, DMsc, Herlev Hospital, University Hospital of Copenhagen

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Actual): February 28, 2025
• Study Completion (Actual): February 28, 2025

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: April 19, 2022
• First Posted (Actual): April 20, 2022

Study Record Updates

• Last Update Posted (Actual): May 15, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: myocardial injury; biomarker; myocardial infarction; clinical assessment; troponin; coronary syndrome
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Infarction; Necrosis; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Ischemia; Ischemia; Chest Pain; Angina Pectoris; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Coronary Artery Disease; Myocardial Infarction; Acute Coronary Syndrome; Angina, Unstable
• Other Study ID Numbers: FSP 20067240

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No