Redefining myocardial infarction

CAP Today

January 2010
Feature Story

Comparability of results is always potentially difficult when assays are produced by different manufacturers, and with troponin there are added twists. Lack of standardization is more of a problem for troponin I than for troponin T, says Elliott Antman, MD, of Brigham and Women’s Hospital. “The difficulty is that if a patient is seen in hospital A and then later evaluated at hospital B and they use two different troponin I assays—or one uses troponin T and the other troponin I— the values are not comparable.” Clinicians may not realize there are different cut points and may incorrectly interpret someone as having abnormally elevated or not elevated troponin I.

This gets even stickier in multicenter trials on new drugs of potential benefit to heart patients, if hospitals are using different assays. “One of the things we measure is whether a patient with coronary artery disease sustained an MI in the course of the trial. The logistics are quite complicated because you need to collect data from each hospital with respect to their assay and the cut points to define an abnormally elevated value.”

The FDA, Joint European Society of Cardiology, and American College of Cardiology are trying to bring some degree of organization to this issue through the Committee for the Redefinition of Myocardial Infarction, an international cardiology task force to which Dr. Antman belongs. It recommended in 2007 that AMI be redefined predicated on a detection of an increase or decrease of cTn with at least one value above the 99th percentile reference value in patients with evidence of myocardial ischemia.

“If we turn the clock back to 1993, in order to diagnose an MI, traditionally one turned to the patient’s history, an EKG, and a blood test which was a biomarker indicating myocardial necrosis had occurred. Originally the biomarker was creatine kinase, CK-MB, and it became the gold standard,” Dr. Antman explains.

“CK-MB is found in heart and skeletal muscle, so there’s always a certain amount present in patients’ blood, but since the mass of skeletal muscle is greater than the mass of cardiac muscle, much of what we routinely see is from skeletal sources. When a patient has an MI, there’s a burst release of CK-MB from the heart into the circulation, and it goes up and comes down.”

“When cardiac troponin assays were introduced, they showed a value close to zero under normal circumstances, and if a patient released a small amount of cTn because of a small amount of myocardial necrosis, the cTn assays could detect that. However, that bump up did not always correlate with the CK-MB.”

But to get approved as a marker, cardiac troponin’s MI detection limit had to be proposed and it had to pivot around CK-MB. “If you have an assay that’s more sensitive and specific than CK-MB, immediately you have almost an unsolvable problem.” So in the early 1990s something called the MI detection limit was proposed for cTn assays when they were introduced. Today it is accepted that troponins are the preferred analytes for detecting a necrosis, he says. “The difficulty is we still have many labs and clinicians around the world that refer to the so-called MI detection limit, when in fact that was an artifact of the regulatory approval process for a new assay.”

The redefinition group is struggling with the fact that it is now saying any elevation of cardiac troponin I indicates myocardial necrosis, or an MI, Dr. Antman says. “This has profound implications for our epidemiological assessments of whether or not we are preventing MIs. On the one hand, we treat hypertension, we treat elevated cholesterol, we give patients more aspirin, and in fact all of this is reducing the burden of coronary heart disease and the incidence of MI is going down each year. But then we suddenly change the definition of an MI, and it’s a little problematic to say whether we did or didn’t do anything.”

The working group has agreed to continue measuring at some centers the classic older biomarkers, as a means of equating results under the differing definitions. But now another change looms, he says. “The ultra-sensitive cTn assays that are coming on the clinical scene in the future will detect even smaller amounts of myocardial necrosis, so we may be revisiting all the difficulties we had between the introduction of cTn in the early ’90s and the present.”

Unfortunately, many medical centers, Dr. Antman notes, are reporting the old MI decision limit. “What we need to hear from them is the upper reference limit—not the artifact of having to compare cTn against CK-MB.” Admittedly, the upper reference limit varies with different assays, and that adds to the problem. “But all of this is something we can solve, and we are making great headway.”

—Anne Paxton