In this report from CAFR, our data collected from 8529 NVAF patients demonstrated that in non--anticoagulated patients, risk of thromboembolic events was higher in PeAF than PaAF before adjusting confounders. However, this difference became not significant after adjusting age, sex, history of stroke, hypertension and vascular diseases. In contrast, in anticoagulated patients, thromboembolic risk did not differ between PaAF and PeAF before and after adjusting possible confounders.
This is one of the first comparisons of thromboembolic outcomes in different NVAF patterns in large Chinese population. As patients receiving catheter ablation treatment had a low incidence of stroke , we excluded those who received catheter ablation and with no AF recurrence, to avoid the dilution effect of low-risk patients. Our results strengthen the recommendation of current guidelines on stroke prevention for NVAF patients, suggesting choosing anticoagulation treatment should not base on the pattern of AF.
Current guidelines recommend that the pattern of AF should not be taken into account when assessing the stroke risk and deciding the choice for thromboembolism prophylaxis treatment in patients with AF [3, 4], despite that the burden of AF is higher in PeAF patients than that in PaAF patients. Whether AF pattern is associated with stroke risk has aroused wide concern over the recent years.
Clinical trial cohorts have reported contradictory findings. A sub-analysis of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Atrial Fibrillation (GISSI-AF) trial  reported a similar rate of thromboembolic events in patients with PeAF and PaAF, with a much lower incidence among the overall population (0.97%) compared with our findings. In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial , the overall risk of stroke or systemic embolism in patients with paroxysmal, persistent, and permanent AF were similar, with rates of 1.32, 1.55, and 1.49% per year, respectively. In contrast, other trials have reported different results. In the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study , patients with PeAF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73% per year, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006) compared with patients with PaAF. The same was found in SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) III and V trials . AF pattern was found to be an independent predictor of stroke in the sub-analysis of AVERROES (Apixaban Versus ASA to Prevent Stroke In AF Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) and ACTIVE A (the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) trials , which only selected aspirin-treated NVAF patients.
Observational cohorts have also reported contradictory findings. The incidence of ischemic stroke adjusted by warfarin and other risk factors was similar in PaAF as in PeAF (2.6 vs. 2.9 per 100 patient years) from the Stockholm Cohort of Atrial Fibrillation . In an Asian cohort, the crude event rate was 2-fold higher among the permanent NVAF patients (2.29%) than paroxysmal (1.16%) or persistent (1.20%) AF patients (P = 0.001), while after adjustment for warfarin use and risk factors, the hazard ratio for thromboembolism did not differ between paroxysmal and permanent groups . In a Japanese study, Takabayashi et al. observed PaAF was independently associated with lower incidence of stroke/systemic embolism than sustained AF in patients with or without anticoagulants .
One of the possible reasons for the inconsistent results may be due to the use of antithrombotic therapy for preventing stroke, which will limit the outcome events and therefore, reduce the power to detect the difference of stroke incidence across AF patterns. Inconsistent anticoagulation strategy by design, imbalances of anticoagulant intensity and differences in the use of OAC rates may act as confounders. Different anti-platelet and/or anticoagulant therapy including aspirin, warfarin and new oral anticoagulants were used in various studies, with different efficacy in preventing thromboembolism. For example, the ACTIVE A and AVERROES trials  observed aspirin-treated NVAF patients and concluded different rates of ischemic stroke were 2.1, 3.0 and 4.2% per year for paroxysmal, persistent, and permanent AF respectively. In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thrombo-embolic Events in Atrial Fibrillation) trial , in which all of the patients were treated with warfarin or NOAC, the rate of stroke or systemic embolism was significantly higher in patients with persistent or permanent AF than paroxysmal group (1.52 vs. 0.98%, adjusted P = 0.015).
Of note, few studies observed thromboembolism incidence according to the stratified application of anticoagulants in different AF types. In our cohort, risk of thromboembolic events were compared between PaAF and PeAF patients based on OAC therapy. Univariate and multivariate analysis of Cox proportional hazards regression models were performed in the absence of OAC therapy to evaluate the predictive value of AF types more accurately. For non-anticoagulated patients, PeAF group demonstrated a trend towards worse outcomes, with higher incidences of stroke/TIA/PT, all-cause death and cardiac/non-cardiac death than PaAF patients. In OAC users, risk of outcomes was comparable between PaAF and PeAF groups. Age ≥ 75 yrs. and prior history of stroke/TIA/PT were independent predictors for thromboembolism, which was consistent with most of the prior studies. The Fushimi Atrial Fibrillation Registry (The Registry Study of Atrial Fibrillation Patients in Fushimi-ku)  reported a lower risk of stroke/systemic embolism in PaAF patients both in non-OAC/OAC users and confirmed PaAF was an independent predictor of lower stroke/systemic embolism risk. However, our data did not find the difference, although our sample size was larger, and patients in our study had higher proportion of PaAF patients and slightly lower CHADS2 /CHA2DS2-VASC score.
Other reasons may possibly explain the conflicting results in different studies. For example, different risk levels of the study population are relevant. The present study showed a majority of baseline variables were evidently different between PeAF and PaAF patients, with higher risk and more underlying comorbidities in PeAF type. PaAF group had a lower CHADS2 (PaAF vs. PeAF:1.7 vs.2.1, P = 0.000) and CHA2DS2-VASc score (PaAF vs. PeAF 2.9 vs. 3.3, P = 0.000), which was similar with ACTIVE-A and AVERROES , but lower than the results from ROCKET-AF  trial (mean CHADS2 score 3.5 for both types). Our data indicated significant variations of stoke risk factors between the two types. In the presence of known risk factors involved in CHA2DS2-VASc score, progression from sinus rhythm to PaAF or more sustained forms is frequently seen along with atrial electrical and structural remodeling. AF types reflect different states in the process of AF progression and may be the consequence of interaction between CHA2DS2-VASC components rather than the risk factor of stroke.
Different proportion of PaAF patients was included in previous studies. The proportion of PaAF (54.4%) among 8529 NVAF patients in our study was similar with that of the Loire Valley Atrial Fibrillation Project (58.4%) , but higher than most of other studies which recruited PaAF patients less than 50%, such as ACTIVE A and AVERROES trials (24%) , ROCKET-AF trial (17.6%) , ACTIVE W(Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events) Substudy (17.9%) , J-RHYTHM Registry (38.3%)  and Fushimi study (48,1%) . In GISSI-AF trial , higher proportion of PaAF patients (62.5%), lower CHADS2 score (1.41 ± 0.84) and lower incidence of thromboembolic events (0.97%) were observed compared with our study. PaAF represented the early stage of AF progression, with lower AF burden than PeAF. The duration and frequency of AF episodes may have contributed to the conflicting results from prior reports.
Definitions of stroke were also different in previous trials, such as ischemic stroke (i.e. cardioembolic, atherothrombotic, or lacunar infarction) or hemorrhagic stroke, or both types. Different criteria of event ascertainment may lead to discrepancy in rate of stroke and systemic embolism. In the ARISTOTLE, Stockholm studies and Fushimi Registry [8, 12, 15], stroke endpoints were defined as a composite of ischemic and hemorrhagic stroke, while in our study and some others [14, 26], only ischemic stroke associated with AF was designed as clinical endpoints that may limit the number of events.
The event rates in our study were lower compared to that reported in other studies, despite the CHADS2 and CHA2DS2-VASc scores were similar . The lower incidence of thromboembolic events may be attributed to our study being a cohort reflecting current practice, with blood pressure, cholesterol and other risk factors well controlled compared to prior studies. In patients with AF and hypertension, having any elevated BP measurements was independently associated with a higher risk of stroke or systemic embolism . This is supported by the post-hoc analysis of GISSI-AF trial , where the event rate was only 0.97% per year in patients without anticoagulants, even lower than our study. We used an independent endpoint adjudication committee to validate stroke event, which is not the usual way in observational studies and excluded about one quarter of stroke events which is self-reported by patients while turned out not to be a true event. Multiple studies have shown a progressive decline in the incidence of thromboembolism in non-anticoagulated patients identified with NVAF over the past several decades, which is evident in the present study that reports crude incident rates of ~ 2/100 patient years for thromboembolism. The progressive decline in thromboembolism of non-anticoagulated NVAF patients is undoubtedly multifactorial and may be secondary to improved treatment of morbidities and also by early identification of lower risk NVAF patients.
We stratified OAC use in different groups and adjusted several risk factors of thromboemblism. Some residual confoundings might still remain even after multivariate adjustment, especially factors like obesity, sleep apnea and smoking etc. Previous studies consistently indicated AF burden detected by implanted devices was associated with an increased risk of ischemic stroke [28, 29], but it is not possible for us to further stratify the PaAF patients into different levels of AF burden to investigate the differences in risk. Future investigations are necessary to indentify the correlation between AF pattern, AF burden and thromboembolic events.