January 11, 2007

In this Issue...

Troponin’s Prognostic Potential Underscores Need for More Sensitive Assays and Cutpoint Clarification

by Julie McDowell

When there is no evidence of heart disease or comorbidities such as high blood pressure or diabetes, clinicians and laboratorians expect a patient’s troponin test result to be negative. However, a new study published in the Journal of the American College of Cardiology found that detectable troponin at concentrations typically reported as negative—below the 99th percentile range—is associated with mortality rates up to twice those seen in patients with undetectable troponin levels. This issue of Strategies looks at how these findings are driving the call for more sensitive troponin assays, and how the next generation of these assays is likely to pose new challenges for both clinicians and laboratorians.

The clinical laboratory community has long been split on the best cutpoint values for troponin assay—some believe it should be set at the 99th percentile of the reference population, while others believe it should be at the level where the particular assay’s coefficient of variation (CV) is less than 10%, with the 10% CV varying by test manufacturer. The National Academy of Clinical Biochemistry endorses the 99th percentile cutoff, believing that this range identifies more at-risk patients.

By current consensus, myocardial infarction (MI) is defined by the presence of troponin above the reference range. A peak troponin that falls below the cutpoint therefore rules out a MI, although the patient might still need to be evaluated for acute coronary syndrome. But new research indicates that even a negative troponin result might be problematic and raises questions about the diagnostic cutoff value. A study of 34,227 patients from two emergency department facilities who had troponin I assays performed between November 2002 and January 2005 revealed that the presence of troponin at any level—even below the 99th percentile and the 10% CV cutoffs—is associated with increased inpatient mortality (Journal of the American College of Cardiology 2006; 48:1755-1762; http://content.onlinejacc.org/cgi/content/abstract/48/9/1755). In fact, researchers found a continuous quantitative relationship between troponin and mortality, with a doubling of the odds of mortality for any 10-fold increase.

“For the assay that we studied, a result of 0.07 μg/L would be considered negative by any current standard, and might be thought of as such by clinicians using the test,” said Daniel Waxman, MD, lead study author and Assistant Professor in the Division of Cardiology and the Department of Emergency Medicine at Beth Israel Medical Center in New York City. “Our study demonstrated, however, that such a patient has more than double the mortality rate of patients with troponin measured at zero. It seems likely that the patient would also have twice the likelihood of having an acute coronary syndrome.” A troponin assay, manufactured by Ortho-Clinical Diagnostics (Raritan, N.J.), was used to evaluate patient populations from the two emergency departments. The manufacturer’s instruction’s identified the lower limit of detection for this assay as 0.038 μg/L, and the researchers reported results to a precision of 0.01 μg/l. The cutoff at the 99th percentile was 0.08 μg/l, and 0.2 μg/l for the 10% CV. Ortho-Clinical has since revised the 10% CV lower limit downward to 0.12 μg/l, according to Waxman.

Based on the robust evidence of the troponin-mortality relationship in disparate clinical populations. Waxman believes that while troponin is specific with regard to its myocardial origin, it is not a specific marker of acute coronary syndrome (ACS), as envisioned when the assay was first developed.

“In patients with a low pre-test probability of disease, the presence of detectable troponin, whether above or below the diagnostic cutoff is difficult to interpret,” said Waxman. “We should therefore move away from the paradigm of troponin as a diagnostic gold standard and think of it more as a probabilistic test that can help guide further management.”

Towards Higher Sensitivity Troponin Tests

In addition to these conclusions about troponin’s prognostic values, some clinicians and laboratorians view the results of Waxman’s study as a call for more sensitive assays. Clinicians will also want to monitor rising levels of troponin. Patients with acute increases will require hospital care, while those with chronic increases will not, although they will need to be evaluated for underlying cardiovascular co-morbidities, explained Allan S. Jaffe, MD, FACC, of the Mayo Clinic and Mayo Medical School, in an accompanying editorial.

There is also concern that the increased sensitivity will prompt complaints from clinicians who are confused about the best strategies to treat patients whose values are elevated. The confusion over high sensitivity results could provide an important role for the clinical laboratory, explained James Januzzi, Jr., MD, Director of the Coronary Care Unit at Massachusetts General Hospital in Boston. “Due to superior analytical precision at the low end, high sensitivity assays, as the name implies, will allow us to more confidently identify even minor amounts of myocardial injury than older troponin assays did. The data are unmistakable—even minor elevations of troponins are clinically important, and having more precise assays to detect these minor elevations is crucial.”

However, clinicians may be confused about what to do when a patient without clear signs of an acute coronary syndrome has an elevated troponin. With these more sensitive assays, this is likely to become a frequent occurrence, said Januzzi. “Clinicians are going to have to learn how these assays perform relative to older troponin assays, and work out a clinical style for how to react to the results from these newer tests,” he said. “The best practice for a clinical laboratory implementing a high sensitivity troponin assay would be to educate clinicians about the change in this biomarker assay. For example, there’s no difference between the high sensitivity assays and the older assays in patients who are resoundingly positive. The upper reference ranges are largely the same, but it’s down around the low levels where the differences are going to be felt.” This is important, he added, because clinicians order troponin assays for their patients frequently, and sometimes on a daily basis. If a result that was previously considered negative is now considered positive, then clinicians may be confused, especially when they read data like in Waxman’s study, which indicate that a patient can still be at risk, even when the risk isn’t obvious.

While Januzzi understands these concerns, the need for more sensitive troponin assays is paramount. While there are a handful of high sensitivity troponin assays on the market, he is excited that more sensitive assays are on the way. “The advantages of the more sensitive assays include their ability to identify risk all the way across a wide range of marker levels, and these assays may be able to identify myocardial injury even earlier than was thought possible for the troponin assays,” he said. “Based on these advantages, there is no way we can hold this back. We have to move forward with these better troponin assays.”

Disclosures: Dr. Waxman and his colleagues do not receive any external funding. Dr. Januzzi receives research support, consulting and speaking fees from Roche Diagnostics (Indianapolis, Ind.), Dade Behring (Deerfield, Ill.), Ortho-Clinical Diagnostics (Raritan, N.J.), and Biosite (San Diego, Calif.).

Julie McDowell is the Editor of Strategies. She can be reached by email.

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