American Heart Association

Monthly Archives: April 2013

Yield of Cather Angiography After Computed Tomography Negative, Lumbar Puncture Positive Subarachnoid Hemorrhage

Waimei Tai, MD

Wallace et. al. presented an interesting case series of 57 patients who had negative imaging but positive lumbar puncture results who presented with worst headache of their life. In this series, 2 out of the 57 patients had a positive catheter angiogram suggested of ruptured aneurysm.  These two patients presented late (5 day from symptom onset) potentially explaining why they had negative CT scans (scant blood on CT may certainly become isodense by day 5). One patient had a vertebral dissection with pseudoaneurysm formation, while another had an ICA bifurcation aneurysm.

There was 1 patient in their series that positive erythrocytes (that did not clear with serial punctures) that had an angiogram with an incidental small aneurysm tht was not thought to be related to the symptom onset, not treated and stable on follow up studies.
Given the paucity of recent data on CSF analyses as a predictor for catheter angiograms in the SAH literature, this study is certainly helpful.

It would have been more helpful if they also reported any additional imaging studies made available (CT angiogram, MR and MR angiogram) which may have revealed some additional information. For example, MRI has been shown to be more sensitive for acute subarachnoid blood even in the setting of negative non-contrast CT and thus, may have been revealing in these patients if the clinical picture fit that of aneurysmal SAH.

Regardless, given the inherent dangers and negative sequelae of aneurysmal SAH (vs. other relatively more benign form of SAH such as perimesecephalic hemorrhage), it is important  for clinicians to keep a high vigilance for patients who present with clinical features suggestive of aneurysmal SAH, especially those who present in a delayed fashion, knowing the inherent pitfalls of non contrast CT imaging, and consider other imaging modalities (such as MRI brain with and without contrast) and CT angiogram, and catheter angiograms.

ICH ADAPT Investigators BP Reduction on CBF

Nerses Sanossian, MD

Intracerebral hemorrhage is the most deadly stroke subtype, and in the past there has been a lot of nihilism about developing effective treatment. There is not much one can do to change the outcome of patients with ICH once the final hematoma volume is established, so much of the focus is on preventing expansion through lowering blood pressure and promoting thrombosis. Aggressive lowering of BP in stroke has always been haunted by the fear of reducing cerebral blood flow and exacerbating brain injury. The ICH ADAPT investigators wanted to study the effect of meaningful BP reduction on peri-hematomal cerebral blood flow.
The ICH ADAPT investigators report that there is no change in CBF in the peri-hematomal region as measured by CT perfusion when BP is reduced by an average of 27 mm Hg over two hours. This was a substantial reduction on BP over a relatively short period of time during the acute phase of ICH.
ICH ADAPT has provided further evidence that early and aggressive blood pressure reduction in ICH is safe. We are eagerly awaiting the results of the definitive studies of BP reduction for ICH, such as the second (main phase) of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial or INTERACT2 to see if this approach is effective. 

Development of a Point-based Prediction Model for the Incidence of Total Stroke

Vasileios-Arsenios Lioutas, MD
Despite the advances in stroke treatment in its acute phase, the burden mortality and disability toll remain considerable. Given that the risk factors are largely treatable, recognizing and modifying them bears particular significance. What appears to be particularly difficult is convincing patients of the importance of addressing certain conditions; the notion that adhering to a seemingly irrelevant treatment significantly increases the odds of surviving free of harmful complications.
In this interesting population-based epidemiologic study, Drs Yatsuya et al. attempt to delineate the epidemiologic landscape in Japan regarding stroke incidence and associated risk factors, aiming to develop a simple, easy to comprehend point-based prediction model.
Salient findings include the reproduction of other epidemiological studies’ finding regarding the significant risk attributed to hypertension, in comparison to the rest of the traditional vascular risk factors. What is more remarkable is the fact that patients with hypertension, even when treated and with optimal blood pressure have higher stroke incidence compared to those without history of hypertension and blood pressure in the same range. It is difficult to know whether this represents delayed detection and treatment initiation or inadequate long-term blood pressure control. Two significant limitations are the marked absence of atrial fibrillation from the prediction model and the lack of stroke subgroup analysis-at least into hemorrhagic vs ischemic.
Lastly, an important question that needs to be investigated in the future is whether the development of a simple, point-based prediction model will indeed improve the physician-patient communication, increase preventive treatment compliance and reduce the incidence of stroke.

Risk of Stroke or Systemic Embolism in Atrial Fibrillation Patients Treated With Warfarin

Aaron Tansy, MD
Atrial fibrillation (AF) is the most common cardiac arrhythmia afflicting adults, and confers an estimated 5-fold increased risk for both ischemic/thromboembolic events and death.  The use of oral anticoagulation (OAC) has been well established to diminish this risk significantly, and is therefore a staple of stroke prevention in the management of AF.  However, despite OAC compliance, some patients still sustain new strokes.  These events occur likely for a variety of reasons that may run the gamut from transient sub-therapeutic OAC levels to poorly treated coexisting risk factors. 
To better understand this occurrence, Ida Albertsen and colleagues present a meta-analysis of recent randomized controlled trials of AF stroke prevention to identify clinical factors that may worsen risk of stroke in AF despite compliant use of warfarin.  After performing a thorough database search and screening, they selected six studies for analysis which identified the following factors that independently increased risk of stroke in treated AF: age >/ 75, female sex, prior stroke/TIA, naïve vitamin K-antagonist status, moderate and severe renal impairment, prior aspirin use, Asian race, and a CHADS2 score >/ 3.  Risk of stroke appeared highest for those either with a prior ischemic event, severe renal impairment, or high CHADS2 score.  Independently, diabetes, hypertension, and heart failure did not worsen stroke risk.  Data regarding etiology/mechanism of new strokes (thromboembolic, ICH, small-vessel disease) were not available to the authors for analysis.
Although lacking information about etiology of new strokes in treated AF, this group’s study provides some surprising and not-so surprising results.  Regarding the former, Asian ethnicity was found to increase stroke risk in treated AF.  But, a few previous studies with largely white populations suggested a decreased risk for Asians.  Why the discrepancy?  Ethnicity may play a true role, or may reflect other underlying factors such as imbalance in ethnic diversity of study populations or even those socioeconomic.  Thus, more ethnically diverse and global epidemiological studies are necessary to better address this finding.  Regarding the latter, prior antiplatelet use increases risk of stroke in treated AF.  Likely this finding reflects concurrent non-AF stroke risk factors.  However, surprisingly, only in aggregate as reflected in the CHADS2 score, did the majority of these well-established independent risk factors for non-AF stroke increase stroke risk in treated AF.  Further studies are required to tease apart the independent risks of each of these in the setting of treated AF, and how, in aggregate, they may confer heightened risk even despite OAC compliance.  Lastly, above all, with the advent of non-vitamin K-antagonist OACs, additional studies are warranted to understand if these newer drugs may be superior to warfarin for stroke prevention in the high-risk sub-groups that this analysis identified.

Accuracy of Diffusion Weighted Imaging in Suspected Cerebral Infarctions

Osman Mir, MD

Wang Y, Xu J, X, Wang D, Wang C, Liu, L, et al. Association of hypertension with stroke recurrence depends on ischemic stroke subtype. Stroke. 2013

Brusner et al. take on an extremely important issue of diagnostic test evaluation. In this era of changing definition of stroke from clinical to tissue based definition they compare one of the most commonly used diagnostic methods in stroke, positive diffusion weighted image to a reference standard. It is a single center study and neuroradiologists were unblinded which are limitations of this study but it was prospective and included more than 700 patients. It verifies that DWI if positive overwhelming supports the diagnosis of acute ischemic stroke. The likelihood ratio is more than 10 in this case. And if negative, diagnosis of acute ischemic stroke should be questioned.

Given this finding this article is a good read before morning report and or stroke rounds to get the details on positive diffusion imaging.

Heritability of ICH risk and outcome

Jose Gutierrez, MD, MPH

When we think of intracranial hemorrhage (ICH), we often think that deep-seated ICH tends to be caused by hypertension and that lobar ICH is suggestive of cerebral amyloid angiopathy. But,  many other unknown factors might influence the risk to develop ICH.  In this paper, Devan et al. obtained genome-wide genotype data for 791 ICH cases and 876 controls looking to quantify the heritability of ICH risk, ICH initial volume and 90-day mortality.  The author stratified the ICH in deep vs. lobar hemorrhage to evaluate the heritability of each ICH subtype. To further evaluate for confounding effects of known risk factors for these hemorrhage subtypes, the authors suppressed genes associated with ICH lobar volume (complement component receptor 1) and those associated with hypertension.

They found a high heritability to ICH. Approximately 44% of ICH variance was accounted for by genetic differences between cases vs. groups; a higher proportion of the variance was attributable to non-APOE loci than to APOE loci. After stratifying by location (deep vs. lobar hemorrhage), non-APOE loci contributed to the variance seen in both types of ICH while APOE locus only contributed to lobar ICH. Suppressing the complement component receptor 1 did change minimally the total heritability of lobar and total ICH and suppressing loci associated with hypertension changed minimally the total and deep ICH. The results were less robust for volume and 90-day mortality. Only APOE focus was significantly associated with lobar ICH volume but not with deep or total ICH volumes. For 90-day mortality, 41% of heritability was found for non-APOE loci and 1 for APOE gene, both were not significant.

The results suggest that many other unknown factors might influence the risk of ICH. Understanding these factors may change our understanding of ICH pathophysiology and help us identify new ways to prevent and treat this devastating disease.  


Osman Mir, MD

Almekhalfi et al. explore the relationship between carotid artery angioplasty and stenting (CAS) and periprocedural stroke in a prospective single arm observational study in a single center cohort. They examined with TCD 30 patients undergoing CAS, and counted the number of microembolic signals (MIS) according to the stage in the procedure when they occurred   

Surprisingly, they did not find any correlation between the number of emboli detected and the number of DWI lesions on the post-procedure MRI. Most patients had DWI lesions, but these were mostly asymptomatic, and the number of lesions was not associated with the symptomatic state of the patients. The fascinating thing is they found the largest number of emboli when a device, such as a stent or protection device, was deployed. 

Given that this is a small single arm, single center non randomized study the novel aspect is which part of the CAS procedure carries the largest risk of embolization. Maybe the deployment stage of the procedure can be modified to make sure that this embolization risk is minimized?

Aneurysm Rupture Risk

Diogo C. Haussen, MD

Defining which modifiable risk factors enhance the risk of cerebral aneurysm rupture is a critical clinical matter. The modifiable feature that has been more often correlated with development of subarachnoid hemorrhage (SAH) is active cigarette smoking. Other putative factors include alcohol consumption and hypertension; however, accurate data on these variables and on other modifiable factors is scant. Vlak et al. report the results of a case-control study that compared 250 SAH individuals with 206 patients with unruptured aneurysms, attempting to shed more light in this penumbra. Firstly, the results reinforce the consideration that active smoking is solidly associated with ruptured status. Migraine (defined by patient self-report on a questionnaire) was found to be independently associated with rupture. The authors acknowledge that this finding may have been generated by misclassification bias; once migraine was defined by as previous diagnosis documented in the medical chart (a more strict characterization), the association with SAH was lost. Hyperlipidemia was found to be protective from the risk of aneurysm rupture. 

Early epidemiological studies revealed an association between low cholesterol and intracerebral hemorrhage; would this also apply for aneurysms? Once the authors performed sensitivity analysis controlling for potential selection bias, hyperlipidemia became non-significantly associated with SAH. The effect of statins on the risk of aneurysm rupture makes this association even more difficult to interpret, and is certainly an interesting research question that must be addressed in future studies. Finally, hypertension was not found to be differently prevalent between unruptured and ruptured aneurysm cases. This brings us an important point: although ruptured and unruptured aneurysms may have a different biology, it is very unlikely for both conditions to have totally distinct pathophysiological mechanisms. Hypertension simply seems to constitute a shared underlying contributor. This report reflects the difficulties in studying epidemiological factors of such a complex disease, and reminds us of the importance lifestyle modification in patients with cerebral aneurysms.

Cost effectiveness of newer agents

Claude Nguyen, MD

  • Harrington AR
  • Armstrong EP
  • Nolan PE, Jr
  • and Malone DC
  • . Cost-effectiveness of apixaban, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke. 2013

    Recently, secondary stroke prevention in those with atrial fibrillation has become more exciting with the recent addition of new anticoagulants such as dabigatran, apixaban, and rivaroxaban to the previous mainstay, warfarin. While the focus has been on the differences in pharmacological properties between these medications, economic differences should also be considered.

    Harrington et al. from the University of Arizona sought to estimate the cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation, comparing those receiving apixaban 5mg, dabigatran 150mg, and rivaroxaban 20mg with warfarin. Using a Markov decision-analysis model, the group sought to account for not only complications and associated costs of the medication using probability of adverse events from recent studies such as ARISTOTLE, RE-LY, and ROCKET-AF, but life expectancy, willingness-to-pay analysis, measured in quality-adjusted-life-years (QALY). The group found that the QALY estimate for apixaban was the highest, whereas the lowest was for that of warfarin.

    This is the first study to compare several of the novel anticoagulants against each other in relation to warfarin. Although this type of study has inherent limitations based on assumptions and variations in data sources, this study is valuable at a time when clinicians are still learning to incorporate these medications into their practice. Until we have better data on such areas as side effects and treatment compliance, this study suggests that the new oral anticoagulants have added economic benefit compared to the time-tested warfarin, providing further incentive to prescribe them.

    Constraint Induced Rx trial

    Shruti Sonni, MD

    Taub E, Uswatte G, Mark VW,Morris DM, Barman J, Bowman MH, et al. Method for Enhancing Real-World Use of a More Affected Arm in ChronicStroke: Transfer Package of Constraint-Induced Movement Therapy. Stroke. 2013.

    Constraint- Induced Movement therapy (CI) for the upper- extremity has shown benefit in post-stroke and cerebral palsy patients, and has suggested benefit in traumatic brain injury and multiple sclerosis as well. In this study, 40 outpatient who were >1 year out with post-stroke hemiparesis were randomly assigned to four groups that differed in the type of training (shaping vs repetition), and presence/ absence of a set of techniques called the Transfer Package (TP). The TP involves behavioral techniques used to facilitate real-world application of therapeutic gains made in the lab by encouraging self-motivation and reinforcing practice at home of lab-learned skills.

    Taub et al. were able to show that using TP resulted in 2.4 times increased spontaneous use of the affected arm regardless of type of training, and these gains persisted beyond 1 year post-treatment. A sub-study also showed that weekly phone contacts for the first month post-treatment bridged half the the gap between groups with and without TP.

    This study reiterates the consensus that real-world functional activity is the most important outcome to pursue, and that use of TP facilitates this process. What makes this method attractive is that it does not involve longer therapist time or other expensive resources, but rather a more psychological approach towards the rehabilitation process. This is a good example of how a multidisciplinary effort between physicians, therapists and psychologists is key in achieving good functional outcomes in our post-stroke patients. The fact that four extra phone calls made a positive difference to outcomes goes to show that these patients need a long lasting system of support and encouragement.