Association between reperfusion therapy and outcomes in patients with acute pulmonary embolism and right heart thrombi

Association between reperfusion therapy and outcomes in patients with acute pulmonary embolism and right heart thrombi To the Editor: Right heart thrombi (RHT) may be detected in <4% of patients with pulmonary embolism (PE) [1], and are associated with worse outcomes [1–4]. Given the limited existing evidence, society guidelines or consensus statements have either not addressed the management of RHT, or have based their recommendations on prior case reports, case series or pooled results of case series [5–8]. It is plausible that reperfusion strategies reduce the adverse outcomes in PE patients with RHT; thrombolysis may dissolve the RHT and emboli, while thrombectomy might reduce the thromboembolic burden. Using the data from RIETE (Registro Informatizado Enfermedad TromboEmbolica), a prospective international venous thromboembolism registry, we sought to compare the outcomes of patients with PE and coexisting RHT, with versus without reperfusion therapy. The design of RIETE has been described previously [9]. Institutional review board approval and informed consent were obtained at participating sites. We included patients with PE (March 2001 to September 2019) and determined the use of reperfusion therapies within 3 days from echocardiographic identification of RHT. Main outcomes were 30-day PE-related mortality (autopsy-confirmed, or death within 10 days from PE, in the absence of an alternative cause), all-cause mortality, major bleeding (events that were overt and required ⩾2 units of blood, or retroperitoneal, spinal or intracranial, or fatal), and recurrent PE. In the primary analysis, 1:1 propensity-score matching was used, matching each patient receiving reperfusion with the nearest patient not receiving reperfusion, within a caliper width of 0.2 times the standard deviation of the log odds of the propensity score. The propensity score was derived from a group of variables thought to influence the use of reperfusion therapies and outcomes, including vital signs, age, history of heart failure and cancer. As confirmatory analyses, we included all patients with RHT in multivariable logistic regression, assessing the association between reperfusion therapies and outcomes. Among 42620 patients with PE, 18803 underwent transthoracic echocardiography with assessment of right ventricular function, of whom 443 (2.4%) had RHT. Among these 443 patients, 102 received reperfusion (thrombolytic therapy in 74, percutaneous or surgical thrombectomy in 28). After propensity-score matching, age was comparable in the two groups (59.1 versus 58.9 years, p=0.94), as was the history of heart failure (14.6% versus 15.9%, p=0.83), active cancer (14.6% versus 13.4%, p=0.82) and immobility (35.3% versus 31.7%, p=0.62). Similarly, presenting vital signs were comparable in the propensity-matched groups (heart rate 108.4 versus 108.7 bpm, p=0.94; systolic blood pressure 107.8 versus 107.3 mmHg, p=0.91; and proportion of patients with oxygen saturation <90% 39.0% versus 40.2%, p=0.87). During 30-day follow-up, 40 (9.0%) patients died, including 24 (5.4%) from PE. In the propensity-matched cohort (82 pairs), use of reperfusion therapy was not associated with significantly reduced odds of 30-day PE-related mortality (OR 0.65, 95% CI 0.20–2.16; p=0.48) or all-cause mortality @ERSpublications Right heart thrombi portend worse outcomes in pulmonary embolism (PE). In propensity-matched analyses of patients from a large registry, reperfusion therapy was not associated with significantly reduced odds of all-cause or PE-related mortality. https://bit.ly/2WRLYnq Cite this article as: Bikdeli B, Jiménez D, Muriel A, et al. Association between reperfusion therapy and outcomes in patients with acute pulmonary embolism and right heart thrombi. Eur Respir J 2020; 56: 2000538 [https://doi.org/10.1183/13993003.00538-2020]. https://doi.org/10.1183/13993003.00538-2020 Eur Respir J 2020; 56: 2000538 | AGORA RESEARCH LETTER (OR 0.86, 95% CI 0.30–2.43; p=0.78). The rate of major bleeding was comparable (OR 1.00, 95% CI 0.25– 3.92; p=0.999). Six patients receiving reperfusion therapy and no control patients had recurrent PE (risk difference 0.08, 95% CI 0.02–0.14). Findings were consistent in multivariable logistic regression analyses of all 443 patients (figure 1). Results were similar in supplemental analyses with 1:2 propensity-score matching. In a post hoc analysis, we assessed the use of thrombolytic therapy, compared with anticoagulation. In the propensity-matched cohort (62 pairs), use of thrombolytic therapy was not associated with significantly reduced odds of 30-day PE-related mortality (OR 0.54, 95% CI 0.14–2.06; p=0.37) or all-cause mortality (OR 0.84, 95% CI 0.25–2.84; p=0.78). The rate of major bleeding was comparable (OR 0.64, 95% CI 0.16– 2.54; p=0.529). In this study of patients with PE and coexisting RHT, we failed to find a significantly reduced odds of PE-related mortality with reperfusion attempt, mainly via thrombolytic therapy. Although this study reports the largest series of patients with RHT from a multinational registry, Type II error is still possible, similar to a prior investigation [10]. We must acknowledge that we cannot exclude a clinically meaningful, but smaller, effect size for improved outcomes with reperfusion (in the form of thrombolytic therapy). In addition, our findings do not exclude the utility of thrombolytic therapy in hemodynamically unstable patients. Such patients should be treated according to standard guideline recommendations [5, 6, 11]. However, the lack of large significant reduction in mortality and the hypothesis-generating increase in recurrent PEs in unselected patients with PE and coexisting RHT deserve further attention. Importantly, patients with PE and coexisting RHT have an increased risk of PE-related mortality. Therefore, although we failed to show reduced mortality with reperfusion (mainly via thrombolytic therapy), alternative strategies, including percutaneous thrombectomy or surgical thrombectomy, require further investigations to see if they could safety improve the outcomes. In the current investigation, small numbers made it unfeasible to provide a matched comparison between patients who underwent thrombectomy versus patients who received anticoagulation only. Given the rarity of this condition, it is unlikely that a large trial will become available in near future. Furthermore, we did not have access to detailed thrombus characteristics, including size, morphology and mobility. Therefore, we are unable to provide subgroup analyses for the comparative efficacy or reperfusion versus standard anticoagulation, based on thrombus characteristics. In conclusion, in patients with PE and coexisting RHT, use of reperfusion therapy, primarily in the form of thrombolytic therapy, was not associated with significantly lower PE-related mortality. Nevertheless, OR 0 b)a) 42 620 patients with PE 30-day PE-related mortality 30-day all-cause mortality 30-day major bleeding 1 Lower with reperfusion Higher with reperfusion 23456 OR 0 c) Primary analysis Confirmatory analysis 30-day PE-related mortality 30-day all-cause mortality 30-day major bleeding 1 Lower with reperfusion Higher with reperfusion 23456 443 had RHT Propensityscore matched pairs 82 with PE+RHT receiving reperfusion therapy 82 with PE+RHT not receiving reperfusion therapy Multivariable logistic regression: 102 with reperfusion and 341 without reperfusion FIGURE 1 a) Cohort selection and outcomes with or without reperfusion: b) propensity-matched cohort (n=164) and c) multivariable logistic regression among all participants (n=443). Matched and adjusted for age, history of active cancer, heart failure, immobilisation, heart rate systolic blood pressure and hypoxaemia. Odds ratio could not be calculated for recurrent pulmonary embolism (PE) in both models. In the matched-pair analysis, use of reperfusion was associated with increased absolute risk (risk difference 0.08, 95% CI 0.02–0.14) for recurrent events. RHT: right heart thrombi. https://doi.org/10.1183/13993003.00538-2020 2 RESEARCH LETTER | B. BIKDELI ET AL. RHT is an indicator of increased PE-related mortality. Additional studies are required to identify alternative effective treatments for this high-risk subgroup. Behnood Bikdeli 1,8 , David Jiménez 2,8 , Alfonso Muriel 3 , Deisy Barrios 2 , Aitor Ballaz 4 , Peter Verhamme 5 , Manuel Monreal 6,7 and the RIETE Investigators 9 1 Division of Cardiology, Dept of Medicine, Columbia University Medical Center, New York, NY, USA. 2 Respiratory Dept, Hospital Ramón y Cajal, Universidad de Alcala (IRYCIS), Madrid, Spain. 3 Biostatistics Clinic Unit, Hospital Ramón y Cajal (IRYCIS), CIBERESP, Nursing Department, Universidad de Alcalá, Madrid, Spain. 4 Dept of Pneumonology, Hospital de Galdakao, Vizcaya, Spain. 5 Dept of Vascular Medicine and Haemostasis, University of Leuven, Leuven, Belgium. 6 Dept of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Spain. 7 Universidad Católica de Murcia, Murcia, Spain. 8 B. Bikdeli and D. Jiménez contributed equally to this manuscript. 9 A full list of the RIETE investigators is given in the acknowledgements section. Correspondence: David Jiménez, Respiratory Dept and Medicine Dept, Ramón y Cajal Hospital, IRYCIS and Alcalá de Henares University, 28034 Madrid, Spain. E-mail: djimenez.hr[email protected] Received: 4 March 2020 | Accepted after revision: 11 May 2020 Acknowledgements: We express our gratitude to Sanofi Spain for supporting this registry with an unrestricted educational grant. We also thank the RIETE Registry coordinating centre, S&H Medical Science Service, for their quality control data, logistic and administrative support. 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), Hanh My Bui (Vietnam). RIETE Registry Coordinating Center: S&H Medical Science Service. Members of the RIETE Group: Spain: Adarraga MD, Agud M, Aibar J, Aibar MA, Alfonso J, Amado C, Arcelus JI, Arramberri M, Azcarate-Agüero P, Ballaz A, Barba R, Barbagelata C, Barrón M, Barrón-Andrés B, Blanco-Molina A, Camon AM, Castro J, Criado J, Culla A, de Miguel J, del Toro J, Demelo-Rodríguez P, Díaz-Pedroche MC, Díaz-Peromingo JA, Díez-Sierra J, Domínguez IM, Escribano JC, Fernández-Capitán C, Fernández-Reyes JL, Fidalgo MA, Flores K, Font C, Font L, Francisco I, Furest I, Gabara C, García MA, García-Bragado F, García-Raso A, Gavín-Blanco O, Gavín-Sebastián O, Gayol MC, Gil-Díaz A, Gómez-Cuervo C, González-Martínez J, Grau E, Gutiérrez J, Hernando E, Iglesias M, Jara-Palomares L, Jaras MJ, Jiménez D, Joya MD, Jou I, Lacruz B, Lalueza A, Lima J, Llamas P, Lobo JL, López-Jiménez L, López-Meseguer M, López-Miguel P, López-Núñez JJ, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Loring M, Lumbierres M, Madridano O, Maestre A, Marchena PJ, Martín-Asenjo M, Martín-Fernández M, Martín-Guerra JM, Martín-Martos F, Mella C, Mellado M, Mercado MI, Moisés J, Monreal M, Morales MV, Muñoz-Blanco A, Muñoz-Guglielmetti D, Nieto JA, Núñez MJ, Olivares MC, Ortega-Michel C, Ortega-Recio MD, Osorio J, Otero R, Paredes D, Parra V, Pedrajas JM, Pellejero G, Pérez-Ductor C, Pérez-Jacoíste A, Pérez-Rus G, Peris ML, Pesántez D, Porras JA, Portillo J, Reig L, Riera-Mestre A, Rivas A, Rodríguez-Cobo A, Rodríguez-Matute C, Rosa V, Rubio CM, Ruiz-Giménez N, Ruiz-Sada P, Sahuquillo JC, Sala-Sainz MC, Salgueiro G, Sampériz A, Sánchez-Muñoz-Torrero JF, Sancho T, Soler S, Suárez S, Suriñach JM, Tapia E, Tiberio G, Torres MI, Tolosa C, Trujillo-Santos J, Uresandi F, Usandizaga E, Valle R, Vela JR, Vidal G, Villares P, Zamora C. Argentina: Gutiérrez P, Vázquez FJ. Belgium: Vanassche T, Vandenbriele C, Verhamme P. Czech Republic: Hirmerova J, Malý R. Ecuador: Salgado E. France: Benzidia I, Bertoletti L, Bura-Riviere A, Debourdeau P, Courtois MC, Farge-Bancel D, Helfer H, Hij A, Mahé I, Moustafa F. Germany: Schellong S. Israel: Braester A, Brenner B, Tzoran I. Italy: Amitrano M, Bilora F, Bortoluzzi C, Brandolin B, Bucherini E, Ciammaichella M, Dentali F, Di Micco P, Grandone E, Imbalzano E, Maida R, Pace F, Pesavento R, Prandoni P, Quintavalla R, Rocci A, Siniscalchi C, Tiraferri E, Tufano A, Visonà A, Vo Hong N, Zalunardo B. Latvia: Kigitovica D, Skride A, Strautmane S. Portugal: Ferreira M. Republic Of Macedonia: Bosevski M, Zdraveska M. Switzerland: Bounameaux H, Mazzolai L. USA: Bikdeli B, Caprini JA, Tafur AJ, Weinberg I, Wilkins H. Vietnam: Bui HM. Conflict of interest: B. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to a specific type of IVC filters. D. Jiménez has nothing to disclose. A. Muriel has nothing to disclose. D. Barrios has nothing to disclose. A. Ballaz has nothing to disclose. P. Verhamme reports honoraria for lectures and consultancy from Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, Pfizer, BMS and Portola. M. Monreal has nothing to disclose. Support statement: This work was supported by Bayer Pharma and Sanofi. Funding information for this article has been deposited with the Crossref Funder Registry. References 1Bikdeli B, Lobo JL, Jiménez D, et al. Early use of echocardiography in patients with acute pulmonary embolism: findings from the RIETE registry. J Am Heart Assoc 2018; 7: e009042. 2KoćM, Kostrubiec M, Elikowski W, et al. Outcome of patients with right heart thrombi: the Right Heart Thrombi European Registry. Eur Respir J 2016; 47: 869–875. 3Barrios D, Rosa-Salazar V, Jiménez D, et al. Right heart thrombi in pulmonary embolism. Eur Respir J 2016; 48: 1377–1385. 4Torbicki A, Galié N, Covezzoli A, et al. 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