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In patients with atrial fibrillation (A-fib) treated with oral anticoagulation, the level of high-sensitivity troponin T independently predicts the risk of stroke and other ischemic outcomes as well as major bleeding, according to a substudy of the ARISTOTLE trial published online October 2, 2013, ahead of print in the Journal of the American College of Cardiology. Analysis showed that adding troponin T levels to risk factor scores improves stratification and may help guide patient management. 

The main ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation) trial randomized 18,201 patients with A-fib and at least 1 stroke risk factor to dose-adjusted warfarin plus placebo, or the oral factor Xa inhibitor apixaban plus placebo. Apixaban proved superior to warfarin for preventing stroke or systemic embolism, the primary endpoint. 

For the prespecified subanalysis, investigators led by Ziad Hijazi, MD, PhD, of Uppsala University (Uppsala, Sweden), looked at the relationship between troponin T levels and outcomes in the 14,897 patients from the main trial with available enzyme results. Troponin T was measurable in virtually all patients (99%); 75% had levels above 7.5 ng/L, 50% above 11.0 ng/L, and 25% above 16.7 ng/L. There was no difference in the distribution of troponin T levels between the treatment groups.

Troponin T Levels, CHA₂DS₂VASc Scores Go Hand in Hand

Except for hypertension, all risk factors that constitute the CHADS₂ and CHA₂DS₂VASc scores (congestive heart failure, hypertension, age ≥ 75 years, diabetes, and stroke for the former, with the addition of age 65-74 years, female gender, and vascular disease for the latter) were more common in patients with higher troponin T levels. Accordingly, among patients with troponin T levels > 16.7 ng/L, 83.6% had CHA₂DS₂VASc > 2  compared with 54.7% of patients with troponin T levels ≤ 7.5 ng/L.

In the overall cohort, the annual rate of stroke or systemic embolism was 3.69%, cardiac death 1.88%, MI 0.52%, and major bleeding 2.61%.

When outcomes were compared in relation to the randomized treatments, no interaction was seen with baseline troponin T levels. There were consistent reductions in stroke, hemorrhagic stroke, overall mortality, the composite of these events, and major bleeding with apixaban across the range of troponin T quartiles (P > 0.10 for all).

Higher troponin T levels were strongly associated with a higher rate of all outcomes even after multivariable adjustment for baseline characteristics including indicators of myocardial and renal dysfunction. In particular, the risk for stroke/systemic embolism was higher in patients with troponin T levels greater than 11.0 ng/L and nearly doubled for the highest vs. the lowest quartile, driven mainly by the incidence of ischemic stroke, while risk for other ischemic events was even higher (table 1).

Table 1. Risk of Outcomes by Troponin T Level: Highest vs. Lowest Quartile

The increased risk of major bleeding with higher troponin T levels was similar when results were adjusted for the HASBLED score.

The annual rates of stroke/systemic embolism rose in tandem with both higher troponin T levels and increasing CHA₂DS₂VASc score. The highest annual rate (≥ 2%/yr) was found in the group with a CHA₂DS₂VASc score > 4 or a troponin T level > 11.0 ng/L. Troponin T and CHA₂DS₂VASc score provided independent prognostic information, with a 23% relative improvement in discrimination when the measures were integrated (P < 0.0001).

Increasing troponin T levels had greater impact on cardiac mortality, the composite of ischemic events and mortality, and major bleeding than did CHA₂DS₂VASc scores, showing relative improvements in discrimination of 314.9%, 207.9%, and 84%, respectively (all P < 0.0001) when added to the CHA₂DS₂VASc score.

The authors observe that even after adjustment for standard risk factors, enzyme levels above the median predict increased stroke risk, while lower levels are associated with increased risk of MI, cardiac mortality, and major bleeding.

Together with similar findings from an analysis of the large-scale RE-LY trial comparing warfarin with dabigatran, these data provide “definitive evidence for the incremental prognostic value of high sensitivity troponin levels” in A-fib patients, Dr. Hijazi and colleagues assert.

Biomarker Information May Alter Therapy

Importantly, this biomarker information enables identification of patients with low CHA₂DS₂VASc scores who nonetheless are at high risk for stroke, and thus should improve therapeutic decision making with regard to oral anticoagulation, they say. Also, since troponin T contributes incremental information to the risk of other ischemic events and major bleeding, it may influence use of therapies beyond anticoagulation, they add.

The mechanisms behind troponin’s independent association with increased stroke risk are likely multifactorial, the investigators say, noting that the enzyme is related to aging and tissue vulnerability, myocardial necrosis and apoptosis, and myocardial stress. Troponin may also be associated with underlying inflammatory and fibrotic processes including endothelial dysfunction and a hypercoagulable state, they add.

An important limitation of the findings, the authors acknowledge, is that all patients were treated with an oral anticoagulant, “which impairs the opportunity to provide clear recommendations on which patients might benefit, or not, from this type of treatment.”

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