Prasugrel for Japanese Patients With Ischemic Heart Disease in Long-Term Clinical Practice (PRASFIT-Practice II)　- Final 2-Year Follow-up Results of a Postmarketing Observational Study.

BACKGROUND: PRASFIT-Practice II is a postmarketing observational study conducted in 4,155 Japanese patients with ischemic heart disease (IHD) who received long-term prasugrel. The data were used to assess the utility of Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria.Methods and Results:Patients in PRASFIT-practice II were clinically followed for 2 years. The primary endpoint was the cumulative incidence of major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding. Patients were divided into 2 groups based on ARC-HBR criteria (HBR (40.1% of patients) and non-HBR (59.9%)) and the effect of HBR on the primary endpoint was assessed. The median duration of dual antiplatelet therapy with prasugrel was 391.0 days. At 2 years, the cumulative incidence of MACE was 3.3%, and of TIMI major/minor bleeding was 2.7%. At 1 year, MACE and TIMI major/minor bleeding in the HBR group (4.0% and 3.4%, respectively) were higher than that in the non-HBR group (1.3% for both). Landmark analysis at 3 months and 1 year showed that the higher risk of MACE or TIMI major/minor bleeding in the HBR group persisted through 2 years. CONCLUSIONS: The results of this study confirmed the safety and effectiveness of long-term treatment with prasugrel, and demonstrated that the ARC-HBR criteria for bleeding risk are applicable in Japanese IHD patients treated with prasugrel.

Prasugrel for Japanese Patients With Ischemic Heart Disease in Long-Term Clinical Practice (PRASFIT-Practice II)　- 1-Year Follow-up Results of a Postmarketing Observational Study.

BACKGROUND: Although the effectiveness and safety of prasugrel for the prevention of cardiovascular events in patients with ischemic heart disease (IHD) undergoing percutaneous coronary intervention (PCI) have been demonstrated, long-term real-world data of Japanese unique doses are insufficient. Therefore, we report the results of an analysis of 1-year follow-up data from a postmarketing observational study (PRASFIT-Practice II).Methods and Results:The safety and effectiveness analysis sets included 4,155 IHD patients receiving prasugrel (loading dose/maintenance dose, 20/3.75 mg) as dual antiplatelet therapy (DAPT) with aspirin. At 360 days (after treatment start), 62.2% continued DAPT. Cumulative incidences of major adverse cardiovascular events and stent thrombosis were 1.6% and 0.2%, respectively. Cumulative incidences of Thrombolysis In Myocardial Infarction (TIMI) major bleeding and TIMI major or minor bleeding were 1.0% and 2.0%, respectively. Risk factors for TIMI major or minor bleeding in the first 30 days of treatment were age ≥80 years, anemia, female sex, and liver disease, and from day 31 to the end of month 12, hypertension and peptic ulcer. CONCLUSIONS: The 1-year follow-up results showed long-term effectiveness and safety of prasugrel at dosages approved in Japan for the treatment of IHD patients undergoing PCI.

Prasugrel for Japanese Patients With Ischemic Heart Disease in Long-Term Clinical Practice (PRASFIT-Practice II)　- A 3-Month Interim Analysis of a Postmarketing Observational Study.

BACKGROUND: A unique dose of prasugrel has been approved exclusively for Japanese patients, but real-world data for prasugrel at that dose in patients with ischemic heart disease (IHD) are limited. Therefore, large-scale, real-world data are needed. Methods and Results: A 2-year observational study of Japanese patients with IHD undergoing percutaneous coronary intervention and being treated with prasugrel to evaluate safety and effectiveness. This report is an interim analysis of data from case report forms (CRFs) after 3 months. CRFs were collected from 4,270 patients, 4,157 of whom were eligible for the safety and effectiveness analysis sets (mean age, 68.3 years; male, 76.5%). The median treatment period was 112 days, and 92.3% of patients continued treatment with prasugrel. The incidence of non-coronary artery bypass grafting-related bleeding adverse events (AEs) was 3.1%, of which Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeding accounted for 0.5% and 0.6%, respectively. The most common bleeding AEs were gastrointestinal disorders, which accounted for 43.2% of the sum of "TIMI major and minor bleeding AEs". The incidence of major adverse cardiovascular events (MACE) was 1.0%, and the cumulative incidence of MACE was 1.4%. The incidence of stent thrombosis was 0.2%. CONCLUSIONS: Interim study results indicated that prasugrel was safe and effective during the early phase of treatment in Japanese patients with IHD in real-world clinical settings.

Bleeding risks associated with anticoagulant therapies after percutaneous coronary intervention in Japanese patients with ischemic heart disease complicated by atrial fibrillation: A comparative study.

BACKGROUND: Current guidelines recommend early termination of triple therapy and the use of direct oral anticoagulants (DOAC) for non-valvular atrial fibrillation (NVAF) patients who undergo percutaneous coronary intervention (PCI), due to safety concerns. However, to date, real-world medication usage and safety outcomes (specifically bleeding) in NVAF patients with stent implantation have not been well assessed. METHODS: This was a retrospective, observational, medical database cohort study in Japanese ischemic heart disease (IHD) patients with NVAF who underwent PCI between 2012 and 2017. The primary outcome was clinically relevant bleeding; secondary outcomes included individual bleeding events. A multivariate analysis was conducted to identify risk factors affecting the occurrence of clinically relevant bleeding events. RESULTS: The analysis population comprised 5695 patients [3530 received DOACs and 2165 received vitamin K antagonists (VKAs)]. The incidence of primary outcome events (clinically relevant bleeding/100 patient-years) was 6.05 in the DOAC group and 8.42 in the VKA group, resulting in a nonsignificant 21% lower risk in the DOAC group. The DOAC group also had a nonsignificant 24%, 24%, and 34% lower risk of bleeding requiring transfusion, intracranial bleeding, and lower gastrointestinal bleeding, respectively, compared with the VKA group. A multivariate analysis of the primary outcome showed a significantly higher risk of bleeding among older patients and those with lower body weight and abnormal renal function. CONCLUSIONS: In this retrospective real-world evaluation of IHD patients with NVAF and PCI, DOAC-treated patients had a lower risk of developing clinically relevant bleeding compared with the VKA group.

[The drug use results survey of Adenoscan injection 60 mg].

To investigate the safety and efficacy of Adenoscan injection 60 mg (adenosine), a pharmacologic stress agent that can be used for coronary vasodilation in patients unable to exercise adequately, the drug use results survey was conducted by consecutive patients-survey method in 166 nationwide medical institutes from 2006 to 2008. Adverse drug reactions (ADRs) occurred at the rate of 16.0% (343/2,150 patients), most of which disappeared shortly with no need for treatment. Major ADRs were chest discomfort at the rate of 4.9%, chest pain 2.0%, atrioventricular block 1.8% and dyspnea 1.4%. There were no differences in the incidences of ADRs between the elderly and the non-elderly. The overall efficacy rate was 97.9% (2,104/2,150 patients) according to the efficacy judgment of each primary physician. The sensitivity, specificity and diagnostic accuracy of myocardial perfusion scintigraphy in 608 patients who underwent coronary angiography were 70.8%, 58.1% and 65.0%, respectively. We conclude that adenosine stress is safe and useful for myocardial perfusion scintigraphy to detect ischemic heart disease for patients who are unable to exercise adequately.

Prasugrel for Japanese patients with acute coronary syndrome in short-term clinical practice (PRASFIT-Practice I): a postmarketing observational study.

Data on prasugrel use in Japanese patients are limited to phase II/III clinical trials. This early postmarketing observational study evaluated the safety and efficacy of short-term prasugrel use in patients with acute coronary syndrome (ACS) in real-world clinical settings in Japan. From May 2014 to January 2015, we enrolled consecutive patients with ACS requiring percutaneous coronary intervention in each institution. Each patient started prasugrel treatment ≥1 month before the end of the study period. Safety outcomes included incidence rates of adverse drug reactions (ADRs) and bleeding adverse events (AEs). Efficacy outcomes were incidence rates of cardiovascular events (including major adverse cardiovascular events [MACE]). Case report forms were collected from 749 patients, 732 of whom were eligible for the safety and efficacy analysis sets. Approximately 95% of patients had a prasugrel loading/maintenance dose of 20 mg/3.75 mg/day. The incidences of ADRs and bleeding AEs were 8.6 and 6.4%, respectively. Twelve patients experienced major bleeding AEs; approximately 60% (seven patients) of which were gastrointestinal disorders. The incidence of bleeding AEs was significantly higher primarily in patients of female sex, aged ≥75 years, with low body weight (≤50 kg), severe cardiovascular disease, or severe renal impairment. The incidence of MACE was 1.9% during prasugrel treatment, and 3.1% at the end of the study period. This short-term study indicated that prasugrel treatment at loading/maintenance doses of 20 mg/3.75 mg/day was safe and effective in Japanese ACS patients in an acute setting. CLINICAL TRIAL REGISTRATION: This study is registered at http://www.umin.ac.jp/ctr/ under the identifier UMIN000014699.

Artist® tablets (carvedilol) for hypertensive patients in Japan: results of a long-term special survey.

BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey. OBJECTIVE: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the ß-adrenergic receptor antagonist (ß-blocker) Artist® tablets 10 mg, 20 mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months). PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment. RESULTS: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5 mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL).[n = 141; p = 0.310]. In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001). CONCLUSIONS: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.

Artist® tablets (carvedilol) for hypertensive patients in Japan: results of a drug use survey.

BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14.4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a drug use survey, which we conducted as a post-marketing survey. OBJECTIVE: This prospective post-marketing drug use survey was conducted to assess the safety and efficacy of the ß-adrenergic receptor antagonist (ß-blocker) Artist® Tablets (carvedilol) in patients with hypertension in Japan. PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: This was a prospective survey conducted over 3 years from October 1993 to September 1996. The standard observation period for the patients was defined as 12 weeks of treatment with carvedilol. RESULTS: We collected data on 4961 patients at 561 medical institutions who had not been previously treated with carvedilol; 4574 patients were included in the safety analysis and 4422 in the efficacy analysis. The incidence of adverse drug reactions (the proportion of patients with adverse drug reactions) was 4.31% (197 of 4574 patients), which is less than that shown in the pre-approval clinical trial of carvedilol (6.85% [68 of 993]). The most common adverse drug reactions were bradycardia, dizziness, hypotension, headache, and feeling light-headed. After 12 weeks' treatment with carvedilol, systolic/diastolic blood pressure (SBP/DBP) was reduced from 168.2 ± 18.6/95.7 ± 11.3 mmHg at baseline to 144.3 ± 17.3/83.4 ± 10.8 mmHg. Patients were classified according to which antihypertensive drug they had been using when carvedilol treatment was initiated. Coadministered agents were calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), diuretics, and α-adrenergic receptor antagonists (α-blockers). At 12 weeks, the change in SBP/DBP in the monotherapy group was -22.7/-12.2 mmHg and that of each combination therapy subgroup, CCB, ACEI, diuretic, and ß-blocker, was -26.1/-12.7 mmHg, -25.4/-11.9 mmHg, -26.3/-13.0 mmHg, and -24.4/-11.5 mmHg, respectively. The achievement rates for target BP (<140/90 mmHg) were 29.5% in the monotherapy group, 34.8% in the CCB group, 31.3% in the ACEI group, 31.8% in the diuretic group, and 32.4% in the ß-blocker group. There was no significant difference in the achievement of target BP among the four combination therapy subgroups (p = 0.475). These results indicate that carvedilol exerts reasonable BP reduction regardless of whether it is used as monotherapy or in combination therapy, and that the effect is not influenced by the coadministered drug. Moreover, carvedilol was also effective in reducing BP levels in elderly patients (≥65 years) and in patients with diabetes mellitus or renal diseases. CONCLUSIONS: The results of this study reflect the results of clinical trials up to the time of approval and it was confirmed that carvedilol is a highly useful drug in the treatment of hypertension.

Effects of water hardness and existence of adsorbent on toxic surface tension of surfactants for aquatic species.

We have studied the effectiveness of surface tension on surfactants risk assessment. gamma(tox) was defined as surface tension at a point where acute aquatic toxicity of a surfactant emerges. Oryzias latipes, Daphnia magna, and Podocopida were used for acute aquatic toxicity test of 7 surfactants and 3 detergents. Gamma(tox)values were plotted on surface tension curves, and the effect of water hardness on toxicity and surface tension were examined. Results showed that gamma(tox) varies greatly by kind of surfactant or detergent. Therefore, aquatic toxicity cannot only be explained by surface tension. The change of aquatic toxicity with varying water hardness, however, could be explained by the change of surface tension. Aquatic toxicity of LAS (Linear Alkylbenzene Sulphonate) increased and aquatic toxicity of SOAP decreased with an increase of water hardness, but both gamma(tox), values were constant. Aquatic toxicity was decreased by an addition of mud soil as adsorbent into surfactant solution. The toxicity change can be explained by the surface tension since gamma(tox) value of solution with and without mud soil were equal. These results showed that the change of aquatic toxicity of a surfactant caused by water property, such as water hardness, could be explained by the change of surface tension.