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.

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).

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).

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.

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.

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.

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.

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.

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.

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

Introduction: The serotonin 5-HT 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.

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.

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.

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 (HRAs).

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 HRA between October 1, 2009 and September 30, 2012 (THIN) or between September 1, 2008 and August 31, 2011 (PHARMO) were included.

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.

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.

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.

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.

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).

The risk of acute liver injury among users of antibiotic medications: a comparison of case-only studies.

Purpose: The aims of this study were two-fold: (i) to investigate the effect of exposure to antibiotic agents on the risk of acute liver injury using a self-controlled case series and case-crossover study and (ii) to compare the results between the case-only studies.

Methods: For the self-controlled case series study relative incidence ratios (IRR) were calculated by dividing the rate of acute liver injury experienced during patients' periods of exposure to antibiotics to patients' rate of events during non-exposed time using conditional Poisson regression. For the case-crossover analysis we calculated Odds Ratios (OR) using conditional logistic regression by comparing exposure during 14- and 30-day risk windows with exposure during control moments.

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.

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.

Diabetes, cardiovascular morbidity, and risk of age-related macular degeneration in a primary care population.

Purpose: Age-related macular degeneration (AMD) is the most common cause of legal blindness in Western patients over 65 years of age. We aimed to establish the incidence of AMD, and the association of diabetes, and cardiovascular and eye diseases with the risk of AMD, in a large cohort of primary care patients in the United Kingdom.

Methods: Using data from The Health Improvement Network database in the United Kingdom, all individuals with a first recorded diagnosis of AMD from 2004 to 2010 were identified (N = 10,516) and frequency-matched to 19,389 AMD-free individuals by age, sex, and calendar year of AMD occurrence.

Risk factors for hyperkalaemia in a cohort of patients with newly diagnosed heart failure: a nested case-control study in UK general practice.

Aims: The aim of this study was to identify risk factors for hyperkalaemia in a cohort of patients with newly diagnosed heart failure in the UK.

Methods And Results: A nested case-control study was conducted using data from The Health Improvement Network primary care database. A cohort of 19 194 patients aged 1-89 years between January 2000 and December 2005 with newly diagnosed heart failure was followed up and cases of hyperkalaemia identified.