The Pulmonary Fibrosis Foundation Patient Registry. Rationale, Design, and Methods.

Detailed understanding of longitudinal behavior, response to therapy, and applicable biomarkers for interstitial lung diseases (ILDs) is lacking. There is a need for a large multicenter registry that provides researchers and clinicians access to well-characterized data not limited to patients with idiopathic pulmonary fibrosis. The Pulmonary Fibrosis Foundation Patient Registry (PFF-PR) is a database that collects baseline and longitudinal demographic and clinical information about patients with ILDs in the United States. The objective of this study is to describe the patient population, data collection process, and opportunities for retrospective and prospective research with the PFF-PR. Individuals 18 years or older who had ILD diagnosed and who were seen at PFF-PR centers who provided informed consent were eligible to participate. Baseline and longitudinal demographic, spirometric, radiographic, morbidity, and mortality data are recorded into a secure electronic data capture system. Starting in 2016, the PFF-PR has collected data on 2,003 patients at 42 clinical sites in the United States. At the time of enrollment, the mean age of participants was 68 years old. Most (62%) of participants were male, and 58% had a positive smoking history. The mean forced vital capacity was 69% predicted, and the mean diffusing capacity of the lung for carbon monoxide was 43% predicted. Forty-one percent of patients were using supplemental oxygen, and 39% were on antifibrotic therapy. Reasons for attrition were mostly death or transplant, with low rates of loss to follow-up or withdrawal. The PFF-PR is a large multicenter United States-based registry that provides researchers and clinicians access to well-characterized ILD patient data.

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial.

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120.

Randomized Trial of Population-Based Clinical Decision Support to Facilitate Care Transitions.

Medicaid beneficiaries in 6 North Carolina counties were randomly assigned to 1 of 3 clinical decision support (CDS) care transition strategies: (1) usual care (Control), (2) CDS messaging to patients and their medical homes (Reports), or (3) CDS messaging to patients, their medical homes, and their care managers (Reports+). We included 7146 Medicaid patients and evaluated transitions from specialist visit, ER and hospital encounters back to the patient's medical home. Patients enrolled in Medicare and Medicaid were not eligible. The number of care manager contacts was greater for patients in the Reports+ Group than in the Control Group. However, there were no treatment-related differences in emergency department (ED) encounter rates, or in the secondary outcomes of outpatient and hospital encounter rates and medical costs. Study monitors found study intervention documentation in approximately 60% of patient charts. These results highlight the importance of effectively integrating information interventions into healthcare delivery workflow systems.

Survival benefit of the primary prevention implantable cardioverter-defibrillator among older patients: does age matter? An analysis of pooled data from 5 clinical trials.

BACKGROUND: The impact of patient age on the risks of death or rehospitalization after primary prevention implantable cardioverter-defibrillator (ICD) placement is uncertain. METHODS AND RESULTS: Data from 5 major ICD trials were merged: the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), the Multicenter UnSustained Tachycardia Trial (MUSTT), the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE), and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Median age at enrollment was 62 (interquartile range 53-70) years. Compared with their younger counterparts, older patients had a greater burden of comorbid illness. In unadjusted exploratory analyses, ICD recipients were less likely to die than nonrecipients in all age groups: among patients aged <55 years: hazard ratio 0.48, 95% posterior credible interval 0.33 to 0.69; among patients aged 55 to 64 years: hazard ratio 0.69, 95% posterior credible interval 0.53 to 0.90; among patients aged 65 to 74 years: hazard ratio 0.67, 95% posterior credible interval, 0.53 to 0.85; and among patients aged ≥75 years: hazard ratio 0.54, 95% posterior credible interval 0.37 to 0.78. Sample sizes were limited among patients aged ≥75 years. In adjusted Bayesian-Weibull modeling, point estimates indicate ICD efficacy persists but is attenuated with increasing age. There was evidence of an interaction between age and ICD treatment on survival (two-sided posterior tail probability of no interaction <0.01). Using an adjusted Bayesian logistic regression model, there was no evidence of an interaction between age and ICD treatment on rehospitalization (two-sided posterior tail probability of no interaction 0.44). CONCLUSIONS: In this analysis, the survival benefit of the ICD exists but is attenuated with increasing age. The latter finding may be because of the higher burden of comorbid illness, competing causes of death, or limited sample size of older patients. There was no evidence that age modifies the association between ICD treatment and rehospitalization.

Outcomes of implantable cardioverter-defibrillator use in patients with comorbidities: results from a combined analysis of 4 randomized clinical trials.

OBJECTIVES: The aim of this study was to determine if the benefit of implantable cardioverter-defibrillators (ICDs) is modulated by medical comorbidity. BACKGROUND: Primary prevention ICDs improve survival in patients at risk for sudden cardiac death. Their benefit in patients with significant comorbid illness has not been demonstrated. METHODS: Original, patient-level datasets from MADIT I (Multicenter Automatic Defibrillator Implantation Trial I), MADIT II, DEFINITE (Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation), and SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) were combined. Patients in the combined population (N = 3,348) were assessed with respect to the following comorbidities: smoking, pulmonary disease, diabetes, peripheral vascular disease, atrial fibrillation, ischemic heart disease, and chronic kidney disease. The primary outcome was overall mortality, using the hazard ratio (HR) of time to death for patients receiving an ICD versus no ICD by extent of medical comorbidity, and adjusted for age, sex, race, left ventricular ejection fraction, use of antiarrhythmic drugs, beta-blockers, and angiotensin-converting enzyme inhibitors. RESULTS: Overall, 25% of patients (n = 830) had <2 comorbid conditions versus 75% (n = 2,518) with significant comorbidity (≥2). The unadjusted hazard of death for patients with an ICD versus no ICD was significantly lower, but this effect was less for patients with ≥2 comorbidities (unadjusted HR: 0.71; 95% confidence interval: 0.61 to 0.84) compared with those with <2 comorbidities (unadjusted HR: 0.59; 95% confidence interval: 0.40 to 0.87). After adjustment, the benefit of an ICD decreased with increasing number of comorbidities (p = 0.004). CONCLUSIONS: Patients with extensive comorbid medical illnesses may experience less benefit from primary prevention ICDs than those with less comorbidity; implantation should be carefully considered in sick patients. Further study of ICDs in medically complex patients is warranted.

Reduced length of hospital stay in colorectal surgery after implementation of an enhanced recovery protocol.

BACKGROUND: Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital. METHODS: Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates. RESULTS: There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02). DISCUSSION: Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals.

Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in CKD: a meta-analysis of patient-level data from 3 randomized trials.

BACKGROUND: The benefit of a primary prevention implantable cardioverter-defibrillator (ICD) among patients with chronic kidney disease is uncertain. STUDY DESIGN: Meta-analysis of patient-level data from randomized controlled trials. SETTING & POPULATION: Patients with symptomatic heart failure and left ventricular ejection fraction<35%. SELECTION CRITERIA FOR STUDIES: From 7 available randomized controlled studies with patient-level data, we selected studies with available data for important covariates. Studies without patient-level data for baseline estimated glomerular filtration rate (eGFR) were excluded. INTERVENTION: Primary prevention ICD versus usual care effect modification by eGFR. OUTCOMES: Mortality, rehospitalizations, and effect modification by eGFR. RESULTS: We included data from the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), MADIT-II, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). 2,867 patients were included; 36.3% had eGFR<60 mL/min/1.73m2. Kaplan-Meier estimate of the probability of death during follow-up was 43.3% for 1,334 patients receiving usual care and 35.8% for 1,533 ICD recipients. After adjustment for baseline differences, there was evidence that the survival benefit of ICDs in comparison to usual care depends on eGFR (posterior probability for null interaction P<0.001). The ICD was associated with survival benefit for patients with eGFR≥60 mL/min/1.73 m2 (adjusted HR, 0.49; 95% posterior credible interval, 0.24-0.95), but not for patients with eGFR<60 mL/min/1.73 m2 (adjusted HR, 0.80; 95% posterior credible interval, 0.40-1.53). eGFR did not modify the association between the ICD and rehospitalizations. LIMITATIONS: Few patients with eGFR<30 mL/min/1.73 m2 were available. Differences in trial-to-trial measurement techniques may lead to residual confounding. CONCLUSIONS: Reductions in baseline eGFR decrease the survival benefit associated with the ICD. These findings should be confirmed by additional studies specifically targeting patients with varying eGFRs.

Economic analysis of endovascular repair versus surveillance for patients with small abdominal aortic aneurysms.

BACKGROUND: The Positive Impact of EndoVascular Options for Treating Aneurysms Early (PIVOTAL) trial enrolled individuals with small (4.0- to 5.0-cm diameter) abdominal aortic aneurysms (AAA) and reported no difference in rupture or aneurysm-related death for patients who received early endovascular repair (EVAR) vs surveillance with serial imaging studies. We evaluated resource use, medical cost, and quality of life outcomes associated with the PIVOTAL treatment strategies. METHODS: This prospective economic and quality of life study was conducted within a randomized trial, with PIVOTAL sites participating in the quality of life (n = 67) and economic (n = 63) studies. The PIVOTAL trial randomized 728 patients (366 early EVAR and 362 surveillance). We used information from 701 quality of life (351 early EVAR and 350 surveillance) and 614 economic (314 early EVAR and 300 surveillance) study participants enrolled in the PIVOTAL trial. The main outcome measures were total medical costs and the aneurysm repair rate at 48 months. RESULTS: After 6 months, the rate of aneurysm repair was 96 vs 10 per 100 patients in the early EVAR and surveillance groups, respectively (difference, 86; 95% confidence interval [CI], 82-90; P < .0001), and total medical costs were greater in the early EVAR group ($33,471 vs $5520; difference, $27,951; 95% CI, $25,156-$30,746; P < .0001). In months 7 through 48, however, the rate of aneurysm repair was 54 per 100 patients in the surveillance group, and total medical costs were higher for patients in the surveillance vs the early EVAR group ($40,592 vs $15,197; difference, $25,394; 95% CI, $15,184-$35,605; P < .0001). At 48 months' follow-up, early EVAR patients had greater cumulative use of AAA repair (97 vs 64 per 100 patients; difference, 34; 95% CI, 21-46; P < .0001), but there was no difference in total medical costs ($48,669 vs $46,112; difference, $2557; 95% CI, -$8043 to $13,156; P = .64). After discounting at 3% per annum, total medical costs for early EVAR and surveillance patients remained similar ($47,765 vs $43,532; difference, 4232; 95% CI, -$5561 to $14,025; P = .40). There were no treatment-related differences in quality of life at 24 months. CONCLUSIONS: A treatment strategy involving early repair of smaller AAA with EVAR is associated with no difference in total medical costs at 48 months vs surveillance with serial imaging studies. Longer follow-up is required to determine whether the late medical cost increases observed for surveillance will persist beyond 48 months.

Decision support for evidence-based pharmacotherapy detects adherence problems but does not impact medication use.

Although evidence-based pharmacotherapies are a principal component of patient care, 30-50% of patients do not take their medications as prescribed. We conducted a randomized trial of two clinical decision support (CDS) interventions in 2219 patients: patient adherence reports to providers (n=744), patient adherence reports to providers + email notices to care managers (n=736), and controls (739). At 18-month follow-up, there were no treatment-related differences in patient medication adherence (overall, by medication class, and by medical condition). There also were no treatment-related differences in patient clinical and economic outcomes. Thus, while this study's CDS information interventions were successfully delivered to providers and care managers, and were effective in identifying medication adherence deficits and in increasing care manager responses to medication adherences issues, these interventions were not able to alter patient medication behavior.

Survival benefit of primary prevention implantable cardioverter-defibrillator therapy after myocardial infarction: does time to implant matter? A meta-analysis using patient-level data from 4 clinical trials.

BACKGROUND: Whether there is an optimal time to place an implantable cardioverter-defibrillator (ICD) more than 40 days after myocardial infarction (MI) in guideline-eligible patients is unknown. OBJECTIVE: To evaluate the effect of time from MI to randomization on mortality, rehospitalizations, and complications. METHODS: Individual data on patients enrolled in 9 primary prevention ICD trials were provided. Clinical trials were eligible for the current analysis if they enrolled patients with an MI more than 40 days prior to randomization to primary prevention ICD therapy vs usual care: Multicenter Automatic Defibrillator Implantation Trial I, Multicenter UnSustained Tachyardia Trial, Multicenter Automatic Defibrillator Implantation Trial II, and Sudden Cardiac Death in Heart Failure Trial. RESULTS: ICD recipients died less frequently than nonrecipients at 5 years across all subgroups of time from MI to randomization. In unadjusted Cox proportional hazards regression, a survival benefit was evident in most subgroups. Adjusted Bayesian Weibull survival modeling yielded hazard ratio (HR) 0.50, 95% posterior credible interval (PCI) 0.20-1.25 41-180 days after MI; HR 0.98, 95% PCI 0.37-2.37 181-365 days after MI; HR 0.22, 95% PCI 0.07-0.59>1-2 years after MI; HR 0.42, 95% PCI 0.17-0.90>2-5 years after MI; HR 0.55, 95% PCI 0.25-1.15>5-10 years after MI; and HR 0.48, 95% PCI 0.20-1.02>10 years after MI. There was no evidence of an interaction between time from MI and all-cause mortality, rehospitalizations, or complications. CONCLUSIONS: In this meta-analysis, there was scant evidence that the efficacy of primary prevention ICD therapy depends on time to implantation more than 40 days after MI. Similarly, there was no evidence that the risks of rehospitalizations or complications depend on time more than 40 days after MI.

A randomized trial of population-based clinical decision support to manage health and resource use for Medicaid beneficiaries.

To determine whether a clinical decision support system can favorably impact the delivery of emergency department and hospital services. Randomized clinical trial of three clinical decision support delivery modalities: email messages to care managers (email), printed reports to clinic administrators (report) and letters to patients (letter) conducted among 20,180 Medicaid beneficiaries in Durham County, North Carolina with follow-up through 9 months. Patients in the email group had fewer low-severity emergency department encounters vs. controls (8.1 vs. 10.6/100 enrollees, p < 0.001) with no increase in outpatient encounters or medical costs. Patients in the letter group had more outpatient encounters and greater outpatient and total medical costs. There were no treatment-related differences for patients in the reports group. Among patients <18 years, those in the email group had fewer low severity (7.6 vs. 10.6/100 enrollees, p < 0.001) and total emergency department encounters (18.3 vs. 23.5/100 enrollees, p < 0.001), and lower emergency department ($63 vs. $89, p = 0.002) and total medical costs ($1,736 vs. $2,207, p = 0.009). Patients who were ≥18 years in the letter group had greater outpatient medical costs. There were no intervention-related differences in patient-reported assessments of quality of life and medical care received. The effectiveness of clinical decision support messaging depended upon the delivery modality and patient age. Health IT interventions must be carefully evaluated to ensure that the resultant outcomes are aligned with expectations as interventions can have differing effects on clinical and economic outcomes.

Population-based clinical decision support: a clinical and economic evaluation.

Governments are investing in health information technologies (HIT) to improve care quality and reduce medical costs. However, evidence of these benefits is limited. We conducted a randomized trial of three clinical decision support (CDS) interventions in 20,180 patients: email to care managers (n=3329), reports to primary care administrators (n=3368), letters to patients (n=3401), and controls (10,082). At 7-month follow-up, the letters to patients group had greater use of outpatient services and higher outpatient and total medical costs; whereas, the other groups had no change in clinical events or medical costs. As our CDS interventions were associated with no change or an increase in medical costs, it appears that investments in HIT without consideration for organizational context may not be sufficient to achieve improvements in clinical and economic outcomes.

Clinical and economic results from a randomized trial of clinical decision support in a rural health network.

BACKGROUND: Replication studies evaluate technologies in usual use settings. METHODS: We conducted a clinical trial to determine whether reductions in clinical and economic results observed in a previous study could be replicated in a larger setting. Subjects were randomized to receive intervention (email notifications for sentinel health events sent to their care managers) or control. MAIN OUTCOME MEASURES: The primary outcome was the rate of emergency department visits for low severity conditions. Secondary outcomes included: medical costs and other clinical event rates. RESULTS: We randomized 13,454 individuals (intervention, 6740; control, 6714). Subjects in both groups had similar rates of clinical events and medical costs. CONCLUSION: The use of email notifications to care managers was associated with no reductions in clinical events or medical costs.

A randomized clinical trial of clinical decision support in a rural community health network serving lower income individuals: study design and baseline characteristics.

Lower income individuals in the US frequently experience difficulties in obtaining access to needed health care services. We describe a randomized clinical trial that seeks to improve the quality of, and access to healthcare services for medically underserved populations in five rural counties of North Carolina. We propose to achieve these improvements by implementing system-to-system integration via a telehealth network with an asynchronous clinical decision support system for health care providers.

Long-term clinical and economic analysis of the Endeavor drug-eluting stent versus the Driver bare-metal stent: 4-year results from the ENDEAVOR II trial (Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions).

OBJECTIVES: This study was designed to evaluate long-term clinical and economic outcomes for subjects receiving Endeavor drug-eluting versus Driver bare-metal stents (both Medtronic CardioVascular, Santa Rosa, California). BACKGROUND: Early studies found that the drug-eluting stent (DES) was a clinically and economically attractive alternative to the bare-metal stent; however, associations between DES and very late stent thrombosis suggest that longer follow-up is required. METHODS: We used clinical, resource use and follow-up data from 1,197 subjects randomized to receive Endeavor (n = 598) versus Driver (n = 599) stents in ENDEAVOR II (Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions) study with Medicare cost weights and quality of life adjustments applied from secondary sources. We compared differences through 4-year follow-up (1,440 days). RESULTS: Patients in both treatment groups had similar baseline characteristics. The use of Endeavor versus Driver reduced 4-year target vessel revascularization rates per 100 subjects (10.4 vs. 21.5; difference: -11.1; 95% confidence interval [CI]: -16.0 to -6.1; p < 0.001), with no difference in the rates per 100 subjects of death (5.0 vs. 5.2; difference: -0.2; 95% CI: -2.7 to 2.4; p = 0.90) or nonfatal myocardial infarction (3.2 vs. 4.4; difference: -1.2; 95% CI: -3.4 to 1.0; p = 0.29). After discounting at a 3% annual rate, there were no differences in quality-adjusted survival days (1,093 vs. 1,090; difference: 3; 95% CI: -13 to 19; p = 0.69) and total medical costs ($21,483 vs. $21,680; difference: -$198; 95% CI: -$1,608 to $1,207; p = 0.78). CONCLUSIONS: The use of Endeavor versus Driver was associated with a significant reduction in target vessel revascularization through 4-year follow-up with no difference in death, nonfatal myocardial infarction, quality-adjusted survival, or total medical costs. These results are comparable to those for other studies evaluating drug-eluting versus bare-metal stents. (Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions [ENDEAVOR II]; NCT00614848).

Long-term clinical and economic analysis of the Endeavor zotarolimus-eluting stent versus the cypher sirolimus-eluting stent: 3-year results from the ENDEAVOR III trial (Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions).

OBJECTIVES: The aim of this study was to evaluate clinical and economic outcomes for subjects receiving zotarolimus-eluting (ZES) (n = 323) versus sirolimus-eluting stents (SES) (n = 113) in the ENDEAVOR III (Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) clinical trial. BACKGROUND: Although previous clinical trials have evaluated long-term clinical outcome for drug-eluting stents, none considered their economic implications. METHODS: We analyzed case report form information with quality-of-life adjustment and Medicare cost weights applied from secondary sources; compared differences in clinical outcomes, quality-adjusted survival, medical resource use, and medical costs; and evaluated cost-effectiveness through 3-year follow-up. RESULTS: The use of ZES versus SES reduced the 3-year rates/100 subjects of death or myocardial infarction (3.9 vs. 10.8; difference, -6.9; 95% confidence interval [CI]: -13.0 to 0.8; p = 0.028), with no difference in target vessel revascularization rates (17.9 vs. 12.2; difference, 5.7; 95% CI: -3.7 to 15.1; p = 0.23) but greater use of coronary artery bypass graft (CABG) surgery (3.5 vs. 0.0; difference 3.5; 95% CI: 1.3 to 5.7; p = 0.002). After discounting at 3% per annum, total medical costs for ZES versus SES were similar ($23,353 vs. $21,657; difference, $1,696; 95% CI: -$1,089 to $4,482, p = 0.23), and the 3-year cost-effectiveness ratio was $57,002/quality-adjusted life year. CONCLUSIONS: Despite a reduction in death or myocardial infarction and no difference in total revascularizations, medical costs were not decreased due to increased CABG repeat revascularization procedures for subjects receiving ZES versus SES. If future trials observe similar differences, improved safety with no difference in medical costs, the use of ZES versus SES will be a clinically and economically attractive treatment strategy. (The Medtronic Endeavor III Drug Eluting Coronary Stent System Clinical Trial [ENDEAVOR III]; NCT00217256).

The economic returns of pediatric clinical trials of antihypertensive drugs.

BACKGROUND: Congress has authorized the United States Food and Drug Administration (FDA) to provide industry sponsors with a 6-month extension of drug marketing rights under the Pediatric Exclusivity Provision if FDA-requested pediatric drug trials are conducted. The cost and economic return of pediatric exclusivity to industry sponsors has been shown to be highly variable. We sought to determine the cost of performing pediatric exclusivity trials within a single therapeutic area and the subsequent economic return to industry sponsors. METHODS: We evaluated 9 orally administered antihypertensive drugs submitted to the FDA under the Pediatric Exclusivity Provision from 1997 to 2004 and obtained key elements of the clinical trial designs and operations. Estimates of the costs of performing the studies were generated and converted into after-tax cash outflow. Market sales were obtained and converted into after-tax inflows based on 6 months of additional patent protection. Net economic return and net return-to-cost ratios were determined for each drug. RESULTS: Of the 9 antihypertensive agents studied, an average of 2 studies per drug was performed, including at least 1 pharmacokinetic study and a safety and efficacy study. The median cost of completing a pharmacokinetic trial was $862,000 (range $556,000 to 1.8 million). The median cost of performing safety and efficacy trials for these agents was $4.3 million (range $2.1-12.9 million). The ratio of net economic return to cost was 17 (range 4-64.7). CONCLUSION: We found that, within a cohort of antihypertensive drugs, the Pediatric Exclusivity Provision has generated highly variable, yet lucrative returns to industry sponsors.