Bridging with GP IIb/IIIa Inhibitors after Abdominal Surgery (Full title below)

From the Division of Cardiology, Washington Hospital Center, Washington, D.C. The authors report no conflicts of interest regarding the content herein. Manuscript submitted November 4, 2008, provisional acceptance given December 8, 2008, final version accepted February 11, 2009 Address for correspondence: Ron Waksman, MD, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, D.C. 20010. E-mail: Ron.Waksman@Medstar.net

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Bridging with GP IIb/IIIa Inhibitors after Abdominal Surgery in a Patient Presenting with Late Stent Thrombosis of a Drug-Eluting Stent and Who Cannot Receive Oral Antiplatelet Treatment

ABSTRACT: Drug-eluting stents were designed to reduce neointimal hyperplasia and thus diminish the likelihood of coronary restenosis. They may, however, carry long-term risks such as delayed stent endothelization and arterial healing. Here we report a case of late stent thrombosis in a drug-eluting stent in the perioperative period after abdominal surgery in a patient who could not absorb oral antiplatelet agents and who was treated with a glycoprotein IIb/IIIa antagonist. We will present issues related to discontinuation of antiplatelet therapy before non-cardiac surgery, coronary intervention in the perioperative period and the strategy for managing patients with stent thrombosis who cannot receive oral antiplatelet treatment.

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J INVASIVE CARDIOL 2009;21:E73–E76 Drug-eluting stents (DES) were designed to reduce neointimal hyperplasia and thus diminish the likelihood of coronary restenosis. They may carry long-term risks such as delayed stent endothelization and arterial healing, however. Stent thrombosis is an uncommon but life-threatening complication that often occurs within the first month after stent implantation. Numerous cases of late stent thrombosis (LST) have been described as occurring months or even years after DES implantation1,2 at a rate of 0.2–0.6% per year up to 3 years after DES implantation.3,4 Often, patients are asked to halt their dual antiplatelet therapy prior to non-cardiac surgery to minimize procedure-related bleeding. Discontinuation of dual antiplatelet therapy and non-cardiac surgery are among the predictors of LST.5–8 Here we report a case of LST in the perioperative period after abdominal surgery in a patient who could not absorb oral antiplatelet agents and was treated with a strategy of intravenous glycoprotein (GP) IIb/IIIa antagonist bridging therapy. We will present issues related to discontinuation of antiplatelet therapy before non-cardiac surgery, coronary intervention in the perioperative period, and the strategy for managing patients with stent thrombosis who cannot receive oral antiplatelet treatment. Case Report. A 72-year-old Caucasian male presented with a history of hypertension, hyperlipidemia, and coronary artery disease since March, 2003. At that time, he presented with new-onset angina and an abnormal stress test, while coronary angiography demonstrated a high-grade lesion of 80% stenosis in the mid-portion of the right coronary artery (RCA). The patient underwent successful deployment of an S670 OTW 3.5 x 12 mm bare-metal stent (BMS) (Medtronic, Inc., Minneapolis,  Minnesota). Clopidogrel and aspirin were given for 3 months. Three years later in January 2006, the patient presented with recurrent chest pain. Repeat coronary angiography revealed a patent stent in the RCA and progression of disease in the left anterior descending artery (LAD) with 80% ostial stenosis and 90% stenosis in the proximal segments. Two Cypher™ sirolimus-eluting stents (Cordis Corp., Miami Lakes, Florida), measuring 3.5 x 13 mm and 3.0 x 28 mm, were deployed under intravascular ultrasound guidance to cover the entire diseased segment. In January 2008, cardiac catheterization was again performed due to an abnormal stress test that demonstrated a widely open stent in the mid-RCA, a patent stent in the ostial LAD and minimal hyperplasia at the stent in the proximal third portion. On August 7, 2008, the patient stopped his aspirin and clopidogrel for a screening colonoscopy, which demonstrated an obstructive anular lesion in the sigmoid colon. Biopsies taken were positive for poorly differentiated adenocarcinoma. The patient did not resume the aspirin and clopidogrel. On August 22, 2008, the patient underwent a sigmoidectomy. At 2 hours’ post surgery, he became diaphoretic and developed ST-elevation anterior wall myocardial infarction (MI). The patient received aspirin 325 mg through a nasogastric tube; however, no bowel activity was noticed. He was transferred emergently to the cardiac catheterization laboratory. The patient was dyspneic and had a blood pressure of 103/55 mmHg. On coronary angiography, the RCA and the left circumflex artery (LCX) were widely patent, but a 100% occlusion involving a thrombus in the proximal stent in the LAD was noted (Figure 1A). The patient underwent percutaneous coronary intervention (PCI) with an anticoagulation regimen limited to 4,000 units of heparin. The occlusion was crossed with a PT Graphix™ Intermediate 0.14 guidewire (Boston Scientific Corp., Natick, Massachusetts) and a 2.5 x 15 mm Sprinter® balloon (Medtronic) was inflated to 15 atm. In order to facilitate crossing of the Export® catheter (Medtronic), aspiration was performed and thrombolysis in myocardial infarction (TIMI) 3 flow was restored. Following intracoronary perfusion of nicardipine, 1,200 µg was administered distally through a Clearway 1.0 RX 20 mm perfusion catheter (Atrium Medical Corp., Hudson, New Hampshire), with improvement of flow and TIMI 3 (Figure 1B). The aspiration material demonstrated white and red thrombus. Due to high wedge pressures, an intra-aortic balloon pump was placed. The patient’s chest pain subsided and on the electrocardiogram, the ST segment was resolved, and he was then transferred to the intensive care unit. At the end of the procedure, the activated clotting time (ACT) was 190 seconds; no further heparin was given, and an infusion of eptifibitide 2 µg/Kg/minute without bolus was initiated. The surgical area, along with the patient’s dressing, were monitored for bleeding. Twenty-four hours later, the patient’s bowel movements resumed, and a nasogastric tube revealed low residuals. Dual antiplatelet therapy was initiated, along with 325 mg of aspirin daily and 75 mg of clopidogrel twice daily. The eptifibitide infusion was stopped 12 hours after initiation of the clopidogrel. No bleeding complications in the surgical wound were noticed, and the patient’s hemoglobin levels remained stable. An echocardiogram showed moderate-to-severe left ventricular dysfunction with anterior wall akinesia. He was discharged to the floor for continued care on aspirin 325 mg daily and clopidogrel 75 mg twice daily. Discussion. We report a case of LST in the perioperative period (abdominal surgery) in a patient who discontinued his dual antiplatelet treatment. Management of this situation poses several treatment dilemmas. First, should the dual antiplatelet treatment be stopped before gastrointestinal evaluation or before the abdominal surgery? If so, should there be a bridge of antiplatelet therapy prior to the surgery? Non-cardiac surgery increases the risk of stent thrombosis because antiplatelet therapy is often discontinued in the periprocedural period. Surgery theoretically creates a prothrombotic state and this may be particularly true when done under general anesthesia.9 Perioperative stent thrombosis has been studied mainly in patients who received a BMS — with an increased risk especially if the surgery was performed within the first 3–6 weeks following BMS placement.7,10 There is limited information regarding the risk of perioperative thrombosis of DES. McFadden et al1 reported DES thrombosis in 3 patients undergoing surgery late (343–442 days) after implantation; and in those patients, both aspirin and clopidogrel were stopped. Nasser et al6 reported DES thrombosis in 2 patients after surgery performed 4 and 21 months after stent implantation. Schouten et al11 reported that stent thrombosis occurred in 3/99 (3%) patients undergoing surgery within 2 years after DES implantation. Compton et al12 reported a single-center series of 38 patients who underwent 41 major and 18 minor noncardiac surgeries a median of 9 months from DES implantation and found that no major adverse cardiac events or death occurred. Delayed endothelialization and hypersensitivity reactions, possibly due to polymers coated on the stent, have been implicated as possible mechanisms for DES thrombosis.13,14 The current America College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines on PCI recommend clopidogrel treatment for ≥ 12 months in patients who receive DES.15 An elective procedure for which there is significant risk of perioperative or postoperative bleeding should be deferred to 12 months after DES implantation.16 If a patient requires a semi-emergent or urgent operation before completing dual antiplatelet therapy, both aspirin and clopidogrel should be continued unless there is significant risk for bleeding. In this case, at least aspirin should be continued. In cases of neurosurgery or retinal surgery, both treatments should be stopped and admittance of the patient 3 days after stopping clopidogrel with close perioperative and postoperative follow up should be considered.17,18 The patient described here discontinued aspirin and clopidogrel 2 years after stent implantation. Within this time period, it is reasonable to stop clopidogrel before the procedure and then resume it with a loading dose just after. However, the current recommendations15 are that aspirin should be continued for its antiplatelet action to mitigate the risk of LST for colonoscopy or abdominal surgery, regardless of the time of DES implantation. Ferraris et al19 reported that patients taking aspirin who were undergoing emergency general surgery did not experience an increased risk of bleeding complications. Burger et al20 reviewed the surgical literature with regard to the risks of stopping low-dose aspirin versus the risks of bleeding and found that in the majority of surgeries, low-dose aspirin may result in increased frequency of procedural bleeding (relative risk 1.5), but not an increase in the severity of bleeding complications or perioperative mortality due to bleeding complications. Possible exceptions are intracranial surgery and prostatectomy. We believe that in patients who undergo DES implantation and in whom a surgery without a high risk for bleeding complications is scheduled, aspirin should be continued and not stopped prior to the surgery, regardless of the time between DES implantation and surgery. If, however, the patient poses a high risk of bleeding and requires antiplatelet coverage up to the time of surgery, this can be done by using GP IIb/IIIa inhibitors with a short half life, such as eptifibatide, that can be stopped 2 hours prior to and resumed immediately after the surgery. The second therapeutic dilemma is how to treat patients who develop STEMI perioperatively or a few hours after surgery. The presentation of acute MI several hours after surgery poses a high bleeding risk to the patient during PCI. Primary PCI is the treatment of choice for perioperative stent thrombosis, while thrombolytic therapy is less effective and carries a prohibitive risk of bleeding. However, primary PCI also carries a risk of bleeding when performed early after surgery because antithrombin and antiplatelet therapies need to be administrated during the procedure. We chose heparin as the antithrombin agent because of the option to reverse the effect with an antidote (protamin sulfate). Administration of a GP IIb/IIIa inhibitor post procedure should be done carefully, with monitoring of the ACT prior to the initiation of treatment to minimize the risk of bleeding. In a retrospective analysis of 48 patients with acute MI occurring within 1 week from surgery in whom aspirin and heparin were administered, only 1 patient had significant bleeding at the operative site, this being a patient who had undergone knee replacement.21 An alternative to heparin is bivalirudin. Its advantages include a very short plasma half life (~20 minutes) and less bleeding complications compared to heparin.22 A disadvantage of bivalirudin is the absence of an antidote in case of emergent bleeding, which can be very relevant in the perioperative period. The third dilemma relates to what the optimal antiplatelet strategy should be in patients who present with acute MI due to stent thrombosis after abdominal surgery who cannot absorb oral antiplatelet agents. For this we must choose an intravenous regimen that prevents stent thrombosis while not posing a bleeding risk to patients post abdominal surgery. One option is intravenous aspirin. Another option of antithrombin agents such as enoxaparin may pose a risk of bleeding and will not have much impact on platelet inhibition.23 Furthermore, the cessation of heparin in a patient not on aspirin or other antiplatelet agents has been shown to cause platelet activation and a rebound phenomenon that may actually increase the likelihood of perioperative stent thrombosis compared to if no heparin “bridging” had been performed. Since stent thrombosis is primarily a platelet-mediated phenomenon, “bridging" with GP IIb/IIIa agents is the most logical substitute to oral antiplatelet therapy for patients who cannot take oral antiplatelets. Data to support the use of “bridging” with GP IIb/IIIa agents are limited to a case report by Broad at el,24 in which 3 patients with DES requiring elective non-cardiac surgery were bridged with a GP IIb/IIIa antagonist as the antiplatelet modality. For the case presented here, we selected a small-molecule, short-acting GP IIb/IIIa antagonist, so that if bleeding occurred, it could be controlled within a short period of time with fresh frozen plasma and an infusion of platelets. “Bridging” with a GP IIb/IIIa antagonist in a patient with high risk of stent thrombosis before their high-risk surgery could reduce the frequency of stent thrombosis. However, more data are required before routinely implementing this approach. To prevent the risk of stent thrombosis without exposing the patient to a high risk of bleeding, we propose a strategy of bridging a GP IIb/IIIa antagonist after surgery in patients with a high risk of stent thrombosis and who cannot take oral antiplatelet treatment. Conclusion. In summary, for patients who have undergone DES implantation and are scheduled to undergo subsequent non-cardiac surgery, aspirin should not be stopped, even if the patient has finished his recommended 1 year of dual antiplatelet therapy. In patients with a high risk for bleeding, a bridge with the use of a GP IIb/IIIa antagonist could be considered as a treatment option for those at high risk for stent thrombosis in their preoperative or postoperative period.

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