Daily Cardiology Research Analysis

BACKGROUND: To date, the only effective treatment of severe aortic stenosis is valve replacement. With the introduction of transcatheter aortic valve replacement and extending indications to younger patients, the use of bioprosthetic valves (BPVs) has considerably increased. The main inconvenience of BPVs is their limited durability because of mechanisms similar as the fibro-calcifying processes observed in native aortic stenosis. One of the major gaps of the field is to identify therapeutic targets to prevent or slow the fibro-calcifying process leading to severe and symptomatic aortic stenosis. METHODS: Explanted valves were collected from patients and organ donor hearts. A comparative transcriptomic analysis was performed on valvular interstitial cells (VIC) obtained from calcified (bicuspid and tricuspid) versus control valves. The mechanisms and consequences of aldehyde dehydrogenase 1 family member A1 (ALDH1A1) downregulation were analyzed in VIC cultures from control human aortic valves. ALDH1A1 was inhibited or silenced and its impact on osteogenic marker expression and calcification processes assessed in VIC. The effect of all-trans retinoic acid on calcification was tested on human VIC cultures and on 2 animal models: the model of subcutaneous implantation of bovine pericardium in rats and the model of xenograft aortic valve replacement in juvenile sheep. RESULTS: Transcriptome analysis of human VIC identified CONCLUSIONS: These results show that ALDH1A1 is downregulated in calcified valves, hence promoting VIC transition into an osteoblastic phenotype. Retinoic acid receptor alpha agonists, including all-trans retinoic acid through a drug repositioning strategy, represent a promising and innovative pharmacological approach to prevent calcification of native aortic valves and BPV.

BACKGROUND: Catheter ablation of ventricular arrhythmias, one of the most rapidly growing procedures in cardiac electrophysiology, is associated with magnetic resonance imaging-detected brain lesions in more than half of cases. Although a retrograde aortic approach is conventional, modern tools enable entry through a transseptal approach that may avoid embolization of debris from the arterial system. We sought to test the hypothesis that a transseptal puncture would mitigate brain injury compared with a retrograde aortic approach. METHODS: The TRAVERSE trial (Transseptal Versus Retrograde Aortic Ventricular Entry to Reduce Systemic Emboli) was a multicenter randomized controlled comparative effectiveness trial. Patients with left ventricular arrhythmias undergoing catheter ablation procedures were randomly assigned to a transseptal puncture approach compared (1:1) with a retrograde aortic approach. The primary outcome was the presence of an acute brain lesion detected by magnetic resonance imaging. Secondary outcomes included clinically manifest complications, procedural efficacy, and 6-month neurocognitive assessments. RESULTS: Among the 62 patients randomly assigned to a retrograde aortic approach with postoperative brain magnetic resonance imaging, 28 (45%) exhibited an acute brain lesion compared with 19 of the 69 (28%) of those randomized to a transseptal puncture ( CONCLUSIONS: Among patients undergoing left ventricular catheter ablation procedures, a transseptal approach reduced the risk of acute brain lesions by nearly half compared with a retrograde aortic approach without sacrificing safety or efficacy. Given a likely embolic pathogenesis, the brain magnetic resonance imaging findings may reflect a propensity to other organ damage; these findings may extend to other procedures requiring left ventricular entry. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03946072.

BACKGROUND: Balancing the risk of thromboembolism and bleeding after transcatheter aortic valve replacement (TAVR) remains clinically challenging. Questions regarding the efficacy and safety of non-vitamin K oral anticoagulants (NOACs) after TAVR still need to be definitively answered. OBJECTIVES: To evaluate the efficacy and safety of NOACs after TAVR in individuals with and without indication for anticoagulation. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Web of Science, ClinicalTrials.gov, and WHO ICTRP on 7 October 2023 together with reference checking and citation searching to identify additional studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that compared NOACs versus antiplatelet therapy or vitamin K antagonists (VKAs) after TAVR in adults with or without an indication for anticoagulation. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods and conducted random-effects pair-wise analyses and network meta-analyses (NMAs). Our primary outcomes were all-cause mortality, cardiovascular mortality, stroke, and major bleeding. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included four RCTs with 4808 participants in the NMA. Of these, one compared rivaroxaban versus antiplatelet therapy in people without an indication for anticoagulation after TAVR; one compared apixaban versus antiplatelet therapy in people without an indication for anticoagulation or versus VKA in people with an indication for anticoagulation after TAVR; one compared edoxaban versus VKA in people with an indication for anticoagulation after TAVR; and one compared edoxaban with antiplatelet therapy in people without an indication for anticoagulation after TAVR. The mean age of trial participants was 81 years. Follow-up duration ranged from 6 to 18 months. Overall, we judged the risk of bias in the included trials to be low in all domains except for blinding, which was assessed as high in all four studies. No studies evaluated dabigatran. In people without an indication for anticoagulation, rivaroxaban and apixaban may increase all-cause mortality after TAVR as compared to antiplatelet therapy (rivaroxaban: risk ratio (RR) 1.67, 95% confidence interval (CI) 1.13 to 2.46; studies = 1, participants = 1644; moderate-certainty evidence; apixaban: RR 1.71, 95% CI 0.97 to 3.02; studies = 1, participants = 1049; low-certainty evidence), while edoxaban may result in little or no difference (RR 1.59, 95% CI 0.27 to 9.36; studies = 1, participants = 229; low-certainty evidence). Low-certainty evidence suggests little or no difference between rivaroxaban, apixaban, or edoxaban and antiplatelet therapy in cardiovascular mortality (rivaroxaban: RR 1.28, 95% CI 0.78 to 2.10; studies = 1, participants = 1644; apixaban: RR 1.30, 95% CI 0.64 to 2.65; studies = 1, participants = 1049; edoxaban: RR 7.44, 95% CI 0.39 to 142.38; studies = 1, participants = 229) and between rivaroxaban or edoxaban and antiplatelets in stroke (rivaroxaban: RR 1.19, 95% CI 0.71 to 2.00; studies = 1, participants = 1644; edoxaban: RR 1.06, 95% CI 0.15 to 7.42; studies = 1, participants = 229). While rivaroxaban versus antiplatelets probably increases major bleeding after TAVR (RR 1.98, 95% CI 1.07 to 3.65; studies = 1, participants = 1644; moderate-certainty evidence), there may be little or no difference between apixaban and antiplatelet therapy (RR 1.07, 95% CI 0.70 to 1.64; studies = 1, participants = 1049; low-certainty evidence). It is unclear if edoxaban has an effect on major bleeding, although the point estimate suggests increased bleeding (versus antiplatelets: RR 2.13, 95% CI 0.54 to 8.30; studies = 1, participants = 229; low-certainty evidence). In people with an indication for anticoagulation, low-certainty evidence suggests apixaban or edoxaban may result in little to no difference in our predefined primary efficacy outcomes after TAVR when compared to VKA (all-cause mortality: apixaban: RR 1.02, 95% CI 0.59 to 1.77; studies = 1, participants = 451; edoxaban: RR 0.91, 95% CI 0.69 to 1.20; studies = 1, participants = 1426; cardiovascular mortality: apixaban: RR 1.43, 95% CI 0.76 to 2.70; studies = 1, participants = 451; edoxaban: RR 1.07, 95% CI 0.72 to 1.57; studies = 1, participants = 1426; stroke: apixaban: RR 1.28, 95% CI 0.35 to 4.70; studies = 1, participants = 451; edoxaban: RR 0.83, 95% CI 0.51 to 1.34; studies = 1, participants = 1426). While apixaban may result in a similar rate of bleeding as VKA in this population, edoxaban probably increases major bleeding after TAVR in people with an indication for anticoagulation (apixaban: RR 0.90, 95% CI 0.53 to 1.54; studies = 1, participants = 451; low-certainty evidence; edoxaban: RR 1.44, 95% CI 1.08 to 1.93; studies = 1, participants = 1426; moderate-certainty evidence). AUTHORS' CONCLUSIONS: In people without an indication for oral anticoagulation, rivaroxaban and apixaban may increase all-cause mortality when compared to antiplatelet therapy, while edoxaban may result in little or no difference. There might be little or no difference between rivaroxaban, apixaban, or edoxaban and antiplatelet therapy in cardiovascular mortality, and between rivaroxaban or edoxaban and antiplatelets in stroke. While rivaroxaban probably increases major bleeding following TAVR, there might be little or no difference between apixaban and antiplatelet therapy, and the effect of edoxaban on major bleeding remains unclear. In people with an indication for anticoagulation, apixaban and edoxaban may be as effective as VKA in preventing all-cause mortality, cardiovascular death, and stroke. Apixaban may lead to a similar rate of major bleeding as VKA in this population. However, edoxaban probably increases major bleeding following TAVR when compared to VKA. Our NMA did not show superiority of one NOAC over another for any of the primary outcomes. Head-to-head trials directly comparing NOACs against each other are required to increase the certainty of the evidence.