Download Prevention and Treatment of Microvascular Obstruction

JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 3, NO. 7, 2010
© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER INC.
DOI: 10.1016/j.jcin.2010.05.004
STATE-OF-THE-ART PAPER
Prevention and Treatment of Microvascular
Obstruction-Related Myocardial Injury
and Coronary No-Reflow Following
Percutaneous Coronary Intervention
A Systematic Approach
Ronen Jaffe, MD,* Alexander Dick, MD,† Bradley H. Strauss, MD, PHD†
Haifa, Israel; and Toronto, Ontario, Canada
Microvascular obstruction (MVO) commonly occurs following percutaneous coronary interventions (PCI),
may lead to myocardial injury, and is an independent predictor of adverse outcome. Severe MVO may manifest angiographically as reduced flow in the patent upstream epicardial arteries, a situation that is termed
“no-reflow.” Microvascular obstruction can be broadly categorized according to the duration of myocardial
ischemia preceding PCI. In “interventional MVO” (e.g., elective PCI), obstruction typically involves myocardium that was not exposed to acute ischemia before PCI. Conversely “reperfusion MVO” (e.g., primary PCI
for acute myocardial infarction) occurs within a myocardial territory that was ischemic before the coronary
intervention. Interventional and reperfusion MVO have distinct pathophysiological mechanisms and may
require individualized therapeutic approaches. Interventional MVO is triggered predominantly by downstream embolization of atherosclerotic material from the epicardial vessel wall into the distal microvasculature. Reperfusion MVO results from both distal embolization and ischemia-reperfusion injury within the subtended ischemic tissue. Management of MVO and no-reflow may be targeted at different levels: the
epicardial artery, microvasculature, and tissue. The aim of the present report is to advocate a systematic
approach to prevention and treatment of MVO in different clinical settings. Randomized clinical trials have
studied strategies for prevention of MVO and no-reflow; however, the efficacy of measures for reversing
MVO once no-reflow has been demonstrated angiographically is unclear. New approaches for prevention
and treatment of MVO will require a better understanding of intracellular cardioprotective pathways such as
the blockade of the mitochondrial permeability transition pore. (J Am Coll Cardiol Intv 2010;3:695–704)
© 2010 by the American College of Cardiology Foundation
The concept of microvascular obstruction (MVO)
following percutaneous coronary interventions (PCI)
refers to myocardial tissue hypoperfusion in the presence of patent epicardial coronary circulation. Severe
MVO may lead to overt reduction in flow in the
patent upstream epicardial arteries, which is termed
From the *Lady Davis Medical Center, Department of Cardiology,
Haifa, Israel; and the †Schulich Heart Programme, Sunnybrook Health
Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
Manuscript received February 21, 2010; revised manuscript received May
10, 2010, accepted May 12, 2010.
“no-reflow.” No-reflow is associated with adverse
clinical outcomes and is caused by MVO (⬍200
␮m), which may result from multiple pathophysiological mechanisms. Diagnostic modalities that have
a role in evaluating microvascular perfusion include
ST-segment resolution on the electrocardiogram,
angiographic measures of coronary flow and tissue
perfusion, contrast echocardiography, magnetic resonance imaging, computed tomography, and intracoronary measurement of flow velocity by Doppler
wire (1). Tissue hypoperfusion following PCI leads to
myocardial ischemia, which may result in elevation of
696
Jaffe et al.
No-Reflow Systematic Approach
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JULY 2010:695–704
serum markers of cardiac injury. We have recently reviewed the
pathophysiology of 2 related clinical entities that are characterized by MVO but differ in several fundamental ways (1). In
MVO following PCI outside of the acute infarct setting, which
we have termed “interventional MVO,” the myocardial tissue
subtended by the treated coronary artery is not typically
subjected to acute ischemia before the intervention, and the
procedure-induced MVO is caused primarily by distal microembolization. In contrast, “reperfusion MVO,” occurring in the
acute infarct setting, results from complex pathophysiological
mechanisms that include ischemic and reperfusion injury as
well as distal microembolization of plaque and thrombus. In
this review, we discuss the therapeutic options for both
prevention and treatment of MVO and no-reflow in these 2
settings.
Prevention and Treatment of MVO and No-Reflow:
Experimental and Clinical Experience
Mechanisms of MVO include mechanical plugging secondary to distal embolization from
the epicardial coronary arteries,
Abbreviations
external compression by edemaand Acronyms
tous tissue, in situ thrombosis,
ACC ⴝ American College
vasospasm, activation of inflamof Cardiology
matory cascades with leukocyte
AHA ⴝ American Heart
stasis and extravasation, and
Association
reperfusion injury (2). IntervenMPTP ⴝ mitochondrial
tions for optimizing tissue perpermeability transition pore
fusion following PCI may be
MVO ⴝ microvascular
obstruction
targeted at the epicardial coronary artery, the microvasculaPCI ⴝ percutaneous
coronary interventions
ture, and the subtended myocardial tissue (Figs. 1 and 2).
Multiple therapies for MVO and no-reflow have been
tested in animals and to a lesser degree in humans. Efficacy
of therapies may depend on the experimental model and
clinical context in which they are studied, as well as the
specific dosage, route of administration, and timing of
treatment in relation to the PCI. Treatments for MVO that
were shown to be effective in pre-clinical research have often
failed to translate into effective human therapies, due to
limitations of the available animal models (2). Current
animal models lack several features, including atherosclerotic vascular substrate and pre-existing microvascular dysfunction. Distal embolization models have rarely used biologically active material. Ischemia-reperfusion models have
not included distal embolization. An ideal experimental
model should incorporate downstream embolization of
plaque constituents or thrombus into a distal coronary bed
that has been subjected to ischemia in a hyperlipidemic or
hyperglycemic animal.
Because alterations in flow (either no-reflow or slow flow)
are dynamic by nature and may spontaneously resolve over
Figure 1. Myocardial Targets for Pharmacological Therapies to Prevent
Reperfusion No-Reflow
The inset depicts a myocardial cell and its subcellular structures involved
in cardioprotective pathways.
time, the contribution of nonrandomized studies to the
current understanding of treatment options is limited.
Although several randomized trials have studied different
preventive strategies, data regarding interventions for reversal of MVO once it exists is confined to retrospective case
reports, due to the rarity and unpredictability of this
phenomenon. End points for clinical trials have been
defined at the level of the microvasculature (tissue perfusion), organ (cardiac function), and clinical outcomes (survival, functional capacity). Whereas reduced tissue perfusion
following PCI is associated with adverse outcomes, therapeutic strategies targeted at MVO must be shown to
improve clinical end points in order to gain widespread
acceptance.
The concept of ischemic pre- and post-conditioning
refers to a variety of pharmacological and nonpharmacological cardioprotective interventions implemented before the
onset of ischemia or at the time of reperfusion. Short
episodes of ischemia before the onset of prolonged ischemia
produce “ischemic preconditioning.” Intermittent reperfusion with repetitive episodes of recurrent ischemia is termed
“ischemic post-conditioning.” Transient ischemia in remote
organs, which prevents ischemia-reperfusion injury at a
distance, is termed “remote ischemic conditioning.” These
interventions involve a complex and incompletely understood network of molecular triggering and signaling pathways. Agonists that may trigger cardioprotection include
adenosine, opioids, nitric oxide, bradykinin, tumor necrosis
factor-alpha, brain and atrial natriuretic peptides, and
interleukin-6. Putative signaling pathways include opening of sarcolemmal and/or mitochondrial adenosine
triphosphate-dependant potassium channels and activation
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Jaffe et al.
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697
osine triphosphate-dependant potassium channel opener
and nitrate and may prevent reperfusion injury by blocking
the MPTP (13). The immunosuppressive agent cyclosporine is also a MPTP blocker with potential cardioprotective
properties.
Myocardial Infarction Reperfusion MVO (Table 1)
Vasodilators. The role of vasodilators in prevention of
Figure 2. Mechanical Strategies to Prevent Reperfusion No-Reflow
In upper left, an angioplasty catheter is inflated at the site of the epicardial arterial occlusion. The inset depicts aspirated thrombus.
of prosurvival kinases (Akt and ERK-1/2), protein kinase
C and G, hypoxia-inducible factor-1 and endothelial
nitric oxide synthase. Blockade of the mitochondrial
permeability transition pore (MPTP) is considered a final
common pathway (3– 6). “Pharmacological pre- and postconditioning” may be achieved by administration of agents
that activate these cytoprotective pathways. Recently, exenatide, an antiapoptotic glucagonlike peptide-1 analogue,
which also activates prosurvival kinases, has been shown to
reduce infarct size after experimental ischemia reperfusion (7).
Pharmacological agents may potentially act at more than
1 level to improve tissue perfusion. Platelet inhibition with
glycoprotein IIb/IIIa inhibitors may reduce downstream
embolization and local generation of thrombus, and reduce
release of vasoactive and chemotactic mediators from platelets (8). Nitroprusside and nitroglycerin are nitric oxide
donors that vasodilate conductance vessels ⬎200 ␮m. Microvessels are unable to metabolize nitroglycerin to nitric
oxide; in contrast, nitroprusside does not require metabolism. Calcium channel blockers may attenuate microvascular
spasm and reduce myocardial ischemia and infarct size by
lowering heart rate and blood pressure. Verapamil may
inhibit platelet aggregation and thrombus formation in the
microvasculature (9) and may have a direct effect on calcium
flux across the sarcolemmal membrane or within intracellular compartments that could protect reversibly injured myocytes (10). Nicardipine, a vasoselective dihydropyridine
calcium channel blocker, offers more potent and prolonged
vasodilation with less risk of serious systemic side effects
than verapamil (11). Adenosine is an endogenous purine
nucleoside, which decreases arteriolar resistance and activates prosurvival kinases (12). Nicorandil is a hybrid aden-
MVO has been studied in several randomized clinical trials.
Intracoronary verapamil administered following primary
PCI and followed by oral treatment improved myocardial
perfusion and regional left ventricular wall motion in treated
patients when compared to a control group (10). Intracoronary adenosine and verapamil administered following primary PCI achieved equivalent improvement of myocardial
perfusion, which was superior to placebo (14). Intracoronary
administration of nitroprusside to the distal vascular bed via
a perfusion catheter before primary PCI failed to improve
coronary flow and myocardial tissue reperfusion when compared to placebo, but was associated with a statistically
borderline improvement in clinical outcomes at 6 months
(p ⫽ 0.05) (15). In small randomized studies, intravenous
(16) and distal intracoronary adenosine administration (17)
during primary PCI achieved superior flow and ventricular
function in comparison to a control group. The larger
AMISTAD-II (Acute Myocardial Infarction Study of
Adenosine-II) trial (18), which compared intravenous adenosine to placebo, did not show a clear clinical benefit in the
treatment arm; however, a post hoc analysis suggested a
reduction in mortality and heart failure in patients treated
within the first 3 h after onset of evolving anterior STsegment elevation myocardial infarction (19). In summary,
vasodilators appear to reduce MVO in the setting of infarct
PCI, although the clinical significance of these findings is
unclear.
Antiplatelet therapy and thrombolysis. Antiplatelet and
thrombolytic therapy may prevent MVO. In randomized
trials of patients undergoing primary PCI, abciximab improved microvascular perfusion and myocardial contractility
when compared to placebo (20,21). In the RELAx-AMI
(Randomized Early Versus Late Abciximab in Acute Myocardial Infarction Treated With Primary Coronary Intervention) trial (22), upstream administration of abciximab
achieved better tissue perfusion and 1-month left ventricular
function than did treatment in the catheterization laboratory. A recent trial (23) showed that intracoronary versus
intravenous administration of abciximab during primary
angioplasty increased tissue perfusion and reduced infarct
size. This was attributed to improved delivery of the drug to
the flow-limiting thrombus, resulting in improved dissolution of thrombi and microemboli at the ruptured plaque
and further downstream in the microcirculation. In the
ON-TIME 2 (Ongoing Tirofiban in Myocardial Infarction
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Table 1. Randomized Clinical Trials of Interventions for Prevention of MVO-Related Myocardial Injury and Coronary No-Reflow Following Primary Infarct PCI
Interventions
Patients, n
End Point Effect
First Author
(Ref. #)
Vasodilators
IC Verapamil vs. placebo
40
Improved tissue perfusion by myocardial contrast echocardiography and
left ventricular function
Taniyama et al. (10)
IV Adenosine vs. placebo
30
Improved tissue perfusion by myocardial contrast echocardiography and
reduced infarct size
Micari et al. (16)
54
Reduced angiographic no-reflow and infarct size, improved clinical outcome
Marzilli et al. (17)
High-dose adenosine reduced infarct size
Ross et al. (18)
Reduced angiographic no-reflow and improved left ventricular function when
compared to placebo. Increased transient heart block with verapamil
Vijayalakshmi et al. (14)
Similar angiographic tissue perfusion and ST-segment resolution, improved
clinical outcome
Amit et al. (15)
IC Adenosine vs. placebo
IV Adenosine (low vs. high dose) vs. placebo
IC Adenosine vs. verapamil vs. placebo
IC Nitroprusside vs. placebo
2,118
150
98
Glycoprotein IIb/IIIa inhibitors, thrombolysis, and
blockade of the complement cascade
IV Abciximab vs. placebo
IV Abciximab vs. placebo: meta-analysis
2,082
Similar ST-segment resolution and myocardial blush grade
Stone et al. (26)
200
Reduced no-reflow by Doppler wire flow velocity and improved
left ventricular function
Neumann et al. (20)
300
Reduced angiographic no-reflow, improved left ventricular function,
and clinical outcome
Montalescot et al. (21)
Increased bleeding, improved overall clinical outcome
Kandzari et al. (25)
Early vs. late IV abciximab
210
Reduced angiographic no-reflow, improved left ventricular function
Maioli et al. (22)
IC vs. IV abciximab
154
IC abciximab reduced infarct size and no-reflow by ST-segment resolution
MRI assessment of tissue perfusion
Thiele et al. (23)
IV Tirofiban vs. placebo
984
Reduced no-reflow by ST-segment resolution
Van’t Hof et al. (24)
Reduced no-reflow by Doppler wire flow velocity. No difference in
left ventricular function
Sezer et al. (27)
Similar clinical outcomes
Armstrong et al. (76)
Reduced angiographic no-reflow, improved ST-segment resolution
and clinical outcomes
Ishii et al. (39)
IC Streptokinase vs. placebo
IV Pexelizumab vs. placebo
3,266
41
5,745
Cardioprotectants
IV Nicorandil vs. placebo
368
No reduction in infarct size
Kitakaze et al. (40)
IV Cyclosporine vs. placebo
1,216
58
Reduced infarct size
Piot et al. (43)
IC hyperoxemic reperfusion
301
Reduced infarct size
Stone et al. (37)
30
Reduced angiographic no-reflow and infarct size
Staat et al. (41)
38
Reduced infarct size and improved left ventricular function
Thibault et al. (42)
96
Improved ST-segment resolution and reduced peak troponin I level
Rentoukas et al. (44)
X-sizer mechanical thrombectomy
201
Reduced angiographic no-reflow, improved ST-segment resolution
Lefevre et al. (77)
Thrombus aspiration
215
Increased infarct size
Kaltoft et al. (30)
1,071
Reduced angiographic no-reflow, improved ST-segment resolution
and clinical outcomes
Vlaar et al. (32) and
Svilaas et al. (78)
100
Reduced angiographic no-reflow, improved ST-segment resolution
Burzotta et al. (28)
148
Reduced angiographic no-reflow, improved ST-segment resolution
Silva-Orrego et al. (31)
Myocardial post-conditioning
Myocardial remote conditioning and morphine
Thrombectomy and distal embolic protection
Thrombus aspiration: meta-analysis
2,417
Reduced angiographic no-reflow and 30-day mortality
De Luca et al. (79)
Thrombectomy: meta-analysis
2,686
Mortality reduction limited to manual thrombectomy devices. Synergistic
benefit of thrombectomy and glycoprotein IIB/IIIA inhibitors
Burzotta et al. (33)
Distal embolic protection
501
Similar ST-segment resolution, infarct size, and clinical outcomes
Stone et al. (34)
Proximal embolic protection
284
Improved ST-segment resolution
Haeck et al. (35)
Thrombus aspiration reduced mortality, mechanical thrombectomy increased
mortality, and distal embolic protection had a neutral effect on mortality
Bavry et al. (80)
Thrombectomy and distal embolic protection
devices: meta-analysis
6,415
IC ⫽ intracoronary; IV ⫽ intravenous; MRI ⫽ magnetic resonance imaging.
Evaluation Trial), patients with acute myocardial infarction
were randomized to receive either pre-hospital tirofiban or
placebo before undergoing primary PCI (24). Tirofibantreated arteries achieved superior tissue perfusion following
angioplasty, as evidenced by resolution of the electrocardiographic ST-segment elevation. A meta-analysis (25) of early
trials comparing abciximab to placebo as adjunctive therapy
in acute infarct PCI showed a significant reduction in early
ischemic adverse events with a trend toward reduction in
mortality. Conversely, in the CADILLAC (Controlled
Abciximab and Device Investigation to Lower Late Angioplasty Complications) study (26), abciximab did not im-
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prove microvascular perfusion when compared to placebo.
This unexpected result may be due to the relatively low-risk
population recruited to the study and a short time interval
from initiation of the therapy to the coronary intervention.
There is a paucity of trials that have reevaluated the current
role of glycoprotein IIb/IIIa inhibitors in patients who
receive adequate thienopyridine loading before acute infarct
PCI. In summary, current data suggests that glycoprotein
IIb/IIIa inhibitors are especially beneficial when given
upstream in patients who have not received thienopyridine
loading.
In a small randomized trial, intracoronary thrombolysis
immediately following primary PCI improved microvascular
integrity and tissue perfusion measured 2 days later by
coronary flow reserve, microvascular resistance, and TIMI
(Thrombolysis In Myocardial Infarction) frame count (27).
These findings suggest a role for in situ microvascular
thrombosis in the pathogenesis of no-reflow, although the
study was underpowered to study the clinical impact of this
approach.
Thrombus aspiration and embolic protection devices. Several mechanical approaches for prevention of distal embolization have been studied in the setting of primary PCI.
Initial small trials of thrombus aspiration reported conflicting results (28 –30). In the study by Kaltoft et al. (30),
thrombectomy did not improve ST-segment resolution and
was associated with increased infarct size. Conversely, in the
REMEDIA (Randomized Evaluation of the Effect of
Mechanical Reduction of Distal Embolization by
Thrombus-Aspiration in Primary and Rescue Angioplasty)
(28) and DEAR-MI (Dethrombosis to Enhance Acute
Reperfusion in Myocardial Infarction) (31) studies, thrombectomy improved microvascular perfusion. In the pivotal
TAPAS (Thrombosis Aspiration During Percutaneous
Coronary Intervention in Acute Myocardial Infarction) trial
(32), thrombectomy improved tissue perfusion and reduced
cardiac death. In a pooled analysis of 11 randomized trials
that examined the role of different thrombectomy devices in
primary PCI, thrombectomy improved survival in patients
treated with glycoprotein IIb/IIIa inhibitors (p ⫽ 0.049)
and survival advantage was confined to manual thrombectomy (p ⫽ 0.011) (33). Another mechanical approach for
prevention of distal embolization consists of deployment of
embolic protection devices before stenting. Distal embolic
protection has several theoretical disadvantages when compared to proximal protection, including potential trauma to
the vessel and induction of embolization as the device is
maneuvered across the lesion before deployment, lack of
protection to side branches located proximal to the device,
and the ability of potent vasoconstrictors to pass through
filter micropores and reach the distal microvasculature.
Distal protection with a balloon occlusion and aspiration
system (GuardWire, Medtronic, Santa Rosa, California)
effectively retrieved embolic debris in the EMERALD
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699
(Enhanced Myocardial Efficacy and Recovery by Aspiration
of Liberated Debris) study (34), but did not improve
microvascular flow, decrease infarct size, or improve clinical
outcome. In the PREPARE (Proximal Embolic Protection
in Acute MI and Resolution of ST-Elevation) trial (35),
proximal embolic protection (Proxis, St. Jude Medical, St.
Paul, Minnesota) improved microvascular flow as reflected
by improved immediate complete ST-segment resolution;
however, the study was underpowered to detect clinical
benefit. No trials have directly compared these different
strategies for prevention of distal microembolization. In
summary, current data supports routine manual thrombectomy during primary PCI. Distal embolic protection is of
unproven benefit and the role of proximal embolic protection, though promising, remains to be defined.
Hyperoxemic reperfusion. Intracoronary hyperoxemic reperfusion has been advocated for prevention of reperfusion injury.
Hyperoxemic reperfusion improved microvascular blood
flow and decreased infarct size in a canine model of ischemia
reperfusion (36). In the AMIHOT-II (Acute Myocardial
Infarction With Hyperoxemic Therapy II) trial (37), this
approach reduced infarct size but was not associated with
improved tissue perfusion as assessed by ST-segment resolution. In this trial, only 22% of the patients underwent
thrombectomy and 67% received glycoprotein IIb/IIIa inhibitors. Because the clinical benefit of hyperoxemic reperfusion has yet to be shown, the routine use of this invasive
strategy in the current era of routine thrombectomy cannot
be recommended at present.
Cytoprotection. Activation of intracellular prosurvival pathways has been studied in the setting of primary PCI. In 1
study, intravenous nicorandil started before PCI improved
myocardial perfusion and ventricular contraction (38), as
well as long-term clinical outcome (39). However, a larger
study found no reduction in infarct size with nicorandil
versus placebo (40). Myocardial post-conditioning after
direct coronary stenting by use of intermittent low-pressure
balloon inflations in the infarct-related artery reduced infarct size and improved microvascular perfusion as assessed
by myocardial blush (41), and long-term functional recovery
(42). Pharmacological post-conditioning by intravenous administration of cyclosporine, a direct MPTP blocker, versus
placebo, at the time of primary PCI decreased infarct size
(43). Remote post-conditioning by intermittent inflations of
a blood pressure cuff on the upper limb before reperfusion
improved ST-segment resolution following primary PCI, an
effect that was enhanced by administration of morphine
(44). These preliminary studies suggest a beneficial role for
conditioning strategies in the setting of primary infarct PCI.
However, their efficacy in patients undergoing thrombectomy and receiving glycoprotein IIb/IIIa inhibitors remains
to be defined.
Reversal of reperfusion no-reflow. Appearance of angiographic no-reflow reflects the presence of severe MVO and
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Table 2. Randomized Clinical Trials of Interventions for Reducing Peri-Procedural Myocardial Injury Following Noninfarct PCI
Interventions
Glycoprotein IIb/IIIa inhibitors vs. placebo for
saphenous vein bypass grafts: pooled analysis
Eptifibatide vs. placebo in patients undergoing
nonurgent coronary intervention
Eptifibatide vs. bivalirudin in patients with
non–ST-segment elevation acute coronary syndromes
Nicorandil vs. verapamil in patients undergoing
rotational atherectomy
Patients, n
627
2,064
857
61
End Point Effects
First Author (Ref. #)
Similar clinical outcomes
Roffi et al. (58)
Reduced periprocedural myocardial infarctions
Blankenship et al. (81)
Eptifibatide reduced angiographic no-reflow and
post-PCI ischemia on continuous Holter monitoring
Gibson et al. (57)
Reduced angiographic no-reflow
Tsubokawa et al. (61)
111
Reduced angiographic no-reflow
Iwasaki et al. (62)
Remote ischemic pre-conditioning
242
Reduced periprocedural myocardial infarctions,
improved clinical outcomes
Hoole et al. (63)
Distal embolic protection in saphenous vein bypass grafts
801
Reduced angiographic no-reflow, improved clinical outcomes
Baim et al. (53)
Proximal embolic protection in saphenous vein bypass grafts
594
Noninferior to distal embolic protection
Mauri et al. (55)
PCI ⫽ percutaneous coronary intervention.
myocardial ischemia and is associated with serious adverse
clinical events. Various interventions for reversal of existing
angiographic no-reflow following primary PCI have been
reported, although no randomized trials have been performed in this setting (45). Nitroglycerin was not been
found to be effective (46). Other reports suggested efficacy
of papaverine (47), nitroprusside (48,49), nicardipine (50),
and abciximab (51). At present, there are no data from
randomized trials showing the clinical benefit of these
therapies.
Interventional MVO (Table 2)
Embolic protection devices. Several randomized trials have
studied the role of embolic protection devices in the
treatment of diseased saphenous vein aortocoronary bypass
grafts. Occlusive protection devices, either distal (GuardWire, Medtronic) or proximal (Proxis, St. Jude Medical)
have a theoretical advantage over distal filter catheters in
that they capture vasoactive, proinflammatory and thrombotic factors that might pass through filter pores and induce
microvascular obstruction (52). However, clinical studies to
date have not demonstrated superiority of a specific protection device. In the SAFER (Saphenous Vein Graft Angioplasty Free of Emboli Randomized Trial) (53), distal
embolic protection with a balloon occlusion and aspiration
system (GuardWire) reduced angiographic no-reflow from
9% to 3% and improved clinical outcome. In the FIRE
(FilterWire Ex Randomized Evaluation) trial (54), distal
protection with a filter-based catheter (FilterWire EX,
Boston Scientific, Natick, Massachusetts) was noninferior
to the GuardWire system. In the PROXIMAL (Proximal
Protection During Saphenous Vein Graft Intervention) trial
(55), the efficacy of proximal embolic protection (Proxis, St.
Jude Medical) was noninferior to distal protection. In an
analysis of the 19,546 vein graft PCI procedures in the
American College of Cardiology–National Cardiovascular
Data Registry (56), use of embolic protection devices was
independently associated with a lower incidence of noreflow (odds ratio: 0.68, p ⫽ 0.032), although these devices
were only used in 22% of the cases. The underuse of this
technology may be due to complexity of use and cost,
reflecting the need for more user-friendly and cheaper
devices.
Antiplatelet therapy and vasodilators. Although distal embolization is the predominant mechanism leading to MVO
and no-reflow in interventional no-reflow, particularly during vein graft interventions, there still may be a role for
vasodilator and antiplatelet therapies to modify the flow
abnormalities. In noninfarct interventions, glycoprotein
IIb/IIIa inhibitors enhanced microvascular perfusion among
patients undergoing PCI to native coronary arteries (57),
but did not improve clinical outcomes in patients undergoing PCI to coronary bypass vein grafts (58). In a registry of
83 consecutive degenerative vein grafts undergoing stenting
following intragraft administration of nicardipine (59), a
significant rise in serum creatine kinase levels was documented in only 4.4% of the cases and no patients sustained
a Q-wave myocardial infarction. In the VAPOR (Vasodilator Prevention of No-Reflow) trial (60), pre-intervention
intragraft verapamil achieved a significant improvement in
coronary flow measured by the TIMI frame count in
patients undergoing PCI to vein grafts. Among patients
undergoing rotational coronary atherectomy, intracoronary
nicorandil reduced no-reflow when compared to verapamil
(61,62).
Cytoprotection. In patients undergoing elective PCI, remote conditioning by transient upper-limb ischemia reduced myocardial injury following the procedure (63).
Reversal of interventional no-reflow. As in the case of
reperfusion no-reflow, angiographic evidence of no-reflow in
the setting of noninfarct PCI reflects severe MVO and
extensive myocardial ischemia. Treatment of existing inter-
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ventional angiographic no-reflow is confined to retrospective reports and case series. Intracoronary diltiazem (64),
verapamil (65,66), nicardipine (50,59), epinephrine (67),
nitroprusside (68), adenosine (69,70), combination of adenosine and nitroprusside (71), and abciximab (72) have all
been reported to be efficacious.
Recommendations for Prevention of MVO
Several caveats should be considered when formulating
practical therapy guidelines. There is a paucity of major
trials comparing different therapeutic strategies and some
interventions are supported by only 1 positive trial. Thrombectomy was not performed in most trials of preventive
strategies. Most studies of glycoprotein IIb/IIIa inhibitors
were performed before the current era of high thienopyridine loading doses.
In the setting of acute ST-segment elevation infarct PCI,
shortening of the symptom-to-balloon time interval is
crucial (73). Glycoprotein IIb/IIIa inhibitors may be given
intravenously (American College of Cardiology/American
Heart Association [ACC/AHA] guideline class IIa) and
abciximab specifically may be administered via the intracoronary route. Upstream administration of glycoprotein
IIb/IIIa inhibitors may be considered before arrival in the
catheterization laboratory when PCI is delayed (ACC/
AHA guideline class IIb) (73). It is reasonable to perform
thrombus aspiration before insertion of other devices into
the infarct-related artery (ACC/AHA guideline class IIa)
(73). Although controversial (74), we believe that current
data does not support the routine use of embolic protection
devices in native coronary arteries. Proximal embolic protection appears promising, although its clinical benefit
remains to be defined.
In the setting of noninfarct PCI, embolic protection
devices should be used for degenerated vein grafts (ACC/
AHA/Society for Cardiovascular Angiography and Interventions guideline class I) (75). Glycoprotein IIb/IIIa inhibitors should be considered when performing PCI in the
native coronary arteries (ACC/AHA/Society for Cardiovascular Angiography and Interventions guideline class I) (75),
especially in the presence of complex anatomy.
No definitive recommendations can be made for treatment of no-reflow once it has occurred because proposed
interventions have not been studied in randomized trials.
However, based on reports from multiple nonrandomized
studies and the paucity of alternative proven therapeutic
options, administration of vasodilators should be considered. Our personal practice is intracoronary administration
of adenosine, verapamil, and nitroprusside in attempt to
reverse MVO in this situation.
Although they may be beneficial in individual patients,
we do not currently recommend the routine use of other
pharmacological and mechanical interventions such as drugs
701
that activate survival pathways and conditioning strategies
because their comparative efficacy and interaction with the
abovementioned interventions has not been investigated.
For example, in trials assessing the utility of cyclosporine
and post-conditioning, PCI was performed by direct stenting without use of thrombectomy.
Summary: Future Directions
and Unanswered Questions
Microvascular obstruction following PCI is a multifactorial
phenomenon with diverse etiologies in different clinical
settings and is associated with adverse outcome. Prevention
of MVO following elective coronary intervention is beneficial in reducing cardiac injury and improving clinical outcome. Until recently, it was unclear whether the unfavorable
outcome associated with MVO following primary infarct
PCI reflected a causal effect or whether the microcirculatory
injury was an epiphenomenon mirroring greater myocardial
damage. The TAPAS study has proven that prevention of
MVO during primary PCI may reduce cardiac injury and
improve clinical outcome. Several preventive measures effectively decrease the degree of MVO and improve clinical
outcome in the setting of both acute infarct and elective
PCI. Unfortunately, there is limited data comparing the
efficacy of different strategies. There is no randomized data
to guide selection of therapies for reversal of existing
no-reflow.
The goal of the various pharmacological and mechanical
therapeutic strategies that are targeted at prevention and
reversal of MVO and no-reflow is to minimize cardiac
injury. Specific interventions targeted at reperfusion injury
that activate intracellular cardioprotective signaling pathways have been shown to improve tissue perfusion and
decrease myocardial injury following PCI. These approaches hold great promise for achievement of further
myocardial preservation. Ultimately, strategies designed to
reduce MVO and to activate intracellular cardioprotective
mechanisms converge at the tissue level. Reduction of
MVO is cardioprotective and cardioprotection is associated
with improved tissue perfusion. Future research should be
directed at refining these techniques and implementing
them for reversal of no-reflow once it has occurred.
Reprint requests and correspondence: Dr. Ronen Jaffe, Cardiology Department, Lady Davis Carmel Medical Center, 7 Michal
Street, Haifa 34362, Israel. E-mail: [email protected].
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Key Words: no-reflow 䡲 microvascular obstruction 䡲
coronary intervention 䡲 distal embolization 䡲 cardioprotection.