Device-detected atrial fibrillation in a large remote-monitored cohort: implications for anticoagulation and need for new pathways of service delivery

For this study, the PaceMate™ RM system was utilized. This system is a partially automated, vendor-neutral RM software system. The system presents RM data acquired from all vendors in a standardized format. The database includes all RM alerts transmitted by CIED patients undergoing RM via PaceMate Live™.

For the study protocol, consecutive AF episodes transmitted via RM from March 2019 until February 2020 were assessed. The study was reviewed and approved by the Human Research Ethics Committees of the Central Adelaide Local Health Network and the University of Adelaide. The study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12620001232921).

Patients were derived from 26 centers in the United States of America and Australia, with devices from multiple manufacturers including Medtronic, Abbott Medical, Boston Scientific, and Biotronik. All patients, who transmitted at least one AF episode with specified episode duration during the twelve-month window, were included and classified according to age, CIED-type, estimated minimum CHA₂DS₂-VASc score (details below), and anticoagulation status.

All AF alerts are received and assessed by device specialists certified by the International Board of Heart Rhythm Examiners (IBHRE). PaceMate device specialists are on-call 24 h a day, 7 days a week for immediate analysis (where possible, depending on the burden of RM transmissions queued for analysis) of RM alerts. After alert analysis, a concise written alert summary is transmitted to patient’s relevant clinic, via an integrated web-based interface, which is streamlined to display alerts from all device manufacturers. The management of incoming alerts/episodes on the PaceMate interface is dictated by each clinic, with allocation of their chosen staff member/s (e.g., cardiac technician, nurse, and physician) to routinely check the interface, and escalation to more senior staff (e.g., physician and electrophysiologist) as per the individualized clinic protocol.

CIED-type was classified as either dual-chamber permanent pacemaker (PPM), dual chamber implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy defibrillator (CRT-D), cardiac resynchronization therapy pacemaker (CRT-P), or implantable loop recorder (ILR). Single-chamber PPMs, leadless PPMs, and single-chamber ICDs were not included in the analysis.

AF episodes without an attached episode duration available in the remote transmission were excluded. All remaining AF episodes were classified according to duration. Episodes occurring within a 24-h period were pooled to create a total duration of AF within 24 h. Pooled episodes were then re-classified into one of four pre-specified AF duration windows: (1) less than 6 min during a 24-h period (AF < 6 min), (2) at least 6 min, but less than 6 h during a 24-h period (AF 6 min–6 h), (3) at least 6 h but less than 24 h during a 24-h period (AF 6–24 h), and (4) 24 h or above (AF ≥ 24 h). Patients were then allocated to one of the four AF duration categories, according to their longest pooled episode duration.

Patient parameters available to estimate CHA₂DS₂-VASc scores included patient age and the presence of a cardiac resynchronization device consistent with heart failure or left ventricular (LV) dysfunction. The RM database did not contain information regarding patient history of hypertension, diabetes mellitus, stroke, vascular disease, or sex.

For the purposes of the study, given the available parameters, we classified the following patients with an AF burden of at least 6 h over 24 h as having an indication for anticoagulation:

Anticoagulation status for each patient was updated following each transmission of an AF episode via bidirectional software system-based communication between PaceMate staff and clinic staff, or by interrogation of the patient’s integrated electronic medical record, which was accessible via the database in some sites. In patients who transmitted an AF episode, whose record did not indicate the current presence of anticoagulation, PaceMate technicians communicated to staff in the relevant clinic the need for consideration of anticoagulation, via the PaceMate web-based interface. Following this communication, clinic staff would respond and the patient’s anticoagulation status would accordingly be updated on the PaceMate user interface. In the absence of a response from clinic staff, PaceMate technicians would continue to re-communicate the anticoagulation query to clinic staff until a response was received, with anticoagulation status clarification. For the purposes of our analysis, anticoagulation status of each patient was as per the PaceMate interface at the close of the 12-month monitoring period.

The final AF alert cohort of 7651 patients included 3120 (40.8%) dual-chamber PPMs, 2260 (29.5%) ILRs, 987 (12.9%) dual-chamber ICDs, 968 (12.7%) CRT-Ds, and 316 (4.1%) CRT-Ps (central figure, Fig. 1, Table 1). Of the 389,188 AF episodes transmitted, 190,041 alerts (48.8%) were transmitted by ILRs, 124,378 alerts (32.0%) by PPMs, 31,973 alerts (8.2%) by CRT-Ds, 28,495 alerts (7.3%) by ICDs, and 14,301 alerts (3.7%) by CRT-Ps (Fig. 1).

The cohort included patients with devices from Medtronic, Abbott Medical, Boston-Scientific, and Biotronik. Medtronic devices accounted for 56.1% (n = 4293) of the cohort, Boston Scientific devices for 26.2% (n = 2001), Abbott Medical devices for 11.4% (n = 875), and Biotronik devices for 4.0% (241) (Table 2).

After calculation of the longest aggregate AF burden within 24 h per patient, 3404 (44.5%) patients had AF < 6 min, 1367 (17.9%) patients had AF 6 min–6 h, 1206 (15.8%) patients had AF 6–24 h, and 1674 (21.9%) patients had AF ≥ 24 h. This equated to 2880 (37.6%) patients having at least 6 h of AF within a 24-h period.

Of the 7651 total patients who transmitted AF episodes, 3841 (50.2%) were aged 75 years or above, with a minimum CHA₂DS₂-VASc score of 2. Of these patients, 642 (16.7%) had AF durations between 6–24 h and 231 (36.0%) of these patients were not anticoagulated. A further 947 (24.7%) patients aged at least 75 years had AF ≥ 24 h and 276 (29.1%) of these patients were not anticoagulated (Fig. 2).

In patients aged at least 75 years with an AF episode of at least 6 h, 1082 (68.1%) of a total 1589 patients were receiving anticoagulation at the end of the 12-month monitoring period, while 507 (31.9%) were not.

Of the 3841 patients aged ≥ 75 years, 682 had a CRT-D or CRT-P in situ, elevating their minimum CHA₂DS₂-VASc score to 3. Of these patients, 92 had AF 6–24 h with 39 (42.4%) not anticoagulated. A further 234 patients had AF ≥ 24 h with 66 (28.2%) not anticoagulated (Fig. 2).

Of the total 326 patients designated a minimum CHA₂DS₂-VASc score of 3, due to a combination of their age and device type, who transmitted an AF episode of at least 6 h in duration, there were 221 (67.8%), who were receiving anticoagulation and 105 (32.2%) who were not.

A total of 2051 patients in the cohort were aged 65–74 years, with a minimum CHA₂DS₂-VASc score of 1. Of these patients, 339 had AF 6–24 h and 104 (30.7%) were not anticoagulated. A further 449 patients had AF ≥ 24 h and 113 (25.2%) were not anticoagulated (Fig. 2). When all patients aged 65–74 years with an AF episode of at least 6 h were pooled, 517 (72.5%) of a total 788 patients were receiving anticoagulation, while 217 (27.5%) were not.

Of the 2051 patients aged 65–74 years, 313 had a CRT-D or CRT-P in situ, elevating their minimum CHA₂DS₂-VASc score to 2. Of these patients, 31 had AF 6–24 h, 10 (32.3%) of whom were not anticoagulated. A further 84 patients had AF ≥ 24 h and 14 (16.7%) were not anticoagulated (Fig. 2).

Of the total, 115 patients aged 65–74 years with a CRT-D or CRT-P in situ, and an AF episode of at least 6 h, 91 (79.1%) were receiving anticoagulation, while 24 (20.9%) were not.

Use of anticoagulation was compared across age categories in all patients aged at least 55 and above, with an AF episode duration of at least 6 h. In patients with AF 6–24 h, anticoagulation was present in 61.2% of those aged 55–64 years, 68.5% of those aged 65–74 years, 68.0% of those aged 75–84 years, and 56.4% of those aged ≥ 85 years (Fig. 3). In patients with AF ≥ 24 h, anticoagulation was present in 77.8% of those aged 55–64 years, 75.2% of those aged 65–74 years, 74.5% of those aged 75–84 years, and 67.6% of those aged ≥ 85 years (Fig. 4).

Early detection of AF and the potential opportunity to intervene to reduce stroke risk is a key benefit of RM. Using a large clinical RM database across multiple centers, we identified the following with regards to AF episodes:

A large proportion (48.8%) of AF episodes were transmitted by ILRs, despite ILRs accounting for only 29.5% of the cohort. This may be partially attributable to the nature of ILR indications, including syncope [10, 11], cryptogenic stroke [12‐14], and palpitations [15, 16], all of which may be caused by AF or its termination. Alternatively, this may represent transmission of false-positive episodes, which are a common occurrence in ILRs, largely due to atrial ectopy or noise [17].

By comparison, despite accounting for the bulk of CIEDs (44.9%) in the cohort, PPMs were responsible for only 35.7% of AF episodes, while defibrillator patients represented 25.6% of the cohort but transmitted only 15.5% of AF episodes. Device programming in PPMs and ICDs may further explain this between-device group disparity; patients with known AF, on appropriate therapy, may be programmed with a longer AF duration threshold for triggering of an RM alert.

While device-detected AF has been established as a risk factor for stroke, questions remain regarding the appropriate AF episode duration threshold for commencement of anticoagulation. A sub-analysis of the ASSERT study demonstrated a significantly increased risk of stroke or systemic embolism in patients with a device-detected AF episode of at least 24 h, with shorter episodes (6 min–24 h) not correlating with an increase in risk [18]. Another study of over 9000 CIED patients over a ten-year period showed device-detected AF of at least 5.5 h was associated with heightened stroke risk [19]. With regards to shorter duration episodes, the LOOP study anticoagulated high-risk patients with at least 6 min of AF detected on a loop recorder and found no significant reduction in stroke of systemic embolism compared to a control group [20]. A recent meta-analysis of studies reporting stroke events in patients with device-detected AF demonstrated a low risk of stroke (0.93 per 100 person years) in association with “short” duration AF episodes [21]; however, there was significant between-study heterogeneity in the definition of such episodes, ranging from below 6 min duration [3] to below 5.5 h burden in one day [22]. The same meta-analysis showed that overall, device-detected AF was associated with an increased stroke risk (absolute annual risk 1.89 per 100 person years, increased to 2.76 per 100 person years in case of mean CHADS₂ score 2.1) [21].

Al-Gibbawi et al. assessed stroke/transient ischemic stroke (TIA) incidence in a high-risk unanticoagulated CIED patient population with an average CHA₂DS₂-VASc score of 4.1 and a 19.9% rate of previous TIA/stroke. They found no correlation between longest AF episode duration and risk of stroke, nor between overall AF burden and risk of stroke[23]. Comparatively, Go et al. demonstrated an association between AF burden determined by wearable cardiac monitors and risk of stroke, in a population with a lower average CHA₂DS₂-VASc score (2.6), and a lower rate of previous TIA/stroke (2.7%) [24]. These contrasting findings raise the possibility that in higher-risk patients (as determined by CHA₂DS₂-VASc scores) with a CIED in situ, AF burden and episode duration are less predictive of stroke [23]. In our cohort, such high-risk patients with CHA₂DS₂-VASc scores of at least 3, with AF of at least 6 h, but less than 24 h, were anticoagulated at a rate of only 57.6%.

The European Heart Rhythm Association guidelines recommend oral anticoagulation in patients with a CHA₂DS₂-VASc score ≥ 2 in the presence of an AF burden of more than 5.5 h in one day [25]. Our analysis demonstrates that among patients with a transmitted AF episode of at least 6 h, and a minimum CHA₂DS₂-VASc score of 2, the overall anticoagulation rate was 68.8% (central figure). Kaplan et al. looked specifically at device-detected AF in a large real-world remote-monitored CIED patient population and described comparatively low rates of anticoagulation. In patients with daily AF burden of between 6 min and 23.5 h, anticoagulation was prescribed in 14.1%, 29.6%, and 44.7% of those with CHA₂DS₂-VASc scores of 2, 3–4, and ≥ 5, respectively. These rates may be explained by inclusion of short-duration episodes for which treating clinicians opted against anticoagulation; however, anticoagulant use remained low in patients with longer duration AF (> 23.5 h), being prescribed in 24.3%, 45.3%, and 67.2% of those with CHA₂DS₂-VASc scores of 2, 3–4, and ≥ 5, respectively. [26]. In contrast, Steinberg et al. compared rates of oral anticoagulation in over 60,000 patients with newly diagnosed clinical AF within two AF registries and found anticoagulation use in 69% (GARFIELD-AF (international)) and 87% (ORBIT-AF II (US-only)) of patients with a CHA₂DS₂VASc score ≥ 2 [27]. The discrepancy in anticoagulation rates may be reflective of physician reluctance in prescribing anticoagulation for patients with device-detected AF, especially as US guidelines do not specify thresholds for the use of anticoagulation in this patient cohort [28]. Given the uncertain benefits of anticoagulation among patients with device-detected AF, particularly in those with episodes shorter than 24 h in duration, outcomes from pending trials (e.g., ARTESIA (NCT01938248) [29] and NOAH-AFNET 6 (NCT02618577)) [30] will hopefully provide further guidance regarding this issue.

Although the CHA₂DS₂-VASc scoring system was not derived for risk stratification specifically in device-detected AF [31], subclinical AF is a known strong predictor of clinical AF [21], and stroke risk in modern AF cohorts is similar to risk in device-detected AF [21]. Thus, it is not unreasonable to estimate a 2.9% annual risk of stroke, TIA, or systemic embolism in accordance with a CHA₂DS₂-VASc score of 2 [32]; our analysis left 31.2% of patients in this category without anticoagulation.

The lowest anticoagulation rates for AF episodes of significant duration were seen in older patients, aged 75 or above. Of these patients with an AF episode of between 6 and 24 h in duration, 64.0% were anticoagulated. In patients aged ≥ 75 years with a CRT device in situ, the anticoagulation rate for an AF episode between 6 and 24 h was even lower, at 57.6%, despite a minimum CHA₂DS₂-VASc score of 3, inferring an approximate 3.2% annual risk of ischemic stroke, and 4.6% annual risk of stroke/TIA/systemic embolism [32]. Anticoagulation rates among patients aged 65–74 years were comparatively higher at 72.5% in those with an AF episode of at least 6 h in duration and as high as 74.8% in those with AF ≥ 24 h. When comparing younger patients in the cohort (age 55–64 years) and older patients (aged at least 85 years) with AF of at least 6 h in duration, we unexpectedly demonstrated higher anticoagulation rates in the younger patients, compared with their older counterparts (61.2% vs. 56.4% for AF 6–24 h, and 77.8% vs. 67.6% for AF 24 h).

Lower anticoagulation rates in older patients, with higher CHA₂DS₂-VASc scores, may be attributable to physician or patient concerns around frailty, falls risk, and bleeding risk, as this demographic tends to also have higher HAS-BLED scores. Studies have shown, however, that the net clinical benefit of anticoagulation in AF patients exceeds the risk of significant bleeding in most patients [33, 34]. In a large cohort study of over 180,000 AF patients, Friberg et al. identified only 0.4% of patients with a CHA₂DS₂-VASc score of ≥ 1 in whom bleeding risk exceeded ischemic stroke risk, with most patients not exhibiting a true contraindication to anticoagulation [33]. Another factor contributing to lower use of anticoagulation in the elderly demographic may be the use of left atrial appendage occlusion to negate the requirement for anticoagulation.

Device-detected AF episode duration of ≥ 24 h has been established as an independent risk factor for embolic events [18, 35]; Botto et al. found episodes of ≥ 24 h in duration to infer an annual embolic event risk of up to 4%, even in patients with a CHADS₂ score of only 1 [36]. The study utilized CHADS₂ scores only; however, some patients may have had a higher CHA₂DS₂-VASc score if calculated. More recently, Kaplan et al. assessed the occurrence of stroke and systemic embolism in over 20,000 unanticoagulated CIED patients and established both increasing AF episode duration and increasing CHA₂DS₂-VASc score to be associated with a heightened embolic risk. Importantly, in patients with long AF episode duration (≥ 23.5 h) and a CHA₂DS₂-VASc score of 1, the annual incidence of stroke/systemic embolism was only 0.56% [37], suggesting that long-duration device-detected AF episodes may not warrant anticoagulation in CHA₂DS₂-VASc-1 patients. Despite this, our study showed that among patients with AF ≥ 24 h, those aged less than 65 years, and those aged 65–74 years, had relatively high anticoagulation rates of 74.9% and 74.8%, respectively. In some patients, this may be reflective of the presence of factors unknown to us, elevating their CHA₂DS₂-VASc score. Again, use of anticoagulation was comparatively lower (70.9%) in patients aged ≥ 75 years, perhaps reflecting physician confidence regarding low bleeding risk in the younger cohort.