The Need for a Smoking Cessation "Care Package".

This Viewpoint from leadership at the US Food and Drug Administration (FDA) proposes the creation of a comprehensive "care package" framework of resources to help maximize cessation of tobacco use, including components focused on strategies at the individual, health system, and population levels.

Clinical Evidence Generation During a Pandemic: Lessons Learned for Sustaining Progress.

ABSTRACT: Because of significant adaptations forced by the COVID-19 pandemic, resultant changes within health care delivery and clinical research introduced the potential for evaluation of novel evidence generation approaches in oncology. On July 26 and 27, 2021, the National Academies of Science, Engineering, and Medicine, National Cancer Policy Forum hosted a virtual workshop entitled "Cancer Care and Cancer Research in the Context of the COVID-19 Pandemic: A Workshop on Lessons Learned." This workshop examined changes in cancer care and cancer research that occurred in response to the COVID-19 pandemic and considered lessons learned from that experience. The goal was to identify what changes could improve the delivery of high-quality cancer care and the conduct of cancer clinical trials in the postpandemic era, with an emphasis on health equity. How can we sustain the valuable lessons learned that might accelerate progress and enhance clinical evidence generation for patients and clinicians? In this overview, we discuss ways in which the COVID-19 experience has catalyzed research efficiencies as well as fostered a broader array of trial design and research methods that may facilitate improved cancer drug development during the pandemic and beyond.

Importance of Social Determinants in Screening for Depression.

IMPORTANCE: The most common screening tool for depression is the Patient Health Questionnaire-9 (PHQ-9). Despite extensive research on the clinical and behavioral implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and social determinants of health and disease. OBJECTIVE: To assess the relationship between the PHQ-9 at intake and other measurements intended to assess social determinants of health. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of 2502 participants from the Baseline Health Study (BHS), a prospective cohort of adults selected to represent major demographic groups in the US; participants underwent deep phenotyping on demographic, socioeconomic, clinical, laboratory, functional, and imaging findings. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Cross-sectional measures of clinical and socioeconomic status (SES). RESULTS: In addition to a host of clinical and biological factors, higher PHQ-9 scores were associated with female sex, younger participants, people of color, and Hispanic ethnicity. Multiple measures of low SES, including less education, being unmarried, not currently working, and lack of insurance, were also associated with higher PHQ-9 scores across the entire spectrum of PHQ-9 scores. A summative score of SES, which was the 6th most predictive factor, was associated with higher PHQ-9 score after adjusting for 150 clinical, lab testing, and symptomatic characteristics. CONCLUSIONS AND RELEVANCE: Our findings underscore that depression should be considered a comorbidity when social determinants of health are addressed, and both elements should be considered when designing appropriate interventions.

Development and Validation of a Natural Language Processing Tool to Generate the CONSORT Reporting Checklist for Randomized Clinical Trials.

Importance: Adherence to the Consolidated Standards of Reporting Trials (CONSORT) for randomized clinical trials is associated with improvingquality because inadequate reporting in randomized clinical trials may complicate the interpretation and the application of findings to clinical care. Objective: To evaluate an automated reporting checklist generation tool that uses natural language processing (NLP), called CONSORT-NLP. Design, Setting, and Participants: This study used published journal articles as training, testing, and validation sets to develop, refine, and evaluate the CONSORT-NLP tool. Articles reporting randomized clinical trials were selected from 25 high-impact-factor journals under the following categories: (1) general and internal medicine, (2) oncology, and (3) cardiac and cardiovascular systems. Main Outcomes and Measures: For an evaluation of the performance of this tool, an accuracy metric defined as the number of correct assessments divided by all assessments was calculated. Results: The CONSORT-NLP tool uses the widely used Portable Document Format as an input file. Of the 37 CONSORT reporting items, 34 (92%) were included in the tool. Of these 34 reporting items, 30 were fully implemented; 28 (93%) of the fully implemented CONSORT reporting items had an accuracy of more than 90% for the validation set. The remaining 2 (7%) had an accuracy between 80% and 90% for the validation set. Two to 5 articles were selected from each of these journals for a total of 158 articles to establish a training set of 111 articles to train CONSORT-NLP for CONSORT reporting items, a testing set of 25 articles to refine CONSORT-NLP, and a validation set of 22 articles to assess the performance of CONSORT-NLP. The CONSORT-NLP tool used the Portable Document Format of the articles as input files. A CONSORT-NLP graphical user interface was built using Java in 2019. The time required to complete the CONSORT checklist manually vs using the CONSORT-NLP tool was compared for 30 articles. Two case studies for randomized clinical trials are provided as an illustration for the CONSORT-NLP tool. For the 30 articles investigated, CONSORT-NLP required a mean (SD) 23.0 (4.1) seconds, whereas the manual reviewer required a mean (SD) 11.9 (2.2), 22.6 (4.6), and 57.6 (7.1) minutes, for 3 reviewers, respectively. Conclusions and Relevance: The CONSORT-NLP tool is designed to assist in the reporting of randomized clinical trials. Potential users of CONSORT-NLP include clinicians, researchers, and scientists who plan to publish a randomized trial study in a peer-reviewed journal. The use of CONSORT-NLP may help them save substantial time when generating the CONSORT checklist. This tool may also be useful for manuscript reviewers and journal editors who review these articles.

Benchmarking the Cost-Effectiveness of Interventions Delaying Diabetes: A Simulation Study Based on NAVIGATOR Data.

OBJECTIVE: To estimate using the UK Prospective Diabetes Study Outcomes Model Version 2 (UKPDS-OM2) the impact of delaying type 2 diabetes onset on costs and quality-adjusted life expectancy using trial participants who developed diabetes in the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research) study. RESEARCH DESIGN AND METHODS: We simulated the impact of delaying diabetes onset by 1-9 years, utilizing data from the 3,058 of 9,306 NAVIGATOR trial participants who developed type 2 diabetes. Costs and utility weights associated with diabetes and diabetes-related complications were obtained for the U.S. and U.K. settings, with costs expressed in 2017 values. We estimated discounted lifetime costs and quality-adjusted life years (QALYs) with 95% CIs. RESULTS: Gains in QALYs increased from 0.02 (U.S. setting, 95% CI 0.01, 0.03) to 0.15 (U.S. setting, 95% CI 0.10, 0.21) as the imposed time to diabetes onset was increased from 1 to 9 years, respectively. Savings in complication costs increased from $1,388 (95% CI $1,092, $1,669) for a 1-year delay to $8,437 (95% CI $6,611, $10,197) for a delay of 9 years. Interventions costing up to $567-$2,680 and £201-£947 per year would be cost-effective at $100,000 per QALY and £20,000 per QALY thresholds in the U.S. and U.K., respectively, as the modeled delay in diabetes onset was increased from 1 to 9 years. CONCLUSIONS: Simulating a hypothetical diabetes-delaying intervention provides guidance concerning the maximum cost and minimum delay in diabetes onset needed to be cost-effective. These results can inform the ongoing debate about diabetes prevention strategies and the design of future intervention studies.

Levels of evidence supporting drug, device, and other recommendations in the American Heart Association/American College of Cardiology guidelines.

Clinical guideline documents reflect the evidence supporting clinical practice, but few recommendations in cardiovascular guidelines are supported by evidence from randomized controlled trials (RCTs), the highest level of evidence. Incentives for generating evidence from RCTs differ by topic of guideline recommendation, and it is uncertain whether evidence supporting guideline recommendations differs based on the topic of the recommendation. METHODS: We abstracted recommendation statements from current ACC/AHA guideline documents (2008-2019). Two reviewers independently characterized each statement into categories based on its primary topic: pharmaceutical, device, non-invasive or minimally invasive therapeutic procedure, surgery, diagnostic invasive procedure or non-invasive imaging, laboratory, care strategies, health services or policy, history/physical examination, lifestyle or counseling. We determined the number and proportion of recommendations in each category characterized as level of evidence (LOE) A (supported by multiple RCTs), B (supported by a single RCT or observational data), and C (supported by expert opinion or limited data). RESULTS: Of 2934 recommendations from 29 clinical guideline documents, 784 (26.7%) were primarily about pharmaceuticals, 503 (17.1%) diagnostic invasive procedure or non-invasive imaging, 366 (12.5%) devices, 349 (11.9%) care strategies, 274 (9.3%) surgery, 216 (7.4%) therapeutic procedures, 162 (5.5%) lifestyle interventions or counseling, 160 (5.5%) health services, care delivery, or policy, 83 (2.8%) laboratory, and 37 (1.3%) elements of the history and physical. Across all recommendations, 257 (8.8%) were characterized as LOE A, with considerable variability by topic. 25.9% of lifestyle/counseling recommendations, 16.9% of lab recommendations, and 14.7% of drug recommendations were classified as LOE A, but <8% of recommendations in all other categories, including 5.5% of device recommendations, 6.0% of therapeutic procedure recommendations, 2.6% of surgery recommendations, and 5.0% of health services or policy recommendations. CONCLUSION: Less than 10% of current ACC/AHA guideline recommendations are supported by high quality evidence from RCTs, with substantial variability by topic and multiple areas with very few recommendations supported by high-quality evidence. Development and implementation of inexpensive methods for generating a higher volume of RCT evidence to support clinical practice are needed, especially in areas where there are not strong incentives to conduct RCTs.

Claims-based cardiovascular outcome identification for clinical research: Results from 7 large randomized cardiovascular clinical trials.

BACKGROUND: Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes. METHODS: We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection. RESULTS: Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest. CONCLUSIONS: Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

Assessing heterogeneity of treatment effect analyses in health-related cluster randomized trials: A systematic review.

BACKGROUND: Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment effect (HTE) for individually randomized trials. Little is known about how frequent demographics are reported and HTE analyses are conducted in CRTs. OBJECTIVES: We sought to understand the prevalence of HTE analyses and the statistical methods used to conduct them in CRTs focused on treating cardiovascular disease, cancer, and chronic lower respiratory diseases. Additionally, we also report on the proportion of CRTs that reported on baseline demographics of its populations and conducted demographic HTE analyses. DATA SOURCES: We searched PubMed and Embase for CRTs published between 1/1/2010 and 3/29/2016 that focused on treating the top 3 Center for Disease Control causes of death (cardiovascular disease, chronic lower respiratory disease, and cancer). Evidence Screening And Review: Of 1,682 unique titles, 117 abstracts were screened. After excluding 53 articles, we included 64 CRT publications and abstracted information on study characteristics and demographic information, statistical analysis, HTE analysis, and study quality. RESULTS: Age and sex were reported in greater than 95.3% of CRTs, while race and ethnicity were reported in only 20.3% of CRTs. HTE analyses were conducted in 28.1% (n = 18) of included CRTs and 77.8% (n = 12) were prespecified analyses. Four CRTs conducted a demographic subgroup analysis. Only 6/18 CRTs used interaction testing to determine whether HTE existed. CONCLUSIONS: Baseline demographic reporting was high for age and sex in CRTs, but was uncommon for race and ethnicity. HTE analyses were uncommon and was rare for demographic subgroups, which limits the ability to examine the extent of benefits or risks for treatments tested with CRT designs.

Medication Discontinuation in the IMPROVE-IT Trial.

BACKGROUND: Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials. METHODS AND RESULTS: We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8-85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%-51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2-8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P=0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates. CONCLUSIONS: Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

Improving Medication Adherence in Cardiometabolic Disease: Practical and Regulatory Implications.

Medication nonadherence, a major problem in cardiovascular disease (CVD), contributes yearly to approximately 125,000 preventable deaths, which is partly attributable to only about one-half of CVD patients consistently taking prescribed life-saving medications. Current interest has focused on how labeling and education influence adherence. This paper summarizes the scope of CVD nonadherence, describes key U.S. Food and Drug Administration initiatives, and identifies potential targets for improvement. We describe key adherence factors, methods, and technological applications for simplifying regimens and enhancing adherence, and 4 areas where additional collaborative research and implementation involving the regulatory system and clinical community could substantially reduce nonadherence: 1) identifying monitoring methods; 2) improving the evidence base to better understand adherence; 3) developing patient/health provider team-based engagement strategies; and 4) alleviating health disparities. Alignment of U.S. Food and Drug Administration approaches to dissemination of information about appropriate use with clinical practice could improve adherence, and thereby reduce CVD death and disability.

Prospective relationships between body weight and physical activity: an observational analysis from the NAVIGATOR study.

OBJECTIVES: While bidirectional relationships exist between body weight and physical activity, direction of causality remains uncertain and previous studies have been limited by self-reported activity or weight and small sample size. We investigated the prospective relationships between weight and physical activity. DESIGN: Observational analysis of data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, a double-blinded randomised clinical trial of nateglinide and valsartan, respectively. SETTING: Multinational study of 9306 participants. PARTICIPANTS: Participants with biochemically confirmed impaired glucose tolerance had annual measurements of both weight and step count using research grade pedometers, worn for 7 days consecutively. Along with randomisation to valsartan or placebo plus nateglinide or placebo, participants took part in a lifestyle modification programme. OUTCOME MEASURES: Longitudinal regression using weight as response value and physical activity as predictor value was conducted, adjusted for baseline covariates. Analysis was then repeated with physical activity as response value and weight as predictor value. Only participants with a response value preceded by at least three annual response values were included. RESULTS: Adequate data were available for 2811 (30%) of NAVIGATOR participants. Previous weight (χ(2)=16.8; p<0.0001), but not change in weight (χ(2)=0.1; p=0.71) was inversely associated with subsequent step count, indicating lower subsequent levels of physical activity in heavier individuals. Change in step count (χ(2)=5.9; p=0.02) but not previous step count (χ(2)=0.9; p=0.34) was inversely associated with subsequent weight. However, in the context of trajectories already established for weight (χ(2) for previous weight measurements 747.3; p<0.0001) and physical activity (χ(2) for previous step count 432.6; p<0.0001), these effects were of limited clinical importance. CONCLUSIONS: While a prospective bidirectional relationship was observed between weight and physical activity, the magnitude of any effect was very small in the context of natural trajectories already established for these variables. TRIAL REGISTRATION NUMBER: NCT00097786.

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).

Comparative assessment of short-term adverse events in acute heart failure with cystatin C and other estimates of renal function: results from the ASCEND-HF trial.

OBJECTIVES: The purpose of this study was to investigate the predictive values of baseline and changes in cystatin C (CysC) and its derived equations for short-term adverse outcomes and the effect of nesiritide therapy on CysC in acute decompensated heart failure (ADHF). BACKGROUND: Newer renal biomarkers or their derived estimates of renal function have demonstrated long-term prognostic value in chronic heart failure. METHODS: CysC levels were measured in sequential plasma samples from 811 subjects with ADHF who were enrolled in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) biomarker sub-study (randomized to nesiritide therapy vs. placebo), and followed for all-cause death (180 days) and recurrent hospital stay (30 days). RESULTS: Median CysC levels were 1.49 (interquartile range [IQR]: 1.20 to 1.96) mg/l at baseline, 1.56 (IQR: 1.28 to 2.13) mg/l at 48 to 72 h, and 1.58 (IQR: 1.24 to 2.11) mg/l at 30 days. Higher baseline (but not follow-up) CysC levels were associated with increased risk of 30-day adverse events and less improvement in dyspnea after 24 h as well as 180-day mortality, although not incremental to blood urea nitrogen. Worsening renal function (defined as a 0.3 mg/l increase in CysC) occurred in 161 of 701 (23%) patients, but it was not predictive of adverse events. Changes in CysC levels were similar between the nesiritide and placebo groups. CONCLUSIONS: Our findings confirmed the prognostic value of baseline CysC levels in the setting of ADHF. However, worsening renal function based on CysC rise was not predictive of adverse events. Nesiritide did not worsen renal function compared with placebo.

Long-term clinical and angiographic outcomes in patients with diabetes undergoing coronary artery bypass graft surgery: results from the Project of Ex-vivo Vein Graft Engineering via Transfection IV trial.

BACKGROUND: There is limited information about the association between diabetes, its treatment, and long-term angiographic and clinical outcomes in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the association of diabetes and its treatment with 1-year angiographic graft failure and 5-year clinical outcomes in patients undergoing CABG. METHODS: Using data from 3,014 patients in PREVENT IV, we analyzed angiographic and clinical outcomes in patients with and without diabetes and among those who did and did not receive insulin before CABG. Logistic regression and Cox proportional hazards models were used to adjust for differences in baseline variables. RESULTS: Overall, 1,139 (37.8%) patients had diabetes. Of these, 305 (26.8%) received insulin. One-year rates of vein graft failure were similar in patients with and without diabetes but, among diabetics, tended to be higher in patients who received insulin compared with those who did not. At 5 years, rates of death, myocardial infarction, or revascularization were higher among patients with compared with those without diabetes (adjusted hazard ratio 1.57; 95% CI 1.26-1.96; P < .001) and, among diabetics, higher among those who received insulin (adjusted hazard ratio 1.15; 95% CI 1.02-1.30; P = .02). CONCLUSIONS: Patients with diabetes had similar rates of vein graft failure but worse clinical outcomes than patients without diabetes. Patients who received insulin had significantly worse clinical outcomes than patients who did not receive insulin. Further studies to better understand the mechanism behind these findings and to improve the outcomes of patients with insulin-requiring diabetes undergoing CABG surgery are warranted.

Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV.

BACKGROUND: Coronary artery bypass grafting success is limited by vein graft failure (VGF). Understanding the factors associated with VGF may improve patient outcomes. METHODS AND RESULTS: We examined 1828 participants in the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial undergoing protocol-mandated follow-up angiography 12 to 18 months post-coronary artery bypass grafting or earlier clinically driven angiography. Outcomes included patient- and graft-level angiographic VGF (≥75% stenosis or occlusion). Variables were selected by using Fast False Selection Rate methodology. We examined relationships between variables and VGF in patient- and graft-level models by using logistic regression without and with generalized estimating equations. At 12 to 18 months post-coronary artery bypass grafting, 782 of 1828 (42.8%) patients had VGF, and 1096 of 4343 (25.2%) vein grafts had failed. Demographic and clinical characteristics were similar between patients with and without VGF, although VGF patients had longer surgical times, worse target artery quality, longer graft length, and they more frequently underwent endoscopic vein harvesting. After multivariable adjustment, longer surgical duration (odds ratio per 10-minute increase, 1.05; 95% confidence interval, 1.03-1.07), endoscopic vein harvesting (odds ratio, 1.41; 95% confidence interval, 1.16-1.71), poor target artery quality (odds ratio, 1.43; 95% confidence interval, 1.11-1.84), and postoperative use of clopidogrel or ticlopidine (odds ratio, 1.35; 95% confidence interval, 1.07-1.69) were associated with patient-level VGF. The predicted likelihood of VGF in the graft-level model ranged from 12.1% to 63.6%. CONCLUSIONS: VGF is common and associated with patient and surgical factors. These findings may help identify patients with risk factors for VGF and inform the development of interventions to reduce VGF. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00042081.

Vein graft preservation solutions, patency, and outcomes after coronary artery bypass graft surgery: follow-up from the PREVENT IV randomized clinical trial.

IMPORTANCE: In vitro and animal model data suggest that intraoperative preservation solutions may influence endothelial function and vein graft failure (VGF) after coronary artery bypass graft (CABG) surgery. Clinical studies to validate these findings are lacking. OBJECTIVE: To evaluate the effect of vein graft preservation solutions on VGF and clinical outcomes in patients undergoing CABG surgery. DESIGN, SETTING, AND PARTICIPANTS: Data from the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 3014 patients at 107 US sites from August 1, 2002, through October 22, 2003, were used. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 planned vein grafts. INTERVENTIONS: Preservation of vein grafts in saline, blood, or buffered saline solutions. MAIN OUTCOMES AND MEASURES: One-year angiographic VGF and 5-year rates of death, myocardial infarction, and subsequent revascularization. RESULTS: Most patients had grafts preserved in saline (1339 [44.4%]), followed by blood (971 [32.2%]) and buffered saline (507 [16.8%]). Baseline characteristics were similar among groups. One-year VGF rates were much lower in the buffered saline group than in the saline group (patient-level odds ratio [OR], 0.59 [95% CI, 0.45-0.78; P < .001]; graft-level OR, 0.63 [95% CI, 0.49-0.79; P < .001]) or the blood group (patient-level OR, 0.62 [95% CI, 0.46-0.83; P = .001]; graft-level OR, 0.63 [95% CI, 0.48-0.81; P < .001]). Use of buffered saline solution also tended to be associated with a lower 5-year risk for death, myocardial infarction, or subsequent revascularization compared with saline (hazard ratio, 0.81 [95% CI, 0.64-1.02; P = .08]) and blood (0.81 [0.63-1.03; P = .09]) solutions. CONCLUSIONS AND RELEVANCE: Patients undergoing CABG whose vein grafts were preserved in a buffered saline solution had lower VGF rates and trends toward better long-term clinical outcomes compared with patients whose grafts were preserved in saline- or blood-based solutions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00042081.

Characteristics of pediatric cardiovascular clinical trials registered on ClinicalTrials.gov.

BACKGROUND: ClinicalTrials.gov is an National Institutes of Health-sponsored registry of federally and privately funded trials. We sought to determine fundamental characteristics of registered pediatric cardiovascular trials (PCVTs). METHODS: A data set including 68,134 interventional clinical trials was downloaded from ClinicalTrials.gov and entered into a relational database. Aggregate data from PCVTs were compared with other trial specialties. Multivariable logistic regression was used to evaluate factors associated with improved trial quality metrics including blinding and randomization. RESULTS: Between July 1, 2005, and September 27, 2010, 5035 (7%) registered trials targeted pediatric populations, including 213 PCVTs (4.2%), 1,176 pediatric infectious disease trials (23%), 664 pediatric mental health trials (13%), and 346 pediatric hematology/oncology trials (7%). Median (interquartile range) PCVT enrollment was 65 subjects (36-186) and median study duration was 2.3 years (1.3-3.7). The most common PCVTs targeted acquired diseases including hypertension (n = 41, 14%), obesity (n = 26, 9%), pulmonary hypertension (n = 25, 9%), and dyslipidemia (n = 19, 7%). Important factors associated with improved quality metrics included National Institutes of Health as opposed to industry funding (OR, 1.9; P < .0001); trial location (trials with both US and foreign enrollment vs trials with US only or foreign only enrollment, P = .02) and trials restricted to younger children as opposed to trials including adolescents (OR, 1.4; P < .0001). CONCLUSION: PCVTs represent a small proportion of clinical trials relative to other pediatric subspecialties. Most PCVTs tend to parallel adult morbidities while there is a relative paucity of trials focused on congenital heart disease. These data may be useful to stakeholders in informing decisions regarding the conduct of PCVTs, and to provide insight into mechanisms to advance PCVT infrastructure.