Eligibility and Cost-Utility Analysis of Dapagliflozin in Patients with Heart Failure Across the Whole Spectrum of Ejection Fraction in South Korea.

BACKGROUND: The DAPA-HF and DELIVER trials demonstrated the clinical benefits of dapagliflozin in heart failure (HF) patients across the entire ejection fraction (EF) spectrum. However, further investigation is needed for the real-world application of dapagliflozin in HF patients. This study examines the proportion of real-world HF patients eligible for dapagliflozin and evaluates the cost-effectiveness of adding dapagliflozin to current HF therapy. METHODS: Data from the nationwide prospective registry, the Korean Acute Heart Failure (KorAHF) registry, were used to determine dapagliflozin eligibility based on the enrollment criteria of the DAPA-HF/DELIVER trials. A cost-utility analysis was conducted using a Markov model to assess the cost-effectiveness of dapagliflozin by comparing it to the standard of care. RESULTS: Out of 5178 KorAHF patients, 48.7% met the enrollment criteria of the DAPA-HF/DELIVER trials, while 89.5% met the label criteria (US Food and Drug Administration, European Medicines Agency, and Korean Ministry of Food and Drug Safety). Eligibility was highest among HF patients with preserved EF (55.3% vs. HF with mildly reduced EF and HF with reduced EF 46.4%). Dapagliflozin proved to be cost-effective, with an incremental cost-effectiveness ratio (ICER) of 4557 US dollar (US$) per quality-adjusted life year, which falls below the US$18,182 willingness-to-pay threshold. The cost-effectiveness benefit was more pronounced in patients with a left ventricular EF (LVEF) ≤ 40% (ICER US$3279 for LVEF ≤ 40% vs. US$8383 for LVEF > 40%). CONCLUSIONS: Discrepancies in dapagliflozin eligibility were observed between real-world data and clinical trial results. The addition of dapagliflozin to HF therapy proved to be highly cost-effective across the entire EF spectrum.

Real-World Eligibility and Cost-Effectiveness Analysis of Empagliflozin for Heart Failure in Korea.

BACKGROUND: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved empagliflozin for reducing cardiovascular mortality and heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). However, limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and potential cost-effectiveness based on a nationwide prospective HF registry. METHODS: A total of 3,108 HFrEF and 2,070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analyzed. Eligibility was estimated by inclusion and exclusion criteria of EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trials and by FDA & EMA label criteria. The cost-utility analysis was done using a Markov model to project the lifetime medical cost and quality-adjusted life year (QALY). RESULTS: Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The incremental cost-effectiveness ratio of empagliflozin was calculated at US$6,764 per QALY in the overall population, which is far below a threshold of US$18,182 per QALY. The cost-effectiveness benefit was more evident in patients with HFrEF (US$5,012 per QALY) than HFpEF (US$8,971 per QALY). CONCLUSION: There is a large discrepancy in real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. Empagliflozin is cost-effective in HF patients regardless of ejection fraction in South Korea health care setting. The efficacy and safety of empagliflozin in real-world HF patients should be further investigated for a broader range of clinical applications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01389843.

Comparative efficacy of vericiguat to sacubitril/valsartan for patients with heart failure reduced ejection fraction: Systematic review and network meta-analysis.

BACKGROUND: Despite the established efficacy of vericiguat compared to placebo, uncertainties remain regarding its comparative efficacy to sacubitril/valsartan for patients with heart failure reduced ejection fraction (HFrEF). This study aimed to assess the relative efficacy of vericiguat and sacubitril/valsartan through a systematic review, network meta-analysis, and non-inferiority tests. METHODS: A systematic review was conducted to identify the randomized phase 3 clinical trials involving vericiguat and sacubitril/valsartan. The hazard ratios (HRs) with 95% confidence intervals (CI) for cardiovascular death (CVD) and hospitalization due to HF (hHF) were extracted from these trials and synthesized via network meta-analysis. Non-inferiority testing of vericiguat was performed using a fixed-margin method with a predefined non-inferiority margin (1.24). Sensitivity analyses explored the impact of the time from hHF to screening. RESULTS: Among the 1366 studies, two trials (VICTORIA and PARADIGM-HF) met the inclusion criteria. Network meta-analysis demonstrated that the HR for CVD or hHF with vericiguat did not significantly differ from that for sacubitril/valsartan (HR: 0.88, 95% CI:0.62-1.23). The upper limit of the 95% CI was less than the predefined margin of 1.24, confirming vericiguat's non-inferiority to sacubitril/valsartan. Sensitivity analyses affirmed the robustness of the base-case results. CONCLUSION: Vericiguat exhibited a comparable risk of CVD or hHF when contrasted with sacubitril/valsartan. Importantly, in patients with HFrEF, vericiguat's efficacy was not statistically inferior to that of sacubitril/valsartan. These findings reinforce the potential of vericiguat as a viable treatment option for this patient population.

Systematic Review of the Economic Evaluation of Sodium-Glucose Cotransporter-2 Inhibitors Used as Treatment in Patients with Heart Failure.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been recently used as therapeutic agents for type 2 diabetes mellitus. Recent clinical trials have shown that they are beneficial for reducing the risk of cardiovascular mortality and hospitalization in patients with heart failure (HF). A comprehensive review regarding the cost-effectiveness of different SGLT2 inhibitors for HF treatment may be necessary to help clinicians and decision-makers select the most cost-effective HF treatment option. OBJECTIVE: This study conducted a systematic review of economic evaluation studies of SGLT2 inhibitors for the treatment of patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). METHOD: We searched PubMed, Cochrane, Embase, and EBSCOhost to identify published economic evaluation studies on SGLT2 inhibitors for HF treatment until May 2023. Studies on the economic evaluation of SGLT2 inhibitors in the treatment of HF were included. We extracted information such as country, population, intervention, type of model, health status, and conclusion of cost-effectiveness. RESULT: Of the 410 studies, 27 were finally selected. All economic evaluation studies used the Markov model, and commonly included health status as stable HF, hospitalization due to HF, and death. All dapagliflozin studies focused on patients with HFrEF (n = 13), and dapagliflozin was cost-effective in 14 countries, but not in the Philippines. All empagliflozin studies focused on the patients with HFrEF also showed the cost-effectiveness of empagliflozin (n = 11). However, empagliflozin use in patients with HFpEF was determined to be cost-effective in studies in Finland, China, and Australia studies but not in studies in Thailand and the USA. CONCLUSIONS: Most of the studies reported the cost-effectiveness of dapagliflozin and empagliflozin in patients with HFrEF. However, the cost-effectiveness of empagliflozin differed from country to country regarding patients with HFpEF. We suggest that further economic evaluation of SGLT2 inhibitors should focus on patients with HFpEF in more countries.

CEACAM1 Marks Highly Suppressive Intratumoral Regulatory T Cells for Targeted Depletion Therapy.

PURPOSE: Regulatory T cells (Tregs) exert immunosuppressive functions and hamper antitumor immune responses in the tumor microenvironment. Understanding the heterogeneity of intratumoral Tregs, and how it changes with tumor progression, will provide clues regarding novel target molecules of Treg-directed therapies. EXPERIMENTAL DESIGN: From 42 patients with renal cell carcinoma and 5 patients with ovarian cancer, immune cells from tumor and peripheral blood were isolated. We performed multicolor flow cytometry and RNA-sequencing to characterize the phenotypes and heterogeneity of intratumoral Tregs. In vitro functional assays were performed to evaluate suppressive capacity of Tregs and effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1)-mediated depletion. The CT26 tumor model was used to evaluate the association between intratumoral Tregs and tumor growth, and examine the in vivo role of CEACAM1+ intratumoral Tregs on antitumor immunity. RESULTS: We found that CEACAM1 was selectively expressed on intratumoral Tregs, whereas its expression on peripheral Tregs or other immune cells was low. The CEACAM1+ intratumoral Tregs accumulated with tumor progression, whereas the CEACAM1- subset did not. Notably, we found that CEACAM1 marked intratumoral Tregs that exhibited highly suppressive and activated phenotypes with substantial clonal expansion. Depletion of CEACAM1-expressing cells from tumor-infiltrating leukocytes led to increased effector functions of tumor-infiltrating T cells. Moreover, CEACAM1+ cell depletion further enhanced anti-PD-1-mediated reinvigoration of exhausted CD8+ T cells. CONCLUSIONS: CEACAM1 marks highly suppressive subset of intratumoral Tregs, and can be a target for selective depletion of intratumoral Tregs. These results may inform future studies on CEACAM1-mediated depletion in patients with cancer.

CD39+ tissue-resident memory CD8+ T cells with a clonal overlap across compartments mediate antitumor immunity in breast cancer.

Despite being a standard treatment option in breast cancer, immune checkpoint inhibitors (ICIs) are only efficacious for a subset of patients. To gain a better understanding of the antitumor immune response in breast cancer, we examined the heterogeneity of CD8+ T cells in tumors, metastatic lymph nodes (mLNs), and peripheral blood from patients with early breast cancer (n = 131). Among tissue-resident memory CD8+ T (TRM) cells, including virus- and tumor-specific CD8+ T cells, CD39 expression was observed in a tumor-specific and exhausted subpopulation in both tumors and mLNs. CD39+ TRM cells from tumors and mLNs exhibited a phenotypic similarity and clonally overlapped with each other. Moreover, tumor or mLN CD39+ TRM cells clonally overlapped with CD39- TRM and non-TRM cells in the same compartment, implying a tissue-specific differentiation process. These inter-subpopulationally overlapping CD39+ TRM clonotypes were frequently detected among effector memory CD8+ T cells in peripheral blood, suggesting a systemic clonal overlap. CD39+ TRM cell enrichment was heterogeneous among molecular subtypes of breast cancer, which is associated with the different role of antitumor immune responses in each subtype. In vitro blockade of PD-1 and/or CTLA-4 effectively restored proliferation of CD39+ TRM cells and enhanced cytokine production by CD8+ T cells from tumors or mLNs, particularly in the presence of CD39+ TRM enrichment. This suggests that CD39+ TRM cells have a capacity for functional restoration upon ICI treatment. Thus, our study indicates that CD39+ TRM cells with a clonal overlap across compartments are key players in antitumor immunity in breast cancer.

A dose-response relationship of renin-angiotensin system blockers and beta-blockers in patients with acute heart failure syndrome: a nationwide prospective cohort study.

AIMS: It remains unclear if patients with acute heart failure syndrome (AHFS) need to reach the maximally tolerated doses of renin-angiotensin system blockers (RASBs) or beta-blockers (BBs) to obtain a survival benefit. This study evaluated the dose-response relationship between RASBs or BBs and survival in AHFS patients. METHODS AND RESULTS: In total, 5331 patients in the Korean Acute Heart Failure registry were analysed based on the doses of RASBs and BBs at discharge. In AHFS patients, RASB use at discharge was associated with a significant reduction in all-cause mortality risk. This effect was dose-dependent for heart failure with reduced ejection fraction (HFrEF) but did not attain statistical significance for heart failure with preserved ejection fraction (HFpEF). BB use at discharge was associated with reduced all-cause mortality in HFrEF patients but not in HFpEF patients. In an additional analysis of 4613 patients with dosage information at the first post-discharge follow-up visit, a significantly higher mortality risk was associated with the maintenance or withdrawal of RASBs compared with up-titrating the dose in HFrEF patients. CONCLUSION: Using RASBs or BBs at discharge was associated with improved survival. A dose-response relationship between RASBs and all-cause mortality was evident in AHFS patients with a reduced ejection fraction but not BBs. It is important to initiate and up-titrate RASBs to the maximally tolerated dose in AHFS patients during the transition period, especially for patients with a reduced ejection fraction.

Tumour-infiltrating bystander CD8+ T cells activated by IL-15 contribute to tumour control in non-small cell lung cancer.

BACKGROUND: Tumour-unrelated, virus-specific bystander CD8+ T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet. METHODS: We studied the characteristics of bystander CD8+ TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy. RESULTS: We show that bystander CD8+ TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8+ TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8+ TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8+ TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment. CONCLUSION: Thus, the study demonstrates that bystander CD8+ TILs can be repurposed by IL-15 for tumour immunotherapy.

Abnormality in the NK-cell population is prolonged in severe COVID-19 patients.

BACKGROUND: Our understanding of adaptive immune responses in patients with coronavirus disease 2019 (COVID-19) is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is still insufficient. OBJECTIVE: We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19. METHODS: We performed RNA sequencing and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved PBMCs. RESULTS: In RNA-sequencing analysis, the NK cells exhibited distinctive features compared with healthy donors, with significant enrichment of proinflammatory cytokine-mediated signaling pathways. Intriguingly, we found that the unconventional CD56dimCD16neg NK-cell population expanded in cryopreserved PBMCs from patients with COVID-19 regardless of disease severity, accompanied by decreased NK-cell cytotoxicity. The NK-cell population was rapidly normalized alongside the disappearance of unconventional CD56dimCD16neg NK cells and the recovery of NK-cell cytotoxicity in patients with mild COVID-19, but this occurred slowly in patients with severe COVID-19. CONCLUSIONS: The current longitudinal study provides a deep understanding of the NK-cell biology in COVID-19.

4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+ CD8 T cells from primary and metastatic sites of epithelial ovarian cancers.

BACKGROUND: Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer. METHODS: Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays. RESULTS: We found that CD39+ CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39+ CD8 TILs with high PD-1 expression (PD-1high) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1high CD39+ CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39+ CD8 TILs, especially on PD-1high cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites. CONCLUSION: Severely exhausted PD-1high CD39+ CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers.

Hollow and microporous triphenylamine networks post-modified with TCNE for enhanced organocathode performance.

Hollow microporous triphenylamine networks (H-MTPN) were post-modified with tetracyanoethylene (TCNE) to generate tetracyanobutadiene moieties in H-MTPN-TCNE. The H-MTPN-TCNE showed the improved electrochemical performance of cathode materials for lithium ion batteries, compared to the original H-MTPN.