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New Risk Markers in Atrial Fibrillation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
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 [en]
atrial fibrillation, stroke risk, cardiac biomarkers, troponin, natriuretic peptides, NT-proBNP, risk stratification
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology
Identifiers
URN: urn:nbn:se:uu:diva-198833ISBN: 978-91-554-8680-8 (print)OAI: oai:DiVA.org:uu-198833DiVA: diva2:618294
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
List of papers
1. 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
Open this publication in new window or tab >>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
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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.

Keyword
atrial fibrillation, cardiac biomarkers, natriuretic peptide, risk prediction, troponin
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-173987 (URN)10.1161/CIRCULATIONAHA.111.038729 (DOI)000302557900011 ()
Available from: 2012-05-14 Created: 2012-05-09 Last updated: 2017-12-07Bibliographically approved
2. N-Terminal Pro-B-Type Natriuretic Peptide for Risk Assessment in Patients With Atrial Fibrillation: Insights from the ARISTOTLE trial
Open this publication in new window or tab >>N-Terminal Pro-B-Type Natriuretic Peptide for Risk Assessment in Patients With Atrial Fibrillation: Insights from the ARISTOTLE trial
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2013 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 61, no 22, 2274-2284 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE:

This study sought to assess the prognostic value of N-terminal pro–B-type natriuretic peptide (NT-proBNP) in patients with atrial fibrillation (AF) enrolled in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial, and the treatment effect of apixaban according to NT-proBNP levels.

BACKGROUND:

Natriuretic peptides are associated with mortality and cardiovascular events in several cardiac diseases.

METHODS:

In the ARISTOTLE trial, 18,201 patients with AF were randomized to apixaban or warfarin. Plasma samples at randomization were available from 14,892 patients. The association between NT-proBNP concentrations and clinical outcomes was evaluated using Cox proportional hazard models, after adjusting for established cardiovascular risk factors.

RESULTS:

Quartiles of NT-proBNP were Q1:≤363, Q2:364-713, Q3:714-1250 and Q4:>1250 ng/L. During 1.8 years the annual rates of stroke or systemic embolism ranged from 0.74% in the bottom NT-proBNP quartile to 2.21% in the top quartile, adjusted hazard ratio (HR) 2.35 (95% CI 1.62-3.40, p<0.0001. Annual rates of cardiac death ranged from 0.86% in Q1 to 4.14% in Q4, adjusted HR 2.50 (1.81-3.45), p<0.0001. Adding NT-proBNP levels to the CHA2DS2VASc score improved C-statistics from 0.62 to 0.65 (p=0.0009) for stroke or systemic embolism and from 0.59 to 0.69 for cardiac death (p<0.0001). Apixaban reduced stroke, mortality, and bleeding regardless of the NT-proBNP level.

CONCLUSIONS:

NT-proBNP levels are often elevated in AF and independently associated with an increased risk of stroke and mortality. NT-proBNP improves risk stratification beyond the CHA2DS2VASc score and might be a novel tool for improved stroke prediction in AF. The efficacy of apixaban compared with warfarin is independent of the NT-proBNP level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE].

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-198153 (URN)10.1016/j.jacc.2012.11.082 (DOI)000320600700008 ()23563134 (PubMedID)
Available from: 2013-04-09 Created: 2013-04-09 Last updated: 2017-12-06Bibliographically approved
3. High Sensitivity Troponin T and Risk Stratification in Patients with Atrial Fibrillation during Treatment with Apixaban or Warfarin
Open this publication in new window or tab >>High Sensitivity Troponin T and Risk Stratification in Patients with Atrial Fibrillation during Treatment with Apixaban or Warfarin
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2014 (English)In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 63, no 1, 52-61 p.Article in journal (Refereed) Published
Abstract [en]

Objectives

The aim of this study was to evaluate the prognostic value of high-sensitivity troponin T (hs-TnT) in addition to clinical risk factors and the CHA2DS2VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) risk score in patients with atrial fibrillation (AF).

Background

The level of troponin is a powerful predictor of cardiovascular events and mortality.

Methods

A total of 14,897 patients with AF were randomized to treatment with apixaban or warfarin in the ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) trial. The associations between baseline hs-TnT levels and outcomes were evaluated using adjusted Cox regression models.

Results

Levels of hs-TnT were measurable in 93.5% of patients; 75% had levels >7.5 ng/l, 50% had levels >11.0 ng/l, and 25% had levels >16.7 ng/l. During a median 1.9-year period, the annual rates of stroke or systemic embolism ranged from 0.87% in the lowest hs-TnT quartile to 2.13% in the highest hs-TnT quartile (adjusted hazard ratio [HR]: 1.94; 95% confidence interval [CI]: 1.35 to 2.78; p = 0.0010). The annual rates in the corresponding groups ranged from 0.46% to 4.24% (adjusted HR: 4.31; 95% CI: 2.91 to 6.37; p < 0.0001) for cardiac death and from 1.26% to 4.21% (adjusted HR: 1.91; 95% CI: 1.43 to 2.56; p = 0.0001) for major bleeding. Adding hs-TnT levels to the CHA2DS2VASc score improved the C statistic from 0.620 to 0.635 for stroke or systemic embolism (p = 0.0226), from 0.592 to 0.711 for cardiac death (p < 0.0001), and from 0.591 to 0.629 for major bleeding (p < 0.0001). Apixaban reduced rates of stroke, mortality, and bleeding regardless of the hs-TnT level.

Conclusions

Levels of hs-TnT are often elevated in patients with AF. The hs-TnT level is independently associated with an increased risk of stroke, cardiac death, and major bleeding and improves risk stratification beyond the CHA2DS2VASc risk score. The benefits of apixaban as compared with warfarin are consistent regardless of the hs-TnT level. (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation [ARISTOTLE];

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-198845 (URN)10.1016/j.jacc.2013.07.093 (DOI)000329838300010 ()
Available from: 2013-04-26 Created: 2013-04-26 Last updated: 2017-12-06Bibliographically approved
4. Importance of Persistent Elevation of Cardiac Biomarkers in Atrial Fibrillation: a RE-LY Substudy
Open this publication in new window or tab >>Importance of Persistent Elevation of Cardiac Biomarkers in Atrial Fibrillation: a RE-LY Substudy
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2014 (English)In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 100, no 15, 1193-1200 p.Article in journal (Other academic) Published
Abstract [en]

Objectives To evaluate the prognostic importance of transient or persistent elevations of cardiac troponin-I (cTnI) and N-terminal-B-type natriuretic peptide (NT-proBNP) in atrial fibrillation (AF). Methods Plasma samples were obtained at randomisation and after 3 months in 2514 patients with AF in the RE-LY trial; median follow-up was 2.0 years. Patients were grouped based on levels at the two time points according to detectable cTnI levels (>= 0.01 mu g/L) or NT-proBNP levels above median (>= 778 ng/L). These groups were related to occurrence of stroke or cardiovascular events evaluated with Cox models adjusting for established risk factors. Results The proportion of patients with detectable cTnI levels at both time points was 48.5%, at one time point 28.5% and at neither time point 21.0%. Patients with detectable cTnI at both time points had substantially higher rates of stroke compared with those with transient elevations and those with no elevation at either time point (p<0.005, effect of cTnI). Persistent elevation of either or both cardiac biomarkers at baseline and 3 months was associated with a higher risk for cardiovascular events and mortality (p<0.0001). Prognostic prediction improved most with the use of repeated measurements of both cardiac biomarkers simultaneously (p<0.05) and achieved C-statistic 0.644 for stroke compared with 0.611 for CHADS2-score. Conclusions Persistent elevation of troponin and NT-proBNP indicates a worse prognosis than transient elevations or no elevations of either marker. Prognostication of stroke, death and thromboembolic events is improved by the use of repeated determinations of cardiac biomarkers.

National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-198848 (URN)10.1136/heartjnl-2013-304872 (DOI)000338728100013 ()24794140 (PubMedID)
Available from: 2013-04-26 Created: 2013-04-26 Last updated: 2017-12-06Bibliographically approved

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