Assessment of Noninferiority Margins in Cardiovascular Medicine Trials.

Background: Noninferiority trials are increasingly common in cardiovascular medicine, but their reporting and interpretation are challenging, particularly when an absolute risk difference is used as noninferiority margin. Objectives: This study aimed to investigate the effect of using absolute rather than relative noninferiority margins in cardiovascular trials. Methods: We reviewed noninferiority trials presented at major cardiovascular conferences from 2015 to 2022 and published within the same period. Based on the actual versus anticipated event rates in the control group, we recalculated the absolute noninferiority margin and re-assessed the trial results. The primary outcome of interest was the proportion of trials with a different interpretation after recalculation. Additionally, we analyzed the conclusion statements of these trials to determine if cautionary notes for the interpretation of study results were included. Results: We analyzed a total of 768 trials, of which 88 had a noninferiority design and 66 used an absolute noninferiority margin. Of 48 comparisons from 45 trials qualifying for the analysis, 11 (22.9%) had divergent results after recalculation of the absolute noninferiority margin based on the observed rather than anticipated event rate. Ten trials originally claiming noninferiority, did not meet it after the margin recalculation. All of them did not include statements suggesting cautionary interpretation of the study results in the conclusion section. Compared with the other trials, these displayed a larger median difference between anticipated and recalculated noninferiority margins (44.7% [IQR: 38.6%-56.7%] vs 15.3% [IQR: -1.5% to 28.9%]; P < 0.001). Conclusions: Recalculating noninferiority margins based on actual event rates, rather than anticipated ones, led to different outcomes in approximately 1 out of 4 cardiovascular trials, with most divergent trials lacking cautionary interpretation. These findings emphasize the importance of using or supplementing the relative noninferiority margin, particularly in studies with significant deviations between observed and expected event rates. This underscores the critical need for enhanced methodological and reporting standards in noninferiority trials, especially those employing absolute margins.

Percutaneous interventions for pulmonary embolism.

Pulmonary embolism (PE) ranks as a leading cause of in-hospital mortality and the third most common cause of cardiovascular death. The spectrum of PE manifestations varies widely, making it difficult to determine the best treatment approach for specific patients. Conventional treatment options include anticoagulation, thrombolysis, or surgery, but emerging percutaneous interventional procedures are being investigated for their potential benefits in heterogeneous PE populations. These novel interventional techniques encompass catheter-directed thrombolysis, mechanical thrombectomy, and hybrid approaches combining different mechanisms. Furthermore, inferior vena cava filters are also available as an option for PE prevention. Such interventions may offer faster improvements in right ventricular function, as well as in pulmonary and systemic haemodynamics, in individual patients. Moreover, percutaneous treatment may be a valid alternative to traditional therapies in high bleeding risk patients and could potentially reduce the burden of mortality related to major bleeds, such as that of haemorrhagic strokes. Nevertheless, the safety and efficacy of these techniques compared to conservative therapies have not been conclusively established. This review offers a comprehensive evaluation of the current evidence for percutaneous interventions in PE and provides guidance for selecting appropriate patients and treatments. It serves as a valuable resource for future researchers and clinicians seeking to advance this field. Additionally, we explore future perspectives, proposing "percutaneous primary pulmonary intervention" as a potential paradigm shift in the field.

Exploring the impact of cardiologists expertise on publication metrics.

BACKGROUND: In the field of academic cardiology, the assessment of an author's scholarly impact and professional progression heavily relies on publications and citations. This study investigates whether specific cardiology expertise correlates with accelerated professional growth. METHODS: Using data from the 2023 European Society of Cardiology congress, 948 faculty attendees with an h-index of 30 or higher were analyzed. Expertises were categorized into six groups, and their association with publications and citations peaks was explored. RESULTS: Interventional cardiologists exhibited the highest annual publication peak, followed by imaging and electrophysiology experts. However, no significant differences were observed in citation peaks among expertise groups. While imaging experts initially appeared to reach citation peaks faster, this effect diminished after statistical adjustments. Additionally, holding multiple expertise areas prolonged the time to reach publication and citation peaks by approximately six years. CONCLUSION: This study underscores the influence of expertise in interventional cardiology on publication peaks but suggests that citation peaks and career progression velocity remain unaffected by expertise type. Furthermore, it highlights that holding multiple areas of expertise slowers the attainment of career peak for scholarly authors.

Antithrombotic strategies for preventing graft failure in coronary artery bypass graft.

Coronary artery bypass graft (CABG) procedures face challenges related to graft failure, driven by factors such as acute thrombosis, neointimal hyperplasia, and atherosclerotic plaque formation. Despite extensive efforts over four decades, the optimal antithrombotic strategy to prevent graft occlusion while minimizing bleeding risks remains uncertain, relying heavily on expert opinions rather than definitive guidelines. To address this uncertainty, we conducted a review of randomized clinical trials and meta-analyses of antithrombotic therapy for patients with CABG. These studies examined various antithrombotic regimens in CABG such as single antiplatelet therapy (aspirin or P2Y12 inhibitors), dual antiplatelet therapy, and anticoagulation therapy. We evaluated outcomes including the patency of grafts, major adverse cardiovascular events, and bleeding complications and also explored future perspectives to enhance long-term outcomes for CABG patients. Early studies established aspirin as a key component of antithrombotic pharmacotherapy after CABG. Subsequent randomized controlled trials focused on adding a P2Y12 inhibitor (such as clopidogrel, ticagrelor, or prasugrel) to aspirin, yielding mixed results. This article aims to inform clinical decision-making and guide the selection of antithrombotic strategies after CABG.

Coronary Angiography, Intravascular Ultrasound, and Optical Coherence Tomography for Guiding of Percutaneous Coronary Intervention: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Results from multiple randomized clinical trials comparing outcomes after intravascular ultrasound (IVUS)- and optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) with invasive coronary angiography (ICA)-guided PCI as well as a pivotal trial comparing the 2 intravascular imaging (IVI) techniques have provided mixed results. METHODS: Major electronic databases were searched to identify eligible trials evaluating at least 2 PCI guidance strategies among ICA, IVUS, and OCT. The 2 coprimary outcomes were target lesion revascularization and myocardial infarction. The secondary outcomes included ischemia-driven target lesion revascularization, target vessel myocardial infarction, death, cardiac death, target vessel revascularization, stent thrombosis, and major adverse cardiac events. Frequentist random-effects network meta-analyses were conducted. The results were replicated by Bayesian random-effects models. Pairwise meta-analyses of the direct components, multiple sensitivity analyses, and pairwise meta-analyses IVI versus ICA were supplemented. RESULTS: The results from 24 randomized trials (15 489 patients: IVUS versus ICA, 46.4%, 7189 patients; OCT versus ICA, 32.1%, 4976 patients; OCT versus IVUS, 21.4%, 3324 patients) were included in the network meta-analyses. IVUS was associated with reduced target lesion revascularization compared with ICA (odds ratio [OR], 0.69 [95% CI, 0.54-0.87]), whereas no significant differences were observed between OCT and ICA (OR, 0.83 [95% CI, 0.63-1.09]) and OCT and IVUS (OR, 1.21 [95% CI, 0.88-1.66]). Myocardial infarction did not significantly differ between guidance strategies (IVUS versus ICA: OR, 0.91 [95% CI, 0.70-1.19]; OCT versus ICA: OR, 0.87 [95% CI, 0.68-1.11]; OCT versus IVUS: OR, 0.96 [95% CI, 0.69-1.33]). These results were consistent with the secondary outcomes of ischemia-driven target lesion revascularization, target vessel myocardial infarction, and target vessel revascularization, and sensitivity analyses generally did not reveal inconsistency. OCT was associated with a significant reduction of stent thrombosis compared with ICA (OR, 0.49 [95% CI, 0.26-0.92]) but only in the frequentist analysis. Similarly, the results in terms of survival between IVUS or OCT and ICA were uncertain across analyses. A total of 25 randomized trials (17 128 patients) were included in the pairwise meta-analyses IVI versus ICA where IVI guidance was associated with reduced target lesion revascularization, cardiac death, and stent thrombosis. CONCLUSIONS: IVI-guided PCI was associated with a reduction in ischemia-driven target lesion revascularization compared with ICA-guided PCI, with the difference most evident for IVUS. In contrast, no significant differences in myocardial infarction were observed between guidance strategies.

Pharmacological and clinical appraisal of factor XI inhibitor drugs.

The evolution of anticoagulation therapy, from vitamin K antagonists to the advent of direct oral anticoagulants (DOACs) almost two decades ago, marks significant progress. Despite improved safety demonstrated in pivotal trials and post-marketing observations, persistent concerns exist, particularly regarding bleeding risk and the absence of therapeutic indications in specific subgroups or clinical contexts. Factor XI (FXI) has recently emerged as a pivotal contributor to intraluminal thrombus formation and growth, playing a limited role in sealing vessel wall injuries. Inhibiting FXI presents an opportunity to decouple thrombosis from haemostasis, addressing concerns related to bleeding events while safeguarding against thromboembolic events. Notably, FXI inhibition holds promise for patients with end-stage renal disease or cancer, where clear indications for DOACs are currently lacking. Various compounds have undergone design, testing, and progression to phase 2 clinical trials, demonstrating a generally favourable safety and tolerability profile. However, validation through large-scale phase 3 trials with sufficient power to assess both safety and efficacy outcomes is needed. This review comprehensively examines FXI inhibitors, delving into individual classes, exploring their pharmacological properties, evaluating the latest evidence from randomized trials, and offering insights into future perspectives.

Association of trial characteristics with simultaneous publication and its impact on citations and mentions: a cross-sectional study.

INTRODUCTION AND OBJECTIVES: Randomized trials are often presented at medical conferences and published simultaneously or later. Predictors of simultaneous publication and its consequences are undetermined. Our aim was to characterize the practice of simultaneous publication, identify its predictors, and evaluate its impact. METHODS: In this cross-sectional study, we included randomized trials presented at late-breaking science sessions of major cardiovascular conferences from 2015 to 2021. The association of trial characteristics with the timing of publication was analyzed. The impact of simultaneous vs nonsimultaneous publication was investigated on the number of 1-year citations and 1-month mentions, and the total citations and mentions at the longest observation follow-up. RESULTS: Of 478 trials included in the analysis, 48.7% were published simultaneously. Simultaneous publications were more likely to be presented in the main conference room (OR, 6.09; 95%CI, 1.34-36.92; P=.029) and were characterized by a shorter review time (OR, 0.95; 95%CI, 0.91-0.96; P<.001). Simultaneous publications were associated with higher 1-year citations (R2, 43.81; 95%CI, 23.89-63.73; P<.001), 1-month mentions (R2, 132.32; 95%CI, 85.42-179.22; P<.001) and total citations (R2, 222.89; 95%CI, 127.98-317.80; P<.001). CONCLUSIONS: Randomized trials presented in the main conference room and with shorter review time were more likely to be published simultaneously. Simultaneous publications were associated with more citations and mentions than nonsimultaneous publications.

PCSK9 inhibitors: current status and emerging frontiers in lipid control.

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, imposing substantial healthcare economic burdens. Among the modifiable risk factors, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in ASCVD development. Novel therapies such as PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors are emerging to address this concern. These inhibitors offer the potential to reduce ASCVD risk by directly targeting LDL-C levels. AREAS COVERED: The article reviews the structural and functional aspects of PCSK9, highlighting its role in LDL receptor regulation. The pharmacological strategies for PCSK9 inhibition, including monoclonal antibodies, binding peptides, gene silencing, and active immunization, are explored. Clinical evidence from various trials underscores the safety and efficacy of PCSK9 inhibitors in reducing LDL-C levels and potentially improving cardiovascular outcomes. Despite these promising results, challenges such as cost-effectiveness and long-term safety considerations are addressed. EXPERT OPINION: Among PCSK9 inhibitors, monoclonal antibodies represent a cornerstone. Many trials have showed their efficacy in reducing LDL-C and the risk for major adverse clinical events, revealing long-lasting effects, with special benefits particularly for statin-intolerant and familial hypercholesterolemia patients. However, long-term impacts, high costs, and patient selection necessitate further research.

Antithrombotic Therapy for Primary and Secondary Prevention of Ischemic Stroke: JACC State-of-the-Art Review.

Stroke is a devastating condition with significant morbidity and mortality worldwide. Antithrombotic therapy plays a crucial role in both primary and secondary prevention of stroke events. Single or dual antiplatelet therapy is generally preferred in cases of large-artery atherosclerosis and small-vessel disease, whereas anticoagulation is recommended in conditions of blood stasis or hypercoagulable states that mostly result in red thrombi. However, the benefit of antithrombotic therapies must be weighed against the increased risk of bleeding, which can pose significant challenges in the pharmacological management of this condition. This review provides a comprehensive summary of the currently available evidence on antithrombotic therapy for ischemic stroke and outlines an updated therapeutic algorithm to support physicians in tailoring the strategy to the individual patient and the underlying mechanism of stroke.

Complete Percutaneous Coronary Revascularization in Acute Coronary Syndromes With Multivessel Coronary Disease: A Systematic Review.

Multivessel disease (MVD) affects approximately 50% of patients with acute coronary syndromes (ACS) and is significantly burdened by poor outcomes and high mortality. It represents a clinical challenge in patient management and decision making and subtends an evolving research area related to the pathophysiology of unstable plaques and local or systemic inflammation. The benefits of complete revascularization are established in hemodynamically stable ACS patients with MVD, and guidelines provide some reference points to inform clinical practice, based on an evidence level that is solid for ST-segment elevation myocardial infarction and less robust for non-ST-segment elevation myocardial infarction and cardiogenic shock. However, several areas of uncertainty remain, such as the optimal timing for complete revascularization or the best guiding strategy for intermediate stenoses. We performed a systematic review of current evidence in the field of percutaneous revascularization in ACS and MVD, also including future perspectives from ongoing trials that will directly compare different timing strategies and investigate the role of invasive and noninvasive guidance techniques. (Complete percutaneous coronary revascularization in patients with acute myocardial infarction and multivessel disease; CRD42022383123).

A review of polypills for the prevention of atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease (ASCVD) is a prevalent chronic condition managed through pharmacotherapy targeting modifiable risk factors. However, ASCVD patients often face poor medication adherence due to a high pill burden from multiple oral drugs, contributing to cardiovascular events. Recent evidence indicates that polypills combining antihypertensive and statin medications effectively control risk factors and improve adherence in various ASCVD risk patients. Randomized clinical trials demonstrate polypill efficacy in reducing major cardiovascular events, making them a convenient strategy for both established ASCVD patients and those without ASCVD. These positive results encourage the incorporation of polypills into comprehensive cardiovascular prevention programs, particularly for socio-economically vulnerable populations. Nevertheless, barriers remain, such as unclear regulatory approval pathways and physician hesitancy. Despite challenges, the benefits of fixed-dose combinations are evident and should be encouraged for secondary and primary prevention, especially in high-risk categories. Technological advancements could further support the successful integration of polypills in clinical practice. This review discusses the evidence, challenges, and perspectives of polypills, emphasizing their potential impact on cardiovascular disease management.

Eligibility to Intensified Antithrombotic Regimens for Secondary Prevention in Patients Who Underwent Percutaneous Coronary Intervention.

Single antiplatelet therapy (SAPT) and intensified antithrombotic regimens (prolonged dual antiplatelet therapy [DAPT] or dual pathway inhibition [DPI]) are recommended for secondary prevention in patients who underwent percutaneous coronary intervention (PCI) after initial DAPT. We aimed to characterize eligibility to such strategies and to explore to what extent guidelines are applied in clinical practice. Patients who underwent PCI for acute or chronic coronary syndrome who completed initial DAPT were analyzed from a prospective registry. Patients were categorized into SAPT, prolonged DAPT/DPI, or DPI groups as per guideline indication by using a risk stratification algorithm. Predictors of receiving intensified regimens and the divergency of practice from guidelines were investigated. Between October 2019 and September 2021, a total of 819 patients were included. Based on the guidelines, 83.7% of patients qualified for SAPT, 9.6% for any intensified regimen (i.e., prolonged DAPT or DPI), and 6.7% for DPI only. At multivariable analysis, patients were more likely to receive an intensified regimen if they had diabetes, dyslipidemia, peripheral artery disease, multivessel disease, or previous myocardial infarction. Conversely, they were less likely to receive an intensified regimen if they had atrial fibrillation, chronic kidney disease, or previous stroke. Guidelines were not followed in 18.3% of cases. In particular, only 14.3% of candidates to intensified regimens were treated accordingly. In conclusion, although the majority of patients who underwent PCI after the initial period of DAPT were eligible for SAPT, 1 out of 6 had an indication to intensified regimens. However, such intensified regimens were underused among eligible patients.

Pharmacology and Clinical Development of Factor XI Inhibitors.

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

Short Duration of DAPT Versus De-Escalation After Percutaneous Coronary Intervention for Acute Coronary Syndromes.

OBJECTIVES: The aim of this study was to compare short dual antiplatelet therapy (DAPT) and de-escalation in a network meta-analysis using standard DAPT as common comparator. BACKGROUND: In patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), shortening DAPT and de-escalating to a lower potency regimen mitigate bleeding risk. These strategies have never been randomly compared. METHODS: Randomized trials of DAPT modulation strategies in patients with ACS undergoing PCI were identified. All-cause death was the primary outcome. Secondary outcomes included net adverse cardiovascular events (NACE), major adverse cardiovascular events, and their components. Frequentist and Bayesian network meta-analyses were conducted. Treatments were ranked on the basis of posterior probability. Sensitivity analyses were performed to explore sources of heterogeneity. RESULTS: Twenty-nine studies encompassing 50,602 patients were included. The transitivity assumption was fulfilled. In the frequentist indirect comparison, the risk ratio (RR) for all-cause death was 0.98 (95% CI: 0.68-1.43). De-escalation reduced the risk for NACE (RR: 0.87; 95% CI: 0.70-0.94) and increased major bleeding (RR: 1.54; 95% CI: 1.07-2.21). These results were consistent in the Bayesian meta-analysis. De-escalation displayed a >95% probability to rank first for NACE, myocardial infarction, stroke, stent thrombosis, and minor bleeding, while short DAPT ranked first for major bleeding. These findings were consistent in node-split and multiple sensitivity analyses. CONCLUSIONS: In patients with ACS undergoing PCI, there was no difference in all-cause death between short DAPT and de-escalation. De-escalation reduced the risk for NACE, while short DAPT decreased major bleeding. These data characterize 2 contemporary strategies to personalize DAPT on the basis of treatment objectives and risk profile.

P2Y12 Inhibitor Monotherapy: Considerations for Acute and Long-Term Secondary Prevention Post-PCI.

Following percutaneous coronary intervention (PCI), an initial course of dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor ( P2Y 12 -i) is recommended to minimize the risk of thrombotic complications. After the initial period of DAPT, antiplatelet monotherapy, usually consisting of aspirin, is administered for long-term secondary prevention. However, over the last few years there has been accruing evidence on P2Y 12 -i monotherapy, both in the acute (i.e., post-PCI; after a brief period of DAPT, transitioning to monotherapy before six or 12 months in patients with chronic or acute coronary syndrome, respectively) and chronic (i.e., long-term secondary prevention; after completion of six or 12 months of DAPT, in patients with chronic or acute coronary syndrome, respectively) settings. In aggregate, most studies of short DAPT with transition to P2Y 12 -i monotherapy showed a reduced risk of bleeding complications, without any significant increase in ischemic events as compared to standard DAPT. On the other hand, the evidence on long-term P2Y 12 -i monotherapy is scarce, but results from a randomized trial showed that clopidogrel monotherapy outperformed aspirin monotherapy in terms of net benefit, ischemic events and bleeding. Antiplatelet therapy is also recommended for patients undergoing PCI and with an established indication for long-term oral anticoagulation (OAC). In this scenario, a brief period of triple therapy (i.e., aspirin, P2Y 12 -i and OAC) is followed by a course of dual antithrombotic therapy (usually with P2Y 12 -i and OAC) and ultimately by lifelong OAC alone. European and American guidelines have been recently updated to provide new recommendations on antithrombotic therapy, including the endorsement of P2Y 12 -i monotherapy in different settings. However, some areas of uncertainty still remain and further randomized investigations are ongoing to fulfil current gaps in knowledge. In this review, we assess the current knowledge and evidence on P2Y 12 -i monotherapy for the early and long-term secondary prevention in patients undergoing PCI, and explore upcoming research and future directions in the field.

Appraising the contemporary role of aspirin for primary and secondary prevention of atherosclerotic cardiovascular events.

INTRODUCTION: Although the role of aspirin for primary prevention of atherosclerotic cardiovascular disease (ASCVD) has been disputed, its use in secondary ASCVD prevention is well established. Recent trials of primary prevention do not suggest a significant net benefit with aspirin, whereas accruing evidence supports adopting aspirin-free strategies in the context of potent P2Y12 inhibition for the secondary prevention of selected patients undergoing percutaneous coronary intervention. AREAS COVERED: This updated review aims at summarizing and appraising the pharmacological characteristics and the contemporary role of aspirin for the primary and secondary prevention of ASCVD. EXPERT OPINION: Recent trials and metanalyses in the context of primary prevention highlighted a modest reduction in ischemic events with aspirin use, counterbalanced by a significant increase in bleeding events. However, ongoing studies on cancer prevention could modify the current paradigm of the unfavorable benefit-risk ratio of aspirin in patients with no overt ASCVD. Conversely, aspirin use is crucial for secondary ASCVD prevention, both in chronic and acute coronary syndromes. Nevertheless, after a brief period of dual antiplatelet therapy, patients at high bleeding risk may benefit from discontinuation of aspirin if a P2Y12 inhibitor is used, hence reducing the bleeding risk with no rebound in thrombotic events.