Context Limited data are available evaluating how the timing and intensity of
statin therapy following an acute coronary syndrome (ACS) event affect clinical
outcome.
Objective To compare early initiation of an intensive statin regimen with delayed
initiation of a less intensive regimen in patients with ACS.
Design, Setting, and Participants International, randomized, double-blind trial of patients with ACS receiving
40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter (n = 2265)
compared with ACS patients receiving placebo for 4 months followed by 20 mg/d
of simvastatin (n = 2232), who were enrolled in phase Z of the A to Z trial
between December 29, 1999, and January 6, 2003.
Main Outcome Measure The primary end point was a composite of cardiovascular death, nonfatal
myocardial infarction, readmission for ACS, and stroke. Follow-up was for
at least 6 months and up to 24 months.
Results Among the patients in the placebo plus simvastatin group, the median
low-density lipoprotein (LDL) cholesterol level achieved while taking placebo
was 122 mg/dL (3.16 mmol/L) at 1 month and was 77 mg/dL (1.99 mmol/L) at 8
months while taking 20 mg/d of simvastatin. Among the patients in the simvastatin
only group, the median LDL cholesterol level achieved at 1 month while taking
40 mg/d of simvastatin was 68 mg/dL (1.76 mmol/L) and was 63 mg/dL (1.63 mmol/L)
at 8 months while taking 80 mg/d of simvastatin. A total of 343 patients (16.7%)
in the placebo plus simvastatin group experienced the primary end point compared
with 309 (14.4%) in the simvastatin only group (40 mg/80 mg) (hazard ratio
[HR], 0.89; 95% confidence interval [CI] 0.76-1.04; P =
.14). Cardiovascular death occurred in 109 (5.4%) and 83 (4.1%) patients in
the 2 groups (HR, 0.75; 95% CI, 0.57-1.00; P = .05)
but no differences were observed in other individual components of the primary
end point. No difference was evident during the first 4 months between the
groups for the primary end point (HR, 1.01; 95% CI, 0.83-1.25; P = .89), but from 4 months through the end of the study the primary
end point was significantly reduced in the simvastatin only group (HR, 0.75;
95% CI, 0.60-0.95; P = .02). Myopathy (creatine kinase
>10 times the upper limit of normal associated with muscle symptoms) occurred
in 9 patients (0.4%) receiving simvastatin 80 mg/d, in no patients receiving
lower doses of simvastatin, and in 1 patient receiving placebo (P = .02).
Conclusions The trial did not achieve the prespecified end point. However, among
patients with ACS, the early initiation of an aggressive simvastatin regimen
resulted in a favorable trend toward reduction of major cardiovascular events.
Conclusions Published online August 30, 2004 (doi:10.1001/jama.292.11.1307).
Long-term therapy with statin drugs has been shown to reduce the risk
for death, myocardial infarction (MI), and stroke among patients with established
coronary artery disease, even when low-density lipoprotein (LDL) cholesterol
levels are not elevated.1-4 Most
of the landmark clinical trials evaluating statins for secondary prevention
enrolled patients who were stable for at least several months after an index
acute coronary syndrome (ACS) event.1-3 More
recently, 2 randomized controlled trials have evaluated earlier initiation
of statin therapy following an ACS event and have noted a corresponding early
reduction in major cardiovascular events.5,6
Phase Z of the A to Z trial was designed to evaluate a strategy of early
initiation of intensive treatment with simvastatin in ACS patients compared
with a delayed, less intensive strategy.
Details of the study design have been reported previously.7 The
A to Z trial is an international trial consisting of 2 overlapping phases.
Phase A was an open-label noninferiority trial comparing enoxaparin with unfractionated
heparin in patients with non–ST-elevation ACS who were treated with
tirofiban and aspirin. Patients were required to have chest pain at rest lasting
10 minutes or longer within the previous 24 hours, which was associated with
either ST elevation or depression of 0.5 mm or higher, or with elevated levels
of creatine kinase–MB or troponin. Results of phase A have been reported.8
Phase Z is a double-blind trial comparing 2 statin regimens in patients
with ACS. Patients between the ages of 21 and 80 years with either non–ST-elevation
ACS or ST-elevation MI were eligible for enrollment if they had a total cholesterol
level of 250 mg/dL (6.48 mmol/L) or lower. Initially, patients were entered
into phase Z only if they presented with non–ST-elevation ACS, were
stabilized during phase A of the trial for at least 12 consecutive hours within
5 days after symptom onset, and met at least 1 of the following high-risk
characteristics: age older than 70 years; diabetes mellitus; prior history
of coronary artery disease, peripheral arterial disease, or stroke; elevation
of serum creatine kinase–MB or troponin levels; recurrent angina with
ST-segment changes; electrocardiographic evidence of ischemia on a predischarge
stress test; or multivessel coronary artery disease determined by coronary
angiography. Patients enrolled in phase A who did not meet stability and high-risk
criteria were not eligible for continuation to phase Z. All patients provided
written informed consent and the protocol was approved by the local institutional
review board of each participating hospital.
The protocol was amended to allow patients with non–ST-elevation
ACS who were not enrolled in phase A and patients with ST-elevation MI to
enter directly into phase Z. Patients in the latter category were required
to receive fibrinolytic therapy or primary percutaneous coronary intervention
(PCI) if they presented within 12 hours of symptom onset and no reperfusion
therapy if symptom onset was longer than 12 hours prior to presentation. Patients
were also required to meet criteria for stability and have at least 1 high-risk
feature in addition to cardiac biomarker elevation.
Patients were excluded from enrollment if they were receiving statin
therapy at the time of randomization, if coronary artery bypass graft surgery
was planned, or if PCI was planned within the first 2 weeks after enrollment.
Patients also were excluded for having an alanine aminotransferase (ALT) level
higher than 20% above the upper limit of normal (ULN); for having an increased
risk for myopathy due to renal impairment (serum creatinine level >2.0 mg/dL
[176.8 µmol/L]) or concomitant therapy with agents known to enhance
myopathy risk, such as fibrates, cyclosporine, macrolide antibiotics, azole
antifungals, amiodarone, or verapamil; or for having a prior history of nonexercise-related
elevations in creatine kinase level or nontraumatic rhabdomyolysis.
Randomization and Follow-up
All patients were encouraged to adopt an American Heart Association
Step I diet. They were randomized to either an early intensive statin treatment
strategy (40 mg/d of simvastatin for 30 days and then 80 mg/d of simvastatin
thereafter) or a less aggressive strategy (placebo for 4 months and then 20
mg/d of simvastatin thereafter). Each center was assigned 1 or more blocks
of 4 allocation numbers and blinded study supplies corresponding to these
allocation numbers. Treatments were assigned randomly to the allocation numbers
using a blocked randomization scheme. A patient was randomized by being assigned
to the next available allocation number at that site.
Clinical and laboratory assessments (lipid levels, high-sensitivity
C-reactive protein serum chemistries, liver function tests, creatine kinase
level, and urine pregnancy tests) were performed prior to study drug initiation
and at months 1, 4, and 8 and every 4 months thereafter until trial completion.
Patients were followed up for at least 6 months and up to 24 months. Patients
who had LDL cholesterol levels that were higher than 130 mg/dL (3.37 mmol/L)
at month 8 or any subsequent visit were provided additional dietary, lifestyle,
and compliance counseling. If after 6 weeks the LDL cholesterol level remained
higher than 130 mg/dL (3.37 mmol/L), the investigator could either add a bile
acid sequestrant or discontinue the study drug and initiate open-label statin
therapy. The study drug was discontinued if the LDL cholesterol level was
40 mg/dL (1.04 mmol/L) or lower.
Patients with levels of ALT or aspartate aminotransferase (AST) that
were higher than 3 times the ULN and creatine kinase levels higher than 5
times the ULN were required to have a repeat measurement within 3 days. Protocol-mandated
withdrawal from study treatment was required for patients with any consecutive
elevations in ALT or AST levels higher than 3 times the ULN, a single measurement
of creatine kinase level higher than 10 times the ULN with muscle symptoms,
or a consecutive measurement of creatine kinase level higher than 10 times
the ULN without symptoms.
The primary efficacy end point of the trial was a composite of cardiovascular
death, nonfatal MI, readmission for ACS (requiring new electrocardiographic
changes or cardiac marker elevation), and stroke. All primary end points were
adjudicated by an independent clinical end point committee blinded to treatment
assignment. Secondary end points included individual components of the primary
end point, revascularization due to documented ischemia, all-cause mortality,
new-onset congestive heart failure (requiring admission or initiation of heart
failure medications), and cardiovascular rehospitalization.
Adverse events were recorded at each study visit, and safety data were
reviewed by an independent data and safety monitoring board. The primary safety
outcomes were elevations in levels of AST or ALT higher than 3 times the ULN
or myopathy (defined as creatine kinase level >10 times the ULN and associated
with muscle symptoms).9 Rhabdomyolysis was
defined as a creatine kinase level higher than 10 000 units/L with or
without muscle symptoms.10
Sample size calculations were based on the following assumptions: (1)
a 1-year event rate of 20% in the placebo plus 20 mg/d of simvastatin group
based on the observed event rate between 4 and 180 days in the tirofiban plus
unfractionated heparin group in the Platelet Receptor Inhibition in Ischemic
Syndrome Management in Patients Limited by Unstable Angina Signs and Symptoms
(PRISM PLUS) study11; (2) a 15% discontinuation
rate; and (3) a 20% reduction in the primary end point rate in the simvastatin
only group (40 mg/d and then 80 mg/d). Based on these assumptions, 970 patients
experiencing a primary end point event would yield 90% power at the 2-sided
5% significance level and 80% power to detect a 17.5% reduction in the hazard
ratio.
The sample size of 4500 patients (2250 per treatment group) was selected
to yield 970 events within 1 year after enrollment. The protocol permitted
a sample size adjustment to achieve the projected number of 970 total primary
end point events, but the executive committee elected to halt enrollment after
the planned 4500 patients were enrolled. During the course of the trial, data
emerged to support statin initiation early after ACS,5 and
practice patterns in participating hospitals changed considerably, so that
it became increasingly difficult to enroll patients into the placebo-controlled
portion of the trial. Moreover, the investigators believed that lengthening
the follow-up period beyond 2 years to accrue more events would fundamentally
alter the hypotheses being tested in the trial.
All efficacy and safety analyses were performed on an intent-to-treat
basis. The cumulative incidence of the primary end point was determined using
the Kaplan-Meier product-limit method. Patients who did not achieve expected
follow-up were censored at the time they withdrew consent or were lost to
follow-up. Statistical comparison between treatment groups was performed using
a Cox proportional hazards model that included covariates for treatment group
and age. Although a significant treatment × time interaction (P = .03) was observed, all end point analyses were performed
as prespecified using the Cox proportional hazards model. The primary end
point analysis required a 2-sided α level of .046 for significance to
account for 2 interim data and safety monitoring board analyses. All other
analyses required a significance level of .05. Comparisons of adverse safety
events were performed using the Fisher exact test. Statistical analyses were
performed using SAS software (version 8.0, SAS Institute Inc, Cary, NC).
Between December 29, 1999, and January 6, 2003, 4497 patients were enrolled
at 322 centers in 41 countries (Figure 1).
The mean time from symptom onset to randomization in phase Z was 3.7 days.
Baseline characteristics were similar between the 2 treatment groups (Table 1). Treatment with guideline-recommended
therapies, such as angiotensin-converting enzyme inhibitors, β-blockers,
and aspirin, was high and similar between the 2 treatment groups (Table 1). There were 1958 (44%) patients
who underwent PCI to treat the index ACS event prior to enrollment. Treatment
was discontinued prematurely in 711 patients (32%) in the placebo plus 20
mg of simvastatin group and 765 (34%) in the simvastatin only group (40 mg/d
and then 80 mg/d). The median follow-up period was 721 days and 22 patients
in each treatment group were lost to follow-up (Figure 1).
Changes in Lipid Parameters
In the placebo plus simvastatin group, median LDL cholesterol levels
increased by 11% during the 4-month placebo period from 111 mg/dL (2.87 mmol/L)
to 124 mg/dL (3.21 mmol/L) and then decreased to 77 mg/dL (1.99 mmol/L) at
month 8 after the initiation of 20 mg of simvastatin (31% change from baseline).
In the simvastatin only group, the median LDL cholesterol levels decreased
by 39% to 68 mg/dL (1.76 mmol/L) over the first month during treatment with
40 mg/d of simvastatin and then decreased an additional 6% to 62 mg/dL (1.61
mmol/L) at month 4 following the increase to the 80 mg/d of simvastatin (Table 2). Changes in lipid and C-reactive
protein values are shown in Table 2.
The latter were equivalent in the 2 groups at baseline and at month 1, but
became significantly lower in the simvastatin only group subsequently.
The primary end point of cardiovascular death, MI, readmission for ACS,
and stroke occurred in 343 patients (16.7%) in the placebo plus simvastatin
group compared with 309 (14.4%) in the simvastatin only group (hazard ratio
[HR], 0.89; 95% confidence interval [CI], 0.76-1.04; P =
.14; Figure 2). Outcomes for selected
secondary end points are shown in Table
3. Cardiovascular death occurred in 109 patients (5.4%) in the placebo
plus simvastatin group compared with 83 (4.1%) in the simvastatin only group
(HR, 0.75; 95% CI, 0.57-1.00; P = .05; number needed
to treat to prevent 1 cardiovascular death, 77). No significant differences
were observed between treatment groups with regard to the secondary end points
of MI, readmission for ACS, revascularization due to documented ischemia,
or stroke. New-onset congestive heart failure was reduced from 5.0% in the
placebo plus simvastatin group to 3.7% in the simvastatin only group (HR,
0.72; 95% CI, 0.53-0.98; P = .04; number needed to
treat to prevent 1 episode of new-onset congestive heart failure, 77; Table 3).
In a post hoc analysis, no difference between treatment groups in the
primary end point was evident over the first 4 months following randomization,
which corresponded to the placebo-controlled comparison period (HR, 1.01;
95% CI, 0.83-1.25; P = .89). However, from 4 months
through the end of the study, the primary end point was reduced from 9.3%
in the placebo plus simvastatin group to 6.8% in the simvastatin only group
(HR, 0.75; 95% CI, 0.60-0.95; P = .02; Figure 3).
No significant treatment interactions were detected in subgroups defined
by demographic variables, index diagnosis, baseline lipid and C-reactive protein
levels, or use of early PCI. There was no evidence of a greater relative treatment
effect among patients with higher baseline levels of LDL cholesterol (Figure 4).
Rates of adverse events according to treatment assignment and time since
randomization are summarized in Table 4. The proportion of patients with consecutive elevations in AST
or ALT levels of more than 3 times the ULN was 0.4% (8/2068) in the placebo
plus simvastatin group and 0.9% (19/2132) in the simvastatin only group (P = .05).
Discontinuation of the study drug due to a muscle-related adverse event
occurred in 1.5% (34/2230) of patients in the placebo plus simvastatin group
and 1.8% (41/2263) in the simvastatin only group (P =
.49). A total of 10 patients developed myopathy (creatine kinase level >10
times the ULN with associated muscle symptoms); 1 patient was in the placebo
plus simvastatin group and 9 patients were in the simvastatin only group (while
taking the 80 mg/d dose) (P = .02). Three of the
9 patients with myopathy had creatine kinase levels higher than 10 000
units/L and met the definition for rhabdomyolysis. Of these 3 patients, 1
patient had contrast-induced renal failure and 1 patient was receiving concomitant
verapamil, which is a known inhibitor of CYP3A4. In addition, 1 patient receiving
80 mg of simvastatin had a creatine kinase level higher than 10 times the
ULN without muscle symptoms, which was associated with alcohol abuse. There
were no cases of myopathy when patients were taking 20 mg of simvastatin or
40 mg of simvastatin.
Among patients with ACS who were stabilized with guideline-based acute
therapies, the early initiation of an intensive simvastatin regimen resulted
in a trend toward reduction in the rate of the primary composite end point
of death, MI, readmission for ACS, and stroke when compared with the delayed
initiation of a less intensive simvastatin regimen. However, the trial did
not achieve the prespecified end point and the 11% relative (2.3% absolute)
reduction in the rate of the primary end point in the early intensive statin
group was not statistically significant. While no differences were observed
between treatment groups with regard to the secondary end points of MI and
readmission for ACS, the early intensive statin regimen was associated with
a reduction in cardiovascular mortality of 25% (absolute reduction, 1.3%; P = .05) and congestive heart failure of 28% (absolute
reduction, 1.3%; P = .04). These findings are qualitatively
consistent with results from the Pravastatin or Atorvastatin Evaluation and
Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI
22)6 and the Reversal of Atherosclerosis with
Aggressive Lipid Lowering (REVERSAL)12 trials,
which demonstrated improved clinical outcomes and reduced progression of atherosclerosis
with a more intensive statin regimen (80 mg/d of atorvastatin) compared with
a less intensive statin regimen (40 mg/d of pravastatin).
Several factors may explain the absence of a statistically significant
benefit with respect to the primary end point in the early intensive statin
group of the A to Z trial. First, the clinical benefit was delayed and of
a smaller magnitude than was anticipated. Second, the trial had less statistical
power than was originally planned due to a lower than expected number of end
points and a higher than expected rate of study drug discontinuation. Although
the study reached its projected enrollment number of 4500 participants, the
primary end point rate was considerably lower than projected, resulting in
only 652 primary end point events, which is short of the 970 events required
to provide adequate power. The 33% rate of study drug discontinuation in the
present study is higher than in previous secondary prevention trials1-4 but similar
to the rate observed in PROVE IT, a trial that also enrolled patients early
after ACS and followed up patients for up to 2 years.6 These
trials highlight challenges in maintaining long-term adherence to even well-tolerated
therapies when they are initiated during the acute phase of illness.
Intensity of Statin Therapy in Patients With ACS
Realizing that there are limitations when making direct comparisons
between clinical trials, the magnitude of clinical benefit observed at the
end of the 2-year follow-up period in the A to Z trial appeared to be less
than was observed in PROVE IT-TIMI 22, a finding that may relate to the smaller
between-group difference in LDL cholesterol level lowering in the A to Z trial
compared with PROVE IT. While the LDL cholesterol levels achieved in the aggressive
statin treatment groups were similar between the 2 trials, the median LDL
cholesterol level in the standard care treatment group of the A to Z trial
was 77 mg/dL (1.99 mmol/L) at 8 months compared with 95 mg/dL (2.46 mmol/L)
in the group receiving 40 mg/d of pravastatin in PROVE IT. Thus, from months
4 through 24, the median difference in LDL cholesterol levels between treatment
groups was approximately 14 mg/dL (0.36 mmol/L) in the A to Z trial (18% relative
difference) compared with 33 mg/dL (0.85 mmol/L) in PROVE IT (33% relative
difference). This difference may in part explain the smaller relative reduction
in the primary end point rate of 11% in the A to Z trial compared with 16%
in PROVE IT. These findings are consistent with analyses included in the recent
update to the National Cholesterol Education Program Adult Treatment Panel
III Guidelines, which support a direct proportional relationship between the
magnitude of LDL cholesterol level lowering and coronary heart disease risk
reduction.13
Timing of Statin Initiation in ACS
Until recently, information regarding the timing of initiation of statin
agents following ACS had been limited to observational studies and post hoc
analyses of clinical trials performed for other purposes.14-17 Including
the A to Z trial, 3 trials have evaluated early initiation of statins after
ACS. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
(MIRACL) study reported a 16% lower rate of death and nonfatal major cardiac
events 4 months after ACS in patients receiving 80 mg/d of atorvastatin compared
with placebo (P = .05).5 No
early differences in mortality or MI were evident in MIRACL, but rehospitalization
for recurrent ischemia was significantly reduced—a finding that is in
contrast to the A to Z trial, in which no effect of aggressive statin therapy
was observed for the end point of readmission for ACS. Because MIRACL excluded
patients with recent or planned revascularization, the use of glycoprotein
IIb/IIIa inhibitors and clopidogrel was low. In contrast to the MIRACL trial,
PROVE IT included an active comparison group (40 mg/d of pravastatin), patients
with both ST-elevation MI and non–ST-elevation ACS, and patients who
were treated with PCI for their index ACS event. A significant benefit with
regard to the primary end point of death, MI, and total revascularization
favoring high-dose atorvastatin was evident within the first 6 months of PROVE
IT and a strong trend was observed at 30 days.
In the A to Z trial, no early divergence in event rates was noted between
treatment groups despite marked differences in LDL cholesterol levels. However,
the primary end point rate was significantly lower in the aggressive simvastatin
group between 4 and 24 months. A number of factors related to patient characteristics
and concomitant treatment strategies may have contributed to the delay in
clinical benefit observed in the A to Z trial. In contrast with the MIRACL
study, glycoprotein IIb/IIIa inhibitor use was mandated in phase A of the
A to Z trial and more than 50% of the patients were treated with an early
invasive management strategy.8 These therapies
may have competed with statin therapy to reduce early nonfatal recurrent ischemic
events.
Differences between the A to Z trial and PROVE IT with regard to the
timing of patient enrollment and practice patterns in the enrolling sites
also may have contributed to differences in early outcomes between the 2 trials.
In PROVE IT, patients were enrolled an average of 7 days after ACS (largely
from centers in the United States) with the consequence that 69% of patients
had undergone revascularization to treat the ACS event prior to randomization.
The culprit lesion and acute thrombotic process may have been stabilized prior
to enrollment in PROVE IT, which is a hypothesis supported by the extremely
low cardiovascular mortality rate (<1.5% at 2 years) observed in both treatment
groups in this trial.6 In contrast, in the
A to Z trial, patients were enrolled 3 to 4 days earlier, were selected to
have higher risk features, and were less likely to undergo PCI prior to enrollment.
These features may have resulted in more patients entering phase Z of the
trial with an ongoing active thrombotic process that was relatively less responsive
to statin therapy.
In contrast with the PROVE IT study,6 the
C-reactive protein concentrations in the A to Z trial did not differ between
the treatment groups at 30 days despite marked differences in LDL cholesterol
levels. The lack of a concurrent anti-inflammatory effect may also have contributed
to the delayed treatment effect that was observed. Patients in the aggressive
simvastatin arm of the A to Z trial were not titrated up to 80 mg/d of simvastatin
until after the first month. It is possible that more intensive therapy is
required immediately after the onset of ACS during the period of greatest
clinical instability to achieve a more rapid clinical benefit.
Influence of LDL Cholesterol Levels
No difference in treatment effect was evident across subgroups defined
by LDL cholesterol levels. These findings are consistent with those from the
Heart Protection Study, which found no interaction based on initial LDL cholesterol
levels in the reduction of major vascular events with 40 mg/d of simvastatin.4
The incidence of consecutive elevations in AST or ALT levels higher
than 3 times the ULN was low in both treatment groups. Muscle-related adverse
events occurred infrequently, including those that led to study drug discontinuation.
Myopathy (creatine kinase level >10 times the ULN with muscle symptoms) occurred
in 9 patients (0.4%) receiving 80 mg/d of simvastatin, which included 3 patients
who developed rhabdomyolysis (creatine kinase level >10 000 units/L);
these rates are consistent with the long-term safety of this dose in patients
with hypercholesterolemia.9 There were no cases
of myopathy in patients receiving 20 mg/d or 40 mg/d doses of simvastatin,
which is also consistent with the overall safety of these doses reported in
other long-term outcome trials.1,4 Clinicians
should be aware that the 80-mg/d dose of simvastatin is associated with a
higher risk of myopathy than lower dosages of the drug and should educate
patients receiving the 80-mg/d dose of simvastatin to pay close attention
to muscle-related symptoms.
The traditional approach to lipid management following ACS has been
to begin with dietary management and then to initiate a statin agent at a
low dose and increase the dose stepwise to achieve target LDL cholesterol
levels. The findings from the A to Z trial, as well as from MIRACL and PROVE
IT, support a strategy of aggressive LDL cholesterol lowering following ACS
to prevent death and major cardiovascular events. Statins should be initiated
early after ACS, with consideration of dosages well above the typical starting
dose, and they should be down-titrated or discontinued if important adverse
effects, such as myopathy or significant liver abnormalities, develop.
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