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Background Thrombin has a pivotal role in the pathogenesis of acute coronary thrombosis. We compared the clinical efficacy of a potent, direct thrombin inhibitor, recombinant hirudin, with that of heparin (an indirect antithrombin agent) in patients with unstable angina or acute myocardial infarction.
Methods At 373 hospitals in 13 countries, 12,142 patients with acute coronary syndromes were randomly assigned to 72 hours of therapy with either intravenous heparin or hirudin. Patients were stratified according to the presence of ST-segment elevation on the base-line electrocardiogram (4131 patients) or its absence (8011 patients), with the latter characteristic considered to indicate unstable angina or non–Q-wave myocardial infarction.
Results At 24 hours, the risk of death or myocardial infarction was significantly lower in the group assigned to hirudin therapy than in the group assigned to heparin (1.3 percent vs. 2.1 percent, P = 0.001). The primary end point of death or nonfatal myocardial infarction or reinfarction at 30 days was reached in 9.8 percent of the heparin group as compared with 8.9 percent of the hirudin group (odds ratio for the risk of the end point in the hirudin group, 0.89; 95 percent confidence interval, 0.79 to 1.00; P = 0.06). The predominant effect of hirudin was on myocardial infarction or reinfarction and was not influenced by ST-segment status. There were no significant differences in the incidence of serious or life-threatening bleeding complications, but hirudin therapy was associated with a higher incidence of moderate bleeding (8.8 percent vs. 7.7 percent, P = 0.03).
Conclusions For acute coronary syndromes, recombinant hirudin provided a small advantage, as compared with heparin, principally related to a reduction in the risk of nonfatal myocardial infarction. The relative therapeutic effect was more pronounced early (at 24 hours) but dissipated over time. The small benefit was consistent across the spectrum of acute coronary syndromes and was not associated with a greater risk of major bleeding complications.
Methods
Patient Population
Patient enrollment began May 19, 1994, and was completed October 17, 1995. The entry criteria consisted of chest discomfort within the previous 12 hours associated either with transient or persistent ST-segment elevation or depression of more than 0.5 mm or with persistent, definite T-wave inversion of more than 1 mm. Patients were excluded if they were taking warfarin at the time of enrollment or if they had active bleeding, a history of stroke, a contraindication to heparin therapy or renal insufficiency (serum creatinine, >2.0 mg per deciliter [177 µmol per liter], a relative contraindication to hirudin therapy), a systolic blood pressure of more than 200 mm Hg, or a diastolic blood pressure of more than 110 mm Hg. Women of childbearing potential were excluded. If a patient was enrolled and was subsequently found to have a serum creatinine concentration of more than 2.0 mg per deciliter at base line, the study-drug infusion was discontinued. The objective was to enroll a representative cross-section of patients with acute coronary syndromes, with a target of 4000 patients with ST-segment elevation and 8000 patients with no ST-segment elevation. In patients with ST-segment elevation, the decision to use thrombolytic therapy was made by the attending physician. Thrombolytic therapy consisted of either streptokinase or a regimen of accelerated tissue plasminogen activator (t-PA) in which t-PA is infused rapidly over a period of 1 1/2 hours so that two thirds of the dose is given in the first 30 minutes.15
The protocol called for the infusion of the study medication for a minimum of three and a maximum of five days, at the discretion of the attending physician. Each patient received either heparin and hirudin placebo or hirudin and heparin placebo on a double-blind basis. Hirudin was initially given in a bolus dose of 0.1 mg per kilogram of body weight intravenously, followed by a continuous infusion of 0.1 mg per kilogram per hour. The desulfated form of recombinant hirudin (desirudin, Ciba–Geigy, Summit, N.J.) was used. Heparin was initially given in a bolus dose of 5000 U intravenously, followed by a continuous infusion of 1000 U per hour.
The activated partial-thromboplastin time was determined before the study drug was infused, at 6 hours, 12 hours, and 24 hours, and then a minimum of once a day during its administration. The activated partial-thromboplastin time was adjusted with the use of a standard nomogram to maintain the value between 60 and 85 seconds.16 In patients undergoing coronary intervention during the administration of the study drug, specific guidelines allowed the use of a bolus infusion of heparin or placebo and hirudin or placebo to achieve an activated clotting time of at least 300 to 350 seconds and preserve the double-blind nature of the study.
End Points
The primary composite end point was death or nonfatal myocardial infarction (or reinfarction) in the first 30 days of follow-up. Myocardial infarction and reinfarction have been defined previously14 and were classified by members of the clinical-events committee, who were unaware of the patients' treatment assignments.
Bleeding complications were categorized according to previous definitions.14,15 Severe or life-threatening bleeding was defined as intracranial hemorrhage or bleeding that caused hemodynamic compromise requiring intervention. Moderate bleeding was defined as bleeding that required transfusion but was not associated with any hemodynamic compromise.
Invasive Cardiologic Procedures
Coronary angiography, percutaneous coronary revascularization, and coronary-artery bypass surgery were discouraged for the duration of the study-drug infusion unless there was evidence of recurrent ischemia. For patients who were undergoing elective coronary-artery bypass surgery, it was recommended that the study drug be stopped six to eight hours before surgery, with heparin therapy initiated if indicated on an open basis. In cases of emergency bypass surgery, unblinding of study drug was permitted to avoid inappropriate use of protamine and facilitate the control of hemostasis.
Statistical Analysis
Interim analyses were planned for the primary end point after each increment of 25 percent of the planned number of patients had been enrolled; they were actually performed after data on the primary end point were available for 2731, 5946, and 9627 patients. To monitor the statistical significance of interim differences between treatments, the method of DeMets and Ware was used.17
The case report was fully documented for 10 percent of patients, and the documentation process included at least one visit by a monitor to the study sites. In addition, all in-hospital deaths, myocardial infarctions and reinfarctions, strokes, life-threatening bleeding complications, and unanticipated, serious life-threatening adverse events were reviewed. Thus, the medical records of 20 percent of the patients were reviewed.
Statistical analyses included all randomized patients according to the intention-to-treat principle. For the full cohort of patients, the Cochran–Mantel–Haenszel test was used to assess differences in the treatment groups with respect to the primary end point,18 with stratification according to whether the patients presented with or without ST-segment elevation. This test was also used to analyze discrete secondary end points. In the group without ST-segment elevation, the conventional chi-square test was used to compare treatment-related differences in the primary end point and discrete secondary end points. For secondary end points involving continuous variables, treatments were compared with use of the nonparametric Wilcoxon rank-sum test. All P values are two-sided.
Results
A total of 12,142 patients were enrolled in 373 hospitals in 13 countries (see the Appendix): 4131 had ST-segment elevation, and 8011 did not. The base-line characteristics of the entire cohort according to treatment assignment and ST-segment status are given in Table 1. As compared with patients with ST-segment elevation, patients without ST-segment elevation were more likely to be older, to be female, to have had prior cardiac disease, and to have an increased prevalence of risk factors for cardiac disease.
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In this trial of acute coronary syndromes, we observed a high (9.4 percent) event rate for the composite end point of death or myocardial infarction at 30 days despite a therapeutic approach that included the use of aspirin, heparin, beta-blockers, nitrates, and calcium-channel blockers. Although patients with ST-segment elevation were younger, were more likely to be male, and had fewer cardiac risk factors and a lower incidence of prior ischemic heart disease than patients without ST-segment elevation, they had a higher risk of death at 30 days (6.1 percent vs. 3.8 percent) and a similar rate of myocardial infarction (5.5 percent vs. 6.0 percent), most cases of which were actually reinfarctions. Although many of the demographic factors were suspected to differ between patients with ST-segment elevation and patients without ST-segment elevation after myocardial infarction or acute ischemia, our results establish that the latter group has a greater number of characteristics that are associated with more advanced coronary artery disease.
We compared the effect of heparin with that of a direct thrombin inhibitor, recombinant hirudin, which is a more potent anticoagulant.7,8,9,10 Mechanistically, hirudin has the advantage of affecting clot-bound thrombin, not requiring any cofactors, and not being inactivated by plasma proteins or platelet factor 4. Although the hypothesis that potent, direct inhibition of thrombin would improve clinical outcomes appears valid on the basis of our observations at 30 days, the extent of the benefit was small (11 percent reduction in risk) and of marginal statistical significance. However, hirudin was associated with a significant and substantial reduction in the risk of death or myocardial infarction at 24 and 48 hours. The small benefit at 30 days was similar in patients with ST-segment elevation and in those without ST-segment elevation.
Our results are discrepant with those of the recent Thrombolysis in Myocardial Infarction (TIMI) 9 trial, which indicated no advantage of hirudin over heparin for patients treated with thrombolytic therapy.19 There was a similar proportionate reduction (14 percent) in reinfarction with hirudin in that trial, but the mortality rate with hirudin therapy was slightly higher than that with heparin therapy (6.1 percent vs. 5.1 percent; odds ratio, 1.21; 95 percent confidence interval, 0.88 to 1.65). The only conspicuous differences between the TIMI 9 trial and our study were a longer interval from randomization to the initiation of the study drug (median, 44 vs. 35 minutes), a longer duration of treatment (96 vs. 75 hours), and fewer patients over 75 years of age (11 percent vs. 18 percent). Accordingly, the reason for the lack of concordance between the two trials remains unclear.
The reasons for the borderline evidence of the incremental efficacy of hirudin over heparin in the current trial are also uncertain. Among the possibilities are an inadequate dose of hirudin, an insufficient duration of treatment, or the lack of durability of the effects of hirudin. In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa trial, a much higher dose of recombinant hirudin was used (a bolus dose of 0.6 mg per kilogram followed by an infusion of 0.2 mg per kilogram per hour), but the bleeding-related side effects could not be tolerated and the incidence of intracerebral hemorrhage among patients receiving thrombolytic therapy was excessive (1.6 percent).14 Even among patients who did not receive thrombolytic therapy, there was a 0.5 percent incidence of hemorrhagic stroke in the group given hirudin as compared with an incidence of 0 percent in the group given heparin. There was no indication of improved efficacy with high doses of both hirudin and heparin: the rate of death or myocardial infarction was 11.7 percent in the hirudin group and 11.0 percent in the heparin group. In a trial involving patients with unstable angina and non–Q-wave myocardial infarction who were given a similar recombinant hirudin at a dose intermediate between that used in GUSTO IIa and the current trial (a bolus dose of 0.4 mg per kilogram followed by an infusion of 0.15 mg per kilogram per hour), the incidence of bleeding complications was twice as high in the hirudin group as in the heparin group.20 Although with the doses of hirudin used in the current trial (a bolus of 0.1 mg per kilogram and an infusion of 0.1 mg per kilogram per hour) there was no worrisome increase in major bleeding complications, there was an increased incidence of intracerebral hemorrhage (1 per 1000 patients treated) and a higher rate of moderate bleeding. Collectively, these data suggest that there is a narrow therapeutic window for treatment with recombinant hirudin and that the administration of doses higher than those tested in the current trial may increase the risk of bleeding complications without substantially improving efficacy. A longer infusion of hirudin might increase efficacy, but the lack of benefit in the TIMI 9 trial, in which therapy was administered an average of 30 percent longer than in the present study, makes this possibility less likely.
Other factors besides the dose or duration of treatment may explain the borderline results. All the beneficial effects of hirudin were evident within the first 24 hours. Beyond that point, the event-rate curves neither diverged nor converged. This failure to prevent events beyond 24 hours may be attributed either to rebound hypercoagulability after the infusion of thrombin inhibitors was stopped or to a lack of "passivation" of the arterial surface that continued to allow the formation of platelet thrombus.21,22,23,24 A similar lack of durability of the effect of thrombin inhibitors has been noted in three recent trials.25,26,27 Serial assays of prothrombin fragment (F 1.2) during hirudin therapy28,29,30 have confirmed the inability of hirudin to block the generation of thrombin. The consequent accumulation of thrombin may have detracted from the ability of hirudin to inhibit the activity of thrombin and thus reduce ischemia.
Our data call into question the existence of a pivotal role for thrombin in acute coronary thrombosis. In contrast, recent trials have provided evidence of the high efficacy of blockade of platelet glycoprotein IIb/IIIa in acute coronary syndromes.21,22,23 Although thrombin is an important agonist of platelet aggregation, it represents 1 pathway of platelet activation among nearly 100.24 At appropriate doses, an effective platelet glycoprotein IIb/IIIa inhibitor, which modulates the final common pathway of aggregation, blocks virtually all these agonists. In the future, the combination of direct thrombin inhibition and blockade of platelet glycoprotein IIb/IIIa, which has shown promise in experimental models,31 may prove to have particular therapeutic value.
Hirudin led to a very consistent anticoagulant effect over time, independently of the use of thrombolytic therapy, a feature that represents a practical advantage. Heparin not infrequently engenders an immune thrombocytopenia, which can result in serious thrombotic complications.32 However, heparin, which is inexpensive, performed quite well as an antithrombin agent in the current trial and should still be regarded as the standard therapy. Recombinant hirudin resulted in a small but demonstrable and consistent effect, especially on the rate of reinfarction, in the group of patients with acute coronary syndromes as a whole. Whether the practical advantage of hirudin, its small clinical benefit, and its somewhat increased bleeding risk will limit its use to select patients with acute coronary syndromes requires independent cost–benefit analysis.
Supported by Ciba–Geigy, (Summit, N.J.), Boehringer Mannheim (Indianapolis), and Guidant (Redwood City, Calif.).
Source Information
Dr. Topol, as study chairman, is responsible for the content of the article.
Address reprint requests to Dr. Eric J. Topol at the Cleveland Clinic Foundation, Dept. of Cardiology F/25, 9500 Euclid Ave., Cleveland, OH 44195.
References
Steering Committee — E. Topol (Study Chairman), USA, R. Califf (Clinical Director, Coordinating Center), USA, F. Van de Werf (Director, Intermediate Coordinating Center), Belgium, P. Aylward, Australia, J. Simes, Australia, J. Col, Belgium, P.W. Armstrong, Canada, A. Vahanian, France, K. Neuhaus, Germany, W. Rutsch, Germany, D. Ardissino, Italy, M. Simoons, the Netherlands, H. White, New Zealand, A. Betriu, Spain, H. Emanuelsson, Sweden, M. Pfisterer, Switzerland, K. Beatt, United Kingdom, E. Bates, USA, J. Cheseboro, USA, S. Ellis, USA, V. Fuster, USA, W.B. Gibler, USA, J. Gore, USA, A. Guerci, USA, J. Hochman, USA, D. Holmes, USA, N. Kleiman, USA, D. Morris, USA, M. Ohman, USA, H. Phillips, USA, W.D. Weaver, USA.
Coordinating Center: Duke University Medical Center, Durham, North Carolina Clinicians: C. Granger, R. Califf. Statistical Director: K. Lee. Administrators: D. Christopher, S. Karnash, J. Melton, M. Scharenbroich, J. Snapp. Coordinators: D. Blackwell, K. Davis, T. Day, B. Fraulo, L. Gray, C. Janning, I. Moffie, M. Moggio, N. Newark, S. Petrycki, W. Sutherland, P. Tenaerts. Coordinator Assistants: M. Harris, M. Hedgpeth, V. Lawrence, M. Lee, P. Lemons, C. Meade, P. Monds, M. Peek, B. Thompson, C. Wang. Pharmacy: D. Christopher, M. Dorsey, L. Fiacco, H. Husn, S. Johnson, K. Johnston, J. Jones, B. Vachieri, A. Watson. Queries: B. Covell, R. Brown, P. Oates, E. Owens, C. Richardson, L. Scott, B. Smith, J. Thayer. Programming: K. Alston, B. Moss, G. Setliff, D. Sumner. CEC: S. Bandy, W. Bradsher, C. Gordon, K. Kruse, M. McClanahan, N. Nare, V. Pleasant, J. Sherron, J. Van Leuven, M. Winchell. CEC Review Physicians: J.H. Alexander, B.S. Crenshaw, R.A. Harrington, W.R. Hathaway, J. Hochrein, K.W. Mahaffey, E.D. Peterson, B.E. Tardiff, M.K. Zabel. Network: C. Blackmon, K. Inch, A.K. Infante, C. Kesler. Randomization: R. Cooper, R. Eckels, D. Kanpie, P. Lewis, D. McGuire, D. Hagins, M. Pamplin, P. Sawyer, A. Skinner, M. Towne, R. Ward, M. Ware, C. Waller. Statisticians: K. Lee, L. Woodlief, T. Bonny, K. Pieper, A. Stebbins. EQOL: D. Mark (PI), N. Clapp-Channing, D. Covington, L. Davidson-Ray, C. Elliott, R. Goldstein, R. Harwood, D. Knight, Y. Li, C. Nelson, J. Parker, H. Read, B. Rhudy. ECG Core Lab: G.S. Wagner (Director of the Core Lab), C. Cambill, K. Gates, Q. Song, S. Starr. Follow-up: G. Wilson. Support Staff: K. Bassett, J. Blanchette, A. Davis, G. Davis, A. Doll, N. Dollar, R. Goldstein, E. Harris, S. Johnson, J. Jones, K. Miller, C. Thomas, K. Wheeler. On-Call Physicians: R. Califf, B. Crenshaw, C. Granger, R. Harrington, B. Hathaway, B. Hillegass, J. Hochrein, K. Mahaffey, M. Ohman, E. Peterson, M.K. Zabel.
Executive Center: Cleveland Clinic Cardiovascular Coordinating Center, Cleveland: E. Topol, V. Castle, L. Konczos, D. Passmore, S. Terranova, T. Zimmerman. CEC: R.S. Augostini, G. Belli, S.J. Brener, A.C. DeFranco, D.S. Eccleston, T.D. Johnson, J. Lefkovits, J.J. Ragan, S.M. Rodkey, W.S. Sheldon, M.J. Silver.
European Coordinating Center: University of Leuven, Leuven, Belgium: F. Van de Werf, A. Luyten, L. Tobback, E. Lesaffre, R. Brower, L. D'Hoore, A. De Clerck, A. Meuris, K. Miscur, D. Van Moll, L. Celis, K. Broos, L. Hutsebaut, C. Luys.
Australia Coordinating Centre: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia: J. Simes, P. Alyward, M. Kava, D. Andreev, A. Keech, C. Thomas, J. Fabri, F. Williams, B. Waite, K. Fraser, L. McClellan, T. Young.
Data Safety and Monitoring Committee: R. Frye, Chairman, M. Cheitlin, D. DeMets, L. Fisher, J. Hirsh, P. Serruys, L. Walters.
United States East 1,078 patients (PA, VA, OH, WV, KY, MD, NY, DE, DC): Danville Regional Medical Center, Danville: G. Miller, D. Walker, B. Zakhary, (Co-PI), St. Agnes Hospital, Baltimore: R. Bahr, H. Peacock, Lancaster General Hospital, Lancaster: S. Worley, J. Ibarra, L. Frey, York Hospital, York: W. Schrading, N. Sonin, Hershey Medical Center, Hershey: I. Gilchrist, H. Zimmerman, Cleveland Clinic Foundation, Cleveland: E. Topol, S. Hejl, St. Joseph Hospital, Lancaster: J. Ibarra, L. Hollywood, Mercy Hospital of Pittsburgh, Pittsburgh: V. Krishnaswami, A. Heyl, Stroobants Heart Center of Virginia, Lynchburg: T. Nygaard, J. White, Audubon Regional Medical Center, Louisville: D. Dageforde, J. Hanrahan, Twin County Community Hospital, Galax: J. Puma, L. Jones, R.W. Johnson, University Hospital, Summit: S. Palmeri, L. Casazza, Surburban Hospital, Bethesda: D. Rosing, C. Clark, St. Luke's Hospital, Bethlehem: H. Dale, T. Moyer, Chester County Hospital, West Chester: T. Boyek, F. Pickering, Licking Memorial Hospital, Newark: B. Morrice, P. Merrick, Good Samaritan Hospital, Dayton: S. Weinberg, C. White, Ohio Valley Medical Center, Wheeling: W. Noble, D. Noble, Good Samaritan Medical Center, Zanesville: J. VanGilder, M. Drake, Shadyside Hospital, Pittsburgh: J. O'Toole, K. Sudina, Medical College of Virginia, Richmond: R. Jesse, C. Roberts, Community Hospital of Lancaster, Lancaster: D. Loss, L. Hollywood, Albert Einstein Medical Center, Philadelphia: J. Wertheimer, F. Incollingo, Brandywine Hospital and Trauma Center, Thorndale: D. Ferrari, J. Tuzi, St. Joseph's Hospital, Parkersburg: M. Santer, D.M. Avington, N. Matheny, Franklin Square Hospital, Baltimore: N. Strahan, P. Heller, Lorain Community/St. Joseph Hospital, Lorain: J. Schaeffer, P. Falasco, Camden Clark Memorial Hospital, Parkersburg: M. Avington, N. Matheny, EMH Regional Medical Center, Elyria: J. Schaeffer, D. Humphrey, C.D. O'Shaughnessy, (Co-PI), Toledo Hospital, Toledo: R. Miller, J. Hofbauer, Bethesda Hospital, Zanesville: J. VanGilder, J. Morris, Louise Obici Hospital, Suffolk: D. Eich, T. Porter, MetroHealth Medical Center, Cleveland: T. Vrobel, M. Woods, The Christ Hospital, Cincinnati: D. Kerieakes, L. Martin, Hamot Medical Center, Erie: S. Sharma, A. Pederson, Delaware County Memorial Hospital, Drexel Hill: W. Beckwith, P. Videtto, Riverside Regional Medical Center, Newport News: P. Micale, S. Gessner, M. Barton, Mansfield General Hospital, Mansfield: W. Polinski, D. Hershner, South, 946 patients (AL, AR, FL, GA, LA, MS, NC, SC, TN): Duke University Medical Center, Durham: C. Granger, E. Berrios, Margaret Pardee Hospital, Hendersonville: P. Goodfield, T. Goodfield, Alamance Regional Medical Center, Burlington: A. Paraschos, L. Paraschos, University Hospital, Augusta: A. Chandler, M. Edwards, McLellan Memorial Veteran's Administration Hospital, Little Rock: J. Talley, S. Ashcraft, University of Arkansas for Medical Sciences, Little Rock: J. Talley, S. Ashcraft, Anderson Area Medical Center, Anderson: H. Morse, D. Spoon, LSU Medical Center, Shreveport: F. Sheridan, R. McRae, R. Whittington, L. Gillespie, Piedmont Hospital, Atlanta: M. Silverman, C. Thomas, G. Lowery, Venice Hospital, Venice: V. Baga, K. Miller, Redmond Regional Medical Center, Rome: J. Ware, J. Sherman, Grace Hospital Inc., Morganton: R. Seagle, J. Macopson, Memorial Mission Hospital, Asheville: W. Maddox, S. Allen, Baptist Medical Center, Jacksonville: J. Schrank, J. Schrank, St. Joseph's Hospital, Savannah: P. Gainey, J. Beatie, D. Baker, R. Greenbush, S. Smith, Alamance Memorial Hospital, Burlington: A. Paraschos, L. Paraschos, Crawford Long Hospital, Atlanta: D. Morris, D. Law-McKenzie, W. Bernard, Presbyterian Hospital, Charlotte: R. Iwaoka, D. Whisnant, HCA-Northwest Medical Center, Margate: R. Schneider, P. Goddard, G. Bruno, East Alabama Medical Center, Opelika: R. Ingram, W.R. Davis, G. Stegall, Floyd Medical Center, Rome: J. Ware, J. Sherman, Roper Hospital, Charleston: K. Hanger, C. Chapuseaux, St. Joseph's Hospital, Asheville: W. Maddox, S. Allen, St. Luke's Hospital, Jacksonville: G. Lane, K. Ebener, Memorial Medical Center, Savannah: W. Beeson, J. Voxnaes, J. Beatie, Tallahassee Memorial Regional Medical Center, Tallahassee: D. Williams, A. Evans, Southeastern Regional Medical Center, Lumberton: C. Beasley, J. Hoekstra, F. Pittman, Morton Plant Hospital, Clearwater: D. Spriggs, S. Wahl, S. Martin, Grady Hospital, Atlanta: R. Schlant, V. Jeffries, Tampa General Hospital: J. Sullebarger, L. Ford, University Community Hospital, Tampa: J. Smith, L. Harrah, West Florida Clinical Research Center, Pensacola: D. Mishkel, J. Lehmann, Bay Medical Center, Panama City: C. Williams, H. Thomason, Mease Health Care Safety Harbor, Safety Harbor: K. Gibbs, P. Hammond, Catawba Memorial Hospital, Hickory: B. Hearon, D. Leger, Orlando Regional Medical Center, Orlando: M. Gonzales, L. Jopperi, Wuesthoff Memorial Hospital, Rockledge: K. Sheikh, F. Quattrocchi, Mease Health Care Center, Dunedin: K. Gibbs, P. Hammond, Northeast Georgia Medical Center, Gainesville: J. Dedonis, D. Schulte, Person County Memorial Hospital, Roxboro: T. Long, S. Best, Cape Fear Valley Medical Center, Fayetteville: K. Popio, D. Carmichael, AMI Frye Regional Medical Center, Hickory: B. Hearon, L. Lewis, Northeast, 691 patients (CT, MA, ME, NH, NY, RI, VT): Wilson Memorial Hospital, Johnson City: N. Jamal, D. Whiting, Maine Medical Center, Portland: C. Lambrew, C. Berg, J. Kane, N. Tooker, Lahey Clinic Medical Center, Burlington: S. Labib, M. Dorland, Mount Sinai Medical Center, New York: D. Vorchheimer, I. Guzman, E. DePeralta, Central Maine Medical Center, Lewiston: R. Weiss, D. Thornton-Chandler, C. Ridley, Leominster Hospital, Leominster: N. Mercadante, B. Kazmierczak, St. Francis Hospital, Roslyn: A. Guerci, C. Gulotta, St. Mary's Regional Hospital, Lewiston: R. Weiss, D. Thornton-Chandler, C. Ridley, Griffin Hospital, Derby: A. Rashkow, J. Shah, Mercy Hospital, Springfield: L. Balleli, S. Traub, J. Holbrook, A. Ranahan, J. Bennet, N. Crane, Rochester General Hospital, Rochester: G. Gacioch, V. Chiodo, St. Lukes-Roosevelt Hospital Center, New York: J. Hochman, A. Palazzo (Co-PI), M. McAnulty, Dartmouth Hitchcock Medical Center, Lebanon: N. Niles, R. Edkins, Greenwich Hospital, Greenwich: H. Seidenstein, H. Reilly, Maimonides Medical Center, Brooklyn: G. Hollander, N. Schulhoff, Northern Westchester Hospital, Mt. Kisco: R. Wallach, K. Keeler, The Memorial Hospital of Rhode Island, Pawtucket: A. Khan, P. O'Neil, Buffalo General Hospital, Buffalo: S. Graham, R. Kohn, M. Henault, M. Bonora, M. Hanna, L. Metzer, Crouse Irving Memorial Hospital, Syracuse: A. Simons, W. Piascik, D. Haig, The Hospital of St. Raphael, New Haven: H. Ward, M. Acampora, N. Valin, Ellis Hospital, Schenectady: R. Parkes, M. Saracco, Medical Center Hospital of Vermont, Burlington: M. Watkins, M. Rowen, Arnot Ogden Medical Center, Elmira: W. DeLuccia, D. Tanner, M. Dooley, Falmouth Hospital, Falmouth: D. Urbach, T. Bull, St. Vincent's Medical Center-Richmond, Staten Island: R. Grodman, M. DeStefano, N. King, University Hospital-North, Staten Island: D. McCord, N. Viswanathan, St. Joseph's Medical Center, Yonkers: M. Bleiberg, M. Rispoli, F. Barker, M. Hoey, Millard Fillmore Hospitals, Williamsville: J. Corbelli, B. Cooke, University of Massachusetts Medical Center, Worcester: J. Gore, S. Ball, University Hospital-South, Staten Island: D. McCord, N. Viswanathan, St. Lukes-Roosevelt Hospital Center, New York: A. Pepe, M. McAnulty, Berkshire Medical Center, Pittsfield: P. Zwerner, A. Droullard, Lowell General Hospital, Lowell: L. Pinsky, L. Pelleriti, York Hospital, York: L. Petrovich, S. Russell, St. Clare's Hospital, Schenectady: B. Lindenberg, M. Saracco, St. Francis Hospital/Medical Center, Hartford: M. Therrien, H. Carney, Mt. Sinai Hospital, Hartford: M. Therrien, H. Carney, New Britain General Hospital, New Britain: M. Sands, P. Malone, Lakes Regional General Hospital, Laconia: A. Rosenfeld, K. Waldron, St. John's Riverside Hospital, Yonkers: S. Sheikh, J. Strauss, Central, 590 patients (IA, IL, IN, KS, MI, MN, MO, ND, NE, OK, SD, WI): Oakwood Hospital, Dearborn: A. Riba, C. Draus, North Memorial Hospital, Robbinsdale: G. Hanovich, A. Antolick, St. Paul-Ramsey Medical Center, St. Paul: L. Swenson, K. Vittum, St. Joseph Mercy Hospital, Ann Arbor: K. Holland, M. Adolphson, C. Trost, University of Michigan Hospital, Ann Arbor: E. Bates, T. Alexandris, A. Galeana, Proctor Hospital, Peoria: P. Schmidt, C. Ness, Butterworth Hospital, Grand Rapids: D. Besley, S. Dunn, Fairview-Southdale Hospital, Edina: W. Hession, S. Sturm, St. Joseph Health Center, St. Charles: F. Ferrigni, B. Magrew, University of Kansas Medical Center, Kansas City: D. Meyers, K. Haffey, Providence Hospital, Southfield: W. Duvernoy, S.W. David, D. Cunningham, Methodist Medical Center, Peoria: P. Schmidt, C. Ness, Christ Hospital, Oak Lawn: B. Abramowitz, K. Wesselhoff, Botsford General Hospital, Farmington Hills: R. Stomel, E. Martin, Deaconess Hospital, Evansville: J. Becker, C. Schaefer, St. Joseph's Hospital/Creighton Cardiology Center, Omaha: A. Mooss, L. Stengel, St. Mary's Medical Centre, Duluth: J. Thompson, C. Neva, T. Gauthier, Bloomington Hospital, Bloomington: L. Calli, J. Smith, C. Beall, DePaul Health Center, Bridgeton: A. Penilla, C. Mir, M. Wiechens, St. Joseph Medical Center, Bloomington: J. McCriskin, M. Hayes, St. Mary's Medical Center, Evansville: R. Millsaps, J. Ernest, St. Joseph Mercy Hospital, Pontiac: J. Heinsimer, T. Lentini, St. Francis Medical Center, Peoria: P. Schmidt, C. Ness, Missouri Delta Medical Center, Sikeston: D. Pfefferkorn, K. Vickery, Trinity Medical Center, Minot: M. Saddin, S. Nelson, Northwestern Memorial Hospital, Chicago: D. Fintel, M. Mistovich, Swedish-American Hospital, Rockford: R. Harner, P. Krause, St. Mary's Hospital, Rochester: S. Kopecky, K. Tucker, Regional Hospital Terre Haute, Terre Haute: P. Andres, R. English, Mercy Medical Center, Cedar Rapids: L. Cook, L. Murray, D. Krichbaum, Elkhart General Hospital, South Bend: F. Wefald, C. Bieber, Blodgett Memorial Medical Center, Grand Rapids: R. Vanderlaan, E. Johnson, Annapolis Hospital, Wayne: J. Love, C. Bodrie, St. Luke's Hospital, Cedar Rapids: L. Cook, M. Jonas, M. Soukup, W. A. Foote Memorial Hospital, Jackson: M. Zands, C. Hanson, St. Francis Medical Center, La Crosse: C. Santolin, S. McBride, St. Luke's Medical Center, Milwaukee: A. Arnold, T. Sommers, St. Alexius Medical Center, Bismarck: R. Oatfield, D. McPherson, Lutheran Hospital, La Crosse: K. Jaeger, D. Larson, Dakota Medical Center, Fargo: E. Dean, J. Quick, West, 438 patients (AZ, CA, CO, ID, MT, NM, NV, OR, TX, WA, WY): Presbyterian Hospital, Albuquerque: H. White, R. Sexson, SW WA Medical Center, Medical Center Campus, Vancouver: R. Swenson, M. Cluzel, St. Mary's Hospital, Tucson: L. Lancaster, D. Lansman, Alameda Hospital, Alameda: S. Raskin, C. Irzyk, Roseville Community Hospital, Roseville: G. Fehrenbacher, L. Frasher, L. Denver, St. Elizabeth Hospital, Beaumont: T. Lombardo, M. Long, Marin General Hospital, Larkspur: B. Strunk, J. Jewell, St. Mark's Hospital, Salt Lake City: J. Perry, W. Schvaneveldt, Memorial Medical Center, Modesto: P. Lai, A. Van Regenmorter, Affiliated Health Services, Mount Vernon: W. Rowe, T. Pearson, V. Seabury, Cottonwood Hospital, Murray: G. Symkoviak, J. Pincock, Pioneer Valley, Salt Lake City: H. Lee, D. Sticinski, J. Balk, Valley Care Medical Center, Pleasanton: H. Kwee, M. Vattuone, HCA Plano, Plano: S. Woolbert, N. Kistler, Santa Rosa Memorial Hospital, Santa Rosa: R. Miller, S. Woods, St. Joseph's Medical Center, Albuquerque: J. Kaplan, G. Steffens, Portland Adventist Medical Center, Portland: B. Titus, J. Shields, UCSF Medical Center, San Francisco: C. Wolfe, O. Dimitratos, Kaweah Delta Hospital, Visalia: D. Cislowski, J. Thompson, Washoe Medical Center, Reno: T. Berndt, K. Locke, Straub Clinic and Hospital, Inc., Honolulu: R. White, C. Morgan, Medical City Dallas Hospital, Dallas: D. Brown, C. Williams, Doctors Hospital, Pinole: D. Hill, P. Gibson, Memorial City Hospital, Houston: G. Hui, K. Carpentier, Spring Branch Medical Center, Houston: G. Hui, P. Torres, Providence Yakima Medical Center, Yakima: R. Spiegel, L. Catts, St. Joseph Hospital, Orange: G. Wesley, A. Keefer-Lynch, L. Pierog, Wyoming Medical Center, Casper: A. Mattern, J. Cann, Tacoma General Hospital, Tacoma: E. Lapin, C. Burton, Yakima Valley Memorial Hospital, Yakima: R. Spiegel, L. Boggess, C. Conally, Mesa Lutheran Hospital, Mesa: M. Stern, C. Hansen, N. Cisar, St. Joseph's Hospital and Medical Center, Phoenix: M. Kraus, K. Enders, K. Harpel, Long Beach Virginia Medical Center, Long Beach: H. Olson, Good Shepherd Medical Center, Longview: R. Scott, C. Hackney, B. Norwood.
Canada (1275): Peterborough Civic Hospital, Peterborough: B.M. Mackenzie, T. Pluard, Royal Alexandra Hospital, Edmonton: W. Hui, L. Kvill, Scarborough General Hospital, Scarborough: S. Roth, J. Smith, Centenary Health Centre, Scarborough: E. Goode, B. Bozek, University of Alberta Hospitals, Edmonton: J. Burton, C. Kee, Grey Nuns Hospital, Edmonton: M.P.J. Senaratne, M. Goeres, Foothills Hospital, Calgary: M. Traboulsi, H. Conradson, Misericordia Hospital, Edmonton: P. Greenwood, A. Prosser, Sunnybrook Health Science Centre, Toronto: C.D. Morgan, K. Freskiw, Ridge Meadows Hospital, Pitt Meadows: F.L. Ervin, S. LeClair, Grace General Hospital, Winnipeg: J.D. McDowell, R. Ziemski, Toronto East General Hospital, Toronto: C.A. Lefkowitz, P. Hambly, Fort McMurray Regional Hospital, Fort McMurray: M. Sauve, Ottawa General Hospital, Ottawa: M. Turek, E. Biro, Victoria Hospital, London: K. Finnie, S. McCreery, Grey Bruce Regional Health Center, Owen Sound: G. Kuruvilla, S. Glass, St. Michael's Hospital, Toronto: A. Langer, W. Sutherland, Scarborough Grace Hospital, Scarborough: J. Charles, J. Simpson, Victoria General Hospital, Halifax: C. Kells, J. Fawcett, Cambridge Memorial Hospital, Cambridge: S. Vizel, J. Laalo, Mission Memorial Hospital, Mission: H. Baillie, J. Holm, Sarnia General Hospital, Sarnia: B. Sahay, M. Zagrodney, Calgary General Hospital, Calgary: D. Roth, P. Beresford, North York General Hospital, Willowdale: B. Lubelsky, J. Penciner, University Hospital, London: G. Jablonsky, M. Allegretti, Rocky View Hospital, Calgary: R. Lesoway, T.F. Cochran, Etobicoke General Hospital, Rexdale: K. Kwok, B. Steinhoffer, Queen Elizabeth Hospital, Charlottetown: C. MacMillan, H. Perry, Mount Sinai Hospital, Toronto: A. Adelman, I. Carter, University of Ottawa Heart Institute, Ottawa: M. Labinaz, S. Kearns.
Italy (1256): Ospedali Riuniti Bergamo: G. Guagliumi, A. Tasca, Istituto Malattie Apparato Cardiovascolare, Bologna: A. Branzi, G. Melandri, Ospedale Morgagni-Pierantoni, Forli. M. Galvani, F. Rusticali, Ospedale Cà Granda Niguarda, Milano: A. Mafrici, M. Paolucci, Ospedale Cà Granda Niguarda, Milano: S. Savonitto, A. Pezzano, Ospedale Maggiore, Novara: G. Fornaro, M.D. Prando, Policlinico San Matteo IRCCS, Pavia: D. Ardissino, E. Colombi, Ospedale S. Maria degli Angeli, Pordenone: D. Zanuttini, F. Pezzetta, Ospedale S. Maria della Croci Ravenna: F. Ottani, S. Bosi, Ospedale Santa Maria dei Battuti, Cà Foncello-Treviso: C. Cavallini, P. Stritoni, Ospedale Maggiore, Trieste: F. Camerini, S. Klugmann, Ospedale di Circolo, Varese: S. Repetto, C. Carella, Ospedale BorgoTrento, Verona: C. Vassanelli, G. Morando, Ospedale di Rho, Rho: E. Rovelli, F. Locati, Ospedale Luigi Sacco, Milano: A. Polese, C. Apruzzese, Ospedale S. Anna, Como: A. Politi, R. Bonatti, Ospedale Civile, Piacenza: A. Capucci, A. Rosi, Ospedale Maurizio Bufalini, Cesena: M. Mambelli, M. Pretolani.
Spain (1234): Hospital Clinico y Provincial, Barcelona: A. Betriu, M. Heras, Hospital Princeps D'Espanya, Hospitalet De Llobregat; Barcelona: X. Sabaté, F. Warner, Residencia Sanitaria Josep Trueta, Gerona: R. Masià, X. Albert, Hospital de Getafe, Madrid: L. López Bescós, M. Montero, Hospital Gregorio Marañon, Madrid: J. López Sendón, E. López de Sà, R. Rubro, Centro de Reanimation Cardiaca, Manresa: L. Jódar, Hospital General de Asturias, Oviedo: A. Rodriquez-Llorian, A. Batalla, Hospital Clinico Universitario, Salamanca: C. Martín-Luengo, P. Pabón, Hospital Mutua de Terrassa, Terrassa: L. Saenz, S. Quintona, Hospital Clinico Universitario, Valladolid: F. Fernadez-Aviles, J. Bermejo, Hospital de Cruces, Barakaldo: J. Froufe, J. Irigoyen, P. Montes, Hospital de Txagorritxu, Vitoria: A. Loma-Osorio, F. Arós, Complejo Hospitalario de León, León: J. Bayón, I. Iglesias.
Australia (1001): Woden Valley Hospital, Woden Act: I. Jeffrey, P. Taverner, Royal North Shore Hospital, St. Leonards: G. Nelson, R. Scammell, Prince of Wales Hospital, Randwick: W. Walsh, V. Tedder, John Hunter Hospital, New Lambton: J. Leitch, U. Grochowicz, St. Vincent's Hospital, Darlinghurst: T. Campbell, C. Corrigan, Sutherland Hospital, Caringbah: J. Healey, F. MacDonald, Illawarra Hospital, Wootongong: D. Owensby, H. Hamilton, St. George Hospital, Kogarah: D. Ramsey, T. Davidson, Prince Henry Hospital, Little Bay: W. Walsh, V. Tedder, The Royal Melbourne Hospital, Parkville: L. Grigg, M. Salaberger, The Alfred Hospital Prahan: J. Ferderman, H. Briggs, Western Hospital, Footscray: R. Newman, C. Peeler, Ballarat Hospital, Ballarat: J. Strickland, L. Taylor, Box Hill Hospital, Box Hill: P. Lim, L. Roberts, Dandenong Hospital, Dandenong: J. Counsell, M. Martin, Royal Brisbane Hospital, Herston: D. Cross, C. Hall, Princess Alexandra Hospital, Woolloongabba: P. Garrahy, C. Hall, Nambour General Hospital, Nambour: S. Coverdale, L. Bullard, Prince Charles Hospital, Chermside: N. Bett, C. Newitt, Gold Coast Hospital, South Port: G. Aroney, P. Hicks, Royal Adelaide Hospital, Adelaide: M. Brown, J. Kealey, Flinders Medical Centre, Bedford Park: P. Aylward, S. Dolan, Lyell McEwin Hospital, Elizabeth Vale: G. Simmons, S. Norton, T. Smith, Queen Elizabeth Hospital, Woodville: J. Horowitz, S. Stewart, Sir Charles Gairdner Hospital, Nedlands: P. Thompson, P. Bradshaw, Royal Perth Hospital, Perth: B. Hockings, T. Cherry, Fremantle Hospital, Fremantle: R. Hendricks, J. Garrett, Royal Hobart Hospital, Hobart: A. Thomson, P. Neid, Launceston General Hospital, Launceston: R. Rankin, J. Shepard.
Netherlands (968): Twenteborg, Almelo: H. Bouma, R.J. Lionarons, Juliana/Lucas Ziekenhuis, Apeldoorn: L. Cozijnsen, E.G. Faber, Rijnstate Ziekenhuis, Arnhem: P. Stolwijk, Slingeland Ziekenhuis Doetinchem: H. Drost, Gelderse Vallei Bennekom, Bennekom: P. van Kalmthout, T.T. van Loenhout, Scheperziekenhuis, Emmen: J. Engbers, R. Tjon Ka Jie, Beatrixziekenhuis, Gorinchem: P. Westendorp, P. van Rossum, St. Jansdal, Harderwijk: J. Voorburg, R. Dijkgraaf, St. Franciscusziekenhuis, Rotterdam: M. Veerhoek, A. Schelling, Ziekenhuis De Heel, Zaandam: Tan Pao-Han, C.L. van Engelen, Lorentzziekenhuis, Zeist: L. Bogerijen, A. Limburg, Sophia Ziekenhuis, Zwolle: A.R. Ramdat Misier, A.T.M. Gosselink, Rijnstate Ziekenhuis, Arnhem: H. Bosker, Maasziekenhuis, Boxmeer: W. Smits, J.R.M. Peters, Andreasziekenhuis, Amsterdam: T.B. Tan.
Belgium (952): Clin. Univ. Saint-Luc, Bruxelles: J. Col, R. Lauwers, Clinique Saint-Jean, Bruxelles: M. Castadot, E. De Wit, Clin. Univ. de Mont-Godinne, Yvoir: E. Installé, E. Schroeder, Hôpital de Jolimont, La Louvière: A. De Meester, U.Z. Gasthuisberg, Leuven: F. Van de Werf, A. Luyten, Hôpital de la Citadelle, Liège: J. Boland, P. Baumans, C.H.U. Sart Tilman, Liège 1: V. Legrand, E. Gobin, Jan Palfijnziekenhuis; Merksem: J. Vanwelden, Clinique Saint-Pierre, Ottignies: B. Pirenne, Onze Lieve Vrouwziekenhuis, Oudenaarde: C. Emmerechts, P. Vandebruaene, H. Hartziekenhuis, Roeselare: R. Beeuwsaert, D. Clement, Stadskliniek, Sint-Niklaas: H. Thiels, F. De Keyser Regionaal Ziekenhuis St. Trudo, Sint-Truiden: J. Beckers, P. Peerenboom, Sint-Elisabethziekenhuis, Turnhout: H. Lesseliers, J. Thoeng, Sint-Augustinuskliniek, Veurne: R. Popeye, J. Peperstraete.
France (533): Hopital Sud, Amiens: J.C. Quiret, G. Jarry, C.H.G. Robert Ballanger, Aulnay s/s/ Bois: J.P. Maroni, G. Hanania, Hopital Ambroise Pare, Boulogne: B. Farah, J.P. Bourdarias, Hopital Morvan, Brest: Y. Etienne, J. Boschat, C.H.R. Rene Dubos, Cergy Pontoise F. Funck, N. Guillard, Centre Hospitalier General, Longjumeau: X. Tran Thanh, C. Jouannon, Hop. Notre Dame du Bon Secours, Metz: K. Khalife, F. Ben Ahmed, Hop. Arnaud de Villeneuve, Montpellier: F. Leclercq, R. Grolleau-Raoux, Centre Hospitalier de Nevers, Nevers: B. Vitoux, Hopital St. Antoine, Paris: A. Cohen, B. Blanchard-Lemoine, Hopital Necker-Enfants Malades, Paris: A. Vacheron, J.P. Metzger, Hopital Font-Pre, Toulon: D. Barreau, P. Sans.
Germany (313): Christina Albrechts Universit, Kiel: R.D. Simon, Krohn, MD, Kreiskrankenhaus Gifhorn, Gifhorn: H.U. Kreft, Städtisches Krankenh Gütersloh, Gütersloh: H. Ditter, Wefers, MD, Med. Univ. Klinik Freiburg, Freiburg: A.M. Zeiher, Schächinger, MD, St. Marien Hospital, Kohn: Weizner, MD, Evangelisches Krankenhaus Kalk, Köln: R. Wacker, F. Schneider, Ernst Möritz Arndt Univ,. Greifs, Greifswald: Marbach, MD, F. Hummal, Ketteler Krankenhaus, Offenbach: H.P. Nast, Schröder, MD, St. Jürgen Krankenhaus Bremen, Bremen: H. Meyer-Hofmann, Schwarze, MD, Kreiskrankenhaus Herford, Herford: U. Schmitz-Hübner, Rosocha, MD, Rupracht Karis Universität Heidelberg: M.C. Bode, Nordt, MD, Klpinder Philips-Univ. Marburg, Marburg: B. Maisch, Gehrke, MD, Krankenhaus am Urban, Berlin Kreuzberg: H. Topp, Nöthel, MD, Freie Universität Berlin, Berlin: W. Rutsch, F. Brunckhorst, Klinikkum Remscheid GmbH, Remscheid: H. Löllgen, Schüler, MD.
New Zealand (263): New Zealand Coordinating Centre: H. White, M. Scott, Middlemore Hospital, Otabuhu: M. Williams, J. Hinge, Wairau Hospital, Blenheim: D.S. Durham, M. Johnston, Rotorua Hospital, Rotorua: B. Bruns, M. Liley, A. Morley, Tauranga Hospital, Tauranga: D. Hayes, V. Watts, Wellington Hospital, Wellington: P. Leslie, D. Middleditch, North Shore Hospital, Auckland: H. Hart, T. Haldane, Christchurch Hospital, Christchurch: H. Ikram, T. Lawson, Hutt Hospital, Lower Hutt: S. Mann, J. Dewar, Nelson Hospital, Nelson: A.R. Kirk, J. Hawke, Timaru Hospital, Timaru: D. Jardine, P. Carstenson, Whangarei Area Hospital, Whangarei: R. Rankin, Ashburton Hospital, Ashburton: M. Audeau, A. Smart, Taranaki Base Hospital, New Plymouth: S. Anandaraja, S. Megee, Green Lane Hospital, Auckland: H. White, J. French, L. Bush.
United Kingdom (253): Bedford General Hospital, Bedford: I. Cooper, D. Flisher, Whipps Cross Hospital, London: J. Hogan, B. Coleman, Hemel Hempstead General Hospital, Hemel Hempstead:D. Hackett, J. Bayliss, Luton and Dunstable Hospital, Luton: C. Travill, W. Piller, Yeovil District Hospital, Yeovil: G. Bridgon, J. Reid, Derriford Hospital, Plymouth: C. Burrell, J. Foren, South Cleveland Hospital, Middlesborough: M. Debelder, C. Khurana, Royal Bournemouth Hospital, Bournemouth: A. Rozkovec, P. Williams, Ealing Hospital, Southall, Middlesex: J. Kooner, N. Smith, Taunton and Somerset Hospital, Taunton: M. James, D. Ghosh, Charing Cross Hospital, London: E. Garcia, J. Aleck.
Sweden (217): Sahlgrenska Hospital, Göteborg: H. Emanuelsson, Mölndal Hospital, Mölndal: M. Risenfors, H. Holmberg.
Switzerland (184): Kantonspital, Basel: M. Pfisterer, U. Klöter, Tiefenauspital, Bern: H.R. Baur, M. Brack, Hopital Cantonal, Geneve: Urban, MD, S. Burgan, Ospedale Civico, Lugano: T. Mocetti, M. Pons, Kantonsspital, St. Gallen: W. Angehrn, M. Diethelm, Stadtspital Triemli, Zurich: O. Bertel, P. Hunziker, Universitatsspital, Zurich: F.W. Amann, P.C. Baumann.
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