Troponin Stratifies Risk in Chest Pain: PROMISE

Batya Swift Yasgur MA, LSW

January 23, 2019

Higher concentrations of high-sensitivity troponin I (hsTnI), even those within the normal range, are associated with a heightened near-term risk for death, acute myocardial infarction (MI), and hospitalization in symptomatic outpatients, new research suggests.

The hsTnI results of more 4000 participants in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial were analyzed in relation to the primary outcomes of death, acute MI, or hospitalization for unstable angina by 1 year, and to a secondary composite outcome of cardiovascular (CV) death and acute MI. Patients were stable but complaining of chest discomfort.

Higher hsTnI concentrations were associated with greater event probabilities for all primary outcomes. Additionally, in multivariable models, hsTnI concentrations independently predicted primary outcomes and the composite outcome.

"I'm actually quite enthusiastic about these results because they reveal potential application for high-sensitivity troponin that has not been unlocked yet," lead author James Januzzi Jr, MD, Hutter Professor of Medicine at Harvard Medical School, Cambridge, and staff cardiologist at Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology.

"This test tells us about what's going on right here, right now, and the likely prognosis predicted by the test identifies patients who had a small amount of myocardial injury related to coronary processes," he continued.

"This suggests that in the future, as our troponin assays get more and more sensitive, we may be able to utilize tests like this, together with clinical judgment, to identify patients with stable coronary syndromes to whom a more directed diagnostic and therapeutic strategy might be taken," he said.

The study was published in the January issue of the Journal of the American College of Cardiology.

Augmenting Triage

"At first presentation, evaluation and management of patients with stable symptoms and suspected coronary artery disease (CAD) may be challenging," the authors write. "In contrast to those with acute coronary syndromes (ACS), patients with more stable presentations have a broader range of risk for progression to complications such as acute myocardial infarction (MI) or death."

Being able to recognize the "uncommon, higher-risk patient within a generally low-risk population is difficult on clinical grounds alone, and currently recommended risk scores substantially overestimate hazard," they note.

"What we do now in a stable but symptomatic patient with suspected CAD is a mixture of different approaches," Januzzi observed.

Beyond the clinical history and examination, patients are sometimes referred for a stress test, coronary CT, or sometimes go directly to cardiac catheterization, he said.

The use of high-sensitivity troponin (hsTn) for diagnostic and prognostic evaluation of patients with suspected acute MI is "well established," and in patients with stable ischemic heart disease, hsTn is prognostic for incident MI or death, the authors point out. However, these studies were performed in patients with established CAD, they note.

hsTn testing for stable but symptomatic patients in the outpatient setting "remains uncertain" but could potentially "measure minute concentrations of the biomarker," thereby allowing "more robust evaluation of such patients."

The PROMISE Study

PROMISE was a randomized trial comparing initial strategies of either coronary CT angiography (CTA) or noninvasive functional testing using exercise electrocardiography (ECG), exercise or pharmacologic nuclear stress testing, or stress echocardiography in symptomatic patients with suspected CAD.

The main findings of the trial, published in the New England Journal of Medicine in 2015, showed no advantage for CTA over functional testing on clinical outcomes over 2 years.

In a recent analysis of PROMISE data, researchers measured concentrations of hsTnI using a high-sensitivity method that "counts" individual molecules of troponin. That study, published in 2018 in the Journal of the American College of Cardiology: Coronary Interventions, showed that concentrations of hsTnI were associated with both the presence and the severity of obstructive CAD in this group.

"Given such an association, in the present study (performed in an even larger cross section of the PROMISE participants) we hypothesized that concentrations of hsTnI would predict risk for major adverse cardiovascular events, particularly in proximity to index presentation," the authors write.

The new analysis focuses on participants (n = 4021) who had available blood samples drawn before invasive angiography (or any other coronary event) and who also had available information regarding vital status at follow-up.

The median follow-up for death, MI, or hospitalization for unstable angina was 735 days (interquartile range [IQR], 524 - 984).

At baseline, in higher hsTnI quartiles, patients were found to have increasing prevalence and number of CAD risk factors and/or preventive treatment for CAD.

Additionally, patients in higher hsTnI quartiles were more likely to have typical angina symptoms, and the Framingham Risk Score was greatest in the highest hsTnI quartile.

Prognostic Implications

By the end of 1 year, a primary end point event (death, acute MI, or hospitalization for unstable angina) was experienced by 75 participants, whereas 28 experienced the composite outcome of CV death or acute MI.

Among participants who had a primary-outcome event by 1 year, median hsTnI concentrations were higher at enrollment, compared with patients who did not experience these events (2.1 vs 1.6 ng/L; P < .001).

Similarly, patients with incident CV death or acute MI by 1 year had higher hsTnI concentrations at enrollment than those who did not (2.4 vs 1.6 ng/L; = .02).

There was a stepwise increase in probability for death, acute MI, or hospitalization for unstable angina by 1 year (from 0.8% to 3.1%) across hsTnI quartiles at enrollment. The event probability for the composite of CV death or acute MI across hsTnI quartiles was not significant, although it was numerically higher.

When the researchers applied multivariable Cox proportional hazards models for prediction of death, acute MI, or hospitalization for unstable angina at 1 year, they found concentrations of hsTnI to be an independent predictor of events (hazard ratio [HR], 1.54 per increase in log hsTnI IQR; 95% CI, 1.33 - 1.78; P < .001).

Of all the covariates tested, hsTnI results most strongly explained the variation in primary outcome.

Age-adjusted Cox proportional hazards models showed that concentrations of hsTnI provided predictive value for the primary end point in women more than in men (P < .001).

When the researchers examined the composite of CV death or acute MI by 1 year, they found that, in Cox proportional hazards, concentrations of hsTnI were significantly predictive of events "in a similar magnitude" (HR, 1.52 per increase in log hsTnI IQR; 95% CI, 1.19 - 1.94; P < .001).

The likelihood ratio test was significant in this model after the addition of hsTnI results (P = .005).

The predictive value was comparable in women and men and was particularly associated with near-term events, compared with longer follow-ups.

An examination of shorter follow-up time horizons revealed that hsTnI strongly predicted events by 30 days (primary end point HR, 1.83; 95% CI, 1.52 - 2.20; and CV death or acute MI HR, 2.18; 95% CI, 1.63 - 2.91; P < .001 for both).

Moreover, the predictive value of hsTnI for events persisted all the way to 90 days (primary end point HR, 1.71; 95% CI, 1.45 - 2.03; and CV death or acute MI HR, 1.75; 95% CI, 1.37 - 2.25; P < .001 for both).

However, in an analysis of patients reaching 90 days without an event, concentrations of hsTnI no longer predicted either the primary end point or the composite of CV death or acute MI for the rest of the follow-up period.

Kaplan–Meier time-to-event analyses suggested that patients with higher concentrations of hsTnI at enrollment had a shorter time to death, acute MI, or hospitalization for unstable angina, with similar findings for CV death or acute MI.

"The most interesting part of our results is that the prognostic implications extended out to the first few months after presentation, although less so the ability to predict more long-events," Januzzi commented.

Patients presenting with stable chest symptoms have "a broad range of risk," with most having "a benign course, but a small number of patients have a much more unstable course with high risk of coronary ischemic complications," he observed.

"Having a tool to support clinical judgment to sort out higher-risk patients mixed in with the large group of lower-risk patients would be very helpful, which is what we found," he said.

Compelling Indication

Commenting on the study for theheart.org | Medscape Cardiology, Christopher deFilippi, MD, vice chair of academic affairs, Inova Heart and Vascular Institute, Falls Church, Virginia, who was not involved with the study, said that clinicians are "often faced with a dilemma of not only determining if these patients have CAD, but are also at short and intermediate risk for a cardiovascular event — a scenario that drives a substantial amount of noninvasive imaging for ischemia or coronary disease in seemingly low-risk patients."

Clinicians "may now begin to consider a compelling indication for measuring a high-sensitive cardiac troponin in an ambulatory population to consider next steps in evaluation."

He expressed concern that the risk stratification offered by this particular high-sensitivity assay, which is "known for its excellent low-end precision," might be relevant to "levels well within the normal range."

However, "whether this can be reproduced by high-sensitivity troponin assays that are currently FDA-approved to aid in the diagnosis of acute MI will have to be determined."

In the meantime, "clinicians should be able to interpret these important study results to provide reassurance that a low level — i.e., below the median; 1.6 ng/L for this assay — indicates both a very low probability of obstructive CAD and, more important, a very low risk for death, MI, or hospitalization for unstable angina over the next year," deFilippi said.

In an accompanying editorial, Paul Collinson, MBBCHR, MD, Department of Clinical Blood Scientists, St. George's University Hospitals, NHG Foundation Trust, London, agrees that the study "adds further compelling evidence to the concept of troponin as a risk marker in the healthy or stable coronary artery disease group."

Januzzi added, "Eventually, all assays we use will have this kind of performance."

This work was sponsored in part by an unrestricted grant from Singulex, Inc., and was also supported by grants from the National Heart, Lung, and Blood Institute (NHLBI). Januzzi is supported in part by the Hutter Family Professorship in Cardiology; has received grant support from Singulex, Abbott, and Prevencio; has received consulting income from Roche Diagnostics, Critical Diagnostics, Philips, Abbott, Prevencio, and Novartis; and participates in clinical end point committees or data safety monitoring boards for Siemens, AbbVie, Pfizer, Amgen, Janssen, and Boehringer Ingelheim. The other authors' disclosures are listed on the original paper. Collinson reports no conflicting interests. deFilippi reports receiving research support from Roche Diagnostics and serving as a consultant for Abbot Diagnostics, Ortho Diagnostics, Roche Diagnostics, and Siemens. He notes that, although all make troponin assays, none of their assays were used in this particular study.

J Am Coll Cardiol. 2019;73:251-260, 261-263. Abstract, Editorial

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