Portal de Periódicos da CAPES

Comparison of Full-Dose vs Moderate-Dose Systemic Thrombolysis for the Treatment of Patients With Acute Pulmonary Embolism

2022; Elsevier BV; Volume: 162; Issue: 2 Linguagem: Inglês

10.1016/j.chest.2022.02.026

1931-3543

Ana Jaureguízar, Cassius Iyad Ochoa Chaar, Alfonso Muriel, Jerónimo Ramón Vela Moreno, Ido Weinberg, Antonella Tufano, José F. Varona, Behnood Bikdeli, David Jiménez, Manuel Monréal,

Sepsis Diagnosis and Treatment

Although anticoagulant therapy is the treatment of choice for most patients with pulmonary embolism (PE), guidelines recommend the use of full-dose systemic thrombolytic therapy for unstable patients who do not have contraindications owing to bleeding risk. However, thrombolytic therapy may increase the risk of major bleeding, and some trials have suggested that the use of a lower dose of the thrombolytic drug might confer benefits similar to full-dose thrombolysis, while limiting the adverse effects.1Wang C. Zhai Z. Yang Y. et al.Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism.Chest. 2010; 137: 254-262Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar,2Sharifi M. Bay C. Skrocki L. et al.Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial).Am J Cardiol. 2013; 111: 273-277Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar However, no head-to-head comparisons exist between patients treated with moderate-dose vs full-dose thrombolytic therapy. This study compared the efficacy and safety of moderate-dose thrombolysis (defined as ≤ 50% of the approved dose of the thrombolytic agent) with full-dose thrombolysis during the first month of therapy for acute PE. Consecutive patients enrolled in RIETE who underwent systemic thrombolytic therapy for acute symptomatic PE from January 1, 2001, through February 8, 2021, were included. Outcomes included all-cause (primary efficacy outcome) and PE-specific mortality, nonfatal recurrent VTE, and major bleeding (primary safety outcome) through 30 days after administration of thrombolysis. We used propensity score matching to compare treatment effects for patients with similar predicted probabilities of receiving moderate-dose thrombolysis. We performed several sensitivity analyses. We examined the effect of moderate-dose thrombolysis in the subgroup of unstable (ie, systolic BP < 90 mm Hg) patients with PE. We also repeated the analyses in subgroups of patients with a high bleeding risk defined by the Bleeding, Age, Cancer, Syncope score.3Jara-Palomares L. Jiménez D. Bikdeli B. et al.Derivation and validation of a clinical prediction rule for thrombolysis-associated major bleeding in patients with acute pulmonary embolism: the BACS score.Eur Respir J. 2020; : 2002336Crossref PubMed Google Scholar The final analysis included 1,021 patients with PE. Overall, 94 of 1,021 patients (9.2%) died through 30 days after the diagnosis of PE (Table 1). No significant difference was found in the mean ± SE delay between diagnosis of PE and administration of thrombolytics (0.87 ± 0.10 days and 0.85 ± 0.06 days for patients who received moderate-dose or full-dose thrombolysis, respectively). Patients treated with moderate-dose systemic thrombolysis (n = 182), compared with those who received full-dose thrombolysis (n = 839), showed a higher relative frequency of male sex (56% vs 48%), recent bleeding (3.8% vs 1.0%), and anemia (33% vs 28%). Use of antiplatelet agents was significantly more common in the moderate-dose group (18% vs 12%).Table 1Unadjusted Clinical Outcomes in the Study CohortsVariableEntire Cohort (N = 45,485)Received Thrombolysis (n = 1,021)Matched Pairs (n = 346)All-cause mortality2,443 (5.4)94 (9.2)30 (8.7)PE-related mortality978 (2.2)61 (6.0)14 (4.0)Recurrent VTE407 (0.9)24 (2.4)8 (2.3)Major bleeding1,617 (3.6)120 (11.8)36 (10.4)Data are presented as No. (%). PE = pulmonary embolism. Open table in a new tab Data are presented as No. (%). PE = pulmonary embolism. Propensity-score matching (173 patients treated with moderate-dose thrombolysis and 173 patients treated with full-dose thrombolysis) showed a higher risk of all-cause death (OR, 1.56; 95% CI, 0.73-3.34; P = .26), PE-related death (OR, 1.85; 95% CI, 0.61-5.62; P = .28), or nonfatal recurrent VTE (OR, 2.39; 95% CI, 0.61-9.43; P = .21) and lower risk of major bleeding (OR, 0.68; 95% CI, 0.34-1.39; P = .29) for patients receiving moderate-dose thrombolysis compared with those who received full-dose systemic thrombolysis that did not reach statistical significance (Table 2). In the subgroup of patients with a Bleeding, Age, Cancer, Syncope score of > 0, a statistically nonsignificant lower risk of PE-related death (OR, 0.60; 95% CI, 0.19-1.92; P = .39) and lower risk of major bleeding (OR, 0.40; 95% CI, 0.08-2.06; P = .27) was found.Table 2Adjusted Clinical Outcomes30-d OutcomeModerate DoseFull DoseOR (95% CI)P ValueOverall cohort All-cause mortality18/173 (10.4)12/173 (6.9)1.56 (0.73-3.34).26 PE-related mortality9/173 (5.2)5/173 (2.9)1.85 (0.61-5.62).28 Recurrent VTE5/173 (2.9)3/173 (1.7)2.39 (0.61-9.43).21 Composite of mortality or recurrent VTE23/173 (13.3)15/173 (8.7)1.62 (0.81-3.22).17 Major bleeding15/173 (8.7)21/173 (12.1)0.68 (0.34-1.39).29 Intracranial bleeding3/173 (1.7)2/173 (1.2)1.46 (0.72-2.93).29Systolic BP < 90 mm HgaMatched pair analyses were independent for each subgroup. Therefore, the sum of pairs and events does not match up to the overall cohort. All-cause mortality7/44 (15.9)4/44 (9.1)1.89 (0.51-7.00).34 PE-related mortality1/44 (2.3)3/44 (6.8)0.32 (0.04-3.12).33 Recurrent VTE1/44 (2.3)0/44 (0)—bCannot be calculated.—bCannot be calculated. Composite of mortality or recurrent VTE8/44 (18.2)4/44 (9.1)2.22 (0.62-8.01).22 Major bleeding3/44 (6.8)6/44 (13.6)0.40 (0.08-2.06).27Systolic BP ≥ 90 mm HgaMatched pair analyses were independent for each subgroup. Therefore, the sum of pairs and events does not match up to the overall cohort. All-cause mortality10/125 (8.0)13/125 (10.4)0.75 (0.32-1.78).51 PE-related mortality8/125 (6.4)8/125 (6.4)1.00 (0.36-2.75)1.00 Recurrent VTE5/125 (4.0)7/125 (5.6)0.70 (0.22-2.27).56 Composite of mortality or recurrent VTE13/125 (10.4)16/125 (12.8)0.79 (0.36-1.72).55 Major bleeding11/125 (8.8)12/125 (9.6)0.91 (0.39-2.14).83BACS score > 0 All-cause mortality11/98 (11.2)13/98 (13.3)0.83 (0.35-1.95).66 PE-related mortality5/98 (5.1)8/98 (8.2)0.60 (0.19-1.92).39 Recurrent VTE6/98 (6.1)1/98 (1.0)6.32 (0.75; 53.5).09 Composite of mortality or recurrent VTE17/98 (17.3)14/98 (14.3)1.28 (0.58-2.82).54 Major bleeding12/98 (12.2)20/98 (20.4)0.40 (0.08-2.06).27Data are presented as No./Total No. (%), unless otherwise indicated. BACS = Bleeding, Age, Cancer, Syncope; PE, pulmonary embolism.a Matched pair analyses were independent for each subgroup. Therefore, the sum of pairs and events does not match up to the overall cohort.b Cannot be calculated. Open table in a new tab Data are presented as No./Total No. (%), unless otherwise indicated. BACS = Bleeding, Age, Cancer, Syncope; PE, pulmonary embolism. The major finding of this study is that deaths were numerically higher (absolute risk increase, 3.5%; 95% CI, –3.0% to 10.0%) in the moderate-dose thrombolysis group, whereas major bleeding events were numerically lower (absolute risk reduction, 3.5%; 95% CI, –3.5% to 10.5%). Therefore, this observational comparative effectiveness analysis does not support a net clinical benefit for moderate-dose thrombolytic therapy in patients with PE, although specific subgroups, including those with high risk of bleeding, may deserve additional investigation. Previous studies have shown that a moderate-dose thrombolytic regimen did not show a significantly different efficacy and perhaps better safety than a full-dose regimen.4Wang T.F. Squizzato A. Dentali F. Ageno W. The role of thrombolytic therapy in pulmonary embolism.Blood. 2015; 125: 2191-2199Crossref PubMed Scopus (40) Google Scholar Several possible explanations exist that may explain the difference with our results, including the differing patient characteristics, residual confounding (eg, clinicians might have provided other aspects of background care differently in the two groups), or the relatively small sample size of the propensity-matched cohorts. This analysis has limitations. Because the RIETE investigators used different agents (alteplase, streptokinase, urokinase, and tenecteplase) with different units, we were not able to analyze whether a linear relationship exists between the dose of thrombolytic agents and outcomes. The matched cohort showed a low mortality rate for patients with a diagnosis of PE who received thrombolysis. Study design and selection bias among providers to administer or withhold aggressive therapy might explain, at least in part, this finding. In conclusion, for patients with PE who require thrombolysis, the results of this analysis did not show a significant difference between moderate-dose and full-dose of thrombolysis in terms of efficacy or safety. The numerical trends suggest that possibly a tradeoff exists between increasing mortality and decreasing bleeding with the use of the lower dose of thrombolysis. Such plausible trends should be confirmed in future larger studies. The role of moderate-dose systemic thrombolysis, particularly in patients with high Bleeding, Age, Cancer, Syncope score, requires further research. ∗ RIETE Investigators: Coordinator of the RIETE Registry: Manuel Monreal. RIETE Steering Committee Members: Paolo Prandoni, Benjamin Brenner, and Dominique Farge-Bancel. RIETE National Coordinators: Raquel Barba (Spain), Pierpaolo Di Micco (Italy), Laurent Bertoletti (France), Sebastian Schellong (Germany), Inna Tzoran (Israel), Abilio Reis (Portugal), Marijan Bosevski (R. Macedonia), Henri Bounameaux (Switzerland), Radovan Malý (Czech Republic), Peter Verhamme (Belgium), Joseph A. Caprini (USA), and Hanh My Bui (Vietnam). RIETE Registry Coordinating Center: S & H Medical Science Service. Members of the RIETE Group: SPAIN: Adarraga MD, Aibar J, Aibar MA, Amado C, Arcelus JI, Ballaz A, Barba R, Barbagelata C, Barrón M, Barrón-Andrés B, Blanco-Molina A, Beddar Chaib F, Botella E, Camón AM, Castro J, Criado J, de Ancos C, de Miguel J, del Toro J, Demelo-Rodríguez P, Díaz-Brasero AM, Díaz-Pedroche MC, Díaz-Peromingo JA, Domínguez IM, Dubois-Silva A, Escribano JC, Farfán-Sedano AI, Fernández-Capitán C, Fernández-Reyes JL, Fidalgo MA, Font C, Francisco I, Gabara C, Galeano-Valle F, García MA, García-Bragado F, García de la Garza R, García-Díaz C, Gil-Díaz A, Gómez-Cuervo C, Gómez-Mosquera AM, González-Martínez J, Grau E, Guirado L, Gutiérrez J, Hernández-Blasco L, Jara-Palomares L, Jaras MJ, Jiménez D, Jiménez R, Jiménez-Alfaro C, Jou I, Joya MD, Lainez-Justo S, Latorre-Díez A, Lalueza A, Lobo JL, López-Brull H, López-Jiménez L, López-Miguel P, López-Núñez JJ, López-Reyes R, López-Sáez JB, Lorenzo A, Lumbierres M, Madridano O, Maestre A, Marchena PJ, Martín-Martos F, Martínez-Urbistondo D, Mella C, Mellado M, Mercado MI, Monreal M, Muñoz-Blanco A, Morales MV, Nieto JA, Núñez-Fernández MJ, Olid-Velilla M, Otalora S, Otero R, Paredes-Ruiz D, Parra P, Parra V, Pedrajas JM, Pellejero G, Peris ML, Porras JA, Portillo J, Roca M, Rosa V, Ruiz-Artacho P, Ruiz-Giménez N, Ruiz-Ruiz J, Ruiz-Sada P, Salgueiro G, Sánchez-Muñoz-Torrero JF, Sancho T, Soler S, Suárez-Rodríguez B, Suriñach JM, Torres MI, Torres-Sanchez A, Trujillo-Santos J, Uresandi F, Usandizaga E, Valle R, Varona JF, Vela L, Vela JR, Villalobos A, Villares P, and Zamora C; AUSTRIA: Ay C, Nopp S, and Pabinger I; BELGIUM: Engelen MM, Vanassche T, and Verhamme P; COLOMBIA: Esguerra G, Montenegro AC, and Roa J; CZECH REPUBLIC: Hirmerova J and Malý R; FRANCE: Accassat S, Bertoletti L, Bura-Riviere A, Catella J, Chopard R, Couturaud F, Espitia O, El Harake S, Helfer H, Le Mao R, Mahé I, Moustafa F, Poenou G, Quere I, Sarlon-Bartoli G, and Suchon P; GERMANY: Schellong S; ISRAEL: Braester A, Brenner B, Kenet G, and Tzoran I; ITALY: Basaglia M, Bilora F, Bortoluzzi C, Brandolin B, Ciammaichella M, De Angelis A, Di Micco P, Imbalzano E, Mastroiacovo D, Merla S, Pesavento R, Prandoni P, Siniscalchi C, Tufano A, Visonà A, Vo Hong N, Zalunardo B; LATVIA: Birzulis J, Dzirnieks K, and Skride A; PORTUGAL: Fonseca S, Manuel M, and Meireles J; REPUBLIC OF MACEDONIA: Bosevski M and Krstevski G; SWITZERLAND: Bounameaux H and Mazzolai L; UNITED STATES: Caprini JA and Weinberg I; VIETNAM: Bui HM. Other contributions: The authors thank the RIETE Registry coordinating center and S&H Medical Science Service for their quality control data and logistic and administrative support. Funding/support: The RIETE Registry was supported by an unrestricted educational grant from Sanofi Spain, Leo Pharma, and ROVI. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: B. B. reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of inferior vena cava filters. M. M. received an unrestricted educational grant to sponsor the RIETE registry. None declared (A. V., C. I. O. C., A. M., J. R., V. M., I. W., A. T., J. F. V., D. J.). Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.