Clinical trials with direct oral anticoagulants for stroke prevention in atrial fibrillation: how representative are they for real life patients?

PURPOSE: To identify the proportion of real-life patients with atrial fibrillation (AF) eligible for direct oral anticoagulant (DOAC) therapy, based on the inclusion and exclusion criteria used in the clinical studies and based on the officially approved indications as mentioned in the Summary of Product Characteristics (SmPC). METHODS: Data for this retrospective cross-sectional study was extracted from the UZ Brussel Stroke Registry, containing anonymized data of 2205 patients with a suspected stroke. Characteristics of patients with documented AF were compared with the patient characteristics in clinical trials and the approved indications in the SmPC. RESULTS: Data of 468 patients with AF was analyzed. Based on the selection criteria of the clinical trials, significantly less patients were eligible for treatment with rivaroxaban compared to dabigatran etexilate (39.3 versus 47.6 %; p = 0.010), but not compared to apixaban (45.5 %; p = 0.055). Based on the indications and contraindications in the SmPC, significantly fewer patients were eligible for apixaban compared to dabigatran etexilate and rivaroxaban (62.0 % for apixaban, 72.9 % for dabigatran etexilate, and 75.6 % for rivaroxaban; p < 0.001 and p < 0.001, respectively). Significantly, more patients were eligible for DOAC therapy based on the indications and contraindications in the SmPC compared to the inclusion and exclusion criteria of the clinical trials (72.9 versus 47.6 %; p < 0.001 for dabigatran; 75.6 versus 39.3 %; p < 0.001 for rivaroxaban and 62.0 versus 45.5 %; p < 0.001 for apixaban). CONCLUSION: When taking into account the selection criteria from the pivotal clinical trials with DOACs for stroke prevention in AF, less than half of real-life patients are eligible for therapy with one of the DOACs. However, the indications mentioned in the SmPCs of these drugs are less strict.

Relationship between pre-stroke cardiovascular medication use and stroke severity.

INTRODUCTION: Stroke is a major health problem with important morbidity and mortality. Various risk factors and cardiovascular medication groups are known to have an influence on stroke incidence, but less is known about the relation between medication use and stroke severity. AIM: To determine if relationships exist between the pre-stroke cardiovascular medication use and stroke severity. METHODS: A retrospective study was conducted on a database with anonymized data of 1974 patients with a suspected stroke, admitted to the Universitair Ziekenhuis (UZ) Brussel. Stroke severity was quantified using the National Institute of Health Stroke Scale (NIHSS). Cardiovascular medication groups were first included in a multivariable linear regression model. Second, to obtain clinically interpretable results, all variables that were retained in the final linear regression model were introduced in a cumulative odds ordinal logistic regression model with proportional odds. RESULTS: Angiotensin II receptor blockers (ARBs), statins, and antiarrhythmics were significantly associated with stroke severity at the 10 % α level in a multivariable linear regression model, suggesting a possible effect of these medication groups on stroke severity. Only pre-stroke statin use showed a significant relationship with the NIHSS score in the ordinal logistic regression model with an adjusted odds ratio of 0.740 (95 % CI 0.580-0.944; p = 0.015). CONCLUSION: Pre-stroke use of statins is significantly associated with lower stroke severity. No significant relationship was detected between pre-stroke use of other medication groups and stroke severity, defined by the NIHSS score.

Intracranial artery dissection.

The aim of this narrative review is to evaluate the pathogenesis, clinical features, diagnosis, treatment and prognosis of intracranial artery dissection (IAD). IAD is a rare and often unrecognized cause of stroke or subarachnoid haemorrhage (SAH), especially in young adults. Two types of IAD can be identified: a subintimal or subadventitial dissection. It is suggested that a subintimal dissection results in luminal stenosis, thromboembolism and subsequently cerebral ischaemia, whilst a subadventitial IAD could result in the formation of a pseudo-aneurysm and compression on brainstem or cranial nerves. Rupture of such a dissecting aneurysm causes SAH. The exact cause of IAD remains unknown but several factors are associated with its development. Diagnosis is based on clinical presentation and specific features seen on multimodal neuroimaging. The management of IAD depends on the clinical presentation. In the case of cerebral ischaemia, anticoagulants or antiplatelet agents are used, whilst in the case of SAH endovascular treatment is primarily advocated. Prognosis depends on clinical presentation. Presentation with SAH has a worse prognosis.

Psychosocial problems associated with depression at 18 months poststroke.

OBJECTIVE: With a prevalence that varies between 20% and 65%, poststroke depression (PSD) is a frequent sequel of stroke. The aim of this study was to determine incidence and risk factors for PSD 18 months after stroke. METHODS: As part of the Middelheim Interdisciplinary Stroke Study, patients were followed up for 18 months in this prospective and longitudinal epidemiological study. Clinically significant signs and symptoms of PSD were quantified by means of the Cornell Scale for Depression (CSD) and the Montgomery and Åsberg Depression Rating Scale. Activities, including social activities, were measured with the Stroke Impact Scale (SIS). Relational problems since stroke onset were defined by a questionnaire. RESULTS: Data analysis was performed on 125 patients who completed follow-up assessments. Depression (CSD score ≥8) was diagnosed in 28% of the patients. Patients with PSD were more dependent for activities of daily living and displayed more physical and cognitive impairment than patients without PSD. The risk to become depressed decreased with 5% when the patient's activities increased with one unit on the SIS (odds ratio (OR) = 0.95; 95% confidence interval (CI) = 0.93-0.97). Patients with persistent relational problems since stroke onset had approximately four and a half times greater risk of becoming depressed than patients without (OR = 4.48; 95%CI = 1.17-16.87). CONCLUSIONS: Multiple regression models indicated that the most determining features for developing PSD at 18 months poststroke include reduced activity and relationship problems due to stroke. Further studies on risk factors for PSD are essential, including psychosocial aspects, given its negative impact on rehabilitation and quality of life.

Underestimated Prevalence of Chronic Heart Failure among the Elderly Residing in Care Homes in Aruba.

OBJECTIVE: Diagnosing chronic heart failure (CHF) is important, since subsequent treatments by medication and cardiac intervention improve quality of life. However, accurate CHF diagnosis in the elderly residing in care homes (residents) is hampered by suboptimal diagnostic tools, co-morbidity and physician's unawareness of CHF. We sought to estimate the CHF prevalence among Aruban residents. METHODS: All eligible residents were clinically assessed and screened for CHF signs and symptoms. The diagnosis of CHF was made by final judgment of a cardiologist. Plasma B-type-natriuretic peptide (BNP) levels were determined. RESULTS: Of the 235 residents, 184 (78%) were excluded, mostly because of decreased cognition. The remaining 51 included residents with a mean age of 78 ± 8 years; 57% was female, 59% had diabetes mellitus Type 2 and 71% had renal dysfunction (< 60 mL/min/1.73 m2). Sixteen (31%) had CHF, of which five (31%) were aware of their diagnosis and 11 (69%) were being diagnosed for the first time. Two (29%) residents were previously incorrectly diagnosed with CHF. Most residents with CHF (94%) also had renal dysfunction and 75% had diabetes mellitus Type 2. At a BNP cut-off value of 100 pg/mL, the sensitivity, specificity and predictive values of positive and negative tests were 0.75, 0.69, 0.52 and 0.86, respectively. CONCLUSION: The CHF prevalence in Aruba residents is high (31%) and underestimated. The high CHF prevalence may be related to the high occurrence of diabetes mellitus Type 2 in Arubans. The use of BNP at a cut-off value of 100 pg/mL adds value to the diagnostic work-up of CHF in the elderly residing in care homes.

Pre-stroke use of beta-blockers does not affect ischaemic stroke severity and outcome.

BACKGROUND AND PURPOSE: It is unclear whether pre-stroke beta-blockers use may influence stroke outcome. This study evaluates the independent effect of pre-stroke use of beta-blockers on ischaemic stroke severity and 3 months functional outcome. METHODS: Pre-stroke use of beta-blockers was investigated in 1375 ischaemic stroke patients who had been included in two placebo-controlled trials with lubeluzole. Stroke severity was assessed by either the National Institute of Health Stroke Scale (NIHSS) or the European Stroke Scale (ESS). A modified Rankin scale (mRS) score of >3 at 3 months was used as measure for the poor functional outcome. RESULTS: Two hundred and sixty four patients were on beta-blockers prior to stroke onset, and 105 patients continued treatment after their stroke. Pretreatment with beta-blockers did not influence baseline stroke severity. There was no difference in stroke severity between nonusers and those on either a selective beta(1)-blocker or a non-selective beta-blocker. The likelihood of a poor outcome at 3 months was not influenced by pre-stroke beta-blocker use or beta-blocker use before and continued after stroke onset. CONCLUSIONS: Pre-stroke use of beta-blockers does not appear to influence stroke severity and functional outcome at 3 months.

Spinal cord stimulation modulates cerebral function: an fMRI study.

INTRODUCTION: Although spinal cord stimulation (SCS) is widely used for chronic neuropathic pain after failed spinal surgery, little is known about the underlying physiological mechanisms. This study aims to investigate the neural substrate underlying short-term (30 s) SCS by means of functional magnetic resonance imaging in 20 patients with failed back surgery syndrome (FBSS). METHODS: Twenty patients with FBSS, treated with externalized SCS, participated in a blocked functional magnetic resonance imaging design with stimulation and rest phases of 30 s each, repeated eight times in a row. During scanning, patients rated pain intensity over time using an 11-point numerical rating scale with verbal anchors (0 = no pain at all to 10 = worst pain imaginable) by pushing buttons (left hand, lesser pain; right hand, more pain). This scale was back projected to the patients on a flat screen allowing them to manually direct the pain indicator. To increase the signal-to-noise ratio, the 8-min block measurements were repeated three times. RESULTS: Marked deactivation of the bilateral medial thalamus and its connections to the rostral and caudal cingulate cortex and the insula was found; the study also showed immediate pain relief obtained by short-term SCS correlated negatively with activity in the inferior olivary nucleus, the cerebellum, and the rostral anterior cingulate cortex. CONCLUSIONS: Results indicate the key role of the medial thalamus as a mediator and the involvement of a corticocerebellar network implicating the modulation and regulation of averse and negative affect related to pain. The observation of a deactivation of the ipsilateral antero-medial thalamus might be used as a region of interest for further response SCS studies.

Fabry disease in a patient with Turner syndrome.

We report a unique case with co-occurrence of Turner syndrome and Fabry disease (OMIM #301500). The latter is a rare X-linked lysosomal storage disease that is characterized by partial or complete deficiency of alpha-galactosidase A (GLA; EC 3.2.1.22) following mutations in the gene (GLA) localized at Xq22.1. Accumulation of metabolic intermediates can occur in many tissues and leads to severe morbidity, especially due to renal failure, cardiac involvement and stroke. It is well established that hemizygous male mutation carriers with Fabry disease are generally more severely affected than heterozygous female mutation carriers, but disabling clinical features and disease progression often occur in female Fabry patients as well. The majority of this patient's cells are of the 45,X type, making her a hemizygous GLA mutation carrier displaying a very severe Fabry disease phenotype.

Organisation of inhospital acute stroke care and minimum criteria for stroke care units. Recommendations of the Belgian Stroke Council.

There is ample evidence from randomized trials that for patients with stroke, stroke unit care is superior to care in general medical or neurological wards. This evidence, which has been adopted by international guidelines has to be implemented into daily stroke care. This consensus document prepared by the Belgian Stroke Council provides a set of minimum criteria to meet international standards for stroke care. It is intended to provide help in the creation of stroke units in centers who do not currently have one and to provide a benchmark for centres already having organised stroke care.

Actigraphic measurement of motor deficits in acute ischemic stroke.

BACKGROUND: This study aimed to investigate the use of actigraphy (accelerometry) to measure disuse of the impaired arm in acute stroke patients. We correlated the National Institute of Health Stroke Scale (NIHSS) and the Fugl-Meyer Assessment arm section (FMA) findings with actigraphic data as a measure of validity. METHODS: Thirty-nine acute ischemic stroke patients were included within 1 week after stroke onset. At inclusion, motor deficits were assessed by the NIHSS, FMA and 48-hour actigraphic recordings of both wrists were performed. RESULTS: Moderate but highly significant correlations (Spearman's rho) between actigraphic recordings and total NIHSS (ratio r = -0.59 and activity of impaired arm r = -0.75; p < 0.001) and FMA (ratio r = 0.54 and activity of impaired arm r = 0.69; p < 0.001) scores were found. Based on actigraphic motor activity scores, ROC curves were calculated following dichotomization of the population based on NIHSS = 7 and FMA = 45, showing good sensitivity and specificity, with negative predictive value of 100% and positive predictive value of 91% for the ratio variable. CONCLUSIONS: Moderate but highly significant correlations were found between actigraphy and the stroke scales NIHSS and FMA. Actigraphy was able to reliably discriminate less impaired from more impaired stroke patients with excellent sensitivity and specificity values. Actigraphy is a simple, valid, objective and reliable clinical research tool that can be used to determine motor impairment of the upper limb in stroke patients.

Procarboxypeptidase U (proCPU, TAFI, proCPB2) in cerebrospinal fluid during ischemic stroke is associated with stroke progression, outcome and blood-brain barrier dysfunction.

Essentials Little is known of procarboxypeptidase U (proCPU) in cerebrospinal fluid (CSF) of stroke patients. ProCPU levels were studied in CSF of controls and non-thrombolyzed acute ischemic stroke patients. ProCPU is elevated in CSF of stroke patients compared with controls. ProCPU in CSF correlates with stroke progression, outcome, and blood-brain barrier dysfunction. SUMMARY: Background Procarboxypeptidase U (proCPU, TAFI, proCPB2), the zymogen of CPU, which is a potent antifibrinolytic enzyme and a modulator of inflammation, has previously been investigated in plasma of stroke patients, but so far, no information on the proCPU levels in cerebrospinal fluid (CSF) during acute ischemic stroke (AIS) is available. Objectives This case-control observational study investigates proCPU in CSF of AIS patients compared with controls with an intact blood-brain barrier (BBB) and evaluates the relationship of CSF/plasma proCPU ratios with stroke parameters. Methods A sensitive HPLC-based enzymatic assay was used to determine proCPU levels in CSF of non-thrombolyzed patients in the hyperacute phase (< 24 h after onset) of AIS (n = 72). Individuals (n = 32) without stroke, an intact BBB and no apparent abnormalities in biochemical and microbiological tests, served as controls. Relations between the CSF/plasma proCPU ratio and (i) stroke severity, (ii) stroke progression/recurrence, (iii) stroke outcome and (iv) BBB dysfunction (CSF/serum albumin ratio) were assessed. Results Mean (SEM) proCPU levels were elevated in the CSF of stroke patients compared with controls (4.36 (0.23) U L-1 vs. 3.50 (0.23) U L-1 ). Higher median [IQR] CSF/plasma proCPU ratios were found in patients with stroke progression ((6.0 [4.2-6.9]) × 10-3 ) and poor outcome ((6.4 [3.9-7.0]) × 10-3 ) after 3 months (modified Rankin Scale; mRS > 3) compared with patients without progression ((3.9 [2.7-5.4]) × 10-3 ) or better outcome ((4.0 [2.8-5.0]) × 10-3 ). In stroke patients with a disrupted BBB, proCPU ratios were higher compared with stroke patients with an intact BBB ((6.4 [5.8-9.0]) × 10-3 vs. (3.7 [2.8-5.0]) × 10-3 ). Conclusions ProCPU is increased in CSF during hyperacute ischemic stroke and is associated with stroke progression and outcome after 3 months, most likely due to BBB dysfunction in the hyperacute phase of ischemic stroke.

Uricase of Bacillus fastidiosus. Properties and regulation of synthesis.

Uricase (urate:oxygen oxidoreductase, EC 1.7.3.3) of Bacillus fastidiosus was purified to homogeneity in a two-step procedure and was crystallized. The native molecule had a molecular weight of 145 000--150 000 and was composed of subunits of two kinds (Mr = 36 000 and 39 000) in a 1 : 1 ratio. The quaternary structure of the enzyme was reversibly altered, with concomitant loss of activity, at temperatures between 40 and 60 degrees C. No evidence was found for the involvement of metal ions or coenzymes in the uricase reaction. The enzyme was inhibited by various metal ions and by cyanide. The isoelectric point of the enzyme was 4.3, and pH optimum 9.5 and the optimal temperature 30--35 degrees C. Only uric acid was oxidized by the enzyme and 9-methyluric acid, xanthine, 8-azaxanthine and oxonic acid were competitive inhibitors. Uricase synthesis was repressed by allantoin and allantoate, even in the presence of uric acid, which induced synthesis of the enzyme. Molecular oxygen was an important environmental factor in the control of uricase synthesis, probably due to its effect, as cosubstrate in the uricase reaction, in assessing the cytoplasmic concentration of allantoin. The highest amounts of uricase, up to half of the intracellular soluble protein content, was found in cells growing under limited oxygen supply in media containing uric acid as the main substrate.

Detection and allele-frequencies of the 833T>C, 844ins68 and a novel mutation in the cystathionine beta-synthase gene.

BACKGROUND: The most common 833T>C/844ins68 in cis double mutation in the cystathionine beta synthase (CBS) gene probably is non-pathogenic because the 68-bp insertion eliminates the 833T>C mutation due to alternative splicing. However, allele frequency and effects of the isolated 833T>C mutation are unclear. METHOD: DNA was isolated from 500 volunteers and used directly for PCR-RFLP of CBS gene exon-8. A new primer design was developed to create annealing sites upstream and downstream of exon-8 for forward and reverse primers, respectively. The design was made to exclude sequence homology of the forward primer with the insert fragment and to introduce an internal Bsr1 digestion site. RESULTS: A new 9276G>A mutation was found in intron 8. Because of this mutation, an extra Bsr1 digestion site is created in intron 8. In Caucasian volunteers, the following allele frequencies were found: 833T>C=0.2%, 833T>C/844ins68=10.2%, and 9276G>A=0.2%. CONCLUSION: The developed PCR-RFLP method is able to detect the 833T>C mutation, the 833T>C/844ins68 polymorphism as well as a new 9276G>A mutation in intron 8. Further study should explore the effect of the isolated 9276G>A mutation.

The appearance of mutagens in urine of rats after the administration of benzidine and some other aromatic amines.

The mutagenicity of urine from rats treated with benzidine or 5 other arylamines (0.25 mmol/kg; i.p.) was studied using the Ames-assay. It was found that samples of urine collected for 24 h after the administration of the carcinogens, benzidine, 4-aminobiphenyl and 2-aminonaphthalene, showed significantly mutagenic activity, whereas no mutagenicity was observed in urine after treatment with 3,3'-5,5'-tetramethylbenzidine, 2-aminobiphenyl and 1-aminonaphthalene. Mutagenic activities were dependent on the use of either hepatic S-9 Mix or cytosol as the activating enzyme preparation. The addition of beta-glucuronidase enhanced mutagenicity, except for 2-aminonaphthalene. The appearance of mutagens in urine was studied at varying doses of benzidine and at different time-intervals after the administration. The different excretion patterns found after the activation either with S-9 Mix or with cytosolic enzyme(s) suggest the presence in urine of different types of mutagenic products.

Metabolic activation of 2-aminofluorene by isolated rat liver cells through different pathways leading to hepatocellular DNA-repair and bacterial mutagenesis.

The aromatic amine 2-aminofluorene (2-AF) is metabolised by isolated rat liver cells to reactive species, thereby causing mutagenic effects in Salmonella typhimurium TA 1538 and evoking DNA-excision repair within the liver cells. The pathway leading to the production of metabolites mutagenic in Salmonella is likely to proceed via direct N-hydroxylation of 2-AF to N-hydroxy-2-aminofluorene (N-OH-2-AF). On the other hand, the formation of intermediates giving rise to hepatocellular DNA-repair is shown to depend upon N-acetylation of 2-AF to 2-acetylaminofluorene(2-AAF), whereas a subsequent conjugation reaction, most likely to be sulfate ester formation, is also essentially involved.

Studies on the metabolic activation of benzidine by isolated rat hepatocytes.

Isolated rat liver cells were shown to metabolize the aromatic amine benzidine to reactive products which are mutagenic to Salmonella typhimurium TA 1538 and which give rise to DNA excision repair within the liver cells. Intact rat liver cells are shown to be more active in the formation of mutagenic metabolites than the 9000-g supernatant from these cells. Data are presented which are in favour of the role of N-acetylation in this respect. Furthermore, indications are presented that a sulfation reaction is involved in the generation of DNA modifying metabolites, whereas formation of mutagenic products is likely to proceed via deacetylation and/or N,O-acyltransfer. Finally, data are given about the extrahepatocellular appearance of premutagenic metabolites which are more prone to metabolic activation by additional metabolic factors in the Salmonella assay than benzidine itself. The impact of these observations on the estimation of the genotoxic potential of benzidine will be discussed.

Involvement of non-oxidative enzymes in mutagenic activation of urine from rats, given benzidine and some other aromatic amines.

Urinary metabolites of rats treated with benzidine and some other genotoxic aromatic amines became mutagenic in the Ames assay after activation with liver cytosol from rat, mouse and guinea pig. Most of the mutagenic metabolites appeared in urine as glucuronides. Strong evidence was found that N,O-acyltransferase is responsible for the mutagenic activation by rat liver cytosol. The inhibitory effect of paraoxon and sodium fluoride indicates that the activation by mouse liver cytosol is due to the action of deacetylase. Mutagenic activation by guinea pig liver cytosol seemed to be mediated in part by deacetylase. The metabolite activated by these enzymes most likely is a glucuronidated, N-acetylated, N-hydroxylated product.

Mutagenic effects of benzo[a]pyrene after metabolic activation by hepatic 9000 g supernatants or intact hepatocytes.

The activating capacities of isolated rat hepatocytes and 9000 g supernatant from these cells with respect to the mutagenic effect of benzo[a]pyrene on Salmonella typhimurium TA100 were investigated. No mutagenicity of benzo[a]pyrene was found with the cell-mediated assay, unless the hepatocytes were disrupted after pre-incubation with benzo[a]pyrene or the intracellular glutathione content was reduced. It is suggested that a retention of active metabolites and an effective detoxication may account for the absence of mutagenic response.

Measurement of DNA-excision repair in suspensions of freshly isolated rat hepatocytes after exposure to some carcinogenic compounds: its possible use in carcinogenicity screening.

When suspensions of freshly isolated rat hepatocytes were exposed to a number of carcinogenic compounds, it was possible to measure an increased UDS by a rapid procedure via liquid-scintillation counting. For a number of carcinogenic compounds and some of their non-carcinogenic structural analogues a good correlation between the carcinogenic property and the ability to induce UDS was demonstrable. Out of 12 carcinogenic compounds, belonging to several different chemical classes, 10 gave rise to an increased UDS, whereas only 2 compounds, the polycyclic aromatic hydrocarbons benzo[alpha]pyrene and benz[alpha]anthracene, did not. All 4 noncarcinogenic compounds tested were negative. Possibly this method can be of value as a routine screening test, in combination with other short-term test systems, thus improving the predictive value of screening in vitro with respect to carcinogenicity.

Neurological complications in renal failure: a review.

Neurological complications whether due to the uremic state or its treatment, contribute largely to the morbidity and mortality in patients with renal failure. Despite continuous therapeutic advances, many neurological complications of uremia, like uremic encephalopathy, atherosclerosis, neuropathy and myopathy fail to fully respond to dialysis. Moreover, dialytic therapy or kidney transplantation may even induce neurological complications. Dialysis can directly or indirectly be associated with dialysis dementia, dysequilibrium syndrome, aggravation of atherosclerosis, cerebrovascular accidents due to ultrafiltration-related arterial hypotension, hypertensive encephalopathy, Wernicke's encephalopathy, hemorrhagic stroke, subdural hematoma, osmotic myelinolysis, opportunistic infections, intracranial hypertension and mononeuropathy. Renal transplantation itself can give rise to acute femoral neuropathy, rejection encephalopathy and neuropathy in graft versus host disease. The use of immunosuppressive drugs after renal transplantation can cause encephalopathy, movement disorders, opportunistic infections, neoplasms, myopathy and progression of atherosclerosis. We address the clinical, pathophysiological and therapeutical aspects of both central and peripheral nervous system complications in uremia.