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Ann Thorac Surg 2009;87:496-502. doi:10.1016/j.athoracsur.2008.05.038
© 2009 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Risk Stratification After Coronary Artery Bypass Surgery by a Point-of-Care Test of Platelet Function

Stefano Bevilacqua, MDa, Al Assal Alkodami, MDa, Elisabetta Volpi, PhDb, Alfredo Giuseppe Cerillo, MDa, Sergio Berti, MDc, Mattia Glauber, MDa, Jacopo Gianetti, MDc,*

a Operative Unit of Cardiac Surgery, Fondazione Gabriele Monasterio, Ospedale del Cuore "G. Pasquinucci," The Institute of Clinical Physiology, The National Research Council, Massa, Italy
b Laboratory of Atherosclerosis and Thrombosis, Fondazione Gabriele Monasterio, Ospedale del Cuore "G. Pasquinucci," The Institute of Clinical Physiology, The National Research Council, Massa, Italy
c Operative Unit of Cardiology, Fondazione Gabriele Monasterio, Ospedale del Cuore "G. Pasquinucci," The Institute of Clinical Physiology, The National Research Council, Massa, Italy

Accepted for publication May 15, 2008.

* Address correspondence to Dr Gianetti, Operative Unit of Cardiology, Fondazione Gabriele Monasterio, Ospedale del Cuore "G. Pasquinucci", CREAS IFC-CNR, Via Aurelia Sud, Massa, 54100, Italy (Email: gianetti{at}ifc.cnr.it).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Aspirin is one of the main therapeutics in prevention of cardiovascular events due to its antiplatelet activity. However, a sufficient inhibition of platelet function by aspirin is not always achieved. This means that the extent of protection from cardiovascular event is limited. Recently, several studies have introduced the concept of residual platelet reactivity during aspirin therapy and suggested that about 40% of aspirin users may not respond adequately. We sought to determine whether the profile and prevalence of residual platelet reactivity, measured with the platelet function analyzer (PFA-100; Dade/Behring, Marburg, Germany) device could predict a recurrent cardiovascular event in patients undergoing coronary artery bypass surgery.

Methods: A cohort of 202 consecutive patients receiving primary coronary artery bypass surgery during 2004 was prospectively recruited. All patients postoperatively received regular standard daily 100 mg aspirin. Platelet function was analyzed by the PFA-100 at 30 ± 6 days after surgery. A PFA100 closure time less than 190 seconds was defined as residual platelet reactivity. Eighty-six patients (43%) showed residual platelet reactivity. The mean follow-up time was 32 ± 10 months and was 100% complete.

Results: A total of 75 cardiovascular events have been registered. The majority of these events were among patients with residual platelet activity (p = 0.001). Out of this number, graft failure was documented in 25 patients. The 42-month freedom from major cardiovascular events was significantly better for patients with adequate platelet inhibition (p = 0.001). At multivariable analysis residual platelet reactivity (p = 0.012), incomplete revascularization (p = 0.029), and diabetes (p = 0.0009) were independently associated with occurrence of negative events.

Conclusions: Our results demonstrate that high residual platelet reactivity independently correlates with a worst clinical outcome in patients treated by coronary artery bypass surgery. The PFA-100 point care test could cheaply and simply discover this condition and contribute to improve the outcome of this subset of patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Due to its ability to inhibit the platelet cyclooxygenase, aspirin is one of the main therapeutics for primary and secondary prevention of thromboembolic vascular events. However, despite regular aspirin assumption, a substantial number of patients present persistent platelet activation. This condition is generally referred to as biochemical aspirin resistance [1]. A persistent platelet hyperreactivity despite a standard antiplatelet therapy can be detected by means of different laboratory methods. The platelet function analyzer-100 (PFA-100; Dade/Behring, Marburg, Germany) is one of the most rapid, sensitive and reproducible tests [2, 3].

The negative prognostic weight of residual platelet activation detected by PFA-100 has been shown in patients with coronary artery disease (CAD) treated with percutaneous coronary interventions (PCI) [3]. However, few data are available on CAD patients treated by coronary artery bypass graft (CABG) surgery. The aim of this prospective study was to define the impact of residual platelet activation, detected with PFA-100, on the clinical outcome of patients undergoing CABG surgery.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patients
All patients undergoing isolated primary CABG surgery from January 1 to December 31, 2004 were considered eligible for this study. Urgency or emergency procedures were not excluded. Preoperative use of oral anticoagulants on a permanent basis or aspirin intolerance were considered exclusion criteria. Patients with known alterations of the coagulation system, as well as patients with severe systemic illness, were also excluded. The medical records of the enrolled patients were reviewed and processed in a structured database, which included demographic, clinical, echocardiographic, and angiographic parameters. The study protocol was approved by the local Ethical Committee and informed consent was obtained from all patients.

Anesthesia and Surgical Management
Total intravenous anesthesia with diazepam, fentanyl, pancuronium, and propofol was used in all patients. Cardiopulmonary bypass was conducted on moderate hypothermia (34°C), with aortic and right atrial cannulation. A standard tubing set [Dideco, Sorin Biomedica, Mirandola, Modena, Italy] and a hollow-fiber membrane oxygenator PRIMO2X [Sorin Biomedica] were utilized. Antegrade hyperkalemic tepid blood cardioplegia was used for myocardial protection. Seventeen patients underwent off-pump CABG. Off-pump CABG surgery was conducted with a standard technique using an Octopus III stabilizer system (Medtronic Italia S.pA., Milano, Italy) and a Starfish-X heart vacuum-assisted positioner (Medtronic Italia S.pA.) [4]. Coronary arteries were temporarily occluded proximally and distally with Silastic loops (Ethiloop; Ethicon Products, Norderstedt, Germany). An intracoronary shunt (ClearView intracoronary shunt; Medtronic Italia S.pA.) was usually used during the construction of distal anastomosis. All patients underwent operations through median sternotomy. The left internal thoracic artery was used as a graft for the left anterior descending artery in all patients. Additional conduits were obtained by harvesting the right internal thoracic artery, segments of the great saphenous vein, and the radial artery as indicated. The revascularization was considered complete when each diseased coronary territory (left anterior descending, circumflex, and right coronary artery) received at least one graft.

Heparin and Protamine Intraoperative Management
During on-pump procedures, heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time (ACT) longer than 480 seconds before the distal transection of the internal mammary artery and commencement of cardiopulmonary bypass. In case of off-pump surgery, heparin (150 IU/kg) was administered to achieve an ACT of 250 to 350 seconds after harvesting the arterial conduit/second. Protamine was administered on completion of the surgical procedure at a ratio of 1:1 in on-pump cases and at a ratio less than 0.5:1 in off-pump cases. Antifibrinolytic drugs or aprotinin were not administered in any patients.

Postoperative Antithrombotic Therapy
During the first three postoperative days, all patients received subcutaneous low molecular weight heparin (nadroparine 5.700 UI activated factor X [anti-Xa] per day). Aspirin administration was started eight hours after the end of the operation at the standard dose of 100 mg per day, if surgical bleeding was ruled out. No patient received platelet transfusions.

Early Postoperative Endpoints
Operative death was defined as any death occurring within 30 days after surgery. Hospital outcomes were defined according to the current guidelines [5]. Early graft failure documented with angiography (with or without the need for early PCI or early reoperation) was registered. Hospital length of stay was computed strictly considering discharge at home.

Blood Collection and PFA-100 Measurement
At one month postoperatively, all patients underwent aspirin resistance assessment with platelet function analyzer-100 (PFA-100; Dade-Behring, Marburg, Germany). Blood samples for analysis of platelet function were collected into evacuated tubes (Vacutainer; Becton Dickinson, Plymouth, UK) containing 3.8% citrate. Platelet function was evaluated using the PFA-100, which provides a quantitative measure of primary platelet-related hemostasis at high shear stress [6].

A total of 0.8 mL of citrated whole blood is transferred into the reservoir of a disposable test cartridge within 4 hours after blood sampling. The blood is warmed to 37°C and drawn under vacuum by means of a 200-µm-diameter stainless-steel capillary (that mimics small or stenosed blood vessels) and a 150-µm-diameter aperture in a nitrocellulose membrane coated with collagen and epinephrine. In response to high shear stress (5,000 to 6,000 seconds– 1) and agonist action, a platelet aggregate forms that blocks blood flow through the aperture; the time taken to occlude the aperture is reported as the collagen-epinephrine closure time (CEPI-CT), and is measured to a maximum of 300 seconds [7]. All measurements were done from 1 to 4 hours after blood sampling. Coefficients of variation for duplicate analysis averaged 15% with a day-to-day variability that was around 10% for both cartridges, as previously reported [8]. A cutoff value of 190 seconds was chosen to define platelet hyperactivity because it has been shown to identify a state of platelet activation at risk for subsequent coronary events [8]. In patients with CEPI-CT less than 190 seconds the test was double confirmed. In any case, patients with CEPI-CT less than 190 seconds continued to take aspirin at the standard dosage.

Follow-Up and Late Postoperative Endpoints
Follow-up data were prospectively collected at our outpatient clinic, according to a routine protocol. The follow-up visits were conducted by cardiologists not involved in the present study. The first clinical and instrumental evaluation was obtained 3 to 4 months after patient discharge. All patients were then reevaluated every 6 months. A stress test was routinely performed at 6 to 8 months postoperatively, and then on an annual basis. Imaging studies for the evaluation of graft patency, multislice computed tomography, or conventional angiography were performed when indicated, in accordance with the current clinical practice or guidelines [9].

Deaths attributed to acute myocardial infarction (AMI), congestive heart failure (CHF), arrhythmias, and sudden deaths without any other specific cause were considered as cardiovascular deaths. Cause of death was established from hospital charts, autopsy reports when available, or from a family physician interview. Nonfatal complications such as recurrence of angina, AMI, documentation of graft failure, repeated revascularization by PCI, stroke, thromboembolism, visceral or cerebral hemorrhage, and CHF episodes were all recorded at follow-up.

The primary endpoint of this study was defined as the composite of death, AMI, recrudescence of angina, and instrumental documentation of ischemia or graft failure, respectively, detected by stress-electrocardiography, stress-echocardiography, myocardial radionuclide imaging, and by repeated coronary angiography or computed tomography scan. All data were collected into a structured, dedicated database. Follow-up was completed during a 2-month interval ending in September 2007.

Statistical Analysis
Continuous variables are expressed as mean and standard deviation. Dichotomous variables are expressed as percentages. Dichotomous patient characteristics were analyzed by the Fisher exact test. Normally distributed continuous variables were analyzed by the unpaired Student t test.

Overall survival and freedom from major cardiac adverse events (composite endpoint as previously defined) were estimated by Kaplan-Meier analysis. Comparison between unadjusted overall group survival and freedom from major adverse events, relative to baseline characteristics, were assessed by the log-rank test. The multivariable relationships of potential predictive factors for simple and composite endpoints were evaluated by multivariable Cox regression analysis. Those variables with a univariate p value 0.1 or less, or those of known biologic significance but failing to meet the critical {alpha} level, were used in the multivariable Cox analysis. Statistical analysis was performed with Stat-View software version 5.0.1 (SAS Inc, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Out of 224 patients operated for isolated primary CABG surgery during 2004, 202 patients were eligible to enter the study (Table 1). Fourteen patients (6.3%) were excluded for oral anticoagulants chronic use, and 2 (0.9%) for aspirin intolerance. Two patients (0.9%) with chronic renal failure requiring dialysis and one patient (0.4) with severe liver disease and platelet dysfunction were also excluded. Three patients (1.3%) undergoing redo CABG were not enrolled. Out of 202 patients 68 (33.7%) underwent urgent surgical procedure. These patients usually stopped antiplatelet therapy a few days before surgery while 7 patients (3.5%) were operated on emergency usually for refractory angina with electrocardiogram modification. Patients undergoing elective surgery usually were requested to stop antiplatelet therapy 7 days before the planned operation. Patients operated on an urgency basis usually stopped antiplatelet therapy 3 to 4 days before surgery and were treated with low molecular weight heparin and nitrate infusion if necessary. Regarding emergency operation, 4 patients received glycoprotein IIb/IIIa receptor antagonists (eptifibatide in 3 patients and tirofiban in 1 patient) until 4 hours before starting the operation, while the other 3 patients were treated with intravenous heparin and nitrates. Most patients (73.3%) received a complete myocardial revascularization, as defined previously. Baseline and operative patients' characteristics are reported in Table 1. In the on-pump group the aortic cross-clamp and cardiopulmonary bypass duration were, respectively, 48.82 ± 11.52 minutes and 65.51 ± 11.36 minutes.


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  		Table 1 Preoperative and Operative Data: Comparison Between Groups
 
There were no operative deaths. The average length of in-hospital stay was 5.8 ± 0.7 days. Postoperative data and complications are reported in Table 2.


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  		Table 2 Postoperative Complications: Comparison Between Groups
 
Residual Platelet Reactivity and Recurrent Myocardial Ischemia
All patients underwent platelet function evaluation within an average of 30.1 ± 6.3 days (median 29 days; range, 20 to 47 days) after the operation. The use of cardiopulmonary bypass did not influence the distribution of platelet reactivity among patients. In the on-pump group 77 of 185 (41.6%) patients showed high residual platelet reactivity, versus 9 of 17 (52.9%) patients in the off-pump group (p = 0.488). Eighty-six patients (42.6%) showed platelet hyperreactivity as defined above (CEPI-CT < 190s). A CEPI-CT less than 190 seconds was more frequent in nonsmoking patients (p = 0.001), and tended to be associated with diabetes (p = 0.06) (Table 1). There were no other significant differences between patients with significant residual platelet activity and the patients with a normal response to aspirin (CEPI-CT > 190s) with regard to preoperative, operative, and early postoperative data (Table 1; Table 2).

Follow-Up
The mean follow-up was 32 ± 10 months and it was 100% complete. Two patients (0.9%) died during the follow-up: one from congestive heart failure and the other from myocardial infarction. Both patients showed residual platelet reactivity on aspirin treatment (p = 0.09). The results of the postoperative reevaluation are summarized in Figure 1.


Figure 1
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  		Fig 1. Follow-up chart showing the fate of the 202 enrolled patients. (a) 82-year old patient with severe preoperative left ventricular dysfunction who had undergone emergency coronary artery bypass graft surgery in the setting of an acute relapsing anterior myocardial infarction. The revascularization was not complete. The patient had atypical chest pain postoperatively. MSCT showed a patent left internal thoracic artery to left anterior descending artery. The patient died at home 7 months postoperatively from congestive heart failure. (b) These four patients were addressed to control angio-CT by the referring cardiologist in the absence of symptoms or documented ischemia. (c) Two asymptomatic patients with a positive stress test were not further evaluated. To date, they are both alive and well. (d) Computed tomography angiography/catheter angiography failed to show graft failure or significant progression of the disease in the native coronary arteries. (e) Development of a significant (>50%) coronary stenosis that was not present at the time of surgery. (f) One patient with chest pain was not further evaluated. To date, he is alive and well. (g) One patient with stable angina died at home 17 months postoperatively while awaiting cardiac catheterization. The death was attributed to acute myocardial infarction. CT = coronary computed tomography angiography; GF/PTCA = graft failure treated by percutaneous transluminal angioplasty; GF/MT = graft failure—patient addressed to medical therapy; NCA-DP = disease progression in the native coronary arteries.

 
Recurrent angina (with/without documentation of ischemia) was complained by 43 patients (21.3%), and 27 patients (13.3%) had a positive stress test in the absence of angina symptoms (silent ischemia). Most of these 70 patients (62.8%) were CEPI-CT < 190s patients. The 42-month freedom from angina-ischemia was significantly better for CEPI-CT > 190 patients. (84.1%; 95% confidence limits [CL]: 76.1 and 92.1 vs 56.4%; 95% CL: 41.2 and 71.6; p = 0.001). Other univariate predictors of recurrent angina (with/without documentation of ischemia) or silent ischemia were diabetes (p = 0.0028; hazard ratio [HR] 2.50, 95% CL: 1.37 and 4.56) and poor left ventricular ejection fraction (LVEF) (p = 0.0435; relative risk [RR] 0.96, 95% CL: 0.92 and 0.99). However, only residual platelet reactivity (p = 0.0048; HR 2.68, 95% CL: 1.35 and 5.32) and diabetes (p = 0.0181; HR 2.12, 95% CL: 1.14 and 3.94) were independently associated with recurrence of angina (with/without documentation of ischemia) or silent ischemia at multivariate analysis (Table 3).


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  		Table 3 Recurrent Angina With/Without Positive Stress Test or Silent Ischemia: Univariable and Multivariable Analysis
 
Graft failure documented by coronary angiography or computed tomographic scan was diagnosed in 25 (12.38%) patients with no significant difference between the two groups (p = 0.31). Eleven of these patients underwent PCI at 11.3 ± 9.6 months after the operation. The 42-month freedom from graft failure of patients with CEPI-CT < 190s was 81.2% (95% CL: 71.5 and 90.9%) compared with 86.3% (95% CL: 78.3% and 94.3%) for patients with CEPI-CT > 190s (p = 0.25) (Fig 2). Only diabetes was independently related to graft failure (p = 0.0216; RR 2.61, 95% CL: 1.15 and 5.89).


Figure 2
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  		Fig 2. Freedom from composite event (death, recurrent angina-ischemia, or graft failure). ({circ}, PFA 100 – = patients with a CEPI-CT > 190 seconds; •, PFA 100 + = patients with a CEPI-CT < 190 seconds; CEPI-CT = collagen-epinephrine closure time; PFA = platelet function analyzer.)

 
Considering a composite endpoint accounting for cardiovascular death plus recurrent angina-ischemia and graft failure, patients with residual platelet reactivity had a significantly worse outcome. The 42-month event-free survival of patients with CEPI-CT < 190s was 43.4% (95% CL: 30.4% and 56.4%) compared with 68.8% (95% CL: 58.5% and 79.0%) for patients with CEPI-CT > 190s (p = 0.001) (Fig 3). Other negative prognostic factors for unadjusted freedom from death plus recurrent angina-ischemia and graft failure were incomplete revascularization (p = 0.076), diabetes (p = 0.0002), and poor LVEF (p = 0.0178) (Table 4). All these factors except the latter remained significant at multivariable analysis (Table 4).


Figure 3
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  		Fig 3. Freedom from graft failure, percutaneous coronary interventions, or redo coronary artery bypass graft surgery. ({circ}, PFA 100 – = patients with a CEPI-CT > 190 seconds; •, PFA 100 + = patients with a CEPI-CT < 190 seconds; CEPI-CT = collagen-epinephrine closure time; PFA = platelet function analyzer.)

 

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  		Table 4 Composite Endpoint: Univariable and Multivariable Analysis
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Our study provides the first documentation that high residual platelet reactivity, as detected by means of a point-of-care test, the PFA-100, correlates with a worst clinical outcome in patients undergoing CABG surgery. In particular, the present results demonstrate that a CEPI-CT less than 190 seconds one month postoperatively is strongly and independently associated with the recurrence of angina, and with the occurrence of a composite endpoint accounting for cardiovascular death, recurrent angina-ischemia, and graft failure.

Several evidences have linked residual platelet reactivity to a higher incidence of thrombotic events in patients after PCI [10–13]. We also have previously shown that patients with a CEPI-CT less than 190 seconds after PCI are at higher risk of subacute in-stent thrombosis and recurrent cardiac events [3]. Given the primary role of platelets in the pathophysiology of coronary syndromes we hypothesized that this observation was extendible also to surgical patients. The results of the present study seem to confirm this idea.

A state of platelet hyperactivity is well known to occur after CABG surgery [14–17]. This condition is strongly time-related and can be partially justified by the systemic proinflammatory response induced by the cardiopulmonary by-pass [16, 17]. For this reason, we decided to collect the blood samples for PFA-100 analysis one month after revascularization, and to stratify the patients according to their residual platelet reactivity despite a standard antiplatelet therapy. We did not use the term "aspirin resistant" patients, elsewhere adopted for similar cut-off limits (CEPI-CT < 190s), because a single PFA-100 test without a pretreatment analysis is not an acceptable measure of aspirin efficacy, as outlined by a recent consensus conference [18].

Even if a strong association was found between a CEPI-CT less than 190 seconds and the occurrence of all cardiovascular events during the follow-up period, survival was apparently not affected by the presence of residual platelet activity in the present series. However, only 2 patients died during follow-up, and this factor could limit the statistical power of our analysis. Of note, however, both these patients were CEPI-CT < 190s patients. Graft failure, documented by coronary angiography or multislice tomography, was also not affected by the results of the PFA-100. This apparent incongruity may be due to the incomplete invasive evaluation of the patients presenting with a positive stress test (25 over 27) or to the different role of platelets in the pathophysiology of acute coronary syndromes compared to the development of accelerated atherosclerosis and intima hyperplasia that are responsible for graft occlusion. Other factors (eg, diabetes, dyslipidemia, hypertension) may have a stronger role in promoting this latter process.

The main limitation of the present study is the relatively small number of patients, followed for a short period. As already observed, the small number of patient-years accumulated was probably responsible for our failure to find an association between a CEPI-CT less than 190 seconds and death. Despite this limit, however, we were able to show a strong and significant association between residual platelet reactivity and the occurrence of adverse cardiovascular events during the follow-up. For this reason, we are convinced that the presence of residual platelet activity should be regarded to as an important risk factor in CABG patients, and that as such it should be aggressively sought and treated.

The results of the present study demonstrate that a high residual platelet reactivity correlates with a worst clinical outcome in CAD patients treated by CABG surgery. This observation suggests the opportunity to stratify the thrombotic risk of CABG patients early during the follow-up. The determination of CEPI-CT by the PFA-100 provides a simple, quick, and economic tool to achieve this goal.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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  3. Gianetti J, Parri MS, Sbrana S, et al. Platelet activation predicts recurrent ischemic events after percutaneous coronary angioplasty: A 6 months prospective study Thromb Res 2006;218:487-493.
  4. Cerillo AG, Sabatino L, Bevilacqua S, et al. Nonthyroidal illness syndrome in off-pump coronary artery bypass grafting Ann Thorac Surg 2003;75:82-87.[Abstract/Free Full Text]
  5. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery) Circulation 2004;110:340-437.
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  8. Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction J Lab Clin Med 2001;138:152-163.[Medline]
  9. Antman EM, Hand M, Armstrong PW. 2007 Chronic angina focused update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to Develop the Focused Update of the 2002 Guidelines for the Management of Patients With Chronic Stable Angina Circulation 2007;116:2762-2772.[Free Full Text]
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  11. Eikelboom JW, Hankey GJ, et al. Aspirin resistance: a new independent predictor of vascular events? J Am Coll Cardiol 2003;41:966-968.[Free Full Text]
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