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Ann Thorac Surg 2000;70:S33-S37
© 2000 The Society of Thoracic Surgeons

Clinical experience in coronary bypass surgery for abciximab-treated patients

^a Legacy Good Samaritan Hospital, Northwest Surgical Associates, Portland, Oregon, USA

Address reprint requests to Dr Lemmer, 2222 NW Lovejoy, Suite 315, Portland, OR 97210
e-mail: jlemmerjr{at}aol.com

Presented at the "Managing the Patient Receiving Platelet Inhibitors in Cardiac Surgery" Roundtable Discussion, San Antonio, TX, Jan 22–23, 1999.

	Abstract

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 
Abciximab effectively inhibits platelet aggregation and, therefore, there is considerable concern regarding bleeding complications in patients who require coronary artery bypass graft (CABG) surgery while affected by the drug. This presentation reviews the available published literature regarding CABG in abciximab-treated patients, the clinical results of emergency CABG in 12 patients, and management suggestions for the abciximab-treated patient requiring emergency surgery.

	Introduction

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 
Administration of abciximab during percutaneous coronary intervention (PCI) procedures such as angioplasty and stent placement reduces the incidence of associated myocardial infarction, need for subsequent revascularization, and death [1]. In addition, the incidence of urgent coronary bypass surgery is reduced by approximately 50% in patients who receive abciximab for PCI procedures, as compared with placebo [2, 3]. Despite these advantages, occasional patients do require coronary artery bypass graft (CABG) while under the effect of the drug. Because of abciximab’s very effective inhibition of platelet aggregation, this clinical situation has been viewed with considerable concern by cardiac surgeons and anesthesiologists, and reports of excessive bleeding and large transfusion requirements have been both rumored and reported.

The standard abciximab loading dose is 0.25 mg/kg, followed by a continuous infusion of 10 µg/kg/min. These lead to a high proportion (> 90%) of blocked glycoprotein (GP) IIb/IIIa receptors with marked inhibition of platelet aggregation and prolongation of the bleeding time [4, 5]. When abciximab is discontinued, a gradual reduction in receptor blockade occurs. At 12 hours after discontinuation of the drug, only about 68% of the receptors are blocked, a level below the 80% receptor blockade associated with significant inhibition of platelet aggregation and bleeding time prolongation [5, 6]. Return of near normal bleeding times 12 hours after abciximab discontinuation has been demonstrated [6]. The return of hemostatic ability 12 hours after discontinuation of abciximab treatment in CABG patients was also observed by Gammie and associates [7]. Thus, for the purposes of this review, in addressing the results of CABG surgery in patients who have been treated with abciximab, it is most relevant to consider those patients who have received the drug within 12 hours of undergoing operation.

	CABG in abciximab-treated patients: results of the clinical trials

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 
Multiple large, randomized, placebo-controlled, clinical trials have been conducted to investigate the effectiveness of abciximab in reducing the complications associated with PCI procedures. In general, use of abciximab is associated with 35% to 65% reductions in myocardial infarction, the need for urgent revascularization, or death at 30 days in addition to significant reductions in the need for urgent CABG because of failed intervention [1–3]. Several published reports have described the results of CABG surgery in patients who participated in these trials and compared the abciximab-treated patients with those who received placebo.

Boehrer and associates published the results of 58 patients who participated in the EPIC (Evaluation of c7E3 to Prevent Ischemic Complications) trial and who required urgent bypass surgery [8]. Overall, 33 of 1,403 (2.4%) abciximab-treated patients required urgent CABG as compared with 25 of 696 (3.6%) of the placebo patients. Red blood cell (RBC) and platelet transfusions were more common in the abciximab-treated patients, although not significantly. Mortality for the abciximab-treated patient group was 18.2% as compared with 8.0% in the placebo group (p = NS). It is important to note that for most of the abciximab-treated patients who required surgery, the duration of time between abciximab therapy and CABG was more than 24 hours [9]. Therefore, the results of the Boehrer report do not fully reflect the impact of abciximab on the surgical and transfusion requirement results for patients who have been recently (within less than 12 hours) treated with the drug. In addition, details regarding numbers of units of blood products transfused and volumes of chest tube drainage were not provided in this report. Interestingly, the incidence of perioperative myocardial infarction was 20% in the placebo group patients as compared with 6% in the abciximab-treated patients. The conclusion of the authors was that CABG surgery could be performed after treatment with abciximab with acceptable mortality and bleeding complications.

The combined results of urgent bypass surgery performed in the EPILOG (Evaluation of PTCA to Improve Long-Term Outcome by c7E3 GP IIb/IIIa Receptor Blockade) and EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) trials were presented at the 1998 American Heart Association meeting by Booth and associates and was published in the form of an abstract [3]. In these two randomized, placebo-controlled trials, 22 of 1,748 (1.6%) patients who received placebo required CABG within 7 days of treatment as compared with 20 of 3,443 (0.6%) of those who received abciximab in conjunction with coronary interventions. RBC transfusion requirements for the two groups were very similar, with 35% of the patients who had received abciximab requiring more than 5 units as compared with 32% of the patients who had received placebo during their PCI. Platelet transfusions were, however, required in more of the abciximab-treated patients (75% as compared with 46% in the placebo group). Chest tube drainage volumes and the details of per-patient transfusion requirements were not provided in this report. The conclusion of the authors was that there does not appear to be an increased bleeding or transfusion risk for CABG patients who received abciximab except for the higher rate of platelet transfusion. It should be noted, however, that because of the inclusion of patients who underwent surgery up to 7 days after abciximab treatment, these results are not necessarily applicable to patients who require emergency CABG within hours of receiving the drug.

Together, these two reports describe CABG procedures in 53 (1.1%) of 4,846 patients who had recently been administered abciximab. In these patients, excessive bleeding or large transfusion requirements were not apparent, but in many of the patients, the time between drug treatment and surgery was longer than 12 hours. The results, therefore, while of interest, do not necessarily apply to the patient who requires emergency CABG for ongoing ischemia shortly after receiving abciximab therapy.

	Emergency CABG in abciximab-treated patients: single institution results

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 
Several publications have described the single-hospital experience of emergency or urgent CABG in small numbers of abciximab-treated patients. Most of these have been published by the surgical groups who have been faced with the clinical problem of performing CABG on patients who have been very recently treated with abciximab. Some of the reports, which described high rates of bleeding and large blood product transfusion requirements, provide management recommendations. These recommendations include delaying of surgery for more than 12 to 24 hours, routine platelet transfusions, and the use of reduced heparin doses for anticoagulation during cardiopulmonary bypass for the CABG procedure.

In 1997, Juergens and associates described the results of surgery for 4 abciximab-treated patients who underwent emergency CABG within 6 hours of failed coronary angioplasty procedures [10]. All patients received standard heparin doses for cardiopulmonary bypass and all patients received platelet transfusions (1 before arrival in the operating room and 3 while separating from bypass). Major blood loss occurred in 1 patient and only 2 required RBC transfusions, although the number of units transfused was not specified. In the author’s words: "The routine use of platelet transfusions to reverse the effects of abciximab in patients proceeding to emergent coronary bypass surgery after failed coronary angioplasty appears reasonable."

In contrast to the Juergen’s experience, Bracey and associates reported, in abstract form, marked bleeding and increases in blood transfusion requirements for 24 abciximab-treated patients undergoing emergency CABG [11]. Major bleeding (hemoglobin drop > 5 g/dL) occurred in 59% and the mean number of total blood product exposures was more than 25 units per patient. As compared with elective CABG patients in their database, the rates of transfusion were significantly increased in association with emergency surgery and abciximab treatment. The authors recommend waiting 24 hours after abciximab treatment before performing surgery.

Alvarez described 3 patients who underwent emergency CABG after abciximab treatment [12]. Large amounts of blood products were required (mean 4.6 units RBCs, 8.3 units fresh-frozen plasma, and 28 units platelets per patient). One patient died as the result of a large, complicated myocardial infarction. The antifibrinolytic agent aprotinin was administered during surgery in all 3 patients. Because of the results, Alvarez concluded, "before giving abciximab, the cardiologist must critically assess the risk of PTCS [coronary stenting] failure, because the impact of abciximab on CABG is not benign."

In 1998, Gammie and associates reported CABG procedures performed in 11 patients who had been recently treated with abciximab [7]. An important observation made by the authors was that the degree of coagulopathy and resultant need for transfusions was dependent upon the amount of time passed between cessation of abciximab administration and the onset of surgery. Those patients who underwent operation within 12 hours of abciximab therapy bled more and required significantly more transfusions than the patients for whom more than 12 hours had passed. Of the 11 patients detailed in this report, 6 patients had required CABG within 12 hours of abciximab treatment. None of the patients died but some did have "substantial transfusion requirements and, at times, massive coagulopathies." Median per patient values for blood product transfusions were RBCs, 6 units; platelets, 20 units; and plasma, 4 units. The authors also noted that the patients who underwent CABG early after abciximab therapy had significantly longer mean activated clotting time (ACT) values during cardiopulmonary bypass (800 seconds vs 528 seconds in the late group). On the basis of the observation of a longer ACT and cited in vitro data, Gammie and associates have altered their management of patients who require CABG within 12 hours of abciximab treatment. This change involves the use of a heparin loading dose of only 150 U/kg and a target ACT level of 400 to 500 seconds for cardiopulmonary bypass. The authors propose that using less heparin for abciximab-treated patients "may minimize perioperative bleeding while maintaining adequate levels of anticoagulation." The results of experience using this reduced heparin regimen for this clinical situation are not, however, provided.

In this author’s surgical practice (Northwest Surgical Associates, Portland, OR), 12 patients underwent emergency CABG at the mean duration of 1.9 hours of receiving abciximab [13]. All operations were performed for ongoing ischemia and 3 patients required preoperative intraaortic balloon pump support. Standard heparin doses were used in all patients (loading dose 450 U/kg plus 10,000 U in the pump prime solution), and each patient was transfused 1 apheresis platelet unit (volume equivalent to 6 random donor units) after protamine administration. Further platelets and other blood product transfusions were given as indicated by the usual criteria. The left internal mammary artery was used in 7 of the 11 patients who required a graft to the left anterior descending artery. There were no deaths. One patient required exploration for bleeding from a branch of the internal mammary artery. The mean 12-hour chest tube drainage volume was 639 mL. The mean per-patient transfusion rates were RBCs, 3.6 units; apheresis platelets, 1.4 units; and fresh-frozen plasma, 1.5 units. This RBC transfusion requirement was not increased above those predicted for comparable non-abciximab-treated patients, and the number of blood product exposures was smaller than those of the 6 patients reported by Gammie and associates [7]. In our experience, the use of standard heparin doses and routine administration of 1 apheresis platelet unit has been successful for the management of abciximab-treated patients requiring emergency CABG.

	Management strategies for the abciximab-treated patient

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 
Abciximab effectively inhibits platelet aggregation by blocking the GP IIb/IIIa receptors, whose role is pivotal in thrombus formation. This interference with clotting is expected to cause increased bleeding and greater need for transfusions in patients who undergo surgical procedures while under the effect of the drug. Furthermore, most of the abciximab-treated patients will have also received aspirin and heparin. After administration of the standard abciximab loading dose, more than 90% of the platelet GP IIb/IIIa receptors are bound and blocked by the drug. Excess nonbound drug is rapidly cleared, and essentially no free abciximab remains in the serum. When donor platelets are transfused, there is no excess abciximab circulating to block the donor platelet receptors. However, the abciximab that is bound to the native platelets subsequently redistributes among all of the platelets, native and donor, resulting in an overall smaller percentage of blocked receptors (Fig 1). When the overall level of blocked receptors falls below 80%, platelet aggregation returns and the bleeding time normalizes [4]. This is the basis for the recommendation that to quickly reverse the effect of abciximab, platelets should be administered. The use of platelets to reverse the abciximab is not unlike the use of protamine to reverse heparin after cardiopulmonary bypass. Both carry a small risk of adverse reaction, but in both instances, this risk would appear to be less than the consequences of severe bleeding. Clinical experience with routine platelet administration supports the recommendation to administer platelets as an antidote to counteract the effect of recently administered abciximab [10, 13]. To avoid subjecting the donor platelets to the adverse effects of cardiopulmonary bypass, it is recommended that the platelet transfusion be given after the administration of protamine rather than before the institution of cardiopulmonary bypass. Furthermore, the use of apheresis platelet units exposes the recipient to only one donor exposure while providing the volume of 6 random donor platelet units.

View larger version (20K): [in this window] [in a new window]   Fig 1. (Left) A series of flow cytometry histograms illustrate the redistribution of abciximab among platelets in vitro. Peaks to the right represent platelets with many bound abciximab molecules (highly fluorescent), while peaks to the left represent unbound platelets. After the addition of abciximab, the population of platelets is highly bound by abciximab and shifts to the right. When unbound platelets are added (to simulate a transfusion), there are initially two platelet populations (one highly bound and one not bound by abciximab). After 30 minutes, the two populations are seen to be converging as abciximab redistributes from the highly bound platelets to the unbound platelets. After 3 hours, the abciximab has evenly distributed among all the platelets, resulting in a population that contains an intermediate amount of abciximab. When the overall receptor blockade rate is less than 80%, partial platelet function is restored. (Right) Bleeding times are plotted against time in cynomolgous monkeys. After abciximab administration, the bleeding time is increased from approximately 2 to 15 minutes. One group received platelet transfusion, resulting in rapid return of the bleeding time toward normal as compared with the group that was not transfused platelets. Adapted from Jordan and associates [20] and Wagner and colleagues [21].

Though the hypothesis that using less heparin for cardiopulmonary bypass will result in less bleeding and smaller transfusion requirements may initially seem logical, data to the contrary are available. A randomized study reported by Despotis and associates found that patients who received larger heparin doses required fewer transfusions of hemostatic factors and had a trend toward less bleeding and fewer RBC transfusions [19]. This may be explained on the basis that patients who receive more heparin experience less consumption of clotting factors during cardiopulmonary bypass, resulting in improved hemostasis after protamine administration.

Based on all of these considerations, the use of reduced heparin doses for cardiopulmonary bypass for abciximab-treated patients requiring emergency CABG is not currently recommended.

	Summary

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 
The potent platelet antiaggregate drug abciximab is effective in reducing complications associated with percutaneous coronary interventions but has the potential for causing serious bleeding complications in patients who require emergency CABG while under the effect of the drug. For the stable patient whose CABG procedure may be safely delayed for 12 to 24 hours, return of platelet aggregation should lead to improved hemostasis. For the unstable patient who requires emergency or urgent myocardial revascularization because of ongoing ischemia, surgery should not be delayed because of the presence of abciximab. It is currently recommended that patients who do require CABG within 12 hours of abciximab treatment receive full standard heparin doses for anticoagulation during cardiopulmonary bypass. After bypass, donor platelet transfusion should effectively reverse the abciximab effect. Clinical experience with full heparin dosing and routine platelet administration has been successful in performing emergency CABG in abciximab-treated patients.

	Addendum

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 
Since the preparation of this manuscript, the author has personally operated on two abciximab-treated patients who did not require platelet transfusions. It has recently been demonstrated by Steinhubl and associates that there is considerable variation between patients in the degree of platelet function inhibition within 3 to 8 hours after abciximab discontinuation [22]. Many patients exhibit less than the 80% inhibition within a few hours of stopping the drug. This variable response may allow some patients to regain sufficient platelet function to provide adequate hemostasis without transfusion of platelets. Thus, rather than "routine" platelet transfusion, selective treatment with platelets may be feasible, based on usual criteria of excessive bleeding after protamine administration. Further clinical experience with this challenging clinical problem should help clarify this issue.

	References

Top Abstract Introduction CABG in abciximab-treated... Emergency CABG in abciximab... Management strategies for the... Summary Addendum References

 

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