Kazuma Oyama

Background: Patients with established atherosclerotic cardiovascular disease (ASCVD) remain at substantial risk of recurrent events despite secondary prevention. Risk stratification may identify patients requiring more intensive prevention. However, most secondary prevention risk models were developed in Western populations and may not reflect the risk profile of Japanese patients, whose cardiovascular risk factors may differ in prevalence and impact. Thus, a risk model for Japanese patients with established ASCVD is needed.Objectives: We aimed to develop a 10-year risk prediction model for recurrent cardiovascular events in Japanese patients with established ASCVD.Methods: We analyzed 3,560 patients with coronary artery disease or ischemic stroke without prior heart failure enrolled in CHART-2. The primary endpoint was a composite of cardiovascular death, myocardial infarction, and stroke. Candidate predictors were selected from established secondary prevention models. Independent predictors were identified using multivariable logistic regression to develop a point-based 10-year risk score.Results: Over a median follow-up of 10.1 years, 756 patients experienced the primary endpoint. Independent predictors included age, smoking, systolic blood pressure, non–high-density lipoprotein cholesterol, diabetes mellitus, renal dysfunction, left ventricular dysfunction, atrial fibrillation, polyvascular disease, and statin use. These predictors were incorporated into a point-based score, termed the J-RECUR score. The score demonstrated a >5-fold gradient in 10-year recurrent cardiovascular risk, with a C-index of 0.66 (95% CI, 0.64–0.68).Conclusions: The J-RECUR score stratified patients across a wide range of 10-year recurrent cardiovascular risk and may provide a practical approach to secondary prevention risk stratification in Japanese patients with established ASCVD.

Aims: B-type natriuretic peptide (BNP) levels of 35–100 pg/mL, common in preclinical heart failure (HF), are associated with heterogeneous prognosis and are influenced by age and renal function. We aimed to characterize risk heterogeneity in preclinical HF patients with BNP levels of 35–100 pg/mL and to develop a practical risk stratification model. Methods and results: Data from the Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) Study, a prospective multicentre cohort with long-term follow-up, were analysed. Among patients with Stage B HF (n = 4074; age 67.6 ± 12.0 years), the predictability of BNP for 10-year HF-related events was evaluated across strata of age and estimated glomerular filtration rate (eGFR). In patients with BNP levels of 35–100 pg/mL, a composite risk score—the Pre-Heart Failure Assessment and Screening Evaluation (PHASE) Index—was developed using classification and regression tree analysis and multivariable Cox proportional hazards modelling. BNP discrimination varied significantly by age and eGFR (P < 0.05), indicating that a single BNP threshold is insufficient for risk stratification in preclinical HF. The PHASE Index, incorporating age, BNP, eGFR, left ventricular ejection fraction, body mass index, and hypertension, stratified patients with BNP levels of 35–100 pg/mL into four categories and demonstrated superior discrimination compared with BNP alone (c-index 0.723 vs. 0.587, P < 0.05). Conclusion: Patients with preclinical HF and BNP levels of 35–100 pg/mL exhibit substantial risk heterogeneity. The PHASE Index improves identification of high-risk individuals and provides a pragmatic tool for risk stratification beyond the conventional BNP threshold.

Background: Clinical characteristics and outcomes of patients with myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) are not fully understood, particularly in Japan. Methods and Results: We enrolled a total of 8881 patients with acute MI from the Miyagi Acute Myocardial Infarction Registry Study (2012–2020), with a median age of 69 years. Among them, 239 patients (2.7%) were diagnosed with MINOCA. Compared with those with MI with obstructive coronary artery disease (MI‐CAD), patients with MINOCA were more often women, had a higher incidence of non–ST‐segment–elevation MI and a lower prevalence of dyslipidemia. Compared with patients with MI‐CAD, patients with MINOCA in all age groups (80 years of age) had a higher incidence of non–ST‐segment–elevation MI. Additionally, those ≤59 years of age were more often women and had a lower prevalence of diabetes and dyslipidemia. In‐hospital mortality increased with age in patients with MI‐CAD (3.9% for 80 years of age; P P =0.36). Compared with patients with MI‐CAD, patients with MINOCA had lower in‐hospital mortality for Killip class IV (40.7% versus 20.0%; adjusted odds ratio [OR], 0.31 [95% CI, 0.10–0.94]; P =0.04) and renal dysfunction (20.0% versus 7.1%; adjusted OR, 0.29 [95% CI, 0.09–0.96]; P =0.04). Conclusions: Patients with MINOCA exhibit distinct clinical characteristics and outcomes compared with those with MI‐CAD, particularly in terms of age, sex, prevalence of comorbidities, and in‐hospital mortality. These findings underscore the importance of tailored clinical approaches for patients with MINOCA.

Background: Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. Methods: FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. Results: Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR] _adj 1.61 [95% CI, 1.42–1.84]; P adj , 1.72 [95% CI, 1.49–1.99]; P P _interaction 0.51; major coronary events: HR, 0.82 [0.75–0.90] versus HR, 0.88 [0.75–1.04]; P _interaction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% ( P _interaction 0.14) and for major coronary events 2.0% versus 0.7% ( P _interaction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69–0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54–0.94]); any PCI (HR, 0.77 [0.69–0.86]); PCI for de novo lesions (HR, 0.76 [0.66–0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63–0.91]). Conclusions: Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.

Background: In the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trial, adding the PCSK9 inhibitor evolocumab to statin therapy reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. Although atherosclerotic coronary, cerebrovascular, and peripheral vascular events share a related pathobiology, the effect of aggressive LDL-C lowering with PCSK9 inhibition on the risk of acute arterial events across all three vascular beds is not well-described. Purpose: To assess the efficacy of evolocumab on acute arterial events in all vascular territories including coronary, cerebral, and peripheral vascular beds. Methods: In the FOURIER trial, patients (n=27,564) with stable atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). Acute arterial events were defined as a composite of coronary (coronary heart disease [CHD] death, myocardial infarction [MI], or urgent coronary revascularization), cerebrovascular (ischemic stroke, transient ischemic attack [TIA], or urgent cerebral revascularization), or peripheral vascular (acute limb ischemia, major amputation, or urgent peripheral revascularization) events. Cox proportional-hazard models were used to assess the efficacy of evolocumab on these outcomes. Landmark and total event analyses were also done. Results: Of the 2,210 first acute arterial events occurring during follow-up, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced the risk of a first acute arterial event by 19% (HR 0.81, 95% CI 0.74–0.88; P<0.001), with significant individual reductions in acute coronary (HR 0.83; 95% CI 0.75–0.91; P<0.001), acute cerebrovascular (HR 0.77; 95% CI 0.65–0.92; P=0.004), and acute peripheral vascular (HR 0.58; 95% CI 0.38–0.88; P=0.01) events (Figure, top). The magnitude of the risk reduction with evolocumab tended to increase over time, with a 16% reduction (HR 0.84; 95% CI 0.75–0.96) in the first year followed by a 24% reduction (HR 0.76; 95% CI 0.67–0.85) thereafter (Figure, bottom). There were 3,780 total acute arterial events (first plus recurrent), with a 22% reduction with evolocumab (incidence rate ratio [RR] 0.78; 95% CI 0.70–0.87). Evolocumab prevented 496 total acute arterial events as compared to 222 first events. Conclusions: The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced the risk of acute arterial events across all vascular territories with a robust effect over time. These findings indicate a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. Funding Acknowledgement: Type of funding sources: Private company. Main funding source(s): The FOURIER trial was supported by Amgen.

We assessed the impact of the proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor evolocumab on acute arterial events across all vascular territories, including coronary, cerebrovascular, and peripheral vascular beds, in patients with established atherosclerotic cardiovascular disease (ASCVD). In the FOURIER trial, 27 564 patients with stable ASCVD on statin therapy were randomly assigned to evolocumab or placebo. Acute arterial events were a composite of acute coronary (coronary heart disease death, myocardial infarction, or urgent coronary revascularization), cerebrovascular (ischaemic stroke, transient ischaemic attack, or urgent cerebral revascularization), or peripheral vascular (acute limb ischaemia, major amputation, or urgent peripheral revascularization) events. Of the 2210 first acute arterial events, 74% were coronary, 22% were cerebrovascular, and 4% were peripheral vascular. Evolocumab reduced first acute arterial events by 19% (hazard ratio [HR] 0.81 [95% confidence interval 0.74–0.88]; P < 0.001), with significant individual reductions in acute coronary (HR 0.83 [0.75–0.91]), cerebrovascular (HR 0.77 [0.65–0.92]), and peripheral vascular (HR 0.58 [0.38–0.88]) events. There were 3437 total events (first plus recurrent), with evolocumab reducing total events by 24% (incidence rate ratio 0.76 [0.69–0.85]). The magnitude of reduction in acute arterial events with evolocumab numerically increased over time, with a 16% reduction (HR 0.84 [0.75–0.95]) in the first year followed by a 24% reduction (HR 0.76 [0.67–0.85]) thereafter. The addition of the PCSK9 inhibitor evolocumab to statin therapy reduced acute arterial events across all vascular territories with a robust effect over time, indicating a pan-vascular impact of aggressive lipid-lowering therapy on these acute and clinically meaningful events. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633. Effect of evolocumab on acute arterial events across all vascular territories. ALI, acute limb ischaemia; CHD, coronary heart disease; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; PAD, peripheral artery disease; PCSK9, proprotein convertase subtilisin-kexin type 9; RR, incidence rate ratio; TIA, transient ischaemic attack.

We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). DECLARE–TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m²): normal (18.5 to 2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: −1.9 to −2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m²) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. In DECLARE–TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534. In the DECLARE–TIMI 58 trial, patients with type 2 diabetes mellitus and higher body mass index were more likely to have hospitalization for heart failure and atrial fibrillation or flutter, and obese patients tended to derive greater absolute risk reduction in obesity-related outcomes, hospitalization for heart failure and atrial fibrillation or flutter from dapagliflozin although relative risk reductions in all the outcomes were consistent across the range of body mass index. AF/AFL, atrial fibrillation or atrial flutter; BMI, body mass index; HF, heart failure; HR, hazard ratio.

We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding. ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS₂ score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log₂-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36–2.23 and adj-HR 1.27; 95% CI 1.07–1.50, respectively] and log₂-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02–1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36–0.65; NRI 0.42; 95% CI 0.33–0.51, respectively]. Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF. Serial assessment of biomarkers and the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation. hsTnT, high-sensitivity troponin T; NT-proBNP, N-terminal pro-brain natriuretic peptide; GDF-15, growth differentiation factor-15; AF, atrial fibrillation; ABC, age, biomarker, and clinical history.