Eduardo Martínez-Vila

Severe sleep apnea and risk of ischemic stroke in the elderly.

Background and Purpose— Convincing evidence of a causal relationship between sleep apnea and stroke has been shown recently in several prospective, well-designed studies. However, these studies have focused on middle-aged people, excluding the elderly population from analysis. To investigate whether sleep apnea represents an independent risk factor in this population, we performed a prospective longitudinal study in a population-based cohort of subjects from 70 to 100 years old. Methods— Within the context of the Vitoria Sleep Project, a population-based study designed to investigate the prevalence of sleep apnea in the population of Vitoria, Spain, we performed a 6-year longitudinal study in a subsample cohort of 394 noninstitutionalized, initially event-free subjects (70 to 100 years old, median 77.28 years, 57.1% males). Demographic and polysomnographic data and known confounding factors (age, sex, smoking and alcohol consumption status, body mass index, systolic and diastolic blood pressure, total serum cholesterol levels, and the presence or absence of diabetes mellitus, atrial fibrillation, and hypertension) were assessed at baseline. Hazard ratio for developing an ischemic stroke in relation to the apnea-hypopnea index at baseline was calculated. Results— Over the 6-year follow-up period, 20 ischemic strokes were registered. After adjustment for confounding factors, subjects with severe obstructive sleep apnea hypopnea (defined as apnea-hypopnea index ≥30) at baseline had an increased risk of developing a stroke (hazard ratio=2.52, 95% CI=1.04 to 6.01, P=0.04). Conclusions— This study shows that severe obstructive sleep apnea hypopnea (defined as apnea-hypopnea index ≥30) increases the risk of ischemic stroke in the elderly population, independent of known confounding factors.

Delay in neurological attention and stroke outcome

Background and Purpose Despite efforts to reduce the delay between stroke onset and new interventional treatments, no studies have analyzed the repercussions of early neurological attention on the clinical outcome of stroke patients. Methods Data were obtained from 721 patients admitted consecutively for a transient ischemic attack or stroke to the neurology departments of 18 Spanish hospitals that followed the same diagnostic and therapeutic guidelines in the acute phase. Factors assessed were age, sex, Canadian Stroke Scale score on admission, previous Barthel Index, and delay before attention by the first physician, by emergency services, by a neurologist, and before hospitalization. Patients’ outcomes were classified as good (Barthel Index >60) or poor (Barthel Index ≤60 or in-hospital death) depending on patients’ functional capacity on discharge. The individual contribution of each of these variables on clinical outcome was estimated with logistic regression analysis. Results Patients in worse neuro...

Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)

BACKGROUND Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. METHODS We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2×500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale ≤1, modified Rankin score ≤1, and Barthel Index ≥95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. RESULTS 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1·03, 95% CI 0·86-1·25; p=0·364). No significant differences were reported in the safety variables nor in the rate of adverse events. INTERPRETATION Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke. FUNDING Ferrer Grupo.

Current Status and Perspectives of Neuroprotection in Ischemic Stroke Treatment

In developed countries, ischemic stroke is one of the leading causes of death and neurological impairment. The two most important therapeutic approaches in patients with acute cerebral ischemia consist of improving cerebral blood flow and blocking the biochemical and metabolic changes at the ischemic cascade level. The significant advances made in the past decade in the knowledge of the physiopathological mechanisms of cerebral ischemia, and the development of new drugs have given rise to true expectations regarding treatment and the rejection of nihilist attitudes. In the past 15 years, based on the excellent results obtained in experimental models of ischemia, many clinical trials have been conducted with different neuroprotective drugs. The results obtained in most studies have been negative, or the studies were terminated early owing to side effects. However, some drugs (citicoline, clomethiazole, piracetam and ebselen) have shown a certain degree of clinical efficacy, limited to subgroups of patients, and with a narrow therapeutic window, longer-lasting in the case of citicoline. The design of new clinical trials with neuroprotective drugs requires adequate preclinical assessment and the use of the new magnetic resonance techniques for the selection of patients and the assessment of the efficacy of treatment. The new trends in neuroprotection in focal cerebral ischemia and the results of the clinical trials published to date are reviewed.

Prothrombin Fragment 1+2 Is Associated With Carotid Intima-Media Thickness in Subjects Free of Clinical Cardiovascular Disease

Background and Purpose— Thrombin, a central enzyme in the clotting cascade, plays a role not only in thrombosis but also in the progression of atherosclerosis. We studied the relationship between prothrombin fragment 1+2 (F1+2), a specific marker of thrombin generation in vivo, and carotid intima-media thickness (IMT), an index of subclinical atherosclerosis. Methods— We examined 181 asymptomatic middle-aged subjects (mean age 55.6 years, 76.7% men) free of overt clinical atherosclerotic disease. F1+2 was measured by enzyme-linked immunosorbent assay and IMT by duplex ultrasonography of carotid artery. Multiple linear regression analysis was used to assess the relationship between the 2 parameters. Results— Compared with individuals in the lowest tertile of F1+2, those in the upper tertile (>0.55 nmol/L) showed significantly higher IMT (P <0.01). In correlation analysis, a positive relationship was found between plasma F1+2 and carotid IMT. F1+2 also correlated positively with cholesterol (P <0.008) and low-density lipoprotein cholesterol (P <0.005), but not with blood pressure or body mass index. In the multivariate analysis, the association of F1+2 with carotid IMT remained significant (P <0.001) after adjustment for age, sex, body mass index, systolic blood pressure, cholesterol, diabetes, and smoking. Conclusions— In a population sample of adults without clinically overt atherosclerotic disease, the plasma levels of F1+2 were significantly associated with carotid IMT, suggesting a relationship between thrombin generation and the development atherosclerosis.

The cost of stroke.

The control of health expenditure has become one of the main axes of health policy. Cost studies are an indispensable tool for determining the economic impact of disease and for assigning the material and human resources required for the prevention, diagnosis, treatment, and follow-up of patients with different diseases. Cost studies in stroke are necessary due to the increasing incidence of this disease which represents a significant cause of death and invalidity in adults and produces important hospital and social spending, and for which patients must be treated in specialized units (stroke units). The principal cost-determining factors in most studies are those generated by hospital admission (principally hospital stay). Other cost-determining factors include severity, stroke subtype or the fate of patients on discharge. Future health policies aimed at optimizing economic resources must be directed towards reducing hospital stay and minimizing patient disability.

Risk of ischemic stroke and lifetime estrogen exposure

Background: Estrogen loss has been related to higher incidence of stroke in postmenopausal women, but randomized trials have demonstrated an increased risk of stroke in women receiving hormone replacement therapy (HRT). Objective: To assess the relationship between exposure to endogenous ovarian hormones and the risk of noncardioembolic ischemic stroke. Methods: We conducted a multicenter, age-matched, case-control study in postmenopausal women (case: nonembolic ischemic stroke; control: no stroke) comparing duration of ovarian activity or lifetime estrogen exposure, which was defined as age at menarche to age at menopause. Embolic cardiopathy and unreliable gynecologic data were exclusion criteria. Cardiovascular disease risk factors were recorded. The relationships of the principal variables to the risk of stroke were assessed using a conditional logistic regression analysis. Results: There were 430 cases and 905 controls in the study. In the multivariate analysis, hypertension (odds ratio [OR]: 2.73; 95% CI: 2.09 to 3.58; p < 0.0001), diabetes (OR: 3.38; 95% CI: 2.53 to 4.52; p < 0.0001), hyperlipidemia (OR: 1.31; 95% CI: 1.01 to 1.7; p = 0.045), lifespan of ovarian activity <34 years (OR: 1.51; 95% CI: 1.13 to 2.03; p = 0.005), and menarche at <13 years of age (OR 1.49; 95% CI: 1.15 to 1.92; p = 0.002) were independently related to an increased risk of stroke. Obesity (OR: 0.73; 95% CI: 0.56 to 0.95; p = 0.021) was related to a lower risk of stroke. Conclusions: Longer lifetime exposure to ovarian estrogens may protect against noncardioembolic ischemic stroke. However, a very early age of exposure onset could be disadvantageous.

Carotid intima-media thickness changes with Mediterranean diet: A randomized trial (PREDIMED-Navarra) ☆

OBJECTIVE Observational studies have reported inverse associations between adherence to the Mediterranean diet (MedDiet) and atherosclerotic disease. We tested the effect of two types of MedDiet on progression of subclinical carotid atherosclerosis. METHODS We randomized 187 high-cardiovascular-risk asymptomatic subjects (51% women, mean age 67 years) to three treatment arms: MedDiet with supplemental virgin olive oil (VOO), n=66; MedDiet with supplemental nuts, n=59; and control diet, n=62. Participants received nutrition behavioral counseling in quarterly group and individual educational sessions. Free supplemental foods were provided to the MedDiet groups. Changes in mean intima-media thickness (IMT) were measured ultrasonographically in the far wall of bilateral common carotid arteries after 1 year. RESULTS Overall, no significant between-group differences in IMT progression were observed after 1-year. However, a significant interaction (p=0.03) between baseline IMT and treatment effect was apparent. Among participants with baseline IMT≥0.9 mm, 1-year IMT changes versus control showed significant differences of -0.079 mm (95% confidence interval, -0.145 to -0.012) for the MedDiet with VOO and -0.072 mm (-0.140 to -0.004) for the MedDiet with nuts. No IMT changes occurred in any intervention group among participants with lower baseline IMT values (<0.9 mm). CONCLUSIONS MedDiets enhanced with VOO or nuts were not effective in inducing ultrasonographic regression of carotid atherosclerosis after 1 year intervention. However, they were effective among subjects with elevated baseline IMT, suggesting that subclinical atherosclerosis may respond to dietary intervention within a relatively short time frame only among subjects with a high initial atherosclerotic burden.

Refractory migraine in a headache clinic population

BackgroundMany migraineurs who seek care in headache clinics are refractory to treatment, despite advances in headache therapies. Epidemiology is poorly characterized, because diagnostic criteria for refractory migraine were not available until recently. We aimed to determine the frequency of refractory migraine in patients attended in the Headache Unit in a tertiary care center, according to recently proposed criteria.MethodsThe study population consisted of a consecutive sample of 370 patients (60.8% females) with a mean age of 43 years (range 14-86) evaluated for the first time in our headache unit over a one-year period (between October 2008 and October 2009). We recorded information on clinical features, previous treatments, Migraine Disability Assessment Score (MIDAS), and final diagnosis.ResultsOverall migraine and tension-type headache were found in 46.4% and 20.5% of patients, respectively. Refractory migraine was found in 5.1% of patients. In refractory migraineurs, the mean MIDAS score was 96, and 36.8% were medication-overusers.ConclusionsRefractory migraine is a relatively common and very disabling condition between the patients attended in a headache unit. The proposed operational criteria may be useful in identifying those patients who require care in headache units, the selection of candidates for combinations of prophylactic drugs or invasive treatments such as neurostimulation, but also to facilitate clinical studies in this patient group.

Dietary fibre intake is inversely associated with carotid intima-media thickness: a cross-sectional assessment in the PREDIMED study

Objective:To assess the association between the intake of dietary fibre and carotid intima-media thickness (IMT) in a Mediterranean population at high cardiovascular risk.Methods:Baseline cross-sectional assessment of 457 men and women (average age 67 years) from two different Spanish centres of the PREDIMED trial. A previously validated food frequency questionnaire (137 food items) was administered by trained dieticians in a face-to-face interview. Mean common carotid IMT was measured using B-mode ultrasound imaging of the right and left carotid arteries by four certified sonographers who used a common protocol. Anthropometric and blood pressure measurements were performed and samples of fasting blood were obtained. Participants were categorized into four groups (roughly quartiles: ⩽21; >21 to ⩽25; >25 to ⩽31 and >31 g/day) of energy-adjusted intake of dietary fibre. Multiple linear regression models were used to adjust for age, sex, centre, smoking, body mass index, diabetes, blood pressure, lipid levels and statin use.Results:In the crude analyses, energy-adjusted fibre intake showed a significant inverse correlation with IMT (r=−0.27, P<0.001). In multivariate analyses, a modest, though statistically significant (P=0.03) inverse association between energy-adjusted fibre intake and IMT was also found. The multivariate-adjusted difference in average IMT was −0.051 mm (95% confidence interval: −0.094 to−0.009, P=0.02) for participants whose intake was >35 g/day, (n=47) when compared with those whose intake was <25 g/day (n=224).Conclusions:Our results suggest that high fibre intake is inversely associated with carotid atherosclerosis.