Opinion
EDITORIAL
Lipid Lowering in Acute Coronary Syndrome
Is Treatment Early Enough?
Stephen J. Nicholls, MBBS, PhD; Peter J. Psaltis, MBBS, PhD
The beneficial effect of lipid lowering with statins in random-
ized clinical trials has had a profound effect on patient out-
comes and informing treatment algorithms for cardiovascu-
lar prevention. These studies
have increasingly empha-
Related article
sized the importance of the
direct relationship between the degree of lipid lowering and
clinical benefit, with the greatest effect observed among pa-
tients at the highest risk of having a subsequent cardiovascu-
lar event.1 Such observations have informed treatment guide-
lines, which strongly advocate for use of intensive statin
therapy for patients with the highest cardiovascular risk.2
The data supporting early use of intensive statin ther-
apy among patients with acute coronary syndrome (ACS)
represented an important change in clinical practice. In the
Myocardial Ischemia Reduction With Aggressive Cholesterol
Lowering (MIRACL) study, administration of atorvastatin,
80 mg/d, within 24 to 96 hours of hospital admission among
3086 patients with ACS reduced the incidence of cardiovascu-
lar events (from 17.4% to 14.8%) during the subsequent 16 weeks
in patients presenting with ACS.3 The Pravastatin or Atorva-
statin Evaluation and Infection Therapy (PROVE-IT) study sub-
sequently demonstrated that among 4162 patients with ACS,
administration of intensive lipid-lowering therapy with ator-
vastatin, 80 mg, was more effective than pravastatin, 40 mg,
with a 16% reduction (from 26.3% to 22.4%) in cardiovascular
events at 24-month follow-up, with benefit evident as early as
30 days.4 These findings had an immediate influence on clini-
cal practice, with prescription of high-intensity statin therapy
becoming common practice in the coronary care unit. The ben-
efit of more intensive lipid-lowering regimens was more re-
cently supported by observation of cardiovascular benefit
via addition of the cholesterol absorption inhibitor ezetimibe,
to simvastatin in 18 144 patients with ACS in the Improved
Reduction of Outcomes: Vytorin Efficacy International Trial
(IMPROVE-IT), albeit after a median follow-up of 6 years.5
These studies made a number of contributions to the
management of patients with ACS. Most importantly, they
supported the early use of high-intensity statin therapy.
However, 2 of these studies (PROVE-IT and IMPROVE-IT)
permitted initiation of therapy up to 10 days following the
index ACS event. Given the diminishing length of hospital
stay for most patients with ACS in contemporary practice,
this suggests that many patients may not have received such
therapy in hospital. This has not proven to be the case in
clinical practice, in which statin prescription on discharge
has become a key performance measure for ACS manage-
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ment. The early clinical benefit with high-dose atorvastatin
in MIRACL and PROVE-IT also suggested potential non–lipid-
lowering effects of statin therapy. This was supported by
observations of an association between C-reactive protein
lowering and favorable effects on both cardiovascular
events6 and progression of coronary atherosclerosis7 with
statin therapy.
Increasing use of statin therapy as part of in-hospital man-
agement of patients with ACS has occurred in parallel with
greater use of coronary angiography and early revasculariza-
tion. This raises the question of whether very early adminis-
tration of statin therapy, prior to any potential revasculariza-
tion, may provide additional clinical benefit. Although early
revascularization has been demonstrated to result in fewer ad-
verse cardiovascular events in patients with ACS,8 percutane-
ous coronary intervention (PCI) has the potential to result in
distal embolization of atheromatous material, which may re-
sult in ischemic complications. This may be more likely to hap-
pen in the setting of lipid-rich plaque and inflammatory plaque
underlying acute ischemic events. Administration of statins
prior to any potential PCI might be of benefit, which is sup-
ported by observations from mechanistic studies demonstrat-
ing that statin use prior to PCI has favorable effects on plate-
let reactivity, oxidative and inflammatory biomarkers,
microvascular obstruction, and circulating markers of
myonecrosis.9 Although small studies have investigated po-
tential effects of statins prior to PCI in patients with ACS,10 the
effect on clinical outcomes in a sufficiently large study has not
been investigated.
In this issue of JAMA, Berwanger and colleagues report
the findings of the Statins Evaluation in Coronary Procedures
and Revascularization (SECURE-PCI) trial, in which they
aimed to determine if periprocedural administration of a
loading dose of atorvastatin reduced the incidence of major
adverse cardiovascular events at 30 days in patients with ACS
undergoing clinically indicated coronary angiography.11 Over
a period of more than 5 years, the investigators randomized
4191 patients with ACS to receive 2 loading doses of atorva-
statin, 80 mg, or placebo before and 24 hours following a
planned PCI procedure. All patients were subsequently
treated with atorvastatin, 40 mg/d, for the remaining 30
days. Two important observations were made during this
study. First, even though many patients proceeded to PCI
(64.7%) or coronary artery bypass graft surgery (8%), more
than one-quarter of patients with ACS did not undergo coro-
nary revascularization. This likely reflects a combination of
patients with no obstructive disease requiring intervention and
(Reprinted) JAMA Published online March 11, 2018 E1
 Opinion Editorial

those with widespread, diffuse disease for which revascular-
ization would not provide a clinically useful option. Such find-
ings provide important insights into the heterogeneity that is
encountered with contemporary patients with ACS.
The primary end point, a composite of all-cause mortal-
ity, myocardial infarction, stroke, and unplanned coronary
revascularization at 30 days, occurred in 6.2% of patients in
the atorvastatin group vs 7.1% of patients in the placebo
group, but this difference did not meet statistical significance
(P = .27). As a result, the take-home message of the SECURE-
PCI study is that the routine use of loading doses of atorva-
statin among ACS patients with intended invasive manage-
ment cannot be supported. To what degree this reflects
sample size, based on an ambitious assumed event rate
reduction, remains uncertain.
However, among patients who did undergo PCI, fewer
events were experienced during the next 30 days among pa-
tients who received the atorvastatin loading doses compared
with those who received placebo (6.0% vs 8.2%; P = .02). The
difference in signal between this subgroup and the entire study
cohort is likely related to the much higher event rate among
patients in the placebo group who underwent PCI compared
with those who did not (8.2% vs 5.0%), suggesting that these
patients were higher risk.
Given that patients presenting with an ST-segment eleva-
tion myocardial infarction typically proceed directly to the
catheterization laboratory when available, the findings from
this study may present new challenges in terms of immediate
statin administration in the emergency department. The dem-
onstration of potential benefit would likely provide further sup-
port for the influence of non–lipid-lowering effects of atorva-
statin, although this continues to require investigation.
Although this prespecified subgroup finding involving pa-
tients who underwent PCI can be viewed only as hypothesis
generating, it provides some ongoing enthusiasm that very
early use of high-intensity statin therapy may be of benefit in
the right patients.
Are there clinical implications of these findings for the
management of patients with ACS? Treatment guidelines
already suggest that such patients should receive high-
intensity statin therapy and that routine in-hospital initiation
is likely to be of benefit for both prevention of subsequent
cardiovascular events and increased long-term adherence to
statin therapy, which is a cornerstone of secondary preven-
tion. Whether such therapy should be administered as soon
as possible in the ACS hospitalization remains to be fully elu-
cidated. SECURE-PCI certainly provides reassurance that
such early administration is not associated with harm. The
subgroup findings suggest potential benefit among patients
who are deemed more likely to undergo PCI at the time of
angiography. To what degree such findings may be exclusive
to intensive statin therapy, or whether similar results would
be observed with early initiation of additional lipid-lowering
agents, some of which do not appear to have pleiotropic
effects in humans, is unknown. While a generation of lipid-
lowering studies has supported the concept “the lower and
longer, the better” and, in ACS patients, “early is good,” it
remains to be established whether this concept will evolve to
“the earlier, the lower, and the longer, the better.” Only suffi-
ciently large clinical trials may provide such answers.

ARTICLE INFORMATION REFERENCES 6. Ridker PM, Cannon CP, Morrow D, et al;

Author Affiliations: South Australian Health and
Medical Research Institute, University of Adelaide,
Adelaide, South Australia, Australia.
Corresponding Author: Stephen J. Nicholls, MBBS,
PhD, South Australian Health and Medical Research
Institute, PO Box 11060, Adelaide, South Australia,
Australia 5001 (stephen.nicholls@sahmri.com).
Published Online: March 11, 2018.
doi:10.1001/jama.2018.2426
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest.
Dr Nicholls reports that he is supported by
a Principal Research Fellowship from the National
Health and Medical Research Council of Australia.
He also reports receiving research support from
AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion,
Novartis, Cerenis, the Medicines Company,
Resverlogix, InfraReDx, Roche, Sanofi-Regeneron,
and Liposcience and consultant fees from
AstraZeneca, Amgen, Eli Lilly, Anthera, Merck,
Takeda, Resverlogix, Sanofi-Regeneron, Kowa, CSL
Behring, Esperion, and Boehringer Ingelheim.
Dr Psaltis reports that he is supported by a Future
Leader Fellowship from the National Heart
Foundation of Australia. He also reports receiving
research support from Abbott Vascular and
honoraria from AstraZeneca, Merck, Pfizer,
Esperion, and Bayer.
1. Baigent C, Blackwell L, Emberson J, et al;
Cholesterol Treatment Trialists’ Collaboration.
Efficacy and safety of more intensive lowering of
LDL cholesterol: a meta-analysis of data from
170,000 participants in 26 randomised trials. Lancet.
2010;376(9753):1670-1681.
2. Stone NJ, Robinson JG, Lichtenstein AH, et al.
2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular
risk in adults: a report of the American College
of Cardiology/American Heart Association
Task Force on Practice Guidelines. J Am Coll Cardiol.
2014;63(25 pt B):2889-2934.
3. Schwartz GG, Olsson AG, Ezekowitz MD, et al;
Myocardial Ischemia Reduction With Aggressive
Cholesterol Lowering Study Investigators. Effects of
atorvastatin on early recurrent ischemic events in
acute coronary syndromes: the MIRACL study:
a randomized controlled trial. JAMA. 2001;285(13):
1711-1718.
4. Cannon CP, Braunwald E, McCabe CH, et al;
Pravastatin or Atorvastatin Evaluation and Infection
Therapy–Thrombolysis in Myocardial Infarction 22
Investigators. Intensive vs moderate lipid lowering
with statins after acute coronary syndromes. N Engl
J Med. 2004;350(15):1495-1504.
5. Cannon CP, Blazing MA, Giugliano RP, et al;
IMPROVE-IT Investigators. Ezetimibe added to
statin therapy after acute coronary syndromes.
N Engl J Med. 2015;372(25):2387-2397.
Pravastatin or Atorvastatin Evaluation and Infection
Therapy–Thrombolysis in Myocardial Infarction 22
Investigators. C-reactive protein levels and
outcomes after statin therapy. N Engl J Med. 2005;
352(1):20-28.
7. Nissen SE, Tuzcu EM, Schoenhagen P, et al;
Reversal of Atherosclerosis With Aggressive Lipid
Lowering Investigators. Statin therapy, LDL
cholesterol, C-reactive protein, and coronary artery
disease. N Engl J Med. 2005;352(1):29-38.
8. Mehta SR, Granger CB, Boden WE, et al; TIMACS
Investigators. Early vs delayed invasive intervention
in acute coronary syndromes. N Engl J Med. 2009;
360(21):2165-2175.
9. Wang CY, Liu PY, Liao JK. Pleiotropic effects of
statin therapy: molecular mechanisms and clinical
results. Trends Mol Med. 2008;14(1):37-44.
10. Patti G, Cannon CP, Murphy SA, et al. Clinical
benefit of statin pretreatment in patients
undergoing percutaneous coronary intervention:
a collaborative patient-level meta-analysis of 13
randomized studies. Circulation. 2011;123(15):1622-
1632.
11. Berwanger O, Santucci EV, de Barros e Silva PGM,
et al; for the SECURE-PCI Investigators. Effect of
loading dose of atorvastatin prior to planned
percutaneous coronary intervention on major
adverse cardiovascular events in acute coronary
syndrome: the SECURE-PCI randomized clinical trial
[published online March 11, 2018]. JAMA. doi:10.1001
/jama.2018.2444

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