Embedding implementation science in the research pipeline.

Clinical and health services researchers seek to discover effective programs, practices, and interventions to improve people's health. The current paradigm for evidence generation is incremental and misaligned to translate evidence-based discoveries into real-world settings. This persistent challenge are "valleys of death" that represent missed opportunities and preventable missteps to actually use scientific advancements in real-world clinical settings where they can improve health and well-being (De Geest S, Zúñiga F, Brunkert T et al. Powering Swiss health care for the future: implementation science to bridge "the valley of death". 2020;150:w20323). Only one in seven of evidence-based interventions is ever implemented. It is after an average of 17 years. We propose embedding the principles of implementation science throughout the research pipeline, from discovery to adoption, to efficiently translate discoveries into real-world contexts (Balas EA, Boren SA. Managing clinical knowledge for health care improvement. 2000;9:65-70). We outline implications for capacity building, including composition of the research team, study design, and competencies that could bolster the value proposition of implementation science. We describe a research paradigm that recognizes scientists' responsibility to ensure their discoveries be translated into real-world settings.

Most innovative research is not used in clinical care settings. When it is, it takes a very long time to get into the real world. This means that patients may not get the best care possible to improve their health. The research community has tools that can help design innovative research in ways that it could work in clinical care settings and tools to help that happen faster, so that clinical care teams and patients can use innovative research. This is called implementation science. We outline why it is important to use implementation science ideas and teams earlier and how we can support infrastructure to do so.

Impact of the COVID-19 pandemic on healthcare resource utilization across selected disease areas in the USA.

Aim: To analyze the impact of the COVID-19 pandemic on US healthcare resource utilization. Methods: Optum claims data were used to compare all-cause healthcare visits and healthcare spending for selected diseases between the prepandemic and pandemic periods. Telemedicine use was only assessed for the pandemic period owing to data availability. Results: During the first wave of the pandemic, all-cause healthcare visits across all selected disease areas displayed a rapid decline compared with the prepandemic period, followed by a period of recovery. A reduction in outpatient and home healthcare spending was observed, whereas inpatient and prescription spending increased. Conclusion: Changes in healthcare resource utilization trends were observed during the pandemic. The magnitude of these changes can inform subsequent studies that utilize COVID-19-era data.

Health Care Utilization and Costs in Patients With Migraine Who Have Failed Previous Preventive Treatments.

OBJECTIVE: To characterize health care utilization (HCU) and associated costs among patients with migraine categorized by the number of preventive treatment failures (TFs; 1 TF, 2 TFs, and 3+ TFs) using real-world data. METHODS: This retrospective analysis identified adults with incident migraine diagnosis in the IBM MarketScan Commercial and Medicare Supplemental database between January 1, 2011, and June 30, 2015. TF was defined in the 2 years after the first migraine diagnosis period. One TF, 2 TFs, and 3+ TFs were defined as patients who had received only 2 preventive treatments (PTs), 3 PTs, and 4+ PTs in the 2-year period, respectively. A negative binomial model was used to analyze HCU data, and a 2-part model was used for cost data controlling for the preindex Deyo-Charlson Comorbidity Index. RESULTS: Overall, 24,282 patients with incident migraine who had failed at least 1 PT were included in the analysis. Of these, 72.7% (n = 17,653) had 1 TF, 20.2% (n = 4,900) had 2 TFs, and 7.1% (n = 1,729) had 3+ TFs. Adjusted annualized rates of all-cause and migraine-specific HCU increased with an increase in the number of TFs (1.4-4 times higher; all p < 0.0001 vs 1 TF). The mean total all-cause health care costs were higher by $3,732 (95% confidence interval [CI]: $2,708-$4,588) in patients with 2 TFs and by $8,912 (95% CI: $7,141-$10,822) in patients with 3+ TFs vs those with 1 TF. Outpatient costs were the key drivers of differences in health care costs. CONCLUSIONS: TF in patients with migraine was associated with a substantial resource and cost burden, which increased with the number of TFs.

Regression-Based Approaches to Patient-Centered Cost-Effectiveness Analysis.

Achieving comprehensive patient centricity in cost-effectiveness analyses (CEAs) requires a statistical approach that accounts for patients' preferences and clinical and demographic characteristics. Increased availability and accessibility of patient-level health-related utility data from clinical trials or observational database provide enhanced opportunities to conduct more patient-centered CEA. Regression-based approaches that incorporate patient-level data hold great promise for enhancing CEAs to be more patient centered; this paper provides guidance regarding two CEA approaches that apply regression-based approaches utilizing patient-level health-related utility and costs data. The first approach utilizes patient-reported preferences to determine patient-specific utility. This approach evaluates how individuals' unique clinical and demographic factors affect their utility and cost levels over the course of treatment. The underlying motivation of this approach is to produce CEA estimates that reflect patient-level utilities and costs while adjusting for socio-demographic and clinical factors to aid patient-centered coverage and treatment decision-making. In the second approach, patient utilities are estimated based on the clinically defined health states through which a patient may transition throughout the course of treatment. While this approach is grounded on the widely used Markov transition model, we refine the model to facilitate an enhancement in conducting regression-based analysis to achieve transparent understanding of differences in utilities and costs across diverse patient populations. We discuss the unique statistical challenges of each approach and describe how these analytical strategies are related to non-regression-based models in health services research.

Linked Patient-Reported Outcomes Data From Patients With Multiple Sclerosis Recruited on an Open Internet Platform to Health Care Claims Databases Identifies a Representative Population for Real-Life Data Analysis in Multiple Sclerosis.

BACKGROUND: An enormous amount of information relevant to public health is being generated directly by online communities. OBJECTIVE: To explore the feasibility of creating a dataset that links patient-reported outcomes data, from a Web-based survey of US patients with multiple sclerosis (MS) recruited on open Internet platforms, to health care utilization information from health care claims databases. The dataset was generated by linkage analysis to a broader MS population in the United States using both pharmacy and medical claims data sources. METHODS: US Facebook users with an interest in MS were alerted to a patient-reported survey by targeted advertisements. Eligibility criteria were diagnosis of MS by a specialist (primary progressive, relapsing-remitting, or secondary progressive), ≥12-month history of disease, age 18-65 years, and commercial health insurance. Participants completed a questionnaire including data on demographic and disease characteristics, current and earlier therapies, relapses, disability, health-related quality of life, and employment status and productivity. A unique anonymous profile was generated for each survey respondent. Each anonymous profile was linked to a number of medical and pharmacy claims datasets in the United States. Linkage rates were assessed and survey respondents' representativeness was evaluated based on differences in the distribution of characteristics between the linked survey population and the general MS population in the claims databases. RESULTS: The advertisement was placed on 1,063,973 Facebook users' pages generating 68,674 clicks, 3719 survey attempts, and 651 successfully completed surveys, of which 440 could be linked to any of the claims databases for 2014 or 2015 (67.6% linkage rate). Overall, no significant differences were found between patients who were linked and not linked for educational status, ethnicity, current or prior disease-modifying therapy (DMT) treatment, or presence of a relapse in the last 12 months. The frequencies of the most common MS symptoms did not differ significantly between linked patients and the general MS population in the databases. Linked patients were slightly younger and less likely to be men than those who were not linkable. CONCLUSIONS: Linking patient-reported outcomes data, from a Web-based survey of US patients with MS recruited on open Internet platforms, to health care utilization information from claims databases may enable rapid generation of a large population of representative patients with MS suitable for outcomes analysis.

Patterns of Treatment Switching in Multiple Sclerosis Therapies in US Patients Active on Social Media: Application of Social Media Content Analysis to Health Outcomes Research.

BACKGROUND: Social media analysis has rarely been applied to the study of specific questions in outcomes research. OBJECTIVE: The aim was to test the applicability of social media analysis to outcomes research using automated listening combined with filtering and analysis of data by specialists. After validation, the process was applied to the study of patterns of treatment switching in multiple sclerosis (MS). METHODS: A comprehensive listening and analysis process was developed that blended automated listening with filtering and analysis of data by life sciences-qualified analysts and physicians. The population was patients with MS from the United States. Data sources were Facebook, Twitter, blogs, and online forums. Sources were searched for mention of specific oral, injectable, and intravenous (IV) infusion treatments. The representativeness of the social media population was validated by comparison with community survey data and with data from three large US administrative claims databases: MarketScan, PharMetrics Plus, and Department of Defense. RESULTS: A total of 10,260 data points were sampled for manual review: 3025 from Twitter, 3771 from Facebook, 2773 from Internet forums, and 691 from blogs. The demographics of the social media population were similar to those reported from community surveys and claims databases. Mean age was 39 (SD 11) years and 14.56% (326/2239) of the population was older than 50 years. Women, patients aged 30 to 49 years, and those diagnosed for more than 10 years were represented by more data points than other patients were. Women also accounted for a large majority (82.6%, 819/991) of reported switches. Two-fifths of switching patients had lived with their disease for more than 10 years since diagnosis. Most reported switches (55.05%, 927/1684) were from injectable to oral drugs with switches from IV therapies to orals the second largest switch (15.38%, 259/1684). Switches to oral drugs accounted for more than 80% (927/1114) of the switches away from injectable therapies. Four reasons accounted for more than 90% of all switches: severe side effects, lack of efficacy, physicians' advice, and greater ease of use. Side effects were the main reason for switches to oral or to injectable therapies and search for greater efficacy was the most important factor in switches to IV therapies. Cost of medication was the reason for switching in less than 0.5% of patients. CONCLUSIONS: Social intelligence can be applied to outcomes research with power to analyze MS patients' personal experiences of treatments and to chart the most common reasons for switching between therapies.

Can statistical linkage of missing variables reduce bias in treatment effect estimates in comparative effectiveness research studies?

AIM: Missing data, particularly missing variables, can create serious analytic challenges in observational comparative effectiveness research studies. Statistical linkage of datasets is a potential method for incorporating missing variables. Prior studies have focused upon the bias introduced by imperfect linkage. METHODS: This analysis uses a case study of hepatitis C patients to estimate the net effect of statistical linkage on bias, also accounting for the potential reduction in missing variable bias. RESULTS: The results show that statistical linkage can reduce bias while also enabling parameter estimates to be obtained for the formerly missing variables. CONCLUSION: The usefulness of statistical linkage will vary depending upon the strength of the correlations of the missing variables with the treatment variable, as well as the outcome variable of interest.

Treatment Frequency and Dosing Interval of Ranibizumab and Aflibercept for Neovascular Age-Related Macular Degeneration in Routine Clinical Practice in the USA.

PURPOSE: To compare treatment patterns of intravitreal ranibizumab and aflibercept for the management of neovascular age-related macular degeneration (nAMD) in a real-world setting over the first 12 months of treatment. METHODS: A proprietary clinical database was used to identify treatment-naïve patients with nAMD in the USA with claims for ranibizumab or aflibercept between November 1, 2011 and November 30, 2013 and with follow-up of at least 12 months. Patients were considered treatment-naïve if they had no anti-VEGF treatment code for 6 months before the index date. Mean numbers of injections and of non-injection visits to a treating physician were compared between the two treatment cohorts (ranibizumab or aflibercept). In addition, the mean interval between doses was also investigated. RESULTS: Patient characteristics were similar for those receiving either ranibizumab (n = 5421) or aflibercept (n = 3506) at the index date. The mean (± standard deviation) numbers of injections received by patients treated with ranibizumab (4.9 ± 3.3) or aflibercept (5.2 ± 2.9) were not clinically different. The mean number of non-injection visits was 2.8 ± 2.8 and 2.1 ± 2.5 for ranibizumab and aflibercept, respectively. Mean dosing interval was 51.0 days (± 41.8 days) in patients receiving ranibizumab and 54.1 days (± 36.0 days) in those receiving aflibercept. Results were robust to sensitivity analyses for definition of treatment-naïve, length of follow-up and treatment in the index eye only. CONCLUSIONS: Limited data exist regarding real-world treatment patterns of aflibercept for the management of nAMD. Our results suggest that, in routine clinical practice, patients receive a comparable number of injections in the first year of treatment with ranibizumab or aflibercept.

Health-related quality of life and treatment of postmenopausal osteoporosis: results from the HORIZON-PFT.

Osteoporosis-related fractures are associated with reductions in health-related quality of life (HRQL). We examined the benefits of zoledronic acid (ZOL) on HRQL in patients sustaining vertebral and clinical fractures from HORIZON-Pivotal Fracture Trial using mini-Osteoporosis quality of life Questionnaire (OQLQ). In this multicenter, double-blind, placebo-controlled trial, 1434 patients from a cohort of postmenopausal women with osteoporosis (mean age 73years) were randomized to receive annual infusions of ZOL 5mg or placebo for 3years. Baseline HRQL scores were comparable between ZOL and placebo groups based on the presence or absence of fractures, with exception of prevalent vertebral fractures where patients (irrespective of the treatment group) had lower baseline HRQL scores than those without prevalent vertebral fractures. Greater number of prevalent vertebral fractures was associated with lower baseline HRQL (p<0.001). No significant difference between ZOL and placebo in the overall summary score was observed but a significant benefit was noted in certain domains with ZOL, especially in patients sustaining incident clinical fractures. Improvements in HRQL were marked at first assessment after a morphometric vertebral fracture with significant differences favouring ZOL in pain (p=0.0115), standing pain (p=0.0125)), physical (lifting, p=0.0333) and emotional function (fear of fractures, p=0.0243; fear of falls, p=0.0075) but not for activities of daily living or leisure domains. HRQL is reduced in patients with vertebral fractures. Treatment with ZOL over 3years was associated with improvements in specific domains of quality of life vs. placebo, particularly in patients sustaining incident fractures.

The efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in osteoporosis: a network meta-analysis.

OBJECTIVE: To evaluate the efficacy of available bisphosphonate therapies regarding the prevention of vertebral, hip, and nonvertebral-nonhip fractures in postmenopausal women with osteoporosis. METHODS: Eight randomized placebo controlled trials investigating the effects of zoledronic acid (1 study), alendronate (3), ibandronate (1), risedronate (2), and etidronate (1) in terms of fractures with a follow-up of 3 years (or 2 years if used for registration purposes) were identified with a systematic literature search. The endpoints of interest were morphometric vertebral fractures, hip fractures, and nonvertebral-nonhip fractures. Results of all trials were analyzed simultaneously with a Bayesian network meta-analysis by which the relative treatment effect of 1 intervention to another can be obtained in the absence of head-to-head evidence. Given the estimated treatment effects and their uncertainty, the Bayesian approach allowed for calculations of the probability of which bisphosphonate is best in terms of overall fracture reductions by weighting the impact of each by type of fracture on costs, quality of life, and incidence. RESULTS: There is a 79% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all bisphophonates compared. Zoledronic acid showed a relative risk (RR) of 0.30 (95% Credible Interval 0.23-0.37) relative to placebo, an RR of 0.55 (0.41-0.76) relative to alendronate, an RR of 0.50 (0.36-0.70) relative to risedronate, and an RR of 0.58 (0.37-0.92) relative to ibandronate. Regarding hip fractures, there is a 47% probability that zoledronic acid shows the greatest risk reduction, followed by alendronate (36%) and risedronate (11%). RRs of zoledronic acid relative to placebo, alendronate, and risedronate were 0.58 (0.41-0.82), 0.95 (0.54-1.68), and 0.73 (0.37-1.44), respectively. Risedronate showed the greatest reduction in nonvertebral-nonhip fractures, followed by zoledronic acid. The RR of zoledronic acid relative to risedronate was 1.28 (0.87-1.90). Overall, there was a 94% probability that zoledronic acid showed the greatest reduction in any fracture. Weighting the impact of the different type of fractures by incidence, cost, or quality of life showed similar results. CONCLUSION: Of the available bisphosphonates for osteoporosis, zoledronic acid has the highest probability of offering the best overall fracture protection.

Influence on persistence and adherence with oral bisphosphonates on fracture rates in osteoporosis.

BACKGROUND AND AIM: Oral bisphosphonates have been shown to reduce the risk of fractures in patients with osteoporosis. It can be assumed that the clinical effectiveness of oral bisphosphonates depends on persistence with therapy. METHODS: The influence of persistence with and adherence to oral bisphosphonates on fracture risk in a real-life setting was investigated. Data from 4451 patients with a defined index prescription of bisphosphonates were included. Fracture rates within 180, 360, and 720 days after index prescription were compared between persistent and non-persistent patients. In an extended Cox regression model applying multiple event analysis, the influence of adherence was analyzed. Persistence was defined as the duration of continuous therapy; adherence was measured in terms of the medication possession ratio (MPR). RESULTS: In patients with a fracture before index prescription, fracture rates were reduced by 29% (p = 0.025) comparing persistent and non-persistent patients within 180 days after the index prescription and by 45% (p < 0.001) within 360 days. The extended Cox regression model showed that good adherence (MPR >/= 0.8) reduced fracture risk by about 39% (HR 0.61, 95% CI 0.47-0.78; p < 0.01). CONCLUSIONS: In patients with osteoporosis-related fractures, good persistence and adherence to oral bisphosphonates reduced fracture risk significantly.

Prevention of vertebral fractures in osteoporosis: mixed treatment comparison of bisphosphonate therapies.

OBJECTIVE: The objective was to compare the efficacy of bisphosphonates regarding the prevention of vertebral fractures in postmenopausal women with osteoporosis. METHODS: Seven randomized placebo controlled trials investigating the effects of zoledronic acid (one study), alendronate (three studies), ibandronate (one study), and risedronate (two studies) in terms of fractures with a follow-up of 3 years were identified with a systematic literature search. The endpoint of interest was vertebral fractures. Results of all trials were analyzed simultaneously with a Bayesian mixed treatment comparison (MTC). With MTC the relative treatment effect of one intervention to another can be obtained in the absence of head-to-head evidence. MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics. RESULTS: There is a 98% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all four bisphophonates compared. Zoledronic acid showed an OR of 0.28 (95% Credible Interval 0.22; 0.35) relative to placebo, an OR of 0.57 (0.36; 0.92) relative to ibandronate, an OR of 0.54 (0.39; 0.75) relative to alendronate, and an OR of 0.49 (0.34; 0.69) relative to risedronate. Alendronate, ibandronate, and risedronate showed comparable vertebral fracture reductions. Indirect comparisons using a conservative random effects model supported these findings. CONCLUSION: An indirect comparison of findings from placebo controlled randomized studies indicates that zoledronic acid provides a greater vertebral fracture risk reduction in postmenopausal women with osteoporosis than ibandronate, alendronate, or risedronate.

Relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures .

OBJECTIVES: To investigate the relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures. METHODS: The PHARMO database was used to identify new female bisphosphonate users, aged ≥ 45 years or with diagnosed post-menopausal osteoporosis in the period of January 1996 - June 2004. Within this cohort a matched case-control study was performed. Cases were defined as patients who were hospitalized for an osteoporotic fracture and were matched to ten controls without a fracture by duration of follow-up. The duration of compliant bisphosphonate use (i.e., medication possession ratio ≥ 80%) preceding the outcome date was determined. RESULTS: Of 14 760 new female bisphosphonate users, 387 fracture patients fulfilled the inclusion criteria. These cases were matched to 3950 controls. Increasing duration of compliant bisphosphonate use was associated with a decreased risk of fracture (trend p < 0.01). Adjusted for several cofactors, 1-2 years of compliant bisphosphonate use and 3-4 years of compliant bisphosphonate use decreased fracture risk by 12% and 46%, respectively, compared to < 1 year of compliant bisphosphonate use (OR 0.88; 95% CI 0.66-1.18 and OR 0.54; 95% CI 0.35-0.84, respectively). Unexpectedly, 5-6 years of compliant bisphosphonate use was no longer associated with a decreased risk of fractures compared to < 1 year of compliant bisphosphonate use (OR 1.12, 95% CI 0.66-1.88). CONCLUSIONS: These results show a direct link between duration of compliant bisphosphonate use and fracture risk, and confirm the importance of continuing the use of bisphosphonates to maintain optimal bone protection. However, this link is inconclusive for bisphosphonate use for more than 4 years.