Rule-In Using High-Sensitivity Cardiac Troponin May Misdiagnose Heart Attacks

One in 20 patients without clinical suspicion of acute myocardial infarction has a high sensitivity cardiac troponin I (hs-cTnI) level greater than the recommended upper limit of normal (ULN), according to a study published March 13 in BMJ. The authors say that the assumption that a result greater than the recommended threshold is a heart attack is flawed and can lead to inappropriate care. The findings show that the true 99th percentile for a general hospital population is not only inconsistent with the recommended ULN, but can vary by patient age and sex.

“The notion of using a single binary value greater than the supplied ULN of any assay to diagnose whether a patient has had an acute myocardial infarction is flawed,” write the authors led by Mark Mariathas, from the University Hospital Southampton NHS Foundation Trust in the United Kingdom. “It is important for frontline clinical staff to understand that using a single cutoff of hs-cTnI to diagnose acute myocardial infarction might be inappropriate and that the ULN of the assay depends on the setting and the clinical characteristics of patients.”

A joint definition released by the Joint European Society of Cardiology, American College of Cardiology, American Heart Association, World Heart Federation Task Force defined acute myocardial infarction as the rise or fall in cardiac troponin concentration with at least one value greater than the 99th centile derived from a reference population of healthy individuals. Further compounding interpretation of hs-cTnI results, the adoption of highly sensitive assays into clinical practice enables detection of troponin at much lower levels than previously possible.

“Using the 99th [per]centile to help rule out a diagnosis of acute myocardial infarction is clear cut and is based on a ‘healthy’ reference population,” writes Mariathas and colleagues. “However, the recommended threshold and its application to patients presenting to hospital to rule in acute myocardial infarction is problematic, particularly when the degree of suspicion is low and other factors might contribute to the cardiac troponin concentration.”

The present study measured Hs-cTnI concentrations among 20,000 consecutive inpatients and outpatients undergoing blood tests for any clinical reason from June 29, 2017, through Aug. 24, 2017. The Beckman Coulter Access AccuTnI+3 assay (Brea, CA, USA) was used and the company funded the study.

The researchers found that the 99th percentile of hs-cTnI for the whole cohort was 296 ng/L versus the manufacturer’s ULN of 40 ng/L. Hs-cTnI concentrations were greater than 40 ng/L for 5.4 percent of all patients tested. When excluding 122 participants diagnosed with acute myocardial infarction and the 1,707 for whom hs-cTnI was requested for clinical reasons, the 99th centile was 189 ng/L for the remaining 18,171 patients.

The 99th percentile varied by clinical setting: 563 ng/L for inpatients and 65 ng/L for outpatients. More specifically, patients from the emergency department had a 99th percentile of 215 ng/L, with 6.07 percent greater than the recommended ULN. Among patients in critical care units, 39.0 percent and 14.16 percent of all medical inpatients had an hs-cTnI concentration greater than the recommended ULN.

Significant independent predictors of a patient having an hs-cTnI concentration greater than the 40 ng/L recommended ULN included advancing age, male sex, and decreasing estimated glomerular filtration rate. Additionally, almost twice the proportion of patients in their 60s had hs-cTnI concentrations greater than the ULN versus patients in their 50s. Levels also tended to be higher in men than in women.

“These results have important clinical implications that are almost certainly relevant to the application of all modern hs-cTn assays,” the authors conclude. “Using the recommended ULN as a ‘rule in’ test for acute myocardial infarction might not be appropriate in patients presenting with atypical symptoms and other comorbidities, such as in the emergency department or on acute medical and surgical wards. This approach could expose patients to inappropriate pharmacological and invasive treatments that have only been shown to be beneficial in true type 1 myocardial infarction populations.”

Takeaway: Use of the recommended ULN to diagnose acute myocardial infarction may be flawed. The true 99th percentile for a hospital population may be inconsistent with the recommended ULN, and can further vary by patient demographics.