Pre-hospital evaluation of chest pain patients using the modified HEART-score: rationale and design.

Background: This study assesses how ambulance paramedics using the modified HEART-score with a point-of-care cardiac troponin (cTn) compare to the emergency physicians using the modified HEART-score with a high-sensitive cTn (hs-cTn) in patients with suspected non-ST-elevation acute coronary syndrome (NSTE-ACS), focusing on interobserver agreement and diagnostic performance. Methods: In this prospective multicenter cohort, we compare four cTn testing strategies (serial point of care and hs-cTn cTn measurement) with and without the HEART-score. Outcomes include the HEART-score's interobserver agreement, NSTE-ACS at discharge, major adverse cardiovascular events (MACE) after 30 days, and diagnostic accuracy of the different strategies. Conclusion: The POPular HEART study aims to improve NSTE-ACS diagnostic pathways, promoting pre-hospital detection and ruling out of NSTE-ACS to minimize unnecessary hospitalizations and associated costs.Clinical Trial Registration: NCT04851418 (ClinicalTrials.gov).

What & why? Many people visit the emergency department (ED) due to chest pain, often worried about the possibility of a heart attack. While acute heart attacks can often be detected through an electrocardiogram (ECG; a test of the heart's electrical activity), a significant number of patients with a heart attack have a normal ECG. These patients require further testing to measure cardiac troponin (cTn; an indicator of heart damage) in the hospital to rule out a heart attack, known as non-ST-elevation acute coronary syndrome (NSTE-ACS). To improve diagnosis and care for these patients, we compared two approaches: ambulance paramedics using a quick bedside cTn test and the HEART-score, versus hospital doctors using a more sensitive cTn test with the HEART-score. The HEART score combines factors like the patient's medical history, ECG results, age, risk factors, and cTn levels to assess the risk of heart problems. In this comparison, the key difference lies in how cTn levels are measured ­ either through a quick finger prick test in an ambulance using a point-of-care device or a more detailed analysis in a hospital laboratory.How? We focused on patients visited by emergency medical services for chest pain suspected of a heart attack and transported to the hospital. We assessed the quick bedside test by paramedics and the detailed hospital test by doctors, alongside the use of the HEART score in both settings. Our evaluation looked at the agreement between these methods and their effectiveness in identifying or excluding an NSTE-ACS.What? Our research, known as the POPular HEART study, seeks to simplify the early identification or rule-out of an NSTE-ACS in patients with chest pain directly by ambulance. This approach aims to decrease unnecessary hospital admissions and reduce healthcare costs.Main points We're exploring innovative methods to safely identify patients with a very low risk of NSTE-ACS in individuals with chest pain outside the hospital. Our objective is to safely minimize hospital admissions that may not be necessary, thereby saving resources. By doing so, we aim to alleviate the pressure on EDs and contribute to more cost-effective healthcare.

Treatment of elderly patients with non-ST-elevation myocardial infarction: the nationwide POPular age registry.

OBJECTIVE: We describe the current treatment of elderly patients with non-ST-elevation myocardial infarction (NSTEMI) enrolled in a national registry. METHODS: The POPular AGE registry is a prospective, multicentre study of patients ≥ 75 years of age presenting with NSTEMI, performed in the Netherlands. Management was at the discretion of the treating physician. Cardiovascular events consisted of cardiovascular death, myocardial infarction and ischaemic stroke. Bleeding was classified according to the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: A total of 646 patients were enrolled between August 2016 and May 2018. Median age was 81 (IQR 77-84) years and 58% were male. Overall, 75% underwent coronary angiography, 40% percutaneous coronary intervention, and 11% coronary artery bypass grafting, while 49.8% received pharmacological therapy only. At discharge, dual antiplatelet therapy (aspirin and P2Y12 inhibitor) was prescribed to 56.7%, and 27.4% received oral anticoagulation plus at least one antiplatelet agent. At 1­year follow-up, cardiovascular death, myocardial infarction or stroke had occurred in 13.6% and major bleeding (BARC 3 and 5) in 3.9% of patients. The risk of both cardiovascular events and major bleeding was highest during the 1st month. However, cardiovascular risk was three times as high as bleeding risk in this elderly population, both after 1 month and after 1 year. CONCLUSIONS: In this national registry of elderly patients with NSTEMI, the majority are treated according to current European Society of Cardiology guidelines. Both the cardiovascular and bleeding risk are highest during the 1st month after NSTEMI. However, the cardiovascular risk was three times as high as the bleeding risk.

The Clinical Implementation of CYP2C19 Genotyping in Patients with an Acute Coronary Syndrome: Insights From the FORCE-ACS Registry.

BACKGROUND: Guidelines recommend prasugrel or ticagrelor for acute coronary syndrome (ACS) patients. However, these P2Y12 inhibitors increase bleeding risk compared to clopidogrel. Although genotype-guided P2Y12-inhibitor selection has been shown to reduce bleeding risk, data on its clinical implementation is lacking. METHODS: The study included ACS patients receiving genotype-guided antiplatelet therapy, utilising either a point-of-care (POC) device or laboratory-based testing. We aimed to collect qualitative and quantitative data on genotyping, eligibility for de-escalation, physician adherence to genotype results, time to de-escalation and cost reduction. RESULTS: Of the 1,530 patients included in the ACS registry from 2021 to 2023, 738 ACS patients treated with ticagrelor received a CYP2C19 genotype test. The median turnover time of genotyping was 6.3 hours (interquartile range [IQR], 3.2-16.7), with 82.3% of the genotyping results known within 24 hours after admission. POC genotyping exhibited significantly shorter turnaround times compared to laboratory-based testing (with respective medians of 5.7 vs 47.8 hours; P < .001). Of the genotyped patients, 81.7% were eligible for de-escalation which was carried out within 24 hours in 70.9% and within 48 h in 93.0%. The time to de-escalation was significantly shorter using POC (25.4 hours) compared to laboratory-based testing (58.9 hours; P < .001). Implementing this strategy led to a reduction of €211,150.50 in medication costs. CONCLUSIONS: CYP2C19 genotype-guided-de-escalation in an all-comers ACS population is feasible. POC genotyping leads to shorter turnaround times and quicker de-escalation. Time to de-escalation from ticagrelor to clopidogrel in noncarriers was short, with high physician adherence to genotype results.

Conservative versus Invasive Strategy in Elderly Patients with Non-ST-Elevation Myocardial Infarction: Insights from the International POPular Age Registry.

This registry assessed the impact of conservative and invasive strategies on major adverse clinical events (MACE) in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Patients aged ≥75 years with NSTEMI were prospectively registered from European centers and followed up for one year. Outcomes were compared between conservative and invasive groups in the overall population and a propensity score-matched (PSM) cohort. MACE included cardiovascular death, acute coronary syndrome, and stroke. The study included 1190 patients (median age 80 years, 43% female). CAG was performed in 67% (N = 798), with two-thirds undergoing revascularization. Conservatively treated patients had higher baseline risk. After propensity score matching, 319 patient pairs were successfully matched. MACE occurred more frequently in the conservative group (total population 20% vs. 12%, adjHR 0.53, 95% CI 0.37-0.77, p = 0.001), remaining significant in the PSM cohort (18% vs. 12%, adjHR 0.50, 95% CI 0.31-0.81, p = 0.004). In conclusion, an early invasive strategy was associated with benefits over conservative management in elderly patients with NSTEMI. Risk factors associated with ischemia and bleeding should guide strategy selection rather than solely relying on age.

Impact of recurrent ischaemic and bleeding events on quality of life in patients with acute coronary syndrome: Insights from the FORCE-ACS registry.

OBJECTIVE: Patients with acute coronary syndrome (ACS) remain at high risk for recurrent ischaemic and bleeding events during follow-up. Our study aimed to quantify and compare the impact of these adverse events on quality of life (QoL). METHODS: Data from patients with ACS prospectively enrolled in the FORCE-ACS registry between January 2015 and December 2019 were used for this study. The primary ischaemic and bleeding events of interest were hospital readmission for ACS and Bleeding Academic Research Consortium type 2 or 3 bleeding during 12 months follow-up. QoL was measured using the EQ-5D Visual Analogue Scale (VAS) score and the 12-item Short Form Survey version 2 derived Physical Component Summary (PCS) and Mental Health Component Summary (MCS) scores at 12 months follow-up. RESULTS: In total, 3339 patients (mean age 66.8 years, 27.9% women) were included. During follow-up, ischaemic events occurred in 202 patients (6.0%) and bleeding events in 565 patients (16.9%). After adjustment for demographic and clinical characteristics, ischaemic events remained independently associated with lower QoL regardless of metric used. Bleeding was also independently associated with lower EQ-5D VAS and PCS scores, but not with a lower MCS score. The QoL decrement associated with ischaemic events was numerically larger than the decrement associated with bleeding. CONCLUSIONS: Ischaemic and bleeding events remain prevalent and are independently associated with lower QoL at 12 months follow-up in patients previously admitted for ACS. The incidence and impact of these adverse events should be considered when balancing individual ischaemic and bleeding risks.

Effects of CYP3A4*22 and CYP3A5 on clinical outcome in patients treated with ticagrelor for ST-segment elevation myocardial infarction: POPular Genetics sub-study.

Aims: To determine the clinical efficacy, adverse events and side-effect dyspnea of CYP3A4*22 and CYP3A5 expressor status in ticagrelor treated patients. Methods and results: Ticagrelor treated patients from the POPular Genetics randomized controlled trial were genotyped for CYP3A4*22 and CYP3A5*3 alleles. Patients were divided based on their genotype. In total 1,281 patients with ST-segment elevation myocardial infarction (STEMI) were included. CYP3A4*22 carriers (n = 152) versus CYP3A4*22 non-carrier status (n = 1,129) were not found to have a significant correlation with the primary thrombotic endpoint: cardiovascular death, myocardial infarction, definite stent thrombosis and stroke [1.3% vs. 2.5%, adjusted hazard ratio 1.81 (0.43-7.62) p = 0.42], or the primary bleeding endpoint: PLATO major and minor bleeding [13.2% vs. 11.3%, adjusted hazard ratio 0.93 (0.58-1.50) p = 0.77]. Among the CYP3A4*1/*1 patients, CYP3A5 expressors (n = 196) versus non-expressors (n = 926) did not show a significant difference for the primary thrombotic [2.6% vs. 2.5%, adjusted hazard ratio 1.03 (0.39-2.71) p = 0.95], or the primary bleeding endpoint [12.8% vs. 10.9%, adjusted hazard ratio 1.13 (0.73-1.76) p = 0.58]. With respect to dyspnea, no significant difference was observed between CYP3A4*22 carriers versus CYP3A4*22 non-carriers [44.0% vs. 45.0%, odds ratio 1.04 (0.45-2.42) p = 0.93], or in the CYP3A4*1/*1 group, CYP3A5 expressors versus CYP3A5 non-expressors [35.3% vs. 47.8%, odds ratio 0.60 (0.27-1.30) p = 0.20]. Conclusion: In STEMI patients treated with ticagrelor, neither the CYP3A4*22 carriers, nor the CYP3A5 expressor status had a statistical significant effect on thrombotic and bleeding event rates nor on dyspnea. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01761786.

Dual versus triple antithrombotic therapy after percutaneous coronary intervention: the prospective multicentre WOEST 2 Study.

BACKGROUND: For patients on oral anticoagulants (OAC) undergoing percutaneous coronary intervention (PCI), European guidelines have recently changed their recommendations to dual antithrombotic therapy (DAT; P2Y12 inhibitor and OAC) without aspirin. AIMS: The prospective WOEST 2 registry was designed to obtain contemporary real-world data on antithrombotic regimens and related outcomes after PCI in patients with an indication for OAC. METHODS: In this analysis, we compare DAT (P2Y12 inhibitor and OAC) to triple antithrombotic therapy (TAT; aspirin, P2Y12 inhibitor, and OAC) on thrombotic and bleeding outcomes after one year. Clinically relevant bleeding was defined as Bleeding Academic Research Consortium classification (BARC) grade 2, 3, or 5; major bleeding as BARC grade 3 or 5. Major adverse cardiac and cerebrovascular events (MACCE) was defined as a composite of all-cause mortality, myocardial infarction, stent thrombosis, ischaemic stroke, and transient ischaemic attack. RESULTS: A total of 1,075 patients were included between 2014 and 2021. Patients used OAC for atrial fibrillation (93.6%) or mechanical heart valve prosthesis (4.7%). Non-vitamin K oral anticoagulants (NOAC) were prescribed in 53.1% and vitamin K antagonists in 46.9% of patients. At discharge, 60.9% received DAT, and 39.1% TAT. DAT was associated with less clinically relevant and similar major bleeding (16.8% vs 23.4%; p<0.01 and 7.6% vs 7.7%, not significant), compared to TAT. The difference in MACCE between the two groups was not statistically significant (12.4% vs 9.7%; p=0.17). Multivariable adjustment and propensity score matching confirmed these results. CONCLUSIONS: Dual antithrombotic therapy is associated with a substantially lower risk of clinically relevant bleeding without a statistically significant penalty in ischaemic events.

External validation of the GRACE risk score and the risk-treatment paradox in patients with acute coronary syndrome.

OBJECTIVES: To validate the Global Registry of Acute Coronary Events (GRACE) risk score and examine the extent and impact of the risk-treatment paradox in contemporary patients with acute coronary syndrome (ACS). METHODS: Data from 5015 patients with ACS enrolled in the FORCE-ACS registry between January 2015 and December 2019 were used for model validation. The performance of the GRACE risk score for predicting in-hospital and 1-year mortality was evaluated based on indices of model discrimination and calibration. Differences in the delivery of guideline-recommended care among patients who survived hospitalisation (n=4911) per GRACE risk stratum were assessed and the association with postdischarge mortality was examined. RESULTS: Discriminative power of the GRACE risk score was good for predicting in-hospital (c-statistic: 0.86; 95% CI: 0.83 to 0.90) and 1-year mortality (c-statistic: 0.82; 95% CI: 0.79 to 0.84). However, the GRACE risk score overestimated the absolute in-hospital and 1-year mortality risk (Hosmer-Lemeshow goodness-of-fit test p<0.01). Intermediate-risk and high-risk patients were 12% and 29% less likely to receive optimal guideline-recommended care compared with low-risk patients, respectively. Optimal guideline-recommended care was associated with lower mortality in intermediate- and high-risk patients. CONCLUSIONS: The GRACE risk score identified patients at higher risk for in-hospital and 1-year mortality, but overestimated absolute risk levels in contemporary patients. Optimal guideline-recommended care was associated with lower mortality in intermediate-risk and high-risk patients, but was less likely to be delivered with increasing mortality risk.

Long-term residual cardiovascular risk after acute coronary syndrome: antithrombotic treatment options.

The residual risk of patients surviving until 1 year after acute coronary syndromes (ACS) is still high, despite secondary prevention. The cornerstone of treatment of patients with ACS is dual antiplatelet therapy (DAPT) consisting of low-dose aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) for 12 months, or less in those patients at higher risk for bleeding. To reduce the residual risk beyond 1 year in those patients not at high bleeding risk who tolerated DAPT and did not suffer an (ischaemic or bleeding) event would intuitively mean to prolong DAPT. However, prolonged DAPT always comes at the cost of more bleeding. Therefore, assessing both ischaemic and bleeding risk in these patients at 1 year after ACS is crucial. In addition, another antithrombotic treatment consisting of low-dose rivaroxaban combined with low-dose aspirin has been shown to reduce ischaemic events. In this review, we describe residual thrombotic risk at 1 year after ACS, evaluate the evidence for antithrombotic options beyond 1 year and provide a practical guide to determine which patients would benefit the most from these therapies.

Patient-tailored antithrombotic therapy following percutaneous coronary intervention.

Dual antiplatelet therapy has long been the standard of care in preventing coronary and cerebrovascular thrombotic events in patients with chronic coronary syndrome and acute coronary syndrome undergoing percutaneous coronary intervention, but choosing the optimal treatment duration and composition has become a major challenge. Numerous studies have shown that certain patients benefit from either shortened or extended treatment duration. Furthermore, trials evaluating novel antithrombotic strategies, such as P2Y12 inhibitor monotherapy, low-dose factor Xa inhibitors on top of antiplatelet therapy, and platelet function- or genotype-guided (de-)escalation of treatment, have shown promising results. Current guidelines recommend risk stratification for tailoring treatment duration and composition. Although several risk stratification methods evaluating ischaemic and bleeding risk are available to clinicians, such as the use of risk scores, platelet function testing , and genotyping, risk stratification has not been broadly adopted in clinical practice. Multiple risk scores have been developed to determine the optimal treatment duration, but external validation studies have yielded conflicting results in terms of calibration and discrimination and there is limited evidence that their adoption improves clinical outcomes. Likewise, platelet function testing and genotyping can provide useful prognostic insights, but trials evaluating treatment strategies guided by these stratification methods have produced mixed results. This review critically appraises the currently available antithrombotic strategies and provides a viewpoint on the use of different risk stratification methods alongside clinical judgement in current clinical practice.

Rationale and Design of the Future Optimal Research and Care Evaluation in Patients with Acute Coronary Syndrome (FORCE-ACS) Registry: Towards "Personalized Medicine" in Daily Clinical Practice.

Diagnostic and treatment strategies for acute coronary syndrome have improved dramatically over the past few decades, but mortality and recurrent myocardial infarction rates remain high. An aging population with increasing co-morbidities heralds new clinical challenges. Therefore, in order to evaluate and improve current treatment strategies, detailed information on clinical presentation, treatment and follow-up in real-world patients is needed. The Future Optimal Research and Care Evaluation in patients with Acute Coronary Syndrome (FORCE-ACS) registry (ClinicalTrials.gov Identifier: NCT03823547) is a multi-center, prospective real-world registry of patients admitted with (suspected) acute coronary syndrome. Both non-interventional and interventional cardiac centers in different regions of the Netherlands are currently participating. Patients are treated according to local protocols, enabling the evaluation of different diagnostic and treatment strategies used in daily practice. Data collection is performed using electronic medical records and quality-of-life questionnaires, which are sent 1, 12, 24 and 36 months after initial admission. Major end points are all-cause mortality, myocardial infarction, stent thrombosis, stroke, revascularization and all bleeding requiring medical attention. Invasive therapy, antithrombotic therapy including patient-tailored strategies, such as the use of risk scores, pharmacogenetic guided antiplatelet therapy and patient reported outcome measures are monitored. The FORCE-ACS registry provides insight into numerous aspects of the (quality of) care for acute coronary syndrome patients.

Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG): A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 mg or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients that had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomly assigned patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 220 patients in the ticagrelor group and 223 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 10.5% (51 of 484 SVGs) versus 9.1% in the placebo group (43 of 470 SVGs), odds ratio, 1.29 [95% CI, 0.73-2.30]; P=0.38. SVG failure occurred in 35 (14.2%) patients in the ticagrelor group versus 29 (11.6%) patients in the placebo group (odds ratio, 1.22 [95% CI, 0.72-2.05]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02352402.

Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The effect of single as compared with dual antiplatelet treatment on bleeding and thromboembolic events after transcatheter aortic-valve implantation (TAVI) in patients who do not have an indication for long-term anticoagulation has not been well studied. METHODS: In a randomized, controlled trial, we assigned a subgroup of patients who were undergoing TAVI and did not have an indication for long-term anticoagulation, in a 1:1 ratio, to receive aspirin alone or aspirin plus clopidogrel for 3 months. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non-procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2) at 1 year, with both outcomes tested sequentially for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: A total of 331 patients were assigned to receive aspirin alone and 334 were assigned to receive aspirin plus clopidogrel. A bleeding event occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin plus clopidogrel (risk ratio, 0.57; 95% confidence interval [CI], 0.42 to 0.77; P = 0.001). Non-procedure-related bleeding occurred in 50 patients (15.1%) and 83 patients (24.9%), respectively (risk ratio, 0.61; 95% CI, 0.44 to 0.83; P = 0.005). A secondary composite 1 event occurred in 76 patients (23.0%) receiving aspirin alone and in 104 (31.1%) receiving aspirin plus clopidogrel (difference, -8.2 percentage points; 95% CI for noninferiority, -14.9 to -1.5; P<0.001; risk ratio, 0.74; 95% CI for superiority, 0.57 to 0.95; P = 0.04). A secondary composite 2 event occurred in 32 patients (9.7%) and 33 patients (9.9%), respectively (difference, -0.2 percentage points; 95% CI for noninferiority, -4.7 to 4.3; P = 0.004; risk ratio, 0.98; 95% CI for superiority, 0.62 to 1.55; P = 0.93). A total of 44 patients (13.3%) and 32 (9.6%), respectively, received oral anticoagulation during the trial. CONCLUSIONS: Among patients undergoing TAVI who did not have an indication for oral anticoagulation, the incidence of bleeding and the composite of bleeding or thromboembolic events at 1 year were significantly less frequent with aspirin than with aspirin plus clopidogrel administered for 3 months. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

TLR4 contributes to the damage of cartilage and subchondral bone in discectomy-induced TMJOA mice.

The abundance of inflammatory mediators in injured joint indicates innate immune reactions activated during temporomandibular joint osteoarthritis (TMJOA) progression. Toll-like receptor 4 (TLR4) can mediate innate immune reaction. Herein, we aimed to investigate the expression profile and effect of TLR4 in the cartilage and subchondral bone of the discectomy-induced TMJOA mice. The expression of TLR4 and NFκB p65 in the synovium of TMJOA patients was measured by immunohistochemistry, Western blotting and RT-PCR. H&E and Masson staining were utilized to assess the damage of cartilage and subchondral bone of the discectomy-induced TMJOA mice. A TLR4 inhibitor, TAK-242, was used to assess the effect of TLR4 in the cartilage and subchondral bone of the discectomy-induced TMJOA mice by Safranin O, micro-CT, immunofluorescence and immunohistochemistry. Western blotting was used to quantify the expression and effect of TLR4 in IL-1ß-induced chondrocytes. The expression of TLR4 and NFκB p65 was elevated in the synovium of TMJOA patients, compared with the normal synovium. TLR4 elevated in the damaged cartilage and subchondral bone of discectomy-induced TMJOA mice, and the rate of TLR4 expressing chondrocytes positively correlated with OA score. Intraperitoneal injections of TAK-242 ameliorate the extent of TMJOA. Furthermore, TLR4 promotes the expression of MyD88/NFκB, pro-inflammatory and catabolic mediators in cartilage of discectomy-induced TMJOA. Besides, TLR4 participates in the production of MyD88/NFκB, pro-inflammatory and catabolic mediators in IL-1ß-induced chondrocytes. TLR4 contributes to the damage of cartilage and subchondral bone in discectomy-induced TMJOA mice through activation of MyD88/NFκB and release of pro-inflammatory and catabolic mediators.

Risk Assessment Using Risk Scores in Patients with Acute Coronary Syndrome.

Risk scores are widely used in patients with acute coronary syndrome (ACS) prior to treatment decision-making at different points in time. At initial hospital presentation, risk scores are used to assess the risk for developing major adverse cardiac events (MACE) and can guide clinicians in either discharging the patients at low risk or swiftly admitting and treating the patients at high risk for MACE. During hospital admission, risk assessment is performed to estimate mortality, residual ischemic and bleeding risk to guide further in-hospital management (e.g., timing of coronary angiography) and post-discharge management (e.g., duration of dual antiplatelet therapy). In the months and years following ACS, long term risk can also be assessed to evaluate current treatment strategies (e.g., intensify or reduce pharmaceutical treatment options). As multiple risk scores have been developed over the last decades, this review summarizes the most relevant risk scores used in ACS patients.

The spatial relation of diabetic retinal neurodegeneration with diabetic retinopathy.

PURPOSE: Diabetic retinal neurodegeneration (DRN) has been demonstrated in eyes of patients with diabetes mellitus (DM), even in the absence of diabetic retinopathy (DR). However, no studies have looked at the rate of change in retinal layers and presence/development of DR over time per quadrant of the macula. In this longitudinal study, we aimed to clarify whether the rate of DRN is associated with the development/presence of DR within 4 different quadrants of the retina. METHODS: 80 eyes of 40 patients with type 1 DM and no/minimal DR were included. At 4 visits over 6 years, SD-OCT and fundus images were acquired. Thickness of the Retinal Nerve Fiber Layer (RNFL), Ganglion Cell Layer (GCL) and Inner Plexiform Layer (IPL) was measured in a 1-6mm circle around the fovea overall and for each quadrant (superior, nasal, inferior, temporal). Fundus images were scored for the presence/absence of DR in these areas. Multilevel analyses were performed to determine the rate of change for each layer overall and per quadrant for eyes/quadrants without and with DR during the follow-up period. RESULTS: RNFL and GCL showed significant thinning over time, IPL significant thickening. These changes were more pronounced for GCL and IPL in eyes/quadrants with DR during the follow-up period. CONCLUSIONS: RNFL and GCL both showed thinning over time, which was more pronounced in eyes with DR for GCL. This holds true even in regional parts of the retina, as quadrant analyses showed similar results, showing that structural DRN is associated with DR per quadrant independently.

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The roles of anticoagulation alone or with an antiplatelet agent after transcatheter aortic-valve implantation (TAVI) have not been well studied. METHODS: We performed a randomized trial of clopidogrel in patients undergoing TAVI who were receiving oral anticoagulation for appropriate indications. Patients were assigned before TAVI in a 1:1 ratio not to receive clopidogrel or to receive clopidogrel for 3 months. The two primary outcomes were all bleeding and non-procedure-related bleeding over a period of 12 months. Procedure-related bleeding was defined as Bleeding Academic Research Consortium type 4 severe bleeding, and therefore most bleeding at the puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction at 12 months (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2), both tested for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: Bleeding occurred in 34 of the 157 patients (21.7%) receiving oral anticoagulation alone and in 54 of the 156 (34.6%) receiving oral anticoagulation plus clopidogrel (risk ratio, 0.63; 95% confidence interval [CI], 0.43 to 0.90; P = 0.01); most bleeding events were at the TAVI access site. Non-procedure-related bleeding occurred in 34 patients (21.7%) and in 53 (34.0%), respectively (risk ratio, 0.64; 95% CI, 0.44 to 0.92; P = 0.02). Most bleeding occurred in the first month and was minor. A secondary composite 1 event occurred in 49 patients (31.2%) receiving oral anticoagulation alone and in 71 (45.5%) receiving oral anticoagulation plus clopidogrel (difference, -14.3 percentage points; 95% CI for noninferiority, -25.0 to -3.6; risk ratio, 0.69; 95% CI for superiority, 0.51 to 0.92). A secondary composite 2 event occurred in 21 patients (13.4%) and in 27 (17.3%), respectively (difference, -3.9 percentage points; 95% CI for noninferiority, -11.9 to 4.0; risk ratio, 0.77; 95% CI for superiority, 0.46 to 1.31). CONCLUSIONS: In patients undergoing TAVI who were receiving oral anticoagulation, the incidence of serious bleeding over a period of 1 month or 1 year was lower with oral anticoagulation alone than with oral anticoagulation plus clopidogrel. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Early Outcomes After Percutaneous Closure of Access Site in Transfemoral Transcatheter Valve Implantation Using the Novel Vascular Closure Device Collagen Plug-Based MANTA.

A new collagen-based MANTA vascular closure device (VCD) was developed for closing large-bore arteriotomies after transfemoral transcatheter aortic valve implantation (TAVI). We evaluated safety and feasibility at 30-day follow-up in terms of vascular and bleeding complications and mortality of the collagen-based MANTA VCD compared with the suture-based Prostar XL VCD in a cohort of 366 patients who underwent transfemoral TAVI between January 2015 and April 2018. The MANTA VCD was used in 168 patients and the Prostar XL VCD in 198 patients, with successful closure of 98.8% and 98.5%, respectively. VARC-2 defined as major vascular and bleeding complications was similar in both groups (MANTA vs Prostar XL): 0.6% versus 1.0% (p = 0.661) and 0.6% versus 1.5% (p = 0.102). Minor vascular and bleeding complications, were significantly more frequent (10.7 vs 18.8 %, p = 0.003 and 13.7 vs 19.7%, p = 0.080, respectively) in the Prostar XL cohort. Thirty-day all-cause mortality was 2.7%, without significant difference between the groups (p = 0.278). The MANTA device is a safe and feasible option for vascular access closure in patients undergoing transfemoral TAVI.