Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research

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 & nbsp;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.Cardiolog

Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research

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.Cardiolog

Right Ventricular-Pulmonary Arterial Coupling in Patients With HF Secondary MR Analysis From the COAPT Trial

OBJECTIVES The aim of this study was to determine the prognostic impact of right ventricular (RV)-pulmonary arterial (PA) coupling in patients with heart failure (HF) with severe secondary mitral regurgitation (SMR) enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial.BACKGROUND RV contractile function and PA pressures influence outcomes in patients with SMR, but the impact of RV-PA coupling in patients randomized to transcatheter edge-to-edge repair (TEER) vs guideline-directed medical therapy (GDMT) is unknown.METHODS RV-PA coupling was assessed by the ratio of RV free wall longitudinal strain derived from speckle-tracking echocardiography and noninvasively measured RV systolic pressure. Advanced RV-PA uncoupling was defined as RV free wall longitudinal strain/RV systolic pressure <= 0.5%/mm Hg. The primary endpoint was a composite of all-cause mortality or HF hospitalization at 24-month follow-up.RESULTS A total of 372 patients underwent speckle-tracking echocardiography, and 70.2% had advanced RV-PA uncoupling. By multivariable analysis, advanced RV-PA uncoupling was strongly associated with an increased risk for the primary 24-month endpoint of death or HF hospitalization (HR: 1.87; 95% CI: 1.31-2.66; P = 0.0005). A similar association was present for all-cause mortality alone (HR: 2.57; 95% CI: 1.54-4.29; P = 0.0003). The impact of RV-PA uncoupling was consistent in patients randomized to TEER and GDMT alone. Compared with GDMT alone, the addition of TEER improved 2-year outcomes in patients with (48.0% vs 74.8%; HR: 0.51; 95% CI: 0.37-0.71) and those without (28.8% vs 47.8%; HR: 0.51; 95% CI: 0.27-0.97) advanced RV-PA uncoupling (P-interaction = 0.98).CONCLUSIONS In the COAPT trial, advanced RV dysfunction assessed by RV-PA uncoupling was a powerful predictor of 2-year adverse outcomes in patients with HF and SMR. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079) (C) 2021 by the American College of Cardiology Foundation.Cardiolog

Left Ventricular Global Longitudinal Strain as a Predictor of Outcomes in Patients with Heart Failure with Secondary Mitral Regurgitation: The COAPT Trial

Background: Left ventricular (LV) global longitudinal strain (GLS) is a sensitive marker of LV function and may help identify patients with heart failure (HF) and secondary mitral regurgitation who would have a better prognosis and are more likely to benefit from edge-to-edge transcatheter mitral valve repair with the MitraClip. The aim of this study was to assess the prognostic utility of baseline LV GLS during 2-year follow-up of patients with HF with secondary mitral regurgitation enrolled in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation trial. Methods: Patients with symptomatic HF with moderate to severe or severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated guideline-directed medical therapy (GDMT) were randomized to transcatheter mitral valve repair plus GDMT or GDMT alone. Speckle-tracking-derived LV GLS from baseline echocardiograms was obtained in 565 patients and categorized in tertiles. Death and HF hospitalization at 2-year follow-up were the principal outcomes of interest. Results: Patients with better baseline LV GLS had higher blood pressure, greater LV ejection fraction and stroke volume, lower levels of B-type natriuretic peptide, and smaller LV size. No significant difference in outcomes at 2-year follow-up were noted according to LV GLS. However, the rate of death or HF hospitalization between 10 and 24 months was lower in patients with better LV GLS (P = .03), with no differences before 10 months. There was no interaction between GLS tertile and treatment group with respect to 2-year clinical outcomes. Conclusions: Baseline LV GLS did not predict death or HF hospitalization throughout 2-year follow-up, but it did predict outcomes after 10 months. The benefit of transcatheter mitral valve repair over GDMT alone was consistent in all subgroups irrespective of baseline LV GLS. (J Am Soc Echocardiogr 2021;34:955-65.)Cardiolog

Evolution and Prognostic Impact of Cardiac Damage After Aortic Valve Replacement

BACKGROUND The impact of aortic valve replacement (AVR) on progression/regression of extravalvular cardiac damage and its association with subsequent prognosis is unknown.OBJECTIVES The purpose of this study was to describe the evolution of cardiac damage post-AVR and its association with outcomes.METHODS 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.RESULTS 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 inw15%, remained unchanged inw60%, and worsened in w25% 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.CONCLUSIONS 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. (C) 2022 by the American College of Cardiology Foundation