As a new technology in the management of valvular heart disease, transcatheter aortic valve replacement (TAVR) has drawn much attention since its emergence. To date, numerous studies have investigated the safety and efficacy of TAVR in patients of various risk profiles with severe aortic stenosis (AS) and demonstrated comparable or superior outcomes of TAVR when compared with surgical aortic valve replacement (SAVR). The favorable outcomes of TAVR in inoperable patients, as well as in high- and intermediate-risk patients, are endorsed in current guidelines, and trials of low-risk patients have shown non-inferior or even superior results of TAVR than for SAVR, suggesting that the clinical indications of TAVR can be expanded to low-risk patients. Moreover, a therapeutic role of TAVR has been suggested in various aortic valve (AV) diseases, such as bicuspid AV, moderate AS with heart failure, aortic regurgitation, and bioprosthetic valve failure. In this review, we summarize the current issues of TAVR in various patient populations and discuss the expanding clinical indications of TAVR, which are driving a major paradigm shift in the management of AV disease.
Background: Treatment with evolocumab reduces mean low-density lipoprotein cholesterol (LDL-C) up to 75% and cardiovascular events by 16% in the first year and 25% thereafter.
Methods and Results: Japanese patients with hypercholesterolemia enrolled in the parent YUKAWA-1-2 studies could enroll, once eligible, in the OSLER studies (n=556). OSLER re-randomized patients 2:1 to evolocumab plus standard of care (SOC; evolocumab+SOC) or SOC alone for 1 year; after year 1, patients could enter the all-evolocumab+SOC open-label extension of OSLER. Patients received evolocumab+SOC from the 2nd year through up to 5 years. Long-term efficacy and safety, including antidrug antibodies, were evaluated. Of 556 patients, 532 continued to the all-evolocumab+SOC extension: mean (standard deviation [SD]) age 61 (10) years, 39% female. A total of 91% of 532 patients completed the studies. Mean (SD) LDL-C change from parent-study baseline with evolocumab from a mean (SD) baseline of 142.3 (21.3) and 105.0 (31.1) mg/dL in OSLER-1 and OSLER-2, respectively, was maintained through the end of the study: −58.0% (19.1%) at year 5 in OSLER-1, −62.7% (25.6%) at year 3 in OSLER-2. The overall safety profile of the evolocumab+SOC periods was similar to that of the year-1 controlled period. Antidrug antibodies were detected transiently in 3 patients. No neutralizing antibodies were detected.
Conclusions: Japanese patients who continued evolocumab+SOC for up to 5 years experienced sustained high LDL-C level reduction. Long-term evolocumab+SOC exposure showed no new safety signals.
Background: Coronary artery disease (CAD) is associated with increased morbidity and mortality after open repair of thoracic aorta. Nevertheless, the efficacy of preoperative coronary angiography (CAG) and revascularization is controversial. The aim of this study was to clarify the effect of preoperative CAD on surgical outcome by reviewing the Japan Adult Cardiovascular Database.
Methods and Results: This study involved 4,596 patients who underwent open surgery for true thoracic aortic aneurysm between 2004 and 2009. After excluding patients with concomitant cardiac operation, except coronary artery bypass grafting (CABG), the remaining 1,904 patients with coronary artery stenosis included 995 cases of simultaneous CABG. The prevalence of CAD was significantly higher in patients with diabetes, renal dysfunction, hyperlipidemia, cerebrovascular disorders, peripheral artery lesions, old myocardial infarction (MI), and coronary intervention. Patients with simultaneous CABG had severe CAD compared with those without, with no other major differences in patient background noted. Thirty-day postoperative and in-hospital mortalities were higher in CAD patients. Incidence of perioperative MI was higher in patients who underwent open aortic repair with simultaneous CABG, but simultaneous CABG did not affect operative mortality.
Conclusions: In patients with surgically treated true aortic aneurysm, CAD was frequently observed, suggesting that aggressive preoperative coronary evaluation is needed.
Background: The presence of residual left atrial low-voltage areas (LVA) has been shown to be strongly associated with atrial fibrillation (AF) recurrence after pulmonary vein isolation. A preliminary study showed that concomitant chronic kidney disease (CKD) increased the rate of AF recurrence. The association between CKD and LVA, however, has not been elucidated. In the present study, we investigated the association between CKD severity and LVA prevalence.
Methods and Results: In total, 183 consecutive AF patients who underwent initial ablation for AF were enrolled in this retrospective observational study. Serum cystatin C before ablation was measured, and the estimated glomerular filtration rate (eGFR) was calculated. LVA were defined as sites of left atrial electrogram amplitude <0.5 mV. Of 183 patients, 76 (42%) had LVA. Patients with LVA had lower eGFR calculated using cystatin C (74±22 vs. 86±24 mL/min/1.73 m2, P=0.001). The optimal cut-off of the calculated eGFR was 71.5 mL/min/1.73 m2, corresponding to a 79.4% sensitivity, 50% specificity, and 67.2% predictive accuracy. LVA occurred more frequently in patients with more severe categories of CKD. On multivariate analysis, eGFR <71.5 mL/min/1.73 m2was an independent predictor of LVA (odds ratio, 3.3; 95% CI: 1.4–7.8; P=0.006).
Conclusions: CKD severity was correlated with left atrial LVA prevalence in patients with AF undergoing catheter ablation.
Background: Practice-based investigations on direct oral anticoagulant (DOAC) treatment for non-valvular atrial fibrillation (NVAF) have shown that off-label under-dosing is increasingly becoming an issue. Here, we investigate the significance of drug monitoring to prevent undesirable under-dosing with DOAC.
Methods and Results: In 255 outpatients with NVAF undergoing treatment with rivaroxaban or apixaban we estimated the cut-offs for bleeding events using drug plasma concentration (PC) data 3 h after drug treatment, that is, at the peak level. Furthermore, we evaluated the appropriateness of labeled and off-label dosing implemented for 348 patients using the obtainable PC threshold. A total of 73 off-label under-dose users of rivaroxaban (37% of all users and 63% of lower dose users) had acceptable peak PC (155–400 ng/mL). Additionally, 46 off-label under-dose users of apixaban (31% of all users and 55% of lower dose users) received appropriate doses according to peak PC threshold (90−386.4 ng/mL). These off-label under-dose users reported no bleeding or thromboembolic events during follow-up.
Conclusions: Anticoagulation monitoring enables personalized and appropriate off-label under-dosing in NVAF patients on rivaroxaban or apixaban through the measurement of peak PC during DOAC use.
Background: Using the standard maintenance dose of prasugrel (10 mg/day) as part of triple therapy with aspirin and an oral anticoagulant (OAC) is not recommended in the current guidelines because it increases the risk of bleeding compared with clopidogrel. However, the safety and efficacy of low-dose prasugrel (3.75 mg/day) as part of triple therapy has not been reported.
Methods and Results: We registered 816 consecutive patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) from January 2011 to June 2016 at 8 hospitals in Japan. We examined the clinical outcomes of patients who received either low-dose prasugrel (n=57) or clopidogrel (n=451) as part of triple therapy after PCI. The incidences of bleeding (TIMI major and minor) and major adverse cerebrocardiovascular events (MACCE; all-cause death, nonfatal myocardial infarction, stent thrombosis, unplanned revascularization, and stroke) were evaluated. The cumulative 1-year incidence of bleeding was not significantly different (prasugrel 5.6% vs. clopidogrel 8.1%, log-rank P=0.55). In addition, the cumulative 1-year incidence of MACCE was also not significantly different (prasugrel 11.5% vs. clopidogrel 12.3%, log-rank P=0.88).
Conclusions: Low-dose prasugrel, as part of triple therapy, did not increase the risk of bleeding compared with clopidogrel. Therefore, it can be an alternative to clopidogrel for patients with AF undergoing PCI.
Background: In Japan, the burden associated with myocardial infarction (MI) and ischemic stroke as well as atherosclerotic cardiovascular disease (ASCVD) generally is high. One key element in measuring disease burden is years of life lost (YLL). The aim of this study was to understand the burden of these diseases by estimating YLL at an overall disease level and average person-YLL (PYLL), a measure of disease burden also used in prior studies.
Methods and Results: Because calculation of YLL and PYLL involves inputs such as disease prevalence, disease-related mortality by age, and general population mortality by age and sex, we searched public databases of disease surveillance to identify comprehensive Japanese-specific inputs. For our reference analysis, disease-specific prevalence and mortality were taken from the Institute for Health Metrics and Evaluation Global Disease Burden study, and background mortality data were from the Japanese life tables published by the Ministry of Health, Labour and Welfare. The average age of patients with MI or stroke was 74 and 70 years, respectively. On average, men comprised 59% and 54% of the MI and stroke population, respectively. The disease-level burden of ASCVD (inclusive of MI, stroke, and peripheral artery disease) was 2,703,711 YLL in 2017. The patient-level burden was 11.99 PYLL for MI and 9.39 PYLL for stroke.
Conclusions: The burden of ASCVD, MI, and stroke in terms of premature mortality is substantial in Japan, both on a population disease level and an individual patient level.
Background: We investigated whether patients with out-of-hospital cardiac arrest (OHCA) and sustained ventricular fibrillation/pulseless ventricular tachycardia (VF/pVT) or conversion to pulseless electrical activity/asystole (PEA/asystole) benefit more from extracorporeal cardiopulmonary resuscitation (ECPR).
Methods and Results: We analyzed data from the Study of Advanced Life Support for Ventricular Fibrillation with Extracorporeal Circulation in Japan, which was a prospective, multicenter, observational study with 22 institutions in the ECPR group and 17 institutions in the conventional CPR (CCPR) group. Patients were divided into 4 groups by cardiac rhythm and CPR group. The primary endpoint was favorable neurological outcome, defined as Cerebral Performance Category 1 or 2 at 6 months. A total of 407 patients had refractory OHCA with VF/pVT on initial electrocardiogram. The proportion of ECPR patients with favorable neurological outcome was significantly higher in the sustained VF/pVT group than in the conversion to PEA/asystole group (20%, 25/126 vs. 3%, 4/122, P<0.001). Stratifying by cardiac rhythm, on multivariable mixed logistic regression analysis an ECPR strategy significantly increased the proportion of patients with favorable neurological outcome at 6 months in the patients with sustained VF/pVT (OR, 7.35; 95% CI: 1.58–34.09), but these associations were not observed in patients with conversion to PEA/asystole.
Conclusions: OHCA patients with sustained VF/pVT may be the most promising ECPR candidates (UMIN000001403).
Background: Prognosis after acute decompensated heart failure (ADHF) is poor. An appropriate risk score that would allow for improved care and treatment of ADHF patients after discharge, however, is lacking.
Methods and Results: We used 2 HF cohorts, the NARA-HF study and JCARE-CARD, as derivation and validation cohorts, respectively. The primary endpoint was all-cause death during the 2-year follow-up, excluding in-hospital death. Age, hemoglobin (Hb), and brain natriuretic peptide (BNP) at discharge were identified as independent risk factors. We determined 3 categorizations on the basis of these parameters, termed A2B score: age (<65 years, 0; 65–74 years, 1; ≥75 years, 2), anemia (Hb <10 g/dL, 2; 10–11.9 g/dL, 1; ≥12 g/dL, 0) and BNP (<200 pg/mL, 0; 200–499 pg/mL, 1; ≥500 pg/mL, 2). We divided patients into 4 groups according to A2B score (extremely low, 0; low, 1–2; medium, 3–4; high, 5–6). For the extremely low-risk group, the 2-year survival rate was 97.8%, compared with 84.5%, 66.1%, and 45.2% for the low-, medium-, and high-risk groups, respectively. Using the JCARE-CARD as a validation model, for the extremely low-risk group, the 2-year survival was 95.4%, compared with 90.2%, 75.0%, and 55.6% for the low-, medium-, and high-risk groups, respectively.
Conclusions: The user-friendly A2B score is useful for estimating survival rate in ADHF patients at discharge.
Background: With aging of the population, the economic burden associated with heart failure (HF) is expected to increase. However, little is known about the hospitalization costs associated with HF in Japan.
Methods and Results: In this cross-sectional study, using data from The Japanese Registry of All Cardiac and Vascular Diseases (JROAD) and JROAD-Diagnosis Procedure Combination databases between 2012 and 2014, we evaluated hospitalization costs for acute cardiovascular diseases (CVDs), including HF. A total of $1,187 million/year (44% of the hospitalization costs for acute CVDs) was spent on patients with HF. We identified 273,865 patients with HF and the median cost per patient was $8,089 ($5,362–12,787) per episode. The top 1% of spenders accounted for 8% ($80 million/year), and the top 5% of spenders accounted for 22% ($229 million/year) of the entire cost associated with HF. The costs associated with HF for patients over 75 years of age accounted for 68% of the total cost.
Conclusions: The costs associated with HF were higher than the hospitalization cost for any other acute CVD in Japan. Understanding how the total hospitalization cost is distributed may allow health providers to utilize limited resources more effectively for patients with HF.
Background: Trans-fatty acid (TFA) intake increases the risk of coronary artery disease (CAD). Our previous cross-sectional survey showed that middle-aged patients with CAD in Japan have elevated serum TFA. In this study, we longitudinally investigated whether elevated TFA is a risk factor in the secondary prevention of CAD for the same-age patients.
Methods and Results: A total of 112 patients (age, 21–66 years) who underwent percutaneous coronary intervention were followed up for up to 2 years. Serum elaidic acid was measured using gas chromatography/mass spectrometry as a marker of TFA intake and divided into quartiles. The primary endpoint was ischemia-driven target lesion revascularization (TLR). The hazard ratio (HR) for TLR increased significantly with higher serum elaidic acid (P<0.01). The significant positive trend remained unchanged after adjusting for conventional lipid profile and bare-metal stent usage. In contrast, although triglycerides and low-density lipoprotein cholesterol were positively correlated with elaidic acid, they were not associated with TLR. On multivariable Cox proportional hazard analysis, elevated elaidic acid was independently associated with TLR risk after adjusting for conventional coronary risks (HR, 10.7, P<0.01).
Conclusions: Elevated elaidic acid is associated with higher TLR rate in middle-aged patients with CAD, suggesting that excessive TFA intake is becoming a serious health problem in Japan.
Background: The novel Acute Myocardial Infarction (AMI) Risk Stratification (nARS) system was recently developed based on original criteria. The use of nARS may reduce the length of hospitalization.
Methods and Results: We allocated 560 AMI patients into the pre-nARS group (before adopting nARS) or the nARS group. Patients in the nARS group were subdivided into the low (L), intermediate (I), and high (H) risk groups, whereas patients in the pre-nARS group were subdivided into the equivalent L (eL), equivalent I (eI), or equivalent H (eH) risk groups based on the nARS criteria. Length of coronary care unit (CCU) stay was significantly shorter in the nARS group (2.8±3.5 days) compared with the pre-nARS group (4.4±5.4 days; P<0.001). Length of hospital stay was also shorter in the nARS group (9.4±8.9 days) compared with the pre-nARS group (13.4±12.8 days; P<0.001). Length of CCU stay was significantly shorter in the L (1.1±1.0 days), I (2.8±3.5 days), and H (5.0±4.8 days) risk groups compared with corresponding eL (2.2±1.1 days), eI (4.4±5.4 days), and eH (7.1±7.8 days) risk groups.
Conclusions: Length of CCU and hospital stay were significantly shorter in the nARS group compared with the pre-nARS group. The use of nARS may save medical resources in the treatment of AMI in the regional health-care system.
Background: Serum levels of lipoprotein (a) (Lp(a)) could be a risk factor for adverse events in patients with coronary artery disease (CAD). However, the effect of Lp(a) on long-term outcomes in patients with left ventricular (LV) systolic dysfunction, possibly through the increased likelihood for development of heart failure (HF), remains to be elucidated. This study aimed to determine the prognostic impact of Lp(a) in patients with CAD and LV systolic dysfunction.
Methods and Results: A total of 3,508 patients who underwent percutaneous coronary intervention were candidates. We analyzed 369 patients with LV systolic dysfunction (defined as LV ejection fraction <50%). They were assigned to groups according to a median level of Lp(a) (i.e., high Lp(a), ≥21.6 mg/dL, n=185; low Lp(a), <21.6 mg/dL, n=184). The primary outcome was a composite of all-cause death and readmission for acute coronary syndrome and/or HF. The median follow-up period was 5.1 years. Cumulative event-free survival was significantly worse for the group with high Lp(a) than for the group with low Lp(a) (P=0.005). In the multivariable analysis, a high Lp(a) level was an independent predictor of the primary outcomes (hazard ratio, 1.54; 95% confidence interval, 1.09–2.18; P=0.014).
Conclusions: A high Lp(a) value could be associated with long-term adverse clinical outcomes among patients with CAD and LV systolic dysfunction.
Background: Beta-blockers are standard therapy for acute myocardial infarction (AMI). However, despite current advances in the management of AMI, it remains unclear whether all AMI patients benefit from β-blockers. We investigated whether admission heart rate (HR) is a determinant of the effectiveness of β-blockers for AMI patients.
Methods and Results: We enrolled 3,283 consecutive AMI patients who were admitted to 28 participating institutions in the Japanese Registry of Acute Myocardial Infarction Diagnosed by Universal Definition (J-MINUET) study. According to admission HR, we divided patients into 3 groups: bradycardia (HR <60 beats/min, n=444), normocardia (HR 60 to ≤100 beats/min, n=2,013), and tachycardia (HR >100 beats/min, n=342). The primary endpoint was major adverse cardiac events (MACE), including all-cause death, non-fatal MI, non-fatal stroke, heart failure (HF), and urgent revascularization for unstable angina, at 3-year follow-up. Beta-blocker at discharge was significantly associated with a lower risk of MACE in the tachycardia group (23.6% vs. 33.0%; P=0.033), but it did not affect rates of MACE in the normocardia group (17.8% vs. 18.4%; P=0.681). In the bradycardia group, β-blocker use at discharge was significantly associated with a higher risk of MACE (21.6% vs. 12.7%; P=0.026). Results were consistent for multivariable regression and stepwise multivariable regression.
Conclusions: Admission HR might determine the efficacy of β-blockers for current AMI patients.
Background: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy.
Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100–149 mg/dL), borderline hypertriglyceridemia (150–199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL.
Conclusions: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.
Background: Evidence from prospective cohort studies regarding the relationship between working hours and risk of cardiovascular disease is limited
Methods and Results: The Japan Public Health Center-Based Prospective Study Cohort II involved 15,277 men aged 40–59 years at the baseline survey in 1993. Respondents were followed up until 2012. During the median 20 years of follow up (257,229 person-years), we observed 212 cases of acute myocardial infarction and 745 stroke events. Cox proportional hazards models adjusted for sociodemographic factors, cardiovascular risk factors, and occupation showed that multivariable-adjusted hazard ratios (HRs) associated with overtime work of ≥11h/day were: 1.63 (95% confidence interval [CI] 1.01–2.63) for acute myocardial infarction and 0.83 (95% CI 0.60–1.13) for total stroke, as compared with the reference group (working 7 to <9 h/day). In the multivariable model, increased risk of acute myocardial infarction associated with overtime work of ≥11 h/day was more evident among salaried employees (HR 2.11, 95% CI 1.03–4.35) and men aged 50–59 years (HR 2.60, 95% CI 1.42–4.77).
Conclusions: Among middle-aged Japanese men, working overtime is associated with a higher risk of acute myocardial infarction.