American Heart Association

prevention

Carotid Endarterectomy is Safe After Intravenous Thrombolysis

Mohammad Anadani, MD

Ijäs P, Aro E, Eriksson H, Vikatmaa P, Soinne L, Venermo M. Prior Intravenous Stroke Thrombolysis Does Not Increase Complications of Carotid Endarterectomy. Stroke. 2018

The benefit of carotid endarterectomy (CEA) for symptomatic carotid stenosis is well established; however, the optimal timing of procedure after stroke is still a matter of debate. Although few studies showed an increased risk of periprocedural stroke and death with early CEA (within 48 hours), others did not. In patients who receive intravenous thrombolysis (IVT), CEA is often delayed due to a concern of increased risk of intracerebral hemorrhage (ICH). However, this delay may result in a theoretical increase in risk of recurrent stroke while waiting for CEA.

In this study, Ijäs and colleagues underwent a retrospective registry study to investigate the safety and optimal timing of CEA after IV thrombolysis (IVT).

Omega-3 Fatty Acid Biomarkers: A Potential Marker of Incident Ischemic Stroke Risk?

Mark R. Etherton, MD, PhD

Saber H, Yakoob MY, Shi P, Longstreth Jr. WT, Lemaitre RN, Siscovick D, et al. Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts. Stroke. 2017

In this entry, I discuss a recent publication by Hamidreza Saber and colleagues regarding the relationship of circulating omega-3 fatty acids levels and incident ischemic stroke.

The authors set out to clarify the impact of omega-3 fatty acids on ischemic stroke incidence. Observational studies of self-reported omega-3 fatty acid consumption and omega-3 fatty acid supplementation trials have previously produced disparate results. As such, the authors quantified circulating omega-3 fatty acid levels in association with ischemic stroke incidence from 3 separate prospective cohort studies.

The authors used data from the Cardiovascular Health Study (CHS), Nurses’ Health Study (NHS), and Health Professionals Follow-Up Study (HPFS). Each of these three cohort studies represent distinct patient populations, which does influence the overall generalizability of these results. CHS is a prospective cohort study of adults aged 65 years and older. The NHS is a prospective cohort study of female registered nurses 30 to 55 years of age. Lastly, HPFS is a cohort study of U.S. male health professionals 40 to 75 years of age. Most participants in each study were white (88% in CHS, for example). The analysis of NHS and HPFS was based on a nested case-control study of age and vascular-risk factor matched controls. Ischemic stroke was subdivided into atherothrombotic, cardioembolic, or other. At the time of enrollment in the studies, blood samples were collected and stored for later analysis of omega-3 fatty acid levels. Of note, there were some differences in collection and storage of blood samples for fatty acid analysis between the three studies.

Author Interview: George Ntaios, MD

George Ntaios

George Ntaios

A conversation with George Ntaios, MD, MSc (ESO Stroke Medicine), PhD, Assistant Professor of Internal Medicine, Department of Medicine, University of Thessaly

Interviewed by Stephen Makin, PhD, Clinical Lecturer at Glasgow University

They will be discussing the paper, “Real-World Setting Comparison of Nonvitamin-K Antagonist Oral Anticoagulants Versus Vitamin-K Antagonists for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Meta-Analysis,” being published in the September 2017 issue of Stroke.

Dr. Makin: Thank you for taking the time to talk to us.

Prof. Ntaios: Thank you for the invitation to discuss our study.

Dr. Makin: Could I begin by asking you to summarize your study and its findings?

Prof. Ntaios: We aimed to summarize all available evidence from high-quality real-world observational studies about the efficacy and safety of non-vitamin-K-oral-anticoagulants (NOACs) compared to vitamin-K-antagonists (VKAs) in patients with atrial fibrillation (AF). Based on 28 identified studies, we found that dabigatran, rivaroxaban and apixaban, as compared to VKAs, are associated with lower risk of intracranial haemorrhage and similar risk of ischemic stroke and ischemic stroke or systemic embolism; apixaban and dabigatran with lower risk of mortality; apixaban with fewer gastrointestinal and major haemorrhages; dabigatran and rivaroxaban with higher risk of gastrointestinal haemorrhage; and dabigatran and rivaroxaban with a similar rate of myocardial infarction.

Elevated Blood Pressure Significantly Associated with Risk of Vascular Dementia

Danny R. Rose, Jr., MD


Vascular dementia is the second most common cause of dementia, but many aspects of the disease are poorly understood. In particular, there is conflicting evidence regarding the relationship between blood pressure and vascular dementia. Elevated blood pressure in midlife has been found to have a positive association with future development of dementia, but several other studies have found low blood pressure in old age to be associated with an increased risk of dementia. One possible explanation of these findings is that it represents “reverse causality,” meaning vascular dementia is responsible for low blood pressure by decreasing sympathetic drive. Blood pressure medication may also play a confounding role in this association. Emdin et al. sought to further clarify this association by conducting an analysis of 4.28 million individuals without vascular disease or dementia, supplemented with an analysis of a prospective population-based cohort of patients with TIA and stroke.

The study included patients from age 30 to 90 and excluded patients with pre-existing cardiovascular disease to minimize the potential of reverse causality related to advanced age and cardiovascular disease causing reduced blood pressure, respectively. The endpoint of the primary analysis was an inclusive definition of vascular dementia based on ICD 10 coding and was inclusive of patients with co-existing Alzheimer’s disease. Secondary analysis excluded these patients and excluded patients treated with medications commonly used to treat AD. The first four years of follow-up were excluded in the primary analysis to mitigate the effect of patients with undiagnosed dementia. Cox models, stratified by practice, were used to determine hazard ratios for the association for clustering of patients by practice. The primary analysis was adjusted for age, sex, body mass index and smoking status. The Oxford Vascular Study cohort was used to confirm findings independently.

Out of a cohort of 4.28 million individuals free of vascular disease and dementia, 14,934 cases were reported to have vascular dementia. After excluding for presentations during the first four years of follow-up, 11,114 cases were included. The association between usual SBP and risk of vascular dementia followed a linear progression within the age groups of 30-50 and 51-70. The age group of 71-90 did not show a significant association. The strength of association decreased with increasing age category. Overall for individuals aged 70 years or less at baseline, 20 mm Hg higher usual SBP was associated with a 26% higher risk of vascular dementia (HR 1.26 CI 1.17, 1.34). Significant negative associations with systolic and diastolic blood pressures were observed for the age group 71-90, but after excluding for the first eight years of follow-up, no significant association was observed. Adjusting for patients in the primary care cohort that had TIA and stroke events reduced the HR to 1.18, indicating that 30% of the excess risk of vascular dementia per 20mm Hg higher SBP is mediated through risk of future stroke and TIA. The OXVASC cohort did not show a relationship between the most recent SBP or DBP in patients relative to their diagnosis of new dementia, but did show significant positive associations with DBP and SBP in 5-9 years prior to the TIA/stroke and particularly 10-20 years prior.

This study supports prior positive associations between blood pressure in mid-life and vascular dementia and also suggests that elevated blood pressure attributes a significant risk for the development of vascular dementia at least until the age of 70. The authors’ rationale for excluding confounders in the cohort appears to be sound and had the intended effect of strengthening the associations studied. The study refutes previous reports of a negative association with blood pressure and vascular dementia in the elderly, likely in part due to the aforementioned adjustments, strengthening the authors’ hypothesis of reverse causality. This study represents by far the largest analysis of the association between blood pressure and risk of vascular dementia and although it is susceptible to limitations related to the diagnosis of dementia in a primary care setting, it represents a significant advancement in our understanding of the complex pathophysiology of vascular dementia.


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