Relationship Between Left Ventricular Ejection Fraction and Treatment Characteristics in Hospitalized Patients With Heart Failure　- A Japanese Database Analysis.

Background: Triple combination therapy with a renin-angiotensin system modulator, a ß-blocker, and a mineralocorticoid receptor antagonist is currently recommended for patients with heart failure (HF) with reduced ejection fraction. However, there is limited evidence on the extent to which triple combination therapy is currently prescribed to patients at the time of discharge from hospital in Japan. Methods and Results: Japanese patients hospitalized for HF (n=3,582) were evaluated in subgroups defined by left ventricular ejection fraction (LVEF) using anonymized claims and electronic health record data. At discharge, triple combination therapy prescription rates were low (40.4%, 30.0%, 20.8%, 14.0%, and 12.5% for patients with LVEF <30%, 30-<40%, 40-<50%, 50-<60%, and ≥60%, respectively). Advanced age, lower levels of B-type natriuretic peptide, and renal impairment were all significantly associated with lower rates of triple combination therapy use in the overall population. There were no significant differences in rehospitalization rates between LVEF subgroups; however, triple combination therapy use was associated with a significantly reduced risk of rehospitalization for HF in patients with LVEF <30%, 30-<40%, and 40-<50%. Conclusions: The use of triple combination therapy was significantly associated with a lower risk of rehospitalization for HF within 1 year of discharge in patients with LVEF <30%, 30-<40%, and 40-<50%. However, patients were undertreated with triple combination therapy.

Achievement Rates for Low-Density Lipoprotein Cholesterol Goals in Patients at High Risk of Atherosclerotic Cardiovascular Disease in a Real-World Setting in Japan.

AIMS: The study aimed to investigate low-density lipoprotein cholesterol (LDL-C) goal achievement rates in patients receiving LDL-C-lowering therapy using recent real-world data, following the 2017 revision of the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases (JAS GL2017). METHODS: Patients with documented LDL-C test results were extracted from the Medical Data Vision claims database between July 2018 and June 2021 and divided into three groups according to JAS GL2017: primary prevention high risk (Group I, LDL-C goal ＜120 mg/dL), secondary prevention (Group II, LDL-C goal ＜100 mg/dL), and secondary prevention high risk (Group III, LDL-C goal ＜70 mg/dL). RESULTS: The mean LDL-C value was 108.7 mg/dL (n=125,235), 94.4 mg/dL (n=57,910), and 90.6 mg/dL (n=33,850) in Groups I, II, and III, respectively. Intensive statin monotherapy (pitavastatin, rosuvastatin, or atorvastatin) was the most frequently prescribed lipid-lowering treatment (21.6%, 30.8%, and 42.7% in Groups I, II, and III, respectively), followed by ezetimibe (2.5%, 7.1%, and 8.5% in Groups I, II, and III, respectively). LDL-C goals were achieved by 65.5%, 60.6%, and 25.4% of patients overall in Groups I, II, and III, respectively. Achievement rates were 83.9%, 75.3%, and 29.5% in patients prescribed intensive statin monotherapy and 82.3%, 86.4%, and 46.4% in those prescribed statin and ezetimibe combinations in Groups I, II, and III, respectively. In Group III, the proportion of patients with familial hypercholesterolemia prescribed statin and ezetimibe combinations achieving LDL-C goals was low (32.5%). CONCLUSIONS: The proportion of patients achieving LDL-C goals for secondary prevention in the high-risk group remains low even with statin and ezetimibe combination therapy.

Burden of Repeated Hospitalizations on Patients with Heart Failure: An Analysis of Administrative and Claims Data in Japan.

BACKGROUND: Repeated hospitalization is a predictor of outcomes in heart failure, indicating the presence of symptoms, a deteriorated condition at pre-admission, and worsened prognosis. OBJECTIVES: The current database study aimed to understand the clinical and economic burden of repeated hospitalizations among patients with heart failure in Japan. The effect of repeated hospitalizations on the subsequent in-hospital mortality was the primary objective; economic burden of heart failure after discharge was investigated as a secondary outcome. METHODS: Between 2013 and 2018, administrative claims and discharge summary data of patients aged ≥ 20 years and diagnosed with heart failure were obtained from a Diagnosis Procedure Combination database maintained by Medical Data Vision. Hospitalization, mortality, and economic burden data were analyzed. RESULTS: This study included 49,094 patients. The mean length of the first hospital stay was 22.9 days. The in-hospital mortality rate was approximately 10%, with one to five repeated hospitalizations. The time interval between repeated hospitalizations for heart failure decreased with an increasing number of hospitalizations. In-hospital mortality did not increase even with an increasing number of hospitalizations. The mean heart failure-related healthcare cost per patient was ¥564,281 ± 990,447 (US$5178 ± 9,088), 67.3% of which was hospitalization costs. Among hospitalization costs, other costs were high, mainly for basic hospitalization fees (71.7%; ¥233,146/person-year). CONCLUSIONS: Repeated hospitalization did not increase in-hospital mortality; however, it may shorten the intervals between heart failure-related hospitalizations, potentially caused by deterioration of the patient's condition, and increase the clinical and economic burden on patients.

Characterizing the role of, and physical and emotional burden on caregivers of patients with heart failure: Results from a cross-sectional survey in Japan.

The aim of this cross-sectional survey was to characterize the role of and burden on caregivers of heart failure (HF) patients in Japan, since such data are limited at present. Data from 126 caregivers whose average age was 63.5 years were analyzed. Helping to prepare meals/cooking was the most frequently reported activity (47% of caregivers); 24% found this the most burdensome. The most frequently reported physical consequence of caregiving was feeling physically tired (44%); emotionally worrying about the patient (62%) was the most frequent psychological consequence. Approximately half of the caregivers reported that caring for patients impacted their lifestyle. Although 40% of caregivers asked questions to physicians regarding diet or lifestyle modifications, 19% did not ask any. Caregivers play a crucial role in the management of HF patients in Japan but experience physical and emotional burden. Solutions are required to reduce the caregiver burden associated with HF.

In-hospital resource utilization, worsening heart failure, and factors associated with length of hospital stay in patients with hospitalized heart failure: A Japanese database cohort study.

BACKGROUND: Our objective was to characterize cases of hospitalized heart failure (HHF) focusing on in-hospital resource utilization (particularly furosemide doses) and worsening heart failure (WHF), and identify which factors are associated with the length of stay (LOS). METHODS: Cases of HHF (≥20 years), excluding those undergoing surgical procedures and in-hospital deaths, were retrieved from the Japanese Diagnosis Procedure Combination database (April 2012 to March 2016). WHF was defined using eight components, including up-titration of intravenous drugs and non-pharmacological management. RESULTS: The mean age of 78,953 cases of HHF was 79 years and 51% were male. The median LOS was 17 days. The maximum daily dose and cumulative dose of furosemide (mean ± standard deviation) were 43.3 ± 56.0 mg and 215.6 ± 450.6 mg, respectively, for intravenous furosemide, and 44.0 ± 37.3 mg and 523.3 ± 675.4 mg, respectively, for oral furosemide. The incidence of WHF was 36.1% during hospitalization and 19.3% from 6th hospital day to discharge. The mean number of WHF components was 1.4 ± 0.7 during hospitalization and 1.3 ± 0.6 from 6th hospital day. Regression analyses showed that the number of WHF components from 6th hospital day, pneumonia, and hyponatremia were strongly associated with longer LOS. CONCLUSIONS: These findings in patients with HHF could be vital to focus future efforts to improve the therapeutic strategies for heart failure.

Burden of Heart Failure on Patient Daily Life and Patient-Physician Discordance in Disease Management　- Results From a Cross-Sectional Survey in Japan.

Background: We investigated the impact of heart failure (HF) on daily life and satisfaction with current HF medication from the patient perspective in a real-world study in Japan. Methods and Results: A cross-sectional survey of 154 HF patients treated by 58 cardiologists was conducted in Japan using patient self-completed questionnaires about their daily life and satisfaction with HF medication, as well as patient record forms completed by their physicians capturing corresponding data. The mean age of patients was 72.7 years. The proportion of patients within New York Heart Association Class I, II, III, and IV was 39%, 44%, 16%, and 1%, respectively. Symptoms reported by patients included dyspnea when active (46%), nocturia (43%), anxiety (18%), and depression (6%). There was a discordance between physician- and patient-reported symptoms, especially for nocturia and inability to sleep. The most frequent lifestyle recommendation from physicians was 'reduce salt/sodium intake', but only 51% of patients receiving this recommendation followed the advice. In all, 44% of patients reported dissatisfaction with their current medication; according to the patients, 27% reported no discussion with their physicians about their prescribed medication, while physicians reported the opposite. Conclusions: HF negatively impacts patient daily life. There is discordance between patients and physicians in symptom reporting, lifestyle modification advice and adherence, and reported medication decision making. Gaps in patient-physician communication exist.

Discovery of a Novel Piperidine-Based Inhibitor of Cholesteryl Ester Transfer Protein (CETP) That Retains Activity in Hypertriglyceridemic Plasma.

Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.

Insulin down-regulates specific activity of ATP-binding cassette transporter A1 for high density lipoprotein biogenesis through its specific phosphorylation.

Insulin resistance/hyperinsulinism is one of the major risks for atherosclerotic vascular diseases and low HDL may be involved in pathogenesis. We examined direct effects of insulin on HDL biosynthesis focusing on the activity of ATP-binding cassette transporter A1 (ABCA1) in culture cells and in experimental animals. Insulin impairs HDL biosynthesis through modulation of ABCA1 activity by two different mechanisms. Insulin enhances degradation of ABCA1. However, even after this effect was cancelled by blocking its specific signal, insulin still reduces HDL biogenesis. This effect was found due to phosphorylation of ABCA1 that leads to decrease of its specific activity. We identified a novel insulin-specific phosphorylation site Tyr1206 of ABCA1 to regulate its specific activity. The observation in a rat model of insulin resistance was consistent with these results. The findings demonstrate a new mechanism for regulation of ABCA1 activity and provide new insights into the link between development of atherosclerosis, and insulin resistance/hyperinsulinism.

Synthesis and structure-activity relationship of novel RXR antagonists: orally active anti-diabetic and anti-obesity agents.

A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.

Synthesis and structure-activity relationship of RXR antagonists based on the diazepinylbenzoic acid structure.

Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.

HMG-CoA reductase inhibitor, fluvastatin, has cholesterol-lowering independent "direct" effects on atherosclerotic vessels in high cholesterol diet-fed rabbits.

Recent clinical studies suggest that some of the beneficial effects of 3-hydroxy-3-metylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the incidence of myocardial infarctions and ischemic strokes may be through their non-cholesterol-lowering "direct" effects on atherosclerotic vessels. We designed this study to test the hypothesis that fluvastatin inhibits atheroma formation and increase plaque stability independent of cholesterol-lowering effects. Rabbits were fed 0.5% high-cholesterol diet for 12 weeks (progression phase) and then fed the high-cholesterol diet either containing or not containing fluvastatin 2mg/kg per day for additional 8 weeks (treatment phase). Rabbits fed normal diet were used as control. Plasma total and LDL-cholesterol concentrations did not differ during the treatment phase of the experiment. Atherosclerotic changes (plaque formation, lipid- and macrophage-rich intimal thickening, the increase in MCP-1, IL-8, TNF-alpha, IL-1beta, M-CSF, MMP-1, MMP-9, MMP-12, and ACE mRNA expression, and the increase in plasma MCP-1 levels) were observed in the high-cholesterol diet group (HC). All of these changes were less in the fluvastatin-treated group (HC+Flu) than in HC. There was no significant difference in aortic collagen (type I and type IV) mRNA expression between groups. Furthermore, fluvastatin increased the extracellular matrix content (collagen) and vascular smooth muscle cell composition in the atherosclerotic lesion, leading to the increase in plaque stability score (collagen+smooth muscle cell area)/(macrophage+lipid deposition area) in HC+Flu. Fluvastatin not only reduced atherogenesis but also to stabilized vulnerable atheromatous plaques in atherosclerotic rabbits, presumably through the macrophage recruitment and activation in the aortic lesion, at a low dose without cholesterol-lowering effects.

Preservation of endothelial function by the HMG-CoA reductase inhibitor fluvastatin through its lipid-lowering independent antioxidant properties in atherosclerotic rabbits.

Recent evidence suggests that the beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on entothelial function and cardiovascular ischemic events may be attributed not only to their lipid-lowering effects but also to cholesterol-lowering independent (direct) effects on the atherosclerotic vessel wall. This study was designed to test the hypothesis that fluvastatin (Flu) preserves the endothelial function by its cholesterol-lowering independent actions. Rabbits were fed a 0.5% high-cholesterol (HC) diet for 12 weeks (progression phase) and then fed the HC diet either containing or not containing Flu 2 mg/kg/day for an additional 8 weeks (treatment phase). Rabbits fed a normal diet were used as controls. Plasma total and low-density lipoprotein cholesterol concentrations did not differ during the treatment phase: Endothelium-dependent/NO-mediated relaxation (acetylcholine and A23187) was impaired in the HC diet group, whereas it was preserved in the HC plus Flu treatment group. The endothelium-independent relaxation (sodium nitroprusside) was similar between the three groups. Interestingly, aortic oxidative stress (lipid peroxides and isoprostane F(2alpha)-III contents) and NADPH oxidase component (p22phox and gp91phox) mRNA expression were increased in the HC group but not in the HC plus Flu group. The A23187-induced nitric oxide production from the aorta was increased in both HC and HC plus Flu groups. There was no significant difference in tissue endothelial-type nitric oxide synthase mRNA expression. Plaque area and intimal thickening of the aorta were significantly lowered in the HC plus Flu group. Flu treatment preserved the endothelial function associated with the decrease in markers of oxidative stress in this experiment. These beneficial endothelial effects of Flu are likely to occur independently of plasma lipid concentrations and to be mediated by its antioxidant action.

Preservation of endothelium-dependent and Nomega-nitro-L-arginine methyl ester- and indomethacin-resistant arterial relaxation in high-cholesterol-diet fed rabbits by treatment with fluvastatin, an HMG-CoA reductase inhibitor.

This study was designed to test the hypothesis that fluvastatin preserves endothelium-dependent and nitric oxide (NO)-independent relaxations in arterial preparations from rabbits fed a high-cholesterol diet in the absence of any cholesterol-lowering action. Rabbits were fed a 0.5% high-cholesterol diet for 12 weeks and then fed the high-cholesterol diet with/without fluvastatin 2 mg/kg/d for an additional 8 weeks. Plasma total and LDL-cholesterol concentrations were not affected by fluvastatin treatment. Endothelium-dependent and NO-mediated relaxation elicited by acetylcholine and A23187 in both the thoracic aorta and femoral artery was impaired in the high-cholesterol group but not in the fluvastatin-treated group. Endothelium-independent relaxation elicited by sodium nitroprusside was similar among the 3 groups. Preincubation of thoracic aortas from each of the 3 groups with Nomega-nitro-L-arginine methyl ester (L-NAME) and indomethacin completely abolished the relaxant response to acetylcholine. In contrast, the maximal response to acetylcholine (1 microM) in femoral artery was only partially reversed in the presence of L-NAME and indomethacin. Fluvastatin treatment preserved the acetylcholine-induced L-NAME and indomethacin-resistant relaxation impaired in the femoral artery from the high-cholesterol diet group. These results suggest that fluvastatin treatment preserves endothelium-dependent, NO-independent function as well as NO-dependent function in absence of its lipid lowering-action.

Antioxidative potential of fluvastatin via the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity.

We previously reported that fluvastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, a strong lipid lowering drug, exerted an anti-atherosclerotic effect at doses insufficient to lower serum lipids in cholesterol fed rabbits. The evidence demonstrated that the superoxide anions from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase plays a critical role in several steps in the development of atherosclerosis. This study was designed to determine the effects of HMG-CoA reductase inhibitors on the production of the superoxide anions of NADPH oxidase in isolated rat peritoneal neutrophils. Fluvastatin (1-10 microM) decreased phorbol 12-myristate 13-acetate (PMA, 10 nM)-dependent reactive oxygen species (ROS) generation in a concentration-dependent manner. It also (10 microM) decreased PMA-dependent O(2) consumption of the rat neutrophils. These effects were reversed by the addition of mevalonate, a metabolite in the HMG-CoA reductase pathway. Treatment with pravastatin did not show any significant changes. Fluvastatin (10 microM) decreased ROS, such as hydroxyl radicals and superoxide anions generated by the Fenton reaction, and by the xanthine-xanthine oxidase system. Rats were treated with either fluvastatin (5 mg/kg per day, p.o.) or pravastatin (5 mg/kg per day, p.o.) for 1 week. Treatment with fluvastatin decreased the PMA-dependent ROS generation. The fluvastatin induced effect on the PMA-dependent ROS generation was reversed by the combined administration with 40 mg/kg mevalonate per day. The antioxidative effect of fluvastatin was thought to have caused not only the scavenging action of the radicals but also to have inhibited ROS generation by inhibiting the NADPH oxidase activity. This antioxidative potential of fluvastatin via the inhibition of NADPH oxidase activity may be profitable in preventing atherosclerosis.

[Preclinical and clinical profile of Valsartan, a selective angiotensin II type-1 receptor blocker].

Valsartan (Diovan) is a potent, orally active, specific, and highly selective blocker for the AT1-receptor subtype. The antihypertensive effects of oral treatment with valsartan were preclinically demonstrated in the sodium-depleted marmosets, renal hypertensive rats (2K1C), spontaneous hypertensive rats (SHR) and stroke-prone SHR. Moreover, valsartan had protective effects against hypertensive end-organ damage such as cardiac hypertrophy and renal disease. In an investigation of pharmacokinetics and pharmacodynamics in normotensive male volunteers, valsartan was rapidly absorbed with the maximal plasma concentration occurring 2-3 h after oral administration. The elimination half-life was about 4-6 h, valsartan was poorly metabolized, and most of the drug was excreted via feces. Valsartan produced persistent reductions of blood pressure in patients with mild to moderate essential hypertension and had a good safety profile with a wide therapeutic window between the effective pharmacological doses and the toxic doses. Therefore, valsartan is expected to be a safe and effective antihypertensive agent for the treatment of essential and severe hypertension.

Dipeptidyl peptidase IV inhibition improves impaired glucose tolerance in high-fat diet-fed rats: study using a Fischer 344 rat substrain deficient in its enzyme activity.

This study was performed to determine the effects of a high-fat diet on glucose metabolism after an oral glucose challenge in high-fat diet-fed dipeptidyl peptidase IV (DPP-IV) positive (+) and deficient (-) Fischer 344 (F344) rats and the effects of novel DPP-IV inhibitor NVP-DPP728 (1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in high-fat diet-fed F344 rats. In DPP-IV(+) rats, a high-fat diet load caused impaired glucose tolerance, such as increases of plasma insulin and blood glucose concentrations after oral glucose challenge, compared with a standard chow-fed group. In contrast, no marked change in glucose tolerance was induced by the high-fat diet in DPP-IV(-) rats. Blood glucose concentrations in DPP-IV(-) rats after glucose challenge were significantly lower than in DPP-IV(+) rats under high-fat diet load conditions. In standard chow and high-fat diet-fed DPP-IV(+) rats, NVP-DPP728 significantly suppressed glucose excursions after glucose challenge by inhibiting the plasma DPP-IV activity, associated with the stimulation of early insulin secretion. NVP-DPP728 did not affect glucose tolerance in DPP-IV(-) rats under both conditions. These results indicate that the amelioration of glucose tolerance by NVP-DPP728 in DPP-IV(+) rats was directly due to the inhibition of plasma DPP-IV activity, which might be via the subsequent increase in endogenous incretin action.

Dipeptidyl peptidase IV inhibitor NVP-DPP728 ameliorates early insulin response and glucose tolerance in aged rats but not in aged Fischer 344 rats lacking its enzyme activity.

The aim of this study was to investigate the effects of aging on glucose metabolism after oral glucose challenge in aged dipeptidyl peptidase IV (DPP-IV) positive (+) Fischer 344 (F344), DPP-IV deficient (-) F344 and DPP-IV(+) Wistar rats and to determine the effect of a DPP-IV inhibitor NVP-DPP728 (1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine monohydrochloride salt) on glucose tolerance in aged rats. Aging caused a decrease in early insulin response after an oral glucose challenge in aged Wistar or DPP-IV(+) F344 rats, but not in aged DPP-IV(-) F344 rats, compared with young control groups. Glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats was better than in aged DPP-IV(+) F344 and Wistar rats associated with the preservation of the early insulin response. NVP-DPP728 improved the glucose tolerance after an oral glucose challenge by potentiating the early insulin response throughout the inhibition of plasma DPP-IV activity in aged DPP-IV(+) Wistar and F344 rats. In contrast, NVP-DPP728 did not affect the glucose tolerance after an oral glucose challenge in aged DPP-IV(-) F344 rats. These results indicate that treatment with NVP-DPP728 ameliorated glucose tolerance in aged rats by the direct inhibition of plasma DPP-IV activity and presumably the subsequent increase in endogenous incretin action.