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

NCT07758023 | Not Yet Recruiting DMC

• 1 other identifier: 2026-18715
• Study Type: interventional
• Target: 520
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of the ACHILLES-HF trial (ACHIeving optimaL medicaL therapy through pErcutaneous treatment of Secondary mitral regurgitation to improve outcome in Patients with Heart Failure with reduced ejection fraction) is to test whether early transcatheter edge-to-edge repair (TEER) in patients with heart failure and reduced ejection fraction (HFrEF) and relevant secondary mitral regurgitation, that are at risk of not receiving full guideline recommended therapy (GDMT), results in faster and more complete GDMT up-titration and whether this translates into improved quality of life and clinical outcomes.

Conditions

Mitral Regurgitation Functional; Heart Failure With Reduced Ejection Fraction (HFrEF)

Keywords

Mitral regurgitation; HFrEF; M-TEER; Guideline directed medical therapy

Outcome Measures

Primary Outcomes (3)

• Difference in Guideline-Directed Medical Therapy (GDMT) Score at 12 Weeks

  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.

  Baseline and 12 weeks post-randomization (post-procedure for Intervention group)

• Difference in Quality of Life (KCCQ Score) at 12 Weeks

  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.

  Baseline and 12 weeks post-randomization (post-procedure for Intervention group), among surviving patients

• Composite of Cardiovascular Death or First Heart Failure Hospitalization at 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.

  From randomization to 24 months

Secondary Outcomes (7)

• 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)

• Total Heart Failure Hospitalizations Through 24 Months

  From randomization to 24 months

• Mitral Regurgitation Severity at 24 Months

  24 months

• NYHA Functional Class Improvement at 12 Months

  Baseline and 12 months

• Change in Left Ventricular End-Diastolic Volume (LVEDV) from Baseline to 12 Months

  Baseline and 12 months

Other Outcomes (5)

• 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

Study Arms (2)

Intervention group

EXPERIMENTAL

Subjects randomized to this arm undergo transcatheter edge-to-edge repair (M-TEER) of the mitral valve within 7 days of randomization, in addition to a standardized, protocol-driven guideline-directed medical therapy (GDMT) up-titration regimen. Starting on the first post-procedural day, subjects are up-titrated toward optimal target doses of a beta-blocker, ACE inhibitor/ARB/ARNI, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor, guided by protocol-defined thresholds for blood pressure, heart rate, potassium, and renal function, with formal safety/tolerability reassessment at 2, 4, 6, 8, 10, and 12 weeks.

Device: M-TEER; Other: Standardized GDMT Up-Titration

Control group

ACTIVE COMPARATOR

Subjects randomized to this arm receive the identical standardized, protocol-driven GDMT up-titration regimen as the Intervention group, without early M-TEER. Up-titration toward optimal target doses of a beta-blocker, ACE inhibitor/ARB/ARNI, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor begins at randomization and follows the same protocol-defined safety thresholds and visit schedule (2, 4, 6, 8, 10, and 12 weeks) as the Intervention group. Subjects may cross over to M-TEER or mitral valve surgery after completion of the 12-week follow-up visit, or earlier in the case of an intervening heart failure hospitalization.

Other: Standardized GDMT Up-Titration

Interventions

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.

Intervention group

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.

Control group; Intervention group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%)
• 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%)
• Suboptimal GDMT therapy corresponding to a GDMT score \<7 points
• Risk factor for not intensification of guideline directed medical therapy (at least one of the following):
• Office systolic blood pressure \<120 mmHG
• Chronic renal failure with eGFR \<60 ml/min/1.73m
• History of acute kidney injury (AKI) at least stage 2 within the last 12 months
• Serum Potassium ≥ 4.8 mmol/L
• Persisting symptoms equalling NYHA functional class II-IVa (ambulatory)
• Patient has had at least one HF hospitalization within 12 months and/or a NT-proBNP ≥1000 pg/ml
• Interventional cardiologist believes secondary MR can be successfully treated by an interventional approach
• 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

You may not qualify if:

• Terminal heart failure or hemodynamic instability
• Primary TR or MR, any other severe valvular heart disease
• Untreated clinically significant CAD (coronary artery disease) requiring revascularization
• LVEF \<35% and left bundle branch block with a QRS duration \>150 ms
• Renal failure requiring dialysis
• Mitral valve orifice area \<4.0 cm² by site assessed TTE
• Life expectancy \<12 months due to non-cardiac conditions
• KCCQ score \> 80 points
• Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease (i.e., noncompliant, perforated)
• Active infections requiring current antibiotic therapy.
• Known hypersensitivity or contraindication to procedural device which cannot be adequately managed medically.
• Patient is pregnant, nursing, or planning to be pregnant
• Concurrent medical condition with a life expectancy of less than 12 months in the judgment of the investigator.
• 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.
• Ineligibility to consent

Sponsors & Collaborators

• University Medical Center Mainz: lead
• Abbott: collaborator

Related Publications (5)

• Anker SD, Friede T, von Bardeleben RS, Butler J, Khan MS, Diek M, Heinrich J, Geyer M, Placzek M, Ferrari R, Abraham WT, Alfieri O, Auricchio A, Bayes-Genis A, Cleland JGF, Filippatos G, Gustafsson F, Haverkamp W, Kelm M, Kuck KH, Landmesser U, Maggioni AP, Metra M, Ninios V, Petrie MC, Rassaf T, Ruschitzka F, Schafer U, Schulze PC, Spargias K, Vahanian A, Zamorano JL, Zeiher A, Karakas M, Koehler F, Lainscak M, Oner A, Mezilis N, Theofilogiannakos EK, Ninios I, Chrissoheris M, Kourkoveli P, Papadopoulos K, Smolka G, Wojakowski W, Reczuch K, Pinto FJ, Wiewiorka L, Kalarus Z, Adamo M, Santiago-Vacas E, Ruf TF, Gross M, Tongers J, Hasenfuss G, Schillinger W, Ponikowski P; RESHAPE-HF2 Investigators. Transcatheter Valve Repair in Heart Failure with Moderate to Severe Mitral Regurgitation. N Engl J Med. 2024 Nov 14;391(19):1799-1809. doi: 10.1056/NEJMoa2314328. Epub 2024 Aug 31.

  PMID: 39216092 BACKGROUND

• Stone GW, Lindenfeld J, Abraham WT, Kar S, Lim DS, Mishell JM, Whisenant B, Grayburn PA, Rinaldi M, Kapadia SR, Rajagopal V, Sarembock IJ, Brieke A, Marx SO, Cohen DJ, Weissman NJ, Mack MJ; COAPT Investigators. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. 2018 Dec 13;379(24):2307-2318. doi: 10.1056/NEJMoa1806640. Epub 2018 Sep 23.

  PMID: 30280640 BACKGROUND

• Packer M, Metra M. Guideline-directed medical therapy for heart failure does not exist: a non-judgmental framework for describing the level of adherence to evidence-based drug treatments for patients with a reduced ejection fraction. Eur J Heart Fail. 2020 Oct;22(10):1759-1767. doi: 10.1002/ejhf.1857. Epub 2020 May 20.

  PMID: 32432391 BACKGROUND

• Adamo M, Tomasoni D, Stolz L, Stocker TJ, Pancaldi E, Koell B, Karam N, Besler C, Giannini C, Sampaio F, Praz F, Ruf T, Pechmajou L, Neuss M, Iliadis C, Baldus S, Butter C, Kalbacher D, Lurz P, Melica B, Petronio AS, von Bardeleben RS, Windecker S, Butler J, Fonarow GC, Hausleiter J, Metra M. Impact of Transcatheter Edge-to-Edge Mitral Valve Repair on Guideline-Directed Medical Therapy Uptitration. JACC Cardiovasc Interv. 2023 Apr 24;16(8):896-905. doi: 10.1016/j.jcin.2023.01.362. Epub 2023 Mar 22.

  PMID: 37100553 BACKGROUND

• Kresoja KP, Adamo M, Rommel KP, Stolz L, Karam N, Giannini C, Melica B, von Bardeleben RS, Butter C, Horn P, Praz F, Kalbacher D, Iliadis C, Thiele H, Hausleiter J, Metra M, Lurz P. Guideline-directed medical therapy assessment in heart failure patients undergoing percutaneous mitral valve repair. ESC Heart Fail. 2024 Jun;11(3):1802-1807. doi: 10.1002/ehf2.14705. Epub 2024 Feb 13.

  PMID: 38351672 BACKGROUND

MeSH Terms

Conditions

Mitral Valve Insufficiency

Condition Hierarchy (Ancestors)

Heart Valve Diseases; Heart Diseases; Cardiovascular Diseases

Study Officials

• Philipp Lurz, Prof

  Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Karl-Patrik Kresoja, MD

CONTACT

+49 6131 178163; Achilles-HF@unimedizin-mainz.de

Vera Jakobi

CONTACT

+49 6131 175082; Studienzentrum-ZfK@unimedizin-mainz.de

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine, Director of the Department of Cardiology

Study Record Dates

• First Submitted: July 30, 2026
• First Posted: August 11, 2026
• Study Start: August 10, 2026
• Primary Completion (Estimated): September 30, 2030
• Study Completion (Estimated): September 30, 2030
• Last Updated: August 11, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Individual participant data and supporting documents (protocol, statistical analysis plan, informed consent form) will be available beginning 9 months after publication of the primary trial results and ending 36 months after publication.
• Access Criteria: Requests will be considered from researchers who provide a methodologically sound research proposal, beginning after publication of the primary trial results and continuing for a defined period thereafter. Access requires review and approval by the ACHILLES-HF Publication Committee and execution of a data use agreement. Data will be shared in a de-identified format consistent with EU data protection requirements (GDPR) and the informed consent provided by trial participants.