Patricia Martínez-Sánchez

Statin Therapy and Outcome After Ischemic Stroke Systematic Review and Meta-Analysis of Observational Studies and Randomized Trials

Background and Purpose— Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke. Methods— The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (⩽72 hours after stroke), and (2) thrombolysis-treated patients. Results— The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29–1.56; P<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9–1.4; P=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62–0.82; P<0.001) and 1 year (OR, 0.80; 95% CI, 0.67–0.95; P=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0–2.24; P=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (P=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02–1.52; P=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90–1.44; 4012 patients). Conclusion— In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. Randomized trials of statin therapy in acute ischemic stroke are needed.

Dopamine Innervation in the Thalamus: Monkey versus Rat

We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease.

Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: a phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial.

BACKGROUND Few studies have evaluated the possible beneficial effect of the administration of stem cells in the early stages of stroke. Intravenous administration of allogeneic mesenchymal stem cells (MSCs) from adipose tissue in patients with acute stroke could be a safe therapy for promoting neurovascular unit repair, consequently supporting better functional recovery. We aim to assess the safety and efficacy of MSC administration and evaluate its potential as a treatment for cerebral protection and repair. MATERIALS A Phase IIa, prospective, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Twenty patients presenting acute ischemic stroke will be randomized in a 1:1 proportion to treatment with allogeneic MSCs from adipose tissue or to placebo (or vehicle) administered as a single intravenous dose within the first 2 weeks after the onset of stroke symptoms. The patients will be followed up for 2 years. Primary outcomes for safety analysis: adverse events (AEs) and serious AEs; neurologic and systemic complications, and tumor development. Secondary outcomes for efficacy analysis: modified Rankin Scale; NIHSS; infarct size; and biochemical markers of brain repair (vascular endothelial growth factor, brain-derived neurotrophic factor, and matrix metalloproteinases 9). RESULTS AND CONCLUSIONS To our knowledge, this is the first, phase II, pilot clinical trial to investigate the safety and efficacy of intravenous administration of allogeneic MSCs from adipose tissue within the first 2 weeks of stroke. In addition, its results will help us define the best criteria for a future phase III study.

Treatment with angiotensin receptor blockers before stroke could exert a favourable effect in acute cerebral infarction

Introduction Evidence from experimental and clinical studies is accumulating about the possible cerebral protective properties of antithypertensive drugs, mainly angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI). Our aim was to analyse the impact of prestroke use of antihypertensive drugs on stroke severity and outcome. Methods We analysed 1968 consecutive patients with first-ever acute cerebral infarction admitted to an acute stroke unit. Stroke severity was evaluated using the Canadian Neurological Scale and the modified Rankin Score (mRS) was used to evaluate the outcome at discharge. Results Previous diagnosis of arterial hypertension was reported in 1212 patients and 73% were on antihypertensive treatment. No significant differences in stroke severity were found between patients with or without previous arterial hypertension, either in patients with or without antihypertensive treatment. Patients taking antihypertensive drugs at stroke onset had lower rates of poor outcome than those not on antihypertensive treatment (47 vs. 53%; P = 0.047) and those taking ARB had better outcomes than those without ARB (mRS ≤ 2: 75 vs. 65.8%; P = 0.029), with no differences in the analysis of other antihypertensive drugs. The multivariable logistic regression analysis showed that previous treatment with ARB was independently associated with reduced stroke severity (OR: 0.40; 95%CI 0.24–0.65; P < 0.001) and against poor outcome (OR: 0.41; 95%CI 0.23–0.78; P = 0.003). Conclusion Our study suggests that prestroke treatment with ARB may be associated with reduced stroke severity and also with better outcome. This finding agrees with experimental data that suggest a cerebral protective effect.

Lipid-Lowering Drugs in Ischemic Stroke Prevention and Their Influence on Acute Stroke Outcome

Introduction: Dyslipidemia is a recognized risk factor for coronary arterial disease, but its role as risk factor for stroke has been controversial for a long time. In the last years, much attention has been paid to lipid-lowering therapies as a key preventive measure to reduce stroke risk. Methods: We conducted a nonsystematic review of published studies analyzing the association between serum lipids and stroke risk, with special attention to the findings of clinical trials with lipid-modifying therapies (LDL-lowering drugs such as statins, HDL-increasing drugs such as torcetrapib) and to the effect of prior statin therapies on acute stroke severity. Results: Data from large cohort prospective studies, case-control studies and clinical trials confirm the association between serum lipids and stroke risk. In secondary stroke prevention, atorvastatin 80 mg is effective in patients with prior transient ischemic attack and noncardioembolic ischemic stroke. Pretreatment with statins in stroke patients is associated with better outcomes. This protective effect is more evident in atherothrombotic and lacunar infarctions. Statin withdrawal during acute stroke is associated with loss of the protective effect, and statin discontinuation after an acute ischemic stroke is also associated with higher mortality at 1 year of follow-up. Conclusions: Dyslipidemia is a modifiable stroke risk factor. Long treatment with atorvastatin 80 mg has been associated with reduced risk of stroke recurrences and other cardiovascular events in patients with noncardioembolic transient ischemic attack or ischemic stroke. Prior statin treatment is associated with lower stroke severity and better outcomes in acute ischemic stroke patients. Statin treatment should never be discontinued in these patients.

The beneficial effect of statins treatment by stroke subtype

Background and purpose:  Statins have shown some protective effect after ischaemic stroke in observational studies. However, this effect has never been assessed by etiological subtypes.

Futile Interhospital Transfer for Endovascular Treatment in Acute Ischemic Stroke The Madrid Stroke Network Experience

Background and Purpose— The complexity of endovascular revascularization treatment (ERT) in acute ischemic stroke and the small number of patients eligible for treatment justify the development of stroke center networks with interhospital patient transfers. However, this approach might result in futile transfers (ie, the transfer of patients who ultimately do not undergo ERT). Our aim was to analyze the frequency of these futile transfers and the reasons for discarding ERT and to identify the possible associated factors. Methods— We analyzed an observational prospective ERT registry from a stroke collaboration ERT network consisting of 3 hospitals. There were interhospital transfers from the first attending hospital to the on-call ERT center for the patients for whom this therapy was indicated, either primarily or after intravenous thrombolysis (drip and shift). Results— The ERT protocol was activated for 199 patients, 129 of whom underwent ERT (64.8%). A total of 120 (60.3%) patients required a hospital transfer, 50 of whom (41%) ultimately did not undergo ERT. There were no differences in their baseline characteristics, the times from stroke onset, or in the delays in interhospital transfers between the transferred patients who were treated and those who were not treated. The main reasons for rejecting ERT after the interhospital transfer were clinical improvement/arterial recanalization (48%) and neuroimaging criteria (32%). Conclusions— Forty-one percent of the ERT transfers were futile, but none of the baseline patient characteristics predicted this result. Futility could be reduced if repetition of unnecessary diagnostic tests was avoided.

Young Women Have Poorer Outcomes than Men after Stroke

Background and Purpose: Gender differences in stroke outcome have not been fully assessed in young patients. Methods: We conducted an observational study of consecutive young ischemic stroke patients (≤50 years of age) admitted to a stroke unit (January 1999 to December 2009). Basal data, subtype of ischemic stroke, stroke severity [Canadian Neurological Scale (CNS)], length of hospital stay, inhospital complications, mortality and functional outcome at discharge [modified Rankin Scale (mRS) score] were analyzed. For stroke severity and outcome analyses, 2 age groups were established: 15–30 (very young group) and 31–50 years old (middle-aged young group). Results: A total of 310 patients were enrolled; 128 females and 182 males. The mean age was similar in women and men (41.07 ± 8.6 vs. 42.12 ± 8.2, NS). Migraine was more frequent in women, whereas arterial hypertension, hyperlipidemia, alcohol abuse, current smoking and atherothrombotic infarction were more frequent in men (p < 0.05). Females presented greater stroke severity than men [median CNS (IQR) = 8 (3.5) vs. 9 (2.5), p = 0.014] except in the very young group [median CNS (IQR) = 9 (1.8) vs. 8 (5), p = 0.022]. Female sex was a predictor of unfavorable outcomes (mRS >2) at discharge in the total sample (OR = 3.33; 95% CI = 1.41–7.84) and in the middle-aged young group (OR = 2.62; 95% CI = 1.05–6.53), adjusted by baseline data, stroke subtype, inhospital complications, length of stay and stroke severity. Conclusions: Female gender is associated with worse outcomes in adult ischemic stroke patients up to 50 years old. However, this effect is not observed in younger patients (15–30 years).

Validation of the FOUR Score (Spanish Version) in Acute Stroke: An Interobserver Variability Study

Background: Methods to assess impaired consciousness in acute stroke typically include the Glasgow Coma Scale (GCS), but the verbal component has limitations in aphasic or intubated patients. The FOUR (Full Outline of UnResponsiveness) score, a new coma scale, evaluates 4 components: eye and motor responses, brainstem reflexes and respiration. We aimed to study the interobserver variability of the FOUR score in acute stroke patients. Methods: We prospectively enrolled consecutive patients with acute stroke admitted from February to July 2008 to the stroke unit of our Neurology Department. Patients were evaluated by neurology residents and nurses using the FOUR score and the GCS. For both scales, we obtained paired and total weighted kappa values (Kw) and intraclass correlation coefficients (ICC). NIH stroke scale was also recorded on admission. Results: We obtained a total of 75 paired evaluations in 60 patients (41 cerebral infarctions, 15 cerebral hemorrhages and 4 transient ischemic attacks). Thirty-three (55%) patients were alert, 17 (28.3%) drowsy and 10 (16.7%) stuporous or comatose. The overall rater agreement was excellent in the FOUR score (Kw 0.93; 95% CI 0.89–0.97) with an ICC of 0.94 (95% CI 0.91–0.96) and in the GCS (Kw 0.96; 95% CI 0.94–0.98) with an ICC of 0.96 (95% CI 0.93–0.97). A good correlation was found between the FOUR score and the GCS (ρ 0.83; p < 0.01) and between the FOUR score and the NIH stroke scale (ρ –0.78; p < 0.001). Conclusions: The FOUR score is a reliable scale for evaluating the level of consciousness in acute stroke patients, showing a good correlation with the GCS and the NIH stroke scale.

Treatment with statins and ischemic stroke severity: Does the dose matter?

Objective: To examine the effects of pretreatment with statins at high doses (40 mg of rosuvastatin or 80 mg of any other statin) and low to moderate doses (<40 mg of rosuvastatin or <80 mg of any other statin) on ischemic stroke (IS) severity in clinical practice. Methods: Observational study of IS admissions to our stroke unit over a 3-year period (2008–2010). Mild stroke severity was defined as NIH Stroke Scale score ≤5 on admission. Multivariable regression models and matched propensity score analyses were used to quantify the association of statin pretreatment at high and low to moderate doses with mild stroke severity. Results: Of the 969 IS patients, 23% were taking low to moderate doses and 4.1% were taking high doses of statins prior to the stroke. Statins were associated with lower NIHSS scores on admission (median [interquartile range] 4 [9] for nonstatin patients, 4 [9] for low to moderate doses of statins, and 2 [4] for high doses of statins; p = 0.010). After multivariable adjustment, pretreatment with statins was associated with a higher probability of mild stroke severity in the unmatched analysis (odds ratio [OR] = 1.637, 95% confidence interval [CI] 1.156–2.319 for the low to moderate doses and OR = 3.297, 95% CI 1.480–7.345 for the high doses of statins) as well as in the propensity score matched analysis (OR = 2.023, 95% CI 1.248–3.281 for the low to moderate doses and OR = 3.502, 95% CI 1.477–8.300 for the high doses of statins). Conclusion: Pretreatment with statins is associated with lower stroke severity, at high as well as at low to moderate doses.