(Circulation. 1999;100:1609-1615.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Intracoronary Thrombus 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)
From the University of Washington School of Medicine (X.-Q.Z.), Seattle, Wash; Montreal Heart Institute (P.T.), Québec, Canada; and Merck Research Laboratories (S.M.S., F.L.S.), West Point, Pa.
Correspondence to Xue-Qiao Zhao, MD, University of Washington, 1914 N 34th St, Suite 105, Seattle, WA 98103. E-mail xueqiao{at}u.washington.edu
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Abstract |
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Background—The present study describes the effects of tirofiban, a nonpeptide platelet glycoprotein (GP) IIb/IIIa receptor blocker, on the characteristics of culprit lesions in patients with unstable angina (UA) or non–Q-wave myocardial infarction (NQWMI).
Methods and Results—Of 1915 patients enrolled in PRISM-PLUS, 1491 had a readable film obtained a median of 65 hours after randomization. A core laboratory examined the culprit lesions for intracoronary thrombus burden (primary end point) and for TIMI flow grade distribution and severity of the obstruction and of underlying coronary artery disease (secondary end points). The combination of tirofiban plus heparin compared with heparin alone significantly reduced the intracoronary thrombus burden of the culprit lesions (OR=0.77, P=0.022), improved the perfusion grade (OR=0.65, P=0.002), and decreased the severity of the obstruction (P=0.037), but it did not influence the severity of the underlying plaque. Persistence of a thrombus in 45% of patients was associated with a 2.4-fold increase in the odds of death at 30 days (P=0.005) and a 2-fold increase in the odds of myocardial infarction (P=0.002).
Conclusions—The addition of tirofiban to heparin reduced the thrombus burden of the culprit lesion and improved distal perfusion in patients with UA or NQWMI, which supports the clinical benefit observed with the combination treatment.
Key Words: thrombus • angiography • platelet aggregation inhibitors • prognosis
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Introduction |
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Unstable angina (UA) and non–Q-wave myocardial infarction (NQWMI) are usually associated with intracoronary thrombus superimposed on disruption of atherosclerotic plaque.1 Histologically, plaque hemorrhage, fissure, and intraluminal thrombus are common in patients dying of acute ischemic syndrome.2 3 4 5 6 Culprit lesions often have a complex appearance on angiography and angioscopy4 5 with an intraluminal thrombus.5 6 Blood markers of platelet activity and fibrin generation are usually increased.7 8 Antithrombotic therapy is effective to prevent complications.9 10 11
Platelet adhesion, activation, and aggregation play a critical role in initiating steps in the pathogenesis of platelet-rich arterial thromboses, and platelet glycoprotein (GP) IIb/IIIa membrane receptor plays a pivotal role in platelet aggregation through fibrinogen binding. A novel class of antiplatelet therapeutics based on GP IIb/IIIa receptor blockade has been developed and has been shown to be effective to prevent the complications associated with UA, NQWMI, and percutaneous coronary interventions.12 13 14 15 The PRISM-PLUS study investigated tirofiban, a nonpeptide platelet GP IIb/IIIa antagonist, as part of the comprehensive management of UA or NQWMI.15 This report describes the results of a prospectively designed angiographic substudy of PRISM-PLUS to characterize the effects of GP IIb/IIIa receptor blockade on culprit lesions.
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Methods |
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Patients and Randomization
The PRISM-PLUS study was performed in 72 hospitals in 14 countries. A total of 1915 patients with UA or NQWMI were randomized. The entry and exclusion criteria were described in the original study publication.15
The initial study design involved double-blind randomization to 1 of 3 treatment groups: (1) tirofiban alone; (2) tirofiban plus heparin; or (3) tirofiban placebo plus heparin.15 The tirofiban-alone group was discontinued prematurely in accordance with a recommendation of the Data Safety Monitoring Board on the basis of an apparent excess mortality at 7 days in this group after enrollment of 345 patients in this arm of the study and of a total of 1031 patients in the trial. This arm had a relatively small sample size and was not strictly comparable with the other groups in the trial cohorts. The present report therefore focused on the comparison between tirofiban plus heparin and heparin alone; the data from the tirofiban-alone arm are provided for descriptive purposes only.
Infusion of study drugs was maintained for a minimum of 48 hours, with any intervention postponed until after this time period unless mandated by a refractory ischemic (RI) condition or by a new myocardial infarction (MI). Angiography was recommended but not required in all patients between 48 and 96 hours after randomization and on study drug infusion.
Coronary Angiography
Of 1915 patients, 1719 had an angiography during the initial
hospitalization, and 1538 underwent angiography during the first 97
hours. Of these, 1491 (78% of the study population) had a readable
angiogram and were included in the angiographic study.
Standard coronary views, with 6- to 7-in image fields, included 5 left and 2 right coronary artery injections suitable for quantitative angiography. Additional views were obtained to clearly visualize the presumed culprit lesion. Sublingual or intracoronary nitroglycerin was used in all patients before the coronary injections.
Angiographic Analysis
The angiograms were first reviewed at the clinical sites by the
clinical investigators to identify the culprit lesion and then were
mailed with a copy of the qualifying ECG to the Core Laboratory when
the patient was clinically stable and had been released from the
study.
All angiograms were analyzed by investigators who were blinded to randomization. Films were projected at high (x7) magnification with an overhead projector. The culprit lesion was identified on the basis of the ECG leads that showed the ischemic ST-T changes and/or the details of the coronary anatomy, particularly the morphology of the lesion(s), such as presence of thrombus, stenosis severity, and other abnormalities of the luminal surface. Concordance between the investigator and Core Laboratory personnel regarding identification of the presumed culprit lesion was present in 92% of patients. The Core Laboratory evaluation prevailed when discordance was present.
The culprit lesions were assessed by techniques developed in the Core Laboratory for characterizing and measuring complex lesions containing thrombus.16 Each culprit lesion was described qualitatively in terms of anatomic location,17 perfusion characteristics,18 morphological features, and intraluminal thrombus.
As illustrated in Figure 1
, globular
intraluminal masses classified as apparent thrombi had rounded or
polypoid shapes and protruded into the lumen. Apparent thrombi were
subclassified (on the basis of quantitative measurement of maximum
dimension of thrombus relative to normal lumen diameter) as small
(<0.5 times normal lumen diameter at greatest dimension, grade 2),
medium (0.5 to 1.5 times normal diameter, grade 3), or large (>1.5
times normal diameter, grade 4). Mural opacities that were only
suggestive of a thrombus were classified as possible thrombus (grade
1). Totally occluded culprit vessels were subdivided into those with
apparently recent thrombotic occlusion (grade 5) if they ended abruptly
with a squared-off or an upstream convex termination, creating a stump
or arterial cul-de-sac from which dye washout was delayed
(Figure 2A), and those with chronic
occlusion (grade 6) if they tapered smoothly to supply a terminal side
branch with a brisk runoff; such vessels usually had a well-developed
distal collateral supply (Figure 2B).
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The underlying plaques, when visualized, were classified as very
eccentric, ulcerated, or intraplaque hemorrhage (Figure 3). Plaques lacking these distinctive
features were simply classified as being eccentric or as having a
smooth or an irregular surface.
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The severity of obstruction and the underlying plaque when visualized were measured by manually tracing the borders of the densely opacified lumen from a "normal" proximal point through the point of greatest narrowing to a distal normal point. The catheter shaft was traced as a scaling reference. A Power Macintosh–based digital caliper system served to provide scaled estimates of normal and minimal lumen diameters and percent stenosis for both obstructive narrowing and underlying plaque.19
Study Hypothesis and Primary and Secondary Angiographic End
Points
On the basis of a high frequency of intracoronary
thrombus detected angiographically in patients with UA or
NQWMI5 6 20 and of platelet-rich thrombus detected by
angioscopy, as opposed to red fibrin-rich thrombus in patients with
acute MI,4 it was hypothesized that profound inhibition of
platelet aggregation with tirofiban would reduce the
intracoronary thrombus burden and improve coronary flow
past the culprit lesion.
The primary angiographic end point was the proportion of patients with each grade of TIMI thrombus (grades 0 to 5). Grade 6 was not included in the primary end-point analysis because chronic total occlusion (grade 6) was unlikely to be the cause of the current episode of UA or NQWMI.
The predefined secondary end points included the proportion of patients with each grade of TIMI flow past the culprit lesion (grades 0 to 3) and the proportion of patients with a culprit lesion in each severity range: (1) 0 to 30% stenosis; (2) 31% to 50%; (3) 51% to 70%; (4) 71% to 99%; and (5) total occlusion.
Statistical Analysis
On the basis of results from TIMI (Thrombolysis In
Myocardial Infarction) IIIA,5 which included patients with
similar characteristics, it was estimated that the sample size of the
trial would provide 95% power to detect an approximate OR of 0.65. The
clinical, ECG, and angiographic characteristics of tirofiban plus
heparin and heparin alone were compared by 
2
test for dichotomous variables and Wilcoxon rank-sum test
for continuous and ordinal variables. A proportional odds model was
used to compare the distribution of thrombus grades in the 2
groups.21 In this model, the odds of thrombus with
tirofiban plus heparin relative to heparin alone are assumed to be
constant, regardless of the grouping of individual grades. Therefore,
the model analyzed general trends toward more severe thrombus
grades in 1 treatment group relative to the other. TIMI flow grade and
disease severity (secondary end points) were analyzed by the
same model. The proportional odds model was also used to identify
patient, treatment, and angiographic variables that were
independently predictive of thrombus. The results are displayed as OR,
95% confidence limits, and 2-sided P value. A P
value <0.05 was considered statistically significant.
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Results |
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Clinical, ECG, and Angiographic Characteristics
The various characteristics studied were similar between patients in the tirofiban-plus-heparin and heparin-alone groups (Table 1
). More than 50% of patients had
hypertension or hypercholesterolemia; 41% had
a previous MI; and 25% had previous PTCA or CABG. The qualifying event
was UA in 56% and NQWMI in 44%. Ninety-four percent of patients
showed ECG evidence of ischemia, with ST-segment elevation in
15%, ST-segment depression in 57%, and T-wave inversion in 54%.
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One-, 2-, and 3-vessel disease was found in 24%, 25%, and 41% of patients, respectively. Ten percent had nonsignificant disease, defined as <50% stenosis in any major coronary artery or branch. Of 1387 culprit lesions located in native coronary arteries, 49% were in the left anterior descending artery (LAD) or its diagonal branches, 34% in the left circumflex (LCx) or its branches, and 17% in the right coronary artery (RCA) or its branches. Culprit lesions were located in a saphenous vein or internal mammary graft or at a graft anastomosis in 7% of patients.
Patients were enrolled a mean of 7±4 hours after chest pain, and angiography was performed a mean of 65 hours after randomization. The infusion period extended for a mean of 8 hours after catheterization.
Treatment Effect on Intracoronary Thrombus (Primary
End Point)
A possible or definite (small, medium, or large)
intracoronary thrombus or a fresh total occlusion was seen in
643 patients (45%) in the present study. Compared with heparin
alone, tirofiban plus heparin significantly reduced both frequency and
severity of thrombus. A significant shift to smaller thrombi was
observed with the combination treatment (OR=0.77, P=0.022
for trend). The number of patients with a fresh total occlusion was
reduced with combination treatment, and the number with no thrombus
increased. (See Table 2.)
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Perfusion Status (Secondary End Point)
Significantly more patients in the tirofiban-plus-heparin group
had TIMI 3 flow and significantly fewer had TIMI 2 flow, TIMI 1 flow,
or no perfusion (OR=0.65, P=0.002 for trend) (Table 3).
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Culprit Lesion Severity (Secondary End Point)
Consistent with the reduction in thrombus burden and
improvement in TIMI flow, treatment with tirofiban plus heparin
resulted in a shift to less-severe obstructive stenoses
(P=0.037 for trend). When the thrombotic component of the
lesion was excluded, the severity of underlying disease was the same in
the tirofiban-plus-heparin and heparin-alone groups. (See Table 4.)
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Predictors of Thrombus
A set of proportional odds models were fit to identify the patient
and therapy variables and angiographic characteristics that were
independently predictive of intracoronary thrombus. First, each
of the variables was included 1 at a time in a separate model;
second, all variables were included together in a multivariable
model. In the univariate models, male sex and patients with
prior CABG, hypercholesterolemia, NQWMI, or
ST-segment depression on the qualifying ECG were predictive of
thrombus. Compared with nonsignificant coronary disease,
single-, double-, and triple-vessel disease had 3.0-, 4.7-, and
5.4-fold higher odds to develop thrombus, respectively. Culprit lesions
located in the RCA or LCx had a significantly higher likelihood of
containing thrombus than lesions located in the LAD. In contrast,
treatment with tirofiban plus heparin significantly reduced the odds of
thrombus by 23% (P=0.02).
In the multivariate model, previous CABG, NQWMI, an increasing number of diseased vessels, and RCA or LCx location were independent predictors of thrombus. Treatment with tirofiban independently reduced the odds of thrombus by 20% (P=0.049).
Prognostic Impact of Thrombus and Impaired Perfusion
Patients in all treatment groups were pooled together to examine
the prognostic impact of thrombus and of impaired TIMI flow (Table 6). Persistence of thrombus increased the
risk of the composite end point of death, MI, or RI at 30 days by
2.1-fold (P<0.001). It also increased by 2-fold or more the
risk of each individual component of the composite end point: death,
MI, or RI (all P
0.005). Patients with thrombus also had
more interventions in the first 30 days: the OR was 1.54
(P<0.001) for PTCA, 1.63 (P<0.001) for CABG,
and 2.23 (P<0.001) for any intervention.
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As shown in Table 6
, suboptimal TIMI flow (grade 0 to 2) also
had an impact on the subsequent event rate: the OR of a composite end
point was increased by 1.7-fold (P<0.001). In component
analysis, the association was statistically significant for
RI.
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Discussion |
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This angiographic study in PRISM-PLUS was the first to examine the effects of platelet GP IIb/IIIa receptor blockade on the culprit lesion in patients with UA or NQWMI. It was also the largest prospective study that examined the angiographic characteristics of culprit lesions and their prognostic significance. The study demonstrated that the combination of tirofiban, heparin, and aspirin significantly reduced the thrombus burden of the culprit lesion by 23% beyond the effects of heparin and aspirin, resulting in decreased coronary obstruction and improved distal flow. These data are consistent with the 32% reduction in risk of death, MI, or RI observed at 7 days with the combination therapy and with the 43% reduction in the risk of death or MI. The present study also provided evidence that persistence of an angiographic thrombus after a course of medical therapy is an indicator of a worse prognosis, which suggests important pathophysiological concepts and therapeutic implications.
The concordance in clinical and angiographic benefits present in this study was not observed in trials with thrombolytic agents in UA or NQWMI.22 23 Although some angiographic improvement and a reduction in diameter stenosis were observed with thrombolysis, clinical events were more frequent.24 25 Enhanced platelet activation and thrombin generation after clot lysis that could exacerbate thrombus formation and precipitate MI could explain the paradoxical findings.20 26 Unlike fibrinolytic agents, GP IIb/IIIa antagonists act on the process of thrombus formation by preventing platelet aggregation and thrombus growth and allowing effective endogenous thrombolysis to dissolve the clot.
The clinical benefits of tirofiban that were seen in PRISM-PLUS were also observed in patients with UA treated with abciximab in the EPIC (Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications)12 and CAPTURE (C7E3 fab AntiPlatelet Therapy in Unstable angina REfractory to standard treatment)13 trials and with eptifibatide in the PURSUIT (Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial.14 It has been postulated that the prevention of platelet accumulation at the plaque level could favor plaque passivation, preventing recurrent ischemic events. Our study provides support for this concept by showing that treatment with tirofiban and heparin was associated with a reduction in the thrombus burden of the culprit lesions and that the absence of a residual thrombus was associated with a better outcome. Plaque passivation could be explained by better dissolution of the thrombus, which is by itself a powerful thrombogenic stimulus.13 Additional mechanisms could be prevention of the release of platelet-active products associated with cell proliferation27 and prevention of platelet-leukocyte interaction.28
The impaired outcome associated with persistence of thrombus has important implications for patient management. In patients with MI, more rapid and complete restoration of blood flow, as assessed by TIMI 3 flow, correlated with better left ventricular performance and reduced mortality.29 30 No such value of angiography has been shown in patients with UA or NQWMI; indeed, angiography in these patients is mainly used to evaluate disease severity and explore the possibility of a revascularization procedure. The demonstration in the present study that persistence of thrombus is a strong predictor of death and MI and that impaired TIMI perfusion is associated with RI extends the utility of angiography beyond its diagnostic role and suggests that lesion characteristics can be used as risk stratifiers to help orient treatment. They can possibly also be used as markers of an uncontrolled disease process, identifying high-risk patients who may benefit from more aggressive therapy.
The relatively high rate (45%) of persistence of thrombus after a period of medical stabilization with aspirin, heparin, and a GP IIb/IIIa antagonist in half the patients reinforces the importance of additional research in the acute coronary syndromes. One direction is to identify better antithrombotic therapy or better combinations of drugs and the optimal treatment duration. Another, considering the limitations of angiography to appreciate intracoronary thrombus, is to identify more sensitive and ideally noninvasive markers of an active disease process.
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Appendix |
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A list of the principal investigators and committee members of the PRISM-PLUS Study Group has been published previously.15
Angiographic Core Laboratory
X.-Q. Zhao, B.G. Brown, E.L. Bolson, and J.W. Davis.
Merck Research Laboratories
F.L. Sax, S.M. Snapinn, L.I. Deckelbaum, A. Ghannam, C. Joy Lis,
B. Haggert, A. Watson, C. Brancato, and D. Fong.
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Footnotes |
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Merck Research Laboratories is a manufacturer of tirofiban.
Received December 22, 1998; revision received June 29, 1999; accepted July 8, 1999.
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References |
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