Intermediate-risk Group Research Articles

Impact of Mutational Burden and IPSS-M on Response to ESAs in Lower Risk Myelodysplastic Neoplasms

INTRODUCTION Lower risk myelodysplastic neoplasms (LR-MDS), as defined by IPSS-R, are frequently presenting with anemia which is primarily treated with erythropoiesis stimulating agents (ESAs). However, response rates are suboptimal due to primary resistance or subsequent loss of response, leading to transfusion dependency and poor quality of life. In 2022 a new prognostic system has been developed considering number and type of somatic mutations in MDS (IPSS-M), showing a stronger prognostic power in MDS. AIMS We aimed to assess whether IPSS-M risk score could predict ESA response in IPSS-R LR-MDS patients. METHODS In this multicentric European study we evaluated baseline IPSS-M score in 397 LR-MDS cases from 14 different centers (Italy, Germany, France and Spain) and correlated with ESA response assessed with IWG criteria. Mutational data were obtained by different next generation sequencing (NGS) panels targeting genes recurrently mutated in myeloid neoplasia and necessary to calculate IPSS-M. RESULTS Median age of patients was 74 years with male preponderance (54.5%). Serum EPO levels (sEPO) were available in 277/397 cases (mean 157U/L, <200 U/L in 80% of the cases). When transfusion history (TH) was known (252/397), 44.6% of cases were transfusion dependent (TD). The majority of the cases received erythropoietin-α and darbepoetin-α with response rate of 52.6% (HI-E) according to IWG criteria and a median duration of response of 30 months (data from 165 responders with follow up information). We observed that IPSS-M score, but not the number of mutations, was significantly lower in ESA responders compared to non-responders (median -1,08 vs -0,63 respectively , p<0.0001). The very low (VL) IPSS-M risk group was enriched in ESA responders (74 vs 26% p=0.036), while groups from moderate low (ML) to very high (VH) were more enriched with non-responders (37.5 vs 62% p=0.001; 45.4 vs 54.6% p=0.045; 29.6 vs 70,4% p=0.0017; 25 vs 75% p=0.021 respectively, Fig.1). In cases with known TH (n=252), non-TD (NTD) ESA responders had lower IPSS-M scores (mean -1,17) compared to i) NTD ESA non-responders (mean -0,61 , p<0.0001), ii) TD ESA responders (mean -0,93, p=0,025) and iii) TD ESA non-responders (mean -0,54, p<0.0001). As observed in other settings, 17% of the cases (n=67) were re-stratified to higher risk IPSS-M categories (8%, 13,4% and 44,3% of IPSS-R very low, low and intermediate risk respectively). Among upstaged cases, most were ESA non-responders especially in the moderate high (MH, 67%), high (H, 61%) and very high-risk (VH, 100%) groups. Only 4% of cases (n=17) were down-staged, all from IPSS-R intermediate risk group, and showed response rates similar to IPSS-R intermediate cases who remained ML or MH. Finally, IPSS-M score, sEPO and TD correlated with response in multivariate logistic regression analysis ( p=0.005, p=0.004 and p=0.014 respectively), but only IPSS-M score and TD were predictive (OR 0.51 and 0.34 respectively). Based on this model, we designed a ROC curve (AUC 0.79) where a cut-off of 0.46 showed a sensitivity of 0.9 and specificity of 0.67 in discriminating responders from non-responders (Fig.2). CONCLUSIONS To our knowledge, this is the first report correlating IPSS-M with ESA response in a large number of LR-MDS cases. IPSS-M scores exhibited predictive power, with lower values in ESA responders compared to non-responders and in NTD compared to TD cases. We also observed that higher IPSS-M categories were inversely correlated with ESA response. A fraction of cases with scarce ESA response was upstaged to IPSS-M higher risk groups. The number of mutations did not correlate with ESA response, while IPSS-M score, which considers the prognostic weight of specific mutations, showed predictive significance. In the multivariate analysis IPSS-M score and TD were strong predictors of ESA response, irrespective of baseline sEPO, potentially defining at diagnosis LR-MDS for whom novel agents like luspatercept could be considered as first line therapeutic option.

Recommendations on Minimal Residual Disease Monitoring in Acute Promyelocytic Leukemia Treated with Combination of All- Trans Retinoic Acid and Arsenic Trioxide

Background All- trans retinoic acid (ATRA)-arsenic trioxide (ATO) combination therapy significantly reduces acute promyelocytic leukemia (APL) relapse compared to ATRA combined with chemotherapy, leading to a cure rate of 80-90% in APL patients. The ideal frequency and duration of minimal residual disease (MRD) monitoring needs to be identified in the era of ATO. Methods A total of 1072 APL patients were enrolled in this study, comprising 855 from the APL2012 trial (NCT01987297) and 217 from our center between January 2018 to June 2022 (APL2018 study). The APL2018 protocol was adjusted for consolidation and maintenance therapy based on APL2012 (Chen et. al. PNAS 2021): In consolidation therapy, low-, intermediate-, and high-risk patients were performed following the ATO-group scheme of corresponding risk stratification in the APL2012 study. From December 2019, chemotherapy was no longer administered to high-risk group during consolidation phase. In maintenance treatment, ATO was replaced with oral arsenic realgar-indigo naturalis formula, and methotrexate was removed. RT-PCR or RQ-PCR was routinely used for MRD monitoring, detecting PML::RARA fusion genes in bone marrow before each consolidation and maintenance therapy. MRD testing was conducted every 3 months within the first year, every 6 months within the second year, and annually from 3 to 5 years after treatment. Results A total of 993 patients achieved complete remission (CR) after induction therapy. The negative MRD rates were observed in 61.7% of patients before 1 st consolidation , 95.4% before 2 nd consolidation, 99.3% before 3 rd consolidation, and 99.5% before maintenance therapy , respectively. The median time to achieve negative MRD was 57 (22-301) days with no significant difference between relapsed and non-relapsed patients (p=0.166). A total of 34 patients (30 in the APL2012 trial and 4 in the APL2018 study) relapsed, including 5 at low risk, 9 at intermediate risk, and 20 at high risk. The median recurrence time was 13.5 (3.5-49.0) months after achieving CR, with 94% (32/34) relapsing within 3 years of achieving CR. After induction remission, the risk of relapse decreased with time (44% occurred within the first year, 29% within the second year, 21% within the third year, and only 6% after three years, Figure 1). The median follow-up for the 179 evaluable patients after achieving CR was 39.7 (3.5 -64.6) months in the APL2018 group. The estimated 5-year disease-free survival (DFS) rates were 95.8% (95% CI 92.8-98.9). Prior to the 1 st, 2 nd, and 3 rd consolidation treatment, and before maintenance therapy, the estimated 5-year DFS rates for MRD positive and negative patients were 92.4% (95% CI 86.1-99.2) versus 97.8% (95% CI 94.8-100), p=0.100; 57.1% (95% CI 30.1-100) versus 97.3% (95% CI 94.7-100), p<0.001; 0 versus 96.5% (95% CI 93.1-100), p<0.001; 0 versus 96.8% (95% CI 94.0-99.6), p<0.001, respectively. The results of the APL2012 study were similar to those of APL2018. In the APL2018 study, the estimated 5-year cumulative incidence of relapse (CIR) was 2.51% (95% CI 2.48-2.54), which was 0%, 1.16% (95% CI 1.13-1.19), and 7.83% (95% CI 7.44-8.22) in the low-risk, intermediate-risk, and high-risk patients, respectively (p=0.057). The estimated 5-year CIR for the low to intermediate risk group was 0.74% (95% CI 0.73-0.75), which was statistically different from high-risk patients (p=0.019). The estimated 5-year CIR for MRD positive and negative patients prior to the 1 st and 2 nd consolidation treatments was 4.92% (95% CI 4.76-5.08) versus 1.10% (95% CI 1.08-1.12), p=0.194; 14.29% (95% CI 10.30-18.28) versus 2.08% (95% CI 2.05-2.11), p=0.010, respectively. Conclusion Our results show that MRD after one course of consolidation treatment, rather than before, is a crucial predictive factor for APL relapse. Patients with positive MRD after 1 st consolidation therapy have a high risk of relapse. ATRA-ATO based treatment has significantly reduced APL relapse, so the value of frequent MRD monitoring may be limited. It is recommended to implement an optimized MRD monitoring for risk stratification. For low to intermediate-risk patients and those with negative MRD after a consolidation treatment, the frequency and duration of MRD testing can be minimized. For high-risk patients with sustained MRD negativity for more than 3 years, MRD testing can be considered for discontinuation.

Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG)

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients’ sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3-ITD, DNMT3A, NPM1 and WT1 mutations and less often complex karyotype, ASXL1, SRSF2, U2AF1, RUNX1, or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients’ sex in analyses of AML biology and prognostication.

A Prospective Ukrainian Multicentre Cohort Study of Pet Value Prognostic Role in Primary Patients with Hodgkin Lymphoma (HL): Six-Year a Brief Review

Introduction : The PET-adapted approach for the treatment of patients with Hodgkin's lymphoma has long been used around the world. In Ukraine, this method has recently become actively used at all stages of treatment, which allows it to meet modern standards. Airms. The primary endpoint was to assess the effectiveness of individualized approaches as a correlation between PET findings and response to therapy, type of regimen and clinical outcome (Event free (EFS) and overall survival (OS)). The second endpoint was to evaluate the impact of risk factors on the survival. Methods. Of 278 evaluable patients, 64% were female; median age 43 years (range, 17-69 years). Patients received a treatment with ABVD or ABVD/AVD (more than 50% pts); BEACOPP-14/esc or “switched-regimens” (ABVD+BEACOPP-esc/14, BEACOPP-esc/14+ABVD). Metabolic PET imaging was performed to routine protocols using Deauville criteria for response assessment. Results. Bulky disease (&amp;gt;10 cm in any dimension) were presented in 74/278 (26.6%) of pts, B symptoms - in 126/278 (45.3%) and extranodal disease had 57/278 (20.5%). 93.8% of patients achieved remission (CR/PR) during the follow-up period (median timeline: 27 months). The ORR for patients with stage I-II was 87.2% (137/157) vs 80.1% (97/121) for patients with stage III-IV. We recorded a disease progression in 44 (15.8%) patients during and after the 1st line therapy, (median time to relapse - 8 months). Only 6 pts died due to HL. In the study group, PET was performed at the beginning of treatment in 150 pts, interim in 248 and at the end of treatment in 190 pts. We found a trend in improved outcome after treatment in patients with at least two follow-up PETs (interim and EOT), indicating the effectiveness of individualized PET-adapted therapy. Interim PET-CT was assessed as DS 1-2 in 127 patients (48.4%), DS 3 in 88 (33.6%), DS 4-5 in 47 pts (17.9%). In total, the disease progression occurred in 48.3% (15/31) of interim PET-positive (PET2+) patients and 11.5% (20/174) of interim PET-negative (PET2-) patients (p&amp;lt;0.05). After 6 year of follow-up EFS decreased in patients with PET2+ by 10% than the previously reported (PET2- pts 85% and vs 44% PET2+ pts, p=0.0001). Perhaps, despite the achievement of a partial metabolic response (DS-4), patients in this group still require intensification of treatment. Intermediate-risk group cohort (2B stage) to improve the EFS levels when the regimens was given BEACOPP-esc/14+ABVD vs ABVD+BEACOPP-esc/14 vs ABVD (80% vs 60% vs 55% respectively, p=0.03) and was independent of PET2 status. Also, a more intensified treatment for patients with stage III-IV of HL showed a significantly better level of EFS compared to the ABVD regimen, and it did not depend on PET2 status (Log-rank test, p=0.0003). OS is the most patient-relevant outcome in oncology; large sample sizes and extended follow-up durations are needed to detect statistically significant differences in OS. After a median follow up of 70 months, the study met its primary endpoint in the PET-2 negative cohort, with 6-year OS of 97% versus 60% (p=0.004). Interestingly, we did not find any correlation between EFS between risk groups 2B+bulky vs 2B without bulky (p=0.9) and also 2A+ (vs) - bulky (p=0.2). But we confirmed OS higher in pts with stage 2A vs 2B (98% vs 75%, respectively, p=0.03). Conclusions . The results of the use of PET in patients with primary HL showed a high predictive value of PET, which affects event-free and overall survival.

Prognostic model using postoperative normalization of C-reactive protein levels in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy.

To improve the prediction of outcomes in patients who will undergo radical nephroureterectomy (RN U) for upper tract urothelial carcinoma (UTUC), we investigated the preoperative prognostic factors and developed a risk classification model. A total of 144 patients who underwent RNU with history of neither neoadjuvant nor adjuvant chemotherapy between 2008 and 2022 were retrospectively reviewed. Associations between perioperative/clinicopathologic factors and outcomes, including cancer-specific survival (CSS), were assessed. We specifically focused on preoperative serum C-reactive protein (CRP) and its postoperative normalization. Non-normalization of postoperative serum CRP level and pathologic T3 stage were identified as independent predictive factors of shorter CSS in univariate and multivariate analysis (p=0.0150 and 0.0037, hazard ratio: 3.628 and 4.470, respectively). We classified the patients into three groups using these factors and found that five-year CSS was 88%, 42.5%, and 0% in the low-risk group (zero factors), intermediate-risk group (one factor), and high-risk group (two factors), respectively (p<0.0001). Non-normalization of postoperative serum CRP level and pathologic T stage were identified as independent postoperative prognostic factors in patients with UTUC who underwent RNU. These factors can stratify three prognostic groups and may help urologists in clinical decision-making for adjuvant therapy.

A Single Dose of PEG-Asparaginase at the Beginning of Induction Not Only Accelerates MRD Clearance but Also Improves Long-Term Outcome in Children with B-Lineage ALL

This report presents the results of the assessment of MRD response by multicolor flow cytometry (MFC) with regard to the randomized use of pegylated asparaginase (PEG). In this study, PEG was randomly administered at a dose of 1000 U/m2 on day 3 of induction therapy in children with B-lineage ALL. Methods. Conventional induction therapy consisted of dexamethasone, vincristine, and daunorubicin. MRD data was available in 502 patients who were randomized at the start of induction therapy, standard-risk (SR) patients into three (conventional induction without PEG, induction with additional PEG and with PEG but without daunorubicin) and intermediate-risk (ImR) patients into two groups (with additional PEG and without PEG). Results. The single administration of PEG resulted in a significantly higher proportion of rapid responders, in SR patients even when no anthracyclines were used for induction. In the SR group, the event-free survival of the MFC-MRD fast responders was similar in the PEG− and PEG+ arms (92.0 ± 3.1% vs. 96.2 ± 1.5%, respectively), and the same unfavorable trend was observed for MFC-MRD slow responders (57.5 ± 12.3% vs. 66.7 ± 15.7%, respectively). Results were similar in ImR patients: (94.3 ± 3.2% vs. 95.1 ± 2.4%, for fast responders and 63.3 ± 7.6% vs. 78.1 ± 7.9%, for slow responders in PEG− and PEG+ arms, respectively). However, there is a large difference between the proportion of MFC-MRD slow responders in the PEG− and PEG+ groups (18.3% vs. 5.2% for the SR group and 44.2% vs. 25.0% for the ImR group). Conclusions. Therefore, early use of PEG-ASP not only leads to an accelerated reduction of blasts, but also to an excellent outcome in a significantly larger proportion of patients in both risk groups.

Preventing Dementia-A Cross-Sectional Study of Outpatients in a Tertiary Internal Medicine Department.

Dementia is a significant health problem worldwide, being the seventh leading cause of death (2,382,000 deaths worldwide in 2016). Recent data suggest there are several modifiable risk factors that, if addressed, can decrease dementia risk. Several national dementia screening programs exist; however, limited-income countries do not have the means to implement such measures. We performed a prospective cross-sectional study in an outpatient department to identify individuals at risk for dementia. Patients with no known cognitive dysfunction seeking a medical consult were screened for dementia risk by means of the cardiovascular risk factors, ageing, and dementia (CAIDE) and modified CAIDE tests. Additionally, we collected demographic and clinical data and assessed each participant for depression, mental state, and ability to perform daily activities. Of the 169 patients enrolled, 63.3% were identified as being in the intermediate-risk or high-risk group, scoring more than seven points on the mCAIDE test. Over 40% of the elderly individuals in the study were assessed as "somewhat depressed" or "depressed" on the geriatric depression scale. Almost 10% of the study population was diagnosed de novo with cognitive dysfunction. In conclusion, using a simple questionnaire such as the mCAIDE in a predefined high-risk population is easy and does not represent a major financial burden. At-risk individuals can subsequently benefit from personalized interventions that are more likely to be successful. Limited-resource countries can implement such screening tools in outpatient clinics.

Population-Based External Validation of the EASIX Scores to Predict CAR T-Cell-Related Toxicities.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61-0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment.

The Role of Neutrophil to Lymphocytes Ratio and It's Common Clinical Outcomes Amount the Patient with Non ST Elevation Acute Coronary Syndrome

Objectives: To evaluate the admission neutrophil-to-lymphocyte ratio (NLR) for risk stratification for in-hospital out-comes and complications in non-ST-elevation acute coronary syndrome (non-ST-ACS) patients.&#x0D; Methodology: Methods: We recruited consecutive patients with non-ST-ACS. The NLR was obtained and stratified as low, inter- mediate, and high-risk based on &lt;3.0, 3.0e6.0, and &gt;6.0, respectively. The new ST-T changes, arrhythmias, contrast-induced nephropathy (CIN), and mortality were recorded.&#x0D; Results: Results: Median NLR was 3 [2.1-5.3] for 346 patients with 19.9% and 30.6% in high- and intermediate-risk group. New ST-T changes were observed in 3.5% (12) out of which 8, 3, and 1 patient in low, intermediate, and high-risk group (p = 0.424), respectively. Arrhythmias were observed in 5.8% (20) with 7, 5, and 8 patients in low, intermediate, and high- risk group (p = 0.067), respectively. CIN was observed in 4.9% (17) with 5, 5, and 7 in low, intermediate, and high-risk group (p = 0.064), respectively. In-hospital mortality was recorded in 1.4% (5) with 2 and 3 patients in high and low-risk group (p = 0.260), respectively.&#x0D; Conclusion: A significant number of non-ST-ACS patients fall in the high-risk category of NLR. Although, the association between NLR and in-hospital mortality and adverse events was not statistically significant but relatively higher rates of events were observed in high risk group.

One-year Follow-up Results of Transperineal Biopsy For Patients Undergoing Irreversible Electroporation Treatment in Localized Prostate Cancer.

This article reports on the early results of a 1-year follow-up study investigating the efficacy of irreversible electroporation in the treatment of localized prostate cancer. The study included 18 out of 40 patients diagnosed with low- and intermediate-risk prostate cancer who underwent irreversible electroporation. Treatment results were evaluated through confirmation biopsies, comparing prostate-specific antigen levels, international prostate symptom scoring, and international index of erectile dysfunction scores before irreversible electroporation and at the 12-month mark. The mean age of the patients was 61.1 years (SD ±6.5). Out of the 18 patients, 16 were tumor free (88.8%), while 2 experienced recurrences, one within the treatment field and the other outside of it (P < .001). Irreversible electroporation significantly reduced mean prostate-specific antigen levels (6.73 ng/mL vs. 2.05 ng/mL, P < .001), indicating a 69.5% reduction within 12 months. Furthermore, there was a significant improvement in mean international prostate symptom scores at the 12-month followup (10.05 vs. 7.52, P=.003). The mean international index of erectile dysfunction scores before treatment was 19.17 (SD ±5.85), and after irreversible electroporation, it was 18.67 (SD ±6.34), with no statistically significant change (P=.065). The short-term oncological results of irreversible electroporation treatment are promising, particularly for patients in the low- and intermediate-risk groups. Additionally, irreversible electroporation does not negatively impact the international index of erectile dysfunction; however, it may lead to a decrease in international prostate symptom scores.

Prognostic Factor Risk Groups for Clinical Stage I Seminoma: An Individual Patient Data Analysis by the European Association of Urology Testicular Cancer Guidelines Panel and Guidelines Office

BackgroundThe relapse rate in patients with clinical stage I (CSI) seminomatous germ cell tumor of the testis (SGCTT) who were undergoing surveillance after radical orchidectomy is 4–30%, depending on tumor size and rete testis invasion (RTI). However, the level of evidence supporting the use of both risk factors in clinical decision-making is low. ObjectiveWe aimed to identify the most important prognostic factors for relapse in CSI SGCTT patients. Design, setting, and participantsIndividual patient data for 1016 CSI SGCTT patients diagnosed between 1994 and 2019 with normal postorchidectomy serum tumor marker levels and undergoing surveillance were collected from nine institutions. Outcome measurements and statistical analysisMultivariable Cox proportional hazard regression models were fit to identify the most important prognostic factors. The primary endpoint was the time to first relapse by imaging and/or markers. Relapse probabilities were estimated by the Kaplan-Meier method. Results and limitationsAfter a median follow-up of 7.7 yr, 149 (14.7%) patients had relapsed. Categorical tumor size (≤2, >2–5, and >5 cm), presence of RTI, and lymphovascular invasion were used to form three risk groups: low (56.4%), intermediate (41.3%), and high (2.3%) risks with 5-yr cumulative relapse probabilities of 8%, 20%, and 44%, respectively. The model outperformed the currently used model with tumor size ≤4 versus >4 cm and presence of RTI (Harrell’s C index 0.65 vs 0.61). The low- and intermediate-risk groups were validated successfully in an independent cohort of 285 patients. ConclusionsThe risk of relapse after radical orchidectomy in CSI SGCTT patients under surveillance is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse. Patient summaryThe risk of relapse after radical orchidectomy in patients with clinical stage I seminomatous germ cell tumor of the testis is low. We propose a new risk stratification model that outperformed the current model and identified a small subgroup with a high risk of relapse.

External validation of PE-SARD bleeding score for early major bleeding in patients with acute pulmonary embolism: Insight from the COMMAND VTE Registry-2

Abstract Background/Introduction The current guidelines and existing bleeding risk scores focus on assessing the risk of anticoagulant-related bleeding in patients with pulmonary embolism (PE) who are candidates for extended anticoagulation therapy. However, there is no consensus on the risk of bleeding in the acute phase. The Syncope, Anemia, Renal Dysfunction (PE-SARD) bleeding score has been developed to predict early major bleeding in acute PE patients. However, the score has not yet been externally validated. Purpose The present study aimed to externally validate the PE-SARD bleeding score, using a large-scale multicenter observational database of patients with venous thromboembolism (VTE). Methods The COMMAND VTE Registry-2 is a multicenter registry enrolling 5197 consecutive acute symptomatic VTE patients among 31 centers in Japan between January 2015 and August 2020. The present study population was consisted of 2722 patients with PE who received anticoagulation therapy during the acute phase and had a calculated PE-SARD bleeding score. The eligible patients were classified into three groups: high-risk group with a PE-SARD score &amp;gt;2.5 points, intermediate-risk group with a score of 1–2.5 points, and low-risk group with a score of 0 point. The discriminatory and calibration ability of the PE-SARD score for 30-day major bleeding were assessed by calculating the area under the receiver operating characteristic curve and creating a calibration plot, respectively. Results The high-risk group accounted for 537 patients (20%), intermediate-risk group for 1381 (51%), and low-risk group for 804 (30%). The proportion of thrombolysis use did not significantly differ across the groups. Among the patients who received direct oral anticoagulants (DOACs), the proportion of high-dose DOAC initiation was highest (54%) in the low-risk group and lowest in the high-risk group (29%). During the first 30 days of anticoagulation therapy, major bleeding occurred in 118 patients. The cumulative 30-day incidence of major bleeding substantially increased in the higher risk categories by the PE-SARD bleeding score (high-risk group: 8.2% [95% CI, 6.2%–10.9%], intermediate-risk group: 4.5% [95% CI, 3.5%–5.8%], and low-risk group: 1.8% [95% CI, 1.0%–3.0%], long-rank P&amp;lt;0.001). The discriminating power of the score was modest with a C-statistic of 0.65 (95%CI 0.61–0.70). Based on the calibration plot, the PE-SARD bleeding score was well calibrated. A sensitivity analysis excluding 275 outpatients showed similar results. Conclusions The risks of 30-day major bleeding in patients with PE substantially increased in the higher risk categories by using the PE-SARD bleeding score. The score is potentially helpful for management of anticoagulation therapy in the acute phase.The Kaplan-Meier curves

Comprehensive risk assessment in patients with pulmonary arterial hypertension referred for lung transplantation: a single-center experience

Abstract Background Current guidelines recommend risk stratification to optimize the timing to refer patients with pulmonary arterial hypertension (PAH) for lung transplantation (LT). However, the optimal timing for referral may vary by country. It is unknown whether risk stratification could be helpful to predict the post-referral outcome in Japan where the waiting period is about 3 years. Purpose We aimed to investigate the predictive value of risk stratification at the LT referral time, and to provide a decision-making tool to refer patients for LT. Methods We performed a retrospective cohort study of consecutive PAH patients referred for LT from May 2014 to December 2021. Risk status was assessed by the ESC/ERS three-strata and four-strata model (Figure 1). For assessment, functional class, six-minute walk distance, brain natriuretic peptide, the ratio of TAPSE to PASP, mean right atrial pressure and cardiac index were used as variables. In the exploratory analysis, the intermediate risk group by the three-strata model was further divided into two groups based on the median proportion of low-risk variables (modified risk assessment): low-intermediate or high-intermediate risk. The primary outcome was all-cause mortality after referral. Results 52 patients were enrolled [median age 30.5 (22.0-40.0) years, 83% idiopathic/heritable PAH]. During a median follow-up period of 2.5 (1.8-3.4) years, 9 patients died, and 13 patients underwent LT. By the three-strata model, 15, 36, and 1 patients were classified as low-, intermediate- and high risk (Figure 2a). There was no significant difference in survival between low- and intermediate risk. By the four-strata model, 33, 16, and 3 patients were classified as low-intermediate-, high-intermediate and high risk (Figure 2b). The four-strata model identified high-risk patients with survival rates of 33% at 1 year, whereas did not discriminate survival between low-intermediate and high-intermediate risk. By the modified risk assessment, 15, 28, 8 and 1 patients were classified as low-, low-intermediate, high-intermediate and high risk (Figure 2c). Patients at high-intermediate risk or higher had significantly worse survival (P&amp;lt;0.001); survival rates at 3 years were 92%, 80% and 34% in the low-, low-intermediate, and high-intermediate or high-risk group, respectively. In Cox regression analysis, high-intermediate or high risk by the modified risk assessment was significantly associated with the primary outcome adjusted for age, sex and PAH etiologies (HR, 6.284; 95% CI, 1.743-22.662; p=0.005). Conclusion The prognosis of high-risk group by the four-strata model was too poor to survive the waiting period. Whereas, the modified risk assessment could discriminate patients who could continue medical therapy or should be referred for LT. Risk stratification could help clinicians to make decisions to refer patients for LT. Further work is needed to refine the assessment tool in the context of LT referral.

Predicting incident atrial fibrillation in patients with embolic stroke of undetermined source

Abstract Introduction Atrial fibrillation (AF) is an important potential embolic source in patients who have suffered an embolic stroke of undetermined source (ESUS). AF has been detected in over 40% of patients when monitored with an implantable loop recorder (ILR). Recent clinical trials, however, have suggested that empirical anticoagulation of all patients with an ESUS is not an effective approach to reduce stroke risk. Thus predicting which patients are most likely to develop AF is of increased importance. Risk models for predicting incident AF exist but they do not incorporate modern techniques such as advanced echocardiographic parameters to create a comprehensive risk model. Purpose We sought to create a multi-parametric risk score for the prediction of incident AF in patients with ESUS. Methods This was a single-centre retrospective study. Consecutive adult patients referred for ILR implantation following ESUS, between March 2009 and November 2019, without prevalent AF or atrial flutter, were included. Patients’ notes were reviewed for clinical and anthropometric data. Each patients’ echo was re-reviewed both for conventional measures, and advanced parameters including left atrial strain using speckle-tracking (figure 1) and atrial electromechanical delay utilising the time from onset of the electrocardiographic P-wave to the lateral tissue Doppler A’ wave- "lateral PA". Univariate and multivariable analyses were performed, and a subsequent Lasso regression analysis used to develop a risk prediction model. Bootstrapping was used to perform internal validation. Results A total of 323 patients with ESUS who underwent a loop recorder implantation were included. Incident AF was detected in 142 patients (47.1%). Increased duration of the time between the electrocardiographic P-wave and the lateral tissue Doppler A’ wave (greater lateral PA), older age, higher diastolic blood pressure, abnormal left atrial reservoir strain were most strongly associated with increased AF risk. These were combined to form the PADS score below. Model discrimination was good, with an area under the curve of 0.72. Conclusion(s) The PADS score is a novel risk score for the prediction of incident AF in patients who have suffered an ESUS, based on the duration of the P-wave to the lateral tissue Doppler A’ wave, Age, Diastolic blood pressure and left atrial strain reservoir . Further work is required to assess whether the PADS score can be used to risk stratify patients into a high risk group which would derive benefit from immediate anticoagulation, an intermediate risk group who require prolonged continuous monitoring and a low risk group who can continue on conventional management for their stroke.PADS formulaLA strain using speckle strain analysis

Prognostic value of cardiac magnetic resonance - LGE distribution in non-ischemic dilated cardiomyopathy for prophylactic implantable-cardioverter defibrillator therapy

Abstract Background/Introduction International guidelines recommend implantable cardioverter-defibrillator (ICD) implantation when patients with nonischemic dilated cardiomyopathy (NICM) have left ventricular ejection fraction (LVEF) of 35% or less. Tissue characterization obtained by cardiac magnetic resonance (CMR) has emerged as a promising tool for better identification of patients at high arrhythmic risk and thus worthy of prophylactic ICD therapy. Purpose Current analysis has the scope to assess the prognostic value of fibrosis as evaluated by late gadolinium enhancement sequences (LGE) specifically regarding its LV wall distribution. The primary endpoint was all-cause mortality. The secondary end-point consisted of major adverse arrhythmic cardiac events (MAACE), defined as combination of SCD, aborted SCD, and sustained ventricular tachycardia. Methods Study population is part of DERIVATE Study, an international, multicenter, prospective, observational registry including consecutive patients from 21 sites across Europe and US referred for heart failure (HF) work-up including transthoracic echocardiography (TTE) and CMR without a history of previous major ventricular arrhythmias. Inclusion criteria were: (i) aged 18 or older, (ii) chronic HF according to the ESC Task force definition, and (iii) LV-EF&amp;lt;50% at initial TTE. All patients underwent TTE and CMR within 3 months. Patients with (i) decompensated within 3 months of enrollment, (ii) recent myocardial infarction (&amp;lt;40 days), (iii) unstable angina, (iv) severe valvular disease, (v) primary or secondary cardiomyopathies other than NICM, (vi) cardiac amyloidosis, and (vii) congenital heart disease were excluded. Results The entire cohort consisted of 1384 subjects [mean age: 56±14 years, male: 948 (68.4%)]. The median follow-up time was 959 days. Mortality and MAACE occurred in 92 (6.6%) and 125 (9%) patients, respectively. SCD, aborted SCD, and sustained VT occurred in 15 (1.1%), 80 (5.8%), and 104 (7.5%), respectively. In the multivariate analyses for all-cause mortality, only the number of segments with LGE at the level of the septum was an independent predictor (p=0.002), while in the analyses for MAACE the only independent predictors were male gender, LVEDVi by CMR, and the number of segments with LGE at the level of septum inferior. Based on the multivariate analysis, the DERIVATE score (including all 1384 patients) ranging from 0 to 8 (Cox regression analysis HR=1.35, 95%CI 1.24-1.46, p&amp;lt; 0.001) was built up. The redistribution of patients according to the CMR composite DERIVATE risk/year MAACE was of 44%, 37% and 32% for the low, intermediate and high risk groups, respectively. Conclusions The arrhythmic risk of patients with NICM is also dependent on the different distribution of fibrosis in the LV. The redistribution of the event rate according to the CMR composite risk score indicates the potential to alter the decision on ICD implantation in a relevant portion of NICM patients.

Predictive value of STEP-HF risk score in patients with ST-segment elevation myocardial infarction (Killip I) treated by primary percutaneous coronary intervention

Abstract Background New-onset heart failure (HF) during the first hospitalization was considered as an earlier indicator for poor prognosis in acute ST-segment elevation myocardial infarction (STEMI) without overt HF (Killip I). Purpose This study aims to develop a practical risk score to predict the in-hospital occurrence of new-onset HF and to evaluate its ability for prognosis. Methods The Chinese STEMI pPCI Registry is registered with ClinicalTrials.gov (NCT04996901). Within 24 h of symptom onset, 2940 STEMI patients with Killip class I on admission were treated by pPCI from five hospitals between January 2015 and January 2021; 1869 patients from three of the hospitals served as a derivation cohort, and 1071 from the other two hospitals constituted the external validation cohort. In-hospital HF was defined as Killip class ≥II at the first hospital presentation (8.7% in the derivation cohort vs. 14.3% in the validation cohort). Multivariable logistic regression was used to develop the in-hospital HF score. For 2-year following-up, all-cause mortality rate was estimated using the Cox regression analysis. Results Eight variables were independently associated with the development of in-hospital HF: age &amp;gt;65 years, previous atrial fibrillation, triple vessel lesion, anterior myocardial infarction, symptom onset-to-balloon time &amp;gt; 5 h, TIMI flow grade 0 before pPCI, neutrophil-to-lymphocyte ratio &amp;gt; 6.3 and aspartate aminotransferase &amp;gt; 65U/L on admission. STEP-HF score was created based on these 8 variables, and classified patients into three risk categories: low (0-3), intermediate (4-7), and high (≥8). Observed in-hospital HF rates were 3.47% (3.5%), 12.35% (8.34%), and 30.8% (17.05%) across the three risk categories, respectively in derivation (validation) cohort. The STEP-HF score demonstrated high discrimination (c-statistic of 0.705 in the derivation cohort, 0.656 in the validation cohort) and adequate calibration (Hosmer-Lemeshow goodness-of-fit test P values &amp;gt; 0.05) in both cohorts. After two-year follow up, 202 patients were lost to follow-up and finally a total of 2738 patients were included. 30-day all-cause mortality occurred in 0.13%, 0.66% and 1.71% of patients in low, intermediate and high risk group, respectively (p = 0.041). The association persisted during 1 year and 2 years of follow-up. Two-year all-cause mortality were 8 (1.03%), 32 (2.33%), and 37 (6.32%) for the low, intermediate, and high score groups, respectively (p&amp;lt;0.001). Receiver operating characteristic (ROC) analysis demonstrated the STEP-HF score can effectively predict all-cause mortality as compared with GRACE score for 30d, 1 year, and 2 years, respectively (STEP-HF: AUC 0.76, 0.71,0.68 vs. GRACE: AUC 0.75, 0.67, 0.67, p = 0.923, 0.202, 0.619, respectively). Conclusion The STEP-HF score can be used to predict prognosis in STEMI (Killip I) with pPCI. Higher scores are associated with higher in-hospital HF at first admission and all-cause mortality for long-term following up.

A polygenic risk score predicts atrial fibrillation in patients with coronary artery disease without severe systolic dysfunction

Abstract Background Genome-wide polygenic risk scores (GPS) comprised of multiple common variants can identify individuals within the general population at significantly higher risk for developing atrial fibrillation AF; however, the clinical utility in general populations is limited by the low absolute risk of AF. Purpose To determine whether a genome-wide polygenic score for AF (GPSAF) can be utilized to identify a patient population at high absolute risk for the development of AF among older patients with established coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) &amp;gt; 30-35%. Methods Participants in the PREDETERMINE study without a prior history of AF who had claims data available in Centers for Medicare and Medicaid Services (CMS) database were followed for incident AF defined as International Classification of Diseases codes 427.3 and I48. A recently validated GPSAF comprised of 1.1 million variants was generated and participants were divided into quintiles based upon the distribution of the GPSAF in the general population. The population was separated into 3 categories of genetic risk, with the top quintile classified as high risk, the second through fourth quintiles classified as intermediate risk, and the bottom quintile classified as low risk. Cumulative incidence curves for incident AF were plotted stratified by the GPSAF categories and the association between GPSAF and incident AF were estimated using Cox proportional hazard models with and without adjusting for established AF risk factors and biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity Troponin I, high sensitivity c-reactive protein). Results Over a median follow-up of 8.0 years, there were 482 incident AF events among 2272 study participants. Overall, median age was 67 [62,73] years and 73.5% were men. Baseline AF risk factors and biomarkers did not differ across GPSAF risk categories. The unadjusted cumulative incidence of AF over the course of the study was 39.2% (29.2%-47.8%) in the high GPSAF risk group, 32.5% (25.8%-38.5%) in the intermediate GPSAF risk group, and 21.6% (13.4%-29.9%) in the low GPSAF risk group (Figure 1). Compared with the participants with low GPSAF risk, participants with high and intermediate GPSAF risk had respectively t 2.32-fold (95% CI, 1.71-3.14; p=0.001) and 1.64-fold (95% CI, 1.27-2.10; p=0.001) increased risk for incident AF, adjusted for age and sex. Both remained significantly elevated after controlling for clinical factors, and biomarkers (Table 1). Conclusion A polygenic risk score for AF is strongly associated with incident AF risk among patients with CAD without severe systolic dysfunction, and clinically meaningful elevations in absolute risk of developing AF were observed in those in the highest quintile of risk. Future research is needed to determine if genetic risk assessment and targeted screening strategies will result in reduce morbidity from AF in this high-risk population.

Improving risk stratification of recurrent myocardial infarction in a large real-world dataset using machine learning

Abstract Background Patient (pt) risk stratification for cardiovascular (CV) events is key to determine the appropriate approach to secondary prevention. Several risk scores have been developed (SCORE2, EUROASPIRE, Thrombolysis in Myocardial Infarction [TIMI] risk score for secondary prevention [TRS 2°P]); these are based on few predictors and have low discriminatory power. Machine learning methods using real-word data (RWD) from electronic health records (EHR) databases and capable of handling a multitude of commonly available variables can serve as powerful tools to improve the discriminatory power and generate efficient and clinically relevant risk scores. Purpose This study used a non-linear machine learning model to build an improved risk score for secondary CV events from a large Israeli EHR database. Methods Records of pts with a first record of atherosclerotic CV disease (ASCVD) admission or coronary procedure and available follow-up data (mean: 1052 days) from the period of 01/2005–11/2020 were considered (n=77432 [67% coronary artery disease, 21% carotid artery disease, 12% peripheral artery disease], a stratified 1:1 randomization by cause of admission yielding in training set [n=38716] and test set [n=38716]). The model’s performance was assessed by comparison with TRS 2°P score on the test set independent of the training set. Twenty-six covariates commonly used in clinical routine and widely available in EHR have been selected and a gradient boosting trees algorithm was applied to the pt data at baseline after the original event to predict recurrent myocardial infarction (MI). The ability of the model to discriminate pts was evaluated using the concordance index (c-index), which expresses how well a predicted risk score describes the observed events (1 implies perfect concordance, 0.5 implies random concordance). Results Prediction accuracy of our model showed a c-index for a future MI of 0.74 (95% confidence interval [CI]: 0.72, 0.76) which is significantly higher than 0.57 (95% CI: 0.56, 0.58) obtained with TRS 2°P. Our 2-tier risk score has successfully discriminated a low-risk group (74% of cohort) with a 3-year MI prevalence of 5% from a high-risk group (26% of cohort) that had a 5-fold higher prevalence (26.6%) (Figure 1). In comparison, the 3-tier TRS 2°P yielded an unbalanced distribution of group sizes with a disproportionate intermediate risk group (22% low, 67% intermediate, 11% of high-risk) with a limited clinical discriminatory power (7.1%, 10,2% and 15.6% of observed events, respectively) (Figure 2). Conclusions Our machine learning based risk score model created on a large set of RWD with a long follow-up seems to offer substantial gain of performance compared to the TRS 2°P. The present 2-tier model shows significant gain of accuracy and clinical discriminatory power paving the way for more individualized prevention strategies.Figure 1Figure 2

Abstract 16613: Study of Modified HEART Score and HEART Pathway as Predictor of Major Adverse Cardiac Events (MACE) in Patients Presenting With Non ST Elevation- Acute Coronary Syndrome (NST-ACS)

Introduction: Among the various scores studied in literature, the modified HEART score and HEART pathway were found to have high discriminatory power of predicting major adverse cardiac events (MACE) in Non ST elevation acute coronary syndrome (NSTEACS) patients in various international studies. This warrants need for evaluation of these scores for better management of patients in hectic emergency departments of Indian healthcare system. Methods: This prospective observational study was conducted between January 2021 and May 2022 in a tertiary care hospital of New Delhi, India. Modified HEART score was calculated based on history, ECG, age, risk factors and highly sensitive troponin I (hsTrop I) values for 60 patients. Collected serum samples of hsTrop I at 0 and 3 hours were measured using ELISA kits. As per the score, patients in low risk group were discharged safely and intermediate and high risk groups were assessed with the help of stress testing and coronary angiography and managed accordingly. The occurrence of MACE was assessed at 30 days from presentation to healthcare facility. Results: The study showed that proportion of patients with MACE was significantly higher in high risk group (82.14%) as compared to low (0%) and intermediate risk group (20.83%) (p value &lt;0.001). Modified HEART score was the best predictor of MACE at cut off point of &gt;6 with 88.1% chances of correctly predicting MACE. Negative predictive value of HEART pathway was found to be 100% which enabled safe disposition of low risk group patients. Conclusions: Hence, when modified HEART score and HEART pathway were used together, it allowed efficient use of resources and prediction of MACE in NSTEACS. This was the first study done on Indian population where modified HEART score and HEART pathway were used simultaneously to predict the occurence of MACE.

Statin therapy in individuals with intermediate cardiovascular risk

BackgroundAs intermediate cardiovascular risk group accounts for a large part of the total population, determining appropriate cholesterol target in this population is critical. Herein, we investigated the optimal low-density lipoprotein cholesterol (LDL-C) level in individuals with intermediate cardiovascular risk after statin therapy. MethodsThis was a nationwide observational and validation cohort study (median duration of follow-up: 7.5 and 8.7 years, respectively), using data from the Korean National Health Insurance Service and a tertiary hospital database. Among individuals who underwent regular health examinations, those with ≥2 cardiovascular risk factors except diabetes mellitus, LDL-C 100–189 mg/dL, and newly used statins were enrolled. Of the 358,694 screened people, 57,594 met the inclusion criteria, of whom 27,793 were finally analyzed. The study population was stratified according to post-treatment LDL-C levels as follows: <100, 100–119, 120–139, and ≥ 140 mg/dL. The primary outcome variable was composite cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). From the patients screened of Severance Hospital cohort, 1859 meeting inclusion criteria were used for validation. ResultsThe rates of composite events ranged from 7.74 to 9.10 (mean 8.38)/1000 person-years in the three lower LDL-C groups. Adjusted hazard ratios (aHRs) ranged from 0.78 to 0.95 in the three groups with lower LDL-C, and a lower event risk was more evident in the groups that achieved LDL-C levels <120 mg/dL (p = 0.001–0.009). The total mortality risk did not differ between groups. In the validation cohort, the mean rate of composite events was 10.83/1000 person-years. aHRs ranged from 0.52 to 0.78 in the groups with lower LDL-C, and a lower risk was more obvious in patients who achieved LDL-C levels <100 mg/dL (p = 0.006–0.03). ConclusionsIndividuals with intermediate cardiovascular risk who achieved LDL-C levels <120 mg/dL after statin therapy had lower event risk. This result provides clinically useful evidence on target LDL-C levels in this population.