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1.
Clin Pharmacol Ther ; 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32320482

RESUMO

Regulators wish to understand whether real-world evidence (RWE) can be used for secondary indications of biologics. Using the secondary indication of adalimumab for ulcerative colitis (UC) as an example, we aimed to replicate the ULTRA-2 RCT finding on the effectiveness of adalimumab in patients with UC using real world data analyses. Adalimumab, a TNF-alpha receptor inhibitor initially approved for Crohn's disease, was approved for moderate to severe UC in 2012. The ULTRA-2 trial had shown improved remission against placebo in patients with UC. Using claims data (2006-2012), we conducted a cohort study of patients with UC who initiated adalimumab and compared them to 1) non-users and 2) new users of infliximab using propensity score matching. The co-primary endpoints were corticosteroid (CS) discontinuation within 8 weeks and 1 year of treatment. We computed hazard ratios (HR) and 95% confidence intervals (CIs). We identified 398 matched pairs of adalimumab users vs non-users and 326 pairs of adalimumab vs infliximab users. Adalimumab users were 28% more likely to achieve CS-discontinuation compared to non-users over 1 year (HR=1.28, 95% CI 0.94 to 1.73). However, unlike in ULTRA-2, this effect was not observed in the first 8 weeks (HR 0.79, 95% CI 0.65-0.97). Compared against infliximab, adalimumab initiators showed no incremental benefit over 1 year (HR=1.08; 0.80 to 1.04), but showed a 22% reduction (HR=0.78; 0.64-0.95) during the first 8 weeks of treatment. In summary, our results highlight opportunities and some limitations of database analysis to identify treatment effects for secondary indications.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32162381

RESUMO

Randomized clinical trials (RCTs) are the gold standard in producing clinical evidence of efficacy and safety of medical interventions. More recently, a new paradigm is emerging-specifically within the context of preauthorization regulatory decision-making-for some novel uses of real-world evidence (RWE) from a variety of real-world data (RWD) sources to answer certain clinical questions. Traditionally reserved for rare diseases and other special circumstances, external controls (eg, historical controls) are recognized as a possible type of control arm for single-arm trials. However, creating and analyzing an external control arm using RWD can be challenging since design and analytics may not fully control for all systematic differences (biases). Nonetheless, certain biases can be attenuated using appropriate design and analytical approaches. The main objective of this paper is to improve the scientific rigor in the generation of external control arms using RWD. Here we (a) discuss the rationale and regulatory circumstances appropriate for external control arms, (b) define different types of external control arms, and (c) describe study design elements and approaches to mitigate certain biases in external control arms. This manuscript received endorsement from the International Society for Pharmacoepidemiology (ISPE).

4.
J Natl Compr Canc Netw ; 18(1): 36-43, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31910385

RESUMO

BACKGROUND: Many new targeted cancer drugs have received FDA approval based on durable responses in nonrandomized controlled trials (non-RCTs). The goal of this study was to evaluate whether the response rates (RRs) and durations of response (DoRs) of targeted cancer drugs observed in non-RCTs are consistent when these drugs are tested in RCTs. METHODS: We used the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling to identify cancer drugs that were approved based on changes in biomarker endpoints through December 2017. We then identified the non-RCTs and RCTs for these drugs for the given indications and extracted the RRs and DoRs. We compared the RRs and median DoR in non-RCTs versus RCTs using the ratio of RRs and the ratio of DoRs, defined as the RRs (or DoRs) in non-RCTs divided by the RRs (or DoRs) in RCTs. The ratio of RRs or DoRs was pooled across the trial pairs using random-effects meta-analysis. RESULTS: Of the 21 drug-indication pairs selected, both non-RCTs and RCTs were available for 19. The RRs and DoRs in non-RCTs were greater than those in RCTs in 63% and 87% of cases, respectively. The pooled ratio of RRs was 1.06 (95% CI, 0.95-1.20), and the pooled ratio of DoRs was 1.17 (95% CI, 1.03-1.33). RRs and DoRs derived from non-RCTs were also poor surrogates for overall survival derived from RCTs. CONCLUSIONS: The RRs were not different between non-RCTs and RCTs of cancer drugs approved based on changes to a biomarker, but the DoRs in non-RCTs were significantly higher than in RCTs. Caution must be exercised when approving or prescribing targeted drugs based on data on durable responses derived from non-RCTs, because the responses could be overestimates and poor predictors of survival benefit.

5.
Clin Pharmacol Ther ; 107(6): 1334-1342, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31872419

RESUMO

The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65-year-old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1-year all-cause mortality outcome. After propensity score fine-stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all-cause mortality outcomes, were 0.97 (0.65-1.46), 0.94 (0.65-1.35), and 0.84 (0.62-1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS-VASc score ≥ 3, and HAS-BLED score ≥ 3 were consistent with the primary analysis.

6.
Epidemiology ; 31(1): 82-89, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31569120

RESUMO

Estimating hazard ratios (HR) presents challenges for propensity score (PS)-based analyses of cohorts with differential depletion of susceptibles. When the treatment effect is not null, cohorts that were balanced at baseline tend to become unbalanced on baseline characteristics over time as "susceptible" individuals drop out of the population at risk differentially across treatment groups due to having outcome events. This imbalance in baseline covariates causes marginal (population-averaged) HRs to diverge from conditional (covariate-adjusted) HRs over time and systematically move toward the null. Methods that condition on a baseline PS yield HR estimates that fall between the marginal and conditional HRs when these diverge. Unconditional methods that match on the PS or weight by a function of the PS can estimate the marginal HR consistently but are prone to misinterpretation when the marginal HR diverges toward the null. Here, we present results from a series of simulations to help analysts gain insight on these issues. We propose a novel approach that uses time-dependent PSs to consistently estimate conditional HRs, regardless of whether susceptibles have been depleted differentially. Simulations show that adjustment for time-dependent PSs can adjust for covariate imbalances over time that are caused by depletion of susceptibles. Updating the PS is unnecessary when outcome incidence is so low that depletion of susceptibles is negligible. But if incidence is high, and covariates and treatment affect risk, then covariate imbalances arise as susceptibles are depleted, and PS-based methods can consistently estimate the conditional HR only if the PS is periodically updated.

7.
Am J Epidemiol ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31845719

RESUMO

Coarsened exact matching (CEM) is a matching method proposed as an alternative to other techniques commonly used to control confounding. We compared CEM with 3 techniques that have been used in pharmacoepidemiology: propensity score matching, Mahalanobis distance matching and fine stratification by propensity score (FS). We evaluated confounding control and effect estimate precision using insurance claims data from the Pharmaceutical Assistance Contract for the Elderly (1999-2002) and Medicaid Analytic eXtract (2000-2007) databases (United States), and from simulated claims-based cohorts. CEM generally achieved the best covariate balance. However, it often led to high bias and low precision of the risk ratio due to extreme losses in study size and numbers of outcomes (i.e., sparse data bias) - especially with larger covariate sets. FS usually was optimal with respect to bias and precision and always created good covariate balance. Propensity score matching usually performed almost as well as FS, especially with higher index-exposure prevalence. The performance of Mahalanobis distance matching was relatively poor. These findings suggest that CEM, though it achieves good covariate balance, may not be optimal for large claims database studies with rich covariate information; it may be ideal if only a few (<10) strong confounders must be controlled.

8.
J Natl Cancer Inst ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31651981

RESUMO

BACKGROUND: The FDA's accelerated approval and later withdrawal for bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC. METHODS: We searched for all published phase 2 or 3 clinical trials testing bevacizumab in first-line mBC. Data was extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated prior to, during, or after the accelerated approval. We used a cumulative random effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a non-linear mixed regression model. RESULTS: Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (HRs) and were meta-analyzed. The cumulative HR for PFS was 0.72 (95%CI 0.65-0.79), and the cumulative HR for OS was 0.90 (95%CI 0.80-1.01). The regression model showed a statistically non-significant association between PFS benefit and OS benefit (ß = 0.43, SE = 0.81). CONCLUSION: The FDA's decision-making in this case was consistent with the evolving state of evidence. However, the fact that 7 clinical trials is insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.

10.
Clin Pharmacol Ther ; 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31541454

RESUMO

Recent legislation mandates that the US Food and Drug Administration issue guidance regarding when real-world evidence (RWE) could be used to support regulatory decision making. Although RWE could come from randomized or nonrandomized designs, there are significant concerns about the validity of RWE assessing medication effectiveness based on nonrandomized designs. We propose an initiative using healthcare claims data to assess the ability of nonrandomized RWE to provide results that are comparable with those from randomized controlled trials (RCTs). We selected 40 RCTs, and we estimate that approximately 30 attempted replications will be completed after feasibility analyses. We designed an implementation process to ensure that each attempted replication is consistent, transparent, and reproducible. This initiative is the first to systematically evaluate the ability of nonrandomized RWE to replicate multiple RCTs using a structured process. Results from this study should provide insight on the strengths and limitations of using nonrandomized RWE from claims for regulatory decision making.

11.
Epidemiology ; 30(6): 861-866, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31430267

RESUMO

BACKGROUND: Self-controlled designs, both case-crossover and self-controlled case series, are well suited for evaluating outcomes of drug-drug interactions in electronic healthcare data. Their comparative performance in this context, however, is unknown. METHODS: We simulated cohorts of patients exposed to two drugs: a chronic drug (object) and a short-term drug (precipitant) with an associated interaction of 2.0 on the odds ratio scale. We analyzed cohorts using case-crossover and self-controlled case series designs evaluating exposure to the precipitant drug within person-time exposed to the object drug. Scenarios evaluated violations of key design assumptions: (1) time-varying, within-person confounding; (2) time trend in precipitant drug exposure prevalence; (3) nontransient precipitant exposure; and (4) event-dependent object drug discontinuation. RESULTS: Case-crossover analysis produced biased estimates when 30% of patients persisted on the precipitant drug (estimated OR 2.85) and when the use of the precipitant drug was increasing in simulated cohorts (estimated OR 2.56). Self-controlled case series produced biased estimates when patients discontinued the object drug following the occurrence of an outcome (estimated incidence ratio [IR] of 2.09 [50% of patients stopping therapy] and 2.22 [90%]). Both designs yielded similarly biased estimates in the presence of time-varying, within-person confounding. CONCLUSION: In settings with independent or rare outcomes and no substantial event-dependent censoring (<50%), self-controlled case series may be preferable to case-crossover design for evaluating outcomes of drug-drug interactions. With frequent event-dependent drug discontinuation, a case-crossover design may be preferable provided there are no time-related trends in drug exposure.

12.
JAMA Netw Open ; 2(7): e198061, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31365106

RESUMO

Importance: Prescription opioid use is common among patients with moderate to severe knee osteoarthritis before undergoing total knee replacement (TKR). Preoperative opioid use may be associated with worse clinical and safety outcomes after TKR. Objective: To determine the association of preoperative opioid use among patients 65 years and older with mortality and other complications at 30 days post-TKR. Design, Setting, And Participants: This cohort study used claims data from January 1, 2010, to December 31, 2014, from a random sample of US Medicare enrollees 65 years and older who underwent TKR. Based on opioid dispensing in 360 days prior to TKR, patients were classified as continuous (≥1 opioid dispensing in each of the past 12 months) or intermittent (any dispensing of opioids in the past 12 months but not continuous use) opioid users or as opioid-naive patients (no opioids dispensed in the past 12 months). Data analyses were conducted from October 3, 2017, to November 8, 2018. Main Outcomes and Measures: Primary outcomes included in-hospital mortality and 30-day post-TKR mortality, hospital readmission, and revision operation. Secondary safety outcomes at 30 days post-TKR included opioid overdose and vertebral and nonvertebral fracture. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs. Results: Of 316 593 patients (mean [SD] age, 73.9 [5.8] years; 214 677 [67.8%] women) who underwent TKR, 22 895 (7.2%) were continuous opioid users, 161 511 (51.0%) were intermittent opioid users, and 132 187 (41.7%) were opioid naive. In-hospital mortality occurred in 276 patients (0.09%). At 30 days post-TKR, 828 patients (0.26%) died, 16 786 patients (5.30%) had hospital readmission, and 921 patients (0.29%) had a revision operation. All primary and secondary outcomes occurred more frequently among continuous opioid users compared with opioid-naive patients. Compared with opioid-naive patients and after adjusting for demographic characteristics, combined comorbidity score, number of different prescription medications, and frailty, continuous opioid users had greater risk of revision operations (HR, 1.63; 95% CI, 1.15-2.32), vertebral fractures (HR, 2.37; 95% CI, 1.37-4.09), and opioid overdose (HR, 4.82; 95% CI, 1.36-17.07) at 30 days post-TKR. However, after adjusting covariates, there were no statistically significant differences in in-hospital (HR, 1.18; 95% CI, 0.73-1.90) or 30-day (HR, 1.05; 95% CI, 0.73-1.51) mortality between continuous opioid users and opioid-naive patients. Conclusions and Relevance: After adjusting for baseline risk profiles, including comorbidities and frailty, continuous opioid users had a higher risk of revision operations, vertebral fractures, and opioid overdose at 30 days post-TKR but not of in-hospital or 30-day mortality, compared with opioid-naive patients. These results highlight the need for better understanding of patient characteristics associated with chronic opioid use to optimize preoperative assessment of overall risk after TKR.

14.
Pharmacoepidemiol Drug Saf ; 28(10): 1299-1308, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31313427

RESUMO

PURPOSE: We sought to determine whether an association study using information contained in clinical notes could identify known and potentially novel risk factors for nonadherence to antihypertensive medications. METHODS: We conducted a retrospective concept-wide association study (CWAS) using clinical notes to identify potential risk factors for medication nonadherence, adjusting for age, sex, race, baseline blood pressure, estimated glomerular filtration rate, and a combined comorbidity score. Participants included Medicare beneficiaries 65 years and older receiving care at the Harvard Vanguard Medical Associates network from 2010-2012 and enrolled in a Medicare Advantage program. Concepts were extracted from clinical notes in the year prior to the index prescription date for each patient. We tested associations with the outcome for 5013 concepts extracted from clinical notes in a derivation cohort (4382 patients) and accounted for multiple hypothesis testing by using a false discovery rate threshold of less than 5% (q < .05). We then confirmed the associations in a validation cohort (3836 patients). Medication nonadherence was defined using a proportion of days covered (PDC) threshold less than 0.8 using pharmacy claims data. RESULTS: We found 415 concepts associated with nonadherence, which we organized into 11 clusters using a hierarchical clustering approach. Volume depletion and overload, assessment of needs at the point of discharge, mood disorders, neurological disorders, complex coordination of care, and documentation of noncompliance were some of the factors associated with nonadherence. CONCLUSIONS: This approach was successful in identifying previously described and potentially new risk factors for antihypertensive nonadherence using the clinical narrative.

15.
JAMA Netw Open ; 2(7): e197591, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31339546

RESUMO

Importance: The US Food and Drug Administration (FDA) created the exception from informed consent (EFIC) pathway in 1996 to allow some emergency trials to enroll patients without informed consent. To protect individual autonomy and preserve public trust, the FDA requires that EFIC trial investigators consult with community members before a trial may begin. Objectives: To analyze data from surveys conducted as part of community consultation ahead of EFIC trials and assess levels of public approval. Data Sources: All trials granted an EFIC must submit documentation of compliance with EFIC regulations to a publicly available docket at the FDA. Submissions between November 1, 1996, and October 23, 2017, were reviewed. Study Selection: Trials with survey data were included. Data Extraction and Synthesis: Data were extracted between January 2018 and June 2018 and were analyzed between June 2018 and August 2018. The quality and validity of data were assessed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A random-effects metaregression was used to assess the association of demographic characteristics with EFIC approval. Main Outcomes and Measures: The primary study outcome was EFIC approval. Results: The FDA docket contained 15 958 pages of material with survey data for 42 448 individuals submitted by 27 trials. Public approval of EFIC varied by question type, with more people willing to approve initiation of EFIC trials in their community (86.5%) than personal enrollment (73.0%), enrollment of a family member (68.6%), or the principle of enrollment without consent (58.4%) (P < .001 for all comparisons). In the United States, African American individuals made up 29.3% of those enrolled in EFIC trials that reported data on race (5064 of 17 302) but only 16.7% of those surveyed as part of community consultation. In the United States and Canada, men made up 42.9% of the surveyed population but 65.6% of those eventually enrolled in EFIC trials (29 961 of 45 694). Groups surveyed with higher proportions of African American and male respondents had lower rates of EFIC approval. Conclusions and Relevance: Public approval of EFIC trials varied by question type and by the respondents' reported race and sex. The demographic characteristics of those surveyed did not match the demographic characteristics of EFIC enrollees. The FDA could strengthen community consultation by standardizing survey instruments and reporting, requiring broader inclusion of African American and male respondents, clarifying the function of surveys in the development and modification of trial protocols, and building more public consensus around the acceptable use of EFIC.

16.
Diabetes Care ; 42(12): 2204-2210, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31239281

RESUMO

OBJECTIVE: Using real-world data (RWD) from three U.S. claims data sets, we aim to predict the findings of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) comparing linagliptin versus glimepiride in patients with type 2 diabetes (T2D) at increased cardiovascular risk by using a novel framework that requires passing prespecified validity checks before analyzing the primary outcome. RESEARCH DESIGN AND METHODS: Within Medicare and two commercial claims data sets (May 2011-September 2015), we identified a 1:1 propensity score-matched (PSM) cohort of T2D patients 40-85 years old at increased cardiovascular risk who initiated linagliptin or glimepiride by adapting eligibility criteria from CAROLINA. PSM was used to balance >120 confounders. Validity checks included the evaluation of expected power, covariate balance, and two control outcomes for which we expected a positive association and a null finding. We registered the protocol (NCT03648424, ClinicalTrials.gov) before evaluating the composite cardiovascular outcome based on CAROLINA's primary end point. Hazard ratios (HR) and 95% CIs were estimated in each data source and pooled with a fixed-effects meta-analysis. RESULTS: We identified 24,131 PSM pairs of linagliptin and glimepiride initiators with sufficient power for noninferiority (>98%). Exposure groups achieved excellent covariate balance, including key laboratory results, and expected associations between glimepiride and hypoglycemia (HR 2.38 [95% CI 1.79-3.13]) and between linagliptin and end-stage renal disease (HR 1.08 [0.66-1.79]) were replicated. Linagliptin was associated with a 9% decreased risk in the composite cardiovascular outcome with a CI including the null (HR 0.91 [0.79-1.05]), in line with noninferiority. CONCLUSIONS: In a nonrandomized RWD study, we found that linagliptin has noninferior risk of a composite cardiovascular outcome compared with glimepiride.

17.
Diabetes Obes Metab ; 21(9): 2029-2038, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31062453

RESUMO

AIM: To review the methodology of observational studies examining the association between glucose-lowering medications and cancer to identify the most common methodological challenges and sources of bias. METHODS: We searched PubMed systematically to identify observational studies on glucose-lowering medications and cancer published between January 2000 and January 2016. We assessed the design and analytical methods used in each study, with a focus on their ability to achieve study validity, and further evaluated the prevalence of major methodological choices over time. RESULTS: Of 155 studies evaluated, only 26% implemented a new-user design, 41% used an active comparator, 33% implemented a lag or latency period, and 51% adjusted for diabetes duration. Potential for immortal person-time bias was identified in 63% of the studies; 55% of the studies adjusted for variables measured during the follow-up without appropriate statistical methods. Aside from a decreasing trend in adjusting for variables measured during the follow-up, we observed no trends in methodological choices over time. CONCLUSIONS: The prevalence of well-known design and analysis flaws that may lead to biased results remains high among observational studies on glucose-lowering medications and cancer, limiting the conclusions that can be drawn from these studies. Avoiding known pitfalls could substantially improve the quality and validity of real-world evidence in this field.

18.
Circulation ; 139(25): 2822-2830, 2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-30955357

RESUMO

BACKGROUND: The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from August 2014 through September 2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor. METHODS: Within 2 commercial and 1 federal (Medicare) claims data sources in the United States, we identified a 1:1 propensity score-matched cohort of T2D patients ≥18 years old initiating empagliflozin or sitagliptin from August 2014 through September 2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HRs) and 95% CIs were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis. RESULTS: After propensity-score matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared with sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR, 0.50; 95% CI, 0.28-0.91), and the risk of HHF-broad by 49% (HR, 0.51;95% CI, 0.39-0.68), over a mean follow-up of 5.3 months. The results were consistent in patients with and without baseline cardiovascular disease, and for empagliflozin at both the 10- and 25-mg daily doses; analyses comparing empagliflozin versus the dipeptidyl peptidase-4 inhibitor class, and comparing sodium-glucose cotransporter-2 inhibitor versus dipeptidyl peptidase-4 inhibitor classes also produced consistent findings. CONCLUSIONS: The first interim analysis from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with T2D as treated in routine care, with and without a history of cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03363464.

19.
Pharmacoepidemiol Drug Saf ; 28(6): 879-886, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31020732

RESUMO

PURPOSE: Bootstrapping can account for uncertainty in propensity score (PS) estimation and matching processes in 1:1 PS-matched cohort studies. While theory suggests that the classical bootstrap can fail to produce proper coverage, practical impact of this theoretical limitation in settings typical to pharmacoepidemiology is not well studied. METHODS: In a plasmode-based simulation study, we compared performance of the standard parametric approach, which ignores uncertainty in PS estimation and matching, with two bootstrapping methods. The first method only accounted for uncertainty introduced during the matching process (the observation resampling approach). The second method accounted for uncertainty introduced during both PS estimation and matching processes (the PS reestimation approach). Variance was estimated based on percentile and empirical standard errors, and treatment effect estimation was based on median and mean of the estimated treatment effects across 1000 bootstrap resamples. Two treatment prevalence scenarios (5% and 29%) across two treatment effect scenarios (hazard ratio of 1.0 and 2.0) were evaluated in 500 simulated cohorts of 10 000 patients each. RESULTS: We observed that 95% confidence intervals from the bootstrapping approaches but not the standard approach, resulted in inaccurate coverage rates (98%-100% for the observation resampling approach, 99%-100% for the PS reestimation approach, and 95%-96% for standard approach). Treatment effect estimation based on bootstrapping approaches resulted in lower bias than the standard approach (less than 1.4% vs 4.1%) at 5% treatment prevalence; however, the performance was equivalent at 29% treatment prevalence. CONCLUSION: Use of bootstrapping led to variance overestimation and inconsistent coverage, while coverage remained more consistent with parametric estimation.

20.
MMWR Morb Mortal Wkly Rep ; 68(6): 140-143, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30763301

RESUMO

During 2017, opioids were associated with 47,600 deaths in the United States, approximately one third of which involved a prescription opioid (1). Amid concerns that overprescribing to patients with acute pain remains an essential factor underlying misuse, abuse, diversion, and unintentional overdose, several states have restricted opioid analgesic prescribing (2,3). To characterize patterns of opioid analgesic use for acute pain in primary care settings before the widespread implementation of limits on opioid prescribing (2,3), patients filling an opioid analgesic prescription for acute pain were identified from a 2014 database of commercial claims. Using a logistic generalized additive model, the probability of obtaining a refill was estimated as a function of the initial number of days supplied. Among 176,607 patients with a primary care visit associated with an acute pain complaint, 7.6% filled an opioid analgesic prescription. Among patients who received an initial 7-day supply, the probability of obtaining an opioid analgesic prescription refill for nine of 10 conditions was <25%. These results suggest that a ≤7-day opioid analgesic prescription might be sufficient for most, but not all, patients seen in primary care settings with acute pain who appear to need opioid analgesics. However, treatment strategies should account for patient and condition characteristics, which might alternatively reduce or extend the anticipated duration of benefit from opioid analgesic therapy.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Atenção Primária à Saúde , Feminino , Humanos , Masculino , Estados Unidos
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