Controlling for unobserved confounders in observational studies using large health care databases by means of instrumental variables in time-to-event analysis

Randomized controlled trials cannot provide all necessary information about drug reactions as they are limited by several factors. Observational studies in free-living populations are therefore necessary. Large health care databases are frequently used for this purpose. A common problem of analyses based on these databases is that confounding variables are often not recorded, so that effects are inconsistently estimated. Under certain conditions instrumental variables can eliminate confounding bias, so that IV estimators can consistently estimate treatment effects. Instrumental variable methods are well established for continuous outcomes using linear regression models, where two-stage least squares are typically used. However, in time-to-event analysis no such common instrumental variable method exists. Even if the proportional hazards model is used, two-stage estimators to account for instrumental variables are only justified for rare events. The aim of this thesis is therefore to explore two-stage instrumental variable estimation for time-to-event outcomes in large health care databases if the assumption of rare events does not hold true

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

Gute Praxis Datenlinkage (GPD) : Good Practice Data Linkage

Das personenbezogene Verknüpfen verschiedener Datenquellen (Datenlinkage) für Forschungszwecke findet in den letzten Jahren in Deutschland zunehmend Anwendung. Jedoch fehlen hierfür konsentierte methodische Standards. Ziel dieses Beitrages ist es, solche Standards für Forschungsvorhaben zu definieren. Eine weitere Intention ist es, dem Lesenden eine Checkliste zur Bewertung geplanter Forschungsvorhaben und Artikel bereitzustellen. Zu diesem Zweck hat eine aus Mitgliedern verschiedener Fachgesellschaften zusammengesetzte Expertengruppe seit 2016 insgesamt 7 Leitlinien mit 27 konkreten Empfehlungen erstellt. Die Gute Praxis Datenlinkage beinhaltet die folgenden Leitlinien: (1) Forschungsziele, Fragestellung, Datenquellen und Ressourcen, (2) Dateninfrastruktur und Datenfluss, (3) Datenschutz, (4) Ethik, (5) Schlüsselvariablen und Linkageverfahren, (6) Datenprüfung/Qualitätssicherung sowie (7) Langfristige Datennutzung für noch festzulegende Fragestellungen. Jede Leitlinie wird ausführlich diskutiert. Zukünftige Aktualisierungen werden wissenschaftliche und datenschutzrechtliche Entwicklungen berücksichtigen

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project

OBJECTIVES: To estimate the risk of AMI for individual NSAIDs.METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) match

Kontrolle für ungemessene Konfounder in Beobachtungsstudien basierend auf großen Gesundheitsdatenbanken mittels instrumenteller Variablen in der Überlebenszeitanalyse

Randomized controlled trials cannot provide all necessary information about drug reactions as they are limited by several factors. Observational studies in free-living populations are therefore necessary. Large health care databases are frequently used for this purpose. A common problem of analyses based on these databases is that confounding variables are often not recorded, so that effects are inconsistently estimated. Under certain conditions instrumental variables can eliminate confounding bias, so that IV estimators can consistently estimate treatment effects. Instrumental variable methods are well established for continuous outcomes using linear regression models, where two-stage least squares are typically used. However, in time-to-event analysis no such common instrumental variable method exists. Even if the proportional hazards model is used, two-stage estimators to account for instrumental variables are only justified for rare events. The aim of this thesis is therefore to explore two-stage instrumental variable estimation for time-to-event outcomes in large health care databases if the assumption of rare events does not hold true

Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Acute Myocardial Infarction in the General German Population: A Nested Case–Control Study

INTRODUCTION: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased relative risk of acute myocardial infarction (AMI), but the label warnings refer particularly to patients with cardiovascular risk factors. The magnitude of relative AMI risk for patients with and without cardiovascular risk factors varies between studies depending on the drugs and doses studied. OBJECTIVES: The aim of our study was to estimate population-based relative AMI risks for individual and widely used NSAIDs, for a cumulative amount of NSAID use, and for patients with and without a prior history of cardiovascular risk factors. METHODS: Based on data from the German Pharmacoepidemiological Research Database (GePaRD) of about 17 million insurance members from four statutory health insurance providers, for the years 2004–2009, a nested case–control study was conducted within a cohort of 3,476,931 new NSAID users classified into current, recent, or past users. Up to 100 controls were matched to each case by age, sex, and length of follow-up using risk set sampling. Multivariable conditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Duration of NSAID use was calculated by the cumulative amount of dispensed defined daily doses (DDDs), and stratified analyses were conducted for potential effect modifiers. RESULTS: Overall, 17,236 AMI cases were matched to 1,714,006 controls. Elevated relative AMI risks were seen for current users of fixed combinations of diclofenac with misoprostol (OR 1.76, 95% CI 1.26–2.45), indometacin (1.69, 1.22–2.35), ibuprofen (1.54, 1.43–1.65), etoricoxib (1.52, 1.24–1.87), and diclofenac (1.43, 1.34–1.52) compared with past use. A low cumulative NSAID amount was associated with a higher relative AMI risk for ibuprofen, diclofenac, and indometacin. The relative risk associated with current use of diclofenac, fixed combinations of diclofenac with misoprostol, etoricoxib, and ibuprofen was highest in the younger age group (<60 years) and similar for patients with or without major cardiovascular risk factors. CONCLUSION: Relative AMI risk estimates differed among the 15 investigated individual NSAIDs. Diclofenac and ibuprofen, the most frequently used NSAIDs, were associated with a 40–50% increased relative risk of AMI, even for low cumulative NSAID amounts. The relative AMI risk in patients with and without cardiovascular risk factors was similarly elevated

Nutzung von Sekundärdaten für die pharmakoepidemiologische Forschung – machen wir das Beste draus!

In Studien mit Sekundärdaten wie Abrechnungsdaten von Krankenkassen wird man häufig vor methodische Herausforderungen gestellt, die v. a. durch die Zeitabhängigkeit, aber auch durch ungemessenes Confounding entstehen. In diesem Paper stellen wir Strategien vor, um verschiedene Biasquellen zu vermeiden und um den durch ungemessenes Confounding entstehenden Bias abzuschätzen. Wir illustrieren das Prinzip der Targets Trials, marginale Strukturmodelle und instrumentelle Variablen anhand von Studien mit der GePaRD Datenbank. Abschließend werden die Chancen und Limitationen von Record Linkage diskutiert, um fehlende Information in den Daten zu ergänzen.Studies using secondary data such as health care claims data are often faced with methodological challenges due to the time-dependence of key quantities or unmeasured confounding. In the present paper, we discuss approaches to avoid or suitably address various sources of potential bias. In particular, we illustrate the target trial principle, marginal structural models, and instrumental variables with examples from the “GePaRD” database. Finally, we discuss the strengths and limitations of record linkage which can sometimes be used to supply missing information

Are prescribers not aware of cardiovascular contraindications for diclofenac? A claims data analysis

OBJECTIVES: To compare diclofenac use before and after implementation of European risk minimization measures in 2013, focusing on diclofenac initiators and prevalence of congestive heart failure (NYHA class II–IV), ischaemic heart disease, peripheral arterial disease and cerebrovascular disease (new contraindications) in these patients in Germany. METHODS: We included adults with health insurance coverage on 1 January 2011 (cohort 2011) or 1 January 2014 (cohort 2014) and during a 1‐year pre‐observation period. We defined diclofenac initiators as persons filling a prescription of systemic diclofenac in 2011 (cohort 2011) or 2014 (cohort 2014) and without such a prescription during the respective pre‐observation period. RESULTS: Each cohort comprised >10 million persons. Between 2011 and 2014, the age‐standardized proportion of persons initiating diclofenac decreased by 29% (from 8.2% to 5.8%) amongst female patients and by 26% (from 8.5% to 6.3%) amongst male patients; in the subgroup of persons with new contraindications, this proportion decreased by 33% (from 9.8% to 6.6%) amongst female patients and by 31% (from 10.0% to 6.7%) amongst male patients. Amongst diclofenac initiators, the proportion of those with new contraindications did not change between 2011 (12.0%) and 2014 (11.8%). CONCLUSION: The overall decline of about 30% in diclofenac initiation between 2011 and 2014 was largely independent of the presence or absence of new contraindications. The proportion of diclofenac initiators with a new contraindication remained at a high level (more than one in ten patients), demonstrating the need for research at the prescriber level (e.g. interventional studies) and further measures to improve patient safety