Sishir Mannava, MD

World Stroke Congress
October 28–29, 2021

Neurocardiology: The Neurologist’s Perspective – Dr. Edip Gurol

Dr. Gurol started by discussing the importance of the neurologist classifying stroke etiologies, and ultimately concern for cardioembolic infarct, and the importance of long-term cardiac monitoring in these patients as highlighted by the findings in the CRYSTAL-AF and REVEAL-AF studies. Another important role of neurologists in these patients is stratifying ICH risk if they require anticoagulation (AC). The FDA approved AC for stroke prevention, include warfarin, direct oral antiocoagulants (DOACs), and left atrial appendage closure (LAAC) with WATCHMAN/Amulet devices. Importantly, AC increased intracranial hemorrhage (ICH) risks, and outcomes of AC-associated ICH are extremely poor. High-risk categories include prior brain bleed (of many types), brain microbleeds on MRI (as highlighted in the CROMIS-2 study), white matter disease on MRI, and cognitive/gait problems. AC has been associated with between 5-7x the risk of ICH as compared to antiplatelets (AP). In a recent trial from the UK, which randomized patients to AC vs AP after spontaneous ICH, 8% (AC) as opposed to 4% (AP) had recurrent ICH. Mortality of AC-related ICH is very high, ~50%. Having a prior history of ICH related to hypertension < mixed-ICH < cerebral amyloid angiopathy ICH significantly increases recurrent ICH risk as well. This concept also applies to patients who have independent evidence of lobar microbleeds. Interestingly, Dr. Gurol highlighted a 2019 study from Neurology that showed moderate/severe white matter hyperintensities were associated with ~6% increased risk of ICH if given AC (Marti-Fabregas et al). Regarding LAAC in nonvalvular atrial fibrillation, the PRAGUE-17 trial showed that stroke prevention and bleeding risks were similar when comparing closure to DOACs. Dr. Gurol closed with discussion of patent foramen ovale (PFO) closure for stroke prevention, highlighting that hypercoagulable states and other causes should be evaluated prior to PFO closure. Ultimately, all decision-making regarding AC or device placement (LAAC, PFO) should be shared with the patient.

Advances in Atrial Fibrillation Detection – Dr. Nicole Beaton Sur

Atrial fibrillation (AF) confers a 5-fold risk of ischemic stroke (CVA) and is associated with high mortality and disability rates. Dr. Beaton Sur highlighted some of the newer devices that have allowed for better detection, ranging from handheld low-cost devices to implantable loop monitors (ILM). She highlighted the prevalence of subclinical AF is high, with one study comparing screening method and stroke risk score, showing a much higher prevalence in those patients who had implantable devices, when monitored longer, and had high CHA2DS2VASC scores. The ASSERT study showed that cumulative incidence of AF increased with increasing years of follow-up (more so in subclinical AF lasting >6 min as opposed to subclinical AF >24h), but that those patients with >24h episodes captured a much higher cumulative event rate of stroke and systemic embolism. Defining the duration of subclinical AF that warrants a “high” concern for stroke is difficult to delineate; some have suggested hour-duration cutoff for longest episodes, whereas other studies have looked more at cumulative AF percentage burden. CRYSTAL-AF demonstrated that ILM has a much higher rate of AF detection after cryptogenic stroke. However, STROKE-AF also showed that detection of AF after stroke caused by small vessel or large artery atherosclerosis also showed high rates of AF (median time from randomization to detection was 99 days; ~78% episodes would have been missed if only 30 days monitoring offered), and small vessel stroke had significantly higher rates of AF detected than patients with large artery atherosclerotic strokes. The PER DIEM trial, which compared 30-day external monitors with 12-month ILM, showed significantly higher AF detection in the ILM group. Overall, Dr. Beaton Sur stated that longer monitoring and selecting patients with greater risk factors lead to higher yields of AF detection, although the optimal duration of monitoring post-stroke is still unknown. She concluded by highlighting current enrolling trials looking at AF, with the NOAH-AFNET6 and ARTESIA trials, which are investigating DOAC effectiveness in subclinical AF, nearing completion.

Left Atrial Appendage Closure: From RCTs to Worldwide Implementation – Dr. Vivek Reddy

Dr. Reddy began by making the point that a recent study (2019, Cresti et al.) demonstrated that >98% of atrial thrombi occurred in the left atrial appendance (LAA). He stated that there is no evidence that DOACs provide any greater benefit than aspirin (ASA) therapy in non-cardioembolic stroke. LAA thrombi also seem to occur even in the presence of AC use, citing a study from 2021 (Lurie et al.). DOAC adherence is also a significant issue, and discontinuation leads to cumulative strokerisk over time. When comparing warfarin and LAAC, a 2017 meta-analysis showed LAAC was favorable for prevention of disabling/fatal stroke and significant reduction in non-procedural bleeding risk. In the PRAGUE-17 trial comparing LAAC and DOACs, the investigators concluded that LAAC was non-inferior to DOAC for their primary endpoint, although interpretation is limited by a small study population (n=402). In a 2020 meta-analysis of the LAAC randomized controlled trials (RCTs), analysis of 1,516 patients showed similar stroke rates between LAAC and AF but significantly reduced (~50%) in non-procedure related major bleeding. In propensity-matched analysis between the AMULET study vs Danish DOAC registry, the LAAC group patients fared better than the DOAC group for composite outcome (stroke, major bleeding, mortality), with a 40% reduction in major bleeding, in the closure group. When it comes to procedural safety, Dr. Reddy showed that new technological improvements to LAAC devices have conferred lower complications. Furthermore, Dr. Reddy discussed mortality and cardiovascular mortality, which seems to be reduced in some studies comparing LAAC vs AC. This is likely weighted by the fact that patients on AC suffer higher rates of hemorrhagic stroke, but when comparing ischemic strokeevents, a 2021 Korean Circulation publication found that LAAC group patients had a lower overall mRS, following ischemic stroke up to 12 months on follow-up. This may be explained with larger thrombi with open LAA in DOAC patients, or possibly due to hemorrhagic conversion of ischemic infarcts in DOAC patients, although the definitive answer remains unclear. Dr. Reddy also showed some data that suggests LAAC may be more cost-efficient over time as compared to AC, when economic analysis is conducted. Finally, Dr. Reddy closed with some important questions, including whether LAAC should be offered as an alternative to DOAC, or whether some patients may even benefit from LAAC + DOAC therapy. Forthcoming trials will provide more answers.

PFO: To Close or Not to Close – Dr. Luciano Sposato

Dr. Sposato showed some data looking at the RCTs of PFO closure, showing that the data demonstrates ~60% lower risk of recurrent stroke with PFO closure as opposed to medical therapy, but a significantly higher risk of incident AF (OR 4.62) in PFO closure groups. The benefit has been demonstrated in the RCTs of PFO closure in age ranges of ~18-60 age patients, with cryptogenic ischemic stroke, and high risk PFOs. No large RCT has addressed transient ischemic attacks and PFO closure to this point. When comparing low vs high risk PFO, major features for high risk are (1) size, (2) aneurysmal interatrial septum, and less often considered features include presence of (3) eustachian valve, and (4) Chiari networks. There is a newly proposed criteria (non-validated) in 2020 that stratifies risk of PFO and causal association with stroke, with highest risk conferred to PFOs with a straddling thrombus, and similar risk for PFOs (with high-risk features) and concomitant pulmonary embolism (PE) or deep venous thrombosis (DVT). In regard to the prevention of recurrent stroke in low vs high risk patients, there is significant evidence to show superiority of PFO closure in patients with high risk PFO features (assuming no other known competing causes of stroke) as opposed to low risk (where closure is more controversial). However, when looking at REDUCE data, benefit found with PFO closure was similar between small and moderate-to-large PFOs. Dr. Sposato stated that although smaller PFO may confer lower risk of stroke, it would not preclude that patient completely from receiving PFO closure, if appropriate. Regarding PFO size, the presence of >10 bubbles for PFO sizing would indicate a high risk PFO. Regarding age, there is some evidence in meta-analyses that indicates some select elderly patients with PFO, may benefit from closure as well, but more evidence is needed, since many elderly patients were excluded from major PFO trials. Interestingly, per Dr. Sposato, the migraine PFO trials (conducted in younger populations) did not show a high rate of peri-procedural AF, but the stroke PFO trials (in older populations) did have this finding. This may mean that closing a PFO in elderly patients could incur a higher peri-procedural AF risk. Finally, Dr. Sposato closed by discussing stroke distributions, highlighting that both cortical and deep (subcortical)strokes seem to benefit from PFO closure.