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VA Cooperative Studies Program #571 (DIVA) was designed to evaluate the efficacy of drug‐eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure when compared with bare‐metal stents (BMS) in participants undergoing stenting of de novo SVG lesions. Participants undergoing clinically indicated stenting of de novo SVG lesions were randomized in a 1:1 ratio to DES or BMS. Randomization was stratified by presence/absence of diabetes mellitus and the number of target SVG lesions (1 vs ≥2) within each participating site. At sites that did not routinely administer 12‐months of dual antiplatelet therapy after SVG stenting participants without acute coronary syndromes received 1 month of open‐label clopidogrel, followed by 11 months of clopidogrel for those assigned to DES and 11 months of placebo for those assigned to BMS. The primary endpoint was the 12‐month incidence of target‐vessel failure (defined as the composite of cardiac death, target‐vessel myocardial infarction, or target‐vessel revascularization). Secondary endpoints included the incidence of other clinical endpoints and the incremental cost‐effectiveness of DES relative to BMS. Due to lower‐than‐anticipated target‐vessel failure rates, target enrollment was increased from 519 to 762. The study had randomized 599 participants when recruitment ended in December 2015. The DIVA trial will provide clarity on the appropriate stent type for de novo SVG lesions.

Knowing the extent to which a clinical trial's findings translate into clinical practice can be challenging. One practical approach to estimating a trial's influence on clinical practice can be achieved by assessing how the trial informed relevant clinical practice guidelines (CPGs). Accordingly, the objectives of this study were to provide an overview of all the clinical trials involving the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) that aimed at informing or resulted in informing the management of high blood pressure and to identify and describe the extent to which these trials informed CPGs for the management of high blood pressure. A total of 26 clinical trials involving the VA CSP were identified. Using bibliographic information, 21 CPGs for the management of hypertension representing over 40 years of treatment recommendations from eight collectives were evaluated to determine how they were informed by trials involving the VA CSP. From 1977 to 2018, 13 of the 26 trials (50.0%) were found to have informed 19 of the 21 CPGs (90.5%) a total of 54 times (mean = 2.6 trial citations per CPG, SD ± 1.8). Clinical trials involving the VA CSP have informed a sizeable proportion of CPGs for the management of high blood pressure over the past 40 years. Because of this impact on the CPGs, these trials are also likely to have had at least moderate influence on clinical practice.

Knowledge of distinct motivations and reasons toward or against future trial participation is invaluable to any organization conducting trial research. Study delays often occur due to lack of recruitment. This study's primary objective was to compare veteran and nonveteran motivations and reasons.People in two outpatient waiting rooms were approached. The questionnaire assessed motivation toward trial involvement through use of five-point Likert-type scales and hypothetical trial scenarios; it also analyzed reasons for participation through subject ranking of reasons.Veterans were more likely to participate in a trial in which all participants received the active treatment (p = 0.025). Veterans had different reasons for participation than nonveterans. Specifically, veterans felt altruism and "paying back" people who treated them were more important (p = 0.024 and p = 0.003) while financial compensation for volunteering was less important (p0.001).Knowledge of the varying reasons for participation could potentially aid recruitment efforts.

Background: Patient characteristics increase the risk of gastrointestinal (GI) complications associated with nonsteroidal antiinflammatory drugs (NSAIDs). Patients at risk may not be prescribed protective therapies that might mitigate their risk of NSAID-associated GI complications. Objective: To assess GI risk among Veterans Affairs (VA) patients on NSAID therapy, determine whether therapy conformed to VA guidelines for lessening the risk of GI complications, and identify patient risk factors associated with conformance. Methods: Using databases from 3 VA medical centers, we retrospectively identified patients receiving NSAIDs and obtained data regarding age, history of GI bleed over 8 years, GI adverse effects associated with NSAIDs, diagnoses, and medication history over one year. We inferred health status from age-adjusted Charlson comorbidity index values. Each patient's risk of developing GI complications over one year was calculated using these data. Among patients at significant or substantial risk, we assessed conformance to VA guidelines. We used logistic regression to identify risk factors associated with conformance and determine adjusted ORs (AORs) with 95% CIs for each risk factor. Results: There were 19122 patients receiving NSAIDs. Of 4589 patients at significant risk and 1246 at substantial risk, 1161 (25.3%) and 356 (28.6%), respectively, were prescribed guideline-conformant therapy. Risk factors associated with conformance (p s 0.001) among patients at significant risk were rheumatoid arthritis (AOR 1.34; 95% CI 1.13 to 1.58) and GI adverse effects (AOR 1.53; 95% CI 1.42 to 1.64). For substantial risk patients, risk factors associated with conformance (p s 0.031) were rheumatoid arthritis (AOR 1.65; 95% CI 1.37 to 1.98), concomitant corticosteroids (AOR 1.21; 95% CI 1.02 to 1.43), GI hospitalization (AOR 2.01; 95% CI 1.57 to 2.59), and GI adverse effects (AOR 1.79; 95% CI 1.47 to 2.18). Conclusions: Many patients at risk for GI adverse events do not receive guideline-conformant therapy. Educational interventions to improve conformance could focus on specific risk factors for GI complications.

Objective To assess the perceptions and attitudes of pharmacists and pharmacy technicians involved in an office-based opioid dependence treatment program using buprenorphine/naloxone. Design Cross-sectional attitudinal assessment. Setting Community, outpatient hospital, and clinic pharmacies. Participants Pharmacists and technicians participating in a clinical trial of opioid dependence treatment using buprenorphine/naloxone. Intervention Written and telephone surveys followed by interviews with open-ended items. Main Outcome Measures Attitudes and perceptions regarding opioiddependent patients and use of buprenorphine/naloxone for treatment of opioid dependence. Results Pharmacies in seven states (New York, Virginia, Illinois, Florida, Texas, California, and Washington) participated in the clinical trial. A total of 40 pharmacists and pharmacy technicians responded to the initial written survey, representing 27 of the 32 pharmacies (84%). Follow-up interviews were obtained from one individual at 30 of those pharmacies (93.8%). Most pharmacy personnel (77.5%) involved with this study were not more concerned about theft or break-ins and would be willing to participate in opioid dependence treatment as the medication became available commercially (70%). The majority of respondents (85%) indicated that patients did not cause problems at their pharmacies. Compared with their experiences in administering other narcotic medications, most respondents did not express increased concern regarding prescription forgery (75%) or diversion (80%) of buprenorphine/naloxone. Conclusion The majority of respondents expressed positive attitudes and perceptions regarding patients treated for opioid dependence with buprenorphine/naloxone.

OBJECTIVE: To review opioid dependence (OD) and its treatment. Pharmacologic treatments, including the use of buprenorphine/naloxone, are presented. Pharmaceutical care functions for outpatient OD treatment are discussed. DATA SOURCES: Primary and review articles were identified by MEDLINE and HEALTHSTAR searches (from 1966 to November 2000) and through secondary sources. Tertiary sources were also reviewed regarding general concepts of OD and its treatment. STUDY SELECTION/DATA EXTRACTION: Relevant articles were reviewed after identification from published abstracts. Articles were selected based on the objectives for this article. Studies of the treatment of OD with buprenorphine were selected based on the topic (pharmacology, pharmacokinetics, adverse reactions) and study design (randomized, controlled clinical trials in patients with OD with active/placebo comparisons and/or comparisons of active OD treatments). Articles regarding pharmacists' activities in the treatment and prevention of OD were reviewed for the pharmaceutical care section. DATA SYNTHESIS: OD is considered a medical disorder with costly adverse health outcomes. Although methadone maintenance treatment (MMT) is cost-effective for OD, only about 12% of individuals with OD receive this treatment. Psychological and pharmacologic modalities are used to treat OD, but patients often relapse. Drug therapy includes α2-agonists for withdrawal symptoms, detoxification regimens with or without opioids, opioid antagonists, and opioid replacement including methadone, levomethadyl acetate, and buprenorphine. The Drug Addiction Treatment Act of 1999 allows for office-based opioid replacement therapies. Sublingual buprenorphine with naloxone can be used in this milieu. Buprenorphine with naloxone is currently under new drug application review with the Food and Drug Administration. Clinical research shows buprenorphine to be equal in effectiveness to methadone, but safer in overdose due to its ceiling effect on respiratory depression. It has lower abuse potential and fewer withdrawal symptoms when discontinued. Naloxone is included to decrease diversion and injection of the tablets. Pharmacists in outpatient settings who are familiar with OD have opportunities to provide pharmaceutical care to patients receiving this treatment. Pharmaceutical care functions for OD include ensuring appropriate drug administration, monitoring adverse effects, alleviating withdrawal symptoms, treating intercurrent illnesses, minimizing diversion, and preventing relapse. CONCLUSIONS: OD is a critical unmet health problem in the US. Buprenorphine combined with naloxone represents an innovative treatment for OD in outpatient settings. This new treatment has advantages over MMT.

In an effort to decrease the complexity of drug administration at the clinic site and increase automation in the packaging, distribution, and administration of clinical trial supplies, the Cooperative Studies Program Clinical Research Pharmacy Coordinating Center developed the Remote Drug Treatment Information System (RDTIS). This system uses bar code technology to assist in the verification of drug assignments, management of dose adjustments, and documentation of clinical doses. The system also assists the clinical site in the collection of adverse medical events, documentation of patient enrollments and terminations, and incorporation of lab findings. Drug accountability is provided through daily monitoring of shipments and drug usage. This paper describes RDTIS, with an overview of the hardware and software design, implementation issues, and issues relevant to clinical trial administration. RDTIS can assist in automating the collection of routine data through the use of bar code technology, help prevent dispensing errors, and assure the maintenance of the blind.

The effectiveness of masking in the Cardiac Arrhythmia Suppression Study (CAPS) was assessed by surveying investigators and study coordinators. CAPS patients were assigned one of five treatments: encainide, flecainide, imipramine, moricizine, or placebo. Had all treatments appeared identical and equal numbers of patients been assigned to each, 20% of guesses of treatment assignment would be correct by chance alone. Since neither was possible in CAPS, higher rates of correct guessing were expected. Overall, respondents correctly identified treatment 39% of the time. Investigators identified the drug 30% of the time with rates of 20%, 24%, 37%, 20%, and 55% for the five treatment groups, respectively, whereas coordinators identified the treatments 47% of the time with scores of 42%, 45%, 50%, 40%, and 60%. Side effects and a suboptimal masking design detracted from masking; electrocardio-graphic changes did not. Imipramine, which caused characteristic side effects, was the most frequently identified active treatment. Scores were higher for investigators who had prior experience with the drugs, but scores did not improve over the course of the trial. Findings suggest that to improve masking all drugs should have been matched in appearance or persons evaluating treatments should not have been allowed to see the drugs.

Few studies have described improvement in health-related quality of life (HRQOL) associated with opioid dependence treatment with buprenorphine (ODT-B).To evaluate HRQOL changes in domain scores, physical and mental component summaries, and health utilities (HUs) associated with ODT-B using the Short Form 36 (SF-36).We assessed HRQOL changes in a substudy of a pharmacokinetic study that compared buprenorphine oral tablet and liquid dosage formulations over 16 weeks. Individuals, aged 18-65 years, were screened for opioid dependence. They were excluded if they would not agree to birth control or had a serious medical condition. Subjects received psychosocial counseling and weekly group therapy. The SF-36 was administered upon enrollment and at 4-week intervals. We used the SF-6D to estimate HUs. We performed intention to treat (ITT) analyses based on the last observation available for each subject. Paired t tests of each domain and HU, limited to remaining patients at each 4-week interval, were also conducted.Of 96 subjects enrolled, cumulative dropouts over time resulted in 80, 69, 59, and 44 subjects remaining at 4, 8, 12, and 16 weeks. There were no significant differences in opioid-positive urines, dropout rates, or dosage changes between formulations. In the ITT analyses, HRQOL improvements over time were bodily pain (62.1 vs. 69.1, P = 0.017), vitality (49.8 vs. 56.5, P = 0.001), mental health (59.9 vs. 66.0, P = 0.001), social function (66.4 vs. 74.7, P = 0.001), role emotional (59.4 vs. 71.9, P = 0.003), role physical (60.9 vs. 70.6, P = 0.005), and mental component summary (41.9 vs. 45.4, P0.001). HU scores also improved (0.674 vs. 0.715, P = 0.001). Results from paired t tests, with only concurrently enrolled patients, showed similar improvements from baseline to 4, 8, 12, or 16 weeks.Buprenorphine, accompanied with psychosocial counseling, was associated with improved HRQOL and HUs.

Objectives. To assess pharmacy students’ knowledge, attitudes, and evaluation of direct-to-consumer advertising (DTCA). Methods. A cross sectional, self-administered, 106-item survey instrument was used to assess first, second, and third professional year pharmacy students’ knowledge about DTCA regulations, attitudes toward DTCA, and evaluation of DTC advertisements with different brief summary formats (professional labeling and patient labeling) and in different media sources (print and television). Results. One hundred twenty (51.3%) of the 234 students enrolled participated in the study. The mean percentage knowledge score was 48.7% 6 12.5%. Based on the mean scores per item, pharmacy students had an overall negative attitude toward DTC advertisements. Students had an overall negative attitude toward television and print advertisements using the professional labeling format but an overall positive attitude toward the print advertisement using the patient labeling format. Conclusions. Lectures discussing DTC advertising should be included in the pharmacy curriculum.

Background Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Selegiline is an irreversible selective inhibitor of monoamine oxidase type B (MAO-B) which may affect cocaine addiction through several potential mechanisms. In this study, selegiline transdermal system (STS) was compared to placebo as a treatment for cocaine dependence. This multi-site, double-blind trial of 300 subjects with cocaine dependence assessed the efficacy of selegiline using subject self-reported cocaine use substantiated by urine benzoylecgonine (BE) as the primary outcome measure. Analysis of the data did not show a significant effect for selegiline over placebo. This study does not support a role for selegiline in treating cocaine dependence. The contrast of this result to earlier, promising preclinical and human pilot data could be due to factors associated with sample size, patient characteristics, dose, or poor predictive validity of preclinical models.

Background & Aims: Colchicine improved survival and reversed cirrhosis in several small clinical trials. We compared the efficacy and safety of long-term colchicine, as compared with placebo, in patients with advanced alcoholic cirrhosis. Methods: Five hundred forty-nine patients with advanced (Pugh B or C) alcoholic cirrhosis were randomized to receive either colchicine 0.6 mg twice per day (n = 274) or placebo (n = 275). Treatment lasted from 2 to 6 years. The primary outcome was all-cause mortality. Secondary outcomes were liver-related morbidity and mortality. Liver biopsy was requested prior to entry and after 24 months of treatment. Results: Attendance at scheduled clinic visits and adherence with study medication were similar in colchicine and placebo groups. Alcohol intake was less than 1 drink per day in 69% of patients. In an intention-to-treat analysis, all-cause mortality was similar in colchicine (49%) and placebo (45%) patients (P = .371). Mortality attributed to liver disease was 32% in colchicine and 28% in placebo patients (P = .337). Fewer patients receiving colchicine developed hepatorenal syndrome. In 54 patients with repeat liver biopsies after 24 or more months of treatment, cirrhosis improved to septal fibrosis in 7 patients (3 colchicine, 4 placebo) and to portal fibrosis in 1 patient (colchicine). Conclusions: In patients with advanced alcoholic cirrhosis, colchicine does not reduce overall or liver-specific mortality. Liver histology improves to septal fibrosis in a minority of patients after 24 months of treatment, with similar rates of improvement in patients receiving placebo and colchicine. Colchicine is not recommended for patients with advanced alcoholic cirrhosis.

Large simple trials (LSTs) emerged in response to the need for large sample sizes to answer important clinical questions in which treatments have a moderate effect on clinical endpoints. Between 1991 and 1996 the National Heart, Lung, and Blood Institute and the Department of Veterans Affairs (VA) Cooperative Studies Program conducted an LST entitled "Digitalis Investigation Group (DIG): Trial to Evaluate the Effect of Digitalis on Mortality in Heart Failure." The VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center served as the DIG pharmacy coordinating center (PCC). As a direct result of involvement in the DIG trial, the PCC identified the need for an increased emphasis on computerization and automated support of clinical trials, especially LSTs.

The ever-increasing concern for the welfare of volunteers participating in clinical trials and for the integrity of the data derived from those trials has generated the concept of Good Clinical Practice (GCP). The Veterans Affairs Cooperative Studies Program, in anticipation of the need to comply with GCP guidelines, developed a Site Monitoring and Review Team (SMART), which consists of a Good Clinical Practice Monitoring Group and a Good Clinical Practice Review Group. The review group conducted 335 site reviews from fiscal years (FY) 1999 through 2001 to assess and encourage adherence to GCP. Data from reviews were compared for two time periods, a 2-year implementation period (FYs 1999/2000, n=204) and a continuing follow-up period (FY 2001, n=131). Overall, high GCP adherence was exhibited by 11.3% (n=23) of study sites in FY 1999/2000 versus 20.6% (n=27) in FY 2001, average to good adherence was exhibited by 84.3% (n=172) in FY 1999/2000 versus 77.0% (n=101) in FY 2001, and below average adherence was exhibited by 4.4% (n=9) versus 1.5% (n=3) in these two periods. These changes were statistically significant by chi square analysis (p=0.029). Moreover, GCP adherence was assessed within eight GCP focus areas: patient informed consent, protocol adherence, safety monitoring, institutional review board interactions, regulatory document management, patient records in investigator file, drug/device accountability, and general site operations. Median assessment scores for all 62 GCP review elements improved from 0.82 to 0.89 (p

Consistent documentation, characterization, and evaluation of adverse events (AEs) are needed during multicenter clinical trials to ensure accuracy of data reported to the US Food and Drug Administration and in the medical literature.The purpose of this study was to identify and characterize variations in the assessment of AEs by clinical trial personnel.During the annual meeting of personnel from a multicenter, controlled clinical trial of an investigational new drug treatment for opioid dependence, an oral presentation of procedures for AE data collection was given to 25 principal investigators and ancillary study personnel who assessed AEs for the study. A post-test using 3 hypothetical AE cases in which AEs were categorized by type of reaction, relatedness to study drug, severity, action taken, and outcome was completed by study participants. Cases and expected responses were reviewed for content and validity by clinical research pharmacists who were not involved with the study. The level of agreement with expected responses was assessed using McNemar symmetry chi-square tests.Assessments of type of AE, relatedness to study drug, and severity were less frequently aligned with expected responses than were action taken and outcome (P0.013). Less consistency with expected responses was found in I case than in the other 2, suggesting that certain types of AEs may be more difficult to assess.There was considerable variability in categorization of AEs in an exercise following training for AE data collection. Type of report, relatedness, and severity were found to have more variability in reporting than did action taken or outcome. The results suggest that unless data are gathered to verify reliability of reporting, subcategorization of AE data should be undertaken cautiously. Further research is needed regarding methods for improving consistency in reporting of AEs.

We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. Results Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P = 0.47). There was no significant difference between the two groups in the duration of renalreplacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. Conclusions Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Background: An important issue in clinical practice is how to treat patients whose blood pressure does not respond to the first antihypertensive drug selected. Objective: To analyze the antihypertensive response of patients who had failed to achieve their diastolic blood pressure goal ( Methods: We initially randomized 1292 men with diastolic blood pressure of 95 to 109 mm Hg to treatment with hydrochlorothiazide, atenolol, captopril, clonidine hydrochloride, diltiazem hydrochloride (sustained release), prazosin hydrochloride, or placebo. Of 410 men in whom initial treatment failed, 352 qualified for randomization to the alternate drug. Results: Of the 352 patients, 173 (49.1%) achieved their goal diastolic blood pressure, in 133 (37.8%) the alternate drug failed, and 46 (13.1%) left the study for various reasons. Overall response rates were as follows: diltiazem, 63%; clonidine, 59%; prazosin, 47%; hydrochlorothiazide, 46%; atenolol, 41%; and captopril, 37%. The best response rate for patients in whom hydrochlorothiazide failed was achieved with diltiazem (70%); after atenolol failure, clonidine (86%); after captopril failure, prazosin (54%); after clonidine failure, diltiazem (100%); after diltiazem failure, captopril (67%); and after prazosin failure, clonidine (53%). The combined response rate for patients initially randomized to an active treatment was 76.0%, which is similar to that achieved by the combination of two drugs in previous studies. Conclusions: We conclude that sequential single-drug therapy is a rational approach for treatment of hypertension in patients in whom initial drug therapy has failed. (Arch Intern Med. 1995;155:1757-1762)

The Food, Drug, and Cosmetic Act requires that clinical investigations conducted in the United States involving unapproved drugs be done under an Investigational New Drug Application (IND). INDs are often sponsored by pharmaceutical firms or noncommercial research institutions. Most INDs, however, are sponsored by individual researchers. Since the procedures for filing an IND may not be well understood, this article seeks to clarify these procedures. Specifically, this article describes a "Sponsor-Investigator IND," the conditions under which one is required, and the possible advantages of filing one. The information presented aids the investigator in determining whether an IND need be submitted. The authors have developed an IND workbook that can be used to organize and present the IND application in a form likely to facilitate expeditious review and approval by the FDA. The authors have also developed IND guidelines to assist investigators in preparing, submitting, and maintaining an IND. Obligations and responsibilities of both sponsors and investigators are discussed.

We assessed the efficacy of lithium carbonate in the treatment of 457 male alcoholics in a double-blind, placebo-controlled Department of Veterans Affairs Cooperative Study. Alcoholics either without depression or with a history of major depression, current major depression, or dysthymic disorder were studied. Two hundred eighty-six alcoholics without depression and 171 alcoholics with depression began the 52-week outpatient study; 172 alcoholics (60.1%) without depression and 108 alcoholics (63.2%) with depression completed the study. Among both all alcoholics who began the study and a subgroup who completed the study, no significant differences between alcoholics who took lithium and those who took placebo were found for the following outcome measures: number of alcoholics abstinent, number of days of drinking, number of alcohol-related hospitalizations, changes in rating of severity of alcoholism, and change in severity of depression. Similarly, no significant differences were found when only the 82 alcoholics compliant in taking lithium and the 89 alcoholics compliant in taking placebo were considered. In our study, lithium treatment did not affect the course of alcoholism in either depressed or nondepressed alcoholics. ( JAMA . 1989;262:1646-1652)