Achieving Optimal Medical Therapy Through Percutaneous Treatment of Secondary Mitral Regurgitation to Improve Outcome in Patients With HFrEF

• M-TEER (Device): Transcatheter edge-to-edge repair (M-TEER) of the mitral valve, performed once, within 7 days of randomization, in subjects randomized to the Intervention arm.
• Standardized GDMT Up-Titration (Other): A protocol-driven regimen applied to all randomized subjects, beginning at randomization (Control arm) or on the first post-procedural day (Intervention arm). Subjects are started on a beta-blocker, ACE inhibitor/ARB/ARNI, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor, targeting at least half of each drug's optimal dose immediately (full dose for the SGLT2 inhibitor), with same-day achievement recommended if hemodynamically stable. Formal reassessment occurs at 2, 4, 6, 8, 10, and 12 weeks, with up-titration to full optimal doses of beta-blocker, ACEi/ARB/ARNI, and MRA targeted by week 6, contingent on tolerability. Medications are not up-titrated if systolic blood pressure is <95 mmHg, potassium is >5.0 mmol/L, eGFR is <30 mL/min/1.73m², or heart rate is <55 bpm (beta-blocker only); diuretic dose reduction is encouraged if eGFR is <30 mL/min/1.73m². Safety and tolerability are formally reassessed at weeks 2, 4, 6, 10, and 12.

Primary outcomes

• Difference in Guideline-Directed Medical Therapy (GDMT) Score at 12 Weeks [Baseline and 12 weeks post-randomization (post-procedure for Intervention group)]: Between-group difference in GDMT intensity score, a 0-12 point composite scoring dosing of ACE inhibitor/ARB/ARNI, beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor relative to trial-defined target doses (0-\[2\]3 points per drug class). Analyzed via a mixed model for repeated measures (fixed effects for site, age group, sex, NYHA class, treatment, visit, and treatment-by-visit interaction; baseline score as covariate; first-order autoregressive covariance structure). Higher scores indicate more complete guideline-directed therapy.
• Difference in Quality of Life (KCCQ Score) at 12 Weeks [Baseline and 12 weeks post-randomization (post-procedure for Intervention group), among surviving patients]: Between-group difference in quality of life among surviving patients, assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score (range 0-100, higher scores indicate better health status), from baseline to 12 weeks. Analyzed via two-sample t-test.
• Composite of Cardiovascular Death or First Heart Failure Hospitalization at 24 Months [From randomization to 24 months]: Time to the first occurrence of cardiovascular death or heart failure hospitalization within 24 months of randomization, centrally adjudicated by an independent Clinical Events Committee blinded to treatment allocation.

Secondary outcomes

• Win Ratio for Cardiovascular Mortality, First Heart Failure Hospitalization, KCCQ Improvement, or GDMT Score Improvement at 24 Months [From randomization to 24 months (GDMT and KCCQ improvement assessed at 12 weeks)]: Hierarchical composite of cardiovascular death, first heart failure hospitalization, a Kansas City Cardiomyopathy Questionnaire (KCCQ) improvement of more than 5 points, and a GDMT score improvement of more than 2 points, ranked in that order and compared between groups using the Finkelstein-Schoenfeld win ratio method. Win ratio and 95% confidence interval reported.
• Total Heart Failure Hospitalizations Through 24 Months [From randomization to 24 months]: Total number of first and recurrent heart failure hospitalizations through 24 months, with cardiovascular death analyzed as a terminal heart failure hospitalization event. Analyzed using the Lin-Wei-Yang-Ying (LWYY) model for recurrent events; treatment effect reported as a rate ratio with 95% confidence interval.
• Mitral Regurgitation Severity at 24 Months [24 months]: Proportion of subjects with residual mitral regurgitation severity of grade 2+ or less at 24 months. Analyzed by logistic regression adjusted for baseline MR grade and etiology; odds ratio and 95% confidence interval reported.
• NYHA Functional Class Improvement at 12 Months [Baseline and 12 months]: Proportion of subjects with an improvement of at least one NYHA functional class from baseline to 12 months. Analyzed using Fisher's exact test; between-group difference in proportions reported with 95% confidence interval.
• Change in Left Ventricular End-Diastolic Volume (LVEDV) from Baseline to 12 Months [Baseline and 12 months]: Change in left ventricular end-diastolic volume, assessed by echocardiography, from baseline to 12 months, reflecting reverse left ventricular remodeling. Analyzed using a two-sample t-test; mean between-group difference reported with 95% confidence interval.
• All-Cause Mortality Within 24 Months [From randomization to 24 months]: All-cause mortality within 24 months of randomization. Analyzed using a Cox proportional hazards model stratified by country and heart failure etiology; hazard ratio and 95% confidence interval reported with Kaplan-Meier estimates.
• Need for Mitral Valve Re-Intervention [From randomization to 24 months]: Occurrence of mitral valve re-intervention, surgical or transcatheter, during follow-up. Analyzed using Fisher's exact test; proportion and 95% confidence interval reported for each group, along with the between-group difference.

Other outcomes

• Composite 30-Day Safety Endpoint (Device-Related MACE) [30 days post-procedure (Intervention group)]
• All-Cause Mortality at 30 Days [30 days]
• All-Cause Mortality Through End of Follow-Up [From randomization through 24 months]
• Freedom from GDMT Up-Titration Complications at 24 Months [From randomization to 24 months]
• Major Adverse Events (MAE) at 24 Months [From randomization to 24 months]: Composite of stroke, myocardial infarction, new need for renal-replacement therapy, non-elective cardiovascular surgery for device-related complications, new-onset atrial fibrillation, endocarditis, gastrointestinal complication requiring surgery, TIMI-defined major bleeding, and cardiac tamponade. Reported descriptively by treatment group as event rates.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%)
2. Clinically significant functional mitral regurgitation (moderate-to severe or severe MR) as defined by European Association of Echocardiography, within 90 days prior to randomization (i.e. EROA ≥0.2 cm² and/or regurgitant fraction >30%)
3. Suboptimal GDMT therapy corresponding to a GDMT score <7 points
4. Risk factor for not intensification of guideline directed medical therapy (at least one of the following):

   1. Office systolic blood pressure <120 mmHG
   2. Chronic renal failure with eGFR <60 ml/min/1.73m
   3. History of acute kidney injury (AKI) at least stage 2 within the last 12 months
   4. Serum Potassium ≥ 4.8 mmol/L
5. Persisting symptoms equalling NYHA functional class II-IVa (ambulatory)
6. Patient has had at least one HF hospitalization within 12 months and/or a NT-proBNP ≥1000 pg/ml
7. Interventional cardiologist believes secondary MR can be successfully treated by an interventional approach
8. The subject has been informed of the nature of the study and agrees to the study's provisions, including the possibility of randomization to the Control group, and has provided written informed consent as approved by the respective clinical site's Ethics Committee

Exclusion Criteria:

1. Terminal heart failure or hemodynamic instability
2. Primary TR or MR, any other severe valvular heart disease
3. Untreated clinically significant CAD (coronary artery disease) requiring revascularization
4. LVEF <35% and left bundle branch block with a QRS duration >150 ms
5. Renal failure requiring dialysis
6. Mitral valve orifice area <4.0 cm² by site assessed TTE
7. Life expectancy <12 months due to non-cardiac conditions
8. KCCQ score > 80 points
9. Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease (i.e., noncompliant, perforated)
10. Active infections requiring current antibiotic therapy.
11. Known hypersensitivity or contraindication to procedural device which cannot be adequately managed medically.
12. Patient is pregnant, nursing, or planning to be pregnant
13. Concurrent medical condition with a life expectancy of less than 12 months in the judgment of the investigator.
14. Currently participating in another investigational therapeutic or interventional clinical trial, or in any trial of an unapproved drug, device or procedure. Note: Subjects participating in observational studies or registries may be considered as eligible.
15. Ineligibility to consent

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• Philipp Lurz, Prof, Principal investigator, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz