Original Article
Reduced Effect of Aspirin and Clopidogrel Following Hybrid Coronary Revascularization
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(7) 603-611 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029615573304 cat.sagepub.com
Ivy Susanne Modrau, MD, DMSc1, Morten Wu¨rtz, MD, PhD2, Steen Dalby Kristensen, MD, DMSc2, and Anne-Mette Hvas, MD, PhD3
Abstract Objective: Reduced effect of antiplatelet therapy following coronary artery bypass grafting is associated with reduced graft patency. We sought to evaluate the impact of hybrid coronary revascularization on the effect of aspirin and clopidogrel and whether high baseline platelet aggregation, high postoperative levels of platelet turnover, and acute-phase response may contribute to the effect. Methods: We prospectively studied platelet aggregation (VerifyNow and Multiplate Analyzer), platelet turnover (immature platelets, mean platelet volume, and thrombopoietin), and acute-phase reactants (C-reactive protein, von Willebrand factor, and coagulation factor VIII) in 40 patients undergoing elective hybrid coronary revascularization (off-pump surgical revascularization through J-hemisternotomy followed by percutaneous coronary intervention [PCI]). Preoperative blood samples on- and off-aspirin were compared with blood samples obtained postoperatively, following PCI when dual antiplatelet therapy had been initiated and at 1-year follow-up. Results: The antiplatelet effect of aspirin was significantly reduced in the early postoperative period as measured by VerifyNow Aspirin but not by Multiplate ASPI test. The antiplatelet effect of clopidogrel was significantly reduced following PCI as measured by VerifyNow P2Y12 and Multiplate ADP test. The level of baseline aggregation did not predict the antiplatelet effect of aspirin or clopidogrel, and no association was found between platelet aggregation and postoperative platelet turnover or acute-phase reaction. Conclusions: A transient reduction in the antiplatelet effect of aspirin and clopidogrel was observed after hybrid coronary revascularization despite limited surgical trauma and offpump technique. Neither baseline platelet aggregation nor postoperatively increased platelet turnover and acute-phase response could explain this finding. ClinicalTrials.gov identifier, NCT02293928. Keywords antiplatelet drugs, in vitro platelet function, vascular and endovascular surgery
Introduction Low-dose aspirin is recommended early after coronary artery bypass graft surgery (CABG) to prevent graft occlusion.1 However, the effect of aspirin on myocardial infarction, stroke, and death is significantly reduced among patients who recently underwent CABG compared to patients with stable coronary artery disease.2 Several laboratory investigations have shown a transient reduction in the antiplatelet effect of aspirin during the first weeks following on-pump CABG.3-6 Evidence is conflicting regarding the antiplatelet effect of aspirin following off-pump CABG.7-11 Reduced antiplatelet effect of aspirin has been shown to be associated with an increased vein graft occlusion rate following on- and off-pump CABG.11,12 Hybrid coronary revascularization combining minimally invasive off-pump CABG and percutaneous coronary intervention (PCI) is increasingly used to minimize the surgical trauma and prevent periprocedural complications. Dual antiplatelet therapy is recommended following hybrid coronary revascularization with implantation of stents to prevent stent thrombosis.13
The impact of hybrid coronary revascularization on the antiplatelet effect of aspirin and clopidogrel has not yet been investigated. The suggested mechanisms explaining a reduced effect of oral antiplatelet therapy are manifold.14 The inhibitory effect of aspirin on platelet aggregation is based on irreversible inhibition of cyclooxygenase leading to blockage of thromboxane production. Clopidogrel exerts its antiplatelet effect by blocking the P2Y12 receptor, which is the major receptor to amplify
1
Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark 2 Department of Cardiology, Aarhus University Hospital, Aarhusm, Denmark 3 Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark Corresponding Author: Ivy Susanne Modrau, Department of Cardiothoracic Surgery, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark. Email: [email protected]
Downloaded from cat.sagepub.com at Stockholm University Library on September 8, 2015
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Clinical and Applied Thrombosis/Hemostasis 21(7)
and sustain platelet activation in response to adenosine diphosphate. Recently, the occurrence of increased platelet turnover has attracted particular attention, as it may cause a reduced antiplatelet effect of aspirin and clopidogrel.15-19 Immature platelets contain messenger RNA enabling de novo synthesis of cyclooxygenase 1 and other hemostatic proteins.16 Moreover, newly formed platelets express more cyclooxygenase 2, which is largely unaffected by low-dose aspirin.16 This theory is substantiated by the fact that increased mean platelet volume (MPV), which is another marker of thrombopoiesis, is associated with prothrombotic and proinflammatory conditions.20 Inflammation may be another contributor to reduced effect of antiplatelet agents.14 Increased levels of C-reactive protein have been linked with reduced antiplatelet effect of aspirin in patients with stable coronary artery disease.21 Furthermore, levels of C-reactive protein and von Willebrand factor antigen are increased shortly after CABG.10,22,23 We hypothesized that hybrid coronary revascularization is associated with a transiently reduced antiplatelet effect of aspirin and clopidogrel. Furthermore, we hypothesized that the reduced antiplatelet effect of aspirin and clopidogrel could be explained by increased platelet turnover and increased inflammatory markers in the early postoperative phase. Thus, the aims of our study were to investigate (1) the impact of hybrid coronary revascularization on the antiplatelet effect of aspirin and clopidogrel, (2) the influence of baseline platelet aggregation on the postoperative antiplatelet effect of aspirin and clopidogrel, and (3) to what extent platelet turnover and the postoperative acute-phase response were associated with the antiplatelet effect of aspirin and clopidogrel.
Material and Method Study Population A total of 40 patients with coronary artery disease were included in this prospective cohort study between October 2010 and April 2012. The study cohort was recruited from a prospective pilot study (n ¼ 100) conducted to assess feasibility and safety of elective hybrid coronary revascularization combining minimally invasive off-pump CABG and PCI (ClinicalTrials.gov identifier: NCT01496664).24 Criteria for inclusion in the present prespecified substudy were age 18 years, symptomatic multivessel coronary artery disease, and treatment with nonenteric-coated aspirin 75 mg once daily. Exclusion criteria were aspirin or clopidogrel allergy or intolerance, conditions prohibitive of aspirin discontinuation prior to surgery (eg, acute coronary syndrome or critical stenoses), use of anticoagulants or any drugs other than aspirin known to affect platelet function, use of immunosuppressive drugs, platelet count 450 109/L, and inability to give informed consent. The predicted mortality was assessed by means of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) I.25 Written informed consent was obtained from all patients. The study conformed to the principles outlined in the
Declaration of Helsinki and was approved by the Central Denmark Region Committee on Biomedical Research Ethics (Project ID M-20100151).
Study Design All patients were treated with nonenteric-coated aspirin 75 mg once daily prior to study participation. Aspirin treatment was discontinued 8 to 10 days prior to surgery and resumed 6 to 9 hours after surgery. Left internal mammary grafting of the left descendent coronary artery was performed off-pump through an inferior J-hemisternotomy (JOPCAB). Anesthesia was induced and maintained using propofol, sufentanyl, and rocuronium. All patients received prophylactic tranexamic acid perioperatively (2 g at induction and 1 g at completion of surgery). Unfractionated heparin 300 IU/kg was administered during harvest of the mammary artery, and additional boluses were given as required to maintain an activated clotting time >400 seconds. After completion of the anastomosis, heparin was neutralized with protamine sulfate. All patients received an oral loading dose of aspirin 300 mg 6 to 9 hours after surgery followed by daily maintenance doses of 75 mg aspirin. An oral loading dose of clopidogrel 300 mg 12 hours prior to PCI was followed by daily maintenance doses of 75 mg for 12 months. Subcutaneous dalteparin 5000 IU was given twice daily from first postoperative day until the day before PCI to prevent deep venous thrombosis. Prior to PCI, unfractionated heparin was given to achieve an activated clotting time >250 seconds. We recorded adverse cardiovascular events during 1-year followup (graft dysfunction, myocardial infarction, stroke, and pulmonary embolism). Six blood samples were obtained from each patient: the first in the outpatient setting while patients were on aspirin 75 mg daily (Pre-OP), the second in the morning prior to surgery after 8 to 10 days of aspirin discontinuation (baseline; off-aspirin), the third on the first postoperative day when aspirin had been resumed (Post-OP), the fourth on the day prior to PCI (PrePCI), the fifth on the first day after PCI following initiation of dual antiplatelet therapy (Post-PCI), and the sixth at 1-year follow-up when patients were still on maintenance aspirin 75 mg and clopidogrel 75 mg (1-year follow-up). The timing of intervention and blood sampling is outlined in Figure 1. All postoperative samples were drawn in the morning prior to ingestion of antiplatelet medication.
Laboratory Measurements Standardized blood sampling was performed between 7 AM and 11 AM after 30 minutes of resting. Samples were drawn from an antecubital vein into vacuum tubes through a 19-G butterfly needle using a minimum of stasis. The first tube was discarded. Blood was collected in tubes containing the following additives: 3.2% sodium citrate for VerifyNow Aspirin and P2Y12 (Accumetrics Inc, San Diego, California), von Willebrand factor (antigen), and coagulation factor VIII (functional); hirudin 25 mg/mL for Multiplate Analyzer (Roche, Roche Diagnostics,
Downloaded from cat.sagepub.com at Stockholm University Library on September 8, 2015
Modrau et al
605
Figure 1. Study design including timing of intervention and blood sampling.
Mannheim, Germany); lithium heparin for C-reactive protein; and EDTA for hematological analyses. Nonsiliconized tubes without any anticoagulant were used for analysis of serum thromboxane B2 and thrombopoietin. Platelet function analyses were performed in whole blood within 2 hours of sampling using Multiplate Analyzer, VerifyNow Aspirin, and VerifyNow P2Y12. For VerifyNow, the intra-assay coefficient of variation was 1% and the interassay coefficient of variation was 3%.26 For Multiplate Analyzer, arachidonic acid (1.0 mmol/L) and adenosine diphosphate (6.4 and 20 mmol/L) were used as agonists. Intraand interassay variability for Multiplate Analyzer were 12% and 23%, respectively.26 Multiplate Analyzer results are expressed as area under the aggregation curve (aggregation units minute). VerifyNow test results are expressed as aspirin reaction units or P2Y12 reaction units. Blood samples for hematological analyses were analyzed within 90 minutes of sampling. Complete blood counts, including immature platelet fraction (IPF), immature platelet count (IPC), and MPV, were performed using a Sysmex XE-5000 hematology analyzer (Sysmex, Kobe, Japan) with upgraded software (XE IPF Master; Sysmex), enabling flow cytometric detection of the IPF as described previously.27 Intra- and interassay coefficients of variation for MPV measurement were
Reduced Effect of Aspirin and Clopidogrel Following Hybrid Coronary Revascularization
Clinical and Applied Thrombosis/Hemostasis 2015, Vol. 21(7) 603-611 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029615573304 cat.sagepub.com
Ivy Susanne Modrau, MD, DMSc1, Morten Wu¨rtz, MD, PhD2, Steen Dalby Kristensen, MD, DMSc2, and Anne-Mette Hvas, MD, PhD3
Abstract Objective: Reduced effect of antiplatelet therapy following coronary artery bypass grafting is associated with reduced graft patency. We sought to evaluate the impact of hybrid coronary revascularization on the effect of aspirin and clopidogrel and whether high baseline platelet aggregation, high postoperative levels of platelet turnover, and acute-phase response may contribute to the effect. Methods: We prospectively studied platelet aggregation (VerifyNow and Multiplate Analyzer), platelet turnover (immature platelets, mean platelet volume, and thrombopoietin), and acute-phase reactants (C-reactive protein, von Willebrand factor, and coagulation factor VIII) in 40 patients undergoing elective hybrid coronary revascularization (off-pump surgical revascularization through J-hemisternotomy followed by percutaneous coronary intervention [PCI]). Preoperative blood samples on- and off-aspirin were compared with blood samples obtained postoperatively, following PCI when dual antiplatelet therapy had been initiated and at 1-year follow-up. Results: The antiplatelet effect of aspirin was significantly reduced in the early postoperative period as measured by VerifyNow Aspirin but not by Multiplate ASPI test. The antiplatelet effect of clopidogrel was significantly reduced following PCI as measured by VerifyNow P2Y12 and Multiplate ADP test. The level of baseline aggregation did not predict the antiplatelet effect of aspirin or clopidogrel, and no association was found between platelet aggregation and postoperative platelet turnover or acute-phase reaction. Conclusions: A transient reduction in the antiplatelet effect of aspirin and clopidogrel was observed after hybrid coronary revascularization despite limited surgical trauma and offpump technique. Neither baseline platelet aggregation nor postoperatively increased platelet turnover and acute-phase response could explain this finding. ClinicalTrials.gov identifier, NCT02293928. Keywords antiplatelet drugs, in vitro platelet function, vascular and endovascular surgery
Introduction Low-dose aspirin is recommended early after coronary artery bypass graft surgery (CABG) to prevent graft occlusion.1 However, the effect of aspirin on myocardial infarction, stroke, and death is significantly reduced among patients who recently underwent CABG compared to patients with stable coronary artery disease.2 Several laboratory investigations have shown a transient reduction in the antiplatelet effect of aspirin during the first weeks following on-pump CABG.3-6 Evidence is conflicting regarding the antiplatelet effect of aspirin following off-pump CABG.7-11 Reduced antiplatelet effect of aspirin has been shown to be associated with an increased vein graft occlusion rate following on- and off-pump CABG.11,12 Hybrid coronary revascularization combining minimally invasive off-pump CABG and percutaneous coronary intervention (PCI) is increasingly used to minimize the surgical trauma and prevent periprocedural complications. Dual antiplatelet therapy is recommended following hybrid coronary revascularization with implantation of stents to prevent stent thrombosis.13
The impact of hybrid coronary revascularization on the antiplatelet effect of aspirin and clopidogrel has not yet been investigated. The suggested mechanisms explaining a reduced effect of oral antiplatelet therapy are manifold.14 The inhibitory effect of aspirin on platelet aggregation is based on irreversible inhibition of cyclooxygenase leading to blockage of thromboxane production. Clopidogrel exerts its antiplatelet effect by blocking the P2Y12 receptor, which is the major receptor to amplify
1
Department of Cardiothoracic Surgery, Aarhus University Hospital, Aarhus, Denmark 2 Department of Cardiology, Aarhus University Hospital, Aarhusm, Denmark 3 Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark Corresponding Author: Ivy Susanne Modrau, Department of Cardiothoracic Surgery, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200 Aarhus N, Denmark. Email: [email protected]
Downloaded from cat.sagepub.com at Stockholm University Library on September 8, 2015
604
Clinical and Applied Thrombosis/Hemostasis 21(7)
and sustain platelet activation in response to adenosine diphosphate. Recently, the occurrence of increased platelet turnover has attracted particular attention, as it may cause a reduced antiplatelet effect of aspirin and clopidogrel.15-19 Immature platelets contain messenger RNA enabling de novo synthesis of cyclooxygenase 1 and other hemostatic proteins.16 Moreover, newly formed platelets express more cyclooxygenase 2, which is largely unaffected by low-dose aspirin.16 This theory is substantiated by the fact that increased mean platelet volume (MPV), which is another marker of thrombopoiesis, is associated with prothrombotic and proinflammatory conditions.20 Inflammation may be another contributor to reduced effect of antiplatelet agents.14 Increased levels of C-reactive protein have been linked with reduced antiplatelet effect of aspirin in patients with stable coronary artery disease.21 Furthermore, levels of C-reactive protein and von Willebrand factor antigen are increased shortly after CABG.10,22,23 We hypothesized that hybrid coronary revascularization is associated with a transiently reduced antiplatelet effect of aspirin and clopidogrel. Furthermore, we hypothesized that the reduced antiplatelet effect of aspirin and clopidogrel could be explained by increased platelet turnover and increased inflammatory markers in the early postoperative phase. Thus, the aims of our study were to investigate (1) the impact of hybrid coronary revascularization on the antiplatelet effect of aspirin and clopidogrel, (2) the influence of baseline platelet aggregation on the postoperative antiplatelet effect of aspirin and clopidogrel, and (3) to what extent platelet turnover and the postoperative acute-phase response were associated with the antiplatelet effect of aspirin and clopidogrel.
Material and Method Study Population A total of 40 patients with coronary artery disease were included in this prospective cohort study between October 2010 and April 2012. The study cohort was recruited from a prospective pilot study (n ¼ 100) conducted to assess feasibility and safety of elective hybrid coronary revascularization combining minimally invasive off-pump CABG and PCI (ClinicalTrials.gov identifier: NCT01496664).24 Criteria for inclusion in the present prespecified substudy were age 18 years, symptomatic multivessel coronary artery disease, and treatment with nonenteric-coated aspirin 75 mg once daily. Exclusion criteria were aspirin or clopidogrel allergy or intolerance, conditions prohibitive of aspirin discontinuation prior to surgery (eg, acute coronary syndrome or critical stenoses), use of anticoagulants or any drugs other than aspirin known to affect platelet function, use of immunosuppressive drugs, platelet count 450 109/L, and inability to give informed consent. The predicted mortality was assessed by means of the logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) I.25 Written informed consent was obtained from all patients. The study conformed to the principles outlined in the
Declaration of Helsinki and was approved by the Central Denmark Region Committee on Biomedical Research Ethics (Project ID M-20100151).
Study Design All patients were treated with nonenteric-coated aspirin 75 mg once daily prior to study participation. Aspirin treatment was discontinued 8 to 10 days prior to surgery and resumed 6 to 9 hours after surgery. Left internal mammary grafting of the left descendent coronary artery was performed off-pump through an inferior J-hemisternotomy (JOPCAB). Anesthesia was induced and maintained using propofol, sufentanyl, and rocuronium. All patients received prophylactic tranexamic acid perioperatively (2 g at induction and 1 g at completion of surgery). Unfractionated heparin 300 IU/kg was administered during harvest of the mammary artery, and additional boluses were given as required to maintain an activated clotting time >400 seconds. After completion of the anastomosis, heparin was neutralized with protamine sulfate. All patients received an oral loading dose of aspirin 300 mg 6 to 9 hours after surgery followed by daily maintenance doses of 75 mg aspirin. An oral loading dose of clopidogrel 300 mg 12 hours prior to PCI was followed by daily maintenance doses of 75 mg for 12 months. Subcutaneous dalteparin 5000 IU was given twice daily from first postoperative day until the day before PCI to prevent deep venous thrombosis. Prior to PCI, unfractionated heparin was given to achieve an activated clotting time >250 seconds. We recorded adverse cardiovascular events during 1-year followup (graft dysfunction, myocardial infarction, stroke, and pulmonary embolism). Six blood samples were obtained from each patient: the first in the outpatient setting while patients were on aspirin 75 mg daily (Pre-OP), the second in the morning prior to surgery after 8 to 10 days of aspirin discontinuation (baseline; off-aspirin), the third on the first postoperative day when aspirin had been resumed (Post-OP), the fourth on the day prior to PCI (PrePCI), the fifth on the first day after PCI following initiation of dual antiplatelet therapy (Post-PCI), and the sixth at 1-year follow-up when patients were still on maintenance aspirin 75 mg and clopidogrel 75 mg (1-year follow-up). The timing of intervention and blood sampling is outlined in Figure 1. All postoperative samples were drawn in the morning prior to ingestion of antiplatelet medication.
Laboratory Measurements Standardized blood sampling was performed between 7 AM and 11 AM after 30 minutes of resting. Samples were drawn from an antecubital vein into vacuum tubes through a 19-G butterfly needle using a minimum of stasis. The first tube was discarded. Blood was collected in tubes containing the following additives: 3.2% sodium citrate for VerifyNow Aspirin and P2Y12 (Accumetrics Inc, San Diego, California), von Willebrand factor (antigen), and coagulation factor VIII (functional); hirudin 25 mg/mL for Multiplate Analyzer (Roche, Roche Diagnostics,
Downloaded from cat.sagepub.com at Stockholm University Library on September 8, 2015
Modrau et al
605
Figure 1. Study design including timing of intervention and blood sampling.
Mannheim, Germany); lithium heparin for C-reactive protein; and EDTA for hematological analyses. Nonsiliconized tubes without any anticoagulant were used for analysis of serum thromboxane B2 and thrombopoietin. Platelet function analyses were performed in whole blood within 2 hours of sampling using Multiplate Analyzer, VerifyNow Aspirin, and VerifyNow P2Y12. For VerifyNow, the intra-assay coefficient of variation was 1% and the interassay coefficient of variation was 3%.26 For Multiplate Analyzer, arachidonic acid (1.0 mmol/L) and adenosine diphosphate (6.4 and 20 mmol/L) were used as agonists. Intraand interassay variability for Multiplate Analyzer were 12% and 23%, respectively.26 Multiplate Analyzer results are expressed as area under the aggregation curve (aggregation units minute). VerifyNow test results are expressed as aspirin reaction units or P2Y12 reaction units. Blood samples for hematological analyses were analyzed within 90 minutes of sampling. Complete blood counts, including immature platelet fraction (IPF), immature platelet count (IPC), and MPV, were performed using a Sysmex XE-5000 hematology analyzer (Sysmex, Kobe, Japan) with upgraded software (XE IPF Master; Sysmex), enabling flow cytometric detection of the IPF as described previously.27 Intra- and interassay coefficients of variation for MPV measurement were
