- Email: [email protected]
Pulmonary Interventional Therapy for Acute Massive and Submassive Pulmonary Embolism in Cases Where Thrombolysis Is Contraindicated
Clinical Research Pulmonary Interventional Therapy for Acute Massive and Submassive Pulmonary Embolism in Cases Where Thrombolysis Is Contraindicated Yan Meng, Junbo Zhang, Qiang Ma, Hao Qin, Bo Zhang, Honggang Pang, Qian Yin, and Hongyan Tian, Xi’an, China
Background: In this study, we sought to analyze the clinical outcomes of pharmacomechanical therapy for massive and submassive acute pulmonary embolism (APE). Methods: We conducted a retrospective investigation of 97 patients who received pharmacomechanical therapy at out center between January 2013 and June 2018 for acute massive and submassive PE because thrombolysis was contraindicated. Results: Of the 97 patients, 46 (47%) were men, and the mean age of the patients was 56 ± 14 years (median, 58 years; range, 21e84 years). Fifty patients had massive PE, whereas the remaining had submassive PE. Analysis of the site of embolus revealed that 67 (69%) had bilateral emboli in the pulmonary arteries (PAs); 5 (5%) only in the left PA, and 25 (26%) only in the right PA. Seventy-nine (81%) of the 97 patients underwent intraoperative placement of the inferior vena caval filters, whereas 3 (3%) required use of a noninvasive ventilator. Two (2%) patients died within 30 days of the interventional therapy because of severe right ventricular failure. The amount of blood loss was nonsignificant. Conclusions: Our results indicate that an optimal pharmacomechanical therapy protocol could yield favorable outcomes for rapid clot debulking in cases of massive and submassive APE where thrombolysis is contraindicated. Pending further randomized trials, pharmacomechanical therapy shows promise as an alternative treatment method in cases of acute massive or submassive PE, with minimal risk of major bleeding.
INTRODUCTION Venous thromboembolism (VTE) is a condition that encompasses both deep venous thrombosis and pulmonary embolism (PE). PE occurs because of The authors declare that they have no conflicts of interest. Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. Correspondence to: Hongyan Tian, Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta Road, Xi’an 710061, China; E-mail: [email protected] Ann Vasc Surg 2019; -: 1–6 https://doi.org/10.1016/j.avsg.2019.09.031 Ó 2019 Elsevier Inc. All rights reserved. Manuscript received: April 29, 2019; manuscript accepted: September 20, 2019; published online: - - -
blockage of the pulmonary artery (PA) or its branches due to an embolus originating from the venous system or the right side of the heart. Statistics from 6 European countries show that the annual incidence of VTE is 100e200 per 100,000 inhabitants, with 34% of the VTE-related fatalities being attributed to PE and 59% of those deaths resulting from previously undiagnosed PE.1 Chronic thromboembolic pulmonary hypertension (CTEPH) occurs as a consequence of PE. Some patients are known to develop CTEPH despite receiving adequate anticoagulant therapy.2,3 Generally, CTEPH develops in the face of persistent blockage of large or medium-sized PAs by organized thrombi.4 Data from a large, prospective international registry suggest that 75% of patients with
1
2 Meng et al.
CTEPH had a positive history of acute PE (APE).5 CTEPH after symptomatic APE is reported to have an incidence rate of 0.4e6.2%.4 Large pulmonary emboli are associated with a high risk of CTEPH.6,7 Therefore, timely and adequate treatment of APE is important for the prevention of CTEPH. The mainstay of PE treatment is anticoagulant therapy. Although systemic thrombolytic therapy is reported to be useful in lowering the risk of early mortality in patients with APE, it also entails an increased risk (20%) of bleeding, including a 2e5% risk of hemorrhagic stroke.8 Owing to the increased risk of bleeding complications, systemic thrombolytic therapy is not applicable in all cases of APE. An alternative to systemic thrombolysis is catheter-directed thrombolysis (CDT), which has been reported to provide favorable outcomes in PE without increasing the risk of hemorrhage.9 The introduction of pharmacomechanical techniques has further shortened the treatment duration and decreased the requirement of thrombolytic agents.9 In our clinical experience, we have observed marked hemodynamic and clinical improvement in patients with APE treated with pharmacomechanical approaches for the removal of large central thrombi in PAs. In this study, we sought to retrospectively analyze the treatment and outcomes of all patients managed with pharmacomechanical techniques for APE at a single institution.
MATERIALS AND METHODS Study Design We conducted a retrospective investigation of 97 consecutive patients who were treated at our center, between January 2013 and June 2018, with a combination of anticoagulant therapy and pharmacomechanical therapy. The pharmacomechanical approach was adopted because thrombolysis was contraindicated in these patients. In addition, we also investigated a group of 89 consecutive patients who were treated during the same period with only anticoagulant therapy. The study protocol was approved by the institutional review board. Subjects Subjects who met the following criteria were included in the study group: (1) acute signs and symptoms of PE; (2) symptom onset of less than 2 weeks; (3) suitable for treatment with our rapid approach, as per the rapid diagnostic assessment with computed tomography pulmonary
Annals of Vascular Surgery
Fig. 1. Contrast-enhanced computed tomography (axial section) showing a large saddle embolus in the pulmonary artery (green cross).
angiography (CTPA) (Fig. 1) and digital subtraction angiography (DSA); (4) history of right ventricular dysfunction (RVD); and (5) provision of informed consent. RVD was evaluated on the basis of pretreatment and follow-up echocardiography. The echocardiography parameters taken into consideration were right ventricular/left ventricular (RV/LV) end-diastolic diameter ratio and PA pressure. RVD was defined by an RV/LV ratio of more than 1.0 or 0.9 in the apical 4-chamber view of echocardiography or spiral CT. The exclusion criteria were as follows: (1) no evidence of embolism of the main PA on CTPA or DSA; (2) patient asymptomatic or symptom duration of greater than 14 days; (3) an age greater than 14 years or less than 85 years; and (4) a lack of patient consent (Fig. 2). Massive PE was defined as a systolic blood pressure of less than 90 mm Hg or at least 40 mm Hg decrease in systolic pressure for 15 min, in the absence of new-onset arrhythmia, hypovolemia, or sepsis. Submassive PE was classified in cases of RVD or if myocardial ischemia was evident, but the patient was normotensive.1 Pharmacomechanical Techniques Pulmonary intervention at our center was performed in the form of fragmentation, suction thrombectomy, and CDT of the pulmonary embolus, which were used alone or in combination, depending on the patient’s condition and the intraoperative findings. Interventional approaches were made via the femoral vein, jugular vein, subclavian vein, or median cubital vein. A 6F pig catheter was used for the fragmentation of the pulmonary trunk thrombi and for pushing the fragments into the distal portion of the PA to relieve the pressure on the main PAs during an acute episode of thrombosis.
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Fig. 2. Study flow chart.
The thrombus was then aspirated using a 7-8F guiding catheter. The AngioJetÔ thrombectomy system was used for the fragmentation of the thrombus and suction of the fragments into the recovery system. CDT was used for the transportation of thrombolytic agents directly into the PAs with a thrombolytic catheter with side apertures, thereby reducing the administered dose of the thrombolytic drug. The dose of urokinase used for CDT via the PAs was about 0.25 to 0.75 million international units, which was discontinued within 24 hr if the following signs were noted: (1) the patient is hemodynamically stable, (2) oxygen saturation level is normal, and (3) the symptoms have improved. Irrespective of whether the PA thrombus was present in the main arteries of one side or both sides, we sought to remove as much of the PA thrombus as possible. Because fragmentation would remove the thrombus in the main pulmonary trunk in the shortest time, we chose fragmentation first. Suction thrombectomy was used as an adjuvant therapy for further thrombectomy. If CDT treatment was used, the total amount of bilateral urokinase was no more than 0.75 million international units. The
AngioJetÔ thrombectomy system was not preferred because of its high cost and risk of adverse reactions. All patients were postoperatively treated with anticoagulants such as low-molecular-weight heparin or direct oral anticoagulants. Statistical Analysis The data are expressed as a mean plus or minus the standard deviation or as percentages. All statistical analyses were performed using the statistical software package SPSS version 24.0 for Windows.
RESULTS The baseline characteristics and distribution of risk factors of the patients in the 2 groups are comparable, as shown in Tables I and II. We observed that 50 and 47 patients in the study group and 38 and 51 patients in the control group had massive and submassive PE, respectively. CTPA was performed in all 89 patients of the control group and in 94 (97%) patients of the study group; in the case of the remaining 3 patients in the study
4 Meng et al.
Annals of Vascular Surgery
Table I. Baseline characteristics for APE
Baseline characteristics
Demographics Age, mean ± SD, year Men, n (%) Symptoms Dyspnea Chest pain Syncope Hemoptysis Hemodynamically unstable Hypoxemia Stratification of APE Massive PE Submassive PE
Study group
Control group
n ¼ 97 (%)
n ¼ 89 (%)
P Value
56 ± 14 46 (47%)
65 ± 13 44 (49%)
0.791 0.449
68 14 24 1 5
68 22 21 1 1
0.211 0.056 0.496 0.729 0.127
(70%) (14%) (25%) (1%) (5%)
(76%) (25%) (24%) (1%) (1%)
3 (3%)
1 (1%)
50 (52%) 47 (48%)
38 (43%) 51 (57%)
0.344 0.144
Table II. Risk factors for development of pulmonary embolism
Condition
Fracture Surgical operation Trauma Prior VTE Autoimmune disease Hormone replacement therapy COPD Cancer Stroke Hypercoagulability Immobility Diabetes mellitus Hypertension Long journey Pregnancy Varicose vein of lower limb Other chronic diseases None
Study group
Control group
n ¼ 97 (%)
n ¼ 89 (%)
P Value
9 5 3 3 2 5
(9%) (5%) (3%) (3%) (2%) (5%)
5 9 1 1 1 1
(6%) (10%) (1%) (1%) (1%) (1%)
0.254 0.158 0.344 0.344 0.532 0.127
3 1 1 4 1 7 12 1 1 6
(3%) (1%) (1%) (4%) (1%) (7%) (12%) (1%) (1%) (6%)
6 5 4 3 5 3 13 1 1 5
(7%) (6%) (4%) (3%) (6%) (3%) (15%) (1%) (1%) (6%)
0.208 0.087 0.158 0.548 0.087 0.203 0.408 0.729 0.729 0.560
3 (3%) 22 (25%)
0.136 0.502
8 (8%) 25 (26%)
group, the diagnosis was made during interventional therapy. Indications for pharmacomechanical techniques are summarized in Table III. Among the patients of the study group, 69% (67/ 97) had bilateral emboli in the PAs, including the main trunk; 5% (5/97) in only the left PA; and 25 (26%) in only the right PA. On the other hand, in the control group, 51 (57%) of the patients had emboli in both PAs, 11 (12%) had emboli in only the left PA, and 27 (30%) in only the right PA.
The intergroup difference in the distribution of the emboli was not significant (0.122). A total of 39 (40%) of the patients in the study group had iliofemoral vein thrombosis. Inferior vena caval filters were intraoperatively inserted in 79 (81%) patients of the study group because of the risk of recurrent PE. Two (2%) of the patients in the study group and 5 (6%) patients in the control group died within 30 days because of severe RV failure; the difference in the mortality rates in the 2
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Table III. Indications for pharmacomechanical techniques for APE in the study group (n ¼ 97) Indications
N (%)
Contraindications for thrombolysis Recent surgical intervention Recent trauma Recent delivery Recent cardiopulmonary resuscitation Moderate to severe anemia Thrombocytopenia Active ulcer Active bleeding Stroke Cancer Age (>75 years) Coagulation disorders Failed systemic thrombolysis Shock before systemic thrombolysis took effect
68 (70%) 13 (13%) 6 (6%) 1 (1%) 1 (1%)
11 (11%) 5 1 17 2 1 2 8 1
(5%) (1%) (19%) (2%) (1%) (2%) (8%) (1%)
28 (29%)
groups was not significant (0.188). No significant bleeding occurred in any of the patients, with the postprocedural hemoglobin level being less than 2 g/L from the preprocedural level. Placement of the noninvasive ventilator was required in 3 (3%) patients of the study group because these patients were critically ill at admission, had unstable oxygen saturation levels, and were not suitable for systemic thrombolysis. The ventilator was not required in the control group.
DISCUSSION The main findings of this study are that pharmacomechanical therapy provides favorable outcomes in patients with massive and submassive APE for whom thrombolysis is contraindicated, without increasing the risk of mortality or bleeding. Furthermore, the pharmacomechanical approach was found to be particularly safe and reliable in patients with a large central clot burden and RVD, which makes them unsuitable for systemic thrombolysis. At our center, CTPA is used for rapid imaging and direct visualization of emboli within the PAs and subsegmental vessels.10 Pharmacomechanical therapy can easily be incorporated as a therapeutic
modality during DSA. One of the advantages of interventional therapy is the low dosage of thrombolytic agent, which further translates as a reduced risk of bleeding events. A wide range of mortality rates have been reported for patients with APE, but, generally, it appears that approximately 10% die within 3 months of a diagnosis.11,12 The mortality rate in patients with hemodynamically unstable massive PE has been reported to be greater than 15%, whereas that in patients with submassive PE who have stable RVD was 3e15%.13,14 Although the 2 groups in our study did not show any statistically significant difference in the 30-day mortality rate, the rates in both groups were significantly lower than those reported previously. Similarly, the rate of bleeding complications was 0 in our study, whereas different rates have been reported previously.8 There has been a widespread increase in the acceptance of pharmacomechanical therapy as an integral part of the therapeutic strategy for patients with both massive and submassive PE. Massive PE is largely defined by the persistence of systemic hypotension or cardiogenic shock with signs of RVD, whereas submassive PE is defined as the presence of medium-sized to large clots, presence of RVD, and normal arterial blood pressure. RVD in the absence of shock is regarded as a controversial indication for pharmacomechanical therapy12; however, we believe that it is reasonable to use pharmacomechanical approaches because the increase in the PAeRV pressure will eventually lead to failure of the right ventricle. Recent studies have shown that CDT is a viable therapeutic option for patients with acute massive PE when (1) thrombolysis is contraindicated, (2) thrombolysis fails, or (3) the patient goes into life-threatening shock before systemic thrombolysis can take effect (e.g., within hours), subject to the availability of the required resources and expertise.15 Our study was based on actual clinical cases, yet there were no instances of significant procedure-related complications, major bleeding complications, or hemorrhagic strokes. Further validation in randomized controlled trials may help determine the actual risk of these complications.
Limitations Our study does have some limitations, mainly its retrospective design. Further investigations planned as prospective randomized trials of medical versus pharmacomechanical therapy would be optimal.
6 Meng et al.
CONCLUSIONS Our findings indicate that an optimal pharmacomechanical therapy protocol could be successfully used for the rapid debulking of the embolus in cases of massive and submassive APE. This treatment approach showed promise as an alternative treatment method in cases of acute massive or submassive PE in which thrombolysis is contraindicated, with minimal risk of major bleeding and favorable clinical outcomes.
This study was supported by the fund for key research and development program project of Shaanxi province, China (No. 2017SF-254) and the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University, China (No. XJTU1AF-CRF-2018e023). REFERENCES 1. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033e69. 3069a-3069k. 2. Yan C, Wang X, Su H, et al. Recent progress in research on the pathogenesis of pulmonary thromboembolism: an old story with new perspectives. Biomed Res Int 2017;2017: 6516791. 3. Lang IM, Pesavento R, Bonderman D, et al. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J 2013;41:462e8. 4. Simonneau G, Torbicki A, Dorfmuller P, et al. The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017;26:160112. 5. Mcneil K, Dunning J. Chronic thromboembolic pulmonary hypertension (CTEPH). Circulation 2011;124:1973e81.
Annals of Vascular Surgery
6. Lang IM, Dorfm€ uller P, Vonk Noordegraaf A. The pathobiology of chronic thromboembolic pulmonary hypertension. Ann Am Thorac Soc 2016;13(Suppl 3):S215e21. 7. Banks DA, Pretorius GV, Kerr KM, et al. Pulmonary endarterectomy: part I. Pathophysiology, clinical manifestations, and diagnostic evaluation of chronic thromboembolic pulmonary hypertension. Semin Cardiothorac Vasc Anesth 2014;18:319e30. 8. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014;311:2414e21. 9. Akin H, Al-Jubouri M, Assi Z, et al. Catheter-directed thrombolytic intervention is effective for patients with massive and submassive pulmonary embolism. Ann Vasc Surg 2014;28:1589e94. 10. Singanayagam A, Chalmers JD, Scally C, et al. Right ventricular dilation on CT pulmonary angiogram independently predicts mortality in pulmonary embolism. Respir Med 2010;104:1057e62. 11. Aujesky D, Jimenez D, Mor MK, et al. Weekend versus weekday admission and mortality after acute pulmonary embolism. Circulation 2009;119:962e8. 12. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402e11. 13. Fremont B, Pacouret G, Jacobi D, et al. Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in patients with acute pulmonary embolism: results from a monocenter registry of 1,416 patients. Chest 2008;133:358e62. 14. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129:479e86. 15. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141: e419Se96S.
Background: In this study, we sought to analyze the clinical outcomes of pharmacomechanical therapy for massive and submassive acute pulmonary embolism (APE). Methods: We conducted a retrospective investigation of 97 patients who received pharmacomechanical therapy at out center between January 2013 and June 2018 for acute massive and submassive PE because thrombolysis was contraindicated. Results: Of the 97 patients, 46 (47%) were men, and the mean age of the patients was 56 ± 14 years (median, 58 years; range, 21e84 years). Fifty patients had massive PE, whereas the remaining had submassive PE. Analysis of the site of embolus revealed that 67 (69%) had bilateral emboli in the pulmonary arteries (PAs); 5 (5%) only in the left PA, and 25 (26%) only in the right PA. Seventy-nine (81%) of the 97 patients underwent intraoperative placement of the inferior vena caval filters, whereas 3 (3%) required use of a noninvasive ventilator. Two (2%) patients died within 30 days of the interventional therapy because of severe right ventricular failure. The amount of blood loss was nonsignificant. Conclusions: Our results indicate that an optimal pharmacomechanical therapy protocol could yield favorable outcomes for rapid clot debulking in cases of massive and submassive APE where thrombolysis is contraindicated. Pending further randomized trials, pharmacomechanical therapy shows promise as an alternative treatment method in cases of acute massive or submassive PE, with minimal risk of major bleeding.
INTRODUCTION Venous thromboembolism (VTE) is a condition that encompasses both deep venous thrombosis and pulmonary embolism (PE). PE occurs because of The authors declare that they have no conflicts of interest. Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. Correspondence to: Hongyan Tian, Department of Peripheral Vascular Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta Road, Xi’an 710061, China; E-mail: [email protected] Ann Vasc Surg 2019; -: 1–6 https://doi.org/10.1016/j.avsg.2019.09.031 Ó 2019 Elsevier Inc. All rights reserved. Manuscript received: April 29, 2019; manuscript accepted: September 20, 2019; published online: - - -
blockage of the pulmonary artery (PA) or its branches due to an embolus originating from the venous system or the right side of the heart. Statistics from 6 European countries show that the annual incidence of VTE is 100e200 per 100,000 inhabitants, with 34% of the VTE-related fatalities being attributed to PE and 59% of those deaths resulting from previously undiagnosed PE.1 Chronic thromboembolic pulmonary hypertension (CTEPH) occurs as a consequence of PE. Some patients are known to develop CTEPH despite receiving adequate anticoagulant therapy.2,3 Generally, CTEPH develops in the face of persistent blockage of large or medium-sized PAs by organized thrombi.4 Data from a large, prospective international registry suggest that 75% of patients with
1
2 Meng et al.
CTEPH had a positive history of acute PE (APE).5 CTEPH after symptomatic APE is reported to have an incidence rate of 0.4e6.2%.4 Large pulmonary emboli are associated with a high risk of CTEPH.6,7 Therefore, timely and adequate treatment of APE is important for the prevention of CTEPH. The mainstay of PE treatment is anticoagulant therapy. Although systemic thrombolytic therapy is reported to be useful in lowering the risk of early mortality in patients with APE, it also entails an increased risk (20%) of bleeding, including a 2e5% risk of hemorrhagic stroke.8 Owing to the increased risk of bleeding complications, systemic thrombolytic therapy is not applicable in all cases of APE. An alternative to systemic thrombolysis is catheter-directed thrombolysis (CDT), which has been reported to provide favorable outcomes in PE without increasing the risk of hemorrhage.9 The introduction of pharmacomechanical techniques has further shortened the treatment duration and decreased the requirement of thrombolytic agents.9 In our clinical experience, we have observed marked hemodynamic and clinical improvement in patients with APE treated with pharmacomechanical approaches for the removal of large central thrombi in PAs. In this study, we sought to retrospectively analyze the treatment and outcomes of all patients managed with pharmacomechanical techniques for APE at a single institution.
MATERIALS AND METHODS Study Design We conducted a retrospective investigation of 97 consecutive patients who were treated at our center, between January 2013 and June 2018, with a combination of anticoagulant therapy and pharmacomechanical therapy. The pharmacomechanical approach was adopted because thrombolysis was contraindicated in these patients. In addition, we also investigated a group of 89 consecutive patients who were treated during the same period with only anticoagulant therapy. The study protocol was approved by the institutional review board. Subjects Subjects who met the following criteria were included in the study group: (1) acute signs and symptoms of PE; (2) symptom onset of less than 2 weeks; (3) suitable for treatment with our rapid approach, as per the rapid diagnostic assessment with computed tomography pulmonary
Annals of Vascular Surgery
Fig. 1. Contrast-enhanced computed tomography (axial section) showing a large saddle embolus in the pulmonary artery (green cross).
angiography (CTPA) (Fig. 1) and digital subtraction angiography (DSA); (4) history of right ventricular dysfunction (RVD); and (5) provision of informed consent. RVD was evaluated on the basis of pretreatment and follow-up echocardiography. The echocardiography parameters taken into consideration were right ventricular/left ventricular (RV/LV) end-diastolic diameter ratio and PA pressure. RVD was defined by an RV/LV ratio of more than 1.0 or 0.9 in the apical 4-chamber view of echocardiography or spiral CT. The exclusion criteria were as follows: (1) no evidence of embolism of the main PA on CTPA or DSA; (2) patient asymptomatic or symptom duration of greater than 14 days; (3) an age greater than 14 years or less than 85 years; and (4) a lack of patient consent (Fig. 2). Massive PE was defined as a systolic blood pressure of less than 90 mm Hg or at least 40 mm Hg decrease in systolic pressure for 15 min, in the absence of new-onset arrhythmia, hypovolemia, or sepsis. Submassive PE was classified in cases of RVD or if myocardial ischemia was evident, but the patient was normotensive.1 Pharmacomechanical Techniques Pulmonary intervention at our center was performed in the form of fragmentation, suction thrombectomy, and CDT of the pulmonary embolus, which were used alone or in combination, depending on the patient’s condition and the intraoperative findings. Interventional approaches were made via the femoral vein, jugular vein, subclavian vein, or median cubital vein. A 6F pig catheter was used for the fragmentation of the pulmonary trunk thrombi and for pushing the fragments into the distal portion of the PA to relieve the pressure on the main PAs during an acute episode of thrombosis.
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Fig. 2. Study flow chart.
The thrombus was then aspirated using a 7-8F guiding catheter. The AngioJetÔ thrombectomy system was used for the fragmentation of the thrombus and suction of the fragments into the recovery system. CDT was used for the transportation of thrombolytic agents directly into the PAs with a thrombolytic catheter with side apertures, thereby reducing the administered dose of the thrombolytic drug. The dose of urokinase used for CDT via the PAs was about 0.25 to 0.75 million international units, which was discontinued within 24 hr if the following signs were noted: (1) the patient is hemodynamically stable, (2) oxygen saturation level is normal, and (3) the symptoms have improved. Irrespective of whether the PA thrombus was present in the main arteries of one side or both sides, we sought to remove as much of the PA thrombus as possible. Because fragmentation would remove the thrombus in the main pulmonary trunk in the shortest time, we chose fragmentation first. Suction thrombectomy was used as an adjuvant therapy for further thrombectomy. If CDT treatment was used, the total amount of bilateral urokinase was no more than 0.75 million international units. The
AngioJetÔ thrombectomy system was not preferred because of its high cost and risk of adverse reactions. All patients were postoperatively treated with anticoagulants such as low-molecular-weight heparin or direct oral anticoagulants. Statistical Analysis The data are expressed as a mean plus or minus the standard deviation or as percentages. All statistical analyses were performed using the statistical software package SPSS version 24.0 for Windows.
RESULTS The baseline characteristics and distribution of risk factors of the patients in the 2 groups are comparable, as shown in Tables I and II. We observed that 50 and 47 patients in the study group and 38 and 51 patients in the control group had massive and submassive PE, respectively. CTPA was performed in all 89 patients of the control group and in 94 (97%) patients of the study group; in the case of the remaining 3 patients in the study
4 Meng et al.
Annals of Vascular Surgery
Table I. Baseline characteristics for APE
Baseline characteristics
Demographics Age, mean ± SD, year Men, n (%) Symptoms Dyspnea Chest pain Syncope Hemoptysis Hemodynamically unstable Hypoxemia Stratification of APE Massive PE Submassive PE
Study group
Control group
n ¼ 97 (%)
n ¼ 89 (%)
P Value
56 ± 14 46 (47%)
65 ± 13 44 (49%)
0.791 0.449
68 14 24 1 5
68 22 21 1 1
0.211 0.056 0.496 0.729 0.127
(70%) (14%) (25%) (1%) (5%)
(76%) (25%) (24%) (1%) (1%)
3 (3%)
1 (1%)
50 (52%) 47 (48%)
38 (43%) 51 (57%)
0.344 0.144
Table II. Risk factors for development of pulmonary embolism
Condition
Fracture Surgical operation Trauma Prior VTE Autoimmune disease Hormone replacement therapy COPD Cancer Stroke Hypercoagulability Immobility Diabetes mellitus Hypertension Long journey Pregnancy Varicose vein of lower limb Other chronic diseases None
Study group
Control group
n ¼ 97 (%)
n ¼ 89 (%)
P Value
9 5 3 3 2 5
(9%) (5%) (3%) (3%) (2%) (5%)
5 9 1 1 1 1
(6%) (10%) (1%) (1%) (1%) (1%)
0.254 0.158 0.344 0.344 0.532 0.127
3 1 1 4 1 7 12 1 1 6
(3%) (1%) (1%) (4%) (1%) (7%) (12%) (1%) (1%) (6%)
6 5 4 3 5 3 13 1 1 5
(7%) (6%) (4%) (3%) (6%) (3%) (15%) (1%) (1%) (6%)
0.208 0.087 0.158 0.548 0.087 0.203 0.408 0.729 0.729 0.560
3 (3%) 22 (25%)
0.136 0.502
8 (8%) 25 (26%)
group, the diagnosis was made during interventional therapy. Indications for pharmacomechanical techniques are summarized in Table III. Among the patients of the study group, 69% (67/ 97) had bilateral emboli in the PAs, including the main trunk; 5% (5/97) in only the left PA; and 25 (26%) in only the right PA. On the other hand, in the control group, 51 (57%) of the patients had emboli in both PAs, 11 (12%) had emboli in only the left PA, and 27 (30%) in only the right PA.
The intergroup difference in the distribution of the emboli was not significant (0.122). A total of 39 (40%) of the patients in the study group had iliofemoral vein thrombosis. Inferior vena caval filters were intraoperatively inserted in 79 (81%) patients of the study group because of the risk of recurrent PE. Two (2%) of the patients in the study group and 5 (6%) patients in the control group died within 30 days because of severe RV failure; the difference in the mortality rates in the 2
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Table III. Indications for pharmacomechanical techniques for APE in the study group (n ¼ 97) Indications
N (%)
Contraindications for thrombolysis Recent surgical intervention Recent trauma Recent delivery Recent cardiopulmonary resuscitation Moderate to severe anemia Thrombocytopenia Active ulcer Active bleeding Stroke Cancer Age (>75 years) Coagulation disorders Failed systemic thrombolysis Shock before systemic thrombolysis took effect
68 (70%) 13 (13%) 6 (6%) 1 (1%) 1 (1%)
11 (11%) 5 1 17 2 1 2 8 1
(5%) (1%) (19%) (2%) (1%) (2%) (8%) (1%)
28 (29%)
groups was not significant (0.188). No significant bleeding occurred in any of the patients, with the postprocedural hemoglobin level being less than 2 g/L from the preprocedural level. Placement of the noninvasive ventilator was required in 3 (3%) patients of the study group because these patients were critically ill at admission, had unstable oxygen saturation levels, and were not suitable for systemic thrombolysis. The ventilator was not required in the control group.
DISCUSSION The main findings of this study are that pharmacomechanical therapy provides favorable outcomes in patients with massive and submassive APE for whom thrombolysis is contraindicated, without increasing the risk of mortality or bleeding. Furthermore, the pharmacomechanical approach was found to be particularly safe and reliable in patients with a large central clot burden and RVD, which makes them unsuitable for systemic thrombolysis. At our center, CTPA is used for rapid imaging and direct visualization of emboli within the PAs and subsegmental vessels.10 Pharmacomechanical therapy can easily be incorporated as a therapeutic
modality during DSA. One of the advantages of interventional therapy is the low dosage of thrombolytic agent, which further translates as a reduced risk of bleeding events. A wide range of mortality rates have been reported for patients with APE, but, generally, it appears that approximately 10% die within 3 months of a diagnosis.11,12 The mortality rate in patients with hemodynamically unstable massive PE has been reported to be greater than 15%, whereas that in patients with submassive PE who have stable RVD was 3e15%.13,14 Although the 2 groups in our study did not show any statistically significant difference in the 30-day mortality rate, the rates in both groups were significantly lower than those reported previously. Similarly, the rate of bleeding complications was 0 in our study, whereas different rates have been reported previously.8 There has been a widespread increase in the acceptance of pharmacomechanical therapy as an integral part of the therapeutic strategy for patients with both massive and submassive PE. Massive PE is largely defined by the persistence of systemic hypotension or cardiogenic shock with signs of RVD, whereas submassive PE is defined as the presence of medium-sized to large clots, presence of RVD, and normal arterial blood pressure. RVD in the absence of shock is regarded as a controversial indication for pharmacomechanical therapy12; however, we believe that it is reasonable to use pharmacomechanical approaches because the increase in the PAeRV pressure will eventually lead to failure of the right ventricle. Recent studies have shown that CDT is a viable therapeutic option for patients with acute massive PE when (1) thrombolysis is contraindicated, (2) thrombolysis fails, or (3) the patient goes into life-threatening shock before systemic thrombolysis can take effect (e.g., within hours), subject to the availability of the required resources and expertise.15 Our study was based on actual clinical cases, yet there were no instances of significant procedure-related complications, major bleeding complications, or hemorrhagic strokes. Further validation in randomized controlled trials may help determine the actual risk of these complications.
Limitations Our study does have some limitations, mainly its retrospective design. Further investigations planned as prospective randomized trials of medical versus pharmacomechanical therapy would be optimal.
6 Meng et al.
CONCLUSIONS Our findings indicate that an optimal pharmacomechanical therapy protocol could be successfully used for the rapid debulking of the embolus in cases of massive and submassive APE. This treatment approach showed promise as an alternative treatment method in cases of acute massive or submassive PE in which thrombolysis is contraindicated, with minimal risk of major bleeding and favorable clinical outcomes.
This study was supported by the fund for key research and development program project of Shaanxi province, China (No. 2017SF-254) and the Clinical Research Award of the First Affiliated Hospital of Xi’an Jiaotong University, China (No. XJTU1AF-CRF-2018e023). REFERENCES 1. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033e69. 3069a-3069k. 2. Yan C, Wang X, Su H, et al. Recent progress in research on the pathogenesis of pulmonary thromboembolism: an old story with new perspectives. Biomed Res Int 2017;2017: 6516791. 3. Lang IM, Pesavento R, Bonderman D, et al. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J 2013;41:462e8. 4. Simonneau G, Torbicki A, Dorfmuller P, et al. The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017;26:160112. 5. Mcneil K, Dunning J. Chronic thromboembolic pulmonary hypertension (CTEPH). Circulation 2011;124:1973e81.
Annals of Vascular Surgery
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