Effect of atorvastatin (80 mg) on recurrent ischemia in unstable angina pectoris or Non–ST-Elevation acute myocardial infarction

A body of evidence has suggested that many cellular actions of statin therapy may acutely improve endothelial function even before affecting the lipid profile.1 Statins can acutely enhance nitric oxide bioavailability via their lipid-independent actions by upregulating endothelial nitric oxide synthase.2 In this randomized clinical trial, we evaluated the effect of high-dose atorvastatin on myocardial ischemia measured by ST-segment monitoring during the first 2 days after an episode of unstable angina pectoris (UAP) or non–Q-wave acute myocardial infarction (AMI). • • • Patients admitted to the coronary care unit of Portuguese Hospital, Salvador, Brazil, due to UAP or non–Q-wave AMI from December 2000 to March 2002 were considered candidates for the study. Inclusion criteria were defined as onset of chest discomfort in the previous 48 hours in patients with electrocardiographic changes consisting of transient ST-segment depression ( 0.05 mV), T-wave inversion ( 0.1 mV) and/or positive troponin I ( 1.0 ng/dl). Patients with positive troponin results were defined as having AMI, otherwise they were characterized as UAP. Patients were excluded if they had left bundle branch block, any liver disease, history of statin intolerance, pregnancy, or lactation. The study was approved by the local ethic committee and all participants provided written informed consent. A first blood sample to measure plasma lipids was drawn before initiation of therapy. The enrolled patients were submitted to a randomized, double-blind, placebo-controlled program with either 80 mg of atorvastatin or placebo administered once a day. ST-segment recording (Holter) was performed during the first 2 days of therapy and treatment efficacy was primarily assessed by comparing the amount of ischemia measured by Holter in the 2 groups. After 5 days, experimental therapy was withdrawn and another blood sample was taken for evaluation of the drug effect on plasma lipids. Cardiovascular events during hospitalization, defined as the composite of death, nonfatal AMI, and recurrent UAP, were also recorded. No other type of lipid-lowering therapy was offered to the patients during the first 5 days. Continuous 2-channel electrocardiographic recordings was performed by a calibrated amplitude-modulated cassette recorder (Dynamis 3000, Sao Paulo, Brazil) to detect reversible ST-segment shifts compatible with ischemia, which was defined as a 0.1 mV ST-segment depression or elevation measured 80 ms after the J point, lasting 1 minute and separated by the last episode by 1 minute. Number of ischemic episodes and total ischemia duration was measured in each patient. Ischemic burden was defined as the product of ischemic duration in minutes by the ST-segment depression in millimeters.3 The time from the first episode of ischemia was also recorded. Commercial enzymatic methods were used for the determination of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides (Dimension Clinical Chemistry System; Dade-Behring, Newark, Delaware).4 HDL cholesterol was determined by the same method used for total cholesterol after precipitation of apolipoprotein B containing lipoproteins with magnesium phosphotungstate. Low-density lipoprotein (LDL) cholesterol was calculated by Friedewald’s formula. Duration of ischemia, number of ischemic epidodes, ischemic burden, and time to the first ischemic episode in each patient were compared between the 2 groups by Wilcoxon’s rank-sum test. The prevalence of patients with ischemia and of patients with 60 minutes of ischemia were compared between the 2 groups by Fisher’s exact test. Baseline characteristics were compared by unpaired Student’s t test for continuous variables and by chi-square or Fisher’s exact tests for categorical variables. Wilcoxon’s sign-rank test was utilized for the paired analysis of plasma lipid changes after therapy in each group. Cardiovascular events were compared between the 2 groups by the chi-square test. Nonparametric tests were applied in most situations because Holter variables were not normally distributed. Analysis of variance and logistic regression were utilized to adjust Holter variables to baseline differences between the groups. We calculated a sample size of 50 patients per group, based on a 2-sided of 5% and a statistical power of 85%, assuming that a 50% reduction in duration of ischemia with atorvastatin would be clinically significant. We based this calculation on the previously described 11 9 minutes of ischemia per patient with UAP per 24 hours.5 One hundred patients were randomized (64 12 years; 51 men); 55 had AMI and 45 had UAP. Fifty From the School of Medicine, Federal University of Bahia, Salvador; Cardiology Division, Portuguese Hospital, Salvador; and Heart Institute (InCor), University of Sao Paulo Medicine School, Sao Paulo, Brazil. Dr. Correia’s address is: Rua do Taruma 90/1002, Salvador BA, Brazil 41.810-440. E-mail: lucorrei@terra.com.br. Manuscript received November 22, 2002; revised manuscript received and accepted February 24, 2003.