Jaff MR, McMurtry MS, Archer SL, et al. Characteristics of the included trials of alteplase, Characteristics of the included trials of streptokinase. 9 Similarly, in the Germany-based Management Strategy and Prognosis of . Dong BR, Hao Q, Yue J, et al. A third study pooled the results of the two studies 19, 20, comparing reduced-dose bolus with full-dose alteplase, but did not perform a meta-analysis of the data 38. These studies showed that thrombolytic therapy + LWMH was as effective as thrombolytic therapy + SH with a lower bleeding risk in the LMWH group, although the difference was not statistically significant [36, 37]. Bircan HA, Alanoglu EG. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eliquis (apixaban) prescribing information. Alteplase infusion has a lower risk of major bleeding episodes when compared with bolus-dose alteplase (RR: 0.64; 95% CI: 0.430.96; p=0.03) and streptokinase (RR: 0.62; 95% CI: 0.40.96; p=0.03). Zhang Z, Zhai ZG, Liang LR, Liu FF, Yang YH, Wang C. Lower dosage of recombinant tissue-type plasminogen activator (rt-PA) in the treatment of acute pulmonary embolism: a systematic review and metaanalysis. https://www.uptodate.com/contents/thrombolytic-fibrinolytic-therapy-in-acute-pulmonary-embolism-and-lower-extremity-deep-veinthrombosis, Severe or worsening right ventricular dysfunction, Patients with acute PE who appear to be decompensating (e.g., elevated cardiac biomarkers, increasing tachycardia), Free-floating thrombus in right atrial or ventricular, Severe uncontrolled hypertension on presentation (SBP>180 mmHg or DBP>110 mmHg), Known structural cerebral vascular lesion, History of ischemic stroke more than 3 months before, Recent (within 2 to 4 weeks) internal bleeding, Significant closed-head trauma or facial trauma within 3 months, Current use of an anticoagulant that produced an elevated INR>1.7 or PT>15 seconds, 10 U IV bolus, twice with 30-min interval, 10000 U bolus single dose in 510 seconds. Key characteristics of the thrombolytic agents are listed in Table 1.2326, Key Characteristics of Thrombolytic Agents2326. However, in situations where cardiac arrest occurs secondary to massive PE, bolus-dose alteplase may be justified in an attempt to ensure that a therapeutic serum level of thrombolytic drug is achieved immediately. PE is a major cause of morbidity and mortality. PTE is usually the result of pulmonary artery obstruction by a thrombus formed in the deep veins of the legs or the pelvic veins. The risk of bleeding increases with aneurysm, tumor, infarction, trauma, or surgical intervention in the cerebral system, advanced age, uncontrolled hypertension, bleeding diathesis, low body weight, and severe heart disease. Interventional Therapies for Acute Pulmonary Embolism: Current Status Five studies were double blinded 4, 6, 14, 19, 20, three were single blinded 8, 21, 22, eight were open randomised trials 5, 1618, 24, 28, 29, 31, and nine were prospective or retrospective studies 15, 23, 2527, 30, 3234. Weinberg I, Jaff MR. Kearon C, Akl EA, Comerota AJ, et al. FOIA It is indicated in the treatment of acute myocardial infarction [35]. Moreover, a retrospective study on the long-term outcomes of low-dose rt-PA reported similar outcomes to those with the standard dose [42]. Thrombolytic drugs are agents that actively dissolve the thrombus by converting plasminogen into plasmin. Lower doses of thrombolytics may also help prevent bleeding complications in elderly, pregnant, and surgical patients.42, When there is a high clinical suspicion of PE, anticoagulation with UFH should be initiated while the diagnostic workup is being completed. Accessibility Emmerich J, Meyer G, Decousus H, Agnelli G. Role of fibrinolysis and interventional therapy for acute venous thromboembolism. Pulmonary thromboembolism (PTE) is a common disease that may be life threatening. 22 Compared with heparin anticoagulation alone, fibrinolysis resulted in a significant reduction in . Meta-analysis of crude cumulative data comparing morbidity and mortality associated with alteplase infusion versus bolus-dose alteplase in the treatment of massive pulmonary embolism (PE) in different studies or subcategories. The severity of PE and the patient's presentation drive treatment selection and the care plan. There are only two comparative studies of alteplase infusion versus bolus-dose alteplase (n=140) 19, 20, two of alteplase infusion versus streptokinase (n=116) 21, 22 and none of bolus-dose alteplase versus streptokinase. Although there are some studies indicating that anticoagulation with LWMH can be continued after thrombolytic therapy, it has not yet been included in the guidelines [9, 36, 37]. Comparison between systemic and catheter thrombolysis in patients with pulmonary embolism. The reference lists of retrieved articles and published reviews were also searched for further published studies. Alteplase infusion achieves clinical thrombolysis in almost twice as many patients as bolus-dose alteplase with a RR of 1.95 (95% CI: 1.193.2; p=0.008), equating to a NNT of three (table5). Haemodynamically unstable pulmonary embolism in the RIETE Registry: systolic blood pressure or shock index? Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. Early hospital mortality in hypotensive PTE cases varies between 25% and 65% [1]. Risk assessment in patients diagnosed with PTE is important to initiate effective treatment as early as possible and prevent mortality. Approach to thrombolytic (fibrinolytic) therapy in acute - UpToDate However, larger prospective studies are required. Systemic thrombolytic therapy should be the first choice in patients with high-risk PTE. Accessibility 7. Pulmonary Embolism Cardiac Arrest - CHEST These differences in mortality rates due to the initial PE are equivalent to a NNH of 25 and 20 if the thrombolytic regimen was switched from alteplase infusions to bolus dose alteplase or streptokinase, respectively (table5). Diagnosis of pulmonary embolism in hospitalised patients: retrospective survey of an institutional standard. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Version 4.2 for Windows. Rali PM, Criner GJ. Therefore, recent studies have demonstrated that low-dose rt-PA (0.6 mg/kg, maximum 50 mg/2 hours) is as effective as the standard dose and much safer in terms of bleeding [3840]. No difference in mortality or reinfarction rates was noted between these agents. The rate of death plus recurrent PE was 1.6% for the heparin/alteplase group compared with 10.0% for the alteplase group (P = 0.0489). ESC Clinical Practice Guidelines 31 Aug 2019 This document follows the previous ESC guidelines focusing on the clinical management of pulmonary embolism (PE) published in 2000, 2008, and 2014. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Conflict of Interest: The author has no conflict of interest to declare. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Both are administered subcutaneously once or twice daily.9, After patients with acute PE have been stabilized, parenteral anticoagulation should be supplemented with vitamin K antagonists. Avoid excessive agitation during dilution; mix by gently swirling and/or slow inversion. We believe that . Data are presented as relative risk (RR) where 0.011 favours infusion and 1100 favours bolus. Submassive Pulmonary Embolism | American Journal of Respiratory and Submassive PE is defined as suspected or confirmed PE with right ventricular dysfunction in the absence of shock.1,4,8. The authors hypothesized that a larger proportion of patients who received tenecteplase would have a favorable composite outcome. The median (interquartile range) quality score was 2 (13). Logan JK, Pantle H, Huiras P, et al. While only about 4% of patients with pulmonary embolism (PE) present with hemodynamic instability or cardiac arrest (CA), evidence shows that up to 65% of massive PEs are fatal. Patients are categorized as intermediate- or low-risk, based on whether sPESI score is >1, and according to the presence of RV dysfunction (ECHO or computed tomography) and positivity of cardiac biomarkers. Sanchez O, Trinquart L, Colombet I, et al. Sometimes, pulmonary embolism is caused by a blood clot in the leg, called a deep vein thrombosis (DVT), breaking free and moving into the lung. Although it is the cheapest fibrinolytic agent, it has more side effects, such as allergic reaction and hypotension. Can the dose of systemic thrombolytic be reduced any further? One-year follow-up of the ASSENT-2 trial: a double-blind, randomized comparison of single-bolus tenecteplase and front-loaded alteplase in 16,949 patients with ST-elevation acute myocardial infarction. Guidelines recommend CDT as an alternative to surgical embolectomy for patients who did not respond to systemic thrombolysis, who are at risk of death before systemic thrombolysis takes effect, and those with contraindications for systemic thrombolysis [3, 18]. The preferred fibrinolytic agent is alteplase as a 100-mg continuous 2-hour infusion. Guideline on the management of bleeding in patients on antithrombotic agents. In addition, findings that rt-PA at a low-dose is as effective as the standard dose raises several questions that must be answered. The most studied form of CDT is ultrasound-assisted thrombolysis (USAT) [46]. Half-dose versus full-dose alteplase for treatment of pulmonary embolism. It is not approved by the FDA for indications other than acute myocardial infarction. Pulmonary embolism, thrombolytic therapy, fibrinolytic agents. The https:// ensures that you are connecting to the Halaby R, Giri J. 1 Compared with the top 2 causes, myocardial infarction and stroke, comparatively little research has focused on novel technologies aimed at reducing morbidity and mortality from this disease. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Sharifi et al. However, the 2004 American College of Chest Physicians guidelines recommended that if alteplase is prescribed for patients who are haemodynamically unstable, a 100mg infusion over 2h should be used 11, which may cause confusion when deciding how to treat massive PE. If standard heparin (SH) therapy was initiated and suspended during thrombolytic therapy, it should be resumed after completing the thrombolytic infusion and checking activated partial thromboplastin time (aPTT). 28,29 These differ from typical administration of alteplase as an infusion of 100 mg over 2 hours. van der Meer RW, Pattynama PM, van Strijen MJ, et al. At follow-up, 16 of the 43 patients (37%) treated with placebo and six of the 40 patients (15%) treated with tenecteplase had at least one adverse outcome (two-sided P = 0.017).39, Meta-analyses of thrombolytic therapies have been conducted in an attempt to develop treatment recommendations based on the current literature. The incidence of hemorrhage due to thrombolytic therapy has clearly decreased from past to present. Thrombolysis in pulmonary embolism: a debatable indication. Garcia DA, Baglin TP, Weitz JI, Samama MM. Indications Patients with massive PE (i.e. The diagnosis of PE was made using the following methods: pulmonary angiography in 16 trials 8, 14, 16, 17, 19, 2124, 2632; isotope-perfusion lung scan or pulmonary angiography in seven trials 4, 6, 15, 18, 20, 25, 33; pulmonary angiography, scintigraphy or necroscopy in one case study 35; and lung perfusion scan only in two trials 5, 34. sharing sensitive information, make sure youre on a federal ESC Guidelines on Acute Pulmonary Embolism (Diagnosis and Management of) Brandt K, McGinn K, Quedado J. Low-dose systemic alteplase (tPA) for the treatment of pulmonary embolism. Diagnosis & Initial Management of Patients with Suspected Pulmonary Embolism. Meta-analysis comparing alteplase infusion with all other thrombolytic regimens for the treatment of pulmonary embolism (PE) in different studies or subcategories. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. PDF Pulmonary Embolism Response Team (PERT) Page 1 of 11 Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. However, major bleeding was significantly more common in the tenecteplase group [21]. Absolute and relative contraindications of thrombolytic therapy are presented in Table 2. Submassive Pulmonary Embolism. Datapharm Communications Ltd. http://emc.medicines.org.uk/ Date last accessed: September 23, 2003; Date last updated: October 2002, Review Manager (RevMan). Venous thromboembolism: Past, present and future. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Individual patient data on objective improvement was not provided in 14 studies, thus increasing the risk of making spurious conclusions. The coprimary endpoints were pulmonary hypertension and a composite endpoint of pulmonary hypertension and recurrent PE at 28 months. Major bleeding was not significantly increased in patients 65 years of age or younger.19 It should be noted that the results of this analysis have been challenged because of purported flaws in the statistical methods.40, In another meta-analysis, Xu and colleagues analyzed data from seven studies involving a total of 1,631 patients with intermediate-risk PE treated with thrombolytics or anticoagulants. This study compared heparin plus alteplase 100 mg with heparin plus placebo, both administered over a period of two hours. 2. . 4. One patient treated with tenecteplase experienced a clinical event (recurrent pulmonary embolism) compared with three patients in the placebo group. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Alteplase is also used to treat a blood clot in the lung (pulmonary embolism). In view of these results, the conclusions of previous meta-analyses 37, 38 may be queried, as the one major assumption that each thrombolytic agent is as effective as the next may be invalid. Oxford, England, The Cochrane Collaboration, 2002. Bethesda, MD 20894, Web Policies Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. and transmitted securely. Contraindications of thrombolytic treatment in acute pulmonary thromboembolism, SBP: systolic blood pressure; DBP: diastolic blood pressure; INR: international normalized ratio; PT: prothrombin time. Konstantinides S, Geibel A, Heusel G, et al. Objectively measured thrombolysis was determined using angiographic evidence of clot lysis in nine studies 8, 16, 17, 2628, 3032, cardiac echocardiogram in two studies 5, 18 and >50% improvement in perfusion lung scan at 24h in one study 4. Ten years clinical experience. Ucar EY, Akgun M, Araz O, et al. Therefore, in the interest of attempting to provide further guidance for treating patients presenting with massive PE (an area of medicine with no firm evidence-based guidelines), an analysis of the summated data from all the reported trials has been performed. However, it also leads to the risk of systemic bleeding. Another randomized study compared low-molecular weight heparin (LMWH) and LMWH + tenecteplase. Sharifi M, Awdisho A, Schroeder B, Jimnez J, Iyer P, Bay C. Retrospective comparison of ultrasound facilitated catheter-directed thrombolysis and systemically administered half-dose thrombolysis in treatment of pulmonary embolism. The potential advantage of CDT is that a lower dose of the lytic agent is administered, resulting in a lower risk of bleeding compared to systemic treatment. persistent hypotension SBP <90 for 15 mins or requiring inotropic support) and acceptable risk of bleeding complications [8] Can be considered in initially hemodynamically stable patients (i.e. The patients mean age was 64 years. Butcher K, Shuaib A, Saver J, et al. Treatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator. However, a recent review stated that there is insufficient evidence to conclude that systemic thrombolysis reduces mortality with an acceptable hemorrhage incidence [27]. The presence of fibrin does not enhance its activity. NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. High-risk (massive) PTE: patients with shock or hypotension (systolic blood pressure <90 mmHg or decrease in systolic blood pressure of 40 mmHg from baseline) and RV dysfunction. Treatment of Pulmonary Embolism - U.S. Pharmacist Sensitivity analysis could not be performed because too few trials were included. No bleeding occurred in either group.37, The randomized, double-blind PEITHO trial compared tenecteplase plus heparin with placebo plus heparin in 1,005 patients with intermediate-risk PE. This is the first recombinant tissue plasminogen activator. These guidelines do not refer to other uses of alteplase, instead refer to Alteplase . Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Derivation and validation of a prognostic model for pulmonary embolism. In the International Cooperative Pulmonary Embolism Registry (ICOPER), the 90-day mortality rate for patients with acute PE and systolic blood pressure <90 mm Hg at presentation (108 patients) was 52.4% (95% confidence interval [CI] 43.3% to 62.1%) versus 14.7% (95% CI 13.3% to 16.2%) in the remainder of the cohort. PDF Alteplase for Pulmonary Embolism - Clinician Summary Specifically, the PEITHO study dosed tenecteplase as high as 50 mg in patients weighing more than 90 kg and as low as 30 mg in patients weighing less than 60 kg.21 In the MOPETT trial, intermediate-risk PE patients weighing less than 50 kg received a weight-based dosing regimen of 0.5 mg/kg (10-mg bolus administered over one minute, with the remainder of the dose administered over two hours).37 A meta-analysis of trials using low-dose recombinant tissue plasminogen activator (rt-PA) in patients with acute PE found that a low dose (50-mg infusion over two hours) was as effective as the standard dose (100-mg infusion over two hours), with fewer major bleeding events.43 In patients with massive PE, lower doses of thrombolytic agents may benefit patients at high risk of bleeding, such as those weighing less than 65 kg. Similarly, alteplase infusion was associated with a RR of 0.5 (95% CI: 0.280.90; p=0.02) for death from all cause compared with streptokinase, again primarily due to a reduction in death from the initial PE (RR: 0.13; 95% CI: 0.040.46; p=0.001). Fixed low-dose ultrasound-assisted catheter-directed thrombolysis for intermediate and high-risk pulmonary embolism. In the crude analysis, the thrombolytic efficacy of streptokinase was shown to be significantly greater than both alteplase regimens, suggesting that it may be the most useful thrombolytic drug. Systemic thrombolytic agents are a viable option in patients with hemodynamically unstable PE, as their potential benefits will almost certainly outweigh the risk of a life-threatening bleed. #: 1.27 risk ratio for streptokinase versus alteplase infusion (Chi-squared test with Yates' correction, p=0.002); : 1.95 risk ratio for alteplase infusion versus bolus-dose alteplase (Chi-squared test with Yates' correction, p=0.008). In conclusion, whilst the present study may assist in clarifying an area of medicine with a poor evidence base, the use of an unvalidated crude analysis involving the inclusion of small underpowered studies means these results should be interpreted with a certain degree of caution, and a firm recommendation on which thrombolytic agent to use cannot be given, due to the potential lack of statistical power.
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