Atrial High-Rate Episodes Are a Comprehensive Surrogate Marker for Thromboembolic and Bleeding Events
Article ID: CJ-21-0343
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Article ID: CJ-21-0343
Ominous foreboding is almost correct. Frequent premature atrial contraction’s (PACs) sometimes precede atrial fibrillation (AF); however, only PACs are usually not targeted for active treatment with anticoagulants or anti-arrhythmic drugs. Asymptomatic subclinical AF (SCAF) has also been overlooked because of its features, but recently available long-term continuous electrocardiographic monitoring systems have revealed that SCAF is not uncommon.1–6 Previous reports suggested that SCAF was a worse prognosis than symptomatic AF;7 however, detecting SCAF remains an essential issue even in the contemporary era.
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In patients with cardiac implantable electrical devices (CIEDs), these asymptomatic, subclinical atrial high-rate episodes (AHREs) can be detected by device recordings. A previous observational study1,8 showed that patients with a pacemaker or transvenous implantable cardioverter defibrillator (TV-ICD) who had not been previously diagnosed with AF had a higher prevalence of AHREs, and AHREs >24 h, predominantly due to SCAF, were detected in 10.7% over a 2.5-year observational period. The Table summarizes several reports regarding the incidence of AHREs.
| Study | Observational period |
AHREs | Stroke and STE prevalence (%/year) |
Bleeding prevalence (%/year) |
|
|---|---|---|---|---|---|
| Duration | Prevalence (%) | ||||
| Healey et al1 (ASSERT trial) | 3 months | >6 min | 10.1 | ||
| 2.5 years | 24.5 | 1.7 | N/A | ||
| Healey et al3 (ASSERT II trial) | 1.4 years | >5 min | 34.4 | N/A | N/A |
| >30 min | 21.8 | N/A | N/A | ||
| >6 h | 7.1 | N/A | N/A | ||
| >24 h | 2.7 | N/A | N/A | ||
| Glotzer et al6 (MOST trial) | 2.3 years | >5 min | 51.5 | 9.2† | N/A |
| Glotzer et al2 (TRENDS study) | 30 days | 0 | None | 1.1 | N/A |
| 0–5.5 h | 12.0 | 1.1 | N/A | ||
| >5.5 h | 12.0 | 2.4 | N/A | ||
| Botto et al5 | 1 year | <5 min | 29.0 | 1.2 | N/A |
| 5 min–24 h | 31.0 | 1.7 | N/A | ||
| >24 h | 39.0 | 4.0 | N/A | ||
| Nishinarita et al4 | 1 year | >5 min | 33.0 | 5.9 | 17.7‡ |
| Ishiguchi et al9 | 4.5 years | <6 min | 50.7 | 5.6 | 5.9 |
| 6 min–24 h | 28.3 | 9.1 | 8.5 | ||
| >24 h | 21.0 | 17.2 | 18.2 | ||
| Observational period |
AHREs | Stroke and STE | |||
| Duration | Prevalence (%) | Adjusted HR (95% CI) vs. no SCAF |
|||
| Van Gelder et al8 (ASSERT trial sub-study) |
2.5 years | 6 min–6 h | 18.8 | 0.75 (0.29–1.96) | |
| 6 h–24 h | 6.9 | 1.32 (0.40–4.37) | |||
| >24 h | 10.7 | 3.24 (1.51–6.95) | |||
†Included death as the primary outcome. ‡Including minor bleeding. AHRE, atrial high-rate episode; CI, confidential interval; HR, hazard ratio; N/A, not applicable; SCAF, subclinical atrial fibrillation; STE, systemic thromboembolism.
There are several reports that device-detected AHREs are associated with thromboembolic events.2,4–6,8 Longer duration of AHREs had a higher incidence of thromboembolic events, and patients with AHREs for >24 h had 3.24-fold higher thromboembolic events than those without (Table, Bottom).8 The prevalence of thromboembolic and bleeding events in AF patients has racial differences; therefore, there was a need for Japanese data. We previously reported that AHREs >5 min were associated with a higher incidence of heart failure, stroke, fatal arrhythmia, bleeding, and all-cause death over a 1-year observation period;4 however, long-term Japanese data of AHREs for these events have been scarce.
In this issue of the Journal, Ishiguchi et al9 evaluated the association between AHREs and ischemic/bleeding events in Japanese patients with CIEDs. They evaluated 710 Japanese patients who had CIEDs implanted, focusing on the role of AHREs in ischemic and major bleeding events for a 4.5 (2.5–7.0)-year observation (3,439 person-years). Ischemic events significantly increased in patients with AHREs >24 h compared to those with AHREs <6 min (17.2% vs. 5.6%, P=0.008); major bleeding events also increased in those patients (>24 h vs. <6 min=18.2% vs. 5.9%, P=0.04). Multivariate analysis revealed that age ≥85 years was an independent predictor for major bleeding events, whereas a history of AF and AHREs >24 h showed a tendency of significance for ischemic and major bleeding events in univariate analysis. Therefore, the authors concluded that longer AHREs are associated with a higher number of major bleeding and ischemic events.
It is straightforward that higher age was associated with a higher rate of ischemic and bleeding events; therefore, the valuable result of the present study was the impact of AHREs on those events. Since there has been no evidence of how AHREs are associated with thromboembolic and bleeding events in Japanese patients, this report provides us with significant findings. The authors also performed a more detailed analysis, and the thromboembolic and major bleeding events were further increased in the >96-h AHRE sub-group, suggesting that much longer AHREs were associated with a further greater incidence of those events.
In contrast, pacemakers or TV-ICDs themselves might cause AHREs because of lead-related tricuspid regurgitation or a non-physiological pacing rhythm. In this regard, in the ASSERT-II trial,3 SCAF was evaluated with subcutaneous electrocardiographic monitoring (i.e., no intravenous devices), which revealed that SCAF lasting more than 24 h was detected in 2.4%/year. Since it seems less than that with intravenous lead devices, the device type or patient characteristics might influence the results; however, the prevalence of SCAF still cannot be negligible.
Other important findings in this study were that longer AHREs was also associated with a higher rate of bleeding events. There have been limited data on the relationship between AHREs and bleeding events. In general, thromboembolic events and bleeding events are contrasting. If AHREs are postulated to be a precursor to AF or AF itself, it is understandable that longer AHREs cause a higher rate of thromboembolic events. However, Brambatti et al10 reported in a sub-study of the ASSRT trial1 that very few patients had SCAF in the month before their stroke or systemic embolism, although SCAF lasting >6 min significantly increased the incidence of stroke and systemic thromboembolism. Therefore, each AHRE might not directly cause thromboembolic events, but might be a surrogate marker of those events. Because the risk scores between thromboembolic and bleeding events share several factors,11,12 those events are, in part, associated with each other. From this perspective, it is reasonable that AHREs are not directly associated with bleeding complications, but they might also be a surrogate marker of future bleeding events.
As a limitation of this observational study, it should be noted that the present study partially included patients who were previously diagnosed with AF, and a greater proportion of those patients were more included in the AHRE >24-h group. Therefore, caution must be exercised to interpret the results. The authors separately analyzed those events in patients without a history of AF, and the same tendencies were observed; however, those became statistically insignificant. It also remains unclear whether those results can be generalized to AF patients without intravenous CIEDs. Further, whether those patients should be treated with anticoagulants is a different story. Several clinical trials are ongoing on this issue, so those will provide us the answer shortly.
It has long been recognized that AHREs are associated with thromboembolic events; however, there has been a paucity of data from Japan. Therefore, the present study is of clinical importance. Clinicians should be aware of the higher risk of thromboembolic and major bleeding events in patients with longer duration AHREs. Further prospective studies will be necessary to more deeply clarify the relationship between the AHREs and clinical events.
H.F. received lecture fees from Boehringer Ingelheim, Daiichi-Sankyo, Bayer Healthcare, Abbott Medical Japan, Biosense Webster Japan, and JAPAN LIFELINE Co, Ltd.
