In this book, four leading experts critique methods used to manage flows in regulated streams and rivers to balance environmental (instream) and out-of-stream uses of water. Intended for managers as ...well as practitioners, the book dissects the shortcomings of commonly used approaches, and offers practical advice for selecting and implementing better ones.
The authors argue that methods for environmental flow assessment (EFA) can be defensible as well as practicable only if they squarely address uncertainty, and provide guidance for doing so. Introductory chapters describe the scientific and social reasons that EFA is hard, and provide a brief history. Because management of regulated streams starts with understanding freshwater ecosystems, this book includes chapters on flow and organisms in streams. The following chapters assess standard and emerging methods, how they should be tested, and how they should (or should not) be applied. The book concludes with practical recommendations for implementing environmental flow assessment.
Abstract
Aims
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.
Methods and results
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.
Conclusions
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.
Graphical Abstract
Surgical aortic valve replacement (SAVR) has long been the mainstay of therapy for severe aortic stenosis. However, transcatheter aortic valve replacement (TAVR) is now generally accepted as the new ...standard of care for patients with symptomatic aortic stenosis who are not candidates for open surgery. Arguably TAVR may also be a preferred alternative to SAVR in carefully selected high-risk, but still operable, patients in whom morbidity and mortality may be reduced. Although TAVR outcomes continue to improve, concerns remain with respect to vascular injury, stroke, paravalvular regurgitation, and valve durability. However, it seems likely that with ongoing refinement of transcatheter valve systems, techniques, and patient selection TAVR is becoming an increasingly appealing option for a much broader range of patients. Randomized trials and ongoing surveillance will play an important role as we enter a new era of rigorous clinical evaluation for minimally invasive therapies for structural heart disease.
In patients with aortic stenosis (AS), risk stratification for aortic valve replacement (AVR) relies mainly on valve-related factors, symptoms and co-morbidities. We sought to evaluate the prognostic ...impact of a newly-defined staging classification characterizing the extent of extravalvular (extra-aortic valve) cardiac damage among patients with severe AS undergoing AVR.
Patients with severe AS from the PARTNER 2 trials were pooled and classified according to the presence or absence of cardiac damage as detected by echocardiography prior to AVR: no extravalvular cardiac damage (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage (Stage 4). One-year outcomes were compared using Kaplan-Meier techniques and multivariable Cox proportional hazards models were used to identify 1-year predictors of mortality. In 1661 patients with sufficient echocardiographic data to allow staging, 47 (2.8%) patients were classified as Stage 0, 212 (12.8%) as Stage 1, 844 (50.8%) as Stage 2, 413 (24.9%) as Stage 3, and 145 (8.7%) as Stage 4. One-year mortality was 4.4% in Stage 0, 9.2% in Stage 1, 14.4% in Stage 2, 21.3% in Stage 3, and 24.5% in Stage 4 (Ptrend < 0.0001). The extent of cardiac damage was independently associated with increased mortality after AVR (HR 1.46 per each increment in stage, 95% confidence interval 1.27-1.67, P < 0.0001).
This newly described staging classification objectively characterizes the extent of cardiac damage associated with AS and has important prognostic implications for clinical outcomes after AVR.
Abstract Background The incidence and prognostic impact of late bleeding complications after transcatheter aortic valve replacement (TAVR) are unknown. Objectives The aim of this study was to ...identify the incidence, predictors, and prognostic impact of major late bleeding complications (MLBCs) (≥30 days) after TAVR. Methods Clinical and echocardiographic outcomes of patients who underwent TAVR within the randomized cohorts and continued access registries in the PARTNER (Placement of Aortic Transcatheter Valves) trial were analyzed after stratifying by the occurrence of MLBCs. Predictors of MLBCs and their association with 30-day to 1-year mortality were assessed. Results Among 2,401 patients who underwent TAVR and survived to 30 days, MLBCs occurred in 142 (5.9%) at a median time of 132 days (interquartile range: 71 to 230 days) after the index procedure. Gastrointestinal complications (n = 58 40.8%), neurological complications (n = 22 15.5%), and traumatic falls (n = 11 7.8%) were identified as the most frequent types of MLBCs. Independent predictors of MLBCs were the presence of low hemoglobin at baseline, atrial fibrillation or flutter at baseline or 30 days, the presence of moderate or severe paravalvular leak at 30 days, and greater left ventricular mass at 30 days. MLBCs were identified as a strong independent predictor of mortality between 30 days and 1 year (adjusted hazard ratio: 3.91; 95% confidence interval: 2.67 to 5.71; p < 0.001). Conclusions MLBCs after TAVR were frequent and associated with increased mortality. Better individualized and risk-adjusted antithrombotic therapy after TAVR is urgently needed in this high-risk population. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894 )
Summary Background Based on the early results of the Placement of Aortic Transcatheter Valves (PARTNER) trial, transcatheter aortic valve replacement (TAVR) is an accepted treatment for patients with ...severe aortic stenosis who are not suitable for surgery. However, little information is available about the late clinical outcomes in such patients. Methods We did this randomised controlled trial at 21 experienced valve centres in Canada, Germany, and the USA. We enrolled patients with severe symptomatic inoperable aortic stenosis and randomly assigned (1:1) them to transfemoral TAVR or to standard treatment, which often included balloon aortic valvuloplasty. Patients and their treating physicians were not masked to treatment allocation. The randomisation was done centrally, and sites learned of the assignment only after a patient had been screened, consented, and entered into the database. The primary outcome of the trial was all-cause mortality at 1 year in the intention-to-treat population, here we present the prespecified findings after 5 years. This study is registered with ClinicalTrials.gov , number NCT00530894. Findings We screened 3015 patients, of whom 358 were enrolled (mean age 83 years, Society of Thoracic Surgeons Predicted Risk of Mortality 11·7%, 54% female). 179 were assigned to TAVR treatment and 179 were assigned to standard treatment. 20 patients crossed over from the standard treatment group and ten withdrew from study, leaving only six patients at 5 years, of whom five had aortic valve replacement treatment outside of the study. The risk of all-cause mortality at 5 years was 71·8% in the TAVR group versus 93·6% in the standard treatment group (hazard ratio 0·50, 95% CI 0·39–0·65; p<0·0001). At 5 years, 42 (86%) of 49 survivors in the TAVR group had New York Heart Association class 1 or 2 symptoms compared with three (60%) of five in the standard treatment group. Echocardiography after TAVR showed durable haemodynamic benefit (aortic valve area 1·52 cm2 at 5 years, mean gradient 10·6 mm Hg at 5 years), with no evidence of structural valve deterioration. Interpretation TAVR is more beneficial than standard treatment for treatment of inoperable aortic stenosis. TAVR should be strongly considered for patients who are not surgical candidates for aortic valve replacement to improve their survival and functional status. Appropriate selection of patients will help to maximise the benefit of TAVR and reduce mortality from severe comorbidities. Funding Edwards Lifesciences.
A previous analysis in this trial showed that among patients with severe, symptomatic aortic stenosis who were at low surgical risk, the rate of the composite end point of death, stroke, or ...rehospitalization at 1 year was significantly lower with transcatheter aortic-valve replacement (TAVR) than with surgical aortic-valve replacement. Longer-term outcomes are unknown.
We randomly assigned patients with severe, symptomatic aortic stenosis and low surgical risk to undergo either TAVR or surgery. The first primary end point was a composite of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure. The second primary end point was a hierarchical composite that included death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis. Clinical, echocardiographic, and health-status outcomes were assessed through 5 years.
A total of 1000 patients underwent randomization: 503 patients were assigned to undergo TAVR, and 497 to undergo surgery. A component of the first primary end point occurred in 111 of 496 patients in the TAVR group and in 117 of 454 patients in the surgery group (Kaplan-Meier estimates, 22.8% in the TAVR group and 27.2% in the surgery group; difference, -4.3 percentage points; 95% confidence interval CI, -9.9 to 1.3; P = 0.07). The win ratio for the second primary end point was 1.17 (95% CI, 0.90 to 1.51; P = 0.25). The Kaplan-Meier estimates for the components of the first primary end point were as follows: death, 10.0% in the TAVR group and 8.2% in the surgery group; stroke, 5.8% and 6.4%, respectively; and rehospitalization, 13.7% and 17.4%. The hemodynamic performance of the valve, assessed according to the mean (±SD) valve gradient, was 12.8±6.5 mm Hg in the TAVR group and 11.7±5.6 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group.
Among low-risk patients with severe, symptomatic aortic stenosis who underwent TAVR or surgery, there was no significant between-group difference in the two primary composite outcomes. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).
Summary Background Transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve demonstrates good 30 day clinical outcomes in patients with severe aortic stenosis who are at intermediate ...risk of surgical mortality. Here we report longer-term data in intermediate-risk patients given SAPIEN 3 TAVR and compare outcomes to those of intermediate-risk patients given surgical aortic valve replacement. Methods In the SAPIEN 3 observational study, 1077 intermediate-risk patients at 51 sites in the USA and Canada were assigned to receive TAVR with the SAPIEN 3 valve 952 88% via transfemoral access) between Feb 17, 2014, and Sept 3, 2014. In this population we assessed all-cause mortality and incidence of strokes, re-intervention, and aortic valve regurgitation at 1 year after implantation. Then we compared 1 year outcomes in this population with those for intermediate-risk patients treated with surgical valve replacement in the PARTNER 2A trial between Dec 23, 2011, and Nov 6, 2013, using a prespecified propensity score analysis to account for between-trial differences in baseline characteristics. The clinical events committee and echocardiographic core laboratory methods were the same for both studies. The primary endpoint was the composite of death from any cause, all strokes, and incidence of moderate or severe aortic regurgitation. We did non-inferiority (margin 7·5%) and superiority analyses in propensity score quintiles to calculate pooled weighted proportion differences for outcomes. Findings At 1 year follow-up of the SAPIEN 3 observational study, 79 of 1077 patients who initiated the TAVR procedure had died (all-cause mortality 7·4%; 6·5% in the transfemoral access subgroup), and disabling strokes had occurred in 24 (2%), aortic valve re-intervention in six (1%), and moderate or severe paravalvular regurgitation in 13 (2%). In the propensity-score analysis we included 963 patients treated with SAPIEN 3 TAVR and 747 with surgical valve replacement. For the primary composite endpoint of mortality, strokes, and moderate or severe aortic regurgitation, TAVR was both non-inferior (pooled weighted proportion difference of −9·2%; 90% CI −12·4 to −6; p<0·0001) and superior (−9·2%, 95% CI −13·0 to −5·4; p<0·0001) to surgical valve replacement. Interpretation TAVR with SAPIEN 3 in intermediate-risk patients with severe aortic stenosis is associated with low mortality, strokes, and regurgitation at 1 year. The propensity score analysis indicates a significant superiority for our composite outcome with TAVR compared with surgery, suggesting that TAVR might be the preferred treatment alternative in intermediate-risk patients. Funding None.
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