Surviving cardiac arrest from severe metformin-associated lactic acidosis using extracorporeal membrane oxygenation and double continuous venovenous haemodialysis.

Metformin-associated lactic acidosis (MALA) is a serious condition with high mortality. This case describes a man in the mid-60s with diabetes mellitus type 2 treated with metformin developing MALA 4 days after coronary stenting for non-ST-elevation myocardial infarction. He presented acutely with severe abdominal pain, a lactate of 19 mmol/L and pH 6.74. Despite treatment for MALA, he went into refractory cardiac arrest and was connected to venoarterial extracorporeal membrane oxygenation (VA-ECMO). He suffered a massive haemothorax due to perforation of the right atrial appendage. It was repaired through a sternotomy while being given massive blood transfusions. The following days, he was on VA-ECMO and double continuous venovenous haemodialysis (CVVHD). He survived with only mild paresis of the left hand. VA-ECMO should be considered a rescue therapy alongside treatment with CVVHD in case of cardiac arrest due to severe MALA.

Plasma concentrations of antipsychotics and QTc prolongation: a pilot study.

Background: Certain antipsychotics are known to cause QTc interval prolongation, which has been associated with increased risk of arrhythmia and sudden death. Previous studies have investigated whether there is an association between oral antipsychotic dose and QTc interval prolongation, however only few have examined the association between antipsychotic plasma concentrations and QTc interval.Material and methods: We performed a cross-sectional study with 22 forensic psychiatric in-patients. We measured the plasma concentration of the prescribed antipsychotics and performed an ECG simultaneously. We used Bazett's formula to calculate QTc and defined QTc as prolonged when: >460 ms for women and >450 ms for men.Results: Seventy-seven percent (n = 17) of the subjects were men (mean age = 40 years) and 91% (n = 20) were diagnosed with schizophrenia. QTc's ranged from 369 to 437 ms. Patients receiving QTc prolonging drugs had significantly greater QTc interval compared to patients receiving non-prolonging drugs. Weak to moderate negative correlations were found between QTc interval and both defined daily dose (DDD) and antipsychotic plasma concentration. There was no statistical difference between the correlations for DDD and plasma concentration versus QTc interval.Conclusion: We did not find a stronger association between antipsychotic plasma concentration and QTc than between antipsychotic dose and QTc. We suggest close monitoring with regular electroencephalogram's until the development of a better marker for predicting the risk of cardiac arrhythmia.

[Alcoholic ketoacidosis].

Alcoholic ketoacidosis is a relatively rare condition, which may have a lethal outcome if left untreated. This review covers definition, pathophysiology, clinical manifestations, diagnostic approach and treatment. Usually, patients respond well and quickly to treatment, if it is started early in the course. Thus, mortality can be significantly reduced.

Utilizing postmortem drug concentrations in mechanistic modeling and simulation of cardiac effects: a proof of concept study with methadone.

Methadone-related poisoning has been found to be the leading and increasing cause of death among intoxication cases in several countries. Aside from respiratory depression, methadone is known to cause QT-prolongation, which may lead to sudden cardiac death. Concentrations in heart tissue should be more accurate for estimating cardiotoxic effects. The aim of this study was to investigate whether the effect of methadone on the QT-interval could be simulated and whether the concentrations in heart tissues allowed for better prediction of the Bazett corrected QT-interval (QTcB). A predictive performance study was conducted using the simulation platform Cardiac Safety Simulator to mimic five literature studies using their described study conditions. Both free and total plasma and heart concentrations were investigated using two different in silico models: the O'Hara-Rudy (ORD) model and the 10 Tusscher (TNNP) model. The results showed that the QTcB of methadone was best predicted either with total plasma using the TNNP model or with free plasma using the ORD model. The ORD model was highly sensitive to the total heart concentrations, resulting in overprediction of the QTcB. The TNNP model also overpredicted the QTcB, but to a lesser degree than the ORD model. Furthermore, due to a low baseline QTcB, the ORD model underpredicted the QTcB for both the free plasma and free heart concentrations. In conclusion, it is possible to simulate the cardiac effects of methadone, yet several elements influence the approach uncertainty including but not limited to biophysically details model of cardiac electrophysiology, exposure data, and input parameters.

Distribution of Eight QT-Prolonging Drugs and Their Main Metabolites Between Postmortem Cardiac Tissue and Blood Reveals Potential Pitfalls in Toxicological Interpretation.

Femoral blood concentrations are usually used in postmortem toxicology to assess possible toxic effects of drugs. This includes QT-prolongation and other cardiac dysrhythmia, which could have been the cause of death. However, blood concentration is only a surrogate for the active site concentration, and therefore cardiac tissue concentration may provide a more accurate toxicological interpretation. Thus, cardiac tissue and femoral and cardiac blood concentrations were examined for eight frequently used QT-prolonging drugs (QTD) and their metabolites in a mentally ill population. In total, 180 cases were included from the Danish autopsy-based forensic study SURVIVE. The concentrations were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry utilizing stable isotopically labeled internal standards. The results showed that the cardiac tissue concentrations were significantly higher compared to femoral and cardiac blood concentrations, with two exceptions. The median cardiac tissue-to-femoral blood concentration ratio (Kb) ranged from 2.2 (venlafaxine) to 15 (nortriptyline). The inter-individual fold difference between the minimum and maximum Kb ranged from 2.6-fold (Z-hydroxynortriptyline) to 61 (venlafaxine). For 12 compounds, postmortem redistribution appeared to be minimal, whereas four compounds displayed some degree of postmortem redistribution. Citalopram and quetiapine were selected for in-depth analysis of the relation between the toxicological interpretation and femoral blood/cardiac tissue concentrations. Within this dataset, citalopram displayed a wide overlap in cardiac tissue concentrations (~50%) between non-toxic and toxic citalopram cases, as estimated from femoral blood concentrations. In contrast, quetiapine displayed no overlap in cardiac tissue concentrations between non-toxic and toxic quetiapine cases based on femoral blood concentrations. The implication of the citalopram finding is that possible intoxications can be overlooked when only considering femoral blood concentrations. Based on the present findings, non-toxic cardiac tissue 10th-90th percentile concentration ranges were estimated for citalopram (0.93-4.4 mg/kg) and quetiapine (0.0073-0.60 mg/kg).

Clinical Pharmacology in Denmark in 2016 - 40 Years with the Danish Society of Clinical Pharmacology and 20 Years as a Medical Speciality.

The Danish Society of Clinical Pharmacology was founded in 1976, and mainly thanks to the persistent efforts of the society, clinical pharmacology became an independent medical speciality in Denmark in 1996. Since then, clinical pharmacology has gone from strength to strength. In the Danish healthcare system, clinical pharmacology has established itself as an indispensible part of the efforts to promote the rational, safe and economic use of drugs. Clinical pharmacologists are active in drug committees both in hospitals and in the primary sector. All clinical pharmacology centres offer a local medicines information service. Some centres have established an adverse drug effect manager function. Only one centre offers a therapeutic drug monitoring service. Clinical pharmacologists are responsible for the toxicological advice at the Danish Poison Information Centre at Bispebjerg University Hospital in the Capital Region. The Department of Clinical Pharmacology at Aarhus University Hospital works closely together with forensic toxicologists and pathologists, covering issues regarding illicit substances, forensic pharmacology, post-mortem toxicology, expert testimony and research. Therapeutic geriatric and psychiatric teach-inns for specialist and junior doctors are among the newest initiatives organized by clinical pharmacologists. Clinical pharmacologists work also in the Danish Medicines Agency and in the Danish pharmaceutical industry, and the latter has in particular a great growth potential for creating new jobs and career opportunities for clinical pharmacologists. As of July 2016, the Danish Society of Clinical Pharmacology has 175 members, and 70 of these are specialists in clinical pharmacology corresponding to approximately 2.5 specialists per 1000 doctors (Denmark has in total 28,000 doctors) or approximately 12 specialists per one million inhabitants.

Risk of prescribing errors in acutely admitted patients: a pilot study.

Background Prescribing errors in emergency settings occur frequently. Knowing which patients have the highest risk of errors could improve patient outcomes. Objective The aim of this study was to test an algorithm designed to assess prescribing error risk in individual patients, and to test the feasibility of medication reviews in high-risk patients. Setting The study was performed at the Acute Admissions Unit at Aarhus University Hospital, Denmark. Methods The study was an interventional pilot study. Patients included were assessed according to risk of prescribing errors with the aid of an algorithm called 'Medication Risk Score' (MERIS). Based on the score, high-risk patients were offered a medication review. The clinical relevance of the medication reviews was assessed retrospectively. Main outcome measure The number and nature of prescribing errors during the patients' hospitalisation. Results The study included 103 patients, all of whom could be risk assessed with the algorithm MERIS. MERIS stratified 38 patients as high-risk patients and 65 as low-risk patients. The 103 patients were prescribed a total of 848 drugs in which 88 prescribing errors were found (10.4 %). Sixty-two of these were found in patients in the high-risk group. In general, the medication reviews were found to be clinically relevant and approximately 50 % of recommendations were implemented. Conclusion MERIS was found to be applicable in a clinical setting and stratified most patients with prescribing errors into the high-risk group. The medication reviews were feasible and found to be clinically relevant by most raters.

Methadone-Related Overdose Deaths in a Liberal Opioid Maintenance Treatment Programme.

BACKGROUND/AIMS: Increasing rates of overdose deaths involving opioid maintenance treatment (OMT) medications and particularly methadone have been observed concurrently with the implementation of liberal OMT strategies (i.e. minimum of control and high doses prescribed). This study examined methadone-related overdose deaths in a liberal OMT programme. METHODS: Drug-overdose deaths (n = 130) with detection of methadone in Copenhagen, Aarhus, and Odense Municipality, Denmark, during the period 2008-2011 were identified from a registry. Cases with and without prescribed methadone as OMT were compared. Treatment delivery strategy among OMT-prescribed methadone cases was investigated. RESULTS: Methadone was detected in 130 overdose deaths (71.4% of all overdose deaths). Among these, 63.1% were receiving methadone maintenance treatment. Of these, 79.3% had co-detection of benzodiazepines. Concomitant detection of heroin, non-prescribed benzodiazepines, and younger age were associated with having non-prescribed methadone in the toxicological findings (adjusted OR 3.1, 4.0 and 9.5, respectively). Of the decedents, 43.8% were prescribed a higher methadone dose than recommended (>120 mg daily), of which 80.0% did not have supervised intake of methadone. CONCLUSIONS: Liberal OMT access does not necessarily prevent overdose deaths overall. Prescription of higher doses of methadone combined with benzodiazepines may result in an increased risk of overdose for individuals in as well as outside OMT.

Quantification of 16 QT-prolonging Drugs and Metabolites in Human Postmortem Blood and Cardiac Tissue Using UPLC-MS-MS.

QT-prolonging compounds present a treatment risk in mentally ill patients. Knowledge of the concentration in the heart compared with blood is necessary to assess the cardiac toxicity of QT-prolonging compounds. To address this issue, this article presents a validated analytical method for the quantification of 16 QT-prolonging drugs (QTD) and metabolites in postmortem whole blood and postmortem cardiac tissue. Samples were prepared by protein precipitation and quantified using ultra-performance liquid chromatography coupled with tandem mass spectrometry. Deuterated internal standards were used. Validation results showed that the bias was ±15% and precision was ≤15% for all compounds in both matrices. The recovery ranged from 78.8 to 127.4%, and the matrix effect ranged from 61.0 to 128.7% across both matrices. The limit of detection and the lower limit of quantification were below the therapeutic concentrations of the prescription drugs. No noteworthy degradation during storage of the extracts was detected. The method was applied in five authentic cases of mentally ill patients. In conclusion, an analytical method was successfully developed and validated for the quantification of QTD in postmortem whole blood and cardiac tissue. To the best of the authors' knowledge, this article presents the first fully validated method for quantification of QTD in cardiac tissue.

Detection of Patients at High Risk of Medication Errors: Development and Validation of an Algorithm.

Medication errors (MEs) are preventable and can result in patient harm and increased expenses in the healthcare system in terms of hospitalization, prolonged hospitalizations and even death. We aimed to develop a screening tool to detect acutely admitted patients at low or high risk of MEs comprised by items found by literature search and the use of theoretical weighting. Predictive variables used for the development of the risk score were found by the literature search. Three retrospective patient populations and one prospective pilot population were used for modelling. The final risk score was evaluated for precision by the use of sensitivity, specificity and area under the ROC (receiver operating characteristic) curves. The variables used in the final risk score were reduced renal function, the total number of drugs and the risk of individual drugs to cause harm and drug-drug interactions. We found a risk score in the prospective population with an area under the ROC curve of 0.76. The final risk score was found to be quite robust as it showed an area under the ROC curve of 0.87 in a recent patient population, 0.74 in a population of internal medicine and 0.66 in an orthopaedic population. We developed a simple and robust score, MERIS, with the ability to detect patients and divide them according to low and high risk of MEs in a general population admitted at acute admissions unit. The accuracy of the risk score was at least as good as other models reported using multiple regression analysis.

[Chronic salicylate poisoning is a challenging diagnosis]. / Kronisk salicylatforgiftning er en svær diagnose.

Chronic salicylate poisoning is often seen in elderly patients as a result of an unintended overdosage, a change in metabolism or kidney function. The symptoms are often unspecific. This case report is about a 55-year-old man who was unconscious when admitted to hospital, and who died three hours after admission. An autopsy and a toxicological test showed a deadly level of salicylate in his blood. Afterwards, his wife told that he had complained about a sudden hearing loss, and that his behaviour had changed prior to his death. It is important to keep this diagnosis in mind when treating especially elderly patients.

Fatal poisoning among patients with drug addiction.

INTRODUCTION: Fatal poisonings among drug addicts in Denmark in 2012 were examined. Cause of death, abuse pattern and geographic differences are discussed and data are compared with previous studies. METHODS: All fatal poisonings examined at the three institutes of forensic medicine in Denmark in 2012 were included in the study. RESULTS: A total of 188 fatal intoxications were recorded. The median age increased from 37.5 in 2007 to 41.5 in 2012. The majority were men (77%). Methadone (59%) was the main intoxicant. The decrease in the frequency of heroin/morphine deaths since 1997 (71%) continued, declining to 44% in 2002, 33% in 2007 and finally to 27% in 2012. Few deaths from central stimulants (amphetamine and cocaine) occurred. Multiple drug use was common and consisted mainly of opioids, cocaine, amphetamine, cannabis, benzodiazepines and alcohol. Heroin/morphine use was most frequent on Funen and in South Jutland. Cocaine was most frequently detected in East Denmark, while amphetamine was more frequent in West Denmark. CONCLUSIONS: The number of fatal poisonings among drug addicts has stabilised around 200. The increase in methadone deaths continued and, as in 2007, methadone was the main intoxicant. The increase in methadone deaths seems to be associated with use of methadone in substitution treatment. Nevertheless, methadone treatment also seems to save lives, as indicated by the increasing median age. Use of antidepressants and antipsychotics increased to a high level compared with 2007, indicating that a considerable number of drug addicts also have psychiatric illness. FUNDING: none. TRIAL REGISTRATION: not relevant.

A fatal poisoning involving 25C-NBOMe.

This paper reports on a fatal overdose case involving the potent hallucinogenic drug 25C-NBOMe (2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine). In the present case, a young male was hospitalized after the recreational use of this potent drug. He died at the hospital at approximately 12h after ingestion, with preceding signs of serotonin toxicity. Medico-legal autopsy was performed on the deceased, during which time peripheral whole blood, urine, vitreous humor, liver and gastric content samples were submitted for toxicological examination. Further, whole blood collected at the hospital at 2-4h following ingestion of the drug was analyzed. 25C-NBOMe and a demethylated and glucuronidated metabolite of 25C-NBOMe were identified in the urine and blood samples using ultra-performance liquid chromatography with high-resolution time-of-flight mass spectrometry (UPLC-HRTOF-MS). Subsequently, 25C-NBOMe was quantified in the peripheral whole blood (0.60µg/kg), urine (2.93µg/kg), vitreous humor (0.33µg/kg), liver (0.82µg/kg) and gastric content (0.32µg total) samples collected during autopsy and in the ante-mortem whole blood (0.81µg/kg) by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). The autopsy findings were consistent with acute poisoning. Based on the toxicological findings, the cause of death was determined to be a fatal overdose of 25C-NBOMe in combination with amphetamine intake. To our knowledge, the present paper reports the first quantification of 25C-NBOMe in biological specimens from a fatal intoxication case.

[Chronic salicylate poisoning is a challenging diagnosis]. / Kronisk salicylatforgiftning er en svær diagnose

Chronic salicylate poisoning is often seen in elderly patients as a result of an unintended overdosage, a change in metabolism or kidney function. The symptoms are often unspecific. This case report is about a 55-year-old man who was unconscious when admitted to hospital, and who died three hours after admission. An autopsy and a toxicological test showed a deadly level of salicylate in his blood. Afterwards, his wife told that he had complained about a sudden hearing loss, and that his behaviour had changed prior to his death. It is important to keep this diagnosis in mind when treating especially elderly patients.

Completeness and positive predictive value of registration of upper limb embolectomy in the Danish National Vascular Registry.

OBJECTIVE: TO EVALUATE COMPLETENESS AND POSITIVE PREDICTIVE VALUE OF THE DANISH NATIONAL VASCULAR REGISTRY REGARDING REGISTRATION OF THE SURGICAL PROCEDURES: embolectomy of brachial, ulnar, or radial artery. STUDY DESIGN AND SETTINGS: The study was based on first-time embolectomies in the brachial, ulnar, or radial artery performed in Denmark from January 1, 1990 to December 31, 2002. The data were primarily retrieved from the Danish National Vascular Registry and secondarily from the Danish National Registry of Patients. Medical records were retrieved using a standardized form. RESULTS: In total, 1433 incident cases of first-time embolectomy were found in both registries. The positive predictive value of the registration was 97.5% (95% confidence interval [CI]; 96.4-98.4). The degree of completeness was 86.5% (95% CI; 84.3-88.5). For the registration period from 1990 till 1996 the degree of completeness was 78.2% (95% CI; 74.4-81.7), and from 1997 till 2002 it was 93.8% (95% CI; 91.6-95.7). CONCLUSION: The completeness and positive predictive value of registration of embolectomy in the upper limb in the Danish National Vascular Registry was 86.5% and 97.5%, respectively. This registry can be a valuable tool for epidemiological research and quality-monitoring.

[Treatment of community-acquired pneumonia--treatment]. / Samfundserhvervet pneumoni--behandling.

Penicillin is the drug of choice for treatment of community-acquired pneumonia (CAP) in Denmark. The primary determinant for therapeutic activity of penicillin is ''penicillin time'' (T>MIC), i.e. time with penicillin concentration above minimum inhibitory concentration. Eradication of S. pneumoniae requires T>MIC above 40-50%. The second determinant for therapeutic activity is the ratio between maximum penicillin concentration in serum and MIC (Cmax/MIC). Considering penicillin pharmacokinetics, intravenous penicillin 2 million units four times a day is recommended as empirical treatment of CAP.

Lost life years attributable to stroke among patients with nonvalvular atrial fibrillation: a nationwide population-based follow-up study.

AIM: We assessed the number of lost life years attributable to stroke among patients with a hospital diagnosis of nonvalvular atrial fibrillation. METHODS: We identified all patients, aged 40-89 years, with an incident hospital diagnosis of atrial fibrillation or flutter in the Danish National Registry of Patients from calendar year 1980 to 2002, and no previous or concomitant diagnosis of stroke or heart valve disease. All patients were followed in the Danish National Registry of Patients for occurrence of an incident diagnosis of stroke of any type (ischemic and/or hemorrhagic) and in the Danish Civil Registration System for emigration or change in vital status. We used multivariate Cox regression analysis with stroke as a time dependent covariate to estimate excess mortality associated with incident stroke. The baseline hazard function for mortality was computed and used for modeling lost life years by sex, age, and time to incident stroke after diagnosis of atrial fibrillation, adjusted for conditions of comorbidity and calendar year of diagnosis of atrial fibrillation. RESULTS: The mean loss of life years attributable to incident stroke within 20 years after a first diagnosis of atrial fibrillation was most frequently less than 5 years, but a mean of up to 10 years of lost life years was observed. The largest number of lost life years was observed in women, in younger patients, and in those who had a stroke early after the diagnosis of atrial fibrillation. The relative loss of life years was up to 90% of the estimated expected remaining lifetime without stroke within 20 years after the diagnosis of atrial fibrillation, and was highest in the elderly. CONCLUSION: Stroke causes a substantial loss of life years in patients with atrial fibrillation.

Age and risk of stroke in atrial fibrillation: evidence for guidelines?

AIM: Guidelines for the clinical management of patients with atrial fibrillation suggest that treatment strategies for prescribing oral anticoagulant therapy should implicate change at age 60, 65 and 75 years. We examined if there is any threshold concerning risk of stroke by age. METHODS: We identified 141,493 subjects, aged 40-89 years, with an incident hospital diagnosis of nonvalvular atrial fibrillation or flutter and no previous or concomitant diagnosis of stroke in the Danish National Registry of Patients from January 1, 1980, to December 31, 2002. The subjects were followed in the Danish National Registry of Patients for the occurrence of an incident diagnosis of stroke of any nature and in the Danish Civil Registration System for emigration and vital status. We examined the risk of stroke by age in men and women using Cox regression models, which included age categorized in intervals, linear splines of age with cut points at age 60 and 75 years, or at age 65 and 75 years. We also analyzed age as a continuous variable in linear and polynomial regression models. RESULTS: During follow-up 15,964 incident strokes were reported to the Danish National Registry of Patients. The risk of stroke increased by increasing age at baseline. We did not find any evidence for a threshold concerning risk of stroke by age, and the best model fit was obtained in a third-order polynomial regression model. CONCLUSION: The risk of stroke increased gradually by increasing age, and we could not detect any threshold concerning risk of stroke by age.

Trend in mortality after stroke with atrial fibrillation.

PURPOSE: To evaluate trend in mortality in stroke associated with atrial fibrillation, we examined mortality trend after stroke with atrial fibrillation by calendar year period (1980-1984, 1985-1989, 1990-1994, 1995-1999, and 2000-2002). We estimated trends separately for each sex in unadjusted analyses. We also adjusted for age, comorbid conditions, and general trend in mortality in the background population. METHODS: We identified all individuals, aged 40-89 years, with an incident diagnosis of stroke of any nature (ischemic or hemorrhagic) and no history of heart valve disease and a previous or concomitant diagnosis of atrial fibrillation or flutter in the Danish National Registry of Patients. Subjects were followed in the Danish Civil Registration System for emigration and vital status. We used multivariate Cox proportional hazards regression analysis to estimate trend in mortality. RESULTS: Incident stroke with a previous or concomitant diagnosis of nonvalvular atrial fibrillation or flutter was diagnosed in 24,470 subjects (11,554 men and 12,916 women). During 34,405 years of observation, 9237 men died, and during 35,381 years of observation, 10,827 women died. The hazard ratio for mortality after stroke in the last 3-year period compared with the first 5-year period was .65 (95% confidence interval [CI], .61-.71) in men and .69 (95% CI, .64-.74) in women. CONCLUSIONS: We observed a substantially better survival in men and women after stroke associated with atrial fibrillation or flutter in Denmark during the years 1980 to 2002. However, we could not control for changes in admission practice, diagnostic performance, or treatment.

Trends in risk of stroke in patients with a hospital diagnosis of nonvalvular atrial fibrillation: National Cohort Study in Denmark, 1980-2002.

AIM: We examined trends in incidence of stroke of any nature (ischemic and/or hemorrhagic) in subjects with a hospital diagnosis of nonvalvular atrial fibrillation or flutter in Denmark from 1980 to 2002 by sex, age and conditions of comorbidity. METHODS: We identified all individuals, aged 40-89 years, with an incident hospital diagnosis of atrial fibrillation or flutter and no history of stroke or heart valve disease in the Danish National Registry of Patients, and subjects were followed in the Danish National Registry of Patients for occurrence of an incident diagnosis of stroke of any nature (ischemic and/or hemorrhagic) and in the Danish Civil Registration System (emigration and vital status). We used multivariate Cox proportional hazard regression analysis to estimate trends in incidence of stroke. RESULTS: Nonvalvular atrial fibrillation or flutter was diagnosed in 141,493 subjects (75,126 men and 66,367 women), and during follow-up 15,964 subjects had an incident diagnosis of stroke. The hazard ratios for stroke in the last 3-year period compared to the first 5-year period, adjusted for 10-year age group, conditions of comorbidity, and general stroke trend in the Danish population were 0.78 (95% CI 0.70-0.86) in men, and 0.80 (95% CI 0.72-0.88) in women. The reduction in risk of stroke by calendar year was most prominent in patients aged 40-74 years. CONCLUSION: We observed a modest decrease in risk of stroke in subject with atrial fibrillation in Denmark during calendar years 1980-2002. However, we could not control for any changes in diagnostic performance, admission practice, and medical management of patients with atrial fibrillation.