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European Heart Journal Mar 2015Thrombolytic therapy induces faster clot dissolution than anticoagulation in patients with acute pulmonary embolism (PE) but is associated with an increased risk of... (Meta-Analysis)
Meta-Analysis Review
AIM
Thrombolytic therapy induces faster clot dissolution than anticoagulation in patients with acute pulmonary embolism (PE) but is associated with an increased risk of haemorrhage. We reviewed the risks and benefits of thrombolytic therapy in the management of patients with acute PE.
METHODS AND RESULTS
We systematically reviewed randomized controlled studies comparing systemic thrombolytic therapy plus anticoagulation with anticoagulation alone in patients with acute PE. Fifteen trials involving 2057 patients were included in our meta-analysis. Compared with heparin, thrombolytic therapy was associated with a significant reduction of overall mortality (OR; 0.59, 95% CI: 0.36-0.96). This reduction was not statistically significant after exclusion of studies including high-risk PE (OR; 0.64, 95% CI: 0.35-1.17). Thrombolytic therapy was associated with a significant reduction in the combined endpoint of death or treatment escalation (OR: 0.34, 95% CI: 0.22-0.53), PE-related mortality (OR: 0.29; 95% CI: 0.14-0.60) and PE recurrence (OR: 0.50; 95% CI: 0.27-0.94). Major haemorrhage (OR; 2.91, 95% CI: 1.95-4.36) and fatal or intracranial bleeding (OR: 3.18, 95% CI: 1.25-8.11) were significantly more frequent among patients receiving thrombolysis.
CONCLUSIONS
Thrombolytic therapy reduces total mortality, PE recurrence, and PE-related mortality in patients with acute PE. The decrease in overall mortality is, however, not significant in haemodynamically stable patients with acute PE. Thrombolytic therapy is associated with an increase of major and fatal or intracranial haemorrhage.
Topics: Acute Disease; Anticoagulants; Fibrinolytic Agents; Hemorrhage; Humans; Publication Bias; Pulmonary Embolism; Randomized Controlled Trials as Topic; Recurrence; Thrombolytic Therapy; Treatment Outcome
PubMed: 24917641
DOI: 10.1093/eurheartj/ehu218 -
The Cochrane Database of Systematic... Oct 2019Pleural infection, including parapneumonic effusions and thoracic empyema, may complicate lower respiratory tract infections. Standard treatment of these collections in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pleural infection, including parapneumonic effusions and thoracic empyema, may complicate lower respiratory tract infections. Standard treatment of these collections in adults involves antibiotic therapy, effective drainage of infected fluid and surgical intervention if conservative management fails. Intrapleural fibrinolytic agents such as streptokinase and alteplase have been hypothesised to improve fluid drainage in complicated parapneumonic effusions and empyema and therefore improve treatment outcomes and prevent the need for thoracic surgical intervention. Intrapleural fibrinolytic agents have been used in combination with DNase, but this is beyond the scope of this review.
OBJECTIVES
To assess the benefits and harms of adding intrapleural fibrinolytic therapy to standard conservative therapy (intercostal catheter drainage and antibiotic therapy) in the treatment of complicated parapneumonic effusions and empyema.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 28 August 2019.
SELECTION CRITERIA
Parallel-group randomised controlled trials (RCTs) in adult patients with post-pneumonic empyema or complicated parapneumonic effusions (excluding tuberculous effusions) who had not had prior surgical intervention or trauma comparing an intrapleural fibrinolytic agent (streptokinase, alteplase or urokinase) versus placebo or a comparison of two fibrinolytic agents.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data. We contacted study authors for further information. We used odds ratios (OR) for dichotomous data and reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence.
MAIN RESULTS
We included in this review a total of 12 RCTs. Ten studies assessed fibrinolytic agents versus placebo (993 participants); one study compared streptokinase with urokinase (50 participants); and one compared alteplase versus urokinase (99 participants). The primary outcomes were death, requirement for surgical intervention, overall treatment failure and serious adverse effects. All studies were in the inpatient setting. Outcomes were measured at varying time points from hospital discharge to three months. Seven trials were at low or unclear risk of bias and two at high risk of bias due to inadequate randomisation and inappropriate study design respectively. We found no evidence of difference in overall mortality with fibrinolytic versus placebo (OR 1.16, 95% CI 0.71 to 1.91; 8 studies, 867 participants; I² = 0%; moderate certainty of evidence). We found evidence of a reduction in surgical intervention with fibrinolysis in the same studies (OR 0.37, 95% CI 0.21 to 0.68; 8 studies, 897 participants; I² = 51%; low certainty of evidence); and overall treatment failure (OR 0.16, 95% CI 0.05 to 0.58; 7 studies, 769 participants; I² = 88%; very low certainty of evidence, with evidence of significant heterogeneity). We found no clear evidence of an increase in adverse effects with intrapleural fibrinolysis, although this cannot be excluded (OR 1.28, 95% CI 0.36 to 4.57; low certainty of evidence). In a sensitivity analysis, the reduction in referrals for surgery and overall treatment failure with fibrinolysis disappeared when the analysis was confined to studies at low or unclear risk of bias. In a moderate-risk population (baseline 14% risk of death, 20% risk of surgery, 27% risk of treatment failure), intra-pleural fibrinolysis leads to 19 more deaths (36 fewer to 59 more), 115 fewer surgical interventions (150 fewer to 55 fewer) and 214 fewer overall treatment failures (252 fewer to 93 fewer) per 1000 people. A single study of streptokinase versus urokinase found no clear difference between the treatments for requirement for surgery (OR 1.00, 95% CI 0.13 to 7.72; 50 participants; low-certainty evidence). A single study of alteplase versus urokinase showed no clear difference in requirement for surgery (OR alteplase versus urokinase 0.46, 95% CI 0.04 to 5.24) but an increased rate of adverse effects, primarily bleeding, with alteplase (OR 5.61, 95% CI 1.16 to 27.11; 99 participants; low-certainty evidence). This translated into 154 (6 to 499 more) serious adverse events with alteplase compared with urokinase per 1000 people treated.
AUTHORS' CONCLUSIONS
In patients with complicated infective pleural effusion or empyema, intrapleural fibrinolytic therapy was associated with a reduction in the requirement for surgical intervention and overall treatment failure but with no evidence of change in mortality. Discordance between the negative largest trial of this therapy and other studies is of concern, however, as is an absence of significant effect when analysing low risk of bias trials only. The reasons for this difference are uncertain but may include publication bias. Intrapleural fibrinolytics may increase the rate of serious adverse events, but the evidence is insufficient to confirm or exclude this possibility.
Topics: Anti-Bacterial Agents; Drainage; Empyema, Pleural; Fibrinolytic Agents; Humans; Pleural Effusion; Randomized Controlled Trials as Topic; Streptokinase; Thrombolytic Therapy; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 31684683
DOI: 10.1002/14651858.CD002312.pub4 -
The Cochrane Database of Systematic... Apr 2021Thrombolytic therapy is usually reserved for people with clinically serious or massive pulmonary embolism (PE). Evidence suggests that thrombolytic agents may dissolve... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Thrombolytic therapy is usually reserved for people with clinically serious or massive pulmonary embolism (PE). Evidence suggests that thrombolytic agents may dissolve blood clots more rapidly than heparin and may reduce the death rate associated with PE. However, there are still concerns about the possible risk of adverse effects of thrombolytic therapy, such as major or minor haemorrhage. This is the fourth update of the Cochrane review first published in 2006.
OBJECTIVES
To assess the effects of thrombolytic therapy for acute pulmonary embolism.
SEARCH METHODS
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 17 August 2020. We undertook reference checking to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared thrombolytic therapy followed by heparin versus heparin alone, heparin plus placebo, or surgical intervention for people with acute PE (massive/submassive). We did not include trials comparing two different thrombolytic agents or different doses of the same thrombolytic drug.
DATA COLLECTION AND ANALYSIS
Two review authors (ZZ, QH) assessed the eligibility and risk of bias of trials and extracted data. We calculated effect estimates using the odds ratio (OR) with a 95% confidence interval (CI) or the mean difference (MD) with a 95% CI. The primary outcomes of interest were death, recurrence of PE and haemorrhagic events. We assessed the certainty of the evidence using GRADE criteria.
MAIN RESULTS
We identified three new studies for inclusion in this update. We included 21 trials in the review, with a total of 2401 participants. No studies compared thrombolytics versus surgical intervention. We were not able to include one study in the meta-analysis because it provided no extractable data. Most studies carried a high or unclear risk of bias related to randomisation and blinding. Meta-analysis showed that, compared to control (heparin alone or heparin plus placebo), thrombolytics plus heparin probably reduce both the odds of death (OR 0.58, 95% CI 0.38 to 0.88; 19 studies, 2319 participants; low-certainty evidence), and recurrence of PE (OR 0.54, 95% CI 0.32 to 0.91; 12 studies, 2050 participants; low-certainty evidence). Effects on mortality weakened when six studies at high risk of bias were excluded from analysis (OR 0.71, 95% CI 0.45 to 1.13; 13 studies, 2046 participants) and in the analysis of submassive PE participants (OR 0.61, 95% CI 0.37 to 1.02; 1993 participants). Effects on recurrence of PE also weakened after removing one study at high risk of bias for sensitivity analysis (OR 0.60, 95% CI 0.35 to 1.04; 11 studies, 1949 participants). We downgraded the certainty of evidence to low because of 'Risk of bias' concerns. Major haemorrhagic events were probably more common in the thrombolytics group than in the control group (OR 2.84, 95% CI 1.92 to 4.20; 15 studies, 2101 participants; moderate-certainty evidence), as were minor haemorrhagic events (OR 2.97, 95% CI 1.66 to 5.30; 13 studies,1757 participants; low-certainty evidence). We downgraded the certainty of the evidence to moderate or low because of 'Risk of bias' concerns and inconsistency. Haemorrhagic stroke may occur more often in the thrombolytics group than in the control group (OR 7.59, 95% CI 1.38 to 41.72; 2 studies, 1091 participants). Limited data indicated that thrombolytics may benefit haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonary hypertension, coagulation parameters, composite clinical outcomes, need for escalation and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and the small number of participants involved warrant caution when interpreting results. The length of hospital stay was shorter in the thrombolytics group than in the control group (mean difference (MD) -1.40 days, 95% CI -2.69 to -0.11; 5 studies, 368 participants). Haemodynamic decompensation may occur less in the thrombolytics group than in the control group (OR 0.36, 95% CI 0.20 to 0.66; 3 studies, 1157 participants). Quality of life was similar between the two treatment groups. None of the included studies provided data on post-thrombotic syndrome or on cost comparison.
AUTHORS' CONCLUSIONS
Low-certainty evidence suggests that thrombolytics may reduce death following acute pulmonary embolism compared with heparin (the effectiveness was mainly driven by one trial with massive PE). Thrombolytic therapy may be helpful in reducing the recurrence of pulmonary emboli but may cause more major and minor haemorrhagic events, including haemorrhagic stroke. More studies of high methodological quality are needed to assess safety and cost effectiveness of thrombolytic therapy for people with pulmonary embolism.
Topics: Acute Disease; Bias; Cause of Death; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Pulmonary Embolism; Randomized Controlled Trials as Topic; Recurrence; Thrombolytic Therapy
PubMed: 33857326
DOI: 10.1002/14651858.CD004437.pub6 -
Blood Jul 2022The current standard of care for moderate to severe ischemic stroke is thrombolytic therapy with tissue plasminogen activator (tPA). Treatment with tPA can significantly...
The current standard of care for moderate to severe ischemic stroke is thrombolytic therapy with tissue plasminogen activator (tPA). Treatment with tPA can significantly improve neurologic outcomes; however, thrombolytic therapy is associated with an increased risk of intracerebral hemorrhage (ICH). The risk of hemorrhage significantly limits the use of thrombolytic therapy, and identifying pathways induced by tPA that increase this risk could provide new therapeutic options to extend thrombolytic therapy to a wider patient population. Here, we investigate the role of protein kinase Cβ (PKCβ) phosphorylation of the tight junction protein occludin during ischemic stroke and its role in cerebrovascular permeability. We show that activation of this pathway by tPA is associated with an increased risk of ICH. Middle cerebral artery occlusion (MCAO) increased phosphorylation of occludin serine 490 (S490) in the ischemic penumbra in a tPA-dependent manner, as tPA-/- mice were significantly protected from MCAO-induced occludin phosphorylation. Intraventricular injection of tPA in the absence of ischemia was sufficient to induce occludin phosphorylation and vascular permeability in a PKCβ-dependent manner. Blocking occludin phosphorylation, either by targeted expression of a non-phosphorylatable form of occludin (S490A) or by pharmacologic inhibition of PKCβ, reduced MCAO-induced permeability and improved functional outcome. Furthermore, inhibiting PKCβ after MCAO prevented ICH associated with delayed thrombolysis. These results show that PKCβ phosphorylation of occludin is a downstream mediator of tPA-induced cerebrovascular permeability and suggest that PKCβ inhibitors could improve stroke outcome and prevent ICH associated with delayed thrombolysis, potentially extending the window for thrombolytic therapy in stroke.
Topics: Animals; Cerebral Hemorrhage; Fibrinolytic Agents; Humans; Infarction, Middle Cerebral Artery; Ischemic Stroke; Mice; Occludin; Phosphorylation; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 35576527
DOI: 10.1182/blood.2021014958 -
Current Neurology and Neuroscience... Aug 2017The purpose of the review is to examine recent evidence on the effects of intravenous thrombolysis and identify the remaining uncertainties. (Review)
Review
PURPOSE OF REVIEW
The purpose of the review is to examine recent evidence on the effects of intravenous thrombolysis and identify the remaining uncertainties.
RECENT FINDINGS
We review the results of two large trials (the third International Stroke Trial (IST-3) and The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)) and the publications from the individual patient data analyses of the trials of alteplase conducted by the Stroke Thrombolysis Trialists Collaboration. Despite about a 2% risk of fatal intracerebral haemorrhage, on average, adult patients of all ages treated with 0.9 mg/kg alteplase within 4.5 h will have better long-term functional outcome. The use of a lower dose of alteplase (0.6 mg/kg) is associated with a lower risk of haemorrhage but its effect on functional outcome has not been proven to be non-inferior to standard dose therapy. Some clinicians feel confident to treat selected patients who present beyond 4.5 h or have unknown time of onset, but many also agree that the current trials and other research is needed to reliably define the optimum imaging methods and treatment eligibility criteria.
Topics: Brain Ischemia; Fibrinolytic Agents; Humans; Stroke; Thrombolytic Therapy
PubMed: 28667504
DOI: 10.1007/s11910-017-0767-5 -
EuroIntervention : Journal of EuroPCR... Oct 2022There is a growing clinical and scientific interest in catheter-directed therapy (CDT) of acute pulmonary embolism (PE). Currently, CDT should be considered for patients...
Percutaneous treatment options for acute pulmonary embolism: a clinical consensus statement by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function and the European Association of Percutaneous Cardiovascular Interventions.
There is a growing clinical and scientific interest in catheter-directed therapy (CDT) of acute pulmonary embolism (PE). Currently, CDT should be considered for patients with high-risk PE, in whom thrombolysis is contraindicated or has failed. Also, CDT is a treatment option for initially stable patients in whom anticoagulant treatment fails, i.e., those who experience haemodynamic deterioration despite adequately dosed anticoagulation. However, the definition of treatment failure (primary reperfusion therapy or anticoagulation alone) remains an important area of uncertainty. Moreover, several techniques for CDT are available without evidence supporting one over the other, and variation in practice with regard to periprocedural anticoagulation is considerable. The aim of this position paper is to describe the currently available CDT approaches in PE patients and to standardise patient selection, the timing and technique of the procedure itself as well as anticoagulation regimens during CDT. We discuss several clinical scenarios of the clinical evaluation of the "efficacy" of thrombolysis and anticoagulation, including treatment failure with haemodynamic deterioration and treatment failure based on a lack of improvement. This clinical consensus statement serves as a practical guide for CDT, complementary to the formal guidelines.
Topics: Acute Disease; Anticoagulants; Fibrinolytic Agents; Humans; Pulmonary Circulation; Pulmonary Embolism; Thrombolytic Therapy; Treatment Outcome; Ventricular Function, Right
PubMed: 36112184
DOI: 10.4244/EIJ-D-22-00246 -
BMJ Open Jan 2023In COVID-19-related acute respiratory distress syndrome (ARDS), the clot play a role in gas exchange abnormalities. Fibrinolytic therapy can improve alveolar ventilation...
INTRODUCTION
In COVID-19-related acute respiratory distress syndrome (ARDS), the clot play a role in gas exchange abnormalities. Fibrinolytic therapy can improve alveolar ventilation by restoring blood flow. In this systematic review and meta-analysis protocol, we aim to assess the safety and efficacy of fibrinolytic therapy in such a population.
METHODS
We will perform a systematic search in MEDLINE, EMBASE, Cochrane CENTRAL and LILACS databases without language restrictions for relevant randomised controlled trials (RCTs) and quasi-RCTs. Two review authors will independently perform data extraction and quality assessments of data from included studies. In case of divergence, a third author will be contacted. The Cochrane handbook will be used for guidance. If the results are not appropriate for a meta-analysis, a descriptive analysis will be performed.
DISCUSSION
This systematic review and meta-analysis protocol will provide current evidence about the safety and efficacy of fibrinolytic therapy in patients with COVID-19 and ARDS. These findings will provide if fibrinolytic therapy might be an option for a desperate clinical setting, where all medical efforts have been used.
PROSPERO REGISTRATION NUMBER
PROSPERO CRD42020187482.
ETHICS AND DISSEMINATION
Ethics committee approval is not necessary. We intend to update the public registry, report any protocol amendments and publish the results in a widely accessible journal.
Topics: Humans; COVID-19; Systematic Reviews as Topic; Meta-Analysis as Topic; Respiratory Distress Syndrome; Thrombolytic Therapy
PubMed: 36593003
DOI: 10.1136/bmjopen-2022-066623 -
Rhode Island Medical Journal (2013) Dec 2019Acute pulmonary embolism (PE) causes significant morbidity and mortality, particularly for patients with subsequent right ventricular (RV) dysfunction. Once diagnosed,... (Review)
Review
Acute pulmonary embolism (PE) causes significant morbidity and mortality, particularly for patients with subsequent right ventricular (RV) dysfunction. Once diagnosed, risk stratification is imperative for therapeutic decision making and centers on evaluation of RV function. Treatment includes supportive care, systemic anticoagulation, and consideration of reperfusion therapy. In addition to systemic anticoagulation, patients with high-risk PE should receive reperfusion therapy, typically with systemic thrombolysis. The role of reperfusion therapies, which include catheter-based interventions, systemic thrombolysis, and surgical embolectomy, are controversial in the management of intermediate risk PE. Catheter directed thrombolysis (CDT) can be considered in certain intermediate risk patients although prospective, comparative data for its use are lacking. Surgical or catheter embolectomy are viable treatment options for high-risk patients in whom reperfusion therapy is warranted but who have absolute contraindications to thrombolysis. Further research is needed to better elucidate which patients with PE would most benefit from advanced reperfusion therapies.
Topics: Clinical Decision-Making; Embolectomy; Evidence-Based Practice; Fibrinolytic Agents; Humans; Patient Selection; Pulmonary Embolism; Randomized Controlled Trials as Topic; Risk Factors; Severity of Illness Index; Thrombolytic Therapy; Treatment Outcome
PubMed: 31795534
DOI: No ID Found -
Molecular Pharmaceutics Dec 2022Antithrombotic and thrombolytic therapies are used to prevent, treat, and remove blood clots in various clinical settings, from emergent to prophylactic. While... (Review)
Review
Antithrombotic and thrombolytic therapies are used to prevent, treat, and remove blood clots in various clinical settings, from emergent to prophylactic. While ubiquitous in their healthcare application, short half-lives, off-target effects, overdosing complications, and patient compliance continue to be major liabilities to the utility of these agents. Biomaterials-enabled strategies have the potential to comprehensively address these limitations by creating technologies that are more precise, durable, and safe in their antithrombotic action. In this review, we discuss the state of the art in anticoagulant and thrombolytic biomaterials, covering the nano to macro length scales. We emphasize current methods of formulation, discuss how material properties affect controlled release kinetics, and summarize modern mechanisms of clot-specific drug targeting. The preclinical efficacy of these technologies in an array of cardiovascular applications, including stroke, pulmonary embolism, myocardial infarction, and blood contacting devices, is summarized and performance contrasted. While significant advances have already been made, ongoing development efforts look to deliver bioresponsive "smart" biomaterials that will open new precision medicine opportunities in cardiology.
Topics: Humans; Fibrinolytic Agents; Biocompatible Materials; Thrombolytic Therapy; Thrombosis; Anticoagulants
PubMed: 36149250
DOI: 10.1021/acs.molpharmaceut.2c00626 -
Kardiologia Polska 2018In this paper the current knowledge of reperfusion therapy in elderly patients with an ST-segment elevation acute myocardial infarction (STEMI) is summarised.... (Review)
Review
In this paper the current knowledge of reperfusion therapy in elderly patients with an ST-segment elevation acute myocardial infarction (STEMI) is summarised. Placebo-controlled trials of fibrinolytic agents, direct comparative trials of fibrinolytic agents and antithrombotic co-therapies, and randomised trials of primary percutaneous coronary intervention (PCI) versus fibrinolytic therapy as well as registries are briefly reviewed, focusing on the impact of age. The benefit and risk of a combined pharma-cological and mechanical approach is presented. Important differences between a "facilitated PCI" and a "pharmaco-invasive strategy", particularly in older STEMI patients, are highlighted. It will become clear at the end of this review that the knowledge about the benefit and risk of reperfusion therapy in the elderly is still incomplete and that more clinical trials in the elderly are needed. Practical recommendations for elderly patients with STEMI based on the current knowledge have been provided.
Topics: Aged; Humans; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Thrombolytic Therapy
PubMed: 29633231
DOI: 10.5603/KP.a2018.0092