Background Assessing risk and weighing the potential benefits from evidence-based therapies are essential in the clinical decision making process of optimizing care and outcomes for patients ...presenting with acute coronary syndromes (ACS). Such practices are advocated in international clinical guidelines of ACS care. While the GRACE risk score (GRS) is a guideline advocated, well-validated risk stratification tool, its utility in improving care and outcomes remains unproven, and its application has been limited in routine clinical practice. Objective This study will assess the effectiveness using the GRS tool and treatment recommendations during patient assessment on improving the application of guideline-recommended therapies in ACS care. Design This study employs a PROBE (prospective cluster hospital-level randomized open-label, blinded endpoint) design to evaluate objective measures of hospital performance, with clinical events adjudicated by a blinded event committee. This randomized study is nested within the established CONCORDANCE registry of ACS patients, with existing methods for data collection and monitoring of care and clinical outcomes. The hospital-level intervention is the integration of the GRS into routine ACS patient assessment process. The study will assess the use of early invasive management, prescription of guideline recommended pharmacology and referral to cardiac rehabilitation by hospital discharge; with the key composite clinical endpoint of cardiovascular death, new or recurrent myocardial infarction, in-hospital heart failure or cardiovascular readmission at 12 months. Health economic impacts of risk stratification implementation will also be evaluated. The study will recruit 3000 patients from 30 hospitals. Summary The AGRIS trial will establish the effect of routine objective risk stratification using the GRACE risk score on ACS care and clinical outcomes.
Background Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces ...low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease. Study Design ACCELERATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients qualified for enrollment if they have experienced an acute coronary syndrome within the prior 30 to 365 days, cerebrovascular accident, or transient ischemic attack; if they have peripheral vascular disease; or they have diabetes with coronary artery disease. A total of 12,092 patients were randomized to evacetrapib 130 mg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to first event of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Treatment will continue until 1,670 patients reached the primary end point; at least 700 patients reach the key secondary efficacy end point of CV death, myocardial infarction, and stroke, and the last patient randomized has been followed up for at least 1.5 years. Conclusions ACCELERATE will establish whether the cholesteryl ester transfer protein inhibition by evacetrapib improves CV outcomes in patients with high-risk vascular disease.
Abstract Background For acute myocardial infarction (AMI) without heart failure (HF), it is unclear if β-blockers are associated with reduced mortality. Objectives The goal of this study was to ...determine the association between β-blocker use and mortality in patients with AMI without HF or left ventricular systolic dysfunction (LVSD). Methods This cohort study used national English and Welsh registry data from the Myocardial Ischaemia National Audit Project. A total of 179,810 survivors of hospitalization with AMI without HF or LVSD, between January 1, 2007, and June 30, 2013 (final follow-up: December 31, 2013), were assessed. Survival-time inverse probability weighting propensity scores and instrumental variable analyses were used to investigate the association between the use of β-blockers and 1-year mortality. Results Of 91,895 patients with ST-segment elevation myocardial infarction and 87,915 patients with non–ST-segment elevation myocardial infarction, 88,542 (96.4%) and 81,933 (93.2%) received β-blockers, respectively. For the entire cohort, with >163,772 person-years of observation, there were 9,373 deaths (5.2%). Unadjusted 1-year mortality was lower for patients who received β-blockers compared with those who did not (4.9% vs. 11.2%; p < 0.001). However, after weighting and adjustment, there was no significant difference in mortality between those with and without β-blocker use (average treatment effect ATE coefficient: 0.07; 95% confidence interval CI: −0.60 to 0.75; p = 0.827). Findings were similar for ST-segment elevation myocardial infarction (ATE coefficient: 0.30; 95% CI: −0.98 to 1.58; p = 0.637) and non–ST-segment elevation myocardial infarction (ATE coefficient: −0.07; 95% CI: −0.68 to 0.54; p = 0.819). Conclusions Among survivors of hospitalization with AMI who did not have HF or LVSD as recorded in the hospital, the use of β-blockers was not associated with a lower risk of death at any time point up to 1 year. (β-Blocker Use and Mortality in Hospital Survivors of Acute Myocardial Infarction Without Heart Failure; NCT02786654 )
We examined the relations between right bundle branch block (RBBB) and clinical characteristics, management, and outcomes among a broad spectrum of patients with acute coronary syndrome (ACS). ...Admission electrocardiograms of patients enrolled in the Global Registry of Acute Coronary Events (GRACE) electrocardiogram substudy and the Canadian ACS Registry I were analyzed independently at a blinded core laboratory. We performed multivariable logistic regression analysis to assess the independent prognostic significance of admission RBBB on in-hospital and 6-month mortality. Of 11,830 eligible patients with ACS (mean age 65; 66% non–ST-elevation ACS), 5% had RBBB. RBBB on admission was associated with older age, male sex, more cardiovascular risk factors, worse Killip class, and higher GRACE risk score (all p <0.01). Patients with RBBB less frequently received in-hospital cardiac catheterization, coronary revascularization, or reperfusion therapy (all p <0.05). The RBBB group had higher unadjusted in-hospital (8.8% vs 3.8%, p <0.001) and 6-month mortality rates (15.1% vs 7.6%, p <0.001). After adjusting for established prognostic factors in the GRACE risk score, RBBB was a significant independent predictor of in-hospital death (odds ratio 1.45, 95% CI 1.02 to 2.07, p = 0.039), but not cumulative 6-month mortality (odds ratio 1.29, 95% CI 0.95 to 1.74, p = 0.098). There was no significant interaction between RBBB and the type of ACS for either in-hospital or 6-month mortality (both p >0.50). In conclusion, across a spectrum of ACS, RBBB was associated with preexisting cardiovascular disease, high-risk clinical features, fewer cardiac interventions, and worse unadjusted outcomes. After adjusting for components of the GRACE risk score, RBBB was a significant independent predictor of early mortality.
Summary Background ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively ...identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods In this phase 1 study, patients with ALK -positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov , number NCT00585195. Findings Between Aug 27, 2008, and June 1, 2011, 149 ALK -positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). Interpretation Crizotinib is well tolerated with rapid, durable responses in patients with ALK -positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding Pfizer.
Abstract Background Several biomarkers have been shown to improve risk stratification in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS); however, they have not been ...integrated into risk prediction tools. Methods C-reactive-protein, N-terminal-pro–brain natriuretic peptide (NT-proBNP), and haemoglobin A1C were measured in 6447 patients with NSTEACS who were enrolled in the Clopidogrel in Unstable Angina to Prevent Recurrent Events trial. A risk score to predict cardiovascular (CV) death, myocardial infarction (MI), or stroke at 1 year was developed by incorporating biomarkers that were independently predictive of events with traditional variables, electrocardiogram, and troponin-T. Model discrimination was evaluated using c-statistic, integrated discrimination improvement, and net reclassification index, and validated using bootstrap methods. Results During 1 year of follow-up, 686 patients experienced a CV event. Each biomarker predicted CV death, MI, or stroke; however, only NT-proBNP and haemoglobin A1C improved model discrimination, increasing the c-statistic (0.66-0.71), integrated discrimination improvement to 3.4%, and net reclassification index to 17.5% ( P < 0.0001 for all measures). A risk score ranging from 0 to 20 points including variables for age, prior MI/stroke, sex, ST-segment deviation, troponin-T, NT-proBNP, and haemoglobin A1C classified individuals into low-, intermediate-, and high-risk groups with rates of CV death, MI, stroke of 3.7%, 9.1%, 17.8%, respectively. The absolute benefit of dual antiplatelet therapy versus aspirin alone was 1.0%, 4.7%, and 3.0% in low-, intermediate-, and high-risk groups, respectively. Conclusions The addition of NT-proBNP and haemoglobin A1C to 5 standard variables creates a 7-variable risk score that improves prediction of CV events at 1 year and aids in risk-based selection of patients with NSTEACS for dual antiplatelet therapy.
Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2 )-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2 -IIA mass or sPLA2 enzyme ...activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events MVE in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2 -IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2 -IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval CI: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2 -IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions Reducing sPLA2 -IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
Background Antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) reduces major cardiovascular events in patients with ST and non–ST-segment-elevation acute coronary syndromes (ACS). ...Recent mechanistic and clinical data suggest that higher loading and maintenance doses of clopidogrel may achieve a more rapid and greater degree of platelet inhibition that translates into improved clinical outcomes, but this is yet to be formally evaluated in an adequately powered randomized trial. Objectives To evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non–ST-segment-elevation ACS managed with an early invasive strategy. Design Multicenter, international, randomized, 2×2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA (300-325 mg daily) versus low-dose ASA (75-100 mg daily) in patients with ST or non–ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients. Conclusions The CURRENT-OASIS 7 trial will help to define optimal dosing regimens for clopidogrel and ASA in patients with ST and non–ST-segment-elevation ACS treated with an early invasive strategy.
Background ST-segment depression (STD) is predictive of adverse outcomes in non–ST-segment elevation acute coronary syndromes (NSTE-ACS), but there are conflicting data on the incremental prognostic ...value of T-wave inversions (TWIs) on the admission electrocardiogram. Methods Admission electrocardiograms of 7,343 patients with NSTE-ACS from the Global Registry of Acute Coronary Events (GRACE) and ACS I registry were independently analyzed at a core laboratory and stratified by TWI and STD status. We performed multivariable analyses to determine the independent prognostic significance of TWI and tested for interaction between TWI and STD for adverse outcomes. Results Patients with TWI and/or STD had a higher prevalence of cardiovascular risk factors, higher Killip class, and higher GRACE risk scores. Among the 2,708 patients with available angiographic data, rates of 3-vessel or left main disease were similar between patients with TWI and those without TWI/STD. After adjusting for other established prognosticators, TWI did not independently predict in-hospital (adjusted odds ratio 1.03, 95% CI 0.75-1.42, P = .85) or 6-month mortality (adjusted odds ratio 1.02, 95% CI 0.80-1.30, P = .88); STD remained a strong independent predictor. There was no interaction between TWI and STD for these outcomes. No contiguous lead groups or cumulative number of leads with TWI provided independent prognostic information. Conclusions TWI is associated with other high-risk clinical features but is not an independent predictor of adverse short- and long-term mortality in NSTE-ACS. T-wave inversion does not provide additional prognostication beyond the GRACE risk model, and its concomitant presence does not alter the prognostic value of STD.
The use of, factors associated with, and long-term outcomes related to statin therapy in patients with acute coronary syndromes and low-density lipoprotein (LDL) levels <100 mg/dl at the time of ...hospital presentation are unclear. This report describes the use of statins at hospital discharge in 8,492 patients with acute coronary syndromes enrolled in the Global Registry of Acute Coronary Events (GRACE; 1999 to 2005) according to baseline LDL levels (<100 vs ≥100 mg/dl) and compares 6-month outcomes in each group stratified by the use or nonuse of statin therapy. Seventy-two percent of patients with LDL levels ≥100 mg/dl, compared with 55% of patients with LDL levels <100 mg/dl, were discharged on statin therapy. Sociodemographic, clinical, and treatment variables varied between patients discharged on statins and those who were not. Patients receiving statins at discharge were twofold (LDL ≥100 mg/dl) to threefold (<100 mg/dl) more likely to be receiving statin therapy at 6 months compared with those not receiving statins at discharge. Statin use at discharge was associated with a significantly lower rate of 6-month cardiac complications in patients with LDL levels <100 mg/dl (adjusted odds ratio for the composite end point of myocardial infarction, stroke, and death 0.64, 95% confidence interval 0.47 to 0.88). In conclusion, data from this large observational study suggest that patients with acute coronary syndromes and LDL levels <100 mg/dl are much less likely to be prescribed statin therapy at hospital discharge or to be receiving statin therapy at 6 months but benefit from the prescription of statins at hospital discharge as much as patients with levels ≥100 mg/dl.
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