The Effects of Tissue Plasminogen Activator, Streptokinase, or Both on Coronary-Artery Patency, Ventricular Function, and Survival after Acute Myocardial Infarction

Patient Population

The study was conducted in 75 North American, European, and Australian hospitals (see the Appendix) in which all patients enrolled in the main GUSTO trial were also enrolled in the angiographic substudy. Previously described entry criteria¹ included chest pain lasting less than six hours and electrocardiographic evidence of acute myocardial infarction (ST-segment elevation). Patients were excluded if they had a history of stroke, recent major surgery, trauma, active bleeding, or an allergy to streptokinase. The study was approved by each center's institutional review board, and all patients gave their informed consent.

Randomization

Patients were randomly assigned to one of four treatment strategies and one of four angiographic study times. The treatment strategies were (1) streptokinase (Kabikinase, Kabi Vitrum, Sweden), given in a dose of 1.5 million U over a 60-minute period, with subcutaneous heparin (sodium heparin, Sanofi, Paris) in a dose of 12,500 U twice daily, beginning 4 hours after the initiation of lytic therapy; (2) streptokinase (1.5 million U) with intravenous heparin administered in an intravenous bolus dose of 5000 U followed by a continuous infusion at 1000 U per hour; (3) t-PA (Activase, Genentech, South San Francisco) administered in an accelerated manner, first in an intravenous bolus dose of 15 mg followed by an infusion of 0.75 mg per kilogram of body weight over a 30-minute period (maximum, 50 mg) and then an infusion of 0.5 mg per kilogram over a 60-minute period (maximum, 35 mg), with intravenous heparin administered as described above; and (4) combination therapy in which 1.0 million U of streptokinase was given over a 60-minute period concomitantly with t-PA (1.0 mg per kilogram, with 10 percent of the total dose given as a bolus, for a total dose ≤ 90 mg), with intravenous heparin also administered as above. The dosage of intravenous heparin was adjusted to maintain the activated partial-thromboplastin time above 60 seconds for at least 48 hours.

The four intervals between the initiation of thrombolytic therapy and coronary angiography were 90 minutes, 180 minutes, 24 hours, and 5 to 7 days. Randomly assigning patients to angiography at different times⁴ after the initiation of thrombolytic therapy permitted the time-patency profile of each treatment to be determined without being affected by the performance of repeated angiography (or angioplasty). The uneven stratification in favor of the group undergoing angiography at 90 minutes allowed a substantial sample to be formed for analysis of reocclusion and ventricular function at uniform times after therapy. The group undergoing the procedure at 90 minutes also underwent follow-up angiography 5 to 7 days later for the assessment of reocclusion and changes in ventricular performance.

Sample Requirements

The sample size was selected to permit us to detect a 20 percent difference between treatments in the rate of patency among infarct-related arteries at 90 minutes with a power of 0.9 and an alpha level of 0.05, and a difference in projected reocclusion rates between a maximum of 12 percent and a minimum of 4 percent, with a power of 0.8 and an alpha level of 0.05. The intended size of the sample was 2400 patients.

Angiography

On the basis of the location of the infarct as assessed by electrocardiography, the presumed infarct-related artery was studied first. At least one pair of orthogonal projections of the infarct-related artery and the uninvolved artery was acquired, followed by a left ventriculogram filmed in the 30-degree right anterior oblique projection. A calibration grid (Namic, Glens Falls, N.Y.) was filmed at magnification settings and distances identical to those at which the ventriculogram was obtained. If angioplasty was performed, it was carried out after ventriculography.

Core-Laboratory Procedures

Cineangiograms, report forms, and the qualifying electrocardiogram were sent to the core laboratory at the George Washington University, Washington, D.C. The evaluators analyzing the angiograms were blinded to the patient's treatment, the interval between therapy and angiography, and the clinical outcome. Films were reviewed with a projector (model 35 AX, Tagarno Corporation, Dover, Del.) whose video output was linked to a semiautomated quantitative image processor (ImageComm, Santa Clara, Calif.). The infarct-related artery was identified by assessing the electrocardiogram, the ventriculographic location of contractile abnormality, and the presence of stenosis or thrombus in the corresponding artery. Flow in the infarct-related artery was determined during the initial injection of contrast agent and graded as described in the Thrombolysis in Myocardial Infarction (TIMI) trial⁵: grade 0 denoted an absence of antegrade flow beyond the point of occlusion; grade 1, partial penetration of contrast agent beyond the obstruction but incomplete distal filling; grade 2, patency with opacification of the entire distal vessel but with delayed filling or washout of contrast agent; and grade 3, normal flow. The ventriculographic silhouettes were acquired digitally at end diastole and end systole, and the borders defined by the core-laboratory angiographer. Ventricular volumes and the ejection fraction were calculated by the area-length method⁶. Further characterization of the infarct zone included the mean excursion of the most abnormal 50 percent of chords in the infarct region (expressed as the number of standard deviations per chord); the number of consecutive chords in the infarct zone more than 2 SD below the norm; and the percentage of patients with no such abnormal chords in the infarct zone. These measures of regional function were obtained with the method of Sheehan and Dodge⁷. If angioplasty was performed, the degree (or lack) of patency was recorded before the intervention. Patients who underwent angioplasty any time before the follow-up study at five to seven days as stipulated by the protocol were excluded from the analysis of reocclusion but not from late ventriculographic analysis.

Quality Control

Participating centers were visited by an investigator from the core laboratory to ensure adherence to the protocol and quantitative angiographic techniques. Every 10th angiogram obtained according to the protocol was reanalyzed to assess the reproducibility of measurements.NAPS Ten percent of the patients' charts were audited for accuracy.

Statistical Analysis

For discrete end points, contingency-table analyses were used to compare responses among the four treatment groups. Chi-square tests were used to identify significant differences among the groups. For continuous end points, results for the groups were compared by analysis of variance. When data deviated from the assumptions required for analysis of variance, tests of significance were based on Wilcoxon scores (rank sums) with use of the Kruskal-Wallis procedure⁸. Nonparametric analysis for ranks based on multiple end points was performed with Friedman's test⁹. All P values are two-tailed except those derived from rank-order analysis. Final data analysis was performed in duplicate, at the core laboratory and independently at the GUSTO coordinating center.

Characteristics of the Patients

Table 1. Table 1. Base-Line and Outcome Variables of Patients in the GUSTO Main Trial and Patients in the Angiographic Substudy.

A total of 2431 patients were enrolled in the GUSTO angiographic substudy, of whom 94 percent had at least one analyzable angiogram. There were 3118 angiograms obtained as stipulated by the protocol (both initial and follow-up angiograms), and 530 other angiograms were obtained because of clinical indications unrelated to the protocol. Of the patients enrolled, 38 (1.6 percent) died without undergoing angiography (6 patients assigned to streptokinase with subcutaneous heparin, 10 assigned to streptokinase with intravenous heparin, 9 assigned to t-PA with heparin, and 13 assigned to t-PA with streptokinase). An additional 56 patients (2.3 percent) did not undergo the procedure for other reasons (refusal by the patient, a decision by the physician, technical problems, or a clinical contraindication). The data were incomplete for 56 patients (2.3 percent). The lack of data was similar among the four treatment groups. There were no differences in selected base-line and outcome variables between the patients in the angiographic substudy and those in the main trial (Table 1), nor were there significant differences in base-line variables among the treatment groups. Angioplasty was performed more frequently among the patients in the angiographic substudy than among those in the main trial (36 percent vs. 15 percent). The use of angioplasty did not differ significantly among the treatment groups.

Complications

Table 2. Table 2. Complications of Coronary Angiography, According to Treatment Group.

The rates of complications among patients undergoing angiography within the first 24 hours after thrombolytic therapy -- hence, those possibly related to a particular thrombolytic regimen -- are shown in Table 2. The frequency of bleeding related to the procedure did not differ significantly among the treatment groups. The need for vascular repair was increased in the group given combination therapy as compared with the group given streptokinase with subcutaneous heparin. More patients in the angiographic substudy required blood transfusions than did those in the main trial (18 percent vs. 10 percent, P<0.001).

Patency

The infarct-related vessel was the right coronary artery in 44 percent of patients, the left anterior descending artery in 39 percent, and the left circumflex artery in 12 percent. It was the left main coronary artery, a vein or arterial graft, or an unidentifiable vessel in the remaining 5 percent.

Table 3. Table 3. Patency and Reocclusion of the Infarct-Related Artery, According to Treatment Group.

There was a significant difference in early (90 minute) overall patency (TIMI grades 2 and 3 combined) in favor of the group given t-PA with heparin (Table 3). Furthermore, coronary flow was normal (TIMI grade 3) in 54 percent of this group, as compared with 29 percent to 38 percent of the other three treatment groups. Differences of similar magnitude in favor of the group given t-PA with heparin were observed regardless of the particular infarct-related artery, the patient's age, or the interval between the onset of pain and therapy.

Angiograms obtained 180 minutes after the start of therapy showed no residual differences in patency among the treatment groups. Few differences were seen at 24 hours or at 5 to 7 days (Table 3).

Reocclusion

Five hundred eighty-six patients had a patent infarct-related artery 90 minutes after treatment and a follow-up angiogram at 5 to 7 days (or earlier if clinically indicated). Table 3 shows the frequency of reocclusion of patent arteries. The rate of reocclusion ranged from 4.9 percent to 6.4 percent. There were no significant differences according to treatment or flow grade (TIMI grade 2 or 3). Twenty-seven patients were excluded from the calculation of the reocclusion rate because they underwent early angioplasty, 34 died before follow-up (7 patients given streptokinase with subcutaneous heparin, 8 given streptokinase with intravenous heparin, 10 given t-PA with heparin, and 9 given t-PA with streptokinase), and 136 (17 percent) of the 783 with initially patent arteries had no repeat study because they or their physician refused the procedure, vascular access was difficult, or they had a clinical contraindication to angiography (e.g., stroke, bypass surgery, or heart failure). The absence of follow-up data was similar among the treatment groups.

Left Ventricular Function According to Treatment

Table 4. Table 4. Left Ventricular Function, According to Group.

Table 4 summarizes the analysis of ventricular function according to treatment assignment. For the 967 patients assigned to angiographic evaluation at 90 minutes whose studies were technically analyzable, the mean time from the start of therapy to angiography was 97 ±12 minutes. The group given t-PA with heparin and the group given the combination treatment had significantly less depression of regional wall motion in the ischemic zone than either group given streptokinase. Also, the group given t-PA with heparin had fewer patients with abnormal chords and more patients with preserved wall motion than any of the other three groups. There were similarly directed trends (not statistically significant) in the global ejection fraction and the end-systolic volume index. Rank-order analysis (in which a score of 1 denoted the best value, and 4 the worst) of all five measurements of left ventricular function taken together showed that the group given t-PA with heparin had fewer abnormal scores than all other groups (P<0.01).

Of the 967 patients with initial angiographic studies at 90 minutes, 733 (76 percent) had follow-up ventriculograms that could be analyzed (Table 4). The lack of follow-up ventriculographic data was similar among the treatment groups. Data were missing for 5 percent of patients because they had died, for 5 percent because they refused ventriculography, for 3 percent because their physician refused it, for 8 percent because they had contraindications, and for 3 percent for other reasons. When values recorded at 5 to 7 days were compared with those recorded at 90 minutes, there were small changes in the ejection fraction and end-systolic volume index and moderate improvement in the other measures of regional function in all treatment groups. The group given t-PA with heparin had 18 to 24 percent fewer abnormal chords and less depression of regional wall motion than the other three groups. Nonparametric analysis of all five end points again demonstrated a superior outcome in the group given t-PA with heparin (P = 0.025).

Mortality

The rates of death from any cause within 30 days according to treatment assignment in the angiographic substudy closely paralleled the rates in the main trial: 6.5 percent among patients given streptokinase with subcutaneous heparin, 7.5 percent among those given streptokinase with intravenous heparin, 5.3 percent among those given t-PA with heparin, and 7.8 percent among those given the combination treatment. Thirty-day mortality was also influenced by the number of coronary vessels with obstruction of at least 75 percent. Sixty-two percent of patients had single-vessel disease, 24 percent had two-vessel disease, and 14 percent had three-vessel disease; the respective mortality rates -- 3.5 percent, 6.5 percent, and 11.2 percent -- differed significantly from each other (one-vessel vs. two-vessel disease, P = 0.003; two-vessel vs. three-vessel disease, P = 0.02; and one-vessel vs. three-vessel disease, P<0.001). The distribution of patients with one-, two-, and three-vessel disease did not differ among the four treatment groups.

Patency and Mortality Analyzed Independently of Treatment

Patency grades, regardless of treatment assignment, were combined and analyzed in relation to 30-day survival. A lack of patency at 90 minutes (TIMI grade 0 or 1) was associated with mortality of 8.9 percent, and patency (TIMI grade 2 or 3) with mortality of 5.7 percent (P = 0.04). The mortality rate among patients with TIMI grade 2 flow was 7.4 percent, and the rate among those with TIMI grade 3 flow was 4.4 percent (P = 0.08). The difference between the mortality rate associated with grade 3 and the rate associated with grade 0 or 1 was significant (P = 0.009).

Table 5. Table 5. Effect of Early Patency on Ventricular Function at Follow-up, According to TIMI Grade.

The association between patency grade at 90 minutes and left ventricular function assessed at both 90 minutes and 5 to 7 days is shown in Table 5. Every measure of left ventricular function was closer to normal in the patients with early (90 minute) TIMI grade 3 flow than in those with TIMI grade 2 flow. The advantage of having TIMI grade 2 flow as compared with grade 0 or 1 flow was smaller. Measures of ventricular function in patients with identical TIMI flow grades at 90 minutes were compared among the four treatment groups. No significant differences were observed among the groups when comparisons were stratified for the same grade of early patency.

Figure 1. Figure 1. Left Ventricular Function 90 Minutes after the Start of Therapy in Patients Who Survived for 30 Days after Infarction and Patients Who Died before 30 Days.

Values are means; horizontal T bars indicate the standard deviation. ESVI denotes end-systolic volume index. Regional wall motion is expressed as the magnitude of depressed infarct-zone chords, in terms of the number of standard deviations from the norm. Chords in the infarct zone were considered abnormal if they were more than 2 SD below the norm.

Ventricular function at 90 minutes in the 52 patients who had early ventriculography but did not survive for 30 days was compared with ventricular function in the 915 patients who survived for 30 days or more (Figure 1). Left ventricular function in the nonsurvivors was consistently worse than in the survivors. Conversely, stratification of patients according to their left ventricular function at 90 minutes produced divergent survival rates: mortality was 3.9 percent among those with ejection fractions above 45 percent, but 14.7 percent among those with ejection fractions of 45 percent or less (P<0.001).

Our study supports the idea that more rapid and complete coronary reperfusion -- which can be achieved with a “front-loaded,” or accelerated, regimen of t-PA -- offers substantial benefit to patients with acute myocardial infarction. A higher rate of early patency with t-PA therapy than with streptokinase therapy was originally demonstrated by the TIMI investigators⁵ and the European Cooperative Study Group¹⁰. Even earlier patency of the infarct-related artery was shown by Neuhaus et al.¹¹ and others¹² when t-PA was administered in the front-loaded fashion. The present study confirms those observations in a very large cohort. The failure of the combination treatment to induce a rate of early patency similar to that induced by the accelerated regimen of t-PA may be ascribed to the use of only a small front-loaded dose of t-PA in the combined-activator strategy. The effect of early intravenous heparin on patency, reocclusion, and left ventricular function in streptokinase-treated patients was minor. When this finding was considered together with the clinical data, intravenous heparin had no advantage over subcutaneous heparin as an adjunct to streptokinase.

This investigation has demonstrated that the rate at which the infarct-related artery becomes patent in patients given streptokinase “catches up” to the rate in those given t-PA; by three hours after the start of treatment, patency rates had become equal. It may be inferred from the data on ventricular function and mortality that despite this catching-up phenomenon, it occurs too late to result in an equally favorable clinical outcome.

The rate of reocclusion was low in all treatment groups and lower than in t-PA-treated patients previously described^5,13. The reasons for the low rate of reocclusion are unproved, but throughout the study we placed a major emphasis on vigilant maintenance of anticoagulation with intravenous heparin, in the light of reports by the investigators of the Heparin-Aspirin Reperfusion Trial¹⁴ and others¹⁵. Alternatively, the accelerated administration of t-PA also may have lowered the rate of reocclusion.

Early patency of the infarct-related artery was associated with improved left ventricular function. The patients with the highest patency rate at 90 minutes -- namely, those given t-PA and those defined as having early patency independent of treatment assignment -- had the least depression of regional wall motion in the infarct zone, the fewest abnormal chords, and the highest frequency of intact systolic function. Differences in ventricular function occurring this early after thrombolysis have not been noted previously and may relate to the large sample and the evaluation of a variety of measures of ventricular function, some of them likely to be more sensitive than the global ejection fraction. Information on the speed of recovery of ischemic myocytes is limited, but early benefits in regional contraction and stores of high-energy phosphates in cardiocytes have been reported in animals after two hours of coronary occlusion followed by four hours of reperfusion¹⁶. Whether differences in ventricular function 90 minutes after reperfusion represent the true beginning of recovery or only the arrest of deterioration cannot be definitely resolved from these data. Moderate improvement in all treatment groups in measures of regional function over the course of a week is consistent with the results of most other studies in the literature^17-20. The analysis of ventriculographic observations five to seven days after thrombolytic therapy included patients in whom angioplasty was performed any time before follow-up ventriculography, in accordance with the intention-to-treat principle. Analysis after the exclusion of patients who underwent angioplasty did not alter the findings.

Earlier administration of thrombolytic therapy and earlier restoration of coronary patency have previously been thought to improve ventricular function and lower mortality,^21-25 but these findings have not been previously confirmed in a large prospective trial with an angiographic component that examined mortality. In fact, previous investigations have been noted to refute a definite association between ventricular performance and survival²⁶. The present study appears to resolve this paradox. The relation between left ventricular function after reperfusion therapy and the risk of subsequent mortality was supported by our observation of substantial early differences in indexes of ventricular size and contraction when we compared values for survivors at 30 days with those for nonsurvivors.

Recent clinical reports^27,28 and previous laboratory studies²⁹ have suggested that greater degrees of reperfusion produce greater clinical benefit; this idea is supported by our results. Among patients with partial flow through the infarct-related artery (TIMI grade 2) at 90 minutes, ventricular function was worse and mortality higher than among patients with normal flow (TIMI grade 3). If grade 2 flow represents an intermediate stage in the progression from complete obstruction to normal flow, then interventions to speed this process, such as angioplasty, may be of value. Alternatively, the sluggish flow that we classify as TIMI grade 2 may result from more extensive, downstream vascular or muscle injury and may therefore be a marker, rather than a cause, of a less favorable outcome.

This study points to important associations between early patency of the infarct-related artery, better preservation of ventricular function, and improved survival after thrombolytic therapy for acute myocardial infarction. We propose that our findings explain the survival advantage of patients in the GUSTO trial who received accelerated t-PA therapy.

The following centers and investigators collaborated in the GUSTO main trial and its angiographic substudy (values in parentheses denote the number of patients enrolled).

GUSTO Angiographic Substudy: Chairman: A.M. Ross; and Cochairman: M.L. Simoons.

Angiographic Substudy Coordinating Center and Core Laboratory, George Washington University, Washington, D.C.: Angiographers: A.M. Ross, C. Lundergan, M. Thompson, J. Reiner, Y. Deychak, and S. Rohrbeck; Coordinators: K. Coyne and P. Walker; Data Management: S. Cho; Data Analysis: S. Greenhouse, K. Lee, C. Granger, and N. Wildermann; Research Assistants: C. Fink, S. Harry, D. Allison, and Y. Draoui; Administrator: G. Costigan; Data Entry: D. Fox, M. Lempel, M. Williams, and J. Ross; Support Staff: R. Floura and J. Hicks.

Non-North American Angiographic Coordinating Center, Cardialysis, Rotterdam, the Netherlands: Angiographers: M. van de Brand and A. Balk; Managing Director: L. Rodenburg; Coordinator: T. Baardman; Technicians: I. Hoekman and D. Amo; Secretary/ Data Entry: I. van Oosterom, G. van Hessem, I. de Zwart, M. Janssen, A. de Pui, C. Terwogt, J. Houweling, N. Corbeau, J. Iwema, and J. Pameijer; Computer Assistant: R. de Jong.

Steering Committee (Main GUSTO Trial): Chairman: E. Topol, United States; Clinical Director, Coordinating Center: R. Califf, United States; P.W. Armstrong, Canada; P. Aylward, Australia; G. Barbash, Israel; E. Bates, United States; A. Betriu, Spain; J. Boissel, France; J. Chesebro, United States; J. Col, Belgium; D. de Bono, United Kingdom; J. Gore, United States; A. Guerci, United States; A. Hampton, United Kingdom; J. Hirsh, Canada; D. Holmes, United States; J. Horgan, Ireland; N. Kleiman, United States; V. Marder, United States; D. Morris, United States; M. Ohman, United States; M. Pfisterer, Switzerland; A.M. Ross, United States; W. Rutsch, Germany; Z. Sadowski, Poland; J. Simes, Australia; M.L. Simoons, the Netherlands; A. Vahanian, France; F. Van de Werf, Belgium; D. Weaver, United States; H. White, New Zealand; R. Wilcox, United Kingdom.

United States (1117): St. Mary's Hospital, Rochester, Minn.: S. Kopecky, A. McLaughlin, and R. Bowman; George Washington University Hospital, Washington, D.C.: A.M. Ross, A. Wasserman, J. Segal, K. Coyne, and P. Walker; Tulsa Regional Medical Center, Tulsa, Okla.: E. Pickering, P. Cotham, and J. Gaber; McKay-Dee Hospital, Ogden, Utah: D. Rigby and S. Whitehead; St. Vincent's Medical Center, Jacksonville, Fla.: G. Pilcher, B. Greene, and A. Hipps; St. Mary's Hospital, Tucson, Ariz.: L. Lancaster and D. Lansman; East Alabama Medical Center, Opelika, Ala.: J. Mitchell and G. Stegall; Proctor Community Hospital, Peoria, Ill.: P. Schmidt, D. Miller, and C. Ness; Mercy Hospital of Pittsburgh, Pittsburgh: V. Krishnaswami, A. Heyl, and R. Simonelli; Mt. Clemens General Hospital, Mt. Clemens, Mich.: J. Kazmierski and L. Thompson; University Hospital of Cleveland, Cleveland: J. Hodgson and L. Hladik; Spartanburg Regional Medical Center, Spartanburg, S.C.: J. Dorchak and T. Robinette; University Community Hospital, Tampa, Fla.: J. Smith and L. Harrah; Humana Medical City, Dallas: D. Brown and T. McCarter; Lahey Clinic Medical Center, Burlington, Mass.: D. Gossman and G. Woodhead; University of Michigan Hospital, Ann Arbor, Mich.: E. Bates and E. Kline-Rogers; Mother Frances Hospital, Tyler, Tex.: N. Israel and R. LeBoeuf; St. Mark's Hospital, Salt Lake City: J. Perry and W. Schvaneveldt; Crawford Long Hospital, Atlanta: D. Morris and W. Bernard; Hahnemann University Hospital, Philadelphia: T. Parris and K. Stoakes; Sioux Valley Hospital, Sioux Falls, S.D.: L. Solberg and A. Brown; St. Joseph's Hospital, Savannah, Ga.: P. Gainey and R. Greenbush; Ochsner Foundation Hospital, New Orleans: C. White and B. Leasure; Good Samaritan Hospital, Cincinnati: A. Razavi, P. Ertel, and D. Hamilton; McLeod Regional Medical Center, Florence, S.C.: A. Blaker and J. Shane; Evanston Hospital, Evanston, Ill.: I. Silverman and S. Weszt; St. Agnes Medical Center, Philadelphia: D. McCormick and S. Luhmann; Medical College of Virginia, Richmond, Va.: R. Jesse and C. Roberts; Glenbrook Hospital, Glenview, Ill.: I. Silverman and S. Weszt; Shadyside Hospital, Pittsburgh: J. O'Toole and S. Heilman; Terre Haute Regional Hospital, Terre Haute, Ind.: P. Andres and D. Bauer; Lutheran Hospital, Fort Wayne, Ind.: B. Lew and C. Matvya; Memorial Medical Center, Corpus Christi, Tex.: C. Schechter and K. Killebrew; Swedish-American Hospital, Rockford, Ill.: R. Harner and M. Fisher; Spohn Hospital, Corpus Christi, Tex.: C. Schechter and K. Killebrew; McKennan Hospital, Sioux Falls, S.D.: K. Kavanaugh and M. Voss; Northern Michigan Hospital, Petoskey, Mich.: W. Meengs and B. Stone; Hackensack Medical Center, Hackensack, N.J.: J. Zimmerman and J. Hart; Lakeside Veterans Affairs Medical Center, Chicago: A. Hsieh and B. McDermott.

France (433): Hopital Cochin, Paris: A. Py; Hopital Tenon, Paris: A. Vahanian and O. Nallet; Centre Hospitalier Universitaire, Caen: G. Grollier and B. Valette; Hopital du Haut-Leveque, Pessac: P. Besse and C. Durrieu; Hopital de Hautepierre, Strasbourg: M. Mossard and R. Arbogast; Hopital Purpan, Toulouse: P. Bernadet and D. Carrie; Hopital Trousseau, Tours: B. Charbonnier; Hopital Hotel Dieu, Rennes: C. Almange and H. Le Breton; Centre Hospitalier, Rennes: J. Daubert; Hopital Saint Jacques, Clermont Ferrand: J. Cassagnes; Hopital Lariboisiere, Paris: P. Beaufils and P. Rapoport; Hopital Bichat, Paris: J. Juliard and G. Steg; Hopital Broussais, Paris: J. Guermonprez, L. Guize, and M. Iliou; Hopital Boucicaut-Vaugirard, Paris: C. Guerot and O. Grenier; CHU La Miletrie, Poitiers: R. Barraine and D. Coisne; Centre Hospitalier Regional, Besancon: J. Bassand and F. Schiele.

Belgium (261): UZ St. Raphael-Gasthuisberg, Leuven: F. Van de Werf and P. Tenaerts; Hopital de la Citadelle, Liege: J. Boland; Clinique Generale Saint-Jean, Brussels: M. Castadot and D. Colsoul; Clinique Univ. de Mont-Godinne, Yvoir: E. Schroeder; AZ Middelheim, Antwerp: P. Van den Heuvel.

The Netherlands (197): Medisch Spectrum, Enschede: G. Molhoek and R. Lalisang; Spaarne, Ziekenhuis Heemstede: E. Muller; Dijkzigt, Rotterdam: M.L. Simoons, M. van de Brand, and P. Kint.

Canada (177): University of Alberta Hospital, Edmonton, Alb.: J. Burton and C. Kee; Victoria General Hospital, Halifax, N.S.: C. Kells and T. Fawcett; Vancouver General Hospital, Vancouver, B.C.: A. Fung and C. Davies; St. Paul's Hospital, Vancouver, B.C.: C. Thompson, D. Heinrich, and L. Robson.

Australia (101): Flinders Medical Centre, Adelaide, S.A.: P. Aylward and C. Thomas; Royal North Shore Hospital, St. Leonards, N.S.W.: G.I.C. Nelson and B. Dwyer.

Switzerland (46): University Clinics, Basel: M. Pfisterer and R. Hammerli.

Germany (42): Krankenhaus am Urban, Berlin: W. Dissmann and H. Topp; Medizinische Universitat zu Lubeck, Lubeck: H. Djonlagic and V. Kurowski.

Spain (31): Hospital Gen. Gregorio Maranon, Madrid: J. Delcan and E. Garcia.

Ireland (26): St. James's Hospital, Dublin: M. Walsh and N. Walsh; Mater Hospital, Dublin: D. Sugrue.