Whether we like it or not, high-sensitivity troponin assays, recently approved by the FDA, will soon replace the 4th generation assays currently in operation. And while many claims have been made regarding their clinical utility, the implications for our standard chest pain workflow are unclear. A recent publication by Chew et al, provides us a glimpse behind the curtain, for a moment revealing the true utility of this new biomarker (1).
Published in Circulation, Chew et al randomized 3378 patients to either a high sensitivity troponin T (hs-cTnT) assay, drawn at 0 and 1-hr, rapid diagnostic strategy, or standard care using a hs-cTnT with a threshold of 29 ng/L. The authors enrolled patients presenting to any of the four participating emergency department with signs concerning for ACS, but were not considered at high risk of ACS, as per the judgement of the treating clinician. Patients randomized to the HS-TN rapid rule out strategy underwent troponin testing at 0-hours and 1-hour. As per protocol, patients were considered “ruled out” with baseline troponin < 5 ng/dL over 3 hours since the onset of symptoms, or in patients with an initial troponin > 5 ng/L but < 12 ng/L, and a change in troponin over 1 hour of <3 ng/L. Patients who were ruled out in the ED were discharged with follow up with the primary care physician. Patients were considered “ruled in” and admitted to the hospital, with baseline troponin ≥52ng/L or a rise over 1 hour of ≥ 5ng/L documented. The remainder of the patients were placed in dispositional purgatory, or what the authors called observation, when the baseline troponin was between 13- 51 ng/L with a change of less than 5 ng/L on repeat, or in patients with an initial troponin less than 12 ng/L and a change of 3-4 ng/L over an hour.
Patients randomized to the standard workup received the same hs-cTnT testing, but the clinicians only received values that were consistent with 4th generation troponin testings and were blinded to any value less than 29 ng/L. The hs-cTnT levels were drawn at baseline and repeated at 3 hours, with discretionary further testing at 6 hours. While the protocol recommended patients with a hs-cTnT level < 29 ng/L at 3-hours to be discharged with outpatient follow up, clinicians discretion was permitted.
Between August 2015 and April 2019, the authors enrolled a total of 3378 patients. Overall a greater proportion of patients in the rapid testing strategy were directly discharged from the ED (45% vs. 33%, p<0.001). In addition, patients in the rapid testing strategy were less frequently referred for functional testing (ECG stress testing, stress echocardiography or perfusion CMR/nuclear). These gains in early discharge and decreased testing were associated with no change in the rate of missed MI or death at 30-days, overall occurring in 1% of patients in both arms of the study. And while on first glance this seems like a win for hs-cTnT and a rapid testing strategy, one has to pause for a moment and inquire, what about the rapid testing strategy led to these improved outcomes?
While more patients were directly discharged from the ED, and less patients received non-invasive testing this does not appear to be a result of hs-cTnT’s superior diagnostic performance. The rate of death or MI in the subsequent 30-days following ED presentation was essentially identical between the two groups. For patients in the standard workup group with an hs-cTnT level below 29 ng/L, the rate of death or MI was 0.6% compared to 0.4% in the patients in the rapid diagnostic strategy who met the “rule out” criteria. And while a decrease in the rate of non-invasive testing initially seems like an advantage for the rapid diagnostic strategy, even this is misleading.
The major downside of non-invasive testing is the downstream invasive testing and interventions it leads to, both of which were higher in the rapid diagnostic strategy group. If hs-cTnT leads to a decrease in non-invasive testing, but increases the number of diagnostic catheterization and revascularization procedures, what have we really accomplished? Seemingly the only true benefit provided by the hs-cTnT was peace of mind of the treating clinician.
As far back as the Pope et al study (2), which famously claimed an excessive number of patients experiencing MIs were inappropriately discharged from the ED, Emergency Physicians have been told we are incapable of appropriately managing chest pain patients in the ED. And yet when one takes a closer look at that study, of the 10,689 patients evaluated, only 19 patients with a MI were sent home, or a miss rate of 0.18%. 19-years later and with a multitude of decision instruments and high sensitivity assays at our fingertips what has changed? Of the 1,646 patients in the hs-cTnT arm, the rapid rule out strategy missed 5 or 0.3%. Mills et al presented the results of their much larger stepwise cluster RCT, at the recent 2019 European Society of Cardiology Congress, which claims to demonstrate a benefit with the use of a high sensitivity troponin assay, but the complete results are yet to be published (3). Certainly, clinicians feel better about discharging someone after a workup which included a hs-cTnT. But is it worth the potential increase in downstream testing associated with its use? Perhaps, the solution is simply conceding we will never achieve perfection, regardless of the sensitivity of our troponin assay.
- Chew DP, Lambrakis K, Blyth A, et al. A Randomized Trial of a 1-Hour Troponin T Protocol in Suspected Acute Coronary Syndromes: The Rapid Assessment of Possible ACS In the Emergency Department with High Sensitivity Troponin T (RAPID-TnT) Study. Circulation. 2019;
- Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med. 2000;342(16):1163-70.
- Mills N. High-sensitivity cardiac troponin at presentation to rule out myocardial infarction (HiSTORIC): a stepped-wedge cluster-randomised controlled trial. Presented at: ESC 2019. September 1, 2019. Paris, France