American Heart Association

Monthly Archives: June 2020

How to Treat LV Thrombus: The Age-Old Question!

Muhammad Rizwan Husain, MD

Robinson AA, Trankle CR, Eubanks G, Schumann C, Thompson P, Wallace RL, Gottiparthi S, Ruth B, Kramer CM, Salerno M, et al. Off-label Use of Direct Oral Anticoagulants Compared With Warfarin for Left Ventricular Thrombi. JAMA Cardiol. 2020;5:685-692.

In this entry, I discuss the RED-VELVT observational study by Austin A. Robinson and colleagues about treating left ventricular (LV) thrombi with direct oral anticoagulants (DOACs) compared to warfarin and looking at rates of embolic events between the two treatment modalities.

Anecdotal data from the nineties, as well as the early 2000s, demonstrated a lower risk of systemic embolization with the use of warfarin or low molecular weight heparin (LMWH) compared to antiplatelets for LV thrombi. However, with the arrival of DOACs, anticoagulation therapy has been revolutionized due to ease of administration, no requirement for daily INR checks, no need for dietary alterations, and lower risk of bleeding events, to name a few. The benefit of DOACs for treatment of left atrial (LA) thrombus was noted in the X-TRA trial, and further benefit of DOACs was also seen in patients requiring anticoagulation for cardioversion (ENSURE-AF, EMANATE). Noting the benefits of DOACs in treating LA thrombus, many physicians have extrapolated the use of DOACs to treat LV thrombus. However, there has been no study to date to evaluate if DOACs fare better, worse, or the same compared to warfarin to reduce embolic events in patients with LV thrombi, and the authors in this study have attempted to answer this question.

Article Commentary: “Randomized Trial of Combined Aerobic, Resistance, and Cognitive Training to Improve Recovery From Stroke: Feasibility and Safety”

Tamaya Van Criekinge, PT

Koch S, Tiozzo E, Simonetto M, Loewenstein D, Wright CB, Dong C, Bustillo A, Perez-Pinzon M, Dave KR, Gutierrez CM, et al. Randomized Trial of Combined Aerobic, Resistance, and Cognitive Training to Improve Recovery From Stroke: Feasibility and Safety. Journal of the American Heart Association. 2020;9.

Approximately 30% of stroke survivors will be cognitively impaired in the five years following their diagnosis. Limited evidence is available on the combined effects of cognitive and physical exercise on the recovery of cognition after stroke. The authors of the current study aimed to explore this unique treatment strategy by providing a dual-approach exercise program of combined aerobic and resistance training (CARET) with cognitive training. They sought to investigate the feasibility, adherence, and safety of this high-intensity treatment protocol prior to targeting effectiveness.

This feasibility study included 131 adult stroke survivors, within one year of diagnosis, and by simple randomization were distributed into an intervention group (n=86), CARET-cognitive, and a control group (n=45). Participants received interventions thrice weekly for 40 to 60 minutes of CARET and 40 minutes of cognitive interventions. The CARET exercises consisted of treadmill or bicycle ergometer for aerobic training, while core exercises and weight machines were used for strength training. Training intensity initiated at approximately 50% of the maximum heart rate and was gradually increased to 65%, if possible. Cognitive training was aimed at improving auditory and visual attention, as well as memory, working memory, processing speed, and executive function. The following selected exercises of the computerized program of BrainHQ from Posit Science were performed: target tracker, double decision, eye for detail, fine tuning, scene crasher, card shark and juggle factor. The control group received sham therapy, including stretching, range of motion exercises, and/or computer games such and anagrams and word searches.

Intravenous Thrombolysis Before Endovascular Thrombectomy In Large Vessel Occlusion: Is It Necessary?

Ravinder-Jeet Singh, MBBS, DM

Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, Peng Y, Han H, Wang J, Wang S, et al, for the DIRECT-MT Investigators. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. N Engl J Med. 2020; 382:1981-1993.

The treatment of patients with stroke having large vessel occlusion involves rapid, complete, and safe recanalization of the occluded vessel. Therefore, rapidity, efficacy and safety are three key attributes of any acute reperfusion therapy to improve functional outcomes. Mechanical retrieval of clot, endovascular thrombectomy (EVT), has all three attributes as shown in recent endovascular stroke trials and their meta-analysis.(1) Whether intravenous thrombolysis (IVT) has a synergistic effect in improving these attributes when combined with EVT remains unclear. Starting IVT before EVT adds some delay to the EVT, increases intracranial hemorrhage rates, and adds cost to the overall procedure. However, it could also lead to very early recanalization as shows in the EXTEND IA TNK trial(2) and improve quality of final reperfusion, possibly by clearing distal small emboli.(3) Functional relevance of these effects was not evident in the previous studies.(4) In DIRECT-MT, Yang et al. compared benefit and risk of administering intravenous alteplase before EVT.(5)

DIRECT-MT was a Chinese multicenter trial with PROBE (prospective, randomized, open-label trial with blinded outcome assessment) design similar to previous EVT trials. The patients (N=656) with ischemic stroke having large vessel occlusion and eligible to both IVT and EVT within 4.5 hours from symptom onset were enrolled. A total of 327 patients were randomized to undergo EVT (thrombectomy-alone group) and 329 to EVT plus IVT with alteplase (combination-therapy group).

Article Commentary: “Decrease in Hospital Admissions for Transient Ischemic Attack, Mild, and Moderate Stroke During the COVID-19 Era”

Burton J. Tabaac, MD

Diegoli H, Magalhães PSC, Martins SCO, Moro CHC, França PHC, Safanelli J, Nagel, V, Venancio VG, Liberato RB, Longo AL. Decrease in Hospital Admissions for Transient Ischemic Attack, Mild, and Moderate Stroke During the COVID-19 Era. Stroke. 2020.

On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic. As of this writing, the global number of cases exceeds 8.1 million. However, despite the rapidly increasing prevalence of COVID-19, many questions remain regarding this unusual and highly lethal disease. The pathogenesis of COVID-19–associated neurologic injury remains to be established. SARS-CoV-2 has been shown to induce a hypercoagulable state, thus increasing the risk of arterial thrombosis with acute ischemic stroke.(1)

From late 2019 to early 2020, COVID-19 started to disrupt the healthcare systems of many nations. From the beginning of the pandemic, it has been a major concern for doctors and public authorities that resources needed to treat other conditions such as stroke are diverted for COVID-19.(2) The authors are keen to note that “patients may be unwilling to go to a hospital for stroke treatment due to fear of becoming contaminated with the disease.” Using a population-based stroke registry, the authors of this original contribution investigated the impact of the onset of the COVID-19 pandemic on stroke admissions in Joinville, Brazil. The authors’ hypotheses were as follows: First, hospital admissions for stroke were reduced after the onset of the COVID-19 pandemic. Next, the reduction occurred only in transient ischemic attacks (TIA) and mild cases. Also, there was a change in the time between stroke onset and hospital admissions. Finally, the number of patients receiving reperfusion therapies (IVT and MT) has decreased.

To Pause or Not to Pause!

Muhammad Rizwan Husain, MD

Douketis JD, Spyropoulos AC, Duncan J, Carrier M, Le Gal G, Tafur AJ, Vanassche T, Verhamme P, Shivakumar S, Gross PL, et al. Perioperative Management of Patients With Atrial Fibrillation Receiving a Direct Oral Anticoagulant. JAMA Intern Med. 2019;179:1469-1478.

In this entry, I discuss a publication by Douketis and colleagues regarding the perioperative management of patients who have atrial fibrillation (AF) and are on a Direct oral anticoagulants (DOAC) and do not undergo a perioperative heparin bridge, who are then evaluated for rates of major bleeding and arterial thromboembolism.

DOACs have been in common use for AF since 2010, and there has been an increased use over the years due to its easy-to-administer dosing, no need for regular INR checks, nor any requirements for dietary adjustments. The concerns of intraoperative and post-operative bleeding with recent DOAC use, followed by the risk of an arterial embolic event like stroke while briefly off DOACs, has raised many concerns amongst physicians about when to stop and resume DOACs in patients scheduled for surgery. Furthermore, is there any benefit to bridge these patients with heparin during the perioperative period? The authors conduced the Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) study to help answer these questions, which involved a simple strategy to hold DOACs briefly depending on the bleeding risk of the elective procedure and to not bridge with heparin so as to keep a simple and standard interruption and resumption protocol for all physicians to follow. The primary outcome was to evaluate major bleeding and arterial thromboembolism (ischemic strokes or TIA and systemic embolism) from the time DOACs were stopped until 30 days post-operatively. Secondary outcomes included non-major bleeding, minor bleeding, death, MI, DVT or PE.

Anticoagulation Initiation in Stroke Patients with Non-Valvular Atrial Fibrillation: Early vs Late?

Piyush Ojha, MBBS, MD, DM

Mizoguchi T, Tanaka K, Toyoda K, Yoshimura S, Itabashi R, Takagi M, Todo K, Shiozawa M, Yagita Y, Yoshimoto T, et al. Early Initiation of Direct Oral Anticoagulants After Onset of Stroke and Short- and Long-Term Outcomes of Patients With Nonvalvular Atrial Fibrillation. Stroke. 2020;51:883–891.

Ischemic strokes due to embolism arising from non-valvular atrial fibrillation (NVAF) account for approximately one-fourth of cases, which further increases with age. Lack of or inadequate anticoagulation may lead to an increased risk of recurrence of stroke during the post stroke period. However, the decision about when to start or resume anticoagulation in such patients is not straightforward and depends on multiple variables. Early anticoagulation may also increase the chances of intracranial hemorrhage/hemorrhagic transformation of the infarct. Recent guidelines allow DOAC administration soon after stroke according to stroke severity based on the 1-3-6-12 day rule, which is based only on expert consensus.

Among the conventional anticoagulants, heparin has shown to cause a nonsignificant reduction in recurrent ischemic stroke within 4 to 14 days, while warfarin was reported to paradoxically increase the risk of stroke during the first 30 days after initiation.

More Than Meets the Eye: Widespread White Matter Changes After Ischemic Stroke

Charlotte Zerna, MD, MSc

Egorova N, Dhollander T, Khlif SM, Khan W, Werden E, Brodtmann. Pervasive White Matter Fiber Degeneration in Ischemic Stroke. Stroke. 2020;51:1507–1513.

Studies have shown that ischemic stroke does not only lead to focal tissue destruction, but can also result in the remote loss of gray matter and disruption of functional connectivity. However, less is known about the remote and regional white matter degeneration after ischemic stroke. Prior studies have been limited by using diffusion-tensor imaging metrics that are non-specific voxel-averaged measures and can lead to erroneous interpretations in locations where white matter fibers are crossing. The objective of the study by Egorova et al. was, therefore, to examine white matter degeneration in a cohort of participants at 3 months post-infarct using a novel fixel-based analysis (fiber population within an MRI voxel). This method allowed the authors to assess complex microstructural fiber geometry in greater detail.

Participants with ischemic stroke (confirmed both clinically and radiologically) were recruited within 6 weeks of their index event at 3 hospitals in Melbourne, Australia. Both patients with first ever (85.6%) and recurrent ischemic stroke (14.4%) in any vascular territory and of any etiology were considered. Age-matched controls (that were also comparable in sex and education status) were selected from a database of volunteers who had previously undertaken MRI research at one of the recruiting hospitals. Of the 165 recruited participants who completed scanning at 3 months, complete usable MRI diffusion data were available for 104 stroke and 40 control participants and could be used for analysis after successfully undergoing pre-processing.

In Quest to Enhance Stroke Recovery, Does Daily Fluoxetine Alone Get Us Closer?

Kate Hayward, PhD, PT

ESO-WSO 2020 Large Clinical Trials Webinar
Presentation: Assessment of fluoxetine in stroke recovery (AFFINITY): A randomised double-blind, placebo-controlled trial
Presenter: Prof. Graeme Hankey

There is much interest in identifying a drug to boost post-stroke recovery. Fluoxetine has received considerable attention since the FLAME trial,1 which demonstrated an improvement in motor recovery (Fugl Meyer Assessment) and functional independence (modified Rankin Scale) in acute stroke patients with moderate to severe hemiparesis.

To address uncertainty that existed concerning the use of fluoxetine,2 a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials were established: EFFECTS (also presented on the ESO-WSO large clinical trials webinar, Sweden), FOCUS (published in 2019,3 United Kingdom), and AFFINITY, which is the focus of this blog post. These international trials collectively aimed to determine whether the routine administration of fluoxetine (20mg daily) for six months after an acute stroke improves patients’ functional outcome.4

Have We EFFECTively Put an End to the Use of SSRIs in Motor Recovery After Acute Stroke?

Abbas Kharal, MD, MPH

ESO-WSO 2020 Large Clinical Trials Webinar
EFFECTS Trial – Efficacy of Fluoxetine: A Randomized Controlled Trial in Stroke
May 13, 2020

Over the past decade, there has been much controversy regarding the potential benefit of selective serotonin reuptake inhibitors (SSRIs) in neuro-recovery and functional independence after stroke. After data from animal stroke studies showed that SSRIs may have potential neuroprotective properties,1 this concept was further analyzed in humans through a Cochrane review2 of 52 studies of a total of 4059 stroke patients, which suggested that SSRIs may improve disability after stroke; however, given the heterogeneity of data, solid conclusions could not be drawn. Furthermore, a randomized controlled clinical trial published in 2011 in Lancet on fluoxetine for motor recovery after acute ischemic stroke (FLAME trial) that enrolled 118 stroke patients showed improved motor recovery after stroke and functional independence (up to 17%) in those treated with fluoxetine versus placebo.3

Pooled evidence from these studies suggested that there was possibly some promising evidence to suggest that the use of SSRIs after acute stroke may lead to neurogenesis, improved motor recovery after stroke and functional independence; however, given the heterogeneity of the data, small sample sizes and methodological limitations, larger well-designed randomized controlled clinical trials were needed to better test this hypothesis in humans.2,4 This led to further development of three large randomized controlled clinical trials, namely FOCUS, EFFECTS ad AFFINITY, which planned to collectively enroll nearly 6000 patients.5,6

Author Interview: Drs. Diogo Haussen, MD, and Yasir Saleem, MD, on “Acute Neurological Deterioration in Large Vessel Occlusions and Mild Symptoms Managed Medically”

Diogo Haussen
Dr. Diogo Haussen
Dr. Yasir Saleem
Dr. Yasir Saleem

A conversation with Diogo Haussen, MD, Assistant Professor of Neurology, Emory School of Medicine/Grady Memorial Hospital, and Yasir Saleem, MD, Assistant Professor of Neurology, Baylor College of Medicine, on the approach to patients with large vessel occlusion (LVO) and mild symptoms.

Interviewed by Jennifer Harris, MD, stroke fellow, Columbia University, and Rachel Forman, MD, stroke fellow, Massachusetts General Hospital.

They will be discussing the article “Acute Neurological Deterioration in Large Vessel Occlusions and Mild Symptoms Managed Medically,” published in the May 2020 issue of Stroke.

Drs. Harris and Forman: Thank you for taking the time to speak with us on this important topic.  

Drs. Haussen and Saleem: Thank you for reaching out. It is a pleasure interacting with you.

Drs. Harris and Forman: As stroke fellows, we run into this scenario from time to time, and it is often a challenging decision that generates good discussion. What was the background for you in wanting to study this specific topic?

Drs. Haussen and Saleem: A common reason for neurological deterioration in patients presenting with mild strokes is the underlying presence of a large vessel occlusion. Importantly, neurological worsening in this setting has been associated with worse clinical outcomes. However, not all individuals with large vessel occlusion and mild presentation end up worsening. We have observed, in our original experience (Haussen DC et al. JNIS 2017 Oct;9(10):917-921), that >40% of patients with LVO medically managed had some degree of neurological deterioration. We wanted to evaluate the potential variables that could potentially predict neurological worsening within patients presenting with minor stroke symptoms and large vessel occlusion.

Drs. Harris and Forman: What is your team’s approach for patients in this category as far as their medical management and ensuring this is optimized (i.e., blood pressure parameters, frequency/duration of neurological monitoring)? Do you include patients with more distal (M3 or PCA) clots in this same category?

Drs. Haussen and Saleem: Although the evidence is lacking, we generally perform a heads-up test in order to stress collaterals and evaluate for acute neurological deterioration in patients with mild presentations. We consider important to optimize the hydration status and to allow the blood pressure to autoregulate. Considering we have observed that patients with large vessel occlusion and mild stroke deteriorate early, it is critical to have patients carefully monitored for the first multiple hours from symptom onset. It is possible that more proximal occlusions (e.g., MCA M1 as compared to MCA M3) may carry a higher risk of deterioration; however, this is anecdotal.

Drs. Harris and Forman: It was interesting to note that there were no clinical or radiological predictors of neurological deterioration on multivariate analysis. From a personal experience, do certain features (either clinically or radiographically) stand out to you where you would be on higher alert in a specific patient?

Drs. Haussen and Saleem: Despite not identifying any predictors, we know that a large proportion of patients deteriorate early. Therefore, all need to be monitored closely. It is relatively clear that rapid improvement may predict subsequent deterioration; therefore, patients that improve and still have an occlusion are at higher risk. Individuals with very high blood pressure levels in order to maintain collaterals could be at risk of failure. In addition to the established factors influencing leptomeningeal collateral strength, large areas of perfusion defect on perfusion imaging, more proximal occlusions, and embolic occlusions (instead of in-situ atherosclerotic thrombosis that generally have better developed collaterals) could be suggested as potential factors influencing the risk of neurological worsening.

Drs. Harris and Forman: In the study, you found that 19.7% of patients had >4 points deterioration on NIHSS and that this occurred pretty rapidly from arrival time (median of 3.6 hours). Did these numbers surprise you, or is it similar to what you have observed in clinical practice?

Drs. Haussen and Saleem: We used a relatively high threshold for defining deterioration, and therefore believe that this number is in line with previous studies and with our experience.

Drs. Harris and Forman: Did the study change your approach to this patient population, and if so, how did it change? Finally, what are the main takeaways you want the readers to have, and what are the next steps with future studies?

Drs. Haussen and Saleem: Significant acute neurological deterioration was observed in a significant proportion of patients (~1/5) with large vessel occlusion and mild symptoms, occurred very early in the hospital course, and impacted functional outcomes. Rescue thrombectomy was associated with improved clinical outcomes and should be considered emergently in patients that worsen during medical management. Considering that we could not identify potential clinical, laboratorial or radiological predictors, it becomes even more evident that controlled studies are needed.

Drs. Harris and Forman: Thank you very much.