Background: Stroke prevention using warfarin is challenging in AF patients with CKD, due to high bleeding risk and difficulties in the INR control. NOACs provide alternative options, but all have greater degrees of renal clearance. This study aimed to compare the outcomes of apixaban, dabigatran, rivaroxaban, and warfarin across the range of kidney function in patients with AF. Methods: Using a US administrative database including private insurance or Medicare Advantage patients with linked claims and laboratory data, we identified 34,569 new users of oral anticoagulants with AF and eGFR ≥15 between 10/1/2010-11/29/2017. Stabilized IPTW balanced four treatment groups on 66 baseline characteristics. The primary outcomes included stroke, major bleeding, and mortality. Weighted Cox proportional hazards models compared treatments in the overall population and in each eGFR subgroup, with mortality as a competing risk for stroke and major bleeding. Results: The proportion of patients using warfarin increased as the kidney function declined - 26.5%, 30.4%, 34.6%, 40.5%, and 55.0% of patients were prescribed warfarin in eGFR ≥90, 60-90, 45-60, 30-45, 15-30 groups, respectively. In comparison to warfarin, apixaban was associated with a lower risk of stroke, major bleeding, and mortality; dabigatran was associated with a similar risk of stroke, and a lower risk of major bleeding and mortality; rivaroxaban was associated with a lower risk of stroke, major bleeding, and mortality (Figure). When comparing one NOAC to another NOAC, apixaban and dabigatran were associated with a lower risk of major bleeding than rivaroxaban (HR 0.61 [0.51-0.73], p<0.001 for apixaban versus rivaroxaban; HR 0.67 [0.50-0.90], p=0.007 for dabigatran versus rivaroxaban); dabigatran was associated with a higher risk of stroke than apixaban (HR 1.65 [1.11-2.46], p=0.01); there was no difference in mortality. There was no significant interaction between treatment and eGFR categories for any outcome, but the number of patients with low eGFR was small. Conclusions: In practice, relative to warfarin, NOACs are progressively less commonly used with increasing degree of renal dysfunction. However, each NOAC was consistently associated with at least equivalent effectiveness and safety compared with warfarin across the range of kidney function.
Abstract Background Epidemiological study reporting is improving but is not transparent enough for easy evaluation or replication. One barrier is insufficient details about design elements in published studies. Methods Using a previously conducted drug safety evaluation in claims as a test case, we investigated the impact of small changes in five key design elements on risk estimation. These elements are index day of incident exposure's determination of look‐back or follow‐up periods, exposure duration algorithms, heparin exposure exclusion, propensity score model variables, and Cox proportional hazard model stratification. We covaried these elements using a fractional factorial design, resulting in 24 risk estimates for one outcome. We repeated eight of these combinations for two additional outcomes. We measured design effects on cohort sizes, follow‐up time, and risk estimates. Results Small changes in specifications of index day and exposure algorithm affected the risk estimation process the most. They affected cohort size on average by 8 to 10%, follow‐up time by up to 31%, and magnitude of log hazard ratios by up to 0.22. Other elements affected cohort before matching or risk estimate's precision but not its magnitude. Any change in design substantially altered the matched control‐group subjects in 1:1 matching. Conclusions Exposure‐related design elements require attention from investigators initiating, evaluating, or wishing to replicate a study or from analysts standardizing definitions. The methods we developed, using factorial design and mapping design effect on causal estimation process, are applicable to planning of sensitivity analyses in similar studies.
This paper presents a spatial analysis of unemployment rates in Germany. The goal of this analysis is to explain the stubbornly low labor productivity and high unemployment rates in Eastern Germany. We build a model of commuting to distinguish between worker and job characteristics as the main causes of the low labor productivity, and use the method of simulated moments to estimate the East-West ratios of worker and job characteristics. The 'slope? of the unemployment rate across the former East-West border serves as the main identification of the model. The preliminary results suggest that East and West German skills are very similar, while job characteristics differ significantly between East and West.
Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness.Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions.Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was <4 pp throughout the study period.Medicare beneficiaries showed a substantive decrease in ESA administration after NCD, with minimal impact by the REMS and its removal. Small changes in RBC transfusion over the study period were likely due to a national secular trend.
Patients with atrial fibrillation and severely decreased kidney function were excluded from the pivotal non-vitamin K antagonist oral anticoagulants (NOAC) trials, thereby raising questions about comparative safety and effectiveness in patients with reduced kidney function. The study aimed to compare oral anticoagulants across the range of kidney function in patients with atrial fibrillation.
Dabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes.To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention.Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016.Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily.Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated.A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS2 score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke.Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.
Abstract While the industry and regulators’ interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient’s experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands.
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