High-Sensitivity Troponin Does Not Improve MI Outcomes

September 04, 2018

MUNICH — The first randomized controlled trial of the latest high-sensitivity cardiac troponin I assay in patients with suspected acute coronary syndrome showed the test increased detection of those with myocardial injury, but only a third of the patients reclassified had a diagnosis of myocardial infarction, and outcomes at 1 year did not improve.

While the length of hospital stay was doubled in the patients reclassified with the new test, it was halved in those without myocardial injury and was reduced by one third across the whole trial population, suggesting that clinicians were more confident ruling out myocardial infarction (MI) with potential benefits for healthcare providers, senior author Nicholas L. Mills, British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, United Kingdom, concluded.

"This test can be extremely helpful, but mainly for ruling out MI rather than ruling it in. We need further research to optimize the way we use this test to help us rule in MI more effectively," Mills commented to theheart.org | Medscape Cardiology.

"This trial has shown this test is useful, but not in the way we thought it might be," he added. "We- were hoping to show it was better at identifying patients with MI and therefore reducing outcomes in these patients. We didn't find this to be the case, but we did find it was very useful in risk-stratifying patients and identifying low-risk patients who can be managed in the outpatient setting."

Mills presented results of the High-STEACS trial August 28 here at the European Society of Cardiology (ESC) Congress 2018. It was also simultaneously published online in the Lancet.

The authors explain that MI is diagnosed by clinical history, electrocardiogram changes, and an increase or decrease in cardiac troponin concentration (as evidence of myocardial necrosis). Improvements in assay sensitivity now permit quantification of very low concentrations of troponin with high precision, which allows the use of lower diagnostic thresholds, and the Universal Definition of Myocardial Infarction recommends that an increase in troponin above the 99th percentile of a normal reference population should be used as the threshold for MI diagnosis.

However, this recommendation is based on expert consensus and observational studies rather than evidence from randomized controlled trials and is regarded as a somewhat contentious issue in clinical practice, with many institutions not using the high-sensitivity assays, they say.  

The High-STEACS trial was therefore undertaken to determine whether the introduction of a high-sensitivity cardiac troponin I assay with a sex-specific 99th percentile diagnostic threshold would reduce subsequent MI or cardiovascular death within 1 year in patients with suspected ACS who would previously have been classified as not having had a myocardial injury.

For the trial, 10 hospitals in Scotland were randomly assigned to using the new high-sensitivity test or the standard contemporary troponin test for decision making on patients who had been admitted to the emergency department with suspected ACS.  

Patients reclassified by the high-sensitivity assay were defined as those with an increased cardiac troponin I concentration but below the diagnostic threshold on the standard assay.

During the 3-year study period, 48,282 consecutive patients were enrolled, of whom 10,360 (21%) had raised cardiac troponin I concentrations signaling myocardial injury identified by either assay.

The high-sensitivity assay reclassified 17% of these patients who were not identified by the standard assay. 

However, only a third of these patients were found to have a diagnosis of type 1 MI, and outcomes were not changed significantly by the introduction of this high-sensitivity assay. The incidence of subsequent MI or death from cardiovascular causes within 1 year was 15% in the validation phase and 12% in the implementation phase (adjusted odds ratio for implementation vs validation phase, 1.10; 95% confidence interval, 0.75 - 1.61; P = .620).

"We expected the patients reclassified by the high-sensitivity test to do better, but they didn't because the majority didn't actually have an MI," Mills said.  

He explained that the standard contemporary test detects cardiac troponin I levels above 50 ng/L, whereas the new high-sensitivity test used in this trial is based on 99th percentile of cardiac troponin I in the general population. This equates to levels above 16 ng/L for women and 34 ng/L for men, as women have lower troponin concentrations than men.

However, most institutions just use a binary test that doesn't distinguish between men and women, which will underdiagnose MI in women and overdiagnose it in men. 

"But we found that using these 99th percentile cardiac troponin I thresholds doesn't necessarily inform us better on who is having an MI (rule in) even when using different thresholds for men and women," he said. "However, we have learned that the high-sensitivity test gives us much more confidence in being able to rule out MI — those that had a negative result went home much quicker — they had a 50% reduction in length of stay." 

He added: "I guess my conclusion after this trial is that we need to rethink entirely our approach of using these 99th percentiles for cardiac troponin for the diagnosis of MI. We need to develop strategies to help cardiologists identify the correct patients for treatment. That is unlikely to be based on a statistical threshold from a reference population. We are working with many groups across the world to optimize diagnostic performance for this test."

Mills believes more variables need to be considered in defining troponin thresholds for diagnosing MI. 

"Heart disease is not a single entity. To use a binary threshold in someone who is 25 years of age vs someone who is 95 years of age is not appropriate," he said. "We need to become more intuitive in the way we interpret these tests — not only including differences between men and women but also how comorbid conditions and age influence cardiac troponin concentrations and incorporate this into the decision-making process."

Commenting for theheart.org | Medscape Cardiology, Richard Becker, MD, professor of medicine at the University of Cincinnati Heart, Lung & Vascular Institute, Ohio, called the High-STEACS study "a very important trial."

"For me, this study has two primary takeaways," he said. "One, the medical community needs to think carefully about what normative data are and whether we should we be using the 99th percentile as a cutoff for diagnosing MI; and two, the greatest impact of the new high-sensitivity troponin tests seems to be for their negative predicative value — so patients who seem to have signs or symptoms of ACS but have negative results on this test are at very low risk and can be sent home. This is a valuable result in itself and should save significant resources."

In a Comment accompanying the Lancet publication, Stefan Blankenberg, Johannes Tobias Neumann, and Dirk Westermann, University Heart Centre, Hamburg, Germany, conclude that several questions remain.

"First, can the application of the high sensitivity troponin assay safely rule out myocardial infarction by use of a baseline and 1-h protocol without affecting outcome? And second, could the application of troponin cutoff concentrations far below the 99th percentile lead to an improvement of clinical outcomes due to changes in treatment strategies in a longer follow-up? Both aspects need to be addressed in future."

The High-STEACS trial was funded by the British Heart Foundation. Mills reports receiving honoraria from Abbott Diagnostics, Roche Diagnostics, and Singulex.

European Society of Cardiology (ESC) Congress 2018. Presented August 28, 2018.

Lancet. Published online August 28. Abstract,. Comment

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