(Circulation. 1995;91:2151-2157.)
© 1995 American Heart Association, Inc.
Articles |
Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Platelet Integrin Glycoprotein IIb/IIIa Blocker Integrelin in Elective Coronary Intervention
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Georgia, November 8-11, 1993.
From the Department of Medicine, Duke University Medical Center (J.E.T., R.A.H., J.A.M., D.M.J., K.N.S., R.M.C.), Durham, NC; the Cleveland Clinic Foundation (K.K.-M., S.G.E., E.J.T.), Cleveland, Ohio; Baylor College of Medicine (N.S.K.), Houston, Tex; Christ Hospital (D.J.K.), Cincinnati, Ohio; Methodist Hospital (M.J.M.), Indianapolis, Ind; Mother Francis Hospital (F.I.N.), Tyler, Tex; Saint Vincent Hospital (J.E.S.), Erie, Pa; Lancaster General Hospital (S.J.W.), Lancaster, Pa; and COR Therapeutics, Inc (M.M.K., C.P.d.M.), South San Francisco, Calif.
Correspondence to James E. Tcheng, MD, Box 3275, Duke University Medical Center, Durham, NC 27710.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Platelet aggregation and thrombosis have been implicated in the pathogenesis of coronary angioplasty complications. Integrelin, a synthetic cyclic heptapeptide with high affinity and marked specificity for platelet integrin glycoprotein IIb/IIIa, effectively blocks ADP-induced platelet aggregation.
Methods and Results In 150 patients undergoing elective percutaneous coronary intervention, random assignment was made to one of three treatment regimens: placebo; a 90-µg/kg bolus of Integrelin before angioplasty followed by a 1.0-µg · kg-1 · min-1 infusion of Integrelin for 4 hours; or a 90-µg/kg bolus followed by a 1.0-µg · kg-1 · min-1 infusion of Integrelin for 12 hours. Patients were followed to 30 days for the composite occurrence of myocardial infarction, stent implantation, repeat urgent or emergency percutaneous intervention or coronary bypass surgery, or death. Pharmacodynamic data were obtained in a subset of 31 patients. Administration of a 90-µg/kg bolus of Integrelin achieved an 86% inhibition of platelet aggregation, and this inhibition was maintained by a 1.0-µg · kg-1 · min-1 infusion. There was a trend toward reduction in end-point events from 12.2% (placebo) to 9.6% (4-hour infusion) to 4.1% (12-hour infusion), although these differences were not statistically significant (P=.13 for the 12-hour group compared with placebo). Major bleeding occurred in 8%, 8%, and 2% of patients, while minor bleeding was observed in 14%, 33%, and 47% of patients, respectively. There was no difference in bleeding index among groups (1.5, 1.7, and 1.3, respectively), defined as [(change in hematocrit/3)+red blood cell units transfused].
Conclusions This first clinical investigation of Integrelin during routine, elective, low- and high-risk coronary intervention supports the potential efficacy of Integrelin in routine coronary interventions. Pharmacodynamic analyses demonstrate that profound and sustained inhibition of platelet function is achieved, although a higher bolus dose may be required. Definitive assessment of efficacy and safety will need to await a large-scale study powered to achieve statistical significance.
Key Words: angioplasty • clinical trials • coronary disease • glycoproteins • peptides • platelet aggregation inhibitors
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Platelet deposition and aggregation have been implicated in the development of the clinical complications of coronary angioplasty.1 2 3 4 5 6 Intimal disruption, exposing subendothelial and subintimal components, results in the initiation of the coagulation cascades and the activation of platelets and leads to thrombus formation. Unfortunately, intimal disruption is obligatory during all percutaneous interventions to increase the luminal caliber of the target lesion.
Recent advances in the molecular biology of the platelet have demonstrated that the platelet integrin glycoprotein IIb/IIIa (GP IIb/IIIa) plays a pivotal role in the final common pathway leading to platelet aggregation.7 8 9 Key adhesive ligands to GP IIb/IIIa include fibrinogen and von Willebrand factor. Novel inhibitors of this integrin include peptides and peptidomimetics that act as competitive inhibitors6 10 11 12 13 ; antibodies directed at this integrin have also been purified and characterized.14 Clinically, the monoclonal antibody c7E3, an Fab fragment that irreversibly binds to GP IIb/IIIa (Centocor), has been shown to be effective in reducing 30-day and 6-month clinical events after high-risk coronary intervention.15 16
Integrelin, a synthetic cyclic heptapeptide with a modified KGD sequence (COR Therapeutics), has high affinity and specificity for the GP IIb/IIIa integrin; binding of Integrelin inhibits platelet aggregation and prevents thrombosis. The agent is highly potent, with a rapid onset of action and a short half-life.17 This report is the first study of Integrelin during coronary angioplasty and is also the first trial of a GP IIb/IIIa antagonist in the setting of elective, routine coronary intervention in a population not preselected for high-risk characteristics.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Trial Design
The Integrelin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis (IMPACT) trial was a randomized, double-blind, placebo-controlled phase II clinical trial performed at 11 investigational centers. A total of 150 patients scheduled for elective coronary balloon angioplasty or directional coronary atherectomy were entered into the study. Exclusion criteria included a known history of bleeding disorder, recent gastrointestinal bleeding, major surgery within 6 weeks, history of stroke or other central nervous system structural abnormality, severe hypertension, pregnancy, elevation of baseline prothrombin time (>1.2 times control), hematocrit <30%, platelet count <100 000/µL, or creatinine >4.0 mg/dL. All patients provided informed consent for participation in this trial. The protocol was approved by the human research committees of the respective institutions. Randomization was designed to provide equal distributions of patients receiving one of three treatments: placebo treatment; a bolus of 90 µg/kg of Integrelin followed by a 1.0-µg · kg-1 · min-1 infusion for 4 hours; or a bolus of 90 µg/kg of Integrelin followed by a 1.0-µg · kg-1 · min-1 infusion for 12 hours. Aspirin (325 mg) was administered at least 2 hours before the coronary intervention and continued thereafter at a dose of 325 mg orally every day. After vascular access was established, a bolus of approximately 10 000 U heparin was given to achieve an initial activated clotting time (ACT) of >300 seconds. The study drug bolus was administered at least 10 minutes before the actual coronary intervention. Coronary intervention was performed in the standard fashion. ACT measurements were obtained in the catheterization laboratories according to local laboratory routine using either a Hemochron 800 Activated Clotting Time monitor (HCH/International Technidyne, Inc) or a HemoTec Activated Clotting Time monitor (Medtronic HemoTec, Inc). It was recommended that an ACT of between 300 and 350 seconds be maintained during the intervention. After angioplasty, a heparin infusion was started at 10 to 15 U · kg-1 · h-1 to achieve a target activated partial thromboplastin time of 2 to 3 times control. Vascular sheaths were removed the following day 4 to 6 hours after discontinuation of heparin. At three centers, 31 patients were also enrolled in a platelet function substudy. Patients in this substudy underwent additional serial determinations of Simplate bleeding time and ex vivo platelet aggregation.
Safety and Efficacy End Points
Patients were followed to 30
days from the date of
randomization. The primary efficacy end point was the composite
occurrence of any of the following within 30 days: death (all-cause
mortality), myocardial infarction (creatine kinase [CK] MB >3
times
the upper limit of normal or new Q waves in two or more contiguous
leads), urgent or emergency coronary intervention, stent implantation,
or coronary artery bypass surgery for ischemia or threatened closure.
No patients were lost to follow-up at 30 days. All clinical end points
were adjudicated by blinded review. Safety end points were identified
by following serial physical examinations (paying particular attention
to unusual or excessive bleeding); transfusion requirements; and
hematology, coagulation, chemistry, and urinalysis assays. Severity of
bleeding was classified according to the Thrombolysis in Myocardial
Infarction (TIMI) study bleeding classification.18 By this
scale, bleeding was characterized as being either minor or major, with
major bleeding defined as any intracranial hemorrhage or a bleeding
event associated with a decrease in hemoglobin of 5 g/dL or a decrease
in hematocrit of 15%. Adjustment for blood transfusion was based on
the method of Landefeld and coworkers.19
Platelet Function Substudy
Assays for determination of ex
vivo inhibition of platelet
aggregation were performed at baseline (before study drug bolus and
coronary intervention), 1 hour after administration of the study drug
bolus, immediately before study drug termination, and 4 hours after
study drug termination. Blood was obtained by a trained technician or
nurse and placed in a 3.8% sodium citrate tube. Platelet aggregation
in platelet-rich plasma was determined by the turbidimetric method in
either a Bio/Data PAP-4 (Bio/Data) or a Chrono-Log aggregometer
(Chrono-Log). Once a stable baseline was observed, aggregation in
response to 20 µmol/L adenosine diphosphate was determined as the
change in light transmission over 5 minutes and recorded as percentage
platelet aggregation. All platelet aggregation assays were performed
within 2 hours of sampling. Simplate bleeding times were obtained at
baseline, 1 hour after study drug bolus, 30 minutes before study drug
termination, and at 15 minutes after study drug termination. These were
performed with a variation of the Ivy technique20 on the
volvar surface of the forearm with the automated Simplate II (Organon
Teknika Corp) bleeding time device. Bleeding times extending beyond 30
minutes were truncated and recorded as 30-minute bleeding times.
Statistical Analyses
Continuous variables are reported as
medians with interquartile
ranges. Platelet aggregation values are displayed as means with 95%
confidence intervals. Discrete variables are expressed as percentages.
The primary efficacy end point was analyzed by comparing each
Integrelin treatment arm with placebo treatment. Both pairwise tests
were performed with a 
2 test. The relations
between immediate interventional results (for example, TIMI flow and
dissection) and treatment were examined by comparing all
Integrelin-treated patients with the placebo group by
2 tests. The 4-hour and 12-hour Integrelin arms
were combined in these analyses, since drug administration through 4
hours was identical. The analysis of maximum ACT was performed in
an analogous fashion, except that a Wilcoxon rank-sum test was
performed. Linear regression was used to explore the relation between
the baseline platelet count and inhibition of platelet aggregation. A
value of P<.05 was considered significant. The protocol was
designed as a preliminary investigation and was therefore not powered
to achieve statistical significance with regard to primary efficacy or
safety end points.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Primary Results
Of the 150 patients enrolled in the trial, 101 were randomized to receive Integrelin (4-hour infusion, n=52; 12-hour infusion, n=49), and 49 received placebo. Table 1
lists selected population
variables by randomization. Characteristics were in general balanced
among groups in the trial, although there was a somewhat lower
frequency of diabetes in the 12-hour Integrelin treatment arm.
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Selected
procedure-related details are listed in Table 2. There were 133
lesions attempted among the 101
patients randomized to receive Integrelin and 64 lesions attempted
among the 49 patients randomized to placebo. Most lesions were
approached with balloon angioplasty alone, although 10% of patients
receiving placebo were treated with directional atherectomy (with or
without balloon angioplasty), and 15% of patients receiving Integrelin
underwent directional atherectomy (with or without balloon
angioplasty). No other interventional techniques were used as a primary
treatment. When the 4-hour and 12-hour treatment groups were grouped
together, the preprocedure and postprocedure percent stenoses were
found to be similar between groups. The only statistically significant
difference was in the incidence of dissection compared with placebo
(P=.015). Other measures of angiographic outcome trended in
favor of treatment (for example, TIMI 3 flow, P=.18) but
were statistically insignificant.
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Fig 1 summarizes the
differences among groups with
respect to the primary composite efficacy end point. The bar graph
displays the percentages of patients in each group sustaining one or
more of the components of the composite end point. The inset table
lists the numbers of patients sustaining a primary end-point event (on
an ordinal scale from top to bottom). Patients treated with Integrelin
for 12 hours experienced the fewest end points; only 2 patients (4.1%;
P=.13 compared with placebo) developed an end-point clinical
complication. Of patients treated with Integrelin for 4 hours, 5
(9.6%; P=.67 compared with placebo) had an end-point event,
while 6 placebo patients (12.2%) experienced clinical complications.
Demographic, clinical, angiographic, and procedural variables were not
predictive of clinical end-point events. Details concerning end-point
events are as follows. Two patients in the placebo group underwent
nonelective stent implantation during the initial intervention for
threatened vessel closure due to major dissection. One patient in each
of the treatment groups sustained a myocardial infarction. In the
placebo group, a myocardial infarction (peak CK, 307 IU/L, with 14%
MB) occurred in 1 patient 5 days after an aborted angioplasty procedure
(no intervention was attempted because of unfavorable lesion
morphology). In the 4-hour Integrelin infusion arm, 1 patient sustained
an infarction (peak CK, 1129 IU/L, with 15% MB) due to target lesion
thrombosis 5 days after successful angioplasty of a bifurcation lesion
involving the left anterior descending and diagonal branches. Among
patients treated for 12 hours with Integrelin, one myocardial
infarction (peak CK, 1313 IU/L with 32% MB) was documented 25 hours
after an unsuccessful angioplasty procedure (due to failure to cross
the target lesion). Other than sustained chest pain, there were no
demonstrable clinical sequelae of these events. There were two deaths
in the study. A patient in the placebo group with a known severe
cardiomyopathy developed hypotension and ventricular tachycardia during
the angioplasty procedure, culminating in cardiopulmonary arrest and
death. The second, a 71-year-old man in the 4-hour arm without known
cerebrovascular disease, underwent an uncomplicated, successful
angioplasty procedure. He received 7500 U heparin during the
intervention, achieving a maximum ACT of 385 seconds. Approximately 8.5
hours after the Integrelin infusion was discontinued (but while
receiving heparin by infusion), the patient developed symptoms of an
intracerebral hemorrhage. He died the following day.
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Table
3 summarizes pertinent laboratory, clinical
safety, and transfusion data. The maximum in-laboratory ACT was higher
(P=.058) in patients treated with Integrelin (395 seconds
[range, 348 to 469 seconds]) compared with patients receiving
placebo
(368 seconds [range, 334 to 422 seconds]). All groups sustained
similar drops in platelet count and hematocrit, even after adjustment
of the hematocrit values for red blood cell transfusions. Three treated
patients developed relative thrombocytopenia (platelet count of
<100 000/µL). In all cases, nadir platelet counts were measured
after termination of study drug. In 1 patient, thrombocytopenia
(48 000/µL) was associated with coronary bypass surgery, a procedure
associated with thrombocytopenia.21 The other 2 patients
developed nadir platelet counts of 98 000/µL and 99 000/µL and
were otherwise asymptomatic. The overall incidence of any bleeding in
patients randomized to either of the Integrelin arms was approximately
twice that of patients treated with placebo. Most bleeding was
classified as minor, occurring primarily at vascular access sites, with
a lesser incidence of gastrointestinal and genitourinary bleeding;
minor bleeding was documented in 40% of patients treated with
Integrelin compared with 14% of patients treated with placebo. Major
bleeding occurred in 5% of patients treated with Integrelin and 8% of
patients treated with placebo. Of note is that according to the
predefined bleeding criteria, red blood cell transfusion per se did not
constitute major bleeding but contributed to the classification after
adjustment according to the method of Landefeld et al.19 A
greater proportion of patients receiving Integrelin required
transfusion of fresh-frozen plasma or random donor platelets. Of the
patients receiving random donor platelets, 3 were given platelets in
the perioperative period at the time of coronary bypass surgery. The
fourth patient received random donor platelets at the time of a
vascular access site repair. Regarding vascular complications, 2
patients (both in the 12-hour arm) required surgical repair of the
vascular access site. One repair was performed because of laceration of
the femoral artery, while the second was an elective repair of a
pseudoaneurysm. Although this is not shown in Table 3, there
were no
other significant hematology, coagulation, chemistry, or urinalysis
laboratory abnormalities.
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Platelet Function Substudy
The platelet function substudy
enrolled 31 patients. These
patients did not differ significantly from the overall population in
regard to baseline demographics, cardiovascular risk factors, or reason
for revascularization. Complete platelet aggregation data were
available on 29 patients (Integrelin, n=21; placebo, n=8) and
are
displayed in Fig 2. Since the study drug dosing regimen
was identical (except for duration) in the 4- and 12-hour infusion
groups, results from these patients are displayed in aggregate.
Platelet inhibition after Integrelin administration was determined to
be rapid, profound, and sustained for the duration of the infusion.
There was no relation between inhibition of platelet aggregation and
baseline platelet count (P=.28). Substantial recovery of ex
vivo platelet aggregation was observed at 4 hours after the termination
of the Integrelin infusion. Fig 3 illustrates changes in
bleeding time after study drug administration. The bleeding time in
patients treated with Integrelin was prolonged at 1 hour after the
Integrelin bolus. This effect persisted to the end of the infusion.
Within 15 minutes of discontinuation of the Integrelin infusion, the
bleeding time returned toward baseline.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This randomized, double-blind, placebo-controlled, multicenter study was the first to use the novel antiplatelet agent Integrelin in the setting of coronary angioplasty. It was also the first to evaluate GP IIb/IIIa blockade in routine, elective, coronary intervention that included both patients with low- and high-risk clinical and/or angiographic characteristics. A favorable trend toward improvement in 30-day composite clinical outcome was observed, and the study also documented that Integrelin could be administered along with aspirin and heparin without an excessive risk of major bleeding. These results thus appear encouraging and support further evaluation of this novel agent.
Efficacy
These results appear to be consistent with studies
of other
antiplatelet agents. Previous randomized trials of aspirin and
ticlopidine have confirmed the central role of antiplatelet
therapy in reducing the ischemic complications of coronary
angioplasty.22 23 24 In a high-risk
angioplasty population,
further reductions in both 30-day ischemic complications as well as
6-month clinical restenosis events have been reported recently by the
EPIC investigators using the potent GP IIb/IIIa inhibitor monoclonal
antibody fragment c7E3 Fab.15 16 This study thus
extends
these observations to suggest that the entire coronary interventional
patient population, regardless of preexisting clinical, anatomic, or
morphological risk characteristics, might benefit from the
administration of potent GP IIb/IIIa antagonists. However, a study with
a sufficient sample size to prove statistical significance will be
needed to confirm the preliminary efficacy suggested in this trial.
Safety and Bleeding Complications
Administration of potent
blockers of GP IIb/IIIa may increase the
risk of bleeding and alter the safety profile of coronary intervention.
In the EPIC study, the overall bleeding risk was approximately doubled
compared with placebo by treatment with a bolus plus 12-hour infusion
of c7E3 Fab.15 Administration of Integrelin was associated
with an increase in clinically evident minor bleeding, primarily at
vascular access sites. Major bleeding, however, was similar among
treatment arms. Importantly, the bleeding index, determined by serial
measurements of hematocrit and incorporating an algorithm to adjust for
red blood cell transfusion, was essentially the same among all groups.
This low overall bleeding complication rate in the face of profound GP
IIb/IIIa blockade may be attributable to the familiarity of the
investigators recruited for this trial; most had previous experience
with GP IIb/IIIa antagonists. Specific modifications (particularly with
regard to vascular access technique, sheath management, and patient
comfort measures) based on the cumulative experience with GP IIb/IIIa
blockade may be critical to further reduction of vascular access site
and other bleeding complications. Clinically important, severe
thrombocytopenia was not observed in this study except in 1 patient
after bypass surgery, an association that has been previously
described.21
Pharmacodynamics
Integrelin appears to have predictable
pharmacodynamic and
activity profiles. The molecule is highly potent, with a rapid onset of
action and a short pharmacological half-life. Because Integrelin can
readily dissociate from platelet GP IIb/IIIa and because clearance of
Integrelin depends principally on plasma compartment clearance
mechanisms and not metabolism of the compound, the half-life of the
drug is relatively short.17 In this trial, the 90-µg/kg
Integrelin bolus provided a mean platelet inhibition of 86%. The 95%
confidence intervals were wide, however, reflecting considerable
variability among individual patients; this suggests that a 90-µg/kg
bolus may not accomplish the same degree of platelet inhibition in all
patients. The inherent limitations of the bleeding time assays
notwithstanding,25 the very rapid (within 15 minutes)
return of the bleeding time toward baseline after termination of
Integrelin infusion suggests rapid restoration of platelet function on
discontinuation of drug. This safety profile may be especially critical
in the patient sustaining a serious bleeding complication or in whom
emergency bypass surgery is contemplated. Interestingly, patients
receiving Integrelin had significantly higher ACT values despite
receiving comparable amounts of heparin. It thus appears that the
antiplatelet effect of Integrelin contributes to an elevation in the
ACT; a similar effect was observed in the EPIC trial.26
This result should not be surprising, since the ACT is a measure of
whole-blood clotting; as such, profound disturbance of the platelet
phase of hemostasis might limit the availability of the phospholipid
surfaces required for efficient prothrombinase complex formation and
thrombin generation.27 28 It may therefore be
possible to
safely perform coronary intervention with less intense heparin
anticoagulation when a potent GP IIb/IIIa integrin blocker is
administered concomitantly.29
With regard to pharmacodynamics, several questions are raised. The ideal Integrelin bolus dose still remains to be defined; it may be greater than that used in this trial. The clinical impracticality of measurement and adjustment of dosing via serial ex vivo platelet aggregation assays dictates that a dose be identified that inhibits platelets reliably in all patients. Additional investigation of the antiplatelet effects over the first few hours also appears warranted; the thrombogenicity of the disrupted artery is most likely at its highest and the risk of abrupt vessel closure is greatest during this period.1 2 3 4 Finally, investigation of extension of the duration of infusion will need to be considered, for two reasons. First, it is unknown whether the antiplatelet effects remain constant over an extended period of time and whether those effects remain readily reversible on discontinuation of the agent. Second, prolonged inhibition of GP IIb/IIIa may be required to achieve optimal efficacy benefits. In the EPIC trial, the treatment strategy associated with the salutary reduction in short- and long-term end points used a bolus plus 12-hour infusion of c7E3 Fab, a dosing regimen that would be expected to block the integrin GP IIb/IIIa for up to 18 to 24 hours.14 15 16 30
Limitations and Conclusions
Several limitations of this study
should be kept in mind. The most
obvious is that this trial was not sufficiently powered to provide
statistically significant clinical efficacy or safety results; a larger
(4000-patient) follow-up study is under way to test the present
findings. The angiography films were not reviewed by a core
angiographic laboratory, since the primary efficacy and safety measures
were defined in terms of clinical, not angiographic, end points. Also,
adenosine diphosphate was used as the agonist in the platelet
aggregation assays; other agents (notably thrombin receptor agonist
peptide) are more effective in inducing platelet aggrega-tion even with
seemingly adequate GP IIb/IIIa blockade. Even with ex vivo measurements
of platelet aggregation, it still remains difficult to extrapolate a
clinically appropriate dose for the interventional patient.
In summary, Integrelin, when administered during percutaneous coronary intervention, leads to rapid and profound inhibition of ex vivo platelet aggregation. These antiplatelet effects are sustained for the duration of the Integrelin infusion and are readily and rapidly reversed by termination of the infusion. While important questions remain as to the optimal dosing and duration of Integrelin during coronary intervention, Integrelin appears to have promise in reducing platelet-mediated ischemic complications of coronary angioplasty regardless of the patient's underlying risk profile. Improvement of the clinical safety profile will probably depend on a combination of improvements in technical aspects of the procedure (especially vascular access site management) and optimization of conjunctive antithrombotic therapy, especially in heparin dosing.28 This initial randomized trial supports further evaluation of the potential clinical efficacy of Integrelin during routine coronary intervention.
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Acknowledgments |
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This work was supported by a grant from COR Therapeutics, Inc, South San Francisco, Calif. The authors wish to recognize and thank Pattie S. Lilley for her expertise, effort, and contributions as the IMPACT monitor and Joyce C. Sizemore for her expert technical and secretarial assistance in the preparation of the manuscript.
Investigating Centers
Christ Hospital,
Cincinnati, Ohio: Dean J. Keriakes, Nancy
Higby. The Cleveland Clinic, Cleveland, Ohio: Eric J. Topol, Stephen G.
Ellis, Nadine Juran. Mercy Hospital, Des Moines, Iowa: Mark A.
Tannenbaum, Mark Polich. Duke University Medical Center, Durham, NC:
Robert M. Califf, James E. Tcheng, Rose Marie Moore, Michele Rund.
Saint Vincent Hospital, Erie, Pa: Jack E. Smith, Patty Henry. Baylor
College of Medicine, Houston, Tex: Neal S. Kleiman, Kathy Trainor, Dale
Rose, Susan Johnson. Texas Heart Institute, Houston, Tex: James J.
Ferguson, Mary Harlan. Methodist Hospital of Indiana, Indianapolis,
Ind: Matthew J. Mick, Diane Kiess. Lancaster General Hospital,
Lancaster, Pa: Seth J. Worley, JoAnn Tuzi. University of Louisville,
Louisville, Ky: J. David Talley, Millie Rawert. Mother Francis
Hospital, Tyler, Tex: Frank I. Navetta, Greg Murphy.
Received July 8, 1994; revision received November 14, 1994; accepted November 25, 1994.
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