ORIGINAL RESEARCH
Repeated Measurements of Cardiac Biomarkers in Atrial Fibrillation and Validation of the ABC Stroke Score Over Time Ziad Hijazi, MD, PhD; Bertil Lindahl, MD, PhD; Jonas Oldgren, MD, PhD; Ulrika Andersson, MSc; Johan Lindb€ack, MSc; Christopher B. Granger, MD; John H. Alexander, MD, MHS; Bernard J. Gersh, MB, ChB; Michael Hanna, MD; Veli-Pekka Harjola, MD, PhD; Elaine M. Hylek, MD, MPH; Renato D. Lopes, MD, PhD; Agneta Siegbahn, MD, PhD; Lars Wallentin, MD, PhD
Background-—Cardiac biomarkers are independent risk markers in atrial fibrillation, and the novel biomarker–based ABC stroke score (age, biomarkers, and clinical history of prior stroke) was recently shown to improve the prediction of stroke risk in patients with atrial fibrillation. Our aim was to investigate the short-term variability of the cardiac biomarkers and evaluate whether the ABC stroke risk score provides a stable short-term risk estimate. Methods and Results-—According to the study protocol, samples were obtained at entry and also at 2 months in 4796 patients with atrial fibrillation followed for a median of 1.8 years in the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial. Cardiac troponin I, cardiac troponin T, and N-terminal pro-B-type natriuretic peptide were measured with high-sensitivity immunoassays. Associations with outcomes were evaluated by Cox regression. C indices and calibration plots were used to evaluate the ABC stroke score at 2 months. The average changes in biomarker levels during 2 months were small (median change cardiac troponin T +2.8%, troponin I +2.0%, and N-terminal pro-B-type natriuretic peptide +13.5%) and within-subject correlation was high (all ≥0.82). Repeated measurement of cardiac biomarkers provided some incremental prognostic value for mortality but not for stroke when combined with clinical risk factors and baseline levels of the biomarkers. Based on 8702 person-years of follow-up and 96 stroke/systemic embolic events, the ABC stroke score at 2 months achieved a similar C index of 0.70 (95% CI, 0.65–0.76) as compared with 0.70 (95% CI, 0.65–0.75) at baseline. The ABC stroke score remained well calibrated using predefined risk classes. Conclusions-—In patients with stable atrial fibrillation, the variability of the cardiac biomarkers and the biomarker-based ABC stroke score during 2 months are small. The prognostic information by the ABC stroke score remains consistent and well calibrated with similar good predictive performance if patients are retested after 2 months. Clinical Trial Registration -—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984. ( J Am Heart Assoc. 2017;6: e004851. DOI: 10.1161/JAHA.116.004851.) Key Words: atrial fibrillation • cardiac biomarkers • natriuretic peptide • risk score • stroke • troponin
A
trial fibrillation (AF) is the most common sustained arrhythmia and constitutes a major risk factor for stroke and mortality.1,2 Cardiac biomarkers, troponin and natriuretic peptides, have repeatedly been shown to provide independent prognostic information for the risk of stroke, vascular events, and mortality in patients with AF treated with
anticoagulation.3–6 Recently, a biomarker-based risk model consisting of the 4 strongest predictors for stroke in patients with AF was developed, the ABC stroke score (age, biomarkers [troponin and NT-proBNP (N-terminal pro-B-type natriuretic peptide)], and clinical history of prior stroke).7 The ABC stroke score was derived in 14 701 patients, validated in 2
From the Uppsala Clinical Research Center (Z.H., B.L., J.O., U.A., J.L., A.S., L.W.), Department of Medical Sciences, Cardiology (Z.H., B.L., J.O., L.W.) and Department of Medical Sciences, Clinical Chemistry (A.S.), Uppsala University, Uppsala, Sweden; Duke University, Medical Center, Durham, NC (C.B.G., J.H.A., R.D.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.); Bristol-Myers Squibb, Princeton, NJ (M.H.); Division of Emergency Care, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland (V.-P.H.); Boston University Medical Center, Boston, MA (E.M.H.). An abstract of this work was previously presented at the American Heart Association’s Scientific Sessions, November 12–16, 2016, in New Orleans, LA. Correspondence to: Ziad Hijazi, MD, PhD, Uppsala Clinical Research Center, Uppsala University, Uppsala Science Park, SE-752 37 Uppsala, Sweden. E-mail:
[email protected] Received October 13, 2016; accepted April 3, 2017. ª 2017 The Authors and Bristol Myers Squibb Co. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
DOI: 10.1161/JAHA.116.004851
Journal of the American Heart Association
1
Cardiac Biomarkers and ABC Stroke Score Over Time
Hijazi et al
Methods The ARISTOTLE Trial The details of the ARISTOTLE trial have been previously published.9,10 Briefly, ARISTOTLE was a double blind, doubledummy, randomized clinical trial that enrolled 18 201 patients with AF and at least one CHADS2 risk factor (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke) for stroke or systemic embolism. Patients were randomized to warfarin (n=9081) or apixaban (n=9120). The primary end point was stroke or systemic embolism. The median duration of follow-up was 1.8 years. The biomarker serial substudy aimed to include 5000 patients to provide blood samples for later biomarker measurements at randomization and at the preplanned outpatient visit after 2 months. Details are provided in Figure 1. Approval by the appropriate institutional review committees was obtained at all sites. All patients provided written informed consent.
End Points The end points in this substudy were new events after 2 months and included the primary efficacy outcome in the ARISTOTLE trial (stroke or systemic embolism) and the secondary efficacy outcomes (all-cause mortality and DOI: 10.1161/JAHA.116.004851
ORIGINAL RESEARCH
external cohorts of 1400 and 8356 patients achieving C indices between 0.65 and 0.68, and showed superiority over contemporary risk scores.7,8 However, so far, there is no information on the variability over time for these biomarkers and the associations between changed levels and clinical events in patients with stable AF. Therefore, the utility of repeated measurements for reevaluation of the ABC stroke score within different time frames needs to be evaluated because changes of the biomarker levels and the ABC score may be potentially useful for monitoring disease progress and the effects of different treatments (eg, for hypertension, heart failure, and rate control) both in clinical trials and in the routine management of patients with AF. In the present prespecified serial biomarkers substudy within the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, we investigated the changes in the concentrations of the cardiac biomarkers, cardiac troponin (cTn) I (cTnI), cTn T (cTnT), and NT-proBNP, at 2 months and whether the added information improved the prognostication of outcomes in patients with AF treated with anticoagulation. The availability of repeated measurements also provided an opportunity to determine whether the novel biomarker–based ABC stroke risk score provided a stable estimate over a period of time.
Participants in the ARISTOTLE trial (n=18,201)
Biomarkers at randomization (n=14,897 )
Serial biomarker substudy (n=7203)
Patients with cardiac biomarker samples at 2 months (n=4868)
Number of participants in is each biomarker group cTnI (n=4648)
cTnT (n=4790)
NT-proBNP (n=4168)
Total number of events in each biomarker group cTnI
cTnT
NT-proBNP
•Stroke/SE (n=94) •All-cause mortality (n=265) •Cardiovascular mortality (n=125)
•Stroke/SE (n=96) •All-cause mortality (n=271) •Cardiovascular mortality (n=128)
•Stroke/SE (n=87) •All-cause mortality (n=237) •Cardiovascular mortality (n=114)
Figure 1. CONSORT flow diagram of the number of participants included in the serial biomarker substudy and total number of patients with events after 2 months stratified for each biomarker. ARISTOTLE indicates Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; cTnI, cardiac troponin I; cTnT, cardiac troponin T; NT-proBNP, N-terminal pro-Btype natriuretic peptide; SE, systemic embolism. cardiovascular death [excluding bleeding and other noncardiac causes]). A blinded clinical events committee using prespecified criteria adjudicated all end points.10
Biochemical Methods At randomization and at 2 months, blood samples were collected in vacutainer tubes containing EDTA and were centrifuged immediately. Plasma was frozen in aliquots and stored at 70°C until analyzed centrally at the Uppsala Clinical Research Center. The cTnI concentration was determined with high-sensitivity sandwich immunoassays on the ARCHITECT i1000SR (Abbott Diagnostics). The dynamic range is 0.7 to 50 000 ng/L, limit of detection in the Uppsala Clinical Research Center laboratory 1.3 ng/L, and the 99th percentile upper reference limit for healthy persons 23 ng/ L.11 The coefficient of variation (CV) for this cTnI assay is 10% at 3.3 with a local CV of 7% at 21 ng/L. The cTnT concentration was determined with high-sensitivity sandwich immunoassays on the Cobas Analytics e601 Immunoanalyzers (Roche Diagnostics). The measuring range is 3 to 10 000 ng/L, limit of detection 5 ng/L, and the 99th percentile upper reference limit for healthy persons 14 ng/ L.12 The CV is 10% at 13 ng/L with a local CV of 3% at 27 ng/ L. NT-proBNP concentration was determined on the Cobas Analytics e601 Immunoanalyzers (Roche Diagnostics). The limit of detection is 5 ng/L. The analytical range is 20 to Journal of the American Heart Association
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Cardiac Biomarkers and ABC Stroke Score Over Time
Hijazi et al
No.
N=4796
Age, median (Q1–Q3), y
70.0 (63.0–76.0)
Male sex
3156 (65.8%)
ORIGINAL RESEARCH
Table 1. Demographics and Clinical Characteristics at Baseline
A
Region, No. (%) Asia/Pacific
684 (14.3)
Europe
2353 (49.1)
Latin America
419 (8.7)
North America
1340 (27.9)
Weight, median (Q1–Q3), kg
83.5 (71.3–96.6)
Renal function, median (Q1–Q3), mL/min (n=4779)
75.5 (58.5–96.7)
Systolic blood pressure, median (Q1–Q3) (n=4788)
130.0 (120–140)
Baseline heart rate, median (Q1–Q3), beats per min (n=4785)
75.0 (65–85)
Smoker, No. (%)
424 (8.8)
Myocardial infarction, No. (%)
650 (13.6)
Prior stroke or TIA, No. (%)
853 (17.8)
Heart failure, No. (%)
1721 (35.9)
Diabetes mellitus, No. (%)
1194 (24.9)
Hypertension, No. (%)
4187 (87.3)
Permanent/persistent atrial fibrillation, No. (%)
4022 (83.9)
Prior VKA status, naive, No. (%)
1802 (37.6)
ACEI or ARB, No. (%)
3397 (70.8)
Aspirin, No. (%)
1401 (29.2)
hs Troponin I, median (Q1–Q3), ng/L (n=4744)
5.1 (3–9)
hs Troponin T, median (Q1–Q3), ng/L (n=4791)
10.8 (8–16)
GDF-15, median (Q1–Q3), ng/L (n=4764)
1363.5 (978–2038)
NT-proBNP, median (Q1–Q3), ng/L (n=4791)
713.0 (366–1231)
B
C
ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; GDF, growth differentiation factor; hs, high-sensitivity; NT-proBNP, N-terminal pro-B-type natriuretic peptide; TIA, transient ischemic attack; VKA, vitamin K antagonist.
35 000 ng/L. The upper reference limit is 269 in men and 391 ng/L in women.13 The CV is 1250
1128
8.9
1.02 (0.97–1.07)
≤7.5
1188
5.8
7.6–11.0
1205
6.0
1.02 (0.98–1.06)
11.1–16.7
1180
6.2
1.06 (1.01–1.10)
>16.7
1072
6.4
1.09 (1.04–1.15)
1.03 (1.00–1.06) 0.0008 1.05 (1.02–1.08) 0.0106
0.5973
0.0007
cTnI indicates cardiac troponin I; NT-proBNP indicates N-terminal pro-B-type natriuretic peptide. *P value from a linear regression model with the natural logarithm of the month 2 biomarker as the outcome variable and log baseline biomarker level and specific baseline characteristic as the independent variables.
variable and the baseline characteristic, randomized treatment, and biomarker at baseline were explanatory variables. Geometric means, calculated by antilogarithms of the modeladjusted means, were compared. Correlations between biomarker changes were evaluated using the Spearman rank correlation coefficient. The intraindividual CV was estimated by pooling individual CVs. Analysis of clinical outcomes included all events from the month 2 measurement until the efficacy cutoff date. For patients with events between randomization and month 2, the first event occurring after month 2 was counted as the first event. The associations between cTn or NT-proBNP and events after 2 months were investigated using Cox proportional hazards regression adjusted for study treatment and baseline levels of the respective biomarker. A relative change value of 50% was used in order to capture clinically significant DOI: 10.1161/JAHA.116.004851
changes.15–17 The increased discriminative value of month 2 measurement of each biomarker was estimated by comparing Harrell’s C index before and after adding the month 2 value to a model with the baseline value (both in continuous form), randomized treatment, other biomarkers (cystatin C and either cTnI or NT-proBNP), and established risk factors (for stroke or systemic embolism outcomes collected at baseline (age, sex, hypertension, diabetes mellitus, heart failure, previous stroke/systemic embolism/transient ischemic attack, and history of vascular disease). For all-cause mortality and cardiovascular death, systolic blood pressure and smoking status were also included. Restricted cubic splines were used to allow for nonlinearities in the association between continuous variables and outcomes. Likelihood ratio tests were performed to evaluate whether the global model fit improved after the addition of the month 2 measurements of each biomarker. Journal of the American Heart Association
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ORIGINAL RESEARCH
Table 2. Baseline Characteristic With Significant Associations With the Continuous cTnI (ng/L) at Month 2 Adjusted for Baseline cTnI Level and Randomized Treatment
Cardiac Biomarkers and ABC Stroke Score Over Time
Hijazi et al
Variable
Variable Value at Baseline
No.
Geometric Mean
Age category, y
1250
1168
11.8
1.01 (0.98–1.04)
≤3.3
1302
11.2
3.4–5.4
1222
11.6
1.03 (1.00–1.06)
5.5–10.1
1173
12.1
1.07 (1.04–1.10)
>10.1
1043
12.0
1.06 (1.03–1.10)
0.97 (0.94–1.00)
