Cross-Validation of Risk Scores for Patients Undergoing Transcatheter Edge-to-Edge Repair for Mitral Regurgitation.

Background: Risk scores may identify patients with mitral regurgitation (MR) who are at risk for adverse events, but who may still benefit from transcatheter edge-to-edge repair (TEER). We sought to cross-validate the MitraScore and COAPT risk score to predict adverse events in patients undergoing TEER. Methods: MitraScore validation was carried out in the COAPT population which included 614 patients with FMR who were randomized 1:1 to guideline-directed medical therapy (GDMT) with or without TEER and were followed for 2 years. Validation of the COAPT risk score was carried out in 1007 patients from the MIVNUT registry of TEER-treated patients with both FMR and degenerative MR who were followed for a mean of 2.1 years. The predictive value was assessed using the area under the receiver operating characteristic curve (AUC) plots. The primary outcome was all-cause mortality. Results: The MitraScore had fair to good predictive accuracy for mortality in the overall COAPT trial population (AUC, 0.67); its accuracy was higher in patients treated with TEER (AUC, 0.74) than GDMT alone (AUC, 0.65). The COAPT risk score had fair predictive accuracy for death in the overall MitraScore cohort (AUC, 0.64), which was similar in patients with FMR and degenerative MR (AUC, 0.64 and 0.66, respectively). There was a consistent benefit of treatment with TEER plus GDMT compared with GDMT alone in the COAPT trial population across all MitraScore risk strata. Conclusions: The COAPT risk score and MitraScore are simple tools that are useful for the prediction of 2-year mortality in patients eligible for or undergoing treatment with TEER.

Comprehensive non-invasive haemodynamic assessment in acute decompensated heart failure-related cardiogenic shock: a step towards echodynamics.

AIMS: Haemodynamic assessment can be determinant in phenotyping cardiogenic shock (CS) and guiding patient management. Aim of this study was to evaluate the correlation between echocardiographic and invasive assessment of haemodynamics in acute decompensated heart failure-related CS (ADHF-CS). METHODS AND RESULTS: All consecutive ADHF-CS patients (SCAI shock stage ≥B) undergoing right heart catheterization (RHC) between 2020 and 2022 were prospectively enrolled. Patients underwent echocardiography 30 min before RHC. The evaluated haemodynamic parameters and their echocardiographic estimates ('e') comprised cardiac index (CI), wedge pressure (WP), pulmonary artery pressures (PAP), cardiac power output (CPO) and pulmonary artery pulsatility index (PAPi). Hundred and one ADHF-CS patients (56 ± 11 years, 64% SCAI shock stage C, left ventricular ejection fraction 29 ± 5%) were included. Good correlation was found for CI, systolic PAP, RAP, and CPO (Pearson r > 0.8 for all), moderate correlation for ePAPi (r = 0.67) and PVR (r = 0.51), while estimation of WP was weak. The sensitivity and specificity of eCI to identify low output state (CI ≤2.2 L/min/m2) were 0.97 and 0.73, respectively, those of eWP for elevated filling pressures (WP >15 mmHg) were 0.84 and 0.55, those of ePAPs for PAPs ≥35 mmHg were 0.87 and 0.63, those of eCPO for CPO <0.6 W were 0.76 and 0.85, those of ePAPi for PAPi <1.85 were 0.89 and 0.92. Echocardiographic phenotyping of CS showed a good agreement with invasive classification (K value 0.457, P < 0.001). CONCLUSION: Echocardiographic estimation of haemodynamics and subsequent phenotypization of CS is feasible with good agreement with invasive evaluation.

Prevalence and prognostic significance of malnutrition in patients with secondary mitral regurgitation undergoing transcatheter edge-to-edge repair.

BACKGROUND: Malnutrition is associated with poor prognosis in several cardiovascular diseases; however, its role in patients with secondary mitral regurgitation (SMR) is poorly known. AIMS: To evaluate the impact of nutritional status, assessed using different scores, on clinical outcomes in patients with SMR undergoing transcatheter edge-to-edge repair (TEER) in a real-world setting. METHODS: A total of 658 patients with SMR and complete nutritional data were identified from the MIVNUT registry. Nutritional status has been assessed using controlling nutritional status index (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) scores. Outcomes of interest were all-cause mortality and all-cause mortality or heart failure (HF) hospitalization. RESULTS: Any malnutrition grade was observed in 79.4%, 16.7%, and 47.9% of patients by using CONUT, PNI, and GNRI, respectively, while moderate to severe malnutrition was noted in 24.7%, 16.7%, and 25.6% of patients, respectively. At a median follow-up of 2.2 years, 212 patients (32.2%) died. Moderate-severe malnutrition was associated with a higher rate of all-cause mortality (HR: 2.46 [95% CI: 1.69-3.58], HR: 2.18 [95% CI: 1.46-3.26], HR: 1.97 [95% CI: 1.41-2.74] for CONUT, PNI, and GNRI scores, respectively). The combined secondary endpoint of all-cause mortality and HF rehospitalization occurred in 306 patients (46.5%). Patients with moderate-severe malnutrition had a higher risk of the composite endpoint (HR: 1.56 [95% CI: 1.20-2.28], HR: 1.55 [95% CI: 1.01-2.19], HR: 1.36 [95% CI: 1.02-1.80] for CONUT, PNI, and GNRI scores, respectively). After adjustment for multiple confounders, moderate-severe malnutrition remained independently associated with clinical outcomes. CONCLUSIONS: Moderate-severe malnutrition was common in patients with SMR undergoing TEER. It was independently associated with poor prognosis regardless of the different scores used.

Quercetin encapsulated polycaprolactone-polyvinylpyrrolidone electrospun membranes as a delivery system for wound healing applications.

The present work focuses on the production of electrospun membranes based on Poly(ε-caprolactone) (PCL) and Polyvinylpyrrolidone (PVP) for the topical release of Quercetin (Q). Membranes were prepared at 0.5, 1.0, 3.0, 7.0 and 15 % wt of Quercetin and studied from a morphological, physical, and biological point of view. The scanning electron microscopy (SEM) evidences micrometric dimensions of the fibres with a good dispersion of the functional molecule. The retention degree of liquids was evaluated by testing four different liquid media while the radical scavenging activity of Quercetin-loaded membranes was evaluated through DPPH analysis. The release kinetics of Quercetin highlights the presence of an initial burst followed by slower release up to attaining an equilibrium state, after roughly 50 h, showing the possibility of a fine-tuning of drug release. Diffusion coefficients were then evaluated by using Fick's law. Finally, to verify the actual biocompatibility of the systems produced and the possible application in the repair of tissue injury, the biological activity of Quercetin released from drug-loaded membranes was analysed in an immortalized human keratinocyte cell line HaCaT by a wound healing assay. So, the reported preliminary data confirm the possibility of applying the electrospun Quercetin-loaded PCL-PVP membranes for wound healing applications.

Transcatheter Mitral Valve Implantation in Failed Transventricular Mitral Valve Repair.

An 84-year-old man presented with dyspnea at rest due to severe mitral regurgitation. He first underwent transventricular mitral valve repair with the Harpoon system, which relapsed owing to rupture of neochords. He was definitively treated with transcatheter mitral valve implantation of the Tendyne system 8 months later.

Peculiar Ca2+ Homeostasis, ER Stress, Autophagy, and TG2 Modulation in Celiac Disease Patient-Derived Cells.

Celiac disease (CD) is an inflammatory intestinal disease caused by the ingestion of gluten-containing cereals by genetically predisposed individuals. Constitutive differences between cells from CD patients and control subjects, including levels of protein phosphorylation, alterations of vesicular trafficking, and regulation of type 2 transglutaminase (TG2), have been reported. In the present work, we investigated how skin-derived fibroblasts from CD and control subjects responded to thapsigargin, an endoplasmic reticulum ER stress inducer, in an attempt to contribute to the comprehension of molecular features of the CD cellular phenotype. We analyzed Ca2+ levels by single-cell video-imaging and TG2 activity by a microplate assay. Western blots and PCR analyses were employed to monitor TG2 levels and markers of ER stress and autophagy. We found that the cytosolic and ER Ca2+ level of CD cells was lower than in control cells. Treatments with thapsigargin differently activated TG2 in control and CD cells, as well as caused slightly different responses regarding the activation of ER stress and the expression of autophagic markers. On the whole, our findings identified further molecular features of the celiac cellular phenotype and highlighted that CD cells appeared less capable of adapting to a stress condition and responding in a physiological way.

Duration and kind of dual antiplatelet therapy for acute coronary syndrome patients: a network meta-analysis.

INTRODUCTION: For acute coronary syndrome (ACS) patients treated with percutaneous coronary intervention (PCI), the choice of the duration and kind of dual antiplatelet therapy (DAPT) offering the most accurate balance between ischemic and bleeding risk remains unknown. EVIDENCE ACQUISITION: A network meta-analysis was performed including all Randomized Controlled Trials (RCTs) comparing different DAPT regimens and duration in ACS patients undergoing PCI. Trial-defined MACE and major bleedings were the primary endpoints. Stroke, stent thrombosis (ST), all-cause and cardiovascular death, myocardial infarction (MI) represented secondary endpoints. EVIDENCE SYNTHESIS: 13 RCTs encompassing 46145 patients were included. Mean age was 62 (61-64) years old, 42% being admitted with STEMI, 33% with NSTEMI and 25% with UA. The competitive arms were: clopidogrel and aspirin for 12 months (6 arms/18183 patients), clopidogrel and aspirin for 6 months (4/3329), clopidogrel and aspirin >12 months (3/2238), ticagrelor and aspirin for 12 months (6/12942) and prasugrel and aspirin for 12 months (3/9453). Trial-defined MACE and major bleedings, stroke and death were similar among the different arms. DAPT with prasugrel and aspirin for 12 months reduced MI compared to aspirin and clopidogrel for 12 months (OR 0.71, 95% CI: 0.54.0.94) and reduced the risk of ST compared to ticagrelor (OR 0.66, 95% CI: 0.49-0.90). Both prasugrel and ticagrelor reduced ST as compared to clopidogrel and aspirin for 12 months. CONCLUSIONS: Different DAPT strategies yield similar risk of MACE, major bleeding, death and stroke in ACS patients. Prasugrel and aspirin for 12 months proved to be the most effective strategy regarding ST and MI.

In-hospital outcomes in nonagenarian patients undergoing primary percutaneous coronary intervention.

BACKGROUND: The aim of the present analysis was to evaluate the incidence and predictors of in-hospital adverse outcomes in nonagenarian patients undergoing primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI). METHODS: Consecutive nonagenarian patients undergoing pPCI for STEMI from 2009 to 2019 were retrospectively included in an international multicenter registry. In-hospital all-cause death was the primary outcome. RESULTS: A total of 308 patients were included (mean age 92.5±2.5 years, 65.6% female). Mean systolic blood pressure (SBP) at hospital admission was 130.7±33.5 mmHg, 46 (17%) patients presented with a Killip class III-IV, mean left ventricle ejection fraction (LVEF) was 40.0±11.5% and 147 (58%) patients were independent in everyday activities. In-hospital death occurred in 99 patients (32%). After multivariate adjustment, lower LVEF (OR per unit reduction 1.08, 95% CI: 1.03-1.11, P value <0.001), lower SBP (OR 1.02 per mmHg reduction, 95% CI: 1.01-1.03, P value 0.001) and being not independent at home (OR 2.56, 95% CI: 1.25-5.26, P value 0.01) resulted independent predictors of in-hospital mortality. A sensitivity analysis performed in final TIMI 3 flow population confirmed the prognostic role of LVEF and independency on in-hospital mortality. CONCLUSIONS: Nonagenarian patients presenting with STEMI and undergoing pPCI have high in-hospital mortality. Independency in everyday life is a strong independent predictor of survival to hospital discharge.

Evolution of tricuspid regurgitation after transcatheter edge-to-edge mitral valve repair for secondary mitral regurgitation and its impact on mortality.

AIM: To evaluate short-term changes in tricuspid regurgitation (TR) after transcatheter edge-to-edge mitral valve repair (M-TEER) in secondary mitral regurgitation (SMR), their predictors and impact on mortality. METHODS AND RESULTS: This is a retrospective analysis of SMR patients undergoing successful M-TEER (post-procedural mitral regurgitation ≤2+) at 13 European centres. Among 503 patients evaluated 79 (interquartile range [IQR] 40-152) days after M-TEER, 173 (35%) showed ≥1 degree of TR improvement, 97 (19%) had worsening of TR, and 233 (46%) remained unchanged. Smaller baseline left atrial diameter and residual mitral regurgitation 0/1+ were independent predictors of TR ≤2+ after M-TEER. There was a significant association between TR changes and New York Heart Association class and pulmonary artery systolic pressure decrease at echocardiographic re-assessment. At a median follow-up of 590 (IQR 209-1103) days from short-term echocardiographic re-assessment, all-cause mortality was lower in patients with improved compared to those with unchanged/worsened TR (29.6% vs. 42.3% at 3 years; log-rank p = 0.034). Baseline TR severity was not associated with mortality, whereas TR 0/1+ and 2+ at short-term follow-up was associated with lower all-cause mortality compared to TR 3/4+ (30.6% and 35.6% vs. 55.6% at 3 years; p < 0.001). A TR ≤2+ after M-TEER was independently associated with a 42% decreased risk of mortality (p = 0.011). CONCLUSION: More than one third of patients with SMR undergoing successful M-TEER experienced an improvement in TR. Pre-procedural TR was not associated with outcome, but a TR ≤2+ at short-term follow-up was independently associated with long-term mortality. Optimal M-TEER result and a small left atrium were associated with a higher likelihood of TR ≤2+ after M-TEER.

Prognostic Impact of Nutritional Status After Transcatheter Edge-to-Edge Mitral Valve Repair: The MIVNUT Registry.

Background Malnutrition is associated with poor prognosis in several cardiovascular diseases. However, its prognostic impact in patients undergoing transcatheter edge-to-edge mitral valve repair (TEER) is not well known. This study sought to assess the prevalence, clinical associations, and prognostic consequences of malnutrition in patients undergoing TEER. Methods and Results A total of 892 patients undergoing TEER from the international MIVNUT (Mitral Valve Repair and Nutritional Status) registry were studied. Malnutrition status was assessed with the Controlling Nutritional Status score. The association of nutritional status with mortality was analyzed with multivariable Cox regression models, whereas the association with heart failure admission was assessed by Fine-Gray models, with death as a competing risk. According to the Controlling Nutritional Status score, 74.4% of patients with TEER had any degree of malnutrition at the time of TEER (75.1% in patients with body mass index <25 kg/m2, 72.1% in those with body mass index ≥25 kg/m2). However, only 20% had moderate-severe malnutrition. TEER was successful in most of patients (94.2%). During a median follow-up of 1.6 years (interquartile range, 0.6-3.0), 267 (29.9%) patients died and 256 patients (28.7%) were admitted for heart failure after TEER. Compared with normal nutritional status moderate-severe malnutrition resulted a strong predictor of mortality (adjusted hazard ratio [HR], 2.1 [95% CI, 1.1-2.4]; P<0.001) and heart failure admission (adjusted subdistribution HR, 1.6 [95% CI, 1.1-2.4]; P=0.015). Conclusions Malnutrition is common among patients submitted to TEER, and moderate-severe malnutrition is strongly associated with increased mortality and heart failure readmission. Assessment of nutritional status in these patients may help to improve risk stratification.

A Score to Assess Mortality After Percutaneous Mitral Valve Repair.

BACKGROUND: Risk stratification for transcatheter edge-to-edge mitral valve repair (TEER) is paramount in the decision-making process for treating severe mitral regurgitation (MR). OBJECTIVES: This study sought to create and validate a user-friendly score (MitraScore) to predict the risk of mortality in patients undergoing TEER. METHODS: The derivation cohort was based on a multicentric international registry that included 1,119 patients referred for TEER between 2012 and 2020. Score discrimination was assessed using Harrell's c-statistic, and the calibration was evaluated with the Gronnesby and Borgan goodness-of-fit test. An external validation was carried out in 725 patients from the GIOTTO registry. RESULTS: After multivariate analysis, we identified 8 independent predictors of mortality during the follow-up (2.1 ± 1.8 years): age ≥75 years, anemia, glomerular filtrate rate <60 mL/min/1.73 m2, left ventricular ejection fraction <40%, peripheral artery disease, chronic obstructive pulmonary disease, high diuretic dose, and no therapy with renin-angiotensin system inhibitors. The MitraScore was derived by assigning 1 point to each independent predictor. The c-statistic was 0.70. Per each point of the MitraScore, the relative risk of mortality increased by 55% (HR: 1.55; 95% CI: 1.44-1.67; P < 0.001). The discrimination and calibration for mortality prediction was better than those of EuroSCORE II (c-statistic 0.61) or Society of Thoracic Surgeons score (c-statistic 0.57). The MitraScore maintained adequate performance in the validation cohort (c-statistic 0.66). The score was also predictive for heart failure rehospitalization and was correlated with the probability of clinical improvement. CONCLUSIONS: The MitraScore is a simple prediction algorithm for the prediction of follow-up mortality in patients treated with TEER.

Predictors of fractional flow reserve/instantaneous wave-free ratio discordance: impact of tailored diagnostic cut-offs on clinical outcomes of deferred lesions.

BACKGROUND: Patient-related and lesion-related factors may influence instantaneous wave-free ratio (iFR)/fractional flow reserve (FFR) concordance, potentially affecting the safety of revascularization deferral. METHODS: Consecutive patients with at least an intermediate coronary stenosis evaluated by both iFR and FFR were retrospectively enrolled. The agreement between iFR and FFR at their diagnostic cut-offs (FFR 0.80, iFR 0.89) was assessed. Predictors of discordance were assessed using multivariate analyses. Tailored iFR cut-offs according to predictors of discordance best matching an FFR of 0.80 were identified. The impact of reclassification according to tailored iFR cut-offs on major cardiovascular events (MACE: cardiovascular death, myocardial infarction or target-lesion revascularization) among deferred lesions was investigated. RESULTS: Two hundred and ninety-nine intermediate coronary stenosis [FFR 0.84 (0.78-0.89), iFR 0.91 (0.87-0.95), 202 left main/left anterior descending (LM/LAD) vessels, 67.6%] of 260 patients were studied. Discordance rate was 23.4% (n = 70, 10.7% iFR-negative discordant, 12.7% iFR-positive discordant). Predictors of discordance were LM/LAD disease, multivessel disease, non-ST-elevation myocardial infarction, smoking, reduced eGFR and hypertension. Lesion reclassification with tailored iFR cut-offs based on patient-level predictors carried no prognostic value among deferred lesions. Reclassification according to lesion location, which was entirely driven by LM/LAD lesions (iFR cut-offs: 0.93 for LM/LAD, 0.89 for non-LM/LAD), identified increased MACE among lesions deferred based on a negative FFR, between patients with a positive as compared with a negative iFR (19.4 vs. 6.1%, P = 0.044), whereas the same association was not observed with the conventional 0.89 iFR cut-off (15 vs. 8.6%, P = 0.303). CONCLUSION: Tailored vessel-based iFR cut-offs carry prognostic value among FFR-negative lesions, suggesting that a one-size-fit-all iFR cut-off might be clinically unsatisfactory.

Clinical Outcomes Following Isolated Transcatheter Tricuspid Valve Repair: A Meta-Analysis and Meta-Regression Study.

OBJECTIVES: The aim of this study was to assess the pooled clinical and echocardiographic outcomes of different isolated transcatheter tricuspid valve repair (ITTVR) strategies for significant (moderate or greater) tricuspid regurgitation (TR). BACKGROUND: Significant TR is a common valvular heart disease worldwide. METHODS: Published research was systematically searched for studies evaluating the efficacy and safety of ITTVR for significant TR in adults. The primary outcomes were improvement in New York Heart Association (NYHA) functional class and 6-minute walking distance and the presence of severe or greater TR at the last available follow-up of each individual study. Random-effect meta-analysis was performed comparing outcomes before and after ITTVR. RESULTS: Fourteen studies with 771 patients were included. The mean age was 77 ± 8 years, and the mean European System for Cardiac Operative Risk Evaluation II score was 6.8% ± 5.4%. At a weighted mean follow-up of 212 days, 209 patients (35%) were in NYHA functional class III or IV compared with 586 patients (84%) at baseline (risk ratio: 0.23; 95% CI: 0.13-0.40; P < 0.001). Six-minute walking distance significantly improved from 237 ± 113 m to 294 ± 105 m (mean difference +50 m; 95% CI: +34 to +66 m; P < 0.001). One hundred forty-seven patients (24%) showed severe or greater TR after ITTVR compared with 616 (96%) at baseline (risk ratio: 0.29; 95% CI: 0.20-0.42; P < 0.001). CONCLUSIONS: Patients undergoing ITTVR for significant TR experienced significant improvements in NYHA functional status and 6-minute walking distance and a significant reduction in TR severity at mid-term follow-up.

Benefit of Extended Dual Antiplatelet Therapy Duration in Acute Coronary Syndrome Patients Treated with Drug Eluting Stents for Coronary Bifurcation Lesions (from the BIFURCAT Registry).

Optimal dual antiplatelet therapy (DAPT) duration for patients undergoing percutaneous coronary intervention (PCI) for coronary bifurcations is an unmet issue. The BIFURCAT registry was obtained by merging two registries on coronary bifurcations. Three groups were compared in a two-by-two fashion: short-term DAPT (≤ 6 months), intermediate-term DAPT (6-12 months) and extended DAPT (>12 months). Major adverse cardiac events (MACE) (a composite of all-cause death, myocardial infarction (MI), target-lesion revascularization and stent thrombosis) were the primary endpoint. Single components of MACE were the secondary endpoints. Events were appraised according to the clinical presentation: chronic coronary syndrome (CCS) versus acute coronary syndrome (ACS). 5537 patients (3231 ACS, 2306 CCS) were included. After a median follow-up of 2.1 years (IQR 0.9-2.2), extended DAPT was associated with a lower incidence of MACE compared with intermediate-term DAPT (2.8% versus 3.4%, adjusted HR 0.23 [0.1-0.54], p <0.001), driven by a reduction of all-cause death in the ACS cohort. In the CCS cohort, an extended DAPT strategy was not associated with a reduced risk of MACE. In conclusion, among real-world patients receiving PCI for coronary bifurcation, an extended DAPT strategy was associated with a reduction of MACE in ACS but not in CCS patients.

Long-term (≥15 years) Follow-up of Percutaneous Coronary Intervention of Unprotected Left Main (From the GRAVITY Registry).

Long term survival and its determinants after Percutaneous Coronary Intervention (PCI) on Unprotected Left Main Coronary Artery (ULMCA) remain to be appraised. In 9 European Centers 470 consecutive patients performing PCI on ULMCA between 2002 and 2005 were retrospectively enrolled. Survival from all cause and cardiovascular (CV) death were the primary end points, while their predictors at multivariate analysis the secondary ones. Among the overall cohort 81.5% of patients were male and mean age was 66 ± 12 years. After 15 years (IQR 13 to 16), 223 patients (47%) died, 81 (17.2%) due to CV etiology. At multivariable analysis, older age (HR 1.06, 95%CI 1.02 to 1.11), LVEF < 35% (HR 2.97, 95%CI 1.24 to 7.15) and number of vessels treated during the index PCI (HR 1.75, 95%CI 1.12 to 2.72) were related to all-cause mortality, while only LVEF <35% (HR 4.71, 95%CI 1.90 to 11.66) to CV death. Repeated PCI on ULMCA occurred in 91 (28%) patients during the course of follow up and did not significantly impact on freedom from all-cause or CV mortality. In conclusion, in a large, unselected population treated with PCI on ULMCA, 47% died after 15 years, 17% due to CV causes. Age, number of vessels treated during index PCI and depressed LVEF increased risk of all cause death, while re-PCI on ULMCA did not impact survival.

Valve-in-Valve-in-Ring: A Bailout Strategy to Tackle Paravalvular Leaks due to Device Malapposition.

A 55-year-old male with a history of severe organic mitral regurgitation treated with surgical mitral valve (MV) repair was referred for a transcatheter MV replacement due to recurrent regurgitation. After the release of the first transcatheter MV, a severe paravalvular leak coming from the lateral side was observed. To promptly tackle this issue, a second valve with further postdilation was successfully implanted and the paravalvular leak disappeared. This case highlights the feasibility of implanting a second valve in case of severe paravalvular leaks after MV-in-ring procedures due to device malapposition.

Antithrombotic strategies in patients needing oral anticoagulation undergoing percutaneous coronary intervention: A network meta-analysis.

BACKGROUND: The optimal antithrombotic regimen in patients with a concomitant indication for oral anticoagulation (OAT) presenting with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) remains unclear. OBJECTIVES: To perform a network meta-analysis of all randomized controlled trials (RCTs) evaluating different antithrombotic regimens among patients with ACS or undergoing PCI requiring OAT. METHODS: Network meta-analysis was performed in a frequentist framework. Antithrombotic regimens were categorized by OAC type (vitamin K antagonist-based [VKA]; non-VKA OAT [NOAC]) and antiplatelet agents (P2Y inhibitor only: dual therapy [DAT]; P2Y plus aspirin: triple therapy [TAT]). Safety outcomes were Thrombolysis in Myocardial Infarction (TIMI) major bleeding and intracranial hemorrhage (ICH). Efficacy outcomes were cardiovascular death, myocardial infarction, stroke and stent-thrombosis (ST). RESULTS: Five RCTs were included, encompassing 10,797 patients (atrial fibrillation 69-100%, ACS 28-62%, PCI 77-100%). Both VKA and NOAC-based DAT regimens reduced the occurrence of TIMI major bleeding compared to VKA TAT (VKA DAT: RR 0.62, 95% CI 0.39-0.98; NOAC DAT: RR 0.52, 95% CI 0.39-0.70). Nevertheless, only NOAC DAT significantly reduced the occurrence of ICH compared to VKA TAT (RR 0.33, 95% CI 0.17-0.64). Ischemic outcomes were similar among the four treatment regimens. However, numerical, potentially clinically important, higher ST occurrence was observed for NOAC DAT as compared to both VKA TAT (1.50, 95% confidence interval [CI] 0.96-2.33) and NOAC TAT (1.86, 95% CI 0.93-3.73). CONCLUSION: DAT regimens present the highest safety profile among antithrombotic strategies, with a NOAC-specific impact on ICH reduction. NOAC DAT might entail clinically important higher ST occurrence, warranting a case-by-case comprehensive evaluation that integrates patient- and procedure-related residual ischemic risk with the patient-specific bleeding risk.