Interpretation of findings

Both algorithms were highly accurate for both ruling-in and ruling-out MI. The 1-hour algorithm had a sensitivity of 97.3% and -LR of 0.04 for both index and 30-day MI. The 2-hour algorithm had 100% sensitivity and -LR of 0.00 for index MI and 98.4% sensitivity and -LR of 0.04 for 30-day MI. These findings suggest that the low-risk criteria of both algorithms confidently rule out MI. Similarly, the high-risk criteria of both algorithms were highly specific for index MI and 30-day MACE, with + LRs ranging from 17.4 to 37.1. These findings suggest that false-positive diagnoses of MI using either algorithm are unlikely. Patients with high-risk hs-cTnT findings should receive immediate treatment and cardiology consultation in the appropriate clinical context.

Not surprisingly, both algorithms were less sensitive for 30-day MACE, emphasizing the continued importance of ECG findings and thorough clinical assessment, in addition to biomarkers in identifying patients at risk of short-term MACE. However, given NPVs for 30-day MACE of ~96% for both algorithms, in the absence of high-risk clinical features, discharge with outpatient follow-up appears safe for the majority of patients with low-risk hs-cTnT results.

Comparison to previous studies

To our knowledge, this is only the second direct comparison of the ESC-recommended 1-hour rapid diagnostic algorithm with a 2-hour hs-cTnT algorithm in the same cohort.^{Reference Wildi, Boeddinghaus and Nestelberger18} These results validate prior work^{Reference Reichlin, Schindler and Drexler5,Reference Reichlin, Twerenbold and Wildi7,Reference McRae, Innes and Graham16,Reference Wildi, Boeddinghaus and Nestelberger18} and confirm that both algorithms can rapidly rule out MI and facilitate early discharge by identifying almost two-thirds of patients as low risk for 30-day MACE. The widespread adoption of similar algorithms across Canadian EDs could reduce ED length of stay, defer testing of low-risk patients to community settings, and decongest EDs and inpatient units, a finding which has already been demonstrated in Europe.^{Reference Twerenbold, Jaeger and Rubini Gimenez25}

While no statistically significant differences in diagnostic test characteristics for any outcomes were observed between the algorithms in our study, the diagnostic accuracy point estimates for the 2-hour algorithm were consistently better than those of the 1-hour algorithm. A similar pattern was recently observed in a recent large comparative analysis.^{Reference Wildi, Boeddinghaus and Nestelberger18} We believe that the superior point estimates for the 2-hour algorithm are observed because the 2-hour algorithm uses larger serial change (delta) values, making it less vulnerable to misclassification owing simply to analytic variability. The lack of a statistically significant difference in the sensitivity of the 2-hour algorithm compared with that of the 1-hour algorithm observed in this study is likely a function of an overall small sample size.

Analytic variability arises primarily from two sources: pre-analytical variation (relating to issues occurring prior to a sample analysis that can affect results, including test-ordering, patient preparation, specimen collection, processing, and storage) and analytical variation (relating to inherent inaccuracies of the assay itself).^{Reference Nichols and Clark26} Suppose a real-world analytical variability of +/-2 ng/L per sample. This is much less likely to result in misclassification using the 2-hour algorithm rule-out delta of < 4 ng/L and a rule-in delta of ≥ 10 ng/L than the 1-hour algorithm rule-out delta of < 3 ng/L and a rule-in delta of ≥ 5 ng/L (see Figure 1). In fact, to improve rule-in specificity, other authors have proposed even much larger rule-in delta cutoffs using the same hs-cTnT assay (≥ 16 ng/L on repeat samples within a 24-hour period).^{Reference Douville and Thériault27}

Strengths and limitations

Strengths of this study include prospective data collection, a relevant patient population (ED patients requiring MI rule-out with serial troponin testing in the opinion of an emergency physician), care provider blinding to 1- and 2-hour hs-cTnT sample results, comprehensive follow-up, two-physician outcome adjudication, and conduct in real-world clinical and laboratory settings.

The primary limitation of this study is the small sample size, which limits the precision of the estimates that can be generated from it. We were unable to achieve our desired sample size owing largely to local practice patterns that included discharging almost half of patients after a single hs-cTnT assay. Furthermore, logistical issues, including an ethics requirement for physician assessment prior to collecting research samples, made it challenging to collect appropriately timed samples, particularly for 1-hour samples, with 200 fewer being collected. This may have led to selection bias, as patients with higher risk presentations may have been assessed more urgently by a physician and thus more likely to be enrolled in the study. However, the practice of assessing higher risk patients more quickly (making them more likely to be successfully enrolled) would result in higher risk patients being concentrated in the study cohorts. The fact that these criteria performed well despite this adds strength to our results.

The prevalence of index MI (~11%) in these cohorts is lower than the original derivation and validation studies, which ranged between 16% and 17%,^{Reference Reichlin, Schindler and Drexler5,Reference Reichlin, Twerenbold and Wildi7,Reference Reichlin, Cullen and Parsonage8} likely owing to the exclusion of patients with acute ischemic ECG changes. Sensitivity analysis reveals that if all 168 patients with acute ischemic ECG changes had been included in the 2-hour cohort and diagnosed with index MI, the prevalence of index MI could have been as high as 32.2%. However, because these patients clearly represent a high-risk subgroup, clinical practice would dictate that, even in the presence of normal serial hs-cTnT concentrations, most are likely to be admitted for further evaluation. Our focus on patients without ischemic ECG changes allows an evaluation of algorithm performance in those patients who specifically need troponin testing to diagnose or rule out MI.

Finally, patients with potential alternative presentations of cardiac ischemia (e.g., dyspnea, weakness, back pain, nausea, and abdominal pain) were not included, and it is possible that this systematically underrepresents women, patients with diabetes, elderly patients, and other subgroups who are less likely to report chest pain. However, requiring a chief symptom of chest pain as one of the primary enrolment criteria has been commonplace in the MI diagnostic literature and may prevent dilution of disease prevalence in the cohort when presentations unlikely to be cardiac are included.

Clinical implications

Based on these data and prior literature, both 1- and 2-hour hs-cTnT algorithms are highly accurate for ruling-in and ruling-out MI in patients with suspected ischemic chest pain. We strongly encourage the adoption of similar hs-cTn algorithms in EDs across Canada given their proven performance and ability to expedite care and improve the objectivity of evaluation. We believe that 2-hour algorithms offer several practical advantages, given potential challenges collecting appropriately timed 1-hour samples in busy EDs, and because the larger serial change (delta) cutoffs are less susceptible to misclassification secondary to analytic variability. Therefore, we believe that it is most prudent for centres implementing new hs-cTn assays to consider 2-hour algorithms, which, while still facilitating rapid decision-making, may be more practical to implement and offer a greater margin of safety – an opinion that is shared by other authors.^{Reference Vasile and Jaffe28,Reference Andruchow, Kavsak and McRae29}

Research implications

Despite the excellent performance of the low- and high-risk criteria for both algorithms, approximately one-quarter of patients remain in a non-diagnostic “observational zone” after serial troponin testing. Because this cohort has an ~11% MI prevalence, careful clinical assessment is required to ensure a safe disposition. To date, there are no clear guidelines on how best to manage these patients; however, recommendations for additional serial hs-cTnT sampling to assess for ongoing myocardial injury, careful consideration of alternative diagnoses, and cautious disposition using a validated risk prediction tool, such as the HEART score, would seem prudent.^{Reference Andruchow, Kavsak and McRae29} Validating an evidence-based pathway to safely disposition observational zone patients should be a priority for future research.