Phillippe Gabriel Steg

Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE)

Background—Few data are available on the impact of heart failure (HF) across all types of acute coronary syndromes (ACS). Methods and Results—The Global Registry of Acute Coronary Events (GRACE) is a prospective study of patients hospitalized with ACS. Data from 16 166 patients were analyzed: 13 707 patients without prior HF or cardiogenic shock at presentation were identified. Of these, 1778 (13%) had an admission diagnosis of HF (Killip class II or III). HF on admission was associated with a marked increase in mortality rates during hospitalization (12.0% versus 2.9% [with versus without HF], P <0.0001) and at 6 months after discharge (8.5% versus 2.8%, P <0.0001). Of note, HF increased mortality rates in patients with unstable angina (defined as ACS with normal biochemical markers of necrosis; mortality rates: 6.7% with versus 1.6% without HF at admission, P <0.0001). By logistic regression analysis, admission HF was an independent predictor of hospital death (odds ratio, 2.2; P <0.0001). Admission HF was associated with longer hospital stay and higher readmission rates. Patients with HF had lower rates of catheterization and percutaneous cardiac intervention, and fewer received &bgr;-blockers and statins. Hospital development of HF (versus HF on presentation) was associated with an even higher in-hospital mortality rate (17.8% versus 12.0%, P <0.0001). In patients with HF, in-hospital revascularization was associated with lower 6-month death rates (14.0% versus 23.7%, P <0.0001; adjusted hazard ratio, 0.5; 95% CI, 0.37 to 0.68, P <0.0001). Conclusions—In this observational registry, heart failure was associated with reduced hospital and 6-month survival across all ACS subsets, including patients with normal markers of necrosis. More aggressive treatment of these patients may be warranted to improve prognosis.

Extent of, and factors associated with, delay to hospital presentation in patients with acute coronary disease (the GRACE registry)

Our primary study aim was to examine extent of, and factors associated with, delay in seeking medical care in a large multinational registry of patients with acute myocardial infarction (AMI) and unstable angina pectoris. A secondary goal was to examine the relation between duration of prehospital delay and receipt and timing of coronary reperfusion strategies. Investigators from 14 countries are participating in the Global Registry of Acute Coronary Events (GRACE) project. The study sample consisted of 3,693 patients with ST-segment elevation AMI, 2,935 with non-ST-segment elevation AMI, and 3,954 patients with unstable angina hospitalized between 1999 and 2001. The average and median delay times were longest in patients with non-ST-segment elevation AMI (6.1 and 3.0 hours, respectively) followed by patients with unstable angina (5.6 and 3.0 hours) and those with ST-segment elevation AMI (4.7 and 2.3 hours). Approximately 41% of patients with ST-segment elevation AMI presented to the 94 study hospitals within 2 hours of the onset of acute coronary symptoms; this compared with approximately one third of patients with non-ST-segment elevation AMI and unstable angina. Several demographic and clinical characteristics were associated with prehospital delay. In patients with ST-segment elevation AMI, duration of prehospital delay was inversely related to the receipt of thrombolytic therapy, but was inconsistently related to the use of percutaneous coronary interventions. The results of this study demonstrate that a large proportion of patients continue to exhibit prolonged delay in seeking medical care after the onset of acute coronary symptoms and remain in need of targeted educational efforts to reduce extent of delay.

Intervention in acute coronary syndromes: do patients undergo intervention on the basis of their risk characteristics? The Global Registry of Acute Coronary Events (GRACE)

Objective: To determine whether revascularisation is more likely to be performed in higher-risk patients and whether the findings are influenced by hospitals adopting more or less aggressive revascularisation strategies. Methods: GRACE (Global Registry of Acute Coronary Events) is a multinational, observational cohort study. This study involved 24 189 patients enrolled at 73 hospitals with on-site angiographic facilities. Results: Overall, 32.5% of patients with a non-ST elevation acute coronary syndrome (ACS) underwent percutaneous coronary intervention (PCI; 53.7% in ST segment elevation myocardial infarction (STEMI)) and 7.2% underwent coronary artery bypass grafting (CABG; 4.0% in STEMI). The cumulative rate of in-hospital death rose correspondingly with the GRACE risk score (variables: age, Killip class, systolic blood pressure, ST segment deviation, cardiac arrest at admission, serum creatinine, raised cardiac markers, heart rate), from 1.2% in low-risk to 3.3% in medium-risk and 13.0% in high-risk patients (c statistic  =  0.83). PCI procedures were more likely to be performed in low- (40% non-STEMI, 60% STEMI) than medium- (35%, 54%) or high-risk patients (25%, 41%). No such gradient was apparent for patients undergoing CABG. These findings were seen in STEMI and non-ST elevation ACS, in all geographical regions and irrespective of whether hospitals adopted low (4.2−33.7%, n  =  7210 observations), medium (35.7−51.4%, n  =  7913 observations) or high rates (52.6−77.0%, n  =  8942 observations) of intervention. Conclusions: A risk-averse strategy to angiography appears to be widely adopted. Proceeding to PCI relates to referral practice and angiographic findings rather than the patient’s risk status. Systematic and accurate risk stratification may allow higher-risk patients to be selected for revascularisation procedures, in contrast to current international practice.

Trends in acute reperfusion therapy for ST-segment elevation myocardial infarction from 1999 to 2006: we are getting better but we have got a long way to go

AIM Many patients who are eligible for acute reperfusion therapy receive it after substantial delays or not at all. We wanted to determine whether over the years more patients are receiving reperfusion therapy. METHODS AND RESULTS This analysis is based on 10 954 patients with ST elevation or left bundle-branch block presenting within 12 h of symptom onset and enrolled in the GRACE registry between April 1999 and June 2006. Over this time, there was an increasing trend in use of primary percutaneous coronary intervention (PCI) from 15% to 44% (P < 0.001), while use of fibrinolytic therapy decreased (from 41 to 16%; P < 0.01). No trend in median time to primary PCI was seen but that for fibrinolysis declined significantly (from 40 to 34%; P < 0.0001). Hospital mortality declined (6.9-5.4%; P < 0.01); the relationship between observed and expected mortality improved over time (P = 0.06). Nevertheless, 33% of patients still received no reperfusion therapy. Factors associated with reperfusion use included age; prior myocardial infarction, heart failure or coronary artery bypass graft surgery; history of diabetes; female sex; and delay from symptom onset to hospital arrival. In 2006, 52% of patients receiving fibrinolysis had door-to-needle times >30 min and 42% of those undergoing primary PCI had door-to-balloon times >90 min. CONCLUSION Primary PCI is now used much more than fibrinolysis. Although hospital mortality and delays to fibrinolytic reperfusion have improved, over 40% of patients reperfused still receive it outside the time window recommended, and one-third of potentially eligible patients receive no reperfusion.

Does Comorbidity Account for the Excess Mortality in Patients With Major Bleeding in Acute Myocardial Infarction

Background— Analyses from randomized controlled trials suggest that bleeding in patients with acute myocardial infarction is associated with poor outcomes. Because these data are not generalizable to all patients with acute myocardial infarction, we sought to better understand the scope of this problem in a “real-world” setting. Methods and Results— We examined the frequency of major bleeding in 40 087 patients with acute myocardial infarction enrolled in the Global Registry of Acute Coronary Events. Regression analyses were used to examine the association between patient and treatment characteristics, bleeding, and hospital and postdischarge outcomes. Major bleeding occurred in 2.8% of patients. These patients were older, more severely ill, and more likely to undergo invasive procedures. Patients with bleeding were more likely to die during hospitalization (hazard ratio, 1.9; 95% confidence interval, 1.6 to 2.2) but not after discharge (hazard ratio, 0.8; 95% confidence interval, 0.6 to 1.0) than patients who did not bleed. Continuation of antithrombotic therapies after day 1 was lower in patients who experienced early bleeding. Moreover, in patients who bled, hospital mortality was increased in those who discontinued aspirin, thienopyridines, or low–molecular-weight heparins. Conclusions— Major bleeding occurred in 1 in 35 patients with acute myocardial infarction; these patients accounted for ≈10% of all hospital deaths. Nevertheless, risk of hospital mortality associated with bleeding was much lower than reported in randomized controlled trials. These data suggest that although bleeding may be causally related to adverse outcomes in some patients in the real-world setting, it is often merely a marker for patients at higher risk for adverse outcomes.

The Global Registry of Acute Coronary Events, 1999 to 2009–GRACE

The aim of GRACE was to provide a large multinational registry of the full spectrum of patients with acute coronary syndromes (ACS) in order to define patient characteristics and outcomes and derive predictive risk scores. The study was designed and administered by an independent steering committee; data analyses were performed under the guidance of the steering committee at the Center for Outcomes Research of the University of Massachusetts. Regular feedback regarding local, regional and international guideline and performance measures was provided to individual hospitals and clusters of hospitals. Regional and international benchmark data were available to all sites. Main GRACE involved 123 hospitals in 14 countries in North and South America, Europe, Australia and New Zealand. GRACE2 (Expanded GRACE) comprised 154 hospitals in Europe, North and South America, Asia, Australasia and China. Continuous recruitment and follow-up took place between 1999 and 2009. The first 10 -20 patients per site (depending on hospital size) were enrolled each month, resulting in the recruitment of 102 341 patients, who were categorized as having ST-segment elevation myocardial infarction, non-ST-elevation myocardial infarction or unstable angina. Standardized case report forms (datafax or electronic) were completed by trained study coordinators, and included fields relating to demographic factors, comorbid conditions, treatments and in-hospital and post-discharge (6-month) events. Blood sampling, genetic analyses and longer-term follow-up were undertaken in GRACE substudies. Prospective individual patient follow-up was carried out. All sites were audited locally; 10% of individual patient records were audited in a 2-year cycle. Less than 1% of 20 key baseline fields, and less than 1% of discharge diagnosis and discharge status data, were missing. Six-month follow-up was 85% complete. Publications and risk scores are available at http://www.outcome.org/grace. Proposals for specific analyses were considered, in competition, by an independent publications committee.

Mortality following placement of drug-eluting and bare-metal stents for ST-segment elevation acute myocardial infarction in the Global Registry of Acute Coronary Events

AIMS To assess mortality after drug-eluting stent (DES) or bare-metal stent (BMS) for ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS In this multinational registry, 5093 STEMI patients received a stent: 1313 (26%) a DES and 3780 (74%) only BMS. Groups differed in baseline characteristics, type, or timing of percutaneous coronary intervention, with a higher baseline risk for patients receiving BMS. Two-year follow-up was available in 55 and 60% of the eligible BMS and DES patients, respectively. Unadjusted mortality was lower during hospitalization, similar for the first 6 months after discharge, and higher from 6 months to 2 years, for DES patients compared with that of BMS patients. Overall, unadjusted 2-year mortality was 5.3 vs. 3.9% for BMS vs. DES patients (P = 0.04). In propensity- and risk-adjusted survival analyses (Cox model), post-discharge mortality was not different up to 6 months (P = 0.21) or 1 year (P = 0.34). Late post-discharge mortality was higher in DES patients from 6 months to 2 years (HR 4.90, P = 0.01) or from 1 to 2 years (HR 7.06, P = 0.02). Similar results were observed when factoring in hospital mortality. CONCLUSION The observation of increased late mortality with DES vs. BMS suggests that DES should probably be avoided in STEMI, until more long-term data become available.

Prehospital Delay in Patients With Acute Coronary Syndromes (from the Global Registry of Acute Coronary Events [GRACE])

Duration of delay in seeking medical care in persons with symptoms of evolving acute myocardial infarction (AMI) is of current interest given the time-dependent benefits associated with early use of coronary reperfusion approaches. The objectives of this multinational study were to describe geographic variation in the extent of and factors associated with prehospital delay in patients enrolled in the GRACE study. Data were collected from 44,695 patients hospitalized with an acute coronary syndrome in 14 countries from 2000 to 2006. The regions under study included Argentina and Brazil (n = 8,203), United States/Canada (n = 12,810), Europe (n = 19,354), and Australia/New Zealand (n = 4,328). Patients with ST-segment elevation AMI, non-ST-segment elevation AMI, and unstable angina comprised the study population. There were marked geographic differences in extent of prehospital delay in patients with ST-segment elevation AMI and those with non-ST-segment elevation AMI/unstable angina. In patients with ST-segment elevation AMI, the shortest duration of prehospital delay was observed in patients from Australia/New Zealand (median 2.2 hours), whereas patients from Argentina and Brazil delayed the longest (median 4.0 hours). Median duration of prehospital delay was shortest (2.5 hours) in patients with ST-segment elevation AMI, whereas patients with non-ST-segment elevation AMI/unstable angina showed considerably longer prehospital delay (3.1 hours). Several demographic and clinical characteristics were associated with prolonged delay overall and in the different geographic locations under study. In conclusion, results of this large multinational registry provided insights into contemporary patterns of care-seeking behavior in patients with acute coronary disease.

Unprotected left main revascularization in patients with acute coronary syndromes

AIMS In acute coronary syndromes (ACS), the optimal revascularization strategy for unprotected left main coronary disease (ULMCD) has been little studied. The objectives of the present study were to describe the practice of ULMCD revascularization in ACS patients and its evolution over an 8-year period, analyse the prognosis of this population and determine the effect of revascularization on outcome. METHODS AND RESULTS Of 43 018 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, 1799 had significant ULMCD and underwent percutaneous coronary intervention (PCI) alone (n = 514), coronary artery bypass graft (CABG) alone (n = 612), or no revascularization (n = 673). Mortality was 7.7% in hospital and 14% at 6 months. Over the 8-year study, the GRACE risk score remained constant, but there was a steady shift to more PCI than CABG over time. Patients undergoing PCI presented more frequently with ST-segment elevation myocardial infarction (STEMI), after cardiac arrest, or in cardiogenic shock; 48% of PCI patients underwent revascularization on the day of admission vs. 5.1% in the CABG group. After adjustment, revascularization was associated with an early hazard of hospital death vs. no revascularization, significant for PCI (hazard ratio (HR) 2.60, 95% confidence interval (CI) 1.62-4.18) but not for CABG (1.26, 0.72-2.22). From discharge to 6 months, both PCI (HR 0.45, 95% CI 0.23-0.85) and CABG (0.11, 0.04-0.28) were significantly associated with improved survival in comparison with an initial strategy of no revascularization. Coronary artery bypass graft revascularization was associated with a five-fold increase in stroke compared with the other two groups. CONCLUSION Unprotected left main coronary disease in ACS is associated with high mortality, especially in patients with STEMI and/or haemodynamic or arrhythmic instability. Percutaneous coronary intervention is now the most common revascularization strategy and preferred in higher risk patients. Coronary artery bypass graft is often delayed and performed in lower risk patients, leading to good 6-month survival. The two approaches therefore appear complementary.

Should patients with acute coronary disease be stratified for management according to their risk? Derivation, external validation and outcomes using the updated GRACE risk score

Objectives Risk scores are recommended in guidelines to facilitate the management of patients who present with acute coronary syndromes (ACS). Internationally, such scores are not systematically used because they are not easy to apply and some risk indicators are not available at first presentation. We aimed to derive and externally validate a more accurate version of the Global Registry of Acute Coronary Events (GRACE) risk score for predicting the risk of death or death/myocardial infarction (MI) both acutely and over the longer term. The risk score was designed to be suitable for acute and emergency clinical settings and usable in electronic devices. Design and setting The GRACE risk score (2.0) was derived in 32 037 patients from the GRACE registry (14 countries, 94 hospitals) and validated externally in the French registry of Acute ST-elevation and non-ST-elevation MI (FAST-MI) 2005. Participants Patients presenting with ST-elevation and non-ST elevation ACS and with long-term outcomes. Outcome measures The GRACE Score (2.0) predicts the risk of short-term and long-term mortality, and death/MI, overall and in hospital survivors. Results For key independent risk predictors of death (1 year), non-linear associations (vs linear) were found for age (p<0.0005), systolic blood pressure (p<0.0001), pulse (p<0.0001) and creatinine (p<0.0001). By employing non-linear algorithms, there was improved model discrimination, validated externally. Using the FAST-MI 2005 cohort, the c indices for death exceeded 0.82 for the overall population at 1 year and also at 3 years. Discrimination for death or MI was slightly lower than for death alone (c=0.78). Similar results were obtained for hospital survivors, and with substitutions for creatinine and Killip class, the model performed nearly as well. Conclusions The updated GRACE risk score has better discrimination and is easier to use than the previous score based on linear associations. GRACE Risk (2.0) performed equally well acutely and over the longer term and can be used in a variety of clinical settings to aid management decisions.