All-cause Mortality Research Articles

Evolution and prognostic impact of left ventricular myocardial work indices after transcatheter aortic valve replacement in patients with severe aortic stenosis

Abstract Introduction Left ventricular myocardial work (LVMW) is an echocardiographic-based technique to evaluate LV function using pressure-strain loops and therefore correcting for the left ventricular (LV) afterload. LVMW indices have been shown to be of prognostic importance in patients with aortic stenosis (AS) before transcatheter aortic valve replacement (TAVR), but no data is available on the evolution and the prognostic value of these parameters after TAVR. Purpose To measure LVMW indices before and after TAVR in patients with severe AS and explore the association with outcome. Methods As previously validated, LV global longitudinal strain (GLS) and LV systolic pressure (as the sum of the brachial arterial blood pressure and mean aortic valve gradient before TAVR and as brachial arterial blood pressure after TAVR) were incorporated to build pressure-strain loops and to calculate the following LVMW indices: global work index (LV GWI), global constructive work (LV GCW), global wasted work (LV GWW) and global work efficiency (LV GWE). The endpoint was all-cause mortality. Results A total of 255 patients were included with a median age of 82 years (IQR 77-85); 51% were men and 67% presented with NYHA class III/IV. After TAVR, LVEF and LV GLS remained in average unchanged (from 56 to 55%, p=0.470 and from 13.6 to 13.2%, p=0.068). While LV GWW remained unchanged after TAVR (from 247 to 258mmHg%, p=0.080), LV GWI, LV GCW and LV GWE significantly decreased (from 1882 to 1291mmHg%, p <0.001, from 2248 to 1671mmHg%, p <0.001 and from 89 to 85%, p <0.001 respectively). During a median follow-up of 59 months (IQR 40-72), 129 patients died. Univariable Cox regression analysis identified an association between all-cause mortality and male sex, diabetes mellitus, chronic obstructive pulmonary disease (COPD), renal function, atrial fibrillation, Charlson comorbidity index, pacemaker implantation, and post-TAVR LV GLS, LV GWI and LV GCW. These clinical parameters were used as a basal multivariable Cox regression model of which on top either post-TAVR LV GLS, LV GWI or LV GCW were added. All these parameters of post-TAVR LV systolic function showed an independent association with all-cause mortality, but LV GWI demonstrated the highest increase in model predictivity (Figure 1). Given the prognostic relevance of post-TAVR LV GWI, the population was divided into LV GWI tertiles. The group with the lowest LV GWI tertile showed a significantly higher proportion of male patients, higher prevalence of atrial fibrillation and also worse pre-TAVR LVEF, LV GLS, LV GWI, LV GCW and LV GWE. Kaplan Meier survival analysis confirmed the worse survival in the group with the lowest LV GWI compared to the highest tertile (log-rank ꭓ2: 8,224, p 0.016, Figure 2). Conclusion LVMW indices change after TAVR and post-TAVR LV GLS, LV GWI, LV GCW are independently associated with all-cause mortality. Among these parameters, LV GWI yielded the highest prognostic value.

Long-term clinical outcomes informed by artificial intelligence-enabled single-lead ECG detection of reduced ejection fraction

Abstract Background * Reduced left ventricular ejection fraction (LVEF) is linked to poor clinical outcomes (1, 2). * Despite its increasing prevalence, reduced LVEF is often undetected due to resource-limited echocardiography and lack of suitable point-of-care diagnostic tools. * Previous studies have shown that an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm can accurately identify patients with reduced LVEF, but may also offer novel insights on long-term prognosis (3, 4). Purpose We aimed to determine if an AI-ECG algorithm designed for detecting reduced LVEF can also independently predict 2-year major adverse cardiovascular events (MACE) and all-cause mortality. Method * A retrospective multicentre observational study investigating the ability of AI-ECG to predict long-term clinical outcomes (i.e. over two years' follow up). * Analysis included a total of 1,007 consecutive unselected patients attending for routine echocardiography, with a single-lead ECG recording performed at the same time. * An AI-ECG algorithm, designed to identify impaired LVEF, was applied to each single-lead ECG. * Occurrence of MACE and all-cause mortality associated with AI-ECG results (Figure 1) was investigated using Cox regression; evaluating performance of AI-ECG results as a classifier (0 or 1) and as a probability score (0 to 1). * The study was approved by the UK Health Research Authority (reference 21/LO/0051). Results * The mean age was 62.3 years. 52.4% of patients were male and 57.5% of patients were White. * Appropriately, patients with a positive AI-ECG had a higher MACE rate compared to those with a negative AI-ECG (34.2% vs. 11.9%; adjusted hazard ratio (aHR) 2.02; 95% CI, 1.46 – 2.81; p < 0.005), primarily driven by increased mortality (23% vs. 9.6%; p < 0.0001; aHR 1.65; 95% CI, 1.12 – 2.43) and heart failure hospitalization (14.5% vs. 1%; p < 0.0001) – Figure 2. * AI-ECG probability score (per 10% increase) was significantly associated with MACE (aHR 1.17; 95% CI, 1.09 – 1.25; p < 0.005) and all-cause mortality (aHR 1.11; 95% CI, 1.02 – 1.20; p = 0.01). * Importantly, sub-analysis of AI-ECG for those who have a normal LVEF (i.e. ≥50%) continued to show association between positive AI-ECG and MACE (27.2% vs. 11.9%; p < 0.0001; aHR 1.70, 95% CI 1.17 – 2.48) and all-cause mortality (20.4% vs. 9.6%; p < 0.0001; aHR 1.53, 95% CI 1.00 – 2.36). Conclusion An AI-ECG algorithm designed to identify impaired LVEF can identify patients at risk of MACE and all-cause mortality from single-lead ECG screening – regardless of their LVEF. Such results may enable further risk stratification for cardiovascular investigations through the simple addition of single-lead ECG recording.

Red blood cell distribution width to albumin ratio as novel prognostic biomarker in cardiovascular disease

Abstract Background The red blood cell distribution width-to-albumin ratio (RAR) is a novel, cost-effective, and accessible biomarker for inflammation. Although numerous studies have investigated the relationship between RAR values and mortality in cardiovascular diseases (CVD), the generalizability and robustness of these individual studies' results remain uncertain, underscoring the necessity for a meta-analysis. Purpose To explore the pooled association between RAR and all-cause mortality in several CVDs. Methods A systematic search for eligible studies was conducted across scientific databases, including Scopus, Web of Science, PubMed, and ProQuest, up to February 1, 2024. Mortality hazard ratios (HRs) for the highest versus lowest RAR categories were pooled using the Generic Inverse Variance method. A dose-response meta-analysis was performed using generalized least-squares regression to estimate trends of HRs across dose categories. Publication bias was assessed by inspecting funnel plots and performing Egger's test. Subgroup analyses were based on the underlying CVDs. Statistical analyses were executed in RStudio software, with the significance threshold set at p < 0.05. Results This systematic review and meta-analysis reviewed 16 high-quality studies published between 2021 and 2024 with 30,933 participants. The underlying diseases in the included studies were Acute Myocardial Infarction (AMI), Heart Failure (HF), Atrial Fibrillation (AF), aortic valvular disease, stroke and pulmonary embolism. The lowest quartile range for RAR was 0.80–1.20 ml/g, while the highest quartile ranged from 6.09 to 15.45 ml/g. Pooled results with a random-effect model showed that patients with higher RAR had significantly increased risk of all-cause mortality (HR 1.88, 95%CI 1.59–2.23, p<0.0001, I² = 91%). Non-linearity was observed in the dose-response relationship; thus, it was primarily illustrated using the restricted cubic spline model, with the linear model provided for comparison. A 1 ml/g increase in RAR corresponded to a 27% rise in the predicted HR for all-cause mortality (HR 1.27, 95%CI 1.16–1.39; p < 0.0001). Subgroup analyses based on the primary CVD diagnoses in the included studies confirmed a significant association between RAR values and all-cause mortality across all subgroups (AMI: HR 2.43, 95%CI 1.52–3.87, I² = 45%; HF: HR 1.78, 95%CI 1.13–2.81, I² = 94%; Stroke: HR 1.58, 95%CI 0.94–2.67, I² = 90%; Other CVD: HR 1.97, 95%CI 1.34–2.89, I² = 57%; p for interaction 0.24). Conclusion This is the first meta-analysis demonstrating the positive dose-response association between RAR values and all-cause mortality in CVD. Thus, RAR may be considered as a simple and practical prognostic biomarker in CVD.Forest plot based on CVD diagnosisDose-response RAR value to HR

All-cause mortality and incidence of appropriate therapy from a primary preventive implantable cardioverter defibrillator in patients with non-ischemic dilated cardiomyopathy

Abstract Background The DANISH study published in 2016 indicated limited benefit of primary prevention implantable cardioverter-defibrillator (ICD) in patients with non-ischemic dilated cardiomyopathy (niDCM). We aimed to investigate the long-term outcome and incidence of ICD therapy in patients with niDCM implanted on primary prevention indication during 2014-2022. Methods A total of 116 patients with niDCM were prospectively included for primary prevention ICD implantation between 2014 and 2022 in the multicenter IMPROVE study (clinical trials NCT02286908). All patients were examined with electrocardiogram, echocardiography and blood sampling at inclusion. The primary outcome was all-cause mortality, and the secondary outcome was appropriate ICD therapy. Outcomes were compared in patients included from 2014 to end of 2016 (DCM2014-16, n=49) and from 2017-2022 (DCM2017-22, n=67). Results At inclusion, patients in DCM2017-22 were younger (54 years [interquartile range (IQR) 44-68] vs. 64 years [IQR 55-70], p=0.001), had higher left ventricular ejection fraction (LVEF) (33% [IQR 25-38] vs. 24% [IQR 21-31], p<0.001) and less frequently received cardiac-resynchronization therapy defibrillator (6% vs. 29%, p=0.001) compared to DCM2014-16. Over a median 4.4-year follow-up, the all-cause mortality was 14%, of which 10% occurred in the DCM2017-22 patients (2.6 events/100 person-years), and 18% in the DCM2014-16 patients (4.0 events/100 person-years), p=0.38. There was no difference in appropriate ICD therapy between the two groups (p=0.90). Conclusion Patients receiving primary prevention ICD for niDCM after publication of the DANISH study were younger with higher LVEF, indicating a change in clinical practice after the publication. Despite this, there was no significant reduction in all-cause mortality or difference in appropriate ICD therapies. Unchanged mortality and event-rates may indicate the correct identification of high-risk patients.

Paracetamol and adverse cardiovascular outcomes in patients with heart failure

Abstract Background Paracetamol is the most widely used pain killer worldwide, yet its potential influence on cardiovascular events among patients with heart failure (HF) remains unclear. Thus, this study aims to investigate both the short-term and long-term effects of paracetamol use on all-cause mortality and cardiovascular events in HF patients. Methods Using the previously validated territory-wide clinical information registry, paracetamol use was identified among all eligible patients with HF (N = 211,409) from 2000 to 2020. A case-crossover design was used to investigate the associations between short-term use of paracetamols and all-cause mortality and cardiovascular outcomes. Defined daily dose (DDD) was used to evaluate the dose-response relationship. Additionally, the marginal structural design was applied to model paracetamol use as a time-varying exposure and evaluate its long-term effects during the follow-up period. Results Of all eligible subjects, the mean age was 73.2±12.3 years, and 43.6% was male. Over a median follow-up of 10.5 years (interquartile range: 5.7-15.8), 113,258 (53.6%) patients were re-hospitalised for HF, HF-related death occurred in 11,892 (5.6%) patients, incident myocardial infarction (MI) in 28223 (13.3%) patients, incident stroke in 26458 (12.5%) patients, cardiovascular death (CVD) in 72,175 (34.1%) patients and all-cause death in 123,505 (58.4%) patients. Associating HF rehospitalisation to previous paracetamol exposure using the case-crossover design displayed an elevated risk (OR 3.62, 95% CI 3.53-3.71). Associations were similar for MI (OR 5.77, 95% CI 5.50-6.05), stroke (OR 2.37, 95% CI 2.25-2.49), HF-related death (OR 1.86, 95% CI 1.75-1.98), CVD (OR 3.64, 95% CI 3.55-3.73), and all-cause mortality (OR 3.32, 95% CI 3.26-3.39). Moreover, compared with paracetamol users taking the reference dose, users of low, medium and high doses of paracetamol had 16%, 17% and 52% higher risk of HF rehospitalisation. During the long-term follow-up, the average weighted hazard ratio (HR) for HF rehospitalisation in paracetamol users was 2.48 (95% CI 2.46–2.50) as compared with paracetamol non-users after accounting for all-cause mortality as a competing risk. Similarly, the average weighted HR for incident MI or stroke was 2.71 (2.62-2.81) and 3.45 (3.34-3.57), respectively. However, neutral results were shown for HF-related death, CVD and all-cause mortality. Conclusion The use of paracetamol among patients with HF is common. Paracetamol was associated with adverse cardiovascular outcomes both in short-term and long-term follow-up with a dose-response relationship, while its impact on long-term mortality remained neutral. Future randomized controlled trials or experimental studies are warranted to gain a comprehensive understanding of the underlying mechanisms driving such associations between paracetamol and adverse cardiovascular outcomes.

The triglyceride-glucose index is a predictor for cardiovascular events and all-cause mortality in young and middle-aged patients with metabolic syndrome

Abstract Aims The association between the triglyceride-glucose (TyG) index and cardiovascular risk in young and middle-aged individuals with Metabolic syndrome (MetS) remains unclear. This study aimed to investigate the relationship between baseline TyG index and cardiovascular events and all-cause mortality in these patients among American adults. Methods This study enrolled 4937 young and middle-aged patients with MetS from the National Health and Nutrition Examination Survey (1999–2018). Mortality outcomes were determined by linking to National Death Index records up to December 31, 2019. Multivariate Cox proportional hazards models were constructed to analyze explore the associations between baseline TyG index and cardiovascular events or all-cause mortality. Non-linear correlations were explored using restricted cubic splines, and a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed. Results During the up to 9.3 years follow-up period, a total of 463 all-cause deaths and 143 cardiovascular events were recorded. The multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) escalate from the lowest to the highest TyG index quartile. Specifically, for cardiovascular events, the HRs range from 1.00 (reference) to 2.29 (1.22, 4.31) with a significant trend (P = 0.004). For all-cause mortality, the HRs vary from 1.00 (reference) to 1.59 (1.09, 2.32), also showing a significant trend (P = 0.003). The restricted cubic splines revealed a J-shaped association between the baseline TyG index with cardiovascular events and all-cause mortality in MetS patients. Conclusions The high TyG index was identified as an independent predictor of elevated rates of cardiovascular events among young and middle-aged patients with MetS. Additionally, a J-shaped curve pattern was observed in the association between these factors.

Impact of symptom-to-balloon time on long-term prognosis: a 3-year follow-up study in non-st-segment elevation myocardial infarction patients with complex lesions

Abstract Background Because no data are available, we compared clinical outcomes in patients with non-ST-segment elevation myocardial infarction (NSTEMI), stratified based on the presence of complex lesions, according to symptom-to-balloon time (SBT, <48 h versus ≥48 h), undergoing newer-generation drug-eluting stents. Methods From the KAMIR (Korea Acute Myocardial Infarction Registry)-NIH dataset, a total of 4373 patients diagnosed with NSTEMI were enrolled and stratified into two groups: the complex group (2106 patients; SBT <48 h, 1365; SBT ≥48 h, 741) and the non-complex group (2267 patients, SBT <48 h, 1573; SBT ≥48 h, 694). The primary outcome was the 3-year all-cause death rate, and the secondary outcome was major adverse cardiac events (MACE), including cardiac death (CD), recurrent MI, and any repeat revascularization. Results The rates of all-cause death (adjusted hazard ratio [aHR], 0.656; p = 0.009) and cardiac death (aHR, 0.633; p = 0.037) in the complex group, and the rate of all-cause death (aHR, 0.773; p = 0.036) in the total study population, were significantly lower for patients with SBT <48 h than for those with SBT ≥48 h. In the non-complex group, all clinical outcomes were not significantly different between the SBT <48 h and SBT ≥48 h groups. In the SBT ≥48 h group, the complex group exhibits higher rates of all-cause death, any repeat revascularization, and MACE than those of the non-complex group Conclusions Reducing SBT was more effective in decreasing 3-year mortality in NSTEMI patients with a complex group compared to the non-complex group.

Impact of atrial fibrillation on mortality and non-fatal clinical outcomes in 28 492 patients who had undergone open-heart aortic versus mitral valve surgery: a statewide population-linkage study

Abstract Background Postoperative atrial fibrillation (AF) is common after cardiac surgery and has been associated with increased mortality and morbidity. Few studies have defined the impact of AF status (New-AF versus Prior-AF) on clinical outcomes during long-term follow-up and compared AF-related clinical outcomes between patients who had undergone isolated aortic valve surgery (AVSx) or mitral valve surgery (MVSx). Purpose This study aims to examine the impact of AF status on clinical outcomes in patients who had undergone AVSx versus MVSx using a statewide-population administrative database. Methods Patients who had open-heart cardiac valve surgery (1 January 2003 to 31 March 2021) identified from the Admitted-Patient-Data-Collection database in an Australian state, were stratified by AF status (No-AF vs New-AF vs Prior-AF during index admission for valve surgery) and followed up to 31 March 2022. A linkage look-back to year-2001 was performed to identify prior-AF history. Kaplan-Meier and multivariable Cox regression were performed to assess the impact of AF status on all-cause mortality. Fine-Gray competing risk analysis to account for the competing death events was used to assess non-fatal clinical outcomes. Results The overall cohort comprised 28 492 patients (median age 71.6yrs [interquartile range (IQR) 62.7–78.3yrs; 65.6% males): AVSx, n=18949; MVSx, n=9543 (Table 1). During a median follow-up of 6.6yrs (3.42–10.5yrs), Prior-AF and New-AF patients had significantly higher all-cause mortality (AVSx – Prior-AF: 1771 (57.9%) vs New-AF: 2854 (41.5%) vs No-AF: 2961 (32.8%); MVSx – Prior-AF: 1126 (41.0%) vs New-AF: 1034 (29.8%) vs No-AF: 747 (22.4%) (both Kaplan-Meier logrank P<0.001). After adjusting for differences in baseline characteristics and admission year-groups, in the AVSx subgroup, both new-AF and prior-AF were independently associated with all-cause mortality (aHR=1.16, 95%CI=1.10–1.22; aHR=1.69, 95%CI=1.59–1.79 respectively, both P<0.001) compared to no-AF patients. In the MVSx subgroup, only prior-AF was associated with increased risk of all-cause mortality (aHR=1.47, 95% CI=1.33–1.61, P<0.001). Competing risk analyses showed higher rehospitalisation rates for AF and congestive cardiac failure for new-AF and prior-AF groups compared to No-AF patients after both AVSx and MVSx, whereas the rehospitalisation rate for ischemic stroke was only significantly higher in the AVSx new-AF and prior-AF subgroups (all p < 0.05) (Table 2). Conclusions Patients undergoing open-heart aortic or mitral valve surgery are at risk of significant adverse clinical outcomes including death, heart failure and ischaemic stroke, with the target valve and baseline AF status having a differential impact on clinical outcomes. Drivers behind these high rates of adverse outcomes should be explored further and strategies should be developed and tailored accordingly to different surgical patient groups to improve their prognosis.

Diabetes and the risk of cardiovascular events and all-cause mortality among older adults: an individual participant data analysis of five prospective studies.

Guidelines and studies provide conflicting information on whether type 2 diabetes (T2D) should be considered a coronary heart disease risk (CHD) equivalent in older adults. We synthesized participant-level data on 82,723 individuals aged ≥65 years from five prospective studies in two-stage meta-analyses. We estimated multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D (presence versus absence) on a primary composite outcome defined as cardiovascular events or all-cause mortality. Secondary outcomes were the components of the composite. We evaluated CHD risk equivalence by comparing outcomes between individuals with T2D but no CHD versus CHD but no T2D. The median age of participants was 71 years, 20% had T2D and 17% had CHD at baseline. A total of 29,474 participants (36%) experienced the composite outcome. Baseline T2D was associated with higher risk of cardiovascular events or all-cause mortality versus no T2D (HR 1.44, 95% CI [1.40-1.49]). The association was weaker in individuals aged ≥75 years versus 65-74 years (HR 1.32 [1.19-1.46] vs. 1.56 [1.50-1.62]; p-value for interaction = .032). Compared to individuals with CHD but no T2D, individuals with T2D but no CHD had a similar risk of the composite outcome (HR 0.95 [0.85-1.07]), but a lower risk of cardiovascular events (HR 0.76 [0.59-0.98]). T2D was associated with increased risk of cardiovascular events and all-cause mortality in older adults, but T2D without CHD conferred lower risk of cardiovascular events compared to CHD without T2D. Our results suggest that T2D should not be considered a CHD risk equivalent in older adults.

Association of Altitude with Mortality among Patients with Hypertension - A Cohort Study

Abstract Background Available evidence falls short in assessing the risk of all-cause mortality and cardiovascular disease (CVD) mortality among individuals with hypertension residing at various altitudes. This study’s objective was to investigate the correlation between residential altitude and the rates of all-cause mortality and CVD mortality among hypertensive patients. Methods This prospective cohort study encompassed 67,275 hypertensive individuals aged 35 years and above in the year 2018. Participants were categorized into four distinct groups based on their residence altitude: those living below 500 meters, between 500 and 1499 meters, 1500 to 2500 meters, and above 2500 meters. The study spanned a mean follow-up duration of 4.78 years. The associations between residential altitude and the risks of all-cause and CVD mortality were analyzed using Cox proportional hazards regression models. Results Among the 67,275 hypertensive patients included in the study (mean age of 63.9 years, with 45.3% being male), 8,768 deaths were recorded, of which 5,666 were attributed to CVD. Following multivariate adjustment, when compared to the group residing at altitudes below 500 meters, the groups living at altitudes of 500-1499 meters, 1500-2500 meters, and above 2500 meters exhibited significantly elevated risks of all-cause mortality [hazard ratio, HR = 1.45 (95% CI: 1.36-1.54), 1.35 (95% CI: 1.36), and 1.41 (95% CI: 1.28-1.54), respectively] and CVD mortality [HR = 1.47 (95% CI: 1.35-1.58), 1.42 (95% CI: 1.33-1.52), and 1.46 (95% CI: 1.31-1.62), respectively]. For each 500-meter increment in altitude, the risk of all-cause and CVD mortality increased by 10% and 11%, respectively. Subgroup analyses and sensitivity assessments consistently supported this association. Conclusions This study’s findings indicate a substantial connection between long-term residential high-altitude exposure and increased risks of all-cause mortality and CVD mortality among individuals with hypertension. Key messages • Increased altitude of residence increases the risk of subsequent all-cause and CVD mortality in hypertensive patients. • This study highlights that relevant guidelines and healthcare providers should consider altitude as an important factor in reducing the burden of hypertension and CVD.

Evaluation of renal tubulointerstitial damage as a residual renal risk factor for adverse cardiac events in patients with aortic valve stenosis

Abstract Background Renal dysfunction, defined as a lower eGFR, has been shown to be related to cardiovascular events in patients with aortic stenosis treated with transcatheter aortic valve implantation (TAVI). However, the contribution of renal tubulointerstitial damage to the predictive value for cardiovascular events remains unclear. The aim of this study was to elucidate whether renal tubulointerstitial damage is associated with the occurrence of all death and heart failure patients who have had TAVI. Methods and results In a cohort of 155 patients, urinary beta2-microglobulin (beta2MG) levels were measured. Patients were monitored for less than three years or until experiencing all-cause mortality or hospitalization due to heart failure. The cumulative all-cause mortality was 11.5%, and heart failure admission rate stood at 5.4%. Stratifying outcomes by beta2MG levels revealed significantly lower rates of all-cause mortality and heart failure in patients with beta2MG <0.20 mg/gCre compared to those with beta2MG ≥0.20 mg/gCre (10.2% versus 24.2%, p=0.01). When outcomes were stratified according to the beta2MG levels in combination with eGFR levels, Kaplan-Meier analyses showed that all-cause mortality and heart failure rates increased depending on an increase in the beta2MG levels (p<0.05) even if eGFR is above 60 ml/min. Moreover, multivariate Cox analyses revealed that high levels of beta2MG were an independent predictor of adverse events. Conclusion Renal tubulointerstitial damage is associated with the occurrence of all death and hospitalization for heart failure independent of renal glomerular function.

5-year valve academic research consortium-3 outcomes and predictors of mortality in a 10-year Asian transcatheter aortic valve implantation registry

Abstract Background Transaortic valvular implantation (TAVI) has revolutionised the management of aortic stenosis (AS). Uptake in Asia has caught up in recent years, after an initial lag due to expensive cost, limited subsidies, and scarce accessibility. Hence, longitudinal outcomes of TAVI remain largely unknown in Asian patients. Purpose This study aims to present the 5-year mortality endpoints in an Asian cohort followed up over a decade. Methods 253 patients with symptomatic severe aortic stenosis status post TAVI were retrospectively enrolled at a tertiary academic hospital from 2010-2021. The main outcomes were defined as short-term (30-day), mid-term (1-year) and long-term (5-year) all-cause mortality. Baseline demographics, procedural findings and clinical outcomes were analysed. Kaplan-Meier curves and multiple Cox regression analyses were constructed. Results The mean age was 75.2 + 10.2 years. 120 (47.4%) patients were female and 167 (66%) were Chinese. 168 patients (66.7%) received balloon-expandable valves, 80 patients (31.7%) underwent self-expandable valves, and 4 patients (1.6%) had mechanical-expandable valves. Malignancy was associated with worse short-term mortality at 30-days (HR 3.65, p = 0.054), while pulmonary disease and previous stroke were associated with worse long-term mortality at 5-years (HR 2.27, p = 0.012 and HR 2.02, p = 0.064). Worse all-cause mortality at 30-days, 1-year and 5-years were associated with high NT-Pro BNP levels (HR 1.04, p = 0.046; HR 1.05, p = 0.002 and HR 1.04, p < 0.001), the presence of peripheral arterial disease (PAD) (HR 4.32, p = 0.056; HR 4.48, p = 0.006 and HR 2.43, p = 0.023) and chronic kidney disease (CKD) (HR 6.19, p = 0.006; HR 6.77, p < 0.001 and HR 2.09, p = 0.008). Society of Thoracic Surgery (STS) score (HR 1.11, p = 0.001; HR 1.13, p < 0.001 and HR 1.12, p < 0.001) and Valve Academic Research Consortium (VARC) III endpoints of acute kidney injury (AKI) (HR 6.68, p = 0.047, HR 10.8, p < 0.001 and HR 6.99, p < 0.001), cardiogenic shock (HR 26.3, p < 0.001, HR 12.0, p < 0.001 and HR 4.29, p = 0.011) and structural complications (HR 40.3, p < 0.001, HR 18.1, p < 0.001 and HR 5.18, p = 0.008) were associated with worse all –cause mortality at time-points of 30-days, 1-year and 5-years respectively. On multivariate analyses adjusted for comorbidities and outcomes, STS score and structural complications were independent predictors of 30-day, 1-year, and 5-year all-cause mortality (HR 1.16; p = 0.003, HR 1.09, p = 0.003 and HR 1.10, p < 0.001) and (HR 62.7, p < 0.007; HR 18.9, p < 0.001 and HR 10.6, p = 0.001) respectively. Angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use was protective of survival within 1-year (HR 0.37, p = 0.022). Conclusions STS score and VARC III endpoints of structural complications were reliable predictors of all-cause mortality in Asian patients with TAVI. ACE inhibitor and ARB use was protective against mortality at 1-year.Cox regression analysesKaplan-Meier curves

Age-based comparison of patients with heart failure treated with sacubitril-valsartan in France: a real-world evaluation

Abstract Background Sacubitril-Valsartan (S/V) was approved in Europe in 2015, for treatment of adults with symptomatic chronic heart failure with reduced left ventricular ejection fraction (HFrEF). In France, S/V had benefited from an early access program (2015-2018) and became available in community pharmacy since October 2018. Purpose Our study aimed to describe characteristics of patients who received S/V in France and to assess real-life mortality in this population regarding age. Methods This non-interventional retrospective study utilized existing claims data from the French National Healthcare Data System (SNDS) allowing long-term follow-up of patients who benefited from at least one reimbursement of S/V. Patient data between April 2012 and December 2020 were extracted from the database. Prespecified subgroup analyses were conducted for subjects aged <75 and ≥75 y to describe characteristics of patients at first reimbursement of S/V. Cardiovascular mortality and all-cause mortality were estimated using Kaplan-Meier method. Results Between 2015 and 2020, 104,910 patients initiated S/V and were followed for an average of 20 months; 42.6% (44,743 patients) were ≥75 y. Mean (SD) age difference between the 2 subgroups was 20.3 years [62.2 (9.6) vs 82.5 (5.2) in patients <75 and ≥75 y respectively]. Patients ≥75 y had a higher prevalence of atrial fibrillation (50.6% vs 31.2%) and chronic renal failure (20.9% vs 10.1%) and were less co-treated with mineralocorticoid-receptor antagonists (21.8% vs 40.5%) and ß-Blockers (64.0% vs 73.8%) compared to those <75 y. Three months after first dispensation, 48.3%, 35.3%, and 16.4% of patients aged ≥75 y received S/V dosages of 24/26mg, 49/51mg, and 97/103mg respectively, compared to 31.4%, 38.2%, and 30.4% for patients aged <75 y. The mean (SD) exposure period was 14.7 (13.6) months in patients ≥75 y vs 19.0 (15.5) months in <75 y patients. As expected, given the age difference, patients ≥75 y had a higher probability of all-cause mortality at 12-month 16.5% vs 6.2% in patients <75 y. Furthermore, 12-month cardiovascular mortality – evaluated during the early access program period (2015-2017) – in patients ≥75 y was 11.0% vs 4.8% in patients <75 y. Figures 1 and 2 show survival curves for cardiovascular mortality and all-cause mortality of these 2 subgroups. Of interest, cardiovascular mortality rate at 12 months was 7% in this study, compared to 6% in PARADIGM-HF, and all-cause mortality at 12-month was higher (10,6% vs 7%), likely due to the profile of the patients, who were older and have more comorbidities in real life. Finally, very few patients were hospitalized for reasons related to angioedema, 16/44,743 in ≥75 y patients and 26/60,167 in those <75 y. Conclusion This is the first French real-world study providing exhaustive nationwide data on S/V mortality over a period of almost 6 years in a very large population of elderly with a mean age of 70.9 y vs 63.8 y in PARADIGM-HF.Figure 1Figure 2

Atrial fibrillation-related complications following short-term use of antibiotics in patients receiving NOAC or warfarin

Abstract Introduction To study the association of antibiotics with ischaemic stroke/systemic embolism (IS/SE) in patients with atrial fibrillation (AF) receiving anticoagulants. Methods This retrospective population-based cohort study applied electronic health data from a territory-wide medical database. Data were collected for patients with AF who were prescribed non-vitamin K antagonist oral anticoagulants (NOAC) or warfarin between Jan 1, 2010 and Dec 31, 2018. We further identify the patients with and without use antibiotics (any classification of antibiotics with prescription period within 7 days) during the NOAC/warfarin treatment period. The primary outcome is IS/SE and the secondary outcomes including hemorrhagic stroke (HS) and all-cause mortality. Patients were followed up for a median of 3.7 years. A self-control case crossover design was adopted to compare the short-term association between use of antibiotics and outcomes of interest among NOAC and warfarin group. Results This study included 40221 patients, consisted of 30617 NOAC users and 9826 warfarin users, while 9604 patients in NOAC group and 3325 patients in warfarin group had concurrent antibiotics use. At baseline, 46.1% of patients in NOAC group were male and the mean (SD) age was 77.4 (9.8) years, and 56.2% of patients in warfarin group were male and the mean (SD) age was 73.8 (11.3) years. Short-term use of antibiotics is associated with increased risk of IS/SE, HS and all-cause mortality in both NOAC and warfarin groups (NOAC vs. warfarin group: IS/SE: hazard ratio [HR]:3.41 [95%CI, 2.78-4.18]; HR: 2.51 [95%CI, 2.00-3.14]; HS: HR: 2.22 [95%CI, 1.78-2.78]; HR: 2.53 [95%CI, 1.86-3.43]; mortality: HR: 1.96 [95%CI, 1.85-2.08]; HR: 1.87 [95%CI, 1.73-2.02]; all P < 0.001). Conclusion The findings of the present study suggest that the short-term antibiotics use was associated with an increased risk of IS/SE, HS and all-cause mortality among patients in both NOAC and warfarin group. These findings further suggest that use of antibiotics may indicate a higher risk of IS/SE, HS and death for patients with AF, even when receiving NOAC/warfarin and that further investigation is warranted.The study design.The odds ratios of different outcomes.

Myocardial work and aortic valve stenosis cardiac damage stages are predictors of all-cause mortality in patients undergoing transcatheter aortic valve replacement

Abstract In aortic stenosis (AS) patients, assessment of left ventricular (LV) systolic function is complicated due to the significant impact of increased afterload on conventional parameters. Myocardial work (MW) analysis, a novel echocardiographic method adjusts myocardial deformation to instantaneous LV pressure which may better reflect the LV contractile state. Importantly, long-term LV pressure overload has marked backward effects beyond the LV: classification of this extravalvular cardiac damage effectively represents the involvement of the cardiopulmonary system in AS. Both MW and cardiac damage staging could hold remarkable prognostic power in the clinically complex population of transcatheter aortic valve replacement (TAVR) candidates. Accordingly, our aim was to assess the prognostic value of MW analysis and cardiac damage staging in patients undergoing TAVR. We enrolled 289 patients (79±6 years, 41% female) prior to TAVR. Echocardiographic measurements were performed one day before the procedure. We calculated LV ejection fraction (EF) and by speckle-tracking echocardiography global longitudinal strain (GLS), as well. Global constructive work (GCW) was quantified with dedicated software and LV pressure was estimated using transaortic mean gradient and systolic blood pressure. Based on the echocardiographic data, we also determined the extent of cardiac damage associated with AS: patients were classified as Stage 0 (no cardiac damage), Stage 1 (LV damage), Stage 2 (mitral valve or left atrial damage), Stage 3 (pulmonary artery vasculature or tricuspid valve damage), or Stage 4 (right ventricular damage). Our primary outcome was all-cause mortality, reached by 68 patients (median follow-up: 26 months). In our cohort, preprocedural EF was 47±13 %, GLS was -12.3±4 %, while GCW was 2043±791 mmHg%. 14 (5%) patients were classified as Stage 0, 61 (21%) as Stage 1, 128 (44%) as Stage 2, 15 (5%) as Stage 3, and 71 (25%) as Stage 4. GCW showed a continuous decline through the AS Stages (from Stage 0-4: 2963±652 vs. 2154±652 vs. 2168±718 vs. 1988±969 vs. 1552±772 mmHg%; p<0.001). Using univariate Cox analysis GCW (HR 0.968 [95% CI 0.938-0.998] per 100 unit change; p=0.034) and AS Staging (HR 1.236 [95% CI 1.015-1.505]; p=0.035) were both associated with all-cause mortality, while EF (HR 0.984 [95% CI 0.966-1.002]; p=0.085) and GLS (HR 1.042 [95% CI 0.984-1.103]; p=0.160) were not. In multivariate Cox regression models, both GCW (HR 0.957 [95% CI 0.922-0.992] per 100 unit change; p=0.018) and AS cardiac damage staging (HR 1.263 [95% CI 1.029-1.549]; p=0.025) were proven to be significant independent predictors of all-cause mortality. In TAVR patients, preoperative GCW values exhibited a persistent decrease across AS Stages. As opposed to EF and GLS, GCW and AS Staging both showed strong association with all-cause mortality in our cohort. Moreover, GCW had higher prognostic value than any other conventional or advanced measure of LV function.

Long-term prognostic value of microvascular obstruction by cardiac magnetic resonance in ST-segment elevation myocardial infarction

Abstract Background Microvascular obstruction (MVO) has been associated with a higher risk of cardiac remodelling and adverse events following ST-segment elevation myocardial infarction (STEMI). However, long-term prognostic implications of MVO in STEMI beyond five years of follow-up have not been assessed to date. Purpose To investigate the relation of MVO with all-cause mortality and recurrent ischemic events at long-term follow-up after STEMI. Methods This is a pooled analysis of three observational studies including 876 prospectively enrolled reperfused first STEMI patients, who underwent cardiac magnetic resonance imaging with late gadolinium enhancement, between 2003-2019, from four university medical centers in the Netherlands and Spain. Median follow-up duration was 6.3 (IQR 3.6-9.3) years. The primary outcome was all-cause mortality. The secondary outcome was a combined endpoint of all-cause mortality and recurrent ischemic events (i.e. myocardial infarction or stroke). We performed Cox regression analyses with a time-dependent covariate. Model 1 included correction for clinical covariates only, i.e. age, sex, smoking, diabetes mellitus, hypertension, and LAD culprit artery. Model 2 included imaging characteristics, i.e. infarct size and left ventricular ejection fraction, in addition to the clinical covariates. Results The study population consisted of 876 patients, mean age 59 years ± 12, 720 men (82%). MVO was present in 499 patients (58%). The presence of MVO was significantly associated with all-cause mortality up to six years post-STEMI, independent from clinical characteristics (Hazard Ratio [HR] 2.23, 95% CI 1.09-4.57, p=0.029), but not after six years post-STEMI (HR 0.98, 95% CI 0.45-2.12, p=0.958). Presence of MVO was not significantly associated with a combined endpoint of all-cause mortality and recurrent ischemic events before or after six years of follow-up (HR 1.27, 95% CI 0.81-1.99, p=0.294 and HR 0.68, 95% CI 0.35-1.31, p=0.244, respectively). All other traditional prognosticators, except age, also lacked predictive value at long-term follow-up beyond six years. Conclusions In STEMI patients, the presence of MVO by cardiac magnetic resonance imaging is associated with a more than two-fold higher risk of all-cause mortality up to six years after the index event. This relation seems to dissipate beyond this time period. Furthermore, presence of MVO was not associated with recurrent ischemic events at long-term follow-up post-STEMI.

Cognitive patterns according to mini-mental state examination domains in patients with AF and association with all-cause mortality: a cluster analysis from a contemporary prospective study

Abstract Background Atrial fibrillation (AF) is associated with cognitive impairment even in the absence of previous stroke. However, data on specific patterns of cognitive impairment and their association with outcomes are limited. Purpose We aimed to identify different phenotypic groups of AF patients stratified according to specific cognitive domains using cluster analysis and evaluate the association between identified clusters and adverse outcomes. Methods We used data from a prospective observational study on AF patients excluding those with previous clinically overt stroke. We performed a hierarchical cluster analysis based on Ward’s Method using data from the Mini-Mental State Examination (MMSE) administered during the enrollment. The MMSE includes 6 distinct cognitive domains. We normalized each domain’s score from 0 to 100 to preserve the ranking and the interpretability of the test. Patients’ clusters were identified by examining the distance between cluster coefficients and by visual inspection of the dendrogram. All-cause mortality was the primary endpoint. Results A total of 872 stroke-free AF patients were included. Three clusters based on MMSE domains were identified: Cluster 1 (n=494, 56.7%); Cluster 2 (n=243, 27.9%) and Cluster 3 (n=135, 15.5%). The clusters greatly differed according to the cognitive domains affected and baseline characteristics (Table). The use of oral anticoagulants did not differ among clusters and it was substantially high (88.6%). Cluster 2 had a higher prevalence of cognitive impairment (37.9% vs 35.6% for Cluster 3 and 1.0% for Cluster 1, p<0.001) with a lower mean MMSE score compared to other clusters. The analysis of MMSE domains showed substantial deficits in the orientation, attention/calculation, and recall domains with peculiar differences among the clusters. Cluster 2 showed the most significant impairment in the copying domain (100%) while Cluster 3 had a higher impairment in attention/calculation and recall domains. After a median follow-up of 629 days, all-cause mortality was 15.9% with a significantly higher prevalence in Cluster 2 (26.9% vs 10.0% and 15.5% for Cluster 1 and Cluster 3 respectively, p<0.001). At the adjusted Cox regression analysis, Cluster 2 was independently associated with a higher risk of all-cause mortality compared with Cluster 1 (HR 1.83, 95% CI 1.18-2.82) while Cluster 3 was not independently associated with the outcome (Figure). Conclusions In a prospective observational cohort of stroke-free AF patients, we identified three clusters showing different patterns of cognitive impairment, affecting specific MMSE domains and resulting in a different risk of mortality. Our findings highlight the clinical implications of cognitive impairment and stress the need for a more holistic approach to AF patients including a comprehensive cognitive assessment, as well as the need for studies on interventions able to positively affect cognitive impairment.Figure

Race/Ethnicity, Education, and All-Cause Mortality in US Adults: Mediation by Telomere Length

Abstract Background Racial/ethnic inequities in mortality risk are pervasive in the United States even after controlling for socioeconomic status indicators such as educational attainment. Although the mechanisms underlying these inequities remain unclear, telomere length (TL) has emerged as a potential mediator. We aimed to investigate the joint association of race/ethnicity and education with all-cause mortality risk, and the contribution of TL to this relationship. Methods We used data from the U.S. National Health and Nutrition Examination Survey, 1999 to 2002, and 2019 Linked Mortality File (n = 6,526 non-institutionalized adults aged 25 years or older, including 2,166 deaths), a retrospective cohort study with a follow-up period to December 31, 2019. Cox proportional hazards regression and causal mediation analysis were used to address these aims. We reported hazard ratios (HR) and 95 % confidence intervals (CI). Furthermore, for the mediation analysis, we reported the total, direct, and indirect effects measured as HR and 95 % CI. Results After adjusting for age and sex, among White individuals, those with less than a high school education had a 2.26 times higher (95% CI: 1.93, 2.65) rate of all-cause mortality compared to those with some college or higher education. When compared with White adults with at least a college degree, Black adults with at least a college degree had a 1.38 higher rate of dying (95% CI: 1.04, 1.84). There was no significant joint association of race/ethnicity and education on all-cause mortality in Mexican Americans. In the mediation analysis, TL did not significantly contribute to the joint association of race/ethnicity and education with all-cause mortality risk. Discussion These findings underscore the need for a better understanding of the joint relationship of race/ethnicity and education on mortality risk inequities and their potential mechanisms to improve population health ultimately. Key messages • Lower educational attainment was associated with higher mortality rates among White individuals, disparities persisted among the Black population, despite higher education levels. • Our analysis did not find a significant mediation effect of telomere length on the joint effect of race/ethnicity and education-mortality relationship.

Correlation between short-term quality of life improvement and clinical outcomes - a post-hoc ISCHEMIA trial analysis

Abstract Background Patients with symptomatic coronary artery disease (CAD) exhibit improvement in quality of life (QoL) after invasive management (percutaneous coronary intervention [PCI] and coronary artery bypass grafting [CABG]). However, it is not clear how QoL improvements after intervention are related to clinical outcomes. Purpose Using the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) population, we sought to assess the relationship between short-term QoL improvement and long-term clinical outcomes. Methods All participants in the ISCHEMIA trial who were randomized to the invasive arm and who had QoL scores available were included in the analysis. QoL improvement was calculated using the difference between the Seattle Angina Questionnaire (SAQ) score at baseline and at six months regarding randomization. The primary outcome was the trial-defined composite outcome (cardiovascular death, myocardial infarction, cardiac arrest or hospitalization for unstable angina/heart failure) and all-cause death. The secondary outcome was all-cause mortality. Median follow-up was 3.3 years. Cox proportional hazards models included clinically relevant demographic and angiographic covariates. Results After the exclusion of the conservative treatment arm and patients without QoL follow-up or covariate data, 1,577 patients were selected for the final analysis (Fig.1). The median baseline SAQ score was 74 (interquartile range, IQR: 60-88), the change in score at six months was 14 (IQR: 2-26), and 76.1% of patients experienced improvement in QoL. Six-month QoL improvement was not associated with a lower risk of the primary outcome (hazard ratio [HR]: 0.961, 95% confidence interval [CI], 0.920-1.005, p=0.081 – Table 1), but was associated with all-cause mortality (HR: 0.919, 95% CI, 0.859-0.982, p=0.013 – Table 1). In this population, increased age (HR: 2.370, 95% CI, 1.710-3.287, p<0.001, per 10 years) was also associated with higher risk of all-cause mortality. Conclusions Among invasive treated patients in ISCHEMIA trial, six-month QoL improvement was associated with a lower risk of long-term all-cause mortality, but not with a lower risk of major adverse events.Figure 1.Study population.

Treatment of kidney disease: an analytical decision model at a Swiss university hospital

Abstract Background An observational hospital-based cohort study, where the kidney disease staging is identified as a digital marker, and the association between the standardised staging of Kidney Disease (KD) and the outcomes is assessed along the treatment process. Methods The clinical and administrative data for all patients are stored in the Clinical Data Warehouse. A specific digital marker for an exact KD staging is applied. Three retrospective patient cohorts for exact and imprecise staging and missing diagnosis are defined and compared regarding the in-hospital mortality, all-cause mortality and disease progression. Results In total, 83146 hospitalisations of 40421 patients with KD, treated in 2014-2023 (2016-2023 will be updated) were identified; the number of the first hospitalisations with exact staging was 847 (2%), unprecise 29934 (72%) and missing diagnosis (26%). The demographic and baseline factors distribution between groups was tested with no association (chi-squared test statistic). The median survival time with a 95% CI was 7.94 (7.66, 8.81) years for the exact and 7.47 (7.42, 7.53) for the imprecise staging group. A log-rank and loglikelihood tests indicated a significant difference in survival between the groups, p < 0.0001. The Cox regression model shows a statistically significant difference in Hazard Ratio; KD staging, age, Elixhauser van Walraven index, treatment, nephrotoxic medication, contrast agent application, and AKI were identified as the significant covariates, C-statistic 0.730, Likelihood ratio test, Wald test, log-rank score on 42 df, p < 2e-16. ANOVA analysis confirmed a significant difference in cost distribution between the groups. An economic decision model proposal integrates the findings, combining a profile-level Markov cohort with a Discreet Time-To-Event Simulation DICE. Conclusions The study demonstrates a better outcome regarding all-cause mortality, in-hospital mortality, and costs if a standardised KD staging was applied. Key messages • Intuition (clinical judgement) and standardised kidney disease staging perform differently regarding clinical outcomes and costs. • The study demonstrates a better outcome regarding all-cause mortality, in-hospital mortality, and costs if a standardised KD staging was applied.