Trials Suggest Need for Prolonged AF Monitoring in More Stroke Patients

Taking a longer look for subclinical atrial fibrillation (AF) after a stroke will turn up more cases compared with shorter-term monitoring—that’s not surprising. But results from two trials published in the June 1, 2021, issue of JAMA suggest that it might be worth doing prolonged monitoring outside of the cryptogenic-stroke setting.

In STROKE-AF, which included patients with strokes tied to large- or small-vessel disease, incident AF was more likely to be detected in those fitted with an insertable cardiac monitor (ICM) for 12 months than in those receiving usual care (12.1% vs 1.8%; P < 0.001), researchers led by Richard Bernstein, MD, PhD (Northwestern University, Chicago, IL), report.

The PER DIEM trial, which did not have requirements regarding stroke etiology, included mostly patients with an undetermined cause of their event, but also a mix of patients with defined reasons. In this study, too, 12 months of monitoring with an ICM increased the rate of detected AF, this time compared with 30 days of monitoring with an external loop recorder (15.3% vs 4.7%; P = 0.005), report Brian Buck, MD (University of Alberta, Edmonton, Canada), and colleagues.

“I think the clear take-home message now from all the trials of cardiac monitoring poststroke is that the longer you look, the more AF you’re going to find,” Buck told TCTMD. He added that what remains unclear—and can’t be answered by either of these trials—is how much AF is needed to justify starting oral anticoagulation to stave off another stroke, although it appears stroke neurologists are erring on the side of treatment in the absence of definitive randomized evidence. All PER DIEM participants who had AF detected during the trial were given a prescription for anticoagulation, mostly with a direct oral anticoagulant (DOAC).

Providing some perspective on that, Bernstein said that anticoagulation to prevent strokes in high-risk AF patients is one of the most effective interventions in all of medicine. “So the onus would be on those who say we can ignore this A-fib to prove that it’s safe to ignore it,” he told TCTMD. “Because we in the stroke field see patients with atrial fibrillation that hasn’t prompted someone to use anticoagulation and those patients have a devastating stroke that could have easily been prevented simply by taking an oral blood thinner. So I think you ignore this A-fib that we found at your peril, and that’s true regardless of whether it is linked causally to the index stroke or not.”

It’s that mindset that could make it difficult to perform a randomized trial to definitively show whether initiating anticoagulation in response to monitoring-detected AF after a stroke reduces future events, Bernstein indicated. “I think most neurologists would be very uncomfortable ignoring atrial fibrillation in a patient who has had an ischemic stroke and not treating them with anticoagulants.”

STROKE-AF

Prior trials, including EMBRACE and CRYSTAL AF, have shown that prolonged cardiac monitoring can pick up subclinical AF in a significant proportion of patients who have had an ischemic stroke or TIA without a clear cause, leading guideline committees to recommend such long-term monitoring in patients with cryptogenic strokes.

I think the clear take-home message now from all the trials of cardiac monitoring poststroke is that the longer you look, the more AF you’re going to find. Brian Buck

Patients who have strokes that can be attributed to a specific cause don’t typically undergo prolonged cardiac monitoring for AF. “However, many recurrent strokes do not have the same mechanism as the initial stroke, so patients with an index stroke due to large- or small-vessel disease can still be at risk for future AF-related stroke, especially if they are only treated with antiplatelet therapy,” Bernstein et al write.

STROKE-AF, conducted at 33 US sites, was designed to examine how much subclinical AF could be detected with extended monitoring in patients who had ischemic strokes attributed to cervical or intracranial large-artery atherosclerosis or small-vessel occlusions. Investigators randomized 492 patients within 10 days of the index stroke to 12 months of continuous monitoring with the Reveal LINQ ICM system (Medtronic) or to usual care that included external cardiac monitoring. The mean age of the patients was 67.1, and 37.6% were women. Median CHA₂DS₂-VASc score was 5.

The primary outcome was incident AF lasting more than 30 seconds, but because of the ICM’s detection algorithms, all episodes measured in that arm were at least 2 minutes in duration. Prolonged monitoring detected more cases of subclinical AF, regardless of whether patients had a stroke caused by large-vessel or small-vessel disease. The bulk of the AF episodes detected in the ICM arm (78%) were found beyond 30 days, suggesting that they would have been missed using conventional 30-day monitoring. Most patients with AF detected using prolonged monitoring had an episode lasting more than 1 hour.

Extended monitoring was associated with a higher rate of oral anticoagulation prescription by 1 year (15.7% vs 5.6%; P < 0.001) and a numerically—but not significantly—lower rate of recurrent ischemic/hemorrhagic stroke (7.2% vs 9.8%; P = 0.30). “Further research is needed to understand whether identifying AF in these patients is of clinical importance,” Bernstein et al write.

In terms of the safety of using an implantable monitor, four patients had a procedure-related adverse event—two with incision-site hemorrhages, one with a site infection, and one with pain at the implant site.

PER DIEM

Buck said PER DIEM, conducted at three centers in Alberta, Canada, differs from prior trials in that it was designed to be a pragmatic, real-world study with no inclusion/exclusion criteria based on the type of index ischemic stroke.

The researchers randomized 300 patients, all within 6 months of stroke, to 12 months of monitoring with the Reveal LINQ ICM linked to the MyCareLink remote monitoring system or 30 days of monitoring with a conventional external loop recorder (SpiderFlash-t; Sorin Group). The median age of the patients was 64.1, and 40.3% were women. Two-thirds of patients had a stroke of undetermined etiology, with the rest having strokes attributed to small-vessel occlusion, large-artery atherosclerosis, cardioembolism (after excluding atrial fibrillation/flutter), or other causes. The median CHA₂DS₂-VASc score was 4.

The primary endpoint was definitive or highly probable AF lasting at least 2 minutes within the first 12 months, and this was found more frequently in patients monitored with the ICM.

Secondary outcomes included a variety of clinical events through 12 months, and there were no differences between trial arms in recurrent ischemic stroke, TIA, intracerebral hemorrhage, or death. The proportion of patients with serious adverse events was higher in the ICM group (9.3% vs 3.3%), although there was only one deemed related to the device—a skin erosion requiring removal 2 months after implantation.

“Further research is needed to compare clinical outcomes associated with these monitoring strategies and relative cost-effectiveness,” Buck et al write.

Feasibility of an Outcomes Trial

On the background of EMBRACE and CRYSTAL AF, these trials “confirm increased subclinical AF detection with more prolonged monitoring, indicate that an ICM yields higher detection rates than 30-day external monitoring, and expand the potential surveillance pool to include patients with non-AF and nonembolic stroke of undetermined source (ESUS) ischemic stroke,” David Tirschwell, MD, and Nazeem Akoum, MD (both University of Washington School of Medicine, Seattle), write in an accompanying editorial.

I think most neurologists would be very uncomfortable ignoring atrial fibrillation in a patient who has had an ischemic stroke and not treating them with anticoagulants. Richard Bernstein

The results of both STROKE-AF and PER DIEM indicate that 10 patients would need to be monitored with an ICM to detect one patient with subclinical AF at 1 year, “which is suggestive of an effective intervention for disease detection,” they add, noting, however, that “evidence is lacking for the final link between subclinical AF detection after ischemic stroke and improved clinical outcomes.” A trial randomizing patients with subclinical AF detected after stroke to anticoagulation or antiplatelet therapy would be the “gold standard” test, the editorialists say. “But does equipoise exist?”

That most treating neurologists chose to start anticoagulation in response to monitoring-detected AF (100% of the time in PER DIEM and 67% of the time in STROKE-AF) calls “the extent of clinical equipoise into question,” Tirschwell and Akoum write.

They conclude that “if neurologists who treat patients with stroke lack equipoise about the need for anticoagulation therapy in those with ischemic stroke and subsequent subclinical AF detection, RCTs may not be feasible. As the population ages and the incidence of AF-related stroke (including subclinical AF) increases, it will be ever more important to ensure a strong evidence base for selecting the best antithrombotic treatment.”

Bernstein said it might be possible to enroll a population of patients with a very low burden of AF, maybe episodes with a duration of 6 minutes or less, into a randomized trial. “But anybody who has episodes like the majority of our patients did, of an hour or more after an ischemic stroke, I think you’d have a hard time convincing a neurologist to put such a patient in a clinical trial,” he added. Bernstein noted that there are trials focused on treatment of subclinical AF mostly in patients without a history of stroke—ARTESiA and NOAH-AFNET 6—"but once somebody has had a stroke, they become very high risk for another stroke and we tend to pounce on any A-fib at all.”

Buck agreed both that the feasibility of a randomized trial looking at the treatment of monitoring-detected AF in patients with a prior stroke is questionable and that it might be possible in a lower-risk group. But citing potential overlap in patient populations, he said the ARTESiA trial might provide enough evidence that another trial wouldn’t be needed.

As to the high rate of treatment observed in response to subclinical AF in STROKE-AF and PER DIEM, Buck said the rates likely would have been lower before the advent of DOACs, when physicians were reliant on warfarin. “We have a group of anticoagulants now that have a 50% lower risk of serious hemorrhage and ultimately are much more effective than aspirin at preventing future stroke with a reasonable hemorrhage risk,” he said.

Time to Change Guidelines?

The fact that STROKE-AF showed that patients with strokes due to large- or small-vessel disease had a substantial amount of subclinical AF that wouldn’t have been detected without more-intensive, prolonged monitoring indicates that guidelines, which focus on patients with cryptogenic strokes, need to be updated, Bernstein said.

“What I think is surprising is that in this particular population we hadn’t been in the habit of looking, and I think now we know that we should,” he said. Using the same logic that formed the basis for recommendations following EMBRACE and CRYSTAL AF, “guidelines need to be extended such that we encourage doctors to do intensive monitoring in a much larger swath of patients with ischemic stroke,” he added.

Buck concurs: “I think both of our trials provide converging evidence that extended cardiac monitoring should not be restricted to the pure cryptogenic stroke population.”