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High-sensitivity troponin testing months after an acute coronary syndrome: noise or notable results
  1. Peter Kavsak1,
  2. PJ Devereaux2
  1. 1 Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
  2. 2 Health Research, Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  1. Correspondence to Dr Peter Kavsak, Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8V 1C3, Canada; kavsakp{at}mcmaster.ca

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High-sensitivity cardiac troponin testing has received much hype over the last decade. Substantial focus on high-sensitivity cardiac troponin testing has occurred due to the combination of diagnostic company marketing, different labelling requirements across regulatory bodies and investigators and journals using different terminology.1 There is a need for agreement on what constitutes a high-sensitivity cardiac troponin assay.1 2 This is not a trivial point, as publications in influential journals still misclassify cardiac troponin assays and their clinical use, despite laboratory recommendations providing some guidance in this area.1 2

So what is a high-sensitivity cardiac troponin assay? The current classification is subjective with the main criterion being that the concentrations are detectable in at least 50% of a healthy population.1 This qualitative approach for classification based on analytical sensitivity has met some resistance; however, it is important to emphasise that this is the first step in developing more rigorous criteria.1 Herein, incorporating clinical utility has the potential to further refine high-sensitivity cardiac troponin assays, and acute coronary syndromes (ACS) represents a crucial setting for refining this test’s characteristics.

Data from prototype assays, to investigational use, to regulatory-approved high-sensitivity cardiac troponin assays in both ACS and secondary prevention populations have demonstrated the ability to identify patients at both low and high risk for long-term cardiovascular outcomes.3–5 In these settings, the risk-stratification ability has been acknowledged, but important gaps remain on how to use high-sensitivity cardiac troponin testing after an ACS diagnosis to aid in patient management and possible treatment for secondary prevention.

In this issue of the Journal, Adamson and colleagues provide important evidence for the measurement of a high-sensitivity cardiac troponin assay months after an ACS diagnosis (ie, 1, 4 and 12 months post ACS).6 In nearly 1800 patients, at 4 months after an ACS diagnosis, not only was high-sensitivity cardiac troponin I (hs-cTnI) concentrations detectable in the population (99% of the patients had detectable concentrations), but also patients with hs-cTnI concentrations >99th percentile were detected to be at five times higher risk for cardiovascular death when compared with patients with hs-cTnI concentrations ≤5 ng/L, with absolute risks of cardiovascular death of 29.5% versus 4.3% at a median of 4.8 years of follow-up, respectively (absolute risk increase 26.2%).6 Patients who had a 4-month hs-cTnI value of 6 ng/L to the 99th percentile had an absolute risk of cardiovascular death of 14.6% and an HR of 2.52 (95% CI, 1.65 to 3.85) compared with the reference group (ie, patients with a 4-month hs-cTnI ≤5 ng/L).

The authors also demonstrated that one in two patients had a decrease of at least 20% whereas one in six patients had an increase of at least 20% in hs-cTnI concentrations from 4 to 12 months, with decreasing or increasing concentrations associated with lower or higher risks for cardiovascular death.6 The authors suggest a framework for hs-cTnI measurements at 4 months post ACS, where patients with hs-cTnI ≤5 ng/L would be at low risk (annual incidence of cardiovascular death approximately 0.5%) and patients with hs-cTnI >99th percentile at high risk (annual event rates near 10%), leaving an intermediate group with hs-cTnI concentrations from 6 ng/L to the 99th percentile, where repeat measurements and concentration changes at 12 months could be used to improve risk stratification/reclassification.6

The authors should be commended on undertaking and executing this study, laying the foundation for a possible testing protocol with high-sensitivity cardiac troponin following ACS. Previous studies assessing high-sensitivity cardiac troponin testing in the noncardiac surgical setting have also taken such an approach for the establishment of testing procedures, concentration cutoffs and most importantly, therapeutic interventions based on cardiac troponin measurements after noncardiac surgery.7 8

Notwithstanding this impressive work on a proposed testing pathway with high-sensitivity cardiac troponin post ACS, a question lingers as to whether current laboratory practices can provide accurate and reproducible results around the thresholds of such a framework.1 6 In this regard, the authors do indicate that different analysers and high-sensitivity reagent lots may result in wider variation but also state that ‘such variation can be kept to a minimum through the careful application of quality control measures as recommended by current guidelines’.6 Current laboratory recommendations support a total error estimate of <3.5 ng/L (with a corresponding SD of 0.8 ng/L) for concentrations ≤10 ng/L and imprecision of ≤10% at the 99th percentile for high-sensitivity cardiac troponin assays.1 Our laboratory programme has contributed to the total error estimates and has been measuring quality control (QC patient material at around 5 and 30 ng/L since 2014 using the above recommendations for quality assurance. To that end, we evaluated if current laboratory testing practices are sufficient for the purpose of patient classification using longitudinal high-sensitivity cardiac troponin measurements, as proposed by Adamson and colleagues.6

The high-sensitivity cardiac troponin I (hs-cTnI) assay used in Adamson and colleagues study (Abbott Laboratories) is the same hs-cTnI assay where we have long-term imprecision estimates established on, with QC testing performed at least daily on five different analysers. To simulate the testing timeline procedure, we set the first measurement performed on the low and high QC patient material as the referent (ie, first test result from baseline time point on the same QC material across the five analysers) and thereafter determined the percent difference between results from the first test result (figure 1). The first result on the low QC was 5.9 ng/L and the high QC was 32.1 ng/L, when rounded would fall into the 6 ng/L to 99-percentile group (99th percentile for men=34 ng/L), and for men, these results would be placed in the intermediate-risk group where concentration changes may improve risk stratification/reclassification.6 The percent difference from the other four analysers on this QC material from the first result at baseline ranged from −25% to 5% and 1% to 14% on the low and high QC, respectively (figure 1). Assessing subsequent percent differences from this first result at 1, 4, 12, 13, 16 and 20 months demonstrated that nearly one-third of the results from the low QC exceeded 20% difference from the first result with no results from the high QC exceeding 15%.

Figure 1

Two different levels of the same QC patient material were tested on five different immunoassay analysers at four different hospitals within the city of Hamilton, Ontario, Canada: (A) low QC patient material; (B) high QC patient material. The earliest results generated on 11 October 2017 were selected as the referent concentrations (5.9 ng/L and 32.1 ng/L, which falls into the 6 ng/L to 99th percentile group), with subsequent concentration from the different analysers and time points (eg, baseline, 1 month, 4 months, 12 months, etc.) calculated as a percent difference from the first result. m, months; QC, quality control.

These simulation data on analytical performance using current laboratory recommendations for high-sensitivity cardiac troponin assays indicate that the percent change criterion as suggested by Adamson and colleagues would be appropriate for concentrations near the 99th percentile but not at the lower concentration limit of 6 ng/L, where absolute changes (rather than percent) in high-sensitivity cardiac troponin at this low concentration range have demonstrated clinical utility.5 Additional approaches for identifying concentration cutoff(s) to separate the low-risk group from the intermediate-risk group, as has been performed in other populations,5 7 may further aid in appropriate risk assignment. Nevertheless, the important finding that nearly one-third of patients with hs-cTnI concentrations >99th percentile at 4 months post ACS had a subsequent cardiovascular death identifies a high-risk group that may benefit from further therapeutic intervention. Collectively, the clinical data, as provided by Adamson and colleagues, are important drivers for clinical laboratories to adopt quality recommendations for high-sensitivity cardiac troponin.1 Furthermore, these data also serve as another important reminder that a test used in acute care management (such as cardiac troponin) may also have a role in ambulatory care, where the burden for appropriate testing for patient care falls on both the clinical and laboratory teams.

References

Footnotes

  • Contributors PK wrote the manuscript with critical revision from PJD.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests PK has received grants/reagents/consultant/advisor/ honoraria from the laboratory diagnostic industry, specifically from Abbott Laboratories, Beckman Coulter, Ortho Clinical Diagnostics, Randox Laboratories, Roche Diagnostics and Siemens Healthcare Diagnostics. McMaster University has filed patents with PK listed as an inventor in the acute cardiovascular biomarker field. PJD is a member of a research group with a policy of not accepting honorariums or other payments from industry for their own personal financial gain. They do accept honorariums/payments from industry to support research endeavours and costs to participate in meetings. Based on study questions PJD originated and grants he has written, he has received grants from Abbott Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, Coviden, Octapharma, Philips Healthcare, Roche Diagnostics and Stryker. He has also participated in an advisory board meeting for GlaxoSmithKline and an expert panel meeting with AstraZeneca, Boehringer Ingelheim and Roche.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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