Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639]

Gasparovic et al. Trials 2012, 13:148 http://www.trialsjournal.com/content/13/1/148 TRIALS STUDY PROTOCOL Open Access Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639] Hrvoje Gasparovic*, Mate Petricevic, Tomislav Kopjar, Zeljko Djuric, Lucija Svetina and Bojan Biocina Abstract Background: Coronary artery disease remains the dominant cause of mortality in developed countries. While platelets have been recognized to play a pivotal role in atherothrombosis, the ideal antiplatelet regime after coronary artery surgery remains elusive. The evolution of CABG has presently moved beyond technical improvements to involve modulation of pharmacologic management designed to improve patient outcomes. The aim of this trial will be to test the hypothesis that the addition of clopidogrel to patients with documented postoperative aspirin resistance will reduce the incidence of major cardiovascular events. Methods: Patients scheduled for isolated coronary artery surgery will be eligible for the study. Patients in whom postoperative multiple electrode aggregometry documents aspirin resistance will be randomized into two groups. The control group will receive 300 mg of aspirin. The dual antiplatelet group will receive 75 mg of clopidogrel in addition to 300 mg of aspirin. Patients will be followed for 6 months. Major adverse cardiac and cerebrovascular events (death from any cause, myocardial infarction, stroke, hospitalization due to cardiovascular pathology) as well as bleeding events will be recorded. Discussion: This will be the first trial that will specifically address the issue of dual antiplatelet therapy in patients undergoing coronary artery surgery who have been found to be aspirin resistant. In the event that the addition of clopidogrel proves to be beneficial in this subset of surgical patients, this study could significantly impact their future antiplatelet management. This randomized controlled trial has been registered at the ClinicalTrials.gov website (Identifier NCT01159639). Keywords: Dual antiplatelet therapy, Coronary artery bypass grafting, Aspirin resistance Background Coronary artery disease is a health care issue of epidemic proportions, and has a profound impact on resource utilization. A quiescent atherosclerotic lesion may follow the course of progressive luminal encroachment, or succumb to an acute thrombotic event. Reduced de novo collagen synthesis and increased extracellular matrix metabolism contribute to weakening of the fibrous cap [1]. Platelet aggregation is a crucial component of this * Correspondence: Department of Cardiac Surgery, University Hospital Center Zagreb, University of Zagreb, Kispaticeva 12, 10 000 Zagreb, Croatia process. Coronary artery bypass grafting (CABG) remains the best management option for patients with severe multi-vessel coronary artery disease [2]. It has been subjected to an unparalleled level of scientific scrutiny. The continuous trend toward improving patient outcomes following CABG stems from refinement of the technical aspects of the procedure, as well as optimization of the adjuvant pharmacologic therapy. Antiplatelet management following CABG Platelet inhibition is paramount in the management of coronary artery disease. Antiplatelet drugs reduce mortality © 2012 Gasparovic et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gasparovic et al. Trials 2012, 13:148 http://www.trialsjournal.com/content/13/1/148 and the incidence of major vascular events in patients with a wide variety of vascular occlusive pathologies [3]. Their beneficial effects must be, however, balanced against the associated risk of bleeding. Acetylsalicylic acid (ASA) is currently recommended after CABG in order to improve long-term graft patency [4]. The recommended doses range from 150 to 325 mg, with a trend towards clinical benefit when higher doses are utilized within the first year [4]. There is no compelling evidence to support the superiority of clopidogrel to ASA monotherapy in optimizing graft patency following CABG [4]. The mechanisms of action of thienopyridines and ASA differ, allowing for a cumulative anti-aggregative effect [3,5]. ASA irreversibly suppresses cyclooxygenase-1 activity thereby reducing thromboxane A2 production, whereas clopidogrel acts on the P2Y12 adenosine diphosphate (ADP) receptor to inhibit ADP-mediated platelet aggregation [6,7]. While dual antiplatelet therapy offers a reduction in atherosclerotic events in patients undergoing percutaneous coronary interventions, this benefit has not been reliably reproduced in other clinical settings [7,8]. Individual variability to antiplatelet agents The incidence of interpatient variability to antiplatelet drugs depends upon the laboratory evaluation used to diagnose it [7]. Novel tools for quantifying drug induced platelet inhibition have brought into focus the individual variations in antiplatelet responses. This underscores the importance of identifying the optimal antiplatelet drug protocol in order to achieve the targeted level of anti-aggregation. Multiple electrode aggregometry (MEA) has been shown to be a useful instrument in the quantification of platelet inhibition by ASA [6]. Its mechanism of assessing platelet inhibition is based on changes in impedance on its sensor wires secondary to platelet adherence. Aspirin resistance has been suggested to range anywhere from 1 to 45% [7]. The efficacy of ASA absorption, TXA2 independent platelet activation pathways, COX-1 gene mutations, as well as ASA interactions with other medications have all been postulated to play a role in inducing aspirin resistance [9]. The response to ASA should best be viewed as a continuous variable. Dichotomizing patients into responders or non-responders is, however, suitable for scientific research and is commonly employed for this purpose [7]. The presence of ASA low-responsiveness has been linked to an increase in cardiovascular morbidity [9]. The clinical correlation of individual patient refractoriness to ASA with an increased incidence of cardiovascular complications is fundamental to the present study. This will be, to the best of our knowledge, the first prospective randomized study that will aim to evaluate whether the combination of ASA and clopidogrel in ASA-resistant CABG patients offers a clinical benefit. Our hypothesis Page 2 of 6 that a dual antiplatelet regime will improve patient outcomes in this setting stems from the convergence of the clinical impact of ASA resistance and the benefit gained from adding clopidogrel to ASA in certain clinical scenarios. Methods Study population All cons (...truncated)