Outcomes in elderly Chinese patients with atrial fibrillation and coronary artery disease. A report from the Optimal Thromboprophylaxis in Elderly Chinese Patients with Atrial Fibrillation (ChiOTEAF) registry

Abstract Background Atrial fibrillation (AF) and coronary artery disease (CAD) are closely related; CAD may precede or complicate the clinical course of AF. Objective To evaluate the impact of CAD on clinical outcomes among elderly Chinese AF patients. Methods The ChiOTEAF registry is a prospective registry conducted in 44 sites from 20 provinces in China between October 2014 and December 2018. Primary outcome was the composite of all‐cause mortality/any thromboembolism (TE)/major bleeding/acute coronary syndrome (ACS). Results The eligible cohort for this analysis included 6403 individuals (mean age 74.8 ± 10.7; 39.2% female); of these, 3058 (47.8%) had a history of CAD. On multivariate analysis, CAD was independently associated with a higher odds ratio for ACS (OR: 1.98; 95% CI: 1.12–3.52) without a significant impact on other adverse outcomes. Independent variables associated with the composite outcome among CAD patients were: (i) the use of OAC (OR: 0.55; 95% CI: 0.42–0.72), age (OR: 1.09; 95% CI: 1.08–1.11), heart failure (OR: 1.95; 95% CI: 1.51–2.50), prior ischemic stroke (OR: 1.29; 95% CI: 1.02–1.64), chronic kidney disease (OR: 1.71; 95% CI: 1.32–2.22), and chronic obstructive pulmonary disease (OR: 1.42; 95% CI: 1.06–1.89). Conclusions AF patients with CAD were at an increased risk of developing ACS but there was no significant difference in the composite outcome, all cause death, cardiovascular death, thromboembolic events or major bleeding compared to the non‐CAD group. OAC use was inversely associated with adverse events, yet their uptake was poor in the AF‐CAD population.


| INTRODUC TI ON
There is a bidirectional relationship between coronary artery disease (CAD) and atrial fibrillation (AF), with multiple shared risk factors. CAD may precede or complicate the clinical course of AF. 1 Indeed, AF-related systemic inflammation may promote a prothrombotic state and ultimately lead to myocardial infarction (MI). 2 Previous studies have shown that AF was associated with a 70% increase in the risk of MI, but gender and race differences have been emphasized. 3,4 On the other hand, about a quarter of the AF population have a history of MI; indeed, MI is considered a risk factor for AF and AF-related complications. 1 Furthermore, CAD is associated with a higher incidence of thromboembolic (TE) events, even in patients without AF. 5,6 The management of AF patients with previous MI or revascularization has attracted much attention because of the complexity of antithrombotic treatment in this setting. [7][8][9][10][11] As data among Asian patients are still sparse, we aimed to evaluate the coexistence and impact of CAD on clinical outcomes among elderly Chinese AF patients enrolled in the nationwide, prospective registry.

| ME THODS
The Optimal Thromboprophylaxis in Elderly Chinese Patients with Atrial Fibrillation (ChiOTEAF) registry is a prospective cohort study conducted between October 2014 and December 2018 in 44 sites from 20 Chinese provinces. A detailed description of the study design has been previously published. 12 Briefly, consecutive AF patients presenting to cardiologists, neurologists, or surgeons were enrolled. Follow-up visits were performed at 6 and 12 months and then annually for the following 2 years. Data were gathered by local investigators at enrollment and follow-up visits and reported into an electronic form.

The registry was approved by the Central Medical Ethics
Committee of Chinese PLA General Hospital, Beijing, China (approval no S2014-065-01) and local institutional review boards.

| Definitions
Variables included in the registry and their definitions were designed to match the EORP-AF Long-term General Registry. 13 CAD was categorized as either a history of acute coronary syndromes (ACS) or chronic coronary syndromes managed pharmacologically or "prior revascularization" (defined as percutaneous coronary intervention or coronary artery bypass graft). 14 "Myocardial infarction" was defined as MI with ST-segment elevation or MI without ST-segment elevation. "Angina" was defined as chronic coronary syndromes with anginal symptoms. The CHA 2 DS 2 -VASc score 15 and the HAS-BLED bleeding score 16 were used to assess the thromboembolic (TE) and bleeding risks. Bleeding events were categorized according to the ISTH definition. 17

| Objectives
The principal objectives of the present analysis were as follows: (i) to describe the baseline characteristics and the incidence of adverse events at 1-year follow-up among AF patients with CAD; (ii) to evaluate the impact of CAD on clinical outcomes, including the composite outcome of all-cause death/any TE (ischemic stroke, transient ischemic attack, or peripheral embolism)/major bleeding/ACS (MI with ST-segment elevation, MI without STsegment elevation, unstable angina); and (iii) to identify potential predictors of the composite outcome in patients with CAD.
The secondary objectives were: (i) to evaluate the impact of CAD on all-cause death, cardiovascular death, TE events, major bleeding, and ACS; and (ii) to assess the effect of prior MI, angina, and prior revascularization on the composite outcome and all-cause death among the CAD group.

| Statistical analysis
Continuous variables were reported as the mean ± standard deviation (SD); between-group comparisons were made using the Student's t-test or the Mann-Whitney U test (based on distribution).
Categorical variables as counts and percentages; between-group comparisons were made by χ 2 test. A logistic univariate regression analysis was used to evaluate the potential association between CAD and clinical outcomes, as well as to evaluate the predictors of the composite outcome and all-cause death in the CAD group. Results were expressed as odds ratios (ORs), 95% confidence intervals (CIs), and P-values. All the significant variables of relevant clinical interests were subsequently included in a multivariate regression model.
In all analyses, a value of p < .05 was considered statistically significant. Statistical analysis was performed using SPSS® version 24 (IBM Corp).
On multivariate analysis, CAD was independently associated with a higher odds ratio for ACS (OR: 1.98; 95% CI: 1.12-3.52) without a statistically significant impact on other adverse outcomes -

| DISCUSS ION
To date, few studies have looked at clinical outcomes in AF patients with CAD, particularly in the elderly Asian population. Our study demonstrates a 47.8% prevalence of CAD among AF patients, a considerably higher number compared with large-scale international registries (approximate prevalence of 36%). 13,18 This may be explained by the older age of the participants in this study, and possibly higher prevalence of other risk factors for CAD within the study population.
In our study, AF-CAD patients were older, with more comorbidities such as hypertension, heart failure, CKD and previous stroke and therefore conferred higher ischemic and bleeding risks as depicted by the mean CHA 2 DS 2 VASc and HASBLED scores compared to patients without CAD. Despite this, only 36.4% of this cohort were prescribed OAC either as monotherapy or alongside an antiplatelet agent, with rates only marginally better in the non-CAD group (50.4%). The vast majority of CAD patients were treated with single (SAPT) or dual antiplatelet therapy (DAPT). Given the lack of precise data on the timing of prior MI or revascularization which could have ranged from years before to until the day before recruitment, it is difficult to elucidate whether the antiplatelet drug regimen was appropriate for that given point in time.
Existing guidelines recommend commencing OAC immediately in settings of ACS or revascularization, alongside SAPT or DAPT, with the latter only recommended for maximum period of 6 months in patients with very high risk of thrombosis. 19,20 This is in view of results from pivotal trials such as WOEST, ISAR-TRIPLE, and PIONEER-AF-PCI which demonstrated that dual therapy (SAPT and OAC) was associated with reduction in major bleeding events with similar efficacy, when compared to triple therapy (DAPT and OAC). [21][22][23] This is supported by the recent meta-analysis which showed no significant increase in mortality, stroke, nonfatal MI, stent thrombosis, and a lower risk of bleeding with dual therapy, compared with triple therapy in AF-CAD patients. 24    not the other adverse outcomes. Fukamachi et al also investigated adverse outcomes in anticoagulated Japanese AF-CAD patients; CAD was associated with a significantly higher risk of cardiovascular events, with no differences in the TE events, bleeding, and mortality risks. 29 These findings add to the debate about whether or not the presence of CAD confers an additional risk of ischemic stroke. After all, acute ischemic strokes are predominantly secondary to TE phenomena much like ACS, and both fall under the realm of "vascular disease," sharing several risk factors and pathophysiological mechanisms. 30,31 The assumption therefore is that an increased risk in one should cause an increased risk in the other. While the presence of significant CAD at coronary angiography confers an increase in ischemic stroke risk, it is less clear if the extent of angiographically proven CAD (i.e., 1-, 2-, or 3-vessel disease) is an independent risk factor for TE. 6,32 CAD has been associated with an increased risk of stroke in several studies. 8 More recently, computed tomography has been used to demonstrate an increased risk of stroke in AF patients with incidental coronary artery calcification; an indicator for underlying CAD. 32 In the study by Tagawa and colleagues, asymptomatic CAD was identified with a positive myocardial scintigraphy test in a quarter of patients with ischemic strokes. 33 Conversely, the reverse has also been described with inconclusive evidence for CAD as an independent risk factor for stroke, consistent with our findings. 34,35 Much of the CAD group in our study comprised of patients with angina who may not have had an angiogram, meaning they may not fall under the strict definition of "angiographically significant CAD" that forms part of the CHA 2 DS 2 VASc score. This may also explain why prior MI but not angina was associated with a significantly elevated risk of the composite outcomes and all-cause death in the sub-analysis of the CAD group. Our data suggest that AF patients with a prior history of MI require more attention with closer monitoring and aggressive risk factor and symptom control, as part of the holistic or integrated care approach to AF case as advocated by current guidelines. 8,36 Adherence with such an integrated care approach has been associated with a major reduction in adverse clinical outcomes, including mortality, cardiovascular mortality, stroke and major bleeding, as well as hospitalizations. 37,38 In the study by Pastori

| Limitations
Our study is subject to the limitations of an observational study design including effects from unaccounted confounders and a degree of bias because of potential selection, ascertainment, and treatment-effect bias. Baseline data were used for analysis and therefore would not have accounted for any medication changes during the follow-up period. The treatment regimens for individual patients will have varied depending on how far along they were from their index MI or revascularization procedure, making it difficult to ascertain whether they were on a suitable drug regimen.
As this registry was primarily focused on AF, there was also a lack of data on factors relating to the revascularization procedures such as the number and types of stents used and history of stent

| CON CLUS ION
AF patients with CAD were at an increased risk of developing ACS but there was no significant difference in the composite outcome, all cause death, cardiovascular death, TE events, or major bleeding compared with the non-CAD group. OAC use was associated with a lower chance of adverse events, yet their uptake was poor in the AF-CAD population indicating that better awareness and guideline adherence is needed, with reinforcement of their safety even in older Chinese patients.

E TH I C S A PPROVA L
This study was performed in line with the principles of the Declaration of Helsinki. Ethics approval was granted by the Central Medical Ethic Committee of Chinese PLA General Hospital (approval no S2014-065-01).

CON S ENT TO PARTI CIPATE
Written informed consent was obtained from all individual participants included in the study.

CO N S E NT FO R PU B LI C ATI O N
Not applicable.
Authors are responsible for correctness of the statements provided in the manuscript.

AVAIL AB ILIT Y OF DATA AND MATERIAL
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

CODE AVAIL AB ILIT Y
Statistical analysis was performed using SPSS® version 24 (IBM Corp, Armonk, NY).

ACK N OWLED G M ENTS
The authors thank all the participants into the ChiOTEAF for their contributions.

FU N D I N G I N FO R M ATI O N
The study was supported by the Beijing Natural Science Foundation,