A Direct Comparison of Intravenous Enoxaparin With Unfractionated Heparin in Primary Percutaneous Coronary Intervention (from the ATOLL Trial)

doi:10.1016/j.amjcard.2013.07.003

The American Journal of Cardiology

Volume 112, Issue 9, 1 November 2013, Pages 1367-1372

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https://doi.org/10.1016/j.amjcard.2013.07.003 Get rights and content

Intravenous enoxaparin did not reduce significantly the primary end point (p = 0.06) compared with unfractionated heparin (UFH) in the randomized Acute Myocardial Infarction Treated with primary angioplasty and intravenous enoxaparin Or unfractionated heparin to Lower ischemic and bleeding events at short- and Long-term follow-up (ATOLL) trial. We present the results of the prespecified per-protocol analysis excluding patients who did not receive the treatment allocated by randomization or received both enoxaparin and UFH. We evaluated all-cause mortality, complication of myocardial infarction, procedural failure, or major bleeding (primary end point) and all-cause mortality, recurrent acute coronary syndrome, or urgent revascularization (main secondary end point). Baseline and procedural characteristics were well balanced between the 2 treatment groups. Of 910 randomized patients, 795 patients (87.4%) were treated according to the protocol with consistent anticoagulation using intravenous enoxaparin (n = 400) or UFH (n = 395). Enoxaparin reduced significantly the rates of the primary end point (relative risk [RR] 0.76, 95% confidence interval [CI] 0.62 to 0.94, p = 0.012) and the main secondary end point (RR 0.37, 95% CI 0.22 to 0.63, p <0.0001). There was less major bleeding with enoxaparin (RR 0.46, 95% CI 0.21 to 1.01, p = 0.050) contributing to the significant improvement of the net clinical benefit (RR 0.46, 95% CI 0.3 to 0.74, p = 0.0002). All-cause mortality was also reduced with enoxaparin (RR 0.36, 95% CI 0.18 to 0.74, p = 0.003). In conclusion, in the per-protocol analysis of the ATOLL trial, pertinent to >87% of the study population, enoxaparin was superior to UFH in reducing ischemic end points and mortality.

Section snippets

Methods

ATOLL was an international, randomized, open-label trial led by the Academic ACTION study group (www.action-coeur.org) evaluating IV enoxaparin versus IV UFH in patients undergoing primary PCI for ST elevation myocardial infarction. The study protocol has been described in detail elsewhere.¹ All patients assigned to enoxaparin by randomization received an IV bolus of 0.5 mg/kg enoxaparin without anticoagulation monitoring as previously described.² After the procedure, prolongation of

Results

In the ATOLL trial, none of the 910 patients received an anticoagulant before randomization. Compliance with interactive voice response system-indicated study drug before and during catheterization was 96% (n = 433) and 97% (n = 444) for IV enoxaparin and IV UFH, respectively. Patients who were administered both heparins numbered 8 (1.8%) and 6 (1.3%) before and during catheterization, respectively, and 42 (9.3%) and 58 (12.6%) during the whole study period in the enoxaparin and UFH groups.

Discussion

In the ATOLL trial, most patients were treated according to the study protocol.¹ Only 1 of 10 patients was crossed to the other study drug during or after revascularization. Crossover to another heparin and simultaneous administration of both anticoagulants were protocol violations and were shown in the past to be associated with worse outcomes.4, 5, 6, 7, 8 Nine of 10 patients were treated consistently with the same anticoagulant, which is a major difference compared with recent trials in

Acknowledgment

The authors are indebted to the patients who agreed to participate in this trial, the study contributors, and the investigators who recruited patients. Prof. Gilles Montalescot had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Cited by (51)

The Evolution of Anticoagulation for Percutaneous Coronary Intervention: A 40-Year Journey
2022, Canadian Journal of Cardiology
Citation Excerpt :
At 30 days, a trend toward reduction in the primary net composite (death, complication of MI, procedure failure, or major bleeding) was observed with enoxaparin (HR, 0.83; 95% CI, 0.68-1.01) with no difference in major bleeding among groups.26 In a per-protocol analysis of ATOLL, enoxaparin was superior to UFH in reducing ischemic end points and mortality.27 A subsequent meta-analysis confirmed the lower rates of mortality and bleeding with enoxaparin in STEMI patients undergoing primary PCI.28
The selection of antithrombotic strategies continue to be of utmost importance during percutaneous coronary intervention (PCI) and have evolved over the past 40 years. Although the backbone of therapy during PCI continues to be a combination of oral antiplatelets and parenteral anticoagulants, a variety of different approaches have been tested over time. In particular, different choices of anticoagulation management have been tested in the stable ischemic heart disease and acute coronary syndrome setting. Evaluation of alternative regimens in the quest to balance ischemic and bleeding risk have undoubtedly improved patient care with PCI. In the current review we highlight the evolution of evidence-based therapeutic options over the past 40 years from the beginning of coronary angioplasty to contemporary PCI. We provide insight into future therapeutic options and provide a contemporary overview of anticoagulation choices for patients who require PCI on the basis of up-to-date evidence balancing ischemic and bleeding risk and according to clinical presentation.
Les stratégies antithrombotiques pour les interventions coronariennes percutanées (ICP) ont grandement évolué au cours de 40 dernières années, et la sélection de la bonne option demeure de la plus haute importance. Bien que l’association d’antiplaquettaires par voie orale et d’anticoagulants par voie parentérale continue d’être le traitement phare lors des ICP, d’autres approches ont été mises à l’essai au fil des années. Plus particulièrement, plusieurs options d’anticoagulothérapie ont été proposées, à la fois dans les cas de cardiopathie ischémique stable et du syndrome coronarien aigu. L’évaluation des différents schémas dans le but de soupeser les risques d’ischémie et de saignement a mené sans l’ombre d’un doute à l’amélioration des soins offerts aux patients faisant l’objet d’une ICP. Notre article de synthèse présente l’évolution des options thérapeutiques basées sur les données probantes recueillies au cours de 40 dernières années, des balbutiements de l’angioplastie coronarienne à l’ICP contemporaine. À la lumière des données probantes les plus récentes, nous présentons un survol des options thérapeutiques à venir et des choix actuels d’anticoagulothérapie pour les patients qui subissent une ICP en tenant compte de l’équilibre entre les risques d’ischémie et de saignement selon le tableau clinique des patients.
Reply: Should Postprocedure Anticoagulation Be Routinely Needed in Acute STEMI Patients Undergoing Primary PCI?
2022, JACC: Cardiovascular Interventions
2019 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Guidelines on the Acute Management of ST-Elevation Myocardial Infarction: Focused Update on Regionalization and Reperfusion
2019, Canadian Journal of Cardiology
Citation Excerpt :
A meta-analysis of 10 studies that compared enoxaparin and UFH in the setting of PPCI for STEMI showed a reduction in mortality (RR,0.51; 95% CI, 0.41-0.61) and major bleeding (RR, 0.68; 95% CI, 0.49-0.94) with enoxaparin; this benefit was more pronounced in STEMI patients with higher risk.194 The Acute Myocardial Infarction Treated with Primary Angioplasty and Intravenous Enoxaparin or Unfractionated Heparin to Lower Ischemic and Bleeding Events at Short- and Long-Term Follow-up (ATOLL) trial randomized STEMI patients to a 0.5 mg/kg I.V. dose of enoxaparin or UFH in the setting of primary PCI.195,196 Although the study failed to meet its combined primary end point (death, MI, procedural failure, and major bleeding at 30 days; 28% with enoxaparin vs 34% with UFH P = 0.06), enoxaparin was superior to UFH in reducing the main secondary end point of death, MI, or major bleeding (7% vs 11%; P = 0.015 and other clinically significant ischemic end points).195,196
Rapid reperfusion of the infarct-related artery is the cornerstone of therapy for the management of acute ST-elevation myocardial infarction (STEMI). Canada’s geography presents unique challenges for timely delivery of reperfusion therapy for STEMI patients. The Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology STEMI guideline was developed to provide advice regarding the optimal acute management of STEMI patients irrespective of where they are initially identified: in the field, at a non-percutaneous coronary intervention-capable centre or at a percutaneous coronary intervention-capable centre. We had also planned to evaluate and incorporate sex and gender considerations in the development of our recommendations. Unfortunately, inadequate enrollment of women in randomized trials, lack of publication of main outcomes stratified according to sex, and lack of inclusion of gender as a study variable in the available literature limited the feasibility of such an approach. The Grading Recommendations, Assessment, Development, and Evaluation system was used to develop specific evidence-based recommendations for the early identification of STEMI patients, practical aspects of patient transport, regional reperfusion decision-making, adjunctive prehospital interventions (oxygen, opioids, antiplatelet therapy), and procedural aspects of mechanical reperfusion (access site, thrombectomy, antithrombotic therapy, extent of revascularization). Emphasis is placed on integrating these recommendations as part of an organized regional network of STEMI care and the development of appropriate reperfusion and transportation pathways for any given region. It is anticipated that these guidelines will serve as a practical template to develop systems of care capable of providing optimal treatment for a wide range of STEMI patients.
La reperfusion rapide de l’artère responsable de l’infarctus est la pierre angulaire thérapeutique de la prise en charge de l’infarctus aigu du myocarde avec élévation du segment ST (STEMI). Les caractéristiques géographiques du Canada posent des défis particuliers pour prodiguer aux patients victimes d’un STEMI une reperfusion dans les délais requis. Les lignes directrices sur l’STEMI de la Société canadienne de cardiologie et de l’Association canadienne de cardiologie d’intervention ont été élaborées pour formuler des recommandations sur la prise en charge aiguë optimale des patients victimes d’un STEMI sans égard à l’endroit où l’infarctus a été initialement constaté, que ce soit à l’extérieur ou dans un établissement en mesure ou incapable de pratiquer une intervention coronarienne percutanée. Nous avions prévu d’évaluer également et d’intégrer la prise en compte du sexe et du genre dans l’élaboration de nos recommandations. Malheureusement, le nombre insuffisant de femmes recrutées dans les essais avec répartition aléatoire, le manque de publications sur les critères d’évaluation principaux stratifiés en fonction du sexe et l’omission fréquente du sexe à titre de variable de l’étude dans la littérature limitaient la faisabilité d’une telle approche. Le système GRADE (« Grading Recommendations, Assessment, Development, and Evaluation ») a été utilisé pour formuler des recommandations précises, fondées sur des données probantes, pour le repérage précoce des patients victimes d’un STEMI, les aspects pratiques concernant le transport des patients, la prise de décision au sujet de la reperfusion au niveau régional, les interventions d’appoint préhospitalières (oxygène, opioïdes, traitement antiplaquettaire), ainsi que les aspects procéduraux de la reperfusion mécanique (voie d’accès, thrombectomie, traitement antithrombotique, étendue de la revascularisation). Une importance particulière est accordée à l’intégration de ces recommandations à un réseau régional structuré de prise en charge du STEMI et à l’élaboration de parcours appropriés de reperfusion et de transport dans chaque région. On s’attend à ce que ces lignes directrices servent de modèle pratique pour l’élaboration de systèmes de soins permettant d’offrir un traitement optimal à un large éventail de patients victimes d’un STEMI.
Reperfusion therapies for acute ST elevation myocardial infarction
2018, Cardiac Intensive Care
Pre-hospital ticagrelor in ST-segment elevation myocardial infarction in the French ATLANTIC population
2017, International Journal of Cardiology
Citation Excerpt :
Lastly, in the French population, radial access and younger age were independently associated with a reduced rate of ischaemic complications, major bleeding complications and mortality. The high rate of use of enoxaparin in the present ATLANTIC substudy is supported by the results of the randomized ATOLL trial [3], together with the ATOLL per-protocol analysis [8] and a meta-analysis of 23 trials [4], both of which favour IV enoxaparin vs IV unfractionated heparin in terms of a reduction in ischaemic and bleeding events. In line with our observations, the recent European guidelines consider that enoxaparin is an alternative to unfractionated heparin in primary PCI [9].
ATLANTIC was a randomized study comparing pre- and in-hospital treatment with a ticagrelor loading dose (LD) in ongoing ST-segment elevation myocardial infarction (STEMI). We sought to compare patient characteristics and clinical outcomes in France with other countries participating in ATLANTIC.
The population comprised 1862 patients, 660 (35.4%) from France and 1202 from 12 other countries. The main endpoints were reperfusion (≥ 70% ST-segment elevation resolution) and TIMI flow grade 3 before (co-primary endpoints) and after percutaneous coronary intervention (PCI). Other endpoints included a composite ischaemic endpoint (death/myocardial infarction/stroke/urgent revascularization/definite stent thrombosis) and bleeding events at 30 days.
In France, median times from first LD to angiography and between first and second LDs were 49 and 35 min, respectively, and were similar to other countries. French patients were younger (mean 58.7 vs 61.9 years, p < 0.0001) and characterized by a higher rate of radial access (89.9% vs 54.8%, p < 0.0001), more frequent use of pre-hospital glycoprotein (GP) IIb/IIIa inhibitors (14.1% vs 3.1%, p < 0.0001) and intravenous enoxaparin (57.3% vs 10.1%, p < 0.0001). In France, as in other countries, the co-primary endpoints did not differ between the two randomization groups. The composite ischaemic endpoint was numerically lower in France (3.3% vs 5.1%, p = 0.07), with a lower mortality (1.4% vs 3.3%, p = 0.01). PLATO major bleeding was numerically less frequent in France (1.8% vs 3.2%, p = 0.07).
The French population appears to have better outcomes than the rest of the study population, and seems related to differences in demographics and management characteristics.
ClinicalTrials.gov (NCT01347580).
Anticoagulation in Acute Coronary Syndrome-State of the Art
2018, Progress in Cardiovascular Diseases
Citation Excerpt :
Enoxaparin also provided a 40% reduction on the secondary composite endpoints of death, recurrence and complication of MI (RR = 0.59, 95% [0.38–0.91], p = .015). Head to head per-protocol analysis found that the primary endpoint, the mortality rate and the bleeding events were reduced in the enoxaparin group18 (RR = 0.76 95%CI [0.62–0.94], p = .012). These findings were confirmed by other randomized controlled trials, where enoxaparin administration was associated with a reduced rate of death and re-infarction without an increased rate of bleeding events19–20 (Fig. 1a and b).
Early intravenous anticoagulation is the corner stone treatment of patients admitted with an acute coronary syndrome: it antagonizes the ongoing coronary thrombosis and facilitates the percutaneous coronary intervention, hence a reduction of mortality and acute stent thrombosis. Unfractionated heparin, enoxaparin, bivalirudin and fondaparinux have been extensively studied in large randomized control trials and meta-analyses with the same objective: reducing the ischemic burden without hiking hemorrhagic events. This conundrum is evolving along the generalization of the radial-artery access, the use of potent P2Y12 and the trend towards a tailored approach regarding the ischemic and bleeding balance. In this systematic review, we aimed at presenting the evidence based data and strategies for each anticoagulant in the setting of acute coronary syndrome with and without ST-segment elevation.

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: This study was conducted by the ACTION study group (www.action-coeur.org) and AP-HP with a grant from Sanofi-Aventis.

: The ATOLL trial is registered at clinicaltrials.gov (NCT00718471).

: See page 1371 for disclosure information.

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Coronary artery diseaseA Direct Comparison of Intravenous Enoxaparin With Unfractionated Heparin in Primary Percutaneous Coronary Intervention (from the ATOLL Trial)

Section snippets

Methods

Results

Discussion

Acknowledgment

Lancet

J Am Coll Cardiol

Lancet

Am Heart J

JACC Cardiovasc Interv

Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention

N Engl J Med

Impact of anticoagulation regimens on sheath management and bleeding in patients undergoing elective percutaneous coronary intervention in the STEEPLE trial

Catheter Cardiovasc Interv

Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial

Circulation

Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial

JAMA

Coronary artery disease
A Direct Comparison of Intravenous Enoxaparin With Unfractionated Heparin in Primary Percutaneous Coronary Intervention (from the ATOLL Trial)