Pre-hospital rule-out of non-ST-segment elevation acute coronary syndrome by a single troponin: final one-year outcomes of the ARTICA randomised trial.

BACKGROUND AND AIMS: The healthcare burden of acute chest pain is enormous. In the randomised ARTICA trial we showed that pre-hospital identification of low-risk patients and rule-out of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) with point-of-care (POC) troponin measurement reduces 30-day healthcare costs with low major adverse cardiac events (MACE) incidence. Here we present the final one-year results of the ARTICA trial. METHODS: Low-risk patients with suspected NSTE-ACS were randomised to pre-hospital rule-out with POC troponin measurement or emergency department (ED) transfer. Primary one-year outcome was healthcare costs. Secondary outcomes were safety, quality of life (QoL) and cost-effectiveness. Safety was defined as one-year MACE, consisting of ACS, unplanned revascularisation or all-cause death. QoL was measured with EuroQol-5D-5 L questionnaires. Cost-effectiveness was defined as one-year healthcare costs difference per QoL difference. RESULTS: Follow-up was completed in all 863 patients. Healthcare costs were significantly lower in the pre-hospital strategy (€1932±€2784 vs €2649±€2750), mean difference €717 (95% confidence interval [CI] €347 to €1087; P < 0.001). In the total population, one-year MACE rate was comparable between groups (5.1% [22/434] in the pre-hospital strategy vs 4.2% [18/429] in the ED strategy; P = 0.54). In the ruled-out ACS population, one-year MACE remained low (1.7% [7/419] vs 1.4% [6/417]), risk difference 0.2% (95% CI -1.4% to 1.9%; P = 0.79). QoL showed no significant difference between strategies. CONCLUSIONS: Pre-hospital rule-out of NSTE-ACS with POC troponin testing in low-risk patients is cost-effective, expressed by a sustainable healthcare costs reduction and no significant effect on QoL. One-year MACE remained low for both strategies. Trial registration: Clinicaltrials.gov: NCT05466591, International Clinical Trials Registry Platform: NTR7346.

Differences in risk and costs between prehospital identified low-risk men and women with chest pain.

OBJECTIVE: Prehospital rule-out of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in low-risk patient with a point-of-care troponin measurement reduces healthcare costs with similar safety to standard transfer to the hospital. Risk stratification is performed identical for men and women, despite important differences in clinical presentation, risk factors and age between men and women with NSTE-ACS. Our aim was to compare safety and healthcare costs between men and women in prehospital identified low-risk patients with suspected NSTE-ACS. METHODS: In the Acute Rule-out of non-ST-segment elevation acute coronary syndrome in the (pre)hospital setting by HEART (History, ECG, Age, Risk factors and Troponin) score assessment and a single poInt of CAre troponin randomised trial, the HEAR (History, ECG, Age and Risk factors) score was assessed by ambulance paramedics in suspected NSTE-ACS patients. Low-risk patients (HEAR score ≤3) were included. In this substudy, men and women were compared. Primary endpoint was 30-day major adverse cardiac events (MACE), secondary endpoints were 30-day healthcare costs and the scores for the HEAR score components. RESULTS: A total of 863 patients were included, of which 495 (57.4%) were women. Follow-up was completed in all patients. In the total population, MACE occurred in 6.8% of the men and 1.6% of the women (risk ratio (RR) 4.2 (95% CI 1.9 to 9.2, p<0.001)). In patients with ruled-out ACS (97% of the total population), MACE occurred in 1.4% of the men and in 0.2% of the women (RR 7.0 (95% CI 2.0 to 14.2, p<0.001). Mean healthcare costs were €504.55 (95% CI €242.22 to €766.87, p<0.001) higher in men, mainly related to MACE. CONCLUSIONS: In a prehospital population of low-risk suspected NSTE-ACS patients, 30-day incidence of MACE and MACE-related healthcare costs were significantly higher in men than in women. TRIAL REGISTRATION NUMBER: NCT05466591.

Rule-out of non-ST-segment elevation acute coronary syndrome by a single, pre-hospital troponin measurement: a randomized trial.

AIMS: Patients with suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are routinely transferred to the emergency department (ED). A clinical risk score with point-of-care (POC) troponin measurement might enable ambulance paramedics to identify low-risk patients in whom ED evaluation is unnecessary. The aim was to assess safety and healthcare costs of a pre-hospital rule-out strategy using a POC troponin measurement in low-risk suspected NSTE-ACS patients. METHODS AND RESULTS: This investigator-initiated, randomized clinical trial was conducted in five ambulance regions in the Netherlands. Suspected NSTE-ACS patients with HEAR (History, ECG, Age, Risk factors) score ≤3 were randomized to pre-hospital rule-out with POC troponin measurement or direct transfer to the ED. The sample size calculation was based on the primary outcome of 30-day healthcare costs. Secondary outcome was safety, defined as 30-day major adverse cardiac events (MACE), consisting of ACS, unplanned revascularization or all-cause death. : A total of 863 participants were randomized. Healthcare costs were significantly lower in the pre-hospital strategy (€1349 ± €2051 vs. €1960 ± €1808) with a mean difference of €611 [95% confidence interval (CI): 353-869; P < 0.001]. In the total population, MACE were comparable between groups [3.9% (17/434) in pre-hospital strategy vs. 3.7% (16/429) in ED strategy; P = 0.89]. In the ruled-out ACS population, MACE were very low [0.5% (2/419) vs. 1.0% (4/417)], with a risk difference of -0.5% (95% CI -1.6%-0.7%; P = 0.41) in favour of the pre-hospital strategy. CONCLUSION: Pre-hospital rule-out of ACS with a POC troponin measurement in low-risk patients significantly reduces healthcare costs while incidence of MACE was low in both strategies. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT05466591 and International Clinical Trials Registry Platform id NTR 7346.

Reprogramming of bone marrow myeloid progenitor cells in patients with severe coronary artery disease.

Atherosclerosis is the major cause of cardiovascular disease (CVD). Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. In patients with atherosclerotic CVD, leukocytes have a hyperinflammatory phenotype. We hypothesize that immune cell reprogramming in these patients occurs at the level of myeloid progenitors. We included 13 patients with coronary artery disease due to severe atherosclerosis and 13 subjects without atherosclerosis in an exploratory study. Cytokine production capacity after ex vivo stimulation of peripheral blood mononuclear cells (MNCs) and bone marrow MNCs was higher in patients with atherosclerosis. In BM-MNCs this was associated with increased glycolysis and oxidative phosphorylation. The BM composition was skewed towards myelopoiesis and transcriptome analysis of HSC/GMP cell populations revealed enrichment of neutrophil- and monocyte-related pathways. These results show that in patients with atherosclerosis, activation of innate immune cells occurs at the level of myeloid progenitors, which adds exciting opportunities for novel treatment strategies.

Acute rule-out of non-ST-segment elevation acute coronary syndrome in the (pre)hospital setting by HEART score assessment and a single point-of-care troponin: rationale and design of the ARTICA randomised trial.

INTRODUCTION: Because of the lack of prehospital protocols to rule out a non-ST-segment elevation acute coronary syndrome (NSTE-ACS), patients with chest pain are often transferred to the emergency department (ED) for thorough evaluation. However, in low-risk patients, an ACS is rarely found, resulting in unnecessary healthcare consumption. Using the HEART (History, ECG, Age, Risk factors and Troponin) score, low-risk patients are easily identified. When a point-of-care (POC) troponin measurement is included in the HEART score, an ACS can adequately be ruled out in low-risk patients in the prehospital setting. However, it remains unclear whether a prehospital rule-out strategy using the HEART score and a POC troponin measurement in patients with suspected NSTE-ACS is cost-effective. METHODS AND ANALYSIS: The ARTICA trial is a randomised trial in which the primary objective is to investigate the cost-effectiveness after 30 days of an early rule-out strategy for low-risk patients suspected of a NSTE-ACS, using a modified HEART score including a POC troponin T measurement. Patients are included by ambulance paramedics and 1:1 randomised for (1) presentation at the ED (control group) or (2) POC troponin T measurement (intervention group) and transfer of the care to the general practitioner in case of a low troponin T value. In total, 866 patients will be included. Follow-up will be performed after 30 days, 6 months and 12 months. ETHICS AND DISSEMINATION: This trial has been accepted by the Medical Research Ethics Committee region Arnhem-Nijmegen. The results of this trial will be disseminated in one main paper and in additional papers with subgroup analyses. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL7148).

Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo.

BACKGROUND AND AIMS: We have recently reported that monocytes can undergo functional and transcriptional reprogramming towards a long-term pro-inflammatory phenotype after brief in vitro exposure to atherogenic stimuli such as oxidized LDL. This process is termed 'trained immunity', and is mediated by epigenetic remodeling and a metabolic switch towards increased aerobic glycolysis. We hypothesize that trained immunity contributes to atherogenesis. Therefore, we investigated the inflammatory phenotype and epigenetic remodeling of monocytes from patients with and without established atherosclerosis. METHODS: Monocytes were isolated from 20 patients with severe symptomatic coronary atherosclerosis (total plaque score >4 on coronary computed tomography angiography) and 17 patients with asymptomatic carotid atherosclerosis and matched controls for both groups. Ex vivo stimulation, RNA analysis and chromatin immunoprecipitation were performed. RESULTS: Monocytes from patients with symptomatic atherosclerosis have a higher production of pro-inflammatory cytokines upon LPS stimulation than healthy controls (TNFα 499 ± 102 vs. 267 ± 45 pg/ml, p = 0.01). This was associated with lower histone 3 lysine 4 trimethylation (H3K4me3) (19% vs. 33%, p = 0.002), and lower H3K27me3 (0.005% vs. 0.8%, p < 0.0001) on the TNFα promoter. Furthermore, relative mRNA expression of the glycolytic rate limiting enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 was higher in patients (0.7 ± 0.2 vs. 0.3 ± 0.1 resp. 1.7 ± 0.2 vs. 1.0 ± 0.1, p = 0.007 resp. 0.003) compared to control individuals. Interestingly, this pro-inflammatory phenotype was only present in patients with symptomatic atherosclerosis, and not in patients with asymptomatic carotid atherosclerosis. CONCLUSIONS: Circulating monocytes of patients with symptomatic, but not asymptomatic, atherosclerosis have a pro-inflammatory phenotype and increased expression of glycolytic enzymes, associated with epigenetic remodeling at the level of histone methylation.

Differential effects of platelets and platelet inhibition by ticagrelor on TLR2- and TLR4-mediated inflammatory responses.

Platelets and platelet-monocyte interaction play an important role in inflammation. Both pro- and anti-inflammatory effects of platelet inhibition have been reported in animal models. This study aimed to investigate the effect of platelets and platelet inhibition by the new P2Y12 receptor antagonist ticagrelor on monocyte function, as assessed by cytokine responses to Toll-like Receptor (TLR) ligands. In a set of in vitro experiments, peripheral blood mononuclear cells (PBMC) incubated with the TLR2 ligand Pam3CSK4 produced less cytokines in the presence of platelets, whereas platelets increased the production of cytokines when PBMC were exposed to TLR4 ligand lipopolysaccharide (LPS). These effects of platelets were dependent on direct platelet-leukocyte aggregation and for the Pam3CSK4-induced response, on phagocytosis of platelets by monocytes. In a double blind, placebo-controlled crossover trial in healthy volunteers, a single oral dosage of 180 mg ticagrelor reduced platelet-monocyte complex (PMC) formation. This was associated with an increase in pro-inflammatory cytokines in blood exposed to Pam3CSK4, but a decrease in these cytokines in blood exposed to LPS. These findings show that platelets differentially modulate TLR2- and TLR4-mediated cytokine responses of PBMC. Through inhibition of platelet-leukocyte interaction, P2Y12 receptor antagonists may either exert a pro- or anti-inflammatory effect during infections depending on the TLR primarily involved.

Clinical impact of second-generation everolimus-eluting stent compared with first-generation drug-eluting stents in diabetes mellitus patients: insights from a nationwide coronary intervention register.

OBJECTIVES: This study sought to study the second-generation everolimus-eluting stent (EES) as compared with first-generation sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in diabetes mellitus (DM) patients. BACKGROUND: There are limited data available comparing clinical outcomes in this setting with EES and SES, whereas studies comparing EES with PES are not powered for low-frequency endpoints. METHODS: All DM patients treated with EES, PES, or SES from January 18, 2007, to July 29, 2011, from the SCAAR (Swedish Coronary Angiography and Angioplasty Registery) were included. The EES was compared with SES or PES for the primary composite endpoint of clinically driven detected restenosis, definite stent thrombosis (ST), and all-cause mortality. RESULTS: In 4,751 percutaneous coronary intervention-treated DM patients, 8,134 stents were implanted (EES = 3,928, PES = 2,836, SES = 1,370). The EES was associated with significantly lower event rates compared with SES (SES vs. EES hazard ratio [HR]: 1.99; 95% confidence interval (CI): 1.19 to 3.08). The same was observed when compared with PES (PES vs. EES HR: 1.33; 95% CI: 0.93 to 1.91) but did not reach statistical significance. These results were mainly driven by lower incidence of ST (SES vs. EES HR: 2.87; 95% CI: 1.08 to 7.61; PES vs. EES HR: 1.74, 95% CI: 0.82 to 3.71) and mortality (SES vs. EES HR: 2.02; 95% CI: 1.03 to 3.98; PES vs. EES HR: 1.69; 95% CI: 1.06 to 2.72). No significant differences in restenosis rates were observed between EES and SES or PES (SES vs. EES HR: 1.26; 95% CI: 0.77 to 2.08; PES vs. EES HR: 1.05; 95% CI: 0.71 to 1.55). CONCLUSIONS: In all-comer DM patients the use of EES was associated with improved outcomes compared with SES and PES mainly driven by lower rates of ST and mortality. These results suggest better safety rather than efficacy with EES when compared with SES or PES.

Sympathoinhibition by atorvastatin in hypertensive patients.

BACKGROUND: Experimental animal data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) might reduce enhanced sympathetic activity, a hallmark of hypertensive patients. This hypothesis was tested for the first time in patients with primary hypertension. METHODS AND RESULTS: Using a prospective, randomized, placebo-controlled, double-blind, cross-over design, a proof-of-principle trial was performed in 13 patients with mild to moderate primary hypertension, who were randomly assigned to a regimen of atorvastatin (80mg/day) for 3 weeks, followed by placebo for 3 weeks or to a regimen of placebo for 3 weeks, followed by atorvastatin (80mg/day) for 3 weeks. Microneurography was used at the end of each treatment period to measure sympathetic nervous system activity (muscle sympathetic nerve activity: MSNA). Heart rate variability (HRV) and plasma norepinephrine concentrations were also measured. Additionally, effects on blood pressure (BP) and heart rate (HR) were assessed by 24-h ambulatory BP measurement. Atorvastatin reduced postganglionic MSNA (atorvastatin 35.0±2.0 vs placebo: 39.2±1.5 bursts/min, P=0.008) and heart frequency corrected MSNA (atorvastatin: 58.5±2.0 vs placebo: 64.7±3.0 bursts/100 beats, P=0.02). Atorvastatin had no significant effect on plasma norepinephrine levels, HRV, BP or HR. CONCLUSIONS: In patients with mild to moderate hypertension, atorvastatin reduces postganglionic MSNA, which supports the hypothesis that HMG-CoA reductase plays a role in sympathetic nervous system activity.

Alpha-receptor blockade improves muscle perfusion and glucose uptake in heart failure.

AIMS: Alpha-adrenergic receptor-mediated vasoconstriction might underlie the insulin resistance seen in conditions associated with increased sympathetic tone, like chronic heart failure (CHF). Alpha-adrenergic receptor blockade by phentolamine could improve forearm blood flow (FBF) and forearm glucose uptake (FGU) in CHF patients. METHODS AND RESULTS: In 8 CHF patients and in 12 healthy volunteers, FBF (plethysmography) and FGU were measured in both forearms during a 150 min hyperinsulinaemic euglycaemic clamp procedure. During the final 30 min of the clamp, phentolamine was infused into one arm (experimental arm) at a dose of 5.0 µg; min(-1) dL(-1) of forearm volume. Insulin infusion (t = 0-120 min) increased FGU in the two groups, without affecting FBF. In the CHF group, α-adrenergic receptor blockade by phentolamine (t = 120-150 min) further increased FGU in the experimental arm from 3.0 ± 0.7 to 5.0 ± 0.9 µmol min(-1) dL(-1) (P = 0.03). Forearm glucose uptake in the contralateral forearm remained unchanged. In the control group, phentolamine infusion did not increase FGU in the experimental forearm. The increase in blood flow in response to phentolamine was similar in both groups (CHF: 2.1 ± 0.3-7.5 ± 1.7 mL min(-1) dL(-1), P < 0.001; controls 1.5 ± 0.2-5.5 ± 0.8 mL min(-1) dL(-1), P < 0.001 for both, CHF vs. control, P = 0.2). Phentolamine did not affect FBF in the control arm in either group. CONCLUSION: Alpha-adrenergic receptor blockade improves FGU in CHF patients. As the increase in FBF is similar in controls and CHF patients, this might be explained by an improved glucose-extraction capacity in CHF patients.

Improving myocardial perfusion by percutaneous coronary intervention reduces central sympathetic activity in stable angina.

BACKGROUND: By stimulating sympathetic afferents, repetitive myocardial ischemia induces a state of increased sympathetic tone. HYPOTHESIS: Removing the ischemic trigger by revascularization using percutaneous coronary intervention (PCI) might thus reduce central sympathetic activity in symptomatically stable angina patients. METHODS: A total of 20 patients with stable angina > or = New York Heart Association (NYHA) class II with persistent symptoms despite maximal pharmacological therapy and a clinical indication for PCI, were included in our study. Sympathetic nervous system activity was measured before and 1 month after PCI by a combination of techniques: direct muscle sympathetic nerve activity (MSNA), neurochemical (plasma catecholamine levels), and heart rate variability (HRV). RESULTS: All patients completed the study. After PCI there was a significant reduction in MSNA (pre-PCI 72 +/- 4 to post-PCI 53 +/- 4 burst/100 beats, P < .05) and low frequency/high frequency (LF/HF) ratio (3.7 +/- 0.6 vs 2.4 +/- 0.4, P < .05) consistent with a decline in sympathetic activity. Plasma norepinephrine levels were reduced after PCI, but this difference did not reach statistical significance (1.84 +/- 0.17 vs 1.73 +/- 0.13 nmol/L, P = not significant). CONCLUSION: Coronary revascularization by PCI reduces sympathetic activity in patients with established myocardial ischemia.

Effect of PCI on inflammatory markers, adiponectin and insulin resistance.

AIMS: Percutaneous coronary interventions (PCI) evoke an inflammatory response and have been reported to decrease adiponectin levels. If persistent over time, the inflammatory response and low adiponectin levels would induce insulin resistance, rendering PCI potentially hazardous for glucose metabolism. We investigated whether PCI decreased insulin sensitivity after one month and if so, whether this was related to a lasting elevation of inflammatory markers and decrease in adiponectin levels. METHODS AND RESULTS: Insulin sensitivity (euglycemic hyperinsulinaemic clamp) was measured in 19 patients with stable coronary artery disease before and one month after PCI. Also, levels of inflammatory mediators and adiponectin were assessed. Insulin sensitivity was not affected by the PCI procedure. There were no persistent increases in IL-6, hs-CRP and adiponectin levels after PCI. CONCLUSIONS: The inflammatory response seen immediately after PCI does not translate to a medium-term negative effect on insulin action.

Sympathoinhibitory effect of statins in chronic heart failure.

OBJECTIVES: Increased (central) sympathetic activity is a key feature of heart failure and associated with worse prognosis. Animal studies suggest that statin therapy can reduce central sympathetic outflow. This study assessed statin effects on (central) sympathetic activity in human chronic heart failure (CHF) patients. METHODS: Sympathetic activity was measured in eight patients with CHF patients during 8 weeks after discontinuation and 4 weeks after restart of statin therapy by microneurography for direct muscle sympathetic nerve recording (MSNA) and measurement of arterial plasma norepinephrine concentrations. RESULTS: During discontinuation of statin therapy, MSNA was significantly increased (73 +/- 4 vs. 56 +/- 5 and 52 +/- 6 bursts/100 beats, p = 0.01). Burst frequency was significantly higher after statin discontinuation (42 +/- 3 burst/min without statin vs. 32 +/- 3 and 28 +/- 3 burst/min during statin therapy, p = 0.004). Mean normalized burst amplitude and total normalized MSNA were significantly higher after statin discontinuation (mean normalized burst amplitude 0.36 +/- 0.04 without statin vs. 0.29 +/- 0.04 and 0.22 +/- 0.04 during statin, p < 0.05; total normalized MSNA 15.70 +/- 2.78 without statin, vs. 9.28 +/- 1.41 and 6.56 +/- 1.83 during statin, p = 0.009). Arterial plasma norepinephrine levels and blood pressure were unaffected. INTERPRETATION: Statin therapy inhibits central sympathetic outflow in CHF patients, as measured by MSNA.