Effect of prasugrel versus clopidogrel on outcomes among patients with acute coronary syndrome undergoing percutaneous coronary intervention without stent implantation: A TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)–Thrombolysis in Myocardial Infarction (TIMI) 38 Substudy

doi:10.1016/j.ahj.2009.06.021

American Heart Journal

Volume 158, Issue 3, September 2009, Pages e21-e26

https://doi.org/10.1016/j.ahj.2009.06.021 Get rights and content

Background

Prasugrel led to a significant reduction in ischemic cardiovascular events among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation compared to clopidogrel. Whether this benefit extends to patients undergoing PCI without stent implantation is unknown.

Methods

In TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38, patients (n = 13 608) undergoing PCI for ACS were randomized to aspirin plus clopidogrel or prasugrel. This postrandomization analysis of a prespecified subgroup was restricted to patients who underwent PCI without stent implantation (n = 569).

Results

Patients who underwent PCI without stent implantation were older and had a higher incidence of hypertension, diabetes, prior myocardial infarction (MI), prior coronary artery bypass (CABG) surgery, and renal dysfunction than patients who underwent stent implantation. In the group that did not undergo stent implantation, baseline characteristics were similar between patients receiving clopidogrel and prasugrel. The composite of cardiovascular death, nonfatal MI, and nonfatal stroke occurred in 14.2% of patients receiving prasugrel and 17.1% of patients receiving clopidogrel (HR 0.82, P = .27). There were significant reductions favoring prasugrel in the rates of urgent target vessel revascularization (TVR; HR 0.46, P = .040) and any TVR (HR 0.40, P = .009) and a trend toward a reduction in the incidence of nonfatal MI (HR 0.65, P = .11). CABG-related TIMI major bleeding was more frequent among patients receiving prasugrel. There were no significant interactions between treatment and PCI type.

Conclusion

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.

Section snippets

Methods

TRITON-TIMI 38 was designed as a collaboration between the TIMI Study Group, the sponsors, and a steering committee of investigators. All key prespecified and exploratory analyses were performed by the TIMI Study Group using an independent copy of the complete database. The academic authors wrote all drafts of the manuscript and vouch for the veracity and completeness of its content.

Results

There were 13 608 patients enrolled in the trial. Of these, 569 (4.2%) underwent PCI without stent implantation. Baseline characteristics comparing patients who did and did not undergo stent implantation are shown in Table I. Patients who did not receive intracoronary stents were more likely to have been enrolled following STEMI, were older, less likely to abuse tobacco and more likely to be of non-white race; to have been enrolled in Eastern Europe; and to have hypertension, diabetes mellitus,

Discussion

Among patients with moderate- to high-risk ACS who underwent PCI without stent implantation, there was no significant interaction between the benefits of treatment with prasugrel as a function of PCI type (stent vs no stent). In the population that did not undergo stent implantation, the magnitude of the relative risk reduction in ischemic CV events with prasugrel was similar to that observed among patients treated with stent implantation. Moreover, prasugrel therapy was associated with

Conclusions

Prasugrel therapy tended to reduce major adverse CV events and to increase bleeding among patients with ACS who underwent PCI without stent implantation to a similar degree as among those who received intracoronary stents. The rates of TVR and urgent TVR were significantly reduced among patients receiving prasugrel, whereas major bleeding was more frequent.

Disclosures

Dr Wiviott has received consulting fees from Sanofi-Aventis, speaking honoraria from Daiichi Sankyo and Eli Lilly, and research funding from Eli Lilly and Daiichi Sankyo. Dr Antman has received consulting fees from and sat on the advisory board of Sanofi-Aventis and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Braunwald has received consulting fees from and sat on the advisory board of Sanofi-Aventis and Daiichi Sankyo; and lecture fees from Eli Lilly and Sanofi-Aventis. Dr Gibson has

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This review aims to provide insights into contemporary therapeutic options for the treatment of patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) and compares current international guidelines. AF is a common cardiac arrhythmia and a major risk factor for stroke. The risk of stroke can be reduced with the use of oral anticoagulant (OAC) therapy. However, for patients with AF, PCI necessitates the use of combined antithrombotic therapies (OAC and antiplatelet therapies) to reduce thrombotic coronary complications. Optimal combinations and durations of OAC and/or antiplatelet therapy remains an area of clinical debate. Nuances exist within the current guidelines regarding duration and combination of antithrombotic therapy for AF patients requiring PCI. However, consensus was found across the following key points: (i) recent evidence supports a preferred role for a dual antithrombotic approach (OAC plus 1 antiplatelet); (ii) limited use of triple antithrombotic therapy is recommended across all guidelines for patients where the ischemic risk outweighs the risk of bleeding, with the duration to be kept as short as possible; and (iii) lifelong management using monotherapy with an OAC from 12 months post PCI is recommended for stable patients across all guidelines.
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Prasugrel is the most recent member of the thienopyridine class of antiplatelet agents [1]. Similarly to other thienopyridines, it is commonly used in the therapy of choice for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation [2,3]. The registered medication brands with prasugrel contain the active substance (API) in the form of hydrochloride salt.
A fast and selective capillary electrophoresis method was developed and validated for the simultaneous determination of the hydrochloride and acetic acid content in prasugrel hydrochloride. Because of the poor chromophore, the indirect detection was chosen. Among different compositions studied as the background electrolyte, the pyromellitic acid with diethylamine (DEA) and myristyltrimethylammonium bromide (TTAB) was chosen. During the validation the specificity, linearity, accuracy, precision, range, and stability of the sample solution were confirmed. The results indicate that the method is suitable for the determination of the counter ion and impurity from the synthetic route of the pharmaceutical drug substance in the same assay
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In addition, other unintentional inclusion or exclusion criteria in clinical trials may have excluded patients with significant comorbidities or those receiving warfarin. The impact of history of AF on ACS management may be related to the higher chronic use of oral anticoagulation therapy, since most of the randomized studies of antiplatelet therapies such as thienopyridine and glycoprotein IIb/IIIa inhibitors excluded patients receiving warfarin.22-31 Patients receiving triple therapy with aspirin, warfarin, and thienopyridine for ACS had more HF, arrhythmias, ischemia, and major bleeding.32,33
The prognostic impact of atrial fibrillation (AF) in the setting of acute coronary syndrome (ACS) is controversial. Furthermore, there are limited real-world data on the management of ACS patients with history of AF.
The Global Registry of Acute Coronary Events (GRACE/GRACE2) and Canadian Registry of Acute Coronary Events (CANRACE) enrolled 14,285 patients across Canada between 1999 and 2008. Patients were stratified by the presence of history of AF. We compared clinical characteristics, medical therapies, cardiac procedures, and clinical outcomes between the 2 groups.
Overall, 1333 of the enrolled patients (9.3%) had history of AF, of whom 51.5% presented with non–ST-segment elevation myocardial infarction, 29.5% with unstable angina, and 19.1% with ST-segment elevation myocardial infarction. Compared with the group without, patients with a history of AF less frequently received evidence-based antiplatelet and antithrombin therapies, left ventricle ejection fraction assessment, and coronary angiography (all P < 0.001); they also had higher unadjusted rates of in-hospital death, myocardial (re)infarction, and heart failure. However, in multivariable analysis, history of AF was not found to be independently associated with in-hospital mortality (adjusted odds ratio [OR] = 1.12; 95% confidence interval (CI), 0.73-1.73; P = 0.61) or death and/or myocardial reinfarction (adjusted OR = 1.15; 95% CI, 0.87-1.5; P = 0.34).
History of AF is common among ACS patients. They received less evidence-based medical and invasive therapies than ACS patients without history of AF. History of AF is a negative independent predictor of in-hospital coronary angiography but was not found to be independently associated with adverse outcomes.
Les conséquences pronostiques de la fibrillation auriculaire (FA) dans le cadre du syndrome coronarien aigu (SCA) sont controversées. Par ailleurs, les données du monde réel sur la prise en charge des patients ayant un SCA associé à des antécédents de FA sont limitées.
Le registre global GRACE (GRACE/GRACE2 : Global Registry of Acute Coronary Events) et le registre canadien CANRACE (Canadian Registry of Acute Coronary Events) ont inscrit 14 285 patients de partout au Canada entre 1999 et 2008. Les patients ont été stratifiés selon la présence d'antécédents de FA. Nous avons comparé les caractéristiques cliniques, les traitements médicaux, les interventions cardiaques et les résultats cliniques entre les 2 groupes.
Dans l'ensemble, 1 333 patients inscrits (9,3 %) avaient des antécédents de FA, parmi lesquels 51,5 % avaient eu un infarctus du myocarde sans sus-décalage du segment ST, 29,5 %, une angine instable, et 19,1 %, un infarctus du myocarde avec sus-décalage du segment ST. Comparativement au groupe sans antécédents de FA, les patients ayant des antécédents recevaient moins fréquemment des traitements aux antiplaquettaires et aux antithrombines basés des preuves, une évaluation de la fraction d'éjection du ventricule gauche et une coronarographie (P < 0,001 pour tous); ils avaient aussi des taux non ajustés plus élevés de décès intrahospitaliers, d'infarctus ou de nouvel infarctus du myocarde, et d'insuffisance cardiaque. Cependant, dans l'analyse multivariable, les antécédents de FA ne s'étaient pas avérés être indépendamment associés à la mortalité intrahospitalière (ratio d'incidence approché ajusté = 1,12; intervalle de confiance de 95 %, 0,73-1,73; P = 0,61) ou au décès ou à un nouvel infarctus du myocarde (ratio d'incidence approché ajusté = 1,15; intervalle de confiance de 95 %, 0,87-1,5; P = 0,34).
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Citation Excerpt :
Other subanalyses of the TRITON-TIMI 38 trial included evaluations of stent placement, timing of thrombotic events, and glycoprotein IIb/IIIa inhibitor (GPI) use.45,48–50,57 A subanalysis by Pride et al48 found that the impact of prasugrel on the reduction of the composite of CV death, nonfatal MI, nonfatal stroke, and rate of increased non-CABG TIMI major or minor bleeding was similar in both patients who received stents and those who did not have stent implantation (Pinteraction = 0.9469, Pinteraction = 0.5236, respectively). Among the 5 patients in this subgroup who had bleeding, 2 had a history of stroke and 1 weighed <60 kg.
Prasugrel is the most recent addition to the available thienopyridine antiplatelet agents used to prevent ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention.
The aim of this article was to review published data on the efficacy and safety profile of prasugrel, cost considerations with its use, and its place in clinical care.
We searched PubMed and Ovid databases for English language clinical trial articles, published through December 2010, involving the use of prasugrel in human subjects. The key word prasugrel was used. The review focused on clinical trials, but other articles and Food and Drug Administration documents were also reviewed for relevant information.
Phase II studies showed that prasugrel had a more powerful antiplatelet effect and was more effective in its inhibition of platelet activation than clopidogrel. In the only Phase III trial completed before its Food and Drug Administration approval, prasugrel demonstrated a decrease in the primary composite efficacy end point of the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke relative to clopidogrel (643 [9.9%] vs 781 [12.1%], respectively; P = 0.001). Prasugrel was associated with a significantly higher risk of bleeding compared with clopidogrel. Non–coronary artery bypass graft-related thrombolysis in myocardial infarction (TIMI) major bleeding occurred in 146 (2.4%) patients in the prasugrel group versus 111 (1.8%) patients in the clopidogrel group (P = 0.03). For every 1000 patients treated with prasugrel instead of clopidogrel, a total of 23 myocardial infarctions could be prevented at the cost of 6 additional TIMI major bleeding events. However, this benefit was diminished with longer-term therapy. Adverse outcomes of prasugrel use outweighed its benefits in certain subgroups, including patients >75 years old, those weighing <60 kg, and patients with a history of stroke or transient ischemic attack.
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Background

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Conclusions

Disclosures

Lancet

Lancet

Am Heart J

Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial

Lancet

Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation

N Engl J Med

Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation

N Engl J Med