Differential Outcomes With Edetate Disodium-Based Treatment Among Stable Post Anterior vs. Non-Anterior Myocardial Infarction Patients.

BACKGROUND: The Trial to Assess Chelation Therapy (TACT) found that chelation therapy significantly reduced clinical events in patients with a history of myocardial infarction (MI). The initial report of TACT included the observation of an interaction between edetate disodium infusions and MI location, as well as diabetes. Thus, we examined in greater detail the effect of edetate disodium chelation therapy as a function of MI location and diabetes. METHODS: Patients (n = 1708) at least 6 weeks post-MI and age ≥ 50 were randomized to receive 40 infusions of a 500 mL chelation solution or placebo (median follow-up 55 months). The effect of edetate disodium on the primary outcome (all-cause mortality, MI, stroke, hospitalization for angina, or coronary revascularization) was assessed as a function of MI location using log-rank test and Cox regression model, adjusting for other prognostic variables. RESULTS: Among patients with post anterior MI (n = 674), chelation was associated with a lower risk of the primary endpoint (HR 0.63, 95% CI 0.47-0.86, p = 0.003) among anterior MI patients, but not in post non-anterior MI (n = 1034) patients (HR 0.96, 95% CI 0.77-1.20, p = 0.702) (p-for-interaction = 0.032). The point estimates for each component of the primary endpoint favored chelation therapy. The differing treatment effect in patients with post anterior vs. non-anterior MI was consistent among patients with or without diabetes and remained significant after adjusting for other prognostic variables (p < 0.01). CONCLUSIONS: Edetate disodium infusions reduced the risk of cardiovascular events among patients with a prior anterior MI. Future studies should focus on replicating these results and understanding the mechanisms of benefit.

Identification of Patients With Stable Chest Pain Deriving Minimal Value From Noninvasive Testing: The PROMISE Minimal-Risk Tool, A Secondary Analysis of a Randomized Clinical Trial.

Importance: Guidelines recommend noninvasive testing for patients with stable chest pain, although many subsequently have normal test results and no adverse clinical events. Objective: To describe a risk tool developed to use only pretest clinical data to identify patients with chest pain with normal coronary arteries and no clinical events during follow-up (minimal-risk cohort). Design, Setting, and Participants: This secondary analysis of a randomized, pragmatic comparative effectiveness trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]) includes stable, symptomatic outpatients without known coronary artery disease referred for noninvasive testing at 193 sites in North America. Interventions: Patients were randomized to receive coronary computed tomography angiography (CCTA) vs functional testing. Main Outcomes and Measures: A low-risk tool was developed and internally validated from July 27, 2010, to September 19, 2013, in 4631 patients receiving CCTA as their initial test, with a median follow-up of 25 months. Logistic regression analysis was used to evaluate pretest variables to determine factors associated with minimal risk using a two-thirds random sample for model derivation (n = 3087) and a one-third sample for testing and validation (n = 1544). The model was then applied to the CCTA and functional testing arms, and test results and event rates were ascertained. Results: A total of 1243 of 4631 patients (26.8%) were in the minimal-risk cohort. The final minimal-risk model included 10 clinical variables that together were correlated with normal CCTA results and no clinical events (C statistic = 0.725 for the derivation and validation subsets; 95% CI, 0.705-0.746): younger age; female sex; racial or ethnic minority; no history of hypertension, diabetes, or dyslipidemia; family history of premature coronary artery disease; never smoking; symptoms unrelated to physical or mental stress; and higher high-density lipoprotein cholesterol level. Across the entire PROMISE cohort, this model was associated with the lowest rates of severely abnormal test results (1.3% for CCTA; 5.6% for functional) and cardiovascular death or myocardial infarction (0.5% for a median of 25 months) among patients at the highest probability (10th decile) of minimal risk. Conclusions and Relevance: In contemporary practice, more than 25% of patients with stable chest pain referred for noninvasive testing will have normal coronary arteries and no long-term clinical events. A clinical tool using readily available pretest variables discriminates such minimal-risk patients, for whom deferred testing may be considered. Trial Registration: clinicaltrials.gov Identifier: NCT01174550.

Tonsillectomy Bleed Rates across the CHEER Practice Research Network: Pursuing Guideline Adherence and Quality Improvement.

OBJECTIVES: (1) Compare postoperative bleeding in the CHEER network (Creating Healthcare Excellence through Education and Research) among age groups, diagnoses, and practice types. (2) Report the incidence of bleeding by individual CHEER practice site based on practice guidelines. STUDY DESIGN: Retrospective data collection database review of the CHEER network based on ICD-9 and CPT codes related to tonsillectomy patients. SETTING: Multisite practice-based network. SUBJECTS AND METHODS: A total of 8347 subjects underwent tonsillectomy as determined by procedure code within the retrospective data collection database, and 107 had postoperative hemorrhage. These subjects had demographic information and related diagnoses based on the CPT and ICD-9 codes collected. Postoperative ICD-9 and CPT codes were used to identify patients who also had postoperative bleed. Variables included age (<12 vs ≥12 years), diagnoses (infectious vs noninfectious), and practice type (community vs academic). Statistical analysis included multivariate logistic regression variables predictive of postoperative bleeding, with P < .05 considered significant. RESULTS: Thirteen sites contributed data to the study (7 academic, 6 community). There was postoperative bleeding for an overall bleed rate of 1.3%. Patients ≥12 years old had a significantly increased bleed rate when compared with the younger group (odds ratio, 5.98; 95% confidence interval: 3.79-9.44; P < .0001). There was no significant difference in bleed rates when practices or diagnoses were compared. CONCLUSION: A site descriptor database built to expedite clinical research can be used for practice assessment and quality improvement. These data were also useful to identify patient risk factors for posttonsillectomy bleed.

Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials.

BACKGROUND: Mortality is an impractical primary endpoint for clinical trials in patients with idiopathic pulmonary fibrosis who have mild-to-moderate physiological impairment because event rates are low. Change in forced vital capacity (FVC) is widely accepted as a surrogate for mortality and is the most common primary endpoint in clinical trials for this disorder. Use of hospital admission as a predictor for mortality, independent of FVC decline, has not been well defined. We aimed to ascertain the independent and combined association of hospital admission and at least a 10% decrease in FVC with all-cause mortality. METHODS: We did a pooled cohort study of 517 patients with idiopathic pulmonary fibrosis from three IPFnet multicentre randomised controlled trials. We compared the incidence of non-elective hospital admission and a 10% or greater reduction in FVC across strata of baseline physiological impairment. We used Cox proportional-hazards models to assess the risk of all-cause mortality associated with these surrogate events, occurring up to a predefined landmark timepoint. The three studies are registered at ClinicalTrials.gov, numbers NCT00650091, NCT00517933, and NCT00957242. FINDINGS: Seven patients died before the landmark timepoint. Of the 510 patients remaining, 38 (7%) were admitted to hospital up to the predefined timepoint and 58 (11%) had a categorical decrease in FVC of at least 10%. Most patients admitted to hospital did not have a 10% or greater decrease in FVC (30 vs eight). Both surrogate events were associated with subsequent time to death from any cause (hazard ratio [HR] for admission 4·05, 95% CI 1·36-12·11 vs HR for 10% or greater decline in FVC 4·68, 1·83-11·99). When causes of hospital admission were considered, only respiratory events were associated with mortality (5·97, 1·81-19·74). INTERPRETATION: Hospital admission might be an appropriate component of a clinically meaningful composite endpoint that improves the feasibility of clinical trials in idiopathic pulmonary fibrosis. Further studies are needed to refine the most appropriate definition of hospital admission for future trials. FUNDING: US National Heart, Lung, and Blood Institute (NHLBI), and The Cowlin Family Fund at the Chicago Community Trust.

Study design implications of death and hospitalization as end points in idiopathic pulmonary fibrosis.

BACKGROUND: The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary end points is an area of uncertainty. Using data from a large well-characterized clinical trial population, this article aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary end point. METHODS: Event rate estimates for death and hospitalization were determined from patients enrolled in National Institutes of Health-sponsored IPF Clinical Research Network clinical trials. Standard equations were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts. RESULTS: Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than those published. An IPF trial with death as its primary end point enrolling subjects designated as GAP stage 1 and 2 over 1 year with a minimum follow-up of 1 year would require an estimated 7,986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary end point enrolling subjects with GAP stage 2 and 3 over 2 years with a minimum follow-up of 1 year would require an estimated 794 subjects for the same power and hazard ratio. CONCLUSIONS: Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time-to-event primary end points such as death and death plus hospitalization.

Characteristics of cancer patients presenting to an integrative medicine practice-based research network.

OBJECTIVE: To assess psychosocial characteristics, symptoms and reasons for seeking integrative medicine (IM) care in cancer patients presenting to IM clinical practices. STUDY DESIGN AND METHODS: A survey of 3940 patients was conducted at 8 IM sites. Patient reported outcome measures were collected and clinicians provided health status data. This analysis compares 353 participants self-identified as cancer patients with the larger noncancer cohort. RESULTS: Mean age of the cancer cohort was 55.0 years. Participants were predominantly white (85.9%), female (76.4%), and well educated (80.5% completed college). For 15.2% of cancer patients, depression scores were consistent with depressive symptoms, and average scores for perceived stress were higher than normal, but neither were significantly different from noncancer patients. The most prevalent comorbid symptoms were chronic pain (39.8%), fatigue (33.5%), and insomnia (23.3%). In the cancer cohort, perceived stress was significantly associated with depression, fatigue, insomnia, pain, and QOL. Cancer patients who chose an IM clinical practice "seeking healthcare settings that address spirituality as an aspect of care" had significantly higher levels of perceived stress, depression, and pain than those not selecting this reason. CONCLUSIONS: Demographic characteristics, depression scores, perceived stress scores, and reasons for seeking integrative cancer care were not significantly different between cancer patients and noncancer patients. Perceived stress may be an important indicator of QOL. The association of perceived stress, depression and pain with seeking spirituality suggests that providing IM interventions, such as effective stress management techniques and pastoral or spiritual counseling, may be helpful to patients living with cancer.

Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials.

BACKGROUND: Abnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF. METHODS: In an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker. FINDINGS: Of the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (-0·06 L, 95% CI -0·11 to -0·01) than did those not taking anti-acid treatment (-0·12 L, -0·17 to -0·08; difference 0·07 L, 95% CI 0-0·14; p=0·05). INTERPRETATION: Anti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed. FUNDING: National Institutes of Health.

Severe acute respiratory syndrome coronavirus group-specific open reading frames encode nonessential functions for replication in cell cultures and mice.

SARS coronavirus (SARS-CoV) encodes several unique group-specific open reading frames (ORFs) relative to other known coronaviruses. To determine the significance of the SARS-CoV group-specific ORFs in virus replication in vitro and in mice, we systematically deleted five of the eight group-specific ORFs, ORF3a, OF3b, ORF6, ORF7a, and ORF7b, and characterized recombinant virus replication and gene expression in vitro. Deletion of the group-specific ORFs of SARS-CoV, either alone or in various combinations, did not dramatically influence replication efficiency in cell culture or in the levels of viral RNA synthesis. The greatest reduction in virus growth was noted following ORF3a deletion. SARS-CoV spike (S) glycoprotein does not encode a rough endoplasmic reticulum (rER)/Golgi retention signal, and it has been suggested that ORF3a interacts with and targets S glycoprotein retention in the rER/Golgi apparatus. Deletion of ORF3a did not alter subcellular localization of the S glycoprotein from distinct punctuate localization in the rER/Golgi apparatus. These data suggest that ORF3a plays little role in the targeting of S localization in the rER/Golgi apparatus. In addition, insertion of the 29-bp deletion fusing ORF8a/b into the single ORF8, noted in early-stage SARS-CoV human and civet cat isolates, had little if any impact on in vitro growth or RNA synthesis. All recombinant viruses replicated to wild-type levels in the murine model, suggesting that either the group-specific ORFs play little role in in vivo replication efficiency or that the mouse model is not of sufficient quality for discerning the role of the group-specific ORFs in disease origin and development.