Patients with peripheral artery disease (PAD) who undergo lower extremity revascularization (LER) are at high risk for cardiovascular and limb-related ischemic events. The role of antithrombotic therapy is to prevent thrombotic complications, but this requires balancing increased risk of bleeding events. The dual pathway inhibition (DPI) strategy including aspirin and low-dose rivaroxaban after LER has been shown to reduce major adverse cardiovascular and limb-related events without significant differences in major bleeding. There is now a need to implement the broad adoption of DPI therapy in PAD patients who have undergone LER in routine practice.

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OBJECTIVE: There is a lack of consensus regarding the optimal strategy for evaluating the efficiency and safety of dual-pathway inhibition (DPI) in preventing femoropopliteal restenosis in patients undergoing repeated endovascular interventions. Despite several therapeutic interventions available for preventing femoropopliteal restenosis post repeated endovascular interventions, the ideal strategy, particularly evaluating the efficacy and safety of DPI, remains a matter of debate.
METHODS: From January 2015 to September 2021, patients who underwent repeated endovascular interventions for femoropopliteal restenosis were compared with those who underwent DPI or dual antiplatelet therapy (DAPT) after surgery using a propensity score-matched analysis. The primary outcome was clinically driven target lesion revascularization (CD-TLR). The principal safety outcome was a composite of major bleeding and clinically relevant non-major (CRNM) bleeding. To further enhance the rigor, Kaplan-Meier plots, Cox proportional hazards modeling, and sensitivity analyses, as well as subgroup analyses were employed, reducing potential confounders.
RESULTS: A total of 441 patients were included in our study, of whom 294 (66.7%) received DAPT and 147 (33.1%) received DPI, with 114 matched pairs (mean age, 72.21 years; 84.2% male). Cumulative probability of CD-TLR at 36 months in the DPI group (17%) trended lower than that in the DAPT group (32%) (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.26-0.78; P =.004). The cumulative probability of freedom from CD-TLR at 36 months in the DPI group was 83%. No significant difference was observed in the composite outcome of major or CRNM bleeding between the DPI and DAPT groups (HR, 1.26; 95% CI, 0.34 to 4.69; P = .730). The DPI group was associated with significantly lower rates of CD-TLR in the main subgroup analyses of diabetes (P = .001), previous smoking history (P = .008), longer lesion length (>10 cm) (P = .003), and treatment with debulking strategy (P = .003).
CONCLUSIONS: In our investigation focused on CD-TLR, we found that DPI exhibited a significant reduction in the risk of reintervention compared with other treatment modalities. This underscores the potential of DPI as a viable therapeutic strategy in preventing reinterventions. Moreover, our assessment of safety outcomes revealed that the bleeding risks associated with DPI were on par with DAPT, thereby not compromising patient safety. These findings pave the way for potential broader clinical implications, emphasizing the effectiveness and safety of DPI in the context of reducing reintervention risks.

Antithrombotic therapy is the cornerstone of secondary cardiovascular prevention after percutaneous coronary intervention (PCI). Improvements in drug-eluting stent (DES) design and materials over the last 2 decades have prompted the development of new antithrombotic strategies. Current guidelines recommend to tailor dual antiplatelet therapy (DAPT) according to clinical presentation and individual ischemic and bleeding risk. Given the growing number of complex PCI procedures performed nowadays, it is a priority to define the optimal antithrombotic treatment in this challenging patient subset. In this review article, we sought to summarize and discuss the current evidence on antiplatelet therapy in patients undergoing complex PCI.

Chronic limb-threatening ischaemia (CLTI) entails dismal outcomes and is an absolute indication to lower extremity revascularization (LER) whenever possible. Antithrombotic therapy is here crucial, but available evidence on best strategies (choice of drugs, combinations, duration) is scarce. We conducted a European internet-based survey on physicians\' use of antithrombotic therapy after revascularization for CLTI, under the aegis of the ESC Working Group on Aorta and Peripheral Vascular Disease in collaboration with other European scientific societies involved in CLTI management and agreeing to send the survey to their affiliates.
225 respondents completed the questionnaire. Antithrombotic therapy following surgical/endovascular LER varies widely across countries and specialties, with dedicated protocols reported only by a minority (36%) of respondents. Dual antiplatelet therapy with aspirin and clopidogrel is the preferred choice for surgical (37%) and endovascular (79%) LER. Dual pathway inhibition (DPI) with aspirin and low-dose rivaroxaban is prescribed by 16% of respondents and is tightly related to the availability of reimbursement (OR 6.88; 95% CI 2.60-18.25) and to the choice of clinicians rather than of physicians performing revascularization (OR 2.69; 95% CI 1.10-6.58). A ≥ 6 months-duration of an intense (two-drug) postprocedural antithrombotic regimen is more common among surgeons than among medical specialists (OR 2.08; 95% CI 1.10-3.94). Bleeding risk assessment is not standardised and likely underestimated.
Current antithrombotic therapy of CLTI patients undergoing LER remains largely discretional, and prescription of DPI is related to reimbursement policies. An individualised assessment of thrombotic and bleeding risks is largely missing.

UNASSIGNED: Dual pathway inhibition (DPI) with rivaroxaban 2.5 mg twice daily plus aspirin has demonstrated reductions in major adverse cardiovascular and limb events in eligible patients with chronic coronary artery disease (CAD), peripheral artery disease, or both. Patients with polyvascular disease, heart failure, renal impairment, or diabetes can benefit particularly from this therapy. We present our clinical experience to elucidate practical issues regarding the selection of patients eligible for DPI and the timing of initiation.
UNASSIGNED: The first patient was at high risk of recurrent cardiovascular events due to his history of multi-vessel CAD, myocardial infarction, heart failure, and diabetes. Following a period of post-myocardial infarction dual antiplatelet therapy, he was transitioned to DPI therapy. The second patient was at high risk of cardiovascular events due to his history of polyvascular disease, diffuse CAD, and diabetes. He was hospitalized for unstable angina, which was medically managed because no target lesion was identified. DPI was initiated a day after admission. The third patient was at high risk of cardiovascular events due to an extensive history of polyvascular disease, revascularization, and renal impairment. Although the patient was asymptomatic at routine follow-up, DPI was initiated to reduce the risk of further cardiovascular events.
UNASSIGNED: In eligible patients who are at high risk of cardiovascular events, DPI therapy with low-dose rivaroxaban should be considered. Treatment can be started at various times, including at the end of dual antiplatelet therapy, at routine follow-up, or after new events or diagnoses.

OBJECTIVE: Dual pathway inhibition (DPI) by adding a vascular dose of rivaroxaban to a single antiplatelet agent has emerged as a promising antithrombotic strategy. However, in most studies the antiplatelet agent of choice used in adjunct to a vascular dose of rivaroxaban was aspirin, and data on a P2Y12 inhibitor and how this DPI regimen compares with standard dual antiplatelet therapy (DAPT) are limited.
RESULTS: This investigation was a substudy analysis conducted in selected cohorts of patients with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group pharmacodynamic (PD) study. We analysed data from 40 patients treated with either clopidogrel- or ticagrelor-based DAPT first, and clopidogrel- or ticagrelor-based DPI thereafter. PD measures explored key pathways involved in thrombus formation and included markers of (1) P2Y12 reactivity, (2) platelet-mediated global thrombogenicity, (3) cyclooxygenase-1 activity, (4) thrombin receptor-activating peptide (TRAP)-induced platelet aggregation, (5) tissue factor (TF)-induced platelet aggregation, and (6) thrombin generation. Compared with DAPT, on a background of the same P2Y12 inhibitor (clopidogrel or ticagrelor), DPI was associated with reduced thrombin generation, increased markers of cyclooxygenase-1 activity and TRAP-induced platelet aggregation, and no differences in markers of P2Y12 signalling, platelet-mediated global thrombogenicity, and TF-induced platelet aggregation. In an analysis according to P2Y12 inhibitor type, ticagrelor reduced markers of platelet-mediated global thrombogenicity, P2Y12 signalling, and rates of high platelet reactivity compared with clopidogrel.
CONCLUSIONS: Compared with DAPT with aspirin and a P2Y12 inhibitor, the use of a P2Y12 inhibitor in adjunct to a vascular dose of rivaroxaban as part of a DPI strategy is associated with similar effects on platelet-mediated global thrombogenicity but reduced thrombin generation. A DPI strategy with ticagrelor is associated with enhanced antithrombotic efficacy, the clinical implications of which warrant larger scale investigations.
BACKGROUND: ClinicalTrials.gov identifier: NCT03718429.

Coronary artery disease (CAD) is one of the leading causes of death in Taiwan. Despite the use of current guideline-recommended therapies for secondary prevention, the residual risk of recurrent cardiovascular events remains high in CAD, warranting the need for new treatment options. Antithrombotic drugs are one of the most important medical therapies for CAD. In this article, we review the unmet needs of the current antithrombotic agents and summarize the results of clinical trials with dual antiplatelet therapy in stable CAD. We also review data from a recent study demonstrating the benefits of a dual pathway inhibition strategy with antiplatelet and anticoagulant therapy, a new option for CAD treatment. Finally, we propose a treatment algorithm for choosing different antithrombotic regimens for CAD based on current scientific evidence and expert opinions.

BACKGROUND: Low-dose direct oral anticoagulants (DOACs) in adjunct to antiplatelet therapy, known as dual pathway inhibition (DPI), have been tested to prevent ischaemic events in patients with cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to determine the overall safety and efficacy of low-dose DOACs vs. placebo on a background of antiplatelet therapy.
METHODS: All randomized controlled trials (RCTs) comparing low-dose DOAC (defined as a dosage below the lowest approved for stroke prevention) vs. placebo among patients with CVD receiving single or dual antiplatelet therapy in at least 50% of the population and followed for at least 6 months, were included. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were used to overcome different follow-up durations across trials. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint major bleeding. A pre-specified subgroup analysis was performed for different DOAC-dose regimens.
RESULTS: A total of 55,782 patients from 7 RCTs were included. Low-dose DOACs vs placebo were associated with significant reductions in MACE (IRR 0.85, 95% CI 0.78-0.91) and myocardial infarction (IRR 0.86, 95% CI 0.78-0.95) and significant increases of major (IRR 2.05, 95% CI 1.50-2.80) or all bleeding (IRR 1.82, 95% CI 1.49-2.22). CV death (IRR 0.90, 95% CI 0.79-1.03), intracranial (IRR 1.18, 95% CI 0.71-1.96) and fatal bleeding (IRR 1.13, 95% CI 0.76-1.69) did not differ significantly between strategies. Non-significant reductions of all-cause death (IRR 0.90, 95% CI 0.80-1.01) and stroke (IRR 0.73, 95% CI 0.53-1.01) favoured low-dose DOACs. Meta-regression analyses showed a significant interaction between percentage of DAPT use and increased risk of major bleeding (p = 0.04), intracranial Haemorrhage (p = 0.035) and stroke (p = 0.0003). Subgroup analysis of very low-dose DOAC, defined as ≤ 1/3 of the lowest approved dose for stroke prevention (i.e., rivaroxaban 2.5 mg twice daily) seems to mitigate the risk of bleeding without any trade-off in efficacy compared to other low-dose DOAC regimens.
CONCLUSIONS: In patients with CVD, a low-dose DOAC regimen vs. placebo, on a background of antiplatelet therapy, is effective in reducing ischaemic events at the expense of increased major and all bleeding, but without significantly increasing intracranial or fatal bleeds, while the reduction of cardiovascular and total mortality is not statistically significant. A DPI with very low-dose DOAC (i.e. rivaroxaban 2.5 mg twice daily) appears particularly advantageous, especially when combined with a single antiplatelet agent and used among patients at high ischaemic and low bleeding risk.
BACKGROUND: This study is registered in PROSPERO (CRD42021232744).