|Year : 2021 | Volume
| Issue : 3 | Page : 169-173
A simple randomized prospective study comparing catheter-directed thrombolysis versus systemic thrombolysis in patients with massive and submassive pulmonary embolism
Suyash Tated1, Dinesh Joshi2, Anand Shukla1, Pratik Raval1, Karthik Natrajan2, Kewal Kanabar1, Surender Kumar3, Jigneshkumar Patel3
1 Department of Cardiology, U. N. Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Ahmedabad, Gujarat, India
2 Department of Cardiology, U. N. Mehta Institute of Cardiology and Research Centre, B. J. Medical College, Ahmedabad, Gujarat, India
3 DM Resident, Department of Cardiology, U. N. Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Ahmedabad, Gujarat, India
|Date of Submission||04-Oct-2021|
|Date of Decision||06-Oct-2021|
|Date of Acceptance||09-Nov-2021|
|Date of Web Publication||22-Dec-2021|
Dr. Pratik Raval
Department of Cardiology, U. N. Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Asarwa, Ahmedabad - 380 016, Gujarat
Source of Support: None, Conflict of Interest: None
Context: Catheter-directed thrombolysis (CDT) is a novel mode of thrombolysis where thrombolytic agents are directed through catheter to a specific area of interest; hence, low-dose thrombolytic agent will be required to produce satisfactory thrombolysis results. This will subsequently decrease the bleeding complications. With this postulation, a study was conducted to compare the outcome of CDT versus systemic thrombolysis (ST) in patients with massive and submassive pulmonary embolism (PE).
Methods: The present study prospectively included the cases of massive and submassive (high-risk) PE and randomly distributed 25 patients into two groups each: Group A underwent CDT, whereas Group B underwent ST. The outcomes of both the groups were studied including mortality and bleeding complications, and patients were followed up for 6 months. At the end of the study, data were analyzed, and outcomes of both the groups were compared.
Results: Baseline characteristics were similar in both the groups. The success rate was 90.4% in Group A (CDT) and 75% in Group B (ST) among patients with massive PE (P = 0.95). The mortality rate was numerically higher in the ST group (12%) than in the CDT group (8%). Bleeding complications were higher in the ST group (20%) than in the CDT group (8%).
Conclusion: CDT was found to be noninferior to ST with respect to primary outcomes of mortality and success rate of thrombolysis. CDT had lower occurrence of bleeding episodes. CDT can be considered viable alternative to ST in patients with high bleeding risk.
Keywords: Catheter-directed thrombolysis, pulmonary embolism, systemic thrombolysis
|How to cite this article:|
Tated S, Joshi D, Shukla A, Raval P, Natrajan K, Kanabar K, Kumar S, Patel J. A simple randomized prospective study comparing catheter-directed thrombolysis versus systemic thrombolysis in patients with massive and submassive pulmonary embolism. Heart India 2021;9:169-73
|How to cite this URL:|
Tated S, Joshi D, Shukla A, Raval P, Natrajan K, Kanabar K, Kumar S, Patel J. A simple randomized prospective study comparing catheter-directed thrombolysis versus systemic thrombolysis in patients with massive and submassive pulmonary embolism. Heart India [serial online] 2021 [cited 2022 Jan 28];9:169-73. Available from: https://www.heartindia.net/text.asp?2021/9/3/169/333298
| Introduction|| |
Venous thromboembolism (VTE) and pulmonary embolism (PE) are a common cardiovascular emergencies and are associated with high mortality and morbidity. In high-risk PE, systemic thrombolysis (ST) is associated with a significant reduction in mortality and recurrent PE but is associated with high bleeding risk. The use of ST for patients at intermediate risk is not well established. The current guidelines do not recommend the routine use of ST in such patients., The mortality benefit of thrombolytic therapy in hemodynamically unstable patients is associated with an increased risk of major bleeding and intracranial hemorrhage (ICH). To overcome this problem, catheter-directed thrombolysis (CDT) can be used, which delivers the thrombolytic agent directly to the clot, reducing total dose and bleeding complications. Published literature on CDT is limited, and majority of studies are observational in nature. Data from various cohort studies and a registry demonstrated improvement in RV function, pulmonary artery (PA) pressure, and lung perfusion in patients with intermediate- or high-risk PE CDT.,, Intracranial hemorrhage was uncommon in these studies. The main objective of our study is to compare the outcome of CDT versus ST in patients with massive and submassive PE.
| Methods|| |
A total of 50 patients with massive or submassive (high-risk) PE were enrolled between September 2018 and January 2021 and randomly assigned into two groups: 25 underwent CDT and 25 patients underwent ST. Patients with acute massive or submassive PE (high-risk) presenting within 14 days with computed tomography (CT) angiographic evidence of proximal PE defined as a filling defect in at least one main or lobar PA were included in the study. Patients younger than 18 years, those having contraindications to thrombolysis or having tumor thrombus in the pulmonary arteries, were excluded from the study.
Massive or high-risk PE was defined as acute PE with sustained hypotension: systolic blood pressure (BP) <90 mmHg for at least 15 min or requiring inotropic support. Submassive or intermediate high-risk PE was defined as acute PE causing right ventricular dilatation and hypokinesia confirmed on echocardiography and/or chest CT with elevated troponin levels without systemic hypotension.
Successful thrombolysis was considered when hemodynamic stability was achieved (systolic BP >100 mmHg; heart rate <100/min; oxygen saturation >90%; PA pressure (right ventricular systolic pressure [RVSP] on echocardiography) fall by 50%). Failed thrombolysis was considered when the patient did not improve hemodynamically or complicated by major life-threatening bleeding after thrombolysis. Major bleeding was defined as bleeding including Bleeding Academic Research Consortium (BARC) type 3a, 3b, 3c and 5a, 5b, whereas minor bleeding included BARC types 0, 1, and 2.
Patients with massive and submassive PE requiring thrombolytic therapy were randomly divided into two groups. Group A included patients undergoing CDT and Group B included patients undergoing ST. Both the group patients were thoroughly evaluated clinically and underwent all the necessary blood as well as radiological investigations. After ruling out contraindications, patient underwent the respective thrombolysis treatment.
Group A (catheter-directed thrombolysis group)
Patients undergoing CDT were taken to the cath laboratory, and under fluoroscopic guidance, pigtail catheter was placed into the main PA. Thrombolytic agent used was UROKINASE (low-dose UROKINASE with 2.5 lakh dose bolus over 10 min followed by 1 lakh units/h). CDT was continued for the next 24–48 h. Following the parameters of the patient were monitored during this period: heart rate, BP, respiratory rate, PA pressure (RVSP on echocardiography), RV function (tricuspid annulus plane systolic excursion [TAPSE]), and depending on that CDT duration is decided.
Group B (systemic thrombolysis)
Patients were thrombolyzed systemically through peripheral intravenous route. Thrombolytic agent used was tenecteplase (0.5 mg/kg (for 50 kg) plus a 5 mg step-up for every 10 kg increase from 60 to 90 kg bolus over 5 s) and urokinase (4400 IU/kg intravenous infusion as a loading dose over 10 min, followed by 4400 IU/kg/h over 12–24 h), decided on the basis of affordability of the patient, with preference given to fibrin-specific agents (tenecteplase).
Postthrombolysis both the group patients were treated with intravenous unfractionated heparin. Long-term oral anticoagulation agent was decided according to patients' affordability and cost concerns, with preference given to NOACs over Vitamin K antagonist.
Our primary outcome was in-hospital mortality. The secondary outcome was bleeding complication. Two-dimensional echocardiography was performed for RV function and PA pressure at 1 month and 6 months. Repeat CT pulmonary angiography was performed after 6 months. Prothrombin time with INR monitoring was done regularly for patients on warfarin.
The data were collected with predesigned pro forma and entered in Microsoft Excel 2010. The data were analyzed with Epi Info version 7.1. Continuous data were presented with mean and standard deviation, whereas the categorical data were presented with frequency and percentage. The comparison of continuous data and categorical data between two groups was done with the t-test and Chi-square test, respectively. P < 0.05 was considered statistically significant.
| Results|| |
We included a total of 50 patients with massive and submassive pulmonary thromboembolism. The study population was randomly divided into two groups: CDT (Group A) and ST (Group B), with 25 patients in each group. The mean age was 46.92 in Group A and 46.88 in Group B (P = 0.99) [Table 1]. The patients were comparable for age in both the groups. In Group A, 72% were male and 28% were female. In Group B, the majority of patients (88%) were male and 12% were female. In Group A, 84% patients had massive and 16% patients had submassive PE, whereas in Group B, 80% patients had massive and 20% patients had submassive pulmonary thromboembolism. Most common chief complaints were shortness of breath, cough, and syncope in both the groups. In Group A, the most common risk factor was deep-vein thrombosis (DVT) (64%) followed by prior history of immobilization (44%) and fracture (20%). In Group B, the most common risk factor was DVT (68%) followed by diabetes mellitus (24%), history of immobilization (20%), and malignancy (12%). The difference was statistically insignificant (P = 0.1932). Sinus tachycardia was the most common electrocardiogram (ECG) finding followed by diffuse ST-T-wave changes and S1Q3T3 pattern in both the groups. The mean Wells score, revised Geneva score, and PE severity index score were similar.
In both the groups, the echocardiographic RVSP fell significantly after treatment (P = 0.0001) is shown in [Table 2]. TAPSE improved significantly in Group A as compared to Group B. Echocardiographic PA dilatation did not show significant difference between pre- and posttreatment values in both the group. However, at 6-month follow-up, the diameter of MPA, RPA, and LPA was significantly reduced in both the groups. Pretreatment value of RV/LV was >1 among all patients in both the groups. RV/LV ratio reversed (RV/LV <1) in 92% patients in Group A and 88% patients in Group B after thrombolytic therapy.
|Table 2: Echocardiographic and computed tomography pulmonary angiographic findings|
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The treatment success was 90.4% in Group A and 75% in Group B among patients with massive PE (P = 0.95). Patients with submassive PE in both the groups had 100% success rate. The overall success rate was 92% in Group A and 88% in Group B, but the difference was statistically insignificant (P = 0.64), as shown in [Table 3].
Primary outcomes (mortality) were numerically lower in CDT group (8%) compared to ST group (12%), (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.097–4.18, P = 0.64). The secondary outcome (bleeding complication) was also lower in CDT group (8%) compared to ST group (20%), (OR 0.38, 95% CI 0.06–2.18, P = 0.28), as shown in [Table 4]. In Group A, no major bleeding was seen, but minor bleeding was present in 8% of patients. In Group B, major bleeding was present in 8% of patients and minor bleeding was present in 12% of patients. However, the difference was statistically insignificant.
|Table 4: Study outcomes in catheter-directed thrombolytic versus systemic groups|
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| Discussion|| |
ST has been established as the standard of care for patients with high-risk PE, but the role of CDT for high-risk patients and ST for intermediate high-risk patients is not yet clear. In clinical practice, the use of ST has not been consistent and is often underused, due to the risk of serious bleeding events, including ICH. CDT is a viable alternative based on the assumption that it is as effective as ST, by decreasing the risk of serious bleeding complications. However, only a few studies have been performed comparing these two treatment modalities face to face.
The prospective multicenter PERFECT registry demonstrated clinical success rates for CDT of 85% for massive PE and 97% for submassive PE with no procedural complications, no major bleeding events, and no hemorrhagic stroke. Kuo et al. reported 86.5% clinical success for massive PE. The present study also demonstrated that thrombolytic therapy is very effective in improving hemodynamic and echocardiographic parameters not only in patients with massive PE but also in those with submassive high-risk PE. Furthermore, the CT pulmonary angiographic parameters showed a significant difference between the pre- and postthrombolysis values in the two groups. Our results for submassive PE are in accordance with two contemporary studies showing a high success rate with CDT for submassive PE with a low likelihood of serious bleeding complications.,
In the present study, the mortality rate was numerically higher in the ST group (12%) than in the CDT group (8%). Similar results were observed in Liang et al., where the mortality rate was significantly higher for the ST group (17%) than for the CDT group (9%). In-hospital mortality was found to be significantly lower in the CDT group as compared to ST group in various similar studies conducted by Patel et al. (CDT: 13.36%, ST: 21.81%), Arora et al. (CDT: 6.12%, ST: 14.94%), and Mishra et al.,,
In our study, bleeding complications were higher in the ST group (20%) than in the CDT group (8%). Similar results were seen in the study conducted by Arora et al. in which bleeding complications were lower in patients who received CDT (8.20%) compared to those who received systemic thrombolytic (18.13%). Mishra et al. also noted that bleeding complications were lower in the cohort with CDT (8.40%) than in ST (18.31%). However, various studies including Yoo et al. (ST: 16.7% and CDT: 16.7%), Liang et al. (ST: 7.8% and CDT: 8.5%), and Patel et al. (CDT: 10.51%, ST: 10.23%) have reported no apparent difference between ST and CDT in terms of major bleeding complications. There was only one serious bleeding event in SEATTLE II study and the ULTIMA study reported no major bleeding events with CDT., The present study reported no major bleeding in CDT group.
The catheter-directed therapy for acute PE is rapidly evolving treatment modality, and recent guidelines have highlighted CDT as a viable treatment option for acute massive PE in patients who are at high bleeding risk. However, there are not enough large prospective studies and the ideal CDT protocol, especially for submassive PE, is still unclear. Therefore, it is imperative that future research be directed toward standardizing thrombolytic regimens and the ideal mode of administration (peripheral intravenous versus direct in pulmonary arteries) to maximize clinical benefit and reduce the risk of bleeding.
The present study has several limitations. The sample size in both the groups was small hence leading to selection bias. In view of cost concerns, the choice of thrombolytic agent was not equally distributed between the two groups. The use of oral anticoagulation was also based on patient preference, affordability, and availability, with preference given to NOACs over Vitamin K antagonists. However, still the distribution of patients taking NOACs or Vitamin K was unequal, hence leading to some bias in the clinical outcomes observed on follow-up.
| Conclusion|| |
CDT was found to be comparable to ST with respect to the primary outcomes of mortality as well as clinical success of thrombolysis with lower occurrence of major as well as minor bleeding complications. In future, further randomized studies with larger sample size and longer follow-up might provide definitive answers regarding comparative effectiveness of these two strategies.
The study involves human participants; the study has been approved by the appropriate Institutional Ethics Committee (UNMICRC/CARDIO/2018/12) and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki. This article does not contain study performed on animals by any of the authors.
Dr. Suyash Tated - Design, Aquisition, Dr. Dinesh Joshi- Analysis, Interpretation, Drafting Dr. Anand Shukla - Aquisition, Analysis, Drafting Dr. Pratik Raval - Conceptualization, Design, Interpretation Dr. Karthik - Aquisition, Analysis Dr. Kewal - Aquisition, Analysis Dr. Surender - Analysis, Dr.Jigneshkumar- Drafting.
Financial support and sponsorship
This work was financially supported by U. N. Mehta Institute of Cardiology and Research Center itself and received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]