Catheter-Directed Thrombolysis in Submassive Pulmonary Embolism: Safety and Efficacy

Case Series From a Community Hospital

Abstract

Objective: The majority of trials for catheter-directed thrombolysis (CDT) in submassive pulmonary embolism (sPE) were done in a tertiary care setting. There is a need to assess the applicability of CDT for sPE in a community hospital setting. Methods: A retrospective chart review was performed from May 2017 to March 2019 to extensively evaluate patients with pulmonary embolism and patients who underwent CDT. An active multidisciplinary process between critical care, interventional cardiology, and interventional radiology facilitated this undertaking. Results: Of the 176 patients with PE, 13% (n=22) of patients who had computed tomography (CT) evidence of right ventricle (RV) strain and elevated cardiac biomarkers were assessed for the possibility of CDT. Of these 22 patients, 10 patients had CDT performed once, and one patient underwent CDT twice. The mean age of the CDT group was 53 years. Of patients in the CDT group, 81.8% (n=9) were female, and 54.5% (n=6) were Caucasian. The time between diagnosis of sPE to CDT was 0 to 3 days while risks and benefits were assessed. The most commonly used access site was femoral (n=5). Total duration of alteplase (tPA) ranged from 6 to 24 hours, with the majority of patients receiving 24 hours duration. The mean total dose was 23.5 mg, and the average length of hospital stay was 6 days. Seventy percent (n=7) of patients were discharged home without oxygen. Two patients were readmitted due to non-adherence with anticoagulation and drug interactions. No mortality or major bleeding was observed. Conclusion: Employing CDT in a community-based setting appears to be efficacious and safe.

VASCULAR DISEASE MANAGEMENT 2020;17(3):E40-E45

Key words: catheter-directed thrombolysis, submassive pulmonary embolism

Patients with PE are stratified into high (massive), intermediate (submassive) and low risk, based on based on hemodynamics, cardiac biomarkers, clot burden, and evidence of right heart strain.^1-4 Patients who have echocardiographic evidence of right ventricular (RV) dysfunction or elevated cardiac biomarkers are referred to as having submassive PE,⁵ which accounts for 25% of all PE patients⁶ and has a mortality rate ranging from 3% to 15%.⁷ Up to 18% of patients with PE have persistent RV dysfunction despite treatment,⁸ which translates into increased short-term mortality.^8,9 

The role of systemic thrombolysis for the treatment of sPE is controversial. No benefit with systemic thrombolysis has been observed in patients with PE who were normotensive.¹⁰ However, in the last decade, there has been increasing evidence showing the efficacy of catheter-directed thrombolysis (CDT) in treating  sPE. As compared to systemic thrombolysis, CDT is associated with lower incidence of death and major bleeding (18.13% vs 8.43%).¹¹  Major studies have showed benefit through either decreased RV dilation¹² or reduced pulmonary artery pressures, with ultimate improvement in RV function.^13,12,14  

Many of the studies in this arena were multicenter studies done in a tertiary care hospital, but around 85% of patients receive care at a community hospital in the United States¹⁵ and the literature regarding the applicability of CDT in a community setting is sparse. 

Methods

Study design and study population

This was a retrospective study performed at Mercy Fitzgerald Hospital and Mercy Philadelphia Hospital, which are located in close proximity to each other in Philadelphia, Pennsylvania. Records from May 2017 to March 2019 were reviewed. Patients ≥18 years of age who had confirmed diagnosis of PE on a computed tomography (CT) chest scan at admission were included in the study. Approval was obtained from the Institutional Review Board of Mercy Health System (MHS #2018-40), and a written informed consent was not necessary because of the retrospective nature of the study. 

Statistical analysis 

Data were entered in Microsoft Excel and then converted to an SPSS version for statistical analysis. Continuous variables were expressed as mean and standard deviation (SD), and categorical data were presented as absolute values and percentages.

Results

Baseline characteristics

Of the 176 patients who were admitted with a confirmed diagnosis of PE over a span of 22 months, 13% (n=22) of patients who had CT evidence of RV strain and elevated cardiac biomarkers were assessed for the possibility of CDT. Of these 22 patients, 10 patients had CDT performed once, and one patient had CDT performed twice (n=11). Eleven patients were evaluated but were not deemed eligible for the procedure.

Nine of the procedures were performed by interventional cardiology, and three were performed by interventional radiology. The mean age of the patients who underwent CDT was 53 years, and their mean BMI was 36 kg/m². Patients who did not have CDT had a mean age of 62 years and a mean BMI of 33 kg/m². 

Hypoxia (saturation <88%) during admission was present in 11 of the 22 patients who were assessed for the possibility of CDT. Six of the patients with hypoxia underwent CDT, and all except 2 of those patients required supplemental oxygen during their hospital stay. Among the CDT group, 2 patients had hypotension that responded to fluid administration, 3 had a history of prior PE, 1 had a history of gastrointestinal bleeding, and 5 had concomitant DVT. The patients with DVT had other risk factors such as hypertension (n=4), diabetes mellitus (n=1), cerebrovascular accident (n=1), and active smoking (n=5). Baseline characteristics and vital signs are outlined in Table 1. 

CT- and echocardiogram-based parameters 

All patients who underwent CDT had bilateral PEs with an RV/LV ratio >0.9 (range 0.9-3.1). All but one patient had echocardiographic evidence of right heart strain. Among the 12 echocardiograms, evidence of abnormal septal motion was seen in half of the echocardiograms, and tricuspid regurgitation was observed in 8 of the echocardiograms. All patients in the CDT group had symptoms for ≤7 days. In the group that did not qualify for CDT, 45% (n=5) of patients had RV hypokinesis on echocardiogram. Findings from CT and echocardiography are outlined in Table 2. 

CDT technique

There were procedural differences between interventional cardiology and interventional radiology techniques for CDT. While Interventional radiology used the traditional femoral vein approach for the 3 cases performed by them, interventional cardiology used the internal jugular vein, brachial vein, and basilic vein approaches, in addition to conventional femoral access. All the patients had two catheters placed in every case of bilateral PE. The duration of alteplase (tPA) differed among the cases, as summarized in Table 3, and the mean total duration of tPA was 23.5 mg. In 11 of the 12 cases, heparin was used along with tPA at a reduced dose. Details of CDT and complications of each case are summarized in Table 3, and a fluoroscopic image of the procedure is depicted in Figure 1.

Follow-up

Among the patients who underwent CDT, 7 had follow-up studies that consisted of either repeat right heart catheterization (RHC), echocardiogram, or chest CT that demonstrated reduction in pulmonary artery pressure or resolution of RV strain. One patient had worsening RV failure and was transferred to a tertiary care hospital. Patient follow-up results are summarized in Table 4.

Discussion 

Of the patient population included in the study, 13% were evaluated for the possibility of CDT, yet only half of the patients underwent the procedure. All the patients who underwent CDT had an RV/LV ratio >0.9 and cardiac biomarkers (troponin elevation or pro-brain natriuretic peptide) above reference range. The patient who had CDT without evidence of RV dysfunction on the echocardiogram had significant troponin elevation and incomplete right bundle branch block on electrocardiogram, suggesting that the echocardiogram may have been an underread. 

The CDT group had a younger mean age and was more obese when compared to the group who did not have CDT. None of the patients had coagulopathy and our study population had risk factors for coagulopathy that were identical to the general population. We did not use ultrasound-assisted thrombolysis; all our cases were conventionally performed. 

Our first case was performed in May 2017 and the duration of tPA given was 12 hours. Since there was no consensus about the duration of tPA and the long-term impact on RV dysfunction, the duration varied in all our cases^16,14 and was based on the level of fibrinogen.¹⁷ Four of 12 cases had tPA for 24 hours. As studies revealed the utility of lower doses for less duration,¹⁶ there was a trend in our hospital toward using minimal doses over time. However, these studies were performed with ultrasound-associated thrombolysis. More data are required to expand the applicability of using lower duration of tPA with standard CDT. The minimal duration of tPA used was in patient 5 for 6 hours; a repeat right heart catheterization was performed 4 days later and showed reduction in pulmonary artery pressure from 78/28 mm Hg to 61/18 mm Hg.

The impact of heparin with tPA on patient outcomes requires further research. Prior studies have shown that there is a significant benefit to using systemic tPA with heparin;^18,19 however, use of systemic tPA together with heparin after CDT has not been studied. While systemic tPA uses a very high dose and increases the risk of major bleeding to range from approximately 9.2%²⁰to 19.2%,²¹ the doses of tPA used in CDT are much lower. We used a reduced dose of heparin with tPA in the majority of cases (n=10). This strategy is in line with many other studies.¹⁴ 

The bolus dose used in the majority of cases was 2 mg, which is similar to the dose used in previous studies.²² We had a few patients who received a lower bolus dose or did not receive any bolus (n=3), as there is no consensus regarding any higher benefit with increased doses. More studies are required to standardize practice. 

The overall success rate for CDT is 86.5%, as noted by Kuo and colleagues.²³ However, this was a cumulative success rate from all catheter-based interventions of PE. The pooled risk of minor and major complication rate in that study was 7.9% and 2.4%, respectively, among the 594 patients evaluated.²³ A study by Arora and colleagues reported an 8.43% overall major bleeding risk in CDT patients,¹¹ and a retrospective study showed evidence of major bleeding that required intervention in 8% of patients.²⁴ None of our patients had any major or minor procedural bleeding, though there were 2 patients who had complications. One patient experienced worsening right heart failure that prompted transfer to a tertiary care center, and the other patient had access site thrombosis. The patient with worsening heart failure also had left ventricular failure during presentation, while all other patients had preserved LV function. We would question whether patients with low LV ejection fractions are candidates to undergo CDT safely, though no conclusion can be drawn from a single case. The other complication was thrombosis of the basilic vein access site. In retrospect, this complication may have been prevented by using larger caliber veins as access sites, such as the right internal jugular vein and femoral veins. 

Interestingly, the use of CDT twice in the same patient had beneficial outcomes. Patient 6 had recurrent PE due to non-adherence with novel oral anticoagulant therapy. We employed CDT again, utilizing a different access site, and the patient seemed to benefit. To the best of our knowledge, literature based on the outcomes of re-employing CDT is sparse. 

Eleven patients were denied CDT, as 6 of them did not show any evidence of RV dysfunction on the echocardiogram. Other reasons for denial of CDT were evidence of pulmonary infarction and increased bleeding risk with tPA, low platelet count that prompted transfer for mechanical thrombectomy, and evidence of concomitant infection and avoidance of aggressive treatment based on patient request. These patients were treated with anticoagulation alone. 

Since this study was a retrospective study in a setting of limited resources, we could not obtain follow-up imaging on every patient to demonstrate benefit. With the limited amount of follow-up imaging possible, we were able to demonstrate the use of this technique successfully in a community setting. Seventy percent of patients were discharged home without oxygen, and all patients had decreased oxygen requirements after the procedure. No mortality was observed, and only 2 patients had 30-day readmissions for non-adherence with anticoagulation and drug interaction. 

Conclusion

Our study demonstrates the efficacy and safety of CDT use in a community-based hospital with limited resources. This retrospective study is unique since it was conducted in a community care setting, did not utilize ultrasound-associated thrombolysis, used alternative access sites in addition to femoral access, and showed the safety of repeated CDT in a patient with recurrent PE.  

Disclosure: The authors report no financial relationships or conflicts of interest regarding the content herein.

Manuscript submitted  June 21, 2019; manuscript accepted October 7, 2019.

Address for correspondence: Reshma Golamari, MD, Chief Medical Resident, Mercy Catholic Medical Center, Darby, PA, 1902. Email: reshma.golamari@gmail.com

REFERENCES

1. Martin C, Sobolewski K, Bridgeman P, Boutsikaris D. Systemic thrombolysis for pulmonary embolism: a review. P T. 2016;41(12):770–775.

2. Corrigan D, Prucnal C, Kabrhel C. Pulmonary embolism: the diagnosis, risk-stratification, treatment and disposition of emergency department patients. Clin Exp Emerg Med. 2016;3(3):117–125. 

3. Furfaro D, Stephens RS, Streiff MB, Brower R. Catheter-directed thrombolysis for intermediate-risk pulmonary embolism. Ann Am Thorac Soc. 2018;15(2):134-144. 

4. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension. Circulation. 2011;123(16):1788-1830. 

5. Clark D, McGiffin DC, Dell’Italia LJ, Ahmed MI. Submassive pulmonary embolism: where’s the tipping point? Circulation. 2013;127(24):2458-2464. 

6. Kuo WT, Sista AK, Faintuch S, et al. Society of Interventional Radiology position statement on catheter-directed therapy for acute pulmonary embolism. J Vasc Interv Radiol. 2018;29(3):293-297. 

7. Teleb M, Porres-Aguilar M, Anaya-Ayala JE, Rodriguez-Castro C, Porres-Muñoz M, Mukherjee D. Potential role of systemic thrombolysis in acute submassive intermediate risk pulmonary embolism: review and future perspectives. Ther Adv Cardiovasc Dis. 2016;10(2):103-110. 

8. Sista AK, Miller LE, Kahn SR, Kline JA. Persistent right ventricular dysfunction, functional capacity limitation, exercise intolerance, and quality of life impairment following pulmonary embolism: systematic review with meta-analysis. Vasc Med. 2016;22(1):37-43. 

9. Coutance G, Cauderlier E, Ehtisham J, Hamon M. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care. 2011;15(2):R103. 

10. Riera-Mestre A, Becattini C, Giustozzi M, Agnelli G. Thrombolysis in hemodynamically stable patients with acute pulmonary embolism: a meta-analysis. Thromb Res. 2014;134(6):1265-1271. 

11. Arora S, Panaich SS, Ainani N, et al. Comparison of in-hospital outcomes and readmission rates in acute pulmonary embolism between systemic and catheter-directed thrombolysis (from the National Readmission Database). Am J Cardiol. 2017;120(9):1653-1661. 

12. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479-486. 

13. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): initial results from a prospective multicenter registry. Chest. 2015;148(3):667-673. 

14. Piazza G, Hohlfelder B, Jaff MR, et al. A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015;8(10):1382-1392. 

15. Fast Facts on U.S. Hospitals, 2019. American Hospital Association. https://www.aha.org/statistics/fast-facts-us-hospitals. Accessed February 20, 2020.

16. Tapson VF, Sterling K, Jones N, et al. A randomized trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial. JACC Cardiovasc Interv. 2018;11(14):1401-1410. 

17. Skeik N, Gits CC, Ehrenwald E, Cragg AH. Fibrinogen level as a surrogate for the outcome of thrombolytic therapy using tissue plasminogen activator for acute lower extremity intravascular thrombosis. Vasc Endovascular Surg. 2013;47(7):519-523. 

18. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. 

19. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277. 

20. 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(23):2414-2421. 

21. Fiumara K, Kucher N, Fanikos J, Goldhaber SZ. Predictors of major hemorrhage following fibrinolysis for acute pulmonary embolism. Am J Cardiol. 2006;97(1):127-129. 

22. Engelberger RP, Kucher N. Catheter-based reperfusion treatment of pulmonary embolism. Circulation. 2011;124(19):2139-2144. 

23. Kuo WT, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol. 2009;20(11):1431-1440. 

24. Lee KA, Cha A, Kumar MH, Rezayat C, Sales CM. Catheter-directed, ultrasound-assisted thrombolysis is a safe and effective treatment for pulmonary embolism, even in high-risk patients. J Vasc Surg Venous Lymphat Disord. 2017;5(2):165-170.