ACCEL | Despite extensive research and evolving diagnostic technology, patients with symptoms suggestive of acute coronary syndrome (ACS) usually undergo investigation for at least 6 hours (and often longer) before acute myocardial infarction (AMI) can be excluded confidently. Thus in many centers, most such patients (74% to 88%) are admitted to the hospital, making up more than one-quarter of acute medical admissions. However, only a minority (approximately 25%) are ultimately diagnosed with an ACS and fewer still (about 25%) are diagnosed with AMI.

While point-of-care cardiac troponin (cTn) testing potentially allows for earlier discharge, these assays historically have worse analytical reliability and sensitivity for the detection of troponin values at low concentrations (i.e., results near clinical cutoff values were not reliable). In practice, this meant that only a minority of patients could benefit from the speed of the test. In the landmark ASPECT study, for example, which validated an accelerated diagnostic point-of-care protocol, only 9.8% of suspected ACS patients were actually candidates to leave the hospital at 2 hours after presentation.¹

Richard Body, MB, ChB, PhD, and colleagues noticed that in a previous study of biomarkers for patients presenting with chest pain, no patient with an undetectable result with a high-sensitivity cardiac troponin T (hs-cTnT) test went on to be diagnosed with an AMI, so they designed a prospective study.² A total of 18% of patients had a confirmed AMI, none of whom had initially undetectable hs-cTnT (negative predictive value [NPV] 100%). This strategy would "rule out" AMI in 28% of patients, and only two (1.0%) of these patients died or had an AMI within 6 months (one periprocedural AMI in a patient with stable angina and one noncardiac death).

However, the real value of their study may be that if the initial troponin is < 3 pg/mL, further troponin testing adds little to outcome prediction. Some will criticize the fact that only 17.5% of the chest pain cohort would be ruled out on the basis of this single test, but in an accompanying editorial comment, W. Frank Peacock, IV, MD, appreciated the study.³ As an emergency department (ED) doctor, he wrote that to send a patient home means that he or she lives or dies based on the negative predictive value of the test.

This is why Dr. Peacock thinks the study by Body et al. is important: most studies report specificity and highly specific cTn assays accurately predict the diagnosis of AMI. However, the consequence of high specificity is poor sensitivity. Dr. Peacock wrote, "Tests with poor sensitivity are of little use to make a discharge decision, and honestly are dangerous if used as the sole basis for a discharge decision. The clinical consequence of a poorly sensitive test means that if I discharge Mr. Jones, who is sitting in front of me, on the basis of a negative test, he is sent home and perhaps dies of a myocardial infarction—not quite the outcome either one of us was hoping for."

The Body study was published in 2011 and further advancements are providing improved sensitivity at low concentrations of troponin. In the ADAPT/APACE studies, improved sensitivity at low concentrations by the use of central lab-based highly-sensitive troponin assays meant that more patients could be safely discharged home from the ED, up to 41.5%.^4,5

What will be the consequence of an accurate point-of-care test? Dr. Peacock said new assays will make it possible to dramatically change the ED experience for most patients with chest pain. This will apply, he said, to "about 75% of people who historically were kept and tested and hung out in the hospital or ED for a day or 2 who can be discharged in an hour—or at least have a decision made on what their clinical course will be in about an hour." And they can be discharged quickly with nearly zero 30-day adverse outcome rates. Moreover, those at a higher risk can go for stress testing the same day, rather than spending the night in medical limbo. Dr. Peacock added that it's a revolution that is coming; it's not available in the US yet, but likely will be here later this year; meanwhile, it is already impacting care elsewhere in the world.

SMALL INCREASES MEAN A LOT

Although some bemoan the fact that high-sensitivity assays produce more positive test results than ever before, small increases in troponin can mean a lot. Changes in cTn levels are required for the diagnosis of non–ST-segment elevation myocardial infarction (NSTEMI), according to the new universal definition of AMI. Bjurman and colleagues evaluated changes in troponin T levels in patients with a clinical diagnosis of NSTEMI using an hs-cTnT assay.⁷

After 6 hours of observation, the relative change in the hs-cTnT level was < 20% in one-quarter of subjects, and the absolute change was < 9 ng/L in 12% of the NSTEMI patients. A relative hs-cTnT change < 20% was linked to higher long-term mortality compared with patients with higher relative changes. Thus, a small hs-cTnT change does not identify a low-risk NSTEMI patient.

A new paper to be published in JACC in April 2015 provides the largest analysis to date examining the implications of introducing hs-cTnT into clinical practice.⁸ In a non-selected but high-risk population of nearly 50,000 patients hospitalized with symptoms suggestive of ACS, one in five (21.6 %) patients had a minor troponin elevation (hs-cTnT 14 to 49 ng/L), a group that may not have been identified by the previous fourth-generation cTnT assay.

IF IT'S UP, IT'S BAD

In this new paper in JACC, among these 10,476 (21.6 %) patients who previously would have been considered cTn-negative, only 18.2 % of them were diagnosed with MI; the majority was considered to have unstable angina pectoris (43.5%) or no ACS at all (38.3 %). Like other recent studies, an increase in all-cause mortality was evident with increasing maximum hs-cTnT levels regardless of the cause of troponin elevation.

Compared with patients who had an increase in hs-cTnT < 6 ng/L, the adjusted HR for individuals with an hs-cTnT of 14 to 49 ng/L was 2.53 (p < 0.001). Indeed, adjusted mortality started to increase at an hs-cTnT level of 14 to 18 ng/l (HR 1.94; p < 0.001); above 14 ng/L, the adjusted mortality increased continuously with increasing hs-cTnT.

According to Dr. Peacock, historically if the troponin was positive, then it was an MI and doctors were done thinking; patients went for catheterization. "The only time troponin was elevated was for MI and those days are completely gone," said Dr. Peacock. "We now know there are hundreds—some say 250—reasons for false positives that are not MI."

However, while not every positive troponin is MI, if cTn moves, it's bad. "The new reality," he said, "is that every single troponin elevation above the 99th percentile is associated with increased mortality. It is only a matter of timing. There is no such thing as a 'good' troponin elevation. So although it may not be a myocardial infarction in terms of the universal definition, from the ED point of view, in a patient with elevated troponin, an immediate discharge is neither the best nor safest strategy."

Put another way, stepping on the brakes before hitting the tree is always the best driving strategy, and Dr. Peacock said it's the same for AMI. Increasing troponin sensitivity well below the 99th percentile has the potential to identify patients at high risk of adverse outcomes, before they suffer the event.

Take-aways

• New high-sensitivity cardiac troponin (hs-cTn) assays will permit an early-discharge strategy, with the potential to decrease the observation periods and admissions for approximately 40% of patients with suspected acute coronary syndrome.
• Although some bemoan the fact that high-sensitivity assays produce more positive test results than ever before, the value of a low hs-cTn assay result has great clinical potential.
• Increasing troponin sensitivity well below the 99th percentile has the potential to identify patients at high risk of adverse outcomes, before they suffer the event.

References

1. Than M, Cullen L, Reid CM, et al. Lancet. 2011;377:1077-84.
2. Body R, Carley S, McDowell G, et al. J Am Coll Cardiol. 2011;58:1332-9.
3. Peacock WP. J Am Coll Cardiol. 2011;58:1340-2.
4. Than M, Cullen L, Aldous S, et al. J Am Coll Cardiol. 2012;59:2091-8.
5. Cullen L, Mueller C, Parsonage WA, et al. J Am Coll Cardiol. 2013;62:1242-49.
6. Peacock WF, Cullen L, Mueller C, Than M. Clin Biochem. 2013;46:1627-8.
7. Bjurman C, Larsson M, Johanson P, et al. J Am Coll Cardiol. 2013;62:1231-8.
8. Melki D, Lugnegard J, Alfredsson J, et al. J Am Coll Cardiol. 2015;65 [in press].

Keywords: ACC Publications, CardioSource WorldNews

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