The paraoxonase gene polymorphism in stroke patients and lipid profile

Objectives –  The paraoxonase (PON) gene can reduce the risk of developing atherosclerosis. We investigated the associations between PON polymorphisms and ischemic stroke. We also investigated the associations between PON polymorphisms and lipid profile in stroke patients.
Methods –  A total of 350 patients with ischemic stroke and 242 control subjects in Korean population were genotyped for the PON1M55 L, PON1Q192R, PON2A148 G and PON2S311C polymorphisms using melting point analysis with LightCycler real-time polymerase chain reaction (PCR) technology.
Results –  There were no significant differences in genotype and allele distribution of the PON polymorphisms between the ischemic stroke patients and control subjects. The concentration of total homocysteine was significantly different in the PON1M55 L polymorphism ( P  = 0.047), and the apolipoprotein (Apo)B concentration was significantly different in the PON1Q192R polymorphism ( P  = 0.02) in stroke patients. The concentrations of low-density lipoprotein (LDL) cholesterol and ApoB were significantly different between the PON2A148 G ( P  = 0.011, P  = 0.000, respectively) and PON2S311C polymorphisms ( P  = 0.046, P  = 0.003, respectively) in stroke patients.
Conclusions –  This study did not provide association between PON gene polymorphisms and ischemic stroke. However, it confirmed that the PON1L55 L allele is associated with plasma concentration of total homocysteine and that the PON2G148 G and PON2S311S allele is associated with plasma concentrations of LDL cholesterol and ApoB.     

Lower postprandial gastric volume response in diabetic patients with vagal neuropathy

Poor relaxation in the stomach after a meal may contribute to disturbed gastric emptying and abdominal discomfort in patients with diabetes mellitus. In this study we aimed to compare barostat-recorded postprandial volume responses in these patients to those in healthy controls, and to study the relationship between the proximal volume responses, antral filling and vagal neuropathy.
We compared 14 consecutively recruited patients with type 1 diabetes mellitus (DM) to 18 healthy controls (HC) with respect to meal-induced gastric volume response assessed by a barostat, antral area recorded by ultrasound, and vagal tone assessed by respiratory sinus arrhythmia (RSA).
Meal-induced volume repsponse of the proximal stomach (area under time–volume curve 0–30 min) was significantly (P = 0.04) lower in DM than in HC, 49.4 min.mL ± 60.7 vs. 114.9 min.mL ± 100.8. Antral area was significantly larger in DM than in HC, both fasting (4.3 cm² ± 1.9 vs. 3.0 cm² ± 0.9) and 10 min after ingestion of meat soup (11.8 cm² ± 3.4 vs. 8.8 cm² ± 2.9), P = 0.03 and P = 0.02, respectively. Vagal tone was significantly (P = 0.01) lower in DM than in HC, 3.7 beats min⁻¹ ± 2.3 vs. 6.1 beats min⁻¹ ± 2.2. No significant correlation was observed between the proximal volume responses and antral widening. Maximal gastric volume response correlated significantly with vagal tone (r = 0.77, P = 0.002). Conclusions: patients with diabetes mellitus type 1 have impaired meal-induced volume response, possibly as a consequence of reduced vagal tone.     

Two different doses of Amitriptyline ER in the prophylaxis of migraine: long-term results and predictive factors

Background and purpose:  The rationale for our study was to examine the prophylactic benefit of two doses of amitriptyline over a 6-month observational period in patients with migraine. We aimed at evaluating whether 50 mg of amitryptiline extended release was more effective than 25 mg in reducing the number of migraine days.
Methods:  Primary outcome measure was the reduction of migraine days in time course (i.e., 3 and 6 months after patient enrolment). As secondary analyses, predictors of treatment response were evaluated. Treatment response was defined as reduction of ≥30% and ≥50% in migraine headache days in time course.
Results:  The intent-to-treat population comprised 132 patients (female 96; male 36) with migraine. Median migraine days per month were reduced from 7 days (range: 6–15) at baseline, to 6 days (range: 4–12; P  < 0.001) at 3 months, and to 6 days (range: 3–12; P  < 0.001) at 6 months, respectively. However, no statistically significant difference in the number of migraine days was seen between the two treatment groups at 3 and 6 months. As a result of secondary analyses, the number of migraine days per month at baseline was the only independent predictor of response to amitriptyline treatment (for both definitions of treatment response, i.e., response rate ≥30% and response rate ≥50%) at 6 months.
Conclusions:  The prophylactic effect of amitriptyline seen in our study was rather weak and did not differ between the two treatment groups. The results of this 6-month, prospective, open-label clinical observation are therefore not encouraging.     

Monocyte count is an underlying marker of lacunar subtype of hypertensive small vessel disease

Background:  In the hypertensive small vessel disease (HSVD), it remains unclear why some patients develop lacunar infarcts (LIs) whilst others develop deep intracerebral hemorrhages (dICHs). Inflammation might be related to LI, and leukocyte and monocyte counts are regarded as an inflammatory marker of ischemic stroke.
Objective:  We investigated the relationship between leukocyte and monocyte counts determined in the first 24 h after stroke onset in HSVD patients.
Methods:  We prospectively studied 236 patients with first acute stroke because of HSVD (129 LI and 107 dICH). We analyzed demographic data, vascular risk factors, and white blood cell count subtypes obtained in the first 24 h after stroke.
Results:  The multivariate analysis showed that LI subtype of HSVD was correlated with hyperlipidemia ( P  <   0.0001), a higher monocyte count ( P  =   0.002), and showed a trend with current smoking ( P  =   0.051), whereas dICH subtype was correlated with low serum total cholesterol ( P  =   0.003), low serum triglycerides ( P  <   0.0001), and high neutrophil count ( P  =   0.050).
Conclusions:  In patients who developed HSVD-related stroke, high monocyte count, current smoking, and hyperlipidemia are prothrombotic factors related to LI, whereas low cholesterol and triglyceride values are related to dICH. Monocyte count might be an inflammatory risk marker for the occlusion of small vessels in hypertensive patients.     

Obesity increases risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage

Background: Not all patients with warfarin-related acute intracranial hemorrhage (ICH) achieve full reversal of international normalized ratio (INR) after the first dose of weight-based prothrombin complex concentrate (PCC). We sought to identify factors associated with anticoagulation reversal failure after the first dose of PCC. Methods: Consecutive patients who were hospitalized with warfarin-related acute ICH at a tertiary center between 1 January 2010 and 31 December 2012 were studied. Anticoagulation reversal failure was defined as INR ≥ 1.5 after the first dose of PCC. Logistic regression was performed to determine the predictors of anticoagulation reversal failure. Results: Fifty-one patients with acute ICH received PCC for warfarin reversal using a weight-based protocol. Overall, 23 (45%) patients did not achieve full reversal of INR after the first dose. Those with anticoagulation reversal failure were obese (body mass index > 30 kg/m²) (41% vs. 14%, p = 0.03), had a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001), and had a higher prevalence of initial INR >2.0 (22% vs. 67%, p = 0.001), compared with those who were successfully reversed. Multivariable logistic regression identified obesity (odds ratio 7.88, 95% CI 1.12 to 55.68) and initial INR >2.0 (odds ratio 12.49, 95% CI 2.27 to 68.87) as independent predictors of anticoagulation reversal failure. Conclusions: Obesity and elevated initial INR are independently associated with anticoagulation reversal failure using the weight-based PCC protocol in patients with warfarin-related acute ICH. Further studies are needed to determine more effective dosing protocols and individualized strategies for anticoagulation reversal after acute ICH, especially among obese patients.     

Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients

Atrial fibrillation (AF) carries an increased risk of ischaemic stroke, and oral anticoagulation with warfarin can reduce this risk. The objective of this study was to evaluate the association between time in therapeutic International Normalised Ratio (INR) range when receiving warfarin and the risk of stroke and mortality. The study cohort included AF patients aged 40 years and older included in the UK General Practice Research Database. For patients treated with warfarin we computed the percentage of follow-up time spent within therapeutic range. Cox regression was used to assess the association between INR and outcomes while controlling for patient demographics, health status and concomitant medication. The study population included 27,458 warfarin-treated (with at least 3 INR measurements) and 10,449 patients not treated with antithrombotic therapy. Overall the warfarin users spent 63% of their time within therapeutic range (TTR). This percentage did not vary substantially by age, sex and CHA2DS2-VASc score. Patients who spent at least 70% of time within therapeutic range had a 79% reduced risk of stroke compared to patients with ≤30% of time in range (adjusted relative rate of 0.21; 95% confidence interval 0.18-0.25). Mortality rates were also significantly lower with at least 70% of time spent within therapeutic range. In conclusion, good anticoagulation control was associated with a reduction in the risk of stroke.     

Proposing the stroke levity scale: a valid, reliable, simple, and time-saving measure of stroke severity

Background and purpose:  National Institutes of Health Stroke Scale (NIHSS) is long and complex. Our objective was to design a valid, reliable, simple, and time-saving stroke severity scale.
Methods:  About 103 and 100 consecutive stroke patients in Berlin (Germany) and Ibadan (Nigeria), respectively were evaluated using the measures listed below. The Stroke Levity Scale (SLS) was calculated as maximum power (0–5) in the dexterous hand + maximum power in the weaker lower limb + mobility score−1(if aphasia present).
Results:  It took less than 2 min to administer the SLS in contrast to 8 min for the NIHSS. The SLS showed significant correlation to the NIHSS ( ρ  = −0.79, P  < 0.0001), the modified Rankin Scale ( ρ  = −0.79, P  < 0.0001), and the health-related quality of life (QOL) in stroke patient's questionnaire ( ρ  = 0.78, P  < 0.0001). It had Cronbach's α of 0.75 (Ibadan) and 0.71 (Berlin). The κ -value for test-retest reliability was 0.77 with P  < 0.0001.
Conclusions:  The SLS is a concise, valid, and reliable stroke impairment scale that can be used routinely to monitor outcome in stroke patients. Because it is brief and simple to apply, non-neurologists can be taught to administer it in addition to QOL and disability scales for stroke survivors without significantly increasing the respondent burden.     

Comparative performance of warfarin pharmacogenetic algorithms in Chinese patients

Introduction

Multiple warfarin pharmacogenetic algorithms have been confirmed to predict warfarin dose more accurately than clinical algorithm or the fixed-dose approach. However, their performance has never been objectively evaluated in patients under low intensity warfarin anticoagulation, which is optimal for prevention of thromboembolism in Asian patients.

Material and methods

We sought to compare the performances of 8 eligible pharmacogenetic algorithms in a cohort of Chinese patients (n = 282) under low intensity warfarin anticoagulation with target international normalized ratio (INR) ranged from 1.6 to 2.5. The performance of each algorithm was evaluated by calculating the percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) between each predicted dose and actual stable dose.

Results

In the entire cohort, the pharmacogenetic algorithms could predict warfarin dose with the average MAE of 0.87 ± 0.17 mg/day (0.73-1.17 mg/day), and the average percentage within 20% of 43.8% ± 8.1% (29.1% - 52.1%). By pairwise comparison, warfarin dose prediction was significantly more accurate with the algorithms derived from Asian patients (48.6% - 50.0%) than those from Caucasian patients (29.1% - 39.7%; odds ratio [OR]: 1.61-3.36, p ≤ 0.02). Algorithms with additional covariates of INR values or CYP4F2*3 performed better than those without the covariates (adding INR: OR: 1.71 (1.08-2.72), p = 0.029; adding CYP4F2*3: OR: 2.67(1.41-5.05), p = 0.004). When the patients were stratified according to the dose range, the algorithms from Caucasian and racially mixed populations tended to perform better in higher dose group (≥ 4.5 mg/day), and algorithms from Asian populations performed better in intermediate dose group (1.5-4.5 mg/day). None of the algorithms performed well in lower dose group (≤ 1.5 mg/day).

Conclusions

No eligible pharmacogenetic algorithm could perform the best for all dosing range in the Chinese patients under low intensity warfarin anticoagulation. Construction of a refinement pharmacogenetic algorithm integrating 3 genotypes (CYP2C9, VKORC1 and CYP4F2) and INR data should be warranted to improve the warfarin dose prediction in such patients.     

No predictors of antidepressant patient response to milnacipran were obtained using the three-factor structures of the Montgomery and Asberg Depression Rating Scale in Japanese patients with major depressive disorders

Aims:  Milnacipran, a new specific serotonin and norepinephrine re-uptake inhibitor, is as effective as tricyclic antidepressants. Symptomatological predictors of antidepressant response to milnacipran have not been studied until now.
Methods:  This study included 101 Japanese patients who fulfilled the DSM-IV criteria for the diagnosis of major depressive disorders and whose score on the Montgomery and Åsberg Depression Rating Scale (MADRS) was ≥21. Eighty-three patients were finally included. Patients with a pretreatment MADRS score ≥31 points were defined as severe ( n  = 28), and the rest as non-severe ( n  = 55). The three-factor model of MADRS was used for analysis; the first factor was defined by three items, the second factor was defined by four items and the third factor was defined by three items representing dysphoria, retardation, and vegetative symptoms, respectively. Milnacipran was administered twice daily for 6 weeks. The initial dose was 50 mg/day; after a week it was increased to 100 mg/day.
Results:  No significant difference was observed in the mean score of first factor, second factor and third factor at pretreatment time between responders and non-responders in both severe and non-severe patients.
Conclusions:  No predictor of antidepressant response to milnacipran was obtained using the three-factor structures of the MADRS in Japanese patients with major depressive disorders.     

Allelic association study between phospholipase A2 genes and bipolar affective disorder

Objectives:  In vivo studies demonstrating that lithium is a powerful phospholipase A2 (PLA2) inhibitor suggest that PLA2 activation, and subsequent cell signaling overactivation by increased fatty acid release may be the primary abnormality in bipolar affective disorder (BPAD), thus making PLA2 genes attractive candidates for the susceptibility to BPAD. The present study investigates polymorphisms in cytosolic phospholipase A2 (cPLA2), calcium-independent phospholipase A2 (iPLA2), and secretory phospholipase (sPLA2) genes in a Brazilian sample.
Methods:  A cross-sectional study was performed with 181 unrelated DSM-IIIR BPAD subjects and 312 controls. A polymerase chain reaction–restriction fragment length polymorphism assay for Ban I cPLA2 and Avr II iPLA2 polymorphisms was performed, and an ATT repeat in sPLA2 was assessed using a semiautomated genetic analyzer (ALFexpress).
Results:  There was no significant difference observed in the allelic and genotypic distribution between the BPAD and control groups for cPLA2 (genotype: χ² = 0.8, 2df, p = 0.6; allele χ² = 0, 1df, p = 0.9), iPLA2 (genotype: χ² = 1.7, 2df, p = 0.4; allele: χ² = 0.3, 1df, p = 0.6), and sPLA2 (allele: χ² = 3.6, 6df, p = 0.8).
Conclusion:  Our results failed to demonstrate that the studied PLA2 polymorphisms were associated with an increased risk for BPAD in our sample.     

The classic lacunar syndromes: clinical and neuroimaging correlates

Background:  Although lacunar syndromes (LSs) are aimed to be linked to lacunar infarcts, the relation between both is still not very well defined.
Purpose:  The present retrospective study tries to define more specifically the clinical and the neuroimaging characteristics of the five most classic LSs.
Patients and methods:  Out of a series of 1617 consecutive stroke patients, admitted to the Ghent University Hospital, 293 presented a classic LS. Magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) was performed within 5 days after stroke onset in 227 patients. An acute territorial infarct was demonstrated in 54 patients. The study population finally consisted of 173 patients with a classic LS in whom the responsible lacune was demonstrated or in the absence of another type of infarct.
Results:  The responsible lacune was demonstrated with DWI in 104 patients. Pure motor stroke (MS) correlated significantly with the presence of the responsible lacune in the internal capsule ( P  = 0.000147) and with the stroke severity ( P  = 0.00724). No significant correlation was observed between the location of the lacunes and the other LS's.
Conclusion:  Pure MS has to be considered as the most specific lacunar syndrome.     

Clobazam in the treatment of Lennox-Gastaut syndrome

Purpose:   This randomized, double-blind, dose-ranging study evaluated safety and efficacy of clobazam (CLB) as adjunctive therapy for drop seizures in patients with Lennox-Gastaut syndrome (LGS).
Methods:   Sixty-eight patients with LGS aged 2–26 years were administered CLB (low dose = target 0.25 mg/kg/day; high dose = target 1.0 mg/kg/day). The study consisted of 4-week baseline, 3-week titration, and 4-week maintenance periods, followed by a 3-week taper or continuation in an open-label study. Seizure frequency was recorded in a diary by the parent/caregiver throughout the study.
Results:   Weekly drop seizure rates were significantly reduced from baseline in both the high-dose and low-dose groups; the reduction was significantly greater in the high-dose group. A significantly greater proportion of patients in the high-dose group experienced reductions in drop seizures of ≥25%, ≥50%, and ≥75% compared to the low-dose group; more patients in the high-dose group experienced a 100% reduction, but the difference was not significant. Nondrop seizures were also reduced in a dose-dependent manner. In both investigator and parent/caregiver global evaluations, patients in the high-dose group showed significantly greater improvements in overall symptoms compared to low-dose CLB. Adverse events were generally mild or moderate, and were similar between dose groups. Five serious adverse events were reported in four patients, but in no case was CLB discontinued.
Conclusions:   Clobazam was well tolerated and reduced drop seizure rates; high-dose CLB was more effective than low-dose CLB. Other seizure types were also reduced.     

Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients

The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU), and cytochrome P450 2C9 (CYP2C9) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6-2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A>C SNP in CYP2C9, known as CYP2C93, and then examined an association of these genotypes with warfarin maintenance doses (mean+/-SD=2.96+/-1.06 mg/day). We found an association of effective warfarin dose with the -1639G>A (p=0.004) and 3730G>A genotypes (p=0.006) in VKORC1, the 8016G>A genotype in GGCX (p=0.022), and the 42613A>C genotype in CYP2C9 (p=0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 -1639G>A, 5.2% for CYP2C9 42613A>C, and 4.6% for GGCX 8016G>A. In addition to polymorphisms in VKORC1 and CYP2C9, we identified GGCX 8016G>A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients.     

EBM of cerebral infarction: message from mega-studies]

A meta-analysis by the Antithrombotic Trialists' Collaboration showed significant reduction of vascular events including stroke. MI, and vascular death by antiplatelet therapy in high risk patients with obstructive vascular disease. Low dose aspirin of 75 to 150 mg was most effective and its very low dose below 75 mg was not proven effective. Cilostazol significantly reduced the risk of recurrence in Japanese patients with ischemic stroke, mostly lacunar stroke. Large randomized controlled trials (RCTs) such as MATCH, ACTIVE, and CHARISMA are ongoing to see an effect of aspirin plus clopidogrel. Among patients with non-valvular atrial fibrillation (NVAF), warfarin is recommended in patients at age over 75 years, and those with history of stroke or TIA, hypertension, congestive heart failure, diabetes or coronary heart disease, while aspirin can be alternative in patients without any of these risk factors of stroke. Target INR of 2.0 to 3.0 is recommended in these NVAF patients, although lower INR of 1.6 to 2.5 is recommended to avoid hemorrhagic stroke in elderly patients with NVAF. SPORTIF was conducted to compare ximelagatran, an oral thrombin inhibitor, with warfarin in NVAF patients with risk factors, and the result showed a comparable efficacy and safety of ximelagatran. WARSS did not show any efficacy of warfarin over aspirin in any subtypes of ischemic stroke patients without NVAF, acute MI, left ventricular thrombi, or prosthetic heart valve. PICSS, a substudy of WARSS, also did not show any efficacy of warfarin over aspirin in stroke patients with patent foramen ovale (PFO), although warfarin might be recommended in PFO patients with deep vein thrombosis.     

Interleukin-1β is increased in the cerebrospinal fluid of patients with small infarcts

Background and purpose:  Interleukin-1beta (IL-1β) and interleukin-6 (IL-6) are involved in inflammatory responses during large vessel occlusion in animal models. The aim of this study was to investigate the intrathecal levels of cytokines in patients with acute small infarcts.
Methods:  Forty patients with acute minor stroke and 32 non-stroke patients (including 29 age- and gender-matched subjects) who received operations with spinal anesthesia were studied prospectively and underwent measurements of cerebrospinal fluid (CSF) IL-1β and IL-6 levels.
Results:  After an age- and gender-matched analysis of 58 patients (29 pairs), the mean intrathecal levels of IL-1β were 0.80 pg/ml in patients with small infarcts and 0.59 pg/ml in non-stroke patients ( P  <   0.0001). In addition, the mean CSF levels of IL-6 were 21.54 pg/ml and 7.52 pg/ml in the stroke and control groups, respectively ( P  =   0.38). These results were consistent with the data without matching. The CSF levels of IL-1β in the 40 stroke patients were significantly higher than in the 32 non-stroke controls ( P  <   0.0001).
Conclusions:  The proinflammatory cytokine IL-1β, but not IL-6, remained elevated in the CSF of patients in the acute stage of small infarcts.     

Tuesday July 4, 200613:30–15:00Poster Session 2Clinical Neurophysiology

¹ D. A. Kasteleijn-Nolst Trenité and ² R. Reed (   ¹ Department of Neurological Sciences, University of Rome, Italy ,   ² Research and Development, Abbott Laboratories, Abbott Park, Illinois, USA )
Purpose: To determine whether the sustained therapeutic effect of sodium valproate (VPA) in treating patients with photosensitive epilepsy is due to its intrinsic pharmacodynamic effect or to natural disease remission. Although evidence exists that demonstrates VPA's continued positive clinical and EEG effect, determination of its true long-term effect is confounded by evidence indicating spontaneous remission. The mere finding of continued suppression of a photoparoxysmal response (PPR) with VPA use after serial testing over time is not sufficient evidence of its sustained efficacy.
Method: A chart review of patients with annual serial testing with standardised intermittent photic stimulation (IPS) was conducted. Those selected had IPS during VPA monotherapy without interruption for ≥ 2 years, and after withdrawal of VPA. Spontaneous remission meant no change in PPR range 30 days after the discontinuation of VPA.
Results: Fourteen patients (11F/3M) met our criteria, age = 10 to 69 yrs. The VPA monotherapy total daily dose (13 as Na salt) ranged between 150 and 1800 mg with a median of 600 mg. The suppressive effect of VPA continued up to 12 years (median = 4 yrs). In 1 patient with abolition of the PPR on VPA 600 mg, no change was seen after withdrawal of VPA at age 32; most likely, this is an age effect.
Conclusion: Repeat IPS PPR testing well after VPA withdrawal indicated spontaneous remission of photosensitivity had not occurred in all but 1 patient selected. VPA has proven sustained efficacy (median = 4 years, up to 12 years).     

Vitamin K intake and sensitivity to warfarin in patients consuming regular diets

The effect of dietary vitamin K intake on warfarin sensitivity is known only from case reports and few small clinical studies. We followed 50 patients commencing warfarin and consuming their regular diets (for 8 weeks) to study this relationship. A one-week recall dietary questionnaire was completed at weeks 2 and 8. Daily intake of nutrients and vitamin K was calculated from standard tables. Warfarin sensitivity index (WSI) was defined as final INR/final warfarin dose (mg/day/m2 of body surface area) (week 8). Vitamin K intake was 17-974 (median: 179) microg/day. Median WSI was 0.82 (0.31-4.47). A WSI value of 1.1 significantly separated excess (>250 microg/day) from normal (<250 microg/day) vitamin K consumers (16/18 vs. 15/32, respectively, p <0.01). The former had lower day 5 INR (median: 1.9 vs. 3.0, p <0.001), needed more warfarin to achieve INR > or =2.0 (32.0+/-9.2 mg vs. 25.4+/-6.4 mg, p = 0.009) and required a higher maintenance steady state warfarin dose (5.7+/-1.7 mg/day vs. 3.5+/-1.0 mg/day, p <0.001). We conclude that in 32% (16/50) of anticoagulated patients under usual dietary conditions sensitivity to warfarin is decreased by vitamin K intake > or =250 microg/day.     

Pre-admission warfarin use in patients with acute ischemic stroke and atrial fibrillation: The appropriate use and barriers to oral anticoagulant therapy

INTRODUCTION: Warfarin reduces the risk of stroke in patients with atrial fibrillation. Despite strong guideline recommendations, studies continue to demonstrate the under-use of warfarin in clinical practice. PURPOSE: To determine the prevalence and predictors of warfarin use in patients presenting with atrial fibrillation and acute ischemic stroke who do not have a documented contraindication to anticoagulants. METHODS: We conducted a retrospective chart review of all patients admitted to the Hamilton General Hospital with a primary diagnosis of ischemic stroke and a coded diagnosis of atrial fibrillation between 1999 and 2004. Using a standardized data abstraction form, the following variables were recorded: baseline demographics, past medical history including risk factors for stroke and major bleeding and known predictors of warfarin under-use. In cases where warfarin was not prescribed, charts were also reviewed for documented contraindications to warfarin use. The following were considered valid contraindications to warfarin: patient refusal, non-compliance with INR monitoring, bleeding diathesis, history of major bleeding or significant alcohol consumption. RESULTS: In total, 196 patients with ischemic stroke and atrial fibrillation were identified. Of these patients, 106 were considered to be appropriate candidates for anticoagulation after excluding patients with no known diagnosis of atrial fibrillation prior to admission (N=59), a valid contraindication to warfarin use (N=18), a CHADS2 score <1 (N=6) or a competing diagnosis for warfarin use (N=7). Of the patients deemed to be suitable candidates for warfarin, 57 (54%) were receiving warfarin therapy on admission. On multivariable analyses, increasing age (OR 0.7; 95% CI 0.5-0.9) was associated with a reduced odds of warfarin use while a history of stroke or TIA (OR 2.6; 95% CI 1.1-6.5) and a history of congestive heart failure (OR 3.2; 95% CI 1.1-9.0) were associated with an increased odds of warfarin use in patients without a contraindication to warfarin. While 75% of patients <75 years old were anticoagulated, only 33% of those >85 years were prescribed warfarin on admission to hospital. CONCLUSIONS: early half of all patients presenting with atrial fibrillation and acute ischemic stroke who were suitable candidates for anticoagulation were not prescribed warfarin. In patients not prescribed warfarin, very few had a documented contraindication. Advanced age appears to be the strongest predictor of warfarin non-use.     

丁苯酞对华法林治疗心源性卒中患者抗凝作用的影响

目的 探讨心源性卒中患者使用丁苯酞对华法林抗凝作用的影响。 方法 前瞻性连续纳入成都医学院第一附属医院神经内科2019年6月—2021年12月期间收治的心源性卒中患者,患者入组后随机分为试验组（华法林+丁苯酞）和对照组（华法林）。监测两组患者的国际标准化比值（international standardized ratio,INR）变化情况并收集两组患者的临床资料,比较分析两组患者的INR达标时间、2周内达标率和90 d mRS评分的差异。 结果 本研究共纳入101例心源性卒中患者,试验组51例,对照组50例。两组基线数据（年龄、性别、用药前INR、收缩压和舒张压）差异无统计学意义,入院时试验组的NIHSS评分[10（3.0～15.0）分 vs. 0（0～6.5）分,P<0.001],溶栓率（27.5% vs. 8.0%,P=0.011）与取栓率（25.5% vs. 2.0%,P=0.001）均高于对照组。试验组INR 2周内达标率与对照组相比差异无统计学意义（43.1% vs. 44.0%,P=0.930）。试验组达标时间较对照组明显缩短[（6.50±2.41）d vs.（9.64±4.40）d,P=0.015]。试验组90 d mRS评分与对照组相比,差异无统计学意义[3（0.5～4.0）分 vs. 2（0～3.0）分,P=0.175]。 结论 丁苯酞联合华法林治疗心源性卒中可能缩短华法林的达标时间,需进一步的研究来验证,但对于INR的达标率和90 d mRS评分无影响。     

Morning surge in circadian periodicity of ischaemic stroke is independent of conventional risk factor status: findings from the Takashima Stroke Registry 1990–2003

Background:  We examined the circadian periodicity of ischaemic stroke (IS) onset and its relationship with conventional risk factors using 14-year stroke registration data.
Methods:  Ischaemic stroke event data were acquired from the Takashima Stroke Registry, which covers a stable population of ≈55 000 in Takashima County in central Japan. During 1990–2003 there were 637 (353 men and 284 women) cases with classifiable onset time. IS incidence was categorized as occurring at night (midnight to 6  am ), morning (6  am to noon), afternoon (noon to 6  pm ), and evening (6  pm to midnight). The OR (with 95% CI) of having an IS in the morning, afternoon, and evening were calculated, with night serving as reference.
Results:  There was significant diurnal variation in IS incidence ( P  <   0.001). The proportion of events was highest in the morning (40.7; 95% CI: 36.9–44.5), and lowest in the night (14.0; 95% CI: 11.5–16.9). In the morning an excess incidence of IS was observed in both genders, in subjects <65 years and ≥65 years, and in all IS subtypes. The morning excess of IS incidence was similar across seasons and days of the week. For all IS, morning excess was higher (odds ratio: 2.91; 95% CI: 2.29–3.70) compared to the night period. Similar trends persisted after adjusting for age, gender, and risk factors.
Conclusion:  In the examination of circadian variation of IS onset, a predominant morning peak independent of conventional risk factors was observed in a Japanese population with similar pattern across seasons of the year and days of the week.