American Heart Association

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Limited Meta-analysis Suggests Patients with Asymptomatic Carotid Occlusion are at Low Risk of Ipsilateral Stroke, High Risk of Non-stroke Mortality

Danny R. Rose, Jr., MD

Hackam DG. Prognosis of Asymptomatic Carotid Artery Occlusion: Systematic Review and Meta-Analysis. Stroke. 2016

Although carotid artery occlusion is estimated to account for 10-15% of all ischemic strokes and transient ischemic attacks, there is little consensus regarding the long-term prognosis of asymptomatic carotid artery occlusion (ACAO), which is most often found incidentally during workup for cerebrovascular disease. Hackam sought to shed light on this issue by conducting a systematic review of studies that enrolled patients with ACAO that collected follow-up information on the occurrence of ipsilateral ischemic stroke as an outcome measure. 


A total of 13 studies were included in the meta-analysis. The studies enrolled 4406 patients, 718 of whom had ACAO (16%). The median age of patients with ACAO was 67 and 23% were female.  All but two studies used ultrasound to define ACAO diagnostically; however the use of angiography was high overall (66% of subjects). Median follow-up was 2.80 years, with an annual ipsilateral stroke rate of 1.3% (95% CI 0.4-2.1%). Two-year and 5-year rates of stroke were 2.5% and 6.3%, respectively. There was substantial heterogeneity in the base estimate (I2=53%). Annual total stroke was 2.0% (95% CI 0.9-3%; I2=40%). 

Eleven studies reported on ipsilateral TIA, with an annual rate of 1% (95% CI 0.3-1.8% I2=40%) and an annual total TIA rate of 3.0% (95% CI 1.9-4.1% I2=0).  Seven studies reported mortality, with an annual rate of death of 7.7% with marked heterogeneity (95% CI 4.3-11.2% I2=83%). Six studies reported stroke-related death, with an annual rate of 1.1% (95% CI 0.07-2.1% I2=63%). Cardiac death was more frequent at 3.3% per year (95% CI 1.2-5.4% I2=83%). In the prescribed subgroup analysis, studies published on or after the year 2000 had a statistically significantly lower aggregate ipsilateral stroke rate than studies published before 2000 (0.9% to 1.5%, p=0.003). Adjusting for publication bias suggested a revised ipsilateral stroke rate of 0.3% per year (95% CI -0.4 to 1.1%).

Although the study was limited by significant heterogeneity, it suggests that the risk from ACAO is low. With subgroup analysis of studies published after the advent of contemporary medical management of vascular disease and trim-and-fill analysis suggesting a lack of studies published to the left of the mean, the rate is likely lower than the 1.3% per year grand mean that was reported. However, the annual risk of death was quite high (7.7%), likely attributable to ACAO being a surrogate marker of systemic atherosclerosis, possibly carrying a higher risk of cardiac death. 

Further study of this population is warranted. Potential avenues for future study would include a prospective cohort of patients with medically managed carotid stenosis and occlusion with matched controls, following a variety of vascular outcomes. Perfusion or more in-depth angiographic imaging to identify a potential subset of patients at higher risk of stroke could also be of use.  

Adherence to DASH Diet Associated With Lower Stroke Risk

Neal S. Parikh, MD

The Dietary Approaches to Stop Hypertension (DASH) diet is known reduce blood pressure in hypertensive and normotensive individuals. The authors assessed whether DASH diet adherence is associated with incident stroke.
The authors performed their analyses in two large, prospective Swedish cohorts of middle-aged to older men and women free of incident stroke.  The participants answered a 350-item questionnaire on diet and vascular risk factors in the late 1990s and were followed by linkage with the National Patient Register and the Cause of Death Register.
The exposure variable was a modified DASH diet score, assessed based on a validated food-frequency questionnaire. Covariates included standard demographics and vascular risk factors (hypertension, hyperlipidemia, diabetes, atrial fibrillation, smoking history, aspirin use, family history of myocardial infarction at early age, and body mass index).  Total caloric intake was included as a covariate, but dietary sodium was not. The outcome measure was incident stroke (ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage).  Participants were classified into quartiles based on their DASH diet score. Multivariate analyses were performed to test the association between DASH adherence and incident stroke.
Participants with high adherence to the DASH diet were fairly similar to participants with low adherence. The mean age was 60 years. Approximately 50% were overweight. Approximately 20% had hypertension, 10% had hyperlipidemia, and 6% had diabetes.  Over 882,727 person-years of follow-up, there were 3,896 ischemic strokes, 560 intracerebral hemorrhages, and 176 subarachnoid hemorrhages. High adherence to the DASH diet was associated with a lower risk of ischemic stroke and a trend towards lower risk of intracerebral hemorrhage. Participants in the highest quartile had a 14% lower risk of ischemic stroke than those in the lowest quartile.
This study adds to two prior studies that suggested that adherence to a DASH diet is associated with lower risk of stroke. The two prior studies and this study are likely underpowered for intracerebral hemorrhage and subarachnoid hemorrhage. The authors note that a similar association between the Mediterranean diet and stroke risk has been identified. Features shared by the DASH and Mediterranean diets may be responsible for lower stroke risk.  
The main limitations of this study are the observational design and the outdated cohort, which likely did not benefit from contemporary vascular risk factor management. However, in the context of prior studies, this study provides compelling evidence in support of a healthy diet for the prevention of stroke.
By |April 11th, 2016|prevention|1 Comment

Risk Analysis of Unruptured Intracranial Aneurysms: Prospective 10-Year Cohort Study

Peggy Nguyen, MD

Murayama Y, Takao H, Ishibashi T, Saguchi T, Ebara M, Yuki I, et al. Risk Analysis of Unruptured Intracranial Aneurysms: Prospective 10-Year Cohort Study. Stroke. 2016

The optimal management of unruptured aneurysms, whether by clipping or coiling, has never been defined in a randomized study.  Inferences can be made from what we know about the natural course of unruptured aneurysms, which have been previously studied in the ISUIA and UCAS. In this study, the authors add to the literature with a 10-year follow up of unruptured aneurysms to define the risk factors of rupture and looked at outcomes of rupture.

A total of 2665 patients with 3434 unruptured intracranial aneurysms (UIAs) were referred to

the institution, of which 1556 patients with 1960 aneurysms were conservatively observed and 937 aneurysms were repaired (793 by coiling, 144 by surgical clipping). In the

conservatively managed group:

  • The mean follow up duration was 7388 aneurysm-years.
  • 56 aneurysms ruptured with an overall annual incidence of subarachnoid hemorrhage of 0.76% with mean duration to rupture from initial consultation being 547 days.
  • Independent risk factors for aneurysm rupture were: (1) aneurysm size, (2) specific location, (3) presence of a daughter sac, and (4) history of SAH.
  • The annual rupture rate of aneurysms < 5 mm was 0.33%, > 5 mm was 3.1%, 7-9 mm was 2.9%, 10-24 mm was 10.2%, and 25+ mm was 33.1%; a cut-off point of 5 mm was associated with a higher risk of rupture, smaller than the 7 mm size which was previously demonstrated.
  • Vertebro-basilar aneurysms demonstrated a significantly higher risk of rupture compared to other locations.
  • Of ruptured aneurysms, only 46.4% patients returned to normal life; 28.6% resulted in an mRS of 3-5, 26.8% resulted in death. 

Given the devastating effects of aneurysm rupture, as confirmed in this study, would it be prudent to coil/clip these aneurysms, even when incidental and unruptured? Unfortunately, this study does not necessarily answer the question of what the best management would be for unruptured aneurysms; it does, however, confirm the size relationship of aneurysm and rupture, at a smaller size than previously reported, which prompts additional questions on what, exactly, is the size of aneurysm which we should be concerned about.

By |March 14th, 2016|prevention|0 Comments

Taiwanese observational cohort suggests better safety and efficacy profile for dabigatran in Asian patients with non-valvular atrial fibrillation

Danny R. Rose, Jr., MD

Chan YH, Yen KC, See LC, Chang SH, Wu LS, Lee HF, et al. Cardiovascular, Bleeding, and Mortality Risks of Dabigatran in Asians With Nonvalvular Atrial Fibrillation. Stroke. 2016

Dabigatran, a competitive direct thrombin inhibitor used for prevention of stroke and systemic embolism in non-valvular atrial fibrillation (AF) patients, was approved by the FDA in 2010 based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Post-marketing studies have raised concerns regarding risk of severe bleeding, particularly in the elderly population and in those with renal impairment. Additionally, as the majority of published studies regarding dabigatran use enrolled patients from the USA and Europe, limited data exists regarding the thromboembolic and bleeding risks in patients of Asian ethnicity. Chan et al. utilized the Taiwan National Health Insurance Research Database (NHIRD) to investigate the efficacy and safety of dabigatran compared to warfarin in AF patients through an observational cohort study.


The authors selected 9,940 dabigatran users and 9,913 warfarin users who were prescribed their respective treatments after June 1, 2012. Propensity score weighting was used to balance covariates across the two study groups, as the dabigatran group was older, had a higher proportion of hypertension, diabetes mellitus, stroke or TIA history, a lower proportion of prescribing anti-platelet agents, and higher CHA2DS2-VASC and HAS-BLED scores compared with the warfarin group. The median follow-up period was 0.67 years for dabigatran users and 0.73 years for warfarin users and was defined as the time from the index date until the first occurrence of any of the six study outcomes or the end of the study period (December 31, 2013).

The six outcomes studied were ischemic stroke, acute myocardial infarction, intracranial hemorrhage (identified using atraumatic hemorrhage discharge diagnosis codes), major gastrointestinal bleeding (requiring transfusion), all major bleeding events, and all-cause mortality. Although some patients accumulated multiple outcomes during the duration of the study, only the initial outcome was counted as patient management was changed due to the outcome in question.

Compared with the warfarin group, the dabigatran group was associated with a significantly reduced risk of ischemic stroke, intracranial hemorrhage, all hospitalized major bleeding events, and all-cause mortality (all p<0.0001) and a marginal decreased risk of acute myocardial infarction (HR 0.67, p=0.0803). There was no difference in major gastrointestinal bleeding between the two study groups (HR 0.99, p=0.9658).

This study highlights potential differences in the risk profile of patients of Asian ethnicity with respect to ischemic and hemorrhagic events while therapeutically anticoagulated. The results stand in contrast to the results of the RE-LY trial, which showed a significant reduction in the risk of both ischemic and hemorrhagic stroke and increased gastrointestinal bleeding risk at the 150 mg dose, which was the dose that was approved by the FDA for use in the USA. Interestingly, a majority (88%) of the patients in this cohort were prescribed the 110 mg dose, which showed comparable stroke and gastrointestinal bleeding risk to warfarin with a significant reduction in the risk of intracranial hemorrhage. The authors speculated this prescribing discrepancy may be due to a combination of a lower average BMI in Asian patients, higher risk of warfarin-related intracranial hemorrhage in Asian patients leading to physician discretion with dosing, and increased proportion of patients that are elderly with chronic kidney or liver disease due to restrictions on dabigatran prescribing under the Taiwanese national health system.

The study’s findings were compatible with subgroup analysis from RE-LY looking at the Asian participants that comprised 15.3% of that study’s population. Given that Asian patients tended to have more complications with warfarin and better efficacy and fewer complications with dabigatran, it may be reasonable to reconsider using dabigatran as a first-line therapy in this specific population. This decision making should also be made with the understanding of the limitations of observational cohort data as compared to prospective randomized data. Whether these findings would extend to a larger prospective randomized trial or with other novel oral anticoagulants with different mechanisms of action in the Asian population remains to be seen and represents an interesting potential avenue for future study.

By |February 22nd, 2016|prevention|0 Comments

Low ankle-brachial index and stroke recurrence, vascular death

 
Citing a need for improved recurrent stroke risk prediction, the authors of this systematic review and meta-analysis explore the association between low ankle-brachial index (ABI) and recurrent stroke risk.

The meta-analysis included only prospective trials that collected at least 12 months of follow-up data regarding recurrent stroke, vascular events and/or vascular death. In pooling the data, their primary endpoints were recurrent stroke and combined vascular events (recurrent vascular event and vascular death). Ischemic stroke and TIA were variably included as outcomes. 


Ultimately, 11 studies with 5,374 participants were included in the meta-analysis. Pooled analysis of relative risks of recurrent stroke and combined vascular endpoint in patients with low ABI were 1.55 (95% CI, 1.28-1.88) and 1.91 (95% CI, 1.65-2.22), respectively.

There was heterogeneity among the studies in terms of covariates entered into individual multivariate models; this limits precise estimation of the association between ABI and recurrent stroke risk. Publication bias was also present, which also limits our ability to draw confident conclusions.

The authors conclude that there is a robust association between low ABI and recurrent stroke and vascular outcome risk.

The bottom line
Even if ABI indeed predicts recurrent stroke independent of traditional vascular risk factors, existing data do not allow us to conclude that ABI measurement provides recurrent stroke predictive value in excess of that provided by advanced standard-of-care stroke diagnostics. Ideal recurrent stroke risk prediction models will incorporate data collected for standard stroke evaluation and will therefore be parsimonious and cost-effective.
By |February 2nd, 2016|prevention|0 Comments

Only 27% of death after stroke can be attributed to modifiable risk factors


In this issue of Stroke, Marileen Portegies and colleagues seek to determine the theoretical impact of pre-morbid cardiovascular risk factors on mortality after stroke. 

The study population was the well-described prospective, population-based Rotterdam cohort. Each patient with incident stroke was age and sex matched with four stroke-free participants. Poisson regression was used to determine age and sex adjusted mortality rate ratios. Interactive Risk Attributable Program, a method to calculate population attributable risks, was used to determine the population attributable risk for each vascular risk factor and for all risk factors (those independently contributing to mortality) combined. Interaction term analysis evaluated for effect modification by stroke.


For this study, they included 1,237 stroke patients and 4,928 non-stroke participants. The mean age was 80 years, and 60.4% were female. Cardiovascular risk factors were measured for a mean of 3.7 (±3.2) years before stroke.

Mortality rates after stroke were highest in the first 30 days and remained double that of the non-stroke group 1 year onward from inclusion. The increased mortality after stroke was largely due to cardiovascular death.

The population attributable risks for the most important modifiable risk factors were as follows:
  • Smoking: 0.13 (in other words, 13% of post-stroke mortality can be attributed to pre-stroke smoking status)
  • Diabetes: 0.06
  • Atrial fibrillation: 0.06
  • Hypertension: 0.06

The cumulative proportion of mortality of included vascular risk factors was 0.27 (95% confidence interval, 0.14-0.45). This means that 27% of post-stroke mortality can be attributed to pre-existing modifiable risk factors. This was only 8% higher than the attributable risk in patients without stroke.

The authors acknowledge that population attributable risks of certain risk factors were driven by the increased prevalence of these risk factors in patients with stroke.

The authors keenly point out that the main conclusion here is that 73% of post-stroke mortality is not explained by premorbid cardiovascular risk factors. Understanding the “other 73%” may yield stroke-specific actionable targets to reduce post-stroke mortality.
By |January 25th, 2016|prevention|1 Comment

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

Is Age the Real Culprit? Worse Outcomes in Older Patients Undergoing Carotid Artery Stenting

Ilana Spokoyny, MD

Voeks JH, Howard G, Roubin G, Farb R, Heck D, Logan W, et al. Mediators of the Age Effect in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). Stroke. 2015 

The CREST trial demonstrated no significant difference between the efficancy of carotid stenting (CAS) versus carotid endarterectomy (CEA) overall, but when the effects of age were studied, older patients had better outcomes with CEA and younger patients with CAS. The biggest factor contributing to this difference in outcomes was that older patients had a higher risk of stroke or death with carotid stenting (CAS), both periprocedurally and during follow up, but the exact pathway for this is not well understood. Is it age itself, or some other factor that increases with age, which accounts for this increased risk? The overall goal, as with any treatment, is to select a group of patients who will benefit most with the least amount of risk. In order to do this, it is crucial to identify the direct contributors. In the case of older patients with worse outcomes after CAS, age is not thought to be a direct contributor, but an umbrella category which happens to include many patients with a certain vascular characteristic predisposing them to a worse outcome.

The authors undertook an analysis of possible factors which included those related to the patient (HTN, diabetes, hyperlipidemia) and those related to the arteries themselves (plaque length, eccentric plaque, ulcerated plaque, percent stenosis, peak systolic velocity, and location), among 1123 patients treated with CAS from the CREST study. The authors identified for each factor: the association it had with age, the association it had with periprocedural stroke or death risk, and for those factors contributing, the authors determined by how much the risk of stroke or death decreased when adjusted for that factor. The idea was that if certain factors mediated the effect significantly, then a select population of older patients (without these offending factors) could still undergo CAS and expect to do well.

Plaque length and tortuosity increased with age. Plaque length, eccentric plaque, ulcerated plaque, and sequential plaque were associated with risk of periprocedural stroke or death. Symptomatic status of the stenotic vessel was not an effect modifier. Unfortunately, only plaque length met all the criteria: it increased with age, was associated with increased risk, and significantly mediated the effect of age. However, adjusting for plaque length decreased the hazard ratio from 1.72 to 1.66 (per 10-years in age), a decrease in the risk by only 8%. Based on this, we are unable to select older patients with short plaques safely for CAS.

This analysis was well done, but limited by the small number of event rates. As baseline MRIs were not done in CREST, baseline white matter disease could not be quantified and included, though this would be an interesting factor to consider, as it is expected to increase with age and potentially worsen outcomes. A critical factor to consider would be the composition of the plaques, as mentioned by the authors. If the plaque hardens with age, this may make the plaques less amenable to CAS, increasing the periprocedural risk. Using new techniques to visualize and quantify the plaque composition, we would be able to determine whether this plays a role, and perform a similar analysis to the one presented here.

By |November 3rd, 2015|prevention|0 Comments

Does intracranial stenting work for any subgroups of patients?

Allison E. Arch, MD

Lutsep HL, Lynn MJ, Cotsonis GA, Derdeyn CP, Tanya N. Turan TN, Fiorella D, et al. Does the Stenting Versus Aggressive Medical Therapy Trial Support Stenting for Subgroups With Intracranial Stenosis? Stroke. 2015

The SAMMPRIS trial showed us that aggressive medical management was superior to stenting plus aggressive medical management to prevent recurrent strokes in patients with symptomatic intracranial stenosis. However, are there any groups of patients who may benefit from intracranial stenting?

A new subgroup analysis by Lutsep, et al, tried to answer this question. The authors utilized SAMMPRIS data to perform 17 subgroup analyses, including 7 subgroups that were prespecified in the SAMMPRIS trial. Categories for analysis included baseline demographics, stroke risk factors, location of stenosis, percent stenosis, qualifying event hypoperfusion symptoms, and days to enrollment in the SAMMPRIS trial. In nearly all the subgroups, the 2 year stroke rate was higher in the intervention group (although not statistically significant). None of the subgroups showed a benefit of stenting.

The data continues to support aggressive medical management over stenting for symptomatic intracranial stenosis. Read the full article for more information!

By |November 2nd, 2015|prevention|0 Comments

A point-of-care test can accurately rule out low concentrations of rivaroxaban

Jay Shah, MD 

Ebner M, Peter A, Spencer C, Härtig F, Birschmann I, Kuhn J, et al. Point-of-Care Testing of Coagulation in Patients Treated With Non–Vitamin K Antagonist Oral Anticoagulants. Stroke. 2015 

Routine clinical use of non-vitamin K antagonists (NOAC) has revolutionized anti-coagulation pharmacotherapy; ending frequent monitoring that was required of vitamin K antagonists. This inability to evaluate level of anti-coagulation, however, has created a quandary in acute ischemic stroke management and urgent surgery. Point of care test (POCT) has been shown to provide prothrombin levels and accelerate time to thrombolyis and such tests have been influenced by NOAC. In this study, the authors attempted to determine the diagnostic accuracy of CoaguChek POCT in ruling out relevant concentrations of rivaroxaban, apixaban, and dabigatran. 

The study was conducted at a single center. Ischemic stroke patients receiving first doses of NOAC for secondary prevention were consecutively enrolled. Blood samples were collected at the following times: before drug intake, 30 minutes, 1, 2, and 8 hours, and prior to 2nd dose and tested using the CoaguChek XS Pro POCT. PT, PTT, and anti-Xa activity were also measured and anti-Xa assay was calibrated to determine rivaroxaban and apixaban concentrations. In total, 60 patients were enrolled. Results demonstrated that results of CoaguChek POCT strongly correlated with rivaroxaban but not with apixaban or dabigatran. Anti-Xa assay also accurately detected low rivaroxaban concentrations but such assays are not routinely available.

The results suggest that POCT-results can be used to rule out relevant rivaroxaban concentrations especially if a low cut-off value is used (<1.0). This is superior to normal PT and PTT values. POCT can be used to in direct clinical practice to determine potential eligibility for thrombolysis. A limitation in this study was assessing NOAC concentrations essentially within the first 24 hours when steady-state has not been achieved. The results should be validated in larger, multi-center trials and ultimately involve trials where treatment decisions are based on POCT results.

By |October 26th, 2015|prevention|0 Comments