Restoring microvascular circulation with diagnostic ultrasound and contrast agent: rationale and design of the REDUCE trial.

OBJECTIVES: This study aims to evaluate the efficacy and cost-effectiveness of sonothrombolysis delivered pre and post primary percutaneous coronary intervention (pPCI) on infarct size assessed by cardiac MRI, in patients presenting with STEMI, when compared against sham procedure. BACKGROUND: More than a half of patients with successful pPCI have significant microvascular obstruction and residual infarction. Sonothrombolysis is a therapeutic use of ultrasound with contrast enhancement that may improve microcirculation and infarct size. The benefits and real time physiological effects of sonothrombolysis in a multicentre setting are unclear. METHODS: The REDUCE (Restoring microvascular circulation with diagnostic ultrasound and contrast agent) trial is a prospective, multicentre, patient and outcome blinded, sham-controlled trial. Patients presenting with STEMI will be randomized to one of 2 treatment arms, to receive either sonothrombolysis treatment or sham echocardiography before and after pPCI. This tailored design is based on preliminary pilot data from our centre, showing that sonothrombolysis can be safely delivered, without prolonging door to balloon time. Our primary endpoint will be infarct size assessed on day 4±2 on Cardiac Magnetic Resonance (CMR). Patients will be followed up for 6 months post pPCI to assess secondary endpoints. Sample size calculations indicate we will need 150 patients recruited in total. CONCLUSIONS: This multicentre trial will test whether sonothrombolysis delivered pre and post primary PCI can improve patient outcomes and is cost-effective, when compared with sham ultrasound delivered with primary PCI. The results from this trial may provide evidence for the utilization of sonothrombolysis as an adjunct therapy to pPCI to improve cardiovascular outcomes in STEMI. ANZ Clinical Trial Registration number: ACTRN 12620000807954.

A Prospective, Multicentre Randomised Controlled Trial Comparing Catheter Ablation Versus Antiarrhythmic Drugs in Patients With Structural Heart Disease Related Ventricular Tachycardia: The CAAD-VT Trial Protocol.

IMPORTANCE: Randomised trials have shown that catheter ablation (CA) is superior to medical therapy for ventricular tachycardia (VT) largely in patients with ischaemic heart disease. Whether this translates to patients with all forms and stages of structural heart disease (SHD-e.g., non-ischaemic heart disease) is unclear. This trial will help clarify whether catheter ablation offers superior outcomes compared to medical therapy for VT in all patients with SHD. OBJECTIVE: To determine in patients with SHD and spontaneous or inducible VT, if catheter ablation is more efficacious than medical therapy in control of VT during follow-up. DESIGN: Randomised controlled trial including 162 patients, with an allocation ratio of 1:1, stratified by left ventricular ejection fraction (LVEF) and geographical region of site, with a median follow-up of 18-months and a minimum follow-up of 1 year. SETTING: Multicentre study performed in centres across Australia. PARTICIPANTS: Structural heart disease patients with sustained VT or inducible VT (n=162). INTERVENTION: Early treatment, within 30 days of randomisation, with catheter ablation (intervention) or initial treatment with antiarrhythmic drugs only (control). MAIN OUTCOMES, MEASURES, AND RESULTS: Primary endpoint will be a composite of recurrent VT, VT storm (≥3 VT episodes in 24 hrs or incessant VT), or death. Secondary outcomes will include each of the individual primary endpoints, VT burden (number of VT episodes in the 6 months preceding intervention compared to the 6 months after intervention), cardiovascular hospitalisation, mortality (including all-cause mortality, cardiac death, and non-cardiac death) and LVEF (assessed by transthoracic echocardiography from baseline to 6-, 12-, 24- and 36-months post intervention). CONCLUSIONS AND RELEVANCE: The Catheter Ablation versus Anti-arrhythmic Drugs for Ventricular Tachycardia (CAAD-VT) trial will help determine whether catheter ablation is superior to antiarrhythmic drug therapy alone, in patients with SHD-related VT. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry (ANZCTR) TRIAL REGISTRATION ID: ACTRN12620000045910 TRIAL REGISTRATION URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377617&isReview=true.

Sonothrombolysis Before and After Percutaneous Coronary Intervention Provides the Largest Myocardial Salvage in ST Segment Elevation Myocardial Infarction.

BACKGROUND: Sonothrombolysis is a therapeutic application of ultrasound with ultrasound contrast for patients with ST elevation myocardial infarction (STEMI). Recent trials demonstrated that sonothrombolysis, delivered before and after primary percutaneous coronary intervention (pPCI), increases infarct vessel patency, improves microvascular flow, reduces infarct size, and improves ejection fraction. However, it is unclear whether pre-pPCI sonothrombolysis is essential for therapeutic benefit. We designed a parallel 3-arm sham-controlled randomized controlled trial to address this. METHODS: Patients presenting with first STEMI undergoing pPCI within 6 hours of symptom onset were randomized 1:1:1 into 3 arms: sonothrombolysis pre-/post-pPCI (group 1), sham pre- sonothrombolysis post-pPCI (group 2), and sham pre-/post-pPCI (group 3). Our primary end point was infarct size (percentage of left ventricular mass) assessed by cardiac magnetic resonance imaging at day 4 ± 2. Secondary end points included myocardial salvage index (MSI) and echocardiographic parameters at day 4 ± 2 and 6 months. RESULTS: Our trial was ceased early due to the COVID pandemic. From 122 patients screened between September 2020 and June 2021, 51 patients (age 60, male 82%) were included postrandomization. Median sonothrombolysis took 5 minutes pre-pPCI and 15 minutes post-, without significant door-to-balloon delay. There was a trend toward reduction in median infarct size between group 1 (8% [interquartile range, 4,11]), group 2 (11% [7, 19]), or group 3 (15% [9, 22]). Similarly there was a trend toward improved MSI in group 1 (79% [64, 85]) compared to groups 2 (51% [45, 70]) and 3 (48% [37, 73]) No major adverse cardiac events occurred during hospitalization. CONCLUSIONS: Pre-pPCI sonothrombolysis may be key to improving MSI in STEMI. Multicenter trials and health economic analyses are required before clinical translation.

Early Catheter Ablation Versus Initial Medical Therapy for Ventricular Tachycardia Storm.

BACKGROUND: Ventricular tachycardia (VT) storm is associated with significantly increased morbidity, mortality, and exponential healthcare utilization. Although catheter ablation (CA) may be curative, there are limited data directly comparing outcomes of early CA with initial medical therapy. METHODS: We compared outcomes of patients presenting with VT storm treated with initial CA versus those treated with initial medical therapy during their first storm presentation in an observational study. Retrospective data from the host institution from January 2014 to April 2020 of 129 patients with their first VT storm presentation were analyzed (58 underwent initial CA, 71 underwent treatment with initial medical therapy). Outcomes were compared in follow-up. RESULTS: Median time to initial CA was 6 days. Over a median follow-up of 702 days, patients who underwent initial CA compared with those treated with initial medical therapy had significantly less: (i) VA recurrence (43% versus 92%; P=0.002); (ii) VT storm recurrence (28% versus 73%; P<0.001); (iii) composite end point of death, heart transplant, VT storm recurrence, and VT-related hospitalization (47% versus 89%; P=0.002); (iv) iatrogenic complications (at 12 months: 17% versus 45%; P<0.001); (v) cardiovascular-related hospitalizations (50% versus 89%; P=0.01); (vi) total number of hospitalizations (median 1 versus 4; P<0.001); and (vi) cumulative days in hospital (median 0.5 versus 18; P<0.001). There were no intraprocedural deaths in patients treated with early CA. CONCLUSION: In an observational setting in which patients presenting with storm, early CA appears superior to initial medical therapy in terms of VT recurrence, storm recurrence, iatrogenic complications, cardiovascular hospitalizations, and cumulative days in hospital in follow-up.

Comparison of 6 and 7 French guiding catheters for percutaneous coronary intervention: results of a randomised trial with a vascular ultrasound endpoint.

OBJECTIVE: To perform a randomized, ultrasound controlled trial to define the procedural and clinical advantages and limitations of 6 French (Fr) compared with 7 Fr transfemoral coronary intervention in the stenting era. BACKGROUND: The use of 7 Fr guiding catheters may facilitate Percutaneous Coronary Intervention (PCI), but may be associated with increased vascular complications when compared with 6 Fr catheters. METHODS: Patients undergoing PCI considered suitable for either a 6 or 7 Fr sheath and guiding catheter system were included. All vascular sheaths were removed with assisted manual compression. Femoral vascular ultrasounds were performed prior to hospital discharge and interpreted by a vascular surgeon blinded to treatment assignment. The primary endpoint was a composite of significant vascular complications including major haematoma, retroperitoneal haematoma, pseudoaneurysm, arterio-venous fistula, or femoral venous or arterial thrombosis. RESULTS: During the study, 414 patients (mean age 61+/-11 years, 27% females) were randomly assigned to 6 Fr or 7 Fr sheath groups. The incidence of major vascular complications was 5.7% in the 6 Fr group and 3.9% in the 7 Fr group (P=0.383). There was no significant difference in procedural or angiographic success between the groups. The use of contrast volume was higher in the 7 Fr group (157+/-58 ml vs. 144+/-58 ml; P=0.029). There was a trend toward better operator satisfaction with the 7 Fr guide (P=0.08). CONCLUSIONS: This prospective, randomized trial indicates no reduction in major peripheral vascular complications with the use of smaller guiding catheters in PCI. There was less contrast used in the 6 Fr group, which may benefit some patient subsets, however operators tended to prefer the larger 7 Fr system. The target coronary anatomy and need for complex device intervention should mandate the choice of guiding catheter size, not a perceived impact on vascular complications.