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Original Article
Volume 328:673-679 March 11, 1993 Number 10
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A Comparison of Immediate Angioplasty with Thrombolytic Therapy for Acute Myocardial Infarction
Cindy L. Grines, Kevin F. Browne, Jean Marco, Donald Rothbaum, Gregg W. Stone, James O'Keefe, Paul Overlie, Bryan Donohue, Noah Chelliah, Gerald C. Timmis, Ronald E. Vlietstra, Michelle Strzelecki, Sylvia Puchrowicz-Ochocki, William W. O'Neill, for The Primary Angioplasty in Myocardial Infarction Study Group

 

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ABSTRACT

Background The success of thrombolytic therapy for acute myocardial infarction is limited by bleeding complications, the impossibility of reperfusing all occluded coronary arteries, recurrent myocardial ischemia, and the relatively small number of patients who are appropriate candidates for this therapy. We hypothesized that these problems could be overcome by the use of immediate percutaneous transluminal coronary angioplasty (PTCA), without previous thrombolytic therapy.

Methods At 12 clinical centers, 395 patients who presented within 12 hours of the onset of myocardial infarction were treated with intravenous heparin and aspirin and then randomly assigned to undergo immediate PTCA (without previous thrombolytic therapy, 195 patients) or to receive intravenous tissue plasminogen activator (t-PA, 200 patients) followed by conservative care. Radionuclide ventriculography was performed to assess ventricular function within 24 hours and at six weeks.

Results Among the patients randomly assigned to PTCA, 90 percent underwent the procedure; the success rate was 97 percent, and no patient required emergency coronary-artery bypass surgery. The in-hospital mortality rates in the t-PA and PTCA groups were 6.5 and 2.6 percent, respectively (P = 0.06). In a post hoc analysis, the mortality rates in the subgroups classified as "not low risk" were 10.4 and 2.0 percent, respectively (P = 0.01). Reinfarction or death in the hospital occurred in 12.0 percent of the patients treated with t-PA and 5.1 percent of those treated with PTCA (P = 0.02). Intracranial bleeding occurred more frequently among patients who received t-PA than among those who underwent PTCA (2.0 percent vs. 0 percent, P = 0.05). The mean (±SD) ejection fractions at rest (53 ±13 percent vs. 53 ±13 percent) and during exercise (56 ±13 percent vs. 56 ±14 percent) were similar in the t-PA and PTCA groups at six weeks. By six months, reinfarction or death had occurred in 32 patients who received t-PA (16.8 percent) and 16 treated with PTCA (8.5 percent, P = 0.02).

Conclusions As compared with t-PA therapy for acute myocardial infarction, immediate PTCA reduced the combined occurrence of nonfatal reinfarction or death, was associated with a lower rate of intracranial hemorrhage, and resulted in similar left ventricular systolic function.

Since the completion of the large, randomized, placebo-controlled trials of thrombolytic therapy, reperfusion therapy for acute myocardial infarction has become the standard of care1,2,3,4,5,6,7. However, the drawbacks of this therapy include failure to achieve arterial patency in 20 percent of cases,8,9,10,11,12 serious bleeding complications,13 and an increased incidence of recurrent ischemia2,3,4,7,14. Because of these limitations, there has been increasing interest in the use of immediate percutaneous transluminal coronary angioplasty (PTCA) as an alternative to thrombolytic therapy in patients with acute myocardial infarction.

Immediate PTCA is associated with early patency rates exceeding 90 percent, and low rates of serious bleeding, recurrent ischemia, and death15,16,17,18,19. Since small randomized trials20,21,22,23 in which patients are assigned to either immediate PTCA or thrombolytic therapy lack the statistical power to detect differences in clinical outcome, we organized an international multicenter study to compare these two approaches to treatment. Our hypothesis was that, as compared with intravenous thrombolytic therapy and "watchful waiting," immediate PTCA would reduce the frequency of recurrent ischemia, death, and serious bleeding complications and would improve ventricular function.

Methods

Selection of Patients

Patients of any age who presented within 12 hours of the onset of ischemic chest pain were considered for enrollment if ST-segment elevation of at least 1 mm was present in two or more contiguous electrocardiographic leads. The exclusion criteria included an inability to provide informed consent, dementia, complete left bundle-branch block, cardiogenic shock, and a higher-than-normal risk of bleeding8,9,10.

Study Protocol

Patients were initially treated with oxygen, intravenous nitroglycerin, aspirin (325 mg, chewed), and intravenous heparin (given as a 10,000-unit bolus). After informed consent was obtained, randomization was performed by means of sealed envelopes. Patients assigned to receive thrombolytic therapy received tissue plasminogen activator (t-PA; Activase) at a dose of 100 mg (or 1.25 mg per kilogram of body weight for patients weighing less than 65 kg) over three hours. After the initiation of therapy with t-PA, the patients were managed conservatively according to protocol 2B of the Thrombolysis in Myocardial Infarction (TIMI) trial24. Patients randomly assigned to PTCA underwent immediate diagnostic catheterization. Angiographic criteria for exclusion from PTCA included stenosis of the left main coronary artery of more than 70 percent (not protected by collateral circulation) and, if the infarct-related vessel was patent, critical three-vessel disease or morphologic features of the lesion known to indicate high risk25. Bypass surgery was recommended for these high-risk patients. Patients were also excluded if they appeared unlikely to benefit from PTCA, because the infarct-related vessels were small, there was stenosis of less than 70 percent, or the infarct-related vessel could not be identified. If the patient was eligible for PTCA, additional heparin was administered (5000 to 10,000 units), and angioplasty was performed with use of exchangeable guide-wire systems; an attempt was made to reduce the degree of residual stenosis at all lesions within the infarct-related vessel to less than 50 percent, with restoration of flow.

In both treatment groups, intravenous heparin was administered for three to five days, with the dose adjusted to achieve a therapeutic level of anticoagulation (partial-thromboplastin time, 1.5 to 2 times the control value, or activated clotting time, 160 to 200 seconds). Patients were routinely treated with intravenous nitroglycerin for at least 24 hours, followed by topical or oral nitrates, aspirin (325 mg by mouth daily), and diltiazem (30 to 60 mg by mouth four times a day). The use of beta-blockers and intravenous lidocaine was left to the discretion of the investigator.

Radionuclide ventriculography was performed within 24 hours of admission while the patients were at rest. Before hospital discharge, treadmill exercise testing (according to the modified Bruce protocol) was performed with single-photon-emission computed tomography and thallium imaging. Radionuclide ventriculography was also performed, both at rest and during exercise, at six weeks. Cardiac medications were not discontinued for either exercise study.

Definitions of Ischemia and Infarction and Indications for Unscheduled Catheterization

Unscheduled catheterization was allowed in cases of failure of thrombolysis, recurrence of unstable ischemia, or abnormal results on a submaximal exercise test. Failure of thrombolysis was defined as continued chest pain with ST-segment elevation more than 120 minutes after the initiation of thrombolytic therapy. At the time of catheterization, it was recommended that "rescue" angioplasty (angioplasty performed after the failure of thrombolysis) be performed if the vessel had TIMI grade 0 to 1 flow26 but that angioplasty be deferred if the vessel was patent. Recurrent ischemia was defined as ischemic chest pain lasting more than 20 minutes despite nitrate therapy with either new ST-segment or T-wave changes, new pulmonary edema, a holosystolic murmur, or hypotension. Reinfarction was defined as recurrent chest pain lasting more than 30 minutes with new ST-segment elevation and either emergency angiographic confirmation of an occluded vessel or recurrent elevation of cardiac enzymes.

Data Collection and Assessment

Data were collected prospectively by research nurses at each of the 12 clinical centers. An independent nurse monitor traveled to each site to review all medical charts, with close attention to ischemic end points. All electrocardiograms were independently reviewed by a physician to ensure that patients met the criteria for an ischemic end point. Cineangiograms were reviewed at a central laboratory to assess the coronary anatomy, visually estimate TIMI flow grades, and determine the degree of stenosis by means of a computerized edge-detection algorithm27. Successful angioplasty was defined as resulting in residual stenosis of less than 50 percent with TIMI grade 2 or 3 flow. The Data and Safety Monitoring Committee, comprising cardiologists who were not active participants in the clinical trial, performed an interim analysis after the first 200 patients were enrolled and recommended that the trial continue to completion.

Statistical Analysis

The sample size was calculated on the assumption that recurrent ischemia or death would occur in 25 percent of the patients who received t-PA24 and in 12 percent of those who underwent immediate PTCA28. Thus, 185 patients were required in each group in order to test for a 13 percent difference with a power of 0.8. Analyses were made on an intention-to-treat basis. In addition, in a post hoc analysis, patients were subgrouped as "low risk" or "not low risk" (the latter was defined as those with anterior infarction, an age of more than 70 years, or a heart rate more than 100 beats per minute at admission)24. Categorical variables were compared by chi-square analysis and continuous variables by Student's t-test29. All P values are two-tailed.

Results

Characteristics of the Patients

Between June 1990 and April 1992, 395 patients were enrolled; 195 were randomly assigned to undergo immediate PTCA, without thrombolytic therapy, and 200 to receive intravenous t-PA. If the criteria of phase 2B of the TIMI trial24 had been applied in our study, 107 patients whom we enrolled would have been excluded because they were older than 75 years or because more than four hours had elapsed since the onset of chest pain. The two treatment groups were closely matched in terms of base-line characteristics (Table 1). The mean length of time from the onset of symptoms to randomization was similar in the two groups. After randomization, it required an average of 32 minutes to start t-PA therapy and 60 minutes to perform angiography in the infarct-related vessel (P = 0.001). Since early angiography was not performed in the t-PA group, the actual time to reperfusion could not be determined. However, chest pain resolved more quickly in the PTCA group (mean [±SD] total duration of chest pain, 290 ±174 minutes) than in the group treated with t-PA (354 ±241 minutes, P = 0.004).

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  		Table 1. Base-Line Characteristics of the Patients.

 
Angiography and PTCA

Of the 195 patients randomly assigned to the PTCA group, all underwent diagnostic angiography. On the basis of the predetermined exclusion criteria, 20 patients (10.3 percent) did not undergo angioplasty. Nine of these patients were considered unlikely to benefit from PTCA because the residual stenosis was minimal (eight patients) or because the occluded vessel supplied a small amount of myocardium (one patient); in one patient the investigator did not perform the PTCA according to the protocol because the infarct-related vessel had been reperfused and the patient was asymptomatic. Another 10 patients were considered to be at high risk for complications associated with PTCA; 9 of them were referred for emergency bypass grafting, and the remaining patient was treated with intracoronary thrombolysis.

The anatomical features of the coronary artery were suitable for the performance of PTCA in 175 patients, and the procedure was successful in 170 (97.1 percent). PTCA was partially successful (flow was restored, but with residual stenosis of more than 50 percent) in four patients (2.3 percent). The vessel remained occluded in one patient (0.6 percent). No patient required emergency bypass grafting because of the failure of PTCA. Among the 195 patients randomly assigned to PTCA, patency was achieved through spontaneous reperfusion, emergency bypass grafting, or angioplasty in 193 (99.0 percent).

Clinical Outcome

In-hospital events are summarized in Table 2. Hemorrhagic strokes occurred more commonly in patients who received t-PA (2.0 percent vs. 0 percent, P = 0.05). The need for blood transfusions was similar in the PTCA and t-PA groups. The most common causes of bleeding among patients assigned to undergo PTCA were emergency bypass grafting in patients in whom PTCA was not performed and complications at the access site. None of the bleeding episodes in the PTCA group were fatal. Serious bleeding episodes in patients who received t-PA occurred at gastrointestinal or intracranial sites or in association with bypass surgery. Four of the deaths in the t-PA group were attributed to intracranial hemorrhage. Ventricular fibrillation (6.7 percent vs. 2.0 percent, P = 0.02) and the need for vascular surgical repair (2.1 percent vs. 0 percent, P = 0.05) occurred more often among PTCA-treated patients than among those who received t-PA.

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  		Table 2. Clinical Events during Hospitalization.

 
Chest pain in the absence of electrocardiographic changes (non-ischemic chest pain) occurred in 8 patients (4.1 percent) in the PTCA group, as compared with 11 in the t-PA group (5.5 percent, P = 0.52). Reinfarction occurred in 2.6 percent of the patients in the PTCA group and 6.5 percent in the t-PA group (P = 0.06) (Table 3). Recurrent ischemia (including reinfarction) occurred in 20 patients assigned to PTCA (10.3 percent), as compared with 56 assigned to receive t-PA (28.0 percent, P<0.001). The in-hospital mortality rates in the PTCA and t-PA groups were 2.6 and 6.5 percent, respectively (P = 0.06), and nonfatal reinfarction or death occurred in 5.1 and 12.0 percent (P = 0.02). The benefit of immediate PTCA in terms of mortality was seen mainly among patients who were classified as "not low risk" according to predefined criteria (Table 3)24. All five deaths in the PTCA group were due to cardiac causes. Four deaths in the t-PA group were due to intracranial bleeding, and the remaining nine deaths were due to cardiac causes. The mean length of the hospital stay was shorter in the PTCA group (7.5 ±3.3 days) than in the t-PA group (8.4 ±4.6 days, P = 0.03). By six months, death had occurred in 3.7 percent of the patients in the PTCA group and 7.9 percent in the t-PA group (P = 0.08), and either death or nonfatal reinfarction had occurred in 8.5 and 16.8 percent, respectively (P = 0.02).

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  		Table 3. In-Hospital Reinfarction and Death.

 
Unscheduled Catheterization

Unscheduled catheterization was performed in 26 patients assigned to PTCA (13.3 percent), as compared with 126 assigned to receive t-PA (63 percent, P<0.001) (Table 4). Unscheduled PTCA was performed in 12 patients assigned to receive PTCA (6.2 percent) and in 72 patients assigned to receive t-PA (36.0 percent, P<0.001). Indications for PTCA in the patients treated with t-PA were the failure of thrombolysis in 14 (7 percent), recurrent unstable ischemia in 35 (12.5 percent), and a positive exercise test in 15 (7.5 percent). Eight patients underwent PTCA for chest pain without electrocardiographic changes or because of the preference of the physician.

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  		Table 4. Indications for Unscheduled Invasive Procedures.

 
Coronary-artery bypass grafting was performed in 16 patients in the PTCA group (8.2 percent) and in 24 in the t-PA group (12.0 percent, P = 0.21). The indications for bypass grafting in the PTCA group were the failure of elective PTCA (1 patient), recurrent unstable angina (4 patients), and high-risk anatomical features, determined on catheterization, in 11 patients who were clinically stable. Among the 24 patients in the t-PA group who underwent bypass grafting, immediate PTCA had failed in 2, 5 had recurrent unstable angina, 2 had mechanical defects, and 15 had high-risk coronary anatomical features.

Exercise Testing

Exercise testing was performed before discharge in 281 of the 377 surviving patients (74.5 percent) (Table 5). None of the patients who underwent bypass surgery had exercise testing. A greater proportion of patients in the t-PA group than in the PTCA group underwent PTCA that was not called for in the study protocol before exercise testing (19.4 vs. 2.7 percent, P<0.001). Exercise workload and duration were similar in the two groups. Exercise testing was clinically positive in 8.6 percent of the patients in the t-PA group and 2.9 percent of those in the PTCA group (P = 0.04), and reversible defects in the infarct zone were evident on thallium scanning in 38.2 and 26.8 percent, respectively (P = 0.06).

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  		Table 5. Results of Exercise Testing.

 
Radionuclide ventriculography was performed six weeks after infarction in 243 of 373 survivors (65.0 percent). The incidence of exercise-induced angina or ischemic electrocardiographic changes did not differ significantly between the t-PA and PTCA groups (24 percent vs. 16 percent, P = 0.13). The left ventricular ejection fraction at rest (53 ±13 percent vs. 53 ±13 percent, P = 0.52) and during exercise (56 ±13 percent vs. 56 ±14 percent, P = 0.73) was similar among patients in the two groups.

Discussion

The purpose of this study was to compare clinical outcomes after the use of two methods of reperfusion -- immediate PTCA and intravenous thrombolytic therapy with t-PA. It is clear from our results that PTCA results in wider patency of the infarct-related coronary vessel than does thrombolysis8,21,30,31 and that immediate PTCA is associated with low rates of recurrent ischemia and death15,16,17,18,19. Since the sample size was too small to provide sufficient statistical power to draw conclusions about mortality, the primary end point of this trial was the combined category of death and nonfatal reinfarction.

The success rate of angioplasty in this study was similar to that in other series,15,16,17,18,19 but in our study no patient required emergency bypass surgery after unsuccessful PTCA. The technical success rate with immediate PTCA appears to be improving over time, probably because of improved catheter technology and case selection, as well as greater understanding of the importance of pretreatment with aspirin7,32,33 and maintenance of adequate anticoagulation during the procedure34,35,36,37. Some have suggested that it is inappropriate to assume that patency rates with PTCA are superior to those with thrombolysis, since approximately 10 percent of patients assigned to PTCA do not undergo the procedure because of angiographic exclusion criteria. In our series as well as in others, however, patients excluded from PTCA either had spontaneous reperfusion or were sent for emergency surgical reperfusion. Thus, in our intention-to-treat analysis, patency was achieved in 193 of 195 patients randomly assigned to undergo PTCA (99 percent).

We selected t-PA as the thrombolytic drug for this study because it is the most commonly used agent in the United States38. We chose to compare PTCA with the only dosing regimen for t-PA approved by the Food and Drug Administration. Accelerated regimens may achieve slightly higher rates of patency than conventional doses of t-PA,11,12 but it is unlikely that this difference will translate into improved clinical outcome39. Moreover, since the rates of reocclusion and reinfarction are similar for t-PA and streptokinase,40 the use of intravenous streptokinase would probably not have changed the results of this trial. Although combinations of t-PA with streptokinase9 or urokinase10 appear to be associated with a lower rate of reocclusion than treatment with t-PA alone, these combinations are not approved by the FDA and are not widely used.

Patients assigned to undergo PTCA had a striking reduction in the frequency of myocardial ischemia during hospitalization, as compared with patients assigned to receive t-PA. The rates of recurrent ischemia observed after intravenous t-PA therapy and PTCA in this study were similar to those observed in other trials conducted in the United States8,10,16,24,28. Since blinding was not feasible in this trial, we were concerned about possible bias in the reporting of ischemia by investigators. However, documentation of ischemic end points in both nurses' and physicians' hospital progress notes was confirmed by an independent nurse monitor. Furthermore, the electrocardiograms were independently reviewed by a physician for the presence of ischemic changes. Chest pain in the absence of electrocardiographic changes was considered non-ischemic.

Among patients assigned to receive t-PA, 7 percent required PTCA after thrombolysis failed and 17.5 percent required the procedure for recurrent ischemia. These rates are lower than those reported in recent myocardial-infarction registries41,42 and similar to that reported in phase 5 of the TIMI trial43. In contrast, only 22.3 percent of patients randomly assigned to the conservative arm of phase 2B of the TIMI trial required mechanical revascularization44. The higher frequency of PTCA after thrombolysis in our study than in TIMI phase 2B may be related to the use of rescue PTCA in 7 percent of our patients. The protocol in that study specifically recommended that no angioplasty be used in patients with totally occluded arteries in the absence of recurrent ischemia45. Concern has been expressed over potential harm due to attempted but unsuccessful rescue PTCA46. Only 2 of the 13 deaths among patients who received t-PA in our study followed rescue angioplasty. The remaining patients died after the onset of recurrent ischemia (nine patients) or intracranial hemorrhage (four patients). Therefore, the majority of deaths could not be attributed to the rescue PTCA procedure. The higher mortality rate after thrombolysis in our study as compared with phase 2B of the TIMI trial may be related to our smaller sample or to the inclusion of elderly patients in our trial. Indeed, 7 of the 13 deaths in the t-PA group occurred in patients who would not have been eligible for inclusion in phase 2B of the TIMI trial. Thus, a reduced rate of recurrent ischemia and intracranial hemorrhage, particularly in patients classified as "not low risk," accounted for the survival advantage associated with immediate PTCA.

The rate of intracranial bleeding after t-PA therapy was higher in our study than in most U.S. trials of thrombolysis; the small sample resulted, however, in a wide 95 percent confidence interval (0.1 to 3.9 percent). The high rate of intracranial bleeding may have been related to the combined use of high-dose intravenous heparin, aspirin, and t-PA in an elderly population (20.5 percent of patients were more than 70 years of age). The higher incidence of ventricular fibrillation in the PTCA group may have been due to the use of radiographic contrast agents47,48 or to the rapid reperfusion of the infarct-related vessel49. In addition, 2 percent of patients in the PTCA group required vascular surgical repair. This rate is higher than that expected for elective PTCA and may be related to the small sample, the use of high-dose intravenous heparin before vascular access was obtained, the continuation of heparin therapy for several days, or the use of intraaortic balloon counterpulsation50.

Although 19.4 percent of the patients treated with t-PA underwent unplanned PTCA before exercise testing, exercise-induced ischemia occurred more often in the t-PA group. The higher incidence of exercise-induced ischemia in that group is consistent with the rate reported in other studies24,51 and may have been caused by high-grade residual stenosis of the vessel supplying viable myocardium.

The left ventricular ejection fractions at rest and during exercise at six weeks were similar in the t-PA and PTCA groups. However, of the 34 patients who had nonfatal reinfarction or who died, only 9 underwent follow-up testing. Thus, the effects of serious ischemic events on left ventricular function could not be ascertained. Since previous trials demonstrated a higher ejection fraction during exercise among patients who underwent PTCA than among those who did not,24,52 we anticipated this finding in our trial, as well. However, our aggressive strategy of performing revascularization if spontaneous or provokable ischemia occurred resulted in the use of angioplasty or bypass surgery in 50 percent of patients assigned to t-PA. Given such a high rate of revascularization, it is not surprising that the results on exercise testing were similar for the two groups at six weeks.

In this study, immediate PTCA was performed safely in patients who had received no previous thrombolytic therapy, and it resulted in a high rate of patency in the infarct-related vessels. As compared with intravenous t-PA therapy, immediate angioplasty resulted in lower rates of intracranial hemorrhage and of nonfatal reinfarction and death (a combined end point) and in similar ventricular function. These data suggest that when the necessary facilities and personnel are available, immediate angioplasty is an attractive alternative to intravenous thrombolysis and may even be preferable for high-risk patients.

We are indebted to Phyllis McKinney for assistance in the preparation of the manuscript.


Source Information

From William Beaumont Hospital, Royal Oak, Mich. (C.L.G., G.C.T., M.S., S.P.-O., W.W.O.); Lakeland Regional Medical Center, Lakeland, Fla. (K.F.B., R.E.V.); Clinique Pasteur, Toulouse, France (J.M.); St. Vincent Hospital, Indianapolis (D.R.); El Camino Hospital, Mountain View, Calif. (G.W.S.); the Mid-America Heart Institute, Kansas City, Mo. (J.O.); St. Mary of the Plains, Lubbock, Tex. (P.O.); Allegheny General Hospital, Pittsburgh (B.D.); and United Hospital, Grand Forks, N.D. (N.C.). The members of the Primary Angioplasty in Myocardial Infarction Study Group are listed in the Appendix.

Address reprint requests to Dr. Grines at the Division of Cardiology, William Beaumont Hospital, 3601 W. Thirteen Mile Rd., Royal Oak, MI 48073-6769.

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Appendix

The following institutions and investigators participated in the Primary Angioplasty in Myocardial Infarction Study Group: William Beaumont Hospital, Royal Oak, Mich. -- W. O'Neill, C. Grines, M. Brodsky, N. Choksi, J. Cieszkowski, M. Elliott, H. Friedman, V. Gangadharan, R. Levin, D. Marsalese, M. May, B. Meany, G. Pavlides, S. Puchrowicz-Ochocki, R. Ramos, R. Safian, V. Savas, T. Schreiber, and M. Strzelecki; Lakeland Regional Medical Center, Lakeland, Fla. -- K. Browne, R. Vlietstra, and R. Roy; Clinique Pasteur, Toulouse, France -- J. Marco, M. Vandormael, and G. Roberts; St. Vincent Hospital, Indianapolis -- D. Rothbaum and M. Klette; El Camino Hospital, Mountain View, Calif. -- G. Stone, C. Bavor, R. Constantino, M. Klughaupt, I. Saah, F. St. Goar, and E. Bough; Mid-America Heart Institute, Kansas City, Mo. -- G. Hartzler, J. O'Keefe, and C. Dreiling; St. Mary of the Plains, Lubbock, Tex. -- P. Overlie and M. Quijada; Allegheny General Hospital, Pittsburgh -- B. Donohue, R. Begg, and L. Zahren; United Hospital, Grand Forks, N.D. -- N. Chelliah, R. Wolf, and N. Endres; Heart Institute of St. Joseph Hospital, Atlanta -- C. Cates, W. Knopf, and J. Sheftel; Florida Hospital South, Orlando -- R. Ivanhoe and C. Simpkiss; and North Central Heart Clinic, Wausau, Wis. -- J. Freeman.

The following are members of the Safety and Data Monitoring Committee: G. Timmis, William Beaumont Hospital, Royal Oak, Mich.; B. Pitt, University of Michigan Medical Center, Ann Arbor; and T. Ryan, University Hospital, Boston.


 

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