1-year Landmark Research Articles

Role of molecular alterations in transplantation decisions for patients with primary myelofibrosis

AbstractThe aim of our study was to analyze the potential survival benefit associated with hematopoietic stem cell transplantation (HSCT) according to clinicobiological scores, which incorporate molecular data (MIPSS70 and MIPSS70+V2) to facilitate decision-making in this context. One transplant (n = 241) and 1 nontransplant cohort (n = 239) were used to test the hypothesis that patients with primary myelofibrosis with higher risk molecular score benefit from HSCT. A weighted propensity score was applied to balance confounding factors with the transplanted cohort as reference. Weighted Cox proportional hazard models and logistic regression analyses were performed. Overall, 105 patients who did not receive transplant could be matched to the 239 patients who did receive transplants. Mean age in matched patients who did and did not undergo transplant was 55.5 and 57.9 years, respectively. Blood cell count and Dynamic International Prognostic Scoring System (DIPSS) score distribution were similar in both groups. HSCT was associated with a higher 6-year overall survival rate in intermediate-2 (60.1% vs 41.5%) and high-risk DIPSS patients (44.4% vs 6.55%), high-risk MIPSS70 (46.5% vs 23.9%), high-risk (73.2% vs 39.7%) or very high-risk MIPSS70+V2 (51.8% vs 24%). Patients with intermediate MIPSS70 scores have an advantage of survival with HSCT only when their myelofibrosis transplant scoring system (MTSS) were low or intermediate. Patients who received transplant had an increased mortality risk the first year, but a significant benefit with HSCT after the 1-year landmark was observed in higher risk patients. This study confirms that, similar to DIPSS, MIPSS70 and MIPSS70+V2 risk score in addition to MTSS can be used to determine which patients with primary myelofibrosis have survival benefit from HSCT over non-HSCT strategies.

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.

Prognostic Implications of Maintaining the Target Thyroid-Stimulating Hormone Status Based on the 2015 American Thyroid Association Guidelines in Patients with Low-Risk Papillary Thyroid Carcinoma after Lobectomy: A 5-Year Landmark Analysis

Background: The 2015 American Thyroid Association guidelines recommend the maintenance of serum thyroid stimulating hormone (TSH) levels ≤2 mIU/L in patients with low-risk papillary thyroid carcinoma (PTC) who underwent lobectomy; however, the evidence is insufficient. We investigated the association between maintaining the TSH status at ≤2 mIU/L and tumor recurrence in patients with low-risk PTC who underwent lobectomy through a 5-year landmark analysis. Methods: Between 2010 and 2016, 662 patients with low-risk PTC were included. The postoperative TSH status was determined using the ‘TSH > 2 ratio’, which was calculated using the TSH test results during the 5-year follow-up. The optimal cutoff value of ‘TSH > 2 ratio’ for tumor recurrence was determined using a receiver operating characteristic curve analysis. Recurrence-free survival (RFS) was compared between the groups using Kaplan–Meier and Cox proportional hazard regression analyses. Results: Patients with ‘TSH > 2 ratio’ > 0.1833 (n = 498) had a worse RFS outcome compared to patients with ‘TSH > 2 ratio’ ≤ 0.1833 (n = 164; p < 0.001). ‘TSH > 2 ratio’ > 0.1833 was a significant risk factor for tumor recurrence after the 5-year landmark (hazard ratio: 4.795, 95% confidence interval: 2.102–10.937, p < 0.001). Conclusions: Maintaining TSH levels ≤ 2 mIU/L below a certain percentage among the total TSH tests during the 5-year follow-up period has a negative impact on tumor recurrence.

Landmark analysis of the risk of recurrence after resection or ablation for HCC: A nationwide study.

The risk of HCC recurrence at particular landmarks since the initial treatment is unknown. With this registry-based study, we aimed to provide a nuanced description of the prognosis following resection or ablation for HCC, including landmark analyses. Using the Danish nationwide health care registries, we identified all patients who received resection or ablation in 2000-2018 as the first HCC treatment. HCC recurrence was defined as a new HCC treatment > 90 days after the first treatment. We conducted competing risk landmark analyses of the cumulative risk of recurrence and death. Among 4801 patients with HCC, we identified 426 patients who received resection and 544 who received ablation. The 2 treatment cohorts differed in cirrhosis prevalence and tumor stage. The 5-year recurrence risk was 40.7% (95% CI 35.5%-45.8%) following resection and 60.7% (95% CI: 55.9%-65.1%) following ablation. The 1-year recurrence risk decreased over the landmarks from 20.4% (95% CI: 16.6%-24.6%) at the time of resection to 4.7% (95% CI: 0.9%-13.9%) at the 5-year landmark. For ablation, the risk decreased from 36.1% (95% CI: 31.9%-40.4%) at the time of treatment to 5.3% (95% CI: 0.4%-21.4%) at the 5-year landmark. The risk of death without recurrence was stable over the landmarks following both resection and ablation. In conclusion, the risk of recurrence or death following resection or ablation for HCC is high from the treatment date, but the risk of recurrence decreases greatly over the survival landmarks. This information is valuable for clinicians and their patients.

Major cardiovascular events in long-term multiple myeloma survivors: a Korean case–control study (the CAREMM-2105 study)

PurposeDespite improvements in multiple myeloma (MM) survival rates, data on cardiovascular outcomes in long-term survivors remain lacking.MethodsThis retrospective case–control study utilized the Korean National Health Insurance Service database (2009–2020) to compare the incidence of cardiovascular disease (CVD) between patients with MM and a matched control group, focusing on long-term (> 5 years) survivors. A preliminary case cohort (n = 15,402 patients with MM) and a matched control cohort (n = 123,216 patients without MM) were established based on birth year and sex. Following 1:1 propensity score matching, the final matched cohorts each comprised 15,402 participants.ResultsThe case and control cohorts were comparable in mean age (66.2 ± 11.5 years vs. 66.1 ± 11.3 years), sex, age distribution, and comorbidities. By the 8-year follow-up, the cumulative incidence of CV events (12.5% vs. 22.1%) and CVD risk were significantly lower in the case cohort. The 5-year landmark analysis revealed significant differences in CVD incidence between the cohorts (7.8% [case cohort] vs. 9.8% [control cohort]), with variations across age groups and sex, highlighting a significantly higher CVD risk among patients aged < 50 years in the case cohort (P < 0.001).ConclusionsThese findings underscore the need for vigilant CVD monitoring in MM long-term survivors, particularly those aged < 50 years at first diagnosis.Implication for Cancer SurvivorsThis study highlights the importance of integrating cardiovascular monitoring and risk management into long-term care for MM survivors, with a focus on younger patients and personalized interventions.

Clinical outcomes of atezolizumab versus standard-of-care docetaxel with and without ramucirumab in patients with advanced non-small-cell lung cancer who received prior immunotherapy.

Atezolizumab is superior to docetaxel for patients with advanced non-small-cell lung cancer (NSCLC) who are pretreated with platinum-based chemotherapy based on the POPLAR and OAK trials. However, patients who received prior immunotherapy were excluded from these trials. The standard of care second-line therapy for these patients remains to be docetaxel with or without ramucirumab. The efficacy and safety of atezolizumab as a subsequent therapy in immunotherapy-pretreated patients are unknown. We conducted a retrospective study of all patients with locally advanced or metastatic NSCLC who were pretreated with immunotherapy at Mayo Clinic Jacksonville and Rochester from 2016 to 2022. Patients who received subsequent therapy of atezolizumab alone (Atezo), docetaxel (Doce), or docetaxel + ramucirumab (Doce+Ram) were included. In this cohort of 165 patients, 12.7% (n=21), 49.1% (n=81), and 38.2% (n=63) patients received subsequent Atezo, Doce, and Doce+Ram, respectively. 1-year landmark progression-free survival (PFS) were 23.8%, 6.2%, and 3.2% (p=0.006), and 2-year landmark PFS were 14.3%, 0%, and 0% (p<0.0001), in the Atezo, Doce, and Doce+Ram groups, respectively. About 20% patients with positive PD-L1 had durable response to atezolizumab. The Atezo group showed significantly greater overall survival (OS) improvement over Doce group (median OS 17.7 vs. 7.7 months, HR 0.47, 95% CI 0.29 - 0.76, p=0.008), and over Doce+Ram group (median OS 17.7 vs. 8.9 months, HR 0.55, 95% CI 0.32 - 0.95, p=0.047). 4 of 21 (19%) patients in the Atezo group developed immune-related adverse events (irAE). We observed statistically significant and clinically meaningful overall survival benefits of atezolizumab monotherapy compared with docetaxel +/- ramucirumab in patients with advanced NSCLC who were pretreated with immunotherapy. The survival benefit seems to be mainly from PD-L1 positive patients. Subsequent immunotherapy with Atezolizumab did not increase irAE rate.

High Prevalence of Iron Deficiency Among Daratumumab-Treated Newly Diagnosed Multiple Myeloma Patients

Background: Iron deficiency (ID), a common cause of anemia, is often overlooked among patients with hematologic malignancies given alternative etiologies. Daratumumab is an anti-CD38 monoclonal antibody used in the management of multiple myeloma (MM). Approximately 45% of patients on daratumumab are anemic. In a study of 22 patients with relapsed refractory AL amyloidosis treated with daratumumab, 40% developed iron deficiency requiring IV iron replacement. It is unclear whether iron deficiency in this setting is specific to AL amyloidosis, or whether it is universally seen with daratumumab treatment. In this study we evaluated iron deficiency parameters, including bone marrow iron stores, in MM patients treated with daratumumab. Methods: We conducted a retrospective study to evaluate the prevalence of ID among newly diagnosed MM patients who were treated uniformly in a phase II study with the combination of daratumumab, ixazomib, lenalidomide and dexamethasone conducted at our center. Laboratory values of ferritin, hemoglobin and MCV were extracted from the medical records at trial enrollment and at 1-year from treatment initiation. ID was defined as ferritin &amp;lt;30 mcg/L. Bone marrow iron stores were assessed at pre-trial and 1-year from therapy initiation by Prussian blue stain of bone marrow clot sections, with grade 0 (absent iron) or grade 1 (trace to low iron) considered as depleted iron storage. Results: Among 54 included patients, 2 (3.7%) had ferritin &amp;lt;30 mcg/L at trial-enrollment, while 27 (50%) developed ID within 1 year and 33 (61%) became iron deficient during their treatment course. All patients (100%) had lower ferritin at 1 year compared to pre-trial value. The median reduction of ferritin at 1-year was 109 (IQR: 41-239 mcg/L), a decrease by 75% (IQR:56- 86%) from baseline value. Fifteen patients (28%) received IV or oral iron replacement, and 4 were already on iron-repletion before the 1-year landmark assessment. The median ferritin improved from 16 to 84 mcg/L (p&amp;lt;.0001) following iron replacement. Forty patients (74%) had improved hemoglobin at 1-year compared to baseline correlated to disease response to therapy. The median increment in hemoglobin was 1.1 (IQR: -0.3 - 2.7 g/dL). Hemoglobin at 1-year was higher in patients having ferritin ≥ 30 mcg/L compared to the ID group: 13.5 (IQR: 12.3-14.1 g/dL) vs 12.8 (IQR: 12.3-13.4 g/dL), p=.05. BM samples from pre-trial (n=37) and 1-year on-trial (n=36) were available for iron staining. Depleted iron storage was more frequent at1-year compared to baseline (63.9% vs 40.5%, p&amp;lt;.05). The median ferritin was lower in patients with iron depleted versus non-iron depleted BM: 58 (IQR: 31-120 mcg/L) vs 243 (IQR: 125-486 mcg/L) at baseline, p=.0002; 27 (IQR: 16-41 mcg/L) vs 59 (IQR: 19-245 mcg/L) at 1-year landmark, p=.07. Comparisons of laboratory markers at initiation and after 1-year on daratumumab trial are listed in Table 1. Conclusions: Our study demonstrated a high prevalence of ID among patients receiving daratumumab-based treatment for newly diagnosed MM. While some decrease in ferritin over treatment course may be caused by myeloma disease control and improved systemic inflammation, this study should increase awareness for ID among MM patients treated with daratumumab. Future studies are needed to better understand the possible role of daratumumab in the pathogenesis of ID in MM and other plasma cell disorders.

Curability of Light Chain (AL) Amyloidosis with Conventional Dose Regimens

Novel immunotherapies in AL amyloidosis (AL) are associated with improved outcomes while the use of ASCT in selected patients can offer long term remissions. Since the plasma cell clones are usually small or modest, sustained hematologic remissions are not uncommon in AL amyloidosis; however, the “curability” of the disease remains to be demonstrated: even in patients (pts) who achieve deep and sustained hematologic responses, irreversible organ damage can lead to inferior survival. To identify clinical and disease characteristics that are associated with potential “functional cure” (“cure”) of the disease we analyzed a cohort of patients with AL treated without ASCT and with a follow up of at least 5 years. We defined“ ”cure“ as survival of at least 5 years without hematologic disease progression (PD) and without need for any salvage therapy. The analysis included consecutive pts with AL, treated in the Department of Clinical Therapeutics, Athens Greece, diagnosed until 6/2018; pts who survived &amp;lt; 6 months were excluded to adjust for early mortality associated with severe cardiac involvement. The final cohort included 210 pts and we focused on pts who: had not had hematologic PD, had not received any salvage therapy, were still alive or had died from causes not related to AL. These pts were defined as “functionally cured” while the rest as “non-cured”. Among the “cured” we identified a group of pts that despite hematologic response they progressed to end-stage renal disease. We considered that this was “predetermined” due to the advanced organ damage already at diagnosis. Lastly, we compared the outcome of “cured” pts with the outcome of “non-cured” pts who were on CR/VGPR and had ≥1-year or ≥5-year OS. The rate of “curability” was 17% (N=35). “Cured” pts had more often renal (84% vs 61%, p=0.045) and less frequent cardiac involvement (53% vs 62%, p=0.049), lower BM infiltration (8% vs 15%, p&amp;lt;0.001) and lower baseline dFLC (p=0.031) but higher levels of baseline proteinuria (p=0.031). The characteristics as well as the differences between “cured” and “non-cured” pts, are shown in Table 1. Most “cured” pts received bortezomib-based therapies (27 pts, 77%), oral melphalan was given in 4 pts (11%), while in 15 pts (42%) treatment also included lenalidomide and in 7 (20%) daratumumab (with or without bortezomib). Regarding hematologic response, 33 (94%) “cured” pts had achieved ≥ VGPR (CR: 22, VGPR: 11) vs 46% for “non-cured” (p&amp;lt;0.001), 18 pts (51%) had ≥ VGPR with low dFLC response criteria (dFLC &amp;lt;10mg/L) vs 20% (p&amp;lt;0.001); 6 pts (17%) had only low dFLC VGPR and 4 (11%) were not evaluable for response due to low dFLC levels. At 1- and 3-months from start of therapy, 24 (68%) and 27 pts (77%) “cured” pts had achieved ≥VGPR. MRD evaluation was available in 19 “cured” pts, and 11 (31%) were MRD negative (vs 3 (2%) for “non-cured” pts, p&amp;lt;0.001). Cardiac response was observed in 9 pts (25%) and renal response in 18 “cured” pts (51%). Among “cured” pts there was a group of 7 pts (20%) with end-stage renal disease; 1 (2.8%) was already on dialysis at the time of diagnosis, while 6 (17%) initiated dialysis during disease course, despite deep hematologic responses (3 CR, 3 VGPR); 3 pts were renal stage 2 and 3 were renal stage 3. Median time to dialysis was 27 months. Baseline clinical and disease characteristics were comparable among pts with and without end-stage renal disease. The median follow-up of the whole cohort was 88 months, and among “cured” pts, 3 (8.5%) died from causes unrelated to AL amyloidosis. The 7- year OS rate for “cured” pts was 100% and for “non-cured” was 41%, respectively. In 1- and 5-year landmark survival analysis, “cured” pts had significantly superior outcome compared to “non-cured” pts with CR/VGPR, with median OS not reached vs 66 months (p&amp;lt;0.001) and not reached vs 98 months (p=0.014), respectively (Fig 1). In conclusion, a subgroup of pts with AL, not treated with ASCT, can have long-term survival (≥ 5 years) without need for additional or salvage therapy. Such patients could be considered as functionally “cured”. High rates of rapid and deep hematologic responses, relatively high rates of MRD negativity and relatively low tumor and free light chain burden characterize this subset, further emphasizing the need for early diagnosis and active therapy to maximize clonal responses. Thus, “curability” in AL amyloidosis is feasible, especially in the era of novel therapies.

Adherence to guideline-directed medical therapy and 3-year clinical outcome following acute myocardial infarction

Abstract Aims Despite the well-established clinical benefits and strong recommendations in clinical guidelines, adherence to guideline-directed medical therapy (GDMT) is known to be insufficient. We investigated the adherence to GDMT and its impact on the 3-year clinical outcomes in patients with acute myocardial infarction (AMI). Methods and results Source data were obtained from KAMIR-NIH, a Korean multicenter observational registry. GDMT was defined according to the ACC/AHA class I recommendations. Adherence to GDMT was assessed at discharge and every year thereafter. The differences in clinical characteristics between patients receiving and those not receiving GDMT were adjusted using propensity score matching (PSM) or inverse probability of treatment weighting (IPTW). The primary endpoint was major adverse cardiovascular events (MACE), which was a composite of all-cause death and non-fatal MACE, including MI, revascularization, or stroke. Of 12,815 patients, GDMT adherence was 70.2% at discharge, and decreased gradually into 54.6% at 3-year. GDMT at discharge was associated with lower MACE risk in the unadjusted analysis (HR=0.51, 95%CI=0.47–0.55, p&amp;lt;0.001) and also in the PSM- or IPTW-adjusted analyses (HR=0.77, 95%CI=0.69–0.86; HR=0.79, 95%CI=0.72–0.86; p&amp;lt;0.001, all). These findings were replicated in the 1-year or 2-year landmark analyses (HR=0.58 to 0.82, p&amp;lt;0.01, all). Conclusion Adherence to GDMT was suboptimal among patients with AMI in Korea. As the adherence to GDMT was associated with a lower incidence of MACE during 3-year follow-up, the maintenance of long-term GDMT might be crucial for patients with AMI.Structured Graphical Abstract

Clopidogrel vs Aspirin Monotherapy Beyond 1 Year After Percutaneous Coronary Intervention

BackgroundIt remains unclear whether clopidogrel is better suited than aspirin as the long-term antiplatelet monotherapy following dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). ObjectivesThis study compared clopidogrel monotherapy following 1 month of DAPT (clopidogrel group) with aspirin monotherapy following 12 months of DAPT (aspirin group) after PCI for 5 years. MethodsSTOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy 2) is a multicenter, open-label, adjudicator-blinded, randomized clinical trial conducted in Japan. Patients who underwent PCI with cobalt-chromium everolimus-eluting stents were randomized in a 1-to-1 fashion either to clopidogrel or aspirin groups. The primary endpoint was a composite of cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) or major bleeding (TIMI major or minor bleeding). ResultsAmong 3,005 study patients (age: 68.6 ± 10.7 years; women: 22.3%; acute coronary syndrome: 38.3%), 2,934 patients (97.6%) completed the 5-year follow-up (adherence to the study drugs at 395 days: 84.7% and 75.9%). The clopidogrel group compared with the aspirin group was noninferior but not superior for the primary endpoint (11.75% and 13.57%, respectively; HR: 0.85; 95% CI: 0.70-1.05; Pnoninferiority < 0.001; Psuperiority = 0.13), whereas it was superior for the cardiovascular outcomes (8.61% and 11.05%, respectively; HR: 0.77; 95% CI: 0.61-0.97; P = 0.03) and not superior for major bleeding (4.44% and 4.92%, respectively; HR: 0.89; 95% CI: 0.64-1.25; P = 0.51). By the 1-year landmark analysis, clopidogrel was numerically, but not significantly, superior to aspirin for cardiovascular events (6.79% and 8.68%, respectively; HR: 0.77; 95% CI: 0.59-1.01; P = 0.06) without difference in major bleeding (3.99% and 3.32%, respectively; HR: 1.23; 95% CI: 0.84-1.81; P = 0.31). ConclusionsClopidogrel might be an attractive alternative to aspirin with a borderline ischemic benefit beyond 1 year after PCI.

Association of intrinsic capacity with incidence and mortality of cardiovascular disease: Prospective study in UK Biobank.

The World Health Organization proposed the concept of intrinsic capacity (IC; the composite of all the physical and mental capacities of the individual) as central for healthy ageing. However, little research has investigated the interaction and joint associations of IC with cardiovascular disease (CVD) incidence and CVD mortality in middle- and older-aged adults. Using data from 443130 UK Biobank participants, we analysed seven biomarkers capturing the level of functioning of five domains of IC to calculate a total IC score (ranging from 0 [better IC] to +4 points [poor IC]). Associations between IC score and incidence of six long-term CVD conditions (hypertension, stroke/transient ischaemic attack stroke, peripheral vascular disease, atrial fibrillation/flutter, coronary artery disease and heart failure), and grouped mortality from these conditions were estimated using Cox proportional models, with a 1-year landmark analysis to triangulate the findings. Over 10.6years of follow-up, CVD morbidity grouped (n=384380 participants for the final analytic sample) was associated with IC scores (0 to +4): mean hazard ratio (HR) [95% confidence interval, CI] 1.11 [1.08-1.14], 1.20 [1.16-1.24], 1.29 [1.23-1.36] and 1.56 [1.45-1.59] in men (C-index=0.68), and 1.17 [1.13-1.20], 1.30 [1.26-1.36], 1.52 [1.45-1.59] and 1.78 [1.67-1.89] in women (C-index=0.70). In regard to mortality, our results indicated that the higher IC score (+4 points) was associated with a significant increase in subsequent CVD mortality (mean HR [95% CI]: 2.10 [1.81-2.43] in men [C-index=0.75] and 2.29 [1.85-2.84] in women [C-index=0.78]). Results of all sensitivity analyses by full sample, sex and age categories were largely consistent independent of major confounding factors (P<0.001). IC deficit score is a powerful predictor of functional trajectories and vulnerabilities of the individual in relation to CVD incidence and premature death. Monitoring an individual's IC score may provide an early-warning system to initiate preventive efforts.

Effects of social determinants of health on mortality and incident liver-related events and cardiovascular disease in steatotic liver disease.

Social determinants of health (SDOH) are becoming increasingly recognised as mediators of human health. In the setting of metabolic dysfunction-associated steatotic liver disease (MASLD), most of the literature on SDOH relates to individual-level risk factors. However, there are very limited data on neighbourhood-level SDOH in MASLD. To assess whether SDOH impact fibrosis progression in patients who already have MASLD. This was a retrospective cohort study of patients with MASLD seen at Michigan Medicine. The primary predictors were two neighbourhood-level SDOH, 'disadvantage' and 'affluence'. The primary outcomes were mortality, incident liver-related events (LREs) and incident cardiovascular disease (CVD). We modelled these outcomes using Kaplan-Meier statistics for mortality and competing risk analyses for LREs and CVD, using a 1-year landmark. We included 15,904 patients with MASLD with median follow-up of 63 months. Higher affluence was associated with lower risk of overall mortality (hazard ratio 0.49 [0.37-0.66], p < 0.0001 for higher vs. lower quartile), LREs (subhazard ratio 0.60 [0.39-0.91], p = 0.02) and CVD (subhazard ratio 0.71 [0.57-0.88], p = 0.0018). Disadvantage was associated with higher mortality (hazard ratio 2.08 [95% confidence interval 1.54-2.81], p < 0.0001 for the highest vs. lowest quartile) and incident CVD (subhazard ratio 1.36 [95% confidence interval 1.10-1.68], p < 0.0001). These findings were robust across several sensitivity analyses. Neighbourhood-level SDOH are associated with mortality, incidence of LREs and incident CVD in patients with steatotic liver disease. Interventions aimed at disadvantaged neighbourhoods may improve clinical outcomes.

Adherence to guideline-directed medical therapy and 3-year clinical outcome following acute myocardial infarction.

Despite the well-established clinical benefits and strong recommendations in clinical guidelines, adherence to guideline-directed medical therapy (GDMT) is known to be insufficient. We investigated the adherence to GDMT and its impact on the 3-year clinical outcomes in patients with acute myocardial infarction (AMI). Source data were obtained from KAMIR-NIH, a Korean multi-centre observational registry. GDMT was defined according to the ACC/AHA Class I recommendations. Adherence to GDMT was assessed at discharge and every year thereafter. The differences in clinical characteristics between patients receiving and those not receiving GDMT were adjusted using propensity score matching (PSM) or inverse probability of treatment weighting (IPTW). The primary endpoint was major adverse cardiovascular events (MACE), which was a composite of all-cause death and non-fatal MACE, including myocardial infarction (MI), revascularization, or stroke. Of 12 815 patients, GDMT adherence was 70.2% at discharge, and decreased gradually into 54.6% at 3-year. GDMT at discharge was associated with lower MACE risk in the unadjusted analysis [hazard ratio (HR) = 0.51, 95% confidence intervals (CI) = 0.47-0.55, P < 0.001] and also in the PSM- or IPTW-adjusted analyses (HR = 0.77, 95% CI = 0.69-0.86; HR = 0.79, 95% CI = 0.72-0.86; P < 0.001, all). These findings were replicated in the 1-year or 2-year landmark analyses (HR = 0.58 to 0.82, P < 0.01, all). Adherence to GDMT was sub-optimal among patients with AMI in Korea. As the adherence to GDMT was associated with a lower incidence of MACE during 3-year follow-up, the maintenance of long-term GDMT might be crucial for patients with AMI.

Abstract P4-03-02: Low-dose aspirin prescriptions and breast cancer recurrence: a Danish nationwide cohort study with up to 23 years of follow-up

Abstract Background Low-dose aspirin irreversibly inhibits the cyclooxygenase enzymes COX-1 and COX-2, which catalyze the formation of prostaglandins and thromboxanes, inhibiting platelet aggregation. Platelets are thought to play a role in tumorigenesis. As such, aspirin may have a beneficial effect on breast cancer prognosis, but results to date are conflicting. Objectives To evaluate the association between aspirin use and breast cancer recurrence up to 23 years after primary diagnosis. Methods We included all women diagnosed with non-metastatic breast cancer during 1996-2004 registered in the Danish Breast Cancer Group (DBCG) clinical database. We obtained information on aspirin prescriptions (&amp;gt;= 2 prescriptions filled between cancer diagnosis and the landmark) from the Danish National Prescription Registry. Information on early and late (&amp;gt;10 years after primary diagnosis) recurrence was obtained using the DBCG database (for recurrence within the first 10 years after diagnosis) and for late recurrence via a previously described and validated algorithm, drawing on data from the Danish National Patient Registry, the Danish Pathology Registry, the Danish Cancer Registry and a contralateral breast cancer database. We used Cox regression to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CI) employing landmark analyses starting follow-up at years 5, 10, 15, and 20 after primary diagnosis. We adjusted for potential confounders including calendar year of diagnosis, menopausal status, comorbidities, estrogen receptor status, clinical stage, grade, surgery type, chemo- and endocrine therapy, diagnostic codes for alcoholism and obesity, as well as co-medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, bisphosphonates, metformin, digoxin, hormone replacement therapy, non-steroidal anti-inflammatory drugs, and vitamin K antagonists). We followed patients until recurrence, death, second cancer, loss to follow-up, or 31 December 2018. Results Among 21,684 women with non-metastatic breast cancer, 4,902 experienced recurrence during 242,427 person-years of follow-up. Our landmark analyses showed a reduced hazard of recurrence in the 5-, 10-, and 15-year landmark cohorts (5-year landmark adjusted HR = 0.80, 95% CI = 0.68, 0.94; 10-year landmark adjusted HR = 0.84, 95% CI = 0.71, 1.00, 15-year landmark adjusted HR = 0.83, 95% CI = 0.61, 1.14). The 20-year landmark analysis revealed an adjusted HR of 1.09 (95% CI = 0.49, 2.46). Conclusions The potential anti-cancer effect of aspirin appears most pronounced in the first 15 years after breast cancer diagnosis. Funding Elisabeth Solmunde is funded by the Danish Cancer Society (R320-A18464-B5768) and the Independent Research Fund Denmark (1149-00013B). This work was supported by grants to Deirdre Cronin-Fenton from the Danish Cancer Society (“Knæk Cancer” R147-A10100). Citation Format: Elisabeth Solmunde, Rikke N Pedersen, Mette Nørgaard, Lene Mellemkjær, Søren Friis, Bent Ejlertsen, Thomas P. Ahern, Deirdre Cronin-Fenton. Low-dose aspirin prescriptions and breast cancer recurrence: a Danish nationwide cohort study with up to 23 years of follow-up [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-02.

Predictive value of C reactive protein (CRP) in patients with metastatic renal cell carcinoma (mRCC) treated with pembrolizumab (pembro) and axitinib (axi).

716 Background: CRP, a biomarker of systemic inflammation, has been shown to have prognostic value in numerous tumour types, including mRCC. The combination of the immune check inhibitor (ICI), pembro, and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) axi is one of several internationally approved combination ICI/VEGFR-TKI treatment options. We evaluated the predictive value of biomarkers of systemic inflammation in a real-world cohort of patients with mRCC treated with pembro and axi. Methods: Retrospective data of patients treated with pembro and axi were collected from a regional electronic database from two large cancer centres. Inflammatory biomarkers from routine blood tests (including haemoglobin, neutrophil count, platelets, albumin and CRP) prior to starting treatment were recorded. The IMDC score and modified Glasgow Prognostic Score (combining albumin and CRP) were calculated. The primary end point, progression free survival (PFS), was defined as the time between initiation of treatment and clinical or radiographical progression or death, or censorship. Overall survival, defined as the time between initiation of treatment and death, or censorship was also calculated. Univariate and multivariate analyses were undertaken using Cox Regression model and the relationship between different markers and PFS was assessed using Kaplan-Meier curves. Results: Data were available for 93 patients. 74 pts (80%) had clear cell histology, 19 pts (20%) had non-clear cell and 11 pts (12%) had sarcomatoid component. 46 patients had previous nephrectomy. 15 (16%), 46 (50%) and 32 (34%) pts respectively were classified as favourable, intermediate, and poor risk group as per IMDC score. Median PFS was 10.7 (IQR 4.6-not reached) months after a minimum 12.5 months follow-up. Baseline CRP was recorded in 77 (83%) patients, reflecting current routine clinical guidelines. On univariate analysis, neutrophils (≤7.5x109/L/&gt;7.5x109/L) (p=0.044), platelets (≤400 x109/L/&gt;400x109/L) (p=0.043), CRP (≤10mg/L/&gt;10mg/L) (p=0.001), mGPS (0/1/2) (p=0.004) and IMDC risk group (low/intermediate/poor) (p=0.038) were predictive of PFS. On multivariate analyses only CRP was associated with PFS (HR2.78 (95% CI, 1.42-5.44) (p=0.003). At a 1-year landmark PFS was 62% (CRP ≤10mg/L) v 29% (CRP &gt;10mg/L) (p=0.002). CRP also predicted OS ((HR4.50 (95% CI, 1.58-12.8) (p=0.005)) with 1-year OS 85% (CRP ≤10mg/L) v 59% (CRP &gt;10mg/L) (p=0.002). Conclusions: CRP, a biomarker of systemic inflammation, predicts survival in mRCC patients undergoing combined ICI/VEGF-TKI therapy. Our findings support comparable studies in the mRCC population and routine recording of CRP in patients with mRCC. We advocate further work to validate utilisation of CRP as a prognostic biomarker for mRCC in clinical practice.

Incidence of thyroid dysfunction following initiation of amiodarone treatment in patients with and without heart failure: a nationwide cohort study.

Thyroid dysfunction is considered the most frequent complication to amiodarone treatment, but data on its occurrence outside clinical trials are sparse. The present study aimed to examine the incidence of thyroid dysfunction following initiation of amiodarone treatment in a nationwide cohort of patients with and without heart failure (HF). In Danish registries, we identified all patients with first-time amiodarone treatment during the period 2000-18, without prior thyroid disease or medication. The primary outcome was a composite of thyroid diagnoses and initiation of thyroid drugs. Outcomes were assessed at 1-year follow-up, and for patients free of events in the first year, in a landmark analysis for the subsequent 5 years. We included 43 724 patients with first-time amiodarone treatment, of whom 16 939 (38%) had HF. At 1-year follow-up, the cumulative incidence and adjusted hazard ratio (HR) of the primary outcome were 5.3% and 1.37 (95% confidence interval 1.25-1.50) in patients with a history of HF and 4.2% in those without HF (reference). In the 1-year landmark analysis, the subsequent 5-year cumulative incidences and adjusted HRs of the primary outcome were 5.3% (reference) in patients with 1-year accumulated dose <27.38 g [corresponding to average daily dose (ADD <75 mg)], 14.0% and HR 2.74 (2.46-3.05) for 27.38-45.63 g (ADD 75-125 mg), 20.0% and HR 4.16 (3.77-4.59) for 45.64-63.88 g (ADD 126-175 mg), and 24.5% and HR 5.30 (4.82-5.90) for >63.88 g (ADD >175 mg). Among patients who initiated amiodarone treatment, around 5% had thyroid dysfunction at 1-year follow-up, with a slightly higher incidence in those with HF. A dose-response relationship was observed between the 1-year accumulated amiodarone dose and the subsequent 5-year cumulative incidence of thyroid dysfunction.

Clinical trajectories and outcomes of patients with heart failure with preserved ejection fraction with normal or indeterminate diastolic function.

We recently reported that nearly half of patients with heart failure with preserved ejection fraction (HFpEF) did not show echocardiographic diastolic dysfunction (DD), but had normal diastolic function (ND) or indeterminate diastolic function (ID). However, the clinical course and outcomes of patients with HFpEF with ND or ID (ND/ID) remain unknown. From the PURSUIT-HFpEF registry, we extracted 289 patients with HFpEF with ND/ID at discharge who had echocardiographic data at 1-year follow-up. Patients were classified according to the status of progression from ND/ID to DD at 1year. Primary endpoint was a composite of all-cause death or HF rehospitalization. Median age was 81years, and 138 (47.8%) patients were female. At 1year, 107 (37%) patients had progressed to DD. The composite endpoint occurred in 90 (31.1%) patients. Compared to patients without progression to DD, those with progression had a significantly higher cumulative rate of the composite endpoint (P < 0.001) and HF rehospitalization (P < 0.001) after discharge and at the 1-year landmark (P = 0.030 and P = 0.001, respectively). Progression to DD was independently associated with the composite endpoint (hazard ratio (HR): 2.014, 95%CI 1.239-3.273, P = 0.005) and HF rehospitalization (HR: 2.362, 95%CI 1.402-3.978) after discharge. Age (odds ratio (OR): 1.043, 95%CI 1.004-1.083, P = 0.031), body mass index (BMI) (OR: 1.110, 95%CI 1.031-1.195, P = 0.006), and albumin (OR: 0.452, 95%CI 0.211-0.969, P = 0.041) were independently associated with progression from ND/ID to DD. More than one-third of HFpEF patients with ND/ID progressed to DD at 1year and had poor outcomes. Age, BMI and albumin were independently associated with this progression. UMIN000021831.

Abstract 14351: Prognostic Impact of a Novel Objective Assessment System for Frailty in Patients Who Undergo Transcatheter Aortic Valve Implantation

Background: Preprocedural assessment of frailty is often used to predict prognosis following transcatheter aortic valve implantation (TAVI). We introduced a novel scoring system, the Saiseikai Frailty Score (SFS), which contains objective indices of physical and mental ability, vitality, nutrition status and comorbidity. Methods and Results Consecutive 431 patients who underwent TAVI were prospectively enrolled. The SFS consists of 7 items; gait speed, grip strength, physical activity, body weight, fatigability, cognitive function and serum albumin levels, and the sum of abnormal items is presented as the SFS. SFS 0-1 are defined as low frailty (LF), 2-3 as intermediate frailty (IF) and 4-7 as high frailty (HF). Prognosis up to 1 year after the procedure and landmark analysis after 1yr were prospectively evaluated according to the frailty (median follow-up period 951 days). Of the 431 patients (age 85.0±4.9yrs [mean±SD], male 29.5%), 116 patients (26.9%) were categorized as LF, 197 (45.7%) as IF and 118 (27.4%) as HF. The cumulative 1-year mortality was significantly higher in the HF group than the other 2 groups (p=0.0038, log-rank test). Post 1-year landmark analysis revealed that only the LF had better prognosis than the other 2 groups (p=0.0013). The modified SFS with information of malignancy, lung and kidney function (LF 0-1, IF 2-3 and HF 4-11) clearly stratify the 3 groups in both the short- and long-term mortality (p=0.0006 and p&amp;lt;0.0001). Conclusions: The SFS enabled sophisticated and objective stratification of prognosis after TAVI. This novel frailty assessment system will be useful to determine the precise indication for TAVI.

Individual Patient Data Meta-analysis of Drug-eluting Versus Bare-metal Stents for Percutaneous Coronary Intervention in Chronic Versus Acute Coronary Syndromes

New-generation drug-eluting stents (DES) strongly reduce restenosis and repeat revascularization compared with bare-metal stents (BMS) for percutaneous coronary intervention. There is residual uncertainty as to whether other prognostically relevant outcomes are affected by DES versus BMS concerning initial presentation (chronic coronary syndrome [CCS] vs acute coronary syndrome [ACS]). We performed an individual patient data meta-analysis of randomized trials comparing new-generation DES versus BMS (CRD42017060520). The primary outcome was the composite of cardiac death or myocardial infarction (MI). Outcomes were examined at maximum follow-up and with a 1-year landmark. Risk estimates are expressed as hazard ratio (HR) with 95% confidence interval (CI). A total of 22,319 patients were included across 14 trials; 7,691 patients (34.5%) with CCS and 14,628 patients (65.5%) with ACS. We found evidence that new-generation DES versus BMS consistently reduced the risk of cardiac death or MI in both patients with CCS (HR 0.83, 95% CI 0.70 to 0.98, p &lt;0.001) and ACS (HR 0.83, 95% CI 0.75 to 0.92, p &lt;0.001) (p-interaction=0.931). This benefit was mainly driven by a similar reduction in the risk of MI (p-interaction=0.898) for both subsets (HR_CCS 0.80, 95% CI 0.65 to 0.97; HR_ACS 0.79, 95% CI 0.70 to 0.89). In CCS and ACS, we found a time-dependent treatment effect, with the benefit from DES accumulating during 1-year follow-up, without offsetting effects after that. In conclusion, patients with CCS were slightly underrepresented in comparative clinical trials. Still, they benefited similarly to patients with ACS from new-generation DES instead of BMS with a sustained reduction of cardiac death or MI because of lower event rates within 1 year.

Association between selective serotonin reuptake inhibitor and risk of peripheral artery disease in diabetes mellitus: Propensity score matching and landmark analysis.

An increasing number of studies have demonstrated the bidirectional hemostatic effect of selective serotonin reuptake inhibitors (SSRIs) on the risk of cerebrovascular and cardiovascular diseases. However, no previous study has focused on the relationship between SSRI and the risk of peripheral artery disease (PAD) in diabetes mellitus (DM). We sought to evaluate the association between SSRIs and the PAD risk in individuals with DM.We conducted a retrospective, population-based cohort study using data from the Longitudinal Health Insurance Database from 1999 to 2010 in Taiwan. A total of 5049 DM patients were included and divided into 2 groups: DM with SSRI users and DM with SSRI non-users. Propensity score matching and 1-year landmark analysis were used for our study design. Stratified Cox proportional hazard regressions were used to analyze the hazard ratio of the PAD risk in certain subgroups.DM with SSRI users did not affect the PAD risk compared to DM with SSRI non-users. These findings were consistent with all sensitivity analyses (i.e., age, sex, SSRI doses, antithrombotic medication use, and medical and psychiatric comorbidities).In this study, we found that there was no significant difference of PAD risk between DM with SSRI users and DM with SSRI non-users. DM with SSRI user did not affect PAD risk across any SSRI dose, age, sex, antithrombotic medications, and multiple comorbidities in the subgroup analysis.