American Heart Association

Monthly Archives: May 2013

A Randomized trial of Unruptured Brain AVMs (ARUBA) shows that conservative therapy may be preferable

Blogging live from the 2013 European Stroke Conference
May 31, 2013

The results of A Randomized trial of Unruptured Brain AVMs (ARUBA) were just presented at the European Stroke Conference in London by Profs. Stapf and Mohr. 



ARUBA was a randomized trial of a multidisciplinary treatment approach to AVMs. It was prospective, planned to enroll 400 patients, and was funded by NINHS. They compared best possible AVM eradication (which is considered the standard of care) vs. conservative therapy (the experimental study arm).

Enrolled subjects had unruptured AVM diagnosed by MRI, and were excluded if there was prior hemorrhage or prior partial AVM treatment or if the AVM was deemed untreatable. Primary endpoint was death or symptomatic stroke; secondary endpoint was a neurological deficit. All enrolled patients were disability-free at enrollment.

The trial was stopped on April 15th by the DSMB when 223 patients were randomized due to overwhelming efficacy of conservative therapy. Baseline data on 223 were balanced with randomization of 109 to medical and 114 intervention. Eventually a total of 126 ended up getting conservative therapy vs. 97 got intervention. Duration of follow-up was 3 years. The primary outcome of death or stroke was seen in 11 medical group (10%) and 33 in intervention group (29%). The intention to treat for the primary endpoint had a Hazard Ratio of 0.29 with a 95% confidence interval of 0.15 to 0.58. Mortality was comparable

The results of ARUBA are striking because of the assumption that interventional therapy was far superior to doing nothing. The results should be taken with caution because all of the risk of intervention is front-leaded during the period of treatment and benefits of intervention are manifest in the decades after treatment. We do not know how the medical therapy arm will fare in the coming decades and subjects were young (mean age 40s). The most important result of ARUBA will be how these groups look in 10 years and potentially in 20 years.


– Nerses Sanossian, MD

A Randomized trial of Unruptured Brain AVMs (ARUBA) shows that conservative therapy may be preferable

Blogging live from the European Stroke Conference:
The results of A Randomized trial of Unruptured Brain AVMs (ARUBA) were just presented at the European Stroke Conference in London by Profs. Stapf and Mohr. 
ARUBA was a randomized trial of a multidisciplinary treatment approach to AVMs. It was prospective, planned to enroll 400 patients, and was funded by NINHS. They compared best possible AVM eradication (which is considered the standard of care) vs. conservative therapy (the experimental study arm).
Enrolled subjects had unruptured AVM diagnosed by MRI, and were excluded if there was prior hemorrhage or prior partial AVM treatment or if the AVM was deemed untreatable. Primary endpoint was death or symptomatic stroke; secondary endpoint was a neurological deficit. All enrolled patients were disability-free at enrollment.
The trial was stopped on April 15th by the DSMB when 223 patients were randomized due to overwhelming efficacy of conservative therapy.  Baseline data on 223 were balanced with randomization of 109 to medical and 114 intervention. Eventually a total of 126 ended up getting conservative therapy vs. 97 got intervention. Duration of follow-up was 3 years. The primary outcome of death or stroke was seen in 11 medical group (10%) and 33 in intervention group (29%). The intention to treat for the primary endpoint had a Hazard Ratio of 0.29 with a 95% confidence interval of 0.15 to 0.58. Mortality was comparable
The results of ARUBA are striking because of the assumption that interventional therapy was far superior to doing nothing. The results should be taken with caution because all of the risk of intervention is front-leaded during the period of treatment and benefits of intervention are manifest in the decades after treatment. We do not know how the medical therapy arm will fare in the coming decades and subjects were young (mean age 40s).  The most important result of ARUBA will be how these groups look in 10 years and potentially in 20 years.

RESPECT PFO and PC Trial analyses presented at the ESC

Blogging live from the 2013 European Stroke Conference 2013
May 30, 2013

At the large clinical trials sessions at the ESC today there were back to back presentations from the Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Embolism (PC) trial by Prof. Mattle and the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial by Prof. Saver. These two clinical trials randomized patients with cryptogenic stroke and patent foramen ovale to percutaneous closure using the Amplatzer PFO occluder device or medical therapy. The Aplatzer device is one of three devices tested in clinical trials of PFO occlusion, the others being the STARflex, and cardioSEAL. The STARflex was the device used in the Closure or Medical Therapy for Cryptogenic Stroke With Patent Foramen Ovale (CLOSURE) and was found to be associated with high rates of device thrombosis and atrial fibrillation.


The presentation by the PC trialists focussed on the analysis of stroke events in addition to the overall events in the primary intention-to-treat analysis. They presented an 80% relative risk reduction on stroke in the device group, but nowhere near the number of subjects enrolled needed to achieve statistical significant. The device seemed to be relatively safe.

The RESPECT presentation focussed on the “device in place” analysis which moved a 3 of the stroke outcome events in the group randomized to device moved over to the medical (i.e. device not in place group). These three strokes occurred in a subject who changed his mind about having the PFO closed, one who was waiting for the procedure and one who had coronary artery disease and needed CABG surgery. This analysis demonstrated a benefit of PFO closure which, unlike the intention to treat analysis, was statistically significant. The trialists concluded that the “device in place” analysis confirms the biological effect of PFO closure for cryptogenic stroke.

Of note was an analysis combining the two studies (PC + RESPECT) shown by Prof. Mattle demonstrating a statistically significant reduction in stroke with PFO occlusion. This is what happens when two clinical trials show a non-statistically significant benefit in reduction of stroke with PFO occlusion are combined.

PFO occlusion with the Amplatzer device is safe and probably effective in preventing stroke in those cases with true cryptogenic stroke. The problem with closure of PFO in cryptogenic stroke is the low rate of recurrent stroke in general in this population and the fact that there are other effective interventions for preventing stroke: diet, lifestyle, and aggressive risk reduction. When a 45 year-old borderline hypertensive patient who is overweight and does not exercise presents with a “cryptogenic” stroke and is found to have a PFO should it be occluded? How about starting low-dose aspirin and intensive lifestyle changes aimed at moderate weight loss and achieving 40 minutes of exercise 5 days a week? It seems much easier to just close the PFO, but that may not be the right thing to do.


– Nerses Sanossian, MD

RESPECT PFO and PC Trial analyses presented at the ESC

Blogging live from the European Stroke Conference:

At the large clinical trials sessions at the ESC today there were back to back presentations from the Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Embolism (PC) trial by Prof. Mattle and the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established
Current Standard of Care Treatment (RESPECT) trial by Prof. Saver. These two clinical trials randomized patients with cryptogenic stroke and patent foramen ovale to percutaneous closure using the Amplatzer PFO occluder device or medical therapy. The Aplatzer device is one of three devices tested in clinical trials of PFO occlusion, the others being the STARflex, and cardioSEAL. The STARflex was the device used in the Closure or Medical Therapy for Cryptogenic Stroke With Patent Foramen Ovale (CLOSURE) and was found to be associated with high rates of device thrombosis and atrial fibrillation.

The presentation by the PC trialists focussed on the analysis of stroke events in addition to the overall events in the primary intention-to-treat analysis. They presented an 80% relative risk reduction on stroke in the device group, but nowhere near the number of subjects enrolled needed to achieve statistical significant. The device seemed to be relatively safe.

The RESPECT presentation focussed on the “device in place” analysis which moved a 3 of the stroke outcome events in the group randomized to device moved over to the medical (i.e. device not in place group). These three strokes occurred in a subject who changed his mind about having the PFO closed, one who was waiting for the procedure and one who had coronary artery disease and needed CABG surgery.  This analysis demonstrated a benefit of PFO closure which, unlike the intention to treat analysis, was statistically significant. The trialists concluded that the “device in place” analysis confirms the biological effect of PFO closure for cryptogenic stroke.

Of note was an analysis combining the two studies (PC + RESPECT) shown by Prof. Mattle demonstrating  a statistically significant reduction in stroke with PFO occlusion. This is what happens when two clinical trials show a non-statistically significant benefit in reduction of stroke with PFO occlusion are combined.

PFO occlusion with the Amplatzer device is safe and probably effective in preventing stroke in those cases with true cryptogenic stroke. The problem with closure of PFO in cryptogenic stroke is the low rate of recurrent stroke in general in this population and the fact that there are other effective interventions for preventing stroke: diet, lifestyle, and aggressive risk reduction. When a 45 year-old borderline hypertensive patient who is overweight and does not exercise presents with a “cryptogenic” stroke and is found to have a PFO should it be occluded? How about starting low-dose aspirin and intensive lifestyle changes aimed at moderate weight loss and achieving 40 minutes of exercise 5 days a week? It seems much easier to just close the PFO, but that may not be the right thing to do.

INTERACT 2 results just presented in London

Blogging Live from the European Stroke Conference:

The second intensive blood pressure reduction in acute cerebral hemorrhage trial (INTERACT 2) results were just presented at the European Stroke Conference and are to be published in the New England Journal of Medicine later today. This is the definitive phase 3 clinical trial of early aggressive BP goal (goal systolic BP <140) vs. more conservative control (goal systolic BP <180) in patients with intracerebral hemorrhage (ICH) on CT presenting less than 6 hours from symptom onset.

Over 4 years a total of 2839 patients were randomized an average of 3.8 hours after symptom onset, over 2/3rd of cases were from China, the vast majority had deep hemorrhages with about 1/3rd having intraventricular hemorrhage as well.  Overall about 12% died, equal in the two groups. The primary of death or disability was seen in 52% of aggressive vs 55%of conservative treatment groups OR 0.87, p=0.06.  When performing the ordinal shift analysis there was a significant wit a 13% improvement.
This study going to change practice and early aggressive lowering of blood pressure in hypertensive ICH is going to be the norm. The first INTERACT study demonstrated that early aggressive BP reduced hemorrhage expansion and that this effect was most potent when treatment was initiated earlier. The results of INTERACT 2 further validate the concept of early aggressive therapy demonstrating a consistent benefit  despite the near miss for significance to a p-values less than 0.05. This may lead to some skepticism about the result, but it should be noted that  the standard treatment arm also received early antihypertensive therapy, albeit in lower doses.
Of interest time from onset of symptoms to recruitment did not have an effect on outcome in INTERACT 2. This was surprising as we would have expected earlier treatment to be better. It was reassuring that aggressive treatment led to no increase in neurological deterioration. The treatment effect of early aggressive therapy was around 4% was less than the expected 7%.
Although there is cause for excitement in the realm of ICH therapy, the results of the INTERACT 2 study beg the question: what is next? How can we improve on these results and get even better outcomes for patients with ICH. Could there be some forms of combination therapies, or earlier treatment which would be even better? For the time being aggressive urgent BP lowering in hypertensive ICH makes sense.

Comparing cIMT with stroke risk factors

Carotid intima-media thickness (cIMT) is a marker for atherosclerosis and cardiovascular disease. Variations in cIMT, particularly in areas free of atherosclerosis, may suggest that non-traditional atherosclerotic risk factors may be at play. Rundek et al. sought to characterize the contribution of traditional and less traditional vascular risk factors toward cIMT. As a sub-project of the Northern Manhattan Study (NOMAS), 1790 healthy subjects received high-resolution 2D carotid ultrasounds to assess cIMT in areas free of plaque. Logistic regression was used to assess the relationship between stroke risk factors (traditional and nontraditional) and cIMT. The authors found that age, male sex, glucose, smoking by pack-years, and LDL levels explain only some of the variation observed in cIMT. Less traditional risk factors (homocysteine, GFR, and inflammatory markers) did not significantly contribute to cIMT variation, even after excluding subjects with known cardiovascular status (CAD, PAD, or MI). Based on their findings, the authors postulate that variations in cIMT may actually be due to the aging processes and does not  indicate atherosclerotic risk.

The role in cIMT when characterizing atherosclerotic risk remains unclear, but underscores the importance of traditional risk factor control in stroke prevention. Control of traditional atherosclerotic risk factors has greatly contributed toward the reduction of stroke mortality over recent years. Yet, we have all observed patients who continue to have strokes despite control of these risk factors. Efforts like these to find ways to identify those at-risk by nontraditional risk factors may eventually lead to the emergence of other biomarkers as routine assessments for stroke risk.

FCRP v MMSE for Old Stroke

Shruti Sonni, MD

  • Sabayan B
  • Gussekloo J
  • de Ruijter W
  • Westendorp RGJ
  • and de Craen AJM. 
  • Framingham Stroke Risk Score and Cognitive Impairment for Predicting First-Time Stroke in the Oldest Old. Stroke. 2013


    The Framingham stroke risk score is composed of conventional vascular risk factors, and predicts stroke risk in middle aged and the younger old population. Studies have suggested that factors like hypertension, hypercholesterolemia and diabetes tend to lose their predictive value with advancing age. In this study, Sabayan et al. set out to compare the performance of the Framingham stroke risk score and the Mini-Mental State Examination (MMSE) in predicting five-year risk of first time stroke in people aged 85 years and older. They found that the Framingham risk score did not predict stroke risk in this population, but the MMSE showed a graded and sustained relationship between decreasing cognitive function and stroke incidence. 

    The relationship between cognitive impairment and increased risk of stroke has been established in earlier large studies. This was the first study to reproduce these findings in the oldest old population, a population that is on the rise in developed countries, and hence of growing public health importance. The drawback of this study is the lack of neuroimaging, rendering the authors unable to identify type of stroke and silent strokes, which would affect risk of recurrent stroke. Also, the MMSE is not ideal to evaluate cognitive impairment due to vascular causes, unlike the Montral Cognitive Assessment (MoCA). Nevertheless, this study builds the case that cognitive impairment is a tool for predicting stroke risk in not only the younger old, but the oldest old as well.

    Stroke Subtype and Recurrence

    Nandakumar Nagaraja, MD

    Jones S, Sen S, Lakshminarayan K, Wayne R. Poststroke Outcomes Vary by Pathogenic Stroke Subtype in TheAtherosclerosis Risk in Communities Study. Stroke. 2013

    Stroke patients are at risk of recurrent stroke and stroke related medical complications such as pneumonia and UTI which result in hospital readmissions. Determining the etiology of stroke helps in instituting appropriate stroke secondary prevention strategies to prevent recurrent strokes. Stroke related medical complications can by minimized with good nursing care. 
    Jones and colleagues in a recent article evaluated the long term stroke outcomes by etiologic subtype in the Atherosclerosis Risk in Communities Study, a population based study. Based on the National Survey of Stroke classification patients were categorized as thrombotic, lacunar, cardioembolic, ICH or SAH. Patients with ICH had highest mortality followed by cardioembolic strokes but it was lower for lacunar infarcts. Higher all-cause hospital readmissions were seen for cardioembolic strokes and lower for lacunar infarcts. About 70% of recurrent strokes were of the same subtype except for lacunar strokes (28%). This probably indicates that either the patient failed or was not compliant with the stroke secondary prevention strategies. 

    Patients with lacunar strokes had lower mortality and hospital readmissions but higher rate of non lacunar (72%) recurrent strokes. So there is probably a window of opportunity during the follow up of lacunar stroke patients to identify new risk factors such as cardioembolic or atherosclerotic large artery disease and provide appropriate management before they have a stroke from non lacunar etiology.

    Because patients with cardioembolic strokes have higher rates of all-cause readmission it is important to make sure that these patients are on appropriate stroke secondary prevention medications and have good discharge planning with follow up. This may reduce the readmissions and health care cost to the society and improve the quality of life of the patient.

                                     

    Role of Balloon Expandable Stents in Intracranial Athersclerotic Disease

    Aaron Tansy, MD


    The advent of intracranial stenting offered the stroke community new hope for the improved treatment of severe intracranial atherosclerosis. Thus, the early termination of the SAMMPRIS trial due to stenting’s inferiority in comparison to medical therapy was for many, at best, a bittersweet result and, at worst, another dashed possibility. However, Anand Alurkar and colleagues’ study that will appear in the upcoming issue of Stroke suggests that we should not abandon all hope for intracranial stenting just yet.

    The group evaluated stroke prevention efficacy of balloon expandable intracranial stents in severe, medically refractive intracranial stenosis. Eligibility included >70% stenotic lesions and symptomatic events attributable to the lesion despite maximal medical therapy. Both non- and drug-eluting stents were used. Maximal medical therapy included aspirin, clopidogrel, and atorvastatin. Post-stenting clinical monitoring occurred every two weeks during the first month and at increasingly longer intervals thereafter for 1 year. Follow up diagnostic cerebral angiogram was performed at 1 year in 121 patients. Over 97% of 198 lesions in 182 patients were successfully stented. Of these, stroke incidence during the post-procedure first month was roughly 6% (1% were major) and at 1 year 10%. DSA at 1 year revealed >20% luminal loss in over 50% of patients who had suffered a stroke during the year of monitoring. Mortality at 1 month was roughly 1%.

    Although this small single-center analysis was notably different (e.g. patient population, device type, trial type) from and cannot be directly compared with SAMMPRIS, its results remain encouraging. Not only did this group show that intracranial stenting is readily feasible, but also efficacious with better outcomes and long-term complication rates than those seen in SAMMPRIS. Hence, the stroke community must continue to investigate intracranial stenting including identifying the specific devices by which and stroke populations for which it may yield the greatest clinical impact and stroke protection.

    ICH Score Comparison

    Nandakumar Nagaraja, MD

    Parry-Jones AR, Abid KA , Di Napoli M, Smith CJ, Vail A, Patel HC, et al. Accuracy and Clinical Usefulness of Intracerebral Hemorrhage Grading ScoresA Direct Comparison in a UK Population. Stroke. 2013

    Intracerebral hemorrhage is a devastating condition associated with high early mortality rate. Physicians managing patients with ICH constantly face challenging management decisions including the choice between aggressive care versus withdrawal of care. Intracerebral hemorrhage grading scores (such as the original ICH score (oICH), modified ICH score (mICH) and ICH Grading Scale (ICH GS)) are used in clinical practice to predict mortality after ICH and guide management.

    Parry-Jones and colleagues evaluated the accuracy and clinical usefulness of the ICH grading scores and GCS to predict outcome in their cohort of 1364 patients. The authors found that all 3 grading scores – oICH, mICH and ICH GS for ICH are highly predictive for 30 day mortality. One of the interesting findings of the study was that GCS alone was as good as three ICH scores in predicting 30 day mortality, thus eliminating the need for measuring hematoma volume. Age was a poor predictor of 30 day mortality.

    A study published in Neurology in 2007 by Zahuranec et al., showed that early limitation of care was independently associated with short and long term mortality after ICH. Therefore, it is probably reasonable to have an aggressive medical approach to manage these patients acutely and use the ICH grading scores or GCS to guide in further management after the acute phase.