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Editor’s Note: American Heart Association Annual Scientific Sessions, November 2000, New Orleans, La.
There is considerable interest in the potential role of statin therapy in acute coronary syndromes (ACS), such as Q-wave myocardial infarction (MI), unstable angina, and non-ST segment elevation MI. Observational studies in ACS have suggested that patients who, on admission or discharge from the hospital, are on a statin enjoy reduced morbidity and mortality. The three large statin trials in patients with established coronary disease (4S, CARE, LIPID) excluded patients with a recent ACS. No prospective study of lipid reduction in ACS has been reported, although several are in progress. The MIRACL Trial (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) enrolled 3086 patients with unstable angina or non-Q-MI and randomized them to atorvastatin (80 mg/d) or placebo for 16 weeks. Drug initiation occurred within the first 24-96 hours. All patients were encouraged to follow a NCEP Step 1 diet. Patients with unstable angina had positive biochemical markers, dynamic ST-T changes, or new wall motion or nuclear perfusion abnormalities. Exclusion criteria included recent MI or revascularization, and LDL-C of greater than 270. Enrollment occurred between June 1997 to January 2000. The primary end point was a composite of death, nonfatal MI, ischemic cardiac arrest, and increasing angina requiring hospitalization with objective ischemia. Secondary end points included revascularization, worsening angina without objective ischemia, and stroke. The study was international and involved 19 countries and 122 hospitals; half were in Europe; one-third in the United States and Canada, as well as South Africa, and Australia-New Zealand.
Baseline characteristics: Mean age was 65; 55% were male, 15% noncaucasian, 25% had a prior MI, and 11% had previous revascularization. More than half were hypertensive, one-fourth were diabetic, and 28% were past/present smokers; 45% presented with unstable angina and 55% with non-Q-MI. The mean time to randomization was 63 hours. Patients were continued on standard medical therapy. Ninety percent were on aspirin and nitrates, 75-80% were on beta-blockers and heparin, and more than 50% were on ACE inhibitors and calcium blockers. Baseline lipids: total cholesterol 206; LDL 124, HDL 46, and TG 183. In the statin cohort, there was a 27% reduction of TC, declining to 147 mg/dL; LDL fell 40% to a mean of 72 mg/dL; HDL rose slightly to 48, and triglycerides decreased to 139 mg/dL, a 16% reduction. The primary end point results favored atorvastatin, with a 16% reduction in relative risk (P = 0.048). Placebo patients had a 17.4% rate of MI or re-hospitalization vs. 14.8% in the statin group. There was a significant decrease in recurrent angina/ischemia, with trends for decreased death and MI. Recurrence of angina decreased by 26% (8.4% placebo vs 6.2% atorvastatin). Stroke was robustly less by 50% (P = 0.045; 1.6% vs 0.8%). All other secondary end points were not significantly different. There was a 2.5% elevation of liver function tests in the atorvastatin patients vs. less than 0.6% with placebo. There was no evidence of myositis.
This study represents a missing link in the lipid-lowering trial data to date, confirming that cholesterol lowering is beneficial over a short period of time in ACS. Of interest, the subjects were not chosen because of hyper-cholesterolemia, and in fact the baseline lipid levels were relatively unremarkable. The absolute reduction of 2.6% in the composite end point was powered primarily by re-hospitalization for angina. Unfortunately, data regarding revascularization during the initial admission as well as readmission were not provided. The mechanism of benefit with atorvastatin cannot be ascertained in this short 16-week trial. Nonetheless, it is likely that the beneficial effects are directly related to reductions in LDL and oxidized LDL cholesterol in the vessel wall, resulting in a decrease in inflammatory state and improved endothelial function. Decreased susceptibility to plaque rupture as well as a diminished thrombotic milieu are possible. Curve separation did not begin until after the first weeks, supporting a plaque stabilizing and antiplatelet-thrombotic mechanisms related to atorvastatin. Inflammatory markers were elevated. The mean achieved LDL-C of 72 mg/dL is the lowest in any of the reported statin trials; it is likely that the baseline TC and LDL-C were actually slightly higher due to rapid decline in lipid levels following hospitalization. The MIRACL results are in contrast to FLORIDA, a trial from The Netherlands also reported at AHA, which failed to find a benefit for fluvastatin 80 mg in 540 patients with acute Q-MI. Lipid lowering therapy or placebo was given for one year; the end point was ambulatory ischemia. The results were negative, with a low incidence of ambulatory ishcemia at baseline (12%), falling in both the placebo and statin cohorts at six weeks and 12 months.
There is now a great deal of evidence supporting the use of a statin for most patients with coronary artery disease, irrespective of the clinical presentation and baseline LDL-C. While the CARE trial has engendered a controversy about how far to go to achieve benefits, and the CARE investigators have suggested a target goal of 125 mg/dL may be sufficient, it is likely that lower is better. MIRACL used a fixed high dose of atorvastatin with beneficial results; baseline lipids were low at 124 mg/dL for LDL-C. Clinical benefits were observed in MIRACL over an extremely short period of time (4 months), which is unique among lipid-lowering trials. Anecdotal and observational data from a number of sources are concordant with the findings of MIRACL, as are the many basic science and vascular biology results supporting the cholesterol hypothesis. The results, while not extraordinarily robust, support the recommendation that all patients with an acute ACS, probably including ST-segment elevation MI (not studied in MIRACL) should be started on a high-dose statin, irrespective of lipid values. There are scant data showing that other pharmacological agents, including beta-blockers, calcium antagonists, nitrates, or ACE inhibitors, result in a comparable decrease in major morbidity and mortality in ACS.