Clinical Context

Not all patients with a history of cardiovascular events are the same, and the authors of the current study describe how the 2018 American Heart Association/American College of Cardiology cholesterol guidelines define persons at very high risk for recurrence of cardiovascular events as those either with a history of 2 major cardiovascular events or with 1 major event with multiple high-risk conditions.

All patients with a history of cardiovascular events should be strongly considered for treatment with statins and antiplatelet therapy. Patients at high risk for recurrent cardiovascular events are advised to continue high-intensity statin therapy indefinitely. In contrast, average-risk patients may discontinue high-intensity statin therapy after age 75 years. Ezetimibe receives a moderate recommendation for high-risk cardiovascular patients, but only a weak recommendation for average-risk patients. Proprotein convertase subtilisin type 9 (PCSK9) inhibitors also receive a moderate recommendation for high-risk patients, but are not recommended for average-risk individuals.

High-sensitivity troponin I (hsTnI) testing has strengthened risk assessment strategies among outpatients. The current study evaluates whether it may help clinicians better identify very high risk individuals for recurrent cardiovascular events.

Study Synopsis and Perspective

Incorporating high-sensitivity troponin testing into risk algorithms for atherosclerotic cardiovascular disease (ASCVD) provides enhanced risk stratification and leads to the reclassification of about 12% of patients into a more appropriate risk group, a new study shows.

"A key finding of this study is that risk stratification using hsTnI appears to be complementary to the 13 clinical risk factors in the guideline-based ASCVD framework," the authors state.

"These analyses suggest that incorporating an inexpensive and widely available biomarker into ASCVD risk assessment could both improve risk stratification and ensure that patients are offered risk-appropriate medical therapies," they conclude.

The study was published online in JAMA Cardiology on August 5.^[1]

The researchers, led by Nicholas Marston, MD, from Brigham and Women's Hospital, Boston, Massachusetts, explain that the 2018 American Heart Association/American College of Cardiology cholesterol management guidelines identified 2 distinct groups of patients with ASCVD.^[2] The first is a high-risk group, classified on the basis of the presence of 2 or more major cardiovascular events or 1 major event with multiple high-risk conditions. The second group includes the remainder of patients with ASCVD, designated as being at lower risk.

They note that on the basis of this clinical risk stratification, the recommendations for the 2 groups differ in 3 important ways. First, patients in the high-risk group are to be treated with a high-intensity statin independent of age. In the lower-risk group, statin therapy is a class I recommendation only for patients aged 75 years or younger.

Second, ezetimibe is a class IIa recommendation for the high-risk group and only a class IIb recommendation for lower-risk patients. Third, PCSK9 inhibitors are recommended as class IIa for patients in the high-risk group with low-density lipoprotein levels of 70 mg/dL or higher but are not recommended for the lower-risk group.

The present study investigated whether the addition of hsTnI to guideline-derived ASCVD risk can improve risk classification and guide downstream treatment recommendations.

The study, a substudy of the Prevention of Cardiovascular Events in Patient with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, included 8635 patients who had had a myocardial infarction 1 to 3 years before enrollment, were at least 50 years of age, and had at least 1 high-risk feature.^[3]

They were categorized as either high-risk or lower-risk on the basis of their cardiovascular history and comorbidities, in line with the guidelines. Patients were also classified on the basis of hsTnI level, using cut points of 2 ng/L (limit of detection) and 6 ng/L (risk threshold), followed by joint classification on the basis of clinical features and hsTnI level.

The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke.

Results showed that when stratified by clinical criteria, the high-risk group had a primary endpoint 3-year event rate of 8.8% compared with 5.0% in the lower-risk group (hazard ratio, 2.01; 95% confidence interval [CI], 1.58-2.57; P<.001).

However, when patients in the high-risk group were further risk stratified on the basis of hsTnI level, 614 (9.0%) of 6789 patients with an undetectable hsTnI level had a 3-year event rate of 2.7% (<1% per year), which was less than the overall rate in the lower-risk ASCVD group.

In the lower-risk ASCVD group, 417 (22.6%) of 1846 patients with an hsTnI level exceeding 6 ng/L had an event rate of 9.1%, comparable to the overall rate in the high-risk ASCVD group.

The addition of hsTnI to guideline-derived ASCVD risk led to a net reclassification index at an event rate of 0.15.

Overall, use of hsTnI reclassified 1031 (11.9%) of 8635 patients and led to 1 of 11 patients originally designated as having high-risk ASCVD and 1 of 4 originally classed as having lower-risk ASCVD being reclassified to the alternate group.

In an accompanying commentary, Harvey White, DSc, from Auckland City Hospital, New Zealand, says the incremental information on cardiovascular disease risk makes hsTn very useful for improving risk assessment.

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

"Following the evidence from this study and other studies, the new mantra regarding troponins and their role in modern cardiology should now be that any increase in hs-troponin levels within the normal range, no matter what the cause, is bad," Dr White writes.

"In addition, the study by Marston and coworkers shows that measuring hs-troponin I levels enables a robust improvement of risk stratification, and patients reclassified at very high risk can receive more intensive statin therapy or the addition of ezetimibe or PCSK9 inhibitors, as appropriate. For patients reclassified to be at low risk despite statin therapy, there is no need to add other evidence-based lipid-modifying therapies. This is important for improving patient care and outcomes," he concludes.

The PEGASUS-TIMI 54 trial was sponsored by AstraZeneca. The troponin assay was provided by Abbott Laboratories. Dr Marston reports receiving grant support from the National Institutes of Health. Dr White reports receiving grant support paid to the institution and personal fees for serving on steering committees of the ACCELERAT Study from Eli Lilly and Company, AEGIS-II study from CSL Behring LLC, CAMELLIA study from Eisai Inc, CLEAR OUTCOMES study from Esperion Therapeutics Inc, DAL-GENE study from DalCor Pharma UK Inc, HEART-FID study from American Regent, ODYSSEY trial from Regeneron Pharmaceuticals, and Sanofi Aventis Australia Pty Ltd, SCORED and SOLOIST-WHF trials from Sanofi Aventis Australia Pty Ltd, and STRENGTH trial from Omthera Pharmaceuticals, Inc; serving on an advisory board for Genentech, Inc; and receiving grants or personal fees from AstraZeneca.

JAMA Cardiol. Published online August 5, 2020.

Clinical Implications

• The 2018 American Heart Association/American College of Cardiology cholesterol guidelines define persons at very high risk for recurrence of cardiovascular events as those with a history of 2 major cardiovascular events or 1 major event with multiple high-risk conditions. Patients with a very high risk for recurrent cardiovascular events may continue high-dose statin therapy past age 75 years and should be more likely to receive ezetimibe and PCSK9 inhibitors.
• The current study demonstrates that hsTnI can reclassify the risk for recurrent cardiovascular events among nearly 12% of patients. Levels of hsTnI less than 2 ng/L were associated with a lower rate of recurrent events, whereas patients considered low risk but with a hsTnI level in excess of 6 ng/L experienced cardiovascular events at a rate similar to high-risk patients.
• Implications for the Healthcare Team: The current study suggests that hsTnI can be a valuable tool in risk assessment among patients with a history of cardiovascular events. All members of the healthcare team should remain current with the most recent research and consider implementation of based on individualized patient needs. Meeting as a team to discuss individualized care may be of benefit to the patient.

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