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The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called 'real-world', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Real-world data (RWD) has been defined as data generated outside of traditional randomized clinical trials (RCTs). Though RWD has received increasing attention from regulatory authorities and professional societies, dividing evidence into that derived from 'real-world' vs. 'non-real-world' sources provides only one element of a much larger framework for evidence evaluation. Evidence should be evaluated on the source of the data, the method of treatment allocation (whether any intervention being evaluated was assigned or simply observed as used in practice) and the context in which the evidence was generated (overall study design). Under this framework, RWD refers only to data source, and a study incorporates RWD when it primarily uses data collected for non-research purposes, such as insurance claims data or the electronic health record, regardless of study design. Separation of study design, data source, and context enables parallel evaluation of two critical elements: (i) whether a study can support claims of causal inference, which can be assured with a high degree of confidence only in studies where patients are assigned treatments by protocol; and (ii) whether the study population and clinical context mirror clinical practice, a strength of observational studies using data from clinical practice or administrative claims. In this review, we describe the strengths and weaknesses of observational and non-observational studies, and studies involving RWD and non-RWD, through the lens of anticoagulation for atrial fibrillation (AF). Observational studies employing RWD are useful for describing how oral anticoagulants are used in clinical practice, but generally cannot be used to make claims regarding comparative treatment effects. Questions regarding treatment effect generally are best answered through an RCT, and additional pragmatic RCTs are needed to compare different antithrombotic agents for the prevention of thrombotic events in AF.

Aim: Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation., Methods and Results: Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6)., Conclusion: In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial., Methods and Results: ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban., Conclusions: Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors., Methods and Results: Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11)., Conclusion: Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: Vascular disease is included in a risk scoring system to predict stroke in patients with non-valvular atrial fibrillation (AF). This post hoc analysis of ROCKET AF aimed to determine the absolute rates of stroke and bleeding, and the relative effectiveness and safety of rivaroxaban vs. warfarin in patients with and without peripheral artery disease (PAD). Peripheral artery disease was defined on the case-report form as the presences of intermittent claudication, amputation for arterial insufficiency, vascular reconstruction, bypass surgery, or percutaneous intervention to the extremities, or previously documented abdominal aortic aneurysm., Methods and Results: ROCKET AF was a double-blind, double-dummy, randomized-controlled trial comparing rivaroxaban and warfarin for the prevention of stroke or systemic embolism. A total of 839 (5.9%) patients in ROCKET AF had PAD. Patients with and without PAD had similar rates of stroke or systemic embolism [HR: 1.04, 95% CI (0.72, 1.50), P = 0.84] and major or non-major clinically relevant (NMCR) bleeding [HR: 1.11, 95% CI (0.96, 1.28), P = 0.17], respectively. The efficacy of rivaroxaban when compared with warfarin for the prevention of stroke or systemic embolism was similar in patients with PAD (HR: 1.19, 95% CI: 0.63-2.22) and without PAD (HR: 0.86, 95% CI: 0.73-1.02; interaction P = 0.34). There was a significant interaction for major or NMCR bleeding in patients with PAD treated with rivaroxaban compared with warfarin (HR: 1.40, 95% CI: 1.06-1.86) compared with those without PAD (HR: 1.03, 95% CI: 0.95-1.11; interaction P = 0.037)., Conclusion: Patients with PAD in ROCKET AF did not have a statistically significant higher risk of stroke or systemic embolism than patients without PAD, and there were similar efficacy outcomes in patients treated with rivaroxaban and warfarin. In PAD patients, there was a higher risk of major bleeding or NMCR bleeding with rivaroxaban when compared with warfarin (interaction P = 0.037). Further investigation is warranted to validate this subgroup analysis and determine the optimal treatment in this high-risk cohort of AF patients with PAD.

Aims: We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients., Methods and Results: In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73-1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59-3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10)., Conclusion: Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.

Aims: Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages., Methods and Results: We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban., Conclusion: Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.

Aims: To determine whether predictors of sudden cardiac death (SCD) vary with time after myocardial infarction (MI)., Methods and Results: We analysed 11 256 patients enrolled in VALIANT. Landmark analysis and Cox proportional hazards modelling were used to predict SCD during hospitalization, from discharge to 30 days, 30 days to 6 months, and 6 months to 3 years. The cumulative incidence of SCD was 8.6% (n = 965). Initially, higher baseline heart rate [HR 1.20 per 10 b.p.m. (95% CI 1.06-1.37)] and impaired baseline creatinine clearance [HR 0.82 per 10 mL/min (95% CI 0.74-0.91)] were stronger predictors of SCD. With long-term follow-up, prior MI [HR 1.71 (95% CI 1.39-2.10)], initial left ventricular ejection fraction <40% [HR 0.67 per 10% (95% CI 0.58-0.78)], and recurrent cardiovascular events [HR 1.47 for rehospitalization (95% CI 1.17-1.86)] were more robust risk stratifiers for SCD. Atrial fibrillation post-MI was associated with an increased risk of SCD over the entire follow-up period. As time passed, the associations between baseline clinical characteristics and SCD decreased and time-updated assessments became more important., Conclusion: Predictors of SCD change with time after MI. Future studies of risk stratification for SCD should account for changes in these factors with time after MI.

Aims: The risk of gastrointestinal (GI) bleeding limits the use of antiplatelet and anticoagulant drugs. Risk factors for GI bleeding in post- myocardial infarction (MI) patients have not been well defined. We sought to identify risk factors for GI bleeding in patients following MI., Methods and Results: The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) enrolled 14 703 post-MI patients with left ventricular dysfunction and/or heart failure and followed them for a median of 24.7 months. In the present secondary analysis, times from baseline to first GI bleeding were identified from the VALIANT serious adverse event database. Potential risk factors were explored from medical history, demographics, clinical profile, and medications, both at baseline and during follow-up. We also explored the relationship between the occurrence of GI bleeding and subsequent mortality. During follow-up, 98 (0.7%) patients had a serious GI bleeding event. These patients were older, had more comorbidities, were more likely to be taking additional antiplatelet drugs, and had worse left ventricular systolic and renal function. The Kaplan-Meier estimated rate of GI bleeding at 6 months was 0.37% (95% CI 0.27-0.47). In a multivariable Cox model, dual antiplatelet therapy was the most powerful predictor of GI bleeding, with an adjusted hazard ratio of 3.18 (95% CI 1.91-5.29). Other predictors were non-white race, history of alcohol abuse, increasing age, worse New York Heart Association class, anticoagulant therapy, diabetes, lower estimated glomerular filtration rate, and male sex. Gastrointestinal bleeding was associated with increased risk of death [adjusted hazard ratio 2.54 (95% CI 1.66-3.89)]., Conclusion: Following MI, clinical characteristics can identify patients with increased risk of GI bleeding. The use of dual antiplatelet agents appears to be the most profound risk factor. Whether these patients would benefit from GI prophylaxis therapy remains unknown.

Aims: The number of patients presenting with an acute myocardial infarction (MI) and prior coronary artery bypass grafting (CABG) is increasing. We compared the baseline characteristics, treatment, and clinical outcomes of patients with and without prior CABG in the VALIANT trial., Methods and Results: Of the 14 703 patients with heart failure (HF), left ventricular systolic dysfunction, or both enrolled in VALIANT, 1026 (7%) had prior CABG. Prior CABG patients were older [mean age (SD): 67 (10) vs. 65 (12) years; P < 0.0001], had more comorbidity, and more frequent non-Q wave MI (66 vs. 30%; P < 0.0001). At hospital presentation, prior CABG patients received less aspirin (82 vs. 90%; P < 0.0001) and thrombolysis (21 vs. 36%; P < 0.0001), but had a similar rate of primary percutaneous coronary intervention (14 vs. 15%; P = 0.2). Prior CABG patients were more likely to experience the composite outcome of cardiovascular death, MI, HF, resuscitated cardiac arrest, or stroke; 3 year Kaplan-Meier rate, 64 vs. 39% (adjusted hazard ratio 1.29, 95% confidence interval 1.17-1.43; P < 0.0001)., Conclusion: Patients with prior CABG had a worse clinical profile and experienced more fatal and non-fatal outcomes. Greater recognition is necessary for these high-risk patients including optimization of evidence-based secondary preventive therapy.

Aims: Elderly patients are at high risk from non-ST-segment elevation acute coronary syndromes (NSTE ACS) as well as from treatment-related complications. Age-associated changes in physiology may alter the risk and benefit expected from therapy. The SYNERGY database was used to study the influence of age on treatment outcomes with enoxaparin vs. unfractionated heparin (UFH) in patients with high-risk NSTE ACS., Methods and Results: Age was analysed as a continuous and categorical variable (<65, 65-74, and >or=75 years, and <75 and >or=75 years) for descriptive purposes. Logistic regression was used to adjust the outcomes of 30-day death, death or myocardial infarction (MI), and major bleeding for baseline characteristics. Odds ratios compared outcomes by age and by treatment within age groups. Model interaction terms were used to test for statistically different outcomes by treatment and age. Overall, 9977 randomized patients had age information, of whom 25.5% (2540) were >or=75 years of age. Elderly patients (>or=75 years) had more cardiovascular risk factors, prior cardiac disease, and higher acuity at presentation. After adjustment, advanced age (per 10 years) was associated with 30-day death or MI [risk odds ratios (ROR): 1.14, P = 0.002], 30-day death (ROR: 1.54, P < 0.0001), and 1-year death (ROR: 1.47, P < 0.0001), as well with TIMI major bleeding (ROR: 1.21, P = 0.001), GUSTO severe bleeding (ROR: 1.20, P = 0.047), and transfusion (ROR: 1.04, P = 0.324). Although there was a higher rate of GUSTO severe bleeding noted with enoxaparin in elderly patients, the overall relationships between treatment (UFH or enoxaparin) and outcomes did not vary significantly as a function of the patient's age., Conclusion: Although higher rates of adverse events are seen in the oldest subgroup (age >or=75 years) treated with enoxaparin, statistical comparisons confirm similar efficacy and safety of enoxaparin and UFH across age subgroups as was demonstrated overall in SYNERGY.

Aims: Non-invasive risk stratification of low- and intermediate-risk non-ST-elevation acute coronary syndromes (NSTE ACS) patients has been recommended, but limited data exist about the variation in clinical practice of stress testing in these patients and the impact of such testing on their outcomes., Methods and Results: Patients with NSTE ACS enrolled in the GUSTO IIb (Global Use of Strategies To Open occluded coronary arteries in acute coronary syndromes-IIb) trial (n = 8011) were analysed to evaluate patterns of stress testing in US and non-US patients and to further evaluate the clinical characteristics, procedure use, and outcomes of patients who underwent stress testing compared with those who did not. Stress testing was performed in 1878 (24%) patients. Compared with patients not undergoing stress testing, those undergoing stress testing had low-risk characteristics and significantly lower death (0.6% vs. 4.8%), and death or myocardial infarction (MI, 3.9% vs. 11%) rates at 30 days. Stress testing was performed as often after as before coronary angiography. Importantly, stress testing was helpful in stratifying patients into low (equivocal or negative test) or high (positive test) risk groups (30 day death 3.1% vs. 5%). Stress testing was performed more often in non-US than US patients, and US patients were 3.5 times more likely to undergo imaging as part of stress testing. However, the risks of 30-day death or MI; 6-month death, MI or revascularization; and 1-year death did not differ between US and non-US patients., Conclusion: Stress testing is commonly performed in low-risk NSTE ACS patients and provides modest additional prognostic information in this cohort. Significant geographical variation exists in the use of stress testing. Therefore, in the current practice environment where cardiac catheterization is often the first diagnostic modality used in patients with NSTE ACS, the role of non-invasive testing both before and after invasive procedure is in need of further study.

Aims: We sought to assess the incidence of and prognostic factors for heart failure (HF) hospitalization among survivors of high-risk acute myocardial infarction (MI)., Methods and Results: We assessed the risk of an initial hospitalization for HF in 11 040 stable MI patients (no major non-fatal cardiovascular events or deaths within 45 days of randomization) without a prior history of HF enrolled in the VALIANT trial. Multivariable models were developed to identify independent predictors of HF and HF or cardiovascular death. Of 11 040 stable post-MI patients, 1139 (10.3%) developed HF during the median 25-month follow-up at a rate of approximately 3.4% per year. Most patients, 824 (72.3%), did not have a symptomatic recurrent MI between randomization and the onset of HF. The most important predictors of HF were older age, antecedent diabetes, prior MI before index MI, and reduced renal function. HF markedly increased the risk of death [HR(hazard ratio) 8.22; 95% CI(confidence interval), 7.49-9.01]., Conclusion: HF post high risk-MI occurs in a time-dependent fashion and is usually not directly related to re-infarction. Patients who experience HF beyond the acute phase have increased mortality. Long-term survivors of high-risk MI should be followed closely and treated aggressively beyond the acute MI period.

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.

Antithrombotic therapy and invasive risk stratification in selected high-risk patients have improved outcomes from non-ST-segment elevation acute coronary syndromes (NSTE-ACS), but carry a risk of bleeding and blood transfusion. Although the true incidence of bleeding depends on the population studied (i.e. clinical trial vs. registry), the definition used, and the use of invasive procedures, it is becoming clear that bleeding is associated with an increased risk for adverse outcomes including myocardial infarction and death. Blood transfusion itself may carry a risk for ischaemic outcomes that is independent of bleeding. Therefore, therapies that provide an adequate level of anticoagulation to reduce ischaemia while simultaneously minimizing the risk of bleeding and transfusion have the potential to improve outcomes among patients with NSTE-ACS. Anticoagulants studied in recent clinical trials that have focused on bleeding reduction include fondaparinux and bivalirudin. In this review, we discuss the clinical trial evidence for these agents, the association between bleeding and clinical outcomes, the biology of blood transfusion and potential mechanisms underlying its association with adverse outcomes, and propose strategies to deal with bleeding complications. Future directions for research and clinical practice are also discussed.

Aims: Patients with myocardial infarction (MI) presenting immediately after symptom onset may be treated less aggressively due to their non-elevated troponin status. We compared the initial treatment and clinical outcomes of patients presenting with evolving MI (EMI) with those presenting with MI., Methods and Results: This study analysed data from the Superior Yield of the New strategy of Enoxaparin, Revascularisation, and Glycoprotein IIb/IIIa inhibitors (SYNERGY) trial, which enrolled patients meeting at least two of the following: age >or= 60 years, elevated cardiac biomarkers, or ST-segment changes. Patients were stratified by troponin results obtained within 12 h of presentation: EMI [initial troponin (-), second troponin (+)], MI [initial troponin (+)], and no MI at enrolment [first and second troponin (-)]. Comparisons were made using Wilcoxon rank-sum and chi(2) tests. Of the 8,309 patients with complete data, 5,503 (66%) had MI, 1,686 (20%) had EMI, and 1,120 (13%) had no MI. Treatment patterns prior to enrolment were similar among EMI and MI patients [aspirin (88 vs. 86%), beta-blockers (62 vs. 61%), heparin (83 vs. 81%), and glycoprotein IIb/IIIa inhibitors (23 vs. 24%)]. Similar rates of percutaneous coronary intervention (48 vs. 50%) and coronary artery bypass grafting (21 vs. 22%) were seen after enrolment. Patients presenting with MI had a higher rate of death or recurrent MI compared with patients with EMI [16 vs. 13%, adjusted OR 1.22 (95% CI 1.04, 1.44)]., Conclusion: Initial treatment patterns were similar among patients with EMI and MI in the SYNERGY trial. Patients with EMI had lower rates of death or re-infarction at 30 days compared with patients presenting with positive troponin results.

Aims: Multiple studies have focused on the relationship of body anthropometric measures with clinical events in ST-elevation myocardial infarction (STEMI) patients, highlighting the 'obesity paradox'. However, the relative prognostic importance of these measures over other baseline variables is less known., Method and Results: We performed a retrospective analysis of 94,108 STEMI patients from seven clinical trials evaluating various reperfusion strategies to study the relationship and prognostic importance of height, weight, body mass index (BMI), and body surface area (BSA) with 30-day death and in-hospital cardiogenic shock, major bleeding, and stroke. Main outcome measures of interest included 30-day death and in-hospital cardiogenic shock, major bleeding, and stroke. Weight, BMI, and BSA were inversely and independently related to all clinical events. Despite being statistically significant (P<0.0001), the prognostic information contributed by weight beyond that conferred by baseline clinical factors was minimal (<1% of total prognostic information) making it of limited clinical relevance for predicting 30-day death and cardiogenic shock. In contrast, weight accounted for 8.4% and 4.3% of the prognostic information in the logistic regression models for major bleeding and for stroke. BMI or BSA added little incremental value over simple measure of weight., Conclusion: Although statistically significantly related to most outcomes in patients with STEMI including death and shock, body weight provided clinically relevant prognostic information only for the risk of major bleeding and of stroke. Furthermore, BMI or BSA contributed little incremental prognostic information beyond that provided by weight alone. Thus, the existing large body of information concerning the strong prognostic importance of anthropometric measures with outcomes after STEMI should be interpreted in the context of other more important risk factors.

Aims: To assess the significance of creatine kinase (CK)-MB elevations in outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who have undergone coronary artery bypass grafting (CABG) surgery., Methods and Results: This analysis includes data from 26 465 patients with NSTE ACS enrolled in four major trials. In total, 4626 (17.5%) of patients had CABG within 30 days. Patients were excluded if CK-MB was elevated within 24 h before surgery and there was no CK-MB measured after surgery. Overall, 4401 patients were included in these analyses. The incidence of mortality increased with peak CK-MB ratios of 0-1, >1-3, >3-5, >5-10, and>10x the upper limit of normal measured at the local lab (P<0.001 across categories): 1.1, 2.8, 2.4, 3.1, and 10.8% in hospital; 1.1, 3.0, 2.9, 3.5, and 10.2% at 30 days; and 1.6, 4.4, 4.7, 6.0, and 10.9% at 180 days. Multivariable predictors of 6-month mortality included age, heart rate and randomization, peak CK-MB ratio, time to CABG, prior angina, signs of congestive heart failure and randomization, three- and two-vessel coronary disease, enrolment infarction, ST-segment depression at enrolment, female sex, experimental treatment, and systolic blood pressure., Conclusion: CK-MB elevations after CABG are independently associated with increased risk of mortality in patients with NSTE ACS.

Aims: Stroke is an uncommon but serious complication after non-ST-segment elevation acute coronary syndrome (NSTE-ACS). We aimed to identify predictors of stroke within 30 days in patients who suffered NSTE-ACS., Methods and Results: We pooled data from six trials (n=31 402) that randomized NSTE-ACS patients either to platelet glycoprotein (GP) IIb/IIIa receptor blockers or to placebo/control therapy. Potential predictors of stroke included treatment, demographic, and clinical characteristics. We identified predictors using univariable and multivariable logistic models, and their performance was evaluated with calibration (Hosmer-Lemeshow test) and discrimination (c-statistic). We found 228 (0.7%) all-cause strokes: 155 (0.5%) non-haemorrhagic, 20 (0.06%) haemorrhagic, and 53 without computed tomography (CT) confirmation. Patients with any type of stroke had a 30-day mortality of 25%. Randomization to GP IIb/IIIa receptor blockers was not significantly associated with all-cause stroke [OR (95% CI) 1.08 (0.83-1.41)]. Older age [OR per 10-year increase 1.5 (1.3-1.7)], prior stroke [2.1 (1.4-3.1)], and elevated heart rate [per 10-beat increase 1.1 (1.0-1.2)] were the strongest predictors of 30-day all-cause stroke. Similar predictors were found for non-haemorrhagic and haemorrhagic strokes. Smoking, previous myocardial infarction, diabetes, and hypertension were not independent predictors of all-cause stroke. The multivariable model to predict all-cause stroke was well calibrated, but its discrimination was only moderate [c-statistic 0.69 (0.65-0.72)]., Conclusion: Stroke is a rare complication occurring early after NSTE-ACS, but is associated with high mortality. We found no evidence that GP IIb/IIIa receptor blockers increase stroke risks. A few clinical characteristics predicted higher stroke risks. Thus, incident strokes in NSTE-ACS patients remain largely unexplained.

Aims: To explore variations in invasive care of the elderly with acute coronary syndromes across international practice., Methods and Results: Using combined populations from the SYMPHONY and 2nd SYMPHONY trials, we describe 30-day cardiac catheterization in elderly (> or = 75 years; n = 1794) vs. younger patients (< 75 years; n = 14,043) after multivariable adjustment and by region of enrolment. The use of cardiac catheterization and revascularization were not protocol-specified. Elderly patients (median age 78 years) were more often female and more frequently had hypertension, diabetes, prior myocardial infarction, and prior coronary bypass surgery. Overall, they underwent less cardiac catheterization than younger patients [53 vs. 63%; adjusted OR 0.53 (0.46, 0.60)]. The absolute rate of cardiac catheterization in the elderly varied from 77% (vs. 91% in younger patients) in the US cohort to 27% (vs. 41% in younger patients) in the non-US cohort. Revascularization of elderly who underwent cardiac catheterization was also higher in US than non-US cohorts (71.3 vs. 53.6%). There was a significant interaction between the patient age and the use of catheterization across US and non-US regions of enrolment, as well as differences in the predictors of catheterization in the elderly. Despite these findings, after adjustment, 90-day rates of death and death or myocardial infarction (MI) were not significantly different in elderly who underwent catheterization compared with those who did not., Conclusion: Although older age is universally predictive of lower use of cardiac catheterization, marked variation in catheterization of the elderly exists across international practice. Demonstrated differences in patterns of use suggest a lack of consensus regarding optimal use of an invasive strategy in the elderly.

Aims: To examine the relationship between revascularization within 7 days and 1-year mortality among ST-elevation myocardial infarction patients enrolled in GUSTO-V trial (n=13 451). To examine the relative contribution of system and patient level factors to the variation in international revascularization rates, and their impact on mortality outcomes., Methods and Results: Patients from North America (USA, Canada), Australia, and Europe (UK, France, Germany, Italy, Spain, Poland, Norway, The Netherlands, Belgium, Finland) were included in the study. Revascularization was associated with lower 1-year mortality. Norway, Belgium, Spain, Poland, and Italy also had lower than expected revascularization rates but higher than expected mortality rates. France and USA had almost two times the expected rate of 7-day revascularization, which was associated with modest mortality benefits. Patients' propensity for revascularization based on clinical factors alone was associated with lower 1-year mortality (OR 0.97, 95% CI: 0.96-0.99). Country-level factors had an impact on propensity for revascularization but no impact on 1-year mortality., Conclusion: Our study reveals the potential for some countries with lower than expected 7-day revascularization rates to improve their clinical outcomes. Also highlighted is the possibility for more economically efficient delivery of care in USA and France.

Aims: To evaluate whether there is an association between 30-day mortality in patients with ST-segment elevation myocardial infarction (STEMI) included in clinical trials and country gross national income (GNI)., Methods and Results: A retrospective analysis of the databases of five randomized trials including 50 310 patients with STEMI (COBALT 7169, GIK-2 2931, HERO-2 17,089, ASSENT-2 17,005, and ASSENT-3 6116 patients) from 53 countries was performed. Countries were divided into three groups according to their GNI based on the World Bank data: low (less than 2900 US dollars), medium (between 2900 US dollars and 9000 US dollars), and high GNI (more than 9000 US dollars per capita). Baseline characteristics, in-hospital management variables, and 30-day outcomes were evaluated. A previously defined logistic regression model was used to adjust for differences in baseline characteristics and to predict mortality. The observed mortality was higher than the predicted mortality in the low (12.1 vs. 11.8%) and in the medium income groups (9.4 vs. 7.9%), whereas it was lower in the high income group (4.9 vs. 5.6%)., Conclusion: An inverse relationship between mortality and GNI was observed in STEMI clinical trials. Most of the variability in mortality can be explained by differences in baseline characteristics; however, after adjustment, lower income countries have higher mortality than the expected.

Aims: We sought to assess the relative contribution of heart failure (HF) on admission for an acute myocardial infarction (MI) to the subsequent in-hospital stroke risk., Methods and Results: The VALsartan In Acute myocardial iNfarcTion (VALIANT) registry enrolled 5573 consecutive MI patients at 84 international sites from 1999 to 2001. We calculated odds ratios (ORs) for stroke and adjusted for baseline characteristics, Killip Class, and risk factors for stroke, such as diabetes and prior HF. In-hospital stroke occurred in 81 (1.5%) patients. HF was present on admission in 38% of patients who developed a stroke and in 24% who did not (P=0.001). Older age (OR 1.03 increase/year, 95% confidence interval (CI) 1.01-1.04), Killip Class III (OR 1.66, CI 0.86-3.19) or IV (OR 4.85, CI 1.69-13.93), history of hypertension (OR 1.73, CI 1.06-2.82), and history of stroke (OR 1.89, CI 1.06-3.37) were more common in patients who had in-hospital stroke. In-hospital mortality in patients with and without stroke was 27.2 and 6.5%, respectively (P<0.001)., Conclusion: Patients with stroke after MI have a dismal prognosis. The presence of HF on admission for an acute MI increases in-hospital stroke risk. HF treatments may modify the risk of stroke.

Aims: We sought to determine whether the extent of myocardial ischaemia on the admission electrocardiogram (ECG) has independent predictive value for short-term risk stratification of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). Although the presence of ischaemic ECG changes on admission has been shown to predict outcome, the relationship between the extent of ECG changes and the risk of cardiac events is still ill defined., Methods and Results: We analysed the admission ECGs of 5192 ACS patients enrolled in the GUSTO-IIb trial, without an ECG indication for thrombolysis. ECG tracings showing one or more of the following were eligible: ST-segment depression >0.5 mm, T-wave inversion >1 mm, and ST-segment elevation >0.5 mm but <1 mm. ECG variables associated with unfavourable 30 day outcomes in a univariable analysis were further assessed in a multivariable logistic regression model including independent clinical predictors. In the multivariable clinical, enzymatic, and ECG model, the sum of ST-segment depression (in millimetres) in all leads was a powerful independent predictor of 30 day death (P<0.0001), with a continuous increase in risk with the extent of ST-segment depression. The sum of ST-segment depression (P<0.0001) and the presence of minimal inferior ST-segment elevation (P<0.0001) or anterior ST-segment elevation (P=0.0182) were also independent predictors of the composite of death and myocardial infarction or reinfarction. The extent of ST-segment depression showed a highly significant correlation with the prevalence of three-vessel (P<0.0001) or left main coronary disease (P<0.0001), and also with the peak levels of creatine kinase (P<0.0001) during the index episode of ACS., Conclusion: In patients with NSTE ACS, the sum of ST-segment depression in all ECG leads is a powerful predictor of all-cause mortality at 30 days, independent of clinical variables and correlates with the extent and severity of coronary artery disease. The presence of even minimal (<1 mm) ST-segment elevation in anterior or inferior leads is independently associated with adverse outcomes.

Aims: We sought to characterize the outcomes of patients with a prior percutaneous coronary intervention (PCI) who presented with a non-ST-segment elevation acute coronary syndrome (ACS)., Methods and Results: We analysed the 30 and 180 day outcomes of 3012 patients with prior PCI and 21 154 patients without prior PCI enrolled in three randomized ACS trials (GUSTO IIb, PURSUIT, and PARAGON-B). The median (25th, 75th percentile) interval between the prior PCI and randomization was 647 (123, 1585) days. Patients with prior PCI had significantly more adverse baseline clinical characteristics, left ventricular dysfunction, and multi-vessel coronary artery disease. After adjusting for baseline characteristics and treatment, we found that patients with prior PCI had a significantly lower mortality rate at 30 days [hazard ratio (HR), 0.60; 95% confidence interval (CI), 0.45-0.80; P=0.0006] and 180 days (HR, 0.81; 95% CI, 0.66-0.98; P=0.029). However, no difference was observed in the composite of death or myocardial infarction (MI) at 30 days (HR, 0.95; 95% CI, 0.83-1.08; P=0.42) or 180 days (HR, 1.01; 95% CI, 0.90-1.13; P=0.90). Patients with prior PCI had a higher rate of MI at 180 days (13.3 vs. 12.0%; P=0.045). Prior-PCI patients had lower incidences of in-hospital cardiogenic shock, congestive heart failure (CHF), and atrial fibrillation., Conclusion: Patients with prior PCI who present with non-ST-segment elevation ACS have a lower mortality rate than those without prior PCI.

Aims: We analysed the contemporary incidence, outcomes, and predictors of heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) before discharge in patients with acute myocardial infarction (MI). The baseline presence of HF or LVSD, or its development during hospitalisation, increases short- and long-term risk after MI, yet its incidence, predictors, and outcomes have not been well described in a large, international, general MI population., Methods and Results: The VALIANT registry included 5573 consecutive MI patients at 84 hospitals in nine countries from 1999 to 2001. A multivariable logistic survival model was constructed using baseline variables to determine the adjusted mortality risk for those with in-hospital HF and/or LVSD. Baseline variables were also tested for associations with in-hospital HF and/or LVSD. Of the 5566 patients analysed, 42% had HF and/or LVSD during hospitalisation. Their in-hospital mortality rate was 13.0% compared with 2.3% for those without HF and/or without LVSD. After adjustment for other baseline risk factors, in-hospital HF and/or LVSD carried a hazard ratio for in-hospital mortality of 4.12 (95% confidence interval: 3.08-5.56). Patients with HF and/or LVSD also had disproportionately higher rates of other cardiovascular events., Conclusions: HF and/or LVSD is common in the general contemporary MI population and precedes 80.3% of all in-hospital deaths after MI. Survivors of early MI-associated HF and/or LVSD have more complications, longer hospitalisations, and are more likely to die during hospitalisation. Although baseline variables can identify MI patients at highest risk for HF and/or LVSD, such patients are less likely to receive indicated procedures and medical therapies.

Aims: In high risk patients with non-ST elevation acute coronary syndromes (ACS), enoxaparin is generally preferred to unfractionated heparin (UFH). However, less is known about the relative merits of these two forms of heparin in patients receiving concomitant glycoprotein IIb/IIIa inhibitors., Methods and Results: The A phase of the A-to-Z trial was an open label non-inferiority trial in which 3987 patients with non-ST elevation ACS were randomised to receive either enoxaparin or UFH in combination with aspirin and tirofiban. Inclusion required either ST depression or cardiac biomarker elevation. While the selection of an early management strategy (invasive or conservative) was at the discretion of the local investigator, investigators were asked to designate their plans for an invasive or conservative strategy on the case record form. An early conservative strategy was specified for 1778 patients (45%); this subgroup forms the population for the present analyses. Among patients with a planned conservative strategy, baseline characteristics were similar between those randomised to UFH (n = 872) and those randomised to enoxaparin (n = 906). The primary endpoint of death, new MI, or documented refractory ischaemia within 7 days of randomisation occurred in 10.6% of patients randomised to UFH and 7.7% of patients randomised to enoxaparin (HR 0.72; 95% CI 0.53-0.99; p = 0.04). The combined rate of TIMI major, minor, or loss no-site bleeding was 1.3% in patients treated with UFH and 1.8% in those treated with enoxaparin (p = ns)., Conclusions: When a conservative approach to catheterisation and PCI was planned for ACS patients receiving tirofiban and aspirin, enoxaparin was associated with superior efficacy and similar bleeding vs UFH.

Aim: To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS)., Methods and Results: Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017)., Conclusions: Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.

Aims: We sought to evaluate international patterns of use and factors influencing use of evidence-based medications early after ACS., Methods and Results: Using a database of 15904 ACS patients enrolled in the SYMPHONY and 2nd SYMPHONY trials in 37 countries, we performed descriptive and logistic regression analyses. After controlling for other factors, region was significantly associated with the use of every class of evidence-based medication, most pronounced for intravenous unfractionated heparin (IV UFH), low-molecular-weight heparin (LMWH), angiotensin II converting enzyme inhibitors (ACEI) and discharge use of lipid-lowering agents. Latin America and Eastern Europe were among the highest users of early ACEI, yet the lowest users of discharge lipid-lowering therapy. Relative to the United States, all regions except Canada had greater use of LMWH and lower use of IV UFH. Compared with patients with acute myocardial infarction, those with unstable angina less often received aspirin, beta-blockers, ACEI, or IV UFH. Older age was associated with lower use of aspirin, beta-blockers, IV UFH, and lipid-lowering agents., Conclusions: Use of evidence-based therapies for management of ACS patients is strongly associated with region. To improve patient outcomes, more research is needed to understand this variation, and to institute appropriate solutions.

Background: Intracranial haemorrhage is an important limitation to pharmacologic reperfusion therapy for acute myocardial infarction. The combination of a glycoprotein IIb/IIIa inhibitor, half-dose plasminogen activator and reduced-dose heparin has been evaluated as an alternative to standard fibrinolytic therapy in this setting., Methods and Results: We evaluated the relation between univariate and multivariate predictors of intracranial haemorrhage and the effect of treatment with either reteplase alone (10 U bolus twice, 30 min apart) with standard-dose heparin (5000 U bolus followed by an infusion of 1000 Uh(-1)for patients > or =80 kg and 800 Uh(-1)for those <80 kg) or combination therapy with abciximab (0.25mg/kg bolus and 0.125 microg/kg/min for 12h) and half-dose reteplase (two boluses of 5U 30 min apart) with reduced-dose heparin (60 Ukg(-1)bolus, maximum 5000 U, followed by an infusion of 7 Ukg(-1)h(-1)) in the 16 588 patients randomized in the GUSTO V trial. Overall, the incidence of intracranial haemorrhage was similar in the two groups (0.6% vs 0.6%; OR 1.05, 95% CI 0.71, 1.56). The median (25th-75th) time from drug administration to intracranial haemorrhage was 5.5 (3.4-11) hours with combination therapy and 9.2 (5.9-22) hours with reteplase (P=0.048). Among the multivariable predictors of intracranial haemorrhage, only age showed a significant interaction with treatment effect (age per treatment interaction chi-square 4.60, P=0.032) with a lower risk of combination therapy for younger patients and a higher risk for the elderly., Conclusions: Although no additional risk of intracranial haemorrhage has been observed with combination therapy in the whole population, a significant age pertreatment interaction exists, with a lower risk with combination therapy in younger patients, and a higher risk in the elderly.

Background: Although the prognostic value of admission ST changes in patients with non-ST elevation acute coronary syndrome (ACS) is established, the utility of the discharge ECG is unknown. Accordingly, using the PARAGON-B Troponin substudy, we assessed the prevalence of ST depression on both admission and discharge ECG, the likelihood of developing new Q-waves at discharge and the additional prognostic value of these changes., Methods and Results: Nine hundred and eighteen patients were studied; 542 patients (59%) had admission ST downward arrow > or =1mm and 376 patients (41%) did not and their 6-month mortality was 4.4 vs 0.8%, P=0.002, respectively. Of patients with ST downward arrow on admission, 320 (59%) normalized their ST segment at discharge. Of patients without ST downward arrow on admission, 35 (9.3%) developed new ST downward arrow at discharge. Patients with persistent ST downward arrow on discharge had a higher 6-month mortality (6.0 vs 0.9%), (re)MI (16.3 vs 7.4%), and death/(re)MI (20.0 vs 8.3%) than those who never had ST downward arrow (all P< or =0.002). Two hundred and fifty-six patients had Q-waves on admission whereas by discharge 320 had Q-waves. Patients with Q-waves on discharge vs those without had a higher mortality (4.8 vs 1.9%), (re)MI (13.8 vs 8.3%), and death/(re)MI (16.4 vs 9.6%) at 6 months (all P< or =0.021)., Conclusions: This study highlights that the dynamic ECG changes which occur between admission and discharge in non-ST elevation ACS patients allows further risk stratification in determining the likelihood of 6-month death and/or re(MI).

Aims: We investigated predictors of 90-day risk among patients surviving the early period after an acute coronary syndrome (ACS)., Methods and Results: The study population included 15 904 stabilized ST-segment elevation or non-ST-segment elevation ACS patients randomized in SYMPHONY and 2nd SYMPHONY. We developed risk models for death, death or myocardial infarction (MI), and death, MI, or severe recurrent ischaemia (SRI) using Cox proportional-hazards techniques. Demographic, history, and pre-randomization clinical and medication variables were tested. Validation techniques included development of individual trial models, backward elimination and bootstrapping. Of 118 variables, 17 independently predicted mortality. The strongest associations included greater age (chi(2)=31.1), higher randomization heart rate (chi(2)=27.4), and heart failure (HF) variables (HF between qualifying event and randomization, chi(2)=21.8; history of HF, chi(2)=12.2). Higher creatinine clearance (chi(2)=17.7) and percutaneous coronary intervention between qualifying event and randomization (chi(2)=11.1) most strongly predicted lower risk. Similar characteristics entered the double and triple composite models, but HF variables and age less strongly predicted these end-points., Conclusions: In patients stabilized after ACS, those at highest risk over the next 90 days can be identified. Typical clinical markers are better at identifying risk of death than non-fatal MI or SRI. Novel risk markers are needed for these outcomes.

Aims: We evaluated timing of adverse cardiac events after thrombolysis to guide length of stay after ST-segment elevation myocardial infarction., Methods and Results: Kaplan-Meier survival curves described timing of major postinfarction complications in 41021 fibrinolytic-treated patients in GUSTO-I. Using model-fitting, these data were best explained by a mixed-exponential survival model: an acute curve describing most adverse events and a chronic curve describing a lower background rate. We replicated this strategy in 15059 fibrinolytic-treated patients in GUSTO-III. From the relation between time and events described by the model's acute curve in GUSTO-III, we proposed times for hospital discharge. The acute curve explained 97% of deaths and 68%-96% of various event composites. Of complications within 10 days, 90% of deaths and 70% of acute curve death, stroke, shock, heart failure, or reinfarction occurred by 24 h. By 2.7 days, 95% of deaths, stroke, shock, heart failure, or reinfarction occurred. Most major ventricular arrhythmias occurred within 24 h, after which the hazard curve was flat., Conclusions: Mixed-exponential survival modelling describes timing of post-infarction complications and supports discharge 4 days after uncomplicated infarction. Such time-based risk assessment could guide decision-making in other settings in which randomized studies are impractical.

Aims: We compared the effects of hirudin and heparin on thrombin generation and activity among 350 patients with acute coronary syndromes enrolled in the GUSTO-IIb trial., Methods and Results: We obtained blood at baseline; at 4, 8, and 24h into infusion; at drug termination; and 6 and 24h after termination. We assayed for thrombin activity (fibrinopeptide A, activated protein C, thrombin-antithrombin complex), thrombin generation (prothrombin fragment 1.2), and platelet activation (platelet factor 4). Median baseline fibrinopeptide A and platelet factor 4 levels were elevated. Thrombin formation tended to increase with hirudin and decrease with heparin; by 8h into infusion, thrombin formation was significantly less for heparin (P<0.01). Most patients showed reduced thrombin activity and platelet activation during infusion of either agent. Hirudin-assigned patients had significantly lower fibrinopeptide A levels during infusion. Six h post-termination, both groups had increased thrombin activity. Thrombin formation was increased in heparin patients (P<0.0001), significantly more than with hirudin (P=0.005). Higher values of haemostasis markers tended to be associated with poorer 30-day outcomes., Conclusion: Although hirudin did not prevent generation of new thrombin, it appeared to inhibit thrombin activity more than did heparin and produced slower increases in thrombin formation after discontinuation. The reelevation of thrombotic markers after stopping intravenous antithrombin therapy and the tendency toward increased thrombotic events with post-treatment increases in marker levels suggest an ongoing, clinically significant prothrombotic state. These results raise the possibility of improving on current antithrombotics by preventing thrombin generation and thrombin activity and by sustained suppression of the prothrombotic state., (Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.)

Background: Many patients with acute coronary syndromes are offered percutaneous coronary intervention. However, the appropriate indications for, and optimal timing of, such procedures are uncertain. We analysed timing of intervention and associated events (death and myocardial infarction) in the PURSUIT trial in which 9461 patients received a platelet glycoprotein IIb/IIIa inhibitor, eptifibatide, or placebo for 72 h. Other treatment was left to the investigators. 2430 patients underwent percutaneous coronary intervention within 30 days. Four groups were distinguished, who underwent percutaneous coronary intervention on day 1; on days 2 or 3; at 4 to 7 days; or between 8 until 30 days, for eptifibatide- and placebo-treated patients., Results: The four groups treated with placebo demonstrated total 30-day events of 15.9% for day 1 percutaneous coronary intervention, 17.7%, 15.0% and 18.2%, respectively, for successive intervals of later intervention. Later intervention was associated with more pre-procedural events (2.2% to 13.7%, P=0.001) which was balanced by a decrease in procedure-related events (12.1 to 3.1%, P=0.001), while the overall 30-day event rates were similar. Eptifibatide-treated patients with percutaneous coronary intervention on day 1 had the lowest rate of 30-day events (9.2%, P<0.05 vs other groups). In this group, pre-procedural risk was only 0.3%, while percutaneous coronary intervention on eptifibatide treatment was associated with low procedural risk (7.2%). The total 30-day event rate for later percutaneous coronary intervention in patients receiving eptifibatide was 14.0 on days 2 and 3, 15.0% for days 4 to 7 and 17.4% for days 7 to 30, respectively., Conclusion: Patients treated with a platelet glycoprotein IIb/IIIa receptor blocker, and early percutaneous coronary intervention (within 24 h) had the lowest event rate in this post hoc analysis. Thus 'watchful waiting' may not be the optimal strategy. Rather an early invasive strategy with percutaneous coronary intervention under protection of a platelet glycoprotein IIb/IIIa receptor blocker should be considered in selected patients. Randomized trials are warranted to verify this issue., (Copyright 2001 The European Society of Cardiology.)

Background: Fibrinolytic therapy increases the risk of bleeding events. TNK-tPA (tenecteplase) is a variant of rt-PA with greater fibrin specificity and reduced plasma clearance that can be given as a single bolus. We compared the incidence and predictors of bleeding events after treatment with TNK-tPA and rt-PA., Methods and Results: In the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-2 trial, 16 949 patients with acute myocardial infarction were randomly assigned a single weight-adjusted bolus of TNK-tPA or a 90-min infusion of rt-PA. A total of 4.66% of patients in the TNK-tPA group experienced major non-cerebral bleeding, in comparison with 5.94% in the rt-PA group (P=0.0002). This lower rate was associated with a significant reduction in the need for blood transfusion (4.25% vs 5.49%, P=0.0003) and was consistent across subgroups. Independent risk factors for major bleeding were older age, female gender, lower body weight, enrolment in the U.S.A. and a diastolic blood pressure <70 mmHg. Females at high risk (age >75 years and body weight <67 kg) were less likely to have major bleeding when treated with TNK-tPA even after other risk factors were taken into account. A total of 0.93% of patients in the TNK-tPA and 0.94% of patients in the rt-PA group experienced an intracranial haemorrhage. Female patients >75 years of age who weighed <67 kg tended to have lower rates of intracranial haemorrhage when treated with TNK-tPA (3/264, 1.14% vs 8/265, 3.02%)., Conclusions: The increased fibrin specificity and single bolus administration of TNK-tPA do not increase the risk of intracranial haemorrhage but are associated with less non-cerebral bleeding, especially amongst high-risk patients., (Copyright 2001 The European Society of Cardiology.)

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., (Copyright 2000 The European Society of Cardiology.)

Aims: We examined the characteristics, outcomes, and effects of hirudin vs heparin treatment of diabetic patients across the spectrum of acute coronary syndromes., Methods and Results: We studied the 12,142 patients enrolled in the randomized GUSTO-IIb study. Diabetic patients (n=2175) were older, more often female, more often had prior cardiovascular disease, hypertension, and hyperlipidaemia, and less often were current smokers. Diabetic patients had a higher overall incidence of death or (re)infarction at 30 days (13.1% vs 8.5%, P=0.0001), whether they presented with ST-segment elevation (13.9% vs 9.9%, P=0.0017) or not (12.8% vs 7.8%, P=0.0001), and at 6 months (18.8% vs 11.4%, P=0.0001). Among diabetic patients, hirudin was associated with a tendency toward a lower risk of death or (re)infarction at 30 days (12.2% vs 13.9% with heparin) and 6 months (17.8% vs 20.2%). Diabetic patients had more major bleeding, stroke, heart failure, shock, atrioventricular block, and atrial arrhythmias, but no increased risk for ocular bleeding., Conclusions: Diabetic patients with acute coronary syndromes had worse 30-day and 6-month outcomes, particularly those without ST-segment elevation. The statistically non-significant trend toward improved outcomes with hirudin was similar among patients with and without diabetes, with a greater point estimate for the absolute difference in patients with diabetes.

Aims: Variations in outcome of patients from different geographic regions have been observed in many large international trials. We analysed the factors that might contribute to the geographic variations in patient outcome and treatment effect as observed in the PURSUIT trial., Methods: In PURSUIT, 9461 patients with acute coronary syndromes without persistent ST-elevation were randomized to the platelet inhibitor eptifibatide or placebo for 72 h in 27 countries in four geographic regions: Western (n=3697) and Eastern Europe (n=1541) as well as North (n=3827) and Latin America (n=396). The primary end-point was the 30-day composite of death or myocardial infarction. In the initial univariate analysis, the treatment effect appeared greater in N. America than in W. Europe, while no benefit was apparent in L. America and E. Europe. However, the confidence intervals were wide and overlapping. To study these differences, a subdivision in an early and late patient outcome and treatment effect was made. Accordingly, we analysed the rate of death or infarction at 72 h censored for percutaneous coronary intervention and the rate between 3 and 30 days, respectively. Additional analyses were performed with different definitions of myocardial infarction using progressively higher thresholds of CK(-MB) elevation. Multivariable analysis was used to evaluate the relation between region and outcome and to determine the adjusted odds ratios for the eptifibatide treatment effect., Results: Major differences in baseline demographics were apparent among the four regions; in particular, more patients from E. Europe had characteristics associated with impaired outcome. Interventional treatment also varied considerably, with more patients from N. America undergoing revascularization. Despite differences in the 72 h event rate, eptifibatide showed a consistent trend towards a reduction in the composite end-point among all four regions and for all definitions of infarction. Relative reductions ranged from 17-42% in W. Europe, 23-35% in N. America, 0-33% in E. Europe, and 55-82% in L. America. After multivariable adjustment, the pattern of benefit with eptifibatide was consistent among the regions. In patients undergoing percutaneous coronary intervention during study drug infusion in W. Europe (n=266) and N. America (n=931), the relative reduction in myocardial infarction during medical therapy ranged from 56-75% in W. Europe and 14-67% in N. America, while the reduction in procedure-related events ranged from 12-44% and 25-61% for different definitions of infarction. After multivariable adjustment neither benefit nor rebound were apparent after study drug discontinuation, or after 3 days in all regions, except in L. America. In general, the differences in outcome and treatment effect were greatest when the protocol definition of myocardial infarction (CK(-MB) >1 upper normal limit) was applied. Under stricter definitions, these differences became smaller and disappeared with the investigator's assessment., Conclusion: The analysis suggests that the apparent differences in patient outcome and eptifibatide treatment effect can be explained largely by differences in baseline demographics and adjunctive treatment strategies as well as by the methodology of myocardial infarction definition and the adjudication process., (Copyright 2000 The European Society of Cardiology.)

Aims: Studies on the glycoprotein IIb-IIIa receptor blocker abciximab in patients undergoing percutaneous coronary intervention consistently show a reduction in procedure-related myocardial infarction. Some such infarcts are characterized by elevated creatine kinase or creatine kinase-MB, without apparent clinical symptoms. The clinical relevance of such 'creatine kinase leaks' has been questioned. Therefore we investigated the relationship between post-procedural creatine kinase-MB elevation and outcome at the 6 month follow-up., Methods and Results: Creatine kinase-MB, or total creatine kinase values were analysed in 5025 out of 6156 patients enrolled in the CAPTURE, EPIC and EPILOG studies. A consistent gradual increase in 6 month mortality was observed as creatine kinase-MB or creatine kinase levels increased: 1.1%, 2.1%, 1.8%, 3. 6% and 6.7% for creatine-MB or creatine ratios (relative to upper limit of normal) <1, 1-3, 3-5, 5-10 and >/=10, respectively. Also the incidence of death or (recurrent) myocardial infarction was related to creatine kinase-MB or creatine kinase ratios. Subsequent revascularization was not related to periprocedural myocardial infarction. By multivariable analysis, correcting for clinical and angiographic characteristics, mortality at 6 months was related to the enzyme (creatine kinase, creatine kinase-MB) ratio, a history of heart failure and age. The combined end-point of death and myocardial infarction was also related to these factors, as well as to a history of bypass surgery and unstable angina., Conclusion: Modest elevation of cardiac enzymes (creatine kinase-MB, creatine kinase) after percutaneous coronary intervention is associated with an increased risk of mortality and reinfarction during the 6 month follow-up. Measures to reduce such periprocedural infarcts are warranted., (Copyright 1999 The European Society of Cardiology.)