Showing papers by "Elliott M. Antman published in 2009"
TL;DR: Carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.
Abstract: Background Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function. Methods We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38. Results In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to ...
2,326 citations
TL;DR: A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based as discussed by the authors, and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) is to respond promptly to new evidence.
1,838 citations
TL;DR: A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based as discussed by the authors, and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) is to respond promptly to new evidence.
Abstract: ### Preamble
A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based. In an effort to respond promptly to new evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA)
1,750 citations
TL;DR: A primary challenge in the development of clinical practice guidelines is keeping pace with the stream of new data on which recommendations are based as mentioned in this paper, and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) is to respond promptly to new evidence.
1,554 citations
TL;DR: In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding.
1,037 citations
TL;DR: The current findings do not support the need to avoid concomitant use of PPIs, when clinically indicated, in patients receiving clopidogrel or prasugrel.
703 citations
TL;DR: Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel, and these pharmacogenetic findings are in contrast to observations with clopidogrel.
Abstract: Background—Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. Methods and Results—The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. Conclusions—Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications. (Circulation. 2009;119:2553-2560.)
592 citations
TL;DR: The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.
Abstract: Aims To examine the extent of platelet inhibition by prasugrel vs . clopidogrel in a TRITON-TIMI 38 substudy.
Methods and results TRITON-TIMI 38 randomized acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) to prasugrel or standard dose clopidogrel. Selected sites prospectively enrolled TRITON-TIMI 38 patients to evaluate adenosine diphosphate (ADP)-attenuated phosphorylation of platelet vasodilator-stimulated phosphoprotein (VASP) ( n = 125 patients) and, in a subset ( n = 31 patients), ADP-stimulated platelet aggregation. VASP platelet reactivity index (PRI) was lower in prasugrel-treated patients than in clopidogrel-treated patients at 1–2 h post-PCI (≥1 h after loading dose) ( P 50%, was more frequent in clopidogrel-treated patients than in prasugrel-treated patients at 1–2 h ( P < 0.001) and 30 days ( P = 0.03).
Conclusions The TRITON-TIMI 38 platelet substudy shows that prasugrel results in greater inhibition of ADP-mediated platelet function in ACS patients than clopidogrel, supporting the hypothesis that greater platelet inhibition leads to a lower incidence of ischaemic events and more bleeding both early and late following PCI.
247 citations
TL;DR: In this paper, the authors compared prasugrel with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention, and found that the latter significantly reduced the risk of myocardial infarction.
Abstract: Background—Prasugrel is a novel thienopyridine that reduces new or recurrent myocardial infarctions (MIs) compared with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. This effect must be balanced against an increased bleeding risk. We aimed to characterize the effect of prasugrel with respect to the type, size, and timing of MI using the universal classification of MI. Methods and Results—We studied 13 608 patients with acute coronary syndrome undergoing percutaneous coronary intervention randomized to prasugrel or clopidogrel and treated for 6 to 15 months in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). Each MI underwent supplemental classification as spontaneous, secondary, or sudden cardiac death (types 1, 2, and 3) or procedure related (Types 4 and 5) and examined events occurring early and after 30 days. Prasugrel significantly reduced the overall risk of MI (7.4% versus 9.7%; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.67 to 0.85; P0.0001). This benefit was present for procedure-related MIs (4.9% versus 6.4%; HR, 0.76; 95% CI, 0.66 to 0.88; P0.0002) and nonprocedural (type 1, 2, or 3) MIs (2.8% versus 3.7%; HR, 0.72; 95% CI, 0.59 to 0.88; P0.0013) and consistently across MI size, including MIs with a biomarker peak 5 times the reference limit (HR. 0.74; 95% CI, 0.64 to 0.86; P0.0001). In landmark analyses starting at 30 days, patients treated with prasugrel had a lower risk of any MI (2.9% versus 3.7%; HR, 0.77; P0.014), including nonprocedural MI (2.3% versus 3.1%; HR, 0.74; 95% CI, 0.60 to 0.92; P0.0069). Conclusion—Treatment with prasugrel compared with clopidogrel for up to 15 months in patients with acute coronary syndrome undergoing percutaneous coronary intervention significantly reduces the risk of MIs that are procedure related and spontaneous and those that are small and large, including new MIs occurring during maintenance therapy. (Circulation. 2009;119:2758-2764.)
154 citations
TL;DR: In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide.
138 citations
TL;DR: Prasugrel significantly reduces the risk of cardiovascular events in patients with acute coronary syndromes after percutaneous coronary intervention regardless of whether or not a GP IIb/IIIa inhibitor is used.
TL;DR: In this issue of Clinical Chemistry, three reports provide valuable insights into possible new applications for more sensitive assays, as well as raise new questions that must be addressed in the course of evaluation of a new generation of high-sensitivity cardiac troponin assays.
Abstract: Despite the facts that cardiac troponin was introduced 2 decades ago and has been established since 2000 as the preferred biomarker for the diagnosis of myocardial infarction (MI)1 (1), the clinical application of cardiac troponin assays continues to evolve substantively. In large part, this evolution has been driven by sustained progress in the analytical performance of commercially available cardiac troponin assays. Because of improved precision at low cardiac troponin concentrations and data establishing the prognostic relevance of quantitatively minor increases in this biomarker, the clinical decision limit for cardiac troponin has been pushed progressively lower. A recently emerged new generation of research assays for cardiac troponin now has reduced the limit of detection by another 10- to 100-fold compared with current commercially available assays (2)(3). In this issue of Clinical Chemistry , the report by Eggers et al. (4) and 2 reports by Wu et al. (5)(6) provide valuable insights into possible new applications for more sensitive assays, as well as raise new questions that must be addressed in the course of evaluation of a new generation of high-sensitivity cardiac troponin assays.
Because cardiac troponin is superior to the previous gold standard (creatine kinase isoenzyme MB) for MI diagnosis, the initial efforts to establish a uniform diagnostic decision limit were difficult and at times controversial. This challenge was (and still is) compounded by a lack of standardization of the multiple commercial assays for cardiac troponin I (cTnI) and the poor precision of some assays around the proposed diagnostic cutoffs; however, the uncertainty regarding the clinical significance of increases in cardiac troponin that are below the concentration equivalent to an abnormal increase in creatine kinase MB has been resolved by consistent epidemiologic data that have established a relationship between “low-level” increases in cardiac troponin among patients …
TL;DR: The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment, and the PK of Pras‐AM was adequately described by a multicompartmental model and consistent with results from previous studies.
Abstract: Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentration data to characterize the PK. The potential influence of body weight, body mass index, age, sex, renal function, diabetes, tobacco use, and other disease status on Bayesian estimates of Pras-AM exposures was assessed. The PK of Pras-AM was adequately described by a multicompartmental model and consistent with results from previous studies. The systemic exposure of prasugrel was not appreciably affected by body mass index, gender, diabetes, smoking, and renal impairment. Pras-AM mean exposure in patients weighing <60 kg (4.1%) was 30% (90% confidence interval [CI] 1.16-1.45) higher than exposure in patients ≥60 kg. Mean Pras-AM exposures for patients ≥75 years (10.5%) were 19% (90% CI: 1.11-1.28) higher compared with patients <75 years.
TL;DR: Despite the use of a standard weight-based unfractionated heparin nomogram in ST-segment elevation myocardial infarction, nontherapeutic anticoagulation is frequent and more likely among certain vulnerable patient groups, with excess anticoAGulation associated with increased bleeding and inadequate anticoague associated with reinfarction.
Abstract: Background— Although weight-based nomograms have improved the efficacy and safety of dosing unfractionated heparin in ST-segment elevation myocardial infarction, achieving therapeutic anticoagulation in practice remains challenging Methods and Results— In the Enoxaparin and Thrombolysis in Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 study, 20 506 patients with ST-segment elevation myocardial infarction were randomized to enoxaparin or unfractionated heparin, the latter dosed according to the American College of Cardiology/American Heart Association weight-based nomogram with centrally monitored activated partial thromboplastin times (aPTTs) A total of 6055 patients received study unfractionated heparin and a fibrin-specific lytic and had an initial aPTT drawn within 4 to 8 hours of starting therapy Despite close adherence to recommended dosing, only 338% of initial aPTTs were therapeutic (150 to 200 times control); 132% were markedly
03 Mar 2009
TL;DR: Among ACS patients who underwent PCI without stent implantation, prasugrel therapy tended to reduce clinical ischemic events and to increase bleeding events to a similar magnitude as among patients who received stents.
28 Apr 2009
TL;DR: The central assumption that coronary artery disease is synonymous in men and women is under revision and the medical community is recognizing the importance of an altered presentation of the myocardial ischemic systolic presentation.
Abstract: Much has changed in the field of myocardial ischemia over the past 3 years. The central assumption that coronary artery disease is synonymous in men and women is under revision. Increasingly, the medical community is recognizing the importance of an altered presentation of the myocardial ischemic sy
TL;DR: The work of the ACC/AHA Task Force on Practice Guidelines has expanded markedly, currently monitoring ≈17 CPG areas (with a major focus on disease management) and determining when revisions or updates are needed to accurately reflect the evolution of evidence in cardiovascular care.
Abstract: Every day, clinicians face difficult decisions on how best to manage a given patient. Important decisions include selection of the appropriate diagnostic tests, procedures, and/or treatments to improve a patient’s outcomes. Ideally, these decisions should be informed and guided by the best medical evidence. In reality, however, clinical practice tends to be highly variable.1 Concerned that a lack of standards for pacemaker implantation was leading to potential overutilization, governmental regulators asked the American Heart Association (AHA) and American College of Cardiology (ACC) in 1984 to evaluate the available evidence and develop recommendations for practice. This led to what became their first clinical practice guideline (CPG).2 Since then, the work of the ACC/AHA Task Force on Practice Guidelines has expanded markedly, currently monitoring ≈17 CPG areas (with a major focus on disease management) and determining when revisions or updates are needed to accurately reflect the evolution of evidence in cardiovascular care.
Article p 1330
The process for developing CPGs was outlined in 2003.3,4 The core focus of CPG writing committees is to review and summarize the evidence in the medical literature, relying heavily on randomized controlled trials (RCTs) and when these are not available to turn to other data sources including other forms of trials, meta-analyses, and registry data. The recommendations put forth in a CPG are rigorously classified according to whether a test, procedure, or other treatment is “useful and effective” in a given setting, as well according to the level of evidence supporting this view.3 A notable example of the effort of the Task Force on Practice Guidelines to provide timely responses to a rapidly changing evidence base has been the development of focused updates, the first 3 of which dealt with ST-elevation myocardial infarction, percutaneous coronary intervention, and chronic stable angina, responding to the …
TL;DR: Among STEMI patients treated with a fibrinolytic agent and aspirin, use of NSAIDs in the week preceding the incident event was associated with a higher incidence of MI, the composite of death and MI as well as the compositeof death, MI, severe heart failure and shock at 30 days.
Abstract: Background Non-steroidal anti-inflammatory drugs (NSAIDs) may be prothrombotic, may worsen hypertension or congestive heart failure and obstruct access to the binding site of aspirin to cyclooxygenase-1 and thereby interfere with aspirin’s mechanism of action in reducing death and recurrent myocardial infarction (MI). We hypothesized that treatment with NSAIDs prior to an index MI would be associated with an increase in the risk of death, heart failure and recurrent MI among patients with ST-segment elevation MI (STEMI) treated with fibrinolytic therapy. Methods In ExTRACT-TIMI 25, patients with STEMI were treated with aspirin and fibrinolytic therapy and randomized to either enoxaparin or unfractionated heparin. We included patients who had received NSAIDs within 7 days of enrollment and evaluated the incidence of MI, the composite of death and MI and the composite of death, MI, severe heart failure and shock through 30 days. Results Of 20,479 patients enrolled, 572 (2.8%) received an NSAID within 7 days of enrollment. NSAID treatment prior to entry was associated with a higher incidence of 30-day death or nonfatal recurrent MI (15.9% vs. 10.8%, univariate P < 0.001). In multivariable models adjusting for randomization group and differences in baseline characteristics, NSAID use was associated with higher odds of MI (adjusted odds ratio [ORadj] 1.44, 95% confidence interval [CI] 1.01–2.07, P = 0.047), the composite of death and MI (ORadj 1.29, 95% CI 1.00–1.66, P = 0.051), and the composite of death, MI, severe heart failure and shock (ORadj 1.29, 95% CI 1.02–1.65, P = 0.037). Conclusions Among STEMI patients treated with a fibrinolytic agent and aspirin, use of NSAIDs in the week preceding the incident event was associated with a higher incidence of MI, the composite of death and MI as well as the composite of death, MI, severe heart failure and shock at 30 days.
TL;DR: The LI is a simple, powerful tool to predict death in STEMI, either separately or with the TRS, and offers additional risk stratification across all TRS groups and improved the discriminatory ability of the T RS.
TL;DR: Fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.
Abstract: Background: Enoxaparin was superior to unfractionated heparin (UFH), regardless of fibrinolytic agent in ST-elevation myocardial infarction (STEMI) patients receiving fibrinolytic therapy in ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction 25) trial. Objective: This post hoc analysis compared outcomes with streptokinase plus enoxaparin to the standard regimen of fibrin-specific lytic (FSL) plus UFH and to the newer combination of FSL plus enoxaparin. Methods: In ExTRACT-TIMI 25, STEMI patients received either streptokinase or a FSL (alteplase, reteplase or tenecteplase) at the physician’s discretion and were randomized to enoxaparin or UFH, stratified by fibrinolytic type. Thirty-day outcomes were adjusted for baseline characteristics, region, in-hospital percutaneous coronary intervention (PCI) and a propensity score for the choice of lytic. Results: The primary trial endpoint of 30-day death/myocardial infarction (MI) occurred in fewer patients in the streptokinase-enoxaparin cohort (n = 2083) compared with FSL-UFH (n = 8141) [10.2% vs 12.0%, adjusted odds ratio [ORadj] 0.76; 95% CI 0.62, 0.93; p = 0.008]. Major bleeding was significantly increased with streptokinase-enoxaparin compared with FSL-UFH (ORadj 2.74; 95% CI 1.81; 4.14; p<0.001) but intracranial haemorrhage (ICH) was similar (ORadj 0.90; 95% CI 0.40, 2.01; p = 0.79). Net clinical outcomes, defined as either death/MI/major bleeding or as death/MI/ICH tended to favour streptokinase-enoxaparin compared with FSL-UFH (ORadj 0.88; 95% CI 0.73, 1.06; p = 0.17; and ORadj 0.77; 95% CI 0.63,0.93; p = 0.008, respectively). Patients receiving FSL-enoxaparin (n = 8142) and streptokinase-enoxaparin therapies experienced similar adjusted rates of the primary endpoint (ORadj 1.08; 95% CI 0.87, 1.32; p = 0.49) and net clinical outcomes. Conclusions: Our results suggest that fibrinolytic therapy with the combination of streptokinase and the potent anticoagulant agent enoxaparin resulted in similar adjusted outcomes compared with more costly regimens utilizing a FSL.
TL;DR: A substantial variation in CK-MB ratios and MI outcomes between the site and core laboratory data was observed in the SYNERGY trial, and patients with MI had lower 1-year survival, making these events potentially clinically important.
Abstract: The effect of nonstandardized creatine kinase (CK)-MB assays on the assessment of myocardial infarction (MI) end points in multicenter international trials has not been evaluated. We compared the site-reported and corresponding core laboratory CK-MB measures from 5 countries participating in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Samples for CK-MB were collected locally, with corresponding samples sent to a core laboratory at enrollment and after recurrent ischemic events, percutaneous coronary intervention, or coronary artery bypass grafting. The measured values were compared to the reported assay upper limits of normal (ULN) used at the site (or core laboratory for the core laboratory samples). The CK-MB results were available locally and from the core laboratory for 913 patients, constituting 4,693 time-matched laboratory values. The agreement between the core and site laboratory CK-MB/ULN ratio was moderate (concordance correlation coefficient 0.45) and varied considerably by geographic location and site. The CK-MB values were elevated (≥2 times the ULN) by the core laboratory but normal (
Journal Article•
TL;DR: In this article, the authors consider the results of the TRITON-TIMI 38 trial to be hypothesis generating, and they consider that the overall results of a clinical trial should be considered to apply to those patients who were included in the clinical trial and that subgroup analyses should be interpreted with caution.
Abstract: We appreciate the letter by Drs Rosenstein and Parra about the diabetes mellitus (DM) analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel: Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38.1 We agree with the general principle that the overall results of a clinical trial should be considered to apply to those patients who were included in the clinical trial and that subgroup analyses should be interpreted with caution. The results should be considered to be hypothesis generating. Clinical trials in general are, and TRITON–TIMI 38 in specific was, not powered for efficacy end points in all individual subgroups. It is impractical to repeat an adequately powered clinical trial in each individual subgroup. We believe that the altered …