American Heart Association

Monthly Archives: November 2015

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

Dialysis-requiring Acute Kidney Injury Portends Poor Prognosis in Patients with Stroke

Alexander E. Merkler, MD 

Nadkarni GN, Patel AA, Konstantinidis I, Mahajan A, Agarwal SK, Sunil Kamat S, et al. Dialysis Requiring Acute Kidney Injury in Acute Cerebrovascular Accident Hospitalizations. Stroke. 2015

Acute kidney injury is not an infrequent complication in patients with stroke. Patients with stroke frequently have risk factors for developing acute kidney injury such as: chronic kidney disease, dehydration, infections, use of contrast dye and hypertonic saline. In the current study by Drs. Nadkarni and Patel et al, the authors evaluate the impact of dialysis-requiring acute kidney injury in patients with stroke. 

The authors utilize the Nationwide Inpatient Sample and Healthcare Cost and Utilization Project to identify all patients with stroke from 2002-2011 using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes. The authors dichotomized patients with stroke into two groups: those who developed dialysis-requiring acute kidney injury (AKI-D), and those who did not (no AKI-D). Mortality and outcomes (as measured by discharge disposition) were compared between the two groups.

Over 4 million patients with stroke were identified. Factors associated with the development of AKI-D were similar for both ischemic stroke and ICH and included: younger age, male sex, African-American race, history of chronic kidney disease, higher comborbidity score, and sepsis during stroke hospitalization. Patients with stroke and AKI-D had a higher risk of mortality, worse discharge disposition, longer hospital-stay, and higher hospital cost. Similar trends were seen for patients with ischemic stroke and ICH. Interestingly there was a two-fold increase in the rate of AKI-D in patients with stroke over the 9-year study period.

Significant limitations include 1) reliance on ICD-9-CM diagnosis codes – therefore the study lacked clinical information such as size and etiology of stroke and 2) lack of information regarding temporal relation between stroke and the development of AKI-D (which came first).

Overall, AKI-D is not an uncommon complication in patients with stroke. AKI-D is associated with higher mortality and worse discharge outcomes in patients with stroke. Further research is needed to better stratify patients with stroke who are at risk for developing AKI-D and to develop methods to prevent this complication.

By |November 17th, 2015|clinical|0 Comments

The Relation of Age to Stroke and Death in Anticoagulated Patients with Nonvalvular Atrial Fibrillation

Allison E. Arch, MD 

Senoo K and Lip GYH. Relationship of Age With Stroke and Death in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: AMADEUS Trial. Stroke. 2015 

Authors Senoo and Lip investigated the relationship between bleeding risk and age in patients taking warfarin for nonvalvular atrial fibrillation. They used the warfarin arm of the AMADEUS trial to conduct a post-hoc analysis. The patient population consisted of patients with atrial fibrillation taking warfarin, and they were divided into tertiles based on age: age <67, age 67-74, and age ≥ 75. The principal safety outcome was any clinically relevant bleeding, and the primary clinical outcome was the composite of cardiovascular death and stroke/systemic embolism. 

Analysis was conducted on 722 patients in the youngest tertile, 747 patients in the middle tertile, and 824 patients in the oldest tertile. The rates of cardiovascular death and stroke/systemic embolism were highest in the oldest age category. The relative risk of any clinically relevant bleeding did not differ significantly across age categories, although the oldest strata did have a higher risk of major bleeding. Additionally, the average amount of time spent in the therapeutic range of warfarin was inversely related to bleeding risk, cardiovascular death and stroke risk in this population.

The authors concluded that elderly patients with atrial fibrillation have a high risk of cardiovascular death and stroke/systemic embolism. These highest risk patients may derive the greatest net clinical benefit from being on warfarin, while their bleeding risk remains similar to other age categories. However, the authors also pointed out that this was a post-hoc analysis, and the results should be interpreted as hypothesis-generating. Nevertheless, this analysis confirms prior studies showing that the net benefit of oral anticoagulation increases as patients get older.

For future research, it will be interesting to see similar analyses using the new oral anticoagulants.

By |November 16th, 2015|prevention|0 Comments