Bivalirudin vs Heparin Anticoagulation in STEMI: Confirmation of the BRIGHT-4 Results.

BACKGROUND: In the BRIGHT-4 (Bivalirudin With Prolonged Full-Dose Infusion During Primary PCI Versus Heparin Trial-4), anticoagulation with bivalirudin plus a 2- to 4-hour high-dose infusion after percutaneous coronary intervention (PCI) reduced all-cause mortality and bleeding without increasing reinfarction or stent thrombosis compared with heparin alone in patients with ST-segment elevation myocardial infarction (STEMI). These findings require external validation. OBJECTIVES: This study sought to determine outcomes of bivalirudin vs heparin anticoagulation during PCI in STEMI. METHODS: We performed an individual-patient-data meta-analysis of all large randomized trials of bivalirudin vs heparin in STEMI patients undergoing primary PCI performed before BRIGHT-4. The primary endpoint was all-cause mortality. RESULTS: Six trials randomizing 15,254 patients were included. Pooled across all regimens of bivalirudin and glycoprotein IIb/IIIa inhibitor (GPI) use, bivalirudin reduced 30-day all-cause mortality (2.5% vs 2.9%; adjusted OR: 0.78; 95% CI: 0.62-0.99), cardiac mortality (adjusted OR: 0.69; 95% CI: 0.54-0.88), and major bleeding (adjusted OR: 0.53; 95% CI: 0.44-0.64) but increased reinfarction (adjusted OR: 1.30; 95% CI: 1.02-1.65) and stent thrombosis (adjusted OR: 1.43; 95% CI: 1.05-1.93) compared with heparin. In 4 trials in which 6,244 patients were randomized to bivalirudin plus a high-dose post-PCI infusion vs heparin without planned GPI use (the BRIGHT-4 regimens), 30-day all-cause mortality occurred in 1.8% vs 2.9% of patients, respectively (adjusted OR: 0.74; 95% CI: 0.48-1.12), and bivalirudin reduced cardiac mortality (adjusted OR: 0.62; 95% CI: 0.39-0.97) and major bleeding (adjusted OR: 0.49; 95% CI: 0.35-0.70), with similar rates of reinfarction (adjusted OR: 0.89; 95% CI: 0.58-1.38) and stent thrombosis (adjusted OR: 0.80; 95% CI: 0.41-1.57). CONCLUSIONS: In STEMI patients undergoing primary PCI, bivalirudin with a 2- to 4-hour post-PCI high-dose infusion reduced cardiac mortality and major bleeding without an increase in ischemic events compared with heparin monotherapy with provisional GPI use, confirming the BRIGHT-4 results.

Transcatheter Aortic Valve Implantation by Valve Type in Women With Small Annuli: Results From the SMART Randomized Clinical Trial.

Importance: Historically, women with aortic stenosis have experienced worse outcomes and inadequate recognition compared to men, being both underdiagnosed and undertreated, while also facing underrepresentation in clinical trials. Objective: To determine whether women with small aortic annuli undergoing transcatheter aortic valve replacement have better clinical and hemodynamic outcomes with a self-expanding valve (SEV) or balloon-expandable valve (BEV). Design, Setting, Participants: The Small Annuli Randomized to Evolut or SAPIEN Trial (SMART) was a large-scale randomized clinical trial focusing on patients with small aortic annuli undergoing transcatheter aortic valve replacement, randomized to receive SEVs or BEVs and included 716 patients treated at 83 centers in Canada, Europe, Israel, and the US from April 2021 to October 2022. This prespecified secondary analysis reports clinical and hemodynamic findings for all 621 women enrolled in SMART. Data for this report were analyzed from February to April 2024. Interventions: Transcatheter aortic valve replacement with an SEV or a BEV. Main Outcomes and Measures: The composite coprimary clinical end point comprised death, disabling stroke, or heart failure-related rehospitalization. The coprimary valve function end point was the incidence of bioprosthetic valve dysfunction, both assessed through 12 months. Secondary end points included the incidence of moderate or severe prosthesis-patient mismatch. Results: A total of 621 women (mean [SD] age, 80.2 [6.2] years; 312 randomized to the SEV group and 309 to the BEV group) were included in the present analysis. At 12 months, there were no significant differences in the coprimary clinical end point between the SEV and BEV groups (9.4% vs 11.8%, absolute risk difference -2.3%; 95% CI -7.2 to 2.5, P = .35). However, SEV implantation was associated with less bioprosthetic valve dysfunction (8.4% vs 41.8%; absolute risk difference, -33.4%; 95% CI, -40.4 to -26.4; P < .001). SEV implantation resulted in lower aortic valve gradients and larger effective orifice areas at 30 days and 12 months and less mild or greater aortic regurgitation at 12 months compared to BEV implantation. Prosthesis-patient mismatch was significantly lower with SEVs, regardless of the definition used and adjustment for body mass index. Use of SEVs was associated with better quality of life outcomes as assessed by the Valve Academic Research Consortium-3 ordinal quality of life measure. Conclusions and Relevance: Among women with severe symptomatic aortic stenosis and small aortic annuli undergoing transcatheter aortic valve replacement, the use of SEVs, compared to BEVs, resulted in similar clinical outcomes and a markedly reduced incidence of bioprosthetic valve dysfunction through 12 months, including a lower risk of prosthesis-patient mismatch and better 12-month quality of life. Trial Registration: ClinicalTrials.gov Identifier: NCT04722250.

Short-Term Dual Antiplatelet Therapy After Drug-Eluting Stenting in Patients With Acute Coronary Syndromes: A Systematic Review and Network Meta-Analysis.

Importance: The optimal duration of dual antiplatelet therapy (DAPT) in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) remains under debate. Objectives: To analyze the efficacy and safety of DAPT strategies in patients with ACS using a bayesian network meta-analysis. Data Sources: MEDLINE, Embase, Cochrane, and LILACS databases were searched from inception to April 8, 2024. Study Selection: Randomized clinical trials (RCTs) comparing DAPT duration strategies in patients with ACS undergoing PCI were selected. Short-term strategies (1 month of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by P2Y12 inhibitors, 3 months of DAPT followed by aspirin, and 6 months of DAPT followed by aspirin) were compared with conventional 12 months of DAPT. Data Extraction and Synthesis: This systematic review and network meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The risk ratio (RR) with a 95% credible interval (CrI) was calculated within a bayesian random-effects network meta-analysis. Treatments were ranked using surface under the cumulative ranking (SUCRA). Main Outcomes and Measures: The primary efficacy end point was major adverse cardiac and cerebrovascular events (MACCE); the primary safety end point was major bleeding. Results: A total of 15 RCTs randomizing 35 326 patients (mean [SD] age, 63.1 [11.1] years; 26 954 male [76.3%]; 11 339 STEMI [32.1%]) with ACS were included. A total of 24 797 patients (70.2%) received potent P2Y12 inhibitors (ticagrelor or prasugrel). Compared with 12 months of DAPT, 1 month of DAPT followed by P2Y12 inhibitors reduced major bleeding (RR, 0.47; 95% CrI, 0.26-0.74) with no difference in MACCE (RR, 1.00; 95% CrI, 0.70-1.41). No significant differences were observed in MACCE incidence between strategies, although CrIs were wide. SUCRA ranked 1 month of DAPT followed by P2Y12 inhibitors as the best for reducing major bleeding and 3 months of DAPT followed by P2Y12 inhibitors as optimal for reducing MACCE (RR, 0.85; 95% CrI, 0.56-1.21). Conclusion and Relevance: Results of this systematic review and network meta-analysis reveal that, in patients with ACS undergoing PCI with DES, 1 month of DAPT followed by potent P2Y12 inhibitor monotherapy was associated with a reduction in major bleeding without increasing MACCE when compared with 12 months of DAPT. However, an increased risk of MACCE cannot be excluded, and 3 months of DAPT followed by potent P2Y12 inhibitor monotherapy was ranked as the best option to reduce MACCE. Because most patients receiving P2Y12 inhibitor monotherapy were taking ticagrelor, the safety of stopping aspirin in those taking clopidogrel remains unclear.

ACTION-ARC Pediatric and Adult Congenital Heart Disease Ventricular Assist Device Adverse Event Definitions-2023.

Adverse events (AEs) experienced by children and adults with congenital heart disease (CHD) on ventricular assist devices (VADs) are sometimes unique to these populations. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and the Academic Research Consortium (ARC) aimed to harmonize definitions of pediatric and CHD AEs for use in clinical trials, registries, and regulatory evaluation. Data from the ACTION registry and adjudication committee were used to adapt general mechanical circulatory support ARC definitions. This ACTION-ARC international expert panel of trialists, clinicians, patients, families, statisticians, biomedical engineers, device developers, and regulatory agencies drafted and iterated definitions harmonized to ACTION data and existing literature during sessions conducted between December 2022 and May 2023, followed by dissemination across clinical/research audiences and professional organizations and further revision. Both email-linked, internet-based surveys and in-person discussions were used as a modified Delphi process. Nineteen AE types were identified and defined, including seven new event types and six event types that were deleted and will no longer be collected, achieving consensus. ACTION-ARC paired rigorous development with methodical stakeholder involvement and dissemination to define pediatric VAD AEs to facilitate assimilation of data across future clinical trials and evaluation of devices for VAD-supported children and adults with CHD.

ApoA-I Infusions and Burden of Ischemic Events After Acute Myocardial Infarction: Insights From the AEGIS-II Trial.

BACKGROUND: Following an acute myocardial infarction (AMI), patients remain at risk for subsequent cardiovascular (CV) events. In the AEGIS-II trial, CSL112, a human apolipoprotein A-I derived from plasma that enhances cholesterol efflux, did not significantly reduce the first occurrence of CV death, myocardial infarction (MI), or stroke through 90 days compared with placebo. However, an analysis involving only the first event may not capture the totality of the clinical impact of an intervention because patients may experience multiple events. OBJECTIVES: This prespecified exploratory analysis examines the effect of CSL112 on total burden of nonfatal ischemic events (ie, recurrent MI and stroke) and CV death. METHODS: A total of 18,219 patients with AMI, multivessel coronary artery disease, and additional CV risk factors were randomized to either 4 weekly infusions of 6 g CSL112 (n = 9,112) or matching placebo (n = 9,107). A negative binomial regression model was applied to estimate the effect of CSL112 compared with placebo on the rate ratio (RR) of ischemic events. RESULTS: For CV death, MI, and stroke, there were numerically fewer total events at 90 days (503 vs 545 events; rate ratio [RR]: 0.88; 95% CI: 0.76-1.03, P = 0.11), and nominally significantly fewer total events at 180 days (745 vs 821 events, RR: 0.87; 95% CI: 0.77-0.99; P = 0.04) and 365 days (1,120 vs 1,211 events; RR 0.89; 95% CI: 0.80-0.99; P = 0.04). Subsequent events constituted 13% of events at 90 days, 17% at 180 days, and 22% at 1 year. Similar findings were seen with the total occurrence of nonfatal MI and CV death. When type II MIs, unlikely to be modified by enhancing cholesterol efflux, were excluded, there were nominally significant reductions in the total occurrence of nonfatal MI (excluding type 2) and CV death at all timepoints (90 days: RR: 0.81; 95% CI: 0.68-0.97; P = 0.02; 180 days: RR: 0.82; 95% CI: 0.71-0.95; P < 0.01; 365 days: RR: 0.86; 95% CI: 0.76-0.98; P = 0.02). CONCLUSIONS: In this prespecified exploratory analysis of the AEGIS-II trial, 4 weekly infusions of CSL112 among high-risk patients after AMI significantly reduced the total burden of nonfatal ischemic events and CV death at 180 and 365 days compared with placebo. (AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome]; NCT03473223).

De-escalation to ticagrelor monotherapy versus 12 months of dual antiplatelet therapy in patients with and without acute coronary syndromes: a systematic review and individual patient-level meta-analysis of randomised trials.

BACKGROUND: Dual antiplatelet therapy (DAPT) for 12 months is the standard of care after coronary stenting in patients with acute coronary syndrome (ACS). The aim of this individual patient-level meta-analysis was to summarise the evidence comparing DAPT de-escalation to ticagrelor monotherapy versus continuing DAPT for 12 months after coronary drug-eluting stent implantation. METHODS: A systematic review and individual patient data (IPD)-level meta-analysis of randomised trials with centrally adjudicated endpoints was performed to evaluate the comparative efficacy and safety of ticagrelor monotherapy (90 mg twice a day) after short-term DAPT (from 2 weeks to 3 months) versus 12-month DAPT in patients undergoing percutaneous coronary intervention with a coronary drug-eluting stent. Randomised trials comparing P2Y12 inhibitor monotherapy with DAPT after coronary revascularisation were searched in Ovid MEDLINE, Embase, and two websites (www.tctmd.com and www.escardio.org) from database inception up to May 20, 2024. Trials that included patients with an indication for long-term oral anticoagulants were excluded. The risk of bias was assessed using the revised Cochrane risk-of-bias tool. The principal investigators of the eligible trials provided IPD by means of an anonymised electronic dataset. The three ranked coprimary endpoints were major adverse cardiovascular or cerebrovascular events (MACCE; a composite of all-cause death, myocardial infarction, or stroke) tested for non-inferiority in the per-protocol population; and Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding and all-cause death tested for superiority in the intention-to-treat population. All outcomes are reported as Kaplan-Meier estimates. The non-inferiority was tested using a one-sided α of 0·025 with the prespecified non-inferiority margin of 1·15 (hazard ratio [HR] scale), followed by the ranked superiority testing at a two-sided α of 0·05. This study is registered with PROSPERO (CRD42024506083). FINDINGS: A total of 8361 unique citations were screened, of which 610 records were considered potentially eligible during the screening of titles and abstracts. Of these, six trials that randomly assigned patients to ticagrelor monotherapy or DAPT were identified. De-escalation took place a median of 78 days (IQR 31-92) after intervention, with a median duration of treatment of 334 days (329-365). Among 23 256 patients in the per-protocol population, MACCE occurred in 297 (Kaplan-Meier estimate 2·8%) with ticagrelor monotherapy and 332 (Kaplan-Meier estimate 3·2%) with DAPT (HR 0·91 [95% CI 0·78-1·07]; p=0·0039 for non-inferiority; τ2<0·0001). Among 24 407 patients in the intention-to-treat population, the risks of BARC 3 or 5 bleeding (Kaplan-Meier estimate 0·9% vs 2·1%; HR 0·43 [95% CI 0·34-0·54]; p<0·0001 for superiority; τ2=0·079) and all-cause death (Kaplan-Meier estimate 0·9% vs 1·2%; 0·76 [0·59-0·98]; p=0·034 for superiority; τ2<0·0001) were lower with ticagrelor monotherapy. Trial sequential analysis showed strong evidence of non-inferiority for MACCE and superiority for bleeding among the overall and ACS populations (the z-curve crossed the monitoring boundaries or the required information size without crossing the futility boundaries or approaching the null). The treatment effects were heterogeneous by sex for MACCE (p interaction=0·041) and all-cause death (p interaction=0·050), indicating a possible benefit in women with ticagrelor monotherapy, and by clinical presentation for bleeding (p interaction=0·022), indicating a benefit in ACS with ticagrelor monotherapy. INTERPRETATION: Our study found robust evidence that, compared with 12 months of DAPT, de-escalation to ticagrelor monotherapy does not increase ischaemic risk and reduces the risk of major bleeding, especially in patients with ACS. Ticagrelor monotherapy might also be associated with a mortality benefit, particularly among women, which warrants further investigation. FUNDING: Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale.

Apolipoprotein A-I Infusions and Cardiovascular Outcomes in Acute Myocardial Infarction According to Baseline LDL-Cholesterol Levels: The AEGIS-II Trial.

BACKGROUND AND AIMS: In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days versus placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C. METHODS: Overall, 18,219 patients with acute MI, multivessel coronary artery disease, and additional risk factors were randomized to either four weekly infusions of 6 g CSL112 or placebo. This exploratory post-hoc analysis evaluated cardiovascular outcomes by baseline LDL-C in patients prescribed guideline-directed statin therapy at the time of randomization (n=15,731). RESULTS: As baseline LDL-C increased, risk of the primary endpoint at 90 days lowered in those treated with CSL112 compared with placebo. In patients with LDL-C ≥100 mg/dL at randomization, there was a significant risk reduction of cardiovascular death, MI, or stroke in the CSL112 vs. placebo group at 90, 180, and 365 days (hazard ratio 0.69 [0.53-0.90], 0.71 [0.57-0.88], and 0.78 [0.65-0.93]). In contrast, there was no difference between treatment groups among those with LDL-C <100 mg/dL at baseline. CONCLUSIONS: In this population, treatment with CSL112 compared to placebo was associated with a significantly lower risk of recurrent cardiovascular events among patients with a baseline LDL-C ≥100 mg/dL. Further studies need to confirm that CSL112 efficacy is influenced by baseline LDL-C.

Clopidogrel Versus Aspirin as Monotherapy Following Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome Receiving a Drug-Eluting Stent: A Systematic Literature Review and Meta-Analysis.

OBJECTIVE: This study aimed to evaluate the comparative effectiveness and safety of clopidogrel versus aspirin as monotherapy following adequate dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome (ACS). METHODS: MEDLINE, Embase, and CENTRAL were searched from database inception to September 1, 2023. Randomized controlled trials (RCTs) and observational studies evaluating the effectiveness or safety of clopidogrel versus aspirin as monotherapy following DAPT in patients with ACS who received a drug-eluting stent were included. Random-effects meta-analyses were conducted to compare risks of major adverse cardiovascular events (MACE) and clinically relevant bleeding. RESULTS: Of 6242 abstracts identified, three unique studies were included: one RCT and two retrospective cohort studies. Studies included a total of 7081 post-percutaneous coronary intervention ACS patients, 4260 of whom received aspirin monotherapy and 2821 received clopidogrel monotherapy. Studies included variable proportions of patients with ST-elevation myocardial infarction (STEMI), non-STEMI, and unstable angina. From the meta-analysis, clopidogrel was associated with a 28% reduction in the risk of MACE compared with aspirin (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.54, 0.98), with no significant difference in clinically relevant bleeding (HR: 0.92; 95% CI: 0.68, 1.24). CONCLUSION: Despite the paucity of published evidence on the effectiveness and safety of clopidogrel versus aspirin in patients with ACS post-drug-eluting stent implantation, this meta-analysis suggests that clopidogrel versus aspirin may result in a lower risk of MACE, with a similar risk of major bleeding. The present results are hypothesis-generating and further large RCTs comparing antiplatelet monotherapy options in ACS patients are warranted.

Systemic inflammation and health outcomes in patients receiving treatment for atherosclerotic cardiovascular disease.

BACKGROUND AND AIMS: The burden and outcomes of inflammation in patients with atherosclerotic cardiovascular disease (ASCVD) are not well defined beyond the controlled settings of trials and research cohorts. METHODS: This was an observational study of ASCVD adults undergoing C-reactive protein testing in Stockholm's healthcare (2007-21). After excluding C-reactive protein tests associated with acute illness or medications/conditions that bias C-reactive protein interpretation, systemic inflammation was evaluated over a 3-month ascertainment window. Determinants of C-reactive protein ≥ 2 mg/L were explored with logistic regression. C-reactive protein categories were compared via negative-binomial/Cox regression for subsequent healthcare resource utilization and occurrence of major adverse cardiovascular events, heart failure hospitalization, and death. RESULTS: A total of 84 399 ASCVD adults were included (46% female, mean age 71 years, 59% with C-reactive protein ≥ 2 mg/L). Female sex, older age, lower kidney function, albuminuria, diabetes, hypertension, and recent anaemia were associated with higher odds of C-reactive protein ≥ 2 mg/L. The use of renin-angiotensin system inhibitors, antiplatelets, and lipid-lowering therapy was associated with lower odds. Over a median of 6.4 years, compared with C-reactive protein < 2 mg/L, patients with C-reactive protein ≥ 2 mg/L had higher rates of hospitalizations, days spent in hospital, outpatient consultations, and dispensed medications (P < .05 for all). They also had a higher rate of major adverse cardiovascular events [hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.27-1.33], heart failure (HR 1.24; 95% CI 1.20-1.30), and death (HR 1.35; 95% CI 1.31-1.39). Results were consistent across subgroups and granular C-reactive protein categories and robust to the exclusion of extreme C-reactive protein values or early events. CONCLUSIONS: Three in five adults with ASCVD have systemic inflammation, which is associated with excess healthcare resource utilization and increased rates of cardiovascular events and death.

Antithrombotic Strategies in Atrial Fibrillation After ACS and/or PCI: A 4-Way Comparison From AUGUSTUS.

BACKGROUND: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) who had an acute coronary syndrome (ACS) or have undergone percutaneous coronary intervention (PCI) is not known. OBJECTIVES: The authors sought to determine which antithrombotic regimen best balances safety and efficacy. METHODS: AUGUSTUS, a multicenter 2 × 2 factorial design randomized trial compared apixaban with vitamin K antagonist (VKA) and aspirin with placebo in patients with AF with recent ACS and/or PCI treated with a P2Y12 inhibitor. We conducted a 4-way analysis comparing safety and efficacy outcomes in the 4 randomized groups. The primary outcome was a composite of all-cause death, major or clinically relevant nonmajor bleeding, or hospitalization for cardiovascular causes over 6-month follow-up. Secondary outcomes included individual components of the primary endpoint. RESULTS: A total of 4,614 patients were enrolled. All patients were treated with a P2Y12 inhibitor. The primary endpoint occurred in 21.9% of patients randomized to apixaban plus placebo, 27.3% randomized to apixaban plus aspirin, 28.0% randomized to VKA plus placebo, and 33.3% randomized to VKA plus aspirin. Rates of major or clinically relevant nonmajor bleeding and hospitalization for cardiovascular causes were lower with apixaban and placebo compared with the other 3 antithrombotic strategies. There was no difference between the 4 randomized groups with respect to all-cause death. CONCLUSIONS: In patients with AF and a recent ACS and/or PCI, an antithrombotic regimen that included a P2Y12 inhibitor and apixaban without aspirin resulted in a lower incidence of the composite of death, bleeding, or cardiovascular hospitalization than regimens including VKA, aspirin, or both. (An Open-label, 2 x 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban vs. Vitamin K Antagonist and Aspirin vs. Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention; NCT02415400).

Impact of sex on outcomes associated with polyvascular disease in patients after PCI.

BACKGROUND: Atherosclerosis in more than 1 vs. 1 arterial bed is associated with increased risk for major adverse cardiovascular events (MACE). This study aimed to determine whether the risk of post percutaneous coronary intervention (PCI) MACE associated with polyvascular disease (PVD) differs by sex. METHODS: We analyzed 18,721 patients undergoing PCI at a tertiary-care center between 2012 and 2019. Polyvascular disease was defined as history of peripheral artery and/or cerebrovascular disease. The primary endpoint was MACE, a composite of all-cause death, myocardial infarction, or stroke at 1 year. Multivariate Cox regression was used to adjust for differences in baseline risk between patients with PVD vs. coronary artery disease (CAD) alone and interaction testing was used to assess risk modification by sex. RESULTS: Women represented 29.2% (N = 5,467) of the cohort and were more likely to have PVD than men (21.7% vs. 16.1%; P < .001). Among both sexes, patients with PVD were older with higher prevalence of comorbidities and cardiovascular risk factors. Women with PVD had the highest MACE rate (10.0%), followed by men with PVD (7.2%), women with CAD alone (5.0%), and men with CAD alone (3.6%). Adjusted analyses revealed similar relative MACE risk associated with PVD vs. CAD alone in women and men (adjusted hazard ratio [aHR] 1.54, 95% confidence interval [CI] 1.20-1.99; P < .001 and aHR 1.31, 95% CI 1.06-1.62; P = .014, respectively; p-interaction = 0.460). CONCLUSION: Women and men derive similar excess risk of MACE from PVD after PCI. The heightened risk associated with PVD needs to be addressed with maximized use of secondary prevention in both sexes.

Milvexian vs apixaban for stroke prevention in atrial fibrillation: The LIBREXIA atrial fibrillation trial rationale and design.

BACKGROUND: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. METHODS: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years. CONCLUSION: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter. TRIAL REGISTRATION: ClinicalTrials.gov NCT05757869.

Cerebrovascular Events in Patients Undergoing Transfemoral Transcatheter Aortic Valve Implantation: A Pooled Patient-Level Study.

BACKGROUND: Cerebrovascular events remain one of the most devastating complications of transcatheter aortic valve implantation (TAVI). Data from real-world contemporary cohorts on longitudinal trends and outcomes remain limited. The aim of this study was to assess incidence, temporal trends, predictors, and outcomes of cerebrovascular events following transfemoral TAVI. METHODS AND RESULTS: The CENTER2 (Cerebrovascular Events in Patients Undergoing Transcatheter Aortic Valve Implantation With Balloon-Expandable Valves Versus Self-Expandable Valves 2) study includes patients undergoing TAVI between 2007 and 2022. The database contains pooled patient-level data from 10 clinical studies. A total of 24 305 patients underwent transfemoral TAVI (mean age 81.5±6.7 years, 56% women, median Society of Thoracic Surgeon Predicted Risk of Mortality 4.9% [3.1%-8.5%]). Of these patients, 2.2% (n=534) experienced stroke in the first 30 days after TAVI, and 40 (0.4%) had a transient ischemic attack. Stroke rates remained stable during the treatment period (2007-2010: 2.1%, 2011-2014: 2.5%, 2015-2018: 2.1%, 2019-2022: 2.1%; Ptrend=0.28). Moreover, 30-day cerebrovascular event rates were similar across Society of Thoracic Surgeon Predicted Risk of Mortality risk categories: 2.1% in low-risk, 2.6% in intermediate-risk, and 2.5% in high-risk patients (P=0.21). Mortality was higher in patients with 30-day stroke than without at 30 days (20.3% versus 4.7%; odds ratio, 5.1 [95% CI, 4.1-6.5]; P<0.001) and at 1 year (44.1% versus 15.0%; hazard ratio, 3.5 [95% CI, 3.0-4.2]; P<0.001). One-year mortality rates for stroke did not decline over time (2007-2010: 46.9%, 2011-2014: 46.0%, 2015-2018: 43.0%, 2019-2022: 39.1%; Ptrend=0.32). At 1 year, 7.0% of patients undergoing TAVI had a stroke. CONCLUSIONS: In 24 305 patients who underwent transfemoral TAVI, 30-day cerebrovascular event incidence remained ≈ 2.2% between 2007 and 2022. Thirty-day stroke rates were similar throughout Society of Thoracic Surgeon Predicted Risk of Mortality risk categories. Mortality rates after stroke remain high. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03588247.

Left Atrial Appendage Closure Compared With Oral Anticoagulants for Patients With Atrial Fibrillation: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Percutaneous left atrial appendage closure (LAAC) has been suggested as an alternative to long-term oral anticoagulation for nonvalvular atrial fibrillation, but comparative data remain scarce. We aimed to assess ischemic and bleeding outcomes of LAAC compared with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for the prevention of cardioembolic events in patients with atrial fibrillation. METHODS AND RESULTS: Embase and MEDLINE were searched for randomized trials comparing LAAC, VKAs, and DOACs. The primary efficacy end point was any stroke or systemic embolism. Treatment effects were calculated from a network meta-analysis and ranked according to the surface under the cumulative ranking curve. Seven trials and 73 199 patients were included. The risk of the primary end point was not statistically different between LAAC versus VKAs (odds ratio [OR], 0.92 [95% CI, 0.62-1.50]) and LAAC versus DOACs (OR, 1.11 [95% CI, 0.71-1.73]). LAAC and DOACs resulted in similar risk of major or minor (OR, 0.93 [95% CI, 0.61-1.42]) and major bleeding (OR, 0.92 [95% CI, 0.58-1.46]); however, after exclusion of procedural bleeding, bleeding risk was significantly lower in those undergoing LAAC. Both LAAC and DOACs reduced the risk of all-cause death  compared with VKAs (LAAC versus VKAs: OR, 0.70 [95% CI, 0.53-0.91]; DOACs versus VKAs: OR, 0.90 [95% CI, 0.85-0.95], respectively). DOACs ranked as the best treatment for stroke or systemic embolism prevention (66.9%) and LAAC for reducing major bleeding (63.9%) and death (96.4%). CONCLUSIONS: As a nonpharmacological alternative to oral anticoagulation for atrial fibrillation, LAAC showed similar efficacy and safety compared with VKAs or DOACs. Prospective confirmation from larger studies is warranted.

Significance of diabetes mellitus status in patients undergoing percutaneous left main coronary artery intervention.

BACKGROUND: Diabetes mellitus (DM) is a modifiable risk factor for patients with coronary artery disease (CAD). Treatment with insulin correlates with advanced disease and has been associated with excess cardiovascular risk, but evidence on outcomes of patients with insulin-treated DM (ITDM) undergoing left main percutaneous coronary intervention (LMPCI) remains scarce. AIMS: The aim of the presented study is to evluate the risk attributable to DM and ITDM in patients undergoing LMPCI. METHODS: We included 869 patients undergoing PCI for unprotected LMCAD. The cohort was divided into three subgroups based on diabetic status: No DM, ITDM, and Non-ITDM. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of death, spontaneous myocardial infarction (MI), or stroke at 1 year. Results were adjusted for clinically relevant baseline characteristics. RESULTS: Amongst participants, 58.7% had no DM, 25.9% non-ITDM, and 15.4% ITDM. Diabetics were younger and more likely to be female. They also exhibited higher body mass index as well as prevalence of comorbidities, including hypertension, anemia, and chronic kidney disease. The number of bifurcation lesions and stents used was similar between groups. At 1 year, when compared to no DM, ITDM (25.4% vs. 10.0%, p < 0.01) but not non-ITDM (10.8% vs. 10.0%, p = 0.94) demonstrated higher MACCE. This finding was driven by increased risk of MI. Mortality was 8.4%, 7.8%, and 17.2% for no DM, Non-ITDM, and ITDM, respectively. Results remained unchanged after adjustment. CONCLUSIONS: In a rather contemporary patient population undergoing PCI for LMCAD, ITDM but not non-ITDM was associated with higher risk of 1-year MACCE, primarily driven by MI.

Treatment of Transcatheter Aortic Valve Thrombosis: JACC Review Topic of the Week.

Transcatheter aortic valve (TAV) thrombosis may manifest as subclinical leaflet thrombosis (SLT) and clinical valve thrombosis. SLT is relatively common (10%-20%) after transcatheter aortic valve replacement, but clinical implications are uncertain. Clinical valve thrombosis is rare (1.2%) and associated with bioprosthetic valve failure, neurologic or thromboembolic events, heart failure, and death. Treatment for TAV thrombosis has been understudied. In principle, anticoagulation may prevent TAV thrombosis. Non-vitamin K oral anticoagulants, as compared to antiplatelet therapy, are associated with reduced incidence of SLT, although at the cost of higher bleeding and all-cause mortality risk. We present an overview of existing literature for management of TAV thrombosis and propose a rational treatment algorithm. Vitamin K antagonists or non-vitamin K oral anticoagulants are the cornerstone of antithrombotic treatment. In therapy-resistant or clinically unstable patients, ultraslow, low-dose infusion of thrombolytics seems effective and safe and may be preferred over redo-transcatheter aortic valve replacement or explant surgery.