++
Treatment of IMR depends on symptoms, the severity of regurgitation, the degree of LV systolic dysfunction, and its potential improvement with medical and surgical interventions. Therapy consists of an appropriate combination of lifestyle, medical, device, percutaneous, and/or surgical interventions. The pathophysiological differences between primary MR and secondary IMR dictate distinct and separate treatment recommendations for these disease processes. Management decisions for more complex patients with IMR should involve a multidisciplinary “heart” team that includes, but is not restricted to, interventional cardiologists, cardiac surgeons, anesthetists, imaging specialists, and heart failure specialists.26 Established surgical risk scores (eg, Society for Thoracic Surgeons [STS] score, EuroSCORE) should be used as adjuncts to clinical assessment for better risk stratification of patients and to inform management decisions.27
++
Patients with IMR and HF with reduced LVEF should receive standard guideline directed medical therapy for HF, including angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibition (ARNI) as indicated, beta-blockers, aldosterone antagonists, and diuretics.14 Patients with IMR and HF with preserved ejection fraction may enjoy symptom relief from a trial of loop diuretic therapy. All patients should be educated regarding lifestyle modifications including sodium restriction, fluid restriction, smoking cessation, and regular aerobic exercise as for any patient with HF. Appropriate secondary prevention with moderate or high-intensity statins and antithrombotic therapy should be emphasized. Anticoagulation is indicated for patients who develop AF.
++
Left ventricular dyssynchrony resulting from left bundle branch block (LBBB) or right ventricular (RV) pacing can contribute to the development of secondary MR.28,29 Cardiac resynchronization therapy (CRT) significantly reduced severity of secondary MR in a small study of 24 patients with HF and LBBB.30 In another study of 98 patients with moderate-to-severe secondary MR who underwent CRT, 49% demonstrated an improvement of ≥ 1 grade in MR at 6 months post-device implantation compared to baseline, and this improvement was associated with improved survival.31 Similarly, Di Biase et al. demonstrated an improvement of ≥ 1 grade in MR after 12 months of CRT in 46% of 275 patients with moderate-to-severe or severe secondary MR at baseline.32 This study also demonstrated that MR improvement after 3 months of CRT predicts subsequent MR improvement at 12 months, and so 3 months has been proposed as a waiting period beyond which MR reduction in response to CRT is unlikely and other treatment options should be considered.33 CRT-mediated improvement in IMR is associated with LV reverse remodeling34 while associated changes in LV contraction and MV apparatus geometry can reduce mitral leaflet tethering.7 Thus, CRT is recommended for symptomatic patients with chronic severe IMR with guideline indications for device therapy, including HF with QRS duration > 150 ms.14 In addition, many patients with IMR will often have a coexisting or independent indication for implantable cardioverter defibrillator (ICD) therapy given the associated LV systolic impairment and history of MI.
++
Significant improvements in surgical techniques and outcomes over recent decades, as reported by high volume-major referral centers of excellence, have lowered the threshold for operative intervention in patients with valvular heart disease. Surgical outcomes depend on the experience of the center and surgeon, and these factors should be considered in decision making. There is general agreement that IMR that is less than moderate in severity does not require surgical intervention. Surgical decisions require consideration of operative morbidity and mortality, type of operation (repair vs replacement), durability of MR reduction, and downstream clinical end points, including functional capacity, HF hospitalizations, and survival. To date, studies have failed to show a survival benefit with surgery for IMR, and thus conservative recommendations have been adopted. Surgical intervention for moderate or severe IMR is discussed below.
+++
Surgery for Moderate IMR
++
Although moderate IMR is common among patients referred for surgical coronary revascularization, the role of MV repair during CABG in these patients remains uncertain. Revascularization alone may result in sufficient LV reverse remodeling to reduce IMR and improve functional capacity. However, improvement in IMR following CABG alone is variable, difficult to predict and likely a complex function of regional myocardial viability, papillary muscle synchrony, and LV size. Because untreated and persistent, moderate IMR may limit the extent of reverse remodeling that can occur with CABG alone, surgeons have traditionally chosen to perform down-sized annuloplasty repair at the time of CABG, though evidence favoring this approach has been largely observational.
++
The first single-center randomized trial of patients with moderate IMR assigned 102 patients to CABG plus MV repair (n = 48) or CABG alone (n = 54) and demonstrated significant decreases in LV end-systolic and end-diastolic dimensions, pulmonary artery systolic pressure, mean MR grade (by qualitative assessment), and New York Heart association (NYHA) functional class with CABG plus MV repair versus CABG alone.8 There was no between-group difference in survival at 5 years. HF outcomes were not reported. Nearly 40% of patients randomized to CABG alone had only trivial or mild MR at 5 year follow-up. Aortic cross-clamp and cardiopulmonary bypass times were significantly longer in the CABG plus MV repair group. The multicenter, single blinded Randomized Ischemic Mitral Evaluation (RIME) trial randomized 73 patients referred for CABG with moderate IMR to CABG alone (n = 39) or CABG with MV repair using a downsized annuloplasty ring (n = 34). Functional capacity as assessed by peak oxygen consumption at year (primary end point) was reported for only 59 patients, but significantly improved in the CABG plus MV repair cohort compared to the CABG alone cohort by a difference of 2.2 mL/kg/min (95% CI 0.7-3.6, P = .004). Similarly, greater LV reverse remodeling and reduction in MR volume and plasma B-type natriuretic peptides (BNP) were observed at 1 year in the CABG plus MV repair cohort. However, the addition of MV repair to CABG was associated with increased operation duration, blood transfusions, intubation duration, and length of hospital stay.35 In contrast, a larger randomized trial that assigned 301 patients with moderate IMR to CABG alone (n = 151) versus CABG plus MV repair (n = 150) failed to demonstrate a clinically meaningful advantage of adding MV repair at 1 year. The degree of LV reverse remodeling (the primary end point of this trial) at 1 year was similar in both groups, despite a reduced prevalence of moderate or severe MR in the CABG plus MV repair group compared to the CABG alone group (11.2% vs 31%, respectively; P < .001). It is interesting to note that the severity of IMR in 69% of patients in the CABG alone group had improved to none or mild MR at 1 year. This trial redemonstrated longer bypass times and longer lengths of hospital stay with combined CABG and MV repair, as well as an increased rate of serious neurologic events (stroke, transient ischemic attack, and metabolic encephalopathy) and supraventricular arrhythmias, but no mortality difference between treatment groups.36 Two-year results from this study did not identify any significant differences in LV reverse remodeling, overall hospital readmissions, mortality or a composite end point of death, stroke, subsequent mitral-valve surgery, hospitalization for HF, or worsening functional class between treatment groups. The frequency of moderate-to-severe MR remained lower in the combined CABG-MV repair group (11.2% vs 32.3% for CABG alone, P < .001). Neurologic events and supraventricular arrhythmias remained more frequent in the combined CABG-MV repair group.37
++
In summary, the addition of MV repair to CABG in patients with moderate IMR does not appear to increase perioperative mortality risk but may increase perioperative morbidity as performed in some centers.38 Studies to date have not been powered to detect differences in survival or functional outcomes between CABG alone and CABG combined with MV repair. Although surgical revascularization alone can decrease MR severity in patients with preoperative moderate IMR, the addition of MV repair is associated with reduced prevalence of moderate or severe MR in follow-up, but whether this translates into clinically meaningful improvements in hard end points remains uncertain. The American Heart Association (AHA)/American College of Cardiology (ACC) Guidelines for Management of Patients With Valvular Heart Disease provide a class IIb recommendation (level of evidence: C) that MV repair may be considered for patients with chronic moderate, secondary MR who are undergoing other cardiac surgery (Table 49–3).14
++
+++
Surgery for Severe IMR
++
Observational data from the STICH trial suggest that adding MV repair to CABG in patients with LVEF ≤ 35% and moderate-to-severe MR may improve survival compared to CABG alone (adjusted hazard ratio (HR) for mortality 0.41 (95% CI, 0.22-0.77); P = .006), though the number of events in this trial was small.5 Current AHA/ACC recommendations state that MV surgery is reasonable for patients with chronic severe IMR (stages C and D) who are undergoing CABG or aortic valve replacement (class of recommendation: IIa; level of evidence: C). Surgery may also be considered for patients with chronic severe IMR (stage D) who remain severely symptomatic (NYHA class III to IV) despite optimal guideline-directed medical therapy for HF (class of recommendation: IIb; level of evidence: B).14 A summary of AHA/ACC and ESC recommendations for surgical management of chronic severe MR is presented in Table 49–3.
++
In the setting of severe IMR, debate has focused on the role of MV repair versus MV replacement (MVR). Repair has been felt safer with lower perioperative mortality and morbidity, though generally associated with a higher rate of recurrent MR compared with replacement. A randomized multicenter trial assigned 251 patients with severe IMR to undergo either MV repair (n = 126) or chordal-sparing MVR (n = 125) and did not demonstrate any significant difference in LV end-systolic volume indexed to body surface area at 1 and 2 years (primary end point). No differences in survival or the incidence of major adverse cardiac and cerebrovascular events were found. The rate of recurrence of moderate or severe MR was significantly higher in the repair compared to the replacement group (32.6% vs 2.3% at 1 year, P < .001; and 58.8% versus 3.8% at 2 years, P < .001), resulting in more adverse events related to HF and cardiovascular readmissions. 6,11 Numerous observational studies have identified echocardiographic predictors of recurrent MR following MV annuloplasty, including an LV end-diastolic diameter > 65 mm, coaptation depth > 1 cm, and systolic sphericity index > 0.7.26 In the randomized trial of repair versus replacement, only basal aneurysms and dyskinesis were significantly associated with recurrent moderate or severe MR in patients following repair for severe IMR.39 It is important to note that none of the prediction models for recurrent MR have been externally validated. Durability of repair is also influenced by the natural history of underlying ventricular dilation over time; progressive dilation will undermine the integrity of MV repair.
+++
Percutaneous Interventions
++
Although a variety of percutaneous therapies for MR have been developed, the MitraClip system (Abbott Vascular, CA, USA) has emerged clinically as the most tolerated and effective approach to date. The MitraClip is a transcatheter mitral device for use in high-risk or inoperable patients with severe MR and suitable anatomic criteria. Favorable and unfavorable anatomic criteria are presented in Table 49–4. By means of venous access, the device is advanced into the left atrium using a transseptal approach and grasps the MV leaflets, achieving edge-to-edge approximation, and thereby creating a double MV orifice (Fig. 49–7). It is currently approved by the US Food and Drug Administration for use in symptomatic patients with primary (degenerative) MR who are at prohibitive risk for surgery; it is not approved for treatment of IMR in the United States, but is under investigation for this indication through the Clinical Outcomes Assessment of MitraClip Percutaneous Therapy for Extremely High-Surgical-Risk Patients (COAPT) trial.16 In contrast, the MitraClip system has already received a class IIb recommendation by the European Society of Cardiology for secondary MR (Table 49–3). Worldwide, it is estimated that approximately two-thirds of the MitraClip procedures have been performed in patients with secondary MR.
++
++
++
Only 27% of patients in the original Endovascular Valve Edge-to-Edge Repair (EVEREST) II study, which was designed to assess the safety and effectiveness of the MitraClip device, had secondary MR.40 In contrast, 77% of 567 patients enrolled in the European prospective, muticenter, nonrandomized postapproval ACCESS-EU study of MitraClip therapy had secondary MR. Of patients with secondary MR in this real-world postapproval experience, 41% were over 75 years of age (mean age = 73 y) and 48% had a logistic EuroSCORE ≥ 20%. Mortality at 1 year for these patients was 17%. Most patients (91.7%) achieved reduction in MR to ≤ 2+ at discharge, but 21.5% manifested > 2+ MR at 12 months. Improvements were observed in NYHA functional class, six-minute walk distance, and Minnesota Living with HF Questionnaire score.41 Fifty-nine percent of the 78 patients with severe symptomatic MR and an estimated surgical mortalityr of ≥ 12% who underwent the MitraClip procedure as part of the EVEREST II high-risk study had secondary MR. In this study, the MitraClip device reduced MR in the majority of patients, resulting in LV reverse remodeling, improvement in NYHA functional class, and improvements in quality of life over 12 months. Furthermore, the 12-month survival rate for this high-risk cohort treated with MitraClip was 76% compared to 55% in a group of patients screened concurrently but not enrolled in the study who received standard of care.42 Direct, nonrandomized comparisons between MitraClip therapy and surgery are difficult because of significant differences in patients referred for either strategy.
++
It will be necessary to continuously reappraise safety and efficacy of MitraClip therapy as experience grows in high-volume centers treating higher surgical risk patients with secondary MR with advanced LV dysfunction/remodeling and greater burden of comorbidities. In summary, percutaneous edge-to-edge repair using the MitraClip system is an alternative that can reduce symptoms and induce LV reverse remodeling, but is often associated with residual and recurrent MR. As such, it can be considered as an adjunct to guideline directed medical therapy (with or without CRT) in stage D IMR who fulfill anatomical criteria and are judged high-risk or inoperable by a multidisciplinary heart team in Europe,26 but it is not currently approved for IMR in the United States outside of clinical trials. Intense investigational efforts are underway in the application of other transcatheter therapies in the management of MR.43
++
Given the causal association of CAD and IMR, guideline-directed management of CAD is important in patients with IMR.44 Prompt reperfusion in the setting of acute ST-segment elevation MI to minimize adverse LV remodeling and injury to papillary muscles is paramount to prevent/reduce subsequent IMR. Evidence of myocardial ischemia and/or myocardial viability on cardiac imaging in patients with IMR should prompt consideration of percutaneous or surgical revascularization, in the hope of promoting LV reverse remodeling.
+++
Management of Atrial Fibrillation
++
AF is commonly associated with MR, and is present in up to 50% of patients undergoing MV surgery.45 Left atrial chamber enlargement as a consequence of increased pressure and volume load to the left atrial from MR is implicated in genesis of AF.46 AF may be a marker of disease progression and worse prognosis in IMR. Management of AF in terms of rate control, rhythm control, and anticoagulation should be according to international practice guidelines.47 Surgical approaches for AF with/without left atrial appendage ligation can be considered in patients undergoing MV surgery. Risk factors for return of AF after the Cox maze procedure include duration of preoperative AF, left atrial size, and reduced LV function.48
+++
Advanced Heart Failure Therapies
++
Select patients with advanced stage D HF and IMR, who are refractory to guideline-directed medical therapy, should be referred to an advanced HF service for consideration of cardiac transplantation and/or durable mechanical circulatory support (eg, left ventricular assist device) either as destination therapy or bridge to transplantation. Advanced age and significant burden of comorbidities render many patients with IMR ineligible for these therapies.
++
The morbidity and mortality associated with IMR increase with severity of disease, and the trajectory of the disease is unpredictable. Therefore, it is important to consider referral to palliative care services at a timely point in this chronic life-limiting illness. Involving palliative care specialists can facilitate conversations around advanced care planning.49