Journal of the American College of Cardiology
© 2001 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 37, No. 1, 2001
ISSN 0735-1097/01/$20.00
PII S0735-1097(00)01101-3
Shifting the Open-Artery Hypothesis
Downstream: The Quest for Optimal Reperfusion
Matthew T. Roe, MD,* E. Magnus Ohman, MD, FACC,* Arthur C. P. Maas, MD,*
Robert H. Christenson, PHD,† Kenneth W. Mahaffey, MD,* Christopher B. Granger, MD, FACC,*
Robert A. Harrington, MD, FACC,* Robert M. Califf, MD, FACC,* Mitchell W. Krucoff, MD, FACC*
Durham, North Carolina and Baltimore, Maryland
Successful reperfusion after acute myocardial infarction (MI) has traditionally been considered to be restoration of epicardial patency, but increasing evidence suggests that disordered
microvascular function and inadequate myocardial tissue perfusion are often present despite
infarct vessel patency. Thus, optimal reperfusion is being redefined to include intact
microvascular flow and restored myocardial perfusion, as well as sustained epicardial patency.
Coronary angiography has been used as the gold standard to define failed reperfusion,
according to the Thrombolysis In Myocardial Infarction (TIMI) flow grades. However, new
angiographic techniques, including the corrected TIMI frame count and myocardial blush
grade, have been used to show that epicardial TIMI flow grade 3 may be an incomplete
measure of reperfusion success. Furthermore, evolving noninvasive diagnostic techniques,
including measurement of infarct size with cardiac marker release patterns or technetium99m–sestamibi single-photon emission computed tomographic imaging and analysis of ST
segment resolution appear to be useful complements to angiography for the assessment of
myocardial tissue reperfusion. Promising adjunctive therapies that target microvascular
dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, and agents designed to
improve tissue perfusion and attenuate reperfusion injury are being evaluated to further
improve clinical outcomes after acute MI. To accelerate development of these new reperfusion
regimens, an integrated approach to phase II clinical trials that incorporates multiple efficacy
variables, including angiography and noninvasive biomarkers of microvascular dysfunction,
should be considered. Thus, as the reperfusion era moves into the next millennium, the
open-artery hypothesis is expected to shift downstream and guide efforts to further improve
myocardial salvage and clinical outcomes after acute MI. (J Am Coll Cardiol 2001;37:9 –18)
© 2001 by the American College of Cardiology
The goal of reperfusion therapy for acute myocardial infarction (MI) is to quickly re-establish the flow of nutritive,
oxygenated blood to myocytes, whose function and survival
are threatened by thrombotic occlusion of the infarct-related
artery (IRA) (1,2). Correlations between sustained patency
of the IRA and improved clinical outcomes culminated in
the “open-artery hypothesis,” which has been the cornerstone of therapeutic strategies for acute MI for over a
decade. The open-artery hypothesis suggests that reestablishing a patent IRA with normal anterograde flow
salvages stunned myocardial tissue, preserves left ventricular
mechanical function and positively influences clinical outcomes (3). The benefits of IRA patency also may extend
beyond myocardial salvage, because late restoration of IRA
patency does not improve global left ventricular function,
but appears to improve long-term survival (4). Approximately 25% of patients with restoration of normal anterograde flow in the epicardial IRA, however, do not have
reperfusion of the myocardium at the tissue level (5). Thus,
the open-artery hypothesis may be an oversimplification,
because the goal of reperfusion therapy should be to restore
From the *Duke Clinical Research Institute, Durham, North Carolina; and the
†Department of Pathology, University of Maryland School of Medicine, Baltimore,
Maryland.
Manuscript received December 8, 1999; revised manuscript received August 1,
2000, accepted September 20, 2000.
not only upstream epicardial patency and flow, but also
downstream myocardial tissue perfusion.
Despite significant advances in the treatment of acute MI
over the last decade, new therapies continue to emerge in an
effort to further improve clinical outcomes. With numerous
potential combinations of primary and adjunctive therapies
for acute MI, however, a more precise and comprehensive
definition of “optimal reperfusion” is needed so that a clear
target for new therapies can be established (6). The purposes
of this review are to explore advances that point us downstream from the open-artery hypothesis to the characterization of myocardial tissue perfusion and to determine the ideal
approach for the evaluation of new reperfusion strategies.
HISTORIC PERSPECTIVE
The therapeutic approach to acute MI was pioneered by
Braunwald and Maroko (7), who focused on treatments
designed to limit infarct size by improving myocardial
oxygen supply and limiting autolytic damage to myocytes.
Techniques used to determine infarct size included mapping
of precordial ST segment elevation and disappearance
curves of serum cardiac markers (8,9). By showing that
quantification of infarct size was critical to the assessment of
new therapies for acute MI, these early studies emphasized
10
Roe et al.
Shifting the Open-Artery Hypothesis Downstream
Abbreviations
CK(-MB)
cTFC
GUSTO-I
IRA
MCE
MI
MRI
SPECT
99m
Tc
TIMI
JACC Vol. 37, No. 1, 2001
January 2001:9–18
and Acronyms
⫽ creatine kinase (MB fraction)
⫽ corrected TIMI frame count
⫽ Global Utilization of Streptokinase and
TPA (alteplase) for Occluded coronary
arteries
⫽ infarct-related artery
⫽ myocardial contrast echocardiography
⫽ myocardial infarction
⫽ magnetic resonance imaging
⫽ single-photon emission computed
tomography
⫽ technetium-99m
⫽ Thrombolysis In Myocardial Infarction
the importance of restoring global myocardial perfusion to
the recovery of left ventricular function.
Despite the initial focus on myocardial tissue perfusion,
attention soon shifted to the epicardial vessel. Using canine
models of coronary occlusion in the late 1970s, Reimer et al.
(1) showed that infarct size was directly related to the
duration of epicardial occlusion—a finding later termed the
“wave front phenomenon” of myocyte death. Although
prompt relief of epicardial occlusion was clearly shown to
halt the wave front of ischemic myocyte death, microvascular dysfunction in the infarct zone was identified as the
limiting factor for the restoration of myocardial tissue
perfusion (this phenomenon was called “no-reflow”) (1,10).
Paradoxically, epicardial reperfusion also was shown to
exacerbate microvascular dysfunction when blood flow was
restored to the infarct region (11,12). Therefore, historic
observations defined the continuum of reperfusion from
upstream epicardial patency to downstream tissue perfusion
and emphasized that the ultimate goal of treatment strategies for acute MI should be the prompt restoration of
normal epicardial and myocardial perfusion.
MICROVASCULAR DYSFUNCTION
Pathophysiology. After plaque rupture and intracoronary
thrombus formation, ischemia causes ultrastructural damage
to myocytes and the coronary microcirculation soon after
coronary occlusion (13). Once epicardial reperfusion occurs
and blood flow to the infarct zone is restored, reperfusion
injury caused by neutrophil infiltration, generation of oxygen free radicals and activation of the complement system
and adhesion molecules may further damage the microcirculation (11,14,15). Damaged myocytes and arterioles are
thought to hinder microvascular flow by increasing distal
vascular resistance, stimulating arteriolar spasm and causing
endothelial dysfunction. In addition, platelet microemboli
are thought to be “showered” downstream of the microcirculation after plaque rupture, causing microvascular obstruction that further limits tissue perfusion once the epicardial
infarct vessel is recanalized (16). Microvascular dysfunction
also appears to occur in non–infarct-related vessels, suggesting that myocardial ischemia may stimulate a global inflam-
Figure 1. Pathophysiology of microvascular dysfunction after epicardial
perfusion.
matory response through the release of cytokines (17).
Thus, microvascular dysfunction after epicardial reperfusion
is a complex process with several probable interrelating
stimuli and factors (Fig. 1).
Clinical significance. Microvascular perfusion is disrupted
in a significant proportion of patients with patent epicardial
infarct-related vessels after fibrinolysis or primary angioplasty (5,18). The clinical significance of microvascular
dysfunction after epicardial reperfusion has been evaluated
in multiple studies that used surrogate markers, such as
myocardial contrast echocardiography (MCE) and ST segment resolution, to evaluate tissue-level reperfusion (19 –24)
(Table 1). These studies collectively showed less recovery of
left ventricular ejection fraction, progressive left ventricular
dilation and increased mortality and congestive heart failure
in patients who had microvascular dysfunction after epicardial reperfusion. However, the extent of myocardial damage
that occurs before reperfusion may limit further myocardial
salvage, even if normal tissue perfusion is restored.
INSIGHTS FROM ANGIOGRAPHY
Since DeWood et al. (2) first used coronary angiography to
show that thrombotic occlusion of the epicardial coronary
artery caused acute MI, angiography has been a valuable tool
for the evaluation of patients treated with reperfusion
therapies. The Thrombolysis In Myocardial Infarction
(TIMI) investigators categorized epicardial coronary flow
into grades to standardize the angiographic characterization
of reperfusion (25). Flow grade 0 or 1 represented failed
reperfusion, whereas flow grade 2 or 3 represented epicardial
patency and successful reperfusion. However, the angiographic substudy of the Global Utilization of Streptokinase
and TPA (alteplase) for Occluded coronary arteries
(GUSTO-I) showed that restoration of TIMI flow grade 3
(normal epicardial flow) alone is associated with improved
survival and enhanced recovery of left ventricular function
(26,27). The survival advantage shown with TIMI flow
Roe et al.
Shifting the Open-Artery Hypothesis Downstream
In-hospital
30 days
1 year
16 months
(mean)
NM
NM
NM
1 89%†
1 10%‡
NM
NM
NM
49% 3 43%†
54% 3 55%‡
206
455
91
44
Gibson et al. (21)/cTFC
Gibson et al. (22)/MPG
Claeys et al. (23)/ST segment resolution
Wu et al. (24)/MRI
72%¶
70%#
36%**
25%
21.8 months
(median)
NM
35% 3 45%†
44% 3 56%‡
52%
50
Sakuma et al. (20)/MCE
*Impaired blood flow to the infarct region supplied by a patent epicardial vessel. †Impaired flow. §⬍3 days after acute MI. ‡Normal flow. 㛳⬎3 days after acute MI. ¶cTFC ⬎20 and ⱕ40. #TIMI MPG 0 to 2. **ST segment resolution
from baseline ⱕ50%.
CHF ⫽ congestive heart failure; cTFC ⫽ corrected TIMI frame count; EDV ⫽ left ventricular end-diastolic volume; LVEF ⫽ left ventricular ejection fraction; MCE ⫽ myocardial contrast echocardiography; MI ⫽ myocardial
infarction; MPG ⫽ myocardial perfusion grade; MRI ⫽ magnetic resonance imaging; NM ⫽ not measured.
12%
1%
1%
13%
0%
0%
8%
0.7%
15%
9%
21%
6%
3%
23%
8%
8%
16%
4.7%
45%
45%
Early CHF§
Late CHF㛳
Death
Death
Repeat MI
CHF
Death, repeat MI, CHF or shock
Mortality
Death, repeat MI or readmission
Death, repeat MI, CHF or stroke
In-hospital
1 24
2 10
38% 3 43%†
46% 3 57%‡
37%
Ito et al. (19)/MCE
127
ml†
ml‡
Clinical Outcomes
Impaired Flow*
Mean ⌬EDV
Mean ⌬LVEF
Microvascular
Dysfunction*
n
Study/Imaging Technique
Table 1. Clinical Outcomes With Microvascular Dysfunction After Epicardial Reperfusion
Follow-Up
Outcome
Normal Flow
JACC Vol. 37, No. 1, 2001
January 2001:9–18
11
Figure 2. Stages of successful reperfusion depicted with angiographic
techniques. As epicardial patency is re-established, tissue perfusion is
restored if microvascular damage is not present. Adapted from Davies and
Ormerod (6), with permission.
grade 3 in the GUSTO-I angiographic substudy closely
matched the mortality rates observed with the different
fibrinolytic regimens tested in the overall trial (28). These
findings, which linked therapeutic efficacy of treatments for
acute MI to the early, complete restoration of anterograde
flow in the epicardial IRA, validated angiography as a
surrogate end point for mortality in trials of acute MI.
Although restoration of TIMI flow grade 3 has been used
as the gold standard for reperfusion success, distal coronary
flow can vary considerably despite flow grade 3 in the
epicardial vessel (29). The corrected TIMI frame count
(cTFC) was developed to quantify distal coronary flow and
can further risk-stratify patients with TIMI flow grade 3
after fibrinolysis into lower-and higher risk subgroups
(21,29). Furthermore, the angiographic “blush” score appears to assess myocardial tissue perfusion more accurately
than does cTFC and may be an even better method of risk
stratification (22,30). Therefore, refinement of the angiographic characterization of reperfusion has emphasized the
importance of restored myocardial tissue perfusion in determining the ultimate success of reperfusion strategies (6)
(Fig. 2). However, angiography is a “snapshot” technique
that may not adequately assess the continuum of reperfusion; it is also expensive and cannot be performed early at
most hospitals (31).
DIAGNOSIS OF REPERFUSION
SUCCESS AT THE CELLULAR LEVEL
Promising diagnostic tests that focus on the identification of
patients with microvascular dysfunction after epicardial
reperfusion may complement the angiographic characterization of reperfusion.
12
Roe et al.
Shifting the Open-Artery Hypothesis Downstream
Coronary Doppler flow wires. Coronary Doppler flow
wires can be used to measure coronary flow velocity and
coronary flow reserve after epicardial reperfusion in order to
estimate the degree of microvascular dysfunction in the
infarct zone. Disruption of coronary flow velocity and
reserve after successful epicardial reperfusion appears to
predict recovery of regional left ventricular function and
contractile reserve (32,33). Myocardial tissue perfusion cannot be assessed directly with coronary Doppler flow wires,
however, coronary angiography is required, and the reproducibility of this technique has not been studied.
Myocardial contrast echocardiography. Myocardial contrast echocardiography was first performed during angiography by injecting a sonicated contrast solution into the
recanalized IRA to evaluate myocardial contrast enhancement in infarct-zone tissue (5). It has shown that up to 25%
of patients with acute MI do not have adequate restoration
of myocardial tissue perfusion in the infarct region, despite
TIMI flow grade 3 in the epicardial IRA (5,18). New
contrast agents that can be injected intravenously are being
developed, but have not been adequately tested in a large
cohort of patients with acute MI (34).
Magnetic resonance imaging. Cardiac magnetic resonance imaging (MRI) appears to be one of the most
comprehensive imaging techniques used to evaluate microvascular dysfunction, because it can be used to assess
coronary flow, myocardial tissue perfusion, left ventricular
volumes and regional and global left ventricular function
(24,35). However, high costs, long procedure times and the
inability to accommodate unstable patients are significant
limitations of cardiac MRI.
Technetium-99m-sestamibi single-photon emission
computed tomography. Cumulative infarct size measurement with technetium-99m (99mTc)-sestamibi singlephoton emission computed tomography (SPECT) appears
to be a promising technique to determine left ventricular
damage and the amount of myocardial salvage after reperfusion therapy (36,37). Initial 99mTc-sestamibi SPECT
imaging is often difficult to perform while treating acute
MI, however. The ideal time to perform follow-up imaging
after administration of reperfusion therapy is unclear.
Cardiac markers. After coronary occlusion, myocyte necrosis leads to the release of cardiac markers into the serum,
including creatine kinase (CK), CK-MB fraction, myoglobin, alpha-hydroxybutyrate dehydrogenase and troponins I
and T. Initial studies by Witteveen et al. (9) and Sobel et al.
(38) showed that the cumulative release of cardiac markers
after acute MI could be used to estimate infarct size, predict
recovery of left ventricular function and predict survival. In
the modern reperfusion era, release patterns of cardiac
markers have been used to compare primary angioplasty
with fibrinolytic agents and to compare different fibrinolytic
regimens (39 – 41). Furthermore, we have shown that the
peak serum CK-MB concentration and the cumulative area
under the CK-MB release curve after fibrinolysis indepen-
JACC Vol. 37, No. 1, 2001
January 2001:9–18
dently predict in-hospital mortality and congestive heart
failure, but do not relate to TIMI flow grades (42). The area
under the curve is a technique that accounts for the
cumulative marker release, regardless of the peak and width
of the curve. The curve of cardiac marker release can
therefore be used to represent an overall measure of myocardial cellular injury. However, the optimal number of
samples needed to assess infarct size accurately, the best
marker to use for infarct size measurement and how curves
of marker release correlate with myocardial salvage and
other markers of reperfusion success remain unclear.
Successful reperfusion is associated with a rapid, early
increase in serum cardiac marker concentrations, which is
thought to represent the “washout” of tissue cardiac markers
after restoration of epicardial coronary blood flow (43) (Fig.
3). Thus, isolated ratios of early cardiac marker levels have
been used to predict successful reperfusion after fibrinolysis
in studies that confirmed epicardial patency angiographically (44 – 47). Myoglobin appears to be the most useful
marker to evaluate early reperfusion success, because it has a
rapid peak and early decay after successful reperfusion (47).
Because isolated cardiac marker levels may represent only a
“snapshot” time point in the process of reperfusion, however, cumulative marker release curves may better reflect
overall reperfusion success. Further study is needed to
determine how to use cardiac markers as surrogate markers
of reperfusion.
ST segment resolution. Evaluating ST segment resolution
with serial electrocardiograms was first recommended as a
useful bedside marker of reperfusion success by Braunwald
and Maroko 25 years ago (48). The clinical impact of the
degree of ST segment resolution was defined by Schroder et
al. (49), who showed a stepwise increase in mortality with
⬍
complete (⬎
⫺70%), partial (31% to 69%) or no ( ⫺30%)
resolution of ST segment elevation after fibrinolytic administration. The prognostic significance of Schroder’s criteria
for ST segment resolution after fibrinolysis has been validated in multiple studies (50 –52) (Table 2). Thus, the
degree of ST segment resolution after reperfusion therapy is
a reliable, noninvasive predictor of mortality.
ST segment resolution appears to reflect restoration of
myocardial tissue perfusion, not just epicardial flow. Rapid
ST segment resolution within 30 to 60 min of successful
primary angioplasty (patent IRA with TIMI flow grade 3)
predicts greater improvement in ejection fraction, reduced
infarct size and improved survival as compared with delayed
ST segment resolution (23,53–55). Microvascular dysfunction may explain these findings because rapid ST segment
resolution after successful primary angioplasty correlates
with microvascular reflow into the infarct region as measured by MCE (56). Therefore, ST segment resolution at
serial, static time points appears to represent a “snapshot” of
global tissue reperfusion. Because reperfusion is a dynamic
and often cyclic process, however, the ideal time to measure
ST segment resolution after fibrinolysis is unclear.
Roe et al.
Shifting the Open-Artery Hypothesis Downstream
JACC Vol. 37, No. 1, 2001
January 2001:9–18
13
Figure 3. Temporal pattern of creatine kinase (CK) release after fibrinolysis for successful (Thrombolysis In Myocardial Infarction [TIMI] flow grade 3)
and unsuccessful (TIMI flow grade 0) reperfusion. Reproduced from Zabel et al. (44), with permission.
Continuous monitoring of ST segment resolution is
advantageous because it can be used to determine the exact
time of reperfusion, to detect intermittent reocclusion that
often occurs after fibrinolysis and to assess ST segment
resolution at multiple time points (57) (Fig. 4). Multiple
studies have shown the potential of continuous ST segment
monitoring for detection of failed reperfusion and early risk
stratification of patients with acute MI (58 – 60). The
temporal pattern of ST segment resolution appears to
estimate infarct size and left ventricular contractile recovery
and can be used to identify ST segment re-elevation, which
signifies infarct vessel reocclusion and is associated with
higher mortality (59,61– 63). Furthermore, compared with
the angiographic assessment of reperfusion, the continuous
ST segment resolution pattern was found to be the only
independent predictor of mortality or congestive heart
failure in patients treated with fibrinolytic agents (64).
Therefore, continuous ST segment monitoring measures
not only the degree of ST segment resolution, but also the
speed and stability of reperfusion, and thus may be more
useful than evaluating ST segment resolution at isolated,
static time points.
IMPROVING REPERFUSION THERAPY
Fibrinolytic therapy is limited by inadequate epicardial
patency and intermittent vessel reocclusion, whereas primary angioplasty is limited by treatment delays and lack of
widespread access to catheterization facilities (31,65). New
fibrinolytic agents that accelerate and enhance clot lysis have
been developed, and coronary stenting produces higher
initial rates of TIMI flow grade 3, as compared with primary
angioplasty, but survival rates have not improved with these
advances (65,66). Targeting the microcirculation with new
adjunctive therapies, however, may help to breach the
therapeutic “plateau” that exists with current reperfusion
strategies.
Antiplatelet therapy. Platelet glycoprotein IIb/IIIa inhibitors are a promising adjunctive therapy for both fibrinolysis
and primary angioplasty (67). In phase II, dose-ranging
trials, the combination of partial-dose fibrinolytic agents
and glycoprotein IIb/IIIa inhibitors accelerated and improved epicardial reperfusion, as compared with fibrinolytic
therapy alone (68,69). The glycoprotein IIb/IIIa inhibitors
also have been shown to improve outcomes in small studies
Table 2. Mortality by Degree of ST Segment Resolution After Fibrinolysis*
Resolution of ST Segment
Elevation
Trial
Time of ST
Segment Analysis
(min)
Follow-Up
(days)
n
Complete
Partial
None
p Value
ISAM (49)
INJECT (50)
HIT-4 (51)
TIMI-14 (52)
180
180
180
90
35
35
35
30
1,516
1,398
998
444
2.8%
2.5%
2.8%
1.0%
4.3%
4.3%
6.0%
4.2%
9.2%
17.5%
14.3%
5.9%
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.001
*Complete ST segment resolution was ⱖ70% from baseline; partial resolution was 31% to 69% from baseline; no resolution was
ⱕ30% from baseline.
HIT ⫽ Hirudin for Improvement inThrombolysis; INJECT ⫽ International Joint Efficacy Comparison of Thrombolytics;
ISAM ⫽ Intravenous Streptokinase inAcute Myocardial infarction; TIMI ⫽ Thrombolysis In Myocardial Infarction.
14
Roe et al.
Shifting the Open-Artery Hypothesis Downstream
JACC Vol. 37, No. 1, 2001
January 2001:9–18
Figure 4. Temporal pattern of ST segment resolution after fibrinolysis, with continuous 12-lead ST segment monitoring. Cyclic patency of the
infarct-related artery (IRA) is depicted by intermittent ST segment re-elevation.
of patients undergoing primary angioplasty (70 –72). Preliminary evidence suggests that reperfusion is enhanced with
adjunctive glycoprotein IIb/IIIa blockade, but large mortality trials are needed to verify that such a strategy would
reduce mortality when used with fibrinolytic agents or
primary angioplasty.
The mechanism of benefit of glycoprotein IIb/IIIa blockade for both pharmacologic and mechanical reperfusion
strategies may be related, in part, to enhanced myocardial
tissue reperfusion. In patients with TIMI flow grade 3 in
the IRA after primary stenting for acute MI, treatment with
abciximab appeared to improve tissue reperfusion by improving peak flow velocity in the recanalized IRA, wall
motion index values and global left ventricular function
(73). Similarly, among patients with TIMI flow grade 3 in
the IRA, the combination of abciximab and partial-dose
alteplase improved distal coronary flow and the degree of ST
segment resolution, as compared with alteplase alone
(52,74). Continuous ST segment monitoring has also
shown that combination therapy with fibrinolytic agents
and glycoprotein IIb/IIIa inhibitors improves the speed and
stability of myocardial tissue reperfusion, as compared with
fibrinolytic monotherapy (75). Adjunctive glycoprotein IIb/
IIIa blockade may improve endothelial function after epicardial reperfusion and may relieve microvascular obstruction caused by platelet-thrombin microemboli, but the
mechanisms by which augmented antiplatelet therapy improves microvascular flow remain unclear.
Agents designed to improve tissue perfusion. Other adjunctive therapies that target microvascular dysfunction are
thought to improve endothelial function of distal arterioles,
restore myocardial metabolic homeostasis and ameliorate
the inflammatory response initiated by myocyte necrosis and
reperfusion injury. When used during a primary percutaneous coronary intervention, the intravenous vasodilators verapamil and nicorandil have been shown to enhance tissue
perfusion in the infarct region, as measured by MCE
(76,77). Glucose/insulin/potassium therapy appears to improve cellular metabolism in the infarct region after acute
MI (78), but this therapy has not been tested in a large
mortality trial (79). Despite promising studies of antiinflammatory therapies in animal models of reperfusion
injury, human clinical trials of agents designed to limit
infarct size have been disappointing (79 – 87) (Table 3). The
recent Acute Myocardial Infarction STudy of ADenosine
(AMISTAD) trial showed a reduction in infarct size when
Roe et al.
Shifting the Open-Artery Hypothesis Downstream
JACC Vol. 37, No. 1, 2001
January 2001:9–18
15
Table 3. Randomized Trials of Agents Designed to Improve Myocardial Tissue Reperfusion
Trial
TIMI-2 (80)
TAMI-4 (81)
TAMI-9 (82)
ISIS-4 (83)
CORE (84)
AMISTAD (85)
HALT-MI (86)
ADMIRE (87)
Agent
IV metoprol
Prostacyclin
Fluosol
Magnesium
RheothRx
Adenosine
Hu23F2G
AMP579
Mechanism of Action
n
Primary End Point(s)
Results
Lowers oxygen demand
Inhibits neutrophils; scavenges free radicals
Inhibits neutrophils; improves oxygen delivery
Stabilizes myocardial membranes
Improves oxygen delivery
Inhibits neutrophils; scavenges free radicals
Inhibits neutrophil adhesion to endothelial cells
Inhibits neutrophils; scavenges free radicals
1,390
50
430
58,050
2,780
236
420
311
EF at discharge
IRA patency, EF
Infarct size
Death at 35 days
Death/shock/repeat MI
Infarct size
Infarct size
Infarct size
Negative (50.5% vs. 50.0%)
Negative (both lower)
Negative (22% vs. 17%)
Negative (7.6% vs. 7.2%)
Negative (13.6% vs. 12.7%)
Positive (13% vs. 19.5%)*
Neutral (17.1% vs. 19.3%)†
Negative (11.8% vs. 9.9%)‡
*The primary end point included a multivariable regression analysis, which revealed a 33% relative reduction in infarct size with adenosine treatment (p ⫽ 0.03). †High dose
Hu23F2G versus placebo. ‡High dose AMP579 versus placebo.
ADMIRE ⫽ AMP579 Delivery for Myocardial Infarction REduction; AMISTAD ⫽ Acute Myocardial Infarction STudy of ADenosine; CORE ⫽ Collaborative
Organization for RheothRx Evaluation; EF ⫽ ejection fraction; HALT-MI ⫽ Hu23F2G antiAdhesion to Limit cytoToxic injury following acute Myocardial Infarction; IRA ⫽
infarct-related artery; ISIS ⫽ International Study of Infarct Survival; MI ⫽ myocardial infarction; TAMI ⫽ Thrombolysis and Angioplasty in Myocardial Infarction; TIMI ⫽
Thrombolysis In Myocardial Infarction.
Adapted from Granger (79), with permission.
adenosine was given with fibrinolytic agents, but clinical
outcomes were not improved in this small study (85).
Ongoing trials of other adjunctive agents, including
complement-activation inhibitors and adhesion molecule
antibodies, are under way, but further study is needed to
determine the therapeutic benefits of agents designed to
improve myocardial salvage and restore tissue perfusion.
IMPLICATIONS FOR CLINICAL TRIALS
Because TIMI flow grades have been shown to correlate
directly with mortality (28), the evaluation of new reperfusion therapies usually involves angiographic verification of
patency in phase II, dose-ranging trials, followed by large,
phase III mortality trials. With an expanded definition of
reperfusion success that includes restoration of microvascular flow and myocardial tissue perfusion, however, other
surrogate end points also appear promising. The amount of
myocardial salvage in fibrinolytic and primary angioplasty
trials, for example, has been determined by measurement of
infarct size with cardiac markers and 99mTc-sestamibi
SPECT (37,39,40,86,87). The relative efficacy of different
fibrinolytic agents with regard to myocardial tissue reperfusion has also been evaluated with ST segment resolution at
serial, static time points and with continuous ST segment
monitoring (52,88 –91). Other techniques to evaluate myocardial tissue perfusion, including coronary Doppler flow
wires, MCE and cardiac MRI, have not been widely tested
in clinical trials comparing reperfusion regimens.
Despite the enthusiasm for these new surrogate end
points (biomarkers) for acute MI trials, they should be
carefully evaluated before they are routinely incorporated
into clinical trials. Such biomarkers should correlate closely
with mortality (the gold standard clinical end point), should
be easily measured in most patients and should statistically
explain the magnitude of the observed treatment effect with
more than one therapy (92). Left ventricular ejection fraction was widely used as a surrogate end point for acute MI
trials early in the development of fibrinolytic agents, but it
later proved to be an unreliable measure of therapeutic
efficacy (93). Despite the potential of infarct size measure-
ment with cardiac markers or 99mTc-sestamibi SPECT and
ST segment resolution as biomarkers of reperfusion success,
therapies associated with reduced infarct size or improved
ST segment resolution have not been proven to reduce
mortality in large, phase III trials (52,85,88).
Given the changing definition of optimal reperfusion,
phase II trials for acute MI should be reconfigured to
include parallel efficacy arms that evaluate both epicardial
and myocardial perfusion with invasive and noninvasive
techniques (Table 4). Because early angiography after fibrinolysis can be performed only at a limited number of sites,
the use of noninvasive techniques may allow more sites to
participate in such trials and may accelerate their completion. Furthermore, the optimal integration of data collected
for disparate biomarkers has not been determined. The use
of parallel efficacy arms in phase II trials may help determine
how to combine data to evaluate the overall therapeutic
efficacy of a new reperfusion regimen and to validate
noninvasive biomarkers as reliable surrogate end points.
However, strategies will need to be developed to account for
missing or uninterpretable data before biomarkers other
than angiography can be routinely incorporated into phase
II clinical trials in acute MI.
Conclusions. As the reperfusion era moves into the new
millennium, the downstream shift of the open-artery hypothesis is expected to redefine the goals of reperfusion
therapies to include not only rapid and sustained epicardial
patency, but also restored microvascular flow and myocardial tissue perfusion. Given the rapid evolution of pharmaTable 4. Redesigning Phase II Acute MI Trials
Invasive End Points
Non-Invasive End Points
Angiography
TIMI flow grades
cTFC
MPG
Myocardial Reperfusion
ST-segment resolution
Serial static ECGs
Continuous ST monitoring
Myocardial Salvage/Infarct Size
Cardiac markers
99m
Tc-sestamibi SPECT imaging
cTFC ⫽ corrected TIMI frame count; ECGs ⫽ electrocardiograms; MPG ⫽
myocardial perfusion grade; SPECT ⫽ single-photon emission computed tomography; TIMI ⫽ Thrombolysis In Myocardial Infarction.
16
Roe et al.
Shifting the Open-Artery Hypothesis Downstream
cologic and mechanical reperfusion strategies, phase II
clinical trials for acute MI will need to be streamlined to
accelerate the development of the most promising therapies
and reperfusion strategies. Noninvasive biomarkers that
assess myocardial tissue perfusion may therefore prove to be
useful complements to angiography for evaluation of new
reperfusion regimens. However, therapies that improve
microvascular flow and myocardial perfusion must be
proven to reduce mortality before the open-artery hypothesis can be shifted downstream.
Reprint requests and correspondence: Dr. Matthew T. Roe,
Duke Clinical Research Institute, P.O. Box 17969, Durham,
North Carolina 27715. E-mail: [email protected].
JACC Vol. 37, No. 1, 2001
January 2001:9–18
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