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Background: Many studies have reported that dipeptidyl peptidase (DPP)-4 inhibitors do not significantly reduce cardiovascular events (CVE). We sought to evaluate whether DPP-4 inhibitors effected the incidence of CVE in diabetic patients with no history of atherosclerotic events. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; heart failure requiring hospitalization; aortic disease; and peripheral artery disease. JPAD patients were divided into a DPP-4 Group and a non-DPP-4 Group based on whether or not they were taking DPP-4 inhibitors at the 2013 follow-up. We investigated the incidence of CVE in 1,107 JPAD patients who had had at least one follow-up by 2019. Results: During the observation period from 2013 to 2019, there were 37 (7%) CVE in the DPP-4 Group (n=520) and 66 (11%) in the non-DPP-4 Group (n=587). The incidence of CVE was significantly lower in the DPP-4 Group than in the non-DPP-4 Group (Log-Rank P=0.0074, Figure). Cox proportional hazards model analysis revealed that use of DPP-4 inhibitors (HR, 0.65: 0.43-0.98, P=0.04) was an independent factor after adjustment for age ≥65 years, hypertension, dyslipidemia, and, insulin usage (Figure). Conclusions: Our study demonstrated that the use of DPP-4 inhibitors was associated with a reduced incidence of CVE after adjustment in diabetic patients without a history of atherosclerotic events. It is necessary to be aware of the cardiovascular event-suppressing effect of DPP-4 inhibitors on diabetic patients.

Background: We sought to evaluate whether there was a difference in the incidence rate of cardiovascular event (CVD) among different hemoglobin (Hb) A1c levels in diabetic patients without a history of atherosclerotic events. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up with the patients until 2019. We defined the cardiovascular events as the following: acute myocardial infarction; stable angina; unstable angina; sudden cardiac death; stroke; transient ischemic attack; aortic disease; and peripheral artery disease. Among 2,535 JPAD patients, HbA1c levels of the JPAD patients were recorded on average 8 times. Based on the mean value of HbA1c, we divided the patients into three groups: a High HbA1c Group (n=899, HbA1c ≥7.5%); a Moderate HbA1c Group (n=581, 7.5% >HbA1c ≥7.0 %); or, a Low HbA1c Group (n=1055, 7.0% >HbA1c). We compared the incidence of CVD among the three groups. Results: The mean HbA1c (%) was 8.6 in the High HbA1c Group, 7.4 in the Moderate HbA1c Group, and 6.6 in the Low HbA1c Group on registration. During an 11.56-year follow-up, the incidence of CVD was significantly higher in the High HbA1c Group (P2 , duration of diabetes ≥7.0% years, medications, eGFR ≥60 ml/min/1.73m 2 , and systolic blood pressure ≥140 mm Hg (Figure). Conclusions: Our study demonstrated that HbA1c ≥7.5% was independently associated with the incidence of CVD in diabetic patients without a history of atherosclerotic events while 7.5% >HbA1c ≥7.0 % was not.

Background: No clinical studies have focused on the factors associated with discharge destination in patients with acute decompensated heart failure. Methods and Results: Of 4,056 consecutive patients hospitalized for ADHF in the KCHF registry, we analyzed 3,460 patients hospitalized from their homes and discharged alive. There were 3009 and 451 patients who were discharged to home (home discharge) and non-home (non-home discharge), respectively. We investigated the factors associated with non-home discharge and compared the outcomes between home discharge and non-home discharge. Factors independently and positively associated with non-home discharge were age ≥80 years (odds ratio [OR]:1.76, 95% confidence interval [CI]:1.28-2.42), body mass index ≤22 kg/m 2 (OR:1.49, 95%CI:1.12-1.97), poor medication adherence (OR:2.08,95%CI:1.49-2.88), worsening heart failure (OR:2.02, 95%CI:1.46-2.82), stroke during hospitalization (OR:3.74, 95%CI:1.75-8.00), functional decline (OR:12.24, 95%CI:8.74-17.14) and length of hospital stay >16 days (OR:4.14, 95%CI:3.01-5.69), while those negatively associated were diabetes mellitus (OR:0.69, 95%CI:0.51-0.94), cohabitants (OR:0.62, 95%CI:0.46-0.85), and ambulatory state before admission (OR:0.25, 95%CI:0.18-0.36). The cumulative 1-year incidence of all-cause death was significantly higher in the non-home discharge group than in the home discharge group. The non-home discharge group compared with the home discharge group was associated with a higher adjusted risk for all-cause death (HR:1.66, P Conclusions: The discharge destination of acute decompensated heart failure patients is influenced by factors such as pre-hospital social background, age, body mass index, low self-care ability, events during hospitalization (worsening heart failure, stroke, etc.), functional decline, and length of hospital stay; moreover, the prognosis of non-home discharge patients is worse than that of home discharge patients.

Background: Rapid and accurate diagnosis of acute coronary syndrome (ACS) is critical to prevent the fatal complication accompanied with the delay of the treatment. However, the diagnosis of non-ST-segment elevation ACS (NSTE-ACS), especially shortly after the onset, is not straightforward because even high-sensitivity cardiac troponin (hs-cTn) is sometimes not elevated at that phase. We previously reported in a retrospective study that serum nardilysin is a potential biomarker for the early detection of NSTE-ACS. Here, we present the results of the Nardi-ACS study, a multicenter prospective study conducted at six centers in Japan to clarify the significance of nardilysin for the early detection of ACS. Methods and Results: We analyzed serum nardilysin and hs-cTnI (Architect; Abbott) in the sequential 2 independent cohorts; phase I primary cohort (435 patients with chest pain who consecutively visited to the emergency room (ER)) and phase II validation cohort (486 patients with a strong suspicion of ACS who underwent coronary angiography). The frequency of non-ACS, STEMI and NSTE-ACS was 64.4, 22.5, and 13.1 (%) in the phase I, and 14.0, 60.0, and 25.9 (%) in the phase II cohort, respectively. The cutoff value of serum nardilysin was set at 1350.9 pg/ml (mean +2SD) obtained in 246 healthy volunteers, while the cutoff of hs-cTnI was set at 52 pg/ml. The initial blood test in the phase I cohort revealed that nardilysin was significantly elevated in ACS patients, compared to non-ACS patients (p Conclusion: Nardilysin could be a potential biomarker for the early diagnosis of troponin-negative NSTE-ACS.

Background: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting. Methods: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months. Results: Mean age was 75.0±7.6 years, and 85.2% of patients were men. OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS 2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79–1.72; P =0.20 for noninferiority, P =0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71–1.39; P =0.016 for noninferiority, P =0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively. Conclusions: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

Background: The prognostic implications of very low body mass index (BMI) values remain unclear in patients with acute decompensated heart failure (ADHF). This study aimed to investigate the prognostic impact of BMI classification based on the World Health Organization criteria in patients with ADHF. Methods and Results: Using data from 4056 consecutive patients with ADHF hospitalized in 19 participating hospitals in Japan between October 2014 and March 2016, we analyzed 3509 patients with available BMI data at discharge. The patients were divided into five groups; (1) Severely underweight: BMI2 , (2) Underweight: BMI≥16 kg/m 2 and 2 , (3) Normal weight: BMI≥18.5 kg/m 2 and 2 , (4) Overweight: BMI≥25 kg/m 2 and 2 (5) Obese: BMI≥30 kg/m 2 . The primary outcome measure was all-cause death. The median follow-up duration was 471 days, with 96.4% follow up at 1-year. The cumulative 1-year incidence of all-cause death was higher in underweight groups, and lower in overweight groups (Severely underweight: 36.3%, Underweight: 23.9%, Normal weight: 14.4%, Overweight: 7.9%, and Obese: 9.0%, P Conclusions: Lower BMI, not obesity, was associated with a higher risk for all-cause death after discharge in patients with ADHF.

Background: Heart failure (HF) is the leading cause of death in patients with atrial fibrillation (AF). Radiofrequency catheter ablation (RFCA) of AF is effective for maintaining sinus rhythm though its impact on heart failure still remains controversial. Purpose: We sought to elucidate whether AF recurrence following RFCA was associated with subsequent HF hospitalizations. Methods: We conducted a large-scale, prospective, multicenter, observational study. A total of 4931 consecutive patients who underwent an initial RFCA for AF with longer than 1-year of follow-up in 26 centers were enrolled (average age, 64±10 years; non-paroxysmal AF, 35.7%). The median follow-up duration was 2.9 years. The primary endpoint was an HF hospitalization more than 1-year after the index RFCA. We compared the patients without AF recurrences (group A) to those with AF recurrences within 1-year post RFCA (group B). Results: The 1-year cumulative incidence of AF recurrences after a single procedure was 30.7% (group A=3418, group B=1513 patients). Group B had a lower body mass index (group A vs. group B,24.1±3.6 vs. 23.8±3.4 kg/m 2 , p=0.014), longer history of AF (1.9 vs. 3.1 years, p Conclusions: Among AF patients receiving RFCA, those with AF recurrences were at a greater risk of subsequent heart failure hospitalizations than those without AF recurrences. Recognition that AF recurrence following RFCA is a risk factor for a subsequent HF-related hospitalization is appropriate in clinical practice.

Introduction: Blood pressure (BP) is a significant predictor for chronic kidney disease (CKD). Hypothesis: We sought to evaluate whether the progression of CKD in diabetic patients, without a history of atherosclerotic events, is dependent on BP control. Methods: The Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study done from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019. We defined late-stage kidney disease (LSKD) as estimated glomerular filtration rate (eGFR) 2 or hemodialysis. Among 2,536 JPAD patients, 27 patients were excluded for eGFR 2 on registration. BP of the JPAD patients was recorded on average 8 times. Based on the mean value of systolic BP (SBP), we divided the patients into three groups: a High BP Group (n=607, SBP≥140 mm Hg); a Moderate BP Group (n=989, 140>SBP≥130 mm Hg); or a Low BP Group (n=913, SBP Results: The mean eGFR (ml/min/1.73m 2 ) was 75.1 in the High BP Group, 72.6 in the Moderate BP Group, and 75.7 in the Low BP Group on registration. During a 11.2-year follow-up, the incidence of LSKD was significantly higher in the High BP and Moderate BP Groups than in the Low BP Group (P2 , duration of diabetes ≥7.0 years, statin usage, aspirin usage, eGFR≥60 ml/min/1.73m 2 , and hemoglobin A1c ≥7.2 % (Figure). Conclusions: Our study demonstrated that SBP was independently associated with the progression to LSKD in diabetic patients, without a history of atherosclerotic events. SBP less than 130 mm Hg is recommended for diabetic patients to prevent progression to LSKD.

Background: The dual antiplatelet therapy (DAPT) score was developed to estimate ischemic and bleeding risks from the DAPT study. However, few studies validated its utility externally. We sought to validate the utility of the DAPT score in the Japanese population. Methods: In a pooled cohort of 3 studies conducted in Japan (the CREDO-Kyoto [Coronary Revascularization Demonstrating Outcome Study in Kyoto] Registry Cohort-2, RESET [Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial], and NEXT [NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial]), we compared risks for ischemic and bleeding events from 13 to 36 months after percutaneous coronary intervention among patients with a DAPT score ≥2 (high DS) and a DAPT score Results: Among 12 223 patients receiving drug-eluting stents who were free from ischemic or bleeding events at 13 months after percutaneous coronary intervention, 3944 patients had high DS and 8279 had low DS. The cumulative incidence of primary ischemic end point (myocardial infarction/stent thrombosis) was significantly higher in high DS than in low DS (1.5% versus 0.9%, P =0.002), whereas the cumulative incidence of primary bleeding end point (GUSTO moderate/severe) tended to be lower in high DS than in low DS (2.1% versus 2.7%, P =0.07). The cumulative incidences of cardiac death, myocardial infarction, and stent thrombosis were also significantly higher in high DS than in low DS (2.0% versus 1.4%, P =0.03; 1.5% versus 0.8%, P =0.002; 0.7% versus 0.3%, P P P =0.03, respectively). Conclusions: In the current population, the DAPT score successfully stratified ischemic and bleeding risks, although the ischemic event rate was remarkably low even in high DS. Further studies would be warranted to evaluate the utility of prolonged DAPT guided by the DAPT score.

Background: The long-term efficacy and safety of low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus are still inconclusive. Methods: The JPAD trial (Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes) was a randomized, open-label, standard care–controlled trial examining whether low-dose aspirin affected cardiovascular events in 2539 Japanese patients with type 2 diabetes mellitus and without preexisting cardiovascular disease. Patients were randomly allocated to receive aspirin (81 or 100 mg daily; aspirin group) or no aspirin (no-aspirin group) in the JPAD trial. After that trial ended in 2008, we followed up with the patients until 2015, with no attempt to change the previously assigned therapy. Primary end points were cardiovascular events, including sudden death, fatal or nonfatal coronary artery disease, fatal or nonfatal stroke, and peripheral vascular disease. For the safety analysis, hemorrhagic events, consisting of gastrointestinal bleeding, hemorrhagic stroke, and bleeding from any other sites, were also analyzed. The primary analysis was conducted for cardiovascular events among patients who retained their original allocation (a per-protocol cohort). Analyses on an intention-to-treat cohort were conducted for hemorrhagic events and statistical sensitivity. Results: The median follow-up period was 10.3 years; 1621 patients (64%) were followed up throughout the study; and 2160 patients (85%) retained their original allocation. Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91–1.42). Multivariable Cox proportional hazard model adjusted for age, sex, glycemic control, kidney function, smoking status, hypertension, and dyslipidemia showed similar results (hazard ratio, 1.04; 95% confidence interval, 0.83–1.30), with no heterogeneity of efficacy in subgroup analyses stratified by each of these factors (all interaction P >0.05). Sensitivity analyses on the intention-to-treat cohort yielded consistent results (hazard ratio, 1.01; 95% confidence interval, 0.82–1.25). Gastrointestinal bleeding occurred in 25 patients (2%) in the aspirin group and 12 (0.9%) in the no-aspirin group ( P =0.03), and the incidence of hemorrhagic stroke was not different between groups. Conclusions: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00110448.

Background— Female sex was reported to be associated with lower risk for midterm restenosis and repeat revascularization after bare-metal stent implantation. However, the influence of sex on very long-term outcomes after bare-metal stent implantation has not been yet reported. Methods and Results— Among the 9877 patients in the multicenter Coronary Revascularization Demonstrating Outcome study in Kyoto (CREDO-Kyoto) registry cohort-1, bare-metal stent implantation was performed in 5313 patients (men, n=3742 and women, n=1571). Follow-up was completed in 4515 patients (85.0%) at 10 years (duration, 10.3±3.1 [0.0–14.1] years). The cumulative incidence of target-lesion revascularization (TLR) was 27% at 1 year and 34% at 10 years (0.8%/y beyond 1 year). Non–target-lesion revascularization (non-TLR) was the dominant coronary revascularization beyond 1 year (13% at 1 year and 31% at 10 years [2.0%/y beyond 1 year]). Cumulative incidence of stent thrombosis was low (1.2% at 1 year and 1.9% at 10 years). Women were older and had greater prevalence of cardiovascular risk factors than men. The cumulative 10-year incidences of and adjusted risk for TLR were significantly higher in men than in women (36% versus 30%, P P Conclusions— TLR and stent thrombosis continued to occur without attenuation up to 10 years after bare-metal stent implantation. Men in comparison with women were associated with higher adjusted 10-year risks for all-cause death, myocardial infarction, stroke, coronary artery bypass grafting, TLR, and non-TLR.

We thank Dr Ahmed and colleagues for their comment on our article recently published in Circulation .1 They are very interested in the sex difference in the effect of low-dose aspirin on the primary prevention of cardiovascular events. As they mentioned, earlier studies indicated that low-dose aspirin may be helpful for reducing the risk of stroke in women,2 whereas it may be advantageous for the risk of myocardial infarction in men.2 However, we did not show significant differences between the sexes in the preventive effect of low-dose aspirin in Japanese patients with diabetes mellitus who have no history of cardiovascular diseases. Their major concern was that the effect of aspirin might differ between premenopausal and postmenopausal women. In our study, we could …

Background— Several recent randomized trials comparing everolimus-eluting stent (EES) and sirolimus-eluting stent (SES) reported similar outcomes. However, only 1 trial was powered for a clinical end point, and no trial was powered for evaluating target-lesion revascularization. Methods and Results— Randomized Evaluation of Sirolimus-eluting versus Everolimus-eluting stent Trial is a prospective multicenter randomized open-label trial comparing EES with SES in Japan. The trial was powered for evaluating noninferiority of EES relative to SES in terms of target-lesion revascularization. From February and July 2010, 3197 patients were randomly assigned to receive either EES (1597 patients) or SES (1600 patients). At 1 year, the primary efficacy end point of target-lesion revascularization occurred in 65 patients (4.3%) in the EES group and in 76 patients (5.0%) in the SES group, demonstrating noninferiority of EES to SES ( P noninferiority P superiority =0.34). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.32% versus 0.38%, P =0.77). An angiographic substudy enrolling 571 patients (EES, 285 patients and SES, 286 patients) demonstrated noninferiority of EES relative to SES regarding the primary angiographic end point of in-segment late loss (0.06±0.37 mm versus 0.02±0.46 mm, P noninferiority P superiority =0.24) at 278±63 days after index stent implantation. Conclusions— One-year clinical and angiographic outcome after EES implantation was noninferior to and not different from that after SES implantation in a stable coronary artery disease population with relatively less complex coronary anatomy. One-year clinical outcome after both EES and SES use was excellent with a low rate of target-lesion revascularization and a very low rate of stent thrombosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01035450.

Background— Age and sex are important considerations in the choice between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in daily clinical practice. Methods and Results— Of 25 816 patients enrolled in the multicenter Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto; Cohort-1, n=9877; Cohort-2, n=15 939), the present study population consisted of 5651 patients (men, n=3998; women, n=1653) with triple-vessel coronary artery disease who were considered to be pertinent in comparisons of PCI with CABG (PCI, n=3165; CABG, n=2486). Patients were divided into 3 groups according to the tertiles of age: ≤65 years (n=1972), 66 to 73 years (n=1820), and ≥74 years (n=1859). The excess adjusted mortality risk of PCI relative to CABG was significant in patients ≥74 years of age (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.10–1.79; P =0.006), whereas the risks were neutral in patients ≤65 years of age (HR, 1.05; 95% CI, 0.73–1.53; P =0.78) and in patients 66 to 73 years of age (HR, 1.03; 95% CI, 0.78–1.36; P =0.85; interaction P =0.003). The excess mortality risk of PCI relative to CABG was significant in men (HR, 1.24; 95% CI, 1.03–1.50; P =0.02) and trended to be significant in women (HR, 1.34; 95% CI, 0.98–1.84; P =0.07) without significant interaction between sex and the mortality risk of PCI relative to CABG (interaction P =0.40). Conclusions— There was a significant association between age and the mortality risk of PCI relative to CABG with excess risk in patients ≥74 years of age and neutral risk in younger patients. There was no significant sex-related difference in the mortality risk of PCI relative to CABG.

Background— Stent thrombosis (ST) after sirolimus-eluting stent implantation has not yet been adequately characterized, mainly because of its low incidence. Methods and Results— The Registry of Stent Thrombosis for Review and Reevaluation (RESTART) is a Japanese nationwide registry of sirolimus-eluting stent–associated ST comprising 611 patients with definite ST (early [within 30 days; EST], 322 patients; late [between 31 and 365 days; LST], 105 patients; and very late [>1 year; VLST], 184 patients). Baseline demographics, clinical presentation, and long-term outcome of sirolimus-eluting stent–associated ST were compared among patients with EST, LST, and VLST. Baseline demographics were significantly different according to the timing of ST. Characteristic demographic factors for LST/VLST versus EST identified by multivariable model were hemodialysis, end-stage renal disease not on hemodialysis, absence of circumflex target, target of chronic total occlusion, prior percutaneous coronary intervention, and age P P P =0.003) or LST (23.5%; P =0.009). Conclusion— ST timing–dependent differences in baseline demographic features, Thrombolysis in Myocardial Infarction flow grade, and mortality rate suggest possible differences in the predominant pathophysiological mechanisms of ST according to timing after sirolimus-eluting stent implantation.

Background— The influences of antiplatelet therapy discontinuation on the risk of stent thrombosis and long-term clinical outcomes after drug-eluting stent implantation have not yet been addressed adequately. Methods and Results— In an observational study in Japan, 2-year outcomes were assessed in 10 778 patients undergoing sirolimus-eluting stent implantation. Data on status of antiplatelet therapy during follow-up were collected prospectively. Incidences of definite stent thrombosis were 0.34% at 30 days, 0.54% at 1 year, and 0.77% at 2 years. Thienopyridine use was maintained in 97%, 62%, and 50% of patients at 30 days, 1 year, and 2 years, respectively. Patients who discontinued both thienopyridine and aspirin had a significantly higher rate of stent thrombosis than those who continued both in the intervals of 31 to 180 days, 181 to 365 days, and 366 to 548 days after stent implantation (1.76% versus 0.1%, P P =0.02; and 2.1% versus 0.14%, P =0.004, respectively). When discontinuation of aspirin was taken into account, patients who discontinued thienopyridine only did not have an excess of stent thrombosis in any of the time intervals studied. Adjusted rates of death or myocardial infarction at 24 months were 4.1% for patients taking thienopyridine and 4.1% for patients not taking thienopyridine ( P =0.99) in the 6-month landmark analysis. Conclusions— Discontinuation of both thienopyridine and aspirin, but not discontinuation of thienopyridine therapy only, was associated with an increased risk of stent thrombosis. Landmark analysis did not suggest an apparent clinical benefit of thienopyridine use beyond 6 months after sirolimus-eluting stent implantation.

Background: In 2013, the blood pressure (BP) control target for diabetic patients was changed in both Europe and USA; however, there was a paucity of supporting evidence. We investigated whether BP control Methods: We performed the Japanese primary prevention of atherosclerosis with aspirin for diabetes (JPAD) trial to examine the efficacy of low-dose aspirin therapy in 2536 type 2 diabetes patients. After completion of the JPAD trial in 2008, we followed up the same subjects until 2013, the JPAD2 cohort. Primary end points were a composite of ischemic heart disease, stroke, peripheral arterial disease, and sudden death. We divided the patients into either a high age 65 (H65) group (n=1360; age≥65 years) or a low age 65 (L65) group (n=1176; age Results: Systolic BP was unchanged 131 mmHg in 2009 and 130 mmHg in 2013 in each JPAD patients. Diastolic BP decreased from 73 mmHg in 2009 to 71 mmHg in 2013. The difference of incidence of atherosclerotic events between BP≥140/90 patients and BP Conclusions: The difference of incidence of atherosclerotic events between BP≥140/90 patients and BP

Background: The impact of second-generation drug-eluting stents (G2-DES) implantation as compared with first-generation drug-eluting stents (G1-DES) for calcified coronary lesion has not been yet adequately addressed. Methods: This pooled analysis compared 2-year clinical outcomes between G1- and G2-DES according to the presence or absence of coronary lesion calcification, using individual patient-level data from 2 large-scale prospective multicenter randomized trials, RESET (Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial) and NEXT (Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent). Among 4583 patients enrolled in the 2 trials, G1-DES (sirolimus-eluting stent) and G2-DES (everolimus- or biolimus-eluting stent) were used in 299 and 1033 patients, respectively, in the Calc stratum (at least 1 moderate to severe calcification), and 1208 and 3550 patients, respectively, in the Non-calc stratum (no or mild calcification). Coronary calcification was assessed by an independent angiographic core laboratory. The primary endpoint of the study was clinically driven target-lesion revascularization (TLR) at 2-year follow-up. Result: In the Calc stratum, the cumulative incidence of clinically driven TLR was significantly lower in G2-DES than in G1-DES (5.7% vs. 9.4%, P=0.03), while it was not significantly different between G1- and G2-DES in the Non-calc stratum (3.6% vs. 4.2%, P=0.35). Cumulative incidence of definite stent thrombosis was not significantly different between G1- and G2-DES in both strata (Calc stratum, 0.6% vs. 1.0%, P=0.44, and Non-calc stratum, 0.2% vs. 0.2%, P=0.98). After adjusting for confounders, the lower risk of G2-DES relative to G1-DES for clinically driven TLR remained significant in the Calc stratum (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35-0.87; P=0.01). There was significant interaction between the generation of DES and presence or absence of calcification (P interaction=0.01). Conclusion: G2-DES as compared with G1-DES was associated with lower risk for clinically driven TLR in patients with calcified coronary lesions.

Introduction: It has been reported that dipeptidyl peptidase (DPP) IV inhibitor treatment increased glucagon like peptide (GLP)-1 and GLP-1 receptor expression levels, and subsequently endothelial nitric oxide synthase levels in experimental studies. It is possible that DPP IV inhibitors modify blood pressure (BP) through the improvement of endothelial function. Hypothesis: The aim of this study was to investigate whether DPP IV inhibitors ameliorated BP in diabetic patients. Methods: The JPAD trial, 2002 to 2008, a multicenter, prospective, randomized, open label, blinded, end-point study, was undertaken to examine the efficacy of aspirin therapy. After completion of the trial in 2008, we followed the same subjects until 2013 as JPAD2 trial cohort. BP was measured in 1244 patients in both 2009 and 2013. Among the 1244 patients, 4 patients received DPPIV inhibitors in 2009, 280 patients in 2011, 573 patients in 2013. We examined the change of BP in the 573 patients. Among them, 344 patients had systolic BP≥140 mmHg or diastolic BP≥90 mmHg or both (high BP group). Results: The systolic BP from 2009 to 2013 did not significantly change in the 1244 patients (Figure). The diastolic BP significantly decreased in the 1244 patients (Figure). The systolic BP from 2009 to 2013 did not significantly change in the 573 patients receiving DPPIV inhibitors (Figure). The diastolic BP significantly decreased in the 573 patients receiving DPPIV inhibitors (Figure). In the high BP group, the systolic BP from 2009 to 2013 significantly decreased in the 148 patients receiving DPPIV inhibitors (Figure). In the high BP group, the diastolic BP significantly decreased in the 148 patients receiving DPPIV inhibitors (Figure). Conclusions: In 4 year-observation of the JPAD2 trial cohort, diastolic BP decreased and systolic BP did not change in diabetic patients. User of DPPIV inhibitors has been dramatically increased, and it significantly modifies systolic BP in high BP diabetic patients.

Background— There is a scarcity of long-term data from large-scale drug-eluting stent registries with a large enough sample to evaluate low-frequency events such as stent thrombosis (ST). Methods and Results— Five-year outcomes were evaluated in 12 812 consecutive patients undergoing sirolimus-eluting stent (SES) implantation in the j-Cypher registry. Cumulative incidence of definite ST was low (30 day, 0.3%; 1 year, 0.6%; and 5 years, 1.6%). However, late and very late ST continued to occur without attenuation up to 5 years after sirolimus-eluting stent implantation (0.26%/y). Cumulative incidence of target lesion revascularization within the first year was low (7.3%). However, late target lesion revascularization beyond 1 year also continued to occur without attenuation up to 5 years (2.2%/y). Independent risk factors of ST were completely different according to the timing of ST onset, suggesting the presence of different pathophysiological mechanisms of ST according to the timing of ST onset: acute coronary syndrome and target of proximal left anterior descending coronary artery for early ST; side-branch stenting, diabetes mellitus, and end-stage renal disease with or without hemodialysis for late ST; and current smoking and total stent length >28 mm for very late ST. Independent risk factors of late target lesion revascularization beyond 1 year were generally similar to those risk factors identified for early target lesion revascularization. Conclusion— Late adverse events such as very late ST and late target lesion revascularization are continuous hazards, lasting at least up to 5 years after implantation of the first-generation drug-eluting stents (sirolimus-eluting stents), which should be the targets for developing improved coronary stents.

Background— Optimal treatment strategies for restenosis of sirolimus-eluting stents (SES) have not been adequately addressed yet. Methods and Results— During the 3-year follow-up of 12 824 patients enrolled in the j-Cypher registry, 1456 lesions in 1298 patients underwent target-lesion revascularization (TLR). Excluding 362 lesions undergoing TLR for stent thrombosis or TLR using treatment modalities other than SES or balloon angioplasty (BA), 1094 lesions with SES-associated restenosis in 990 patients treated with either SES (537 lesions) or BA (557 lesions) constituted the study population for the analysis of recurrent TLR and stent thrombosis after the first TLR. Excluding 24 patients with both SES- and BA-treated lesions, 966 patients constituted the analysis set for the mortality outcome. Cumulative incidence of recurrent TLR in the SES-treated restenosis lesions was significantly lower than that in the BA-treated restenosis lesions (23.8% versus 37.7% at 2 years after the first TLR; P P P =0.4) and 0.6% versus 0.6%, respectively. Conclusions— Repeated implantation of SES for SES-associated restenosis is more effective in preventing recurrent TLR than treatment with BA, without evidence of safety concerns.

Background— Long-term outcomes after stenting of an unprotected left main coronary artery (ULMCA) with drug-eluting stents have not been addressed adequately despite the growing popularity of this procedure. Methods and Results— j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P P =0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion revascularization for the ULMCA lesions (3.6% versus 17.1%, P =0.005), with similar cardiac death rates at 3 years (9.8% versus 7.6%, P =0.41). Among patients with bifurcation lesions, patients with stenting of both the main and side branches (n=119) had significantly higher rates of cardiac death (12.2% versus 5.5%; P =0.02) and target-lesion revascularization (30.9% versus 11.1%; P Conclusions— The higher unadjusted mortality rate of patients undergoing ULMCA stenting with a sirolimus-eluting stent did not appear to be related to ULMCA treatment itself but rather to the patients’ high-risk profile. Although long-term outcomes in patients with ostial/shaft ULMCA lesions were favorable, outcomes in patients with bifurcation lesions treated with stenting of both the main and side branches appeared unacceptable.

A prior single center study reported that early lipid-lowering therapy with atorvastatin 20 mg/day in patients (pts) with acute coronary syndrome (ACS) significantly reduced coronary plaque volume (PV) of the non-culprit site by intravascular ultrasound (IVUS) evaluation. Effect of statins other than atorvastatin on PV has not been evaluated yet in the setting of ACS. A prospective, randomized open-label parallel group study with blinded endpoint evaluation was perfomed at 33 centers in Japan. Pts with ACS undergoing IVUS-guided percutaneous coronary intervention (PCI) were randomly assigned to receive either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin within 72 hours after PCI. The primary endpoint was the percentage change in non-culprit coronary PV by IVUS from baseline to 8 –12 months follow-up. The study was powered to evaluate non-inferiority of pitavastatin to atorvastatin. Between November 2005 and October 2006, 307 pts (pitavastatin group 153 pts and atorvastatin group 154 pts) were enrolled; 252 pts (82%) had IVUS image qualified for evaluation both at baseline and at follow-up. Low-density lipoprotein cholesterol (LDL-C) decreased from 130.9±33.3mg/dL at baseline to 81.1±23.4mg/dL at 8 –12 months follow-up (p= 0.001) in the pitavastatin group and from 133.8±31.4mg/dL to 84.1±27.4mg/dL (p= 0.001) in the atorvastatin group. PV decreased from 49.8±28.8mm 3 to 41.6±25.0mm 3 (p= 0.001) in the pitavastatin group and from 63.9±33.9mm 3 to 53.3±31.7mm 3 (p= 0.001) in the atorvastatin group. Mean percentage change in PV was −16.9±13.9% and −18.1±14.2% (p=0.5) in the pitavastatin and atorvastatin group, respectively. Upper limit of the 95% confidence interval of the mean difference in percentage change in PV between the two groups (1.11% (−2.27 to 4.48)) did not exceed the pre-defined non-inferiority margin of 5%. There was no significant correlation between percent change in plaque volume and LDL-C at baseline or at follow-up. Early intensive statin therapy with 4mg/day of pitavastatin or 20mg/day of atorvastatin in Japanese patients with ACS resulted in remarkable regression of coronary PV. The effect of pitavastatin 4mg/day on coronary PV was similar to that of atorvastatin 20mg/day.

Background— Observational registries comparing coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) have reported long-term survival results that are discordant with those of randomized trials. Methods and Results— We conducted a multicenter study in Japan enrolling consecutive patients undergoing first CABG or PCI between January 2000 and December 2002. Among 9877 patients enrolled, 5420 (PCI: 3712, CABG: 1708) had multivessel disease without left main involvement. Because age is an important determinant when choosing revascularization strategies, survival analysis was stratified by either age ≥75 or P =0.26). After adjustment for baseline characteristics, survival outcome tended to be better after CABG (hazard ratio for death after PCI versus CABG [HR], 95% confidence interval [CI]: 1.23 [0.99-1.53], P =0.06). Adjusted survival outcomes also tended to be better for CABG among elderly patients (HR [95%CI]: 1.37 [0.98-1.92] P =0.07), but not among nonelderly patients (HR [95% CI]: 1.09 [0.82-1.46], P =0.55). Unadjusted and adjusted survival outcome for CABG and PCI were not significantly different in any subgroups when elderly patients were excluded from analysis. Conclusions— In the CREDO-Kyoto registry, survival outcomes among patients

Background: Unsolved issue about Sirolimus-eluting stent is thrombosis, especially, the potential for late stent thrombosis (ST). Methods: To clarify the incidence and predictors of ST, two-year data of the j-Cypher Registry were examined using ARC definition. Design of this registry was multi-center prospective enrollment of 15,216 consecutive patients (pts) with anti-platelet regimen of aspirin and ticlopidine in Japan. Results: Pts’ characteristics of this cohort were as follows, age 68+/−10 years, male in 75%, diabetes in 42%, emergency procedure in 6.6%, hemodialysis in 5%, CKD ( CCr . Annual increase slope of late ST (ARC definite) was 0.25% per year. During follow-up, 439 Surgical operations excluding endovascular and CABG were needed. Within 30 days of operation, clinical event rates were death in 2.2%, MI in 0.65% and ST in 0.44%. Multivariate analysis identified 3 independent predictors of early ST (within three-month); Hemodialysis: Odds Ratio (OR) = 1.75 (95%CI 1.02–2.69) p=0.042, Male gender: OR = 2.00 (1.20–4.08) p=0.0051, and Emergency procedure: OR = 2.15 (1.36–3.22) p= 0.0017. Also, multivariate analysis identified one independent predictor of late ST (beyond three-month); Hemodialysis: OR = 2.44 (1.29–4.14) p=0.042. Conclusions : Stent thrombosis rate up to two years under Ticlopidine anti-platelet regimen in Japan seemed to be lower as compared with those reported from other registries in the real world, despite the fact that high risk pts were more prevalent in the j-Cypher registry. Hemodialysis was identified to be independent predictor of early and late stent thrombosis through two years. Cumulative stent thrombosis rates in j-Cypher registry