The optimal cutoff of atrial high‐rate episodes for neurological events in patients with dual chamber permanent pacemakers

Abstract Background Patients with atrial high‐rate episode (AHRE) are at higher risk of neurological events. This study aimed to identify the optimal cutoff threshold for AHRE duration in patients with dual chamber permanent pacemakers (PPM) without prior atrial fibrillation. Methods We included 355 consecutive patients receiving dual chamber pacemaker implantation. Primary outcome was composite endpoint of subsequent neurological events after various AHRE durations. AHRE was defined as >175 bpm (MEDTRONIC) or > 200 bpm (BIOTRONIK) for longer than 30 s. Cox regression analysis with time‐dependent covariates was conducted. Results The mean age of included patients was 75.6 ± 11.3 years. Among 355 included patients, some had multiple AHREs; 125 patients (35.2%) developed AHRE ≥2 min, 107 (30.1%) had ≥5 min, 55 (15.5%) had ≥6 h, and 37 (10.4%) had ≥24 h. The mean follow‐up was 42.1 ± 31.2 months. During follow‐up, 19 neurological events occurred. After adjustment for CHA2DS2‐VASc score and device type, multivariate Cox regression analysis indicated AHRE ≥2 min (HR 13.605, 95% CI 3.010–61.498), and AHRE ≥5 min (HR 5.819, 95% CI 2.056–16.470) were significantly associated with neurological events. Hence, the optimal AHRE cutoff value was 2 min with the highest Youden index (sensitivity, 89.5%; specificity, 67.8%; AUC, 0.823, 95% CI, 0.763–0.884; p < 0.001). Conclusions Patients with dual chamber PPM who develop AHRE have increased risk of neurological events. Comprehensive assessment of the risks and benefits of prescribing anticoagulants should be considered in PPM patients with AHRE ≥2 min.

T A B L E 1 Baseline characteristics of the overall study group were fully anonymized before we accessed them and the ethics committee waived the requirement for informed consent.

| Data collection and definitions
Patients' medical history, comorbidities, and echocardiographic parameters were collected from chart records for retrospective evaluation. Diabetes mellitus was defined by the presence of symptoms and a random plasma glucose concentration ≥ 200 mg/dl, fasting plasma glucose concentration ≥ 126 mg/dl, 2 h plasma glucose concentration ≥ 200 mg/dlL, from a 75 g oral glucose tolerance test, or taking medication for diabetes mellitus. 9 Hypertension was defined as in-office systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic BP (DBP) ≥ 90 mmHg or taking antihypertensive medication. 10  tachycardia and visually confirmed AF in the detected AHRE (Supplement

| Univariate analysis and multivariate Cox regression analysis of associations between duration of AHRE and neurological events in all patients
Univariate analysis found an association of gender, device type,

| ROC-AUC determination of AHRE cutoff values for association with future neurological events
The optimal AHRE cutoff value for association with future neurological events was determined to be 2 min, with the highest Youden index  (Figure 1). With AHRE of 5 min, we found: sensitivity, 73.7%; specificity, 72.3%; positive predictive value, 13.1%; negative predictive value, 98.0%; positive likelihood ratio, 2.66; negative likelihood ratio, 0.38. Figure 2 shows the Cox regression eventfree survival curves for neurological events.

| DISCUSSION
The main finding of this study is that AHRE duration ≥2 min, as detected by dual chamber PPMs, was significantly associated with neurological events in a Taiwanese population that had no history of AF. However, further investigation is warrant to confirm the current findings and to implement early aggressive anti-thromboembolic therapy to prevent future neurological events based on detection of AHRE ≥2 min in Taiwanese population.
The ASSERT study 15  In our study, the ROC curve showed that the best cutoff duration time of AHRE for predicting the risk of neurological events was 2 min.
Compared to 5 min, our results showed that the cutoff value of 2 min had a higher positive likelihood ratio and negative predictive value, and lower negative likelihood ratio, indicating that 2 min is a more sensitive cutoff value for ruling out subsequent neurological events.
Current guidelines 1 recommend that AF be diagnosed using a 12-lead EKG for a duration of more than 30 s. Both artifacts and false detection of far-field R-wave by the atrial lead could misclassify AHRE if of too short a duration. Previously, the 5 min cutoff value excluded most episodes of over-sensing due to mechanical problems and appropriately detected clinical AF. 16 In order to prevent over-diagnosing SCAF we should focus on SCAF detected using our optimal cutoff value of AHRE ≥2 min confirmed by experienced electrophysiologists.
Although both AHRE duration ≥ 6 h and AHRE duration ≥ 24 h are significantly different in patients with or without neurologic events in Table 1, however, in our multivariate analysis in Third, this study did not reach any conclusions about the nature of heart rhythms at the time of the onset of stroke or TIA. Fourth, not all patients with neurological events underwent brain magnetic resonance imaging/angiography to pursue the etiologies of embolic origin, however, the neurologists confirmed the all neurologic events. Finally, the number of neurological outcomes is relatively small; therefore, there is a problem of over-fitting with the multivariable analyses.

| CONCLUSIONS
Stroke or TIA events are relatively common in Taiwanese patients with dual chamber PPMs. AHRE lasting for ≥2 min is an independent risk factor for neurological events in this population. AHRE of different durations appear to be consistently associated with neurological events. When AHRE ≥2 min is detected in patients with dual chamber PPMs, a comprehensive assessment of the risks and benefits of prescribing an anticoagulant should be considered.