High-Sensitivity Troponin Hones ASCVD Risk in Secondary Prevention

A clinical strategy that adds high-sensitivity cardiac troponin I (hs-cTnI) measurements to the mix of other variables used for cardiovascular risk assessment can help reclassify patients into a more appropriate risk category, according to the results of a new analysis from the PEGASUS-TIMI 54 trial.

Among 8,635 patients with established atherosclerotic cardiovascular disease (ASCVD), the use of hs-cTnI shifted the cardiovascular assessment of 1,031 patients, moving roughly one in four lower-risk patients to a higher-risk category and reclassifying one in 11 higher-risk patients as lower risk. 

The reclassification of risk in this secondary-prevention population has clinical implications because patients at risk are treated differently under the 2018 American Heart Association/American College of Cardiology (AHA/ACC) cholesterol guidelines, according to lead investigator Nicholas Marston, MD (Brigham and Women’s Hospital, Boston, MA).

“This personalization of risk is important because not all ASCVD patients are the same,” Marston told TCTMD. “If you’re going to determine who gets access to a therapy like a PCSK9 inhibitor based on risk, that’s great, but you just want to make sure you classify that risk as accurately as possible. That was what we wanted to do.”

For secondary prevention, the 2018 AHA/ACC cholesterol guidelines classify patients with ASCVD as “very high risk” if they have had two or more major cardiovascular events or one major event with multiple high-risk conditions. According to the guidelines, these patients should be treated with a high-intensity statin regardless of age; ezetimibe is a class IIa recommendation, as is the addition of a PCSK9 inhibitors if LDL cholesterol levels are 70 mg/dL or greater. For ASCVD patients not considered to be at very high risk, high-intensity statins are only recommended in those 75 years and younger. Here, ezetimibe is a class IIb recommendation, while PCSK9 inhibitors are not recommended in this lower-risk group.  

Nearly 90% Have Detectable hs-cTnI

Published 5 years ago in the New England Journal of Medicine, the PEGASUS-TIMI 54 trial showed that adding ticagrelor to aspirin in stable patients with a prior MI lowered the 3-year risk of cardiovascular mortality, MI, or stroke but increased the risk of bleeding.

In this analysis, which was published August 5, 2020, in JAMA Cardiology, researchers assigned patients to the AHA/ACC cholesterol guideline-derived risk categories and 78.6% of ASCVD patients met clinical criteria for being at very high risk, with more than 93% qualifying based on one major cardiovascular event and multiple high-risk conditions. Patients were also categorized based on hs-cTnI levels: undetectable (< 2 ng/L), low (2-6 ng/L), and high (> 6 ng/L). Overall, 89.3% of patients had a detectable hs-cTnI level, including 35% with levels exceeding 6 ng/L.

In total, 8.8% of patients classified as very high risk based on the AHA/ACC criteria had a primary endpoint event compared with 5.0% of patients in the lower-risk category. When stratifying patients by hs-cTnI alone, 13.5% of patients with high levels had a primary endpoint event compared with 5.5% of those with low levels. In an adjusted regression model, patients with low hs-cTnI levels had a twofold higher risk of cardiovascular death, MI, or stroke compared to those with undetectable levels. The risk was nearly fivefold higher in those with high hs-cTnI levels.

Combining guideline-derived ASCVD risk assessment with hs-cTnI, investigators observed a gradient of risk with increasing hs-cTnI levels. In the very-high-risk patients, the respective 3-year risk of the primary endpoint was 2.7%, 6.5%, and 14.3% in patients with undetectable, low, and high hs-cTnI levels. In the lower-risk group, the 3-year risk of cardiovascular death, MI, or stroke was 3.1%, 4.0%, and 9.0% in those with undetectable, low, and high hs-cTnI levels, respectively. Adding hs-cTnI levels to guideline-derived ASCVD risk improved the net reclassification index at event rate 0.15 (95% CI 0.10-0.21).

In total, 11.9% of patients in PEGASUS-TIMI 54 were reclassified into a different risk category when hs-cTnI was added to the AHA/ACC risk algorithm.

“Many physicians, specifically cardiologists in academic cardiology, have always known that higher troponin is associated with greater risk, just like high-sensitivity C-reactive protein is also associated with risk of coronary events, but unless you have something to do about it then we’re probably not going to check it in clinic,” Marston said. The 2018 guidelines, however, do allow physicians to alter how they’d treat a very-high-risk ASCVD patient as opposed to someone with established disease who is considered lower risk.     

“If I have a patient I’ve deemed as lower ASCVD risk, am I confident in that or do I also want to check a high-sensitivity troponin? Or if it’s high, do I want to re-evaluate their risk level?” said Marston. “I hope this paper gets people thinking along those lines.”

Marston noted that less than 10% of patients deemed very high risk were reclassified as lower risk based on hs-cTnI levels, which makes sense because once a patient is deemed very high risk it’s typically for good reason. “It’s harder clinically if you have a patient in front of you who meets the criteria for very high risk not to treat them aggressively based on a biomarker,” said Marston. “Certainly, reclassifying upwards, those you’d consider lower risk but who are actually higher risk and where you can be more aggressive, that would certainly be helpful and that’s where we saw the greatest proportion of reclassification.”   

Not Just for Ruling Out ACS Anymore

Christie Ballantyne, MD (Baylor College of Medicine, Houston, TX), who wasn’t involved in the study, said there are now numerous publications showing that high-sensitivity troponin testing can improve cardiovascular risk assessment. Last year, Ballantyne, along with lead author Xiaoming Jia, MD (Baylor College of Medicine), published data from the ARIC study showing that hs-cTnI was strongly linked with a higher risk of ASCVD in patients without established disease.

The data is now very good showing that this is a very powerful biomarker that can be used in primary and secondary prevention. Christie Ballantyne

“It’s a little paradoxical, and maybe it’s the way we were trained thinking [high-sensitivity troponin testing] is just useful for diagnosing acute events, but the data is now very good showing that this is a very powerful biomarker that can be used in primary and secondary prevention,” said Ballantyne. “I deal a lot with lipids and there are many special lipid biomarkers that have way less value than these tests in terms of really determining who’s at risk. A lot of the advanced lipid testing, a lot of the things that we’re doing, it’s not as good as these [troponin] tests for discrimination and yet they’re used a lot more.”

In an editorial, Harvey White, DSc (Auckland City Hospital, New Zealand), said that it’s not clear why increased high-sensitivity troponin within the normal range was associated with increased risk, but even without completely knowing the underlying mechanism for the higher levels, the incremental information provided by measuring hs-cTnI is very useful for improving risk assessment.

“Troponin levels should not be viewed just as a marker for myocardial injury and diagnosis of MI in acute coronary syndrome but should be used more frequently for assessing CVD risk in stable patients with ischemic heart disease,” he writes.

From a practical perspective, Ballantyne said that by measuring these troponin levels and further refining risk stratification beyond the current AHA/ACC risk algorithm, physicians can tease out very-high-risk patients who might benefit from newer and more-expensive medical therapy. These drugs include the PCSK9 inhibitors evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi/Regeneron), as well as other agents that might be options for patients with established ASCVD, such as icosapent ethyl (Vascepa; Amarin), low-dose rivaroxaban (Xarelto; Janssen Pharmaceuticals), and sodium glucose co-transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists for patients with ASCVD and diabetes.

“I think this concept will be expanded as we go forward because there are lots of new therapies targeted for the very-high-risk patients,” he told TCTMD. “It’s one of those things where we talk about precision medicine and I think it’s an important concept because as we get these new therapies, we can’t afford to given them to everybody.”

Ballantyne noted that the guidelines now incorporate coronary artery calcium screening in primary prevention to help refine patient risk and to help make treatment decision. While he believes regular high-sensitivity troponin testing outside the emergency department is “ready for prime time,” he acknowledged there are no data yet showing that treating reclassified patients improves clinical outcomes. Such trials, however, could be conducted since they wouldn’t need to be too large given that event rates in this higher-risk secondary prevention population would be high.