Feil Professor and Chairman, Department of Neurology, and Assistant Dean of Clinical Affairs, Weill Cornell Medical College; Neurologist-in-Chief, New York Presbyterian Hospital
Dr. Fink reports no financial relationships relevant to this field of study.
Message from the editor: The following reviews of studies presented at the 2018 International Stroke Conference were written after my personal attendance at the presentations, followed by review of the simultaneous publications in the journals Stroke, The New England Journal of Medicine, JAMA Neurology, and the Journal of the American Medical Association. All comments and opinions are solely those of this editor.
Combined Treatments with Medications for Hypertension and Hyperlipidemia Dramatically Reduce the Risk of Stroke
SOURCE: Bosch J, Lonn E, Zhu J, et al. First stroke reduced 44% by well-tolerated medications. Stroke outcomes from the heart outcomes prevention evaluation 3 study. Stroke 2018;49:A104.
Seventy-five percent of strokes are first strokes, and primary prevention by reducing risk factors is crucial for reducing the global burden of stroke. Bosch et al investigated the effectiveness of fixed-dose antihypertensive therapy and statin therapy for primary stroke prevention. They randomized 12,705 participants from 21 countries who had an intermediate risk of cardiovascular disease in a 2 × 2 factorial design to a fixed-dose candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily vs. placebo, and to rosuvastatin 10 mg daily or placebo.
The mean age of the patients was 66 years, 46% were women, and 166 strokes occurred during a median follow-up of 5.6 years. Mean baseline blood pressure was 138/82 mmHg and the blood pressure difference between the treatment groups during follow-up averaged 6.0/3.0 mmHg. During the follow-up period, stroke was reduced by 20% (95% confidence interval [CI], 0.59-1.08; P = 0.14) with candesartan/hydrochlorothiazide and 30% (95% CI, 0.5-20.95) with rosuvastatin. In a subgroup analysis, participants in the upper third of systolic blood pressure (> 143.5 mmHg) had stroke reduced by 42% (95% CI, 0.37-0.90; P < 0.02). Rosuvastatin reduced all stroke by 30%, but considering hemorrhagic strokes, 15 occurred among those assigned rosuvastatin vs. 12 with rosuvastatin placebo. Those assigned to both rosuvastatin and candesartan/hydrochlorothiazide had stroke reduced by 44% (95% CI, 0.36-0.87; P = 0.009). There was no difference in the rates of medication discontinuation between the groups that took active drugs compared to placebo-assigned patients. In this real-world study, fixed-dose candesartan/hydrochlorothiazide combined with low-dose rosuvastatin reduced first stroke by 44% in patients at intermediate risk of cardiovascular disease and was well tolerated, with minimum dropout of patients. This approach should be considered more widely in our efforts to reduce the global burden of stroke.
Preeclampsia Increases a Woman’s Risk of Early Stroke
SOURCE: Miller EC, Boehme AK, Moon YP, et al. Preeclampsia and early stroke incidence in the California Teachers Study. Stroke 2018;49:A174.
Preeclampsia occurs in 3-8% of all pregnancies and doubles women’s long-term risk of stroke. However, limited data are available to determine the rate at which this risk develops, and whether stroke risk occurs early in life or later in life. These investigators used prospective data collected from the California Teachers Study to determine when the risk of stroke was greatest and if that risk would be modified using aspirin or statins.
The participants in the California Teachers Study were enrolled if they were ≤ 60 years of age and had no prior stroke at the time of enrollment in 1995. Miller et al obtained a detailed history, which included pregnancy history and any evidence for preeclampsia. Women who enrolled in the study were followed prospectively, and stroke outcomes were obtained via linkage with California hospital records up to and including Dec. 31, 2012. Risks for subsequent stroke were calculated among those with and without a history of preeclampsia, and stratified analyses were done to assess the impact of self-reported use of aspirin and/or statins.
Of the 60,817 women included in the analysis, 6.1% had preeclampsia. Early stroke, defined as stroke before the age of 60 years, occurred in 1.3% of women in the preeclampsia group and 0.8% in the non-preeclampsia group. Risk of early stroke incidence was greater in women with preeclampsia, with an unadjusted risk ratio of 1.7. When adjusted for age, hypertension, diabetes, migraine, and obesity, the risk ratio remained higher in the preeclampsia group at 1.4. The stratified analysis showed that this risk was mitigated in women who were taking aspirin or statins, but continued to be elevated in those not taking them. In conclusion, women with a prior history of preeclampsia were 40% more likely than those without preeclampsia to develop early stroke, controlling for other risk factors. Long-term use of aspirin and/or statins might benefit these women, but randomized trials will be needed to determine if this approach is clearly beneficial.
After Myocardial Infarction, Increased Risk for Ischemic Stroke Persists for 12 Weeks
SOURCE: Merkler AE, Diaz I, Murthy SB, et. al. Duration of heightened stroke risk after acute myocardial infarction. Stroke 2018;49:A172.
These investigators performed a retrospective cohort study using inpatient and outpatient claims data from 2008 through 2015 from a nationally representative 5% sample of Medicare beneficiaries ≥ 66 years of age. Diagnosis of acute myocardial infarction (MI) and ischemic stroke were ascertained using validated ICD-9 diagnosis codes. Strokes were included only if they occurred after discharge from the acute MI hospitalization to make sure that periprocedural strokes related to coronary interventions were excluded. Cox regression models were used to sort the groups and perform the analyses, and risk of ischemic stroke was adjusted for demographics, stroke risk factors, and other comorbidities. Survival probabilities were used to compute a hazard ratio for each four-week interval after discharge from the hospital following acute MI.
Among 1,746,476 beneficiaries, 46,182 were hospitalized for acute MI and 80,466 were hospitalized for ischemic stroke. Compared to patients without acute MI, patients with stroke and acute MI were older and had more stroke risk factors. After adjusting for demographics, risk factors, and comorbidities, the risk of ischemic stroke was highest in the first four weeks after discharge from the MI hospitalization (hazard ratio [HR] = 2.7) and remained elevated substantially during weeks five to eight (HR = 2.0) and weeks nine to 12 (HR = 1.6) and no longer was elevated significantly after 12 weeks. Established stroke classification systems categorize MI-associated stroke as occurring in the 30-day period following MI. This study establishes that the elevated short-term risk of stroke extends beyond 30 days and remains elevated for up to 12 weeks following acute MI.
Stroke May Be Difficult to Diagnose During Pregnancy
SOURCE: Mayer C, Murillo J, De Havenon A. Predictors of ischemic stroke and stroke mimic during pregnancy. Stroke 2018;49:ANS4.
The risk of ischemic stroke is significantly higher during pregnancy and the puerperium, but often diagnosis is delayed or mistaken because stroke symptoms are mimicked by other conditions. Since acute ischemic stroke requires immediate intervention, it is important to identify these patients quickly. These investigators performed a retrospective chart review on pregnant patients at the University of Utah from 2009 through 2014 using ICD-9 codes to identify stroke and other conditions. Diagnosis was based on the neurologist’s evaluation and neuroimaging. Variables were identified to develop a predictable model using interactive variable selection, which then was fit into a logistic regression model to help make the diagnosis of ischemic stroke.
Thirty-eight patients met the inclusion criteria, of whom 13 had ischemic stroke. Mimic diagnoses included venous sinus thrombosis in eight patients, intracerebral hemorrhage in two patients, complicated migraine in seven patients, nonepileptic seizures in three patients, epileptic seizures in two patients, transient ischemic attack in one patient, and conversion disorder in two patients. The best model to predict ischemic stroke included age greater than 29 years and a history of a first-degree relative with stroke. Validation of the scoring system will require prospective application in a larger cohort of pregnant patients. However, the index of suspicion should remain high and pregnant women with stroke symptoms should be investigated intensively to make an accurate diagnosis and to initiate appropriate treatment.
Patients with Mild Non-disabling Ischemic Stroke Do Not Benefit From IV Alteplase
SOURCE: Khatri P, Kleindorfer D, Devlin T, et al. Alteplase for the treatment of acute ischemic stroke in patients with low NIHSS and not clearly disabling deficits: Primary results of the PRISMS trial. Stroke 2018;49:LB9. Presented at: ISC 2018. Jan. 25, 2018. Los Angeles.
More than half of patients with acute ischemic stroke have a mild deficit with a National Institutes of Health stroke scale (NIHSS) score of 0-5 at presentation. As a result, most of these patients are excluded from trials that have evaluated the benefits of intravenous thrombolysis. Therefore, these investigators sought to evaluate the safety and efficacy of alteplase administration in patients with NIHSS scores of 0-5 who did not have disabling deficits. Disabling was defined as making it impossible to return to work or perform basic activities of daily living (i.e., isolated aphasia).
PRISMS was designed as a 948-patient, Phase III, double-blind, randomized, placebo-controlled trial of IV alteplase compared to placebo in patients treated ≤ 3 hours from onset of symptoms. The primary outcome measure was the modified Rankin scale of 0-1 at 90 days, adjusted for age, treatment time, and NIHSS score at presentation. The primary safety endpoint was symptomatic intracranial hemorrhage. This study was terminated early because of slow recruitment and concern regarding completion of the trial.
From May 1, 2014, until Dec. 21, 2016, the investigators enrolled 313 patients with a median NIHSS score of 2 and treatment time of 2.7 hours. Thirteen percent had a final diagnosis of a neurovascular mimic. Five alteplase-treated patients vs. zero controls had a symptomatic intracranial hemorrhage. At 90 days, 78% of the alteplase-treated patients vs. 81% of controls achieved a modified Rankin scale score of 0-1. Since the study was terminated prematurely, even though there was no significant difference in outcome between the two groups, it is impossible to determine with certainty whether there was no benefit at all or if the numbers were too small and the study was underpowered to give a meaningful conclusion. However, the interim analysis suggests no benefit to treating patients who have mild deficits with alteplase.
Hospital Mortality From Intracerebral Hemorrhage Is Lower in Patients Taking NOACs Compared to Warfarin
SOURCE: Simultaneously published in JAMA. Inohara T, Xian Y, Liang L, et al. Association of intracerebral hemorrhage among the patients taking non-vitamin K antagonist versus vitamin K antagonist oral anticoagulants with in-hospital mortality. JAMA 2018;319:463-473.
The use of oral anticoagulants is increasing with the aging population and increasing prevalence of atrial fibrillation. Over the last several years, there has been an increasing shift in the use of non-vitamin K oral anticoagulants (NOACs) compared to warfarin. This study was designed to assess the association between preceding oral anticoagulant use and in-hospital mortality among patients with intracerebral hemorrhage.
The investigators reviewed the Get With the Guidelines stroke database and included 141,311 patients with intracerebral hemorrhage hospitalized from October 2013 to December 2016. They selected patients who had a record of anticoagulation therapy before intracerebral hemorrhage occurred, defined as any use of oral anticoagulants within seven days prior to hospital arrival. The main outcome measure was in-hospital mortality.
Among the cohort of 141,311 patients with intracerebral hemorrhage, mean age was 68.3 years, and 48.1% were women. Of these patients, 10.6% were taking warfarin, and 3.5% were taking NOACs preceding intracerebral hemorrhage. Twenty-eight percent and 4.1% were taking concomitant single or dual antiplatelet agents, respectively. Patients with a prior use of warfarin or NOACs were older and had a higher prevalence of atrial fibrillation and prior stroke. Acute intracerebral hemorrhage severity, as measured by the NIH Stroke Scale, was not significantly different across the three groups. In-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for patients who were on no oral anticoagulants. Compared with patients without prior use of oral anticoagulants, the risk of in-hospital mortality was higher among patients with prior use of warfarin (odds ratio [OR], 1.62) or NOACs (OR, 1.21). Compared with patients with prior use of warfarin, patients who had prior use of NOACs had a lower risk of in-hospital mortality, with adjusted OR of 0.75 (97.5% confidence interval, 0.69-0.81). The difference in mortality between patients taking warfarin vs. NOACs was greater numerically among patients with prior use of dual antiplatelet agents compared to those without prior antiplatelet therapy.
Among patients with intracerebral hemorrhage, prior use of warfarin or NOACs was associated with a higher in-hospital mortality compared with no exposure to oral anticoagulants. Prior use of NOACs, compared to prior use of warfarin, was associated with a lower risk of in-hospital mortality.
DAWN: Endovascular Thrombectomy 6 to 24 Hours After Onset Results in Significant Benefit
SOURCE: Saver JL. Magnitude of benefit of endovascular thrombectomy 6-24 hours after onset in acute ischemic stroke patients with clinical-core mismatch. Presented at: ISC 2018. Jan. 24, 2018. Los Angeles.
The recently reported DAWN trial established that endovascular thrombectomy improves outcomes among late-presenting acute ischemic stroke patients, six to 24 hours after last known well, if there is a clinical-core mismatch as evidence of salvageable brain tissue. Further analysis of the data was undertaken, and the investigators looked at adjusted 90-day modified Rankin scale outcome distributions in the DAWN patients and medical control patients, evaluating the number needed to treat for benefit and also evaluating the benefit per 100 patients treated. Using individual cut points of the modified Rankin score, the number needed to treat for one additional good outcome at 90 days was 19 patients for one to completely recover, 2.8 patients for one to reach functional independence, and three patients for one to reach an ambulatory state. For any patient to improve by one level of disability in the Rankin score, the number needed to treat was two. Overall, endovascular thrombectomy at six to 24 hours, in carefully selected patients with a clinical-core mismatch, confers a major benefit, improving 90-day disability levels in one-half of the patients and resulting in functional independence in one-third.
DEFUSE 3: Patients With Large Vessel Occlusions and Salvageable Brain Tissue Can Benefit From Thrombectomy Up to 16 Hours From Onset of Symptoms
SOURCE: Published simultaneously in N Engl J Med. Albers G, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med Jan 24, 2018; doi: 10.1056/NEJMoa1713973.
Endovascular thrombectomy has been shown to be effective for the treatment of acute ischemic stroke in patients with occlusion of the proximal middle cerebral artery or occlusion of the internal carotid artery if initiated within six hours of symptom onset. The recently reported DAWN trial (see January 2018 issue of Neurology Alert1) showed that the time window for the thrombectomy may be extended to 24 hours after the patient was last known to be well if patients are selected carefully based on a severe clinical deficit that is disproportionate to the size of the infarct on imaging. The DAWN trial used CT-perfusion imaging or MR-diffusion and perfusion imaging to estimate the amount of permanently damaged ischemic tissue. These techniques can be used to identify patients who might recover, regardless of the time from onset of symptoms until initiation of treatment for reperfusion.
The DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) was designed to test the hypothesis that patients who had salvageable ischemic brain tissue as identified by perfusion imaging would have a better functional outcome than patients treated with standard medical therapy in the interval from six to 16 hours after their last known normal. Patients were selected if they had a proximal middle cerebral artery or internal artery occlusion and an initial infarct size of < 70 mL, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more. Patients were assigned randomly to thrombectomy plus standard medical therapy or standard medical therapy alone. The primary outcome was the score on the modified Rankin scale “range 0-6” at the 90.
The investigators randomized 182 patients before an interim analysis, and the study was terminated early. Endovascular therapy plus medical therapy, compared to medical therapy alone, was associated with a favorable functional outcome on the modified Rankin scale at 90 days (odds ratio, 2.77; P < 0.001). There was a shift in the modified Rankin scale, which resulted in a higher percentage of patients who were functionally independent with a score of 0-2 at 90 days (45% vs. 17%; P < 0.001). The 90-day mortality rate was 14% in the endovascular group and 26% in the medical group (P = 0.05). There was no significant difference between the groups in the frequency of symptomatic intracranial hemorrhage (7% vs. 4%) or other serious adverse events (43% vs. 53%).
DEFUSE 3 results showed that endovascular thrombectomy for ischemic stroke six to 16 hours after the patient was last known well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with large artery occlusion (i.e., proximal middle cerebral artery and internal carotid artery occlusions), if there was a significant region of tissue that was ischemic but not yet infarcted. The success of this study was highly dependent on careful patient selection using imaging mismatch, and it did not address patients who sustained ischemic stroke in the vertebrobasilar circulation. Taken in conjunction with the recently published DAWN results, we can conclude that properly selected patients can benefit from endovascular thrombectomy up to 24 hours following last known well, with the requirement that they undergo proper imaging to determine the volume of the ischemic core and the surrounding ischemic penumbra. These measurements can be calculated accurately using either MRI technology or CT technology.
- Fink ME. Thrombectomy is effective up to 24 hours after stroke – the DAWN trial. Neurol Alert 2018;37:39.
Bone Marrow-derived Mesenchymal Stem Cells for Treatment of Chronic Ischemic Stroke Patients
SOURCE: Steinberg GK, Kondziolka D, Wechsler L, et. al. Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow derived mesenchymal stem cells: A phase 1/2a study. Presented at: ISC 2018. Jan. 25, 2018. Los Angeles, CA.
Dr. Gary Steinberg and his collaborators at Stanford University and the University of Pittsburgh reported on the results of a two-year, open-label, single-arm study to evaluate safety and clinical outcomes associated with surgical implantation of bone marrow-derived mesenchymal stem cells in 18 patients who had stable chronic ischemic stroke. Although all patients experienced adverse events related to the procedure (headaches), no patients withdrew because of adverse events, and there were no dose-limiting toxicities or deaths. Seven patients experienced a serious adverse event that resolved. Sixteen patients completed 24 months of treatment and follow-up and showed statistically significant improvements from baseline in the European Stroke Scale, the NIH Stroke Scale, the Fugl-Meyer (F-M) total score, and the F-M motor function total score at 24 months. However, there were no statistically significant changes in the modified Rankin scale. Transient lesions were detected on T2 FLAIR imaging in the ipsilateral cortex near the region of implantation approximately one to two weeks following the procedure. The cause of these transient lesions and the pathology is unknown at this time. Further follow-up of patients will be required before a Phase III trial is initiated. The preliminary findings certainly are encouraging, but require explanation as far as mechanism and the long-term expectations. It is believed that the changes are related to immune modulation and not actual implantation and growth of the stem cells into new brain cells.