After a long wait, the U.S. Food and Drug Administration (FDA) has finally approved the Elecsys Troponin T Gen 5 STAT (T Gen 5) blood test. Recently, the Beckman high-sensitivity troponin I (hsTnI) assay was also approved. These high-sensitivity troponin assays will benefit emergency departments (EDs) across the country because the results will allow for earlier and faster recognition of acute myocardial infarction (AMI)—which interrupts the blood supply to an area of the heart—or a heart attack. Thus, ED physicians will be able to more quickly diagnose and treat patients with acute ischemic heart disease with greater confidence in their decisions. Unlike earlier generations, these assays detect even the smallest rise in troponin levels. However, this may also challenge ED physicians, hospitals, and laboratories with devising strategies to manage more patients with elevated troponin concentrations.
“One of the most critical issues in using this test to evaluate patients with possible myocardial infarction is that one needs to make a pretest assessment of how likely you think a troponin elevation is due to ischemic heart disease,” says Allan Jaffe, M.D., a cardiologist and Professor of Laboratory Medicine and Professor of Medicine at Mayo Clinic.
Considered a pioneer in clinical studies on the utility and use of troponin assays, Dr. Jaffe has consulted with many companies on the development of troponin assays, including this latest generation.
“If one has a low probability of ischemic heart disease, the likelihood of a given elevation being due to ischemic heart disease—even if it is right at or slightly above the 99th percentile—is relatively low. As values increase, they become more likely to be associated with ischemic heart disease. If the patient has a high probability of acute ischemic heart disease, then an elevation is almost clearly diagnostic, and the very high elevations have high specificity for ischemic heart disease.”
Although these assays are most-often used to evaluate ED patients with possible acute ischemic heart disease, they also show promise for a variety of uses in managing heart disease. For example, the tests have great potential for use in the outpatient environment to determine risk of future cardiac events and for the secondary and primary prevention of heart disease. Obviously, prevention is much better than having patients end up in the ER.
“The assay can be used in an outpatient setting to triage patients at risk for a variety of cardiac events,” says Dr. Jaffe. “It could identify, for example, those with atrial fibrillation who are at risk for emboli, which often go to the brain, or it could be used to predict heart failure in at-risk patients. A high-sensitivity assay of this kind can only have beneficial impact on the practice. It has been used in Europe and around the world for eight years, so there is a fair degree of expertise about how to use it properly.”
The principles articulated above for acute presentations apply to all uses of high-sensitivity cardiac troponin (hscTn) assays. Before using this assay in any clinical setting, cardiologists are advised to “think through” what it is they expect, then add that pretest probability to the eventual value in making a clinical determination. Dr. Jaffe continues, “If one has underlying heart disease, even if the values are within the normal range, those values that are higher suggest greater risk of cardiac events. Eventually, it’s likely we’ll lever that sort of possibility to follow patients over time to see if and when they develop degree signals of heart disease. But, we’re not quite ready to do that yet.”
Even in the absence of known heart disease, higher values of hscTn can be used to predict one’s risk of heart disease over time.
“In the outpatient environment, you now have an assay in which many patients tested will have detectable troponin values, even if they’re not elevated,” says Brad Karon, M.D., Ph.D., a pathologist and Director of Mayo’s Hospital Clinical Laboratory. “So, for patients at risk of heart disease, you can establish a baseline measure that lets you know if there’s a change—say, two or three years into the future. And that’s the major gain in the use of this fifth-generation test on healthy outpatients. With conventional, less-sensitive troponin tests, the vast majority of patients who are tested in an outpatient setting would not have detectable levels, so you don’t have a baseline.”
That said, neither Dr. Jaffe nor Dr. Karon suggest that such an approach is ready for immediate implementation. “For each disease state, one needs to figure out the critical value that indicates sufficient risk to warrant an intervention,” says Dr. Jaffe. “Then, one needs to know exactly what the optimal intervention is.”
The normal troponin values recommended by Dr. Jaffe’s team are 10 ng/L for women and 15 ng/L for men. Even for values that are close to that range, or only marginally elevated, one study found that, in terms of risk stratification for patients with atrial fibrillation, these values significantly augment the predictive accuracy of the CHA2DS2-VASc score—a score that attempts to evaluate the likelihood of stroke in patients who have atrial fibrillation. These patients are at a greater risk for stroke due to a tendency for them to form clots in their hearts, which can travel to the brain and result in a stroke.
“High-sensitivity troponin markedly augments that score,” says Dr. Jaffe. “For example, a modestly increased value, or one in the upper range of ‘normal,’ even if you have a low CHA2DS2-VASc score, puts you at substantial risk.”
Similar results have been found in other areas as well. In one investigation, called The Heart and Soul Study, patients with stable ischemic heart disease were followed longitudinally. Those who had even minor troponin elevations manifested a significant increase in risk of subsequent adverse events.
“This means that the frequency of heart failure, death, and recurrent AMI goes up very substantially in those individuals,” says Dr. Jaffe. “So the sub-setting of patients with chronic ischemic heart disease may be possible this way. The important question is what should be done with these patients, and that is unclear at present.”
These are just two of many examples in the literature.
“Most of the risk factors—hypertension, diabetes, hyperlipidemia, sleep-disturbed breathing, and inflammatory states—for heart disease cause increases in troponin, albeit within the normal range,” says Dr. Jaffe. “Levels tend to go up commensurate with the severity of the risk factors, and all of them are additive. If one sees higher values even within the normal range, it helps to identify those who are at risk because they have some cardiovascular comorbidities, and those who are not at risk.”
Thus, hscTn can predict those patients at risk for incidental heart failure because their comorbidities end up leading to heart failure.
“The importance of this, long term, is that there have been a couple of studies done with natriuretic peptides that suggest, again, using low values, if one identifies patients at risk, angiotensin-converting enzyme—or ACE—inhibitors and routine therapy for the underlying comorbidities are capable of reducing the frequency of heart failure,” says Dr. Jaffe. “So, this is an area that is very ripe, potentially, for intervention studies that will help patients.”
HscTn assays involve some slightly different complexities and nuances when interpreting results. However, the real reasons for the slow approval process in the United States are unknown and only speculative. The fact that many physicians have been wary of the increased sensitivity of the assays may be part of the reason.
“Troponin tests before this fifth-generation assay were simpler, and they came closer to giving ER staff a binary result—‘heart attack or no heart attack,’” says Jake Elo, Senior Product Manager for cardiology testing at Mayo Clinic Laboratories. “So, there’s been a lot of concern that physicians might have difficulty interpreting this more-sensitive test that identifies many more patients with subtler forms of heart disease. I think that’s why it took the FDA so long to approve it. And it’s taken up a lot of Drs. Jaffe and Karon’s time to educate our staff, both on the cardiology side and the ED side. Clinicians need to be more thoughtful now.”
Within a few years, experts expect nearly all U.S. institutions and practices will be using hscTn assays. Meanwhile, until they can get fully educated and comfortable with this test, cardiologists with outpatient practices can rely on Mayo Clinic Laboratories in Rochester, Minnesota, for help.
On that note, Mayo Clinic Laboratories is the first reference laboratory in the U.S. to offer this high-sensitivity troponin T assay (Test ID: TRPS), designed by Roche, a large biotech company, as an outpatient assay.
“For stable outpatients, who, for example, have diabetes, high blood pressure, or renal disease, or who are at risk for future heart disease, cardiologists might elect to send us their samples. We can perform the assay and give them a baseline value for future comparisons,” says Dr. Karon. “Some may have unexpected increases that should lead to some scrutiny to define the etiology of the increases so that treatment, if appropriate, can be properly targeted. However, given that the treatment benefits are not yet totally defined, clinicians need to be thoughtful in deploying this approach.”
Turnaround time for results would be quick, according to Elo.
“The test is a simple blood draw, and it’s recommended that the specimen be frozen,” he says. “As long as the logistics are in place, anyone can send a sample to Mayo Clinic Laboratories, even if you haven’t worked with us before. And since we run this test continuously, you won’t have to wait long for results—usually a day or less, barring any extreme circumstances. Ultimately, we want to help extend the lives of patients with chronic heart disease and better manage those who are at risk.”