There has been substantial progress in the field since the publication of the 2014 American College of Cardiology /American Heart Association Guideline for the Management of Valvular Heart Disease, thus mandating a timely update. Major modifications that were highlighted in the 2017 Focused Update include the treatment choice for aortic stenosis, management of mitral regurgitation, the selection of prosthetic valve type and antiplatelet/antithrombotic therapy for bioprostheses. The current review aims at providing a reasonable interpretation of the most important messages conveyed in the 2017 Focused Update and their implications for the future development of this area.
引用本文： . 2017 ACC/AHA Focused Update of the Guideline for the Management of Patients with Valvular Heart Disease: key messages and future insights. 華西醫學, 2018, 33(2): 173-180. doi: 10.7507/1002-0179.201801144 復制
Introduction
The management of valvular heart disease, particularly transcatheter valve therapies, is a rapidly evolving area that draws extensive attention from the community. The continuously growing body of evidence in this area after the publication of the 2014 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline for the Management of Valvular Heart Disease mandates an update,[1] in order to disseminate the best patient care that meets the current standard. Indeed, the results of several major randomized controlled trials which compare outcomes of different interventions have been reported since then,[2-5] and some of them have already changed decision making of the heart team. The major areas of modification that were highlighted in the 2017 Focused Update include the treatment choice for aortic stenosis, management of mitral regurgitation (MR), the selection of prosthetic valve type and antiplatelet/antithrombotic therapy for bioprostheses.[6] The purpose of the current review is to summarize and interpret the key messages of the 2017 Focused Update that should be remembered and incorporated into daily practice, and provide some reasonable insights into the future development of the field.
1 Treatment choice for aortic stenosis
Transcatheter aortic valve replacement (TAVR) has already established its role as the mainstay of treatment in the real-world practice for patients with severe symptomatic aortic stenosis who are deemed at high or prohibitive surgical risk, and has been increasingly used to treat intermediate-risk (now in commercial practice) and even low-risk patients (as part of randomized controlled trials). In the 2017 Focused Update, new evidence from longer-term follow-up of patients with prohibitive and high surgical risk who have undergone TAVR and additional trials in lower-risk patients has strengthened the recommendation of TAVR across different risk categories.[2-3, 7-8]
1.1 Patients at prohibitive surgical risk
In the 2014 Guideline, TAVR has been recommended as the treatment of choice for patients with severe symptomatic aortic stenosis and at prohibitive risk for surgical aortic valve replacement (SAVR) if the predicted duration of survival post TAVR is over 12 months (class of recommendation Ⅰ, level of evidence B)[1], based on the 2-year results of the randomized PARTNER (Placement of AoRTic TraNscathetER Valve Trial) ⅠB trial, which demonstrated that TAVR was superior to conventional medical therapy (including balloon aortic valvuloplasty) with significantly lower mortality [43.3% vs. 68.0%; hazard ratio (HR)=0.58, 95% confidence interval (CI) (0.36, 0.92), P=0.02].[9] In the 2017 Focused Update, TAVR remains a class Ⅰ recommendation for patients with prohibitive surgical risk, and the level of evidence upgraded from B to A, in view of the 5-year results of the PARTNER ⅠB trial and the additional evidence from a single-arm observational study where a different device (the self-expandable CoreValve) was used to treat patients at extreme surgical risk.[7, 10] The latter showed that 1-year all-cause mortality was 26% with TAVR, significantly lower than that could be expected from conventional therapy (43%).[10]
1.2 Patients at high surgical risk
In patients who are still candidates for SAVR but have high risk, TAVR has now taken on a stronger position in the 2017 Focused Update. The 2014 Guideline considered TAVR as a reasonable alternative to SAVR in this patient group based on the mid-term results of the randomized PARTNER ⅠA trial (class of recommendation Ⅱa, level of evidence B), which demonstrated that TAVR was noninferior to SAVR in this group of patients with comparable mortality at two-year follow-up.[11] Following the publication of the 2014 Guideline, the 5-year results of the PARTNER ⅠA trial was available in 2015, which demonstrated the noninferiority of TAVR versus SAVR in terms of patients’ survival and the durable performance of transcatheter valves up to 5 years.[8] In addition, the US CoreValve High Risk Study which randomized 795 patients showed for the first time that TAVR was superior to SAVR among surgically high-risk patients with a significantly lower all-cause mortality at 1-year follow-up (14.2% vs. 19.1%).[2] The 3-year results of the study further validated these findings by showing a significantly lower risk for death or stroke following TAVR versus SAVR (37.3% vs. 46.7%; P=0.006).[12] Besides, numerous national or multi-center registries including large numbers of patients also consistently reported excellent results of TAVR in the real-world setting.[13-17] Therefore, the class of recommendation for TAVR in high-risk patients has been raised from Ⅱa to Ⅰ, and the level of evidence has been upgraded from B to A in the 2017 Focused Updates.[6] The 2017 Guideline recommends an individualized approach to the choice between TAVR and SAVR for high-risk patients, which should integrate the individual characteristics of each patient, including their values, comorbidities, anatomical characteristics, and life expectancy into decision making.[10]
1.3 Patients at intermediate surgical risk
The expansion of TAVR into lower-risk patients has been a hotly discussed topic for years. After the PARTNER Ⅱ randomized trial achieving its noninferiority end-points, TAVR has now taken its place for the first time in the ACC/AHA Guideline which considers TAVR as a reasonable alternative to SAVR for symptomatic patients with severe aortic stenosis who are deemed at intermediate surgical risk (class of recommendation Ⅱa, level of evidence B-R).[6] The PARTNER Ⅱ trial demonstrated that TAVR with a balloon-expandable valve was noninferior to SAVR in terms of all-cause death or disabling stroke at 2 years [HR=0.89, 95%CI (0.73, 1.09), P=0.25].[3] More recently, another landmark trial, SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation), corroborated the findings of PARTNER Ⅱ by showing that TAVR with a self-expandable valve was non-inferior to SAVR with comparable rates of the primary endpoint of all-cause death or disabling stroke at 2 years for the treatment of severe aortic stenosis in intermediate-risk patients [12.6% vs. 14.0%; 95%CI (Bayesian analysis) for difference (–5.2%, 2.3%); posterior probability of noninferiority, >0.999]. [18] However, the results of SURTAVI trial were released just one week after the publication of the 2017 Focused Update, therefore have not been incorporated into the latter, otherwise the recommendation for TAVR in intermediate risk patients should have been strengthened. Furthermore, it should be noted that most of the TAVR devices used in the PARTNER Ⅱ and SURTAVI trials belong to the first-generation, the TAVR groups could have performed better if treating with newer-generation devices. In a propensity score-matched comparison between TAVR patients with the newer-generation balloon-expandable valve (SAPIEN 3) and SAVR patients from the PARTNER Ⅱ trial, TAVR was superior to SAVR for the primary composite endpoint of mortality, strokes, and moderate or severe aortic regurgitation [pooled weighted proportion difference=–9.2%, 95%CI (–13.0%, –5.4%), P<0.000 1].[19] In view of these, a class Ⅰ recommendation for TAVR in intermediate-risk patients could be anticipated in future guidelines.
Again, the Guideline strengthened the importance of patient-specific variables, including procedural risks, values, and preferences, in the choice of intervention mode for the intermediate-risk group. Indeed, TAVR and SAVR are associated with specific risks, despite of the comparable post-procedural survival according to randomized trials.[3, 18] SAVR is associated with more serious bleeding events, acute kidney injury, and new-onset atrial fibrillation, while TAVR is associated with higher rates of vascular complications and pacemaker implantation (if using a self-expandable valve).[3, 18] However, there is no doubt that any patient would strongly prefer a less-invasive procedure with no surgical scar, faster recovery and shorter hospitalization which at the same time performs at least equally well, and TAVR is such a procedure that would have a major role to play for the treatment of patients with aortic stenosis, including those at low surgical risk. Indeed, such arguments have supported the existing commercial approval of balloon-expandable or self-expanding TAVR for patients at intermediate surgical risk in the United States.
1.4 Patients at low surgical risk
At present, SAVR remains the guideline-recommended treatment modality for symptomatic and indicated asymptomatic patients with severe aortic stenosis and low surgical risk (class of recommendation Ⅰ, level of evidence B-R).[6] However, there is already use of TAVR to treat low-risk patients in both real-world and clinical trial settings.[20-23] The all-comers NOTION (Nordic Aortic Valve Intervention) trial randomized 280 patients (81% were deemed at low surgical risk) to undergo TAVR with the self-expandable valve or SAVR, and found that the primary outcome of all-cause death, stroke and myocardial infarction at 1-year were similar between the two groups (13.1% vs. 16.3%; P=0.43 for superiority).[23] Although the NOTION trial was underpowered to change practice, it did lend some important insights into the future landscape of aortic stenosis treatment. Currently, the NOTION 2 trial (ClinicalTrials.gov Identifier: NCT02825134) is ongoing and will include 992 low-risk patients aged≤75 years and randomize 1:1 to TAVR or SAVR, thus allow the evaluation of TAVR durability. This trial will enroll patients with bicuspid aortic valve, another critical issue to the expansion of TAVR in China and into the younger low-risk patient population of the Western world. Besides, there are two other large-scale randomized trials (designed to include about 1 300 patients each) being conducted in low-risk population, the PARTNER Ⅲ (ClinicalTrials.gov Identifier: NCT02675114) and the Medtronic TAVR in Low Risk Patients (ClinicalTrials.gov Identifier: NCT02701283) studies, which involve the use of the Edwards SAPIEN 3 and the Medtronic CoreValve Evolut R Systems in the TAVR cohort, respectively. These ongoing trials will contribute robust evidence to help us better understand the potential of TAVR and shape the future landscape of this promising technique.
2 Management of MR
2.1 Primary MR
The indication of mitral valve surgery for patients with primary MR in the 2017 Focused Update remains generally the same as the 2014 Guideline, so does the strong preference on mitral valve repair over replacement in certain subsets.[1, 6] Mitral valve repair is favored among surgically indicated patients with severe primary MR involving the anterior leaflet or both leaflets when successful and durable repair can be expected (class of recommendation Ⅰ, level of evidence B), or if the lesion is limited to the posterior leaflet (class of recommendation Ⅰ, level of evidence B).[6] Actually, mitral valve replacement is contraindicated for isolated severe primary MR confined to less than one half of the posterior leaflet unless repair has been attempted and failed (class of recommendation Ⅲ: Harm, level of evidence B).[6]
An important new message in the 2017 Focused Update is related to the timing of surgery for asymptomatic patients with severe primary MR. Overall, MR leads to ventricular and annular dilatation, which in turn increases MR (“MR begets MR”). This perpetual cycle will eventually lead to irreversible left ventricular (LV) dysfunction and poor prognosis if not interrupted timely. According to the 2014 Guideline, evidence of LV dysfunction [impaired left ventricular ejection fraction (LVEF)<60% and/or left ventricular end-systolic diameter (LVESD)≥40 mm] is required to meet an indication for surgical intervention if the patient is asymptomatic (class of recommendation Ⅰ, level of evidence B).[1] However, emerging studies suggest that it could be too late to intervene only after LV dysfunction develops. Data from the Mitral Regurgitation International Database registry showed that among patients with primary MR, LVEF<60% was an independent predictor of death (adjustedHR=1.39, 95%CI (1.03, 1.88), and early surgery compared with watchful waiting was associated with significantly better long-term survival (86% vs. 69% at 10 years, P<0.001) and lower risk of heart failure (7%vs. 23% at 10 years, P<0.001).[24-25] Additionally, a prior study suggested that for the best preservation or post-operative recovery of left ventricular function among patients with primary MR, mitral valve repair should be performed when LVEF≥64% and LVESD<37 mm.[26] Therefore, it is considered reasonable in the 2017 Focused Update to perform mitral valve surgery earlier before reaching the conventional thresholds of LVEF<60% or LVESD≥40 mm if there is a trend of deterioration toward these thresholds on serial studies (class of recommendation Ⅱa, level of evidence C-LD).[6]
2.2 Secondary MR
The prognosis of secondary MR is largely determined by the underlying cardiomyopathy and LV functional status, the benefits of surgical or percutaneous intervention on mitral valve remains less clear, as has been reflected in the 2017 Focused Update.
The previous class Ⅱa recommendation for concomitant mitral valve surgery in the time of coronary artery bypass graft (CABG) or SAVR and class Ⅱb indication for isolated surgery in symptomatic patients with severe secondary MR remains unchanged in the Focused Update.[6] However, the role of mitral valve repair in the setting of secondary MR has weakened in view of the unfavorable results toward repair in two recent randomized controlled trials.[4-5]
One trial involving 251 patients with ischemic MR showed that the recurrence rate of moderate or severe MR over 2 years was much higher following repair than following replacement (58.8% vs. 3.8%, P<0.001), despite of the similar survival rate and LV remodeling.[4] Hence, chordal-sparing mitral valve replacement is now favored over downsized annuloplasty repair in the 2017 Focused Update among severely symptomatic patients [New York Heart Association (NYHA) class Ⅲ to Ⅳ] with chronic severe ischemic MR and persistent symptoms despite optimal medical treatment for heart failure including cardiac resynchronization therapy (class of recommendation Ⅱa, level of evidence B-R).[6]
Furthermore, another randomized trial observed that concomitant mitral valve repair generated no benefit in terms of survival or LV remodeling but higher rates of neurologic events and supraventricular arrhythmias on 2-year follow-up compared with isolated CABG among patients with moderate ischemic MR.[5] These findings challenged previous guideline recommendations, where mitral repair for such patients was supported.[1] The 2017 Focused Updates now do not recommend concomitant mitral valve repair in patients with chronic moderate ischemic MR undergoing CABG, as the usefulness of this is considered to be uncertain in this patient subset.[6]
2.3 The role of transcatheter mitral valve intervention
Open-heart surgery, with proven satisfactory and durable outcomes demonstrated over time, remains the standard treatment for severe MR. However, at least 50% of patients with severe MR did not undergo surgery owning to various reasons, particularly an increased operative risk.[27] Transcatheter mitral valve repair is an attractive alternative for these patients with its less invasive nature and good early safety profile. At present, the MitraClip edge-to-edge repair system is the only device approved by US Food and Drug Administration (FDA) for transcatheter mitral valve repair, with its labeled use limited to patients with primary degenerative MR and deemed at prohibitive surgical risk. Additional evidence from the final 5-year outcome of the EVEREST Ⅱ (Endovascular Valve Edge-to-Edge Repair Study) trial and registry studies has not earned a strengthened recommendation for MitraClip in the Focused Update.[28] In line with the 2014 Guideline, transcatheter mitral valve repair (with MitraClip) now remains a class Ⅱb indication for patients with severely symptomatic chronic severe primary MR (NYHA class Ⅲ to Ⅳ) despite optimal medical therapy, who had favorable anatomy, reasonable life expectancy and prohibitive surgical risk.[6] It is still unknown till now as to whether transcatheter mitral valve repair has a role to play in the treatment of secondary MR. The ongoing COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial (ClinicalTrials.gov Identifier: NCT01626079) aims at evaluating the comparative efficacy of transcatheter mitral valve repair with MitraClip relative to optimal medical treatment for secondary MR.
Transcatheter mitral valve replacement represents the new frontier in the field of cardiac structural interventions. However, this technology is still at the preliminary stage of development. Multiple dedicated devices of different designs are under preclinical early feasibility trials. It appears this field will grow much more slowly compared with TAVR, in view of the more complex mitral valve anatomy and pathology. In the near future, transcatheter mitral valve replacement might potentially serve as a therapeutic option for patients with severe MR who are considered unsuitable for valve repair or surgical valve replacement due to unfavorable anatomy or prohibitive surgical risk.
3 Prosthetic valve type and antithrombotic therapy
3.1 Selection of prosthetic valve
The 2014 Guideline recommended mechanical aortic or mitral prosthesis for patients younger than 60 years and bioprosthesis for those over 70 years of age, and suggested an individualized approach to the selection between mechanical and bioprosthetic valve for patients aged between 60 and 70 years.[1] The 2017 Focused Update now lowers the age limit for mechanical prosthesis down to 50 years, in view of the similar long-term prognosis among patients 50 to 70 years of age following bioprosthetic versus mechanical aortic or mitral valve replacement as shown in several recent large studies and the future opportunity of transcatheter valve-in-valve for failed bioprosthesis.[6, 29-33] The results of valve-in-valve are generally promising thanks to the rapid evolvement of TAVR, despite of the potential risk of significant residual pressure gradient and patient-prosthesis mismatch in those with an initially small surgical bioprosthesis.[32-33] The US FDA granted for aortic valve-in-valve using the Medtronic Corevalve system in 2015 and approval for aortic and mitral valve-in-valve procedures using the Edwards SAPIEN 3 transcatheter heart valve in 2017.
According to the guideline, the intermediate age range of 50 to 70 years old is a “gray area”, where uncertainty remains and the choice of prosthetic valve type should be a shared decision-making process that based primarily on the trade-offs between durability and the risk of bleeding and thromboembolism, taking into account patient preference, compliance and aortic root dimensions.[6] Besides, patients should be informed of the viable choice of transcatheter valve-in-valve for failed surgical bioprosthesis. Importantly, if bioprosthesis is selected and there is potential requirement for reintervention during the patient’s lifetime, the largest possible size should be considered so as to preserve the future opportunity for valve-in-valve.[32]
Undoubtedly, controversies will continue over the issue. Nevertheless, there has been a trend toward increasing use of bioprosthetic valve in either aortic or mitral position. For example, according to the US national Society of Thoracic Surgeons (STS) database, the use of bioprosthetic valves for SAVR increased from 37.7% to 63.5% from 1998 to 2011.[34] While the trend was seen across all age groups, it was most pronounced among patients aged 55 to 64 years. Data from the German Aortic Valve Registry also showed a temporal trend of the increasing use of bioprosthetic aortic valves in patients younger than 65 years from 50.1% in 2011 to 65.7% in 2015.[35] Similarly, from the STS database, the use of mechanical valve in mitral position declined remarkably from 68% in 2000 to 37% in 2007.[36]
3.2 Antithrombotic therapy for bioprosthetic valves
While the 2017 recommendations of antithrombotic therapy for mechanical valve remain generally the same as the 2014 Guideline, those for surgical or transcatheter bioprostheses trend toward a prolonged or intensified regimen.
The 2014 Guideline considered it reasonable to maintain anticoagulation with a vitamin K antagonist (VKA) for the first 3 months after surgical aortic or mitral bioprosthetic valve replacement (class of recommendation Ⅱa and Ⅱb for bioprosthesis in mitral and aortic position, respectively), which coincides with the observation that device endothelialization is completed at about 3 months after the procedure and the risk of thromboembolic events is highest within the first 3 months.[6] However, there has been a large observational study demonstrating a significantly higher risk of cardiovascular death with the discontinuation of VKA treatment 3 months after bioprosthetic SAVR.[37] The estimated rate of cardiovascular death per 100 person-years within 90 to 179 days after surgery was 6.50 [95%CI (4.67, 9.06)] in patients not treated with VKA versus 2.08 [95%CI (0.99, 4.36); adjusted incidence rate ratio=3.51, 95%CI (1.54, 8.03)] in those on VKA.[37] Besides, a more recent study reported a higher-than-expected incidence (11.6%) of surgical bioprosthetic valve thrombosis, raising further concerns over the optimal antithrombotic strategy for surgical bioprosthesis.[38] Therefore, the 2017 Focused Update now recommends the extension of anticoagulation with a VKA to achieve an international normalized ratio (INR) of 2.5 to as long as 6 months after surgical aortic or mitral bioprosthetic valve replacement if the risk of bleeding is low (class of recommendation Ⅱa, level of evidence B-NR).[6]
For patients undergoing TAVR, the 2014 Guideline recommended dual antiplatelet therapy with aspirin (75 to 100 mg daily) and clopidogrel (75 mg daily) for 1 to 6 months followed by indefinite use of aspirin, which is currently the most commonly used antithrombotic regimen. However, the selection of this regimen is actually based on the experiences from early clinical trials and expert consensus, without the support of any robust evidence.[39] A recent study based on four-dimensional computerized tomography observed the phenomenon of hypo-attenuating opacities and reduced leaflet motion in up to 40% of patients treated with TAVR, suggesting that the prevalence of bioprosthetic valve thrombosis could have been substantially underestimated.[40] Importantly, reduced leaflet motion in this study was seen exclusively in patients not on warfarin therapy, and appeared to be associated with an increased risk of stroke.[40] These findings, which were corroborated in later studies,[41-42] have raised extensive concerns over the potency of the currently-recommended antiplatelet-based antithrombotic regimen. In view of the above, the 2017 Focused Update now states that anticoagulation with a VKA to achieve an INR of 2.5 may be reasonable for at least 3 months after TAVR in patients at low risk of bleeding (class of recommendation Ⅱb, level of evidence B-NR),[6] which is a new recommendation compared with the 2014 Guideline.[1] Meanwhile, dual antiplatelet therapy with clopidogrel and aspirin is stated as a reasonable antithrombotic regimen for the first 6 months after TAVR. However, recent randomized data not yet incorporated in the guidelines have suggested no benefit from dual antiplatelet therapy and that aspirin monotherapy may confer a lower risk of bleeding complications.[43] Moreover, there is no recommendation regarding the choice between dual antiplatelet therapy and anticoagulation. Indeed, in this respect, randomized trials incorporating various regimens of VKA and new oral anticoagulants versus antiplatelet therapy are underway to define the best antiplatelet/antithrombotic strategy for TAVR patients, who are frailer compared with SAVR population and may have different risk/benefit ratio for specific pharmacotherapies.
4 Conclusion
In summary, the progress made in the field of transcatheter valve interventions keeps revolutionizing the care of patients with valvular heart disease, as is reflected in the updated guideline. TAVR has been taking a stronger position in the treatment of aortic stenosis as well as failed bioprostheses. While surgery will remain as the mainstay of treatment for MR, transcatheter mitral valve repair and replacement could serve as an indispensable choice for certain subset of patients with elevated surgical risk. The major ongoing trials in the area will continue to transform our concepts and practice.
Introduction
The management of valvular heart disease, particularly transcatheter valve therapies, is a rapidly evolving area that draws extensive attention from the community. The continuously growing body of evidence in this area after the publication of the 2014 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline for the Management of Valvular Heart Disease mandates an update,[1] in order to disseminate the best patient care that meets the current standard. Indeed, the results of several major randomized controlled trials which compare outcomes of different interventions have been reported since then,[2-5] and some of them have already changed decision making of the heart team. The major areas of modification that were highlighted in the 2017 Focused Update include the treatment choice for aortic stenosis, management of mitral regurgitation (MR), the selection of prosthetic valve type and antiplatelet/antithrombotic therapy for bioprostheses.[6] The purpose of the current review is to summarize and interpret the key messages of the 2017 Focused Update that should be remembered and incorporated into daily practice, and provide some reasonable insights into the future development of the field.
1 Treatment choice for aortic stenosis
Transcatheter aortic valve replacement (TAVR) has already established its role as the mainstay of treatment in the real-world practice for patients with severe symptomatic aortic stenosis who are deemed at high or prohibitive surgical risk, and has been increasingly used to treat intermediate-risk (now in commercial practice) and even low-risk patients (as part of randomized controlled trials). In the 2017 Focused Update, new evidence from longer-term follow-up of patients with prohibitive and high surgical risk who have undergone TAVR and additional trials in lower-risk patients has strengthened the recommendation of TAVR across different risk categories.[2-3, 7-8]
1.1 Patients at prohibitive surgical risk
In the 2014 Guideline, TAVR has been recommended as the treatment of choice for patients with severe symptomatic aortic stenosis and at prohibitive risk for surgical aortic valve replacement (SAVR) if the predicted duration of survival post TAVR is over 12 months (class of recommendation Ⅰ, level of evidence B)[1], based on the 2-year results of the randomized PARTNER (Placement of AoRTic TraNscathetER Valve Trial) ⅠB trial, which demonstrated that TAVR was superior to conventional medical therapy (including balloon aortic valvuloplasty) with significantly lower mortality [43.3% vs. 68.0%; hazard ratio (HR)=0.58, 95% confidence interval (CI) (0.36, 0.92), P=0.02].[9] In the 2017 Focused Update, TAVR remains a class Ⅰ recommendation for patients with prohibitive surgical risk, and the level of evidence upgraded from B to A, in view of the 5-year results of the PARTNER ⅠB trial and the additional evidence from a single-arm observational study where a different device (the self-expandable CoreValve) was used to treat patients at extreme surgical risk.[7, 10] The latter showed that 1-year all-cause mortality was 26% with TAVR, significantly lower than that could be expected from conventional therapy (43%).[10]
1.2 Patients at high surgical risk
In patients who are still candidates for SAVR but have high risk, TAVR has now taken on a stronger position in the 2017 Focused Update. The 2014 Guideline considered TAVR as a reasonable alternative to SAVR in this patient group based on the mid-term results of the randomized PARTNER ⅠA trial (class of recommendation Ⅱa, level of evidence B), which demonstrated that TAVR was noninferior to SAVR in this group of patients with comparable mortality at two-year follow-up.[11] Following the publication of the 2014 Guideline, the 5-year results of the PARTNER ⅠA trial was available in 2015, which demonstrated the noninferiority of TAVR versus SAVR in terms of patients’ survival and the durable performance of transcatheter valves up to 5 years.[8] In addition, the US CoreValve High Risk Study which randomized 795 patients showed for the first time that TAVR was superior to SAVR among surgically high-risk patients with a significantly lower all-cause mortality at 1-year follow-up (14.2% vs. 19.1%).[2] The 3-year results of the study further validated these findings by showing a significantly lower risk for death or stroke following TAVR versus SAVR (37.3% vs. 46.7%; P=0.006).[12] Besides, numerous national or multi-center registries including large numbers of patients also consistently reported excellent results of TAVR in the real-world setting.[13-17] Therefore, the class of recommendation for TAVR in high-risk patients has been raised from Ⅱa to Ⅰ, and the level of evidence has been upgraded from B to A in the 2017 Focused Updates.[6] The 2017 Guideline recommends an individualized approach to the choice between TAVR and SAVR for high-risk patients, which should integrate the individual characteristics of each patient, including their values, comorbidities, anatomical characteristics, and life expectancy into decision making.[10]
1.3 Patients at intermediate surgical risk
The expansion of TAVR into lower-risk patients has been a hotly discussed topic for years. After the PARTNER Ⅱ randomized trial achieving its noninferiority end-points, TAVR has now taken its place for the first time in the ACC/AHA Guideline which considers TAVR as a reasonable alternative to SAVR for symptomatic patients with severe aortic stenosis who are deemed at intermediate surgical risk (class of recommendation Ⅱa, level of evidence B-R).[6] The PARTNER Ⅱ trial demonstrated that TAVR with a balloon-expandable valve was noninferior to SAVR in terms of all-cause death or disabling stroke at 2 years [HR=0.89, 95%CI (0.73, 1.09), P=0.25].[3] More recently, another landmark trial, SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation), corroborated the findings of PARTNER Ⅱ by showing that TAVR with a self-expandable valve was non-inferior to SAVR with comparable rates of the primary endpoint of all-cause death or disabling stroke at 2 years for the treatment of severe aortic stenosis in intermediate-risk patients [12.6% vs. 14.0%; 95%CI (Bayesian analysis) for difference (–5.2%, 2.3%); posterior probability of noninferiority, >0.999]. [18] However, the results of SURTAVI trial were released just one week after the publication of the 2017 Focused Update, therefore have not been incorporated into the latter, otherwise the recommendation for TAVR in intermediate risk patients should have been strengthened. Furthermore, it should be noted that most of the TAVR devices used in the PARTNER Ⅱ and SURTAVI trials belong to the first-generation, the TAVR groups could have performed better if treating with newer-generation devices. In a propensity score-matched comparison between TAVR patients with the newer-generation balloon-expandable valve (SAPIEN 3) and SAVR patients from the PARTNER Ⅱ trial, TAVR was superior to SAVR for the primary composite endpoint of mortality, strokes, and moderate or severe aortic regurgitation [pooled weighted proportion difference=–9.2%, 95%CI (–13.0%, –5.4%), P<0.000 1].[19] In view of these, a class Ⅰ recommendation for TAVR in intermediate-risk patients could be anticipated in future guidelines.
Again, the Guideline strengthened the importance of patient-specific variables, including procedural risks, values, and preferences, in the choice of intervention mode for the intermediate-risk group. Indeed, TAVR and SAVR are associated with specific risks, despite of the comparable post-procedural survival according to randomized trials.[3, 18] SAVR is associated with more serious bleeding events, acute kidney injury, and new-onset atrial fibrillation, while TAVR is associated with higher rates of vascular complications and pacemaker implantation (if using a self-expandable valve).[3, 18] However, there is no doubt that any patient would strongly prefer a less-invasive procedure with no surgical scar, faster recovery and shorter hospitalization which at the same time performs at least equally well, and TAVR is such a procedure that would have a major role to play for the treatment of patients with aortic stenosis, including those at low surgical risk. Indeed, such arguments have supported the existing commercial approval of balloon-expandable or self-expanding TAVR for patients at intermediate surgical risk in the United States.
1.4 Patients at low surgical risk
At present, SAVR remains the guideline-recommended treatment modality for symptomatic and indicated asymptomatic patients with severe aortic stenosis and low surgical risk (class of recommendation Ⅰ, level of evidence B-R).[6] However, there is already use of TAVR to treat low-risk patients in both real-world and clinical trial settings.[20-23] The all-comers NOTION (Nordic Aortic Valve Intervention) trial randomized 280 patients (81% were deemed at low surgical risk) to undergo TAVR with the self-expandable valve or SAVR, and found that the primary outcome of all-cause death, stroke and myocardial infarction at 1-year were similar between the two groups (13.1% vs. 16.3%; P=0.43 for superiority).[23] Although the NOTION trial was underpowered to change practice, it did lend some important insights into the future landscape of aortic stenosis treatment. Currently, the NOTION 2 trial (ClinicalTrials.gov Identifier: NCT02825134) is ongoing and will include 992 low-risk patients aged≤75 years and randomize 1:1 to TAVR or SAVR, thus allow the evaluation of TAVR durability. This trial will enroll patients with bicuspid aortic valve, another critical issue to the expansion of TAVR in China and into the younger low-risk patient population of the Western world. Besides, there are two other large-scale randomized trials (designed to include about 1 300 patients each) being conducted in low-risk population, the PARTNER Ⅲ (ClinicalTrials.gov Identifier: NCT02675114) and the Medtronic TAVR in Low Risk Patients (ClinicalTrials.gov Identifier: NCT02701283) studies, which involve the use of the Edwards SAPIEN 3 and the Medtronic CoreValve Evolut R Systems in the TAVR cohort, respectively. These ongoing trials will contribute robust evidence to help us better understand the potential of TAVR and shape the future landscape of this promising technique.
2 Management of MR
2.1 Primary MR
The indication of mitral valve surgery for patients with primary MR in the 2017 Focused Update remains generally the same as the 2014 Guideline, so does the strong preference on mitral valve repair over replacement in certain subsets.[1, 6] Mitral valve repair is favored among surgically indicated patients with severe primary MR involving the anterior leaflet or both leaflets when successful and durable repair can be expected (class of recommendation Ⅰ, level of evidence B), or if the lesion is limited to the posterior leaflet (class of recommendation Ⅰ, level of evidence B).[6] Actually, mitral valve replacement is contraindicated for isolated severe primary MR confined to less than one half of the posterior leaflet unless repair has been attempted and failed (class of recommendation Ⅲ: Harm, level of evidence B).[6]
An important new message in the 2017 Focused Update is related to the timing of surgery for asymptomatic patients with severe primary MR. Overall, MR leads to ventricular and annular dilatation, which in turn increases MR (“MR begets MR”). This perpetual cycle will eventually lead to irreversible left ventricular (LV) dysfunction and poor prognosis if not interrupted timely. According to the 2014 Guideline, evidence of LV dysfunction [impaired left ventricular ejection fraction (LVEF)<60% and/or left ventricular end-systolic diameter (LVESD)≥40 mm] is required to meet an indication for surgical intervention if the patient is asymptomatic (class of recommendation Ⅰ, level of evidence B).[1] However, emerging studies suggest that it could be too late to intervene only after LV dysfunction develops. Data from the Mitral Regurgitation International Database registry showed that among patients with primary MR, LVEF<60% was an independent predictor of death (adjustedHR=1.39, 95%CI (1.03, 1.88), and early surgery compared with watchful waiting was associated with significantly better long-term survival (86% vs. 69% at 10 years, P<0.001) and lower risk of heart failure (7%vs. 23% at 10 years, P<0.001).[24-25] Additionally, a prior study suggested that for the best preservation or post-operative recovery of left ventricular function among patients with primary MR, mitral valve repair should be performed when LVEF≥64% and LVESD<37 mm.[26] Therefore, it is considered reasonable in the 2017 Focused Update to perform mitral valve surgery earlier before reaching the conventional thresholds of LVEF<60% or LVESD≥40 mm if there is a trend of deterioration toward these thresholds on serial studies (class of recommendation Ⅱa, level of evidence C-LD).[6]
2.2 Secondary MR
The prognosis of secondary MR is largely determined by the underlying cardiomyopathy and LV functional status, the benefits of surgical or percutaneous intervention on mitral valve remains less clear, as has been reflected in the 2017 Focused Update.
The previous class Ⅱa recommendation for concomitant mitral valve surgery in the time of coronary artery bypass graft (CABG) or SAVR and class Ⅱb indication for isolated surgery in symptomatic patients with severe secondary MR remains unchanged in the Focused Update.[6] However, the role of mitral valve repair in the setting of secondary MR has weakened in view of the unfavorable results toward repair in two recent randomized controlled trials.[4-5]
One trial involving 251 patients with ischemic MR showed that the recurrence rate of moderate or severe MR over 2 years was much higher following repair than following replacement (58.8% vs. 3.8%, P<0.001), despite of the similar survival rate and LV remodeling.[4] Hence, chordal-sparing mitral valve replacement is now favored over downsized annuloplasty repair in the 2017 Focused Update among severely symptomatic patients [New York Heart Association (NYHA) class Ⅲ to Ⅳ] with chronic severe ischemic MR and persistent symptoms despite optimal medical treatment for heart failure including cardiac resynchronization therapy (class of recommendation Ⅱa, level of evidence B-R).[6]
Furthermore, another randomized trial observed that concomitant mitral valve repair generated no benefit in terms of survival or LV remodeling but higher rates of neurologic events and supraventricular arrhythmias on 2-year follow-up compared with isolated CABG among patients with moderate ischemic MR.[5] These findings challenged previous guideline recommendations, where mitral repair for such patients was supported.[1] The 2017 Focused Updates now do not recommend concomitant mitral valve repair in patients with chronic moderate ischemic MR undergoing CABG, as the usefulness of this is considered to be uncertain in this patient subset.[6]
2.3 The role of transcatheter mitral valve intervention
Open-heart surgery, with proven satisfactory and durable outcomes demonstrated over time, remains the standard treatment for severe MR. However, at least 50% of patients with severe MR did not undergo surgery owning to various reasons, particularly an increased operative risk.[27] Transcatheter mitral valve repair is an attractive alternative for these patients with its less invasive nature and good early safety profile. At present, the MitraClip edge-to-edge repair system is the only device approved by US Food and Drug Administration (FDA) for transcatheter mitral valve repair, with its labeled use limited to patients with primary degenerative MR and deemed at prohibitive surgical risk. Additional evidence from the final 5-year outcome of the EVEREST Ⅱ (Endovascular Valve Edge-to-Edge Repair Study) trial and registry studies has not earned a strengthened recommendation for MitraClip in the Focused Update.[28] In line with the 2014 Guideline, transcatheter mitral valve repair (with MitraClip) now remains a class Ⅱb indication for patients with severely symptomatic chronic severe primary MR (NYHA class Ⅲ to Ⅳ) despite optimal medical therapy, who had favorable anatomy, reasonable life expectancy and prohibitive surgical risk.[6] It is still unknown till now as to whether transcatheter mitral valve repair has a role to play in the treatment of secondary MR. The ongoing COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial (ClinicalTrials.gov Identifier: NCT01626079) aims at evaluating the comparative efficacy of transcatheter mitral valve repair with MitraClip relative to optimal medical treatment for secondary MR.
Transcatheter mitral valve replacement represents the new frontier in the field of cardiac structural interventions. However, this technology is still at the preliminary stage of development. Multiple dedicated devices of different designs are under preclinical early feasibility trials. It appears this field will grow much more slowly compared with TAVR, in view of the more complex mitral valve anatomy and pathology. In the near future, transcatheter mitral valve replacement might potentially serve as a therapeutic option for patients with severe MR who are considered unsuitable for valve repair or surgical valve replacement due to unfavorable anatomy or prohibitive surgical risk.
3 Prosthetic valve type and antithrombotic therapy
3.1 Selection of prosthetic valve
The 2014 Guideline recommended mechanical aortic or mitral prosthesis for patients younger than 60 years and bioprosthesis for those over 70 years of age, and suggested an individualized approach to the selection between mechanical and bioprosthetic valve for patients aged between 60 and 70 years.[1] The 2017 Focused Update now lowers the age limit for mechanical prosthesis down to 50 years, in view of the similar long-term prognosis among patients 50 to 70 years of age following bioprosthetic versus mechanical aortic or mitral valve replacement as shown in several recent large studies and the future opportunity of transcatheter valve-in-valve for failed bioprosthesis.[6, 29-33] The results of valve-in-valve are generally promising thanks to the rapid evolvement of TAVR, despite of the potential risk of significant residual pressure gradient and patient-prosthesis mismatch in those with an initially small surgical bioprosthesis.[32-33] The US FDA granted for aortic valve-in-valve using the Medtronic Corevalve system in 2015 and approval for aortic and mitral valve-in-valve procedures using the Edwards SAPIEN 3 transcatheter heart valve in 2017.
According to the guideline, the intermediate age range of 50 to 70 years old is a “gray area”, where uncertainty remains and the choice of prosthetic valve type should be a shared decision-making process that based primarily on the trade-offs between durability and the risk of bleeding and thromboembolism, taking into account patient preference, compliance and aortic root dimensions.[6] Besides, patients should be informed of the viable choice of transcatheter valve-in-valve for failed surgical bioprosthesis. Importantly, if bioprosthesis is selected and there is potential requirement for reintervention during the patient’s lifetime, the largest possible size should be considered so as to preserve the future opportunity for valve-in-valve.[32]
Undoubtedly, controversies will continue over the issue. Nevertheless, there has been a trend toward increasing use of bioprosthetic valve in either aortic or mitral position. For example, according to the US national Society of Thoracic Surgeons (STS) database, the use of bioprosthetic valves for SAVR increased from 37.7% to 63.5% from 1998 to 2011.[34] While the trend was seen across all age groups, it was most pronounced among patients aged 55 to 64 years. Data from the German Aortic Valve Registry also showed a temporal trend of the increasing use of bioprosthetic aortic valves in patients younger than 65 years from 50.1% in 2011 to 65.7% in 2015.[35] Similarly, from the STS database, the use of mechanical valve in mitral position declined remarkably from 68% in 2000 to 37% in 2007.[36]
3.2 Antithrombotic therapy for bioprosthetic valves
While the 2017 recommendations of antithrombotic therapy for mechanical valve remain generally the same as the 2014 Guideline, those for surgical or transcatheter bioprostheses trend toward a prolonged or intensified regimen.
The 2014 Guideline considered it reasonable to maintain anticoagulation with a vitamin K antagonist (VKA) for the first 3 months after surgical aortic or mitral bioprosthetic valve replacement (class of recommendation Ⅱa and Ⅱb for bioprosthesis in mitral and aortic position, respectively), which coincides with the observation that device endothelialization is completed at about 3 months after the procedure and the risk of thromboembolic events is highest within the first 3 months.[6] However, there has been a large observational study demonstrating a significantly higher risk of cardiovascular death with the discontinuation of VKA treatment 3 months after bioprosthetic SAVR.[37] The estimated rate of cardiovascular death per 100 person-years within 90 to 179 days after surgery was 6.50 [95%CI (4.67, 9.06)] in patients not treated with VKA versus 2.08 [95%CI (0.99, 4.36); adjusted incidence rate ratio=3.51, 95%CI (1.54, 8.03)] in those on VKA.[37] Besides, a more recent study reported a higher-than-expected incidence (11.6%) of surgical bioprosthetic valve thrombosis, raising further concerns over the optimal antithrombotic strategy for surgical bioprosthesis.[38] Therefore, the 2017 Focused Update now recommends the extension of anticoagulation with a VKA to achieve an international normalized ratio (INR) of 2.5 to as long as 6 months after surgical aortic or mitral bioprosthetic valve replacement if the risk of bleeding is low (class of recommendation Ⅱa, level of evidence B-NR).[6]
For patients undergoing TAVR, the 2014 Guideline recommended dual antiplatelet therapy with aspirin (75 to 100 mg daily) and clopidogrel (75 mg daily) for 1 to 6 months followed by indefinite use of aspirin, which is currently the most commonly used antithrombotic regimen. However, the selection of this regimen is actually based on the experiences from early clinical trials and expert consensus, without the support of any robust evidence.[39] A recent study based on four-dimensional computerized tomography observed the phenomenon of hypo-attenuating opacities and reduced leaflet motion in up to 40% of patients treated with TAVR, suggesting that the prevalence of bioprosthetic valve thrombosis could have been substantially underestimated.[40] Importantly, reduced leaflet motion in this study was seen exclusively in patients not on warfarin therapy, and appeared to be associated with an increased risk of stroke.[40] These findings, which were corroborated in later studies,[41-42] have raised extensive concerns over the potency of the currently-recommended antiplatelet-based antithrombotic regimen. In view of the above, the 2017 Focused Update now states that anticoagulation with a VKA to achieve an INR of 2.5 may be reasonable for at least 3 months after TAVR in patients at low risk of bleeding (class of recommendation Ⅱb, level of evidence B-NR),[6] which is a new recommendation compared with the 2014 Guideline.[1] Meanwhile, dual antiplatelet therapy with clopidogrel and aspirin is stated as a reasonable antithrombotic regimen for the first 6 months after TAVR. However, recent randomized data not yet incorporated in the guidelines have suggested no benefit from dual antiplatelet therapy and that aspirin monotherapy may confer a lower risk of bleeding complications.[43] Moreover, there is no recommendation regarding the choice between dual antiplatelet therapy and anticoagulation. Indeed, in this respect, randomized trials incorporating various regimens of VKA and new oral anticoagulants versus antiplatelet therapy are underway to define the best antiplatelet/antithrombotic strategy for TAVR patients, who are frailer compared with SAVR population and may have different risk/benefit ratio for specific pharmacotherapies.
4 Conclusion
In summary, the progress made in the field of transcatheter valve interventions keeps revolutionizing the care of patients with valvular heart disease, as is reflected in the updated guideline. TAVR has been taking a stronger position in the treatment of aortic stenosis as well as failed bioprostheses. While surgery will remain as the mainstay of treatment for MR, transcatheter mitral valve repair and replacement could serve as an indispensable choice for certain subset of patients with elevated surgical risk. The major ongoing trials in the area will continue to transform our concepts and practice.