Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators.

BACKGROUND AND PURPOSE: Stroke risk increases with age in patients who have nonvalvular atrial fibrillation. It is uncertain whether the efficacy of stroke prevention therapies in atrial fibrillation changes as patients age. The objective of this study was to determine the effect of age on the relative efficacy of oral anticoagulants (OAC) and antiplatelet (AP) therapy (including acetylsalicylic acid and triflusal) on ischemic stroke, serious bleeding, and vascular events in patients with atrial fibrillation. METHODS: This is an analysis of the Atrial Fibrillation Investigators database, which contains patient level-data from randomized trials of stroke prevention in atrial fibrillation. We used Cox regression models with age as a continuous variable that controlled for sex, year of randomization, and history of cerebrovascular disease, diabetes, hypertension, and congestive heart failure. Outcomes included ischemic stroke, serious bleeding (intracranial hemorrhage or systemic bleeding requiring hospitalization, transfusion, or surgery), and cardiovascular events (ischemic stroke, myocardial infarction, systemic embolism, or vascular death). RESULTS: The analysis included 8932 patients and 17 685 years of observation from 12 trials. Patient age increased risk of ischemic stroke (adjusted hazard ratio per decade increase 1.45; 95% CI, 1.26 to 1.66), serious bleeding (1.61; 1.47 to 1.77), and cardiovascular events (1.43; 1.33 to 1.53). Compared with placebo, OAC and AP significantly reduced the risk of ischemic stroke (OAC, 0.36; 0.29 to 0.45; AP, 0.81; 0.72 to 0.90) and cardiovascular outcomes (OAC, 0.59; 0.52 to 0.66; AP, 0.81; 0.75 to 0.88), whereas OAC increased risk of serious bleeding (1.56; 1.03 to 2.37). The relative benefit of OAC versus placebo or AP did not vary by patient age for any outcome. Compared with placebo, the relative benefit of AP for preventing ischemic stroke decreased significantly as patients aged (P=0.01). CONCLUSIONS: As patients with atrial fibrillation age, the relative efficacy of AP to prevent ischemic stroke appears to decrease, whereas it does not change for OAC. Because stroke risk increases with age, the absolute benefit of OAC increases as patients get older.

Quality of care and mortality among patients with stroke: a nationwide follow-up study.

BACKGROUND: The relationship between process and outcome measures among patients with stroke is unclear. OBJECTIVES: To examine the association between quality of care and mortality among patients with stroke in a nationwide population-based follow-up study. METHODS: Using data from The Danish National Indicator Project, a quality improvement initiative with participation of all Danish hospital departments caring for patients with stroke, we identified 29,573 patients hospitalized with stroke between January 13, 2003 and October 31, 2005. Quality of care was measured in terms of 7 specific criteria: early admission to a stroke unit, early initiation of antiplatelet or oral anticoagulant therapy, early examination with computed tomography/magnetic resonance imaging scan, and early assessment by a physiotherapist, an occupational therapist, and of nutritional risk. Data on 30- and 90-day mortality rates were obtained through the Danish Civil Registration System. RESULTS: Six of 7 of these criteria were associated with lower 30- and 90-day mortality rates. Adjusted mortality rate ratios corrected for clustering by department ranged from 0.41 to 0.83. We found indication of an inverse dose-response relationship between the number of quality of care criteria met and mortality; the lowest mortality rate was found among patients whose care met all criteria compared with patients whose care failed to meet any criteria (ie, adjusted 30-day mortality rate ratios: 0.45, 95% confidence interval: 0.24-0.66). When analyses were stratified by age and sex, the dose-response relationship was found in all subgroups. CONCLUSIONS: Higher quality of care during the early phase of stroke was associated with substantially lower mortality rates.

Diffusion tensor imaging during recovery from severe traumatic brain injury and relation to clinical outcome: a longitudinal study.

Diffusion tensor imaging (DTI) has been proposed as a sensitive biomarker of traumatic white matter injury, which could potentially serve as a tool for prognostic assessment and for studying microstructural changes during recovery from traumatic brain injury (TBI). However, there is a lack of longitudinal studies on TBI that follow DTI changes over time and correlate findings with long-term clinical outcome. We performed a prospective longitudinal study of 30 adult patients admitted for subacute rehabilitation following severe traumatic brain injury. DTI and conventional MRI were acquired at mean 8 weeks (5-11 weeks), and repeated in 23 of the patients at mean 12 months (9-15 months) post-trauma. Using a region-of-interest-based approach, DTI parameters were compared to those of healthy matched controls, scanned during the same time period and rescanned with a similar interval as that of patients. At the initial scan, fractional anisotropy was reduced in all the investigated white matter regions in patients compared to controls (P

Older patients with acute stroke in Denmark: quality of care and short-term mortality. A nationwide follow-up study.

BACKGROUND AND PURPOSE: age may predict level of care and subsequent outcome among patients with stroke. We examined fulfilment of quality-of-care criteria according to age and the possible impact of any age-related differences on short-term mortality in a population-based nationwide follow-up study in Denmark. METHODS: we identified 29,549 patients admitted with stroke between January 2003 and October 2005 in the Danish National Indicator Project (DNIP). Data on 30- and 90-day mortality were obtained from the Civil Registration System. We compared proportions of patients receiving adequate care across age groups, as measured by admission to a specialised stroke unit, administration of antiplatelet or anticoagulant therapy, examination with CT/MR scan, assessment by a physiotherapist and an occupational therapist, or assessment of nutritional risk. Further, we estimated 30- and 90-day mortality rate ratios (MRRs) across age groups, adjusted for fulfilment of quality-of-care criteria and patient characteristics. RESULTS: the proportion of eligible patients who received adequate care declined with age for all the examined processes. The relative risk (RR) of receiving specific components of care ranged from 0.66 (95% confidence interval (CI): 0.60-0.73) to 0.97 (95% CI: 0.95-0.99) when comparing patients >80 years of age with patients < or =65 years of age. Although mortality increased with age, adjusting for the age-related differences in care did not alter the magnitude of the increase. CONCLUSIONS: elderly stroke patients in Denmark receive a lower quality of care than do younger stroke patients, however, the age-related differences are modest for most examined quality-of-care criteria and do not appear to explain the higher mortality among older patients.

Anticoagulation in women with non-valvular atrial fibrillation in the stroke prevention using an oral thrombin inhibitor (SPORTIF) trials.

AIMS: The risk of stroke is greater among women with atrial fibrillation (AF) than men. Warfarin protects against stroke, but treatment-related bleeding occurs more often in women than in men. METHODS AND RESULTS: SPORTIF III (open label, n=3410) and V (double-blind, n=3922) included 2257 women with AF and one or more stroke risk factors randomized to warfarin [target international normalized ratio (INR) 2.0-3.0] or ximelagatran (36 mg twice daily). Primary outcomes were all stroke (ischaemic/haemorrhagic) and systemic embolic event. Women were older, on average, than men, 73.4+/-8.0 vs. 69.8+/-9.0 years (P<0.0001). More women were >75-years old and women had more risk factors than men had (P<0.0001). The INR on warfarin (mean 2.5+/-0.7) was within target range for 67% of follow-up regardless of gender. Women more often developed primary events [2.08%/year, 95% confidence interval (CI) 1.60-2.56%/year vs. 1.44%/year, 95% CI 1.18-1.71%/year in men; P=0.016). Major bleeding rates were similar (P=0.766) but women experienced more overall (major/minor) bleeding (P<0.001). Warfarin was associated with more overall bleeding in both genders and more major bleeding in women than in men (P=0.001). CONCLUSION: When compared with men with AF, women in these studies were older and had more stroke risk factors. Women were more prone to anticoagulant-related bleeding; the higher rate of thrombo-embolism among women was related to more frequent interruption of anticoagulant therapy.

Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.

CONTEXT: In patients with nonvalvular atrial fibrillation, warfarin prevents ischemic stroke, but dose adjustment, coagulation monitoring, and bleeding limit its use. OBJECTIVE: To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, multicenter trial (2000-2001) conducted at 409 North American sites, involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors. INTERVENTIONS: Adjusted-dose warfarin (aiming for an international normalized ratio [INR] 2.0 to 3.0) or fixed-dose oral ximelagatran, 36 mg twice daily. MAIN OUTCOME MEASURES: The primary end point was all strokes (ischemic or hemorrhagic) and systemic embolic events. The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0% per year according to the intention-to-treat model. RESULTS: During 6405 patient-years (mean 20 months) of follow-up, 88 patients experienced primary events. The mean (SD) INR with warfarin (2.4 [0.8]) was within target during 68% of the treatment period. The primary event rate with ximelagatran was 1.6% per year and with warfarin was 1.2% per year (absolute difference, 0.45% per year; 95% confidence interval, -0.13% to 1.03% per year; P<.001 for the predefined noninferiority hypothesis). When all-cause mortality was included in addition to stroke and systemic embolic events, the rate difference was 0.10% per year (95% confidence interval, -0.97% to 1.2% per year; P = .86). There was no difference between treatment groups in rates of major bleeding, but total bleeding (major and minor) was lower with ximelagatran (37% vs 47% per year; 95% confidence interval for the difference, -14% to -6.0% per year; P<.001). Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0% of patients treated with ximelagatran, usually within 6 months and typically declined whether or not treatment continued; however, one case of documented fatal liver disease and one other suggestive case occurred. CONCLUSIONS: The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy, but the potential for hepatotoxicity requires further investigation.

Ximelagatran--a promising new drug in thromboembolic disorders.

Ximelagatran is an oral direct thrombin inhibitor (DTI), the active form of which is melagatran. Approximately 20% of an oral ximelagatran dose becomes bioavailable as melagatran, which binds noncovalently and reversibly to both fibrin-bound and freely circulating thrombin. Oral ximelagatran dosing not only inhibits thrombin activity rapidly, competitively, and potently, but also delays and suppresses thrombin generation. In humans, oral ximelagatran exhibits anticoagulant, antiplatelet, and profibrinolytic effects, with only minor prolongation of the capillary bleeding time. Oral ximelagatran exhibits a stable and predictable pharmacokinetic profile during repeated dosing, with low intra- and inter-individual variation, and a low potential for interaction with other medications. It is excreted primarily as melagatran via the kidney, without unexpected bioaccumulation. Dosing requirements do not vary with age, gender, ethnicity, obesity, or food or alcohol intake. Clinical trials (total n>30,000) have evaluated oral ximelagatran in four indications: the prevention of venous thromboembolism (VTE, comprising deep venous thrombosis with or without and pulmonary embolism) after elective hip- or knee-replacement surgery (with approval granted by France, as the Reference Member State for the European Union); treatment and long-term secondary prevention of VTE; the prevention of stroke and other systemic embolic events associated with nonvalvular atrial fibrillation; and the prevention of cardiovascular events after an acute myocardial infarction. The results of these trials suggest that the benefit-risk profile of oral ximelagatran therapy, administered at a fixed-dose without coagulation monitoring, compares favorably with that of currently approved standard therapy.

[The last case of smallpox in Denmark--the organizing conditions in 1970]. / Det sidste tilfaelde af kopper i Danmark--og de organisatoriske forhold i 1970.

Smallpox contributed to many deaths in Denmark up to the introduction of the vaccination in the beginning of the 19th. Century. The last minor smallpox epidemic in Denmark was in 1924, and subsequently no doctors had special experience in smallpox. In September 1970 a Norwegian medical student died from smallpox in Copenhagen after returning from a journey to Afghanistan, where he has been hospitalized for enteritis. During the 5 days in Copenhagen before hospitalization he had had extensive contacts with many people. He was hospitalized at Blegdamshospital and was isolated, and the diagnosis of smallpox was verified on day 5. He was then totally isolated in a pavilion with 2 nurses and one doctor. The initial diarrhoea (Salmonella typhimurium), and later septicaemia with salmonella, the copious expectoration up to 1 1/2 l pr day (Streptococcus pneumoniae, Klebsiella pneumoniae, E. coli, 9-streptococci), the enormous exudation from the desquamated skin caused large problems concerning water, electrolytes and protein balance, requiring an input up to 13 1 per day. It was necessary to perform tracheotomy and artificial ventilation. He was treated as a patient with extensive burns with metal sheets and when his body temperature fell to 30 degrees C with electrical heat. He died after 25 days of smallpox with complicating extensive skin ulavs corresponding to a pathological picture of toxic epidermal necrolysis (TEN). The containment was successful in cooperation with the Danish National Board on Health, the Medical Officer of Health from Copenhagen and the county (where the patient lived), police, State Serum Institute, and Ministries of the Interior and Foreign Affairs. Vaccination of the exposed persons and the hospital staff, isolation in small groups (maximum 20 persons) of 589 primary contacts in the hospital pavilion-wards and 12 military tents were performed. No secondary cases occurred. The outbreak of smallpox in Copenhagen ended, and the city was not declared "local infected area", and we avoided a panic mass vaccination of large group of people. The article describes these activities, which are effectuated within a few days and headed by a capable and unanimous leadership, in a serious and complicated situation and with an engaged cooperation from the whole staff.

Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin.

BACKGROUND: The rate of stroke in atrial fibrillation (AF) depends on the presence of comorbid conditions and the use of antithrombotic therapy. Although adjusted-dose warfarin is superior to aspirin for reducing stroke in AF, the absolute risk reduction of warfarin depends on the stroke rate with aspirin. This prospective cohort study tested the predictive accuracy of 5 stroke risk stratification schemes. METHODS AND RESULTS: The study pooled individual data from 2580 participants with nonvalvular AF who were prescribed aspirin in a multicenter trial (Atrial Fibrillation, Aspirin, Anticoagulation I study [AFASAK-1], AFASAK-2, European Atrial Fibrillation Trial, Primary Prevention of Arterial Thromboembolism in patients with nonrheumatic Atrial Fibrillation in primary care study, and Stroke Prevention and Atrial Fibrillation [SPAF]-III high risk or SPAF-III low risk). There were 207 ischemic strokes during 4887 patient-years of aspirin therapy. All schemes predicted stroke better than chance, but the number of patients categorized as low and high risk varied substantially. AF patients with prior cerebral ischemia were classified as high risk by all 5 schemes and had 10.8 strokes per 100 patient-years. The CHADS(2) scheme (an acronym for Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack) successfully identified primary prevention patients who were at high risk of stroke (5.3 strokes per 100 patient-years). In contrast, patients identified as high risk by other schemes had 3.0 to 4.2 strokes per 100 patient-years. Low-risk patients identified by all schemes had 0.5 to 1.4 strokes per 100 patient-years of therapy. CONCLUSIONS: Patients with AF who have high and low rates of stroke when given aspirin can be reliably identified, allowing selection of antithrombotic prophylaxis to be individualized.

New approaches to anticoagulation in atrial fibrillation.

Oral direct thrombin inhibitors (DTIs) are a potential alternative to vitamin K antagonists, such as warfarin, for anticoagulant therapy. The oral DTI at the most advanced stage of clinical development is ximelagatran, which is rapidly absorbed and bioconverted to the active form melagatran. Oral ximelagatran has been evaluated in randomized, controlled trials for several indications, including stroke prevention in atrial fibrillation (AF). Recently, two pivotal phase III trials demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin. Oral ximelagatran was generally well tolerated and caused less total (major plus minor) bleeding than warfarin. In a minority of ximelagatran-treated patients, elevated serum alanine aminotransferase levels were reported, but were typically not associated with specific symptoms, and returned toward the pretreatment baseline whether treatment was continued or discontinued. In AF, oral ximelagatran promises a better benefit to risk ratio than warfarin.

Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study.

OBJECTIVES: We sought to compare the tolerability and safety of three fixed doses of ximelagatran versus warfarin in patients with nonvalvular atrial fibrillation (NVAF). BACKGROUND: Anticoagulants such as warfarin lower the risk of stroke in patients with NVAF. Ximelagatran is a novel, oral direct thrombin inhibitor with predictable pharmacokinetics and no known food or pharmacokinetic drug interactions. METHODS: This was a 12-week, randomized, parallel-group, dose-guiding study of NVAF patients with at least one additional risk factor for stroke. The primary end point was the number of thromboembolic events and bleedings. Three groups received ximelagatran (n = 187) at 20, 40, or 60 mg twice daily, given in a double-blind fashion, without routine coagulation monitoring. In a fourth group, warfarin (n = 67) was managed and monitored according to normal routines, aiming for an International Normalized Ratio of 2.0 to 3.0. RESULTS: A total of 254 patients received study drug. One ischemic stroke (nonfatal) and one transient ischemic attack (TIA) occurred in the ximelagatran group. Two TIAs occurred in the warfarin group. No major bleeds were observed in the ximelagatran group. One major bleed occurred in a warfarin-treated patient. The number of minor and multiple minor bleeds was low, but there was a slight increase by ximelagatran dose. The 60-mg dose resulted in the same number of bleeding events as that with warfarin. S-alanine aminotransferase was increased in eight patients (4.3%) taking ximelagatran, but normalized with continuous treatment or cessation of the drug. CONCLUSIONS: Fixed oral doses of ximelagatran up to 60 mg twice daily were well tolerated, without the need for dose adjustment or coagulation monitoring.

A clinical prediction rule to identify patients with atrial fibrillation and a low risk for stroke while taking aspirin.

BACKGROUND: We sought to derive and internally validate a simple and easily applied clinical prediction rule to identify patients with nonvalvular atrial fibrillation (AF) whose stroke risk while taking aspirin is, irrespective of age, low enough that oral anticoagulation therapy is unnecessary. METHODS: We included 2501 patients with AF treated with aspirin during participation in 6 clinical trials. Patients were randomly divided into derivation and validation sets. Recursive partitioning was used to identify patients in the derivation set whose risk for stroke (ischemic or hemorrhagic) or transient ischemic attack was comparable to that observed in an age- and sex-matched cohort from the Framingham Heart Study. The derived prediction rules were tested on the validation set. RESULTS: Overall, 166 patients (6.6%) had an event during 4688.6 person-years (PYs) of observation for an incident rate of 3.5 events per 100 PYs. Patients in the derivation set classified as low risk (no previous stroke or transient ischemic attack, no treated hypertension or systolic blood pressure equal to or exceeding 140 mm Hg, no symptomatic coronary artery disease, and no diabetes) experienced 1.0 events per 100 PYs, compared with an age- and sex-matched rate of 1.2 events per 100 PYs. In the validation set, low-risk patients experienced 1.1 events per 100 PYs (expected rate of 1.2 events per 100 PYs). Low-risk patients made up 24% of the cohort and 16% of patients older than 75 years. Low-risk patients who were randomized to therapeutic oral anticoagulation therapy experienced 1.5 events per 100 PYs. CONCLUSION: Irrespective of age, patients with AF and none of these 4 clinical features and who take aspirin have stroke rates comparable to those of age-matched community cohorts and would not benefit substantially from anticoagulation.

Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis.

CONTEXT: Patients with nonvalvular atrial fibrillation (AF) have an increased risk of stroke and other vascular events. OBJECTIVE: To compare the risk of vascular and bleeding events in patients with nonvalvular AF treated with vitamin K -inhibiting oral anticoagulants or acetylsalicylic acid (aspirin). DESIGN: Pooled analysis of patient-level data from 6 published, randomized clinical trials. PATIENTS: A total of 4052 patients with AF randomly assigned to receive therapeutic doses of oral anticoagulant or aspirin with or without low-dose oral anticoagulants. MAIN OUTCOME MEASURES: Ischemic and hemorrhagic stroke, other cardiovascular events, all-cause death, and major bleeding events. Person-year incidence rates were calculated to provide crude comparisons. Relative efficacy was assessed using proportional hazards modeling stratified by study. The variation of the oral anticoagulant's relative effect by pertinent patient factors was explored with interaction terms. All analyses were conducted using the intention-to-treat principle. RESULTS: Patients receiving oral anticoagulant and aspirin were balanced for important prognostic factors. There was no significant heterogeneity between trials in the relative efficacy of oral anticoagulant vs aspirin for any outcome. Patients receiving oral anticoagulant were significantly less likely to experience any stroke (2.4 vs 4.5 events per 100 patient-years; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.43-0.71), ischemic stroke (HR, 0.48; 95% CI, 0.37-0.63), or cardiovascular events (HR, 0.71; 95% CI, 0.59-0.85) but were more likely to experience major bleeding (2.2 vs 1.3 events per 100 patient-years; HR, 1.71; 95% CI, 1.21-2.41). The reduction in ischemic stroke risk was similar in patients with paroxysmal AF (1.5 vs 4.7 events per 100 patient-years; HR, 0.32; 95% CI, 0.16-0.61; P<.001). Treating 1000 patients with AF for 1 year with oral anticoagulant rather than aspirin would prevent 23 ischemic strokes while causing 9 additional major bleeds. Overall all-cause survival did not differ but appeared to improve for oral anticoagulant patients 3 years after therapy was started. CONCLUSIONS: Compared with aspirin, oral anticoagulant significantly decreases the risk of all strokes, ischemic strokes, and cardiovascular events for patients with nonvalvular chronic or paroxysmal AF but modestly increases the absolute risk of major bleeding. The balance of benefits and risks varies by patient subgroup.