Impact of Dual Antiplatelet Therapy on Outcomes Among Aspirin-Resistant Patients Following Coronary Artery Bypass Grafting

Coronary artery bypass grafting is pivotal in the contemporary management of complex coronary artery disease. Interpatient variability to antiplatelet agents, however, harbors the potential to compromise the revascularization benefit by increasing the incidence of adverse events. This study was designed to define the impact of dual antiplatelet therapy (dAPT) on clinical outcomes among aspirin-resistant patients who underwent coronary artery surgery. We randomly assigned 219 aspirin-resistant patients according to multiple electrode aggregometry to receive clopidogrel (75 mg) plus aspirin (300 mg) or aspirin-monotherapy (300 mg). The primary end point was a composite outcome of all-cause death, nonfatal myocardial infarction, stroke, or cardiovascular hospitalization assessed at 6 months postoperatively. The primary end point occurred in 6% of patients assigned to dAPT and 10% of patients randomized to aspirin-monotherapy (relative risk 0.61, 95% confidence interval 0.25 to 1.51, p = 0.33). No significant treatment effect was noted in the occurrence of the safety end point. The total incidence of bleeding events was 25% and 19% in the dAPT and aspirin-monotherapy groups, respectively (relative risk 1.34, 95% confidence interval 0.80 to 2.23, p = 0.33). In the subgroup analysis, dAPT led to lower rates of adverse events in patients with a body mass index >30 kg/m2 (0% vs 18%, p <0.01) and those <65 years (0% vs 10%, p = 0.02). In conclusion, the addition of clopidogrel in patients found to be aspirin resistant after coronary artery bypass grafting did not reduce the incidence of adverse events, nor did it increase the number of recorded bleeding events. dAPT did, however, lower the incidence of the primary end point in obese patients and those <65 years. Coronary artery bypass grafting is pivotal in the contemporary management of complex coronary artery disease. Interpatient variability to antiplatelet agents, however, harbors the potential to compromise the revascularization benefit by increasing the incidence of adverse events. This study was designed to define the impact of dual antiplatelet therapy (dAPT) on clinical outcomes among aspirin-resistant patients who underwent coronary artery surgery. We randomly assigned 219 aspirin-resistant patients according to multiple electrode aggregometry to receive clopidogrel (75 mg) plus aspirin (300 mg) or aspirin-monotherapy (300 mg). The primary end point was a composite outcome of all-cause death, nonfatal myocardial infarction, stroke, or cardiovascular hospitalization assessed at 6 months postoperatively. The primary end point occurred in 6% of patients assigned to dAPT and 10% of patients randomized to aspirin-monotherapy (relative risk 0.61, 95% confidence interval 0.25 to 1.51, p = 0.33). No significant treatment effect was noted in the occurrence of the safety end point. The total incidence of bleeding events was 25% and 19% in the dAPT and aspirin-monotherapy groups, respectively (relative risk 1.34, 95% confidence interval 0.80 to 2.23, p = 0.33). In the subgroup analysis, dAPT led to lower rates of adverse events in patients with a body mass index >30 kg/m2 (0% vs 18%, p <0.01) and those <65 years (0% vs 10%, p = 0.02). In conclusion, the addition of clopidogrel in patients found to be aspirin resistant after coronary artery bypass grafting did not reduce the incidence of adverse events, nor did it increase the number of recorded bleeding events. dAPT did, however, lower the incidence of the primary end point in obese patients and those <65 years. Coronary artery bypass grafting (CABG) remains the standard of care in the management of complex coronary artery disease.1Serruys P.W. Morice M.C. Kappetein A.P. Colombo A. Holmes D.R. Mack M.J. Stahle E. Feldman T.E. van den Brand M. Bass E.J. Van Dyck N. Leadley K. Dawkins K.D. Mohr F.W. Investigators SPercutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease.N Engl J Med. 2009; 360: 961-972Crossref PubMed Scopus (3352) Google Scholar Improvements in postoperative outcomes rely both on technical refinements of the procedure and optimization of medical management. The long-term benefits of CABG depend upon the durability of nonobstructed flow through bypass grafts. Inhibition of platelet aggregability plays a crucial role in improving graft patency. Aspirin is currently the most commonly employed antiplatelet agent after CABG.2Zimmermann N. Gams E. Hohlfeld T. Aspirin in coronary artery bypass surgery: new aspects of and alternatives for an old antithrombotic agent.Eur J Cardiothorac Surg. 2008; 34: 93-108Crossref PubMed Scopus (69) Google Scholar Dual antiplatelet therapy (dAPT) may improve the venous graft patency,3Gao G. Zheng Z. Pi Y. Lu B. Lu J. Hu S. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial.J Am Coll Cardiol. 2010; 56: 1639-1643Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar but this benefit has not been reliably reproduced in a wider clinical arena.4Kulik A. Le May M.R. Voisine P. Tardif J.C. Delarochelliere R. Naidoo S. Wells G.A. Mesana T.G. Ruel M. Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) Trial.Circulation. 2010; 122: 2680-2687Crossref PubMed Scopus (174) Google Scholar The combination of clopidogrel and aspirin results in the cumulation of their individual antiaggregatory effects, because their individual mechanisms of antiplatelet activity differ.5Awidi A. Saleh A. Dweik M. Kailani B. Abu-Fara M. Nabulsi R. Bener A. Measurement of platelet reactivity of patients with cardiovascular disease on-treatment with acetyl salicylic acid: a prospective study.Heart Vessels. 2011; 26: 516-522Crossref PubMed Scopus (26) Google Scholar Dual platelet inhibition may be of particular importance in patients exhibiting single antiplatelet drug resistance.6Petricevic M. Biocina B. Konosic S. Kopjar T. Kunac N. Gasparovic H. Assessment of platelet function by whole blood impedance aggregometry in coronary artery bypass grafting patients on acetylsalicylic acid treatment may prompt a switch to dual antiplatelet therapy.Heart Vessels. 2013; 28: 57-65Crossref PubMed Scopus (31) Google Scholar Defining the role of dAPT in the contemporary surgical practice is paramount before recommending it without reservations, however, as it may increase the incidence of bleeding.7Yusuf S. Zhao F. Mehta S.R. Chrolavicius S. Tognoni G. Fox K.K. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.N Engl J Med. 2001; 345: 494-502Crossref PubMed Scopus (6085) Google Scholar The incidence of low response to aspirin is not uniform across the available spectrum of platelet function tests. It has been reported to range from 1% to 45%.8Ben-Dor I. Kleiman N.S. Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy.Am J Cardiol. 2009; 104: 227-233Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Although clear outlines of this phenomenon remain to be defined, its adverse clinical impact has been validated.9Gluckman T.J. McLean R.C. Schulman S.P. Kickler T.S. Shapiro E.P. Conte J.V. McNicholas K.W. Segal J.B. Rade J.J. Effects of aspirin responsiveness and platelet reactivity on early vein graft thrombosis after coronary artery bypass graft surgery.J Am Coll Cardiol. 2011; 57: 1069-1077Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar We hypothesized that augmentation of platelet inhibition with clopidogrel in patients with high postoperative on-aspirin platelet reactivity would lead to improvement in clinical outcomes. The convergence of the clinical impact of aspirin resistance with the beneficial effects of dAPT in other clinical scenarios was the foundation of this trial's design. This is, to the best of our knowledge, the first prospective randomized study that selectively implemented dAPT after CABG in patients with aggregometry-documented aspirin resistance. The study was conducted at the University Hospital Center Zagreb in Zagreb, Croatia. Patient enrollment started in June 2010 and was completed in February 2013. Details of the study design, eligibility, and exclusion criteria have been published previously.10Gasparovic H. Petricevic M. Kopjar T. Djuric Z. Svetina L. Biocina B. Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639].Trials. 2012; 13: 148Crossref PubMed Scopus (12) Google Scholar Briefly, adult patients scheduled to undergo elective primary CABG were eligible for enrollment. Exclusion criteria included valvular pathology warranting surgical correction, off-pump CABG, requirement for dual antiplatelet management, anticoagulation, and critical condition before randomization. Patients who underwent CABG following a recent acute coronary syndrome were excluded, as there are data to suggest that they might benefit from dAPT.11Sorensen R. Abildstrom S.Z. Hansen P.R. Hvelplund A. Andersson C. Charlot M. Fosbol E.L. Kober L. Madsen J.K. Gislason G.H. Torp-Pedersen C. Efficacy of post-operative clopidogrel treatment in patients revascularized with coronary artery bypass grafting after myocardial infarction.J Am Coll Cardiol. 2011; 57: 1202-1209Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar On postoperative day (POD) 4, patients underwent an aggregometry-based assessment of their on-aspirin platelet reactivity. Patients found to be aspirin responders were excluded from further analysis, whereas aspirin-resistant patients were randomized into either the control or intervention groups. The trial was approved by the Ethics committee of the University Hospital Center Zagreb. Ethical standards in line with the Declaration of Helsinki were adhered to. Written informed consent was obtained from all patients before enrollment. Multiple electrode aggregometry was used for quantifying platelet reactivity in the study cohort (Multiplate, Dynabyte, Munich, Germany). Platelet aggregation, as evaluated by multiple electrode aggregometry, is responsible for the variability in sensor wire impedances. The numerical multiple electrode aggregometry output describes the electrical resistance sensor is to platelet A. S. H. Multiple electrode a new to platelet in whole Google Scholar acid and were as platelet for the and The platelet and is a for aspirin Although aspirin response is as a patients into and is commonly for I. Kleiman N.S. Lev E. Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy.Am J Cardiol. 2009; 104: 227-233Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Aspirin resistance in the study was in line with individual responsiveness into M. Biocina B. Konosic S. I. F. Svetina L. Gasparovic H. of acetylsalicylic acid resistance whole blood impedance aggregometry in patients coronary artery 2013; Google Scholar Patients were as aspirin resistant their the point the M. Biocina B. Konosic S. I. F. Svetina L. Gasparovic H. of acetylsalicylic acid resistance whole blood impedance aggregometry in patients coronary artery 2013; Google Scholar This was by data from multiple other B. I. J. patency of the artery in patients with acute myocardial is to platelet response to J Cardiol. 2010; Full Text Full Text PDF PubMed Scopus Google C. K. M. B. B. blood multiple electrode aggregometry is a of platelet 2009; PubMed Scopus Google Scholar the criteria for aspirin resistance on 4, patients scheduled for CABG were randomly into either on of aspirin or of platelet inhibition with of clopidogrel plus of aspirin was used for into the control or intervention H. Petricevic M. Kopjar T. Djuric Z. Svetina L. Biocina B. Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639].Trials. 2012; 13: 148Crossref PubMed Scopus (12) Google Scholar platelet inhibition with aspirin was to the day of surgery. patients clopidogrel the drug before the surgical bypass and were used in all study was on a combination of and patients a and a were selectively and to Aspirin was the first 6 of surgery. In aspirin the postoperative antiplatelet was on in line with the study The primary end point was the incidence of adverse and events at 6 was a composite outcome all-cause nonfatal myocardial and cardiovascular The outcomes were bleeding events and individual We adhered to the in the safety end point R. A. J. S. E. M. P. H. bleeding for cardiovascular clinical a from the 2011; PubMed Scopus Google Scholar The of of for the of was implemented in patients to have myocardial R. A. J. S. E. M. P. H. bleeding for cardiovascular clinical a from the 2011; PubMed Scopus Google Scholar Patients with new or those an acute on an study were to have a I. B. S. on of for the of in patients with or a for from the 2011; PubMed Scopus Google Scholar The study was designed to the incidence of at 6 on an in aspirin-resistant patients randomized to either on aspirin or receive dual inhibition of platelet The to the was by an F. E. A. a for the and PubMed Scopus Google Scholar The effect was for an 10% to 219 patients were to the with an of and a of of the safety end point was in patients to the study The data are as with their standard are as with The was used to data the control and intervention groups. among were with in the platelet reactivity in response to surgery were evaluated with the were used as a of the the intervention and clinical outcomes. The 95% confidence were p was to be significant for all p were obtained and for to in The data were the and the patients were for total of aspirin-resistant patients with CABG were randomly assigned to receive aspirin = or aspirin plus clopidogrel = of the enrollment and is in The and clinical were the of the patients were and the of is of the contemporary surgical were commonly in the dAPT before surgery. The of other antiplatelet agents, did not the data are in did not the with the of clopidogrel was to the protocol and clinical = = = p was as of the of or total or of to was as or or or of to the in patients with a of high coronary platelet reactivity are as and = platelet = body mass = blood = for = p was as of the of or total or of to was as or or or of to the in patients with a of high in a new and postoperative = = p data platelet reactivity are as and = = platelet = p in a new are as and = platelet = body mass = blood = for = are as and = = platelet = were in platelet aggregability the The evaluated on were the control and intervention in both were the aspirin response and resistance. the postoperative did not the We however, a significant in platelet reactivity in with the The across the cohort from to This platelet aggregability was by an increase in the p for a in the early postoperative was found in the of We a and significant increase in in response to the surgical procedure vs p The increase in platelet aggregability was in both groups, of the antiplatelet management was completed in and patients in the aspirin and dAPT groups, The study outcomes are in from at the of the was in the control and in the dAPT The incidence of the primary end point was not by the antiplatelet management vs 0.61, 95% 0.25 to 1.51, p = p = in the composite end point of was with of platelet inhibition p = p = The of individual was not by the antiplatelet management The of in the control patients were stroke, and patients in the dAPT a that led to death, whereas the other of by and study outcomes = = p end or or cardiovascular end bleeding are as = = not p in a new are as = = not significant in the incidence of bleeding events the of the increase in the of total bleeding events was noted with the addition of clopidogrel to aspirin-resistant patients vs 1.34, 95% 0.80 to 2.23, p = p = patients the was The incidence of bleeding events in the did not from the in the dAPT vs 19% in the aspirin 95% to p = p = The incidence of the primary end point was in according to the or of individual or clinical We found a significant in the of in patients <65 years (0% vs 10%, p = 0.02). patients with a body mass index >30 kg/m2 were to benefit from platelet inhibition with clopidogrel on the of aspirin therapy in the of the composite adverse The of among obese patients were with the dAPT versus in the The subgroup are in dAPT did not increase the incidence of bleeding events in patients <65 years vs 95% to p = p = dAPT did not increase bleeding among patients with a body mass index >30 kg/m2 vs 95% to p = p = bleeding rates were noted in all other and p of the primary end p kg/m2 disease disease = body mass = for = = not p in a new = body mass = for = = not The of this trial was to the impact of platelet inhibition with clopidogrel in the of standard therapy in aspirin-resistant patients with CABG on the incidence of adverse events. This is the first prospective randomized study to the clinical impact of antiplatelet therapy after CABG in patients with aggregometry-documented aspirin resistance. are mechanisms that are as critical to bleeding as they are to S.P. The role of in Am 2011; PubMed Scopus Google Scholar are at a and an in both of S.P. The role of in Am 2011; PubMed Scopus Google Scholar platelet aggregability is an in the management of coronary artery disease. The for clopidogrel in patients with a of surgery has been in the versus Aspirin in Patients at of trial of clopidogrel versus aspirin in patients at risk of events Full Text Full Text PDF PubMed Scopus Google Scholar The of in the incidence of death, stroke, or in the CABG subgroup the benefits in the versus Aspirin in Patients at of study trial of clopidogrel versus aspirin in patients at risk of events Full Text Full Text PDF PubMed Scopus Google Scholar In the in to clopidogrel to in the of A. S. Mehta S.R. Fox Tognoni G. Zhao F. Chrolavicius S. M. of clopidogrel in patients with acute coronary syndromes without ST-segment in risk PubMed Scopus Google Scholar The of risk with dAPT the with the benefit in the risk A. S. Mehta S.R. Fox Tognoni G. Zhao F. Chrolavicius S. M. of clopidogrel in patients with acute coronary syndromes without ST-segment in risk PubMed Scopus Google Scholar The in the of with dAPT was in the CABG subgroup 95% to Mehta S.R. R. Zhao F. N. S. and of the combination of clopidogrel and aspirin in patients surgical revascularization for acute coronary the clopidogrel in to events PubMed Scopus Google Scholar The composite end point of and was in a cohort of patients with revascularized with CABG who were R. Abildstrom S.Z. Hansen P.R. Hvelplund A. Andersson C. Charlot M. Fosbol E.L. Kober L. Madsen J.K. Gislason G.H. Torp-Pedersen C. Efficacy of post-operative clopidogrel treatment in patients revascularized with coronary artery bypass grafting after myocardial infarction.J Am Coll Cardiol. 2011; 57: 1202-1209Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar graft patency was by the dAPT protocol in with aspirin G. Zheng Z. Pi Y. Lu B. Lu J. Hu S. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial.J Am Coll Cardiol. 2010; 56: 1639-1643Abstract Full Text Full Text PDF PubMed Scopus (150) Google J.C. A. T. H. S. S. S. trial of aspirin and clopidogrel versus aspirin alone for the of coronary artery bypass graft the aspirin and postoperative in coronary artery bypass grafting J. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar G. Zheng Z. Pi Y. Lu B. Lu J. Hu S. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial.J Am Coll Cardiol. 2010; 56: 1639-1643Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar randomized CABG patients to receive either aspirin = or aspirin plus clopidogrel = vein graft patency in the dual antiplatelet treatment In a study design, J.C. A. T. H. S. S. S. trial of aspirin and clopidogrel versus aspirin alone for the of coronary artery bypass graft the aspirin and postoperative in coronary artery bypass grafting J. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar in the patients who completed clopidogrel was to in artery graft was that a aspirin was to mg) in the in the G. Zheng Z. Pi Y. Lu B. Lu J. Hu S. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial.J Am Coll Cardiol. 2010; 56: 1639-1643Abstract Full Text Full Text PDF PubMed Scopus (150) Google J.C. A. T. H. S. S. S. trial of aspirin and clopidogrel versus aspirin alone for the of coronary artery bypass graft the aspirin and postoperative in coronary artery bypass grafting J. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar has been found to after N. P. J. Gams E. K. Hohlfeld T. Aspirin resistance after coronary artery bypass Surg. 2001; Full Text Full Text PDF PubMed Scopus (108) Google Scholar The impact of individual responsiveness to aspirin was not reported in G. Zheng Z. Pi Y. Lu B. Lu J. Hu S. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial.J Am Coll Cardiol. 2010; 56: 1639-1643Abstract Full Text Full Text PDF PubMed Scopus (150) Google J.C. A. T. H. S. S. S. trial of aspirin and clopidogrel versus aspirin alone for the of coronary artery bypass graft the aspirin and postoperative in coronary artery bypass grafting J. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar The combination of clopidogrel and aspirin in clinical outcomes in patients who underwent off-pump coronary artery bypass H. A. clopidogrel outcome after off-pump coronary artery bypass graft surgery: a prospective J Cardiothorac Surg. PubMed Scopus Google Scholar The postoperative platelet responsiveness in off-pump coronary artery bypass in with patients with CABG, as by to the platelet inhibition in this F. P. T. H. M. Z. P. Platelet activity and aspirin after off-pump with coronary artery bypass surgery: results from the prospective randomized trial and of Surg. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar The potential of dual antiplatelet inhibition its benefits have not been in all its In the for and and trial patients with cardiovascular dAPT was in the composite end point of death, or Fox P. G. S.R. L. J. E.J. and aspirin versus aspirin alone for the of Engl J Med. PubMed Scopus Google Scholar study from the in that it the CABG that high platelet aggregability aspirin We found that of patients who underwent elective CABG inhibition of platelet reactivity with The aggregometry-based for aspirin responders and a in the with tests. It used whole blood at the for analysis, platelet activity their of aspirin resistance were M. Biocina B. Konosic S. Kopjar T. Kunac N. Gasparovic H. Assessment of platelet function by whole blood impedance aggregometry in coronary artery bypass grafting patients on acetylsalicylic acid treatment may prompt a switch to dual antiplatelet therapy.Heart Vessels. 2013; 28: 57-65Crossref PubMed Scopus (31) Google Scholar study multiple of postoperative We found that the surgical procedure an increase in both and platelet reactivity. Although there are data to suggest that aspirin resistance is a J. S. R. P. A. C. to aspirin in patients after coronary artery bypass grafting is impact on the of aspirin antiplatelet PubMed Scopus Google Scholar this early may the this The and of the and platelet in of platelet A. Saleh A. Dweik M. Kailani B. Abu-Fara M. Nabulsi R. Bener A. Measurement of platelet reactivity of patients with cardiovascular disease on-treatment with acetyl salicylic acid: a prospective study.Heart Vessels. 2011; 26: 516-522Crossref PubMed Scopus (26) Google Scholar hypothesized to be in patients exhibiting single antiplatelet drug resistance. however, did not that the combination of aspirin and clopidogrel was in the of the primary end point to aspirin in aspirin-resistant patients with results the from a of found benefit for dAPT aspirin after S. M. of aspirin versus clopidogrel plus aspirin after coronary artery bypass graft 2009; PubMed Scopus Google Scholar vein graft as by in the for Coronary study was not by dAPT = in with an antiplatelet = A. Le May M.R. Voisine P. Tardif J.C. Delarochelliere R. Naidoo S. Wells G.A. Mesana T.G. Ruel M. Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) Trial.Circulation. 2010; 122: 2680-2687Crossref PubMed Scopus (174) Google Scholar data did, however, suggest that patients <65 years and those with a body mass index >30 kg/m2 might benefit from dAPT in the of aspirin resistance. This was not by increasing bleeding events in the study cohort nor of the We that a study the potential of aspirin-resistant to on of antiplatelet therapy is study has significant The of the to the was on an F. E. A. a for the and PubMed Scopus Google Scholar We reliably the that the study may have been In a in the primary end point was noted with the addition of clopidogrel to aspirin in the of aspirin resistance. results may an for the of a study of a design. potential of our study from the of an of aspirin resistance. in our study a in individual platelet inhibition to The of multiple platelet function aspirin response and resistance are on the clinical data their of platelet function of high platelet reactivity. results on platelet assessment a of platelet function of has been We for The have of to