pacman schreef op 28 januari 2021 09:42:
Severe aortic stenosis (AS) is the most common valvular heart disease in the elderly with a prevalence of 4 to 10% and a mean survival of only 0.5 to 5 years if left untreated. Transcatheter aortic valve implantations (TAVI) have evolved as standard of care for high-, intermediate and potentially even low surgical risk candidates due to a lower perioperative risk compared to surgical aortic valve replacement (SAVR). Despite its relative safety compared to SAVR, cerebral embolic events including cerebrovascular events and acute renal injury are major complications following TAVI in the acute and subacute period, and are associated with increased morbidity including cognitive decline and mortality. While cerebral embolic protection devices (CEPD) were designed to reduce the burden of cerebral embolic events, their impact on clinical events has yet to be determined, and other prophylactic options are currently not available. Ischemia/reperfusion injury (IRI) is a key pathophysiological mechanism involved in cerebral and renal embolic events after TAVI resulting in activation of endothelial cells, the contact and the complement system and attraction of neutrophils to the site of injury. In this regard, recombinant human C1 esterase inhibitor (rhC1INH), a potent inhibitor of the complement and the contact system has been shown to reduce the size of cerebral ischemic damage and of renal injury in experimental IRI models, and has already been investigated in a pilot study of acute kidney injury following the administration of contrast media.Aims: To assess the safety and effect of rhC1INH (conestat alfa, Ruconest®) on renal and cerebral ischemic events in patients undergoing TAVI for severe symptomatic AS compared to placebo. Hypothesis: Administration of rhC1INH before and three hours after the TAVI procedure is safe and associated with a reduced cerebral ischemic lesion burden and less renal injury compared to placebo.Methodology: The PAIR-TAVI study is a single-center, randomized, double-blind, placebo-controlled investigational study. The primary endpoint will be the total volume of new cerebral ischemic lesions as evaluated by magnetic resonance imaging (MRI) on day 2 (+/-1 day) after transfemoral TAVI. Secondary endpoints will include the occurrence of acute kidney injury, and neurological and cognitive outcome up to 90 days. All clinical endpoint-qualifying events will be assessed by an independent critical event committee. Consecutive patients scheduled for elective transfemoral TAVI will be randomized in a 1:1 ratio to receive rhC1INH before and 3 hours after TAVI or placebo, while being stratified to the use of a CEPD. 104 evaluable patients will ensure a power of 80% to detect a 50% relative reduction in the total new cerebral lesion volume as significant deviation from the null-hypothesis. Assuming a 15% drop-out rate, we will include 122 patients. Potential significance: The current study proposes an innovative approach to renal and neuroprotection in patients undergoing TAVI by investigating the prophylactic administration of a multiple-action multiple-target inhibitor. If rhC1INH proves to decrease IRI in vulnerable organs such as the brain or the kidneys following transfemoral TAVI, the attenuation of some the most feared complications of TAVI might offer new perspectives in the treatment of patients with severe symptomatic AS but also for other indications such as ischemic stroke. Collaborators and setting: Cardiology and Internal Medicine Unit of the University Hospital Basel. The Neurology, Radiology and Clinical Trial Unit of the University Hospital Basel will provide scientific, logistic and statistical support for the study, respectively.
" by investigating the prophylactic administration of a multiple-action multiple-target inhibitor. If rhC1INH proves to decrease IRI in vulnerable organs such as the brain or the kidneys following transfemoral TAVI, the attenuation of some the most feared complications of TAVI might offer new perspectives in the treatment of patients with severe symptomatic AS but also for other indications such as ischemic stroke"....
hmm.....