High Burden of CAD in Chest Pain Patients With ‘Normal’ Troponin

(UPDATED) Patients presenting with chest pain who are excluded for myocardial infarction but have troponin levels that fall into the intermediate range are more likely to have coronary artery disease and a greater burden of atherosclerosis than those with low troponin levels, a new study shows.

Based on the findings, investigators say that high-sensitivity cardiac troponin (hs-cTn) assays, rather than simply ruling out MI, might be used to make decisions about the need for further testing with coronary CT angiography (CTA) so as to identify those who would warrant more-aggressive preventive therapy.

“Different countries around the world have adopted [the use of] high-sensitivity troponin in different ways, but we’re all left with this group in the middle,” said senior investigator Nicholas Mills, MD (University of Edinburgh, Scotland). “We’ve ruled out a heart attack, but the troponin concentrations are intermediate—they’re measurable and they’re telling us something about risk and what do we do? This suggests that coronary CT angiography as an outpatient test might be a very effective way of managing risk for those patients.”

In an editorial accompanying the study, which was published September 27, 2021, in the Journal of the American College of Cardiology, Kavitha Chinnaiyan, MD (Beaumont Health, Royal Oak, MI), and James L. Januzzi Jr, MD (Massachusetts General Hospital, Boston, MA), state that one of the remarkable strengths of the highly sensitive troponin assays is also its weakness: “Clinicians often trust the sensitivity of these tests, frequently considering patients in the ‘normal range’ of hs-cTn as a homogenous, lower risk group, when in truth a wide range of risk exists among those with ‘normal’ troponin, including many with obstructive CAD.”

As a result, hs-cTn may help guide doctors toward the possible presence of CAD in patients with chest pain but without acute MI. “One might leverage the information from hs-cTn in the normal range for further decision making beyond simple discharge,” write the editorialists.

Mills agrees.

“They come to hospital with chest pain, the tests haven’t been entirely reassuring, and further investigation [with CTA] and targeted treatment would be reasonable,” he said. “It’s quite a promising strategy.”  

Three Times Higher Risk of CAD

Chest pain remains one of the most common reasons patients present to the emergency department, though the vast majority of these patients do not have MI, said Mills. While physicians can confidently exclude MI with serial cardiac troponin testing, it’s challenging to identify those in need of further testing. In the past, physicians have relied largely on symptoms, he said.

“Do we think they might have angina?” said Mills. “If so, we might order a stress test or perfusion study. We’d certainly do some form of further investigation. If we’re not sure, and these are the majority of patients with a one-off episode of chest pain, they’re often discharged with very little follow-up or investigation. What we’ve learned since the introduction of high-sensitivity troponin is that the lower the troponin, the longer you live. Patients who have a heart attack ruled out with very low troponin concentrations are at very low risk of future myocardial infarction or death.”

In contrast, those with “normal” troponin concentrations in the intermediate range have a roughly 10 times higher risk of adverse cardiac events compared with those with low troponin concentrations, said Mills.

In the British Heart Foundation-funded study, known as PRECISE-CCTA, researchers included 250 patients presenting to the emergency department with suspected ACS. All patients had been ruled out for MI but were included in the study if they had high-sensitivity cardiac troponin I levels (ARCHITECT_STAT troponin I assay; Abbott Laboratories) above and below the threshold of 5 ng/L, a value derived from a previous validation study. Intermediate hs-cTn levels ranged from 5 ng/L to the sex-specific 99th percentile threshold (n = 167), while levels less than 5 ng/L were classified in the low range (n = 83). All patients underwent coronary CTA as an outpatient as soon as possible after the emergency room visit.

We’ve ruled out a heart attack, but the troponin concentrations are intermediate—they’re measurable and they’re telling us something about risk and what do we do? Nicholas Mills

Overall, 94 of the 250 patients had normal coronary arteries on CTA while 90 had nonobstructive disease and 66 had obstructive disease. Patients with intermediate hs-cTn levels were three times more likely to have CAD than those with low levels (71.9% vs 43.4%; OR 3.33; 95% CI 1.92-5.78) and more likely to have obstructive CAD (29.9% vs 19.3%; OR 1.79; 95% CI 0.05-3.39). Those with intermediate-range hs-cTn also had a larger burden of atherosclerosis than those with low hs-cTn. Most patients with CAD on CTA did not have a known history of disease.

Median hs-cTn levels for those with obstructive and nonobstructive CAD were 7.5 ng/L, respectively, which were both higher compared with those without CAD (4.5 ng/L; P < 0.001 for both comparisons). Patients with intermediate-range hs-cTn were older than those with low levels and had higher TIMI and GRACE risk scores, but otherwise they were well matched in terms of presenting symptoms and medical history, say investigators.

To TCTMD, James de Lemos, MD (UT Southwestern Medical Center, Dallas, TX), who wasn’t involved in the study, said that troponin assays, because of their ability to detect even minor cardiac injury, can cause some consternation among managing physicians.

“There’s a wealth of information from [emergency room] populations like this, as well as in pretty much any other population [where] you measure it, showing that troponins in this range predict higher rates of cardiac events,” he explained. “Interestingly, it’s usually heart failure and death more than MI, but it definitely is not optimal to have a troponin in this range.”

Depending on the clinical context, de Lemos said, different tests might be requested. If acute ischemia isn’t suspected, he might send the patient for an echocardiogram to check for structural heart disease because mildly elevated hs-cTn is known to correlate with echocardiographic abnormalities.

At their center, de Lemos said they use a different troponin assay, but have an MI rule-out protocol integrating hs-cTn information with the modified HEART score (history, ECG, age, and risk factors) to guide decisions on discharge and secondary testing for patients with chest pain. Patients with intermediate-range troponin levels and higher HEART risk scores would undergo further testing with CTA before discharge.

“The downside of additional testing is: what are you going to do with the information?” he said. “You don’t think they’re having a heart attack, but you found coronary artery disease. What should happen next? If it’s nonobstructive, most of us would feel very comfortable with intensifying preventive therapy, such as maximizing statins and treating with low-dose aspirin. The difficult question comes when you detect obstructive coronary disease in somebody who didn’t have a heart attack. That wasn’t a trivial number of proportion of individuals in this study.

‘Tests Not Entirely Reassuring’

To TCTMD, Mills said use of coronary CTA in patients with intermediate-range hs-cTn could lead to targeted prevention efforts in those with CAD. Putting the numbers into context, Mills said that roughly one in five patients showing up in the emergency department with suspected MI have intermediate troponin concentrations.

Interestingly, patients with intermediate-range hs-cTn had a higher prevalence of CAD than those with low hs-cTn levels, both with and without anginal symptoms. While patients with angina symptoms are much more likely to undergo further testing, Mills said their study showed that even those with noncardiac pain had the same prevalence of CAD as those with anginal symptoms.

“It tells us that the clinical history is not as reliable a way of identifying patients in need for further follow-up,” he said.       

In their editorial, Chinnaiyan and Januzzi write that one of the limitations of the study is the lack of clinical outcomes, but it can be assumed that a greater burden of CAD would translate into worse outcomes.

An outcomes trial is coming, said Mills, noting that they have already enrolled 1,000 patients in the TARGET-CTCA study. In that 2,000-patient trial, researchers are testing whether use of CTA in patients with intermediate-range hs-cTn leads to changes in treatment that would reduce the risk of MI/cardiac death compared with usual care. Results from that trial are not expected for several more years.    

Both Chinnaiyan and Januzzi are optimistic that interplay of cardiac biomarkers and imaging would lead to “better recognition and treatment of higher-risk patients.” Simply using a “normal” hs-cTn concentration to rule out MI appears to only capture the “tip of the iceberg” when it comes to ischemic risk, they write, noting that a better understanding of the range of hs-cTn could capture risk “under the waterline when it comes to the burden of CAD.”