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Circulation. 1996;94:298-307

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(Circulation. 1996;94:298-307.)
© 1996 American Heart Association, Inc.

Articles

Beneficial Effects of RheothRx Injection in Patients Receiving Thrombolytic Therapy for Acute Myocardial Infarction

Results of a Randomized, Double-Blind, Placebo-Controlled Trial

Gary L. Schaer, MD; Leo J. Spaccavento, MD; Kevin F. Browne, MD; Karol A. Krueger, PharmD; Daniel Krichbaum, PharmD; John M. Phelan, MD; William O. Fletcher, MD; Cindy L. Grines, MD; Suzanne Edwards, DrPH; Michael K. Jolly, PharmD; Raymond J. Gibbons, MD

the Section of Cardiology (G.L.S.), Rush Medical College, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill; University Medical Center of Southern Nevada (Las Vegas) (L.J.S.); Lakeland Regional Medical Center (K.F.B), Lakeland, Fla; Department of Cardiovascular Medicine (K.A.K., M.K.J.) and the Clinical Statistics Department (S.E.), Burroughs Wellcome Co, Research Triangle Park, NC; Cardiology Department (D.K.), Christ Hospital and Medical Center, Oak Lawn, Ill; Section of Cardiology (J.M.P.), Rush North Shore Medical Center, Skokie, Ill; Appleton Medical Center (W.O.F.), Appleton, Wis; William Beaumont Hospital (C.L.G.), Royal Oak, Mich; and the Section of Cardiovascular Diseases (R.J.G.), Mayo Clinic, Rochester, Minn.


*    Abstract
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 *Abstract
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 down arrowMethods
 down arrowResults
 down arrowDiscussion
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Background RheothRx (poloxamer 188) is a surfactant with hemorheological and antithrombotic properties that reduces myocardial reperfusion injury in animal models of myocardial infarction. The purpose of the present study was to evaluate the safety and efficacy of adjunctive therapy with poloxamer 188 in patients receiving thrombolytic therapy for acute myocardial infarction.

Methods and Results In this multicenter trial, we randomized 114 patients to a 48-hour infusion of poloxamer 188 or vehicle placebo beginning immediately after the initiation of thrombolytic therapy. Tomographic imaging with 99mTc sestamibi before reperfusion and again 5 to 7 days after the infarction was used to determine myocardium at risk for infarction, infarct size, and myocardial salvage. Radionuclide angiography at 5 to 7 days after infarction was used to measure left ventricular ejection fraction. The treated and control groups had comparable baseline characteristics, time to thrombolytic administration, and time to treatment with poloxamer 188 or placebo. Poloxamer 188-treated patients demonstrated a 38% reduction in median myocardial infarct size (25th and 75th percentile) compared with placebo (16% [7, 30] versus 26% [9, 43]; P=.031), greater median myocardial salvage (13% [7, 20] versus 4% [1, 15]; P=.033), and a 13% relative improvement in median ejection fraction (52% [43, 60] versus 46% [35, 60]; P=.020). Poloxamer 188 treatment also resulted in a reduced incidence of reinfarction (1% versus 13%; P=.016). Poloxamer 188 was well tolerated without adverse hemodynamic effects or significant organ toxicity.

Conclusions Adjunctive therapy with poloxamer 188 resulted in substantial benefit in this randomized trial, including significantly smaller infarcts, greater myocardial salvage, better left ventricular function, and a lower incidence of in-hospital reinfarction. Although the mechanisms are unproven, poloxamer 188 treatment may accelerate thrombolysis, reduce reocclusion, and ameliorate reperfusion injury.


Key Words: poloxamer 188 • myocardial infarction • reperfusion • microcirculation • leukocytes • thrombolysis


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
 down arrowAppendix
 down arrowReferences
 
Thrombolytic therapy for acute myocardial infarction reduces mortality by as much as 30% when treatment is begun within 6 hours of symptom onset.1 2 3 4 Despite this impressive benefit, thrombolytic therapy has important limitations, including a 46% to 71% failure to achieve complete patency (Thrombolysis in Myocardial Infarction trial grade 3) at 90 minutes5 and a 4% to 6.5% risk of reinfarction after successful reperfusion.3 6 7 In addition, there is considerable experimental evidence suggesting that successful thrombolysis may be accompanied by reperfusion injury, an inflammatory event occurring within the reperfused myocardium that may cause additional myocyte injury and necrosis.8 9

To improve the outcome of patients receiving thrombolytic therapy, a variety of adjunctive therapies have been tested. Although aspirin,10 heparin,11 ß-blockers12 and ACE inhibitors7 13 have each been shown to be beneficial, newer adjunctive therapies are needed to further reduce morbidity and mortality. Important goals of newer adjunctive therapies include enhancing the speed of reperfusion, reducing reocclusion, and, possibly, reducing myocardial reperfusion injury.

RheothRx Injection is an intravenous formulation of poloxamer 188, a nonionic block copolymer surfactant that may be a useful adjunctive therapy. Its molecular structure consists of a central hydrophobic chain (block) of polyoxypropylene flanked by two long, flexible hydrophilic chains (blocks) of polyoxyethylene (average molecular weight of 8400 Da). Its surface active properties have led to wide-ranging uses as an emulsifying agent in pharmaceuticals (eg, perfluorochemical emulsion [Fluosol]14 ), in the manufacture of cosmetics, and in a variety of industrial applications. In biological systems, poloxamer 188 has beneficial hemorheological effects. Its surfactant properties cause poloxamer 188 to avidly adhere to molecules or cell surfaces that are more hydrophobic than the surrounding medium.15 After intravenous administration, it is hypothesized that the hydrophobic core of the poloxamer 188 molecule associates with the surface of cell membranes (eg, red blood cells, neutrophils, endothelial cells) and circulating macromolecules (eg, fibrinogen and soluble fibrin), and the long, flexible hydrophilic arms then sterically hinder adhesive interactions between these cells or molecules. Thus, by reducing surface tension between cellular elements and macromolecules in blood, poloxamer 188 reduces red blood cell aggregation16 and whole blood viscosity at low shear rates.15 These hemorheological properties are believed to be responsible for the enhanced microcirculatory blood flow and improved outcome observed with poloxamer 188 administration in animal models of cerebral ischemia,17 prolonged hypothermic circulatory arrest,18 frostbite,19 and hemorrhagic shock.20

There are multiple actions of poloxamer 188 that may benefit patients with acute myocardial infarction. First, its hemorheological effects may be beneficial, including a reduction in blood viscosity15 21 and red blood cell aggregation.22 23 Second, poloxamer 188 may act synergistically with TPA or streptokinase to accelerate the time to thrombolysis in vitro24 25 and in animal models of thrombotic occlusion (Oliver W Jr, Berger H Jr, Wastila W, Burroughs Wellcome Co, July 1, 1991, unpublished data). Third, although poloxamer 188 is not an anticoagulant and does not alter bleeding times, it has been shown to diminish thrombotic coronary occlusion after arterial injury and stent placement in a porcine model.26 Fourth, poloxamer 188 has been demonstrated to ameliorate myocardial reperfusion injury (reduce infarct size and improve LV function) in a canine model of 90 minutes of coronary artery occlusion and 3 days of reperfusion, possibly due to inhibition of neutrophil function.27 Finally, poloxamer 188 has no known adverse hemodynamic effects that might otherwise limit its usefulness in the early phase of myocardial infarction. It is renally cleared,28 and when administered to healthy male volunteers, poloxamer 188 had an elimination half-life of {approx}5 hours.29

To evaluate the potential benefits of adjunctive therapy with poloxamer 188 in the setting of thrombolysis for acute myocardial infarction, we conducted this randomized, multicenter, placebo-controlled trial. Evaluation of the safety of poloxamer 188 in acute myocardial infarction was the main objective. However, we also sought to assess efficacy by quantifying the myocardium at risk, infarct size, and myocardial salvage with the use of tomographic imaging with 99mTc sestamibi (hexakis-2-methoxyisobutyl isonitrile) injections before reperfusion and before hospital discharge30 and by assessing LV ejection fraction through the use of radionuclide angiography before discharge.


*    Methods
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 *Methods
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Study Patients
The study group consisted of 114 patients enrolled between March 24, 1992, and August 16, 1993, at 1 of 11 centers (see "Appendix"). The protocol was approved by the institutional review board of each of the 11 participating centers. Eligible patients met the following inclusion criteria: ongoing chest pain of >=30 minutes' duration clinically consistent with acute myocardial infarction and 12-lead ECG evidence of anterior infarction (ST-segment elevation of >=2.0 mm in at least two contiguous leads [V1-4]) or nonanterior infarction (ST-segment elevation of >=1.0 mm in at least two contiguous inferior leads [II, III, aVF] or in two contiguous lateral leads [I, aVL >=1.0 mm, or V4-6 >=2.0 mm]). Patients were excluded from the study if they (1) could not receive thrombolytic therapy and study medication within 6 hours of onset of symptoms, (2) had a known serum creatinine level of >=3.0 mg/dL (amended to 2.5 mg/dL near the end of study enrollment on June 28, 1993), (3) were <18 years old, (4) had had a previous myocardial infarction during the current hospitalization, (5) had left bundle-branch block, (6) had any condition that contraindicated the administration of a thrombolytic agent, (7) had a serious, advanced illness with a reduced life expectancy, (8) had a serious infection, (9) had aortic dissection, (10) had received thrombolytic therapy for the qualifying myocardial infarction before entering the study, (11) had received previous treatment with RheothRx Injection, (12) had received Fluosol in the preceding 30 days, or (13) had received 99mTc sestamibi or thallium in the preceding 48 hours.

Randomization
Eligible patients who gave informed consent were randomized in a 2:1 ratio to receive poloxamer 188 (formulated as RheothRx Injection, Burroughs Wellcome Co) or placebo. Study medication was administered immediately after the initiation of thrombolytic therapy and injection of 99mTc sestamibi (see below). Randomization was stratified by infarct location (anterior and nonanterior) based on the enrolling 12-lead ECG. The initial 45 patients enrolled were randomized to receive placebo or a low-dose regimen of poloxamer 188 (150 mg·kg-1·h-1 over 1 hour and then 15 mg·kg-1·h-1 over 47 hours). Once this dose was determined to be safe by a safety committee, the final 69 patients received placebo or a high-dose poloxamer 188 regimen (300 mg·kg-1·h-1 over 1 hour and then 30 mg·kg-1·h-1 over 47 hours). A 48-hour infusion of poloxamer 188 was chosen because prior work in a canine model of 90 minutes of coronary occlusion and 72 hours of reperfusion demonstrated superior reduction in myocardial infarct size with a 48-hour poloxamer 188 infusion compared with a 4-hour infusion or a saline placebo.27

Study medication was packaged by the sponsor in 500-mL glass bottles. Each bottle of RheothRx Injection contained 75 g of poloxamer 188 (150 mg/mL) in buffered saline, resulting in a clear, colorless solution. Placebo consisted of the vehicle for RheothRx Injection. The glass bottles were covered with aluminum foil to maintain blinding of all parties throughout the treatment period.

Thrombolytic and Concurrent Therapy
All patients in this trial received thrombolytic therapy with TPA or streptokinase as soon as possible after presentation. The choice of the thrombolytic agent was at the discretion of the investigator. The recommended regimen for TPA was 100 mg over 3 hours (weight adjusted for patients of <65 kg), although the majority of investigators chose to administer an accelerated regimen over 90 minutes after the release of the GUSTO-1 results.3 For streptokinase, the dose was 1.5 million units over 1 hour. Unless contraindicated, all patients received chewable aspirin, nitrates, and intravenous ß-blockers. Heparin was administered as a 5000-unit bolus immediately after administration of the thrombolytic agent, followed by a continuous infusion for >=48 hours, with the activated partial thromboplastin time adjusted to 1.5 to 2 times the control value. For patients receiving streptokinase, heparin administration could be delayed for <=4 hours. Daily doses of aspirin and ß-blockers were given throughout the study period unless contraindicated.

During the 7-day treatment phase, cardiac catheterization, PTCA, and CABG were discouraged by protocol. However, these invasive procedures were permitted at any time during the study in patients with an urgent clinical indication (ie, persistent ischemic pain after thrombolytic therapy, recurrent myocardial ischemia after reperfusion, or hemodynamic instability) at the discretion of the investigator.

Acquisition of Radionuclide Data
To assess myocardium at risk, 20 to 30 mCi of 99mTc sestamibi (Cardiolite) was injected within 15 minutes after initiation of intravenous thrombolytic therapy. This was followed immediately by infusion of poloxamer 188 (or placebo). Because sestamibi has a very slow washout from the myocardium with minimal redistribution,31 imaging to determine the area at risk for infarction could be delayed for <=6 hours. Imaging was performed when the patient was clinically stable with the use of SPECT. To assess ultimate myocardial infarct size, a second injection of sestamibi and identical tomographic imaging were repeated 5 to 7 days later.

Tomographic acquisitions were obtained with a rotating single-headed gamma camera and a circular orbit. Thirty images were acquired for 40 seconds each over a 180° arc, starting in a 45° right anterior oblique projection and ending in a 45° left posterior oblique projection. The nuclear cardiology laboratories in all participating centers performed standardized quality control tests of system uniformity, collimator quality, and gantry alignment on their gamma camera systems that were reviewed at a core laboratory (Mayo Clinic). They also performed nine studies on a cardiac phantom to demonstrate their ability to replicate the results previously reported by the core laboratory.32 As reported elsewhere,33 the correlation coefficient relating true and measured defect size in these experiments was .995±.008; the mean error in estimating defect size was 2.1±0.7% of the LV.

To assess global LV function before discharge, a resting equilibrium radionuclide angiogram was performed >=48 hours before, or 24 hours after, the second sestamibi scan (5 to 7 days after randomization).

Analysis of Imaging Data
Analysis of myocardium at risk and final infarct size were assessed by personnel at the core laboratory (Mayo Clinic, Rochester, Minn) who were without knowledge of the treatment assignment. Sestamibi images were reconstructed with standard back-projection algorithms and a Ramp-Hanning filter.34 Quantification of the area of absent perfusion was performed with a five-slice technique.35 Short-axis slices of the LV were obtained every 6 mm and normalized to the peak counts in each slice. The apical and basal slices were chosen according to predetermined rules. The three remaining short-axis slices were spaced equally between the apical and basal slices. Count profiles were generated for the five representative short-axis slices by identifying the highest counts in every 6° sector around the circumference of the LV and normalizing this value in relation to the peak counts in the profile. With this method, we defined (1) myocardium at risk (percent of LV) as acute perfusion defect (initial SPECT sestamibi scan), (2) final infarct size (percent of LV) as final perfusion defect (days-5-to-7 SPECT sestamibi scan), and (3) myocardial salvage (percent of LV) as acute perfusion defect minus final perfusion defect.

This method of quantification of myocardium at risk and final infarct size has been previously validated in cardiac phantoms32 and in animal models of permanent coronary occlusion36 and reperfusion.37 The limit for detection of infarction by this technique has been shown to be 3% of the LV.34 This infarct size measurement correlates closely with other parameters that have been used clinically to estimate infarct size, including global and regional LV function,34 38 39 40 201Tl infarct size,41 42 and myocardial enzyme release.39 Most recently, infarct size measured with this technique has been significantly correlated (r=.80) with end-systolic volume measured with cine CT scanning 1 year later43 and with both overall mortality (P=.003) and cardiac mortality (P<.001) over the next 2 years.44 Infarct size measured by tomographic perfusion imaging with 99mTc sestamibi is closely correlated (r=.95, P=.002) with the scar size quantified through pathology in explanted human hearts at the time of cardiac transplantation.45

Analysis of the radionuclide angiograms was performed at each participating institution according to standard methods46 by physicians without knowledge of the treatment assignment.

Poloxamer 188 Plasma Samples
Blood samples (five or six per patient) were taken at various times during and after the infusion of the study medication using a population pharmacokinetics design. Plasma was harvested and frozen at -20°C until analysis at Burroughs Wellcome Co. These data will be combined with data from other clinical trials of RheothRx Injection for the population pharmacokinetic analysis; no concentration results are reported here.

Study Objective
The primary objective of this study was to evaluate the safety of RheothRx Injection (poloxamer 188 N.F.) compared with placebo in patients receiving thrombolytic therapy for acute myocardial infarction. Safety was assessed through periodic monitoring of ECG, laboratory values, and physical examination. In addition, information regarding adverse experiences and bleeding events were collected through hospital day 7 or to discharge, whichever came first. Major bleeding was defined as any intracranial hemorrhage documented through CT scanning or bleeding from any site that caused hemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical intervention. All other bleeding was classified as "minor."

A unique efficacy end point of this study was the assessment of myocardial infarct size and salvage through the use of SPECT imaging with 99mTc sestamibi, according to methods described. In addition, global LV ejection fraction was assessed through the use of radionuclide angiography performed at days 5 to 7 after randomization. Clinical efficacy end points included in-hospital death, cardiogenic shock, heart failure, reinfarction, and recurrent myocardial ischemia.

Cardiogenic shock was diagnosed if the systolic blood pressure fell to <90 mm Hg for >1 hour (unresponsive to fluid resuscitation alone) and the patient had clinical evidence of hypoperfusion despite adequate or elevated filling pressure. Heart failure was diagnosed if there were signs and symptoms (dyspnea, rales, peripheral edema, orthopnea, jugular venous distention, S3 gallop) believed to be secondary to cardiac dysfunction and there was evidence of pulmonary congestion on chest radiography. Reinfarction was diagnosed if any two of the following criteria were met: symptoms of myocardial ischemia persisting >15 minutes and occurring after resolution of the symptoms associated with the qualifying myocardial infarction, occurrence of new ST-T wave changes or new Q waves, a second elevation of CK-MB isoenzymes above the upper limit of the reference range (or, if the CK-MB was already elevated, a further increase of >20%), and angiographic evidence of occlusion of a previously patent (angiographically proven) infarct-related artery. Recurrent myocardial ischemia was diagnosed if in the absence of an exercise stress test the patient had ECG evidence of ischemia and either symptoms of myocardial ischemia or new hypotension or pulmonary edema believed to be secondary to myocardial ischemia.

Statistical Analysis
Differences between the study groups with respect to efficacy end points (eg, infarct size, myocardial salvage, LV ejection fraction) were analyzed with the use of a linear model with the following protocol-specified covariates: infarct location (anterior versus nonanterior), thrombolytic agent (streptokinase versus TPA), and time from chest pain onset to administration of thrombolytic. Myocardium at risk was also included as a covariate for the analysis of infarct size. As specified in the study protocol, patients with no coronary artery disease were excluded from all efficacy analyses. Also, as specified in the study protocol, SPECT data were excluded from analysis if the data suggested that reperfusion occurred before the administration of sestamibi (myocardium at risk was <20% of the LV for anterior infarcts or <5% of the LV for nonanterior infarcts) or that sestamibi was administered improperly.

Because of the skewness of the data, results are expressed as medians and interquartile ranges. Although the values of infarct size and ejection fraction were skewed, the residuals from the linear models were normally distributed. Results are shown for the high- and low-dose regimens pooled because the treatment effects were similar for the two dose regimens. Treatment comparisons of binary variables were done with the use of Fisher's exact test. The treatment comparison for myocardium at risk was done with a Wilcoxon rank sum test. For within-subgroup comparisons (low dose versus high dose, location of infarction, and thrombolytic agent used), no statistical analysis was performed, and the summary statistics are cited for descriptive purposes only. Values of P<.05 were considered statistically significant. All P values were two sided.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowAppendix
 down arrowReferences
 
Study Population
Of the 114 patients enrolled in the trial, 75 were randomized to receive poloxamer 188 and 39 to receive placebo, consistent with the protocol-specified 2:1 randomization scheme. Baseline characteristics were not significantly different between the two groups (Table 1Down). Anterior infarction occurred in 47% of poloxamer 188–treated patients and in 44% of those receiving placebo (P=NS). All patients in the trial received a thrombolytic agent. The treating physician administered TPA in 57% of the poloxamer 188 group and in 56% of the placebo group, with the remaining patients receiving streptokinase. The mean time from onset of chest pain to administration of the thrombolytic agent was comparable in the two groups: 2.9 hours in the poloxamer 188 group and 2.7 hours in the placebo group. The mean time from onset of chest pain to initiation of the study drug was also similar: 3.2 hours in the poloxamer 188 group and 3.0 hours in the placebo group. Likewise, the mean time from beginning the thrombolytic agent to starting the infusion of the study drug was similar: 0.27 hours in the poloxamer 188 group and 0.33 hours in the placebo group. ß-Blocker therapy was received by 85% of both groups; aspirin was administered to 100% of the poloxamer 188 group and 97% of the placebo group. All patients received intravenous heparin according to protocol.


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  		Table 1. Clinical Characteristics of Study Population

Patients were excluded from the efficacy analysis if they met criteria prespecified in the protocol (Table 2Down). One patient (placebo group) was excluded from all efficacy analyses because of the absence of evidence of coronary artery disease. Three patients (one from the poloxamer 188 group and two from the placebo group) were excluded from the analysis of infarct size and salvage because there was evidence of reperfusion before the initial sestamibi injection (see "Statistical Analysis"). Additional data not included in the efficacy analysis were obtained from patients with missing values (due to death or technical problems).


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  		Table 2. Patients Excluded From Analysis

Safety Findings
Evaluation of safety was the major study objective, and both low- and high-dose poloxamer 188 regimens were found to be well tolerated. The initial 1-hour infusion of poloxamer 188 was also not associated with any untoward effects on blood pressure or heart rate.

Stroke occurred in 3 of 75 (4%) poloxamer 188–treated patients (nonhemorrhagic and nonfatal in 2, hemorrhagic and fatal in 1) but in none of the 39 placebo-treated patients (P=.550, by two-sided Fisher's exact test). There was no statistically significant difference in major or minor bleeding events in the two groups. Blood transfusion (not due to CABG) was required in 5 of 75 (7%) of the poloxamer 188 group and in 4 of 39 (10%) of the placebo group. Mean hemoglobin loss was also similar in the two groups: 3.3±1.8 in the poloxamer 188–treated group versus 3.0±1.5 in the placebo group (P=.274).

Reversible elevations (>2.0 mg/dL) of serum creatinine at study days 5 to 7 were noted in 4 of 75 (5%) poloxamer 188–treated patients and in none of the 39 placebo-treated patients (P=.297). Mean serum creatinine values were not different between treatment groups. Other clinical laboratory tests (including electrolytes, glucose, white blood cell count, neutrophil count, hemoglobin, platelet count, and liver function tests) were unaffected by treatment. No statistically significant differences were observed between poloxamer 188–treated and placebo-treated patients with respect to acute myocardial infarction–related events (eg, fever, arrhythmias, hypotension, vomiting) or adverse experiences (eg, headache, back pain, confusion, dizziness).

Invasive Procedures
Coronary angiography was performed in 51% of the placebo group and 41% of poloxamer 188 group (Table 3Down). Although more poloxamer 188–treated patients subsequently underwent PTCA (31% versus 18%, P=.184), only seven PTCA procedures (four [5.3%] in poloxamer 188–treated patients and three [7.9%] in placebo-treated patients) were performed for urgent indications (within 12 hours of treatment initiation because of ongoing ischemia after thrombolytic therapy or for recurrent myocardial ischemia after reperfusion), when they would be most likely to affect reinfarction rate, infarct size, and ejection fraction. The remainder underwent PTCA for elective indications, soon before hospital discharge in most cases. CABG was performed during the hospital stay in 8.0% of the poloxamer 188 group and in 7.9% of the placebo group. The need for urgent revascularization (PTCA or CABG) was comparable: 8.0% of the poloxamer 188 group and 7.9% of the placebo group. Intra-aortic balloon pump placement was required in 8% of the placebo group and 4% of poloxamer 188 group.


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  		Table 3. Revascularization Procedures Performed

Nuclear Medicine Assessments
The median myocardium at risk, as assessed with sestamibi injection before reperfusion (Fig 1Down), was 36% of the LV in the poloxamer 188 group and 28% of the LV in the placebo group (P=.85). Despite a slightly larger myocardium at risk, median infarct size (assessed with sestamibi injection at days 5 to 7 after infarction) was significantly smaller in poloxamer 188–treated patients than in placebo-treated patients (16% versus 26% of the LV, P=.031). Poloxamer 188–treated patients also demonstrated substantially greater myocardial salvage than placebo-treated patients (Fig 2Down). Median myocardial salvage was 13% of the LV in the poloxamer 188 group but only 4% of the LV in the placebo group (P=.033). Both the low- and high-dose poloxamer 188 regimens were associated with greater myocardial salvage than their respective placebo-control groups. The low-dose poloxamer 188 group had a median myocardial salvage of 11% compared with only 4% salvage in the corresponding placebo group. The high-dose poloxamer 188 group also had greater salvage than the corresponding placebo group (13% versus 10%), although the higher dose of poloxamer 188 did not appear to confer any additional benefit.



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  		Figure 1. Box plot demonstrating the myocardium at risk and myocardial infarct size (expressed as a percentage of the LV) in poloxamer 188– and placebo-treated patients. Measurements were obtained with SPECT sestamibi scanning before reperfusion (myocardium at risk) and at 5 to 7 days after infarction (infarct size). Bottom and top borders, interquartile ranges (25th and 75th percentiles). The P value for the treatment comparison of infarct size is after adjustment for myocardium at risk, infarct location, thrombolytic agent, and time from onset of chest pain to initiation of thrombolytic therapy. The adjusted estimate of the treatment difference (poloxamer 188 minus placebo) in infarct size is 6.5 with 95% CI (0.7, 12.3).



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  		Figure 2. Box plot demonstrating myocardial salvage (expressed as a percentage of the LV) in poloxamer 188– and placebo-treated patients. Myocardial salvage was calculated as the difference between the myocardium at risk and the final infarct size. Bottom and top borders, interquartile ranges (25th and 75th percentiles). The P value for the treatment comparison of myocardial salvage is after adjustment for infarct location, thrombolytic agent, and time from onset of chest pain to initiation of thrombolytic therapy. The adjusted estimate of the treatment difference (poloxamer 188 minus placebo) in myocardial salvage is 6.5 with 95% CI (0.6, 12.4).

LV function, assessed through radionuclide angiography at days 5 to 7 after infarction (Fig 3Down), also was found to be superior in the poloxamer 188–treated group. Median LV ejection fraction was 52% in the poloxamer 188 patients and 46% in the placebo-treated patients (P=.020). Both the low- and high-dose poloxamer 188 regimens also had higher ejection fractions than their respective placebo groups (51% versus 46% for the high-dose regimen and 55% versus 46% for the low-dose regimen).



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  		Figure 3. Box plot demonstrating the global LV ejection fraction in poloxamer 188– and placebo-treated patients. Measurements were obtained through radionuclide angiography performed 5 to 7 days after infarction. Bottom and top borders, interquartile ranges (25th and 75th percentiles). The P value for the treatment comparison of ejection fraction is after adjustment for infarct location, thrombolytic agent, and time from onset of chest pain to initiation of thrombolytic therapy. The adjusted estimate of the treatment difference (poloxamer 188 minus placebo) in ejection fraction is 6.4 with 95% CI (1.1, 11.6).

When patients who underwent urgent (ongoing ischemic chest pain within 12 hours of thrombolytic therapy or recurrent ischemic pain after reperfusion) PTCA or CABG were excluded, the P values for the adjusted treatment comparisons were essentially unchanged (P=.037 for infarct size, P=.046 for myocardial salvage, P=.016 for ejection fraction).

Myocardial Salvage in Prespecified Subgroups
Concurrent infusion of poloxamer 188 resulted in greater myocardial salvage compared with placebo, regardless of the thrombolytic agent used. Median salvage (25th through 75th percentile) for the poloxamer 188 group versus the placebo group was 16% (9% to 22%, n=35) versus 5% (1% to 18%, n=18) in patients who received TPA and 10% (5% to 16%, n=25) versus 4% (0% to 14%, n=12) in patients who received streptokinase.

As expected, anterior infarcts were associated with considerably greater myocardial salvage compared with nonanterior infarcts.30 However, myocardial salvage was greater with poloxamer 188 treatment than with placebo treatment for both anterior infarcts (19% [15% to 37%, n=28] versus 13% [10% to 32%, n=13]) and nonanterior infarcts (9% [6% to 13%, n=32] versus 3% [1% to 4%, n=17]).

Clinical Outcomes
The incidence of reinfarction was much lower in the poloxamer 188–treated group than in the placebo-treated group (Table 4Down). The placebo group had a reinfarction rate of 13% (5 of 38) compared with 1% (1 of 75) in the poloxamer 188 group (P=.016). Patients with reinfarction met the following criteria: recurrent ischemic pain of >15 minutes' duration, new ST-T wave changes or new Q waves, and a new CK-MB increase of >20% (in two placebo patients and one poloxamer 188 patient); recurrent ischemic pain of >15 minutes' duration and new ST-T wave changes or new Q waves (in two placebo patients); and a new CK-MB increase of >20% and angiographic evidence of reocclusion (in one placebo patient).


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  		Table 4. Clinical Outcomes

No significant differences were observed in the frequencies of in-hospital death, cardiogenic shock, heart failure at days 5 to 7, or recurrent myocardial ischemia.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowAppendix
 down arrowReferences
 
Major Study Findings
The major findings from this randomized, double-blind, placebo-controlled trial are that a 48-hour infusion of poloxamer 188, started soon after the administration of thrombolytic therapy, resulted in significantly smaller infarcts, markedly greater myocardial salvage, and significantly higher predischarge LV ejection fractions compared with the use of placebo. Poloxamer 188 treatment was associated with similar benefits regardless of infarct location, thrombolytic agent administered, or whether a low- or high-dose poloxamer 188 regimen was used. In addition, poloxamer 188–treated patients demonstrated a much lower frequency of in-hospital reinfarction.

Evaluation of safety was the major study objective, and poloxamer 188 was found to be well tolerated. Importantly, in this population of acute myocardial infarction patients receiving thrombolytic therapy, poloxamer 188 was not associated with any alteration in blood pressure or heart rate, and there was no significant increase in the frequency of bleeding complications. Although poloxamer 188 was not associated with any statistically significant evidence of organ toxicity, reversible elevations of serum creatinine occurred in 5% of treated patients. In addition, stroke occurred in 3 of 75 (4%) poloxamer 188–treated patients but in none of the 39 placebo-treated group, which is a higher stroke rate than has been reported in recent trials of thrombolytic therapy.1 2 3 4 Although this result may have occurred by chance given the small sample size, the findings are of potential concern and will require further evaluation in larger future trials of poloxamer 188 in acute myocardial infarction.

Potential Mechanisms of Benefit of Poloxamer 188
Although in this trial we did not investigate the mechanism of action of poloxamer 188 in acute myocardial infarction, several possibilities can be considered. First, poloxamer 188 may accelerate thrombolysis, thus reducing the time to reperfusion and increasing early Thrombolysis in Myocardial Infarction Trial grade 3 patency. In vitro and in vivo models of thrombosis have shown that the addition of poloxamer 188 to either TPA or streptokinase substantially increases the rate of clot lysis.24 25 Poloxamer 188 also has been shown to produce clots that are more susceptible to fibrinolysis,25 by increasing the length of fibrin strands and altering fibrin assembly in vitro. In addition, by reducing adhesive hydrophobic interactions among fibrinogen, fibrin, platelets, and red blood cells, poloxamer 188 may alter thrombus geometry, facilitating thrombolytic delivery and promoting more efficient removal of cleaved products.24 25 The clinical importance of achieving early complete patency was emphasized by the GUSTO Angiographic Investigators,5 who demonstrated that therapies that produce more rapid and complete reperfusion of the infarct-related vessel result in improved ventricular performance and lower mortality. Thus, acceleration of the speed and extent of thrombolysis by poloxamer 188 could have been responsible for the beneficial effects on myocardial salvage, infarct size, and LV function observed in the current trial.

A second beneficial mechanism may involve a secondary antithrombotic effect of poloxamer 188. Despite the absence of anticoagulant or antiplatelet effects, poloxamer 188 has been shown in vivo to reduce adherence of clot to artificial surfaces47 and to reduce the formation of intracoronary thrombus in a pig model of intracoronary stent placement.26 These effects may be due to the ability of poloxamer 188 to reduce the hydrophobic interactions among platelets, fibrin, and red blood cells, which favor clot adherence, and to promote secondary propagation of thrombus.26 This antithrombotic effect may have been largely responsible for the markedly lower incidence of reinfarction (1% in the poloxamer 188 group and 13% in the placebo group) and likely contributed to the findings of greater myocardial salvage, ultimately smaller infarcts, and better predischarge LV function in the current trial.

A third mechanism contributing to the benefits observed with poloxamer 188 therapy in this clinical trial may involve its ability to ameliorate myocardial reperfusion injury. Although reperfusion-induced myocardial necrosis has not been proven clinically,8 there is substantial evidence from several animal models using a variety of therapeutic agents that suggests that this is an important problem.27 48 49 50 51 52 53 The mechanism of reperfusion injury appears to involve an inflammatory response that develops within the reperfused zone immediately on reperfusion and may persist for as long as 24 hours after reperfusion.54 55 In a placebo-controlled dog model of 90 minutes of left anterior descending coronary artery occlusion and 72 hours of reperfusion, our laboratory demonstrated that a 48-hour infusion of poloxamer 188 (started 15 minutes before reperfusion) reduced infarct size by 42% and significantly increased LV ejection fraction.27 A 4-hour infusion of poloxamer 188 was associated with a 25% reduction in infarct size (P=NS) without an associated improvement in LV function. Poloxamer 188 may lessen reperfusion injury via inhibition of neutrophil function.27 56 57 Indeed, Justicz and coworkers53 showed reduced neutrophil infiltration in the reperfused myocardium at 24 hours after infarction in dogs receiving poloxamer 188 compared with control animals. Poloxamer 188 may inhibit neutrophil function through a process of neutrophil activation (initiated by phagocytosis of micelles of poloxamer 188) and subsequent deactivation.27 58 Neutrophils deactivated by poloxamer 188 exhibit diminished chemotaxis27 and impaired release of free radicals when stimulated.56 Thus, after intravenous administration of poloxamer 188, neutrophils would be activated and deactivated in the peripheral circulation, rendering them less harmful to vulnerable postischemic myocytes on reperfusion. Poloxamer 188 may also reduce the "no reflow phenomenon" (impaired microcirculatory blood flow, which contributes to myocardial necrosis after reperfusion59 60 ) by lowering blood viscosity15 and reducing neutrophil adhesiveness.57

A final mechanism that may have contributed to the beneficial effects of poloxamer 188 in this trial could involve enhanced collateral blood flow, as previously demonstrated in a canine model.61 Enhanced collateral flow would be expected to improve oxygen delivery and lessen myocardial ischemia after drug administration but before adequate coronary patency was achieved. Although its beneficial hemorheological and antineutrophil properties suggest that poloxamer 188 would improve collateral blood flow, recent research from our laboratory in a canine model of 3 hours of coronary artery occlusion and 3 hours of reperfusion failed to demonstrate any significant improvement in collateral blood flow when poloxamer 188 was administered during the final 2 hours of coronary occlusion.62

Other Clinical Studies of Poloxamer 188 in Acute Myocardial Infarction
A companion study to the present thrombolytic trial evaluated the benefits of adjunctive therapy with poloxamer 188 in patients undergoing primary PTCA for acute myocardial infarction. The PTCA trial randomized 150 patients to the high-dose poloxamer 188 regimen (300 mg·kg-1·h-1 over 1 hour, then 30 mg·kg-1·h-1 over 47 hours) or placebo in a 2:1 ratio. Drug was administered before PTCA-induced reperfusion, and the study end points were identical to those of the present trial. The preliminary results of the PTCA trial presented previously63 demonstrated no significant differences between the treatment groups in infarct size, myocardial salvage, LV ejection fraction, or incidence of reinfarction.

Poloxamer 188 has been administered in two clinical trials of acute myocardial infarction as a component of Fluosol therapy,64 65 with differing results. Fluosol is a synthetic, acellular, oxygen-carrying perfluorochemical emulsion66 67 that contains 2.7% (27 mg/mL) poloxamer 188 used as an emulsifying agent. In a randomized pilot trial of patients (n=12) with anterior myocardial infarction, Forman and coworkers64 tested intracoronary Fluosol (40 mL/min over 30 minutes) immediately after primary PTCA. They found treatment to be associated with a significant reduction in infarct size and improvement in regional ventricular function. The mechanism of benefit was not investigated but was suggested to involve inhibition of neutrophil function and enhanced oxygen delivery to the reperfused microcirculation. In a more recent and larger randomized trial, TAMI-9,65 the benefits of intravenous Fluosol were studied as an adjunct to thrombolytic therapy (TPA) in acute myocardial infarction. Patients (n=430) were randomized to receive Fluosol (15 mL/kg IV over 1 hour begun after thrombolytic administration) plus 100% inspired oxygen, or no Fluosol. In contrast to the Fluosol/PTCA pilot trial64 and the present trial of poloxamer 188 and thrombolytic therapy, the Thrombolysis in Acute Myocardial Infarction 9 trial failed to show any significant benefits of Fluosol therapy on infarct size or ventricular function. However, Fluosol therapy was associated with a significant reduction in recurrent ischemic episodes and a trend toward reduced reinfarction. Not surprisingly given the large volume load, the incidence of congestive heart failure or pulmonary edema was significantly greater in the Fluosol-treated patients compared with control patients.

The preliminary results of two additional randomized trials of poloxamer 188 in acute myocardial infarction were recently reported. In a study by Weaver,68 patients with suspected acute myocardial infarction who were not candidates for thrombolytic therapy or primary PTCA (primarily because of nondiagnostic ECGs) were randomized to a 48-hour infusion of poloxamer 188 or placebo. The trial was terminated early because poloxamer 188 treatment was associated with an increased frequency of renal dysfunction. No beneficial effects of treatment were observed in these nonreperfused patients. In a preliminary report by Yusuf,69 various dosing regimens of poloxamer 188 were evaluated in acute myocardial infarction patients presenting with ST elevation or bundle-branch block. An increased incidence of renal dysfunction was observed in patients with baseline creatinine of >1.5 mg/dL or age of >75 years and in those receiving higher doses of poloxamer 188. This necessitated modification of the study protocol to exclude patients with a creatinine level of >1.5 mg/dL or age of >=75 years and to restrict the poloxamer 188 treatment regimens to those with lower doses.

Study Limitations
A potential limitation of the present trial is the more frequent use of PTCA in the poloxamer 188 group compared with the placebo group (31% versus 18%, P=.184). This could have confounded the results by lowering the incidence of reinfarction and beneficially impacting infarct size and ejection fraction in the treated group. We believe this to be unlikely because the majority of PTCA procedures in the poloxamer 188 group were performed for elective indications at 5 to 7 days after infarction, a time when reinfarction would be less likely. Although the protocol discouraged PTCA during the 7-day study period unless an urgent indication existed, many investigators chose to revascularize patients before hospital discharge for elective indications.

Another limitation of the present trial was the fact that some enrolled patients were excluded from some measures of efficacy (Table 2Up), including 12.3% who were excluded from infarct size assessment, 21.1% who were excluded from myocardial salvage assessment, and 16.7% who were excluded from ejection fraction assessment. Although this is a sizable number of exclusions, especially for a small trial, we do not believe that these exclusions importantly confound our results because the incidence of exclusion for each measure of efficacy was similar in both groups, and all exclusion criteria were prespecified in the study protocol.

Conclusions
This randomized, prospective, double-blind, placebo-controlled trial demonstrated that the addition of poloxamer 188 to treatment with TPA or streptokinase resulted in smaller myocardial infarcts, greater myocardial salvage, superior LV function, and a lower incidence of in-hospital reinfarction than did treatment with TPA or streptokinase alone. Although the mechanisms of benefit were not investigated in this trial, poloxamer 188 may enhance early coronary patency by accelerating the time to thrombolysis, may reduce reinfarction by an antithrombotic effect, and may contribute to reduced myocardial infarct size and improved LV function by reducing reperfusion injury. Poloxamer 188 was well tolerated in this trial without adverse hemodynamic effects or significant organ toxicity. The beneficial actions of poloxamer 188 will require confirmation in subsequent trials.


*    Appendix
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *Appendix
down arrowReferences
 
Investigators and Institutions
Leo J. Spaccavento, MD, University Medical Center of Southern Nevada, Las Vegas, Nev; Daniel Krichbaum, PharmD, Bruce M. Abramowitz, MD, Ann Reda, RN, Christ Hospital and Medical Center, Oak Lawn, Ill; Kevin F. Browne, MD, Lakeland Regional Medical Center, Lakeland, Fla; John M. Phelan, MD, Sue Brown, RN, Rush North Shore Medical Center, Skokie, Ill; Gary L. Schaer, MD, Clifford Kavinsky, MD, R. Jeffrey Snell, MD, Tess Maloney, RN, Luz Ramirez-Morgen, RN, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill; William O. Fletcher, MD, Appleton Medical Center, Appleton, Wis; Cindy L. Grines, MD, William Beaumont Hospital, Royal Oak, Mich; Peter B. Kurnik, MD, Memorial Hospital of Burlington County, Mount Holly, NJ; Mitchell Greenspan, MD, Grandview Hospital, Sellersville, Pa; Marcus A. DeWood, MD, Sacred Heart Medical Center, Spokane, Wash; John M. Kalbfleisch, MD, St Francis Hospital, Tulsa, Okla.

Nuclear Medicine Core Laboratory
Raymond J. Gibbons, MD, Timothy C. Christian, MD, Todd D. Miller, MD, Mayo Clinic, Rochester, Minn.


*    Selected Abbreviations and Acronyms
 
CK = creatine kinase
LV = left ventricular, ventricle
SPECT = single-photon emission computed tomography
TPA = tissue-type plasminogen activator


*    Acknowledgments
 
The study was supported by a grant from Burroughs Wellcome Co (Research Triangle Park, NC).


*    Footnotes
 
Reprint requests to Dr Gary L. Schaer, Director, Cardiac Catheterization Laboratories, Rush-Presbyterian-St Luke's Medical Center, 1653 W Congress Pkwy, Chicago, IL 60612. E-mail GSchaer@RUSH.edu.

Presented in part at the 43rd Scientific Sessions of the American College of Cardiology, Atlanta, Ga, March 13-17, 1994.

Received October 26, 1995; revision received February 8, 1996; accepted February 16, 1996.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 up arrowAppendix
 *References
 

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