Enhancing Coronary Intervention Outcomes Using Intravascular Ultrasound: Analysis of Long-Term Benefits in a Japanese Multicenter Registry.

Background: Although the use of intravascular ultrasound (IVUS) during percutaneous coronary intervention (PCI) has been shown to improve clinical outcomes, its utilization remains inconsistent. We aimed to assess the association between IVUS-guided PCI and long-term outcomes in Japan, where a high proportion of patients undergo IVUS. Methods: We analyzed 8721 consecutive patients in a multicenter PCI registry. The primary outcome was a composite of death, acute coronary syndrome, and heart failure requiring admission and coronary artery bypass grafting at 2 years after discharge. The secondary outcome was each component of the primary outcome. We used inverse probability-weighted analysis for adjustment. Subgroup analysis was conducted on patients with complex coronary anatomy (eg, those with bifurcation, chronic total occlusion, type C lesion, left main and those who underwent rotational atherectomy). Results: Overall, 83.8% of patients underwent IVUS-guided PCI (mean age, 68.3 ± 11.3 years). After adjustments, the IVUS group had significantly lower rates of death and coronary bypass compared to no IVUS group (hazard ratio [HR], 0.73; 95% CI, 0.55-0.96; and HR, 0.62; 95% CI, 0.39-0.98) at 2-year follow-up, although the primary outcome showed only marginal differences (HR, 0.85; 95% CI, 0.71-1.01). In the subgroup analysis of complex coronary anatomy, the use of IVUS was significantly associated with a reduced risk of the primary outcome (HR, 0.72; 95% CI, 0.55-0.93) as well as death, coronary bypass, and heart failure. Conclusions: IVUS was frequently utilized in our registry and demonstrated potential benefit in reducing mortality and need for coronary bypass surgery, particularly in patients with complex coronary anatomy.

Low-Dose Prasugrel vs. Standard-Dose Clopidogrel for Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Low-dose prasugrel (3.75 mg) is used as maintenance therapy for percutaneous coronary intervention; however, data on long-term outcomes are scarce.Methods and Results: We analyzed 5,392 participants in the KiCS-PCI registry who were administered low-dose prasugrel or clopidogrel at discharge between 2008 and 2018 and for whom 2-year follow-up data were available. We adjusted for confounders using matching weight analyses and multiple imputations. Similarly, we used inverse probability- and propensity score-weighted analyses. We also performed instrumental variable analyses. The primary outcomes were acute coronary syndrome (ACS) and bleeding requiring readmission. Secondary outcomes were all-cause death and a composite outcome of ACS, bleeding, heart failure, stroke, coronary bypass requiring admission, and all-cause death. In this cohort, 12.2% of patients were discharged with low-dose prasugrel. Compared with clopidogrel, low-dose prasugrel was associated with a reduced risk of ACS (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.39-0.85), bleeding (HR 0.62; 95% CI 0.40-0.97), and the composite outcome (HR 0.71; 95% CI 0.59-0.86). Inverse probability-weighted analysis yielded similar results; however, matching weight analysis without multiple imputations and propensity score-matched analyses showed similar outcomes in both groups. Instrumental variable analyses showed reduced risks of ACS and composite outcome for those on low-dose prasugrel. All-cause mortality did not differ in all analyses. CONCLUSIONS: Low-dose prasugrel demonstrates comparable outcomes to clopidogrel in terms of ACS and bleeding.

Association of door-to-balloon time and one-year outcomes in hospital survivors of ST-elevation myocardial infarction.

In this study of 19,824 ST-elevated myocardial infarction (STEMI) patients from the J-PCI OUTCOME registry (January 1, 2017, to December 31, 2018), we investigated the association between door-to-balloon time (DTB) and 1-year post-discharge cardiovascular outcomes. Patients with DTB >90 min were older and had higher comorbidities. The incidence of 1-year major adverse cardiovascular events (MACE) showed an incremental increase: 3.7 %, 4.8 %, and 7.7 % for DTB ≤60, DTB 60-90, and DTB >90 groups, respectively. Adjusted hazard ratios (aHR) compared to the DTB 60-90 group were 0.83 (DTB ≤60, p = 0.03) and 1.25 (DTB >90, p = 0.005). Subgroup analysis revealed higher risk for MACE in DTB >90 group for patients aged <70, men, no history of coronary revascularization, and those with cardiac arrest or cardiogenic shock. Conversely, DTB ≤60 group without previous history had a lower MACE risk (aHR 0.80, p = 0.02). This study, the largest of its kind, demonstrates that a DTB below 90 min is associated with lower 1-year MACE risk, supporting current guidelines, and indicating additional benefits for specific patient subgroups, especially those experiencing their first acute coronary event. The findings suggest the importance of early intervention in primary prevention and emphasize the need for prompt detection of vulnerable plaque.

State-of-the-art percutaneous coronary intervention for left main coronary artery disease in Japan.

Percutaneous coronary intervention for left main coronary artery disease (LM-PCI) represents a high-risk yet life-saving procedure that has evolved significantly over the years. This review outlines the current state-of-the-art practices for LM-PCI in Japan in detail, emphasizing the integration of coronary physiology and intracoronary imaging alongside with evidence-based standardized technique using latest drug-eluting stents. These advancements enable precise lesion assessment, stent sizing, and optimal deployment, thereby enhancing procedural safety and efficacy. Despite discrepancies between current guidelines favoring coronary artery bypass grafting and real-world practice trends towards increased LM-PCI adoption, particularly in elderly populations with multiple comorbidities, careful patient selection and procedural planning are critical. Future perspectives include further refining LM-PCI through conducting randomized controlled trials integrating advanced techniques and addressing the issue of ostial left circumflex lesions and nationwide standardization of medical care for LM disease.

Effects of Transradial Access on In-Hospital Outcomes in Percutaneous Coronary Intervention for Coronary Artery Bypass Graft: Insights from the Japanese Nationwide Database.

Because of its superior safety profile and improved outcomes, trans-radial percutaneous coronary intervention (TRI) has become the preferred access in percutaneous coronary intervention (PCI) of native coronary disease. This study investigated the impact of TRI on in-hospital outcomes after PCI for coronary artery bypass graft vessels (GV-PCI). We analyzed patients who underwent GV-PCI in 2019-2022 from the Japanese nationwide registry. Patients were categorized into the TRI and trans-femoral PCI (TFI) groups. We assessed the association between TRI and in-hospital outcomes. The primary outcome was a composite of in-hospital death and major bleeding. In this study, 2,295 patients were analyzed.. The primary outcomes occurred in 29 patients (1.3%), including 17 deaths (0.7%). Major bleeding occurred in 12 patients (0.5%), and access site bleeding in 7 patients (0.3%). The TRI group (n = 1,521) showed lower crude rates of the primary outcome (0.9% vs 1.9%, p = 0.039), major bleeding (0.3% vs 1.0%, p = 0.027), and access site bleeding (0.1% vs 0.6%, p = 0.047) compared with the TFI group (n = 774). Univariable logistic regression demonstrated a significant association of TRI with reduced primary outcome (odd ratio [OR] 0.47, 95% confidence interval [CI] 0.22 to 0.98), major bleeding (OR 0.25, 95% CI 0.07 to 0.80), and access site bleeding (OR 0.20, 95% CI 0.03 to 0.94). In the multivariable analysis, TRI was still significantly associated with a decrease in major bleeding events (OR 0.29, 95% CI 0.07 to 0.93). In conclusion, the use of TRI was associated with a reduction in bleeding events when referenced to TFI in the context of GV-PCI.

Primary Prevention of Coronary and Other Cardiovascular Diseases: A Focused Review.

In 2022, the Japan Atherosclerosis Society (JAS) updated its prevention guidelines, the "Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022" (JAS2022GL), expanding its scope from coronary artery disease (CAD) to atherosclerotic cardiovascular diseases (ASCVDs), including atherothrombotic stroke. The following year, the Japanese Circulation Society (JCS) updated its guidelines for primary prevention entitled "JCS 2023 Guideline on the Primary Prevention of Coronary Artery Disease" (JCS2023GL). Since those publications, scientific advancements in relevant fields have continued. This review article outlines the current recommendations provided by the guidelines, provides background information supporting these recommendations, introduces scientific findings subsequent to prior publications, and discusses future directions on select topics for the primary prevention of CVD. The topics covered in this review are traditional risk factors, including dyslipidemia and hypertension, the application of comprehensive risk stratification or risk scoring systems, patient-specific topics, salt and alcohol, and environmental factors. These topics were deliberate and selected by the authors, who were involved in the compilation of either or both JAS2022GL and JCS2023GL. This review not only emphasizes the pivotal role of continuously updated guidelines in shaping clinical practice but also stresses the urgent need for ongoing research to bridge existing knowledge and practice gaps.

Impact of intravascular ultrasound-guided endovascular therapy on periprocedural outcomes in patients with lower-extremity artery disease.

BACKGROUND: Although technological improvements in intravascular ultrasound (IVUS) may reduce technical failures in endovascular therapy (EVT), perioperative complications (POCs) associated with IVUS use may increase. AIMS: This study investigated the impact of IVUS on periprocedural outcomes in symptomatic lower-extremity artery disease (LEAD) patients undergoing EVT. METHODS: This study evaluated 28,088 symptomatic LEAD patients who underwent EVT between January 2021 and December 2021 using a prospective nationwide registry in Japan. Outcome measures included periprocedural outcomes, including technical failure and POCs. To compare outcomes with and without IVUS use, propensity score matching analysis was performed for overall and for each arterial region (aortoiliac [AI], femoropopliteal [FP], and infrapopliteal [IP] arteries) using a binary logistic regression model. RESULTS: IVUS was used in 75%, 72%, and 37% of AI, FP, and IP lesions, respectively. After propensity matching extraction, the IVUS group had a tendency of lower technical failure rate than the non-IVUS group, although not statistically different (3.9% vs. 5.4%, p = 0.054), without an increase in the POC rate (1.8% vs. 1.6%, p = 0.54). Regarding the per-regional analysis, the technical failure rate of FP-EVT was significantly lower in the IVUS group (3.1% vs. 4.2%, p = 0.006), whereas those of AI-EVT (2.2% vs. 3.1%, p = 0.12) and IP-EVT (6.8% vs. 6.1%, p = 0.37) were not significantly different between the two groups. Furthermore, IVUS did not increase the POC rate for any region (AI-EVT: 1.3% vs. 1.3%, p = 1.00; FP-EVT: 1.8% vs. 1.7%, p = 0.75; and IP-EVT: 2.0% vs. 1.7%, p = 0.56). CONCLUSION: The current study revealed that IVUS did not increase the POCs and technical failure for overall lesions but reduced the incidence of FP-EVT technical failure.

Supra-normal and mildly reduced ejection fraction in women -An overlooked vulnerable subpopulation in heart failure.

BACKGROUND: Recently, patients with supra-normal left ventricular ejection fraction (snEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. METHODS: The multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3943 patients (age 77 years; 40.1% female) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF. The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. RESULTS: In HFmrEF, implementation of guideline-directed medical therapy (GDMT) such as the combination of renin-angiotensin-system inhibitor (RASi) and ß-blocker at discharge was significantly lower in women than men even after adjustment for covariates (p = 0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint showing higher event rate in HFmrEF and HFsnEF in women, but such relationship was not observed in men (p for interaction = 0.037). CONCLUSIONS: In women, mrEF and snEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for further exploration, which might lead to creation of sex-specific guidelines to optimize HF management.

Renin-angiotensin system inhibitors for patients with mild or moderate chronic kidney disease and heart failure with mildly reduced or preserved ejection fraction.

BACKGROUND: Renin-angiotensin system inhibitors (RASI) reduce adverse cardiovascular events in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤40% and mild or moderate chronic kidney disease (CKD). However, RASI administration rate and its association with long-term outcomes in patients with CKD complicated by HF with LVEF >40% remain unclear. METHODS: We analyzed 1923 consecutive patients with LVEF >40% registered within the multicenter database for hospitalized HF. We assessed RASI administration rate and its association with all-cause mortality among patients with mild or moderate CKD (estimated glomerular filtration rate [eGFR]: 30-60 mL/min/1.73 m2). Exploratory subgroups included patients grouped by age (<80, ≥80 years), sex, previous HF hospitalization, B-type natriuretic peptide (higher, lower than median), eGFR (30-44, 45-59 mL/min/1.73 m2), systolic blood pressure (<120, ≥120 mmHg), LVEF (41-49, ≥50%), and mineralocorticoid receptor antagonists (MRA) use. RESULTS: Among patients with LVEF >40%, 980 (51.0%) had mild or moderate CKD (age: 81 [74-86] years; male, 52.6%; hypertension, 69.7%; diabetes, 25.9%), and 370 (37.8%) did not receive RASI. RASI use was associated with hypertension, absence of atrial fibrillation, and MRA use. After multivariable adjustments, RASI use was independently associated with lower all-cause mortality over a 2-year median follow-up (hazard ratio: 0.58, 95% confidence interval: 0.43-0.79, P = 0.001), and the mortality rate difference was predominantly due to cardiac death, consistent in all subgroups. CONCLUSIONS: Approximately one-third of HF patients with mild or moderate CKD and LVEF >40% were discharged without RASI administration and demonstrated relatively guarded outcomes.

Cardiac arrest and post-discharge mortality in patients with myocardial infarction: A large-scale nationwide registry analysis.

Background: Cardiac arrest is a serious complication of acute myocardial infarction. The implementation of contemporary approaches to acute myocardial infarction management, including urgent revascularization procedures, has led to significant improvements in short-term outcomes. However, the extent of post-discharge mortality in patients experiencing cardiac arrest during acute myocardial infarction remains uncertain. This study aimed to determine the post-discharge outcomes of patients with cardiac arrest. Methods: We analysed data from the J-PCI OUTCOME registry, a Japanese prospectively planed, observational, multicentre, national registry of percutaneous coronary intervention involving consecutive patients from 172 institutions who underwent percutaneous coronary intervention and were discharged. Patients who underwent percutaneous coronary intervention for acute myocardial infarction between January 2017 and December 2018 and survived for 30 days were included. Mortality in patients with and without cardiac arrest from 30 days to 1 year after percutaneous coronary intervention for acute myocardial infarction was compared. Results: Of the 26,909 patients who survived for 30 days after percutaneous coronary intervention for acute myocardial infarction, 1,567 (5.8%) had cardiac arrest at the onset of acute myocardial infarction. Patients with cardiac arrest were younger and more likely to be males than patients without cardiac arrest. The 1-year all-cause mortality was significantly higher in patients with cardiac arrest than in those without (11.9% vs. 2.8%, p < 0.001) for all age groups. Multivariable analysis showed that cardiac arrest was an independent predictor of all-cause long-term mortality (hazard ratio: 2.94; 95% confidence interval: 2.29-3.76). Conclusions: Patients with acute myocardial infarction and concomitant cardiac arrest have a worse prognosis for up to 1 year after percutaneous coronary intervention than patients without cardiac arrest.

Benchmarking System Monitoring on Quality Improvement in Percutaneous Coronary Intervention: A Nationwide Registry in Japan.

Background: Quality indicators (QIs) have been developed to improve and standardize care quality in percutaneous coronary intervention (PCI). In Japan, consecutive PCI procedures are registered in a nationwide database (the Japanese Percutaneous Coronary Intervention registry), which introduces a benchmarking system for comparing individual institutional performance against the national average. Objectives: The aim of this study was to assess the impact of the benchmarking system implementation on QI improvement at the hospital level. Methods: A total of 734,264 PCIs were conducted at 1,194 institutions between January 2019 and December 2021. In January 2018, a web-based benchmarking system encompassing 7 QIs for PCI at the institutional level, including door-to-balloon time and rate of transradial intervention, was introduced. The process by which institutions tracked their QIs was centrally monitored. Results: During the 3-year study period, the benchmarking system was reviewed at least once at 742 institutions (62.1%) (median 4 times; Q1-Q3: 2-7 times). The institutions that reviewed their records had higher PCI volumes. Among these institutions, although door-to-balloon time was not directly associated, the proportion of transradial intervention increased by 2.3% in the system review group during the initial year compared with 0.7% in their counterparts. However, in the subsequent year, the association between system reviews and QI improvement was attenuated. Conclusions: The implementation of a benchmarking system, reviewed by participating institutions in Japan, was partially associated with improved QIs during the first year; however, this improvement was attenuated in the subsequent year, highlighting the need for further efforts to develop effective and sustainable interventions to enhance care quality in PCI.

Impact of Sex Differences on Clinical Outcomes in Patients Following Primary Revascularization for Acute Myocardial Infarction　- Insights From the Japanese Nationwide Registry.

BACKGROUND: Women with acute myocardial infarction (AMI) often present a worse risk profile and experience a higher rate of in-hospital mortality than men. However, sex differences in post-discharge prognoses remain inadequately investigated. We examined the impact of sex on 1-year post-discharge outcomes in patients with AMI undergoing percutaneous coronary intervention. METHODS AND RESULTS: We extracted patient-level data for the period January 2017-December 2018 from the J-PCI OUTCOME Registry, endorsed by the Japanese Association of Cardiovascular Intervention and Therapeutics. One-year all-cause and cardiovascular mortality and major adverse cardiovascular events were compared between men and women. In all, 29,856 AMI patients were studied, with 6,996 (23.4%) being women. Women were significantly older and had a higher prevalence of comorbidities than men. Crude all-cause mortality was significantly higher among women than men (7.5% vs. 5.4% [P<0.001] for ST-elevation myocardial infarction [STEMI]; 7.0% vs. 5.2% [P=0.006] for non-STEMI). These sex-related differences in post-discharge outcomes were attenuated after stratification by age. Multivariate analysis demonstrated an increase in all-cause mortality in both sexes with increasing age and advanced-stage chronic kidney disease (CKD). CONCLUSIONS: Within this nationwide cohort, women had worse clinical outcomes following AMI than men. However, these sex-related differences in outcomes diminished after adjusting for age. In addition, CKD was significantly associated with all-cause mortality in both sexes.

Predictors and incidence of health status deterioration in patients with early atrial fibrillation.

BACKGROUND: Various treatment approaches for atrial fibrillation (AF) have demonstrated improved health status, yet the significance of these therapeutic interventions in individual patients remains unclear. OBJECTIVE: This study aimed to evaluate health status changes in patients with early AF, focusing on those who experience clinically significant deterioration after treatment initiation. METHODS: We analyzed data from a multicenter, prospective registry of newly diagnosed patients with AF. One-year changes in health status across different treatment strategies were assessed by the Atrial Fibrillation Effect on QualiTy-of-life Overall Summary (AFEQT-OS) score. Clinically relevant deterioration and improvement in health status were defined as ≥5-point decrease and increase in AFEQT-OS score, respectively; no change was -5 to 5 points. RESULTS: Overall, 1960 patients with AF were evaluated. Mean AFEQT-OS scores at baseline and 1-year follow-up were 76.7 ± 17.7 and 85.4 ± 14.8, respectively. Although most patients (53.9%) experienced clinically important improvement, a considerable proportion had no change (28.7%) or deterioration (17.4%) in their health status. Proportions of patients with no change or deterioration varied by treatment strategy: 59.9%, 53.9%, and 32.0% in rate control, antiarrhythmic drug, and catheter ablation groups, respectively. The multivariable model identified older age, female sex, heart failure, coronary artery disease, and higher baseline AFEQT-OS score as independent predictors of worsening health status, regardless of treatment strategy. CONCLUSION: Many patients with early AF experience worsening or no change in health status irrespective of treatment strategy. Standardizing patients' health status assessment, especially for patients with comorbidities, may aid in patients' selection and their outcomes.

Physician Estimates and Patient-Reported Health Status in Atrial Fibrillation.

Importance: A primary objective in managing atrial fibrillation (AF) is to optimize patients' health status, which can be done only if physicians accurately quantify the outcomes associated with AF in patients' lives. Objective: To explore physicians' estimation of the health status of patients with AF and its association with subsequent care and outcomes. Design, Setting, and Participants: A multicenter, prospective cohort study was conducted in 2 outpatient practices in Tokyo, Japan. Participants included patients with newly diagnosed AF or those referred for initial treatment of AF at outpatient practices and treating physicians from November 8, 2018, to April 1, 2020. Data analysis was performed from December 22, 2022, to July 7, 2023. Exposures: Participating patients completed the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire, a 20-item tool covering 4 domains with a 7-point Likert scale; 3 domains (symptoms, daily activities, and treatment concerns) were used in this study. Blinded to patients' responses, treating physicians answered a 3-item questionnaire quantifying each patient's AFEQT domain with a single item. Patients' mean Likert scale responses within each AFEQT domain were subtracted from the physicians' assessments so that higher scores (≥0.5 points) indicate physician underestimation, while lower scores (≤0.5 points) indicate physician overestimation of the health status of patients with AF. Main Outcomes and Measures: The independent association of physician-patient concordance with treatment escalation (alteration or initiation of antiarrhythmic drugs, cardioversion, or catheter ablation) and 1-year adjusted changes in AFEQT scores. Results: Among 330 patients (238 [72.1%] men; mean [SD] age, 67.9 [11.9] years; 163 [49.4%] with paroxysmal AF), physicians correctly estimated health status in 112 patients (33.9%), underestimated it in 42 patients (12.7%), and overestimated it in 176 patients (53.3%). Treatment escalation occurred in 63.6% of patients whose health status was correctly estimated, 47.6% of those whose health status was underestimated, and 66.3% of patients whose health status was overestimated. After multivariable adjustment, underestimation of health status was independently associated with less treatment escalation (adjusted odds ratio, 0.43; 95% CI, 0.20-0.90) and less frequent AFEQT overall summary score improvement at 1 year (underestimated, 2.5 [95% CI, -1.6 to 6.7] vs correctly and overestimated health status, 8.4 [95% CI, 7.0-9.9] points; P = .01). Conclusions and Relevance: In this cohort study, physician underestimation of the health status of patients with AF was common and associated with less aggressive treatment and less health status improvement at 1 year.

Clinical Features of 544 Patients With Ruptured Aortic Aneurysm　- A Report From the Tokyo Acute Aortic Super Network Database.

BACKGROUND: Epidemiological data on ruptured aortic aneurysms from large-scale studies are scarce. The aims of this study were to: clarify the clinical course of ruptured aortic aneurysms; identify aneurysm site-specific therapies and outcomes; and determine the clinical course of patients receiving conservative therapy.Methods and Results: Using the Tokyo Acute Aortic Super Network database, we retrospectively analyzed 544 patients (mean [±SD] age 78±10 years; 70% male) with ruptured non-dissecting aortic aneurysms (AAs) after excluding those with impending rupture. Patient characteristics, status on admission, therapeutic strategy, and outcomes were evaluated. Shock or pulselessness on admission were observed in 45% of all patients. Conservative therapy, endovascular therapy (EVT), and open surgery (OS) accounted for 32%, 23%, and 42% of cases, respectively, with corresponding mortality rates of 93%, 30%, and 29%. The overall in-hospital mortality rate was 50%. The prevalence of pulselessness was highest (48%) in the ruptured ascending AA group, and in-hospital mortality was the highest (70%) in the ruptured thoracoabdominal AA group. Multivariable logistic regression analysis indicated in-hospital mortality was positively associated with pulselessness (odds ratio [OR] 10.12; 95% confidence interval [CI] 4.09-25.07), and negatively associated with invasive therapy (EVT and OS; OR 0.11; 95% CI 0.06-0.20). CONCLUSIONS: The outcomes of ruptured AAs remain poor; emergency invasive therapy is essential to save lives, although it remains challenging to reduce the risk of death.

Rationale and protocol of the LAQUA-HF trial: a factorial randomised controlled trial evaluating the effects of neurohormonal and diuretic agents on health-status reported outcomes in heart failure patients.

INTRODUCTION: The current guidelines strongly recommend early initiation of multiple classes of cardioprotective drugs for patients with heart failure with reduced ejection fraction to improve prognosis and health status. However, evidence on the optimal sequencing of approved drugs is scarce, highlighting the importance of individualised treatment plans. Registry data indicate that only a portion of these patients can tolerate all four recommended classes, underscoring the need to establish the favoured sequence when using these drugs. Additionally, the choice between long-acting and short-acting loop diuretics in the present era remains uncertain. This is particularly relevant given the frequent use of angiotensin receptor-neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitor, both of which potentiate natriuretic effects. METHODS AND ANALYSIS: In a prospective, randomised, open-label, blinded endpoint method, LAQUA-HF (Long-acting vs short-acting diuretics and neurohormonal Agents on patients' QUAlity-of-life in Heart Failure patients) will be a 2×2 factorial design, with a total of 240 patients randomised to sacubitril/valsartan versus dapagliflozin and torsemide versus furosemide in a 1:1 ratio. Most enrolment sites have participated in an ongoing observational registry for consecutive patients hospitalised for heart failure involved dedicated study coordinators, and used the same framework to enrol patients. The primary endpoint is the change in patients' health status over 6 months, defined by the Kansas City Cardiomyopathy Questionnaire. Additionally, clinical benefit at 6 months defined as a hierarchical composite endpoint will be assessed by the win ratio as the secondary endpoint. ETHICS AND DISSEMINATION: The medical ethics committee Keio University in Japan has approved this trial. All participants provide written informed consent prior to study entry. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses. TRIAL REGISTRATION NUMBER: UMIN000045229.