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Aims We sought to better understand the role of percutaneous coronary intervention (PCI) in patients with stable coronary artery disease (CAD) and moderate or severe left ventricular systolic dysfunction. Methods and results Using data from the Duke Databank for Cardiovascular Disease, we analysed patients who underwent coronary angiography at Duke University Medical Center (1995–2012) that had stable CAD amenable to PCI and left ventricular ejection fraction ≤35%. Patients with acute coronary syndrome or Canadian Cardiovascular Society class III or IV angina were excluded. We used propensity‐matched Cox proportional hazards to evaluate the association of PCI with mortality and hospitalizations. Of 901 patients, 259 were treated with PCI and 642 with medical therapy. PCI propensity scores created from 24 variables were used to assemble a matched cohort of 444 patients (222 pairs) receiving PCI or medical therapy alone. Over a median follow‐up of 7 years, 128 (58%) PCI and 125 (56%) medical therapy alone patients died [hazard ratio 0.87 (95% confidence interval 0.68, 1.10)]; there was also no difference in the rate of a composite endpoint of all‐cause mortality or cardiovascular hospitalization [hazard ratio 1.18 (95% confidence interval 0.96, 1.44)] between the two groups. Conclusions In this well‐profiled, propensity‐matched cohort of patients with stable CAD amenable to PCI and moderate or severe left ventricular systolic dysfunction, the addition of PCI to medical therapy did not improve long‐term mortality, or the composite of mortality or cardiovascular hospitalization. The impact of PCI on other outcomes in these high‐risk patients requires further study.

INTRODUCTION The optimal choice of oral P2Y 12 receptor inhibitors has the potential to significantly influence outcomes. We seek to compare the safety and efficacy of the three most commonly used oral P2Y 12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor) in acute coronary syndromes (ACS) via a comprehensive systematic review and network meta-analysis. EVIDENCE ACQUISITION In line with the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, we performed a comprehensive search for RCTs which compared cardiovascular and hemorrhagic outcomes after use of at least two of the distinct oral P2Y 12 receptor inhibitors (i.e. clopidogrel, prasugrel, and ticagrelor). A search strategy has been designed to systematically search multiple databases, including MEDLINE with PubMed interface, The Cochrane Central Register of Controlled Trials, and Embase. In addition, key inclusion criteria will be trial size of at least 100 patients and at least 1 month of follow-up time. Several prespecified subgroups will be explored, including Asian patients, patients presenting with ST-elevation myocardial infarction, patients of advanced age, and others. EVIDENCE SYNTHESIS Exploratory frequentist pairwise meta-analyses will be based primarily on a random-effects method, relying on relative risks (RR) for short-term outcomes and incidence rate ratios (IRR) for long-term outcomes. Inferential frequentist network meta-analysis will be based primarily on a random-effects method, relying on RR and IRR as specified above. Results will be reported as point summary of effect, 95% CI, and P values for effect, and graphically represented using forest plots. CONCLUSIONS An international collaborative network meta-analysis has begun to comprehensively analyze the safety and efficacy of prasugrel, ticagrelor and clopidogrel, each on a background of aspirin, for management of patients with ACS. It is our hope that the rigor and breadth of the undertaking described herein will provide novel insights that will inform optimal patient care for patients with ACS treated conservatively, or undergoing revascularization.

Aims The aim of this study was to determine the effect of ticagrelor monotherapy on clinically relevant bleeding and major ischaemic events in relation to clinical presentation with and without non-ST elevation acute coronary syndromes (NSTE-ACS) among patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Methods and results We conducted a pre-specified subgroup analysis of The Ticagrelor With Aspirin or Alone in High Risk Patients After Coronary Intervention (TWILIGHT) trial, which enrolled 9006 patients with high-risk features undergoing PCI with DES. After 3 months of dual antiplatelet therapy (DAPT) with ticagrelor plus aspirin, 7119 adherent and event-free patients were randomized in a double-blind manner to ticagrelor plus placebo versus ticagrelor plus aspirin for 12 months. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding while the composite of all-cause death, myocardial infarction (MI), or stroke was the key secondary outcome. Among patients with NSTE-ACS (n = 4614), ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding by 53% [3.6% vs. 7.6%; hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.36–0.61; P < 0.001) and in stable patients (n = 2503) by 24% (4.8% vs. 6.2%; HR 0.76; 95% CI 0.54–1.06; P = 0.11; nominal P int = 0.03). Rates of all-cause death, MI, or stroke among those with (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74–1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61–1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation (P int = 0.96). Conclusion Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS. Trial registration Clinicaltrials.gov identifier: NCT02270242.

Patients with peripheral artery disease (PAD) are known to have an increased risk of ischemic cardiovascular events. However, the influence of concomitant PAD on first and subsequent recurrent ischemic events after an acute coronary syndrome (ACS) remains poorly characterized.We analyzed the combined data set from 4 randomized trials (PLATO, APPRAISE-2, TRA-CER, and TRILOGY ACS) in ACS for a follow-up length of 1 year. Using multivariable regression, we examined the association between PAD and major adverse cardiovascular events, a composite of cardiovascular death, myocardial infarction, and stroke. Among patients with a nonfatal first event, we evaluated the incidence and type of a second recurrent event.A total of 4,098 of 48,094 (8.5%) post-ACS patients had a history of PAD. The unadjusted frequency of major adverse cardiovascular events was 2-fold higher in patients with PAD (14.3% vs 7.5%) over a median (25th-75th) follow-up of 353 (223-365) days with an adjusted hazard ratio of 1.63 (95% CI: 1.48-1.78; P .001). The frequency of recurrent ischemic events among those patients with a first, nonfatal event was higher among those with PAD (40.0% vs 27.7%). The relative frequency of each event type (cardiovascular death, noncardiovascular death, myocardial infarction, or stroke) within first and subsequent ischemic events was similar regardless of PAD status at baseline.Patients with PAD have a significantly higher risk of first and recurrent ischemic events in the post-ACS setting. These findings highlight the opportunity for improved treatments in patients with PAD who experience an ACS.

Objective Acute coronary syndrome (ACS) trials typically use a composite primary outcome (myocardial infarction [MI], stroke, or cardiovascular death), but differential patient characteristics, timing, and consequences associated with individual component end points as first events have not been well studied. We compared patient characteristics and prognostic significance associated with first cardiovascular events in the post-ACS setting for initially stabilized patients. Methods We combined patient-level data from 4 trials of post-ACS antithrombotic therapies (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) to characterize the timing of and characteristics associated with first cardiovascular events (MI, stroke, or cardiovascular death). Landmark analysis at 7 days after index ACS presentation was used to focus on spontaneous, postdischarge events that were not confounded by in-hospital procedural complications. Using a competing risk framework, we tested for differential associations between prespecified covariates and the occurrence of nonfatal stroke vs MI as the first event, and we examined subsequent events after the first nonfatal event. Results Among 46,694 patients with a median follow-up of 358 (25th, 75th percentiles 262, 486) days, a first ischemic event occurred in 4,307 patients (9.2%) as follows: MI in 5.8% (n = 2,690), stroke in 1.0% (n = 477), and cardiovascular death in 2.4% (n = 1,140). Older age, prior stroke/transient ischemic attack, prior atrial fibrillation, and higher diastolic blood pressure were associated with a significantly greater risk of stroke vs MI, whereas prior percutaneous coronary intervention was associated with a greater risk of MI vs stroke. Second events occurred in 32% of those with a first nonfatal stroke at a median of 13 (3, 59) days after the first event and in 32% of those with a first nonfatal MI at a median of 35 (5, 137) days after the first event. The most common second event was a recurrent MI among those with MI as the first event and cardiovascular death among those with stroke as the first event. Conclusions Approximately 9% of patients experienced a first cardiovascular event in the post-ACS setting during a median follow-up of 1 year. Although the profile and prognostic implications of stroke vs MI as the first nonfatal event differ substantially, approximately one-third of these patients experienced a second event, typically soon after the first event. These findings have implications for improving post-ACS care and influencing the design of future cardiovascular trials.

Background: Patient centeredness is an essential component of high-quality care, yet little is published regarding the patient experience during procedures performed in the cardiac catheterization lab. Available literature focuses on the safe delivery of sedation, but does not address patient-reported satisfaction, comfort, or procedural experience. Further delineation of how procedural factors impact the patient experience is needed. Methods and Results: We conducted a retrospective, exploratory analysis of adult cardiac catheterization outpatients receiving nurse-administered, physician-prescribed procedural sedation (benzodiazepine and/or opioids) between April-June, 2017. Data were abstracted from the procedural database, EHR and Press Ganey© surveys. Patients (n=375) had a mean age of 63, were male 60% (226/375), White 73% (271/375), and overweight / obese (mean BMI = 29). Procedural sedation was given in 93% (348/375) of cases. Press Ganey© results showed good satisfaction with pain control (>75 th percentile) and staff concern for comfort in all patients. There was no significant difference in pre- and post-procedural patient reported pain scores. The median patient received 1.63 doses of midazolam with either 1.48 doses of fentanyl or 1.33 doses of hydromorphone. Median time interval between administration of initial sedative dose and local anesthetic was 6.2 minutes. Patients with longer intervals had less frequent dosing (p Conclusions: Extended duration of sedation intervals was associated with lower overall sedation administration with similar patient satisfaction. Optimizing processes for administering peri-procedural sedation may allow for less total medication without impacting patient experience.

Background Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied. Methods Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded. Results In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs. Conclusions Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

Chronic hypertension (HTN) may result in left ventricular (LV) hypertrophy and is a predictor of mortality after ST-segment elevation myocardial infarction (STEMI). It is unclear if hypertensive patients with STEMI have distinct infarct characteristics compared with those without HTN. Using pooled

The outcomes for patients transferred with cardiogenic shock and later treated with revascularization and Impella support have not previously been studied. To evaluate these outcomes, patients in cardiogenic shock were recruited from the catheter-based ventricular assist device registry, a prospective registry enrolling patients who underwent percutaneous coronary intervention with hemodynamic support using Impella 2.5 or CP. Analysis was performed on subgroups of patients who were characterized as those directly admitted to a tertiary care hospital (direct), or those transferred from an outside hospital (transfer). Patients who were transferred with acute myocardial infarction with cardiogenic shock (AMICS) more often presented in shock were in shock longer than 24 hours, and were more likely to be on intra-aortic balloon pump but were less likely to sustain cardiac arrest. The number of pressors, EF, diseased, and treated vessels were similar between the 2 groups. Despite baseline differences, the mortality was similar in the transfer versus direct patients (47.0% vs 53.5% p = 0.19). In a multivariate model, the factors independently associated with 30-day mortality in AMICS treated with revascularization and Impella support were cardiopulmonary resuscitation (CPR) (p0.01), age (p0.01), and ST-segment elevation myocardial infarction (STEMI) (p = 0.02). Whether the patient was transferred or directly admittedly with AMICS was not an independent predictor of death. In conclusion, these findings suggest that considerations should be given to transfer patients with AMICS to allow them to be treated in a contemporary manner.

Greater optimism regarding recovery from chronic illness is associated with improved quality of life and clinical outcomes. We performed a post-hoc analysis on the association between optimism and outcomes in Ranolazine in Patients with Incomplete Revascularization after Percutaneous Coronary Intervention (RIVER-PCI), a randomized trial in patients with chronic angina pectoris who had incomplete revascularization following percutaneous coronary intervention. At baseline, patients answered how much they agreed with the phrase, "I am optimistic about my future and returning to a normal lifestyle." We evaluated the association between baseline optimism and time to ischemia-driven hospitalization or revascularization using a Cox model, and the association between baseline optimism and change in frequency of angina pectoris using a mixed measures model. Of 2,389 patients, 782 (33.2%) were very optimistic ("strongly agree"), 1,000 (42.4%) were optimistic ("agree"), 451 (19.1%) were neutral ("undecided"), and 123 (5.2%) were not optimistic ("disagree" or "strongly disagree"). Very optimistic patients had a lower prevalence of co-morbidities and less severe angina at baseline than less optimistic patients. The rate of ischemia-driven revascularization or hospitalization was higher in neutral and not optimistic patients compared with very optimistic patients; this finding persisted after adjustment for co-morbidities and baseline angina frequency (hazard ratio 1.42, 95% confidence interval 1.14 to 1.77 for neutral vs very optimistic; hazard ratio 1.38, 95% confidence interval 0.98 to 1.94 for not optimistic vs very optimistic). Neutral and not optimistic patients also had less improvement in angina than very optimistic patients. In conclusion, in patients with angina, those with more self-reported optimism had better health status outcomes. Whether structured interventions targeting optimism improve outcomes in these patients warrants further study.

Background In the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial of patients with non-ST-segment elevation acute coronary syndrome managed medically without revascularization, treated with prasugrel versus clopidogrel for less than or equal to 30 months after index acute coronary syndrome, post-hoc analyses showed a divergence of treatment effect in favor of prasugrel after 12 months. Potential influential factors, including a potential late treatment effect after early study drug discontinuation in the intention-to-treat analysis, have not been explored. Patients and methods We carried out an exploratory, post-hoc analysis of 1436 patients who received at least one dose of the study drug and discontinued the drug 7-365 days after randomization. Kaplan-Meier event rates were evaluated starting at the landmark timepoint of study discontinuation through 2 years of follow-up, and were compared between prasugrel and clopidogrel. Results The unadjusted rates of the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke were 20.1 versus 24.4% in the prasugrel versus clopidogrel groups (log-rank P=0.069). Similar findings were observed for cardiovascular death (13.3 vs. 18.0%, log-rank P=0.022), and cardiovascular death or myocardial infarction (19.3 vs. 23.3%, log-rank P=0.042). In multivariable analyses, there were no significant differences in the adjusted risk of these outcomes between the prasugrel and clopidogrel groups. Conclusion In this hypothesis-generating analysis, high rates of ischemic events were observed after study drug discontinuation, with a lower frequency of events among patients treated with prasugrel versus clopidogrel that did not persist after multivariable adjustment. This analysis highlights the complexities of ascertaining downstream effects of antithrombotic therapies after drug discontinuation.

Background The COMPASS trial showed that a combination of rivaroxaban and aspirin improved outcomes in patients with stable vascular disease compared with aspirin alone, but at the cost of an overall increase in bleeding. Purpose Describe the baseline characteristics and outcomes of relevant subgroups within the COMPASS-eligible population (CEP) in the REACH Registry and identify subgroups with higher ischemic and lower bleeding risk profile. Methods Within the CEP, (fulfilling COMPASS inclusion and exclusion criteria) we identified the following subgroups: diabetes, MI 65 years, asymptomatic carotid stenosis > 70%, heart failure (HF), and stage III chronic kidney disease (CKD). We describe the composite outcome of MI, stroke or CV death, expressed as rates per 100 patient-years and serious bleeding rate at 1 year (bleeding requiring transfusion, hospitalization or hemorrhagic stroke) Results From the overall CEP (n = 16.875), 81.5% were aged > 65 years, 41.0% had diabetes, 40.2% had stage III CKD, 13.3% had HF, 8.7% had asymptomatic carotid stenosis and 5.9% had a history of MI Fig. 1 ). Patients with a history of MI Table 1 ). Conclusions Within the COMPASS-eligible patients, those with a history of MI

Mortality and morbidity in acute coronary syndromes (ACSs), caused principally by plaque erosion or rupture leading to thrombus formation and myocardial ischemia, have been reduced by a combination of antithrombotic agents (antiplatelet drugs and anticoagulants) and early revascularization. Aspirin is the foundation antiplatelet agent. New P2Y12 receptor inhibitors (prasugrel and ticagrelor) have clear benefits compared with clopidogrel for dual antiplatelet therapy, and cangrelor or vorapaxar, a thrombin receptor inhibitor, may be of value in specific settings. Anticoagulation uses 1 of 4 choices: bivalirudin, unfractionated heparin, enoxaparin, and fondaparinux. Moreover, some patients (such as those who have chronic atrial fibrillation) require triple therapy with aspirin, clopidogrel, plus an anticoagulant, frequently a vitamin K antagonist. New oral anticoagulants have been shown to be at least as effective as vitamin K antagonists in atrial fibrillation and led to fewer bleeding complications. Finally, the combination of aspirin, clopidogrel, and low-dose rivaroxaban has recently been approved by the European Medicines Agency (but not the Food and Drug Administration) for secondary prevention after ACS. Several strategies have been developed to balance the potential benefit of antithrombotic therapy against the risk of bleeding complications, for example, radial access in coronary angiography or restricted use of combination therapy, and others are under investigation, such as discontinuation of aspirin. This overview summarizes the current status of antithrombotic therapy in ACS and describes strategies currently explored to optimize its benefit/risk ratio.

The goal of this study was to characterize determinants of infarct size in the multicenter randomized Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP-AMI) trial. Contemporary determinants of infarct size in patients presenting with acute anterior myocardial infarction without shock and undergoing percutaneous revascularization have been incompletely characterized. In CRISP-AMI, 337 patients with acute anterior ST segment elevation myocardial infarction but without cardiogenic shock at 30 sites in 9 countries were randomized to initiation of intra-aortic balloon counterpulsation before primary percutaneous coronary intervention versus standard of care. The primary outcome was infarct size as measured by cardiac magnetic resonance imaging 3 to 5 days after percutaneous coronary intervention. Of 337 randomized patients, complete periprocedural and infarct size data were available in 250 patients (74%). After a comparison of baseline characteristics to ensure no significant differences, patients with missing data were excluded. Using multiple linear regression of 23 variables, time from symptom onset to first device (β = 0.022, p = 0.047) and preprocedural Thrombolysis In Myocardial Infarction flow 0/1 (β = 15.28, p0.001) were independent predictors of infarct size. Infarct size increased by 0.43% per 30 minutes in early reperfusion and by 0.63% every 30 minutes in late reperfusion. In conclusion, in patients with acute anterior ST elevation myocardial infraction without cardiogenic shock, total ischemic time and preprocedural Thrombolysis In Myocardial Infarction flow 0/1 were associated with increased infarct size as determined by cardiac magnetic resonance imaging. These findings underscore the importance of systems of care aimed at reducing total ischemic time to open infarct arteries.

Objective Patients with diabetes mellitus (DM) presenting with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI) derived enhanced benefit with dual antiplatelet therapy (DAPT) with prasugrel vs. clopidogrel. The risk profile and treatment response to DAPT for medically managed ACS patients with DM remains uncertain. Methods The TRILOGY ACS trial compared aspirin + prasugrel vs. aspirin + clopidogrel for up to 30 months in non-ST-segment elevation (NSTE) ACS patients managed medically without revascularization. We compared treatment-related outcomes among 3539 patients with DM vs. 5767 patients without DM. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. Results Patients with vs. without DM were younger, more commonly female, heavier, and more often had revascularization prior to the index ACS event. The frequency of the primary endpoint through 30 months was higher among patients with vs. without DM (24.8% vs. 16.3%), with a higher risk for those patients with DM treated with insulin vs. those treated without insulin (35.3% vs. 19.9%). There was no significant difference in the frequency of the primary endpoint by treatment with prasugrel vs. clopiodgrel in those with or without DM ( P int = 0.82) and with or without insulin treatment among those with DM ( P int = 0.304). Conclusions Among NSTE ACS patients managed medically without revascularization, patients with DM had a higher risk of ischemic events that was amplified among those treated with insulin. There was no differential treatment effect with a more potent DAPT regimen of aspirin + prasugrel vs. aspirin + clopidogrel.

Aspirin was established more than a quarter century ago as an evidence-based therapy to reduce recurrent cardiovascular events in patients with coronary artery disease based on limited data by contemporary standards. Indeed it is unclear how regulatory agencies would define the optimal dose or duration of aspirin therapy if assessed in the current era. Subsequent clinical investigation has focused on the addition of antithrombotic agents on top of baseline aspirin therapy in the acute and chronic setting to reduce patient's risk of further ischemic events, at the cost of increased bleeding complications. The current armamentarium of potent and predictable antiplatelet and antithrombotic agents has ushered in a new era where clinicians and scientists are contemplating withdrawal of previously established agents to minimize bleeding risk while sustaining efficacy; indeed, subtraction may lead to the next advance in the treatment of acute and chronic ischemic vascular disease.

Dual antiplatelet therapy (DAPT), the combination of aspirin and a P2Y12 inhibitor, given for 12 months remains the standard of care after presentation with acute coronary syndrome (ACS) because it has been shown to be associated with a significant reduction in ischemic events compared with aspirin monotherapy. The factor Xa inhibitor rivaroxaban was shown to be associated with a significant reduction in the composite of cardiovascular death, myocardial infarction, and stroke, and resulted in a nominal reduction in cardiovascular death, when added to background DAPT in the ATLAS ACS 2-TIMI 51 trial; however, there was excessive bleeding with this "triple-therapy" approach. The combination of rivaroxaban with P2Y12 inhibition in a "dual-pathway" approach may be an effective therapeutic regimen for the treatment of ACS, given the known importance of P2Y12 inhibition after stenting and intriguing data that the combination of an anticoagulant with clopidogrel after stenting in patients with atrial fibrillation appears an attractive option to this patient population. GEMINI-ACS-1 is a prospective, randomized, double-dummy, double-blind, active-controlled trial that will assess the safety of dual antithrombotic therapy (rivaroxaban [2.5 mg twice daily] + P2Y12 inhibitor) as compared with DAPT (aspirin [100 mg] + P2Y12 inhibitor) within 10 days of an ACS event in 3,000 patients. Patients will be randomized in a 1: 1 ratio stratified by intended P2Y12 inhibitor use (clopidogrel 75 mg daily or ticagrelor 90 mg twice daily), with 1500 patients expected in each P2Y12 inhibitor strata. The primary end point is Thrombolysis in Myocardial Infarction clinically significant bleeding (major, minor, or requiring medical attention). The exploratory efficacy determination will be a composite of cardiovascular death, myocardial infarction, ischemic stroke, and stent thrombosis. GEMINI-ACS-1 will assess the safety and feasibility of dual antithrombotic therapy with rivaroxaban and a P2Y12 inhibitor compared with conventional DAPT for the treatment for patients with recent ACS.

Valentin Fuster, MD, PhD, FACC, FAHA, FESC, Co-Chair; Lars E. Ryden, MD, PhD, FACC, FESC, FAHA, Co-Chair; David S. Cannom, MD, FACC; Harry J. Crijns, MD, FACC, FESC; Anne B. Curtis, MD, FACC, FAHA; Kenneth A. Ellenbogen, MD, FACC, FHRS† Jonathan L. Halperin, MD, FACC, FAHA; G. Neal Kay, MD, FACC

AIMS: Presentation with an acute coronary syndrome (ACS) on chronic aspirin therapy is an independent predictor of adverse short-term outcomes. Whether this finding applies to chronic thienopyridine use, and with the contemporary invasive management of ACS, is unknown. METHODS AND RESULTS: In ACUITY, 13819 patients with moderate and high-risk ACS were studied; patients transferred from an outside hospital were excluded from the present analysis, given uncertain preadmission antiplatelet status. Endpoints included major adverse cardiovascular events (MACE: death, myocardial infarction, or unplanned revascularization), major bleeding, and net adverse clinical events (NACE). Among 11313 study patients, 31 % were naive for antiplatelet agent, 49% were receiving aspirin alone, and 20% were on dual antiplatelet therapy. Chronic antiplatelet users were older and had a higher risk profile. After adjusting for baseline differences, chronic antiplatelet therapy (single or dual) was not associated with an increased incidence of 30-day MACE, bleeding, or NACE. However, patients on chronic aspirin or dual antiplatelet therapy at presentation had significantly higher 1-year rates of MACE [odds ratio (95% confidence interval) = 1.17 (1.01–1.36), P = 0.03 and 1.29 (1.02–1.64), P = 0.03, respectively]. Patients presenting on dual antiplatelet therapy had significantly greater adjusted MACE at 1-year than those on aspirin alone [odds ratio (95% confidence interval) = 1.34 (1.15–1.56), P

Optimism regarding recovery is variably associated with quality of life and outcomes in patients with chronic illness, but this association has not been evaluated in chronic angina patients. RIVER-PCI was a randomized trial in patients with chronic angina testing ranolazine's effect on a primary

Aims To develop a risk score to quantify bleeding risk in outpatients with or at risk of atherothrombosis. Methods and results We studied patients in the REACH Registry, a cohort of 68 236 patients with/at risk of atherothrombosis. The outcome of interest was serious bleeding (non-fatal haemorrhagic stroke or bleeding leading to hospitalization and transfusion) over 2 years. Risk factors for bleeding were assessed using modified regression analysis. Multiple potential scoring systems based on the least complex models were constructed. Competing scores were compared on their discriminative ability via logistic regression. The score was validated externally using the CHARISMA population. From a final cohort of 56 616 patients, 804 (1.42%, 95% confidence interval 1.32–1.52) experienced serious bleeding between baseline and 2 years. A nine-item bleeding risk score (0–23 points) was constructed (age, peripheral arterial disease, congestive heart failure, diabetes, hypertension, smoking, antiplatelets, oral anticoagulants, hypercholesterolaemia). Observed incidence of bleeding at 2 years was: 0.46% (score ≤6); 0.95% (7–8); 1.25% (9–10); 2.76% (≥11). The score's discriminative performance was consistent in CHARISMA and REACH (c-statistics 0.64 and 0.68, respectively); calibration in the CHARISMA population was very good (modified Hosmer-Lemeshow c 2 = 4.74; P = 0.69). Conclusion Bleeding risk increased substantially with a score >10. This score can assist clinicians in predicting the risk of serious bleeding and making decisions on antithrombotic therapy in outpatients.

Mechtouff L, Touze´E,StegPG,OhmanEM,Goto S, Hirsch AT, Ro¨ther J, Aichner FT, Weimar C,Bhatt DL, Alberts MJ, Mas J-L, on behalf of theREACH Registry Investigators (Paris-Descartes Uni-versity; Universite´ Paris 7; Paris, France, Duke Uni-versity,DurhamNC,USA,TokaiUniversity,Isehara,Japan, University of Minnesota, Minneapolis, MN,USA,AcademicTeachingHospitalHannoverMedicalSchool, Minden, Germany, Academic TeachingHospital Wagner-Jauregg, Linz, Austria, Universityof Duisburg-Essen, Essen, Germany, VA BostonHealthcareSystem,andBrighamandWomen’sHos-pital,Boston,MA;andNorthwesternUniversityMed-ical School, Chicago, IL;USA).Worse blood pressurecontrolinpatientswithcerebrovascularorperipheralarterial disease compared with coronary artery dis-ease.JInternMed2010;267:621–633.Objectives. Poorblood pressure(BP)controliscommonamongst patients with symptomatic atherothrom-botic disease. It is unclear whether BP control andmanagement differ across atherothrombotic diseasesubtypes.Methods. We analysed the baseline data of 44 984 pa-tients with documented coronary artery disease(CAD) only (n = 30 414), cerebrovascular disease(CVD) only (n = 11 359) and peripheral arterial dis-ease (PAD) only (n = 3211) from the internationalREduction of Atherothrombosis for ContinuedHealth Registry and investigated the impact of ath-erothromboticdiseasesubtypeonBPcontrolanduseofantihypertensivedrugs.Results. The proportion of patients with BP controlled(

Objective: To assess variables associated with the occurrence of atrial fibrillation (AF) and the relation of AF with short- and long-term outcomes and with other in-hospital complications in patients with acute coronary syndromes (ACS) with and without ST-segment elevation. Design: Pooled database of 120 566 patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation (NSTE) ACS enrolled in 10 clinical trials. Multivariable logistic regression and Cox proportional hazards modelling were used to identify factors associated with AF and its relation with clinical outcomes. Setting: ACS complicated by AF. Patients: 120 566 patients with STEMI and NSTE-ACS in 10 clinical trials. Interventions: None evaluated. Main outcome measure: Short- and long-term mortality. Results: Occurrence of AF was 7.5% in the overall population (STEMI 8.0% (n = 84 161); NSTE-ACS = 6.4% (n = 36 405)). Seven-day mortality was higher for patients with AF (5.1%) than for those without (1.6%). After adjusting for confounders, association of AF with 7-day mortality was present in STEMI (hazards ratio (HR) = 1.65; 95% CI 1.44 to 1.90) and NSTE-ACS (HR = 2.30; 95% CI 1.83 to 2.90; p interaction = 0.015). Risk of long-term mortality (day 8 to 1 year) was also higher in STEMI (HR = 2.37; 95% CI 1.79 to 3.15) and NSTE-ACS (HR = 1.67; 95% CI 1.41 to 1.99). AF had a larger impact in NSTE-ACS on risk of short-term mortality (p Conclusions: AF is more common in patients with STEMI. An association of AF with short- and long-term mortality among patients with STEMI and NSTE-ACS was found. Understanding these findings may lead to better care of patients with this common arrhythmia.

Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines/rules). In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 . View this table: Table 1 Classes of recommendations View this table: Table 2 Levels of evidence The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the …

Therapies that reverse pathologic left ventricular (LV) remodeling are often associated with improved outcomes. The incidence and impact of reverse LV remodeling after high-risk percutaneous coronary intervention (PCI) are unknown.The PROTECT II study was a multicenter trial in patients with complex, multivessel coronary artery disease and reduced ejection fraction (EF) that revealed an increase in visual EF after high-risk PCI. Among patients with quantitative echocardiography (LV volumes and biplane EF), we assessed the extent and predictors of reverse LV remodeling, defined as improved systolic function with an absolute increase in EF ≥5% and correlated these findings with clinical events.Quantitative echocardiography was performed in 184 patients at baseline and longest follow-up. Mean EF at baseline was 27.1%. Ninety-three patients (51%) demonstrated reverse LV remodeling with an absolute increase in EF of 13.2% (P.001). End-systolic volume decreased from 137.7 to 106.6 mL (P = .002). No significant change in EF or end-systolic volume was seen among non-remodelers. Reverse LV remodeling occurred more frequently in patients with more extensive revascularization (odds ratio, 7.52; 95% CI [1.31-43.25]) and was associated with significantly fewer major adverse events (composite of death/myocardial infarction/stroke/transient ischemic attack): 9.7% versus 24.2% (P = .009). There was also a greater reduction in New York Heart Association class III/IV heart failure among reverse LV remodelers (66.7% to 24.0%) than non-remodelers (56.3% to 34.4%), P = .045.Reverse LV remodeling can occur after high-risk PCI in patients with complex coronary artery disease and reduced EF and is associated with improved clinical outcomes.

Women with acute coronary syndromes (ACS) are less likely to undergo invasive revascularization than men, but sex-specific differences in long-term outcomes and platelet reactivity among medically managed ACS patients remain uncertain. We examined sex-specific differences in long-term ischemic and bleeding outcomes and platelet reactivity for medically managed ACS patients randomized to prasugrel versus clopidogrel plus aspirin.Data from 9,326 patients enrolled in TRILOGY ACS were analyzed to determine differences in long-term ischemic and bleeding outcomes between women (n = 3,650 [39%]) and men (n = 5,676 [61%]) randomized to prasugrel 10 mg/d (5 mg/d for patients ≥75 years and/or60 kg) versus clopidogrel 75 mg/d. Sex-specific differences in 30-day platelet reactivity were analyzed in 2,564 (27%) patients participating in a platelet function substudy.Compared with men, women were older, weighed less, were less likely to have prior myocardial infarction or revascularization, and had lower baseline creatinine clearance and hemoglobin level values. Rates of the composite of cardiovascular death/myocardial infarction/stroke (20.2% vs 19.1%; P = .56), all-cause mortality (12.2% vs 11.7%; P = .88), and Global Use of Strategies to Open Occluded Arteries severe/life-threatening/moderate bleeding (3.8% vs 2.8%; P = .74) through 30 months were similar in women versus men. After adjustment, women had significantly lower risk for ischemic outcomes and all-cause mortality. There were no sex-specific, treatment-related differences in 30-day platelet reactivity.Long-term ischemic and bleeding outcomes in medically managed ACS patients were similar for women versus men, as was treatment-related platelet reactivity. Women had a higher baseline risk profile and, after adjustment, significantly lower risk of the primary composite end point and all-cause death through 30 months.

Despite substantial progress in the diagnosis and treatment of acute ST-segment elevation myocardial infarction (STEMI), implementation of this knowledge into routine clinical practice has been variable. It has become increasing clear that primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion if it can be performed in a timely manner. Recent European data suggest that transfer for direct PCI may also be preferable to fibrinolytic therapy. We believe it is time to establish a national policy for treatment of patients with STEMI to develop a coordinated system of care similar to that of the level 1 trauma system.

Objectives We studied the outcome of diabetics enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) V trial to assess whether the combination of half-dose reteplase and abciximab provides any propitious benefits over standard fibrinolytic therapy in diabetic patients. Background Diabetics with acute ST-segment elevation myocardial infarction (MI) have a worse outcome compared with nondiabetics. Higher-risk patients are usually more likely to benefit from advances in medical therapy. Methods We analyzed diabetic patients enrolled in the GUSTO V trial to assess the outcome of those randomized to the combination of half-dose reteplase and abciximab versus those randomized to reteplase. We also evaluated whether any differences existed in presentation and outcome of MI among the diabetics versus the nondiabetics enrolled in the study. Results The trial enrolled 13,782 nondiabetics and 2,633 diabetics. Compared to nondiabetics, diabetics had a significantly higher mortality at 30 days (8.5% vs. 5.1%, p Conclusions Compared to nondiabetics, diabetics continue to have a worse outcome with MI. Although combination therapy did not provide a survival benefit, nonfatal ischemic outcomes, including reinfarction, recurrent ischemia, and urgent revascularization, were substantially reduced.

Background Immediate, as well as early, revascularisation is of benefit in patients with acute coronary syndromes (ACS) presenting with ST elevation. However, trials comparing invasive versus medical treatment in patients with an acute coronary syndrome without ST elevation do not consistently show improvement in survival after revascularisation. Accordingly, additional data are warranted. Methods The effect of revascularisation within 30 days on one-year survival in the GUSTO IV ACS trial was investigated. A total of 7800 patients were included with an acute coronary syndrome without ST elevation, documented by either elevated cardiac troponin or transient or persistent ST-segment depression. In this trial, comparing abciximab versus placebo as initial medical therapy, coronary angiography within 60 h after randomisation was discouraged. In 30-day survivors, those who underwent revascularisation were compared with 30-day survivors without revascularisation. Adjustments were made for patient characteristics, and for a propensity score that was adjusted for covariates associated with the likelihood of early revascularisation. Findings Of the 7496 patients who survived at least 30 days, 2265 (30%) underwent coronary revascularisation within 30 days: 789 patients CABG, 1450 PCI and 26 both CABG and PCI. Procedure-related mortality was low at 1.8%. Patients with revascularisation had a lower one-year mortality compared to medically treated patients (2.3% vs. 5.6%, p

Background— This study was designed to investigate long-term effects of the glycoprotein IIb/IIIa inhibitor abciximab in patients with acute coronary syndrome without ST elevation who were not scheduled for coronary intervention. Methods and Results— A total of 7800 patients were included with an acute coronary syndrome without ST elevation, documented by either elevated cardiac troponin or transient or persistent ST-segment depression. They were randomized to abciximab bolus and 24-hour infusion, abciximab bolus and 48-hour infusion, or matching placebo. The overall 1-year mortality rate was 8.3% (649 patients). One-year mortality was 7.8% in the placebo group and 8.2% in the 24-hour and 9.0% in the 48-hour abciximab infusion group. Compared with placebo, the hazard ratio for the 24-hour infusion of abciximab was 1.1 (95% CI 0.86 to 1.29), and for the 48-hour infusion, it was 1.2 (95% CI 0.95 to 1.41). The lack of benefit of abciximab was observed in every subgroup studied. Patients with negative troponin or elevated C-reactive protein had a higher mortality rate after treatment with abciximab for 48 hours than with placebo: 8.5% versus 5.8% in those with negative troponin ( P =0.02), 16.3% versus 12.1% in those with elevated C-reactive protein ( P =0.04). Conclusions— Compared with placebo, abciximab did not provide any survival benefit at 1 year in patients admitted with an acute coronary syndrome with ST depression and/or elevated troponin who were not scheduled to undergo early coronary revascularization. In subgroups of patients, in particular those with low cardiac troponin or elevated C-reactive protein, abciximab was associated with excess mortality.

Background Adjunctive therapies that increase the incidence of normal reperfusion after thrombolysis for acute myocardial infarction (MI) could enhance clinical outcomes. Direct thrombin inhibitors may offer an advantage over standard adjunctive therapies. Methods We randomized 336 patients with acute MI at 33 sites to receive 1 of 5 doses of efegatran sulfate, a direct thrombin inhibitor, or heparin for 72 to 96 hours, both with accelerated alteplase and aspirin. The primary end point was the incidence of thrombolytic failure (death, reinfarction, or TIMI grade 0-2 flow in the infarct artery from 90 minutes to discharge or 30 days, whichever occurred earlier). Results Significantly more patients randomized to efegatran had evidence of heart failure at admission. The lowest-dose efegatran arm was terminated at 15 patients because of unacceptably increased thrombolytic failure. The primary end point occurred in 53.0% of patients treated with heparin, in 53.8% of patients treated with efegatran overall (P =.90), and in 55.4% of patients given intermediate-dose efegatran (P =.74). These findings were unaffected after adjustment was done for baseline differences. Most bleeding was minor; major bleeding and the use of blood transfusions did not differ significantly by treatment. Three patients in the high-dose efegatran group had intracranial hemorrhage, as did 1 patient in the heparin group. Continuous ST monitoring showed a shorter time to recovery for the efegatran group (median 107 minutes) compared with the heparin group (154 minutes; P =.025). Conclusions Efegatran sulfate appeared to offer no clear advantage over heparin as an adjunct to thrombolysis for acute myocardial infarction, although there may be a modest improvement in time to reperfusion.

Over the last several decades a number of cardiovascular trials have provided unexpected findings that did not fit the pharmacological effects of what is known for a particular compound. The scientific community finds this very unsettling and usually within a few months there are a plethora of “potential” reasons for these unexpected findings. Dr. Frank Harrell, a noted biostatistician, some 20 years ago stated that “medical scientists are programmed to provide a plausible scientific explanation for an observation even if there is none, while biostatisticians try to determine if the observation is real in statistical terms.” In this issue of Thrombosis and Haemostasis Dr. Serebruany (1) has attempted to provide plausible “scientific” answers for some unusual observations from the PLATelet inhibition and clinical Outcomes (PLATO) trial (2) published in 2009. In this trial there was a significant reduction in cardiovascular (CV) mortality as part of a composite clinical endpoint (death, stroke and myocardial infarction). Using a hierarchical statistical testing strategy for the primary endpoint, to preserve statistical power, they concluded that the ticagrelor was superior to clopidogrel in acute coronary syndrome (ACS) for the composite endpoint, and the individual components myocardial infarction (MI) and CV mortality, but not for stroke. All-cause mortality was numerically lower as well, but statistically could not be inferred for the primary endpoint, as then adjustments had to be made to account for the multiple statistical tests that were performed. Dr. Serebruany has focused on the all-cause mortality rate which he notes was higher in the PLATO trial compared with other ACS trials. There are several flaws with his arguments as will be pointed out. The argument that the all-cause mortality observed in the PLATO trial is not consistent with other ACS trials cannot be made for many reasons. First, none of the trials quoted have included the same type of ACS patients. The PLATO trial (2) enrolled 40% ST-segment elevation myocardial infarction (STEMI) patients (with known high early mortality), while CURE (3) and ACUITY (4) included none; CHARISMA (5) was a chronic prevention trial where stable patients were enrolled (about 30% up to one year after MI (not necessarily STEMI)) and CREDO (6) was a PCI trial with only a portion of ACS patients. It is therefore expected that the overall mortality rates should be substantially different in these trials, particularly as patients were enrolled in different countries over the last decade. Second, we do not believe it is appropriate to compare the conduct and, specifically, the monitoring of the PLATO trial with other trials and to suggest that problems with these processes contributed to the mortality rates observed in the PLATO trial. Experienced clinical trial researchers understand that the operational conduct of a large, global cardiovascular trial is very complex and cannot be adequately judged or evaluated by outside “experts” who have little experience in these matters, and specifically, no role in the operational conduct of the trial in quesCorrespondence to: Prof. Magnus Ohman, MB, FRCPI, FESC, FACC Duke University Medical Center Box 3126 DUMC Durham, NC 27710, USA Tel.: +1 919 681 2069, Fax: +1 919 681 6443 E-mail: ohman001@mc.duke.edu

Introduction: The relationship of low “on-treatment” platelet reactivity to longitudinal risks of major bleeding following acute coronary syndromes (ACS) has not been clearly delineated. Methods: We analyzed 2428 patients with non-ST-elevation ACS (NSTE ACS) from the TRILOGY ACS trial who were managed without revascularization and had platelet reactivity measurements (P2Y12 reaction units [PRUs]) collected in a platelet function substudy. Patients received aspirin + prasugrel (10 mg/d; 5 mg/d for those ≥75 y or Results: Through 30 months, there were 27 GUSTO severe/moderate bleeds and 37 TIMI major/minor bleeds, with gastrointestinal bleeding the most common. Baseline characteristics were stratified by tertiles of PRU values at 5 d, and significant differences were seen across tertiles (Table). Unadjusted bleeding rates appeared highest among those in the lowest PRU tertile but no reliable PRU cut point was found that significantly distinguished bleeding risk. Unadjusted analyses showed continuous measures of PRUs were not associated with GUSTO (HR=1.00, 95% CI: 0.96-1.04) or TIMI bleeding (HR=1.03, 95% CI: 0.99-1.06). This relationship did not change after multivariable adjustment. Conclusions: Among NSTE-ACS patients managed without revascularization and receiving dual antiplatelet therapy, PRU values were not significantly associated with long-term bleeding risk. The relatively small number of bleeding events accrued limited study power, but these results suggest that low “on-treatment” platelet reactivity does not independently predict post-ACS bleeding risk.

Aims: We used the GUSTO-I and GUSTO-III databases to evaluate our performance in treating cardiogenic shock patients over much of the 1990s. Methods and Results: GUSTO-I (1990-1993) and GUSTO-III (1995-1997) prospectively identified all patients with cardiogenic shock complicating acute myocardial infarction. Demographics, clinical presentation and outcomes for cardiogenic shock patients in the two trials were compared. Only patients enrolled with cardiogenic shock in countries common to both trials were included in these analysis. The 695 patients with cardiogenic shock in GUSTO-III were compared with the 2814 patients with cardiogenic shock in GUSTO-I. GUSTO-III patients were older (P=0.0001) and more likely to be diabetic (P=0.009) and hypertensive (P=0.025). They had a higher Killip class (P=0.002) and significantly greater index anterior infarction than cardiogenic shock patients enrolled in GUSTO-I. Time to treatment, presentation heart rate, and diastolic blood pressure were similar; however, systolic blood pressure at presentation was higher among GUSTO-III patients (P=0.002). Rates of coronary angiography, pulmonary artery catheterization, and mechanical ventilation declined in GUSTO-III compared with GUSTO-I (P=0.001); rates of angioplasty and bypass surgery were similar. Cardiogenic shock mortality in GUSTO-III was significantly higher than in GUSTO-I (62 vs 54%, P=0.001), as were rates of reinfarction (14 vs 11%, P=0.013) and recurrent ischaemia (35 vs 27%, P=0.00001). Mortality at non-U.S. sites (68 and 64%) was higher than at U.S. sites (53 and 50%) in both GUSTO-I and GUSTO-III studies, respectively. Angioplasty, bypass surgery, and balloon pump rates were lower for non-U.S. patients. Conclusions: Cardiogenic shock continues to be associated with high mortality in thrombolytic-treated patients. Lower mortality observed in the U.S.A. supports consideration for percutaneous and surgical revascularization. (C) 2000 The European Society of Cardiology.

Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilintrade mark) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 microg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.

Point-of-care (POC) or "near-patient" testing allows diagnostic assays to be performed in locations such as the emergency department or intensive care unit where treatment decisions are made and care is delivered based on the results of these assays. Presently, there exist POC immunoassays for several cardiac markers including creatine kinase MB (CK-MB), myoglobin, troponin I, and troponin T that yield qualitative and quantitative results comparable to traditional central lab assays. In the evaluation of emergency room patients with chest pain, POC cardiac markers may improve triage and clinical outcomes. Existing POC assays combining myoglobin and CK-MB have high sensitivity and specificity for diagnosing acute myocardial infarction and may provide the earliest identification of myocardial injury. POC Troponin T assays are the most studied POC cardiac marker assays. Along with POC troponin I assays, these tests provide more sensitive identification of myocardial injury and valuable prognostic information. Prior studies of POC cardiac marker assays have not addressed whether POC testing affects patient outcome or process of care. In situations in which caregivers base triage, treatment and monitoring decisions on time-sensitive diagnostic results, POC tests linked with improved triage and treatment strategies may improve resource utilization and clinical outcomes.

Pharmacological reperfusion therapy for acute myocardial infarction with intravenous fibrinolytic agents improves survival yet fails to achieve early and complete coronary blood flow in nearly half of treated patients. In principle, glycoprotein (GP) IIb/IIIa inhibitors, potent antiplatelet agents, might improve the efficacy and clinical outcomes associated with fibrinolysis. Preclinical research suggests more rapid and effective reperfusion with combined platelet GP IIb/IIIa inhibition and fibrinolysis. Early clinical studies confirm improved early patency and more rapid electrocardiographic resolution, but increased bleeding complications, with the addition of GP IIb/IIIa antagonists to conventional fibrinolysis. Future studies may combine reduced-dose fibrinolytic therapy with GP IIb/IIIa inhibition to optimize efficacy and safety.

Results Shock occurred in 260 (5·3%) of 4921 patients randomized to alteplase and 560 (5·5%) of 10 138 patients randomized to reteplase. Of these patients, 28 (10·8%) and 55 (9·8%) randomized to alteplase and reteplase, respectively, presented with shock. In-hospital, 35% and 37% of shock patients assigned to alteplase or reteplase, respectively, underwent coronary angiography, with similar rates of percutaneous (211‐13%) or surgical (22‐3%) revascularization procedures subsequently performed. Death within 30 days occurred in 169 (65%) and 353 (63%) shock patients randomized to alteplase and reteplase, respectively (P=0·59). Of patients presenting with shock, 64% and 58% of patients randomized to alteplase or reteplase died within 30 days (P=0·59). Conclusion Compared with alteplase, reteplase did not improve outcome among patients who presented with shock or developed shock after receiving thrombolytics. The newer-generation thrombolytic agents remain of limited eYcacy in the treatment and prevention of shock. (Eur Heart J 1999; 20: 128‐135)

Background —The baseline cardiac troponin T (cTnT) level strongly predicts short-term mortality in acute coronary syndromes, but the added value of later measures to predict short- and long-term outcome and in the context of baseline clinical characteristics is unclear. Methods and Results —Relations between baseline, peak, and 8- and 16-hour (late) cTnT results and outcomes were assessed in 734 patients in a GUSTO-IIa substudy. Proportional-hazards models assessed the prognostic information gained from late cTnT when added to a mortality model containing the baseline cTnT result and clinical factors. At baseline, 260 patients were cTnT-positive (>0.1 ng/mL), 323 became positive later, and 151 remained negative (≤0.1 ng/mL). Mortality at 30 days was 10% in the baseline-positive group, 5% in late-positive patients, and 0% in negative patients. After adjustment for baseline characteristics, any positive cTnT result predicted 30-day mortality (baseline, χ 2 =8.96, P =0.0113; 8-hour, χ 2 =6.51, P =0.0107; 16-hour, χ 2 =8.40, P =0.0038). Both the 8- and the 16-hour results added to the strength of the baseline result (baseline+8-hour, χ 2 =12.04, P =0.0072; baseline+16-hour, χ 2 =13.52, P =0.0036). Only age and ST-segment elevation were stronger predictors of 30-day mortality than baseline cTnT; results were similar for prediction of 1-year mortality. Most of the mortality difference between cTnT-positive and -negative patients occurred within the first 30 days. Conclusions —The cTnT level is a strong, independent predictor of short-term outcome in acute coronary syndromes. The addition of later samples to a baseline level is useful to evaluate the risk of serious cardiac events.

The pathophysiologic basis for potent platelet inhibition in the acute coronary syndromes has been established. In the setting of PTCA for unstable angina and non-Q-wave myocardial infarction, there are clear data for a benefit of GP IIb/IIIa inhibition, whereas for primary PTCA in evolving myocardial infarction, preliminary data are very encouraging and a large-scale clinical trial is nearly completed. Glycoprotein IIb/IIIa inhibition as an adjunct to medical therapy for unstable angina is also the subject of encouraging preliminary data, and 3 large-scale clinical trials have just been completed. Preliminary data have also been accrued for GP IIb/IIIa inhibition as conjunctive therapy with thrombolytic agents, and large clinical trials are now commencing.

Background —Impaired platelet function has been reported in acute myocardial infarction (AMI) and stroke. However, prospective data on the changes of platelet status in patients before the occurrence of hemorrhagic stroke after thrombolytic therapy are unavailable. Case Description —An 86-year-old male patient was among the 23 AMI patients enrolled in the platelet study for the GUSTO-III trial. He received 325 mg of aspirin daily for at least 6 years, suffered an AMI, and was successfully reperfused with alteplase, but after 44 hours developed a large hemorrhagic stroke resulting in paraplegia. Platelet aggregation and receptor expression were measured by flow cytometry and ELISA before thrombolysis and at 3, 6, 12, and 24 hours thereafter. The percentage of platelet aggregation was lower in the stroke patient at every time point when induced by 5 μmol/L of ADP, by 10 μmol/L of ADP, and by thrombin than in the rest of the AMI group. Ristocetin and collagen-induced aggregability were within the group range. Decreased platelet glycoprotein Ib, IIb, IIIa, and IIb/IIIa and vitronectin receptor expression were observed in the stroke patient. No other differences in p24 (CD9), very late antigen-2, P-selectin, and platelet/endothelial cell adhesion molecule-1 expression were determined. Conclusions —Profound depression of platelet status preceded the occurrence of hemorrhagic stroke in an elderly long-term aspirin user treated with thrombolytic therapy. Initial “exhausted” platelets may be responsible for the increased risk for hemorrhagic stroke after coronary thrombolysis.

OBJECTIVE To compare baseline characteristics, complications, and treatment-specific outcomes of women and men with acute myocardial infarction treated with thrombolytic therapy. DESIGN Randomized controlled trial. PATIENTS AND SETTING A total of 10315 women and 30706 men with acute myocardial infarction treated in 1081 hospitals in 15 countries as part of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I). INTERVENTION One of four thrombolytic regimens: (1) streptokinase with subcutaneous heparin; (2) streptokinase with intravenous heparin; (3) streptokinase plus alteplase (tissue-type plasminogen activator) with intravenous heparin; or (4) accelerated alteplase with intravenous heparin. MAIN OUTCOME MEASURES Mortality, stroke, and nonfatal complications during 30-day follow-up. RESULTS Women were on average 7 years older than men and delayed 18 minutes (median) longer after symptom onset before presenting to the hospital. After adjustment for age, women more often had a history of diabetes, hypertension, and smoking than men. Time to treatment was significantly longer in women (1.2 vs 1.0 hours; P

BACKGROUND Differences in the management of acute myocardial infarction have been reported among countries, but few studies have investigated this issue in regions of the United States. METHODS We compared the management of acute myocardial infarction among census regions across the United States, using data from the first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial (GUSTO-1) comprising 21,772 patients, and from the American Hospital Association. RESULTS We found substantial regional variation in the management of acute myocardial infarction in the United States. Beta-blockers (prescribed for a range of 55 to 81 percent of patients in the various regions), nitrates (prescribed for 61 to 77 percent), and angiotensin-converting-enzyme inhibitors (prescribed for 18 to 23 percent) were used most often in New England, whereas calcium-channel blockers (31 to 42 percent) and lidocaine (14 to 43 percent) were used least often there. Similarly, the proportion of patients undergoing various cardiac procedures differed among regions (range for angiography, 52 to 81 percent of patients; angioplasty, 22 to 35 percent; and coronary-artery bypass surgery, 9 to 17 percent) and was lowest in New England. The regional use of cardiac procedures was closely related to their availability, except in New England. After the analysis was adjusted for clinical and hospital variables, patients in New England were found to be less likely to undergo angiography than patients in the other regions (odds ratio, 0.37; 95 percent confidence interval, 0.32 to 0.42). There was no apparent relation between the use of cardiac procedures and rates of recurrent infarction or death at 30 days or 1 year. CONCLUSIONS There is substantial regional variation in the use of cardiac medications and procedures to manage acute myocardial infarction in the United States. The use and availability of cardiac procedures are closely related. The management of acute myocardial infarction in New England is atypical in that the relatively limited availability of cardiac procedures does not account for their relatively low use in that region.

Aims Bleeding complications have been associated with short-term mortality in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Their association with long-term outcomes is less clear. This study examines mortality associated with in-hospital bleeding during NSTEMI over time intervals starting from hospital discharge and extending past 3 years. Methods and results We studied 32 895 NSTEMI patients aged ≥65 years, using patient-level data from the CRUSADE registry linked with Medicare claims data. We assessed the association of in-hospital major bleeding with short (30 days), intermediate (1 year), and long-term (3 years) mortality among hospital survivors overall, as well as in those patients treated with or without a percutaneous coronary intervention (PCI). We calculated adjusted hazard ratios (HRs) for mortality for bleeders vs. non-bleeders over time intervals from: (i) discharge to 30 days; (ii) 31 days to 1 year; (iii) 1 year to 3 years; and (iv) beyond 3 years. Overall, 11.9% ( n = 3902) had an in-hospital major bleeding event. Cumulative mortality was higher in those who had a major bleed vs. those without at 30 days, 1 year, and 3 years. Even after adjustment, major bleeding continued to be significantly associated with higher mortality over time in the overall population: (i) discharge to 30 days [adjusted HR 1.33; 95% confidence interval (CI) 1.18–1.51]; (ii) 31 days to 1 year (1.19; 95% CI 1.10–1.29); (iii) 1 year to 3 years (1.09; 95% CI 1.01–1.18), and (iv) attenuating beyond 3 years (1.14; 95% CI 0.99–1.31). In-hospital bleeding among patients treated with PCI continued to be significantly associated with higher adjusted mortality even beyond 3 years (1.25; 95% CI 1.01–1.54). Conclusion In-hospital major bleeding is associated with short-, intermediate-, and long-term mortality among older patients hospitalized for NSTEMI—this association is strongest within the first 30 days, but remains significant long term, particularly among PCI-treated patients. Despite a probable early hazard related to bleeding, the longer duration of risk in patients who bleed casts doubt on its causal relationship with long-term mortality. Rather, major bleeding likely identifies patients with an underlying risk for mortality.

Patients with established atherothrombosis are at high risk of cardiovascular events. The risk of recurrent events and the severity of those events are unclear. We evaluated the risk of initial and recurrent cardiovascular events in patients in the REACH Registry, an international cohort of