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of the authors and THE JOURNAL and not those of
High-Dose Statins in
Acute Coronary Syndromes
Not Just Lipid Levels
Steven E. Nissen, MD
statin clinical trial literature. Two other trials in ACS pa-
tients showed safety and efficacy (TABLE
). The Myocardial
mulated a remarkable record of successful clinical
(MIRACL) trial compared 80 mg/d of atorvastatin with pla-
trials, demonstrating robust evidence for reduction
cebo for 4 months in 3086 patients and showed a 16% re-
in clinical events, including myocardial infarction,
duction in events.6 The Pravastatin or Atorvastatin Evalu-
stroke, and cardiovascular death in primary and secondary
ation and Infection Therapy trial (PROVE IT) compared
prevention populations.1-4 Recent trials have shown that in-
outcomes of 4162 patients receiving 80 mg/d of atorvas-
tensive statin therapy is superior to moderate therapy for
tatin or 40 mg/d of pravastatin and also showed a signifi-
reducing morbidity following an acute coronary syndrome
cant 16% event reduction.5 Both studies demonstrated a rapid
(ACS) event5,6 and for slowing the progression of coronary
onset of clinical benefit. In MIRACL, the study duration was
atherosclerosis.7 Statin trials have also demonstrated a fa-
only 4 months, whereas in PROVE IT the event curves sepa-
vorable safety profile with only rare and isolated cases of
rated within the first 30 days, reaching statistical signifi-
serious toxicity.8 Given the spectacular success of this class
cance by 6 months. In contrast, post hoc analysis of the A
of drugs, the failure of a statin clinical trial to meet its pre-
to Z trial showed no effect during the first 4 months (haz-
specified objective and evidence of an adverse safety pro-
ard ratio, 1.01), but there did appear to be some later ben-
file are unusual and mandate careful analysis of potential
Explaining the lack of efficacy for high-dose simvastatin
Phase Z of the A to Z trial,9 published in this issue of JAMA
in the A to Z trial is difficult. The authors emphasize that fewer
is to date the largest trial testing the effects of aggressive statin
events occurred than anticipated by power calculations. While
therapy in ACS. The investigators randomized approxi-
correct, this observation only partially explains the lack of
mately 4500 patients following an ACS event to receive either
statistical efficacy. Consider the following comparison be-
high-dose simvastatin (40 mg/d for 1 month and then 80
tween the A to Z trial and the MIRACL trial. Both studies
mg/d thereafter) or to a regimen of placebo for 4 months
showed large low-density lipoprotein (LDL) cholesterol dif-
and then a 20-mg/d dose of simvastatin thereafter. The high-
ferences between the group receiving active treatment and
dose regimen failed to show a statistically significant ben-
the group receiving placebo during the first 4 months (62
efit for reducing the primary composite end point of car-
mg/dL [1.61 mmol/L] in the A to Z trial and 63 mg/dL [1.63
diovascular death, myocardial infarction, readmission for
mmol/L] in the MIRACL trial). Despite nearly identical lipid
ACS, or stroke (absolute risk reduction, 2.3%; hazard ra-
level effects, the A to Z trial showed no risk reduction dur-
tio, 0.89 [95% confidence interval, 0.76-1.04] P
= .14). In
ing the first 4 months, whereas MIRACL showed a 16% re-
addition, the high-dose simvastatin regimen was associ-
duction in similar end points (Table).
ated with an unusually high rate of myopathy. Ten patients
How can identical lipid level lowering with 2 drugs yield
(9 in the high-dose treatment group) experienced elevated
such different outcomes? The authors propose that im-
creatine kinase levels greater than 10 times the upper limit
proved concomitant therapies “competed” for risk reduc-
of normal with accompanying muscle symptoms and 3 pa-
tion in the A to Z trial, thereby reducing drug efficacy. How-
tients developed frank rhabdomyolysis (creatine kinase lev-
ever, PROVE IT used similar contemporary therapies and
els Ͼ10000 units/L). Because 32 clinical events were avoided,approximately 1 adverse myopathic event occurred for ev-
Department of Cardiology, Cleveland Clinic Foundation, Cleve-
Dr Nissen has been a consultant to Merck, Astra Zeneca,
Both the lack of efficacy and the unfavorable adverse event
Pfizer, Sankyo, Sanofi, Eli Lilly, Takeda, Novo Nordisk, Atherogenics, Lipid Sci-ences, GlaxoSmithKline, Hoffman LaRoche, Kos, and Wyeth. Dr Nissen also has
profile would seem improbable to those familiar with the
directed clinical trials in collaboration with Astra Zeneca, Pfizer, Sankyo, Eli Lilly,
Takeda, Atherogenics, and Lipid Sciences.Corresponding Author:
Steven E. Nissen, MD, Department of Cardiology, Cleve-
See also p 1307.
land Clinic Foundation, 9500 Euclid Ave, Desk F15, Cleveland, OH 44195(email@example.com).
2004 American Medical Association. All rights reserved.
(Reprinted) JAMA, September 15, 2004—Vol 292, No. 11 1365
The myopathy rate in the A to Z trial, while low, is higher
Intensive Statin Therapy in Acute Coronary Syndromes
than observed in most other clinical statin trials. In trials
using submaximal doses of pravastatin, lovastatin, fluvas-
tatin, or simvastatin, myopathy has occurred rarely.8 Six stud-
ies treated patients with the highest dose of atorvastatin (80
mg/d), randomizing more than 10 000 patients, with no re-
ported cases of myopathy (defined as 10 times the upper
limit of normal creatine kinase levels with muscle symp-
toms) or frank rhabdomyolysis.5-7,15-17 The myopathy rate
of 0.4% observed in the A to Z trial occurred despite pa-
tient selection criteria that sought to specifically exclude pa-
Abbreviations: LDL, low-density lipoprotein; MIRACL, Myocardial Ischemia Reduction
tients at greater risk.9 However, this rate is consistent with
with Aggressive Cholesterol Lowering; NA, data not available; PROVE IT, Pravastatinor Atorvastatin Evaluation and Infection Therapy.
the reported 0.6% myopathy rate reported in a meta-
SI conversion factor: To convert LDL cholesterol to mmol/L, multiply by 0.0259.
*Measured 120 days after randomization.
analysis of the efficacy and safety of the 80-mg/d dose of
†Measured 90 days after randomization.
‡Measured at trial completion.
§Elevation of creatine kinase level higher than 10 times the upper limit of normal.
The myopathy rate of the 80-mg/d dose of simvastatin ob-
served in the A to Z trial and the previously reported meta-analysis are not particularly surprising. For many years fol-
showed a 16% reduction in events, which was evident by
lowing its introduction, the maximum dose of simvastatin
30 days and was virtually constant for the trial duration. Even
approved by the Food and Drug Administration (FDA) was
more surprisingly, PROVE IT achieved statistical signifi-
40 mg/d. However, in 1997 the manufacturer undertook a
cance while comparing intensive statin therapy with mod-
development program to study 2 higher doses of simvasta-
erate statin therapy, not placebo, achieving only 33 mg/dL
tin (80 mg/d and 160 mg/d).8,19,20 Although a favorable re-
(0.85 mmol/L) greater LDL cholesterol reduction in the in-
port appeared in the medical literature,20 development of
the 160-mg/d dose was abandoned due to high muscle tox-
Taken together, MIRACL, PROVE IT, and A to Z dem-
icity.8,19 Although never reported in the scientific litera-
onstrate that the beneficial effects of statin therapy in ACS
ture, the financial community was informed that the rate
cannot be predicted entirely from the degree of LDL cho-
of muscle-related symptoms was 5.7% for the 160 mg/d
lesterol reduction. What other explanations are possible?
dose.19 The dose of 80 mg/d of simvastatin was eventually
All statins exhibit a variety of anti-inflammatory and anti-
approved, but in 2002, the FDA product label was modi-
proliferative effects commonly described as “pleiotropic”
fied to include warnings about concomitant medications than
effects.10-13 The most widely examined inflammatory
inhibit cytochrome P450 3A4, the major metabolic path-
biomarker—high sensitivity C-reactive protein—is com-
way for simvastatin elimination.21 This warning was pro-
monly measured in statin clinical trials. In the 2 successful
voked by cases of rhabdomyolysis when simvastatin was ad-
ACS trials (MIRACL and PROVE IT), the difference in
C-reactive protein between treatment subgroups was 34%
There are several lessons to be learned from these events.
and 38%, respectively, at trial completion. In the A to Z
The failure of the 160-mg/d dose of simvastatin and the en-
trial, the between-group reduction was much smaller
hanced toxicity that occurred with 3A4 inhibitors should
(16.7%; Table). This finding suggests an intriguing
probably have served as a warning that the 80-mg/d dose
hypothesis, specifically, that the early benefits of statin
of simvastatin might border on a toxic threshold. Rela-
therapy are derived largely from the anti-inflammatory
tively minor differences in the rate of elimination, a low body
effects of the drugs, whereas the delayed benefits are lipid-
mass index, mild renal insufficiency, or other unknown fac-
tors appear capable of pushing simvastatin blood levels into
These findings emphasize a critical principal of appro-
the toxic range. The failure to publish the actual results of
priate, evidence-based interpretation of clinical trials. It is
studies using the 160-mg/d dose (negative publication bias)
hazardous to assume that similar agents always yield iden-
arguably prevented the medical and scientific community
tical results. While a class effect for statins is likely, each
from fully appreciating the myopathic potential of high-
agent requires careful testing in clinical trials to establish
dose simvastatin. In addition, the voluntary nature of the
the extent of benefit and risk. These observations are even
US postmarketing surveillance system may have compro-
more important when applied to nonstatin LDL–cholesterol-
mised the ability of the FDA to recognize increased risk of
lowering therapies. Because these agents, such as ezeti-
the 80-mg/d dose. Indeed, it took several years to recog-
mibe, have not demonstrated anti-inflammatory effects in
nize that cerivastatin was associated with a 16- to 80-fold
the absence of concomitant statin administration,14 their value
increase in risk of myopathy prior to its withdrawal.22
in reducing events cannot be assumed and must be tested
It must be emphasized that the cluster of myopathy events
in well-designed clinical outcome trials.
in the A to Z trial may be partially explained by chance alone.
JAMA, September 15, 2004—Vol 292, No. 11 (Reprinted)
2004 American Medical Association. All rights reserved.
Although potentially alarming, 9 myopathic events in 2250
lowering with statins after acute coronary syndromes. N Engl J Med.
treated patients are insufficient to recommend withdrawal
Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early
of the 80-mg/d dose of simvastatin. Fortunately, there is a
recurrent ischemic events in acute coronary syndromes: the MIRACL study: a ran-
larger ongoing trial randomizing 12 000 patients to either
domized controlled trial. JAMA.
Nissen SE, Tuzcu EM, Brown BG, et al. Effect of intensive compared with mod-
80 mg/d or 20 mg/d of simvastatin.23 In addition, the FDA
erate lipid-lowering therapy on progression of coronary atherosclerosis: a ran-
maintains a high degree of vigilance in this area and un-
domized controlled trial. JAMA.
Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA.
doubtedly will subject high-dose simvastatin to additional
scrutiny. If either FDA monitoring or ongoing clinical trials
de Lemos JA, Blazing MA, Wiviott SD, et al, for the A to Z Investigators. Early
confirm that a regimen of 80 mg/d of simvastatin consti-
intensive vs a delayed conservative simvastatin strategy in patients with acute coro-nary syndromes: phase Z of the A to Z trial. JAMA.
tutes an unacceptable risk, this dosage level should be with-
Kinlay S, Schwartz GG, Olsson AG, et al, for the Myocardial Ischemia
Reduction with Aggressive Cholesterol Lowering Study Investigators. High-doseatorvastatin enhances the decline in inflammatory markers in patients with
It is important to reassure practicing physicians and pa-
acute coronary syndromes in the MIRACL study. Circulation.
tients that the unfavorable risk-benefit relationship ob-
Schonbeck U, Libby P. Inflammation, immunity, and HMG-CoA reductase in-
served in the A to Z trial does not in any way diminish the
hibitors: statins as anti-inflammatory agents? Circulation.
2004;109(21 suppl 1):
value of intensive statin treatment in secondary preven-
tion, including ACS patients. There was a trend toward re-
Waehre T, Yndestad A, Smith C, et al. Increased expression of interleukin-1
in coronary artery disease with downregulatory effects of HMG-CoA reductase
duced events in the A to Z trial, a finding that supports the
lower is better concept. The increased myopathy rate ap-
Rosenson RS. Pluripotential mechanisms of cardioprotection with HMG-CoA
reductase inhibitor therapy. Am J Cardiovasc Drugs.
plies only to a specific dose of a single agent and should not
Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadmin-
tarnish this remarkable class of drugs.24 It must also be em-
istered with atorvastatin in 628 patients with primary hypercholesterolemia: a pro-
phasized that simvastatin in doses of up to 40 mg/d has shown
spective, randomized, double-blind trial. Circulation.
Pitt B, Waters D, Brown WV, et al, for the Atorvastatin versus Revasculariza-
excellent safety and efficacy in a series of clinical trials. For
tion Treatment Investigators. Aggressive lipid-lowering therapy compared with an-
now, though, the 80-mg/d dose of simvastatin should be used
gioplasty in stable coronary artery disease. N Engl J Med.
Smilde TJ, van Wissen S, WollersheimH, et al. Effect of aggressive versus con-
with caution, particularly because other effective agents are
ventional lipid lowering on atherosclerosis progression in familial hypercholester-
available. Finally, in an era when criticism of selective re-
Taylor AJ, Kent SM, Flaherty PJ, et al. ARBITER: Arterial Biology for the In-
porting of positive trial results is common,25 the A to Z in-
vestigation of the Treatment Effects of Reducing Cholesterol: a randomized trial
vestigators are to be commended for their prompt and thor-
comparing the effects of atorvastatin and pravastatin on carotid intima medial thick-
ough reporting of a critically important major trial that did
Davidson MH, Stein EA, Hunninghake DB, et al, for the Worldwide Ex-
panded Dose Simvastatin Study Group. Lipid-altering efficacy and safety of sim-vastatin 80 mg/day: worldwide long-term experience in patients with hypercho-lesterolemia. Nutr Metab Cardiovasc Dis.
Available at: http://www.impostertrial.com/physician.htm. Accessed Au-
Scandinavian Simvastatin Survival Study Group. Randomized trial of choles-
terol lowering in 4,444 patients with coronary heart disease. Lancet.
Davidson MH, Stein EA, Dujovne CA, et al. The efficacy and six-week toler-
ability of simvastatin 80 and 160 mg/day. Am J Cardiol.
Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary
Food and Drug Administration letter. Available at: http://www.fda.gov/cder
events after myocardial infarction in patients with average cholesterol levels.
/foi/appletter/2002/19766s51ltr.pdf. Accessibility verified August 20, 2004.
N Engl J Med.
Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis.
Sever PS, Dahlof B, Poulter NR, et al, for the ASCOT Investigators. Prevention
N Engl J Med.
of coronary and stroke events with atorvastatin in hypertensive patients who have
MacMahon M, Kirkpatrick C, Cummings CE, et al. A pilot study with simva-
average or lower-than-average cholesterol concentrations, in the Anglo-
statin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness
Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA). Lancet.
of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab
Heart Protection Study Collaborative Group. MRC/ BHF Heart Protection Study
Topol EJ. Intensive statin therapy—a sea change in cardiovascular preven-
of cholesterol lowering with simvastatin in 20,536 high-risk individuals. Lancet.
tion. N Engl J Med.
Olson CM, Rennie D, Cook D, et al. Publication bias in editorial decision mak-
Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid
2004 American Medical Association. All rights reserved.
(Reprinted) JAMA, September 15, 2004—Vol 292, No. 11 1367
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