Publications by authors named "Joshua J Gagne"

232 Publications

Frailty and Clinical Outcomes of Direct Oral Anticoagulants Versus Warfarin in Older Adults With Atrial Fibrillation : A Cohort Study.

Ann Intern Med 2021 Jul 20. Epub 2021 Jul 20.

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (A.P., J.J.G., L.G.B., H.L., R.J.G., S.S.).

Background: The role of differing levels of frailty in the choice of oral anticoagulants for older adults with atrial fibrillation (AF) is unclear.

Objective: To examine the outcomes of direct oral anticoagulants (DOACs) versus warfarin by frailty levels.

Design: 1:1 propensity score-matched analysis of Medicare data, 2010 to 2017.

Setting: Community.

Patients: Medicare beneficiaries with AF who initiated use of dabigatran, rivaroxaban, apixaban, or warfarin.

Measurements: Composite end point of death, ischemic stroke, or major bleeding by frailty levels, defined by a claims-based frailty index.

Results: In the dabigatran-warfarin cohort ( = 158 730; median follow-up, 72 days), the event rate per 1000 person-years was 63.5 for dabigatran initiators and 65.6 for warfarin initiators (hazard ratio [HR], 0.98 [95% CI, 0.92 to 1.05]; rate difference [RD], -2.2 [CI, -6.5 to 2.1]). For nonfrail, prefrail, and frail persons, HRs were 0.81 (CI, 0.68 to 0.97), 0.98 (CI, 0.90 to 1.08), and 1.09 (CI, 0.96 to 1.23), respectively. In the rivaroxaban-warfarin cohort ( = 275 944; median follow-up, 82 days), the event rate per 1000 person-years was 77.8 for rivaroxaban initiators and 83.7 for warfarin initiators (HR, 0.98 [CI, 0.94 to 1.02]; RD, -5.9 [CI, -9.4 to -2.4]). For nonfrail, prefrail, and frail persons, HRs were 0.88 (CI, 0.77 to 0.99), 1.04 (CI, 0.98 to 1.10), and 0.96 (CI, 0.89 to 1.04), respectively. In the apixaban-warfarin cohort ( = 218 738; median follow-up, 84 days), the event rate per 1000 person-years was 60.1 for apixaban initiators and 92.3 for warfarin initiators (HR, 0.68 [CI, 0.65 to 0.72]; RD, -32.2 [CI, -36.1 to -28.3]). For nonfrail, prefrail, and frail persons, HRs were 0.61 (CI, 0.52 to 0.71), 0.66 (CI, 0.61 to 0.70), and 0.73 (CI, 0.67 to 0.80), respectively.

Limitations: Residual confounding and lack of clinical frailty assessment.

Conclusion: For older adults with AF, apixaban was associated with lower rates of adverse events across all frailty levels. Dabigatran and rivaroxaban were associated with lower event rates only among nonfrail patients.

Primary Funding Source: National Institute on Aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M20-7141DOI Listing
July 2021

Association of California's Prescription Drug Coupon Ban With Generic Drug Use.

JAMA 2021 06;325(23):2399-2402

Program on Regulation, Therapeutics, and Law (PORTAL), Brigham and Women's Hospital, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2021.6568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207236PMC
June 2021

Factors Associated With Generic Drug Uptake in the United States, 2012 to 2017.

Value Health 2021 Jun 22;24(6):804-811. Epub 2021 Apr 22.

Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Objectives: In the United States, brand-name prescription drugs remain expensive until market exclusivity ends and lower-cost generics become available. Delayed generic drug uptake may increase spending and worsen medication adherence and patient outcomes. We assessed recent trends and factors associated with generic uptake.

Methods: Among 227 drugs facing new generic competition from 2012 to 2017, we used a national claims database to measure generic uptake in the first and second year after generic entry, defined as the proportion of claims for a generic version of the drug. Using linear regression, we evaluated associations between generic uptake and key drug characteristics.

Results: Mean generic uptake was 66.1% (standard deviation 22.1%) in the first year and 82.7% (standard deviation 21.6%) in the second year after generic entry. From 2012 to 2017 generic uptake decreased 4.3% per year in the first year (95% confidence interval, 2.8%-5.8%, P < .001) and 3.2%/year in the second year (95% confidence interval, 1.2%-5.1%). Generic uptake was lower for injected than oral drugs in the first year (38.5% vs 70.0%, P < .001) and second year (50.3% vs 86.9%, P < .001). In the second year, generic uptake was higher among drugs with an authorized generic (86.1 vs 80.1%, P = .045) and those with ≥3 generic competitors (87.7% vs 78.6%, P = .055).

Conclusion: Early generic uptake decreased over the past several years. This trend may adversely affect patients and increase prescription drug spending. Policies are needed to encourage generic competition, particularly among injected drugs administered in a hospital or clinic setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jval.2020.12.020DOI Listing
June 2021

Coprescription of Opioids With Other Medications and Risk of Opioid Overdose.

Clin Pharmacol Ther 2021 May 28. Epub 2021 May 28.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Polypharmacy is common among patients taking prescription opioids long-term, and the codispensing of interacting medications may further increase opioid overdose risk. To identify nonopioid medications that may increase opioid overdose risk in this population, we conducted a case-crossover-based screening of electronic claims data from IBM MarketScan and Optum Clinformatics Data Mart spanning 2003 through 2019. Eligible patients were 18 years of age or older and had at least 180 days of continuous enrollment and 90 days of prescription opioid use immediately before an opioid overdose resulting in an emergency room visit or hospitalization. The main analysis quantified the odds ratio (OR) between opioid overdose and each nonopioid medication dispensed in the 90 days immediately before the opioid overdose date after adjustment for prescription opioid dosage and benzodiazepine codispensing. Additional analyses restricted to patients without cancer diagnoses and individuals who used only oxycodone for 90 days immediately before the opioid overdose date. The false discovery rate (FDR) was used to account for multiple testing. We identified 24,866 individuals who experienced opioid overdose. Baclofen (OR 1.56; FDR < 0.01; 95% confidence interval (CI), 1.29 to 1.89), lorazepam (OR 1.53; FDR < 0.01; 95% CI, 1.25 to 1.88), and gabapentin (OR 1.16; FDR = 0.09; 95% CI, 1.04 to 1.28), among other nonopioid medications, were associated with opioid overdose. Similar patterns were observed in noncancer patients and individuals who used only oxycodone. Interventions may focus on prescribing safer alternatives when a potential for interaction exists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2314DOI Listing
May 2021

Using a Simple Prescription Gap to Determine Warfarin Discontinuation Can Lead to Substantial Misclassification.

Thromb Haemost 2021 May 13. Epub 2021 May 13.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States.

Background:  Warfarin remains widely used and a key comparator in studies of other direct oral anticoagulants. As longer-than-needed warfarin prescriptions are often provided to allow for dosing adjustments according to international normalized ratios (INRs), the common practice of using a short allowable gap between dispensings to define warfarin discontinuation may lead to substantial misclassification of warfarin exposure. We aimed to quantify such misclassification and determine the optimal algorithm to define warfarin discontinuation.

Methods:  We linked Medicare claims data from 2007 to 2014 with a multicenter electronic health records system. The study cohort comprised patients ≥65 years with atrial fibrillation and venous thromboembolism initiating warfarin. We compared results when defining warfarin discontinuation by (1) different gaps (3, 7, 14, 30, and 60 days) between dispensings and (2) having a gap ≤60 days or bridging larger gaps if there was INR ordering at least every 42 days (60_INR). Discontinuation was considered misclassified if there was an INR ≥2 within 7 days after the discontinuation date.

Results:  Among 3,229 patients, a shorter gap resulted in a shorter mean follow-up time (82, 95, 117, 159, 196, and 259 days for gaps of 3, 7, 14, 30, 60, and 60_INR, respectively;  < 0.001). Incorporating INR (60_INR) can reduce misclassification of warfarin discontinuation from 68 to 4% ( < 0.001). The on-treatment risk estimation of clinical endpoints varied significantly by discontinuation definitions.

Conclusion:  Using a short gap between warfarin dispensings to define discontinuation may lead to substantial misclassification, which can be improved by incorporating intervening INR codes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-1508-8187DOI Listing
May 2021

A Multi-modal Approach to Evaluate the Impact of Risk Evaluation and Mitigation Strategy (REMS) Programs.

Drug Saf 2021 Jul 27;44(7):743-751. Epub 2021 Apr 27.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Introduction: Since 2007, the US Food and Drug Administration has had the authority to require risk evaluation and mitigation strategy (REMS) programs for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. Such programs can include requirements for patient monitoring, restrictions on dispensing or administration, and physician and pharmacy training and certification. However, there has been only scattered evidence on the impact of REMS programs on informed decision making, medication access, or patient outcomes.

Objective: The objective of this article was to describe a study that researchers at Brigham and Women's Hospital and Harvard Medical School will conduct in partnership with the Food and Drug Administration's Office of Surveillance and Epidemiology to investigate systematically how REMS programs have operated in practice.

Methods: Investigations include health insurance claims-based analyses to understand patterns of drug use, adherence to safety requirements, and patient outcomes under REMS programs; surveys and interviews to understand physician and patient experiences with REMS; and REMS program material-based and interview-based analyses to understand the effectiveness of risk communication in REMS programs.

Conclusions: These research activities will evaluate the performance of REMS programs, provide information on the benefits and burdens to patients and healthcare providers, and generate recommendations for actionable steps to improve REMS programs overall.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40264-021-01070-2DOI Listing
July 2021

Control yourself: ISPE-endorsed guidance in the application of self-controlled study designs in pharmacoepidemiology.

Pharmacoepidemiol Drug Saf 2021 Jun 1;30(6):671-684. Epub 2021 Apr 1.

Clinical Pharmacology and Pharmacy, IST, University of Southern Denmark, Odense, Denmark.

Purpose: Consensus is needed on conceptual foundations, terminology and relationships among the various self-controlled "trigger" study designs that control for time-invariant confounding factors and target the association between transient exposures (potential triggers) and abrupt outcomes. The International Society for Pharmacoepidemiology (ISPE) funded a working group of ISPE members to develop guidance material for the application and reporting of self-controlled study designs, similar to Standards of Reporting Observational Epidemiology (STROBE). This first paper focuses on navigation between the types of self-controlled designs to permit a foundational understanding with guiding principles.

Methods: We leveraged a systematic review of applications of these designs, that we term Self-controlled Crossover Observational PharmacoEpidemiologic (SCOPE) studies. Starting from first principles and using case examples, we reviewed outcome-anchored (case-crossover [CCO], case-time control [CTC], case-case-time control [CCTC]) and exposure-anchored (self-controlled case-series [SCCS]) study designs.

Results: Key methodological features related to exposure, outcome and time-related concerns were clarified, and a common language and worksheet to facilitate the design of SCOPE studies is introduced.

Conclusions: Consensus on conceptual foundations, terminology and relationships among SCOPE designs will facilitate understanding and critical appraisal of published studies, as well as help in the design, analysis and review of new SCOPE studies. This manuscript is endorsed by ISPE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pds.5227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251635PMC
June 2021

A General Propensity Score for Signal Identification Using Tree-Based Scan Statistics.

Am J Epidemiol 2021 Jul;190(7):1424-1433

The tree-based scan statistic (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) is a data-mining method that adjusts for multiple testing of correlated hypotheses when screening thousands of potential adverse events for signal identification. Simulation has demonstrated the promise of TreeScan with a propensity score (PS)-matched cohort design. However, it is unclear which variables to include in a PS for applied signal identification studies to simultaneously adjust for confounding across potential outcomes. We selected 4 pairs of medications with well-understood safety profiles. For each pair, we evaluated 5 candidate PSs with different combinations of 1) predefined general covariates (comorbidity, frailty, utilization), 2) empirically selected (data-driven) covariates, and 3) covariates tailored to the drug pair. For each pair, statistical alerting patterns were similar with alternative PSs (≤11 alerts in 7,996 outcomes scanned). Inclusion of covariates tailored to exposure did not appreciably affect screening results. Inclusion of empirically selected covariates can provide better proxy coverage for confounders but can also decrease statistical power. Unlike tailored covariates, empirical and predefined general covariates can be applied "out of the box" for signal identification. The choice of PS depends on the level of concern about residual confounding versus loss of power. Potential signals should be followed by pharmacoepidemiologic assessment where confounding control is tailored to the specific outcome(s) under investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/aje/kwab034DOI Listing
July 2021

Non-warfarin oral anticoagulant copayments and adherence in atrial fibrillation: A population-based cohort study.

Am Heart J 2021 03 14;233:109-121. Epub 2021 Jan 14.

Program On Regulation, Therapeutics, And Law; Division of Pharmacoepidemiology and Pharmacoeconomics; Department of Medicine; Brigham and Women's Hospital; Boston, MA; Harvard Medical School, Boston, MA.

Background: In patients with atrial fibrillation, incomplete adherence to anticoagulants increases risk of stroke. Non-warfarin oral anticoagulants (NOACs) are expensive; we evaluated whether higher copayments are associated with lower NOAC adherence.

Methods: Using a national claims database of commercially-insured patients, we performed a cohort study of patients with atrial fibrillation who newly initiated a NOAC from 2012 to 2018. Patients were stratified into low (<$35), medium ($35-$59), or high (≥$60) copayments and propensity-score weighted based on demographics, insurance characteristics, comorbidities, prior health care utilization, calendar year, and the NOAC received. Follow-up was 1 year, with censoring for switching to a different anticoagulant, undergoing an ablation procedure, disenrolling from the insurance plan, or death. The primary outcome was adherence, measured by proportion of days covered (PDC). Secondary outcomes included NOAC discontinuation (no refill for 30 days after the end of NOAC supply) and switching anticoagulants. We compared PDC using a Kruskal-Wallis test and rates of discontinuation and switching using Cox proportional hazards models.

Results: After weighting patients across the 3 copayment groups, the effective sample size was 17,558 patients, with balance across 50 clinical and demographic covariates (standardized differences <0.1). Mean age was 62 years, 29% of patients were female, and apixaban (43%), and rivaroxaban (38%) were the most common NOACs. Higher copayments were associated with lower adherence (P < .001), with a PDC of 0.82 (Interquartile range [IQR] 0.36-0.98) among those with high copayments, 0.85 (IQR 0.41-0.98) among those with medium copayments, and 0.88 (IQR 0.41-0.99) among those with low copayments. Compared to patients with low copayments, patients with high copayments had higher rates of discontinuation (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.08-1.19; P < .001).

Conclusions: Among atrial fibrillation patients newly initiating NOACs, higher copayments in commercial insurance were associated with lower adherence and higher rates of discontinuation in the first year. Policies to lower or limit cost-sharing of important medications may lead to improved adherence and better outcomes among patients receiving NOACs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2020.12.010DOI Listing
March 2021

Drug-Drug Interaction Surveillance Study: Comparing Self-Controlled Designs in Five Empirical Examples in Real-World Data.

Clin Pharmacol Ther 2021 May 17;109(5):1353-1360. Epub 2020 Dec 17.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Self-controlled designs, specifically the case-crossover (CCO) and the self-controlled case series (SCCS), are increasingly utilized to generate real-world evidence (RWE) on drug-drug interactions (DDIs). Although these designs share the advantages and limitations of within-individual comparison, they also have design-specific assumptions. It is not known to what extent the differences in assumptions lead to different results in RWE DDI analyses. Using a nationwide US commercial healthcare insurance database (2006-2016), we compared the CCO and SCCS designs, as they are implemented in DDI studies, within five DDI-outcome examples: (1) simvastatin + clarithromycin and muscle-related toxicity; (2) atorvastatin + valsartan, and muscle-related toxicity; and (3-5) dabigatran + P-glycoprotein inhibitor (clarithromycin, amiodarone, and verapamil) and bleeding. Analyses were conducted within person-time exposed to the object drug (statins and dabigatran) and adjusted for bias associated with the inhibiting drugs via control groups of individuals unexposed to the object drug. The designs yielded similar estimates in most examples, with SCCS displaying better statistical efficiency. With both designs, results varied across sensitivity analyses, particularly in CCO analyses with small number of exposed individuals. Analyses in controls revealed substantial bias that may be differential across DDI-exposed and control individuals. Thus, both designs showed no association between amiodarone or verapamil and bleeding in dabigatran-exposed but revealed strong positive associations in controls. Overall, bias adjustment via a control group had a larger impact on results than the choice of a design, highlighting the importance and challenges of appropriate control group selection for adequate bias control in self-controlled analyses of DDIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpt.2119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058240PMC
May 2021

Trends in Medicare Part D Inhaler Spending: 2012-2018.

Ann Am Thorac Soc 2021 03;18(3):548-550

Brigham and Women's Hospital Boston, Massachusetts and.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1513/AnnalsATS.202008-1082RLDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919157PMC
March 2021

Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program.

Drug Saf 2021 Mar 18;44(3):327-335. Epub 2020 Nov 18.

Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St., Suite 3030, Boston, MA, 02120, USA.

Introduction: Risk evaluation and mitigation strategy (REMS) programs are intended to improve safe use of US Food and Drug Administration-approved drugs. However, controversy exists over whether they consistently accomplish this goal.

Objective: We aimed to assess how initiation of the erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin alfa changed following implementation and enforcement (following a 1-year post-implementation grace period) of a prominent REMS program warning physicians against use in cancer patients with hemoglobin above 10 g/dL.

Methods: Using claims data from a large US commercial insurance company, we conducted interrupted time-series analyses of darbepoetin alfa and epoetin alfa initiation among adult cancer patients in the 12 months before REMS program implementation, after REMS program implementation, and after REMS program enforcement. We also evaluated differences in inappropriate initiation (hemoglobin tests all above 10 g/dL in the prior month) between the periods.

Results: In total, we identified 3456 darbepoetin alfa initiators and 2632 epoetin alfa initiators. Over the study period, the monthly number of initiators per 100,000 patients with cancer fell from 119 to 32 for darbepoetin alfa and from 82 to 34 for epoetin alfa. However, non-significant post-REMS program implementation level and slope changes per 100,000 adult patients with cancer were observed for darbepoetin alfa (level 0.03 [95% confidence interval (CI) -14.98 to 15.05]; slope 1.94 [95% CI -0.22 to 4.10]) and epoetin alfa (level -4.10 [95% CI -16.85 to 8.65]; slope -0.52 [95% CI -2.35 to 1.32]). Non-significant post-REMS program enforcement level and slope changes were also seen for both drugs (darbepoetin alfa level 1.58 [95% CI -0.58 to 3.74, slope -0.28 [95% CI -15.29 to 14.73]; epoetin alfa level 1.58 (95% CI -0.26 to 3.42], slope 5.74 [95% CI -7.01 to 18.49]). Finally, non-significant changes in inappropriate darbepoetin alfa (60% vs. 53% vs. 57%, p = 0.68) and epoetin alfa (53% vs. 53% vs. 46%, p = 0.41) initiation were observed between the three study periods.

Conclusion: REMS program implementation and enforcement were not associated with significant changes in ESA initiation, adding to concerns over the degree to which certain REMS programs enhance patient safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40264-020-01017-zDOI Listing
March 2021

Pharmacotherapy for Hospitalized Patients with COVID-19: Treatment Patterns by Disease Severity.

Drugs 2020 Dec;80(18):1961-1972

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.

Background: Treatment decisions for Coronavirus Disease 2019 (COVID-19) depend on disease severity, but the prescribing pattern by severity and drivers of therapeutic choices remain unclear.

Objectives: The objectives of the study were to evaluate pharmacological treatment patterns by COVID-19 severity and identify the determinants of prescribing for COVID-19.

Methods: Using electronic health record data from a large Massachusetts-based healthcare system, we identified all patients aged ≥ 18 years hospitalized with laboratory-confirmed COVID-19 from 1 March to 24 May, 2020. We defined five levels of COVID-19 severity at hospital admission: (1) hospitalized but not requiring supplemental oxygen; (2-4) hospitalized and requiring oxygen ≤ 2, 3-4, and ≥ 5 L per minute, respectively; and (5) intubated or admitted to an intensive care unit. We assessed the medications used to treat COVID-19 or as supportive care during hospitalization.

Results: Among 2821 patients hospitalized for COVID-19, we found inpatient mortality increased by severity from 5% for level 1 to 23% for level 5. As compared to patients with severity level 1, those with severity level 5 were 3.53 times (95% confidence interval 2.73-4.57) more likely to receive a medication used to treat COVID-19. Other predictors of treatment were fever, low oxygen saturation, presence of co-morbidities, and elevated inflammatory biomarkers. The use of most COVID-19 relevant medications has dropped substantially while the use of remdesivir and therapeutic anticoagulants has increased over the study period.

Conclusions: Careful consideration of disease severity and other determinants of COVID-19 drug use is necessary for appropriate conduct and interpretation of non-randomized studies evaluating outcomes of COVID-19 treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40265-020-01424-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643089PMC
December 2020

Empirical assessment of case-based methods for identification of drugs associated with acute liver injury in the French National Healthcare System database (SNDS).

Pharmacoepidemiol Drug Saf 2021 03 19;30(3):320-333. Epub 2020 Nov 19.

Univ. Bordeaux, INSERM CIC-P1401, Bordeaux PharmacoEpi, Bordeaux, France.

Purposes: Drug induced acute liver injury (ALI) is a frequent cause of liver failure. Case-based designs were empirically assessed and calibrated in the French National claims database (SNDS), aiming to identify the optimum design for drug safety alert generation associated with ALI.

Methods: All cases of ALI were extracted from SNDS (2009-2014) using specific and sensitive definitions. Positive and negative drug controls were used to compare 196 self-controlled case series (SCCS), case-control (CC), and case-population (CP) design variants, using area under the receiver operating curve (AUC), mean square error (MSE) and coverage probability. Parameters that had major impacts on results were identified through logistic regression.

Results: Using a specific ALI definition, AUCs ranged from 0.78 to 0.94, 0.64 to 0.92 and 0.48 to 0.85, for SCCS, CC and CP, respectively. MSE ranged from 0.12 to 0.40, 0.22 to 0.39 and 1.03 to 5.29, respectively. Variants adjusting for multiple drug use had higher coverage probabilities. Univariate regressions showed that high AUCs were achieved with SCCS using exposed time as the risk window. The top SCCS variant yielded an AUC = 0.93 and MSE = 0.22 and coverage = 86%, with 1/7 negative and 13/18 positive controls presenting significant estimates.

Conclusions: SCCS adjusting for multiple drugs and using exposed time as the risk window performed best in generating ALI-related drug safety alert and providing estimates of the magnitude of the risk. This approach may be useful for ad-hoc pharmacoepidemiology studies to support regulatory actions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pds.5161DOI Listing
March 2021

Differences in characteristics of Medicare patients treated by ophthalmologists and optometrists.

PLoS One 2020 14;15(9):e0227783. Epub 2020 Sep 14.

Department of Ophthalmology, University of Washington, Seattle, WA, United States of America.

Purpose: To quantify differences in the age, gender, race, and clinical complexity of Medicare beneficiaries treated by ophthalmologists and optometrists in each of the United States.

Design: Cross-sectional study based on publicly accessible Medicare payment and utilization data from 2012 through 2017.

Methods: For each ophthalmic and optometric provider, demographic information of treated Medicare beneficiaries was obtained from the Medicare Provider Utilization and Payment Data from the Centers for Medicare and Medicaid Services (CMS) for the years 2012 through 2017. Clinical complexity was defined using CMS Hierarchical Condition Category (HCC) coding.

Results: From 2012 through 2017, ophthalmologists in every state treated statistically significantly older beneficiaries, with the greatest difference (4.99 years in 2014) between provider groups seen in Rhode Island. In most states there was no gender difference among patients treated by the providers but in 46 states ophthalmologists saw a more racially diverse group of beneficiaries. HCC risk score analysis demonstrated that ophthalmologists in all 50 states saw more medically complex beneficiaries and the differences were statistically significant in 47 states throughout all six years.

Conclusions: Although there are regional variations in the characteristics of patients treated by ophthalmologists and optometrists, ophthalmologists throughout the United States manage older, more racially diverse, and more medically complex Medicare beneficiaries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227783PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489526PMC
October 2020

Risk of Renal Cell Carcinoma Associated with Calcium Channel Blockers: A Nationwide Observational Study Focusing on Confounding by Indication.

Epidemiology 2020 11;31(6):860-871

From the Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark.

Background: We examined whether the apparent association between renal cell carcinoma (RCC) and use of dihydropyridine calcium channel blockers (CCBs) was explained by confounding by indication since hypertension, the main indication for CCBs, is a risk factor for RCC.

Methods: Using Danish health registries, we conducted a nested case-control study including 7315 RCC cases during 2000-2015. We matched each case with up to 20 controls on age and sex using risk-set sampling. We estimated odds ratios (ORs) for long-term CCB use associated with RCC using conditional logistic regression. We addressed confounding by indication by (1) adjusting for hypertension severity indicators; (2) evaluating dose-response patterns; (3) examining whether other first-line anti-hypertensives were associated with RCC; and (4) using an active comparator new user design by nesting the study in new users of CCBs or angiotensin-converting enzyme inhibitors (ACEIs).

Results: The adjusted OR for RCC associated with long-term CCB use compared to non-use was 1.76 (1.63-1.90). After we additionally adjusted for hypertension severity indicators, the OR remained elevated (OR 1.37; confidence interval [CI] 1.25, 1.49) with evidence of a dose-response pattern. Other anti-hypertensives were also associated with RCC, for example, ACEIs (OR 1.27; 95% CI = 1.16, 1.39) and thiazides (OR 1.22; 95% CI = 1.12, 1.34). In the active comparator new user design, the OR was 1.21 (95% CI = 0.95, 1.53) for use of CCBs compared with ACEIs.

Conclusions: In this population, confounding by indication appeared to explain at least part of the association between RCC and dihydropyridine CCBs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/EDE.0000000000001256DOI Listing
November 2020

Association of Fluoroquinolones With the Risk of Aortic Aneurysm or Aortic Dissection.

JAMA Intern Med 2020 Dec;180(12):1596-1605

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Importance: Previous observational studies have suggested that fluoroquinolones are associated with aortic aneurysm or dissection, but these studies may be subject to confounding by indication or surveillance bias.

Objective: To assess the association of fluoroquinolones with risk of aortic aneurysm or aortic dissection (AA/AD) while accounting for potential confounding by fluoroquinolone indication and bias owing to differential surveillance.

Design, Setting, And Participants: In an observational cohort study using a US commercial claims database, 2 pairwise 1:1 propensity score-matched cohorts were identified: patients aged 50 years or older with a diagnosis of pneumonia 3 days or less before initiating treatment with a fluoroquinolone or azithromycin and patients aged 50 years or older with a urinary tract infection (UTI) diagnosis 3 days or less before initiating a fluoroquinolone or combined trimethoprim and sulfamethoxazole. Hazard ratios (HRs) and 95% CIs were estimated controlling for 85 baseline confounders. In a secondary analysis, patients receiving fluoroquinolones were compared with those receiving amoxicillin, both with and without considering baseline aortic imaging, to address differences in detection of AA/AD before antibiotic use. Data on patients within the database from January 1, 2003, through September 30, 2015, were analyzed. Data analysis was conducted from July 23, 2019, to July 6, 2020.

Main Outcomes And Measures: Hospitalization for AA/AD occurring within 60 days following treatment initiation.

Results: After propensity score matching, patient characteristics were well balanced, with 279 554 patients (mean [SD] age, 63.66 [10.93] years; 149 976 women [53.6%]) in the pneumonia cohort and 948 364 patients (mean [SD] age, 62.06 [10.33] years; 823 667 women [86.9%]) in the UTI cohort. Initiators of fluoroquinolones (n = 139 772 pairs in the pneumonia cohort and n = 474 182 pairs in the UTI cohort) had an increased rate of AA/AD compared with initiators of azithromycin (HR, 2.57; 95% CI, 1.36-4.86; incidence, 0.03% for fluoroquinolones vs 0.01% for azithromycin) but no increased rate compared with initiators of combined trimethoprim and sulfamethoxazole (HR, 0.99; 95% CI, 0.62-1.57; incidence, <0.01% in both UTI groups). Secondary analysis using amoxicillin as a comparator (n = 3 976 162 pairs) produced results consistent with those from earlier studies (HR, 1.54; 95% CI, 1.33-1.79; incidence, <0.01% in both groups). Requiring baseline imaging in this cohort (n = 542 649 pairs) to address surveillance bias attenuated the increased rate (HR, 1.13; 95% CI, 0.96-1.33; incidence, 0.06% for fluoroquinolones vs 0.05% for amoxicillin).

Conclusions And Relevance: The findings of this nationwide cohort study of adults with pneumonia or UTI suggest an increased relative rate of AA/AD associated with fluoroquinolones within the pneumonia cohort but not within the UTI cohort. In both cohorts, the absolute rate of AA/AD appeared to be low (<0.1%). The increased relative rate observed in the pneumonia cohort may be due to residual confounding or surveillance bias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2020.4199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489402PMC
December 2020

Preferences for and experiences with pill appearance changes: national surveys of patients and pharmacists.

Am J Manag Care 2020 08;26(8):340-347

Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, Suite 3030, Boston, MA 02120. Email:

Objectives: To better understand patients' and pharmacists' preferences for and experiences with changes in pill appearance (size, shape, color, and markings).

Study Design: Cross-sectional.

Methods: We conducted independent national surveys of patients 50 years and older taking generic drugs for depression, diabetes, epilepsy, HIV, hyperlipidemia, or hypertension and of licensed pharmacists practicing in chain, franchise, or independent pharmacies. Responses were collected between January and April 2016.

Results: Of 1000 patient respondents (30% response rate), most reported experiencing changes in pill appearance (51%) and preferred to be notified about them (82%), but less than half recalled being notified (verbally: 36%; via sticker: 45%). Among patients who reported experiencing a change, 12% reported stopping their medication or using it less frequently. Of 710 pharmacist respondents (33% response rate), many reported changes in pill appearance occurring frequently in their pharmacies (47% reported that changes occurred 6 or more times per month) and more than three-fourths reported notifying patients about them often (verbally: 88%; via sticker: 77%).

Conclusions: Our findings reveal opportunities to improve patients' experiences with pill appearance changes through better notification practices and patient education.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.37765/ajmc.2020.44070DOI Listing
August 2020

Screening Medications for Association with Progression to Wet Age-Related Macular Degeneration.

Ophthalmology 2021 02 7;128(2):248-255. Epub 2020 Aug 7.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Purpose: There is an urgent need for treatments that prevent or delay development to advanced age-related macular degeneration (AMD). Drugs already on the market for other conditions could affect progression to neovascular AMD (nAMD). If identified, these drugs could provide insights for drug development targets. The objective of this study was to use a novel data mining method that can simultaneously evaluate thousands of correlated hypotheses, while adjusting for multiple testing, to screen for associations between drugs and delayed progression to nAMD.

Design: We applied a nested case-control study to administrative insurance claims data to identify cases with nAMD and risk-set sampled controls that were 1:4 variable ratio matched on age, gender, and recent healthcare use.

Participants: The study population included cases with nAMD and risk set matched controls.

Methods: We used a tree-based scanning method to evaluate associations between hierarchical classifications of drugs that patients were exposed to within 6 months, 7 to 24 months, or ever before their index date. The index date was the date of first nAMD diagnosis in cases. Risk-set sampled controls were assigned the same index date as the case to which they were matched. The study was implemented using Medicare data from New Jersey and Pennsylvania, and national data from IBM MarketScan Research Database. We set an a priori threshold for statistical alerting at P ≤ 0.01 and focused on associations with large magnitude (relative risks ≥ 2.0).

Main Outcome Measures: Progression to nAMD.

Results: Of approximately 4000 generic drugs and drug classes evaluated, the method detected 19 distinct drug exposures with statistically significant, large relative risks indicating that cases were less frequently exposed than controls. These included (1) drugs with prior evidence for a causal relationship (e.g., megestrol); (2) drugs without prior evidence for a causal relationship, but potentially worth further exploration (e.g., donepezil, epoetin alfa); (3) drugs with alternative biologic explanations for the association (e.g., sevelamer); and (4) drugs that may have resulted in statistical alerts due to their correlation with drugs that alerted for other reasons.

Conclusions: This exploratory drug-screening study identified several potential targets for follow-up studies to further evaluate and determine if they may prevent or delay progression to advanced AMD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ophtha.2020.08.004DOI Listing
February 2021

Comparison of a new 3-item self-reported measure of adherence to medication with pharmacy claims data in patients with cardiometabolic disease.

Am Heart J 2020 10 24;228:36-43. Epub 2020 Jun 24.

Center for Healthcare Delivery Sciences (C4HDS), Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: Less than half of patients with cardiometabolic disease consistently take prescribed medications. While health insurers and some delivery organizations use claims to measure adherence, most clinicians do not have access during routine interactions. Self-reported scales exist, but their practical utility is often limited by length or cost. By contrast, the accuracy of a new 3-item self-reported measure has been demonstrated in individuals with HIV. We evaluated its concordance with claims-based adherence measures in cardiometabolic disease.

Methods: We used data from a recently-completed pragmatic trial of patients with cardiometabolic conditions. After 12 months of follow-up, intervention subjects were mailed a survey with the 3-item measure that queries about medication use in the prior 30 days. Responses were linearly transformed and averaged. Adherence was also measured in claims in month 12 and months 1-12 of the trial using proportion of days covered (PDC) metrics. We compared validation metrics for non-adherence for self-report (average <0.80) compared with claims (PDC <0.80).

Results: Of 459 patients returning the survey (response rate: 43.5%), 50.1% were non-adherent in claims in month 12 while 20.9% were non-adherent based on the survey. Specificity of the 3-item metric for non-adherence was high (month 12: 0.83). Sensitivity was relatively poor (month 12: 0.25). Month 12 positive and negative predictive values were 0.59 and 0.52, respectively.

Conclusions: A 3-item self-reported measure has high specificity but poor sensitivity for non-adherence versus claims in cardiometabolic disease. Despite this, the tool could help target those needing adherence support, particularly in the absence of claims data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ahj.2020.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508975PMC
October 2020

Using the Case-Crossover Design to Assess Short-Term Risks of Bleeding and Arterial Thromboembolism After Switching Between Oral Anticoagulants in a Population-Based Cohort of Patients With Atrial Fibrillation.

Am J Epidemiol 2020 12;189(12):1467-1477

Using nationwide Danish registries, we conducted a population-based case-crossover study evaluating the association between switching from a vitamin K antagonist (VKA) to a direct oral anticoagulant (DOAC), and vice versa, and 30-day risks of bleeding and arterial thromboembolism in patients with atrial fibrillation (AF). The case-crossover population was identified among oral anticoagulant users during 2011-2018 (n = 123,217) as patients with AF with 1) a case-defining outcome and 2) an anticoagulant switch during the 180 days preceding the outcome. Odds ratios were estimated using conditional logistic regression by comparing the occurrence of switching during the 30-day window immediately preceding the outcome to that in reference windows in the same individual 60-180 days before the outcome. The case-crossover populations for switching from VKA to DOAC and DOAC to VKA comprised 1,382 and 287 case patients, respectively. Switching from VKA to DOAC, but not from DOAC to VKA, was associated with an increased short-term risk of bleeding (odds ratio = 1.42; 95% confidence intervals: 1.13, 1.79, and 1.06; and 0.64, 1.75, respectively) and ischemic stroke (odds ratio = 1.74; 95% confidence intervals: 1.21, 2.51, and 0.92; and 0.46, 1.83, respectively). Our findings suggest that switching from VKA to DOAC is an intermittent risk factor of bleeding and ischemic stroke in patients with AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/aje/kwaa133DOI Listing
December 2020

Risk of sudden cardiac arrest and ventricular arrhythmia with sulfonylureas: An experience with conceptual replication in two independent populations.

Sci Rep 2020 06 22;10(1):10070. Epub 2020 Jun 22.

Center for Pharmacoepidemiology Research and Training, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Sulfonylureas are commonly used to treat type 2 diabetes mellitus. Despite awareness of their effects on cardiac physiology, a knowledge gap exists regarding their effects on cardiovascular events in real-world populations. Prior studies reported sulfonylurea-associated cardiovascular death but not serious arrhythmogenic endpoints like sudden cardiac arrest (SCA) or ventricular arrhythmia (VA). We assessed the comparative real-world risk of SCA/VA among users of second-generation sulfonylureas: glimepiride, glyburide, and glipizide. We conducted two incident user cohort studies using five-state Medicaid claims (1999-2012) and Optum Clinformatics commercial claims (2000-2016). Outcomes were SCA/VA events precipitating hospital presentation. We used Cox proportional hazards models, adjusted for high-dimensional propensity scores, to generate adjusted hazard ratios (aHR). We identified 624,406 and 491,940 sulfonylurea users, and 714 and 385 SCA/VA events, in Medicaid and Optum, respectively. Dataset-specific associations with SCA/VA for both glimepiride and glyburide (vs. glipizide) were on opposite sides of and could not exclude the null (glimepiride: aHR 1.17, 95% CI 0.96-1.42; aHR 0.84, 0.65-1.08; glyburide: aHR 0.87, 0.74-1.03; aHR 1.11, 0.86-1.42). Database differences in data availability, populations, and documentation completeness may have contributed to the incongruous results. Emphasis should be placed on assessing potential causes of discrepancies between conflicting studies evaluating the same research question.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-66668-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308403PMC
June 2020

Bias in case-crossover studies of medications due to persistent use: A simulation study.

Pharmacoepidemiol Drug Saf 2020 09 16;29(9):1079-1085. Epub 2020 Jun 16.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Purpose: The case-crossover design is increasingly used to evaluate the effects of chronic medications; however, as traditionally implemented in pharmacoepidemiology, with referent period preceding the outcome, it may lead to bias in the presence of persistent exposures. We aimed to evaluate the extent and magnitude of bias in case-crossover analyses of chronic and persistent exposures, using simulations.

Methods: We simulated cohorts with either 30-day, 180-day, or 2-year exposure duration; and with varying degrees of persistence (10%, 30%, 50%, 70%, or 90% of patients not stopping exposure). We evaluated all scenarios under the null and the scenario with 30% persistence under varying exposure effects (odds ratios of 0.25 to 4.0). Cohorts were analyzed using conditional logistic regression that compared the odds of exposure on the outcome day to the odds of exposure on a referent day 30 days prior to the outcome. We further implemented the case-time-control design to evaluate its ability to adjust for bias from persistence.

Results: Case-crossover analyses produced unbiased estimates across all scenarios without persistent users, regardless of exposure duration. In scenarios where some patients persisted on treatment, case-crossover analyses resulted in upward bias, which increased with increasing proportion of persistent users, but did not vary substantially in relation to the magnitude of the true effect. Case-time-control analyses removed bias in all scenarios.

Conclusions: Investigators should be aware of bias due to treatment persistence in unidirectional case-crossover analyses of chronic medications, which can be remedied with a control group of similarly persistent noncases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pds.5031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501161PMC
September 2020

Empirical assessment of case-based methods for identification of drugs associated with upper gastrointestinal bleeding in the French National Healthcare System database (SNDS).

Pharmacoepidemiol Drug Saf 2020 08 10;29(8):890-903. Epub 2020 Jun 10.

Bordeaux PharmacoEpi, INSERM CIC1401, Université de Bordeaux, Bordeaux, France.

Purpose: Upper gastrointestinal bleeding (UGIB) is a severe and frequent drug-related event. In order to enable efficient drug safety alert generation in the French National Healthcare System database (SNDS), we assessed and calibrated empirically case-based designs to identify drug associated with UGIB risk.

Methods: All cases of UGIB were extracted from SNDS (2009-2014) using two definitions. Positive and negative drug controls were used to compare 196 self-controlled case series (SCCS), case-control (CC) and case-population (CP) design variants. Each variant was evaluated in a 1/10 population sample using area under the receiver operating curve (AUC) and mean square error (MSE). Parameters that had major impacts on results were identified through logistic regression. Optimal designs were replicated in the unsampled population.

Results: Using a specific UGIB definition, AUCs ranged from 0.64 to 0.80, 0.44 to 0.61 and 0.50 to 0.67, for SCCS, CC and CP, respectively. MSE ranged from 0.07 to 0.39, 0.83 to 1.33 and 1.96 to 4.6, respectively. Univariate regressions showed that high AUCs were achieved with SCCS with multiple drug adjustment and a 30-day risk window starting at exposure. The top-performing SCCS variant in the unsampled population yielded an AUC = 0.84 and MSE = 0.14, with 10/36 negative controls presenting significant estimates.

Conclusions: SCCS adjusting for multiple drugs and using a 30-day risk window has the potential to generate UGIB-related alerts in the SNDS and hypotheses on its potential population impact. Negative control implementation highlighted that low systematic error was generated but that protopathic bias and confounding by indication remained unaddressed issues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pds.5038DOI Listing
August 2020

Using Data From Routine Care to Estimate the Effectiveness and Potential Limitations of Outcomes-Based Contracts for Diabetes Medications.

Value Health 2020 04 13;23(4):434-440. Epub 2020 Mar 13.

Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Objectives: Outcomes-based contracts tie rebates and discounts for expensive drugs to outcomes. The objective was to estimate the utility of outcomes-based contracts for diabetes medications using real-world data and to identify methodologic limitations of this approach.

Methods: A population-based cohort study of adults newly prescribed a medication for diabetes with a publicly announced outcomes-based contract (ie, exenatide microspheres ["exenatide"], dulaglutide, or sitagliptin) was conducted. The comparison group included patients receiving canagliflozin or glipizide. The primary outcome was announced in the outcomes-based contract: the percentage of adults with a follow-up hemoglobin A1C <8% up to 1 year later. Secondary outcomes included the percentage of patients diagnosed with hypoglycemia and the cost of a 1-month supply.

Results: Thousands of adults newly filled prescriptions for exenatide (n = 5079), dulaglutide (n = 6966), sitagliptin (n = 40 752), canagliflozin (n = 16 404), or glipizide (n = 59 985). The percentage of adults subsequently achieving a hemoglobin A1C below 8% ranged from 83% (dulaglutide, sitagliptin) to 71% (canagliflozin). The rate of hypoglycemia was 25 per 1000 person-years for exenatide, 37 per 1000 person-years for dulaglutide, 28 per 1000 person-years for sitagliptin, 18 per 1000 person-years for canagliflozin, and 34 per 1000 person-years for glipizide. The cash price for a 1-month supply was $847 for exenatide, $859 for dulaglutide, $550 for sitagliptin, $608 for canagliflozin, and $14 for glipizide.

Conclusion: Outcomes-based pricing of diabetes medications has the potential to lower the cost of medications, but using outcomes such as hemoglobin A1C may not be clinically meaningful because similar changes in A1C can be achieved with generic medications at a far lower cost.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jval.2019.11.004DOI Listing
April 2020

Trends in Utilization of Prescribed Controlled Substances in US Commercially Insured Adults, 2004-2019.

JAMA Intern Med 2020 07;180(7):1006-1008

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2020.0989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171580PMC
July 2020

Rates and Costs of Dispensing Naloxone to Patients at High Risk for Opioid Overdose in the United States, 2014-2018.

Drug Saf 2020 07;43(7):669-675

From the Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St., Suite 3030, Boston, MA, 02120, USA.

Introduction: Clinical practice guidelines recommend co-prescribing naloxone to patients at high risk of opioid overdose, but few such patients receive naloxone. High costs of naloxone may contribute to limited dispensing.

Objective: The aim of this study was to evaluate rates and costs of dispensing naloxone to patients receiving opioid prescriptions and at high risk for opioid overdose.

Methods: Using claims data from a large US commercial insurance company, we conducted a retrospective cohort study of new opioid initiators between January 2014 and December 2018. We identified patients at high risk for overdose defined as a diagnosis of opioid use disorder, prior overdose, an opioid prescription of ≥ 50 mg morphine equivalents/day for ≥ 90 days, and/or concurrent benzodiazepine prescriptions.

Results: Among 5,292,098 new opioid initiators, 616,444 (12%) met criteria for high risk of overdose during follow-up, and, of those, 3096 (0.5%) were dispensed naloxone. The average copayment was US$24.83 for naloxone (standard deviation [SD] 67.66) versus US$9.74 for the index opioid (SD 19.75). The average deductible was US$6.18 for naloxone (SD 27.32) versus US$3.74 for the index opioid (SD 25.56), with 94% and 88% having deductibles of US$0 for their naloxone and opioid prescriptions, respectively. The average out-of-pocket cost was US$31.01 for naloxone (SD 73.64) versus US$13.48 for the index opioid (SD 34.95).

Conclusions: Rates of dispensing naloxone to high risk patients were extremely low, and prescription costs varied greatly. Since improving naloxone's affordability may increase access, whether naloxone's high cost is associated with low dispensing rates should be evaluated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40264-020-00923-6DOI Listing
July 2020

Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study.

Ann Intern Med 2020 04 10;172(7):463-473. Epub 2020 Mar 10.

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (S.S., K.F.H., K.J.L., J.J.G.).

Background: Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking.

Objective: To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation.

Design: New-user, active-comparator, retrospective cohort study.

Setting: A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019.

Patients: Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706).

Measurements: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding.

Results: 39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1).

Limitation: Unmeasured confounding, incomplete laboratory data.

Conclusion: In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban.

Primary Funding Source: Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7326/M19-2522DOI Listing
April 2020

Empirical assessment of case-based methods for drug safety alert identification in the French National Healthcare System database (SNDS): Methodology of the ALCAPONE project.

Pharmacoepidemiol Drug Saf 2020 09 4;29(9):993-1000. Epub 2020 Mar 4.

Bordeaux PharmacoEpi, INSERM CIC1401, Université de Bordeaux, Bordeaux, France.

Objectives: To introduce the methodology of the ALCAPONE project.

Background: The French National Healthcare System Database (SNDS), covering 99% of the French population, provides a potentially valuable opportunity for drug safety alert generation. ALCAPONE aimed to assess empirically in the SNDS case-based designs for alert generation related to four health outcomes of interest.

Methods: ALCAPONE used a reference set adapted from observational medical outcomes partnership (OMOP) and Exploring and Understanding Adverse Drug Reactions (EU-ADR) project, with four outcomes-acute liver injury (ALI), myocardial infarction (MI), acute kidney injury (AKI), and upper gastrointestinal bleeding (UGIB)-and positive and negative drug controls. ALCAPONE consisted of four main phases: (1) data preparation to fit the OMOP Common Data Model and select the drug controls; (2) detection of the selected controls via three case-based designs: case-population, case-control, and self-controlled case series, including design variants (varying risk window, adjustment strategy, etc.); (3) comparison of design variant performance (area under the ROC curve, mean square error, etc.); and (4) selection of the optimal design variants and their calibration for each outcome.

Results: Over 2009-2014, 5225 cases of ALI, 354 109 MI, 12 633 AKI, and 156 057 UGIB were identified using specific definitions. The number of detectable drugs ranged from 61 for MI to 25 for ALI. Design variants generated more than 50 000 points estimates. Results by outcome will be published in forthcoming papers.

Conclusions: ALCAPONE has shown the interest of the empirical assessment of pharmacoepidemiological approaches for drug safety alert generation and may encourage other researchers to do the same in other databases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pds.4983DOI Listing
September 2020

Comparison of Different Case-Crossover Variants in Handling Exposure-Time Trend or Persistent-User Bias: Using Dipeptidyl Peptidase-4 Inhibitors and the Risk of Heart Failure as an Example.

Value Health 2020 02 24;23(2):217-226. Epub 2019 Oct 24.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Medicine, National Taiwan University, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan. Electronic address:

Objectives: Inappropriate use of the case-crossover design, which is efficient for examining associations between brief exposure and abrupt outcomes, in evaluating the effects of medications in the presence of exposure-time trends or persistent drug use may generate spurious associations. We compared different approaches to adjusting for these sources of bias by examining the risk of heart failure hospitalization (HFH) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors. Overall, existing evidence does not suggest a higher risk of HFH associated with DPP-4 inhibitors; however, case-crossover analyses of these medications may be susceptible to bias.

Methods: We conducted case-crossover; age, sex, risk-set (ASR) matched case-time-control; disease risk score (DRS)-matched case-time-control; and case-case-time-control analyses to assess the association between DPP-4 inhibitors and HFH among patients with diabetes mellitus (DM) in a population-based Taiwanese database. We also examined metformin and sulfonylureas, both with assumed null associations.

Results: Among 362 022 DM patients, 4105 (case-crossover), 4103 (ASR-matched case-time-control), 3957 (DRS-matched case-time-control), and 2812 (case-case-time-control) HFH cases were identified. The OR for DPP-4 inhibitors and HFH was elevated in the case-crossover analysis (1.52; 95% confidence interval [95% CI] 0.95-2.42). The ASR-matched case-time control, DRS-matched case-time-control, and case-case-time control analyses yielded near-null associations (0.90 [95% CI 0.45-1.83], 0.96 [95% CI 0.46-2.02], and 0.92 [95% CI 0.39-2.21], respectively). Null effects were observed for metformin across designs and for sulfonylureas in the case-case-time control analysis.

Conclusions: Our case-crossover analysis suggested DPP-4 inhibitors may be associated with HFH; however, each method for adjusting for exposure-time and persistent user bias attenuated the findings. The case-case-time-control analysis had the least precision.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jval.2019.09.2746DOI Listing
February 2020
-->