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Background: Proton pump inhibitors (PPIs) reportedly reduce upper gastrointestinal bleeding (UGIB) in patients undergoing percutaneous coronary intervention (PCI). However, whether the benefits of PPIs differ in high-risk subgroups is unknown., Methods and Results: Among 24,563 patients undergoing first PCI in the CREDO-Kyoto registry Cohort-2 and -3, we evaluated long-term effects of PPI for UGIB, defined as GUSTO moderate/severe bleeding, in several potential high-risk subgroups. In the study population, 45.6% of patients were prescribed PPIs. Over a median 5.6-year follow-up, PPIs were associated with lower adjusted risk of UGIB (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.50-0.80; P<0.001) and a non-significant but numerically lower risk of any gastrointestinal bleeding (HR 0.84; 95% CI 0.71-1.01; P=0.06). PPIs were not associated with a lower risk of GUSTO moderate/severe bleeding (HR 1.04; 95% CI 0.94-1.15; P=0.40) or a higher adjusted risk of myocardial infarction or ischemic stroke (HR 1.00; 95% CI 0.90-1.12; P=0.97), but were associated with higher adjusted mortality risk (HR 1.18; 95% CI 1.09-1.27; P<0.001). The effects of PPIs for UGIB, myocardial infarction or ischemic stroke, and all-cause death were consistent regardless of age, sex, acute coronary syndrome, high bleeding risk, oral anticoagulant use, and type of P2Y 12 inhibitor., Conclusions: PPIs were associated with a lower risk of UGIB and a neutral risk of ischemic events regardless of high-risk subgroup.

Background: Polypharmacy was reported to be associated with major bleeding in various populations. However, there are no data on polypharmacy and its association with bleeding in patients undergoing percutaneous coronary intervention (PCI)., Methods and results: Among 12,291 patients in the CREDO-Kyoto PCI Registry Cohort-3, we evaluated the number of medications at discharge and compared major bleeding, defined as Bleeding Academic Research Consortium Type 3 or 5 bleeding, across tertiles (T1-3) of the number of medications. The median number of medications was 6, and 88.0% of patients were on ≥5 medications. The cumulative 5-year incidence of major bleeding increased incrementally with increasing number of medications (T1 [≤5 medications] 12.5%, T2 [6-7] 16.5%, and T3 [≥8] 20.4%; log-rank P<0.001). After adjusting for confounders, the risks for major bleeding of T2 (hazard ratio [HR] 1.21; 95% confidence interval [CI] 1.08-1.36; P=0.001) and T3 (HR 1.27; 95% CI 1.12-1.45; P<0.001) relative to T1 remained significant. The adjusted risks of T2 and T3 relative to T1 were not significant for a composite of myocardial infarction or ischemic stroke (HR 0.95 [95% CI 0.83-1.09; P=0.47] and HR 1.06 [95% CI 0.91-1.23; P=0.48], respectively)., Conclusions: In a real-world population of patients undergoing PCI, approximately 90% were on ≥5 medications. Increasing number of medications was associated with a higher adjusted risk for major bleeding, but not ischemic events.

Background: The relationship between very low on-treatment low-density lipoprotein cholesterol (LDL-C) level and cardiovascular event risk is still unclear in patients receiving the same doses of statins., Methods and results: From the REAL-CAD study comparing high-dose (4 mg/day) with low-dose (1 mg/day) pitavastatin therapy in patients with stable coronary artery disease, 11,105 patients with acceptable statin adherence were divided into 3 groups according to the on-treatment LDL-C level at 6 months (<70 mg/dL, 70-100 mg/dL, and ≥100 mg/dL). The primary outcome measure was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission. The adjusted risks of the LDL-C <70 mg/dL group relative to the LDL-C 70-100 mg/dL group (reference) was not significantly different for the primary outcome measure in both 1 mg/day and 4 mg/day strata (HR 0.84, 95% CI 0.58-1.18, P=0.32, and HR 1.25, 95% CI 0.88-1.79, P=0.22). The adjusted risk of the LDL-C ≥100 mg/dL group relative to the reference group was not significant for the primary outcome measure in the 1 mg/day stratum (HR 0.82, 95% CI 0.60-1.11, P=0.21), whereas it was highly significant in the 4 mg/day stratum (HR 3.32, 95% CI 2.08-5.17, P<0.001)., Conclusions: A very low on-treatment LDL-C level (<70 mg/dL) was not associated with lower cardiovascular event risk compared with moderately low on-treatment LDL-C level (70-100 mg/dL) in patients receiving the same doses of statins.

Background: There is a scarcity of studies comparing the clinical outcomes after percutaneous coronary intervention (PCI) for women and men stratified by the presentation of acute coronary syndromes (ACS) or stable coronary artery disease (CAD)., Methods and results: The study population included 26,316 patients who underwent PCI (ACS: n=11,119, stable CAD: n=15,197) from the CREDO-Kyoto PCI/CABG registry Cohort-2 and Cohort-3. The primary outcome was all-cause death. Among patients with ACS, women as compared with men were much older. Among patients with stable CAD, women were also older than men, but with smaller difference. The cumulative 5-year incidence of all-cause death was significantly higher in women than in men in the ACS group (26.2% and 17.9%, log rank P<0.001). In contrast, it was significantly lower in women than in men in the stable CAD group (14.2% and 15.8%, log rank P=0.005). After adjusting confounders, women as compared with men were associated with significantly lower long-term mortality risk with stable CAD but not with ACS (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.69-0.82, P<0.001, and HR: 0.92, 95% CI: 0.84-1.01, P=0.07, respectively). There was a significant interaction between the clinical presentation and the mortality risk of women relative to men (interaction P=0.002)., Conclusions: Compared with men, women had significantly lower adjusted mortality risk after PCI among patients with stable CAD, but not among those with ACS.

Background: Current guidelines equally recommend direct oral anticoagulants (DOACs) and warfarin for atrial fibrillation (AF) patients with a bioprosthetic valve (BPV); however, there are limited data comparing DOACs and warfarin in AF patients with an aortic BPV., Methods and results: This post-hoc subgroup analysis of a multicenter, prospective, observational registry (BPV-AF Registry) aimed to compare DOACs and warfarin in AF patients with an aortic BPV. The primary outcome was a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or BPV reoperation. The analysis included 479 patients (warfarin group, n=258; DOAC group, n=221). Surgical aortic valve replacement was performed in 74.4% and 36.7% of patients in the warfarin and DOAC groups, respectively. During a mean follow up of 15.5 months, the primary outcome occurred in 45 (17.4%) and 32 (14.5%) patients in the warfarin and DOAC groups, respectively. No significant difference was found in the primary outcome between the 2 groups (adjusted hazard ratio: 0.88, 95% confidence interval: 0.51-1.50). No significant multiplicative interaction was observed between the anticoagulant effects and type of aortic valve procedure (P=0.577)., Conclusions: Among AF patients with an aortic BPV, no significant difference was observed in the composite outcome of adverse clinical events between patients treated with warfarin and those treated with DOACs, suggesting that DOACs can be used as alternatives to warfarin in these patients.

Background: The clinical benefits of neurohormonal antagonists for patients with heart failure (HF) with mid-range and preserved ejection fraction (HFmrEF and HFpEF) are uncertain., Methods and results: This study analyzed 858 consecutive patients with HFmrEF (EF: 40-49%) or HFpEF (EF ≥50%), who were hospitalized for acute HF, and who were discharged alive, and were not taking angiotensin-converting enzyme inhibitors (ACE)-I/ angiotensin II receptor blockers (ARB) or β-blockers at admission. The study population was classified into 4 groups according to the status of prescription of ACE-I/ARB and β-blocker at discharge: no neurohormonal antagonist (n=342, 39.9%), ACE-I/ARB only (n=128, 14.9%), β-blocker only (n=189, 22.0%), and both ACE-I/ARB and β-blocker (n=199, 23.2%) groups. The primary outcome measure was a composite of all-cause death or HF hospitalization. The cumulative 1-year incidence of the primary outcome measure was 41.2% in the no neurohormonal antagonist group, 34.0% in the ACE-I/ARB only group, 28.6% in the β-blocker only group, and 16.4% in the both ACE-I/ARB and β-blocker group (P<0.001). Compared with the no neurohormonal antagonist group, both the ACE-I/ARB and β-blocker groups were associated with a significantly lower risk for a composite of all-cause death or HF hospitalization (HR: 0.46, 95% CI: 0.28-0.76, P=0.002)., Conclusions: In hospitalized patients with HFmrEF and HFpEF, starting both ACE-I/ARB and a β-blocker was associated with a reduced risk of the composite of all-cause death or HF hospitalization compared with patients not starting on an ACE-I/ARB or β-blocker.

Background: It is unknown whether beneficial effects of higher-dose statins on cardiovascular events are different according to the thrombotic risk in patients with chronic coronary syndrome (CCS)., Methods and results: The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study is a randomized trial comparing 4 mg and 1 mg pitavastatin in patients with CCS. This study categorized 12,413 patients into 3 strata according to the CREDO-Kyoto thrombotic risk score: low-risk (N=9,434; 4 mg: N=4,742, and 1 mg: N=4,692), intermediate-risk (N=2,415; 4 mg: N=1,188, and 1 mg: N=1,227); and high-risk (N=564; 4 mg: N=269, and 1 mg: N=295). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. Cumulative 4-year incidence of the primary endpoint was significantly higher in the high-risk stratum than in the intermediate- and low-risk strata (11.0%, 6.3%, and 4.5%, P<0.0001). In the low-risk stratum, the cumulative 4-year incidence of the primary endpoint was significantly lower in the 4 mg than in the 1 mg group (4.0% and 4.9%, P=0.02), whereas in the intermediate- and high-risk strata, it was numerically lower in the 4 mg than in the 1 mg group. There was no significant treatment-by-subgroup interaction for the primary endpoint (P-interaction=0.77)., Conclusions: High-dose pitavastatin therapy compared with low-dose pitavastatin therapy was associated with a trend toward lowering the risk for cardiovascular events irrespective of the thrombotic risk in patients with CCS.

Background: Optimal intensity is unclear for P2Y 12 receptor blocker therapy after percutaneous coronary intervention (PCI) in real-world clinical practice., Methods and results: From the CREDO-Kyoto Registry, the current study population consisted of 25,419 patients (Cohort-2: n=12,161 and Cohort-3: n=13,258) who underwent their first PCI. P2Y 12 receptor blocker therapies were reduced dose of ticlopidine (200 mg/day), and global dose of clopidogrel (75 mg/day) in 87.7% and 94.8% of patients in Cohort-2 and Cohort-3, respectively. Cumulative 3-year incidence of GUSTO moderate/severe bleeding was significantly higher in Cohort-3 than in Cohort-2 (12.1% and 9.0%, P<0.0001). After adjusting 17 demographic factors and 9 management factors potentially related to the bleeding events other than the type of P2Y 12 receptor blocker, the higher bleeding risk in Cohort-3 relative to Cohort-2 remained significant (hazard ratio (HR): 1.52 95% confidence interval (CI) 1.37-1.68, P<0.0001). Cohort-3 compared with Cohort-2 was not associated with lower adjusted risk for myocardial infarction/ischemic stroke (HR: 0.96, 95% CI: 0.87-1.06, P=0.44)., Conclusions: In this historical comparative study, Cohort-3 compared with Cohort-2 was associated with excess bleeding risk, which might be at least partly explained by the difference in P2Y 12 receptor blockers.

Background: Although bioprosthetic valve (BPV) replacements are becoming more common within our aging society, there are limited prospective data on the appropriate antithrombotic therapy for East Asian patients with atrial fibrillation (AF) and BPV replacement. Antithrombotic therapy and thrombotic and hemorrhagic event rates in Japanese patients with AF and BPV replacement are investigated., Methods and results: This multicenter, prospective, observational study enrolled patients with BPV replacement and AF. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. Of the 894 patients analyzed, 54.7%, 29.4%, and 9.6%, were treated with warfarin-based therapy, direct oral anticoagulant (DOAC)-based therapy, or antiplatelet therapy without anticoagulants, respectively; 6.3% did not receive any antithrombotic drugs. The mean observation period was 15.3±4.0 months. The event rates for stroke or systemic embolism and major bleeding were 1.95%/year and 1.86%/year, respectively. The multivariate adjusted hazard ratios for DOAC vs. warfarin were 1.02 (95% confidence intervals [CI], 0.30-3.41 [P=0.979]) for systemic embolic events and 0.96 (95% CI, 0.29-3.16 [P=0.945]) for major bleeding., Conclusions: Approximately 30% of patients with AF and BPV replacement were treated with DOAC. The risks of major bleeding and stroke or systemic embolism were similar between warfarin- and DOAC-treated patients with AF who had BPV replacement. Treatment with DOACs could be an alternative to warfarin in this population.

Background: The clinical significance of concomitant mitral regurgitation (MR) has not been well addressed in patients with severe aortic stenosis (AS)., Methods and results: We analyzed 3,815 patients from a retrospective multicenter registry of severe AS in Japan (CURRENT AS registry). We compared the clinical outcomes between patients with moderate/severe MR and with none/mild MR according to the initial treatment strategy (initial aortic valve replacement [AVR] or conservative strategy). The primary outcome measure was a composite of aortic valve-related death or heart failure hospitalization. At baseline, moderate/severe MR was present in 227/1,197 (19%) patients with initial AVR strategy and in 536/2,618 (20%) patients with a conservative strategy. The crude cumulative 5-year incidence of the primary outcome measure was significantly higher in patients with moderate/severe MR than in those with none/mild MR, regardless of the initial treatment strategy (25.2% vs. 14.4%, P<0.001 in the initial AVR strategy, and 63.3% vs. 40.7%, P<0.001 in the conservative strategy). After adjusting confounders, moderate/severe MR was not independently associated with higher risk for the primary outcome measure in the initial AVR strategy (hazard ratio [HR] 1.11, 95% confidence interval [CI] 0.67-1.83, P=0.69), and in the conservative strategy (HR 1.13, 95% CI 0.93-1.37, P=0.22)., Conclusions: Concomitant moderate/severe MR was not independently associated with higher risk for the primary outcome measure regardless of the initial treatment strategy.

Background: The additional effects of single-antiplatelet therapy (SAPT) on anticoagulant therapy are still unclear in patients with atrial fibrillation (AF) after bioprosthetic valve replacement., Methods and results: We conducted a subanalysis of a multicenter, retrospective, observational registry of patients with bioprosthetic valves and AF in Japan. Patients administered anticoagulants alone comprised the ACA group (n=107), and patients given concomitant SAPT and anticoagulant therapy comprised the On SAPT group (n=82). The primary efficacy endpoint was the incidence of stroke/systemic embolism, and the primary safety endpoint was the incidence of major bleeding. The observation period was 46.3±24.6 months. The primary efficacy endpoint occurred in 12 patients, and the cumulative incidence of primary efficacy events was significantly higher in the ACA group compared with the On SAPT group (P=0.039). The primary safety endpoint occurred in 22 patients, and the cumulative incidence of primary safety events was similar between groups (P=0.66). No differences between the groups were observed for cardiac events., Conclusions: Additional SAPT on anticoagulant therapy in patients with bioprosthetic valves and AF was associated with a reduction in stroke/systemic embolic events, although the cumulative incidence of bleeding was similar, regardless of additional SAPT. These findings suggest that additional SAPT on anticoagulant therapy may be safe and effective in real-world clinical settings.

Background: Outcomes of cryoballoon ablation for persistent atrial fibrillation (AF) are unclear, especially in Japanese patients, so the effectiveness and safety of cryoballoon ablation in clinical practice were retrospectively compared with those of contact force-sensing radiofrequency (CFRF) ablation including the high-power protocol., Methods and results: Consecutive patients with persistent AF were reviewed, and 253 and 265 patients who underwent cryoballoon and CFRF ablation, respectively, were enrolled. The primary endpoint was atrial arrhythmia recurrence. The secondary endpoints were periprocedural complications and repeat ablation. The rate of additional left atrial (LA) ablation after pulmonary vein isolation (PVI) was similar between groups (68.8% cryoballoon vs. 74.0% CFRF, P=0.19). Freedom from atrial arrhythmia recurrence was comparable between groups over a follow-up of 25.5±12.5 months (72.3% cryoballoon vs. 69.8% CFRF; adjusted hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.59-1.21, P=0.36). Outcomes were similar in the subgroups of PVI alone and PVI plus additional LA ablation. LA posterior wall isolation, absence of defragmentation, and low creatine clearance, but not catheter selection, were associated with the primary endpoint. Periprocedural complications (adjusted HR 0.73, 95% CI 0.34-1.54, P=0.41) and repeat ablation (adjusted HR 1.11, 95% CI 0.71-1.74, P=0.64) were similar for both procedures., Conclusions: Cryoballoon ablation for persistent AF in Japanese clinical practice had acceptable outcomes comparable to those of advanced CFRF ablation.

Background: Data evaluating the effects of acute coronary syndrome (ACS) relative to stable coronary artery disease (CAD) on bleeding risk after percutaneous coronary intervention (PCI) are scarce., Methods and results: From the CREDO-Kyoto Registry Cohort-3, 13,258 patients undergoing first PCI (5,521 ACS; 7,737 stable CAD) were identified. Patients were further stratified according to ACS presentation and Academic Research Consortium High Bleeding Risk (HBR): ACS/HBR: n=2,502; ACS/no-HBR: n=3,019; stable CAD/HBR: n=3,905; and stable CAD/no-HBR: n=3,832. The primary bleeding endpoint was Bleeding Academic Research Consortium 3/5 bleeding, whereas the primary ischemic endpoint was myocardial infarction (MI)/ischemic stroke. Compared with stable CAD, ACS was associated with a significantly higher adjusted risk for bleeding (hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.68-2.03; P<0.0001), with a markedly higher risk within 30 days (HR 4.24; 95% CI 3.56-5.06; P<0.0001). Compared with the stable CAD/no-HBR group, the ACS/HBR, no-ACS/HBR, and ACS/no-HBR groups were associated with significantly higher adjusted risks for bleeding, with HRs of 3.05 (95% CI 2.64-3.54; P<0.0001), 1.89 (95% CI 1.66-2.15; P<0.0001), and 1.69 (95% CI 1.45-1.98; P<0.0001), respectively. There was no excess adjusted risk of the ACS relative to stable CAD group for MI/ischemic stroke (HR 1.07; 95% CI 0.94-1.22; P=0.33)., Conclusions: Bleeding risk after PCI depended on both ACS presentation and HBR, with a significant effect of ACS within 30 days.

Background: The prevalence of and expected bleeding event rate in patients with the Japanese version of high bleeding risk (J-HBR) criteria are currently unknown in real-world percutaneous coronary intervention (PCI) practice., Methods and results: We applied the J-HBR criteria in the multicenter CREDO-Kyoto registry cohort-3 that enrolled 13,258 consecutive patients who underwent first PCI. The J-HBR criteria included Japanese-specific major criteria such as heart failure, low body weight, peripheral artery disease and frailty in addition to the Academic Research Consortium (ARC)-HBR criteria. There were 8,496 patients with J-HBR, and 4,762 patients without J-HBR. The J-HBR criteria identified a greater proportion of patients with HBR than did ARC-HBR (64% and 48%, respectively). Cumulative incidence of the Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding was significantly higher in the J-HBR group than in the no-HBR group (14.0% vs. 4.1% at 1 year; 23.1% vs. 8.4% at 5 years, P<0.0001). Cumulative 5-year incidence of BARC 3/5 bleeding was 25.1% in patients with ARC-HBR, and 23.1% in patients with J-HBR. Cumulative incidence of myocardial infarction or ischemic stroke was also significantly higher in the J-HBR group than in the no-HBR group (6.9% vs. 3.6% at 1 year; 13.2% vs. 7.1% at 5 years, P<0.0001)., Conclusions: The J-HBR criteria successfully identified those patients with very high bleeding risk after PCI, who represented 64% of patients in this all-comers registry.

Background: The effect of body weight (BW) on bleeding and ischemic events has not been adequately evaluated in real-world percutaneous coronary intervention (PCI) practice., Methods and results: 12,690 consecutive patients undergoing first PCI in the CREDO-Kyoto registry cohort-2 were divided into 3 groups according to tertiles of BW stratified by sex (male; Tertile 1 [<60.0 kg], 2 [60.0-68.0 kg], and 3 [>68.0 kg], and female; Tertile 1 [<47.9 kg], 2 [47.9-55.8 kg], and 3 [>55.8 kg]). Cumulative 5-year incidences of the primary bleeding (GUSTO moderate/severe) and ischemic (myocardial infarction/ischemic stroke) endpoints increased incrementally with decrease in BW in both strata (male Tertiles 1, 2, and 3: 13.7%, 10.3%, and 8.0%, P<0.001, and 13.9%, 11.3%, and 10.2%, P<0.001; female Tertiles 1, 2, and 3: 17.9%, 12.9%, and 10.1%, P<0.001, and 17.9%, 12.9%, and 10.1%, P<0.001). Compared with Tertile 3, the adjusted risks of Tertile 1 for the primary bleeding and ischemic endpoints remained significant in the female stratum (hazard ratio (HR): 1.45, 95% confidence interval (CI): 1.14-1.87, P=0.003, and HR:1.49, 95% CI:1.13-1.95, P=0.004), but not in the male stratum (HR:1.10, 95% CI:0.92-1.32, P=0.31, and HR:1.06, 95% CI:0.90-1.27, P=0.47)., Conclusions: Cumulative incidences of bleeding and ischemic events increased incrementally as BW decreased in both men and women. The adjusted risks of underweight relative to overweight for bleeding and ischemic events were significant only in women.

Background: The transradial approach is reportedly associated with reduced bleeding complications and mortality after percutaneous coronary intervention (PCI). It is unknown whether the clinical benefits of transradial vs. transfemoral PCI differ between high bleeding risk (HBR) and non-HBR patients.Methods and Results:After excluding patients with acute myocardial infarction, dialysis, and a transbrachial approach from the 13,087 patients undergoing first PCI in the CREDO-Kyoto Registry Cohort-2, 6,828 patients were eligible for this study. Patients were divided into 2 groups according to bleeding risk based on Academic Research Consortium HBR criteria, and then divided into a further 2 groups according to access site, radial or femoral: HBR-radial, n=1,054 (38.3%); HBR-femoral, n=1,699 (61.7%); non-HBR-radial, n=1,682 (41.3%); and non-HBR-femoral, n=2,393 (58.7%). In the HBR group, the 30-day incidence and adjusted risk for major bleeding (1.9% vs. 4.7% [P<0.001]; adjusted hazard ratio [aHR] 0.44, 95% confidence interval [CI] 0.26-0.71 [P<0.001]) and all-cause death (0.3% vs. 0.9% [P=0.04]; aHR 0.30, 95% CI 0.07-0.93 [P=0.04]) were significantly lower in the radial than femoral group. There were no significant differences in the 30-day incidence and adjusted risk for major bleeding (0.5% vs. 1.0% [P=0.09]; aHR 0.68, 95% CI 0.30-1.45 [P=0.33]) or all-cause death (0.1% vs. 0.1% [P=0.96]; aHR 1.51, 95% CI 0.19-9.54 [P=0.67]) between the radial and femoral approaches in the non-HBR group., Conclusions: Compared with transfemoral PCI, transradial PCI was associated with lower risk for 30-day major bleeding and mortality in HBR but not non-HBR patients.

Background: The effect of diabetes mellitus (DM) status on the long-term risk for heart failure (HF) in patients undergoing coronary revascularization has not been adequately evaluated.Methods and Results:In this study, 15,231 patients who underwent coronary revascularization in the CREDO-Kyoto Registry Cohort-2 were divided into 2 groups according to DM status (DM group: n=5,999; Non-DM group: n=9,232). The DM group was further divided into 2 groups according to insulin treatment (insulin-treated DM [ITDM]: n=1,353; non-insulin-treated DM [NITDM]: n=4,646). The primary outcome measure was HF hospitalization. The cumulative 5-year incidence of HF hospitalization was significantly higher in the DM than non-DM group (11.0% vs. 6.6%, respectively; log-rank P<0.0001), and in the ITDM than NITDM group (14.6% vs. 10.0%, respectively; log-rank P<0.0001). After adjusting for confounders, the increased risk of HF hospitalization with DM relative to non-DM remained significant (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.30-1.67, P<0.0001), whereas the risk associated with ITDM relative to NITDM was not significant (HR 1.17, 95% CI 0.96-1.43, P=0.12)., Conclusions: The adjusted long-term risk for HF hospitalization after coronary revascularization was significantly higher in DM than non-DM patients, regardless of revascularization strategy, but did not differ between ITDM and NITDM patients.

Background: In patients with severe coronary artery disease (CAD) requiring coronary revascularization, the prevalence of surgical ineligibility and its clinical effect on long-term outcomes remain unclear.Methods and Results:Among 15,939 patients with first coronary revascularization in the CREDO-Kyoto percutaneous coronary intervention (PCI)/coronary artery bypass grafting (CABG) registry cohort-2, we identified 3,982 patients with triple-vessel or left main disease (PCI: n=2,188, and CABG: n=1,794). Surgical ineligibility as documented in hospital charts was present in 142 (6.5%) of 2,188 PCI-patients, which was mainly related to comorbidities and advanced age. The cumulative 5-year incidence of the primary outcome measure (all-cause death/myocardial infarction/stroke) was much higher in PCI-patients with surgical ineligibility than in PCI-patients without surgical ineligibility and in CABG-patients (52.5%, 27.6%, and 24.0%, respectively, log-rank P<0.001). After adjusting for confounders, the excess risk of PCI-patients with surgical ineligibility relative to CABG-patients was substantial (hazard ratio [HR] 1.97, 95% CI 1.51-2.58, P<0.001), while the excess risk of PCI-patients without surgical ineligibility relative to CABG-patients was modest, but remained significant (HR 1.37, 95% CI 1.19-1.59, P<0.001)., Conclusions: Among patients with severe CAD, PCI-patients with surgical ineligibility had worse long-term outcomes as compared with those without surgical ineligibility and CABG-patients.

Background: There is a scarcity of reports on the clinical characteristics and management practice in contemporary all-comer patients with acute decompensated heart failure (ADHF). Methods and Results: The Kyoto Congestive Heart Failure (KCHF) registry is a prospective observational cohort study enrolling 4,056 consecutive patients who had hospital admission due to ADHF without any exclusion criteria between October 2014 and March 2016 in the 19 participating hospitals in Japan. Baseline characteristics, clinical presentations, management, and in-hospital outcomes were compared between heart failure (HF) with reduced left ventricular ejection fraction (LVEF; HFrEF, LVEF <40%), HF with mid-range LVEF (HFmrEF, LVEF 40-49%), and HF with preserved LVEF (HFpEF, LVEF ≥50%). Of the 4,041 patients with documented LVEF, 1,744 (43%) had HFpEF; 746 (19%), HFmrEF; and 1,551 (38%), HFrEF. The median age was 80 years (IQR, 72-86 years) in the entire population, and was higher with increasing LVEF (P<0.001). The in-hospital mortality rate was higher in the HFrEF than in the HFmrEF and HFpEF groups (9.2%, 4.8%, and 5.1%, respectively, P<0.001)., Conclusions: This registry elucidated the clinical features and clinically relevant in-hospital outcomes in contemporary consecutive patients with ADHF in real-world clinical practice in Japan. When classified by LVEF, significant differences in characteristics and in-hospital outcomes existed between patients with HFrEF, HFmrEF, and HFpEF.

Background: There is no large-scale study comparing postoperative mortality after aortic valve replacement (AVR) for asymptomatic severe aortic stenosis (AS) between initial treatment with AVR vs. eventual AVR after conservative management. Methods and Results: We analyzed data from a multicenter registry enrolling 3,815 consecutive patients with severe AS. Of 1,808 asymptomatic patients, 286 patients initially underwent AVR (initial AVR group), and 377 patients were initially managed conservatively and eventually underwent AVR (AVR after watchful waiting group). Mortality after AVR was compared between the 2 groups. Subgroup analysis according to peak aortic jet velocity (Vmax) at diagnosis was also conducted. There was no significant difference between the 2 groups in 5-year overall survival (OS; 86.0% vs. 84.1%, P=0.34) or cardiovascular death-free survival (DFS; 91.3% vs. 91.1%, P=0.61), but on subgroup analysis of patients with Vmax ≥4.5 m/s at diagnosis, the initial AVR group was superior to the AVR after watchful waiting group in both 5-year OS (88.4% vs. 70.6%, P=0.003) and cardiovascular DFS (91.9% vs. 81.7%, P=0.023)., Conclusions: Asymptomatic severe AS patients who underwent AVR after watchful waiting had a postoperative survival rate similar to those who initially underwent AVR. In a subgroup of patients with Vmax ≥4.5 m/s at diagnosis, however, the AVR after watchful waiting group had worse postoperative survival rate than the initial AVR group.

Background: In ST-segment elevation myocardial infarction (STEMI), QRS score at presentation ECG may reflect the progression of infarction and facilitate prediction of the degree of myocardial salvage achieved by reperfusion therapy.Methods and Results:Admission electrocardiogram (ECG) was studied in 2,607 patients with STEMI undergoing primary percutaneous coronary intervention (PCI) within 24 h of symptom onset. Patients were classified into 3 groups according to QRS score: low (0-3, n=1,227), intermediate (4-7, n=810), and high (≥8, n=570). An increase of infarct size estimated by median peak creatine phosphokinase was observed as QRS score increased (low score, 1,836 IU/L; inter-quartile range (IQR), 979-3,190 IU/L; intermediate score, 2,488 IU/L; IQR, 1,126-4,640 IU/L; high score, 3,454 IU/L; IQR, 1,759-5,639 IU/L; P<0.001). Higher QRS score was associated with higher long-term mortality (low, intermediate, and high score, 15.6%, 19.7%, and 23.7% at 5 years, respectively; log-rank P<0.001). The positive relationship of QRS score with mortality was consistently seen when stratified by infarct location. The association of high QRS score with increased mortality was most remarkably seen in patients with early (≤2 h) presentation (low, intermediate, and high score: 16.7%, 16.6%, and 28.1% at 5 years, respectively; log-rank P<0.001)., Conclusions: Higher QRS score at presentation ECG was associated with larger infarct size, and higher long-term mortality in patients with STEMI undergoing primary PCI. QRS score appears to be important in the early risk stratification for STEMI.

Background: There is a paucity of data on the sex differences in the prevalence, clinical presentation, and prognosis of aortic stenosis (AS).Methods and Results:A total of 3,815 consecutive patients with severe AS were enrolled in the multicenter CURRENT AS registry between January 2003 and December 2011. The registry included 1,443 men (38%) and 2,372 women (62%). Women were much older than men (79±10 vs. 75±10 years, P<0.0001), and the ratio of women to men increased with age. The cumulative 5-year incidence of all-cause death was significantly higher in men than in women (47% vs. 41%, P=0.003), although women were more symptomatic and much older. The 5-year mortality was similar between men and women at age <65 years (16% vs. 15%, P=0.99), whereas it was significantly higher in men than in women at age ≥65 years (65-74 years, 38% vs. 19%, P<0.0001; 75-84 years, 55% vs. 34%, P<0.0001; ≥85 years: 82% vs. 72%, P=0.03)., Conclusions: A large Japanese multicenter registry of consecutive patients with severe AS included a much higher proportion of women than men, with the female:male sex ratio increasing with age. The 5-year mortality rate of women was lower than that of men. Lower 5-year mortality rates in women were consistently seen across all age groups >65 years.

Background: Few studies have evaluated the prevalence and clinical outcomes of ad hoc percutaneous coronary intervention (PCI), performing diagnostic coronary angiography and PCI in the same session, in stable coronary artery disease (CAD) patients.Methods and Results:From the CREDO-Kyoto PCI/CABG registry cohort-2, 6,943 patients were analyzed as having stable CAD and undergoing first PCI. Ad hoc PCI and non-ad hoc PCI were performed in 1,722 (24.8%) and 5,221 (75.1%) patients, respectively. The cumulative 5-year incidence and adjusted risk for all-cause death were not significantly different between the 2 groups (15% vs. 15%, P=0.53; hazard ratio: 1.15, 95% confidence interval: 0.98-1.35, P=0.08). Ad hoc PCI relative to non-ad hoc PCI was associated with neutral risk for myocardial infarction, any coronary revascularization, and bleeding, but was associated with a trend towards lower risk for stroke (hazard ratio: 0.78, 95% confidence interval: 0.60-1.02, P=0.06)., Conclusions: Ad hoc PCI in stable CAD patients was associated with at least comparable 5-year clinical outcomes as with non-ad hoc PCI. Considering patients' preference and the cost-saving, the ad hoc PCI strategy might be a safe and attractive option for patients with stable CAD, although the prevalence of ad hoc PCI was low in the current study population.

Background: Very limited data exist on the outcomes of transcatheter aortic valve implantation (TAVI) since Japanese marketing approval of the first TAVI device.Methods and Results:The Kyoto University-related hospital Transcatheter Aortic Valve Implantation (K-TAVI) registry includes prospectively collected data from 6 participating hospitals in Japan. We included 302 patients with severe aortic stenosis who underwent TAVI using the SAPIEN XT balloon-expandable valve via transfemoral (TF; n=203, 67%) or transapical (TA; n=99, 33%) approach between October 2013 and September 2015. Device success rate, based on the Valve Academic Research Consortium-2 criteria, was very high in the TF (97.0%) and TA (99.0%) groups. The 30-day mortality rates were 1.5% and 1.0% in the TF and TA groups, respectively. Major complications included stroke (transient or persistent: 2.3%), annulus rupture (1.0%), coronary intervention (1.0%), major vascular complications (1.7%), and permanent pacemaker implantation (5.4%). The procedure times of the post-proctoring period (n=210) were decreased compared with those of the proctoring period (n=89) without affecting the clinical outcomes. The survival rates at 6 and 12 months were 96.9% and 92.5% in the TF group, and 93.9% and 91.8% in the TA group, respectively., Conclusions: The K-TAVI registry data revealed that the early outcomes of TAVI using the SAPIEN XT were favorable in real-world Japanese patients.

Background: Hyogo Prefecture is the 2nd prefecture in Japan, after Kanagawa, to enact a ban with penal code on smoking in public places, although the restriction is partial.Methods and Results:This study included consecutive patients with acute coronary syndrome (ACS) who were admitted to 33 major hospitals in the Hyogo District during the 12 months before implementation of the legislation and during the 24 months thereafter. Consecutive patients with ACS from Gifu Prefecture who were admitted to 20 major hospitals were enrolled as geographical controls. The number of ACS admissions did not change from the years 2012-2015 in both Hyogo District (1,774 in the pre-year, 1,784 in the 1st year, and 1,720 in the 2nd year) and Gifu Prefecture (1,226 in the pre-year, 1,174 in the 1st year, and 1,206 in the 2nd year). However, a clear reduction was observed in the subanalysis for Kobe City (895 in the preceding year, 830 (-7.3%) in the 1st year, and 792 (-11.5%) in the 2nd year), where adherence to the smoking ban was higher than in other Hyogo districts., Conclusions: The primary endpoint did not show a significant change. However, the subanalysis showed a significant decrease in ACS admissions in Kobe City. These results suggest that ACS reduction may depend on the degree of adherence to a smoking ban. (Circ J 2016; 80: 2528-2532).

Background: Inter-facility transfer for primary percutaneous coronary intervention (PCI) from referring facilities to PCI centers causes a significant delay in treatment of ST-segment elevation acute myocardial infarction (STEMI) patients undergoing primary PCI. However, little is known about the clinical outcomes of STEMI patients undergoing inter-facility transfer in Japan., Methods and results: In the CREDO-Kyoto acute myocardial infarction (AMI) registry that enrolled 5,429 consecutive AMI patients in 26 centers in Japan, the current study population consisted of 3,820 STEMI patients who underwent primary PCI within 24 h of symptom onset. We compared long-term clinical outcomes between inter-facility transfer patients and those directly admitted to PCI centers. The primary outcome measure was a composite of all-cause death or heart failure (HF) hospitalization. There were 1,725 (45.2%) inter-facility transfer patients, and 2,095 patients (54.8%) with direct admission to PCI centers. The cumulative 5-year incidence of death/HF hospitalization was significantly higher in the inter-facility transfer patients than in those with direct admission (26.9% vs. 22.2%; log-rank P<0.001). After adjusting for potential confounders, the risk for death/HF hospitalization was significantly higher (adjusted hazard ratio: 1.22, 95% confidence interval: 1.07-1.40, P<0.001) in the inter-facility transfer patients than in those directly admitted., Conclusions: Inter-facility transfer was associated with significantly worse long-term clinical outcomes for patients with STEMI undergoing primary PCI. (Circ J 2016; 80: 1764-1772).

Background: We investigated the effects of age and low diastolic blood pressure (DBP) on cardiovascular death in patients with coronary artery disease (CAD) after coronary revascularization., Methods and results: Stable, chronic CAD patients after coronary revascularization in the CREDO-Kyoto registry cohort-1 were allocated to the Young (≤64 years, n=2,619), Young-Old (65-74 years, n=2,932), and Old-Old (≥75 years, n=1,629) groups. Kaplan-Meier analysis showed that the crude cumulative incidence of cardiovascular death was higher in Young-Old patients with DBP <70 mmHg (P<0.001) and in Old-Old patients with DBP <60 mmHg (P=0.017), but not <70 mmHg (P=0.629), compared with each counterpart. Low DBP did not increase cardiovascular death in young patients. After adjustments with independent predictors, DBP <60 mmHg did not increase the cardiovascular death in the Old-Old group (HR=1.579 [95% CI, 0.944-2.642], P=0.082) and DBP <70 mmHg remained a predictor in the Young-Old group (HR=1.665 [1.094-2.532], P=0.017). On multivariate stepwise Cox proportional hazard regression analysis, independent predictors for cardiovascular death in low DBP patients were creatinine clearance (CCr; inversely), prior cerebrovascular disease, and aortic disease in the Young-Old group and CCr (inversely) and malignancy in the Old-Old group., Conclusions: DBP <60 mmHg was not an independent factor for predicting cardiovascular death in Old-Old revascularized CAD patients, whereas DBP <70 mmHg remained a predictor in the Young-Old. (Circ J 2016; 80: 1232-1241).

Background: We assessed the current status of treatment strategy in ST-segment elevation myocardial infarction (STEMI) with multivessel disease (MVD) in real world practice, focusing on the benefit of staged percutaneous coronary intervention (PCI)., Methods and results: From the CREDO-Kyoto AMI Registry, 2,010 STEMI patients with MVD undergoing primary PCI were analyzed. Only 96 patients (4.8%) received acute multivessel PCI, and the majority of patients (n=1,914, 95.2%) had culprit-only PCI acutely. After excluding 699 patients (acute multivessel PCI, Killip class ≥3, age ≥90 years, coronary artery bypass grafting within 90 days, or clinical events within 90 days), 681 MVD patients underwent staged PCI for angiographically significant non-culprit lesions within 90 days (staged PCI group), while 630 MVD patients received primary PCI only (culprit-only PCI group). The cumulative 5-year incidence of and adjusted risk for all-cause death were significantly lower in the staged PCI group compared with the culprit-only PCI group (9.5% vs. 16.0%, P<0.001; HR, 0.69; 95% CI: 0.50-0.96, P=0.03). The risks for MI and any coronary revascularization favored the staged PCI strategy., Conclusions: The staged PCI strategy for angiographically significant non-culprit lesions was associated with lower 5-year mortality compared with the culprit-only PCI strategy in STEMI patients with MVD who underwent primary PCI.

Background: In the setting of elective percutaneous coronary intervention (PCI), intravascular ultrasound (IVUS)-guided PCI is associated with a reduction in the incidence of target vessel revascularization (TVR), but the impact of IVUS on long-term clinical outcome in the setting of emergency PCI for ST-segment elevation acute myocardial infarction (STEMI) is still unclear., Methods and results: The subjects consisted of 3,028 STEMI patients who underwent primary PCI within 24 h of symptom onset in the CREDO-Kyoto acute myocardial infarction registry. Of these, 932 patients (31%) underwent IVUS-guided PCI. Compared with the angiography-guided PCI without IVUS, IVUS-guided PCI was associated with significantly lower incidences of TVR (primary outcome measure; 22% vs. 27%, log-rank P<0.001) and definite stent thrombosis (ST; 1.2% vs. 3.1%, log-rank P=0.003). The cumulative incidence of all-cause death was not significantly different between the 2 groups. After adjusting for confounders, however, there were no significant differences between the 2 groups in risk for TVR (adjusted HR, 1.14; 95% CI: 0.86-1.51, P=0.38) and definite ST (adjusted HR, 0.58; 95% CI: 0.19-1.72, P=0.33)., Conclusions: IVUS-guided PCI was not associated with a lower risk for TVR or ST in STEMI patients undergoing primary PCI.

Background: Studies evaluating long-term (≥5 years) outcome of percutaneous coronary intervention (PCI) compared with coronary artery bypass grafting (CABG) in patients with unprotected left main coronary artery disease (ULMCAD) are still limited, despite concerns for late adverse events after drug-eluting stents implantation., Methods and Results: We identified 1,004 patients with ULMCAD (PCI: n=364, CABG: n=640) among 15,939 patients with first coronary revascularization enrolled in the CREDO-Kyoto PCI/CABG registry cohort-2. The primary outcome measure in the current analysis was a composite of death, myocardial infarction, and stroke (death/MI/stroke). The cumulative 5-year incidence of and the adjusted risk for death/MI/stroke were significantly higher in the PCI group than in the CABG group (34.5% vs. 24.1%, log-rank P<0.001, adjusted hazard ratio (HR): 1.48 [95% confidence interval (CI): 1.07-2.05, P=0.02]). The adjusted risks for all-cause death was not significantly different between the 2 groups. Regarding the stratified analysis by the SYNTAX score, the adjusted risk for death/MI/stroke was not significantly different between the 2 groups in patients with low (<23) or intermediate (23-33) SYNTAX score, whereas it was significantly higher in the PCI group than in the CABG group in patients with high (≤33) SYNTAX score., Conclusions: CABG as compared with PCI was associated with better long-term outcome in patients with ULMCAD, especially those with high anatomical complexity.

Background: In hypertensive patients, left ventricular hypertrophy (LVH) may persist despite satisfactory blood pressure (BP) control. The efficacy of thiazide diuretics in Western countries has been reported, but whether this applies to hypertensive Japanese patients is uncertain. METHODS AND RESULTS: We randomly assigned 94 patients whose BP was poorly controlled with usual doses of angiotensin-II receptor blockers (ARB), to losartan/hydrochlorothiazide (HCTZ) fixed-dose combination vs. maximum doses of ARB. After 6 months follow-up, decrease in BP, regression of electrocardiographic LVH, and changes in laboratory measurements were examined. Although a similar decrease in BP was observed in both groups, the decrease in LV Sokolow-Lyon voltage, from 34.4±9.2 to 29.4±8.8 mm in the losartan/HCTZ vs. from 29.9±10.2 to 29.1±8.4 mm in the ARB group (P=0.0003), and the decrease in serum B-type natriuretic peptide (BNP) level, from 30.1±28.5 to 26.8±28.0 pg/ml vs. from 23.7±14.8 to 29.8±29.3 pg/ml (P=0.045) were greater in the losartan/HCTZ group. By single variable logistic regression analysis, ∆BNP (P=0.012) and treatment with losartan/HCTZ (P<0.0001) correlated with the regression of LVH. By multiple variable logistic regression analysis, both ∆BNP (P=0.035) and treatment with losartan/HCTZ (P=0.0003) remained significant. No major adverse effects were observed., Conclusions: Greater regression of LVH was safely achieved with losartan/HCTZ in patients whose BP was poorly controlled with an ARB.

Background: A prior phase I/IIa clinical trial provided evidence for safety, feasibility and potential efficacy of i.m. injection of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ cells in patients with critical limb ischemia (CLI)., Methods and Results: A phase II trial of CD34+ cell therapy was conducted in patients with CLI to explore endpoint selection and timing. No-option CLI patients (n=11) underwent i.m. transplantation of G-CSF-mobilized CD34+ cells isolated by magnetic sorting. Ischemic rest pain scales improved from week 2 vs. baseline (P<0.05). Skin perfusion pressure (P=0.0175), transcutaneous partial oxygen pressure (P=0.0446) and pain-free walking distance (P=0.0056) improved from week 2, total walking distance from week 8 (P=0.0182) and toe brachial pressure index from week 12 (P=0.0174) vs. baseline. These parameters peaked at week 36 or 52. Rutherford's category improved from week 24 vs. baseline (P=0.0065). CLI-free ratio serially increased and peaked (85.7%) at week 36. Serial change in Rutherford's category correlated with that in Rest Pain Scale (P=0.0374), but not with that in any physiological parameters., Conclusions: Ischemic rest pain scales and physiological parameters improved relatively early after cell therapy, then plateaued later accompanied by recovery from the CLI state. Rutherford's category and CLI-free ratio at week 36 or later may be suitable endpoints in cell therapy clinical trials for CLI. Functional parameters should be evaluated independently of such clinical endpoints for ischemia severity. (, Clinical Trial Registration: URL: https://dbcentre3.jmacct.med.or.jp/jmactr/Default.aspx. Unique identifier: JMA-IIA00022)

Background: SYNTAX score II (SSII) provides individualized estimates of 4-year mortality after coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in order to facilitate decision-making between these revascularization methods. The purpose of the present study was to assess SSII in a real-world multicenter registry with distinct regional and epidemiological characteristics., Methods and Results: Long-term mortality was analyzed in 3,896 patients undergoing PCI (n=2,190) or CABG (n=1,796) from the Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/CABG registry cohort-2. SSII discriminated well in both CABG and PCI patient groups (concordance index [c-index], 0.70; 95% CI: 0.68-0.72; and 0.75, 95% CI: 0.72-0.78) surpassing anatomical SYNTAX score (SS; c-index, 0.50; 95% CI: 0.47-0.53; and 0.59, 95% CI: 0.57-0.61). SSII had the best discriminative ability to separate low-, medium- and high-risk tertiles, and calibration plots showed good predictive performance for CABG and PCI groups. Use of anatomical SS as a reference improved the overall reclassification provided by SSII, with a net reclassification index of 0.5 (P<0.01)., Conclusions: SSII has robust prognostic accuracy, both in CABG and in PCI patient groups and, compared with the anatomical SS alone, was more accurate in stratifying patients for late mortality in a real-world complex coronary artery disease Eastern population.

Background: It is controversial whether angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) provide significant survival benefits in patients with coronary artery disease (CAD) but without myocardial infarction (MI). This study investigated whether the association of ACEI/ARB therapy with clinical outcome in patients undergoing percutaneous coronary intervention (PCI) was affected by history of MI., Methods and Results: A total of 11,590 patients undergoing first PCI were divided into 2 groups: those with MI and those without MI. All-cause and cardiovascular mortality were compared between the patients with and without ACEI/ARB at discharge in each group. In patients with MI, significantly lower 3-year all-cause/cardiovascular mortality for patients with ACEI/ARB relative to those without ACEI/ARB was noted in the total patients (all-cause: 6.6% vs. 11.7%, P<0.0001; cardiovascular: 3.8% vs. 6.9%, P<0.0001) and in the 1,007 propensity score-matched pairs (all-cause: 8.2% vs. 11.3%, P=0.018; cardiovascular: 3.7% vs. 5.7%, P=0.014). In patients without MI, however, all-cause (5.2% vs. 5.6%, P=0.56) and cardiovascular (3.2% vs. 3.0%, P=0.23) mortality were similar regardless of whether ACEI/ARB were used or not; and similarly in the 2,061 propensity score-matched pairs (all-cause: 4.1% vs. 5.4%, P=0.33; cardiovascular: 1.4% vs. 2.1%, P=0.30)., Conclusions: Use of ACEI/ARB at hospital discharge was associated with lower all-cause/cardiovascular mortality in revascularized CAD patients with MI, but not in those without MI.

Background:  Limited data are available for sex-based differences in Japanese patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI)., Methods and Results:  The study patients comprised 1,197 women and 3,182 men who underwent primary PCI for AMI in 2005-2007. Compared with the men, the women were significantly older, and had significantly longer onset-to-balloon time and lower rate of follow-up coronary angiography. In-hospital mortality was higher among women than men (8.7% vs. 4.9%, P<0.001). Although the cumulative incidence of all-cause death at 3 years was also higher for women (17.7% vs. 10.7%, P<0.001), the adjusted risk for all-cause death was comparable [hazard ratio (HR, women vs. men)=0.94, 95% confidence interval (CI): 0.71-1.24, P=0.66]. The incidence (12.1% vs. 12.4%, P=0.77) and the adjusted risk (HR=0.99, 95% CI 0.78-1.24, P=0.92) for any clinically-driven coronary revascularization were both comparable. However, regarding any non-clinically-driven coronary revascularization, the incidence (19.6% vs. 27.8%, P<0.001) and the adjusted risk (HR=0.79, 95% CI 0.65-0.95, P=0.012) were both lower in women relative to men., Conclusions:  In current Japanese clinical practice for AMI, onset-to-balloon time was significantly longer in women than in men. Female sex was associated with lower follow-up coronary angiography rate and lower incidence of any non-clinically-driven coronary revascularization, whereas the incidence of any clinically-driven coronary revascularization was comparable between the sexes.

Background: We explored the determinants of mortality in order to develop and validate the Kyoto model, which predicts outcomes after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)., Methods and Results: A total of 9,393 patients who underwent their first coronary revascularization without concomitant valvular, left ventricular, or major vascular surgery were followed over a median follow-up of 3.5 years in the CREDO-Kyoto Registry. We fitted separate Cox regression to mortality after PCI and CABG. The best-fitting model was internally validated by 10-fold cross-validation. The Cox regression identified the following predictors: age, sex, body mass index, ejection fraction, atrial fibrillation, diabetes mellitus, hyperlipidemia, current smoker, stroke, peripheral vascular disease, chronic obstructive pulmonary disease, malignancy, kidney disease, anemia, liver cirrhosis, diseased vessel, left main disease, proximal left anterior descending artery disease, and total occlusion. This model simulated that the 3-year mortality for a hypothetical 70-year-old man with 2-vessel disease is 2.0% after PCI and 2.6% after CABG, or 4.2% and 5.1% if he has diabetes and chronic kidney disease. The Hosmer-Lemeshow test showed no significant deviations between the observed and predicted events. The C statistics were greater than 0.78., Conclusions: The Kyoto model can assist clinicians and patients in adherence to medication and lifestyle changes after revascularization and in individualized decision making. A web application is available at http://www.biostatistics.jp/prediction/kyoto-model.

Background: Association of the type of statin and the achieved level of low-density lipoprotein cholesterol (LDL-C) with cardiovascular outcome has not been fully elucidated., Methods and Results: The study included 14,866 patients who underwent a first coronary revascularization in 2005-2007. We identified 7,299 patients with statin therapy at discharge (so-called strong statins [atorvastatin, rosuvastatin, and pitavastatin]: 4,742 patients; standard statins [pravastatin, simvastatin, and fluvastatin]: 2,557 patients). Unadjusted 3-year incidence of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction and stroke) was significantly lower (7.5% vs. 9.6%, P=0.0008) in the strong statin group, and there was a trend in adjusted risk of MACE favoring strong statins (hazard ratio [HR] 0.87, [95% confidence interval (CI) 0.73-1.04], P=0.13). Among 4,846 patients with follow-up LDL-C data available, outcomes were evaluated according to achieved LDL-C level (<80, 80-99 [reference], 100-119, ≥120 mg/dl). Compared with the reference group, the risk for MACE was significantly higher in the ≥120 mg/dl group (adjusted HR 1.74 [95%CI 1.11-2.71], P=0.01), although it was comparable in the 100-119 mg/dl group (adjusted HR 1.23 [95%CI 0.78-1.94], P=0.38) and in the <80 mg/dl group (adjusted HR 1.15 [95%CI 0.75-1.75], P=0.52)., Conclusions: Strong statin therapy was associated with a trend toward lower cardiovascular risk compared with standard statin therapy. When LDL-C <120 mg/dl was achieved, risks for cardiovascular events were comparable irrespective of achieved LDL-C level.

Background: Limited data are available for gender-based differences in patients undergoing coronary revascularization. This study aimed to identify gender-based differences in risk factor profiles and outcomes among Japanese patients undergoing coronary revascularization., Methods and Results: The subjects consisted of 2,845 women and 6,843 men who underwent first percutaneous coronary intervention or coronary artery bypass grafting in 2000-2002. The outcome measures were all-cause death, major adverse cardiovascular events (MACE) as the composite of cardiovascular death, myocardial infarction and stroke, and any coronary revascularization. The females were older than the males and more frequently had histories of heart failure, diabetes, hypertension, chronic kidney disease, anemia, and dyslipidemia. Unadjusted survival analysis revealed a significantly lower incidence of any revascularization in women (at 3 years: 28.2% vs. 31.2%, P = 0.0037), although no significant gender-based differences were shown in the incidence of all-cause death (at 3 years: 8.8% vs. 8.5%, P = 0.37) or MACE (at 3 years: 12.0% vs. 11.5%, P = 0.61). Multivariate analysis revealed that female gender was associated with significantly lower risks of any revascularization (relative risk = 0.93, 95% confidence interval [CI] = 0.88-0.99, P = 0.014) and all-cause death (relative risk = 0.86, 95%CI = 0.77-0.96, P = 0.005)., Conclusions: In Japanese patients undergoing first coronary revascularization, the coronary risk factor burden appeared greater in women than in men. Despite the greater modifiable risk factor accumulation, female gender was associated with a lower incidence of repeated revascularization relative to male gender.

Background: The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) score was proposed as a method to evaluate the complexity of coronary anatomy. However, the reproducibility of assessment for the SYNTAX score in unprotected left main coronary artery (ULMCA) disease has not yet been adequately evaluated. The purpose of this study is to assess inter- and intra-observer variability for the assessment of the SYNTAX score in patients undergoing ULMCA stenting in daily clinical practice., Methods and Results: The SYNTAX score of 101 consecutive patients who underwent ULMCA stenting with sirolimus-eluting stent was independently assessed by 2 experienced interventional cardiologists. One of the 2 cardiologists evaluated all the cases again 6 months after the initial assessment. The κ value for inter-observer variability in estimating the SYNTAX score was 0.62 according to the dichotomized analysis (≥ 33, < 33) and 0.58 according to the tertile analysis (< 23, 23 ≤ - < 33, ≥ 33), while the intra-observer variability was 0.78 and 0.69, respectively. Patients with a high SYNTAX score (≥ 33, n = 55) compared with those with low or intermediate score (< 33, n = 46) had a significantly higher rate of target-lesion revascularization (TLR) of the ULMCA lesion at 2 years (24% vs. 4.4%, P = 0.01)., Conclusions: Both inter- and intra-observer variability for estimating the SYNTAX score were within an acceptable range and a high SYNTAX score showed a higher rate of TLR in patients undergoing ULMCA stenting in daily clinical practice.

Background: Among hemodialysis (HD) patients, those who have diabetes have poorer cardiovascular outcomes than non-diabetic patients, but the impact of diabetes on cardiovascular outcomes has not been fully elucidated in HD patients undergoing coronary revascularization., Methods and Results: We identified 375 HD patients (203 diabetes, 172 non-diabetes) and 9,006 patients without HD (3,455 diabetes, 5,551 non-diabetes) in the database of the CREDO-Kyoto registry of patients undergoing their first coronary revascularization. In non-HD patients, significantly higher risks of death (10.8% vs. 7.7%, P < 0.0001; adjusted hazard ratio (HR) 1.29, P < 0.0001) and major adverse cardiovascular events (MACE), a composite of death, myocardial infarction and stroke (18.8% vs. 13.3%, P < 0.0001; HR 1.36, P < 0.0001) were seen in diabetic patients than in non-diabetic patients through 4-year follow-up. Analysis in HD patients showed that the duration of HD before first coronary revascularization was significantly shorter in diabetic patients than in non-diabetic patients (median interval: 858 vs. 2,216 days, P < 0.0001). In contrast to the results in non-HD patients, the risks of death (41.9% vs. 39.1%, P=0.75; HR 0.98, P=0.93) and MACE (45.6% vs. 45.8%, P=0.83; HR 0.87, P=0.50) after first revascularization were comparable between diabetic and non-diabetic HD patients. There were significant interactions between HD and diabetes for death and for MACE., Conclusions: HD patients who require coronary revascularization have extremely poor outcomes irrespective of concomitant diabetes.

Background: The prevalence of coronary artery disease (CAD) is increasing in young adults. Risk factor profiling will help to prevent heart attacks in young patients. This study aimed to analyze the risk factor profile and predictors of major cardiovascular events (MACE) in young CAD patients., Methods and Results: From the Coronary REvascularization Demonstrating Outcome study in the Kyoto (CREDO-Kyoto) registry of Japanese patients undergoing their first coronary revascularization, 6,320 patients with complete data for all variables for statistical analyses were divided into younger (< or =55 years; n=898; 14.3%) and older (>55 years; n=5,422; 85.7%) patients. The risk factors that were more prevalent in the younger patients than in the older patients included: male sex, body mass index of >25 kg/m(2), current smoker, family history of CAD, dyslipidemia and metabolic syndrome-like risk factor accumulation. Multivariate analyses revealed that chronic kidney disease (CKD) was the only significant predictor of MACE, the composite of cardiovascular death, myocardial infarction and cerebrovascular accident, in the younger patients. Importance of CKD as a prognostic factor was consistently shown by a multivariate analysis in the older patients., Conclusions: Accumulation of multiple risk factors is prevalent and CKD is associated with MACE in young Japanese CAD patients.

Background: Contrast-induced nephropathy (CIN) is the third leading cause of all hospital-acquired renal insufficiency, accounting for 10%, and is associated with increased long-term mortality. The incidence of and risk factors for CIN after cardiac catheterization in Japanese patients are, however, unknown at present., Methods and Results: The 1,157 consecutive patients who underwent cardiac catheterization at Kyoto University Hospital from January 2003 to December 2004 were retrospectively examined. The incidence of CIN defined as an absolute increase in serum creatinine (SCr) > or =0.5 mg/dl, a relative > or =25% increase in SCr, and either an absolute or relative increase after cardiac catheterization were 4.0%, 13.8%, and 13.9%, respectively. Multivariate logistic models revealed that preexisting renal insufficiency and the use of high-volume contrast were independently associated with an absolute increase in SCr > or =0.5 mg/dl. Female gender, underweight, and high-volume contrast usage were independently associated with a relative > or =25% increase and either an absolute or relative increase in SCr., Conclusions: Although the incidence of and risk factors for CIN after cardiac catheterization varied in the study population according to the definition of CIN, careful attention should be paid to patients who have risk factors identified by each definition of CIN.

Background: Dual antiplatelet therapy with acetylsalicylic acid (ASA) and a P2Y(12) ADP-receptor blocker is standard for prevention of coronary stent thrombosis. Clopidogrel, a 2(nd)-generation P2Y(12) blocker, has recently become available in Japan and this study aimed to evaluate its antiplatelet effects in Japanese patients., Methods and Results: Thirty Japanese patients scheduled for elective coronary stent implantation were enrolled. Under low-dose ASA therapy, 300 mg clopidogrel was loaded on the 1(st) day and a daily 75-mg dose was administered on the following days. Assessed by optical aggregometer, rapid inhibition occurred at 4 h, when the inhibition of platelet aggregation rate (IPA) was 16.4+/-12.8% using 5 mumol/L ADP as the stimulus. The antiplatelet efficacy of clopidogrel was reasonably constant in each patient throughout the study period, although there was a broad inter-individual variation. At 48 h after clopidogrel loading, the ratios of responders (IPA > or =30%), hypo-responders (10%< or =IPA<30%), and non-responders (IPA <10%) were 36%, 50%, and 14%, respectively., Conclusions: The antiplatelet effectiveness of clopidogrel appeared individual-specific with wide inter-individual variation. The rate of clopidogrel non-responders was 14% among the examined Japanese patients.

Background: The importance of statins in cardiovascular prevention has been demonstrated in various patient subsets. This study aimed to evaluate the effects of statins on long-term outcomes of Japanese patients undergoing their first coronary revascularization., Methods and Results: A total of 9,225 patients undergoing their first coronary revascularizations during 2000--2002 were divided into 2 groups according to the use of statins at discharge; patients with acute myocardial infarction were not included. Statins was administered to only 28.5% (n=2,630) of the patients. The median follow-up period was 3.5 years. Patients on statin therapy showed lower all-cause (5.2% vs 10.0%; p<0.0001) and cardiovascular (3.2% vs 6.2%; p<0.0001) mortality than those without statins (n=6,595) by Kaplan-Meier analysis and log-rank test. After adjustment by multivariate analysis according to 29 variables, statin therapy remained as an independent predictor of reduced all-cause (relative risk ratio (RR) 0.71, 95% confidence interval (CI) 0.59-0.86, p=0.0005) and cardiovascular (RR 0.72, 95% CI 0.56-0.91, p=0.0067) mortality. The validity of RR of statin therapy in multivariate analysis was further confirmed by risk adjustment using propensity scores (all-cause mortality: propensity-adjusted RR 0.70, 95% CI 0.58-0.85, p=0.0003; cardiovascular mortality: propensity-adjusted RR 0.70, 95% CI 0.54-0.89, p=0.0038)., Conclusions: Statin therapy started at hospital discharge was associated with increased chance of survival in Japanese patients undergoing their first coronary revascularization.

Background: Congestive heart failure (CHF) is associated with altered energy homeostasis and myocardial inflammation, hypertrophy, and fibrosis. Adiponectin, an insulin-sensitizing adipocytokine, may affect these pathogenic factors, and the circulating adiponectin level may serve as a biological marker of CHF. This study aimed to assess the significance of serum adiponectin as a prognostic marker for Japanese CHF patients., Methods and Results: The serum adiponectin levels were compared between 54 (24 ischemic and 30 non-ischemic) CHF patients with left ventricular systolic dysfunction and 55 age- and gender-matched control subjects. The CHF patients also underwent simultaneous clinical assessment and measurements for brain natriuretic peptide (BNP) and parameters of lipid or glucose metabolism. Compared with the controls, the CHF patients showed significantly increased serum adiponectin levels [6.7 (4.9-12.6) vs 14.6 (9.7-25.4) microg/ml, p<0.0001]. In the CHF patients, the log-transformed values of the serum adiponectin levels positively correlated with the log-transformed values of the plasma BNP levels (p=0.0003, r=0.48) and inversely correlated with the body mass index (p=0.0006, r=-0.46). Furthermore, an increase in the serum adiponectin level was associated with higher mortality (p<0.05), particularly in the ischemic CHF patients (p<0.005)., Conclusions: An increase in the circulating adiponectin level was associated with higher mortality in the ischemic CHF patients. Adiponectin may be an informative risk marker for Japanese CHF patients.