One-Hour Window for High-Sensitivity Troponin MI Rule-Out Backed in Studies

 Patrice Wendling

June 06, 2016

HAMBURG, GERMANY and BRISTOL, UK — High-sensitivity cardiac troponin I (hs-cTnI) assays used with low cutoff values, performed within the first hour after presentation, safely and effectively ruled out MI in patients presenting to the emergency department with chest pain in two European studies.

In a single-center German study[1], the negative predictive value (NPV) for non–ST-segment-elevation MI (NSTEMI) type 1 was 99.8% using a 1-hour rule-out algorithm with a cutoff of 6 ng/L, far lower than the currently recommended 99th percentile upper reference limit of 27 ng/L for the assay, reported Dr Johannes Tobias Neumann (University Hospital Hamburg-Eppendorf, Hamburg, Germany) and colleagues.

In a pooled analysis[2], the NPV was 99.5% using a hs-cTnI assay at a cutoff of 1.2 ng/L, the lower limit of detection, in combination with nonischemic ECG at presentation. This allowed for early discharge of 18.8% of patients, according to Dr Edward Carlton (North Bristol National Health Service Trust, Bristol, UK) and colleagues.

High-sensitivity troponin assays are currently used in many countries, generally with a rule-out time window longer than 1 hour, but remain unapproved in the US.

Both studies were reported online June 1, 2016 in JAMA Cardiology.

Dr David A Morrow (Brigham and Women's Hospital, Boston, MA) writes in an accompanying editorial[3] that the findings "lend strong support to the notion that accelerated diagnostic protocols that incorporate hsTn can facilitate earlier triage while maintaining an acceptable NPV."

He adds, however, that, "despite many strengths of the available evidence, there are some reasons that these data may overstate the diagnostic performance of rapid strategies to exclude acute coronary syndromes."

Morrow calls for additional studies in diverse healthcare settings, observing that the proportion of patients with hsTn in the very low range varies with demographics in the local emergency department and that the NPV depends on the MI prevalence in the local population. The NPVs reported in the studies also will be misleading if the accelerated diagnostic protocol is applied in high-risk patients.

"At present, because hsTn assays are not available in the United States, serial testing at presentation and 3 to 6 hours with a contemporary sensitive assay remains the US standard of care," he concludes.

European Society of Cardiology (ESC) guidelines recommend the use of hs-troponin assays on admission and after 3 hours with a cutoff above the 99th percentile of the specific assay[4]. Studies suggesting that acute MI can be diagnosed much earlier using cutoffs below the 99th percentile have prompted a step change in the last year in Europe and the addition of the rapid rule-out after 1-hour approach to the NSTEMI ESC 2015 guidelines as an alternative to the standard 3-hour approach.

"The ESC guidelines are beginning to creep into practice in Europe," Carlton told heartwire from Medscape. "There have been some debates about their applicability, but I think the Neumann paper does add strength to the assertions from the ESC that 0- and 1-hour troponin sampling strategies are safe for clinical implementation."

Carlton suggests it's also time for things to change across the pond. "Now that we're getting these studies published in US journals, I think that will undoubtedly have influence upon the FDA decision. I suspect within the next year that these assays will be approved for clinical use in the US."

One-Hour Rule-Out

As previously reported by heartwire at last year's ESC Congress, the Biomarkers in Acute Cardiac Care (BACC) study involved 1040 patients (median age 65 years; 64.7% male) presenting to the emergency department with acute chest pain from July 19, 2013 to December 31, 2014. Blood was drawn at admission, after 1 hour, and after 3 hours, and acute MI diagnosed according to the ESC guidelines based on a high-sensitivity troponin T assay (Elecys, Roche Diagnostics). Troponin I levels used for the 1-hour algorithm were determined using an hs-cTnI assay (Architect i2000SR, Abbott Diagnostics).

The accuracy of the 1-hour–rule-out algorithm was comparable to the standard 3-hour approach for NSTEMI type 1 (NPV 99.8% vs 100%) and for all NSTEMI (NPV 99.0% vs 99.5%).

"The algorithm performed evenly well in clinically important subgroups, whereas only atrial fibrillation had an effect on the [positive predictive value] PPV," Neumann noted.

In contrast, use of the 99th percentile as a cutoff (27 ng/L) resulted in "substantially lower NPVs" after 1 hour (94.8%) and after 3 hours (97%) compared with the 6-ng/L cutoff.

Further, use of the low 6-ng/L cutoff resulted in lower mortality through 1 year of follow-up than the routinely used 99th percentile cutoff (1% vs 3.7%).

The 1-hour algorithm was also validated in two independent cohorts (ADAPT and APACE trials) that included 4009 patients.

"The 1-hour approach does not yet integrate any clinical measurement such as electrocardiography, which will further increase the safety of this rule-out strategy," he noted, but added that it "prevents inappropriate cost-intensive management, which includes possibly harmful coronary angiographies."

Admission-Only Testing

The pooled analysis included five prospective cohort studies from Australia, New Zealand, and England involving 3155 patients (mean age 57.4 years: 56.1% male) who presented to the emergency department with symptoms suggestive of cardiac ischemia from November 1, 2007 to August 10, 2013. Of these, 291 developed an acute MI.

The 1.2-ng/L cutoff provided a sensitivity of 99% and a NPV of 99.5%, as noted above. The sensitivity for acute MI was similar in men and women and when stratified by age, cardiac risk-factor burden, and history of coronary artery disease.

Sensitivity decreased with increasing cutoff levels, with all rounded cutoff values above 1.2 ng/L (up to and including 5 ng/L) with sensitivities less than 98%, albeit with NPVs >99%, the authors reported.

Carlton stressed to heartwire , however, that none of the patients were actually discharged on the basis of any of the low troponin results. All were admitted and had prolonged observation in the hospital and further testing done either as an early outpatient or inpatient. "So I still think this discharge strategy really needs testing in a clinical environment where these patients are actually discharged."

He added that there's certainly a gap in the literature with regard to incorporating these very low cutoff values with existing risk scores such as TIMI, GRACE, and the HEART score. "What we need to find is whether we can incorporate those risk scores with these low-detection strategies; how many patients we can still send home on the basis of a single blood test; and also risk-stratify patients according to what further tests are needed such as exercise or stress testing."

The BACC study was supported by the German Center of Cardiovascular Research, the European Union Seventh Framework Programme, and an unrestricted grant from Abbott Diagnostics, which also provided test reagents for high-sensitive troponin I measurements. Dr Neumann declared no relevant financial relationships. Funding information for ADAPT and APACE and coauthor financial disclosures are available in the paper. The cohort studies in the pooled analysis were funded predominantly by the Christchurch Heart Institute, Queensland Emergency Medicine Research Foundation, Abbott, Alere, the Royal College of Emergency Medicine of the United Kingdom, the UK National Institute for Health Research (NIHR), and the NIHR Clinical Research Network. Dr Cullen reports undertaking research under collaborative agreements with Abbott and Randox Laboratories. Disclosures for the coauthors are listed in the paper. Dr Morrow reports receiving grants from Abbott Laboratories, Amgen, AstraZeneca, Daiichi Sankyo/Eli Lilly, diaDexus, Eisai, Gilead, GlaxoSmithKline, Merck, Novartis, and Roche Diagnostics; and personal fees from Abbott, AstraZeneca, Daiichi Sankyo/Eli Lilly, diaDexus, Eisai, Gilead, GlaxoSmithKline, Instrumentation Laboratory, Merck, Novartis, Provencio, and Roche Diagnostics.

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