Tsuyoshi Shiga

Sudden Cardiac Death and Left Ventricular Ejection Fraction During Long-Term Follow-up After Acute Myocardial Infarction in the Primary Percutaneous Coronary Intervention Era. Results from the HIJAMI-II Registry

Objective: To determine the incidence of sudden cardiac death (SCD) according to left ventricular ejection fraction (LVEF) in survivors of myocardial infarction (MI) in the primary percutaneous coronary intervention (PCI) era. Design: A multicentre observational prospective registered cohort study. Setting: 18 medical centres in Japan. Patients: 4122 consecutive patients (mean age 66 (SD 12) years, 73.7% male) with acute MI, who were discharged alive. Main outcome measures: The primary end-point was SCD, and a secondary end-point was death from any cause. Results: Patients were categorised into three groups: LVEF >40% (n = 3416), LVEF ⩽40% and >30% (n = 507) and LVEF ⩽30% (n = 199). Among all patients, 77.8% received PCI and 3.7% received coronary artery bypass graft surgery. During an average follow-up of 4.1 years, SCD was 1.2% and mortality was 13.1%. Patients with LVEF ⩽30% and LVEF ⩽40% and >30% were at increased risk for SCD (HR 5.99, 95% CI 2.73 to 13.14, p<0.001, HR 3.37, 95% CI 1.74 to 6.50, p<0.001, respectively), and mortality (HR 3.85, 95% CI 2.96 to 5.00, p<0.001, HR 2.06, 95% CI 1.66 to 2.57, p<0.001, respectively), compared to patients with LVEF >40%. Kaplan-Meier estimates of SCD in patients with LVEF ⩽30% were 2.9%, 5.1% and 5.1% at 1, 3 and 5 years, respectively. Conclusion: There is a low incidence of SCD in survivors of MI in the primary PCI era, although LVEF is a predictor of increased risk for SCD.

Long-term prognosis of diabetic patients with acute myocardial infarction in the era of acute revascularization

BackgroundThe long-term prognosis of diabetic patients with acute myocardial infarction (AMI) treated by acute revascularization is uncertain, and the optimal pharmacotherapy for such cases has not been fully evaluated.MethodsTo elucidate the long-term prognosis and prognostic factors in diabetic patients with AMI, a prospective, cohort study involving 3021 consecutive AMI patients was conducted. All patients discharged alive from hospital were followed to monitor their prognosis every year. The primary endpoint of the study was all-cause mortality, and the secondary endpoint was the occurrence of major cardiovascular events. To elucidate the effect of various factors on the long-term prognosis of AMI patients with diabetes, the patients were divided into two groups matched by propensity scores and analyzed retrospectively.ResultsDiabetes was diagnosed in 1102 patients (36.5%). During the index hospitalization, coronary angioplasty and coronary thrombolysis were performed in 58.1% and 16.3% of patients, respectively. In-hospital mortality of diabetic patients with AMI was comparable to that of non-diabetic AMI patients (9.2% and 9.3%, respectively). In total, 2736 patients (90.6%) were discharged alive and followed for a median of 4.2 years (follow-up rate, 96.0%). The long-term survival rate was worse in the diabetic group than in the non-diabetic group, but not significantly different (hazard ratio, 1.20 [0.97-1.49], p = 0.09). On the other hand, AMI patients with diabetes showed a significantly higher incidence of cardiovascular events than the non-diabetic group (1.40 [1.20-1.64], p < 0.0001). Multivariate analysis revealed that three factors were significantly associated with favorable late outcomes in diabetic AMI patients: acute revascularization (HR, 0.62); prescribing aspirin (HR, 0.27); and prescribing renin-angiotensin system (RAS) inhibitors (HR, 0.53). There was no significant correlation between late outcome and prescription of beta-blockers (HR, 0.97) or calcium channel blockers (HR, 1.27). Although standard Japanese-approved doses of statins were associated with favorable outcome in AMI patients with diabetes, this was not statistically significant (0.67 [0.39-1.06], p = 0.11).ConclusionsAlthough diabetic patients with AMI have more frequent adverse events than non-diabetic patients with AMI, the present results suggest that acute revascularization and standard therapy with aspirin and RAS inhibitors may improve their prognosis.

Effect of cimetidine and probenecid on pilsicainide renal clearance in humans

To investigate the effect of cimetidine and probenecid on the renal clearance of pilsicainide in healthy subjects.

Meta-Analysis: Effects of Probiotic Supplementation on Lipid Profiles in Normal to Mildly Hypercholesterolemic Individuals

Introduction Recent experimental and clinical studies have suggested that probiotic supplementation has beneficial effects on serum lipid profiles. However, there are conflicting results on the efficacy of probiotic preparations in reducing serum cholesterol. Objective To evaluate the effects of probiotics on human serum lipid levels, we conducted a meta-analysis of interventional studies. Methods Eligible reports were obtained by searches of electronic databases. We included randomized, controlled clinical trials comparing probiotic supplementation with placebo or no treatment (control). Statistical analysis was performed with Review Manager 5.3.3. Subanalyses were also performed. Results Eleven of 33 randomized clinical trials retrieved were eligible for inclusion in the meta-analysis. No participant had received any cholesterol-lowering agent. Probiotic interventions (including fermented milk products and probiotics) produced changes in total cholesterol (TC) (mean difference –0.17 mmol/L, 95% CI: –0.27 to –0.07 mmol/L) and low-density lipoprotein cholesterol (LDL-C) (mean difference –0.22 mmol/L, 95% CI: –0.30 to –0.13 mmol/L). High-density lipoprotein cholesterol and triglyceride levels did not differ significantly between probiotic and control groups. In subanalysis, long-term (>4-week) probiotic intervention was statistically more effective in decreasing TC and LDL-C than short-term (≤4-week) intervention. The decreases in TC and LDL-C levels with probiotic intervention were greater in mildly hypercholesterolemic than in normocholesterolemic individuals. Both fermented milk product and probiotic preparations decreased TC and LDL-C levels. Gaio and the Lactobacillus acidophilus strain reduced TC and LDL-C levels to a greater extent than other bacterial strains. Conclusions In conclusion, this meta-analysis showed that probiotic supplementation could be useful in the primary prevention of hypercholesterolemia and may lead to reductions in risk factors for cardiovascular disease.

Clinical outcome in Japanese elderly patients with non-valvular atrial fibrillation taking warfarin: A single-center observational study

BACKGROUND Although a lower target prothrombin time-international normalized ratio (PT-INR) with warfarin therapy is recommended in Japan for atrial fibrillation (AF) patients ≥70 years of age, few studies have provided supporting data. The current study aimed to evaluate the clinical outcome in elderly Japanese patients with non-valvular AF who were taking warfarin. METHODS We conducted a cohort study of 845 consecutive non-valvular AF patients ≥70 years of age who were taking warfarin (median age, 74 years; 30.5% women) with a median follow-up period of 27 months (4-69 months). Of these patients, 29.7% had a history of stoke/transient ischemic attack (TIA), and 73.1% of the patients had a CHADS(2) score ≥2. The occurrence of thromboembolic events, including ischemic stroke, TIA and other systemic embolisms, and major bleeding events were validated through a review of medical records. RESULTS The incidence of thromboembolic and major bleeding events were 3.8 and 2.1% per year, respectively. A higher incidence of both events was observed in patients with a CHADS(2) score ≥3. The multivariate analysis showed that prior stroke/TIA (odds ratio 1.7, 95% CI 1.0-2.7) and diabetes (odds ratio 1.7, 95% CI 1.0-2.8) were independent risks of thromoembolic events. A HAS-BLED score ≥3 represented a risk for major bleeding (hazard ratio 2.8, 95% CI 1.7-4.6). A PT-INR of 1.5-2.5 indicated a low incidence of thromboembolic and major bleeding events in patients with a CHADS(2) score ≥2. CONCLUSIONS Our results demonstrate that a target PT-INR of 2.0 and a range of 1.5-2.5 may be safe for elderly Japanese patients with non-valvular AF.

Role of Desethylamiodarone in the Anticoagulant Effect of Concurrent Amiodarone and Warfarin Therapy

Background: The concurrent use of amiodarone and warfarin inhibits metabolism of S-war-farin by cytochrome P450 (CYP) 2C9, thereby increasing the anticoagulant effect of war-farin. Amiodarone primarily inhibits CYP1A2 and CYP3A4, and desethylamiodarone primarily inhibits CYP2C9. We investigate whether a relationship exists between the plasma concentration of desethylamiodarone and anticoagulation when amiodarone is administered to patients receiving warfarin therapy. Methods and Results: The correlation between the plasma concentration of either amiodarone or desethylamiodarone, and prolongation of prothrombin time-international normalized ratio/dose of warfarin (A INR/Dose) on day 7 of amiodarone administration was studied in 25 patients (22-74 years old) with structural heart disease and refractory arrhythmias receiving stable warfarin therapy. Results: No correlation was found between the plasma concentration of amiodarone and A INR/Dose, but a correlation was found between the plasma concentration of desethylamiodarone and A INRIDose. Conclusions: It was suggested that inhibition of CYP2C9 by desethylamiodarone, the active metabolite of amiodarone, plays an important role in the interaction of warfarin and amiodarone.

Comparison of cilostazol and ticlopidine for one-month effectiveness and safety after elective coronary stenting

AbstractPurpose: To compare the oral antiplatelets, phosphodiesterase III inhibitor cilostazol and the thienopyridine ticlopidine, for one-month effectiveness and safety as an adjunctive therapy after coronary stenting. Methods: Published studies retrieved through Medline and other databases from 1966–2002. Meta-analyses evaluated effectiveness and adverse side effects for one-month administrations of aspirin plus cilostazol or aspirin plus ticlopidine therapy after coronary stenting. Major adverse cardiac events (MACE), stent-associated thrombosis or adverse side effects after coronary stenting were compared between the two study arms and expressed with the odds ratios (OR) specific for the individual studies and meta-analytic summary for OR. Results: Five clinical studies met the inclusion criteria, and 4 of these studies underwent meta-analysis. With regard to the comparison of the OR summary for MACE and stent-associated thrombosis for the clinical outcome, there were no statistical significant differences between aspirin plus cilostazol and aspirin plus ticlopidine. While, the incidence of adverse side effects tended to be lower, they were not statistically significant in patients with aspirin plus cilostazol. Conclusions: Our meta-analysis results indicated that there were no differences between cilostazol (plus aspirin) and ticlopidine (plus aspirin) with regard to effectiveness and safety for a one-month period when used as an adjunctive therapy after coronary stenting.

Differences of Chronopharmacokinetic Profiles Between Propranolol and Atenolol in Hypertensive Subjects

Previous studies have shown that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the night dosage than after the morning dosage in nocturnal rodents. The present study examines whether such a difference in chronopharmacokinetic proxies between lipophilic and hydrophilic agents also exists in humans. Propranolol (20 mg), a lipophilic β‐blocker, or atenolol (50 mg), a hydrophilic β‐blocker, was given orally to 13 hypertensive patients at 9:00 am (day trial) or 9:00 pm (night trial) by a crossover design. Plasma concentrations of propranolol and its metabolites, 4‐hydroxypropranolol and naphthoxylactic acid, and atenolol were determined just before and at 0.5, 1, 1.5, 2, 3, 4, 6, 12, and 24 hours after treatment. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) of propranolol in the day trial were significantly greater than those in the night trial Time to maximum plasma concentration (tmax) was significantly shorter in the day trial. No significant difference was observed in the elimination half‐life between the two trials. There were similar administration time‐dependent changes in the Cmaxfor 4‐hydroxypropranolol and naphthoxylactic acid. On the other hand, although the Cmax of atenolol was greater and its tmax was shorter in the day trial, the differences did not reach significance. These results suggest that propranolol, but not atenolol is absorbed more rapidly after the morning dosage than after the night dosage. Based on these findings, the authors speculate that the absorption rate of a lipophilic, but not hydrophilic, agent is faster after the morning dosage than after the night dosage in humans.

Persistence of non-vitamin K antagonist oral anticoagulant use in Japanese patients with atrial fibrillation: A single-center observational study

Non‐vitamin K antagonist oral anticoagulants (NOACs) show a favorable balance between efficacy and safety compared with warfarin for patients with non‐valvular atrial fibrillation (NVAF). In “real‐world” practice, however, NOAC adherence and persistence among patients are not clear. The aim of this study is to evaluate NOAC and warfarin persistence in Japanese patients with NVAF who newly started these drugs.

Differences in hemodynamic responses between intravenous carperitide and nicorandil in patients with acute heart failure syndromes

While recent guidelines for the treatment of acute heart failure syndromes (AHFS) recommend pharmacotherapy with vasodilators in patients without excessively low blood pressure (BP), few reports have compared the relative efficiency of vasodilators on hemodynamics in AHFS patients. The present study aimed to assess the differences in hemodynamic responses between intravenous carperitide and nicorandil in patients with AHFS. Thirty-eight consecutive patients were assigned to receive 48-h continuous infusion of carperitide (n = 19; 0.0125–0.05 μg/kg/min) or nicorandil (n = 19; 0.05–0.2 mg/kg/h). Hemodynamic parameters were estimated at baseline, and 2, 24, and 48 h after drug administration using echocardiography. After 48 h of infusion, systolic BP was significantly more decreased in the carperitide group compared with that in the nicorandil group (22.1 ± 20.0 % vs 5.3 ± 10.4 %, P = 0.003). While both carperitide and nicorandil significantly improved hemodynamic parameters, improvement of estimated pulmonary capillary wedge pressure was greater in the carperitide group (38.2 ± 14.5 % vs 26.5 ± 18.3 %, P = 0.036), and improvement of estimated cardiac output was superior in the nicorandil group (52.1 ± 33.5 % vs 11.4 ± 36.9 %, P = 0.001). Urine output for 48 h was greater in the carperitide group, but not to a statistically significant degree (4203 ± 1542 vs 3627 ± 1074 ml, P = 0.189). Carperitide and nicorandil were differentially effective in improving hemodynamics in AHFS patients. This knowledge may enable physicians in emergency wards to treat and manage patients with AHFS more effectively and safely.