High-sensitivity Troponin-T

From Guide to YKHC Medical Practices

see Acute Coronary Syndrome Wiki Supplement Page for other information associated with Acute Coronary Syndrome

On November 12, 2019, the Yukon-Kuskokwim Delta Regional Hospital (YKDHR) switched cardiac troponin assay to the Roche Diagnostics Elecsys® Troponin T Gen 5 STAT. This is a high-sensitivity fifth-generation cardiac troponin assay. Details are available in the manufacturer's package insert.

Cardiac troponin assays measure the concentration of either troponin-T or troponin-I. Both high-sensitivity and traditional troponin assays measure the exact same molecule, but high-sensitivity assays measure much more precisely and at much lower concentrations. The high-sensitivity and traditional assays can be distinguished by the units in which they are reported: high-sensitivity assays are reported in ng/L whereas the traditional assays are reported in ng/mL.

Conversion between the results can be done by moving the decimal point three places: a traditional concentration of 0.4 ng/mL is equivalent to a high-sensitivity concentration of 400 ng/L, and a high-sensitivity concentration of 14 ng/L is equivalent to a traditional concentration of 0.014 ng/mL. This latter conversion illustrates that the high-sensitivity assays accurately measure concentrations which are two orders of magnitude lower than the assay we were previously using.

Though high-sensitivity troponin assays have been used in Europe and Canada since approximately 2009, the first U.S. FDA approval occurred in 2017.

NOTE: The information below is not a guideline, but rather excerpts and links intended to augment and/or help develop clinical judgement.




Definition

To qualify as high-sensitivity (or highly-sensitive), a cardiac troponin assay must be able to detect a level of cardiac troponin in >50% of normal individuals.[1] This means that the majority of patients without cardiac ischemia will have a detectable level of cardiac troponin. This has substantial implications for how clinicians conceptualize and interpret cardiac troponin levels.

Statistical/Epidemiological Properties

Diagnostic Performance

High-sensitivity troponin assays have a much higher sensitivity for ACS than conventional assays, which yields a much higher negative predictive value (NPV). This allows clinicians to more quickly and accurately identify those chest pain patients who do not have ACS and who are at very low risk of 30-day MACE (major adverse cardiac events).
Yet the increased sensitivity comes at the cost of decreased specificity, yielding a lower positive predictive value (PPV). The clinical consequence of this is summed up well by Dr. Rebecca Vigen of UTSWMS (University of Texas Southwestern Medical Center) grand rounds transcript:
As the MI probability goes down, the additional positive test results with the hs-cTnT assay vs. the standard assay increases (false positives). Therefore, the proportion of positive tests with the high-sensitivity assay who do not have myocardial infarction will increase.[2]


The following data reported by de Lemos et al. (2011)[3] illustrates the effect:


Additional cTnT values above the MI-detection threshold with a highly sensitive (hs) cTnT assay, compared with a standard cTnT assay, across differing MI probabilities in the target population.
MI probability Positive tests with standard assay, /1000 patients Positive tests with hs assay, /1000 patients Additional positive tests with hs assay vs standard assay meeting MI definition, /1000 patients Additional positive tests with hs assay vs standard assay not meeting MI definition, /1000 patients
17% 199 328 21 108
10% 146 275 12 117
5% 108 237 8 121
3% 93 222 3 126


de Lemos derived these outcomes from calculations using the limit of detection for the conventional troponin assay and with the 99th percentile for the high-sensitivity troponin assay. However, clinicians must recognize that these calculations to not include the delta troponin (discussed below), but rather single values.


Population Distribution

The manufacturer recommended rule-out cutoffs (99% ULN) are based upon the following distribution:



Troponin-T distribution in healthy individuals.[4]



Delta (Δ) versus Level

With traditional troponin assays, a troponin level was not detectable in most patients who lack cardiac ischemia. Emergency departments typically performed serial measurements to see if the troponin level became detectable over time. Therefore the level of the troponin was the focus while quantifying the magnitude of the delta (Δ) (i.e. the change of the level over time) was a secondary consideration.

Due to the high-sensitivity assays' ability to detect a troponin level in most patients who lack cardiac ischemia, many experts recommend a reversal in diagnostic thinking with regard to ACS/AMI: for most patients the delta (Δ) should be the focus while the level is a secondary consideration.[5]

However, there are initial levels below which a delta is not required:

  • If >= 3 hours since onset of symptoms and a normal EKG, then an initial troponin level < 6 ng/L can rule-out ACS.



Troponin Delta

Terminology

For verbal communiction, delta's are most easily understood with the phrase Δ1h ("delta-1-h"). Starting the phrase with "delta" signals the listener that which is coming (i.e. a duration and magnitude).[6]


Relative versus Absolute Delta (Δ)

With traditional troponin assays, a delta of 20% was often used to rule-in ACS.
However, common situations arise with high-sensitivity troponin assays where relative deltas can lead to both over- and underdiagnosis. For example, if the initial troponin level is 5 ng/L, then a delta of 1 ng/L is a 20% rise, despite the change being within the expected margin of error of the assay. Alternately, the 20% relative change can miss ACS in patients with chronically elevated troponin levels.
Therefore many experts recommend using an absolute delta to rule-out or rule-in ACS.


Delta Cutoffs

The YKDHR Laboratory recommends that a Δ1h < 3 ng/L be used to rule-out ACS.
However, the ACC's (American College of Cardiology) whitepaper specifically recommends against this Δ1h cutoff due to being too similar to the Roche assay's margin of error; they explicitly suggest a cutoff of Δ2h < 4 ng/L.[1]


Troponin Level

Level Cutoffs

Hs-cTnT is considered "positive" when above the gender-specific 99th percentile URL (upper reference range). Per eMail from Scott Cox (YKDHR Director of Diagnostic Services) on 11/10/2019, the following cutoff are recommended for our assay:

Positive Values
Women >= 14 ng/L
Men >= 22 ng/L



Per the ACC white paper (see below):

  • A single Hs-cTnT >= 100 ng/L is diagnostic of AMI (in the appropriate clinical context).
  • When chest pain has been present for >= 3 hours, a single Hs-cTnT < 6 ng/L has been reported to rule out AMI with essentially 100% negative predictive value.


Diagnostic Algorithms

ACC

The following diagnostic algorithm has been proposed for high-sensitivity cardiac troponin-T by the ACC (American College of Cardiology), though they caution that "The safety of this approach is currently unclear":[1]
ACC Whitepaper Figure-1 2018-07-16.PNG


UTSW/Parkland

The algorithm used by University of Texas Southwestern Medical Center is shown for illustrative purposes in an ACEP Webinar (see below, page 16):

UTSW-Parkland hs-cTnT pathway.PNG

Note that this algorithm does not include risk stratification, such as with the HEART score. Yet the same Webinar contains other algorithms which separate out Hs-cTnT and call the risk stratification a HEAR score (or "modified-HEART" score) and guide diagnosis/management based upon different combinations of Hs-cTnT and HEAR values. Yet other algorithms in the same Webinar recommend skipping risk stratification in those who have low- or high-risk EKG/Hs-cTnT results and only risk stratifying those with intermediate-risk EKG/Hs-cTnT results.

Australian ACRE Project

This diagnostic algorithm guides the user to one of four etiologies for HS-cTnT elevation:

  1. Type-1 MI
  2. Type-2 MI
  3. Acute myocardial injury
  4. Chronic myocardial injury

However, users will note that the following two terms are used without definition:

  1. Evidence for acute myocardial ischemia
  2. Evidence of acute coronary atherothrombosis

Per recommendation of the author, this algorithm has been edited to contain the cutoffs specific to our lab/assay:

ACRE Algorithm modified-cutoffs.svg.png

The original PDF is available here (archived)



Helpful Links

ACC (American College of Cardiology)

High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI (July 16, 2018)
SUMMARY: Fourth Universal Definition of Myocardial Infarction (Aug 25, 2018)


ACEP

Webinar: Incorporating High-Sensitivity Troponin into Your ED
Critical Issues in the Evaluation and Management of Emergency Department Patients with Suspected Non–ST-Elevation Acute Coronary Syndromes (Jun 2018)


MD Calc

HEART Score for Major Cardiac Events


ACEPNow Articles

03-19-2019: High Sensitivity Cardiac Troponin Tests for Acute Myocardial Infarction May be Flawed
09-18-2019: Chest-Pain Patients and High-Sensitivity Troponin Tests: the New Frontier


PodCasts

02-20-2020: EMCrit #266: High Sensitivity Troponins with Louise Cullen (Duration: 26:04) Archived
01-18-2020: SGEM #280: THIS OLD HEART OF MINE AND TROPONIN TESTING (Duration: 30:10) Archived
07-30-2019: Emergency Medicine Cases (Ep 128) Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift (Duration: 1:34:36) Archived


High-sensitivity troponin Myths versus Reality

Myths:

  • more patients will undergo catheterization
  • ED stays will be longer
  • there will be fewer ED discharges
  • there will be more stress tests


FACT: the APACE trial showed that adoption of a high-sensitivity troponin assay was associated with no change in the number of catheterizations, decreased "normal cath" results, shorter ED stays, more ED discharges, and fewer stress tests.[7]

FACT: Across numerous trials, increasing troponin sensitivity has shown a dose-response relationship with increased ED discharges.

Controversies

Recommended 99% URL Cutoffs

Mariathas el al (Mar 2019)

In March 2019 Mariathas el al. reported in the BMJ[8] that they found a very different distribution and 99% ULR when they analyzed 20,000 consecutive blood samples collected in all settings (outpatient, ED, inpatient, etc.) drawn for any reason in a large UK hospital. Overall, over five percent of patients had a troponin-I result greater than the manufacturer recommended 99% cutoff of 40 ng/L, and far too many older patients and inpatients exceed this recommended cutoff:


The implications of such a degree of variation are substantial, and may indicate that individual institutions need to calculate their own age-adjusted 99% cutoffs in order to obtain the intended outcomes. Additionally, clinicians likely need to integrate patient age and clinical context into their interpretation of hs-Tn levels. Though hs-Tn's have been shown to improve outcomes when evaluating acute chest pain in emergency departments, there is no data to indicate that diagnosing myocardial injury in 15% of medical ward patients, 20% of older persons, and 40% of ICU patients will lead to patient-important improvements.
However... readers are strongly encouraged to read all seven of the responses. In particular, Paul Collinson makes a strong argument that the authors are mis-interpreting their data because they are including a substantial number of UNhealthy individuals (i.e with CHF, CKI, etc.), whereas the appropriate cutoffs are [by definition] derived from healthy individuals. All of the responses are thoughtful, and both the article and the responses provide interesting thoughts about troponin levels and binary versus Bayesian interpretation of results.



The significance of Myocardial Injury

Acute

There is no standard-of-care workup for this finding in the absence of myocardial ischemia. Can it be attributed to a tachyarrythmia, sepsis, etc? Or should a PE be ruled-out? Does it mandate an echocardiogram?

Chronic

This is certainly not amenable to ED intervention. Again, it is not clear what the standard-of-care disposition of this finding will be.



Definitions

  • Myocardial injury
Elevated cardiac troponin values (cTn) with at least one value above the 99th percentile upper reference limit (URL).[9] NOTE: "myocardial injury" is NOT synonymous with ischemia, as injury can be due to non-ischemic conditions such as infiltrative diseases, trauma, inflammation, heart failure, etc.
  • Acute myocardial injury
Myocardial injury with a diagnostic rise and/or fall of cTn values.[9]
  • Acute myocardial infarction (types 1, 2 and 3 MI)
Acute myocardial injury and at least one of the following:[9]
- Symptoms consistent with acute coronary occlusion;
- New ischemic ECG changes;
- Development of pathological Q waves;
- Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology;
- Identification of a coronary thrombus by angiography or autopsy (not for type 2 or 3 MIs).




References

  1. 1.0 1.1 1.2 High-Sensitivity Cardiac Troponin in the Evaluation of Possible AMI. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2018/07/16/09/17/high-sensitivity-cardiac-troponin-in-the-evaluation-of-possible-ami. Accessed December 3, 2019.
  2. Vigen R. Providing High Value Care to Patients with Acute Chest Pain. Grand Rounds Presentation presented at the: Grand Rounds; June 14, 2019; University of Texas Southwestern Medical Center. https://cme.utsouthwestern.edu/sites/default/files/em1906g_061419_protocol_vigen.pdf. Accessed December 5, 2019.
  3. de Lemos JA, Morrow DA, deFilippi CR. Highly sensitive troponin assays and the cardiology community: a love/hate relationship? Clin Chem. 2011;57(6):826-829. doi:10.1373/clinchem.2011.163758
  4. Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical validation of a high-sensitivity cardiac troponin T assay. Clin Chem. 2010;56(2):254-261. doi:10.1373/clinchem.2009.132654
  5. Helman, A. McRae, A. Lang, E. Low Risk Chest Pain and High Sensitivity Troponin – A Paradigm Shift. Emergency Medicine Cases. July, 2019. https://emergencymedicinecases.com/low-risk-chest-pain-high-sensitivity-troponin. Accessed December 2, 2019.
  6. Personal opinion of Andrew W. Swartz, MD
  7. Twerenbold R, Jaeger C, Rubini Gimenez M, et al. Impact of high-sensitivity cardiac troponin on use of coronary angiography, cardiac stress testing, and time to discharge in suspected acute myocardial infarction. Eur Heart J. 2016;37(44):3324-3332. doi:10.1093/eurheartj/ehw232
  8. Mariathas M, Allan R, Ramamoorthy S, et al. True 99th centile of high sensitivity cardiac troponin for hospital patients: prospective, observational cohort study. BMJ. 2019;364:l729. doi:10.1136/bmj.l729
  9. 9.0 9.1 9.2 Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Journal of the American College of Cardiology. 2018;72(18):2231-2264. doi:DOI: 10.1016/j.jacc.2018.08.1038