Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary
Syndromes

The MIRACL Study: A Randomized Controlled Trial

Author Information <http://jama.ama-assn.org/issues/v285n13/rfull/#aainfo>
Gregory G. Schwartz, MD, PhD; Anders G. Olsson, MD, PhD; Michael D.
Ezekowitz, MD, PhD; Peter Ganz, MD; Michael F. Oliver, MD; David Waters, MD;
Andreas Zeiher, MD; Bernard R. Chaitman, MD; Sally Leslie, PhD; Theresa
Stern, PhD; for the Myocardial Ischemia Reduction with Aggressive
Cholesterol Lowering (MIRACL) Study Investigators
Context  Patients experience the highest rate of death and recurrent
ischemic events during the early period after an acute coronary syndrome,
but it is not known whether early initiation of treatment with a statin can
reduce the occurrence of these early events.
Objective  To determine whether treatment with atorvastatin, 80 mg/d,
initiated 24 to 96 hours after an acute coronary syndrome, reduces death and
nonfatal ischemic events.
Design and Setting  A randomized, double-blind trial conducted from May 1997
to September 1999, with follow-up through 16 weeks at 122 clinical centers
in Europe, North America, South Africa, and Australasia.
Patients  A total of 3086 adults aged 18 years or older with unstable angina
or non–Q-wave acute myocardial infarction.
Interventions  Patients were stratified by center and randomly assigned to
receive treatment with atorvastatin (80 mg/d) or matching placebo between 24
and 96 hours after hospital admission.
Main Outcome Measures  Primary end point event defined as death, nonfatal
acute myocardial infarction, cardiac arrest with resuscitation, or recurrent
symptomatic myocardial ischemia with objective evidence and requiring
emergency rehospitalization.
Results  A primary end point event occurred in 228 patients (14.8%) in the
atorvastatin group and 269 patients (17.4%) in the placebo group (relative
risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P = .048). There
were no significant differences in risk of death, nonfatal myocardial
infarction, or cardiac arrest between the atorvastatin group and the placebo
group, although the atorvastatin group had a lower risk of symptomatic
ischemia with objective evidence and requiring emergency rehospitalization
(6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P = .02). Likewise, there were
no significant differences between the atorvastatin group and the placebo
group in the incidence of secondary outcomes of coronary revascularization
procedures, worsening heart failure, or worsening angina, although there
were fewer strokes in the atorvastatin group than in the placebo group (12
vs 24 events; P = .045). In the atorvastatin group, mean low-density
lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72
mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of
normal) were more common in the atorvastatin group than in the placebo group
(2.5% vs 0.6%; P<.001).
Conclusion  For patients with acute coronary syndrome, lipid-lowering
therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the
first 16 weeks, mostly recurrent symptomatic ischemia requiring
rehospitalization.
JAMA. 2001;285:1711-1718
JOC10254
Blood cholesterol lowering with statins has been regarded as a long-term
strategy to reduce death and ischemic cardiovascular events in patients with
stable coronary heart disease, with significant effects evident after
approximately 2 years of treatment. 1-3
<http://jama.ama-assn.org/issues/v285n13/rfull/#r1>  Previous trials
excluded patients who had experienced recent unstable angina or acute
myocardial infarction (MI). However, it is within the early period after an
acute coronary syndrome (ACS) that patients experience the highest rate of
death and recurrent ischemic events. 4
<http://jama.ama-assn.org/issues/v285n13/rfull/#r4> , 5
<http://jama.ama-assn.org/issues/v285n13/rfull/#r5>  To date, it has not
been determined whether initiation of treatment with a statin soon after an
ACS can reduce the occurrence of these early events.
Recent studies indicate that statins have salutary physiologic effects
within weeks. In conjunction with lowering total and low-density lipoprotein
(LDL) cholesterol, statins may improve endothelial function, 6-8
<http://jama.ama-assn.org/issues/v285n13/rfull/#r6>  decrease platelet
aggregability and thrombus deposition, 9
<http://jama.ama-assn.org/issues/v285n13/rfull/#r9> , 10
<http://jama.ama-assn.org/issues/v285n13/rfull/#r10>  and reduce vascular
inflammation. 11 <http://jama.ama-assn.org/issues/v285n13/rfull/#r11> , 12
<http://jama.ama-assn.org/issues/v285n13/rfull/#r12>  Each of these
mechanisms might be expected to have a favorable impact in the early period
following an ACS.
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
(MIRACL) study tested the hypothesis that treatment with atorvastatin (80
mg/d), initiated soon after presentation with unstable angina or non–Q-wave
acute MI, reduces the occurrence of early, recurrent ischemic events and
death.



METHODS



Study Population

The design of the MIRACL study has been described in detail previously. 13
<http://jama.ama-assn.org/issues/v285n13/rfull/#r13>  It was conducted at
122 centers in Europe, North America, South Africa, and Australasia.
Eligible patients were adults aged 18 years or older with chest pain or
discomfort of at least 15 minutes' duration that occurred at rest or with
minimal exertion within the 24-hour period preceding hospitalization and
represented a change from their usual anginal pattern. In addition,
diagnosis of unstable angina required evidence of myocardial ischemia by at
least 1 of the following 13
<http://jama.ama-assn.org/issues/v285n13/rfull/#r13> : new or dynamic
ST-wave or T-wave changes in at least 2 contiguous standard
electrocardiographic leads, a new wall motion abnormality by
echocardiography, a new and reversible myocardial perfusion defect by
radionuclide scintigraphy, or elevation of cardiac troponin to a level not
exceeding 2 times the upper limit of normal (ULN). Diagnosis of non–Q-wave
acute MI required elevation of serum creatine kinase or its MB fraction, or
troponin to a level exceeding 2 times the ULN.
Patients were excluded if the serum total cholesterol level at screening
exceeded 270 mg/dL (7 mmol/L) (sites in Poland and South Africa used levels
of 310 mg/dL [8 mmol/L]). There was no lower limit on cholesterol level at
entry. Patients were excluded if coronary revascularization was planned or
anticipated at the time of screening. Other exclusion criteria were:
evidence of Q-wave acute MI within the preceding 4 weeks; coronary artery
bypass surgery within the preceding 3 months; percutaneous coronary
intervention within the preceding 6 months; left bundle-branch block or
paced ventricular rhythm; severe congestive heart failure (New York Heart
Association class IIIb or IV); concurrent treatment with other
lipid-regulating agents (except niacin at doses of 500 mg/d), vitamin E
(except at doses 400 IU/d), or drugs associated with rhabdomyolysis in
combination with statins; severe anemia; renal failure requiring dialysis;
hepatic dysfunction (alanine aminotransferase greater than 2 times ULN);
insulin-dependent diabetes; pregnancy or lactation.
Study Design

The study was performed in accordance with the ethical principles set forth
in the Declaration of Helsinki and was approved by local ethics committees
or institutional review boards. Written informed consent was obtained from
all patients. Between 24 and 96 hours after hospital admission, eligible
patients were randomly assigned with stratification by center to
double-blind treatment with atorvastatin (80 mg/d) or matching placebo for
16 weeks. Treating physicians were requested not to perform any
determinations of serum lipid levels in the local hospital laboratory during
the study period. The protocol did not restrict or specify any other
diagnostic or therapeutic measures, except as noted in the exclusion
criteria. All patients received instruction and counseling to promote
compliance with a National Cholesterol Education Program Step I diet. 14
<http://jama.ama-assn.org/issues/v285n13/rfull/#r14>  Patients were seen in
follow-up 2, 6, and 16 weeks after the initiation of therapy. Laboratory
testing was performed centrally at baseline and at 6 and 16 weeks. An
independent data and safety monitoring board reviewed the results of 3
planned interim analyses using P<.001 for the primary end point analysis as
a statistical stopping guideline. On each occasion, continuation of the
study was recommended.
End Points

Patients were monitored for ischemic events for 16 weeks after
randomization. All end points were adjudicated by a committee of 6
cardiologists, who were blinded to treatment assignment. The primary
combined end point was death, nonfatal acute MI, cardiac arrest with
resuscitation, or recurrent symptomatic myocardial ischemia with objective
evidence requiring emergency rehospitalization. A blinded core laboratory
confirmed electrocardiographic entry criteria and diagnosis of acute MI from
electrocardiographic and cardiac enzyme data, using previously published
criteria. 15 <http://jama.ama-assn.org/issues/v285n13/rfull/#r15>  Cardiac
arrest with resuscitation and recurrent symptomatic myocardial ischemia with
objective evidence and emergency rehospitalization were diagnosed according
to previously published criteria. 13
<http://jama.ama-assn.org/issues/v285n13/rfull/#r13>  The latter diagnosis
required both exacerbation of the patient's usual symptoms and new objective
evidence of ischemia (electrocardiographic, echocardiographic, or
scintigraphic) with a definite change from a comparison study performed
after the index (inclusion) ischemic event. 13
<http://jama.ama-assn.org/issues/v285n13/rfull/#r13>
Secondary end points were the occurrence of each primary end point component
as well as nonfatal stroke, new or worsening congestive heart failure
requiring hospitalization, worsening angina requiring rehospitalization but
without new objective evidence of ischemia, coronary revascularization by
surgical or percutaneous means, time to first occurrence of any primary or
secondary end point, and percentage changes in blood lipid levels from
baseline to end of study. 13
<http://jama.ama-assn.org/issues/v285n13/rfull/#r13>  When recurrent
symptomatic ischemia with objective evidence or worsening congestive heart
failure occurred during the index hospitalization or a subsequent
hospitalization for another reason, the event was classified as an end point
if the end point committee judged that the event would have required
rehospitalization had it occurred outside of hospital.
Statistical Analysis

The initial sample size requirement was 2100 patients, based on the
assumption of 20% occurrence of a primary end point event among
placebo-treated patients and 14% occurrence among atorvastatin-treated
patients (ie, an average occurrence of 17% in both treatment groups),
2-sided significance level of .05, and 95% power. 13
<http://jama.ama-assn.org/issues/v285n13/rfull/#r13>  Pooled data (blinded
to treatment assignment) from the first 1260 patients indicated that the
occurrence of primary end points was 13% (ie, 4% less than predicted).
Consequently, the steering committee recommended an increase in sample size
to 3000 patients to maintain 95% power to detect a 30% relative treatment
effect and 80% power to detect a 25% relative treatment effect.
The primary combined end point was analyzed by time of first event, using a
Cox proportional hazards model 16
<http://jama.ama-assn.org/issues/v285n13/rfull/#r16>  stratified by country
and inclusion event (unstable angina or non–Q-wave acute MI). The occurrence
of each end point was analyzed using the Cochran Mantel-Haenszel method, 17
<http://jama.ama-assn.org/issues/v285n13/rfull/#r17>  stratified by country
and inclusion event. All end point analyses were performed on an
intention-to-treat basis, with all randomized patients included in the
analyses. Censoring occurred for patients who did not experience an end
point prior to completing the study as planned or prior to early withdrawal
from the study. In the case of censoring, the survival time corresponded to
the day of final study contact. Interaction of treatment assignment with
baseline demographic and clinical characteristics and baseline lipid levels
was examined. Percent changes from baseline in blood lipid levels were
adjusted using an analysis of covariance model with treatment assignment,
country, inclusion event, and baseline value as covariates. Lipid analyses
were performed on a modified intention-to-treat basis, with all randomized
patients who had both a baseline measurement and at least 1 double-blind
measurement included in the analyses. The last double-blind measurement
collected after randomization was carried forward for patients who did not
have a lipid measurement at 16 weeks.
The study protocol specified 3 interim analyses of safety and efficacy by
the data safety and monitoring board. A significance level of P = .001 was
used for each interim analysis, with a significance level for the final
analysis adjusted to P = .049 to preserve to the overall type I error rate
at P = .05. The testing of all secondary objectives was done at the 2-sided
P = .05 level of significance.



RESULTS



Patients

Between May 1997 and September 1999, 3086 patients were enrolled; 1538 were
randomly assigned to receive atorvastatin and 1548 to receive placebo
 Figure 1
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_f1.html> ).
Demographic and clinical characteristics of the patients assigned to the 2
treatment groups were similar at baseline ( Table 1
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_t1.html> ). The
mean time between hospitalization for the inclusion event and randomization
into the study was 63 hours in both groups. Information was collected as
planned for all study patients except 8 (0.5%) in the atorvastatin group and
3 (0.2%) in the placebo group who were lost to follow-up. Intended follow-up
was 112 days (16 weeks). A patient was considered lost to follow up if
he/she withdrew early and there was no final follow-up data for the patient
or if he/she was followed up for less than 100 days without experiencing a
primary end point.
Compliance

Compliance with prescribed study treatment, defined as the number of days
that patients took study medication (determined by last day of study
medication) divided by the number of days of intended treatment (112 days),
was 86% in the atorvastatin group and 88% in the placebo group. Treatment
was discontinued prematurely in 173 (11.2%) atorvastatin-treated patients
and 160 (10.3%) placebo-treated patients, a nonsignificant difference.
Twenty-three patients in the atorvastatin group and 26 patients in the
placebo group were treated with an open-label lipid-lowering medication
after premature discontinuation of study medication. Reasons for premature
discontinuation of treatment are indicated in Figure 1
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_f1.html> .
Concurrent Medications

Similar medications were administered to patients in the placebo and
atorvastatin groups, both prior to and after admission to hospital for the
inclusion ischemic event ( Table 2
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_t2.html> ).
Aspirin, heparin, nitrates, and beta-blockers were administered to a
majority of patients; however, platelet glycoprotein IIb/IIIa receptor
antagonists were used in only 1% of patients.
Serum Lipid Levels

At the time of randomization, serum lipid levels were nearly identical in
both groups ( Figure 2
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_f2.html> ) with
mean LDL cholesterol level of 124 mg/dL (3.2 mmol/L), mean triglycerides
level of 184 mg/dL (2.0 mmol/L), and mean HDL cholesterol level of 46 mg/dL
(1.2 mmol/L). At 6 weeks, reductions in total and LDL cholesterol and
triglycerides with atorvastatin were essentially complete. At the end of the
study, LDL cholesterol had increased by an adjusted mean of 12% to 135 mg/dL
(3.5 mmol/L) in the placebo group and decreased by an adjusted mean of 40%
to 72 mg/dL (1.9 mmol/L) in the atorvastatin group. Triglycerides increased
by an adjusted mean of 9% to 187 mg/dL (2.1 mmol/L) in the placebo group and
decreased by an adjusted mean of 16% to 139 mg/dL (1.6 mmol/L) in the
atorvastatin group. Changes in HDL cholesterol during the study were minor
in both groups.
End Point Events

During the 16-week study period, a primary end point event occurred in 228
patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the
placebo group, an absolute difference of 2.6% ( Figure 3
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_f3.html>  and
Table 3
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_t3.html> ).
Atorvastatin treatment significantly reduced the risk of the primary
combined end point (relative risk [RR], 0.84; 95% confidence interval [CI],
0.70-1.00; P = .048). There were no significant differences in risk of
death, nonfatal acute MI, or cardiac arrest with resuscitation between the
atorvastatin group and the placebo group, although the atorvastatin group
had a lower risk of recurrent symptomatic myocardial ischemia with objective
evidence requiring emergency rehospitalization (RR, 0.74; 95% CI, 0.57-0.95;
P = .02) ( Table 3
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_t3.html>  and
Figure 4
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_f4.html> ).
There were no significant interactions between treatment assignment and any
of the baseline characteristics listed in Table 1
<http://jama.ama-assn.org/issues/v285n13/fig_tab/joc10254_t1.html>  or the
baseline values of any of the measured serum lipid levels. In particular,
the reduction of primary ischemic events by atorvastatin did not appear to
depend on the baseline level of LDL cholesterol. Among patients who had
baseline LDL cholesterol levels of less than or equal to the median value of
121 mg/dL (3.1 mmol/L), primary end point events occurred in 231 patients
(15.0%) in the atorvastatin group and 288 patients (18.6%) in the placebo
group (RR, 0.77; 95% CI, 0.59-0.98). Among patients who had baseline LDL
cholesterol levels greater than the median value, primary end point events
occurred in 231 patients (15.0%) in the atorvastatin group and 257 patients
(16.6%) in the placebo group (RR, 0.92; 95% CI, 0.71-1.19). Moreover, among
atorvastatin-treated patients, there was no significant association between
the percentage change in LDL cholesterol from baseline to end of study
(dichotomized by the median percentage change) and the occurrence of a
primary end point event.
There were no significant differences between groups in the incidence of
coronary revascularization procedures, worsening heart failure, worsening
angina without objective evidence of ischemia occurrence of at least 1
secondary end point, or occurrence of at least 1 primary or secondary end
point. There were significant differences between groups for incidence of
nonfatal stroke, which occurred in 9 patients in the atorvastatin group,
compared with 22 patients in the placebo group (RR, 0.41; 95% CI, 0.20-0.87;
P = .02) and either fatal or nonfatal stroke, which occurred in 12 patients
in the atorvastatin group, compared with 24 patients in the placebo group
(RR, 0.50; 95% CI, 0.26-0.99; P = .045).
Safety

No serious adverse event occurred with a frequency of more than 1% in either
group. Abnormal liver transaminase levels (>3 times ULN) occurred in 38
patients (2.5%) in the atorvastatin group and in 9 patients (0.6%) in the
placebo group (P<.001). Three of these 38 patients in the atorvastatin group
were hospitalized with a diagnosis of hepatitis (elevated liver
transaminases associated in 2 cases with jaundice and/or fever). In each
case these abnormalities resolved following discontinuation of the drug.
There were no documented cases of myositis.
The number needed to treat to prevent 1 primary end point event (death,
nonfatal MI, cardiac arrest with resuscitation, or recurrent symptomatic
myocardial ischemia with objective evidence requiring emergency
hospitalization) was 38. The number needed to treat to prevent 1 primary end
point event or nonfatal stroke was 33. The number needed to treat to cause 1
case of elevated liver transaminases (>3 times ULN on 2 determinations) was
53.



COMMENT



In this trial, early treatment with atorvastatin 80 mg/d reduced recurrent
ischemic events over a 16-week treatment period among patients with unstable
angina or non–Q-wave acute MI. There was a 2.6% absolute reduction and a 16%
relative reduction in the primary combined end point of death, nonfatal
acute MI, cardiac arrest with resuscitation, or worsening symptomatic
myocardial ischemia with objective evidence and emergency rehospitalization.
Our finding that treatment with 80 mg/d of atorvastatin, initiated 24 to 96
hours after an ACS, reduces the risk of recurrent ischemic events extends
the findings of previous studies that used conventional doses of other
statins in patients with stable coronary heart disease. In these previous
studies, small differences in event rates were noted in the early period
after randomization, but 1 to 2 years of treatment were required before a
significant reduction in cardiovascular events could be documented. 1-3
<http://jama.ama-assn.org/issues/v285n13/rfull/#r1>  While the relative
benefit of treatment observed in the present trial over 16 weeks is less
than that observed in the previous trials over periods of 5 to 7 years, the
absolute reduction in events (2.6%) in the present trial is greater than
that achieved during a comparable length of time in a stable population.
This study was not powered to detect differences between treatment groups in
the individual components of the primary composite end point. Although,
death, nonfatal MI, and cardiac arrest occurred slightly less frequently in
the atorvastatin group than in the placebo group, the differences in these
end points were not statistically significant. Most of the intergroup
difference in the combined primary end point resulted from a reduction in
recurrent symptomatic myocardial ischemia with objective evidence and
emergency rehospitalization (absolute risk reduction 2.2%; 26% reduction in
RR in the atorvastatin group; P = .02).
The occurrence of stroke was significantly reduced in the atorvastatin group
compared with the placebo group, suggesting that atorvastatin treatment also
may produce beneficial effects on cerebrovascular events within 16 weeks,
although the number of stroke events in each group was small.
Patients with Q-wave acute MI were excluded from this study because factors
that are unlikely to be affected by cholesterol lowering, such as left
ventricular dysfunction, ventricular arrhythmias, and mechanical
complications represent the major determinants of short-term outcome.
Patients for whom a coronary revascularization procedure was planned or
anticipated at the time of screening were excluded so that adverse events
related to the procedures or to restenosis after angioplasty would not
complicate assessment of the effect of atorvastatin treatment. The effects
of atorvastatin for these groups of patients are unknown.
Despite a low rate of revascularization, patients in our trial experienced a
similar incidence of death and nonfatal acute MI as patients in another
large, contemporary trial of ACSs. 5
<http://jama.ama-assn.org/issues/v285n13/rfull/#r5>  In comparing event
rates among trials, it is noteworthy that our trial did not include as end
points events that occurred during the median 63-hour period between
hospital admission and randomization.
In this study, the benefit of treatment with 80 mg/d of atorvastatin was
observed in a population with a mean baseline LDL cholesterol level of 124
mg/dL (3.2 mmol/L). While this cholesterol level may have been slightly
decreased by the acute coronary event, as suggested by the subsequent
increase in LDL cholesterol in the placebo group to a mean level of 135
mg/dL (3.5 mmol/L) at the end of the study, this level is lower than the
mean baseline LDL cholesterol levels in the 3 previous long-term trials of
statins in patients with coronary heart disease (139-188 mg/dL [3.6-4.9
mmol/L]). 1-3 <http://jama.ama-assn.org/issues/v285n13/rfull/#r1>  Moreover,
the benefit of atorvastatin in our study did not appear to depend on
baseline LDL cholesterol levels or baseline levels of other lipid fractions.
This is consistent with subgroup analysis of one 18
<http://jama.ama-assn.org/issues/v285n13/rfull/#r18>  but not another 2
<http://jama.ama-assn.org/issues/v285n13/rfull/#r2>  long-term study of a
statin in patients with average LDL cholesterol levels. In our study, it is
possible that the finding is related to more serious illness and therefore
greater acute phase decreases of serum lipoprotein levels among patients
with lower baseline lipid levels. Nonetheless, the observation suggests that
the decision to initiate intensive lipid-lowering therapy after an ACS
should not necessarily be influenced by serum lipid levels at the time of
the event.
Despite relatively low baseline levels of LDL cholesterol in our study, 16
weeks of atorvastatin treatment produced a further reduction to a mean level
of 72 mg/dL (1.9 mmol/L), a level lower than that achieved with active
treatment in the Scandinavian Simvastatin Survival Study (4S), 1
<http://jama.ama-assn.org/issues/v285n13/rfull/#r1>  Cholesterol and
Recurrent Events trial (CARE), 2
<http://jama.ama-assn.org/issues/v285n13/rfull/#r2>  or Long-Term
Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. 3
<http://jama.ama-assn.org/issues/v285n13/rfull/#r3>  Some available evidence
suggests that greater LDL cholesterol lowering (with higher doses of a
statin) results in greater reduction of ischemic cardiovascular events than
moderate LDL cholesterol lowering (with lower doses of a statin). 19
<http://jama.ama-assn.org/issues/v285n13/rfull/#r19>  In the present trial,
we were able to test the effects of 1 dose of atorvastatin. We chose the
80-mg dose to produce a large average reduction in serum cholesterol levels.
Our data do not allow us to determine if a lower dose of atorvastatin, or
gradual dose titration to a predetermined LDL cholesterol level, would
achieve similar benefits.
The sample size for this trial was determined on the basis of an expected
25% to 30% reduction of primary end points in the atorvastatin group
compared with the placebo group. Therefore, the trial had lower power to
detect the actual reduction of 16%, resulting in a marginally significant P
value for the primary efficacy analysis. These results suggest a need for
further trials of statins in ACSs and may be helpful in determining the
sample size of such trials.
Atorvastatin was generally well tolerated in this patient population. There
were no documented cases of myositis, which is the most serious adverse
effect of statins. Levels of serum transaminases exceeding 3 times the ULN
were detected in 2.5% of atorvastatin-treated patients and 0.6% of
placebo-treated patients.
In conclusion, the results of this trial indicate that treatment with 80
mg/d of atorvastatin, initiated during the acute phase of unstable angina or
non–Q wave acute MI, reduces the risk of early, recurrent ischemic events,
primarily recurrent symptomatic ischemia requiring hospitalization.



Author/Article Information


Author Affiliations: Cardiology Section, Veterans Affairs Medical Center and
University of Colorado Health Sciences Center, Denver (Dr Schwartz); Faculty
of Health Sciences, University of Linköping, Linköping, Sweden (Dr Olsson);
Hahnemann University, Philadelphia, Pa (Dr Ezekowitz); Cardiovascular
Division, Brigham and Women's Hospital and Harvard Medical School, Boston,
Mass (Dr Ganz); Cardiac Medicine, National Heart and Lung Institute,
Imperial College, London, England (Dr Oliver); Division of Cardiology, San
Francisco General Hospital and University of California, San Francisco (Dr
Waters); Cardiology Department, Johann Wolfgang Goethe University,
Frankfurt, Germany (Dr Zeiher); Division of Cardiology, St Louis University
School of Medicine, St Louis, Mo (Dr Chaitman); Pfizer Pharmaceutical
Research, New York, NY (Dr Leslie); and Pfizer Pharmaceutical Research, Ann
Arbor, Mich (Dr Stern). Dr Oliver is now retired.

Corresponding Author and Reprints: Gregory G. Schwartz, MD, PhD, Cardiology
Section (111B), Denver VA Medical Center, 1055 Clermont St, Denver, CO 80220
(e-mail: [log in to unmask] <mailto:[log in to unmask]> ).
Author Contributions: Dr Schwartz, as principal investigator of the
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)
Study, had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the data
analyses.
Study concept and design: Schwartz, Olsson, Ezekowitz, Ganz, Oliver, Waters,
Zeiher.
Acquisition of data: Schwartz, Olsson, Ezekowitz, Ganz, Oliver, Waters,
Zeiher, Chaitman, Leslie, Stern.
Analysis and interpretation of data: Schwartz, Olsson, Ezekowitz, Ganz,
Oliver, Waters, Zeiher, Chaitman, Leslie, Stern.
Drafting of the manuscript: Schwartz, Olsson, Ezekowitz, Ganz, Oliver,
Waters, Zeiher, Stern.
Critical revision of the manuscript for important intellectual content:
Schwartz, Olsson, Ezekowitz, Ganz, Oliver, Waters, Zeiher, Chaitman, Leslie,
Stern.
Statistical expertise: Stern.
Obtained funding: Schwartz, Olsson.
Administrative, technical, or material support: Ganz, Leslie.
Study supervision: Schwartz, Olsson, Ezekowitz, Ganz, Oliver, Waters,
Zeiher.
Financial Disclosures: Dr Schwartz served as a consultant to Parke Davis and
Pfizer Pharmaceutical research, but he received no personal remuneration,
instead a consultant's fee was paid to a nonprofit research foundation to
support his basic research laboratory. Dr Olsson has been a consultant for
AstraZeneca, NEGMA, Novartis, and Pfizer and has received research grants
from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck, NEGMA, Pfizer, and
Pharmacia. Dr Ezekowitz is in Pfizer's speaker's program and also serves as
a consultant for Pfizer for a different program outside this study. Dr
Oliver received funding from Parke Davis and Pfizer during the trial for
expenses incurred in relation to the trial. Dr Waters has received honoraria
for lectures and payment for consulting from Pfizer. Dr Chaitman served as
the principal investigator for the Core ECG Laboratory and received a
research contract for his work.
Funding/Support: Supported by a grant from Pfizer Inc. Pfizer provided the
atorvastatin and matching placebo used in this study.
MIRACL Investigators, Participating Centers, and Committee Members:
Investigators: Australia (117 patients): Auchenflower: D. Colquhoun; Bedford
Park: R. Minson; Chermside: C. Aroney; Herston: D. Cross; Nedlands: P.
Thompson; Prahan: A. Dart; St. Leonards: G. Nelson. Austria (43 patients):
Graz: W. Klein; Wien: R. Karnik and D. Glogar. Canada (873 patients):
Alberta: Calgary: D. Roth and P. Ma; Edmonton: V. Dzavik; Vancouver, British
Columbia: R. Carere; New Brunswick: Moncton: M. D'Astous; Saint John: D.
Marr; Halifax, Nova Scotia: B. O'Neill; Ontario: Barrie: B. Burke; Brampton:
D. Borts; Brockville: J. Hynd; Cornwall: J. P. DeYoung; Downsview: T.
Bhesania; Etobicoke: K. Kwok; Hamilton: A. Kitching; Mississauga: H. Strauss
and P. Kannampuzha; Newmarket: A. Hess; Niagara Falls: Y. K. Chan; Oshawa:
R. Bharagava; Ottawa: L. Higginson; Richmond Hill: E. Gangbar; Scarborough:
N. Singh; Toronto: R. Bauer, P. Gladstone, C. Lefkowitz, B. Gilbert, and S.
Goodman; Weston: M. T. Cheung; Willowdale: B. Lubelsky; Winnipeg: J. Ducas;
Quebec: Drummondville: R. Roux; Lévis-Lauzon: P. Auger; Longueuil: J. Lenis;
Montreal: C. Constance, M. Smilovitch, and J. Diodati; Pointe-Claire: F.
Sandrin; Rivière du Loup: B. Verret; Saint-Hyacinthe: C. Kieu; Saint-Jérôme:
Y. Pesant; Regina, Saskatchewan: R. Zimmerman. Czech Republic (115
patients): Brno: J. Spinar; Brno-Bohunice: B. Semrad; Jihlava: P. Svitil;
Litomerice: I. Brambaski; Prague: J. Münz, V. Stanek, and J. Bultas; Pribam:
O. Jerabek. Finland (4 patients): Tampere: A. Pasternack. France (4
patients): Toulouse: J. Puel. Germany (24 patients): Frankfurt: A. Zeiher;
Ludwigshafen: B. Winkelmann. Greece (334 patients): Athens: C. Merkouris; L.
Anthopoulos; Salonica: A. Kontopoulos; Voula: S. Christakos. Italy (76
patients): Genova: C. Brunelli; Milan: C. Fiorentini; Pavia: G. Specchia;
Rome: A. Maseri. The Netherlands (192 patients): Delft: A. J. A. M.
Withagen; Dordrecht: I. Stoel; Goes: A. H. Liem; Groningen: A. J. van Boven;
Nieuwegein: J. H. Kingma. New Zealand (55 patients): Christchurch: R. Scott.
Poland (84 patients): Bydgoszcz: W. Rajewski; Kielce: M. Janion; Krakow: W.
Piotrowski; Lublin: W. Ruminski; Otwock: M. Regulski; Zielona Gora: K. Kuc.
Portugal (15 patients): Almada: M. Carrageta; Lind' A Velha: R. Seabra
Gomes; Lisbon: L. Patricio. South Africa (339 patients): Bloemfontein: J. D.
Marx; Capetown: A. Doubell; P. Commerford; Durban: S. Cassim; Pretoria: D.
Myburgh. Spain (433 patients): Barcelona: J. Gumá; Cordoba: M. Anguita;
Madrid: A. Pozuelo; L. M. Jadraque; C. Macaya; Marbella: F. Torres; Seville:
J. M. Cruz Fernandez; Tarragona: A. Bardají; Vitoria: J. Martinez Ferrer;
Zaragoza: I. Ferreira; L. Placer. Sweden (124 patients): Halmstad: M.
Lindgren; Huddinge: G. Rasmanis; Karlsham: S. Jensen; Stockholm: L.
Svensson. Switzerland (17 patients): Luzern: P. Erne. United Kingdom (81
patients): England: Birmingham: N. Buller; Cambridge: P. Weissberg;
Newcastle upon Tyne: J. Bourke; Glasgow, Scotland: S. Cobbe. United States
(156 patients): Tucson, Ariz: C. Hoover; California: Burbank: D. Eisenberg;
San Francisco: G. Schwartz; Connecticut: Hartford: P. Thompson; West Haven:
M. Ezekowitz; Washington, DC: D. Lu; Florida: Gainesville: C. Pepine;
Jacksonville: T. Bass; Baltimore, Md: M. Miller; N. Carliner; Richmond, Va:
J. Funai.
Steering Committee: A. G. Olsson and G. G. Schwartz (cochairs); M.
Ezekowitz, P. Ganz, M. F. Oliver, D. Waters, A. Zeiher.
Data and Safety Monitoring Board: E. Rapaport (chair); P. W. Armstrong, A.
Gotto, S. J. Pocock.
End Point Committee: P. Stone (chair); M. Knudtson, J. M. La Blanche, H.
Levine, C. O'Connor, B. O'Neill.
Writing Subcommittee: G. G. Schwartz (chair); M. F. Oliver, A. G. Olsson, D.
Waters.
Data Analysis: T. Stern.
Core Electrocardiographic Laboratory: St Louis University (B. R. Chaitman,
director). Central Laboratories: Clinical Research Laboratories, Zaventem,
Belgium; Medical Research Laboratories, Highland Heights, Ken.
Study Management and Monitoring Offices (Pfizer Inc): D. Black, S. Leslie,
D. MacDougall, J. Nawrocki, M. Pressler, K. Roberts, H. Schwende.




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Edward E. Rylander, M.D.
D.A.B.F.P and D.A.B.P.M.