Ryan Ferguson

A point-of-care clinical trial comparing insulin administered using a sliding scale versus a weight-based regimen

Background Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care. Purpose We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial – POC-CT) of a ‘learning healthcare system,’ and settles a clinical question of interest to the VA. Methods This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA’s automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently ‘winning’ strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy. Limitations Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of clinical results to other healthcare systems may be limited by differences in patient population. Generalizability of the POC-CT method depends on the level of informatics and statistics infrastructure available to a healthcare system. Conclusions The methods proposed will demonstrate outcome-based evaluation of control of hyperglycemia in hospitalized veterans. By institutionalizing a process of statistically sound and efficient learning, and by integrating that learning with automatic implementation of best practice, the participating VA Healthcare Systems will accelerate improvements in the effectiveness of care.

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 VAs 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.

Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine

Background Intravenous sodium bicarbonate and oral acetylcysteine are widely used to prevent acute kidney injury and associated adverse outcomes after angiography without definitive evidence of their efficacy. Methods Using a 2‐by‐2 factorial design, we randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention‐to‐treat analysis. The primary end point was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast‐associated acute kidney injury was a secondary end point. Results The sponsor stopped the trial after a prespecified interim analysis. There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary end point (P=0.33). The primary end point occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group as compared with 116 of 2482 (4.7%) in the sodium chloride group (odds ratio, 0.93; 95% confidence interval [CI], 0.72 to 1.22; P=0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group as compared with 112 of 2498 (4.5%) in the placebo group (odds ratio, 1.02; 95% CI, 0.78 to 1.33; P=0.88). There were no significant between‐group differences in the rates of contrast‐associated acute kidney injury. Conclusions Among patients at high risk for renal complications who were undergoing angiography, there was no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebo for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of contrast‐associated acute kidney injury. (Funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia; PRESERVE ClinicalTrials.gov number, NCT01467466.)

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.

Chemoprevention of basal and squamous cell carcinoma with a single course of fluorouracil, 5%, cream: A randomized clinical trial

Importance Keratinocyte carcinoma (ie, cutaneous basal and squamous cell carcinoma) is the most common cancer in the United States. Objective To determine whether topical fluorouracil could prevent surgically treated keratinocyte carcinoma. Design, Setting, and Participants The Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial was a randomized, double-blind, placebo-controlled trial of topical fluorouracil for chemoprevention of keratinocyte carcinoma. Participants were recruited from May 2009 to September 2011 from 12 Veterans Affairs medical centers and followed until June 30, 2013. Participants were veterans (n = 932) with a history of at least 2 keratinocyte carcinomas in the past 5 years; almost all were white males and the median age was 70 years. Interventions Application of fluorouracil, 5%, (n = 468) or vehicle control cream (n = 464) to the face and ears twice daily for 2 to 4 weeks upon randomization. Main Outcomes and Measures Surgically treated keratinocyte, basal cell, and squamous cell carcinoma risk on the face and ears in the first year after enrollment; and time to first surgically treated keratinocyte, basal cell, and squamous cell carcinoma. The a priori hypothesis was that fluorouracil would be effective in preventing these cancers. Results Of 932 participants (916 men [98%]; 926 white [99%]; median age, 70 years), 299 developed a basal cell carcinoma end point (95 in year 1) and 108 developed a squamous cell carcinoma end point (25 in year 1) over 4 years (median follow-up, 2.8 years). Over the entire study, there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma. During the first year, however, 5 participants (1%) in the fluorouracil group developed a squamous cell carcinoma vs 20 (4%) in the control group, a 75% (95% CI, 35%-91%) risk reduction (P = .002). The 11% reduction in basal cell carcinoma risk during year 1 (45 [10%] in the fluorouracil group vs 50 [11%] in the control group) was not statistically significant (95% CI, 39% reduction to 31% increase), nor was there a significant effect on keratinocyte carcinoma risk. However, a reduction in keratinocyte carcinomas treated with Mohs surgery was observed. Conclusions and Relevance A conventional course of fluorouracil to the face and ears substantially reduces surgery for squamous cell carcinoma for 1 year without significantly affecting the corresponding risk for basal cell carcinoma. Trial Registration clinicaltrials.gov Identifier: NCT00847912

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 healthcare 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.

Scientific and Organizational Collaboration in Comparative Effectiveness Research: The VA Cooperative Studies Program Model

Comparative effectiveness research (CER) has the ability to improve health and inform patients, clinicians, and decision makers. However, calls for more devoted efforts with regard to CER have been countered by methodological, resource, and translational challenges related to conducting these studies. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) is a clinical research infrastructure that has contributed much evidence to support clinical practice for several decades. Although the CSP does not exclusively focus on CER, it employs strategies that lend themselves toward the planning and execution of studies that seek to compare interventions and/or strategies for treating disease. Consequently, the CSP provides a model for addressing important scientific, structural, and operational factors for clinical research, including large, national and multinational comparative effectiveness studies. Exploration of the difficulties the CSP has encountered can help to elucidate barriers that face CER. This article discusses factors and approaches for collaboratively developing and conducting definitive studies that produce outcomes aimed at influencing clinical practice, lessons that have resulted from such efforts, and ongoing challenges. Future program directions are also presented to highlight areas of emphasis and implications for CER within the VA and nationally.

Gender differences in substance abuse, PTSD and intentional self-harm among veterans health administration patients

BACKGROUND Epidemiologic studies have reported substance abuse and posttraumatic stress disorder (PTSD) diagnoses as risk factors for suicide among Veterans Health Administration (VHA) patients. Research on risk factors for suicide may not generalize to our understanding of non-fatal intentional self-harm (ISH), given the evidence that these outcomes have unique risk factors. The aims of this study were to examine (1) gender-stratified rates of non-fatal ISH in VHA patients with alcohol abuse/dependence, drug abuse/dependence, and PTSD and (2) gender-stratified interaction between alcohol abuse and dependence and drug abuse and dependence and PTSD in predicting non-fatal ISH. METHODS Participants include all VHA care users who received a PTSD diagnosis in Massachusetts from 2000 to 2008 (n=16,004) and an age- and gender-matched comparison group (n=52,502). Data were obtained from the VHA administrative registries. RESULTS We found evidence of stronger interactions between substance abuse diagnoses and PTSD in predicting non-fatal ISH for females than for males. The interaction contrast (IC) for alcohol abuse and dependence and PTSD in predicting non-fatal ISH among female VHA patients was 62.35/100,000 person-years; for male VHA patients the comparable IC was 21.49/100,000 person-years. For female VHA patients the IC for drug abuse and dependence and PTSD predicting ISH was 256.33/100,000 person-years; no interaction was observed for male VHA patients. CONCLUSIONS This study contributes to the scant literature on gender differences in substance abuse and PTSD among VHA patients. The findings highlight comorbid diagnoses as particularly important risk factors for non-fatal ISH among female VHA patients.

Posttraumatic stress disorder, depression, and non-fatal intentional self-harm in Massachusetts Veterans

BackgroundThe literature on the association between Posttraumatic Stress Disorder (PTSD) and fatal and non-fatal intentional self-harm (ISH) among Veterans who receive care within the Veterans Health Administration (VHA) is limited in scope and contradictory. The current study examines the association between PTSD and non-fatal ISH in a gender-stratified sample of patients who received care at a Massachusetts VHA treatment facility between 2000 and 2008.MethodsVHA electronic medical record data were obtained for patients who received a PTSD diagnosis at a Massachusetts treatment facility (n = 16,004) and a gender/age matched comparison group (n = 52,502). Rate ratios for the association between PTSD and non-fatal ISH were computed adjusting for marital status, depression, alcohol or drug abuse or dependence, anxiety disorder diagnoses and prior ISH and clustering by hospital using Poisson regression. The interaction between PTSD and depression diagnoses in predicting non-fatal ISH was assessed as the departure from additive effects by calculating the interaction contrast (IC) while adjusting for identified confounders.ResultsOver the eight year study period 146 (0.91%) of those with PTSD experienced non-fatal ISH, while 71 (0.14%) of those without PTSD experienced non-fatal ISH. Strong adjusted associations between PTSD and non-fatal ISH were found for both male (RR = 3.3, 95% CI = 2.3, 4.6) and female (RR = 16, 95% CI = 4.7, 55) VHA patients. Evidence of an interaction between PTSD and depression diagnoses in predicting non-fatal ISH was found as a departure from additive effects for both sexes, but this association was more marked among women than among men.ConclusionsOur results indicate that non-fatal ISH among women may be more strongly related to PTSD than prior work focusing on suicide has suggested and highlight the importance of gender-stratified examinations of these associations. Further, our results suggest that suicide prevention approaches in the VHA should integrate treatment for PTSD and depression.

Data Sharing, Clinical Trials, and Biomarkers in Precision Oncology: Challenges, Opportunities, and Programs at the Department of Veterans Affairs

Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non‐small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.