Controversy in cardiology: clopidogrel or acetylsalicylic acid in the treatment of chronic coronary syndromes?

Secondary prevention of patients with chronic coronary syndrome is based on the long-term use of a single anti-aggregating drug which is traditionally represented by acetylsalicylic acid (ASA) in light of the results of studies and meta-analyses which have demonstrated a clear anti-ischaemic efficacy against of an acceptable increase in the risk of bleeding, especially intracranial and gastrointestinal bleeding. The availability of drugs such as clopidogrel, which inhibits platelet activity through the P2Y12 receptor pathway, has called into question this paradigm, also in consideration of the fact that the scientific evidence that supports the use of ASA in secondary prevention is based on dated studies with some limitations. Over the last few years, randomized trials have demonstrated how clopidogrel has an efficacy profile comparable to that of ASA and a safety profile that is sometimes even better. In light of the new evidence, it is therefore legitimate to ask whether in this clinical scenario, ASA should still be considered the drug of choice or whether clopidogrel could represent the preferable alternative.

Application of the Academic Research Consortium High Bleeding Risk criteria in patients treated with coronary bioresorbable polymer everolimus-eluting stents: Insights from the POEM trial.

BACKGROUND: Previous studies have investigated a 1 to 6-month short dual antiplatelet therapy (S-DAPT) after percutaneous coronary intervention (PCI) with modern drug eluting-stents to reduce bleeding events. OBJECTIVES: To investigate cardiovascular outcomes in patients at high bleeding risk (HBR) according to the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria after PCI with the Synergy bioresorbable-polymer everolimus-eluting stents (EES). METHODS: We applied ARC-HBR criteria in the population of the prospective, single-arm, multicenter POEM (Performance of Bioresorbable Polymer-Coated Everolimus-Eluting Synergy Stent in Patients at HBR Undergoing Percutaneous Coronary Revascularization Followed by 1-Month Dual Antiplatelet Therapy) trial. The primary endpoint was a composite of cardiac death, myocardial infarction, or definite or probable stent thrombosis at 12 months. RESULTS: The original POEM cohort included 356 patients (80.4 %) fulfilling ARC-HBR criteria. Oral anticoagulant (OAC) usage and age ≥75 years were the most frequent major and minor ARC-HBR criteria, respectively. The ARC-HBR group was mainly represented by men (71.1 %), with 74.4 ± 9.3 years and a high burden of cardiovascular risk factors. DAPT was prescribed in 79.3 %, and single antiplatelet (SAPT) with OAC in 18.7 %. 12-month follow-up was completed in 96.2 %. The primary endpoint occurred in 5.2 % (95 % CI 3.29-8.10) of patients, whereas bleeding Academic Research Consortium type 3-5 occurred in 2.7 % (95 % CI, 1.39 %-5.05 %). CONCLUSION: Previous results of the POEM trial showed positive outcomes regarding ischemic and bleeding events with an S-DAPT regimen after Synergy EES. These results are also confirmed in sub-group analysis when ARC-HBR criteria are applied.

Novel and Emerging LDL-C Lowering Strategies: A New Era of Dyslipidemia Management.

Atherosclerotic cardiovascular disease (ASCVD) represents a major global health challenge, significantly contributing to mortality rates. This chronic inflammatory condition affecting blood vessels is intricately linked to hypercholesterolemia, with elevated levels of low-density lipoprotein cholesterol (LDL-C) recognized as a central and modifiable risk factor. The effectiveness of lipid-lowering therapy (LLT) in mitigating ASCVD risk is well established, with studies revealing a substantial reduction in major ischemic events correlating with LDL-C reduction. While statins, often combined with ezetimibe, remain fundamental in dyslipidemia management, a significant proportion of patients on statin therapy continue to experience cardiovascular events. Recent pharmacological advancements, driven by a deeper understanding of atherogenesis, have unveiled novel therapeutic targets and potent drugs. Notably, agents like bempedoic acid and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (evolocumab, alirocumab, inclisiran) have emerged as effective options to intensify LLT and achieve LDL-C goals, addressing limitations associated with statins, such as myopathy. Molecular insights into alternative pathways have spurred the investigation of emerging agents, offering promising perspectives for novel medications with efficacy comparable to established treatments, associated with advantages in cost and administration. This review provides a comprehensive overview of the evolving landscape of lipid-lowering strategies, highlighting the progress made in addressing ASCVD risk and the potential of upcoming therapies to further optimize cardiovascular prevention.

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.

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.

The temptation of anticoagulant therapy after transcatheter aortic valve implantation.

The choice of the best antithrombotic strategy after transcatheter aortic valve implantation (TAVI) must be based on the careful balance between the ischaemic risk and the bleeding risk and on the evaluation of some concomitant conditions, such as atrial fibrillation or coronary artery disease which may lead to the choice of anticoagulant treatment or antiplatelet therapy. Another element to consider is the possibility, albeit remote in post-TAVI patients, of thrombosis of the valve leaflets, an event whose clinical impact has yet to be fully clarified and which however appears to present a lower incidence in patients treated with anticoagulants. Recent evidence has shown that in patients who do not require anticoagulant therapy, single therapy with aspirin represents the best treatment compared to dual antiplatelet or to the addition of anticoagulant which in post-TAVI patients should be reserved only for those with a clear indication such as atrial fibrillation. It is still much debated whether in this case the choice should fall on vitamin K antagonists or on the new direct-acting anticoagulants, as the comparison studies have produced inconclusive results.

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.

Antiplatelet therapy after noncardioembolic ischemic stroke or transient ischemic attack.

INTRODUCTION: Antiplatelet therapy is key to prevent recurrences in patients with an acute or prior non-cardioembolic stroke or transient ischemic attack (TIA). The narrow balance between the risks of ischemic recurrence and major bleeding is a relevant clinical dilemma in this population. AREAS COVERED: This review covers the current evidence on antiplatelet therapy for patients with non-cardioembolic stroke or TIA. Randomized controlled trials of antithrombotic strategies for patients with these conditions were searched in Pubmed/Medline from 1970 to 2022. EXPERT OPINION: Numerous randomized controlled trials have defined the current indications to the use of antiplatelet drugs for patients with non-cardioembolic ischemic stroke or TIA. For the management of these subjects, single antiplatelet therapy with aspirin or clopidogrel, or the combination of aspirin and dipyridamole, is usually recommended. After an acute stroke or TIA, a short course of dual antiplatelet therapy with aspirin in combination with clopidogrel or ticagrelor should be considered. The risk of bleeding might be higher with ticagrelor, but a direct comparison with clopidogrel is not available in this setting. The introduction of newer strategies, such as dual-pathway inhibition with aspirin and a direct oral anticoagulant (including emerging factor XI inhibitors under clinical development) may open a new research avenue in this challenging area.

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.

Efficacy and Safety of Aspirin for Primary Cardiovascular Risk Prevention in Younger and Older Age: An Updated Systematic Review and Meta-analysis of 173,810 Subjects from 21 Randomized Studies.

AIMS: The efficacy and safety of aspirin for primary cardiovascular disease (CVD) prevention is controversial. The aim of this study was to investigate the efficacy and safety of aspirin in subjects with no overt CVD, with a focus on age as a treatment modifier. METHODS AND RESULTS: Randomized trials comparing aspirin use versus no aspirin use or placebo were included. The primary efficacy outcome was all-cause death. The primary safety outcome was major bleeding. Secondary ischemic and bleeding outcomes were explored. Subgroup analyses were conducted to investigate the consistency of the effect sizes in studies including younger and older individuals, using a cut-off of 65 years. A total of 21 randomized trials including 173,810 individuals at a mean follow-up of 5.3 years were included. Compared with control, aspirin did not reduce significantly the risk of all-cause death (risk ratio: 0.96; 95% confidence interval: 0.92-1.00, p = 0.057). Major adverse cardiovascular events were significantly reduced by 11%, paralleled by significant reductions in myocardial infarction and transient ischemic attack. Major bleeding, intracranial hemorrhage, and gastrointestinal bleeding were significantly increased by aspirin. There was a significant age interaction for death (p for interaction = 0.007), with aspirin showing a statistically significant 7% relative benefit on all-cause death in studies including younger patients. CONCLUSION: The use of aspirin in subjects with no overt CVD was associated with a neutral effect on all-cause death and a modest lower risk of major cardiovascular events at the price of an increased risk in major bleeding. The benefit of aspirin might be more pronounced in younger individuals.

Suitability for elderly with heart disease of a QR code-based feedback of drug intake: Overcoming limitations of current medication adherence telemonitoring systems.

BACKGROUND: Current medication adherence telemonitoring systems have several limitations prompting the need for simpler, low-cost and widely applicable tools. To meet these needs, we propose a novel method consisting in sending a digital feedback of medication intake by just reading a pre-defined Quick Response (QR) code attached on the pills box. METHODS: To assess the potential clinical applicability of the proposed QR code-based task, its feasibility was tested among elderly with heart diseases. The primary endpoint was the learning success defined as a correct execution of all QR code-based digital task steps within 10 min. Study outcomes were compared between patients 65-75 years old (younger cohort) and those aged >75 years (older cohort) admitted to the Cardiology ward of a tertiary center. RESULTS: A total of 262 patients were included: 128 (48.9%) were younger and 134 (51.1%) older. Despite a baseline low smartphone use in the overall population (41.2%), patients learning success of the digital task was as high as 75.6%, with lower rates among older vs. younger (67.9% vs. 83.6%, p = 0.005). After adjustment no significant independent association between age and success in learning the QR code-based task was found. Differently, increasing age was a negative independent predictor of smartphone use. The learning time was overall small, but longer in the older group (126 ± 100 vs. 100 ± 60 s, p = 0.03). CONCLUSIONS: The QR code-based digital task was highly feasible for elderly with heart diseases suggesting its potential large-scale clinical application and encouraging the investigation of QR code-based systems for medication adherence telemonitoring.