Long-Term Ticagrelor in Patients With Prior Coronary Stenting in the PEGASUS-TIMI 54 Trial.

Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long-term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS-TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug-eluting stent and first- versus later-generation drug-eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelorpooled reduced major adverse cardiovascular events (7.0% versus 8.0%; hazard ratio [HR], 0.85; 95% CI, 0.75-96) regardless of stent type (bare metal stent versus drug-eluting stent: pinteraction=0.767; first versus later generation: pinteraction=0.940). The rate of any stent thrombosis was numerically lower with ticagrelorpooled (0.7% versus 0.9%; HR, 0.73; 95% CI, 0.50-1.05) and Thrombolysis in Myocardial Infarction major bleeding was increased (HR, 2.65; 95% CI, 1.90-3.68). Conclusions Long-term ticagrelor reduces major adverse cardiovascular events in patients with prior myocardial infarction and coronary stenting regardless of stent type, with the benefit driven predominantly by reduction in de novo events. Nonfatal major bleeding is increased with ticagrelor. Registration Information clinicaltrials.gov. Identifier: NCT01225562.

Prediction of cardiogenic shock using plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone [corrected] concentrations in ST elevation myocardial infarction: an analysis from the ASSENT-4 Percutaneous Coronary Intervention Trial.

OBJECTIVE: Cardiogenic shock is a major cause of death in ST elevation myocardial infarction. We investigated whether determination of plasma [corrected] B-type natriuretic peptide and the N-terminal fragment of its pro-hormone in the acute phase of ST elevation myocardial infarction could identify patients prone to development of cardiogenic shock. DESIGN: Retrospective analysis of a multicenter, randomized open-label trial (ASSENT-4 PCI; ClinicalTrials.gov Identifier: NCT00168792). METHODS: Plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone were determined in available stored samples of 1016 ST elevation myocardial infarction patients without signs of cardiogenic shock at randomization to primary percutaneous coronary intervention or to full-dose tenecteplase before percutaneous coronary intervention. The end point of the present analysis was in-hospital cardiogenic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 57 (5.6%) patients had cardiogenic shock during index hospitalization. In-hospital cardiogenic shock increased precipitously with higher baseline concentrations of plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone (B-type natriuretic peptide and the N-terminal fragment of its pro-hormone < or =67 pg/mL: 1.9%; 68-1482 pg/mL: 5.9%; >1482 pg/mL: 14.9%; p < .001). Higher plasma [corrected] B-type natriuretic peptide and the N-terminal fragment of its pro-hormone concentrations were predictors of in-hospital shock, especially among those patients with relatively low clinical risk (no requirement of inotropic support before angiography, systolic blood pressure >100 mm Hg, heart rate <100 bpm, Global Utilization of Streptikonase and Tissue-Plasminogen Activator for Occluded Coronary Arteries score of <122). In multivariate Cox regression analysis, higher plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone concentrations remained significant predictors of shock, in addition to age, systolic blood pressure, heart rate, and randomization to facilitated percutaneous coronary intervention and Killip classification. Furthermore, plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone significantly predicted in-hospital shock independently of the validated Global Utilization of Streptikonase and Tissue-Plasminogen Activator for Occluded Coronary Arteries score (p = .014). CONCLUSION: Plasma B-type natriuretic peptide and the N-terminal fragment of its pro-hormone concentrations measured early in the acute phase of ST elevation myocardial infarction are useful in predicting the development of in-hospital cardiogenic shock.

Plasma N-terminal fragment of the prohormone B-type natriuretic peptide concentrations in relation to time to treatment and Thrombolysis in Myocardial Infarction (TIMI) flow: a substudy of the Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT IV-PCI) trial.

BACKGROUND: We investigated the prognostic significance of plasma N-terminal fragment of the prohormone B-type natriuretic peptide (Nt-proBNP) concentrations in addition to time to reperfusion and Thrombolysis in Myocardial Infarction (TIMI) flow before and after coronary intervention in patients with ST elevation myocardial infarction (STEMI) from the database of the Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT IV-PCI) trial. METHODS: Plasma Nt-proBNP was available in 1,037 patients with STEMI. Patients were randomized either to primary (p-PCI) or to full-dose tenecteplase before PCI (f-PCI).The study end point was the composite of death, cardiogenic shock, or congestive heart failure at 90 days. RESULTS: According to classification tree analysis, patients with Nt-proBNP levels >694 pg/mL had the highest primary end point rates (33.8% vs 11%, P < .001). In Cox regression analysis, Nt-proBNP >694 pg/mL strongly predicted 90-day survival even among patients with short treatment delay (f-PCI < or =3 hours: hazard ratio [HR] 2.63, P = .002 and p-PCI < or =3 hours: HR 4.87, P < .001, respectively). Patients with TIMI 3 flow after coronary intervention were at significantly higher risk of the primary end point if admission Nt-proBNP exceeded 694 pg/mL (f-PCI: HR 2.88, P < .001 and p-PCI: HR 3.84, P < .001, respectively). In multivariable analysis, Nt-proBNP >694 pg/mL significantly (P = .001) predicted 90-day survival in addition to age (P < .001), TIMI flow after PCI (P < .001), body mass index (P = .026), anterior wall infarction (P = .035), and systolic blood pressure at randomization (P = .036), respectively. CONCLUSION: Elevated plasma concentrations of Nt-proBNP in the early phase of STEMI determine in-hospital and 90-day outcome after infarction irrespective of time to treatment and pre- or postinterventional TIMI flow.

Reperfusion before percutaneous coronary intervention in ST-elevation myocardial infarction patients is associated with lower N-terminal pro-brain natriuretic peptide levels during follow-up, irrespective of pre-treatment with full-dose fibrinolysis.

AIMS: N-terminal pro-brain natriuretic peptide (NT-proBNP) levels predict outcomes in ST-elevation myocardial infarction patients treated with fibrinolysis or primary percutaneous coronary intervention (PCI). However, its role in facilitated PCI has not yet been assessed; it may be a tool to evaluate the lower event rates with primary PCI in ASSENT-4. METHODS AND RESULTS: In ASSENT-4, 1667 patients were randomized to tenecteplase (TNK) followed by PCI or primary PCI alone. Baseline, discharge/Day 7, and 90-day NT-proBNP levels were available for 1008, 971, and 813 patients. Increasing quartiles of baseline NT-proBNP levels were associated with a higher risk of the combined endpoint of death, heart failure, and shock at 90 days and 1-year mortality (P < 0.001). Events were more common with TNK + PCI, regardless of baseline NT-proBNP quartile. When analysing baseline NT-proBNP as a continuous variable, no treatment interaction was observed for the primary endpoint (P = 0.17) or 1-year mortality (P = 0.08). Overall, NT-proBNP levels at Day 7 or 90 were not different between the two treatments. In patients with TIMI 2-3 flow before PCI, NT-proBNP at Day 90 was lower in PCI-only patients (P = 0.01), although no interaction was observed (P = 0.14). In TNK-pre-treated patients without reperfusion (TIMI 0-1) after PCI, NT-proBNP levels at Day 7 or 90 were not significantly higher than in PCI patients. CONCLUSION: Baseline NT-proBNP predicts outcome at 90 days and 1 year in patients undergoing PCI with or without facilitation with TNK. A higher rate of reperfusion in lytic-pre-treated patients did not result in lower NT-proBNP during follow-up. Thus, baseline and subsequent NT-proBNP levels do not explain the lower mortality rate with PCI alone seen in this trial.

Transfusion and mortality in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention.

AIMS: Red blood cell transfusion is associated with increased mortality among patients with acute coronary syndromes, but little is known about the consequences of transfusion in a contemporary setting of ST-segment elevation myocardial infarction. We describe the association between transfusion and 90-day mortality among patients with acute myocardial infarction treated with primary percutaneous coronary intervention. METHODS AND RESULTS: Analyses were performed on 5532 patients with ST-elevation myocardial infarction from the Assessment of Pexelizumab in Acute Myocardial Infarction trial. The primary objective of this analysis was to ascertain the relation between red blood cell transfusion and 90-day mortality in patients with recent myocardial infarction. We initially determined the baseline and in-hospital predictors of transfusion (multivariable logistic regressions) and subsequently assessed the association between transfusion and mortality using a series of Cox proportional hazards regression combined to a landmark analyses. A total of 213 patients (3.9%) received a transfusion. Transfusion remained significantly associated with mortality [hazards ratio = 2.16 (1.20-3.88)], despite adjustment for baseline characteristics, in-hospital co-interventions, and for propensity of receiving a transfusion. Among patients who survived to hospital discharge, however, the hazard of death was not different in patients treated with transfusion. CONCLUSION: Transfusion is associated with 90-day mortality in acute myocardial infarction treated with primary percutaneous coronary intervention. Although transfusion may be causally related to mortality, it is likely that at least part of the association is due to confounding. This association illustrates the complex relationship between transfusion, bleeding, and mortality and underscores the need for further research to understand the relationship between transfusion and clinical outcomes.

ST-segment recovery and outcome after primary percutaneous coronary intervention for ST-elevation myocardial infarction: insights from the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.

BACKGROUND: Primary percutaneous coronary angioplasty is an effective and widely adopted treatment for acute myocardial infarction. A simple method of determining prognosis after primary percutaneous coronary intervention (PCI) would facilitate appropriate care and expedite hospital discharge. Thus, we determined the prognostic importance of various measures of ST-segment-elevation recovery after primary PCI in a large, contemporary cohort of patients with ST-elevation myocardial infarction. METHODS AND RESULTS: We analyzed ECG data describing the magnitude and extent of ST-segment elevation and deviation before and early after (ie, 30 minutes) primary PCI in the study cohort of 4866 subjects with electrocardiographically high-risk ST-elevation myocardial infarction enrolled in the Assessment of PEXelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Associations among 6 methods for calculating ST-segment recovery, biomarker estimates of infarct size (ie, peak creatine kinase, creatine kinase-MB, and troponin I and T), and prespecified clinical outcomes (ie, rates of 90-day death and 90-day death, heart failure, or shock) were examined. All ST-segment-recovery methods provided strong prognostic information regarding clinical outcomes. A simple ST-segment-recovery method of residual ST-segment elevation measurement in the most affected lead on the post-PCI ECG performed as well as complex methods that required comparison of pre- and post-PCI ECGs or calculation of summed ST-segment deviation in multiple leads (ie, worst-lead residual ST elevation: adjusted hazard ratio for 90-day death rate [reference <1 mm]: 1 to <2 mm, 1.23 [95% CI 0.74 to 2.03]; > or =2 mm, 2.22 [95% CI 1.35 to 3.65], corrected c-index=0.832; 90-day death/congestive heart failure/shock [reference <1 mm]: 1 to <2 mm, 1.55 [95% CI 1.06 to 2.26]; > or =2 mm, 2.33 [95% CI 1.59 to 3.41], corrected c-index=0.802). Biomarker estimates of infarct size declined in association with enhanced ST-segment recovery. CONCLUSIONS: An ECG performed early after primary PCI is a simple, widely available, inexpensive, and powerful prognostic tool applicable to patients with ST-elevation myocardial infarction.

Cardiovascular disease on a global scale: defining the path forward for research and practice.

During the 2006 World Congress of Cardiology meeting in Barcelona, the Virtual Coordinating Centre for Global Collaborative Cardiovascular Research (VIGOUR) group held a symposium examining potential approaches to understanding and controlling the explosive worldwide growth of cardiovascular disease and its attendant morbidity and mortality. Over the last 20 years, the global nature of many problems in health care has become much more evident. In the realm of health, this has meant that countries across the globe have started to experience the same kinds of behavioural shifts (overeating, reduced physical activity and smoking), and with them massive increases in cardiovascular risk factors, observed over the last century particularly in North America and Western Europe. This VIGOUR symposium focused on what actions can be taken now to prepare for this future in which prevention and treatment of cardiovascular disease will be a major public health issue in a much larger proportion of the world's countries. The participants focused on four major areas where they saw important opportunities: (i) the development of high quality, contemporaneous data sources that can be used to study and improve the processes, treatments and outcomes of cardiovascular diseases globally; (ii) the feasibility and resource/health economic implications of any proposed potential solutions need to be carefully defined; (iii) models/systems must be identified that can be used to guide effective interventions targeting health problems of large populations at an affordable price; (iv) academic research organizations need to assume a more active role in the health-care system both through their traditional activities in discovery research and developing evidence-based medicine along with translation of research findings into effective interventions that improve the public health.

Age, outcomes, and treatment effects of fibrinolytic and antithrombotic combinations: findings from Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-3 and ASSENT-3 PLUS.

BACKGROUND: Elderly patients with acute myocardial infarction are at particularly high risk for death and bleeding complications. The efficacy and safety of antithrombotic strategies in these patients remain unclear. METHODS: To provide more insight into the risk and benefit of antithrombotic strategies in the elderly, we examined patients from the ASSENT-3 and ASSENT-3 PLUS trials with STEMI who were treated with tenecteplase (TNK) and unfractionated heparin (UFH) or enoxaparin, or half-dose TNK with abciximab and reduced-dose UFH. RESULTS: Older patients had a higher risk profile, and lower use of concomitant therapies and revascularization procedures. We found an interaction between age and treatment effect for the efficacy end point (P = .0007) and the efficacy plus safety end point (P < .0001). Younger patients (<65 years) had a lower risk of the composite efficacy plus safety end point with enoxaparin (relative risk [RR] 0.84, 95% CI 0.74-0.94) or abciximab (RR 0.79, 95% CI 0.69-0.90) compared with UFH. In patients >65 years of age, the benefit of enoxaparin appeared to be offset by an increased risk of bleeding complications. The risk of the efficacy plus safety end point tended to be higher in elderly patients receiving abciximab and half-dose TNK (RR 1.18, 95% CI 0.91-1.51 for 76-85 years of age and RR 1.48, 95% CI 0.88-2.49 for >85 years of age). CONCLUSIONS: Although TNK with either enoxaparin or abciximab appeared to be more effective than with standard UHF in younger patients, these combinations tended to be less effective and even may be unsafe in the elderly. Development of new combination strategies and dosing schemes of fibrinolytics and antithrombotics with improved efficacy and safety in the elderly remains a high priority.

Patients with prolonged ischemic chest pain and presumed-new left bundle branch block have heterogeneous outcomes depending on the presence of ST-segment changes.

OBJECTIVES: The purpose of this research was to examine the prognostic value of ST-segment changes (concordant ST-segment elevation and/or precordial V1 to V3 ST-segment depression) during presumed-new left bundle branch block (LBBB) in patients receiving fibrinolytic therapy. BACKGROUND: These patients are often considered high-risk, but their outcome is not well-defined. METHODS: The Hirulog and Early Reperfusion or Occlusion (HERO)-2 trial compared bivalirudin with heparin in patients receiving streptokinase for ST-segment elevation or presumed-new LBBB. Each patient with LBBB was matched with a control (with normal intraventricular conduction) for age, gender, pulse rate, systolic blood pressure, Killip class, and region. RESULTS: A total of 300 patients had LBBB (92 with and 208 without ST-segment changes) and 15,340 had normal conduction. Acute myocardial infarction (AMI) occurred in 80.7% of LBBB patients and 88.7% of controls (p = 0.006). ST-segment changes were specific (96.6%) but not sensitive (37.8%) for enzymatic diagnosis of AMI. Mortality at 30 days was similar in LBBB patients with ST-segment changes (21.7%) and controls (25.0%, p = 0.563), but lower in LBBB patients without ST-segment changes than in controls (13.5% vs. 21.6%, p = 0.022). In the whole HERO-2 cohort, the LBBB patients with ST-segment changes had higher mortality than patients with normal conduction (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.78 to 2.42). The LBBB patients without ST-segment changes had lower mortality than patients with normal conduction (OR 0.52, 95% CI 0.33 to 0.80). CONCLUSIONS: ST-segment changes during LBBB are specific for the diagnosis of AMI and predict 30-day mortality; LBBB patients without ST-segment changes have lower adjusted 30-day mortality than those with normal conduction. Trials are required to determine the best treatment for high-risk and low-risk patients with LBBB.

Global patterns of health care for acute coronary syndromes.

PURPOSE OF REVIEW: Despite similar guidelines, remarkable global differences exist in the management of acute coronary syndromes. This review describes recent insights in global patterns of patient baseline characteristics, treatment strategies, medication use, and outcome in acute coronary syndromes. RECENT FINDINGS: Results from recent registries and randomized clinical trials suggest that the arrival of many novel medications and treatment options for acute coronary syndromes has led to interregional heterogeneity in the management and treatment of patients with acute coronary syndromes. These differences in health care and adherence to national and international guidelines appear to be influenced by geographical, social, cultural, and economic factors, resulting in regional variation in hospital characteristics, physician attitude, access to resources or advanced cardiovascular care, access to the literature, and the availability of drugs. SUMMARY: Significant differences in diagnosis and treatment of acute coronary syndrome patients can be observed globally, despite similar guidelines based on the same randomized clinical trials. Guidelines are not adapted promptly worldwide, influencing outcome and health care expenditure.

Efficacy of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: one-year follow-up results of the Assessment of the Safety of a New Thrombolytic-3 (ASSENT-3) randomized trial in acute myocardial infarction.

BACKGROUND: In the ASsessment of the Safety of a New Thrombolytic 3 (ASSENT-3) study, full-dose tenecteplase plus enoxaparin or half-dose tenecteplase plus abciximab reduced the frequency of ischemic complications of acute myocardial infarction, when compared to full-dose tenecteplase plus unfractionated heparin. The aim of the present study was to determine the effect of these fibrinolytic regimens on 1-year mortality. METHODS AND RESULTS: Vital status at 1 year was available for 5942 patients (97.5%) of the 6095 initially enrolled in the study. At 1 year, 515 patients (8.7%) had died. Elderly or female patients and patients with low body weight, previous myocardial infarction, anterior wall myocardial infarction, and diabetes were at increased risk for death at 1 year. Mortality at 1 year was 7.9 % (n = 161) in the heparin group, 8.1% (n = 166) in the enoxaparin group, and 9.3% (n = 188) in the abciximab group (P =.226). Overall, pairwise comparisons did not show a significant difference among treatment regimens: relative risk 1.03 (95% CI 0.82-1.30) for enoxaparin versus heparin (P =.794) and relative risk 1.18 (95% CI 0.95-1.47) for abciximab versus heparin (P =.144). However, 1-year outcome tended to be worse with abciximab in diabetic patients. CONCLUSION: Mortality at 1 year after acute myocardial infarction remains high. Despite a reduction in ischemic complications after acute myocardial infarction with the use of full-dose tenecteplase plus enoxaparin or half-dose tenecteplase plus abciximab, mortality at 1 year was similar in these treatment groups.

Chlamydia pneumoniae induces neointima formation in coronary arteries of normal pigs.

OBJECTIVES: We evaluated the role of intracoronary, intrapulmonary and macrophage-mediated delivery of C. pneumoniae (Cp) on coronary lesion formation. METHODS: Pigs were allocated to one of three coronary protocols (intracoronary, macrophage or control groups) or to a fourth-a pulmonary group. In the intracoronary group Cp was injected into the wall of the left anterior descending (LAD) and right coronary arteries (RCA) and vehicle into the circumflex (CX). In the macrophage group autologous macrophages preincubated with Cp or not were injected into the LAD and CX wall, respectively. Animals in the control group received vehicle in LAD and CX. In the pulmonary group aerosolised Cp was given intrabronchially, after a single injection of vehicle into the LAD wall. Delivery into the coronary artery wall was performed with a balloon catheter with low-profile injector ports. RESULTS: Seroconversion occurred in the following proportions: 5/6 (intracoronary group), 4/5 (macrophage group), 0/6 (control group), and 1/6 (intrapulmonary group). Significantly higher maximal intimal thickness (MIT) was observed in LADs of intracoronary and pulmonary groups when compared to corresponding CXs. The presence of Cp antigen was associated with higher MIT (r=0.73; P<0.0001). Injection of macrophages into the coronary artery wall did not induce proliferation. Arteries without coronary interventions were morphologically normal. CONCLUSIONS: Intracoronary and intrapulmonary but not macrophage-mediated Cp inoculation were associated with moderate intimal proliferation in the absence of a lipid-rich diet. Pre-existing coronary lesions seem a prerequisite for Cp-induced proliferation.