Study protocol for assessment of the coagulation potential of concomitantly used factor VIII concentrates in patients with haemophilia A with emicizumab prophylaxis (CAGUYAMA Study): a multicentre open-label non-randomised clinical trial.

INTRODUCTION: Emicizumab prophylaxis substantially reduces bleeding episodes in patients with haemophilia A (HA). The haemostatic efficacy of emicizumab in patients with HA is estimated as approximately 15% based on mimic activity of factor (F) VIII. Although it has been proven effective in preventing bleeding, its haemostatic effect during breakthrough bleeding or surgery is considered insufficient. Therefore, haemostatic management of emicizumab-treated patients with HA without inhibitors frequently requires FVIII replacement therapy. In haemostatic management of emicizumab-treated patients with HA, conventional FVIII dosage calculations are used in clinical practice without considering the coagulant effects of emicizumab. METHODS AND ANALYSIS: In the CAGUYAMA study, 100 patients with HA without inhibitors will be enrolled for a maximum duration of 1 year, and samples of 30 events following the concomitant use of FVIII concentrates (30±5 U/kg) with emicizumab will be collected. An 'event' is defined as obtaining blood samples at preadministration and postadministration of FVIII concentrates during a breakthrough bleeding or a surgical procedure. Global coagulation assays will be used to measure the coagulation potential of the obtained samples. Clot waveform analysis (CWA) is used to identify the primary end-point, that is, the degree of improvement in the maximum coagulation rate at preadministration and post-administration of fixed-dose FVIII concentrations. The parameter obtained from CWA, which is triggered by an optimally diluted mixture of prothrombin time reagent and activated partial thromboplastin time reagent, is reported to be an excellent marker for assessing the degree of improvement of the coagulation potential in emicizumab-treated plasmas. ETHICS AND DISSEMINATION: The CAGUYAMA study was approved by the Japan-Certified Review Board of Nara Medical University (Approval ID; nara0031). The study results will be communicated through publication in international scientific journals and presentations at (inter)national conferences. TRIAL REGISTRATION NUMBER: jRCTs051210137.

Assessment of the accuracy of an intermittent-scanning continuous glucose monitoring device in patients with type 2 diabetes mellitus undergoing hemodialysis (AIDT2H) study.

FreeStyle Libre has been approved for use in patients undergoing hemodialysis (HD) in Japan, unlike Europe and the United States; however, evidence regarding its accuracy in such patients is sparse. Forty-one participants with type 2 diabetes undergoing HD were recruited. The overall mean absolute relative difference and mean absolute difference were 23.4% and 33.9 mg/dL, respectively. Sensor glucose levels and capillary glucose levels were significantly correlated (r = 0.858, P < .01), although the sensor glucose levels were significantly lower than the capillary glucose levels. The accuracy of FreeStyle Libre in patients undergoing HD became deteriorated with the days of usage. The percentage of sensor results in Zones A and B in the consensus error grid analysis and in the Clarke error grid analysis were 99.7% and 99.0%, respectively. Its insufficient accuracy necessitates adjunct usage of FreeStyle Libre with self-monitoring of blood glucose in patients undergoing HD.

Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity after reperfusion therapy in patients with first ST-segment elevation myocardial infarction and normal low-density lipoprotein cholesterol.

BACKGROUND: Statin treatment reduces enhanced cardiac sympathetic nerve activity (CSNA) in patients with heart disease, and reduces adverse cardiac events in patients with coronary artery disease. METHODS: We retrospectively evaluated the first ST-segment elevation myocardial infarction (STEMI) patients and low-density lipoprotein cholesterol < 120 mg/dL in our database who underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy 3 weeks after admission. Sixty STEMI patients after primary coronary angioplasty were selected, and used propensity score matching to compare patients treated with strong statin (n = 30), and those who did not (n = 30). Moreover, echocardiographic left ventricular (LV) parameters were determined, and plasma procollagen type III amino terminal peptide (PIIINP) was also measured before and 3 weeks after treatment. RESULTS: Following primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine phosphokinase concentration, and recanalization time were similar in the two groups. However, the statin group showed significantly lower delayed total defect score and washout rate evaluated by 123I-MIBG scintigraphy (22.4 ± 8.1 vs. 29.6 ± 10.5; P < 0.01, and 30.4 ± 8.9% vs. 40.1 ± 11.4%; P < 0.005, respectively) and higher delayed heart/mediastinum count ratio (2.17 ± 0.38 vs. 1.96 ± 0.30, P < 0.05) compared with the non-statin group. Moreover, the degree of change in LV parameters and PIIINP was more favorable in the statin group than in the non-statin group. CONCLUSIONS: Administration of statin improves CSNA after reperfusion therapy in patients with first STEMI.

Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity and cardiac events in patients with ischemic cardiomyopathy and mild to moderate heart failure.

INTRODUCTION: We determined whether statin therapy improved cardiac sympathetic nerve activity as evaluated using iodine-123-metaiodobenzylguanidine (I-MIBG) scintigraphy, and whether this therapy affects prognosis in patients with ischemic cardiomyopathy. PATIENTS AND METHODS: This study was a subanalysis of our previous report of the result that the serial I-MIBG scintigraphic studies were the most useful prognostic indicator in patients with heart failure. Patients with heart failure [left ventricular ejection fraction (LVEF) <45%] but no cardiac events for at least 5 months before the study were identified according to their history of decompensated acute heart failure requiring hospitalization. The patients underwent I-MIBG scintigraphy and echocardiography immediately before hospital discharge and after 6 months. The % denervation, heart/mediastinum count ratio, and washout rate were determined from the I-MIBG scintigraphy, and the left ventricular end-diastolic volume, left ventricular end-systolic volume, and LVEF were also determined from echocardiography. We selected 76 patients with old myocardial infarction without active ischemia and used propensity score matching to compare patients who received oral statin (n=38) with those who did not (n=38). The patients were followed up for a median of 4.74 years, with the primary and secondary study end points defined as incidences of fatal cardiac events and major adverse cardiac events (MACEs), respectively. RESULTS: After treatment, the I-MIBG scintigraphic and echocardiographic parameters were improved in the statin and nonstatin groups. However, the extent of change in the % denervation was -12.3±10.3 and -6.2±9.6 (P<0.01), whereas that in the heart/mediastinum count ratio was 0.19±0.14 and 0.08±0.15 (P<0.01), and that in washout rate was -8.1±7.2 and -0.5±9.2% (P<0.01). The extent of change in left ventricular end-diastolic volume, left ventricular end-systolic volume, and LVEF in the statin group tended to exceed than in the nonstatin group, but these changes were not statistically significant. Of the 76 patients, 18 experienced fatal cardiac events and 32 experienced MACEs during the study. Multivariate Cox regression analyses revealed that the nonstatin therapy was a significant predictor of both cardiac death and MACEs in our patients. On Kaplan-Meier analysis, the rates of freedom from cardiac death or MACEs were significantly higher in the statin group than those in the nonstatin group (all, P<0.05). CONCLUSION: Statin therapy improved cardiac sympathetic nerve activity in patients with ischemic cardiomyopathy and mild to moderate heart failure. Furthermore, statin is potentially effective for reducing cardiac events in these patients.

A pooled analysis of multicenter cohort studies of (123)I-mIBG imaging of sympathetic innervation for assessment of long-term prognosis in heart failure.

OBJECTIVES: The study objectives were to create a cardiac metaiodobenzylguanidine (mIBG) database using multiple prospective cohort studies and to determine the quantitative iodine-123-labeled mIBG indices for identifying patients with chronic heart failure (HF) at greatest and lowest risk of lethal events. BACKGROUND: Although the prognostic value of cardiac mIBG imaging in patients with HF has been shown, clinical use of this procedure has been limited. It is required to define universally accepted quantitative thresholds for high and low risk that could be used as an aid to therapeutic decision-making using a large cohort database. METHODS: Six prospective HF cohort studies were updated, and the individual datasets were combined for the present patient-level analysis. The database consisted of 1,322 patients with HF followed up for a mean interval of 78 months. Heart-to-mediastinum ratio (HMR) and washout rate of cardiac mIBG activity were the primary cardiac innervation markers. The primary outcome analyzed was all-cause death. RESULTS: Lethal events were observed in 326 patients, and the population mortality rate was 5.6%, 11.3%, and 19.7% at 1, 2, and 5 years, respectively. Multivariate Cox proportional hazard model analysis for all-cause mortality identified age (p < 0.0001), New York Heart Association (NYHA) functional class (p < 0.0001), late HMR of cardiac mIBG activity (p < 0.0001), and left ventricular ejection fraction (LVEF) (p = 0.0029) as significant independent predictors. Analysis of the 512-patient subpopulation with B-type natriuretic peptide (BNP) results showed BNP (p < 0.0001), greater NYHA functional class (p = 0.0002), and late HMR (p = 0.0011) as significant predictors, but LVEF was not. The receiver-operating characteristic-determined threshold of HMR (1.68) identified patients at significantly increased risk in any LVEF category. Survival rates decreased progressively with decreasing HMR, with 5-year all-cause mortality rates >7% annually for HMR <1.25, and <2% annually for HMR ≥1.95. Addition of HMR to clinical information resulted in a significant net reclassification improvement of 0.175 (p < 0.0001). CONCLUSIONS: Pooled analyses of independent cohort studies confirmed the long-term prognostic value of cardiac mIBG uptake in patients with HF independently of other markers, such as NYHA functional class, BNP, and LVEF, and demonstrated that categoric assessments could be used to define meaningful thresholds for lethal event risk.

Sex-related differences in Japanese patients with peripheral arterial disease.

OBJECTIVE: The goal of the study was to examine possible sex-related differences in the clinical characteristics and risk factors in Japanese patients with peripheral arterial disease (PAD). METHODS: Sex-related differences in clinical profiles, risk factors and treatments were examined in 730 consecutive patients with PAD (148 women (20.3%) and 582 men (79.7%)). RESULTS: The mean age of the women was higher than that of the men (73.6 ± 11.2 vs. 70.9 ± 9.1 years old, p = 0.002) and the proportion of subjects aged ≥ 75 years old was also higher in women (P=0.005). Women more frequently had critical limb ischemia (P < 0.001) and diabetes mellitus (P = 0.026), but less frequent smoking and alcohol intake, compared to men (P< 0.001). Total cholesterol (P < 0.001) and LDL cholesterol (P = 0.014) were higher in women. Fontaine stages were correlated with age, diabetes, cerebral infarction and women (p < 0.001). The prevalence of iliac artery lesions was higher in men (p< 0.001), whereas that for below the knee lesions was higher in women (p < 0.001). The number of affected below the knee arteries was also higher in women than in men (p < 0.001). The prevalence of medical treatment was higher in women (P = 0.009) and major amputation tended to be higher in women (p = 0.056). CONCLUSIONS: Women had more severe symptomatic states and uncontrolled risk factors. The prevalence of iliac artery lesions was lower, but below the knee lesions were more severe in women.

Combined assessment of myocardial perfusion and function by ECG-gated myocardial perfusion single-photon emission computed tomography for the prediction of future cardiac events in patients with type 2 diabetes mellitus.

BACKGROUND: The mid-term prognostic significance of ECG-gated single-photon emission computed tomography (SPECT) remains unclear in Japanese patients with type 2 diabetes mellitus (DM). In the present study rates of future cardiac events (nonfatal acute myocardial infarction (AMI), cardiac death (CD) and severe heart failure (HF) requiring hospitalization) were compared in patients with and without DM. METHODS AND RESULTS: 1,810 patients (563 DM and 1,247 non-DM) we followed for a mean of 26.3±15.5 months. Summed stress score (SSS), summed difference score (SDS), poststress ejection fraction (EF) and resting end-diastolic volume (EDV) were calculated. In total, 20 cases of AMI (9 in DM (1.59%) and 11 in non-DM (0.88%)), 20 of CD (7 in DM patients (1.24%) and 13 in non-DM (1.04%)) and 54 of severe HF (31 in DM (5.5%) and 23 in non-DM (1.84%)) occurred. Univariate Cox analysis showed that, in DM patients, predictors of total cardiac events were poststress EF (Wald 60.4; P<0.001), resting EDV (Wald 53.8; P<0.001), SSS (Wald 39.6; P<0.001), SDS (Wald 26.1; P<0.001), history of prior MI (Wald 4.32; P<0.05) and hemoglobin A(1c) value (Wald 4.30; P<0.05). Multivariate Cox analysis showed that poststress EF (Wald 9.85; P<0.01) and SDS (Wald 6.19; P<0.01) were independent predictors of total cardiac events. CONCLUSIONS: Combined assessment of perfusion and function by ECG-gated SPECT may predict future cardiac events in type 2 DM patients.