Outcomes with hybrid catheter-directed therapy compared with aspiration thrombectomy for patients with intermediate-high risk pulmonary embolism

doi:10.21203/rs.3.rs-3186380/v1

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Research Article

Outcomes with hybrid catheter-directed therapy compared with aspiration thrombectomy for patients with intermediate-high risk pulmonary embolism

https://doi.org/10.21203/rs.3.rs-3186380/v1

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Journal Publication

published 02 Apr, 2024

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Purpose

Intermediate-high-risk pulmonary embolism (IHR PE) is a challenging form of embolism obstruction that causes right ventricular dysfunction. The optimal management of IHR PE has not been established. This single-center prospective, observational study aimed to evaluate the efficacy and safety of hybrid therapy (CDT)- catheter-directed mechanical aspiration thrombectomy (CDMT) in comparison to CDMT supplemented with catheter-directed thrombolysis (hybrid CDT) for IHR PE.

Methods

A propensity score based on Pulmonary Embolism Severity Index class and Miller Obstruction Index (MOI) was calculated, and 21 hybrid CDT cases (mean age 54.8 (14.7) years, 9/21 women) were matched with 21 CDMT cases (mean age 58.8 [14.9] years, 13/21 women). The baseline demographics and clinical and treatment characteristics were analyzed.

Results

No significant differences were detected regarding baseline demographics and PE severity parameters. Hybrid CDT demonstrated a higher reduction in mean pulmonary artery pressure (mPAP) (hybrid CDT: median mPAP reduction 8 mmHg [IQR: 6–10 mmHg] vs CDMT: median mPAP reduction 6 mmHg [IQR: 4–7 mmHg; P = 0.019), MOI score (hybrid CDT: median change − 5 points [IQR:5–6 points] vs CDMT median change − 3 points [IQR:3–5 points]; P = 0.019), and median RV: Left ventricular ratio (hybrid CDT: median change 0.4 [IQR:0.3–0.45] vs CDMT median change 0.26 [IQR:0.2–0.4]); P = 0.007). No major bleeding was observed. Both the hybrid CDT and CDMT alone treatments are safe and effective in managing IHR PE.

Conclusions

Hybrid CDT is a promising technique for the management of IHR PE with insufficient thrombus load reduction by CDMT.

Trial registration number:

NCT0447356 – registration date 16 July 2020

catheter-directed mechanical thrombectomy

catheter-directed thrombolysis

right ventricular dysfunction

pulmonary obstruction

Pulmonary embolism (PE) remains the third leading cause of cardiovascular mortality leading to hundreds of thousands of deaths worldwide every year [1–3]. PE is characterized by a wide spectrum of clinical presentations, which should be considered a disease severity continuum. More than half of PE cases are low-risk without hemodynamic consequences and may be initially treated with oral anticoagulants and early discharge. On the other side of the spectrum is the life-threatening high-risk PE accounting for approximately 5% of cases and causing rapid hemodynamic collapse which requires immediate reperfusion therapy [2]. The last one-third is the most challenging to manage intermediate-high risk (IHR) PE which includes patients with evidence of right ventricular dysfunction in imaging studies and increased concentration of biomarkers of myocardial injury due to obstruction of a significant part of the pulmonary vascular bed but without overt hypotension [3–5].

The optimal management strategy of IHR PE has not yet been well established. In IHR treatment initial systemic thrombolysis (ST) is not recommended because the potential benefits do not outweigh the risk of serious bleeding [4,5]. However, a significant percentage of IHR PE patients may suddenly deteriorate and become hemodynamically unstable. In such a clinical scenario the current European Society of Cardiology (ESC) guidelines recommend ST or catheter-directed therapy (CDT), or surgical embolectomy (SE) as an alternative [5–6]. Over the last few years, the management of IHR PE has changed significantly with the constantly growing interventional approach as part of the integrated treatment guided by PE Response Teams (PERTs), these therapies include catheter-directed mechanical thrombectomy (CDMT), catheter-directed thrombolysis (CDL) or implantation of inferior vena cava filters in certain cases [5,7–10]. Catheter-directed therapies aim to quickly decompress the pulmonary bed and allow blood to flow through local lytic drug delivery or mechanical fragmentation and aspiration of part of the embolic material while minimalizing bleeding risk [11–12]. Early reduction of the pulmonary artery obstruction leads to improved patient hemodynamics and RV function.

Nevertheless, there is a lack of definitive data and consistent recommendations regarding the criteria indicating urgent CDT, the specific modality, or even the dose of drugs delivered locally into the thrombus leading decision at the operator’s discretion. Therefore, we aimed to evaluate the acute efficacy and safety of CDMT and a hybrid strategy with CDMT complimented by CDL for IHR PE in a real-world population.

Study design and population

This prospective, observational study was conducted by institutional PERT (PERT-POZ) in a tertiary cardiology center between January 2019, and October 2022. The details concerning our institutional PERT organization were published elsewhere [7].

The protocol of this prospective observational study was in accordance with the current ESC guidelines and with respect to the principles of the Declaration of Helsinki. The institutional bioethics committee approved the study protocol (approval number 879/19). The study was also registered in the ClinicalTrials.gov.database (NCT04473560). All the patients accepted the treatment and provided informed consent to participate in the study.

All adult patients with acute IHR PE who were qualified for CDT by PERT were eligible for enrolment according to ESC guidelines and symptoms duration shorten than 7 days [7,13]. Briefly, IHR PE was defined by the presence of right ventricular (RV) dysfunction assessed as RV-to-left ventricular diameter ratio (RV: LV ratio) ≥ 0.9 on imaging studies [transthoracic echocardiography (TTE) or computed tomography pulmonary angiography (CTPA)], elevated serum levels of troponin I and pulmonary embolism severity index (PESI) class III-V or simplified PESI (sPESI) score ≥ 1 [6]. Patients were enrolled if they: (1) demonstrated at least one sign of clinically severe PE longer than 24 hours including, heart rate (HR) ≥ 100 bpm, or systolic blood pressure (SBP) 90–100 mmHg, or arterial blood saturation (SaO2) ≤ 90% on room air; (2) had the central location of clots in main or lobar pulmonary arteries on CTPA; (3) were considered to be at increased risk of bleeding complications when treated with full-dose ST. In case of hemodynamic deterioration (sudden occurrence of one or more of the abovementioned signs of severe PE, the patient was also involved. Key exclusion criteria included unstable patients with high-risk PE, patients with absolute contraindications to thrombolysis, patients unable to receive anticoagulation, and those with a life expectancy of less than a month due to comorbidities (as determined by the physician). Details are provided in Supplementary Table 1. Follow-up assessments were performed at 48 hours, 30 days (± 7 days), and 90 days (± 21 days).

Procedure

Catheter-directed mechanical thrombectomy procedures were performed as previously described [14] in the cardiac catheterization suite. Initially, the common femoral vein was accessed with a 7-F vascular sheath and a 7-F Swan-Ganz catheter was used to measure right heart and pulmonary pressures with the Fick method implementation for cardiac output and pulmonary vascular resistance assessment. Then, the main pulmonary arteries (PAs) were catheterized with a 6-F pigtail, and an initial selective angiogram was performed revealing detailed thrombi burden and location. Thrombi load was assessed according to the MOI score as previously described [15–16]. On the angiographic assessment, 1 point was given in the case of partial (> 50%) or complete segmental artery occlusion. Nine segmental arteries were assigned to the right PA (three to the upper lobe, two to the middle lobe, and four to the lower lobe), while only seven segmental arteries to the left PA were assigned (two to the upper lobe, two to the lingula, and three to the lower lobe). If proximal arteries were involved (lobar or main) the awarded score was the sum of distally occluded segmental arteries, up to a maximal score of 16 points. Details are presented in Fig. 1.

Subsequently, a 115cm, 8F CDMT catheter (Indigo CAT8 XTORQ; Penumbra, Alameda, California, USA) was placed in PA close to the clot through a 90cm, 8F Flexor sheath (Cook; Bloomington, Indiana) to perform the procedure. A direct-aspiration first-pass approach was performed to attach a large thrombus to the catheter tip by suction and then pull it out through the sheath. After that, a separator wire was repeatedly passed through the thrombus to break it up and facilitate aspiration. In case of anatomical difficulties, a Judkins Right coronary diagnostic catheter or Multipurpose one catheter was used to simplify access to the lobar or segmental artery. Termination of the intervention was at the operator's discretion after careful evaluation of hemodynamical status (normalization of SBP, HR, or increase of SaO2 ≥ 92%), degree of clot clearance, and the total amount of aspirated blood (should not exceed 300 ml).

At the end of each procedure, PAP pressures and the angiographic residual thrombus burden were assessed. If thrombus clearance was unsatisfactory, defined as a residual Miller obstruction index of at least 12 points (number proved to be related to persistent RV dysfunction) [16] the procedure was extended by CDL with the infusion of alteplase at a dose of 1 mg/h/catheter for 10 hours via a Fountain 4-F or 5-F catheter (Merit Medical, South, Jordan, Utah, USA). Based on the thrombus distribution during control angiography, the operating physician decided whether to perform unilateral or bilateral CDL. All patients were monitored in the cardiac intensive care unit throughout the CDL period and underwent repeat invasive PAP pressure measurement and angiography at 12–24 hours.

Outcomes

The primary efficacy endpoints were the change in PAPs (systolic and mean) after the CDT and clot clearance assessed with the change in the Miller obstruction index score. Secondary efficacy measures were the change in the RV strain assessed in the TTE and/or CTPA assessed 24 hours after the procedure, reduction of symptoms, HR, and oxygen supplementation requirements, and change in SBP.

The primary safety endpoints were death caused by PE (RV failure) during the index hospitalization or follow-up period and all-cause mortality during the index hospitalization or follow-up period. Secondary safety outcomes were major bleeding according to the Bleeding Academic Research Consortium (BARC) [17] classification and any procedure-related major adverse events. Major bleeding was defined as fatal bleeding, causing a hemoglobin drop of at leading to transfusion of at least 2 units of blood products, symptomatic bleeding in a critical area or organ, assessed as BARC type 3a or greater [17].

Statistical analysis

Patients' characteristics are expressed as absolute and percentage frequencies for categorical variables and median with interquartile range (IQR) or mean with standard deviation (SD) for continuous variables. The normality distribution was assessed with the Shapiro-Wilk test. Continuous variables (nonparametric) were compared using the Mann U- Whitney test or Student’s t-test (parametric), and categorical variables were compared using the χ2 or Fisher's exact test, as appropriate. The significance of the change in continuous variables between the initial and final assessments was evaluated using the Wilcoxon signed-rank test for paired nonparametric variables. As there was a concern that patients who received CDMT and hybrid CDT differed in unmeasured confounding factors, propensity score matching was performed using Pulmonary Embolism Severity Index class and Miller Obstruction Index (MOI) score before comparisons between the groups were made. Patients were matched at a ratio of 1:1 from the CDMT and hybrid CDT groups, according to their propensity to receive hybrid CDT. Patients were matched within a 10% probability window. A two-tailed alpha of 0.05 was considered statistically significant. Statistical analysis was performed using MedCalc Software Ltd. version 20.215 (Ostend, Belgium).

Baseline demographics and clinical characteristics

A total of 89 IHR PE patients’ cases treated with CDT were analyzed. After exclusion, 76 patients remained with 21 in the hybrid group and 55 in the CDMT group. Details are presented in Fig. 2.

The mean age of patients who underwent hybrid CDT was 54.8 (14.7) years and 58.8 (14.9) years for those who underwent CDMT. There were no significant differences regarding baseline demographics and clinical parameters pertinent to PE severity between hybrid CDT and CDMT groups. Details are presented in Table 1. The median symptom duration before diagnosis in both groups was 3 days. PE severity on presentation was comparable, with a median PESI score of 115 points noted in the hybrid CDT (IQR:109–125 points) and CDMT (IQR: 108–127 points) groups, respectively. Additional clinical features of RV dysfunction including cardiac biomarkers concentrations and echocardiographic parameters were similar in both groups.

Table 1

Baseline patients’ and pulmonary embolism severity characteristics.
Variables	Hybrid CDT (CDMT + CDL), n = 21	CDMT (matched cases) n = 21	P value
Male sex	12 (57.14)	8 (38.1)	0.35
Age, years^#	54.8 (14.7)	58.8 (14.9)	0.38
BMI, kg/m^2#	29.4 (5.7)	29.2 (4.6)	0.89
Co-morbidities
Arterial hypertension	9 (42.9)	10 (47.6)	0.76
Congestive heart failure	2 (9.5)	-	0.49
Diabetes mellitus	4 (19)	2 (9.5)	0.66
Concomitant deep vein thrombosis	17 (81.0)	16 (76.2)	0.99
Coronary artery disease	2 (9.5)	1 (4.8)	0.99
Chronic obstructive pulmonary disease	2 (9.5)	-	0.49
COVID-19	-	2 (9.5)	0.49
Chronic kidney disease	5 (23.8)	2 (9.5)	0.41
Risk factors for PE
Obesity, BMI ≥ 30 kg/m²	7 (33.3)	8 (38.1)	0.99
Malignancy	5 (23.8)	5 (23.8)	1.0
Surgery within last two weeks	7 (33.3)	6 (28.6)	0.99
Immobilization	2 (9.5)	2 (9.5)	1
Thrombophilia	6 (28.6)	8 (38.1)	0.74
History of PE	4 (19.1)	3 (14.3)	0.99
Oral contraceptive	2 (9.5)	2 (9.5)	1
PE clinical presentation
Syncope Dyspnea at rest Chest pain	- 21 (100) -	2 (9.5) 18 (85.7) 1 (4.8)	0.44
Symptoms duration, days	3 (2–7)	3 (3–4)	0.28
PE severity
PESI score	115 (108–127)	115 (109–125)	0.66
PESI class	4 (4–5)	4 (4–5)	0.34
PESI class I-II III IV V	2 (9.5) 2 (9.5) 8 (38.1) 9 (42.9)	2 (9.5) 4 (19) 11 (52.4) 5 (23.8)	0.34
Heart rate, bpm	115 (107–121)	110 (105–120)	0.41
Respiratory rate, pm	33 (30–34)	30 (30–32)	0.074
Arterial oxyhemoglobin saturation, %	90 (86–95)	92 (89–94)	0.47
Systolic blood pressure, mmHg	106 (104–120)	120 (98–140)	0.44
Diastolic blood pressure, mmHg	74 (70–80)	80 (68–87)	0.77
hs Troponin I level, ng/ml^$	0.43 (0.03–0.79)	0.33 (0.19–0.78)	0.54
NT-proBNP level, pg/ml^	3987 (1734–7261)	2349 (1276–4767)	0.35
Lactate level, mmol/l	2.4 (2.-3.1)	2.1 (1.-2.4)	0.167
RV:LV ratio, mm/mm	1.5 (1.1–1.5)	1.2 (1.2–1.5)	0.5
TAPSE, mm	15 (13–16)	15 (13–16)	0.78
S’ wave, cm/s	13 (9–14)	12 (11–13)	0.54
RVSP, mmHg	58 (45–60)	54 50–60)	0.95
Data are n (%) or median (IQR). ^# – Data presented as mean (SD).
^$ – normal range < 0.005 ng/ml. ^ – normal range < 125 pg/ml.
Abbreviations: See Fig. 2 and Fig. 3. BMI – body mass index; hs – high sensitive; PESI – pulmonary embolism severity index; RVSP – right ventricular systolic pressure; TAPSE – tricuspid annular plane systolic excursion

Procedural characteristics

Procedural characteristics are summarized in Table 2. The total procedure duration time (89.2 ± 17.6 minutes vs 80.3 ± 23 minutes, P = 0.17), the total amount of contrast medium (170 ml [140–200 ml] vs 140 ml [IQR:100–170 ml], P = 0.13), and the median estimated blood loss per procedure (320 ml [260–400 ml] vs 290 ml [IQR:290–330 ml], P = 0.37) were comparable in both groups. The median length of post-procedure hospital stay was also parallel 5 days (IQR: 3–7) in hybrid CDT and 4 days (4–8) in the CDMT group.

Table 2

Comparison of procedural characteristics and clinical outcomes.
Variables	Hybrid CDT (CDMT + CDL) n = 21	CDMT (matched cases) n = 21	P value
Procedure duration time, min^#	89.2 (17.6)	89.2 (17.6	0.17
Radiation dose, mGy,	184 (166–231)	126.5 (64–286)	0.055
Fluoroscopy time, min	27 (18–35)	17 (12.5–26)	0.01
Amount of contrast administrated ml	170 (140–200)	140 (100–170)	0.13
Amount of blood loss, ml	320 (260–400)	290 (290–330)	0.37
Access site Right internal jugular vein Right common femoral vein Left common femoral vein	- 20 1	1 21 -	0.99
Length of hospitalization, days	7 (5–9)	6 (5–10)	0.76
Length of hospitalization after procedure, days	5 (3–7)	4 (4–8)	0.76
PE location Bilateral Saddle and main arteries Lobar and segmental Segmental and subsegmental	21 3 18 -	21 5 16 -	0.7
Initial MOI score, points	14 (13–15)	14 (13–15)	0.87
Final MOI score, points	9 (8–9)	11 (9–11)	0.0035
Change in MOI score, points	5 (5–6)	3 (3–5)	0.007
Initial systolic PAP, mmHg	59 (43–62)	54 (46–62)	0.94
Final systolic PAP, mmHg	39 (38–56)	44 (38–56)	0.007
Change in systolic PAP, mmHg	17 (12–20)	9 (5–10)	0.003
Initial diastolic PAP, mmHg	20 (19–24)	20 (19–25)	0.94
Final diastolic PAP, mmHg	14 (13–18)	14 (12–20)	0.94
Change in diastolic PAP, mmHg^#	6 (5–8)	5 (4–8)	0.75
Initial mean PAP, mmHg	29 (27–33)	34 (29–36)	0.085
Final mean PAP, mmHg	23 (20–25)	27 (22–31)	0.001
Change in mean PAP, mmHg	8 (6–10)	6 (4–7)	0.019
Hemoglobin concentration before procedure, mmol/l	8.2 (7.5–9.6)	7.5 (7.1–9.3)	0.43
Hemoglobin concentration 24 hours after the procedure, mmol/l	7.35 (6.7–8.4)	7.4 (7.0-8.7)	0.84
Arterial pO₂ before procedure, mmHg	60 (47–72)	60 (58–66)	0.98
Arterial pO₂ after the procedure, mmHg	87 (80–94)	69 (65–78)	0.0001
Change in arterial pO₂, mmHg	27.8 (14-34.6)	10.8 (6-19.4)	0.039
Data are n (%) or median (IQR). ^# – Data presented as mean (SD).
Abbreviations: See Fig. 2 and Fig. 3.

Clinical outcomes

The initial catheter-derived, MOI score medians, thrombus location, and systolic, mean, and diastolic pulmonary arterial pressure medians were similar in both the hybrid CDT and the CDMT groups. All patients had bilateral central PE. Hemodynamic and vital outcomes are presented in Table 2. Immediately following the procedure, the mean PAP median change differed significantly between both groups, in the hybrid therapy the mean PAP decreased from 29 mmHg (IQR:27–33 mmHg) to 23 mmHg (IQR: 20–25 mmHg) (–8 mmHg [IQR: 6–10 mmHg] median change), while in CDMT group the mean PAP decreased from 34 mmHg (IQR:29–36 mmHg) to 27 mmHg (IQR: 22–31 mmHg) (–6 mmHg [IQR: 4–7 mmHg] median change), P = 0.019. The median systolic PAP change was also significantly higher in the hybrid CDT group, 17 mmHg (IQR: 12–20 mmHg) in the hybrid CDT vs 9 mmHg (IQR:5–9 mmHg) in the CDMT group (P = 0.003), respectively. The median MOI score also decreased significantly from 14 points (IQR:13–15 points) to 9 points (IQR:8–9 points) (–5 points [IQR:5–6 points] median change) in the hybrid CDT group in comparison to the CDMT group, from 14 points (IQR:13–15 points) to 11 points (IQR:9–11 points) (–3 points [IQR:3–5 points] median change), P = 0.019. The median RVLV ratio improved from 1.5 (IQR: 1.1–1.5) to 0.95 (IQR:0.84–1.05); with the median change of 0.4 (IQR:0.3–0.45) after hybrid CDT, and from 1.5 (IQR: 1.1–1.5) to 1.05 (IQR:0.9–1.2); median change 0.26 [IQR:0.2–0.4]) after CDMT (P = 0.007). The median arterial pO₂ improved from 60 mmHg (IQR:47–72 mmHg) to 87 mmHg (IQR:80–94 mmHg) (+ 27.8 mmHg [IQR: 14-34.6 mmHg] median change) after hybrid CDT and from 60 mmHg (IQR:58–66 mmHg) to 69 mmHg (IQR:65–78 mmHg) (+ 10.8 mmHg [IQR: 6-19.4 mmHg] median change) (P = 0.0039). Key effectiveness outcomes are summarized in Fig. 3.

Safety outcomes

There were no catheter-related complications. No major bleeding related to the hybrid CTD or CDMT procedure was observed. There were two minor bleeding complications in each group. All were access-related groin hematomas that resolved with manual compression. One patient in the CDMT group developed an ischemic stroke with aphasia and left-side paralysis several hours after the procedure. There were no intraprocedural deaths. One death in the hybrid CDT group at the 48-day follow-up was unrelated to the procedure. There were an additional two deaths at 30-day follow-up in both groups, all adjudicated as unrelated to the study procedure. These two deaths were due to pre-existing malignancies - ovarian cancers. The one 90-day all-cause readmission in the hybrid CDT group was related to the reoccurrence of DVT. There were no further complications within the following 90 days of anticoagulation. Safety outcomes are displayed in Table 3.

Table 3

Safety outcomes.
Variables	Hybrid CDT (CDMT + CDL) n = 21	CDMT (matched cases) n = 21
Minor bleeding complication (BARC < 3)	2 (9.5)	2 (9.5)
Major bleeding complication (BARC ≥ 3a)	0 (0)	0 (0)
Cardiac arrest after the initial procedure	0 (0)	0 (0)
Stroke	0 (0)	1 (4.8)
Heparin-induced thrombocytopenia	0 (0)	1 (4.8)
All-cause 30-day mortality	1 (4.8)	1 (4.8)
PE-related 30-day mortality	0 (0)	0 (0)
All-cause 30-day readmission	0 (0)	0 (0)
PE or procedure-related 30-day readmission	0 (0)	0 (0)
All-cause 90-day mortality	0 (0)	0 (0)
PE-related 90-day mortality	0 (0)	0 (0)
All-cause 90-day readmission	1 (4.8)	0 (0)
Data are n (%).
Abbreviations: See Fig. 2. BARC – Bleeding Academic Research Consortium

Main findings

This study demonstrated that both hybrid CDT with CDMT with 8F Indigo catheter complimented by CDL with a total dose of 8–16 mg of alteplase derived with an 8-hour infusion and CDMT monotherapy performed with the same equipment was safe and effective treatment modalities for managing IHR PE. To our knowledge, this is the first study reporting on the acute hemodynamic effects of a hybrid CDT treatment strategy in IHR PE. Our study showed that hybrid CDT resulted in substantial thrombi removal, improvement in clinical status and pulmonary, and right heart hemodynamics as compared to CDMT alone in PE patients at IHR of early death.

Right ventricular strain improvement

The role of catheter-directed therapies in the treatment of acute PE is rapidly evolving. However, the optimal protocol for patients and CDT method selection, particularly for IHR PE, remains a matter of debate. The principal aim of CDMT is to rapidly restore the patency of occluded pulmonary arteries by debulking central occlusive clots [12]. The efficient clot removal reduces the strain and afterload of the RV and increases pulmonary and systemic perfusion.

Increased RV: LV diameter ratio assessed by echocardiography or CTPA is a reproducible and validated tool for identifying patients with acute PE and increase risk of adverse events, particularly early mortality [18–19]. In the present study, the median RV: LV diameter ratio change was significantly higher after hybrid CDT (0.4; IQR: 0.3–0.45) as compared to RV: LV diameter ratio change (0.26; IQR: 0.2–0.4) after standard CDMT. Regardless of the differences between the groups, our results align with the previous studies assessing the efficacy of different percutaneous therapies [20–22]. In the EXTRACT-PE study conducted on 119 patients who underwent CDMT with the Indigo 8F catheter the mean reduction of RV: LV diameter ratio was 0.43 48 hours post-procedure [20]. In the FLASH registry patients treated with large-bore FlowTriever (Inari Medical, Irvine, California, US) CDMT had an average reduction in RV: LV diameter ratio of 0.25 [21]. In the SEATTLE II study, which evaluated ultrasound-assisted catheter-directed thrombolysis USAT EkoSonic System (EKOS, Boston Scientific, Marlborough, US) an average reduction in the RV: LV diameter ratio was 0.42 [22]. The RESCUE study with the Bashir catheter designed for pharmacomechanical local thrombolysis showed a mean RV: LV change of 0.56 and initial results of mechanical-electric thrombectomy with Magneto 20F device demonstrated a mean RV: LV change of 0.45 (23–24). What is more, the results of this study indicated a significant change in surrogate markers of RV dysfunction including tachycardia, troponin, NT-proBNP, and lactate levels 48 hours after CDMT.

Of note, we also observed that surrogate markers of RV dysfunction HR, troponin, and NT-proBNP levels faster decreased after hybrid CDT treatment as compared to standard CDMT.

Hemodynamic and angiographic improvement

Importantly, PAPs have been demonstrated to serve as valuable prognostic markers in acute PE [25]. In this study, the reduction of mean PAP was significantly higher in hybrid CDT (17 mmHg [IQR: 12–20 mmHg]) in comparison to (9 mmHg [IQR:5–9 mmHg]) in the CDMT group. Similarly, the change in mean PAP differed significantly between both groups, in favor of the hybrid CDT therapy (8 mmHg [IQR: 6–10 mmHg] vs 6 mmHg [IQR: 4–7 mmHg]). The change of systolic and mean PAPs in the hybrid group were comparable to those reported previously in the large cohort FLASH registry and SEATTLE II study, but lower than reported in the PERCECT registry [21–22, 26]. Avgerinos et al. also found additional improvement in all assessed hemodynamic parameters after CDMT complemented with CDL [27]. Interestingly, a recent study by Feroze et al. comparing large-bore CDMT with CDL demonstrated no difference in the change of PAPs between those two therapies [28].

We found that supplementing CDMT with CDL was associated with an improvement in angiographic perfusion assessed by MOI. The median MOI score reduction in the hybrid CDT group was 5 points (IQR:5–6 points) as compared to 3 points (IQR:3–5 points) in the standard CDMT group. In contrast to other vascular beds, subtotal thrombectomy within the pulmonary artery tree is not accomplishable in most cases. Unfortunately, we were unable to discuss our results with other studies, due to missing or inconsistent data regarding the change in angiographic obstruction ratio. However, it seems reasonable that thrombus fragmentation with CDMT increases the surface area for thrombolysis, and in combination with CDL delivered directly into the thrombus facilitates its dissolution [29]. The administration of CDL improved the blood flow through pulmonary arteries including distal arteries. It was previously reported that increased blood flow through the distal pulmonary arteries correlated with the reduction in RV volume assessed in CT scans. Locally derived fibrinolysis can reach the distal lung perfusing branches, whereas the CDMT devices alone can remove mainly more proximally located thrombi [27]. Therefore, in case of difficult CDMT catheter placement into PA branches and increased risk of complications, CDL should be considered to improve outcomes by increasing thrombi clearance. The advantage of the hybrid CDT in treating patients with acute PE is its low profile (8F) and its ease of use compared to large-bore CDMT systems (up to 24F), which may be challenging to position and operate, especially in unstable patients with PE.

Safety outcomes

This study demonstrated equivalent outcomes in terms of PE-related and all-cause mortality, bleeding complications, length of stay, and other safety outcomes between both groups. The all-cause 30-day mortality was 4.8% in both groups. None of the death was due to PE, all were related to advanced ovarian cancers. Although the analysis is limited owing to the small number of patients in each group, the results are like those previously reported. The SEATTLE II and PERFECT studies, which evaluated the use of CDT, reported 30-day mortality of 2.7% and 1.0%, respectively [22, 26]. In the EXTRACT-PE trial, the 30-day mortality was 2.5% [20]. Advanced oncological disease is reported to be the most common cause of death in the posthospital period [30–32]. A recent study indicated three times higher mortality during 12 months after PE diagnosis as compared to non-oncological patients [33]. There was one case of ischemic stroke after the CDMT procedure in our cohort. Avgerinos et al. reported one episode of hemorrhagic transformation in a patient with a prior embolic stroke, therefore ischemic stroke should be emphasized as an important contraindication to the administration of any thrombolytic drug even at a low dose [27].

There was no major bleeding in this study. In the other studies with a reduced dose of the locally administered lytic drug (total dose of alteplase ≤ 20 mg) the overall major bleeding rate was also low 4.0% in the OPTALYSE study, 2.5% in the SUNSET sPE study, 2.1% in the CANARY study, and 0.9% in the RESCUE study, respectively [23, 34–36].

One of the concerns of any kind of CDMT is the potential for increased blood loss, especially if not embedded in the thrombus. Both groups had no significant differences regarding the amount of blood loss during the procedure and the change in hemoglobin concentration 24 hours after the intervention. No patients required a blood transfusion due to aspiration. These results are in line with other reports with the use of Penumbra 8F catheter with estimated overall blood loss < 400 ml [20, 30]. Similar results were obtained when comparing large-bore CDMT with CDL [37].

This study focused on the short-term outcomes of a hybrid strategy in IHR PE patients. Although some authors reported the application of a hybrid strategy, none of them indicated the clear criteria and detailed circumstances of its implementation [21, 38]. In the American nationwide analysis of CDT procedures in 3216 patients with high-risk PE, 27% received CDMT, 58% received CDL, and 15% received both procedures, which is a significant part of all procedures [38]. In this study, we used the MOI index at the end of CDMT to guide the decision to apply or not the CDL after CDMT.

Limitations

The current study is burdened by several limitations. One of the study's limitations is its observational character, which may also be considered a strong point and reflects the real-life nature of our cohort. The study included a small number of patients from a single center. Despite the statistical significance observed in variables after the intervention, the small number of studied patients unpowered these results. Another limitation is the lack of a matched control group that did not undergo intervention which would allow an evaluation of mortality outcomes with conservative therapies. Regardless of these limitations, the current study provides an initial glimpse into the outcomes of the comparison of endovascular techniques in PE treatment.

In our cohort, we have achieved significant improvements in right ventricular dysfunction, decreased PAPs, and improved oxygenation in IHR pulmonary embolism patients after the implementation of transcatheter therapy, additional improvements in all assessed clinical and hemodynamic parameters were observed after complementation of CDMT with CDL, with similar safety outcomes between groups. Currently, experts have no consensus about the optimal method for CDT therapy of PE. Future randomized studies with long-term clinical outcomes assessment are necessary to firmly establish an ideal catheter-based therapy protocol.

Conflict of interests: None declared

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Authors’ contributions

All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Sylwia Sławek-Szmyt and Aleksander Araszkiewicz. The first draft of the manuscript was written by Sylwia Sławek-Szmyt and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval

his study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Poznan University of Medical Science (09.2019 No. 879).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent to publish.

The authors affirm that human research participants provided informed consent for publication of the images in Figures 1b and 1c.”

Acknowledgments

None.

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Outcomes with hybrid catheter-directed therapy compared with aspiration thrombectomy for patients with intermediate-high risk pulmonary embolism

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