Impact of Department of Veterans Affairs Cooperative Studies Program clinical trials on practice guidelines for high blood pressure management.

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 ±â€¯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.

Total integrated performance excellence system (TIPES): A true north direction for a clinical trial support center.

This paper presents the quality journey taken by a Federal organization over more than 20 years. These efforts have resulted in the implementation of a Total Integrated Performance Excellence System (TIPES) that combines key principles and practices of established quality systems. The Center has progressively integrated quality system frameworks including the Malcom Baldrige National Quality Award (MBNQA) Framework and Criteria for Performance Excellence, ISO 9001, and the Organizational Project Management Maturity Model (OPM3), as well as supplemental quality systems of ISO 15378 (packaging for medicinal products) and ISO 21500 (guide to project management) to systematically improve all areas of operations. These frameworks were selected for applicability to Center processes and systems, consistency and reinforcement of complimentary approaches, and international acceptance. External validations include the MBNQA, the highest quality award in the US, continued registration and conformance to ISO standards and guidelines, and multiple VA and state awards. With a focus on a holistic approach to quality involving processes, systems and personnel, this paper presents activities and lessons that were critical to building TIPES and establishing the quality environment for conducting clinical research in support of Veterans and national health care.

Angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers for end-stage renal disease/mortality in type 2 diabetes.

AIMS: To compare angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) for end-stage renal disease (ESRD) development and all-cause mortality in veterans with macroalbuminuria and with newly documented type 2 diabetes. METHODS: A retrospective cohort study utilizing data from the national Department of Veterans Affairs (VA) databases. The study followed 5166 subjects without a history of use of ACEIs or ARBs. To control for differences in baseline characteristics between groups, comparisons of subjects ACEIs and ARBs were made by incorporating propensity scores analysis into multivariate logistic regression. This resulted in adjusted odds ratios and 95% confidence intervals for ESRD development and all-cause mortality. RESULTS: The sample was followed up to five years with a mean follow-up of three years. Subjects taking ACEIs has lower odds of ESRD development (OR, 0.33 [95% CI, 0.13-0.82]) and all-cause mortality (OR, 0.10 [95% CI, 0.04-0.21]) than ARBs. CONCLUSIONS: This study shows that ACEIs are associated with lower ESRD development and all-cause mortality than ARBs. This may have implications for guidelines which currently suggest that these two therapeutic classes provide similar benefits in people with newly diagnosed type 2 diabetes and macroalbuminuria.

Health-related quality of life changes associated with buprenorphine treatment for opioid dependence.

BACKGROUND: Few studies have described improvement in health-related quality of life (HRQOL) associated with opioid dependence treatment with buprenorphine (ODT-B). OBJECTIVE: 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). METHODS: 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. RESULTS: 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, P<0.001). 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. CONCLUSION: Buprenorphine, accompanied with psychosocial counseling, was associated with improved HRQOL and HUs.

Pharmacy students' knowledge, attitudes, and evaluation of direct-to-consumer advertising.

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% +/- 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.

A comparison of veteran and nonveteran motivations and reasons for participating in clinical trials.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 (p < 0.001). CONCLUSIONS: Knowledge of the varying reasons for participation could potentially aid recruitment efforts.

GI risk factors and use of GI protective agents among patients receiving nonsteroidal antiinflammatory drugs.

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 19 122 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 < or = 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 < or = 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.

Assessment of the impact of a patient clinical trials handbook among pharmacy students.

BACKGROUND: Patient education in the basic concepts of clinical trials is necessary to promote understanding of the informed consent process and enhance patients' decision-making. It has been suggested that patients' knowledge and attitudes are improved by being given general written information about clinical trials. OBJECTIVE: This pilot study was conducted to determine the effect of a patient education handbook on the knowledge, attitudes, and motivations of pharmacy students regarding clinical trials. METHODS: A patient clinical trials handbook was developed at a 7th-grade reading level for the Department of Veterans Affairs Cooperative Studies Program and tested in PharmD students. Students were randomized to the experimental group (received handbook) or the control group (no handbook). They were given 15 to 20 minutes to read the handbook, after which they were asked to respond to a questionnaire adapted from previous studies. The questionnaire included 25 true/false questions testing participants' knowledge of clinical trials, 5 questions on attitudes toward clinical trials scored on a 5-point Likert scale, and 6 questions concerning their motivation toward participation in hypothetical clinical trial scenarios scored on a 5-point Likert scale. The experimental group was also asked to rate the informativeness, helpfulness, and clarity of the handbook on a 5-point Likert scale. RESULTS: There were 40 students in the experimental group and 50 in the control group. Knowledge scores were significantly higher in the experimental group compared with the control group (mean [SD] percentage of correct answers, 88.7% [8.0%] vs 82.6% [9.0%], respectively; P < 0.001). Positive attitudes toward clinical trials were also increased in the experimental group compared with the control group; specifically, participants expressed significantly greater clarity of understanding of clinical trials (mean score, 1.4 [0.5] vs 0.8 [0.6]; P < 0.001) and relief associated with knowing about clinical trials (mean score, 0.8 [0.8] vs 0.4 [0.7]; P = 0.017). There were no between-group differences in students' motivation to participate in the hypothetical clinical trial scenarios. A high proportion of students (95%) found the handbook informative, helpful, and understandable. CONCLUSIONS: The patient clinical trials handbook increased knowledge and positive attitudes regarding clinical trials among pharmacy students participating in this study.

Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival.

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.

Pharmacists' and technicians' perceptions and attitudes toward dispensing buprenorphine/ naloxone to patients with opioid dependence.

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 opioid-dependent 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.

The role of the pharmacy coordinating center in the DIG trial.

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.

Promoting good clinical practices in the conduct of clinical trials: experiences in the Department of Veterans Affairs Cooperative Studies Program.

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<0.001). Median assessment scores for the 14 selected critical GCP items improved from 0.78 to 0.89 (p<0.001). Median scores for five of the eight GCP focus areas improved significantly (p<0.001) between the two time periods. These data suggest that the site-oriented activities of SMART combined with centralized quality assurance activities of the coordinating centers represent an integrated, versatile program to promote and assure GCP adherence and data integrity in Cooperative Studies Program trials.

Opioid dependence treatment, including 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 alpha 2-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.