Advances in Neurocardiology: Focus on Atrial Fibrillation.

Abstract

HomeStrokeVol. 52, No. 11Advances in Neurocardiology: Focus on Atrial Fibrillation Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAdvances in Neurocardiology: Focus on Atrial Fibrillation Luciano A. Sposato, MD, MBA and Mahmut Edip Gurol, MD, MSc Luciano A. SposatoLuciano A. Sposato https://orcid.org/0000-0001-6425-9343 Departments of Clinical Neurological Sciences, Anatomy and Cell Biology, and Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, Heart and Brain Laboratory, and Robarts Research Institute, Western University, London, ON, Canada (L.A.S.). Search for more papers by this author and Mahmut Edip GurolMahmut Edip Gurol Correspondence to: Mahmut Edip Gurol, MD, MSc, Massachusetts General Hospital, Harvard Medical School, 175 Cambridge St, Suite 300, Boston, MA 02114. Email E-mail Address: [email protected] https://orcid.org/0000-0002-2169-4457 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston (M.E.G.). Search for more papers by this author Originally published25 Oct 2021https://doi.org/10.1161/STROKEAHA.121.033970Stroke. 2021;52:3696–3699Neurocardiology is an emerging area fostering the collaboration between neurologists, stroke physicians, and cardiologists in clinical and research aspects of the brain and heart relationship. In this article, we have highlighted the results of recent studies and randomized controlled trials of prolonged cardiac monitoring (PCM) and left atrial appendage closure (LAAC) for stroke prevention in patients with atrial fibrillation (AF), topics with a potential strong impact on clinical practice and future research.PCM PoststrokeIn 2021, 6 important randomized controlled trials evaluating PCM for AF detection were published. Three in patients with ischemic stroke and 3 in patients with and without a previous cerebrovascular event (Table).1–3 MonDAFIS (Monitoring for Detection of Atrial Fibrillation in Ischemic Stroke) compared 7 days of inhospital Holter monitoring versus usual care in patients with unselected (cryptogenic and noncryptogenic) ischemic stroke or transient ischemic attack (TIA).1 The study showed no differences between groups in the primary end point of the proportion of patients receiving anticoagulants at 12 months.1 There were no differences in AF diagnostic rates or the risk of recurrent stroke at 12 months either (Table). In PER DIEM (Post-Embolic Rhythm Detection With Implantable vs External Monitoring), ischemic stroke and patients with TIA were randomly assigned to an implantable loop recorder (ILR) or 28-day external loop recording.2 The primary outcome of a new diagnosis of AF at 12 months was found in 15.3% of participants assigned to ILR versus 4.7% of those wearing external loop recording (between-group difference 10.7% [95% CI, 4.0%–17.3%]). The total number of participants receiving oral anticoagulants at 12 months was not reported and there were no differences in stroke recurrences between intervention arms (Table). STROKE-AF (Stroke of Known Cause and Underlying Atrial Fibrillation) included large-vessel or small-vessel ischemic stroke patients older than 60 years of age or aged 50 to 59 years with at least 1 stroke risk factor of known cause and underlying atrial fibrillation included large-vessel or small-vessel ischemic stroke patients older than 60 years of age or aged 50 to 59 years with at least one stroke risk factor.3 Participants were randomized to receiving ILR or usual care. The primary end point was AF detection at 12 months and was higher in the ILR group than in the control group (12.1% versus 1.8%, P<0.01). While the proportion of participants receiving oral anticoagulants at 12 months was higher in the ILR arm, there were no differences in stroke recurrences between groups (Table). The LOOP study (Implantable Loop Recorder Detection of Atrial Fibrillation to Prevent Stroke) randomized individuals aged 70 to 90 years without AF with and at least one stroke risk factor to ILR versus usual care.4 This study found no differences in the primary outcome of time to first stroke or systemic embolism between ILR and usual care (4.5% versus 5.6%, P=0.11) despite significantly higher anticoagulation rates in the intervention arm (Table). In STROKESTOP (Clinical Outcomes in Systematic Screening for Atrial Fibrillation) all residents from 2 Swedish regions aged 75 to 76 years were randomized to screening for AF with a thumb ECG twice daily for 14 days or usual care.5 Only 51.3% of individuals invited to the screening group agreed to participate. Nonparticipating residents had more AF at baseline, comorbidities, medications, and poorer sociodemographic factors (eg, income and education). At baseline 12.1% and 12.8% of participants in the intervention and control groups had AF. On intention to treat analyses, the primary composite end point of ischemic or hemorrhagic stroke, systemic embolism, bleeding causing hospitalization, and all-cause death was marginally lees frequent in the intervention group than in the control arm (Table). Clinical outcomes in systematic screening for AF did not show differences in the risk of ischemic or hemorrhagic stroke between groups.Table. Randomized Clinical Trials of Prolonged Cardiac Monitoring Published Between January and September 2021StudyPopulationInterventionControlPrimary end pointProportion with AF detection at 12 moProportion on oral anticoagulants at 12 moProportion with recurrent stroke at 12 moPCMControlRisk (95% CI)PCMControlRisk (95% CI)PCMControlRisk (95% CI)Randomized controlled trials in patients with cerebrovascular events MonDAFIS1Unselected AIS/TIA7-d IH Holter (n=1484)Usual care* (n=1436)OAC at 12 mo9.78.1OR 1.2 (0.9–1.6)13.711.8OR 1.2 (0.9–1.5)6.16.4OR 0.9 (0.7–1.1) PER DIEM2Unselected AISILR (n=150)28 d ELR (n=150)AF at 12 mo15.34.7RR 3.3 (1.5–7.4)NA†NA†NA†4.06.0OR 0.7 (0.2–1.9)‡ STROKE-AF3LVD and SVD AISILR (n=242)Usual care§ (n=250)AF at 12 mo12.11.8HR 7.4 (2.6–21.3)15.75.6OR 3.1 (1.7–6.0)7.29.8HR 0.7 (0.4–1.4)Randomized controlled trials in patients with and without cerebrovascular events LOOP470–90 y and 1 risk factor∥ILR (n=1501)Usual care (n=4503)Time to first stroke/SE31.812.2HR 3.2 (2.8–3.6)29.713.1HR 2.7 (2.4–3.1)4.55.6HR 0.8 (0.6–1.1) STROKESTOP575–76 y¶14-d iECG (n=13 979)Usual care (n=13 996)Composite end point#15.114.1P=0.02211.310.8P=0.195.55.9HR 0.9 (0.8–1.0)Proportions were rounded to a single decimal and 0.05 values were rounded to the higher decimal (eg, 1.05=1.1). 14-d iECG indicates 14-d intermittent thumb ECG performed twice daily; 7-d IH, 7-day in hospital; AF, atrial fibrillation; AIS, acute ischemic stroke; ELR, external loop recorder; ILR, implantable loop recorder; LOOP, Implantable Loop Recorder Detection of Atrial Fibrillation to Prevent Stroke; LVD, large-vessel disease; MonDAFIS, Monitoring for detection of AF in ischemic stroke; OAC, oral anticoagulants; OR, odds ratio; PCM, prolonged cardiac monitoring; PER DIEM, post-embolic rhythm detection with implantable versus external monitoring; STROKE-AF, stroke of known cause and underlying atrial fibrillation; STROKESTOP, clinical outcomes in systematic screening for AF; SVD, small-vessel disease; and TIA, transient ischemic attack.* The definition of usual care for MonDAFIS was established by the German Diagnosis Related Groups system and was defined as follows: diagnostic ECG standard of care in hospital including (monitor-based) ECG monitoring on the stroke unit.† Information on oral anticoagulation was only provided for patients with atrial fibrillation.‡ Estimated, not provided in the original publication.§ Usual care in STROKE-AF was defined as external cardiac monitoring such as 12-lead electrocardiograms, Holter monitoring, telemetry, or event recorders.∥ Included 24.7% and 25.1% of patients with a previous ischemic stroke, TIA, or systemic embolism in the intervention and control groups, respectively.¶ Included 11.1% and 10.8% of patients with a previous ischemic stroke, TIA, or systemic embolism in the intervention and control groups, respectively.# Composite end point of ischemic or hemorrhagic stroke, systemic embolism, bleeding causing hospitalization, and all-cause death. Results represent the primary composite end point; recurrent ischemic and hemorrhagic stroke were reported separately and there were no significant differences between arms.Knowledge GapsOverall, these recent randomized clinical trials confirmed that PCM is associated with increased AF detection,1–5 even among patients with strokes caused by atherothrombotic and atheroembolic mechanisms (small and large artery disease).3 Whether AF detected after noncardioembolic events is associated with the same embolic risk as AF diagnosed in patients with cryptogenic strokes, remains unknown. Importantly, these randomized clinical trials also suggest that higher AF detection leading to increased oral anticoagulant use does not necessarily result in lower stroke incidence or recurrence rates.4,6 It must be noted that trials conducted among patients with a previous stroke or TIA were underpowered for evaluating the effect of PCM on the risk of stroke recurrence. However, a meta-analysis of these trials did not show an association between PCM and lower stroke recurrences either.7 Future research should focus not only on patients with higher odds of being diagnosed with AF through PCM but also on those who are more likely to benefit from oral anticoagulation or LAAC based on a thorough review of embolic and hemorrhagic risks.LAAC for Stroke Prevention in Patients With AFThe last year saw important advances in the field of stroke prevention in AF especially using nonpharmacological approaches and these studies impacted Food and Drug Administration (FDA) approvals of LAAC devices. PRAGUE-17 (Left Atrial Appendage Closure Versus Direct Oral Anticoagulants in High-Risk Patients With Atrial Fibrillation) was a multicenter, randomized, noninferiority trial comparing LAAC with either Amplatzer Amulet or Watchman devices with direct oral anticoagulants (DOAC) in patients with nonvalvular AF and high risk of either ischemic or hemorrhagic events.8 Mean age of the patient population enrolled was 73.3±7, mean CHA2DS2-VASc score was 4.7±1.5 and 32% had a past history of cardioembolic stroke; these baseline variables were similar between the 2 study arms. Over ≈20 months of follow-up, the annual rates of the primary outcome (composite of stroke, TIA, systemic embolism, cardiovascular death, major or nonmajor clinically relevant bleeding, or procedure/device-related complications) were 10.99% with LAAC and 13.42% with DOAC (P=0.44; P=0.004 for noninferiority). All stroke/TIA rates were similar (subdistribution hazard ratio=1) while nonprocedural major/nonmajor bleeding tended to be less frequent with LAAC compared with DOAC (subdistribution hazard ratio=0.53 [95% CI, 0.26–1.06]). This first stroke prevention randomized controlled trial in AF a decade after the original DOAC studies thus showed noninferiority of LAAC over DOACs with a signal for lower hemorrhagic complications, paving the way to 2 large randomized controlled trials comparing LAAC with Watchman FLX (CHAMPION AF: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04394546) and Amplatzer Amulet (CATALYST: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04226547) devices to DOACs in a general nonvalvular AF population. If these large-scale studies powered to prove noninferiority of LAAC over DOAC confirm PRAGUE-17 findings, LAAC can become a first line stroke prevention strategy in AF.The PINNACLE FLX (Primary Outcome Evaluation of a Next-Generation Left Atrial Appendage Closure Device) was a prospective, multicenter FDA study aimed at evaluating the safety and effectiveness of the next-generation Watchman FLX device for LAAC.9 Mean age of the patient population enrolled was 73.8±8.6, mean CHA2DS2-VASc score was 4.2±1.5 and 22.3% had a past history of ischemic stroke or TIA. Out of the 400 patients enrolled, the incidence of the primary safety end point (occurrence of death, ischemic stroke, systemic embolism, or device- or procedure-related events requiring cardiac surgery) was 0.5%, meeting the performance goal of 4.2% (P<0.0001). The incidence of the primary effectiveness end point (effective LAAC with peri-device flow ≤5 mm) was 100%, again meeting the performance goal of 97% (P<0.0001). DOAC was used within the first 45 days after Watchman FLX implant. The study resulted in the FDA approval of the Watchman FLX device for stroke prevention in nonvalvular AF patients who have an appropriate rationale to seek a nonpharmaceutical alternative to long-term anticoagulation. FDA labeling was also updated to include DOACs as an alternative during the first 45 days immediately after the implant.The recently published AMULET IDE (Amplatzer Amulet Left Atrial Appendage Occluder IDE) randomized controlled trial aimed to evaluate the safety and effectiveness of LAAC with the Amulet device compared with the first-generation Watchman device.10 Mean age of the patient population enrolled was 75±7.6 while the mean CHA2DS2-VASc score was 4.6±1.4, without a significant difference between treatment arms. Although a combined rate of ischemic stroke or TIA was not provided, past history of ischemic stroke was reported to be present in 18% in Amulet and 19.9% in the Watchman arms. A history of TIA was present in 10.7% of Amulet and 12% of the Watchman arm. Nonvalvular AF patients who received Amulet were more likely to have procedure-related complications than Watchman (4.5% versus 2.5%) but also higher rates of adequate LAAC at 45 days (98.9% versus 96.8%). The Amulet device was noninferior to the old-generation Watchman for both the primary effectiveness end point (2.8% versus 2.8%) and primary safety end point (14.5% versus 14.7%, P<0.001 for noninferiority for both comparisons). The Amulet device was thus approved by the FDA for the same nonpharmacological stroke prevention indication as the Watchman device in AF.The LAAOS III study (Left Atrial Appendage Occlusion During Cardiac Surgery to Prevent Stroke) randomized 4811 patients to undergo (n=2400) or not undergo (n=2411) LAAC at the time of cardiac surgery for another indication.11 One of the following techniques were used for surgical LAAC: amputation and closure (preferred), stapler closure, double-layer linear closure from within the atrium in participants undergoing minithoracotomy, or closure with an approved surgical occlusion device. Mean age of the patient population enrolled was 71.2±8.3, mean CHA2DS2-VASc score was 4.2±1.5 and 9.1% had a past history of stroke. These baseline variables were similar between the 2 interventional treatment arms. LAAC during cardiac surgery significantly decreased the risk of stroke or systemic embolism (4.8% versus 7.0%, hazard ratio, 0.67 [95% CI, 0.53–0.85]; P=0.001) over a mean of 3.8 years follow-up despite similar rates of remaining on therapeutic long-term anticoagulation. The incidence of perioperative complications, such as bleeding, heart failure, and death, did not differ significantly between the trial arms, suggesting that there was no safety concern for the additional surgical LAAC procedure. This important randomized controlled trial not only confirms that LAAC prevents strokes but also shows that the combination of LAAC and long-term anticoagulation can be beneficial and therefore studied in appropriate populations.The recent randomized controlled trials and other FDA studies that led to the approval of new LAAC devices improve the clinician’s options for stroke prevention in AF. A good understanding of these options by stroke neurologists is essential to the care of patients with AF at high brain hemorrhage or other bleeding risk as well as patients who encounter other problems with regular daily use of anticoagulants lifelong. Future studies should also focus on the potential benefit of LAAC on other AF patient populations with unmet needs such as high hemorrhage risk patients as well as patients who have a stroke while using oral anticoagulants.Sources of FundingDr Sposato reports Kathleen & Dr Henry Barnett Chair in Stroke Research (Western University); Saraydar Neurosciences Fund (London Health Sciences Foundation). Dr Gurol received funding from the National Institutes of Health (R01NS114526 and NS083711).Disclosures Dr Sposato reports speaker, consulting honoraria, and research grants from Pfizer, Bayer, Gore, Daiichi Sankyo Company LTD, and Boehringer Ingelheim; Chair, WSO Brain & Heart Task Force; Member, Editorial Board of NEUROLOGY, STROKE, and JAHA. Neurocardiology section editor, STROKE. Associate Guest Editor, JAHA. Dr Gurol reports Neurocardiology section editor, STROKE; Chair, WSO Task Force on Cerebral Small Vessel Diseases and Vascular Cognitive Impairment; Member, WSO Brain & Heart Task Force; MEG’s hospital received research funding from AVID, Pfizer, and Boston Scientific Corporation.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 3699.Correspondence to: Mahmut Edip Gurol, MD, MSc, Massachusetts General Hospital, Harvard Medical School, 175 Cambridge St, Suite 300, Boston, MA 02114. Email [email protected]harvard.edu