Metabolome-based signature of disease pathology in MS.

BACKGROUND: Diagnostic delays are common for multiple sclerosis (MS) since diagnosis typically depends on the presentation of nonspecific clinical symptoms together with radiologically-determined central nervous system (CNS) lesions. It is important to reduce diagnostic delays as earlier initiation of disease modifying therapies mitigates long-term disability. Developing a metabolomic blood-based MS biomarker is attractive, but prior efforts have largely focused on specific subsets of metabolite classes or analytical platforms. Thus, there are opportunities to interrogate metabolite profiles using more expansive and comprehensive approaches for developing MS biomarkers and for advancing our understanding of MS pathogenesis. METHODS: To identify putative blood-based MS biomarkers, we comprehensively interrogated the metabolite profiles in 12 non-Hispanic white, non-smoking, male MS cases who were drug naïve for 3 months prior to biospecimen collection and 13 non-Hispanic white, non-smoking male controls who were frequency matched to cases by age and body mass index. We performed untargeted two-dimensional gas chromatography and time-of-flight mass spectrometry (GCxGC-TOFMS) and targeted lipidomic and amino acid analysis on serum. 325 metabolites met quality control and supervised machine learning was used to identify metabolites most informative for MS status. The discrimination potential of these select metabolites were assessed using receiver operator characteristic curves based on logistic models; top candidate metabolites were defined as having area under the curves (AUC) >80%. The associations between whole-genome expression data and the top candidate metabolites were examined, followed by pathway enrichment analyses. Similar associations were examined for 175 putative MS risk variants and the top candidate metabolites. RESULTS: 12 metabolites were determined to be informative for MS status, of which 6 had AUCs >80%: pyroglutamate, laurate, acylcarnitine C14:1, N-methylmaleimide, and 2 phosphatidylcholines (PC ae 40:5, PC ae 42:5). These metabolites participate in glutathione metabolism, fatty acid metabolism/oxidation, cellular membrane composition, and transient receptor potential channel signaling. Pathway analyses based on the gene expression association for each metabolite suggested enrichment for pathways associated with apoptosis and mitochondrial dysfunction. Interestingly, the predominant MS genetic risk allele HLA-DRB1×15:01 was associated with one of the 6 top metabolites. CONCLUSION: Our analysis represents the most comprehensive description of metabolic changes associated with MS in serum, to date, with the inclusion of genomic and genetic information. We identified atypical metabolic processes that differed between MS patients and controls, which may enable the development of biological targets for diagnosis and treatment.

Alternative splicing: a mechanism for phenotypic rescue of a common inherited defect.

Approximately 2% of Caucasians and African-Americans are homozygous for a nonsense mutation in exon 2 of the AMPD1 (AMP deaminase) gene. These individuals have a high grade deficiency of AMPD activity in their skeletal muscle. More than 100 patients with AMPD1 deficiency have been reported to have symptoms of a metabolic myopathy, but it is apparent many individuals with this inherited defect are asymptomatic given the prevalence of this mutant. Results of the present study provide a potential molecular explanation for "correction" of this genetic defect. Alternative splicing eliminates exon 2 in 0.6-2% of AMPD1 mRNA transcripts in adult skeletal muscle. Expression studies document that AMPD1 mRNA, which has exon 2 deleted, encodes a functional AMPD peptide. A much higher percentage of alternatively spliced transcripts are found during differentiation of human myocytes in vitro. Transfection studies with human minigene constructs demonstrate that alternative splicing of the primary transcript of human AMPD1 is controlled by tissue-specific and stage-specific signals. Alternative splicing of exon 2 in individuals who have inherited this defect provides a mechanism for phenotypic rescue and variations in splicing patterns may contribute to the variability in clinical symptoms.

Trends in use of anti-thrombotic agents and outcomes in patients with non-ST-segment elevation myocardial infarction (NSTEMI) managed with an invasive strategy.

OBJECTIVE: To analyze trends in utilization of anti-thrombotic agents (ATA) and in-hospital clinical outcomes in non-ST-elevation myocardial infarction (NSTEMI) patients managed with an invasive strategy from 2007 to 2010. METHODS & RESULTS: Using ACTION Registry(®)-GWTG™ data, we analyzed trends in use of ATA and in-hospital clinical outcomes among 64,199 NSTEMI patients managed invasively between 2007 and 2010. ATA included unfractionated heparin (UFH), low molecular weight heparin (LMWH), glycoprotein IIb/IIIa inhibitors (GPI) and bivalirudin. Although the proportion of NSTEMI patients treated with PCI within 48h of hospital arrival was similar in 2007 and 2010, percentage use of bivalirudin (13.4-27.3%; p<0.01) and UFH increased (60.0-67.5%, p<0.01), and that of GPI (62.3-41.0%; p<0.01) and LMWH (41.5-36.8%; p<0.01) declined. Excess dosing of UFH (75.9-59.3%, p<0.01), LMWH (9.6-5.2%; p<0.01) and GPI (8.9-5.9%, p<0.01) was also significantly lower in 2010 compared with 2007. Though in-hospital mortality rates were similar in 2007 and 2010 (2.3-1.9%, p=0.08), the rates of in-hospital major bleeding (8.7-6.6%, p<0.01) and non-CABG related RBC transfusion (6.3-4.6%, p<0.01) were significantly lower in 2010 compared with 2007. CONCLUSION: Compared with 2007, patients with NSTEMI, who were managed invasively in 2010 received GPI and LMWH less often and bivalirudin and UFH more frequently. There were sizeable reductions in the rates of excess dosing of UFH (though still occurred in 67% of patients), GPI and LMWH. In-hospital major bleeding complications and post-procedural RBC transfusion were lower in 2010 compared with 2007.

Bedside multimarker testing for risk stratification in chest pain units: The chest pain evaluation by creatine kinase-MB, myoglobin, and troponin I (CHECKMATE) study.

BACKGROUND: Earlier, rapid evaluation in chest pain units may make patient care more efficient. A multimarker strategy (MMS) testing for several markers of myocardial necrosis with different time-to-positivity profiles also may offer clinical advantages. METHODS AND RESULTS: We prospectively compared bedside quantitative multimarker testing versus local laboratory results (LL) in 1005 patients in 6 chest pain units. Myoglobin, creatine kinase-MB, and troponin I were measured at 0, 3, 6, 9 to 12, and 16 to 24 hours after admission. Two MMS were defined: MMS-1 (all 3 markers) and MMS-2 (creatine kinase-MB and troponin I only). The primary assessment was to relate marker status with 30-day death or infarction. More patients were positive by 24 hours with MMS than with LL (MMS-1, 23.9%; MMS-2, 18.8%; LL, 8.8%; P=0.001, all comparisons), and they became positive sooner with MMS-1 (2.5 hours, P=0.023 versus LL) versus MMS-2 (2.8 hours, P=0.026 versus LL) or LL (3.4 hours). The relation between baseline MMS status and 30-day death or infarction was stronger (MMS-1: positive, 18.8% event rate versus negative, 3.0%, P=0.001; MMS-2: 21.9% versus 3.2%, P=0.001) than that for LL (13.6% versus 5.5%, P=0.038). MMS-1 discriminated 30-day death better (positive, 2.0% versus negative, 0.0%, P=0.007) than MMS-2 (positive, 1.8% versus negative, 0.2%; P=0.055) or LL (positive, 0.0% versus negative, 0.5%; P=1.000). CONCLUSIONS: Rapid multimarker analysis identifies positive patients earlier and provides better risk stratification for mortality than a local laboratory-based, single-marker approach.

Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin t-positive status: the paragon-B troponin T substudy.

BACKGROUND: Troponin T (TnT) is valuable for short- and long-term risk stratification of patients with acute coronary syndromes (ACS). It also may predict which ACS patients will benefit from glycoprotein (GP) IIb/IIIa blockade. METHODS AND RESULTS: We prospectively studied 1160 patients with non-ST-segment elevation ACS randomized in PARAGON-B to receive lamifiban, an intravenous GP IIb/IIIa antagonist, or placebo. TnT levels were obtained before study treatment began and 24 to 72 hours later; assays were performed by a blinded core laboratory. At baseline, 40.2% of patients were TnT-positive (>/=0.1 ng/mL); these patients were older and more often male or smokers. Patients positive at baseline had a significantly higher rate of the primary end point (composite of death, myocardial [re]infarction, or severe recurrent ischemia at 30 days; odds ratio, 1.5; 95% CI, 1.1 to 2.1) than those who were TnT-negative. Lamifiban was associated with significant reduction in the primary end point (from 19.4% to 11.0%, P=0.01) among TnT-positive patients but not among TnT-negative patients (11.2% for placebo versus 10.8% for lamifiban, P=0.86; P=0.08 for test of interaction between TnT status and treatment assignment). This pattern held for the end points of death alone and death or myocardial (re)infarction at 30 days. Peak TnT level at 48 hours did not differ with lamifiban treatment. CONCLUSIONS: TnT predicts poor short-term outcomes in non-ST-segment elevation ACS. Treatment benefit with lamifiban is limited almost exclusively to TnT-positive patients, reducing 30-day adverse outcomes to a rate nearly identical to that of negative patients.

Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction.

BACKGROUND: Recent advances in high-throughput genomics technology have expanded our ability to catalogue allelic variants in large sets of candidate genes related to premature coronary artery disease. METHODS AND RESULTS: A total of 398 families were identified in 15 participating medical centers; they fulfilled the criteria of myocardial infarction, revascularization, or a significant coronary artery lesion diagnosed before 45 years in men or 50 years in women. A total of 62 vascular biology genes and 72 single-nucleotide polymorphisms were assessed. Previously undescribed variants in 3 related members of the thrombospondin protein family were prominent among a small set of single-nucleotide polymorphisms that showed a statistical association with premature coronary artery disease. A missense variant of thrombospondin 4 (A387P) showed the strongest association, with an adjusted odds ratio for myocardial infarction of 1.89 (P=0.002 adjusted for covariates) for individuals carrying the P allele. A variant in the 3' untranslated region of thrombospondin-2 (change of thymidine to guanine) seemed to have a protective effect against myocardial in individuals homozygous for the variant (adjusted odds ratio of 0.31; P=0.0018). A missense variant in thrombospondin-1 (N700S) was associated with an adjusted odds ratio for coronary artery disease of 11.90 (P=0.041) in homozygous individuals, who also had the lowest level of thrombospondin-1 by plasma assay (P=0.0019). CONCLUSIONS: This large-scale genetic study has identified the potential of multiple novel variants in the thrombospondin gene family to be associated with familial premature myocardial infarction. Notwithstanding multiple caveats, thrombospondins specifically and high-throughput genomic technology in general deserve further study in familial ischemic heart disease.

Early discharge in the thrombolytic era: an analysis of criteria for uncomplicated infarction from the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial.

OBJECTIVES: This study sought to readdress the definition of uncomplicated myocardial infarction and to apply clinical criteria for early discharge of such patients in the thrombolytic era. BACKGROUND: Previous studies proposed early hospital discharge at day 7 to 10 after acute myocardial infarction. The potential for earlier discharge of patients with uncomplicated infarction after thrombolysis remains undemonstrated. METHODS: We defined "uncomplicated infarction" a priori as the absence of death, reinfarction, ischemia, stroke, shock, heart failure (Killip class > 1), bypass surgery, balloon pumping, emergency catheterization or cardioversion or defibrillation in the first 4 hospital days. We applied this definition to 41,021 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial. We examined death at 30 days and 1 year and rates of in-hospital reinfarction, heart failure, recurrent ischemia, shock and stroke in the uncomplicated and complicated groups created by application of our definition. We also assessed lengths of hospital and cardiac care unit stay. RESULTS: Application of our clinical criteria yielded 23,497 (57.3%) patients in the uncomplicated group at day 4 with a very low risk of death and in-hospital complications: 30-day mortality 1%, reinfarction 1.7%, heart failure 2.6%, recurrent ischemia 6.7%, shock 0.4% and stroke 0.2%. One-year mortality was 3.6%. The median hospital stay was 9 days (7, 12 [25th, 75th percentiles, respectively]), and the median cardiac care unit stay 3 days (3, 5). CONCLUSIONS: Simple clinical characteristics can identify a very low risk post-myocardial infarction population by hospital day 4. Use of these criteria for early discharge planning could substantially reduce length of stay for patients with uncomplicated acute myocardial infarction.

Time from symptom onset to treatment and outcomes after thrombolytic therapy. GUSTO-1 Investigators.

OBJECTIVES: This study sought to examine the relations among patient characteristics, time to thrombolysis and outcomes in the international GUSTO-I trial. BACKGROUND: Studies have shown better left ventricular function and decreased infarct size as well as increased survival with earlier thrombolysis, but the relative benefits of various thrombolytic agents with earlier administration are uncertain. METHODS: We evaluated the relations of baseline characteristics to three prospectively defined time variables: symptom onset to treatment, symptom onset to hospital arrival (presentation delay) and hospital arrival to treatment (treatment delay). We also examined the relations of delays to clinical outcomes and to the relative 30-day mortality benefit with accelerated tissue-type plasminogen activator (t-PA) versus streptokinase. RESULTS: Female, elderly, diabetic and hypertensive patients had longer delays at all stages. Previous infarction or bypass surgery was an additional risk factor for treatment delay. Early thrombolysis was associated with lower overall mortality rate (< 2 h, 5.5%; > 4 h, 9.0%), but no additional relative benefit resulted from earlier treatment with accelerated t-PA versus streptokinase (p = 0.38). Longer presentation and treatment delays were both associated with increased mortality rate (presentation delay < 1 h, 5.6% and > 4 h, 8.6%; treatment delay < 1 h, 5.4%, and > 90 min, 8.1%). As time to treatment increased, the incidence of recurrent ischemia or reinfarction decreased, but the rates of shock, heart failure and stroke increased. CONCLUSIONS: Earlier treatment resulted in better outcomes, regardless of thrombolytic strategy. Elderly, female and diabetic patients were treated later, adding to their already substantial risk.

Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up.

OBJECTIVES: This study explored the association between the initiation of hormone replacement therapy (HRT) and early cardiac events (<1 year) in women with a recent myocardial infarction (MI). BACKGROUND: Observational studies have linked postmenopausal hormone use with a reduced risk of death from heart disease. However, a recent randomized trial of HRT found no long-term benefit, primarily due to an increase in cardiac events in the first year. METHODS: The Coumadin Aspirin Reinfarction Study (CARS) database contains information on HRT use and menopausal status for women with a recent MI. We classified the 1,857 postmenopausal women in CARS as prior/current HRT users if they took HRT before enrollment, new users if they began HRT during the study period or never users. We assessed the incidence of cardiac events (death, MI, unstable angina [UA]) during follow-up. RESULTS: In our cohort, 28% (n = 524) used HRT at some point. Of these, 21% (n = 111) began HRT after their MI. New users had a higher incidence of death/MI/UA (41% vs. 28%, p = 0.001) during follow-up than never users, largely due to a higher incidence of UA (39% vs. 20%, p = 0.001). After adjustment, new users still had a significantly higher risk of death/MI/UA than never users during follow-up (relative risk [RR] = 1.44 [1.05-1.99]). Prior/current users had no excess risk of the composite end point after adjustment. Users of estrogen/progestin had a lower incidence of death/MI/UA during follow-up than users of estrogen only (RR = 0.56 [0.37-0.85]). CONCLUSIONS: Postmenopausal women who initiated HRT after a recent MI had an increased risk of cardiac events largely due to excess UA during follow-up.

Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes.

BACKGROUND: to date, only three groups have reported data from large scale genetic association studies of coronary heart disease using a case control design. METHODS AND RESULTS: to extend our initial report of 62 genes, we present data for 210 polymorphisms in 111 candidate genes genotyped in 352 white subjects with familial, premature coronary heart disease (onset age for men, 45; for women, 50) and a random sample of 418 population based whites. Multivariate logistic regression analysis was used to compare the distributions of genotypes between cases and the comparison group while controlling for age, sex, body mass, diabetes, and hypertension. Significant associations were found with polymorphisms in thrombospondin-4 (THBS4), thrombospondin-2 (THBS2) and plasminogen activator inhibitor-2 (PAI2), the strongest being with the A387P variant in THBS4 (p = 0.002). The THBS2 and THBS4 associations have since been replicated. We evaluated polymorphisms in 40 genes previously associated with coronary heart disease and found significant (p<0.05) associations with 10: ACE, APOE, F7, FGB, GP1BA, IL1RN, LRP1, MTHFR, SELP, and THPO. For five of these genes, the polymorphism associated in our study was different from that previously reported, suggesting linkage disequilibrium as an explanation for failure to replicate associations consistently across studies. We found strong linkage disequilibrium between polymorphisms within and between genes, especially on chromosome 1q22-q25, a region containing several candidate genes. CONCLUSIONS: despite known caveats of genetic association studies, they can be an effective means of hypothesis generation and complement classic linkage studies for understanding the genetic basis of coronary heart disease.

How much do we gain by reducing time to reperfusion therapy?

Emphasis continues to be placed on the need to minimize the time elapsed between the onset of symptoms of myocardial infarction and the initiation of thrombolytic therapy. Numerous large-scale trials have revealed an inverse relation between time-to-treatment and the degree of reduction in the risk of adverse clinical outcomes. Still to be resolved is the question of whether additional benefit can be gained by treating within the first hour. Many factors that influence delays to presentation are also associated with a higher risk of mortality, and these factors vary with patient characteristics. These same factors are also associated with longer treatment delay and greater mortality risk. Although the greatest opportunity for reducing time-to-treatment lies in reducing presentation time, public education efforts have been largely unsuccessful. Despite the fact that treatment delay generally accounts for a smaller proportion of total delay time than does presentation delay, it may be more amenable to shortening through measures such as transmission of electrocardiograms from the field; emergency department protocols for the rapid triage, assessment, and treatment of patients with chest pain; training emergency department physicians to administer thrombolytic therapy without a cardiology consult; and storing thrombolytic agents in the emergency department.

Comparison of cardiac troponin T versus creatine kinase-MB for risk stratification in a chest pain evaluation unit.

We evaluated cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) for risk stratification of chest pain unit (CPU) patients. We studied 383 consecutive patients with chest pain assigned to our CPU by emergency department physicians. At baseline all had normal or nondiagnostic electrocardiograms, no high-risk clinical features, and negative CK/CK-MB. CK-MB and electrocardiograms were taken at 0, 4, 8, and 12 hours and cTnT at 0, 4, and 8 hours. Eight patients (2.1%) were CK-MB positive and 39 (10.2%) were cTnT positive, including all but 1 CK-MB-positive patient. All marker-positive patients were detected by 8 hours. Seven cTnT-positive patients and 1 cTnT-negative patient had myocardial infarction (p <0.0001). cTnT-positive patients were older, less likely to be women or smokers, and more often had diabetes mellitus or known coronary disease (CAD). Seventy-one percent of patients underwent diagnostic testing. cTnT-positive patients more often underwent angiography (46% vs 20%) and underwent stress testing less often (28% vs 57%) than cTnT-negative patients. When performed, their stress tests were more often positive (46% vs 14%) and they more often had angiographically significant lesions (89% vs 49%) and multivessel disease (67% vs 29%). There were no short-term deaths. Long-term mortality was higher in cTnT-positive patients (27% vs 7%, p <0.0001). Thus, cTnT identified more CPU patients with myocardial necrosis and multivessel CAD than CK-MB and a population with high long-term mortality risk. Routine use of cTnT in CPUs could facilitate risk stratification and management.

Relation of temporal creatine kinase-MB release and outcome after thrombolytic therapy for acute myocardial infarction. TAMI Study Group.

Measuring biochemical marker release after acute myocardial infarction helps in estimating infarct size and prognosis. We sought to relate in-hospital outcomes and curve-fitted creatine kinase (CK)-MB variables after thrombolysis. We measured CK-MB mass initially and at 30 and 90 minutes, and at 3, 8, and 20 hours after thrombolysis in 130 patients also undergoing cardiac catheterization at 90 minutes and at 5 to 7 days. Data were fitted, and maximums and curve areas calculated. CK-MB maximums related to infarct location (p = 0.014) and time to therapy (p = 0.002); curve area did not. Neither maximums nor curve area related to Thrombolysis in Myocardial Infarction trial flow grade at 90 minutes. Maximums related to ejection fraction at 90 minutes (p = 0.0004) and at 5 to 7 days (p = 0.0014), as did curve area (p = 0.0076 and 0.030, respectively). Maximums related to infarct zone function at 90 minutes (p = 0.024) and at 5 to 7 days (p = 0.042); curve area related only at 90 minutes (p = 0.027). Both maximums and curve area predicted congestive heart failure (p = 0.008 and p = 0.042, respectively) and a composite of congestive heart failure or death (p = 0.004 and p = 0.047, respectively); however, after adjusting for maximums, curve area no longer predicted congestive heart failure (p = 0.92). Maximums predicted the composite outcome after adjustment for curve area, and showed a trend toward predicting congestive heart failure (p = 0.089). We conclude that CK-MB maximums relate to infarct zone function, left ventricular function, and in-hospital outcomes after thrombolysis for acute myocardial infarction.

Cardiac markers: point of care testing.

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

Short- and long-term outcomes following atrial fibrillation in patients with acute coronary syndromes with or without ST-segment elevation.

OBJECTIVE: To assess variables associated with the occurrence of atrial fibrillation (AF) and the relation of AF with short- and long-term outcomes and with other in-hospital complications in patients with acute coronary syndromes (ACS) with and without ST-segment elevation. DESIGN: Pooled database of 120 566 patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation (NSTE) ACS enrolled in 10 clinical trials. Multivariable logistic regression and Cox proportional hazards modelling were used to identify factors associated with AF and its relation with clinical outcomes. SETTING: ACS complicated by AF. PATIENTS: 120,566 patients with STEMI and NSTE-ACS in 10 clinical trials. INTERVENTIONS: None evaluated. MAIN OUTCOME MEASURE: Short- and long-term mortality. RESULTS: Occurrence of AF was 7.5% in the overall population (STEMI 8.0% (n = 84 161); NSTE-ACS = 6.4% (n = 36,405)). Seven-day mortality was higher for patients with AF (5.1%) than for those without (1.6%). After adjusting for confounders, association of AF with 7-day mortality was present in STEMI (hazards ratio (HR) = 1.65; 95% CI 1.44 to 1.90) and NSTE-ACS (HR = 2.30; 95% CI 1.83 to 2.90; p interaction = 0.015). Risk of long-term mortality (day 8 to 1 year) was also higher in STEMI (HR = 2.37; 95% CI 1.79 to 3.15) and NSTE-ACS (HR = 1.67; 95% CI 1.41 to 1.99). AF had a larger impact in NSTE-ACS on risk of short-term mortality (p<0.001), stroke (p<0.001), ischaemic stroke (p<0.001) and moderate or severe bleeding (p<0.001). CONCLUSIONS: AF is more common in patients with STEMI. An association of AF with short- and long-term mortality among patients with STEMI and NSTE-ACS was found. Understanding these findings may lead to better care of patients with this common arrhythmia.

Relation between baseline risk and treatment decisions in non-ST elevation acute coronary syndromes: an examination of international practice patterns.

OBJECTIVES: To examine the interaction between ST segment depression on the baseline ECG and subsequent in-hospital revascularisation on six month mortality among patients with non-ST elevation acute coronary syndromes. To examine whether ST segment depression influenced clinical decision making and whether there was international variation in the use of cardiac procedures across ST segment depression categories. METHODS: 11 453 patients enrolled in GUSTO-IIB (global use of strategies to open occluded coronary arteries), PARAGON (platelet IIb/IIIa antagonism for the reduction of acute coronary syndrome events in a global organisation network) -A, and PARAGON-B were studied. Patients were categorised as having no ST segment depression, 1 mm ST segment depression in two contiguous leads, and ST segment depression > or = 2 mm in two contiguous leads. International practice across four geographic regions was examined: USA, Canada, Europe, and Australia/New Zealand. RESULTS: Revascularisation appeared to have no impact on survival among patients with no ST segment depression; however, revascularisation was associated with a significant survival benefit among patients with ST segment depression > or = 1 mm. There was an inverse relation between the extent of ST segment depression and the use of angiography as well as angioplasty (p < 0.01). However, patients with ST segment depression > or = 2 mm were more likely to undergo bypass surgery. The only significant trend of increasing use of revascularisation procedures with increasing ST segment depression was observed in the USA. CONCLUSIONS: International practice patterns in procedure use appear to be insensitive to the extent of ST segment depression. Major opportunities for more efficient delivery of care exist in all regions.

Long-term oral platelet glycoprotein IIb/IIIa receptor antagonism with sibrafiban after acute coronary syndromes: study design of the sibrafiban versus aspirin to yield maximum protection from ischemic heart events post-acute coronary syndromes (SYMPHONY) trial. Symphony Steering Committee.

BACKGROUND: Despite progress, atherosclerotic vascular disease remains a major cause of morbidity and mortality. Intravenous therapy with platelet glycoprotein (GP) IIb/IIIa receptor antagonists improves outcome in patients with acute coronary syndromes (ACS). Whether potent long-term antiplatelet therapy with oral GP IIb/IIIa antagonists will further improve outcome at a dose that is tolerable in long-term treatment is unknown. TRIAL DESIGN: SYMPHONY (Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary syndromes) was a randomized, double-blind, aspirin-controlled trial with 2 concentration regimens of sibrafiban, an oral peptidomimetic GP IIb/IIIa antagonist, for long-term treatment instead of aspirin in patients after an ACS. Patients were eligible for SYMPHONY if they presented within 7 days of an ACS (>/=20 minutes of ischemic symptoms), had been clinically stable for at least 12 hours, and met one of the following inclusion criteria: ST-segment depression or elevation of at least 0.5 mm or new left bundle branch block with the ACS or elevated creatinine kinase MB more than the upper limit of normal and >3% of total creatine kinase or, if creatine kinase MB was not measured, an elevated level of troponin T or I. Approximately 9000 patients post ACS were randomized 1:1:1 to treatment with either aspirin (80 mg every 12 hours) or high-dose or low-dose sibrafiban every 12 hours. Assignment of tablet strength (3, 4.5, or 6 mg) within the sibrafiban arms was based on body weight and renal function to achieve a target steady-state plasma concentration. The duration of study drug therapy was 90 days. Patients who had intracoronary stenting during the course of the study initially received a blinded stent medication assignment for 2 to 4 weeks based on their initial randomization as follows: aspirin/ticlopidine 250 mg twice daily, low-dose sibrafiban/ticlopidine placebo twice daily, and high-dose sibrafiban/ticlopidine placebo twice daily. After the second interim safety assessment by the Data and Safety Monitoring Board the stent regimen for the low-dose group was modified to include ticlopidine 250 mg twice daily. END POINTS: The primary efficacy end point of SYMPHONY was the 90-day incidence of a composite of all-cause mortality, myocardial infarction or reinfarction, and severe recurrent ischemia. A clinical events classification committee was established to determine the end points of reinfarction and severe recurrent ischemia. The primary safety end points were the incidence of major bleeding or minor bleeding and the combined incidence of major and minor bleeding. Bleeding classification was done by computer algorithm. Tolerability was assessed by the rate of study drug discontinuation from bleeding.

Oral glycoprotein IIb/IIIa antagonists: new insights from the SYMPHONY trial.

Platelet aggregation plays a central role in the pathophysiology of acute coronary syndromes, and the platelet glycoprotein IIb/IIIa receptor has been identified as the critical final mediator of this process. Antagonists of this receptor used parenterally during both acute coronary syndromes and percutaneous coronary interventions reduce the likelihood of subsequent major cardiac complications. However, after the treatment period little further benefit accrues. Based on these observations and that of the significant benefit of aspirin in cardiovascular secondary prevention, oral glycoprotein IIb/IIIa receptor antagonists are being evaluated with the goal of extending the benefit of glycoprotein IIb/IIIa inhibition into chronic secondary prevention. This paper will review the results of the SYMPHONY study of one such oral agent, sibrafiban, and the current state of the oral glycoprotein IIb/IIIa inhibitor field.

Oral platelet glycoprotein IIb/IIIa inhibition.

Platelet aggregation plays a central role in the pathogenesis of thrombosis and the acute coronary syndromes. When given intravenously, potent selective antagonists of fibrinogen binding to the glycoprotein (GP) IIb/IIIa receptor, the final common pathway for platelet aggregation, have been effective in the treatment of acute coronary syndromes. Their benefit ceases, however, with the end of the infusion. Aspirin reduces the incidence of secondary vascular events by 25% to 30% after an acute coronary syndrome, and clopidogrel provides modest improvement over aspirin. However, both are relatively weak antiplatelet agents that each block only one of many pathways to platelet activation and surface membrane expression of the competent GP IIb/IIIa receptor. With the success of the intravenous GP IIb/IIIa antagonists in the acute setting, recent interest has focused on the potential benefit of oral GP IIb/IIIa antagonists used long-term for secondary prevention. The oral agents tested in phase III studies thus far have not performed up to expectations, however. The following paper reviews these studies and the implications of their results.