Clinical Outcomes After Percutaneous Coronary Intervention in East Asian Patients　- 30-Month Results of the PENDULUM Registry.

BACKGROUND: The 12-month results of the PENDULUM registry showed that after implantation of second-generation drug-eluting stents (DES), high P2Y12reaction unit (HPR) were independently associated with ischemic but not bleeding events.Methods and Results: This study analyzed cumulative incidences of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding (Bleeding Academic Research Consortium type 3 and 5) at 30 months after index percutaneous coronary intervention (PCI) (primary endpoints). Of 6,422 patients undergoing PCI with DES, 5,796 completed the 30-month follow up. The continuation rate of dual antiplatelet therapy decreased to 59.3% at 12 months and 26.4% at 30 months. At 30 months, the cumulative incidence of MACCE increased linearly and reached 9.5% (95% confidence interval 8.8-10.2) and that of major bleeding had the inflection point at 12 months and was 4.4% (3.9-5.0). MACCE and bleeding events were higher in HPR patients (unadjusted P value). After covariate adjustment, P2Y12reactivity units measured immediately after index PCI was not an independent risk factor for MACCE or major bleeding at 30 months. CONCLUSIONS: MACCE consistently increased after 12 months post-PCI, whereas the increase in major bleeding events slowed down after 12 months in Japanese PCI patients in a real-world clinical setting. HPR patients had increased MACCE and bleeding complications, but HPR was not an independent risk factor of events at 30 months.

Early P2Y12 Inhibitor Single Antiplatelet Therapy for High-Bleeding Risk Patients After Stenting　- PENDULUM Mono 24-Month Analysis.

BACKGROUND: In PENDULUM mono, Japanese patients with high bleeding risk (HBR) received short-term dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) with prasugrel after percutaneous coronary intervention (PCI). One-year data from PENDULUM mono showed better outcomes with prasugrel monotherapy after short-term DAPT compared with matched patients in the PENDULUM registry with longer DAPT durations according to guidelines at that time. This study presents 2-year results.Methods and Results: We compared 24-month data from PENDULUM mono (n=1,107; de-escalation strategy group) and the PENDULUM registry (n=2,273; conventional strategy group); both were multicenter, non-interventional, prospective registry studies, using the inverse probability of treatment weighting (IPTW) method. In the PENDULUM mono group, the cumulative incidence of clinically relevant bleeding (CRB) at 24 months post-PCI (primary endpoint) was 6.8%, and that of major adverse cardiac and cerebrovascular events (MACCE) was 8.9%. After IPTW adjustment, the cumulative incidence of CRB was 5.8% and 7.2% in PENDULUM mono and the PENDULUM registry, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.57-1.04; P=0.086), and that of MACCE was 8.0% and 9.5%, respectively (HR 0.77; 95% CI 0.59-1.01; P=0.061). CONCLUSIONS: Japanese PCI patients with HBR prescribed prasugrel SAPT after short-term DAPT had a lower ischemic event risk than those prescribed long-term DAPT, and this was particularly relevant for ischemic events after 1 year.

Ischemic and Bleeding Events in PENDULUM Patients With High Bleeding Risk and High Platelet Reactivity.

BACKGROUND: The balance between thrombotic and bleeding risk is of great concern in high bleeding risk (HBR) patients. This study evaluated the relationship between perioperative antiplatelet reactivity and thrombotic and bleeding events in patients at HBR undergoing percutaneous coronary intervention (PCI).Methods and Results: In this post hoc analysis of the PENDULUM (Platelet rEactivity in patieNts with DrUg eLUting stent and balancing risk of bleeding and ischeMic event) registry, patients undergoing PCI were categorized as HBR or non-HBR, and stratified as having high platelet reactivity (HPR; P2Y12reaction unit [PRU] >208) or non-HPR (PRU ≤208). Cumulative incidences of cardiovascular and cerebrovascular events (Journal of the American College of Cardiology expert definitions) and bleeding events (Bleeding Academic Research Consortium criteria) were assessed 12 months after index PCI. The incidence of ischemic and bleeding events was ~3-fold higher in HBR vs. non-HBR patients. Thrombotic/ischemic events were significantly more common in the HPR subgroup in HBR patients (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.11-2.28; P=0.012), but there was no difference in non-HBR patients. After adjustment for covariates, HPR in HBR patients remained an independent factor for thrombotic and ischemic events (HR: 1.69; 95% CI: 1.13-2.54; P=0.011), but not for bleeding events (HR: 1.56; 95% CI: 0.78-3.11; P=0.210). CONCLUSIONS: Maintaining adequate PRU levels during PCI is an important factor in improving clinical outcomes, especially for HBR patients.

Relationship between platelet aggregation and stroke risk after percutaneous coronary intervention: a PENDULUM analysis.

In patients undergoing percutaneous coronary intervention (PCI) with a stent, high on-treatment platelet reactivity may be associated with an increased risk of stroke. This post hoc analysis of the PENDULUM registry compared the risk of post-PCI stroke according to on-treatment P2Y12 reaction unit (PRU) values. Patients aged ≥ 20 years who underwent PCI were stratified by baseline PRU (at 12 and 48 h post-PCI) as either high (HPR, > 208), optimal (OPR, > 85 to ≤ 208), or low on-treatment platelet reactivity (LPR, ≤ 85). The incidences of non-fatal ischemic and non-ischemic stroke through to 12 months post-PCI were recorded. Almost all enrolled patients (6102/6267 [97.4%]) had a risk factor for ischemic stroke, and most were receiving dual antiplatelet therapy. Of the 5906 patients with PRU data (HPR, n = 2227; OPR, n = 3002; LPR, n = 677), 47 had a non-fatal stroke post-PCI (cumulative incidence: 0.68%, ischemic; 0.18%, non-ischemic stroke). Patients with a non-fatal ischemic stroke event had statistically significantly higher post-PCI PRU values versus those without an event (P = 0.037). The incidence of non-fatal non-ischemic stroke was not related to PRU value. When the patients were stratified by PRU ≤ 153 versus > 153 at 12-48 h post-PCI, a significant difference was observed in the cumulative incidence of non-fatal stroke at 12 months (P = 0.044). We found that patients with ischemic stroke tended to have higher PRU values at 12-48 h after PCI versus those without ischemic stroke.Clinical trial registration: UMIN000020332.

Single Antiplatelet Therapy With Prasugrel vs. Dual Antiplatelet Therapy in Japanese Percutaneous Coronary Intervention Patients With High Bleeding Risk.

BACKGROUND: Outcomes with prasugrel single antiplatelet therapy (SAPT) vs. dual antiplatelet therapy (DAPT) in Japanese percutaneous coronary intervention (PCI) patients with high bleeding risk (HBR) are currently unknown.Methods and Results:Data from 1,173 SAPT and 2,535 DAPT patients from the PENDULUM mono and PENDULUM registry studies (respective median DAPT durations: 108 vs. 312 days) were compared. The adjusted cumulative incidence of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding from 1 to 12 months after PCI (primary endpoint) was 2.8% (95% confidence interval [CI], 1.9-4.2) and 4.1% (95% CI, 3.3-5.1), respectively (hazard ratio [HR], 0.69; 95% CI, 0.45-1.06; P=0.090). The adjusted cumulative incidences of BARC 2, 3, or 5 bleeding from 0 to 12 months after PCI (secondary endpoint) were 3.8% (95% CI, 2.7-5.3) and 5.6% (95% CI, 4.7-6.7), respectively (HR, 0.68; 95% CI, 0.47-0.98; P=0.039). There was no significant difference in major adverse cardiac and cerebrovascular events (MACCE) from 1 to 12 months after PCI (HR, 0.93; 95% CI, 0.63-1.37; P=0.696) and at 12 months after PCI (HR, 0.85; 95% CI, 0.61-1.19; P=0.348) between the groups. CONCLUSIONS: Prasugrel SAPT may reduce BARC 2, 3, or 5 bleeding, without increasing MACCE, in Japanese patients with HBR.

Evolution of patients with chronic thromboembolic pulmonary hypertension treated by balloon pulmonary angioplasty, according to their anticoagulant regimens.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) need anticoagulant therapy for life. Conventionally, vitamin K antagonists (VKAs) have been used and data about direct oral anticoagulants (DOACs) in CTEPH patients are lacking. Recently, balloon pulmonary angioplasty (BPA) has emerged as a treatment option for CTEPH. However, there are no reports examining the effects of DOACs and VKAs on the hemodynamics of patients after BPA. The aim of this study was to compare DOACs and VKAs regarding the hemodynamic changes in patients with CTEPH treated by BPA. Patients who were treated by BPA and underwent follow-up right heart catheterization 6 ± 1 months after the final BPA procedure were included in this study. The subjects were divided into two groups based on the anticoagulant administered, and hemodynamic changes (mean pulmonary artery pressure, mPAP; pulmonary vascular resistance, PVR; cardiac index, CI) were assessed. Of the 65 consecutive patients, 29 met the inclusion criteria (DOAC-group n = 14, VKA-group n = 15). Compared to pre-BPA, post-BPA hemodynamic parameters were improved in both groups. There was no significant difference between the two groups regarding pre-BPA, post-BPA, 6Mo-f/u and Δhemodynamic parameters (difference between 6Mo-f/u and post-BPA, ΔmPAP, - 0.7 ± 3.3 vs. - 2.7 ± 5.4 mmHg, p = 0.24; ΔPVR, - 41.9 ± 80.9 vs. - 16.4 ± 74.1 dyne s/cm5, p = 0.38; ΔCI, - 0.06 ± 0.35 vs. - 0.10 ± 0.35 L/min/m2, p = 0.80; DOAC-group vs. VKA-group, respectively). Hemodynamic improvement by BPA was maintained over 6 months of follow-up irrespective of the type of anticoagulant administered in CTEPH patients.

Monotherapy With Prasugrel After Dual-Antiplatelet Therapy for Japanese Percutaneous Coronary Intervention Patients With High Bleeding Risk　- A Prospective Cohort Study (PENDULUM mono Study).

BACKGROUND: The risks of bleeding and cardiovascular events in high bleeding risk (HBR) Japanese patients undergoing percutaneous coronary intervention (PCI) while receiving single-antiplatelet therapy (SAPT) remains unknown. We aimed to evaluate the frequency of bleeding and cardiovascular events associated with prasugrel monotherapy after short-term dual-antiplatelet therapy (DAPT) in Japanese HBR patients after PCI.Methods and Results:The PENDULUM mono study was a multicenter, non-interventional, prospective registry (n=1,173). The primary endpoint was the cumulative incidence of clinically relevant bleeding (CRB; Bleeding Academic Research Consortium types 2, 3, and 5) from 1 to 12 months after PCI. Secondary endpoints included major adverse cardiac and cerebrovascular events (MACCE). The proportion of patients who received prasugrel monotherapy at 12 months after PCI was 79.7%, and no cases of stent thrombosis were observed among these patients. The cumulative incidence of CRB was 3.2% from 1 to 12 months after PCI; that of MACCE was 3.8%. Severe anemia, chronic kidney disease, oral anticoagulant use at discharge, and heart failure were significantly associated with CRB. CONCLUSIONS: Among HBR patients undergoing PCI who were not suitable for concomitant aspirin and were scheduled for prasugrel monotherapy, most patients were on prasugrel monotherapy after DAPT. Cumulative incidences of CRB and MACCE after periprocedural period were 3.2% and 3.8%, respectively, and no cases of stent thrombosis were reported. SAPT might be a suitable alternative to DAPT.

The predictors of complications in balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension.

OBJECTIVES: The aims of this study were to (1) evaluate risk factors of complications of balloon pulmonary angioplasty (BPA) and (2) assess the mechanism of the complications. BACKGROUND: BPA represents a promising treatment option in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, the complication ratio differs across reports, and the causes remain controversial. METHODS: All complications found by angiography and non-contrasted computerized tomography (CT) immediately after BPA were recorded. New emergences of a ground-glass pattern or consolidation in CT after BPA that were not recognized on CT images before BPA were counted as pulmonary bleeding. Lesion morphologies were classified into four types (web, ring, abrupt narrowing and occlusive lesions) according to selective pulmonary angiography. RESULTS: Thirty patients consented to analysis of the BPA-related images, and 879 lesions (112 sessions) were evaluated. One hundred and twenty-two (99.2%) of 123 complications were confirmed to be associated with BPA procedures at the local area. In the multivariate analysis, occlusive lesions were the sole independent predictor of procedure-related complications (adjusted odds ratio 5.83, 95%CI [1.94-17.47], p = 0.002). Hemodynamic parameters were not predictors of complications. CT images after BPA presented the predictive value for the occurrence of hemoptysis. CONCLUSIONS: Almost all complications were attributed to operators' procedures. Lesion morphology was the sole predictor of BPA-related complications, while hemodynamic parameters were not associated with the frequency of complications. CT scan images after BPA were useful to identify bleeding complications and to predict hemoptysis.

Clinical Outcomes of Drug-Coated Balloons in Coronary Artery Disease Unsuitable for Drug-Eluting Stent Implantation.

BACKGROUND: The aim of this study was to investigate whether drug-coated balloon (DCB) treatment is effective for de novo coronary lesions that are unsuitable for drug-eluting stent (DES) implantation.Methods and Results:This retrospective study included 118 de novo lesions that were not suitable for DES implantation. Of the lesions, 40% was treated because of very small vessel disease. Patients with planned non-cardiac surgery and at high bleeding risk were 3% and 19%, respectively, and lesions that easily develop stent fracture comprised 26%. Clinically driven target lesion revascularization (TLR) was the primary endpoint. The rate of suboptimal lesion preparation before DCB treatment was set as the secondary endpoint. Optimal lesion preparation was defined as acquisition of Thrombolysis in Myocardial Infarction flow grade 3, minor coronary dissection, and residual stenosis ≤30%. The rate of suboptimal lesion preparation was 2.5% and 3 patients needed bail-out stenting. Accordingly, 115 patients were treated with a DCB. Clinically driven TLR had occurred in 8 patients (7.0%) at the 8-month follow-up. The presence of chronic total occlusion was identified as an independent predictor for TLR (odds 11.57; 95% confidence interval, 1.38-135.54; P=0.02). CONCLUSIONS: For lesions that are unsuitable for stent implantation, stent-less intervention using a DCB should be considered initially. The present study also highlighted that lesion preparation is key to a successful DCB strategy.

Vascular response to biolimus A-9 eluting stent in patients with shorter and prolonged dual antiplatelet therapy: optical coherence tomography sub-study of the NIPPON trial.

Dual antiplatelet therapy (DAPT) with thienopyridine and aspirin is the standard care for the prevention of stent thrombosis. However, the optimal duration and effect of the duration of DAPT on intra-stent thrombus (IS-Th) formation are unknown. The NIPPON study (Nobori Dual Antiplatelet Therapy as Appropriate Duration) was an open label, randomized multicenter, assessor-blinded, trial designed to demonstrate the non-inferiority of shorter (6-month) DAPT to prolonged (18-month) DAPT, after biolimus A9 eluting stent implantation in 3773 patients at 130 sites in Japan. Among them, 101 patients were randomly allocated for an optical coherence tomography (OCT) sub-study to assess the difference of local IS-Th formation between the two groups. In addition to standard OCT parameters, the number of IS-Th formed was counted in each target stent at 8 months. Baseline patient characteristics were not different between the 6- and 18-month groups. IS-Th was detected in 9.8% of the cases and the presence of IS-Th was not significantly different between the two groups (10.9% in 6-month vs. 9.1% in 12-month, P = 0.76). Furthermore, the number of IS-Th formed was not significantly different between the two groups. This OCT sub-study was in line with the main NIPPON study which demonstrated the non-inferiority of 6-month DAPT to 18-month DAPT. Shorter DAPT duration did not promote progressive IS-Th formation at the mid-term time point.

Congenital Absence of Left Atrial Appendage Diagnosed by Multimodality Imaging.

A 70-years-old male with a history of hypertension and drug resistant paroxysmal atrial fibrillation (AF) presented to our hospital for catheter ablation to his symptomatic AF. He had no prior surgical or percutaneous procedure to close or exclude the left atrial appendage (LAA). A transesophageal echocardiography (TEE) was performed to rule out intra-cardiac thrombus prior to the ablation procedure. Although the TEE imaging at multiple acquisition angles was obtained, the LAA could not be visualized and an absence of the LAA was suspected. An absence of the LAA was confirmed using cardiac computed tomography (CT), which included 3D reconstruction. Additionally, the LAA was not visualized with left atrium (LA) angiography. During the ablation procedure, 3D voltage mapping in LA was created and no low voltage area or abnormal potential was recorded around the usual root location of the LAA. Successful electrical pulmonary vein isolation was achieved with no major complications. After six months of follow-up, the patient remained in sinus rhythm without any antiarrhythmic drugs and showed no related clinical symptoms. He stopped his anticoagulation therapy due to lack of evidence of AF recurrence and an absence of LAA. Multimodality imaging allowed us to identify the congenital absence of LAA.

A pan-coronary artery angiographic study of the association between diabetes mellitus and progression or regression of coronary atherosclerosis.

The frequency and pattern of progression or regression of coronary atherosclerosis in contemporary patients with diabetes remain unknown. This study included 605 patients with coronary artery disease (CAD). Two coronary angiographic examinations at baseline and after 2 years were performed. The analysis focused on non-stented segments with diameter stenosis ≥25 %. Atherosclerosis progression (or regression) was defined as a decrease (or increase) in the mean minimal lumen diameter (MLD) in the 2-year angiogram compared to mean MLD in the baseline angiogram of >0.2 mm. Statins were prescribed in 576 patients (95.2 %). The primary outcome was atherosclerosis progression or regression in the 2-year angiogram. One hundred sixty-nine patients (28 %) had diabetes. Diabetic patients had greater reduction of mean MLD in the 24 angiogram compared to baseline angiogram than nondiabetic patients (0.11 ± 0.18 vs. -0.08 ± 0.15 mm, P < 0.001). Atherosclerosis progression was observed in 37 patients with diabetes and 16 nondiabetic patients (21.9 vs. 3.7 %; P < 0.001). Atherosclerosis regression was observed in two diabetic patients and 78 nondiabetic patients (1.2 vs. 17.9 %; P < 0.001). A progression pattern across all coronary segments was observed in 70 patients (41.4 %) with diabetes and 60 patients (13.8 %) without diabetes (P < 0.001). Diabetic patients with a low-density lipoprotein cholesterol ≥70 mg/dl showed more atherosclerosis progression than diabetic patients with LDL cholesterol <70 mg/dl (delta-MLD: 0.12 ± 0.19 vs. 0.08 ± 0.16 mm; P = 0.04). In conclusion, in contemporary patients with CAD treated with moderate-intensity statin therapy, diabetes is associated with the increased risk of progression and decreased probability of regression of coronary atherosclerosis.

Association of progression or regression of coronary artery atherosclerosis with long-term prognosis.

BACKGROUND: The association between coronary atherosclerosis progression or regression and long-term prognosis remains poorly defined. We assessed the association of atherosclerosis progression or regression with long-term mortality and factors that promote angiographic progression or regression of coronary atherosclerosis in patients with angiographically proven coronary artery disease. METHODS: The study included 605 patients with coronary artery disease who underwent coronary angiography at baseline and at 2 years later. Pan-coronary artery tree quantitative coronary angiography was performed. Of 6259 coronary segments (10.3 lesions per patient) analyzed, 1790 non-stented segments with ≥25% diameter stenosis at baseline were included. Atherosclerosis progression or regression was defined as a decrease or increase in the mean minimal lumen diameter (MLD) of the non-stented segments of ≥0.2 mm in the 2-year angiography compared to baseline angiography. The primary outcome was all-cause mortality. RESULTS: Based on the change in mean MLD between baseline and 2-year angiography, patients were divided into 3 groups: the group with progression of atherosclerosis (n=53; 8.8%), the group with no progression or regression of atherosclerosis (n=472; 78.0%) and the group with regression of atherosclerosis (n=80; 13.2%). There were 126 deaths over 8-year follow-up: 17 deaths among patients with progression, 103 deaths among patients with no progression/regression and 6 deaths among patients with regression (Kaplan-Meier estimates of mortality, 37.5%, 25.2% and 8.9%, respectively; adjusted hazard ratio=1.16, 95% confidence interval 1.05 to 1.29, P=.004 for 0.1 mm reduction in mean MLD). CONCLUSIONS: Progression or regression of coronary atherosclerosis in non-treated coronary segments was significantly associated with 8-year mortality.