Higher Risk of Ischemic Stroke After an Intracerebral Hemorrhage Than in General Population: A Cohort Study From the United Kingdom.

[Figure: see text].

Use of non-vitamin K antagonist oral anticoagulants in Colombia: A descriptive study using a national administrative healthcare database.

PURPOSE: We aimed to describe time-trends in the use of NOACs among a group of ambulatory patients with nonvalvular atrial fibrillation (NVAF) in Colombia and to describe treatment patterns and user characteristics. METHODS: Using the Audifarma S.A administrative healthcare database in Colombia, we identified 10 528 patients with NVAF aged at least 18 years between July 2009 and June 2017 with a first prescription (index date) for apixaban, dabigatran or rivaroxaban (index NOAC) and followed them for at least year (max, 8.0 years, mean 2.2 years). We described patient characteristics, NOAC use over time, and the dose of the first NOAC prescription. RESULTS: A total of 2153 (20.5%) patients started on apixaban, 3089 (29.3%) on dabigatran and 5286 (50.2%) on rivaroxaban. The incidence of new users of apixaban and rivaroxaban increased over study years while for dabigatran it decreased. Mean age at the index date was: 78.5 years (apixaban), 76.5 years (dabigatran), 76.0 years (rivaroxaban). The percentage of patients started NOAC therapy on the standard dose was: apixaban 38.0%, dabigatran 30.9%, rivaroxaban 56.9%. The percentage still prescribed their index NOAC at 6 months was apixaban 44.6%, dabigatran 51.4%, rivaroxaban 52.7%. Hypertension was the most common comorbidity (>80% in each NOAC cohort). CONCLUSION: During the last decade, the incidence of NOAC use in patients with NVAF affiliated with a private healthcare regime in Colombia has markedly increased. Future studies should evaluate whether the large number of patients with NVAF starting NOAC treatment on a reduced dose are done so appropriately.

Ascertainment and validation of major bleeding events in a primary care database.

PURPOSE: The purpose of the study is to evaluate the impact of validation on the identification of major bleeding events in The Health Improvement Network (THIN) database in patients receiving anticoagulant therapy. METHODS: Patients aged 2 to 89 years with a first prescription for an anticoagulant (rivaroxaban or warfarin) between 2012 and 2015 were identified in THIN. Major bleeding events, defined as bleeding events necessitating hospitalization or referral to accident and emergency services or a specialist clinic, were identified using a 2-step ascertainment process based on read codes only, and then validated using a 2-step process requiring manual review of patients' records. RESULTS: The positive predictive value for the ascertainment of major intracranial (IC) bleeds using only read codes was 96.9%, compared with 70.4% for gastrointestinal (GI) bleeds and 64.1% for urogenital (UG) bleeds. The incidence rate of major IC bleeding events was therefore similar when it was calculated before and after validation (0.32 per 100 person-years and 0.31 per 100 person-years, respectively). The incidence rate of major GI bleeds identified using read codes alone was reduced following validation from 2.05 to 0.94 per 100 person-years, and that of major UG bleeds decreased from 2.45 to 1.11 per 100 person-years. CONCLUSIONS: Major GI and UG bleeding events ascertained from THIN using read codes require validation using additional information to prevent outcome misclassification. The absence of validation may lead to overestimated incidence rates of major bleeding for GI and UG bleeds.

Lack of Association Between Proton Pump Inhibitor Use and Cognitive Decline.

BACKGROUND & AIMS: Studies of association between use of proton pump inhibitors (PPI) and dementia have yielded conflicting results. We investigated the effects of PPIs on cognitive decline in a study of middle-aged and elderly twins in Denmark. METHODS: In a prospective study, we collected data from surveys of middle-aged individuals (46-67 years old; the Middle Aged Danish Twin study) and older individuals (the Longitudinal Study of Aging Danish Twins) who underwent cognitive assessments (a 5-component test battery) over a 10-year period (middle-age study, n = 2346) or a 2-year period (longitudinal study of aging: n = 2475). We determined cumulative use of PPIs 2 years prior study enrollment and during follow up, in defined daily doses (DDDs) of PPIs, using data from a nationwide prescription register. Multi-variable linear regression models were used to examine associations between cumulative PPI use and a composite score of cognitive function at baseline and decreases in scores during the follow-up periods. RESULTS: Use of PPIs before study enrollment was associated with a slightly lower mean cognitive score at baseline in the middle age study. The adjusted difference in mean score of individuals with high consumption of PPIs (≥400 DDD) was lower than that of non-users in the middle-age study (mean crude score for high PPI use, 43.4 ± 13.1 vs for non-use, 46.8 ± 10.2; adjusted difference of 0.69 points; 95% CI, -4.98 to 3.61). In the longitudinal study of aging twins, individuals with high consumption of PPI had higher adjusted scores than non-users (mean crude score for high PPI use, 35.2 ± 10.8 vs for non-use, 36.2 ± 11.1; adjusted difference of 0.95 points; 95% CI, -1.88 to 3.79). In analyses of cognitive decline, among individuals with high consumption of PPIs in the longitudinal study of aging, the adjusted mean difference between baseline score and follow-up score was lower than that of non-users (mean crude score for high PPI use at baseline, 36.6 ± 10.1 and at follow up, 34.3 ± 12.3 vs for non-use at baseline, 38.1 ± 10.5 and at follow up, 37.6 ± 11.3; adjusted difference of -1.22 points; 95% CI, -3.73 to 1.29). In the middle-age study, users with the highest consumption of PPIs (≥1600 DDD) had slightly less cognitive decline than non-users (baseline mean crude score for high PPI use, 43.4 ± 10.1 and follow-up mean crude score, 41.3 ± 9.7 vs baseline score of 49.1 ± 10.2 for non-users and follow-up score of 46.3 ± 9.9 for non-users; adjusted difference of 0.94 points; 95% CI, -1.63 to 3.50). No stated differences in scores between PPI users and non-users were significant. CONCLUSIONS: In analyzing data from 2 large population-based studies of twins in Denmark, we found no association between PPI use and cognitive decline.

Challenges of evaluating chronic heart failure and acute heart failure events in research studies using large health care databases.

Epidemiological studies on heart failure (HF) using large health care databases are becoming increasingly frequent, as they represent an invaluable opportunity to characterize the importance and risk factors of HF from a population perspective. Nevertheless, because of its complex diagnosis and natural history, the heterogeneous use of the relevant terminology in routine clinical practice, and the limitations of some disease coding systems, HF can be a challenging condition to assess using large health care databases as the main source of information. In this narrative review, we discuss some of the challenges that researchers may face, with a special focus on the identification and validation of chronic HF cases and acute HF decompensations. For each of these challenges, we present some potential solutions inspired by the literature and/or based on our research experience, aimed at increasing the internal validity of research and at informing its interpretation. We also discuss future directions on the field, presenting constructive recommendations aimed at facilitating the conduct of valid epidemiological studies on HF in the coming years.

Statins and the Risk of Intracerebral Hemorrhage in Patients With Previous Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Although there is no overall association between statin use and intracerebral hemorrhage (ICH), whether there is an increased risk among those with a history of ischemic stroke (IS) or transient ischemic attack (TIA) remains controversial. We evaluated the relationship of preadmission statin use with the risk of ICH in patients with a history of IS or TIA in a population-based cohort. METHODS: The Health Improvement Network primary care database in the United Kingdom was used to identify new users of low-dose aspirin and a matched comparison. Both cohorts were followed to identify incident cases of ICH, with validation by manual review of patient records and linkage to hospitalization data. In a nested case-control study, we compared the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for ICH based on statin use in the subgroup of individuals with history of IS/TIA. RESULTS: Last statin use within 1 year of ICH (OR, 0.92; 95% CI [confidence interval], 0.60-1.4), last use between 8 days and 1 year (OR, 1.81; 95% CI, 0.99-3.28), and statin use at the time of ICH (OR, 0.77; 95% CI, 0.49-1.21) were not associated with the overall ICH risk among 157 patients with ICH and 884 controls with a history of IS/TIA. There was also no difference in 30-day rates of fatal (OR, 0.82; 95% CI, 0.41-1.64) or nonfatal (OR, 0.90; 95% CI, 0.51-1.57) ICH. CONCLUSIONS: Statin use was not associated with an increased risk of ICH among patients with a previous history of IS/TIA.

Statins and polyneuropathy revisited: case-control study in Denmark, 1999-2013.

AIM: In a previous study, we found a positive association between statin use and polyneuropathy risk. Other studies reported equivocal results. The present study aimed to confirm our findings with a design similar to that used in our previous study but with a larger data set. METHODS: We searched medical registry data to identify patients diagnosed with incident polyneuropathy of no known cause (idiopathic polyneuropathy) between 1999 and 2013; we verified diagnoses through medical records. For each case, we recruited 20 general population controls with no previous history of polyneuropathy. Controls were matched to their respective case for age and gender. We ascertained the prior statin use of cases and controls through a prescription registry. Based on this information, exposure to statins was categorized into 'ever use' or 'never use'. Ever use of statins was classified by how recently they had been used ('current use' or 'past use'); current use was further classified into long-term use (5+ years) and high- or low-intensity use. We used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to examine associations between polyneuropathy and statin use. RESULTS: We included 370 validated cases and 7400 controls. Ever use of statins was not associated with an elevated risk of polyneuropathy (OR 1.14, 95% CI 0.84, 1.54). Similarly, we found no associations between polyneuropathy risk and current use (OR 1.11, 95% CI 0.79, 1.53), long-term use (OR 1.13, 95% CI 0.66, 1.92) or high-intensity statin use (OR 1.05, 95% CI 0.59, 1.84). CONCLUSION: Statin use was not associated with an increased risk of idiopathic polyneuropathy.

Association of Antithrombotic Drug Use With Subdural Hematoma Risk.

IMPORTANCE: Incidence of subdural hematoma has been reported to be increasing. To what extent this is related to increasing use of antithrombotic drugs is unknown. OBJECTIVES: To estimate the association between use of antithrombotic drugs and subdural hematoma risk and determine trends in subdural hematoma incidence and antithrombotic drug use in the general population. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of 10 010 patients aged 20 to 89 years with a first-ever subdural hematoma principal discharge diagnosis from 2000 to 2015 matched by age, sex, and calendar year to 400 380 individuals from the general population (controls). Subdural hematoma incidence and antithrombotic drug use was identified using population-based regional data (population: 484 346) and national data (population: 5.2 million) from Denmark. Conditional logistic regression models were used to estimate odds ratios (ORs) that were adjusted for comorbidity, education level, and income level. EXPOSURES: Use of low-dose aspirin, clopidogrel, a vitamin K antagonist (VKA), a direct oral anticoagulant, and combined antithrombotic drug treatment. MAIN OUTCOMES AND MEASURES: Association of subdural hematoma with antithrombotic drug use, subdural hematoma incidence rate, and annual prevalence of treatment with antithrombotic drugs. RESULTS: Among 10 010 patients with subdural hematoma (mean age, 69.2 years; 3462 women [34.6%]), 47.3% were taking antithrombotic medications. Current use of low-dose aspirin (cases: 26.7%, controls: 22.4%; adjusted OR, 1.24 [95% CI, 1.15-1.33]), clopidogrel (cases: 5.0%, controls: 2.2%; adjusted OR, 1.87 [95% CI, 1.57-2.24]), a direct oral anticoagulant (cases: 1.0%, controls: 0.6%; adjusted OR, 1.73 [95% CI, 1.31-2.28]), and a VKA (cases: 14.3%, controls: 4.9%; adjusted OR, 3.69 [95% CI, 3.38-4.03]) were associated with higher risk of subdural hematoma. The risk of subdural hematoma was highest when a VKA was used concurrently with an antiplatelet drug (low-dose aspirin and a VKA: 3.6% of cases and 1.1% of controls; adjusted OR, 4.00 [95% CI, 3.40-4.70]; clopidogrel and a VKA: 0.3% of cases and 0.04% of controls; adjusted OR, 7.93 [95% CI, 4.49-14.02]). The prevalence of antithrombotic drug use increased from 31.0 per 1000 individuals from the general population in 2000 to 76.9 per 1000 individuals in 2015 (P < .001 for trend). The overall subdural hematoma incidence rate increased from 10.9 per 100 000 person-years in 2000 to 19.0 per 100 000 person-years in 2015 (P < .001 for trend). The largest increase was among older patients (>75 years; n = 4441) who experienced an increase from 55.1 per 100 000 person-years to 99.7 per 100 000 person-years (P < .001 for trend). CONCLUSIONS AND RELEVANCE: In Denmark, antithrombotic drug use was associated with higher risk of subdural hematoma; and the highest odds of subdural hematoma was associated with combined use of a VKA and an antiplatelet drug. The increased incidence of subdural hematoma from 2000 to 2015 appears to be associated with the increased use of antithrombotic drugs, particularly use of a VKA among older patients.

Use of tricyclic antidepressants and risk of glioma: a nationwide case-control study.

BACKGROUND: A protective effect of tricyclic antidepressants (TCAs) against gliomas has been suggested by a small number of studies. We investigated this putative association in a nationwide setting. METHODS: Using a case-control design, we identified all patients with histologically verified glioma (cases) in Denmark between 2000 and 2012 and matched these 1 : 20 to population controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) for glioma associated with long-term (⩾3 years) use of TCAs. Similar analyses were performed for selective serotonin reuptake inhibitors (SSRIs). RESULTS: We identified 3767 glioma cases and 75 340 population controls. Long-term use of TCAs was inversely associated with risk of glioma (OR 0.72, 95% CI: 0.41-1.25). Long-term SSRI use was not associated with glioma risk (OR 0.93, 95% CI: 0.75-1.16). CONCLUSIONS: Our study indicated that long-term use of TCAs may be associated with a reduced risk of glioma, however, the statistical precision was limited. A similar pattern was not observed for use of SSRIs.

Subdural hematoma cases identified through a Danish patient register: diagnosis validity, clinical characteristics, and preadmission antithrombotic drug use.

PURPOSE: This study aimed to assess the usefulness of Danish patient registers for epidemiological studies of subdural hematoma (SDH) and to describe clinical characteristics of validated cases. METHODS: Using a patient register covering a geographically defined area in Denmark, we retrieved hospital contacts recorded under SDH International Classification of Diseases version 10 codes S065 and I620 in 2000-2012. Neurosurgeons reviewed medical records of all potential cases. Based on brain scan results, verified cases were classified by SDH type (chronic SDH (cSDH) or acute SDH (aSDH)). Thirty-day mortality and preadmission antithrombotic drug use were established through linkage to population-based registers. We calculated the positive predictive value of the SDH code and compared mortality and preadmission antithrombotic drug use of cSDH with those of aSDH (age-adjusted and sex-adjusted odds ratio (OR), 95% confidence interval (95%CI)). RESULTS: We verified the diagnosis in 936 of 1185 identified patients. The positive predictive value was highest for hospital contacts with principal discharge diagnosis code S065 (96%) but was low for other contact types under code S065 (25-54%), and only moderate for patients recorded under code I620 (62%). cSDH represented 57% of verified cases, and aSDH the remaining 43%. cSDH differed markedly from aSDH with regard to a number of clinical characteristics, including a much lower mortality (OR 0.2, 95%CI 0.1-0.3). However, preadmission antithrombotic drug use did not vary by SDH type (OR 0.9, 95%CI 0.6-1.2). CONCLUSIONS: Danish patient registers are a useful resource for SDH studies. However, choice of International Classification of Diseases code markedly influences diagnostic validity. Distinction between cSDH and aSDH is not possible based on SDH diagnosis codes only. Copyright © 2016 John Wiley & Sons, Ltd.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.

Risk of acute liver injury associated with use of antibiotics. Comparative cohort and nested case-control studies using two primary care databases in Europe.

PURPOSE: To assess the impact of varying study designs, exposure and outcome definitions on the risk of acute liver injury (ALI) associated with antibiotic use. METHODS: The source population comprised of patients registered in two primary care databases, in the UK and in Spain. We identified a cohort consisting of new users of antibiotics during the study period (2004-2009) and non-users during the study period or in the previous year. Cases with ALI were identified within this cohort and classified as definite or probable, based on recorded medical information. The relative risk (RR) of ALI associated with antibiotic use was computed using Poisson regression. For the nested case-control analyses, up to five controls were matched to each case by age, sex, date and practice (in CPRD) and odds ratios (OR) were computed with conditional logistic regression. RESULTS: The age, sex and year adjusted RRs of definite ALI in the current antibiotic use periods was 10.04 (95% CI: 6.97-14.47) in CPRD and 5.76 (95% CI: 3.46-9.59) in BIFAP. In the case-control analyses adjusting for life-style, comorbidities and use of medications, the OR of ALI for current users of antibiotics was and 5.7 (95% CI: 3.46-9.36) in CPRD and 2.6 (95% CI: 1.26-5.37) in BIFAP. CONCLUSION: Guided by a common protocol, both cohort and case-control study designs found an increased risk of ALI associated with the use of antibiotics in both databases, independent of the exposure and case definitions used. However, the magnitude of the risk was higher in CPRD compared to BIFAP.

Prevalence of antibiotic use: a comparison across various European health care data sources.

PURPOSE: There is widespread concern about increases in antibiotic use, but comparative data from different European countries on rates of use are lacking. This study was designed to measure and understand the variation in antibiotic utilization across five European countries. METHODS: Seven European healthcare databases with access to primary care data from Denmark, Germany, the Netherlands, Spain and the UK were used to measure and compare the point and 1-year-period prevalence of antibiotic use between 2004 and 2009. Descriptive analyses were stratified by gender, age and type of antibiotic. Separate analyses were performed to measure the most common underlying indications leading to the prescription of an antibiotic. RESULTS: The average yearly period prevalence of antibiotic use varied from 15 (Netherlands) to 30 (Spain) users per 100 patients. A higher prevalence of antibiotic use by female patients, the very young (0-9 years) and old (80+ years), was observed in all databases. The lowest point prevalence was recorded in June and September and ranged from 0.51 (Netherlands) to 1.47 (UK) per 100 patients per day. Twelve percent (Netherlands) to forty-nine (Spain) percent of all users were diagnosed with a respiratory tract infection, and the most common type of antibiotic prescribed were penicillin. CONCLUSION: Using identical methodology in seven EU databases to assess antibiotic use allowed us to compare drug usage patterns across Europe. Our results contribute quantitatively to the true understanding of similarities and differences in the use of antibiotic agents in different EU countries.

New-onset type 2 diabetes, elevated HbA1c, anti-diabetic medications, and risk of pancreatic cancer.

BACKGROUND: Associations between type 2 diabetes, anti-diabetic medications and pancreatic cancer are controversial. This study aims to clarify such associations with new-onset type 2 diabetes and repeated measurements of glycated haemoglobin (HbA1c) levels. METHODS: A nested case-control study was initiated from the Health Improvement Network (THIN) in UK from 1996 to 2010. Information of pancreatic cancer cases was retrieved electronically from the medical records and manually validated. Control subjects were randomly selected and frequency-matched to the cases on sex, age, and calendar years. Multivariable unconditional logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI), and adjusted for potential confounders. RESULTS: Among 1,574,768 person-years of follow-up, 529 pancreatic cancer cases and 5000 controls were identified. Type 2 diabetes, or changed HbA1c levels (rather than HbA1c levels at diabetes diagnosis) in diabetes patients (⩾4 mmol mol(-1) compared with <0 mmol mol(-1)) were followed by an increased OR of pancreatic cancer (OR, 2.16, 95% CI 1.72-2.72 and OR, 5.06, 95% CI 1.52-16.87, respectively). Among the anti-diabetic medications in diabetes patients, the OR for insulin users was 25.57 (95% CI 11.55-56.60), sulphonylureas 2.22 (95% CI 1.13, 4.40), and metformin users 1.46 (95% CI 0.85-2.52), compared with no use of any anti-diabetic medications. CONCLUSIONS: New-onset type 2 diabetes and, particularly, diabetes with rising HbA1c seem to be independent risk factors for pancreatic cancer. The relation between different anti-diabetic medications and pancreatic cancer seems to vary in strength, with the highest risk among users of insulin.

The continuation rates of long-acting reversible contraceptives in UK general practice using data from The Health Improvement Network.

PURPOSE: The purpose of this study was to determine the continuation rates of new users of long-acting reversible contraceptive (LARC) methods in the UK, using data from general practice. METHODS: We conducted an observational study using a general practitioner (GP) database, The Health Improvement Network (THIN). The methods studied were copper intrauterine devices (Cu-IUDs), levonorgestrel-releasing intrauterine system (LNG-IUS), progestogen-only implants and progestogen-only injections. The study population comprised women in THIN aged 18-44 years during the period 2004-2009 who had been registered with their GP for at least 5 years, with a computerized prescription history of at least 1 year. Using computer algorithms, the database was searched for the Read and Multilex codes for each LARC method. New LARC users were identified and followed until there was a record indicating termination of use or the study period ended. RESULTS: The proportion of women who discontinued use during the same year of administration was 7.5% for Cu-IUDs, 10.6% for LNG-IUS, 13.2% for progestogen-only implants and 54.4% for progestogen-only injections. By the end of the study, a higher proportion of Cu-IUD and LNG-IUS users (21.1 and 18.6%, respectively) undertook consecutive use of the same method than progestogen-only implant users (10.7%). Manual review of computerized profiles demonstrated the validity of this approach. CONCLUSIONS: In the UK, the continuation rates of LARCs are high, and approximately one fifth of women chose to have a second intrauterine device fitted after expiry of the first device. A validation step demonstrated the reliability of the methodology and computer algorithms used.

Use of long-acting reversible contraceptives in the UK from 2004 to 2010: analysis using The Health Improvement Network Database.

OBJECTIVES: To determine the use of long-acting reversible contraceptives (LARCs) in the UK over the period 2004 to 2010, using the general practice database The Health Improvement Network (THIN). METHODS: Women in THIN, aged 18 to 44 years during 2004 to 2010, who had been registered with their general practitioner for at least five years, with a prescription history of at least one year were included. THIN was searched using the Read and MULTILEX codes for: copper intrauterine devices (Cu-IUDs), the levonorgestrel releasing-intrauterine system (LNG-IUS), progestogen-only implants, and progestogen-only injections. RESULTS: The prevalence of progestogen-only implant use rose from 0.5 to 3.4%, and that of the LNG-IUS from 3.1 to 5.2%. The annual incidence and prevalence of progestogen-only implant use increased for all age groups but was most marked in younger women, whereas the use of the LNG-IUS augmented with increasing age. For all women, there was a small decrease in the prevalence of use of Cu-IUDs (from 5.4 to 4.8%) and progestogen-only injections (from 3.6 to 3.2%). CONCLUSIONS: Uptake of progestogen-only implants and the LNG-IUS increased over the period 2004 to 2010 in the UK, but LARC use in young women remains low.

Recurrent Ischemic Stroke in Patients With Atrial Fibrillation While Receiving Oral Anticoagulants.

Importance: Patients with atrial fibrillation (AF) can have an ischemic stroke (IS) despite oral anticoagulant (OAC) treatment. Knowledge regarding the association between OAC discontinuation and the subsequent risk of recurrent IS in patients with AF is limited. Objectives: To determine the risk of recurrent IS in patients with AF receiving OAC and to evaluate the association between OAC discontinuation and the risk of recurrent IS. Design, Setting, and Participants: This is a nationwide cohort study of patients aged 50 years or older in Denmark who had AF and an IS (entry IS) and were initiating or restarting subsequent OAC treatment after being discharged between January 2014 and December 2021. Patients were followed up for recurrent IS until June 2022. Within this study cohort, a nested case-control analysis was performed in which patients with recurrent IS were matched to patients receiving OAC who had not yet experienced a stroke. Data were analyzed from May 25, 2023, to April 18, 2024. Exposure: Use of OAC at the time of recurrent IS or the equivalent date in matched controls based on redeemed prescriptions. Main Outcomes and Measures: The primary outcome was recurrent IS. Crude and adjusted cumulative incidences of recurrent IS and all-cause mortality were calculated in cohort analyses, and adjusted odds ratios (aORs) were determined for recurrent IS associated with OAC discontinuation in nested case-control analyses. Results: The study cohort included 8119 patients (4392 [54.1%] male; mean [SD] age, 78.4 [9.6] years; median (IQR) CHA2DS2-VASc score, 4.0 [3.0-5.0]). Over a mean (SD) follow-up of 2.9 (2.2) years, 663 patients had a recurrent IS, of whom 533 (80.4%) were receiving OAC at the time of their recurrent IS. The crude cumulative incidence of recurrent IS at 1 year was 4.3% (95% CI, 5.9%-7.1%), and the crude cumulative incidence of all-cause mortality was 15.4% (95% CI, 14.7%-16.2%). Adjusted analysis showed similar results. Patients who discontinued OACs had a higher risk of recurrent IS (89 cases [13.4%], 180 controls [6.8%]; aOR, 2.13; 95% CI, 1.57-2.89) compared with patients still receiving OAC. Conclusions and Relevance: The risks of recurrent IS and mortality were high in patients with AF despite secondary prevention with OAC, and OAC discontinuation doubled the risk of recurrent IS compared with patients who continued OAC. This finding highlights the importance of OAC continuation and the need for improved secondary stroke prevention in patients with AF.

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism in four European countries.

BACKGROUND: The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. METHODS: Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. RESULTS: Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9-63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. CONCLUSIONS: This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials.

Challenges and lessons learned from a long-term postauthorisation safety study programme of rivaroxaban in Europe.

OBJECTIVES: To describe opportunities and challenges experienced from the four pharmacoepidemiological database studies included in the rivaroxaban post authorisation safety study (PASS) programme and propose ways to maximise the value of population-based observational research when addressing regulatory requirements. DESIGN: PASS programme of rivaroxaban carried out as part of the regulatory postapproval commitment to the European Medicines Agency. SETTING: Clinical practice in Germany, the Netherlands, Sweden and the UK (electronic health records)-undertaken by pharmacoepidemiology research teams using country-specific databases with different coding structures. PARTICIPANTS: 355 152 patients prescribed rivaroxaban and 338 199 patients prescribed vitamin K antagonists. RESULTS: Two major challenges that were encountered throughout the lengthy PASS programme were related to: (1) finalising country-tailored study designs before the extent of rivaroxaban uptake was known, and (2) new research questions that arose during the programme (eg, those relating to an evolving prescribing landscape). RECOMMENDATIONS: We advocate the following strategies to help address these major challenges (should they arise in any future PASS): conducting studies based on a common data model that enable the same analytical tools to be applied when using different databases; maintaining early, clear, continuous communication with the regulator (including discussing the potential benefit of studying drug use as a precursor to planning a safety study); consideration of adaptive designs whenever uncertainty exists and following an initial period of data collection; and setting milestones for the review of study objectives.

Incidence of hemorrhagic stroke in the general population: validation of data from The Health Improvement Network.

PURPOSE: The Health Improvement Network (THIN) is a UK healthcare database composed of computerized information from primary care physicians (PCPs). We analyzed the validity of our method for identifying cases of intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) within THIN and assessed the incidence of these events. METHODS: Patients aged 20-89 years were identified and followed until (i) ICH or SAH was detected, (ii) the patient reached 90 years old (iii) death, or (iv) the end of the study. Computerized patient profiles were reviewed manually; those not discarded became potential cases. A validation study was undertaken in 400 computer-detected cases (333 confirmed as potential cases; 67 discarded). PCPs completed a questionnaire to determine the actual incidence of ICH and SAH among these cases. We also assessed the incidence of ICH and SAH in the total cohort. RESULTS: A total of 4330 patients with a READ code suggesting hemorrhagic stroke were identified. Computerized profiles with free-text comments were reviewed manually to identify 3633 potential cases. Responses to the PCP questionnaire were received for 306 potential cases and 63 discarded cases (92% response rate); 82% of potential cases were confirmed. Finally, we identified 3137 cases of hemorrhagic stroke. Crude incidence was 15 per 100,000 person-years for ICH and 11 per 100,000 person-years for SAH; the overall incidence increased sharply with age. CONCLUSIONS: Computer detection of cases of hemorrhagic stroke in THIN followed by manual review of clinical profiles is a valid method. The incidence of hemorrhagic stroke increases sharply with age.