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270 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
therapy, the cost is balanced by a reduction in recurrent cardiac events. A cost-effectiveness
analysis from PURSUIT found that the cost per year of life saved was approx $16,000, well
within the generally acceptable range for medical interventions (47). As noted above in the
section on risk stratification, benefit appears to be greatest in patients at higher risk, as evi-
denced by those who have a positive troponin level at baseline (19,23), those with diabetes
(27), or recurrent angina, or those with prior aspirin use (48). In these high-risk subgroups
of patients, the absolute benefit is greater and the therapy is even more cost-effective.
A recent analysis from TACTICS-TIMI 18 has shown that the overall strategy of early
GPIIb/IIIa inhibition and an invasive strategy was very cost-effective relative to a conser-
vative strategy (49). Estimated cost per year of life gained for the invasive strategy, based
on projected life expectancy, was approx $17,000. In high-risk patients with a positive tro-
ponin level or ST-segment changes, these figures were. Thus, in patients with UA/NSTEMI
treated with the GPIIb/IIIa inhibitor tirofiban, the clinical benefit of an early invasive strat-
egy is achieved with a small increase in cost, yielding very favorable projected estimates
of cost per year of life gained. These results provide further support for the broader use of
an early invasive strategy utilizing early GPIIb/IIIa inhibition with tirofiban.
CONCLUSIONS
GPIIb/IIIa inhibition has been shown to be beneficial in patients with UA/NSTEMI,
regardless of the treatment strategy ultimately used. However, those who are managed
invasively have a double benefit—that achieved during the medical treatment phase and
that achieved during a PCI. Accordingly, the 2002 American College of Cardiology/Ameri-
can Heart Association Guidelines for UA/NSTEMI present a class I recommendation (and
level of evidence A) that GPIIb/IIIa inhibition be used in patients managed with an inva-
sive strategy. For high-risk patients, these guidelines recommend an invasive strategy, and
thus GPIIb/IIIa inhibition should be used. However, if a high-risk patient is managed conser-
vatively, the guidelines give a class IIa recommendation for the use of GPIIb/IIIa inhibition.
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272 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
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2405–2412.
36. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events
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of TIMI IIIB and TACTICS-TIMI 18. Circulation 2001;104(Suppl II):II–549.
38. van den Brand M, Laarman GJ, Steg PG, et al. Assessment of coronary angiograms prior to and after
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39. Zhao X-Q, Theroux P, Snapinn SM, Sax FL, for the PRISM-PLUS Investigators. Intracoronary throm-
bus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non-Q-wave
myocardial infarction. Angiographic results from the PRISM-PLUS trial (Platelet Receptor Inhibition
for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms). Circulation
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40. Gibson M, Murphy SA, Weisberg S, Pai R, et al. Early initiation of tirofiban therapy before percutaneous
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41. Januzzi JL, Hahn SS, Chae CU, et al. Effects of tirofiban plus heparin versus heparin alone on troponin
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Chapter 11 / Platelet GPIIb/IIIa Inhibitors and an Invasive Strategy 273
48. Alexander JH, Harrington RA, Tuttle RH, et al. Prior aspirin use predicts worse outcomes in patients
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274 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
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Chapter 12 / Adjunctive Therapy to PCI 275
275
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
12 Glycoprotein IIb/IIIa Receptor
Blockade in Myocardial Infarction
Adjunctive Therapy to Percutaneous
Coronary Interventions
Franz-Josef Neumann, MD
CONTENTS
INTRODUCTION
THE ILLUSION OF TIMI GRADE 3 FLOW
ROLE OF PLATELETS IN LIMITING REPERFUSION
EFFECT OF GPIIb/IIIa BLOCKADE ON MICROVASCULAR REPERFUSION,
R
ECOVER OF CONTRACTILE FUNCTION, AND MYOCARDIAL SALVAGE
EFFECT OF GPIIb/IIIa BLOCKADE ON CLINICAL OUTCOME
FUTURE PROSPECTS
SUMMARY
REFERENCES
INTRODUCTION
In acute myocardial infarction, early, complete, and sustained restoration of blood flow
in the occluded coronary artery can salvage myocardium at risk and improve survival. Ran-
domized trials (1) as well as large registries (2,3) have shown that direct percutaneous
transluminal coronary angioplasty (PTCA) is more efficacious in achieving this goal than
thrombolysis. Additional placement of a stent improves long-term clinical outcome by
reducing the need for target lesion revascularization but has no beneficial effect on the qual-
ity of reperfusion or the risk of early complications, such as death and reinfarction (4–6).
For percutaneous coronary interventions (PCIs) in the absence of acute myocardial
infarction, glycoprotein (GP) IIb/IIIa receptor blockade has been shown to reduce the early
hazard of ischemic complications by up to about one-half (see Chapters 5–8). This peri-
interventional effect translates into a long-term clinical benefit that can be verified as late
as 3 yr after the intervention (7). If GPIIb/IIIa blockade is equally effective in acute myo-
cardial infarction, the combination of stenting with GPIIb/IIIa blockade may afford a highly
efficient and durable reperfusion strategy.
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276 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
This chapter discusses the role of GPIIb/IIIa blockade as an adjunct to PCI in acute
myocardial infarction. Among the three agents approved for clinical use with PCI, abcixi-
mab is the only agent for which randomized clinical studies in the setting of acute myo-
cardial infarction have yet been published. Therefore, this review focuses on the role of
abciximab for PCI in acute myocardial infarction.
THE ILLUSION OF TIMI GRADE 3 FLOW
In acute myocardial infarction, myocardial salvage after timely recanalization of the
infarct-related artery is critically dependent on coronary blood flow to the area at risk. Only
in patients in whom Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow can be
achieved can recanalization of the coronary artery occlusion improve regional ejection
fraction in the infarct area and afford a clinical benefit (8–10).
Normalization of large vessel flow by angiographic criteria, however, does not mean
complete recovery of microvascular perfusion. Even in the presence of large-vessel TIMI
grade 3 flow, positron emission tomography (Fig. 1) or myocardial contrast echocardi-
ography frequently reveal substantial perfusion defects (11–14). Likewise, Doppler flow
velocity measurements show depressed coronary flow velocities and flow reserve during
early reperfusion despite optimal vessel patency (11). In general, the initial microvascular
incompetence in the infarct region is partially reversible within the first 2 wk of reperfusion.
However, the pattern of reperfusion varies considerably between patients, from complete
normalization in some to even deterioration in others (11). Variations of tissue reperfusion
within the spectrum of TIMI grade 3 flow, as assessed by flow velocity measurements (11,
15–18), TIMI frame counts (19,20), or myocardial blush (21,22), are important predictors
of myocardial recovery and clinical outcome. Reversal of the early microvascular incom-
Fig. 1. Impairment of microvascular reperfusion in acute myocardial infarction (MI) despite TIMI
grade 3 flow as assessed by positron emission tomography (11). (Left) Example of patient with anterior
myocardial infarction (courtesy of Professor M. Schwaiger, Nuclear Medicine, Technical University
of Munich.) (Right) Mean adenosine-induced myocardial blood (SD) in the remote region and in
the infarct region.
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Chapter 12 / Adjunctive Therapy to PCI 277
petence is thus an important prerequisite for recovery of contractile function in the infarct
region. These considerations underscore the need to address not only large-vessel patency
but also microvascular perfusion when treating acute myocardial infarction.
ROLE OF PLATELETS IN LIMITING REPERFUSION
Previous investigations on experimental models of myocardial infarction documented
the preeminent role of platelets in limiting blood flow during reperfusion in acute myocar-
dial infarction (23). By occlusive thrombus formation, distal embolization of small aggre-
gates, and release of vasoconstrictive mediators, platelets interfere with both large-vessel
patency and microvascular flow (23).
Activated platelets can also adhere to the endothelial cells in the reperfused region (24–
27). During reperfusion in experimental myocardial infarction, platelets accumulate in
the microvasculature of the infarct region (28). In isolated guinea pig hearts, this platelet
accumulation was associated with impaired recovery of external work after ischemia (29).
It was concluded that platelet adhesion to the coronary endothelium during reperfusion
after myocardial ischemia impairs cardiac recovery. The potential of platelets to contrib-
ute to both impaired reperfusion and cardiac dysfunction after myocardial ischemia is
also demonstrated by experiments in isolated perfused rat hearts (30). In these experi-
ments, reperfusion with either platelet or neutrophil suspensions reduced coronary flow
and contractile function (dP/dt
max
) during reperfusion after ischemia by <12% compared
with cell-free perfusate. However, ischemic hearts reperfused with both neutrophils and
platelets exhibited decreases of 50–60% in all measurements of coronary flow and car-
diac function (p < 0.001) (Fig. 2). These results provided strong evidence that platelets
Fig. 2. Myocardial blood flow in isolated ischemic and reperfused guinea pig hearts during reper-
fusion with cell-free perfusate and suspensions of platelets, leukocytes, or both (30).
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278 Part III / GPIIb/IIIa Blockade for Ischemic Syndromes
and neutrophils act synergistically in provoking post-reperfusion cardiac microvascular
and contractile dysfunction.
Tethering of platelets to activated endothelium is P-selectin-mediated, and subsequent
firm adhesion is caused by interaction of GP IIb/IIIa-bound fibrinogen with endothelial
vitronectin receptors and intercellular adhesion molecule-1 (ICAM-1) (25–27). In acti-
vated endothelium, expression of vitronectin receptors is enhanced on the luminal aspect
(25). Through stimulation by CD40L and platelet-bound interleukin-1 activity, binding of
activated platelets to endothelial cells stimulates the expression of monocyte chemo-
attractant protein-1 and of ICAM-1 via an NF-κB-dependent mechanism (25,31,32). Acti-
vated platelets thus modulate chemotactic and adhesive properties of endothelial cells and
direct leukocyte attachment, as shown in cell culture studies (33).
Platelets can also directly support leukocyte adhesion. Heterotypic interactions of endo-
thelium-bound platelets appear to play an important role in the recruitment of leukocytes
to the site of vascular injury (34). In these interactions, primary attachment of platelets to
myeloid leukocytes occurs by tethering of the platelet P-selectin to P-selectin glycoprotein
ligand-1 (PSGL-1) on leukocytes (35–40). Secondarily, the heterotypic adhesion is stabi-
lized by binding of Mac-1 to an unknown counter-receptor on the platelet (38–41). This is
enabled by Mac-1 activation as a consequence of tyrosine phosphorylation and mitogen-
activated protein (MAP) kinase activation owing to PSGL-1 ligation (39,42). Leukocyte
activation by binding of stimulated platelets is further enhanced by CD40L-dependent sig-
nal transduction pathways (31). In vitro, binding of activated platelets to myeloid leukocytes
induces expression of proinflammatory cytokines, oxidative burst, and increased surface
expression of tissue factor and Mac-1 (43–46). Mac-1 is known to play a key role in leuko-
cyte-dependent reperfusion injury (47–49).
In patients with acute myocardial infarction, there are abundant platelet-leukocyte aggre-
gates in peripheral blood (44). GPIIb/IIIa receptor blockade with abciximab in patients
with acute myocardial infarction reduces platelet-monocyte interaction by decreasing
the mass of platelets attached to monocytes (50). Through this mechanism, abciximab
decreases Mac-1 surface expression on circulating monocytes (50). This effect is comple-
mented by the direct Mac-1-blocking properties of abciximab (51). In addition, cell cul-
ture experiments show that abciximab can prevent firm adhesion of platelets to activated
endothelial cells by blockage of both GPIIb/IIIa and the vitronectin receptor (25,52). The
inhibitory effect of abciximab on heterotypic platelet interactions during ischemia and
reperfusion could be confirmed by experiments in isolated guinea pig hearts (53). In these
experiments, inhibition of heterotypic platelet interactions by abciximab improved the
recovery of contractile function (53). These studies demonstrate the functional importance
of heterotypic platelet interactions during ischemia and reperfusion.
EFFECT OF GPIIb/IIIa BLOCKADE
ON MICROVASCULAR REPERFUSION, RECOVERY
OF CONTRACTILE FUNCTION, AND MYOCARDIAL SALVAGE
The principle goal of reperfusion therapy is preservation of contractile function by myo-
cardial salvage. Optimization of both large-vessel patency and microvascular perfusion
is pivotal to this goal. Modern interventional techniques are highly successful in restoring
large-vessel patency. To improve distal circulation, additional measures need to be taken.
GPIIb/IIIa blockade is highly promising for this end. GPIIb/IIIa blockade appears to pre-
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Chapter 12 / Adjunctive Therapy to PCI 279
vent distal embolization of platelet aggregates from the treated plaque. Moreover, abcixi-
mab, because of its ability to block not only GP IIb/IIIa but also vitronectin receptors and
Mac-1 (51,52), can interfere with heterotypic platelet and leukocyte interactions that
limit microvascular reflow.
The role of GPIIb/IIIa receptor blockade in optimizing microvascular reperfusion could
be confirmed clinically in ISAR-2 (Intracoronary Stenting and Antithrombotic Regimen)
(18,54). In this prospective study, patients undergoing stenting in acute ST-elevation and
non-ST-elevation myocardial infarction within 48 h after onset of symptoms were ran-
domly assigned to receive either open-label standard-dose heparin or abciximab plus low-
dose heparin. In the first 200 patients of ISAR-2, flow velocities in the recanalized vessel
were assessed with the Doppler wire immediately after the procedure and at 14-d angio-
graphic follow-up (18). At the same time points, regional wall motion was analyzed in left
ventricular angiograms by the centerline method. Abciximab significantly improved the
recovery of peak flow velocity in the recanalized vessel compared with standard heparin
treatment (Fig. 3) (18). As quantitative coronary angiography did not reveal any differ-
ence in angiographic outcome between the two treatment groups, the beneficial effect of
abciximab reflected improvement of microvascular function. Consistent with the close
relation between microvascular and contractile recovery, the improvement of wall motion
index in the infarct region was significantly greater in patients assigned to abciximab than
in those on heparin alone (Fig. 3) (18). At 14-d follow-up, the abciximab treatment group
had a higher global left ventricular (LV) ejection fraction than the heparin treatment group
[mean (95% confidence interval), 62 (59–65) % vs 56 (53–59) %, p = 0.003].
The study demonstrated that in acute myocardial infarction abciximab has important
effects beyond the maintenance of large-vessel patency. It improves the recovery coronary
perfusion at the level of the distal vascular bed and concomitantly enhances the restora-
Fig. 3. Increase between 14-d follow-up and initial postinterventional study in papaverine-induced
peak flow velocity in the recanalized and stented infarct-related artery (left) and in wall motion index
within the infarct region (right). Columns represent the mean difference. Error bars indicate the 95%
confidence interval. Error bars not including zero indicate that the change between initial study and
follow-up is statistically significant at the 0.05 level. p values above the columns refer to the differ-
ence between the two treatment groups. (From ref. 18, with permission.)
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