Abstract
Objectives
Endovascular therapy with ultrasound-assisted catheter-directed thrombolysis (UACDT) theoretically provides higher efficacy while reducing the bleeding risk compared with conventional systemic thrombolysis. The clinical outcomes of UACDT in treating intermediate-to-high-risk pulmonary embolism (PE) are lacking in an Asian population.
Methods
Forty-two patients who presented with intermediate-to-high-risk PE received UACDT. The patients were divided into two groups based on the incidence of procedure-related bleeding events, and baseline demographics were compared between the two groups. A paired-Student’s t test was conducted to evaluate the efficacy of UACDT. Univariate and multivariate logistic regression analyses were conducted to identify independent risk factors for significant bleeding events.
Results
The average age was 58.93 ± 20.48 years, and 33.33% of the study participants were male. A total of 85.7% of the participants had intermediate-risk PE. Compared with pre-intervention pulmonary artery pressure, the mean pulmonary artery pressure decreased significantly (37.61 ± 9.57 mmHg vs. 25.7 ± 9.84 mmHg, p < 0.01) after UACDT. The cumulative total tissue plasminogen activator dosage and total infusion duration were 44.54 ± 20.55 mg and 39.14 ± 19.06 hours respectively. Overall, 21.43% of the participants had severe bleeding events during the endovascular fibrinolysis treatment period. Forward conditional multivariate logistic regression analysis revealed that the lowest fibrinogen level during thrombolysis was an independent factor associated with moderate-to-severe bleeding (odds ratio: 0.40, 95% confidence interval: 0.19-0.88, p = 0.02).
Conclusions
UACDT exhibited high efficacy, but resulted in a higher-than-expected bleeding rate in this real-world study of an Asian population. The lowest fibrinogen level during thrombolysis was an independent risk factor associated with procedure-related bleeding events.
Keywords: Endovascular therapy, Pulmonary embolism, Ultrasound-assisted thrombolysis
INTRODUCTION
Venous thromboembolism is the third most frequent cardiovascular disease and it is associated with significant morbidity and mortality.1 Acute pulmonary embolism (PE) is the most serious form of venous thromboembolism.2 Based on the clinical presentation, patients with acute PE are stratified into three risk groups.3 Patients with normal blood pressure and no evidence of right ventricular (RV) dysfunction are classified as the low-risk group. Patients with low-risk PE have a good prognosis with a 90-day mortality rate < 3%. In this group, systemic anticoagulation therapy is the treatment of choice. Intermediate-risk PE is defined as patients with normal blood pressure and clinical evidence of RV dysfunction, and these patients have a higher risk of early mortality because RV dysfunction is an independent risk factor for adverse events in acute PE.4-7 In this group, systemic thrombolysis therapy (STT) may revert acute RV pressure overload and improve the clinical event-free survival rate,8,9 however the benefit of STT is offset by its potential bleeding risk.9 High-risk PE is defined as patients with both hypotension and clinical evidence of RV dysfunction. This group has a poor prognosis with an early mortality rate > 50%.4,10 In this group, STT is considered to be the standard of therapy to reduce the mortality rate. However, more than half of the patients with high-risk PE have contraindications for STT11 due to the inherent risk of major bleeding in approximately 20% of cases and a 3-5% risk of intracerebral hemorrhage.12
Endovascular therapy has been developed to provide a minimally invasive method to quickly alleviate the hemodynamic burden and RV strain caused by acute PE. Ultrasound-assisted catheter-directed thrombolysis (UACDT) therapy uses low-intensity, high-frequency ultrasound energy to dissociate fibrin strands in combination with the local infusion of thrombolytic drugs delivered via a catheter deep into the thrombus.11 Theoretically, this therapy can increase the efficacy with a lower thrombolytic dosage and reduce the bleeding risk. Its promising results and acceptably low risk of bleeding have been validated in two prospective clinical trials.13,14 However, clinical data on its application in real-world practice are still limited, especially in Asian countries. We retrospectively collected patients who presented with intermediate- or high-risk PE and received UACDT therapy and investigated their clinical outcomes and risk factors for major bleeding.
MATERIAL AND METHODS
Study design
From November 2016 to July 2018, 42 patients who presented to our emergency department with intermediate-to-high-risk PE received UACDT therapy. All of the patients were diagnosed with PE using computed tomography (CT) of the chest with contrast enhancement. Patients with high-risk PE were defined as those with a sustained systolic blood pressure < 90 mmHg or requiring inotropic agents for hemodynamic stability, demonstrable filling defects in at least one main or bilateral lobar pulmonary arteries and a right ventricle (RV)/left ventricle (LV) ratio > 0.9 as observed in the chest CT scan. Patients with intermediate-risk PE were defined as those with a systolic blood pressure > 90 mmHg and electrocardiographic, laboratory, and the chest CT evidence of RV strain. After the diagnosis of intermediate-to-high-risk PE, an immediate intravenous bolus of heparin 5000 units was administered and an emergency cardiovascular specialist consultation was consulted. The patients were instructed on the benefits and risks of systemic intravenous anticoagulation or thrombolysis treatment, endovascular catheter-directed thrombolysis therapy, and surgical embolectomy. The patients who selected endovascular catheter-directed thrombolysis therapy were then sent to the cardiovascular catheterization laboratory for endovascular treatment and admitted to an intensive care unit for further care.
Endovascular therapy
UACDT therapy was performed by an experienced operator. The procedure is summarized as follows. The vascular access for the procedure was obtained through ultrasound-guided puncturing of the common femoral vein or internal jugular vein to avoid bleeding from the puncture wound. Bilateral pulmonary angiography was performed with a 6-Fr pig-tail catheter (Boston Scientific, Inc. Massachusetts, USA) to identify the location of the thrombi. An intraclot injection of tissue plasminogen activator (t-PA) with a dose of 5-10 mg was administered using a 4-Fr Fountain infusion system with an infusion segment of 5 cm (Merit Medical System, Inc. Utah, USA). After the local delivery of t-PA loading doses, the 5.4-Fr infusion catheter of an EkoSonic Endovascular System (EKOS Corporation, Bothell, Washington, USA) was inserted through a 0.35 guidewire into the thrombus located at the main or lower lobe of pulmonary arteries. The number of inserted infusion catheters per patient was determined by the involvement of the thrombi in unilateral or bilateral pulmonary arteries. Follow-up pulmonary angiography was scheduled daily to evaluate the efficacy of thrombus resolution and pulmonary artery pressure (PAP) reduction. The whole procedure was deemed successful and terminated if the clinical symptoms improved, hemodynamic parameters stabilized, the RV/LV ratio decreased as evidenced by echocardiographic imaging, the thrombus burden was reduced, and bilateral pulmonary arteries were well perfused.
Thrombolysis therapy
After successfully placing the EKOS infusion catheter, a continuous infusion of t-PA at 1 mg/h (1 mg/h per catheter if there was only a single catheter; 0.5 mg/h per catheter if there were two catheters placed bilaterally) through the drug port, and saline infusion at 40 mL/h through the coolant port accompanied with intravascular ultrasound delivery were initiated. The plasma fibrinogen level was regularly checked every 3-4 h and the infusion rate of t-PA was adjusted accordingly to maintain the plasma fibrinogen level > 200 mg/dL. Intravenous unfractionated heparin was infused at a starting dose of 500 IU/h through the drug port and adjusted to maintain a targeted activated partial thromboplastin time of 40-60 s.
Echocardiography examination
An echocardiography study was arranged within 72 h after the endovascular therapy. The echocardiographic measurement of the RV/LV ratio as the clinical outcome was defined as follows: first, an end-diastolic image was obtained just before closing of the tricuspid valve from an apical 4-chamber view; second, the RV and LV subannular lines were obtained 1 cm above and parallel to the tricuspid and mitral annular lines. The dimensions of RV and LV subannular lines were determined with endocardial borders; third, the dimension of the RV subannular line indexed to that of the LV subannular line was defined as the RV/LV ratio.1
Clinical outcomes
Data on clinical outcomes were collected mainly by chart reviews. Bleeding events were strictly monitored using serial measurements of the plasma hemoglobin (HB) level every 3-4 h in patients undergoing UACDT therapy during the whole procedure. The clinical significance of bleeding events was determined objectively using the Global Utilization of Streptokinase and TPA For Occluded Arteries definition for bleeding (the GUSTO bleeding criteria).2 Severe or life-threatening bleeding was defined as any intracerebral hemorrhage or clinically overt bleeding resulting in hemodynamic compromise requiring an intervention. Moderate bleeding was defined as clinically overt bleeding requiring a blood transfusion, but not resulting in hemodynamic compromise. Adverse clinical outcomes were defined as any occurrence of < 30-day mortality, > 30-day mortality and procedure-related moderate-to-severe bleeding events. The procedure-related bleeding events was defined as any occurrence of moderate-to-severe bleeding events from the index procedure to 72 h after termination of the UACDT therapy. The follow-up duration was estimated from the date of the index procedure to the date of the occurrence of adverse clinical outcomes or until March, 2019. This study was approved by the Institutional Review Committee at our hospital (CMUH107-REC3-120), and the requirement to obtain any informed consent was waived.
Statistics
Differences in baseline demographics, and laboratory data between the patients with and without procedure-related moderate-to-severe bleeding events were compared using an independent Student’s t test or chi-square test, as appropriate. For non-normally distributed variables, differences were compared using nonparametric analysis, such as the Mann-Whitney U test. To evaluate the efficacy of endovascular therapy, the RV/LV ratio and PAP before and after the intervention were compared using the paired Student’s t test. Univariate and multivariate logistic regression analyses were conducted to investigate independent factors associated with procedure-related moderate-to-severe GUSTO bleeding events. The significance level was set at 0.05, and the tests were two-tailed.
RESULTS
Comparisons of baseline demographics between the patients with and without major bleeding events are demonstrated in Table 1. The average age of the overall study population was 58.93 ± 20.48 years, and 33.33% of the study subjects were men. A total of 85.7% of the patients were categorized as having intermediate-risk PE, and the average pulmonary embolism severity index (PESI) score was 128.79 ± 39.68, indicating that most of the patients had an intermediate-to-high risk. The patients with bleeding were predominantly female (74.07% vs. 26.67%, p < 0.01) and had higher rates of autoimmune diseases (51.9% vs. 20.0%, p = 0.04) and infusion rates of t-PA (1.42 ± 0.84 mg/h vs. 1.03 ± 0.34 mg/h, p = 0.04) than those without bleeding. Comparisons of laboratory test results are presented in Table 2. Overall, the HB level decreased by 3.53 ± 2.54 g/dL. Compared to the patients without bleeding events, those with bleeding events had a significantly lower fibrinogen level at baseline (290.56 ± 65.86 mg/dL vs. 455.24 ± 193.89 mg/dL, p < 0.01) and lower fibrinogen level during the index procedure (194.49 ± 82.50 mg/dL vs. 386.15 ± 203.06 mg/dL, p < 0.01). No significant differences between the patients with and without bleeding were noted in plasma D-dimer, platelets, HB at baseline, and troponin I levels. The clinical efficacy and adverse outcomes of the patients with intermediate-to-high-risk PE undergoing UACDT are summarized in Table 3. Compared with pre-intervention PAP, pulmonary artery systolic pressure (PASP), pulmonary artery diastolic pressure (PADP), and mean PAP decreased significantly (60.77 ± 14.68 mmHg vs. 41.95 ± 14.07 mmHg, p < 0.01; 26.35 ± 8.42 mmHg vs. 17.51 ± 8.44 mmHg, p < 0.01; 37.61 ± 9.57 vs. 25.7 ± 9.84, p < 0.01) after UACDT. Compared with the pre-intervention RV/LV ratio, there was a significant reduction in the RV/LV ratio after UACDT (1.46 ± 0.50 vs. 0.79 ± 0.15; p < 0.01). The overall severe bleeding rate defined according to the GUSTO classification was 21.43% during the endovascular fibrinolysis treatment period. The < 30-day mortality rate from the index procedure was 7.14%. Clinically severe bleeding events during endovascular therapy are summarized in Table 4. Three patients with intracerebral hemorrhage required emergent surgery, one patient with hemopericardium and cardiac tamponade required emergent pericardiocentesis, and one patient with severe gastrointestinal bleeding and hemodynamic compromise required cardiopulmonary resuscitation. Univariate logistic regression analysis was used to identify potential factors associated with moderate-to-severe GUSTO bleeding. Sex [odds ratio (OR): 0.13, 95% confidence interval (CI): 0.03-0.53; p < 0.01], smoking (OR: 0.08, 95% CI: 0.01-0.74; p = 0.03), baseline fibrinogen level (OR: 0.31, 95% CI: 0.13-0.78; p = 0.01), and lowest fibrinogen level during thrombolysis (OR: 0.36, 95% CI: 0.17-0.75; p < 0.01) were associated with moderate-to-severe GUSTO bleeding. Autoimmune disease (OR: 4.31, 95% CI: 0.99-18.8; p = 0.052) showed a trend toward an association with moderate-to-severe GUSTO bleeding (Table 5A). All of these factors were considered in the forward conditional multivariate logistic regression an-alysis, but only sex (OR: 0.18, 95% CI: 0.035-0.964; p = 0.045) and lowest fibrinogen level (OR: 0.40, 95% CI: 0.19-0.88; p = 0.02) during thrombolysis were selected into the model and both were associated with moderate-to-severe GUSTO bleeding (Table 5B). Comparisons of different treatment strategies and clinical outcomes between our study and other clinical trials are presented in Table 6. Compared with other clinical trials and registries, our patients had higher PASP before the intervention and higher total t-PA dosage. However, higher-than-expected severe bleeding (21.43%) was noted in our study.
Table 1. Baseline demographics of patients with pulmonary embolism undergoing ultrasound-assisted catheter directed thrombolysis.
| Overall (n = 42) | Patients with bleeding (n = 27) | Patients without bleeding (n = 15) | p value | |
| Age | 58.93 ± 20.48 | 60.85 ± 21.55 | 55.47 ± 18.60 | 0.42 |
| Sex (male/female) | 18/24 | 44032 | 44139 | < 0.01 |
| BMI (kg/m2) | 25.53 ± 4.42 | 25.84 ± 4.58 | 25.03 ± 4.25 | 0.57 |
| PE classification | 0.29 | |||
| Massive PE | 6 (14.3%) | 5 (18.5%) | 1 (6.7%) | |
| Submassive PE | 36 (85.7%) | 22 (81.5%) | 14 (93.3%) | |
| SBP (mmHg) | 127.74 ± 25.57 | 128.56 ± 26.59 | 124.60 ± 22.87 | 0.63 |
| DBP (mmHg) | 81.07 ± 20.81 | 81.11 ± 22.69 | 80.33 ± 17.09 | 0.91 |
| Pulse pressure (mmHg) | 44.93 ± 12.69 | 44.74 ± 13.86 | 44.27 ± 9.90 | 0.91 |
| Mean BP (mmHg) | 95.55 ± 21.43 | 95.72 ± 22.53 | 94.24 ± 19.15 | 0.83 |
| Heart rate (/min) | 111.67 ± 20.33 | 108.78 ± 21.01 | 115.33 ± 17.92 | 0.31 |
| Respiratory rate (/min) | 25.62 ± 14.63 | 23.00 ± 5.77 | 29.01 ± 24.15 | 0.22 |
| PESI score | 128.79 ± 39.68 | 135.33 ± 37.76 | 121.00 ± 38.94 | 0.25 |
| Immobility | 14 (35.0%) | 10 (37.0%) | 5 (33.3%) | 0.81 |
| Atrial fibrillation | 4 (9.5%) | 3 (11.1%) | 1 (6.7%) | 0.64 |
| Diabetes mellitus | 12 (28.6%) | 8 (29.6%) | 4 (26.7%) | 0.84 |
| Hypertension | 11 (26.2%) | 9 (33.3%) | 2 (13.3%) | 0.16 |
| Hyperlipidemia | 12 (28.6%) | 8 (29.6%) | 4 (26.7%) | 0.84 |
| eGFR (ml/min per 1.73 m2) | 70.38 ± 29.91 | 65.56 ± 28.43 | 79.20 ± 31.68 | 0.16 |
| Cancer | 10 (23.8%) | 5 (18.5%) | 5 (33.3%) | 0.28 |
| CHF | 4 (9.5%) | 3 (11.1%) | 1 (6.7%) | 0.64 |
| IHD | 8 (19.0%) | 7 (25.9%) | 1 (6.7%) | 0.13 |
| Stroke | 5 (11.9%) | 5 (18.5%) | 0 (0.0%) | 0.08 |
| Autoimmune | 17 (40.5%) | 14 (51.9%) | 3 (20.0%) | 0.04 |
| DVT | 28 (66.7%) | 18 (66.7%) | 10 (66.7%) | 1.00 |
| COPD | 4 (9.5%) | 1 (3.7%) | 3 (20.0%) | 0.09 |
| Pregnancy | 3 (7.1%) | 3 (11.1%) | 0 (0.0%) | 0.19 |
| Smoking | 6 (14.3%) | 1 (3.7%) | 5 (33.3%) | < 0.01 |
| Surgery | 9 (21.4%) | 4 (14.8%) | 5 (33.3%) | 0.16 |
| Total-tPA (mg) | 44.54 ± 20.55 | 44.92 ± 21.59 | 43.74 ± 19.28 | 0.86 |
| Total infusion duration (hr) | 39.14 ± 19.06 | 36.52 ± 17.99 | 43.87 ± 20.62 | 0.24 |
| Average Infusion rate (mg/hr) | 1.28 ± 0.72 | 1.42 ± 0.84 | 1.03 ± 0.34 | 0.04 |
BMI, body mass index; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; hr, hours; IHD, ischemic heart disease; PE, pulmonary embolism; PESI, pulmonary embolism severity index; SBP, systolic blood pressure; tPA, tissue plasminogen activator.
Patients with bleeding was defined as any occurrence of procedure-related moderate to severe bleeding.
Table 2. Comparisons of laboratory tests results in patients with pulmonary embolism undergoing ultrasound-assisted catheter directed thrombolysis.
| Overall (n = 42) | Patients with bleeding (n = 27) | Patients without bleeding (n = 15) | p value | |
| WBC (/mm3) | 12492.86 ± 5089.85 | 12774.07 ± 5493.46 | 11986.67 ± 4404.20 | 0.64 |
| Platelet (/mm3) | 181380.95 ± 72572.24 | 181111.11 ± 65718.71 | 181866.67 ± 86038.92 | 0.98 |
| D-dimer (mg/L) | 8020 (5440.5; 10750) | 9855 (6760; 18225) | 7190 (4475.85; 10000) | 0.15 |
| HB at baseline (g/dL) | 13.27 ± 2.18 | 13.12 ± 2.11 | 13.55 ± 2.35 | 0.55 |
| Lowest HB during thrombolysis (g/dL) | 9.70 ± 2.27 | 8.70 ± 2.00 | 11.49 ± 1.50 | < 0.01 |
| Δ HB (g/dL) | 3.53 ± 2.54 | 4.38 ± 2.68 | 2.05 ± 1.38 | < 0.01 |
| Fibrinogen at baseline (mg/dL) | 349.35 ± 148.22 | 290.56 ± 65.86 | 455.24 ± 193.89 | < 0.01 |
| Lowest fibrinogen during thrombolysis (mg/dL) | 262.94 ± 164.42 | 194.49 ± 82.50 | 386.15 ± 203.06 | < 0.01 |
| Troponin I | 0.089 (0.027; 0.235) | 0.095 (0.05; 0.35) | 0.06 (0.01; 0.11) | 0.13 |
HB, hemoglobin; WBC, white blood cell counts; Δ fibrinogen, (Fibrinogen at baseline) minus (Lowest fibrinogen during thrombolysis); Δ HB, (Hemoglobin at baseline) minus (Lowest HB during thrombolysis).
Patients with bleeding was defined as any occurrence of procedure-related moderate to severe bleeding.
Variables that do not fit the normal distribution were expressed as median (upper tertile; lower tertile).
Patients with bleeding was defined as any occurrence of procedure-related moderate to severe bleeding.
Table 3. Clinical efficacy (A) and adverse clinical outcomes (B) in patients with pulmonary embolism undergoing ultrasound-assisted catheter directed thrombolysis.
| (A) | |||
| Before UACDT | After UACDT | p value | |
| PASP (mmHg) | 60.77 ± 14.68 | 41.95 ± 14.07 | < 0.01 |
| PADP (mmHg) | 26.35 ± 8.42 | 17.51 ± 8.44 | < 0.01 |
| mean PA (mmHg) | 37.61 ± 9.57 | 25.7 ± 9.84 | < 0.01 |
| RV/LV ratio | 1.46 ± 0.50 | 0.79 ± 0.15 | < 0.01 |
| (B) | |||
| Overall (n = 42) | |||
| GUSTO bleeding | |||
| Moderate/severe | 18/9 | ||
| < 30-day mortality | 3 (7.14%) | ||
| > 30-day mortality | 3 (7.14%) | ||
| FU duration (m) | 18.69 ± 5.11 |
FU, follow-up; GUSTO, global utilization of streptokinase and tPA for occluded arteries; m, months; PADP, pulmonary arterial diastolic pressure; PASP, pulmonary arterial systolic pressure; UACDT, ultrasound-assisted catheter-directed thrombolysis therapy.
Table 4. Clinical characteristics of patients with pulmonary embolism undergoing ultrasound-assisted catheter-directed thrombolysis who had in-hospital severe bleeding events defined by the GUSTO classification.
| Age | Sex | Pulmonary embolism | Hemoglobin drop (g/dL) | Baseline fibrinogen (mg/dL) | Bleeding site | |
| 1 | 66 | F | Submassive | 3.8 | 297 | ICH |
| 2 | 72 | F | Submassive | 10.7 | 314 | Gastrointestinal bleeding |
| 3 | 78 | M | Submassive | 4.4 | 340 | Inguinal hematoma |
| 4 | 75 | F | Submassive | 2.6 | 321.7 | ICH |
| 5 | 85 | M | Submassive | 5.5 | 217.3 | Aortic aneurysm rupture |
| 6 | 31 | F | Massive | 8.4 | 328.6 | Inguinal bleeding |
| 7 | 17 | M | Submassive | 9.1 | 321 | Arm hematoma |
| 8 | 72 | F | Submassive | 1.3 | 335.8 | ICH |
| 9 | 70 | F | Submassive | 2.6 | 302.4 | Cardiac tamponade |
F, female; GUSTO, global utilization of streptokinase and tPA for occluded arteries; ICH, intracranial hemorrhage; M, male.
Table 5. Univariate and multivariate logistic regression analysis of factors associated with procedure-related moderate-to-severe bleeding events determined by the GUSTO classification.
| (A) | |||
| OR | 95% C.I. | p value | |
| Age (per 10-year increase) | 1.14 | 0.83-1.56 | 0.41 |
| Sex (male vs. female) | 0.13 | 0.03-0.53 | < 0.01 |
| PE type (massive vs. submassive) | 3.18 | 0.34-30.16 | 0.31 |
| BMI (kg/m2) | 1.05 | 0.90-1.23 | 0.53 |
| SBP (mmHg) | 1.004 | 0.98-1.03 | 0.78 |
| DBP (mmHg) | 1.00 | 0.97-1.03 | 0.99 |
| Pulse pressure (mmHg) | 0.997 | 0.95-1.05 | 0.90 |
| mean BP (mmHg) | 1.001 | 0.97-1.03 | 0.95 |
| PASP (mmHg) | 0.98 | 0.94-1.02 | 0.35 |
| PADP (mmHg) | 0.94 | 0.87-1.01 | 0.11 |
| Mean PA (mmHg) | 0.95 | 0.89-1.02 | 0.16 |
| Heart rate (/min) | 0.98 | 0.95-1.01 | 0.21 |
| Respiratory rate (/min) | 0.94 | 0.85-1.05 | 0.29 |
| Immobility | 1.38 | 0.37-5.15 | 0.64 |
| Atrial fibrillation | 1.75 | 0.17-18.48 | 0.64 |
| DM | 1.16 | 0.28-4.75 | 0.84 |
| HTN | 3.25 | 0.60-17.62 | 0.17 |
| Hyperlipidemia | 1.16 | 0.28-4.75 | 0.84 |
| eGFR (min/mL per 1.73 m2) | 0.98 | 0.96-1.01 | 0.17 |
| Cancer | 0.46 | 0.11-1.93 | 0.29 |
| CHF | 1.75 | 0.17-18.48 | 0.64 |
| IHD | 4.90 | 0.54-44.39 | 0.16 |
| Autoimmune | 4.31 | 0.99-18.80 | 0.052 |
| DVT | 0.73 | 0.18-2.94 | 0.66 |
| COPD | 0.15 | 0.01-1.64 | 0.12 |
| Pregnancy | 0.00 | 0.00-0.00 | 1.00 |
| Smoking | 0.08 | 0.01-0.74 | 0.03 |
| Surgery | 0.35 | 0.08-1.57 | 0.17 |
| PESI score | 1.01 | 0.995-1.03 | 0.16 |
| Total t-PA dosage (mg) | 1.003 | 0.97-1.03 | 0.87 |
| t-PA infusion duration (hour) | 0.98 | 0.95-1.01 | 0.24 |
| t-PA infusion rate (mg/hour) | 3.29 | 0.69-15.65 | 0.13 |
| WBC (/mm3) | 1.00 | 1.00-1.00 | 0.63 |
| Platelet (/mm3) | 1.00 | 1.00-1.00 | 0.97 |
| Hemoglobin at baseline (g/dL) | 0.91 | 0.67-1.23 | 0.54 |
| D-dimer (mg/L) | 1.00 | 1.00-1.00 | 0.17 |
| Fibrinogen at baseline (per 100 mg/dL increase) | 0.31 | 0.13-0.78 | 0.01 |
| Lowest fibrinogen level (per 100 mg/dL increase) | 0.36 | 0.17-0.75 | < 0.01 |
| (B) | |||
| Sex (men versus female) | 0.18 | 0.035-0.964 | 0.045 |
| Lowest fibrinogen level (per 100 mg/dL increase) | 0.40 | 0.19-0.88 | 0.02 |
BMI, body mass index; CHF, congestive heart failure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; DM, diabetes mellitus; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; GUSTO, global utilization of streptokinase and tPA for occluded arteries; HTN, hypertension; IHD, ischemic heart disease; OR, odd’s ratio; PADP, pulmonary artery diastolic pressure; PASP, pulmonary artery systolic pressure; PE, pulmonary embolism; PESI, pulmonary embolism severity index; SBP, systolic blood pressure; t-PA, tissue plasminogen activator; WBC, white blood cell counts.
Multivariate logistic regression analysis with forward conditional method was applied to investigate the independent factors for moderate-to-severe GUSTO bleeding.
Table 6. Comparisons of differences of treatment protocols and clinical outcomes between our study and other clinical trials.
| Our study | SEATTLE II | ULTIMA | PERFECT | |
| Case number | N = 42 | N = 150 | N = 59 | N = 101 |
| Study design | Single-center, retrospective, observational study | Multicenter, prospective, clinical trial | Multicenter, prospective, randomized controlled trial | Multicenter, prospective, registry |
| Enrolled criteria | Both intermediate- and high-risk PE | Both massive and submassive PE | Only intermediate-risk PE | Both massive and submassive PE |
| Treatment arm | Only USAT | Only USAT | USAT vs. heparin | USAT vs. CDT |
| t-PA dosage | 44.54 ± 20.55 mg | 24 mg | 10-20 mg | 28 ± 11 mg |
| PASP baseline | 60.36 ± 15.32 mmHg | 51.4 ± 16 mmHg | 52.0 ± 11.5 mmHg | 49.83 ± 11.14 mmHg |
| PASP post-USAT | 42.61 ± 14.89 mmHg | 37.5 ± 11.9 mmHg | 39.7 ± 10.3 mmHg | 36.07 ± 9.62 mmHg |
| Severe bleeding | 21.43% | 1.3% | 0% | 0% |
CDT, catheter-directed thrombolysis; PASP, pulmonary artery systolic pressure; PE, pulmonary embolism; t-PA, tissue plasminogen activator; USAT, ultrasound-assisted catheter-directed thrombolysis.
DISCUSSION
There are several implications to this study: First, UACDT could significantly reduce PAP and RV pressure overload as evidenced by reversal of the RV/LV ratio. Second, the baseline fibrinogen level was an independent factor for procedure-related moderate-to-severe bleeding events as defined according to the GUSTO classification.
Principles and applications of UACDT
An earlier study demonstrated that eddies form proximally to the thrombotic obstruction of the pulmonary artery; hence, most systemically administered thrombolytic drugs are diverted away from the obstructed segment.15 The present study underscores the importance of the local delivery of intraclot thrombolytic drugs. Accordingly, catheter-directed thrombolysis provides better efficacy of thrombus resolution with a lower risk of bleeding than conventional systemic thrombolysis. Application of UACDT using an EKOS system may theoretically further reduce the lysis time and total t-PA dosage required for clinical hemodynamic improvements in patients with PE. The EKOS system is composed of three parts: a 5.2-Fr drug delivery outer catheter, a core wire containing multiple ultrasound transducers distributed over the entire treatment zone, and the EKoSonic control unit.14,16 The ultrasound core can deliver high-frequency (2.2 GHz) and low-energy (0.5 W per transducer) ultrasound waves to disaggregate uncross-linked fibrin fibers and enhance the deep penetration of the thrombolytic drugs into the thrombus through acoustic streaming.17,18 The EKOS endovascular device is currently the only FDA-approved modality for the endovascular treatment of PE. Previous studies have implicated the use of an EKOS system for treating patients with massive and submassive PE, and massive PE patients with failed systemic thrombolysis.11,13,14,19-23 All of these studies have demonstrated promising clinical success and low bleeding rates. Our data provided evidence on the application of UACDT for intermediate-to-high-risk patients with PE in real-world practice in a single center experience in Taiwan.
Identifying independent factors associated with moderate-to-severe bleeding events
Previous randomized clinical trials have suggested low bleeding rates ranging from 6.7% to 10% in patients with submassive or massive PE being treated with an EKOS system.13,14 In the current study, a higher-than-expected bleeding rate was noted. Nevertheless, only one patient had fatal bleeding, and five patients had bleeding into critical organs (one patient had pericardial hemorrhage, three patients had intracranial hemorrhage, one patient had retroperitoneal hemorrhage). Most of the bleeding events could be solved by conservative management such as blood transfusion. This study also demonstrated that the lowest plasma fibrinogen level during thrombolysis was independently associated with moderate-to-severe GUSTO bleeding events. This indicates that close monitoring of the plasma fibrinogen level during fibrinolysis is mandatory, and the judicious administration of t-PA to avoid hypofibrinogenemia may reduce significant bleeding events. Compared with previous clinical trials,13,14 a higher cumulative t-PA dosage was prescribed with a longer infusion duration in the current study. (44.54 ± 20.55 mg for 39.14 ± 19.06 h, vs. 10-24 mg for 12-24 h). The main reason is that in real-world practice we followed up pulmonary angiography on a daily basis, and observed that some patients may have had suboptimal results after a cumulative t-PA infusion dosage of 24 mg according to the recommended dosage in the SEATTLE II trial. Therefore, instead of routinely discontinuing the catheter-directed thrombolysis therapy at a prespecified t-PA infusion dosage, we persisted with the catheter-directed thrombolysis therapy until the patients had stable hemodynamic parameters, improved respiratory distress and successful reversal of RV/LV ratio, or when the patients could not tolerate the procedure due to significant bleeding. Although the higher total t-PA dosage in our study may have increased bleeding tendency, this may not totally explain the higher-than-expected bleeding rate. In previous clinical trials,13,14 patients with relative or absolute contraindications for STT were mainly excluded. However, in our registry, 24 of 42 patients (57.14%) had relative contraindications for STT. These 24 patients included three patients who are pregnant, six who are > 75 years, eight with recent major surgery, one with systolic blood pressure > 180 mmHg, four with old stroke, two with prolonged cardiopulmonary resuscitation > 10 min, and one with an aortic aneurysm. Thus, careful selection of cases without any contraindications for thrombolysis may further reduce the risk of bleeding. In the SEATTLE II trial, multiple venous access attempts were an independent factor for major bleeding.24 This underscores the importance of developing strategies to improve venous access. We advocate the routine use of ultrasound-guided vascular puncture to optimize venous access and to minimize potential hematoma at puncture sites.
Study limitation
This study has several limitations. First, it included a small sample size with inadequate power; therefore, the identification of risk factors for significant in-hospital bleeding events requires further verification with a large-scale registry. Second, we lacked a control group; as a result, we could not provide evidence of the effectiveness and safety of PE patients undergoing treatment with an EKOS system compared to PE patients receiving conservative pharmacological therapy. Third, we did not enroll patients who received catheter-based thrombolysis without ultrasound-assistance for treatment of PE; therefore, we could not determine the contribution of the EKOS system to the effectiveness of endovascular therapy for PE. However, our study provides preliminary insights into the usefulness of endovascular treatment with an EKOS system for intermediate-to-high-risk of PE.
CONCLUSION
Therapy for patients with intermediate-to-high-risk PE using ultrasound-assisted catheter-directed treatment showed promising efficacy but a higher-than-expected bleeding rate in a single center experience in Taiwan. The lowest fibrinogen level during fibrinolysis was an independent risk factor associated with procedure-related moderate-to-severe GUSTO bleeding events. Large-scale studies are required to verify our findings.
Acknowledgments
Not applicable.
CONFLICT OF INTEREST
All authors declare that there is no conflict of interest.
REFERENCES
- 1.Khan F, Rahman A, Carrier M, et al. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ. 2019;366:l4363. doi: 10.1136/bmj.l4363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Konstanides S, Meyer G, Becattini C, et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). The task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Heart J. 2019;00:1–61. [Google Scholar]
- 3.Giri J, Sista AK, Weinberg I, et al. Interventional therapies for acute pulmonary embolism: current status and principles for the development of novel evidence: a scientific statement from the American Heart Association. Circulation. 2019;140:e774–e801. doi: 10.1161/CIR.0000000000000707. [DOI] [PubMed] [Google Scholar]
- 4.Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353:1386–1389. doi: 10.1016/s0140-6736(98)07534-5. [DOI] [PubMed] [Google Scholar]
- 5.Hepburn-Brown M, Darvall J, Hammerschlag G. Acute pulmonary embolism: a concise review of diagnosis and management. Intern Med J. 2019;49:15–27. doi: 10.1111/imj.14145. [DOI] [PubMed] [Google Scholar]
- 6.Barco S, Mahmoudpour SH, Planquette B, et al. Prognostic value of right ventricular dysfunction or elevated cardiac biomarkers in patients with low-risk pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2019;40:902–910. doi: 10.1093/eurheartj/ehy873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Carroll BJ, Heidinger BH, Dabreo DC, et al. Multimodality assessment of right ventricular strain in patients with acute pulmonary embolism. Am J Cardiol. 2018;122:175–181. doi: 10.1016/j.amjcard.2018.03.013. [DOI] [PubMed] [Google Scholar]
- 8.Konstantinides S, Geibel A, Heusel G, et al. Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347:1143–1150. doi: 10.1056/NEJMoa021274. [DOI] [PubMed] [Google Scholar]
- 9.Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402–1411. doi: 10.1056/NEJMoa1302097. [DOI] [PubMed] [Google Scholar]
- 10.Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006;113:577–582. doi: 10.1161/CIRCULATIONAHA.105.592592. [DOI] [PubMed] [Google Scholar]
- 11.Todoran TM, Sobieszczyk P. Catheter-based therapies for massive pulmonary embolism. Prog Cardiovasc Dis. 2010;52:429–437. doi: 10.1016/j.pcad.2010.01.002. [DOI] [PubMed] [Google Scholar]
- 12.Kuo WT. Endovascular therapy for acute pulmonary embolism. J Vasc Interv Radiol. 2012;23:167–179. doi: 10.1016/j.jvir.2011.10.012. [DOI] [PubMed] [Google Scholar]
- 13.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. J Am Coll Cardiol Intv. 2015;8:1382–1392. doi: 10.1016/j.jcin.2015.04.020. [DOI] [PubMed] [Google Scholar]
- 14.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;129:479–486. doi: 10.1161/CIRCULATIONAHA.113.005544. [DOI] [PubMed] [Google Scholar]
- 15.Schmitz-Rode T, Kilbinger M, Günter RW. Stimulated flow pattern in massive pulmonary embolism: significance for selective intrapulmonary thrombolysis. Cardiovascu Intervent Radiol. 1998;21:199–204. doi: 10.1007/s002709900244. [DOI] [PubMed] [Google Scholar]
- 16.Garcia MJ. Endovascular management of acute pulmonary embolism using the ultrasound-enhanced EkoSonic system. Semin Interv Radiol. 2015;32:384–387. doi: 10.1055/s-0035-1564707. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Engelberger RP, Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. Eur Heart J. 2014;35:758–764. doi: 10.1093/eurheartj/ehu029. [DOI] [PubMed] [Google Scholar]
- 18.Jaber WA, Fong PP, Weisz G, et al. Acute pulmonary embolism: with an emphasis on an interventional approach. J Am Coll Cardiol. 2016;67:991–1002. doi: 10.1016/j.jacc.2015.12.024. [DOI] [PubMed] [Google Scholar]
- 19.McCabe JM, Huang PH, Riedl L, et al. Usefulness and safety of ultrasound-assisted catheter-directed thrombolysis for submassive pulmonary emboli. Am J Cardiol. 2015;115:821–824. doi: 10.1016/j.amjcard.2014.12.050. [DOI] [PubMed] [Google Scholar]
- 20.Fuller TJ, Paprzycki CM, Zubair MH, et al. Initial experience with endovascular management of submassive pulmonary embolism: is it safe? Ann Vasc Surg. 2017;38:158–163. doi: 10.1016/j.avsg.2016.09.002. [DOI] [PubMed] [Google Scholar]
- 21.Kuo WT, Gould MK, Louie JD, et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol. 2009;20:1431–1440. doi: 10.1016/j.jvir.2009.08.002. [DOI] [PubMed] [Google Scholar]
- 22.Kennedy RJ, Kennedy HH, Dunfee BL. Thrombus resolution and hemodynamic recovery using ultrasound-accelerated thrombolysis in acute pulmonary embolism. J Vasc Interv Radiol. 2013;24:841–848. doi: 10.1016/j.jvir.2013.02.023. [DOI] [PubMed] [Google Scholar]
- 23.Sag S, Nas OF, Kaderli AA, et al. Catheter-directed ultrasound-accelerated thrombolysis may be life-saving. Thrombolysis. 2016;42:322–328. doi: 10.1007/s11239-016-1370-3. [DOI] [PubMed] [Google Scholar]
- 24.Sadiq I, Goldhaber SZ, Liu PY, Piazza G. Risk factors for major bleeding in the SEATTLE trial. Vasc Med. 2017;22:44–50. doi: 10.1177/1358863X16676355. [DOI] [PMC free article] [PubMed] [Google Scholar]