Cardiol Res

Cardiology Research, ISSN 1923-2829 print, 1923-2837 online, Open Access

Article copyright, the authors; Journal compilation copyright, Cardiol Res and Elmer Press Inc

Journal website https://www.cardiologyres.org

Review

Volume 14, Number 3, June 2023, pages 161-166

Ultrasound-Accelerated Catheter-Directed Thrombolysis

**Table 1.** Summary of Each Trial
Study	Study design	Sample size	Purpose	Findings	Conclusion
AC: anticoagulation; CI: confidence interval; CTA: computed tomography angiography; DVT: deep venous thrombosis; LV: left ventricular; OR: odds ratio; PE: pulmonary embolism; PTS: post-thrombotic syndrome; PTV: percutaneous transluminal venoplasty; QOL: quality of life; RV: right ventricular; ST: standard thrombolysis; tPA: tissue plasminogen activator; USAT: ultrasound-accelerated thrombolysis; USCDT: ultrasound-facilitated catheter-directed thrombolysis.
CAVA	Multi-center, single-blind, randomized, superiority, parallel-group study	184 individuals. 91 participants were randomized to receive additional ultrasound-accelerated catheter-directed treatment, whilst 93 patients received only the normal course of therapy.	To assess the effects of USCDT on the development of PTS following acute iliofemoral DVT in comparison to standard post-thrombotic therapy	19 of the 62 patients in the intervention group (30.6%) and 26 of the 44 patients in the control group (44.8%) developed PTS at the median follow-up of 39 months (OR, 0.54; 95% CI, 0.26 to 1.15 (P = 0.11)).	With no statistically significant difference groups at the 12-month follow-up, the number of patients forgoing compression therapy increased.
ACCESS PTS	Open-label, single-arm, prospective study that involved multiple centers	113 participants were eligible, 81 patients gave their assent to the trial. 75 participants underwent evaluation at a 30-day follow-up visit after 78 patients successfully completed the study intervention.	To evaluate the efficacy of combined PTV and USAT in the management of symptoms and QOL in PTS patients with chronic veno-occlusive disease	At 1 year, the Villalta score had decreased by ≥ 4 in 77.3% of the limbs. The average Villalta score at the outset was 15.5 (± 5.2). At 30, 90, 180, and 365 days after surgery, the Villalta scores changed by -5.9 (± 5.8), -6.9 (± 6.5), -7.8 (± 6.1), and -8.2 (± 6.4), respectively (P = 0.0001).	The use of PTV and USAT in combination to treat chronic venous obstruction following DVT led to clinical improvements over a year as well as a quantitative and long-lasting improvement in venous patency.
ULTIMA	Randomized, open-label	363 individuals, 304 patients were excluded because of screening failure, or 84% of the total. The 59 patients who were still alive got heparin alone in 29 cases and USAT with heparin in 30 cases, with primary evaluable outcomes of 25 and 28, respectively.	To examine whether AC alone is more effective than USAT in reversing RV dilatation in intermediate-risk PE patients	The mean RV/LV ratio in the USAT group decreased from 1.28 ± 0.19 at baseline to 0.99 ± 0.17 at 24 h (P = 0.001). The average RV/LV ratio in the heparin group was 1.20 ± 0.14 at baseline and 1.17 ± 0.20 at 24 h (P = 0.31).	In PE patients at intermediate risk of death, a standardized USAT regimen was more effective than AC with heparin alone in reversing RV dilatation after 24 h, and this was achieved without an increase in bleeding issues.
DUET	Multi-center, randomized, and controlled study	60 patients with acute limb ischemia due to recently (7 - 49 days) thrombosed infrainguinal bypass grafts or native arteries were randomly assigned to receive either ST (n = 32) or USAT with the endowave system (n = 28).	The time required to achieve continuous flow by thrombolysis was the primary outcome (> 95% thrombus destruction) with at least one below-the-knee artery achieving outflow.	It took substantially less urokinase (2.8 ± 1.6 × 10⁶ IU in the ST group vs. 1.8 ± 1.0 × 10⁶ IU in the USAT group, P = 0.01) and thrombolysis was completed much quicker (17.7 ± 2.0 h) in the USAT group than in the ST group (29.5 ± 3.2 h, P = 0.009) to achieve a continuous flow.	In comparison to ST, USAT significantly shortened the time required for thrombolysis in patients with freshly thrombosed infrainguinal native arteries or bypass grafts.
SEATLE II	Multi-center, single-arm, and prospective trial	150 individuals with acute massive (n = 31) or sub-massive (n = 119) PE.	The primary effectiveness outcome was the core laboratory-measured change in the RV/LV diameter ratio from baseline, as assessed by contrast-enhanced chest CT imaging at baseline and at 48 ± 6 h after the start of the treatment.	From baseline to 48 h post-surgery, mean pulmonary artery systolic pressure (51.4 mm Hg vs. 36.9 mm Hg; P < 0.00001), mean RV/LV diameter ratio (1.55 vs. 1.13; mean difference, - 0.42; P < 0.00001), and modified Miller index score (22.5 vs. 15.8; P < 0.00001) were all seen to decrease.	In patients suffering from acute massive and sub-massive PE, ultrasound-facilitated, low-dose fibrinolysis that was catheter-directed lowered pulmonary hypertension, RV dilatation, anatomic thrombus load, and minimized intracranial hemorrhage.
OPTALYSE	Randomized, multi-center, parallel-group trial	101 were enrolled who had a proximal PE in one main or proximal lobar pulmonary artery, intermediate-risk acute PE (less than 14 days in duration), normal systolic blood pressure (> 90), RV to LV diameter ratio greater than or equal to 0.9 on chest CTA, and were symptomatic.	To determine the lowest ideal tPA delivery and dose duration using USCDT.	All of the groups showed improvement in the refined modified Miller score: arm 1 through arm 4: 0.40 (24%; P = 0.0001), 0.35 (22.6%; P = 0.0001), 0.42 (26.3%; P = 0.0001), and 0.48 (25.5%; P = 0.0001), respectively.	In comparison to baseline, treatment with USCDT utilizing a shorter delivery period and lower-dose tPA was linked to enhanced RV function and decreased clot load.

Table 1. Summary of Each Trial

Study

Study design

Sample size

Purpose

Findings

Conclusion

AC: anticoagulation; CI: confidence interval; CTA: computed tomography angiography; DVT: deep venous thrombosis; LV: left ventricular; OR: odds ratio; PE: pulmonary embolism; PTS: post-thrombotic syndrome; PTV: percutaneous transluminal venoplasty; QOL: quality of life; RV: right ventricular; ST: standard thrombolysis; tPA: tissue plasminogen activator; USAT: ultrasound-accelerated thrombolysis; USCDT: ultrasound-facilitated catheter-directed thrombolysis.

CAVA

Multi-center, single-blind, randomized, superiority, parallel-group study

184 individuals. 91 participants were randomized to receive additional ultrasound-accelerated catheter-directed treatment, whilst 93 patients received only the normal course of therapy.

To assess the effects of USCDT on the development of PTS following acute iliofemoral DVT in comparison to standard post-thrombotic therapy

19 of the 62 patients in the intervention group (30.6%) and 26 of the 44 patients in the control group (44.8%) developed PTS at the median follow-up of 39 months (OR, 0.54; 95% CI, 0.26 to 1.15 (P = 0.11)).

With no statistically significant difference groups at the 12-month follow-up, the number of patients forgoing compression therapy increased.

ACCESS PTS

Open-label, single-arm, prospective study that involved multiple centers

113 participants were eligible, 81 patients gave their assent to the trial. 75 participants underwent evaluation at a 30-day follow-up visit after 78 patients successfully completed the study intervention.

To evaluate the efficacy of combined PTV and USAT in the management of symptoms and QOL in PTS patients with chronic veno-occlusive disease

At 1 year, the Villalta score had decreased by ≥ 4 in 77.3% of the limbs. The average Villalta score at the outset was 15.5 (± 5.2). At 30, 90, 180, and 365 days after surgery, the Villalta scores changed by -5.9 (± 5.8), -6.9 (± 6.5), -7.8 (± 6.1), and -8.2 (± 6.4), respectively (P = 0.0001).

The use of PTV and USAT in combination to treat chronic venous obstruction following DVT led to clinical improvements over a year as well as a quantitative and long-lasting improvement in venous patency.

ULTIMA

Randomized, open-label

363 individuals, 304 patients were excluded because of screening failure, or 84% of the total. The 59 patients who were still alive got heparin alone in 29 cases and USAT with heparin in 30 cases, with primary evaluable outcomes of 25 and 28, respectively.

To examine whether AC alone is more effective than USAT in reversing RV dilatation in intermediate-risk PE patients

The mean RV/LV ratio in the USAT group decreased from 1.28 ± 0.19 at baseline to 0.99 ± 0.17 at 24 h (P = 0.001). The average RV/LV ratio in the heparin group was 1.20 ± 0.14 at baseline and 1.17 ± 0.20 at 24 h (P = 0.31).

In PE patients at intermediate risk of death, a standardized USAT regimen was more effective than AC with heparin alone in reversing RV dilatation after 24 h, and this was achieved without an increase in bleeding issues.

DUET

Multi-center, randomized, and controlled study

60 patients with acute limb ischemia due to recently (7 - 49 days) thrombosed infrainguinal bypass grafts or native arteries were randomly assigned to receive either ST (n = 32) or USAT with the endowave system (n = 28).

The time required to achieve continuous flow by thrombolysis was the primary outcome (> 95% thrombus destruction) with at least one below-the-knee artery achieving outflow.

It took substantially less urokinase (2.8 ± 1.6 × 10⁶ IU in the ST group vs. 1.8 ± 1.0 × 10⁶ IU in the USAT group, P = 0.01) and thrombolysis was completed much quicker (17.7 ± 2.0 h) in the USAT group than in the ST group (29.5 ± 3.2 h, P = 0.009) to achieve a continuous flow.

In comparison to ST, USAT significantly shortened the time required for thrombolysis in patients with freshly thrombosed infrainguinal native arteries or bypass grafts.

SEATLE II

Multi-center, single-arm, and prospective trial

150 individuals with acute massive (n = 31) or sub-massive (n = 119) PE.

The primary effectiveness outcome was the core laboratory-measured change in the RV/LV diameter ratio from baseline, as assessed by contrast-enhanced chest CT imaging at baseline and at 48 ± 6 h after the start of the treatment.

From baseline to 48 h post-surgery, mean pulmonary artery systolic pressure (51.4 mm Hg vs. 36.9 mm Hg; P < 0.00001), mean RV/LV diameter ratio (1.55 vs. 1.13; mean difference, - 0.42; P < 0.00001), and modified Miller index score (22.5 vs. 15.8; P < 0.00001) were all seen to decrease.

In patients suffering from acute massive and sub-massive PE, ultrasound-facilitated, low-dose fibrinolysis that was catheter-directed lowered pulmonary hypertension, RV dilatation, anatomic thrombus load, and minimized intracranial hemorrhage.

OPTALYSE

Randomized, multi-center, parallel-group trial

101 were enrolled who had a proximal PE in one main or proximal lobar pulmonary artery, intermediate-risk acute PE (less than 14 days in duration), normal systolic blood pressure (> 90), RV to LV diameter ratio greater than or equal to 0.9 on chest CTA, and were symptomatic.

To determine the lowest ideal tPA delivery and dose duration using USCDT.

All of the groups showed improvement in the refined modified Miller score: arm 1 through arm 4: 0.40 (24%; P = 0.0001), 0.35 (22.6%; P = 0.0001), 0.42 (26.3%; P = 0.0001), and 0.48 (25.5%; P = 0.0001), respectively.

In comparison to baseline, treatment with USCDT utilizing a shorter delivery period and lower-dose tPA was linked to enhanced RV function and decreased clot load.