Catheterization and Cardiovascular Diagnosis 26:177-184 (1992)
Multicenter Dose-Finding Trial for Thrombolysis With Urokinase Preactivated Pro-Urokinase (TCL 598) in Acute Myocardial Infarction Dietrich C. Gulba, MD, MSc, Christoph Bode, MD, Semi Sen, MD, Jurgen Topp, MD, Klaus Fischer, MD, Helmut Wolf, MD, MSC, Hartmut Hecker, PhD, and the German Preactivated Pro-Urokinase Study Group In a multicenter do-finding study, the thrombolytic potency of urokinase preactivated pro-urokinase was evaluated. Sixty-two patients were randomly assigned to receive 250,000 U of uroklnasie plus either 4.5 mega U (group I: n =33) or 6.5 mega U (group II: n=29) of prwrokinase. Patency rates were 36.4% (20.4-54.9%) vs. 54.5% (36.3-71.9%) (n=27) at 60 minutes and 55.6% (32.5-70.6%) vs. 62.1% (42.3-79.3%) at 90 min into thrombolysis (n.8.). in a third group of 12 patients treated with 500,OOO U of urokinase pius 6.5 mega U of pro-urokinase patency was achieved in 33.3% (9.9451%) and 41.7% (15.2-72.3%) at 60and 90 mln, respectively. Patency rates at 24 hr follow-up angiography (n= 35)were 78.6% (49.2-95.3%), 85.7% (57.2-98.2%), and 85.7% (42.1-99.6%). Coagulb tion analysis in 37 patients reveaied similar alterations in W three treatment groups with minor decreases In fibrinogen levels, moderate drops in plasminogen and u2-antiplasmln levels, and moderate increases in the concemtrations of the total fibrinogen/fibrln degradation products, the differences between the groupa not being slgnlficant. Bleeding complications were observed In 12.9%, 13.8%, and 25% of patients In groups I, 11, and 111, respectively, mainly related to catheter sites. Hence, the safety profile of urokinase preactivated pro-uroklnase seems comparable to other thrombolytic regimens. Reopening of occluded coronary arteries, however, is achieved relatively slowly. Thus, In its use for thrombolysis In myocardial Infarction, urokinase preactlvated prourokinase does not seem to offer superior advantages. Q 1992 WIIOY-UU, im. Key words: thrombolytic therapy, patency rates, UWPUK regimen
tor-pro-urokinase (PUK)or single-chain urokinase type plasminogen activator (scu-PA) [ 13,141-has become In a series of randomized placebo controlled trials, available for clinical research. First clinical experience in thrombolysis has proven to significantly reduce early patients suffering from AM1 revealed, however, that pamortality of acute myocardial infarction (AMI) [l-41. tency rates of some 70% with this plasminogen activator Now, as this therapy is transferred from the specialists can only be achieved by excessively high doses [ 15-1 71, into general clinical practice, there is increasing demand for safer thrombolytic agents than those presently available. This has prompted intense activities in new drug From the Cardiology Divisions of Hannover Medical School, Rudevelopment [5]. Recombinant tissue type plasminogen precht Karls University Heidelberg, University of Homburg, Hospital activator (rt-PA), the first drug resulting from these re- ‘am Urban’ Berlin, ‘Vinzenz’ Hospital Hannover, and Sandoz AG, search activities, has recently been introduced into the Numberg, Institute for Biostatistics, Hannover Medical School, Germarket. With this plasminogen activator, 90 min patency many. rates from 60-91% have been reported from various clin- Received September 27, 1991; revision accepted Janaury 30, 1992. ical trials [6-121. These findings indicate a substantial benefit in thrombolytic efficacy over streptokinase, a sub- Address reprint requests to Dietrich C. Gulba, Cardiology Division, stance which may achieve patency rates of 40-65% only Hannover Medical School, Konstanty-Gutschow-StraSe8, D-3000 [6-181. For its only limited fibrin specificity and unex- Hannover 61, Germany. pectedly high bleeding rates, however, it has already been Abbreviations: A M , acute myocardial infarction; PUK, pro-urokiquestioned whether rt-PA will fulfill its promise. nase; UK, urokinase; rt-PA, recombinant tissue type plasminogen acRecently, another fibrin specific plasminogen activa- tivator. INTRODUCTION
0 1992 Wiley-Liss, Inc.
178
Gulba et al.
leading to a major loss of the fibrin specificity in some studies [ 16,181. The mechanism of action of PUK is not yet completely elucidated. Two plausible mechanisms have been suggested [ 19,201, both of which support the hypothesis that PUK might be activated by the administration of a low dose urokinase (UK) bolus, either by accelerating the process of self activation [ 191 or by creating lys-binding sites at the clot surface [20]. By both mechanisms, the inherent lag phase of the substance [5,14] could be overcome. Recent clinical findings further promote this hypothesis [15,21]. This study has therefore been designed as a multicenter dose-finding trial for UK preactivated PUK. MATERIALS AND METHODS Patient Selection Patients of either sex with symptoms characteristic for AM1 with the onset of symptoms 75 years, 3) pregnancy, 4) history of recent cerebrovascular accident, 5 ) recent major trauma or surgery, 6) recent gastrointestinal bleeding, 7) known bleeding tendency or coumarin therapy, and 8) all other contraindicationsto either thrombolytic therapy or cardiac catheterization. A history of remote AM1 was not regarded an exclusion criterion for the study. Written informed consent was obtained from all patients prior to enrollment into the study.
Coronary angiography was performed according to the Judkins technique. Arterial and venous access was obtained from the right groin. The first coronary angiogram was recorded not later than 60 min after thrombolysis had been commenced. If, at 60 min into therapy, the coronary artery was still occluded, thrombolysis was allowed to continue for another 30 min without administration of additional thrombolytics. At 90 min into thrombolysis an additional coronary angiogram was recorded. If the infarct related coronary artery was still occluded, it was left to the discretion of the investigator to perform “rescue” coronary angioplasty. In case of patency of the infarct related vessel the investigators were also free to decide to continue with immediate coronary angioplasty. In patients not undergoing immediate coronary interventions, the investigators were encouraged to record a third coronary angiogram approximately 24 hr after thrombolysis. Patients were randomly assigned to the treatment groups (I and 11). Randomization was performed separately for each particpating center in blocks of 10 patients prior to the start of patient enrollment. In a second phase of the trial patients were consecutively assigned to the third treatment group. Prior to the study, the study protocol had been approved by the local ethics committees. Power Calculations Power calculations were based on the following assumptions: 1) a 15% (absolute) difference in the patency rates between the treatment groups, and 2) an expected patency rate of 60-65% in the lower dose group. Based on these assumptions, the study was scheduled for the inclusion of 200 patients, to detect a significant difference between the treatment groups (alpha error: C0.05; beta error
Multicenter Dose-Finding Trial for Thrombolysis With Urokinase Preactivated Pro-Urokinase (TCL 598) in Acute Myocardial Infarction Dietrich C. Gulba, MD, MSc, Christoph Bode, MD, Semi Sen, MD, Jurgen Topp, MD, Klaus Fischer, MD, Helmut Wolf, MD, MSC, Hartmut Hecker, PhD, and the German Preactivated Pro-Urokinase Study Group In a multicenter do-finding study, the thrombolytic potency of urokinase preactivated pro-urokinase was evaluated. Sixty-two patients were randomly assigned to receive 250,000 U of uroklnasie plus either 4.5 mega U (group I: n =33) or 6.5 mega U (group II: n=29) of prwrokinase. Patency rates were 36.4% (20.4-54.9%) vs. 54.5% (36.3-71.9%) (n=27) at 60 minutes and 55.6% (32.5-70.6%) vs. 62.1% (42.3-79.3%) at 90 min into thrombolysis (n.8.). in a third group of 12 patients treated with 500,OOO U of urokinase pius 6.5 mega U of pro-urokinase patency was achieved in 33.3% (9.9451%) and 41.7% (15.2-72.3%) at 60and 90 mln, respectively. Patency rates at 24 hr follow-up angiography (n= 35)were 78.6% (49.2-95.3%), 85.7% (57.2-98.2%), and 85.7% (42.1-99.6%). Coagulb tion analysis in 37 patients reveaied similar alterations in W three treatment groups with minor decreases In fibrinogen levels, moderate drops in plasminogen and u2-antiplasmln levels, and moderate increases in the concemtrations of the total fibrinogen/fibrln degradation products, the differences between the groupa not being slgnlficant. Bleeding complications were observed In 12.9%, 13.8%, and 25% of patients In groups I, 11, and 111, respectively, mainly related to catheter sites. Hence, the safety profile of urokinase preactivated pro-uroklnase seems comparable to other thrombolytic regimens. Reopening of occluded coronary arteries, however, is achieved relatively slowly. Thus, In its use for thrombolysis In myocardial Infarction, urokinase preactlvated prourokinase does not seem to offer superior advantages. Q 1992 WIIOY-UU, im. Key words: thrombolytic therapy, patency rates, UWPUK regimen
tor-pro-urokinase (PUK)or single-chain urokinase type plasminogen activator (scu-PA) [ 13,141-has become In a series of randomized placebo controlled trials, available for clinical research. First clinical experience in thrombolysis has proven to significantly reduce early patients suffering from AM1 revealed, however, that pamortality of acute myocardial infarction (AMI) [l-41. tency rates of some 70% with this plasminogen activator Now, as this therapy is transferred from the specialists can only be achieved by excessively high doses [ 15-1 71, into general clinical practice, there is increasing demand for safer thrombolytic agents than those presently available. This has prompted intense activities in new drug From the Cardiology Divisions of Hannover Medical School, Rudevelopment [5]. Recombinant tissue type plasminogen precht Karls University Heidelberg, University of Homburg, Hospital activator (rt-PA), the first drug resulting from these re- ‘am Urban’ Berlin, ‘Vinzenz’ Hospital Hannover, and Sandoz AG, search activities, has recently been introduced into the Numberg, Institute for Biostatistics, Hannover Medical School, Germarket. With this plasminogen activator, 90 min patency many. rates from 60-91% have been reported from various clin- Received September 27, 1991; revision accepted Janaury 30, 1992. ical trials [6-121. These findings indicate a substantial benefit in thrombolytic efficacy over streptokinase, a sub- Address reprint requests to Dietrich C. Gulba, Cardiology Division, stance which may achieve patency rates of 40-65% only Hannover Medical School, Konstanty-Gutschow-StraSe8, D-3000 [6-181. For its only limited fibrin specificity and unex- Hannover 61, Germany. pectedly high bleeding rates, however, it has already been Abbreviations: A M , acute myocardial infarction; PUK, pro-urokiquestioned whether rt-PA will fulfill its promise. nase; UK, urokinase; rt-PA, recombinant tissue type plasminogen acRecently, another fibrin specific plasminogen activa- tivator. INTRODUCTION
0 1992 Wiley-Liss, Inc.
178
Gulba et al.
leading to a major loss of the fibrin specificity in some studies [ 16,181. The mechanism of action of PUK is not yet completely elucidated. Two plausible mechanisms have been suggested [ 19,201, both of which support the hypothesis that PUK might be activated by the administration of a low dose urokinase (UK) bolus, either by accelerating the process of self activation [ 191 or by creating lys-binding sites at the clot surface [20]. By both mechanisms, the inherent lag phase of the substance [5,14] could be overcome. Recent clinical findings further promote this hypothesis [15,21]. This study has therefore been designed as a multicenter dose-finding trial for UK preactivated PUK. MATERIALS AND METHODS Patient Selection Patients of either sex with symptoms characteristic for AM1 with the onset of symptoms 75 years, 3) pregnancy, 4) history of recent cerebrovascular accident, 5 ) recent major trauma or surgery, 6) recent gastrointestinal bleeding, 7) known bleeding tendency or coumarin therapy, and 8) all other contraindicationsto either thrombolytic therapy or cardiac catheterization. A history of remote AM1 was not regarded an exclusion criterion for the study. Written informed consent was obtained from all patients prior to enrollment into the study.
Coronary angiography was performed according to the Judkins technique. Arterial and venous access was obtained from the right groin. The first coronary angiogram was recorded not later than 60 min after thrombolysis had been commenced. If, at 60 min into therapy, the coronary artery was still occluded, thrombolysis was allowed to continue for another 30 min without administration of additional thrombolytics. At 90 min into thrombolysis an additional coronary angiogram was recorded. If the infarct related coronary artery was still occluded, it was left to the discretion of the investigator to perform “rescue” coronary angioplasty. In case of patency of the infarct related vessel the investigators were also free to decide to continue with immediate coronary angioplasty. In patients not undergoing immediate coronary interventions, the investigators were encouraged to record a third coronary angiogram approximately 24 hr after thrombolysis. Patients were randomly assigned to the treatment groups (I and 11). Randomization was performed separately for each particpating center in blocks of 10 patients prior to the start of patient enrollment. In a second phase of the trial patients were consecutively assigned to the third treatment group. Prior to the study, the study protocol had been approved by the local ethics committees. Power Calculations Power calculations were based on the following assumptions: 1) a 15% (absolute) difference in the patency rates between the treatment groups, and 2) an expected patency rate of 60-65% in the lower dose group. Based on these assumptions, the study was scheduled for the inclusion of 200 patients, to detect a significant difference between the treatment groups (alpha error: C0.05; beta error
