JACC: CARDIOVASCULAR INTERVENTIONS
3, 2010
© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
EDITORIAL COMMENT
High-Dose Atorvastatin
in Acute Coronary and
Cerebrovascular Syndromes*
Carl J. Lavie, MD, Richard V. Milani, MD
New Orleans, Louisiana
Substantial evidence has now supported vigorous lipid
intervention in primary and secondary prevention of coro-
nary heart disease (CHD) (1,2), and the evidence support-
ing intensive lipid intervention with high-dose statins to
produce clinical event reduction is especially powerful in the
setting of acute coronary syndrome (ACS) (3–5), including
the setting of percutaneous coronary intervention (PCI) (6),
and acute cerebrovascular disease (7). Guidelines from the
National Cholesterol Education Program (8), the American
Heart Association/American College of Cardiology (9), and
the American Heart Association/American Stroke Associ-
ation (10) all support recommendations to lower low-
density lipoprotein cholesterol (LDL-C) to at least under
100 mg/dl, with recommendations to lower LDL-C ⬍70
mg/dl as a “therapeutic option.” Data to support LDL-C
⬍70 mg/dl are especially applicable in patients following
ACS (3–5).
See page 332
Following PCI, a recent substudy (6) of 2,868 patients
randomized to atorvastatin 80 mg or pravastatin 40 mg in
PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evalu-
ation and Infection Therapy–Thrombolysis In Myocardial
Infarction 22) trial demonstrated a 22% reduction (p ⫽
0.002) in the composite end point of major cardiovascular
events as well as significant reductions in both target vessel
revascularization (TVR) (–39%, p ⫽ 0.001) and non-TVR
(– 42%, p ⫽ 0.017) in those treated with high-dose atorv-
astatin. After adjustment for on-treatment LDL-C and
C-reactive protein levels, the odds of reducing TVR with
*Editorials published in JACC: Cardiovascular Interventions reflect the views of the
authors and do not necessarily represent the views of JACC: Cardiovascular Interven-
tions or the American College of Cardiology.
From the Division of Cardiovascular Diseases, Ochsner Health System, New
Orleans, Louisiana. Dr. Lavie is a speaker and consultant for Pfizer, GlaxoSmith
Kline, Bristol-Myers Squibb, Sanofi Aventis, Abbott, and Solvay. Dr. Milani is a
speaker and consultant for Pfizer, AstraZeneca, Bristol-Myers Squibb, and Sanofi
Aventis.
Downloaded From: http://interventions.onlinejacc.org/ on 06/14/2016
VOL. 3, NO.
ISSN 1936-8798/10/$36.00
DOI: 10.1016/j.jcin.2010.01.002
atorvastatin remained significant, suggesting that the reduc-
tion in TVR may be in part mediated by pleiotropic effects
not accounted for by reductions in LDL-C and systemic
inflammation (6,11).
Following PCI, an increase in cardiac biomarkers has
been shown to occur in 5% to 30% of patients (12,13), and
this elevation of cardiac enzyme is indicative of cell death
and a high risk of periprocedural mortality (14). In fact, we
recently demonstrated that even borderline increases in
troponin following elective PCI predicted a higher mortality
(14). Compelling data suggest that the statins may reduce
the rate of periprocedural myocardial infarction (MI)
(12,13,15).
Briguori (13) assessed the value of a single 80 mg loading
dose of atorvastatin the day before elective PCI in 668
statin-naïve patients. They reported a 44% reduction (p ⫽
0.01) in periprocedural MI in the atorvastatin-treated pa-
tients, with significant reductions also in the median crea-
tine kinase-myocardial band isoenzyme (p ⫽ 0.01) and the
frequency of cardiac troponin I elevation ⬎3⫻ the upper
limit of normal. In an accompanying editorial, Tsimikas
(15) reviewed 6 studies, including 2 in ACS (16,17), of over
2,000 PCI patients (4 studies with atorvastatin [3 using 80
mg and 1 using 40 mg] (13,17–19), 1 with rosuvastatin 40
mg (16), and the other using various statins), demonstrating
statistically significant reductions in periprocedural MI us-
ing statin therapy. Tsimikas suggested that high doses of a
potent statin should be given similar priority as aspirin and
clopidogrel prior to patients undergoing PCI.
In this issue of JACC: Cardiovascular Interventions, Kim
et al. (20) assessed the efficacy of high-dose atorvastatin (80
mg) versus low-dose atorvastatin (10 mg) in 171 ACS
patients with ST-segment elevation MI. This was similar to
the regimen used in the large-scale TNT (Treatment to
New Targets) trial (21), which demonstrated the efficacy of
high-dose (80 mg) atorvastatin versus low-dose (10 mg)
atorvastatin in mostly stable patients with established CHD.
Although the lipid arms in these 2 trials were similar, the
recent PCI in ST-segment elevation MI trial was relatively
small with only 30-day follow-up, whereas TNT random-
ized over 10,000 patients followed for 5 years. Unfortu-
nately, despite the fact that 80 mg atorvastatin was associ-
ated with a 46% reduction in the primary end point (death,
nonfatal MI, and TVR), the study was not nearly powered
enough to assess this end point, because these events
occurred in only 9 patients in the low-dose atorvastatin
group (compared with 5 events in the high-dose group, p ⫽
0.26). Also, as the investigators mentioned, serial measure-
ment of cardiac enzymes were not available for all patients,
and they were unable to calculate enzymatic infarct size
using creatine kinase-myocardial band. Nevertheless, imme-
diate high-dose statin loading before PCI showed beneficial
effects on myocardial perfusion, including significant reduc-
 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 3, 2010
MARCH 2010:340 –2
tions in the corrected Thrombolysis In Myocardial Infarc-
tion (TIMI) flow grade count (p ⫽ 0.01), as well as
increases in myocardial blush grade (p ⫽ 0.02) and ST-
segment resolution at 90 min after PCI (p ⫽ 0.01), all
suggesting an improvement in microvascular myocardial
perfusion with high-dose (80 mg) versus low-dose (10 mg)
atorvastatin in ST-segment elevation MI.
With the current level of knowledge, how should clini-
cians treat patients with CHD, including those undergoing
PCI electively or in the setting of ACS? In our opinion, all
patients should be treated with a high dose of a potent
statin, which should be started as outpatients or, in the
setting of ACS, as soon as possible on hospital arrival and
certainly before PCI. High-dose (80 mg) simvastatin
showed some benefit during 2-year follow-up compared
with low-dose (20 mg) simvastatin following ACS (5), but
as we have recently reviewed elsewhere (1,2,22), although
lower doses of simvastatin are generally well-tolerated this
high dose of simvastatin (80 mg) has perhaps the most
drug-to-drug interactions and the greatest propensity
among the statins for myopathy/rhabdomyolysis, and we
believe that this dose (80 mg) should be used with consid-
erable caution. Rosuvastatin 40 mg, which is probably the
most potent statin, was recently associated with a 40% to
50% reduction in periprocedural MI in 445 patients with
PCI in ACS (16), and rosuvastatin 20 mg recently produced
dramatic benefits in primary CHD prevention (22). At
present, however, 80 mg atorvastatin is the dose with proven
efficacy and safety in 2 large-scale ACS trials (3,4), as well
as the large PCI substudy (6), 2 large secondary CHD trials
(21,23), a large acute cerebrovascular trial (7), and in at least
4 trials before PCI (12,17,18,20), including in the report by
Kim et al. (20) in the present issue. Therefore, atorvastatin
80 mg probably has the most compelling evidence, with
established efficacy and safety in ACS, before and following
PCI, as well as in stable CHD. Further trials will likely
determine if rosuvastatin’s greater potency translates to
additional clinical benefits in ACS as well as in other
high-risk patients.
Future studies are needed to determine if doses of statins
even higher than standard lipid-lowering doses will result in
additional benefit. As suggested by Tsimikas (15), we agree
that based on the current data, a rationale for further testing
of higher anti-inflammatory doses in well-designed studies
is present, as well as doses with other potentially important
pleiotropic effects, as suggested by the recent PROVE IT
TIMI 22 substudy (6). Finally, there is evidence that high
levels of triglycerides and non-high-density lipoprotein
cholesterol predicts prognosis following ACS (24). There-
fore, as in stable CHD, studies of lipid agents with greater
effects on the triglycerides/high-density lipoprotein axis are
needed following ACS and in the PCI patient (25,26).
Downloaded From: http://interventions.onlinejacc.org/ on 06/14/2016
Lavie and Milani 341
Editorial Comment
Reprint requests and correspondence: Dr. Carl J. Lavie, Ochsner
Health System, 1514 Jefferson Highway, New Orleans, Louisiana
70121. E-mail: clavie@ochsner.org.
REFERENCES
1. Lavie CJ, Milani RV, O’Keefe JH. Statin wars— emphasis on potency
vs event reduction and safety? Mayo Clin Proc 2007;82:539 – 42.
2. Maroo BP, Lavie CJ, Milani RV. Efficacy and safety of intensive statin
therapy in the elderly. Am J Geriatr Cardiol 2008;17:92–100.
3. Wiviott SD, Cannon CP, Marrow DA, Ray II, Pfeffer MA, Braunwald
E, PROVE IT–TIMI 22 Investigators. Can low-density lipoprotein be
too low? The safety and efficacy of achieving very low low-density
lipoprotein with intensive statin therapy a PROVE IT–TIMI 22
substudy (errata in J Am Coll Cardiol 2006;47:472). J Am Coll Cardiol
2005;46:1411– 6.
4. Waters DD, Schwartz GG, Olsson AG, et al., on behalf of MIRACL
Study Investigators. Effects of atorvastatin on stoke in patients with
unstable angina or non–Q-wave myocardial infarction: a Myocardial
Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL)
substudy. Circulation 2002;106:1690 –5.
5. de Lemos JA, Blazing MA, Wiviott SD, et al., on behalf of A to Z
Investigators. Early intensive vs a delayed conservative simvastatin
strategy in patients with acute coronary syndromes: phase Z of the A to
Z trial. JAMA 2004;292:1307–16.
6. Gibson CM, Pride YB, Hochberg CP, et al. Effect of intensive statin
therapy on clinical outcomes among patients undergoing percutaneous
coronary intervention for acute coronary syndrome. J Am Coll Cardiol
2009;54:2290 –5.
7. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels
(SPARCL) Investigators. High-dose atorvastatin after stroke or tran-
sient ischemic attack. N Eng J Med 2006;355:549 –59.
8. Grundy SM, Cleeman JI, Merz CN, et al., on behalf of Coordinating
Committee of the National Cholesterol Education Program. Implica-
tions of recent clinical trials for the National Cholesterol Education
Program Adult Treatment III guidelines. Circulation 2004;110:227–
39, corrections 763.
9. Smith SC, Allen J, Blain SN, et al., on behalf of American Heart
Association, American College of Cardiology, National Heart, Lung,
and Blood Institute. AHA/ACC guidelines for secondary prevention
for patients with coronary and other atherosclerotic vascular disease:
2006 update endorsed by the National Heart, Lung, and Blood
Institute. J Am Coll Cardiol 2006;47:2130 –9.
10. Adams RJ, Albers G, Alberts MJ, et al., on behalf of American Heart
Association, American Stroke Association. Update to the AHA/ASA
recommendations for the prevention of stroke in patients with stroke
and transient ischemic attack. Stroke 2008;39:1647–52.
11. Lavie CJ, Milani RV. C-reactive protein and cardiovascular diseases—
is it ready for primetime? Am J Med Sci 2009;338:486 –92.
12. Hermann J. Peri-procedural myocardial injury: 2005 update. Eur
Heart J 2005;26:2493–519.
13. Briguori C, Visconti G, Focaccio A, et al. Novel approaches for
preventing or limiting events (Naples) II trial. J Am Coll Cardiol
2009;54:2157– 63.
14. Milani RV, Fitzgerald R, Milani JN, Lavie CJ. The impact of micro
troponin leak on long-term outcomes following elective percutane-
ous coronary intervention. Catheter Cardiovasc Interv 2009;74:
819 –22.
15. Tsimikas S. High-dose statins prior to percutaneous coronary inter-
vention. J Am Coll Cardiol 2009;54:2164 – 6.
16. Yun KH, Jeong MH, Oh SK, et al. The beneficial effect of high
loading dose of rosuvastatin before percutaneous coronary interven-
tion in patients with acute coronary syndrome. Int J Cardiol
2009;137:246 –51.
17. Patti G, Pasceri V, Colonna A, et al. Atorvastatin pretreatment
improves outcomes in patients with acute coronary syndromes under-
going early percutaneous coronary intervention: results of the
 342 Lavie and Milani
Editorial Comment
ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007;49:
1272– 8.
18. Di Sciascio G, Patti G, Pasceri V, Gaspardone A, Colonna G,
Montinaro A. Efficacy of atorvastatin reload in patients on chronic
statin therapy undergoing percutaneous coronary intervention: results
of the ARMYDA-RECAPTURE (Atorvastatin for Reduction of
Myocardial Damage During Angioplasty) randomized trial. J Am Coll
Cardiol 2009;54:558 – 65.
19. Pasceri V, Patti G, Nusca A, et al., on behalf of ARMYDA Investigators.
Randomized trial of atorvastatin for reduction of myocardial damage
during coronary intervention: results from the ARMYDA (Atorvastatin
for Reduction of MYocardial Damage during Angioplasty) study. Circu-
lation 2004;110:674 – 8.
20. Kim JS, Kim J, Choi D, et al. Efficacy of high-dose atorvastatin loading
before primary percutaneous coronary intervention in ST-segment
elevation myocardial infarction: the STATIN-STEMI trial. J Am Coll
Cardiol 2010;3:332–39.
21. LaRosa JC, Grundy SM, Waters DD, et al., on behalf of Treating to
New Targets (TNT) Investigators. Intensive lipid lowering with
atorvastatin in patients with stable coronary disease. N Engl J Med
2005;352:1425–35.
22. O’Keefe JH, Carter MD, Lavie CJ, Bell DSH. The gravity of
JUPITER (Justification for the Use of Statins in Primary Prevention:
Downloaded From: http://interventions.onlinejacc.org/ on 06/14/2016
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 3, 2010
MARCH 2010:340 –2
An Intervention Trial Evaluating Rosuvastatin). Postgrad Med 2009;
121:113– 8.
23. Pedersen TR, Faegerman O, Kastelein JJ, et al. High-dose atorvastatin
vs usual-dose simvastatin for secondary prevention after myocardial
infarction: the IDEAL study: a randomized controlled trial. JAMA
2005;294:2437– 45.
24. Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels
beyond low-density lipoprotein cholesterol after acute coronary syn-
drome in PROVE IT–TIMI 22 trial. J Am Coll Cardiol 2008;51:
724 –30.
25. Lavie CJ, Milani RV. Shedding light on high-density lipoprotein
cholesterol. The post-ILLUMINATE era. J Am Coll Cardiol 2008;
51:56 – 8.
26. Cardenas GA, Lavie CJ, Cardenas V, Milani RV, McCullough PA.
The importance of recognizing and treating low levels of high-density
lipoprotein cholesterol: a new era in atherosclerosis management. Rev
Cardiovasc Med 2008;9:239 –58.
Key Words: acute coronary syndrome 䡲 coronary heart
disease 䡲 low-density lipoprotein cholesterol 䡲 myocardial
infarction 䡲 percutaneous coronary intervention 䡲 target
vessel revascularization.