Atrial Tachyarrhythmia and Cryptogenic Stroke

The association between atrial tachyarrhythmia, particularly atrial fibrillation (AF) or fast atrial tachycardia (AT), and the risk for cardioembolic stroke has been established.^1-4 Classically, this risk of stroke with AT/AF has been attributed to activation of the coagulation system through engagement of all three limbs of Virchow's triad: (1) increased blood stasis in the left atrium (LA) and left atrial appendage (LAA) from ineffective contraction, (2) subclinical endothelial damage from adverse atrial structural remodeling during fast AT or AF, and finally (3) induction of a prothrombotic, hypercoagulable state through increased levels of von Willebrand factor, fibrinogen, plasma D-dimer, and prothrombin fragments.² Taken together, there is enhanced platelet activation and initiation of the coagulation cascade which leads to the formation of intracardiac (and extracardiac) thrombi which can later embolize.³ Standard work-up for a cerebrovascular accident (CVA) or transient ischemic attack (TIA) therefore includes electrocardiographic evaluation during initial hospitalization with ECG and inpatient telemetry, along with further outpatient monitoring with either Holter, wearable event, or implantable cardiac monitors.

Despite many known etiologies and risk factors of CVAs and TIAs, as high as one-quarter to just under one-half of all strokes are categorized as cryptogenic,⁴ defined as "strokes without cause after extensive investigation."⁵ While AF is a proven risk factor and culprit for CVA overall, it is often difficult to diagnose, as is frequently paroxysmal. Further complicating this assessment is that overall burden of paroxysmal AF can be particularly difficult to gauge as it is frequently asymptomatic.^6,7 In addition, the determination of stroke may be delayed or late, particularly in subclinical or 'silent' strokes. Indeed, a causative role for AT/AF in silent embolic phenomenon has been estimated to range from 21 to 40%.⁸

Studies have shown that longer term cardiac monitoring correlates with a higher rate of diagnosis of AF. The sensitivity of AT or AF detection longer than five minutes in patients with history of brady-tachy syndrome was 44.4%, 50.4%, and 65.1% for 24-hour, 1-week, and 1-month monitoring periods with dual-chamber pacemakers, respectively.⁹ Similar findings have also been shown with wearable event recorders and implantable cardiac monitors (ICMs). In patients with cryptogenic stroke and negative ECG and 24-holter monitors, the overall yield of AT/AF detection ranged from 6% with 7-day monitors, 11-23% with 30-day monitors, and up to 27.3-28% in patients 1-year ICMs.^13-17

Risk and Temporal Relationship Between Device-Detected Atrial Tachyarrhythmia (DDAT) and TE

Although an increased risk of TE and AT/AF has been shown in multiple studies, a clear temporal correlation of AT/AF with subsequent risk of CVA or TIA has not yet been elucidated. Multiple studies have shown significant associations between relatively low overall AT burdens and risk of CVA or TIA. A sub-analysis of the Mode Selection Trial (MOST), which evaluated outcomes in 312 patients, noted a 2.79-fold increase in risk of death or nonfatal stroke associated with patients with greater than 5 minutes of recorded AT.¹⁵ In 2009, the TRENDS study (A Prospective Study of the Clinical Significance of Atrial Arrhythmias Detected by Implanted Device Diagnostics) examined a larger cohort of 3,045 patients with cardiac monitoring devices and at least one CHADS₂ score criteria. It showed that an AT burden of greater than 5.5 hours conferred a doubling in the risk of TE event, but the results were weakly powered as the rate of TE in the study population was low.¹⁶ More recently, the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) trial described outcomes in a prospectively assembled cohort of 2,580 patients greater than 65-years-old with medically-treated hypertension, placement of pacemaker or ICD, on no anticoagulation, and with no prior TE events. Results indicated that patients with even 6 minutes of AT had a markedly increased risk of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P = 0.007).¹⁷ Finally, in 2014, a pooled analysis of 3 prospective observational studies, totaling 10,016 patients (including the TRENDS study), noted a two-fold increase in CVA or TIA risk in patients with a daily AF burden of 5 minutes or greater.¹⁸

Most recent studies have monitored patients for DDAT and followed-up for a specified period of time to determine TE event risk. Conversely, a 2015 study looked for subclinical strokes in all patients by having patients undergo CT scans after one year of follow-up. Among 109 patients prospectively monitored for AT events at least 5 minutes in duration, there was an almost 10-fold increased risk of a coexisting subclinical TE event, as evidenced by CT scan.¹⁹

Attempts at proving a temporal relationship between recorded AT and timing of subsequent strokes continued with a sub-analysis of the ASSERT trial. However, it showed that despite the observed increased risk of stroke and embolism, only 8% of patients had episodes of sub-clinical AT lasting greater than 6 minutes in the month preceding their event. Perhaps more surprisingly, 16% of patients did not have any recorded AT/AF episodes until after the TE event, despite a median of 228 days of monitoring prior to event.²⁰ Similar data was reported from the TRENDS study, which found that among 40 patients with a TE event, 50% did not have any recorded AT prior to the event. Even among the 20 patients that did have AT prior to TE, 45% did not have any AT in the 30 days prior to the TE event.²¹ Similar findings have now been reported in the heart failure population; a prospective study of 560 patients with cardiac resynchronization therapy (CRT) devices showed that the majority of patients with a TE event had a mean interval of 46.7 +/- 71.9 days (range 0-194 days) between the AT episode and the TE event.²²

The lack of association between AT/AF episode timing and TE event has challenged our understanding of the mechanism of stroke or systemic embolism in patients with AT/AF. Certainly, a simplistic assertion of Virchow's triad for intracardiac thrombus does not appear sufficient. Based on data evaluating LAA occlusion devices such as WATCHMAN, there does appear to be some reduction in ischemic stroke from appendage closure, supporting the classical view.²³ Taking into account the preponderance of device-based AT/AF data; however, this is likely not the only etiopathology of TE events for these patients. Indeed, AT/AF is a marker of atrial myopathy which itself may be a marker for increased vascular risk. Further research on fundamental principles is clearly needed.

Anticoagulation for DDAT

While it is clear there that: (1) underlying AT/AF, even when subclinical or silent, is associated with increased risk of TE, and (2) longer-term cardiac monitoring increases the rate of diagnosis of AT/AF; it is not known whether the initiation of anticoagulation based on device-detected AT/AF modifies the risk of subsequent TE. This assertion may come as a surprise, since multiple studies have shown that therapeutic anticoagulation (AC)—via vitamin K-antagonist, direct thrombin inhibitor, or direct Factor Xa inhibitor—reduces risk of stroke in patients with non-valvular AF.²⁴ With that said, initiation and continuation of AC based on DDAT has also not yet been established.

Usually, the decision to use AC is determined by patients' risk, as calculated by a CHADS₂ or CHA₂DS₂-VASc score. A 2009 study looked to combine device-detected AT/AF burden and CHADS₂ score to calculate risk of TE events for 568 patients over a 1-year time frame. Patients with CHADS₂ score of 0 had a significantly lower risk of TE events when compared to patients with CHADS₂ score of 3 or greater, regardless of the presence of AF (0.8% vs 5%, p < 0.035). Patients with CHADS₂ scores of 1 or 2 were able to be stratified into either the low risk (0.8%) or high risk (5%) group based on their overall AF burden, with CHADS₂ score of 2 and AF burden > 5 minutes notably in the high-risk group.²⁵ The ASSERT trial further expanded on the use of risk calculation in combination with DDAT. It showed a correlation between subclinical AT, increasing CHADS₂ score, and absolute rate of stroke, with the highest rate being 3.78% per year in patients with subclinical AT longer than 6 minutes and CHADS₂ score greater than 2. There was no comparison made however between patients on and off AC, and thus, the impact of device-detected arrhythmia diagnosis and benefit of earlier initiation of anticoagulation remains uncertain.²⁶

Previous studies have attempted to assess the benefit of anticoagulation in post-hoc analyses. The TRENDS study observed no significant difference in TE event outcome between patients with AT/AF with use of aspirin and warfarin versus those that did not, but the confidence intervals were wide, and no INR was measured to evaluate for therapeutic level of anti-coagulation.²⁷ Similarly, the Cryptogenic Stroke and Underlying AF (CRYSTAL-AF) trial showed that there was an increased rate of AC usage in patients undergoing prolonged cardiac monitoring compared to control group (38.5% vs 8.3%), and in the three-year follow-up, 20 patients in the AC group and 24 in the control group had recurrent stroke or TIA. However, the study was underpowered for this end point.²⁸

Inconsistent and variable use of anticoagulation in studies has been the main problem with assessing significance of AC. A meta-analysis of 4 randomized controlled trials evaluating prolonged cardiac monitoring greater than 7 days versus less than 48 hours in patients with cryptogenic stroke or TIA, concluded that there was an increased use of AC in patients undergoing prolonged monitoring (2.21 [1.52-3.21]; p<0.0001), but there was no difference in the rate of recurrent stroke or TIA (0.78[0.40-1.55];p=0.48) or mortality (1.33[0.29-6.00];p=0.71) between the two groups.²⁹

More recently, the IMPACT study (Combined Use of BIOTRONIK Home Monitoring and Predefined Anticoagulation to Reduce Stroke Risk), a prospective, randomized trial with 2,718 patients with ICD or CRT device, was designed with the primary intervention being initiation or discontinuation of oral anticoagulants based on presence and duration of DDAT and associated CHADS₂ score. Patients in the control arm received AC based on conventional clinical diagnosis of AT and CHADS₂ score. Surprisingly, there was no significant difference found between the two arms of the study, and it was concluded that stopping and starting anti-coagulation based on presence of DDAT had no significant effect on outcomes, including ischemic stroke.³⁰ The implication of IMPACT is that device-detection of AT/AF may best be used as an indicator of increased overall intrinsic risk, irrespective of overall AT/AF burden, and that AC should not be stopped based simply on confirmation of restoration of sinus rhythm. The ongoing Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) trial seeks to address this question directly. It is a prospective, randomized, double-blinded trial evaluating whether AC reduces the risk of stroke and systemic embolism in patients without history of AF, but with DDAT greater than 6 minutes.³¹

Recommendations and our approach

The clinical significance of DDAT as it relates to risk of TE and indication for anti-coagulation is not fully elucidated. It is evident that patients with DDAT have an increased risk for TE, but the use of anti-coagulation based solely on presence of this rhythm has not yet been shown to be significant. However, patients with a DDAT burden of ≥ 5 minutes and an elevated risk of TE, as calculated by CHADS₂ and CHA₂DS₂-VASc scores ≥ 2, have shown to have an increased incidence of TE, on par with patients with known AT or AF.

Therefore, we recommend using CHADS₂ and CHA₂DS₂-VASc risk scores to determine need for AC in patients DDAT detected. TE risk can be determined with evaluation of these risk scores in the setting of the duration of DDAT burden. In addition, we suggest further delineating patients' risk with use of the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) risk score in patients initially categorized as low risk. ATRIA is an externally validated risk calculator that places increased emphasis on age and history of stroke. It is superior to CHADS₂ and CHA₂DS₂-VASc discriminating low from higher risk patients,^32,33 and can help determine need for anticoagulation in patients with intermediate risk scores. We suggest utilizing an approach of shared decision making using this (Figure 1) until randomized controlled trials, such as ARTESiA, are able to provide significant evidence correlating duration of AT and the role of AC in decreasing risk of TE events.

Conclusion

DDAT is a valuable tool in the real-time detection of clinically silent atrial arrhythmias. The presence of DDAT has clearly been shown to be associated with an increased risk of stroke and other TE, although a causal association has not yet been elucidated. The role of anticoagulation in reducing risk in patients with AF; however, is established. Using implantable devices to identify and initiate treatment early is an opportunity which is actively being investigated in current randomized study, and enough data is available to start those discussions with patients today.

Figure 1: Use of anti-coagulation for primary prevention of TE in patients with DDAT

* Exclude:

• Errors of over-sensing: T-wave, R-wave, myopotentials
• Device malfunction: lead fracture, insulation break, loose set screw, air in header
• Pacemaker-related arrhythmia: pacemaker-mediated tachycardia (PMT), repetitive non-reentrant ventriculoatrial synchrony (RNRVAS)^34,35
• Other exogenous interference: electromagnetic interference (EMI), e.g. magnetic resonance imaging (MRI), electrocautery, external cardioversion, radiotherapy, anti-theft dectors, and welding equipment, among others.^36,37

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Keywords: Anticoagulants, Atrial Appendage, Atrial Fibrillation, Cardiac Resynchronization Therapy, Electric Countershock, Electrocardiography, Electrocoagulation, Electromagnetic Phenomena, Embolism, Factor Xa Inhibitors, Fibrinogen, Heart Failure, Hypertension, International Normalized Ratio, Ischemic Attack, Transient, Magnetic Resonance Imaging, Monitoring, Ambulatory, Primary Prevention, Pyrazoles, Risk Factors, Stroke, Tachycardia, Thrombosis, Tomography, X-Ray Computed, Warfarin

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