Management and prognosis of chronic secondary mitral regurgitation

INTRODUCTION — Secondary mitral regurgitation (MR; also known as functional MR) is defined as MR that is a consequence of left ventricular (LV) dysfunction with normal mitral valve leaflets and chords. LV dysfunction may be due to coronary heart disease (CHD) or (nonischemic) cardiomyopathy. Secondary MR caused by CHD (generally with myocardial infarction [MI]) is also known as ischemic MR. By contrast, primary MR is caused by primary abnormality of one or more components of the valve apparatus. Identification of the cause and type (primary or secondary) of MR is required for appropriate management of MR and associated conditions. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

The management and prognosis of chronic secondary MR is presented here.

Related issues are presented separately:

●(See "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

●(See "Pathophysiology and natural history of chronic mitral regurgitation".)

MONITORING AND EVALUATION

Serial assessment — Patients with chronic secondary MR require serial monitoring following initial evaluation and staging. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation".)

The goals of monitoring are to assess changes in clinical status by history and physical examination and to assess changes in severity of MR and LV function by echocardiography, as these changes can occur in the absence of a change in symptoms. Secondary MR is often progressive since the regurgitant volume imposes a hemodynamic burden on the LV that leads to dilation and eccentric geometry, which may contribute to an increase in the severity of MR. (See "Pathophysiology and natural history of chronic mitral regurgitation", section on 'Secondary MR'.)

●Follow-up of all patients with valve disease includes at least annual history and physical examination. All patients with secondary MR have LV systolic dysfunction and should be followed as recommended for this principal disease process. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Follow-up and preventive care' and "Treatment and prognosis of heart failure with mid-range ejection fraction", section on 'Serial assessment'.)

●Serial transthoracic echocardiography (TTE) is performed to assess the severity of MR, as well as LV size and function. We suggest a frequency of follow-up based upon the severity of MR and symptoms of heart failure (HF):

•Asymptomatic patients with moderate (2+) or less (regurgitant fraction <40 percent) secondary MR should undergo echocardiography every one to two years.

•Patients with symptoms and/or moderate to severe or severe (3+ to 4+) secondary MR should be seen every 6 to 12 months (sooner if symptoms worsen). Repeat TTE should be obtained at these visits. The six-month interval is preferred if stability has not been documented or there is evidence of worsening MR or symptoms.

Staging — Staging of secondary MR is based upon symptoms, valve anatomy, and valve hemodynamics (severity of MR), which are associated with LV dysfunction (due to coronary artery disease [CAD] or cardiomyopathy) (table 1) [1]. Since secondary MR is caused by LV dilation and dysfunction, evaluation of the severity and cause of HF is also important. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and 'Determining the cause of LV dysfunction' below.)

●Symptoms – Patients with secondary MR are generally symptomatic due to LV systolic dysfunction. In addition, they may experience a further decrease in exercise tolerance or increase in dyspnea and fatigue due to superimposed MR. [1,2]. (See "Clinical manifestations and diagnosis of chronic mitral regurgitation", section on 'Clinical manifestations'.)

●Echocardiography – The severity of MR can be assessed quantitatively and semiquantitatively by Doppler echocardiography, as described in the table (table 1) [1]. Echocardiography is also helpful for assessing LV chamber size, wall thicknesses, global and regional function, and estimating pulmonary artery pressures. TTE usually provides the necessary information. If TTE assessment of severity of MR is suboptimal, transesophageal echocardiography (TEE) may be helpful. (See "Echocardiographic recognition of cardiomyopathies" and 'Transesophageal echocardiography' below.)

Determining the cause of LV dysfunction — Evaluation of patients with chronic secondary MR includes evaluation to determine the cause of LV dysfunction, since identification of the cause (particularly CAD) impacts management and prognosis. Evaluation of the cause of LV dysfunction is discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Evaluation of hibernating myocardium".)

For patients with LV dysfunction, evaluation for CAD is performed even if chest pain is absent:

●Stress testing – The evaluation generally includes a stress imaging test to identify myocardial ischemia and assess viability, unless the patient has an indication to proceed directly to cardiac angiography (such as unstable angina). For evaluation of viability in patients with suspected significant coronary disease with secondary MR, stress positron emission tomography radionuclide myocardial perfusion imaging (PET rMPI) or stress cardiovascular magnetic resonance (CMR) imaging is preferred, if local resources and expertise are available. If neither of those modalities is available, stress testing is performed using stress rMPI or stress echocardiography. (See "Selecting the optimal cardiac stress test".)

●Other noninvasive imaging – The use of rest CMR is described below. (See "Determining the etiology and severity of heart failure or cardiomyopathy", section on 'Cardiovascular magnetic resonance' and "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Myocardial disease'.)

●Coronary angiography – Invasive coronary angiography is performed if noninvasive imaging suggests coronary artery disease. Coronary angiography is also recommended prior to mitral valve surgery in patients who have known coronary disease or are at risk for coronary disease [1]. Most patients requiring surgery for chronic secondary MR (which includes ischemic MR as well as MR associated with nonischemic cardiomyopathy) have significant CAD. (See "Surgical procedures for severe chronic mitral regurgitation", section on 'Evaluation for coronary disease'.)

Evaluation for nonischemic cardiomyopathy is discussed separately. (See "Determining the etiology and severity of heart failure or cardiomyopathy".)

Additional testing if needed

Transesophageal echocardiography — TEE is not indicated for routine follow-up of chronic secondary MR but is indicated when noninvasive imaging fails to determine the severity or cause of MR (including distinguishing primary from secondary MR) [1]. TEE also has a role in preoperative and intraoperative evaluation for mitral valve surgery to determine valve anatomy if mitral valve repair is attempted.

The severity of ischemic MR should be assessed under baseline conditions since variations in hemodynamic load and inotropic state can alter the severity of regurgitation. Intraoperative TEE assessment of MR severity can be misleading because of the LV pressure and volume unloading effects of general anesthesia. The severity of ischemic MR has been observed to decrease after induction of anesthesia, with the severity returning to baseline after combined intravenous volume loading to adjust preload and appropriate medications to return systolic pressure to baseline [3].

Cardiovascular magnetic resonance imaging — CMR is not indicated for routine monitoring of MR but is indicated when echocardiography is not adequate to assess MR severity and LV and right ventricular (RV) volumes and systolic function [1]. CMR may also be helpful in evaluating ischemia (via stress CMR) and viability with the aid of delayed enhancement to assess for scar. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Regurgitant valve disease' and 'Determining the cause of LV dysfunction' above.)

Other — Natriuretic peptide elevation may be a marker for worse outcomes, but a role for serial natriuretic peptide testing has not been established. The prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was suggested by a study of 207 patients with chronic secondary MR [4]. NT-proBNP level increased with MR severity and was an independent predictor of cardiac death as well as the strongest predictor of cardiac death or HF-related hospitalization. Some clinicians may consider severe elevation in natriuretic peptide level as a factor favoring transcatheter mitral valve repair in patients with moderate to severe or severe (3+ to 4+) secondary MR amenable to durable transcatheter repair. (See 'Indications' below.)

APPROACH TO MANAGEMENT — The approach to management of chronic secondary MR includes the following components:

●First-line therapy for secondary MR is evidence-based medical management of HF with reduced ejection fraction (HFrEF), including pharmacologic therapy as well as cardiac resynchronization therapy (CRT), as indicated. (See 'Pharmacologic therapy' below and 'Pacemaker therapy' below.)

●Treatment of secondary MR includes assessment and management of concurrent conditions, particularly CAD. Standard recommendations for coronary revascularization apply. This includes surgical revascularization for patients with ischemic cardiomyopathy (LV ejection fraction [LVEF] ≤35 percent) with CAD amenable to revascularization, as discussed separately. (See 'Revascularization' below and "Treatment of ischemic cardiomyopathy".)

●Mitral valve intervention (transcatheter mitral valve repair or mitral valve surgery) is indicated in selected patients with secondary MR, with criteria including severe MR and persistence of symptoms on optimal medical therapy, or presence of a concurrent indication for cardiac surgery (coronary artery bypass graft surgery [CABG] or aortic valve surgery). (See 'Indications' below.)

Pharmacologic therapy

Recommendations for pharmacologic therapy — Chronic secondary MR develops as a consequence of LV systolic dysfunction. Patients with chronic secondary MR and HFrEF should receive standard evidence-based therapy for HFrEF, including angiotensin converting enzyme inhibitor (ACE) inhibitor (or angiotensin II receptor blocker [ARB] or angiotensin receptor-neprilysin inhibitor [ARNI]), beta blocker and mineralocorticoid receptor antagonist (MRA; if indicated), and diuretic therapy as needed to treat volume overload. (See "Overview of the management of heart failure with reduced ejection fraction in adults" and "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults" and "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults".)

Asymptomatic patients with chronic secondary MR and LV systolic dysfunction should receive standard therapy for asymptomatic LV dysfunction, including ACE inhibitor and beta blocker therapy. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)

Standard recommendations for pharmacologic therapy for HFrEF (as well as for asymptomatic LV systolic dysfunction) generally include a threshold LVEF of ≤40 percent.

Evidence for drug therapy — Randomized clinical trials have shown that ACE inhibitor (or ARB or ARNI), beta blocker, and MRA can produce an improvement in cardiac function, relieve symptoms, and enhance survival. (See "Overview of the management of heart failure with reduced ejection fraction in adults".)

More limited data suggest that ACE inhibitors and beta blockers also reduce LV volumes and the degree of secondary MR [5-10]. The supporting evidence primarily comes from small studies, as illustrated by the following findings:

●In a randomized trial, 28 patients with chronic systolic HF (mean LVEF 29 percent) were randomly assigned to increasing doses of captopril or placebo [6]. All patients had secondary MR with at least 5 cm² regurgitant area on color flow Doppler. Among the 23 patients who completed the study, the 10 treated with captopril had 3.1 and 5.3 cm² reductions in regurgitant area at doses of 50 and 100 mg/day, respectively, in association with an increase in forward stroke volume.

●In a second report, 45 consecutive patients with chronic ischemic and nonischemic HF (mean LVEF 24 percent) were treated with carvedilol and compared with a matched control group [8]. The patients receiving carvedilol had an increase in LVEF (24 to 29 percent), a reduction in LV end-systolic volume, and a significant fall in mitral regurgitant volume (50 versus 16 mL/min compared with no significant difference [57 versus 47 mL/min] in the control group). The reduction in MR was closely associated with an increase in forward stroke volume.

Treatment of volume overload may also be helpful, as illustrated by a study in patients with end-stage kidney disease in which ultrafiltration eliminated or reduced the severity of MR [11].

Pacemaker therapy — Pacing strategies that may reduce MR include atrioventricular (AV) optimization in those patients with a dual-chamber pacemaker, and CRT. Standard indications for CRT apply to patients with functional MR.

AV optimization — In patients who have a dual-chamber pacemaker, some studies suggest that AV optimization can reduce MR, but an impact on clinical outcomes has not been established. Several small studies have evaluated the impact of dual-chamber pacing with optimal AV delay on hemodynamic and clinical parameters in patients with significant MR [12-14]:

●In a prospective series of 20 patients with symptomatic complete AV block and dual-chamber pacemakers, optimal AV delay was determined by echocardiographic parameters [12]. The mean optimal AV delay was 98 ms, which reduced the severity of MR. Additionally, the cardiac output and systolic blood pressure improved.

●A trial enrolled 38 patients in sinus rhythm with HF and randomly assigned them to optimal medical therapy or optimal medical therapy with dual-chamber pacing [14]. AV delay was optimized according to echocardiographic parameters and generally ranged between 100 to 120 ms (in 14 of 19 patients). There was no difference between the two arms in most clinical endpoints, although the degree of MR and systolic LV diameter were both reduced in patients assigned to dual-chamber pacing.

Cardiac resynchronization therapy

Use — Patients with chronic secondary MR should receive CRT according to standard evidence-based guidelines for such therapy. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

CRT improves survival in selected patients with systolic HF and ventricular dyssynchrony. CRT often improves secondary MR in patients with ventricular dyssynchrony, and CRT is recommended in patients with secondary MR who meet criteria for CRT. However, careful patient selection is required for CRT, particularly in the setting of ischemic MR, since it may not be possible to pace scarred regions.

Evidence — CRT often improves secondary MR in patients with ventricular dyssynchrony. The acute effects of CRT on secondary MR were evaluated in a study of 24 patients with biventricular (BiV) pacemakers [15]. The effective regurgitant orifice area (EROA) was assessed during BiV pacing and with BiV pacing turned off. Active CRT was associated with almost a 50 percent reduction in the EROA (25 to 13 mm²). Long-term benefits were noted in the CARE-HF and MIRACLE randomized trials of CRT [16,17]. Compared with controls, CRT produced significant reductions in LV end-systolic and end-diastolic dimensions and in mitral regurgitant jet area (eg, -2.7 versus -0.5 cm² at six months in MIRACLE) [17].

The preceding observations were made in patients with predominantly mild (1+) to moderate (2+) MR. The impact of CRT on moderate to severe MR (3+) to severe MR (4+) was evaluated in a study of 98 patients with indications for CRT [18]. In the 85 patients surviving to eight-month follow-up, significant improvement in MR (reduction by at least one grade) occurred in 42 patients (49 percent). An ischemic cause of HF was significantly more common in MR nonimprovers than among MR improvers (74 versus 48 percent). Survival rates were higher in MR improvers compared with MR nonimprovers (97 versus 88 percent at one year and 92 versus 67 percent at two years). MR improvement was an independent predictor of survival (hazard ratio [HR] 0.35, 95% CI 0.13-0.94). The findings suggest a significant benefit from CRT in this population and also highlight the importance of careful patient selection for this treatment, particularly in those with ischemic MR. Lack of response to CRT among patients with ischemic MR may be due to an inability to pace scarred regions. These issues are discussed in detail separately. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system" and "Cardiac resynchronization therapy in heart failure: Implantation and other considerations".)

The benefits of CRT rapidly wane if therapy is discontinued. The magnitude of this effect was illustrated in a report of 20 patients with advanced HF treated with CRT [19]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".)

Management of concurrent conditions — Patients requiring mitral valve intervention frequently have concurrent conditions that require management. These include CAD, atrial fibrillation, and significant tricuspid regurgitation. Some of these conditions may be surgically managed at the time of mitral valve surgery (eg, surgical ablation for atrial fibrillation). These issues are discussed in detail separately. (See "Surgical procedures for severe chronic mitral regurgitation" and "Atrial fibrillation: Surgical ablation".)

Revascularization — Standard recommendations for coronary revascularization apply (including activity-limiting angina despite maximum medical therapy, significant left main CAD, or multivessel CAD with a reduction of LVEF and a large area of potentially ischemic myocardium). Revascularization may also reduce the severity of MR if a significant area of stunned or hibernating (ischemic yet viable) myocardium is present. Revascularization in patients with ischemic cardiomyopathy is discussed separately. (See "Treatment of ischemic cardiomyopathy".)

Observational data suggest that revascularization may improve survival in patients with ischemic MR with a broad range of LVEFs. In a retrospective study that included 4989 patients with moderate or severe ischemic MR with mean LVEF 46 percent (25^th to 75^th percentile of 30 to 60 percent), 36 percent received medical therapy alone, 26 percent underwent percutaneous coronary intervention (PCI), 33 percent underwent CABG, and 5 percent underwent CABG plus surgical mitral valve repair or replacement [20]. During median follow-up of 5.4 years, significantly lower mortality compared with medical therapy alone was observed in patients treated with CABG (adjusted HR 0.56, 95% CI 0.51-0.62), CABG plus surgical mitral valve repair or replacement (adjusted HR 0.69, 95% CI 0.57-0.82), or PCI (adjusted HR 0.83, 95% CI 0.76-0.92). However, these results do not establish a clinical benefit, given the risk of residual bias despite propensity score adjustment. Other studies of the impact of mitral valve surgery in patients undergoing CABG are discussed below. (See 'Evidence on concurrent mitral valve surgery and CABG' below.)

Revascularization in patients with chronic ischemic MR is less likely to reduce MR than revascularization in the setting of acute ischemic MR. Observational studies suggest that reperfusion (by primary PCI or thrombolysis) in patients with acute inferior or posterior (inferolateral) ST-elevation MI substantially reduces the incidence of moderate to severe ischemic MR (eg, 2.5 versus 11.1 percent in patients not receiving reperfusion) [21-23]. Revascularization reduces the severity of chronic ischemic MR in some but not all patients, as illustrated by the following observations:

●In a series of 136 patients with moderate to severe ischemic MR undergoing CABG, 40 percent continued to have moderate to severe (3+ to 4+) MR, 51 percent had some improvement to moderate (2+) MR, and 9 percent had no or mild (0 to 1+) MR [24].

●Preoperative evaluation may help identify patients in whom ischemic MR is likely to improve following CABG. At one-year follow-up of 135 patients with moderate ischemic MR who had undergone CABG, 57 had no or mild MR, 64 patients had no change or worse MR, and 14 had died [25]. The majority (93 percent) of surviving patients with large extent of viable myocardium (≥5 segments by single-photon emission computed tomography) and lack of dyssynchrony of segments underlying the papillary muscles showed reduced MR, while only 34 and 18 percent of patients with <5 viable segments and dyssynchrony, respectively, showed improvement in MR. The group with decreased MR also had a marked improvement in LVEF and a decrease in LV volumes, consistent with the mechanism of improvement being reperfusion of viable myocardium. Patients with a decrease in MR demonstrated symptomatic improvement and improved survival compared with those without improvement in MR.

Other management issues

Endocarditis prophylaxis — In accordance with the 2007 American Heart Association (AHA) guidelines on infective endocarditis and the 2020 American College of Cardiology (ACC)/AHA valvular heart disease guidelines [1,26], antibiotic prophylaxis is not recommended when patients with mitral valve disease (in the absence of prosthetic repair or replacement or history of infective endocarditis) undergo dental or other invasive procedures that produce bacteremia with organisms associated with endocarditis. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures".)

Pregnancy — MR during pregnancy is more commonly primary than secondary MR. For pregnant patients with secondary MR, maternal and fetal risk are primarily related to HF severity, LVEF, and pulmonary pressures, not MR severity. Peripartum cardiomyopathy is a cause of HF late in pregnancy (or during the five months after delivery) and may be associated with secondary MR, although the MR is not usually severe. Management of HF and MR during pregnancy, as well as peripartum cardiomyopathy, is discussed separately. (See "Management of heart failure during pregnancy" and "Peripartum cardiomyopathy: Treatment and prognosis" and "Pregnancy and valve disease", section on 'Mitral regurgitation'.)

Exercise — In patients with chronic secondary MR, concerns regarding exercise are related to presence of MR as well as presence of CAD in patients with ischemic MR and the presence of cardiomyopathy in patients with nonischemic LV dysfunction. Exercise has a variable effect on the regurgitant fraction in patients with chronic MR [27]. The reduction in systemic vascular resistance may result in no change or a mild reduction in the regurgitant fraction. On the other hand, an elevation in blood pressure, as occurs with static exercise, can lead to marked increases in regurgitant volume and pulmonary venous pressure.

Evidence on the safety of exercise in patients with chronic secondary MR is scant, so exercise recommendations are based largely on expert opinion. The 2015 AHA/ACC scientific statement on eligibility recommendations for competitive athletes includes recommendations for MR, CAD, and cardiomyopathy, but does not provide recommendations specifically targeting patients with chronic secondary MR.

●We suggest that patients with cardiomyopathy with secondary MR not participate in competitive sports, with the possible exception of low-intensity class IA sports in asymptomatic individuals.

●We suggest that patients with CAD and secondary MR not participate in competitive sports, with the possible exception of low-intensity class IA sports in asymptomatic individuals who have been screened by exercise testing on medications.

●We agree with the guidelines in prohibiting participation in competitive sports for patients with CAD in the following two settings:

•For at least three months after an acute MI or coronary revascularization procedure.

•If they have increasing frequency or worsening ischemic symptoms.

Recommendations for exercise after mitral valve replacement or repair are discussed separately. (See "Overview of the management of patients with prosthetic heart valves", section on 'Exercise recommendations'.)

MITRAL VALVE INTERVENTION

Indications — Indications and choice of intervention are based upon the clinical presentation and whether or not there is a concurrent indication for other cardiac surgery.

●Patients with persistent symptoms despite optimum therapy – For most patients with moderate to severe or severe (3+ to 4+) chronic secondary MR with LVEF ≤50 percent and New York Heart Association (NYHA) functional class II, III, or IVa (ambulatory) HF despite optimum evidence-based management (pharmacologic therapy plus cardiac resynchronization therapy, as indicated), we suggest referral to a heart valve team to assess the feasibility and potential benefit and risk of transcatheter edge-to-edge repair (TEER). Evidence-based management of HF should be optimal for at least one month followed by repeat clinical evaluation including echocardiography before consideration of intervention [28].

However, for some patients, durable TEER is not feasible due to technical issues. Likewise, TEER may not be appropriate when life expectancy is less than one year or comorbidities limit the likelihood of improvement in the patient’s quality of life.

Recommendations for TEER for secondary MR are evolving as randomized trials were completed after publication of major society guidelines.

●Patients undergoing cardiac surgery for a concurrent condition – For patients with chronic severe secondary MR who are undergoing coronary artery bypass graft surgery (CABG) or surgical aortic valve replacement, we suggest mitral valve surgery. The choice between mitral valve replacement and mitral valve repair is discussed below. This recommendation for mitral valve surgery in the setting of another indication for cardiac surgery is similar to a recommendation in the 2020 American College of Cardiology (ACC)/American Heart Association (AHA) valvular heart disease guidelines [1] and in broad agreement with recommendations in the 2021 European Society of Cardiology (ESC) valvular heart disease guidelines [2]. (See 'Evidence on concurrent mitral valve surgery and CABG' below.)

For patients with severe chronic secondary MR, we suggest not performing isolated mitral valve surgery (repair or replacement). In this setting there is no proven mortality benefit and uncertain durable effect on symptoms. (See 'Evidence on isolated mitral surgery' below.)

Evidence

Transcatheter edge-to-edge repair — Two randomized controlled trials assessing the efficacy of TEER using the MitraClip compared with continued medical therapy alone in patients with secondary MR yielded disparate results [29,30].

●The COAPT trial enrolled 614 patients with moderate to severe or severe secondary MR and an LVEF of 20 to 50 percent with NYHA class II, III, or IVa (ambulatory) HF despite maximal medical therapy [29].

•One or more MitraClip devices (mean 1.7 clips; range one to four) were implanted in 98 percent of patients in whom implantation was attempted. At discharge, the MR grade was 1+ or less in 82.3 percent in the intervention group.

•The postprocedural 30-day mortality rate was 2.3 percent, and the rate of stroke was 0.7 percent. The rate of freedom from device-related complications at 12 months was 96.6.

•TEER significantly reduced mortality compared with control medical therapy at two years (29.1 versus 46.1 percent).

•Hospitalization for HF within 24 months was also significantly reduced (35.8 versus 67.9 percent per patient-year). In addition, the change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and change in six-minute walk distance were significantly better with TEER.

•Regarding the timing of benefit, while the lower rate of hospitalization for HF with TEER was evident within 30 days after treatment, a significantly lower mortality rate with TEER emerged more than one year after the intervention.

●The smaller MITRA-FR randomized trial enrolled 304 patients with moderate to severe (2+ to 4+) secondary MR, an LVEF of 15 to 40 percent, and symptomatic HF [30].

•One or more MitraClip devices (one device in 45.7 percent, two devices in 44.9 percent, three or more in 9.4 percent) were implanted in 96 percent of patients in whom implantation was attempted. At discharge, the MR grade was 1+ or less in 75.6 percent in the intervention group.

•Periprocedural complications were observed in 14.6 percent of patients.

•At 12 months, there was no significant difference in the rate of all-cause mortality between the intervention and control groups (24.3 versus 22.4 percent; hazard ratio [HR] 1.11, 95% CI 0.69-1.77) or in the rate of unplanned hospitalization for HF (48.7 versus 47.4 percent; HR 1.13, 95% CI 0.81-1.56).

•The rate of the composite outcome of all-cause mortality or unplanned hospitalization for HF was also similar in the two groups (54.6 versus 51.3 percent; odds ratio 1.16, 95% CI 0.73-1.84).

•The frequency of serious adverse events at one year was similar in the two groups (82.2 and 79.6 percent). (See "Transcatheter mitral valve repair", section on 'Use for secondary MR'.)

Compared with the MITRA-FR trial, the COAPT trial was larger, included longer follow-up and included patients with higher B-type natriuretic peptide levels (mean 1043 versus 800 ng/L), smaller LV end-diastolic volume and more severe MR (mean effective regurgitant orifice area [EROA] 0.41 versus 0.31 cm², although this measure has limited reliability in secondary MR [31]) [32]. These differences are potential causes for the differences in trial results. These findings suggest that TEER may reduce hospitalizations for HF and mortality for selected patients with moderate to severe to severe (mean EROA = 40.5) secondary MR with HF symptoms despite optimum evidence-based therapy [29] but not in patients with moderate (mean EROA = 31) secondary MR [30].

Earlier observational data suggested that in selected patients with secondary MR, TEER had high rates of technical success and improved symptoms of HF. Secondary MR was present in 70 percent of 327 high-risk patients with 3 to 4+ MR and estimated surgical mortality risk of ≥12 percent based upon the Society of Thoracic Surgeons risk calculator with 12 months of follow-up [33]. Most of the patients (70 percent) had secondary MR. TEER was associated with acute reduction in MR to ≤2+ in 86 percent of patients. Eighty-three percent of patients were NYHA functional class I/II at 12 months, and the annualized hospitalization rate also fell after TEER (from 0.79 to 0.41 percent).

The use of TEER in patients with primary MR is discussed separately. (See "Transcatheter mitral valve repair".)

Evidence on concurrent mitral valve surgery and CABG — The rationale for performing mitral valve surgery concurrently with CABG is that CABG alone is less likely to reduce MR and persistent (and progressive) MR may lead to worse outcomes. However, the results of studies of the impact of mitral valve surgery (generally mitral valve repair) at the time of CABG for patients with ischemic MR have been mixed. Although mitral valve repair at the time of CABG reduces MR compared with CABG alone, the data suggest that an improvement in symptoms and exercise tolerance is possible, but it does not appear that there is a survival benefit.

A randomized trial, as well as some observational studies, found no improvement in symptoms or risk of mortality from the addition of mitral valve surgery to CABG compared with CABG alone [34-37]. In the largest randomized trial, 301 patients with moderate ischemic MR were randomly assigned to CABG alone or CABG combined with mitral valve repair [37,38]. At one- and two-year follow-up, the degree of reverse remodeling (measured as LV end-systolic volume index), readmission rates, and mortality rates (7.3 versus 6.7 percent at one year; 10.6 versus 10 percent at two years) were similar in the two groups. In the combined procedure group, postoperative moderate or severe MR was less frequent (11.2 versus 32.3 percent in the CABG alone group at two years), but the combined procedure group had a longer bypass time, longer hospital stay after surgery, and more frequent neurologic events and supraventricular arrhythmias than the CABG alone group. Quality-of-life scores improved similarly in the two groups except that the Duke Activity Status Index (DASI) was significantly better in the combined procedure group at two years. Longer follow-up is needed to determine whether the reduction in MR leads to a long-term clinical benefit.

In contrast, two earlier, smaller randomized trials and an observational study suggested a functional benefit from concomitant mitral valve surgery at the time of CABG [39-41] and an observational study suggested a survival benefit from the addition of mitral valve repair to CABG [42]. A randomized trial included 102 patients with moderate (2+) ischemic MR who underwent CABG plus mitral valve repair or CABG alone [40]. Mortality rates at five years were not significantly different for the two groups (6.3 versus 11.2 percent), but the functional status of patients undergoing mitral valve repair was significantly better, with fewer patients with NYHA functional class II or greater (15.5 versus 43.7 percent). Similarly, the Randomized Ischemic Mitral Evaluation (RIME) multicenter randomized trial of 73 patients with moderate ischemic MR found that the addition of mitral annuloplasty to CABG did not affect mortality rates but improved functional capacity (peak oxygen consumption) and LV reverse remodeling [41].

Evidence on isolated mitral surgery — Limited data are available on the efficacy and safety of isolated mitral valve surgery (without CABG) for secondary MR [43]. There are no randomized trials of medical versus surgical therapy for secondary MR or of revascularization alone versus revascularization plus mitral surgery for the subgroup of patients with ischemic MR.

In small, early observational studies, mitral valve repair in patients with dilated or ischemic cardiomyopathy led to a reduction in end-diastolic volume and improvements in LVEF, cardiac output, and NYHA functional class [44-46]. There are only limited, long-term observational data regarding surgical mitral valve repair for severe HF associated with secondary severe MR [45-47]. In a study of 419 patients with LVEF ≤30 percent and at least moderate to severe MR, surgical mitral valve repair was performed in 126 (30 percent) [47]. The majority of patients had CAD. Thirty-day postoperative mortality was 4.8 percent. At long-term follow-up (to >2000 days), there was no significant difference between patients who did or did not undergo mitral valve repair in terms of mortality (48 versus 38 percent with medical therapy alone) or in the combined end point of death, implantation of an LV assist device, or urgent heart transplantation (49 versus 41 percent). Baseline characteristics in the two groups were largely similar, although confounding by indication (eg, operating on sicker patients) could not be completely excluded [48].

Choice of surgical procedure — For patients undergoing mitral valve surgery for secondary MR, the choice of procedure (surgical mitral valve repair or replacement) varies with the cause of MR. These recommendations are based upon a randomized trial comparing surgical mitral valve repair with mitral valve replacement for secondary MR.

●For patients with ischemic MR who undergo mitral valve surgery (which usually occurs with concurrent CABG), we suggest mitral valve replacement with chordal sparing, rather than surgical mitral valve repair.

●For patients with nonischemic MR who undergo mitral valve surgery, we suggest mitral valve replacement with chordal sparing unless valve anatomy is favorable for surgical mitral repair and intraoperative TEE demonstrates minimal residual MR after repair.

The available evidence suggests that for patients with severe ischemic MR, survival is similar following mitral valve replacement with chordal sparing and surgical mitral valve repair. However, recurrent MR is much more frequent following surgical mitral valve repair. A randomized trial found that surgical mitral valve repair resulted in a significantly higher rate of cardiovascular admission and a borderline significantly higher rate of HF-related adverse events, as discussed below.

A randomized trial enrolling 251 patients with severe ischemic MR compared surgical mitral valve repair and chordal-sparing mitral valve replacement [49,50]:

●There was no difference in survival at one year (85.7 versus 82.4 percent) [49] and at two years (81.0 versus 76.8 percent) [50].

●The rate of recurrent moderate or severe MR was significantly higher in patients undergoing repair (32.6 versus 2.3 percent at one year; 58.8 versus 3.8 percent at two years).

●The rates of a composite of major adverse cardiac or cerebrovascular events were similar in the two groups (42.1 and 42.4 percent at two years). However, the repair group had more serious HF events (borderline significant) at two years (24.0 versus 15.2 per 100 patient-years, p = 0.05).

●The treatment groups had similar overall readmission rates, but the rate of readmission for cardiovascular causes was significantly higher in the repair group (48.3 versus 32.2 per 100 patient-years).

Of note, the results of this randomized trial contradict findings from earlier studies, including two meta-analyses of observational studies that suggested improved short- and long-term survival with surgical mitral valve repair [51,52]. The differences in results may have been caused by greater use of chordal-sparing mitral valve replacement in the trial and/or by inadequate adjustment for baseline difference in the observational studies.

The rate of late recurrent MR (moderate or severe) following surgical mitral valve repair is as high as 58.8 percent [49,50,53,54]. Adverse LV remodeling contributes to recurrent MR because ring annuloplasty reduces tethering at the annular but not the ventricular end [55]. The time course of recurrent MR was illustrated in a review of 585 patients with ischemic MR [54]. The rate of moderate to severe MR was 28 percent at six months and remained stable thereafter. Although the rate of recurrent MR was high, the five-year rate of requiring mitral valve replacement was only 3 percent. There are at least three explanations for the low rate of repeat surgery at five years: The degree of MR may have limited importance compared with the underlying cardiovascular disease; almost one-half of patients died within five years, which limited the number of patients in whom reoperation could be performed; and surgeons may be reluctant to perform a repeat operation in this older, high-risk population.

Preoperative clinical and echocardiographic parameters may help identify patients at greatest risk for recurrent MR. A study of 365 patients undergoing surgical mitral valve repair for ischemic MR found three independent predictors of annuloplasty failure: a larger mitral annular diameter, higher tethering area, and greater MR severity [56]. Specific risk factors are associated with worse outcomes in patients undergoing mitral valve repair. A study of mitral valve repair for secondary MR (80 percent ischemic) found that mitral valve coaptation depth and markers of RV dysfunction (tricuspid annular plane systolic excursion ≤12 mm and tricuspid annular peak systolic velocity ≤10 cm/s) were predictors of worse early and five-year mortality [57].

Scant data are available comparing surgical mitral valve repair and replacement in patients with nonischemic secondary MR. In a study of 104 patients with idiopathic dilated cardiomyopathy undergoing annuloplasty for secondary MR, 25 patients (24 percent) had recurrent MR (defined as ≥2+) at six-month follow-up, with postoperative mitral competence highly dependent on distal anterior leaflet mobility [58].

Choice of prosthetic valve — For patients with an indication for mitral valve surgery who undergo valve replacement, the choice of mechanical versus bioprosthetic valve should follow guidelines for valve choice based on patient age, risks of long-term anticoagulation, and patient preferences (table 2) [1]. Given the limited life expectancy of many patients with secondary MR, it is reasonable to consider a bioprosthetic valve rather than mechanical prosthetic valve when life expectancy is shorter than the expected life-span of a bioprosthetic valve. In addition, preserving the subvalvular apparatus is less technically demanding and associated with fewer valve-related complications when a bioprosthesis is used. (See "Choice of prosthetic heart valve for surgical aortic or mitral valve replacement" and "Diagnosis of mechanical prosthetic valve thrombosis or obstruction" and "Surgical procedures for severe chronic mitral regurgitation", section on 'Chordal preservation'.)

OTHER INTERVENTIONS

Cardiac transplantation — Some heart centers consider cardiac transplantation an option for patients with secondary MR and severe LV dysfunction [59]. While this may be appropriate for some subsets of patients and may be associated with improved survival compared with mitral valve surgery, many patients with secondary MR (particularly patients with ischemic MR who are often older adults) have contraindications to cardiac transplantation. (See "Heart transplantation in adults: Indications and contraindications".)

Investigational approaches — Given the limited durability of surgical mitral valve repair, a variety of approaches to eliminate leaflet tethering and improve mitral leaflet coaptation have been studied. These include subvalvular procedures (such as chordal cutting and papillary muscle repositioning, posterior leaflet extension, and variations in the annuloplasty ring) [53,60-63]. The effect of these mitral valve repair techniques on clinical outcomes has not been established.

PROGNOSIS — Secondary MR is associated with adverse prognosis beyond that seen with LV dysfunction alone in patients with ischemic or nonischemic cardiomyopathy. As discussed above, there is evidence that transcatheter mitral valve repair can improve outcomes in selected patients with secondary MR. Surgical correction of secondary MR (surgical mitral valve repair or replacement) may improve symptoms of secondary MR, but there is no evidence that it improves survival. (See 'Mitral valve intervention' above.)

There are limited data from observational studies on the prognostic significance of secondary MR in patients with LV systolic dysfunction [64-66]. In a chart review of 1421 consecutive patients with LVEF ≤35 percent, patient survival at a mean follow-up of one year varied inversely with MR grade: 1004, 795, and 628 days with no to mild, moderate, and severe MR, respectively [65]. Severe MR was an independent predictor of mortality (relative risk [RR] 1.84). The severity of tricuspid regurgitation was also a predictor of mortality (RR 1.55) and often occurred with severe MR. Other predictors of poor outcome included CAD and cancer.

RV dysfunction may be a predictor of poor outcome among patients with secondary MR. In a prospective study of 356 chronic HF patients with LVEF ≤45 percent and moderate to severe MR, RV systolic function (as assessed by tricuspid annular plane systolic excursion) was an independent predictor of freedom from all-cause mortality or hospitalization for worsening HF [67]. Pulmonary artery systolic hypertension was a predictor of mortality upon univariate but not multivariate analysis, and pulmonary artery systolic pressure was not significantly different in the groups with and without evidence of RV systolic dysfunction.

Ischemic MR following MI is associated with increased mortality as well as risk of development of HF [68-81]. The degree of mortality risk is illustrated by the following observations:

●In an analysis from the CADILLAC trial of 1976 patients with an acute ST-elevation MI, 192 (10 percent) had mild MR and 58 (3 percent) had moderate to severe MR [72]. Patients with worse MR had significantly higher mortality rates at 30 days (1.4, 3.7, and 8.6 percent for no MR, mild MR, and moderate to severe MR, respectively) and at one year (2.9, 8.5, and 20.8 percent).

●A similar increase in risk over the longer term was noted in a prospective study of 303 patients with a previous Q-wave MI, 194 of whom had ischemic MR [76]. At five years, those with ischemic MR had a higher rate of cardiac mortality (50 versus 30 percent). The magnitude of the mortality risk correlated with the severity of the MR (figure 1).

●In a report limited to patients with a non-ST-elevation acute coronary syndrome, survival at 431 days decreased as the severity of MR increased [74]. MR was the only predictor of poor survival in multivariate analysis.

Ischemic MR is also an important predictor of the development of HF, even in patients with a normal LVEF at the time of the MI. The following observations were noted in different studies.

●At five years after ST-elevation MI, patients with ischemic MR had a much higher risk of HF than those without ischemic MR (53 versus 18 percent, adjusted RR 3.65) [81].

●At five years after MI, survival free of HF was related to the severity of MR in another report (74 and 35 percent with mild and moderate to severe MR, respectively) [73].

●The eventual risk of HF is increased in patients with MI and secondary MR independent of LVEF [75].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: What can go wrong after a heart attack? (The Basics)" and "Patient education: Mitral regurgitation (The Basics)")

●Beyond the Basics topic (see "Patient education: Mitral regurgitation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Serial monitoring by clinical evaluation and echocardiography is warranted in patients with chronic secondary mitral regurgitation (MR). As secondary MR is often progressive, the goals of monitoring are to assess changes in clinical status and changes in severity of MR and left ventricular (LV) function. (See 'Serial assessment' above.)

●Staging of secondary MR is based upon symptoms, valve anatomy, and valve hemodynamics (severity of MR), which are associated with LV dysfunction due to coronary artery disease (CAD) or cardiomyopathy (table 1). (See 'Staging' above.)

●Evaluation of patients with chronic secondary MR includes testing to determine the cause of LV dysfunction, since identification of the cause (particularly CAD) impacts management. (See 'Determining the cause of LV dysfunction' above.)

●Secondary MR is associated with adverse prognosis (beyond that seen with LV dysfunction alone) in patients with ischemic or nonischemic cardiomyopathy. (See 'Prognosis' above.)

●The approach to management of chronic secondary MR includes the following components:

•First-line therapy for secondary MR is evidence-based management of heart failure with reduced ejection fraction (HFrEF; including pharmacologic therapy as well as cardiac resynchronization therapy [CRT], as indicated). (See 'Pharmacologic therapy' above and 'Pacemaker therapy' above.)

•Treatment of secondary MR includes assessment and management of concurrent conditions, particularly CAD. Standard recommendations for coronary revascularization apply. This includes surgical revascularization for patients with ischemic cardiomyopathy (LV ejection fraction [LVEF] ≤35 percent) with CAD amenable to revascularization, as discussed separately. (See 'Management of concurrent conditions' above and 'Revascularization' above and "Treatment of ischemic cardiomyopathy".)

•Patients with persistent symptoms and severe MR – For most patients with severe chronic secondary MR with LVEF ≤50 percent and New York Heart Association (NYHA) functional class II, III, or IVa (ambulatory) HF despite optimum evidence-based management (pharmacologic therapy plus CRT, as indicated) and appropriate anatomy for transcatheter edge-to-edge repair (TEER), we suggest TEER (Grade 2B). TEER may not be appropriate when life expectancy with intervention is less than one year or when comorbidities limit the likelihood of improvement in the patient’s quality of life. Evidence-based management of HF should be optimal for at least one month followed by repeat clinical evaluation including echocardiography before consideration of intervention. (See 'Transcatheter edge-to-edge repair' above.)

•For patients with severe ischemic MR undergoing coronary artery bypass graft surgery (CABG) or surgical aortic valve replacement, we suggest mitral valve surgery (Grade 2C). (See 'Evidence on concurrent mitral valve surgery and CABG' above.)

•For patients with severe ischemic MR, we suggest not performing isolated mitral valve surgery (Grade 2C). (See 'Evidence on isolated mitral surgery' above.)

•For patients with secondary MR who have an indication for mitral valve surgery, the choice between mitral valve replacement or surgical mitral valve repair is based upon the cause of secondary MR:

-For patients with severe ischemic MR who are undergoing mitral valve surgery, we suggest concurrent bioprosthetic mitral valve replacement with chordal sparing, rather than surgical mitral valve repair (Grade 2B). Recurrent MR is much more common after mitral valve repair than after mitral valve replacement. (See 'Choice of surgical procedure' above.)

-For patients with nonischemic MR who are undergoing mitral valve surgery, we suggest mitral valve replacement with chordal sparing unless valve anatomy is favorable for surgical mitral valve repair and intraoperative transesophageal echocardiography demonstrates minimal residual MR after repair (Grade 2C). (See 'Choice of surgical procedure' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William H Gaasch, MD (deceased), who contributed to an earlier version of this topic review.