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Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin.This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models.The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of β-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011).In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

The CARTOFINDER mapping system analyzes activation patterns using unipolar potentials during atrial fibrillation (AF), where isoproterenol (ISP) is conventionally used to induce non-pulmonary vein (PV) foci and confirm PV arrhythmogenicity. In 20 patients with persistent AF who underwent ablation at our hospital, arrhythmogenic foci were evaluated using both these methods.Before pulmonary vein isolation (PVI), PV and left atrium (LA) were analyzed during AF using CARTOFINDER, and the isolation line was determined based on the results. After PVI, ISP was loaded after return of sinus rhythm and confirmation of the presence of arrhythmogenic foci. The activation site in LA was ablated at the discretion of the surgeon.Focal activation sites detected by CARTOFINDER correlated with the arrhythmogenic foci induced by ISP in the PVs. The results also showed that a greater number of focal activation sites in the PVs correlated to an increased response to ISP administration. In one patient, it was observed that the focal activation site identified in the PV also coincided with the site of the origin of automaticity induced by ISP after PVI.CARTOFINDER and ISP both reliably determined the presence of arrhythmogenic foci in PV, in patients with persistent AF. Knowledge of the nature of arrhythmogenic foci in non-PV is considered to be a topic for future studies, and further data collection is required.

Ultra‐high‐resolution mapping is useful in the ablation of accessory pathways. However, in patients with accessory pathways in the coronary sinus (CS) diverticulum, treatment with endocardial ablation may be challenging. Patients suspected of having subepicardial accessory pathways may require the examination of the venous anomaly using CS angiography.

Cardiac involvement of malignant lymphoma is relatively common, although such a phenomenon has subclinical manifestations that are difficult to detect. We herein describe a patient with atrial fibrillation and sick sinus syndrome as the main symptoms. Computed tomography showed a mass in the right atrium extending into the superior vena cava (SVC). We implanted the patient with a leadless pacemaker. Transvenous biopsy revealed a diffuse large B-cell lymphoma. The patient was treated successfully with chemotherapy including rituximab. This case suggested that cardiac lymphoma may cause sick sinus syndrome, and leadless pacemaker implantation is a safe treatment option in patients with partial SVC obstruction.

Background Spontaneous coronary artery dissection (SCAD) has recently been recognized as a cause of acute coronary syndrome (ACS), especially in young women. However, the characteristics, optimal treatment, and prognosis of patients who experience SCAD have not been fully described. Methods Data were retrospectively collected from a multicenter registry. Among 187 young women less than 60 years of age who underwent percutaneous coronary intervention, 19 (10.2%) with SCAD were identified through coronary angiography. Clinical characteristics and outcomes were investigated. Results Those with SCAD less frequently exhibited coronary risk factors, such as diabetes, dyslipidemia, and smoking, than those without SCAD. Intense emotional and/or physical stress was more frequently observed as a prominent precipitating factor in cases of SCAD. All 19 SCAD patients presented with ACS, 7 of whom were treated using stents, and the other 12 treated without stents. During a median follow-up of 960 days (interquartile range, 686-1504 days), two recurrent coronary artery dissections occurred within 7 days, both of which occurred in a vessel other than that in which primary dissection occurred. There were no deaths or recurrent dissection after 1 week. Conclusion SCAD was not uncommon among young Japanese women requiring percutaneous coronary intervention. Patients with SCAD exhibited fewer coronary risk factors and more precipitating factors than those without SCAD, and long-term clinical outcomes after an early period appeared to be favorable.

We treated a patient with PCCD whose single left AT appeared as two different types on preoperative surface and intracardiac ECG from a pacemaker. The diagnosis was hindered by the fact that the conduction block encompassed interatrial block and the pacemaker A‐wave was captured at the right atrial appendage.

We present a patient with isolated bilateral external iliac artery dissections associated with emotional stress. The diagnosis should be kept in mind in young, fit patients presenting lower back pain occurring subsequent to emotional stress.

Purpose Compared with conventional pulmonary vein isolation (PVI) with radiofrequency ablation, PVI with cryoballoon is an easier and shorter procedure without reconnection, particularly in the superior pulmonary vein. However, the durability of the cryoballoon may be reduced due to anatomical factors and the position of the pulmonary vein (PV). Further, inadequate isolation of the carina leads to recurrence of atrial fibrillation (AF). We aimed to determine whether using contrast-enhanced computed tomography (CT) for patient selection improves the early success rate and prevents the recurrence of AF in PVI with cryoballoon. Methods We evaluated patients who underwent ablation for paroxysmal atrial fibrillation in our hospital between July 2019 and November 2020. After excluding patients with contraindications for cryoablation, 50 patients were selected through visual inspection of the results of preoperative contrast-enhanced CT. A treatment plan was established, and the clinical course and outcomes were followed up. Results Of the 200 PVs of the 50 patients, only 8 PVs (4%) were incompletely isolated with a single cryoablation. Six of the eight PVs were successfully isolated with additional cryoablation. Only 2 patients (4%) underwent additional PVI with radiofrequency ablation. Four patients had AF recurrence within a mean follow-up period of 14.3 ± 5.1 months. The rate of sinus rhythm maintenance was 92%. PV reconnection was observed in 2 patients. None of the patients had postoperative atrial flutter. Conclusions Selecting patients for cryoablation according to contrast-enhanced CT findings made the procedure easier to perform, leading to improved early success rates and clinical course.

Background Whether a dipeptidyl peptidase-4 (DPP-4) inhibitor can attenuate atherosclerosis is still controversial. Some clinical trials reported that DPP-4 inhibitors in diabetes patients without a previous history of cardiovascular (CV) events could reduce carotid intima-media thickness (IMT). However, in the PROLOGUE study, which enrolled diabetes patients both with and without previous CV events, sitagliptin failed to slow the progression of carotid IMT relative to conventional therapy. Aim and methods We hypothesized that the effect of DPP-4 inhibitors on carotid atherosclerosis might be different between the primary and secondary prevention groups. We performed a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in carotid IMT in subgroups with or without previous CV events. Results No significant difference in the IMT changes between the treatment groups was found in the secondary prevention subgroup (sitagliptin, N = 102; conventional, 111). However, in the primary prevention subgroup (sitagliptin, 120; conventional, 109), we found significant inhibitory effects of sitagliptin on mean and max internal carotid artery IMT [estimated group difference: −0.096 mm (95% CI −0.175 to −0.018, p = 0.017) and −0.162 mm (95% CI −0.272 to −0.052, p = 0.004), respectively], although there was no significant difference in the common carotid artery IMT. Conclusions Our data suggest that there is a favorable effect of DPP-4 inhibitor treatment on carotid atherosclerosis in diabetes patients without previous CV events.

Background Catheter ablation for atrial fibrillation (AF) is an established therapy. However, postoperative recurrence is a serious issue caused by the reconduction of the isolated pulmonary veins (PV) and the onset of non-PV foci. The objectives of this study were to elucidate dormant conduction, confirm PV arrhythmia substrate, induce non-PV foci after PV isolation, and assess the acute efficacy of high dose isoproterenol (ISP) when administered in addition to adenosine. Methods The study consisted of 100 patients with drug-refractory AF (paroxysmal and persistent) who underwent ablation therapy (either radio-frequency or cryoballoon ablation) as the first-line of therapy at our hospital. All patients first underwent PV isolation (PVI) and were administered adenosine followed by ISP (6 μg × 5 min). The effects were observed, and the therapeutic strategy was evaluated. Results Persistent dormant conduction due to ISP administration was observed in 13 patients. In over half of the patients, arrhythmia substrates were identified in the PV. Ten patients presented with persistent PV firing. The ablation of non-PV foci was additionally performed in 23 patients. Conclusions We found that dormant conduction, as a result of ISP administration, is persistent and ISP is useful when performing an ablation. In addition, ISP administration is useful for the identification of PV arrhythmia substrates and induction of non-PV foci. However, the effectiveness of ISP may be partially due to the complementary effect of adenosine, and, therefore, a combination of the two drugs seems preferable.

Factor-Xa inhibitors (FXaIs) are widely used for the treatment of non-valvular atrial fibrillation (NVAF). Although we have previously reported the distribution of the anti-factor Xa activity (AXA) values of three different FXaIs in NVAF patients, the differences in the distribution of AXA values among the different FXaIs in patients with renal impairment (RI) have not been fully elucidated. Trough and peak AXA values were measured in 94 patients taking rivaroxaban, 124 patients taking apixaban, and 66 patients taking edoxaban. Of them, we identified 26 patients with moderate RI [creatinine clearance (CrCl) 30–49 mL/min] and 17 patients with severe RI (CrCl 15–29 mL/min) in the rivaroxaban cohort, 37 patients with moderate RI and 17 patients with severe RI in the apixaban cohort, and 21 patients with moderate RI and 9 patients with severe RI in the edoxaban cohort. AXA values were measured using chromogenic AXA assays. Both trough and peak AXA values were compared between patients with moderate RI and those with severe RI in each cohort, and differences in the peak-to-trough ratio among the different drugs were assessed. In the rivaroxaban cohort, the peak AXA value was significantly higher in patients with severe RI than in those with moderate RI. In the apixaban cohort, neither the trough nor peak AXA values significantly differed between patients with moderate RI and those with severe RI. In the edoxaban cohort, the trough AXA value was significantly higher in patients with severe RI than in those with moderate RI, and peak AXA tended to be higher in patients with severe RI. The peak-to-trough ratio of AXA values was significantly lower in patients taking apixaban than in those taking rivaroxaban and edoxaban. Among Japanese NVAF patients with RI, the peak or trough AXA values were higher in patients with severe RI than in those with moderate RI when taking rivaroxaban and edoxaban, whereas both the peak and trough AXA values were similar between patients with severe RI and those with moderate RI when taking apixaban. The peak-to-trough ratio of AXA values was the lowest in patients taking apixaban.

Background:It is known that once heart failure occurs in older patients with diabetes, the overall prognosis is extremely poor. We investigated whether early initiation of SGLT2 inhibitor therapy after admission was beneficial for diabetic patients requiring inpatient treatment for acute heart failure.Methods:We retrospectively assessed consecutive patients with comorbid diabetes who were admitted to the Department of Cardiology in Tosei General Hospital for treatment of acute heart failure. Patients were divided into two groups: those who initiated SGLT2 inhibitor therapy (SGLT2 inhibitor group; mean age: 73 ± 9 years) and those who did not receive the inhibitors during hospitalization (conventional treatment group; mean age: 75 ± 10 years).Results:No intergroup differences were observed in the distribution of either the severity or classes of heart failure on admission. Glycosylated hemoglobin levels were significantly higher in the SGLT2 inhibitor group (HbA1c: 8.1% ± 0.8%) than in the conventional treatment group (HbA1c: 7.1% ± 0.8%) ( p = 0.003). After admission, patients in both groups recovered equally well, and in almost the same period of time, before discharge. The rate of diuretics use at the time of discharge in the SGLT2 inhibitor group ( n = 8, 67%) was significantly lower than that in the conventional treatment group ( n = 19, 100%) ( p = 0.016). In particular, the dose of loop diuretics in the conventional treatment group was 34 ± 4 mg/day while that in the SGLT2 inhibitor group was significantly lower at 13 ± 5 mg/day ( p = 0.008). During hospitalization, the incidence of acute kidney injury was significantly higher in the conventional treatment group ( n = 11, 58%) than in the SGLT2 inhibitor group ( n = 2, 16%) ( p = 0.031).Conclusions:For the treatment and management of heart failure in patients with diabetes, early initiation of SGLT2 inhibitor therapy appears to be effective.

Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e’) assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

Background: Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated. Methods: Changes in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open-label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI. Results: The average trough DC was significantly higher without PPI than with PPI (83 ± 42.3 vs. 55.5 ± 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 ± 107.7 vs. 124 ± 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types. Conclusions: PPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered. Keywords: Dabigatran, Proton pump inhibitor, Drugâdrug interaction

Aim Sodium–glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long-term use of SGLT2 inhibitors in older patients with diabetes. Methods A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016. Results The mean age of the patients was 73.7 ± 10.0 years. During the follow-up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow-up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment. Conclusions In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108–114.

Background Anti-Xa activity (AXA) in patients with nonvalvular atrial fibrillation (NVAF) and relationship to bleeding events remains unclear. Methods We evaluated AXA in 94 patients at both trough and peak rivaroxaban concentrations. Rivaroxaban dosage was determined according to creatinine clearance (CrCl): 10 and 15 mg once daily for patients with CrCl 15–49 and CrCl ≥50 mL/min, respectively. AXA value distribution and its association with bleeding events were examined in enrolled subjects. Results The mean peak AXA level was significantly higher than the mean trough level (1.98 ± 0.81 vs. 0.16 ± 0.15 IU/mL; p

Objectives The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a multicenter randomized investigation of the noninferiority of short-term versus long-term dual antiplatelet therapy (DAPT) in patients with implantation of the Nobori drug-eluting stent (DES) (Terumo, Tokyo, Japan), which has a biodegradable abluminal coating. Background The optimum duration of DAPT for patients with a biodegradable polymer-coated DES is unclear. Methods The subjects were 3,773 patients with stable or acute coronary syndromes undergoing Nobori stent implantation. They were randomized 1:1 to receive DAPT for 6 or 18 months. The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (all-cause mortality, myocardial infarction, stroke, and major bleeding) from 6 to 18 months after stenting. Intention-to-treat analysis was performed in 3,307 patients who were followed for at least 6 months. Results NACCE occurred in 34 patients (2.1%) receiving short-term DAPT and 24 patients (1.5%) receiving long-term DAPT (difference 0.6%, 95% confidence interval [CI]: 1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of −2%, noninferiority of short-term DAPT was confirmed. Mortality was 1.0% with short-term DAPT versus 0.4% with long-term DAPT, whereas myocardial infarction was 0.2% versus 0.1%, and major bleeding was 0.7% versus 0.7%, respectively. The estimated probability of NACCE was lower in the long-term DAPT group (hazard ratio: 1.44, 95% CI: 0.86 to 2.43). Conclusions Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open-label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227)

Background Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus. Methods and results ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups. Conclusions Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

The pharmacokinetics and pharmacodynamics of warfarin remained unaffected by tolvaptan during clinical trials. However, tolvaptan prolonged the prothrombin time-international normalized ratio (PT-INR) level of patients with cardiovascular disease taking warfarin. Tolvaptan was prescribed to 576 patients from December 2010 to December 2015. Of these patients, 37 underwent anticoagulant therapy. We investigated PT-INR fluctuation immediately before tolvaptan therapy was initiated. PT-INR remained unchanged in the control group and in groups administered with less than 7.5 mg/d tolvaptan, whereas it was significantly increased (p=0.03) in the group administered with more than 7.5 mg/d tolvaptan. This result indicates the possibility that tolvaptan affects the pharmacodynamics of warfarin in vivo. However, further research is necessary to clarify the mechanism of this phenomenon.

BackgroundRivaroxaban is currently used to prevent stroke in patients with atrial fibrillation. Measuring coagulation function may help clinicians to understand the effects of this drug and the associated risk of bleeding.Methods and resultsRivaroxaban was given to 136 patients with non-valvular atrial fibrillation. Mean age was 74.5±9.0 years (men: 63.2%) and mean CHADS2 score (±SD) was 1.8±1.2. Prothrombin times (PTs) and plasma soluble fibrin (SF) levels were examined in 84 out of 136 patients at baseline and at least 2 weeks thereafter. In 48 patients we were able to collect blood at exact times, namely just before and 3h after rivaroxaban administration, corresponding to the trough and peak concentrations. Mean peak PT in 48 patients was 17.1±3.6s and median peak SF level was 1.46μg/mL. Multiple regression analysis showed that female sex, high brain natriuretic peptide, and high dose were independent factors prolonging the peak PT. Patients with peak PTs ≥20s experienced significantly more bleeding events. Among 29 of 46 patients newly treated with rivaroxaban without any previous anticoagulant, we examined coagulation function at the exact trough and peak times. In 29 patients, peak PT was significantly more prolonged than the baseline or trough PT (p

BACKGROUND Chromogenic anti-factor Xa activity (AXA) assay is reported to be the most appropriate method to measure the pharmacodynamics of apixaban, but the distribution of AXA in non-valvular atrial fibrillation (NVAF) patients on apixaban therapy has not been fully elucidated. METHODS AND RESULTS Steady-state trough and peak AXA were measured in 124 NVAF patients taking apixaban. In 25 patients, baseline, first peak, and trough AXA were also examined, and were 0.01±0.02 IU/ml, 0.83±0.43 IU/ml, and 0.34±0.17 IU/ml, respectively. First trough AXA was significantly lower than steady-state trough AXA, although it was significantly higher than baseline (P

Background Serelaxin, a recombinant form of human relaxin-2, is in development for treating acute heart failure (AHF) and a Phase II study in Japanese AHF patients was conducted. Methods and results A randomized, double-blind, placebo-controlled study of serelaxin at 10 and 30 µg·kg(-1)·day(-1)continuous intravenous infusion for up to 48 h, added to standard care for Japanese AHF patients. Primary endpoints were adverse events (AEs) through Day 5, serious AEs (SAEs) through Day 14, and serelaxin pharmacokinetics. Secondary endpoints included changes in systolic blood pressure (SBP) and cardiorenal biomarkers. A total of 46 patients received the study drug and were followed for 60 days. The observed AE profile was comparable between the groups, with no AEs of concern. Dose-dependent increase in the serum concentration of serelaxin was observed across the 2 dose rates of serelaxin. A greater reduction in SBP was observed with serelaxin 30 µg·kg(-1)·day(-1)vs. placebo (-7.7 [-16.4, 1.0] mmHg). A greater reduction in NT-proBNP was noted with serelaxin (-50.8% and -54.9% for 10 and 30 µg·kg(-1)·day(-1), respectively at Day 2). Conclusions Serelaxin was well tolerated in this study with Japanese AHF patients, with no AEs of concern and favorable beneficial trends on efficacy. These findings support further evaluation of serelaxin 30 µg·kg(-1)·day(-1)in this patient population.

Background The distribution of anti-factor Xa activity (AXA) values in non-valvular atrial fibrillation (NVAF) patients on edoxaban therapy has not been fully elucidated. Methods and results The steady-state trough and peak AXA values were measured in 66 NVAF patients. The trough AXA value did not differ significantly between the 60-mg and the 30-mg OD groups (0.17±0.13 IU/ml vs. 0.12±0.11 IU/ml, respectively; P=0.17). Similarly, the peak AXA value did not differ significantly between the 2 groups (1.45±0.81 IU/ml vs. 1.25±0.48 IU/ml, respectively; P=0.26). Conclusions Recommended dosing should be followed for sufficient efficacy of edoxaban. (Circ J 2016; 80: 745-747).

Objective: Sirolimus-eluting stent (SES) has shown a significant efficacy in reducing restenosis after percutaneous coronary interventions. However, an increase in total number of SES use along with targeting more complex lesions generated a large number of SES restenosis. This study aimed to investigate the clinical and angiographic outcomes of different revascularization strategies for SES restenosis. Methods and Results: A total of 176 lesions in 149 patients were included in the study. Fifteen patients underwent coronary artery bypass graft surgery (CABG group) and the remaining patients were treated with percutaneous coronary intervention (PCI). Stent reimplantation was performed in 88 patients (Stent group), whereas 46 patients received balloon therapy (Balloon group). Among 176 lesions, major cardiac adverse event (MACE) occurred in 41 lesions (23.3%) during a median follow-up of 310 days (interquartile range: 146–517 days). The Kaplan–Meier method with a log-rank test revealed no significant difference in MACE rates between the three groups (6%, 25%, 26%, p = 0.13; CABG group, Stent group, Balloon group, respectively). However, when the Balloon group and Stent group were combined together as a PCI group, PCI group had a significantly higher rate of MACE compared with the CABG group (p = 0.04). In addition, angiographic restenosis was significantly less prevalent in the CABG group when compared with the other two groups (8%, 57%, 46%, p = 0.006; CABG group, Stent group, Balloon group, respectively). Conclusions: CABG surgery for patients with SES restenosis is associated with the better clinical outcomes as well as better angiographic outcomes when compared with that of PCI. doi: 10.1111/jocs.12056 (J Card Surg 2013;28:97–101)

Background Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM). Methods and Findings We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged ≥30 y with T2DM (6.2% ≤ HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of −0.009 mm (97.2% CI −0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference −0.159, 95% CI −0.278 to −0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation. Conclusions In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment. Trial Registration University Hospital Medical Information Network Clinical Trials Registry UMIN000004490, In a randomized controlled trial, Koichi Node and colleagues assess the efficacy of sitagliptin in limiting atherosclerosis among patients over 29 years of age living in Japan., Author Summary Why Was This Study Done? Translational research suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors, which are drugs for type 2 diabetes mellitus (T2DM), may prevent cardiovascular disease to a greater extent than other T2DM drugs. However, recently published large clinical trials showed no additional efficacy for DPP-4 inhibitors beyond that expected for the drugs’ glycemic control. Possibly these studies showed no benefit to cardiovascular health because they assessed cardiovascular mortality and other relatively rare outcomes. Change in carotid intima-media thickness (IMT) is a simple, noninvasive method to assess atherosclerosis, an intermediate and more common condition that can precede cardiovascular disease. What Did the Researchers Do and Find? We conducted a trial to evaluate whether DPP-4 inhibitors affect atherosclerosis in people with T2DM. In all, 463 participants recruited at 48 medical centers were randomly divided into two groups and treated with sitagliptin, a DPP-4 inhibitor, or other conventional drugs for two years. Carotid IMT was evaluated with ultrasonography in a blinded manner. We found that annual changes in carotid IMT were not significantly different between the two groups. On the other hand, the decrease in HbA1c and in the incidence of hypoglycemia with sitagliptin were superior to conventional therapy. The rate of other adverse events was not different between the two groups. What Do These Findings Mean? These findings provide no evidence that sitagliptin slows the progression of carotid intima-media thickening in participants with T2DM to a greater extent than conventional drugs. As some of the conventional anti-T2DM drugs have shown anti-atherosclerotic effects in clinical trials, the present findings do not mean that sitagliptin does not possess anti-atherosclerotic properties in participants with T2DM. Importantly, however, sitagliptin is useful for controlling hyperglycemia for clinical setting.

Although reports suggest that tolvaptan does not reduce survival or subsequent hospitalization rates in heart failure patients, its continuous use has shown good outcomes in some patients who cannot be effectively managed with high doses of loop diuretics. Therefore, we investigated the association of patient characteristics and continued tolvaptan use in heart failure patients with changes in the frequency and annual duration of patient hospitalization due to heart failure. We carefully reviewed the medical records of patients hospitalized due to heart failure who began tolvaptan therapy and continued with outpatient treatment between December 2010 and November 2013 (tolvaptan group); patients hospitalized for heart failure between May 2008 and March 2009 served as controls. We set the reference dates as the start of tolvaptan therapy (tolvaptan group) or as the date of admission (control group). The changes in hospitalization frequency and total hospitalization time due to heart failure, before and after the reference dates, were not significantly different between the tolvaptan and control groups. In the tolvaptan group, a high estimated glomerular filtration rate was a predictor of decreased hospitalization. Continuous tolvaptan use did not decrease hospitalization duration in all heart failure patients, but good renal function was predictive of a good response.

Sirolimus-eluting stent (SES) has shown a significant efficacy in reducing restenosis after percutaneous coronary interventions. However, an increase in total number of SES use along with targeting more complex lesions generated a large number of SES restenosis. This study aimed to investigate the clinical and angiographic outcomes of different revascularization strategies for SES restenosis.A total of 176 lesions in 149 patients were included in the study. Fifteen patients underwent coronary artery bypass graft surgery (CABG group) and the remaining patients were treated with percutaneous coronary intervention (PCI). Stent reimplantation was performed in 88 patients (Stent group), whereas 46 patients received balloon therapy (Balloon group). Among 176 lesions, major cardiac adverse event (MACE) occurred in 41 lesions (23.3%) during a median follow-up of 310 days (interquartile range: 146-517 days). The Kaplan-Meier method with a log-rank test revealed no significant difference in MACE rates between the three groups (6%, 25%, 26%, p = 0.13; CABG group, Stent group, Balloon group, respectively). However, when the Balloon group and Stent group were combined together as a PCI group, PCI group had a significantly higher rate of MACE compared with the CABG group (p = 0.04). In addition, angiographic restenosis was significantly less prevalent in the CABG group when compared with the other two groups (8%, 57%, 46%, p = 0.006; CABG group, Stent group, Balloon group, respectively).CABG surgery for patients with SES restenosis is associated with the better clinical outcomes as well as better angiographic outcomes when compared with that of PCI.

A 54-year-old man presented with recurrent hemoptysis of one year duration. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a saccular aneurysm of the ascending aorta. The aneurysm was intraoperatively found to have formed on the superior surface of the site of aortotomy suture placed during previous repair of rupture of the sinus of Valsalva and to have a fistulous communication to the lung. CT and MRI were very useful in the diagnosis of the aneurysm as the cause of hemoptysis.