Long-Term Follow-up Study of Hospitalizations for Acute Coronary Syndrome in Kobe-City and Other Districts Under the Hyogo Smoking Ban Legislation　- A Nationwide Database Study.

BACKGROUND: Hyogo Prefecture has managed smoking ban legislation with partial restrictions in public places (Hyogo-L) since 2013. Previous studies have reported a significant decrease in admissions for acute coronary syndrome (ACS) in Kobe-city, but not in other districts of Hyogo Prefecture in the 2 years after Hyogo-L. The aim of the present study was to define the long-term effect of Hyogo-L.Methods and Results: The JROAD-DPC dataset was used to collect information on the number of hospitalizations for ACS in Hyogo Prefecture, and in Osaka-city without smoking ban legislation, from April 2013 to March 2020. Poisson regression analysis was performed to calculate incident rate ratios (IRRs) and 95% confidence intervals (CIs). ACS records of 3,101 in Kobe-city, 11,375 in areas of Hyogo Prefecture other than Kobe-city and 11,079 in Osaka-city were collected for admissions. The incidence of ACS reduced significantly over time in Kobe-city [IRR (95% CI); 0.96 (0.94-0.97)], but did not reduce in the others. The decrease in Kobe-city was observed in ACS patients without smoking, hypertension, and hyperlipidemia, but not in those with such risk factors. CONCLUSIONS: The long-term ACS reduction or non-reduction under Hyogo-L was determined at the initial period and the same scenario continued, supporting the importance of legislation and compliance with the smoking ban. The lowering effect was remarkable in ACS patients without risk factors such as non-smoking.

Effects of a 14-week community health program of exercise and learning/education in older adults: A single-arm pre-post comparison study.

This study was initiated in 2022 in Miyaki Town, Saga Prefecture, Japan, to determine the impact of an intervention that combined brain and physical function training and health education in older residents. Miyaki has a population of approximately 26,000, 35% of whom are considered to be aging. A 14-week program consisting of strength training, brain function training, and health lectures was conducted with 34 older residents of the community. Body composition, motor function, brain function, and various blood tests were evaluated before and after the intervention. Brain function was assessed using the Trail Making Test-A. Physical function was assessed by Open-Close Stepping, Functional Reach Test, Open-Leg Standing Time, and Two-Step Test. The intervention group showed significant improvements in brain function (p< 0.0001), physical function (p = 0.0037), body composition (p = 0.0053), and LDL-C (p = 0.017). This study provides substantial evidence that community-based combined programs can be beneficial for older adults.

Impact of Chronic Kidney Disease on In-Hospital and 3-Year Clinical Outcomes in Patients With Acute Myocardial Infarction Treated by Contemporary Percutaneous Coronary Intervention and Optimal Medical Therapy　- Insights From the J-MINUET Study.

BACKGROUND: The impact of chronic kidney disease (CKD) on long-term outcomes following acute myocardial infarction (AMI) in the era of modern primary PCI with optimal medical therapy is still in debate.Methods and Results:A total of 3,281 patients with AMI were enrolled in the J-MINUET registry, with primary PCI of 93.1% in STEMI. CKD stage on admission was classified into: no CKD (eGFR ≥60 mL/min/1.73 m2); moderate CKD (60>eGFR≥30 mL/min/1.73 m2); and severe CKD (eGFR <30 mL/min/1.73 m2). While the primary endpoint was all-cause mortality, the secondary endpoint was major adverse cardiac events (MACE), defined as a composite of all-cause death, cardiac failure, myocardial infarction (MI) and stroke. Of the 3,281 patients, 1,878 had no CKD, 1,073 had moderate CKD and 330 had severe CKD. Pre-person-days age- and sex-adjusted in-hospital mortality significantly increased from 0.014% in no CKD through 0.042% in moderate CKD to 0.084% in severe CKD (P<0.0001). Three-year mortality and MACE significantly deteriorated from 5.09% and 15.8% in no CKD through 16.3% and 38.2% in moderate CKD to 36.7% and 57.9% in severe CKD, respectively (P<0.0001). C-index significantly increased from the basic model of 0.815 (0.788-0.841) to 0.831 (0.806-0.857), as well as 0.731 (0.708-0.755) to 0.740 (0.717-0.764) when adding CKD stage to the basic model in predicting 3-year mortality (P=0.013; net reclassification improvement [NRI] 0.486, P<0.0001) and MACE (P=0.046; NRI 0.331, P<0.0001) respectively. CONCLUSIONS: CKD remains a useful predictor of in-hospital and 3-year mortality as well as MACE after AMI in the modern PCI and optimal medical therapy era.

Validation of the atherothrombotic risk score for secondary prevention in patients with acute myocardial infarction: the J-MINUET study.

Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS2°P) is a contemporary risk scoring system for secondary prevention based on nine clinical factors. However, this scoring system has not been validated in other populations. The aim of this study was to validate the TRS2°P in patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI) in a nationwide registry cohort. Among 3283 consecutive patients with AMI enrolled in the Japanese registry of acute Myocardial INfarction diagnosed by Universal dEfiniTion (J-MINUET), a total of 2611 patients who underwent primary PCI were included in this study. The performance of the TRS2°P to predict major adverse cardiovascular events (MACE) composed of all-cause death, non-fatal MI, and non-fatal stroke up to 3 years in the present cohort was evaluated. The TRS2°P had modest discriminative performance in this J-MINUET cohort with a c-statistic of 0.63, similar to that in the derived cohort (TRA2°P-TIMI50, c-statistic 0.67). A strong graded relationship between the TRS2°P and 3-year cardiovascular event rates was also observed in the J-MINUET cohort. Age ≥ 75 years, Killip ≥ 2, prior stroke, peripheral artery disease, anemia, and non-ST-elevation myocardial infarction were identified as independent factors for the incidence of MACE. The TRS2°P modestly predicted secondary cardiovascular events among patients with AMI treated by primary PCI in a nationwide cohort of Japan. Further studies are needed to develop a novel risk score better predicting secondary cardiovascular events.

Long-Term Clinical Impact of Cardiogenic Shock and Heart Failure on Admission for Acute Myocardial Infarction.

Long-term clinical outcomes among patients with cardiogenic shock (CS) and heart failure (HF) who survive the early phase of acute myocardial infarction (AMI) remain uncertain. We investigated 3283 consecutive patients with AMI, selected from a prospective, nation-wide multicenter registry (J-MINUET) database comprising 28 institutions in Japan between July 2012 and March 2014. The 3263 eligible patients were divided into the following three groups: CS-/HF- group (n = 2467, 75.6%); CS-/HF+ group (n = 479, 14.7%); and CS+ group (n = 317, 9.7%). The thirty-day mortality rate in CS+ patients was 32.8%, significantly higher than in CS- patients. Among CS+ patients, multivariate logistic regression analysis identified statin use before admission (Odds ratio (OR) 0.32, 95% confidence interval (CI) 0.14-0.66, P = 0.002), renal deficiency (OR 8.72, 95%CI 2.81-38.67, P < 0.0001) and final thrombolysis in myocardial infarction flow grade (OR 0.42, 95%CI 0.18-0.99, P = 0.046) were associated with 30-day mortality. Landmark Kaplan-Meier analysis showed that mortality rates after 30 days were comparable between CS+ and CS-/HF+ groups but were lower in the CS-/HF- group. Multivariate Cox hazard analysis also showed that hazard risk of mortality after 30 days was comparable between the CS+ and CS-/HF+ groups (Hazard ratio (HR) 1.03, 95%CI 0.63-1.68, P = 0.90), and significantly lower in the CS-/HF- group (HR 0.44, 95%CI 0.32-059, P < 0.0001). In conclusion, AMI patients with CS who survived 30 days experienced worse long-term outcomes compared with those without CS up to 3 years. Attention is required for patients who show HF on admission without CS to improve long-term AMI outcomes.

Correction to: Randomized trial of an increased dose of calcium channel blocker or angiotensin II type 1 receptor blocker as an add-on intensive depressor therapy in type 2 diabetes mellitus patients with uncontrolled essential hypertension: the ACADEMIE Study.

In the Original publication of the article, the legend appearing inside the flow chart has been incorrectly published.

Prognostic Impact of B-Type Natriuretic Peptide on Long-Term Clinical Outcomes in Patients with Non-ST-Segment Elevation Acute Myocardial Infarction Without Creatine Kinase Elevation.

Although B-type natriuretic peptide (BNP) has gradually gained recognition as an indicator in risk stratification for patients with acute myocardial infarction (AMI), the prognostic impact on long-term clinical outcomes in patients with non-ST-segment elevation acute myocardial infarction (NSTEMI) without creatine kinase (CK) elevation remains unclear.This prospective multicenter study assessed 3,283 consecutive patients with AMI admitted to 28 institutions in Japan between 2012 and 2014. We analyzed 218 patients with NSTEMI without CK elevation (NSTEMI-CK) for whom BNP was available. In the NSTEMI-CK group, patients were assigned to high- and low-BNP groups according to BNP values (cut-off BNP, 100 pg/mL). The primary endpoint was defined as a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina up to 3 years. Primary endpoints were observed in 60 (33.3%) events among patients with NSTEMI-CK. Kaplan-Meier analysis revealed a significantly higher event rate for primary endpoints among patients with high BNP (log-rank P < 0.001). After adjusting for covariates, a higher BNP level was significantly associated with long-term clinical outcomes in NSTEMI-CK (adjusted hazard ratio, 4.86; 95% confidence interval, 2.18-12.44; P < 0.001).The BNP concentration is associated with adverse long-term clinical outcomes among patients with NSTEMI-CK who are considered low risk. Careful clinical management may be warranted for secondary prevention in patients with NSTEMI-CK with high BNP levels.

Admission During Off-Hours Does Not Affect Long-Term Clinical Outcomes of Japanese Patients with Acute Myocardial Infarction.

Discordant results have been reported on outcomes of acute myocardial infarction (AMI) patients who present during off-hours.We investigated 3283 consecutive patients with AMI who were selected from the prospective, nationwide, multicenter registry (J-MINUET) database comprising 28 institutions in Japan between July 2012 and March 2014 to determine the current impact of off-hours presentation (defined as weekends, holidays, and weekdays from 8:01 PM to 7:59 AM) at hospitals on long-term clinical outcomes. The primary endpoint was a composite of all-cause death, non-fatal MI, non-fatal stroke, cardiac failure, and urgent revascularization for unstable angina for up to 3 years from the index event.During off-hours, 52% of patients presented. Primary percutaneous coronary intervention was performed in 85% of patients, and the door-to-balloon time was comparable between off-hours and regular hours (74, interquartile range [IQR] 52 to 113 versus 75, IQR 52 to 126 minutes, P = 0.34). Rate of overall primary endpoint overall did not overall significantly differ (25.3% versus 23.5%, log-rank P = 0.26), in patients with ST-elevation myocardial infarction (STEMI) (log-rank P = 0.93) and in patients with non-ST-elevation myocardial infarction (NSTEMI) (log-rank P = 0.14). Multivariate Cox regression analysis showed that off-hours presentation was not significantly associated with long-term clinical events in all cohorts.The impact of presentation during off-hours or regular hours on the long-term clinical outcomes of Japanese patients with AMI is comparable in contemporary practice.

Admission Heart Rate Is a Determinant of Effectiveness of Beta-Blockers in Acute Myocardial Infarction Patients.

BACKGROUND: Beta-blockers are standard therapy for acute myocardial infarction (AMI). However, despite current advances in the management of AMI, it remains unclear whether all AMI patients benefit from ß-blockers. We investigated whether admission heart rate (HR) is a determinant of the effectiveness of ß-blockers for AMI patients. Methods and Results: We enrolled 3,283 consecutive AMI patients who were admitted to 28 participating institutions in the Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) study. According to admission HR, we divided patients into 3 groups: bradycardia (HR <60 beats/min, n=444), normocardia (HR 60 to ≤100 beats/min, n=2,013), and tachycardia (HR >100 beats/min, n=342). The primary endpoint was major adverse cardiac events (MACE), including all-cause death, non-fatal MI, non-fatal stroke, heart failure (HF), and urgent revascularization for unstable angina, at 3-year follow-up. Beta-blocker at discharge was significantly associated with a lower risk of MACE in the tachycardia group (23.6% vs. 33.0%; P=0.033), but it did not affect rates of MACE in the normocardia group (17.8% vs. 18.4%; P=0.681). In the bradycardia group, ß-blocker use at discharge was significantly associated with a higher risk of MACE (21.6% vs. 12.7%; P=0.026). Results were consistent for multivariable regression and stepwise multivariable regression. CONCLUSIONS: Admission HR might determine the efficacy of ß-blockers for current AMI patients.

Correction to: Association between plasma levels of PCSK9 and the presence of coronary artery disease in Japanese.

In the original publication of the article, Tables 1, 2 and 3 was published incorrectly. Unnecessary inequality symbols were added to all the numbers in the 'p value' of Tables 1, 2 and 3. The correct tables should be as follows.

Association between plasma levels of PCSK9 and the presence of coronary artery disease in Japanese.

The ability of pro-protein convertase subtilisin/kexin type 9 (PCSK9) levels to predict the presence or severity of coronary artery disease (CAD) remains controversial. The purpose of this study was to investigate these associations. We enrolled 393 patients who were clinically suspected to have CAD or who had at least one cardiac risk factor and underwent multidetector-row computed tomography coronary angiography. The presence of CAD (≥50% coronary stenosis), the number of significantly stenosed coronary vessels, and plasma levels of PCSK9 by ELISA were analyzed. Plasma PCSK9 levels (log-transformed data) were significantly associated with the presence of CAD. Next, we divided the patients into two groups (non-statin and statin groups) according to statin treatment. PCSK9 levels in the non-statin group were significantly lower than those in the statin group. There were no significant differences in PCSK9 levels between the absence and presence of CAD in the statin group. However, in the non-statin group, PCSK9 levels in patients with CAD were significantly higher than those in patients without CAD. PCSK9 levels, in addition to age, gender, BMI, DM and HDL-C, were independently associated with the presence of CAD by a multivariable analysis. In conclusion, our results demonstrated that plasma PCSK9 levels may be a marker for evaluating the presence of CAD.

Correction to: Association between discordance of LDL-C and non-HDL-C and clinical outcomes in patients with stent implantation: from the FU-Registry.

Unfortunately, the Fig. 1 was published incorrectly in the original publication of the article. The correct figure is as below.

Influence of chronic kidney disease on coronary plaque components in coronary artery disease patients with both diabetes mellitus and hypertension.

Chronic kidney disease (CKD) is well known to be associated with an increased incidence of coronary artery disease (CAD). Diabetes mellitus (DM) and hypertension (HTN), both of which are traditional risk factors for CAD, are the two most common causes of CKD. However, the influence of CKD on coronary atherosclerosis in CAD patients who have both DM and HTN remains uncertain. In these patients, we examined the relationship between CKD and coronary plaque using integrated backscatter intravascular ultrasound (IB IVUS). Two hundred two CAD patients with both DM and HTN who underwent percutaneous coronary intervention using IB IVUS were included. The patients were divided into two groups: CKD group (n = 106) and non-CKD group (n = 96). Gray-scale and IB IVUS examinations were conducted for the non-culprit segment of a coronary artery. As a result, although there was no significant difference in the percentage of plaque volume, the percentage of lipid volume was significantly higher in the CKD group than in the non-CKD group [median (IQR): 56.7% (45.4-67.0%) vs. 52.0% (38.3-60.2%), p = 0.03]. In all of the patients, estimated glomerular filtration rate levels were negatively correlated with the percentage of lipid volume (r = - 0.15, p = 0.03) and positively correlated with the percentage of fibrosis volume (r = 0.15, p = 0.04). A multivariate regression analysis showed that CKD was an independent predictor associated with the increased lipid volume (ß = 0.15, p = 0.047) and decreased fibrosis volume (ß = - 0.16, p = 0.03) in coronary plaques. In conclusion, among CAD patients who had both DM and HTN, CKD was associated with lipid-rich coronary plaques. CKD may contribute to the vulnerability of coronary plaque in these very high-risk patients.

Randomized trial of an increased dose of calcium channel blocker or angiotensin II type 1 receptor blocker as an add-on intensive depressor therapy in type 2 diabetes mellitus patients with uncontrolled essential hypertension: the ACADEMIE Study.

There is a lack of data on how to treat hypertensive patients with diabetes when treatment with medium doses of calcium channel blocker and angiotensin II type 1 receptor blocker (ARB) is insufficient to achieve the target blood pressure (BP). A total of 121 participants with type 2 diabetes and uncontrolled essential hypertension, who were receiving medium doses of amlodipine (5 mg/day) and ARB, were enrolled. Participants were randomized to receive either a high dose of amlodipine (10 mg/day) plus a medium dose of ARB (high-AML) or a medium dose of amlodipine (5 mg/day) plus a high dose of ARB (high-ARB). The depressor effects of these two regimens were monitored using a telemonitoring home BP-measuring system. Fifty-four patients were excluded after an observation period, and the remaining 67 eligible participants were randomized into the two groups; 42 which had a record of their home BP for analysis. The change in morning home systolic and diastolic BP was greater in the high-AML than in the high-ARB (systolic BP; - 7.9 mmHg vs. + 2.7 mmHg; p = 0.0002, diastolic BP; - 3.9 mmHg vs. + 0.6 mmHg; p = 0.0007). In addition, the home systolic and diastolic BP before going to bed and office systolic BP were significantly reduced from week 0 only in the high-AML. An increased dose of amlodipine, but not ARB, reduced home morning BP in hypertensive patients with type 2 diabetes who were already receiving combination therapy with medium doses of amlodipine and ARB.

Association of onset-season with characteristics and long-term outcomes in acute myocardial infarction patients: results from the Japanese registry of acute myocardial infarction diagnosed by universal definition (J-MINUET) substudy.

It is known that incidence and short-term mortality rate of acute myocardial infarction (AMI) tend to be higher in the cold season. The aim of our study was to investigate the association of onset-season with patient characteristics and long-term prognosis of AMI. This was a prospective, multicenter, Japanese investigation of 3,283 patients with AMI who were hospitalized within 48 h of symptom onset between July 2012 and March 2014. Patients were divided into 3 seasonal groups according to admission date: cold season group (December-March), hot season group (June-September), and moderate season group (April, May, October, and November). We identified 1356 patients (41.3%) admitted during the cold season, 901 (27.4%) during the hot season, and 1026 (31.3%) during the moderate season. We investigated the seasonal effect on patient characteristics and clinical outcomes. Baseline characteristics of each seasonal group were comparable, with the exception of age, Killip class, and conduction disturbances. The rates of higher Killip class and complete atrioventricular block were significantly higher in the cold season group. The 3-year cumulative survival free from major adverse cardiac events (MACE) rate was the lowest in the cold season (67.1%), showing a significant difference, followed by the moderate (70.0%) and hot seasons (72.9%) (p < 0.01). Initial severity and long-term prognoses were worse in patients admitted during the cold season. Our findings highlight the importance of optimal prevention and follow-up of AMI patients with cold season onset.

Impact of the triglyceride level on coronary plaque components in female patients with coronary artery disease treated with statins.

Several studies have reported that elevated triglyceride (TG) levels may be more strongly associated with an increased risk of coronary artery disease (CAD) in females than in males. We examined gender differences in the relationship between TG levels and coronary atherosclerosis using integrated backscatter intravascular ultrasound (IB IVUS) in CAD patients treated with statins. Three hundred seventy-eight CAD patients (105 females and 273 males) who underwent percutaneous coronary intervention using IB IVUS, and who were already receiving statin treatment, were included. Gray-scale and IB IVUS examinations were performed for the non-culprit segment of a coronary artery and fasting serum TG concentrations were measured. We found that TG levels were significantly correlated with increased lipid (r = 0.40, p < 0.001) and decreased fibrous (r = - 0.37, p < 0.001) plaque components in females, but not in males. Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were not related to either the gray-scale or IB IVUS parameters in both genders. After adjustment for conventional coronary risk factors by a multivariate stepwise regression analysis, higher TG levels in females were independently associated with increased lipid (ß = 0.31, p< 0.001) contents in coronary plaques. In conclusion, among CAD patients treated with statins, TG levels were associated with lipid-rich coronary plaques in females, but not in males. TG levels may be more important indicators of residual risk after statin treatment in females than in males.

Association between discordance of LDL-C and non-HDL-C and clinical outcomes in patients with stent implantation: from the FU-Registry.

It is not yet clear whether the discordance of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) predicts the follow-up clinical outcome (major adverse cardiovascular events: MACEs) in patients with coronary stent implantation. Among 2015 patients with coronary stent implantation (Fukuoka University [FU]-Registry), excluding those with acute coronary syndrome or hemodialysis, we selected 801 patients who had undergone successful stent implantation with a follow-up until 18 months, and classified them into 3 groups according to baseline LDL-C and non-HDL-C levels [percentile(P)non-HDL-C more than (P)LDL-C, (P)non-HDL-C equal to (P)LDL-C, and (P)non-HDL-C less than (P) LDL-C]. We found that the discordance of (P)LDL-C and (P)non-HDL-C was not a significant predictor of MACEs. Higher LDL-C level was consistently and independently associated with higher incidences of MACEs after controlling for conventional risk factors and the type of stent used by multivariate Cox regression analyses. In conclusion, LDL-C levels are more important than non-HDL-C levels and the discordance of LDL-C and non-HDL-C levels as predictors of MACEs in patients with stable angina after stent implantation.

Association Between the Presence or Severity of Coronary Artery Disease and Pericardial Fat, Paracardial Fat, Epicardial Fat, Visceral Fat, and Subcutaneous Fat as Assessed by Multi-Detector Row Computed Tomography.

The associations between the presence or severity of coronary artery disease (CAD) and measurements of various kinds of fat as assessed by multidetector row computed tomography (MDCT) are unclear. We enrolled 300 patients who were clinically suspected to have CAD or who had at least one cardiac risk factor and had undergone MDCT. The number of significantly stenosed coronary vessels (VD), and measurements of pericardial fat index, paracardial fat index, epicardial fat index, visceral fat index, and subcutaneous fat index were quantified using MDCT. Plasma levels of adiponectin, pentaxin-3, and high-sensitivity C-reactive protein factors were also measured. Pericardial fat index, paracardial fat index, and visceral fat index in a CAD group were significantly greater than those in a non-CAD group. In addition, the levels of these fat indices tended to increase as the number of VD increased and were positively correlated with the Gensini score. The area-under-the-curve for paracardial fat index was significantly greater than those for the other parameters of fat index measured by a receiver-operating characteristic curve analysis. The cut-off level of paracardial fat index that gave the greatest sensitivity and specificity for the diagnosis of CAD was 54.9 cm3/m2 (sensitivity 0.710, specificity 0.552). The presence of CAD was independently associated with paracardial fat index, in addition to age and diabetes mellitus, by a multiple logistic regression analysis. In conclusion, paracardial fat index may be a marker for evaluating the presence or severity of CAD.

Duration of Prehospital Resuscitation Efforts After Out-of-Hospital Cardiac Arrest.

BACKGROUND: During out-of-hospital cardiac arrest, it is unclear how long prehospital resuscitation efforts should be continued to maximize lives saved. METHODS AND RESULTS: Between 2005 and 2012, we enrolled 282 183 adult patients with bystander-witnessed out-of-hospital cardiac arrest from the All-Japan Utstein Registry. Prehospital resuscitation duration was calculated as the time interval from call receipt to return of spontaneous circulation in cases achieving prehospital return of spontaneous circulation or from call receipt to hospital arrival in cases not achieving prehospital return of spontaneous circulation. In each of 4 groups stratified by initial cardiac arrest rhythm (shockable versus nonshockable) and bystander resuscitation (presence versus absence), we calculated minimum prehospital resuscitation duration, defined as the length of resuscitation efforts in minutes required to achieve ≥99% sensitivity for the primary end point, favorable 30-day neurological outcome after out-of-hospital cardiac arrest. Prehospital resuscitation duration to achieve prehospital return of spontaneous circulation ranged from 1 to 60 minutes. Longer prehospital resuscitation duration reduced the likelihood of favorable neurological outcome (adjusted odds ratio, 0.84; 95% confidence interval, 0.838-0.844). Although the frequency of favorable neurological outcome was significantly different among the 4 groups, ranging from 20.0% (shockable/bystander resuscitation group) to 0.9% (nonshockable/bystander resuscitation group; P<0.001), minimum prehospital resuscitation duration did not differ widely among the 4 groups (40 minutes in the shockable/bystander resuscitation group and the shockable/no bystander resuscitation group, 44 minutes in the nonshockable/bystander resuscitation group, and 45 minutes in the nonshockable/no bystander resuscitation group). CONCLUSIONS: On the basis of time intervals from the shockable arrest groups, prehospital resuscitation efforts should be continued for at least 40 minutes in all adults with bystander-witnessed out-of-hospital cardiac arrest. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: 000009918.

BK-UM in patients with recurrent ovarian cancer or peritoneal cancer: a first-in-human phase-I study.

BACKGROUND: BK-UM (CRM197) is a mutant form of diphtheria toxin and a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF). We assessed the safety, pharmacokinetics, recommended dose, and efficacy of BK-UM in patients with recurrent ovarian cancer (OC) or peritoneal cancer (PC), and measured HB-EGF levels in serum and abdominal fluid after BK-UM administration. METHODS: Eleven patients with advanced or recurrent OC or PC were enrolled and treated with BK-UM via the intraperitoneal route. The dose was escalated (1.0, 2.0, 3.3, and 5.0 mg/m2) using a 3 + 3 design. RESULTS: Eight of 11 patients completed treatment. No dose-limiting toxicity (DLT) was experienced at dose levels 1 (1.0 mg/m2) and 2 (2.0 mg/m2). Grade 3 transient hypotension as an adverse event (defined as a DLT in the present study) was observed in two of four patients at dose level 3 (3.3 mg/m2). Treatment with BK-UM was associated with decreases in HB-EGF levels in serum and abdominal fluid in seven of 11 patients and five of eight patients, respectively. Clinical outcomes included a partial response in one patient, stable disease in five patients, and progressive disease in five patients. CONCLUSIONS: BK-UM was well tolerated at doses of 1.0 and 2.0 mg/m2, with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0 mg/m2 BK-UM is recommended for subsequent clinical trials. TRIAL REGISTRATION: This trial was prospectively performed as an investigator-initiated clinical trial. The trial numbers are UMIN000001002 and UMIN000001001, with registration dates of 1/30/2008 and 2/4/2008, respectively. UMIN000001001 was registered as a trial for the continuous administration of BK-UM after UMIN000001002 .