Original Manuscript
Should Low-Molecular-Weight Heparin be Preferred Over Unfractionated Heparin After Thrombolysis for Severity Pulmonary Embolism?
Clinical and Applied Thrombosis/Hemostasis 1-5 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614564863 cat.sagepub.com
Aysegul Senturk, MD1, Elif Yilmazel Ucar, MD2, Serdar Berk, MD3, Tevfik Ozlu, MD4, Bulent Altınsoy, MD5, Gul Dabak, MD6, Ebru Cakır, MD7, Esra Ekbic Kadıoglu, MD8, Hadice Selimoglu Sen, MD9, Savas Ozsu, MD4, and The TUPEG Study Investigators
Abstract Purpose: The role of low-molecular-weight heparin (LMWH) in managing nonmassive pulmonary embolism (PE) is well known. In unstable cases, especially after thrombolytic therapy for massive PE, unfractionated heparin (UFH) is preferred for PE management. This study aimed to investigate the effectiveness and safety of LMWH after thrombolytic therapy. Methods: A prospective, observational multicenter trial was performed in 249 patients with acute PE who required thrombolysis. Massive and submassive PEs were categorized into 2 groups depending on whether they were treated with LMWH or UFH after thrombolytic treatment. The primary end point was all-cause mortality during the first 30 days; the secondary end point included all-cause mortality, nonfatal symptomatic recurrent PEs, or nonfatal major bleeding. Results: The mean age at diagnosis was 60.7 + 15.5 years. The PE severity was massive in 186 (74.7%) patients and submassive in 63 (25.3%). The incidence of all-cause 30-day death was 8.2% and 17.3% in patients with LMWH and UFH, respectively (P ¼ .031). Major hemorrhage occurred in 4% (n ¼ 5) and 7.9% (n ¼ 10) of patients and minor hemorrhage occurred in 9% (n ¼ 11) and 13.4% (n ¼ 17) of the cases treated with LMWH and UFH, respectively. Conclusion: These results suggest that LMWH treatment can be used safely in patients with PE after thrombolytic therapy. Keywords pulmonary thromboembolism, low-molecular-weight heparin, unfractionated heparin
Introduction
1
Pulmonary embolism (PE) remains poorly understood, despite advances in diagnosis and therapy.1 Early anticoagulation has been the cornerstone of PE treatment for many years and is lifesaving. The European and American guidelines recommend unfractionated heparin (UFH) as the only compound for concomitant use with thrombolysis.2,3 However, patients with low-risk PE may be candidates for anticoagulation with low-molecularweight heparin (LMWH). The LMWH and UFH have been shown to have equivalent efficacy and safety for the management of nonmassive PE.4 On the other hand, LMWH has been shown to be superior to UFH in patients with deep venous thrombosis (DVT) and in those with DVT having PE because LMWH reduces mortality, recurrent thrombosis, and serious bleeding events.5 The effect of using LMWH after thrombolytic treatment when managing acute massive PE is not clear; many clinicians continue to treat acute PE, which is a high-risk situation, with UFH. We aimed to compare UFH and LMWH management after thrombolytic treatment in acute massive and submassive PEs.
Department of Pulmonary Medicine, Ankara Atatu¨rk Training and Research Hospital, Ankara, Turkey 2 Department of Pulmonary Medicine, Atatu¨rk University School of Medicine, Erzurum, Turkey 3 Department of Pulmonary Medicine, Cumhuriyet University, School of Medicine, Sivas, Turkey 4 Department of Pulmonary Medicine, Karadeniz Technical University, School of Medicine, Trabzon, Turkey 5 Department of Pulmonary Medicine, Bu¨lent Ecevit University School of Medicine, Zonguldak, Turkey 6 Department of Pulmonary Medicine, Istanbul Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital, _Istanbul, Turkey 7 Department of Pulmonary Medicine, Trakya University, School of Medicine, Edirne, Turkey 8 Department of Pulmonary Medicine, Erzurum Regional Training and Research Hospital, Erzurum, Turkey 9 Department of Pulmonary Medicine, Dicle University School of Medicine, Diyarbakır, Turkey Corresponding Author: Aysegul Senturk, Department of Pulmonary Medicine, Ankara Atatu¨rk Training and Research Hospital, Ankara, Turkey. Email: [email protected]
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 14, 2015
2
Clinical and Applied Thrombosis/Hemostasis
Methods Study Design
Table 1. Demographics and General Patient Characteristics.
This study was conducted between January and November 2013 as part of a large prospective, multicenter, and observational study in 25 centers in Turkey. The study population included 249 patients with the diagnosis of PE confirmed by multidetector computed tomography (CT). The study protocol was approved by the local ethics committee at the coordinating center, and written informed consent was obtained from all patients.
Patients and Setting Consecutive patients older than 18 years of age with clinically suspected acute PE were considered for the study. The study consisted of 249 patients who were admitted with massive and submassive PEs. Before the patients could be included, PE had to be objectively documented by multidetector CT. All patients’ demographic characteristics and clinical and laboratory parameters were obtained from the hospital’s electronic database. A Wells score for PE was calculated for each patient. The results of imaging studies and laboratory tests (D-dimer, high-sensitivity troponin-I or troponin-T, and natriuretic peptide levels) were reported according to local standards. Comorbidities considered were history of venous thromboembolism, malignancy, chronic obstructive pulmonary disease (COPD), coronary artery disease, cerebrovascular occlusion, or congestive heart failure. The PE severity was classified into 3 groups according to European Society of Cardiology guidelines: high risk (patients with shock or hypotension), intermediate risk (presence of a positive marker for myocardial injury or right ventricular dysfunction), or low risk (absence of right ventricular dysfunction or negative marker of myocardial injury).6 Inclusion criteria were hemodynamic instability and cardiogenic shocks accompanied by vital signs and echo findings. Exclusion criteria were absolute contraindications for thrombolytic therapy or nonmassive PE. A total of 186 (74.7%) patients with massive PE and 63 (25.3%) patients with submassive PE were classified. High and moderate risks of mortality were taken into consideration, after which the decision to use thrombolytic therapy was made. Thrombolytic therapy was administered to each patient in the first 14 days after onset of the symptoms. The patients received either LMWH or UFH after thrombolytic therapy. Both groups continued with warfarin, with the target-activated partial thromboplastin time being defined as 60 to 80 seconds; oral anticoagulants were used for at least 3 months.
Outcomes Thirty-day clinical follow-up data were obtained for all patients. The primary end point was all-cause mortality during the first 30 days; the secondary end point included all-cause mortality, nonfatal symptomatic recurrent PE, or nonfatal major bleeding.
LMWH Group UFH Group (n ¼ 122) (n ¼ 127) Age, mean + SD, year Gender (M/F), n Massive (%) Submassive (%) Admission (PaO2), mean + SD RV dysfunction, n Concomitant diseases, n Dyspnea, n Chest pain, n Cough, n Syncope, n Confusion Presence of malignancy (%)
72 + 15.0 58/64 81 (43.5%) 41 (22%) 53 + 16.6 116/6 67/55 115/7 80/42 11/111 31/91 18/104 13 (10.7%)
59.4 + 15.8 51/76 105 (56.5%) 22 (34.9%) 58.76 + 19.4 122/5 60/67 119/8 77/50 20/107 33/94 22/105 12 (9.4%)
P .180 .240 .003 .003 .013 .765
Should Low-Molecular-Weight Heparin be Preferred Over Unfractionated Heparin After Thrombolysis for Severity Pulmonary Embolism?
Clinical and Applied Thrombosis/Hemostasis 1-5 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029614564863 cat.sagepub.com
Aysegul Senturk, MD1, Elif Yilmazel Ucar, MD2, Serdar Berk, MD3, Tevfik Ozlu, MD4, Bulent Altınsoy, MD5, Gul Dabak, MD6, Ebru Cakır, MD7, Esra Ekbic Kadıoglu, MD8, Hadice Selimoglu Sen, MD9, Savas Ozsu, MD4, and The TUPEG Study Investigators
Abstract Purpose: The role of low-molecular-weight heparin (LMWH) in managing nonmassive pulmonary embolism (PE) is well known. In unstable cases, especially after thrombolytic therapy for massive PE, unfractionated heparin (UFH) is preferred for PE management. This study aimed to investigate the effectiveness and safety of LMWH after thrombolytic therapy. Methods: A prospective, observational multicenter trial was performed in 249 patients with acute PE who required thrombolysis. Massive and submassive PEs were categorized into 2 groups depending on whether they were treated with LMWH or UFH after thrombolytic treatment. The primary end point was all-cause mortality during the first 30 days; the secondary end point included all-cause mortality, nonfatal symptomatic recurrent PEs, or nonfatal major bleeding. Results: The mean age at diagnosis was 60.7 + 15.5 years. The PE severity was massive in 186 (74.7%) patients and submassive in 63 (25.3%). The incidence of all-cause 30-day death was 8.2% and 17.3% in patients with LMWH and UFH, respectively (P ¼ .031). Major hemorrhage occurred in 4% (n ¼ 5) and 7.9% (n ¼ 10) of patients and minor hemorrhage occurred in 9% (n ¼ 11) and 13.4% (n ¼ 17) of the cases treated with LMWH and UFH, respectively. Conclusion: These results suggest that LMWH treatment can be used safely in patients with PE after thrombolytic therapy. Keywords pulmonary thromboembolism, low-molecular-weight heparin, unfractionated heparin
Introduction
1
Pulmonary embolism (PE) remains poorly understood, despite advances in diagnosis and therapy.1 Early anticoagulation has been the cornerstone of PE treatment for many years and is lifesaving. The European and American guidelines recommend unfractionated heparin (UFH) as the only compound for concomitant use with thrombolysis.2,3 However, patients with low-risk PE may be candidates for anticoagulation with low-molecularweight heparin (LMWH). The LMWH and UFH have been shown to have equivalent efficacy and safety for the management of nonmassive PE.4 On the other hand, LMWH has been shown to be superior to UFH in patients with deep venous thrombosis (DVT) and in those with DVT having PE because LMWH reduces mortality, recurrent thrombosis, and serious bleeding events.5 The effect of using LMWH after thrombolytic treatment when managing acute massive PE is not clear; many clinicians continue to treat acute PE, which is a high-risk situation, with UFH. We aimed to compare UFH and LMWH management after thrombolytic treatment in acute massive and submassive PEs.
Department of Pulmonary Medicine, Ankara Atatu¨rk Training and Research Hospital, Ankara, Turkey 2 Department of Pulmonary Medicine, Atatu¨rk University School of Medicine, Erzurum, Turkey 3 Department of Pulmonary Medicine, Cumhuriyet University, School of Medicine, Sivas, Turkey 4 Department of Pulmonary Medicine, Karadeniz Technical University, School of Medicine, Trabzon, Turkey 5 Department of Pulmonary Medicine, Bu¨lent Ecevit University School of Medicine, Zonguldak, Turkey 6 Department of Pulmonary Medicine, Istanbul Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital, _Istanbul, Turkey 7 Department of Pulmonary Medicine, Trakya University, School of Medicine, Edirne, Turkey 8 Department of Pulmonary Medicine, Erzurum Regional Training and Research Hospital, Erzurum, Turkey 9 Department of Pulmonary Medicine, Dicle University School of Medicine, Diyarbakır, Turkey Corresponding Author: Aysegul Senturk, Department of Pulmonary Medicine, Ankara Atatu¨rk Training and Research Hospital, Ankara, Turkey. Email: [email protected]
Downloaded from cat.sagepub.com at CMU Libraries - library.cmich.edu on September 14, 2015
2
Clinical and Applied Thrombosis/Hemostasis
Methods Study Design
Table 1. Demographics and General Patient Characteristics.
This study was conducted between January and November 2013 as part of a large prospective, multicenter, and observational study in 25 centers in Turkey. The study population included 249 patients with the diagnosis of PE confirmed by multidetector computed tomography (CT). The study protocol was approved by the local ethics committee at the coordinating center, and written informed consent was obtained from all patients.
Patients and Setting Consecutive patients older than 18 years of age with clinically suspected acute PE were considered for the study. The study consisted of 249 patients who were admitted with massive and submassive PEs. Before the patients could be included, PE had to be objectively documented by multidetector CT. All patients’ demographic characteristics and clinical and laboratory parameters were obtained from the hospital’s electronic database. A Wells score for PE was calculated for each patient. The results of imaging studies and laboratory tests (D-dimer, high-sensitivity troponin-I or troponin-T, and natriuretic peptide levels) were reported according to local standards. Comorbidities considered were history of venous thromboembolism, malignancy, chronic obstructive pulmonary disease (COPD), coronary artery disease, cerebrovascular occlusion, or congestive heart failure. The PE severity was classified into 3 groups according to European Society of Cardiology guidelines: high risk (patients with shock or hypotension), intermediate risk (presence of a positive marker for myocardial injury or right ventricular dysfunction), or low risk (absence of right ventricular dysfunction or negative marker of myocardial injury).6 Inclusion criteria were hemodynamic instability and cardiogenic shocks accompanied by vital signs and echo findings. Exclusion criteria were absolute contraindications for thrombolytic therapy or nonmassive PE. A total of 186 (74.7%) patients with massive PE and 63 (25.3%) patients with submassive PE were classified. High and moderate risks of mortality were taken into consideration, after which the decision to use thrombolytic therapy was made. Thrombolytic therapy was administered to each patient in the first 14 days after onset of the symptoms. The patients received either LMWH or UFH after thrombolytic therapy. Both groups continued with warfarin, with the target-activated partial thromboplastin time being defined as 60 to 80 seconds; oral anticoagulants were used for at least 3 months.
Outcomes Thirty-day clinical follow-up data were obtained for all patients. The primary end point was all-cause mortality during the first 30 days; the secondary end point included all-cause mortality, nonfatal symptomatic recurrent PE, or nonfatal major bleeding.
LMWH Group UFH Group (n ¼ 122) (n ¼ 127) Age, mean + SD, year Gender (M/F), n Massive (%) Submassive (%) Admission (PaO2), mean + SD RV dysfunction, n Concomitant diseases, n Dyspnea, n Chest pain, n Cough, n Syncope, n Confusion Presence of malignancy (%)
72 + 15.0 58/64 81 (43.5%) 41 (22%) 53 + 16.6 116/6 67/55 115/7 80/42 11/111 31/91 18/104 13 (10.7%)
59.4 + 15.8 51/76 105 (56.5%) 22 (34.9%) 58.76 + 19.4 122/5 60/67 119/8 77/50 20/107 33/94 22/105 12 (9.4%)
P .180 .240 .003 .003 .013 .765
