In situ formed depot of elastin-like polypeptide-hirudin fusion protein for long-acting antithrombotic therapy.

Thrombosis, induced by abnormal coagulation or fibrinolytic systems, is the most common pathology associated with many life-threatening cardio-cerebrovascular diseases. However, first-line anticoagulant drugs suffer from rapid drug elimination and risk of hemorrhagic complications. Here, we developed an in situ formed depot of elastin-like polypeptide (ELP)-hirudin fusion protein with a prodrug-like feature for long-term antithrombotic therapy. Highly secretory expression of the fusion protein was achieved with the assistance of the Ffu312 tag. Integration of hirudin, ELP, and responsive moiety can customize fusion proteins with properties of adjustable in vivo retention and controllable recovery of drug bioactivity. After subcutaneous injection, the fusion protein can form a reservoir through temperature-induced coacervation of ELP and slowly diffuse into the blood circulation. The biological activity of hirudin is shielded due to the N-terminal modification, while the activated key proteases upon thrombus occurrence trigger the cleavage of fusion protein together with the release of hirudin, which has antithrombotic activity to counteract thrombosis. We substantiated that the optimized fusion protein produced long-term antithrombotic effects without the risk of bleeding in multiple animal thrombosis models.

Treatments for COVID-19.

The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as remdesivir and nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., as outpatient therapy) and for less severe disease. Immunomodulatory therapies, such as dexamethasone and interleukin-6 or Janus kinase inhibitors, are most useful in severe disease or critical illness. The role of anti-SARS-CoV-2 monoclonal antibodies has diminished because of the emergence of viral variants that are not anticipated to be susceptible to these treatments, and there still is not a consensus on the use of convalescent plasma. COVID-19 has been associated with increased rates of venous thromboembolism, but the role of antithrombotic therapy is limited. Multiple investigational agents continue to be studied, which will alter current treatment paradigms as new data are released.

Demystifying the Contemporary Role of 12-Month Dual Antiplatelet Therapy After Acute Coronary Syndrome.

For almost two decades, 12-month dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) has been the only class I recommendation on DAPT in American and European guidelines, which has resulted in 12-month durations of DAPT therapy being the most frequently implemented in ACS patients undergoing percutaneous coronary intervention (PCI) across the globe. Twelve-month DAPT was initially grounded in the results of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which, by design, studied DAPT versus no DAPT rather than the optimal DAPT duration. The average DAPT duration in this study was 9 months, not 12 months. Subsequent ACS studies, which were not designed to assess DAPT duration, rather its composition (aspirin with prasugrel or ticagrelor compared with clopidogrel) were further interpreted as supportive evidence for 12-month DAPT duration. In these studies, the median DAPT duration was 9 or 15 months for ticagrelor and prasugrel, respectively. Several subsequent studies questioned the 12-month regimen and suggested that DAPT duration should either be fewer than 12 months in patients at high bleeding risk or more than 12 months in patients at high ischemic risk who can safely tolerate the treatment. Bleeding, rather than ischemic risk assessment, has emerged as a treatment modifier for maximizing the net clinical benefit of DAPT, due to excessive bleeding and no clear benefit of prolonged treatment regimens in high bleeding risk patients. Multiple DAPT de-escalation treatment strategies, including switching from prasugrel or ticagrelor to clopidogrel, reducing the dose of prasugrel or ticagrelor, and shortening DAPT duration while maintaining monotherapy with ticagrelor, have been consistently shown to reduce bleeding without increasing fatal or nonfatal cardiovascular or cerebral ischemic risks compared with 12-month DAPT. However, 12-month DAPT remains the only class-I DAPT recommendation for patients with ACS despite the lack of prospectively established evidence, leading to unnecessary and potentially harmful overtreatment in many patients. It is time for clinical practice and guideline recommendations to be updated to reflect the totality of the evidence regarding the optimal DAPT duration in ACS.

2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Damage to endothelial barriers and its contribution to long COVID.

The world continues to contend with COVID-19, fueled by the emergence of viral variants. At the same time, a subset of convalescent individuals continues to experience persistent and prolonged sequelae, known as long COVID. Clinical, autopsy, animal and in vitro studies all reveal endothelial injury in acute COVID-19 and convalescent patients. Endothelial dysfunction is now recognized as a central factor in COVID-19 progression and long COVID development. Different organs contain different types of endothelia, each with specific features, forming different endothelial barriers and executing different physiological functions. Endothelial injury results in contraction of cell margins (increased permeability), shedding of glycocalyx, extension of phosphatidylserine-rich filopods, and barrier damage. During acute SARS-CoV-2 infection, damaged endothelial cells promote diffuse microthrombi and destroy the endothelial (including blood-air, blood-brain, glomerular filtration and intestinal-blood) barriers, leading to multiple organ dysfunction. During the convalescence period, a subset of patients is unable to fully recover due to persistent endothelial dysfunction, contributing to long COVID. There is still an important knowledge gap between endothelial barrier damage in different organs and COVID-19 sequelae. In this article, we mainly focus on these endothelial barriers and their contribution to long COVID.

Antithrombotic Strategies With Left Ventricular Assist Devices.

Long-term outcomes of patients with advanced heart failure treated with durable left ventricular assist devices (LVADs) have been augmented due to improved durability and hemocompatibility on the backbone of pump engineering enhancements. The incidence of hemocompatibility-related adverse events (pump thrombosis, stroke and nonsurgical bleeding events) are device specific and vary by type of engineered pump. A fully magnetically levitated rotor containing LVAD in concert with use of antithrombotic therapy has successfully overcome an increased risk of pump thrombosis and stroke-risk, albeit with only modest reduction in bleeding events. Modifications to antithrombotic strategies have focused on reduced-dose vitamin K antagonist use or use of direct oral anticoagulants with demonstration of safety and progress in reduction of mucosal bleeding episodes with elimination of antiplatelet agents. This review outlines the current landscape of advances in anticoagulation management in LVAD patients, highlighting the need for ongoing research and cautious application of emerging therapies and technologies.

Bleeding and thrombotic risk of different antiplatelet regimens posttranscatheter edge-to-edge mitral valve repair in patients with an indication for oral anticoagulation: Results from an all-comers national registry.

BACKGROUND: Evidence-based recommendations for antithrombotic treatment in patients who have an indication for oral anticoagulation (OAC) after transcatheter edge-to-edge mitral valve repair (TEER) are lacking. AIMS: To compare bleeding and thrombotic risk for different antithrombotic regimens post-TEER with MitraClip in an unselected population with the need for OACs. METHODS: Bleeding and thrombotic complications (stroke and myocardial infarction) up to 3 months after TEER with mitraclip were evaluated in 322 consecutive pts with an indication for OACs. These endpoints were defined by the Mitral Valve Academic Research Consortium criteria and were compared between two antithrombotic regimens: single antithrombotic therapy with OAC (single ATT) and double/triple ATT with a combination of OAC and aspirin and/or clopidogrel (combined ATT). RESULTS: Collectively, 108 (34%) patients received single ATT, 203 (63%) received double ATT and 11 (3%) received triple ATT. Bleeding events occurred in 67 patients (20.9%), with access site related events being the most frequent cause (37%). Bleeding complications were observed more frequently in the combined ATT group than in the single ATT group: 24% versus 14% [p = 0.03, adjusted RR: 0.55 (0.3-0.98)]. Within the combined group, the bleeding risk was 23% in the double ATT and 45% in the triple ATT group. Thrombotic complications occurred in only three patients (0.9%), and all belonged to the combined ATT group. CONCLUSIONS: In patients with an indication for OACs, withholding of antiplatelet therapy post-TEER with Mitraclip was associated with a 45% reduction in bleeding and without a signal of increased thrombotic risk.

Combined transcatheter aortic valve and tricuspid valve-in-valve implantation in a patient with a mitral mechanical prosthesis.

Despite progressively uncommon in Western countries, rheumatic heart disease still portrays a significant global burden. In elderly or high-surgical risk patients, plurivalvular disease may require a complex percutaneous approach. Transcatheter aortic valve implantation (TAVI) in patients with previous monoleaflet mitral prosthesis is challenging due to interference between the aortic valve and the rigid mitral mechanical prosthesis "ring." Prior cases report the use of CoreValve or Edwards Sapien aortic valves in patients with adequate mitro-aortic distance. Performing a second major procedure, such as tricuspid valve-in-valve (TVIV), sequentially during a single percutaneous intervention, increases treatment complexity. An 83-year-old woman with rheumatic heart disease, with previous implantation of a Bjork-Shiley monoleaflet mitral prosthesis, and Carpentier-Edwards 29 tricuspid bioprosthesis presented with decompensated heart failure due to severe aortic stenosis and tricuspid bioprosthesis stenosis. After HeartTeam discussion, the patient was deemed as inoperable due to a prohibitive surgical risk. As an alternative, a TAVI (Navitor FlexNav) and a transcatheter TVIV replacement (Edwards Sapiens 3 Ultra) were discussed and proposed, with both techniques being performed sequentially in a single procedure. TAVI in a patient with a previous monoleaflet mitral mechanical prosthesis and TVIV may be a feasible approach in inoperable patients with plurivalvular disease.

Antithrombotic Therapy and Freedom From Bridging Stent Occlusion After Elective Branched Endovascular Repair: A Multicenter International Cohort Study.

CLINICAL IMPACT: Based on our study, no antithrombotic therapy is significantly associated with bridging stent occlusion, and no evidence of the superiority of other antithrombotic therapy exists. Nevertehless, due to the low number of bridging stent occlusions, this study can neither support nor reject the PRINCE2SS recommendations. Further studies with larger cohorts are needed to determine clear guideliness of the best antithrombotic treatment regimen after complex enfovascular aortic repair.

Dual Antithrombotic Therapy versus Anticoagulant Monotherapy for Major Adverse Limb Events in Patients with Concomitant Lower Extremity Arterial Disease and Atrial Fibrillation: A Propensity Score Weighted Analysis.

OBJECTIVE: Patients with symptomatic lower extremity arterial disease (LEAD) are recommended to receive antiplatelet therapy, while direct oral anticoagulants (DOACs) are standard for stroke prevention in patients with atrial fibrillation (AF). For patients with concomitant LEAD and AF, data comparing dual antithrombotic therapy (an antiplatelet agent used in conjunction with a DOAC) vs. DOAC monotherapy are scarce. This retrospective cohort study, based on data from the Taiwan National Health Insurance Research Database, aimed to compare the efficacy and safety of these antithrombotic strategies. METHODS: Patients with AF who underwent revascularisation for LEAD between 2012 - 2020 and received any DOAC within 30 days of discharge were included. Patients were grouped by antiplatelet agent exposure into the dual antithrombotic therapy and DOAC monotherapy groups. Inverse probability of treatment weighting was used to mitigate selection bias. Major adverse limb events (MALEs), ischaemic stroke or systemic embolism, and bleeding outcomes were compared. Patients were followed until the occurrence of any study outcome, death, or up to two years. RESULTS: A total of 1 470 patients were identified, with 736 in the dual antithrombotic therapy group and 734 in the DOAC monotherapy group. Among them, 1 346 patients received endovascular therapy as the index revascularisation procedure and 124 underwent bypass surgery. At two years, dual antithrombotic therapy was associated with a higher risk of MALEs than DOAC monotherapy (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.15 - 1.56), primarily driven by increased repeat revascularisation. Dual antithrombotic therapy was also associated with a higher risk of major bleeding (SHR 1.43, 95% CI 1.05 - 1.94) and gastrointestinal bleeding (SHR 2.17, 95% CI 1.42 - 3.33) than DOAC monotherapy. CONCLUSION: In patients with concomitant LEAD and AF who underwent peripheral revascularisation, DOAC monotherapy was associated with a lower risk of MALEs and bleeding events than dual antithrombotic therapy.

Antithrombotic therapy at discharge and prognosis in patients with chronic coronary syndrome and atrial fibrillation who underwent PCI: a real-world study.

BACKGROUND: This study aimed to describe the status of antithrombotic therapy at discharge and prognosis in patients with atrial fibrillation (AF) and chronic coronary syndrome (CCS) who underwent percutaneous coronary intervention (PCI). METHODS: This was an observational, prospective study. The primary endpoint was major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction, stroke/transient ischemic attach (TIA), systemic embolism or ischemia-driven revascularization. Bleeding events were collected according to the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: Between 2017 and 2019, a cohort of 516 patients (mean age 66, [SD 9], of whom 18.4% were female) with AF and CCS who underwent PCI were evaluated, with a median followed-up time of 36 months (Interquartile range: 22-45). MACE events occurred in 13.0% of the patients, while the TIMI bleeding events were observed in 17.4%. Utilization of TAT (triple antithrombotic therapy) (P < 0.001) and oral anticoagulation (OAC) therapy (P < 0.001) increased through years. History of heart failure (HF) (Hazard ratio [HR], 1.744; 95% confidence interval [CI], 1.011-3.038) and TAT (HR, 2.708; 95%CI, 1.653-4.436) had independent associations with MACE events. OAC (HR, 10.378; 95%CI, 6.136-17.555) was identified as a risk factor for bleeding events. A higher creatine clearance (HR, 0.986; 95%CI, 0.974-0.997) was associated with a lower incidence of bleeding events. CONCLUSIONS: Antithrombotic therapy has been improved among patients with AF and CCS who underwent PCI these years. History of HF and TAT were independently associated with MACE events. Higher creatine clearance was protective factor of bleeding events, while OAC was a risk factor for TIMI bleeding events.

Integrated proteomic and metabolomic profiling of lymph after trauma-induced hypercoagulopathy and antithrombotic therapy.

BACKGROUND: Routine coagulation tests are not widely accepted diagnostic criteria of trauma-induced hypercoagulopathy (TIH) due to insensitivity. Lymphatic vessels drain approximately 10% of the interstitial fluid into the lymphatic system and form lymph. SUBJECTIVE: The purpose of this study was to identify the potential lymph biomarkers for TIH. METHODS: Eighteen male Sprague-Dawley rats were randomly assigned to the sham (non-fractured rats with sham surgery and vehicle treatment), the VEH (fractured rats with vehicle treatment) and the CLO (fractured rats with clopidogrel treatment) group. Thoracic duct lymph was obtained to perform proteomics and untargeted metabolomics. RESULTS: A total of 1207 proteins and 16,695 metabolites were identified. The top 5 GO terms of lymph proteomics indicated that oxidative stress and innate immunity were closely associated with TIH and antithrombotic therapy. The top 5 GO terms of lymph metabolomics showed that homocystine and lysophosphatidylcholine were the differential expressed metabolites (DEMs) between the sham and VEH groups, while cholic acid, docosahexaenoic acid, N1-Methyl-2-pyridone-5-carboxamide, isoleucine and testosterone are the DEMs between the VEH and CLO group. CONCLUSIONS: This study presents the first proteomic and metabolomic profiling of lymph after TIH and antithrombotic therapy, and predicts the possible lymph biomarkers for TIH.

Pathological Interplay and Clinical Complications between COVID-19 and Cardiovascular Diseases: An Overview in 2023.

BACKGROUND: The coronavirus disease 2019 (COVID-19) involves all organs of the body, of which the interaction with cardiovascular diseases is the most important. SUMMARY: Numerous studies have reported that COVID-19 patients complicated with cardiovascular comorbidities (hypertension, coronary heart disease, chronic heart failure (HF), cerebrovascular disease) are more likely to develop into critical illness and have higher mortality. Conversely, COVID-19 may also cause myocardial injury in patients through various pathological mechanisms such as direct virus attack on cardiomyocytes, overactivation of immune response, microthrombus formation, which may lead to fatal acute ST-segment elevation myocardial infarction, arrhythmia, acute worsening of chronic HF, etc. In addition, the symptoms of the so-called long-COVID may remain in some patients who survived the acute viral infection. Positional tachycardia has been widely reported, and cardiovascular autonomic disorders are thought to play a pathogenic role. KEY MESSAGE: The review summarizes the interaction between COVID-19 and cardiovascular disease in terms of pathological mechanism, clinical features, and sequelae. Therapeutic and rehabilitation programs after COVID-19 infection are compiled and need to be further standardized in the future.

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.

Recent advances in microfluidic technology of arterial thrombosis investigations.

Microfluidic technology has emerged as a powerful tool in studying arterial thrombosis, allowing researchers to construct artificial blood vessels and replicate the hemodynamics of blood flow. This technology has led to significant advancements in understanding thrombosis and platelet adhesion and aggregation. Microfluidic models have various types and functions, and by studying the fabrication methods and working principles of microfluidic chips, applicable methods can be selected according to specific needs. The rapid development of microfluidic integrated system and modular microfluidic system makes arterial thrombosis research more diversified and automated, but its standardization still needs to be solved urgently. One key advantage of microfluidic technology is the ability to precisely control fluid flow in microchannels and to analyze platelet behavior under different shear forces and flow rates. This allows researchers to study the physiological and pathological processes of blood flow, shedding light on the underlying mechanisms of arterial thrombosis. In conclusion, microfluidic technology has revolutionized the study of arterial thrombosis by enabling the construction of artificial blood vessels and accurately reproducing hemodynamics. In the future, microfluidics will place greater emphasis on versatility and automation, holding great promise for advancing antithrombotic therapeutic and prophylactic measures.

What is the context? To study the mechanism of arterial thrombosis, including the platelet adhesion and aggregation behavior and the coagulation process.Microfluidic technology is commonly used to study thrombosis. Microfluidic technology can simulate the real physiological environment on the microscopic scale in vitro, with high throughput, low cost, and fast speed.As an innovative experimental platform, microfluidic technology has made remarkable progress and has found applications in the fields of biology and medicine.What is new? This review summarizes the different fabrication methods of microfluidics and compares the advantages and disadvantages of these methods. Recent developments in microfluidic integrated systems and modular microfluidic systems have led to more diversified and automated microfluidic chips in the future.The different types and functions of microfluidic models are summarized. Platelet adhesion aggregation and coagulation processes, as well as arterial thrombus-related shear force changes and mechanical behaviors, were investigated by constructing artificial blood vessels and reproducing hemodynamics.Microfluidics can provide a basis for the development of personalized thrombosis treatment strategies. By analyzing the mechanism of action of existing drugs, using microfluidic technology for high-throughput screening of drugs and evaluating drug efficacy, more drug therapy possibilities can be developed.What is the impact?This review utilizes microfluidics to further advance the study of arterial thrombosis, and microfluidics is also expected to play a greater role in the biomedical field in the future.

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.

Antithrombotics alter intracerebral hemorrhage presentation without affecting minimally invasive endoscopic evacuation.

OBJECTIVES: Intracerebral hemorrhages are associated with significant morbidity and mortality. While the ENRICH trial supports the efficacy of surgical evacuation for lobar hemorrhages, the impact of antithrombotic therapies on minimally invasive surgery outcomes remains unexplored. This study evaluates the effects of chronic anticoagulants and antiplatelets on the technical and longterm outcomes of minimally invasive intracerebral hemorrhage evacuation. MATERIALS AND METHODS: A prospectively collected registry of patients undergoing minimally invasive surgery for intracerebral hemorrhage from a single institution was analyzed (December 2015-September 2022). Data included key demographics, comorbidities, antithrombotic/reversal status, presenting clinical/radiographic characteristics, procedural metrics, and clinical outcomes. Patients were divided into control (neither therapy), antiplatelet-only, and anticoagulant-only groups, with antiplatelet/anticoagulant reversals conducted per current American Heart Association/American Stroke Association guidelines. Variables significant in univariate analyses (p<0.05) were advanced to multivariable regression models. RESULTS: Among 226 intracerebral hemorrhage patients treated with minimally invasive surgery, 41% (N=93) had antithrombotic medication history; 28% (N=64) received antiplatelets, and 9% (N=21) received anticoagulants. Patients on both therapies (N=6) were excluded. The antiplatelet group presented more frequently with lobar hemorrhages (56% vs. 37%; p=0.022), while patients on anticoagulants showed increased rates of intraventricular hemorrhage co-presentation (62% vs. 46%; p=0.011) compared to controls. Despite univariate analyses showing a higher postoperative hematoma volume (3.9 vs. 2.9 milliliters; p=0.020) and lower evacuation percentage (88% vs. 92%; p=0.019) for the antiplatelet group, and longer procedures for patients on anticoagulants (2.3 vs. 1.7 hours; p=0.042) compared to control, multivariable analyses indicated that antiplatelets and anticoagulants had no significant impact on these technical outcomes. Longitudinally, antithrombotics were not associated with increased rebleeding, less frequent discharge to home, lower 30-day mortality, or worse, 6-month Modified Rankin Scale scores. CONCLUSIONS: Patients on chronic antiplatelets and anticoagulants exhibited characteristic intracerebral hemorrhage phenotypes without worse technical or long-term outcomes after minimally invasive intracerebral hemorrhage evacuation, suggesting the procedure's safety for these patients.

[GDF-15 and the risk of bleeding in patients with stable CAD receiving multicomponent antithrombotic therapy: the results of the prospective REGATA register].

AIM: To evaluate the prognostic value of GDF-15 in relation the development of bleeding and events in stable CAD patients, receiving combined antithrombotic therapy. MATERIALS AND METHODS: The data was obtained from the prospective registry REGATA, 343 CAD patients (249 males), median age 68 [IQR 62; 75] years) were enrolled. Patients with sinus rhythm and concomitant PAD received acetylsalicylic acid in combination with rivaroxaban 2.5 mg bid (31.8%) or clopidogrel (24.8%). Other 43.4% with concomitant atrial fibrillation (AF) received direct oral anticoagulants in combination with antiplatelet therapy after elective percutaneous coronary interventions. Median follow-up was 12 months [IQR 9.0; 18.0]. The safety end point was major and clinically relevant bleedings (type 2-5) according to the BARC classification. Plasma samples for GDF-15 identification were taken at the inclusion and analyzed using ELISA assay. RESULTS: Frequency of BARC 2-5 bleedings was 16% (BARC 2 - 46; BARC 3 - 9; BARC 4-5 - 0), median GDF-15 level was 1185.0 pg/ml [850.0; 1680.0]. In patients with AF and concomitant MFA, the level of GDF-15 was significantly higher than in the subgroups of patients with only AF or MFA (p=0.0022). According to the quintile analysis, GDF-15 values in the top three quintiles of distribution (cut-off value >943 pg/ml) were associated with higher frequency of bleeding events: 23.2% versus 5.1%; p=0.0001. The multivariable logistic regression model demonstrated that bleeding events were independently associated with GDF-15 level>943 pg/ml (OR 2.65, 95% CI 1.11-6.30; p=0.0275), AF (OR 2.61, 95% CI 1.41-4.83; p=0.0023) and chronic kidney disease (OR 1.92, 95% CI 1.03-3.60; p=0.0401). Clinical factors determining the risk of bleeding events also determined a GDF-15 elevation. CONCLUSION: Assessment of GDF-15 level may improve bleeding risk stratification in CAD patients with concomitant AF and/or PAD receiving combined antithrombotic therapy.

Rivaroxaban in patients with symptomatic peripheral artery disease after lower extremity bypass surgery with venous and prosthetic conduits.

BACKGROUND: Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the VOYAGER PAD (efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described. METHODS: In the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician's discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline. RESULTS: Among 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P < .001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P < .001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (Pinteraction = .254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance. CONCLUSIONS: Surgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.

Non-ST Elevation Myocardial Infarction in the Elderly. Antithrombotic Therapy and Beyond.

Non-ST segment elevation myocardial infarction (NSTEMI) is the most frequent type of acute coronary syndrome in the elderly. Antithrombotic therapy is the cornerstone of pharmacological therapy in the setting of an acute ischemic event, a clinical scenario in which thrombotic and bleeding risks ought to be considered, particularly in older patients. In this article, specific aspects of antithrombotic therapy in elderly patients with NSTEMI are reviewed, including pharmacokinetic and pharmacodynamic characteristics and different clinical situations. The role of frailty and other common geriatric conditions, that are associated with worse prognosis in elderly patients with cardiovascular disease, is also addressed.