Evaluation of long-term practical training of graduate students at an off-campus hospital-questionnaire survey of graduate students and pharmacists-.

The graduate students in our laboratory underwent 4-5 months of training at Maizuru Kyosai Hospital. To evaluate the effectiveness of this long-term practical training course of the off-campus hospital, we conducted a questionnaire survey before and after the course among the students and the pharmacists. The results of the survey suggest that the students gained experience regarding pharmaceutical management and came to understand the importance of pharmaceutical care during the course. They had an opportunity to connect clinical practice with the research activities conducted at the university. With regard to the pharmacists, this course has motivated them to act as mentors during the practical training, and therefore was also of significance to them. However, this long-term practical training at the off-campus hospital necessitated a change in lifestyle and living arrangements for the students, which placed stress on them. They required emotional support from university staff before and during the placement. These results show that in order to maintain close collaboration with the hospital and to ensure the success of long-term practical training at an off-campus hospital, academic and emotional support for the students is necessary.

[Fundamental study of coronary angiography using gadolinium contrast agent].

To investigate the clinical usefulness of coronary arteriography using a gadolinium contrast medium (hereinafter referred to as Gd contrast medium) in patients with iodine allergy, images obtained using an iodinated contrast medium and a Gd contrast medium were compared using respective phantoms. Within the range of the effective energy (34.8 to 41.0 keV) in clinical use, the tube-voltage dependency of the Gd contrast medium was lower than that of the iodinated contrast medium. The contrast ratios were found to be comparable for the images obtained by a 4-fold-diluted iodinated contrast medium and the undiluted Gd contrast medium. Although the assessment of stenotic ratio was difficult to obtain by visual evaluation of the clinical images, due to unclear borders of the blood vessels, the presence or absence of significant stenosis was discriminative by arteriography using the Gd contrast medium. Based on these findings, it was considered necessary to make a confirmed diagnosis using a Gd contrast medium with concurrent diagnosis by intravascular echography. In conclusion, coronary arteriography and PCI using a Gd contrast medium are considered to offer benefit to the diagnosis and treatment of patients with iodine allergy.

Clinical efficacy of thrombus aspiration on 5-year clinical outcomes in patients with ST-segment elevation acute myocardial infarction undergoing percutaneous coronary intervention.

BACKGROUND: Adjunctive thrombus aspiration (TA) during primary percutaneous coronary intervention (PCI) was reported to promote better coronary and myocardial reperfusion. However, long-term mortality benefit of TA remains controversial. The objective of this study is to investigate the clinical impact of TA on long-term clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. METHODS AND RESULTS: The CREDO-Kyoto AMI Registry is a large-scale cohort study of acute myocardial infarction patients undergoing coronary revascularization in 2005-2007 at 26 hospitals in Japan. Among 5429 patients enrolled in the registry, the current study population consisted of 3536 patients who arrived at the hospital within 12 hours after the symptom onset and underwent primary PCI. Clinical outcomes were compared between the 2 patient groups with or without TA. During primary PCI procedures, 2239 out of 3536 (63%) patients underwent TA (TA group). The cumulative 5-year incidence of all-cause death was significantly lower in the TA group than in the non-TA group (18.5% versus 23.9%, log-rank P<0.001). After adjusting for confounders, however, the risk for all-cause death in the TA group was not significantly lower than that in the non-TA group (hazard ratio: 0.90, 95% CI: 0.76 to 1.06, P=0.21). The adjusted risks for cardiac death, myocardial infarction, stroke, and target-lesion revascularization were also not significantly different between the 2 groups. CONCLUSIONS: Adjunctive TA during primary PCI was not associated with better 5-year mortality in STEMI patients.

Impact of lesion morphology and associated procedures for left main coronary stenting on angiographic outcome after intervention: sub-analysis of Heart Research Group of Kanazawa, HERZ, Study.

Whether the lesion morphology and associated interventional procedures for the left main coronary artery disease (LMCA) could affect clinical outcome is still controversial. Therefore, we examined the impact of lesion morphology and associated procedures on clinical and angiographic outcomes of stenting for the LMCA. Among 7,660 patients with coronary intervention registered, we analyzed early angiographic results of 228 patients (179 men, mean age 69.4 years) concerned with LMCA lesions. In 121 out of 228 patients having long-term angiographic results, we examined the occurrence of major adverse coronary events (MACE) particularly in terms of the presence of acute coronary syndrome (ACS), the kind of stents, bear metal or drug eluting, the lesion morphology and associated procedures. Early angiographic success rate of LMCA stenting was 100 %, and clinical success rate was 94.3 %. During follow-up period for 3 years, MACE was observed in 17 patients. Under these conditions, multiple stenting (p < 0.01) and complicated procedures such as such as Y-stent, T-stent and crush stent (p < 0.01) were listed as risks for MACE, although there was no statistical difference in kinds of stent. Multivariate analysis demonstrated the significant disadvantage of complicated procedures using the bear metal stent on the occurrence of MACE (p < 0.01). These results demonstrate that the complicated procedures have great impact on clinical and angiographic outcomes after stenting for LMCA lesions, and suggest the simple procedure with a single stent for LMCA lesions in the present cohort. Whether the presence of ACS can affect the prognosis should further be sought.

Incidence and outcome of surgical procedures after coronary bare-metal and drug-eluting stent implantation: a report from the CREDO-Kyoto PCI/CABG registry cohort-2.

BACKGROUND: There still remain safety concerns on surgical procedures after coronary drug-eluting stents (DES) implantation, and optimal management of perioperative antiplatelet therapy (APT) has not been yet established. METHODS AND RESULTS: During 3-year follow-up of 12 207 patients (DES=6802 patients and bare-metal stent [BMS] only=5405 patients) who underwent coronary stent implantation in the CREDO-Kyoto registry cohort-2, surgical procedures were performed in 2398 patients (DES=1295 patients and BMS=1103 patients). Surgical procedures (early surgery in particular) were more frequently performed in the BMS group than in the DES group (4.4% versus 1.9% at 42-day and 23% versus 21% at 3-year, log-rank P=0.0007). Cumulative incidences of death/myocardial infarction (MI)/stent thrombosis (ST) and bleeding at 30 days after surgery were low, without differences between BMS and DES (3.5% versus 2.9%, P=0.4 and 3.2% versus 2.1%, P=0.2, respectively). The adjusted risks of DES use relative to BMS use for death/MI/ST and bleeding were not significant (hazard ratio: 1.63, 95% confidence interval: 0.93 to 2.87, P=0.09 and hazard ratio: 0.6, 95% confidence interval: 0.34 to 1.06, P=0.08, respectively). The risks of perioperative single- and no-APT relative to dual-APT for both death/MI/ST and bleeding were not significant; single-APT as compared with dual-APT tended to be associated with lower risk for death/MI/ST (hazard ratio: 0.4, 95% confidence interval: 0.13 to 1.01, P=0.053). CONCLUSIONS: Surgical procedures were commonly performed after coronary stent implantation, and the risk of ischemic and bleeding complications in surgical procedures was low. In patients selected to receive DES or BMS, there were no differences in outcomes. Perioperative administration of dual-APT was not associated with lower risk for ischemic events.

First human trial of KW39 slotted-tube stents: for percutaneous coronary intervention.

The KW39 stent is a balloon-expandable, stainless-steel, slotted-tube stent, newly designed to adjust to the shape of the coronary arteries. We evaluated the clinical efficacy and safety of KW39 stent-based percutaneous coronary interventions in human native coronary arteries. A total of 105 patients (110 lesions), with a diagnosis of stable angina, acute coronary syndrome, or asymptomatic myocardial ischemia, were included in this prospective study. The primary endpoint was the target-lesion revascularization rate at the conclusion of a 6-month follow-up period. The secondary endpoints were the rates of technical and procedural success and the rate of major adverse cardiac events (defined as cardiac death, myocardial infarction, and target-lesion revascularization) in the course of the 6 months after stent placement. The 6-month target-lesion revascularization rate was 8.6%. The KW39 stent was highly satisfactory in regard to all secondary endpoint comparisons. Binary (>50%) in-stent restenosis was observed in 22 of 110 lesions (20%). The mean diameter stenosis at 6 months after percutaneous coronary intervention was 35.1% ± 14.4%, and the mean late lumen loss was 1.06 ± 0.48 mm. Stepwise multivariate analysis showed probable causal associations between adverse local environments for stent implantation and the subsequent need for target-lesion revascularization. We conclude that KW39 stent implantation was technically feasible and clinically safe in the patient population that we studied. The results of the safety endpoints, including cardiac death and acute myocardial infarction, were acceptable.

Three-year outcome of sirolimus-eluting stent implantation in coronary bifurcation lesions: the provisional side branch stenting approach versus the elective two-stent approach.

AIMS: To explore optimal management strategies for bifurcation lesions with sirolimus-eluting stents (SES). METHODS AND RESULTS: Among 12,824 patients enrolled in the j-Cypher Registry, we identified 2,122 patients with 2,250 non-left main bifurcation lesions (average age: 69 years; diabetes: 39%; acute coronary syndrome: 24%; lesion length ≥30 mm: 17%; true bifurcation: 53%) treated exclusively with SES. The majority of lesions (1,978 lesions, 88%) were treated by provisional side branch stenting approach with a 4.5% crossover rate, while the elective two-stent approach (stenting both main and side branches) was adopted in 272 lesions. The 3-year incidence of target-lesion revascularisation (TLR) was significantly higher in the elective two-stent group than in the provisional group (18.5% vs. 9.8%, p<0.0001). The incidence of definite stent thrombosis was not different between the two groups (1.3% vs. 0.61%, p=0.21). Among 1,871 lesions with main branch stenting alone, final kissing balloon dilatation (FKB) was performed in 938 lesions (50%). The incidence of TLR was not different between the two groups with or without FKB (9.9% vs. 9.2%, p=0.98). CONCLUSIONS: The provisional approach provided a good long-term outcome in the majority of lesions with low crossover rate to the two-stent approach. Lesions treated with FKB had similar TLR outcome to those without FKB after main branch stenting alone.

Long-term safety and efficacy of sirolimus-eluting stents versus bare-metal stents in real world clinical practice in Japan.

Long-term safety and efficacy of drug-eluting stents remains controversial. The CREDO-Kyoto registry cohort-2 is a physician-initiated non-company sponsored multi-center registry enrolling consecutive patients undergoing first coronary revascularization in 26 centers in Japan. We compared 3-year outcome between patients treated with sirolimus-eluting stent (SES) only (5092 patients) and bare-metal stent (BMS) only (5405 patients). SES-use as compared with BMS-use was associated with significantly lower adjusted risk for all-cause death [hazard ratio (HR) [95% confidence interval (CI)] 0.72 (0.59-0.87), P = 0.0007], which was mainly driven by the reduction in non-cardiac death [HR (95% CI) 0.64 (0.48-0.85), P = 0.002]. The risk of cardiac death [HR (95% CI) 0.82 (0.63-1.07), P = 0.15], myocardial infarction [HR (95% CI) 0.73 (0.51-1.03), P = 0.07] and definite stent thrombosis [HR (95% CI) 0.62 (0.35-1.09), P = 0.1] was not different between the two groups. Despite longer duration of thienopyridine administration, SES-use was associated with significantly lower risk for bleeding [HR (95% CI) 0.75 (0.6-0.95), P = 0.02] and similar risk for stroke [HR (95% CI) 1.0 (0.75-1.34), P = 1.0]. The risk for target-lesion revascularization (TLR) was markedly lower in the SES group [HR (95% CI) 0.42 (0.36-0.48), P < 0.0001]. The direction and magnitude of the effect of SES relative to BMS in patients presenting acute myocardial infarction (AMI) were similar to those in patients presenting otherwise. In conclusion, SES-use as compared with BMS-use was associated with marked reduction of TLR without any increases in death, myocardial infarction, stent thrombosis, stroke and bleeding in real world clinical practice regardless of clinical presentation including AMI.

Association of the use of proton pump inhibitors with adverse cardiovascular and bleeding outcomes after percutaneous coronary intervention in the Japanese real world clinical practice.

Previous studies have shown inconsistent results regarding the effects of concomitant use of clopidogrel and proton pump inhibitors (PPI) on cardiovascular outcomes. We sought to evaluate the clinical impact of PPI-use in patients treated with thienopyridines after percutaneous coronary intervention (PCI) in a large Japanese observational database. Among 12446 patients discharged alive on thienopyridines (ticlopidine 90.4% and clopidogrel 9.6%), 3223 patients were treated with PPIs and 9223 patients without PPI at the time of hospital discharge. The PPI group included more patients with co-morbidities than the non-PPI group. The adjusted hazard ratio (HR) of PPI-use for a composite of cardiovascular death, myocardial infarction, and stroke was 1.26 (95% confidence interval (CI) 1.09-1.47, p = 0.002). The adjusted HR of PPI-use for bleeding was 1.26 (95% CI 1.05-1.52, p = 0.013). Cardiovascular and bleeding outcomes were not different among the three groups receiving three different types of PPI. The negative effect of PPI on cardiovascular outcome was consistently seen in both drug-eluting stent (DES) [HR 1.31 (95% CI 1.07-1.6, p = 0.0097)] and non-DES strata [HR 1.25 (95% CI: 0.99-1.57, p = 0.057)] (Interaction p = 0.79) despite the fact that the duration of thienopyridine administration was significantly longer in patients receiving DES. In conclusion, cardiovascular outcomes after PCI were significantly worse in patients with PPI than in patients without PPI in the Japanese real clinical practice. However, the observed poorer cardiovascular outcome in patients receiving PPI was most likely to be related to residual confounding and seemed not causally related to attenuation of antiplatelet effect of thienopyridine through interaction with PPI.

Incidence and outcome of surgical procedures after sirolimus-eluting stent implantation: a report from the j-Cypher registry.

The incidence of surgical procedures after sirolimus-eluting stent (SES) implantation and, more importantly, the rate of perioperative stent thrombosis (ST) and/or other adverse events have not yet been adequately addressed. The incidence and outcome of the surgical procedures after SES implantation were prospectively evaluated in a large-scale multicenter registry of patients undergoing SES implantation. Among 12,824 patients enrolled in the registry, cumulative incidences of surgical procedures were 0.7% at 60 days, 5.1% at 1 year and 14.7% at 3 years. Surgical procedures were performed in 1,430 patients including non-coronary artery bypass graft (CABG) surgery in 1,275 patients and CABG in 189 patients. The incidences of death/myocardial infarction/ST (definite or probable) and ST (definite or probable) at 30 days after surgical procedures were 2.7 and 0.35%, respectively. Surgery performed within 60 days after SES implantation as compared with that performed beyond 60 days was associated with significantly higher incidences of death/myocardial infarction/ST (definite or probable) and ST (definite or probable) at 30 days after surgical procedures (6.4 vs. 2.5%: P = 0.02 and 2.2 vs. 0.23%: P = 0.002, respectively). Surgery within 60 days as well as hemodialysis and small body mass index were independent risk factors of death/myocardial infarction/ST (definite or probable) identified by multivariable analysis. Surgical procedures were required fairly often after SES implantation. The incidences of adverse cardiac events including ST after surgical procedures were acceptably low. Surgery within 60 days after SES implantation carried significantly higher risks as compared with those beyond 60 days.

Incidence and risk factors of late target lesion revascularization after sirolimus-eluting stent implantation (3-year follow-up of the j-Cypher Registry).

It yet has not been clarified whether there is a late catch-up phenomenon in target lesion revascularization (TLR) after sirolimus-eluting stent (SES) compared to bare metal stent (BMS) implantation. In 12,824 patients enrolled in the j-Cypher Registry, incidences of early (within first year) and late (1 year to 3 years) TLR were compared between 17,050 lesions treated with SESs and 1,259 lesions treated with BMSs. Incidences of TLR in SES-treated lesions were 5.7% at 1 year, 8.1% at 2 years, and 10.0% at 3 years, whereas those in BMS-treated lesions were 14.2%, 15.5%, and 15.5%, respectively (p <0.0001, log-rank test). Incidences of late TLR were significantly higher with SESs compared to BMSs (2.6% vs 1.4% at 2 years and 4.5% vs 1.4% at 3 years, p = 0.0007, log-rank test). A multivariable logistic regression model identified 7 independent risk factors for late TLR at 3 years after SES implantation: hemodialysis, low estimated glomerular filtration rate, ostial right coronary artery, lesion length >or=30 mm, 2 stents for bifurcation, American Heart Association/American College of Cardiology type B2/C, and vessel size <2.5 mm. Of these, 5 factors were common to those for early TLR. In conclusion, a late catch-up phenomenon was observed as indicated by the increasing incidence of late TLR after SES, but not after BMS, implantation. Risk factors for late TLR were generally common to those for early TLR.

Effects of turmeric extract on the pharmacokinetics of nifedipine after a single oral administration in healthy volunteers.

The effects of turmeric extracts on the pharmacokinetics of nifedipine were examined in 10 healthy volunteers. An open-label and randomized crossover study was performed at 2-week intervals. In the control experiment, after a 10 h overnight fast, 10 mg of nifedipine (Adalat® capsule) was administered orally and blood was collected at 0, 0.5, 1, 2, 3, 4, 5, 6, and 8 h. In the combination experiment, the volunteers were orally administered 10 mg of nifedipine together with six tablets containing concentrated turmeric extract (480 mg of curcuminoid per six tablets), which is the general daily dose, and blood was sampled as above. The time profile of the plasma concentration of nifedipine in the control was comparable to that in combination with turmeric extract, as were the pharmacokinetic parameters: that is, the mean ratio of turmeric extract/control group (90% confidence interval: CI); C(max), 0.98 (0.95, 1.01) and AUC(0 - ∞) 1.00 (0.98, 1.02). In addition, the volunteers all completed the study without any serious adverse events. Consumption of the turmeric extract did not affect the pharmacokinetics of nifedipine after a single oral administration.

Association of Gln222Arg polymorphism in the deoxyribonuclease I (DNase I) gene with myocardial infarction in Japanese patients.

AIMS: We have recently reported that serum deoxyribonuclease I (DNase I) activity, which may be involved in apoptosis, increases abruptly in the early phase of acute myocardial infarction (MI) [Kawai Y, Yoshida M, Arakawa K, Kumamoto T, Morikawa N, Masamura K, Tada H, Ito S, Hoshizaki H, Oshima S, Taniguchi K, Terasawa H, Miyamori I, Kishi K, Yasuda T. Diagnostic use of serum deoxyribonuclease I activity as a novel early-phase marker in acute myocardial infarction. Circulation 2004;109:2398-2400]. Death of vascular smooth muscle cells, in part because of apoptosis, is postulated to heighten susceptibility to disruption of vulnerable plaque, resulting in onset of MI. The present study evaluated the possibility that Gln222Arg polymorphism of the DNase I gene may be one of the factors involved in predisposition to MI. METHODS AND RESULTS: We assessed 611 Japanese patients: 311 with MI and 300 with stable angina pectoris (AP). Three common phenotypes determined by two common codominant alleles, DNASE1*1 and *2, whose corresponding gene products exhibit different properties, were found in these patient groups. The prevalence of DNASE1*2 was significantly higher in patients with MI than in those with AP (0.543 vs. 0.428, P < 0.001), being confirmed by phenotyping of the second study population. Multiple logistic regression analysis showed that the odds ratio of DNASE1*2 was 1.51 [95% confidence interval (CI) 1.04-2.18]. The association of the DNASE1*2 allele with MI was statistically significant, being independent of other conventional risk factors. CONCLUSION: Our data demonstrate that Gln222Arg polymorphism in the DNase I gene is associated with MI in the Japanese patients.

Ten-year follow-up of familial hypercholesterolemia patients after intensive cholesterol-lowering therapy.

To prevent coronary artery disease, it is necessary for patients with familial hyper-cholesterolemia (FH) to maintain a low cholesterol level. Recently a combination therapy of low-density lipoprotein (LDL) apheresis and statins has been used for FH patients, but their long-term prognosis over 10 years is unknown. In this single center prospective report, 18 FH patients with severe coronary stenosis received LDL apheresis every 2 or 4 weeks and statin therapy for 9.8 +/- 3.0 years. Probucol was given to 17 of the 18 patients. We observed their clinical events as well as coronary stenosis findings and ejection fractions for 10.7 +/- 2.6 years. Total and LDL cholesterol levels before therapy were 345 +/- 46 and 277 +/- 48 mg/dL, respectively. Immediately following LDL-apheresis, these levels decreased to 104 +/- 7.5 and 66 +/- 16 mg/dL, respectively. There were no cardiac deaths and 4 patients were free from any coronary events. There was one noncardiac death. Nonfatal myocardial in-farction occurred in 2 patients and coronary bypass surgery was required in one patient. Twelve patients received additional coronary angioplasty. There was little change in coronary stenosis and ejection fraction following 10 years of the combination therapy. Univariate Cox regression analysis revealed that the calculated mean LDL cholesterol level was the predictive value of treatment efficacy (mean LDL cholesterol < 140 mg/dL, hazard ratio 0.23, P = 0.028). The combination therapy of LDL-apheresis and antilipid drugs delayed the progression of coronary atherosclerosis and prevented a major cardiac event, although complete inhibition was limited to a small group. Additional coronary angioplasty is likely to be required for a favorable clinical outcome in FH patients.

Differentiation between patients with takotsubo cardiomyopathy and those with anterior acute myocardial infarction.

BACKGROUND: There has not been a comparison of the electrocardiographic (ECG) finding of ST-segment elevation in the precordial leads in patients with takotsubo cardiomyopathy (TC) and those with anterior acute myocardial infarction (AMI), with regard to the location of the culprit lesion. METHODS AND RESULTS: The present study evaluated 18 patients with TC, and 85 with anterior AMI who were divided into 3 groups: group A had the culprit lesion proximal to both the first septal branch (S1) and the first diagonal branch (D1), group B had the culprit lesion proximal to either S1 or D1, and group C had the culprit lesion distal to both S1 and D1. In patients with TC, reciprocal ST-segment depression in the inferior leads was observed less frequently than in patients in groups A (p<0.0001) and B (p=0.0002), and abnormal Q waves and ST-segment elevation in the inferior leads were observed more frequently than in group A (p=0.0007, p=0.0057, respectively). The ECG findings in TC did not differ from those in group C. CONCLUSION: Electrocardiographic findings may differentiate TC from AMI with a proximal lesion of left anterior descending coronary artery, but not those with distal lesions.