American Heart Association

Monthly Archives: February 2014

Predicting the risk of recurrent stroke: Can CRP help?


Elkind M, Luna J, McClure L, Zhang Y, Coffey C, Roldan A, et al. C-Reactive Protein as a Prognostic Marker After Lacunar Stroke: Levels of Inflammatory Markers in the Treatment of Stroke Study. Stroke. 2014

There is evidence provided by basic and clinical research that inflammation plays an important role in atherosclerosis and cardiovascular disease. Several studies have demonstrated utility of high sensitivity assay for C-reactive protein (hsCRP) as a marker of future risk of coronary artery disease. The relationship of hsCRP with risk of recurrent stroke is not very clear at present. There are some studies with focus on first ever stroke that have looked at hsCRP as a prognostic marker but there are few that have studied it for secondary prevention of ischemic stroke.

Elkind and colleagues report the results of Levels of Inflammatory Markers in Treatment of Stroke (LIMITS) trial that was an ancillary study nested within Secondary Prevention of Small Subcortical Strokes (SPS3). Of the total population enrolled in SPS3, 1244 were enrolled in LIMITS. Within this group, there were 83 recurrent ischemic strokes and 115 major vascular events (stroke, myocardial infarction, vascular death). hsCRP was measured during the subacute phase (median time after stroke 60 days). There was an increased risk of recurrent stroke in those with hsCRP>4.86 mg/L (unadjusted HR 2.54, 95%CI 1.30-4.96). The risk remained high (adjusted HR 2.32, 95%CI 1.15-4.68) even after adjustment for traditional risk factors (smoking, statin use, hypertension, diabetes etc) and demographics (age, sex, race). There was no linear relationship with hsCRP levels and no interaction with randomized anti-platelet treatment.

This study provides evidence that hsCRP predicts risk of recurrent ischemic stroke after a recent lacunar stroke. Although there was prognostic value of hsCRP in this study, it could not predict response to dual anti-platelet use. It is unclear at this time if this prognostic information can be used to alter the treatment regimen to provide better secondary prevention measures that would drive the risk of recurrent stroke further down. It will be interesting to see whether hsCRP can be used to stratify patients for research in future, especially secondary prevention treatment trials.
By |February 12th, 2014|Uncategorized|0 Comments

Post-Stroke stroke-related disability; not a contraindication to thrombolysis therapy

Tareq Kass-Hout, MD

Michal Karlinski, Adam Kobayashi, Anna Czlonkowska, Robert Mikulik, Daniel Vaclavik, Miroslav Brozman, et al. Role of Preexisting Disability in Patients Treated With IntravenousThrombolysis for Ischemic Stroke. Stroke. 2014

Karlinski et al. conducted a retrospective data analysis recently published online in stroke, that is looking at the risk of symptomatic intracranial hemorrhage sICH post intravenous thrombolysis in patients with previous stroke-related disability. This study sheds a light on the impact of different levels of pre-stroke disability on patients’ profile and outcome after intravenous thrombolysis. This subgroup of patients is usually excluded from most stroke trials, which giv
es an extra value to this study.

Patients, a total of 7250, retrieved from the Safe Implementation of Thrombolysis for Stroke – Eastern Europe, with no pre-stroke disability (modified Rankin Scale [mRS] score 0) patients used as a reference in based on demographics and co-morbidities. Patients with pre-existing disability were divided in 3 groups based on their presentation mRS as 1,2, and ≥3. The analysis showed that thrombolysis in patients with pre-existing stroke-related stroke does not increase the risk of sICH. On the other hand, pre-existing stroke-related disability patients have an increased risk of death at 90 days and lower chance of achieving favorable outcomes.

In short, this study reinforcing that, even though patients who have pre-stroke disability had a higher mortality rate compared to patients with no previous disability, they had no increased risk of sICH.  In other words, these patients should not be routinely excluded from thrombolysis therapy. 
By |February 10th, 2014|Uncategorized|0 Comments

Clinical associations and causes of convexity sub-arachnoid hemorrhage.

Sebina Bulic, MD

Khurram A, Kleinig T, and Leyden J. Clinical Associations and Causes of Convexity Subarachnoid Hemorrhage. Stroke. 2014

This very interesting study is coming from South Australia. The authors retrospectively reviewed electronic discharges for subarachnoid hemorrhage (SAH)-coded cases rom South Australian public hospitals between January 2005-July 2011 and extracted non-traumatic convexity SAH cases. Despite major difficulty in identifying etiology of SAH due to incomplete work up and retrospective nature of data analysis, this work managed to highlight incidence and etiology of this clinically very important entity.

cSAH represents 30-50% of non aneurysmal SAH or 6% of all SAH. As expected (beware that this number is just going to increase as population gets older), leading cause of cSAH is cerebral amyloid antipathy (CAA) with 39%. This number could potentially be higher because patients that were sub-optimally investigated (20%) were mostly over 65 year old, population at risk for CAA. Clinical presentation and patient age for CAA was very different from  the second cause of cSAH;RCVS that occurred in 17% cases, mostly in patients less than 60. Followed cerebral venous sinus thrombosis (CVST) 10%, severe vascular stenosis, 10% PRES 5% and cryptogenic 19% (this was under-investigated group).
Clinical presentation of cSAH for CAA occurred mostly in patients older than 65, symptoms were milder, commonly mistaken for TIA, and was mismanaged with antiplatelets, I take it as “warning for IPH”, but that is a whole another story.
This work raises awareness of this clinically very important entity. One has to look for it, because it can easily be overlooked and consequences can be significant.
My take on cSAH is; in the case of CAA if symptoms are milder, gives me a golden opportunity for aggressive risk factor modification for IPH prevention. In the case of more severe symptoms, as well as in management of other entities, my patient would need close monitoring and aggressive medical management. In either case, I cannot afford to miss it.
By |February 7th, 2014|Uncategorized|0 Comments

A pill for prevention: Counseling prior to OCP use

Peter Hannon, MD

Ryan KA, Cole JW, Saslow K, Mitchell BD, McArdle PF, Sparks MJ, et al. Prevention Opportunities for Oral Contraceptive–Associated Ischemic Stroke. Stroke. 2014

OCP use has long been known to have an association with increased stroke risk, especially in the setting of concurrent risk factors such as smoking.  Utilizing data from the Stroke-Prevention-in-Young-Women-Study, authors Ryan and colleagues re-investigated these associations, however with an additional focus on whether or not participants recall getting advice from physicians to not take OCPs due to their underlying stroke risk.  Exclusion criteria included being currently or recently pregnant, nursing, or being status-post hysterectomy or tubal ligation. After exclusion criteria, 224 young women ages 15-49 who suffered stoke and 348 matched controls were included in this study, and information was gathered using a standardized face-to-face interview. 

In line with previous studies, the authors found a high correlation with stroke in the setting of OCP use in the presence of one or more additional risk factors (OR=3.12; 95%CI=1.62-6.00), though this association was not found to be statistically significant in participants without additional risk factors.  Current smokers had the highest risk (OR 4.29), followed by those with headaches (OR 3.82). Of 256 women with one or more risk factors (99 cases, 157 controls), only 38% recalled being advised not to start an OCP and 36% recalled being told to stop based on their risk modifier profile. Interestingly, at the time of stroke or interview, 24% of those advised not to start OCPs and 15% of those advised to stop taking them were on oral contraceptives despite that advice. 

This study has some limitations, noted by authors, such as a small sample size and the significant potential of recall bias. However, this study does reaffirm known stroke risks with OCP use in the setting of additional risk-modifiers, and more importantly highlights the role that improved physician communication and counseling could play in helping to prevents OCP-related stroke. Clearly, the more we can do to educate our patients about potential stroke risks, the better.  For a significant portion of participants interviewed in this study at least, it appears that message is not being relayed effectively.
By |February 5th, 2014|Uncategorized|0 Comments

Argatroban preserves learning and memory in a rat stroke model

Matthew Edwardson, MD

Patrick Lyden, Benedict Pereira, Bo Chen, Lifu Zhao, Jessica Lamb, I-farn Lei, et al. Direct Thrombin Inhibitor Argatroban Reduces Stroke Damage in 2 Different Models. Stroke. 2014

A pilot study on acute stroke patients testing the direct thrombin inhibitor Argatroban in combination with IV-TPA led to increased recanalization rates and similar rates of symptomatic ICH compared to historical studies of IV-TPA alone. In addition to synergizing recanalization with IV-TPA, however, Argatroban may have neuroprotective properties. Thrombin injures neurons through protease activated receptors. A direct thrombin inhibitor like Argatroban may therefore benefit patients regardless of recanalization status. Lyden and colleagues sought to test the neuroprotective qualities of Argatroban in a rat model of stroke. 

The authors performed 2 separate experiments. In the first experiment, 64 rats were randomized to Argatroban, thrombin, or saline infusion administered over 2 hrs during MCA occlusion. Behavioral measures of learning and memory were assessed several weeks later. In the second experiment, 272 rats were randomized to 2 separate doses of Argatroban administered at different time delays post-MCA occlusion. The rats treated with Argatroban demonstrated improved learning curves (P < 0.05), spatial memory (P < 0.05), and searching behavior (P = 0.03). Argatroban was beneficial when administered from 0-3 hrs post-MCA occlusion, but not at 4 hrs. Argatroban administered 0-1 hr post-MCA occlusion significantly reduced the histological size of the lesion.

The goals of this study were to demonstrate the neuroprotective effects of Argatroban using more robust behavioral endpoints and to identify an appropriate time window for administration. Both goals were achieved. Certain aspects of the methodology, however, raise questions as to how well these results translate to human subjects. The rats engaged in the behavioral experiment received Argatroban at the time of MCA occlusion. Delivering Argatroban 3 hrs post-MCA occlusion – a time window more realistic in humans – may possibly negate the benefits to learning and memory. One also wonders if 2 hrs of MCA occlusion is sufficient to simulate human stroke. The percentage of stroke patients who spontaneously recanalize by 2 hrs is likely quite low. These caveats aside, the authors clearly show that Argatroban has neuroprotective properties. They raise the possibility of testing other thrombin inhibitors in the future, which would help to validate the proposed mechanism of benefit. An additional avenue of research may be to identify an Argatroban dose that is optimal both for neuroprotection and increasing recanalization rates in combination with IV-TPA.

By |February 4th, 2014|Uncategorized|0 Comments

Venous phase CTA and ‘Spot Sign’ detection

Vivek Rai, MD

Rodriguez-Luna D, Dowlatshahi D, Aviv RI, Molina CA, Silva Y, Dzialowski I, et al. Venous Phase of Computed Tomography Angiography Increases SpotSign Detection, but Intracerebral Hemorrhage Expansion Is Greater inSpot Signs Detected in Arterial Phase. Stroke. 2014.

The ‘Spot Sign’, a tiny, enhancing foci within acute hematoma detected on CT Angiogram, has been shown to be of predictive value for expansion of intracerebral hemorrhage (ICH). The predicting hematoma growth and outcome in intracerebral hemorrhage using contrast bolus CT (PREDICT) study validated the computed tomography angiography (CTA) spot sign for predicting significant ICH expansion in a prospective multicenter study. However, the accuracy of this sign was only modest. The authors hypothesized that variability in CTA acquisition may be one reason.

Aiming to determine the frequency of spot sign and its relationship with ICH expansion, Rodriguez-Luna et al present the results of this post-hoc analysis of CTA source images of the entire PREDICT cohort. The authors report that out of 371 patients, spot sign was present in 29.9% and was more frequently seen in venous phase as compared with arterial phase (39% versus 27.3%, P=0.041). CTA spot sign was also closely associated with total hematoma enlargement and significant hematoma expansion.

In this study, most (77.9%) of the CTA images were obtained in arterial phase, which may have limited the statistical power to analyze the differences between the two phases. Even so, the results support the existing evidence that later phase study may be more sensitive for detection of spot sign. The results may have important implications for ongoing and future clinical trials studying hemostatic therapies for ICH.

The results suggests that multiphase CTA including arterial and venous acquisitions could be optimal in ICH patients and this may help is identifying the patients most likely to expand and, by extension, likely to benefit from early hemostatic therapies. More research is needed to understand whether this will translate into better clinical outcomes but this study definitely lays the groundwork for more studies in future.
By |February 3rd, 2014|Uncategorized|0 Comments