A Randomized Trial of a Single Bolus Dosage Regimen of Recombinant Tissue Plasminogen Activator in Patients with Acute Pulmonary Embolism

doi:10.1378/chest.98.6.1473

Chest

Volume 98, Issue 6, December 1990, Pages 1473-1479

https://doi.org/10.1378/chest.98.6.1473 Get rights and content

Experiments in animals have demonstrated that recombinant tissue plasminogen activator (rt-PA) produces continuing thrombolysis after it is cleared from the circulation and that thrombolysis is both increased and accelerated, and bleeding is reduced when rt-PA is administered over a short period. In previous studies in patients with thrombotic disease, rt-PA has been shown to be an effective thrombolytic agent when administered by continuous infusion over a period between 90 minutes and 8 hours. To determine whether a short course regimen of rt-PA can achieve thrombolysis, a double-blind randomized trial has been conducted in which patients with objectively established acute symptomatic pulmonary embolism who were receiving heparin were allocated to either a 2-minute infusion of rt-PA at a dose of 0.6 mg/kg (33 patients) or saline placebo (25 patients). Perfusion lung scanning was used to assess the change in pulmonary perfusion at 24 hours and seven days post-study drug administration. Thirty-four percent of the rt-PA patients had a greater than 50 percent resolution in the perfusion defect at 24 hours compared to 12 percent of placebo patients (p = 0.026). At 24 hours, the mean relative improvement in the perfusion defect was 37.0 percent in rt-PA treated patients compared to 18.8 percent in the placebo group (p = 0.017). By day 7, no difference in lung scan resolution was detected between the groups. There were no major bleeds in either group nor were there any differences in transfusion requirements between groups. Minor bleeding occurred in 15 of the rt-PA patients mainly at angiogram-catheter insertion and venipuncture sites. These results suggest that a bolus regimen of rt-PA produces accelerated thrombolysis and provides an alternative and convenient approach to thrombolytic therapy in patients with pulmonary embolism.

Section snippets

Patients

The study population consisted of patients with acute symptomatic pulmonary embolism documented by either pulmonary angiography, or a high probability ventilation-perfusion lung scan (defined as a segmental or greater perfusion defect with ventilation mismatch²¹), plus deep vein thrombosis confirmed by venography or B-mode ultrasonography. Patients were excluded if they had an active bleeding process, active peptic ulcer disease, familial or acquired bleeding diathesis, or a platelet count

Patient Population

Fifty-eight patients with acute pulmonary embolism were randomized to either rt-PA (33 patients) or placebo (25 patients). The presenting symptom in patients who received rt-PA was chest pain in 20 (60.6 percent), dyspnea in 27 (81.8 percent), hemoptysis in five (15 percent), while six (18 percent) had syncope. In the placebo group, chest pain was experienced by 23 (92 percent), dyspnea in 22 (88 percent), hemoptysis in seven (28 percent), and five (20 percent) presented with syncope.

ACKNOWLEDGMENTS

We gratefully acknowledge the support of the members of the Departments of Medicine, Radiology and Nuclear Medicine at Henderson General Hospital and Hamilton General Hospital, Hamilton, Ontario and Hotel Dieu Hospital, Montreal, Quebec; the contribution of the hematology laboratories at the participating centers; the support of the study coordinator, M. Klimek, and study nurses is also recognized.

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Cited by (279)

Safety and efficacy of clot-dissolving therapies for submassive pulmonary embolism: A network meta-analysis of randomized controlled trials
2024, Cardiovascular Revascularization Medicine
Acute pulmonary embolism (PE) is a serious condition that needs quick and effective treatment. Anticoagulation therapy is the usual care for most PE patients but may not work well for higher-risk ones. Thrombolysis breaks the clot and improves blood flow. It can be given systemically or locally. Ultrasound-assisted catheter-directed thrombolysis (USAT) is a new technique that boosts clot-busting drugs. This network meta-analysis compares death, bleeding, and benefits of four treatments in acute submassive PE.
We comprehensively searched relevant databases up to July 2023 for RCTs. The outcomes encompassed all-cause mortality, major and minor bleeding, PE recurrence, and hospital stay duration. Bayesian network meta-analysis computed odds ratios (OR) and 95 % CI estimates.
In this network meta-analysis of 23 RCTs involving 2521 PE patients, we found that SCDT had the most favorable performance for mortality, as it had the lowest odds ratio (OR) among the four interventions (OR 5.41e−42; 95 % CI, 5.68e−97, 1.37e−07). USAT had the worst performance for major bleeding, as it had the highest OR among the four interventions (OR 4.73e+04; 95 % CI, 1.65, 9.16e+13). SCDT also had the best performance for minor bleeding, as it had the lowest OR among the four interventions (OR 5.68e−11; 95 % CI, 4.97e−25, 0.386).
Our meta-analysis suggests that SCDT is the most effective treatment intervention in improving the risks of All-cause mortality and bleeding. Thrombolytic therapy helps in improving endpoints including the risk of PE recurrence and the duration of hospital stay.
Breaking the fibrinolytic speed limit with microwheel co-delivery of tissue plasminogen activator and plasminogen
2022, Journal of Thrombosis and Haemostasis
To reestablish blood flow in vessels occluded by clots, tissue plasminogen activator (tPA) can be used; however, its efficacy is limited by transport to and into a clot and by the depletion of its substrate, plasminogen.
To overcome these rate limitations, a platform was designed to co‐deliver tPA and plasminogen based on microwheels (µwheels), wheel‐like assemblies of superparamagnetic colloidal beads that roll along surfaces at high speeds.
The biochemical speed limit was determined by measuring fibrinolysis of plasma clots at varying concentrations of tPA (10–800 nM) and plasminogen (1–6 µM). Biotinylated magnetic mesoporous silica nanoparticles were synthesized and bound to streptavidin‐coated superparamagnetic beads to make studded beads. Studded beads were loaded with plasminogen and tPA was immobilized on their surface. Plasminogen release and tPA activity were measured on the studded beads. Studded beads were assembled into µwheels with rotating magnetic fields and fibrinolysis of plasma clots was measured in a microfluidic device.
The biochemical speed limit for plasma clots was ~15 µm/min. Plasminogen‐loaded, tPA‐immobilized µwheels lyse plasma clots at rates comparableto the biochemical speed limit. With the addition of a corkscrew motion, µwheels penetrate clots, thereby exceeding the biochemical speed limit (~20 µm/min) and achieving lysis rates 40‐fold higher than 50 nM tPA.
Co‐delivery of an immobilized enzyme and its substrate via a microbot capable of mechanical work has the potential to target and rapidly lyse clots that are inaccessible by mechanical thrombectomy devices or recalcitrant to systemic tPA delivery.
Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report
2021, Chest
This is the 2nd update to the 9th edition of these guidelines. We provide recommendations on 17 PICO (Population, Intervention, Comparator, Outcome) questions, four of which have not been addressed previously.
We generate strong and weak recommendations based on high-, moderate-, and low-certainty evidence, using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology.
The panel generated 29 guidance statements, 13 of which are graded as strong recommendations, covering aspects of antithrombotic management of VTE from initial management through secondary prevention and risk reduction of postthrombotic syndrome. Four new guidance statements have been added that did not appear in the 9th edition (2012) or 1st update (2016). Eight statements have been substantially modified from the 1st update.
New evidence has emerged since 2016 that further informs the standard of care for patients with VTE. Substantial uncertainty remains regarding important management questions, particularly in limited disease and special patient populations.
Accelerated treatment with rtPA for pulmonary embolism induced circulatory arrest
2021, Thrombosis Research
Patients with circulatory arrest due to pulmonary embolism (PE) should be treated with fibrinolytics. Current guidelines do not specify which regimen to apply, and it has been suggested that the regimen of 100 mg rtPA/2 h should be used, because this is recommended for hemodynamic instable PE in the ESC/ERS Guideline. This two hour regimen, however, is incompatible with key principles of cardiopulmonary resuscitation (CPR), such as employment of interventions that allow fast evaluation of effectiveness, and limitation of the total duration of CPR to avoid poor neurological outcomes. Additionally, the low flow-state during CPR has important consequences for the pharmacokinetic properties of rtPA. Arguably, the volume of distribution is lower, the metabolism reduced and the half life time longer. Therefore, these changes largely discard the rationale to use high dosages of rtPA over a prolonged period of time.
More importantly, these changes highlight that the guideline recommendations, based on studies in patients without circulatory arrest, cannot be easily translated to the situation of circulatory arrest. An accelerated regimen of rtPA (0.6 mg/kg/15 min., max 50 mg) is mentioned by the 2019 ESC/ERS Guideline. However, empirical support or a rationale is not provided. Due to the rarity of the situation and ethical difficulties associated with randomizing unconscious patients, a randomized head-to-head comparison between the two regimens is unlikely to ever be performed.
With this comprehensive overview of the pharmacokinetics of rtPA and current literature, a strong rationale is provided that the accelerated protocol is the regimen of choice for patients with PE-induced circulatory arrest.
Reperfusion therapies in pulmonary embolism–state of the art and expert opinion: A position paper from the “Unité de Soins Intensifs de Cardiologie” group of the French Society of Cardiology
2020, Archives of Cardiovascular Diseases
Acute pulmonary embolism is a frequent cardiovascular emergency with an increasing incidence. The prognosis of patients with high-risk and intermediate-high-risk pulmonary embolism has not improved over the last decade. The current treatment strategies are mainly based on anticoagulation to prevent recurrence and reduce pulmonary vasculature obstruction. However, the slow rate of thrombus lysis under anticoagulation is unable to acutely decrease right ventricle overload and pulmonary vasculature resistance in patients with severe obstruction and right ventricle dysfunction. Therefore, patients with high-risk and intermediate-high-risk pulmonary embolism remain a therapeutic challenge. Reperfusion therapies may be discussed for these patients, and include systemic thrombolysis, catheter-directed therapies and surgical thrombectomy. High-risk patients require systemic thrombolysis, but may have contraindications as a result of the high risk of bleeding. In addition, intermediate-high-risk patients should not receive systemic thrombolysis, despite its high efficacy, because of prohibitive bleeding complications. Recently, percutaneous reperfusion techniques have been developed to acutely decrease pulmonary vascular obstruction with lower-dose or no thrombolytic agents and, thus, potentially higher safety than systemic thrombolysis. Some of these techniques improve key haemodynamic variables. Cardiac surgical techniques and venoarterial extracorporeal membrane oxygenation as temporary circulatory support may be useful in selected cases. The development of pulmonary embolism centres with multidisciplinary pulmonary embolism teams is mandatory to enable adequate use of reperfusion and improve outcomes. We aim to present the state of the art regarding reperfusion therapies in pulmonary embolism, but also to provide guidance on their indications and patient selection.
L’embolie pulmonaire aiguë est une urgence cardiovasculaire fréquente. Son incidence augmente rapidement tandis que sa mortalité reste stable. Le pronostic des patients à haut risque et à risque intermédiaire élevé reste médiocre sans amélioration au cours de la dernière décennie. Les stratégies de traitement actuelles reposent sur l’anticoagulation pour prévenir les récidives et réduire l’obstruction vasculaire pulmonaire. Cependant, la lyse du thrombus sous anticoagulant est lente et ne permet pas une diminution rapide de la surcharge du ventricule droit et des résistances vasculaires pulmonaires chez les patients présentant une obstruction sévère et une dysfonction ventriculaire droite. La prise en charge de ces patients reste un défi thérapeutique et peut amener à discuter des thérapies de reperfusion comme la thrombolyse systémique, les techniques percutanées par cathéter et la thrombectomie chirurgicale. La thrombolyse systémique est indiquée chez les patients à haut risque en l’absence de contre-indication formelle en raison du risque hémorragique. Mais elle ne devrait pas être utilisée chez les patients à risque intermédiaire élevé malgré son efficacité élevée en raison de complications hémorragiques rédhibitoires. Récemment, les techniques de reperfusion percutanées ont été développées visant à diminuer de manière aiguë l’obstruction vasculaire pulmonaire avec un dose réduite ou sans thrombolytique et en conséquence un profil de sécurité amélioré. Certaines de ces techniques ont démontré une grande efficacité sur les paramètres hémodynamiques clés. Enfin, les techniques de chirurgie cardiaque et le support circulatoire temporaire par ECMO veno-artérielle se sont améliorées et peuvent être utiles dans certains cas. Le développement de centres spécialisés avec une équipe multidisciplinaire est obligatoire afin de permettre une utilisation adéquate de la reperfusion pour améliorer le pronostic des patients. Ce document vise à faire un état de l’art concernant les thérapies de reperfusion de l’embolie pulmonaire tout en discutant leurs indications et la sélection des patients.
Current Controversies in Caring for the Critically Ill Pulmonary Embolism Patient
2020, Emergency Medicine Clinics of North America

View all citing articles on Scopus

: Supported in part by the Ontario Ministry of Health and the Heart and Stroke Foundation of Ontario.

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Chest

Preliminary ReportA Randomized Trial of a Single Bolus Dosage Regimen of Recombinant Tissue Plasminogen Activator in Patients with Acute Pulmonary Embolism

Section snippets

Patients

Patient Population

ACKNOWLEDGMENTS

J Biol Chem

Lancet

Lancet

Thromb Res

Blood

Lancet

Am J Cardiol

J Am Coll Cardiol

Venous thromboembolism

Phase I results

JAMA

Phase II results

JAMA

Hemorrhagic complications of thrombolytic therapy in the treatment of myocardial infarction and venous thromboembolism

Chest

Biological properties of human tissue-type plasminogen activator obtained by expression of recombinant DNA in mammalian cells

J Pharm Exp Therapy

Cloning and expression of human tissue-type plasminogen activator cDNA in E coli

Nature

Tissue-type plasminogen activator: therapeutic potential in thrombotic disease states

Drugs

Preliminary Report
A Randomized Trial of a Single Bolus Dosage Regimen of Recombinant Tissue Plasminogen Activator in Patients with Acute Pulmonary Embolism