Coronary Artery Bypass Graft Surgery in Patients Receiving Antiplatelet Therapy: Can We “Fine-Tune” the Balance of Safety and Efficacy?

Oral dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, most often clopidogrel, has been demonstrated to reduce the composite risk of ischemic morbidity and mortality across a wide range of patient groups including those with acute coronary syndromes (ACS) and post-percutaneous coronary intervention (PCI).^1-3 In the case of patients presenting with non-ST segment elevation ACS, pre-angiography use of DAPT is both common clinical practice and strongly endorsed by the American College of Cardiology Foundation/American Heart Association Unstable Angina/Non-ST Elevation Myocardial Infarction Practice Guidelines.⁴ As the ischemic benefit associated with early use of DAPT extends to conservatively managed and revascularized patients alike, so too does the risk of major bleeding with proportionally greater bleeding risk incurred in patients undergoing invasive and surgical procedures. In the overall CURE trial population, a rather modest 1.1% absolute increase in major, protocol-specified bleeding was noted in DAPT-treated patients as compared to patients randomized to aspirin and placebo, but this relative bleeding risk tripled (3.3%) in those patients who required coronary artery bypass graft (CABG) surgery within 5 days of their last dose of DAPT. For patients in whom surgery was performed >5 days after their last dose of DAPT, the CABG bleeding risk was comparable to those treated with aspirin/placebo. Thus, the guideline-based recommendation stands that in DAPT-treated ACS patients with surgical coronary disease, CABG surgery should be delayed if possible for 5-7 days following the last dose of clopidogrel.⁴ Admittedly, however, this recommendation is predicated on the post hoc findings detailed above and has not been prospectively validated on a large scale. Both ischemic protection and bleeding risk are widely presumed to be linked with the level of platelet inhibition achieved on DAPT, yet remarkably, there have been few successful attempts to improve patient outcomes via prospective use of platelet function testing. In this issue of the Journal of Invasive Cardiology, Brizzio and colleagues offer insights into the opportunities and challenges surrounding the issue of timing CABG surgery based on objective measures of platelet inhibition.⁵

In this single-center, prospective, observational study of 482 patients undergoing isolated off-pump coronary artery bypass grafting surgery (OPCABG) over a 2-year period, patients were stratified on the basis of clopidogrel exposure and in the subset of patients who had received clopidogrel, dichotomized on the basis of inhibition of platelet aggregation (IPA) ≤20% versus ≥21%, thus yielding 4 groups: clopidogrel-naïve controls, able to proceed to CABG immediately (Group 1); clopidogrel-treated controls with no platelet inhibition testing (PIT) with median time to CABG of 6 days based on local practice (Group 2); clopidogrel-treated patients, surgery delayed until IPA ≤20% achieved (Group 3); and clopidogrel-treated, surgery undertaken with IPA ≥21% due to clinical urgency/inability to wait (Group 4). The specific method used for IPA assessment in this study, VerifyNow P2Y12 (Accumetrics), employs a turbidimetric-based, optical detection system to quantify platelet co-agglutination with agonist-coated styrene microbeads. This methodology has demonstrated good correlation with conventional, laboratory-based aggregometry and importantly, is a whole-blood assay entailing low cost and minimal sample prep, therefore rendering it suitable for point-of-care use in clinical practice.^6-8 Platelet aggregation ascribable to adenosine diphosphate (ADP) P2Y12 activity is measured in a channel containing 20 µM/L ADP buffered with prostaglandin E1 (PGE1) in order to minimize the contribution of ADP P2Y1 receptor-mediated platelet activation. Output from this channel is reported in P2Y12 reaction units (PRU) and may be regarded as a raw measure of residual platelet reactivity. A second channel (BASE), containing thrombin receptor activating peptide and PAR-4 activating peptide, measures maximal platelet aggregation independent of ADP P2Y12 activity. A ratio of these two values serves as the derived IPA (%) value (in the absence of a drug-naïve/pre-treatment, “reference” value) and was the metric employed in this study.

The most notable findings of this study centered on the interaction between IPA and perioperative bleeding, as well as with the time to CABG, in the clopidogrel-treated cohort.⁵ A significant increase in postoperative blood transfusion and a trend toward greater intraoperative transfusion were seen in clopidogrel-treated patients with the highest rate in Group 4 (IPA ≥21%). Interestingly, all clopidogrel-treated patients had numerically higher bleeding rates than clopidogrel-naïve patients, despite a 5-7 day pre-CABG wait in Group 2 or IPA ≤20% in Group 3. These findings seem to support the broad concept that even a modest degree of residual platelet inhibition post-DAPT increases surgical bleeding. In an unblinded analysis, however, the impact of ascertainment bias is difficult to quantify and impossible to exclude completely. In Group 4, representing those patients with the greatest residual platelet inhibition, the investigators noted the highest rate of reoperation for bleeding. The prosaic interpretation of this finding again invokes the inverse relationship between platelet inhibition and hemostatic competency. It should be noted though that given the fact that these patients had to undergo CABG surgery with greater urgency than Groups 1-3 and were therefore fundamentally different at least in this regard than the comparator groups, one cannot discount the impact of other, unquantified variables which may have independently contributed to bleeding risk/need for reoperation. It was also noted that patients who underwent IPA assessment (Groups 3 and 4) waited a shorter period of time than clopidogrel-treated patients who waited the prescribed 5-7 days without PIT guidance, although this may have been partly influenced by the treatment urgency in Group 4.

The aforementioned limitations notwithstanding, point-of-care IPA assessment for optimization of CABG timing in DAPT-treated patients potentially represents an important, and as yet, unfulfilled opportunity to improve the quality, safety, and efficiency of patient care. A number of unresolved and unaddressed issues remain, however. Firstly, the optimal “cutpoint” for IPA in preoperative patients remains unknown. Sibbing et al have demonstrated that post-PCI non-CABG related TIMI major bleeding events were more common in patients demonstrating enhanced response to clopidogrel using multiple-electrode-aggregometry (Multiplate analyzer; Dynabyte BioLabs).⁹ It stands to reason, however, that these types of spontaneous or access-site bleeds differ significantly from intra/postoperative bleeding and further, that bleeding thresholds may also vary with the type and technique employed during a given surgical procedure. A second issue is regarding the most appropriate methodology for rapid assessment of IPA. VerifyNow is one of a limited number of methodologies that have demonstrated predictive value for post-PCI ischemic sequelae both in comparative analyses against other PITs as well as in pooled analyses evaluating the prognostic significance of high on-treatment platelet reactivity post-PCI.^10-12 Even so, uncertainty remains regarding the use of raw platelet reactivity (PRU) versus derived IPA (as was implemented by Brizzio et al) for optimal prediction of events.

In summary, the wide response variability and unpredictable offset of oral P2Y12 inhibition coupled with the ubiquity of treatment with DAPT creates an unfilled niche for tailored antiplatelet therapy in patients continuing treatment and assessment of platelet function recovery in patients discontinuing treatment in anticipation of surgery. Future studies hoping to parse this latter issue should necessarily incorporate blinding, randomization, and ideally, multiple platelet reactivity thresholds into the study design. As pharmacotherapy for acute coronary syndromes and myocardial infarction continues to intensify and become ever more complex, the relevance and impact of such investigations will likely grow further. 

References

1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
2. Steinhubl SR, Berger PB, Mann JT 3rd, et al; CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.
3. Rossini R, Musumeci G, Nijaradze T, et al. Clopidogrel bisulfate: a review of its use in the management of acute coronary syndromes. Clin Med Ther. 2009;1:899-910.
4. 2011 ACC/AHA focused update of the Guidelines for the Management of Patients with Unstable Angina/Non-ST Elevation Myocardial Infarction (updating the 2007 guideline). A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;57(19):1920-1959.
5. Brizzio ME, Shaw RE, Bosticco B, et al. Use of an objective tool to assess platelet inhibition prior to off-pump coronary surgery to reduce blood usage. J Invasive Cardiol. 2012;24(2):49-52. 
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7. Varenhorst C, James S, Erlinge D, et al. Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin. Am Heart J. 2009;157(3):562.E561-E569.
8. Godino C, Mendolicchio L, Figini F, et al. Comparison of VerifyNow P2Y12 test and flow cytometry for monitoring individual platelet response to clopidogrel. What is the cut-off value for identifying patients who are low responders to clopidogrel therapy? Thromb J. 2009;7:4.
9. Sibbing D, Schulz S, Braun S, et al. Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost. 2010;8(2):250-256.
10. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303(8):754-762.
11. Brar SS, ten Berg J, Marcucci R, et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention: a collaborative meta-analysis of individual participant data. J Am Coll Cardiol. 2011;58(19):1945-1954.
12. Stone G. Assessment of dual antiplatelet therapy with drug-eluting stents (ADAPT-DES). Oral presentation at Transcatheter Cardiovascular Therapeutics (TCT) 2011, San Francisco, CA. November 9, 2011.

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From the University of Chicago Medical Center, Chicago, Illinois.
Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Nathan has received honoraria and consulting fees from Sanofi Aventis, has served as an advisor to Daiichi Sankyo, and holds a research grant from Accumetrics. The author reports no conflicts of interest regarding the content herein.
Address for correspondence: Sandeep Nathan, MD, MSc, FACC, FSCAI, Assistant Professor of Medicine, Interventional Cardiology Staff, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 5076, Section of Cardiology, Chicago, IL  60637-1470. Email: snathan@medicine.bsd.uchicago.edu