Exploratory rivaroxaban trial for isolated calf deep vein thrombosis with a risk factor of thrombosis extension: an open-label, multicenter, randomized controlled trial.

Background: Limited evidence exists regarding the incidence of recurrent venous thromboembolism (VTE) in patients diagnosed with isolated distal deep vein thrombosis (DVT) who are at risk of thrombosis extension whether they receive anticoagulation therapy or not. Objectives: The study aimed to investigate the incidence of recurrent VTE and the impact of rivaroxaban in this patient population. Methods: This open-label, exploratory, and randomized controlled trial was conducted at 7 centers in Japan between April 2019 and April 2022. Adult patients with isolated distal DVT at risk of thrombosis extension received either rivaroxaban combined with physical therapy or physical therapy alone for 90 days. Whole-leg ultrasound was performed at 14 and 90 days. We assessed a composite outcome of symptomatic or asymptomatic proximal DVT or symptomatic pulmonary embolism as the primary outcome until the end of the treatment period using an intention-to-treat analysis. Major bleeding was evaluated as a key secondary outcome. Results: Out of 90 enrolled patients, 3 were excluded due to withdrawal of consent; therefore, we analyzed 87 participants. The rivaroxaban group (n = 42) reported no primary outcomes (0%; 95% CI, 0.0%-8.4%), whereas the physical therapy group (n = 45) had 2 cases of symptomatic proximal DVT (4.4%; 95% CI, 0.5%-15.1%). Major bleeding events occurred in 4 patients in the rivaroxaban group (9.5%; 95% CI, 2.7%-22.6%), whereas no events occurred in the physical therapy group (0%; 95% CI, 0%-7.9%). Conclusion: Preliminary data suggest that rivaroxaban may reduce the risk of VTE recurrence among this patient subset, albeit with an increased incidence of bleeding events.

Incidence of stroke, systemic embolism and bleeding events in patients without anticoagulation based on real-world data in Japan: a retrospective cohort study.

OBJECTIVES: To examine the incidence of stroke or systemic embolic events (SSEs) and bleeding events in untreated patients with non-valvular atrial fibrillation (NVAF) after widespread use of direct oral anticoagulant agents (DOACs). DESIGN: Multicentre, non-interventional, observational, retrospective cohort study using real-world data in Japan (2016-2018). SETTING: The Mie, Musashino University study of NVAF, which used the Mie-Life Innovation Promotion Center Database. This is a regional clinical database involving one university hospital and eight general hospitals in Mie Prefecture in Japan. PARTICIPANTS: Japanese patients with NVAF (n=7001). PRIMARY AND SECONDARY OUTCOME: The incidence of SSEs and bleeding events. RESULTS: A total of 7001 patients with NAVF were registered, and 53.0% were treated with DOACs, 10.6% were treated with warfarin and 36.4% had no treatment. Additionally, 29.5% of patients with a CHADS2 (congestive heart failure, hypertension, age≥75 years, diabetes, previous stroke or transient ischemic attack) score of 3-6 were untreated. In the no treatment group, the SSE rates by the CHADS2 score (0, 1, 2 and 3-6) were 1.4%, 1.4%, 3.2% and 8.0%, respectively. The rates of bleeding events by the CHADS2 score (0, 1, 2 and 3-6) in the no treatment group were 0.7%, 1.0%, 1.2% and 2.9%, respectively. A multivariate analysis of SSEs in components of the CHADS2 showed that the adjusted HRs were 2.32 for heart failure, 1.66 for an age ≥75 years, 1.81 for diabetes mellitus and 5.84 for prior stroke or transient ischaemic attack. CONCLUSIONS: Approximately one-third of the patients do not receive any anticoagulation in the modern DOAC era in Japan. The SSE rate increases by the CHADS2 score. The SSE rate is low in patients with a CHADS2 score <1, supporting no indication of anticoagulation in current guidelines. In patients with a CHADS2 score >1, the use of anticoagulant drug therapy is recommended because of a higher risk of stroke.

Blood Pressure Level and Variability During Long-Term Prasugrel or Clopidogrel Medication After Stroke: PRASTRO-I.

BACKGROUND AND PURPOSE: High blood pressure increases bleeding risk during treatment with antithrombotic medication. The association between blood pressure levels and the risk of recurrent stroke during long-term secondary stroke prevention with thienopyridines (particularly prasugrel) has not been well studied. METHODS: This was a post hoc analysis of the randomized, double-blind, multicenter PRASTRO-I trial (Comparison of Prasugrel and Clopidogrel in Japanese Patients With Ischemic Stroke-I). Patients with noncardioembolic stroke were randomly assigned (1:1) to receive prasugrel 3.75 mg/day or clopidogrel 75 mg/day for 96 to 104 weeks. Risks of any ischemic or hemorrhagic stroke, combined ischemic events, and combined bleeding events were determined based on the mean level and visit-to-visit variability, including successive variation, of systolic blood pressure (SBP) throughout the observational period. These risks were also compared between quartiles of mean SBP level and successive variation of SBP. RESULTS: A total of 3747 patients (age 62.1±8.5 years, 797 women), with a median average SBP level during the observational period of 132.5 mm Hg, were studied. All the risks of any stroke (146 events; hazard ratio, 1.318 [95% CI, 1.094-1.583] per 10-mm Hg increase), ischemic stroke (133 events, 1.219 [1.010-1.466]), hemorrhagic stroke (13 events, 3.247 [1.660-6.296]), ischemic events (142 events, 1.219 [1.020-1.466]), and bleeding events (47 events, 1.629 [1.172-2.261]) correlated with increasing mean SBP overall. Similarly, an increased risk of these events correlated with increasing successive variation of SBP (hazard ratio, 3.078 [95% CI, 2.220-4.225] per 10-mm Hg increase; 3.051 [2.179-4.262]; 3.276 [1.172-9.092]; 2.865 [2.042-4.011]; 2.764 [1.524-5.016], respectively). Event rates did not differ between the clopidogrel and prasugrel groups within each quartile of SBP or successive variation of SBP. CONCLUSIONS: Both high mean SBP level and high visit-to-visit variability in SBP were significantly associated with the risk of recurrent stroke during long-term medication with either prasugrel or clopidogrel after stroke. Control of hypertension would be important regardless of the type of antiplatelet drugs. Registration: URL: https://www.clinicaltrials.jp; Unique identifier: JapicCTI-111582.

Efficacy and Safety of Prasugrel by Stroke Subtype: A Sub-Analysis of the PRASTRO-I Randomized Controlled Trial.

AIMS: The efficacy of antiplatelet therapy may vary among different disease subtypes. Prasugrel is generally a more potent, consistent, and fast-acting platelet inhibitor than clopidogrel. This sub-analysis of the phase III comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO-I) trial aimed to assess the differences in efficacy of these treatments for each stroke subtype. METHODS: In the PRASTRO-I trial, a total of 3,753 patients with ischemic stroke were recruited from 224 centers throughout Japan and randomized (1:1) to prasugrel (3.75 mg/day) or clopidogrel (75 mg/day) for 96 weeks. For the sub-analysis, strokes were classified as large-artery atherosclerosis, small-artery occlusion (lacunar), stroke of other etiology, and stroke of undetermined etiology. The cumulative incidence of primary events (ischemic stroke, myocardial infarction, and death from other vascular cause) and hazard ratios (HRs) were calculated for each subgroup. RESULTS: For patients with large-artery atherosclerosis, the primary event incidence was 3.8% in the prasugrel group and 4.8% in the clopidogrel group (HR 0.79; 95% confidence interval [CI] 0.45-1.41). For patients with small-artery occlusion, the incidence was 3.3% in the prasugrel group and 3.9% in the clopidogrel group (HR 0.82; 95% CI 0.45-1.50). For patients with stroke of undetermined etiology, the incidence was 4.6% in the prasugrel group and 3.0% in the clopidogrel group (HR 1.56; 95% CI 0.90-2.72). The incidence of bleeding was similar across subtypes. CONCLUSIONS: Although statistical significance was not reached, the efficacy of prasugrel was potentially different between stroke subtypes, warranting further studies.

DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).

Safety and Efficacy of Prasugrel in Elderly/Low Body Weight Japanese Patients with Ischemic Stroke: Randomized PRASTRO-II.

INTRODUCTION: The safety of prasugrel in elderly and/or low body weight Japanese patients with ischemic stroke who have a relatively high bleeding risk with antiplatelet therapy remains unknown. OBJECTIVE: We aimed to investigate the safety and efficacy of long-term prasugrel monotherapy for stroke prevention compared with clopidogrel in elderly and/or low body weight Japanese patients with non-cardioembolic ischemic stroke. METHODS: In this randomized, double-blind, comparative, phase III study, elderly (age ≥75 years) and/or low body weight (≤50 kg) Japanese patients with a previous history of non-cardioembolic ischemic stroke were assigned to a prasugrel 3.75 mg (PRA3.75) group, a prasugrel 2.5 mg (PRA2.5) group, or a clopidogrel 50 mg (CLO50) group and followed up for 48 weeks. The primary safety endpoint was the combined incidence of primary safety events, defined as life-threatening, major, and other clinically relevant bleeding. The efficacy endpoint was a composite of ischemic stroke, myocardial infarction, and death from other vascular causes. RESULTS: A total of 654 patients (age 76.4 ± 7.3 years, body weight 55.6 ± 9.3 kg, women 43.9%) from 74 medical institutions within Japan were enrolled. The combined incidence (95% CI) of primary safety events was 4.2% (1.9-7.8%), 1.9% (0.5-4.7%), and 3.6% (1.6-6.9%) in the PRA3.75 group (n = 216), PRA2.5 group (n = 215), and CLO50 group (n = 223), respectively (hazard ratios [HR] PRA3.75/CLO50, 1.13 [0.44-2.93]; PRA2.5/CLO50, 0.51 [0.15-1.69]). The incidences of bleeding leading to treatment discontinuation (95% CI) were 2.3% (0.8-5.3%), 0.9% (0.1-3.3%), and 2.2% (0.7-5.2%) in the PRA3.75, PRA2.5, and CLO50 groups, respectively (HRs PRA3.75/CLO50, 1.01 [0.29-3.48]; PRA2.5/CLO50, 0.41 [0.08-2.12]). There was no significant difference in all bleeding events between groups. The incidence of ischemic stroke, myocardial infarction, and death from other vascular causes was lower, but not significantly so, in patients treated with prasugrel than in patients treated with clopidogrel: PRA3.75, 0.0% (0/216); PRA2.5, 3.3% (7/215); and CLO50, 3.6% (8/223; HRs PRA3.75/CLO50, 0.00 [0.00-0.00]; PRA2.5/CLO50, 0.90 [0.32-2.47]). CONCLUSIONS: Elderly and/or low body weight -Japanese patients with previous non-cardioembolic ischemic stroke who received PRA3.75 showed similar results in terms of primary safety endpoint, and a numerically lower incidence of ischemic stroke, myocardial infarction, and death from other vascular causes, compared with those who received CLO50.

Association between High Platelet Reactivity Following Dual Antiplatelet Therapy and Ischemic Events in Japanese Patients with Coronary Artery Disease Undergoing Stent Implantation.

AIM: Although high on-treatment platelet reactivity (HTPR) with dual antiplatelet therapy (DAPT) correlates with long-term adverse outcomes in patients undergoing percutaneous coronary intervention, the correlation in Japanese patients remains unclear. Therefore, we examined the relationship between platelet reactivity during DAPT with aspirin and clopidogrel and 1-year clinical outcomes following successful coronary stent implantation. METHODS: A prospective, multicenter registry study (j-CHIPS) was conducted in patients undergoing coronary stenting and receiving aspirin and clopidogrel at 16 hospitals in Japan. A VerifyNow point-of-care assay was used to assess platelet reactivity, and a cutoff value to define HTPR was established. RESULTS: Between February 2011 and May 2013, 1047 patients were prospectively enrolled, of which 854 patients with platelet function evaluation at 12-24 h after PCI were included in the final analysis. After 1 year of follow-up, the incidence of the primary endpoint (a composite of all-cause mortality, myocardial infarction, stent thrombosis, and ischemic stroke) was significantly higher in patients with HTPR than in those without (5.9% vs. 1.5%, p=0.008), and HTPR showed a modest ability to discriminate between patients who did and did not experience major adverse cardiac and cerebrovascular events (area under the curve, 0.60; 95% confidence interval, 0.511-0.688, p=0.039). HTPR status did not identify patients at risk for major or minor bleeding events. CONCLUSION: HTPR was significantly associated with adverse ischemic outcomes at 1 year after PCI in Japanese patients receiving maintenance DAPT, indicating its potential as a prognostic indicator of clinical outcomes in this high-risk patient population.

Comparison of prasugrel and clopidogrel in patients with non-cardioembolic ischaemic stroke: a phase 3, randomised, non-inferiority trial (PRASTRO-I).

BACKGROUND: The effect of prasugrel in terms of the prevention of recurrence of ischaemic stroke is unknown. We investigated the non-inferiority of prasugrel to clopidogrel for prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes in Japanese patients with non-cardioembolic stroke. METHODS: In this phase 3 randomised, double-blind, non-inferiority trial, patients aged 20-74 years who had had a non-cardioembolic stroke in the previous 1-26 weeks were recruited from 224 hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive prasugrel (3·75 mg/day) or clopidogrel (75 mg/day) orally for 96-104 weeks. Randomisation was stratified according to stroke subtype. The randomisation schedule was generated by an independent statistician who created a computer-generated random number sequence. Patients, investigators, and the funder were masked to treatment allocation. The primary endpoint was combined incidence of ischaemic stroke (fatal and non-fatal), myocardial infarction (fatal and non-fatal), and death from other vascular causes in the intention-to-treat population. The safety endpoint was incidence of bleeding events, comprising life-threatening bleeding, major bleeding, and clinically relevant bleeding. The safety analysis was done in the population excluding trial patients with serious Good Clinical Practice violations, and those who had not taken the trial drug. The predefined non-inferiority margin was an upper 95% CI limit for the risk ratio (RR) of 1·35. The trial was registered with the Japan Pharmaceutical Information Center (JapicCTI-111582). FINDINGS: Patients were recruited between Sept 1, 2011, and June 12, 2015. 3747 patients (797 [21%] women) were enrolled, with a mean age of 62·1 (SD 8·5) years. 3753 patients were randomly assigned to treatment and, of these patients, 1885 in the prasugrel group and 1862 in the clopidogrel group were confirmed to have taken the trial drug at least once, and six patients withdrew from the trial before administration of the trial drug. Thus, a total of 3747 patients were included in the full analysis set. 73 (4%) of 1885 patients in the prasugrel group and 69 (4%) of 1862 patients in the clopidogrel group reached the primary endpoint (RR 1·05, 95% CI 0·76-1·44). The incidence of bleeding events was not significantly different between treatment groups; life-threatening bleeding was observed in 18 (1%) patients in the prasugrel group and 23 (1%) patients in the clopidogrel group (RR 0·77, 0·41-1·42). INTERPRETATION: The non-inferiority of prasugrel to clopidogrel for the prevention of ischaemic stroke, myocardial infarction, and death from other vascular causes was not confirmed in Japanese patients with non-cardioembolic stroke. No safety concerns were identified. FUNDING: Daiichi Sankyo.

TADAFER II: Tadalafil treatment for fetal growth restriction - a study protocol for a multicenter randomised controlled phase II trial.

INTRODUCTION: There is no proven therapy to reverse or ameliorate fetal growth restriction (FGR). Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has been reported to potentially play a therapeutic role in FGR, but this has not been established. Tadalafil is also a selective PDE5 inhibitor. We have demonstrated the efficacy of tadalafil against FGR along with short-term outcomes and the feasibility of tadalafil treatment. Based on the hypothesis that tadalafil will safely increase the likelihood of increased fetal growth in FGR, we designed this phase II study to prospectively evaluate the efficacy and safety of tadalafil against FGR. METHODS AND ANALYSIS: This study is a multicentre, randomised controlled phase II trial. A total of 140 fetuses with FGR will be enrolled from medical centres in Japan. Fetuses will be randomised to receive either the conventional management for FGR or a once-daily treatment with 20 mg of tadalafil along with the conventional management until delivery. The primary endpoint is fetal growth velocity from the first day of the protocol-defined treatment to birth (g/day). To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery was established in this study. The investigator will evaluate fetal baseline conditions at enrolment and will decide the timing of delivery based on this fetal indication. Infants will be followed up for development until 1.5 years of age. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board of Mie University Hospital and each participating institution. Our findings will be widely disseminated through peer-reviewed publications. TRIAL REGISTRATION NUMBER: UMIN000023778.

Influence of cytochrome P450 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke previously treated with clopidogrel.

This randomized double-blind crossover study aimed to investigate the influence of cytochrome P450 (CYP) 2C19 polymorphisms on the antiplatelet effects of prasugrel in patients with non-cardioembolic stroke treated with clopidogrel. Patients received clopidogrel 75 mg/day for > 4 weeks. Subsequently, patients received prasugrel 3.75 mg/day (group A; n = 64) or 2.5 mg/day (group B; n = 65) for 4 weeks followed by a 4 week switched-dose regimen. To assess the influence of CYP2C19 polymorphisms, patients were classified as extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs). The primary endpoint was P2Y12 reaction units (PRU) at the end of each 4 week treatment. A significant reduction in PRU was noted after treatment with prasugrel 3.75 mg/day compared with the pre-dose value (after treatment with clopidogrel) (p < 0.0001). By CYP2C19 phenotypes, a significant reduction in PRU was noted in IMs and PMs after treatment with prasugrel 3.75 mg/day and in PMs after treatment with prasugrel 2.5 mg/day, as compared with the pre-dose value (p < 0.0001). The plasma concentration of the active metabolite of clopidogrel was relatively low in PMs compared to EMs and IMs; prasugrel was similar across all CYP2C19 phenotypes. No major or clinically significant hemorrhagic adverse events occurred. By CYP2C19 phenotype, the antiplatelet effects of prasugrel were greater with 3.75 mg/day in IMs and PMs, and with 2.5 mg/day in PMs compared with clopidogrel 75 mg/day, without safety concerns. CYP2C19 polymorphisms did not affect the plasma concentration of the active metabolite of prasugrel or its antiplatelet effects. (JapicCTI-101044).

A noninferiority confirmatory trial of prasugrel versus clopidogrel in Japanese patients with non-cardioembolic stroke: rationale and study design for a randomized controlled trial - PRASTRO-I trial.

BACKGROUND: This comparison of PRAsugrel and clopidogrel in Japanese patients with ischemic STROke (PRASTRO)-I trial investigates the noninferiority of prasugrel to clopidogrel sulfate in the prevention of recurrence of primary events (ischemic stroke, myocardial infarction, and death from other vascular causes), and the long-term safety of prasugrel in Japanese patients with non-cardioembolic stroke. RESEARCH DESIGN AND METHODS: This was an active-controlled, randomized, double-blind, double-dummy, parallel-group study conducted between July 2011 and March 2016 at multiple centers around Japan. Patients had to meet eligibility criteria before receiving 3.75 mg prasugrel or 75 mg clopidogrel orally once daily for a period of 96-104 weeks. RESULTS: A total of 3747 patients were included in this trial; 1598 in the 3.75 mg prasugrel group and 1551 in the 75 mg clopidogrel group completed the study. During the study period, 287 (15.2%) patients in the prasugrel group and 311 (16.7%) in the clopidogrel group discontinued treatment. Baseline characteristics, safety, and efficacy results are forthcoming and will be published separately. CONCLUSIONS: This article presents the study design and rationale for a trial investigating the noninferiority of prasugrel to clopidogrel sulfate with regards to the inhibitory effect on primary events in patients with non-cardioembolic stroke.

Echocardiographic Assessment of Cardiac Structural and Functional Abnormalities in Patients With End-Stage Renal Disease Receiving Chronic Hemodialysis.

BACKGROUND: The aim of this study was to assess the echocardiographic characteristics of chronic hemodialysis (HD) patients with end-stage renal disease (ESRD) in a multicenter prospective cohort study.Methods and Results:Three hundred and fifteen patients with ESRD (67.9±10.6 years, 47.6% male) on chronic HD for ≥1 year were examined on transthoracic echocardiography, including Doppler-derived aortic valve area (AVA) measurement. Only 11.5% and 3.4% of all patients had normal left ventricular (LV) geometry and normal LV filling pattern, respectively. The majority of patients had aortic and mitral valvular calcification, and approximately 50% of all 315 patients had aortic valve narrowing with AVA <2.0 cm2. Patients were divided into 3 groups according to AVA index tertile: group 1, highest tertile; group 2, middle tertile; and group 3, lowest tertile. Group 3 was older, had a greater cardiothoracic ratio on chest X-ray, higher plasma brain natriuretic peptide and total LV afterload, and lower stroke volume index than the other 2 groups. Age and intact parathyroid hormone (PTH) level were independently associated with low AVA index. CONCLUSIONS: Patients with ESRD on chronic HD have a high prevalence of cardiac structural and functional abnormalities including calcified aortic sclerosis. High age and PTH were associated with aortic valve narrowing in these patients.

Antialbuminuric effect of eplerenone in comparison to thiazide diuretics in patients with hypertension.

This study investigated the effects and safety of eplerenone or thiazide diuretics in patients with hypertension and albuminuria (pretreatment urinary albumin/creatinine ratio ≥10 mg/gCr) treated with an angiotensin II receptor blocker. The primary end point was the mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks. An efficacy analysis was performed in 195 patients (98 in the eplerenone group and 97 in the thiazide group). Systolic and diastolic blood pressures at 48 weeks were similar in the two groups. The mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks was similar in the two groups (P=.804). In the safety analysis, the withdrawal rates for adverse events were similar in both groups. The antialbuminuric effects and safety of eplerenone therapy were similar to those of thiazide diuretics when combined with an angiotensin II receptor blocker in patients with hypertension and albuminuria.

Risk of bleeding and repeated bleeding events in prasugrel-treated patients: a review of data from the Japanese PRASFIT studies.

Prasugrel is a third-generation thienopyridine that achieves potent platelet inhibition with less pharmacological variability than other thienopyridines. However, clinical experience suggests that prasugrel may be associated with a higher risk of de novo and recurrent bleeding events compared with clopidogrel in Japanese patients undergoing percutaneous coronary intervention (PCI). In this review, we evaluate the risk of bleeding in Japanese patients treated with prasugrel at the doses (loading/maintenance doses: 20/3.75 mg) adjusted for Japanese patients, evaluate the risk factors for bleeding in Japanese patients, and examine whether patients with a bleeding event are at increased risk of recurrent bleeding. This review covers published data and new analyses of the PRASFIT (PRASugrel compared with clopidogrel For Japanese patIenTs) trials of patients undergoing PCI for acute coronary syndrome or elective reasons. The bleeding risk with prasugrel was similar to that observed with the standard dose of clopidogrel (300/75 mg), including when bleeding events were re-classified using the Bleeding Academic Research Consortium criteria. The pharmacodynamics of prasugrel was not associated with the risk of bleeding events. The main risk factors for bleeding events were female sex, low body weight, advanced age, and presence of diabetes mellitus. Use of a radial puncture site was associated with a lower risk of bleeding during PCI than a femoral puncture site. Finally, the frequency and severity of recurrent bleeding events during continued treatment were similar between prasugrel and clopidogrel. In summary, this review provides important insights into the risk and types of bleeding events in prasugrel-treated patients.Trial registration numbers: JapicCTI-101339 and JapicCTI-111550.

Successful treatment by prednisolone for interstitial pneumonia associated with anagrelide in a patient with essential thrombocythemia.

Anagrelide is a cytoreductive agent for essential thrombocythemia and its common side effects are anemia, headache, palpitation, diarrhea, and fluid retention. However, severe pulmonary adverse effects are rare. A 66-year-old Japanese man with essential thrombocythemia presented with hemoptysis 2 months after starting anagrelide treatment. Interstitial pneumonia was diagnosed based on physical and radiographic findings. Discontinuation of anagrelide and institution of corticosteroids resulted in the improvement of interstitial pneumonia. Severe lung injury associated with anagrelide is a rare but an important adverse event that must be addressed when treating interstitial pneumonia.

Cardiovascular events occur independently of high on-aspirin platelet reactivity and residual COX-1 activity in stable cardiovascular patients.

Several studies have indicated that approximately 25 % of patients treated with aspirin exhibit high on-treatment platelet reactivity (HTPR), which is potentially associated with cardiovascular events (CVEs). However, this association is still controversial, since the mechanisms by which HTPR contributes to CVEs remain unclear and a no standardised definition of HTPR has been established. To determine whether HTPR is associated with CVE recurrence and what type of assay would best predict CVE recurrence, we conducted a multicentre prospective cohort study of 592 stable cardiovascular outpatients treated with aspirin monotherapy for secondary prevention. Their HTPR was determined by arachidonic acid- or collagen-induced aggregation assays using two different agonist concentrations. Residual cyclooxygenase (COX)-1 activity was assessed by measuring serum thromboxane (TX)B2 or urinary 11-dehydro TXB2. Shear-induced platelet thrombus formation was also examined. We followed all patients for two years to evaluate how these seven indexes were related to the recurrence of CVEs (cerebral infarction, transient ischaemic attack, myocardial infarction, unstable angina, revascularisation, other arterial thrombosis, or cardiovascular death). Of 583 patients eligible for the analysis, CVEs occurred in 69 (11.8 %). A Cox regression model identified several classical risk factors associated with CVEs. However, neither HTPR nor high residual COX-1 activity was significantly associated with CVEs, even by applying cut-off values suggested in previous reports or a receiver-operating characteristic analysis. In conclusion, recurrence of CVEs occurred independently of HTPR and residual COX-1 activity. Thus, our findings do not support the use of platelet or COX-1 functional testing for predicting clinical outcomes in stable cardiovascular patients.

Developmental Changes in Neonatal and Infant Skin Structures During the First 6 Months: In Vivo Observation.

BACKGROUND/OBJECTIVES: Developmental changes of structures in neonatal and infant skin have not been well characterized. The purpose of this study was to clarify changes in skin structures during neonatal and infant growth in vivo. METHODS: Fifteen healthy, full-term neonates (seven girls, eight boys) were studied. The measurements were performed 4 to 7 days (neonate) and 1, 3, and 6 months after birth on the buttock, upper thigh, and ventral forearm skin using a confocal laser scanning microscope. Developmental changes in dermoepidermal junction structures, stratum corneum thickness, epidermal thickness, and microvascular development were investigated. RESULTS: A significant decrease in stratum corneum thickness was observed over the 3 months after birth. Dermal papillae were not observed in neonatal skin but were observed gradually over the next 3 months. Epidermal thickness, determined from the skin surface to the bottom of the epidermal layer, increased significantly from 4 to 7 days to 1 month of age, indicating the formation of dermal papillae and rete ridges. Complicated microvascular structures were observed in neonatal skin but disappeared gradually and were observed only at the dermal papillae at 3 months of age. CONCLUSIONS: Our results reveal that infant skin is in a developmental stage structurally up to 3 months of age, paralleling skin functional and developmental maturation.

Effects of CYP2C19 allelic variants on inhibition of platelet aggregation and major adverse cardiovascular events in Japanese patients with acute coronary syndrome: The PRASFIT-ACS study.

BACKGROUND: We examined the effects of cytochrome P450 2C19 (CYP2C19) polymorphisms on the efficacy and safety of prasugrel and clopidogrel in a post hoc analysis of the PRASugrel compared with clopidogrel For Japanese patIenTs with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) (PRASFIT-ACS) study. METHODS: Japanese ACS patients undergoing PCI were randomized (double-blind) to receive prasugrel (loading/maintenance dose: 20/3.75mg) or clopidogrel (300/75mg) plus aspirin for 24-48 weeks. Pharmacogenomic analyses were conducted in 773/1363 patients. P2Y12 reaction units (PRU) were determined using the VerifyNow(®) P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotypes were classified as extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). RESULTS: Overall, 39.2% and 60.8% of patients in the prasugrel group and 35.2% and 64.8% of patients in the clopidogrel group were classified as EM and IM+PM, respectively. Among EM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group at 2-4 and 5-12h after the loading dose, but was similar in both groups from week 4 onwards. Among IM+PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study. Among EM patients, the incidence of major adverse cardiovascular events (MACE) at 24 weeks was 11.8% in the prasugrel group and 11.9% in the clopidogrel group [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.50-1.96]. Among IM+PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78, 95% CI: 0.45-1.35). The incidences of major, minor, and clinically relevant bleeding were similar between the two groups for each genotype. CONCLUSIONS: Prasugrel showed more consistent antiplatelet effects than clopidogrel in Japanese ACS patients irrespective of the CYP2C19 phenotype.

No association between on-treatment platelet reactivity and bleeding events following percutaneous coronary intervention and antiplatelet therapy: A post hoc analysis.

INTRODUCTION: Few studies have examined the relationship between the pharmacodynamics of antiplatelet drugs and the risk of clinically significant bleeding following percutaneous coronary intervention (PCI) for treating acute coronary syndrome (ACS). We examined the associations between the pharmacodynamics of prasugrel and clopidogrel and the incidence of bleeding events in the acute and chronic phases after PCI. MATERIALS AND METHODS: We performed a post hoc analysis of the PRASFIT-ACS (PRASugrel compared with clopidogrel For Japanese patIenTs with ACS undergoing PCI) study of patients in whom platelet reactivity was determined as P2Y12 reaction units (PRU; VerifyNow® P2Y12 assay) or vasodilator-stimulated phosphoprotein-phosphorylation reactivity index (VASP-PRI). Japanese patients were randomized to prasugrel (loading/maintenance dose: 20/3.75 mg) or clopidogrel (300/75 mg), both in combination with aspirin, for 24-48 weeks. The bleeding outcome was a composite of major, minor, and clinically relevant bleeding. RESULTS: Overall, 66/685 (9.6%) and 65/678 (9.6%) of prasugrel- and clopidogrel-treated patients, respectively, experienced major, minor, or clinically relevant bleeding. PRU and VASP-PRI at 5-12h or in steady state conditions (at 4 weeks) were not associated with the risk of bleeding in the acute (to day 3) or chronic (from day 4 to 14 days after treatment discontinuation) phases of treatment, respectively. Less than 9% of patients with low on-treatment platelet reactivity (defined as PRU<85 or VASP-PRI<16) experienced bleeding events. CONCLUSION: No direct association of the pharmacodynamics of prasugrel and clopidogrel with the risk of bleeding was observed in this cohort of Japanese ACS patients following PCI.