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Cardiac Biomarkers Are Associated With an Increased Risk of Stroke and Death in Patients With Atrial Fibrillation: A Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Substudy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. (Kardiologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. (Kardiologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
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2012 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 125, no 13, 1605-1616 p.Article in journal (Refereed) Published
Abstract [en]

Background—Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.

Methods and Results—Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS2 and CHA2DS2-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 μg/L, n=2663; 0.010 to 0.019 μg/L, n=2006; 0.020 to 0.039 μg/L, n=1023; ≥0.040 μg/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17–3.39]; P=0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41–4.07]; P=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05–6.29]; P<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95–11.49]; P<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P<0.0001, for a composite of thromboembolic events.

Conclusions—Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables.

Place, publisher, year, edition, pages
2012. Vol. 125, no 13, 1605-1616 p.
Keyword [en]
atrial fibrillation, cardiac biomarkers, natriuretic peptide, risk prediction, troponin
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-173987DOI: 10.1161/CIRCULATIONAHA.111.038729ISI: 000302557900011OAI: oai:DiVA.org:uu-173987DiVA: diva2:526622
Available from: 2012-05-14 Created: 2012-05-09 Last updated: 2017-12-07Bibliographically approved
In thesis
1. New Risk Markers in Atrial Fibrillation
Open this publication in new window or tab >>New Risk Markers in Atrial Fibrillation
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atrial fibrillation (AF) confers an independent increased risk of stroke and death. The stroke risk is very heterogeneous and current risk stratification models based on clinical variables, such as the CHADS2 and CHA2DS2VASc score, only offer a modest discriminating value.

The aims of this thesis were to study cardiac biomarkers, cardiac troponin and natriuretic peptides e.g. N-terminal prohormone-B-type natriuretic peptide (NT-proBNP), and describe levels in AF patients, investigate the association with stroke or systemic embolism, cardiovascular event, major bleeding and mortality, and to assess how levels of cardiac biomarkers change over time. Cardiac troponin was analyzed with contemporary assays and high sensitivity assays. The study populations consisted of patients with atrial fibrillation and one risk factor for stroke included in the RE-LY (n=6189) and the ARISTOTLE (n=14892) biomarker substudies. Median follow-up time was 2.2 years and 1.9 years, respectively. In a subset of participants (n=2514) data from repeated measurements was available at three months.

Cardiac troponin was detectable in 57.0% with the contemporary assay and 99.4% with the high sensitivity assay. NT-proBNP was elevated in approximately three quarters of the participants. In Cox models adjusted for established risk factors the cardiac biomarkers levels was independently associated with stroke or systemic embolism, cardiovascular events, and mortality. Only cardiac troponin was associated with major bleeding. In ROC analyses the prediction of stroke or systemic embolism, cardiovascular events, and mortality increased significantly by addition of cardiac troponin or NT-proBNP to the models. Persistent detectable cardiac troponin (contemporary assay) and elevated NT-proBNP levels were found in a large number of participants. Persistent detectable or elevated levels conferred significantly higher risk for stroke or systemic embolism, cardiovascular events, and mortality. By using both cardiac biomarkers simultaneously the risk stratification improved even further for all outcomes.

In conclusion the analyses for the first time display that elevation of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke, cardiovascular events and mortality. Persistent elevation of troponin and NT-proBNP indicate a worse prognosis than transient elevations or no elevations of either marker. The cardiac biomarkers added substantial improvements to existing risk stratification models.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 906
Keyword
atrial fibrillation, stroke risk, cardiac biomarkers, troponin, natriuretic peptides, NT-proBNP, risk stratification
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
urn:nbn:se:uu:diva-198833 (URN)978-91-554-8680-8 (ISBN)
Public defence
2013-06-13, Ebba Enghoffsalen, Ingång 50, bv. Akademiska Sjukhuset, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-05-21 Created: 2013-04-25 Last updated: 2013-08-30Bibliographically approved

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Hijazi, ZiadOldgren, JonasAndersson, UlrikaSiegbahn, AgnetaWallentin, Lars

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