The residual risk of inflammation and remnant cholesterol in acute coronary syndrome patients on statin treatment undergoing percutaneous coronary intervention.

BACKGROUND: Residual risk assessment for acute coronary syndrome (ACS) patients after sufficient medical management remains challenging. The usefulness of measuring high-sensitivity C-reactive protein (hsCRP) and remnant cholesterol (RC) in assessing the level of residual inflammation risk (RIR) and residual cholesterol risk (RCR) for risk stratification in these patients needs to be evaluated. METHODS: Patients admitted for ACS on statin treatment who underwent percutaneous coronary intervention (PCI) between March 2016 and March 2019 were enrolled in the analysis. The included patients were stratified based on the levels of hsCRP and RC during hospitalization. The primary outcome was ischemic events at 12 months, defined as a composite of cardiac death, myocardial infarction, or stroke. The secondary outcomes included 12-month all-cause death and cardiac death. RESULTS: Among the 5778 patients, the median hsCRP concentration was 2.60 mg/L and the median RC concentration was 24.98 mg/dL. The RIR was significantly associated with ischemic events (highest hsCRP tertile vs. lowest hsCRP tertile, adjusted hazard ratio [aHR]: 1.52, 95% confidence interval [CI]: 1.01-2.30, P = 0.046), cardiac death (aHR: 1.77, 95% CI:1.02-3.07, P = 0.0418) and all-cause death (aHR: 2.00, 95% CI: 1.24-3.24, P = 0.0048). The RCR was also significantly associated with these outcomes, with corresponding values for the highest tertile of RC were 1.81 (1.21-2.73, P = 0.0043), 2.76 (1.57-4.86, P = 0.0004), and 1.72 (1.09-2.73, P = 0.0208), respectively. The risks of ischemic events (aHR: 2.80, 95% CI: 1.75-4.49, P < 0.0001), cardiac death (aHR: 4.10, 95% CI: 2.18-7.70, P < 0.0001), and all-cause death (aHR: 3.00, 95% CI, 1.73-5.19, P < 0.0001) were significantly greater in patients with both RIR and RCR (highest hsCRP and RC tertile) than in patients with neither RIR nor RCR (lowest hsCRP and RC tertile). Notably, the RIR and RCR was associated with an increased risk of ischemic events especially in patients with adequate low-density lipoprotein cholesterol (LDL-C) control (LDL-C < 70 mg/dl) (Pinteraction=0.04). Furthermore, the RIR and RCR provide more accurate evaluations of risk in addition to the GRACE score in these patients [areas under the curve (AUC) for ischemic events: 0.64 vs. 0.66, P = 0.003]. CONCLUSION: Among ACS patients receiving contemporary statin treatment who underwent PCI, high risks of both residual inflammation and cholesterol, as assessed by hsCRP and RC, were strongly associated with increased risks of ischemic events, cardiac death, and all-cause death.

Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia.

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. METHODS AND RESULTS: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. CONCLUSIONS: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

Ticagrelor vs clopidogrel when coadministered with bivalirudin in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Background: The optimal perioperative antithrombotic strategy for patients with acute coronary syndrome (ACS) during percutaneous coronary intervention (PCI) remains controversial. Objectives: To determine the safety and effectiveness of bivalirudin plus ticagrelor vs bivalirudin plus clopidogrel in patients with ACS undergoing PCI in the real world. Methods: Between March 2016 and March 2019, 7234 patients with ACS who had undergone PCI, received bivalirudin periprocedurally, and were prescribed ticagrelor or clopidogrel were enrolled in a single-center, all-comer, modern, retrospective cohort study. Incidence rates of 12-month ischemia (cardiac death, myocardial infarction, or stroke), all-cause death, Bleeding Academic Research Consortium (BARC) type 2,3,5 bleeding, and BARC type 3,5 bleeding were compared between different groups. Results: In total, 4960 patients received bivalirudin plus clopidogrel and 2274 patients received bivalirudin plus ticagrelor. Compared with bivalirudin plus clopidogrel, bivalirudin plus ticagrelor was associated with lower ischemic events (1.74% vs 2.84%; relative risk, 0.61; 95% CI, 0.41-0.91; P = .02) and stroke (0.05% vs 1.01%, P < .001) within 12 months after PCI without excessive risk of bleeding (BARC type 2,3,5 bleeding: 4.49% vs 3.76%, P = .22; BARC type 3,5 bleeding: 2.84% vs 2.02%, P = .08). The beneficial effects of bivalirudin plus ticagrelor were consistent among subgroups. Conclusion: As an initial treatment strategy, bivalirudin plus ticagrelor could reduce the 12-month risk of ischemic events compared with bivalirudin plus clopidogrel significantly without increasing the bleeding risk in ACS patients undergoing PCI.

Extended Clopidogrel Monotherapy vs DAPT in Patients With Acute Coronary Syndromes at High Ischemic and Bleeding Risk: The OPT-BIRISK Randomized Clinical Trial.

Importance: Purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a certain period of dual antiplatelet therapy (DAPT) may be an attractive option of maintenance antiplatelet treatment for patients undergoing percutaneous coronary intervention (PCI) who are at both high bleeding and ischemic risk (birisk). Objective: To determine if extended P2Y12 inhibitor monotherapy with clopidogrel is superior to ongoing DAPT with aspirin and clopidogrel after 9 to 12 months of DAPT after PCI in birisk patients with acute coronary syndromes (ACS). Design, Setting, and Participants: This was a multicenter, double-blind, placebo-controlled, randomized clinical trial including birisk patients with ACS who had completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months at 101 China centers between February 2018 and December 2020. Study data were analyzed from April 2023 to May 2023. Interventions: Patients were randomized either to clopidogrel plus placebo or clopidogrel plus aspirin for an additional 9 months. Main Outcomes and Measures: The primary end point was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding 9 months after randomization. The key secondary end point was major adverse cardiac and cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization). The primary end point was tested for superiority, and the MACCE end point was tested for sequential noninferiority and superiority. Results: A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 4575 male [59.0%]) were included in this study. The primary end point of BARC types 2, 3, or 5 bleeding occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (hazard ratio [HR], 0.75; 95% CI, 0.57-0.97; difference, -0.8%; 95% CI, -1.6% to -0.1%; P = .03). The incidence of MACCE was 2.6% (101 of 3873 patients) in the clopidogrel plus placebo group and 3.5% (136 of 3885 patients) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, -0.9%; 95% CI, -1.7% to -0.1%; P < .001 for noninferiority; P = .02 for superiority). Conclusions and Relevance: Among birisk patients with ACS who completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months before randomization, an extended 9-month clopidogrel monotherapy regimen was superior to continuing DAPT with clopidogrel in reducing clinically relevant bleeding without increasing ischemic events. Trial Registration: ClinicalTrials.gov Identifier: NCT03431142.

Net clinical benefit of clopidogrel versus ticagrelor in elderly patients carrying CYP2C19 loss-of-function variants with acute coronary syndrome after percutaneous coronary intervention.

BACKGROUND AND AIMS: Elderly patients with acute coronary syndrome (ACS) tend to choose clopidogrel over potent P2Y12 receptor inhibitor such as ticagrelor after percutaneous coronary intervention (PCI) in China considering higher risks of bleeding. CYP2C19 genotype is regarded as a major factor influencing the efficacy of clopidogrel. The present study aims to investigate the efficacy and safety of ticagrelor relative to clopidogrel in elderly ACS patients after PCI in China with reduced CYP2C19 metabolism. METHODS: Between January 2016 and March 2019, 2751 ACS patients over 65 years old with CYP2C19 loss-of-function (LOF) variants after PCI were enrolled. All patients were treated with aspirin and P2Y12 receptor inhibitor, among whom 2056 received clopidogrel and 695 received ticagrelor. Net adverse clinical events (NACE), a composite of cardiac death, myocardial infarction (MI), ischemic stroke, target vessel revascularization and clinically relevant bleeding including Bleeding Academic Research Consortium (BARC) types 2, 3, 5 bleeding, were compared between the two groups at 12 months after PCI. Propensity score matching (PSM) was conducted to balance the baseline characteristics between the two groups. RESULTS: Before and after PSM, NACE was significantly increased in ticagrelor group compared with clopidogrel group at 12 months post PCI (Before PSM, 15.18% vs. 25.61% p<0.001; After PSM, 11.66% vs. 26.01% p<0.001). MACE was comparable between the two groups (Before PSM, 5.45% vs. 5.32% p>0.999; After PSM, 3.59% vs. 5.38% p=0.146). BARC types 2, 3, 5 bleeding events were significantly increased in patients treated with ticagrelor relative to clopidogrel (Before PSM, 10.31% vs. 21.01% p<0.001; After PSM, 8.22% vs. 21.38% p<0.001), which was mainly attributed to a higher incidence of BARC type 2 bleeding events in ticagrelor group (Before PSM, 8.12% vs. 18.56% p<0.001; After PSM, 6.43% vs. 18.83% p<0.001). CONCLUSIONS: In the present real-world study, selection of ticagrelor over clopidogrel showed a significant increase in NACE with a higher incidence of bleeding and similar ischemic events in elderly ACS patients carrying CYP2C19 LOF variants after PCI.

Progression of Gastrointestinal Injury During Antiplatelet Therapy After Percutaneous Coronary Intervention: A Secondary Analysis of the OPT-PEACE Randomized Clinical Trial.

Importance: Gastrointestinal injury progression induced by antiplatelet therapy in patients after percutaneous coronary intervention (PCI) has not been well studied. Objective: To assess the association of aspirin, clopidogrel, and their combination with gastrointestinal injury progression among patients without high bleeding risk after PCI. Design, Setting, and Participants: This secondary analysis assessed data from the Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by ANKON Magnetically Controlled Capsule Endoscopy (OPT-PEACE) double-masked, placebo-controlled, multicenter randomized clinical trial. The OPT-PEACE trial was conducted at 28 centers in China, and recruitment took place from July 13, 2017, to July 13, 2019. The trial included patients with stable coronary artery disease or acute coronary syndromes without ST-segment elevation after PCI. Statistical analysis was conducted from September 13, 2022, to January 23, 2023. Interventions: Patients underwent magnetically controlled capsule endoscopy (MCE) at baseline and after 6 months of dual antiplatelet therapy (DAPT) with aspirin (100 mg/d) plus clopidogrel (75 mg/d). Those with no evidence of gastrointestinal ulcers or bleeding (ie, the intention-to-treat [ITT] cohort) were randomized (1:1:1) to aspirin (100 mg/d) plus matching placebo (aspirin alone), clopidogrel (75 mg/d) plus matching placebo (clopidogrel alone), or DAPT for an additional 6 months. A third MCE was performed 12 months after PCI. Main Outcomes and Measures: The primary outcome was the rate of gastric injury progression as assessed with the results of the 3 MCEs (at baseline, 6 months, and 12 months) in the modified intention-to-treat (mITT) population. The key secondary outcome was the rate of small-intestinal injury progression. Gastric or small-intestinal injury progression was defined as a quantitative increase in erosions or ulcers between the second and third MCEs (at 6 and 12 months, respectively). Results: This study included the 394 patients in the mITT cohort. Their mean (SD) age was 56.9 (8.7) years, and most were men (296 [75.1%]). A total of 132 patients were randomized to aspirin alone, 132 to clopidogrel alone, and 130 to DAPT. Gastric injury progression occurred in 49 aspirin users (37.1%), 64 clopidogrel users (48.5%), and 69 DAPT users (53.1%) (P = .02), reflecting a lower rate of gastric injury progression among aspirin users vs DAPT users (risk ratio [RR], 0.70 [95% CI, 0.49-0.99]; P = .009). No significant difference was observed between clopidogrel alone and DAPT (48.5% vs 53.1%; P = .46) or between aspirin alone and clopidogrel alone (37.1% vs 48.5%; P = .06). A total of 51 aspirin users (38.6%), 65 clopidogrel users (49.2%), and 71 DAPT users (54.6%) (P = .03) developed progressive small-intestinal injury, reflecting a lower rate of small-intestinal injury among aspirin users vs DAPT users (RR, 0.71 [95% CI, 0.50-0.99]; P = .01). No difference was observed between patients treated with clopidogrel vs DAPT (49.2% vs 54.6%; P = .38) or with aspirin vs clopidogrel (38.6% vs 49.2%; P = .08). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, ongoing use of aspirin, clopidogrel, or their combination between 6 and 12 months after PCI was associated with progressive gastric and small-intestinal injury in a substantial proportion of patients, more so with DAPT than with monotherapy. Clopidogrel was at least as likely as aspirin to induce gastrointestinal injury progression. Future research is warranted to determine what impact the findings from MCEs would have on decision-making of antiplatelet therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT03198741.

Effect of dual antiplatelet therapy prolongation in acute coronary syndrome patients with both high ischemic and bleeding risk: insight from the OPT-CAD study.

Background: In current clinical practice, controversy remains regarding the clinical benefits of prolonged dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) patients facing high risks of both ischemia and bleeding ("bi-risk") following percutaneous coronary intervention (PCI). This study aimed to investigate the feasibility of identifying a group of bi-risk ACS patients after PCI using the OPT-BIRISK criteria, emphasizing extended DAPT treatment safety and efficacy beyond 12 months in these bi-risk ACS after PCI in real-world conditions. Methods: This analysis compared extended DAPT and single antiplatelet therapy (SAPT) at 12-24 months in ACS patients undergoing PCI complicated with both ischemic and bleeding risk as defined by OPT-BIRISK criteria without premature DAPT discontinuation before 9 months or major clinical adverse events within 12 months. This was a post hoc analysis of the Optimal antiPlatelet Antiplatelet Therapy for Chinese Patients with Coronary Artery Disease (OPT-CAD) study. The main research outcome was the incidence of ischemic events within 12-24 months, which was determined as a composite of stroke, myocardial infarction, and cardiac death events. Through propensity score matching (PSM), groups were balanced. For the external validation of the OPT-BIRISK criteria to identify a bi-risk ACS patient, ischemic events, BARC 2, 3, 5 bleeding events, and BARC 3, 5 bleeding events at 5 years were analyzed. Results: The total number of ACS patients analyzed in this analysis was 7,049, of whom 4,146 (58.8%) were bi-risk patients and 2,903 (41.2%) were not. The frequency of ischemic events was significantly different between the two groups at 5 years (11.70% vs. 5.55%, P < 0.001), and the incidence of BARC 2,3,5 bleeding was significantly higher in the bi-risk group (6.90% vs. 4.03%, P < 0.001) than in the non-bi-risk group. Among the bi-risk patients without any clinical adverse events within 12 months that underwent extended DAPT treatment (n = 2,374, 75.7%) exhibited a lower risk of stroke at 12-24 months (1.10% vs. 2.10%, P = 0.036) relative to those that underwent SAPT (n = 763, 24.3%), while bleeding risk did not differ significantly between these groups. PSM cohort analysis results were consistent with those of overall group analyses. Conclusion: In conclusion, the findings showed that using the OPT-BIRISK criteria could help physicians identify ACS patients at a high risk of developing recurrent ischemia and bleeding episodes after PCI. Compared to antiplatelet monotherapy, a strategy of extended DAPT may offer potential benefits in lowering the risk of stroke without carrying a disproportionately high risk of serious bleeding problems among these patients who were event-free after a year of DAPT.

Contemporary Use of Ticagrelor vs Clopidogrel in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: A GRACE Risk Score Stratification-Based Analysis in a Large-Scale, Real-World Study From China.

OBJECTIVE: To evaluate potential gains in outcomes from ticagrelor-based strategy according to risk stratification by Global Registry of Acute Coronary Events (GRACE) score. METHODS: A total of 19,704 patients discharged alive post-acute coronary syndrome who underwent percutaneous coronary intervention and received ticagrelor or clopidogrel between March 2016 and March 2019 were included in the study. The primary endpoint was ischemic events at 12 months, composed of cardiac death, myocardial infarction, and/or stroke. Secondary outcomes included all-cause mortality and Bleeding Academic Research Consortium type 2 to 5 and 3 to 5 bleeding. RESULTS: The ticagrelor group comprised 6432 (32.6%) patients and the clopidogrel group comprised 13,272 (67.4%) patients. During the follow-up period, there was a significant reduction in the incidence of ischemic events in patients treated using ticagrelor who had excessive risk of bleeding. According to the GRACE score, among low-risk patients, ticagrelor use compared with clopidogrel was not associated with decreased ischemic events (HR, 0.82; 95% CI, 0.57 to 1.17; P=.27) with excessive risk of Bleeding Academic Research Consortium type 3 to 5 bleeding (HR, 1.59; 95% CI, 1.16 to 2.17; P=.004). The risk of ischemic events (HR, 0.60; 95% CI, 0.41 to 0.89; P=.01) were lower in the intermediate- to high-risk patients treated with ticagrelor without significant difference in BARC type 3 to 5 bleeding risk (HR, 1.11; 95% CI, 0.75 to 1.65; P=.61). CONCLUSION: There was still a gap between guideline-indicated therapy and the clinical practice in a sizable subset of patients with acute coronary syndrome who underwent percutaneous coronary intervention. The GRACE risk score could identify patients who would derive benefit from the ticagrelor-based antiplatelet strategy.

Rivaroxaban in patients with abdominal aortic aneurysm and high-sensitivity C-reactive protein elevation (BANBOO): study protocol for a randomized, controlled trial.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a fatal disease due to the tendency to rupture. The drug treatment for small AAA without surgical indications has been controversial. Previous studies showed that high-sensitivity C-reactive protein (hs-CRP) had become a potential biomarker of the disease, and the anti-inflammatory effect of rivaroxaban for AAA had been well established. Thus, we hypothesized that rivaroxaban could control the progression of AAA in patients with hs-CRP elevation. METHODS: The study is a prospective, open-label, randomized, controlled clinical trial. Sixty subjects are recruited from the General Hospital of Northern Theatre Command of China. Subjects are randomly assigned (1:1) to the intervention arm (rivaroxaban) or control arm (aspirin). The primary efficacy outcome is the level of serum hs-CRP at 6 months. The secondary outcomes include imaging examination (the maximal diameter of AAA, the maximal thickness of mural thrombus, and the length of aneurysm), major adverse cardiovascular and cerebrovascular events (MACCE, including AAA transformation, non-fatal myocardial infarction, acute congestive heart failure, stent thrombosis, ischemia-driven target vessel revascularization, vascular amputation, stroke, cardiovascular death, and all-cause death), and other laboratory tests (troponin T, interleukin 6, D-dimer, and coagulation function). DISCUSSION: The BANBOO trial tested the effect of rivaroxaban on the progression of AAA in patients with elevated Hs-CRP for the first time. TRIAL REGISTRATION: ChiCTR2100051990, ClinicalTrials.gov, registered on 12 October 2021.

N-terminal pro-B-type natriuretic peptide improves the predictive value of CHA2 DS2 -VASc risk score for long-term cardiovascular events in acute coronary syndrome patients with atrial fibrillation.

BACKGROUND: It is important to identify patients with co-morbid acute coronary syndrome (ACS) and atrial fibrillation (AF) at high risk and adopt proper management strategies to improve their prognosis. HYPOTHESIS: The addition of N-terminal pro-B-type natriuretic peptide (NT-proBNP) could improve predictive value for long-term cardiovascular events beyond the CHA2 DS2 -VASc score in patients with co-morbid ACS and AF. METHODS: A total of 1223 patients with baseline NT-proBNP between January 2016 and December 2019 were included in the study. The primary endpoint was all-cause death at 12 months. The secondary outcomes included 12-month cardiac death and major adverse cardiovascular and cerebrovascular event (MACCE), defined as a composite of all-cause death, myocardial infarction, or stroke. RESULTS: A higher serum of NT-proBNP levels was strongly associated with increased risks of all-cause death (adjusted hazard ratio [HR]: 1.05, 95% confidence interval [CI], 1.03-1.07), cardiac death (adjusted HR: 1.05, 95% CI, 1.03-1.07), and MACCE (adjusted HR: 1.04, 95% CI, 1.02-1.06). The prognostic accuracy of the CHA2 DS2 -VASc score was improved when combined with NT-proBNP to yield a 9%, 11%, and 7% increment for the discrimination of long-term risk for all-cause mortality (area under curve [AUC]: from 0.64 to 0.73), cardiac death (AUC: from 0.65 to 0.76), and MACCE (AUC: from 0.62 to 0.69), respectively. CONCLUSIONS: In patients with ACS and AF, NT-proBNP is a potential biomarker to enhance risk discrimination for all-cause death, cardiac death, and MACCE in combination with the CHA2 DS2 -VASc score.

Safety and Efficacy of Ticagrelor versus Clopidogrel in East Asian Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention Treated with Dual Antiplatelet Therapy: A Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The treatment strategy for dual antiplatelet therapy (DAPT) with ticagrelor has been controversial in East Asian patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Our meta-analysis aimed to demonstrate whether intensified antithrombotic regimens with ticagrelor plus aspirin have more beneficial effects and fewer adverse events compared to those of clopidogrel plus aspirin in East Asian patients with ACS undergoing PCI. METHODS: We searched PubMed, Embase, Web of Science, ScienceDirect, Clinical Trials, Cochrane Library, and Chinese Clinical Trial Registry for randomized controlled trials (RCTs) comparing the efficacy of DAPT with ticagrelor or clopidogrel plus aspirin for secondary prevention of ACS in East Asian patients undergoing PCI. Risk ratios (RRs) and 95% confidence intervals (CIs) were used as the metrics of choice for assessing treatment effects. The primary endpoint was bleeding events, and the secondary endpoints were major adverse cardiovascular and cerebrovascular events (MACCEs, including cardiovascular death, nonfatal myocardial infarction [MI], and stroke), all-cause death, and definite/probable/possible stent thrombosis. The I2 index was used to assess heterogeneity. RESULTS: Six RCTs involving a total of 2,725 patients met the inclusion criteria. The incidence of all bleeding events with ticagrelor was higher than that with clopidogrel (RR, 1.65; 95% CI, 1.31-2.07), but the incidence of MACCE was not significantly different between the two groups (RR, 1.08; 95% CI, 0.54-2.16). All-cause death (RR, 1.10; 95% CI, 0.67-1.79), cardiovascular death (RR, 1.42; 95% CI, 0.68-2.98), nonfatal MI (RR, 0.92; 95% CI, 0.48-1.78), stroke (RR, 1.00; 95% CI, 0.40-2.50), and stent thrombosis (RR, 0.76; 95% CI, 0.19-2.98) were not statistically different between the two groups. CONCLUSION: Ticagrelor increased the risk of bleeding and did not increase treatment efficacy compared to that of clopidogrel in the East Asian population who have ACS treated with PCI.

Corrigendum: Untargeted metabolomics identified kynurenine as a predictive prognostic biomarker in acute myocardial infarction.

[This corrects the article DOI: 10.3389/fimmu.2022.950441.].

Association of systemic immune inflammatory index with all-cause and cause-specific mortality in hypertensive individuals: Results from NHANES.

Background: The relationship between the systemic immune inflammatory index (SII) and the prognosis of hypertensive patients is unclear. This study aims to explore the association of SII with all-cause and cause-specific mortality in patients with hypertension. Methods: This study included 8524 adults with hypertension from the National Health and Nutritional Examination Surveys (NHANES) 2011-2018, and followed for survival through December 31, 2019. Cox proportional hazards models were used to investigate the associations between SII and mortality from all causes, cardiovascular disease (CVD), and cancer. Restricted cubic spline, piecewise linear regression, subgroup and sensitivity analyses were also used. Results: During a median follow-up of 4.58 years, 872 all-cause deaths occurred. After adjusting for covariates, higher SII was significantly associated with an elevated risk of CVD mortality. There was a 102% increased risk of CVD mortality per one-unit increment in natural log-transformed SII (lnSII) (P < 0.001). Consistent results were also observed when SII was examined as categorical variable (quartiles). The associations of SII with all-cause and cancer mortality were detected as U-shaped with threshold values of 5.97 and 6.18 for lnSII respectively. Below thresholds, higher SII was significantly associated with lower all-cause mortality (HR=0.79, 95%CI=0.64-0.97) and cancer mortality (HR=0.73, 95%CI=0.53-1.00). Above thresholds, SII was significantly positive associated with all-cause mortality (HR=1.93, 95%CI=1.55-2.40) and cancer mortality (HR=1.93, 95%CI=1.22-3.05). The results were robust in subgroup and sensitivity analyses. Conclusion: Higher SII (either as a continuous or categorical variable) were significantly associated with a higher risk of CVD mortality. The U-shaped associations were observed between SII and all-cause and cancer mortality.

Dietary Inflammatory Index and All-Cause Mortality in Older Adults with Hypertension: Results from NHANES.

Both diet and inflammation are strongly associated with hypertension. However, the relationship between the dietary inflammatory index (DII) and the prognosis of hypertensive patients over 65 years of age is unclear. The objective of this study is to investigate the correlation between DII and all-cause mortality in older adults with hypertension. Data were obtained from the 2011−2018 National Health and Nutrition Examination Survey (NHANES) and followed for survival through December 31, 2019. DII was calculated by the 24 h dietary history interview. Cox proportional hazards models were used to investigate the associations. A total of 2531 participants were finally included. During a median follow-up of 4.33 years, 471 participants were determined as all-cause mortality. After adjusting for confounding factors, DII was positively correlated with the risk of all-cause mortality (HR = 1.08, 95% CI = 1.01−1.16). Compared with the anti-inflammatory diet group (DII < 0), the pro-inflammatory diet group (DII > 0) had a 54% increased risk of all-cause death (HR = 1.54, 95% CI = 1.13−2.10). The results were robust in subgroup and sensitivity analyses. DII was positively correlated with the all-cause mortality of elderly hypertensive patients. The results provided an aid to dietary evaluation in the nonpharmacologic management of hypertension.

Clonal hematopoiesis of indeterminate potential in patients with acute coronary syndrome undergoing percutaneous coronary intervention in the absence of traditional risk factors.

AIMS: To investigate the frequency of clonal hematopoiesis of indeterminate potential (CHIP) and evaluate its impacts on outcomes in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in the absence of traditional cardiovascular risk factors (CVRFs). METHODS: Whole-exome sequencing was performed to detect the presence of CHIP in 183 patients underwent PCI for the treatment of ACS. The association between CHIP-related mutations and major adverse cardiac or cerebral events (MACCEs, a composite of all-cause mortality, coronary revascularization, myocardial infarction, or stroke) was analyzed in such cohort. RESULTS: Of 179 patients [median age, 65 years; 84 female (46.9%)] included in this analysis, CHIP-related mutations were detected in 36 (20.1%) patients. The somatic mutations most frequently occurred in the genes DNMT3A (17 mutations), TET2 (6 mutations), and ASXL1 (4 mutations). Clinical outcomes at median 635 follow-up days showed that DNMT3A/TET2/ASXL1-CHIP mutations were associated with significantly higher risk of MACCEs, compared with non-CHIP carriers in the CVRFs-absent ACS cohort (26.1% vs. 4.2%, log-rank P = 0.001). Multivariable regression showed that DNMT3A/TET2/ASXL1-CHIP driver mutations (HR 4.015; 95% CI 1.236-13.046; P = 0.021) were independent predictors of adverse clinical outcomes. CONCLUSION: The most frequent CHIP-related mutations, DNMT3A, TET2, and ASXL1 are significantly associated with increased risk of recurrent cardiovascular events. Our study may be valuable target to reduce residual risk in patients with ACS carrying specific mutations.

Safety and Efficacy of Bivalirudin versus Unfractionated Heparin Monotherapy in Patients with CAD and DM Undergoing PCI: A Retrospective Observational Study.

Introduction: Optimal anticoagulants for patients with diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI) are unclear. This retrospective observational study is aimed at evaluating efficacy and safety of bivalirudin versus unfractionated heparin (UFH) monotherapy in patients with DM undergoing PCI. Methods: A total of 3890 diabetic patients receiving PCI in the General Hospital of Northern Theater Command were divided into the bivalirudin group (n = 869) and the UFH group (n = 3021) according to different anticoagulant therapy regimens. Indication for PCI was in accordance with current guidelines including national cardiovascular data registry. The primary endpoint was 30-day net adverse clinical events (NACEs). The secondary endpoints included 30-day major adverse cardiac and cerebral events (MACCEs), bleeding events defined according to the Bleeding Academic Research Consortium (BARC) definition, and stent thrombosis (ST). Patients were matched by propensity score at a ratio of 1 : 1. Results: After propensity score matching, the bivalirudin group was associated with a lower incidence of NACEs (3.0% vs. 6.0%, P = 0.003) than the UFH group. The incidence of MACCE (1.7% vs. 3.3%, P = 0.033) was significantly lower in the bivalirudin group, mainly due to a lower mortality rate (0.6% vs. 2.0%, P = 0.010). In addition, patients in the bivalirudin group had less bleeding (1.4% vs. 3.0%, P = 0.022) than those in the UFH group, although BARC 2, 3, and 5 bleeding (0.1% vs. 0.6%, P = 0.218) was numerically lower. Conclusion: In diabetic patients undergoing PCI, bivalirudin was significantly associated with reduced risks of 30-day NACE and MACCE, mainly driven by the lower rates of bleeding and mortality, compared with heparin monotherapy.

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial.

BACKGROUND: Previous randomised trials of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) have reported conflicting results, in part because of treatment with different pharmacological regimens. We designed a large-scale trial examining bivalirudin with a post-PCI high-dose infusion compared with heparin alone, the regimens that previous studies have shown to have the best balance of safety and efficacy. METHODS: BRIGHT-4 was an investigator-initiated, open-label, randomised controlled trial conducted at 87 clinical centres in 63 cities in China. Patients with STEMI undergoing primary PCI with radial artery access within 48 h of symptom onset who had not received previous fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors were randomly assigned (1:1) to receive bivalirudin with a post-PCI high-dose infusion for 2-4 h or unfractionated heparin monotherapy. There was no masking. Glycoprotein IIb/IIIa inhibitor use was reserved for procedural thrombotic complications in both groups. The primary endpoint was a composite of all-cause mortality or Bleeding Academic Research Consortium (BARC) types 3-5 bleeding at 30 days. This trial is registered with ClinicalTrials.gov (NCT03822975), and is ongoing. FINDINGS: Between Feb 14, 2019, and April 7, 2022, a total of 6016 patients with STEMI undergoing primary PCI were randomly assigned to receive either bivalirudin plus a high-dose infusion after PCI (n=3009) or unfractionated heparin monotherapy (n=3007). Radial artery access was used in 5593 (93·1%) of 6008 patients. Compared with heparin monotherapy, bivalirudin reduced the 30-day rate of the primary endpoint (132 events [4·39%] in the heparin group vs 92 events [3·06%] in the bivalirudin group; difference, 1·33%, 95% CI 0·38-2·29%; hazard ratio [HR] 0·69, 95% CI 0·53-0·91; p=0·0070). All-cause mortality within 30 days occurred in 118 (3·92%) heparin-assigned patients and in 89 (2·96%) bivalirudin-assigned patients (HR 0·75; 95% CI 0·57-0·99; p=0·0420), and BARC types 3-5 bleeding occurred in 24 (0·80%) heparin-assigned patients and five (0·17%) bivalirudin-assigned patients (HR 0·21; 95% CI 0·08-0·54; p=0·0014). There were no significant differences in the 30-day rates of reinfarction, stroke, or ischaemia-driven target vessel revascularisation between the groups. Within 30 days, stent thrombosis occurred in 11 (0·37%) of bivalirudin-assigned patients and 33 (1·10%) of heparin-assigned patients (p=0·0015). INTERPRETATION: In patients with STEMI undergoing primary PCI predominantly with radial artery access, anticoagulation with bivalirudin plus a post-PCI high-dose infusion for 2-4 h significantly reduced the 30-day composite rate of all-cause mortality or BARC types 3-5 major bleeding compared with heparin monotherapy. FUNDING: Chinese Society of Cardiology Foundation (CSCF2019A01), and a research grant from Jiangsu Hengrui Pharmaceuticals.

Untargeted metabolomics identified kynurenine as a predictive prognostic biomarker in acute myocardial infarction.

Objective: The occurrence of cardiovascular adverse events in the first year after ST-acute myocardial infarction (STEMI) remains high; therefore, identification of patients with poor prognosis is essential for early intervention. This study aimed to evaluate the prognostic value of metabolomics-based biomarkers in STEMI patients and explore their functional mechanisms. Methods: Metabolite profiling was performed using nuclear magnetic resonance. The plasma concentration of Kynurenine (Kyn) was measured using ultraperformance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Major adverse cardiac and cerebral events were assessed for 1 year. A functional metabolomics strategy was proposed for investigating the role of Kyn in both vitro and vivo models. Results: The adjusted hazard ratios in STEMI patients for Kyn in the 4th quartile 7.12(5.71-10.82) was significantly higher than that in the 3rd quartile 3.03(2.62-3.74), 2nd quartile 1.86(1.70-2.03), and 1st quartile 1.20(0.93-1.39).The incidence of MACCE was significantly different among Kyn quartiles and the highest incidence of MACCE was observed in the 4th quartile when compared with the 1st quartile (9.84% vs.2.85%, P<0.001).Immunofluorescence staining indicated that indoleamine-pyrrole 2,3-dioxygenase (IDO1) was located in the CD68 positive staining area of thrombi from STEMI patients and Kyn was induced in the early phase after myocardial infarction. Kyn could trigger inflammation and oxidative stress of macrophage cells by activation of the Sirt3-acSOD2/IL-1ß signaling pathway in vitro. Conclusions: Plasma Kyn levels were positively associated with the occurrence of STEMI. Kyn could induce macrophage cells inflammation and oxidative stress by activating the Sirt3-acSOD2/IL-1ß pathway following myocardial ischemia injury. Kyn could be a robust biomarker for STEMI prognosis and reduction of Kyn could be beneficial in STEMI patients.

Impact of Ticagrelor vs. Clopidogrel in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention After Risk Stratification With the CHA2DS2-VASc Score.

Backgrounds: The clinical benefit of ticagrelor vs. clopidogrel in unselected patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) remains controversial in the real world. This study was aimed to investigate the impact of ticagrelor vs. clopidogrel in subjects with ACS without atrial fibrillation or flutter (AF) after PCI based on risk stratification using the CHA2DS2-VASc score. Methods: In 2016-2019, patients who underwent PCI with at least one stent implanted in the General Hospital of Northern Theater Command were classified as low- or high-risk groups according to the CHA2DS2-VASc score. Incidences of 12-month ischemia [cardiac death, myocardial infarction (MI), or stroke], all-cause death, Bleeding Academic Research Consortium (BARC) 2,3,5 bleeding, BARC 3,5 bleeding, and net adverse clinical events (NACEs) (all-cause death, MI, stroke, or BARC 3, 5 bleeding) with aspirin plus different P2Y12 inhibitors (clopidogrel or ticagrelor) were appraised among different risk groups. Propensity score matching (PSM) and Cox multivariate analysis were used to balance the groups. Results: A total of consecutive 17,037 patients with ACS were enrolled. The optimal cut-off value of the CHA2DS2-VASc score for ischemic events by the Youden test was 3 points. Among patients with high risk (CHA2DS2-VASc ≥ 3, n = 6,151), ticagrelor was associated with slightly lower risks of ischemic events (2.29% vs. 3.54%, P = 0.02) and stroke (0.39% vs. 1.08%, P = 0.01) without excessive risk of BARC 3, 5 bleeding events (2.16% vs. 2.11%, P = 0.92) compared to clopidogrel within 12 months after PCI. For patients with low risk (CHA2DS2-VASc < 3, n = 10,886), a statistically significant difference was seen in the incidence of overall 12-month BARC 2, 3, 5 bleeding events by P2Y12 receptor inhibitor (4.00% vs. 3.26%) with a similar incidence of the ischemic events (1.40% vs. 1.52%). Results in the PSM cohort and the adjustment with Cox multivariate analysis were consistent with the main outcomes. Conclusion: Higher CHA2DS2-VASc scores were associated with a higher incidence of 1-year ischemic events for the patients with ACS after PCI. Compared with clopidogrel, ticagrelor was associated with lower ischemic events within 12 months after PCI without excessive risk of bleeding in high-risk patients but shows poor safety with excess bleeding in low-risk patients.

Determination of Optimal Fluoroscopic Angulations for Left Main Coronary Artery Ostial Interventions: 3-Dimensional Computed Tomography Validation.

Background: Current recommendations for the best views for the left main coronary artery (LMCA) ostium intervention are empirical. Objectives: To determine the optimal projection to visualize the LMCA ostium using only fluoroscopy. Methods: The optimal projection to visualize the LMCA ostium was determined using fluoroscopic images of superimposing the lowest points of the distal ends of two J tipped wires in the noncoronary cusp (NCC) and right coronary cusp (RCC). This was validated independently using 3-dimensional computed tomography (3D-CT) reconstruction. Results: Satisfactory images of the overlapping wires in NCC and RCC could be obtained in 90% (45/50). Between the fluoroscopic and the 3D-CT reconstruction approaches, the mean difference for NCC and RCC overlapping at horizontal axes is -1.8 with a 95% limit of agreement between -3.94 and 0.34 (p=0.10) and at vertical axes -1.6 with a 95% limit of agreement between -3.46 and 0.26 (p=0.09); and the mean difference for the optimal projection to visualize the LMCA ostium at horizontal axes is -3.22 with a 95% limit of agreement between -7.26 and 0.81 (p=0.11) and at vertical axes -2.31 with a 95% limit of agreement between -5.83 and 1.21 (p=0.09). The 3D angulation deviation for the optimal projection to visualize the LMCA ostium was 8.5° ± 4.7° when the LMCA ostium faced the NCC-RCC commissure (n = 32) and 22.3° ± 16.0° (p=0.009) when it did not (n = 13). Conclusions: The optimal projection for LMCA ostial intervention can be determined using fluoroscopic images of superimposing wires in the NCC and RCC when the LMCA ostium faces the NCC-RCC commissure, as was the case in 71% of the patients studied.