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CME / ABIM MOC / CE

Should Age Be Considered with Troponin Testing for Myocardial Injury?

  • Authors: News Author: Sue Hughes; CME Author: Charles P. Vega, MD 
  • CME / ABIM MOC / CE Released: 6/23/2023
  • Valid for credit through: 6/23/2024, 11:59 PM EST
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Target Audience and Goal Statement

This activity is intended for primary care clinicians, cardiologists, nurses, nurse practitioners, physician assistants, and other members of the healthcare team who treat and manage patients with possible acute coronary syndrome.

The goal of this activity is for members of the healthcare team to be better able to analyze patient characteristics when establishing cutoff values for abnormal cardiac troponin levels.

Upon completion of this activity, participants will:

  • Assess the interpretation of cardiac troponin levels
  • Analyze cutoff values for abnormal cardiac troponin levels
  • Outline implications for the healthcare team


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News Author

  • Sue Hughes

    Freelance writer, Medscape

    Disclosures

    Sue Hughes has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine

    Disclosures

    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: Boehringer Ingelheim Pharmaceuticals, inc.; GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Editor/Nurse Planner

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

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    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

Compliance Reviewer

  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC

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    Yaisanet Oyola, MD, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / ABIM MOC / CE

Should Age Be Considered with Troponin Testing for Myocardial Injury?

Authors: News Author: Sue Hughes; CME Author: Charles P. Vega, MD Faculty and Disclosures

CME / ABIM MOC / CE Released: 6/23/2023

Valid for credit through: 6/23/2024, 11:59 PM EST

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Clinical Context

Acute coronary syndrome is one of the most urgent and important diagnoses for healthcare professionals, so having accurate objective data for this diagnosis is critical. McCarthy and colleagues provide a review of biomarker use in testing for acute coronary syndrome in an editorial that accompanies the current study[2].

For 20 years, cardiac troponin has been the preferred biomarker is assessing for acute coronary syndrome, supplanting the less sensitive creatine kinase MB assay. The original cutoff values for cardiac troponin could overdiagnose possible cases of acute coronary syndrome, so expert groups recommended the higher cutoff of the 99th percentile of cardiac troponin levels among health adult cohorts.

However, there remain problems with this cutoff value. Men and older adults tend to have higher levels of cardiac troponin, but adjustment in cardiac troponin interpretation accounting for these variables has not been widely accepted. Moreover, there remain individuals with cardiac damage, but not acute coronary syndrome, who have an abnormal troponin value.

Given these limitations, the authors of the current study assessed cardiac troponin 99th percentile cutoff values in a cohort of healthy US adults and compared 99th percentile values with those provided by industry[1]

Study Synopsis and Perspective

Using age-specific thresholds for troponin measurement would more accurately diagnose myocardial injury when assessing patients for suspected myocardial infarction (MI), a new study suggests.

The study shows that the 99th percentile for the upper reference limit (used to define myocardial injury) for high sensitivity (hs)-troponin T in the new analysis matched those reported by manufacturers. However, the same threshold for hs-troponin I was lower than was manufacturer-reported levels when considering the whole population.

And for both hs-troponin T and hs-troponin I, there were significant differences in 99th percentile levels by age.

“Our data suggest that some cases of myocardial injury may be missed in the whole population by using current non-age-specific thresholds of troponin I,” lead author, John McEvoy, MB, University of Galway, Ireland, told theheart.org | Medscape Cardiology. “If the non-age-specific threshold was lowered to that in our cohort, then we would pick up more people with myocardial injury.”

“However,” McEvoy added, “if age-specific thresholds were deployed, then our data suggest that thresholds used to diagnose myocardial injury would need to be higher in older adults, somewhat lower in middle-aged individuals, and much lower in younger people.”

The study was published online in the Journal of the American College of Cardiology on May 15.[1]

The authors explain that the 99th percentile upper reference limit threshold is the common benchmark of abnormality for all troponin assays. Five high-sensitivity cardiac troponin assays have been cleared by the US Food and Drug Administration for clinical use and allow for earlier diagnosis of MI.

However, there has been variability in the approach used to define the 99th percentile upper reference limits for these assays, with definitions of healthy reference populations differing and the various assays available are not standardized or harmonized. So troponin concentrations at 99th percentiles do not align across assays, and the generalizability of manufacturer-reported reference upper reference limits for hs-troponin assays to the US adult population is unknown.

They note that though sex-specific 99th percentile upper reference limits for hs-troponin have been recommended since 2018, age-specific thresholds are not yet endorsed, and whether thresholds differ by race or ethnicity is also controversial.

They aimed to investigate these issues using stored serum samples from adults aged 18 years or older who participated in the 1999-2004 National Health and Nutrition Examination Survey (NHANES).

McEvoy described the NHANES database as “the gold standard cohort for representation of the US adult population,” noting that other studies conducted by the manufacturers of the troponin tests have often used convenience samples from patients attending hospital clinics and blood donors, which he said were not representative of the whole population.

For the study, the researchers estimated that the 99th percentile upper reference limit for 4 hs-troponin assays (1 troponin T and 3 troponin I) in a strictly defined the healthy reference subgroup of 2746 individuals from the NHANES cohort.

Results showed that the NHANES 99th percentile upper reference limit for hs–troponin T (19 ng/L) matched the manufacturer-reported level (19 ng/L). However, the NHANES upper reference levels for 3 troponin I assays were lower than the levels stated by the manufacturers.

The NHANES levels were 13 ng/L for the Abbott hs-troponin I assay (manufacturer: 28 ng/L), 5 ng/L for the Ortho hs-troponin I assay (manufacturer: 11 ng/L), and 37 ng/L for the Siemens hs-troponin I assay (manufacturer: 46.5 ng/L).

Furthermore, the 99th percentile upper reference limits for all 4 hs-troponin assays were statistically significantly lower in healthy adults younger than 40 years compared with healthy adults older than 60 years.

There were also significant differences in upper reference limits by sex, but none by race/ethnicity.

McEvoy explained that NHANES is a very well phenotyped database with information on individuals’ health, body mass index, and other biomarkers. “This allows us to define a completely healthy subgroup of people, which could explain why the 99th percentile threshold for hs–troponin I was lower than previously reported from other cohorts,” he added.

Although there may be concern that such a healthy subgroup would mean that the sample is enriched with younger people, whereas the typical person having their troponin measured would be older, McEvoy pointed out that there were more than 400 people older than 60 years in the healthy group. “This is probably the biggest cohort of super healthy older US adults ever sampled in this regard,” he commented.

McEvoy said that the overall results from the study suggested that different thresholds might need to be considered for troponin I. “This could lead to threshold levels used to diagnose myocardial injury being cut in the population as a whole.”

However, he added, a more important message was the need for age-specific thresholds.

“We found that troponin levels track with age. Even in individuals who age in a very heathy way, their troponin levels are greater than in younger people. This is the first time this has been shown with such clear statistical significance,” McEvoy said. “We think this data provides a compelling case for the use of age-specific cutoffs.”

He explained that if age-specific thresholds were used to diagnose myocardial injury, the cut point from the current data would be higher than it would be from current manufacturers’ recommendations in those older than 60 years, so fewer people in this age group would be labeled as having myocardial injury.

“Our results suggest that at present, we are seeing more false positives in older people leading to more unnecessary tests.” Using age-specific cutoff points will reduce the number of false positives in older people. McEvoy noted a similar change in the way D-dimer blood tests have been used to diagnose pulmonary embolism in recent years.

Using age-specific cutoffs for hs-troponin would also reduce the number of false negatives in younger people, McEvoy added.

Further Studies Needed?

In an accompanying editorial, Cian McCarthy, MB; Austin Vyas, BS; and James Januzzi, MD, Massachusetts General Hospital, Boston, note that although there are substantial shortcomings to using the 99th percentile upper reference limit of troponins for the diagnosis of cardiac injury, they believe that this measurement should persist as a central component of the MI diagnostic criteria, with the caveat that this is only 1 component of the definition of MI and does not alone define it.[2]

“[Cardiac troponin] measurement is one of the most commonly utilized blood tests in hospital-based settings, and yet important questions remain about what exactly is a normal value for this test,” the editorialists comment.

They say that this new study emphasizes the importance of age and sex in interpretation of troponin levels.

“Although the use of such cutoffs may further complicate MI diagnostic criteria, this is superseded by the benefits of improved diagnostic accuracy in younger and female patients (a critical health equity step) while reducing MI overdiagnosis in the elderly, with the resultant harms that might follow, adverse psychosocial patient impact, and unnecessary health care expenditure from cascade testing,” they write.

They conclude that further large studies derived from healthy cohorts should be conducted to answer this question in a definitive fashion.

J Am Coll Cardiol. Published online May 15, 2023.

Study Highlights

  • Adults who provided stored blood samples as part of the US National Health and Nutrition Examination Survey between 1999 and 2004 were eligible for analysis.
  • There was a long list of exclusion criteria for the patient sample, including any history of cardiovascular disease, diabetes, or hypertension; extremes of body mass index; current smoking or heavy alcohol use; hospitalization within the past year; and moderate to severe chronic kidney disease.
  • Cardiac troponin levels were measured using 4 different commercial assays. The main goal of the study was to compare the 99th percentile values of the study sample with the recommended 99th percentile cutoffs on the labels of the commercial assays.
  • 2746 adults provided blood for testing. The mean age of participants was 37.4 years, and the cohort was almost evenly split between women and men.
  • The 1 test for cardiac troponin T found good agreement with the 99th percentile value in the healthy adult population (19 ng/L) and the manufacturer-recommended cutoff value (19 ng/L).
  • However, the healthy adult population’s 99th percentile values for troponin I were consistently lower than the manufacturers’ recommended cutoff value (13 vs 28, 37 vs 46.5, and 5 vs 11 ng/L for the 3 different assays, respectively).
  • For troponin I values, the mean value in the healthy adult sample failed to overlap with the 95% confidence intervals in 2 of the manufacturers’ recommended cutoff values.
  • As expected, cardiac troponin levels were higher among men compared with women. In addition, cardiac troponin tended to increase with age.
  • However, cardiac troponin levels did not vary on the basis of the race/ethnicity of participants.
  • Researchers also broadened their inclusion criteria to exclude only adults with chronic kidney disease and previous cardiovascular disease, resulting in a cohort of 10,704 adults. Mean cardiac troponin levels in this larger sample were higher than in the healthy adult sample.
  • In this larger group, 87% of participants had cardiac troponin T levels higher than the limit of detection suggested by the assay manufacturer; 49% to 66% of participants had cardiac troponin I levels above the limit of detection.

Clinical Implications

  • Expert groups have recommended the 99th percentile of cardiac troponin levels among health adult cohorts as a cutoff for acute coronary syndrome. However, men and older adults tend to have higher levels of cardiac troponin, and there remain individuals with cardiac damage but not acute coronary syndrome who have an abnormal troponin value.
  • In the current study, the healthy adult population’s 99th percentile values for troponin I were consistently lower than the manufacturers’ recommended cutoff value. Cardiac troponin levels were higher among men compared with women, and cardiac troponin increased with age. However, cardiac troponin levels did not vary on the basis of the race/ethnicity of participants.
  • In order to improve diagnostic accuracy, members of the healthcare team should factor in age and sex when interpreting cardiac troponin levels for the presence of acute coronary syndrome.

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