Anticoagulation in Embolic Stroke of Undetermined Source

A series of neutral trials on anticoagulation in embolic stroke of undetermined source (ESUS) has moved the needle scientifically but left physicians with questions about secondary prevention and the diagnosis itself. 

ESUS is defined as nonlacunar ischemic stroke without a clear source after sufficient diagnostic evaluation. It accounts for about 20% of all ischemic strokes and has a recurrence rate of about 4%-5% per year.

ESUS is a subset of cryptogenic stroke — a heterogenous group that also includes patients with multiple etiologies or incomplete diagnostic workup. 

The ESUS construct was proposed in 2014 to facilitate research. At that time, ESUS was said to have a clear indication for anticoagulation. Covert atrial fibrillation (AF) was thought to be the primary cause, a theory supported by the CRYSTAL AF and EMBRACE trials, where underlying AF was detected with longer cardiac monitoring in up to one third of patients who had an unexplained stroke.

A trio of recent trials, however, failed to show that direct oral anticoagulants (DOACs) are superior to aspirin for prevention of recurrent stroke in patients with ESUS. 

Rivaroxaban and dabigatran fell short in a general population of ESUS patients in NAVIGATE ESUS and RE-SPECT ESUS, and apixaban missed its mark earlier this year in an enriched population of patients with atrial cardiopathy in ARCADIA.

“Antiplatelet therapy remains the standard of care, and there’s no evidence that would support using a DOAC, or warfarin for that matter, for patients with unexplained stroke,” Mitchell Elkind, MD, MPhil, principal investigator of ARCADIA and professor of neurology and epidemiology, Columbia University Irving Medical Center, New York City, told Medscape Medical News.

Subanalyses of NAVIGATE ESUS and secondary work being done in ARCADIA show benefit for patients with enlarged left atrium, for example, but these are secondary analyses and just generate hypotheses for the next round of clinical trials, he noted.

“I feel like everybody’s kind of gone to ground trying to figure out what the next best way of identifying patients who will benefit might be,” Elkind said.

The Humble Aspirin Holds On

According to US secondary stroke prevention guidelines, patients with ESUS should not be treated with anticoagulants or ticagrelor (Brilinta) owing to a lack of benefit. Antiplatelet therapy and risk factor control are recommended for patients with noncardioembolic ischemic stroke without an identified cause.

“Currently, the standard of therapy for these patients remains aspirin, which has a modest about 20% risk reduction but is not a very effective antithrombotic in these patients,” Mukul Sharma, MD, a NAVIGATE investigator and professor of neurology and Michael DeGroote Chair of Stroke Prevention, McMaster University, Hamilton, Ontario, Canada, said in an interview. 

Standard therapy long-term is aspirin or another single antiplatelet, such as clopidogrel, and a short-term combination of aspirin plus clopidogrel for up to 4 weeks may be used in selected higher-risk patients, he said. 

“People make the case for using a DOAC in patients who have patent foramen ovale (PFO), but we really don’t have independent trial data to suggest that they would benefit,” Sharma said. “The subgroup in our NAVIGATE ESUS trial did seem to benefit, but that wasn’t the case in RE-SPECT ESUS.”

Elkind pointed out that recurrence rates were closer to 8% in older studies of unexplained stroke but have been whittled down through the use of aspirin, statins, and risk factor control.

He encourages a more holistic approach to risk reduction. “We tend to focus a lot on aspirin vs anticoagulation as if that’s the solution, but it’s a much more multifaceted problem and statins, blood pressure control, and lifestyle change probably account for as much, if not more, of the way to reduce risk,” he said.

How Much AF Is Too Much?

Dipyridamole (Aggrenox) is also an option for monotherapy. Richard A. Bernstein, MD, professor of neurology and distinguished physician in vascular neurology, Feinberg School of Medicine, Northwestern University, Chicago, said he treats patients long-term after ESUS with either aspirin, dipyridamole, or clopidogrel and suggests putting in a loop recorder if they’re over age 65 or have a lot of other stroke risk factors.

“If they have Afib on their loop recorder, I generally switch them to anticoagulation, but I could not argue with someone who said the evidence is not strong enough to do that,” he said. 

Bernstein usually uses a threshold of 6 minutes of AF based on the ARTESIA trial. “And it needs to be read by a cardiologist, not me. That’s a logistical detail, but I do think it’s important.” 

Compared with aspirin, apixaban cut the risk for stroke or systemic embolism by 37% but had more major bleeding in patients with at least one episode of AF lasting 6 minutes to 24 hours in ARTESIA. Most of these patients, however, did not have a history of stroke and had pacemakers or defibrillators, not loop recorders, he noted. 

“We need a trial in stroke patients because they don’t always respond the way nonstroke patients do to medication,” Bernstein said. “They’re more fragile and more high risk than the average nonstroke patient. So, it leaves us with a lot of uncertainty.”

He considers ESUS “a big embarrassment to the stroke field” because they still don’t know what caused stroke in thousands of patients despite a battery of tests. “Not that anyone is doing anything wrong, but we’ve just got a tremendous amount of scientific work to do to understand where these strokes are coming from,” said Bernstein.

All three neurologists say the use of loop recorders has dramatically changed thinking about secondary prevention, but it remains an open question whether AF found months to years after a stroke could really be the cause of that stroke. Also unknown is the minimum AF burden that merits anticoagulation.

Elkind said that neurologists are quick to put patients on anticoagulation “if they have just a few seconds of what looks like atrial fibrillation.” Cardiologists, on the other hand, tend to have a higher threshold; “some say 5 minutes, some say 6 minutes, some say 24 hours of AFib before it’s a risk factor. But in a patient whose already had a stroke, I think the threshold has to be lower,” he said.

How best to gauge the level of AF that warrants anticoagulation is unknown. Elkin explained that it might be duration, or total burden if you add up all the episodes, or frequency of episodes, “or is it that plus a biomarker like NTproBNP [N-terminal pro-B-type natriuretic peptide] and something else?” 

Time to Reassess ESUS 

It’s obvious the focus needs to shift from AF to the atherosclerotic path, George Ntaios, MD, professor of internal medicine at the University of Thessaly, Larissa, Greece, and treasurer of the European Society of Cardiology Council on Stroke, told Medscape Medical News. 

He believes the three neutral anticoagulation trials “should change the way people look at ESUS for the moment but…some of us, a significant proportion, are still looking hard for atrial fibrillation even if the evidence gets weaker and weaker,” he said. 

The trials have added traction to calls to reassess the ESUS construct. A new multidisciplinary clinical consensus statement, co-authored by Ntaios and published this April, is the latest to call for a “paradigm shift,” away from an embolic stroke diagnosis due to a presumed single cause. 

The panel proposes a comprehensive, multidimensional assessment of the overall thromboembolic risk in patients with ESUS through synthesis of the individual risks linked to six potential pathologies: supracardiac atherosclerosis, cancer, left ventricular disease, left atrial disease, PFO, and valvular heart disease.

“The main thinking of this paper is that it tries to provide some guidance, some consensus on which are the characteristics that point towards causal association and which are those characteristics that probably are associated with less clinically or perhaps with innocent pathologies,” Ntaios said. 

Elkind reports serving as principal investigator of ARCADIA, which was funded by the National Institutes of Health and received study drug in-kind from the BMS-Pfizer Alliance. Ntaios reports advisory boards/research support/speaker fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Javelin Medical, Novartis, and Sanofi, and serving on clinical trial steering/executive committees for Janssen and Javelin Medical. Sharma reports serving as principal investigator of OCEANIC and on the steering committees for NAVIGATE ESUS and COMPASS, all three of which were sponsored by Bayer, and serving on the ARCADIA steering committee. Bernstein reports having no relevant financial conflicts of interest.