Rivaroxaban or Apixaban for Non-Valvular Atrial Fibrillation　- Efficacy and Safety of Off-Label Under-Dosing According to Plasma Concentration.

BACKGROUND: Practice-based investigations on direct oral anticoagulant (DOAC) treatment for non-valvular atrial fibrillation (NVAF) have shown that off-label under-dosing is increasingly becoming an issue. Here, we investigate the significance of drug monitoring to prevent undesirable under-dosing with DOAC. Methods and Results: In 255 outpatients with NVAF undergoing treatment with rivaroxaban or apixaban we estimated the cut-offs for bleeding events using drug plasma concentration (PC) data 3 h after drug treatment, that is, at the peak level. Furthermore, we evaluated the appropriateness of labeled and off-label dosing implemented for 348 patients using the obtainable PC threshold. A total of 73 off-label under-dose users of rivaroxaban (37% of all users and 63% of lower dose users) had acceptable peak PC (155-400 ng/mL). Additionally, 46 off-label under-dose users of apixaban (31% of all users and 55% of lower dose users) received appropriate doses according to peak PC threshold (90-386.4 ng/mL). These off-label under-dose users reported no bleeding or thromboembolic events during follow-up. CONCLUSIONS: Anticoagulation monitoring enables personalized and appropriate off-label under-dosing in NVAF patients on rivaroxaban or apixaban through the measurement of peak PC during DOAC use.

Does Treatment of Impaired Glucose Tolerance Improve Cardiovascular Outcomes in Patients with Previous Myocardial Infarction?

PURPOSE: We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT). METHODS: This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure. RESULTS: The age, ratio of males, and HbA1C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints. CONCLUSION: Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00212017.

Prolonged delirium during hospitalization is associated with worse long-term and short-term outcomes in patients with acute heart failure.

BACKGROUND: The association between prolonged delirium during hospitalization and long-term prognosis in patients with acute heart failure (AHF) admitted to the cardiac intensive care unit (CICU) has not been fully elucidated. METHODS: We conducted a prospective registry study of patients with AHF admitted to the CICU at 2 hospitals from 2013 to 2021. We divided study patients into 3 groups according to the presence or absence of delirium and prolonged delirium as follows: no delirium, resolved delirium, or prolonged delirium. Main outcomes were in-hospital mortality and 3-year mortality after discharge. RESULTS: A total of 1555 patients with AHF (median age, 80 years) were included in the analysis. Of these, 406 patients (26.1%) developed delirium. We divided patients with delirium into 2 groups: the resolved delirium group (n = 201) or the prolonged delirium group (n = 205). Multivariate Cox proportional hazards models for long-term prognosis demonstrated that the prolonged delirium group had a higher incidence of all-cause death (hazard ratio [HR], 1.52; 95% CI, 1.08 to 2.14) and non-cardiovascular death (HR, 1.84; 95% CI, 1.21 to 2.78) than the resolved delirium group. Regarding in-hospital outcomes, multivariate logistic regression modeling showed that prolonged delirium is associated with all-cause death (odds ratio [OR], 9.55; 95% confidential interval [CI], 2.99 to 30.53) and cardiovascular death (OR, 13.02; 95% CI, 2.86 to 59.27) compared with resolved delirium. CONCLUSIONS: Prolonged delirium is associated with worse long-term and short-term outcomes than resolved delirium in patients with AHF.

Decreased serum ghrelin levels in patients with acute myocardial infarction.

Ghrelin is a novel growth hormone-releasing peptide isolated from the stomach and possesses various cardioprotective effects, including energy balance improvement and regulation of autonomic nervous system activity. We investigated the changes in serum ghrelin levels and its association with cardiac function and myocardial infarct size in patients with acute myocardial infarction (AMI). Forty-seven consecutive patients were divided into the following 4 groups: 16 patients with AMI, 12 patients with unstable angina pectoris (UAP), 13 patients with stable angina pectoris (SAP), and 6 control patients. Serum levels were measured with the ELISA kit. Compared to the control (72 ± 26 fmol/mL), SAP (69 ± 47 fmol/mL), and UAP (72 ± 31 fmol/mL) groups, serum ghrelin levels on admission were significantly lower in the AMI group (27 ± 12 fmol/mL, P < 0.01). After admission, the serum ghrelin level gradually increased (30 ± 15 fmol/mL on day 2 and 39 ± 18 fmol/mL on day 7) and became significantly higher on day 14 (49 ± 28 fmol/mL, P < 0.01), compared to the level on admission. In patients with AMI, the ratio of day 14 to admission serum ghrelin levels, an index of AMI-related acute changes in ghrelin, correlated positively with peak creatine phosphokinase levels (R = 0.72, P < 0.01) and the double products (R = 0.60, P < 0.01) and inversely with left ventricular ejection fraction (R = -0.53, P < 0.05). In conclusion, serum ghrelin levels are significantly decreased in association with myocardial infarct size and cardiac function.

Safety and Efficacy Re-Evaluation of Edoxaban and Rivaroxaban Dosing With Plasma Concentration Monitoring in Non-Valvular Atrial Fibrillation: With Observations of On-Label and Off-Label Dosing.

Background: Off-label dosing of direct oral anticoagulants (DOAC) as a treatment for non-valvular atrial fibrillation (NVAF) is problematic. Here, we investigated the status of rivaroxaban and edoxaban dosing by monitoring plasma concentrations (PCs). Methods and Results: We monitored drug PCs in 391 and 333 outpatients receiving rivaroxaban and edoxaban, respectively, for NVAF. Drug doses were adjusted if the PC was above the cut-off value (rivaroxaban: 404 ng/mL; edoxaban: 402 ng/mL), determined from receiver operating characteristic curves for predicting bleeding events. On-label standard dosing was reduced to off-label underdosing due to high PCs above the cut-off more often for rivaroxaban (28.1%) than edoxaban (12.6%; P<0.001). Over a median follow-up of 13 months for rivaroxaban and 10 months for edoxaban, the annual incidence of bleeding events was higher with rivaroxaban than with edoxaban (4.88 vs. 3.73 patient-years; P<0.05), although no thromboembolic events occurred in either group. Furthermore, for patients with creatinine clearance >50 mL/min and body weight ≤60 kg, there was a greater incidence of bleeding events with rivaroxaban on-label 15 mg dosing than with edoxaban on-label 30 mg dosing (22.2% vs 2.9%; P<0.01). Conclusions: Monitoring the PCs of rivaroxaban and edoxaban in NVAF patients enables dose adjustments to reduce bleeding risk. The incidence of bleeding under drug PC monitoring was less in the edoxaban than rivaroxaban group.

CORRIGENDUM: Safety and Efficacy Re-Evaluation of Edoxaban and Rivaroxaban Dosing With Plasma Concentration Monitoring in Non-Valvular Atrial Fibrillation: With Observations of On-Label and Off-Label Dosing.

[This corrects the article DOI: 10.1253/circrep.CR-22-0076.].

The first clinical pilot study of intravenous adrenomedullin administration in patients with acute myocardial infarction.

Adrenomedullin (AM) is a 52-amino-acid vasodilator peptide that was originally isolated from human pheochromocytoma. In the previous experimental study with rat ischemia/reperfusion model, AM reduced infarct size and inhibited myocyte apoptosis. AM also suppressed the production of oxygen-free radicals. The present study was designed to evaluate the feasibility of intravenous administration of AM in patients with acute myocardial infarction. We studied 10 patients with first acute myocardial infarction [male to female ratio: 9 to 1, age: 65 ± 9 (mean ± SD) years, peak creatine phosphokinase level: 4215 ± 1933 (SD) U/L], who were hospitalized within 12 hours of symptom onset. Proceeding reperfusion therapy, AM infusion was initiated and continued at concentration of 0.0125-0.025 µg·kg·min for 12 hours. Follow-up coronary angiography and left ventriculography were performed at 3 months. Cardiac magnetic resonance was examined at 1 month and 3 months after AM therapy. During infusion of AM, hemodynamics kept stable except 2 patients. Wall motion index in the infarct area at 3 months was significantly improved compared with that at baseline, and infarct size evaluated by cardiac magnetic resonance was significantly decreased at 3 months. In conclusion, intravenous administration of AM, which possesses a variety of potential cardiovascular protective actions, can be adjunctive to percutaneous coronary intervention.

Significant association of coronary artery calcification in stent delivery route with restenosis after sirolimus-eluting stent implantation.

BACKGROUND: Sirolimus-eluting stent (SES) has revolutionized interventional cardiology. Its application is spreading to complex, high-risk subsets of patients and lesions. Therefore, it is important to determine the factors associated with post-SES restenosis. METHODS AND RESULTS: The study investigated 341 patients with angina pectoris, in whom SES was implanted. The coronary artery calcification (CAC) degree was assessed using the angiographic scoring system as follows: 0, none; 1, blocky or spotty calcification; 2, linear calcification compromising 1 side of the arterial lumen; 3, linear calcification found unidirectionally compromising both sides of the arterial lumen; 4, linear calcification found bidirectionally compromising both sides of the arterial lumen; and 5, blanket/circumferential and dense calcification. Restenosis was observed in 23 patients (7.3%). The target lesion (1.8 +/-1.7 vs 0.7 +/-1.1 [mean +/- SD]) and stent delivery route CAC scores (3.1 +/-2.5 vs 1.4 +/-2.0) were significantly higher in patients with restenosis than in those without it (P<0.0001). In multivariate analysis, the CAC score of the stent delivery route was independently associated with restenosis (odds ratio of 6.804, P<0.05), although CAC score of the target lesion was not. CONCLUSIONS: CAC in the stent delivery route is an important determinant of post-SES restenosis.

Quantitative coronary angiographic studies of patients with angina pectoris and impaired glucose tolerance.

OBJECTIVE: We investigated the morphological characteristics of coronary arteries in patients with impaired glucose tolerance (IGT) using computer-assisted quantitative coronary angiography. IGT is an independent risk factor for cardiovascular disease. However, the morphological changes developing in the coronary arteries of patients with IGT remain unknown. RESEARCH DESIGN AND METHODS: A total of 534 patients with angina pectoris were studied. Of these, 144 patients were being treated for diabetes. The remaining 390 patients were classified as follows depending on the results of a 75-g oral glucose tolerance test: normal glucose tolerance (NGT) (n = 117), impaired fasting glucose (n = 3), IGT (n = 136), and diabetes pattern (preclinical diabetes) (n = 134). The diameters of the middle section of all major coronary artery segments were measured and averaged to determine the averaged vessel diameter (AVD). We defined segments of a diameter of < or = 1.5 mm as diseased lesions and determined the averaged lesion length (ALL). RESULTS: AVD and ALL were significantly different among patients with IGT and those with NGT. Patients with diabetes (preclinical and/or treated) had smaller AVD and longer ALL than those with IGT. By multivariate analysis, postprandial glucose levels were shown to be independently associated with an AVD <3.0 mm and an ALL >20 mm. CONCLUSIONS: Diffuse coronary artery narrowing develops not only in patients with diabetes but also in those with IGT. This morphological change is associated with postprandial hyperglycemia.

Aldehyde dehydrogenase 2 gene is a risk factor for myocardial infarction in Japanese men.

In epidemiological studies, moderate alcohol consumption has been consistently associated with a reduced risk of myocardial infarction (MI). About half of Japanese show an extremely high sensitivity to alcohol (ethanol), which is due to a missense mutation from glutamic acid (Glu) to lysine (Lys) at codon 487 in an isoenzyme of aldehyde dehydrogenase (ALDH2) with a low Km. We obtained a preliminary result that subjects homozygous for the Lys 487 allele had higher risk for myocardial infarction. The purpose of the present study was to assess this hypothesis by employing a larger cohort of subjects with MI. The experimental group consisted of 342 male subjects with demonstrated MI who were selected randomly from our outpatient clinic. As controls, we employed 1,820 male subjects with no cardiovascular complications who were selected from the Suita Study. All subjects provided their written informed consent to participate in the genetic analyses. Subjects with MI were older and had higher body mass index, higher prevalence of diabetes mellitus, higher prevalence of smoking habit, higher prevalence of the Lys/Lys genotype (homozygous for Lys 487 allele), and lower high density lipoprotein (HDL) cholesterol level (HDL-C). The ALDH2 genotype affected the level of alcohol consumption, and HDL-C. Multiple logistic analyses indicated that the odds ratio of the Lys/Lys genotype to the Lys/Glu+Glu/Glu genotype was 1.56 (p=0.0359). Inclusion of HDL-C as one of the independent variables downplayed the importance of the ALDH2 genotype. This may indicate that the ALDH2 genotype affects MI via its effects on HDL-C. In conclusion, the ALDH2 Lys/Lys genotype is a risk factor for myocardial infarction in Japanese men due to its influence on HDL cholesterol level.

Exercise training without ventricular remodeling in patients with moderate to severe left ventricular dysfunction early after acute myocardial infarction.

BACKGROUND: The purpose of this study was to determine whether or not patients with moderate to severe left ventricular (LV) dysfunction benefit from exercise training starting early after acute myocardial infarction (AMI) without deteriorating LV remodeling. METHODS: We investigated changes in exercise capacity and LV end-diastolic dimension (LVDd by two-dimensional echocardiography) before and after exercise training in 126 patients after AMI. Patients were divided into three groups according to LV ejection fraction (EF) at the beginning of exercise training: 74 patients with LVEF>/=45% (Group H), 35 patients with 35%