Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Safety of Moderate Hypothermia With Antegrade Cerebral Perfusion in Total Aortic Arch Replacement.

BACKGROUND: Total aortic arch replacement (TOTAL) is a complicated operation and has traditionally required deep hypothermic circulatory arrest. In this study, the impact of moderate hypothermic circulatory arrest (MHCA) and antegrade cerebral perfusion (ACP) for TOTAL were examined. METHODS: The ARCH International aortic database was queried and 3,265 patients undergoing TOTAL using ACP were identified. Patients were divided into groups based on lowest cooling temperature: MHCA (20° to 28°C) or deep hypothermia (DHCA) (12° to 20°C). Propensity-matched scoring using 15 variables was used in 669 matched pairs. Multivariable analyses were performed. RESULTS: In the unmatched cohort, more patients underwent MHCA (2,586; 79.2%) who were also younger (p < 0.001) and more frequently underwent emergent operations (p < 0.001) than DHCA patients. For the propensity-matched patients, there were significant differences in cardiopulmonary bypass (CPB) time (MHCA 200 minutes versus DHCA 243 minutes, p < 0.001), aortic crossclamp time (MHCA 120 minutes versus DHCA 142 minutes, p < 0.001), and cerebral perfusion time (MHCA 63 minutes versus DHCA 58 minutes, p < 0.001). Of note, there was no difference in neurologic outcomes nor in-hospital mortality for the two temperature groups. Multivariable analysis of risk factors for mortality included CPB time (odds ratio [OR] 1.006; p < 0.001), concomitant mitral valve surgery (OR 3.070; p = 0.003), emergent operation (OR 2.924; p < 0.001), and poor ejection fraction (OR 3.133; p = 0.011). Independent risk factors for stroke included coronary artery disease (OR 1.856; p < 0.001), cerebral vascular disease (OR 2.172; p < 0.001), emergent operation (OR 2.109; p < 0.001), and CPB time (OR 1.004; p < 0.001). CONCLUSIONS: In this series, TOTAL with MHCA and ACP can be safely performed with acceptable operative risk. MHCA and ACP represent an effective strategy for TOTAL and may obviate the need for DHCA.

Balloon Versus Computed Tomography Sizing of the Aortic Annulus for Transcatheter Aortic Valve Replacement and the Impact of Left Ventricular Outflow Tract Calcification and Morphology on Sizing.

OBJECTIVES: To evaluate the role of balloon annular sizing in transcatheter aortic valve replacement (TAVR). BACKGROUND: Multidetector cardiac computed tomography (MDCT) is the gold standard for aortic annular sizing in TAVR. Balloon sizing is increasingly used in patients with borderline annular size and severe calcification. A comparison between these two techniques is needed. METHODS: We retrospectively compared baseline characteristics and 30-day outcomes of patients undergoing balloon-expandable TAVR using annular MDCT or balloon sizing. Paravalvular leak (PVL) rates were compared adjusting for access site, valve generation, size, and valve calcification. RESULTS: A total of 205 patients underwent TAVR with MDCT (n = 110) or balloon sizing (n = 95). Balloon-sized patients were older (83 years vs 81 years; P=.03), had more valve calcification (60.2% vs 30.9%; P<.001), and underwent more minimalist TAVR (61.1% vs 40%; P=.03). Although we found no difference between balloon and MDCT sizing in rates of acute renal failure (3.2% vs 0.9%; P=.34), annular rupture (1.1% vs 1.8%; P>.99), ≥ mild PVL by angiography (40% vs 35.5%; P=.57), or 30-day transthoracic echocardiography (40.7% vs 29.3%; P=.78), balloon-sized patients had a higher aortic regurgitation index (≥25) of 74.4% vs 54.1% (P=.01). Thirty-day rates of ≥ moderate PVL were 7.0% with balloon and 5.7% with MDCT sizing (P=.34). Balloon sizing recommended a different valve size in 34.0% of patients who underwent both methods (n = 50). A different recommendation occurred more often in patients with moderate/severe annular calcification (50.0% vs 33.3%; P=.01) and non-tubular left ventricular outflow tracts (LVOTs) (70.6% vs 30.3%; P=.01). CONCLUSION: Balloon sizing can be a complement to MDCT for annular sizing in TAVR, especially in patients with moderate/severe annular calcification, borderline annular size, and non-tubular LVOT.

Transcatheter aortic valve replacement has improved short-term but similar midterm outcomes in isolated aortic valve replacement after prior coronary artery bypass grafting.

BACKGROUND: An increasing number of patients with prior coronary artery bypass grafting (CABG) now present with severe aortic stenosis. The proposed benefit of surgical (SAVR) vs transcatheter aortic valve replacement (TAVR) is unknown. The objective of this study was to compare short-term and midterm outcomes of patients undergoing isolated SAVR vs TAVR in those with prior CABG. METHODS: A retrospective analysis was performed of 255 patients who underwent isolated SAVR after prior CABG from January 2002 to February 2013 at Emory University. Outcomes of 148 patients undergoing SAVR (2002 to 2013) and 107 undergoing TAVR (2007 to 2013) were compared using multivariable logistic regression and analysis of variance techniques, adjusting for The Society of Thoracic Surgeons (STS) risk score. Kaplan-Meier plots were used to determine survival rates, and midterm survival between groups was compared using the Cox proportional hazards model. RESULTS: TAVR patients were older (79.8 ± 7.9 years vs 72.5 ± 8.8 years, p < 0.001) but were gender equivalent (female: 24% vs 22%, p = 0.61). The preoperative ejection fraction was similar between groups (TAVR: 0.433 ± 0.131 vs SAVR: 0.469 ± 0.148%, p = 0.60). The TAVR group had a significantly higher the STS risk scores (11.8% vs 7.1%, p < 0.001). All-cause 30-day mortality was 1.9% for TAVR and 4.1% for SAVR (p = 0.32), a result that marginally favors TAVR after risk adjustment (adjusted odds ratio, 0.19; p = 0.07). Postoperative morbidity and resource utilization was significantly higher in the SAVR patients. Midterm survival was similar between the two groups after adjustment (adjusted hazard ratio, 0.78, p = 0.46). CONCLUSIONS: Excellent outcomes can be achieved in SAVR or TAVR after prior CABG. Although TAVR improves short-term outcomes and resource utilization compared with SAVR, midterm mortality outcomes are similar.