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On the Horizon: Blood Tests to Rapidly Rule out Heart Attack

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January 30, 2012

Each year, millions of people visit emergency departments with chest pain that may be due to a heart attack. People who present at the hospital with severe chest pain are usually admitted, but those with vague signs and symptoms may not have had a heart attack and therefore may not require admission. Although an electrocardiogram (ECG) can help make the diagnosis of heart attack, it cannot exclude it. Currently, doctors rely on blood tests for cardiac troponins, proteins released into the blood by damaged heart muscle cells, to help diagnose heart attacks. Evaluation of patients using the current versions of the troponin tests takes many hours to be sure whether a heart attack has occurred. Now, findings from several recent studies indicate that newer versions of troponin tests may be useful in helping to rapidly rule out heart attacks.

As reported in 2009, highly sensitive tests** for troponins (hs-troponin) have been developed but are not yet approved for use in the U.S. (see New troponin tests may help identify heart attacks earlier). These assays can reliably measure low levels of these proteins within just a few hours of presentation and may help to confirm a diagnosis of heart attack much earlier than conventional troponin assays. However, to rule out a heart attack confidently and allow safe discharge from the hospital, a series of troponin blood tests taken over several hours is still needed.

An evaluation of four of the new highly sensitive troponin tests, published in the August 27, 2009 issue of the New England Journal of Medicine, suggested the possibility that a heart attack could be ruled out reliably in many patients on the basis of an undetectable first measurement. However, the authors noted that studies conducted in clinical settings were needed to verify this. Several recent studies have been published that lend additional support for the use of hs-troponin tests, with and without an additional biomarker, in quickly ruling out heart attack in people who present with chest pain but have not had a heart attack, thus cutting down the time these people spend unnecessarily in the emergency room.

Such a "rule out" study in clinical practice was included in a report by Dr. Richard Body and colleagues from Manchester, United Kingdom and Rochester, Minnesota that was published in the September 20, 2011 issue of the Journal of the American College of Cardiology. Doctors at Manchester Royal Infirmary were asked to take a blood sample from patients with chest pain when they arrived in the emergency department and another more than 12 hours later for highly sensitive cardiac troponin T testing. During the next three months of the study, 915 patients had at least two tests. Of the 160 patients (17.5%) who had undetectable cardiac troponin on admission, only one had a subsequent rise to a level diagnostic of a heart attack, suggesting that a negative initial troponin could be effective in ruling out heart attack.

Two recent research reports from Germany suggest that the proportion of patients who have a heart attack ruled out could be improved by measuring two different biomarkers in the first blood sample. In addition to troponin, both groups measured copeptin, a hormone that increases rapidly in the blood in response to any stress, for example any tissue injury or an acute infection. The level of copeptin is likely to be increased in people who have had a heart attack.

The report from the first German study was published in Clinical Chemistry on October 1, 2011; the second was published in Vascular Health and Risk Management online on August 19, 2011. The first study was able to rule out a heart attack in 41% of 207 patients, the second in 32% of 142 patients. It is important to note, however, that two of the patients in the first study had low copeptin with high troponin. These patients were subsequently diagnosed as having heart attack and therefore the copeptin values may have been incorrect in classifying the patients as negative for heart attack (false negative).

Biomarker tests to rapidly rule out heart attacks appear to hold promise of improving the quality of care of many patients, making some hospital admissions unnecessary and allowing early discharge from the emergency department. However, these assays are not yet on the market in the U.S. – for use either in diagnosis or excluding heart attack – and are still under evaluation.

Concerns with highly sensitive troponin tests
In the U.S., concerns persist that the assays, in their ability to measure low levels of the protein, may be less specific for heart attack than conventional assays. Several studies have shown the presence of low levels of troponin in people with other cardiac conditions such as heart failure and stable angina, and even in those with chronic high blood glucose or with no cardiac conditions. These same studies also show, however, that the presence of troponin can identify patients at increased long-term risk of cardiac events such as a heart attack and death.

The question remains as to whether people with a positive hs-troponin test have indeed experienced a heart attack (true positive), regardless of underlying conditions. Scientists believe that one solution may be to perform a series of tests over a few hours to detect increasing troponin levels. Even with the current assays, criteria require that a rise and/or fall in troponin is needed to diagnose that a recent heart attack has occurred. Further research is planned to determine if this process is also clinically helpful with the new hs-troponin tests.

**Note: The term “highly sensitive” is used to refer to the emerging generation of cardiac troponin assays that are able to detect very low levels of troponin in blood. A precise definition for “highly sensitive” troponin assays is under development and currently there is no consensus on this.

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NOTE: This article is based on research that utilizes the sources cited here as well as the collective experience of the Lab Tests Online Editorial Review Board. This article is periodically reviewed by the Editorial Board and may be updated as a result of the review. Any new sources cited will be added to the list and distinguished from the original sources used.

Giannitsis E. et al. Combined Testing of High-Sensitivity Troponin T and Copeptin on Presentation at Prespecified Cutoffs Improves Rapid Rule-Out of Non–ST-Segment Elevation Myocardial Infarction. Clinical Chemistry. Available online at http://www.clinchem.org/cgi/content/abstract/57/10/1452 through http://www.clinchem.org. Accessed January 2012.

Lotze U, Lemm H, Heyer A, Müller K. Combined determination of highly sensitive troponin T and copeptin for early exclusion of acute myocardial infarction: first experience in an emergency department of a general hospital. Vascular Health and Risk Management. August 2011 Volume 2011:7 Pages 509 - 515. Available online at http://www.dovepress.com/combined- determination-of-highly-sensitive-troponin-t-and-copeptin-for-peer-reviewed-article-VHRM through http://www.dovepress.com. Accessed January 2012.

Body R, et al. Rapid Exclusion of Acute Myocardial Infarction in Patients With Undetectable Troponin Using a High-Sensitivity Assay. J Am Coll Cardiol, 2011; 58:1332-1339. Available online at http://content.onlinejacc.org/cgi/content/abstract/58/13/1332 through http://content.onlinejacc.org. Accessed January 2012.

Reichlin T et al. Early Diagnosis of Myocardial Infarction with Sensitive Cardiac Troponin Assays. N Engl J Med 2009; 361:858-867. Available online at http://www.nejm.org/doi/full/10.1056/NEJMoa0900428 through http://www.nejm.org. Accessed January 2012.

Kelley WE, Januzzi JL, Christenson RH. Increases of cardiac troponin in conditions other than acute coronary syndrome and heart failure. Clin Chem. 2009 Dec;55(12):2098-112. Available online at http://www.ncbi.nlm.nih.gov/pubmed/19815610. Accessed January 2012.

Keller T, Munzel T, Blackenburg S. Making it More Sensitive: A New Era of Troponin Use, Editorial. Circulation 2011, 123:1361-1363.

Rubin J, et al. Chronic Hyperglycemia and Subclinical Myocardial Injury. J Am Coll Cardiol, 2012; 59:484-489.

Robert H. Christenson, Ph.D., DABCC, FACB. Professor of Pathology, Professor of Medical and Research Technology. Director, Rapid Response Laboratories, University of Maryland School of Medicine, Baltimore, Maryland.

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