William F. Krol

Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure: The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial

Background— Chronic heart failure remains a major cause of mortality and morbidity. The role of antithrombotic therapy in patients with chronic heart failure has long been debated. The objective of this study was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm. Methods and Results— This prospective, randomized clinical trial of open-label warfarin (target international normalized ratio of 2.5 to 3.0) and double-blind treatment with either aspirin (162 mg once daily) or clopidogrel (75 mg once daily) had a 30-month enrollment period and a minimum of 12 months of treatment. We enrolled 1587 men and women ≥18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of ≤35%. The primary outcome was the time to first occurrence of death, nonfatal myocardial infarction, or nonfatal stroke. For the primary composite end point, the hazard ratios were as follows: for warfarin versus aspirin, 0.98 (95% CI, 0.86 to 1.12; P=0.77); for clopidogrel versus aspirin, 1.08 (95% CI, 0.83 to 1.40; P=0.57); and for warfarin versus clopidogrel, 0.89 (95% CI, 0.68 to 1.16; P=0.39). Warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel. Hospitalization for worsening heart failure occurred in 116 (22.2%), 97 (18.5%), and 89 (16.5%) patients treated with aspirin, clopidogrel, and warfarin, respectively (P=0.02 for warfarin versus aspirin). Conclusion— The primary outcome measure and the mortality data do not support the primary hypotheses that warfarin is superior to aspirin and that clopidogrel is superior to aspirin.

Diagnostic inconsistencies in Barrett's esophagus

Abstract Background/Aims: Few studies have compared the precision of various diagnostic tests used to determine the presence of Barretts esophagus. The aim of this study was to compare the results of histological, endoscopic, and manometric tests for patients with Barretts esophagus in two closely spaced examinations. Methods: In a Veterans Administration Cooperative Study, 192 patients with complicated gastroesophageal reflux disease had esophageal manometry and endoscopy performed at baseline and after 6 weeks. At each examination, the endoscopist localized the most proximal level of Barretts epithelium and the lower esophageal sphincter and obtained esophageal biopsy specimens. Results: One hundred sixteen patients met the criteria for Barretts esophagus on at least one of the two endoscopic examinations. Among patients with specialized columnar epithelium, 20% had specialized columnar epithelium found on only one of the two examinations. Although the mean lower esophageal sphincter level did not change, approximately 10% of patients had a change ≥4 cm on endoscopy and manometry between examinations. This led to an apparent change in the diagnosis in 18% of patients with Barretts esophagus. Conclusions: From one endoscopic examination to another, inconsistencies in the ability to detect specialized columnar epithelium are common. This may lead to substantial problems in establishing an accurate diagnosis of Barretts esophagus.

Development for and results of the use of a gastroesophageal reflux disease activity index as an outcome variable in a clinical trial

Due to the significant expense of obtaining frequent endoscopy and pH monitoring measures as outcome variables available for use in a multihospital clinical trial of gastroesophageal reflux disease, and the lack of a suitable inexpensive index of disease activity, evaluated for both reliability and validity, the study planning committee decided to develop an index of gastroesophageal reflux disease activity in a pilot study--to precede the clinical trial. In particular, the purpose of the pilot study was to find a reliable, valid, and inexpensive index of gastroesophageal reflux disease which could be obtained independently of the treating physician and used as an outcome variable in the clinical trial. This paper describes the pilot study and the statistical methodology used to derive and evaluate a gastroesophageal reflux disease activity index model. In addition, the results of the activity indexs use in the subsequent clinical trials longitudinal analyses are presented. Comparisons with the more expensive, and thus less frequently obtained, endoscopy and pH monitoring outcome variables are described.

A comparison of anterior chamber and posterior chamber intraocular lenses after vitreous presentation during cataract surgery: the Department of Veterans Affairs Cooperative Cataract Study

PURPOSE To compare the efficacy and safety of anterior chamber (AC) intraocular lenses (IOLs) and posterior chamber (PC) IOLs implanted after vitreous presentation during extracapsular cataract extraction (ECCE). DESIGN The study was a prospective, long-term, randomized clinical trial conducted at 19 Department of Veterans Affairs medical centers across the United States. METHODS There were 438 eyes (438 patients) that met preliminary eligibility criteria, suffered vitreous presentation during ECCE (phacoemulsification or classical extracapsular technique), and had sufficient capsular support for a PC IOL without sutures after anterior vitrectomy randomized to either a PC IOL (230 patients) or an AC IOL (208 patients). Patients were examined at 3, 6, and 12 months post-surgery and yearly thereafter. Minimum follow-up was 1 year. The primary outcome measure of best-corrected visual acuity at 1 year was obtained by a masked certified examiner. RESULTS More PC IOL patients (91%) achieved visual acuity of 20/40 or better at 1 year than AC IOL patients (79%), a highly significant difference (P =.003). There was no significant difference between the two groups for patients rating of vision or adverse events. Over 84% of the PC IOL patients and over 77% of the AC IOL patients rated their vision as good or better at 1 year as opposed to only 7% giving such ratings before surgery. For at least one rating period during the first year, 13.2% of the combined study patients had cystoid macular edema, 8.5% had posterior capsule opacification, 5.7% had glaucoma, and 3.7% had retinal detachment. CONCLUSION In the presence of sufficient capsular support, a PC IOL should be implanted after vitreous presentation during ECCE.

The “constant intake rate” assumption in interim recruitment goal methodology for multicenter clinical trials

A primary concern of any multihospital clinical trial is the recruitment of a predetermined number of patients during a prespecified interval of time. In several recent papers a Poisson based model was used to estimate the time needed to recruit a predetermined number of patients and the probabilities of recruiting specified fractions of the sample during subintervals. The Poisson model requires the assumption that patients be recruited at a constant rate over the entire length of the interval. In this paper we test the adequacy of this model and assumption using patient intake data from nine multihospital VA clinical trials and propose an alternative Bayesian model.

The Multicenter Clinical Trials Coordinating Center Statistician: “More than a Consultant”

Abstract Over the past several decades the employment of statisticians in the area of medical clinical trials in private industry, academic centers, and the federal government has increased significantly. This trend does not appear to be slowing, particularly in those organizations that have come to be termed coordinating centers. In this article we will describe the expanded role that statisticians employed in these centers are expected to be able to fill.

PMH1 USEFULNESS OF ELECTRONIC COMPLIANCE DATA IN AN EFFECTIVENESS TRIAL

formally evaluate the validity of the screens with regards to their ability to correctly identify ADEs. Validity was expressed as positive predictive value (PPV). RESULTS: Ten studies published between 1992 and 2000 met the inclusion criteria. Three approaches used to measure ADE incidence were identified. Two studies screened for generic adverse outcomes (e.g., inpatient deaths), the average PPVs were 1% and 17.4%. Five studies exclusively screened for surrogate outcomes (antidotes commonly used to treat ADEs, or critical lab values, such as elevated creatinine or drug levels) to predict the occurrence of an ADE, with PPVs of 9, 12, 13, 18 and 37%. Three studies tested screens that combined medications and intermediate outcomes (PPVs 12.4, 45 and 53%). CONCLUSIONS: Automated health care data screens show promise as ADE incidence measure. Their current validity, however, does not appear to be sufficient for cross-sectional comparisons or the evaluation of quality improvement initiatives. Increasing sophistication of the screens by including multiple variables that link process components (e.g. medication) along with adverse outcomes or surrogates (e.g. lab values, antidotes) appear to increase screen validity.