Download Myocardial Infarct Size Reduction With Pexelizumab

JACC: CARDIOVASCULAR IMAGING
© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
VOL. 3, NO. 1, 2010
ISSN 1936-878X/10/$36.00
DOI:10.1016/j.jcmg.2009.10.006
EDITORIAL COMMENT
Myocardial Infarct Size Reduction With Pexelizumab
The Role of Chance Is Patently Clear*
C. Michael Gibson, MS, MD, Yuri B. Pride, MD
Boston, Massachusetts
The goal of ST-segment elevation myocardial infarction (STEMI) management is rapid and sustained reperfusion of the infarct-related artery
(1–3). Primary percutaneous coronary intervention
(PCI) is the preferred reperfusion method if it can
be performed promptly and by an experienced
operator (4). Despite widespread improvements in
clinical pathways to improve door-to-balloon time
and the development of novel antiplatelet and
antithrombotic agents and subsequent improved
clinical outcomes, STEMI remains a cause of considerable morbidity and mortality (5). As such,
numerous pharmacologic and device-based strategies have been developed with the aim of improving
outcomes among STEMI patients.
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Although primary PCI sufficiently restores epicardial patency in the majority of STEMI patients,
a large subset suffer from impaired myocardial
perfusion, which has been associated with larger
infarct size and a higher incidence of adverse
cardiovascular events (6). Impaired myocardial perfusion may result from embolization of thrombotic
and atherosclerotic debris and platelet microaggregates, endothelial dysfunction, inflammatory
changes, or a combination of these events that occur
in the myocardial microcirculation downstream of
ruptured plaque.
The role of inflammation, specifically the complement pathway, in myocardial injury following
*Editorials published in JACC: Cardiovascular Imaging reflect the views of
the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
From the Cardiovascular Division, Department of Medicine, Beth
Israel Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts.
STEMI has been an area of active investigation (7).
The C5 component of the complement pathway,
when cleaved via activation of more proximal components of the pathway, yields C5a, a proinflammatory cytokine, and C5b, which initiates production of the membrane attack complex, a multimeric
protein that inserts itself into the cell membrane
and leads to membrane destabilization and, ultimately, cell death. Therefore, inhibition of the
cleavage of C5 into C5a and C5b would appear to
be an attractive target in the reduction of infarct size
and, potentially, adverse clinical events following
STEMI.
Pexelizumab, a humanized monoclonal antibody
that binds C5, showed promise in a phase 2 study of
STEMI patients undergoing primary PCI, the
COMMA (COMplement inhibition in Myocardial
infarction treated with Angioplasty) trial (8). Paradoxically, administration of intravenous pexelizumab following primary PCI did not lead to a
significant reduction in enzymatic infarct size, but
was associated with a significant reduction in mortality (5.9% vs. 1.9%, p ⫽ 0.014). The authors
postulated that although pexelizumab had no effect
on infarct size, as might have been expected, its
anti-inflammatory properties must have had some
unmeasured pleiotropic effect(s) in order to lead to
a reduction in mortality. Unfortunately, a subsequent phase 3 trial of high-risk STEMI patients,
the APEX-AMI (Assessment of Pexelizumab in
Acute Myocardial Infarction) study, did not confirm this reduction in either mortality or in the
composite of death, shock, and congestive heart
failure at 30 or 90 days following STEMI (9).
In this issue of iJACC, Patel et al. (10) present the
cardiac magnetic resonance (CMR) substudy of the
APEX-AMI trial. In this 99-patient substudy, the administration of pexelizumab was associated with a significant reduction in infarct size and a higher left ventricular
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Gibson and Pride
Editorial Comment
JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 1, 2010
JANUARY 2010:61–3
ejection fraction compared with placebo, a surprising result, considering administration of pexelizumab had no significant effect on mortality, shock,
or congestive heart failure in the entire study
population.
At first blush, the results of this substudy appear
to present the opposite paradox from what was seen
in the COMMA trial: in COMMA, pexelizumab
did not reduce enzymatic infarct size but was
associated with a significant reduction in mortality;
in APEX-AMI, pexelizumab was associated with a
reduction in CMR infarct size but had no effect on
mortality.
The authors present 3 possible explanations for
the significantly smaller infarct size in the pexelizumab group: 1) that pexelizumab does, in fact,
reduce infarct size, but has some unknown deleterious effect; 2) that CMR may have been inaccurate;
or 3) that there was selective bias inherent in this
subgroup analysis.
Upon closer inspection of the patients enrolled in
the CMR substudy of APEX-AMI, however, it
becomes readily apparent why patients who received pexelizumab had, on average, smaller infarct
size: they were significantly and substantially more
likely to have a patent culprit artery at the time of
initial angiography (42.9% with Thrombolysis In
Myocardial Infarction [TIMI] flow grade 2 or 3 in
the pexelizumab group versus 14.6% in the placebo
group). Although pexelizumab was administered
prior to balloon inflation, it is unlikely that it had
such a dramatic effect on culprit artery patency and
far more likely that the disparate baseline characteristics occurred because of chance. Moreover,
there was no significant difference in initial TIMI
REFERENCES
1. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI)
trial. Phase I findings. N Engl J Med
1985;312:932– 6.
2. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both
on coronary-artery patency, ventricular function, and survival after acute
myocardial infarction. N Engl J Med
1993;329:1615–22.
3. Anderson JL, Karagounis LA, Becker
LC, Sorensen SG, Menlove RL.
TIMI perfusion grade 3 but not grade
2 results in improved outcome after
thrombolysis for myocardial infarction. Ventriculographic, enzymatic,
and electrocardiographic evidence
Flow Grade in the entire study population between
the pexelizumab and placebo groups.
Although pexelizumab likely had little effect on
either infarct size or clinical outcomes among patients with STEMI— only anterior infarct location
and initial TIMI flow grade were significantly
associated with infarct size in a multivariate analysis—the results presented in this analysis further
emphasize the importance of early epicardial patency in the management of STEMI.
Numerous studies have shown a significant association between initial TIMI flow grade at the time
of primary PCI and both infarct size and clinical
outcomes (11). Efforts to increase early patency,
most specifically those aimed at improving door-toreperfusion time, have been associated with improved clinical outcomes (12). Further pharmacologic strategies to improve early epicardial patency,
namely in the form of fibrinolytic therapy prior to
PCI, have, however, been met with disappointing
results to date (13).
Likewise, APEX-AMI failed to demonstrate any
tangible benefit of complement inhibition in the
management of STEMI. Although this CMR substudy suggests that perhaps pexelizumab leads to a
significant reduction in infarct size, this may reflect,
at least in part, an imbalance in baseline characteristics between the small patient populations. What
this substudy does support, however, is the continued pursuit of early epicardial patency as a means to
reduce morbidity and mortality in STEMI.
Reprint requests and correspondence: Dr. C. Michael
Gibson, Beth Israel Deaconess Medical Center, 330
Brookline Avenue, Boston, Massachusetts 02215.
E-mail: [email protected].
from the TEAM-3 study. Circulation
1993;87:1829 –39.
4. Antman EM, Hand M, Armstrong
PW, et al. 2007 focused update of the
ACC/AHA 2004 guidelines for the
management of patients with STelevation myocardial infarction: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines.
J Am Coll Cardiol 2008;51:210 – 47.
5. Gibson CM, Pride YB, Frederick PD,
et al. Trends in reperfusion strategies,
door-to-needle and door-to-balloon
times, and in-hospital mortality
among patients with ST-segment elevation myocardial infarction enrolled
in the National Registry of Myocardial Infarction from 1990 to 2006.
Am Heart J 2008;156:1035– 44.
6. Gibson CM, Schomig A. Coronary
and myocardial angiography: angiographic assessment of both epicardial
and myocardial perfusion. Circulation
2004;109:3096 –105.
7. de Zwaan C, van Dieijen-Visser MP,
Hermens WT. Prevention of cardiac
cell injury during acute myocardial
infarction: possible role for complement inhibition. Am J Cardiovasc
Drugs 2003;3:245–51.
8. Granger CB, Mahaffey KW, Weaver
WD, et al. Pexelizumab, an anti-C5
complement antibody, as adjunctive
therapy to primary percutaneous coronary intervention in acute myocardial
infarction: the COMplement inhibition in Myocardial infarction treated
with Angioplasty (COMMA) trial.
Circulation 2003;108:1184 –90.
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JANUARY 2010:61–3
9. Armstrong PW, Granger CB, Adams
PX, et al. Pexelizumab for acute STelevation myocardial infarction in patients undergoing primary percutaneous
coronary intervention: a randomized
controlled trial. JAMA 2007;297:
43–51.
10. Patel MR, Worthley SG, Stebbins
A, et al. Pexelizumab and infarct size
in patients with acute myocardial
infarction undergoing primary percutaneous coronary intervention: a
delayed enhancement cardiac mag-
netic resonance substudy from the
APEX-AMI trial. J Am Coll Cardiol Img 2010;3:52– 60.
11. Stone GW, Dixon SR, Grines CL, et
al. Predictors of infarct size after primary coronary angioplasty in acute
myocardial infarction from pooled
analysis from four contemporary trials.
Am J Cardiol 2007;100:1370 –5.
12. Rathore SS, Curtis JP, Chen J, et al.
Association of door-to-balloon time
and mortality in patients admitted to
hospital with ST elevation myocardial
Gibson and Pride
Editorial Comment
infarction: national cohort study. BMJ
2009;338:b1807.
13. Ellis SG, Tendera M, de Belder MA,
et al. Facilitated PCI in patients with
ST-elevation myocardial infarction.
N Engl J Med 2008;358:2205–17.
Key Words: ST-segment
elevation myocardial infarction
y myocardial perfusion y TIMI
flow grade.
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