Percutaneous mitral repair as treatment in HFrEF (MitraClip/TEER) Treatment

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Nehal Eid, M.D.[2]

Treatment

This microchapter addresses treatment of ventricular secondary mitral regurgitation (SMR) in heart failure with reduced ejection fraction (HFrEF), focusing on guideline-directed medical therapy (GDMT) before and after mitral transcatheter edge-to-edge repair (M-TEER), antithrombotic therapy, and comparison with surgery. Atrial functional MR has a different therapeutic pathway in which rhythm control may substantially reduce MR and is not covered here.

Medical therapy before M-TEER

The 2020 ACC/AHA Valvular Heart Disease Guideline gives a Class I, level A recommendation that patients with chronic severe SMR, reduced LVEF, and stage C or D disease receive standard HF GDMT. It separately gives a Class I, level C-EO recommendation that a cardiologist with expertise in HF and LV systolic dysfunction serve as the primary multidisciplinary-team member responsible for implementing and monitoring optimal GDMT.

Symptoms should not be considered refractory, and surgical or transcatheter intervention should not be selected, until guideline-recommended HF therapy has been fully optimized by the multidisciplinary team. Appropriate coronary revascularization and cardiac resynchronization therapy (CRT) should also be completed when indicated because reverse remodeling may reduce SMR severity.

Foundational HFrEF therapy

Contemporary four-pillar therapy consists of:

• An angiotensin receptor-neprilysin inhibitor (ARNI), or an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker when ARNI cannot be used
• An evidence-based beta blocker
• A mineralocorticoid receptor antagonist
• A sodium-glucose cotransporter-2 inhibitor

Diuretics should be used to control congestion. Modeling of the cumulative evidence for the four foundational drug classes estimates an approximately 73% relative reduction in all-cause mortality compared with no therapy; this is an indirect cross-trial estimate rather than a randomized comparison of all four drugs against no treatment.

GDMT sequencing need not follow the historical order in which trials were published. Rapid, parallel initiation of the four classes, as clinically tolerated, avoids unnecessary delay and permits earlier identification of SMR that remains clinically important despite contemporary therapy.

Effect of GDMT on MR severity

Approximately 40%–45% of patients with ventricular SMR experience clinically important improvement in MR severity after appropriately titrated medical therapy.

In the PRIME trial (n=118), the change in effective regurgitant orifice area was −0.058±0.095 cm² with sacubitril/valsartan and −0.018±0.105 cm² with valsartan (P=0.032). Regurgitant volume was also lower with sacubitril/valsartan, with a between-group mean difference of −7.3 mL (95% CI −12.6 to −1.9; P=0.009).

There were no significant between-group differences in incomplete mitral-leaflet closure area or LV volumes, except for LV end-diastolic volume index (P=0.044), and blood-pressure changes did not differ. The observed MR reduction therefore was not accompanied by consistent evidence of reverse remodeling.

A review-reported estimate suggests that sacubitril/valsartan initiation reduced potential eligibility for mitral repair by 44%; the primary study provenance for this estimate was not provided in the supplied evidence.

COAPT and MITRA-FR were initiated before full contemporary incorporation of ARNI and SGLT2-inhibitor therapy. Trial-era “optimal medical therapy” therefore should not automatically be regarded as equivalent to current four-pillar GDMT.

Barriers and real-world implementation

Low systolic blood pressure, renal dysfunction, hyperkalemia or other electrolyte abnormalities, and medication adverse effects frequently limit target dosing. In a COAPT post hoc analysis, only 2.2% of patients tolerated target doses of all three trial-era GDMT classes; hypotension and kidney dysfunction were the most frequent limiting factors. “Optimized” GDMT should therefore mean maximally tolerated evidence-based therapy with documented reasons for nonuse or subtarget dosing, rather than mandatory achievement of every target dose.

GDMT completeness before M-TEER is a prognostic variable rather than an administrative prerequisite. In the STS/ACC Transcatheter Valve Therapy Registry of 4,199 patients, only 19.2% received triple therapy with an ACE inhibitor/ARB/ARNI, beta blocker, and mineralocorticoid receptor antagonist. Triple therapy was associated with an approximately 27% lower adjusted risk of death or HF hospitalization at 1 year compared with treatment with no drug class or one drug class; this observational association does not establish causality.

MR severity should be reassessed after GDMT, decongestion, revascularization, and indicated CRT. Persistent symptoms and clinically important SMR should then be reviewed by the multidisciplinary Heart Team; detailed anatomic eligibility belongs to the patient-selection and echocardiography microchapters.

Antithrombotic therapy

Antithrombotic therapy after M-TEER is based predominantly on trial protocols, observational evidence, and expert consensus. No completed randomized trial has established one universally preferred regimen.

COAPT periprocedural protocol

In COAPT:

• At operator discretion, clopidogrel ≥300 mg or aspirin 325 mg was recommended within 24 hours before the procedure.
• Intravenous unfractionated heparin was administered after transseptal crossing to maintain an activated clotting time greater than 250 seconds.
• In patients without an indication for oral anticoagulation, clopidogrel 75 mg daily and/or aspirin 81 mg daily was required for at least 6 months after clip implantation.

Post-procedural strategy

Practical antithrombotic strategies after M-TEER

Clinical setting	Suggested strategy	Evidence limitation
No independent indication for long-term oral anticoagulation	Aspirin plus clopidogrel for approximately 1–6 months, with a shorter duration favored when bleeding risk is high, followed by aspirin monotherapy.	Expert-consensus strategy; the optimal combination and duration have not been established in a randomized trial.
Established indication for long-term oral anticoagulation, such as atrial fibrillation	Continuing long-term oral anticoagulation alone may be reasonable. Antiplatelet therapy should not be added routinely unless another indication exists.	Based on consensus and extrapolation; the preferred anticoagulant and need for temporary combination therapy remain uncertain.

Interruption and resumption of chronic anticoagulation should be individualized according to renal function, bleeding and thromboembolic risk, vascular-access management, and the original indication for anticoagulation.

Investigational strategies

STAR-TEER is an ongoing randomized program evaluating post-M-TEER antithrombotic strategies in patients with and without an established indication for oral anticoagulation. The registered studies are NCT06901466 and NCT07007143 and use hierarchical testing, first for superiority regarding bleeding and then for noninferiority regarding ischemic events. Until results are available, the tested strategies should not be presented as established standards.

Medical therapy after M-TEER

M-TEER does not replace chronic HF therapy. Successful MR reduction may improve forward stroke volume, blood pressure, and renal perfusion, creating an opportunity to initiate missing GDMT classes or titrate existing therapy.

In the EuroSMR analysis:

• Only 12.4%, 21.8%, and 18.5% of patients received at least 50% of target doses of ACE inhibitor/ARB/ARNI, beta blocker, and mineralocorticoid receptor antagonist, respectively, at baseline.
• GDMT was uptitrated in 38% of patients during the first 6 months after M-TEER.
• MR reduction by at least three grades was the only independent predictor of subsequent GDMT uptitration.
• Uptitration was associated with an approximately 40% lower adjusted risk of death and an approximately 50% lower adjusted risk of death or HF hospitalization at 3 years.

These findings are observational and do not demonstrate that uptitration caused the improved outcomes.

Structured post-procedural titration

Phase	Recommended actions
Before discharge or early follow-up	Reconcile HF medications and document reasons for omitted classes. Assess symptoms, congestion, heart rate, blood pressure, renal function, and serum electrolytes.
Active initiation and uptitration	Reassess as frequently as every 1–2 weeks according to symptoms, vital signs, renal function, electrolytes, and adverse effects. Initiate missing pillars and titrate toward trial-proven target or maximally tolerated doses.
Adverse effects during titration	Delay the planned dose increase until adverse effects at the lower dose have resolved. A failed initial attempt does not establish permanent intolerance; repeated attempts may succeed after clinical stabilization.
Long-term follow-up	Continue periodic assessment of adherence, symptoms, volume status, renal function, electrolytes, cardiac-device therapy, and residual or recurrent MR.

Titration to trial-proven target doses carries a Class I, level A recommendation. Reassessment and titration as frequently as every 1–2 weeks can be useful and carries a Class IIa, level C-EO recommendation.

Interdisciplinary HF-clinic and pharmacist-supported pathways should be considered. Across a heterogeneous systematic review of 28 randomized trials, interdisciplinary interventions improved GDMT utilization by approximately 5–8 percentage points and improved achievement of target beta-blocker and renin-angiotensin-system inhibitor doses by approximately 30–38 percentage points. A formal meta-analysis was not performed because of between-study heterogeneity.

M-TEER compared with surgery

Guideline recommendations for surgery in ventricular SMR are deliberately conservative because surgery may improve symptoms and quality of life but has not demonstrated a survival benefit in this population.

Contemporary transatlantic guideline comparison

Clinical setting	ACC/AHA	ESC/EACTS
GDMT and management by a collaborative Heart Team before intervention	Class I, level C-EO for multidisciplinary optimization and monitoring. This is distinct from the Class I, level A recommendation for standard HF pharmacotherapy.	Class I, level B.
Severe SMR during CABG or another cardiac operation	Mitral surgery during CABG is reasonable: Class IIa, level B-NR.	Mitral surgery during CABG or other cardiac surgery is recommended: Class I, level B in the 2021 VHD guideline comparison.
Isolated surgery for chronic severe ventricular SMR caused by LV systolic dysfunction, LVEF <50%, and persistent NYHA class III–IV symptoms despite optimal GDMT	Surgery may be considered: Class IIb, level B-NR.	Surgery may be considered when the patient is judged appropriate for surgery: Class IIb, level C.
M-TEER for persistent symptomatic severe SMR with features suggesting a favorable response	M-TEER is reasonable with suitable anatomy and COAPT-like criteria, including LVEF 20%–50%, LVESD ≤70 mm, and SPAP ≤70 mm Hg: Class IIa, level B-R. Surgical ineligibility is not required by the recommendation.	M-TEER should be considered only when the patient is not eligible or appropriate for surgery and meets criteria suggesting an increased probability of response: Class IIa, level B.
M-TEER or another transcatheter therapy in a high-risk symptomatic patient who is not eligible for surgery and does not meet criteria suggesting an increased probability of response	No corresponding recommendation; American guidance instead uses explicitly graded selection and futility criteria.	May be considered only after careful evaluation for left ventricular assist device or heart transplantation: Class IIb, level C.

Two structural differences are particularly important:

• European guidance positions M-TEER only in patients who are not eligible or appropriate for mitral surgery, whereas the American recommendation is based on COAPT-like physiology and suitable anatomy without requiring surgical ineligibility.
• American guidance defines and grades procedural-risk and futility thresholds more explicitly. European guidance instead provides an ungraded set of considerations including LVEF, myocardial viability, coronary anatomy and revascularization targets, the required concomitant procedure, TEER eligibility, probability of durable surgical repair, potential need for replacement, local expertise, and expected clinical improvement. In the European framework, intervention is generally regarded as futile when LVEF is below 15%.

An additional severity-threshold difference may affect referral. The ACC/AHA/HFSA framework requires severe MR before M-TEER consideration, exemplified by EROA ≥40 mm², whereas European supporting text permits at least moderate-to-severe MR, exemplified by EROA ≥30 mm².

Guideline-comparison documents also grade European concomitant surgery differently depending on their source guideline. The VHD comparison reports Class I, level B, whereas the HF-guideline comparison tabulates Class IIa. This difference should be reported rather than harmonized.

2017 ESC/EACTS LVEF-stratified framework

The following recommendations reflect the 2017 ESC/EACTS framework and its level C evidence designations; they should not be blended with the updated levels reported in the 2021 guideline comparison:

• Surgery was indicated for severe SMR during CABG when LVEF was >30%: Class I, level C.
• Surgery was to be considered in symptomatic severe SMR with LVEF <30% when coronary revascularization was planned and myocardial viability was present: Class IIa, level C.
• Without an indication for revascularization, surgery could be considered when LVEF was >30%, symptoms persisted despite maximal medical therapy and indicated CRT, and predicted surgical risk was low: Class IIb, level C.
• Without an indication for revascularization and when surgical risk was not low, percutaneous edge-to-edge repair could be considered when LVEF was >30%, valve morphology was suitable, and the Heart Team judged meaningful clinical improvement likely: Class IIb, level C.
• With LVEF <30% and no revascularization option, surgery or percutaneous edge-to-edge repair could be considered only after careful evaluation for LVAD or transplantation and according to individual patient characteristics: Class IIb, level C.

Moderate SMR during CABG

Moderate and severe SMR should not be treated as equivalent surgical indications. In multivessel coronary disease with moderate SMR, repair using a downsized annuloplasty ring may be considered during CABG, but its clinical benefit remains uncertain. This is materially weaker than recommendations for concomitant treatment of severe SMR.

Choice of surgical procedure

In patients with coronary artery disease, chronic severe SMR caused by LV systolic dysfunction (LVEF <50%), and severe persistent NYHA class III–IV symptoms despite optimal GDMT, chordal-sparing mitral valve replacement may be reasonable in preference to downsized annuloplasty repair: ACC/AHA Class IIb, level B-R. Randomized evidence showed more recurrent moderate or severe MR, HF events, and cardiovascular readmissions after repair. The final procedure should be selected by an experienced surgeon with the multidisciplinary team.

The ESC/EACTS guidelines express no general preference between repair and replacement. Repair may restore valve competence, improve symptoms, and support reverse remodeling, whereas replacement more reliably prevents recurrent MR.

Atrial secondary MR

Although atrial SMR is outside this microchapter’s main scope, the American guideline permits mitral surgery in selected patients with atrial annular dilatation, preserved LV systolic function, and persistent severe symptoms despite HF and atrial-fibrillation therapy: Class IIb, level B-NR. This recommendation has no direct European counterpart in the supplied comparison.

MATTERHORN trial

MATTERHORN randomized 210 patients with secondary MR after a Heart Team determined that both M-TEER and surgery were technically feasible. Mean age was 70.5±7.9 years and mean LVEF was 43.0±11.7%; the study should not be characterized as a prohibitive-surgical-risk trial.

At 1 year:

• The composite of death, HF hospitalization, mitral reintervention, assist-device implantation, or stroke occurred in 16.7% of the M-TEER group and 22.5% of the surgery group, an absolute difference of −6 percentage points (95% CI −17 to 6), meeting the prespecified noninferiority criterion.
• Major adverse events at 30 days occurred in 14.9% after M-TEER and 54.8% after surgery. The difference was driven primarily by less major bleeding and less new-onset atrial fibrillation with M-TEER, and the safety advantage persisted through 1 year.
• Surgery provided effective MR correction: 98.6% of surgical patients had MR grade ≤2+ at 1 year.

MATTERHORN supports M-TEER as a noninferior, less invasive alternative in appropriately selected patients for whom both approaches are feasible, while also demonstrating effective 1-year MR control with surgery. Its findings should not be extrapolated to primary MR, patients requiring concomitant cardiac surgery, or populations not represented in the trial.

The final choice should integrate surgical eligibility, COAPT-like physiology, TEER anatomy, the need for CABG or another cardiac operation, expected repair durability, the potential need for chordal-sparing replacement, procedural risk, frailty, and patient preference. Patients with advanced HF and potential procedural futility require advanced-HF evaluation; detailed futility criteria belong to the patient-selection microchapter.