It is unknown whether transcatheter valves will have similar durability as surgical bioprosthetic valves. Definitions of structural valve deterioration (SVD), based on valve related reintervention or ...death, underestimate the incidence of SVD.
This study sought to determine and compare the 5-year incidence of SVD, using new standardized definitions based on echocardiographic follow-up of valve function, in intermediate-risk patients with severe aortic stenosis given transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) in the PARTNER (Placement of Aortic Transcatheter Valves) 2A trial and registry.
In the PARTNER 2A trial, patients were randomly assigned to receive either TAVR with the SAPIEN XT or SAVR, whereas in the SAPIEN 3 registry, patients were assigned to TAVR with the SAPIEN 3. The primary endpoint was the incidence of SVD, that is, the composite of SVD-related hemodynamic valve deterioration during echocardiographic follow-up and/or SVD-related bioprosthetic valve failure (BVF) at 5 years.
Compared with SAVR, the SAPIEN-XT TAVR cohort had a significantly higher 5-year exposure adjusted incidence rates (per 100 patient-years) of SVD (1.61 ± 0.24% vs. 0.63 ± 0.16%), SVD-related BVF (0.58 ± 0.14% vs. 0.12 ± 0.07%), and all-cause (structural or nonstructural) BVF (0.81 ± 0.16% vs. 0.27 ± 0.10%) (p ≤ 0.01 for all). The 5-year rates of SVD (0.68 ± 0.18% vs. 0.60 ± 0.17%; p = 0.71), SVD-related BVF (0.29 ± 0.12% vs. 0.14 ± 0.08%; p = 0.25), and all-cause BVF (0.60 ± 0.15% vs. 0.32 ± 0.11%; p = 0.32) in SAPIEN 3 TAVR were not significantly different to a propensity score matched SAVR cohort. The 5-year rates of SVD and SVD-related BVF were significantly lower in SAPIEN 3 versus SAPIEN XT TAVR matched cohorts.
Compared with SAVR, the second-generation SAPIEN XT balloon-expandable valve has a higher 5-year rate of SVD, whereas the third-generation SAPIEN 3 has a rate of SVD that was not different from SAVR. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII A PARTNERII A; NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - PARTNER II - PARTNERII - S3 Intermediate PARTNERII S3i; NCT03222128)
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The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and ...surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research.
Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs.
Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.
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Summary Background The relative safety of drug-eluting stents and bare-metal stents, especially with respect to stent thrombosis, continues to be debated. In view of the overall low frequency of ...stent thrombosis, large sample sizes are needed to accurately estimate treatment differences between stents. We compared the risk of thrombosis between bare-metal and drug-eluting stents. Methods For this network meta-analysis, randomised controlled trials comparing different drug-eluting stents or drug-eluting with bare-metal stents currently approved in the USA were identified through Medline, Embase, Cochrane databases, and proceedings of international meetings. Information about study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. Findings 49 trials including 50 844 patients randomly assigned to treatment groups were analysed. 1-year definite stent thrombosis was significantly lower with cobalt-chromium everolimus eluting stents (CoCr-EES) than with bare-metal stents (odds ratio OR 0·23, 95% CI 0·13–0·41). The significant difference in stent thrombosis between CoCr-EES and bare-metal stents was evident as early as 30 days (OR 0·21, 95% CI 0·11–0·42) and was also significant between 31 days and 1 year (OR 0·27, 95% CI 0·08–0·74). CoCr-EES were also associated with significantly lower rates of 1-year definite stent thrombosis compared with paclitaxel-eluting stents (OR 0·28, 95% CI 0·16–0·48), permanent polymer-based sirolimus-eluting stents (OR 0·41, 95% CI 0·24–0·70), phosphorylcholine-based zotarolimus-eluting stents (OR 0·21, 95% CI 0·10–0·44), and Resolute zotarolimus-eluting stents (OR 0·14, 95% CI 0·03–0·47). At 2-year follow-up, CoCr-EES were still associated with significantly lower rates of definite stent thrombosis than were bare-metal (OR 0·35, 95% CI 0·17–0·69) and paclitaxel-eluting stents (OR 0·34, 95% CI 0·19–0·62). No other drug-eluting stent had lower definite thrombosis rates compared with bare-metal stents at 2-year follow-up. Interpretation In randomised studies completed to date, CoCr-EES has the lowest rate of stent thrombosis within 2 years of implantation. The finding that CoCr-EES also reduced stent thrombosis compared with bare-metal stents, if confirmed in future randomised trials, represents a paradigm shift. Funding The Cardiovascular Research Foundation.
The Placement of Aortic Transcatheter Valves (PARTNER) trial showed that among high-risk patients with aortic stenosis, the 1-year survival rates are similar with transcatheter aortic-valve ...replacement (TAVR) and surgical replacement. However, longer-term follow-up is necessary to determine whether TAVR has prolonged benefits.
At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either surgical aortic-valve replacement or TAVR. All patients were followed for at least 2 years, with assessment of clinical outcomes and echocardiographic evaluation.
The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval CI, 0.71 to 1.15; P=0.41) and at 2 years (Kaplan-Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P=0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P=0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P=0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001).
A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.).
We conducted a formal meta-analysis of peer-reviewed, published, randomized studies comparing intravascular ultrasound (IVUS)-guidance and angiographic-guided bare metal stent implantation. A total ...of 8 studies were identified. Because the Balloon Equivalent to Stent (BEST) study was a noninferiority trial designed to compare 2 very different percutaneous coronary intervention strategies—IVUS-guided aggressive balloon angioplasty (with bail-out stenting) and angiographic-guided deliberate bare metal stent implantation—it was eliminated. An unadjusted random-effects meta-analysis was used to compare the IVUS-guided and non–IVUS-guided stenting in the 7 remaining studies. A total of 2,193 patients were randomized in 5 multicenter and 2 single-center studies. IVUS guidance was associated with a significantly larger postprocedure angiographic minimum lumen diameter. The mean difference was 0.12 mm (95% confidence interval CI 0.06 to 0.18, p <0.0001). IVUS guidance was also associated with a significantly lower rate of 6-month angiographic restenosis (22% vs 29%, odds ratio 0.64, 95% CI 0.42 to 0.96, p = 0.02), a significant reduction in the revascularization rate (13% vs 18%, odds ratio 0.66, 95% CI 0.48 to 0.91, p = 0.004), and overall major adverse cardiac events (19% vs. 23%, odds ratio 0.69, 95% CI 0.49 to 0.97, p = 0.03). However, no significant effect was seen for myocardial infarction (p = 0.51) or mortality (p = 0.18). In conclusion, IVUS guidance for bare metal stent implantation improved the acute procedural results (angiographic minimum lumen diameter) and thereby reduced angiographic restenosis and repeat revascularization and major adverse cardiac events, with a neutral effect on death and myocardial infarction during a follow-up period of 6 months to 2.5 years.
The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI)clinical endpoints to make ...them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection.
A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous.
Two in-person meetings (held in September 2011 in Washington, DC, USA, and in February 2012 in Rotterdam, the Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and non-interventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints.
This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavours of applying definitions to other transcatheter valve therapies (for example, mitral valve repair).
Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, ...myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
The impact of aortic valve replacement (AVR) on progression/regression of extravalvular cardiac damage and its association with subsequent prognosis is unknown.
The purpose of this study was to ...describe the evolution of cardiac damage post-AVR and its association with outcomes.
Patients undergoing transcatheter or surgical AVR from the PARTNER (Placement of Aortic Transcatheter Valves) 2 and 3 trials were pooled and classified by cardiac damage stage at baseline and 1 year (stage 0, no damage; stage 1, left ventricular damage; stage 2, left atrial or mitral valve damage; stage 3, pulmonary vasculature or tricuspid valve damage; and stage 4, right ventricular damage). Proportional hazards models determined association between change in cardiac damage post-AVR and 2-year outcomes.
Among 1,974 patients, 121 (6.1%) were stage 0, 287 (14.5%) stage 1, 1,014 (51.4%) stage 2, 412 (20.9%) stage 3, and 140 (7.1%) stage 4 pre-AVR. Two-year mortality was associated with extent of cardiac damage at baseline and 1 year. Compared with baseline, cardiac damage improved in ∼15%, remained unchanged in ∼60%, and worsened in ∼25% of patients at 1 year. The 1-year change in cardiac damage stage was independently associated with mortality (adjusted HR for improvement: 0.49; no change: 1.00; worsening: 1.95; P = 0.023) and composite of death or heart failure hospitalization (adjusted HR for improvement: 0.60; no change: 1.00; worsening: 2.25; P < 0.001) at 2 years.
In patients undergoing AVR, extent of extravalvular cardiac damage at baseline and its change at 1 year have important prognostic implications. These findings suggest that earlier detection of aortic stenosis and intervention before development of irreversible cardiac damage may improve global cardiac function and prognosis. (PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - XT Intermediate and High Risk PII A, NCT01314313; The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves - PII B PARTNERII B, NCT02184442; and PARTNER 3 Trial: Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis P3, NCT02675114)
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The use of transcatheter aortic-valve replacement has been shown to reduce mortality among high-risk patients with aortic stenosis who are not candidates for surgical replacement. However, the two ...procedures have not been compared in a randomized trial involving high-risk patients who are still candidates for surgical replacement.
At 25 centers, we randomly assigned 699 high-risk patients with severe aortic stenosis to undergo either transcatheter aortic-valve replacement with a balloon-expandable bovine pericardial valve (either a transfemoral or a transapical approach) or surgical replacement. The primary end point was death from any cause at 1 year. The primary hypothesis was that transcatheter replacement is not inferior to surgical replacement.
The rates of death from any cause were 3.4% in the transcatheter group and 6.5% in the surgical group at 30 days (P=0.07) and 24.2% and 26.8%, respectively, at 1 year (P=0.44), a reduction of 2.6 percentage points in the transcatheter group (upper limit of the 95% confidence interval, 3.0 percentage points; predefined margin, 7.5 percentage points; P=0.001 for noninferiority). The rates of major stroke were 3.8% in the transcatheter group and 2.1% in the surgical group at 30 days (P=0.20) and 5.1% and 2.4%, respectively, at 1 year (P=0.07). At 30 days, major vascular complications were significantly more frequent with transcatheter replacement (11.0% vs. 3.2%, P<0.001); adverse events that were more frequent after surgical replacement included major bleeding (9.3% vs. 19.5%, P<0.001) and new-onset atrial fibrillation (8.6% vs. 16.0%, P=0.006). More patients undergoing transcatheter replacement had an improvement in symptoms at 30 days, but by 1 year, there was not a significant between-group difference.
In high-risk patients with severe aortic stenosis, transcatheter and surgical procedures for aortic-valve replacement were associated with similar rates of survival at 1 year, although there were important differences in periprocedural risks. (Funded by Edwards Lifesciences; Clinical Trials.gov number, NCT00530894.).
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