The year in cardiovascular medicine 2021: valvular heart disease

The increasing burden of valvular heart disease (VHD)—in particular in an ageing population—is recognized by medical experts, although there is less awareness of these conditions by the general public and relevant stakeholders. Together with emerging non-surgical interventional treatment options, this has led to intense research interest in VHD with an enormous number of publications during the last year. Many of these publications address interventional treatment, including technical refinements and outcomes compared with surgery or medical therapy. In addition, attention has focused on pathophysiological aspects, improved diagnosis, risk stratification, and optimal timing for intervention. Importantly, new guidelines for the management of VHD have been published by both the ESC/EACTS and ACC/AHA.1,2 This short overview can neither address all changes in the guidelines nor acknowledge all appreciable research efforts over this year. Thus, we have selected a few papers as examples that reflect the breadth of ongoing research, with the expectation that interested readers will find additional articles using online searches. There is increasing evidence that disease-modifying therapies for calcific aortic stenosis (AS) may be possible. Preclinical and observational studies had suggested that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms but in a double-blind randomized controlled trial (RCT) neither denosumab nor alendronic acid was shown to affect the progression of aortic valve calcification.3 Lee et al.4 reported in a retrospective analysis of patients with diabetes and mild-to-moderate AS that dipeptidyl peptidase-4 inhibitors with favourable pharmacokinetic and pharmacodynamic properties were associated with lower risk of AS progression. Pérez de Isla et al.5 reported a higher incidence of aortic valve replacement (AVR) in patients with familial hypercholesterolaemia (FH) based on data from SAFEHEART—a long-term prospective cohort study of a population with and non-affected relatives including a total of 5022 subjects. Cox regression analysis demonstrated an association between FH and AVR [hazard ratio (HR): 3.89; 95% confidence interval (CI): 1.20–12.63; P = 0.024], with older age, previous atherosclerotic cardiovascular disease, hypertension, increased LDL-cholesterol Lp(a) —years, and elevated Lp(a) being independently predictive of an event suggesting that reduction in LDL-cholesterol and Lp(a) together with control of hypertension could retard the progression of AS in FH. All these studies, however, remain only hypothesis generating, and further research is required to evaluate potential treatment options. The diagnosis of severe AS and identification of patients who benefit from intervention remains challenging in the setting of low-gradient AS. Mosleh et al.6 reported a similar benefit of transcatheter aortic valve implantation (TAVI) in patients with high-gradient AS and paradoxical low-flow–low-gradient AS using propensity score matching. A meta-analysis including 32 studies found the similar benefit of AVR in patients with classical low-flow–low-gradient AS, paradoxical low-flow–low-gradient AS, and even normal flow–low-gradient AS (HR for all-cause mortality 0.41–0.42).7 Conversely, Freitas-Ferraz et al.8 reported that one-third of patients with paradoxical low-flow–low-gradient AS failed to benefit from intervention. Bienjounetti-Boudreau et al.9 reported that in patients with low-gradient AS, women had lower survival compared with men, possibly related to a lower rate of AVR, raising concerns about correct diagnosis and clinical decision-making for women in this setting. These studies emphasize the importance of an integrated approach, including additional parameters such as quantification of valve calcification, in the setting of low-gradient AS1 to avoid both, over- or undertreatment. An integrated approach also may be appropriate in patients with normal flow–low-gradient AS. Availability of the international consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy will be helpful for clinical, surgical, interventional, and research purposes.10 The updated ESC/EACTS and ACC/AHA guidelines continue to recommend AVR only in selected patients with asymptomatic AS although results from ongoing RCTs are awaited.1,2 Recently, the results of the AVATAR (Aortic Valve ReplAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis) Trial were published.11 In 157 patients with severe asymptomatic AS (including a negative exercise test) who were randomly allocated to early surgery or conservative treatment, the surgical group had a significantly lower incidence of the primary composite endpoint (all-cause mortality, acute myocardial infarction, stroke or unplanned hospitalization for heart failure). These findings require confirmation in larger studies and over a longer follow-up time, given the use of a combined endpoint and the issue of valve durability over the patient’s lifetime. In the current guidelines, the thresholds where intervention should be considered (Class IIa recommendation) in asymptomatic patients with severe AS were lowered to left ventricular ejection fraction (LVEF) < 55% and peak transvalvular velocity ≥5 m/s in surgical low-risk patients1 (Figure 1). Selected important new recommendations in the 2021 ESC/EACTS guidelines for the management of valvular heart disease. Reproduced with permission from Vahanian et al.1 Selected important new recommendations in the 2021 ESC/EACTS guidelines for the management of valvular heart disease. Reproduced with permission from Vahanian et al.1 Jean et al.12 reported that in a series of patients with heart failure (HF) and reduced ejection fraction, moderate AS was associated with a marked incremental risk of mortality. Aortic valve replacement, and especially TAVI during follow-up, was associated with improved survival supporting the realization of RCTs to assess the effect of early transcatheter AVR in these patients. Patients with established indication for AVR require timely treatment. This was once more emphasized by a study reporting significant mortality on the waiting list for surgical as well transcatheter AVR.13 The choice between TAVI and surgical AVR (SAVR) remains a matter of controversy in patients suitable for both interventions. In a meta-analysis of currently available RCTs, Zhang et al.14 raise concerns regarding the long-term outcome of TAVI. While 2-year results for all-cause mortality, the combined endpoint of all-cause mortality and stroke, and cardiovascular mortality were similar for the two modalities, 2- to 5-year results favoured surgery. Possible explanations for this observation include higher rates of more than mild paravalvular regurgitation and conduction disturbances (pacemaker requirement, left bundle branch block) after TAVI which may affect long-term, but not short-term, outcomes. The 2-year analysis of PARTNER 3 (balloon-expandable TAVI vs. SAVR in low-risk patients) found a decreasing but still significant difference in favour of TAVI for the composite of death, stroke, and rehospitalization for HF but no longer a significant difference for death or stroke alone.15 The 8-year results of the NOTION trial16—so far the longest follow-up for an RCT with the majority of patients included being at low surgical risk—continue to show no difference in all-cause mortality (Figure 2) or the composite of all-cause mortality, stroke, and myocardial infarction. Haemodynamic results were slightly but still significantly better for TAVI with a lower rate of structural valve deterioration although the latter was driven by the higher residual gradients in the surgical group. For the more clinically relevant endpoint of prosthetic valve failure (valve-related death, severe structural valve deterioration, or valve re-intervention), there was no difference between study groups. This trial supports non-inferiority of TAVI in the long-term but has several limitations (small patient numbers, incomplete echo data and no core lab, and a significant proportion of surgical valve types with known suboptimal results). Therefore, long-term data still need to be collected carefully and the extension of TAVI to younger low-risk patients must be considered with caution. In addition to higher rates of paravalvular regurgitation and conduction disturbances the issue of valve durability, which appears to be valve specific, remains a concern. For the balloon-expandable Edwards valve, the performance of the second generation was worse than for the surgical valve while the third generation was non-inferior.18 Outcome of transcatheter vs. surgical aortic valve implantation. The left panel shows death or disabling stroke over 5 years in the PARTNER 2 trial (intermediate risk patients) as an example of a trial where lines cross between 2 and 3 years raising concerns about long-term outcome of TAVI compared with SAVR. Reproduced with permission from Makkar et al.17 The right panel shows 8-year all-cause mortality in the NOTION trial (mainly low-risk patients) without such a signal. Reproduced with permission from Jørgensen et al.16 SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation; TAVR, transcatheter aortic valve replacement. Outcome of transcatheter vs. surgical aortic valve implantation. The left panel shows death or disabling stroke over 5 years in the PARTNER 2 trial (intermediate risk patients) as an example of a trial where lines cross between 2 and 3 years raising concerns about long-term outcome of TAVI compared with SAVR. Reproduced with permission from Makkar et al.17 The right panel shows 8-year all-cause mortality in the NOTION trial (mainly low-risk patients) without such a signal. Reproduced with permission from Jørgensen et al.16 SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation; TAVR, transcatheter aortic valve replacement. Potentially limited access to the coronary arteries after TAVI also remains a matter of concern. Although high success rates for the cannulation of coronaries have been reported, in particular for short stent-frame prosthesis, failure of percutaneous coronary intervention (PCI) was close to 10%19,20 and must be expected to markedly increase after redo-TAVI.21 Patients with ST-elevation myocardial infarction after TAVI had a significantly longer door-to-balloon time and a four-fold higher PCI failure rate associated with poor outcome compared with patients without TAVI.22 Current ACC/AHA guidelines opened the range where individual shared decision-making (heart team and patient weigh individual advantages and disadvantages of TAVI and SAVR) to patients between age 65 and 80 years or life expectancy 10–20 years, respectively.2 The ESC/EACTS guidelines remained more conservative recommending SAVR for all low-risk patients younger than 75 years (IB) and TAVI for patients 75 years and older or patients at high surgical risk (IA) while leaving the remaining patients for individual decision.1 Although the stroke rate has become relatively low after TAVI, it remains one of the most devastating complications and embolic protection devices that may potentially further reduce this risk are intensively investigated. In a meta-analysis, more than 70% of patients had evidence of silent brain injury after TAVI which was associated with increased incidence of early cognitive dysfunction but still unclear long-term effects.23 Cerebral embolic protection devices reduced the volume but did, however, not affect the incidence and the number of injuries per patient. Several other studies could so far not demonstrate a reduction in clinical event rates with the use of protection devices.24–26 After TAVI, the current recommendation is to use single platelet therapy in patients without other indication for oral anticoagulation or dual antiplatelet therapy, and to use oral anticoagulation only in those with established indication and no other indication for antiplatelet therapy, based on results from several RCTs.27 Non-vitamin K antagonist oral anticoagulants (NOACs) may be a good alternative to warfarin when oral anticoagulation is indicated28,29 —although a recent RCT reported a higher bleeding rate.30 One study reported that clopidogrel may be superior to aspirin for single antiplatelet therapy.31 In another RCT of low-risk patients, warfarin was associated with less subclinical valve thrombosis without increased bleeding risk.32 However, considering the still unclear impact of subclinical valve thrombosis, the use of routine anticoagulation remains questionable even in these patients. Significant residual mitral regurgitation (MR) after TAVI has been shown once more to have negative impact on outcome33 and percutaneous mitral valve repair may then improve symptoms and outcome,34 but further prospective studies will be required to prove this concept. Calcific mitral valve disease (CMVD) is due to mitral annular calcification (MAC) that extends into the leaflets and can present as mitral stenosis (MS), MR, or a combination of both. Patients with CMVD are mostly elderly, with a strong female predominance and multiple comorbidities.35 They are often left untreated even when symptomatic and experienced a poor outcome predicted by severity of the disease (valve area/gradient) and pulmonary artery pressure. The independent prognostic value of the transmitral gradient—irrespective of MR in a second is to but is on conditions volume and heart The for these two improved for severity and thresholds of and for moderate and severe a better risk than the thresholds of 5 and is high and transcatheter mitral valve have as an alternative but remain associated with high mortality and to left ventricular and paravalvular and clinical outcomes could be using as in the prospective but of patients had to be of high risk of or In patients with mitral valve in two myocardial replacement using in the and was associated with MR left ventricular volume and ventricular and with an increased risk of cardiovascular to the between and ventricular was more in patients with or moderate MR than in patients with severe MR the hypothesis that of the mitral valve to for ventricular than a of An association between mitral annular or disease, and ventricular has been and mortality rate increased with ventricular especially conservative However, the between and mortality remained in patients with normal heart who a the of was reported to be high In addition, the of to the a good but a low compared with or prospective studies are to the and of and to better the risk of and as well as the potential of to for surgery in patients with severe primary In asymptomatic patients with primary MR, both the ESC/EACTS and ACC/AHA guidelines recommend surgery when The ESC/EACTS guidelines also emphasize the importance of left or in asymptomatic patients in with and surgical risk low and of repair high when surgery is in a Valve (Class IIa The ACC/AHA guidelines valve repair in asymptomatic patients with severe MR, normal and low surgical risk and a valve, of the left The during to trial has the and of left no in patients in and a score of had a mitral valve The trial a reduction of the risk of stroke or embolic event vs. = P = in those with The data current ACC/AHA and guidelines that or with surgical pulmonary or a are in patients with VHD and who are surgical intervention. recent studies have the association between mitral regurgitation and outcome even with only mild However, the new ESC/EACTS guidelines have the for severe ACC/AHA guidelines have of an or volume that a lower or volume may be especially the is or in The supporting this is the of evidence that surgical or transcatheter treatment improved outcome in patients with lower or volume moderate In the patients randomized to mitral transcatheter repair to show a higher lower mortality, and higher compared with medical therapy, with a reduction in MR severity 3 years (Figure prognostic in the population include pulmonary hypertension, regurgitation and The importance of these parameters and of right ventricular dysfunction have also been reported in observational However, mitral still was even in patients with poor prognostic as as a significant reduction in MR severity was is that patients, as those with severe pulmonary hypertension or right ventricular dysfunction were from the of all-cause mortality or heart failure follow-up in the population and analysis of the outcomes of patients in the medical therapy group who over to treatment compared with those who to be with medical therapy and those who were to treatment. Reproduced with permission from et of all-cause mortality or heart failure follow-up in the population and analysis of the outcomes of patients in the medical therapy group who over to treatment compared with those who to be with medical therapy and those who were to treatment. Reproduced with permission from et The of MR has been as a to the results of the and In a of a of those patients in not in all-cause mortality or HF at However, still had a significant benefit on the other no benefit of the intervention was in of patients with the MR or In a of reduced MR at was associated with improved outcome 2-year follow-up the MR reduction was by or medical therapy. one-third in the latter group had or less at studies have the prognostic impact of residual MR severity well as of MR especially in patients with less disease suggesting that in those with disease the benefit of the intervention remains Although the for the results between the two RCTs are still not the ESC/EACTS and ACC/AHA guidelines recommend with a in the of the need for in selected patients with severe the who optimal medical therapy by an HF and are as close as to the patients in the the increasing number of the management and outcomes of patients with failed to in is of In the patients with failed who a surgery were between and mortality was and repair rate only most patients with failed are these data are as are to lower risk and younger patients. The Valve In Valve reported the clinical, and outcome of mitral valve in valve = and valve in = between and This that residual and regurgitation were and associated with worse complications and survival were markedly worse in than in The transcatheter valve therapy reported and results of implantation with the in a cohort of patients experienced significant and but as in the the was in access was associated with a lower mortality rate than access vs. P = There are concerns about potential injury due to the of to transcatheter A was and after intervention in patients (mainly and a high rate of new injury often and predicted by longer time, suboptimal and the number of in an ageing population with use of or antiplatelet this study shows the need to alternative and to There is evidence that more severe is associated with a higher risk of cardiovascular outcomes as in several studies over the last year. For in a single of patients over a time et patients age years, with after those with primary valve disease, of right ventricular and medical conditions with risk such as heart or In these patients, a volume or a fraction a (Figure with increase in volume associated with an of for death based on analysis that included clinical and of mortality to volume and fraction for mild volume of or fraction of moderate of or fraction of and severe of and fraction of are Reproduced with permission from et of mortality to volume and fraction for mild volume of or fraction of moderate of or fraction of and severe of and fraction of are Reproduced with permission from et outcomes with surgery are In a of patients who surgery over a were an in valve in and valve in patients had vs. primary often due to with higher mortality vs. and lower 5-year survival rates of HF vs. but the of outcome was the clinical and not the The effect of repair during mitral valve surgery for MR in patients with moderate or but with annular was in a recent Patients with repair had a lower incidence of a event for progression of by two or severe or at 2 The reduction was driven by less progression of These findings demonstrate the of repair in the reduction of over However, long-term follow-up based on clinical is to clinical benefit of reduction the higher risk of a Several types of transcatheter devices can be to reduce the severity of with an low rate of and However, it remains challenging to patients most to benefit from these Although remains the primary for patients with severe and is to a transcatheter repair more recent data that parameters additional in patient In an international study of patients transcatheter survival was only in those with pulmonary hypertension compared with in those without pulmonary hypertension and in those with pulmonary Although there is evidence that more severe is associated with a higher risk of there is less evidence that to reduce severity those outcomes. a of increased risk or is there between severity and outcome that is independent of associated disease such as mitral valve disease, pulmonary hypertension, and right ventricular controlled of surgery and transcatheter compared with optimal medical therapy and to are of prosthetic is improved with In a prospective study for the and impact of classification was in of patients with prosthetic and with management was in and of patients, less has an impact on the management of patients with In a cohort of patients with women were older and had more than was less in women vs. including in mortality was higher in women vs. as was mortality 95% These findings attention on in the management of TAVI in patients with of the incidence of was was at and was increased in of after TAVI and was associated with a strong increase in A patients who transcatheter pulmonary valve replacement that was with an incidence of age, and high but not the of increased the risk of In an analysis of AVR and mitral valve in the between and the of from to in aortic and from to in mitral use of was in all age and was more after the which may reflect changes in and the of transcatheter The of for is based on a single study using a A randomized trial a with warfarin in aortic is and have an impact on The quantification of aortic calcification using and clinical as in a series of patients a of years after The quantification of calcification may patients at high risk of valve and as a endpoint for is a of valve calcification and of early In a prospective study on patients by TAVI and patients by SAVR, was an independent predictive of of transcatheter and aortic There was no difference in the of between TAVI vs. surgical this study also ongoing calcification in the aortic valve the TAVI therapy after AVR remains and recommendations on early anticoagulation have been In a analysis of patients, to warfarin was associated with a lower incidence of stroke 95% and than single antiplatelet therapy, at the of an increased risk of stroke 95% and in the analysis of analysis the need for randomized The randomized trial an important is the use of in patients with a mitral and in patients with were or in previous In patients, was to warfarin for a primary composite endpoint of death, cardiovascular or bleeding at (Figure 1). can be with higher of evidence in patients with a This important new in diagnosis, and treatment of VHD but left and important to be in the there are several ongoing which on of the of VHD and to with its progression remains a diagnosis, of patients who benefit from and appropriate timing remain important in general and in particular in mitral and interventional treatment require further of and outcome compared with surgical treatment or optimal medical treatment. 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