Effects of Aortic Valve Replacement on Severe Aortic Stenosis and Preserved Systolic Function: Systematic Review and Network Meta-analysis.
ABSTRACT: The survival benefits of aortic valve replacement (AVR) in the different flow-gradient states of severe aortic stenosis (AS) is not known. A comprehensive search in PubMed/MEDLINE, Embase, Cochrane Library, CNKI and OpenGrey were conducted to identify studies that investigated the prognosis of severe AS (effective orifice area ≤1.0 cm2) and left ventricular ejection fraction ≥50%. Severe AS was stratified by mean pressure gradient [threshold of 40 mmHg; high-gradient (HG) and low-gradient (LG)] and stroke volume index [threshold of 35 ml/m2; normal-flow (NL) and low-flow (LF)]. Network meta-analysis was conducted to assess all-cause mortality among each AS sub-type with rate ratio (RR) reported. The effects of AVR on prognosis were examined using network meta-regression. In the pooled analysis (15 studies and 9,737 patients), LF states (both HG and LG) were associated with increased mortality rate (LFLG: RR 1.88; 95% CI: 1.43-2.46; LFHG: RR: 1.77; 95% CI: 1.16-2.70) compared to moderate AS; and NF states in both HG and LG had similar prognosis as moderate AS (NFLG: RR 1.11; 95% CI: 0.81-1.53; NFHG: RR 1.16; 95% CI: 0.82-1.64). AVR conferred different survival benefits: it was most effective in NFHG (RR with AVR /RR without AVR : 0.43; 95% CI: 0.22-0.82) and least in LFLG (RR with AVR /RR without AVR : 1.19; 95% CI: 0.74-1.94).
Project description:Background No randomized comparison of early (ie, ?3 months) aortic valve replacement (AVR) versus conservative management or of transcatheter AVR (TAVR) versus surgical AVR has been conducted in patients with low-flow, low-gradient (LFLG) aortic stenosis (AS). Methods and Results A total of 481 consecutive patients (75±10 years; 71% men) with LFLG AS (aortic valve area ?0.6 cm<sup>2</sup>/m<sup>2</sup> and mean gradient <40 mm Hg), 72% with classic LFLG and 28% with paradoxical LFLG, were prospectively recruited in the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study. True-severe AS or pseudo-severe AS was adjudicated by flow-independent criteria. During follow-up (median [IQR] 36 [11-60] months), 220 patients died. Using inverse probability of treatment weighting to address the bias of nonrandom treatment assignment, early AVR (n=272) was associated with a major overall survival benefit (hazard ratio [HR], 0.34 [95% CI, 0.24-0.50]; <i>P</i><0.001). This benefit was observed in patients with true-severe AS but also with pseudo-severe AS (HR, 0.38 [95% CI, 0.18-0.81]; <i>P</i>=0.01), and in classic (HR, 0.33 [95% CI, 0.22-0.49]; <i>P</i><0.001) and paradoxical LFLG AS (HR, 0.42 [95% CI, 0.20-0.92]; <i>P</i>=0.03). Compared with conservative management in the conventional multivariate model, trans femoral TAVR was associated with the best survival (HR, 0.23 [95% CI, 0.12-0.43]; <i>P</i><0.001), followed by surgical AVR (HR, 0.36 [95% CI, 0.23-0.56]; <i>P</i><0.001) and alternative-access TAVR (HR, 0.51 [95% CI, 0.31-0.82]; <i>P</i>=0.007). In the inverse probability of treatment weighting model, trans femoral TAVR appeared to be superior to surgical AVR (HR [95% CI] 0.28 [0.11-0.72]; <i>P</i>=0.008) with regard to survival. Conclusions In this large prospective observational study of LFLG AS, early AVR appeared to confer a major survival benefit in both classic and paradoxical LFLG AS. This benefit seems to extend to the subgroup with pseudo-severe AS. Our findings suggest that TAVR using femoral access might be the best strategy in these patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01835028.
Project description:Background Normal-flow, low-gradient severe aortic stenosis (NF-LG-SAS), defined by aortic valve area <1 cm<sup>2</sup>, mean gradient <40 mm Hg, and indexed stroke volume >35 mL/m<sup>2</sup>, is the most prevalent form of low-gradient aortic stenosis (AS). However, the true severity of AS and the management of NF-LG-SAS are controversial. The aim of this study was to evaluate the outcome of patients with NF-LG-SAS compared with moderate AS (MAS) and with high-gradient severe-AS (HG-SAS). Methods and Results A total of 154 patients with NF-LG-SAS, 366 with MAS (aortic valve area between 1.0 and 1.3 cm<sup>2</sup>), and 1055 with HG-SAS were included. On multivariate analysis, after adjustment for covariates of prognostic importance, NF-LG-SAS patients did not exhibit an excess risk of mortality compared with MAS patients under medical management (hazard ratio=1.13 [95% CI, 0.82-1.56]; <i>P</i>=0.45) and under medical and surgical management (hazard ratio 1.06 [95% CI, 0.79-1.43]; <i>P</i>=0.70), even after further adjustment for aortic valve replacement (hazard ratio=1.09 [95% CI, 0.81-1.48]; <i>P</i>=0.56). The 6-year cumulative incidence of aortic valve replacement (performed in accordance with guidelines) was comparable between the 2 groups (39±4% for NF-LG-SAS and 35±3% for MAS, <i>P</i>=0.10). After propensity score matching (n=226), NF-LG-SAS and MAS patients also had comparable outcomes under medical (<i>P</i>=0.41) and under medical and surgical management (<i>P</i>=0.52). NF-LG-SAS had better outcomes than HG-SAS patients (adjusted hazard ratio 1.84 [95% CI, 1.18-2.88]; <i>P</i><0.001). Conclusions This study shows that patients with NF-LG-SAS have a comparable outcome to those with MAS when aortic valve replacement is performed during follow-up according to guidelines, mostly at the stage of HG-SAS. Rigorous echocardiographic assessment to rule out measurement errors and close follow-up are essential to detect progression to true severe AS in NF-LG-SAS.
Project description:<h4>Aims</h4>We aimed to investigate the role of aortic valve tissue composition from quantitative cardiac computed tomography angiography (CTA) in patients with severe aortic stenosis (AS) for the differentiation of disease subtypes and prognostication after transcatheter aortic valve implantation (TAVI).<h4>Methods and results</h4>Our study included 447 consecutive AS patients from six high-volume centres reporting to a prospective nationwide registry of TAVI procedures (POL-TAVI), who underwent cardiac CTA before TAVI, and 224 matched controls with normal aortic valves. Components of aortic valve tissue were identified using semi-automated software as calcific and non-calcific. Volumes of each tissue component and composition [(tissue component volume/total tissue volume) × 100%] were quantified. Relationship of aortic valve composition with clinical outcomes post-TAVI was evaluated using Valve Academic Research Consortium (VARC)-2 definitions.High-gradient (HG) AS patients had significantly higher aortic tissue volume compared to low-flow low-gradient (LFLG)-AS (1672.7 vs. 1395.3 mm3, P < 0.001) as well as controls (509.9 mm3, P < 0.001), but increased non-calcific tissue was observed in LFLG compared to HG patients (1063.6 vs. 860.2 mm3, P < 0.001). Predictive value of aortic valve calcium score [area under the curve (AUC) 0.989, 95% confidence interval (CI): 0.981-0.996] for severe AS was improved after addition of non-calcific tissue volume (AUC 0.995, 95% CI: 0.991-0.999, P = 0.011). In the multivariable analysis of clinical and quantitative computed tomography parameters of aortic valve tissue, non-calcific tissue volume [odds ratio (OR) 5.2, 95% CI 1.8-15.4, P = 0.003] and history of stroke (OR 2.6, 95% CI 1.1-6.5, P = 0.037) were independent predictors of 30-day major adverse cardiovascular event (MACE).<h4>Conclusion</h4>Quantitative CTA assessment of aortic valve tissue volume and composition can improve detection of severe AS, differentiation between HG and LFLG-AS in patients referred for TAVI as well as prediction of 30-day MACEs post-TAVI, over the current clinical standard.
Project description:Background The prevalence and outcomes of the different subtypes of severe low-gradient aortic stenosis (AS) in routine clinical cardiology practice have not been well characterized. Methods and Results Data were derived from the National Echocardiography Database of Australia. Of 192 060 adults (aged 62.8±17.8 [mean±SD] years) with native aortic valve profiling between 2000 and 2019, 12 013 (6.3%) had severe AS. Of these, 5601 patients (47%) had high-gradient and 6412 patients (53%) had low-gradient severe AS. The stroke volume index was documented in 2741 (42.7%) patients with low gradient; 1750 patients (64%) with low flow, low gradient (LFLG); and 991 patients with normal flow, low gradient. Of the patients with LFLG, 1570 (89.7%) had left ventricular ejection fraction recorded; 959 (61%) had paradoxical LFLG (preserved left ventricular ejection fraction), and 611 (39%) had classical LFLG (reduced left ventricular ejection fraction). All-cause and cardiovascular-related mortality were assessed in the 8162 patients with classifiable severe AS subtype during a mean±SD follow-up of 88±45 months. Actual 1-year and 5-year all-cause mortality rates varied across these groups and were 15.8% and 49.2% among patients with high-gradient severe AS, 11.6% and 53.6% in patients with normal-flow, low-gradient severe AS, 16.9% and 58.8% in patients with paradoxical LFLG severe AS, and 30.5% and 72.9% in patients with classical LFLG severe AS. Compared with patients with high-gradient severe AS, the 5-year age-adjusted and sex-adjusted mortality risk hazard ratios were 0.94 (95% CI, 0.85-1.03) in patients with normal-flow, low-gradient severe AS; 1.01 (95% CI, 0.92-1.12) in patients with paradoxical LFLG severe AS; and 1.65 (95% CI, 1.48-1.84) in patients with classical LFLG severe AS. Conclusions Approximately half of those patients with echocardiographic features of severe AS in routine clinical practice have low-gradient hemodynamics, which is associated with long-term mortality comparable with or worse than high-gradient severe AS. The poorest survival was associated with classical LFLG severe AS.
Project description:An important proportion of patients with aortic stenosis (AS) have a 'low-gradient' AS, i.e. a small aortic valve area (AVA <1.0 cm(2)) consistent with severe AS but a low mean transvalvular gradient (<40 mmHg) consistent with non-severe AS. The management of this subset of patients is particularly challenging because the AVA-gradient discrepancy raises uncertainty about the actual stenosis severity and thus about the indication for aortic valve replacement (AVR) if the patient has symptoms and/or left ventricular (LV) systolic dysfunction. The most frequent cause of low-gradient (LG) AS is the presence of a low LV outflow state, which may occur with reduced left ventricular ejection fraction (LVEF), i.e. classical low-flow, low-gradient (LF-LG), or preserved LVEF, i.e. paradoxical LF-LG. Furthermore, a substantial proportion of patients with AS may have a normal-flow, low-gradient (NF-LG) AS: i.e. a small AVA-low-gradient combination but with a normal flow. One of the most important clinical challenges in these three categories of patients with LG AS (classical LF-LG, paradoxical LF-LG, and NF-LG) is to differentiate a true-severe AS that generally benefits from AVR vs. a pseudo-severe AS that should be managed conservatively. A low-dose dobutamine stress echocardiography may be used for this purpose in patients with classical LF-LG AS, whereas aortic valve calcium scoring by multi-detector computed tomography is the preferred modality in those with paradoxical LF-LG or NF-LG AS. Although patients with LF-LG severe AS have worse outcomes than those with high-gradient AS following AVR, they nonetheless display an important survival benefit with this intervention. Some studies suggest that transcatheter AVR may be superior to surgical AVR in patients with LF-LG AS.
Project description:Background The optimal threshold of left ventricular ejection fraction (LVEF) that should prompt aortic valve replacement (AVR) in asymptomatic patients with high-gradient severe aortic stenosis (AS) is controversial. The aim of this study was to assess the relationship between LVEF and mortality benefit in comparing early AVR versus watchful waiting in asymptomatic patients with severe AS. Methods and Results MEDLINE, Embase, Web of Science, and Google Scholar were searched for observational studies and randomized controlled trials on adults with asymptomatic severe AS. Severe AS was defined by a peak aortic velocity ≥4 m/s and/or mean aortic valve gradient ≥40 mm Hg and/or calculated aortic valve area <1.0 cm<sup>2</sup> or an indexed valve area <0.6 cm<sup>2</sup>. Studies comparing AVR with conservative management were included and meta-analysis on all-cause mortality was performed. Ten eligible studies were identified with a total of 3332 patients. In 5 observational studies comparing early AVR versus watchful waiting, our meta-analysis showed early AVR was associated with lower mortality with a hazard ratio (HR) of 0.41 (CI, 0.23-0.71; <i>P</i><0.01). In 4 observational studies comparing AVR versus no AVR, our meta-analysis showed AVR was associated with lower mortality with a HR of 0.31 (CI, 0.17-0.58; <i>P</i><0.001). In a meta-regression analysis pooling all 10 studies, there was no statistically significant correlation between study mean LVEF and the size of mortality benefit of AVR (<i>P</i>=0.83). Conclusions Among asymptomatic patients with high-gradient severe AS, AVR was associated with a mortality benefit across the spectrum of LVEF. Our study calls into question the need of an LVEF threshold for recommending AVR in this patient population.
Project description:Background Many patients with severe aortic stenosis (AS) and an indication for aortic valve replacement (AVR) do not undergo treatment. The reasons for this have not been well studied in the transcatheter AVR era. We sought to determine how patient- and process-specific factors affected AVR use in patients with severe AS. Methods and Results We identified ambulatory patients from 2016 to 2018 demonstrating severe AS, defined by aortic valve area [Formula: see text]1.0 cm<sup>2</sup>. Propensity scoring analysis with inverse probability of treatment weighting was used to evaluate associations between predictors and the odds of undergoing AVR at 365 days and subsequent mortality at 730 days. Of 324 patients with an indication for AVR (79.3±9.7 years, 57.4% men), 140 patients (43.2%) did not undergo AVR. The odds of AVR were reduced in patients aged >90 years (odds ratio [OR], 0.24 [95% CI, 0.08-0.69]; <i>P</i>=0.01), greater comorbid conditions (OR, 0.88 per 1-point increase in Combined Comorbidity Index [95% CI, 0.79-0.97]; <i>P</i>=0.01), low-flow, low-gradient AS with preserved left ventricular ejection fraction (OR, 0.11 [95% CI, 0.06-0.21]), and low-gradient AS with reduced left ventricular ejection fraction (OR, 0.18 [95% CI, 0.08-0.40]) and were increased if the transthoracic echocardiogram ordering provider was a cardiologist (OR, 2.46 [95% CI, 1.38-4.38]). Patients who underwent AVR gained an average of 85.8 days of life (95% CI, 40.9-130.6) at 730 days. Conclusions The proportion of ambulatory patients with severe AS and an indication for AVR who do not receive AVR remains significant. Efforts are needed to maximize the recognition of severe AS, especially low-gradient subtypes, and to encourage patient referral to multidisciplinary heart valve teams.
Project description:Among patients with severe aortic stenosis (AS) and preserved ejection fraction, those with low gradient (LG) and reduced stroke volume may have an adverse prognosis. We investigated the prognostic impact of stroke volume using the recently proposed flow-gradient classification.We examined 1704 consecutive patients with severe AS (aortic valve area <1.0 cm(2)) and preserved ejection fraction (?50%) using 2-dimensional and Doppler echocardiography. Patients were stratified by stroke volume index (<35 mL/m(2) [low flow, LF] versus ?35 mL/m(2) [normal flow, NF]) and aortic gradient (<40 mm?Hg [LG] versus ?40 mm?Hg [high gradient, HG]) into 4 groups: NF/HG, NF/LG, LF/HG, and LF/LG. NF/LG (n=352, 21%), was associated with favorable survival with medical management (2-year estimate, 82% versus 67% in NF/HG; P<0.0001). LF/LG severe AS (n=53, 3%) was characterized by lower ejection fraction, more prevalent atrial fibrillation and heart failure, reduced arterial compliance, and reduced survival (2-year estimate, 60% versus 82% in NF/HG; P<0.001). In multivariable analysis, the LF/LG pattern was the strongest predictor of mortality (hazard ratio, 3.26; 95% confidence interval, 1.71-6.22; P<0.001 versus NF/LG). Aortic valve replacement was associated with a 69% mortality reduction (hazard ratio, 0.31; 95% confidence interval, 0.25-0.39; P<0.0001) in LF/LG and NF/HG, with no survival benefit associated with aortic valve replacement in NF/LG and LF/HG.NF/LG severe AS with preserved ejection fraction exhibits favorable survival with medical management, and the impact of aortic valve replacement on survival was neutral. LF/LG severe AS is characterized by a high prevalence of atrial fibrillation, heart failure, and reduced survival, and aortic valve replacement was associated with improved survival. These findings have implications for the evaluation and subsequent management of AS severity.
Project description:<h4>Objectives</h4>The association between extracellular volume (ECV) measured by computed tomography angiography (CTA) and clinical outcomes was evaluated in low-flow low-gradient (LFLG) aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR).<h4>Background</h4>Patients with LFLG AS comprise a high-risk group with respect to clinical outcomes. Although ECV, a marker of myocardial fibrosis, is traditionally measured with cardiac magnetic resonance, it can also be measured using cardiac CTA. The authors hypothesized that in LFLG AS, increased ECV may be associated with adverse clinical outcomes.<h4>Methods</h4>In 150 LFLG patients with AS who underwent TAVR, ECV was quantified using pre-TAVR CTA. Echocardiographic and clinical information including all-cause death and heart failure rehospitalization (HFH) was obtained from electronic medical records. A Cox proportional hazards model was used to evaluate the association between ECV and death+HFH.<h4>Results</h4>During a median follow-up of 13.9 months (range 0.07 to 28.9 months), there were 31 death+HFH events (21%). Patients who experienced death+HFH had a greater median Society of Thoracic Surgery score (9.9 vs. 4.7; p < 0.01), lower left ventricular ejection fraction (42.3 ± 20.2% vs. 52.7 ± 17.2%; p < 0.01), lower mean transvalvular gradient (24.9 ± 8.9 mm Hg vs. 28.1 ± 7.3 mm Hg; p = 0.04) and increased mean ECV (35.5 ± 9.6% vs. 29.9 ± 8.2%; p < 0.01) compared with patients who did not experience death+HFH. In a multivariable Cox proportional hazards model, increase in ECV was associated with increase in death+HFH, (hazard ratio per 1% increase: 1.04, 95% confidence interval: 1.01 to 1.09; p < 0.01).<h4>Conclusions</h4>In patients with LFLG AS, CTA measured increase in ECV is associated with increased risk of adverse clinical outcomes post-TAVR and may thus serve as a useful noninvasive marker for prognostication.
Project description:OBJECTIVE:First-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis. METHODS:EF1 was measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ?2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death. RESULTS:Total follow-up of the 149 participants (69.8% male, 70 (65-76) years, mean gradient 33 (21-42) mm Hg) was 238?029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (<25%) despite normal ejection fraction (67% (62%-71%)). Patients with low EF1 had more severe aortic stenosis (mean gradient 39 (34-45) mm Hg vs 24 (16-35) mm Hg, p<0.001) and more myocardial fibrosis (indexed extracellular volume (iECV) (24.2 (19.6-28.7) mL/m2 vs 20.6 (16.8-24.3)?mL/m2, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, p<0.001). Zva, iECV and infarct LGE were independent predictors of EF1. EF1 improved post-AVR (n=57 with post-AVR EF1 available, baseline 16 (12-24) vs follow-up 27% (22%-31%); p<0.001). Low baseline EF1 was an independent predictor of AVR/death (HR 5.6, 95% CI 3.4 to 9.4), driven by AVR. CONCLUSION:EF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR.