Association Between Thrombolytic Treatment and the Prognosis of Hemodynamically Stable Patients With Major Pulmonary Embolism
Results of a Multicenter Registry
Background Thrombolytic treatment has been shown to accelerate resolution of major pulmonary embolism and lead to a rapid improvement of right-side hemodynamics. However, the association between these favorable effects and the clinical outcome of patients who have no severe hemodynamic compromise at presentation remains unknown.
Methods and Results The present multicenter registry included 719 consecutive patients with major pulmonary embolism according to clinical, echocardiographic, scintigraphic, and cardiac catheterization criteria. Symptom onset was acute (<48 hours) in 63% of patients. All patients were hemodynamically stable (ie, without evidence of cardiogenic shock) at presentation. Primary thrombolytic treatment (within 24 hours of diagnosis) was given to 169 patients (23.5%), whereas the remaining 550 patients were initially treated with heparin alone. Overall 30-day mortality was significantly lower in the patients who received thrombolytic agents (4.7 versus 11.1%, P=.016). Clinical factors associated with a higher death rate were syncope (P=.012), arterial hypotension (P=.021), history of congestive heart failure (P=.013), and chronic pulmonary disease (P=.032). However, only primary thrombolysis was found by multivariate analysis to be an independent predictor of survival (odds ratio for in-hospital death, 0.46; 95% confidence interval, 0.21 to 1.00). Patients who underwent early thrombolytic treatment had a reduced rate of recurrent pulmonary embolism (7.7 versus 18.7%, P<.001) but also a higher frequency of major bleeding episodes (21.9% versus 7.8%, P<.001). Cerebral bleeding occurred in 2 patients in each treatment group, and 1 patient in each group died of a bleeding complication.
Conclusions The results of our study suggest that thrombolysis may favorably affect the clinical outcome of hemodynamically stable patients with major pulmonary embolism.
Thrombolytic agents are frequently used in the setting of acute major pulmonary embolism. In particular, thrombolytic treatment is advocated for patients who present with hemodynamic instability, refractory hypoxemia, or echocardiographic findings indicating right ventricular failure.1 However, the existing clinical evidence in support of these recommendations cannot be considered conclusive. During the past 3 decades, several studies compared the efficacy of streptokinase2 3 or alteplase (recombinant tissue plasminogen activator4 5 6 with conventional heparin anticoagulation and demonstrated the superiority of thrombolysis in restoring patency of occluded pulmonary vessels. It could further be shown that rapid clot lysis was accompanied by resolution of pulmonary hypertension5 and echocardiographically detected right ventricular afterload stress.6 On the other hand, the impact of this rapid hemodynamic improvement on the clinical outcome of patients with major pulmonary embolism has not yet been investigated in large-scale clinical trials.7 8 Therefore, it currently is unsettled whether the potential clinical benefits of thrombolysis compared with heparin anticoagulation clearly outweigh the risk of serious hemorrhagic complications1 5 9 and thus justify this form of treatment even in patients who present without severe hemodynamic compromise caused by failure of the right side of the heart.
The present study was based on a large multicenter registry of patients with major pulmonary embolism. Its aim was to assess the clinical efficacy and safety of thrombolytic treatment as opposed to conventional heparin anticoagulation in patients who were hemodynamically stable (ie, without cardiogenic shock or circulatory collapse) at presentation. Our hypothesis was that early thrombolysis (within 24 hours of diagnosis) favorably affects the clinical outcome of these patients during the in-hospital phase, especially with regard to mortality and recurrent pulmonary thromboembolism, at an acceptably low risk of life-threatening bleeding complications.
The study population was derived from the patients included in the Management Strategy and Prognosis of Pulmonary Embolism Registry.10 11 The registry was conducted between September 1993 and December 1994. During this period, the 204 participating centers throughout Germany (listed in the “Appendix”) registered a total of 1001 consecutive patients in whom the diagnosis of major pulmonary embolism was made according to predefined criteria. The inclusion criteria of the registry consisted of the following clinical, echocardiographic, and cardiac catheterization findings signifying failure of the right side of the heart and/or pulmonary hypertension caused by pulmonary embolism: (1) arterial hypotension, defined as systolic blood pressure <90 mm Hg or a pressure drop of ≥40 mm Hg for >15 minutes if not caused by new-onset arrhythmia, hypovolemia, or sepsis; (2) cardiogenic shock in which the presence of arterial hypotension as defined above was accompanied by clinical signs of organ hypoperfusion and hypoxia (altered level of consciousness, urine output <30 mL/h, and cold and clammy extremities); (3) circulatory collapse with need for cardiopulmonary resuscitation; (4) echocardiographic findings indicating right ventricular afterload stress and/or pulmonary hypertension (right ventricular dilation, ie, a right ventricle appearing larger than the left ventricle from the apical or subcostal view, paradoxical septal wall motion, loss of inspiratory collapse of the inferior vena cava, or tricuspid regurgitation jet velocity >2.8 m/s or >2.5 m/s in the absence of inspiratory collapse of the inferior vena cava) without evidence of mitral valve disease or left ventricular dysfunction; and (5) diagnosis of precapillary pulmonary hypertension (mean pulmonary artery pressure >20 mm Hg in the presence of normal pulmonary artery occlusion pressures) by catheterization of the right side of the heart.
Patients with clinically suspected pulmonary embolism were included in the registry if they met at least one of the above criteria at presentation together with a diagnostic pulmonary angiogram, a lung scan indicating high probability of pulmonary embolism, or at least three of the following findings obtained from clinical examination, blood gas analysis, or the initial ECG: (1) syncope, (2) tachycardia (heart rate >100 bpm), (3) dyspnea and/or tachypnea (breathing rate >24 breaths per minute or need for mechanical ventilation), (4) arterial hypoxemia (partial arterial pressure of oxygen <70 mm Hg while breathing room air or <80 mm Hg under supplemental oxygen of ≥2 L/min) in the absence of pulmonary infiltrates on chest roentgenogram, and (5) ECG signs of right ventricular strain (at least one of the following: complete or incomplete right bundle-branch block, S waves in lead I combined with Q waves in lead III, or negative T waves in the precordial leads V1 through V3).
The present study considered for statistical evaluation only those registry patients who had evidence of pulmonary hypertension and/or right ventricular afterload stress on echocardiography or catheterization of the right side of the heart but no arterial hypotension at presentation and patients who initially had arterial hypotension resulting from pulmonary embolism but no clinical signs of cardiogenic shock or need for catecholamine infusion (except ≤5 μg · kg−1 · min−1 dopamine). Patients presenting with severe hemodynamic compromise (cardiogenic shock or circulatory collapse) were not included in this analysis.
Two groups of patients were defined on the basis of the therapeutic strategy followed after diagnosis of pulmonary embolism. The first, or thrombolysis, group consisted of those patients who underwent primary thrombolytic treatment, defined as treatment given within 24 hours of diagnosis, followed by heparin anticoagulation. The second group included patients who were treated with heparin alone and those who initially received heparin and were judged by the attending physician to require thrombolytic treatment later during the hospital course (ie, after the first 24 hours). Intravenous anticoagulation was continued for 5 to 7 days in both treatment groups, and the dose (infusion rate) of heparin was adjusted to keep the activated partial thromboplastin time at 2.0 to 3.0 times normal. After overlapping administration with warfarin for 3 to 4 days (in patients without contraindications to oral anticoagulants), heparin was discontinued when the international normalized ratio reached the therapeutic range of 2.0 to 3.0.
The therapeutic approach, particularly the decision to proceed to thrombolytic treatment and the choice of the thrombolytic regimen, was based on the judgment of the physicians involved in each case. The Steering Committee of the registry did not exert any influence on the management strategy followed by the participating centers and physicians.
Complete information on the clinical course and the diagnostic and therapeutic management of the patients entering the registry was obtained by means of a standardized questionnaire (case report form). Data were collected on (1) the clinical symptoms and signs of the patients at diagnosis, including arterial blood gases and chest roentgenograms; (2) the presence of underlying diseases or predisposing factors for pulmonary thromboembolism; (3) the findings of all diagnostic procedures performed, including ECG, echocardiographic, and nuclear imaging studies, catheterization of the right side of the heart, and pulmonary angiography; (4) the treatment given to the patients (heparin anticoagulation, thrombolysis, surgical pulmonary embolectomy, catheter thrombus fragmentation, and caval filter implantation); and (5) the in-hospital clinical course of the patients, including recurrent pulmonary embolism and bleeding complications or causes of death and autopsy findings for those who died during the acute phase.
Definition of Clinical End Points
The primary clinical end point of the present study was overall 30-day mortality. Secondary end points were clinically apparent recurrence of pulmonary embolism (as diagnosed by the on-site clinical investigator) and major bleeding episodes during the hospital stay. Major bleeding was defined as hemorrhagic stroke confirmed by computed tomography or autopsy or as a bleeding episode that fulfilled at least one of the following criteria: a decrease in hemoglobin levels of at least 2 g/dL, requirement for a blood transfusion of 2 U or more, retroperitoneal bleeding, or bleeding that required surgical intervention or discontinuation of heparin anticoagulation or thrombolytic treatment.
For descriptive purposes, quantitative variables are presented as mean±SD; qualitative variables, as absolute and relative frequencies. According to the intent-to-treat principle, patient assignment to the two treatment groups was based on the primary treatment (ie, thrombolysis or heparin anticoagulation) given within 24 hours of diagnosis regardless of changes in treatment undertaken later during the hospital course. Patients belonging to the two groups were compared by Fisher’s exact test for dichotomous variables and by the Wilcoxon rank test for continuous variables. The impact of primary thrombolytic treatment and other clinically important baseline variables on 30-day mortality and the secondary clinical end points was analyzed univariately by Fisher’s exact test. To investigate whether the prognostic effect of early thrombolysis is independent of other clinical variables, a multiple logistic regression model was also applied to the major end point of overall 30-day mortality. In this model, we took into account all clinical variables that reached a value of P<.20 in the univariate comparison of treatment assignment or mortality. The results of the logistic regression models are presented as estimated odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). All significance tests were two-sided, with a value of P<.05 considered to indicate clinical significance. Data processing and analysis were performed with the Statistical Analysis System.
Clinical and Echocardiographic Findings at Diagnosis
The population analyzed in this report was made up of 719 patients, 428 women and 291 men, with a mean age of 62.7±15.2 years (range, 16.2 to 89.7 years). A high-probability lung scan was available in 467 patients (65%), and pulmonary angiography was performed in 136 patients (19%), confirming the presence of pulmonary thromboembolic obstruction. Overall, 528 study patients (73%) had confirmation of pulmonary embolism by at least one of these imaging studies. Echocardiographic examination performed in 552 patients (77%) revealed the presence of right ventricular pressure overload and/or pulmonary hypertension in 441 of these patients (80%). Furthermore, 168 patients (23%) underwent catheterization of the right side of the heart that disclosed the presence of precapillary pulmonary hypertension in all patients.
B-mode and/or Doppler ultrasonographic or phlebographic studies were performed in 605 patients (84%) and established the diagnosis of deep vein thrombosis in 467 of the patients studied (77%). Of these, 360 patients (77%) had proximal vein thrombosis, whereas the remaining 107 patients had isolated calf vein thrombosis.
After diagnosis of major pulmonary embolism, 169 patients (24%) received thrombolytic treatment within the first 24 hours. The thrombolytic agents used were alteplase in 104 patients (62%), streptokinase in 29 (17%), and urokinase in 36 (21%). The remaining 550 patients initially underwent conventional heparin anticoagulation. In 125 of these patients (23%), the attending physicians proceeded to thrombolytic treatment later during the hospital stay (ie, after the first 24 hours).
Table 1⇓ gives the clinical characteristics of the two patient groups. The mean age of patients who underwent primary thrombolysis was 59.1±14 years compared with 63.8±15.4 years in the heparin group. A history of deep vein thrombosis was more frequent in patients initially given thrombolytic agents (37% versus 28%, P=.035). On the other hand, congestive heart failure and chronic pulmonary disease were both less frequent in this group (16% versus 36% and 3.6% versus 12%, respectively; Table 1⇓). There was no significant difference between the thrombolysis and heparin groups with regard to mean systolic blood pressure at presentation (114±26 versus 111±33 mm Hg, P=.36), breathing rate (26 versus 25 breaths per minute, P=.44), or partial arterial pressure of oxygen while breathing room air (56.3 versus 56.6 mm Hg, P=.70).
Overall 30-Day Mortality
The mean duration of hospital stay after diagnosis of major pulmonary embolism was 25±15 days. Overall 30-day mortality was 9.6%, and death was directly related to the pulmonary thromboembolic event in the vast majority of cases (65 of 69 deaths; 94%). As Table 2⇓ shows, overall mortality was significantly lower in the group of patients who underwent primary thrombolysis compared with those who were initially treated with heparin alone (4.7% versus 11.1%, P=.016). Univariate analysis also revealed that the following clinical characteristics at presentation were significantly associated with a higher death rate during the acute phase (Table 3⇓): syncope (14.4% versus 7.8%), arterial hypotension (12.6% versus 7.3%), history of congestive heart failure (13.9% versus 7.7%), and chronic pulmonary disease (17.1% versus 8.8%).
Dilation of the right ventricle, a very sensitive index of right ventricular pressure overload,12 was detected in 380 of the 552 patients who underwent echocardiography (69%). Thirty-day mortality was 10% in these patients as opposed to 4.1% in those without a dilated right ventricle (P=.018). Finally, 30-day mortality was higher in patients who were found to have proximal vein thrombosis by ultrasonographic or phlebographic studies (7.8%) compared with patients with negative studies or those with evidence of calf (ie, distal) vein thrombosis (4.5%). However, this difference did not reach statistical significance (P=.13).
Multiple logistic regression analysis demonstrated that the reduction of 30-day mortality associated with primary thrombolytic treatment still remained evident after adjustment for the influence of other relevant clinical characteristics at presentation (OR, 0.46; 95% CI, 0.21 to 1.00). In fact, primary thrombolysis was the only clinical variable that reached statistical significance as an independent predictor of outcome in our patient population (P=.051; Table 4⇓).
In an attempt to identify those patients of the registry population who might have particularly benefited from thrombolytic treatment, we examined the association between primary thrombolysis and overall 30-day mortality within the patient subgroups defined on the basis of the clinical characteristics at diagnosis (as displayed in Table 1⇑). It was found that in patients <65 years of age, mortality after primary thrombolysis was as low as 3.0%, approximately one third of the mortality rate observed in the heparin group (9.2%, P=.07). On the other hand, mortality rates of older patients (> 65 years of age) were 7.1% and 12.6% in the thrombolysis and heparin groups, respectively (P=.30). The difference between the mortality rates of the two treatment groups was also especially prominent in patients presenting with arterial hypotension (4.4% versus 14.9%) or syncope (4.4% versus 17.9%) compared with patients without those clinical findings at diagnosis (5.0% versus 8.1% and 4.9% versus 8.9%, respectively). Patients without a history of recent major surgery had a low 30-day mortality after primary thrombolysis (2.9% compared with 12.3% after heparin anticoagulation), whereas thrombolytic treatment was associated with a tendency toward increased mortality in the setting of postoperative pulmonary embolism (12.5% versus 7.6%). Finally, analysis of the patients with echocardiographically detected right ventricular enlargement revealed a mortality rate of 4.7% in the thrombolysis group compared with 11.1% in the heparin group (P=.16).
Other Clinical Events During the Hospital Stay
Clinically apparent recurrence of pulmonary embolism was diagnosed in 116 patients (16%). As Table 2⇑ shows, recurrent pulmonary embolism was significantly less frequent in patients who were initially treated with thrombolytic agents compared with those treated with heparin alone (7.7% versus 18.7%, P<.001). On the other hand, there was a tendency toward a higher rate of recurrence in patients with proximal vein thrombosis (17.2% versus 11.4%, P=.06) and among the 45 patients in whom two-dimensional echocardiography detected the presence of right-side thrombi (26.7% versus 15.7%, P=.09).
Major bleeding episodes occurred in 80 patients (11.1%). The rate of major bleeding was significantly higher in the 169 patients in the thrombolysis group (21.9 versus 7.8%; Table 2⇑) and required discontinuation of thrombolytic treatment and/or surgical intervention in 19 of these patients (11%). On the other hand, cerebral hemorrhage was rare, occurring in 2 patients in each group (1.2% and 0.4%, respectively). One patient in each group died as a result of a bleeding complication.
The present multicenter study examined the prognostic impact of thrombolytic treatment in 719 hemodynamically stable patients with major pulmonary embolism. The clinical end points of our study were 30-day mortality, clinically apparent recurrence of pulmonary embolism, and the occurrence of major bleeding complications during the hospital stay. Primary thrombolysis (ie, within 24 hours of diagnosis) was shown to be associated with a significant reduction in both overall mortality and the rate of recurrent pulmonary embolism at a 1.2% risk of cerebral hemorrhage. The association between thrombolysis and improved survival was especially prominent in patients <65 years of age and in those presenting with arterial hypotension or syncope, whereas patients with postoperative pulmonary embolism did not appear to benefit from thrombolytic treatment.
Compared with conventional heparin anticoagulation, thrombolytic agents are known to accelerate the resolution rate of pulmonary thromboembolic occlusion3 4 and have a favorable effect on right-side hemodynamics.5 6 These changes are evident within 24 hours of the beginning of thrombolytic treatment,2 6 13 whereas resolution of pulmonary embolism treated with heparin alone usually takes 2 weeks or more.14 15 Thrombolysis may have lifesaving potential in patients with major pulmonary embolism and hemodynamic instability at presentation.16 Mortality of these patients with severe right-side failure is known to be as high as 32%, and most deaths are expected to occur within the first 24 hours.17 On the other hand, no adequate data were available until now to answer the question of whether patients with major pulmonary embolism who present without evidence of cardiogenic shock are also likely to benefit from thrombolytic treatment. This patient group has a relatively low in-hospital mortality (between 5% and 10%17 18 ), a fact that justifies concern that the rapid hemodynamic improvement achieved with thrombolysis might be overshadowed by the risk of life-threatening bleeding complications.
The patients included in our study had pulmonary thromboembolism with evidence of pulmonary hypertension and/or failure of the right side of the heart. In this patient population, overall 30-day mortality was associated with the presence of chronic pulmonary disease and a history of congestive heart failure, a finding that is in accordance with previous reports.18 Multivariate logistic regression analysis demonstrated that early thrombolytic treatment remained an independent predictor of survival during the in-hospital phase after adjustment for the relevant clinical findings at diagnosis. The favorable effect of thrombolysis on the patients’ prognoses was probably a result of the rapid improvement in right ventricular dysfunction previously reported by other authors.6 In the present registry, a 58% reduction in mortality was observed after the use of thrombolytic agents in the subgroup of patients with echocardiographically detected right ventricular enlargement at diagnosis.
Early thrombolysis was associated with a significantly lower rate of clinically apparent recurrent pulmonary embolism in our patients, a result that is in agreement with the observations of Goldhaber et al.6 Recurrent pulmonary embolism has also been found to be related to the presence of proximal deep vein thrombosis.19 In our registry, pulmonary embolism recurred in 17.2% of the patients with sonographic or phlebographic evidence of proximal vein thrombosis as opposed to 11.4% in patients with calf vein thrombosis or negative imaging studies.
It should be noted that the aim of our study was to examine the clinical efficacy and safety of primary thrombolysis as opposed to heparin anticoagulation and not to compare various thrombolytic agents or regimens. It has been suggested that resolution of pulmonary embolism is faster after alteplase treatment compared with urokinase,9 20 but the hemodynamic effects of the two agents were equivalent by 12 to 24 hours in those studies. The clinical implications of the differences observed between the pharmacodynamics of the various thrombolytic agents, if any, remain unknown.7
The present study was based on a multicenter registry designed to investigate current management strategies in major pulmonary embolism. Assignment of the patients to the two treatment arms (thrombolysis versus heparin) was thus nonrandomized, and the choice of treatment was left to the discretion of the physicians caring for the patient. With such an observational design, selection bias is likely. We found that the distribution of the following clinical variables was significantly different between the two patient groups: age, history of venous thrombosis, history of congestive heart failure, presence of chronic pulmonary disease, and history of stroke. In particular, patients who received thrombolytic treatment were younger than patients treated with heparin alone. Furthermore, a history of preexisting cardiac or pulmonary disease was less frequent in patients of the thrombolysis group. Therefore, our analysis with regard to the major end point of 30-day mortality was based on a multivariate regression model that took the relevant prognostic parameters into account. However, even multivariate analysis cannot be expected to eliminate the biasing effect of all known and potentially unknown confounding factors. Finally, the effect of thrombolysis on the recurrence of pulmonary embolism might have been influenced by bias in the clinical diagnosis of recurrent thromboembolic events by the on-site investigators.
The results of our study suggest that early thrombolytic treatment may favorably affect the in-hospital clinical outcome of hemodynamically stable patients with major pulmonary embolism. Thrombolysis appears to reduce overall mortality and recurrence of pulmonary embolism without a high risk of severe bleeding complications. Thus, the present registry provides a first link between the hemodynamic benefits of thrombolysis and clinically relevant end points in the setting of pulmonary embolism. These promising results emphasize the need for a prospective randomized trial that will definitely clarify the role of thrombolytic agents in a group of patients whose potentially life-threatening disorder is masked by an apparent hemodynamic stability at presentation.
The following centers and physicians in Germany participated in the Management and Prognosis of Pulmonary Embolism Registry.
Luisen-Hospital, Aachen: Drs J. Ontyd and D. Wolter; Kreis- krankenhaus Achern: Dr P. Reimling; Kreiskrankenhaus Altenburg: Dr J. Janitschek; Kreiskrankenhaus am Plattenwald, Bad Friedrichshall: Dr N. Röhrig; Evangelisches Krankenhaus Bad Gandersheim: Dr R. Zahn; Caritas Krankenhaus Bad Mergentheim: Drs H. Bechtold, Haag, N. Heller, and M. Klein; William Harvey Klinik, Bad Nauheim: Dr Stahl; Schüchtermann-Klinik, Bad Rothenfelde: Dr W. Kranig; Kreiskrankenhaus Bad Urach: Drs T. Antenrieth and B. Jung; Stadtklinik Baden-Baden: Drs W. Kaschner and L. Lévai; Krankenhaus Ballenstedt: Dr B.U. Franz; Krankenhaus Hohe Warte, Bayreuth: Dr J. Kothmann; Klinikum Bayreuth: Drs Mang and S. Schmitt; Evangelisches Krankenhaus Bergisch Gladbach: Drs H.J. Schmitz and P. Schweizer; Marienkrankenhaus Bergisch Gladbach: Dr S. Hinzmann; Krankenhaus im Friedrichshain: Dr U. Abet; Universitätsklinikum Rudolf Virchow, Berlin: Drs D. Gulba, H.J. Kleiner, and S. Kubitza; Humboldt-Krankenhaus, Berlin: Drs R. Bartels, Mazur, U. Pohlmann, and J. Weber; DRK Kliniken Westend, Berlin: Dr J. F. Schröder; Krankenhaus Bethel, Berlin: Dr A. Stolper; Malteser-Krankenhaus, Berlin: Dr L. Wieczorkowski; Städtische Krankenanstalten Bielefeld-Mitte: Dr B. Leeuw; Städtisches Krankenhaus Bietigheim: Dr D. Hey; Heilig-Geist-Hospital, Bingen: Dr W. Schmidt; St Josef Hospital, Bochum: Dr Böckenförde; Augusta-Kranken-Anstalt, Bochum-Linden: Dr Lessmann; Berufsgenossenschaftliche Kliniken Bergmannsheil, Bochum: Dr Machraoui; Universitätsklinik Bonn: Dr T. Brecht; Evangelisches Krankenhaus Bonn-Bad Godesberg: Dr J. von Düsterlho; St Marien-Hospital, Bonn: Drs S. Kern and Runkel; St Petrus-Krankenhaus, Bonn: Dr H. Hüneburg; Städtisches Klinikum Brandenburg: Dr U. Huber; Städtisches Klinikum Braunschweig: Dr Kooymann; Zentralkrankenhaus Bremen-Nord: Dr W. Bürgener; Zentralkrankenhaus Bremen-Ost: Dr T. Hilmer; Krankenhaus Bruchsal: Dr M. Braun, Dr J. Koster; Kreiskrankenhaus Buchen: Drs Rauchenbach, H. Ribwitzky, and Zöll; Kreiskrankenhaus Burghausen: Drs Saswatendu and S. Sarkar; Kreiskrankenhaus Burglenfeld: Dr F. J. Riedhammer; Lukas-Krankenhaus, Bünde: Drs D. Brunswig and M. Hilgedieck; Evangelisches Krankenhaus Castrop-Rauxel: Dr W. Jaedicke; Städtische Kliniken Chemnitz: Dr T. Vieth; St Josefs-Hospital, Cloppenburg: Dr A. Bleuer; St Vincenz-Hospital, Coesfeld: Dr M. Greguletz; Städtische Kliniken Darmstadt: Dr Evers; St Vincenz-Krankenhaus, Datteln: Dr R. Grün; Kreiskrankenhaus Demmin: Dr V. Brümmer; Herz-Jesu-Krankenhaus, Dernbach: Dr M. Schollen; Klinikum Lippe-Detmold: Dr U. Tebbe; Krankenhaus St Elisabeth, Dillingen: Dr Emmert; Evangelisches Krankenhaus Dinslaken: Dr R. O. Scheemann; Katholisches Krankenhaus Dortmund-West: Dr U. Hanheide; Städtische Kliniken Dortmund: Dr K. Sondern; Krankenhaus Düren: Drs G. Hanenberg, E. von der Lohe, and W. Winkels; Krankenhaus Ebersbach: Dr B. Neumann; Kreiskrankenhaus Ehingen: Dr B. Platt; Kreiskrankenhaus Ellwangen: Dr Dietterle; Kreiskrankenhaus Emmendingen: Dr S. Bölch; Medizinische Hochschule Erfurt: Drs C. Schubert and G. Vogel; Alfried Krupp von Bohlen und Halbach Krankenhaus Essen: Dr M. Benn; St Markus-Krankenhaus, Frankfurt/M.: Dr O. Ludwig; Krankenhaus Sachsenhausen, Frankfurt/M: Dr H. Wetzel; Universitätsklinik Freiburg: Drs M. Redecker and J.A. Rump; Stadtkrankenhaus Friedberg/Bayern: Dr A. Stiebens; Bürgerhospital Friedberg/Hessen: Dr A. Jäckel; Hospital zum Heiligen Geist, Fritzlar: Dr W. Beinroth; Kreiskrankenhaus Gaildorf: Dr Richardt; Universitätsklinik Giessen: Drs F. Nix and G. Schütterle; Kreiskrankenhaus Rudolf Virchow, Glauchau: Drs G. J. Hermsdorf and K. Meyer; Klinik am Eichert, Göppingen: Drs M. Egle and H. Giesler; Evangelisches Krankenhaus Göttingen-Weende: Dr K. Würm; Klinik für Innere Medizin der Universität Greifswald: Dr M. Wierbitzky; Kreiskrankenhaus Gross-Gerau: Dr Litschke; Kreiskrankenhaus Güstrow: Drs S. Duda and P. Ring; St Elisabeth-Hospital, Gütersloh: Dr A. Neuwirth; Städtisches Krankenhaus Gütersloh: Drs H. Heusslein and Wefers; Evangelisches Krankenhaus Hagen-Haspe: Drs W. Liman, P. Peter, and F. Strauch; Allgemeines Krankenhaus Wandsbek, Hamburg: Dr Güttschmidt; Evangelisches Krankenhaus Bethesda, Hamburg: Dr K. P. Stadler; Krankenhaus Hameln: Dr K. Meyne; Marienhospital Hamm: Dr W. Schürhoff; Universitätsklinik Heidelberg: Drs Katus and C. Tiefenbacher; St Josefs- krankenhaus Heidelberg: Dr M. Reichardt; Städtisches Krankenhaus Heilbronn: Drs J. Cyran and J. Berentelg; Paracelsus-Klinik, Henstedt-Ulzburg: Drs U. Jander-Kleinau and H. Krukemeyer; Kreiskrankenhaus Herford: Dr S. Rosocha; Evangelisches Krankenhaus Herne: Dr W. Sehnert; St Elisabeth-Krankenhaus, Hünfeld: Dr A. Greiner; von Bodelschwingh-Krankenhaus, Ibbenbüren: Dr R. Volkmar; Städtische Krankenanstalten Idar-Oberstein: Dr R. Grossmann; St Elisabeth-Hospital, Iserlohn: Dr M. Bermes; Evangelisches Krankenhaus Bethanien, Iserlohn: Dr Lilienbeck; Evangelisches Diakonissen-Krankenhaus, Karlsruhe: Dr M. Rohlehr; Krankenhauszweckverband Kaufbeuren-Ostallgäu: Dr H. Meyer-Borchert; Städtisches Krankenhaus Kiel: Dr G. Becker; Krankenhaus Evangelische Stift St Martin, Koblenz: Dr N. Kaul; Krankenanstalten Konstanz: Dr T. Hannemann; St Elisabeth-Krankenhaus, Köln: Dr J. Schoenemann; St Franziskus-Hospital, Köln: Dr E. Jennen; Kreiskrankenhaus Kösching: Dr F. Lacher; Krankenhaus Maria-Hilf, Krefeld: Drs M. Dichgans and P. Ohlert; Städtische Krankenanstalten Krefeld: Drs Knoch and G. Smits; Kreiskrankenhaus Lahr: Dr B. Wiedemer; St Johannis-Krankenhaus Landstuhl: Dr M. Vesmanis-Johannes; Dreieich-Krankenhaus Langen: Dr K. Rudolph; Städtisches Krankenhaus Lauchhammer: Dr I. Franke; Kreiskrankenhaus Lehrte: Dr C. Hauptmann; Städtisches Klinikum St Georg, Leipzig: Drs F. Mickley and G. Thiele; Evangelisches Krankenhaus Lengerich: Drs Amshoff-Jacobs, H. Fromm, and Pfeiff; Kreiskrankenhaus Giessen in Lich: Drs Borowek and K. H. Hohmann; Helmut-G.-Walther-Kreiskrankenhaus, Lichtenfels: Dr E. Dünninger; Kreiskrankenhaus Limbach-Oberfrohna: Dr M. Schellner; Kreiskrankenhaus Lohr/Main: Dr R. Meininger; Städtisches Krankenhaus Lörrach: Dr M. Frank; St Marienkrankenhaus, Ludwigshafen: Dr V. Biliati; Klinikum der Stadt Ludwigshafen/Rhein: Dr R. Zahn; Kreiskrankenhaus Lübbecke: Dr M. Grosse; Spreewald-Klinik Lübben: Drs H. Reinhold and F. Schwertfeger; Städtisches Krankenhaus Lüneburg: Dr H. Niederstadt; Mühlenberg-Klinik Malente: Dr W. Grote; Kreiskrankenhaus Mallersdorf: Dr W. Feldmeier; Klinikum Mannheim: Dr J. Harenberg; Paracelsus-Klinik Marl: Dr R. Klähn; Krankenhaus Ludmillenstift, Meppen/Ems: Dr H. Hoetz; Kreiskrankenhaus Merzig: Dr Jöst; Kreiskrankenhaus Miltenberg/Main: Dr G. Voigt; Klinikum Minden: Dr W. Lengfelder; Kamillianer-Krankenhaus Mönchengladbach: Dr P. Linsenmann; Stauferklinik Schwäbisch Gmünd, Mutlangen: Dr C. Büchmann; Kreiskrankenhaus Mühlacker: Dr G. Kleine; Kreiskrankenhaus Mühldorf: Dr K. Igerl; Kreiskrankenhaus Müllheim: Drs C. Hans and Moser; Kreiskrankenhaus München-Pasing: Dr C. Wonkas; Städtisches Krankenhaus München-Neuperlach: Dr M. Spinner; Kreiskrankenhaus Münsingen: Dr Hohlstein; Universitätsklinik Münster: Drs R. Mesters and H. Ostermann; Clemenshospital Münster: Dr R. Plagwitz; Klinken St Elisabeth, Neuburg/Donau: Dr E. Huber; St Josef-Krankenhaus Neunkirchen: Dr M. Bollen; Ruppiner Klinikum, Neuruppin: Dr K. J. Schmailzl; Krankenhaus Hetzelstift, Neustadt: Drs B. Menges, Nitsch, and T. Thürauf; Krankenhaus Nienburg: Dr A. Roth; Städtisches Krankenhaus Norderney: Dr K. Platte; Klinikum der Stadt Nürnberg: Dr J. Herold; Kreiskrankenhaus Nürtingen: Dr J. Breuning, Dr H.H. Krause; Krankenhaus Oberstdorf: Dr B. Ricken; Kreiskrankenhaus Offenburg: Dr U. Stephinger; Städtische Kliniken Oldenburg: Dr Bruns; Paracelsus-Krankenhaus Ruit, Ostfildern: Dr G. Späth; Kreiskrankenhaus Otterndorf: Dr S. Senger; St Johannisstift Paderborn: Dr J. Matzke; Marienhospital Papenburg: Dr H.J. Jantke; Kreiskrankenhaus Peine: Dr F. Weyn; Städtisches Krankenhaus Pforzheim: Dr H. Vollmer; Krankenhaus Pfullendorf: Dr D. Widmann; Klinikum Ernst von Bergmann, Potsdam: Dr H. Gunold; St Joseph-Krankenhaus Prüm: Dr L. Czikajlo; Kreiskrankenhaus Radebeul: Dr A. Mütze; Krankenhaus der Barmherzigen Brüder, Regensburg: Dra B. Fichtl and Niederer; Krankenanstalten der Stadt Remscheid: Dr U. Fahrenkrog; Kreiskrankenhaus Reutlingen: Drs M. H. Hust and W. Spengler; Jakobi-Krankenhaus Rheine: Dr D. Bauer; Kreiskrankenhaus Riesa: Dr A. Hedrich; Kreiskrankenhaus Rockenhausen: Dr H. Burkhardt; Kreiskrankenhaus Rodewisch/Obergöltzsch: Dr A. Lambert; Diakoniekrankenhaus Rotenburg: Dr T. Richardt; Kreiskrankenhaus Roth: Dr A. Struntz; Kreiskrankenhaus Rotthalmünster: Dr J. Baum; Krankenhaus Vinzentinum, Ruhpolding: Dr G. Meurers; Krankenhaus Saarlouis vom Deutschen Roten Kreuz: Dr Lehmann; Nordwest Krankenhaus Sanderbusch, Sande: Dr R. Keymling; Kreiskrankenhaus Schkeuditz: Dr R. Oettel; Krankenhaus Kloster-Grafschaft, Schmallenberg-Grafschaft: Dr B. Schönhofer; Leopoldina-Krankenhaus Schweinfurt: Dr D. Siebenlist; Klinikum Schwerin: Dr P. Lazarus; Kreiskrankenhaus Sinsheim: Dr M. Bollhorst; Hellmuth-Ulrici-Klinik, Sommerfeld: Drs B. Schneider and G. Schulz; Stadtkrankenhaus Sonthofen/Oberallgäu: Drs M. Baumgarten and H. K. Giesen; Krankenhaus der Evangelischen Diakonissenanstalt, Speyer: Dr G. Tippel; Krankenhaus Stade: Dr Missler; Klinikum der Hansestadt Stralsund: Drs B. Flor and G. Müller-Esch; Karl-Olga-Krankenhaus Stuttgart: Dr W. Presmeier; Kreiskrankenhaus Sulingen: Dr Bokelmann; Kreiskrankenhaus Titisee-Neustadt: Dr L. Herkel; Kreiskrankenhaus Traunstein: Drs W. Drost and K. Schlotterbeck; Krankenanstalt Mutterhaus der Borromäerinnen, Trier: Dr H. Siebner; Marienkrankenhaus Trier: Dr A. Traut; Kreiskrankenhaus Tuttlingen: Dr E. Kauder; Albert-Schweitzer-Krankenhaus Uslar: Dr Kamrad; Klinikum der Stadt Villingen-Schwenningen: Dr Kohler; Krankenhaus St Michael, Völklingen/Saar: Dr P. Krüger; St Antonius Krankenhaus, Wegberg: Dr C. Härtel; Kreiskrankenhaus Weinheim: Dr F. Hoeltermann; Krankenhaus Wermeiskirchen: Dr R. Böhm; Krankenhaus Wettin: Dr M. Meisel; St Josefs-Hospital Wiesbaden: Drs B. Busse, Elsner, A. Furtwängler, A. Meyer, A. Roth, and M. Werner; Katharinen-Hospital, Willich: Dr Krahnstöver; Städtisches Krankenhaus Wismar: Dr F. Hauzeur, Dr S. Plietzsch; Kreiskrankenhaus Wolfach: Dr H.H. Braun; Stadtkrankenhaus Wolfsburg: Dr B. Gerecke; Stadtkrankenhaus Worms: Drs A. Müller and W. Schmalz; Krankenhaus Marienhöhe, Würselen: Dr R. Harlacher; Missionsärztliche Klinik Würzburg: Dr A. Horowitz; Kreiskrankenhaus Zwiesel: Drs K. H. Hurka and C. Propfe.
This work was supported by a combined grant from Dr Karl Thomae, GmbH, and Behringwerke AG Pharmaceuticals.
- Received December 16, 1996.
- Revision received February 27, 1997.
- Accepted March 9, 1997.
- Copyright © 1997 by American Heart Association
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