Uncertainties About Cardiac Monitoring After Cryptogenic Stroke

Cryptogenic stroke, or stroke of unknown cause, is an elusive diagnosis accounting for up to 40 percent of ischemic strokes, and it has recently been a subject of great interest.1,2 Most cryptogenic strokes are embolic, sharing similar radiographic and pathologic features with the better characterized cardioembolic strokes, but the sources of the emboli are unknown. Consequently, much attention has now been focused on finding occult atrial fibrillation (AF), the most common cause of cardioembolic stroke. The paroxysmal and often asymptomatic nature of AF often eludes standard techniques such as 24-hour ECG or inpatient telemetry monitoring, which have a detection rate of approximately four to seven percent.3 Cardiac monitoring devices have evolved to provide longer detection with greater sensitivity.

There is now a wide variety of cardiac monitoring devices available, ranging from external loop recorders and mobile cardiac outpatient telemetry (MCOT) that can be worn for weeks, to implantable devices that can record for years. The introduction of these outpatient cardiac monitors has begun to change routine post-stroke management. Landmark studies including the Cryptogenic Stroke and Underlying AF (CRYSTAL-AF) trial and the 30-Day Cardiac Event Monitor Belt for Recording AF After a Cerebral Ischemic Event (EMBRACE) trial have shown that prolonged cardiac monitoring provides a higher yield of AF detection than the standard approach.4,5 In CRYSTAL AF, an implantable loop recorder was used for up to three years, with a detection rate at six months of 8.9 percent, which increased to 12.4 percent at 12 months. The authors also reported 30 percent detection rate at 36 months, although only 48 of the 441 patients remained in the study at this time.4 In EMBRACE, an external loop recorder was employed with a detection rate at 30 days of 16.1 percent.5 These results reinforce the notion that more monitoring is better. Not surprisingly, in both trials, there was greater use of anticoagulation in patients in whom AF was detected. 

If We Find Atrial Fibrillation, Then What Should We Do?

What these studies do not demonstrate however, is a causal link between AF detected by these devices and cryptogenic stroke. These tools are highly sensitive for detecting short periods of arrhythmia (on the order of seconds to a few minutes) that could in fact be too short to be clinically important. Neither the CRYSTAL-AF nor EMBRACE trial demonstrated lower rates of recurrent ischemic events with the respective device. Additionally, neither assessed the incidence of AF in a control group of patients without strokes. Rabinstein et al. addressed this issue by directly comparing the incidence of paroxysmal AF in patients with strokes of cryptogenic versus known causes through a prospective case-control analysis.6 Among 128 patients who had strokes within the prior three months and were monitored with MCOT for 21 days, they found no significant difference in the rate of detection of AF. Further, there was no difference in the number of AF episodes, overall AF burden, or time to detection. The Find-AF trial (Finding Atrial Fibrillation in Stroke - Evaluation of Enhanced and Prolonged Holter Monitoring) showed a three-fold higher rate of AF detection (13.5 percent) in patients assigned to repeated short-term Holter monitoring at zero, three, and six months compared to the standard of care (4.5 percent).7 The majority of patients with newly detected AF were treated with anticoagulation. Despite no significant difference in recurrent stroke or death rates at 12 months, the investigators concluded that enhanced monitoring should be used in patients with all types of ischemic stroke, but an alternative interpretation of these results could be that occult AF is an incidental finding in a minority of subjects after stroke of known or unknown cause.

Subsequent meta-analyses have continued to emphasize the higher yield of detection with increased monitoring, but the question of whether finding AF after a stroke actually caused the stroke or puts the patient at risk of future stroke remains unanswered.8,9 The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) found that patients with subclinical atrial tachyarrhythmias, detected through a pacemaker or defibrillator, had a 2.5-fold increased risk of ischemic stroke and a five-fold increased risk of clinical AF.10 A subsequent analysis of these patients showed there was no temporal relationship between AF and stroke. Within the 51 patients who had stroke, approximately half (26) had subclinical atrial fibrillation, and among these patients, 14 developed AF greater than 30 days before stroke, while eight developed AF after stroke.11

Thus, while the data for increased detection of AF with long-term cardiac devices are robust, better detection in itself does not equate to an etiology or a clear indication for treatment. The Apixaban for the Reduction of Thrombo-Embolism in Patients with Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) is a prospective study to assess whether anticoagulation is superior to aspirin in reducing the risk of stroke and systemic embolism in patients with device-detected subclinical atrial fibrillation.12 Until that study is completed, there are no simply no reliable data currently available to guide our management.

Should we Just Anticoagulate Everyone?

A major practical concern with long-term cardiac monitoring is how to treat the patient with a recent cryptogenic stroke while waiting to see if AF is detected during the ensuing weeks, months, or even years of monitoring. In general, the standard approach is to use antiplatelet therapy until AF is found, as anticoagulation has not been shown to be effective or safe in patients with noncardioembolic stroke. If the patient does in fact have occult and undetected AF and is truly at high risk of future stroke, then waiting may not be the best strategy. One strategy might be to identify the cryptogenic stroke population at highest risk of developing AF and targeting them for early aggressive therapy. Several studies have examined clinical, cardiac, and radiographic features that may help predict detection of atrial fibrillation. All of the following have been reported to be associated with AF, but the data are highly inconsistent across studies. Age, female sex, male sex, the PR interval on ECG, premature atrial contractions, premature ventricular contractions, left atrial enlargement, the pattern of acute strokes on diffusion weighted imaging, and the pattern of chronic strokes on MRI have been reported to increase the likelihood of finding AF in some studies, with the same findings refuted in others.13-16 Blood biomarkers, specifically brain natriuretic peptide (BNP) and NT-proBNP, may be promising indicators, as they are significantly elevated in patients with cardioembolic stroke, independent of other clinical factors.17 An exploratory analysis in 1,028 patients with cryptogenic stroke found a 70 percent lower risk of stroke or vascular death when patients with NT-proBNP levels above 750pg/mL were treated with warfarin rather than aspirin.18 Thus these biomarkers may help select patients with cryptogenic strokes who may be at greatest risk for AF, but further studies are needed to validate these results.

Importantly, there are many other potential causes of cryptogenic stroke that might theoretically benefit from anticoagulation, including undetected aortic arch atheroma or ulcerated non-stenosing large artery plaques with superimposed thrombus, unknown prothrombotic disorders including undiagnosed cancer, as well as others. But, again, there are no randomized trials or guidelines to support such an approach. The emergence of these causes has prompted a new term—embolic strokes of undetermined source (ESUS)—which defines cryptogenic stroke based on established criteria rather as the default when no other etiology is determined. Diagnostic criteria for ESUS include: Brain CT or MRI to demonstrate non-lacunar stroke, extracranial and intracranial imaging to exclude greater than 50 percent proximal stenosis, and electrocardiography, echocardiography, and cardiac rhythm monitoring after 24 hours to exclude known cardioembolic sources.19 The only available data comparing anticoagulation to antiplatelet therapy in cryptogenic stroke was described in a post-hoc analysis of the Warfarin vs. Aspirin for Recurrent Stroke Study (WARSS), which originally demonstrated no advantage of warfarin over aspirin in secondary prevention of noncardioembolic strokes.20 In the subgroup analysis of cryptogenic strokes whose imaging showed an embolic pattern, warfarin was associated with one-third fewer recurrent strokes than aspirin though the outcome was not statistically significant.21 The result in this subgroup, along with the advent of newer and safer direct-acting oral anticoagulants (DOACs), has led some investigators to reconsider the strategy of empiric anticoagulation without the requirement for prolonged cardiac monitoring. Two randomized controlled trials currently underway—Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (NAVIGATE ESUS), and Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source (RE-SPECT ESUS)—are comparing the DOACs to aspirin for the secondary prevention of strokes in patients with recent cryptogenic stroke. These are large pragmatic trials with fairly broad criteria for the diagnosis of cryptogenic stroke taking place on a global scale. These trials, if successful, could completely transform the current landscape of antithrombotic therapy after stroke, while cardiac monitoring could become largely unnecessary in this population.

Awaiting Answers

We now have compelling data from randomized clinical trials that prolonged cardiac monitoring enhances AF detection. It seems logical to treat newly detected subclinical atrial fibrillation with anticoagulation, but that is an unproven strategy for those with very short runs of AF, especially when found months to years after stroke. Until more data are available, it is not clear if we are improving the outlook for ischemic stroke patients by monitoring them and subsequently committing patients to life-long anticoagulation once any AF is detected. Alternatively, cryptogenic stroke is likely a heterogeneous disorder for which anticoagulation could be widely effective even in the absence of AF, but we do not know if that hypothesis is correct.

We have a spectrum of options for current practice. The most conservative approach would be to monitor only the patients at highest risk and anticoagulate them only if long runs of AF are discovered. The most liberal approach would be to anticoagulate them all. And of course there are many options between these extremes, but all are based on our convictions rather than real data. The answers will come from key ongoing clinical trials and clinicians are encouraged to refer patients to those studies. Until then, there is great uncertainty and we should all keep our fingers on the pulse of this unsteady beat. n

Cen Zhang, MD is an Assistant Professor of Neurology in the Stroke Division at New York University.

Scott E. Kasner, MD is the Ruth M. and Tristam C. Colket, Jr. President’s Distinguished Professor of Neurology at the University of Pennyslvania, where he is also Director of the Comprehensive Stroke Center.

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