VA Cooperative Study Research Articles

Prospective ten-year patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery Steven Goldman, Karen Zadina, Thomas Moritz, Theron Ovitt, Gulshan Sethi, Jack Copeland, William Henderson, VA Cooperative Study #364. Southern Arizona VA Healthcare System, Tucson, AZ, Edward Hines, Jr., VA Hospital, Hines, IL

Prospective ten-year patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery Steven Goldman, Karen Zadina, Thomas Moritz, Theron Ovitt, Gulshan Sethi, Jack Copeland, William Henderson, VA Cooperative Study #364. Southern Arizona VA Healthcare System, Tucson, AZ, Edward Hines, Jr., VA Hospital, Hines, IL

Changing Presentation of Seizures with Aging: Clinical and Etiological Factors

Background: The historically higher incidence of seizures in children has changed, the elderly now have a higher incidence than any age-group, 2–3 times of that found in children. Classical teachings on etiologies, clinical presentation and progression of seizures are based on observations of a younger population and need to be revised in view of features unique to this age-group. The findings of two large VA cooperative studies show that even in sophisticated medical environments, up to 30% of patients 60 years and older with recurrent partial seizures go undiagnosed for more than 1 year of seizure onset. Objective: (a) To characterize the manifestations of auras, seizures and postictal states in the elderly and the relevance of various etiologies to these presentations. (b) To identify and discuss factors that contribute to the difficulties in the diagnosis of seizures in this population. Methods: A review of our experience in treating a large population of elderly patients in a university epilepsy center and a review of the literature relating to the problem. Conclusions: Seizures in the elderly are both overdiagnosed and underdiagnosed: either situation can have serious adverse consequences. Diversity of etiologies and atypical presentations make recognition of seizures difficult. Histories are frequently inadequate: complaints of multiple physical symptoms confuse the picture, unwillingness of elderly patients to admit to problems they believe are physiological in nature by the fear others may think they are ‘losing their mind’ and high staff turnover result in erratic identification of problems. The significant morbidity and mortality associated with poorly controlled seizures in this population are in large part preventable since excellent response to treatment can be achieved in more than 80% of individuals. The correct diagnosis of seizures is more likely if both physician and patients are familiar with the nuances of epilepsy in the elderly.

Effect of finasteride and/or terazosin on serum PSA: Results of VA cooperative study #359

BACKGROUND Medical management of benign prostatic hyperplasia (BPH) giving rise to lower urinary tract symptomatology (LUTS) has emerged as the mainstay for first-line therapy. Prostate-specific antigen (PSA) is the most important method of detecting prostate carcinoma. The effect of finasteride on PSA has been widely reported. Little data exist with respect to alpha-adrenergic blocking therapy in men treated for BPH. In the present investigation we set out to evaluate the effect of these two forms of therapy. METHODS Patients enrolled in the VA Cooperative Study #359 trial were evaluated. This study evaluated men with moderate LUTS owing to BPH in four treatment groups: placebo (P), finasteride (F), terazosin (T), and combination of finasteride plus terazosin (C). Men were recruited at 31 VA medical centers and had a baseline in 52-week PSA determination at the respective sites. RESULTS There was no significant difference in baseline PSA between four groups (mean range, 2.0–2.9 ng/ml). Statistically significant reduction in PSA levels was observed at 52 weeks in the F and C arms (P < 0.001), whereas significant increases were observed in the T and P arms (P < 0.01). Additionally, there was no significant difference in PSA response between the T and P arms. Thirty percent of men in the C or F arms had more than 40–60% reduction of PSA. In contrast, the majority of men on T or P had less than 40% change in PSA. Only 35% of men on F or C had the expected 40–60% reduction in PSA level. CONCLUSIONS These data demonstrate no clinically significant effect of T on PSA level. The heterogeneity of PSA response to F may make monitoring patients for the development of prostate cancer problematic. Prostate 39:234–239, 1999. © 1999 Wiley-Liss, Inc.

The antigenic heterogeneity of the bile duct epithelium in alcoholic liver disease. VA Cooperative Study Group 275.

The chronic alcoholic patient is usually immunosuppressed, but the significance of this phenomenon in terms of bile duct injury is unclear. The immunoreactivity of the bile duct cells was examined in a series of 69 frozen liver biopsy specimens obtained from patients with alcoholic liver disease, comprising 29 cases of cirrhosis, 26 of alcoholic hepatitis, 10 cases of alcoholic fatty liver, and 4 specimens from normal livers. Liver diseases such as primary biliary cirrhosis and human hepatic allograft rejection, known to have an autoimmune basis, share the characteristic feature of damage to the bile duct epithelial cells. In both instances the damage seems to be immune mediated, but the nature of the antigens involved is not established. We used the avidin-biotin-peroxidase complex method to test in alcoholic liver disease for the expression of a battery of surface antigen markers that have been incriminated in tissue injury and are usually present in lymphoid cells but also expressed by epithelium. In this study we investigated the expression of the following molecules: HLA class I (ABC) and class II (HLA-DR, HLA-DP, HLA-DQ), CD29, CD45RA, CD45RO, CD56, interleukin 1 (IL-I), IL-2, IL-4, interferon (IFN-gamma), tumor necrosis factor beta, and transforming growth factor beta1 (TGF-beta1). The bile duct epithelial cells strongly expressed HLA-ABC in all cases, CD56 in 47 of 55, IL-4 in 15 of 41, TGF-beta1 in 14 of 25, and CD29 in 4 of 25 cases. The other markers including IFN-gamma, HLA-DR, HLA-DP, and HLA-DQ were not expressed by bile duct cells. The expression of HLA class I agrees with previous observations while the absence of class II expression does not. The expression by the bile duct epithelium of CD56 confirms our own previous report. A new observation is the finding of molecules such as IL-4, TGF-beta1, and CD29 strongly expressed in the bile ducts cells. The presence of these molecules, taken together with the lack of IFN-gamma expression, contradicts previous speculations that attributed to IFN-gamma a role in the induction of major histocompatibility antigens and adhesion molecules in immune-mediated alcoholic liver disease.

Measuring costs in multisite randomized controlled trials: lessons from the VA Cooperative Studies Program.

The interest in the economic impact of new health care interventions has increased dramatically over recent years; however, the results can be highly variable depending upon the economic assumptions made and the approaches taken in collecting the data and in conducting the analyses. This paper describes experiences from the VA Cooperative Studies Program in measuring health care utilization and costs for studies that evaluate clinical interventions. Experiences from two multisite randomized clinical trials (RCTs) are highlighted to illustrate strategies used to measure costs by directly measuring health care utilization and economic data within the context of the trials. Despite the substantial resources required to gather evidence about the cost of care for health care innovations, future VA multisite studies should include accepted health economic approaches to make important contributions to health planning and health policy within and outside the VA health care system.

Two- to three-year follow-up of patients with single-vessel coronary artery disease randomized to PTCA or medical therapy (results of a VA cooperative study)

Despite increasing use of percutaneous transluminal coronary angioplasty (PTCA) to treat stenotic coronary artery disease, there are relatively few prospective studies evaluating its long-term effectiveness. We prospectively randomized 212 stable patients with provocable myocardial ischemia and single-vessel subocclusive coronary disease to receive primary therapy with either PTCA or medical therapy. This report presents the clinical follow-up of these patients at a mean, after randomization, of 2.4 years for interview and 3.0 years for exercise testing. Of the 212 patients originally randomized, 175 received an extended follow-up interview, and 132 underwent exercise testing; 62% of patients in the PTCA group were angina free compared with 47% of patients in the medical group (p <0.05). Furthermore, exercise duration as measured by treadmill testing was prolonged by 1.33 minutes over baseline in the PTCA group, whereas it decreased by 0.28 minutes in the medical group (p <0.04). Although the angina-free time on the treadmill was not different (p = 0.50), fewer patients in the medical group developed angina on the treadmill at 3 years than those in the PTCA group (p = 0.04). By 36 months, excluding the initial randomized PTCA, use of PTCA and use of coronary artery bypass surgery were not different in the 2 treatment groups. These data indicate that some of the early benefits derived from PTCA in patients with single-vessel coronary artery disease are sustained, making it an attractive therapeutic option for these patients.

Issues surrounding tight glycemic control in people with type 2 diabetes mellitus.

To review the prospective evidence surrounding the issue of tight glycemic control in people with type 2 diabetes mellitus and resultant long-term complications. Conference proceedings and a MEDLINE search (1966-February 1998) identified pertinent English-language publications on type 2 diabetes in humans. Key search terms included insulin resistance, diabetes mellitus, non-insulin-dependent, macrovascular complications, microvascular complications, and intensive glycemic control. Selection of prospective epidemiologic and clinical studies were limited to those focusing on the management of type 2 diabetes. All articles with pertinent information relevant to the scope of this article were reviewed. The pathophysiology of type 1 and type 2 diabetes differ; however, both share chronic complications that significantly affect morbidity and mortality. People with type 1 diabetes have an absolute deficiency of insulin, whereas people with type 2 diabetes have varying degrees of insulin resistance and an inadequate compensatory insulin secretory response. The Diabetes Control and Complications Trial (DCCT) has clearly indicated that intense control of blood glucose in type 1 diabetes prevents and slows the progression of microvascular (i.e., retinopathy, nephropathy) and neuropathic complications. The Kumamoto study showed similar results in nonobese patients with type 2 diabetes. Intense insulin therapy in both populations has proven advantageous, thus supporting a common pathophysiologic process for the microvascular and neuropathic complications. Trends were seen toward fewer macrovascular (atherosclerotic disease) complications in the intensive insulin arm of the DCCT. Conversely, trends were seen toward an increase in macrovascular complications in the VA Cooperative study in people with type 2 diabetes using intensive insulin therapy. This may suggest a discordance in the pathophysiology of macrovascular disease between type 1 and type 2 diabetes. Additionally, it remains uncertain whether tight glycemic control prevents the onset or slows the progression of macrovascular disease. Two studies (the University Group Diabetes Program and the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes) to date have examined pharmacotherapy options for patients with type 2 diabetes and resultant macrovascular complications. It has yet to be determined whether any therapeutic intervention will decrease the morbidity and mortality of macrovascular disease in this population. In type 2 diabetes, limited prospective evidence does support tight glycemic control to help prevent or slow the progression of microvascular and neuropathic complications. It is uncertain whether tight glycemic control decreases macrovascular complications and which pharmacotherapeutic agent(s) is/are the best options. However, therapy that improves glucose control in combination with aggressive risk factor management should be initiated and enforced in patients with type 2 diabetes in an effort to reduce long-term complications.

Long-term treatment effects of vitamin E for tardive dyskinesia

Background: Several studies have found that alpha-tocopherol (vitamin E) can effectively treat tardive dyskinesia (TD). A limitation of these trials is their short treatment durations (maximum of 12 weeks), which do not allow us to address the effects of long-term treatment. Methods: To participate, patients had to have TD and be on stable oral medications. The study enrolled 40 patients who received up to 36 weeks of treatment with d-vitamin E (1600 IU per day) or placebo. Results: Using the Abnormal Involuntary Movements Scale (AIMS) score (sum of items #1–7) to measure TD severity, the study found a significant difference (3 points) in mean AIMS scores, in favor of vitamin E, starting at 10 weeks of treatment and continuing through the full 36 weeks. We used linear mixed-effects regression to quantify the impact of several covariates, and found that treatment assignment, TD duration, and chlorpromazine equivalents had significant effects on decreasing the AIMS score. Conclusions: The study’s finding that vitamin E is effective in treating TD agrees with results from prior studies and provides evidence that the effect may extend to treatment of up to 36 weeks. These findings are in direct contrast to those of VA Cooperative Study #394, a much larger, long-term, multi-site study, conducted by many of the same investigators, in which Vitamin E was not superior to placebo (see Editorial in this issue).

Twenty-Two-Year Follow-Up in the VA Cooperative Study of Coronary Artery Bypass Surgery for Stable Angina

We evaluated the 22-year results of initial coronary artery bypass surgery with saphenous vein grafts compared with initial medical therapy on survival, incidence of myocardial infarction, reoperation, and symptomatic status in 686 patients (average age 51) with stable angina in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery. Between 1972 and 1974, 354 patients were assigned to medical treatment and 332 to surgical revascularization. In the surgical cohort, 312 patients underwent operation (operative mortality 5.8%) and 25% subsequently underwent repeat operation (operative mortality 10.3%). In the medical cohort, 160 patients crossed over to surgery (operative mortality 4.4%) and 21% of these patients had reoperation (operative mortality 9.1%). Neither crossover nor reoperation was predictable by angiographic or clinical risk factors measured at baseline. The overall 22-year cumulative survival rates were 25% and 20% in the medical and surgical cohorts (p = 0.24). Corresponding rates in low-risk patients who had 1 or 2 vessels diseased, or 3 vessels diseased with normal left ventricular function were 31% and 24% (p = 0.024). Although significant at 10 years, there was also no long-term survival benefit for high-risk patients assigned to bypass surgery. The probabilities of remaining free of myocardial infarction and of being alive without infarction were significantly higher with initial medical therapy, 57% versus 41% (p = 0.02) and 18% versus 11% (p = 0.0031), respectively. This trial provides strong evidence that initial bypass surgery did not improve survival for low-risk patients, and that it did not reduce the overall risk of myocardial infarction. Although there was an early survival benefit with surgery in high-risk patients (up to a decade), long-term survival rates became comparable in both treatment groups. In total, there were twice as many bypass procedures performed in the group assigned to surgery without any long-term survival or symptomatic benefit.

Heart rate data from the VA cooperative study

Heart rate data from the VA cooperative study

Predicting outcomes in HIV-infected veterans: II. survival after AIDS

This article (Part II) and the preceding article (Part I) report the development of two clinical staging systems for HIV-infected individuals. The objective of the research reported here (Part II) was to construct a clinical staging system to predict survival in patients with AIDS. We analyzed data from VA Cooperative Study Number 298, a multicenter, double-blind, randomized trial that compared immediate versus deferred zidovudine therapy in HIV-infected individuals. Baseline variables obtained at the onset of AIDS in 204 individuals were tested in univariate Cox regression for their relationship to survival, and those that appeared predictive were examined in multivariable analysis. Based on these analyses, we constructed a new AIDS Clinical Staging System. The system is based on age, CD4+ cell count, type of first AIDS-defining condition, and functional status. The stages of the system were significant predictors of survival ( p = 0.0001, log-rank test). In conclusion, valid, simple clinical staging systems for patients with AIDS can be developed based on a few variables that are readily available in clinical settings.

Predicting outcomes in HIV-infected veterans: I. progression to AIDS

This article and the following article (Parts I and II) report the development of two clinical staging systems for HIV-infected individuals. The objective of the research reported here (Part I) was to construct a clinical staging system to predict progression to AIDS. We analyzed data from VA Cooperative Study Number 298, a multicenter, double-blind, randomized trial that compared immediate versus deferred zidovudine therapy in 338 HIV-infected individuals who did not have AIDS at enrollment. Baseline variables were tested in univariate Cox regression for their relationship to progression to AIDS, and those that appeared predictive were examined in multivariable analysis. Based on these analyses, we constructed a new clinical staging system based on CD4+ cell count, age, hemoglobin, oral hairy leukoplakia or oral thrush, and fever. The stages of the system were significant predictors of progression to AIDS ( p = 0.0001, log-rank test). In conclusion, simple, valid, clinical staging systems for HIV-infected patients can be constructed using information that is readily available in clinical practice settings. Such systems provide better prognostic distinction than CD4+ cell count alone by taking into account the known prognostic effects of other variables.

22-year rates of crossover and reoperation in the VA cooperative study of coronary artery bypass surgery for stable angina

22-year rates of crossover and reoperation in the VA cooperative study of coronary artery bypass surgery for stable angina

Lessons on the interaction of race and antihypertensive drugs from the VA cooperative study group on antihypertensive agents

The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents, organized by Dr. Edward D. Freis, has made numerous contributions to our knowledge about hypertension and its treatment. In the late 1970s the group observed post hoc that there were racial differences in response to hydrochlorothiazide and propranolol. Subsequent studies were designed to seek out racial differences if they existed. A series of observations led to the design of a comparative study of six drugs and placebo used as single-drug therapy of mild to moderate hypertension in men. Further analyses of those data have indicated that racial differences still exist when a second drug is substituted for a failed first drug. A combination of two drugs that had previously failed to achieve control of blood pressure did produce control in 58% of the patients. Electrocardiographic data suggested that black patients were much more likely to have left ventricular hypertropy (LVH) than whites, but analysis of echocardiograms showed that there was no racial difference in the prevalence of LVH. Additional analyses are in progress addressed to serum lipid changes, proteinuria, and drug-induced changes in left ventricular mass.

Diabetes Guidelines, Outcomes, and Cost-Effectiveness Study: A Protocol, Prototype, and Paradigm

It is a milestone for our profession to have practice guidelines tested in a clinical trial that also provides cost-effectiveness data. Dietetics practitioners now have a model for studies examining MNT in other disorders and diseases. We also have an array of questions that can be asked in future studies. The challenges include examining the long-term management of diseases using MNT; determining changes in quality-of-life issues; and segmenting subjects according to variables likely to affect outcomes, such as duration of the disease. As a result of this and other studies related to diabetes (both completed and in progress), millions of people with NIDDM will be guided to achieve the best glycemic control possible within the framework of their lifestyles. The results of the DCCT may have implications for persons with NIDDM (18), as well as for dietitians (8). The UK Prospective Diabetes Study results should be released in the near future (19), and the VA Cooperative Study on Glycemic Control and Complications in Type II Diabetes (20) is examining intensive therapy for this population. Each of these studies emphasizes a treatment approach that places management of the disease in the hands of the client. This approach clearly is a paradigm shift: no longer are we talking about "diabetic diets." But then, maybe we just need to read a little history. In 1906, Hutchison (21) wrote," ... there is no such thing as 'a diabetic diet.'" And think about the information (or lack thereof) available to him.

P24 Factors in successful patient recruitment applying the six-box organizational model in a large VA cooperative study

This study reviews the literature of online peer-to-peer (P2P) lending from 2008 until 2020 as an emergent but fast spreading phenomenon in the context of digital finance. Previous literature is geographically skewed towards United States and China with focus on determinants of funding success and loan attributes. Recent studies shift from using logit and survival analysis methods to examine funding success and default predictions, towards applying artificial intelligence. There is a controversial debate regarding adopting a self-regulatory approach versus stricter financial institutions-based regulations with a few studies suggesting a hybrid approach. We suggest several avenues for future research, such as examining the determinants and performance of P2P lending platforms in emerging and developing markets; regulatory differences, the effects of behavioral characteristics such as cultural impact, language, information technology literacy, and the innovation quotient on P2P funding attributes; and the relationship between P2P lending and traditional finance channels.

P24 Factors in successful patient recruitment applying the six-box organizational model in a large VA cooperative study

P24 Factors in successful patient recruitment applying the six-box organizational model in a large VA cooperative study

Pretreatment fibrinogen levels are associated with response to chemotherapy in patients with small cell carcinoma of the lung: Department of Veterans Affairs Cooperative Study 188.

Small cell carcinoma of the lung (SCCL) responds commonly to combination chemotherapy but resistance to therapy follows. Prior reports have suggested that a relationship may exist between plasma fibrinogen levels and response to therapy in SCCL. This study was designed to determine the possible predictive value of the fibrinogen level for tumor response (chemoresistance) in SCCL. Pretreatment fibrinogen levels were correlated with outcome and response to therapy in a cohort of 119 previously untreated patients with SCCL who were admitted to VA Cooperative Study 188. Higher pretreatment fibrinogen levels at diagnosis correlated significantly with more advanced stage of disease at entry (P < 0.001) and with reduced overall survival (P = 0.030). In addition, higher pretreatment fibrinogen levels were correlated significantly with a reduced likelihood of achieving subsequent disease regression with combination chemotherapy (P = 0.005). Because several clinical trials have shown that anticoagulant therapy improves tumor response rates and survival of SCCL, we postulate that tumor cell thrombin generation not only promotes SCCL growth but may also be primarily responsible for both increased fibrinogen levels and for resistance to chemotherapy. These findings provide incentive for studies of thrombin effects on the development of multidrug resistance, and for new clinical trials of more potent and specific inhibitors of thrombin that may further improve tumor response and survival in SCCL.

Monotherapy or polytherapy for epilepsy revisited: a quantitative assessment.

Some investigators argue that treating epilepsy with several antiepileptic drugs (AEDs) simultaneously (polytherapy) may give rise to more adverse effects than monotherapy, but this argument lacks supporting quantitative data. To reexamine this issue, we recruited a cohort of patients from the outpatients of the Special Centres for Epilepsy in The Netherlands and from the outpatients of the Department of Neurology, Nijmegen University, The Netherlands. Two tools were used for analysis. All daily doses of antiepileptic drugs (AEDs) were standardized by the ratio of prescribed daily dose to defined daily dose (PDD/DDD). The DDD is the assumed average effective daily dose for a drug used for its main indication in adults. The assignment of DDD values is the task of the World Health Organization (WHO) Collaborating Centre for Drugs Statistics Methodology and Nordic Council on Medicines, which regularly publishes Guidelines for Defined Daily Doses. The severity of adverse effects (AE) was assessed by using the Neurotoxicity Index and the Systemic Toxicity Index as developed by the VA Cooperative Study Group for their recent studies comparing the efficacy and tolerability of AEDs. One hundred sixty-one patients received monotherapy; all had a PDD/DDD ratio < or = 2/day; 128 of 262 patients receiving polytherapy also had < or = 2 PDD/DDD ratios/day. The mono- and polytherapy groups were stratified according to the PDD/DDD ratio. The prevalence of neurological AE for patients with similar PDD/DDD ratios was 50-80% for monotherapy patients and 50-82% for polytherapy patients. The difference between the mono- and polytherapy groups was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Colonic crypt proliferation (labeling) index measurements in multicenter studies: Initial experience of va cooperative study on adenomatous polyps: [formula omitted], L. Ramsey, K. Kraus, D. Lieberman and VA Cooperative Study 380 Group, Dept. of Veterans Affairs Medical Centers, Tucson, AZ and Portland, OR

Colonic crypt proliferation (labeling) index measurements in multicenter studies: Initial experience of va cooperative study on adenomatous polyps: [formula omitted], L. Ramsey, K. Kraus, D. Lieberman and VA Cooperative Study 380 Group, Dept. of Veterans Affairs Medical Centers, Tucson, AZ and Portland, OR