Empagliflozin cost-effectiveness analysis in Japanese heart failure with mildly reduced and preserved ejection fraction.

AIMS: Empagliflozin, a sodium-glucose co-transporter 2 inhibitor, was shown to be effective in patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial. The present study aims to evaluate the cost-effectiveness of empagliflozin among Japanese patients with HFpEF. METHODS AND RESULTS: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin added to standard of care (SoC) compared with SoC alone in patients with HFpEF from the perspective of the Japanese healthcare system and with a lifetime horizon. In addition to clinical events, the progression of disease severity was modelled based on the migration of Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (KCCQ-CSS). Model inputs, including risk of clinical events, costs, and utilities/disutilities, were derived from EMPEROR-Preserved trial data, a claims database and published literature. The generalizability of model results was investigated by applying various subgroups including age, body mass index (BMI), and region Asia, based on the subgroup analysis of EMPEROR-Preserved data. In the base-case analysis, empagliflozin yielded additional quality-adjusted life years (QALYs; 0.11) with an incremental cost of $1408 per patient for Japanese patients with HFpEF. Incremental cost, mainly derived from drug acquisition cost ($1963 per patient), was largely offset by reduced cost in hospitalization for heart failure (HHF) and cardiovascular death (-$537 per patient and -$166 per patient, respectively). Treatment of empagliflozin provided incremental 0.11 QALYs and 0.08 life years compared with SoC alone. The incremental cost-effectiveness ratio (ICER) was $12 772 (¥1 662 689)/QALY, which was below the Japanese willingness-to-pay (WTP) threshold of $38 408 (¥5 000 000)/QALY. The results were consistent across all the subgroups considered, and empagliflozin was dominant over SoC alone in the region Asia and BMI < 25 kg/m2 subgroups. ICERs for the remaining subgroups ranged from $7520/QALY (¥978 972/QALY, patients with baseline age ≥ 75 years) to $31 049/QALY (¥4 041 896/QALY, patients with baseline New York Heart Association class III/IV). Deterministic sensitivity analysis result showed that the treatment effect on HHF is the biggest driver of the cost-effectiveness analysis, while the ICER will be still under the threshold even if no effect of empagliflozin on HHF was assumed. The probabilistic sensitivity analysis result showed that 64% of simulations were cost-effective based on the Japanese WTP threshold. CONCLUSIONS: Empagliflozin was demonstrated to be cost-effective for patients with HFpEF in Japan based on EMPEROR-Preserved trial data.

Cost-effectiveness analysis of empagliflozin in patients with heart failure with reduced ejection fraction in Japan based on the EMPEROR-Reduced trial.

BACKGROUND: Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan. METHODS: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database. RESULTS: The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of -¥166,160/patient (-$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY). CONCLUSIONS: Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data.

Primary Percutaneous Coronary Intervention in Elderly Patients With Acute Myocardial Infarction　- An Analysis From a Japanese Nationwide Claim-Based Database.

BACKGROUND: Primary percutaneous coronary intervention (pPCI) is strongly recommended by guidelines for patients presenting with acute myocardial infarction (AMI), but its applications in elderly patients are less clear.Methods and Results:The JROAD-DPC is a Japanese nationwide registry for patients with cardiovascular diseases combined with an administrative claim-based database. Among 2,369,165 records from 2012 to 2015, data for 115,407 AMI patients were extracted for this study. Elderly patients (≥75 years) comprised 45,645 subjects (39.6%), and received pPCI less frequently (62.2%) than younger patients (79.2%, P<0.001). Clinical variables such as higher age, female sex, higher Killip class, and renal dysfunction, but not functional status on admission, were predictors of non-application of pPCI. Endpoint 30-day mortality increased with aging, and was significantly higher in elderly patients (10.7%) than in younger patients (3.8%, P<0.001). Indeed, pPCI was independently associated with lower 30-day mortality only in subgroups of patients aged ≥60 years. Propensity score-matching analysis confirmed a similar reduction in endpoint 30-day mortality with pPCI in elderly patients. Duration of hospitalization was significantly shorter and functional ability on discharge was significantly better in elderly patients who underwent pPCI. CONCLUSIONS: Elderly patients with AMI underwent pPCI less frequently, but it was consistently associated with better clinical outcome in these patients. Our findings support the proactive application of pPCI for elderly AMI patients when they are eligible for an invasive strategy.

Hospitalization Costs for Patients With Acute Congestive Heart Failure in Japan.

BACKGROUND: With aging of the population, the economic burden associated with heart failure (HF) is expected to increase. However, little is known about the hospitalization costs associated with HF in Japan. Methods and Results: In this cross-sectional study, using data from The Japanese Registry of All Cardiac and Vascular Diseases (JROAD) and JROAD-Diagnosis Procedure Combination databases between 2012 and 2014, we evaluated hospitalization costs for acute cardiovascular diseases (CVDs), including HF. A total of $1,187 million/year (44% of the hospitalization costs for acute CVDs) was spent on patients with HF. We identified 273,865 patients with HF and the median cost per patient was $8,089 ($5,362-12,787) per episode. The top 1% of spenders accounted for 8% ($80 million/year), and the top 5% of spenders accounted for 22% ($229 million/year) of the entire cost associated with HF. The costs associated with HF for patients over 75 years of age accounted for 68% of the total cost. CONCLUSIONS: The costs associated with HF were higher than the hospitalization cost for any other acute CVD in Japan. Understanding how the total hospitalization cost is distributed may allow health providers to utilize limited resources more effectively for patients with HF.

Effect of intravenous carperitide versus nitrates as first-line vasodilators on in-hospital outcomes in hospitalized patients with acute heart failure: Insight from a nationwide claim-based database.

BACKGROUNDS: Carperitide is a recombinantly produced intravenous formulation of human atrial natriuretic peptide. Despite of negative impacts of nesiritide on clinical outcomes for acute heart failure (AHF), carperitide has been used for around a half of Japanese AHF patients as a vasodilator based on limited evidences. We sought to determine the effect of carperitide compared to nitrates in the early care for AHF patients treated with vasodilators. METHODS AND RESULTS: We conducted a cohort study of patients admitted with AHF to 808 hospitals from April 2012 to March 2014. Patients were extracted from 1,422,703 hospitalizations according to ICD-10 heart failure codes. Patients who had sepsis or mechanical supports during hospitalization were excluded. Outcomes were in-hospital death, length of hospitalization and cost of hospitalization. Among 76,924 patients, 45,595 were in patients treated with either carperitide or nitrates during the first 2 days (carperitide; 33,386, nitrates; 12,209). After application of inverse probability of treatment weighting with variables including demographics, comorbidities and treatments, there was perfect balance in both groups. Patients who were treated with carperitide had substantially higher covariate adjusted in-hospital mortality (HR 1.49 95%CI 1.35-1.64), longer length of hospitalization (Coefficients 0.062 95%CI 0.048 to 0.076) and greater cost of hospitalization (Coefficients 0.024 95%CI 0.010 to 0.037) compared to those treated with nitrates. CONCLUSIONS: In Japanese AHF patients during their early inpatient care, carperitide use was significantly associated with worse outcomes when compared to nitrates use, suggesting the routine use of carperitide might not be recommended as a first-line vasodilator for AHF.

Assessment of Coronary Flow Velocity Reserve in the Left Main Trunk Using Phase-contrast MR Imaging at 3T: Comparison with 15O-labeled Water Positron Emission Tomography.

PURPOSE: The aim of this study was to verify coronary flow velocity reserve (CFVR) on the left main trunk (LMT) in comparison with myocardial flow reserve (MFR) by 15O-labeled water positron emission tomography (PET) (MFR-PET) in both the healthy adults and the patients with coronary artery disease (CAD), and to evaluate the feasibility of CFVR to detect CAD. METHODS: Eighteen healthy adults and 13 patients with CAD were evaluated. CFVR in LMT was estimated by 3T magnetic resonance imaging (MRI) with phase contrast technique. MFR-PET in the LMT territory including anterior descending artery and circumflex artery was calculated as the ratio of myocardial blood flow (MBF)-PET at stress to MBF-PET at rest. RESULTS: There was a significant positive relationship between CFVR and MFR-PET (R = 0.45, P < 0.0001). Inter-observer calculations of CFVR showed good correlation (R2 = 0.93, P < 0.0001). The CFVR in patients with CAD was significantly lower than that in healthy adults (1.90 ± 0.61 vs. 2.77 ± 1.03, respectively, P = 0.01), which were similar to the results of MFR-PET (2.23 ± 0.84 vs. 3.96 ± 1.04, respectively, P < 0.0001). For the detection of patients with CAD, the area under the curve was 0.78 (P = 0.01). The sensitivity was 0.77 and specificity was 0.72 when a cut-off of 2.15 was used. CONCLUSION: CFVR by 3T was validated with MFR-PET. CFVR could detect the patients with CAD. This method is a simple and reliable index without radiation or contrast material.

The Current Status of Cardiovascular Medicine in Japan　- Analysis of a Large Number of Health Records From a Nationwide Claim-Based Database, JROAD-DPC.

BACKGROUND: Since cardiovascular disease accounts for one-quarter of deaths in the Japanese population, we developed a nationwide database using the administrative case-mix Diagnostic Procedure Combination (DPC) system (ie, theJapaneseRegistryOfAll cardiac and vascularDiseases (JROAD)-DPC) to reveal the current status of cardiovascular medicine in Japan.Methods and Results:The JROAD-DPC database included 704,593 health records' data of 2012 from 610 certificated hospitals of the Japanese Circulation Society. The 35,824 patients with acute myocardial infarction (AMI) and 108,665 patients with heart failure (HF) were admitted to hospitals. Increased hospital case volume was associated with reduced in-hospital mortality rates for both AMI and HF (P for trend <0.001). Although there was little variation among AMI patients in terms of aspirin use at discharge (median prescription rate, 83.0%; interquartile range [IQR], 76.9-88.0%), there were wide variations in the proportions of patients prescribed ß-blockers (BB) and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin-receptor blockers (ARB) at discharge (BB, 41.4%, IQR 27.6-55.7%; ACEI/ARB, 52.0%, IQR 40.3-62.3%). In patients with HF, there were between-hospital variations in medications at discharge (BB, 38.1%, IQR, 27.8-47.6%; ACEI/ARB, 41.0%, IQR 31.7-49.1%). CONCLUSIONS: A nationwide administrative database of patients with cardiovascular diseases (JROAD-DPC) provided useful information that will contribute to improved quality of medical care, especially in the aging society of Japan, where HF has become an important health problem. (Circ J 2016; 80: 2327-2335).

Assessment of quality of life during long-term treatment of tolvaptan in refractory heart failure: design and rationale of the AQUA-TLV study.

The vasopressin type 2 receptor antagonist tolvaptan (TLV) has recently become available to treat congestion in in-hospital patients with heart failure (HF). However, there is no evidence confirming the long-term efficacy of TLV. The Assessment of Quality of life during long-term treatment of TLV in refractory heart failure (AQUA-TLV) study is a multicenter, open-labeled, randomized, controlled clinical trial that will enroll 100 patients from 18 hospitals in Japan. Patients with HF assigned to New York Heart Association class III or IV, who had a previous history of hospitalization due to congestive HF during the past 1 year and ongoing symptomatic congestion with baseline urine osmolality > 350 mOsm/L regardless of being prescribed daily furosemide ≥ 60 mg are randomized to the conventional diuretics group (50 patients) and TLV add-on group (50 patients), and their quality of life will be assessed using the Minnesota Living with Heart Failure Questionnaire after 6 months of treatment. This study is the first multicenter prospective randomized study in Japan to evaluate the long-term clinical effectiveness of TLV compared with conventional treatment in patients with congestive HF (UMIN Clinical Trial Registry Number: UMIN 000009604).

Clinical efficacy of cardiac resynchronization therapy with an implantable defibrillator in a Japanese population: results of the MIRACLE-ICD outcome measured in Japanese indication (MOMIJI) study.

BACKGROUND: Cardiac resynchronization therapy (CRT) is effective in reducing morbidity and mortality in systolic heart failure patients with cardiac dyssynchrony as demonstrated in studies with primarily Western populations. Although CRT devices with a defibrillator (CRT-D) became available in Japan since 2006, their efficacy remains uncertain in Japanese patients. In this prospective, multicenter study, the efficacy of CRT-D therapy in an all-Japanese population was compared with the study conducted in the US, Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE-ICD). METHODS AND RESULTS: Ninety-three patients were evaluated according to the subject selection criteria of the MIRACLE-ICD study, and 80 patients were enrolled. Results at baseline and 6-month post-CRT-D implantation were compared in terms of composite clinical response (CCR) and other secondary endpoints. Quality of life (QOL) was assessed with a validated Japanese version of the Minnesota Living with Heart Failure questionnaire. CCR was improved in 55 patients (68.8%), unchanged in 14 (17.5%), and worsened in 11 patients (13.7%) (MIRACLE-ICD general phase: 62.0%, 13.4% and 24.6%, respectively). Non-inferiority was verified by 1-sided test with 10% equivalence margin. QOL score improved significantly (50.0±26.2 vs. 23.6±20.2, P<0.01). CONCLUSIONS: The MOMIJI study demonstrated that CRT-D effectiveness as assessed with CCR was non-inferior to the trials conducted outside Japan, thus suggesting that the benefits of CRT-D are similar between Japanese and non-Japanese patients.

Myocardial oxidative metabolism is increased due to haemodynamic overload in patients with aortic valve stenosis: assessment using 11C-acetate positron emission tomography.

PURPOSE: The relationship between myocardial oxidative metabolism and pressure overload in aortic valve stenosis (AS) is not fully elucidated. We identified the determinants of myocardial oxidative metabolism by measuring its changes after aortic valve replacement (AVR) in patients with AS. METHODS: Myocardial 11C-acetate clearance rate constant (Kmono), an index of oxidative metabolism, was measured non-invasively by using positron emission tomography in 16 patients with moderate to severe AS and 7 healthy controls. The severity of AS was assessed by echocardiography. Of 16 patients, 5 were reexamined at 1 month after AVR. RESULTS: Kmono was significantly higher in patients with AS than healthy controls by 42% (0.068±0.014 vs 0.048±0.007/min, p<0.01). Kmono was significantly correlated with age (r=0.58, p<0.01), left ventricular (LV) mass index (r=0.61, p<0.01) and estimated systolic LV pressure (r=0.81, p<0.001) measured by echocardiography. By multivariate analysis, estimated LV systolic pressure was an independent predictor of Kmono (ß=0.93, p<0.01). After AVR, Kmono (from 0.075±0.012 to 0.061±0.014/min, p=0.043) and LV mass index (from 183±49 to 124±41 g/ml2, p=0.043) were significantly decreased despite no significant changes in rate-pressure product. CONCLUSION: Myocardial oxygen metabolism was increased in patients with AS, which was decreased after AVR. The increased myocardial oxidative metabolism in AS was largely attributable to the pressure overload of the LV.