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.
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
Office systolic blood pressure <120 mmHG
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
Parallel
M-TEER
DeviceTranscatheter 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 interventionA 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.
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.
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.
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.
Win Ratio for Cardiovascular Mortality, First Heart Failure Hospitalization, KCCQ Improvement, or GDMT Score Improvement at 24 Months
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
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
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
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.
Composite 30-Day Safety Endpoint (Device-Related MACE)
All-Cause Mortality at 30 Days
All-Cause Mortality Through End of Follow-Up
Freedom from GDMT Up-Titration Complications at 24 Months
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University Medical Center Mainz
Lead sponsor
Abbott
Collaborator
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