Research Design And Methods
The HOPE study evaluated vitamin E in 9,541 patients at high risk for CV events. The study was designed to enroll a large proportion of diabetic patients (>35%), and analyses of the effects of vitamin E in the study participants with a baseline diagnosis of diabetes were preplanned. The Microalbuminuria Cardiovascular Renal Outcomes (MICRO-HOPE) was a substudy of the HOPE trial, which evaluated the effects of the study interventions on nephropathy. Detailed descriptions of the HOPE and MICRO-HOPE study designs and protocols have been published.[12,13,14] A brief summary is listed below.
The HOPE trial enrolled people with and without diabetes at high risk for CV events. Patients were eligible if they were 55 years or older, had a history of CV disease (coronary artery disease, stroke, or peripheral arterial disease) or diabetes in the presence of at least one additional CV risk factor (total cholesterol >5.2 mmol/l, HDL cholesterol ≤ 0.9 mmol/l, hypertension, defined as use of medication[s] to treat high blood pressure, or blood pressure at time of recruitment >160 mmHg systolic or >90 mmHg diastolic, known microalbuminuria, or current smoking). Key exclusion criteria included dipstick-positive proteinuria, diabetic nephropathy, serum creatinine >200 µmol/l, history of congestive heart failure or known low left ventricular ejection fraction (<40%), hyperkalemia, uncontrolled hypertension, myocardial infarction (MI), unstable angina or stroke within 1 month before study enrolment, and use of or intolerance to vitamin E or ACE inhibitors. All study participants provided written informed consent, and the study protocol was approved by the research ethics board of each participating center.
This publication presents analyses restricted to patients with a baseline diagnosis of diabetes. Diabetes status was established at baseline based on history and confirmation by source documentation. Participants were judged to have type 2 diabetes if the diagnosis was made at age 30 years or older or if they were not taking insulin.
After randomization, patients were evaluated at 1 month and thereafter every 6 months. HbA1c and serum creatinine were assayed for all HOPE study participants with a history of diabetes in each study centers local laboratory at baseline and yearly thereafter. Urinary albumin excretion was measured at baseline, at 1 year, and at study end, by measuring the albumin-to-creatinine ratio in the first morning urine sample. Urine was stored at -70°C. Albumin-to-creatinine ratio was measured at four laboratories, which served as central laboratories for the study regions (Canada, U.K., Argentina, and Brazil). Microalbuminuria was defined based on definitions available in 1993 at the time of study initiation, as an albumin-to-creatinine ratio of 2 mg/mmol or higher. Participants with albumin-to-creatinine ratio >36 mg/mmol after randomization were asked to provide a 24-h urine sample that was assayed in their local laboratory for total protein or urinary albumin. Results of these measurements were sent to the Project Office and all cases of overt nephropathy were adjudicated. Overt nephropathy was diagnosed if the 24-h urine albumin was 300 mg or more, if the 24-h urine total protein excretion was 500 mg or more, or if the measured albumin-to-creatinine ratio was >36 mg/mmol and no 24-h urine result was available.
Definitions of the study outcomes have been previously published.[12,13,14] The primary study outcome was the composite of nonfatal MI, stroke, or CV death. Secondary end points were total mortality, hospital admission for congestive heart failure, hospital admission for unstable angina, revascularization procedures, and the development of overt nephropathy. All primary and secondary outcomes were adjudicated by an events adjudication committee unaware of the participants assigned treatments. Additional outcomes were determined by history and summary records, which were obtained for all hospital admissions and were reviewed by the Project Office.
Plasma vitamin E levels were measured by liquid chromatography (Waters 625 LC system; Millipore, Milford, MA) at baseline and at 2 years in 163 randomly selected patients in the vitamin E group and in 34 randomly selected patients in the placebo group.
All analyses were carried out using SAS 6.02 (SAS Institute, Cary, NC) and were by intention to treat. Baseline characteristics were compared by t tests or 2 tests as appropriate. All outcome analyses were stratified according to randomization to ramipril or placebo by Cox regression in order to account for the factorial study design. Relative risks (RRs) and 95% CIs are reported for the primary, secondary, and other outcomes of interest. Kaplan-Meier curves were used to estimate survival and were compared by log-rank tests. Treatment effect in subgroups and potential interactions were evaluated by Cox regression analysis. Changes in continuous variables (HbA1c, serum creatinine, albumin-to-creatinine ratio, and blood pressure) from baseline were compared by ANOVA, adjusted for baseline values. Results of HbA1c were expressed as the percentage higher than the upper limit of normal for the assay used. Albumin-to-creatinine ratios were transformed to account for nonnormality, and values were adjusted for the laboratories in which the assays were performed.
Diabetes Care. 2002;25(11) © 2002 American Diabetes Association, Inc.
Cite this: Effects of Vitamin E on Cardiovascular and Microvascular Outcomes in High-Risk Patients With Diabetes - Medscape - Nov 01, 2002.