Independent Causal Effect of Remnant Cholesterol on Atherosclerotic Cardiovascular Outcomes: A Mendelian Randomization Study.

BACKGROUND: Observational studies suggested that residual risk of cardiovascular events after LDL (low-density lipoprotein) cholesterol lowering may be linked to remnant cholesterol (RC). We conducted a large-scale Mendelian randomization study to investigate the causal role of RC to predict coronary artery disease (CAD), myocardial infarction (MI), and stroke risk. METHODS: We extracted single-nucleotide polymorphisms for RC and LDL from large-scale genome-wide association databases. We estimated the genetic association with outcomes from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics), the Metastroke consortium, as well as the GLGC (Global Lipids Genetics Consortium). Genetic variants were used as instruments, thereby minimizing residual confounding and reverse causation biases of observational studies. RESULTS: By leveraging data from a combined sample of 958 434 participants, we found evidence for a significant causal effect of RC on the risk of CAD (odds ratio [OR], 1.51 per SD unit increase in RC [95% CI, 1.42-1.60]; P=5.3×10-5), MI (OR, 1.57 [95% CI, 1.21-2.05]; P=9.5×10-4), and stroke (OR, 1.23 [95% CI, 1.12-1.35]; P=3.72×10-6). There was no evidence of pleiotropy. The effect of RC on CAD and MI remained consistent after accounting for the effects of RC-associated genetic variants on LDL cholesterol: OR, 1.49 (95% CI, 1.37-1.61) for CAD and OR, 1.80 (95% CI, 1.70-19.1) for MI without a meaningful indirect effect exerted on these outcomes via the LDL cholesterol mediator. CONCLUSIONS: This large-scale Mendelian randomization study showed a robust genetic causal association between RC and cardiovascular outcomes. The effect on CAD and MI is independent of LDL cholesterol. Early screening for RC along with long-term inhibition of RC should be the focus of future therapeutic interventions.

Randomized, Placebo-Controlled Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Lecithin Cholesterol Acyltransferase in Acute ST-Segment-Elevation Myocardial Infarction: Results of REAL-TIMI 63B.

BACKGROUND: High-density lipoprotein plays a key role in reverse cholesterol transport. In addition, high-density lipoprotein particles may be cardioprotective and reduce infarct size in the setting of myocardial injury. Lecithin-cholesterol acyltransferase is a rate-limiting enzyme in reverse cholesterol transport. MEDI6012 is a recombinant human lecithin-cholesterol acyltransferase that increases high-density lipoprotein cholesterol. Administration of lecithin-cholesterol acyltransferase has the potential to reduce infarct size and regress coronary plaque in acute ST-segment-elevation myocardial infarction. METHODS: REAL-TIMI 63B (A Randomized, Placebo­controlled Phase 2b Study to Evaluate the Safety and Efficacy of MEDI6012 in Acute ST Elevation Myocardial Infarction) was a phase 2B multinational, placebo-controlled, randomized trial. Patients with ST-segment-elevation myocardial infarction within 6 hours of symptom onset and planned for percutaneous intervention were randomly assigned 2:1 to MEDI6012 (2- or 6-dose regimen) or placebo and followed for 12 weeks. The primary outcome was infarct size as a percentage of left ventricular mass by cardiac MRI at 10 to 12 weeks, with the primary analysis in patients with TIMI Flow Grade 0 to 1 before percutaneous intervention who received at least 2 doses of MEDI6012. The secondary outcome was change in noncalcified plaque volume on coronary computed tomographic angiography from baseline to 10 to 12 weeks with the primary analysis in patients who received all 6 doses of MEDI6012. RESULTS: A total of 593 patients were randomly assigned. Patients were a median of 62 years old, 77.9% male, and 95.8% statin naive. Median time from symptom onset to randomization was 146 (interquartile range [IQR], 103-221) minutes and from hospitalization to randomization was 12.7 (IQR, 6.6-24.0) minutes, and the first dose of drug was administered a median of 8 (IQR, 3-13) minutes before percutaneous intervention. The index myocardial infarction was anterior in 69.6% and TIMI Flow Grade 0 to 1 in 65.1% of patients. At 12 weeks, infarct size did not differ between treatment groups (MEDI6012: 9.71%, IQR 4.79-16.38; placebo: 10.48%, [IQR, 4.92-16.61], 1-sided P=0.79. There was also no difference in noncalcified plaque volume (geometric mean ratio, 0.96 [95% CI, NA-1.10], 1-sided P=0.30). There was no significant difference in treatment emergent serious adverse events. CONCLUSIONS: Administration of MEDI6012 in patients with acute ST-segment-elevation myocardial infarction did not result in a significant reduction in infarct size or noncalcified plaque volume at 12 weeks. MEDI6012 was well tolerated with no excess in overall serious adverse events. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03578809.

Cardiac mortality in patients randomised to elective coronary revascularisation plus medical therapy or medical therapy alone: a systematic review and meta-analysis.

AIMS: The value of elective coronary revascularisation plus medical therapy over medical therapy alone in managing stable patients with coronary artery disease is debated. We reviewed all trials comparing the two strategies in this population. METHODS AND RESULTS: From inception through November 2020, MEDLINE, EMBASE, Google Scholar, and other databases were searched for randomised trials comparing revascularisation against medical therapy alone in clinically stable coronary artery disease patients. Treatment effects were measured by rate ratios (RRs) with 95% confidence intervals, using random-effects models. Cardiac mortality was the pre-specified primary endpoint. Spontaneous myocardial infarction (MI) and its association with cardiac mortality were secondary endpoints. Further endpoints included all-cause mortality, any MI, and stroke. Longest follow-up data were abstracted. The study is registered with PROSPERO (CRD42021225598). Twenty-five trials involving 19 806 patients (10 023 randomised to revascularisation plus medical therapy and 9783 to medical therapy alone) were included. Compared with medical therapy alone, revascularisation yielded a lower risk of cardiac death [RR 0.79 (0.67-0.93), P < 0.01] and spontaneous MI [RR 0.74 (0.64-0.86), P < 0.01]. By meta-regression, the cardiac death risk reduction after revascularisation, compared with medical therapy alone, was linearly associated with follow-up duration [RR per 4-year follow-up: 0.81 (0.69-0.96), P = 0.008], spontaneous MI absolute difference (P = 0.01) and percentage of multivessel disease at baseline (P = 0.004). Trial sequential and sensitivity analyses confirmed the reliability of the cardiac mortality findings. All-cause mortality [0.94 (0.87-1.01), P = 0.11], any MI (P = 0.14), and stroke risk (P = 0.30) did not differ significantly between strategies. CONCLUSION: In stable coronary artery disease patients, randomisation to elective coronary revascularisation plus medical therapy led to reduced cardiac mortality compared with medical therapy alone. The cardiac survival benefit after revascularisation improved with longer follow-up times and was associated with fewer spontaneous MIs.

Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome: Network Meta-Analysis of 52 816 Patients From 12 Randomized Trials.

BACKGROUND: New randomized, controlled trials have become available on oral P2Y12 inhibitors in acute coronary syndrome. We aimed to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor, and clopidogrel in acute coronary syndrome by a meta-analysis of randomized controlled trials. METHODS: We performed a network meta-analysis and direct pairwise comparison analysis of efficacy and safety outcomes from 12 randomized controlled trials including a total of 52 816 patients with acute coronary syndrome. RESULTS: In comparison with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio [HR], 0.82 [95% CI, 0.72-0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75-0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80-1.01] and HR, 0.92 [95% CI, 0.84-1.02], respectively). In comparison with each other, there were no significant differences in mortality (HR prasugrel versus ticagrelor, 1.10 [95% CI, 0.94-1.29] and 1.12 [95% CI, 0.98-1.28]). In comparison with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67-0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78-1.22]). Differences between prasugrel and ticagrelor were not statistically significant. Stent thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel (28%-50% range of reduction). In comparison with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01-1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04-1.55]) significantly increased major bleeding. There were no significant differences between prasugrel and ticagrelor for all outcomes explored. CONCLUSIONS: Prasugrel and ticagrelor reduced ischemic events and increased bleeding in comparison with clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019155648.

Endogenous fibrinolysis-Relevance to clinical thrombosis risk assessment.

The development of an obstructive luminal thrombus is pathological and considered a failure of endogenous fibrinolysis. The consequences may be fatal, or result in lasting downstream organ damage. Therefore, assessment of endogenous fibrinolytic status in an individual may identify those at risk of occlusive thrombus formation and provide prognostic information. Arterial thrombi are more platelet rich and more resistant to fibrinolysis than venous thrombi. Several recent studies using global tests of fibrinolysis in patients with acute coronary syndromes (ACS) have shown that despite dual antiplatelet therapy, patients with impaired fibrinolytic status have an increased risk of adverse cardiovascular events, compared with those with effective fibrinolytic function. Such data add significantly to the predictive value of established cardiovascular risk factors and conventional biomarkers. Most data reported have been obtained with the Global Thrombosis Test and the turbidimetric plasma clot lysis assay. A few small studies in patients with ischaemic stroke suggest a similar predictive role of fibrinolytic status assessment in these patients. Studies reporting an association between impaired fibrinolysis and future venous thrombotic events are limited, and in the form of case-control studies. Viscoelastic assays may have a role in the prediction of venous thromboembolic risk. Assays of fibrinolytic function should be used to obtain a more accurate risk of future thrombotic events, particularly in the setting of ACS. The availability of point-of-care tests helps facilitate this and should encourage future studies to assess personalised antithrombotic treatment combinations to optimise fibrinolytic status and reduce thrombosis risk.

Efficacy and safety of intracoronary epinephrine versus conventional treatments alone in STEMI patients with refractory coronary no-reflow during primary PCI: The RESTORE observational study.

OBJECTIVES: We aimed to compare intracoronary (IC) epinephrine versus conventional treatments alone in patients with ST-elevation myocardial infarction and refractory coronary no-reflow during primary percutaneous coronary intervention (PPCI). METHODS: Thirty consecutive patients with severe refractory coronary no-reflow (TIMI 0-1, MBG 0-1) during PPCI were prospectively included after initial failure of conventional treatments. Conventional treatments used in both groups included IC nitrates, thrombectomy. Glycoprotein IIb/IIIa inhibitors and adenosine. Patients received IC epinephrine or no epinephrine. RESULTS: Intracoronary administration of epinephrine yielded significantly better coronary flow patterns (28.6% TIMI 3, 64.3% TIMI 2, 7.1% TIMI 1, and 0% TIMI 0), compared to those after treatment with conventional agents alone (18.8% TIMI 3, 12.5% TIMI 2, 37.5% TIMI 1, and 31.3% TIMI 0) (p value between groups = .004). In the IC epinephrine vs. no epinephrine group there was a significant reduction of 30-day composite of death or heart failure (35.7% vs. 81.25%), improvement of ejection fraction (p = .01) and ST-segment resolution (p = .01). CONCLUSIONS: The findings of this proof-of-concept study suggest that as compared to use of conventional agents alone, IC epinephrine provides substantial improvement of coronary flow in STEMI patients with refractory no-reflow during PPCI that may result into improved prognosis.

Glasgow Coma Scale score of more than four on admission predicts in-hospital survival in patients after out-of-hospital cardiac arrest.

AIM: The aim of the study was to assess the usefulness of the Glasgow Coma Scale (GCS) score assessed by EMS team in predicting survival to hospital discharge in patients after out-of-hospital cardiac arrest (OHCA). METHODS: Silesian Registry of OHCA (SIL-OHCA) is a prospective, population-based regional registry of OHCAs. All cases of OHCAs between the 1st of January 2018 and the 31st of December 2018 were included. Data were collected by EMS using a paper-based, Utstein-style form. OHCA patients aged ≥18 years, with CPR attempted or continued by EMS, who survived to hospital admission, were included in the current analysis. Patients who did not achieve return of spontaneous circulation (ROSC) in the field, with missing data on GCS after ROSC or survival status at discharge were excluded from the study. RESULTS: Two hundred eighteen patients with OHCA, who achieved ROSC, were included in the present analysis. ROC analysis revealed GCS = 4 as a cut-off value in predicting survival to discharge (AUC 0.735; 95%CI 0.655-0.816; p < 0.001). Variables significantly associated with in-hospital survival were young age, short response time, witnessed event, previous myocardial infarction, chest pain before OHCA, initial shockable rhythm, coronary angiography, and GCS > 4. On the other hand, epinephrine administration, intubation, the need for dispatching two ambulances, and/or a physician-staffed ambulance were associated with a worse prognosis. Multivariable logistic regression analysis revealed GCS > 4 as an independent predictor of in-hospital survival after OHCA (OR of 6.4; 95% CI 2.0-20.3; p < 0.0001). Other independent predictors of survival were the lack of epinephrine administration, previous myocardial infarction, coronary angiography, and the patient's age. CONCLUSION: The survival to hospital discharge after OHCA could be predicted by the GCS score on hospital admission.

C-Reactive Protein as a Risk Marker for Post-Infarct Heart Failure over a Multi-Year Period.

Inflammatory activation during acute ST-elevation myocardial infarction (STEMI) can contribute to post-infarct heart failure (HF). This study aimed to determine prognostic value of high-sensitivity C-reactive protein concentration (CRP) for HF over a long-term follow-up in 204 patients with a first STEMI undergoing guideline-based therapies including percutaneous coronary intervention. CRP was measured at admission, 24 h (CRP24), discharge (CRPDC), and one month (CRP1M) after index hospitalization for STEMI. Within a median period of 5.6 years post-index hospitalization for STEMI, hospitalization for HF (HFH) which is a primary endpoint, occurred in 24 patients (11.8%, HF+ group). During the study, 8.3% of HF+ patients died vs. 1.7% of patients without HFH (HF- group) (p = 0.047). CRP24, CRPDC, and CRP1M were significantly higher in HF+ compared to HF- group. The median CRP1M in HF+ group was 2.57 mg/L indicating low-grade systemic inflammation, in contrast to 1.54 mg/L in HF- group. CRP1M ≥ 2 mg/L occurred in 58.3% of HF+ vs. 42.8% of HF- group (p = 0.01). Kaplan-Meier analysis showed decreased probability of survival free from HFH in patients with CRP24 (p < 0.001), CRPDC (p < 0.001), and CRP1M (p = 0.03) in quartile IV compared to lower quartiles. In multivariable analysis, CRPDC significantly improved prediction of HFH over a multi-year period post-STEMI. Persistent elevation in CRP post STEMI aids in risk stratification for long-term HF and suggests that ongoing cardiac and low-grade systemic inflammation promote HF development despite guideline-based therapies.

Diurnal variations in tissue factor and tissue factor pathway inhibitor concentrations in relation to on-treatment platelet reactivity: an analysis of patients with acute myocardial infarction.

The aim of the study was to evaluate diurnal changes of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) concentrations in relation to on-treatment platelet reactivity. The study group included 51 patients with acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention and dual antiplatelet therapy. TF and TFPI concentrations were assessed using enzyme-linked immunosorbent assay kits. We found a significant increase of TF concentration in clopidogrel-resistant, but not clopidogrel-sensitive, patients at 10.00 a.m. (410.66 pg/mL) in comparison with 6.00 a.m. (250.99 pg/mL), 14.00 p.m. (255.12 pg/mL) and 19.00 p.m. (267.58 pg/mL). Moreover, TF concentration at 10.00 a.m. was 30% higher in clopidogrel-resistant than clopidogrel-sensitive patients (p = .043). We failed to demonstrate diurnal variation in TFPI concentration in clopidogrel-resistant patients. However, TFPI concentration in clopidogrel-sensitive patients was significantly higher at 10.00 a.m. as compared with other sampling points (p < .05). We observed a marked elevation in TF concentration at 10.00 a.m. only in aspirin-resistant patients and a significant increase in TFPI concentration at 10 a.m. only in aspirin-sensitive patients. Our findings suggest the presence of diurnal variations in TF and TFPI concentrations in AMI patients, with the highest thrombotic risk in patients with high on-treatment platelet reactivity in the midmorning.

Enhanced Inflammation is a Marker for Risk of Post-Infarct Ventricular Dysfunction and Heart Failure.

Acute ST-segment elevation myocardial infarction (STEMI) activates inflammation that can contribute to left ventricular systolic dysfunction (LVSD) and heart failure (HF). The objective of this study was to examine whether high-sensitivity C-reactive protein (CRP) concentration is predictive of long-term post-infarct LVSD and HF. In 204 patients with a first STEMI, CRP was measured at hospital admission, 24 h (CRP24), discharge (CRPDC), and 1 month after discharge (CRP1M). LVSD at 6 months after discharge (LVSD6M) and hospitalization for HF in long-term multi-year follow-up were prospectively evaluated. LVSD6M occurred in 17.6% of patients. HF hospitalization within a median follow-up of 5.6 years occurred in 45.7% of patients with LVSD6M vs. 4.9% without LVSD6M (p < 0.0001). Compared to patients without LVSD6M, the patients with LVSD6M had higher CRP24 and CRPDC and persistent CRP1M ≥ 2 mg/L. CRP levels were also higher in patients in whom LVSD persisted at 6 months (51% of all patients who had LVSD at discharge upon index STEMI) vs. patients in whom LVSD resolved. In multivariable analysis, CRP24 ≥ 19.67 mg/L improved the prediction of LVSD6M with an increased odds ratio of 1.47 (p < 0.01). Patients with LVSD6M who developed HF had the highest CRP during index STEMI. Elevated CRP concentration during STEMI can serve as a synergistic marker for risk of long-term LVSD and HF.

Safety and efficacy of self-apposing Stentys drug-eluting stent in left main coronary artery PCI: Multicentre LM-STENTYS registry.

BACKGROUND: There is a paucity of data on left main (LM) percutaneous coronary intervention (PCI) therapy with dedicated DES platforms. The LM-STENTYS is a multicenter registry aimed at evaluating clinical outcome after PCI of LM performed with a self-apposing Stentys DES implantation. METHODS: The registry consists of 175 consecutive patients treated with Stentys DES implanted to LM. The primary endpoint was the composite of major adverse cardiac and cerebral events (MACCE) defined as cardiac death, myocardial infarction (MI), target lesion revascularization (TLR), and stroke assessed after 1 year. The secondary endpoint was stent thrombosis (ST) at 1 year. RESULTS: The median age was 69 years (IQR, 62-78 years). Acute coronary syndrome (ACS) was the presenting diagnosis in 117 (66.9%) patients [74 (63.2%) unstable angina, 31 (26.5%) NSTEMI, 12 (10.3%) STEMI] and stable angina (SA) was present in 58 (33.1%) patients. The median SYNTAX score was 23.0 (IQR, 18.7-32.2) in the SA group and 25.0 (IQR, 20.0-30.7) in the ACS group. During 1-year follow-up in the SA group two (3.4%) MACCE occurred, both of them were cardiac deaths. In ACS patients there were 19 (16.2%) MACCE [9 (7.7%) cardiac deaths, 11 (9.4%) MIs, 11(9.4%) TLR, 1(0.9%) stroke]. Altogether, three (1.7%) cases of acute ST were noted, all of them in ACS subset. CONCLUSION: LM PCI using self-apposing Stentys DES showed favorable clinical outcomes at 1-year in patients with SA. Events of ST in the ACS group warrant further research.

A study of biological and lifestyle factors, including within-subject variation, affecting concentrations of growth differentiation factor 15 in serum.

Background Growth differentiation factor 15 (GDF-15) is an emerging cardiovascular biomarker, and a fully automated immunoassay has recently become available. The objectives of the study were to identify biological and lifestyle factors affecting serum GDF-15 concentrations and derive robust reference intervals, and to estimate GDF-15 within-subject biological variation and derived indices. Methods A presumably healthy population of 533 questionnaire-screened adults was used to identify the biological and lifestyle determinants of serum GDF-15. Following stringent exclusion criteria, a final group of 173 individuals was selected to establish GDF-15 reference interval. Twenty-six healthy volunteers were enrolled in the biological variation substudy. Results Using a multiple regression model, age, B-type natriuretic peptide and C-reactive protein as well as smoking status were significantly related to serum GDF-15 concentrations. The upper reference limit (URL) for serum GDF-15 concentrations (90% confidence interval [CI]) was 866 ng/L (733-999 ng/L), with no sex-related difference. Although GDF-15 tended to increase with age, the weak dependence of marker from age does not justify age-related URL. The within-subject CV was 6.3% (95% CI, 4.5%-8.5%), with no sex difference in intraindividual variances. The reference change value (RCV) for GDF-15 was 23%, and two are the specimens required to ensure that the mean GDF-15 result is within ±10% of the individual's homeostatic set point. Conclusions By identifying the main factors influencing serum GDF-15 concentrations, we robustly established the URL to be applied in adult population. As intraindividual variation of GDF-15 is relatively low, monitoring longitudinal changes in its concentrations over time using RCV can be a good alternative for interpreting GDF-15 in clinical setting.

Morphine Interaction with Aspirin: a Double-Blind, Crossover Trial in Healthy Volunteers.

Aspirin is a cornerstone in the antiplatelet therapy for acute coronary syndromes. Coadministration of morphine may potentially influence the intestinal absorption, pharmacokinetics, and pharmacodynamics, as seen with P2Y12 inhibitors. In this trial, healthy volunteers were randomized to receive morphine (5 mg, i.v. bolus injection) at one of seven different time points before, after, or with aspirin (162 mg, p.o.) in a double-blind, placebo-controlled fashion. After a 14-day washout, subjects received placebo instead of morphine. Pharmacokinetics were determined by liquid chromatography, and aspirin's effects were measured by platelet function tests (whole-blood platelet aggregation: multiplate, platelet plug formation: PFA-100). Morphine increased the total acetylsalicylic acid exposure by 20% compared with placebo when given simultaneously with aspirin, whereas Cmax and tmax were not altered. Morphine had no significant effect on aspirin-induced platelet inhibition. In contrast to coadministration with P2Y12 inhibitors, morphine appears to have negligible interaction with aspirin.

Plasma midregional proadrenomedullin (MR-proADM) concentrations and their biological determinants in a reference population.

BACKGROUND: Midregional proadrenomedullin (MR-proADM) is emerging as a prognostic biomarker for detecting the failure of multiple organs. Establishment of scientifically robust reference intervals facilitates interpretation of laboratory test results. The objectives of this study were (i) to establish reliable reference intervals for plasma MR-proADM using a commercially available automated fluoroimmunoassay in apparently healthy individuals, and (ii) to identify biological determinants of MR-proADM concentrations. METHODS: A total of 506 questionnaire-identified apparently healthy adults were enrolled in a single-center, cross-sectional study. A final reference group (n=172) was selected after exclusion of obese individuals, those with increased values of laboratory biomarkers indicating asymptomatic myocardial injury or dysfunction, ongoing inflammation, diabetes, dyslipidemia and renal dysfunction and outliers. RESULTS: The 2.5th and 97.5th percentile intervals for MR-proADM values in the reference group (90% confidence interval) were 0.21 (0.19-0.23) and 0.57 (0.55-0.59) nmol/L, respectively. Although older age, higher values of HbA1c, C-reactive protein, B-type natriuretic peptide and body mass index, together with a history of smoking and a decreased estimated glomerular filtration rate were significantly associated with increasing concentrations of MR-proADM in both univariate and multivariate analyses, magnitudes of these relationships were modest and did not substantially influence MR-proADM reference intervals. Sex-dependent difference in MR-proADM reference intervals was not detected [0.19 (0.16-0.22)-0.56 (0.54-0.60) nmol/L in females vs. 0.22 (0.20-0.25)-0.58 (0.57-0.63) nmol/L in males]. CONCLUSIONS: Our study successfully established robust reference intervals for MR-proADM concentrations in plasma. Considering the negligible influence of potential biological determinants on plasma MR-proADM, we recommend the adoption of single reference intervals for adult population as a whole.

Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy: A Systematic Review and Meta-analysis.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) have a role in preventing cardiac arrest in patients at risk for life-threatening ventricular arrhythmias. PURPOSE: To compare ICD therapy with conventional care for the primary prevention of death of various causes in adults with ischemic or nonischemic cardiomyopathy. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, and EMBASE databases, as well as several Web sites, from 1 April 1976 through 31 March 2017. STUDY SELECTION: Randomized controlled trials, published in any language, comparing ICD therapy with conventional care and reporting mortality outcomes (all-cause, sudden, any cardiac, or noncardiac) in the primary prevention setting. DATA EXTRACTION: 2 independent investigators extracted study data and assessed risk of bias. DATA SYNTHESIS: Included were 11 trials involving 8716 patients: 4 (1781 patients) addressed nonischemic cardiomyopathy, 6 (4414 patients) ischemic cardiomyopathy, and 1 (2521 patients) both types of cardiomyopathy. Mean follow-up was 3.2 years. An overall reduction in all-cause mortality, from 28.26% with conventional care to 21.37% with ICD therapy (hazard ratio [HR], 0.81 [95% CI, 0.70 to 0.94]; P = 0.043), was found. The magnitude of reduction was similar in the cohorts with nonischemic (HR, 0.81 [CI, 0.72 to 0.91]) and ischemic (HR, 0.82 [CI, 0.63 to 1.06]) disease, although the latter estimate did not reach statistical significance. The rate of sudden death fell from 12.15% with conventional care to 4.39% with ICD therapy (HR, 0.41 [CI, 0.30 to 0.56]), with a similar magnitude of reduction in patients with ischemic (HR, 0.39 [CI, 0.23 to 0.68]) and those with nonischemic disease (HR, 0.44 [CI, 0.17 to 1.12]). Noncardiac and any cardiac deaths did not differ significantly by treatment. LIMITATION: Heterogeneous timing of ICD placement; heterogeneous pharmacologic and resynchronization co-interventions; trials conducted in different eras; adverse events and complications not reviewed. CONCLUSION: Overall, primary prevention with ICD therapy versus conventional care reduced the incidence of sudden and all-cause death. PRIMARY FUNDING SOURCE: None.

Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta-analysis.

Importance: Effects on specific fatal and nonfatal end points appear to vary for low-density lipoprotein cholesterol (LDL-C)-lowering drug trials. Objective: To evaluate whether baseline LDL-C level is associated with total and cardiovascular mortality risk reductions. Data Sourcesand Study Selection: Electronic databases (Cochrane, MEDLINE, EMBASE, TCTMD, ClinicalTrials.gov, major congress proceedings) were searched through February 2, 2018, to identify randomized clinical trials of statins, ezetimibe, and PCSK9-inhibiting monoclonal antibodies. Data Extraction and Synthesis: Two investigators abstracted data and appraised risks of bias. Intervention groups were categorized as "more intensive" (more potent pharmacologic intervention) or "less intensive" (less potent, placebo, or control group). Main Outcomes and Measures: The coprimary end points were total mortality and cardiovascular mortality. Random-effects meta-regression and meta-analyses evaluated associations between baseline LDL-C level and reductions in mortality end points and secondary end points including major adverse cardiac events (MACE). Results: In 34 trials, 136 299 patients received more intensive and 133 989 received less intensive LDL-C lowering. All-cause mortality was lower for more vs less intensive therapy (7.08% vs 7.70%; rate ratio [RR], 0.92 [95% CI, 0.88 to 0.96]), but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with greater reductions in all-cause mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.91 [95% CI, 0.86 to 0.96]; P = .001; absolute risk difference [ARD], -1.05 incident cases per 1000 person-years [95% CI, -1.59 to -0.51]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Cardiovascular mortality was lower for more vs less intensive therapy (3.48% vs 4.07%; RR, 0.84 [95% CI, 0.79 to 0.89]) but varied by baseline LDL-C level. Meta-regression showed more intensive LDL-C lowering was associated with a greater reduction in cardiovascular mortality with higher baseline LDL-C levels (change in RRs per 40-mg/dL increase in baseline LDL-C, 0.86 [95% CI, 0.80 to 0.94]; P < .001; ARD, -1.0 incident cases per 1000 person-years [95% CI, -1.51 to -0.45]), but only when baseline LDL-C levels were 100 mg/dL or greater (P < .001 for interaction) in a meta-analysis. Trials with baseline LDL-C levels of 160 mg/dL or greater had the greatest reduction in all-cause mortality (RR, 0.72 [95% CI, 0.62 to 0.84]; P < .001; 4.3 fewer deaths per 1000 person-years) in a meta-analysis. More intensive LDL-C lowering was also associated with progressively greater risk reductions with higher baseline LDL-C level for myocardial infarction, revascularization, and MACE. Conclusions and Relevance: In these meta-analyses and meta-regressions, more intensive compared with less intensive LDL-C lowering was associated with a greater reduction in risk of total and cardiovascular mortality in trials of patients with higher baseline LDL-C levels. This association was not present when baseline LDL-C level was less than 100 mg/dL, suggesting that the greatest benefit from LDL-C-lowering therapy may occur for patients with higher baseline LDL-C levels.

High-sensitivity cardiac troponin assays: From improved analytical performance to enhanced risk stratification.

Implementation of cardiac troponin (cTn) assays has revolutionized the diagnosis, risk stratification, triage and management of patients with suspected myocardial infarction (MI). The Universal Definition of MI brought about a shift in the diagnostics of MI, from an approach primarily based on electrocardiography (ECG) to one primarily based on biomarkers. Currently, detection of a rise and/or fall in concentration or activity of myocardial necrosis biomarkers, preferentially cTns, with at least one value above the 99th percentile upper reference limit (URL), is the essential component for the diagnosis of MI. High-sensitivity cardiac troponin (hs-cTn) assays with their superior analytical performance were designed to further facilitate clinical decision making. The ability of hs-cTn assays to detect measurable cTn concentrations in at least 50% of healthy individuals, along with their improved precision (expressed as coefficient of variation ≤10% at the 99th percentile URL) associated with increased recognition of changing values, leads to enhanced risk stratification of patients with suspected MI, and also enables them to be used as prognostic tools potentially useful in other patient subsets. In this comprehensive review, we aim to integrate updated laboratory and clinical knowledge regarding hs-cTn assays in order to promote their optimal use in daily practice. We primarily focus on the role of hs-cTn assays in patients with suspected MI, discussing recommended diagnostic algorithms and result interpretation. Emphasis is also placed on the release of cTns following myocardial injury, the characteristics of antibodies used in available cTn immunoassays, and analytical performance of hs-cTn assays. In this paper, we also review potential challenges related to the selection of a healthy reference population in determining 99th percentile values, biological variation of hs-cTns, inequality between hs-cTn assays, and outline the current status of cTnI standardization. Finally, we discuss in detail the diagnostic and prognostic value of hs-cTn assays, including non-coronary causes of cTn elevation, the potential benefits and risks of point-of-care testing, and the unjustified skepticism of some clinicians regarding implementation of hs-cTn assays. In everyday clinical practice, hs-cTn assays are an important diagnostic advance, predominantly for patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), with suspected non-ST-segment elevation myocardial infarction (NSTEMI). In the NSTE-ACS setting, recently introduced short diagnostic algorithms using hs-cTn assays integrated with careful clinical and ECG assessment were found to substantially reduce the time to final diagnosis, shorten visits to the emergency department and allow earlier safe discharge of low risk subjects. Hs-cTn assays have significantly higher sensitivity and negative predictive value for NSTEMI in comparison to contemporary cTn tests, particularly in early NSTE-ACS presenters. However, due to frequently occurring mild hs-cTn elevations, they are also associated with lower specificity and reduced positive predictive value when compared to previous generations of assays. Our review underscores the need for the education of clinicians and medical laboratory professionals regarding appropriate use and interpretation of hs-cTn assays. Adequate training and clinical experience in using these tests are essential to translate the improved analytical performance of hs-cTn assays into enhanced risk stratification and hopefully better patient outcomes.

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial.

AIMS: The currently available data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction. METHODS AND RESULTS: In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0-12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0-12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0-12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine. CONCLUSIONS: Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878.

Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a randomized trial in healthy volunteers.

BACKGROUND: Our recent drug interaction trial with clopidogrel shows that morphine decreases the concentrations and pharmacodynamic effects of clopidogrel, which could lead to treatment failure in susceptible individuals. We hypothesized that the pharmacodynamic consequences of drug-drug interactions would be less between morphine and ticagrelor. MATERIALS AND METHODS: Twenty-four healthy subjects received a loading dose of 180 mg ticagrelor together with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, crossover trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and ticagrelor pharmacodynamic effects were measured by platelet function tests (whole blood platelet aggregation: multiplate, platelet plug formation: PFA-100, vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay). RESULTS: Concomitant i.v. injection of morphine slows drug resorption of ticagrelor and its active metabolite (P < 0·05) by 1 h and decreases plasma levels of ticagrelor and its active metabolite by 25-31% (P ≤ 0·03) and the drug exposure (area under the curve) by 22-23% (P ≤ 0·01). Importantly, however, the pharmacodynamic effects of ticagrelor on platelet aggregation in whole blood, platelet plug formation and VASP phosphorylation are not affected by morphine. CONCLUSIONS: Morphine co-administration moderately decreases ticagrelor plasma concentrations but does not inhibit its pharmacodynamic effects in healthy volunteers within 6 h after drug administration. Limitations of our trial include the investigation in healthy volunteers under standardized conditions, which does not necessarily reflect a realistic emergency scenario.