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Patent Foramen Ovale Closure Reduces Clinical but Not Silent Brain Infarcts

Mona Al Banna, MB BCh, Msc(Res)
@DrMonaAlBanna

Messé SR, Erus G, Bilello M, Davatzikos C, Andersen G, Iversen HK, Roine RO, Sjöstrand C, Rhodes JF, Søndergaard L, Kasner SE, and on behalf of the Gore REDUCE Study Investigators. Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial. Stroke. 2021;52:3419–3426.

Patent foramen ovale (PFO) is found in one quarter of the population. However, in cryptogenic strokes, PFOs have been found in approximately one half of patients. (1) The association is even stronger in younger patients with a stroke, as a four-fold greater incidence of PFO has been detected compared to a stroke-free age- and sex-matched control group. (2) The pathophysiology of PFO-related stroke involves the paradoxical embolism of a clot from the venous circulation to the arterial circulation through a right-to-left shunt. Therefore, PFO closure to eradicate the right-to-left shunt has been proposed as an intervention to reduce PFO-related stroke. Percutaneous PFO closure devices have been in use for many years. However, up until recently, clinical trials did not show significantly lower rates of recurrent stroke with PFO closure compared to standard medical therapy alone. (3-5) A sub-group analysis of the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial showed significant reduction of stroke recurrence in patients with larger sized PFOs and atrial septal aneurysm. (6) The latest randomized controlled trials investigating the benefit of PFO closure utilized stricter inclusion criteria, in which patients were only eligible for closure if they had PFOs with an associated large interatrial shunt or atrial septal aneurysm, cortical stroke, and were <60 years old. (7-9) These trials concluded that the rate of recurrent stroke was significantly lower with closure, with one stroke avoided at 2 years for every 24 treated patients. (7)However, due to feasibility, these trials used an open label design where the patients and the treating clinicals were aware of the treatment assignment, increasing the risk of bias.

Antithrombotic Regimen for Stroke Patients: Where to Draw the Line?

Wern Yew Ding, MBChB

Li ZX, Xiong Y, Gu HQ, Fisher M, Xian Y, Johnston SC, Wang YJ. P2Y12 Inhibitors Plus Aspirin Versus Aspirin Alone in Patients With Minor Stroke or High-Risk Transient Ischemic Attack. Stroke. 2021;52:2250–2257.

Patients with ischemic stroke or transient ischaemic attack (TIA) are at risk of further events. Previously, these patients were treated with single antiplatelet therapy. However, contemporary guidelines recommend that dual-antiplatelet therapy (DAPT) may be considered in the acute phase: the duration of treatment depending on stroke severity. Several studies have investigated the use of different DAPT regimens in patients with minor stroke or high-risk TIA.

In this study by Li and colleagues, the authors undertook a systematic review and meta-analysis of 4 randomized controlled trials that included a total of 21493 patients with acute minor stroke (NIHSS score ≤3/≤5) or high-risk TIA (ABCD2 ≥4/≥6) who were randomized to receive either DAPT or aspirin alone within 24 hours of symptom onset. Three of the 4 studies used clopidogrel while the remaining study investigated the use of ticagrelor. The authors reported that DAPT reduced the risk of stroke recurrence by 24%. However, there was no statistical difference in all-cause mortality between the groups, and those on DAPT were exposed to a 2.2-fold greater risk of moderate or severe bleeding.

Article Commentary: “Endovascular Thrombectomy for Treatment of Acute Ischemic Stroke During Pregnancy and the Early Postpartum Period”

Ericka Teleg, MD

Dicpinigaitis AJ, Sursal T, Morse CA, Briskin C, Dakay K, Kurian C, Kaur G, Sahni R, Bowers C, Gandhi CD, et al. Endovascular Thrombectomy for Treatment of Acute Ischemic Stroke During Pregnancy and the Early Postpartum Period. Stroke. 2021.

This study begins with emphasizing the lack of evidence in the management of pregnant patients or those in the early postpartum period confronted with acute ischemic stroke within the time window for endovascular therapy. In the advent of the landmark clinical trials on the benefit of endovascular therapy for acute ischemic stroke, it is the authors’ hypothesis that this particular group will also show a favorable clinical course and short-term outcomes likened to those found in the general population. Pregnant and postpartum women were systematically excluded from the clinical trials in acute reperfusion therapies for acute ischemic stroke. Acute reperfusion therapy with endovascular thrombectomy in the setting of pregnancy and the postpartum period is an important area to navigate. Pathophysiology of stroke among this population includes a hypercoagulable physiological state. It is important that this study answers this need in terms of benefit, complications, and outcomes, as stroke physicians are bound to encounter these complex cases in their lifetime. 

PCSK9 Inhibitors Are Potential Alternatives to Statins in Patients with High Risk of Intracerebral Hemorrhage

Praveen Hariharan, MD

Sanz-Cuesta BE, Saver JL. Lipid-Lowering Therapy and Hemorrhagic Stroke Risk: Comparative Meta-Analysis of Statins and PCSK9 Inhibitors. Stroke. 2021.

Since the birth of statins in the late 20th century, statins have become an integral part of cardiovascular disease management. However, several studies showing increased risk of hemorrhagic stroke with statin use have raised concerns, and the risk is currently being evaluated with ongoing randomized clinical trials. PCSK9 (proprotein convertase subtilisin kexin 9) inhibitors are the most potent novel antihyperlipidemic medications and could serve as potential alternatives to statins.

In this study, Drs. Sanz-Cuesta and Saver investigated the hemorrhagic stroke rates of PCSK9 inhibitors by undertaking a meta-analysis of data available from randomized clinical trials (RCTs) comparing low or high dose statins with each other or controls, and low and high dose PCSK9 inhibitors with each other or controls. Assuming a gradient risk based on the history of ischemic or hemorrhagic stroke and medication dosing, RCTs were planned to be grouped into 4 subcategories: 1) all patients/any dose; 2) all patients/high dose; 3) history of ischemic stroke/any dose; and 4) history of hemorrhagic stroke/any dose.

By |September 27th, 2021|clinical, treatment|0 Comments

Direct Oral Anticoagulants Versus Warfarin in Cancer Patients with Atrial Fibrillation

Mona Al Banna, MB BCh, MSc

Chan YH, Chao TF, Lee HF, Chen SW, Li PR, Liu JR, et al. Clinical Outcomes in Atrial Fibrillation Patients With a History of Cancer Treated With Non-Vitamin K Antagonist Oral Anticoagulants: A Nationwide Cohort Study. Stroke. 2021.

Atrial fibrillation is a known risk factor for stroke, increasing stroke risk 5-fold and mortality 2-fold compared to patients without atrial fibrillation. Cancer causing a hypercoagulable state is another well-known risk factor for stroke. Current guidelines recommend direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation. In patients with cancer who develop atrial fibrillation, warfarin or low-molecular weight heparin have traditionally been preferred over the direct oral anticoagulants.

In this study, Chan et al. investigated the effectiveness and safety of the DOACs when compared to warfarin in this population. A nationwide retrospective cohort study was performed using the Taiwan National Health Insurance Research Database. They identified 85,641 patients diagnosed with atrial fibrillation and treated with an anticoagulation over a 5-year period. Of those AF patients with a diagnosis of cancer, 6274 were treated with DOACs and 1681 were treated with warfarin. The DOAC group had a lower risk of ischemic stroke, acute myocardial infarction, major adverse limb events and venous thrombosis compared to the warfarin group. DOAC use was associated with a lower risk of ICH and major bleeding when compared to warfarin. Subgroup analysis was also performed to determine how different DOACs or different dosages of DOACs compared to warfarin. In general, there was lower risk of thrombotic events and major bleeding for DOACs over warfarin irrespective of DOAC type and whether it was standard-dose or low-dose. In addition, this benefit of DOACs over warfarin was consistent across patients with different types of cancer and at different stages of disease activity.

By |September 24th, 2021|clinical, treatment|0 Comments

Article Commentary: “Fluid-Attenuated Inversion Recovery May Serve As a Tissue Clock in Patients Treated With Endovascular Thrombectomy”

Parth Upadhyaya, DO

Aoki J, Sakamoto Y, Suzuki K, Nishi Y, Kutsuna A, Takei Y, et al. Fluid-Attenuated Inversion Recovery May Serve As a Tissue Clock in Patients Treated With Endovascular Thrombectomy. Stroke. 2021;52:2232–2240.

Based on WAKE-UP (2018), THAWS (2020), and smaller single-center trails, the concept of FLAIR signal change as a surrogate timekeeper in hyperacute stroke has shown both safety and efficacy for intravenous thrombolysis. Now, in the age of extended window endovascular thrombectomy (EVT), predictors of good clinical outcome beyond time, age and medical risk factors become prudent for patient selection. In this study, Aoki et al. hypothesize if FLAIR signal change can predict clinical outcome after EVT.

From a prospective registry of 324 consecutive EVT patients presenting with acute ischemic stroke, 227 were retrospectively enrolled from September 2014 to December 2018. Those with premorbid mRS score 0 to 1 with available FLAIR imaging were included; patients with contraindications to MRI were excluded. FLAIR positivity was defined by new hyper-intense signal at DWI-positive lesion site; subtle changes were measured using contralateral signal intensity ratio of 1.2. The median age of patients was 74, NIHSS 15, and symptoms onset to imaging 155 minutes. Ischemic core volume and NIHSS were not significantly different in timing to FLAIR imaging from less than 2 hours to greater than 12 hours. 

By |September 10th, 2021|clinical, treatment|0 Comments

ESOC 2021 Session: “Non-Reperfusion Therapies for Acute Ischemic Stroke Treatment: Something New in the Pipeline?”

Karissa Arthur, MD

European Stroke Organisation Conference
September 1–3, 2021

Dual Antiplatelet Therapy for Minor Acute Ischemic Stroke: Clopidogrel vs Ticagrelor: Pierre Amarenco, Paris University

In this session, Dr. Amarenco compared clopidogrel versus ticagrelor for minor acute ischemic stroke. He first summarized data for aspirin monotherapy showing that it reduces the risk of ischemic stroke by 60%, and the 6-week risk of disabling stroke by 70%. He then called to attention the CHANCE and POINT trials, as well as a pooled analysis of both, showing that dual antiplatelet therapy with aspirin plus clopidogrel after a minor stroke or TIA is 34% superior to aspirin alone in preventing stroke in the first 21 days. Dr. Amarenco went on to discuss the shortcomings of clopidogrel, with specific regard to CYP2C19 loss of function carriers in which there is less efficacy for stroke prevention. In contrast to clopidogrel, ticagrelor is a direct acting drug which does not require biotransformation, binds reversibly to platelets, has faster onset, higher platelet inhibition, and faster offset and therefore has a more attractive profile than clopidogrel. 

ESOC 2021 Session: “Scientific Communication 06 – Acute Treatment and Thrombolysis”

Vignan Yogendrakumar, MD, MSc
@VYogendrakumar

European Stroke Organisation Conference
September 1–3, 2021

This session opened with a presentation by Dr. Mikhail Kalinin and the CEREHETIS Investigators on the potential neuroprotective effect of Cerebrolysin as an add-on therapy during acute reperfusion. In a pilot RCT designed to assess safety, patients were randomized to cerebrolysin + IV tPA versus IV tPA alone. The primary outcome of the study was post-treatment symptomatic hemorrhagic transformation. 117 patients were randomized to the intervention arm, while 201 were randomized to the control arm.  Symptomatic hemorrhagic transformation occurred at lower rates in those who received cerebrolysin + thrombolysis, compared to thrombolysis alone. However, functional outcomes (mRS ≤ 2) did not differ between the two groups.

This was followed by a presentation by Dr. Wayneho Kan and the American Heart Association Get With The Guidelines-Stroke group. Using the registry of 160,000+ patients, Dr. Kan presented on the outcomes of tPA use in patients who were on a NOAC versus those not on anticoagulation using propensity score overlap weighting and regression modelling. Adjusting for baseline clinical factors, the risks of symptomatic intracranial hemorrhage did not differ between the two groups (sICH: aOR, 0.88 [95%CI, 0.70-1.10]; in-hospital mortality: aOR, 0.84 [95%CI, 0.69-1.01]). Of note, the exact time of last NOAC dose was not measured in this registry, and levels of factor Xa were also not available. Based on an analysis of a smaller registry used within this study which reported time of NOAC dose, a large majority of NOAC patients treated with lysis had taken their last dose more than 24 hours prior to the stroke event.

Fluoxetine in Stroke Fails to Deliver

Muhammad Rizwan Husain, MD
@RIZWANHUSAINMD  

Lundström E, Isaksson E, Greilert Norin N, Näsman P, Wester P, Mårtensson B, Norrving B, Wallén H, Borg J, Hankey GJ, et al. Effects of Fluoxetine on Outcomes at 12 Months After Acute Stroke: Results From EFFECTS, a Randomized Controlled Trial. Stroke. 2021.

The Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke (EFFECTS) was a randomized clinical trial whose primary outcome was to assess if oral fluoxetine initiated within 2-15 days of an acute stroke (ischemic or hemorrhagic) and taken up to 6 months improved functional outcomes. The initial trial results, which were published in August 2020, demonstrated no improvement in functional outcomes (modified Rankin Score-mRS-adjusted odds ratio: 0.94 [95% CI 0.78–1.13]) at 6 months with fluoxetine use and noted an increased rate of fractures and hyponatremia, though occurrence of depression was reduced (by 4%).

The authors now report 12-month follow-up results on outcomes that include the mRS, health status, quality of life, fatigue, mood and depression to see if any effects of fluoxetine persisted or were delayed.

Article Commentary: “Switching to Tenecteplase for Stroke Thrombolysis: Real-World Experience and Outcomes in a Regional Stroke Network”

Ericka Samantha Teleg, MD

Mahawish K, Gommans J, Kleinig T, Lallu B, Tyson A, Ranta A. Switching to Tenecteplase for Stroke Thrombolysis: Real-World Experience and Outcomes in a Regional Stroke Network. Stroke. 2021.

Accessibility to stroke services, timely treatment and management differ in regions and locations throughout the world. Each geographic location is different in terms of barriers to stroke treatment. Evidence translated to real-world findings is an important key element in this article by Mahawish et al. The New Zealand Central Region Hyper-Acute Stroke Network switched to tenecteplase driven by data supporting probable improvement of large vessel occlusion (LVO) recanalization in areas wherein, first, endovascular accessibility is a challenge due to geographical limitations, and second, the ease of tenecteplase administration. This model can contribute to other regions that have similar landscape in terms of medical resources and accessibility to tertiary or regional centers with endovascular administration infrastructure.