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Importance听 The adverse outcomes associated with atrial fibrillation (AF) have been studied in predominantly white cohorts. Racial differences in outcomes associated with AF merit continued investigation.

Objective听 To evaluate the race-specific associations of AF with stroke, heart failure, coronary heart disease (CHD), and all-cause mortality in a community-based cohort.

Design, Setting, and Participants听 The Atherosclerosis Risk in Communities (ARIC) Study is a prospective, observational cohort. From 1987 through 1989, the ARIC Study enrolled 15鈥�792 men and women and conducted 4 follow-up examinations (2011-2013) with active surveillance for vital status and hospitalizations. Race was determined by self-report and categorized as white, black, or other.

Main Outcomes and Measures听 Atrial fibrillation (adjudicated using electrocardiograms, hospital discharge codes, and death certificates), stroke, heart failure, CHD, and mortality.

Results听 After exclusions, 15鈥�080 participants (mean [SD] age, 54.2鈥塠5.8] years; 8290 women [55.5%]; 3831 black individuals [25.4%]) were included in this analysis. During a mean鈥�(SD) follow-up of 20.6鈥�(6.2) years, there were 2348 cases of incident AF. The incident rates of AF per 1000 person-years were 8.1 (95% CI, 7.7-8.5) in white individuals and 5.8 (95% CI, 5.2-6.3) in black individuals. The rates of stroke, heart failure, CHD, and mortality were higher in black individuals with AF than white individuals with AF. The association of AF with these outcomes, estimated with rate differences (rate of the end point in those with AF minus the rate in those without AF per 1000 person-years), also differed by race. The rate difference for stroke in individuals with AF was 10.2 (95% CI, 6.6-13.9) in white individuals and 21.4 (95% CI, 10.2-32.6) in black individuals. For heart failure and CHD, the rate differences were 1.5- to 2.0-fold higher in black individuals than white individuals. White individuals with AF had a rate difference of 55.9 (95% CI, 48.1-63.7) for mortality compared with black individuals, who had a rate difference of 106.0 (95% CI, 86.0-125.9).

Conclusions and Relevance听 In the prospective ARIC Study, the outcome of AF on the rates of stroke, heart failure, CHD, and mortality was considerably larger in black individuals than white individuals. These results indicate the vulnerability and increased risk in black individuals with AF. Continued investigation of racial differences in AF and its related adverse outcomes are essential to identify and mitigate racial disparities in the treatment of AF.

Atrial fibrillation (AF) is a common cardiac arrhythmia with significant adverse outcomes and high social and medical costs.¹ In the United States, AF affects approximately 1% of the adult population and more than 5% of those 65 years and older.^2,3 Atrial fibrillation has been associated with increased risks of stroke by 5.0-fold, heart failure by 3.0-fold, and mortality by 2.0-fold.^4-7 The study of AF and its associated clinical adverse outcomes has been conducted predominantly in cohorts with participants of mostly white race.

Several factors contribute to the more limited study of AF in racially or ethnically diverse cohorts compared with white cohorts. Multiple health care registries, databases, and community-based studies^8-14 have identified differences in the prevalence of AF by race, such that reports^8-14 have consistently identified AF as being less prevalent in racial and ethnic minorities. In addition, it is well established that ethnic and racial minorities have less participation and recruitment in cardiovascular studies and trials compared with white individuals.¹⁵ The deficit of minority participation in clinical studies extends to AF because many landmark trials in AF have not reported or had limited enrollment of ethnic or racial minorities.¹⁶ However, alongside the established racial differences in AF prevalence are critical differences in the treatments to prevent outcomes associated with AF, particularly stroke.^11,17-19

Estimating the relations of AF to adverse outcomes in nonwhite cohorts has evident public health relevance. Observational cohorts may identify racial differences. Understanding such differences may guide interventions to address and mitigate disparities. To improve our understanding of the morbidity associated with AF in black individuals, we examined data from the Atherosclerosis Risk in Communities (ARIC) Study,²⁰ a large, mostly biracial, community-based cohort. Specifically, we evaluated and compared the race-specific associations of AF with stroke, heart failure, coronary heart disease (CHD), and mortality between white and black individuals in this cohort.

Box Section Ref ID

The ARIC Study is a community-based cohort designed to investigate determinants of atherosclerosis and cardiovascular disease in the general population. Detailed methods have been published elsewhere.²⁰ Briefly, from 1987 through 1989, a total of 15鈥�792 men and women aged 45 to 64 years were recruited from 4 communities in the United States: Forsyth County, North Carolina; Jackson, Mississippi; northwest suburbs of Minneapolis, Minnesota; and Washington County, Maryland. Participants were followed up prospectively through examination 4 (2011-2013). Participants in the Minneapolis and Washington County sites were mostly white individuals, whereas only black individuals were recruited in Jackson. In addition to the baseline examination, the ARIC Study has conducted 4 follow-up examinations (1990-1992, 1993-1995, 1996-1998, and 2011-2013) along with annual telephone calls to determine vital status and obtain information on hospitalizations during the previous year. Ongoing surveillance of local hospitals has simultaneously been used to identify hospitalizations of ARIC Study participants, and trained abstractors have collected information on discharge diagnoses.

In the present analysis, we excluded the ARIC Study participants with prevalent AF at baseline (n鈥�=鈥�37), those missing baseline electrocardiograms (ECGs) (n鈥�=鈥�242), those lacking data on essential covariates (n鈥�=鈥�330), and those of race other than white or black (n鈥�=鈥�103). After exclusions, 15鈥�080 participants were included in the present analysis. The ARIC Study has been approved by institutional review boards at participating institutions, and all participants provided written informed consent.

Ascertainment of AF in the ARIC Study has been previously described^12,21 and conducted using 3 methods: study ECGs, hospital discharge codes, and death certificates. Standard, 10-second, 12-lead ECGs were obtained at baseline and at each of the subsequent follow-up examinations. Tracings were performed in the supine position using MAC PC Personal Cardiographs (Marquette Electronics Inc) and transmitted electronically to the ARIC ECG Reading Center (Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina), where they underwent automated reading and coding. Tracings with AF were reviewed by a cardiologist. Incident AF was identified from hospitalizations or death certificates using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 427.31 or 427.32. Incident AF in the setting of cardiothoracic surgery was not defined as AF in the ARIC Study. Use of discharge coding for AF identification has been reported as having a median positive predictive value of 89% across multiple studies.²²

The outcomes of stroke, heart failure, and CHD were determined by physicians using validated adjudication protocols. Stroke was defined as sudden neurologic insult of 24-hour duration or longer or a neurologic insult associated with death without evidence of a nonstroke cause of death.²³ Stroke events were ascertained from surveillance of ARIC Study participant hospitalization using ICD-9-CM codes 430 through 438 through 1997 and codes 430 through 436 thereafter. Strokes were classified by physician review and computer algorithm with standardized criteria and determined as hemorrhagic or ischemic. Heart failure was ascertained by review of hospitalization records and death certificates for a heart failure diagnosis. Specifically, incident cases with an ICD-9-CM code of 428 (428.0-428.9) or International Statistical Classification of Diseases, 10th Revision code I50 were classified as heart failure.²⁴ Coronary heart disease was determined using study surveillance and adjudicated as previously described.²⁵ Symptoms, biomarkers, and ECGs were incorporated into a computerized algorithm.²⁶ Disagreement between discharge coding and computer algorithm was adjudicated by the ARIC Mortality and Morbidity Classification Committee. For the present analysis, CHD was defined as definite or probable myocardial infarction or definite fatal CHD. All-cause mortality was determined as identification of death by telephone contact with participant proxy, obituaries, hospital records, death certificates, or vital statistics from the National Death Index.

Age, race (categorized as white, black, or other), smoking status, and highest level of education were provided by self-report. Body mass index was calculated as weight in kilograms divided by height in meters squared. Hypertension was defined as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure higher than 90 mm Hg, or use of medications to treat hypertension. Blood samples were obtained after individuals had fasted for 8 hours. Diabetes was determined by self-report of a physician diagnosis of diabetes, nonfasting blood glucose level of 200 mg/dL or higher, fasting blood glucose level of 126 mg/dL or higher (to convert glucose to millimoles per liter, multiply by 0.0555), or use of insulin or other oral hypoglycemic medications. Measurement of serum creatinine in the ARIC Study has been described previously.²⁷ Estimated glomerular filtration rate at visits 1, 2, and 4 was calculated from serum creatinine as described by the Chronic Kidney Disease Epidemiology Collaboration,²⁸ and a value less than 60 mL/min/1.73 m² was used to define baseline chronic kidney disease. Prevalent chronic obstructive pulmonary disease, stroke, and CHD at baseline were ascertained by self-report history of a diagnosis by a physician. Prevalent heart failure was identified as previously described using the Gothenburg criteria and review of medications.²⁴ Incident chronic kidney disease and chronic obstructive pulmonary disease were defined using standardized methods articulated by the Centers for Medicare & Medicaid Chronic Condition Data Warehouse.²⁹

We determined the distributions of continuous and categorical variables. The primary analysis was the relation of incident AF to the outcomes of stroke, heart failure, CHD, and all-cause mortality. We examined AF as a time-dependent exposure because we considered that increased duration of AF would contribute toward the risk of the outcome. To limit confounding by the covariates changing over time, we updated covariates across examinations. Covariates that could not be updated were used from the most immediate examination before the diagnosis of AF. We determined the age- and sex-standardized incidence of AF per 1000 person-years by race and examined the rates of the outcomes according to AF status and stratified by race. We calculated the rate ratio and rate difference of each outcome comparing participants with and without AF. We then examined the risk of the outcomes of stroke, heart failure, CHD, and mortality associated with incidence of AF in multivariable Cox proportional hazards models separately by race. For the analysis that examined stroke as an outcome, we additionally excluded participants with prevalent stroke (n鈥�=鈥�269), yielding a sample size of 14鈥�811. For heart failure, we excluded participants with prevalent heart failure (n鈥�=鈥�686), yielding a sample size of 14鈥�394. For CHD, we excluded participants with prevalent CHD (n鈥�=鈥�722), yielding a sample size of 14鈥�358. We examined the cumulative incidence of AF prospectively and constructed Kaplan-Meier curves for each outcome event stratifying by race. Study participants contributed observation time in the cohort without AF until the time of incident AF, when they began contributing toward the cohort with AF. All analyses were adjusted initially for age and sex (model 1); then for age, sex, educational level, body mass index, smoking status, hypertension, diabetes, chronic kidney disease, estimated glomerular filtration rate, chronic obstructive pulmonary disease, and cardiovascular disease, including prevalent CHD, stroke, and heart failure (model 2); and then adjusted for all covariates as time-dependent (model 3).

After exclusions, at the baseline ARIC Study examination there were 15鈥�080 participants (Table 1) with a mean鈥�(SD) age of 54.2鈥�(5.8) years. Participants included 8290 women (55.5%) and 3831 black individuals (25.4%). Noteworthy racial differences in covariates at the baseline examination included body mass index (mean [SD], 27.0鈥塠4.9] in white individuals and 29.6鈥塠6.2] in black individuals) and the higher prevalence of hypertension and diabetes in black individuals.

Follow-up extended from the baseline examination (1987-1989) through the end of 2012. During a mean鈥�(SD) follow-up of 20.6鈥�(6.2) years, there were 2348 cases of incident AF, 1914 in white individuals with an incidence rate of 8.1 (95% CI, 7.7-8.5) per 1000 person-years and 434 in black individuals with an incidence rate of 5.8 (95% CI, 5.2-6.3) per 1000 person-years.

The age- and sex-standardized event rates per 1000 person-years stratified by race and AF status are listed in Table 2. Event rates were greater in black individuals for all outcomes in ARIC Study participants with and without AF. Overall, the association of AF with outcomes, as measured by the rate ratio, was similar in both racial groups. In both black and white individuals, stroke rates with AF were increased 5.0-fold compared with those without AF. The rate ratio for heart failure in individuals with AF was 13.7 (95% CI, 10.5-17.9) in white individuals and 9.7 (95% CI, 5.9-16.1) in black individuals compared with individuals without AF. White individuals with AF and black individuals with AF had a 6.0- to 7.0-fold increased rate of CHD than either race without AF and a 6.0-fold increased rate of all-cause mortality. The rate ratio for the association of AF with mortality was likewise 6.0-fold greater in white and black individuals with AF.

Marked racial differences were identified in examining the absolute (rather than relative) risk of outcomes associated with AF, as estimated using risk differences. The age- and sex-adjusted rate differences for stroke, heart failure, and CHD comparing black individuals with AF with those without AF were considerably greater than the estimates for white individuals. The rate difference for stroke in black individuals with AF compared with black individuals without AF was twice that of white individuals with AF. Heart failure and CHD rate differences were 1.5- to 2.0-fold higher in black individuals than the estimates for white individuals. The rate difference in black individuals with AF (rate difference, 106.0; 95% CI, 86.0-125.9) was roughly twice that of white individuals (rate difference, 55.9; 95% CI, 48.1-63.7). Figure 1 presents the rate differences by race for the 4 outcomes.

The multivariable hazard ratios for association of AF with the outcomes by race are summarized in Table 3. Atrial fibrillation was associated with more than 3 times the risk of CHD in black individuals with AF compared with black individuals without AF. Atrial fibrillation in black individuals was associated with a more than 4.0-fold increased risk of mortality compared with black individuals without AF. In contrast, AF in white individuals was associated with a 3.6-fold increased risk of all-cause mortality.

Figure 2 shows the Kaplan-Meier curve by AF status separately in white and black individuals. In all outcomes, black individuals without AF have lower event-free survival rates compared with white individuals without AF. With AF, black individuals similarly have lower event-free survival rates than white individuals. The curves for stroke in those with AF (Figure 2A) diverge early and rapidly. In Figure 2B, black individuals with AF rapidly accumulate heart failure events, stabilizing after approximately 15 years. There is a similarly steeper descent in black individuals with AF and CHD (Figure 2C) compared with white individuals. Black individuals with AF had a rapid accumulation of mortality events (Figure 2D). The log-rank tests for comparing events by race were all statistically significant (P鈥�<鈥�.001 for all outcomes).

We examined the associations of AF with adverse outcomes in the ARIC Study extending from the baseline examination to more than 20 years of follow-up. Consistent with a prior report¹² from the ARIC Study, we observed a higher incidence of AF in white individuals compared with black individuals. Both white and black individuals with AF had markedly increased risks of the outcomes of stroke, heart failure, CHD, and all-cause mortality. We appreciated that the estimates of the associations with the outcomes had consistent overlap in black and white individuals. Importantly, the rate differences (the difference in incidence rates in those with and without AF) of the outcomes differed by race. We observed that black individuals with AF had an approximately 1.5- to 2.0-fold greater rate difference for each outcome than white individuals with AF. Our results indicate that black ARIC Study participants with AF are at considerably greater risk for associated adverse outcomes than white individuals with AF.

The distinction between the concepts of racial differences and disparities has been well articulated.³⁰ Racial differences are independent of social factors, whereas racial disparities result from biases or practices with a systemic origin. Whether our findings may be described as racial differences or racial disparities merits attention. We have identified clear racial differences in adverse outcomes associated with AF but are not able to assert whether such findings are the result of racial disparities. The ARIC Study is a prospective, observational cohort; hence, we are not able to dissect or identify the causes of our findings. We consider that our results contribute toward an increasing number of observations describing significant racial differences in AF outcomes and complement the extant literature that suggests disparities in AF treatment.^8,18,19,31

The racial differences in the outcomes examined in this study have been demonstrated outside the study of AF. In the ARIC Study and other cohorts,^32,33 blacks have been previously found to have a greater incidence of the study outcomes. There has been limited study of racial differences in AF. In a large, hospital-based registry (Get with the Guidelines鈥揌eart Failure) of black and white patients with heart failure, racial differences in in-hospital mortality were not observed.⁸ A large study¹¹ of Medicare beneficiaries identified that black individuals with AF have a 2.0-fold greater incidence of strokes than white individuals and along with community-based and registry studies^8,11,18 identified that black individuals have concomitant decreased treatment with anticoagulation. Other literature corroborates the decreased use of anticoagulation in black individuals for stroke prevention in general.^31,34 Our investigation indicates that racial differences in the outcome of AF on adverse outcomes extend beyond stroke to other conditions associated previously with AF, specifically, heart failure, CHD, and all-cause mortality. These findings are derived from an established community-based cohort with carefully adjudicated cardiovascular end points and long follow-up.

Our findings have important public health implications. First and most immediate is the need to bolster prevention of adverse outcomes in black individuals with AF. Our results indicate the increased vulnerability of black individuals to the outcomes of stroke, CHD, heart failure, and mortality relative to white individuals. Racial disparities in outcomes associated with AF are not cited in professional statements and guidelines for treating AF and preventing its complications.^35,36 The inclusion of racial disparities in AF as part of such documents may contribute toward improved treatment of AF in black individuals and other racial and ethnic minorities. It is further imperative that registries, such as the Get with the Guidelines鈥揂FIB,³⁷ increase our understanding of racial differences in outcomes associated with AF and optimize identifying the systemic causes for racial disparities.

Second, our results underscore the necessity of improving AF prevention in black individuals because the social and medical costs of the associated morbidity are high. Much has been made of the decreased incidence of AF in black individuals despite the increased prevalence of risk factors. The observation has been cited by the most recent professional society guidelines on AF evaluation and management.³⁶ A priority is now to address the high public health costs of AF in black individuals. Efforts need to focus on detecting and addressing AF in black individuals to prevent its associated complications.

Third, black individuals and other racial and ethnic minorities have had markedly limited participation in clinical trials in AF. The AF Follow-up Investigation of Rhythm Management (n鈥�=鈥�4060) included only 263 black individuals (<7% of the study cohort).³⁸ Black individuals comprise 1% to 4% of participants in AF registries.^39,40 Pivotal studies^41-43 of AF rate and rhythm control have unknown generalizability to black individuals. The sentinel clinical trials of novel oral anticoagulants included uniformly limited numbers of participants with nonwhite race or ethnicity. For example, less than 2% of trial participants assessing the safety of rivaroxaban were of black race,⁴⁴ and subgroup analyses by race have not been uniformly reported in the novel oral anticoagulant trials.⁴⁵ Increased enrollment of racial and ethnic minorities would strengthen statistical power and enhance generalizability of trial findings to vulnerable populations. Furthermore, improving minority recruitment and enrollment to such studies is central to understanding mechanisms for disparities in AF.

Fourth, it is recognized that AF identification in black individuals has been challenging and may rely on the method of detection and ascertainment.⁴⁶ Broader initiatives with contemporary monitoring will improve AF identification and may challenge the notion of racial differences in AF prevalence. Increased surveillance of AF in black individuals may also enhance recruitment to clinical trials and registries.

Our analysis has several strengths, including the long-term, prospective follow-up conducted in the ARIC Study, along with consistent ascertainment and adjudication of AF and the studied outcomes. The analysis is further strengthened by inclusion of more than 14鈥�000 participants and the generalizability enhanced by the geographic diversity of ARIC Study participant sites.

There are important limitations to the analysis that also merit attention. First, AF misclassification was possible. Reliance on ICD coding may have resulted in incomplete identification of participants with AF. We would expect that misclassification of AF status by ICD codes would be nondifferential with respect to the outcomes examined in this study, biasing our results toward the null. Second, subclinical AF, not recognized as a clinical diagnosis and hence not recorded using ICD coding, may also have been present in ARIC Study participants. It is possible that such individuals would be healthier and less likely to experience hospitalization. Third, although the ARIC Study participants come from 4 distinct sites, the black participants included in this study are primarily recruited from Mississippi. The generalizability of our findings to black individuals living in other geographic regions in the United States is limited. Fourth, we did not adjust for treatments of AF, such as anticoagulation, cardioversion, or medications, which may confound the relation of AF and the examined outcomes. Likewise, we are not able to exclude residual confounding, particularly from exposures associated with adverse outcomes in AF (eg, left atrial volume and sleep-disordered breathing). Fifth, the ARIC Study is a predominantly biracial, community-based cohort, and as such generalizability to other races or ethnicities is also limited.

We observed markedly increased rates of stroke, heart failure, CHD, and mortality in black individuals with AF compared with white individuals in the prospective, community-based ARIC Study. Our results contribute toward understanding the significant racial differences in black and white individuals with AF. Further study must now address the mechanisms for such differences to improve treatment of AF and prevent complications. Likewise, continued investigation of the causes and origins for such racial differences may identify racial disparities and suggest approaches to address and mitigate them.

Accepted for Publication: March 24, 2016.

Corresponding Author: Jared W. Magnani, MD, MSc, Division of Cardiology, Department of Medicine, UPMC Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA 15213 (magnanij@pitt.edu).

Published Online: June 22, 2016. doi:10.1001/jamacardio.2016.1025.

Author Contributions: Drs Magnani and Alonso had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Magnani, Norby, Soliman, Alonso.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Magnani.

Critical revision of the manuscript for important intellectual content: Norby, Agarwal, Soliman, Chen, Loehr, Alonso.

Statistical analysis: Magnani, Norby.

Obtained funding: Magnani, Alonso.

Administrative, technical, or material support: Magnani, Agarwal, Alonso.

Study supervision: Alonso.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: The ARIC Study is performed as a collaborative study supported by contracts HHSN268201100005C, HHSN268201100006C, HHSN 268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN 268201100012C from the National Heart, Lung, and Blood Institute. This study was additionally funded by grant 16EIA26410001 from the American Heart Association and grant R01-HL122200 from the National Heart, Lung, and Blood Institute. This work was supported by grant 2015084 from the Doris Duke Charitable Foundation (Dr Magnani).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Additional Contributions: We thank the staff and participants of the ARIC Study for their important contributions.