Impact of atrial fibrillation on the development of ischemic stroke among cancer patients classified by CHA2DS2-VASc score-a nationwide cohort study

Purpose The current study aimed to explore the impact of atrial fibrillation (AF) on risk of ischemic stroke among cancer patients classified by CHA2DS2-VASc score. Methods Study participants were identified from Registry for Catastrophic Illness Patient Database. All cancer patients whether they had comorbid AF or not were divided into 4 groups according to their CHA2DS2-VASc score-a score of 0–1, 2–3, 4–5 and >5. Competing risk analysis was used to evaluate the subhazard ratios (SHRs) and 95% confidence intervals (CIs) of incident ischemic stroke between cancer patients with and without AF according to their CHA2DS2-VASc score. Results A total of 781473 patients with cancer were identified. Of them, 21134 had comorbid AF whereas the remaining 760339 patients did not. After controlling for the confounding factors and the competing risk of death, among cancer patients, those with AF were associated with the highest risk of ischemic stroke than those without AF while their CHA2DS2-VASc score was 0∼1 (adjusted SHR [aSHR] = 4.15, 95% CI = 3.29–5.23). Among those with a CHA2DS2-VASc score of >5, the AF group exhibited a 1.82-fold higher risk of ischemic stroke than the non-AF group (95% CI = 1.34–2.47). Conclusions The impact of AF on risk of ischemic stroke was attenuated with advancing CHA2DS2-VASc score in patients with cancer.

Atrial fibrillation (AF), a well-recognized risk factor for ischemic stroke, is a common comorbidity in cancer patients [10][11][12]. In addition, the prognostic impact of AF on the clinical outcomes among patients with cancer has also been investigated [10,[13][14]. Furthermore, current guidelines suggest that CHA 2 DS 2 -VASc score is a useful discrimination tool for stratifying ischemic stroke risk among patients with AF [15][16][17]. Recently, CHA 2 DS 2 -VASc score has been shown to be helpful for stroke risk stratification even in individuals without AF [18][19].
To our knowledge, currently there is no study specifically addressing the issue of the link between Research Paper cancer, AF and ischemic stroke. To bridge the gaps of knowledges, the current study aimed to identify the impact of AF on risk of developing ischemic stroke among cancer patients stratified by CHA 2 DS 2 -VASc score. The predictive capacity of CHA 2 DS 2 -VASc scores for stroke risk discrimination among cancer patients whether they have comorbid AF or not was also explored.

Data source
We undertook a retrospective nationwide cohort study using the Registry of Catastrophic Illness Patient Database (RCIPD) of the Taiwan National Health Insurance (NHI) program. A compulsory NHI program was implemented in Taiwan since 1995 and it covered nearly 99% of all residents (23.74 million beneficiaries) of Taiwan [20]. The details of the RCIPD have been described previously [21][22]. This study complied with the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of China Medical University and Hospital (CMUH-104-REC2-115). The diagnostic codes were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 codes).

Statistical analysis
Demographic characteristics and comorbidity prevalence were compared between the AF and the non-AF groups. The difference of categorical variables between the two groups was examined using the χ 2 test whereas the difference of continuous variables between the two groups was examined with the t-test. Cancer patients with and without AF were divided into 4 groups according to their CHA 2 DS 2 -VASc score-a score of 0-1, 2-3, 4-5 and >5.
The incidence of ischemic stroke and death in patients with cancer whether they had comorbid AF or not were estimated according to their CHA 2 DS 2 -VASc score. The cumulative incidence of ischemic stroke stratified by CHA 2 DS 2 -VASc score among cancer patients with and without AF was assessed using the Kaplan-Meier method, and the differences between the curves were evaluated using a log-rank test. To quantify the discriminatory properties of the CHA 2 DS 2 -VASc score in predicting ischemic stroke among cancer patients with and without AF, we plotted the receiver operating characteristic (ROC) curves and calculated the area under the ROC curves. Considering the competing risk of death, the Fine and Gray model was used to extend the standard univariable and multivariable Cox proportional hazards models and the subhazard ratios (SHRs) and 95% confidence intervals (CIs) of incident ischemic stroke between cancer patients with and without AF according to their CHA 2 DS 2 -VASc score were obtained (27). All data processing and statistical analyses were performed with the SAS software version 9.4 (SAS Institute, Inc., Cary, NC, USA). A p-value of <0.05 was considered statistically significant.

RESULTS
A total of 781473 cancer patients were identified from RCIPD. Among them, 21134 patients had comorbid AF whereas 760339 patients did not (Table 1). Most cancer patients with AF were aged 75 years or older (57.1%) whereas most cancer patients without AF were aged 64 years or younger (56.4%). The mean (SD) ages was 75.3 (9.83) and 61.2 (14.9) years in the AF and the non-AF group, respectively. The percentage of women in AF group was significantly higher than the non-AF group (65.2% vs 55.2%, p < 0.001). The AF group was associated with a higher prevalence of all comorbidities than the non-AF group. The 3 major cancers in the AF group were colon cancer (18.3%), lung cancer (17.1%) and hepatoma (13.2%) whereas colon cancer (13.8 %), hepatoma (13.4%) and female breast cancer (11.4%) were three most common cancers in the non-AF groups. The mean CHA 2 DS 2 -VASc score of the AF and the non-AF group were 3.86 (SD = 1.72) and 1.89 (SD = 1.56). The mean follow up period for the AF and the non-AF group was 1.79 years (SD = 2.19 years) and 3.00 years (SD = 3.07 years), respectively.
The incidence of ischemic stroke was highest in cancer patients whether they had comorbid AF or not while their CHA 2 DS 2 -VASc score was 4~5 (6.02% vs 3.71%) ( Table 2). Kaplan-Meier analyses illustrated the cumulative incidence curves of incident ischemic stroke according to CHA 2 DS 2 -VASc score in cancer patients without atrial fibrillation ( Figure 1A) and with atrial fibrillation ( Figure 1B). Among cancer patients without and with comorbid AF, the area under the ROC curves of the CHA 2 DS 2 -VASs score as a predictor of ischemic stroke was 0.62 (95% CI = 0.61-0.62) (Figure    (Figure 2B), respectively. The incidence of mortality was highest in cancer patients whether or not AF was present while their CHA 2 DS 2 -VASc score was greater than 5 (49.5% vs 47.0%) ( Table 3). Estimation of incident ischemic stroke risk in the study cohorts while considering the competing risk of death was shown in Table 4. After controlling for the confounding factors and the competing risk of death, among cancer patients, those with comorbid AF were associated with the highest risk of ischemic stroke than those without AF while their CHA 2 DS 2 -VASc score was 0~1 (adjusted SHR [aSHR] = 4.15, 95% CI = 3.29-5.23). Additionally, among cancer patients with a CHA 2 DS 2 -VASc score of >5, the AF group exhibited a 1.82-fold higher risk of ischemic stroke than the non-AF group (95% CI = 1.34-2.47).

DISCUSSION
We reported for the first time regarding the impact of AF on incident ischemic stroke among cancer patients stratified by CHA 2 DS 2 -VASc score. Additionally, the use of CHA 2 DS 2 -VASc score in ischemic stroke risk discrimination among cancer patients with and without comorbid AF was also addressed.
Using CHA 2 DS 2 -VASc score for stratifying patients into four groups (0-1, 2-3, 4-5, and >5), the incidence of mortality increased in parallel with increasing score in cancer patients whether AF was present or not. Nevertheless, the linear shape phenomenon was not observed in the incident ischemic stroke among cancer patients with and without AF. Possible factor for the explanation is that death is a major competing risk for ischemic stroke in cancer patients, leading to the lowest incidence of ischemic stroke in those with the highest score [1][2][3][4][5][6].
In the current study, we found that cancer patients with AF were older and had more underlying medical comorbidities. After controlling for the potential confounding factors with the competing risk regression model approach, the risk of developing ischemic stroke for cancer patients with AF relative to those without AF was in an inverse relationship with advancing CHA 2 DS 2 -VASc score. Possible explanation for our results is that a higher CHA 2 DS 2 -VASc score is associated with a significantly higher rate of ischemic stroke, which in turn might lead to the attenuated role of AF in those with a higher score.
Several advantages of the current study deserve to be highlighted. First, the study was analyzed from a large insurance administrative database which has been validated [28][29][30]. Second, this study is a large scale investigation with large patient population and reasonable follow up duration with the attempt to explore this clinically significant issue. Finally, statistical procedure with competing risk analysis approach was used in order to minimize the study bias [27].

Limitations
First, the absence of relevant case information from the insurance claims data is potentially a major limitation and should be outlined. However, several validation studies have been conducted and the reliability of the nationwide dataset has been confirmed [28][29][30]. Second, detailed personal health-associated behaviors were uncertain in this database. Finally, potential unmeasured confounding variables involved in the analyses are possible. Despite the limitations presented here, this study was extracted from a large nationwide dataset with the appropriate methodology approach to provide new insights into this context.

CONCLUSIONS
The impact of AF on risk of ischemic stroke was attenuated with the advancement of CHA 2 DS 2 -VASc score in cancer patients.

CONFLICTS OF INTEREST
The authors have declared no conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.