Effects of Atorvastatin on Early Recurrent
Ischemic Events in Acute Coronary Syndromes
The MIRACL Study: A
Randomized Controlled Trial
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
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 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, 5 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 decrease
platelet aggregability and thrombus deposition,9, 10 and reduce vascular
inflammation.11, 12 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.
Study Population
The design of the MIRACL study has been described in detail previously.13 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 following13: 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 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 Cardiac arrest with
resuscitation and recurrent symptomatic myocardial ischemia with objective
evidence and emergency rehospitalization were diagnosed according to previously
published criteria.13 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
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 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 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 model16 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 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.
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).
Demographic and clinical characteristics of the patients assigned to the 2
treatment groups were similar at baseline (Table 1).
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.
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).
Aspirin, heparin, nitrates, and -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)
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
and Table 3).
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
and Figure 4).
There were no significant interactions between
treatment assignment and any of the baseline characteristics listed in Table 1
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.
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 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 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 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 one18 but not another2 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 Cholesterol and
Recurrent Events trial (CARE),2 or Long-Term
Intervention with Pravastatin in Ischaemic Disease (LIPID) trial.3 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 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]).
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.
1.
Scandinavian Simvastatin Survival Study Group.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart
disease: the Scandinavian Simvastatin Survival Study (4S).
Lancet.
1994;344:1383-1389.
MEDLINE
2.
Sacks FM, Pfeiffer MA, Moye LA, et al.
The effect of pravastatin on coronary events after myocardial infarction in
patients with average cholesterol levels.
N Engl J Med.
1996;335:1001-1009.
MEDLINE
3.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study
Group.
Prevention of cardiovascular events and death with pravastatin in patients with
coronary heart disease and a broad range of initial cholesterol levels.
N Engl J Med.
1998;339:1349-1357.
MEDLINE
4.
Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients
Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators.
Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in
unstable angina and non-Q wave myocardial infarction. Platelet Receptor
Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable
Signs and Symptoms (PRISM-PLUS) Study Investigators.
N Engl J Med.
1998;338:1488-1497.
MEDLINE
5.
Fragmin and Fast Revascularisation During Instability in Coronary Artery
Disease (FRISC II) Investigators.
Invasive compared with non-invasive treatment in unstable coronary-artery
disease: FRISC II prospective randomised multicentre study.
Lancet.
1999;354:708-715.
MEDLINE
6.
O'Driscoll G, Green D, Taylor RR.
Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial
function within 1 month.
Circulation.
1997;95:1126-1131.
MEDLINE
7.
Huggins GS, Pasternak RC, Alpert NM, Fischman AJ, Gewirtz H.
Effects of short-term treatment of hyperlipidemia on coronary vasodilator
function and myocardial perfusion in regions having substantial impairment of
baseline dilator reserve.
Circulation.
1998;98:1291-1296.
MEDLINE
8.
Dupuis J, Tardif J-C, Cernacek P, Théroux P.
Cholesterol reduction rapidly improves endothelial function after acute
coronary syndromes: the RECIFE (Reduction of Cholesterol in Ischemia and
Function of Endothelium) Trial.
Circulation.
1999;99:3227-3333.
MEDLINE
9.
Lacoste L, Lam JYT, Hung J, Letchacovski G, Solymoss CB, Waters D.
Hyperlipidemia and coronary disease: correction of the increased thrombogenic
potential with cholesterol reduction.
Circulation.
1995;92:3172-3177.
MEDLINE
10.
Notarbartolo A, Davì G, Averna M, et al.
Inhibition of thromboxane biosynthesis and platelet function by simvastatin in
type IIa hypercholesterolemia.
Arterioscler Thromb Vasc Biol.
1995;15:247-251.
MEDLINE
11.
Bustos C, Hernández-Presa MA, Ortego M, et al.
HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in
a rabbit model of atherosclerosis.
J Am Coll Cardiol.
1998;32:2057-2064.
MEDLINE
12.
Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E, for the Cholesterol and
Recurrent Events (CARE) Investigators.
Long-term effects of pravastatin on plasma concentration of C-reactive protein.
Circulation.
1999;100:230-235.
MEDLINE
13.
Schwartz GG, Oliver MF, Ezekowitz MD, et al.
Rationale and design of the Myocardial Ischemia Reduction with Aggressive
Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable
angina pectoris and in non-Q-wave acute myocardial infarction.
Am J Cardiol.
1998;81:578-581.
MEDLINE
14.
National Cholesterol Education Program.
Second Report of the Expert Panel on
Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
Bethesda, Md: National Institutes of Health; 1993.
15.
Rautaharju PM, Calhoun HP, Chaitman BR.
NOVACODE serial ECG classification system for clinical trials and epidemiologic
studies.
J Electrocardiol.
1992;24(suppl):179-187.
MEDLINE
16.
Cox DR.
Regression models and life tables.
J R Stat Soc [B].
1972;34:187-202.
17.
Mantel N.
Evaluation of survival data and two new rank order statistics arising in its
consideration.
Cancer Chemother Rep.
1966;50:163-170.
MEDLINE
18.
Gotto AM, Whitney E, Stein EA, et al.
Relation between baseline and on-treatment lipid parameters and first acute
major coronary events in the Air Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/TexCAPS).
Circulation.
2000;101:477-484.
MEDLINE
19.
Knatterud GL, Rosenberg Y, Campeau L, et al, for the Post CABG Investigators.
Long-term effects on clinical outcomes of aggressive lowering of low-density
lipoprotein cholesterol levels and low-dose anticoagulation in the Post
Coronary Artery Bypass Graft Trial.
Circulation.
2000;102:157-165.
MEDLINE
Edward
E. Rylander, M.D.
D.A.B.F.P and
D.A.B.P.M.