Gout and Risk of Ischemic Stroke in Patients With Atrial Fibrillation: A Nationwide Cohort Study

 

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Gout and Risk of Ischemic Stroke in Patients With Atrial Fibrillation: A Nationwide Cohort Study

Antti Palomäki, MD, PhD https://orcid.org/0000-0002-8835-8116, 

Ville Langén, MD, PhD https://orcid.org/0000-0002-2382-7962, 

K.E. Juhani Airaksinen, MD, PhD https://orcid.org/0000-0002-0193-568X, 

Olli Halminen, PhD https://orcid.org/0000-0001-9266-8435,

Jari Haukka, PhD https://orcid.org/0000-0003-1450-6208, 

Jussi Jaakkola, MD, PhD https://orcid.org/0000-0002-3398-4283, 

Elis Kouki, MD https://orcid.org/0000-0002-5759-0916,

… Show All … , and Konsta Teppo, MD, PhD https://orcid.org/0000-0002-4460-0994 jkitep@utu.fiAuthor Info & Affiliations

Stroke

New online

https://doi.org/10.1161/STROKEAHA.126.055194

 

Abstract

 BACKGROUND:

Gout is an emerging cardiovascular risk factor. We aimed to assess whether gout is associated with an increased risk of stroke in patients with atrial fibrillation (AF).

METHODS:

The nationwide registry-linkage FinACAF study (Finnish Anticoagulation in Atrial Fibrillation) included all patients with AF in Finland between 2007 and 2018 from all levels of care. Based on diagnosis codes and pharmacy claims data, the association of gout and urate-lowering therapy with the incidence of ischemic stroke was assessed.

RESULTS:

We identified 229 565 patients with new-onset AF (50.0% female; mean age, 72.7 years; mean follow-up, 4.0 years), of whom 6 910 (3.0%) had a history of gout. A total of 16 296 (7.1%) patients experienced an ischemic stroke. Gout was associated with higher stroke rates in both unadjusted and adjusted analyses (incidence rate ratio, 1.35 [95% CI, 1.22–1.49] and incidence rate ratio, 1.12 [95% CI, 1.02–1.24], respectively). Analyses restricted to follow-up without anticoagulation yielded consistent results with slightly higher point estimates (incidence rate ratio, 1.88 [95% CI, 1.63–2.17] unadjusted; incidence rate ratio 1.26 [95% CI, 1.09–1.46] adjusted). In patients with gout and AF, time-dependent exposure to urate-lowering therapy was associated with a 30% lower stroke rate. Nonanticoagulated crude stroke rates were 1.5, 1.0, and 4.8 per 100 patient-years for gout patients with CHA2DS2-VA scores of 0, 1, and ≥2, respectively.

CONCLUSIONS:

Gout is an important risk factor for ischemic stroke in patients with AF, and considering gout could improve stroke risk stratification. Urate-lowering therapy was associated with reduced stroke risk, suggesting that gout is a modifiable risk factor in patients with AF.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04645537.

Graphical Abstract

 Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting up to 5.2% of the adult population.1 It is a major cause of ischemic stroke, with the risk of stroke varying considerably among individuals based on their specific comorbidities and other characteristics.2,3 With optimal therapy, including oral anticoagulant (OAC) treatment as well as management of relevant comorbidities, the risk of stroke can be significantly reduced.4 Identifying patients who would benefit from OAC therapy and have modifiable stroke risk factors is therefore essential for improving their prognosis.

Gout is the most common form of inflammatory arthritis with increasing prevalence globally.5 It is characterized by recurrent painful flares caused by an inflammatory reaction against monosodium urate crystals deposited in joints and surrounding tissues as a result of hyperuricemia.6 Gout has been associated with the risk of cardiovascular events, including myocardial infarction, stroke, and venous thromboembolism.7–10 AF is common in patients with gout and hyperuricemia, and patients with gout often share many risk factors for AF, particularly older age, male sex, obesity, hypertension, chronic kidney disease, and alcohol use.11–14 Gout is also often undertreated, with both low rates of urate-lowering therapy initiation and poor treatment adherence.15

In patients with AF, it remains uncertain whether gout contributes to an additional and potentially modifiable risk of stroke. Moreover, while there is some evidence that long-term urate-lowering therapy may lower the risk of acute coronary syndrome and stroke in patients with gout, whether this also applies to stroke risk in patients with coexisting AF and gout is unknown.16–18 These questions are clinically important, as appropriate management of gout might offer a relatively simple and cost-effective strategy to improve outcomes in patients with AF. Therefore, we conducted a nationwide retrospective cohort study to examine the association of gout with ischemic stroke in patients with AF. Additionally, we explored whether urate-lowering therapy is associated with a reduced stroke risk in patients with gout and AF.

METHODS

Data Availability Statement

Because of the sensitive nature of the data collected for this study, requests to access the data set from qualified researchers trained in human subject confidentiality protocols may be sent to the Finnish national register holders (Social Insurance Institution of Finland, Finnish Institute for Health and Welfare, Population Register Center, and Tax Register) through Findata (https://findata.fi/en/). In the interest of research transparency and reproducibility, the analysis code used in this study has been made publicly available on GitHub and permanently archived on Zenodo under DOI 10.5281/zenodo.17228485. It can be accessed directly online at https://doi.org/10.5281/zenodo.17228485.

Study Population

The FinACAF study (Finnish Anticoagulation in Atrial Fibrillation; ENCePP Identifier: EUPAS29845) is a nationwide retrospective cohort study that includes all patients documented with AF in Finland from 2004 to 2018.19 Patients were identified using all available national health care registers, including hospitalizations and outpatient specialist visits, and primary health care. and the National Reimbursement Register maintained by the Social Insurance Institute. The cohort inclusion criterion was an International Classification of Diseases, Tenth Revision diagnosis code of I48, encompassing AF and atrial flutter, collectively referred to as AF, recorded between 2004 and 2018. Exclusion criteria encompassed permanent emigration abroad before December 31, 2018, and age below 20 years at AF diagnosis. The present substudy was conducted within a cohort of patients with incident AF from 2007 to 2018, established in previous studies of the FinACAF cohort.20–22 The patient selection process is summarized in Figure S1.

Follow-Up

The follow-up period was evaluated using 2 distinct approaches. In both strategies, the follow-up started from the first diagnosis of AF. In the main approach, follow-up continued until the occurrence of the first ischemic stroke event, death, or the end of the observation period on December 31, 2018, whichever occurred first. In this approach, the regressions were adjusted for the use of OACs in a time-dependent manner. Moreover, since it is the nonanticoagulated stroke rate that drives the clinical decision-making regarding stroke prevention with OACs, the second approach focused exclusively on the follow-up without OAC therapy.23 Thus, in the second approach, the follow-up ended on the first OAC purchase, the first stroke event, death, or the end of the observation period, whichever occurred first.

Definition of Gout

Patients were classified as having gout if they had recorded gout diagnosis codes (International Classification of Diseases, Tenth Revision: M10 or International Classification of Primary Care, Second Edition: T92) in any of the nationwide hospital or primary care registers before or at the date of the first AF diagnosis. Furthermore, to explore gout severity and gauge potential causality between gout and stroke (on the assumption that a causal risk factor should show stronger associations with greater severity), we classified patients into 2 groups: those with a hospital-recorded diagnosis of gout (a surrogate for more severe disease requiring hospital-level care) and those with gout diagnosis recorded only in primary care (a surrogate for less severe disease). Additionally, gout patients were categorized into those with a pharmacy purchase of urate-lowering therapy (allopurinol or febuxostat) within the year before their first AF diagnosis and those without urate-lowering drug purchases.

Exposure to Urate-Lowering Therapy

We considered allopurinol and febuxostat, the most commonly used urate-lowering therapies in Finland, in our analyses. First, we assessed stroke risk in patients with gout with and without these drug purchases at baseline, defined as at least 2 pharmacy purchases of allopurinol or febuxostat within the year before the first AF diagnosis (start of follow-up), including the date of diagnosis. Second, among patients with gout, we analyzed the effect of these drugs on stroke risk using a time-dependent exposure definition. In this approach, exposure to urate-lowering therapy began at the first pharmacy purchase occurring within 1 year before or any time after cohort entry and was assumed to continue until 120 days after the last recorded purchase. Follow-up with exposure to urate-lowering therapy was then compared with time without urate-lowering therapy. Purchases made >1 year before cohort entry were not considered as therapy initiation. The 120-day interval was chosen because, in Finland, medications can be reimbursed for up to 90 days at a time, with an additional 30-day grace period allowed to account for potential stockpiling and waning of the urate-lowering effect.

Definition of Ischemic Stroke

In patients without prior ischemic stroke before the first AF diagnosis, an ischemic event was considered to occur on the first date of a recorded I63 or I64 International Classification of Diseases, Tenth Revision diagnosis code in the hospital care register after the cohort entry. In patients with prior ischemic stroke, the event was considered to occur on the date of the first new hospitalization with I63 or I64 International Classification of Diseases, Tenth Revision code as the main diagnosis, with at least a 90-day gap from the prior event, which had occurred before AF diagnosis.

Study Ethics

The study protocol was approved by the Ethics Committee of the Medical Faculty of Helsinki University, Helsinki, Finland (nr. 15/2017 and 15/2024), and received research permission from the Helsinki University Hospital (HUS/46/2018 and HUS/217/2024). Respective permissions were obtained from the Finnish register holders (KELA 138/522/2018; Finnish Institute for Health and Welfare 2101/5.05.00/2018; Population Register center VRK/1291/2019-3; Statistics Finland TK-53-1713-18/ u1281; and Tax Register VH/874/07.01.03/2019). Patients’ personal identification numbers were pseudonymized, and the research group received individualized but unidentifiable data. Informed consent was waived due to the retrospective registry nature of the study. The study conforms to the Declaration of Helsinki as revised in 2024. This study is reported in accordance with the STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology; Supplemental Material).

Statistical Analyses

We calculated incidence rates and incidence rate ratios (IRRs) for ischemic stroke using the Poisson regression model. The model employed a Lexis-type data structure, incorporating 2 time scales: follow-up time from AF diagnosis and age.24 This statistical approach was selected to address age progression over the relatively long observation period (2007–2018). Adjusted IRRs accounted for age (categorical variable with 10-year intervals), calendar year period, sex, heart failure, diabetes, hypertension, prior ischemic stroke, vascular disease, dyslipidemia, prior bleeding, alcohol use disorder, renal failure, cancer, dementia, psychiatric disorders, and income level (divided into tertiles). The definitions of the comorbidities are presented in Table S1. In analyses that also included follow-up with anticoagulation, OAC use was treated in a time-dependent manner, with treatment initiation marked by the first OAC purchase and continuation until 120 days after the last drug purchase. Additionally, we assessed the association between urate-lowering therapy (allopurinol or febuxostat) exposure and stroke risk among patients with gout. In these analyses, urate-lowering therapy use was modeled in a time-dependent manner (as detailed above in the exposure to urate-lowering therapy paragraph), and adjusted models included the aforementioned variables, including OAC use. Sensitivity analyses were conducted among patients without baseline stroke, as first-ever strokes may be more reliably defined than recurrent events in administrative registry data. Moreover, we assessed whether the association between gout and stroke risk differed across stroke risk categories by fitting a Poisson regression model including gout, stroke risk category (3 groups: CHA2DS2-VA scores 0, 1, or ≥2), and their interaction term. Baseline variables were compared using the χ2 test, Student t test, and ANOVA. Standardized mean differences of baseline variables are also reported. All tests were 2-sided, with statistical significance assessed using a P value threshold of 0.05 or the 95% CIs. Statistical analyses were conducted using IBM SPSS Statistics software version 28.0 (SPSS Inc, Chicago, IL) and R version 4.0.5 (R Core Team, Vienna, Austria; https://www.R-project.org).

RESULTS

We identified 229 565 patients with new-onset AF (50.0% female; mean age, 72.7 years; mean follow-up time, 4.0 years). Overall, 6 910 patients (3.0%) had a history of gout, of whom 3 796 (1.7%) were diagnosed at the hospital level, and 3 114 (1.4%) had a gout diagnosis recorded only in primary care. Of the patients with gout, 2 978 (43.1%) had purchased urate-lowering therapies within a year before the first AF diagnosis. Patients with gout had a higher overall prevalence of comorbidities than patients without gout, which was also reflected in their higher stroke and bleeding risk scores (Table). Of all patients with gout, 103 (1.5%), 443 (6.4%), and 6 364 (92.1%) were classified as low (CHA2DS2-VA=0), moderate (CHA2DS2-VA=1), and high (CHA2DS2-VA≥2) stroke risk, respectively. Patients with gout diagnosed in a hospital setting had a higher prevalence of comorbidities compared with those diagnosed only in primary care. Similarly, patients with urate-lowering medication at baseline had more comorbidities than those without urate-lowering treatment (Table S2). None of the patients in the cohort used colchicine at baseline. Patients with gout were more likely to initiate OAC therapy during the follow-up period, compared with patients without gout (73.7% versus 70.4%; P<0.001). Moreover, mortality during follow-up was higher in those with gout than in those without gout (35.0% versus 33.2%; P<0.001).