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.

Safety and effectiveness of rivaroxaban for prevention of stroke in patients with nonvalvular atrial fibrillation: analysis of routine clinical data from four countries.

BACKGROUND: The safety and effectiveness of rivaroxaban versus vitamin K antagonists (standard of care [SOC]) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) was evaluated in Europe. RESEARCH DESIGN AND METHODS: Observational studies were conducted in the UK, the Netherlands, Germany, and Sweden. Primary safety outcomes were hospitalization for intracranial hemorrhage, gastrointestinal bleeding, or urogenital bleeding among new users of rivaroxaban and SOC with NVAF; outcomes were analyzed using cohort (rivaroxaban or SOC use) and nested case-control designs (current vs nonuse). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. RESULTS: Overall, 162,919 rivaroxaban users and 177,758 SOC users were identified. In the cohort analysis, incidence ranges for rivaroxaban users were 0.25-0.63 events per 100 person-years for intracranial bleeding, 0.49-1.72 for gastrointestinal bleeding, and 0.27-0.54 for urogenital bleeding. Corresponding ranges for SOC users were 0.30-0.80, 0.30-1.42, and 0.24-0.42, respectively. In the nested case-control analysis, current SOC use generally presented a greater risk of bleeding outcomes than nonuse. Rivaroxaban use (vs nonuse) was associated with a higher risk of gastrointestinal bleeding, but a similar risk of intracranial or urogenital bleeding, in most countries. Ischemic stroke incidence ranged from 0.31 to 1.52 events per 100 person-years for rivaroxaban users. CONCLUSIONS: Incidences of intracranial bleeding were generally lower with rivaroxaban than with SOC, whereas incidences of gastrointestinal and urogenital bleeding were generally higher. The safety profile of rivaroxaban for NVAF in routine practice is consistent with findings from randomized controlled trials and other studies.

Identification and Validation of Major Cardiovascular Events in the United Kingdom Data Sources Included in a Multi-database Post-authorization Safety Study of Prucalopride.

INTRODUCTION: A multinational post-authorization safety study assessed cardiovascular safety in initiators of prucalopride for chronic constipation compared with a matched cohort of polyethylene glycol 3350 initiators. The primary safety outcome was major adverse cardiovascular events (MACE), a composite of hospitalization for acute myocardial infarction, stroke, or in-hospital cardiovascular death. We report the validation process for MACE endpoints in United Kingdom (UK) data sources: Clinical Practice Research Datalink (CPRD GOLD), The Health Improvement Network (THIN), and the Information Services Division (ISD) Scotland. METHODS: Modified electronic algorithms from prior research identified potential MACE cases. Validation followed a common protocol, adapted for each database, with all information anonymized: (1) direct confirmation via linkage to hospital records (CPRD GOLD); (2) requests for additional clinical information through questionnaires (CPRD GOLD), free-text (THIN), or abstraction of hospital records (ISD); (3) manual review of electronic records of potential events retrieved by the algorithm (CPRD GOLD/THIN); and (4) event adjudication by three clinicians, blinded to exposure, for all remaining events. RESULTS: Electronic algorithms identified 260 potential MACE cases: 38 confirmed via linkage to hospital records (CPRD GOLD), 56 ruled out as non-cardiovascular death cases (THIN), and three unavailable for review (ISD), leaving 163 potential cases. After manual review with additional information (steps 2 and 3), 45 were considered noncases (CPRD GOLD/THIN). Upon final adjudication (step 4), remaining potential events were adjudicated as definite (n = 62), probable (n = 10), possible (n = 13), or noncases (n = 33). CONCLUSIONS: Given the limitations of relying solely on computer algorithms to identify cardiovascular outcomes, validation with clinical review is essential to guide interpretation.

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.

Validation of venous thromboembolism diagnoses in patients receiving rivaroxaban or warfarin in The Health Improvement Network.

PURPOSE: To describe the effect that validation of venous thromboembolism (VTE) coded entries in the health improvement network (THIN) has on incidence rates of VTE among a cohort of rivaroxaban/warfarin users. METHODS: Among 36 701 individuals with a first prescription for rivaroxaban/warfarin between 2012 and 2015, we performed a two-step VTE case identification process followed by a two-step case validation process involving manual review of patient records. A valid case required a coded entry for VTE at some point after their first rivaroxaban/warfarin prescription with evidence of referral/hospitalization either as a coded entry or entered as free text. Positive predictive values (PPVs) with 95% confidence intervals (CIs) were calculated using validated cases as the gold standard. Incidence rates were calculated per 1000 person-years with 95% CIs. RESULTS: We identified 2166 patients with a coded entry of VTE after their initial rivaroxaban/warfarin prescription; incidence rate of 45.31 per 1000 person-years (95% CI: 43.49-47.22). After manual review of patient records including the free text, there were 712 incident VTE cases; incidence rate of 14.90 per 1000 person-years (95% CI: 13.85-16.02). The PPV for coded entries of VTE alone was 32.9%, and the PPV for coded entries of VTE with a coded entry of referral/hospitalization was 39.8%; this increased to 69.6% after manual review of coded clinical entries in patient records. CONCLUSIONS: Among rivaroxaban/warfarin users in THIN, valid VTE case identification requires manual review of patient records including the free text to prevent outcome misclassification and substantial overestimation of VTE incidence rates.

Rationale and design of a European epidemiological post-authorization safety study (PASS) program: rivaroxaban use in routine clinical practice.

BACKGROUND: Rivaroxaban is a highly selective factor Xa inhibitor approved for use in Europe for multiple indications. STUDY DESIGN AND METHODS: The European rivaroxaban epidemiological post-authorization safety study (PASS) program consists of seven complementary observational studies. For four of the studies, data are obtained from health-care databases in the UK, the Netherlands, Germany, and Sweden. These database studies describe patterns of rivaroxaban use and patient characteristics over time, and investigate safety and effectiveness outcomes in new users of rivaroxaban using a cohort analysis and nested case-control analysis. To put these results in context, safety outcomes are also analyzed in new users of standard of care. In addition, a modified prescription event monitoring study conducted in the early post-launch phase in primary care, and two specialist cohort event monitoring studies that investigated rivaroxaban use in the secondary care hospital setting, systematically collected drug utilization and safety data via questionnaires completed by health-care professionals in the UK. DISCUSSION: The European rivaroxaban epidemiological PASS is a comprehensive program of complementary studies generating evidence from patients treated in routine clinical practice that will expand our understanding of the risk-benefit profile of rivaroxaban.

Discontinuation of non-Vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation: a population-based cohort study using primary care data from The Health Improvement Network in the UK.

OBJECTIVE: To determine discontinuation rates, patterns of use and predictors of discontinuation of non-vitamin K antagonist oral anticoagulants (NOACs) among patients with non-valvular atrial fibrillation (NVAF) in the first year of therapy. DESIGN: Population-based cohort study. SETTING: UK primary care. POPULATION: 11 481 patients with NVAF and a first prescription (index date) for apixaban, dabigatran or rivaroxaban (January 2012 to December 2016) with at least 1 year of follow-up and at least one further NOAC prescription in the year following the index date were identified. 1 year rates and patterns of discontinuation were described. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome measures were the percentage of patients who, in the first year from starting NOAC therapy, discontinued with their oral anticoagulant (OAC) therapy (discontinuation was defined as a gap in OAC therapy of >30 days); switched OAC within 30 days; discontinued and reinitiated OAC therapy. Predictors of discontinuation were also evaluated. RESULTS: 1 year discontinuation rates according to the index NOAC were 26.1% for apixaban, 40.0% for dabigatran and 29.6% for rivaroxaban. Reinitiation rates were 18.1% for apixaban, 21.7% for dabigatran and 17.3% for rivaroxaban, and switching rates were 2.8% for apixaban, 8.8% for dabigatran and 4.9% for rivaroxaban. More than 93% of reinitiations were with the index NOAC. Patients starting on dabigatran were more likely to switch OAC therapy than those starting on apixaban; ORs 4.28 (95% CI 3.24 to 5.65) for dabigatran and 1.89 (95% CI 1.49 to 2.39) for rivaroxaban. Severely reduced renal function was a predictor of any discontinuation, OR 1.77 (95% CI 1.28 to 2.44). CONCLUSION: While the majority of patients with NVAF in the UK initiating NOAC treatment received continuous therapy in the first year of treatment, a substantial proportion of patients experienced gaps in treatment leaving them less protected against thromboembolism during these periods.

Appropriateness of initial dose of non-vitamin K antagonist oral anticoagulants in patients with non-valvular atrial fibrillation in the UK.

OBJECTIVE: To evaluate the appropriateness of the initial prescribed daily dose of non-vitamin K antagonist oral anticoagulants (NOACs) according to label in patients with non-valvular atrial fibrillation (NVAF) in the UK. DESIGN: Population-based cross-sectional study. SETTING: UK primary care. POPULATION: 30 467 patients with NVAF and a first prescription for apixaban, dabigatran or rivaroxaban between January 2011 and December 2016. MAIN OUTCOME MEASURES: Percentage of patients prescribed a NOAC dose according to the European Union (EU) labels (appropriately dosed), and not according to the EU labels (inappropriately dosed-including both underdosed and overdosed patients); percentage of patients prescribed an initial NOAC dose according to renal function status. RESULTS: A total of 15 252 (50.1%) patients started NOAC therapy on rivaroxaban, 10 834 (35.6%) on apixaban and 4381 (14.4%) on dabigatran. Among patients starting NOAC therapy on rivaroxaban, 17.3% were eligible to receive a reduced dose compared with 12.8% of patients starting on apixaban and 53.8% of patients starting on dabigatran. The majority of patients were prescribed an appropriate dose according to the EU labels: apixaban 74.9 %, dabigatran, 74.4%; rivaroxaban, 84.2%. Underdosing occurred in 21.6% (apixaban), 8.7% (dabigatran), 9.1% (rivaroxaban). Overdosing was more frequent for dabigatran (16.9%) than for rivaroxaban (6.6%) or apixaban (3.5%). There was a trend towards dose reduction with increasing renal impairment. Among patients with severe renal impairment, the majority received a reduced dose NOAC: apixaban, 91.1%, dabigatran, 80.0%, rivaroxaban, 83.0%. CONCLUSION: Between 2011 and 2016, the majority of patients starting NOAC therapy in UK primary care were prescribed a daily dose in line with the approved EU drug label. Underdosing was more than twice as common among patients starting on apixaban than those starting on dabigatran or rivaroxaban. Research into the patient characteristics that may influence inappropriate underdosing of NOACs in UK primary care is warranted.

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study.

INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90-10.39) for patients initiating prucalopride and 10.24 (6.97-14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36-1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350.

INTRODUCTION: Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.

Facility ownership and mortality among older adults residing in care homes.

BACKGROUND AND OBJECTIVES: Nursing or care home characteristics may have a long-term impact on the residents' mortality risks that has not been studied previously. The study's main objective was to assess the association between facility ownership and long-term, all-cause mortality. RESEARCH DESIGN AND METHODS: We conducted a mortality follow-up study on a cohort of 611 nursing-home residents in the city Madrid, Spain, from their 1998-1999 baseline interviews up to September 2013. Residents lived in three types of facilities: public, subsidized and private, which were also sub-classified according to size (number of beds). Residents' information was collected by interviewing the residents themselves, their caregivers and facility physicians. We used time-to-event multivariable models and inverse probability weighting to estimate standardized mortality risk differences. RESULTS: After a 3728 person-year follow-up (median/maximum of 4.8/15.2 years), 519 participants had died. In fully-adjusted models, the standardized mortality risk difference at 5 years of follow-up between medium-sized private facilities and large-sized public facilities was -18.9% (95% confidence interval [CI]: -33.4 to -4.5%), with a median survival (95% CI) of 3.6 (0.5 to 6.8) additional years. The fully-standardized 5-year mortality difference (95% CIs) between for-profit private facilities and not-for-profit public institutions was -15.1% (-31.1% to 0.9%), and the fully-standardized median survival difference (95% CIs) was 3.0 (-1.7 to 7.7) years. DISCUSSION AND IMPLICATIONS: These results are compatible with an association between factors related with the ownership of facilities and the long-term mortality risk of their residents. One of these factors, the facility size, could partly explain this association.

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.

Characteristics of children and adolescents first prescribed proton pump inhibitors or histamine-2-receptor antagonists: an observational cohort study.

OBJECTIVE: To describe the characteristics of pediatric patients prescribed proton pump inhibitors (PPIs) vs those of pediatric patients prescribed histamine-2-receptor antagonists (H2RAs). METHODS: Observational studies were conducted using The Health Improvement Network (THIN) and the PHARMO Database Network. Patients aged 0-18 years who were first prescribed a PPI or H2RA between October 1, 2009 and September 30, 2012 (THIN) or between September 1, 2008 and August 31, 2011 (PHARMO) were included. Patient characteristics were identified and compared between the PPI and H2RA cohorts using odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age and sex. RESULTS: The mean age (years) was higher in the PPI than in the H2RA cohorts (THIN 12.3 [n = 8204] vs 5.4 [n = 7937], PHARMO 11.0 [n = 15 362] vs 7.1 [n = 6168]). Previous respiratory disease was more common in the PPI than in the H2RA cohort in THIN (OR = 1.19, 95% CI = 1.08-1.30), as were asthma and respiratory medication use in PHARMO (OR = 1.27, 95% CI = 1.12-1.45 and OR = 1.23, 95% CI = 1.10-1.38, respectively) and oral corticosteroid use in both databases (OR = 1.45, 95% CI = 1.10-1.92 [THIN]; OR = 2.80, 95% CI = 2.11-3.71 [PHARMO]). Non-steroidal anti-inflammatory drugs, antibiotics, and oral contraceptives were also more common in PPI than in H2RA cohorts in both databases. CONCLUSIONS: Pediatric patients receiving PPIs and those receiving H2RAs may represent different patient populations. PPIs may be more commonly prescribed than H2RAs among patients with respiratory diseases.

Heart failure hospitalization: An important prognostic factor for heart failure re-admission and mortality.

BACKGROUND: Few studies have evaluated incidence rates and risk factors for heart failure hospitalization (HFH) and mortality starting at initial heart failure (HF) diagnosis. METHODS: Patients with a first ever recorded diagnosis of HF between January 2000 and December 2005 (N=3516) were identified from The Health Improvement Network primary care database and followed until April 2011 to identify HFHs (through linked hospitalization data) and deaths. HF patients were stratified by hospitalization status at HF diagnosis (start date), and hazard ratios (HRs) for HFH and death were estimated using Cox regression. Predictors of HF re-admission were identified by nested case-control analysis among patients hospitalized at start date, using patients with a new HFH during follow-up as cases and a set of age and sex matched controls. RESULTS: During a mean follow-up of 4.5years, 32% of incident HF patients (n=1119) had a HFH and 58.5% died (n=2056). Compared with patients not hospitalized at initial HF diagnosis (N=2759), a two-fold increased risk of HFH during follow-up, consistent over time, was seen in patients hospitalized at initial HF diagnosis (N=757); adjusted HR 2.14 (95% CI: (1.88-2.44). Major predictors of HFH were renal impairment, diabetes and prior HFH. Mortality rates were higher in HF patients hospitalized at initial HF diagnosis, but the major determinant of mortality was HFH during follow-up: HR 3.88 (95% CI: 3.53-4.26) irrespective of HFH status at initial diagnosis. CONCLUSION: Patients hospitalized at initial HF diagnosis or with a HFH thereafter are at high risk of worse outcomes.

Impact of hyperkalaemia definition on incidence assessment: implications for epidemiological research based on a large cohort study in newly diagnosed heart failure patients in primary care.

BACKGROUND: Various definitions of hyperkalaemia have been used in clinical research, and data from routine clinical practice on its incidence are sparse. We aimed to establish the incidence of hyperkalaemia in patients with newly diagnosed heart failure in the UK general population using different definitions for the condition. METHODS: We conducted a large retrospective cohort study using data from The Health Improvement Network primary care database. Patients with newly diagnosed heart failure (N = 19,194) were identified and followed until the first occurrence of hyperkalaemia. Different serum potassium (K(+)) thresholds were evaluated as possible definitions for hyperkalaemia, and incidence rates (IRs) calculated using a final operational definition both overall and among patient sub-groups. RESULTS: IRs of hyperkalaemia ranged from 0.92-7.93 per 100 person-years according to the definition. Based on considerable differences in the serum K(+) normal range used between practices, 2176 (11.3 %) individuals were identified with a record of hyperkalaemia using our operational definition of a proportional increase of ≥10 % above the upper bound of the normal range: IR 2.90 per 100 person-years (95 % CI 2.78-3.02) over a mean follow-up of 3.91 years. Incidence rates were higher in older patients, and in those with diabetes or renal impairment. CONCLUSIONS: Hyperkalaemia is a common finding in heart failure patients in primary care, but its incidence can vary nearly ten-fold depending on its definition. Since assessment of hyperkalaemia risk is essential for therapeutic decision making in heart failure patients, this finding warrants consideration in future epidemiological studies.

Incidence and risk factors for atrial fibrillation in patients with newly diagnosed heart failure.

AIMS: We aimed to identify the incidence and risk factors for first ever atrial fibrillation among patients with newly diagnosed heart failure following initial heart failure diagnosis. METHODS: A heart failure inception cohort of patients aged 20-89 years without atrial fibrillation or cancer (N = 14 457) from 2000 to 2005 was identified from The Health Improvement Network primary care database in the United Kingdom and followed for a mean of 2.67 years. First ever cases of atrial fibrillation were identified and controls (N = 3000) were frequency matched to cases by age and sex. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression. RESULTS: One thousand four hundred and eighty-nine patients (10.3%) developed a first episode of atrial fibrillation: incidence rate 27.3/1000 person-years. A three-fold increased risk of atrial fibrillation was seen in the first 6 months after heart failure diagnosis, OR 3.62 (95% CI: 2.97-4.42) with the risk decreasing thereafter. Other risk factors were excessive alcohol consumption (OR 2.91, 1.60-5.30) and valvular heart disease (OR 1.98, 1.63-2.40) and use of oral steroids (OR 1.76, 95% CI: 1.40-2.22). Reduced risks of atrial fibrillation were found with use of statins (OR 0.65, 95% CI: 0.56-0.76) and ß-blockers (OR 0.78, 95% CI: 0.67-0.91). CONCLUSIONS: The incidence of first ever atrial fibrillation among newly diagnosed heart failure patients is high, especially in the first 6 months after diagnosis. This time relationship, together with the identified risk factors for atrial fibrillation, warrants consideration in the medical care of patients with heart failure.

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.

Incidence and risk factors for severe renal impairment after first diagnosis of heart failure: A cohort and nested case-control study in UK general practice.

OBJECTIVE: We aimed to evaluate the incidence, time-course and risk factors for severe renal impairment (SRI) among incident heart failure (HF) patients. METHODS AND RESULTS: Patients aged 1-89years from 2000 to 2005 with incident HF and without SRI or cancer (N=18,049) were identified from The Health Improvement Network (a primary care database representative of the UK population). Patients with a first ever record of SRI during follow-up were identified and eligible non-cases used as controls (N=5377; mean age 74years). Cohort and nested case-control analyses were conducted to identify risk factors for SRI. 2818 patients (15.6%, mean age 75years) in the HF cohort developed SRI over a mean of 2.84years with incidence highest in the first year following HF diagnosis. Hazard ratios (HRs) with 95% confidence intervals (CIs) were as follows: diabetes (1.96, 1.80-2.14), hypertension (1.23, 1.14-1.33), peripheral artery disease (1.29, 1.15-1.45), ischemic cerebrovascular disease (1.14, 1.03-1.26), and anemia (1.19, 1.06-1.34). Several cardiovascular medications were associated with SRI in the case-control analysis, odds ratios (95% CIs): 5.07 (3.87-6.64) for all diuretics, 3.22 (2.83-3.66) for potassium-sparing diuretics, 2.40 (1.96-2.93) for thiazide and related diuretics and 3.27 (2.67-4.01) for loop-diuretics. CONCLUSION: SRI is a frequent complication in patients with newly diagnosed HF. Comorbidities may contribute to its development and should be adequately treated. Robust clinical trial data on beneficial or possibly deleterious effects of diuretics, especially loop-diuretics and potassium-sparing diuretics, on SRI development in HF patients are warranted.