NACB - Scientific Shorts
NACB - Scientific Shorts (formerly NACB Blog)
By Allan S. Jaffe, MD, FACB
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There have been a multiplicity of recent articles in both acute coronary syndromes and heart failure indicating that high sensitivity assays for cardiac troponin provide additional diagnostic and prognostic information but may do so at the cost of specificity for the underlying diagnosis.  The pros and cons of such assays are described below.

 

First, a definition of high sensitivity assays is needed.  The only one thus far proposed is by Apple who suggests that a definition based on the number of normal subjects who have detectable values.  His classification is enclosed.  In his analysis, of the presently available assays in the U.S., only the Beckman assay was better than a class 1, at class 2.  Other research only assays were at class 3 or 4. 

 

The Upside

Initial clinical experience with these assays is limited but increasing rapidly.  In patients with acute coronary syndromes, they provide for an earlier diagnosis (often on admission) and include more patients at risk for events.  These assays appear to provide between an 8 and 10% increase in the number of patients detected.  In addition, the data support the idea that these assays will also be very valuable in defining the short and long term risk in patients with heart failure.  Finally, these assays are very likely to unmask additional causes of cardiac injury and in the long run will probably be used to detect the development of structural heart disease since values seem to rise when structural heart disease is present.

 

The Downside

It is clear that with these high sensitivity assays that a larger percentage of elevations in troponin will be due to disease processes other than acute ischemic heart disease which may be problematic to clinicians.  Some of these may be chronic due to structural heart disease and some acute due to processes like pulmonary emboli or sepsis.  In addition, many more of the elevations associated with ischemic heart disease may reflect possibly stable disease or fixed disease or endothelial dysfunction with supply-demand imbalance and not necessarily acute plaque related events.  The idea of using a rising and/or falling pattern has been suggested to distinguish the chronic elevations from the acute ones and there is some support for such an approach but the exact metrics for defining that pattern have not been totally defined.  In addition, this technique may not work well if patients present late after the onset of symptoms or when the onset of symptoms is unknown.  Finally, minor analytical problems which with less sensitive assays rarely cause diagnostic confusion might be more of a problem with such high sensitivity approaches.  Fro example, it appears that with some high sensitive assays, there are differences between men and women. 

 

References

Wu AH, Jaffe AS.  The clinical need for high-sensitivity cardiac troponin assays for acute

 coronary syndromes and the role for serial testing.  Am Heart J 2008;155:208-214.

 

Apple FS.  A new season for cardiac troponin assays: its time to keep a scorecard.  Clinical Chemistry 2009;55:1303-1306.

 

Apple FS.  High-Sensitivity Cardiac Troponin Assays: What Analytical and Clinical Issues Need to Be Addressed before Introduction into Clinical Practice? Clinical Chemistry 2010; 56:886-891.

 

Jaffe AS, Apple FS.  High-Sensitivity Cardiac Troponin: Hype, Help, and Reality. Clinical Chemistry 2010;56:342-344.

 

Latini R, Masson S, Anand IS, et al. Val-HeFT Investigators. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007;116:1242-9.

 

Omland T, de Lemos JA, Sabatine MS, et al. Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. New England Journal of Medicine 2009;361:2538-47.

 

 

Scorecard Designations for cTn Assays

 

 

Acceptance Designation

Total Imprecision at the 99th Percentile, CV%

Guideline acceptable

≤ 10

Clinically usable

>  10 to ≤ 20

Not acceptable

>  20

Assay Designation

Measurable Normal Values Below the 99th Percentile, %

Level 4 (third generation, hs)

≥ 95

Level 3 (second generation, hs)

 75 to < 95

Level 2 (first generation, hs)

50 to <  75

Level 1 (contemporary)

<  20

 

 

Reference: Apple, FS. Clinical Chemistry 2009; 55(6):1303-1306.

 

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Posted by AACC\bgarman
On 2/3/2011

This is a difficult issue. The problem you allude to may be much worse with high sensitivity assays. I am sure companies are attempting to upgrade their processes to prevent problems but at present, we do not know enough about the details of most of these novel assays or what additional measures have been developed to help with the issues you pose to provide intelligent opinions about how successful these efforts will be. What we as clinicians and laboratorians would benefit from is more transparency and more interaction about these issues so we can help to define the metrics that will be needed. I suspect that the diagnostic industry understands that and would hope that something like will occur over time. Allan Jaffe, MD

Posted by
On 2/2/2011

Any idea how vendors might mitigate "false positives" with hs-cTn? With some contemporay assays, this is a vexing problem necessitating (by many if not most labs) an automatic repeat of all elevated samples due to the high degree of matrix effects. For example, an assay using an ubiquitous substrate such as ALP can react with the solid phase (well above the URL) when small amounts of fibrin, platelets, etc. and not completely removed during final wash steps. Thanks, Jack Montgomery Rogue Valley Medical Center Medford, OR

Posted by AACC\bgarman
On 1/17/2011

1. It appears that hscTn assays will increase the rapidity which which a rule in and/or rule out diagnosis of an acute event, including AMI might be made. It appears that all the rule ins are likely within 3 hours at worst and it may be that up to 40 or 50% of rule outs might be achievable on admission however, the hard data for these approaches is still being developed. The converse down side is that there will be many more acute and chronic elevations not due to ischemic heart disease which will challenge clinicians. That is why distinguishing acute from chronic elevations will be so important. 2. Distinguishing acute from chronic elevations will be key but exactly how to do that is unclear. Most acute events show a very marked rising and/or falling pattern. What is not known yet is what is the minimal change that might be important. Some have suggested using biological variation as a standard but with some assays (eg hscTnT) this is a fairly high number (85%) and it may be that minimal change criteria will be less than biological variation with some assays. This is an area of intense interest as to whether an absolute or percentage value should be used so stay tuned. 3. I agree totally that hscTn assays will be used to track chronic disease and will be extremely helpful in detecting early cardiac comorbidities. In addition, baseline values will help immensely when patients present acutely given #2 above. Allan Jaffe, MD

Posted by
On 1/14/2011

Very nice blog. Do you feel that hs-troponin assays will be useful in the ER setting? Do you think serial measurements will be able to differentiate between acute events and more or less stable ischemic events? I wonder if hs-troponin assays may be more useful for detecting early heart disease and montioring it's progression over time. Patti Children's Medical Center Dallas

About the Author
Allan S. Jaffe, MD, FACB
Allan S. Jaffe, MD, FACB 
 
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Additional Resource

deFilippi CR, de Lemos JA, Christenson RH, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA 2010;304(22):2494-502.