A Randomised 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
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 5,175
- 试验地点
- 22
- 主要终点
- 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
研究概览
简要总结
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 utilised 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 analysed using one troponin T assay and four troponin I assays. Second, the DANSPOT study is a nationwide cluster-randomised trial with a "stepped-wedge" design, with participation of all 22 Danish hospital laboratories and associated departments of cardiology. With one-month intervals, each of the 22 centres is randomised to shift from the presently applied uniform 99th percentile URL of troponin to our newly determined population- and sex-specific 99th percentile URL. 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 percentile 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.
详细描述
The present use of non-sex-specific diagnostic cut-off levels of troponins in the diagnosis of acute myocardial infarction (MI) leads to underdiagnosis of acute MI in women and overdiagnosis in men. The purpose of this study is to document this through a randomised 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, are 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 compared with healthy men; i.e., levels are twice as high 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 URLs of cardiac troponins is 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 depends on patient sex, the reference population selected, and the definition of "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 URLs for cardiac troponins in Denmark.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Diagnostic
- 盲法
- Single (Outcomes Assessor)
盲法说明
A readmission diagnosis of acute MI and unplanned coronary revascularisation will be adjudicated for all individuals in the primary cohort by an endpoint committee consisting of three cardiologists from another region in Denmark.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
- •Presenting complaints suggestive of ACS
- •At least one cTn measurement within 24 hours of admission
- •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.
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Implementation of the new population and sex-specific 99th percentile URL for cardiac troponin (Diagnostic Test)
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 utilised at Danish hospitals as a diagnostic cutoff for acute MI for both men and women
结局指标
主要结局
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
时间窗: The 12-month period starting from 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 revascularisation. All-cause mortality will be ascertained from national patient data extracts. For the diagnosis of type 2 infarctions, we will utilise the criteria established by Saaby et al. Unplanned coronary revascularisation 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 revascularisation.
次要结局
- Non-fatal myocardial infarction (MI) occurring during the index admission(During index admission)
- Length of stay during the index admission in the primary cohort(During index admission)
- Unplanned coronary revascularisation (PCI or CABG) performed during any readmission within 12 months(Within 12 months from the first troponin measurement during the index admission)
- Myocardial injury occurring during any readmission within 12 months(Within 12 months from the first troponin measurement during the index admission)
- Documented initiation or continuation of guideline-directed medical therapy for myocardial infarction during the index admission(During the index admission)
- Coronary revascularisation (PCI or CABG) performed during the index admission or planned during the index admission and subsequently performed within 3 months(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 revascularisation within 3 months(During the index admission or within 3 months of discharge)
- All-cause mortality within 12 months(Within 12 months from the first troponin measurement during the index admission)
- Non-fatal myocardial infarction (MI) occurring during any readmission within 12 months(Within 12 months from the first troponin measurement during the index admission)
- Myocardial injury occurring during the index admission(During index admission)
- Coronary angiography or coronary computed tomography performed during the index admission(During index admission)
研究者
Kasper Iversen
Professor, Consultant, DMSc
Herlev Hospital