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Analysis Blasts Disregard for Unsolved High cTn in Suspected ACS

Elevated cardiac troponin (cTn) levels predicted late major adverse events (MAE) like death, myocardial infarction (MI), or stroke in a large registry cohort of patients with suspected acute coronary syndrome (ACS) who were discharged without receiving a specific diagnosis.

They predicted MAE risk over about 5 years even among those without a history of MI, coronary disease, heart failure, reduced left-ventricular ejection fraction, stroke, or renal disease.

“Troponin elevation even in the absence of a clear-cut explanation should be considered as a serious indicator something is wrong,” Kai M. Eggers, MD, PhD, Uppsala University, Sweden, told theheart.org | Medscape Cardiology.

So clinicians, he said, “should not be reluctant to make a diagnosis in these patients, and not negate the importance of troponin results.” 

Eggers is lead author on the analysis based on a Swedish nationwide registry, SWEDEHEART, which was published online January 7 in the Journal of the American College of Cardiology.

“Most of these patients were admitted because of chest pain or discomfort, so there was clinical suspicion of acute coronary syndrome,” he said. “If such a patient has an elevated troponin, then the patient should be scheduled for appropriate in-hospital evaluation, including echocardiography and some sort of coronary imaging, whether it be invasive angiography or a CT scan.”

Even when the tests don’t suggest coronary disease, “the patients are still at risk, and should at least be followed appropriately and liberally treated with statins and maybe ACE inhibitors, medications we know are cardioprotective.”

Such cautions are in line with the fourth universal definition of myocardial infarction, released in 2018, which classifies troponin elevation without objective evidence of ischemia as myocardial injury — which may have any number of causes.

Myocardial injury and infarction “are two separate entities. They ought to be thought of separately,” said Allan S. Jaffe, MD, Mayo Clinic, Rochester, Minnesota, a coauthor of the 2018 report redefining MI.

It’s well established that “critically ill patients who have elevated troponins have an adverse prognosis even if they get discharged and they’re doing well,” he told theheart.org | Medscape Cardiology. “The problem is that a lot of clinicians don’t understand that. Once acute myocardial infarction has been excluded, many clinicians think all is well.”  

Jaffe, who is not a coauthor of the current study, said it’s a reminder that patients with elevated troponin without ischemia deserve further scrutiny.

“My suspicion, although this is not well studied, is that one of the reasons they have an adverse prognosis is because once the patient goes home, the troponin is out of sight, out of mind.” And that happens with both standard and high-sensitivity assays, he noted.

“What should occur, in my opinion, is that when these patients come back for follow-up, preferably sooner rather than later, one would ask whether there is something causing the troponin elevation.”

The analysis included 48,872 patients with a first-time admission for suspected ACS from 2005 to 2013 who were discharged without having received a specific diagnosis; patients with an acute MI within the prior 8 weeks were excluded.

Elevations were defined in cTn-level tertiles above the reference ≤ 99th percentile concentrations relevant to each specific cTn assay, which included both conventional and high-sensitivity assays for cTnI and cTnT from a number of companies.

About 80% of the cohort, 39,072 patients, showed cTn levels at or below the 99th percentile. In the remaining 9800 patients with higher levels, the prevalence of cardiovascular (CV) risk factors and comorbidities rose with increasing cTn tertile.

Of the total cohort, 15.4% experienced an MAE, defined as death by any cause, MI, readmission for heart failure, or stroke, over a median of 4.9 years.

Risks for the composite MAE endpoint and each of its individual components went up significantly with each step up in cTn tertile. Risks in the highest tertile were increased at least twofold for each type of MAE, and were more than tripled for CV mortality and for heart failure.

The hazard ratios (HR) for MAE adjusted for age, sex, admitting center, year of admission, and type of cTn assay, compared with patients in the ≤ 99th percentile for cTn levels, were:

  • 1.25 (95% CI, 1.18 – 1.34) for tertile 1

  • 1.53 (95% CI, 1.40 – 1.67) for tertile 2

  • 2.59 (95% CI, 2.39 – 2.80) for tertile 3

These findings were significant at P < .001 for all three tertiles.

Adjusted HR (95% CI)* for Individual Major Adverse Events, Highest Two cTn-Level Strata vs Lowest Stratum (≤ 99th percentile)

Endpoints Tertile 2, HR (95% CI) Tertile 3, HR (95% CI)
All-Cause Mortality 1.58 (1.43 – 1.75) 2.76 (2.52 – 3.02)
CV Mortality 2.00 (1.74 – 2.31) 3.27 (2.88 – 3.72)
Non-CV Mortality 1.30 (1.13 – 1.49) 2.37 (2.09 – 2.68)
MI 2.08 (1.72 – 2.51) 2.85 (2.36 – 3.45)
Heart Failure 1.77 (1.46 – 2.14) 3.38 (2.86 – 4.00)
Stroke 1.35 (1.09 – 1.68) 1.98 (1.59 – 2.46)

P < .001 for all HRs except stroke in tertile 2 (P = .005).

*Reference stratum: ≤ 99th percentile (lowest) for cTn concentration. Lowest stratum and higher successive tertiles of cTn concentration defined for each conventional cTnI assay from Abbott, Beckman Coulter, and Siemens (46.5% of cohort), and conventional (38.5% of cohort) and high-sensitivity (15% of cohort) cTnT assays from Roche.

 

In a low-risk cohort of patients without CV comorbidities, renal dysfunction, left ventricular dysfunction, or significant coronary stenosis, the HR was 3.57 (95% CI, 2.30 – 5.54).

Clinicians sometimes shrug off elevated troponin in patients with suspected ACS who test negative for ischemia by giving it nonspecific names like troponinemia, note Eggers and his coauthors.

That term “is most often used in patients in whom you do not know what has happened, you do not have an explanation so you try to trivialize it. This is because clinicians don’t want to be bothered with a patient who they do not understand,” Eggers said.

“Myocardial injury is not a benign condition and should not be trivialized with awkward and nonsensical monikers such as troponinemia,” contends an editorial accompanying the analysis.

Although there are no evidence-based therapies specifically for myocardial injury, “undertaking a thorough history and physical examination is crucial when evaluating patients in this circumstance and addressing whatever medical disarray exists,” observe James L. Januzzi, Jr, MD, and Cian P. McCarthy, MB, BCh, BAO, Massachusetts General Hospital, Boston.

“To the extent that injury may reflect whatever burden of medical conditions is present at the time of diagnosis,” they write, “it is sensible to optimize medical therapies for cardiovascular comorbidities such as hypertension, hyperlipidemia, and diabetes mellitus, and ensuring guideline-directed medical therapy goals for high-risk conditions such as heart failure are met.”

Eggers has disclosed receiving a research grant from Abbott Laboratories, which markets cTn assays. Disclosures for the other authors are included in the report. Jaffe said, “Either currently or over the years, I have consulted for almost all of the major diagnostic companies.” Januzzi has disclosed receiving grant support from Roche Diagnostics, Abbott Diagnostics, Singulex, Prevencio, and Cleveland Heart Labs; consulting for Roche Diagnostics, MyoKardia, Abbott, and Critical Diagnostics; and participating in clinical-endpoint committees or data safety monitoring boards for Boehringer Ingelheim, Amgen, AbbVie, Janssen, Abbott, and Siemens Diagnostics. McCarthy has reported no relevant financial relationships.

J Am Coll Cardiol. Published online January 7, 2019. Article, Editorial

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.




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