Prognostic study of cardiac events in Japanese patients with chronic kidney disease using ECG-gated myocardial Perfusion imaging: Final 3-year report of the J-ACCESS 3 study.

BACKGROUND: Myocardial perfusion imaging (MPI) is considered useful for risk stratification among patients with chronic kidney disease (CKD), without renal deterioration by contrast media. METHODS AND RESULTS: The Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS 3) is a multicenter, prospective cohort study investigating the ability of MPI to predict cardiac events in 529 CKD patients without a definitive coronary artery disease. All patients were assessed by stress and rest MPI with 99mTc-tetrofosmin and data were analyzed using a defect scoring method and QGS software. Major cardiac events were analyzed for 3 years after registration. The mean eGFR was 29.0 ± 12.8 (mL/minute/1.73 m2). The mean summed stress/rest/difference (SSS, SRS, SDS) scores were 1.9 ± 3.8, 1.1 ± 3.0, and 0.8 ± 1.8, respectively. A total of 60 cardiac events (three cardiac deaths, six sudden deaths, five nonfatal myocardial infarctions, 46 hospitalization cases for heart failure) occurred. The event-free survival rate was lower among patients with kidney dysfunction, higher SSS, and higher CRP values. Multivariate Cox regression analysis independently associated SSS ≥8, eGFR <15 (mL/minute/1.73 m2), and CRP ≥0.3 (mg/dL) with cardiac events. CONCLUSIONS: Together with eGFR and CRP, MPI can predict cardiac events in patients with CKD.

Prognostic impact of reducing myocardial ischemia identified using ECG-gated myocardial perfusion SPECT in Japanese patients with coronary artery disease: J-ACCESS 4 study.

AIM: Whether myocardial ischemia identified using myocardial perfusion imaging (MPI) can be an alternative target of coronary revascularization to reduce the incidence of cardiac events remains unclear. METHODS AND RESULTS: This multicenter, prospective cohort study aimed to clarify the prognostic impact of reducing myocardial ischemia. Among 494 registered patients with possible or definite coronary artery disease (CAD), 298 underwent initial pharmacological stress 99mTc-tetrofosmin MPI before, and eight months after revascularization or medical therapy, and were followed up for at least one year. Among these, 114 with at least 5% ischemia at initial MPI were investigated. The primary endpoints were cardiac death, non-fatal myocardial infarction and hospitalization for heart failure. Ischemia was reduced ≥5% in 92 patients. Coronary revascularization reduced ischemia (n = 89) more effectively than medical therapy (n = 25). Post-stress cardiac function also improved after coronary revascularization. Ejection fraction significantly improved at stress (61.0% ±â€¯10.7% vs. 65.4% ±â€¯11.3%; p < 0.001) but not at rest (67.1% ±â€¯11.3% vs. 68.3% ±â€¯11.6%; p = 0.144), among patients who underwent revascularization. Rates of coronary revascularization and cardiac events among the 114 patients were significantly higher (13.6%, p = 0.035) and lower (1.1% p = 0.0053), respectively, in patients with, than without ≥5% ischemia reduction. Moreover, patients with complete resolution of ischemia at the time of the second MPI had a significantly better prognosis. CONCLUSIONS: Reducing ischemia by ≥5% and the complete resolution of ischemia could improve the prognosis of patients with stable CAD.

Abdominal admittance helps to predict the amount of fluid accumulation in patients with acute heart failure syndromes.

BACKGROUND: Predicting fluid volume that needs to be removed in acute heart failure syndromes (AHFS) patients remains challenging. Thoracic admittance (TA), the reciprocal of thoracic impedance measured by bioelectrical impedance, reflects the amount of fluid in the thorax. Abdominal organs play an important role in AHFS as systemic fluid reservoirs. We investigated the relationship between abdominal admittance (AA) at the time of admission for AHFS and net fluid loss (NFL) during hospitalization. METHODS: Sixty-two consecutive patients hospitalized for AHFS [age 71±10 years, left ventricular ejection fraction (LVEF) 39±17%] were studied. The admittance values, i.e. the reciprocals of the impedance values, were derived using a BioZ(®) (CardioDynamics, San Diego, CA, USA). The change in weight from admission to discharge was used as a surrogate of amount of NFL. RESULTS: At the time of admission, a significant correlation was detected between TA and AA (r=0.46, p=0.0001). TA at admission was significantly correlated with the LV structural variables (end-diastolic dimension and end-systolic dimension), and serum sodium level. AA at admission was significantly correlated with New York Heart Association (NYHA) class and plasma BNP, and also correlated with LVEF and variables related to systemic congestion [minimal inferior vena cava (IVC) diameter and tricuspid regurgitation grade]. Neither TA nor AA values were significantly correlated with weight at admission. During hospitalization, TA and AA declined from 44±8kΩ(-1) to 36±6kΩ(-1) (p<0.0001) and from 74±25kΩ(-1) to 56±17kΩ(-1) (p<0.0001), respectively. Weight fell from 60.1±10.8kg to 54.5±9.4kg (p<0.0001), while NFL was 5.8kg (range, 0.1-17.5kg). In univariate analyses, the admission NYHA class, TA, AA, weight, and IVC diameter correlated with NFL. Multivariate analysis demonstrated that only admission weight [standardized partial regression coefficient (SPRC)=0.596], AA (SPRC=0.529), and NYHA class (SPRC=0.277) were independent predictors of NFL. CONCLUSION: Abdominal admittance measurement helps to predict the amount of fluid volume to be removed in patients with AHFS.

Quantitative Assessment of Fluid Accumulation Using Bioelectrical Impedance Analysis in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Acute decompensated heart failure (ADHF) is generally considered to be a problem of fluid volume overload, therefore accurately quantifying the degree of fluid accumulation is of critical importance in assessing whether adequate decongestion has been achieved. The aim of this study was to develop and validate a method to quantify the degree of fluid accumulation in patients with ADHF. METHODS AND RESULTS: Using multi-frequency bioelectrical impedance analysis (BIA), we measured extracellular water (ECW) volume in 130 ADHF patients on admission and at discharge. We also predicted optimal ECW volume using original equations based on data from 60 control subjects without the signs of HF. Measured/predicted (M/P) ratio of ECW in ADHF patients was observed to decrease from 1.26±0.25 to 1.04±0.17 during hospitalization (P<0.001). The amount of ECW volume reduction was significantly correlated with reduction in body weight (r=0.766, P<0.001). On multivariate analysis, higher M/P ratio of ECW at discharge was associated with increased risk of ADHF readmission or cardiac death within 6 months after discharge. CONCLUSIONS: Multi-frequency BIA-measured ECW was found to offer valuable information for analyzing the pathophysiology of ADHF, and may be a useful guide in the management of this disease.

Benefit of cilostazol in patients with high risk of bleeding: subanalysis of cilostazol stroke prevention study 2.

BACKGROUND: The Cilostazol Stroke Prevention Study 2 (CSPS 2) showed that cilostazol significantly reduced the risk of stroke by 25.7% relative to aspirin, with significantly fewer hemorrhagic events, in patients with prior ischemic stroke, excluding cardioembolic stroke. However, whether the benefit of cilostazol is sustained in patients with a high risk of bleeding has not been examined. METHODS: We conducted a subanalysis of CSPS 2 to examine whether known risk factors for hemorrhagic stroke, such as stroke subtype and systolic blood pressure (SBP), influence the efficacy of the study drugs on hemorrhagic stroke. The relative risk reduction of hemorrhagic stroke was determined from the incidences calculated by the person-year method. The cumulative incidence rates of ischemic stroke and hemorrhagic stroke were estimated and plotted using the Kaplan-Meier method. Incidences of serious hemorrhage and hemorrhage requiring hospital admission were also evaluated in the two treatment groups. Hazard ratios (HR) and 95% confidence intervals (95% CI) calculated by the Cox proportion hazard model for cilostazol versus aspirin were assessed, and a log-rank test was used for the comparison between treatments. RESULTS: The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group among patients with prior lacunar stroke (0.36 vs. 1.20% in person-year, HR 0.35, 95% CI 0.18-0.70, p < 0.01), but not among those with prior atherothrombotic stroke (0.31 vs. 0.59% in person-year, HR 0.53, 95% CI 0.14-2.0, p = 0.34). The incidence of hemorrhagic stroke was significantly lower in the cilostazol group than in the aspirin group throughout all SBP categories (Poisson regression model including time-dependent covariates, p < 0.01) including SBP above 140 mm Hg (cilostazol 0.45% vs. aspirin 1.44% in person-year; Poisson regression model including time-dependent covariates, p = 0.02). Cilostazol, compared with aspirin, significantly reduced the incidence of cerebral hemorrhage (HR 0.36, 95% CI 0.19-0.70, p < 0.01), overall hemorrhage requiring hospital admission (HR 0.53, 95% CI 0.29-0.97, p = 0.04), and gastrointestinal (GI) bleeding requiring hospital admission (HR 0.44, 95% CI 0.21-0.90, p = 0.03). CONCLUSIONS: Hemorrhagic stroke was less frequent in the cilostazol group than in the aspirin group among patients with lacunar stroke as well as those with increased blood pressure levels. As for extracranial hemorrhage requiring hospitalization, GI bleeding was also less frequent in the cilostazol than in the aspirin group. Cilostazol is supposed to be a therapeutic option to replace aspirin for secondary stroke prevention, especially in these subgroups with high risks for hemorrhagic events.

Myocardial perfusion imaging for predicting cardiac events in Japanese patients with advanced chronic kidney disease: 1-year interim report of the J-ACCESS 3 investigation.

PURPOSE: Whether myocardial perfusion imaging (MPI) can predict cardiac events in patients with advanced conservative chronic kidney disease (CKD) remains unclear. METHODS: The present multicenter prospective cohort study aimed to clarify the ability of MPI to predict cardiac events in 529 patients with CKD and estimated glomerular filtration rates (eGFR) < 50 ml/min per 1.73(2) without a definitive diagnosis of coronary artery disease. All patients were assessed by stress-rest MPI with (99m)Tc-tetrofosmin and analyzed using summed defect scores and QGS software. Cardiac events were analyzed 1 year after registration. RESULTS: Myocardial perfusion abnormalities defined as summed stress score (SSS) ≥4 and ≥8 were identified in 19 and 7 % of patients, respectively. At the end of the 1-year follow-up, 33 (6.2 %) cardiac events had occurred that included cardiac death, sudden death, nonfatal myocardial infarction, and hospitalization due to heart failure. The event-free rates at that time were 0.95, 0.90, and 0.81 for groups with SSS 0-3, 4-7, and ≥8, respectively (p = 0.0009). Thus, patients with abnormal SSS had a higher incidence of cardiac events. Multivariate Cox regression analysis showed that SSS significantly impacts the prediction of cardiac events independently of eGFR and left ventricular ejection fraction. CONCLUSION: MPI would be useful to stratify patients with advanced conservative CKD who are at high risk of cardiac events without adversely affecting damaged kidneys.

High rate of awarding compensation for claims of injuries related to clinical trials by pharmaceutical companies in Japan: a questionnaire survey.

INTRODUCTION: International norms and ethical standards have suggested that compensation for research-related injury should be provided to injured research volunteers. However, statistical data of incidence of compensation claims and the rate of awarding them have been rarely reported. METHOD: Questionnaire surveys were sent to pharmaceutical companies and medical institutions, focusing on industry-initiated clinical trials aiming at new drug applications (NDAs) on patient volunteers in Japan. RESULTS: With the answers from pharmaceutical companies, the incidence of compensation was 0.8%, including 0.06% of monetary compensation. Of the cases of compensation claims, 99% were awarded. In turn, with the answers from medical institutions, the incidence of compensation was 0.6%, including 0.4% of serious but not death cases, and 0.04% of death cases. Furthermore, most claims for compensation were initiated by medical institutions, rather than by the patients. On the other hand, with the answers from clinical trial volunteers, 3% of respondents received compensations. These compensated cases were 25% of the injuries which cannot be ruled out from the scope of compensation. CONCLUSION: Our study results demonstrated that Japanese pharmaceutical companies have provided a high rate of compensation for clinical trial-related injuries despite the possibility of overestimation. In the era of global clinical development, our study indicates the importance of further surveys to find each country's compensation policy by determining how it is being implemented based on a survey of the actual status of compensation coming from statistical data.

Rationale and design of J-ACCESS 4: prognostic impact of reducing myocardial ischemia identified using ECG-gated myocardial perfusion SPECT in Japanese patients with coronary artery disease.

BACKGROUND: The findings of our recent study entitled, "Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS)" showed that myocardial perfusion single photon emission computed tomography (MPS) can detect coronary artery disease (CAD) and help to predict future cardiac events in patients with suspected or extant CAD. However, the extent of the benefit conferred by percutaneous coronary intervention (PCI) as an initial management strategy compared with optimal medical therapy remains controversial. Little evidence supports the notion that myocardial ischemia identified using MPS is an alternative target of coronary revascularization to reduce the likelihood of developing cardiac events. METHODS: The multicenter, prospective cohort J-ACCESS 4 study aims to clarify the prognostic impact of reducing myocardial ischemia determined using electrocardiogram-gated MPS in Japanese patients with coronary artery disease. We started to register patients in J-ACCESS 4 at 74 facilities during June 2012 and will continue to do so until December 2013 or until the cohort comprises 500 patients who will participate in the study from one month before, until two months after stress/rest MPS assessment. Imaging data, the background of the patients including coronary risk factors and treatment before MPS assessments will be analyzed. The patients will undergo coronary revascularization within two months after MPS and/or receive appropriate medical therapy. The second stress/rest MPS will be performed from 4 to 10 months after coronary revascularization or registration. They will be followed up for over one year after the second MPS assessment. The primary endpoints will be cardiac death, sudden death of unknown cause, non-fatal myocardial infarction, and hospitalization for heart failure. The secondary endpoints will comprise death due to all causes including non-cardiac death and any cardiovascular events. This study will be completed in 2015. Here, we describe the design of the J-ACCESS 4 study.

Improved lipid profiles are associated with reduced incidence of coronary vascular events in asymptomatic patients with type 2 diabetes and impaired myocardial perfusion.

AIM: Individuals with type 2 diabetes are at high risk for cardiovascular events; however, a modality that could reduce risk has not been fully evaluated. We examined the annual incidence rate of cardiovascular events in asymptomatic Japanese diabetic patients who underwent gated myocardial perfusion single-photon computed tomography (SPECT). METHODS: Asymptomatic patients (n= 485) aged ≥50 years and with either a maximal carotid artery intima-media thickness of ≥1.1 mm, or urinary albumin ≥30 mg/g creatinine, or at least two of abdominal obesity, low HDL cholesterol, high triglyceride levels and hypertension were evaluated at 50 institutions using gated SPECT with the stress-rest protocol and were followed up for three years. In the patients with summed stress scores (SSS) of ≥9, the initial high cardiovascular incidence rate in the first year declined significantly (p<0.001) from 21% to 2% during the second and third year. RESULTS: The incident rate was consistent among diabetics with low SSS during follow-up. Baseline LDL and non-HDL cholesterol levels significantly reduced (123±6.4 to 99±6.1 mg/dL; p<0.05) during the first year in diabetic patients with high SSS, but did not significantly change in diabetic patients with low (<9) SSS. CONCLUSION: The immediate improvement of lipid levels within one year correlated with the significant reduction in CVD events arising in diabetic patients with moderate or severe myocardial ischemia. Thus, rapidly lowering hyperlipidemia is very effective for patients with type 2 diabetes at high risk for cardiac events.

Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells.

OBJECTIVES: The goal of this study was to conduct a direct head-to-head comparison of different stem cell types in vitro for various assays of potency and in vivo for functional myocardial repair in the same mouse model of myocardial infarction. BACKGROUND: Adult stem cells of diverse origins (e.g., bone marrow, fat, heart) and antigenic identity have been studied for repair of the damaged heart, but the relative utility of the various cell types remains unclear. METHODS: Human cardiosphere-derived cells (CDCs), bone marrow-derived mesenchymal stem cells, adipose tissue-derived mesenchymal stem cells, and bone marrow mononuclear cells were compared. RESULTS: CDCs revealed a distinctive phenotype with uniform expression of CD105, partial expression of c-kit and CD90, and negligible expression of hematopoietic markers. In vitro, CDCs showed the greatest myogenic differentiation potency, highest angiogenic potential, and relatively high production of various angiogenic and antiapoptotic-secreted factors. In vivo, injection of CDCs into the infarcted mouse hearts resulted in superior improvement of cardiac function, the highest cell engraftment and myogenic differentiation rates, and the least-abnormal heart morphology 3 weeks after treatment. CDC-treated hearts also exhibited the lowest number of apoptotic cells. The c-kit(+) subpopulation purified from CDCs produced lower levels of paracrine factors and inferior functional benefit when compared with unsorted CDCs. To validate the comparison of cells from various human donors, selected results were confirmed in cells of different types derived from individual rats. CONCLUSIONS: CDCs exhibited a balanced profile of paracrine factor production and, among various comparator cell types/subpopulations, provided the greatest functional benefit in experimental myocardial infarction.

Cardiac event risk in Japanese subjects estimated using gated myocardial perfusion imaging, in conjunction with diabetes mellitus and chronic kidney disease.

BACKGROUND: Cardiac event risk is estimated using quantitative gated myocardial perfusion imaging (MPI) and clinical background in patients with ischemic heart disease. The aim of the present study was to calculate major cardiac event risk and tabulate it in the Heart Risk Table for clinical use of risk stratification. METHODS AND RESULTS: Multivariate logistic regression was performed based on a multicenter prognostic database (Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated Single-photon emission computed tomography [J-ACCESS investigation]) using MPI (n=2,395). The risk of major cardiac events (cardiac death, non-fatal myocardial infarction and heart failure requiring hospitalization) was estimated using age, ejection fraction (EF), estimated glomerular filtration rate (eGFR) and presence of diabetes mellitus (DM). Age-matched standard eGFR was determined in 77 subjects. Major cardiac event risk was calculated using the equation: risk (%/3 years)=1/(1+Exp(-(-4.699-0.0151×eGFR+0.7998×DM+0.0582×age+0.697×SSS-0.0359×EF))×100, where SSS refers to summed stress scores. Risk was determined without eGFR (the initial version) and using the present formula with eGFR (revised version), with consistent results. DM and chronic kidney disease were major determinants of cardiac events. CONCLUSIONS: Cardiac event risk was estimated using MPI defect score and left ventricular EF in conjunction with eGFR and the presence of DM. The risk table might be used for risk evaluation in Japanese patients undergoing MPI.

Incremental prognostic value of myocardial perfusion single photon emission computed tomography for patients with diabetes and chronic kidney disease.

PURPOSE: This study estimates whether myocardial perfusion single photon emission computed tomography (SPECT) can predict the prognostic risk of cardiac events among patients with diabetes and relatively mild chronic kidney disease (CKD). METHODS: Data from 2423 patients in the Japanese Assessment of Cardiac Events and Survival Study were examined. Patients were classified into group A (diabetes-, CKD-), B (diabetes-, CKD+), C (diabetes+, CKD-), and D (diabetes+, CKD+). After 3 years of follow-up, the incidence of cardiac events and the ability of myocardial perfusion SPECT to estimate prognosis were evaluated. RESULTS: A total of 119 (4.9%) events (28 cardiac deaths, 25 myocardial infarctions, and 66 severe heart failures) occurred. Each type of event occurred more frequently in CKD compared with non-CKD groups with both diabetic and nondiabetic populations. Risk was higher in patients with high summed stress scores. Risk gradually increased in nondiabetic groups according to the decrease in the estimated glomerular filtration rate and roughly consisted of two diabetic groups with a cutoff of eGFR equal to 50 ml/min. CONCLUSION: A high incidence of cardiac events is associated with CKD in both nondiabetic and diabetic patients. Summed stress scores obtained by myocardial perfusion SPECT have a highly incremental value for predicting the cardiac prognosis of patients with diabetes and CKD. These scores are useful for the risk stratification of asymptomatic patients with relatively mild renal dysfunction requiring neither dialysis nor renal transplantation.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial.

BACKGROUND: The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS: Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS: Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564-0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296-0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION: Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING: Otsuka Pharmaceutical.

Prognostic value of gated myocardial perfusion imaging for asymptomatic patients with type 2 diabetes: the J-ACCESS 2 investigation.

OBJECTIVE: Individuals with type 2 diabetes are at high risk for cardiovascular events. We evaluated the prognostic value of gated myocardial perfusion single-photon computed tomography (SPECT) for asymptomatic diabetic patients in a Japanese population. RESEARCH DESIGN AND METHODS: Asymptomatic patients (n=485) aged≥50 years with either a maximal carotid artery intima-media thickness of ≥1.1 mm, or a urinary albumin ≥30 mg/g creatinine or who had at least two of the following, abdominal obesity, low HDL cholesterol, high triglyceride levels, and hypertension, were enrolled at 50 institutions. The patients were evaluated using gated SPECT with the stress-rest protocol and followed up for 3 years. RESULTS: During the follow-up period, 62 (13%) events occurred, including 5 cardiac deaths and 57 cardiovascular events. Patients with summed stress scores (SSS) of ≥9 had a significantly higher incidence (of either death or cardiovascular events) than those with SSS scores of <9 (23 vs. 12%; P=0.009). Multivariate Cox regression analysis showed that significant variables were SSS≥9, a low estimated glomerular filtration rate, and being a current smoker. Univariate Cox regression analysis showed that ticlopidine and insulin use are potent medical modulators of cardiovascular events. CONCLUSIONS: The incidences of cardiovascular events and death were significantly high in a select population of type 2 diabetic patients with SPECT abnormalities. A targeted treatment strategy is required for asymptomatic but potentially high-risk patients with type 2 diabetes.

Prognostic study of cardiac and renal events in Japanese patients with chronic kidney disease and cardiovascular risk using myocardial perfusion SPECT: J-ACCESS 3 study design.

Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease. Recent studies have indicated that the incidence of cardiovascular disease increases inversely with estimated glomerular filtration rate. Although coronary angiography is considered the gold standard for detecting coronary artery disease, contrast-induced nephropathy or cholesterol microembolization remain serious problems; therefore, a method of detecting coronary artery disease without renal deterioration is desirable. From this viewpoint, stress myocardial perfusion single photon emission computed tomography (SPECT) might be useful for patients with chronic kidney disease. We recently performed the Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS) investigating patients with suspected or extant coronary artery disease and the J-ACCESS 2 study of patients with diabetes. The findings from these studies showed that SPECT can detect coronary artery disease and help to predict future cardiac events. Thus, we proposed a multicenter, prospective cohort study called "J-ACCESS 3" in patients with chronic kidney disease and cardiovascular risk. The study aimed at predicting cardiovascular and renal events based on myocardial perfusion imaging and clinical backgrounds. We began enrolling patients in J-ACCESS 3 at 74 facilities from April 2009 and will continue to do so until 31 March 2010, with the aim of having a cohort of 800 patients. These will be followed up for three years. The primary endpoints will be cardiac death and sudden death. The secondary endpoints will comprise any cardiovascular or renal events. This study will be completed in 2013. Here, we describe the design of the J-ACCESS 3 study.

Incremental prognostic value of stress/rest gated perfusion SPECT in patients with coronary artery disease--subanalysis of the J-ACCESS study.

BACKGROUND: This study aimed to reveal the incremental prognostic implications of perfusion/function variables by stress/rest gated single-photon emission computed tomography (SPECT) over clinical risks in patients with known coronary artery disease (CAD). METHODS AND RESULTS: Using the Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS) database, the 3-year follow-up data of 2,200 patients who had established CAD were analyzed. Major cardiac events (cardiac death, myocardial infarction, heart failure, and unstable angina) were observed in 167 (7.6%) patients. Multivariate logistic regression analysis identified peripheral artery disease, diabetes mellitus, no use of statins, typical chest pain, pharmacological stress test, heart rate at rest, left ventricular end-systolic volume index derived from gated SPECT (LVESVI), and summed difference score (SDS) as independent significant predictors of the major cardiac events, with odds ratios of 1.025 to 2.291 (P=0.0309-0.0008). Global chi-square values increased by combining the independent predictors, and the greatest values (nearly 110) were observed when LVESVI or SDS was added to the pre-scan clinical information. CONCLUSIONS: Perfusion/function measures by stress/rest gated SPECT contribute to a significant improvement in risk stratification and secondary prevention strategy in combination with pre-scan clinical risks in patients with known CAD.

Cardiovascular events in Japanese asymptomatic patients with type 2 diabetes: a 1-year interim report of a J-ACCESS 2 investigation using myocardial perfusion imaging.

PURPOSE: Diabetic patients have a high risk for cardiovascular events. The role of myocardial perfusion imaging was investigated in asymptomatic diabetic patients to evaluate short-term prognosis in a Japanese population. METHODS: A total of 506 asymptomatic patients ≥ 50 years of age who had carotid artery maximum intima-media thickness ≥ 1.1 mm, urinary albumin excretion of ≥ 30 mg/g creatinine, with additional criteria of abdominal obesity, low HDL cholesterol, high triglyceride level, and hypertension were enrolled and followed up over a 3-year period. Gated SPECT with stress-rest protocol was performed and analyzed by summed defect scores and QGS software. One-year cardiovascular events were analyzed. RESULTS: Myocardial ischemia was observed in 17% of patients, and abnormal perfusion findings of ischemia and/or scar were observed in 32% of patients. By the end of the 1-year follow-up, 33 (6.5%) cardiovascular events occurred including 6 all-cause deaths. Patients with summed stress score (SSS) >8 had a higher incidence of either death or cardiovascular events. Event-free survival rates for SSS 0-3, 4-8, 9-13, and ≥ 14 were 0.96, 0.95, 0.82, and 0.76, respectively. Multivariate Cox regression analysis showed that significant variables were SSS, history of cerebrovascular accident, and electrocardiographic abnormality at rest. CONCLUSION: The 1-year interim summary showed that cardiovascular events were significantly higher in patients with SPECT abnormality, although hard cardiac event rate was relatively low. Targeted treatment strategy is required for asymptomatic but potentially high-risk diabetic patients.

Prognostic value of myocardial perfusion and ventricular function in a Japanese multicenter cohort study (J-ACCESS): the first-year total events and hard events.

OBJECTIVE: To determine the prognostic value of myocardial ischemia, function and coronary risk factors on total and hard cardiac events using myocardial perfusion imaging in a Japanese population. METHODS: A prospective cohort study was performed in 117 Japanese hospitals, each with a nuclear cardiology facility. A total of 4,031 patients with suspected or confirmed ischemic heart disease were registered. The patients were followed up for a year to investigate total and hard events, and those who had any events were followed up for 3 years to evaluate subsequent hard events. A stress-rest gated myocardial perfusion study was performed with (99m)Tc-tetrofosmin using gated single-photon emission computed tomography (SPECT) and analyzed by semi-quantitative scores. RESULTS: During the 1-year follow-up period, 263 (6.5%) patients had total events comprising all-cause death, non-fatal myocardial infarction (MI), heart failure, unstable angina, angina pectoris and coronary revascularization. Cardiac death occurred in 23 patients (0.6%) and non-fatal MI in 11 (0.3%). Among patients with ejection fraction (EF) of <45% and a summed difference score (SDS) of >/=2, 18.7% (2.4% for cardiac death and 0.6% for non-fatal MI) experienced total events compared with 3.9% (0.3% for cardiac death and 0.2% for non-fatal MI; P < 0.0001) of those with EF >/= 45% and SDS < 2. Multivariate analysis identified EF, SDS, age, history of revascularization and diabetes as significant predictors of all events, while the significant predictors were age and EF for hard events. When the patients who had heart failure in the first year were followed up, 9 of 41 (22.0%) experienced cardiac death in the subsequent 3-year follow-up period. CONCLUSIONS: Myocardial ischemia defined by SDS and ventricular function were the main predictors of total events despite the relatively low incidence of hard events in this Japanese population. In patients with cardiac events in a year, closer attention should be paid to subsequent hard events particularly in patients with heart failure.

Right atrial spontaneous echo contrast indicates a high incidence of perfusion defects in pulmonary scintigraphy in patients with atrial fibrillation.

This study investigated the relationship between right atrial SEC (RA-SEC) and silent pulmonary embolism (PE) in patients with nonvalvular atrial fibrillation (NVAF). Spontaneous echo contrast (SEC) within the cardiac chambers is associated with an increased risk of thromboembolism. However, most studies have examined the relationship between left atrial SEC and systemic thromboembolic disease. Transesophageal echocardiography (TEE) was performed in 210 patients with NVAF to assess a risk of thromboembolism. Right atrial SEC was detected in 37 patients, and 35 of these patients with RA-SEC and 29 patients without RA-SEC were enrolled in this study. However, patients with a history of symptomatic PE or deep vein thrombosis were excluded. Spontaneous echo contrast was diagnosed by TEE as the presence of smoke-like echoes that swirled in a circular pattern. PE was diagnosed by pulmonary scintigraphy. Thrombotic and thrombolytic parameters, including serum concentrations of plasmin-alpha-plasmin inhibitor complex (PIC), thrombin-antithrombin complex (TAT), D-dimer, and fibrinogen were measured in all patients. Left ventricular dimension, cardiac function, and hematologic parameters were similar in the two groups. Nevertheless, the incidence of perfusion defects in pulmonary scintigraphy was significantly higher in the group with RA-SEC (40%) than in the group without RA-SEC (7%; chi-square, P=0.006). The increased incidence of perfusion defects in pulmonary scintigraphy in patients with RA-SEC indicates that right atrial SEC may be a predictable factor at a high risk of PE.