Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Dialysis

BackgroundPatients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown.ObjectivesThis study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis.MethodsMEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding.ResultsThis study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant.ConclusionsThis meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.     

Rivaroxaban Plus Aspirin in Patients With Vascular Disease and Renal Dysfunction: From the COMPASS Trial

BackgroundChronic kidney disease is associated with an increased risk of both bleeding and ischemic cardiovascular events.ObjectiveThe purpose of this study was to determine the balance of risks and benefits from the dual pathway antithrombotic regimen (rivaroxaban 2.5 mg twice daily [bd] plus aspirin, compared with aspirin) in vascular patients with or without moderate renal dysfunction.MethodsThis was a secondary analysis of the COMPASS (Cardiovascular OutcoMes for People using Anticoagulation StrategieS) trial involving 27,395 patients with chronic coronary or peripheral artery disease.ResultsIn COMPASS, 21,111 patients had an estimated glomerular filtration rate (GFR) at baseline of ≥60 ml/min, 6,276 had a GRF of <60 ml/min. Both the primary efficacy outcome (cardiovascular death, myocardial infarction, or stroke) and major bleeding were more frequent in those with renal dysfunction, and the frequency of these outcome events was inversely related to GFR. However, the primary outcome was consistently reduced with rivaroxaban 2.5 mg bd plus aspirin, irrespective of GFR category (GFR ≥60 ml/min, 3.5% rivaroxaban plus aspirin, 4.5% aspirin alone, hazard ratio [HR]: 0.76, 95% confidence interval [CI]: 0.64 to 0.90; GFR <60 ml/min, 6.4% rivaroxaban plus aspirin, 8.4% aspirin alone, HR: 0.75; 95% CI: 0.60 to 0.94). Major bleeding was more frequent with rivaroxaban 2.5 mg plus aspirin versus aspirin alone in those with GFR ≥60 ml/min (2.9% rivaroxaban plus aspirin, 1.6% aspirin alone, HR: 1.81; 95% CI: 1.44 to 2.28) and similarly in those with GFR <60 ml/min (3.9% rivaroxaban plus aspirin, 2.7% aspirin alone, HR: 1.47, 95% CI: 1.05 to 2.07).ConclusionsThe benefits of the dual pathway COMPASS regimen (rivaroxaban 2.5 mg bd plus aspirin), versus aspirin alone, are preserved in patients with moderate renal dysfunction without evidence of an excess hazard of bleeding.     

Direct Oral Anticoagulants in Patients With Atrial Fibrillation and Liver Disease

BackgroundAdvanced liver disease is known to increase the risk for bleeding and affects the hepatic clearance and metabolism of drugs. Subjects with active liver disease were excluded from pivotal clinical trials of direct oral anticoagulants (DOACs), so the evidence regarding the efficacy and safety of DOACs in patients with liver disease is lacking.ObjectivesThe aim of this study was to compare DOACs with warfarin in patients with nonvalvular atrial fibrillation and liver disease.MethodsUsing the Korean National Health Insurance Service database, subjects with atrial fibrillation and active liver disease treated with oral anticoagulation were included (12,778 with warfarin and 24,575 with DOACs), and analyzed ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, major bleeding, all-cause death, and the composite outcome. Propensity score weighting was used to balance covariates between the 2 groups.ResultsDOACs were associated with lower risks for ischemic stroke (hazard ratio [HR]: 0.548; 95% confidence interval [CI]: 0.485 to 0.618), intracranial hemorrhage (HR: 0.479; 95% CI 0.394 to 0.581), gastrointestinal bleeding (HR: 0.819; 95% CI: 0.619 to 0.949), major bleeding (HR: 0.650; 95% CI: 0.575 to 0.736), all-cause death (HR: 0.698; 95% CI: 0.636 to 0.765), and the composite outcome (HR: 0.610; 95% CI: 0.567 to 0.656) than warfarin. Among the total study population, 13% of patients (n = 4,942) were identified as having significant active liver disease. A consistent benefit was observed in patients with significant active liver disease (HR for the composite outcome: 0.691; 95% CI: 0.577 to 0.827).ConclusionsIn this large Asian population with atrial fibrillation and liver disease, DOACs showed better effectiveness and safety than warfarin, which was consistent in those with significant active liver disease.     

Aspirin for Primary Prevention of Cardiovascular Events

BackgroundThe efficacy and safety of aspirin for primary prevention of cardiovascular disease (CVD) remain debatable.ObjectivesThe purpose of this study was to examine the clinical outcomes with aspirin for primary prevention of CVD after the recent publication of large trials adding >45,000 individuals to the published data.MethodsRandomized controlled trials comparing clinical outcomes with aspirin versus control for primary prevention with follow-up duration of ≥1 year were included. Efficacy outcomes included all-cause death, cardiovascular (CV) death, myocardial infarction (MI), stroke, transient ischemic attack (TIA), and major adverse cardiovascular events. Safety outcomes included major bleeding, intracranial bleeding, fatal bleeding, and major gastrointestinal (GI) bleeding. Random effects DerSimonian-Laird risk ratios (RRs) for outcomes were calculated.ResultsA total of 15 randomized controlled trials including 165,502 participants (aspirin n = 83,529, control n = 81,973) were available for analysis. Compared with control, aspirin was associated with similar all-cause death (RR: 0.97; 95% confidence interval [CI]: 0.93 to 1.01), CV death (RR: 0.93; 95% CI: 0.86 to 1.00), and non-CV death (RR: 0.98; 95% CI: 0.92 to 1.05), but a lower risk of nonfatal MI (RR: 0.82; 95% CI: 0.72 to 0.94), TIA (RR: 0.79; 95% CI: 0.71 to 0.89), and ischemic stroke (RR: 0.87; 95% CI: 0.79 to 0.95). Aspirin was associated with a higher risk of major bleeding (RR: 1.5; 95% CI: 1.33 to 1.69), intracranial bleeding (RR: 1.32; 95% CI: 1.12 to 1.55), and major GI bleeding (RR: 1.52; 95% CI: 1.34 to 1.73), with similar rates of fatal bleeding (RR: 1.09; 95% CI: 0.78 to 1.55) compared with the control subjects. Total cancer and cancer-related deaths were similar in both groups within the follow-up period of the study.ConclusionsAspirin for primary prevention reduces nonfatal ischemic events but significantly increases nonfatal bleeding events.     

Rivaroxaban Monotherapy in Patients With Atrial Fibrillation After Coronary Stenting: Insights From the AFIRE Trial

ObjectivesThe aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting.BackgroundOf 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment.MethodsThe benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment.ResultsEfficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097).ConclusionsIn patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612, NCT02642419)     

Bleeding and Ischemic Outcomes With Ticagrelor Monotherapy According to Body Mass Index

BackgroundThere is a paucity of data regarding the safety and efficacy of different antiplatelet regimens according to standardized body mass index (BMI) categories.ObjectivesThe aim of this study was to investigate bleeding and ischemic outcomes according to BMI in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial.MethodsThe TWILIGHT trial randomized high-risk patients to ticagrelor plus aspirin or ticagrelor plus placebo at 3 months after percutaneous coronary intervention. In this secondary analysis, patients were stratified by standard BMI categories, as recommended by the European Society of Cardiology Working Group on Thrombosis (normal weight [BMI 18.5-24.99 kg/m²], overweight [BMI 25-29.99 kg/m²], and obese [BMI ≥30 kg/m²]) and by median BMI, as prespecified in the protocol.ResultsAmong 7,038 patients randomized and with available BMI, 1,807 (25.7%) were normal weight, 2,927 (41.6%) were overweight, and 2,304 (32.7%) were obese. In normal-weight, overweight, and obese patients, ticagrelor monotherapy, compared with ticagrelor plus aspirin, reduced the primary endpoint of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding (normal weight: HR: 0.48 [95% CI: 0.32-0.73]; overweight: HR: 0.57 [95% CI: 0.41-0.78]; obese: HR: 0.63 [95% CI: 0.44-0.91]; P for interaction = 0.627), without any increase in the composite ischemic endpoint of all-cause death, myocardial infarction, or stroke (normal weight: HR: 1.36 [95% CI: 0.84-2.19]; overweight: HR: 0.92 [95% CI: 0.63-1.35]; obese: HR: 0.84 [95% CI: 0.56-1.25]; P for interaction = 0.290). These findings were consistent with the prespecified analysis by median BMI.ConclusionsAmong high-risk patients undergoing percutaneous coronary intervention, ticagrelor monotherapy, compared with ticagrelor plus aspirin, reduced bleeding events without any increase in ischemic risk across different BMI categories.     

Clinical Outcomes Associated With Left Atrial Appendage Occlusion Versus Direct Oral Anticoagulation in Atrial Fibrillation

ObjectivesThis study sought to investigate clinical outcomes associated with left atrial appendage occlusion (LAAO) versus direct oral anticoagulants (DOACs) in patients with high-risk atrial fibrillation (AF).BackgroundLAAO has been shown to be noninferior to warfarin for stroke prevention in AF. However, anticoagulation with DOACs is now preferred over warfarin as thromboprophylaxis in AF.MethodsPatients with AF enrolled in the Amulet Observational Registry (n = 1,088) who had successful LAAO with the Amplatzer Amulet device (n = 1,078) were compared with a propensity score–matched control cohort of incident AF patients (n = 1,184) treated by DOACs identified from Danish national patient registries. Propensity score matching was based on the covariates of the CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism, vascular disease, age 65–74 years, sex category) and HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs or alcohol) scores for predicting stroke and bleeding. The primary outcome was a composite of ischemic stroke, major bleeding (Bleeding Academic Research Consortium ≥3), or all-cause mortality, and follow-up was 2 years.ResultsAF patients treated with LAAO had a significantly lower risk of the primary composite outcome as compared with patients treated with DOACs (hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.49 to 0.67). Total events and event rates per 100 patient-years were (LAAO vs. DOACs) 256 vs. 461 and 14.5 vs. 25.7, respectively. The risk of ischemic stroke was comparable between groups (HR: 1.11; 95% CI: 0.71 to 1.75), while risk of major bleeding (HR: 0.62; 95% CI: 0.49 to 0.79) and all-cause mortality (HR: 0.53; 95% CI: 0.43 to 0.64) were significantly lower in patients treated with LAAO.ConclusionsAmong high-risk AF patients, LAAO in comparison with DOACs may have similar stroke prevention efficacy but lower risk of major bleeding and mortality.     

Elevated LDL Triglycerides and Atherosclerotic Risk

BackgroundIt is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD).ObjectivesThis study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually.MethodsThe study investigators used the Copenhagen General Population Study, which measured LDL triglycerides in 38,081 individuals with a direct automated assay (direct LDL triglycerides) and in another 30,208 individuals with nuclear magnetic resonance (NMR) spectroscopy (NMR LDL triglycerides). Meta-analyses aggregated the present findings with previously reported results.ResultsDuring a median follow-up of 3.0 and 9.2 years, respectively, 872 and 5,766 individuals in the 2 cohorts received a diagnosis of ASCVD. Per 0.1 mmol/L (9 mg/dL) higher direct LDL triglycerides, HRs were 1.26 (95% CI: 1.17-1.35) for ASCVD, 1.27 (95% CI: 1.16-1.39) for ischemic heart disease, 1.28 (95% CI: 1.11-1.48) for myocardial infarction, 1.22 (95% CI: 1.08-1.38) for ischemic stroke, and 1.38 (95% CI: 1.21-1.58) for peripheral artery disease. Corresponding HRs for NMR LDL triglycerides were 1.26 (95% CI: 1.20-1.33), 1.33 (95% CI: 1.25-1.41), 1.41 (95% CI: 1.31-1.52), 1.13 (95% CI: 1.05-1.23), and 1.26 (95% CI: 1.10-1.43), respectively. The foregoing results were not entirely statistically explained by apolipoprotein B levels. In meta-analyses for the highest quartile vs the lowest quartile of LDL triglycerides, random-effects risk ratios were 1.50 (95% CI: 1.35-1.66) for ASCVD (4 studies; 71,526 individuals; 8,576 events), 1.62 (95% CI: 1.37-1.93) for ischemic heart disease (6 studies; 107,538 individuals; 9,734 events), 1.30 (95% CI: 1.13-1.49) for ischemic stroke (4 studies; 78,026 individuals; 4,273 events), and 1.53 (95% CI: 1.29-1.81) for peripheral artery disease (4 studies; 107,511 individuals; 1,848 events).ConclusionsElevated LDL triglycerides were robustly associated with an increased risk of ASCVD and of each ASCVD component individually in 2 prospective cohort studies and in meta-analyses of previous and present studies combined.     

P2Y12 Inhibitor Monotherapy or Dual Antiplatelet Therapy After Complex Percutaneous Coronary Interventions

BackgroundIt remains unclear whether P2Y₁₂ inhibitor monotherapy preserves ischemic protection while limiting bleeding risk compared with dual antiplatelet therapy (DAPT) after complex percutaneous coronary intervention (PCI).ObjectivesWe sought to assess the effects of P2Y₁₂ inhibitor monotherapy after 1-month to 3-month DAPT vs standard DAPT in relation to PCI complexity.MethodsWe pooled patient-level data from randomized controlled trials comparing P2Y₁₂ inhibitor monotherapy and standard DAPT on centrally adjudicated outcomes after coronary revascularization. Complex PCI was defined as any of 6 criteria: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion. The primary efficacy endpoint was all-cause mortality, myocardial infarction, and stroke. The key safety endpoint was Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding.ResultsOf 22,941 patients undergoing PCI from 5 trials, 4,685 (20.4%) with complex PCI had higher rates of ischemic events. The primary efficacy endpoint was similar between P2Y₁₂ inhibitor monotherapy and DAPT among patients with complex PCI (HR: 0.87; 95% CI: 0.64-1.19) and noncomplex PCI (HR: 0.91; 95% CI: 0.76-1.09; P_interaction = 0.770). The treatment effect was consistent across all the components of the complex PCI definition. Compared with DAPT, P2Y₁₂ inhibitor monotherapy consistently reduced BARC 3 or 5 bleeding in complex PCI (HR: 0.51; 95% CI: 0.31-0.84) and noncomplex PCI patients (HR: 0.49; 95% CI: 0.37-0.64; P_interaction = 0.920).ConclusionsP2Y₁₂ inhibitor monotherapy after 1-month to 3-month DAPT was associated with similar rates of fatal and ischemic events and lower risk of major bleeding compared with standard DAPT, irrespective of PCI complexity. (PROSPERO [P2Y12 Inhibitor Monotherapy Versus Standard Dual Antiplatelet Therapy After Coronary Revascularization: Individual Patient Data Meta-Analysis of Randomized Trials]; CRD42020176853)     

Ticagrelor Monotherapy Versus Dual-Antiplatelet Therapy After PCI: An Individual Patient-Level Meta-Analysis

ObjectivesThe aim of this study was to compare ticagrelor monotherapy with dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stents.BackgroundThe role of abbreviated DAPT followed by an oral P2Y₁₂ inhibitor after PCI remains uncertain.MethodsTwo randomized trials, including 14,628 patients undergoing PCI, comparing ticagrelor monotherapy with standard DAPT on centrally adjudicated endpoints were identified, and individual patient data were analyzed using 1-step fixed-effect models. The protocol was registered in PROSPERO (CRD42019143120). The primary outcomes were the composite of Bleeding Academic Research Consortium type 3 or 5 bleeding tested for superiority and, if met, the composite of all-cause death, myocardial infarction, or stroke at 1 year, tested for noninferiority against a margin of 1.25 on a hazard ratio (HR) scale.ResultsBleeding Academic Research Consortium type 3 or 5 bleeding occurred in fewer patients with ticagrelor than DAPT (0.9% vs. 1.7%, respectively; HR: 0.56; 95% confidence interval [CI]: 0.41 to 0.75; p < 0.001). The composite of all-cause death, myocardial infarction, or stroke occurred in 231 patients (3.2%) with ticagrelor and in 254 patients (3.5%) with DAPT (HR: 0.92; 95% CI: 0.76 to 1.10; p < 0.001 for noninferiority). Ticagrelor was associated with lower risk for all-cause (HR: 0.71; 95% CI: 0.52 to 0.96; p = 0.027) and cardiovascular (HR: 0.68; 95% CI: 0.47 to 0.99; p = 0.044) mortality. Rates of myocardial infarction (2.01% vs. 2.05%; p = 0.88), stent thrombosis (0.29% vs. 0.38%; p = 0.32), and stroke (0.47% vs. 0.36%; p = 0.30) were similar.ConclusionsTicagrelor monotherapy was associated with a lower risk for major bleeding compared with standard DAPT, without a concomitant increase in ischemic events.     

Ticagrelor Monotherapy After PCI in High-Risk Patients With Prior MI: A Prespecified TWILIGHT Substudy

ObjectivesThe aim of this study was to evaluate if patients with prior myocardial infarction (MI) could benefit from ticagrelor monotherapy in terms of bleeding reduction without any compromise in ischemic event prevention.BackgroundPatients with history of MI who undergo percutaneous coronary intervention (PCI) remain at risk for recurrent ischemic events. The optimal antithrombotic strategy for this cohort remains debated.MethodsIn this prespecified analysis of the randomized TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial, the authors evaluated the impact of history of MI on treatment effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients undergoing PCI with drug-eluting stent with at least 1 clinical and 1 angiographic high-risk feature and free from adverse events at 3 months after index PCI. The primary endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, and the key secondary endpoint was the composite of all-cause death, MI, or stroke, both at 12 months after randomization.ResultsA total of 1,937 patients (29.7%) with and 4,595 patients (70.3%) without prior MI were randomized to ticagrelor and placebo or ticagrelor and aspirin. At 1 year after randomization, patients with prior MI experienced higher rates of death, MI, or stroke (5.7% vs 3.2%; P < 0.001) but similar BARC types 2 to 5 bleeding (5.0% vs 5.5%; P = 0.677) compared with patients without prior MI. Ticagrelor monotherapy consistently reduced the risk for the primary bleeding outcome in patients with (3.4% vs 6.7%; HR: 0.50; 95% CI: 0.33-0.76) and without (4.2% vs 7.0%; HR: 0.58; 95% CI: 0.45-0.76; P_interaction = 0.54) prior MI. Rates of the key secondary ischemic outcome were not significantly different between treatment groups irrespective of history of MI (prior MI, 6.0% vs 5.5% [HR: 1.09; 95% CI: 0.75-1.58]; no prior MI, 3.1% vs 3.3% [HR: 0.92; 95% CI: 0.67-1.28]; P_interaction = 0.52).ConclusionsTicagrelor monotherapy is associated with significantly lower risk for bleeding events compared with ticagrelor plus aspirin, without any compromise in ischemic prevention, among high-risk patients with history of MI undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242)     

Thoracic Aortic 18F-Sodium Fluoride Activity and Ischemic Stroke in Patients With Established Cardiovascular Disease

BackgroundAortic atherosclerosis represents an important contributor to ischemic stroke risk. Identifying patients with high-risk aortic atheroma could improve preventative treatment strategies for future ischemic stroke.ObjectivesThe purpose of this study was to investigate whether thoracic ¹⁸F-sodium fluoride positron emission tomography (PET) could improve the identification of patients at the highest risk of ischemic stroke.MethodsIn a post hoc observational cohort study, we quantified thoracic aortic and coronary ¹⁸F-sodium fluoride activity in 461 patients with stable cardiovascular disease undergoing PET combined with computed tomography (CT). Progression of atherosclerosis was assessed by change in aortic and coronary CT calcium volume. Clinical outcomes were determined by the occurrence of ischemic stroke and myocardial infarction. We compared the prognostic utility of ¹⁸F-sodium fluoride activity for predicting stroke to clinical risk scores and CT calcium quantification using survival analysis and multivariable Cox regression.ResultsAfter 12.7 ± 2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aortic ¹⁸F-sodium fluoride activity (n = 140; r = 0.31; P = 0.00016). In 461 patients, 23 (5%) patients experienced an ischemic stroke and 32 (7%) a myocardial infarction after 6.1 ± 2.3 years of follow-up. High thoracic aortic ¹⁸F-sodium fluoride activity was strongly associated with ischemic stroke (HR: 10.3 [95% CI: 3.1-34.8]; P = 0.00017), but not myocardial infarction (P = 0.40). Conversely, high coronary ¹⁸F-sodium fluoride activity was associated with myocardial infarction (HR: 4.8 [95% CI: 1.9-12.2]; P = 0.00095) but not ischemic stroke (P = 0.39). In a multivariable Cox regression model including imaging and clinical risk factors, thoracic aortic ¹⁸F-sodium fluoride activity was the only variable associated with ischemic stroke (HR: 8.19 [95% CI: 2.33-28.7], P = 0.0010).ConclusionsIn patients with established cardiovascular disease, thoracic aortic ¹⁸F-sodium fluoride activity is associated with the progression of atherosclerosis and future ischemic stroke. Arterial ¹⁸F-sodium fluoride activity identifies localized areas of atherosclerotic disease activity that are directly linked to disease progression and downstream regional clinical atherothrombotic events. (DIAMOND–Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND], NCT02110303; Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis [SALTIRE II], NCT02132026; Novel Imaging Approaches To Identify Unstable Coronary Plaques, NCT01749254; and Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis, NCT01358513)     

Left Atrial Appendage Closure Versus Direct Oral Anticoagulants in High-Risk Patients With Atrial Fibrillation

BackgroundPercutaneous left atrial appendage closure (LAAC) is noninferior to vitamin K antagonists (VKAs) for preventing atrial fibrillation (AF)–related stroke. However, direct oral anticoagulants (DOACs) have an improved safety profile over VKAs, and their effect on cardiovascular and neurological outcomes relative to LAAC is unknown.ObjectivesThis study sought to compare DOACs with LAAC in high-risk patients with AF.MethodsLeft Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation (PRAGUE-17) was a multicenter, randomized, noninferiority trial comparing LAAC with DOACs. Patients were eligible to be enrolled if they had nonvalvular AF; were indicated for oral anticoagulation (OAC); and had a history of bleeding requiring intervention or hospitalization, a history of a cardioembolic event while taking an OAC, and/or a CHA₂DS₂-VASc of ≥3 and HAS-BLED of >2. Patients were randomized to receive LAAC or DOAC. The primary composite outcome was stroke, transient ischemic attack, systemic embolism, cardiovascular death, major or nonmajor clinically relevant bleeding, or procedure-/device-related complications. The primary analysis was by modified intention to treat.ResultsA high-risk patient cohort (CHA₂DS₂-VASc: 4.7 ± 1.5) was randomized to receive LAAC (n = 201) or DOAC (n = 201). LAAC was successful in 181 of 201 (90.0%) patients. In the DOAC group, apixaban was most frequently used (192 of 201; 95.5%). At a median 19.9 months of follow-up, the annual rates of the primary outcome were 10.99% with LAAC and 13.42% with DOAC (subdistribution hazard ratio [sHR]: 0.84; 95% confidence interval [CI]: 0.53 to 1.31; p = 0.44; p = 0.004 for noninferiority). There were no differences between groups for the components of the composite endpoint: all-stroke/TIA (sHR: 1.00; 95% CI: 0.40 to 2.51), clinically significant bleeding (sHR: 0.81; 95% CI: 0.44 to 1.52), and cardiovascular death (sHR: 0.75; 95% CI: 0.34 to 1.62). Major LAAC-related complications occurred in 9 (4.5%) patients.ConclusionsAmong patients at high risk for stroke and increased risk of bleeding, LAAC was noninferior to DOAC in preventing major AF-related cardiovascular, neurological, and bleeding events. (Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation [PRAGUE-17]; NCT02426944)     

Clopidogrel Monotherapy After 1-Month Dual Antiplatelet Therapy in Patients With Diabetes Undergoing Percutaneous Coronary Intervention

BackgroundDiabetes was reported to be associated with an impaired response to clopidogrel.ObjectivesThe aim of this study was to evaluate the safety and efficacy of clopidogrel monotherapy after very short dual antiplatelet therapy (DAPT) in patients with diabetes undergoing percutaneous coronary intervention (PCI).MethodsA subgroup analysis was conducted on the basis of diabetes in the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent–2) Total Cohort (N = 5,997) (STOPDAPT-2, n = 3,009; STOPDAPT-2 ACS [Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent–2 for the Patients With ACS], n = 2,988), which randomly compared 1-month DAPT followed by clopidogrel monotherapy with 12-month DAPT with aspirin and clopidogrel after cobalt-chromium everolimus-eluting stent implantation. The primary endpoint was a composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) or bleeding (TIMI [Thrombolysis In Myocardial Infarction] major or minor) endpoints at 1 year.ResultsThere were 2,030 patients with diabetes (33.8%) and 3967 patients without diabetes (66.2%). Regardless of diabetes, the risk of 1-month DAPT relative to 12-month DAPT was not significant for the primary endpoint (diabetes, 3.58% vs 4.12% [HR: 0.87; 95% CI: 0.56-1.37; P = 0.55]; nondiabetes, 2.46% vs 2.49% [HR: 0.99; 95% CI: 0.67-1.48; P = 0.97]; P_interaction = 0.67) and for the cardiovascular endpoint (diabetes, 3.28% vs 3.05% [HR: 1.10; 95% CI: 0.67-1.81; P = 0.70]; nondiabetes, 1.95% vs 1.43% [HR: 1.38; 95% CI: 0.85-2.25; P = 0.20]; P_interaction = 0.52), while it was lower for the bleeding endpoint (diabetes, 0.30% vs 1.50% [HR: 0.20; 95% CI: 0.06-0.68; P = 0.01]; nondiabetes, 0.61% vs 1.21% [HR: 0.51; 95% CI: 0.25-1.01; P = 0.054]; P_interaction = 0.19).ConclusionsClopidogrel monotherapy after 1-month DAPT compared with 12-month DAPT reduced major bleeding events without an increase in cardiovascular events regardless of diabetes, although the findings should be considered as hypothesis generating, especially in patients with acute coronary syndrome, because of the inconclusive result in the STOPDAPT-2 ACS trial. (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent–2 [STOPDAPT-2], NCT02619760; Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent–2 for the Patients With ACS [STOPDAPT-2 ACS], NCT03462498)     

Ticagrelor or Prasugrel in Patients With Acute Coronary Syndrome in Relation to Estimated Glomerular Filtration Rate

ObjectivesThe aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs).BackgroundThe outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined.MethodsPatients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m²), intermediate eGFR (≥60 and <90 mL/min/1.73 m²), and high eGFR (≥90 mL/min/1.73 m²). The primary endpoint was a composite of all-cause death, myocardial infarction, and stroke; the secondary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding, both at 1 year.ResultsPatients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding.ConclusionsThese results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800)     

Incidence,Predictors, and Outcomes of Endocarditis After Transcatheter Aortic Valve Replacement in the United States

ObjectivesThis study sought to evaluate the incidence and outcomes of endocarditis after transcatheter aortic valve replacement (TAVR).BackgroundData about endocarditis after TAVR are limited.MethodsThe study investigated Medicare patients who underwent TAVR from 2012 to 2017 and identified patients admitted with endocarditis during follow-up using a validated algorithm. The main study outcome was all-cause mortality.ResultsOf 134,717 patients who underwent TAVR, 1868 patients developed endocarditis during follow-up (incidence 0.87%/year), with majority of infections (65.0%) occurring within 1 year. Incidence of endocarditis declined in recent years. The most common organisms were Staphylococcus (22.0%), Streptococcus (20.0%), and Enterococcus (15.5%). Important predictors for endocarditis were younger age at TAVR, male sex, prior endocarditis, end-stage renal disease, repeat TAVR procedures, liver and lung disease, and post-TAVR acute kidney injury. Thirty-day and 1-year mortality were 18.5% and 45.6%, respectively. After adjusting for comorbidities and procedural complications, endocarditis after TAVR was associated with 3-fold higher risk of mortality (44.9 vs. 16.2 deaths per 100 person-years; adjusted hazard ratio [aHR]: 2.94; 95% confidence interval [CI]: 2.77 to 3.12; p < 0.0001). End-stage renal disease (aHR: 2.12; 95% CI: 1.72 to 2.60), endocarditis complicated by cardiogenic shock (aHR: 2.50, 95% CI: 1.56 to 4.02), ischemic stroke (aHR: 1.56; 95% CI: 1.07 to 2.28), intracerebral hemorrhage (aHR: 1.67; 95% CI: 1.01 to 2.76), acute kidney injury (aHR: 1.44; 95% CI: 1.27 to 1.63), blood transfusion (aHR: 1.28; 95% CI: 1.09 to 1.50), staphylococcal (aHR: 1.71; 95% CI: 1.49 to 1.97), and fungal endocarditis (aHR: 1.72; 95% CI: 1.23 to 2.39) (p < 0.05 for all) portended higher mortality following endocarditis.ConclusionsThe incidence of endocarditis after TAVR is low and declining. However, it is associated with poor prognosis with one-half the patients dying within 1 year.     

New-Onset Atrial Fibrillation After Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis

ObjectivesThe authors aimed to identify risk factors and outcomes associated with new-onset atrial fibrillation (NOAF) after transcatheter aortic valve replacement (TAVR).BackgroundNOAF is a common complication after TAVR, although estimates of the precise occurrence are variable. This study sought to quantify the occurrence of NOAF after TAVR and to explore the outcomes and predictors associated with this complication.MethodsWe searched Medline, EMBASE, and the Cochrane database from 2016 to 2020 for articles that reported NOAF after TAVR. We extracted data for studies published before 2016 from a previous systematic review. We pooled data using a random effects model.ResultsWe identified 179 studies with 241,712 total participants (55,271 participants with pre-existing atrial fibrillation (AF) were excluded) that reported NOAF from 2008 to 2020. The pooled occurrence of NOAF after TAVR was 9.9% (95% CI: 8.1%-12%). NOAF after TAVR was associated with a longer index hospitalization (mean difference = 2.66 days; 95% CI: 1.05-4.27), a higher risk of stroke in the first 30 days (risk ratio [RR]: 2.35; 95% CI: 2.12-2.61), 30-day mortality (RR: 1.76; 95% CI: 1.12-2.76), major or life-threatening bleeding (RR: 1.60; 95% CI: 1.39-1.84), and permanent pacemaker implantation (RR: 1.12; 95% CI: 1.05-1.18). Risk factors for the development of NOAF after TAVR included higher Society of Thoracic Surgeons score, transapical access, pulmonary hypertension, chronic kidney disease, peripheral vascular disease, and severe mitral regurgitation, suggesting that the risk for NOAF is highest in more comorbid TAVR patients.ConclusionsNOAF is common after TAVR. Whether AF after TAVR is a causal factor or a marker of sicker patients remains unclear.     

Prevalence and Impact of High Bleeding Risk in Patients Undergoing Left Main Artery Disease PCI

ObjectivesThe aim of this study was to determine the prevalence and prognostic impact of high bleeding risk (HBR), as determined by the Academic Research Consortium HBR criteria, in real-world patients undergoing left main (LM) percutaneous coronary intervention (PCI).BackgroundLM PCI is often reserved for patients at increased risk for periprocedural adverse events. Patients at HBR represent a relevant percentage of this cohort, but their outcomes after LM PCI are still poorly investigated.MethodsAll patients undergoing LM PCI between 2014 and 2017 at a tertiary care center were prospectively enrolled. Patients were defined as having HBR if they met at least 1 major or 2 minor Academic Research Consortium HBR criteria. The primary endpoint was the composite of all-cause death, myocardial infarction (MI), or stroke at 12 months.ResultsAmong 619 enrolled patients, 55.3% were at HBR. The rate of the primary endpoint was 4-fold higher in patients at HBR compared with those without HBR (20.5% vs 4.9%; HR: 4.43; 95% CI: 2.31-8.48), driven by an increased risk for all-cause death (HR: 3.88; 95% CI: 1.88-8.02) and MI (HR: 6.18; 95% CI: 1.83-20.9). Rates of target vessel or lesion revascularization and stent thrombosis were comparable in the 2 groups. Bleeding occurred more frequently in patients at HBR (HR: 3.77; 95% CI: 1.83-7.76). Consistent findings were observed after Cox multivariable regression adjustment.ConclusionsAmong patients undergoing LM PCI, those with HBR are at increased risk for all-cause death, MI, and bleeding. Conversely, rates of repeat revascularization and stent thrombosis were comparable, suggesting frailty and comorbidities as primary causes of worse outcomes in patients at HBR.     

Antithrombotic Therapy for Patients With Left Ventricular Mural Thrombus

BackgroundContemporary data are lacking regarding the prognosis and management of left ventricular thrombus (LVT).ObjectivesThe purpose of this study was to quantify the effect of anticoagulation therapy on LVT evolution using sequential imaging and to determine the impact of LVT regression on the incidence of thromboembolism, bleeding, and mortality.MethodsFrom January 2011 to January 2018, a comprehensive computerized search of LVT was conducted using 90,065 consecutive echocardiogram reports. Only patients with a confirmed LVT were included after imaging review by 2 independent experts. Major adverse cardiovascular events (MACE), which included death, stroke, myocardial infarction, or acute peripheral artery emboli, were determined as well as major bleeding events (BARC ≥3) and all-cause mortality rates.ResultsThere were 159 patients with a confirmed LVT. Patients were treated with vitamin K antagonists (48.4%), parenteral heparins (27.7%), and direct oral anticoagulants (22.6%). Antiplatelet therapy was used in 67.9% of the population. A reduction of the LVT area from baseline was observed in 121 patients (76.1%), and total LVT regression occurred in 99 patients (62.3%) within a median time of 103 days (interquartile range: 32 to 392 days). The independent correlates of LVT regression were a nonischemic cardiomyopathy (hazard ratio [HR]: 2.74; 95% confidence interval [CI]: 1.43 to 5.26; p = 0.002) and a smaller baseline thrombus area (HR: 0.66; 95% CI: 0.45 to 0.96; p = 0.031). The frequency of MACE was 37.1%; mortality 18.9%; stroke 13.3%; and major bleeding 13.2% during a median follow-up of 632 days (interquartile range: 187 to 1,126 days). MACE occurred in 35.4% and 40.0% of patients with total LVT regression and those with persistent LVT (p = 0.203). A reduced risk of mortality was observed among patients with total LVT regression (HR: 0.48; 95% CI: 0.23 to 0.98; p = 0.039), whereas an increased major bleeding risk was observed among patients with persistent LVT (9.1% vs. 12%; HR 0.34; 95% CI: 0.14 to 0.82; p = 0.011). A left ventricular ejection fraction ≥35% (HR: 0.46; 95% CI: 0.23 to 0.93; p = 0.029) and anticoagulation therapy >3 months (HR: 0.42; 95% CI: 0.20 to 0.88; p = 0.021) were independently associated with less MACE.ConclusionsThe presence of LVT was associated with a very high risk of MACE and mortality. Total LVT regression, obtained with different anticoagulant regimens, was associated with reduced mortality.