Yuki Obayashi

Background: There are no studies evaluating mortality and causes of death in severe aortic stenosis (AS) according to symptoms and treatment strategies in contemporary transcatheter aortic valve replacement era. Methods: Among 3369 consecutive patients with severe AS in the CURRENT AS registry-2, we comprehensively evaluated mortality rates and causes of death in patients with severe AS according to symptoms and treatment strategies. Results: There were 2011 patients with symptomatic severe AS [initial aortic valve replacement (AVR) strategy: N = 1410, and conservative strategy: N = 601] and 1358 patients with asymptomatic severe AS (initial AVR strategy: N = 332, and conservative strategy: N = 1026). During median 2.2 years follow-up, all-cause death occurred in 736 patients, including 297 patients with cardiac death (40.4% of total mortality), 44 patients with vascular death (6.0% of total mortality), and 351 patients with non-cardiovascular death (47.7% of total mortality). In patients with cardiac death, the most common cause was heart failure (22.6% of total mortality), and the second most common cause was sudden death (11.7% of total mortality). In patients with non-cardiovascular death, the most common cause was infection (19.3% of total mortality), and the second most common cause was malignancy (12.2% of total mortality). Cumulative 3-year incidence of all-cause death (proportions of cardiac and non-cardiovascular death) was 22.9% (30.2% and 58.2% of total mortality) in symptomatic severe AS with initial AVR strategy, 53.1% (56.1% and 35.6% of total mortality) in symptomatic severe AS with conservative strategy, 15.5% (23.7% and 68.4% of total mortality) in asymptomatic severe AS with initial AVR strategy, and 24.7% (35.7% and 46.9% of total mortality) in asymptomatic severe AS with conservative strategy. Conclusions: There was a great difference in mortality and causes of death according to symptoms and treatment strategies in severe AS. Non-cardiovascular death was one of the major components of death in patients who were managed not only invasively but also conservatively.

Background: Current guidelines classify normal‐flow low‐gradient (LG) aortic stenosis (AS) with left ventricular ejection fraction (LVEF) ≥50% as “moderate.” However, the prognostic impact of LVEF remains incompletely understood across various hemodynamic subtypes of AS. Methods: We analyzed 3363 consecutive patients with severe AS from the CURRENT AS Registry‐2 (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis). Patients were classified into LG AS with normal flow (N=1005), and LG AS with low flow (N=372), and high‐gradient AS (N=1986). Patients were further divided according to baseline LVEF: P P =0.003) with hazards comparable to those with LVEF P =0.59). Conclusions: These findings suggest that LVEF may provide additional prognostic stratification within severe AS phenotypes, particularly in normal‐flow LG AS. Registration: URL: https://center6.umin.ac.jp ; Unique Identifier: UMIN000034169.

Background: A valve syndrome framework (stable valve syndrome [SVS], progressive valve syndrome [PVS], and acute valve syndrome [AVS]) integrates clinical presentation with objective markers, but its prognostic implications remain incompletely characterized. Methods: Among 3369 consecutive patients with severe aortic stenosis (AS) in the CURRENT AS Registry‐2, we analyzed 2824 patients with natriuretic peptide (NP) and left ventricular ejection fraction (LVEF) data. Patients were classified as SVS (no symptoms with low NP), PVS (mild symptoms and/or mildly elevated NP), or AVS (acute deterioration and/or markedly elevated NP or reduced LVEF), and stratified by initial aortic valve replacement (AVR) and conservative strategies. The primary outcome was a composite of death or heart failure hospitalization. Subgroup analyses further classified patients into five phenotypes: SVS, progressive valve signs without symptoms, progressive valve symptoms, acute valve signs without symptoms, and acute valve symptoms. Results: In the initial AVR stratum, AVS was associated with higher risk for the primary outcome compared with SVS (adjusted HR 2.34, 95% CI 1.19–4.59, P=0.01), whereas PVS was not. In the conservative stratum, SVS demonstrated a very low early event rate (1.0% at 6 months), while AVS and PVS had higher risk than SVS. In the five‐phenotype analysis, patients with progressive valve signs without symptoms underwent AVR at rates comparable to SVS yet had worse outcomes than SVS in the conservative stratum (adjusted HR 1.89, 95% CI 1.18‐3.03, P=0.008). Conclusions: A valve syndrome framework highlights limitations of symptom‐based risk stratification and may refine surveillance and intervention strategies in severe AS.

BACKGROUND: Clopidogrel may have ischemic benefit over aspirin as long-term monotherapy in patients receiving percutaneous coronary intervention. METHODS: Both the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy-2) and STOPDAPT-2 ACS (Short and Optimal Duration of Dual Antiplatelet Therapy-2 Study for the Patients With Acute Coronary Syndrome) were multicenter, open-label, adjudicator-blinded, randomized clinical trials in Japan, with the same protocol except that the STOPDAPT-2 ACS enrolled patients with acute coronary syndrome, exclusively. The patients after percutaneous coronary intervention with cobalt-chromium everolimus-eluting stents were randomized into 1-month dual antiplatelet therapy followed by clopidogrel monotherapy (clopidogrel group) or 12-month dual antiplatelet therapy followed by aspirin monotherapy (aspirin group). Follow-up duration was 5 years. The clinical effect between clopidogrel and aspirin monotherapy was compared by the 1-year landmark analysis in the STOPDAPT-2 ACS and STOPDAPT-2 total cohort, a pooled cohort of the 2 trials. The primary end point was the composite of cardiovascular end point (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) and bleeding end point (Thrombolysis in Myocardial Infarction major/minor). The major secondary end points were each of the cardiovascular composite end point and the bleeding end point. RESULTS: Of 2986 patients (clopidogrel group: 1492, aspirin group: 1494) in the 5-year analysis of the STOPDAPT-2 ACS, 2875 (96.3%) completed follow-up. By the 1-year landmark analysis, clopidogrel group was superior to aspirin group for both the primary end point (6.18% and 8.27%; hazard ratio, 0.75 [95% CI, 0.57–0.997]; P =0.048) and the major secondary cardiovascular end point (4.73% and 6.77%; hazard ratio, 0.70 [95% CI, 0.51–0.96]; P =0.03). In the STOPDAPT-2 total cohort, including 5991 patients, the superiority of clopidogrel over aspirin for the cardiovascular end point was highly significant (hazard ratio, 0.74 [95% CI, 0.60–0.91]; P =0.004), although the superiority on the primary end point was insignificant (hazard ratio, 0.86 [95% CI, 0.72–1.03]; P =0.11). There was no between-groups difference in the major secondary bleeding end point, both in the STOPDAPT-2 ACS and STOPDAPT-2 total cohort. CONCLUSIONS: Clopidogrel monotherapy was superior to aspirin monotherapy for cardiovascular outcomes beyond 1 year after percutaneous coronary intervention, without increased bleeding risk. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02619760 and NCT03462498.

BACKGROUND: Mitral regurgitation (MR) is a frequent comorbidity in patients with hypertrophic cardiomyopathy (HCM), which includes distinct subtypes with various characteristics. However, data on the long-term prognostic impact of MR and its progression or regression over time remain limited, particularly across individual HCM subtypes. METHODS: Patients with HCM were retrospectively included from a Japanese multicenter registry and compared by MR severity (moderate or greater versus mild or less) within each subtype: hypertrophic obstructive cardiomyopathy (HOCM), end-stage HCM (ES-HCM), and other HCM (including nonobstructive, midventricular obstruction, and apical HCM). RESULTS: Among 3602 patients (HOCM: n=837; ES-HCM: n=275; other HCM: n=2490), the prevalence of moderate or greater MR was highest in HOCM (36.3%), followed by ES-HCM (21.5%) and other HCM (8.5%). During a median follow-up of 5.3 (interquartile range, 2.1–9.3) years, the cumulative 5-year incidence of all-cause death or heart failure hospitalization was not significantly different between the moderate or greater MR and mild or less MR groups in HOCM (14.6% versus 12.4%; P =0.35) or ES-HCM (60.7% versus 54.7%; P =0.84). After adjustment for clinical covariates, no significant association was observed in either subtype (HOCM: hazard ratio, 1.13 [95% CI, 0.79–1.60], P =0.51; ES-HCM: hazard ratio, 0.84 [95% CI, 0.55–1.28], P =0.42). In contrast, in other HCM, moderate or greater MR was significantly associated with the higher 5-year cumulative incidence of all-cause death or heart failure hospitalization (34.2% versus 13.9%, P P =0.01; P _interaction =0.02). MR severity improved over time in HOCM, showed no clear change in ES-HCM, and worsened in other HCM ( P P _interaction <0.001). CONCLUSIONS: In patients with HCM, moderate or greater MR was not associated with worse outcomes in HOCM or ES-HCM, but had significant prognostic implications in other HCM subtypes, suggesting the need for HCM subtype-specific MR management.

BACKGROUND: There were no previous studies comparing aspirin with clopidogrel on top of oral anticoagulation (OAC) within 1 year after percutaneous coronary intervention when dual therapy with OAC and clopidogrel was recommended. METHODS: We conducted a subgroup analysis stratified by OAC in the 1-year follow-up of the STOPDAPT-3 trial (Short and Optimal Duration of Dual Antiplatelet Therapy-3), which randomly compared 1-month dual antiplatelet therapy followed by aspirin monotherapy (aspirin group) with 1-month prasugrel monotherapy followed by clopidogrel monotherapy (clopidogrel group). This subgroup analysis compared aspirin with clopidogrel in patients with or without OAC by the 30-day landmark analysis. The coprimary end points were the cardiovascular (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke), and bleeding end points (Bleeding Academic Research Consortium 3 or 5). RESULTS: In the 30-day landmark analysis (N=5809), there were 788 patients (13.6%) with OAC at discharge. Regardless of OAC, the incidence rates beyond 30 days up to 1 year were similar between the aspirin and clopidogrel groups for cardiovascular end point (OAC: 3.7% versus 3.9%, hazard ratio, 0.92 [95% CI, 0.44–1.93]; no OAC: 3.7% versus 3.6%; hazard ratio, 1.03 [95% CI, 0.77–1.38]; P interaction=0.78) and for bleeding end point (OAC: 3.5% versus 4.2%, hazard ratio, 0.82 [95% CI, 0.39–1.73]; no OAC 1.5% versus 1.4%, hazard ratio, 1.07 [95% CI, 0.66–1.72]; P interaction=0.57). CONCLUSIONS: Aspirin compared with clopidogrel was associated with similar cardiovascular and bleeding outcomes beyond 30 days and up to 1 year after percutaneous coronary intervention regardless of OAC at discharge. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04609111.

BACKGROUND: The effects of the aspirin-free strategy on bleeding and cardiovascular events were unknown in patients with high bleeding risk (HBR), with or without acute coronary syndrome (ACS), undergoing percutaneous coronary intervention. METHODS: We conducted a subgroup analysis stratified by ACS among patients with HBR in the STOPDAPT-3 trial (Short and Optimal Duration of Dual Antiplatelet Therapy-3), which randomly compared no-aspirin (prasugrel monotherapy) with dual antiplatelet therapy (DAPT) in patients with ACS and HBR. RESULTS: There were 3258 patients with HBR, including 1803 ACS and 1455 non-ACS patients. The effects of no-aspirin compared with DAPT at 1 month after percutaneous coronary intervention were not significant for major bleeding regardless of ACS or non-ACS (7.3% versus 7.9%; hazard ratio [HR], 0.91 [95% CI, 0.65–1.28], and 3.1% versus 2.9%; HR, 1.06 [95% CI, 0.58–1.93]; P interaction=0.66). There was a numerically higher risk in the no-aspirin group relative to the DAPT group for a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke in patients with ACS, but not in patients with non-ACS (7.9% versus 5.8%; HR, 1.39 [95% CI, 0.97–1.99], and 2.4% versus 3.0%; HR, 0.78 [95% CI, 0.41–1.47]; P interaction=0.12). There was a significant treatment-by-subgroup interaction for myocardial infarction (1.6% versus 0.3%; HR, 4.57 [95% CI, 1.31–15.89], and 1.4% versus 1.8%; HR, 0.78 [95% CI, 0.34–1.77]; P interaction=0.02). CONCLUSIONS: The aspirin-free strategy compared with the DAPT strategy failed to reduce major bleeding in patients with HBR irrespective of ACS. There was a signal of the excess risk of the aspirin-free strategy relative to the DAPT strategy for cardiovascular events, myocardial infarction in particular, in patients with ACS, but not in patients with non-ACS. The aspirin-free strategy may be considered as a potential treatment option after percutaneous coronary intervention in patients with non-ACS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04609111.

Aims: There were no previous studies comparing aspirin vs. P2Y12 inhibitor monotherapy following short dual antiplatelet therapy (DAPT) after complex percutaneous coronary intervention (PCI). Methods and results: We conducted a pre-specified subgroup analysis based on complex PCI in the 1-year results of the STOPDAPT-3 (ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-3) trial, which randomly compared 1-month DAPT followed by aspirin monotherapy (aspirin group) with 1-month prasugrel monotherapy followed by clopidogrel monotherapy (clopidogrel group). The main analysis in the present study was the 30-day landmark analysis. The co-primary endpoints were cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) and major bleeding (Bleeding Academic Research Consortium 3 or 5). In the 30-day landmark analysis (N = 5833), there were 1415 patients (24.3%) who underwent complex PCI. There was a significant interaction between complex PCI and the effect of the aspirin group relative to the clopidogrel group for cardiovascular events (complex PCI: 3.3% vs. 5.2%, non-complex PCI: 4.3% vs. 3.6%, interaction P = 0.04) and net adverse clinical events (complex PCI: 4.8% vs. 7.2%, non-complex PCI: 5.3% vs. 4.4%, interaction P = 0.02), but not for bleeding events (complex PCI: 2.1% vs. 2.7%, non-complex PCI: 1.7% vs. 1.4%, interaction P = 0.35). Conclusions: There was a significant interaction between complex PCI and the effect of aspirin monotherapy relative to clopidogrel monotherapy beyond 1 month and up to 1 year for cardiovascular events due to numerically lower risk of aspirin monotherapy in patients with complex PCI, while the effect of aspirin monotherapy relative to clopidogrel monotherapy was not different for bleeding regardless of complex PCI. Clinical trial registration: ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3 [STOPDAPT-3]; NCT04609111.

Safety of aspirin-free strategy immediately after percutaneous coronary intervention (PCI) for cardiovascular events in patients with diabetes was unknown. We conducted the prespecified subgroup analysis on diabetes in the STOPDAPT-3 trial, which randomly compared prasugrel (3.75 mg/day) monotherapy (2984 patients) to dual antiplatelet therapy (DAPT) with prasugrel and aspirin (2982 patients) in patients with acute coronary syndrome or high bleeding risk. The co-primary endpoints were major bleeding events (Bleeding Academic Research Consortium 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month. Of 5966 study patients, there were 2715 patients (45.5%) with diabetes. Patients with diabetes more often had chronic coronary syndrome, heart failure or cardiogenic shock, and comorbidities than those without. Patients with diabetes compared to those without had higher incidences of major bleeding and cardiovascular events. Regardless of diabetes, the effect of no-aspirin relative to DAPT was not different for the co-primary bleeding (diabetes: 5.05% versus 5.47%; HR, 0.92; 95%CI, 0.66–1.28 and non-diabetes: 3.99% versus 4.07%; HR, 0.98; 95%CI, 0.69–1.38; P for interaction = 0.81) and cardiovascular (diabetes: 5.54% versus 5.15%; HR, 1.08; 95%CI, 0.78–1.49 and non-diabetes: 2.95% versus 2.47%; HR, 1.20; 95%CI, 0.79–1.82; P for interaction = 0.70) endpoints. The incidences of subacute definite or probable stent thrombosis and any coronary revascularization were higher in the no-aspirin group than in the DAPT group regardless of diabetes. The effects of an aspirin-free prasugrel monotherapy (3.75 mg/day) relative to DAPT for major bleeding and cardiovascular events were not different regardless of diabetes. Clinical trial registration: ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3 [STOPDAPT-3]; NCT04609111

Background and Aims: There was no previous trial comparing aspirin monotherapy with a P2Y12 inhibitor monotherapy following short dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents. Methods: In the STOPDAPT-3, patients with acute coronary syndrome or high bleeding risk (HBR) were randomly assigned to either 1-month dual antiplatelet therapy with aspirin and prasugrel followed by aspirin monotherapy (aspirin group) or 1-month prasugrel monotherapy followed by clopidogrel monotherapy (clopidogrel group). This secondary analysis compared aspirin monotherapy with clopidogrel monotherapy by the 30-day landmark analysis. The co-primary endpoints were the cardiovascular endpoint defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischaemic stroke and the bleeding endpoint defined as Bleeding Academic Research Consortium 3 or 5. Results: Of the 6002 assigned patients, 5833 patients (aspirin group: N = 2920 and clopidogrel group: N = 2913) were included in the 30-day landmark analysis. Median age was 73 (interquartile range 64–80) years, women 23.4%, acute coronary syndrome 74.6%, and high bleeding risk 54.1%. The assigned monotherapy was continued at 1 year in 87.5% and 87.2% in the aspirin and clopidogrel groups, respectively. The incidence rates beyond 30 days and up to 1 year were similar between the aspirin and clopidogrel groups for both cardiovascular endpoint [4.5 and 4.5 per 100 person-year, hazard ratio 1.00 (95% confidence interval .77–1.30), P = .97], and bleeding endpoint [2.0 and 1.9, hazard ratio 1.02 (95% confidence interval .69–1.52), P = .92]. Conclusions: Aspirin monotherapy compared with clopidogrel monotherapy was associated with similar cardiovascular and bleeding outcomes beyond 1 month and up to 1 year after percutaneous coronary intervention with drug-eluting stents (STOPDAPT-3 ClinicalTrials.gov number, NCT04609111).