Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: Initial patency and influence of maintained infusion on reocclusion rate

doi:10.1016/0002-9149(87)90219-0

The American Journal of Cardiology

Volume 60, Issue 4, 1 August 1987, Pages 231-237

https://doi.org/10.1016/0002-9149(87)90219-0 Get rights and content

Abstract

An intravenous infusion of 40 mg of recombinant tissue-type plasminogen activator (rt-PA) was given intravenously over 90 minutes to 123 patients with acute myocardial infarction (AMI) of less than 4 hours' duration. A coronary angiogram was recorded at the end of the infusion in 119 patients. Central assessment of the angiograms revealed a patent infarct-related artery in 78 patients (patency rate 66%, 95% confidence limits 57 to 74%). Patients with a patent infarct-related artery at the first angiogram were randomized in a double-blind manner to receive a subsequent 6-hour infusion of either 30 mg of rt-PA or placebo. All patients had received an initial bolus of 5,000 IU of heparin and then 1,000 IU/hour until a second angiogram was recorded 6 to 24 hours after the start of the second perfusion. At central assessment of the second coronary angiogram the reocclusion rate was 2 of 36 patients who received rt-PA at the second infusion and 3 of 37 patients not receiving this drug (or the 2 groups combined 7%, 95% confidence limits 2 to 15%). Three of 60 patients (5%, 95% confidence limits 1 to 14%) with patent arteries on both previous angiograms had a later occlusion as judged on the angiogram recorded at hospital discharge. No difference in late reocclusion rates between the 2 treatment groups was observed.

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Cited by (91)

HTUPA as a new thrombolytic agent for acute myocardial infarction: A multicenter, randomized study
2014, International Journal of Cardiology
Citation Excerpt :
In our study, the all-cause mortality within 30 d (5.5% in the rt-PA group and 6.3% in the HTUPA group) was lower than that reported by Keeley et al. (9%) in a quantitative review of 23 randomized trials [17]. It is reported that early re-occlusion occurs in 5–30% of patients who undergo successful recanalization by thrombolytic therapy using a first or second-generation agent [18–20]. The relatively short half-life of the currently available thrombolytic agents is the major reason for re-occlusion.
It is necessary to develop a new thrombolytic agent which can be used by a single bolus at first aid sites to decrease the time to reperfusion in clinical practice. HTUPA, a genetically engineered new thrombolytic with a longer half-life, is well qualified. We aim to compare the thrombolytic efficacy and safety of human tissue urokinase type plasminogen activator (HTUPA) to recombinant tissue plasminogen activator (rt-PA) in Chinese patients with acute myocardial infarction (AMI).
AMI patients (n = 221) were randomized to rt-PA (a standard protocol) or HTUPA (25 mg bolus) treatment groups. All patients also received oral aspirin and intravenous heparin. Coronary angiography was performed 90 min after therapy initiation to determine infarct-related coronary artery (IRA) patency. Clinical outcomes and changes of clotting variables, heart rate, blood pressure, left ventricular ejection fraction (LVEF), and electrocardiogram were evaluated.
Patent IRA [thrombolysis in myocardial infarction (TIMI) grade 2 or 3] was observed in 77% of HTUPA-treated patients, compared to 76% of rt-PA-treated patients (P = 0.76). TIMI grade 3 patency rates were 52% and 44% in the HTUPA and rt-PA groups, respectively (P = 0.37). The total patency rate was 77% (86/111 patients) in the HTUPA group and 73% (80/110 patients) in the rt-PA group (P = 0.41). Adverse events were infrequent in both groups, and no significant differences were detected in mortality, re-occlusion rate, revascularization rate, adverse effects, clotting index, LVEF, or electrocardiogram between the two groups.
Intravenous HTUPA had a safe and efficacious profile as good as rt-PA in patients with AMI.
Failed reperfusion after thrombolytic therapy: Recognition and management
2002, Heart and Lung: Journal of Acute and Critical Care
Citation Excerpt :
TIMI 3 flow in the infarct-related artery after thrombolysis has been associated with decreased mortality when compared with TIMI 2 (slow) flow and TIMI 0 or 1 (none or minimal) flow, as well as decreased incidence of congestive cardiac failure, recurrent ischemia and improved left ventricular ejection fraction.13 However it has been reported that reperfusion fails to occur at all in 25% of patients,6,14,15 and in 50% to 70% of patients at 90 minutes after thrombolytic administration.5,6 It is not entirely clear why some patients fail to reperfuse with thrombolytic therapy.
Background: Failed reperfusion after thrombolysis occurs in as many as 30% of patients with acute myocardial infarction (MI). Furthermore, some patients have incomplete tissue perfusion despite reperfusion of the infarct-related artery. Close assessment of the efficacy of thrombolytic administration in people with evolving acute MI is necessary, particularly with regard to myocardial perfusion status, because some patients may benefit from incremental pharmacologic or invasive reperfusion strategies. Purpose and Method: This article reviews a number of strategies to assess infarct-related artery patency and myocardial tissue perfusion. These include coronary angiography, continuous ST-segment monitoring, serial electrocardiography, obtaining serial serum biochemical markers of myocardial necrosis, monitoring for reperfusion arrhythmias, and assessment of changes in chest pain intensity. Conclusion: The early detection of failed reperfusion is critical if incremental strategies to enhance myocardial salvage are to be considered. Continuous ST-segment monitoring is a relatively inexpensive, reliable, and accurate tool for assessing real-time myocardial perfusion. (Heart Lung® 2002;31:113-21.)
Interaction of heparin with fibrinogen using surface plasmon resonance technology: Investigation of heparin binding site on fibrinogen
1996, Thrombosis Research
Regulation of plasminogen activator inhibitor activity in endothelial cells by tissue-type plasminogen activator
1996, Fibrinolysis
Tissue-type plasminogen activator (t-PA) may stimulate the expression of plasminogen activator inhibitor type 1 (PAI-1) mRNA in cultured human umbilical vein endothelial cells. The PAI-1 antigen in the conditioned medium of cells, pretreated with t-PA, was less than the control, probably due to the formation and degradation of the t-PA·PAI-1 complex. However, the PAI activity of the t-PA-pretreated cells reached the same level as control group, 24 h after the residual t-PA activity was rapidly neutralized by the newly synthesized PAI-1. To test the release of PAI-1 from the substratum of the endothelial cells, the cultured cells were metabolically prelabeled with ³⁵S-methionine for 3h and then treated with t-PA. The ³⁵S-PAI-1 of 46 kDa was found in the substratum and culture medium of cultured endothelial cells as analyzed by the SDS-PAGE after immunoprecipitation. During the treatment of endothelial cells with t-PA, the PAI-1 of 46 kDa in the cell substratum disappeared, and the 110kDa t-PA·PAI-1 complex, the 81 kDa degraded t-PA·PAI-1, and the 44 kDa degraded PAI-1 products concomitantly appeared in the conditioned medium instead. In summary, t-PA can regulate the fibrinolytic activity of endothelial cells by enhancing PAI-1 mRNA biosynthesis and release PAI-1 from the substratum to neutralize t-PA activity. The PAI-1 which released into the medium was immediately converted to the inactive latent form in the absence of active t-PA.
Ridogrel as an adjunct to thrombolysis in acute myocardial infarction
1995, International Journal of Cardiology
An open pilot study was performed to assess the safety and preliminary efficacy of ridogrel, a selective thromboxane-A₂ synthetase inhibitor and thromboxane-A₂/prostaglandin endoperoxide receptor blocker, as adjunct to thrombolysis with alteplase and heparin. In 50 patients with acute myocardial infarction, 300 mg ridogrel was injected intravenously in addition to alteplase and heparin. Ridogrel was continued orally (300 mg) twice daily for 5 days. Patency rate at initial (90 min) angiography, defined as thrombolysis in myocardial infarction perfusion grades 2 or 3, was 86%. Rescue percutaneous transluminal coronary angioplasty was performed in 10 patients; immediate results were good in nine, while a large dissection occurred in one patient. New ischemia occurred in 10 patients within 24 h, and after the second angiogram in seven cases. Three underwent coronary artery bypass grafting and seven percutaneous transluminal coronary angioplasty without further complication. Patency rate at second angiography (between 6 and 24 h) was 94%. New Q-waves appeared in 56% of the patients; 36% had a non-Q-wave infarction and 8% had no enzyme rise. Enzymatic infarct size, estimated by the cumulative quantity of a-hydroxybutyrate dehydrogenase released in 72 h, was substantially smaller than in comparable studies with rt-PA and heparin. One patient died due to a cerebrovascular hemorrhage. No other deaths occurred. Bleeding complications were seen in 18 patients (36%), necessitating blood transfusion in three. Reinfarction did not occur. Eventually 49 patients were discharged in good condition. Safety with regard to bleeding complications of ridogrel in conjunction with alteplase is about the same as that of aspirin. Immediate and late patency rates were high. Rescue percutaneous transluminal coronary angioplasty could be performed with relative safety and early reocclusion could be successfully dealt with by repeat percutaneous transluminal coronary angioplasty. Further studies with this or similar compounds seem warranted.
Concurrent nitroglycerin administration reduces the efficacy of recombinant tissue-type plasminogen activator in patients with acute anterior wall myocardial infarction
1995, American Heart Journal
The aim of this study was to evaluate the impact of concurrent nitroglycerin administration on the thrombolytic efficacy of recombinant tissue-type plasminogen activator (rTPA) in patients with acute anterior myocardial infarction (AMI). Sixty patients (53 men, 7 women; mean age 54 ± 7 years) with AMI entered the study. Thirty-three patients were randomized to receive rTPA alone (100 mg in 3 hours) (group A) and 27 to receive rTPA plus nitroglycerin (100 μg/min) (group B). Time from the onset of chest pain and delivery of rTPA was similar in the two groups of patients. Patients in group A had signs of reperfusion more often than the patients in group B (25 of 33 or 75.7% vs 15 of 27 or 55.5%, p < 0.05). Time to reperfusion was also shorter in group A than in group B (19.6 ± 9.4 minutes vs 37.8 ± 5.9 minutes, p < 0.05). Group B had a greater incidence of in-hospital adverse events (9 of 27 vs 5 of 33, p < 0.05) and a higher incidence of coronary artery reocclusion (8 of 15 or 53.3% vs 6 of 25 or 24%, p < 0.05). Peak plasma levels of rTPA antigen were higher in group A compared with group B (1427 ± 679 vs 512 ± 312 ng/ml, p < 0.01). In conclusion, concurrent nitroglycerin administration reduces the thrombolytic efficacy of rTPA in patients with AMI probably by lowering the plasma levels of rTPA antigen. The diminished efficacy of rTPA is associated with an adverse outcome.

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Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: Initial patency and influence of maintained infusion on reocclusion rate

Abstract

Lancet

Lancet

Am Heart J

Am J Cardiol

Am Heart J

JACC

Am J Cardiol

Am J Cardiol

Am J Cardiol

Lancet

Am J Cardiol

Blood

Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial

Circulation

The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings

N Engl J Med