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Atrial fibrillation, venous thromboembolism, ischemic stroke, and all‐cause mortality: The Tromsø study

Abstract Background Atrial fibrillation (AF) is associated with increased risk of ischemic stroke and all‐cause mortality. Patients with AF are also at increased risk of venous thromboembolism (VTE), but information on how AF impacts VTE‐related mortality is scarce. Objectives To investigate the impact of AF on all‐cause mortality in subjects with and without a thromboembolic event (VTE or ischemic stroke). Methods We followed 29 833 participants from the Tromsø study (1994‐2008) through 2013 and recorded all deaths during follow‐up. Incident AF, VTE, and ischemic stroke were registered as time‐dependent exposures. We calculated mortality rates (MRs) by exposure during follow‐up and obtained hazard ratios (HRs) for death with 95% confidence intervals (CIs). Results A total of 2087 AF cases, 756 VTEs, and 1279 ischemic strokes were registered during a median follow‐up of 18.7 years, and 4797 people (16.1%) died. The age‐adjusted MR for participants without any event was 1.19 per 100 person‐years (PY; 95% CI, 1.15‐1.23). Compared to these participants, subjects with the joint AF + VTE exposure had a 3.7‐fold increased risk of death (HR, 3.67; 95% CI, 2.77‐4.66) in age‐ and sex‐adjusted analyses, similar to the risk observed for VTE alone (HR, 3.76; 95% CI, 3.28‐4.30). Participants with stroke had a 2.9‐fold increased risk of death (HR, 2.85; 95% CI, 2.56‐3.18), and the risk was further increased in participants with both AF and stroke (HR, 4.38; 95% CI, 3.85‐4.98). Conclusions AF was significantly associated with increased risk of death in participants with incident stroke. In contrast, concomitant AF was not associated with excess mortality risk in VTE patients.


| INTRODUCTION
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia of clinical significance, and a major contributor to the public health burden. 1,2 AF independently predicts excess morbidity and increases all-cause mortality rates 2-fold in the general population. 1,3 The most detrimental complication of AF is ischemic stroke, and the risk of stroke is up to 5-fold increased in patients with AF. 1,4 Furthermore, stroke patients with AF have increased short-and long-term case-fatality rates. 5,6 Epidemiologic studies have reported 2-fold higher mortality rates in stroke patients with AF compared to those without. 7,8 Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third-leading cause of cardiovascular death after myocardial infarction (MI) and ischemic stroke and affects 1 to 3 per 1000 persons annually in Western populations. 9,10 While the impact of AF on the risk of ischemic stroke have been known for decades, recent epidemiologic studies have demonstrated that AF also increases the risk of VTE. [11][12][13] A population-based Taiwanese study reported a 3-fold increased risk of VTE in subjects with AF. 11 Similarly, Sundbøll et al 12 found a 2.4-fold higher incidence rate for PE in the first year following AF diagnosis. In a previous publication from the Tromsø study, the risk of VTE, and PE in particular, was significantly higher in subjects with incident AF than in those without. 13 Further cause-specific analyses demonstrated that the excessive PE risk conveyed by AF could not be explained by the intermediate development of ischemic stroke. 4 Despite diagnostic and therapeutic advances during the past decades, the all-cause mortality rates after VTE, especially after PE, remain substantial. 14 Whether AF is a prognosticator in VTE has not been extensively studied, even though the 2 conditions frequently coexist. [15][16][17] AF upon hospital admittance was associated with reduced survival after VTE in some studies, 18,19 while others report no impact on mortality regardless of AF onset. 16,20 A recently published meta-analysis found AF at admission to be predictive of in-hospital death in patients with PE in unadjusted analyses. 21 To what extent AF impacts VTE mortality in the general population is unclear. In the present study, we therefore aimed to investigate the joint effect of AF and VTE on the risk of all-cause mortality. For comparison, we simultaneously assessed the joint effect of AF and ischemic stroke on the risk of mortality within the same population.

| Study population
Participants were recruited from the fourth (1994)(1995) 22 We excluded all participants who withdrew their consent to medical research after the Tromsø study inclusion date (n = 181); participants not officially registered as residents of Tromsø (n = 23); and those with VTE (n = 87), ischemic stroke (n = 215), or AF (n = 247) prior to study enrollment. A total of 29 833 participants were included in the study, and followed from the inclusion date to December 31, 2013. Incident cases of AF, VTE, and ischemic stroke, as well as deaths among all study participants were registered throughout follow-up. The study was approved by the Regional Committee for Medical and Health Research Ethics, and all participants gave their informed, written consent.

| Baseline measurements
Information on body mass index (BMI), hypertension, self-reported diabetes, smoking, and total cholesterol was obtained on the date the participant attended the Tromsø study. Blood pressure measurements were carried out using an automatic device (Dinamap Vital Signs Monitor, 1846; Critikon Inc). After 2 minutes of seated rest, 3 recordings were taken on the upper right arm at 1-minute intervals, and the mean of the last 2 values was used in the analyses. Those with systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg or currently using antihypertensive drugs were classified as having hypertension. Nonfasting blood samples were obtained from all study participants, and serum total cholesterol was measured as previously detailed. 23 Height and weight were measured with the participant in light clothing and no shoes. BMI was calculated as weight in kilograms divided by the height in meters squared (kg/m 2 ). History of diabetes and current smoking was obtained from self-administered questionnaires, and information on prior MI was obtained from the cardiovascular end point registry of the Tromsø study. Information regarding cancer diagnosis, either prior to study inclusion or during followup, was obtained by linkage to the Cancer Registry of Norway.
Participants with a diagnosis of nonmelanoma skin cancer were classified as cancer free.

| Ascertainment of VTE
Incident VTE cases were identified by searching the hospital discharge diagnosis registry, the autopsy registry, and the radiology procedure registry at the University Hospital of North Norway as previously described in detail. 24

| Ascertainment of ischemic stroke
Information on first-ever ischemic strokes was obtained by linkage to the diagnostic registries of the University Hospital of North Norway and the Norwegian Cause of Death Registry at The Norwegian Institute of Public Health, using the ICD, Eighth Revision (ICD-8) and ICD-9 codes 430-438, and ICD-10 codes I60-I69 (cerebrovascular diseases). Systematic text searches were also performed in the medical records for patients with ICD-8 and ICD-9 diagnosis codes 410-414 and 798-799, and ICD-10 codes I20-I25 and R96, R98 and R99, to ensure case completeness. The World Health Organization definition was used to define ischemic stroke: rapidly developing clinical signs of focal or global disturbance of cerebral function, with symptoms lasting ≥24 hours or leading to death with no apparent cause other than vascular origin. 25 Moreover, imaging tests (computed tomography or magnetic resonance imaging) or autopsy were required in order to exclude intracerebral or subarachnoid hemorrhage. An independent end point committee followed a detailed protocol according to established diagnostic criteria for case validation.

| Outcome
Information on deaths was retrieved from the Norwegian Population Registry by use of the unique national person identification number.

| Statistical analyses
We performed statistical analyses using STATA version 15.0 (Stata Corporation). Attained age was used as the time scale, defining the participant's age at enrollment as entry time, and the age at the time of a censoring event (ie, death, migration, or study end) as exit time. We calculated crude mortality rates (MRs) and hazard ratios (HRs) for death during follow-up by exposure status during followup (no event, AF only, VTE only, ischemic stroke only, or >1 exposure). Poisson regression models were used to obtain age-adjusted MRs. All participants contributed with nonexposed person-time from the baseline inclusion date to the date of a first event, and then with exposed time from that date onward. For participants who developed both AF and VTE, AF and ischemic stroke, or VTE and ischemic stroke, a third observational period was counted from the date of the second diagnosis through the end of follow-up, and for those who experienced all 3 events (AF, VTE, and ischemic stroke), a fourth observational period was counted from the date of the third diagnosis through the end of follow-up ( Figure 1). In total, 29 833 subjects contributed with 33 899 observational periods. We further performed stratified analyses by type of VTE (PE or DVT), separate analyses of unprovoked and provoked VTEs, and analyses in which participants with cancer were censored on the date of cancer diagnosis. We tested the assumption of proportional hazards using Schoenfeld residuals and found that the "VTE only" and the "AF + VTE" exposures violated the assumption of proportional hazards. We consequently calculated HRs in different age groups (younger vs older participants). Statistical interactions between the different exposures and sex were tested by including cross-product terms in the Cox regression models. A borderline significant interaction term was found for sex and AF, and sex and ischemic stroke, and we further performed analyses stratified on sex. The number of participants included in the adjusted regression models varied slightly due to missing data for some covariates (in total 1.1% missing).

| RESULTS
A total of 756 VTE events, 1279 ischemic strokes, and 2087 cases of AF were registered during a median of 18.7 years (range, 6 days to 19.3 years) of follow-up. The baseline characteristics of those who developed incident events (AF, stroke, or VTE) during followup are summarized in Table 1. Participants with any event during follow-up were markedly older at inclusion than those without an event. Subjects with the joint AF and VTE exposure were on average 20 years older at inclusion, and those with AF and ischemic stroke 22 years older, than participants without any event during follow-up (Table 1). Furthermore, hypertension, diabetes, and a history of MI was more prevalent in those who later developed AF and ischemic stroke. Participants with all 3 events (AF, VTE, and ischemic stroke) had the highest baseline age, BMI, and cholesterol levels and the largest proportion of hypertension, diabetes, and previous MI ( Table 1).
The association between AF, VTE, ischemic stroke, and the joint exposures on risk of death is shown in  Contributed with nonexposed person-time from inclusion, then with "exposed to VTE" person-time from the date of VTE until AF diagnosis, then with "exposed to AF + VTE" person-time from that day onward until death. Person B: Nonexposed to any event throughout the study period. Person C: Contributed with nonexposed person-time from inclusion, then with "exposed to stroke" person-time from the date of ischemic stroke until death. Person D: Contributed with nonexposed person-time from inclusion, with "exposed to VTE" person-time from the date of VTE until stroke diagnosis, then with "exposed to VTE + stroke" person-time to AF diagnosis, and then with "exposed to AF + VTE + stroke" person-time until end of follow-up. Person E: Contributed with nonexposed person-time from inclusion until AF diagnosis, then with "exposed to AF" until end of follow-up. Person F: Contributed with nonexposed person-time from inclusion, with "exposed to AF" persontime form the date of AF until stroke diagnosis, and then with "exposed to AF + stroke" person time until death. AF, atrial fibrillation; VTE, venous thromboembolism Non-exposed Exposed to AF Exposed to AF+VTE Exposed to AF+stroke Exposed to VTE+stroke The highest risk of death was observed for subjects with VTE and ischemic stroke (HR, 6.32; 95% CI, 4.26-9.37) ( Table 2).
In analyses in which participants with a cancer diagnosis prior to inclusion (n = 839) were excluded, and those diagnosed with cancer during follow-up (n = 2938) were censored at the time of cancer diagnosis, the risk estimates for death by VTE were markedly attenuated. In these analyses, the age-adjusted MR was half of that observed in the total study population (3.77 per 100 PY; 95% CI, 3.07-4.47), and the HR of death reduced to 2.05 (95% CI, 1.70-2.49). In contrast, risk estimates in cancer-free subjects having incident stroke during follow-up were virtually unchanged ( for unprovoked and provoked VTEs, respectively (data not shown).
When analyzing PE and DVT events separately, both events were associated with higher HRs for death compared to AF alone in age-(as time scale) and sex-adjusted analyses (  (Table 4). In analyses stratified by sex, all HRs were higher in women than in men, but the CIs overlapped (

| DISCUSSION
In this cohort study, we found that incident AF without concurrent VTE or ischemic stroke during follow-up doubled the risk of allcause mortality. VTE alone was associated with a 4-fold increased risk of death, and was similar to the risk found for AF in combination with ischemic stroke. In patients with VTE, concurrent presence of AF did not further increase the risk estimates for death.
The increase in absolute and relative risks of death by AF observed in our study is in agreement with previous reports. 1,3,[26][27][28] While the excess mortality may be attributable to heart failure, either as a cause or a consequence of AF, 27 others have reported that TA B L E 3 All-cause mortality rates (MRs) and hazard ratios (HRs) for death by exposure during follow-up; participants are censored upon cancer diagnosis In a large registry-based study with over 270 000 participants, AF was independently associated with all-cause mortality, with higher relative risks for death observed for women across all age groups.
Among concomitant diseases, malignancy, chronic renal failure, and chronic obstructive pulmonary disease contributed most to the excess mortality in AF patients. 28 The role of concurrent AF as a prognosticator in patients with VTE has not been extensively studied. The majority of studies to date have investigated AF in the setting of hospitalization for PE and its impact on short-term case fatality. 15,18,19,29 In a retrospective study involving 270 patients with acute PE, a history of AF was associated with increased intrahospital 1-month and 6-month death rates independent of age. 15 Similarly, Geibel and coworkers found atrial arrhythmias to be associated with increased 30day mortality in patients admitted with major PE. 18 In the present study, we found that VTE alone was associated with an overall of subgroups in which there are low numbers of the exposure(s) and outcome(s) of interest. In analyses investigating the joint exposures of AF and VTE, or AF and ischemic stroke, we did not take the temporal sequence of events into consideration. However, a bidirectional association exists between AF and VTE, 4,13,32 and although AF is an established risk factor for ischemic stroke, the diagnosis is made after the incident stroke in a significant number of cases. 33 Knowledge of the latter may introduce surveillance bias, as patients with idiopathic ischemic stroke are monitored for potential AF after the incident event. For the scope of the present analysis, we assumed that the temporality of events for the joint outcomes would be of little importance.
In conclusion, the present study confirms the aggravated risk of death by AF in the general population. While concurrent AF is associated with a worse prognosis in subjects with ischemic stroke, the high relative mortality risk in VTE patients is not further increased by the presence of AF.

ACKNOWLEDGMENTS
K. G. Jebsen TREC is supported by an independent grant from the KG Jebsen Foundation. E. M. Hald receives a grant from the Northern Norway Regional Health Authority.

RELATIONSHIP DISCLOSURES
The authors report nothing to disclose.

AUTHOR CONTRIBUTIONS
EMH contributed to data collection, data analysis, and writing of the manuscript. M-LL, EBM, and IN contributed to data collection and revision of the manuscript. TW provided statistical support and contributed to revision of the manuscript. SKB contributed to data collection, data interpretation, statistical support, and revision of the manuscript. J-BHansen contributed to the conception and design of the study, data collection, and interpretation and revision of the manuscript.