American Heart Association

Monthly Archives: November 2015

Pre-hospital Treatment in Acute Stroke: How Close Are We?

Ilana Spokoyny, MD 

Lorenz MW, Lauer A, and Foerch C. Quantifying the Benefit of Prehospital Rapid Treatment in Acute Stroke: Benchmark for Future Innovative Clinical Trials. Stroke. 2015  
​”Time is Brain,” so systems of care interventions in acute stroke have focused on decreasing the onset-to-treatment time (OTT). Such interventions have focused on prehospital time delay (i.e. increasing patient education on stroke warning signs, to decrease the onset-to-EMS call time), as well as in-hospital factors (i.e. transporting patients directly to CT, pharmacy at bedside for tPA administration). One novel method of decreasing prehospital delay is the use of a mobile CT scanner, which demonstrated a decrease in OTT of 40 minutes in a rural area, and 25 minutes in an urban area. Another approach has focused on the use of a blood test for GFAP (plasma glial fibrillary acidic protein) to rule out hemorrhage. GFAP has been shown to have a sensitivity of 80% for ICH, with a negative predictive value of 96%. The revolutionary idea of substituting the blood test in the prehospital phase for the pre-treatment CT scan would allow EMS to treat with tPA en route to the ED. One obvious concern is the risk of treating ICH patients with a false-negative GFAP with tPA.

The authors took an innovative approach to the problem of determining the benchmark for these novel prehospital interventions. They created decision models based on a mixed cohort of patients (ischemic stroke, ICH, SDH, SAH, and mimics) who were assumed to present within 4.5 hours, with NIHSS 4-22 and no exclusion criteria. Based on the available literature, estimations were made of the proportion of patients in each disease category, and the distribution of outcomes, with favorable outcome defined as mrs 0-1 at 90 days.

A model was created for prehospital mobile CT-guided tPA. A time gain of 60 minutes corresponded to a 6.6% increase in the likelihood of a favorable outcome. Treatment with tPA increased this likelihood by 7%, so an hour of decreased delay essentially doubled the benefit. The mobile CT scanner decreased the OTT by 40 minutes in a rural area, which would correspond to a 4.6% increased likelihood of favorable outcome. The 25 minutes saved by the mobile CT in an urban area increased the likelihood by 3%. Another model examined the use of prehospital CT (with CTA) to take patients directly to a stroke center with endovascular capability, but this only minimally increased the likelihood of favorable outcome.

A hypothetical blood-test-based prehospital tPA algorithm increased the likelihood of a favorable outcome by 3.9% when OTT was reduced by 40 minutes, and 5.9% with a time gain of 60 minutes. Using sensitivity analysis, the critical variables to this algorithm were time gain and sensitivity of the blood test to detect ICH. With an 80% sensitivity, a time gain of only 5 minutes was enough to justify the algorithm with the endpoint of “favorable outcome”. When quality-adjusted life years (QALY) was used as the endpoint, however, a minimum time gain of 32 minutes was required to compensate for the risk. The number needed to treat (when the time saved was between 40-60 minutes) to save one QALY was between 4 and 12.5, which amounted to 400 to 1250 Euros per QALY. Comparing this to the cost of a QALY with mobile CT, which is around 32000 Euros, the blood test is cost-effective.

The prehospital mobile CT does not increase risk, potentially increases benefit, and its only downside seems to be cost. The prehospital blood test has the potential to increase treatment rates and decrease treatment times, and is cheaper to implement, making it seemingly ideal for low-tech areas with long delays to CT scan (due to distance needing to be traveled) or without access to CT at all. However, the use of this test as a substitute for CT raises significantly more ethical issues than does the substitution of the mobile CT. While more patients may be treated and treated earlier, imparting better outcomes, there will be more patients who will be put in known danger – because we would be foregoing a reliable and safe test for a faster but less reliable one. As we shift to more patient-centered care, will we give patients the option of having the blood test (a high-risk-high-reward) versus the standard in-hospital CT (assuming mobile CT is not at play here)? Since these are pre-hospital interventions, will consent for tPA be obtained? Will EMS be responsible for reviewing the exclusion criteria? We will also be relying on EMS to determine the last known normal time, and there is data to show that these are often inaccurate. Will there be more complications since EMS is not perfect at identifying stroke syndromes, both having a low sensitivity (especially for posterior circulation strokes) and a relatively low specificity (difficulty weeding out mimics). Maybe the presence of a physician via telemedicine would help in the determination of appropriateness of tPA.

This excellent paper sets up the foundation for several important next steps, the first of which is further rigorous testing of the GFAP blood test. Once this is thought to be ready for prime-time, the next step would be an ambulance based “road test” of the blood test, in which the treatment decision is made based on the blood test, but the actual treatment is administered based on standard-of-practice in-hospital CT, and the results are compared. This will help determine the actual sensitivity of the test, the diagnoses of patients who would have been treated, and the accuracy of EMS at determining not only the last known normal time but identifying which patients are having stroke syndromes. If this is a success, we may consider whether a clinical trial of the blood test, in which patients are randomized to the blood test or an in-hospital CT and treated based on the results, is safe and ethical to implement.

By |November 13th, 2015|treatment|1 Comment

Author Interview: Opeolu Adeoye, MD MS FACEP FAHA

Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke-Full Dose Regimen Stroke Trial
Interview Conducted by Mark N. Rubin, MD

Dr. Rubin: If you do not mind, Dr. Adeoye, I would like to get down to brass tacks. Where is the best place to eat in Cincinnati? 
Dr. Adeoye: The important stuff! It’s a bit pricey but my favorite place by far is an Italian restaurant called Nicola’s. I don’t get to go often but always good for a special dinner, like every time colleagues visit Cincinnati and I get to pick where we go.

Dr. Rubin: What would you like readers to know about you? 
Dr. Adeoye: I’m a very proud father of two incredible children, ages 5 and 8. Maybe they won’t be so incredible in about 10 years but for now it’s pretty fantastic.

Dr. Rubin: What was the research question you wanted to answer with this trial? Please explain the interventions trialed and the rationale for getting at this question.  
Dr. Adeoye: Our goal was to estimate the safety of combining full dose tPA with eptifibatide in ischemic stroke patients treated with tPA within three hours of symptom onset. We had previously studied escalating doses of half dose (0.45mg/kg) and two thirds dose (0.6mg/kg) tPA combined with eptifibatide. Those combinations were safe with regard to symptomatic ICH rates. Being able to use full dose tPA (i.e., standard of care) in a phase III trial would be simplest to execute, and if safe may be most likely to show benefit given the possibility of improved lysis compared to lower doses of tPA. So, we sought to estimate whether such a combination would be safe enough to pursue in a large trial.

Dr. Rubin: How many sites were involved? Was enrollment protocol standardized across all sites? How did you herd so many cats (e.g., coordinate with so many physicians)? How did you ensure that participation in the study did not delay the use of standard tPA?  
Dr. Adeoye: Luckily, we were able to use eight hospitals in the Greater Cincinnati region to complete enrollment in the study. All hospitals had a standardized protocol for managing tPA treated patients. Fortunately, the monitoring and clinical care for the combination patients is essentially the same as that for tPA treated patients. To ensure we didn’t delay tPA administration, we encouraged treating physicians to proceed as rapidly as possible with initiation of tPA. Once the bolus was in and infusion started, THEN we approached the patient or family regarding participation in the study. 

Dr. Rubin: Why eptifibatide? Any reason other than it is not abciximab?
Dr. Adeoye: It’s definitely not abciximab which may have an anti-thrombotic effect for days after it’s been discontinued. There are multiple 2b/3a molecules beyond the ones that are well known. Eptifibatide was one of the early ones specifically developed to ensure rapid inhibition of platelet aggregation (within 15 minutes), a short half-life (~2 hours) and rapid dissociation from platelets with 50% restoration of platelet function within 2-4 hours of discontinuation. A series of papers by Drs. Robert Scarborough and David Phillips in the 1990s detail this development. In the context of stroke, these properties offer a quick on/quick off advantage that when combined with tPA allows augmentation of thrombolysis without a prolonged anti-thrombotic effect that may lead to symptomatic ICH.

Dr. Rubin: This study seemed to have relatively complex enrollment. Standard tPA was started in all patients soon after arrival to the hospital and you had 40 minutes to enroll the patient after tPA was started; how were you able to inform patients and get consent to participation within that time frame? What were the greatest challenges?
Dr. Adeoye: Actually, I think we were pretty fortunate in conducting this study. The protocol is fairly straightforward and investigators were able to adhere to the protocol without difficulty. As with any acute stroke trial, the challenge is in administering standard therapies rapidly while also obtaining consent and initiating study procedures in a timely manner.

Dr. Rubin: What is the one-sentence take-away for readers? Please comment on efficacy and safety of the intervention.  
Dr. Adeoye: The addition of eptifibatide to tPA in ischemic stroke appears to be safe in the doses we’ve studied and justifies a larger trial to determine it if improves stroke outcomes.

Dr. Rubin: What is the next step? 
Dr. Adeoye: We’ve submitted an application to the NIH for a Phase III trial called MOST (Multi-arm Optimization of Stroke Thrombolysis). This is a collaborative effort with me and Dr. Joe Broderick in Cincinnati and Drs. Andrew Barreto and Jim Grotta in Houston. We will use an adaptive design to determine whether eptifibatide plus tPA or argatroban plus tPA result in better outcomes than tPA alone for ischemic stroke.

Dr. Rubin: I understand that further studies looking at combinations of lytics are planned or underway. How does eptifibatide +tPA fit in the armamentarium in the era of data-supported efficacy of endovascular reperfusion therapies? 
Dr. Adeoye: That’s a great question. The aggregate data for the trials published in the past year showed that the overall TICI 2b/3 recanalization rate in endovascular patients was about 67%. That means a third of patients receiving endovascular therapy had inadequate recanalization/reperfusion. Our goal in the coming years is to determine whether eptifibatide may improve these recanalization rates. Hopefully, we can establish a role for eptifibatide in augmenting recanalization rates in patients treated with endovascular therapy.

Dr. Rubin: Can Andy Dalton win in the playoffs? 
Dr. Adeoye: It’s best not to tempt fate. No comments.

IV-TPA does not increase hemorrhage risk if used within 3 months of previous stroke

Jay Shah, MD

Karlinski M, Kobayashi A, Czlonkowska A, Mikulik R, Vaclavik D, Brozman M, et al. Intravenous Thrombolysis for Stroke Recurring Within 3 Months From the Previous Event. Stroke. 2015

Contraindications of intravenous tissue plasminogen activator (TPA) are based on the original 1995 NINDS trial. Continued use and growing experience has allowed for off-label use. However, there is limited data on TPA safety for subsequent stroke treatment with prior infarct within 3 months. Prior infarct within this timeframe remains a contraindication in the labeling of alteplase. Therefore, this patient population may be excluded from treatment that can potentially offer benefit. In this study, the authors investigated if history of recent infarct conferred a higher hemorrhage risk.

This retrospective study analyzed data from a registry across an 11-year span. Patients were eligible if data about previous stroke and 24-hour outcome were available. Patients were divided into 2 groups: previous stroke and first-ever stroke. Of 13,007 patients treated with TPA, 249 had a prior stroke within 3 months. There were no significant differences in hemorrhage occurrence and 3-month outcome between the two groups.

This study concluded that history of infarct within 3 months did not increase hemorrhage risk after treatment with TPA for a subsequent stroke. However, the relatively low number of patients with history of stroke treated with TPA could represent a selection bias. Furthermore, it may be relevant to determine how many patients were denied treatment of TPA on basis of recent ischemic history but this current study was designed to evaluate solely patients treated with TPA. Within the registry, there was no data available regarding two specific variables that can greatly influence hemorrhage risk: time (in days) from previous infarct and size of infarct. Despite such limitations, withholding TPA based solely on recent infarct less than 3 months may be inappropriate. Further prospective studies can potentially elucidate if there is a specific time and size threshold.

By |November 11th, 2015|treatment|0 Comments

Copeptin: a promising marker in risk stratification after ischemic stroke and TIA

Luciana Catanese, MD

Griesenegger S, Segal HC, Burgess AI, Poole DL, Mehta Z, Rothwell PM. Copeptin and Long-Term Risk of Recurrent Vascular Events after TIA and Ischemic Stroke: Population-Based Study. Stroke. 2015.

Copeptin is a stress hormone released in an equal proportion to vasopressin (AVP), and serves a surrogate marker for the hypothalamo-pituitary-adrenal axis. Prior literature has suggested that Copeptin is a promising prognostic biomarker in vascular diseases such as MI, CHF and ischemic stroke/TIA. However, the prognostic value of Copeptin in regard to long-term risk of vascular events after TIA and stroke remains uncertain.

In this issue of Stroke, Griesenegger et al. present a longitudinal population-based study with a mean follow–up of 5.7 years, to determine whether Copeptin levels could predict the long-term risk of vascular events in patients with TIA or ischemic stroke. The authors also contrasted Copeptin level amongst different etiological subtypes of stroke/TIA.

Of 92,728 individuals in the Oxford Vascular Study, 1076 eligible patients (mean age 75) with TIA, minor and major ischemic stroke recruited from 2002-2007, were included. Copeptin level was obtained at baseline (median time to sampling 5 days) and repeated in 384 patients after one year.

After about 6000 patient-years of follow-up, the cox regression analysis including age, sex, hypertension, diabetes, previous MI, stroke, peripheral vascular disease, smoking, CHF, atrial fibrillation, and treatment with antiplatelets, statins or antihypertensive agents, showed that Copeptin significantly predicted subsequent vascular events (HR 1.47), recurrent ischemic stroke (HR 1.22), vascular death (HR 1.85) and all cause death (HR 1.75). The predictive value of Copeptin was greatest following a cardioembolic cerebrovascular event. Moreover, Copeptin outperformed other circulating biomarkers of thrombosis, inflammation and neuronal/myocardial injury within this population.

Inclusion of Copeptin into a model containing the aforementioned vascular risk factors improved the model’s predictive ability for recurrent vascular events, vascular death, death and recurrent stroke by 32%, 55%, 66% and 16%, respectively.

Overall, Copeptin seems to be a promising biomarker in risk stratification after ischemic stroke and TIA, particularly in patients with cardiogenic strokes/TIA. One of the main limitations of the study is the lack of adjustment for other possible confounding factors, such as indices of cardiac function. Therefore, further validation of these findings with the inclusion of cardiac markers is warranted.

By |November 10th, 2015|prognosis|0 Comments

Research methodology and ascertainment of post-stroke dementia

Neal S Parikh, MD

Pendlebury ST, Chen PJ, Welch SJV, Cuthbertson FC, Wharton RM, Mehta Z, and Peter M. Rothwell PM. Methodological Factors in Determining Risk of Dementia After Transient Ischemic Attack and Stroke: (II) Effect of Attrition on Follow-Up. Stroke. 2015

In a recently published article in Stroke, Sarah Pendlebury and her colleagues examine the methodological problems associated with ascertainment of post-stroke dementia.

This article is the third in a series of three articles on this topic. In their first two papers, they demonstrated that baseline selection criteria and selective attrition from face-to-face follow-up result in under-representation of those patients with the greatest likelihood of having dementia. In this paper, they specifically aim to understand the extent to which the feasibility of cognitive testing is limited. They also assessed factors that are associated with untestability with short cognitive tests (MMSE, MoCA, Telephone Interview for Cognitive Status and abbreviated mental test score). 

Patients were prospectively recruited from 2002 to 2007 for the Oxford Vascular Study (OXVASC) after TIA or stroke. Cognitive testing was attempted at ascertainment and then on a pre-determined schedule.

Of the 1,236 patients recruited (mean age 75.2 years), 403 had TIA and the remainder were predominantly ischemic stroke patients (5% primary intracerebral hemorrhage). They dichotomized stroke as minor or major, with major defined as NIHSS>3; 370 (30%) had major stroke.

The percentage testable was 76% at cohort entry, 82% at 1 month, 88% at 6 months, 87% at 1 year and 83% at 5 years. Only 46% of patients with major stroke were testable. Notably, being testable was associated with younger age, less pre-morbid disability and less pre-morbid dementia. Reasons for untestability included stroke-related deficits such as dysphasia, hemiparesis, reduced level of consciousness and acute confusion. The proportion of testable stroke patients increased with time after stroke (perhaps due to recovery and also death of sicker patients). Untestability was less of a problem for TIA patients.

A number of papers have recently demonstrated the “mixed pathology” seen in brains of patients with dementia. Understanding the contribution of vascular disease to dementia is crucial for the intelligent design of dementia therapeutics and prevention strategies. This series of papers delineates the methodological issues that result in the possible underestimation of the contribution of vascular disease to dementia. Future studies of stroke-related dementia should anticipate and account for the limitations described by these authors.

By |November 9th, 2015|clinical|1 Comment

Markers on non-contrast CT head that predict later hematoma expansion

Peggy Nguyen, MD

Blacquiere D, Demchuk AM, Al-Hazzaa M, Deshpande A, Petrcich W, Aviv RI, et al. Intracerebral Hematoma Morphologic Appearance on Noncontrast Computed Tomography Predicts Significant Hematoma Expansion. Stroke. 2015 

Hematoma expansion occurs in approximately one-third of patients with intracerebral hemorrhage (ICH), but markers for predicting expansion are not well defined. The PREDICT study, aimed at prospectively validating the spot sign on CT angiography, found the spot sign had a sensitivity of 51% for predicting expansion. Markers present on non-contrast CT head previously published elsewhere as associated with hematoma expansion or larger ICH include hematoma density, shape, presence of fluid-levels, and regularity, but predictive models utilizing these markers are not widely used. Here, the authors hypothesized that these non-contrast CT head markers (irregular margins, heterogeneous density, and fluid-blood levels) would predict expansion both independently and together with the spot sign on CTA, with the aim of identifying non-contrast measures which would be reliable markers of hematoma expansion and to create a more sensitive prediction model.

Analyzing a PREDICT cohort of 311 patients, the authors found a high inter-observer agreement for fluid levels, and relatively good agreement for scoring of heterogeneity and irregularity. All 3 non-contrast CT markers were significantly associated with hematoma expansion on follow up CT scan; in addition, all 3 non-contrast CT markers were significantly associated with the spot sign on CTA and with absolute hematoma growth at 24 hours. Margin irregularity was the most sensitive and fluid levels was the most specific, but the spot sign remained the most specific predictor of hematoma expansion, with the highest positive and negative predictive values of hematoma expansion. The predictive value of the spot sign was not altered when the non-contrast markers were added to the model, confirming the spot sign as the most reliable marker for hematoma expansion. However, given the ease of scoring, the relatively good inter-observer agreement, and the ease of obtaining a non-contrast CT scan, especially in situations where contrast may be contraindicated, it does appear that heterogeneity, irregularity, and fluid-blood levels might also be appropriate surrogate markers.

By |November 6th, 2015|hemorrhage|0 Comments

Author Interview: Ken Butcher, MD, PhD, FRCP(C)

Dabigatran Therapy in Acute Ischemic Stroke Patients Without Atrial Fibrillation 
Interview Conducted by Chirantan Banerjee, MD

Dr. Banerjee: Tell us about the key findings from your recent article in Stroke.   

Dr. Butcher:The key findings are that acute treatment with the Direct Oral Anticoagulant (DOAC) dabigatran within 24 hours of an acute ischemic stroke is feasible. Given the small sample size, we have not definitively proven safety of course, but the lack of symptomatic hemorrhagic transformation, and indeed the paucity of even subclinical HT on susceptibility weighted MRI, is encouraging. Certainly we saw no safety signal that would preclude pursuing this approach in a larger study, as we are currently. 

Dr. Banerjee: What prompted you and your co-authors to perform this study? 
Dr. Butcher: It is now recognized that early recurrent stroke after TIA/minor stroke is a frequent problem and new treatment target. Efforts to date have focused on anti-platelet approaches (CHANCE, POINT, SOCRATES). However, it has also been shown that occult paroxysmal AF is common in this population (CRYSTAL AF and EMBRACE). Thus, many patients with acute minor stroke/TIA will not benefit from anti-platelet approaches. 
What has prevented routine anticoagulant use in the past is that any benefits were outweighed by increased hemorrhagic complications (primarily symptomatic HT). These studies were done with heparin/LMWH. Dabigatran, in the RE-LY trial had an intracranial hemorrhagic complication rate that was comparable to ASA. Thus, there appeared to be an opportunity to protect patients from all potential recurrent thromboembolic events, without increasing the risk of HT or other hemorrhages. Our rationale for 30 days of treatment was that this is the period of highest stroke recurrence. We aimed to protect patients during this high risk period, but also give clinicians time to determine which patients had potential cardiac sources of embolism (TTE, Holter). 
Dr. Banerjee: Tell us about the biggest challenge you came across while conducting this study. 
Dr. Butcher: There were really three:
1. The first was actually convincing some of our colleagues that hyper acute DOAC use was a reasonable concept. There was initially some trepidation on the part of some of our colleagues.
2. All patients needed an MRI scan before treatment, all within 24 hours. Even in a research center such as ours, this was a challenge. 3. Finally, there were competing trials that made enrollment a challenge (POINT and SOCRATES). 
Dr. Banerjee: What are the major implications of this work?  
Dr. Butcher: The implications are that it may be reasonable to protect all patients with minor stroke, using dabigatran. Of course, this needs to be tested in a larger RCT. This is what we are doing now, with DATAS II, which randomizes 300 patients to ASA or dabigatran for 30 days.   
The findings also support the safety of the approach being tested in the ESUS trials, one of which uses dabigatran. The difference between these trials and ours is that we do not make the assumption that all subcortical strokes are not embolic—some may therefore benefit from acute DOAC therapy. These patients are excluded from ESUS trials. In addition, the short term nature of the therapy, combined with a more extensive cardiac interrogation may lead ultimately to more selective therapy with DOACs. Each approach has its merits. A small study like DATAS supports the safety of both.  
Dr. Banerjee: What do you plan to do next, based on these current findings?  
Dr. Butcher: We are currently conducting DATAS II, as described above.  
Dr. Banerjee: What do you like to do in your free time? 
Dr. Butcher: I spend time with my kids. We all like to ski in the winter (cross country and downhill). I also play hockey (badly) and enjoy triathlon when time permits.

Induced hypertension for aneurysmal subarachnoid hemorrhage not beneficial in small study

Peggy Nguyen, MD

Gathier CS, Dankbaar JW, van der Jagt M, Verweij BH, Oldenbeuving AW, Rinke GJE, et al. Effects of Induced Hypertension on Cerebral Perfusion in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial. Stroke. 2015

One of the mainstay treatments of aneurysmal subarachnoid hemorrhage for DCI (delayed cerebral ischemia) secondary to cerebral vasospasm is triple-H therapy: hypervolemia, (relative) hypertension, and hemodilution; however, despite the fact that it is standard of practice, the efficacy of this therapy in improving clinical outcomes is not quite clear.

Here, 13 patients were randomized to induced hypertension and 12 patients were induced to no induced hypertension. Patients randomized to induced hypertension received intravenous norepinephrine drip for at least 24-48 hours until neurologic deficits improved, a complication occurred, or a maximum MAP of 130 mmHg or maximum SBP of 230 mmHg was reached. Although the control group did not undergo induced hypertension, the authors note that hypotension was avoided by giving vasopressors to avoid MAP < 80 mmHg. Change in cerebral blood flow (CBF) was calculated between the intervention and comparison group. There was no statistically significant difference in the change in CBF between the two groups; authors note that there was a trend towards improved CBF in follow up CTP in the lowest perfused region, but it does not appear to be statistically significant.  

At least in this small exploratory, no statistically significant improvement was seen with randomization to induced hypertension. A much larger study (authors note 225-250 patients per group would) be needed to find a statistically significant difference in change in overall CBF between intervention and control, and in fact, the trend towards improved CBF in areas of lowest perfusion suggests that an improvement may be detected with a larger sample size. In addition, there were some variables which could have confounded the study results including a higher proportion of high grade WFNS patients in the hypertension group. At this point, however, clinical practice is not likely to be impacted even in light of this negative study given the size of the study and possible confounders.

By |November 5th, 2015|treatment|0 Comments

Alcohol Intake and the Risk of Stroke

Alexander E. Merkler, MD 
Jones SB, Loehr L, Avery CL, Gottesman RF, Wruck L, Shahar E, and Rosamond WD. Midlife Alcohol Consumption and the Risk of Stroke in the Atherosclerosis Risk in Communities Study. Stroke. 2015

The association between alcohol use and stroke has been well studied. Based on prior reports and meta-analyses, light alcohol consumption is thought to be protective against ischemic stroke whereas heavy alcohol consumption may increase the risk of ischemic stroke. On the other hand, alcohol consumption only seems to increase the risk of intracerebral hemorrhage (ICH). As the authors point out, previous studies had multiple limitations including lack of information regarding previous alcohol use, socioeconomic data, or were retrospective analyses. 

The current study by Jones et al, evaluates the relationship between mid-life alcohol use and stroke using the Atherosclerosis Risk in Communities Study (ARIC). More than 15,000 patients were enrolled in ARIC, a prospective study of middle aged adults, performed at four socioeconomically diverse locations in the United States. Patients were followed for up to 25 years. In this study, patients included had no history of prior stroke and either were current alcohol consumers or lifetime abstainers. Thus, patients who were former alcohol consumers were excluded from the study. Alcohol use was assessed using questionnaires at the initial enrollment visit. Alcohol use was divided into 4 groups: never drinkers, light drinkers (less than 3 drinks / week), moderate drinkers (4-17 drinks/week) and heavy drinkers (>18 drinks/week).

Of the 12,000 ARIC subjects included in the analysis, more than one third were light drinkers, one-third reported lifetime abstinence from alcohol, and just 5% were heavy alcohol consumers. After adjustment for confounders, any amount of alcohol use was neither harmful nor protective against the development of ischemic stroke, which does not support the classic “J-shaped” relationship of alcohol use and risk of ischemic stroke. There was a trend that light alcohol consumption may be protective against ischemic stroke in white women and harmful in black men, but the confidence intervals were wide and crossed 1. On the other hand, moderate-to-heavy alcohol use was significantly associated with ICH (HR 1.99, 95% CI

The main limitation is that alcohol consumption was only evaluated at one time during the study – the initial visit. Thus, it is very possible that each patient’s alcohol consumption varied as the study progressed. Other limitations include the lack of knowledge regarding type of alcohol consumed, the reliance of questionnaires, and the fact that the study power was too low to detect significant differences in certain study subgroups such as heavy alcohol use.

Overall, the results of this large, prospectively gathered, heterogeneous population show neither a protective nor harmful effect of alcohol consumption on ischemic stroke risk. On the other hand, the results are consistent with prior reports showing a significant association between moderate-heavy alcohol consumption and development of ICH. Future research will be necessary to tease out the relationship between alcohol use and ischemic stroke.

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