Cooperative Studies Program Research Articles

Clinical trials proposed for the VA Cooperative Studies Program: Success rates and factors impacting approval

The process by which funding organizations select among the myriad number of proposals they receive is a matter of significant concern for researchers and the public alike. Despite an extensive literature on the topic of peer review and publications on criteria by which clinical investigations are reviewed, publications analyzing peer review and other processes leading to government funding decisions on large multi-site clinical trials proposals are sparse. To partially address this gap, we reviewed the outcomes of scientific and programmatic evaluation for all letters of intent (LOIs) received by the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) between July 4, 2008, and November 28, 2016. If accepted, these LOIs represented initial steps towards later full proposals that also underwent scientific peer review. Twenty-two of 87 LOIs were ultimately funded and executed as CSP projects, for an overall success rate of 25%. Most proposals which received a negative decision did so prior to submission of a full proposal. Common reasons for negative scientific review of LOIs included investigator inexperience, perceived lack of major scientific impact, lack of preliminary data and flawed or confused experimental design, while the most common reasons for negative reviews of final proposals included questions of scientific impact and issues of study design, including outcome measures, randomization, and stratification. Completed projects have been published in high impact clinical journals. Findings highlight several factors leading to successfully obtaining funding support for clinical trials. While our analysis is restricted to trials proposed for CSP, the similarities in review processes with those employed by the National Institutes of Health and the Patient Centered Outcomes Research Institute suggest the possibility that they may also be important in a broader context.

Neurotoxicant exposures and rates of Chronic Multisymptom Illness and Kansas Gulf War Illness criteria in Gulf War deployed women veterans

AimsThis study analyzed deployment-related exposures and risk of Persian Gulf War Illness (GWI) in women veterans from the Veterans Affairs (VA) Cooperative Studies Program 585 Gulf War Era Cohort and Biorepository (GWECB CSP#585). Main methodsWe examined the associations between GW deployment-related exposures and case definitions for GWI in deployed GW women. Multivariate regression analyses controlling for demographic outcomes were performed. Key findingsSurveys were obtained from 202 GW deployed women veterans. Self-reported exposure to smoke from oil well fires as well as chemical and biological warfare were the only exposures significantly associated with the Center for Disease Control and Prevention (CDC) GWI criteria. Seventy-nine women were excluded from the rest of the analyses as they met Kansas GW illness exclusion criteria. Eligible women who self-reported deployment-related exposure to smoke from oil wells, pyridostigmine bromide (PB) pills, pesticide cream, pesticide treated uniforms, and insect baits were significantly more likely to meet the Kansas GWI criteria (n = 123) than those unexposed and exposures were related to Kansas symptom subdomain endorsements. SignificanceThese results suggest that women GW veterans reporting deployment related exposures of pesticide, oil well fire and PB pills are significantly more likely to meet the Kansas GWI criteria in this national cohort of GW women suggesting its utility in future studies. In addition, based on these results it appears that women exposed to particular toxicants during the war may benefit from more targeted treatment strategies dependent upon the mechanism of exposure of their toxicant induced outcomes.

Characterizing chronological accumulation of comorbidities in healthy veterans: a computational approach

Understanding patient accumulation of comorbidities can facilitate healthcare strategy and personalized preventative care. We applied a directed network graph to electronic health record (EHR) data and characterized comorbidities in a cohort of healthy veterans undergoing screening colonoscopy. The Veterans Affairs Cooperative Studies Program #380 was a prospective longitudinal study of screening and surveillance colonoscopy. We identified initial instances of three-digit ICD-9 diagnoses for participants with at least 5 years of linked EHR history (October 1999 to December 2015). For diagnoses affecting at least 10% of patients, we calculated pairwise chronological relative risk (RR). iGraph was used to produce directed graphs of comorbidities with RR > 1, as well as summary statistics, key diseases, and communities. A directed graph based on 2210 patients visualized longitudinal development of comorbidities. Top hub (preceding) diseases included ischemic heart disease, inflammatory and toxic neuropathy, and diabetes. Top authority (subsequent) diagnoses were acute kidney failure and hypertensive chronic kidney failure. Four communities of correlated comorbidities were identified. Close analysis of top hub and authority diagnoses demonstrated known relationships, correlated sequelae, and novel hypotheses. Directed network graphs portray chronologic comorbidity relationships. We identified relationships between comorbid diagnoses in this aging veteran cohort. This may direct healthcare prioritization and personalized care.

Estimation of ambient PM2.5 in Iraq and Kuwait from 2001 to 2018 using machine learning and remote sensing

Iraq and Kuwait are in a region of the world known to be impacted by high levels of fine particulate matter (PM2.5) attributable to sources that include desert dust and ambient pollution, but historically have had limited pollution monitoring networks. The inability to assess PM2.5 concentrations have limited the assessment of the health impact of these exposures, both in the native populations and previously deployed military personnel. As part of a Department of Veterans Affairs Cooperative Studies Program health study of land-based U.S. military personnel who were previously deployed to these countries, we developed a novel approach to estimate spatially and temporarily resolved daily PM2.5 exposures 2001–2018. Since visibility is proportional to ground-level particulate matter concentrations, we were able to take advantage of extensive airport visibility data that became available as a result of regional military operations over this time period. First, we combined a random forest machine learning and a generalized additive mixed model to estimate daily high resolution (1 km × 1 km) visibility over the region using satellite-based aerosol optical depth (AOD) and airport visibility data. The spatially and temporarily resolved visibility data were then used to estimate PM2.5 concentrations from 2001 to 2018 by converting visibility to PM2.5 using empirical relationships derived from available regional PM2.5 monitoring stations. We adjusted for spatially resolved meteorological parameters, land use variables, including the Normalized Difference Vegetation Index, and satellite-derived estimates of surface dust as a measure of sandstorm activity. Cross validation indicated good model predictive ability (R2 = 0.71), and there were considerable spatial and temporal differences in PM2.5 across the region. Annual average PM2.5 predictions for Iraq and Kuwait were 37 and 41 μg/m3, respectively, which are greater than current U.S. and WHO standards. PM2.5 concentrations in many U.S. bases and large cities (e.g. Bagdad, Balad, Kuwait city, Karbala, Najaf, and Diwaniya) had annual average PM2.5 concentrations above 45 μg/m3 with weekly averages as high as 150 μg/m3 depending on calendar year. The highest annual PM2.5 concentration for both Kuwait and Iraq were observed in 2008, followed by 2009, which was associated with extreme drought in these years. The lowest PM2.5 values were observed in 2014. On average, July had the highest concentrations, and November had the lowest values, consistent with seasonal patterns of air pollution in this region. This is the first study that estimates long-term PM2.5 exposures in Iraq and Kuwait at a high resolution based on measurements data that will allow the study of health effects and contribute to the development of regional environmental policies. The novel approach demonstrated may be used in other parts of the world with limited monitoring networks.

Development of a Multi-Study Repository to Support Research on Veteran Health: The VA Cooperative Studies Program Epidemiology Center-Durham (CSPEC-Durham) Data and Specimen Repository.

Federal agencies, including the Department of Veterans Affairs (VA), have prioritized improved access to scientific data and results collected through federally funded research. Our VA Cooperative Studies Program Epidemiology Center in Durham, North Carolina (CSPEC-Durham) assembled a repository of data and specimens collected through multiple studies on Veteran health issues to facilitate future research in these areas. We developed a single protocol, request process that includes scientific and ethical review of all applications, and a database architecture using metadata (common variable descriptors) to securely store and share data across diverse studies. In addition, we created a mechanism to allow data and specimens collected through older studies in which re-use was not addressed in the study protocol or consent forms to be shared if the future research is within the scope of the original consent. Our CSPEC-Durham Data and Specimen Repository currently includes research data, genomic data, and study specimens (e.g., DNA, blood) for three content areas: colorectal cancer, amyotrophic lateral sclerosis, and Gulf War research. The linking of the study specimens and research data can support additional genetic analyses and related research to improve Veterans' health.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Genetic Colorectal Cancer and Adenoma Risk Variants Are Associated with Increasing Cumulative Adenoma Counts.

The genetic basis for most individuals with high cumulative lifetime colonic adenomas is unknown. We investigated associations between known colorectal cancer-risk single-nucleotide polymorphisms (SNP) and increasing cumulative adenoma counts. The Cooperative Studies Program #380 screening colonoscopy cohort includes 612 selected participants age 50 to 75 with genotyped blood samples and 10 years of clinical follow-up. We evaluated 41 published "colorectal cancer-risk SNPs" for associations with individual cumulative adenoma counts or having ≥10 cumulative adenomas. SNPs were analyzed singly or combined in a polygenic risk score (PRS). The PRS was constructed from eight published SNPs associated with multiple adenomas, termed "adenoma-risk SNPs." Four colorectal cancer-risk SNPs were associated with increasing cumulative adenoma counts (P < 0.05): rs12241008 (gene: VTI1A), rs2423279 (BMP2/HAO1), rs3184504 (SH2B3), and rs961253 (FERMT1/BMP2), with risk allele risk ratios of 1.31, 1.29, 1.24, and 1.23, respectively. Three colorectal cancer-risk SNPs were associated with ≥10 cumulative adenomas (P < 0.05), with risk allele odds ratios of 2.09 (rs3184504), 2.30 (rs961253), and 1.94 (rs3217901). A weighted PRS comprised of adenoma-risk SNPs was associated with higher cumulative adenomas (weighted rate ratio = 1.57; P = 0.03). In this mostly male veteran colorectal cancer screening cohort, several known colorectal cancer-risk SNPs were associated with increasing cumulative adenoma counts and the finding of ≥10 cumulative adenomas. In addition, an increasing burden of adenoma-risk SNPs, measured by a weighted PRS, was associated with higher cumulative adenomas. Future work will seek to validate these findings in different populations and then augment current colorectal cancer risk prediction tools with precancerous, adenoma genetic data.

Increasing access to clinical research using an innovative mobile recruitment approach: The (MoRe) concept

BackgroundAccess to healthcare delivery programs and systems is a primary correlate to the overall health and well-being of Veterans and the general population. Participation in clinical research is a gateway to novel therapies that are intended to address current global health issues. Meeting or exceeding recruitment goals in clinical research is one of the key determinants of the timely and successful completion of a study. The travel and time burdens experienced by study participants are often considered barriers to their enrollment into clinical research. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) established a consortium of nine VA medical centers (VAMCs) called the Network of Dedicated Enrollment Sites (NODES). The NODES program provides study site-level expertise and innovative approaches that address challenges to clinical research execution. In alignment with our mission, our program developed an approach to increase study participant access to clinical research through implementing “Mobile Recruitment (MoRe)” units. This manuscript describes the utility and challenges associated with employing this strategy to address three common barriers to clinical research participation: 1) research participant travel burden, 2) participant access to study opportunities, and 3) low participant enrollment. MethodsA plan to introduce the Mobile Recruitment (MoRe) unit as a recruitment strategy was piloted for a high-volume, observational cohort study and mega biobank in the VA health care system, the “Million Veteran Program (MVP)”. MoRe is a recruitment strategy for CSP research integrating mobile technology and atypical research recruitment locations. Recruitment locations include primary or main VA hospitals and their assigned VA Community-Based Outpatient Clinics (CBOCs). Each Node site (n = 9) received components of the MoRe unit including a laptop, printer, portable cart with storage space, cooler/ice packs for specimen storage and transport. Each site's usage of these components varied based on its respective needs. Activities focused on both VA main facilities and CBOC facilities for recruitment. ResultsSeven of the nine Node sites compared the effectiveness of the MoRe unit on MVP study enrollment outcomes over three-time points: pre-intervention period, intervention period, and post-intervention period. The utilization of MoRe in the intervention period demonstrated a 36.9% increase in enrollment compared to the previous six months (pre-intervention period). There was a 2% enrollment increase at the six-month post-intervention period as compared to the intervention period. When comparing the pre-intervention period to the post-intervention period (duration of eighteen months), enrollment increased by 38.9%. ConclusionFive of the seven sites experienced an increase in enrollment during the intervention and post-intervention periods. The two sites without an increase in enrollment experienced various extenuating factors. Characteristics of sites using MoRe included the ability to utilize a smaller, unconventional space, i.e. not a traditional clinical research exam space for recruitment. MoRe was utilized in hospital laboratory space, CBOCs, primary care clinics, and other subspecialty clinics that allowed recruitment activities but did not have dedicated space to offer the research teams for that purpose. This initiative successfully demonstrated the benefit of deploying the unit, proving its utility in cases in where there was a lack of space or alternative workstations for research activities. The implementation of MoRe by NODES as a recruitment strategy for MVP may be transferable to other VA clinical research studies, as well as to other healthcare settings executing similar clinical research activities.

S173. GENOME-WIDE ASSOCIATION STUDIES OF SCHIZOPHRENIA AND BIPOLAR DISORDER IN A DIVERSE COHORT OF US VETERANS

BackgroundSchizophrenia and bipolar disorder are debilitating neuropsychiatric illnesses collectively affecting 2% of the world’s population, and which cause tremendous human suffering that impacts patients, their families and their communities. Recognizing the major impact of these disorders on the psychosocial function of more than 200,000 US Veterans, the Department of Veterans Affairs (VA) recently genotyping of nearly 9,000 veterans with schizophrenia or bipolar I disorder in Cooperative Studies Program (CSP) #572: “Genetics of Functional Disability in Schizophrenia and Bipolar Illness”, all of whom were extensively assessed for neurocognitive function and disability, and genotyped using a custom Affymetrix Axiom Biobank array.MethodsPrimary genome-wide association studies (GWAS) of schizophrenia and bipolar disorder were performed across and within ancestry goups, with attempted replication in matched subjects from the PGC and Genomic Psychiatry Cohort (GPC). We combined results for CSP#572 with available summary statistics from the PGC, Indonesia Schizophrenia Consortium and Genetic REsearch on schizophreniA neTwork-China and Netherland (GREAT-CN) study, and multi-ethnic GPC cohorts, achieving among the largest and most diverse studies of these disorders to date.ResultsPolygenic risk scores based on published PGC summary statistics for schizophrenia or bipolar disorder were significantly associated with case status among EA (P<10–30) and AA (P<0.0005) participants in CSP#572. Our primary analyses of schizophrenia yielded a single genome-wide significant association with variants in CHD7 at 8q12.2 for European-American (EA) participants, which remained significant in a joint analysis of EA and African-American (AA) subjects (P=4.62e-08). While no genome-wide significant associations were detected by our within-ancestry analyses of bipolar disorder, a cross-ancestry meta-analysis of CSP#572 participants yielded a significant finding at 10q25 with variants in SORCS3 (P=2.62e-08). Among loci attaining P<0.0001 in our within-ancestry analyses, 4 and 8 subsequently achieved genome-wide significance, respectively, when jointly analyzed with matched subjects from the PGC and GPC. Combining our results with published summary statistics, we performed a cross-ancestry GWAS meta-analysis of 69,280 schizophrenia cases and 138,379 controls, identifying 200 genome-wide significant loci of which 76 are newly reported here. Cross-ancestry analysis of 28,326 bipolar cases and 90,570 controls identified 24 genome-wide significant loci, including novel associations with common variants in PAX5, DOCK2, MACROD2, BRE, KCNG1, and LINC01378.DiscussionWe newly describe genome-wide analyses in a diverse cohort of US Veterans with schizophrenia or bipolar disorder, benchmarking the predictive value of polygenic risk scores based on published GWAS findings. Leveraging available summary statistics from studies of global populations, we add to burgeoning lists of genomic loci implicated in the etiologies of these disorders.

Long-term negative emotional outcomes of warzone TBI

Objective Many veterans of the Iraq and Afghanistan Wars have experienced traumatic brain injury (TBI). Although prior work has examined associations between TBI and development of psychiatric syndromes, less is known about associations between TBI and component emotions constituting these syndromes, especially in the long term. The purpose of this study was to examine the long-term emotional consequences of deployment-related TBI. Methods As part of VA Cooperative Studies Program #566, we assessed a sample of n = 456 US Army soldiers prior to an index deployment to Iraq, and again an average of 8.3 years (SD = 2.4 years) after their deployment for a long-term follow-up assessment. In this report, we used adjusted regression analyses to examine the relationship of deployment TBI to depression, anxiety, and stress symptom severity measured at the long-term follow-up assessment. A structured interview was used to determine TBI history; the Depression, Anxiety, and Stress Scale, 21-item version (DASS-21) was used to determine emotional status at the follow-up evaluation. Results Warzone TBI events, particularly when greater than mild in severity, were independently associated with depression, anxiety, and stress severity at long-term follow-up, even after taking into account variance attributable to pre-deployment emotional distress and war-zone stress. Post-hoc analyses did not detect independent associations of either number of events or injury mechanism with outcomes. Conclusions These findings highlight the potentially enduring and multi-faceted emotional effects of deployment TBI, underscoring the need for early assessment of negative affectivity in warzone veterans reporting TBI.

Prevalence and Patterns of Symptoms Among Female Veterans of the 1991 Gulf War Era: 25 Years Later.

Background: A new national cohort of Gulf War (GW) veterans of 1,318 participants was created from the Veterans Affairs Cooperative Studies Program 585 Gulf War Era Cohort and Biorepository (GWECB) pilot study. However, female veteran health outcomes have not been reported separately for those deployed versus nondeployed to the 1990-1991 GW. Methods: Using data from the cooperative studies program (CSP) #585 GWECB, this study examined whether excess prevalence and patterns of Gulf War Illness (GWI) symptoms were present among female veterans who served during the GW compared with female veterans who did not deploy to the GW (GW-Era). Results: A total of 301 women veterans participated in the survey (203 GW, 98 GW-era). Mean ages in 2016 were 53 years among GW women veterans and 54 years among GW-era women. Participant groups did not differ by age, race, ethnicity, or education, but GW women were more likely to have served in the army or navy and less likely to have served in the air force. Compared with GW-era women, GW-deployed women were significantly more likely to report 7 out of 34 symptoms related to cognitive, neurological, and mood problems and respiratory complaints when controlling for age, race, GW deployment, branch of service, and smoking status in logistic regression analyses. Ordered logistic regression was also used to estimate the association between the total number of self-reported symptoms and deployment status, age, race, branch of service, and smoking status. Results showed deployed GW veterans to have a nearly twofold risk of reporting more symptoms than GW-era women, with younger, nonwhite, army-enlisted GW women significantly more likely to report more total symptoms. Discussion: Twenty-five years after the war, GWECB women GW veterans continued to report a wide variety of symptoms at a significantly higher excess frequency prevalence than GW-era women. Our results showed at least a 14% excess frequency prevalence in all seven significantly different symptoms encompassing two out of the six Kansas GWI criteria, including neurological/mood/cognition, and respiratory domains. These results suggest that further study of these symptom domains is warranted in GW women veterans.

Veterans Affairs Cooperative Studies Program Study #553: Chemotherapy After Prostatectomy for High-risk Prostate Carcinoma: A Phase III Randomized Study

BackgroundThe Veterans Affairs Cooperative Studies Program study #553 was designed to evaluate the efficacy of adjuvant chemotherapy added to the standard of care (SOC) for patients who are at high risk for relapse after prostatectomy. ObjectiveTo test whether addition of chemotherapy to surgery for high-risk prostate cancer improves progression-free survival (PFS). Design, setting, and participantsEligible patients after prostatectomy were randomized to the SOC group with observation or to the chemotherapy group with docetaxel and prednisone administered every 3 wk for six cycles. Randomization was stratified for prostate-specific antigen, Gleason, tumor stage, and surgical margin status. Outcome measurements and statistical analysisThe primary endpoint was PFS. Secondary endpoints included overall, prostate cancer–specific, and metastasis-free survival, and time to androgen deprivation therapy. Results and limitationsA total of 298 of the planned 636 patients were randomized. The median follow-up was 59.1 mo (0.2–103.7 mo). For the primary endpoint, the two groups did not statistically differ in PFS (median 55.5 mo in the chemotherapy group and 42.2 mo in the SOC group; test adjusted for site via gamma frailty p=0.21; adjusted hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.58–1.11; p=0.18). Prespecified subgroup analyses showed benefit in PFS for patients with tumor stage ≥T3b (HR 0.54, 95% CI 0.32–0.92; p=0.022) and patients with Gleason score ≤7 (HR 0.65, 95% CI 0.43–0.99; p=0.046). Secondary endpoint analyses are hampered by low event rates. The most common adverse events (≥grade 3 related or possibly related to chemotherapy) included neutropenia (43%), hyperglycemia (20%), and fatigue (5%), with febrile neutropenia in 2%. ConclusionsAdjuvant chemotherapy in high-risk prostate cancer using docetaxel and prednisone did not lead to statistically significant improvement in PFS for the intention-to-treat population as a whole. The analysis was challenged by lower power due to accrual limitation. Subgroup analyses suggest potential benefit for patients with Gleason grade ≤7 and stage≥pT3b (ClinicalTrials.gov number NCT00132301). Patient summaryIn this randomized trial, we tested whether addition of chemotherapy to surgery for high-risk prostate cancer decreased the risk of prostate-specific antigen rise after surgery. We found no benefit from docetaxel given after radical prostatectomy, although some subgroups of patients may benefit.

Student dropout and retention: An event history analysis among students in cooperative higher education

There are many reasons why students dropout of higher education. Some reasons may be unique for students who are enrolled in a cooperative study program, because of a second educational player, which is the workplace training side, and the above-average study load may be another factors influencing the student’s decision to leave the program. We analyse a sample of 19,769 cooperative students in Germany, including 852 dropouts. A Cox regression analysis was applied to identify indicators for dropout risk. The results show that personality and commitment to one’s company matter alongside the known determinants of cognitive skills. Recommendations for agents (student advisory services, companies, etc.) that wish to counteract dropout and motivate students’ workplace commitment are incorporated in the conclusions.

Genome-wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder.

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

Epiaortic Ultrasound for Assessment of Intraluminal Atheroma; Insights from the REGROUP Trial

To assess the use of epiaortic ultrasound in contemporary cardiac surgery, as well as its impact on surgical cannulation strategy and cerebrovascular events. Epiaortic ultrasound data was prospectively collected in the Randomized Endovein Graft Prospective (REGROUP) trial (VA Cooperative Studies Program #588, ClinicalTrials.gov, NCT01850082), which randomized 1,150 coronary artery bypass graft patients between 2014 and 2017 to endoscopic or open-vein graft harvest. Sixteen cardiac surgery programs within the Veterans Affairs Healthcare System with expertise at performing endoscopic vein-graft harvesting. Veterans Affairs patients, greater than 18 years of age, undergoing elective or urgent coronary artery bypass grafting with cardiopulmonary bypass and cardioplegic arrest with at least one planned saphenous vein graft were eligible for enrollment. Epiaortic ultrasound was performed by the surgeon using a high frequency (>7 MHz) ultrasound transducer. Two-dimensional images of the ascending aorta in multiple planes were acquired before aortic cannulation and cross-clamping. Epiaortic ultrasound was performed in 34.1% (269 of 790) of patients in REGROUP. Among these patients, simple intraluminal atheroma was observed in 21.9% (59 269), and complex intraluminal atheroma comprised 2.2% (6 of 269). The aortic cannulation or cross-clamp strategy was modified based on these findings in 7.1% of cases (19 of 269). There was no difference in stroke between patients who underwent epiaortic ultrasound and those who did not (1.9% v 1.2% p = 0.523). Despite current guidelines recommending routine use of epiaortic ultrasound (IIa/B) to reduce the risk of stroke in cardiac surgery, in this contemporary trial, use remains infrequent, with significant site-to-site variability.

Randomized Trial of Medical versus Surgical Treatment for Refractory Heartburn

BackgroundHeartburn that persists despite proton-pump inhibitor (PPI) treatment is a frequent clinical problem with multiple potential causes. Treatments for PPI-refractory heartburn are of unproven efficacy and focus on controlling gastroesophageal reflux with reflux-reducing medication (e.g., baclofen) or antireflux surgery or on dampening visceral hypersensitivity with neuromodulators (e.g., desipramine).MethodsPatients who were referred to Veterans Affairs (VA) gastroenterology clinics for PPI-refractory heartburn received 20 mg of omeprazole twice daily for 2 weeks, and those with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and multichannel intraluminal impedance–pH monitoring. If patients were found to have reflux-related heartburn, we randomly assigned them to receive surgical treatment (laparoscopic Nissen fundoplication), active medical treatment (omeprazole plus baclofen, with desipramine added depending on symptoms), or control medical treatment (omeprazole plus placebo). The primary outcome was treatment success, defined as a decrease of 50% or more in the Gastroesophageal Reflux Disease (GERD)–Health Related Quality of Life score (range, 0 to 50, with higher scores indicating worse symptoms) at 1 year.ResultsA total of 366 patients (mean age, 48.5 years; 280 men) were enrolled. Prerandomization procedures excluded 288 patients: 42 had relief of their heartburn during the 2-week omeprazole trial, 70 did not complete trial procedures, 54 were excluded for other reasons, 23 had non-GERD esophageal disorders, and 99 had functional heartburn (not due to GERD or other histopathologic, motility, or structural abnormality). The remaining 78 patients underwent randomization. The incidence of treatment success with surgery (18 of 27 patients, 67%) was significantly superior to that with active medical treatment (7 of 25 patients, 28%; P=0.007) or control medical treatment (3 of 26 patients, 12%; P<0.001). The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% confidence interval, −5 to 38; P=0.17).ConclusionsAmong patients referred to VA gastroenterology clinics for PPI-refractory heartburn, systematic workup revealed truly PPI-refractory and reflux-related heartburn in a minority of patients. For that highly selected subgroup, surgery was superior to medical treatment. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT01265550.)

Baseline Colonoscopy Findings Associated With 10-Year Outcomes in a Screening Cohort Undergoing Colonoscopy Surveillance

Few studies have evaluated long-term outcomes of ongoing colonoscopic screening and surveillance in a screening population. We aimed to determine the 10-year risk for advanced neoplasia (defined as adenomas ≥10mm, adenomas with villous histology or high-grade dysplasia, or colorectal cancer [CRC]) and assessed whether baseline colonoscopy findings were associated with long-term outcomes. We collected data from the Department of Veterans Affairs Cooperative Studies Program Study on 3121 asymptomatic veterans (50-75 years old) who underwent a screening colonoscopy from 1994 through 1997 at 13 medical centers and were then followed for 10 years or until death. We included 1915 subjects with at least 1 surveillance colonoscopy and estimated cumulative incidence of advanced neoplasia by Kaplan-Meier curves. We then fit a longitudinal joint model to estimate risk of advanced neoplasia at each subsequent examination after baseline, adjusting for multiple colonoscopies within individuals. Through 10 years of follow-up, there were 146 individuals among all baseline colonoscopy groups found to have at least 1 incident advanced neoplasia. The cumulative 10-year incidence of advanced neoplasia was highest among those with baseline CRC (43.7%; 95% CI 13.0%-74.4%), followed by those with baseline advanced adenoma (AA) (21.9%; 95% CI 15.7-28.1). The cumulative 10-year incidence of advanced neoplasia was 6.3% (95% CI 4.1%-8.5%) and 4.1% (95% CI 2.7%-5.4%) for baseline 1 to 2 small adenomas (<1cm, and without villous histology or high-grade dysplasia) and no neoplasia, respectively (log-rank P= .10). After adjusting for prior surveillance, the risk of advanced neoplasia at each subsequent examination was not significantly increased in veterans with 1 or 2 small adenomas at baseline (odds ratio 0.96; 95% CI 0.67-1.41) compared with veterans with no baseline neoplasia. Baseline screening colonoscopy findings associate with advanced neoplasia within 10 years. Individuals with only 1 or 2 small adenomas at baseline have a low risk of advanced neoplasia over 10 years. Alternative surveillance strategies, could be considered for these individuals.

Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up

BackgroundWe previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.MethodsWe observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.ResultsThere were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P=0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).ConclusionsParticipants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.)

Accelerating the Growth of Evidence-Based Care for Women and Men Veterans.

Accelerating the Growth of Evidence-Based Care for Women and Men Veterans.

Characterization of temporal relationships of comorbidities developed following cancer diagnoses in veterans.

e18049 Background: Understanding patient trajectories and common sequences of comorbidity accrual among those newly diagnosed with cancer is critical for precision approaches to care and prevention. The Veterans Affairs (VA) Cooperative Studies Program (CSP) #380 cohort includes 3,121 healthy asymptomatic veterans who underwent screening colonoscopy and were followed for at least ten years. The current analysis leverages computational approaches to characterize the temporal relationships of diagnoses in CSP #380 participants following diagnosis of colorectal or other cancers. Methods: Patients enrolled in CSP #380 with at least 5 years of linked electronic health record data from the VA Corporate Data Warehouse (October 1999-December 2015) were included. Cancer diagnoses and their most common subsequent new diagnoses were identified per patient by the first instance of each three-digit ICD-9 diagnosis affecting at least 50 patients. Pairwise chronological relative risks (RR) between subsequent diagnoses were represented as a directed network graph, which maps the probability of developing a diagnosis following a prior diagnosis. Results: A total of 2,210 patients were included. The most common cancer diagnoses were prostate (436), thoracic (169), bladder (120), colon (72), and kidney cancers (65). Most first diagnoses following a cancer diagnosis were related to progressive cancer or acute/subacute treatment toxicity. For prostate cancer, comorbidities with greatest RR were carcinoma in situ (RR 6.85), unspecified (NOS) metastases (2.75), and urethral stricture (2.53). For lung cancer, they were metastases of respiratory and digestive sites (12.24), lymph nodes (6.47), and NOS (5.68), pneumothorax and air leak (4.16), and convalescence and palliative care (3.07). In bladder cancer, they were carcinoma in situ (9.00), cystitis (6.78), kidney or other urinary cancer (6.19), attention to artificial openings (3.40), and urethral stricture (2.78). These and other results were visualized with network graphs. Conclusions: Computational techniques can identify and visualize future health concerns following cancer diagnoses. In this cohort of initially healthy and asymptomatic veterans on a prospective screening colonoscopy study, most subsequent diagnoses were related to cancer or toxicities of therapy, as might be expected in an aging cohort. Future work may focus on streamlining in-clinic identification of potential high likelihood comorbidities.