American Heart Association

Yearly Archives: 2015

Shaping the endovascular railroad in severe stroke patients: a positive pooled analysis by the IMS III and MR CLEAN investigators.

The recent influx of positive endovascular trials in acute ischemic stroke (AIS) has forged a change in paradigm that is still evolving. Eight pivotal trials, including IMS III and MR CLEAN, have shaped our current guidelines (published in the October edition of Stroke) and have provided the stroke community with new data for further pooled analyses.

Hereof, based on the data of the most severe (NIHSS ≥20) AIS participants from the IMS III and MR CLEAN trials, the authors aimed to determine whether individuals who underwent endovascular treatment in addition to intravenous (IV) t-PA within 6 hours from symptom onset had improved 90-day outcomes compared to those who received IV t-PA alone. All subjects with severe strokes prior to IV t-PA treatment (IMS III) or randomization (MR CLEAN) who received t-PA within 3 hours of stroke onset were included. The methodological differences between the two trials were many and described in detail in the paper, however the lack of required vascular imaging prior to enrollment and the limited use of stent retrievers (~12% vs. 82%) in IMS III versus MR CLEAN constituted some of the most salient discrepancies. The primary outcome was the modified Rankin Scale (mRS) at 90 days. Secondary outcomes were Barthel Index (BI) and the EQ-5D-3L health-related quality-of-life (EQ-5D-3L). The pre-specified covariates for the adjusted analysis included NIHSS, age, previous stroke, diabetes and atrial fibrillation. A comparison of the proportion of symptomatic intracranial hemorrhage (sICH) and the TICI 2b3 scores between the two groups were also reported.

Among the 342 patients included in the pooled analysis, the endovascular group had overall superior functional outcomes as measured per the 90-day mRS (ordinal regression; adjusted OR 1.78) [Figure], with a 2-fold increase in functional independence (mRS≤2, aOR 1.97), as well as significant improvements in BI (aOR1.80) and EQ-5D-3L (adjusted regression coefficient of 0.10) scores, in comparison to the IV t-PA group. When looking into safety, the proportion of sICH was not significantly different between groups. Finally, TICI 2b3 reperfusion score was reached in 45% for the pooled cohort although no comment regarding differences between treatment groups was made.
                      Figure: Distribution of 90-day outcomes for the pooled cohort.

While limited by methodologic differences between the trials, this pooled analysis of IMS III and MR CLEAN demonstrates that endovascular therapy following IV t-PA within 3 hours from symptom onset improves functional outcome at 90 days in AIS patients presenting with severe neurologic deficits. The findings reinforce the overwhelming therapeutic effect on endovascular therapy in AIS patients observed in the other mechanical thrombectomy trials published following MR CLEAN. Pooled analysis including all recently published stent retriever trials are surely underway and much awaited!  

By |December 2nd, 2015|treatment|0 Comments

Asian patients with paroxysmal AFib have lower stroke risk than those with sustained AFib

Ilana Spokoyny, MD

Takabayashi K, Hamatani Y, Yamashita Y, Takagi D, Unoki T, Ishii M, et al. Incidence of Stroke or Systemic Embolism in Paroxysmal Versus Sustained Atrial Fibrillation: The Fushimi Atrial Fibrillation Registry. Stroke. 2015 

Afib is a major risk factor for stroke, and oral anticoagulation (OAC) has been shown to be the most effective preventative treatment. Since OAC is associated with increased bleeding risk, efforts have been made to stratify risk by identifying patient characteristics which increase the risk of stroke in AFib patients (CHF, Hypertension, Age, Diabetes, etc.). Until recently, paroxysmal and persistent AFib were reported to have the same associated risk of thromboembolic events, and the guidelines recommend OAC treatment for prevention, regardless of the type of AFib. It does seem intuitive that someone in constant AFib for years would have a higher risk of stroke than a patient who had half an hour of AFib after surgery. Several recent studies have shown a lower stroke rate in paroxysmal AFib compared to sustained AFib. There is also limited data in Asian patients, so some equipoise existed which prompted this study. 

Data was obtained from the Fushimi AF Registry, whose only inclusion criteria was the documentation of AF on a 12-lead EKG or Holter monitoring at any time. Paroxysmal AF was defined as lasting under 7 days; persistent AF lasted longer than 7 days was but able to be terminated by medication or electrical cardioversion; permanent AF was refractory to medical or electrical cardioversion. Persistent and permanent AF were combined in this study as SAF (sustained AF), due to difficulty differentiating these in daily clinical practice. Multivariate analyses were performed for the vascular risk factors in both the CHADS2 and CHA2DS2-VASc scores, and also included the variable of “low body weight” (which was shown to correlate with stroke risk in Japanese AF patients).

3304 patients were included, split about evenly between paroxysmal and sustained AF. PAF patients were younger, more often symptomatic (palpitations), and less likely to have a history of stroke, CHF, or CKD. The CHADS2/CHA2DS2-VASc scores were lower in PAF patients, and there was a lower rate of OAC use among PAF patients at any age or CHADS2 score compared to SAF patients. About 10 percent of PAF patients progressed to SAF, and there was a significantly higher rate of stroke/systemic embolism among those who progressed compared to those who did not. PAF patients had lower risk of stroke/systemic embolism overall, and this persisted when the patients were stratified by OAC use and CHADS2 score. On multivariate analysis, PAF was an independent risk factor for a reduced risk of stroke/systemic embolism, while age ≥75 and history of stroke portended increase risk. PAF remained significant even when CHADS2 and CHA2DS2-VASc criteria were added to the model, as well as when age was added as a continuous variable. Low body weight (≤50kg) was indeed an independent risk factor for increased risk of stroke/systemic embolism.

This study did not measure the AFib burden, which may be the key to risk stratification in AFib. The other Asian registry mentioned, J-RHYTHM, did not enroll patients who maintained sinus rhythm for over a year, while this registry did. J-RHYTHM showed more thromboembolism in SAF patients, but this difference disappeared after adjusting for vascular risk factors. Neither registry used long-term monitoring or included AF burden as a variable. In this study, patients with PAF were more likely to receive anti-arrhythmic drugs or catheter ablation, which may have decreased AF burden and stroke risk.

In order for these results to influence the guidelines on treatment of PAF, it would have been important to compare the anticoagulated PAF to non-anticoagulated PAF, as well as to age and risk-matched non-AFib patients. However, since this was a registry, it is difficult to make a comparison between treated and untreated patients as there are other contributing factors which influence the initiation of OAC. This can be seen here, as the incidence rate of stroke/systemic embolism per 100 person-years in OAC-treated patients is higher than in untreated patients (and this difference persists for ischemic stroke).

The discrepancies between PAF and SAF shown in this observational registry study are important and may lend evidence to the idea that AF burden is associated with stroke risk. As monitoring technology advances, we are identifying PAF earlier and more often (and committing patients to OAC sooner), but we also have the capability to quantify the AFib burden. Despite guidelines recommending OAC for PAF, only 39% of patients in this registry were prescribed OAC. So, it would be ethical to perform a study of PAF patients which quantifies AFib burden (via wearable or implanted monitor) and randomizes those with low vascular risk scores and a low AF burden to antiplatelet therapy. This would be very useful in creating safe and evidence-based recommendations on the need for OAC therapy in PAF patients.

When is it safe to surgically intervene on symptomatic carotid stenosis? A meta-analysis of periprocedure risk.

Jay Shah, MD

De Rango P, Brown MM, Chaturvedi S, Howard VJ, Jovin T, Mazya MV, et al. Summary of Evidence on Early Carotid Intervention for Recently Symptomatic Stenosis Based on Meta-Analysis of Current Risks. Stroke. 2015

Carotid surgery is recommended for stroke prevention in patients with symptomatic severe carotid stenosis. However, the appropriate timing of intervention remains ambiguous. Trials assessing carotid endarterectomy (CEA) were conducted in the early 1990’s when medical therapy may have been less optimal compared to current standards. Current guidelines recommend revascularization within 2 weeks of index event. This study reviewed data for periprocedure stroke and death following CEA and carotid artery stenting (CAS) in recently symptomatic carotid stenosis in three stratified timeframes: Timing was stratified into 3 timeframes: 0-48 hours, 0-7 days, and 0-15 days. 

The authors reviewed outcome data on patients undergoing CEA and CAS from 2008 to 2015 within 15 days of index ischemic event. Of note, there were no randomized clinical trials with direct comparison of outcomes according to timing and studies included case series. The pooled risk of stroke and death within 15 days of CEA or CAS were 3.8% and 6.9%, respectively. CEA performed within 7 days, pooled risk was 3.6% and 6.6% in CAS. Risk of CEA and CAS performed within 40 hours was 5.7% and 5.4%, respectively. This risk was higher when the index event was an infarct versus TIA for both interventions at all three time points.

This data suggests very early carotid revascularization (within 48 hours) may be associated with increased periprocedural stroke risks but revascularization within the first week is associated with a more favorable risk. This data also suggests that risk profile is more optimal in patients with TIA rather than infarction. However, this data is not derived from studies that randomized patients to intervention based on timing. Furthermore, patients included in these studies were not randomized to aggressive medical therapy, which perhaps could be an appropriate alternate strategy. The authors pointed out that reporting of indication of urgent revascularization and patient criteria was variable thereby limiting its interpretation. This can introduce a self-fulfilling prophecy where patients who are felt to be ideal candidates for early intervention are selectively chosen. Prospective randomized trials should be conducted to shed light on ideal timing of revascularization in the background of modern medical therapy.

By |November 30th, 2015|treatment|0 Comments

Benefits of the Mobile Stroke Unit: The BEST-MSU Run In Phase

It has been written that 1.9 billion neurons are lost every minute during acute ischemic stroke. The earlier we can intervene, the better, it seems, the outcome would be. However, due to the time necessary for triage, imaging, and evaluation, most patients receive thrombolytics after 2 hours of ictus. In Germany, development of a mobile stroke unit (MSU) has been shown to reduce the median time to tPA delivered. Here, authors describe outcomes of the first MSU developed and initiated in the United States compared to standard management (SM), in a pre-specific, non-randomized run-phase of the BEST-MSU study.

In total, 26 patients were enrolled, with 24 patients enrolled for treatment on the MSU and 2 patients enrolled during the 2 weeks in which patients were treated under SM. On average, 1.5 treatments were given per week on the MSU. Of the 24 MSU patients, 13 patients were tPA eligible of which 12 were treated with tPA. Pertinently, 4 received tPA within 0-60 minutes, 4 within 61-80 minutes, and 4 within 81-270 minutes. The average time from EMS activation by 911 to tPA was 47 minutes while average on scene time from MSU arrival to tPA bolus was 25 minutes, inclusive of laboratory and imaging data obtained on board the MSU.

Observations gleaned from this study are summarized in the full text of the study, but some salient points are that 33% of patients treated with tPA on the MSU were treated within the first hour, with one of the fastest “door to needle times” documented of 25 minutes and a MSU is feasible (although the lack of back up equipment may be an issue) and certainly, enrollment of patients into the study is feasible. In addition, 4 of 24 MSU patients had ICH, and were able to receive early blood pressure management. It is possible that in the future, the MSU could be equipped to deal with not just eraly management of ischemic strokes but also hemorrhagic strokes. Further steps would be possibly the addition of CTA capability to enable routing of patients to comprehensive stroke centers for thrombectomy in the appropriate population, which would further decrease the delay between ictus and treatment.
By |November 27th, 2015|treatment|1 Comment

Effects of blood pressure in acute ischemic stroke

Allison E. Arch, MD
Does anyone know how to optimally manage blood pressure during the first 24 hours after acute ischemic stroke?

Berge, et al., addressed the complex question of blood pressure and acute ischemic stroke in an analysis of patients enrolled in the Third International Stroke Trial (IST-3). The IST-3 was a randomized trial comparing recombinant plasminogen activator (rt-PA) to open control within 6 hours of symptom onset. Berge and colleagues used this population to study the short- and long-term effects of blood pressure and blood pressure lowering treatment in acute stroke. Blood pressure was measured at randomization, at the start of treatment, and at 30 minutes, 1 hour, and 24 hours after the start of treatment. The use of anti-hypertensive medications within the first 24 hours was also recorded. The primary clinical outcomes were early adverse events, early death, and functional outcome at 6 months.

The authors found that high baseline blood pressure and high blood pressure variability during the first 24 hours were associated with increased numbers of adverse events and early deaths. Functional outcome at 6 months was improved in patients who were given anti-hypertensive medications during the first 24 hours, and in those who had a larger decline in blood pressure in the acute post-stroke period. The one negative outcome of a lower blood pressure was recurrent ischemic stroke: a large decline in systolic blood pressure during the first 24 hours showed a non-significant higher risk of early recurrent ischemic stroke. However, all other outcomes, including clinical outcome at 6 month, were improved if blood pressure was lowered acutely (although not all were statistically significant).

This was not a randomized controlled trial and instead used a patient population that was enrolled in an entirely different study. It is therefore subject to the bias and confounding factors that can plague observational studies. However, the results are nonetheless intriguing and offer a different perspective on acute blood pressure management following ischemic stroke. Is it time to put an end to “permissive hypertension” in the early post-stroke period?  

By |November 25th, 2015|treatment|0 Comments

Magnesium Fails as a Neuroprotectant: Now Even Earlier Than Before!

The search for an effective neuroprotective agent has not been a fruitful one. We had high hopes for magnesium, but it failed both as a neuroprotectant after aneurysmal SAH (MASH-I, IMASH, MASH-II, MASH trials), and in the prehospital setting as a neuroprotectant when administered early after suspected ischemic stroke (FAST-MAG). The authors of this meta-analysis hypothesized that earlier treatment with magnesium after SAH may in fact be effective, but that prior trials administered it too late and were underpowered to show effect in the small numbers of patients who were treated earlier. 

Five trials comprising 1981 patients were included, and the patients were binned according to how long after symptom onset they received magnesium (<6 hours, 6-12 hours, 12-24 hours, >24 hours). FAST-MAG included 5 patients with SAH (as the criteria were clinical stroke symptoms), so these 5 patients were incorporated into this meta-analysis. The primary endpoint was poor clinical outcome (mrs 4-5) or death at 3-6 months, with a secondary endpoint of delayed cerebral ischemia (which was determined differently by each trial).

Unfortunately, no benefit was seen with early magnesium treatment after SAH with respect to either functional outcome or delayed cerebral ischemia. A possible criticism is that only 83 patients (of a total 1981) were in the <6 hour group. However, if there were a strong effect in this early group, we would expect to at least detect a trend in improved outcome, which there was not. So long, magnesium; on to the next!

By |November 24th, 2015|treatment|1 Comment

Atrial fibrillation – related strokes are associated with substantial long-term morbidity and mortality

Neal S. Parikh, MD

Hayden DT, Hannon N, Callaly E, Chroíiniín DN, Horgan G, Kyne L, et al. Rates and Determinants of 5-Year Outcomes After Atrial Fibrillation–Related Stroke: A Population Study. Stroke. 2015

In this issue of Stroke, Dr. Hayden and colleagues report on 5-year outcomes and secondary prevention utilization rates after atrial fibrillation – related strokes (AF-strokes) from North Dublin city.

AF-strokes are associated with greater severity and poor outcomes; however, the authors, in light of the increasing prevalence of atrial fibrillation (AF), seek to report population-level long-term outcomes of AF-strokes.

The data are derived from the Northern Dublin Population Stroke study, a prospective cohort of TIA and stroke patients established in 2006. Only stroke patients with a diagnosis of AF prior to the index stroke or an AF diagnosis within 3 months of the stroke were included in this study. Their outcomes were: 5-year survival, stroke recurrence, disability (by mRS), and nursing home residence in addition to prescription rates for secondary prevention anti-thrombotic medications.

They identified 177 patients with AF-stroke with a mean age of 76.5 and median CHA2DS2-VASc score of 6. Survival data was complete for nearly all patients. For survivors, outcome data was available for at least 90% for each outcome.

Key findings at 5 years:
· Only 39.2% of ischemic AF-stroke survivors were alive. Statin and warfarin prescription were protective.
· Only 14% were alive and independent.
· 21.5% had recurrent stroke.
· 25.9% had required nursing home residence at some time.
· In those surviving at least 28 days, 54.5% were prescribed an anti-platelet alone and 36% received an oral anticoagulant medication.
· Statins were prescribed in 74.1% of patients.

The findings of this study vitally underscore the morbidity and mortality associated with AF and AF-stroke. Additionally, this study confirms the widespread under-utilization of effective secondary prevention measures in this high risk population. The data are increasingly compelling; AF-related stroke prevention is crucial. The time is right to begin uniformly and systematically applying existing therapies.

Can the air we breathe be a risk factor for stroke?

Jay Shah, MD

Scheers H, Jacobs L, Casas L, Nemery B, and Nawrot TS. Long-Term Exposure to Particulate Matter Air Pollution Is a Risk Factor for Stroke: Meta-Analytical Evidence. Stroke. 2015 

Particle pollution, also known as particulate matter (PM), is a mixture of solid particles and liquid droplets found in the air. Inhalable coarse particles (diameter between 2.5-10 micrometers) and fine particles (diameter less than 2.5 micrometers) pose the greatest threat to human health. Potential mechanism includes inducing chronic systemic oxidative stress and inflammation which in-turn may promote atherosclerosis at the vasculature level. Thus, it has been postulated that PM exposure is an under recognized stroke risk factor. Recent meta-analyses characterized the short-term effects of PM on stroke hospitalization and mortality. However, the long-term effects of PM are relatively less known. Therefore, the authors conducted a meta-analysis to quantify the association between stroke risk and long-term PM exposure. The authors reviewed the literature for original studies assessing the association of long-term exposure of PM10 and PM2.5 to stroke events or stroke mortality. 

In total, 20 publications were included with combined >10 million persons and >200,000 stroke events. The studies were fairly evenly balanced between North America, Europe, and Eastern Asia. Hazard ratio with 95% CI was 1.061 for stroke event secondary long-term PM10 exposure and concluded that there exists a positive association between risk of stroke and PM exposure with 2-21% excess risk. Expectedly, there was significant geographical variation.

There are several limitations to this study. Three Chinese and two Japanese studies were excluded from sensitivity analysis due to dissimilarity. This certainly can be confounding as the Chinese studies had demonstrated significantly high PM levels. Another potential confounding variable, as pointed out by the authors, is the possible inaccuracy in determining exposure levels. Authors of the individual trials used data from central monitor stations and made efforts to obtain data from stations in closest proximity to the individual. However, this strategy can be problematic and does not account for important variables such as occupation, location of employment, and time spent outdoors. Several studies also did not capture smoking status and socioeconomic status within their data.

Therefore, data from this meta-analysis should be interpreted with caution. However, this is not to suggest that PM concentrations are not a public health concern. Clearly, there are enough reasons to reduce air pollution ranging from practical purposes (i.e. to improve visibility) to ecological reasons (i.e. to hasten the process of global warming). Furthermore, there is more robust evidence of harmful effects of particle pollution to pulmonary disease. Therefore, policy to decrease particle pollution will clearly be beneficial and may also decrease cardiovascular disease as this meta-analysis suggest.

Risk Factors Associated with Presence of Unruptured Intracranial Aneurysms in a Large, Cross-sectional Imaging Study

The detection of unruptured intracranial aneurysms (UIAs) has increased as the use of noninvasive cerebral angiography has becomes more widespread. It has been posited that UIAs in different locations may have different pathophysiological mechanisms and consequently, different risk factor profiles. Kang and Kim et al. conducted a cross-sectional study of 18,954 consecutively enrolled subjects who had magnetic resonance angiography (MRA) of the cerebral vessels as part of a routine health examination over an approximately ten year period.

MRA was performed with 1.5-T and 3-T scanners. Subjects with aneurysms less than 3 mm or having fusiform, mycotic, traumatic, or treated aneurysms were excluded. The location of aneurysms was classified as distal internal carotid artery (dICA), middle cerebral artery (MCA), MCA bifurcation, anterior cerebral artery (ACA), anterior communicating artery (Acom), posterior communicating artery (Pcom), or posterior circulation artery (including vertebral, basilar, posterior cerebral, and anterior and posterior inferior cerebellar arteries). Overall age, sex, and vascular risk factors were compared for those with and without an UIA and separately for each aneurysm location subgroup. UIA distribution in the study population was also compared with a group of 12,702 subjects who had MRA as part of an outpatient evaluation for headache at the same institution.

Compared to patients having an MRA for headache, those in the health screening group tended to be younger (57.2 ± 8.5 vs 63.1 ± 12.5) and less frequently women (39% vs 64.4%). The prevalence of UIA was higher in the headache evaluation group as compared to the health screening group (2.38% vs 1.94% p=0.007). The prevalence of UIA was similar in men and women in the two groups and similarly increased in both groups in women over age 50 years.

Patients in the health screening group with an UIA tended to be older (57.2 ± 8.5 vs 55.8 ±9.0 p=0.005) and more frequently women (50.7% vs 38.8% p<0.001) than those without aneurysms. Interestingly, coronary artery disease was less prevalent in the aneurysm group (10.1% vs 24.2% p<0.001). In multivariable analysis, advanced age, female sex, hypertension, smoking and CAD each had independent associations with UIAs.

In order of descending frequency, UIAs were most commonly found in the distal ICA (45.2%), followed by the MCA bifurcation (13.4%) and the Acom (13.4%). Pcom aneurysms were observed in 10.4% of patients, whereas MCA and ACA aneurysms were found in 6.5% and 5.7% of subjects, respectively. Female sex, hypertension, and CAD were independently associated (CAD was negatively associated) with dICA, MCA bifurcation and Pcom aneurysms, whereas MCA aneurysms were associated with advanced age, smoking and negatively associated with CAD. Posterior circulation aneurysms were only associated with hypertension.

The findings of this study are consistent with previous work finding associations between vascular risk factors and the presence of UIAs, particularly with respect to age, female sex and hypertension. The analysis of the relationship between risk factors and UIAs by location supports the possibility of varying pathophysiologic mechanisms for aneurysm formation depending on site. The negative association with CAD is particularly intriguing; it is somewhat counter intuitive to assume that one form of vascular degeneration could be protective against another. Additional research aimed at understanding the mechanical and molecular basis of IA formation would be helpful to further elucidate the issue.

The study does have limitations. The possibility for selection bias should be acknowledged. It is also possible that the presumed race-ethnic homogeneity of the subjects (recruited from sites in Korea) limits the generalizability. Additional studies in other sites using a similar protocol will be needed to validate these findings.

A question still unanswered: The efficacy of nitric oxide donors in hyperacute ischemic stroke

The initiation of early neuroprotection for acute ischemic stroke remains a tantalizing goal for vascular neurologists given the limiting window for IV tPA and the time delay to endovascular therapy. Preclinical studies showed that nitric oxide donors might improve outcomes after stroke by reducing infarct size and increasing cerebral blood flow. In the ENOS study, transdermal nitroglycerin (GTN) given to patients with stroke within 48 hours, GTN was found to be safe but did not lead to improved outcomes. In a subset of these patients, however, in a group of 273 patients where GTN was given within 6 hours from randomization, improved outcomes on modified Rankin scale was seen.

Here, the authors performed a more thorough analysis of that specific subset of patients who received GTN early. Unlike the patients who were randomized later than 6 hours from ictus, this group of patients was more likely to have an ICH, more severe stroke, a cardioembolic cause for ischemic stroke, and to receive thrombolysis. In addition, the group randomized to GTN had less severe strokes and lower rates of cortical stroke syndromes. Blood pressure was lowered an average of 9.4/3.3 mmHg in the treatment group. There was a statistically significant shift to a lower/better mRS at 90 days in the group randomized to GTN, with a number need to treat (NNT) of 5.2 to shift mRS. In addition, there were improvements in the 90-day measures of Barthel Index, quality of life, cognition, and mood.

As the authors point out, however, positive subgroup analyses within large trials are often spurious and due to chance. Perhaps more pertinently, significant confounders exist in this subgroup analysis, where improved outcomes could potentially be explained by the lower stroke severity and lower rates of cortical stroke syndromes in the treatment group. The results here are promising, but should be interpreted with caution. The RIGHT-2 trial will further assess safety and efficacy of GTN delivered in the hyper-acute setting by paramedics in a larger population, and may give us some more answers.

By |November 18th, 2015|treatment|0 Comments