American Heart Association

author interview

Author Interview: Søren Bache, MD

Søren Bache

Søren Bache

A conversation with Søren Bache, MD, from the Neurointensive Care Unit, Department of Neuroanaesthesiology and Centre for Genomic Medicine, Rigshospitalet, University of Copenhagen, Denmark, about microRNA changes after subarachnoid hemorrhage.

Interviewed by José G. Merino, MD, Associate Professor of Neurology, University of Maryland School of Medicine.

They will be discussing the paper, “MicroRNA Changes in Cerebrospinal Fluid After Subarachnoid Hemorrhage,” published in the September 2017 issue of Stroke.

​Dr. Merino: Thank you for agreeing to the interview. First, I would like you to explain some things about delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) for our readers: How common is it? How soon after SAH does it develop? How does it affect outcome after SAH?

Dr. Bache: The reported prevalence of DCI after SAH varies, but newer randomized clinical trials have found a risk of 21–38% in patients who survive the initial bleeding and aneurism-securing surgery. The variation in calculated risk may be due to discrepancies both in case definition (i.e. the numerator) and in the definition of which patients are entered into the denominator. Today, most researchers base their case definition of DCI on the criteria suggested by Vergouwen et al. (Vergouwen MD, et al. Stroke. 2010). Before this consensus work, the definition varied even more, and many used their own criteria for DCI, delayed ischemic neurological deficits (DIND) or cerebral vasospasm. However, not all patients are conscious enough to be assessed clinically for a deterioration in consciousness, and such patients may be either included or excluded in the total number of patients; hence, the variation in the denominator. Based on Vergouwen’s criteria, in our center, we found a prevalence of 23% in 450 patients admitted from 2009–12 with SAH (unpublished data). These patients all receive prophylactic nimodipine, which lowers the risk of DCI; therefore, one should expect publications from the pre-nimodipine era to report a higher prevalence of DCI (Dorhout Mees SM, et al. Cochrane Database of Systematic Reviews. 2007).

Delayed cerebral ischemia occurs a median of 6–7 days after hemorrhage, but this varies, with a typical reported range from 3 to 14 days. DCI may be reversible, but in some cases it progresses to permanent brain injury, thereby affecting outcome.

Author Interview: George Ntaios, MD

George Ntaios

George Ntaios

A conversation with George Ntaios, MD, MSc (ESO Stroke Medicine), PhD, Assistant Professor of Internal Medicine, Department of Medicine, University of Thessaly

Interviewed by Stephen Makin, PhD, Clinical Lecturer at Glasgow University

They will be discussing the paper, “Real-World Setting Comparison of Nonvitamin-K Antagonist Oral Anticoagulants Versus Vitamin-K Antagonists for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis,” being published in the September 2017 issue of Stroke.

Dr. Makin: Thank you for taking the time to talk to us.

Prof. Ntaios: Thank you for the invitation to discuss our study.

Dr. Makin: Could I begin by asking you to summarize your study and its findings?

Prof. Ntaios: We aimed to summarize all available evidence from high-quality real-world observational studies about the efficacy and safety of non-vitamin-K-oral-anticoagulants (NOACs) compared to vitamin-K-antagonists (VKAs) in patients with atrial fibrillation (AF). Based on 28 identified studies, we found that dabigatran, rivaroxaban and apixaban, as compared to VKAs, are associated with lower risk of intracranial haemorrhage and similar risk of ischemic stroke and ischemic stroke or systemic embolism; apixaban and dabigatran with lower risk of mortality; apixaban with fewer gastrointestinal and major haemorrhages; dabigatran and rivaroxaban with higher risk of gastrointestinal haemorrhage; and dabigatran and rivaroxaban with a similar rate of myocardial infarction.

Author Interview: Robert G. Kowalski, MD, MS

Robert G. Kowalski

Robert G. Kowalski

A conversation with Robert G. Kowalski, MD, MS, Principal Investigator, Craig Hospital, and Assistant Clinical Professor of Neurology and PM&R, University of Colorado School of Medicine, about stroke following traumatic brain injury.

Interviewed by José G. Merino, MD, Associate Professor of Neurology, University of Maryland School of Medicine.

They will be discussing the paper, “Acute Ischemic Stroke After Moderate to Severe Traumatic Brain Injury: Incidence and Impact on Outcome,” published in the July issue of Stroke.

Dr. Merino: Thank you for agreeing to the interview. Can you first briefly describe the methods and main findings of the analysis published in Stroke?

Dr. Kowalski: The study was a research collaboration between the Centers for Disease Control and Prevention (CDC) and the Traumatic Brain Injury Model Systems (TBIMS) program. It was led by researchers at Craig Hospital in Englewood, CO. Investigators studied more than 6,400 traumatic brain injury (TBI) patients over a 7.5-year period to evaluate risk factors for onset, incidence, and predictors of outcome in ischemic stroke occurring acutely after TBI. We found that 2.5% of individuals who experience a moderate to severe TBI also suffer an acute ischemic stroke (AIS) at the time of the injury. In half of these cases, the individuals experiencing stroke concurrent with brain trauma were age 40 or younger. Additionally, the study found the risk of acute ischemic stroke immediately following traumatic brain injury was 10 times the risk of ischemic stroke in the general population.

Author Interview: Philippa Lavallée, MD

A conversation with Philippa Lavallée, MD, Department of Neurology and Stroke Centre, Bichat University Hospital, about the importance of atypical symptoms in patients with TIA.

Interviewed by José G. Merino, MD, FAHA, Associate Professor of Neurology, University of Maryland School of Medicine.

They will be discussing the paper, “Clinical Significance of Isolated Atypical Transient Symptoms in a Cohort With Transient Ischemic Attack,” published in the June 2017 issue of Stroke.

Dr. Merino: Could you please briefly summarize the key findings and put them into context of what was known before you did the study?

Dr. Lavallée: Conventional wisdom considers that some transient symptoms such as diplopia, vertigo, dysarthria and even a sensory deficit limited to one limb or the face are not compatible with the diagnosis of TIA when they occur in isolation. Daily experience in the stroke unit and TIA clinic shows that it is not true. In our study, we enrolled 1,850 patients seen in our TIA clinic who had transient symptoms and found that 10% of the patients with stroke or TIA had one of these isolated atypical symptoms and that 10% of the patients with atypical symptoms had an acute infarct on brain MRI and 18% had an underlying disease that placed them at high risk of stroke recurrence.

Author Interview: Seung-Hoon Lee, MD, PhD

Seung-Hoon Lee

Seung-Hoon Lee

A conversation with Seung-Hoon Lee, MD, PhD, Professor of Neurology, Seoul National University Hospital, about the role of the susceptibility vessel sign on SWI to predict stroke subtype and recanalization.

Interviewed by José G. Merino, MD, Associate Professor of Neurology, University of Maryland School of Medicine.

They will be discussing the paper, “Prediction of Stroke Subtype and Recanalization Using Susceptibility Vessel Sign on Susceptibility-Weighted Magnetic Resonance Imaging,” published in the June 2017 issue of Stroke.

Dr. Merino: Could you please briefly describe the study and summarize the key findings, putting them into context of what was known before you did the study?

Dr. Lee: I’m glad to talk about our research in this interview. Thrombi in the cerebral arteries appear hypointense on susceptibility-weighted MRI (SWMRI). We call them “the susceptibility vessel sign” (SVS). The methodological strength of this study is that SWI MRI is much more sensitive than GRE and thus can quantify the size of the SVS. In this study, we analyzed the relationship between the size of the SVS, the stroke mechanism, and whether successful recanalization occurred in patients receiving endovascular treatment. Cardiac emboli are large but fragile because they are rich in RBCs but have scant platelets. We hypothesized that because the SVS reflects the red blood cell component of the clot, patients with larger SVS are more likely to have a cardioembolic source and thus more likely to have successful recanalization. We found that as the SVS size increased, the probability of cardioembolic stroke was higher, but that SVS size did not show any positive or negative correlation with successful recanalization. This is probably due to the high recanalization rate with the stent-retrievers, irrespective of stroke etiology. No association between SVS size and recanalization can be partly explained by clot fragility in cardioembolic stroke.

Author Interview: Alexandros Rentzos, MD, and Pia Löwhagen Hendén, MD, PhD

Alexandros Rentzos, MD, and Pia Löwhagen Hendén, MD, PhD

Alexandros Rentzos, MD, and Pia Löwhagen Hendén, MD, PhD

A conversation with Alexandros Rentzos, MD, Diagnostic and Interventional Neuroradiology, Sahlgrenska University Hospital, and Pia Löwhagen Hendén, MD, PhD, Anesthesiology and Intensive Care department, Sahlgrenska University Hospital, about the role of anesthesia and conscious sedation for patients undergoing embolectomy for stroke.

Interviewed by José G. Merino, MD, Associate Professor of Neurology, University of Maryland School of Medicine.

They will be discussing the paper, “General Anesthesia Versus Conscious Sedation for Endovascular Treatment of Acute Ischemic Stroke: The AnStroke Trial (Anesthesia During Stroke),” published in the June 2017 issue of Stroke.

Dr. Merino: Could you please summarize the key findings of your study and put them in context of what was known on the topic?

Drs. Rentzos and Löwhagen: Since a number of retrospective studies showed that general anesthesia during endovascular stroke treatment was associated with poor neurological outcome, conscious sedation became the main method in most neurointerventional centers after 2010. However, the retrospective studies were limited by important selection bias, such as inclusion of posterior strokes (in some of the series) and, importantly, more severe stroke in patients treated under GA. Furthermore, most retrospective studies on anesthesia technique did not describe the anesthesia technique, nor the anesthetic management!

At our institute, we have used mainly general anesthesia since 1991 when we started with endovascular stroke treatment, and, in our experience, patients treated with GA did not have worse neurological outcome. That is why we started the randomized trial AnStroke in 2013. The results were presented in ESOC 2017 in Prague on May 18. In our trial, general anesthesia did not lead to worse neurological outcome compared to conscious sedation.

Author Interview: Santosh Murthy, MD, MPH

Santosh Murthy

Santosh Murthy

A conversation with Santosh Murthy, MD, MPH, Assistant Professor of Neurology and Neuroscience, Weill Cornell Medicine, about the decision on when to restart anticoagulation after intracranial hemorrhage.

Interviewed by José G. Merino, MD, Associate Professor of Neurology, University of Maryland School of Medicine.

They will be discussing the paper “Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis,” published in the June 2017 issue of Stroke.

Dr. Merino: Can you please summarize the key findings of your study and place them in context of what was already known on the topic?

Dr. Murthy: There is a lack of standardized recommendations regarding the use of anticoagulant therapy after intracerebral hemorrhage (ICH). Our meta-analysis of observational studies suggests that compared with withholding anticoagulation, resumption of anticoagulant therapy after ICH significantly lowers the risk of ischemic stroke and myocardial infarction (MI) with no discernable elevation in the risk of ICH recurrence. While our results help summarize the existing literature and may serve as a guide to clinicians in making informed decisions, randomized clinical trials are needed to determine the true risk-benefit profile of anticoagulation resumption after ICH.

Author Interview: Colin Derdeyn, MD

Colin Derdeyn

Colin Derdeyn

A conversation with Colin Derdeyn, MD, Chair and Departmental Executive Officer of the Department of Radiology, University of Iowa Carver College of Medicine, about the late complications of stenting for intracranial atherosclerotic disease and the challenges posed by new stroke treatments.

Interviewed by José G. Merino, MD, Associate Professor of Neurology, University of Maryland School of Medicine.

They will be discussing the paper, “Nonprocedural Symptomatic Infarction and In-Stent Restenosis After Intracranial Angioplasty and Stenting in the SAMMPRIS Trial (Stenting and Aggressive Medical Management for the Prevention of Recurrent Stroke in Intracranial Stenosis),” published in the June 2017 issue of Stroke.

Dr. Merino: Good afternoon. Can you tell us what prompted this secondary analysis of the SAMMPRIS data?
Dr. Derdeyn: From SAMMPRIS, we learned that there’s potentially great value for dual antiplatelets and statins, along with aggressive risk factor management for patients with intracranial atherosclerotic disease (ICAD).  We also learned that in this setting, there is a much higher complication rate from stenting than we thought, mainly due to a lot of perforator strokes, particularly in the basilar territory, and that the procedure is associated with a risk of intracranial hemorrhage, perhaps due to reperfusion. These short-term complications limit the value of stenting for ICAD.

Author Interview: Braxton D. Mitchell, PhD

Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2
Interview conducted by Michelle Christina Johansen, MD

Dr. Johansen: Dr. Mitchell, could you summarize for us the major findings of your recent article in Stroke?
Dr. Mitchell: Our study focused on young onset stroke since stroke occurring at younger ages may have a stronger genetic component. We performed a large genome-wide association study, or GWAS, that included 5,500 ischemic stroke cases and over 30,000 controls amassed from 8 different studies. We identified a DNA variant that was significantly associated with stroke, with the risk allele increasing stroke risk in young people by about 40%. This variant is near a gene called HABP2, which encodes an enzyme involved in the regulation of the clotting cascade. In an independent population from Sweden, we then found this variant also to be associated with enzyme levels.

Our study also suggests that the effects at the HABP2 locus may be specific to (or at least more pronounced in) early onset stroke because the association was largely absent in METASTROKE studies, a very large consortium that includes predominantly older stroke cases.

Dr. Johansen: Why do you feel that there is a stronger genetic component for stroke in the young?
Dr. Mitchell: It is clear from family and twin studies that stroke aggregates in families. The best available evidence suggests that stroke at younger ages has an even stronger genetic basis than stroke occurring at older ages. For example, younger stroke cases more often report a parental history of stroke than older stroke cases.

One unanswered question is whether the stronger familial aggregation observed in early- compared to later-onset stroke is due to differences in the in the distribution of stroke subtypes at different ages. For example, large artery and small vessel stroke are more prominent at older compared to younger ages, while stroke due to other determined etiologies are more common at younger ages. It is thus possible that the enrichment of stroke with some of these other causes accounts for the stronger genetic component for stroke in the young.

Dr. Johansen: How did you reach 60 years old as the parameter for stroke in the young?
Dr. Mitchell: We wanted to differentiate stroke occurring in young and middle age vs that occurring in older ages. Our decision to use a threshold of 60 years for early onset stroke, instead of say 50 or 55 years, was in part a practical one so that we would have a large enough sample for our study.

Dr. Johansen: Why do you feel that you were unable to find any subtype specific stroke susceptibility loci in your cohort?
Dr. Mitchell: We did perform additional analyses to determine if the stroke-associated variant we detected in HABP2 was associated with particular subtypes. In this analysis, we found the variant to be associated with each of the three major stroke subtypes, cardioembolic stroke, large artery atherosclerotic stroke, and small vessel occlusion. However, one major caveat is that the sample sizes were much smaller in these subtype-specific analyses, so we cannot be fully confident in these results. We are aware that the 7 or so variants robustly associated with ischemic stroke in very large GWAS studies all seem to be subtype-specific. Whether this is also true for the variant in HABP2 is premature to say.

Dr. Johansen: What do you feel is the biggest strength of your study?
Dr. Mitchell: I think our study has three major strengths. First, our study included a very large number of early onset cases. Second, not only did we detect a statistically significant association of this variant with stroke, but in an independent population of non-stroke cases, we also found this variant to be associated with circulating plasma levels of factor VII-activating protease levels, the product of this gene. Third, because the association was largely absent in the METASTROKE Consortium, we are able to conclude that the locus is probably specific to younger onset cases.

Dr. Johansen: How do you foresee the findings of this study influencing further research?
Dr. Mitchell: First, these results reinforce the heterogeneous nature of stroke as HABP2 does not appear to be associated with common forms of late onset stroke. Second, these results suggest the need to look comprehensively at genetic determinants of thrombosis and coagulation in early onset ischemic stroke. A better understanding the pathogenesis of early onset stroke may improve strategies to prevent recurrences. In addition, the pathways involved may have relevance also to some forms of older onset stroke.

Dr. Johansen: There are some naysayers who challenge the clinical value of GWAS stroke studies. Would you like to respond to this criticism?
Dr. Mitchell: I don’t believe that GWAs studies were ever intended to provide clinical or predictive value for most complex diseases. Most loci identified through GWAs have relatively small effect sizes and they do not do a very good job, even in aggregate, of predicting disease, although there are a few exceptions, such as for age-related macular degeneration. But GWAS have been enormously important in identifying variants and genes associated with a large number of diseases. This understanding is essential for development of new drugs targeting novel mechanisms.

Author Interview: Opeolu Adeoye, MD MS FACEP FAHA

Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial
Interview Conducted by Mark N. Rubin, MD

Dr. Rubin: If you do not mind, Dr. Adeoye, I would like to get down to brass tacks. Where is the best place to eat in Cincinnati? 
Dr. Adeoye: The important stuff! It’s a bit pricey but my favorite place by far is an Italian restaurant called Nicola’s. I don’t get to go often but always good for a special dinner, like every time colleagues visit Cincinnati and I get to pick where we go.

Dr. Rubin: What would you like readers to know about you? 
Dr. Adeoye: I’m a very proud father of two incredible children, ages 5 and 8. Maybe they won’t be so incredible in about 10 years but for now it’s pretty fantastic.

Dr. Rubin: What was the research question you wanted to answer with this trial? Please explain the interventions trialed and the rationale for getting at this question.  
Dr. Adeoye: Our goal was to estimate the safety of combining full dose tPA with eptifibatide in ischemic stroke patients treated with tPA within three hours of symptom onset. We had previously studied escalating doses of half dose (0.45mg/kg) and two thirds dose (0.6mg/kg) tPA combined with eptifibatide. Those combinations were safe with regard to symptomatic ICH rates. Being able to use full dose tPA (i.e., standard of care) in a phase III trial would be simplest to execute, and if safe may be most likely to show benefit given the possibility of improved lysis compared to lower doses of tPA. So, we sought to estimate whether such a combination would be safe enough to pursue in a large trial.

Dr. Rubin: How many sites were involved? Was enrollment protocol standardized across all sites? How did you herd so many cats (e.g., coordinate with so many physicians)? How did you ensure that participation in the study did not delay the use of standard tPA?  
Dr. Adeoye: Luckily, we were able to use eight hospitals in the Greater Cincinnati region to complete enrollment in the study. All hospitals had a standardized protocol for managing tPA treated patients. Fortunately, the monitoring and clinical care for the combination patients is essentially the same as that for tPA treated patients. To ensure we didn’t delay tPA administration, we encouraged treating physicians to proceed as rapidly as possible with initiation of tPA. Once the bolus was in and infusion started, THEN we approached the patient or family regarding participation in the study. 

Dr. Rubin: Why eptifibatide? Any reason other than it is not abciximab?
Dr. Adeoye: It’s definitely not abciximab which may have an anti-thrombotic effect for days after it’s been discontinued. There are multiple 2b/3a molecules beyond the ones that are well known. Eptifibatide was one of the early ones specifically developed to ensure rapid inhibition of platelet aggregation (within 15 minutes), a short half-life (~2 hours) and rapid dissociation from platelets with 50% restoration of platelet function within 2-4 hours of discontinuation. A series of papers by Drs. Robert Scarborough and David Phillips in the 1990s detail this development. In the context of stroke, these properties offer a quick on/quick off advantage that when combined with tPA allows augmentation of thrombolysis without a prolonged anti-thrombotic effect that may lead to symptomatic ICH.

Dr. Rubin: This study seemed to have relatively complex enrollment. Standard tPA was started in all patients soon after arrival to the hospital and you had 40 minutes to enroll the patient after tPA was started; how were you able to inform patients and get consent to participation within that time frame? What were the greatest challenges?
Dr. Adeoye: Actually, I think we were pretty fortunate in conducting this study. The protocol is fairly straightforward and investigators were able to adhere to the protocol without difficulty. As with any acute stroke trial, the challenge is in administering standard therapies rapidly while also obtaining consent and initiating study procedures in a timely manner.

Dr. Rubin: What is the one-sentence take-away for readers? Please comment on efficacy and safety of the intervention.  
Dr. Adeoye: The addition of eptifibatide to tPA in ischemic stroke appears to be safe in the doses we’ve studied and justifies a larger trial to determine it if improves stroke outcomes.

Dr. Rubin: What is the next step? 
Dr. Adeoye: We’ve submitted an application to the NIH for a Phase III trial called MOST (Multi-arm Optimization of Stroke Thrombolysis). This is a collaborative effort with me and Dr. Joe Broderick in Cincinnati and Drs. Andrew Barreto and Jim Grotta in Houston. We will use an adaptive design to determine whether eptifibatide plus tPA or argatroban plus tPA result in better outcomes than tPA alone for ischemic stroke.

Dr. Rubin: I understand that further studies looking at combinations of lytics are planned or underway. How does eptifibatide +tPA fit in the armamentarium in the era of data-supported efficacy of endovascular reperfusion therapies? 
Dr. Adeoye: That’s a great question. The aggregate data for the trials published in the past year showed that the overall TICI 2b/3 recanalization rate in endovascular patients was about 67%. That means a third of patients receiving endovascular therapy had inadequate recanalization/reperfusion. Our goal in the coming years is to determine whether eptifibatide may improve these recanalization rates. Hopefully, we can establish a role for eptifibatide in augmenting recanalization rates in patients treated with endovascular therapy.

Dr. Rubin: Can Andy Dalton win in the playoffs? 
Dr. Adeoye: It’s best not to tempt fate. No comments.