Use of an Objective Tool to Assess Platelet Inhibition Prior to Off-Pump Coronary Surgery to Reduce Blood Usage

Abstract: Background. The current standard of care is to delay coronary surgery 5-7 days after clopidogrel exposure to prevent bleeding complications. We sought to determine the utility of an objective tool (ie, the VerifyNow assay) to measure platelet inhibition (PI) in patients receiving preoperative clopidogrel prior to off-pump coronary artery bypass grafting surgery (OPCABG). Patients and Methods. Between June 2007 and July 2009, a total of 482 isolated OPCABG procedures were performed at our institution. In 160 patients, the VerifyNow assay results were used to determine timing of the OPCABG. These patients were compared to the remaining 322 patients. We divided the cohort into 4 subgroups: Group 1 patients (n = 205) were not taking clopidogrel; Group 2 patients (n = 117) were taking clopidogrel, but the test was not performed; Group 3 patients (n = 122) were taking clopidogrel and had a preoperative PI result of ≤20%; and Group 4 patients (n = 38) had ≥21% preoperative PI. Results. Demographic and clinical factors were compared in all groups. The median waiting time for surgery from the last dose of clopidogrel was 6 days for the control groups and 3 days for the groups where the test was performed (P<.001). Reoperation for bleeding occurred most often in Group 4 (7.9%; P=.003). Blood utilization was lower in Group 1 (24.4%) than in Groups 2 (34.2%), 3 (40.2%), or 4 (55.3%) (P<.001). Major complications and postoperative length of stay were similar in all groups. Conclusions. Utilization of a PI tool in the preoperative assessment of OPCABG patients exposed to clopidogrel can provide valuable information to guide the timing of coronary surgery and may lead to a decrease in reoperation for bleeding and blood usage.

J INVASIVE CARDIOL 2012;24:49-52

Key words: off-pump coronary surgery, clopidogrel

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The thienopyridine agent clopidogrel is widely accepted as an effective platelet inhibitor. Published studies have demonstrated the efficacy of its use in addition to aspirin to prevent death, myocardial infarction, and stroke in patients with coronary syndromes.¹ Its benefits can be seen in medically-treated patients and those receiving coronary revascularization.² However, effective platelet inhibition (PI) with these agents can cause an increased risk of bleeding, which is more evident in patients who eventually need surgical revascularization. Moreover, it has been estimated that over 50% of patients undergoing coronary artery bypass graft (CABG) surgery were or are currently taking clopidogrel at the time of surgery.³ Many trials demonstrate that the risk of postoperative bleeding is higher when clopidogrel is discontinued within less than 5 days of the surgery date.^1-4

Based on the current evidence, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for managing patients with coronary artery disease who undergo CABG recommend withholding clopidogrel for 5 to 7 days before the surgical procedure. No mention is made regarding the utilization of platelet inhibition tests (PITs).⁵ However, recent revisions to the Society of Thoracic Surgeons (STS) and the Society for Cardiovascular Anesthesiologists (SCA) Blood Conservation Guidelines acknowledge that the time between clopidogrel discontinuation and surgery can be as short as 3 days. Moreover, they mention that point-of-care testing, which encompasses PITs, can be used to identify patients who do not respond to clopidogrel and thus will not need to wait for operative coronary revascularization after drug discontinuation.⁶
PITs have been previously evaluated in patients who are on dual antiplatelet therapy and need CABG.⁷ In this study, we sought to determine the impact of these tests in reducing pre-surgical waiting time and predict the occurrence of bleeding complications. We do not endorse any particular PIT, but rather advocate for the use of a PIT that is most appropriate for the institution.

Methods

Patient population. This was a prospective observational study in which the length of time between discontinuation of clopidogrel and the initiation of off-pump CABG (OPCABG) surgery was determined by the results of the platelet reactivity value obtained from the VerifyNow assay (Accumetrics). The study was approved by our Institutional Review Board (IRB), and informed consent was obtained from all patients participating in the study. Clinical, procedural, and in-hospital outcome data for these patients and controls were obtained from the Society of Thoracic Surgeons (STS) database approved by the IRB and collected prospectively on all OPCABG procedures performed at our institution between June 2007 and July 2009.

A total of 482 consecutive patients undergoing OPCABG were available for inclusion. In 160 patients, the VerifyNow assay results were used to determine timing of the OPCABG. These patients were compared to the remaining 322 patients. Of the total cohort, 277 (57.4%) were taking preoperative dual antiplatelet therapy that included aspirin and clopidogrel, while the remainder of the patients (n = 205; 42.6%) were not taking clopidogrel. We divided the cohort into 4 groups. Group 1 (G1; n = 205) included patients who were not taking clopidogrel (control: no clopidogrel), and Group 2 patients (G2; n = 117) were taking clopidogrel, but PITs were not performed (control: clopidogrel). Group 3 patients (G3; n = 122) were taking clopidogrel and had a preoperative PIT result of ≤20% PI, whereas Group 4 (G4; n = 38) had a PIT result of ≥21% PI. The timing of the test was in an elective setting with the exception of those require more urgent surgery.

None of these patients had a preoperative platelet count below 150,000 per µL of blood or a hematocrit below 30, as these are requirements for the VerifyNow test to be performed with accurate results. Initial comparisons of the demographics and preoperative morbidities of the patient population are detailed in Table 1.

The control group (G2) waited a median time of 6 days to have the surgery. In G3, surgery was delayed until a PITs result of ≤20% PI was achieved. G4 went to surgery immediately with a PIT result >21% due to instability of the coronary syndrome.

The endpoints evaluated were preoperative waiting time, postoperative bleeding, re-operation for bleeding, blood utilization, 30-day mortality, and postoperative length of stay.

Blood sampling and platelet inhibition test. A 2 mL whole venous blood sample was obtained from each patient using Greiner tubes and analyzed using the VerifyNow P2Y12 assay. This assay calculates the percentage of PI after exposure to any previous dose of clopidogrel by measuring platelet-induced aggregation as an increase in light transmittance in whole blood in response to adenosine diphosphate (ADP) activation.⁸ Clopidogrel and similar antiplatelet therapies have an antagonistic effect on the platelet P2Y12 receptor, thereby preventing blood clotting^.9,10 The VerifyNow assay is a relatively inexpensive test (approximately $40 per test) and has been shown to be one of the most suitable tests to evaluate platelet function in patients with various cardiovascular conditions.^8,10,11

Based on manufacturer recommendations, a test with a result equal to or less than 20% PI is considered a very low grade of inhibition and “acceptable” bleeding risk to undergo a surgical procedure. In contrast, a result equal to or more than 21% was considered a high level of inhibition and “elevated” risk of bleeding during a surgical intervention. We used this parameter to define our “cutoff” to make the decision whether or not to operate, as it defined the groups for this study. For low responders to clopidogrel, a threshold of 15% PI can be utilized.¹²

Surgical technique. OPCABG procedures were performed using standard median sternotomy and one of several commercially available stabilizing devices. Since 4 different surgeons were involved in the procedures, there were some minor variations in the surgical technique. Heparinization was accomplished with 0.5 mg/kg of intravenous heparin given prior to performing the first anastomosis. Protamine sulfate was used to reverse the heparin effect at the end of the last anastomosis. Cell saver was used in all patients. Strict postoperative chest tube output monitoring and evaluation of patient hemodynamics were utilized to define postoperative bleeding and to decide whether to perform surgical re-exploration for the cause of bleeding. There were no uniform criteria to dictate when blood product transfusion was used. However, our institution has an established blood conservation program so that the “threshold” to transfuse any patient is dictated by several factors, which include hemoglobin level below 7, hypotension, or low cardiac index not responding to colloid and crystalloid administration. Blood use in OPCABG patients for our center is consistently lower than the norms published in national STS registry reports.

Data analysis. Data were prospectively collected and stored in a database certified by the STS. Continuous data are displayed as means with standard deviations. Categorical data are expressed as proportions. Univariate statistical tests for continuous data included tests of mean differences using ANOVA for multi-group testing and the Student’s t-test for pairwise comparisons. Individual groups were not compared unless the overall F statistic from the ANOVA was statistically significant. For non-normally distributed continuous data (eg, time from discontinuation of clopidogrel to surgery), the Kruskal-Wallis rank test was used to compare groups. Categorical variables were analyzed using the Chi-square test. A value of P<.05 was used to determine the statistical significance of all tests used. Analyses were performed using the SPSS statistical software package version 17.0 (SPSS Inc). 

Results

Patient demographics and presenting clinical characteristics were comparable in the 4 groups with a few notable exceptions (Table 1). G4 patients generally had a lower body mass index and were more likely to have a past history of cardiovascular disease than the other groups. G2 patients had the highest prevalence of past myocardial infarction and cerebrovascular accident of all groups studied.

Major complications, 30-day mortality, and postoperative length of stay were somewhat similar in all groups (Table 2). As a whole, more G1 and G3 patients experienced postoperative atrial fibrillation. The overall re-operation for bleeding rate was 1.5% (7 patients), with G4 having the highest (3 patients; 7.0%). Blood product transfusion was lowest in G1, where 50 patients (24.4%) received at least one transfusion of any blood product. About 40 patients (34.2%) in G2, 49 patients (40.2%) in G3, and 21 patients (56.3%) in G4 received blood transfusion. Notably, there was no significant difference between G2 and G3 (Table 2).

The median waiting time before surgery after the last dose of clopidogrel for G2 (control group) was 6 days, whereas the median waiting time for patients who underwent PITs (G3 and G4) was 3 days (P<.001) (Table 3). There was no significant difference between the dose of clopidogrel given preoperatively and waiting time for surgery (Table 4). 

Discussion

This study yielded several findings on how PITs affect pre-surgical waiting time and the development of complications. First, we found that blood utilization and re-operation for bleeding were significantly higher in groups of patients who had a history of taking clopidogrel preoperatively. Also, postoperative outcomes, including 30-day mortality, perioperative myocardial infarction, permanent stroke, renal failure, and other complications, were comparable in all groups studied. However, the prevalence of postoperative atrial fibrillation, re-operation for bleeding, and postoperative blood transfusion differed among the groups, particularly for G4.

Interestingly, patients exposed to clopidogrel who also underwent PITs had their presurgical waiting times reduced from the standard 5-7 days to 3 days. A PIT result equal to or greater than 21% indicated a high level of platelet inhibition and was associated with a significant increase in the rate of blood product usage and risk of re-operation for bleeding.

The results of this study suggest that an objective assessment test of platelet activity may be useful in evaluating patients about to undergo coronary bypass surgery. The current pre-surgery waiting time of 5-7 days is a universal value that applies to all patients on clopidogrel. This standard waiting time does not account for the fact that patients react differently to clopidogrel, so that the waiting times for certain patients may fall outside this range. By individually assessing PI, PITs can provide an objective measure of how effectively clopidogrel is inhibiting platelets in a particular patient, providing information that may help to adjust the time between discontinuation of clopidogrel and the CABG surgery. However, since our study included patients who underwent OPCABG, these results may not apply to patients who require on-pump CABG.

The use of PITs in our study resulted in a decrease in waiting time for patients requiring OPCABG, which may translate into potential benefits for patients, physicians, surgeons, and the hospital. The shorter waiting time may allow physicians and surgeons to more effectively and promptly deliver their care in these types of case. Moreover, the judicious use and monitoring of clopidogrel via PITs may significantly decrease the need for blood transfusions and re-operation for bleeding in similar patients.

In our study, the rates of bleeding complication and blood product transfusion were significantly higher when the patient was preoperatively exposed to clopidogrel. In addition, this analysis demonstrated that PIT values of equal to or greater than 21% of PI in patients exposed to clopidogrel were associated with higher risk for bleeding complications and need for blood product transfusion during the postoperative course. Our results suggest that information from the PIT can be used to guide timing in patients requiring CABG and receiving dual antiplatelet therapy, which in our study led to a 50% reduction in the recommended waiting time of 5-7 days for an elective coronary operation in stable patients.

Study limitations. In this study, the PIT strategy used was not randomized, nor was a multivariable analysis performed. Therefore, the results may be biased and can be viewed as hypothesis generating. These results should be confirmed in a prospective randomized trial. This is a single institution study where the operations were performed by 4 different surgeons with slightly different techniques. Patients were evaluated for only the first 30-day postoperative outcomes, as defined in the STS database, and longer-term outcomes were not analyzed.

Conclusions

In our study, the utilization of information from a PIT in the preoperative assessment of OPCABG patients exposed to clopidogrel reduced the waiting time for surgical intervention by 3 days. A PIT result of equal to or greater than 21% of PI was associated with an increased risk of re-operation for bleeding and blood product utilization.

References

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From ¹the Valley Heart and Vascular Institute, Ridgewood, New Jersey and ²Columbia College of Physicians & Surgeons, New York, New York.
This study was presented as an oral presentation at the International Society for Minimally Invasive Cardiothoracic Surgery, Annual Scientific Meeting in Berlin, Germany in June 2010.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted August 16, 2011, provisional acceptance given August 25, 2011, final version accepted November 7, 2011.
Address for correspondence: Mariano E. Brizzio, The Valley Heart and Vascular Institute, 223 North van Dien Avenue, Ridgewood, NJ 07450. Email: mbrizzio@gmail.com