AF Detection Should Take Priority After Cryptogenic Stroke

June 25, 2014

Two new studies show a high detection of atrial fibrillation (AF) with prolonged electrocardiography (ECG) monitoring in patients who have had a cryptogenic stroke.

The 30-Day Cardiac Event Monitor Belt for Recording Atrial Fibrillation after a Cerebral Ischemic Event (EMBRACE) trial, which tested an external device for 30 days, found an AF incidence of 16% in this time period, compared with just 3.2% in the control group who received 24-hour Holter monitoring. Before entering the study, all patients had initial 24-hour Holter monitoring — the current standard of care — that did not detect AF.

The other trial, called Cryptogenic Stroke and Underlying AF (CRYSTAL-AF), tested an implanted device that can monitor the ECG for years. Results showed an AF detection rate of 8.9% at 6 months (vs 1.4% of patients in the control group), 12.4% at 12 months, and 30% at 3 years.

"In this randomized trial comparing long-term monitoring by means of an ICM [insertable cardiac monitor] with conventional follow-up in patients with a recent cryptogenic stroke, monitoring resulted in a significantly higher rate of detection of atrial fibrillation, with greater use of oral anticoagulants," the researchers, with lead author Tommaso Sanna, MD, Catholic University of the Sacred Heart, Institute of Cardiology, Rome, Italy, conclude.

Prescription of oral anticoagulants was more than doubled in the monitored group at both 6 and 12 months, "probably as a result of the higher rates of detection of atrial fibrillation," they write. "Fewer patients had a recurrent TIA [transient ischemic attack] in the ICM group than in the control group; however, our study was not powered for this end point."

Both trials are published June 26 in the New England Journal of Medicine. Preliminary results from these studies have been presented and reported by Medscape Medical News previously; the EMBRACE study at the International Stroke Conference 2013 and the CRYSTAL-AF study at the same meeting this year.

A Modifiable Risk Factor

In an editorial accompanying publication of the EMBRACE and CRYSTAL-AF studies, Hooman Kamel, MD, Weill Cornell Medical College, New York, says that "[T]he weight of current evidence suggests that subclinical atrial fibrillation is a modifiable risk factor for stroke recurrence, and its presence should be thoroughly ruled out in this high-risk population. Therefore, most patients with cryptogenic stroke or transient ischemic attack should undergo at least several weeks of rhythm monitoring."

Dr. Kamel notes that relatively inexpensive external loop recorders, such as those used in the EMBRACE trial, will probably be cost-effective, while the value of more expensive implantable loop recorders is less clear.

He recommends that patients in whom AF is detected should generally be switched from antiplatelet therapy to anticoagulant therapy or at least followed closely to detect progression to clinically apparent AF, in which case the evidence unambiguously supports anticoagulant therapy for the secondary prevention of stroke.

Consistent Results

Lead author of the EMBRACE study, David J. Gladstone, Sunnybrook Health Sciences Center, University of Toronto, Ontario, Canada, told Medscape Medical News that the 2 studies complemented each other very well.

"The results are very consistent," he commented. "The higher rate of AF detection in EMBRACE is probably due to the fact that we had older patients in our study. The 16% figure that we found is exactly in line with a recent meta-analysis of observational studies investigating prolonged heart monitoring for cryptogenic stroke."

In the EMBRACE trial, patients receiving the longer-term monitoring strategy had detection rates increased 5-fold and anticoagulant treatment rates doubled compared with patients undergoing standard 24-hour Holter monitoring, he added. "This research is relevant to millions of people worldwide who have cryptogenic strokes."

We must make it a priority to detect AF in patients, especially older high-risk patients, who have had an unexplained embolic stroke. Dr. David J. Gladstone

"There is much excitement about the advances in technology that are making it more possible than ever before to perform long-term monitoring of patients at home and are enabling better detection of AF," Dr. Gladstone said. "We must make it a priority to detect AF in patients, especially older high-risk patients, who have had an unexplained embolic stroke as AF can be treated very effectively with anticoagulation, which we know reduces recurrent stroke rates."

These long-term monitoring devices are not available everywhere yet. Dr. Gladstone noted that in Canada, they are not reimbursed in all provinces. "But we hope that this research will drive policy change and allow these advances to become more widely available for patients who are appropriate candidates."

The EMBRACE trial tested a noninvasive external device that has electrodes built into a belt worn around the chest. This is attached by a wire to a loop recorder about the size of a smart phone, which can be carried in a pocket or clipped onto a belt. Patients are asked to wear it as much as possible day and night, taking it off for bathing, for up to a month. If AF was detected before 30 days, monitoring was stopped.

"We thought 30 days was about the limit of tolerance for wearing this sort of device, but it appears from the CRYSTAL-AF study that a higher detection rate can be achieved with longer monitoring periods," Dr. Gladstone said. "In our study, we found the highest detection rate early on, with half the AF cases found within the first week of monitoring and 75% of cases detected in the first 2 weeks."

"But the AF rate didn't plateau so we would have found more patients if we continued monitoring for longer, and that is exactly what the CRYSTAL-AF study found."

He explained that the belt used in EMBRACE has advantages over some other external devices in that the electrodes were not stuck to the chest, thereby avoiding the problems of skin irritation caused by adhesives.

"Newer technologies have become available which may be even better, such as an ECG patch monitor which has no wires or extra devices, as the recording device is built into the patch," he said. "This is a rapidly evolving field."

Stepped Approach

Dr. Gladstone advocates a stepped-care approach model to AF detection, moving from less invasive, less costly methods to more invasive, more costly methods.

"We'll have to see how it unfolds but I favor starting with a noninvasive approach like the one we tested for the first 30 days, but if we haven't detected AF and still have a high index of suspicion that a patient may have AF then we could move on to an implantable device, such as the one used the CRYSTAL study, for longer-term monitoring."

He pointed out that anticoagulant treatment of patients with convincing AF can reduce the risk for stroke by two thirds. But the degree of benefit of anticoagulation for only very brief episodes of subclinical AF — those of just a few minutes' duration — is not completely clear. In the EMBRACE trial, the 16% figure relates to AF episodes lasting 30 seconds or longer.

The maximum duration of AF recordable by the device used in EMBRACE was 2.5 minutes, and AF episodes of this duration or longer were identified in 9.9% of patients in the 30-day study period.

Does Brief Subclinical AF Justify Anticoagulation?

"Expert opinion differs on what is the minimum duration of AF necessary to be captured on ECG monitoring to warrant long-term anticoagulation. We don't know the answer to that yet," Dr. Gladstone commented. "We know that AF of 5 to 6 minutes is a significant predictor of future stroke risk. However, in CRYSTAL-AF, which used a device that records continuously, many of the AF episodes captured lasted several hours. It appears that a little bit of AF is a marker for longer-duration episodes."

He noted that newer external devices can also continually record ECG data with real-time wireless transmission, giving essentially unlimited recording capacity.

On how to manage a 30-second episode of AF, Dr. Gladstone said there was uncertainty. "I individualize these decisions, but often do prescribe anticoagulation provided that there is a very high suspicion of AF, based on older age, evidence of a clot on brain vascular imaging, and especially if the patient is known to have very frequent atrial premature beats, which seems to be a strong predictor of paroxysmal AF. But this treatment approach hasn't yet been proven in trials to reduce stroke, as the treatment trials to date included patients with longer durations of clinically manifest AF."

Studies of anticoagulant treatment in patients with less severe AF are now underway. Other studies are investigating anticoagulant treatment for all patients with embolic stroke of undetermined source. That is working off the assumption that even if AF is not present, patients may still benefit from anticoagulation.

"I would suspect that the patients with subclinical AF will derive the most benefit in such trials, but it will be interesting to see if all cryptogenic stroke patients benefit," he said.

EMBRACE was supported by peer-reviewed operating grants from the Canadian Stroke Network, one of the Networks of Centres of Excellence of Canada. Dr. Gladstone was supported by a Clinician-Scientist Award from the Heart and Stroke Foundation of Ontario, the Bastable-Potts Chair in Stroke, the Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, the University of Toronto Department of Medicine and the Eaton Scholar Award, the University of Toronto Division of Neurology New Initiatives Program, the Department of Medicine Research Committee and the Brain Sciences Program at Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, Sunnybrook Foundation, the Sam Sorbara family, and the Bril Chair in Neurology, University of Toronto. Dr. Gladstone reports receiving travel support and fees for participating on advisory boards from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, and Pfizer and consulting and lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer. Disclosures for coauthors appear in the paper. CRYSTAL-AF was supported by Medtronic. Dr. Sanna reports receiving fees from Medtronic as a steering committee member for CRYSTAL-AF. Disclosures for coauthors are available with the full text at Dr. Kamel reports grant support from National Institutes of Health/National Institute of Neurological Disorders and Stroke, and personal fees from Genentech outside the submitted work.

N Engl J Med. 2014;370:2467-2477, 2478-2486, 2532-2533. EMBRACE abstract CRYSTAL-AF abstract Editorial


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