Central retinal artery occlusion as a first sign of atrial fibrillation: A 3‐year retrospective single‐center analysis

Abstract Background Central retinal artery occlusion ((C)RAO) is known to be associated with stroke and/or atrial fibrillation (AF). Nevertheless, patients often present at the ophthalmologist initially and it is unknown how many of these receive an adequate cardiological/neurological work‐up (CWU/NWU), including a 24 h‐Holter‐ECG. Hypothesis Hypothesis of this study was that patients with (C)RAO do not undergo CWU on regular basis and that new‐onset AF is more often detected in patients with CWU. Methods and results We performed a retrospective analysis of n = 292 consecutive patients who presented at an ophthalmology department with the diagnosis of (C)RAO during a 3‐year period. After excluding patients with known AF, meeting exclusion criteria, inability to comply with the protocol, missed land phoneline, or death during follow‐up a total of 174 patients were enrolled; mean follow‐up was 20 ± 12 months. The CHA2DS2‐VASc score of the cohort was 5.3 ± 1.4. Our analysis revealed that only 50.6% of patients received a CWU including a single Holter‐ECG after the index‐event. In 12.6% cases new‐onset AF was diagnosed, while the rate was higher in patients with CWU compared to patients without CWU (18.2 vs. 7.0%; p = 0.26). Evaluation of oral anticoagulation (OAC) therapy showed that only 66% of patients with AF were treated according to guidelines. Conclusion Only half of patients with (C)RAO underwent CWU. Despite minimal monitoring, rate of new diagnosed AF was high. Our results confirm that (C)RAO identifies a high‐risk population for AF. These results illustrate the importance to implement standardized CWU in (C)RAO patients presenting at the ophthalmologist.

monitored, showed a higher incidence of AF compared to patients, who received a routine work-up with 24 h-Holter-ECG. 1 Based on these findings studies were initiated to evaluate the potential benefit of an oral anticoagulation for prevention of recurrent stroke in patients after an ESUS (embolic stroke of unknown source). [2][3][4] Another disease type with a close pathophysiological similarity is the (central) retinal artery occlusion ((C)RAO), which could be considered as a stroke equivalent. (C)RAO has an incidence between 1 and 15/10.000 und can be classified in thromboembolic, non-arteritic (ca. 95%), or arteritic (ca. 5%) occlusion. 5 The mean age of affected patients is 60 to 65 years and the majority of patients (>90%) are older than 40 years. 6,7 Men are more often affected than women (2/3 to 1/3). 8 Patients who suffer from (C)RAO present with acute and painless reduction or even loss of monocular vision. The main time for presenting at an ophthalmologist is 23 h. 9 Reasons for such a long waiting period are mainly misjudgment and the poor knowledge of this disease in the general population. 10 Furthermore, the initial presentation is mainly performed at an ophthalmologist due to loss of vision. This frequently prevents a timely neurological or cardiological diagnostic work-up regarding the thromboembolic source. However, there is no therapeutic approach.
Intra-arterial fibrinolysis warrants in CRAO no outcome improvement. 11 As another consequence, the required diagnostic work-up evaluating central atherosclerotic disease or the presence of AF is not regularly performed, prohibiting a potential required prevention therapy. With respect to the underlying causes of (C)RAO atherosclerosis of ipsilateral carotid artery is one of the two main causes. Depending on studies, the prevalence of significant stenosis of brain supplying arteries differs ranging from 10% to 70%. [12][13][14][15] The second important cause is cardiogenic embolism with a prevalence ranging up to 48%. 14 Commonly associated risk factors of (C)RAO are arterial hypertension, atrial fibrillation, coronary heart disease as well as hypercholesterinemia, diabetes mellitus, and smoking which further underline the fact that we are dealing with a systemic condition. 14,16 Registry studies showed that after experiencing a (C)RAO event the risk of subsequent stroke is increased 2-4 times within 3 years. 17,18 These numbers highlight that AF, stroke and (C)RAO are related to each other and that a cardiovascular/neurological diagnostic work-up is justified and recommended by current guidelines. 19 2 | HYPOTHESIS Objective of this study was to investigate the number of patients admitted to a ophthalmology department with the diagnosis of (C) RAO, who received further cardiological/neurological work-up regarding potential AF diagnosis or carotid disease screening identifying the underlying pathophysiological cause. In addition, we aimed to evaluate in how many patients new-onset AF was detected by a regular cardiological routine work-and follow-up in comparison to patients who did not undergo any cardiological work-up or specific rhythm monitoring.

| Patient enrollment
This retrospective monocentric (LMU University Hospital, Munich) study enrolled all patients, who presented with the diagnosis of (C) F I G U R E 1 In 3 years (01/2014-11/2016), 292 patients presented at our department of ophthalmology; 24 patients met exclusion criteria. Of the 268 patients meeting inclusion criteria, 94 patients were excluded (82 patients were unable to comply study protocol or missed land phone line; 12 patients died in follow-up of 20 ± 12 months). Overall, 174 patients could be included. AF, atrial fibrillation RAO at the department of ophthalmology in the period between 01/2014 and 11/2016. They were identified by using ophthalmic hospital's ''Smart eye Database''. 20 Inclusion criteria were documented diagnosis of (C)RAO, age ≥ 18 and ≤ 80 and given informed consent. Main exclusion criteria were documented history of atrial fibrillation, inability to comply study protocol, missed land phonelines as well as decease during follow up.

| Predefined endpoints
The primary endpoint was the percentage of patients who had undergone a cardiological work-up (CWU), which was defined as receiving at least one Holter-ECG for ≥ 24 h after the index (C)RAO event.
A key secondary endpoint was the number of patients who were diagnosed with de-novo AF during the follow-up period

| Follow-up
After obtaining informed consent for retrospective evaluation, we investigated the patient follow-up since the index event and used a standardized questionnaire concerning follow-up examinations (CWU and NWU), cardiovascular risk factors (arterial hypertension, diabetes mellitus), antiplatelet or anticoagulation therapy, if the patient had already a stroke or (C)RAO prior to the index event, any vascular disease (coronary/periphery/carotid artery disease) or a history of heart failure. The mean follow-up time was 20 ± 12 months.

| Study design and trial flow chart
Between 01/2014 and 11/2016, 292 patients with a (C)RAO event were admitted at our ophthalmology department ( Figure 1). Of these, 268 patients met the inclusion criteria; 24 patients were excluded based on an existing history of AF. Furthermore 94 patients were excluded due to different reasons, for example, inability to comply with the protocol, missing land phoneline (n = 82) or death during follow-up (n = 12).

| Statistical analysis
Continuous variables were presented as mean ± standard deviation, categorical variables as numbers and percentages. Normally distributed data were compared using the unpaired Student's t test and non-parametric variables using the Mann-Whitney-U test, respectively. All statistical analyses were performed using the SPSS software (version 20.0; SPSS Institute, Chicago, IL); a pvalue <0.05 was considered statistically significant.

| Cardiological work-up
Analysis of primary endpoint performance of a CWU defined as at least one ≥ 24 h-Holter-ECG, revealed a CWU rate of 50.6% (CWU+) within the whole study cohort (Figure 2(A)). In most cases (79.5) the screening was performed in an outpatient setting. Figure 2 Table S1).

| Neurological work-up
In a next step, we evaluated the degree of neurological work-up in all patients in FU. In contrast to CWU, the majority of 86.7% patients

| Antithrombotic therapy and recurrent ischemic events
Further we analyzed antithrombotic treatment after the index event.
About 70% of the patients were treated with anti-platelet therapy whereas 8.0% received an OAC. Both anti-platelet therapy as well as OAC was noted in 3.4%, while no specific therapy was present in 18.4% of the patients (Figure 4(A)). Figure 4(B) depicts the subgroup of patients with established diagnosis of AF and with respect to the type of secondary prevention. Our retrospective analysis showed that patients with new-onset AF were in consequence in 64% treated with OAC, while 36% did actually not receive any guideline recommended therapy for prevention of further thromboembolic events (TE) despite the diagnosis of AF on the past.
In addition to the prevention therapy, we investigated recurrent embolic events after index event. During follow-up 23/174 patients suffered from a stroke or recurrent (C)RAO (see Figure S1). In a subanalysis, we aimed to evaluate if patients with new-onset AF had more recurrent TE than patients without AF. Our analysis revealed that patients with new-onset AF (n = 22) experienced as often as patients without AF a recurrent thromboembolic event (13.6% vs. 13.2%, p = 0.95; see Figure S1a).

| DISCUSSION
According to guidelines, acute retinal arterial ischemia is a stroke equivalent and demand equal diagnostic work-up and at least monitoring over 24 h. 19 In this study we could show, that in a selected sub-form of a stroke-equivalent, (C)RAO, there is a clear lack of a cardiological diagnostic work-up in the daily routine, which could have potential impact on re-current events and clinical outcome.

| Potential role of AF
The American Heart Association and National Stroke Association recommend in patients with stroke an immediate evaluation in certified stroke centers which include an ECG as soon as possible after the event. Prolonged cardiac monitoring (inpatient telemetry or Holter monitor) should be performed in (C)RAO patients with an unclear etiology after initial brain/vessel imaging and ECG. 23,25,26 Besides the fact of an insufficient CWU in our studied (C)RAO cohort we aimed to

| Mode of action
In other studies, severe atherosclerosis of carotid artery seems to be the most common finding with respect to the underlying cause in (C) RAO patients. In the literature the prevalence of significant stenosis of brain supplying arteries differs from 10% to 70% in (C)RAO patients. [12][13][14][15] In our (C)RAO patients with NWU+, severe carotid artery stenosis (≥NASCET criteria) was diagnosed in 27.8% and fits quite well with previous studies.

| Therapeutic consequences on treatment strategy
Taking (C)RAO as an equivalent of stroke, treatment with an antiplatelet agent is recommended, if there is no contraindication. In our retrospective analysis, over 16% of patients did not take any bloodthinning drug at all which could indicate patients missed an adequate internal assessment after (C)RAO. This hypothesis could also explainat least in some extendthe high number of untreated AF (1/3 of cases). Severe bleeding events in the past could be a reason for withholding OAC in 2 patients. Still, taking the CHA 2 DS 2 -VASc score into account, there were 8/15 patients in which no objective reason for withholding OAC despite a diagnosis AF could be found.
As mentioned above, registry studies provide evidence that patients after (C)RAO have a significantly elevated risk for further cerebral events. One retrospective study, in which even after correcting for cardiovascular risk factors, patients with AF and (C)RAO had an increased risk for future ischemic events (stroke/TE/TIA) with a hazard ratio of 1.39 (95%, CI 1.08-1.79). 24 In our study population, we obtained rates of recurrent thromboembolic eventstroke or recurrent (C)RAOin more than 13% of patients during a mean FU of 20 months, which is remarkably high.  of an OAC will translate in better outcome is completely unclear and has to be addressed by future trials.

| Potential limitations
This is retrospective study in a very selected group (C)RAO patients, who initially presented at the ophthalmological department. We did not perform a prospective comparison to patients presenting at first at the neurological department. Based on the retrospective nature there was no uniform standard of CWU performed. Data collection were primary based on patient record files and telephone interviews.
In our study, patients with new-onset AF experienced a recurrent thromboembolic event as often as patients without AF in the followup, which is quite surprising. On one hand the number of patients is quite small so and the total number of events is a limitation. Furthermore, the mode of follow-up was based on the retrospective nature of this study, which might lead to an underestimation of clinical events. On the other hand, the duration of follow up was rather short with 20 ± 12 months, which could explain the similar rates of thromboembolic events in both groups.
Still, in perspective of the lack of data, in this special entity our analyses revealed relevant results and can be taken as hypothesisgenerating for future prospective studies.

| CONCLUSION
Our study illustrates that patients with (C)RAO usually presenting to an ophthalmologist at first, although the main cause is potentially a systemic embolic condition. The rate of systematical CWU performed was very low, but rate of AF diagnosis was relatively high. Although these results represent common sense, to the best of our knowledge there is a clear lack of systematic data or previous studies on this topic. Our data highlight a current gap between the diagnosis of (C) RAO and subsequent further diagnostics and therapy, which should be addressed in the future. Implementation of SOPs with recommendation to screen for AF might be required to improve secondary prevention measures in these patients.