Thrombolytic Therapy for Acute Limb Ischaemia: Updates on Current Practices and Implementation of a Novel Strategy

The first part of this thesis provided an update on the outcomes of thrombolytic treatment for acute limb ischaemia. In Chapter 2 a systematic review and meta-analysis gathered the short- and long-term outcomes of catheter directed thrombolysis (CDT) for not-immediately threatening (Rutherford I) acute limb ischaemia (ALI). Despite demonstrating high angiographic success, long-term limb patency of these patients following CDT was poor and there was a substantial risk of mortality. The long-term outcome of CDT for not-immediately threatened and marginally threatened ALI was investigated in Chapter 3. Retrospective analysis showed that thrombolytic treatment may serve as an effective first-line approach for Rutherford I ALI, yielding more favourable functional outcomes compared to those categorised as Rutherford II ALI. Nonetheless, the need for re-interventions and the substantial risk of (bleeding) complications remain high. The identification of patients at risk for major bleeding complications is of paramount importance, given the significant peri-procedural morbidity and mortality associated with such bleeding events. In Chapter 4 we retrospectively evaluated the outcomes of 443 patients undergoing thrombolysis at two centres between 2004 and 2021. The clinical outcome was adversely affected by the incidence of major bleeding, resulting in decreased rates of both angiographic success and 30-day amputation-free survival. This study furthermore showed that a decrease in fibrinogen level to <1 g/L, increasing age, cardiac history, and high thrombolytic dose regimens were significant predictors of major bleeding during thrombolysis. Patients who undergo successful revascularization with thrombolytic therapy continue to face an increased risk of re-occlusion. According to Chapter 5, thrombolytic therapy is an effective revascularization approach for both early and late re-occlusions with a clinical success rate of 80%. Nevertheless, the 5-year long-term patency rates following thrombolysis of re-occlusions are largely unfavourable, standing at 19.1±8% for the early re-occlusion group and 25.1±12% for the late re-occlusion group. The potential benefit of various treatments for ALI can potentially be assessed by implementing a core outcome set that outlines a minimum set of outcome parameters essential to all stakeholders (i.e., patients, physicians, researchers, and clinical experts) involved. Chapter 6 describes the initial stage of developing a core outcome set, which involves reviewing the previously reported outcomes on different treatment approaches for ALI. This review encompassed 158 studies, from which 1242 verbatim outcomes were extracted, and subsequently classified into 283 agreed outcomes. The most reported “agreed outcomes” were mortality, amputation, and limb salvage. In the second part of this thesis the potential therapeutic application of contrast-enhanced ultrasound during thrombolytic treatment for ALI is evaluated. In Chapter 7, the safety and feasibility of contrast-enhanced ultrasound during thrombolytic therapy were evaluated in 20 ALI patients in a first-in-men study. In this study there were no severe adverse events related to the intravenous injected microbubbles and transdermal ultrasound. In light of these encouraging findings, the next phase involves conducting a Phase III multicenter trial. This proposed trial is set to include a substantial patient cohort, randomized to receive either the standard CDT or contrast-enhanced ultrasound-accelerated thrombolysis. The primary objective of this trial is to rigorously compare the efficacy of this novel thrombolytic approach with conventional thrombolytic modalities. In Chapter 8, another novel thrombolytic technique was evaluated, namely the feasibility and lytic efficacy of intra-arterial administered microbubbles through an ultrasound-integrated catheter. In-vitro experiments demonstrated that intra-arterial infusion of microbubbles through an ultrasound-catheter led to a significant decrease in microbubble concentration and higher D-dimer concentrations at the end of the experiment when compared to standard thrombolysis alone. The efficacy of this combination was further examined in a porcine model, revealing a significant reduction in thrombus weight and length when compared to controls treated with standard thrombolysis.