Drug development for major chronic health conditions-aligning with growing public health needs: Proceedings from a multistakeholder think tank.

The global pharmaceutical industry portfolio is skewed towards cancer and rare diseases due to more predictable development pathways and financial incentives. In contrast, drug development for major chronic health conditions that are responsible for a large part of mortality and disability worldwide is stalled. To examine the processes of novel drug development for common chronic health conditions, a multistakeholder Think Tank meeting, including thought leaders from academia, clinical practice, non-profit healthcare organizations, the pharmaceutical industry, the Food and Drug Administration (FDA), payors as well as investors, was convened in July 2022. Herein, we summarize the proceedings of this meeting, including an overview of the current state of drug development for chronic health conditions and key barriers that were identified. Six major action items were formulated to accelerate drug development for chronic diseases, with a focus on improving the efficiency of clinical trials and rapid implementation of evidence into clinical practice.

Regulatory and HTA Considerations for Development of Real-World Data Derived External Controls.

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real-world data (RWD) to generate real-world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD-derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit-for-purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD-derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.

Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions.

Real-world data (RWD)-derived external controls can be used to contextualize efficacy findings for investigational therapies evaluated in uncontrolled trials. As the number of submissions to regulatory and health technology assessment (HTA) bodies using external controls rises, and in light of recent regulatory and HTA guidance on the appropriate use of RWD, there is a need to address the operational and methodological challenges impeding the quality of real-world evidence (RWE) generation and the consistency in evaluation of RWE across agencies. This systematic review summarizes publicly available information on the use of external controls to contextualize outcomes from uncontrolled trials for all indications from January 1, 2015, through August 20, 2021, that were submitted to the European Medicines Agency, the US Food and Drug Administration, and/or select major HTA bodies (National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), and Gemeinsamer Bundesausschuss (G-BA)). By systematically reviewing submissions to regulatory and HTA bodies in the context of recent guidance, this study provides quantitative and qualitative insights into how external control design and analytic choices may be viewed by different agencies in practice. The primary operational and methodological aspects identified for discussion include, but are not limited to, engagement of regulators and HTA bodies, approaches to handling missing data (a component of data quality), and selection of real-world endpoints. Continued collaboration and guidance to address these and other aspects will inform and assist stakeholders attempting to generate evidence using external controls.

Fitness of real-world data for clinical trial data collection: Results and lessons from a HARMONY Outcomes ancillary study.

BACKGROUND: Despite the extensive use of real-world data for retrospective, observational clinical research, our understanding of how real-world data might increase the efficiency of data collection in patient-level randomized clinical trials is largely unknown. The structure of real-world data is inherently heterogeneous, with each source electronic health record and claims database different from the next. Their fitness-for-use as data sources for multisite trials in the United States has not been established. METHODS: For a subset of participants in the HARMONY Outcomes Trial, we obtained electronic health record data from recruiting sites or Medicare claims data from the Centers for Medicare & Medicaid Services. For baseline characteristics and follow-up events, we assessed the level of agreement between these real-world data and data documented in the trial database. RESULTS: Real-world data-derived demographic information tended to agree with trial-reported demographic information, although real-world data were less accurate in identifying medical history. The ability of real-world data to identify baseline medication usage differed by real-world data source, with claims data demonstrating substantially better performance than electronic health record data. The limited number of lab results in the collected electronic health record data matched closely with values in the trial database. There were not enough follow-up events in the ancillary study population to draw meaningful conclusions about the performance of real-world data for identification of events. Based on the conduct of this ancillary study, the challenges and opportunities of using real-world data within clinical trials are discussed. CONCLUSION: Based on a subset of participants from the HARMONY Outcomes Trial, our results suggest that electronic health record or claims data, as currently available, are unlikely to be a complete substitute for trial data collection of medical history or baseline lab results, but that Medicare claims were able to identify most medications. The limited size of the study population prevents us from drawing strong conclusions based on these results, and other studies are clearly needed to confirm or refute these findings.

Clinician Specialty, Access to Care, and Outcomes Among Patients with Peripheral Artery Disease.

BACKGROUND: Understanding the relationship between patterns of peripheral artery disease and outcomes is an essential step toward improving care and outcomes. We hypothesized that clinician specialty would be associated with occurrence of major adverse vascular events (MAVE). METHODS: Patients with at least 1 peripheral artery disease-related encounter in our health system and fee-for-service Medicare were divided into groups based on the specialty of the clinician (ie, cardiologist, surgeon, podiatrist, primary care, or other) providing a plurality of peripheral artery disease-coded care in the year prior to index encounter. The primary outcome was MAVE (a composite of all-cause mortality, myocardial infarction, stroke, lower extremity revascularization, and lower extremity amputation). RESULTS: The cohort included 1768 patients, of whom 30.0% were Black, 23.9% were Medicaid dual-enrollment eligible, and 31.1% lived in rural areas. Patients receiving a plurality of their care from podiatrists had the highest 1-year rates of MAVE (34.4%, P <.001), hospitalization (65.9%, P <.001), and amputations (22.6%, P <.001). Clinician specialty was not associated with outcomes after adjustment. Patients who were Medicaid dual-eligible had higher adjusted risks of mortality (adjusted hazard ratio [HRadj] 1.54, 95% confidence interval [CI] 1.11-2.14) and all-cause hospitalization (HRadj 1.20, 95% CI 1.03-1.40) and patients who were Black had a higher adjusted risk of amputation (HRadj 1.49, 95% CI 1.03-2.15). CONCLUSIONS: Clinician specialty was not associated with worse outcomes after adjustment, but certain socioeconomic factors were. The effects of clinician specialty and socioeconomic status were likely attenuated by the fact that all patients in this study had health insurance; these analyses require confirmation in a more representative cohort.

Clinical Effectiveness of Sacubitril/Valsartan Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real-world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines-Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Over 12-month follow-up, compared with a discharge prescription of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all-cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72-0.94; P=0.004) but not all-cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89-1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91-1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all-cause mortality (adjusted HR, 0.69; 95% CI, 0.60-0.79; P<0.001), all-cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82-0.98; P=0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82-1.08; P=0.40). Conclusions Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all-cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.

Life expectancy and voting patterns in the 2020 U.S. presidential election.

INTRODUCTION: In the 2016 U.S. Presidential election, voters in communities with recent stagnation or decline in life expectancy were more likely to vote for the Republican candidate than in prior Presidential elections. We aimed to assess the association between change in life expectancy and voting patterns in the 2020 Presidential election. METHODS: With data on county-level life expectancy from the Institute for Health Metrics and Evaluation and voting data from a GitHub repository of results scraped from news outlets, we used weighted multivariable linear regression to estimate the association between the change in life expectancy from 1980 to 2014 and the proportion of votes for the Republican candidate and change in the proportion of votes cast for the Republican candidate in the 2020 Presidential election. RESULTS: Among 3110 U.S counties and Washington, D.C., change in life expectancy at the county level was negatively associated with Republican share of the vote in the 2020 Presidential election (parameter estimate -7.2, 95% confidence interval, -7.8 to -6.6). With the inclusion of state, sociodemographic, and economic variables in the model, the association was attenuated (parameter estimate -0.8; 95% CI, -1.5 to -0.2). County-level change in life expectancy was positively associated with change in Republican vote share 0.29 percentage points (95% CI, 0.23 to 0.36). The association was attenuated when state, sociodemographic, and economic variables were added (parameter estimate 0.24; 95% CI, 0.15 to 0.33). CONCLUSION: Counties with a less positive trajectory in life expectancy were more likely to vote for the Republican candidate in the 2020 U.S. Presidential election, but the Republican candidate's share improved in some counties that experienced marked gains in life expectancy. Associations were moderated by demographic, social and economic factors.

The association of healthcare disparities and patient-specific factors on clinical outcomes in peripheral artery disease.

BACKGROUND: PAD increases the risk of cardiovascular mortality and limb loss, and disparities in treatment and outcomes have been described. However, the association of patient-specific characteristics with variation in outcomes is less well known. METHODS: Patients with PAD from Duke University Health System (DUHS) between January 1, 2015 and March 31, 2016 were identified. PAD status was confirmed through ground truth adjudication and predictive modeling using diagnosis codes, procedure codes, and other administrative data. Symptom severity, lower extremity imaging, and ankle-brachial index (ABI) were manually abstracted from the electronic health record (EHR). Data was linked to Centers for Medicare and Medicaid Services data to provide longitudinal follow up. Primary outcome was major adverse vascular events (MAVE), a composite of all-cause mortality, myocardial infarction (MI), stroke, lower extremity revascularization and amputation. RESULTS: Of 1,768 patients with PAD, 31.6% were asymptomatic, 41.2% had intermittent claudication (IC), and 27.3% had chronic limb-threatening ischemia (CLTI). At 1 year, patients with CLTI had higher rates of MAVE compared with asymptomatic or IC patients. CLTI and Medicaid dual eligibility were independent predictors of mortality. CLTI and Black race were associated with amputation. CONCLUSIONS: Rates of MAVE were highest in patients with CLTI, but patients with IC or asymptomatic disease also had high rates of adverse events. Black and Medicaid dual-eligible patients were disproportionately present in the CLTI subgroup and were at higher risk of amputation and mortality, respectively. Future studies must focus on early identification of high-risk patient groups to improve outcomes in patients with PAD.

Chemotherapy-induced peripheral neuropathy (CIPN) and its treatment: an NIH Collaboratory study of claims data.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication of many chemotherapies. We investigated the feasibility of using health plan claims and administrative data to identify CIPN occurrence by comparing patients who received neurotoxic and non-neurotoxic chemotherapies. METHODS: The sample included over 53,000,000 patients from two regional and one national insurer in the USA (> 400,000 exposed to chemotherapy). Peripheral neuropathy was identified using a broad definition (definition 1) and a specific definition (i.e., drug-induced polyneuropathy code) (definition 2). RESULTS: CIPN incidence as measured by definition 1 within 6 months of chemotherapy initiation was 18.1% and 6.2% for patients who received neurotoxic and non-neurotoxic chemotherapy, respectively (relative risk neurotoxic vs. non-neurotoxic (RR), 2.93 (95% CI, 2.87-2.98)). For definition 2, these incidences were 3.6% and 0.1% (RR, 25.2 (95% CI, 22.8-27.8)). The incidences of new analgesic prescriptions for neurotoxic and non-neurotoxic groups were as follows: gabapentin, 7.1%/1.7%; pregabalin, 0.69%/0.31%; and duloxetine, 0.78%/0.76%. The incidence of CIPN as defined by definitions 1 and 2 was low compared with that of published research studies, but the relative risk of CIPN among patients who received neurotoxic chemotherapies compared with those who received non-neurotoxic chemotherapies was high using definition 2. CONCLUSIONS: These data suggest that as used currently by clinicians, administrative codes likely underestimate CIPN incidence. Thus, studies using administrative data to estimate CIPN incidence are not currently feasible. However, the drug-induced polyneuropathy code is a specific indicator of CIPN in administrative data and may be useful for investigating predictors or potentially preventive therapies of CIPN.

Care continuity impacts medicare expenditures of older adults: Fact or fiction?

BACKGROUND: Older adults with cardiometabolic conditions are typically seen by multiple providers. Management by multiple providers may compromise care continuity and increase health expenditures for older adults, which may partly explain the inverse association between continuity and Medicare expenditures found in prior studies. This study sought to examine whether all-cause admission, outpatient expenditures or total expenditures were associated with the number of prescribers of cardiometabolic medications. METHODS: Medicare fee-for-service beneficiaries with diabetes (n = 100,191), hypertension (n = 299,949) or dyslipidemia (n = 243,598) living in 10 states were identified from claims data. The probability of an all-cause hospital admission in 2011 was estimated via logistic regression and Medicare (outpatient, total) expenditures in 2011 were estimated using generalized linear models, both as a function of the number of prescribers in 2010. Regressions were adjusted for demographic characteristics, Medicaid status, number of prescriptions, and 17 chronic conditions. RESULTS: In all three cohorts, older adults with more prescribers in 2010 had modestly higher adjusted odds of all-cause inpatient admission than older adults with a single prescriber. Compared to a single prescriber, outpatient and total expenditures in 2011 were 3-10% higher for older adults with diabetes and multiple prescribers, 2-6% higher for older adults with hypertension and multiple prescribers, and 2-5% higher for older adults with dyslipidemia and multiple prescribers. CONCLUSIONS AND IMPLICATIONS: These results provide some evidence that older adults with multiple prescribers also have modestly higher Medicare utilization than those with a single prescriber; thus care continuity may impact patient utilization. LEVEL OF EVIDENCE: Level III (retrospective cohort analysis).

Ischemic and Bleeding Outcomes in Patients With Atrial Fibrillation and Contraindications to Oral Anticoagulation.

OBJECTIVES: This study sought to describe clinical outcomes among patients with atrial fibrillation (AF) and contraindications to oral anticoagulation (OAC). BACKGROUND: Treatment with OAC prevents stroke and death in patients with AF, but may be contraindicated among patients at high bleeding risk. METHODS: This was an observational, longitudinal analysis of a nationally representative 5% Medicare sample of patients with chronic AF and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65-74 years, sex category) score ≥2. They were stratified by both the presence of high bleeding risk contraindications to OAC and by OAC use. We assessed 3-year ischemic and bleeding outcomes using multivariable Cox proportional hazards models adjusted for relevant patient characteristics. RESULTS: Among 26,684 AF patients not treated with OAC, 8,283 (31%) had a high bleeding risk contraindication, primarily a blood dyscrasia (75%) or history of gastrointestinal bleeding (40%). Without OAC, patients with contraindications had worse ischemic and bleeding outcomes at 3 years compared with those without contraindications. We also identified 12,454 patients with OAC contraindications who received OAC. Compared with patients not receiving OAC, use of OAC was associated with reduced mortality (adjusted hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.76 to 0.83), stroke (adjusted HR: 0.90; 95% CI: 0.83 to 0.99), and all-cause hospitalization (adjusted HR: 0.93; 95% CI: 0.90 to 0.96) but increased risk of intracranial hemorrhage (adjusted HR: 1.42; 95% CI: 1.17 to 1.72). CONCLUSIONS: High bleeding risk contraindications to OAC are common among older patients with AF, and these patients have higher mortality compared with untreated patients without OAC contraindications. The use of OAC in these patients is associated with lower rates of all-cause stroke, hospitalization, and death but higher risk of intracranial hemorrhage.

Claims-based cardiovascular outcome identification for clinical research: Results from 7 large randomized cardiovascular clinical trials.

BACKGROUND: Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes. METHODS: We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection. RESULTS: Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest. CONCLUSIONS: Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

Addressing guideline and policy changes during pragmatic clinical trials.

While conducting a set of large-scale multi-site pragmatic clinical trials involving high-impact public health issues such as end-stage renal disease, opioid use, and colorectal cancer, there were substantial changes to both policies and guidelines relevant to the trials. These external changes gave rise to unexpected challenges for the trials, including decisions regarding how to respond to new clinical practice guidelines, increased difficulty in implementing trial interventions, achieving separation between treatment groups, and differential responses across sites. In this article, we describe these challenges and the approaches used to address them. When deliberating appropriate action in the face of external changes during a pragmatic clinical trial, we recommend considering the well-being of the participants, clinical equipoise, and the strength and quality of the evidence associated with the change; involving those charged with data and safety monitoring; and where possible, planning for potential external changes as the trial is being designed. Any solution must balance the primary obligation to protect the well-being of participants with the secondary obligation to protect the integrity of the trial in order to gain meaningful answers to important public health questions.

Use of Medicare Claims to Identify Adverse Clinical Outcomes After Mitral Valve Repair.

BACKGROUND: Clinical event committees are commonly employed for event validation in clinical studies, but little is known about the comparative performance of administrative claims data versus clinician-triggered event adjudication for ascertainment of adverse events in structural heart disease studies. METHODS AND RESULTS: Medicare claims were linked to 418 patients >65 years of age who underwent transcatheter mitral valve repair (MitraClip) for severe mitral regurgitation from 2007 to 2013 as part of the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study II) High-Risk Registry or the REALISM (Real World Expanded Multicenter Study of the MitraClip System) Continued-Access Registry. Each registry adjudicated mortality, heart failure hospitalization, renal failure, ventilation, and bleeding/transfusion within 1 year. Concordance of claims-based outcomes with events was assessed in 3 ways: 1-year occurrence, cumulative incidence, and synchrony of first events. For event occurrence, positive predictive value (PPV) of claims versus adjudication was the highest for mortality (PPV=97%) and heart failure hospitalization (PPV=69%) but lower for bleeding (PPV=40%) and renal failure (PPV=19%). Whereas claims-based cumulative incidence for mortality, heart failure hospitalization, and renal failure were consistent with clinician-triggered adjudication, incidence curves for bleeding events and ventilation diverged, with claims identifying a greater number of events. When events were detected by both methods, however, over 75% of event dates matched exactly. Mitral valve reinterventions were identified through claims with perfect sensitivity and specificity relative to physician adjudication. CONCLUSIONS: Ascertainment of mortality, heart failure hospitalization, and renal failure was highly concordant between physician adjudication and administrative claims. Further work is necessary to determine the role of administrative claims in event ascertainment in both prospective and retrospective studies of structural heart disease.

The Emergence of Population Health in US Academic Medicine: A Qualitative Assessment.

Importance: In response to rapidly growing interest in population health, academic medical centers are launching department-level initiatives that focus on this evolving discipline. This trend, with its potential to extend the scope of academic medicine, has not been well characterized. Objective: To describe the emergence of departments of population health at academic medical centers in the United States, including shared areas of focus, opportunities, and challenges. Design, Setting, and Participants: This qualitative study was based on a structured in-person convening of a working group of chairs of population health-oriented departments on November 13 and 14, 2017, complemented by a survey of core characteristics of these and additional departments identified through web-based review of US academic medical centers. United States medical school departments with the word population in their name were included. Centers, institutes, and schools were not included. Main Outcomes and Measures: Departments were characterized by year of origin, areas of focus, organizational structure, faculty size, teaching programs, and service engagement. Opportunities and challenges faced by these emerging departments were grouped thematically and described. Results: Eight of 9 population health-oriented departments in the working group were launched in the last 6 years. The 9 departments had 5 to 97 full-time faculty. Despite varied organizational structures, all addressed essential areas of focus spanning the missions of research, education, and service. Departments varied significantly in their relationships with the delivery of clinical care, but all engaged in practice-based and/or community collaboration. Common attributes include core attention to population health-oriented research methods across disciplines, emphasis on applied research in frontline settings, strong commitment to partnership, interest in engaging other sectors, and focus on improving health equity. Tensions included defining boundaries with other academic units with overlapping areas of focus, identifying sources of sustainable extramural funding, and facilitating the interface between research and health system operations. Conclusions and Relevance: Departments addressing population health are emerging rapidly in academic medical centers. In supporting this new framing, academic medicine affirms and strengthens its commitment to advancing population health and health equity, to improving the quality and effectiveness of care, and to upholding the social mission of medicine.

Linking a Total Ankle Arthroplasty Registry to Medicare Inpatient Claims without Unique Identifiers.

BACKGROUND: Linking clinical registries to administrative claims data enables researchers to capitalize on the specific strengths of each data source with respect to the depth, breadth, and completeness of information. The objectives of this study were to link a health-system-based orthopaedic surgery registry to U.S. Medicare claims data without the use of unique identifiers and to assess the representativeness of the linked records. METHODS: The registry included clinical data for patients ≥65 years of age who underwent elective, inpatient total ankle arthroplasty (TAA) in a single health system during the period of 2007 through 2012. Registry participants were identified within the Medicare data by linking registry procedures to TAA procedures within the claims data using a combination of procedure date, patient date of birth, and patient sex. We assessed the representativeness of the linked records by comparing them to both unlinked registry records and unlinked Medicare records for TAA procedures. Additionally, we described the availability of postsurgical data for linked records. RESULTS: Of 360 TAA registry participants ≥65 years of age, 280 (77.8%) were matched to a Medicare record; 250 (89.3%) of those 280 participants were matched on the basis of a linking rule that required an exact match for procedure date, date of birth, and sex. The 280 linked records comprised 5.5% of all Medicare TAA procedures among beneficiaries ≥65 years of age enrolled in the fee-for-service Medicare program (n = 5,070). Compared with linked records, unlinked records were more likely to be for patients 65 to 69 years old, but the 2 groups were similar in terms of sex, body mass index, and availability of clinical measurements. Of the linked records, 214 (76.4%) had ≥3 years of postoperative follow-up claims data. CONCLUSIONS: Linkage without unique patient identifiers between an orthopaedic registry and Medicare claims data is feasible, allows for assessment of representativeness, and creates a unique resource of longitudinal data for research.

Advanced imaging and hospice use in end-of-life cancer care.

INTRODUCTION: Advanced imaging can inform prognosis and may be a mechanism to de-escalate unnecessary end-of-life care in patients with cancer. Associations between greater use of advanced imaging and less-aggressive end-of-life care in real-world practice has not been examined. METHODS: We conducted a retrospective analysis of SEER-Medicare data on patients who died from breast, lung, colorectal, or prostate cancer between 2002 and 2007. Hospital referral region (HRR)-level use of computerized tomography (CT), magnetic resonance imaging, and positron emission tomography was categorized by tertile of imaging use and correlated with hospice enrollment overall and late hospice enrollment using multivariable logistic regression. RESULTS: A total of 55,058 patients met study criteria. Hospice use ranged from 50.8% (colorectal cancer) to 62.1% (prostate cancer). In multivariable analyses, hospital referral regions (HRRs) with high rates of CT imaging were associated with lower odds of hospice enrollment (odds ratio, 0.80; 95% CI, 0.70-0.90) and late enrollment among those who did enroll (odds ratio, 1.49; 95% CI, 1.26-1.76). HRRs with the highest rates of CT use were predominantly located in the Midwest and Northeast and associated with higher percentage population of black patients (14.5 vs 5.6%), greater comorbidity (28.4 vs 23.7%), metropolitan residence (93.9 vs 78.5%), and less than high school education (26.4 vs 19.3%). CONCLUSION: In this population-based retrospective study, we did not observe evidence that overall and timely hospice are associated with higher rates of imaging near the end of life. An observed association between higher rates of imaging, particularly CT, may be explained in part by HRR-level differences in practice patterns and patient demographic characteristics. Further research is warranted to explore the ability of oncologic imaging to appropriately de-escalate care.

Permanent pacemaker use among patients with heart failure and preserved ejection fraction: Findings from the Acute Decompensated Heart Failure National Registry (ADHERE) National Registry.

BACKGROUND: Heart failure with preserved ejection fraction may be associated with chronotropic incompetence, but little is known about the incidence and prevalence of permanent pacemaker use in this population or factors associated with its use. METHODS: We analyzed patients with heart failure with preserved ejection fraction (ie, left ventricular ejection fraction greater than 40%) from the ADHERE registry (2001-2006) linked with Medicare claims. We described the use of both prevalent and incident permanent pacemakers in heart failure with preserved ejection fraction and determined factors associated with pacemaker use with logistic regression models. RESULTS: Among 13,881 patients with heart failure with preserved ejection fraction, 3136 (22.6%) had a permanent pacemaker, and of these patients, 636 had a permanent pacemaker implanted during hospitalization. Permanent pacemaker use was more common among older patients (81 vs 79 years; P < .001), men (38% vs 34%; P < .001), patients with atrial fibrillation (58% vs 36%; P < .001), and patients with wider QRS duration (140 ms vs 94 ms; P < .001). Rates of digoxin, aldosterone antagonist, and loop diuretic use were slightly higher in patients with a permanent pacemaker compared with patients with no permanent pacemaker. Factors associated with both prevalent and incident pacemaker use included age, fast or slow heart rate, atrial fibrillation, and lower body mass index. CONCLUSIONS: Use of permanent pacemakers is relatively common among patients with heart failure with preserved ejection fraction.

Hospital and clinical care costs associated with atrial fibrillation for Medicare beneficiaries in the Cardiovascular Health Study and the Framingham Heart Study.

BACKGROUND: Atrial fibrillation is increasingly prevalent as the US population ages and is associated with significant morbidity and mortality. Care for patients with atrial fibrillation can be costly, US health care costs are comparatively high, and there are few cost estimates available that incorporate detailed measurement of comorbidities and their effects on costs. METHODS AND RESULTS: In the Cardiovascular Health Study and the Framingham Heart Study, participants aged 65 years or older with newly diagnosed atrial fibrillation were matched on age and follow-up time to referents free of atrial fibrillation. The total clinical and hospital medical costs paid by Medicare Parts A and B (drug costs from Medicare Part D costs were not included) in the year prior to diagnosis (or matching) were compared with costs in the following year. Estimates were adjusted for other medical conditions and adjusted to 2009 dollars. In the Cardiovascular Health Study, 513 participants were diagnosed with new-onset atrial fibrillation and survived 30 days post-atrial fibrillation diagnosis, and 513 referents (as a control cohort) were identified, with a mean age of 77 years. In the Framingham Heart Study, we identified 336 participants diagnosed with atrial fibrillation, who survived 30 days post-atrial fibrillation diagnosis and matched these participants to 336 referents. We compared these new-onset atrial fibrillation participants with referents, using a difference in difference design to account for both time trends and differences between the two groups. The adjusted incremental cost for participants with atrial fibrillation, compared with referents, was US$18,060 (95% confidence interval: US$14,965-US$21,155) in the Cardiovascular Health Study and US$20,012 (95% confidence interval: US$15,057-US$24,966) in the Framingham Heart Study. The pooled estimate was US$18,601 (95% confidence interval: US$15,981-US$21,234). CONCLUSION: Atrial fibrillation was associated with increased costs in the year after diagnosis in two community-based cohorts, even after careful accounting for age, time period, and systematically measured comorbidities.