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- 1. Series 1324 www.thelancet.com Vol 387 March 26, 2016 Valvular heart disease 2 Mitral valve disease—current management and future challenges Rick A Nishimura, AlecVahanian, Mackram F Eleid, Michael J Mack The field of mitral valve disease diagnosis and management is rapidly changing. New understanding of disease pathology and progression, with improvements in and increased use of sophisticated imaging modalities, have led to early diagnosis and complex treatment. In primary mitral regurgitation, surgical repair is the standard of care. Treatment of asymptomatic patients with severe mitral regurgitation in valve reference centres, in which successful repair is more than 95% and surgical mortality is less than 1%, should be the expectation for the next 5 years. Transcatheter mitral valve repair with a MitraClip device is also producing good outcomes in patients with primary mitral regurgitation who are at high surgical risk. Findings from clinical trials of MitraClip versus surgery in patients of intermediate surgical risk are expected to be initiated in the next few years. In patients with secondary mitral regurgitation, mainly a disease of the left ventricle, the vision for the next 5 years is not nearly as clear. Outcomes from ongoing clinical trials will greatly inform this field. Use of transcatheter techniques, both repair and replacement, is expected to substantially expand. Mitral annular calcification is an increasing problem in elderly people, causing both mitral stenosis and regurgitation which are difficult to treat. There is anecdotal experience with use of transcatheter valves by either a catheter-based approach or as a hybrid technique with open surgery, which is being studied in early feasibility trials. Introduction Mitral valve disease is the most common of the valvular heart disorders, particularly in ageing populations, with a prevalence of more than 10% in people aged older than 75 years.1 Mitral regurgitation is divided into either primary (a structural or degenerative abnormality of the mitral valve apparatus) or secondary (a disease of the left ventricle, which interferes with the function and integrity of the mitral valve apparatus) mitral regurgitation (table).2,3 Mitral stenosis is usually due to rheumatic disease, but heavy calcification of the mitral annulus with extension into the leaflets might cause obstruction to left ventricular inflow, particularly in the elderly population.2,4 Treatment of these various valve disorders is dependent on the underlying cause, pathophysiology, and natural history of each disorder. This Review highlights the clinical presentation, diagnosis, and current and future managementforpatientswithprimarymitralregurgitation, secondary mitral regurgitation, and mitral stenosis due to annular calcification. A separate report on rheumatic heart disease will cover rheumatic mitral stenosis.5 Primary mitral regurgitation Causes, pathophysiology, and natural history The most common cause of primary mitral regurgitation is degenerative mitral valve disease, in which there is myxomatous degeneration of the mitral valve leaflets and elongated and redundant chordal apparatus.6 Thickened redundant leaflets will prolapse back into the left atrium causing malcoaptation of leaflet edges and subsequent regurgitation. Rupture of chordal structures is not uncommon in patients with mitral regurgitation, especially in older men, which will then cause a further increase in the severity of mitral regurgitation because of unsupported segments of the mitral valve leaflets. Other causes of primary mitral regurgitation include rheumatic disease, with rare causes being drug-induced mitral valve disease, healed infective endocarditis, and mitral regurgitation associated with systemic disease. A diagnosis of severe mitral regurgitation is made if 50% of the total stroke volume is diverted to regurgitant flow.7 The compensatory response to this volume overload is a progressive increase in left ventricular volume with a normalisation of wall stress, resulting in a chronic asymptomatic stage of mitral regurgitation.7,8 However, long-standing volume overload can result in progressive left ventricular enlargement and stretching of the myocytes beyond their normal contractile length. This stretching will lead to a decreased contractile state Lancet 2016; 387: 1324–34 See Editorial page 1252 This is the second in a Series of three papers about valvular heart disease Mayo Clinic, Rochester, MN, USA (R A Nishimura MD, M F Eleid MD); Hospital Bichat, Paris, France (AVahanian MD); and Baylor Scott andWhite Health, Plano,TX, USA (M J Mack MD) Correspondence to: Dr Michael J Mack, Baylor Scott andWhite Health, Plano, TX 75093, USA michael.mack@baylorhealth. edu Search strategy and selection criteria We searched Embase, PubMed, MEDLINE, and the Cochrane Library for reports published between Jan 1, 2005, and Feb 15, 2016.We used the search terms “mitral valve”, “mitral regurgitation”, “mitral annular calcification”, “mitral valve repair”, “mitral valve replacement”, and “mitral stenosis”, which we combined with many search terms for “pathophysiology”, “epidemiology”, “natural history”, “diagnosis”, “management”, and “current issues”.We focused on the latest publications, but did not exclude highly regarded older publications. In addition to the search results, we searched the references of relevant articles retrieved by the search strategy.
- 2. Series www.thelancet.com Vol 387 March 26, 2016 1325 from reduced myofibre content and interstitial fibrosis with an increase in left atrial and left ventricular diastolic pressures, producing symptoms of dyspnoea.7–9 The left ventricular dysfunction might occur before the onset of symptoms, might not be identified by conventional measurements of ejection fraction, and portends a poor prognosis. Patients presenting with severe primary mitral regurgitation have an excess mortality rate of 6·3% per year7 compared with the expected survival rate. This disease is associated with a high morbidity, with 10-year incidence of atrial fibrillation of 30% and heart failure (36% vs 63%). During 10 years, 90% of patients with severe mitral regurgitation will have died or undergone surgical repair because of developing mitral regurgitation symptoms.10,11 Sudden death might also occur and is responsible for about a quarter of deaths in patients receiving medical treatment.12 However, so-called watchful waiting of patients with asymptomatic severe mitral regurgitation has been shown to be a reasonable therapeutic strategy if meticulous regular follow-up for symptoms and changes in left ventricular performance are completed.13 Presentation and diagnosis Most patients with severe, chronic, primary mitral regurgitation remain asymptomatic for many years due to compensatory ventricular dilation. Symptoms of exertional dyspnoea and exercise intolerance will slowly develop as the compensatory mechanisms are over- whelmed by the volume overload, and irreversible left ventricular dysfunction occurs. However, if an inter- vention can be undertaken before or at the onset of symptoms or at the onset of left ventricular dysfunction, there is an excellent chance of improved survival for patients. Thus, it is important to diagnose mitral regurgitation, establish its severity, and document the effect of the volume overload on the left ventricle. Two-dimensional and Doppler echocardiography have become standard for the assessment of patients presenting with mitral regurgitation2,3 (figure 1). In patients with the primary form of this disease, the morphology of the mitral valve and its pathoanatomic abnormalities (eg, presence and location of prolapse and unsupported segments of the mitral valve) will establish the feasibility of valve repair. Other anatomical abnor- malities should be assessed because heavy calcification Figure 1:Transoesophageal echocardiogram and operative photo of a patient with primary mitral regurgitation (A)Two-dimensional still frame image during systole, showing a flail posterior leaflet (arrow) resulting in non-coaptation of the mitral leaflets. (B) Colour flow imaging shows severe mitral regurgitation with a large colour jet coursing anteriorly. Quantitative analysis revealed an effective orifice area of 0·6 cm². (C) Flail posterior leaflet portion of the posterior mitral leaflet. LA=left atrium. LV=left ventricle. A B C Primary mitral regurgitation Secondary mitral regurgitation Causes Disease of the valve (degenerative or rheumatic) Disease of the ventricle (ischaemic or functional) Medical therapy None GDMT for left ventricle dysfunction (ACE inhibitors, β blockers, aldosterone antagonists, resynchronisation if appropriate) Indications for intervention (accepted) Symptoms (any extent of severity); left ventricle dysfunction (ejection fraction <60%, end systolic dimension >40 mm) Severe symptoms unresponsive to optimum GDMT Indications for intervention (controversial) Repairable valve* NA Type of intervention (surgical) Repair if possible Replacement† Type of intervention (current catheter based) MitraClip MitraClip‡ Type of intervention (future catheter based) Annuloplasty, chordae replacement, mitral valve replacement Annuloplasty, chordae replacement, left ventricle remodelling devices, mitral valve replacement GDMT=guideline-directed medical therapy. ACE=angiotensin converting enzyme. NA=not applicable. *>95% probability of durable repair with <1% operative risk. †Replacement over repair if inferobasal aneurysm, severe leaflet tethering, or severe left ventricle dilatation. ‡Currently in Europe but not in the USA. Table: Summary of primary and secondary mitral regurgitation
- 3. Series 1326 www.thelancet.com Vol 387 March 26, 2016 of the mitral annulus, as well as calcification, thickening, and retraction of the mitral valve leaflets might preclude a successful and durable repair of the mitral valve. Size and function of the left ventricle is important to obtain by use of measurements of ejection fraction and end systolic and end diastolic dimensions. The severity of mitral regurgitation needs to be able to be established since an intervention could be considered for severe mitral regurgitation, even for patients who are asymptomatic.2,3 Quantitative assessment with proximal isovelocity surface area has become the standard to establish mitral regurgitation severity and provides measures of effective orifice area, regurgitant volume, and regurgitant fraction.14 In patients in whom a discrepancy exists between the mitral regurgitation severity (based on the clinical presentation and echocardiography results), further evaluation with other methods (eg, volume quantitation by echocardiography, MRI, CT, or cardiac catheterisation with left ventriculography) might be needed.15 Current treatments Medical therapy No known medical therapy has altered the natural history of patients with severe primary mitral regurgitation. For patients who are symptomatic with severe primary mitral regurgitation, diuretics and afterload reduction might relieve signs and symptoms of heart failure, but the ultimate treatment is intervention.2,3 Surgical repair or replacement Surgical intervention with repair or replacement is indicated in patients with severe mitral regurgitation and symptoms or left ventricular dysfunction (ejection fraction of <60% or end systolic diameter >40 mm).2,3 Surgical repair is the preferred treatment for patients with primary mitral regurgitation and is associated with better outcomes than mitral replacement.16–18 The spectrum of disease ranges from fibroelastic deficiency— resulting in leaflet prolapse or a flail leaflet segment due to ruptured chordae tendinae, most commonly of the middle portion of the posterior leaflet—to Barlow’s disease with excessive tissue and prolapse of both anterior and posterior leaflets.19 Mitral regurgitation can usually be repaired by either resection of the flail and prolapsing leaflet segment or by reconstructive techniques using artificial polytetrafluoroethylene chords.20 Annular dilation occurs secondary to the mitral regurgitation caused by the leaflet pathology and is most commonly corrected with a complete or partial annuloplasty ring. Posterior leaflet prolapse is the most common problem, causing severe mitral regurgitation and has higher success of durable repair than anterior leaflet disease or severe bileaflet disease.21 Success of durable repair should exceed 95%. A clear relationship has been documented between volume of procedures completed and success of durable repair.22,23 The most important factor of long-term durable success for mitral repair is the experience and expertise of the surgeon. This has led to the establishment of reference centres for mitral valve surgery in which successful repairs exceed 95%, and have an operative mortality of less than 1%.3,19 The definition of what a reference centre is was detailed in a multistakeholder consensus by Bridgewater.24 Criteria include that surgeons should have specialised training in mitral surgery, intraoperative transoesophageal echocardiography be completed by echo accredited anaesthesiologists and cardiologists, surgeons should do more than 25 mitral operations a year, and centres have more than 50 operations a year. Referring physicians should have access to a transparent audit of patient outcomes. Many reports from reference centres show repair rates exceeding 95% with operative mortality of less than 1%. Castillo and colleagues25 reported a 99·9% successful repair rate and 0·8% mortality in 743 patients with mitral regurgitation during 2002–10. Johnston and colleagues26 reported a 97% repair rate and 0·07% in-hospital mortality in 3074 patients who had posterior leaflet repair from 1995 to 2008. Several other similar series have been reported.27,28 Studies from the Society of Thoracic Surgeons database indicate that the repair rate increases if the number of individual surgeons do more than 25–40 mitral valve operations per year.22,29 On the basis of these studies,22,25–29 physicians should consider patient referral to a reference centre for an operation, especially for patients with complex bileaflet disease.30 Besides standard surgical approaches of a median sternotomy, standard minimally invasive techniques now represent 21% of surgical procedures.29 In a review29 of 61201 patients undergoing mitral valve surgery in the USA, 14% were done by a minimally invasive approach and 7% by a robotic approach. Both these approaches included partial sternotomies and restricted or mini-right thoracotomies.31,32 Although concerns were raised about additional vascular complications and an increased risk of stroke with the minimally invasive approaches, many series now exist attesting to the safety of these less invasive techniques with preservation of the high percentage of successful repairs.32,33 Although it is hard to show improved patient outcomes with a less invasive approach, a reduction in time to recovery, use of resources, and blood transfusion have been noted. All other things being equal, minimally invasive surgical techniques are becoming more widely available with equivalent outcomes with open approaches. Transcatheter mitral valve repair Although surgery is the gold standard intervention in patients with severe primary mitral regurgitation, a rationale exists for the use of transcatheter mitral valve therapies. Many patients who need treatment are elderly with several comorbidities, so surgery is high risk or even contraindicated, leading to its underuse in clinical
- 4. Series www.thelancet.com Vol 387 March 26, 2016 1327 practice.34 However, transcatheter mitral valve therapy is much more complicated than transcatheter aortic valve replacement, because of the complexity and heterogeneity of mitral valve disease, a more difficult valve delivery is needed, and use of enhanced imaging modalities are required. In current practice, transcatheter mitral valve intervention is mainly limited to the edge to edge repair technique with MitraClip (Abbott Vascular Inc, Santa Clara, CA, USA) therapy (figure 2). This technique reproduces the surgical Alfieri technique of edge to edge leaflet repair by clipping together the free edges of valve leaflets at the mid-portion of the leaflets. The procedure is completed with the patient under general anaesthesia, using fluoroscopic and most importantly trans- oesophageal echocardiographic guidance.35 More than 30000 patients worldwide have been treated with this procedure to date. The randomised EVEREST II trial36 compared MitraClip to surgery and showed a higher percentage of patients with significant residual mitral regurgitation in those who had received MitraClip compared with surgery (mitral regurgitation grade ≥2: 57% vs 24%, p<0·001).36 Results of 5-year follow-up showed that the need for surgery was higher in those after having MitraClip (27·9% vs 8·9%).37 Worldwide multicentre registries of high-risk or inoperable patients report a high success, good safety, and functional improvement after MitraClip procedures in patients with primary and secondary mitral regurgitation, despite incomplete relief of this disease.38–41 The technique is more challenging in cases of primary mitral regurgitation, but long-term survival and need for those who are readmitted to hospital seem to be better in primary than in secondary forms of this disease, probably due to the better cardiac and extra-cardiac conditions patients receive.39,40 The MitraClip is only approved for use in patients with primary mitral regurgitation who have severe symptoms and are at high or prohibitive risk of surgery in the USA, but is approved for clinical use for both primary and secondary mitral regurgitation in Europe. In the past 5 years two transcatheter techniques of placing artificial chords by a transapical approach have been developed. Neochord (St Louis Park, MN, USA)42 has received CE Mark approval, and Harpoon Medical (Baltimore, MD, USA) has started early human feasibility studies (ClinicalTrials.gov number NCT02432196). Treatment controversies When to operate on asymptomatic patients with severe mitral regurgitation Patients with severe primary mitral regurgitation and symptoms or left ventricular systolic dysfunction should undergo mitral valve intervention.2,3 However, these symptoms define a subset of patients in whom an operation is too late, because irreversible left ventricular dysfunction has already occurred. With the advent of mitral valve repair and its excellent short-term and long-term outcomes, a proposal was made that patients with severe primary mitral regurgitation should undergo early operation if they have a high probability of a successful durable repair with a low operative risk—before the onset of symptoms or decrease in ejection fraction.16,43–45 Others have proposed the pathway of watchful waiting, in which patients with mitral regurgitation are medically followed up until they reach the criteria of left ventricular dysfunction.13 After reaching these criteria, no patients developed residual left ventricular dysfunction after an operation, although a substantial percentage of patients eventually needed an operation. Non-randomised studies46,47 showed improved out- comes in patients undergoing early surgery compared with a similar group undergoing medical management. However, the benefit from early operation is dependent on a successful, durable mitral valve repair, and being of an extremely low operative risk. The clinician should have the benefit of transparency of surgical results to know the feasibility of a successful durable repair in each institution. Referral to so-called valve centres of excellence that report surgical success in mitral valve repair was recommended if early operation was to be undertaken.2,3 If a conservative approach is undertaken, the patient and physician must be willing to complete meticulous and frequent follow-up, with operation done Figure 2: MitraClip device (A) andtransoesophageal echocardiogram of a patient after MitraClip procedure (B) (B)Three-dimensional image of the mitral valve from the left atrial view showing the clip bringing together the mid-portion of the anterior and posterior leaflet, resulting in a double orifice during diastole.The catheter used for insertion is still attached to the clip. (C)Two-dimensional image during systole showing the clip (arrow) bringing together the anterior and posterior leaflet. (D) Colour-flow imaging during systole showing a thin jet of mitral regurgitation (red) indicating mild residual regurgitation. LA=left atrium. LV=left ventricle. A B C D
- 5. Series 1328 www.thelancet.com Vol 387 March 26, 2016 at the onset of symptoms or changes in left ventricular function. In an asymptomatic patient, of crucial importance is for the clinician to accurately assess the severity of the mitral regurgitation and consider all other available factors, such as an objective measurement of a patient’s functional capacity and of parameters of left atrial size, diastolic function, and pulmonary pressure.48 The final treatment of each patient should be a shared decision making process, with the heart team describing the risks and benefits of early operation versus watchful waiting, and the patient sharing their individual needs and preferences (panel 1). Surgery versus MitraClip The European Society of Cardiology and the European Association of CardioThoracic Surgeons (ESC/EACTS),2 and the American College of Cardiology and the American Heart Association (ACC/AHA)3 guidelines state that MitraClip therapy can be considered in patients with symptomatic, severe, primary mitral regurgitation who fulfil the echocardiography criteria of eligibility, are judged inoperable or at high surgical risk by a heart team (who have particular expertise in valvular heart disease, including cardiologists, cardiac surgeons, imaging specialists, anaesthetists, and, if needed, general practitioners, geriatricians, or intensive care specialists),2 and have a life expectancy of longer than 1 year. Further evidence should be accumulated in randomised studies comparing MitraClip with surgery. Ongoing studies include the HiRiDE (High and Intermediate Risk Degenerative Mitral Regurgitation Treatment; NCT02534155) randomised trial that will enrol intermediate-risk and high-risk patients, aiming to show superiority for safety and non-inferiority for efficacy between these two treatments.49 Treatment in the next 5years In parallel with developments in the field of aortic stenosis since the advent of transcatheter aortic valve replacement, the introduction of MitraClip has led to a large increase in patient referrals for treatment of mitral regurgitation. As an indirect effect, the number of patients undergoing surgery, especially for mitral valve repair, has also increased.50 Surgery will probably remain the standard treatment in low-risk or intermediate-risk patients with primary mitral regurgitation in the next 5 years. Transcatheter intervention will provide a satisfactory palliation in high- risk or inoperable patients. In primary, degenerative mitral regurgitation it is expected that there will be the ability to combine repair techniques to try to mimic surgical techniques by adding catheter delivered annuloplasty51 to chordal replacement or the MitraClip.52 Transcatheter valve implantation is being developed for primary mitral regurgitation due to more complex disease.53 Secondary mitral regurgitation Causes, pathophysiology, and natural history Secondary mitral regurgitation is mainly a disease of the left ventricle. Mitral regurgitation occurs when the mitral valve leaflets are normal, but left ventricular dilation results in leaflet tethering and annular dilation that prevents coaptation.54 Secondary mitral regurgitation includes both ischaemic and non-ischaemic functional mitral regurgitation causes. Studies54,55 have shown adverse outcome at a smaller calculated regurgitation orifice area than for primary mitral regurgitation. A dysfunctional cycle of volume overload occurs, leading to progressive annular dilation, myocardial thinning, cavity dilation, increased left ventricular wall stress, and increased leaflet tethering, resulting in progressive further loss of leaflet coaptation.54,56 Presentation and diagnosis As left ventricular dysfunction usually precedes the onset of substantial mitral regurgitation, symptoms of exertional dyspnoea and exercise intolerance are initially present but might progressively worsen as the cycle of volume overload and progressive mitral regurgitation continues. Identification of the mechanism of secondary mitral regurgitation by echocardiography is essential to understand potential therapies for which a patient could be a candidate for (figure 3). In ischaemic mitral regurgitation, there is tethering of the posterior leaflet which is associated with an akinetic or hypokinetic posterolateral segment of the left ventricular myocardium, resulting in a posteriorly directed jet of mitral regurgitation into the left atrium. In non-ischaemic functional mitral Panel 1: Current controversies in mitral valve disease treatment • The timing of surgery in asymptomatic severe primary mitral regurgitation • Does correction of secondary mitral valve repair impact survival and quality of life? • Should all mitral valve surgery be performed in reference centres? • Do minimally invasive approaches offer a significant advantage over open approaches? • The efficacy and durability of MitraClip for treatment of intermediate and high-risk patients with primary mitral regurgitation • The role of MitraClip in the treatment of secondary mitral regurgitation • The feasibility and effectiveness of novel transcatheter mitral annuloplasty techniques • The feasibility and effectiveness of transcatheter mitral valve replacement • The feasibility and effectiveness of balloon expandable valve replacement in non-rheumatic mitral stenosis due to mitral annular calcification
- 6. Series www.thelancet.com Vol 387 March 26, 2016 1329 regurgitation, tethering of both the posterior and anterior leaflets is often present due to global myocardial systolic dysfunction, with a resulting central jet of mitral regurgitation due to loss of leaflet coaptation. Current treatment Medical therapy First-line treatment for patients with chronic secondary mitral regurgitation consists of guideline-directed medical therapy for left ventricular dysfunction, including angiotensin converting enzyme inhibitors, angiotensin- receptor antagonists, β blockers, and aldosterone antagonists.2,3 For patients with chronic secondary mitral regurgitation and conduction system abnormalities (eg, left-bundle branch block), cardiac resynchronisation therapy with biventricular pacing might improve left ventricular function and reduce mitral regurgitation severity.2,3 Surgical valve replacement and repair Secondary mitral regurgitation is a disease of the left ventricle, therefore intervention should be undertaken only if severe continued symptoms are unresponsive to optimum medical therapy. Correction of secondary mitral regurgitation by repair techniques with an undersized annuloplasty was first described in the 1990s.54 The principle underlying the procedure was that annular dilation is a late event occurring secondary to the leaflet tethering from ventricular dilation. By over- correction of the annular dilation the leaflet coaptation can be restored and mitral regurgitation corrected. Although this technique can abolish mitral regurgitation acutely with short-term symptomatic improvement, the recurrence rate is high (about 33% of patients in a year) and improvement in long-term survival has not been shown. These figures have led to wider use of valve sparing mitral valve replacement.57 In the past 2 years randomised trials58,59 assessing mitral valve repair versus replacement in secondary mitral regurgitation showed equivalent clinical outcomes but a lower recurrence of mitral regurgitation with replacement after 2 years. Additionally, these studies58,59 clarified predisposing factors for recurrence with repair, which included inferobasal aneurysm or dyskinesis, severe leaflet tethering, significant ventricular dilation, or depressed ejection fraction. Hence, patients with these factors should have replacement surgery.60 Transcatheter mitral valve repair Secondary mitral regurgitation is currently the most common indication for MitraClip use in Europe. Many registries show the safety of this procedure and improvements in patient symptoms and quality of life after 1 year, but most patients still have some residual mitral regurgitation.39–41 However, the fundamental question remains about the efficacy of any valve intervention for patients with secondary mitral regurgitation. European guidelines2 both on manage- ment of heart failure and valvular heart disease state that the MitraClip procedure can be considered as an option—mostly to improve symptoms—in patients who are symptomatic despite optimum medical therapy, fulfil the echocardiography criteria of eligibility, are judged to be inoperable or at high surgical risk by a team of cardiologists and cardiac surgeons, and have a life expectancy of more than 1 year.2,61 In the ACC/AHA Heart Failure guidelines62 transcatheter mitral valve repair is deemed to be of uncertain benefit. Other techniques to treatment secondary mitral regurgitation are at an early phase of development. These include coronary sinus annuloplasty (with the Carrillon device [Cardiac Dimensions, Kirkland, WA, USA])63 or direct annuloplasty (with a Cardioband [Valtech Cardio, Or Yehuda, Israel]),51,53,64 which better reproduces a surgically effective technique. More than ten other repair techniques are currently at the experimental or first-in-human stages. A B C D E F Figure 3:Transoesophageal echocardiogram of a patient with secondary (ischaemic) mitral regurgitation (A)Two-dimensional image during systole showing retraction and tenting of the posterior leaflet (arrows), resulting in non-coaptation of the mitral leaflets. (B) Colour-flow imaging showing severe mitral regurgitation with a large colour jet coursing posteriorly; quantitative analysis showed an effective orifice area of 0·5 cm². (C) Operative appearance of undersized annuloplasty and its (D and E) replacement. (F)Three-dimensional echocardiorgam of two MitraClip devices placed for secondary mitral regurgitation. LA=left atrium. LV=left ventricle.
- 7. Series 1330 www.thelancet.com Vol 387 March 26, 2016 Current trials and controversies MitraClip in secondary mitral regurgitation—does correction make a difference? Non-randomised comparisons with historical controls have suggested that in patients with severe secondary mitral regurgitation and left ventricular dysfunction, MitraClip might have a benefit (compared with medical therapy) at reducing the need for readmission to hospital and improve patient survival.65,66 However, data from randomised trials is needed to show that any intervention to correct secondary mitral regurgitation and interrupt the dysfunctional cycle of volume overload from mitral regurgitation thus causing more mitral regurgitation, results in improved long-term outcome. Several ongoing randomised trials (ie, COAPT [NCT01626079], RESHAPE-HF 1 [NCT02444286], MITRA-FR [NCT01920698])67 are comparing only optimal medical management with MitraClip therapy and optimal medical management, using the primary endpoint of death or admission to hospital for heart failure. Of importance will be to establish the short-term and long-term effects of optimum medical therapy, including resynchronisation therapy if indicated, because many patients with secondary mitral regurgitation will show substantial symptomatic improvement and decrease in mitral regurgitation severity, obviating the need for interventional therapy. Results from these trials will help identify the clinical efficacy and applicability of MitraClip in patients with secondary mitral regurgitation. Transcatheter mitral valve replacement early feasibility trials The feasibility of transcatheter mitral valve replacement has been reported in a small number of patients at extreme risk (<100 patients) with native, mitral valve disease, but does not allow for any firm conclusions. On the one hand, implantation of a valve in a non-calcified mitral valve raises several important challenges: its positioning and anchoring, causing obstruction of the left ventricular outflow tract, or coronary circumflex artery or paravalvular leak. On the other hand, transcatheter mitral valve replacement has several theoretical advantages, compared with valve repair, because it is versatile and durably eliminates mitral regurgitation.53 Of the ten ongoing studies, four are early feasibility trials in the USA (Neovasc Tiara Mitral Valve System [TIARA-I; NCT02276547], Tendyne Mitral Valve System [NCT02321514], CardiAQ TMVI System [Transfemoral and Transapical DS; NCT02515539], and Twelve Transcatheter Mitral Valve Replacement [TMVR; NCT02428010]). Treatment in the next 5years A combination of percutaneous techniques—eg, MitraClip plus annuloplasty—could be considered for patients with secondary mitral regurgitation in the future (panel 2). Further developments in technology will refine transcatheter mitral valve replacement devices. As with surgery, the two techniques will probably be comple- mentary: repair being preferred at an early stage of the mitral regurgitation and in the case of less complex anatomy and replacement in those with more advanced and greater leaflet tethering and ventricular dilation. Additional evidence should be accumulated by randomised studies comparing these new techniques with medical therapy or possibly surgery or MitraClip when indicated. The usefulness of left ventricular remodelling devices should also be evaluated. Non-rheumatic mitral stenosis Causes, pathophysiology, and natural history Mitral annular calcification is a chronic degenerative condition of the fibrous mitral annulus, resulting in progressive calcification, particularly involving the posterior annulus.68 The estimated prevalence of mitral annular calcification is 10% of elderly patients, with 1–2% of whom develop stenosis.68–70 Risk factors for mitral annular calcification include older age, being a woman, having chronic kidney disease, and diseases predisposing to left ventricular hypertrophy (ie, hypertension and aortic stenosis).4 Mitral annular calcification seems to be a multifactorial condition resulting from a varying combination of abnormal calcium and phosphorus metabolism,71 increased mitral valve haemodynamic stress,72 and atherosclerotic processes.73–76 Presentation and diagnosis Patients with isolated mitral annular calcification are typically asymptomatic for many years, but then develop symptoms of dyspnoea and exercise intolerance, similar to rheumatic mitral stenosis. Although severe mitral annular calcification can often be seen on chest radiograph and cinefluoroscopy during cardiac catheterisation, echocardiography and CT are the imaging Panel 2: Expectations during the next 5 years • Increase in worldwide prevalence of degenerative mitral regurgitation and non-rheumatic mitral stenosis • Increased knowledge of the epidemiology of secondary mitral regurgitation • Progress in multimodality imaging for pre-procedural screening and procedural performance of transcatheter mitral valve repair and replacement • Increasing rates of durable surgical mitral valve repair versus replacement at low operative mortality • Continued growth in minimally invasive surgical mitral valve repair techniques • Continued development of new transcatheter mitral valve repair technologies • Investigation of hybrid transcatheter repair combining annuloplasty with MitraClip • Ongoing study of transcatheter mitral valve implantation for native mitral valve disease and secondary mitral regurgitation
- 8. Series www.thelancet.com Vol 387 March 26, 2016 1331 tests of choice for diagnosis. With two-dimensional transthoracic echocardiography, mitral annular cal- cification is seen as a bright echo-dense, band-like structure located at the junction of the atrioventricular groove and the posterior mitral leaflet74,77 (figure 4). Severe mitral annular calcification has been defined as a substantial echodensity, involving more than a half of the circumference of the mitral annulus or with intrusion into the left ventricular outflow tract.74 CT allows for quantitation and detailed spatial assessment of the extent of mitral annular calcification (figure 4).78 Mitral annular calcification can be quantified by the Agatston method.79 Specific data regarding the extent of mitral annular calcification, obtained from CT, is useful in procedural planning for potential interventions, particularly if a transcatheter valve implantation is being considered. Mitral stenosis due to mitral annular calcification might become haemodynamically substantial (eg, cause valve dysfunction, either stenosis or regurgitation) if cal- cification extends beyond the annulus and into the mitral leaflets, resulting in restricted leaflet motion in the absence of commissural fusion. Although the transmitral gradient can be accurately assessed by non-invasive Doppler echocardiography, the use of pressure half time for calculation of mitral valve area might not be accurate for non-rheumatic mitral stenosis because of mitral annular calcification.69 Thus, alternative echocardiographic techniques to calculate mitral valve area, such as planimetry or continuity equation, are preferred. Although no universally accepted criteria exist for severe mitral stenosis due to mitral annular calcification, a mitral valve area of 1·5 cm² or smaller has been used in initial, early- phase trials (eg, MITRAL [Mitral Implantation of TRAnscatheter vaLves; NCT02370511]).80 Current treatment Surgery Open surgical techniques to address mitral annular calcification range from extensive debridement of annular calcium to replacement of the valve and leaving the calcium generally intact to place balloon expandable transcatheter aortic valve replacement valves under direct vision during open surgery.81–83 Although reports showed good results with extensive surgical debridement and complex reconstructive techniques with autologous and bovine pericardium and other materials, the procedure is fraught with neurological complications due to calcium embolisation and with the devastating complication of atrioventricular disruption, which is often fatal. Therefore, extensive surgical debridement of annular calcification is not used frequently by most surgeons.83 Placement of stented bioprostheses with techniques using large sutures and excising the anterior leaflet is possible, but the mitral annular calcification frequently restricts the procedure to placement of only small-sized prosthetic valves.84 Case reports and investigative studies are now examining the technique of placement of balloon expandable transcatheter aortic valve replacement valves under direct vision with minimal native valve excision and supporting surgical sutures to prevent embolisation.85 Balloon valvotomy In the absence of commissural fusion, balloon valvulo- plasty is not indicated in patients with degenerative mitral stenosis and mitral annular calcification. Transcatheter valve implantation Case reports and case series presented preliminary experience of implantation of transcatheter aortic valve replacement devices in patients with severe mitral annular calcification who were deemed inoperable or at high risk.86–89 Although the procedural success is high (90%) the 30-day mortality is 35%, occurrence of left ventricular outflow tract obstruction is 11%, and valve embolisation is 7%.80 Experience and procedural and device refinements will be key in patient selection and procedural performance90 and further studies are needed. In this respect, the MITRAL (NCT02370511) trial is a pilot study assessing the results of a transcatheter balloon expandable prosthesis in patients with severe mitral annular calcification who were deemed inoperable. Conclusions The field of mitral valve disease diagnosis and management is rapidly developing. New understanding of disease pathological changes, improvements, and wider uptake of sophisticated imaging modalities (including three-dimensional echo, four-dimensional CT, and cardiac magnetic resonance) are providing new insights leading Figure 4: Mitral annular calcification (MAC) Top row: two-dimensional echocardiographic parasternal short-axis views of two patients with mild (A) and severe (B) MAC (arrows). Bottom row: corresponding gated cardiac CT angiography studies provide more detailed information regarding the density and circumferential extent of calcification in the same patients with mild (C) and severe (D) MAC. A B C D
- 9. Series 1332 www.thelancet.com Vol 387 March 26, 2016 to early diagnosis and complex treatment. In primary mitral regurgitation, surgical repair—often through minimally invasive approaches—is becoming the more commonly used treatment. Treatment of even asymptomatic patients with severe mitral regurgitation in valve reference centres that have high success for repairs and low surgical mortality should be patients’ expectations during the next 5 years. Transcatheter mitral valve repair with MitraClip is also producing excellent outcomes in patients who are of high surgical risk. Clinical trials of MitraClip versus surgery in intermediate risk patients should be expected to begin in the next few years. In patients with secondary mitral regurgitation, the vision for the next 5 years is not as clear. Outcomes from the clinical trials in progress, especially the COAPT trial (NCT01626079), will greatly inform this field of research. If findings from these trials show MitraClip is better than medical therapy regarding patient death and readmission to hospital 1 year after treatment, the use of transcatheter techniques (both repair and replacement) is expected to greatly increase. However, if findings from these trials are not positive, use of these techniques for secondary mitral regurgitation will be slowed. With four early feasibility trials on transcatheter mitral valve replacement underway in the USA, we are likely to see pivotal trials of one or more of these devices in 2017. Mitral annular calcification is an increasing problem in elderly people and is difficult to treat. Use of transcatheter valves by either a catheter-based approach or as a hybrid technique with open surgery are now being assessed in early feasibility trials. Contributors All authors equally contributed to the scientific literature search, writing, editing, and final analyses. 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