Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes Robert F. Storey, Steen Husted, Robert ...A. Harrington, Stanley Heptinstall, Robert G. Wilcox, Gary Peters, Mark Wickens, Håkan Emanuelsson, Paul Gurbel, Peer Grande, Christopher P. Cannon In a substudy of the DISPERSE2 study, we compared the effects of clopidogrel and AZD6140 on adenosine diphosphate-induced platelet aggregation in both clopidogrel-naïve and clopidogrel-pretreated patients with non–ST-segment elevation acute coronary syndromes. AZD6140 exhibited greater mean inhibition of platelet aggregation than clopidogrel. Additionally, AZD6140 further suppressed platelet aggregation in patients already treated with clopidogrel.
Background Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the ...first reversible oral P2Y12 receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate–receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS. Methods PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non–ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life. Conclusion The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.
Objectives This study sought to review cardiac troponin (cTn) trends during non–ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) ...in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndromes) and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) studies and to study the relationship between post-PCI cTn and mortality. Background The prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI). Methods Time and cTn (indexed by upper limit of normal ULN) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-myocardial band and 1-year mortality. Results Patients with cTn (re-)elevation post-PCI not evaluable were identified and excluded from further analysis (4,198 41% with cTn rising prior to PCI; 229 2% with missing cTn). Among the remainder (n = 5,772 57%), in the multivariable model, peak cTn post-PCI was associated with a 7% increase in mortality (hazard ratio HR for 10× ULN increase: 1.07, 95% confidence interval CI: 1.02 to 1.11; p = 0.0038). Peak post-PCI creatine kinase-myocardial band was significantly associated with 1-year mortality (HR for 1× ULN increase: 1.13, 95% CI: 1.05 to 1.21; p = 0.0013). Conclusions We used a methodology that differentiated post-PCI cTn (re-)elevation from that of presenting MI in more than one-half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implications for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis.
Since the original publication of the IMPROVE-IT Trial design,1 controversy over the impact of ezetimibe on the risk of cardiovascular events, as well as the drug's effect on the balance of benefit ...and risk for overall health outcomes, has persisted.2,3 This controversy has kept IMPROVE-IT in the public awareness,4 and questions have been raised about whether the trial will be completed.5 The purpose of this report is 2-fold: first, to describe the rationale for helping to ensure that IMPROVE-IT will accurately detect the effect of ezetimibe on cardiovascular events as a function of the expected relationship between low-density lipoprotein cholesterol (LDL-C) and cardiovascular outcomes seen with statin drugs, and second, to provide an update on the trial's expected completion date. ...IMPROVE-IT is focused on patients with relatively low LDL-C values at incident ACS, in whom treatment with simvastatin 40 mg + placebo is likely to result in achievement of the 2004 NCEP ATP III Update LDL-C goals.7 Although it is not absolutely known whether the relationship between LDL-C lowering and change in CVD risk is log-linear at the lowest LDL-C levels (due to limited amounts of data gathered from the lower range of measurements), it is reasonable to assume that this relationship holds at lower LDL-C ranges. Because available systematic reviews consistently demonstrate a log-linear relationship on a relative scale (curvilinear on an absolute scale) between absolute reduction in LDL-C levels and reduction in cardiovascular events,8 and because the expected LDL-C treatment group difference is smaller than in placebo-controlled trials, the expected difference in event rates at the lower end of LDL-C values addressed by this trial is likely to be relatively modest in absolute terms, compared with most other CVD outcomes trials.
Background Non–ST-segment myocardial infarction (NSTEMI) can be complicated by high-degree atrioventricular (AV) block, asystole, or electromechanical dissociation (EMD), but these events are not ...well characterized in the contemporary era. This analysis assesses the incidence of and factors associated with these dysrhythmias in acute NSTEMIs. Methods Patients with NSTEMI in the EARLY ACS, PLATO, and TRACER trials were included in the pooled cohort (N = 29,677). Logistic regression was used to identify factors associated with in-hospital high-degree AV block and asystole or EMD, and Kaplan-Meier methods were used to assess mortality. Results High-degree AV block occurred in 112 (0.4%) patients, asystole in 157 (0.5%), and EMD in 38 (0.1%). Pacemakers were inserted in 241 patients (0.8%) during the index hospitalization: 30 (12%) for AV block. Among patients with high-degree AV block, we observed more frequent right coronary artery lesions (47% vs 29%). Age, diabetes, lower heart rate, and lower blood pressure were associated with high-degree AV block. Higher Killip class, ST-segment depression, prior myocardial infarction, and peripheral vascular disease were most strongly associated with asystole or EMD. Ten-day unadjusted survival was 90% for patients with high-degree AV block and 43% for those with asystole or EMD. Conclusions Although high-degree AV block, asystole, and EMD were infrequent complications of NSTEMI, they were associated with substantial short-term mortality. Only 1 in 8 pacemakers placed in NSTEMI patients during the acute hospitalization was for high-degree AV block.
Background Female sex is an established risk factor for bleeding, which is an important safety end point in patients presenting with non–ST-segment elevation acute coronary syndromes (NSTE ACS). ...However, it is unknown whether the association between bleeding and mortality is modulated by sex in this patient population. Methods We examined the interaction between sex and bleeding and 30-day mortality outcomes among 2,975 women and 6,431 men with high-risk NSTE ACS enrolled in the EARLY ACS trial. The Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria were used to identify moderate or severe bleeds. Results Women were older and had more comorbid disease compared with men. Bleeding rates were higher among women (8.2%) than among men (5.5%; P < .01). However, the association of bleeding and 30-day mortality was stronger among men (odds ratio 5.8, 95% CI 3.9-8.8) than among women (odds ratio 1.5, 95% CI 0.8-2.9; sex * bleeding interaction P < .01). Sex differences in the association of bleeding and mortality persisted in a landmark analysis of 120-hour survivors. Conclusions In a contemporary high-risk NSTE ACS cohort, women had higher bleeding rates than did men. Paradoxically, the association between bleeding and mortality was worse among men than among women.
Antithrombotics in Acute Coronary Syndromes Bonaca, Marc P., MD; Steg, Philippe Gabriel, MD; Feldman, Laurent J., MD ...
Journal of the American College of Cardiology,
09/2009, Volume:
54, Issue:
11
Journal Article
Peer reviewed
Open access
Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary ...syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management.
Background We examined the prevalence of undiagnosed diabetes or prediabetes and associations with ischemic outcomes among non–ST-segment elevation acute coronary syndrome (ACS) patients. Methods We ...categorized 8795 EARLY ACS trial patients into one of the following groups: “known diabetes” (n = 2860 32.5%; reported on the case report form), “undiagnosed diabetes” (n = 1069 12.2%; no diabetes history and fasting glucose ≥126 mg/dL or hemoglobin A1c ≥6.5%), “prediabetes” (n = 947 10.8%; fasting glucose ≥110 to <126 mg/dL, or “normal” (n = 3919 44.5%). Adjusted associations of known diabetes, undiagnosed diabetes, and prediabetes (versus normal) with 30-day and 1-year outcomes were determined. Results Undiagnosed diabetes was associated with greater 30-day death or myocardial infarction (MI) (ORadj 1.28, 95% CI 1.05-1.57), driven primarily by greater 30-day mortality (ORadj 1.65, 95% CI 1.09-2.48). Known diabetic patients had 30-day death or MI outcomes similar to those of normal patients, but 30-day mortality was higher (ORadj 1.40, 95% CI 1.01-1.93). Prediabetic patients had 30-day death or MI outcomes similar to those of normal patients. One-year mortality was greater among known diabetic patients (HRadj 1.38, 95% CI 1.13-1.67) but not among those with undiagnosed diabetes or prediabetes. Conclusions Undiagnosed diabetes and prediabetes were common among high-risk non–ST-segment elevation ACS patients. Routine screening for undiagnosed diabetes may be useful since these patients seem to have worse short-term outcomes and deserve consideration of alternative management strategies.
Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for ...Clinical Event Reduction in Acute Coronary Syndrome) study patients with non–ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). Conclusions In non–ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome TRA·CER Study P04736AM3; NCT00527943 )
Background Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO ...trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits. Methods Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses. Results Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 95% CI, 1.07-1.94); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 95% CI, 0.68-1.00) and ex/nonsmokers (adjusted HR, 0.89 95% CI, 0.79-1.00) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 0.39-0.91) and ex/nonsmokers (adjusted HR, 0.69 95% CI, 0.45-1.07) (interaction P = .61). Conclusions In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.
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