The objective CORE score allows early rule out in acute chest pain patients.

OBJECTIVES: Chest pain is a common complaint in the emergency department (ED), and it is a challenge to identify low-risk chest pain patients eligible for early discharge. We aimed to develop a simple objective decision rule to exclude 30-day major adverse cardiac events (MACE) in ED chest pain patients. DESIGN: We analyzed prospectively included patients presenting with chest pain. Low risk patients were identified with the clinical objective rule-out evaluation (CORE). CORE was based on high sensitivity cardiac troponin T (hs-cTnT) tests at ED presentation (0 h) and 2 h later together with a simplified risk score consisting of four objective variables: age ≥65 years and a history of arterial disease, hypertension or diabetes. For the patient to be classified as low risk in the CORE rule, hs-cTnT had to be ≤14 ng/L both at 0 and 2 h, and the sum of the risk score had to be 0. The primary outcome was MACE within 30 days. RESULTS: Among the 751 patients in the final analysis, 90 (11.9%) had a MACE. CORE identified 248 (33%) of patients as low risk with a sensitivity of 98.9% (CI 93.1-99.9) and a negative predictive value of 99.6% (95% CI 97.4-100) for 30-day MACE. Adding the ED physician's interpretation of the ECG to CORE did not improve diagnostic performance. CONCLUSION: A simple objective decision rule (CORE) identified one-third of all patients as having a very low 30-day risk of MACE. These patients may potentially be discharged without additional investigations for acute coronary syndrome.

Prasugrel 5 mg inhibits platelet P-selectin and GPIIb-IIIa expression in very elderly and non elderly: results from the GENERATIONS trial, a pharmacodynamic study in stable CAD patients.

UNLABELLED: Platelet P-selectin and activated glycoprotein IIb-IIIa (GPIIb-IIIa) are markers of platelet activation and mediates platelet aggregation. Prasugrel (Pras) 5 mg may be used in very elderly (VE) acute coronary syndrome (ACS) patients undergoing PCI, but its effect on platelet P-selectin and activated GPIIb-IIIa in those patients is not known. Stable ACS patients, VE (78 ± 5 years, n = 23) and non-elderly (NE) (55 ± 5 years, n = 22) were randomized to Pras (5 or 10 mg) or clopidogrel (Clop) 75 mg during three 12-day periods. Platelet activation markers were measured by flow cytometry on unstimulated or stimulated (adenosine diphosphate (ADP) 20 µM) platelets, before and after each dosing period. RESULTS: At baseline there was no difference in platelet activation markers, either unstimulated or ADP-stimulated, between NE and VE. Pras 5 mg reduced both ADP-stimulated platelet P-selectin and activated GPIIb-IIIa in VE (p < 0.01 for both analyses) and NE (p < 0.001 and p < 0.05, respectively). Clop 75 mg had a similar effect as Pras 5 mg but did not significantly reduce activated GPIIb-IIIa in VE. Prasugrel 10 mg resulted in decreased platelet activation in both age groups compared to Clop 75 mg (p < 0.01). CONCLUSIONS: In VE and NE-patients, Pras 5 mg inhibited platelet P-selectin expression similar to Clop 75 mg and Pras 10 mg. Prasugrel 10 mg inhibited platelet P-selectin expression better than Clop 75 mg. Prasugrel 10 mg and 5 mg, but not Clop 75 mg, significantly inhibited activated GPIIb-IIIa in VE. This platelet reactivity data support the use of Pras 5 mg for VE patients.

Predictive role of high sensitivity troponin T within four hours from presentation of acute coronary syndrome in elderly patients.

BACKGROUND: Previous studies indicate that the introduction of high-sensitivity troponin T (HsTnT) as a diagnostic tool for chest pain patients in the emergency department (ED) creates a high rate of false-positive tests. In the present study, we aimed to evaluate if the diagnostic performance of HsTnT for acute coronary syndrome (ACS) up to 3-4 h after presentation in elderly patients can be improved. METHODS: A total of 477 consecutive patients ≥ 75 years, admitted to in-hospital care for chest pain suspicious of ACS, were retrospectively included. HsTnT values at presentation (0 h) and at 3-4 h were analysed. Receiver operating characteristic (ROC) curves were created for absolute and relative changes from 0 to 3-4 h. ACS, non-elective percutaneous coronary intervention, coronary artery bypass grafting and death of all causes were recorded for all patients during a follow-up of 60 days. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were analysed for different HsTnT cut-off values at 0 and 3-4 h and for the combination of a HsTnT at presentation and an absolute change from 0 to 3-4 h. RESULTS: Twenty-seven percent of the patients had ACS and 21 % acute myocardial infarction (AMI) during the hospital stay. The standard cut-off 14 ng/L gave sensitivity and NPV for ACS of 88 and 90 % at 3-4 h. Specificity and PPV was 38 and 32 % respectively. Analysing for non-ST elevation myocardial infarction (NSTEMI) alone gave a sensitivity and NPV of 100 % but did not improve specificity and PPV. The area under the ROC-curve was larger for absolute than relative HsTnT changes from 0 to 3-4 h. A combination of HsTnT at presentation > 30 ng/L and/or a change > 5 ng/L up to 3-4 h gave a 63 % specificity and a PPV of 46 %, a 99 % sensitivity and a NPV of 99 % for NSTEMI. CONCLUSION: Our study indicates that HsTnT can neither exclude nor confirm ACS within 3-4 h from presentation in patients ≥ 75 years. NSTEMI can be excluded with HsTnT within 3-4 h, but HsTnT cannot be used to rule in NSTEMI during the first 3-4 h, not even by using a combination of the initial HsTnT result and the change from 0 to 3-4 h. With combined criteria, the majority of the positive tests were still false positive. Our results indicate that in patients > 75 years, HsTnT should be used primarily as an early rule-out tool for AMI.

The combination of high sensitivity troponin T and copeptin facilitates early rule-out of ACS: a prospective observational study.

BACKGROUND: The combination of the new high sensitivity troponin T (hsTnT) assays and copeptin, a biomarker of endogenous stress, has been suggested to have the potential of early rule-out of acute coronary syndrome (ACS). The aim of this study was to examine the ability of this combination to rule out ACS in patients presenting with chest pain and to compare the diagnostic performance to hsTnT alone. METHOD: In this prospective observational study, patients with chest pain admitted for observation were consecutively included. Patients presenting with ST elevation were excluded. Copeptin and hsTnT were analyzed at admission and hsTnT was thereafter determined approximately every 3rd hour as long as clinically indicated. The follow-up period was 60 days. A combined primary endpoint of ACS, non-elective percutanous coronary intervention, non-elective coronary artery bypass surgery and death of all causes was used. RESULTS: 478 patients were included. 107 (22%) patients were diagnosed with ACS during hospital stay. 70 (14%) had non-ST-segment elevation myocardial infarction (NSTEMI) and 37 (8%) had unstable angina pectoris (UAP). CONCLUSIONS: In patients presenting with chest pain admitted for observation, the combination of hsTnT and copeptin analyzed at admission had a significantly higher sensitivity to diagnose ACS than hsTnT alone. We report a sensitivity of 83% and a NPV of 91% for the combination of hsTnT and copeptin and we conclude that biomarkers alone are not sufficient to rule out ACS. However, the combination of hsTnT and copeptin seems to have a significantly higher sensitivity to identify ACS than a repeated hsTnT test, and thus enables an earlier risk stratification of chest pain patients. This can be time-saving and beneficial for the individual patient by contributing to early decisions on treatment, need of further assessment and level of care.

[Poor compliance with guidelines for decisions regarding treatment restrictions]. / Riktlinjer följdes dåligt vid beslut att avstå livsuppehållande behandling.

This study investigates decisions regarding treatment restrictions at Helsingborg Hospital. Current guidelines require these decisions to be communicated to the patient and/or relative. This study shows that in a majority of cases the order had not been communicated according to guidelines. The study could not find the reason of these deviations. Several of the included patients were deemed as appropriate for an earlier decision for treatment restriction by their primary care physician. These orders would, most likely, be more thoroughly assessed and better communicated with the patient and/or their relatives.

Positive inotropic effects by uridine triphosphate (UTP) and uridine diphosphate (UDP) via P2Y2 and P2Y6 receptors on cardiomyocytes and release of UTP in man during myocardial infarction.

The aim of this study was to examine a possible role for extracellular pyrimidines as inotropic factors for the heart. First, nucleotide plasma levels were measured to evaluate whether UTP is released in patients with coronary heart disease. Then, inotropic effects of pyrimidines were examined in isolated mouse cardiomyocytes. Finally, expression of pyrimidine-selective receptors (a subgroup of the P2 receptors) was studied in human and mouse heart, using real time polymerase chain reaction, Western blot, and immunohistochemistry. Venous plasma levels of UTP were increased (57%) in patients with myocardial infarction. In electrically stimulated cardiomyocytes the stable P2Y(2/4) agonist UTPgammaS increased contraction by 52%, similar to beta1-adrenergic stimulation with isoproterenol (65%). The P2Y6-agonist UDPbetaS also increased cardiomyocyte contraction (35%), an effect abolished by the P2Y6-blocker MRS2578. The phospholipase C inhibitor U73122 inhibited both the UDPbetaS and the UTPgammaS-induced inotropic effect, indicating an IP3-mediated effect via P2Y6 receptors. The P2Y14 agonist UDP-glucose was without effect. Quantification of mRNA with real time polymerase chain reaction revealed P2Y2 as the most abundant pyrimidine receptor expressed in cardiomyocytes from man. Presence of P2Y6 receptor mRNA was detected in both species and confirmed at protein level with Western blot and immunohistochemistry in man. In conclusion, UTP levels are increased in humans during myocardial infarction, giving the first evidence for UTP release in man. UTP is a cardiac inotropic factor most likely by activation of P2Y2 receptors in man. For the first time we demonstrate inotropic effects of UDP, mediated by P2Y6 receptors via an IP3-dependent pathway. Thus, the extracellular pyrimidines (UTP and UDP) could be important inotropic factors involved in the development of cardiac disease.

A 1-h Combination Algorithm Allows Fast Rule-Out and Rule-In of Major Adverse Cardiac Events.

BACKGROUND: A 1-h algorithm based on high-sensitivity cardiac troponin T (hs-cTnT) testing at presentation and again 1 h thereafter has been shown to accurately rule out acute myocardial infarction. OBJECTIVES: The goal of the study was to evaluate the diagnostic accuracy of the 1-h algorithm when supplemented with patient history and an electrocardiogram (ECG) (the extended algorithm) for predicting 30-day major adverse cardiac events (MACE) and to compare it with the algorithm using hs-cTnT alone (the troponin algorithm). METHODS: This prospective observational study enrolled consecutive patients presenting to the emergency department (ED) with chest pain, for whom hs-cTnT testing was ordered at presentation. Hs-cTnT results at 1 h and the ED physician's assessments of patient history and ECG were collected. The primary outcome was an adjudicated diagnosis of 30-day MACE defined as acute myocardial infarction, unstable angina, cardiogenic shock, ventricular arrhythmia, atrioventricular block, cardiac arrest, or death of a cardiac or unknown cause. RESULTS: In the final analysis, 1,038 patients were included. The extended algorithm identified 60% of all patients for rule-out and had a higher sensitivity than the troponin algorithm (97.5% vs. 87.6%; p < 0.001). The negative predictive value was 99.5% and the likelihood ratio was 0.04 with the extended algorithm versus 97.8% and 0.17, respectively, with the troponin algorithm. The extended algorithm ruled-in 14% of patients with a higher sensitivity (75.2% vs. 56.2%; p < 0.001) but a slightly lower specificity (94.0% vs. 96.4%; p < 0.001) than the troponin algorithm. The rule-in arms of both algorithms had a likelihood ratio >10. CONCLUSIONS: A 1-h combination algorithm allowed fast rule-out and rule-in of 30-day MACE in a majority of ED patients with chest pain and performed better than the troponin-alone algorithm.

Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels.

BACKGROUND: To be fully activated platelets are dependent on two positive feedback loops; the formation of thromboxane A2 by cyclooxygenase in the platelets and the release of ADP. We wanted to evaluate the effect of aspirin on platelet function in patients with acute coronary syndromes and we hypothesized that increased levels of ADP in patients with acute coronary syndromes could contribute to aspirin resistance. METHODS: Platelet activity in 135 patients admitted for chest pain was assessed with PFA-100. An epinephrine-collagen cartridge (EPI-COLL) was used for the detection of aspirin resistance together with an ADP-collagen cartridge (ADP-COLL). ADP was measured with hplc from antecubital vein samples. Three subgroups were compared: chest pain with no sign of cardiac disease (NCD), NonST-elevation myocardial infarction (NSTEMI) and STEMI. RESULTS: Platelet activation was increased for the STEMI group compared NCD. Aspirin resistance defined as <193 sec in EPI-COLL was 9.7 % in NCD, and increased to 26.0 % (n.s.) in NSTEMI and 83.3 % (p < 0.001) in STEMI. Chronic aspirin treatment significantly reduced platelet aggregation in NCD and NSTEMI, but it had no effect in STEMI. Plasma levels of ADP were markedly increased in STEMI (905 +/- 721 nmol/l, p < 0.01), but not in NSTEMI (317 +/- 245), compared to NCD (334 +/- 271, mean +/- SD). ADP levels correlated with increased platelet activity measured with ADP-COLL (r = -0.30, p < 0.05). Aspirin resistant patients (EPI-COLL < 193 sec) had higher ADP levels compared to aspirin responders (734 +/- 807 vs. 282 +/- 187 nmol/l, mean +/- SD, p < 0.05). CONCLUSION: Platelets are activated and aspirin resistance is more frequent in STEMI, probably due to a general activation of platelets. ADP levels are increased in STEMI and correlates with platelet activation. Increased levels of ADP could be one reason for increased platelet activity and aspirin resistance.

Contractions in human coronary bypass vessels stimulated by extracellular nucleotides.

BACKGROUND: The present study was designed to evaluate the relative contribution of different contractile P2 receptors in human saphenous vein compared with internal mammary artery obtained during coronary artery surgery. METHODS: The isometric tension in endothelium-denuded isolated vessel segments was recorded in vitro. The P2 receptor mRNA expression was quantified by real-time polymerase chain reaction. RESULTS: The P2X(1) receptor agonist, alphabeta-MeATP (alphabeta-methylene-adenosine triphosphate), was the most potent vasoconstrictor, with more efficacious contractions in the saphenous vein than in the internal mammary artery. The selective P2Y(6) receptor agonist, UDPbetaS (uridine 5'-O-thiodiphosphate), stimulated more potent contractions in saphenous vein compared with internal mammary artery. Furthermore, UDPbetaS induced long-lasting contractions for more than 2 hours, explained by the low desensitization rate of the P2Y(6) receptor. The ATP-induced vasoconstriction could not be abolished by desensitization of P2X(1) receptors with alphabeta-MeATP, or P2Y(2/4) receptors with UTPgammaS (uridine 5'-O-3-thiotriphosphate), indicating the presence of yet another contractile ATP receptor. Based on quantification with real-time polymerase chain reaction, the P2Y(11) receptor could be responsible for this ATP contraction. CONCLUSIONS: The P2X(1) and P2Y(6) receptors elicit more prominent contractions in the saphenous vein as compared with the internal mammary artery. These results may present one explanation for the differences in the two conduits. It is possible that selective antagonists of P2X(1) and P2Y(6) receptors could be used to prevent vasospasm and restenosis in the saphenous vein during and after revascularization surgery.

High-sensitivity troponin T as a diagnostic tool for acute coronary syndrome in the real world: an observational study.

BACKGROUND: The 2011 European Society of Cardiology guidelines state that acute coronary syndrome (ACS) may be excluded with a rapid 3 h high-sensitivity troponin T (HsTnT) sampling protocol. We aimed to evaluate the diagnostic and prognostic performance of HsTnT in patients with chest pain admitted with possible ACS in routine care. METHODS: A total of 773 consecutive patients admitted for in-hospital care for chest pain suspicious of ACS were included retrospectively. HsTnT values at admission and at 3-4 and 6-7 h were analysed for diagnostic performance. In addition, prognostic performance towards a combined 60-day endpoint of ACS, nonelective revascularization or death of all causes was studied. RESULTS: Twenty-three per cent of the patients had ACS during the hospital stay and 1.6% had an endpoint after discharge but within 60 days. The sensitivity of HsTnT for ACS at admission, 3-4 and 6-7 h was only 68, 79 and 81%, respectively. Sensitivity and negative predictive value for acute myocardial infarction alone were 80 and 93% on admission and 97 and 99% at 3-4 h. Among patients aged 75 years and older, 63% had a positive HsTnT on admission, but only 39% of these had an ACS during hospital stay. CONCLUSION: Our data confirm that prolonged testing with HsTnT after 3-4 h does not improve diagnostic performance for ACS. However, although sensitivity for acute myocardial infarction was very good, sensitivity for ACS was insufficient to rule out ACS even at 6-7 h. Less than half of all recorded positive HsTnT were true positives. On the basis of these results, we find it unlikely that HsTnT has improved the diagnosis of ACS in the emergency care setting.

P2 receptor expression profiles in human vascular smooth muscle and endothelial cells.

P2 receptors mediate the actions of the extracellular nucleotides ATP, ADP, UTP, and UDP, regulating several physiologic responses including cardiac function, vascular tone, smooth muscle cell (SMC) proliferation, platelet aggregation, and the release of endothelial factors. P2 receptor characterization has been hampered by the lack of selective antagonists. The aim of the current study was to investigate the mRNA and protein expression of P2X and P2Y receptors in human SMC and in endothelial cells (EC). Smooth muscle cells were obtained from human mammary artery and EC from human umbilical vein. Using real-time PCR, the authors established quantitative mRNA assays. Protein expression was studied using Western blotting with recently developed antibodies. The P2X1 receptor was highly specific for human SMC, while the P2X4 was the highest expressed receptor in EC. The P2Y2 receptor was present in both SMC and EC. UTP-mediated effects in these cells are likely to be mediated by P2Y2 and not P2Y4 receptors since the latter had considerably lower expression. The P2Y6 receptor was expressed in both SMC and EC. The P2Y1 and surprisingly the P2Y11 receptors were the most abundantly expressed P2Y receptors in the endothelium. Overall, Western blotting confirmed the mRNA findings in most aspects, and most interestingly, indicated oligomerization of the P2Y1 receptor that may be important for its function. In conclusion, P2X1, P2Y2, and P2Y6 are the most expressed P2 receptors in SMC and are thus probably mediating the contractile and mitogenic actions of extracellular nucleotides. The P2X4, P2Y11, P2Y1, and P2Y2 are the most expressed P2 receptors in EC, and are most likely mediating release of nitric oxide, endothelium-dependent hyperpolarizing factor (EDHF), and t-PA induced by extracellular nucleotides. These findings will help to direct future cardiovascular drug development against the large P2 receptor family.