Landmark Analysis Research Articles

Bioadaptor implant versus contemporary drug-eluting stent in percutaneous coronary interventions in Sweden (INFINITY-SWEDEHEART): a single-blind, non-inferiority, registry-based, randomised controlled trial.

Persistent non-plateauing adverse event rates in patients who underwent percutaneous coronary intervention (PCI) remain a challenge. A bioadaptor is a novel implant that addresses this issue by restoring the haemodynamic modulation of the artery, allowing cyclic pulsatility, vasomotion, and adaptative remodelling, by unlocking and providing dynamic support to the artery. We aimed to assess outcomes with the device versus a contemporary drug-eluting stent (DES) in a representative PCI population. INFINITY-SWEDEHEART is a single-blind, non-inferiority, registry-based, randomised controlled study conducted in 20 hospitals in Sweden. Patients aged 18-85 years, with chronic or acute coronary syndrome ischaemic heart disease, with an indication for PCI, with up to three de novo lesions suitable for implantation with one single device per lesion, and successful pre-dilatation were identified via the Swedish Coronary Angiography and Angioplasty Registry and eligible for enrolment. Participants were randomly assigned (1:1), using block randomisation with random variation in block size and stratified by site, to either the DynamX bioadaptor (Elixir Medical, Milpitas, CA, USA) or a zotarolimus-eluting DES (Resolute Onyx and Onyx Trustar, Medtronic, Minneapolis, MN, USA). The primary endpoint was the device-oriented clinical endpoint of target lesion failure at 12 months (a composite of cardiovascular death, target vessel myocardial infarction, and ischaemia-driven target lesion revascularisation), assessed in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment, regardless of treatment received) who had either experienced an event up to 12 months or completed the trial up to 12 months. Non-inferiority was established if the upper limit of the two-sided 95% CI for the absolute risk difference was less than 4·2%. Powered secondary endpoints were landmark analyses from 6 months onwards for target lesion failure, target vessel failure (composite of cardiovascular death, target vessel myocardial infarction, and ischaemia-driven target vessel revascularisation), and target lesion failure for patients with acute coronary syndrome assessed in the ITT population). This study is registered with ClinicalTrials.gov, NCT04562805, and follow-up to 5 years is ongoing. Between Sept 30, 2020, and July 11, 2023, 2399 patients were randomly assigned to receive the bioadaptor (n=1201) or DES (n=1198; ITT population). Median age was 69·5 years (IQR 61·2-75·6), 575 (24·0%) of 2399 patients were female, and 1824 (76·0%) were male (data on race and ethnicity were not collected), and 1838 (76·6%) patients presented with acute coronary syndrome. The primary endpoint of 12-month target lesion failure occurred in 28 (2·4%) of 1189 assessable patients in the bioadaptor group versus 33 (2·8%) of 1192 assessable patients in the DES group, with a risk difference of -0·41% (95% CI -1·94 to 1·11; pnon-inferiority<0·0001). In the prespecified landmark analysis from 6 months to 12 months, the Kaplan-Meier estimates of target lesion failure were 0·3% (with events in three of 1170 patients) in the bioadaptor group versus 1·7% (with events in 16 of 1176 patients) in the DES group (hazard ratio 0·19 [95% CI 0·06 to 0·65]; p=0·0079), of target vessel failure were 0·8% (events in eight of 1167) versus 2·5% (events in 23 of 1174; 0·35 [0·16 to 0·79]; p=0·011), and of target lesion failure in patients with acute coronary syndrome were 0·3% (events in two of 906) versus 1·8% (events in 12 of 895; 0·17 [0·04 to 0·74]; p=0·018). The rate of definite or probable device thrombosis, which was recorded as a safety outcome, was low and did not differ between groups (eight [0·7%] of 1201 in the bioadaptor group vs six [0·5%] of 1198 in the DES group; difference in event rates of 0·16% [95% CI -0·50 to 0·83]). Among patients with coronary artery disease, including those with acute coronary syndrome, treatment with the bioadaptor was non-inferior to contemporary DES, showing potential to mitigate non-plateauing device-related events and improving outcomes in patients undergoing PCI. The additional planned follow-up will help to reinforce the clinical significance of the 1-year findings. Elixir Medical.

Accuracy of web-based automated versus digital manual cephalometric landmark identification.

The purpose of this study was to assess the accuracy of two web-based automated cephalometric landmark identification and analysis programs. Manual landmark identification using Dolphin Imaging software was used as reference. 105 cephalograms were selected and divided into three groups of 35 subjects each, Class I, II and III. Radiographs were traced using Dolphin imaging software. WebCeph™ (South Korea) and Cephio™ (Poland) were used for the automated cephalometric analysis. Bland-Altman limits of agreement and the concordance correlation coefficient (CCC) were calculated. Kruskal Wallis test was used to compare the accuracy of WebCeph™ and Cephio™ measurements between the three groups. Mann-Whitney U test was used to compare the absolute difference between cephalometric measurements obtained using WebCeph™ and Cephio™. The mean difference (MD) between AI and manually-derived measurements was less than 1mm/degree and ranged from 0.01 to 0.8 except for upper lip protrusion (MD 1.35°), nasolabial angle (MD 5.01°), SN-GoGn (MD 1.41°), Ramus height (MD 1.46°), and IMPA (MD 1.94°). The mean CCC was 0.91 (range 0.60 to 0.96). No statistically significant differences were found between the three malocclusion groups for most of the measurements (P > 0.05). For most of the measurements, automated cephalometric measurements were clinically acceptable. Few differences were found between Webceph™ and Cephio™ for most measurements. Measurements including SNA, SN-PP, IMPA as well as soft tissue measurements require extra consideration and manual adjustment of respective landmarks for higher precision and improved efficiency.

Venous thromboembolism in adolescents and young adults with acute lymphoblastic leukemia treated on a pediatric-inspired regimen

Asparaginase (ASP)-containing regimens for acute lymphoblastic leukemia (ALL) are associated with venous thromboembolism (VTE). We evaluated the prevalence, risk factors, role of prophylaxis and clinical impact of VTE among adolescents and young adult (AYA) patients (15–50 years) treated on Dana-Farber Cancer Institute (DFCI) ALL protocols. The 1- and 2-year cumulative incidence of VTE were 31.9% (95% CI: 27.0%, 36.9%) and 33.5% (95% CI: 28.5%, 38.5%) respectively, with most events occurring during ASP-based consolidation phase (68.6%). VTE was more frequent in patients with overweight/obese vs. normal BMI (39.2% vs. 29.0%, p = 0.048). In a 1-year landmark analysis, the 4-year overall survival was 91.5%, without difference between patients with vs. without VTE (93.8% vs. 90.0%, p = 0.93). Relapse and non-relapse mortality rates were also similar. Among patients treated at Dana-Farber/Harvard Cancer Center, cerebral sinus vein thrombosis occurred in 3.6% of patients (8.5% of VTE events) in comparison to pulmonary embolism (32.9%) and deep vein thromboses (58.6%, 24.4% line-associated). In a Cox regression model for VTE free-time, elevated BMI was associated with shorter VTE free-time (HR 1.94 [95% CI 1.13-3.35], p = 0.018), while low molecular weight heparin (LMWH) prophylaxis as time-varying covariate was not. In conclusion, we found that VTE was frequent in AYAs treated on DFCI ALL protocols but did not impact survival outcomes. Overweight/obese BMI increased risk for VTE.

A phase 2, multicenter, clinical trial of CPX-351 in older patients with secondary or high-risk acute myeloid leukemia: PETHEMA-LAMVYX.

LAMVYX was a multicenter, single-arm, phase 2 trial designed to validate the safety and efficacy of CPX-351 in patients aged 60-75 years with newly diagnosed, secondary acute myeloid leukemia and to generate evidence on key issues not addressed in the preceding regulatory pivotal trial. The primary end point of the study was the complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate after induction. Eligible patients were recommended to undergo allogeneic hematopoietic stem cell transplantation after the first consolidation cycle. Alternatively, patients could undergo up to six maintenance cycles with CPX-351. Twenty-nine patients (49%; 95% exact confidence interval [CI], 37%-62%) patients achieved a CR/CRi after one or two cycles of induction, with a measurable residual disease negativity rate of 67% as assessed by centralized, multiparameter flow cytometry. Among patients who had serial next-generation sequencing analyses available, clearance of somatic mutations that were present at diagnosis was achieved in 7 (35%). The median follow-up among survivors was 16.8 months (range, 8.7-24.3 months). The median event-free survival was 3.0 months (95% CI, 1.4-7.3 months), and the median overall survival was 7.4 months (95% CI, 3.7-12.7 months). In landmark analyses at day +100 from diagnosis, the 1-year overall and event-free survival rate among patients who underwent allogeneic hematopoietic stem cell transplantation was 70% (95% CI, 47%-100%) and 70% (95% CI, 47%-100%), respectively. The corresponding values were 89% (95% CI, 71%-100%) and 44% (95% CI, 21%-92%), respectively, for patients who entered the maintenance phase. No significant longitudinal changes were observed in severity index or quality-of-life visual analog scale scores. The current data provide novel insights that might inform the clinical positioning and optimal use of CPX-351, complementing previous results (ClinicalTrials.gov identifier NCT04230239).

Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy.

Immune-related adverse events (irAEs) occur in various organs, and sometimes multiply following treatment with immune checkpoint inhibitors (ICIs). This study aimed to determine the association between the number of irAEs and clinical outcomes. This was a retrospective study that included patients with lung cancer, melanoma, and head and neck cancer who were treated with anti-programmed cell death (ligand) 1 (PD-1/PD-L1) monotherapy. We evaluated the association between the number of irAEs and progression-free survival (PFS) in the simple Cox regression analysis. To eliminate the immortal-time bias, an additional landmark analysis was performed. In total, 92, 69, and 37 patients were allocated to the no, single, and multisystem irAEs groups, respectively. The multisystem irAEs were associated with better PFS compared to the no irAE group. In contrast, at the 12-week landmark, multisystem irAEs were associated with poor PFS compared to the no irAEs group. Furthermore, the rate of treatment suspension owing to irAEs in the multisystem irAEs group (62.5%) was higher than that in the single irAE group (17.3%) at the 12-week landmark. The incidence of multisystem irAEs was associated with improved clinical outcomes in patients with lung cancer, melanoma, and head and neck cancer treated with PD-1/PD-L1 inhibitor monotherapy. However, these results may be influenced by a potential immortal-time bias. When accounting for this bias, the early development of multisystem irAEs within 12 weeks was linked to treatment suspension and poorer clinical outcomes.

Long-term clinical course of heart failure across left ventricular ejection fraction phenotypes

Abstract Background Studies examining changes in cardiac features and long-term outcomes across heart failure (HF) phenotypes, particularly for normal and supranormal left ventricular ejection fraction (LVEF), are limited. Objectives Our objective was to assess changes in echocardiographic parameters and biomarkers over three years and investigate long-term outcomes across LVEF phenotypes in chronic HF. Methods Patients from the SUPPORT trial (mean age 66 years, 25% female, mean LVEF 54%), a prospective, randomized, open-label blinded endpoint study performed in Japan to determine the additional benefit of olmesartan on top of standard therapy in hypertensive patients with HF, were classified into four HF phenotypes based on baseline LVEF: reduced (HFrEF [LVEF ≤40%], n=200 [17.6%]), mildly reduced (HFmrEF [41% ≤ LVEF &amp;lt;50%], n=229 [20.1%]), normal (HFnEF [51% ≤ LVEF &amp;lt;65%], n=403 [35.4%]), and supranormal (HFsnEF [LVEF ≥65%], n=306 [26.9%]). Changes in echocardiographic parameters and biomarkers were assessed in patients with data available at baseline and three years. The composite outcome of HF hospitalization or all-cause death was analysed from baseline and three years (landmark analysis). Results Over three years, all-cause mortality rates were 15% in HFrEF, 10.0% in HFmrEF, 5.5% in HFnEF, and 4.2% in HFsnEF. The most significant decrease in left ventricular (LV) end-diastolic and -systolic diameter occurred in HFrEF (median percent change; LVDd -5.8% and LVDs -8.8%). Left atrial diameter did not change across HF phenotypes. N-terminal pro-brain natriuretic peptide (NT-proBNP) decreased in HFrEF (-35.7%) but increased in HFnEF and HFsnEF (12.5% and 18.2%, respectively). Troponin increased in all groups except for HFrEF. Growth differentiating factor-15 (GDF15) increased consistently across all HF phenotypes (18.5% in HFrEF, 18.0% in HFmrEF, 16.0% in HFnEF, 22.8% in HFsnEF) (Figure 1). Over a median follow-up of 8.6 years, compared to HFnEF, the risk of the composite outcome was higher in HFrEF (adjusted HR 1.40, 95% CI [1.08-1.82]), but was not different in HFmrEF (1.15, [0.90-1.47]). This trend persisted in the landmark analysis. Up to three years, the risk in HFsnEF compared to HFnEF was not different (1.13, [0.70-1.82]), but it was lower after three years (0.73, [0.55-0.95]). The incident curves show a diverging time point at around three years between HFnEF and HFsnEF (Figure 2). Conclusions In patients with chronic HF and three-year follow-up data, there was minimal decrease in LV dimension, most pronounced in HFrEF. Changes in biomarkers were more diverse, except for consistently elevated GDF15 across all HF phenotypes. The risk of HF hospitalization or all-cause death diverged between HFnEF and HFsnEF after three years.Figure 1Figure 2

Assessing one-year risk of heart failure following first time myocardial infarction and subsequent five-year mortality risk: a nationwide study of 34,401 patients

Abstract Introduction A comprehensive understanding of the post-myocardial infarction (MI) trajectory leading to heart failure (HF) and its profound impact on long-term mortality is imperative for effective secondary prevention and risk assessment. Methods We conducted a registry-based nationwide cohort study of all Danish patients with a first MI during 2014 to 2020. Excluding patients with prior HF, individuals were followed for one year post-MI, assessing HF incidence through hospital admissions and visits to elective HF ambulatory clinics. Among those who survived one year, long-term mortality 1-6 years post-index MI was assessed using landmark analysis and Cox proportional hazards models adjusting for age, gender and comorbidities and hazard. Patients were categorized into three groups: not HF, referred for elective HF outpatient follow-up, and acute admission for HF. Results Among 34,301 individuals with a first MI and surviving the first year (median age 67.5, and 66.9 % male), 3.3 % were admitted acute for HF while 11.2 % had an elective HF outpatient follow-up within one year of the MI event (see Figure 1a). We observed a significant association between acute HF admissions post-MI and increased five-year mortality risk (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.40-1.90, p-value &amp;lt;0.001, see Figure 1b) (absolute 5-year risk: 18.4 %). In contrast, the five-year mortality risk for patients with elective outpatient HF follow-up was comparable to that of individuals without HF (HR 1.06 [0.94-1.19], p-value 0.34) (absolute 5-year risk: 9.6 vs 8.5 %). Conclusion Our findings suggest that acute admission for HF after a first time MI occur in 3.3 % of the patients with a subsequent significantly increased mortality risk compared to patients that do not develop clinical HF. Admission for HF in patients with a first time MI should be considered as a relatively rare but fatal complication.

Prognostic importance of persistent elevations in high-sensitivity troponin T in the early convalescent phase (two weeks) following high-risk myocardial infarction: insights from the PARADISE-MI trial

Abstract Introduction Myocardial infarction (MI) is defined by a rise and fall in cardiac troponin (cTn) with clinical evidence of acute myocardial ischemia. How often cTn remains elevated in high-risk patients stabilized following MI and the relation between convalescent cTn levels and subsequent clinical outcomes in these patients is unknown. Aims To evaluate the prognostic importance of high-sensitivity cTn T (hs-cTnT) in the early convalescent phase of a MI for a range of cardiovascular (CV) outcomes in patients enrolled in the Prospective ARNI vs ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI). Methods Patients ≥18 years without prior heart failure (HF) (n=5661) were randomized to sacubitril/valsartan or ramipril within 0.5 to 7 days of MI complicated by transient pulmonary congestion, LVEF ≤40%, or both. Hs-cTnT was measured using the Roche Elecsys Troponin T-high-sensitive assay in 1093 patients two weeks after randomization (median 2.6 weeks after the index MI). Associations between log (2)-transformed hs-cTnT and clinical outcomes were investigated in landmark analyses using Cox regression models adjusted for clinical covariates of known prognostic importance and NT-proBNP (Figure). Results Median week 2 hs-cTnT concentration was 34 ng/L [IQR 17-94 ng/L] and exceeded the 99th percentile upper reference limit in 69% of patients. Patients with persistently elevated hs-cTnT concentrations (n=753) were older, more likely men, more commonly had atrial fibrillation and lower estimated glomerular filtration rate and less likely had a prior MI. They more commonly had presented with ST-segment elevation MI and pulmonary congestion and had higher concentrations of NT-proBNP. Rates of primary reperfusion were similar. Log(2)-transformed hs-cTnT was only weakly correlated with LVEF (rho = -0.15, p&amp;lt;0.001), irrespective of the type of MI. hs-cTnT was independently and linearly associated with the primary composite outcome of CV death or incident HF (adj HR 1.17 per doubling; 95% CI, 1.03 – 1.34), all-cause death (adj HR 1.20; 95% CI, 1.01 – 1.44) and CV death (adj HR 1.25; 95% CI, 1.02 – 1.52) but not with non-CV death (adj HR 1.04; 95% CI, 0.70-1.54). hs-cTnT was not significantly associated with recurrent fatal or non-fatal MI (adj HR 1.00; 95% CI, 0.85-1.18) (Figure). Concentrations of week 2 hs-cTnT were not altered by sacubitril/valsartan relative to ramipril (+4%; 95% CI, -8% to 18%). Conclusions Persistent elevations in hs-cTnT during the early convalescent phase following high-risk MI are common and are associated with heightened risk of all-cause death, CV death and incident HF but not of recurrent MI or non-CV death. hs-cTnT measured ~2.5 weeks after high-risk MI provides incremental prognostic information beyond traditional risk factors and NT-proBNP.

The prognosis of acute myocardial infarction due to stent thrombosis after 2nd generation drug eluting stents era (comparative study with acute myocardial infarction due to plaque rupture or erosion)

Abstract Backgrounds Stent thrombosis (ST) is a rare complication after percutaneous coronary intervention (PCI), and more than 70% of ST cases result in acute myocardial infarction (AMI). Although a new generation of drug-eluting stents (DES) and newer antiplatelet therapies have been shown to reduce the incidence of ST, ST-related AMI continues to be observed in contemporary practice. The prevalence and prognosis of ST results in AMI have not been well evaluated after the 2nd generation DES (G2-DES) era. Purpose The purpose of this study was to evaluate the prevalence and prognosis of AMI due to ST after the G2-DES era compared with AMI due to plaque rupture or erosion. Methods Among 6601 AMI patients enrolled in the Mie ACS registry from January 2013 to November 2022, 6273 AMI patients with AMI due to ST(ST) and AMI due to plaque rupture and erosion (AMI:P) were included for this analysis after excluding other types of AMI. ST was confirmed by angiography. The primary endpoint was defined as all-cause mortality, and revascularization after PCI for AMI was also evaluated. Results Seventy-eight patients, or 1.2% of all AMI in this study, had AMI due to ST, including early ST n=13 (16.7%), late ST n=4 (5.1%), and very late ST n=61 (78.2%). Stent types were G2-DES n=35 (44%), G1-DES n=18 (23.1%), bare metal stent (BMS) n=12 (15.4%), and unknown n=13 (16.7%). According to the KM survival curve, the 30-day mortality rate of ST was 2.6%, while the AMI:P rate was 6.7%, which was not statistically significant, but the ST was half the mortality rate. Furthermore, in the landmark analysis, the 2-year mortality rates were 6.2% for ST and 7.0% for AMI:P (P=0.66, Figure 1). ST was not an independent predictor of poor prognosis by multivariate Cox regression analysis. Even after the propensity score matching analysis as a sensitivity analysis, ST was not an independent predictor of poor prognosis in AMI patients. Among ST patients, 82.2% were treated with balloon angioplasty (without additional stenting) at the time of AMI, whereas 9.7% of AMI:P patients were treated with balloon angioplasty (P&amp;lt;0.001). Compared to patients with AMI:P, patients with ST had a higher incidence of revascularization after PCI for AMI within 2 years (21.8% vs. 11.2%; P=0.02, Figure 2A). Multivariate Cox regression analysis also showed that ST was an independent predictor of revascularization after PCI for AMI with a hazard ratio of 2.00 (P&amp;lt;0.01, Figure 2B). Conclusion The prognosis of ST patients tended to be better than that of AMI:P patients. The proportion of ST in AMI has decreased in the G2-DES era, and the higher proportion of VLST in ST suggests that its prognosis may be better than that of AMI:P . However, the rate of revascularization is higher in ST patients because stenting was not performed in the acute phase of PCI for AMI, and the appropriate use of stents depending on the type of ST may lead to a reduction in revascularization.Figure1Figure2

Discordance between symptomatic response and changes in cardiac structure and function one year after transcatheter aortic valve implantation

Abstract Background Symptomatic improvement is one of the main goals of transcatheter aortic valve implantation (TAVI) in patients with severe symptomatic aortic stenosis. We hypothesized that the degree of symptomatic response after TAVI is associated with improvement in cardiac structure and function after TAVI. Purpose We aimed to evaluate 1) the change in symptomatic burden measured by New York Heart Association (NYHA) and Canadian Cardiovascular Society (CCS) functional class after TAVI, 2) the change in echocardiographic structural and functional parameters after TAVI, and 3) the association of symptomatic response with echocardiographic response as well as long-term survival. Methods In patients undergoing TAVI, we assessed New York Heart Association (NYHA) and Canadian Cardiovascular Society (CCS) functional class at 12 months. Symptomatic response was defined as NYHA/CCS class I or ≥ 1 improvement in NYHA/CCS class compared to baseline at 12 months. Echocardiographic images at baseline and 6-18 months post-TAVI were analysed using an automated, validated, deep-learning workflow. Logistic regression was used to assess association between change in echocardiographic parameters and symptomatic change at 12 months. The association of symptomatic response and echocardiographic changes in the first 12 months after TAVI with survival beyond 12 months, was evaluated by landmark analysis using Kaplan-Meier analysis. Results Among 868 TAVI patients (median age 80 years, 53% female), the majority (74%) had NYHA/CCS class III at baseline and 77% of patients experienced improvement in symptoms at 12 months post-TAVI (Figure 1). Patients without an improvement in symptoms more often had COPD, atrial fibrillation and more heart failure medications compared to responders. Left ventricular systolic function did not show improvement compared to baseline, whereas a modest improvement in left atrial volume index, left ventricular mass index, E/A ratio, E/e’ ratio, mean e’ and tricuspid regurgitation peak jet velocity was observed. Symptomatic response was not associated with echocardiographic response. Beyond 12 months, patients with symptomatic improvement had lower mortality than those without symptomatic improvement (1.5 vs. 2.4 per 10 patient years; p = .001), whereas changes in echocardiographic parameters were not associated with subsequent mortality (Figure 2). Conclusion Patients undergoing TAVI for symptomatic severe aortic stenosis, showed substantial symptomatic improvement at one year after the procedure, whereas only a modest improvement in echocardiographic parameters was observed. Improvement in symptoms was not associated with improvement in echocardiographic measures of cardiac structure and function. Symptomatic improvement, but not improvement in cardiac structure and function at 12 months, was a strong predictor of subsequent survival.Change in NYHA/CCS class after TAVISymptoms and echo versus mortality

Left ventricular dilatation in patients with significant aortic regurgitation: association with mortality

Abstract Background In aortic regurgitation (AR), left ventricular (LV) dilatation occurs as a response to volume and pressure overload. Current guidelines recommend the use of LV end-systolic diameter index (LVESDi) to give indication for intervention, but recent studies suggested that volumetric measures may be more accurate in identifying LV remodeling in AR as compared to linear dimensions. Purpose To characterize LV dilatation in patients with significant AR (≥moderate), based on linear and volumetric dimensions, and to determine their prognostic value. Methods A total of 1070 patients (56 ± 18 years,65% male) were included. Cut-off values of 20 mm/m2 for LVESDi and 45 ml/m2 for end-systolic volume index (LVESVi) were used to identify the following LV remodeling patterns: No-significant LV dilatation (N=485), when both LVESDi and LVESVi were below the cut-off values; Discordant LV dilatation (N=279) if only one positive criterion was present; and Concordant LV dilatation (N=306) when both LVESDi and LVESVi were enlarged (Figure 1). The primary endpoint was all-cause mortality. Results Baseline characteristics differed across the 3 LV dilatation groups. Compared to patients with no-significant or discordant LV dilatation, those with concordant LV dilatation were more likely to be men, had a lower prevalence of systemic arterial hypertension and were more symptomatic. Concerning the echocardiographic characteristics, patients with concordant LV dilatation showed more severe AR, worse LV systolic function and larger left atrial volumes compared to the other two LV dilatation groups. During a median follow-up of 89 (IQR,54-132) months, 168 (16%) patients died and 484 (45%) underwent aortic valve surgery (AVS). Patients with concordant LV dilatation had worse 10-year survival (72%) compared to the groups (Figure 2), but benefited more from AVS based on a landmark analysis (p=0.001). In multivariable analysis, a significant association with the risk of all-cause mortality was observed for the presence of discordant (HR 1.645, 95%CI 1.077-2.513;p=0.021) or concordant LV dilatation (HR 2.695, 95% CI 1.710 to 4.249;p&amp;lt;0.001) after adjusting for the variables significant in the univariate analysis such as, age, male gender, NYHA class III-IV, AVS as a time-dependent covariate and LV ejection fraction (LVEF) ≤55%. Moreover, the addition of LV dilatation groups to a basal model including the above mentioned clinical and echocardiographic variables led to a significant increase in the predictivity of the model (Chi-square difference=21.1,p&amp;lt;0.001). Conclusion In patients with significant AR, LV dilatation detected by linear and/or volumetric measures was independently associated with increased mortality. Combining both methods for assessment of LV remodeling may improve risk stratification of these patients.

Comparative analysis of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor and mineralocorticoid receptor antagonists in heart failure with mildly reduced ejection fraction

Abstract Background Apart from sodium-glucose co-transporter 2 inhibitors, the efficacy of renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI)j8788 as well as mineralocorticoid receptor antagonist (MRA) in patients with heart failure with mildly reduced ejection fraction remains uncertain. We assessed the association between these medications and outcomes in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods Patients with HFmrEF from our university hospital-integrated Medical Database were included. Associations between the medications and cardiovascular mortality/heart failure hospitalization were evaluated using Cox regressions in a 1:1 propensity score-matched cohort. Inverse probability of treatment weighting was employed to balance baseline patient characteristics. Results Of 2584 patients with HFmrEF, 17% received MRA and 43% received RASI/ARNI. Predictors of MRA use included older age, slightly higher ejection fraction, lower NT-proBNP level, and eGFR &amp;gt;60 mL/min/1.73 m^2. Predictors of RASI/ARNI use included higher body mass index, lower NT-proBNP level, normal uric acid level, normal potassium level, and eGFR &amp;gt;60 mL/min/1.73 m^2. MRA use was not associated with a lower risk of cardiovascular death and hospitalization for heart failure (hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.78–1.02 and HR = 1.01, 95% CI: 0.94–1.09, respectively). Conversely, RASI/ARNI use was associated with a lower risk of cardiovascular death but not hospitalization for heart failure (HR = 0.82, 95% CI: 0.71–0.94 and HR = 0.995, 95% CI: 0.924–1.07, respectively). Notably, landmark analysis revealed no significant difference in the risk of outcomes when the follow-up duration exceeded two years. Conclusions The effect of MRA on cardiovascular death and hospitalization for heart failure was neutral, whereas RASI/ARNI was associated with a lower risk of cardiovascular death. Our findings suggest that RASi use may be more beneficial than MRA use in patients with HFmrEF.

Intravascular ultrasound-guided versus angiography-guided percutaneous coronary intervention for acute myocardial infarction with cardiogenic shock

Abstract Background Intravascular ultrasound (IVUS) potentially improves short and long-term clinical outcomes of percutaneous coronary intervention (PCI). However, evidence regarding its efficacy in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) is limited. Objectives This study investigated the impact of IVUS-guided PCI in patients with AMI and CS. Methods From the pooled data based on a series of Korean AMI registries during 2011–2020, we identified 1,418 consecutive patients who underwent PCI with second generation drug-eluting stent (DES) for AMI and CS. The primary endpoint was the 1-year rate of target lesion failure (TLF), defined as the composite of cardiac death, target vessel myocardial infarction, and ischemic-driven target lesion revascularization. Results Among the patients, 294 (20.7%) and 1,124 (79.3%) underwent IVUS-guided and angiography-guided PCI with second generation DES implantation, respectively. No significant difference was observed in the 1-year TLF between both groups after IPTW analysis (hazard ratio 0.93, 95% confidence interval 0.65–1.34, p=0.70) (Figure A). Additionally, the adjusted landmark analysis for TLF at 30 days and between 30 days and 1 year after PCI demonstrated no significant difference between the groups (Figure B). Conclusions In patients with AMI and CS who underwent PCI with second-generation DES, IVUS-guided PCI did not improve clinical outcomes with respect to 1-year TLF compared with angiography-guided PCI.Figure

Assessment of healthy worker survivor bias among middle-aged manufacturing employees in Korea

Abstract Background Healthy Worker Survivor Bias (HWSB) describes a selection bias where those continuously employed tend to exhibit superior health outcomes compared to their unemployed counterparts. This bias challenges for adjustments due to its time-dependent nature. This study aims to evaluate the extent of HWSB related to changes in employment status among middle-aged manufacturing workers using comprehensive national data from Korea. Methods The study analyzed data from the National Health Insurance Service, targeting individuals aged 40-49 who maintained consistent insurance coverage-either as manufacturing employees or non-employees (self-employed or unemployed)-from 2008 to 2010. The observation period spanned from January 2011 to December 2022, with all-cause mortality as the primary outcome. We employed landmark analysis to quantify HWSB related to employment status by comparing age-standardized mortality ratios between employees and the general population from the initial assessment to the last landmark period (up to 7 years), calculating 95% confidence intervals (CI) using Poisson distribution. Results The cohort included 4,621,983 participants (726,616 manufacturing employees and 3,895,367 (84.3%) non-employees). Throughout an average follow-up of 10.9 years (43.1% male; median age of 44), there were 116,418 deaths (11,530 (1.6%) among manufacturing employees and 104,888 (2.7%) among non-employees). Analysis revealed a consistent linear increase in HWSB over time. Notably, the bias was more pronounced among females (7-year HWSB-ES [95% CI]: 0.27 [0.17-0.37]) compared to males (7-year HWSB-ES [95% CI]: 0.18 [0.14-0.22]). Conclusions This study quantifies the extent of HWSB among middle-aged manufacturing workers in Korea, highlighting its significant impact, notably in females. These findings are vital for occupational health research, emphasizing the necessity to consider HWSB to prevent the underestimation of health risks associated with hazardous exposures. Key messages • Findings suggest HWSB is more pronounced in female manufacturing workers, indicating the need for targeted occupational health interventions. • The study underscores the importance of accounting for HWSB in occupational health studies to avoid underestimating health risks associated with workplace exposures.

Trends in Takotsubo syndrome

Abstract Background Previously considered a rare and relatively benign cardiac condition, Takotsubo syndrome (TTS) has undergone a significant shift in perception over the last two decades. This shift was mainly driven by results indicating that TTS is associated with signicant mortality and morbidity. Consequently, also the criteria for diagnosing TTS have been updated to reflect its recognition as a complex, multifactorial disease. Purpose The aim of the present study was to investigate trends in clinical presentation, demographics, and outcomes of patients with TTS. Methods The study analyzed 3,675 patients diagnosed with TTS from 2004 to 2021. Participants were divided into groups based on diagnosis, using three-year intervals, to perform trend analyses on demographics, risk factors, clinical presentations, and outcomes. The Cochran-Mantel-Haenszel test was used for categorical data trends, while the Mann-Kendall test assessed numerical variables. Mortality rates were compared using the log-rank test. Findings: The study period saw a steady increase in male patients (from 10% to 15%, p = 0.003). While apical TTS continued to be the most common type, the occurrence of midventricular TTS increased (from 18% to 37%, p = 0.002). Emotional triggers remained constant, whereas the prevalence of physical triggers significantly rose (from 35% to 50%, p = 0.034). The incidence of cardiogenic shock increased (from 11% to 20%, p=0.030), leading to a rise in in-hospital mortality rates (from 2% to 9%, p&amp;lt;0.001). A landmark analysis showed a significant increase in 60-day mortality rates (p &amp;lt; 0.001), but no difference in one-year mortality over the years (p = 0.140, Figure 1). Summary: This study of temporal trends in TTS highlights a shift in patients demographic with agrowing prevalence among males, increasing recognition of midventricular TTS type, and increased rates of cardiogenic shock and mortality in recent years. This shift aligns with the rising prevalence of physical triggers, as an expression of increased recognition of TTS in association with acute comorbidities.

Standard modifiable risk factors (SMuRF) paradox for the prognosis in the patients with acute myocardial infarction

Abstract Background Hypertension, diabetes, dyslipidemia and smoking are recognized as standard modifiable risk factors (SMuRFs) for adverse cardiovascular events such as acute myocardial infarction (AMI). Recent studies have shown that AMI patients without SMuRFs are associated with increased mortality compared to those with SMuRFs. However, the relationship between the number of SMuRFs in patients with AMI and mortality has not been well evaluated. Purpose The purpose of this study was to evaluate the clinical characteristics and prognosis of AMI patients stratified by the number of SMuRFs. Methods We studied 6,706 AMI patients between 2013 and 2021 using data from the Mie ACS registry, a retrospective and multicenter registry. For the purpose of this study, only AMI patients as their first cardiovascular events were included in this analysis. Therefore, after excluding patients with a known history of coronary artery disease (n=982), 5724 AMI patients were included in the current analysis. All-cause mortality was compared with 30-day and after 30-day mortality in AMI patients stratified by the number of SMuRFs as the primary outcome. In addition, all-cause mortality rate was compared in AMI patients without and with SMuRFs after propensity score matching on age, sex, body mass index, Killip classification, cardiac arrest before presentation, multivessel disease, left main truck disease, hemoglobin and emergent percutaneous coronary intervention. Results Among 5,724 AMI patients, 672 patients (11.7%) did not have SMuRFs. The median age of patients without SMuRFs was higher than that of patients with any SMuRFs (73 y.o. vs. 70 y.o, P&amp;lt;0.001), and higher prevalence of female and severe Killip class was observed in patients without SMuRFs compared with those with any SMuRFs (P&amp;lt;0.001, respectively). According to the KM survival curves stratified by number of SMURFs, an increased number of SMURFs was associated with higher 30-day survival rates (P=0.035), and the 30-day landmark analysis showed a trend toward higher survival in patients with the highest number of SMURFs, although not statistically significant (Figure1). Multivariate Cox regression analysis showed that 0 SMuRF was an independent prognostic factor for 30-day mortality with hazard ratio of 1.55 (95%CI; 1.13-2.13, P&amp;lt;0.001). In addition, KM survival curves after propensity score matched analysis showed the poor 30-day mortality in 0 SMuRF group (P=0.036), there was no significant difference in after 30-day mortality between the two groups (Figure 2). Conclusions Patients without SMuRFs had a high 30-day mortality rate, but once they survived the acute phase, their prognosis was comparable to patients with SMuRFs. Moreover, the SMuRF paradox was recognized in the acute phase. This finding highlights the need for early identification of the individuals at risk of developing MI despite the absence of SMuRFs and strict acute management regardless of the number of SMuRFs.

Prevalence of multiple native valvular heart disease in TAVR patients: a multicenter study assessing the impact of staged transcatheter edge-to-edge repair

Abstract Background Multiple valvular heart disease (VHD) is associated with poor prognosis in patients undergoing TAVR. Existing research focuses either on mitral or tricuspid regurgitation (MR, TR), without providing comparative analysis of their long-term effects. Moreover, whether staged transcatheter edge-to-edge repair (TEER) improves outcomes in these patients is unknown. Purpose This multicenter study aimed to evaluate the prevalence of multiple VHD within a recent TAVR cohort and to assess and compare the impact of concomitant severe MR and TR on outcomes at both one and five years post-TAVR. Additionally, we aimed to examine the potential impact of staged TEER for severe VHD in patients treated with TAVR. Methods The study cohort consisted of 2,823 patients undergoing TAVR at our Heart Center between 2015 and 2022. This representative cohort was used to investigate the prevalence of multiple VHD in a contemporary TAVR population and to assess and compare the impact of severe MR and TR on outcomes following TAVR. Additionally, this cohort, along with TAVR cohorts from other Heart Centers, was screened for additional valvular intervention. Patients who underwent staged transcatheter edge-to-edge repair for severe MR (n=147) or TR (n=59) were included. Results A concomitant persistent severe VHD was observed in 369 (13.1%) patients, with 208 (7.4%) having a severe MR, and 161 (5.7%) having a severe TR. The one-year mortality was significantly higher in patients with a severe VHD compared to the overall cohort (9.0 vs 5.2 per 100 PY, p&amp;lt;0.01). Notably, the highest one-year mortality was observed in patients with severe TR (13.3 per 100 PY) followed by patients with severe MR (6.4 per 100 PY) and those with no or a mild VHD (3.9 per 100 PY, p&amp;lt;0.01). This difference persisted over five years, with mortality rates of 27.8 per 100 PY in TR patients compared to 16.7 and 10.6 per 100 PY in MR patients and those with no or a mild VHD (p&amp;lt;0.01), Figure 1A. The landmark analysis revealed lower one-year mortality in patients who underwent staged TEER compared to those with severe VHD (4.1 vs 12.1 per 100 PY, p&amp;lt;0.001). This trend continued at the five-year follow-up, with a mortality rate of 11.6 per 100 PY in the staged TEER group versus 25.8 per 100 PY in the group with severe VHD (p&amp;lt;0.001), Figure 1B. The multivariate analyses revealed that concomitant severe TR was independently associated with one-year mortality (HR: 1.75 [95% CI: 1.14 – 2.67], p&amp;lt;0.01). Conclusion A concomitant clinically significant VHD was prevalent among patients with AS undergoing TAVR. The persistence of severe VHD was associated with increased one- and five-year mortality following TAVR. Specifically, severe TR was associated with higher mortality rates compared to severe MR. The potential benefit of an additional staged TEER for concomitant VHD should be carefully considered, as it shows promise in improving outcomes for patients with persistent severe VHD after TAVR.

Plasma Protein Biomarkers and Long-Term Cardiovascular Mortality Risk in Patients With Chronic Coronary Heart Disease.

Protein biomarkers that reflect different pathophysiological pathways have been associated with the risk of adverse cardiovascular events. However, it is uncertain whether these associations are sustained with increasing years after the biomarkers are measured. In this cohort study, 7745 patients with coronary heart disease who participated in the LIPID (Long-Term Intervention With Pravastatin in Ischemic Disease) trial, BNP (B-type natriuretic peptide), troponin I, cystatin-C, C-reactive protein, d-dimer and midregional proadrenomedullin were measured at baseline and after 1 year. Discrimination of plasma biomarker concentrations for cardiovascular death were evaluated in landmark analyses from 1 year for the next 5 years of the randomized trial, and for 10 additional years after trial completion. All 6 biomarkers were associated with risk of cardiovascular death (n=1903) both during and after the clinical trial (each P<0.001). C-statistics for BNP were 0.706 and 0.704; cystatin-C, 0.686 and 0.693; troponin I, 0.686 and 0.689; C-reactive protein, 0.655 and 0.684; d-dimer, 0.670 and 0.679, and midregional adrenomedullin, 0.686 and 0.688, respectively. In multivariable models, adding all 6 biomarkers to models with clinical risk factors increased the C-statistic for cardiovascular death from 0.709 to 0.775 during the clinical trial, and from 0.713 to 0.751 during 10-year follow-up after the randomized trial (P<0.001 for both). In patients with chronic coronary heart disease, biomarkers that reflect different pathophysiological pathways are associated with the risk of cardiovascular death for at least the next 15 years.

Post-transplant cyclophosphamide with post-engraftment anti-thymocyte globulin reduce moderate to severe chronic graft-versus-host disease in peripheral stem cell transplantation from HLA-matched unrelated and haploidentical donors.

Post-transplantation cyclophosphamide (PTCy) has unique advantages for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this single-center retrospective landmark analysis, we evaluated chronic GVHD (cGVHD) and clinical outcomes in patients receiving PTCy, tacrolimus, and post-engraftment low-dose anti-thymocyte globulin (PTCy-ATG) as GVHD prophylaxis after HLA-matched unrelated or haploidentical donor transplantation. Two historical patient groups receiving calcineurin inhibitor-based GVHD prophylaxis were used as control groups. A total of 71 patients with myeloid malignancies undergoing allo-HSCT with myeloablative conditioning regimens were included in the analysis. The 3-year cumulative incidences of cGVHD and moderate to severe cGVHD (M/S cGVHD) were 39.2% (95%CI 27.4%-51.0%) and 11.5% (95%CI 4.1%-18.9%), respectively, in the PTCy-ATG group, and only one instance of bronchiolitis obliterans (BO) was observed. The disease-free survival (DFS), overall survival (OS), and GVHD-free and relapse-free survival rates were 94.0% (95%CI 88.3%-99.7%), 93.0% (95%CI 87.1%-98.9%) and 83.8% (95%CI 75.0%-92.6%) respectively. Of note, the PTCy-ATG group presented with a significantly lower incidence of M/S cGVHD and BO, which translated into superior OS in multivariate analysis. In this retrospective analysis, we observed that PTCy-ATG-based GVHD prophylaxis was associated with a lower incidence of M/S cGVHD and better transplantation outcomes beyond day 100, which invites prospective evaluation.

Evolution of Left Ventricular Thrombus on Serial Cardiovascular Magnetic Resonance Imaging.

Current management of left ventricular (LV) thrombus relies on limited, non-contemporary, echocardiography-based studies. Data on LV thrombus evolution and the associated embolic risk are scarce. We aimed to describe the evolution of LV thrombus on serial cardiovascular magnetic resonance imaging (CMR) - the current reference standard for the detection of LV thrombus, and identify correlates of no resolution and the embolic risk associated with resolution status. We conducted a retrospective cohort study of 107 consecutive patients with LV thrombus who had 213 serial CMRs at a median of 255 days after the index CMR. Of these, 97.2% were anticoagulated. At 3 months after detection by CMR, 75% (47/63) had no resolution of LV thrombus; at 6 months, 53% (35/66) had no resolution; and at 12 months, 37% (23/63) had no resolution. Correlates of no resolution at 6 months included a history of myocardial infarction, LV aneurysm, ischemic etiology of cardiomyopathy, and larger thrombus volume. Recurrence of LV thrombus was rare at 5.3%. On survival analysis using the landmark analysis method, embolic events often occurred beyond 6 months, more frequently in patients with unresolved LV thrombus. Our findings challenge previous literature by demonstrating a lower rate of resolution of LV thrombus and substantial embolic risk beyond 6 months associated with unresolved LV thrombus on serial CMR. Our findings advocate for extended anticoagulation, particularly in patients with markers associated with no resolution. These findings have important implications for clinical practice and research into managing patients with LV thrombus.