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BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.
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BACKGROUND & AIMS: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage. METHODS: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients. RESULTS: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality. CONCLUSIONS: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Carcinoma Hepatocelular/patologia , Estudos de Coortes , Estudos Retrospectivos , Neoplasias Hepáticas/patologia , Fígado/patologia , Cirrose Hepática/patologia , BiópsiaRESUMO
AIM: The noninvasive tests (NITs) Agile 3+ and Agile 4 effectively identify patients with nonalcoholic fatty liver disease (NAFLD) complicated with advanced fibrosis (F3-4) and cirrhosis (F4), respectively. Little information is available on associations between Agile scores and intra-/extrahepatic events. The aim of this study was to determine the predictive performance of Agile scores for intra-/extrahepatic events in Asian patients with biopsy-proven NAFLD. METHODS: We undertook a retrospective multicenter cohort study to investigate associations between intra-/extrahepatic events and two Agile scores, Agile 3+ and Agile 4. The scores were obtained by combining clinical parameters and liver stiffness measurement using transient elastography. RESULTS: Among 403 enrolled patients, 11 had liver-related events (LREs), including seven with hepatocellular carcinoma (HCC). The incidence of LREs and HCC showed a stepwise increase in the advanced fibrosis group (F3-4), Agile 3+ rule-in (F3-4, highly suspected), and Agile 4 rule-in (F4, highly suspected) groups, compared to their counterparts. Hazard ratios for LREs in the advanced fibrosis group, Agile 3+ rule-in, and Agile 4 rule-in groups were 4.05 (p = 0.03), 23.5 (p = 0.003), and 45.5 (p < 0.001), respectively. The predictive performance results for Agile 3+ and Agile 4 were 0.780 and 0.866, respectively, which were higher than for fibrosis (0.595). Unlike for LREs, Agile scores failed to identify patients with extrahepatic events, including cardiovascular events and extrahepatic cancer. CONCLUSIONS: Agile 3+ and Agile 4 scores are excellent NITs for predicting LREs in patients with NAFLD, possibly without histological assessment.
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AIM: Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study. METHODS: One thousand three hundred ninety-eight patients were included in this subanalysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected. RESULTS: During a median follow-up period of 4.6 years (range, 0.3-21.6 years), which corresponds to 8874 person-years, 37 patients developed HCC. Using a cut-off baseline platelet count of 192 × 109/L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; p < 0.001). This cut-off value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192 × 109/L, patients with platelet counts of 100 × 109/L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81-14.2) and an adjusted HR of 11.2 (95% CI, 3.81-32.7; p < 0.001), adjusting for age, sex, NASH, and diabetes. CONCLUSIONS: Baseline platelet counts of 192 × 109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance.
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BACKGROUND AND AIMS: Noninvasive tests (NITs) have prognostic potential, but whether NITs are comparable with liver biopsy is unclear. This study aimed to examine the prognostic accuracy of NITs for liver-related mortality (LRM) and events (LREs) in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). METHODS: We investigated 1313 patients with NAFLD. Patients were assigned to low-risk, indeterminate-risk, and high-risk groups using conventional cutoff values of each FIB-4 and NAFLD fibrosis score (NFS) and to stage 0-2 and stage 3-4 groups using the fibrosis stage. Survival and Cox regression analyses of the prognostic potential of NITs for LRM/LREs were conducted. RESULTS: During a median follow-up of 4.5 years, regarding to FIB-4, the incidence rate (/1000 person-years) in the low risk was zero for LRM and 0.5 for LREs. In contrast, the rate in stage 0-2 was 1.3 for LRM and 2.8 for LRE. The adjusted hazard ratios (aHRs) for LREs in the high risk compared with the low risk were 32.85 (P < 0.01). The aHRs in stage 3-4 compared with stage 0-2 were 2.68 (P = 0.02) for LREs and 2.26 (P = 0.582) for LRM. In the same fibrosis stage, the incidence of LRM/LREs was more frequent with a higher risk stratification. The same trend was observed for NFS. CONCLUSIONS: NITs accurately predict LRM and LREs as well as a liver biopsy in Japanese patients with NAFLD. Patients in the low risk may not require close follow-up for at least 5 years. The simple NITs could be an acceptable alternative method to performing a liver biopsy for the prognosis of NAFLD.
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Clione , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Cirrose Hepática/etiologia , Fígado/patologia , Prognóstico , Biópsia , Índice de Gravidade de DoençaRESUMO
BACKGROUND AND AIMS: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. METHODS: We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. RESULTS: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3-4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2 ). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. CONCLUSIONS: Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.
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Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Teorema de Bayes , Aprendizado de Máquina não Supervisionado , Prognóstico , Fenótipo , Fibrose , Cirrose Hepática/etiologia , Cirrose Hepática/complicações , Biópsia , Índice de Gravidade de Doença , Fígado/patologiaRESUMO
BACKGROUND: Ventricular-arterial coupling (V-A coupling) recently gathers attention from clinicians to evaluate the interaction between afterload and left ventricular systolic function. We aimed to describe the chronological demographics of V-A decoupling in patients with sepsis and septic shock through the clinical course. METHOD: We conducted a single-center prospective observational study comprising adult patients with sepsis and septic shock admitted to the tertiary care hospital between 04/2017 and 03/2019. Patients' characteristics, lab data on admission, and echocardiographic parameters including Ea and Ees on the day- 1, 2, 3, 7, and 14-28 were collected. V-A decoupling was defined as Ea/Ees ≥ 1.36. RESULTS: Seventy-one patients with sepsis or septic shock were enrolled. The prevalence of V-A decoupling was as follows; day-1: 25.4%, day-2: 23.8%, day-3: 13.3%, day-7: 18.5%, day-14-28: 30.3%, respectively. Ea was higher in patients with V-A decoupling than those without throughout the clinical course (day1; 2.8 vs. 1.8, p < 0.01, day2; 2.7 vs. 1.9, p < 0.01, day3; 2.8 vs. 2.1, p = 0.06, day7; 2.7 vs. 1.9, p = 0.02, day14-28; 2.4 vs. 1.8, p = 0.08). This increase in Ea was mainly induced by reduced stroke volume (SV) as well as high systolic blood pressure (SBP) in the earlier course of sepsis but only by increased SBP in the later course of sepsis. Ees was lower in patients with V-A decoupling than those without throughout the clinical course (day1; 1.3 vs. 2.1, p < 0.01, day2; 1.5 vs. 2.3, p < 0.01, day3; 1.6 vs. 2.3, p = 0.02, day7; 1.8 vs. 2.3, p = 0.01, day14-28; 1.2 vs. 1.9, p = 0.07). CONCLUSION: We reported that V-A decoupling was commonly seen in patients with sepsis and septic shock. In patients with V-A decoupling, both Ea and Ees were significantly altered, but the causes of these alterations appeared to be changing over the clinical course of sepsis.
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Sepse , Choque Séptico , Adulto , Humanos , Sepse/complicações , Artérias , Progressão da Doença , DemografiaRESUMO
BACKGROUND AND AIMS: The association between body mass index (BMI) and clinical outcomes of patients with non-valvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs) are controversial, and we thus analyzed the large registry data to elucidate them. METHODS AND RESULTS: We conducted a historical cohort study at 71 centers in Japan and included outpatients with NVAF taking vitamin K antagonists (VKAs). Physicians in charge could change VKAs to direct OACs based on their judgement during follow-up period. We categorized patients into four BMI groups (kg/m2): underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), and obese (30 ≤ BMI). The effects of each BMI group relative to the normal weight group on clinical outcomes consisting of all-cause death, ischemic events, and bleeding events were estimated using Cox proportional hazard models adjusting for potential confounders. We also constructed restricted cubic spline regression model adjusted by multivariable Cox proportional hazard models. We included 6927 patients consisting of an underweight (n = 386), normal weight (n = 3785), overweight (n = 2174), and obese (n = 582) groups. The median follow-up period was 3.9 years. In the underweight group, the adjusted hazard ratios (HRs) for all-cause death and ischemic events were 1.75 (1.30-2.34) and 1.61 (1.04-2.50). The HR for all-cause death was 0.63 (0.49-0.82) in the overweight group. Restricted cubic spline regression models confirmed that lower BMI showed significantly higher risks for all-cause death and ischemic events. CONCLUSION: Among NVAF patients taking OACs, underweight patients had higher risks of all-cause death and ischemic events than other patients. Overweight patients had lower risk of all-cause death.
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Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Fibrilação Atrial/complicações , Sobrepeso/induzido quimicamente , Sobrepeso/complicações , Índice de Massa Corporal , Estudos de Coortes , Magreza , Anticoagulantes/efeitos adversos , Obesidade/complicações , Administração Oral , Acidente Vascular Cerebral/etiologiaRESUMO
OBJECTIVES: We performed our standard air leak, leak percentage, and cuff leak percentage tests in pediatric patients intubated with microcuff pediatric tracheal tubes (MPTTs) just before extubation. We examined the association between test findings and the subsequent occurrence of post-extubation laryngeal edema (PLE). DESIGN: Prospective, single-center, observational study. SETTING: PICU (June 1, 2020 to May 31, 2021). PATIENTS: Pediatric patients intubated and scheduled for extubation during the day shift in the PICU. INTERVENTIONS: Multiple pre-extubation leak tests were performed on each patient immediately before extubation. In our center, the standard leak test is positive if a leak is audible at 30 cm H 2 O applied pressure with the MPTT cuff deflated. Two other tests were calculated in the pressure control-assist control ventilator mode using the following formulas: leak percentage with deflated cuff = (inspiratory tidal volume [V t ]-expiratory V t ) × 100/inspiratory V t ; cuff leak percentage = (expiratory V t with inflated cuff-expiratory V t with deflated cuff) × 100/expiratory V t with inflated cuff. MEASUREMENTS AND MAIN RESULTS: The diagnostic criteria for PLE was made by at least two healthcare professionals and included upper airway stricture with stridor-requiring nebulized epinephrine. Eighty-five pediatric patients (< 15 yr) who had been intubated for at least 12 hours using the MPTT were included. Positive rates for the standard leak, leak percentage (cutoff 10%), and cuff leak percentage (cutoff 10%) tests were 0.27, 0.20, and 0.64, respectively. The standard leak, leak percentage, and cuff leak tests showed sensitivities of 0.36, 0.27, and 0.55, respectively; and specificities of 0.74, 0.81, and 0.35, respectively. PLE occurred in 11 of 85 patients (13%), and there were no instances of needing reintubation. CONCLUSIONS: The pre-extubation leak tests in current practice for intubated pediatric patients in the PICU all lack diagnostic accuracy for PLE.
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Edema Laríngeo , Laringe , Humanos , Criança , Edema Laríngeo/diagnóstico , Edema Laríngeo/etiologia , Estudos Prospectivos , Extubação/efeitos adversos , Intubação Intratraqueal/efeitos adversos , Unidades de Terapia Intensiva PediátricaRESUMO
OBJECTIVE: In subjects with chronic kidney disease (CKD), the effect of low-protein diet (LPD) is expected to alleviate uremic symptoms. However, whether LPD is effective in preventing loss of kidney function is controversial. The aim of this study was to evaluate the association between LPD and renal outcomes. METHODS: We conducted a multicenter cohort study of 325 patients who suffered CKD stage 4 and 5 with eGFR ≥10 mL/min/1.73 m,2 between January 2008 and December 2014. The primary diseases of the patients were chronic glomerulonephritis (47.7%), nephrosclerosis (16.9%), diabetic nephropathy (26.2%), and others (9.2%). The patients were divided into four groups, based on the mean protein intake (PI)/day, group 1 (n = 76): PI < 0.5 g/kg ideal body weight/day, group 2 (n = 56): 0.5 ≤ PI < 0.6 g/kg/day, group 3 (n = 110): 0.6 ≤ PI < 0.8 g/kg/day, group 4 (n = 83): PI ≥ 0.8 g/kg/day. Dietary supplementation with essential amino acids and ketoanalogues was not used. The outcome measure was occurrence of renal replacement therapy (RRT) (hemodialysis, peritoneal dialysis, renal transplantation (excluding preemptive transplantation)) and all-cause mortality until December 2018. Cox regression models were used to examine whether LPD was associated with the risk of outcomes. RESULTS: During a mean follow-up of 4.1 ± 2.2 years. Thirty-three patients (10.2%) died of all causes, 163 patients (50.2%) needed to start RRT, and 6 patients (1.8%) received a renal transplant. LPD therapy of 0.5 g/kg/day or less was significantly related to a lower risk of RRT and all-cause mortality [Hazard ratio = 0.656; 95% confidence interval, 0.438 to 0.984, P = .042]. CONCLUSIONS: These results suggest that non-supplemented LPD therapy of 0.5 g/kg/day or less may prolong the initiation of RRT in stage 4 and 5 CKD patients.
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Dieta com Restrição de Proteínas , Insuficiência Renal Crônica , Humanos , Japão , Estudos de Coortes , Progressão da Doença , Terapia de Substituição RenalRESUMO
BACKGROUND: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.MethodsâandâResults: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG ≥150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C ≥170 mg/dL; and high-risk group (n=19) with TG ≥150 mg/dL and non-HDL-C ≥170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index ≥7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. CONCLUSIONS: Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.
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Doença da Artéria Coronariana , Colesterol , HDL-Colesterol , LDL-Colesterol , Doença da Artéria Coronariana/diagnóstico por imagem , Dilatação , Humanos , Lipoproteínas , Prognóstico , Fatores de Risco , TriglicerídeosRESUMO
BACKGROUND AND AIM: Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LREs). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with non-alcoholic fatty liver disease (NAFLD). METHODS: We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1395 patients with biopsy-proven NAFLD. The median follow-up was 4.6 years. RESULTS: The median age was 57 years, and 36.2% had T2DM. The median body mass index (BMI) was 27.4, and 28.5% were severely obese (BMI ≥ 30). During follow-up, 37 patients developed hepatocellular carcinoma (HCC), and 58 patients developed LRE. In patients younger than 65 years, advanced fibrosis (hazard ratio [HR] 7.69, P < 0.001) and T2DM (HR 3.37, P = 0.017) were HCC risk factors, and advanced fibrosis (HR 9.40, P < 0.001) and T2DM (HR 2.51, P = 0.016) were LRE risk factors. In patients 65 years and older, advanced fibrosis (HR 4.24, P = 0.010) and obesity (HR 4.60, P = 0.006) were HCC risk factors, and advanced fibrosis (HR 4.22, P = 0.002) and obesity (HR 4.22, P = 0.002) were LRE risk factors. CONCLUSION: Type 2 diabetes mellitus and obesity contributed to LRE in younger and older patients, respectively, along with advanced fibrosis. Therefore, controlling T2DM in patients younger than 65 years and controlling weight in patients 65 years and older could prevent LRE. The development of age-dependent screening and management strategies is necessary for patients with NAFLD.
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Carcinoma Hepatocelular , Clione , Diabetes Mellitus Tipo 2 , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Estudos Retrospectivos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Obesidade/complicações , Obesidade/epidemiologia , FibroseRESUMO
In patients with atrial septal defect (ASD), atrial left-to-right shunting causes left atrial (LA) remodeling and dysfunction, leading to atrial fibrillation (AF). In adults with ASD and concomitant AF, LA function should be evaluated after ASD closure plus AF radiofrequency catheter ablation (RFCA).This multicenter retrospective cohort study included patients who underwent transcatheter ASD closure at one of the four leading hospitals. Patients with a history of AF also underwent preceding RFCA. The association between AF history and LA ejection fraction (EF) (indicating LA global function) at 6-12 months following ASD closure was evaluated. To account for differences in baseline characteristics between patients with and without a history of AF, we conducted the following statistical methods: (1) multivariate regression analysis in the prepropensity score (PS)-matched cohort and (2) univariate comparisons in the PS-matched cohort.Overall, this study included 231 patients (30 with AF history, 201 without). Multiple regression analysis showed that AF history was independently associated with impaired LAEF (ß = -10.425, P < 0.001, model created prior to propensity matching). A one-to-one PS matching (25 pairs) showed that the LAEF at 6-12 months following ASD closure was significantly impaired in patients with ASD and AF history compared to that in patients without history of AF (median LAEF, 37.5% (interquartile range [IQR] 29.4%-48.5%) versus 52.3 [IQR 50.0%-56.6%]; P < 0.001).LA function was impaired in patients with ASD and a history of AF at 6-12 months after successful transcatheter ASD closure and on maintenance of sinus rhythm by RFCA.
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Fibrilação Atrial , Remodelamento Atrial , Ablação por Cateter , Comunicação Interatrial , Adulto , Fibrilação Atrial/cirurgia , Função do Átrio Esquerdo , Comunicação Interatrial/complicações , Comunicação Interatrial/cirurgia , Humanos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUNDS/AIM: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). METHODS: The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. RESULTS: In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by - 2.23% (95% CI - 5.72 to 1.25) at week 4, - 8.07% (- 12.76 to - 3.37) at week 12, and - 5.60% (- 9.87 to - 1.32) at week 24; eEV by - 70.3 mL (95% CI - 136.8 to - 3.8) at week 4, - 135.9 mL (- 209.6 to - 62.3) at week 12, and - 144.4 mL (- 226.3 to - 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. CONCLUSIONS: Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.
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Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Volume Plasmático/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Idoso , Compostos Benzidrílicos/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Feminino , Deslocamentos de Líquidos Corporais , Glucosídeos/efeitos adversos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear. METHODS: The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin. RESULTS: Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference - 8.5 [95% confidence interval (CI) - 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (- 0.54 [95% CI - 1.07 to - 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers. CONCLUSION: Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.
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Compostos Benzidrílicos/uso terapêutico , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Controle Glicêmico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Compostos Benzidrílicos/efeitos adversos , Biomarcadores/sangue , Glicemia/metabolismo , Doenças Cardiovasculares/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Método Duplo-Cego , Feminino , Glucosídeos/efeitos adversos , Hemoglobinas Glicadas/metabolismo , Humanos , Japão , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Risk factors of mortality in chronic hemodialysis patients have not yet been sufficiently evaluated. In particular, chronological transits and interactions of the impact of risk factors have rarely been described. METHODS: This study is a post hoc analysis of the participants in the Olme-sartan Clinical Trial in Okinawan Patients under OKIDS (OCTOPUS) study conducted between June 2006 and June 2011. We additionally followed up on the prognosis of the participants until July 31, 2018. Standardized univariable and multivariable Cox regression analyses were used to evaluate the influences of the participants' baseline characteristics on all-cause mortality. We also evaluated chronological changes in the impacts of risk factors, interactions among predictors, and the influence of missing values using sensitivity analyses. RESULTS: Of the 469 original trial participants, 461 participants were evaluated. The median time of follow-up was 10.2 years. A total of 211 (45.8%) participants were deceased. The leading causes of death were infection (n = 72, 34.1%) and cardiovascular disease (n = 66, 31.3%). Univariate and multivariate Cox regression analyses revealed that the impact of diabetes mellitus, history of coronary intervention, and hypoalbuminemia were significant risk factors for mortality during the whole follow-up period. During the early follow-up period (≤3 years), standardized univariate Cox regression analyses revealed that history of amputation (hazard ratio [HR] = 4.61, p < 0.001), lower dry weight, higher cardiothoracic ratio, and lower potassium levels were statistically significant risks. In those who survived for longer than 3 years, a history of stroke (HR = 1.73, p = 0.006), higher systolic blood pressure, lower serum sodium levels, and higher levels of hemoglobin, and serum phosphate were significant risks. We also observed a stable interaction between the impacts of serum phosphate and albumin on all-cause mortality. CONCLUSION: In chronic hemodialysis patients, targets to improve the short-term prognosis and long-term prognosis are not equivalent. Hyperphosphatemia was a significant risk factor for the all-cause mortality among patients with normal serum albumin levels but not among patients with compromised albumin levels.
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Diálise Renal , Insuficiência Renal/mortalidade , Insuficiência Renal/terapia , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Causas de Morte , Feminino , Seguimentos , Humanos , Hiperfosfatemia/mortalidade , Hipertensão/complicações , Infecções/mortalidade , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal/complicações , Fatores de Risco , Albumina Sérica/metabolismo , Taxa de SobrevidaRESUMO
BACKGROUND: The number of women with congenital heart disease (CHD) who are of childbearing age is increasing due to advancements in medical management. Nonetheless, data on the outcomes of delivery in women with CHD remain limited. Therefore, we conducted a retrospective cohort study using a nationwide database of deliveries by women with CHD. METHODS: Deliveries by women with CHD discharged from acute-care hospitals between April 2017 and March 2018 were identified based on the Diagnosis Procedure Combination database which covers almost all acute-care hospitals in Japan. By using this database, we tried to include relatively high-risk deliveries by women with CHD. Subjects were divided into three groups according to the underlying disease complexity: simple, moderate, and great complexity. The clinical characteristics and incidence of peripartum cardiovascular events were compared among the three groups. RESULTS: A total of 249 deliveries from 107 hospitals were included. The largest facility had 29 deliveries per year. Given the uncertainty of underlying cardiac anomalies, 48 women were excluded, and the remaining 201 women (median age, 32 years) were analyzed. In-hospital maternal death, use of extracorporeal membrane oxygenation, intra-aortic balloon pump, pacemaker, and direct current cardioversion were not observed. Nine patients (4.5%) required intravenous diuretic administration. However, the difference in the frequency of diuretic use was not significant among the three groups (simple, 1.9%; moderate, 7.2%; great, 6.9%; P = 0.204). One participant required valve replacement surgery at 22 days after a successful cesarean section. As the disease complexity increased, deliveries occurred more frequently at university hospitals (simple, 41.7%; moderate, 52.2%; great, 72.4%; P = 0.013) and the length of hospitalization was significantly longer, with median durations of 9.0 (interquartile range [IQR] 7.0-11.0) days, 10.0 (IQR 8.0-24.0) days, and 11.0 (IQR 8.0-36.0) days in the simple, moderate, and great complexity groups, respectively (P = 0.002). CONCLUSIONS: Appropriate patient selection and management by specialized tertiary institutions may contribute to positive outcomes in pregnancies in women with CHD.
Assuntos
Parto Obstétrico , Cardiopatias Congênitas/terapia , Hospitais Universitários , Admissão do Paciente , Complicações Cardiovasculares na Gravidez/terapia , Resultado da Gravidez , Adulto , Cesárea , Bases de Dados Factuais , Parto Obstétrico/efeitos adversos , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/fisiopatologia , Humanos , Japão/epidemiologia , Tempo de Internação , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
PURPOSE: Antiplatelet therapy (APT) is challenging in patients taking oral anticoagulants (OACs) for nonvalvular atrial fibrillation (NVAF) with concomitant atherosclerotic diseases. We scrutinized the generalizability of recent randomized clinical trials showing OAC use alone was superior to OAC plus antiplatelet use in patients with NVAF and coronary artery diseases (CAD). METHODS: We conducted a historical multicenter registry at 71 centers in Japan. The inclusion criterion was taking OACs for NVAF. The exclusion criteria were mechanical heart valves or history of pulmonary thrombosis or deep vein thrombosis. Consecutive patients (N = 7826) were registered in February 2013 and were followed until February 2017. The co-primary endpoints were ischemic events and major bleedings. Secondary endpoints were ischemic stroke, hemorrhagic stroke, and all-cause mortality. RESULTS: The mean patient age was 73 years; 67% were men. Antiplatelets were administered in 25% of patients and 27% had history of CAD. Cumulative incidences of ischemic events and major bleedings at 4 years were 5.9% and 9.6% in the APT group and 5.3% and 7.0% in the No-APT group, respectively. The adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) of the APT group for ischemic events and major bleedings were 1.12 (0.84-1.49) and 1.26 (1.01-1.57), respectively. The adjusted HRs (95% CIs) for ischemic stroke, hemorrhagic stroke, and all-cause mortality were 1.16 (0.86-1.57), and 1.31 (0.70-2.48), and 1.02 (0.82-1.26), respectively. CONCLUSIONS: APT in patients taking OACs for NVAF did not prevent ischemic events but significantly increased major bleedings in the real-world setting.
Assuntos
Fibrilação Atrial , Inibidores da Agregação Plaquetária , Idoso , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Humanos , Japão/epidemiologia , Inibidores da Agregação Plaquetária/efeitos adversosRESUMO
BACKGROUND: An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. METHODS AND FINDINGS: The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10-60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat - control], -0.007 mm [95% confidence interval (CI) -0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, -0.016 mm [95% CI -0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI -0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI -0.5% to 3.3%] in the control group (n = 193); mean between-group difference, -0.2% [95% CI -2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI -0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, -2.62 mg/dL [95% CI -2.86 mg/dL to -2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia. CONCLUSIONS: In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry UMIN000012911.
Assuntos
Doenças Assintomáticas/terapia , Doenças das Artérias Carótidas/prevenção & controle , Progressão da Doença , Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Hiperuricemia/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas/epidemiologia , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/epidemiologia , Espessura Intima-Media Carotídea , Febuxostat/farmacologia , Feminino , Supressores da Gota/farmacologia , Humanos , Hiperuricemia/sangue , Hiperuricemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego , Ácido Úrico/antagonistas & inibidores , Ácido Úrico/sangueRESUMO
BACKGROUND: Fatty acid-binding protein 4 (FABP4) acts as a novel adipokine, and elevated FABP4 concentration is associated with obesity, insulin resistance and atherosclerosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a class of antidiabetic drugs, have distinct structures among the drugs, possibly leading to a drug class effect and each drug effect. Sitagliptin, a DPP-4 inhibitor, has been reported to decrease FABP4 concentration in drug-naïve and sulfonylurea-treated patients with type 2 diabetes mellitus. Anagliptin, another DPP-4 inhibitor, was shown to decrease low-density lipoprotein cholesterol (LDL-C) level to a greater extent than that by sitagliptin in the Randomized Evaluation of Anagliptin vs. Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. AIM AND METHODS: As a sub-analysis study using data obtained from the REASON trial, we investigated the effects of treatment with anagliptin (n = 148, male/female: 89/59) and treatment with sitagliptin (n = 159, male/female: 93/66) for 52 weeks on FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular events who were receiving statin therapy. RESULTS: The DPP-4 inhibitor had been administered in 82% of the patients in the anagliptin group and 81% of the patients in sitagliptin group prior to randomization. Serum FABP4 level was significantly decreased by 7.9% by treatment with anagliptin (P = 0.049) and was not significantly decreased by treatment with sitagliptin (P = 0.660). Change in FABP4 level was independently associated with basal FABP4 level and changes in waist circumference and creatinine after adjustment of age, sex and the treatment group. CONCLUSION: Anagliptin decreases serum FABP4 concentration independent of change in hemoglobin A1c or LDL-C in patients with type 2 diabetes mellitus and dyslipidemia who are on statin therapy. Trial registration ClinicalTrials.gov number NCT02330406. Registered January 5, 2015, https://clinicaltrials.gov/ct2/show/NCT02330406.