American Heart Association

Monthly Archives: June 2014

Incidence of Symptomatic Hemorrhage in Patients with Lobar Microbleeds

Sebina Bulic, MD

van Etten ES, Auriel E, Haley KE, Ayres AM, Vashkevich AV, Schwab KM, et al. Incidence of Symptomatic Hemorrhage in Patients With Lobar Microbleeds. Stroke. 2014

Cerebral amyloid angiopathy (CAA) represents amyloid β-peptide deposition in small and medium-sized blood vessels in the brain, leading to hemorrhagic and ischemic injury. Lobar microbleeds on MRI have also been identified as a marker of CAA severity. There is estimation that prevalence of CAA in the elderly population is 11 to 24%. This number is expected to increase as the life expectancy increases. Need for use of anticoagulation also is expected to increase because of 2 reasons. A-Fib is condition more prevalent in elderly. We also achieved significant improvement in detecting paroxysmal A-Fib. 

In this timely and well-conducted prospective study, 379 patients were enrolled between January 1993 and January 2012. Patients were grouped into two categories: those presenting with two or more lobar microbleeds in the absence of lobar ICH and those presenting with a lobar ICH with at least one lobar microbleed. In the second group, patients who survived the first 90 days after ICH were studied.

In addition to evaluation of fatality, ICH and white matter hyperintensity, Apolipoprotein E (APOE) genotype (ε2 and ε4 alleles) was determined in a large subset of patients.

Baseline demographics (age, gender), vascular risk factors, and APOE genotype did not differ significantly between microbleed-only and ICH groups. The lobar microbleed count was significantly higher in microbleed-only patients which was explained by referral of those patients.

In follow up, microbleed group had higher white matter hyperintensity (again explained by referral) and overall mortality. ICH group had higher rate of repeat ICH, but this did not reach statistical significance. Warfarin use and older age were independently associated with time to incident ICH. Use of ASA was not associated with increased ICH risk.

This study is highlighting that even patients with microbleeds in addition to those with CAA and ICH are at substantial risk future ICH. Also, it is raising very important question; whether this risk of future ICH is sufficient to tip the risk vs. benefit calculation away from anticoagulant treatment this significant subset of patients. This can only be answered in large, prospective trial. Till that time, caution with anticoagulation in patients with CAA.

In PURSUIT of faster door-to-needle times, is telemedicine the answer?

Jennifer Dearborn, MD

Wu TC, Nguyen C, Androm C, Yang J, Persse D, Vahidy F, et al. Prehospital Utility of Rapid Stroke Evaluation Using In-Ambulance Telemedicine: A Pilot Feasibility Study. Stroke. 2014

“Time is brain” and current research efforts, such as utilization of the mobile stroke unit, have sought to decrease the door-to-needle time to deliver thrombolysis therapy (r-tPA) quickly and efficiently. Tzu-Ching Wu et al. explore how telemedicine can facilitate shorter door-to-needle times by performing the stroke assessment while en route to a nearby stroke facility. In this pilot study, EMS providers are trained to interact with a telemedicine program that communicates with a remote vascular neurologist to perform the NIH stroke scale. This pilot study was a feasibility and reliability assessment of the technology, which used trained actors in different settings to complete remote and real-time assessments of the same scenarios. The authors found that the telemedicine approach was feasible in the majority (85%) of scenarios, and that common reasons for malfunction was due to cell phone connections through the network. There was also moderate to excellent reliability with the NIHSS compared to real-time raters.

This pilot study is important because it shows that an easy to introduce technology that is commonly used in other hospital emergency rooms is feasible in the ambulance and emergency setting. This approach has the potential to rapidly triage patients upon arrival in the emergency room to thrombolysis, with the final decision pending only a CT scan evaluating for hemorrhage. As the majority of thrombolysis cases are staffed by a vascular neurologist upon hospital arrival, this approach does not add many costly resources, and instead could save time and brain. I am excited to see if use of this technology is incorporated into EMS care. If it is proven to be effective in one system, other regions will incorporate it into the ambulance-based care of stroke patients.

Expression of Inflammatory Genes: A Prelude to Intracranial Aneurysmal Rupture.

Hassanain Toma, MD

Nakaoka H, Tajima A, Yoneyama T, Hosomichi K, Kasuya H, et al. Gene Expression Profiling Reveals Distinct Molecular Signatures Associated With the Rupture of Intracranial Aneurysm. Stroke. 2014

Nakaoka et al. sought to investigate genes associated with rupture of saccular intracranial aneurysms. They employed gene clustering methods to compare gene expression between ruptured (RIAs) and unruptured (UIAs) aneurysms.

Their analysis revealed that RIAs segregated into two distinct subgroups, with an average age of 46.6 and 80.7. Furthermore, RIAs from younger patients had 430 up-regulated, and 617 down-regulated genes, as compared to UIAs. The up-regulated genes were associated with phagocytosis, inflammatory and immune responses, while the down-regulated genes suggest mechanical weakness of aneurysm walls.

The results of this study suggest that the pathophysiology of aneurysmal rupture in young and old patients is different. Aneurysms of younger patients rupture because of elevated immune responses, while aneurysms of older patients rupture due to longstanding “wear and tear”.

The findings of Nakaoka et al. raise the question of whether statins should be given to young patients with intracranial aneurysms. Previously, the JUPITER trial demonstrated that statins are associated with a 48% relative risk reduction of total strokes in patients with normal LDL levels and elevated CRP. This is presumed to be due to the statins’ anti-inflammatory properties. Thus, the hypothesis of medically managing intracranial aneurysms with statins is not far fetched, especially since some data suggest that statin therapy is associated with a decreased expansion rate in patients with small abdominal aortic aneurysms.

IV-tPA + MCA occlusion: which patients benefit?

Deepa Bhupali, MD

Rohan V, Baxa J, Tupy R, Cerna L, Sevcik P, Friesl M, et al. Length of Occlusion Predicts Recanalization and Outcome After Intravenous Thrombolysis in Middle Cerebral Artery Stroke. Stroke. 2014

In a recent article, Rohan et al explore predictors of successful IV-tPA recanalization and outcome in patients with proximal MCA occlusion as measured by 4D CTA imaging. They looked at 80 patients with M1-M2 occlusion (the majority had isolated M1 occlusions), calculated the length of the occlusion, recorded the NIHSS at presentation and at 24 hours after tPA and assessed clinical outcome at three months using the mRS (favorable outcome=mRS 0-2). Successful recanalization was defined as a TIMI grade 2 or 3. With univariate analysis, they found that a lower baseline NIHSS, length of occlusion and ASPECTS score were significant predictive factors of favorable outcome. In multivariate analysis, only baseline NIHSS and length of occlusion in the M1 segment were significant independent predictors of favorable outcome.

I really enjoyed this article. It speaks to our desire to improve our practice and deliver better care. We’ve been administering IV-tPA to treat acute stroke for years but we’re still learning about how it performs in different situations. We are facing a newer, similar challenge in the endovascular world: trying to identify the patients who will benefit most from the interventional reperfusion. Overall, the results of this study are not surprising: patients with better NIHSS, smaller lengths of occlusion and less area of ischemia benefit more from IV-tPA than their counterparts.

One of the limitations of the study is that it cannot be applied at the bedside at this point. The imaging modalities used to determine the length of the occlusion are not yet feasible or practical in the acute setting. Even if we know the length of the occlusion at the time we’re considering administering tPA , it would most likely not affect our decision as to whether or not to give the medication. But, just as meaningfully, knowing the relationship between occlusion length, IV-tPA and clinical outcome with more certainty would surely help us when speaking with patients and families about potential outcomes and expectations.

It’s important to constantly evaluate how we can deliver care more effectively and this article is an example of that pursuit. It brings up an interesting topic and although the results are not yet ready for prime-time clinical use, as more information is gathered, it may factor into our treatment decisions and it will certainly factor in to our discussions with patients and their families.

Warfarin-Associated Intracerebral Hemorrhage after Ischemic Stroke

Sebina Bulic, MD

Åsberg S, Eriksson M, Henriksson KM, and Terént A. Warfarin-Associated Intracerebral Hemorrhage After Ischemic Stroke. Stroke. 2014

Warfarin continues to be major player for anticoagulation. NOAC became equally acceptable alternative. In safety analyzes of subgroups of patients with previous stroke, the annual rate of ICH in patients allocated warfarin was 0.8%, 1.0% and 0.5% for dabigatran, apixaban, and rivaroxaban trials respectively. In this register-based observational study, comprised of patients with first-ever ischemic stroke, who were discharged on warfarin, results were somewhat different.

Data from the two Swedish national registers linked through the patient’s unique personal identification numbers were used; The Swedish Stroke Register and Cause of Death Register. Data were analyzed for 2 periods; period 1 from January 2001 to December 2004, and period 2 from January 2005 to December 2008. Mean time of follow-up was 2.6 years, with a minimum follow-up time of 1 year.During the two 4-year periods, all ischemic stroke survivors discharged on warfarin (n=12,790) were included in the study. The proportion of patients with AF increased from 63.9% (n=3857) in the first period to 72.1% (n=4870) in the second period. During 31,800 person-years, there were 1237 recurrent strokes, of which 127 were ICH. Annual rates of ICH ranged from 0.37% in the first period to 0.39% in the second period, showing that incidence of ICH did not significantly change despite increased use of warfarin. Reasons for discrepancy of ICH incidence between this register-based observational study and subgroup analysis of the randomized prospective trials was not offered, but these results are certainly reassuring. 

Did the Presence of Collaterals Undermined the SWIFT Study Results?

Hassanain Toma, MD

Liebeskind DS, Jahan R, Nogueira RG, Zaidat OO, and Saver JL. Impact of Collaterals on Successful Revascularization in Solitaire FR With the Intention for Thrombectomy. Stroke. 2014

The presence of collateral circulation has been shown to be associated with improved recanalization after thrombolysis and mechanical thrombectomy. However, with the advent of stent retrievers, it is hypothesized that improved recanalization can be achieved irrespective of collaterals. To test this, Liebeskind et al. retrospectively analyzed angiographic collateral grade prior to endovascular therapy in the SWIFT (SOLITAIRE™ FR With the Intention For Thrombectomy) study to ascertain the potential impact of collaterals on revascularization without symptomatic hemorrhage. They also sought to identify predictors of collateral grade in that study population.

They authors revealed a significant association between elevated blood glucose and systolic blood pressure at presentation and worse collaterals. In addition, the absence of prior HTN, a positive history for smoking, and high blood glucose were predictors of worse collaterals. Furthermore, low ASPECTS at baseline and at 24 hrs post-intervention were associated with worse collaterals.

The presence of collaterals was closely linked with improved reperfusion and revascularization without symptomatic hemorrhage, and overall better clinical outcome at defined by NIHSS at day 7 and mRS at day 90.

These data undermine the credibility of the SWIFT study results. You may recall that the SWIFT study compared the Solitaire device to the Merci retriever. The study concluded that the Solitaire device achieved substantially better angiographic, safety, and clinical outcomes than did the Merci Retrieval System. The current study by Liebeskind et al. reveals that collateral grade (partly driven by HTN, DM, and smoking) ultimately made a significant difference in outcome, irrespective of device used (although the authors did not discuss this point). The presence of collaterals was a confounding variable that was unadjusted for in the SWIFT trial. Perhaps the hype about the Solitaire device is unwarranted. It would be interesting to see the outcome of the SWIFT study after adjusting for the collateral grade.

Does more rehab = better outcome?

Matthew Edwardson, MD

Lohse KR, Lang CE, and Boyd LA. Is More Better? Using Metadata to Explore Dose–Response Relationships in Stroke Rehabilitation. Stroke. 2014

The more time spent in rehabilitation therapy, the better the recovery.  Although widely believed by the stroke community, this theory becomes less clear after exploring the scientific evidence.  For example, one study suggested that high doses of intense occupational therapy shortly after stroke actually led to worse outcomes.  In addition, compared to acute stroke trials, most rehabilitation trials enrolled only a small number of subjects.  How generalizable could the results really be?  Lohse and colleagues tackled this problem using a meta-data approach combining the results of high quality stroke rehabilitation trials.  They discovered that more time in therapy does indeed improve recovery, but the timing of delivery post-stroke may be less important.

The authors identified 37 high quality randomized controlled stroke rehabilitation trials that differed in the amount of therapy delivered between groups.  Outcome measures for each study were converted to standard effect-sizes in order to combine results.  Timing of therapies post-stroke varied considerably with a mean of ~1 year.  Overall results showed improved outcomes in those receiving more therapy (g = 0.35, [0.26, 0.45], p < 0.001).  Regression modeling suggested significant improvement for every 10 additional hours of therapy independent of when therapy was started post-stroke.  There was weak evidence to suggest that every additional 10 hours of therapy may provide diminishing returns.

This study provides strong evidence that time spent in rehabilitation therapy matters and raises several questions with regard to current clinical practice.  Insurance reimbursement largely dictates time allotted to inpatient and outpatient therapies in the U.S.  Should we be advocating for more time?  At what point does more therapy provide no clinically significant benefit?  By taking into account that the control groups in all of these studies received a standard amount of time in therapy, it would appear that under-treatment is the norm and advocating for more time is warranted.  While the current study suggested no difference with regard to the timing of therapy post-stroke, many of us feel this question has not been adequately addressed in human trials.  Animal stroke models suggest earlier is better.  Complicating matters is the lack of a one-size-fits-all approach to stroke rehab.  Patients enrolled into stroke rehabilitation trials typically have pure-motor stroke and a moderate degree of weakness.  Those with very mild or very severe strokes may not benefit from additional therapy.  In summary, more is generally better, but the best approach in clinical practice remains in debate. 

Computer Modeling to Affect Change: A Systems simulation approach to stroke care

Waimei Tai, MD

Lich KH, Tian Y, Beadles CA, Williams LS, Bravata DM, Cheng EM, et al. Strategic Planning to Reduce the Burden of Stroke Among Veterans:Using Simulation Modeling to Inform Decision Making. Stroke. 2014

Lich et. al. developed an interesting way to look at the stroke systems of care problem: applying engineering approach to identify areas of highest potential impact in an all inclusive system of care- the national Veterans Affairs health system. 

I have had the opportunity to speak with some of the authors of this paper from prior work in stroke systems of care. I think what they’re doing makes a lot of sense. If you have to oversee a large initiative (the entire VA health system’s stroke care program) with limited resources, it makes sense to look at what you can get for “greatest bang for your buck.” And hopefully with this tool, they’ve identified hypotheses that are worth pursuing in a prospective manner to gain more health quality for their patients.

The interventions they identified as potentially most efficient in deriving more QALYs via number needed to treat (faster tpa), or size of overall cumulative effect (hypertension control in high risk patients), and better care early care for vets with TIA, and transition to rehab. These are similar to interventions suggested by literature review or by expert opinion. It does go to show that the clinicians’ sense tends to hone in on achievable gains that can potentially dramatically improve quality of life.

One limitation (or strength, one could argue) is that the data is largely VA specific, but they’re answering a question that is unique to their population. Given the VA’s large presence in the healthcare system, their inclusive nature, they have a unique ability to analyze health statistics for a large population of patients.

In this day and age, when so much attention has been drawn on some negative aspects of VA health care system, I think this study highlights the great attention and care that the VA health care providers and staff are offering to our veterans and their plan to maximize the utility of the taxpayers’ dollars by focusing on highest impact, highest efficiency interventions. I’m grateful for these colleagues. I believe while this data set maybe limited to the VA population, that lessons learned from this modeling is applicable in other resource constrained environments such as other county or public health systems, as well as older medicare population as well.

More is more: Dose-response benefits of therapy after stroke

For any of us who have fought with insurance companies to allow for better access to intensive therapies for patients after a stroke, it seems inherent that “more is more” when it comes stroke rehab. A number of studies and review articles have shown evidence to this effect, and in their current article, authors Lohse and colleagues have made the case for a reliable dose-response relationship between the time scheduled for therapy and improvement on clinical measures of function and impairment.

30 RCT articles investigating were included for review, and details of the interventions and time scheduled for interventions were extracted. Regression models were used to predict improvement during therapy as a function of total time scheduled and for therapy and years post stroke. Outcomes were restricted to “validated behavioral measures of function or impairment.” Authors found that overall, treatment groups receiving more therapies improved beyond control groups that received less, and that analysis suggests a “reliable dose-response relationship between time schedule for therapy and a improvement on clinical measures of function and impairment.”

One of the more interesting aspects of this study for me was the lack of interaction between time post stroke and the intensity of interventions, suggesting that even if rehab occurs months or years out, it may still have significant benefit.This study did not clarify stroke type or severity of participants, nor the “validated behavioral measures” utilized as outcomes, and per exclusion criteria, up to 30% of those included may have not had strokes. Authors were limited to using time scheduled as a proxy for rehab intensity, and note that further RCTs would benefit from reporting active time or repetitions of an exercise as a more accurate representation of the dose of therapy received.  Studies are ongoing to find the optimal mix of intensity and timing of rehab after stroke, however this study adds weight to the growing evidence that on a broad scope, more really is better when it comes to therapies after stroke.

Cognitive Decline and Vascular Reactivity, an association, or causal mechanism?

Jennifer Dearborn, MD 

Buratti L, Balucani C, Viticchi G, Falsetti L, Altamura C, Avitabile E, et al. Cognitive Deterioration in Bilateral Asymptomatic Severe CarotidStenosis. Stroke. 2014

Buratti et al. recently examined the question, what might the mechanism of cognitive impairment be in patients with large vessel (carotid) atherosclerosis? The authors had a hypothesis that cognitive dysfunction, if present, might be mediated by impaired cerebrovascular reactivity at the arteriolar level, as a result of more proximal, large vessel occlusion. To test this hypothesis, they evaluated patients presenting to a vascular ultrasound laboratory on a referral basis. Duplex sonography was used to evaluate neck and intracranial arteries. The major predictors were CVR (a measure of the arteriolar dilation in response to stimuli) using the breath holding index (BHI) test, and carotid intima media thickness (IMT). The outcome was change in Mini-mental status examination in the 3-year study period.

The authors found, after adjustments for hypertension age, sex and coronary artery disease that an abnormal BHI bilaterally was associated with a greater change in MMSE, and interestingly, this did not differ by carotid IMT. The authors suggest that the technique may show that chronic hypoperfusion contributes to cognitive decline. They acknowledge, however, that it is difficult to sort out the effects of generalized vascular disease, which may coexist with carotid disease and be the causual agent, rather than the presence of carotid disease itself. Therefore extrapolation of this studies results to suggestion of a mechanism of cognitive decline should be interpreted with caution, as it is difficult to adequately control for underlying vascular risk factors completely to show an independent association between BHI and hemodynamics and cognitive decline. However this study does suggest that the mechanism of cognitive decline should be investigated more carefully, perhaps by correlating hemodynamic measures with MRI markers of brain pathology in larger sample. For example, white matter hyperintesities, or more lacunes, may also be present in those with impaired BHI, and this would be an alternate and equally interesting explanation of the association.