Dorothee B. Bartels

The Measurement of Multiple Chronic Diseases—A Systematic Review on Existing Multimorbidity Indices

BACKGROUND Multimorbidity, defined as the coexistence of 2 or more chronic diseases, is a common phenomenon especially in older people. Numerous efforts to establish a standardized instrument to assess the level of multimorbidity have failed until now, and indices are primarily characterized by their high heterogeneity. Thus, the objective is to provide a comprehensive overview on existing instruments on the basis of a systematic literature review. METHODS The review was performed in MedLine. All articles published between January 1, 1960 and August 31, 2009 in German or English language, with the primary focus either on the development of a weighted index or on the effect of multimorbidity on different outcomes, were identified. RESULTS A total of 39 articles met the inclusion criteria. In the majority of studies (59.0%), the list of included diseases was presented without any selection criteria. Only the high prevalence of diseases (17.9%), their impact on mortality, function, and health status served as a point of reference. Information on the prevalence of chronic conditions mostly rely on self-reports. On average, the 39 indices included 18.5 diseases, ranging between 4 and 102 different conditions. Most frequently mentioned diseases were diabetes mellitus (in 97.5% of indices), followed by stroke (89.7%), hypertension, and cancer (each 84.6%). Overall, three different weighting methods could be distinguished. CONCLUSIONS The systematic literature further emphasis the heterogeneity of existing multimorbidity indices. However, one important similarity is that the focus is on diseases with a high prevalence and a severe impact on affected individuals.

Antithrombotic Treatment Patterns in Patients with Newly Diagnosed Nonvalvular Atrial Fibrillation: The GLORIA-AF Registry, Phase II

BACKGROUND The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) was designed to provide prospectively collected information on patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke, with the aim of addressing treatment patterns and questions of effectiveness and safety. METHODS AND RESULTS In this predefined analysis from GLORIA-AF, the baseline characteristics and initial antithrombotic management of the first 10,000 patients in Phase II of this large Registry Program are presented. Overall, 32.3% of patients received vitamin K antagonists (VKAs) and 47.7% received non-VKA oral anticoagulants (NOACs), while 12.3% received antiplatelet treatment and 7.6% did not receive any antithrombotic treatment. Among patients with CHA2DS2-VASc score ≥2, 6.7% received no antithrombotic treatment and 10.0% received aspirin. In Europe, treatment with dabigatran was as common as treatment with VKAs (38.8% and 37.8%, respectively). More than half of the patients were treated with NOACs (52.4%), while antiplatelet treatment was given to 5.7%, and 4.1% did not receive any antithrombotic treatment. In North America, treatment with dabigatran (25.0%) was as common as with VKAs (26.1%), but overall NOAC use was more common (52.1%) than with VKAs (26.1%); however, 14.1% received antiplatelet treatment, while 7.6% received no antithrombotic treatment. In Asia, treatment with VKAs (31.9%) was more prevalent than NOACs (25.5%), but antiplatelet treatment was given to 25.8%, and 16.9% did not receive any antithrombotic treatment. In Asia, only 60.7% of patients with high stroke risk received oral anticoagulants (OACs). Paroxysmal atrial fibrillation and minimally symptomatic (or asymptomatic) patients were often undertreated with OACs. CONCLUSION In this analysis, OAC use was high in Europe and North America, with overall NOAC use higher than VKA use. A considerable percentage of high-risk patients in North America still received antiplatelet treatment or were untreated, while Asian patients had a high proportion of aspirin use and nontreatment.

Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation

The RE-LY study demonstrated the safety and efficacy of dabigatran relative to warfarin for stroke prevention in non-valvular atrial fibrillation. It is important to further evaluate safety and effectiveness of drugs in routine care. This study used a sequential cohort design with propensity score matching to compare dabigatran with warfarin among patients in two commercial health insurance databases. New users of these anticoagulants were followed from initiation until discontinuation, the end of the study, or the occurrence of a study outcome (primary study outcomes were stroke and major bleeding). Proportional hazards regression was conducted separately within each data source and results were pooled. Among 19,189 matched dabigatran and warfarin initiators (mean age: 68 years, 36 % female), as-treated follow-up (average of 5 months for dabigatran, 4 months for warfarin) identified 62 and 69 strokes, respectively (pooled HR = 0.77; 95 % CI = 0.54 to 1.09), and 354 and 395 major haemorrhages, respectively (HR = 0.75; 0.65 to 0.87). No meaningful heterogeneity was identified across subgroups, but numeric trends suggest more pronounced stroke prevention by dabigatran relative to warfarin among patients age 75+ (HR = 0.57; 0.33 to 0.97) or with < 6 months of use (HR = 0.51; 0.19 to 1.42). Major bleeds were reduced more by dabigatran among patients aged < 55 (HR = 0.51; 0.30 to 0.87) and with CHADS2 < 2 (HR = 0.58; 0.44 to 0.77). In conclusion, in routine care of patients with non-valvular atrial fibrillation, dabigatran treatment resulted in improved health outcomes compared with warfarin.

Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: A global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation

BACKGROUND Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1% to 2% of the population and raising the risk of stroke 5-fold. Until recently, the only treatment choices for stroke prevention in patients with AF have been vitamin K antagonists (VKA) or antiplatelet drugs. With approval of novel oral anticoagulants (NOACs) antithrombotic treatment, patterns are changing. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with nonvalvular AF and to collect data on outcomes of antithrombotic therapy in clinical practice. METHODS The GLORIA-AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke, enrolling up to 56,000 patients in nearly 50 countries. We will collect and analyze data from routine care using an inception cohort design. Phase I includes patients before approval of NOACs. Phase II, beginning early after approval of dabigatran, monitors dabigatran safety and addresses potential channeling across treatment options based on propensity scoring to assess comparability of baseline characteristics of patients treated with dabigatran or VKA. Phase III entails analysis of large treatment groups, adjusting for differences in propensity score, to provide information about the relative effectiveness and safety of NOACs and VKA in routine clinical care. CONCLUSIONS Novel features of this registry program will add data from clinical practice to those from randomized trials to expand knowledge of antithrombotic treatment in patients with AF.

Metrics for covariate balance in cohort studies of causal effects

Inferring causation from non-randomized studies of exposure requires that exposure groups can be balanced with respect to prognostic factors for the outcome. Although there is broad agreement in the literature that balance should be checked, there is confusion regarding the appropriate metric. We present a simulation study that compares several balance metrics with respect to the strength of their association with bias in estimation of the effect of a binary exposure on a binary, count, or continuous outcome. The simulations utilize matching on the propensity score with successively decreasing calipers to produce datasets with varying covariate balance. We propose the post-matching C-statistic as a balance metric and found that it had consistently strong associations with estimation bias, even when the propensity score model was misspecified, as long as the propensity score was estimated with sufficient study size. This metric, along with the average standardized difference and the general weighted difference, outperformed all other metrics considered in association with bias, including the unstandardized absolute difference, Kolmogorov-Smirnov and Lévy distances, overlapping coefficient, Mahalanobis balance, and L1 metrics. Of the best-performing metrics, the C-statistic and general weighted difference also have the advantage that they automatically evaluate balance on all covariates simultaneously and can easily incorporate balance on interactions among covariates. Therefore, when combined with the usual practice of comparing individual covariate means and standard deviations across exposure groups, these metrics may provide useful summaries of the observed covariate imbalance.

Population-based cohort study of warfarin-treated patients with atrial fibrillation: incidence of cardiovascular and bleeding outcomes

Objectives Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice. Design Pharmacoepidemiological cohort study using observational data. Methods/setting This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and others. The main focus of the study was on outcome events requiring hospitalisation using the HES data. Results The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal. Conclusions This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective.

Long-Term Use of Angiotensin Receptor Blockers and the Risk of Cancer

The association between angiotensin receptor blockers (ARBs) and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK) General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan) entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years). When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96–1.03) or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06–1.20 and RR: 1.19; 95% CI: 1.12–1.27, respectively). This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.

How to weight chronic diseases in multimorbidity indices? Development of a new method on the basis of individual data from five population-based studies

OBJECTIVE In multimorbidity indices, chronic conditions are often weighted according to their severity or their impact on different outcomes. These weights are mostly developed on the basis of only one study population by using very specific study participants, such as hospital patients. To overcome the limited validity of the indices, mean weights across five population-based studies were calculated according to the impact of diseases on self-reported health status. STUDY DESIGN AND SETTING Individual data was provided from the National Health Interview and Examination Survey (n=1,010), Dortmund Health Study (n=281), Memory and Morbidity in Augsburg Elderly Study (n=385), Survey of Health, Aging and Retirement in Europe Study (n=1,278), and Study of Health in Pomerania Study (n=962). By using logistic regression analysis, odds ratios (ORs) were calculated for reporting a fair or poor health status resulting from one of 10 different chronic conditions compared with a reference group without the specific disease, controlling for age and sex. If the results were homogenous across studies (I(2)<40%), significant pooled ORs were considered valid weights for a multimorbidity index. RESULTS Myocardial infarction has the highest impact on self-reported health status across studies with a pooled OR of 3.9, followed by chronic obstructive pulmonary disease (pooled OR: 3.1). A medium impact was observed for arthrosis, asthma, diabetes mellitus, and osteoporosis. CONCLUSION This method provided valid weights for seven chronic conditions.

Antithrombotic therapy use in patients with atrial fibrillation before the era of non-vitamin K antagonist oral anticoagulants: the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) Phase I cohort

Aims The introduction of non-VKA oral anticoagulants (NOACs), which differ from the earlier vitamin K antagonist (VKA) treatments, has changed the approach to stroke prevention in atrial fibrillation (AF). GLORIA-AF is a prospective, global registry programme describing the selection of antithrombotic treatment in newly diagnosed AF patients at risk of stroke. It comprises three phases: Phase I, before the introduction of NOACs; Phase II, during the time of the introduction of dabigatran, the first NOAC; and Phase III, once NOACs have been established in clinical practice. Methods and results In Phase I, 1063 patients were eligible from the 1100 enrolled (54.3% male; median age 70 years); patients were from China (67.1%), Europe (EU; 27.4%), and the Middle East (ME; 5.6%). The majority of patients using VKAs had high stroke risk (CHA2DS2-VASc ≥ 2; 86.5%); 13.5% had moderate risk (CHA2DS2-VASc = 1). Vitamin K antagonist use was higher for persistent/permanent AF (47.7%) than that for paroxysmal (23.9%). Most patients in China were treated with antiplatelet agents (53.7%) vs. 27.1% in EU and 28.8% in ME. In China, 25.9% of patients had no antithrombotic therapy, vs. 8.6% in EU and 8.5% in ME. Conclusion Phase I of GLORIA-AF shows that VKAs were mostly used in patients with persistent/permanent (vs. paroxysmal) AF and in those with high stroke risk. Furthermore, there were meaningful geographical differences in the use of VKA therapy in the era before the availability of NOACs, including a much lower use of VKAs in China, where most patients either received antiplatelet agents or no antithrombotic treatment.

Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations

BackgroundRecent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved.MethodsWe reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges.ResultsFrom the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods.Conclusions/interpretationObservational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.