Quantifying the Survival Loss Linked to Late Therapeutic Indication in High-Gradient Severe Aortic Stenosis.

Background: International guidelines recommend aortic valve replacement (AVR) as Class I triggers in high-gradient severe aortic stenosis (HGSAS) patients with symptoms and/or left ventricular ejection fraction (LVEF) <50%. The association between waiting for these triggers and postoperative survival penalty is poorly studied. Objectives: The purpose of this study was to examine the impact of guideline-based Class I triggers on long-term postoperative survival in HGSAS patients. Methods: 2,030 patients operated for HGSAS were included and classified as follows: no Class I triggers (no symptoms and LVEF >50%, n = 853), symptoms with LVEF >50% (n = 965), or LVEF <50% regardless of symptoms (n = 212). Survival was compared after matching (inverse probability weighting) for clinical differences. Restricted mean survival time was analyzed to quantify lifetime loss. Results: Ten-year survival was better without any Class I trigger than with symptoms or LVEF <50% (67.1% ± 3% vs 56.4% ± 3% vs 53.1% ± 7%, respectively, P < 0.001). Adjusted death risks increased significantly in operated patients with symptoms (HR: 1.45 [95% CI: 1.15-1.82]) or LVEF <50% (HR: 1.47 [95% CI: 1.05-2.06]) than in those without Class I triggers. Performing AVR with LVEF >60% produced similar outcomes to that of the general population, whereas operated patients with LVEF <60% was associated with a 10-year postoperative survival penalty. Furthermore, according to restricted mean survival time analyses, operating on symptomatic patients or with LVEF <60% led to 8.3- and 11.4-month survival losses, respectively, after 10 years, compared with operated asymptomatic patients with a LVEF >60%. Conclusions: Guideline-based Class I triggers for AVR in HGSAS have profound consequences on long-term postoperative survival, suggesting that HGSAS patients should undergo AVR before trigger onset. Operating on patients with LVEF <60% is already associated with a 10-year postoperative survival penalty questioning the need for an EF threshold recommending AVR in HGSAS patients.

Additive Prognostic Value of Left Ventricular Dispersion and Deformation in Patients With Severe Aortic Stenosis.

BACKGROUND: Speckle tracking strain echocardiography allows one to visualize the timing of maximum regional strain and quantifies left ventricular-mechanical dispersion (LV-MD). Whether LV-MD and LV-global longitudinal strain (LV-GLS) provide similar or complementary information in mortality risk stratification in patients with severe aortic stenosis (SAS) remains unknown. OBJECTIVES: The authors hypothesized that LV mechanical dyssynchrony assessed by LV-MD is associated with an increased risk of mortality and provides additional prognostic information on top of LV-GLS in patients with SAS. METHODS: A total of 364 patients with SAS (aortic valve area indexed ≤0.6 cm2/m2 and/or aortic valve area ≤1 cm2), LV ejection fraction ≥50% and no or mild symptoms were enrolled. The endpoint was overall mortality. RESULTS: During a median follow-up period of 41 months, 149 patients died. After adjustment, LV-MD ≥68 ms was significantly associated with an increased risk of mortality (adjusted HR: 1.41; 95% CI: 1.01-1.96; P = 0.044). Adding LV-MD ≥68 ms to a multivariable Cox regression model including LV-GLS ≥-15% improved predictive performance in terms of overall mortality, with improved global model fit, reclassification, and better discrimination. Patients with both criteria had an important increase in mortality compared to patients with none or one criterion (adjusted HR: 2.02; 95% CI: 1.34-3.03; P = 0.001). Interobserver reproducibility of LV-MD was good with an intraclass correlation coefficient of 0.90 (95% CI: 0.72-0.97). CONCLUSIONS: LV-MD is a reproducible parameter independently associated with an increased risk of mortality in SAS. Increased LV-MD associated with depressed LV-GLS identifies a subgroup of patients with an increased mortality risk. Whether early aortic valve replacement improves the outcome of these patients deserves further studies.

Impact of left atrial and diastolic ventricular dysfunction on mortality in patients with aortic stenosis.

BACKGROUND: Diastolic dysfunction (DD) is common in severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF≥50%). AIM: To determine the impact of American Society of Echocardiography/European Association of Cardiovascular Imaging-recommended DD grading and left atrial strain on mortality in a cohort of patients with severe AS and preserved LVEF. METHODS: We studied patients with severe AS (aortic valve area indexed<0.6 cm2/m2 and/or aortic valve area<1cm2), LVEF≥50% and no or mild AS-related symptoms. The endpoint was all-cause mortality. RESULTS: A total of 387 patients (median age 76years; 53% women) were studied. During a median follow-up of 57 (interquartile range 37; 83) months, 158 patients died. After adjustment for prognostic factors, patients with grade II or III DD had an increased mortality risk versus patients with grade I DD (adjusted hazard ratio (aHR) 1.62, 95% confidence interval (CI) 1.11-2.38; P=0.013; aHR 4.73, 95% CI 2.49-8.99; P<0.001; respectively). Adding peak atrial longitudinal strain (PALS)≤14% to a multivariable model including DD grade improved predictive performance, with better global model fit, reclassification and discrimination. Patients with grade III DD or grade II DD+PALS≤14% displayed an increased mortality risk versus patients with grade I DD+PALS>14% (aHR 4.17, 95% CI 2.46-7.06; P<0.0001). Those with grade I DD+PALS≤14% or grade II DD+PALS>14% were at intermediate risk (aHR 1.63, 95% CI 1.07-2.49; P=0.024). CONCLUSIONS: Our results demonstrate the strong relationship between DD and mortality in patients with severe AS and preserved LVEF. Patients with grade III or grade II DD and impaired PALS are at very high risk. These data demonstrate the importance of a comprehensive assessment of diastolic function in patients with severe AS.

Limited benefit of systematic head CT for mild traumatic brain injury in patients under antithrombotic therapy.

BACKGROUND AND PURPOSE: Mild traumatic brain injury (mTBI) in patients on antiplatelet (AP), anticoagulant (AC) or direct oral anticoagulant (DOAC) medication has become a systematic indication for head CT. However, the over-risk and impact of the intracranial hemorrhages (IH) detected with CT in this population remain unclear and need to be assessed. MATERIALS AND METHODS: We prospectively assessed head CTs performed in adults taking AP/AC/DOAC referred after a mTBI to our Emergency Departments between September 2016 and January 2018. Frequency, type and severity of IH were described and frequency was analyzed as a function of treatment. RESULTS: 840 patients were prospectively included. 58.9% were treated with AP, 23.7% with AC, 11.7% with DOAC and 5.7% with a combination of antithrombotic agents. The rate of IH detected with head CT was 5.8% (n...=...49), of which 81.6% (n...=...40) and 18.4% (n...=...9) with minor and intermediate severity respectively. No patient required surgical care and no death occurred. No statistically significant difference was found in treatment distribution between patients with or without IH (p...=...0.98). Among the patients who discontinued their antithrombotic treatment after mTBI, three experienced thrombotic events during the hospitalization. CONCLUSIONS: Our results showed a low frequency and severity of IH in mTBI patients indifferently treated with AP, AC or DOAC, without secondary neurological deterioration, death or need of surgical care. Our study suggests the limited benefit of systematic CT head scan as a standard practice for the management of mTBI patients under antithrombotic therapy.

Prognostic Implications of Discordant Low-Gradient Severe Aortic Stenosis: Comprehensive Analysis of a Large Multicenter Registry.

Background: Up to 30% of patients with severe aortic stenosis (SAS) (indexed aortic valve area [AVAi] <0.6 cm2/m2) exhibit low-transvalvular gradient despite normal ejection fraction. There is intense debate regarding the prognostic significance of this entity. Objectives: The purpose of this study was to compare the outcome of patients with discordant low-gradient SAS (DLG-SAS) vs moderate aortic stenosis (MAS) and high-gradient SAS (HG-SAS). Methods: We used the BEL-F-ASt (Belgium-France-Aortic Stenosis) registry including consecutive patients with AS. Survival was compared overall and after matching (inverse probability weighting and propensity-score matching) for clinical and imaging variables. The analysis was first performed in the overall population (n = 2,582) and then in the population of unoperated patients (n = 1,812). Results: After-inverse probability weighting-matching, the 3 groups were balanced. Five-year survival was better in MAS than in DLG-SAS and HG-SAS-patients (58.9% vs 47% vs 41.2%, P < 0.001). Similar results were obtained in unoperated patients (54.1% vs 37.9% vs 28.1%, P < 0.001). To explore the impact of MG (≤40 vs >40 mmHg) and AVAi (<0.6 vs ≥0.6 cm2/m2) on outcomes, survival of propensity score-matched cohorts of HG-vs DLG-SAS and MAS vs DLG-SAS were compared. After matching for MG, survival was better in MAS than in DLG-SAS (52% vs 40%, P < 0.001). After matching for AVAi, survival was better in DLG-SAS than in HG-SAS patients (45% vs 33%, P < 0.001). Conclusions: Survival of DLG-SAS is better than that of HG-SAS and worse than that of MAS patients. At comparable MG, the lower the AVAi, the worse the prognosis, whereas at comparable AVAi, the higher the MG, the worse the prognosis. These data argue that DLG-SAS is an intermediate form in the disease continuum.

Unsupervised clustering of patients with severe aortic stenosis: A myocardial continuum.

BACKGROUND: Traditional statistics, based on prediction models with a limited number of prespecified variables, are probably not adequate to provide an appropriate classification of a condition that is as heterogeneous as aortic stenosis (AS). AIMS: To investigate a new classification system for severe AS using phenomapping. METHODS: Consecutive patients from a referral centre (training cohort) who met the echocardiographic definition of an aortic valve area (AVA) ≤ 1 cm2 were included. Clinical, laboratory and imaging continuous variables were entered into an agglomerative hierarchical clustering model to separate patients into phenogroups. Individuals from an external validation cohort were then assigned to these original clusters using the K nearest neighbour (KNN) function and their 5-year survival was compared after adjustment for aortic valve replacement (AVR) as a time-dependent covariable. RESULTS: In total, 613 patients were initially recruited, with a mean±standard deviation AVA of 0.72±0.17 cm2. Twenty-six variables were entered into the model to generate a specific heatmap. Penalized model-based clustering identified four phenogroups (A, B, C and D), of which phenogroups B and D tended to include smaller, older women and larger, older men, respectively. The application of supervised algorithms to the validation cohort (n=1303) yielded the same clusters, showing incremental cardiac remodelling from phenogroup A to phenogroup D. According to this myocardial continuum, there was a stepwise increase in overall mortality (adjusted hazard ratio for phenogroup D vs A 2.18, 95% confidence interval 1.46-3.26; P<0.001). CONCLUSIONS: Artificial intelligence re-emphasizes the significance of cardiac remodelling in the prognosis of patients with severe AS and highlights AS not only as an isolated valvular condition, but also a global disease.

Relationship Between the Ratio of Acceleration Time/Ejection Time and Mortality in Patients With High-Gradient Severe Aortic Stenosis.

Background The ratio of acceleration time/ejection time (AT/ET) is a simple and reproducible echocardiographic parameter that integrates aortic stenosis severity and its consequences on the left ventricle. No study has specifically assessed the prognostic impact of AT/ET on outcome in patients with high-gradient severe aortic stenosis (SAS) and no or mild symptoms. We sought to evaluate the relationship between AT/ET and mortality and determine the best predictive AT/ET cutoff value in these patients. Methods and Results A total of 353 patients (median age, 79 years; 46% women) with high-gradient (mean pressure gradient ≥40 mm Hg and/or aortic peak jet velocity ≥4 m/s) SAS, left ventricular ejection fraction ≥50%, and no or mild symptoms were studied. The impact of AT/ET ≤0.35 or >0.35 on all-cause mortality was retrospectively studied. During a median follow-up of 39 (25th-75th percentile, 23-62) months, 70 patients died. AT/ET >0.35 was associated with a considerable increased mortality risk after adjustment for established prognostic factors in SAS under medical and/or surgical management (adjusted hazard ratio [HR], 2.54; 95% CI, 1.47-4.37; P<0.001) or conservative management (adjusted HR, 3.29; 95% CI, 1.70-6.39; P<0.001). Moreover, AT/ET >0.35 improved the predictive performance of models including established risk factors in SAS with better global model fit, reclassification, and discrimination. After propensity matching, increased mortality risk persisted when AT/ET >0.35 (adjusted HR, 2.10; 95% CI, 1.12-3.90; P<0.001). Conclusions AT/ET >0.35 is a strong predictor of outcome in patients with SAS and no or only mild symptoms and identifies a subgroup of patients at higher risk of death who may derive benefit from earlier aortic valve replacement.

Dimensionless Index in Patients With Low-Gradient Severe Aortic Stenosis and Preserved Ejection Fraction.

Background Risk stratification of patients with low-gradient (LG) severe aortic stenosis (AS) despite preserved left ventricular ejection fraction remains challenging. We sought to evaluate the relationship between the dimensionless index (DI)-the ratio of the left ventricular outflow tract time-velocity integral to that of the aortic valve jet-and mortality in these patients. Methods Seven hundred fifty-five patients with LG severe AS (defined by aortic valve area ≤1 cm2 or aortic valve area indexed to body surface area ≤0.6 cm2/m2 and mean aortic pressure gradient <40 mm Hg) and preserved left ventricular ejection fraction ≥50% were studied. Flow status was defined according to stroke volume index <35 mL/m2 (low flow, LF) or ≥35 mL/m2 (normal flow, NF). Results After adjustment for age, sex, body mass index, Charlson comorbidity index, history of hypertension, history of atrial fibrillation, AS-related symptoms, left ventricular ejection fraction, indexed left ventricular ventricular mass, aortic valve area, and aortic valve replacement as a time-dependent covariate, patients with LG-LF and DI<0.25 exhibited a considerable increased risk of death compared with patients with LG-NF and DI≥0.25 (adjusted hazard ratio, 2.41 [95% CI, 1.61-3.62]; P<0.001), LG-NF and DI<0.25 (adjusted hazard ratio, 1.84 [95% CI, 1.24-2.73]; P=0.003), and LG-LF and D≥0.25 (adjusted hazard ratio, 2.27 [95% CI, 1.42-3.63]; P<0.001). In contrast, patients with LG-LF and DI≥0.25, LG-NF and DI<0.25, and LG-NF and DI≥0.25 had similar outcome. DI<0.25 showed incremental prognostic value in patients with LG-LF severe AS but not in patients with LG-NF severe AS. Conclusions Among patients with LG severe AS and preserved left ventricular ejection fraction, decreased DI<0.25 is a reliable parameter in patients with LF to identify a subgroup of patients at higher risk of death who may derive benefit from aortic valve replacement.

Prognostic Importance of Left Ventricular Global Longitudinal Strain in Patients with Severe Aortic Stenosis and Preserved Ejection Fraction.

BACKGROUND: Impaired left ventricular (LV) speckle-tracking-derived global longitudinal strain (GLS) magnitude (GLS worse than 14.7%) has been associated with poor outcome in patients with severe aortic stenosis (AS) and preserved LV ejection fraction (EF). OBJECTIVES: To test the hypothesis that GLS magnitude ≤ 15% obtained with vendor-independent speckle-tracking strain software may be able to identify patients with severe AS who are at higher risk of death, despite preserved LVEF and no or mild symptoms. METHODS: GLS was retrospectively obtained in 332 patients with severe AS (aortic valve area indexed [AVAi] < 0.6 cm2/m2), no or mild symptoms, and LVEF ≥ 50%. Absolute values of GLS were collected. Survival analyses were carried out to study the impact of GLS magnitude on all-cause mortality. RESULTS: During a median follow-up period of 42 (37-46) months, 105 patients died. On multivariate analysis, and after adjustment of known clinical and/or echocardiographic predictors of outcome and aortic valve replacement as a time-dependent covariate, GLS magnitude ≤ 15% was independently associated with mortality during follow-up (all P < .01). Adding GLS magnitude ≤ 15% (adjusted hazard ratio = 1.99 [1.17-3.38], P = .011) to a multivariate model including clinical and echocardiographic variables of prognostic importance (aortic valve replacement, aortic valve area, LV stroke volume index < 30 mL/m2, and LVEF<60%) improved the predictive performance with improved global model fit, reclassification, and better discrimination. After propensity score matching (n = 196), increased risk of mortality persisted among patients with GLS magnitude ≤ 15% compared with those with GLS > 15% (hazard ratio = 2.10; 95% confidence interval, 1.20-3.68; P = .009). CONCLUSIONS: In this series of patients with severe AS, no or mild symptoms, and LVEF ≥ 50%, GLS obtained with vendor-independent speckle-tracking strain software was an effective tool to identify patients with a poor outcome. Detection of myocardial dysfunction by identifying GLS magnitude < 15% in patients with severe AS, no or mild symptoms, and LVEF ≥ 50%, can aid in risk assessment.

Prognostic Impact of the Ratio of Acceleration Time to Ejection Time in Patients With Low Gradient Severe Aortic Stenosis and Preserved Ejection Fraction.

The clinical management of patients with low gradient severe aortic stenosis (LG-SAS) and preserved left ventricular ejection fraction (LVEF) remains challenging owing to their heterogeneity. The aim to this study was to evaluate the relation between an ejection dynamic parameter linked to AS severity and outcome, the ratio of acceleration time (AT) to ejection time (ET), in a cohort of patients with LG-SAS and preserved LVEF. Three hundred and fifty-six patients with LG-AS (defined by AVA ≤1 cm² and/or AVAi ≤0.6 cm²/m² and mean aortic pressure gradient <40 mm Hg) and preserved LVEF ≥50% were studied. The relation between AT/ET and all-cause and cardiac mortality during follow-up was studied. Median follow-up was 41 months (interquartile range, 35 to 47 months). Median AT/ET was 0.32 (interquartile range, 0.29 to 0.36). The 5-year estimates of all-cause and cardiac mortality were respectively 57 ± 7%, 36 ± 7% for patients with AT/ET >0.36 versus 43 ± 4%, 16 ± 3% for patients with AT/ET ≤0.36 (p = 0.024 and p <0.001, respectively). After adjustment on known predictors of outcome including aortic valve replacement used as a time-dependent covariate, there was a significant increase in all-cause mortality risk for patients with AT/ET >0.36 (adjusted hazard ratio 2.04 [95% confidence interval, 1.32 to 3.13]; p = 0.001) and cardiac mortality risk (adjusted hazard ratio 2.89 [95% confidence interval, 1.54 to 5.43]; p<0.001) compared with patients with AT/ET ≤0.36. The association of AT/ET >0.36 and all-cause or cardiac mortality risk was consistent in subgroups of patients with LG-SAS and preserved EF. In conclusion, an AT/ET ratio of more than 0.36 is an independent predictor of mortality in patients with LG-SAS and preserved EF.