American Heart Association

author interview

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.

Author Interview: Ken Butcher, MD, PhD, FRCP(C)

Dabigatran Therapy in Acute Ischemic Stroke Patients Without Atrial Fibrillation 
Interview Conducted by Chirantan Banerjee, MD

Dr. Banerjee: Tell us about the key findings from your recent article in Stroke.   

Dr. Butcher:The key findings are that acute treatment with the Direct Oral Anticoagulant (DOAC) dabigatran within 24 hours of an acute ischemic stroke is feasible. Given the small sample size, we have not definitively proven safety of course, but the lack of symptomatic hemorrhagic transformation, and indeed the paucity of even subclinical HT on susceptibility weighted MRI, is encouraging. Certainly we saw no safety signal that would preclude pursuing this approach in a larger study, as we are currently. 

Dr. Banerjee: What prompted you and your co-authors to perform this study? 
Dr. Butcher: It is now recognized that early recurrent stroke after TIA/minor stroke is a frequent problem and new treatment target. Efforts to date have focused on anti-platelet approaches (CHANCE, POINT, SOCRATES). However, it has also been shown that occult paroxysmal AF is common in this population (CRYSTAL AF and EMBRACE). Thus, many patients with acute minor stroke/TIA will not benefit from anti-platelet approaches. 
What has prevented routine anticoagulant use in the past is that any benefits were outweighed by increased hemorrhagic complications (primarily symptomatic HT). These studies were done with heparin/LMWH. Dabigatran, in the RE-LY trial had an intracranial hemorrhagic complication rate that was comparable to ASA. Thus, there appeared to be an opportunity to protect patients from all potential recurrent thromboembolic events, without increasing the risk of HT or other hemorrhages. Our rationale for 30 days of treatment was that this is the period of highest stroke recurrence. We aimed to protect patients during this high risk period, but also give clinicians time to determine which patients had potential cardiac sources of embolism (TTE, Holter). 
Dr. Banerjee: Tell us about the biggest challenge you came across while conducting this study. 
Dr. Butcher: There were really three:
1. The first was actually convincing some of our colleagues that hyper acute DOAC use was a reasonable concept. There was initially some trepidation on the part of some of our colleagues.
2. All patients needed an MRI scan before treatment, all within 24 hours. Even in a research center such as ours, this was a challenge. 3. Finally, there were competing trials that made enrollment a challenge (POINT and SOCRATES). 
Dr. Banerjee: What are the major implications of this work?  
Dr. Butcher: The implications are that it may be reasonable to protect all patients with minor stroke, using dabigatran. Of course, this needs to be tested in a larger RCT. This is what we are doing now, with DATAS II, which randomizes 300 patients to ASA or dabigatran for 30 days.   
The findings also support the safety of the approach being tested in the ESUS trials, one of which uses dabigatran. The difference between these trials and ours is that we do not make the assumption that all subcortical strokes are not embolic—some may therefore benefit from acute DOAC therapy. These patients are excluded from ESUS trials. In addition, the short term nature of the therapy, combined with a more extensive cardiac interrogation may lead ultimately to more selective therapy with DOACs. Each approach has its merits. A small study like DATAS supports the safety of both.  
Dr. Banerjee: What do you plan to do next, based on these current findings?  
Dr. Butcher: We are currently conducting DATAS II, as described above.  
Dr. Banerjee: What do you like to do in your free time? 
Dr. Butcher: I spend time with my kids. We all like to ski in the winter (cross country and downhill). I also play hockey (badly) and enjoy triathlon when time permits.

World Stroke Day 2015 – “I am Woman”

In recognition of World Stroke Day 2015 and the theme “I am woman”, Stroke interviewed Cheryl Bushnell, MD, MHS, Professor of Neurology, Director at Wake Forest Baptist Stroke Center. Learn more about World Stroke Day

Stroke: World Stroke Day is on Thursday the 29th October 2015. The World Stroke Organization’s theme for World Stroke Day 2015 is ‘I am Woman’. What is the most important message for women when it comes to stroke?
Dr. Bushnell:
The most important message for women is to know what a stroke is, what to do if one is occurring, and how to prevent a stroke. Women have unique risk factors, including pregnancy complications and use of hormones, so they need to know that these are risks of stroke. One of the key messages of our stroke prevention in women guidelines is that women with a history of preeclampsia (high blood pressure during pregnancy plus protein in the urine) are at risk for stroke for up to 30 years after childbirth.

Stroke: Are women at higher risk of stroke?
Dr. Bushnell:
No, if you measure stroke incidence, men are at higher risk. But, because women live longer, they are at higher risk over an entire lifetime. Women have a 20% lifetime risk of stroke after age 55, whereas men have a 17% lifetime risk.

Stroke: How does pregnancy affect a woman’s risk of stroke?
Dr. Bushnell:
Yes, it appears to double the risk of stroke compared to a woman who is not pregnant. This is especially true in the postpartum time period, and applies to most stroke types, including ischemic and hemorrhagic stroke, as well as cerebral venous thrombosis.

Stroke: Does taking birth control pills or hormonal replacement affect a woman’s stroke risk? 
Dr. Bushnell: Yes, birth control pills double the risk of stroke compared to women not taking these pills. However, the absolute risk of a healthy young woman taking these pills is still low. For example, a young woman’s risk of stroke may be 10/100,000, and taking OCPs increases this to 20/100,000. However, if a woman has high blood pressure, high cholesterol, diabetes, obesity, or smokes cigarettes, all of these accentuate the risk of stroke in a woman using OCPs compared to women not taking OCPs. For hormone replacement, older women have about a 40% increased risk of stroke compared to women not taking the drug. It is important to realize these women were at least 10 years past menopause on average. The recent study of women who are recently menopausal (within 5 years), had no significant increase in markers of stroke risk (carotid wall thickening) compared to women not using hormone therapy. Therefore, hormone replacement is not recommended for older women and those with an increased risk of stroke (such as hypertension, diabetes, high cholesterol, prior heart disease).

Stroke: Are women underrepresented in clinical research studies of stroke?
Dr. Bushnell:
Yes, with only a couple of exceptions, women make up 35% to 40% of stroke prevention trials.

Stroke: What can health care providers do to reduce the burden of stroke in women? 
Dr. Bushnell: Improve stroke awareness and what to do, and promote a healthy lifestyle. Women who incorporate the most healthy strategies in their daily lives have a 70% decreased risk of stroke compared to women with none of these strategies. This includes regular physical activity, healthy diet, normal body mass index, moderate alcohol use, and not smoking. Another important strategy is to maintain normal blood pressure. The healthy lifestyle can do this, but women tend to have high blood pressure at older ages, and these women are also less likely to have their blood pressure controlled. Therefore, education about blood pressure in older women is extremely important.

Stroke: A recent study showed that 81% of stroke center directors are men. What can be done to increase the role of women in stroke leadership positions?
Dr. Bushnell:
For those of us in these leadership positions, hopefully we function as role models to promote more women as stroke center directors as a career choice. More women are going into stroke fellowships, so this will take time for the next generation to reach these leadership roles. Given the multidisciplinary nature of stroke centers and the tendencies for women to be collaborative, I believe women are likely to be successful in this role.  

Learn more about World Stroke Day

Author Interview: Valery L. Feigin, MD, PhD

New Strategy to Reduce the Global Burden of Stroke
Interview conducted by Deepa P. Bhupali, MD

Dr. Bhupali: Can you give a brief overview on the tool you developed and address in your article? 
Dr. Feigin:
The Stroke Riskometer was developed with the main purpose of improving primary prevention of stroke on a global level.
The application provides users with their absolute and relative risks of stroke, along with how that risk is modified as their health care profiles change. Users can monitor their results, chart progress, receive education regarding stroke symptoms, and if they choose to, share their information via email with a person of their choice. The application is available on iOS and Android platforms, and there are two versions: the Lite version which is free and the Pro version which can be purchased. The Pro version provides additional information on how to reduce stroke risk, based on one’s individual risk profile, but both versions calculate and identify risk factors, provide stroke education and offer the ability to collect data for research. This research will provide significant epidemiological insights, which are vital to improved prevention and treatment of stroke 

Dr. Bhupali: What prompted you and your co-authors to create this tool?
Dr. Feigin:
Our work grew out of two major observations. First, stroke is a major non-communicable disorder (NCD). Despite decrease in incidence and mortality, the overall number of people affected by NCDs – stroke, MI, diabetes, dementia – is growing. This suggests that primary prevention is not sufficiently effective. If this is not addressed and we carry on with business as usual, the burden will continue to grow.
Secondly, there is a research problem. Despite pushes for epidemiological research for NCDs, the majority of countries don’t have reliable data on frequency, determinants and distribution of stroke and other NCDs. This is not because of a lack of understanding regarding research methodology. The void in data is largely related to the expense of conducting the research. Consequently, without accurate data, we cannot develop evidence based health care, planning and prevention strategies. We hope to address these two major problems — the growing burden and lack of data — with this app. This is what excites us.  

Dr. Bhupali: What is innovative about this work?
Dr. Feigin:
There is currently nothing else comparable to the app’s ability to capture accurate data from around the world. As an example of that, the application will be available in world’s most common languages, giving it the ability to reach the global population. Additionally, we worked very hard on the privacy aspects of this application and have implemented unique strategies to guarantee the security of users’ data and their anonymity, if they consent to participate in data collection.

Dr. Bhupali: What is one of the challenges you anticipate in introducing this tool?
Dr. Feigin:
At this time, our main challenge is to let people know that the app is available. We want people to know that there is a tool that will inform them about their absolute and relative stroke risk, provide education regarding stroke symptoms and will monitor their progress and recalculate their stroke risk based on the improvements they seek to make to their health. 

Dr. Bhupali: What is the key take-away message from your article?
Dr. Feigin:
Stroke is highly preventable. It does not happen at random, rather it affects people who are at risk of having a stroke – and these people can reduce their risk.
We implore people to use the app now – learn about your risk factors and how to manage them. Stroke is much easier to prevent than to treat, we want to let people know that they can help prevent stroke and safeguard their health and well-being. 

For more information on Dr. Feigin and the Stroke Riskometer click here.
To read the article in Stroke click here.