In this experimental pilot study, the addition of contrast-enhanced US accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. Further clinical studies are warranted.
Background The CAVA trial did not show the anticipated risk reduction for postthrombotic syndrome (PTS) after thrombus removal via additional ultrasound-accelerated catheter-directed thrombolysis (UACDT) in patients with acute iliofemoral deep vein thrombosis (IFDVT). Difficulties in achieving an effective degree of recanalization through thrombolysis may have influenced outcomes. We therefore assessed whether successful UACDT (restored patency ≥ 90%) did reduce the development of PTS. Methods This CAVA trial post hoc analysis compared the proportion of PTS at 1-year follow-up between patients with successful UACDT and patients that received standard treatment only. In addition, clinical impact as well as determinants of successful thrombolysis were explored. Results UACDT was initiated in 77 (50.7%) patients and considered successful in 41 (53.2%, interrater agreement κ = 0.7, 95% confidence interval 0.47–0.83). PTS developed in 15/41 (36.6%) patients in the successful UACDT group versus 33/75 (44.0%) controls (p = 0.44). In this comparison, successful UACDT was associated with lower Venous Clinical Severity Score (3.50 ± 2.57 vs. 4.82 ± 2.74, p = 0.02) and higher EuroQOL-5D (EQ-5D) scores (40.2 ± 36.4 vs. 23.4 ± 34.4, p = 0.01). Compared with unsuccessful UACDT, successful UACDT was associated with a shorter symptom duration at inclusion (p = 0.05), and higher rates of performed adjunctive procedures (p < 0.001) and stent placement (p < 0.001). Conclusion Successful UACDT was not associated with a reduced proportion of PTS 1 year after acute IFDVT compared with patients receiving standard treatment alone. There was, however, a significant reduction in symptom severity and improvement of generic quality of life according to the EQ-5D. Better patient selection and optimization of treatment protocols are needed to assess the full potential of UACDT for the prevention of PTS. Trial Registration Number ClinicalTrials.gov number, NCT00970619.
WHAT THIS PAPER ADDS Current thrombolysis protocols for peripheral arterial occlusions are based on evidence from randomised controlled trials performed >20 years ago. To this day, there is no consensus on the optimum fibrinolytic agent or dose regimens to use. Numerous devices and techniques, such as mechanical thrombectomy and ultrasound assisted thrombolysis, have been proposed and investigated to improve the results of thrombolysis. Major bleeding complications remain a substantial clinical problem of thrombolytic therapy. The present systematic review of the literature provides an update of all reported patient cohorts with peripheral arterial occlusions treated by catheter directed thrombolysis. Objective: Catheter directed thrombolysis (CDT) for peripheral arterial occlusions is a well established alternative to thrombo-embolectomy in patients with (sub)acute limb ischaemia. However, protocols are heterogeneous and need optimisation to improve results and lower bleeding risks. The objective was to review the results and outcomes of different CDT protocols for patients with peripheral arterial occlusions. Data sources: Electronic information sources (MEDLINE, Embase, Cochrane) and reference lists were searched to identify studies reporting results of CDT of peripheral arterial occlusions. Methods: Two independent observers performed study selection, quality assessment and data extraction. Primary outcomes were treatment duration, success rates, and bleeding complications. Secondary outcomes were mortality and amputation rates. Results: One hundred and six studies were included: 19 randomised controlled trials (RCTs), 38 prospective studies, 48 retrospective studies, and one mixed cohort study. The studies comprised a total number of 10,643 cases of which 9877 received CDT for lower extremity arterial occlusion, with a mean treatment duration of 21.4 h (95% confidence interval [CI] 21.0e21.8), an angiographic patency of 75% (95% CI 74.6e 75.1), and freedom from amputation rate of 91% (95% CI 90.3e90.7). Pooled results showed a thrombolysis duration with high dose protocols of 21.9 h (95% CI 21.4e22.5) and 32.7 h with low dose protocols, with bleeding rates of 16.7% (95% CI 16.3e17.1) and 13.4% (95% CI 12.8e14.0), respectively. Weighted mean results for all RCTs and prospective cohorts of >100 cases analysed separately, showed comparable results to all observational cohorts pooled. Bleeding complications occurred in 18% (95% CI 17.8e18.3) of patients and remain an important risk of CDT. Conclusion: CDT is an effective treatment for peripheral arterial occlusions, the main concern is bleeding complications. Although no formal meta-analysis could be performed, the pooled results suggest that lower doses of fibrinolytics lead to similar success rates at a cost of longer treatment duration but with less bleeding. There is large variation in treatment protocols and the available literature suffers from absence of reporting standards and high heterogeneity.
IntroductionAcute peripheral arterial occlusions can be treated with intra-arterial catheter-directed thrombolysis as an alternative to surgical thromboembolectomy. Although less invasive, this treatment is time-consuming and carries a significant risk of haemorrhagic complications. Contrast-enhanced ultrasound using microbubbles could accelerate dissolution of thrombi by thrombolytic medications due to mechanical effects caused by oscillation; this could allow for lower dosages of thrombolytics and faster thrombolysis, thereby reducing the risk of haemorrhagic complications. In this study, the safety and practical applicability of this treatment will be investigated.Methods and analysisA single-arm phase II trial will be performed in 20 patients with acute peripheral arterial occlusions eligible for thrombolytic treatment. Low-dose catheter-directed thrombolysis with urokinase will be used. The investigated treatment will be performed during the first hour of thrombolysis, consisting of intravenous infusion of 4 Luminity phials (6 mL in total, diluted with saline 0.9% to 40 mL total) of microbubbles with the use of local ultrasound at the site of occlusion. Primary end points are the incidence of complications and technical feasibility. Secondary end points are angiographic and clinical success, duration of thrombolytic infusion, treatment-related mortality, amputations, additional interventions and quality of life.Ethics and disseminationEthical approval for this study was obtained in 2015 from the Medical Ethics Committee of the VU University Medical Center, Amsterdam, the Netherlands. A statement of consent for this study was given by the Dutch national competent authority. Data will be presented at national and international conferences and published in a peer-reviewed journal.Trial registration numbersDutch National Trial Registry: NTR4731; European Clinical Trials Database of the European Medicines Agency: 2014-003469-10; Pre-results.
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