Reamputation rate, mortality and the incidence of risk factors for ipsilateral reamputation among patients with dysvascular major lower limb amputation.

INTRODUCTION: A major lower-limb amputation (LLA) for dysvascular disease carries the risk of disturbed wound healing necessitating reamputation at a higher level. A reamputation causes a delay in prosthetic fitting and recovery of walking ability. The combination of a prolonged open wound and inability to walk can worsen of the physical and psychological situation. Prevention of reamputation seems therefore important. This study aims to identify risk factors for reamputation, and to evaluate a possible altered mortality rate after a dysvascular major LLA. These issues are crucial for shared decision-making prior to surgery. METHODS: Retrospective study investigating a Dutch regional cohort of patients with a dysvascular below-knee, through-knee, or above-knee LLA. RESULTS: 516 Dysvascular major LLAs were included (2014-2018). One hundred reamputations were performed within 1 year after initial amputation (19.4%). Risk factors for ipsilateral reamputation were diabetes mellitus, lipid-lowering drugs usage, and lower level of amputation (respectively P = < 0.01, 0.037, and < 0.01). The 30-day mortality rates were 1% and 12% for the reamputation group and the non-reamputation group respectively (P = < 0.01). The 1-year mortality rates were 23% and 27% for the reamputation group and the non-reamputation group respectively (P = 0.423). CONCLUSIONS: Ipsilateral reamputation within one year after initial amputation is common. Several risk factors for reamputation were identified. The 30-day and 1-year mortality rate is high, but not significantly different after one year. A clinical decision tool for dysvascular patients needs to be developed to improve shared decision-making, reduce reamputation rates, and improve survival.

Impact of CYP2C19 Genotype Status on Clinical Outcomes in Patients with Symptomatic Coronary Artery Disease, Stroke, and Peripheral Arterial Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Clopidogrel is widely used for the secondary prevention of atherothrombotic events in patients with coronary artery disease (CAD), ischemic stroke, and peripheral arterial disease (PAD). CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results. PURPOSE: To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD). METHODS: A comprehensive search in Pubmed, EMBASE, and MEDLINE from their inception to July 23rd 2023 was performed. Randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment, and cohort studies and post hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke. RESULTS: Forty-four studies were identified: 11 studies on CAD, 29 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE [risk ratio (RR) 0.60, 95% confidence interval (CI) 0.43-0.83], myocardial infarction (RR 0.53, 95% CI 0.42-0.68), and stent thrombosis (RR 0.64, 95% CI 0.43-0.94), compared with standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70-1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.61, 95% CI 1.25-2.08) and recurrent ischemic stroke (RR 1.89, 95% CI 1.48-2.40) compared with non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43-1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events. CONCLUSIONS: Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI. In patients with history of stroke, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. The available evidence in PAD with regard to major adverse limb events is too limited to draw meaningful conclusions. REGISTRATION: PROSPERO identifier no. CRD42020220284.

Dual-Pathway Inhibition with Rivaroxaban and Low-Dose Aspirin Does Not Alter Immune Cell Responsiveness and Distribution in Patients with Coronary Artery Disease.

INTRODUCTION: Cardiovascular diseases (CVD) are the leading cause of death globally. Inflammation is an important driver of CVD where tissue damage may lead to the formation of deadly thrombi. Therefore, antithrombotic drugs, such as platelet inhibitors, are crucial for secondary risk prevention in coronary artery disease (CAD) and peripheral artery disease (PAD). For severe forms of the disease, dual-pathway inhibition (DPI) where low-dose aspirin is combined with rivaroxaban has shown improved efficacy in reducing cardiovascular mortality. METHODS: Given this greater improvement in mortality, and the importance of inflammation in driving atherosclerosis, the potential for off-target inflammation-lowering effects of these drugs was evaluated by looking at the change in immune cell distribution and responsiveness to ex vivo lipopolysaccharide (LPS) stimulation after 3 months of DPI in patients with CAD. RESULTS: We observed no changes in whole blood or peripheral blood mononuclear cell (PBMC) immune cell responsiveness to LPS after 3 months of DPI. Additionally, we did not observe any changes in the distribution of total white blood cells, monocytes, neutrophils, lymphocytes, or platelets during the study course. Signs of systemic inflammation were studied using Olink proteomics in 33 patients with PAD after 3 months of DPI. No changes were observed in any of the inflammatory proteins measured after the treatment period, suggesting that the state of chronic inflammation was not altered in these subjects. CONCLUSION: Three months of DPI does not result in any meaningful change in immune cell responsiveness and distribution in patients with CAD or PAD. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05210725.

Vascular Function, Systemic Inflammation, and Coagulation Activation 18 Months after COVID-19 Infection: An Observational Cohort Study.

INTRODUCTION: Among its effect on virtually all other organs, COVID-19 affects the cardiovascular system, potentially jeopardizing the cardiovascular health of millions. Previous research has shown no indication of macrovascular dysfunction as reflected by carotid artery reactivity, but has shown sustained microvascular dysfunction, systemic inflammation, and coagulation activation at 3 months after acute COVID-19. The long-term effects of COVID-19 on vascular function remain unknown. MATERIALS AND METHODS: This cohort study involved 167 patients who participated in the COVAS trial. At 3 months and 18 months after acute COVID-19, macrovascular dysfunction was evaluated by measuring the carotid artery diameter in response to cold pressor testing. Additionally, plasma endothelin-1, von Willebrand factor, Interleukin(IL)-1ra, IL-6, IL-18, and coagulation factor complexes were measured using ELISA techniques. RESULTS: The prevalence of macrovascular dysfunction did not differ between 3 months (14.5%) and 18 months (11.7%) after COVID-19 infection (p = 0.585). However, there was a significant decrease in absolute carotid artery diameter change, 3.5% ± 4.7 vs. 2.7% ± 2.5, p-0.001, respectively. Additionally, levels of vWF:Ag were persistently high in 80% of COVID-19 survivors, reflecting endothelial cell damage and possibly attenuated endothelial function. Furthermore, while levels of the inflammatory cytokines interleukin(IL)-1RA and IL-18 were normalized and evidence of contact pathway activation was no longer present, the concentrations of IL-6 and thrombin:antithrombin complexes were further increased at 18 months versus 3 months (2.5 pg/mL ± 2.6 vs. 4.0 pg/mL ± 4.6, p = 0.006 and 4.9 µg/L ± 4.4 vs. 18.2 µg/L ± 11.4, p < 0.001, respectively). DISCUSSION: This study shows that 18 months after COVID-19 infection, the incidence of macrovascular dysfunction as defined by a constrictive response during carotid artery reactivity testing is not increased. Nonetheless, plasma biomarkers indicate sustained endothelial cell activation (vWF), systemic inflammation (IL-6), and extrinsic/common pathway coagulation activation (FVII:AT, TAT) 18 months after COVID-19 infection.

Prevalence, pathophysiology, prediction and health-related quality of life of long COVID: study protocol of the longitudinal multiple cohort CORona Follow Up (CORFU) study.

INTRODUCTION: The variety, time patterns and long-term prognosis of persistent COVID-19 symptoms (long COVID-19) in patients who suffered from mild to severe acute COVID-19 are incompletely understood. Cohort studies will be combined to describe the prevalence of long COVID-19 symptoms, and to explore the pathophysiological mechanisms and impact on health-related quality of life. A prediction model for long COVID-19 will be developed and internally validated to guide care in future patients. METHODS AND ANALYSIS: Data from seven COVID-19 cohorts will be aggregated in the longitudinal multiple cohort CORona Follow Up (CORFU) study. CORFU includes Dutch patients who suffered from COVID-19 at home, were hospitalised without or with intensive care unit treatment, needed inpatient or outpatient rehabilitation and controls who did not suffer from COVID-19. Individual cohort study designs were aligned and follow-up has been synchronised. Cohort participants will be followed up for a maximum of 24 months after acute infection. Next to the clinical characteristics measured in individual cohorts, the CORFU questionnaire on long COVID-19 outcomes and determinants will be administered digitally at 3, 6, 12, 18 and 24 months after the infection. The primary outcome is the prevalence of long COVID-19 symptoms up to 2 years after acute infection. Secondary outcomes are health-related quality of life (eg, EQ-5D), physical functioning, and the prevalence of thromboembolic complications, respiratory complications, cardiovascular diseases and endothelial dysfunction. A prediction model and a patient platform prototype will be developed. ETHICS AND DISSEMINATION: Approval was obtained from the medical research ethics committee of Maastricht University Medical Center+ and Maastricht University (METC 2021-2990) and local committees of the participating cohorts. The project is supported by ZonMW and EuroQol Research Foundation. Results will be published in open access peer-reviewed scientific journals and presented at (inter)national conferences. TRIAL REGISTRATION NUMBER: NCT05240742.

Dual pathway inhibition as compared to acetylsalicylic acid monotherapy in relation to endothelial function in peripheral artery disease, a phase IV clinical trial.

Objective: Dual pathway inhibition (DPI) by combining acetylsalicylic acid (ASA) with low-dose rivaroxaban has been shown to reduce cardiovascular events in patients with peripheral arterial disease (PAD) when compared to ASA monotherapy. A potential explanation is that inhibition of factor Xa improves endothelial function through crosstalk between coagulation and inflammatory pathways, subsequently attenuating the occurrence of cardiovascular events. We hypothesize that the addition of rivaroxaban to ASA in PAD patients leads to improved endothelial function. Design: An investigator-initiated, multicentre trial investigating the effect of DPI on endothelial function. Methods: Patients, diagnosed with PAD, were enrolled in two cohorts: cohort A (Rutherford I-III) and cohort B (Rutherford IV-VI). Participants received ASA monotherapy for a 4-weeks run-in period, followed by 12 weeks of DPI. Macro- and microvascular endothelial dysfunction were studied by measuring carotid artery reactivity upon sympathetic stimulus and by measuring plasma endothelin-1 concentrations, respectively. All measurements were performed during the use of ASA (baseline) and after 12 weeks of DPI. Results: 159 PAD patients (111 cohort A, 48 cohort B) were enrolled. Twenty patients discontinued study drugs early. Carotid artery constriction upon sympathetic stimulation at baseline (ASA) and after 12 weeks of DPI was similar in the total group, 22.0 vs. 22.7% (p = 1.000), and in the subgroups (Cohort A 22.6 vs. 23.7%, p = 1.000; cohort B 20.5 vs. 20.5%, p = 1.000), respectively. The mean concentration of plasma endothelin-1 at baseline and after 12 weeks of DPI did not differ, 1.70 ± 0.5 vs. 1.66 ± 0.64 pmol/L (p = 0.440) in the total group, 1.69 ± 0.59 vs. 1.62 ± 0.55 pmol/L in cohort A (p = 0.202), and 1.73 ± 0.53 vs. 1.77 ± 0.82 pmol/L in cohort B (p = 0.682), respectively. Conclusion: Macro- and microvascular endothelial dysfunction, as reflected by carotid artery reactivity and plasma endothelin-1 concentrations, are not influenced in PAD patients by addition of low-dose rivaroxaban to ASA monotherapy for 12 weeks. Trial registration: https://clinicaltrials.gov/ct2/show/NCT04218656.

Antithrombotic Therapy for Symptomatic Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD. METHODS: A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group. RESULTS: Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking. CONCLUSION: Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.

Current State of MRI-Guided Endovascular Arterial Interventions: A Systematic Review of Preclinical and Clinical Studies.

BACKGROUND: MRI guidance of arterial endovascular interventions could be beneficial as it does not require radiation exposure, allows intrinsic blood-tissue contrast, and enables three-dimensional and functional imaging, however, clinical applications are still limited. PURPOSE: To review the current state of MRI-guided arterial endovascular interventions and to identify the most commonly reported challenges. STUDY TYPE: Systematic review. POPULATION: Pubmed, Embase, Web of Science, and The Cochrane Library were systematically searched to find relevant articles. The search strategy combined synonyms for vascular pathology, endovascular therapy, and real-time MRI guidance. FIELD STRENGTH/SEQUENCE: No field strength or sequence restrictions were applied. ASSESSMENT: Two reviewers independently identified and reviewed the original articles and extracted relevant data. STATISTICAL TESTS: Results of the included original articles are reported. RESULTS: A total of 24,809 studies were identified for screening. Eighty-eight studies were assessed for eligibility, after which data were extracted from 43 articles (6 phantom, 33 animal, and 4 human studies). Reported technical success rates for animal and human studies ranged between 42% to 100%, and the average complication rate was 5.8% (animal studies) and 8.8% (human studies). Main identified challenges were related to spatial and temporal resolution as well as safety, design, and scarcity of current MRI-compatible endovascular devices. DATA CONCLUSION: MRI guidance of endovascular arterial interventions seems feasible, however, included articles included mostly small single-center case series. Several hurdles remain to be overcome before larger trials can be undertaken. Main areas of research should focus on adequate imaging protocols with integrated tracking of dedicated endovascular devices.

ChAdOx1 vaccination, blood coagulation, and inflammation: No effect on coagulation but increased interleukin-6.

BACKGROUND: Vaccination is the leading approach in combatting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. ChAdOx1 nCoV-19 vaccination (ChAdOx1) has been linked to a higher frequency of rare thrombosis and thromboembolism. This study aimed to explore markers related to the blood coagulation system activation and inflammation, before and after ChAdOx1 vaccination. PATIENTS AND METHODS: An observational cohort study including 40 health care workers. Whole blood samples were collected before, and either 1 or 2 days after vaccination. Activated coagulation factors in complex with their natural inhibitors were determined by custom ELISAs, including thrombin:antithrombin (T:AT), kallikrein:C1-esterase-inhibitor (PKa:C1Inh), factor(F)IXa:AT, FXa:AT, FXIaAT, FXIa:alpha-1-antitrypsin (α1AT), FXIa:C1inh, and FVIIa:AT. Plasma concentrations of interleukin (IL)-6 and IL-18 were quantified via ELISA. Analyses were performed using Wilcoxon signed-rank test. RESULTS: Levels of FVIIa:AT decreased with a median (IQR) of 707 (549-1028) pg/ml versus 598 (471-996) pg/ml, p = 0.01; and levels of IL-6 increased, 4.0 (1.9-6.8) pg/ml versus 6.9 (3.6-12.2) pg/ml, p = 0.02, after vaccination. No changes were observed in T:AT, PKa:C1Inh, FIXa:AT, FXa:AT, FXIaAT, FXIa:α1AT, FXIa:C1inh, and IL-18. CONCLUSION: ChAdOx1 leads to an inflammatory response with increased levels of IL-6. We did not observe activation of the blood coagulation system 1-2 days following vaccination.