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Thromboprophylaxis for atrial arrhythmias in congenital heart disease: A multicenter study
Thromboprophylaxis for atrial arrhythmias in congenital heart disease: A multicenter study Paul Khairy, Jamil Aboulhosn, Craig S. Broberg, Scott Cohen, Stephen Cook, Annie Dore, Susan M. Fernandes, Anne Fournier, Joseph Kay, Sylvie Levesque, Laurent Macle, Franc¸ois Marcotte, Blandine Mond´esert, Franc¸oisPierre Mongeon, Alexander R. Opotowsky, Anna Proietti, Lena Rivard, Jennifer Ting, Bernard Thibault, Ali Zaidi, Robert Hamilton PII: DOI: Reference:
S0167-5273(16)31930-1 doi: 10.1016/j.ijcard.2016.08.223 IJCA 23494
To appear in:
International Journal of Cardiology
Received date: Accepted date:
7 July 2016 12 August 2016
Please cite this article as: Khairy Paul, Aboulhosn Jamil, Broberg Craig S., Cohen Scott, Cook Stephen, Dore Annie, Fernandes Susan M., Fournier Anne, Kay Joseph, Levesque Sylvie, Macle Laurent, Marcotte Fran¸cois, Mond´esert Blandine, Mongeon Fran¸cois-Pierre, Opotowsky Alexander R., Proietti Anna, Rivard Lena, Ting Jennifer, Thibault Bernard, Zaidi Ali, Hamilton Robert, Thromboprophylaxis for atrial arrhythmias in congenital heart disease: A multicenter study, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.08.223
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ACCEPTED MANUSCRIPT Thromboprophylaxis for Atrial Arrhythmias in Congenital Heart Disease: a Multicenter Study
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Paul Khairy, MD, PhD;1,9 Jamil Aboulhosn, MD;2 Craig S. Broberg, MD;3 Scott Cohen, MD;4 Stephen Cook, MD;5 Annie Dore, MD;1 Susan M. Fernandes, LPD, PA-C;6 Anne Fournier, MD;7 Joseph Kay, MD;8 Sylvie Levesque, MSc;9 Laurent Macle, MD;1 François Marcotte, MD;1 Blandine Mondésert, MD;1 François-Pierre Mongeon, MD, SM;1 Alexander R. Opotowsky, MD;10 Anna Proietti, RN;1 Lena Rivard, MD;1 Jennifer Ting, MD;11 Bernard Thibault, MD;1 Ali Zaidi, MD;12 Robert Hamilton, MD;13 on behalf of The AntiCoagulation Therapy In Congenital Heart Disease (TACTIC) investigators and the Alliance for Adult Research in Congenital Cardiology (AARCC)
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Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada University of California, Los Angeles, California, USA 3 Oregon Health and Science University, Portland, Oregon, USA 4 The Wisconsin Adult Congenital Heart (WAtCH) Program, Medical College of Wisconsin, Milwaukee, Wisconsin, USA 5 Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA 6 Stanford University, Palo Alto, California, USA 7 Hôpital Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada 8 University of Colorado Denver, Aurora, Colorado, USA 9 Montreal Health Innovations Coordinating Center (MHICC), Montreal, Quebec, Canada 10 Boston Adult Congenital Heart Service, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA 11 Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, USA 12 Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, USA 13 Co-PI, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Brief Title: TACTIC Word Count: 5015
Grant Support: The study was funded by an investigator-initiated unrestricted grant from Boehringer Ingelheim. The sponsor had no role in study design, data collection, analysis, interpretation, writing of the paper, and decision to submit the manuscript for publication. Potential Conflicts of Interest: The authors have no potential conflicts to disclose other than source of funding. Key Words: congenital heart disease; atrial tachycardia; thromboembolic event; bleeding; antiplatelet therapy; anticoagulation
Correspondence: Dr. Paul Khairy, Montreal Heart Institute Adult Congenital Center, Montreal Heart Institute, 5000 Belanger St. E., Montreal, QC, Canada, H1T 1C8; Tel: (514) 376-3330 ext 3800; Fax: (514) 593-2581; e-mail: [email protected]
ACCEPTED MANUSCRIPT STRUCTURED ABSTRACT BACKGROUND—There is
a paucity of data to guide decisions regarding thromboprophylaxis
METHODS—A retrospective
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for atrial arrhythmias in congenital heart disease. multicenter cohort study enrolled patients with documented
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sustained atrial arrhythmias and congenital heart disease from 12 North American centers to quantify thromboembolic and bleeding rates associated with antiplatelet and anticoagulation
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therapy, and explore associated factors. A blinded committee adjudicated all qualifying arrhythmias and outcomes.
of 482 patients, 45.2% female, age 32.0±18.0 years, were followed for
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RESULTS—A total
11.3±9.4 years since the qualifying arrhythmia. Antiplatelet therapy was administered to
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37.8%, anticoagulation to 54.4%, and neither to 7.9%. Congenital heart disease complexity was simple, moderate, and severe in 18.5%, 34.4%, and 47.1%, respectively. Freedom from
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thromboembolic events was 84.7±2.7% at 15 years, with no difference between anticoagulation versus antiplatelet therapy (P=0.97). Congenital heart disease complexity
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was independently associated with thromboembolic events, with rates of 0.00%, 0.93%, and
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1.95%/year in those with simple, moderate, and severe forms (P<0.001). CHADS2 and CHA2DS2-VASc scores were not predictive of thromboembolic risk. Annualized bleeding rates with antiplatelet and anticoagulation therapy were 0.66% and 1.82% (P=0.039). In multivariable analyses, anticoagulation [hazard ratio (HR) 4.76, 95% CI (1.05-21.58), P=0.043] and HAS-BLED score [HR 3.15, 95% CI (1.02, 9.78), P=0.047] were independently associated with major bleeds. CONCLUSION—Current
management of atrial arrhythmias in congenital heart disease is
associated with a modest rate of thromboembolic events, which is predicted by disease complexity but not CHADS2/CHA2DS2-VASc scores. HAS-BLED score is applicable to the congenital population in predicting major bleeds.
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ACCEPTED MANUSCRIPT ABBREVIATIONS Alliance for Adult Research in Congenital Cardiology
ANOVA
Analysis of variance
CHADS2
A risk score that assigns one point each to history of congestive heart failure, hypertension, and diabetes mellitus, one point for age >75 years, and two points for prior stroke, transient ischemic attack (TIA), or systemic emboli
CHA2DS2-VASc
A risk score that assigns one point each to history of congestive heart failure, hypertension, diabetes mellitus, vascular disease, and female sex, one point for age 65 to 74 years, two points for age ≥75 years, and two points for prior stroke, TIA, or systemic emboli
CI
Confidence interval
CRF
Case-report form
HAS-BLED
A risk score that assigns one point each for history of hypertension, renal disease, liver disease, history of stroke, prior major bleeding or predisposition to bleeding, labile international normalized ratio, age >65 years, antiplatelet or non-steroidal anti-inflammatory drug, and alcohol consumption (>8 drinks/week) or illicit drug use
HR
Hazard ratio
IART
Intra-atrial reentrant tachycardia
MHICC NAFAT
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Inter-quartile range
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IQR
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AARCC
Montreal Health Innovations Coordinating Center Non-automatic focal atrial tachycardia
NOAC
Newer oral anticoagulant
NYHA
New York Heart Association
TACTIC
The AntiCoagulation Therapy In Congenital Heart Disease study
TIA
Transient ischemic attack
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ACCEPTED MANUSCRIPT INTRODUCTION Atrial tachyarrhythmias are increasingly prevalent in the growing population with congenital
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heart disease [1]. It has been estimated that over 50% of patients with congenital heart disease will suffer from an atrial tachyarrhythmia before 65 years of age [2]. These
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arrhythmias are the leading cause of morbidity and hospital admissions [3] and contribute to an increased risk for sudden death [4, 5]. While few studies have explored the association between atrial tachyarrhythmias and thromboembolic events in congenital heart disease [2, 6,
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7], thromboprophylaxis is a cornerstone of patient management. Thromboembolic and
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bleeding rates remain poorly defined, with little data to guide clinical decisions regarding the choice of antiplatelet therapy, anticoagulation, or no thromboprophylaxis [8]. We, therefore, conducted The AntiCoagulation Therapy In Congenital Heart Disease
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(TACTIC) study to quantify the incidence of thromboembolic events in patients with
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congenital heart disease and atrial arrhythmias, assess the rate of bleeding complications associated with antiplatelet and anticoagulation therapy, and identify factors associated with
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thromboembolic and hemorrhagic events.
METHODS
STUDY POPULATION
The study population consisted of patients with congenital heart disease born in July 2011 or earlier with at least one electrocardiographically documented episode of sustained atrial reentrant tachycardia or fibrillation. Subjects were enrolled from 12 centers across North America (3 Canadian; 9 USA) via the Alliance for Adult Research in Congenital Cardiology (AARCC) from January 1, 2013 to March 1, 2015. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by each
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ACCEPTED MANUSCRIPT institution's human research committee. The study adhered to the principles outlined by the International Council of Harmonization Tripartite Guidelines for Good Clinical Practice.
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Atrial reentrant tachycardia was defined as a regular atrial rhythm of abrupt onset, with a constant rate ≥100 bpm, originating outside the region of the sinus node [9]. It was
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classified as non-automatic focal atrial tachycardia (NAFAT) if well formed P-waves were distinguishable electrocardiographically and separated by an isoelectric interval, or if electrophysiology study demonstrated a circumscribed origin of activation with centrifugal
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spread. Otherwise, the atrial reentrant tachycardia was considered macroreentrant, so-called
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intra-atrial reentrant tachycardia (IART) [9]. Atrial fibrillation was defined as the absence of consistent P waves, with rapid oscillations or fibrillatory waves that varied in size, shape, and timing, and were associated with an irregular ventricular response when atrioventricular
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conduction was intact [10]. The following arrhythmias for which thromboprophylaxis is not
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generally indicated [8] did not qualify for inclusion: automatic focal atrial tachycardia (characterized by gradual onset or termination and/or non-response to electrical cardioversion
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or pace termination), accessory-pathway mediated tachycardia, atrioventricular nodal
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reentrant tachycardia, and junctional tachycardia.
STUDY DESIGN AND MANAGEMENT
TACTIC consisted of a multicenter retrospective cohort study conducted according to clinical trial data management standards, including blinded adjudication of qualifying arrhythmias and all outcomes, and data quality control. The study was coordinated by the Montreal Health Innovations Coordinating Center (MHICC), which oversaw data collection, data integration, data entry, quality edit checks, management and resolution of data discrepancies, tracking of adverse events, and analyses. Data quality control consisted of a double data entry process; procedures for flagging illegible data, invalid formats, and invalid codes; systematic
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ACCEPTED MANUSCRIPT range and consistency checks; and inspection by an independent internal quality control group, with full review of a randomly selected sample of √n +1 subjects (where n = total study
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population), comparing electronic data to case-report forms (CRF) and to corrections provided by data clarification forms. The acceptable error rate was predefined as <0.5%. The
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observed error rate prior to database lock was 0.02%.
OUTCOMES
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Main outcomes consisted of thromboembolic events, bleeding complications, and deaths. Thromboembolic events were classified as systemic, pulmonary, or intracardiac. Systemic
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thromboemboli were categorized as neurologic, peripheral arterial, renal, or mesenteric [11]. Neurologic events included transient ischemic attacks (TIA) or strokes. TIA was defined as a
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transient focal neurological defect of sudden onset associated with a motor deficit or aphasia,
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corresponding to a recognizable vascular territory, and lasting <24 hours, with no confirmatory evidence of acute cerebral infarction by imaging [12, 13]. Stroke was defined as
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a new focal neurological deficit of sudden onset, corresponding to a recognizable vascular
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territory, and either persisting ≥24 hours, treated by thrombolysis/thrombectomy, or lasting <24 hours with confirmatory evidence of acute cerebral infarction by imaging [12]. Peripheral arterial emboli were characterized by pain, paresthesia, numbness, and coldness in the involved extremity with loss of pulses, cyanosis or pallor, mottling, and decreased skin temperature [14]. Confirmatory imaging studies were mandated for renal and mesenteric emboli. Pulmonary thromboemboli required diagnostic invasive (i.e., pulmonary angiography) or non-invasive testing (e.g., ultrasonography, ventilation/perfusion lung scintigraphy, and/or computed tomographic imaging). Intracardiac thrombi were categorized according to cardiac chamber as determined by imaging studies.
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ACCEPTED MANUSCRIPT Bleeding events were classified as major or minor on the basis of published criteria [15]. Major bleeding was defined as a reduction in hemoglobin level by at least 20 g per liter,
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transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ. Deaths were classified as non-cardiovascular or cardiovascular (i.e., sudden death of
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presumed or documented arrhythmic etiology, congestive heart failure, myocardial infarction/acute ischemia, thromboembolic, hemorrhagic, aortic dissection/rupture, post-
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cardiac procedure/surgery).
DATA COLLECTION AND ADJUDICATION
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Data were extracted from existing electronic databases, medical and surgical records, and chart review. Baseline characteristics collected at the time of the qualifying arrhythmia
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included age, sex, body mass index, type and complexity of congenital heart disease, cardiac
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surgeries, comorbidities, systemic ventricular ejection fraction, atrial dimensions, New York Heart Association (NYHA) functional class, CHADS2, CHA2DS2-VASc, and HAS-BLED
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scores, resting oxygen saturation, presence of a pacemaker or implantable cardioverter-
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defibrillator, and serum hemoglobin, hematocrit, sodium, and creatinine levels. Congenital heart disease complexity was modeled as an ordinal variable (i.e., simple, moderate, severe) according to a previously proposed classification system (Table S1 in the Supplementary Appendix) [16]. Criteria for CHADS2 [17], CHA2DS2-VASc [18], and HAS-BLED [19] scores are listed in Tables S2, S3, and S4 in the Supplementary Appendix. The blinded adjudicating committee consisted of four individuals who reviewed all qualifying atrial arrhythmias and thromboembolic events, bleeding complications, and deaths. In addition to CRFs, the adjudicating committee examined supportive documents to guide decisions about protocol-defined events. Discrepancies were subject to committee discussions for final adjudication.
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ACCEPTED MANUSCRIPT DATA ANALYSIS
Continuous variables are expressed as mean±standard deviation or median and interquartile
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range ([IQR]; 25th, 75th percentile) depending on normality of distribution. Categorical values are presented as frequencies and percentages. Comparisons of baseline characteristics
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according to antiplatelet therapy, anticoagulation, or neither were performed by analysis of variance (ANOVA), χ2, or Fisher’s exact tests where appropriate. Freedom from thromboembolic events, major bleeds, and major or minor bleeds combined were plotted
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using the Kaplan-Meier product limit method, with comparisons by logrank tests. Patients were censored at the time of change in therapy (discontinuation or initiation of a new therapy)
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or study termination (last follow-up, transplantation, or death). Factors associated with thromboembolic events, major bleeds, and cardiovascular mortality were assessed in
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univariable and multivariable Cox regression models. All variables listed in Table 1 were
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considered and those significant at the 0.2 level in univariable analyses were entered in multivariable models using stepwise selection, with forced retention of thromboprophylactic
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therapy. In primary analyses, time 0 was defined as time of the qualifying arrhythmia or, if
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initial thromboprophylaxis was administered after that date, as time of first therapy. In sensitivity analyses, thromboprophylaxis was modeled as a time-dependent variable to incorporate changes to therapy and account for the potential, albeit minimal, latency between time of qualifying arrhythmia and initiation of thromboprophylaxis [i.e., median 0 (IQR 0, 19) days for antiplatelet therapy; median 0 (IQR 0, 9) days for anticoagulation]. Linearity and proportional hazards assumptions were verified for all Cox models. Two-sided P-values <0.05 were considered statistically significant. Analyses were performed using SAS software version 9.4 (SAS Institute, Cary, North Carolina, USA).
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ACCEPTED MANUSCRIPT RESULTS BASELINE CHARACTERISTICS
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A total of 482 patients were enrolled, 45.2% female, mean age 32.0±18.0 years. Table 1 summarizes baseline characteristics in all patients and according to whether antiplatelet
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therapy alone (N=182; 37.8%), anticoagulation (N=262; 54.4%), or no thromboprophylaxis (N=38; 7.9%) was administered. Anticoagulation was achieved by newer oral anticoagulants (NOAC) in 22 (8.3%) patients, with the remainder prescribed vitamin K antagonists. Patients
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who received no thromboprophylaxis were younger, had a lower prevalence of atrial fibrillation, and were more likely to present with NAFAT. Baseline characteristics were
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otherwise comparable.
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THROMBOEMBOLIC EVENTS
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Thromboembolic events, summarized in Table 2, occurred in 42 (8.7%) patients during 11.3±9.4 years of follow-up, a median of 5.9 (IQR 2.5, 5.6) years after the qualifying
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arrhythmia. Event-free survival rates were 92.6%±1.4%, 89.3%±1.8%, and 84.7±2.7% at 5, 10, and 15 years, respectively. The corresponding annualized thromboembolic event rate was
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1.14%, with no differences according to initial thromboprophylactic therapy (P=0.97) and by modeling thromboprophylaxis as a time-dependent variable (P=0.35). Patients with thromboembolic events were younger at the time of the qualifying arrhythmia (23.1±16.3 versus 32.8±18.0 years, P=0.001), had a higher prevalence of severe congenital heart disease (81.0% versus 47.1%, P<0.001), a greater number of cardiac surgeries (2.6±1.5 versus 1.9±1.3, P=0.005), and a lower systemic ventricular ejection fraction (49.4±13.9 versus 54.8±11.0, P=0.045). CHADS2 (0.2±0.5 versus 0.3±0.8, P=0.10) and CHA2DS2-VASc (0.7±0.7 versus 0.9±0.9, P=0.26) scores were similar in patients with and without events. Factors associated with thromboemboli are presented in Table 3.
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ACCEPTED MANUSCRIPT Complexity of congenital heart disease was the only factor independently associated with thromboembolic events. As depicted in Figure 1, annualized thromboembolic event rates in
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patients with simple, moderate, and severe forms of congenital heart disease were 0.00%,
predictive of thromboembolic events (P=0.23).
BLEEDING COMPLICATIONS
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0.93%, and 1.95% per year, respectively (P<0.001). Type of atrial tachyarrhythmia was not
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A total of 40 (8.3%) patients had 44 bleeding events listed in Table 2, 19 (43.2%) of which were major. Major bleeds occurred a median of 8.9 (IQR 3.3, 17.6) years after the qualifying
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arrhythmia. Anticoagulation [HR 4.99, 95% CI (1.10-22.61), P=0.037], age [HR 1.037 per year, 95% CI (1.003-1.073), P=0.034], and HAS-BLED score [HR 3.30, 95% (1.09-10.05),
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P=0.035] were significantly associated with major bleeds in univariable analyses. There was
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no association between complexity of congenital heart disease and major bleeds (P=0.88). In multivariable analyses, anticoagulation [HR 4.76, 95% CI (1.05-21.58), P=0.043] and HAS-
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BLED score [HR 3.15, 95% CI (1.02-9.78), P=0.047] were independently associated with
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major bleeds. Figure 2 depicts freedom from major bleeding (Panel A) and major or minor bleeding (Panel B) according to thromboprophylactic therapy. Annualized major bleeding rates with antiplatelet and anticoagulation therapy were 0.07% and 0.77%, respectively (P=0.047). Corresponding annualized rates for major or minor bleeding with antiplatelet and anticoagulation therapy were 0.66% and 1.82% (P=0.039).
MORTALITY
A total of 22 (4.6%) patients died a median of 12.4 (IQR 3.6, 18.8) years after the qualifying arrhythmia. Causes of death are listed in Table 2. In univariable analyses, cardiovascular mortality was associated with a history of congestive heart failure [HR 4.48, 95% CI (1.62,
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ACCEPTED MANUSCRIPT 12.37), P=0.004], serum creatinine [HR 1.013 per μmol/L, 95% CI (1.005, 1.022), P=0.003], and CHADS2 [HR 1.89, 95% CI (1.09, 3.24), P=0.023] and CHA2DS2-VASc [HR 1.65, 95%
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CI (1.03, 2.66), P=0.039] scores. Cardiovascular mortality rates were no different according
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to thromboprophylactic therapy (P=0.74).
DISCUSSION
Prevention of thromboembolic complications is central to the management of atrial
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arrhythmias. Validated scores to estimate stroke and bleeding risks guide
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thromboprophylaxis management in the general population with atrial fibrillation or flutter [10]. In contrast, there is little data to inform clinical decisions in the growing population with congenital heart disease in whom atrial arrhythmias are highly prevalent. We, therefore,
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designed the multicenter TACTIC study to address this important knowledge gap.
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A few prior studies have suggested a link between atrial arrhythmias and thromboemboli in congenital heart disease [2, 6, 7, 20]. For example, in a series of 19
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patients with atrial arrhythmias and varied forms of congenital heart disease, thrombus was
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detected by pre-cardioversion transesophageal echocardiography in 37% [20]. To our knowledge, no study previously assessed the association between type of atrial arrhythmia and thromboemboli. In TACTIC, thromboembolic risk was similar irrespective of the presenting atrial arrhythmia. While firm conclusions cannot be drawn regarding the relative thrombogenic proclivity of NAFAT given its low prevalence (<10%), these results are consistent with the general literature, which somewhat controversially suggests that atrial fibrillation and flutter confer comparable risks [21]. Importantly, the quantified thromboembolic event rate (i.e., 1.14%/year) does not reflect the "natural history" of atrial arrhythmias in congenital heart disease. Rather, it is a measure of residual thromboembolic risk despite current thromboprophylactic management as
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ACCEPTED MANUSCRIPT practiced at a dozen sites in North America with expertise in congenital heart disease. Reasons as to why anticoagulation did not outperform antiplatelet therapy in multivariable
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analyses remain speculative. Possibilities include similar treatment effects, difficulties achieving and maintaining therapeutic INR levels with vitamin K antagonists, residual
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confounding, and/or insufficient power.
The higher rate of major bleeding observed with anticoagulation is consistent with meta-analyses comparing vitamin K antagonists to aspirin [22]. While we selected a strict
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definition for major bleeds used by clinical trials [15], it is worthwhile noting that minor
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bleeds were not necessarily trivial and included bleeding leading to hospitalization, surgery, or transfusion of <2 units of blood. The combined major and minor bleeding rate of 1.82%/year observed with anticoagulation is coherent with hemorrhagic rates reported in
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relatively young lower risk populations [23]. Moreover, our results suggest that the HAS-
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BLED score, the most widely applied tool to predict bleeding complications [19, 23], could reasonably be extended to the congenital heart disease population. As a general guide, in
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patients with atrial fibrillation at large, bleeding rates only exceed thromboembolic events
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when the HAS-BLED score is ≥4 [23]. In the younger TACTIC population, no patient had a score ≥4 and only one had a score of 3. As such, a prohibitive bleeding risk is not a major deterrent to thomboprophylaxis in this population. Management guidelines have advocated that congenital heart disease complexity be considered in guiding thromboprophylaxis for atrial arrhythmias [8]. Long-term anticoagulation for IART or atrial fibrillation is deemed indicated (Class I) and reasonable (Class IIA) in adults with severe and moderate forms of congenital heart disease, respectively. In contrast, a Class IIB recommendation contends that it may be reasonable for patients with simple non-valvular forms of congenital heart disease to receive an oral anticoagulant, aspirin, or no thrombophylaxis on the basis of established risk scores [8].
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ACCEPTED MANUSCRIPT The TACTIC study lends credence to the notion that congenital heart disease complexity is a key factor to consider in thromboprophylaxis management decisions. This
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may reflect interactions between various predisposing factors such as sluggish flow, dilated cardiac chambers, venous stasis, intracardiac shunts, endocardial pacemaker or defibrillator
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leads, prosthetic material, platelet abnormalities, hypercoagulable states, and multi-organ involvement [6, 7, 11, 24-28]. On the basis of these results, it can be proposed that CHADS2 and CHA2DS2-VASc scores, which did not adequately capture residual thromboembolic risk,
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be modified to incorporate congenital heart disease complexity (e.g., one point for moderate
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and two points for severe forms). Considering that no thromboembolic event occurred in patients with simple congenital heart disease despite lack of anticoagulation in 44%, there is no evidence to justify routine long-term anticoagulation as a de facto thromboprophylactic
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strategy for atrial arrhythmias in the subgroup with simple defects.
LIMITATIONS
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While every effort was made to maximize data accuracy, including various levels of quality
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control, the study is retrospective and subject to associated limitations. Multivariable analyses cannot adjust for unknown or unmeasured confounders. Decisions regarding thromboprophylaxis were at the discretion of treating physicians and approaches to follow-up were not standardized. To limit subjectivity in assessing outcomes, uniform definitions were applied by a blinded adjudicating committee. Particular attention was directed to defining TIAs, considering that they may be mimicked by other conditions including epileptic seizures and migraine attacks [29]. Greater specificity was favored by restricting qualifying events to those associated with motor deficit or aphasia [12, 13], at the expense of sensitivity. Thromboembolic event rates may, therefore, be underestimated. Finally, study power was
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ACCEPTED MANUSCRIPT insufficient for subgroup analyses of anticoagulated patients who received a NOAC (8.3%) or
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combination therapy with an antiplatelet agent (5.3%).
CONCLUSION
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In conclusion, for patients with congenital heart disease and atrial arrhythmias, a basic scheme that classifies disease complexity into simple, moderate, or severe forms is the most useful metric in stratifying thromboembolic risk. Standard CHADS2 and CHA2DS2-VASc
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scores are generally low and not predictive of residual thromboembolic events in this young population. In contrast, major bleeds, which are significantly higher with anticoagulation
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compared to antiplatelet therapy, are independently associated with the HAS-BLED score. These results suggest that congenital heart disease complexity and the HAS-BLED score
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should be considered when balancing the risks and benefits of thromboprophylaxis for atrial
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arrhythmias in congenital heart disease.
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ACCEPTED MANUSCRIPT ACKNOWLEDGMENTS The authors wish to thank the followings individuals for their assistance: Marie-Claude
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Villeneuve, MSc and Dominique Johnson, PhD (Montreal Health Innovations Coordinating Center); Aynun Naher, MBBS, MS (Oregon Health and Science University); William R.
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Davidson, Jr, MD, John J. Kelleman, MD, Elizabeth E. Adams, DO, and Dena Jefferson RN, BSN, CCRC (Hershey Medical Center); Morgan Hindes (Children's Hospital of Pittsburgh), Ryan Williams and Gwen Derk (University of California, Los Angeles); Michael G. Earing,
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MD, Jonathan W. Cramer, MD and Emily Reinhardt, RN (Medical College of Wisconsin);
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and Meena Fatah (Hospital for Sick Children, Toronto).
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Khairy P, Aboulhosn J, Gurvitz MZ, Opotowsky AR, Mongeon FP, Kay J, et al. Arrhythmia burden in adults with surgically repaired tetralogy of Fallot: a multiinstitutional study. Circulation. 2010;122:868-75. Bouchardy J, Therrien J, Pilote L, Ionescu-Ittu R, Martucci G, Bottega N, et al. Atrial arrhythmias in adults with congenital heart disease. Circulation. 2009;120:1679-86. Engelfriet P, Boersma E, Oechslin E, Tijssen J, Gatzoulis MA, Thilen U, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. Eur Heart J. 2005;26:2325-33. Silka MJ, Hardy BG, Menashe VD, Morris CD. A population-based prospective evaluation of risk of sudden cardiac death after operation for common congenital heart defects. J Am Coll Cardiol. 1998;32:245-51. Oechslin EN, Harrison DA, Connelly MS, Webb GD, Siu SC. Mode of death in adults with congenital heart disease. Am J Cardiol. 2000;86:1111-6. Khairy P, Fernandes SM, Mayer JE, Jr., Triedman JK, Walsh EP, Lock JE, et al. Longterm survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation. 2008;117:85-92. Hoffmann A, Chockalingam P, Balint OH, Dadashev A, Dimopoulos K, Engel R, et al. Cerebrovascular accidents in adult patients with congenital heart disease. Heart. 2010;96:1223-6. Khairy P, Van Hare GF, Balaji S, Berul CI, Cecchin F, Cohen MI, et al. PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease: Developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital Heart Disease (ISACHD). Heart Rhythm. 2014;11:e102-65. Saoudi N, Cosio F, Waldo A, Chen SA, Iesaka Y, Lesh M, et al. A classification of atrial flutter and regular atrial tachycardia according to electrophysiological mechanisms and anatomical bases; a Statement from a Joint Expert Group from The Working Group of Arrhythmias of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J. 2001;22:1162-82. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary. Circulation. 2014;130:2071-104. Khairy P, Landzberg MJ, Gatzoulis MA, Mercier LA, Fernandes SM, Cote JM, et al. Transvenous pacing leads and systemic thromboemboli in patients with intracardiac shunts: a multicenter study. Circulation. 2006;113:2391-7. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al. 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials. Circulation. 2015;132:302-61. Josephson SA, Sidney S, Pham TN, Bernstein AL, Johnston SC. Higher ABCD2 score predicts patients most likely to have true transient ischemic attack. Stroke. 2008;39:3096-8. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with
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[1]
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[11]
[12]
[13]
[14]
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[21] [22]
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[24] [25]
[26]
[27]
[28]
[29]
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[19]
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peripheral artery disease (updating the 2005 guideline). J Am Coll Cardiol 2011;58:2020-45. Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, et al. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157:805-10. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA, et al. ACC/AHA 2008 guidelines for the management of adults with congenital heart disease: executive summary. J Am Coll Cardiol. 2008;52:1890-947. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864-70. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137:263-72. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138:1093-100. Feltes TF, Friedman RA. Transesophageal echocardiographic detection of atrial thrombi in patients with nonfibrillation atrial tachyarrhythmias and congenital heart disease. J Am Coll Cardiol. 1994;24:1365-70. Sparks PB, Kalman JM. Is atrial flutter a risk factor for stroke? J Am Coll Cardiol. 2001;38:785-8. Vazquez FJ, Gonzalez JP, LeGal G, Carrier M, Gandara E. Risk of major bleeding in patients receiving vitamin K antagonists or low doses of aspirin. A systematic review and meta-analysis. Thromb Res. 2016;138:1-6. Gallego P, Roldan V, Torregrosa JM, Galvez J, Valdes M, Vicente V, et al. Relation of the HAS-BLED bleeding risk score to major bleeding, cardiovascular events, and mortality in anticoagulated patients with atrial fibrillation. Circ Arrhythm Electrophysiol. 2012;5:312-8. Khairy P. Thrombosis in congenital heart disease. Expert Rev Cardiovasc Ther. 2013;11:1579-82. Jahangiri M, Shore D, Kakkar V, Lincoln C, Shinebourne E. Coagulation factor abnormalities after the Fontan procedure and its modifications. J Thorac Cardiovasc Surg. 1997;113:989-92. van Nieuwenhuizen RC, Peters M, Lubbers LJ, Trip MD, Tijssen JG, Mulder BJ. Abnormalities in liver function and coagulation profile following the Fontan procedure. Heart. 1999;82:40-6. Potter BJ, Leong-Sit P, Fernandes SM, Feifer A, Mayer JE, Jr., Triedman JK, et al. Effect of Aspirin and warfarin therapy on thromboembolic events in patients with univentricular hearts and Fontan palliation. Int J Cardiol. 2013;168:3940-3. Valente AM, Bhatt AB, Cook S, Earing MG, Gersony DR, Aboulhosn J, et al. The CALF (Congenital Heart Disease in Adults Lower Extremity Systemic Venous Health in Fontan Patients) study. J Am Coll Cardiol. 2010;56:144-50. Amort M, Fluri F, Schafer J, Weisskopf F, Katan M, Burow A, et al. Transient ischemic attack versus transient ischemic attack mimics: frequency, clinical characteristics and outcome. Cerebrovasc Dis. 2011;32:57-64.
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ACCEPTED MANUSCRIPT FIGURE LEGENDS
Figure 1. Freedom from thromboembolic events according to congenital heart disease
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complexity
Figure 2. Freedom from A) major bleeds and B) major and minor bleeds combined
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according to thromboprophylactic therapy
18
ACCEPTED MANUSCRIPT TABLES Table 1. Baseline characteristics Anticoagulant Therapy N=262 34.2±18.1 117 (44.7) 25.0±6.9
89 (18.5) 166 (34.4) 227 (47.1)
33 (18.1) 57 (31.3) 92 (50.5)
50 (19.1) 92 (35.1) 120 (45.8)
6 (15.8) 17 (44.7) 15 (39.5)
2.0±1.4
2.0±1.3
2.0±1.4
2.0±1.5
46 (9.5) 297 (61.6) 139 (28.8)
18 (9.9) 110 (60.4) 54 (29.7)
19 (7.3) 162 (61.8) 81 (30.9)
9 (23.7) 25 (65.8) 4 (10.5)
69 (14.3) 23 (4.8) 15 (3.1) 31 (6.4) 36 (7.5) 8 (1.7) 36 (7.5)
26 (14.3) 6 (3.3) 7 (3.8) 11 (6.0) 14 (7.7) 2 (1.1) 12 (6.6)
41 (15.6) 15 (5.7) 7 (2.7) 17 (6.5) 20 (7.6) 6 (2.3) 24 (9.2)
2 (5.3) 2 (5.3) 1 (2.6) 3 (7.9) 2 (5.3) 0 (0.0) 0 (0)
0.26 0.48 0.84 0.88 1.00 0.63 0.10
55.5±10.6
53.7±15.5
54.1±12.7
0.47
AC
23.2±15.9 20 (52.6) 22.0±6.2
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NU
MA
ED
PT
54.4±11.3
Neither N=38
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Antiplatelet Therapy N=182 30.7±17.7 81 (44.5) 23.8±6.3
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Age, years Female, N (%) Body mass index, kg/m2 Congenital heart disease complexity, N (%) Simple Moderate Severe Number of cardiac surgeries Qualifying atrial tachyarrhythmia, N (%) Non-automatic focal atrial tachycardia Intra-atrial reentrant tachycardia Atrial fibrillation Hypertension, N (%) Diabetes mellitus, N (%) Prior stroke or TIA, N (%) Dyslipidemia, N (%) Current smoking history, N (%) Coronary artery disease, N (%) History of congestive heart failure, N (%) Systemic ventricular ejection fraction, N (%) NYHA functional class, N (%) I II III IV CHADS2 score*, N (%) 0 1 2 ≥3 CHA2DS2-VASc score†, N (%) 0 1 2 3 ≥4
All Patients N=482 32.0±18.0 218 (45.2) 24.3±6.7
Overall P-value <0.001 0.64 0.06 0.58
0.97 0.006
0.52
288 (59.8) 146 (30.3) 44 (9.1) 4 (0.8)
114 (62.6) 53 (29.1) 14 (7.7) 1 (0.5)
137 (56.1) 84 (32.1) 28 (10.7) 3 (1.1)
27 (71.1) 9 (23.7) 2 (5.3) 0 (0.0)
365 (75.7) 83 (17.2) 28 (5.8) 6 (1.2)
141 (77.5) 27 (14.8) 11 (6.0) 3 (1.6)
191 (72.9) 52 (19.8) 16 (6.1) 3 (1.2)
33 (86.8) 4 (10.5) 1 (2.6) 0 (0.0)
198 (41.1) 196 (40.7) 60 (12.4) 24 (5.0) 4 (0.8)
75 (41.2) 77 (42.3) 18 (9.9) 12 (6.6) 0 (0.0)
107 (40.8) 100 (38.2) 40 (15.3) 11 (4.2) 4 (1.5)
16 (42.1) 19 (50.0) 2 (5.3) 1 (2.6) 0 (0.0)
0.63
0.40
19
ACCEPTED MANUSCRIPT HAS-BLED score‡, N (%) 0 1 ≥2
0.42 349 (72.4) 100 (20.7) 33 (6.8)
133 (73.1) 36 (19.8) 13 (7.1)
183 (69.8) 60 (21.9) 19 (7.3)
33 (86.8) 4 (10.5) 1 (2.6)
TIA denotes transien t ischemi c attack; NYHA, New York Heart Associa tion
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Resting oxygen saturation, % 94.3±7.8 93.9±7.7 94.2±8.3 97.3±2.6 0.23 QRS duration, ms 122±35 120±34 124±35 125±33 0.51 Systemic venous atrium transverse 51±14 50±9 53±15 41±6 0.35 diameter, mm Pulmonary venous atrium 43±11 43±10 44±11 36±15 0.06 anteroposterior diameter, mm Pacemaker, N (%) 180 (37.3) 66 (36.3) 103 (39.3) 11 (28.9) 0.44 Implantable cardioverter35 (7.3) 16 (8.8) 15 (5.7) 4 (10.5) 0.28 * The defibrillator, N (%) CHADS Serum hemoglobin, g/L 140.8±25.1 140.6±23.8 141.9±25.5 132.4±28.9 0.28 2 score Hematocrit, % 0.41±0.08 0.41±0.07 0.42±0.08 0.40±0.09 0.59 assigns Serum sodium, mmol/L 138.7±3.2 138.7±3.5 138.8±2.8 138.3±4.0 0.79 one Serum creatinine, μmol/L 83.8±41.9 81.7±26.7 87.3±50.5 66.9±25.4 0.10 point each to history of congestive heart failure, hypertension, and diabetes mellitus, one point for age >75 years, and two points for prior stroke, TIA, or systemic emboli. †
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The CHA2DS2-VASc score assigns one point each to history of congestive heart failure, hypertension, diabetes mellitus, vascular disease, and female sex, one point for age 65 to 74 years, two points for age ≥75 years, and two points for prior stroke, TIA, or systemic emboli. ‡
AC
CE
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The HAS-BLED score assigns one point each for history of hypertension, renal disease, liver disease, history of stroke, prior major bleeding or predisposition to bleeding, labile INR, age >65 years, antiplatelet or non-steroidal anti-inflammatory drug, and alcohol consumption (>8 drinks/week) or illicit drug use.
20
All Patients N=482
Antiplatelet Therapy N=182
42 (8.7)
18 (9.9)
PT
Anticoagulant Therapy N=262
Neither N=38
23 (8.8)
1 (2.6)
6 (3.3)
8 (3.1)
0 (0.0)
1 (0.2)
0 (0.0)
1 (0.4)
0 (0.0)
Peripheral arterial
2 (0.4)
0 (0.0)
2 (0.8)
0 (0.0)
Intracardiac thrombosis
20 (4.1)
10 (5.5)
9 (3.4)
1 (2.6)
Pulmonary
5 (1.0)
2 (1.1)
3 (1.1)
0 (0.0)
5 (2.7)
11 (4.2)
1 (2.6)
19
5
13
1
2 (0.4)
1 (0.5)
1 (0.4)
0 (0.0)
7 (1.5)
1 (0.5)
6 (2.3)
0 (0.0)
15 (3.1)
3 (1.6)
11 (4.2)
1 (2.6)
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ACCEPTED MANUSCRIPT
14 (2.9)
Renal emboli
23 (4.8)
10 (5.5)
12 (4.6)
1 (2.6)
25
10
14
1
Spontaneous skin hematoma, N (%)
2 (0.4)
2 (1.1)
0 (0.0)
0 (0.0)
Spontaneous epistaxis, N (%)
7 (1.5)
3 (1.6)
3 (1.1)
1 (2.6)
Macroscopic hematuria, N (%)
4 (0.8)
0 (0.0)
4 (1.5)
0 (0.0)
Spontaneous rectal bleeding, N (%)
4 (0.8)
2 (1.1)
2 (2.3)
0 (0.0)
Gingival bleeding for more than 5
1 (0.2)
0 (0.0)
1 (0.4)
0 (0.0)
2 (0.4)
0 (0.0)
2 (2.3)
0 (0.0)
1 (0.2)
0 (0.0)
1 (0.4)
0 (0.0)
6 (1.2)
4 (2.2)
2 (2.3)
0 (0.0)
Number of deaths
22 (4.6)
6 (3.3)
15 (5.7)
1 (2.6)
Non-cardiovascular
2 (0.4)
1 (0.5)
1 (0.4)
0 (0.0)
Sepsis
2 (0.4)
1 (0.5)
1 (0.4)
0 (0.0)
20 (4.1)
5 (2.7)
14 (5.3)
1 (2.6)
8 (1.7)
3 (1.6)
5 (1.9)
0 (0.0)
7 (1.5)
21 2 (1.1)
5 (1.9)
0 (0.0)
Number of patients with
SC RI
Thromboembolic events, N (%)
Stroke or transient ischemic attack
*
Major bleeds
Number of major bleeding events Reduction in hemoglobin level ≥20 g/L,
ED
N (%)
17 (3.5)
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Number of patients with major bleeds, N (%)
Transfusion of at least 2 units of blood, N (%)
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Symptomatic bleeding in a critical area or organ, N (%) Minor bleeds*
Number of patients with minor bleeds, N (%)
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Number of minor bleeding events
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thromboembolic events
minutes, N (%) Bleeding leading to hospitalization and/or surgery, N (%) Bleeding leading to transfusion of <2 units of blood, N (%) Other bleeding considered relevant by investigator, N (%) Deaths, N (%)
Cardiovascular Sudden death of presumed arrhythmic etiology Congestive heart failure
ACCEPTED MANUSCRIPT Acute post-operative (following
3 (0.6)
0 (0.0)
2 (2.3)
1 (0.0)
2 (0.4)
0 (0.0)
2 (2.3)
0 (0.0)
cardiac surgery) Hemorrhage
*
AC
CE
PT
ED
MA
NU
SC RI
Subcategories of major and minor bleeds are not mutually exclusive
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Table 2. Adjudicated thromboembolic events, bleeding complications, and deaths in all patients and according to initially prescribed therapy
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ACCEPTED MANUSCRIPT Table 3. Factors associated with thromboembolic events in univariable and multivariable Cox regression analyses *
Per unit increase in category (i.e., from simple to moderate to severe)
Univariable analyses Anticoagulation Age, year Complexity of congenital heart disease* Number of cardiac surgeries Body mass index, kg/m2 Oxygen saturation, % Pacemaker Multivariable analysis Anticoagulation Complexity of congenital heart disease*
NU
1.01 0.976 3.62 1.32 0.91 0.96 1.73
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Hazard Ratio 95% Confidence Interval P-value
AC
CE
PT
ED
MA
1.07 3.47
23
0.55-1.86 0.957-0.996 1.83, 7.18 1.07-1.62 0.85-0.99 0.92-1.00 0.94-3.20
0.97 0.02 <0.001 0.008 0.02 0.05 0.08
0.58-1.98 1.75-6.87
0.82 <0.001
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Variable
ACCEPTED MANUSCRIPT FIGURES
AC
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SC RI
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Figure 1
24
ACCEPTED MANUSCRIPT
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Figure 2
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S0167-5273(16)31930-1 doi: 10.1016/j.ijcard.2016.08.223 IJCA 23494
To appear in:
International Journal of Cardiology
Received date: Accepted date:
7 July 2016 12 August 2016
Please cite this article as: Khairy Paul, Aboulhosn Jamil, Broberg Craig S., Cohen Scott, Cook Stephen, Dore Annie, Fernandes Susan M., Fournier Anne, Kay Joseph, Levesque Sylvie, Macle Laurent, Marcotte Fran¸cois, Mond´esert Blandine, Mongeon Fran¸cois-Pierre, Opotowsky Alexander R., Proietti Anna, Rivard Lena, Ting Jennifer, Thibault Bernard, Zaidi Ali, Hamilton Robert, Thromboprophylaxis for atrial arrhythmias in congenital heart disease: A multicenter study, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.08.223
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Thromboprophylaxis for Atrial Arrhythmias in Congenital Heart Disease: a Multicenter Study
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Paul Khairy, MD, PhD;1,9 Jamil Aboulhosn, MD;2 Craig S. Broberg, MD;3 Scott Cohen, MD;4 Stephen Cook, MD;5 Annie Dore, MD;1 Susan M. Fernandes, LPD, PA-C;6 Anne Fournier, MD;7 Joseph Kay, MD;8 Sylvie Levesque, MSc;9 Laurent Macle, MD;1 François Marcotte, MD;1 Blandine Mondésert, MD;1 François-Pierre Mongeon, MD, SM;1 Alexander R. Opotowsky, MD;10 Anna Proietti, RN;1 Lena Rivard, MD;1 Jennifer Ting, MD;11 Bernard Thibault, MD;1 Ali Zaidi, MD;12 Robert Hamilton, MD;13 on behalf of The AntiCoagulation Therapy In Congenital Heart Disease (TACTIC) investigators and the Alliance for Adult Research in Congenital Cardiology (AARCC)
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1
Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada University of California, Los Angeles, California, USA 3 Oregon Health and Science University, Portland, Oregon, USA 4 The Wisconsin Adult Congenital Heart (WAtCH) Program, Medical College of Wisconsin, Milwaukee, Wisconsin, USA 5 Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA 6 Stanford University, Palo Alto, California, USA 7 Hôpital Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada 8 University of Colorado Denver, Aurora, Colorado, USA 9 Montreal Health Innovations Coordinating Center (MHICC), Montreal, Quebec, Canada 10 Boston Adult Congenital Heart Service, Boston Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA 11 Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, USA 12 Nationwide Children's Hospital, Ohio State University, Columbus, Ohio, USA 13 Co-PI, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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2
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Brief Title: TACTIC Word Count: 5015
Grant Support: The study was funded by an investigator-initiated unrestricted grant from Boehringer Ingelheim. The sponsor had no role in study design, data collection, analysis, interpretation, writing of the paper, and decision to submit the manuscript for publication. Potential Conflicts of Interest: The authors have no potential conflicts to disclose other than source of funding. Key Words: congenital heart disease; atrial tachycardia; thromboembolic event; bleeding; antiplatelet therapy; anticoagulation
Correspondence: Dr. Paul Khairy, Montreal Heart Institute Adult Congenital Center, Montreal Heart Institute, 5000 Belanger St. E., Montreal, QC, Canada, H1T 1C8; Tel: (514) 376-3330 ext 3800; Fax: (514) 593-2581; e-mail: [email protected]
ACCEPTED MANUSCRIPT STRUCTURED ABSTRACT BACKGROUND—There is
a paucity of data to guide decisions regarding thromboprophylaxis
METHODS—A retrospective
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for atrial arrhythmias in congenital heart disease. multicenter cohort study enrolled patients with documented
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sustained atrial arrhythmias and congenital heart disease from 12 North American centers to quantify thromboembolic and bleeding rates associated with antiplatelet and anticoagulation
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therapy, and explore associated factors. A blinded committee adjudicated all qualifying arrhythmias and outcomes.
of 482 patients, 45.2% female, age 32.0±18.0 years, were followed for
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RESULTS—A total
11.3±9.4 years since the qualifying arrhythmia. Antiplatelet therapy was administered to
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37.8%, anticoagulation to 54.4%, and neither to 7.9%. Congenital heart disease complexity was simple, moderate, and severe in 18.5%, 34.4%, and 47.1%, respectively. Freedom from
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thromboembolic events was 84.7±2.7% at 15 years, with no difference between anticoagulation versus antiplatelet therapy (P=0.97). Congenital heart disease complexity
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was independently associated with thromboembolic events, with rates of 0.00%, 0.93%, and
AC
1.95%/year in those with simple, moderate, and severe forms (P<0.001). CHADS2 and CHA2DS2-VASc scores were not predictive of thromboembolic risk. Annualized bleeding rates with antiplatelet and anticoagulation therapy were 0.66% and 1.82% (P=0.039). In multivariable analyses, anticoagulation [hazard ratio (HR) 4.76, 95% CI (1.05-21.58), P=0.043] and HAS-BLED score [HR 3.15, 95% CI (1.02, 9.78), P=0.047] were independently associated with major bleeds. CONCLUSION—Current
management of atrial arrhythmias in congenital heart disease is
associated with a modest rate of thromboembolic events, which is predicted by disease complexity but not CHADS2/CHA2DS2-VASc scores. HAS-BLED score is applicable to the congenital population in predicting major bleeds.
2
ACCEPTED MANUSCRIPT ABBREVIATIONS Alliance for Adult Research in Congenital Cardiology
ANOVA
Analysis of variance
CHADS2
A risk score that assigns one point each to history of congestive heart failure, hypertension, and diabetes mellitus, one point for age >75 years, and two points for prior stroke, transient ischemic attack (TIA), or systemic emboli
CHA2DS2-VASc
A risk score that assigns one point each to history of congestive heart failure, hypertension, diabetes mellitus, vascular disease, and female sex, one point for age 65 to 74 years, two points for age ≥75 years, and two points for prior stroke, TIA, or systemic emboli
CI
Confidence interval
CRF
Case-report form
HAS-BLED
A risk score that assigns one point each for history of hypertension, renal disease, liver disease, history of stroke, prior major bleeding or predisposition to bleeding, labile international normalized ratio, age >65 years, antiplatelet or non-steroidal anti-inflammatory drug, and alcohol consumption (>8 drinks/week) or illicit drug use
HR
Hazard ratio
IART
Intra-atrial reentrant tachycardia
MHICC NAFAT
CE
Inter-quartile range
AC
IQR
PT
ED
MA
NU
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AARCC
Montreal Health Innovations Coordinating Center Non-automatic focal atrial tachycardia
NOAC
Newer oral anticoagulant
NYHA
New York Heart Association
TACTIC
The AntiCoagulation Therapy In Congenital Heart Disease study
TIA
Transient ischemic attack
3
ACCEPTED MANUSCRIPT INTRODUCTION Atrial tachyarrhythmias are increasingly prevalent in the growing population with congenital
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heart disease [1]. It has been estimated that over 50% of patients with congenital heart disease will suffer from an atrial tachyarrhythmia before 65 years of age [2]. These
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arrhythmias are the leading cause of morbidity and hospital admissions [3] and contribute to an increased risk for sudden death [4, 5]. While few studies have explored the association between atrial tachyarrhythmias and thromboembolic events in congenital heart disease [2, 6,
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7], thromboprophylaxis is a cornerstone of patient management. Thromboembolic and
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bleeding rates remain poorly defined, with little data to guide clinical decisions regarding the choice of antiplatelet therapy, anticoagulation, or no thromboprophylaxis [8]. We, therefore, conducted The AntiCoagulation Therapy In Congenital Heart Disease
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(TACTIC) study to quantify the incidence of thromboembolic events in patients with
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congenital heart disease and atrial arrhythmias, assess the rate of bleeding complications associated with antiplatelet and anticoagulation therapy, and identify factors associated with
AC
CE
thromboembolic and hemorrhagic events.
METHODS
STUDY POPULATION
The study population consisted of patients with congenital heart disease born in July 2011 or earlier with at least one electrocardiographically documented episode of sustained atrial reentrant tachycardia or fibrillation. Subjects were enrolled from 12 centers across North America (3 Canadian; 9 USA) via the Alliance for Adult Research in Congenital Cardiology (AARCC) from January 1, 2013 to March 1, 2015. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by each
4
ACCEPTED MANUSCRIPT institution's human research committee. The study adhered to the principles outlined by the International Council of Harmonization Tripartite Guidelines for Good Clinical Practice.
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Atrial reentrant tachycardia was defined as a regular atrial rhythm of abrupt onset, with a constant rate ≥100 bpm, originating outside the region of the sinus node [9]. It was
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classified as non-automatic focal atrial tachycardia (NAFAT) if well formed P-waves were distinguishable electrocardiographically and separated by an isoelectric interval, or if electrophysiology study demonstrated a circumscribed origin of activation with centrifugal
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spread. Otherwise, the atrial reentrant tachycardia was considered macroreentrant, so-called
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intra-atrial reentrant tachycardia (IART) [9]. Atrial fibrillation was defined as the absence of consistent P waves, with rapid oscillations or fibrillatory waves that varied in size, shape, and timing, and were associated with an irregular ventricular response when atrioventricular
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conduction was intact [10]. The following arrhythmias for which thromboprophylaxis is not
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generally indicated [8] did not qualify for inclusion: automatic focal atrial tachycardia (characterized by gradual onset or termination and/or non-response to electrical cardioversion
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or pace termination), accessory-pathway mediated tachycardia, atrioventricular nodal
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reentrant tachycardia, and junctional tachycardia.
STUDY DESIGN AND MANAGEMENT
TACTIC consisted of a multicenter retrospective cohort study conducted according to clinical trial data management standards, including blinded adjudication of qualifying arrhythmias and all outcomes, and data quality control. The study was coordinated by the Montreal Health Innovations Coordinating Center (MHICC), which oversaw data collection, data integration, data entry, quality edit checks, management and resolution of data discrepancies, tracking of adverse events, and analyses. Data quality control consisted of a double data entry process; procedures for flagging illegible data, invalid formats, and invalid codes; systematic
5
ACCEPTED MANUSCRIPT range and consistency checks; and inspection by an independent internal quality control group, with full review of a randomly selected sample of √n +1 subjects (where n = total study
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population), comparing electronic data to case-report forms (CRF) and to corrections provided by data clarification forms. The acceptable error rate was predefined as <0.5%. The
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observed error rate prior to database lock was 0.02%.
OUTCOMES
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Main outcomes consisted of thromboembolic events, bleeding complications, and deaths. Thromboembolic events were classified as systemic, pulmonary, or intracardiac. Systemic
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thromboemboli were categorized as neurologic, peripheral arterial, renal, or mesenteric [11]. Neurologic events included transient ischemic attacks (TIA) or strokes. TIA was defined as a
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transient focal neurological defect of sudden onset associated with a motor deficit or aphasia,
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corresponding to a recognizable vascular territory, and lasting <24 hours, with no confirmatory evidence of acute cerebral infarction by imaging [12, 13]. Stroke was defined as
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a new focal neurological deficit of sudden onset, corresponding to a recognizable vascular
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territory, and either persisting ≥24 hours, treated by thrombolysis/thrombectomy, or lasting <24 hours with confirmatory evidence of acute cerebral infarction by imaging [12]. Peripheral arterial emboli were characterized by pain, paresthesia, numbness, and coldness in the involved extremity with loss of pulses, cyanosis or pallor, mottling, and decreased skin temperature [14]. Confirmatory imaging studies were mandated for renal and mesenteric emboli. Pulmonary thromboemboli required diagnostic invasive (i.e., pulmonary angiography) or non-invasive testing (e.g., ultrasonography, ventilation/perfusion lung scintigraphy, and/or computed tomographic imaging). Intracardiac thrombi were categorized according to cardiac chamber as determined by imaging studies.
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ACCEPTED MANUSCRIPT Bleeding events were classified as major or minor on the basis of published criteria [15]. Major bleeding was defined as a reduction in hemoglobin level by at least 20 g per liter,
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transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ. Deaths were classified as non-cardiovascular or cardiovascular (i.e., sudden death of
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presumed or documented arrhythmic etiology, congestive heart failure, myocardial infarction/acute ischemia, thromboembolic, hemorrhagic, aortic dissection/rupture, post-
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cardiac procedure/surgery).
DATA COLLECTION AND ADJUDICATION
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Data were extracted from existing electronic databases, medical and surgical records, and chart review. Baseline characteristics collected at the time of the qualifying arrhythmia
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included age, sex, body mass index, type and complexity of congenital heart disease, cardiac
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surgeries, comorbidities, systemic ventricular ejection fraction, atrial dimensions, New York Heart Association (NYHA) functional class, CHADS2, CHA2DS2-VASc, and HAS-BLED
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scores, resting oxygen saturation, presence of a pacemaker or implantable cardioverter-
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defibrillator, and serum hemoglobin, hematocrit, sodium, and creatinine levels. Congenital heart disease complexity was modeled as an ordinal variable (i.e., simple, moderate, severe) according to a previously proposed classification system (Table S1 in the Supplementary Appendix) [16]. Criteria for CHADS2 [17], CHA2DS2-VASc [18], and HAS-BLED [19] scores are listed in Tables S2, S3, and S4 in the Supplementary Appendix. The blinded adjudicating committee consisted of four individuals who reviewed all qualifying atrial arrhythmias and thromboembolic events, bleeding complications, and deaths. In addition to CRFs, the adjudicating committee examined supportive documents to guide decisions about protocol-defined events. Discrepancies were subject to committee discussions for final adjudication.
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ACCEPTED MANUSCRIPT DATA ANALYSIS
Continuous variables are expressed as mean±standard deviation or median and interquartile
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range ([IQR]; 25th, 75th percentile) depending on normality of distribution. Categorical values are presented as frequencies and percentages. Comparisons of baseline characteristics
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according to antiplatelet therapy, anticoagulation, or neither were performed by analysis of variance (ANOVA), χ2, or Fisher’s exact tests where appropriate. Freedom from thromboembolic events, major bleeds, and major or minor bleeds combined were plotted
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using the Kaplan-Meier product limit method, with comparisons by logrank tests. Patients were censored at the time of change in therapy (discontinuation or initiation of a new therapy)
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or study termination (last follow-up, transplantation, or death). Factors associated with thromboembolic events, major bleeds, and cardiovascular mortality were assessed in
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univariable and multivariable Cox regression models. All variables listed in Table 1 were
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considered and those significant at the 0.2 level in univariable analyses were entered in multivariable models using stepwise selection, with forced retention of thromboprophylactic
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therapy. In primary analyses, time 0 was defined as time of the qualifying arrhythmia or, if
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initial thromboprophylaxis was administered after that date, as time of first therapy. In sensitivity analyses, thromboprophylaxis was modeled as a time-dependent variable to incorporate changes to therapy and account for the potential, albeit minimal, latency between time of qualifying arrhythmia and initiation of thromboprophylaxis [i.e., median 0 (IQR 0, 19) days for antiplatelet therapy; median 0 (IQR 0, 9) days for anticoagulation]. Linearity and proportional hazards assumptions were verified for all Cox models. Two-sided P-values <0.05 were considered statistically significant. Analyses were performed using SAS software version 9.4 (SAS Institute, Cary, North Carolina, USA).
8
ACCEPTED MANUSCRIPT RESULTS BASELINE CHARACTERISTICS
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A total of 482 patients were enrolled, 45.2% female, mean age 32.0±18.0 years. Table 1 summarizes baseline characteristics in all patients and according to whether antiplatelet
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therapy alone (N=182; 37.8%), anticoagulation (N=262; 54.4%), or no thromboprophylaxis (N=38; 7.9%) was administered. Anticoagulation was achieved by newer oral anticoagulants (NOAC) in 22 (8.3%) patients, with the remainder prescribed vitamin K antagonists. Patients
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who received no thromboprophylaxis were younger, had a lower prevalence of atrial fibrillation, and were more likely to present with NAFAT. Baseline characteristics were
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otherwise comparable.
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THROMBOEMBOLIC EVENTS
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Thromboembolic events, summarized in Table 2, occurred in 42 (8.7%) patients during 11.3±9.4 years of follow-up, a median of 5.9 (IQR 2.5, 5.6) years after the qualifying
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arrhythmia. Event-free survival rates were 92.6%±1.4%, 89.3%±1.8%, and 84.7±2.7% at 5, 10, and 15 years, respectively. The corresponding annualized thromboembolic event rate was
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1.14%, with no differences according to initial thromboprophylactic therapy (P=0.97) and by modeling thromboprophylaxis as a time-dependent variable (P=0.35). Patients with thromboembolic events were younger at the time of the qualifying arrhythmia (23.1±16.3 versus 32.8±18.0 years, P=0.001), had a higher prevalence of severe congenital heart disease (81.0% versus 47.1%, P<0.001), a greater number of cardiac surgeries (2.6±1.5 versus 1.9±1.3, P=0.005), and a lower systemic ventricular ejection fraction (49.4±13.9 versus 54.8±11.0, P=0.045). CHADS2 (0.2±0.5 versus 0.3±0.8, P=0.10) and CHA2DS2-VASc (0.7±0.7 versus 0.9±0.9, P=0.26) scores were similar in patients with and without events. Factors associated with thromboemboli are presented in Table 3.
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ACCEPTED MANUSCRIPT Complexity of congenital heart disease was the only factor independently associated with thromboembolic events. As depicted in Figure 1, annualized thromboembolic event rates in
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patients with simple, moderate, and severe forms of congenital heart disease were 0.00%,
predictive of thromboembolic events (P=0.23).
BLEEDING COMPLICATIONS
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0.93%, and 1.95% per year, respectively (P<0.001). Type of atrial tachyarrhythmia was not
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A total of 40 (8.3%) patients had 44 bleeding events listed in Table 2, 19 (43.2%) of which were major. Major bleeds occurred a median of 8.9 (IQR 3.3, 17.6) years after the qualifying
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arrhythmia. Anticoagulation [HR 4.99, 95% CI (1.10-22.61), P=0.037], age [HR 1.037 per year, 95% CI (1.003-1.073), P=0.034], and HAS-BLED score [HR 3.30, 95% (1.09-10.05),
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P=0.035] were significantly associated with major bleeds in univariable analyses. There was
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no association between complexity of congenital heart disease and major bleeds (P=0.88). In multivariable analyses, anticoagulation [HR 4.76, 95% CI (1.05-21.58), P=0.043] and HAS-
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BLED score [HR 3.15, 95% CI (1.02-9.78), P=0.047] were independently associated with
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major bleeds. Figure 2 depicts freedom from major bleeding (Panel A) and major or minor bleeding (Panel B) according to thromboprophylactic therapy. Annualized major bleeding rates with antiplatelet and anticoagulation therapy were 0.07% and 0.77%, respectively (P=0.047). Corresponding annualized rates for major or minor bleeding with antiplatelet and anticoagulation therapy were 0.66% and 1.82% (P=0.039).
MORTALITY
A total of 22 (4.6%) patients died a median of 12.4 (IQR 3.6, 18.8) years after the qualifying arrhythmia. Causes of death are listed in Table 2. In univariable analyses, cardiovascular mortality was associated with a history of congestive heart failure [HR 4.48, 95% CI (1.62,
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ACCEPTED MANUSCRIPT 12.37), P=0.004], serum creatinine [HR 1.013 per μmol/L, 95% CI (1.005, 1.022), P=0.003], and CHADS2 [HR 1.89, 95% CI (1.09, 3.24), P=0.023] and CHA2DS2-VASc [HR 1.65, 95%
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CI (1.03, 2.66), P=0.039] scores. Cardiovascular mortality rates were no different according
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to thromboprophylactic therapy (P=0.74).
DISCUSSION
Prevention of thromboembolic complications is central to the management of atrial
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arrhythmias. Validated scores to estimate stroke and bleeding risks guide
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thromboprophylaxis management in the general population with atrial fibrillation or flutter [10]. In contrast, there is little data to inform clinical decisions in the growing population with congenital heart disease in whom atrial arrhythmias are highly prevalent. We, therefore,
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designed the multicenter TACTIC study to address this important knowledge gap.
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A few prior studies have suggested a link between atrial arrhythmias and thromboemboli in congenital heart disease [2, 6, 7, 20]. For example, in a series of 19
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patients with atrial arrhythmias and varied forms of congenital heart disease, thrombus was
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detected by pre-cardioversion transesophageal echocardiography in 37% [20]. To our knowledge, no study previously assessed the association between type of atrial arrhythmia and thromboemboli. In TACTIC, thromboembolic risk was similar irrespective of the presenting atrial arrhythmia. While firm conclusions cannot be drawn regarding the relative thrombogenic proclivity of NAFAT given its low prevalence (<10%), these results are consistent with the general literature, which somewhat controversially suggests that atrial fibrillation and flutter confer comparable risks [21]. Importantly, the quantified thromboembolic event rate (i.e., 1.14%/year) does not reflect the "natural history" of atrial arrhythmias in congenital heart disease. Rather, it is a measure of residual thromboembolic risk despite current thromboprophylactic management as
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ACCEPTED MANUSCRIPT practiced at a dozen sites in North America with expertise in congenital heart disease. Reasons as to why anticoagulation did not outperform antiplatelet therapy in multivariable
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analyses remain speculative. Possibilities include similar treatment effects, difficulties achieving and maintaining therapeutic INR levels with vitamin K antagonists, residual
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confounding, and/or insufficient power.
The higher rate of major bleeding observed with anticoagulation is consistent with meta-analyses comparing vitamin K antagonists to aspirin [22]. While we selected a strict
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definition for major bleeds used by clinical trials [15], it is worthwhile noting that minor
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bleeds were not necessarily trivial and included bleeding leading to hospitalization, surgery, or transfusion of <2 units of blood. The combined major and minor bleeding rate of 1.82%/year observed with anticoagulation is coherent with hemorrhagic rates reported in
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relatively young lower risk populations [23]. Moreover, our results suggest that the HAS-
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BLED score, the most widely applied tool to predict bleeding complications [19, 23], could reasonably be extended to the congenital heart disease population. As a general guide, in
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patients with atrial fibrillation at large, bleeding rates only exceed thromboembolic events
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when the HAS-BLED score is ≥4 [23]. In the younger TACTIC population, no patient had a score ≥4 and only one had a score of 3. As such, a prohibitive bleeding risk is not a major deterrent to thomboprophylaxis in this population. Management guidelines have advocated that congenital heart disease complexity be considered in guiding thromboprophylaxis for atrial arrhythmias [8]. Long-term anticoagulation for IART or atrial fibrillation is deemed indicated (Class I) and reasonable (Class IIA) in adults with severe and moderate forms of congenital heart disease, respectively. In contrast, a Class IIB recommendation contends that it may be reasonable for patients with simple non-valvular forms of congenital heart disease to receive an oral anticoagulant, aspirin, or no thrombophylaxis on the basis of established risk scores [8].
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ACCEPTED MANUSCRIPT The TACTIC study lends credence to the notion that congenital heart disease complexity is a key factor to consider in thromboprophylaxis management decisions. This
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may reflect interactions between various predisposing factors such as sluggish flow, dilated cardiac chambers, venous stasis, intracardiac shunts, endocardial pacemaker or defibrillator
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leads, prosthetic material, platelet abnormalities, hypercoagulable states, and multi-organ involvement [6, 7, 11, 24-28]. On the basis of these results, it can be proposed that CHADS2 and CHA2DS2-VASc scores, which did not adequately capture residual thromboembolic risk,
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be modified to incorporate congenital heart disease complexity (e.g., one point for moderate
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and two points for severe forms). Considering that no thromboembolic event occurred in patients with simple congenital heart disease despite lack of anticoagulation in 44%, there is no evidence to justify routine long-term anticoagulation as a de facto thromboprophylactic
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strategy for atrial arrhythmias in the subgroup with simple defects.
LIMITATIONS
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While every effort was made to maximize data accuracy, including various levels of quality
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control, the study is retrospective and subject to associated limitations. Multivariable analyses cannot adjust for unknown or unmeasured confounders. Decisions regarding thromboprophylaxis were at the discretion of treating physicians and approaches to follow-up were not standardized. To limit subjectivity in assessing outcomes, uniform definitions were applied by a blinded adjudicating committee. Particular attention was directed to defining TIAs, considering that they may be mimicked by other conditions including epileptic seizures and migraine attacks [29]. Greater specificity was favored by restricting qualifying events to those associated with motor deficit or aphasia [12, 13], at the expense of sensitivity. Thromboembolic event rates may, therefore, be underestimated. Finally, study power was
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ACCEPTED MANUSCRIPT insufficient for subgroup analyses of anticoagulated patients who received a NOAC (8.3%) or
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combination therapy with an antiplatelet agent (5.3%).
CONCLUSION
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In conclusion, for patients with congenital heart disease and atrial arrhythmias, a basic scheme that classifies disease complexity into simple, moderate, or severe forms is the most useful metric in stratifying thromboembolic risk. Standard CHADS2 and CHA2DS2-VASc
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scores are generally low and not predictive of residual thromboembolic events in this young population. In contrast, major bleeds, which are significantly higher with anticoagulation
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compared to antiplatelet therapy, are independently associated with the HAS-BLED score. These results suggest that congenital heart disease complexity and the HAS-BLED score
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should be considered when balancing the risks and benefits of thromboprophylaxis for atrial
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arrhythmias in congenital heart disease.
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ACCEPTED MANUSCRIPT ACKNOWLEDGMENTS The authors wish to thank the followings individuals for their assistance: Marie-Claude
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Villeneuve, MSc and Dominique Johnson, PhD (Montreal Health Innovations Coordinating Center); Aynun Naher, MBBS, MS (Oregon Health and Science University); William R.
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Davidson, Jr, MD, John J. Kelleman, MD, Elizabeth E. Adams, DO, and Dena Jefferson RN, BSN, CCRC (Hershey Medical Center); Morgan Hindes (Children's Hospital of Pittsburgh), Ryan Williams and Gwen Derk (University of California, Los Angeles); Michael G. Earing,
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MD, Jonathan W. Cramer, MD and Emily Reinhardt, RN (Medical College of Wisconsin);
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and Meena Fatah (Hospital for Sick Children, Toronto).
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ACCEPTED MANUSCRIPT FIGURE LEGENDS
Figure 1. Freedom from thromboembolic events according to congenital heart disease
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complexity
Figure 2. Freedom from A) major bleeds and B) major and minor bleeds combined
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according to thromboprophylactic therapy
18
ACCEPTED MANUSCRIPT TABLES Table 1. Baseline characteristics Anticoagulant Therapy N=262 34.2±18.1 117 (44.7) 25.0±6.9
89 (18.5) 166 (34.4) 227 (47.1)
33 (18.1) 57 (31.3) 92 (50.5)
50 (19.1) 92 (35.1) 120 (45.8)
6 (15.8) 17 (44.7) 15 (39.5)
2.0±1.4
2.0±1.3
2.0±1.4
2.0±1.5
46 (9.5) 297 (61.6) 139 (28.8)
18 (9.9) 110 (60.4) 54 (29.7)
19 (7.3) 162 (61.8) 81 (30.9)
9 (23.7) 25 (65.8) 4 (10.5)
69 (14.3) 23 (4.8) 15 (3.1) 31 (6.4) 36 (7.5) 8 (1.7) 36 (7.5)
26 (14.3) 6 (3.3) 7 (3.8) 11 (6.0) 14 (7.7) 2 (1.1) 12 (6.6)
41 (15.6) 15 (5.7) 7 (2.7) 17 (6.5) 20 (7.6) 6 (2.3) 24 (9.2)
2 (5.3) 2 (5.3) 1 (2.6) 3 (7.9) 2 (5.3) 0 (0.0) 0 (0)
0.26 0.48 0.84 0.88 1.00 0.63 0.10
55.5±10.6
53.7±15.5
54.1±12.7
0.47
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23.2±15.9 20 (52.6) 22.0±6.2
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MA
ED
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54.4±11.3
Neither N=38
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Antiplatelet Therapy N=182 30.7±17.7 81 (44.5) 23.8±6.3
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Age, years Female, N (%) Body mass index, kg/m2 Congenital heart disease complexity, N (%) Simple Moderate Severe Number of cardiac surgeries Qualifying atrial tachyarrhythmia, N (%) Non-automatic focal atrial tachycardia Intra-atrial reentrant tachycardia Atrial fibrillation Hypertension, N (%) Diabetes mellitus, N (%) Prior stroke or TIA, N (%) Dyslipidemia, N (%) Current smoking history, N (%) Coronary artery disease, N (%) History of congestive heart failure, N (%) Systemic ventricular ejection fraction, N (%) NYHA functional class, N (%) I II III IV CHADS2 score*, N (%) 0 1 2 ≥3 CHA2DS2-VASc score†, N (%) 0 1 2 3 ≥4
All Patients N=482 32.0±18.0 218 (45.2) 24.3±6.7
Overall P-value <0.001 0.64 0.06 0.58
0.97 0.006
0.52
288 (59.8) 146 (30.3) 44 (9.1) 4 (0.8)
114 (62.6) 53 (29.1) 14 (7.7) 1 (0.5)
137 (56.1) 84 (32.1) 28 (10.7) 3 (1.1)
27 (71.1) 9 (23.7) 2 (5.3) 0 (0.0)
365 (75.7) 83 (17.2) 28 (5.8) 6 (1.2)
141 (77.5) 27 (14.8) 11 (6.0) 3 (1.6)
191 (72.9) 52 (19.8) 16 (6.1) 3 (1.2)
33 (86.8) 4 (10.5) 1 (2.6) 0 (0.0)
198 (41.1) 196 (40.7) 60 (12.4) 24 (5.0) 4 (0.8)
75 (41.2) 77 (42.3) 18 (9.9) 12 (6.6) 0 (0.0)
107 (40.8) 100 (38.2) 40 (15.3) 11 (4.2) 4 (1.5)
16 (42.1) 19 (50.0) 2 (5.3) 1 (2.6) 0 (0.0)
0.63
0.40
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ACCEPTED MANUSCRIPT HAS-BLED score‡, N (%) 0 1 ≥2
0.42 349 (72.4) 100 (20.7) 33 (6.8)
133 (73.1) 36 (19.8) 13 (7.1)
183 (69.8) 60 (21.9) 19 (7.3)
33 (86.8) 4 (10.5) 1 (2.6)
TIA denotes transien t ischemi c attack; NYHA, New York Heart Associa tion
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SC RI
PT
Resting oxygen saturation, % 94.3±7.8 93.9±7.7 94.2±8.3 97.3±2.6 0.23 QRS duration, ms 122±35 120±34 124±35 125±33 0.51 Systemic venous atrium transverse 51±14 50±9 53±15 41±6 0.35 diameter, mm Pulmonary venous atrium 43±11 43±10 44±11 36±15 0.06 anteroposterior diameter, mm Pacemaker, N (%) 180 (37.3) 66 (36.3) 103 (39.3) 11 (28.9) 0.44 Implantable cardioverter35 (7.3) 16 (8.8) 15 (5.7) 4 (10.5) 0.28 * The defibrillator, N (%) CHADS Serum hemoglobin, g/L 140.8±25.1 140.6±23.8 141.9±25.5 132.4±28.9 0.28 2 score Hematocrit, % 0.41±0.08 0.41±0.07 0.42±0.08 0.40±0.09 0.59 assigns Serum sodium, mmol/L 138.7±3.2 138.7±3.5 138.8±2.8 138.3±4.0 0.79 one Serum creatinine, μmol/L 83.8±41.9 81.7±26.7 87.3±50.5 66.9±25.4 0.10 point each to history of congestive heart failure, hypertension, and diabetes mellitus, one point for age >75 years, and two points for prior stroke, TIA, or systemic emboli. †
ED
The CHA2DS2-VASc score assigns one point each to history of congestive heart failure, hypertension, diabetes mellitus, vascular disease, and female sex, one point for age 65 to 74 years, two points for age ≥75 years, and two points for prior stroke, TIA, or systemic emboli. ‡
AC
CE
PT
The HAS-BLED score assigns one point each for history of hypertension, renal disease, liver disease, history of stroke, prior major bleeding or predisposition to bleeding, labile INR, age >65 years, antiplatelet or non-steroidal anti-inflammatory drug, and alcohol consumption (>8 drinks/week) or illicit drug use.
20
All Patients N=482
Antiplatelet Therapy N=182
42 (8.7)
18 (9.9)
PT
Anticoagulant Therapy N=262
Neither N=38
23 (8.8)
1 (2.6)
6 (3.3)
8 (3.1)
0 (0.0)
1 (0.2)
0 (0.0)
1 (0.4)
0 (0.0)
Peripheral arterial
2 (0.4)
0 (0.0)
2 (0.8)
0 (0.0)
Intracardiac thrombosis
20 (4.1)
10 (5.5)
9 (3.4)
1 (2.6)
Pulmonary
5 (1.0)
2 (1.1)
3 (1.1)
0 (0.0)
5 (2.7)
11 (4.2)
1 (2.6)
19
5
13
1
2 (0.4)
1 (0.5)
1 (0.4)
0 (0.0)
7 (1.5)
1 (0.5)
6 (2.3)
0 (0.0)
15 (3.1)
3 (1.6)
11 (4.2)
1 (2.6)
CE
ACCEPTED MANUSCRIPT
14 (2.9)
Renal emboli
23 (4.8)
10 (5.5)
12 (4.6)
1 (2.6)
25
10
14
1
Spontaneous skin hematoma, N (%)
2 (0.4)
2 (1.1)
0 (0.0)
0 (0.0)
Spontaneous epistaxis, N (%)
7 (1.5)
3 (1.6)
3 (1.1)
1 (2.6)
Macroscopic hematuria, N (%)
4 (0.8)
0 (0.0)
4 (1.5)
0 (0.0)
Spontaneous rectal bleeding, N (%)
4 (0.8)
2 (1.1)
2 (2.3)
0 (0.0)
Gingival bleeding for more than 5
1 (0.2)
0 (0.0)
1 (0.4)
0 (0.0)
2 (0.4)
0 (0.0)
2 (2.3)
0 (0.0)
1 (0.2)
0 (0.0)
1 (0.4)
0 (0.0)
6 (1.2)
4 (2.2)
2 (2.3)
0 (0.0)
Number of deaths
22 (4.6)
6 (3.3)
15 (5.7)
1 (2.6)
Non-cardiovascular
2 (0.4)
1 (0.5)
1 (0.4)
0 (0.0)
Sepsis
2 (0.4)
1 (0.5)
1 (0.4)
0 (0.0)
20 (4.1)
5 (2.7)
14 (5.3)
1 (2.6)
8 (1.7)
3 (1.6)
5 (1.9)
0 (0.0)
7 (1.5)
21 2 (1.1)
5 (1.9)
0 (0.0)
Number of patients with
SC RI
Thromboembolic events, N (%)
Stroke or transient ischemic attack
*
Major bleeds
Number of major bleeding events Reduction in hemoglobin level ≥20 g/L,
ED
N (%)
17 (3.5)
MA
Number of patients with major bleeds, N (%)
Transfusion of at least 2 units of blood, N (%)
PT
Symptomatic bleeding in a critical area or organ, N (%) Minor bleeds*
Number of patients with minor bleeds, N (%)
AC
Number of minor bleeding events
NU
thromboembolic events
minutes, N (%) Bleeding leading to hospitalization and/or surgery, N (%) Bleeding leading to transfusion of <2 units of blood, N (%) Other bleeding considered relevant by investigator, N (%) Deaths, N (%)
Cardiovascular Sudden death of presumed arrhythmic etiology Congestive heart failure
ACCEPTED MANUSCRIPT Acute post-operative (following
3 (0.6)
0 (0.0)
2 (2.3)
1 (0.0)
2 (0.4)
0 (0.0)
2 (2.3)
0 (0.0)
cardiac surgery) Hemorrhage
*
AC
CE
PT
ED
MA
NU
SC RI
Subcategories of major and minor bleeds are not mutually exclusive
PT
Table 2. Adjudicated thromboembolic events, bleeding complications, and deaths in all patients and according to initially prescribed therapy
22
ACCEPTED MANUSCRIPT Table 3. Factors associated with thromboembolic events in univariable and multivariable Cox regression analyses *
Per unit increase in category (i.e., from simple to moderate to severe)
Univariable analyses Anticoagulation Age, year Complexity of congenital heart disease* Number of cardiac surgeries Body mass index, kg/m2 Oxygen saturation, % Pacemaker Multivariable analysis Anticoagulation Complexity of congenital heart disease*
NU
1.01 0.976 3.62 1.32 0.91 0.96 1.73
PT
Hazard Ratio 95% Confidence Interval P-value
AC
CE
PT
ED
MA
1.07 3.47
23
0.55-1.86 0.957-0.996 1.83, 7.18 1.07-1.62 0.85-0.99 0.92-1.00 0.94-3.20
0.97 0.02 <0.001 0.008 0.02 0.05 0.08
0.58-1.98 1.75-6.87
0.82 <0.001
SC RI
Variable
ACCEPTED MANUSCRIPT FIGURES
AC
CE
PT
ED
MA
NU
SC RI
PT
Figure 1
24
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
MA
NU
SC RI
PT
Figure 2
25