None of the Usual Suspects? Troponin Elevation Still Warrants Attention

A new Swedish analysis should serve as a reminder to physicians: elevated cardiac troponin, even in the absence of standard cardiac and noncardiac diseases known to cause a troponin rise, remains an important marker of increased risk. This is particularly important given the oft-heard concerns that the advent of high-sensitivity (hs) cardiac troponin (cTn) assays have led to a glut of positive results that, in turn, have led to expensive, unnecessary tests and follow-up in people who don’t need it.

On the contrary, write Kai Eggers, MD, PhD (Uppsala Clinical Research Center, Sweden), and colleagues, more than 15% of patients with an initially elevated troponin who are discharged without a diagnosis related to their test results go on to die or have a major cardiovascular event in the next 5 years.

“These patients deserve appropriate evaluation and if you do not find any clear-cut conditions explaining troponin leakage, then at least the value that you're getting should be recognized as a signal that something wrong is going on in the heart, and that these patients at least should be targeted for appropriate follow-up,” Eggers told TCTMD. “Don't discharge these patients without having made up a plan for them.”

Eggers explained that the analysis was prompted by his own frustration with the term “troponinemia,” used in the clinic to refer to a patient with an unexplained troponin elevation. It is not an established medical term per se, but rather one that’s used informally: PubMed contains just two mentions, while a Google search yielded over 2,000 hits. “You hear, ‘Oh, it's all about high-sensitivity troponin. You capture so many nonspecific elevations! This patient just has classical troponinemia,’” Eggers explained. “This is really irritating, in my opinion, because [this term] negates the prognostic importance of troponin in these patients.”

According to Eggers, the sizeable group of patients sent home with a high troponin test result but no diagnosis have not been well-studied. The intention of the paper, published in the January 8/15, 2019, issue of the Journal of the American College of Cardiology, “was to have a closer look at these patients, who they are, and how they are doing—just to give a hint as to which way we could do better in managing these patients in the CCU,” he said.

Delving Into Swedish Data

Eggers et al’s analysis used the TOTAL-AMI data set, itself drawn from the SWEDEHEART registry, to identify patients who had undergone troponin testing following admission for chest pain, had no CVD found or intervened upon, and were subsequently discharged without a specific diagnosis. In all, 48,872 discharged patients were stratified according to cTn levels—above or below the 99th percentile, depending on the tests—and further by assay-specific cTn tertiles when levels were high.

They found that nearly 10,000 patients (20%) had troponin values above the 99th percentile. Not surprisingly, cardiac risk factors as well as cardiac and noncardiac comorbidities increased in parallel with tertiles of cTn. The rate of major adverse events (MAE; all-cause death, MI, readmission for heart failure, or stroke) was 15.4% in the cohort overall, but was significantly increased for each of the three tertiles of troponin elevation (patients with troponin values at or below the 99th percentile made up the reference group). MAE rates were highest for patients with the highest troponin values.

In further analyses, Eggers and colleagues examined the data set according to three “subcohorts,” based on how many cTn-linked conditions had been ruled out. Subcohort 1 was made up of patients without previous MI, previous coronary revascularization, previous stroke, and known congestive heart failure—more than 38,000 patients. Subcohort 2 (which added an exclusion based existing kidney disease) included 31,822 patients. Subcohort 3 further excluded patients with a left ventricular ejection fraction ≤ 0.50 or significant coronary artery disease, leaving just 1,951 patients.

Across all subcohorts, MAE risk was increased for each tertile of troponin and rose in parallel with troponin level. Of note, that increase was particularly striking for subcohort 3, in which the risk of a major adverse event among patients in the highest tertile for cTn was threefold higher than that seen in patients with troponin levels at or below the cutoff.

The Higher the Troponin, the Higher the Risk

To TCTMD, Eggers noted the advent of hs-cTn tests in North America has ushered in fears that ubiquitous positive troponin tests would lead to too many patients being labelled as “at risk” despite a clear diagnosis, prompting a cascade of tests. Other data from Sweden, however, have suggested that the proportion of patients discharged without a specific diagnosis has actually decreased since the introduction of the sensitive tests, Eggers said. In part this reflects a growing awareness of other conditions that can increase troponin values, but it’s also due to subsequent revisions to the universal definition of MI, which designates acute elevated troponin levels and coronary ischemia as MI, even in the absence of a corroborating coronary angiogram.

“The key message from my paper is to not just label these patients without a specific diagnosis: make up your mind. If it's a myocardial infarction according to the universal definition criteria, then label it myocardial infarction and follow up the patients in this way, because then you won't risk losing these patients due to a serious adverse event,” Eggers said. “Even if you cannot establish a clear-cut cardiac condition, then these patients are still at an increased risk and you need to be aware of this.”

You need to be aware that these patients should be targeted for secondary prevention measures: lower the cholesterol levels, stop smoking, get physical exercise, appreciate a healthy lifestyle—this is very, very important. Kai Eggers

Eggers and colleagues conclude their paper urging clinicians to avoid using the term “troponinemia,” which might “trivialize” the patient’s actual risk.

That position is echoed in an accompanying editorial by James L. Januzzi Jr, MD, and Cian P. McCarthy, MD (both of Massachusetts General Hospital, Boston, MA). They point out that the latest universal definition of MI uses the term “myocardial injury” to denote nonischemic myocardial damage accompanied by troponin elevation, further suggesting that the patients in the Eggers paper meet this definition.

“Myocardial injury is not a benign condition and should not be trivialized with awkward and nonsensical monikers such as ‘troponinemia,’” they write. “It is injury, and should be referred to as such. Information on definitive management for these high-risk patients will depend on outcome of much-needed clinical trials currently planned or ongoing.”

Indeed, while Eggers and colleagues advocate for “liberal referral for echocardiography and invasive or noninvasive coronary imaging,” the fact remains that there are no established therapies for myocardial injury. All the same, said Eggers, “You need to be aware that these patients should be targeted for secondary prevention measures: lower the cholesterol levels, stop smoking, get physical exercise, appreciate a healthy lifestyle—this is very, very important.”

Commenting on the study for TCTMD, Saul Schaefer, MD (University of California, Davis), agreed in principle with Eggers et al’s strategy of using echocardiography to rule out left ventricular dysfunction and imaging to rule out coronary artery disease. But he also urged physicians to be more “thoughtful about the underlying disease state.” That means recognizing that patients with sepsis, renal failure on dialysis, and a number of other conditions will also have high troponin levels.

“A low level of troponin elevation, with a known disease state that causes troponin elevation, doesn't need a workup,” Schaefer said. On the other hand, he continued, “the higher the troponin level, the worse the prognosis, and that needs to be investigated aggressively regardless of the underlying cause.”

But Schaefer doesn’t necessarily agree that the term “troponinemia” should be avoided.

“That’s probably overstating the situation, as long as it’s used thoughtfully,” he said. “In instances of elevated troponin, if there's an explanation for it, then treat the underlying disease. And you always address risk factors in these high-risk populations and if [their troponin] is markedly elevated or there is no explanation, then you know that they should be worked up because the prognosis is worse.”