TRISCEND II: Novel Randomized Trial Design for Transcatheter Tricuspid Valve Replacement.

BACKGROUND: Severe tricuspid regurgitation remains largely undertreated given limited treatment options. Transcatheter tricuspid valve interventions have emerged as a promising therapy for these patients, and the TRISCEND II pivotal trial is the first randomized controlled trial to evaluate transcatheter tricuspid valve replacement (TTVR). OBJECTIVES: The TRISCEND II pivotal trial studies the transcatheter EVOQUE tricuspid valve replacement system using an FDA Breakthrough Device Designation - a program intended to provide timely access to medical devices by speeding up development, assessment, and review. METHODS: The TRISCEND II trial is a prospective, multicenter trial that randomizes patients with symptomatic severe tricuspid regurgitation to treatment with either TTVR in conjunction with optimal medical therapy or optimal medical therapy alone. The trial's novel 2-phase design evaluates 30-day safety and 6-month effectiveness endpoints for the first 150 patients in the initial phase and a 1-year safety and effectiveness endpoint for the full cohort of 400 patients in the second phase. RESULTS: The TRISCEND II trial's 2-phase trial design provided an opportunity for early review and led to the first commercial approval of a TTVR system. CONCLUSIONS: The design of the TRISCEND II trial will likely inform future transcatheter tricuspid device trials. CONDENSED ABSTRACT: The TRISCEND II pivotal trial is the first randomized controlled trial of transcatheter tricuspid valve replacement (TTVR). It was designed under the FDA's Breakthrough Device Program to bring a novel TTVR therapy to patients with limited treatment options. A 2-phase design allowed for early review of safety and effectiveness outcomes followed by a full-cohort safety and effectiveness endpoint in the second phase at 1 year. This approach led to approval of the first commercial transcatheter therapy for tricuspid valve replacement.

Left Atrial Improvement in Patients With Secondary Mitral Regurgitation and Heart Failure: The COAPT Trial.

BACKGROUND: Functional mitral regurgitation induces adverse effects on the left ventricle and the left atrium. Left atrial (LA) dilatation and reduced LA strain are associated with poor outcomes in heart failure (HF). Transcatheter edge-to-edge repair (TEER) of the mitral valve reduces heart failure hospitalization (HFH) and all-cause death in selected HF patients. OBJECTIVES: The aim of this study was to evaluate the impact of LA strain improvement 6 months after TEER on the outcomes of patients enrolled in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. METHODS: The difference in LA strain between baseline and the 6-month follow-up was calculated. Patients with at least a 15% improvement in LA strain were labeled as "LA strain improvers." All-cause death and HFH were assessed between the 6 and 24-month follow-up. RESULTS: Among 347 patients (mean age 71 ± 12 years, 63% male), 106 (30.5%) showed improvement of LA strain at the 6-month follow-up (64 [60.4%] from the TEER + guideline-directed medical therapy [GDMT] group and 42 [39.6%] from the GDMT alone group). An improvement in LA strain was significantly associated with a reduction in the composite of death or HFH between the 6-month and 24-month follow-up, with a similar risk reduction in both treatment arms (Pinteraction = 0.27). In multivariable analyses, LA strain improvement remained independently associated with a lower risk of the primary composite endpoint both as a continuous variable (adjusted HR: 0.94 [95% CI: 0.89-1.00]; P = 0.03) and as a dichotomous variable (adjusted HR: 0.49 [95% CI: 0.27-0.89]; P = 0.02). The best outcomes were observed in patients treated with TEER in whom LA strain improved. CONCLUSIONS: In symptomatic HF patients with severe mitral regurgitation, improved LA strain at the 6-month follow-up is associated with subsequently lower rates of the composite endpoint of all-cause mortality or HFH, both after TEER and GDMT alone. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [COAPT]; NCT01626079).

Comparison of Transcatheter Edge-to-Edge Mitral Valve Repair for Primary Mitral Regurgitation Outcomes to Hospital Volumes of Surgical Mitral Valve Repair.

BACKGROUND: Transcatheter edge-to-edge mitral valve (MV) repair (TEER) is an effective treatment for patients with primary mitral regurgitation at prohibitive risk for surgical MV repair (MVr). High-volume MVr centers and high-volume TEER centers have better outcomes than low-volume centers, respectively. However, whether MVr volume predicts TEER outcomes remains unknown. We hypothesized that high-volume MV surgical centers would have superior risk-adjusted outcomes for TEER than low-volume centers. METHODS: We combined data from the American College of Cardiology/Society of Thoracic Surgeons Transcatheter Valve Therapy registry and the Society of Thoracic Surgeons adult cardiac surgery database. MVr was defined as leaflet resection or artificial chords with or without annuloplasty and was evaluated as a continuous variable and as predefined categories (<25, 25-49, and ≥50 MV repairs/year). A generalized linear mixed model was used to evaluate risk-adjusted in-hospital/30-day mortality, 30-day heart failure readmission, and TEER success (mitral regurgitation ≤2+ and gradient <5 mm Hg). RESULTS: The study comprised 41 834 patients from 500 sites of which 332 (66.4%) were low, 102 (20.4%) intermediate, and 66 (13.2%) high-volume surgical centers (P<0.001). TEER success was 54.6% and was not statistically significantly different across MV surgical site volumes (P=0.4271). TEER mortality at 30 days was 3.5% with no significant difference across MVr volume on unadjusted (P=0.141) or adjusted (P=0.071) analysis of volume as a continuous variable. One-year mortality was 15.0% and was lower for higher MVr volume centers when adjusted for clinical and demographic variables (P=0.027). Heart failure readmission at 1 year was 9.4% and was statistically significantly lower in high-volume centers on both unadjusted (P=0.017) or adjusted (P=0.015) analysis. CONCLUSIONS: TEER can be safely performed in centers with low volumes of MV repair. However, 1-year mortality and heart failure readmission are superior at centers with higher MVr volume.

The Evolving Concept of Secondary Mitral Regurgitation Phenotypes: Lessons From the M-TEER Trials.

Conflicting results from 2 randomized clinical trials of transcatheter mitral valve edge-to-edge repair in secondary mitral regurgitation (SMR) have led to the recognition that SMR is a heterogeneous disease entity presenting with different functional and morphological phenotypes. This review summarizes the current knowledge on SMR caused primarily by atrial secondary mitral regurgitation (aSMR) and ventricular SMR pathology. Although aSMR is generally characterized by severe left atrial enlargement in the setting of preserved left ventricular anatomy and function, different patterns of mitral annular distortion cause different phenotypes of aSMR. In ventricular SMR, the relation of SMR severity to left ventricular dilation as well as the degree of pulmonary hypertension and right ventricular dysfunction are important phenotypic characteristics, which are key for a better understanding of prognosis and treatment response.

Right Heart Remodeling and Outcomes in Patients With Tricuspid Regurgitation: A Literature Review and Meta-Analysis.

BACKGROUND: Functional tricuspid regurgitation (TR) can develop either because of right ventricular (RV) remodeling (ventricular functional TR) and/or right atrial dilation (atrial functional TR). OBJECTIVES: This meta-analysis aimed to investigate the association between right heart remodeling and long-term (>1 year) all-cause mortality in patients with significant TR (at least moderate, ≥2+). METHODS: MEDLINE, ISI Web of Science, and SCOPUS databases were searched. Studies reporting data on at least 1 RV functional parameter and long-term all-cause mortality in patients with significant TR were included. This study was designed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) requirements. RESULTS: Out of 8,902 studies, a total of 14 were included, enrolling 4,394 subjects. The duration of follow-up across the studies varied, ranging from a minimum of 15.5 months to a maximum of 73.2 months. Overall, long-term all-cause mortality was 31% (95% CI: 20%-41%; P ≤ 0.001). By means of meta-regression analyses, an inverse relation was found between tricuspid annular plane systolic excursion (11 studies enrolling 3,551 subjects, -6.3% [95% CI: -11.1% to -1.4%]; P = 0.011), RV fractional area change (9 studies, 2,975 subjects, -4.4% [95% CI: -5.9% to -2.9%]; P < 0.001), tricuspid annular dimension (7 studies, 2,986 subjects, -4.1% [95% CI: -7.6% to -0.5%]; P = 0.026), right atrial area (6 studies, 1,920 subjects, -1.9% [95% CI: -2.5% to -1.3%]; P < 0.001) and mortality. CONCLUSIONS: RV dysfunction parameters are associated to worse clinical outcomes in patients with TR, whereas right atrial dilatation is linked to a better prognostic outcome. Further studies are needed to unravel the pathophysiological differences within the functional TR spectrum. (Right heart remodeling and outcomes in patients with tricuspid regurgitation; CRD42023418667).

Tricuspid regurgitation burden following transcatheter aortic valve replacement requiring early pacemaker implantation.

Background: Conduction abnormality requiring the implantation of a permanent pacemaker (PPM) is a well-known and clinically important complication of transcatheter aortic valve replacement (TAVR). However, PPM implantation may result in lead-associated tricuspid valve regurgitation (TR). This study sought to determine the incidence and progression of TR following PPM implantation after TAVR. Methods: This was a retrospective review of all echocardiograms of patients who underwent PPM following TAVR at the Baylor Scott & White hospitals from 2012 to 2021. The primary endpoint was TR progression at 30 days and 1 year. A subanalysis comparing the change in TR progression between small and large TAVR devices was also conducted. Secondary outcomes included all-cause death at 30 days and 1 year. Results: Out of the 2744 patients who underwent TAVR between April 2012 and August 2021, 177 patients (6.5%) subsequently received a new PPM. There was a statistically significant progression of TR at 1-year follow-up (McNemar's P value = 0.02). TR progression rates were comparable between the small and large valve groups at 1-year follow-up (4% vs 11%, P = 0.09, respectively). Conclusion: In this single healthcare system study, we demonstrated a significant progression of TR in patients with PPM post TAVR at 1 year.

Echocardiographic Outcomes With Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients.

BACKGROUND: The CLASP IID randomized trial (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial) demonstrated the safety and effectiveness of the PASCAL system for mitral transcatheter edge-to-edge repair (M-TEER) in patients at prohibitive surgical risk with significant symptomatic degenerative mitral regurgitation (DMR). OBJECTIVES: This study describes the echocardiographic methods and outcomes from the CLASP IID trial and analyzes baseline variables associated with residual mitral regurgitation (MR) ≤1+. METHODS: An independent echocardiographic core laboratory assessed echocardiographic parameters based on American Society of Echocardiography guidelines focusing on MR mechanism, severity, and feasibility of M-TEER. Factors associated with residual MR ≤1+ were identified using logistic regression. RESULTS: In 180 randomized patients, baseline echocardiographic parameters were well matched between the PASCAL (n = 117) and MitraClip (n = 63) groups, with flail leaflets present in 79.2% of patients. Baseline MR was 4+ in 76.4% and 3+ in 23.6% of patients. All patients achieved MR ≤2+ at discharge. The proportion of patients with MR ≤1+ was similar in both groups at discharge but diverged at 6 months, favoring PASCAL (83.7% vs 71.2%). Overall, patients with a smaller flail gap were significantly more likely to achieve MR ≤1+ at discharge (adjusted OR: 0.70; 95% CI: 0.50-0.99). Patients treated with PASCAL and those with a smaller flail gap were significantly more likely to sustain MR ≤1+ to 6 months (adjusted OR: 2.72 and 0.76; 95% CI: 1.08-6.89 and 0.60-0.98, respectively). CONCLUSIONS: The study used DMR-specific echocardiographic methodology for M-TEER reflecting current guidelines and advances in 3-dimensional echocardiography. Treatment with PASCAL and a smaller flail gap were significant factors in sustaining MR ≤1+ to 6 months. Results demonstrate that MR ≤1+ is an achievable benchmark for successful M-TEER. (Edwards PASCAL TrAnScatheter Valve RePair System Pivotal Clinical Trial [CLASP IID]; NCT03706833).

Regurgitant Volume to LA Volume Ratio in Patients with Secondary MR: The COAPT Trial.

AIMS: The conceptual framework of proportionate versus disproportionate mitral regurgitation (MR) translates poorly to individual patients with heart failure (HF) and secondary MR. A novel index, the ratio of MR severity to left atrial volume (LAV), may identify patients with "disproportionate" MR and a higher risk of events. The objectives, therefore, were to investigate the prognostic impact of MR severity to LAV ratio on outcomes among HF patients with severe secondary MR randomized to transcatheter edge-to-edge repair (TEER) with the MitraClipTM device plus guideline-directed medical therapy (GDMT) vs. GDMT alone in the COAPT trial. METHODS AND RESULTS: The ratio of preprocedural regurgitant volume (RVol) to LAV was calculated from baseline transthoracic echocardiograms. The primary endpoint was 2-year covariate-adjusted rate of HF hospitalization (HFH).Among 567 patients, the median RVol/LAV was 0.67 (IQR 0.48-0.91). In patients randomized to GDMT alone, lower RVol/LAV was independently associated with an increased 2-year risk of HFH (adjHR: 1.77; 95% CI: 1.20-2.63). RVol/LAV was a stronger predictor of adverse outcomes than RVol or LAV alone. Treatment with TEER plus GDMT compared with GDMT alone was associated with lower 2-year rates of HFH both in patients with low and high RVol/LAV (Pinteraction = 0.28). Baseline RVol/LAV ratio was unrelated to 2-year mortality, health status, or functional capacity in either treatment group. CONCLUSIONS: Low RVol/LAV ratio was an independent predictor of 2-year HFH in HF patients with severe MR treated with GDMT alone in the COAPT trial. TEER improved outcomes regardless of baseline RVol/LAV ratio. CLINICAL TRIAL REGISTRATION: Trial Name: Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial) (COAPT) ClinicalTrial.gov Identifier: NCT01626079 URL: https://clinicaltrials.gov/ct2/show/NCT01626079.

Transfemoral tricuspid valve replacement and one-year outcomes: the TRISCEND study.

BACKGROUND AND AIMS: For patients with symptomatic, severe tricuspid regurgitation (TR), early results of transcatheter tricuspid valve (TV) intervention studies have shown significant improvements in functional status and quality of life associated with right-heart reverse remodelling. Longer-term follow-up is needed to confirm sustained improvements in these outcomes. METHODS: The prospective, single-arm, multicentre TRISCEND study enrolled 176 patients to evaluate the safety and performance of transcatheter TV replacement in patients with ≥moderate, symptomatic TR despite medical therapy. Major adverse events, reduction in TR grade and haemodynamic outcomes by echocardiography, and clinical, functional, and quality-of-life parameters are reported to one year. RESULTS: Enrolled patients were 71.0% female, mean age 78.7 years, 88.0% ≥ severe TR, and 75.4% New York Heart Association classes III-IV. Tricuspid regurgitation was reduced to ≤mild in 97.6% (P < .001), with increases in stroke volume (10.5 ± 16.8 mL, P < .001) and cardiac output (0.6 ± 1.2 L/min, P < .001). New York Heart Association class I or II was achieved in 93.3% (P < .001), Kansas City Cardiomyopathy Questionnaire score increased by 25.7 points (P < .001), and six-minute walk distance increased by 56.2 m (P < .001). All-cause mortality was 9.1%, and 10.2% of patients were hospitalized for heart failure. CONCLUSIONS: In an elderly, highly comorbid population with ≥moderate TR, patients receiving transfemoral EVOQUE transcatheter TV replacement had sustained TR reduction, significant increases in stroke volume and cardiac output, and high survival and low hospitalization rates with improved clinical, functional, and quality-of-life outcomes to one year. Funded by Edwards Lifesciences, TRISCEND ClinicalTrials.gov number, NCT04221490.

Tricuspid Valve Academic Research Consortium Definitions for Tricuspid Regurgitation and Trial Endpoints.

Interest in the pathophysiology, etiology, management, and outcomes of patients with tricuspid regurgitation (TR) has grown in the wake of multiple natural history studies showing progressively worse outcomes associated with increasing TR severity, even after adjusting for multiple comorbidities. Historically, isolated tricuspid valve surgery has been associated with high in-hospital mortality rates, leading to the development of transcatheter treatment options. The aim of this first Tricuspid Valve Academic Research Consortium document is to standardize definitions of disease etiology and severity, as well as endpoints for trials that aim to address the gaps in our knowledge related to identification and management of patients with TR. Standardizing endpoints for trials should provide consistency and enable meaningful comparisons between clinical trials. A second Tricuspid Valve Academic Research Consortium document will focus on further defining trial endpoints and will discuss trial design options.

Tricuspid Valve Academic Research Consortium Definitions for Tricuspid Regurgitation and Trial Endpoints.

Interest in the pathophysiology, etiology, management, and outcomes of patients with tricuspid regurgitation (TR) has grown in the wake of multiple natural history studies showing progressively worse outcomes associated with increasing TR severity, even after adjusting for multiple comorbidities. Historically, isolated tricuspid valve surgery has been associated with high in-hospital mortality rates, leading to the development of transcatheter treatment options. The aim of this first Tricuspid Valve Academic Research Consortium document is to standardize definitions of disease etiology and severity, as well as endpoints for trials that aim to address the gaps in our knowledge related to identification and management of patients with TR. Standardizing endpoints for trials should provide consistency and enable meaningful comparisons between clinical trials. A second Tricuspid Valve Academic Research Consortium document will focus on further defining trial endpoints and will discuss trial design options.

Tricuspid Valve Academic Research Consortium Definitions for Tricuspid Regurgitation and Trial Endpoints.

Interest in the pathophysiology, etiology, management, and outcomes of patients with tricuspid regurgitation (TR) has grown in the wake of multiple natural history studies showing progressively worse outcomes associated with increasing TR severity, even after adjusting for multiple comorbidities. Historically, isolated tricuspid valve surgery has been associated with high in-hospital mortality rates, leading to the development of transcatheter treatment options. The aim of this first Tricuspid Valve Academic Research Consortium document is to standardize definitions of disease etiology and severity, as well as endpoints for trials that aim to address the gaps in our knowledge related to identification and management of patients with TR. Standardizing endpoints for trials should provide consistency and enable meaningful comparisons between clinical trials. A second Tricuspid Valve Academic Research Consortium document will focus on further defining trial endpoints and will discuss trial design options.

Beyond Aortic Stenosis: Addressing the Challenges of Multivalvular Disease Assessment.

Aortic stenosis (AS) can often coexist with other valvular diseases or be combined with aortic regurgitation (AR), leading to unique pathophysiological conditions. The combination of affected valves can vary widely, resulting in a lack of standardized diagnostic or therapeutic approaches. Echocardiography is crucial in assessing patients with valvular heart disease (VHD), but careful consideration of the hemodynamic interactions between combined valvular defects is necessary. This is important as it may affect the reliability of commonly used echocardiographic parameters, making the diagnosis challenging. Therefore, a multimodality imaging approach, including computed tomography or cardiac magnetic resonance, is often not just beneficial but crucial. It represents the future of diagnostics in this intricate field due to its unprecedented capacity to quantify and comprehend valvular pathology. The absence of definitive data and guidelines for the therapeutic management of AS in the context of multiple valve lesions makes this condition particularly challenging. As a result, an individualized, case-by-case approach is necessary, guided primarily by the recommendations for the predominant valve lesion. This review aims to summarize the pathophysiology of AS in the context of multiple and mixed valve disease, with a focus on the hemodynamic implications, diagnostic challenges, and therapeutic options.

Ventricular Remodeling and Outcomes After Mitral Transcatheter Edge-to-Edge Repair in Heart Failure: The COAPT Trial.

BACKGROUND: The relationship between left ventricular (LV) remodeling and clinical outcomes after treatment of severe mitral regurgitation (MR) in heart failure (HF) has not been examined. OBJECTIVES: The aim of this study was to evaluate the association between LV reverse remodeling and subsequent outcomes and assess whether transcatheter edge-to-edge repair (TEER) and residual MR are associated with LV remodeling in the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial. METHODS: Patients with HF and severe MR who remained symptomatic on guideline-directed medical therapy (GDMT) were randomized to TEER plus GDMT or GDMT alone. Baseline and 6-month core laboratory measurements of LV end-diastolic volume index and LV end-systolic volume index were examined. Change in LV volumes from baseline to 6 months and clinical outcomes from 6 months to 2 years were evaluated using multivariable regression. RESULTS: The analytical cohort comprised 348 patients (190 treated with TEER, 158 treated with GDMT alone). A decrease in LV end-diastolic volume index at 6 months was associated with reduced cardiovascular death between 6 months and 2 years (adjusted HR: 0.90 per 10 mL/m2 decrease; 95% CI: 0.81-1.00; P = 0.04), with consistent results in both treatment groups (Pinteraction = 0.26). Directionally similar but nonsignificant relationships were present for all-cause death and HF hospitalization and between reduced LV end-systolic volume index and all outcomes. Neither treatment group nor MR severity at 30 days was associated with LV remodeling at 6 or 12 months. The treatment benefits of TEER were not significant regardless of the degree of LV remodeling at 6 months. CONCLUSIONS: In patients with HF and severe MR, LV reverse remodeling at 6 months was associated with subsequently improved 2-year outcomes but was not affected by TEER or the extent of residual MR. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] and COAPT CAS [COAPT]; NCT01626079).

Guideline-Directed Medical Therapy Tolerability in Patients With Heart Failure and Mitral Regurgitation: The COAPT Trial.

BACKGROUND: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, a central committee of heart failure (HF) specialists optimized guideline-directed medical therapies (GDMT) and documented medication and goal dose intolerances before patient enrollment. OBJECTIVES: The authors sought to assess the rates, reasons, and predictors of GDMT intolerance in the COAPT trial. METHODS: Baseline use, dose, and intolerances of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs) were analyzed in patients with left ventricular ejection fraction (LVEF) ≤40%, in whom maximally tolerated doses of these agents as assessed by an independent HF specialist were required before enrollment. RESULTS: A total of 464 patients had LVEF ≤40% and complete medication information. At baseline, 38.8%, 39.4%, and 19.8% of patients tolerated 3, 2, and 1 GDMT classes, respectively (any dose); only 1.9% could not tolerate any GDMT. Beta-blockers were the most frequently tolerated GDMT (93.1%), followed by ACEIs/ARBs/ARNIs (68.5%), and then MRAs (55.0%). Intolerances differed by GDMT class, but hypotension and kidney dysfunction were most common. Goal doses were uncommonly achieved for beta-blockers (32.3%) and ACEIs/ARBs/ARNIs (10.2%) due to intolerances limiting titration. Only 2.2% of patients tolerated goal doses of all 3 GDMT classes. CONCLUSIONS: In a contemporary trial population with HF, severe mitral regurgitation, and systematic HF specialist-directed GDMT optimization, most patients had medical intolerances prohibiting 1 or more GDMT classes and achieving goal doses. The specific intolerances noted and methods used for GDMT optimization provide important lessons for the implementation of GDMT optimization in future clinical trials. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial] [COAPT]; NCT01626079).

Five-Year Follow-up after Transcatheter Repair of Secondary Mitral Regurgitation.

BACKGROUND: Data from a 5-year follow-up of outcomes after transcatheter edge-to-edge repair of severe mitral regurgitation, as compared with outcomes after maximal doses of guideline-directed medical therapy alone, in patients with heart failure are now available. METHODS: We randomly assigned patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite the use of maximal doses of guideline-directed medical therapy to undergo transcatheter edge-to-edge repair plus receive medical therapy (device group) or to receive medical therapy alone (control group) at 78 sites in the United States and Canada. The primary effectiveness end point was all hospitalizations for heart failure through 2 years of follow-up. The annualized rate of all hospitalizations for heart failure, all-cause mortality, the risk of death or hospitalization for heart failure, and safety, among other outcomes, were assessed through 5 years. RESULTS: Of the 614 patients enrolled in the trial, 302 were assigned to the device group and 312 to the control group. The annualized rate of hospitalization for heart failure through 5 years was 33.1% per year in the device group and 57.2% per year in the control group (hazard ratio, 0.53; 95% confidence interval [CI], 0.41 to 0.68). All-cause mortality through 5 years was 57.3% in the device group and 67.2% in the control group (hazard ratio, 0.72; 95% CI, 0.58 to 0.89). Death or hospitalization for heart failure within 5 years occurred in 73.6% of the patients in the device group and in 91.5% of those in the control group (hazard ratio, 0.53; 95% CI, 0.44 to 0.64). Device-specific safety events within 5 years occurred in 4 of 293 treated patients (1.4%), with all the events occurring within 30 days after the procedure. CONCLUSIONS: Among patients with heart failure and moderate-to-severe or severe secondary mitral regurgitation who remained symptomatic despite guideline-directed medical therapy, transcatheter edge-to-edge repair of the mitral valve was safe and led to a lower rate of hospitalization for heart failure and lower all-cause mortality through 5 years of follow-up than medical therapy alone. (Funded by Abbott; COAPT ClinicalTrials.gov number, NCT01626079.).