JAMA 2001;285:1711-18.
Background Statin therapy had been shown to improve blood cholesterol and improve long-term outcomes in patients with stable coronary artery disease with significant effects evident after 2 years of treatment.
These early trials excluded patients with recent acute coronary syndromes and thus, the possibility of early benefit from statin therapy in this patient population was untested. But, patients with ACS are the most vulnerable to experiencing recurrent events in the early period following an initial event and certain physiologic effects of statins were theorized to be beneficial during this period. These effects included improvement in endothelial function, decreased platelet aggregation and thrombus deposition, and reduced vascular inflammation.
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study sought to test the hypothesis that early treatment with high dose atorvastatin in patients with unstable angina or non-Q-wave AMI would reduce early ischemic events and death.
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Patients Eligible patients were ≥18 years of age of experienced unstable angina or non-Q-wave AMI within the 24-hour period before hospitalization. The definition of unstable angina was strictly applied and in contemporary practice, all would meet criteria for NSTEMI. Patients were excluded for the following reasons: serum cholesterol >270 mg/dl but there was no lower limit; if coronary revascularization was planned or anticipated at the time of screening; evidence of Q-wave AMI within preceding 4 weeks; CABG surgery within the preceding 3 months; PCI within the preceding 6 months; left bundle branch block or paced rhythm; severe CHF; concurrent treatment with other lipid-lowering agents, vitamin E, drugs associated with rhabdomyolysis in combination with statins; severe anemia; renal failure requiring dialysis; hepatic dysfunction (ALT >2 ULN); insulin-dependent diabetes; pregnancy or lactation.
Baseline characteristics The average age of patients was 65 years and two-thirds were men; 86% were white. Approximately one quarter of patients had a prior MI, 23% had non-insulin-dependent diabetes and 55% had hypertension. The average time to randomization from hospital admission was about 2.5 days. The inclusion event was unstable angina in 46% and non-Q-wave AMI in the remainder. Non-cholesterol lowering cardiac medicines were similar prior to, during and following the hospitalization index event.
Procedures Between 24 and 96 hours after hospital admission, patients received either atorvastatin 80 mg per day or matching placebo for 16 weeks. Treating physicians were instructed not measure serum lipid levels in the local hospital laboratory during the study period. All patients received instruction and counseling on a low cholesterol diet. Patients were seen in follow-up 2, 6, and 16 weeks after initiation of therapy. Laboratory testing was performed centrally at baseline and at 6 and 16 weeks.
Endpoints The primary endpoint was a composite of all-cause death, nonfatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence requiring emergency hospitalization. The recurrent ischemia endpoint required both exacerbation of the patient’s usual symptoms and new objective evidence of ischemia with definite change from a comparison study performed after the index ischemic event. Secondary endpoints were occurrence of each component of the primary composite endpoint as well as nonfatal stroke; new or worsening heart failure requiring hospitalization, worsening angina requiring hospitalization but without objective evidence of ischemia, coronary revascularization, time to first occurrence of any primary or secondary endpoint, and percentage changes in blood lipid levels from baseline to 16 weeks.
An initial sample size requirement of 2,100 was based on an assumption of a 20% primary composite event rate in the control group and 14% rate in the atorvastatin-treated group (17% overall rate), with an alpha of 0.05 and 95% power. The sample size was then increased to 3,000 upon the recommendation of the steering committee. This, after a blinded analysis of pooled data from the first 1,260 patients indicated the event rate was lower than anticipated (13% overall). A sample size of 3,000 would confer 95% power to detect a 30% relative treatment effect and 80% power to detect a 25% relative effect at an alpha of 0.05.
Results 3,086 patients were included in the final analysis; 1,548 in the placebo group and 1,538 in the atorvastatin group. All patients were followed for 16 weeks. Compared to placebo, atorvastatin significantly reduced the risk of the primary composite endpoint (RR 0.84; 14.8% vs 17.4%%; 95% CI 0.70-1.00; p=0.048). For the individual components, there were no significant differences in death (4.2% vs 4.4%), nonfatal MI (6.6% vs 7.3%), or resuscitated cardiac arrest (0.5% vs 0.6%), but there was a statistically significant reduction in the endpoint of emergency rehospitalization for recurrent symptomatic ischemia (RR 0.74; 6.2% vs 8.4%; 95% CI 0.57-0.95).
For the secondary endpoints, there were significant reductions in stroke in the atorvastatin group but this was based on a small number of events.
Perhaps unexpectedly, there was a numerical increase in coronary revascularization procedures in the atorvastatin group despite there being a statistically significant reduction in emergency hospitalizations for recurrent ischemia as mentioned above.
Data on subgroups was not presented.
Compliance with prescribed study treatment was 86% in the atorvastatin group and 88% in the placebo group. Treatment was discontinued prematurely in 11.2% of the atorvastatin group compared to 10.3% in the placebo group. No serious adverse events occurred with a frequency of more than 1% in either group. An increase in LFTs (>3x ULN) occurred in 2.5% in the atorvastatin group and 0.6% of patients in the placebo group; 3 of these patients in the atorvastatin group were hospitalized with hepatitis and each case resolved following discontinuation of the drug. There were no documented cases of myositis.
After 16 weeks, LDL cholesterol had increased by an adjusted mean of 12% to 135 mg/dl in the placebo group and decreased by an adjusted mean of 40% to 72 mg/dl in the atorvastatin group. Total cholesterol and triglycerides also decreased significantly in the atorvastatin group compared to placebo and there were no significant changes in HDL cholesterol.
Conclusions In patients admitted to the hospital with non-Q-wave acute coronary syndromes, high dose atorvastatin significantly reduced a composite primary endpoint of cardiovascular events over the first 16 weeks of treatment with an NNT of 38; however, this was driven by a reduction in emergency hospitalizations for recurrent ischemia.
There is no evidence from this trial that high dose statin therapy reduces the individual endpoints of death or nonfatal MI over this period; nor did it reduce coronary revascularization, which is counterintuitive given the significant increase in emergency hospitalizations for recurrent ischemia. Coronary revascularization events were twice as likely to occur as emergency hospitalizations.
The external validity of the trial is limited by the restricted nature of the study population. Patients were excluded if revascularization was planned during initial admission, which in many places is the standard of care for ACS up to the present day. Furthermore, higher risk ACS subgroups were excluded, including patients with insulin-dependent diabetes, advanced heart failure and ESRD. The relatively unimpressive clinical benefit observed in MIRACL should not be assumed to extend to such patients. It would not be unreasonable to conclude that the results from MIRACL do not apply to the average patient with ACS in contemporary practice.
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