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

Rodrı́guez, Luis A. Garcı́a; Wallander, Mari‐Ann; Friberg, Leif; Ruigómez, Ana; Schink, Tania; Bezemer, Irene D.; Herings, Ron M. C.; Shakir, Saad; Evans, Alison; Davies, Miranda; Suzart-Woischnik, Kiliana; Vora, Pareen; Balabanova, Yanina; Soriano‐Gabarró, Montse; Brobert, Gunnar

doi:10.1080/14740338.2020.1798928

Cited by 6 publications

(19 citation statements)

References 31 publications

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“…The data sources for the PASS included the following: the IQVIA Medical Research Data-UK database, UK (formerly The Health Improvement Network); the German Pharmacoepidemiological Research Database (GePaRD); the PHARMO Database Network, Netherlands (for the general practitioner sub-cohort in this analysis, data were extracted from the Out-patient Pharmacy Database, Hospitalisation Database and General Practitioner Database); and Swedish nationwide health registries [10].…”

Section: Data Sourcesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In clinical trials in patients with VTE, rivaroxaban was associated with a lower rate of major bleeding than the standard of care (enoxaparin and either warfarin or acenocoumarol) [9]. Shortly after the rst approval of rivaroxaban in Europe in 2011, a pharmacoepidemiological post-authorization safety study (PASS) programme was initiated to monitor patterns of rivaroxaban use, patient characteristics and safety and effectiveness outcomes in rst-time users of rivaroxaban and vitamin K antagonists (VKAs) treated for the condition in routine clinical practice [10].The rivaroxaban PASS incorporates four observational cohort studies, collectively covering the UK, the Netherlands, Germany and Sweden over 5 years.The safety outcomes investigated within the PASS were intracranial, gastrointestinal, urogenital and other bleeding events leading to hospitalization, selected based on the outcomes included in pivotal randomized controlled trials (RCTs) of rivaroxaban [11,12]. Additionally, risk of death among rivaroxaban users was evaluated.…”

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Safety profile of rivaroxaban in first-time users treated for venous thromboembolism (deep vein thrombosis and pulmonary embolism) in four European countries

Ruigómez

Schink

Voss

et al. 2023

Preprint

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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 healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients given 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 that led to hospitalization (intracranial, gastrointestinal, urogenital or other bleeding), or death or until study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed, and adjusted odds ratios for risk factors were generated from nested case-control analyses. Results Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher numerical incidence rates for gastrointestinal bleeding in rivaroxaban users than for vitamin K antagonist users. Rivaroxaban and vitamin K antagonist use was associated with increased bleeding risk compared with non-use. Gastrointestinal bleeding exhibited the most consistent odds ratios (95% confidence interval) across countries, ranging from 2.24 (1.79–2.82) to 4.10 (1.90–8.87) and from 2.24 (1.76–2.84) to 6.76 (2.20–20.80) for rivaroxaban use and vitamin K antagonist use, respectively. Bleeding risks decreased with increasing treatment duration. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. Conclusions These data broadly support safety findings from randomized clinical trials; no unexpected safety concerns related to bleeding risks were found.

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Section: Introductionmentioning

confidence: 99%

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Safety profile of rivaroxaban in first-time users treated for venous thromboembolism (deep vein thrombosis and pulmonary embolism) in four European countries

Ruigómez

Schink

Voss

et al. 2023

Preprint

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“…The contextual cohort design has been utilised previously in a Specialist Cohort Event Monitoring (SCEM) study [15], evaluating the safety and utilisation in patients prescribed rivaroxaban for the prevention of stroke in patients with atrial fibrillation (AF), the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrent DVT and PE in a secondary care setting in England and Wales, using the SCEM technique [16][17][18]. Rivaroxaban is a direct oral anticoagulant (DOAC), a class of drug recommended as an alternative to conventional anticoagulant treatment with vitamin K antagonists (VKAs) in international guidelines [19,20].…”

Section: Examples Of Contextual Cohort Usementioning

confidence: 99%

“…Rivaroxaban is a direct oral anticoagulant (DOAC), a class of drug recommended as an alternative to conventional anticoagulant treatment with vitamin K antagonists (VKAs) in international guidelines [19,20]. The Rivaroxaban Observational Safety Evaluation (ROSE) study included a contextual cohort of patients prescribed warfarin, in order to compare reasons for choice of anticoagulation type and to explore differences in both the clinical setting of initiation and baseline risk of bleeding and stroke [16][17][18]. Bleed outcomes could be estimated, but due to the differences between the rivaroxaban and warfarin cohorts, direct comparisons between them were not appropriate.…”

Section: Examples Of Contextual Cohort Usementioning

confidence: 99%

The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology

2021

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In pharmacoepidemiology, comparison studies can provide a useful estimate of the level of increased or decreased risk of specific events with a medication (through a measure of effect). A key focus of pharmacoepidemiological studies is the safety and effectiveness of medicines in their real-world use, and adequate comparisons of effect estimates are critical. However, consideration of guidelines, pharmacoeconomic assessments, and policies for reimbursement have made comparisons in pharmacoepidemiological studies far more difficult to conduct in recent years. Where certain subject characteristics influence the probability of being exposed to a treatment, this can introduce issues of selection bias and confounding. Methodologies are available to minimise selection bias (through case-only and randomised study designs) and deal with confounding (such as regression modelling or propensity score matching methods), however these each have their own limitations. Where prescribing guidelines are present, conducting comparisons in pharmacoepidemiology produces many challenges and not all of these can be easily overcome. Patient channelling can be more frequent with adherence to clinical guidelines compared with when prescribing decisions by doctors are based predominantly on their clinical judgement. Use of a contextual cohort could be considered as an option to characterise the adoption of new medications into clinical practice and describe the prevalence of clinical characteristics and risk factors in the two cohorts, rather than compare event rates and produce an estimate of effect. Key PointsGuidelines, pharmacoeconomic assessments, and policies for reimbursement can make comparisons in pharmacoepidemiological studies difficult to conduct due to selection bias and confounding.Use of a contextual cohort could be considered as an option to characterise the adoption of new medications into clinical practice and describe the prevalence of clinical characteristics and risk factors.

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Time Trends in Patient Characteristics of New Rivaroxaban Users with Atrial Fibrillation in Germany and the Netherlands

Voss

Smits

Swart

et al. 2023

Drugs - Real World Outcomes

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Background Use of the direct oral anticoagulant rivaroxaban has strongly increased in Europe since its market approval for non-valvular atrial fibrillation in 2011. Patients characteristics of rivaroxaban initiators may have changed over time but this has not been investigated so far. Objective We aimed to describe time trends of patient baseline characteristics among new rivaroxaban users with nonvalvular atrial fibrillation from 2011 to 2016/17 in two European countries. Methods We used data from Germany (German Pharmacoepidemiological Research Database) and the Netherlands (PHARMO Database Network). We included new rivaroxaban users with (i) a first dispensing between 2011 and 2016/17, (ii) ≥ 2 years of age, and (iii) a diagnosis of non-valvular atrial fibrillation and described their baseline medication and comorbidity prior to starting rivaroxaban stratified by year of inclusion. Results Overall, 130,652 new rivaroxaban users were included during the study period (Germany: N = 127,743, the Netherlands: N = 2909). The sex ratio and median age remained relatively stable over time. The proportion of patients without prior use of oral anticoagulants before initiation of rivaroxaban increased in both countries between 2011 and 2016/17 (Germany: from 51 to 76%, the Netherlands: from 57 to 85%). In Germany, we observed a relative decrease by 27% in the proportion of new rivaroxaban users with a history of ischemic stroke and by 18% in the proportion with a transient ischemic attack at baseline. No such a pattern was observed in the Netherlands. The proportion of patients with heart failure at baseline showed a three-fold increase in the Netherlands, while there was a relative decrease by 12% in Germany. Conclusions Patient characteristics of new rivaroxaban users with non-valvular atrial fibrillation changed between 2011 and 2016/17, but changes differed between countries. These patterns have methodological implications. They have to be considered in the interpretation of observational studies comparing effectiveness and safety of oral anticoagulants, especially regarding potential bias due to unmeasured confounding.

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

Cited by 6 publications

References 31 publications

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism (deep vein thrombosis and pulmonary embolism) in four European countries

Safety profile of rivaroxaban in first-time users treated for venous thromboembolism (deep vein thrombosis and pulmonary embolism) in four European countries

The Role of the Contextual Cohort to Resolve Some Challenges and Limitations of Comparisons in Pharmacoepidemiology

Time Trends in Patient Characteristics of New Rivaroxaban Users with Atrial Fibrillation in Germany and the Netherlands

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