ÌÇÐÄvlog

ImportanceÌý A substantial proportion of patients with atrial fibrillation (AF) die of noncardiovascular causes, and recent studies suggest a link between AF and cancer.

ObjectiveÌý To evaluate the associations between AF and cancer in a large, long-term prospective cohort study.

Design, Setting, and ParticipantsÌý In this cohort study, a total of 34 691 women 45 years or older and free of AF, cardiovascular disease, and cancer at baseline were prospectively followed up between 1993 and 2013, for incident AF and malignant cancer within the Women’s Health Study, a randomized clinical trial of aspirin and vitamin E for the prevention of cardiovascular disease and cancer. Cox proportional hazards models using time-updated covariates were constructed to assess the association of new-onset AF with subsequent cancer and to adjust for potential confounders. Data analysis was performed from December 2014 to May 2015.

ExposureÌý New-onset AF.

Main Outcomes and MeasuresÌý Incident malignant cancer confirmed by an end point committee.

ResultsÌý During a median follow-up of 19.1 years of 34 691 study participants (interquartile range [IQR], 17.6-19.7 years), new-onset AF and malignant cancer were confirmed among 1467 (4.2%) and 5130 (14.8%) participants, respectively. Median age at baseline among participants with new-onset AF and new-onset cancer during follow-up was 58 years (IQR, 52-64 years) and 55 years (IQR, 50-61 years), respectively. Atrial fibrillation was a significant risk factor for incident cancer in age-adjusted (hazard ratio [HR], 1.58; 95% CI, 1.34-1.87; P < .001) and multivariable-adjusted (HR, 1.48; 95% CI, 1.25-1.75; P < .001) models. The relative risk of cancer was highest in the first 3 months after new-onset AF (HR, 3.54; 95% CI, 2.05-6.10; P < .001) but remained significant beyond 1 year after new-onset AF (adjusted HR, 1.42; 95% CI, 1.18-1.71; P < .001), and a trend toward an increased cancer mortality was observed (adjusted HR, 1.32; 95% CI, 0.98-1.79; P = .07). In contrast, among women with new-onset cancer, the relative risk of AF was increased only within the first 3 months (HR, 4.67; 95% CI, 2.85-7.64; P < .001) but not thereafter (HR, 1.15; 95% CI, 0.95-1.39; P = .15).

Conclusions and RelevanceÌý In this large, initially healthy cohort, women with new-onset AF had an elevated cancer risk beyond 1 year of AF diagnosis. Shared risk factors and/or common systemic disease processes might underlie this association.

Atrial fibrillation (AF), the most common cardiac arrhythmia,^1,2 is associated with an increased risk of major cardiovascular complications.^3-5 A previous study⁶ suggested that patients with AF also face a substantial risk of death from noncardiovascular causes. In a contemporary AF population treated with oral anticoagulation, more than one-third of all deaths were owing to noncardiovascular causes, and malignant tumors accounted for the largest proportion of these deaths.⁶

In a retrospective case-control study,⁷ patients with cancer were more likely to have AF documented at the time of their diagnosis. Recent registry data suggested that an AF diagnosis is associated with higher-than-expected cancer incidence rates, although an internal control group was lacking in this study.⁸ Prior studies^9-11 had limited ability to control for shared risk factors, which could underlie the association. In addition, the temporal nature of the association between AF and cancer is difficult to discern in retrospective study designs, especially given the potential latency of both diagnoses.

An increased risk of malignant cancer among individuals with AF would be of substantial public health importance given the high prevalence and associated costs of both disorders. We therefore examined the associations between AF and cancer in a large, well-characterized prospective cohort of initially healthy women who were followed up for up to 20.4 years.

Box Section Ref ID

The study design of the Women’s Health Study, a completed, randomized clinical trial that examined the effects of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer, has been described in detail previously.^12,13 Between 1993 and 1995, a total of 39 876 female health professionals from the United States who were 45 years or older and free of cardiovascular disease and cancer at baseline were randomized to receive 100 mg of aspirin every other day, 600 IU of vitamin E every other day, both agents, or placebo. Randomized treatment ended on March 31, 2004, and all women were subsequently invited to participate in an observational cohort study. Data analysis was performed from December 2014 to May 2015. Written informed consent was obtained from all participants. The institutional review board of Brigham and Women’s Hospital approved the study.

For the purpose of this analysis, we excluded women with a history of AF (n = 879), malignant cancer (n = 52), or a major cardiovascular event (n = 56) before randomization. Women lost to follow-up during the randomized trial period (n = 1243 [3.1%]) or who opted out of the observational follow-up (n = 2955 [7.4%]) were also excluded because of the inability to reliably confirm AF and subsequent events in these women, as described below. However, the number of self-reported AF events in the excluded subpopulation was only 129. The final study population consisted of 34 691 women (87.0%).

Confirmation of AF in the Women’s Health Study has been described previously.^14,15 Women were asked to report diagnoses of incident AF at baseline, at 48 months, and then on each questionnaire thereafter. In 2006, we systematically collected permission to review medical records of women who indicated at least 1 AF episode on any questionnaire between 1993 and 2006. After 2006, medical records were reviewed biannually if AF was reported on subsequent questionnaires. For deceased participants who had reported AF, family members were contacted to obtain consent and additional details for event confirmation. All medical records were reviewed by an end point committee of cardiologists (D.C., J.A.W., R.K.S., and C.M.A.) to confirm a self-reported AF diagnosis according to predefined criteria. Electrocardiographic AF documentation or a medical report that documented a diagnosis of AF was the criterion used for AF confirmation. The date of AF onset was set as the earliest date in the medical records when AF documentation was believed to have occurred. Only confirmed AF events are included in this study. The AF confirmation rate by medical record review was 86%.

The most severe AF pattern within 2 years of AF onset was used to classify women as having paroxysmal or nonparoxysmal AF.¹⁶ Paroxysmal AF was defined as self-terminating AF that lasted less than 7 days and did not require cardioversion.^16,17

Information on demographics, risk factors, and study outcomes was obtained from questionnaires distributed every 6 months during the first year and every 12 months thereafter. A large number of covariates were assessed at study entry and at several points of follow-up. Race/ethnicity was self-reported as white, black, Hispanic American, Asian American, or other.

Cancer ascertainment in the Women’s Health Study has been described.¹⁸ When cancer was reported by questionnaire or death certificate, written consent for medical record review was obtained from the participant or family members if the participant was deceased. Subsequently, medical records were collected from hospitals or treating physicians. An end point committee of physicians adjudicated all end points according to predefined criteria. Reports of cancer were confirmed on the basis of pathology or cytology reports or rarely based on strong clinical and radiologic or laboratory marker evidence when pathology or cytology review was not conducted. The date of cancer onset was usually set as the diagnosis confirmation date on the histology report. The primary cancer end point for the Women’s Health Study was any invasive cancer, excluding nonmelanoma skin cancer. Secondary cancer end points included the incidence of breast, colorectal, and lung cancer. The cancer confirmation rate by medical record review was 82%.

Deaths were usually reported by family members or postal authorities or ascertained through the National Death Index. A death was attributable to cancer if it was a consequence of the disease itself or of treatment of the disease, as judged by the end point committee.

Baseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ² tests for categorical variables. Person-years of follow-up were calculated from the date of return of the baseline questionnaire to the occurrence of first end point, death, loss to follow-up, or October 1, 2013, whichever came first.

To compare the risk of incident cancer among women with and without new-onset AF, we calculated hazard ratios (HRs) and 95% CIs using multivariable, time-varying Cox proportional hazards models adjusted for age, randomized treatment assignment, educational level, race/ethnicity, and height at study entry and time-dependent measures for body mass index (calculated as the weight in kilograms divided by height in meters squared), hypertension, hypercholesterolemia, diabetes mellitus, smoking, number of cigarettes smoked per day, alcohol consumption, physical activity, hormone replacement therapy, presence of a recent breast (mammography) or colon cancer (colonoscopy or sigmoidoscopy) screening test, and incident nonfatal cardiovascular events (congestive heart failure, myocardial infarction, or stroke). Categorical variables were entered in the regression models as indicated in Table 1.

We performed several additional analyses. First, to determine whether the risk of cancer differs according to AF pattern, we constructed Cox models in which our exposure of interest was limited to either new-onset paroxysmal or nonparoxysmal AF.¹⁶ Second, to evaluate whether the risk of cancer differs according to the time elapsed after new-onset AF, we constructed multivariable models for incident cancer using 3 separate AF indicator variables for the periods 0 to 3 months, 3 to 12 months, and beyond 12 months of new-onset AF. Third, we assessed the risk of cancer subtypes after new-onset AF. Fourth, to further address the possibility of detection bias among women with an AF diagnosis, we evaluated the association between new-onset AF and subsequent cancer mortality. Finally, we assessed the robustness of our findings in 2 sensitivity analyses in which we removed the adjustment for screening procedures or only considered AF events occurring in or after 2006, when the AF validation process started. The same covariates listed above were used in all of these models.

We then assessed the risk of incident AF among women with new-onset cancer using Cox proportional hazards models with the same time-dependent covariates detailed above. We again performed an analysis in which we separately assessed the risk of incident AF before or after 3 months of new-onset cancer and before or after 1 year after new-onset cancer.

To address the issue that aspirin has been variably associated with cancer, we assessed the interactions of new-onset AF or cancer with the randomized treatment assignments, and we performed another analysis that was limited to the randomized trial period. As a final sensitivity analysis, we repeated the main models using subdistribution hazards models proposed by Fine and Gray¹⁹ to compare cumulative hazards in the presence of competing risks. All models were constructed using complete-case analyses without imputation for missing data, and no model excluded more than 902 participants (2.6%) because of missing data. All statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc). A 2-tailed P < .05 was considered to indicate statistical significance.

Baseline characteristics of the study participants stratified by AF status are given in Table 1. During a median follow-up of 19.1 years (interquartile range, 17.6-19.7 years), new-onset AF and malignant cancer were confirmed among 1467 (4.2%) and 5130 (14.8%) participants, respectively. Women with new-onset AF were significantly older and taller at baseline; had a higher body mass index; had a higher prevalence of hypertension, diabetes, and hypercholesteremia; had a lower educational level; and were more often white. Similar differences in risk factors were observed when women with and without incident cancer were compared with the exception of educational level, smoking status, and number of screening tests performed for breast and colon cancer (Table 2).

Among the 1467 women with new-onset AF, 147 (10.0%) developed cancer during subsequent follow-up. The incidence of cancer among women with and without new-onset AF was 1.4 and 0.8 events per 100 person-years of follow-up. As indicated in Table 3, AF was significantly associated with incident cancer (multivariable adjusted HR, 1.48; 95% CI, 1.25-1.75; P < .001). Neither the assignment to aspirin nor the assignment to vitamin E modified this association (P = .27 and .16 for interaction).

The risk of cancer was significantly elevated in women with paroxysmal or nonparoxysmal AF (Table 3). With respect to timing of incident cancer events, 14 and 27 cancer diagnoses were made within 3 months and 1 year of AF diagnosis. Although the risk of cancer was highest within the first 3 months of incident AF (incidence, 3.8 per 100 person-years; adjusted HR, 3.54; 95% CI, 2.05-6.10; P < .001), the risk remained significant beyond 3 months (incidence, 1.4 per 100 person-years; adjusted HR, 1.39; 95% CI, 1.17-1.66; P < .001) and beyond 1 year (incidence, 1.3 per 100 person-years; adjusted HR, 1.42; 95% CI, 1.18-1.71; P < .001) after new-onset AF. When we limited our analysis to fatal cancers using total cancer mortality as the outcome (n = 1284), new-onset AF was not significantly associated with cancer mortality in multivariable-adjusted models (HR, 1.32; 95% CI, 0.98-1.79; P = .07) during the entire range of follow-up. However, the adjusted association with cancer mortality became of borderline significance during the period 3 months (HR, 1.36; 95% CI, 1.00-1.85; P = .048) or 1 year (HR, 1.38; 95% CI, 1.00-1.90; P = .048) after new-onset AF.

Similar results were obtained when only AF events in 2006 or thereafter were considered (adjusted HR, 1.57; 95% CI, 1.13-2.18), when we removed the adjustment for screening procedures (adjusted HR, 1.47; 95% CI, 1.24-1.74), or when the analysis was restricted to the randomized trial period (adjusted HR, 1.52; 95% CI, 1.15-2.01).

Results of the models that assessed the risk of cancer subtypes are given in Table 4. The multivariable-adjusted HR associated with new-onset AF was highest and statistically significant for colon cancer, whereas multivariable-adjusted associations for lung and breast cancer were not statistically significant.

Among the 5130 women diagnosed as having cancer during follow-up, 142 (2.8%) subsequently developed AF. Of these, 16 and 21 incident AF events occurred within 3 months and 1 year of cancer diagnosis. The incidence of AF among women with and without new-onset cancer was 0.38 and 0.24 events per 100 person-years of follow-up. The HR for incident AF after cancer was 1.25 (95% CI, 1.05-1.48; P = .01) in age-adjusted and 1.20 (95% CI, 1.01-1.44; P = .04) in multivariable-adjusted models. However, this finding was primarily owing to an increased AF risk within 3 months after a cancer diagnosis, during which time the multivariable-adjusted HR for AF was 4.67 (95% CI, 2.85-7.64; P < .001). The relative risk of incident AF was not increased beyond 3 months (HR, 1.10; 95% CI, 0.91-1.32; P = .34) or beyond 1 year (HR, 1.15; 95% CI, 0.95-1.39; P = .15) after new-onset cancer. No significant interaction with randomized treatment assignment was observed (P = .70 and .12).

After a diagnosis of new-onset cancer, the risk of death was 4.2% (n = 216) at 3 months and 10.1% (n = 516) at 1 year. After a diagnosis of new-onset AF, the risk of death was 0.3% (n = 4) and 1.2% (n = 18), respectively. In the Fine and Gray subdistribution hazards models, the multivariable-adjusted HR for subsequent AF associated with a new cancer diagnosis was no longer significant (HR, 1.03; 95% CI, 0.86-1.24; P = .76). In contrast, the HR for the association between AF and incident cancer was 1.47 (95% CI, 1.23-1.75; P < .001), and the remaining associations for cancer subtypes were also not materially different from the standard models (eTable 1 and eTable 2 in the Supplement).

In this large prospective cohort study of initially healthy women, participants with new-onset AF had a significantly increased risk of incident cancer during subsequent follow-up, even after extensive multivariable adjustment. The relative increase in risk was higher within 3 months of new-onset AF, but more modest elevations in risk persisted in the long term. Of the cancer subtypes examined, AF was most strongly associated with colon cancer. In contrast, among women with new-onset cancer, the risk of AF was increased only within the first 3 months but not thereafter.

To our knowledge, our work is the first large prospective cohort study with multivariable adjustment for potential confounders on this important topic. In an AF registry, which lacked a non-AF control group and adjustment for confounders, individuals diagnosed as having new-onset AF during hospitalization had higher rates of malignant cancers compared with the national mean, with the highest rates observed for lung, kidney, and colon cancer.⁸ Similar to our findings, there was a modest absolute increase in cancer, which was highest within the first 3 months after AF diagnosis. However, the registry found relatively lower elevations in the rate of cancer after 3 months. The rapid decrease in the rate ratio after the initial 3 months suggested that most cancers were likely to have been present at the time of AF diagnosis, although the ability to estimate dates of diagnosis of AF and cancer with certainty in a hospital-based registry is limited. In contrast, in our prospective cohort in which medical records were reviewed and date of onset of both diagnoses was determined by end point committees, we found that the relative risk for malignant cancer remained significantly elevated beyond 1 year of AF diagnosis, suggesting that not all cancers were present at the time of AF diagnosis.

The potential mechanisms underlying the increased long-term risk of cancer among individuals with AF are currently unknown. Shared risk factors could be one explanation (Figure).^{10,11,14,20-23} The similar risk factor profiles among women with new-onset AF and new-onset cancer (Table 1 and Table 2) provide support to this concept. These similarities also underscore the importance of properly adjusting for these variables when evaluating this association. Although we used comprehensive multivariable adjustment, residual confounding may still persist. In particular, body mass index may not ideally represent body fat distribution and metabolic fat activity, which may be more strongly related to certain forms of cancer.²²

Alternatively, AF may be an early sign of occult cancer or an initial manifestation of a systemic process, which increases the risk for both diseases (Figure). Inflammation or oxidative stress could represent combined predisposing processes.^9,24-28 Both disease processes are associated with prothrombotic states.^29,30 In addition, apoptosis plays a potential role in AF development,³¹ and resultant disruption of the counterregulatory balance between proapoptotic and antiapoptotic factors could contribute to carcinogenesis by reducing apoptosis in cancer cells.³²

Finally, detection bias must be considered as a possible explanation for our findings. Women with new-onset AF and cancer are more exposed to health care and therefore might be more likely to have cancer or AF detected than women without these diseases. The higher short-term risk of cancer after new-onset AF could be explained by a diagnostic workup at the time of AF diagnosis. The longer-term elevation in the relative risk of cancer in patients with AF is more difficult to explain solely on the basis of detection bias. Cancer screening was not increased in patients with AF, and adjustment for screening did not affect the results. We also did not observe an analogous elevation in AF risk among surviving patients with cancer, although both diagnoses result in ongoing exposure to the health care system. The long-term use of anticoagulants among patients with AF could have led to earlier detection of cancers owing to bleeding, particularly colon cancer. However, if present, earlier detection did not translate into lower cancer mortality. In contrast, cancer mortality tended to be higher beyond 3 months of AF diagnosis. Although cancer may be detected earlier in patients with AF, their mortality related to cancer may be higher than in individuals without AF, potentially providing an explanation for the high noncardiovascular mortality documented in patients with AF.⁶

Our data may have clinical implications. Although the absolute increase in cancer risk among women with new-onset AF was modest in this low-risk cohort of initially healthy women, it may be higher in older populations with a higher burden of risk factors. These data further emphasize the importance of risk factor reduction in patients with AF to not only reduce recurrent AF episodes³³ but also potentially decrease other adverse outcomes. Additional analyses are needed to evaluate whether incorporating AF into cancer prediction models improve their performance.

Some potential limitations should be taken into account. First, the present study was performed in women who are predominantly white, and the generalizability of our findings to other populations is uncertain. Second, despite stringent follow-up methods, some asymptomatic AF cases may have gone undetected. However, if present, undetected cases should have biased our results toward the null. Nevertheless, it is unclear whether our results also apply to asymptomatic AF. Third, defining the exact date of onset of AF and cancer is challenging, especially in the context of a high short-term risk for both disease entities, and likely there is some imprecision in our date of diagnosis. Finally, although AF was assessed on a yearly basis, some other risk factors were less regularly updated, which may have led to some imprecision on the covariate status in time-updated models.

In this large prospective cohort study, new-onset AF was a significant risk factor for the subsequent diagnosis of incident cancer. The relative risk was higher early after an AF diagnosis but persisted in the long term. Future studies are needed to assess the mechanisms underlying this association and to determine whether a diagnosis of AF incrementally adds to existing cancer risk prediction algorithms. Regardless, optimal risk factor control in patients with AF seems prudent.

Accepted for Publication: February 16, 2016.

Corresponding Author: David Conen, MD, MPH, Department of Medicine, University Hospital, Petersgraben 4, 4031 Basel, Switzerland (david.conen@usb.ch).

Published Online: May 25, 2016. doi:10.1001/jamacardio.2016.0280.

Author Contributions: Dr Conen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Conen, Albert.

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

Drafting of the manuscript: Conen, Albert.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Conen, Wong, Cook.

Obtained funding: Conen, Lee, Albert.

Administrative, technical, or material support: Lee, Albert.

Study supervision: Albert.

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: This study was supported by grant HL-093613 from the National Heart, Lung, and Blood Institute (Dr Albert) and grants PP00P3_133681 and PP00P3_159322 from the Swiss National Science Foundations (Dr Conen). The Women’s Health Study was supported by grants HL-043851, HL-080467, and HL-099355 from the National Heart, Lung, and Blood Institute and grant CA-047988 from the National Cancer Institute.

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 decision to submit the manuscript for publication.