Practical issues in pragmatic trials: the implementation of the Diuretic Comparison Project.

BACKGROUND/AIMS: The US Department of Veterans Affairs Point of Care Clinical Trial Program conducts studies that utilize informatics infrastructure to integrate clinical trial protocols into routine care delivery. The Diuretic Comparison Project compared hydrochlorothiazide to chlorthalidone in reduction of major cardiovascular events in subjects with hypertension. Here we describe the cultural, technical, regulatory, and logistical challenges and solutions that enabled successful implementation of this large pragmatic comparative effectiveness Point of Care clinical trial. METHODS: Patients were recruited from 72 Veterans Affairs Healthcare Systems using centralized processes for subject identification, obtaining informed consent, data collection, safety monitoring, site communication, and endpoint identification with minimal perturbation of the local clinical care ecosystem. Patients continued to be managed exclusively by their clinical care providers without protocol specified study visits, treatment recommendations, or data collection extraneous to routine care. Centralized study processes were operationalized through the application layer of the electronic health record via a data coordinating center staffed by clinical nurses, data scientists, and statisticians without site-based research coordinators. Study data was collected from the Veterans Affairs electronic health record supplemented by Medicare and National Death Index data. RESULTS: The study exceeded its enrolled goal (13,523 subjects) and followed subjects for the 5-year study duration. The key determinant of program success was collaboration between researchers, regulators, clinicians, and administrative staff at the site level to customize study procedures to align with local clinical practice. This flexibility was enabled by designation of the study as minimal risk and determination that clinical care providers were not engaged in research by the Veterans Affairs Central Institutional Review Board. Cultural, regulatory, technical, and logistical problems were identified and solved through iterative collaboration between clinical and research entities. Paramount among these problems was customization of the Veterans Affairs electronic health record and data systems to accommodate study procedures. CONCLUSIONS: Leveraging clinical care for large-scale clinical trials is feasible but requires a rethinking of traditional clinical trial design (and regulation) to better meet requirements of clinical care ecosystems. Study designs must accommodate site-specific practice variation to reduce the impact on clinical care. A tradeoff thus exists between designing trial processes tailored to expedite local study implementation versus those to produce a more refined response to the research question. The availability of a uniform and flexible electronic health record in the Department of Veterans Affairs played a major role in the success of the trial. Conducting Point of Care research in other healthcare systems without such research-friendly infrastructure presents a more formidable challenge.

Challenges to Using Big Data in Cancer.

Big data in healthcare can enable unprecedented understanding of diseases and their treatment, particularly in oncology. These data may include electronic health records, medical imaging, genomic sequencing, payor records, and data from pharmaceutical research, wearables, and medical devices. The ability to combine datasets and use data across many analyses is critical to the successful use of big data and is a concern for those who generate and use the data. Interoperability and data quality continue to be major challenges when working with different healthcare datasets. Mapping terminology across datasets, missing and incorrect data, and varying data structures make combining data an onerous and largely manual undertaking. Data privacy is another concern addressed by the Health Insurance Portability and Accountability Act, the Common Rule, and the General Data Protection Regulation. The use of big data is now included in the planning and activities of the FDA and the European Medicines Agency. The willingness of organizations to share data in a precompetitive fashion, agreements on data quality standards, and institution of universal and practical tenets on data privacy will be crucial to fully realizing the potential for big data in medicine.

Case Studies for Overcoming Challenges in Using Big Data in Cancer.

The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges. These efforts are CancerLinQ, the American Association for Cancer Research Project GENIE, Project Data Sphere, the National Cancer Institute Genomic Data Commons, and the Veterans Health Administration Clinical Data Initiative. Critical factors in the development of these systems include attention to the use of robust pipelines for data aggregation, common data models, data deidentification to enable multiple uses, integration of data collection into physician workflows, terminology standardization and attention to interoperability, extensive quality assurance and quality control activity, incorporation of multiple data types, and understanding how data resources can be best applied. By describing some of the emerging resources, we hope to inspire consideration of the secondary use of such data at the earliest possible step to ensure the proper sharing of data in order to generate insights that advance the understanding and the treatment of cancer.

Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project.

BACKGROUND: Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. METHODS: The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. RESULTS: Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. CONCLUSIONS: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION: NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].

Creatinine standardization: a key consideration in evaluating whole blood creatinine monitoring systems for CKD screening.

Early detection of CKD using point of care creatinine and eGFR testing improves patient management outcomes. We undertook a field study to evaluate the use of a whole blood creatinine/eGFR device to screen a rural Nicaraguan population to determine the variability between creatinine methods and specimen types. All specimens including capillary and venous dried blood spots (DBS) were tested with an isotope dilution liquid chromatography mass spectrometry (ID-LCMS) gold standard method. This is to our knowledge the first time a capillary whole blood (POC) method has been directly compared to the gold standard IDMS method, through the novel approach of using dried blood spots. Capillary and venous whole blood specimens were obtained and tested directly with the BCMS method, and then, DBS samples were prepared. Venous plasma specimens were tested using three laboratory analyzer creatinine methods. DBS were sent to the site performing ID-LCMS. Control samples were also prepared to assess the stability of shipment and storage of DBS. The ID-LCMS method was aligned using primary and secondary standards. Sixty-six (66) patients participated in the study, and the CKD prevalence rate was 7.8%. While all creatinine methods showed a good correlation to ID-LCMS, there was a positive bias (mean absolute bias range: 0.21-0.63 mg/dL). All methods used were 100% sensitive, but specificity varied from 62.7 to 94.9% with PPV ranging from 25 to 62.5%. A correction factor was used to align the values from each method to ID-LCMS which improved the specificity of each method. This study used a unique DBS approach to align capillary whole blood creatinine to ID-LCMS. To ensure reliability of BCMS for identifying screened patients with CKD, it is important to establish IDMS traceability and alignment prior to undertaking CKD studies.

Prevalence and Risk Factors for CKD in the General Population of Southwestern Nicaragua.

BACKGROUND: Studies have described Mesoamerican nephropathy among agricultural workers of El Salvador and northwestern Nicaragua. Data on prevalence and risk factors for CKD beyond agricultural workers and in other regions in Nicaragua are sparse. METHODS: We recruited participants from 32 randomly selected communities in the Department of Rivas's ten municipalities in two phases. In phase 1, we screened participants using a field-based capillary creatinine measuring system and collected self-reported information on lifestyle and occupational, exposure, and health histories. Two years later, in phase 2, we enrolled 222 new participants, performing serum creatinine testing in these participants and confirmatory serum creatinine testing in phase 1 participants. RESULTS: We enrolled 1242 of 1397 adults (89%) living in 533 households (median age 41 years; 43% male). We confirmed CKD (eGFR<60 ml/min per 1.73 m2) in 53 of 1227 (4.3%) evaluable participants. In multivariable testing, risk factors for prevalent CKD included age (odds ratio [OR], 1.92; 95% confidence interval [95% CI], 1.89 to 1.96) and self-reported history of hypertension (OR, 1.95; 95% CI, 1.04 to 3.64), diabetes (OR, 2.88; 95% CI, 1.40 to 5.93), or current or past work in the sugarcane industry (OR 2.92; 95% CI, 1.36 to 6.27). CONCLUSIONS: Adjusted CKD prevalence was about 5% with repeat confirmatory testing in southwest Nicaragua, lower than in the northwest region. Risk factors included diabetes, hypertension, and current or prior work in the sugarcane industry but not in other forms of agricultural work. Formal CKD surveillance programs in Nicaragua are needed to assess the overall burden of CKD nationally, with a focus on agricultural workers.

Identification of Acute Decompensated Heart Failure Hospitalizations Using Administrative Data.

Hospitalization for acute decompensated heart failure (ADHF) is an important outcome in clinical trials and heart failure registries; however, the optimal strategy to identify these hospitalizations using International Classification of Diseases, Ninth Revision (ICD-9) codes is uncertain. We sought to identify diagnostic codes that improve ascertainment of ADHF hospitalizations. Heart failure-related ICD-9 principal discharge codes were used to identify 2,202 hospitalizations within the Minneapolis Veterans Affairs Medical Center from 2009 to 2014. Two independent reviewers adjudicated 447 of these hospitalizations to determine the accuracy of each code. We then applied our findings to an unadjusted nationwide sample containing the same ICD-9 codes of interest, from which overall positive predictive value (PPV), sensitivity, and accuracy were calculated. Use of 428.x alone resulted in a PPV of 91.3% (95% confidence interval [CI] 91.0 to 91.7), sensitivity of 97.5% (95% CI 97.3 to 97.6), and accuracy of 89.7% (95% CI 89.4 to 90.0). Combining 428.x with 402.x1, 404.x1, 415, and 518.4 resulted in improved sensitivity (99.2%; 95% CI 99.0 to 99.3) and accuracy (90.7%; 95% CI 90.4 to 91.1) while maintaining a PPV of 91.1% (95% CI 90.7 to 91.4). Excluding chronic heart failure codes (428.22, 428.32, and 428.42) from the proposed strategy resulted in an improvement of PPV to 92.3% (95% CI 92.0 to 92.6), although sensitivity and accuracy decreased to 96.6% (95% CI 96.3 to 96.8) and 90.0% (95% CI 89.6 to 90.3), respectively. In conclusion, a combination of codes including 428.x, 402.x1, 404.x1, 415, and 518.4 improves sensitivity and overall accuracy in ascertaining ADHF events compared with 428.x alone. This strategy could be further improved by manual adjudication of chronic heart failure codes.

Streamlining cardiovascular clinical trials to improve efficiency and generalisability.

Controlled trials provide the most valid determination of the efficacy and safety of an intervention, but large cardiovascular clinical trials have become extremely costly and complex, making it difficult to study many important clinical questions. A critical question, and the main objective of this review, is how trials might be simplified while maintaining randomisation to preserve scientific integrity and unbiased efficacy assessments. Experience with alternative approaches is accumulating, specifically with registry-based randomised controlled trials that make use of data already collected. This approach addresses bias concerns while still capitalising on the benefits and efficiencies of a registry. Several completed or ongoing trials illustrate the feasibility of using registry-based controlled trials to answer important questions relevant to daily clinical practice. Randomised trials within healthcare organisation databases may also represent streamlined solutions for some types of investigations, although data quality (endpoint assessment) is likely to be a greater concern in those settings. These approaches are not without challenges, and issues pertaining to informed consent, blinding, data quality and regulatory standards remain to be fully explored. Collaboration among stakeholders is necessary to achieve standards for data management and analysis, to validate large data sources for use in randomised trials, and to re-evaluate ethical standards to encourage research while also ensuring that patients are protected. The rapidly evolving efforts to streamline cardiovascular clinical trials have the potential to lead to major advances in promoting better care and outcomes for patients with cardiovascular disease.

The Rivas Cohort Study: design and baseline characteristics of a Nicaraguan cohort.

BACKGROUND: A lack of advanced healthcare information systems and validated scientific cohorts in Nicaragua makes it difficult to estimate disease prevalences and other public health statistics. Although there is concern of an "epidemic" of chronic kidney disease (CKD) in this country, statistics regarding its magnitude are derived from only a small number of non-representative studies. Budgetary constraints and the logistical problems of maintaining a study cohort make longitudinal studies difficult. The Rivas Cohort was created to measure disease burden of CKD and other public health priorities in the Department of Rivas, Nicaragua. Using primarily volunteer research students and technologic innovation including GPS, digital photography and point of care biochemical analysis, the ability to establish a longitudinal chronic disease cohort is demonstrated. METHODS: Subjects were recruited from consecutive adjacent households in thirty-two randomly selected communities in the ten municipalities that comprise the Department of Rivas in southern Pacific coastal Nicaragua. The study was conducted in two phases. In the first phase, subjects were enrolled into the cohort and consented for future re-contact. In Phase II, conducted two years later, attempts were made to re-contact 400 of these subjects for additional data collection. Demographic, lifestyle, occupational, exposure and health data was collected for both phases of the study. Blood and urine testing and height, weight and blood pressure measurements were also performed. GPS coordinates of homes were recorded and maps of remote communities created. RESULTS: Of 1397 adults living in 533 households approached for participation a total of 1242 (89 %) were enrolled in the cohort. The median age is 41 years and 43 % are male, demographics in agreement with Nicaraguan census data for the Department of Rivas. During Phase II we attempted to re-contact 400 subjects for a follow-up study of CKD. It was possible to re-contact 84 % of these participants and of those re-contacted 95 % agreed to participate in the follow-up study. Of subjects that were not successfully re-contacted the majority had either moved (32) or were not at home (22) at the time of the study team visits. CONCLUSION: The Rivas Cohort Study enrolled a representative sample of 1242 adults living in the Department of Rivas, Nicaragua. The high re-contact and participation rates at two years suggests that the cohort is suitable for long-term studies and presents opportunities for investigations of disease prevalence, incidence, treatment and other public health matters. GPS coordinates and maps are available for future researchers who wish to use the cohort for additional studies.

The VA Point-of-Care Precision Oncology Program: Balancing Access with Rapid Learning in Molecular Cancer Medicine.

The Department of Veterans Affairs (VA) recognized the need to balance patient-centered care with responsible creation of generalizable knowledge on the effectiveness of molecular medicine tools. Embracing the principles of the rapid learning health-care system, a new clinical program called the Precision Oncology Program (POP) was created in New England. The POP integrates generalized knowledge about molecular medicine in cancer with a database of observations from previously treated veterans. The program assures access to modern genomic oncology practice in the veterans affairs (VA), removes disparities of access across the VA network of clinical centers, disseminates the products of learning that are generalizable to non-VA settings, and systematically presents opportunities for patients to participate in clinical trials of targeted therapeutics.

Implementation of a Precision Oncology Program as an Exemplar of a Learning Health Care System in the VA.

The program determines and disseminates precision oncology best practices; enhances patient and provider engagement; and fosters collaboration among the VA, National Cancer Institute, academia, other health care systems, and industry to provide cancer patients with access to clinical trial participation.

Million Veteran Program: A mega-biobank to study genetic influences on health and disease.

OBJECTIVE: To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system. STUDY DESIGN AND SETTING: Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses. RESULTS: Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented. CONCLUSIONS: By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine.

Chronic kidney disease prevalence in Rivas, Nicaragua: use of a field device for creatinine measurement.

OBJECTIVE: An epidemic of chronic kidney disease (CKD) has been identified in Pacific coastal regions of Central America, and screening in the field in these low income countries remains logistically problematic. We tested the performance characteristics of a point of care creatinine analyzer compared to standardized serum creatinine measurements. METHODS: Measurements were conducted in 100 persons from a local health center (n=34) and hospital (n=66) in Rivas, Nicaragua using both a point-of-care analyzer (StatSensor Xpress, Nova Biomedical) and serum creatinine by Jaffe kinetic method with a Roche Cobas Integra 400 analyzer. Percent coefficient of variation, sensitivity and specificity of the StatSensor Xpress were determined. RESULTS: The average coefficient of variation (CV) was 1.28% for the serum creatinine and CV for the StatSensor Xpress analyzer was 6.8%. The median intra-individual creatinine results obtained with the StatSensor Xpress device were 0.32 mg/dL higher than those by serum creatinine by Jaffe kinetic method. The sensitivity and specificity of the StatSensor Xpress device for identifying subjects with abnormal creatinine (defined as >1.2 mg/dL) was 100% and 79%, respectively. CONCLUSIONS: Point of care testing for creatinine demonstrated acceptable repeatability, excellent sensitivity (100%) and modest specificity (79%). Using the point of care testing will allow for generalized screening in the field in low income countries; however, confirmation for elevated levels >1.2 mg/dL will require a second laboratory test confirmation.

Veterans Healthcare Administration providers' attitudes and perceptions regarding pragmatic trials embedded at the point of care.

Background The Veterans Healthcare Administration (VA) is implementing an adaptation of a pragmatic trial program, Point of Care Research (POC-R). The goal of POC-R is to embed research into clinical practice, contributing to a Learning Healthcare System. Provider acceptance and participation in POC-R is essential to its successful implementation. The purpose of this study is to evaluate provider's perceptions and beliefs regarding the POC-R program. Methods Provider focus groups and interviews were conducted at seven VA medical facilities involving 62 providers. A semi-structured script was used that included descriptions of four use cases and targeted questions regarding perceptions, concerns, and attitudes about the POC-R program. Sessions were audio-taped, de-identified, transcribed, and analyzed using systematic qualitative techniques to create response categories and overarching themes. Results The emergent themes were as follows: (1) POC-R is a valuable component of evidence-based practice, providing an opportunity to base clinical practice on more generalizable evidence as well as providing tools to improve local practice; (2) POC-R highlights the tension between the need for autonomy of practice and compliance with protocols; (3) POC-R may create increased time and burden resulting from added research responsibilities; (4) concern about the scientific validity and reliability of results; (5) potential for a negative impact on the provider-patient relationship; and (6) uncertainty regarding what constitutes equipoise, given differences in provider knowledge and preferences. Despite substantive concerns, barriers were generally felt to be solvable. Implementation should include provider education, careful attention to workflow for all arms of the study, inclusion of the entire team, and adequate oversight. Limitations The study design is qualitative with limited implications for causal inference. Participants are from the VA and may not be representative of other clinicians. Conclusion VA providers are supportive of the importance and value of pragmatic trials in general and of POC-R in particular. However, providers have significant concerns regarding the burden, ethics, and evidence regarding equipoise. Results are discussed in terms of implementation recommendations.

Measuring use of evidence based psychotherapy for posttraumatic stress disorder.

To improve methods of estimating use of evidence-based psychotherapy for posttraumatic stress disorder in the Veteran's health administration, we evaluated administrative data and note text for patients newly enrolling in six VHA outpatient PTSD clinics in New England during the 2010 fiscal year (n = 1,924). Using natural language processing, we developed machine learning algorithms that mimic human raters in classifying note text. We met our targets for algorithm performance as measured by precision, recall, and F-measure. We found that 6.3 % of our study population received at least one session of evidence-based psychotherapy during the initial 6 months of treatment. Evidence-based psychotherapies appear to be infrequently utilized in VHA outpatient PTSD clinics in New England. Our method could support efforts to improve use of these treatments.

A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations: a randomized, controlled trial.

BACKGROUND: Improving a patient's ability to self-monitor and manage changes in chronic obstructive pulmonary disease (COPD) symptoms may improve outcomes. OBJECTIVE: To determine the efficacy of a comprehensive care management program (CCMP) in reducing the risk for COPD hospitalization. DESIGN: A randomized, controlled trial comparing CCMP with guideline-based usual care. (ClinicalTrials.gov registration number: NCT00395083) SETTING: 20 Veterans Affairs hospital-based outpatient clinics. PARTICIPANTS: Patients hospitalized for COPD in the past year. INTERVENTION: The CCMP included COPD education during 4 individual sessions and 1 group session, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. Patients in both the intervention and usual care groups received a COPD informational booklet; their primary care providers received a copy of COPD guidelines and were advised to manage their patients according to these guidelines. Patients were randomly assigned, stratifying by site based on random, permuted blocks of variable size. MEASUREMENTS: The primary outcome was time to first COPD hospitalization. Staff blinded to study group performed telephone-based assessment of COPD exacerbations and hospitalizations, and all hospitalizations were blindly adjudicated. Secondary outcomes included non-COPD health care use, all-cause mortality, health-related quality of life, patient satisfaction, disease knowledge, and self-efficacy. RESULTS: Of the eligible patients, 209 were randomly assigned to the intervention group and 217 to the usual care group. Citing serious safety concerns, the data monitoring committee terminated the intervention before the trial's planned completion after 426 (44%) of the planned total of 960 patients were enrolled. Mean follow-up was 250 days. When the study was stopped, the 1-year cumulative incidence of COPD-related hospitalization was 27% in the intervention group and 24% in the usual care group (hazard ratio, 1.13 [95% CI, 0.70 to 1.80]; P= 0.62). There were 28 deaths from all causes in the intervention group versus 10 in the usual care group (hazard ratio, 3.00 [CI, 1.46 to 6.17]; P= 0.003). Cause could be assigned in 27 (71%) deaths. Deaths due to COPD accounted for the largest difference: 10 in the intervention group versus 3 in the usual care group (hazard ratio, 3.60 [CI, 0.99 to 13.08]; P= 0.053). LIMITATIONS: Available data could not fully explain the excess mortality in the intervention group. Ability to assess the quality of the educational sessions provided by the case managers was limited. CONCLUSION: A CCMP in patients with severe COPD had not decreased COPD-related hospitalizations when the trial was stopped prematurely. The CCMP was associated with unanticipated excess mortality, results that differ markedly from similar previous trials. A data monitoring committee should be considered in the design of clinical trials involving behavioral interventions.

Implementation of the Department of Veterans Affairs' first point-of-care clinical trial.

OBJECTIVES: The Massachusetts Veterans Epidemiology Research and Information Center in collaboration with the Stanford Center for Innovative Study Design set out to test the feasibility of a new method of evidence generation. The first pilot of a point-of-care clinical trial (POCCT), adding randomization and other study processes to an electronic medical record (EMR) system, was launched to compare the effectiveness of two insulin regimens. MATERIALS AND METHODS: Existing functionalities of the Veterans Affairs (VA) computerized patient record system (CPRS)/veterans health information systems and technology architecture (VISTA) were modified to support the activities of a randomized controlled trial including enrolment, randomization, and longitudinal data collection. RESULTS: The VA's CPRS/VISTA was successfully adapted to support the processes of a clinical trial and longitudinal study data are being collected from the medical record automatically. As of 30 June 2011, 55 of the 67 eligible patients approached received a randomized intervention. DISCUSSION: The design of CPRS/VISTA made integration of study workflows and data collection possible. Institutions and investigators considering similar designs must carefully map clinical workflows and clinical trial workflows to EMR capabilities. POCCT study teams are necessarily interdisciplinary and interdepartmental. As a result, executive sponsorship is critical. CONCLUSION: POCCT represent a promising new method for conducting clinical science. Much work is needed to understand better the optimal uses and designs for this new approach. Next steps include focus groups to measure patient and clinician perceptions, multisite deployment of the current pilot, and implementation of additional studies.