(Circulation. 1997;95:1755-1759.)
© 1997 American Heart Association, Inc.
Articles |
Restoration of Coronary Flow in Myocardial Infarction by Intravenous Chimeric 7E3 Antibody Without Exogenous Plasminogen Activators
Observations in Animals and Humans
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10-13, 1996, and previously published in abstract form (Circulation. 1996;94[suppl I]: I-553).
From the Cardiac Unit, Department of Medicine, Massachusetts General Hospital, Boston.
Correspondence to Herman K. Gold, MD, Ambulatory Care Center, Suite 480, Massachusetts General Hospital, Boston, Mass 02114. E-mail gold{at}olorin.mgh.harvard.edu
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Abstract |
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Background Coronary thrombus is composed of platelets and fibrin, and during thrombolytic treatment, reflow may be slowed by platelet deposition. It may be possible to initiate coronary reflow without exogenous plasminogen activators by blocking platelet aggregation while fibrin generation is impeded with heparin.
Methods and Results In 14 dogs, left anterior descending
coronary artery thrombosis was produced by
endothelial trauma and thrombin instillation in the
presence of stenosis distally. Reflow was monitored by flow
probe during treatment with (1) heparin, (2) heparin and aspirin, and
(3) heparin, aspirin, and intravenous 7E3. Eighty percent
of dogs treated with the third combination showed stable reflow (
25%
of prestenotic flow) in 50±9 minutes. In addition, 13 patients
were studied during intravenous administration of c7E3 10
minutes before primary angioplasty for acute myocardial infarction and
Thrombolysis In Myocardial Infarction (TIMI) grade 0 or 1
flow. Pretreatment included heparin and oral aspirin. Flow increased
during a 10-minute period by at least one TIMI grade in 11 (85%) of 13
and reached TIMI grade 2 or 3 in 7 (54%) of 13 patients. Average TIMI
grade flow increased from 0.31±0.5 to 1.54±0.8 (P<.001).
Thrombus length 10 minutes after c7E3 was 5.1±3.5 mm. All but 1
patient then underwent angioplasty. There were no complications.
Conclusions Coronary reflow can be initiated by intravenous 7E3 administration in the presence of heparin and aspirin. In human patients, this flow can be observed in 10 minutes without exogenous thrombolytic agents.
Key Words: 7E3 • myocardial infarction • platelet aggregation inhibitors • reperfusion
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Introduction |
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The components of an occluding thrombus in acute myocardial infarction include platelets and fibrin, with the highest platelet concentration at the site of plaque rupture.1 Whereas the fibrin component is very sensitive to lysis by plasminogen activators, the platelets resist dissociation.2 Additionally, as fibrinolysis proceeds, platelets accumulate on the clot surface, slowing the reflow process.3
We4 5 previously found in animal models that coronary reflow can be accelerated by glycoprotein IIb/IIIa platelet receptor inhibition combined with very low doses of recombinant tissue plasminogen activator (rTPA). In the present study, we evaluated coronary reflow in animals using murine 7E36 without exogenous rTPA and in humans with the chimeric Fab fragment of monoclonal antibody 7E3 (c7E3).7 The patients studied had been selected for primary angioplasty after acute myocardial infarction. The purpose of these studies was to determine whether preventing platelet aggregation during clot remodeling might be adequate to initiate reflow.
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Methods |
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Animal Studies
Left anterior descending coronary artery stenosis and thrombosis were induced in 14 dogs anesthetized with pentobarbital sodium (35 mg/kg IV) by a previously described method.3 4 Left anterior descending thrombosis was induced with a mixture of thrombin and blood after local endothelial damage by clamping and after external stenosis was constructed just distal to the clotted site. This preparation differed from previous preparations in that the induced stenosis was less severe, adjusted to abolish postocclusion hyperemia and to slightly reduce resting flow. Twenty minutes after induction of a stable, fibrin-rich coronary thrombosis, intravenous heparin was given to all animals to maintain the activated clotting time at
250 seconds. The animals were
then divided into three groups. Five animals (group I) were then given
aspirin (17 mg/kg IV) and, after 10 more minutes of observed
coronary occlusion, 7E3 0.8 mg/kg IV (provided by Centocor,
Malvern, Pa), a dose previously shown to block >80% of
glycoprotein IIb/IIIa platelet receptors.4
Four animals (group II) received aspirin, followed in 10 minutes by
placebo, and 5 (group III) received placebo. Reflow was defined as flow
reaching 25% of prestenotic flow, measured by external
coronary flow probe.
Patient Studies
Between November 1995 and May 1996, 34 patients with acute
myocardial infarction referred for primary angioplasty were given
preangioplasty c7E3 (ReoPro [abciximab]; Eli Lilly) according to
FDA-approved guidelines. All patients gave consent for preangioplasty
platelet blockade. This report describes the angiographic responses
in the 13 patients from this group who met the following criteria: (1)
evidence of transmural infarction with ST-segment elevation of 0.1 mV
in two adjacent ECG leads; (2) no previous infarction in this zone; (3)
symptoms >30 minutes and <6 hours old; (4) age >21 years; (5) no
contraindication to c7E3; (6) no recent thrombolysis;
and (7) coronary occlusion with TIMI grade 0 or 1 flow. These
criteria were selected to single out patients with initial infarctions
without confounding lytic therapy who were in a reasonable therapeutic
window for myocardial salvage.
All patients were given nitroglycerin (50 to 200 µg/min IV), heparin (5000 U bolus), and aspirin (160 to 325 mg PO) in the emergency department as part of our standard protocol. They were then taken as quickly as possible to the cardiac catheterization laboratory, where Judkins coronary angiography was performed. After demonstration of TIMI grade 0 or 1 flow in the culprit artery, the catheter was placed in the ascending aorta, and c7E3 (0.25 mg/kg) was given by bolus intravenously, followed by a maintenance infusion at 0.125 µg·kg-1·h-1 for 12 hours. Intracoronary nitroglycerin was not used because only intravenous therapy was being assessed. After the 10 minutes required to obtain platelet-receptor blockade,8 "road-map" angiography was repeated in the single-plane view that best delineated the obstructed artery. Films were reviewed by a cardiac radiologist twice independently for qualitative assessment of TIMI flow and quantitative assessment by corrected TIMI frame count.9 Thrombus was defined as a convex filling defect or a convex leading edge of an occlusion. Thrombus length was measured on the 10-minute film by digital caliper (Medis imaging systems). Collateral supply to the culprit artery before administration of c7E3 was graded (0 to 3) as follows: 0, none; 1, to branches of artery; 2, faint or partial filling of artery; and 3, complete filling of artery distal to obstruction. Twelve patients then proceeded to have direct angioplasty with or without stenting, 11 immediately and 1 24 hours later.
Statistical Methods
Results are expressed as mean±SD. Student's t test
for paired analysis was used to compare treatment-related
differences involving continuous variables, and Fisher's exact
test was performed to analyze discrete end points. The
relationship between TIMI flow and collateral score was determined by
regression analysis by use of the RSI program (Research System
1; BBN Systems). Probability values are two-sided.
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Results |
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Animal Studies
Results are shown in Table 1
. Four of five animals
(group I) treated with heparin, aspirin, and 7E3 showed stable reflow
at 50±9 minutes. Reflow in each instance was sustained. No other
animals showed even transient reflow (P<.05). The
observation time was 2 hours. Fig 1 is a scanning
electron micrograph of the thrombosed segment of a canine left anterior
descending artery from group I obtained 1 hour after 7E3-induced
reflow. Channels are seen through a large, segmented residual
thrombus.
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Patient Observations
Patient characteristics, peak creatine phosphokinase (CPK), and
posttreatment platelet counts are given in Table 2.
Average age was 58 years. No patient was in shock. The average time
from onset of pain to arrival in the catheter laboratory was 3±1.4
hours, with a maximal delay of 6.8 hours. No single coronary
artery predominated. ST-segment elevation always corresponded to the
zone of the culprit artery. No patient had been taking coumadin, and
none were receiving balloon counterpulsation.
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The angiographic TIMI scores, collateral grades, and thrombus lengths
are shown in Table 3. Flow increased during a 10-minute
period by at least one TIMI grade in 11 (85%) of 13 patients and
reached TIMI grade 2 or 3 flow in 7 (54%) of 13. The average TIMI
grade flow increased from 0.31±0.5 to 1.5±0.8 (P<.001).
The average thrombus length, when measurable, was 5.1±3.5 mm.
There was no relation between thrombus length and reflow. There was,
however, significantly better reflow in patients without pretreatment
collateral flow (P<.03). Angiograms from patient No. 5 are
shown in Fig 2. Flow in that patient increased from TIMI
grade 0 without collaterals to TIMI grade 2 at 10 minutes.
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The one patient (patient 9) who did not undergo angioplasty showed a rapid increase in TIMI flow from grade 0 to grade 2 during a 10-minute period with complete resolution of pain. At that point, 25 mg of rTPA was given in a bolus intravenously, and flow increased to TIMI grade 3 10 minutes later. Another 25 mg of rTPA was then given during a 15-minute period. The clot size decreased from 3.3 mm at 10 minutes to two 1-mm fragments 60 minutes after rTPA. Residual stenosis was 60%.
There were no significant bleeding episodes, no allergic reactions, and no cases of thrombocytopenia. All angioplasties were successful, and five patients received stents. Postprocedure anticoagulation was either aspirin or aspirin and ticlopidine (for stents). All patients were discharged in stable condition.
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Discussion |
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The fundamental problem in current reflow management of myocardial infarction, without regard to the technique used, is time.10 Lytic therapy takes 45 to 90 minutes to produce TIMI grade 2 or 3 flow, and reocclusion prolongs ischemic time.11 12 13 14 Direct angioplasty usually takes 60 minutes to organize.13 Coronary thrombosis is thought to be a dynamic process initially, with simultaneous fibrin and platelet deposition and partial lysis.4 It follows that inhibition of platelet accumulation and reaccumulation by c7E3 may render the forming clot increasingly susceptible to unopposed endogenous fibrinolysis. There is also a possible accelerating effect of c7E3 on endothelium-based fibrinolysis. This possibility has been substantiated recently in vitro by demonstration of significantly increased elaboration of urokinase plasminogen activator, concomitant with diminished synthesis of plasminogen activator inhibitor-1, by cultured human arterial microvascular endothelial cells exposed to c7E3.15 Recently, 7E3 has been shown to additionally reduce thrombin generation by tissue factor.16
In our animal model, the coronary thrombus is fibrin rich. Nevertheless, neither heparin nor heparin and aspirin produced reflow. 7E3 in the absence of exogenous plasminogen activator produced channels in the fibrin thrombus, initiating coronary flow and increasing the surface of the thrombus exposed to circulating plasma. In this model, the time to reflow was longer than that observed in humans. However, once flow had begun through the large thrombus, reocclusion did not occur.
There was an unexpected significant correlation between initiation of reflow and absence of collateral circulation to the infarct zone. It is tempting to speculate that hemodynamic factors, such as the pressure drop across the thrombus, could play a role in clearing loosened platelet clumps. Alternatively, the absence of collaterals could reflect sudden occlusion without preceding ischemia, suggesting less severe underlying stenosis. This finding would then correspond to the observation that it was necessary to prepare the animal model differently from previous studies of high-dose rTPA.3 The associated stenosis had to be less severe to observe 7E3 reflow without exogenous plasminogen activators. Whatever the mechanism, this phenomenon is encouraging because patients without collateral flow are often at greater risk early in infarction.
Patency of the infarct-related artery has also been reported in aspirin-treated patients after bolus heparin 150 to 300 IU/kg.17 18 19 TIMI grade 2 or 3 flow has been seen in 34% to 71% of cases at 70 to 90 minutes without control angiography. Our rate was 54% in 10 minutes with control angiography.
We recognize limitations to our study. These are serial observations in patients who were not randomized. We excluded patients for whom thrombolysis was unsuccessful, patients with pain lasting >6 hours, and patients who had already spontaneously developed reflow. We sought to observe what might happen if c7E3 were given at the earliest possible time to patients with complete coronary obstruction. We also were not able to serially observe patients beyond 10 minutes because of the planned interventional strategy.
This study is the first to systematically evaluate the potential of c7E3 to dissolve thrombus in acute myocardial infarction. Other studies have used agents that block the platelet glycoprotein IIb/IIIa receptor after or during full-dose lytic therapy. Another, as yet unstudied approach would be full-dose c7E3 combined with reduced administration of thrombolytic agents.
These observations raise the possibility that c7E3 might become an agent for intravenous administration in combination with heparin and aspirin by emergency teams on the way to the hospital. The intracerebral bleed rate is low,20 the onset of action is rapid, and the effect would persist for 6 hours. If TIMI grade 2 flow were to result, the rate of myocardial necrosis would be slowed, and completion of treatment in the hospital with angioplasty or possibly with low-dose plasminogen activator could be more deliberate. The early administration of both c7E3 and plasminogen activators will require evaluation in larger trials.
Received November 13, 1996; revision received January 30, 1997; accepted February 7, 1997.
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