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Journal of Clinical Anesthesia (2007) 19, 386–396

Special article

A tale of two stents: perioperative management of patients with drug-eluting coronary stents
Diane E. Head MD (Assistant Professor of Anesthesiology)a,⁎, Joshua J. Sebranek MD (Instructor of Anesthesiology)a , Cameron Zahed MD (Resident Physician in Anesthesiology)a , Douglas B. Coursin MD (Professor of Anesthesiology and Medicine)a , Richard C. Prielipp MD, MBA, FCCM (Professor and Chair)b
a b

Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792 Department of Anesthesiology, University of Minnesota School of Medicine, Minneapolis, MN 55455

Received 23 January 2007; revised 12 February 2007; accepted 13 February 2007

Keywords:
Antiplatelet therapy; Coronary artery stenosis; Drug delivery systems; Drug-eluting stent; Thrombosis

Abstract Drug-eluting stents were introduced into clinical practice to decrease coronary stent restenosis rates. Though remarkably effective in reducing this complication, recent data reveal that drug-eluting stents pose a significant risk for late stent thrombosis, an event strongly correlated with discontinuation of anti-platelet therapy. Because anti-platelet agents are often discontinued perioperatively, patients with DES are at risk for perioperative stent thrombosis and myocardial infarction. Along with a review of the recent literature, we present two cases of patients with drug-eluting stents scheduled for renal transplantation. Two distinct antithrombotic management strategies illustrate the risk of either approach—bleeding and transfusion versus stent thrombosis and myocardial infarction. © 2007 Elsevier Inc. All rights reserved.

1. Introduction
Drug-eluting coronary stents (DES), introduced into clinical practice in the United States in 2003, accounted for more than 8 of 10 coronary stents1,2 [1] placed at the beginning of 2006. With nearly 6 million stents in place worldwide, DES represent an important advance in percutaneous coronary intervention (PCI) because they significantly reduce arterial restenosis rates and the subsequent need for repeat coronary intervention1,2 [2-9]. However, as DES reduce the risk of restenosis, the con⁎ Corresponding author. Clinical Sciences Center, Madison, WI 537923272, USA. E-mail address: dehead@wisc.edu (D.E. Head). 0952-8180/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2007.02.004

comitant delay in stent endothelialization after deployment significantly increases the risk of stent thrombosis for months or even years after deployment. In the last year, data suggesting that DES pose a significant risk for late stent thrombosis have continued to mount. Multiple case reports and observational studies describe late thrombosis of DES as an event associated with high mortality [10-15]. Ironically, many of these patients discontinued antiplatelet therapy based on medical advice in anticipation of elective noncardiac surgery [10-13].
Boston Scientific Corp, Natick, MA. Information available at bostonscientific.com and personal communication (DEH, July 2006). 2 Cordis Corp (a Johnson & Johnson Company), Miami Lakes, FL. Information available at cordis.com and personal communication (DEH, July 2006).
1

Drug-eluting stents in the perioperative period In the two case reports presented, the challenges of perioperative management of such patients with DES are presented. The two distinct antithrombotic management strategies demonstrate the risks of either approach—bleeding and transfusion versus stent thrombosis and myocardial infarction (MI).

387 After an uneventful 45-min stay in the PACU, the patient was transferred to the surgical ward. Shortly thereafter, he began to complain of right-sided chest pain similar to that experienced during his previous MI. He was immediately treated with two mg of morphine, 5 mg of intravenous (IV) metoprolol, and 325 mg of oral aspirin. An ECG showed STsegment elevation in leads III and aVF as well as reciprocal ST depression in leads V5 and V6. The patient was taken emergently to the cardiac catheterization laboratory. Coronary angiography showed 100% occlusion of the RCA stent consistent with thrombus and the likely cause of the postoperative MI. Successful balloon angioplasty was followed by placement of a BMS within the previously deployed DES. Post-stent angiography showed no residual stenosis. The remainder of the angiographic examination was unchanged. A heparin infusion was initiated, and the patient received 300 mg of oral clopidogrel. The patient's troponin-I peaked at 167 ng/mL. Transthoracic echocardiogram before hospital discharge showed inferior and posterior wall hypokinesis, with an ejection fraction of 0.40, decreased from 0.75 preoperatively.

2. Case reports
2.1. Case 1
A 56-year-old man with end-stage renal disease secondary to type II diabetes mellitus and known coronary artery disease (CAD), presented for a living-related renal transplant. At the time of an MI suffered 7 years earlier, multivessel CAD was treated with balloon angioplasty and a bare metal stent (BMS) in the left anterior descending (LAD) artery. Eight months before scheduled renal transplantation, repeat cardiac catheterization showed a patent LAD BMS, total occlusion of the midcircumflex artery, an 85% stenosis of the obtuse marginal artery, and a complex lesion at the bifurcation of the right coronary artery (RCA). Two paclitaxel DES were placed in the RCA, and a paclitaxel DES was placed in the obtuse marginal artery lesion. The patient continued aspirin therapy and was started on clopidogrel 75 mg daily. Two weeks before his scheduled surgery, repeat coronary angiography showed a patent LAD BMS, a 40% occlusion within the obtuse marginal artery DES (in-stent restenosis), and a widely patent DES within the RCA. Because the patient was asymptomatic and reported moderate activity (biking 15 min/day) without shortness of breath or chest pain, no further coronary interventions were deemed necessary. Preoperative medications included furosemide, metoprolol, olmesartan, rosuvastatin, insulin, clonazepam, and omeprazole. He discontinued clopidogrel and aspirin 7 days before surgery on the advice of the surgeon in consultation with his cardiologist. Electrocardiography (ECG) showed normal sinus rhythm with a left anterior fascicular block. Standard ASA monitors were placed in the operating room. After preoxygenation of the patient, anesthesia was induced with lidocaine, propofol, fentanyl, and cisatracurium. Metoprolol 2.5 mg was given twice shortly after induction to maintain the heart rate less than 80 beats per minute (bpm). The patient's oxygen saturation via pulse oximetry (SpO2) was greater than 95%, and his systolic blood pressure was maintained between 120 and 180 mmHg throughout the anesthetic. Surgery proceeded without complications. An estimated blood loss of 750 mL was replaced with two units of packed red blood cells (PRBCs), 500 mL of 5% albumin, and 3800 mL of normal saline. The patient's trachea was extubated, and he was taken to the postanesthesia care unit (PACU) taking supplemental oxygen.

2.2. Case 2
A 54-year-old man with end-stage renal failure secondary to hypertension and type I diabetes mellitus was evaluated for deceased donor kidney-pancreas transplant. Cardiac catheterization before transplantation showed diffuse CAD (80% stenosis of the distal circumflex and midobtuse marginal arteries, 70% proximal RCA, and 99% posterior descending coronary artery). After complex angioplasty, two DES were placed in his RCA, one BMS in his posterior descending artery, and two DES in his left circumflex artery. Lifelong therapy with clopidogrel 75 mg daily and aspirin 81 mg daily was recommended. After 6 months of combined antiplatelet therapy, the patient presented for kidney-pancreas transplant; clopidogrel and aspirin were discontinued one day before surgery on the advice of the surgical team. The intraoperative course was uneventful with immediate transplant graft function. Aspirin was resumed on postoperative day 1, and clopidogrel was restarted on day 2. That evening, he passed a single maroon stool with a decrease in hematocrit (Hct) from 35% to 26%. Two units of PRBCs were transfused, and IV octreotide therapy was instituted. On postoperative day 6, the patient's abdomen became distended, with associated hypotension and with a decrease in Hct from 34% to 25%. Urgent exploratory laparotomy identified a single source of bleeding at the anastomotic suture line in the left iliac vein, which was repaired. A total of 7 units of PRBCs was required to stabilize his Hct at 31%. The remainder of his hospital course was unremarkable. Clopidogrel and aspirin therapy were resumed three days after emergent exploratory laparotomy; no further bleeding episodes occurred.

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3. Discussion
Because of the dramatic increase in DES use in the U.S. many patients are presenting for noncardiac surgery after DES placement. Unique considerations exist for the management of these patients in the perioperative period due to the risk of DES thrombosis after discontinuation of antiplatelet medications. When it occurs, stent thrombosis is likely to have significant clinical consequences, often MI or death. Conversely, continuation of antiplatelet therapy through the perioperative period may lead to significant bleeding complications. Drug-eluting stents represent a significant development in the evolution of PCI. Percutaneous transluminal coronary angioplasty (PTCA), routinely successful in relieving atheromatous plaque obstructions, often caused excessive arterial wall damage from high balloon pressures [16]. Abrupt vessel wall collapse would sometimes occur, causing myocardial ischemia. The success of PTCA was also limited by 6-month restenosis rates of 30% or more [17-22]. The development of intracoronary BMS in the late 1980s improved PTCA success by reducing the risk of immediate arterial wall collapse and restenosis associated with PCI [17,18]. At first, however, there was a high incidence of acute and subacute stent thrombosis (b30 days) [18-20]. Initial attempts at anticoagulation with heparin and coumadin had limited success [9,19,20]. Thrombotic events after BMS placement were not significantly reduced until antiplatelet therapy with aspirin and thienopyridines, such as ticlopidine and clopidogrel, became standard [21-25]. The incidence of stent thrombosis with BMS is 0.5% to 1.9%, with most cases occurring at the time of the procedure or within the first few days [26]. The incidence of late thrombotic complications with BMS is similarly low, at 0.6% to 0.8% [26]. With routine use of BMS, restenosis rates decreased from 30% to 40% with angioplasty alone to 20% to 30% with angioplasty plus stenting [9,19,20,22]. Stent restenosis is characterized by neointimal hyperplasia and vascular remodeling rather than by reaccumulation of atherosclerotic plaque (Fig. 1). Formation of neointima and vascular smooth muscle hypertrophy is the result of the inflammation induced by angioplasty and stenting [27-30]. The localized reaction is reparative in nature but may result in excessive fibrin and cellular hyperplasia formation [9]. Restenosis has not been shown definitively to affect long-term mortality and generally has a benign clinical course [31,32]. However, because of the need for repeat PCI, it remains an important clinical, financial, and psychological problem. Drug-eluting stents were developed to diminish the incidence of stent restenosis. Through localized delivery of antiproliferative and immunosuppressive medications, DES blunt neointimal and vascular smooth muscle proliferation [27,28]. In clinical trials, DES decrease restenosis rates to 0%-10% [2-8] with acceptable safety profiles [33]. Metaanalyses of clinical trials comparing DES with BMS report no difference in the risk of stent thrombosis [34-36].

Fig. 1 Pathologic mechanisms leading to restenosis theory and development of the drug-eluting stents (DES). SMC = smooth muscle cells. (Reprinted with permission from Cath Lab Digest volume 11, issue 4, with CME funding provided by Cordis Corp/Johnson and Johnson Co., Miami, FL).

Drug-eluting stents vary by stent design, polymer coating, drug eluted, and drug release kinetics [9]. Two DES are in clinical use in the U.S., the sirolimus-eluting stent (SES; “CYPHER,” Cordis Corporation/Johnson and Johnson Co, Miami Lakes, FL) (Fig. 2A) and paclitaxel-eluting stent (PES; “TAXUS,” Boston Scientific Corp, Natick, MA) (Fig. 2B). The SES was approved for use in 2003, the PES in 2004 (Fig. 2). Both stents are composed of stainless steel and have drug contained in a nonresorbable polymer matrix. Sirolimus (also known as Rapamycin) is an immunosuppressant and antiproliferative drug that inhibits the response to interleukin-2 and blocks B-cell and T-cell lymphocyte activation [9,37,38]. The SES elutes 80% of its drug within 30 days and 100% within 45 days. In contrast, paclitaxel (Taxol) interferes with mitosis by binding to microtubules and inhibiting mitotic spindle breakdown [9,37,38]. The release kinetics of the PES differ in that 10% of the drug is eluted by 10 days with the remaining 90% staying indefinitely [38,39]. The advantage of DES in reducing neointimal proliferation and restenosis, however, comes at the “cost” of delayed stent endothelialization. Bare metal coronary stents show near complete endothelialization by 28 days in animal models and by 6 weeks in humans [40,41]. As a result, patients routinely receive antiplatelet therapy for 4 to 6 weeks after BMS placement [42]. This action allows for arterial healing to progress and the stent to endothelialize [42]. In contrast, the process of endothelialization is prolonged with DES, leaving the devices vulnerable to acute thrombosis for extended periods, perhaps even indefinitely [10-14,39].

Drug-eluting stents in the perioperative period

389 14 patients, two were taking monotherapy with aspirin or clopidogrel, and, significantly, 7 were receiving dual therapy at the time of thrombosis. Kotani et al [45], using angioscopy to evaluate neointimal coverage of SES versus BMS, found incomplete coverage of SES three to 6 months after placement, which was associated with thrombus not seen on angiography. Of 15 SES evaluated, three (20%) had grade 0 neointimal coverage and only two (13.3%) had complete coverage. However, all 22 BMS (100%) evaluated showed complete neointimal coverage. The small number of subjects, a short follow-up time, and lack of inclusion of PES, limit this study. In addition to delayed endothelialization, reported risk factors for DES thrombosis include overlapping stents, longer stent length, inadequate stent apposition to vessel wall, strut penetration into necrotic lipid plaque, and stenting of ostial or bifurcation lesions [26,39,44,46]. Because of the risk of delayed stent endothelialization, longer periods of antiplatelet therapy are necessary with DES than with BMS [39,46]. The Food and Drug Administration (FDA) approved the SES and PES for three and 6-month courses of postimplantation antiplatelet treatment, respectively. Such therapy usually consists of dual therapy with aspirin and clopidogrel. Controlled clinical trials and meta-analysis of DES have not shown significant increases in late stent thrombosis compared with the BMS, with rates ranging from 0.23% to 0.7% [4-37,40]. However, recent case reports and observational studies have raised concerns (Table 1). In late 2004, McFadden et al [10] published 4 cases of angiographically confirmed stent thrombosis that occurred late (N335 days) after DES placement. Each case resulted in ST-elevation acute MI (STEMI) and occurred soon after cessation of

Fig. 2 A, Cordis' Cypher stent. B, Boston Scientific's TAXUS stent. (Courtesy of Cordis Corp/Johnson and Johnson Co., Miami, FL and USA Today.)

Both the SES and PES delay endothelialization in animals and humans [27,39,40,43,44]. Animals treated with DES show persistent inflammatory changes and delayed endothelialization [40,41]. A review of human autopsy specimens with coronary stents in place found that both the SES and PES, unlike the BMS, exhibited delayed endothelialization [39]. The authors identified 40 patient autopsy specimens with DES in place (68 total stents). Twenty-three specimens had DES (32 total stents) more than 30 days old; these were compared with a matched group of 25 autopsy specimens of BMS more than 30 days old. Of 23 patients (11 SES, 12 PES) with DES more than 30 days, 14 had evidence of late stent thrombosis that was the suspected cause of death in 13 of the 23 patients. The SES and PES, compared with the BMS, exhibited more delayed healing as manifested by poorer endothelialization and persistent fibrin deposition (Fig. 3). In addition, DES with late stent thrombosis evidenced more signs of delayed healing than did patent DES. In patients with late stent thrombosis, antiplatelet therapy had been withdrawn in 5 of

Fig. 3 Graph comparing percentage endothelialization of drugeluting stents (DES) versus bare metal stents (BMS) over time. Data were obtained from 40 human autopsy specimens with DES versus 25 autopsy specimens with BMS. Drug-eluting stents consistently show less endothelialization than BMS regardless of time. Note that beyond 40 months, DES are not fully endothelialized, whereas BMS show almost complete endothelialization by 6 months. (Reprinted with permission and courtesy of Joner et al [39].)

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Table 1 Summary of clinical events with DES Cases DES thrombosis/ type of DES McFadden et al [10] Rodriguez et al [12] Iakovou et al [11] Ong et al [13] 4 (2 SES, 2 PES) 7/225 (4 SES, 3 PES) 29/2229 (9 SES, 20 PES) 7/2006 a (3 SES, 5 PES) % DES thrombosis N/A 3.1 1.3 0.35 Type DES thrombosis All late 3 subacute, 4 late 14 subacute, 15 late All late d/c APT 4/4 6/7 5/29 5/8 STEMI 4/4 6/7 20/29 8/8

D.E. Head et al.

Case fatality rate, n (%) 0% 3/74 (3) 13/29 (45) 2/7 (28)

Late = thrombosis N30 days; subacute = thrombosis b30 days; d/c APT = discontinuation of antiplatelet therapy. a Eight angiographically conferred late thrombotic events in 7 patients.

antiplatelet therapy. Three of the 4 events involved patients undergoing noncardiac surgery. Interestingly, in two patients with both types of stents in place, the DES was thrombosed while the BMS remained patent. Rodriguez et al recently reported a 3.1% frequency of stent thrombosis in 225 patients followed for 18 months after DES placement [12]. Drug-eluting stent thrombosis was defined by clinical presentation (sudden cardiac death, STEMI) or angiographic evidence of stent thrombosis. Of 7 patients, three experienced stent thrombosis at less than 30 days, three from 31 to 365 days, and one at 927 days after implantation. Of the 7 episodes, 6 (86%) were related to discontinuation of clopidogrel, and the consequence of thrombosis was high with three deaths (43%) and 6 STEMI (86%). Other information comes from Iakovou et al [11], who prospectively followed 2,229 consecutive patients after SES and PES implantation in a routine clinical practice [13]. The frequency of subacute (b30 days) and late stent thrombosis (N30 days) was determined angiographically or by presentation with sudden cardiac death or MI [11]. All patients were prescribed long-term aspirin therapy and clopidogrel or ticlopidine according to established guidelines (three mo after SES and 6 mo after PES). They reported a 1.3% frequency of subacute and late stent thrombosis at 9-month follow-up, 0.8% with SES (9 patients), and 1.7% with PES (20 patients) (P = 0.09). Of the 29 patients with a thrombotic event, 14 occurred less than 30 days after DES (0.6%); the remaining 15 had late stent thrombosis (0.7%). Of 29 patients with DES thrombosis (both subacute and late stent thrombosis), 13 died (45% mortality rate). Independent predictors of stent thrombosis were premature antiplatelet therapy discontinuation, renal failure, diabetes, lower ejection fraction, and bifurcation lesions. The most important predictor of stent thrombosis was premature cessation of antiplatelet therapy. In a specific effort to evaluate the frequency of late stent thrombosis, Ong et al [13] prospectively followed 2,006 patients who had received a SES or PES for a minimum of one year. Late stent thrombosis was defined as angiographically proven thrombosis at more than 30 days. They report a frequency of thrombosis of 0.35% to 0.72%, with events occurring from two to 26 months. Of 8 thrombotic episodes, three were related to complete cessation of antiplatelet therapy; two occurred during aspirin monotherapy less than one month after clopidogrel was discontinued; and three cases

occurred in patients previously “stable” taking aspirin monotherapy. There were no instances of late stent thrombosis in patients receiving dual antiplatelet therapy. Two of the patients with late thrombosis died (28% mortality rate). Long-term follow-up from the BASKET (Basel stent cost-effectiveness trial) suggests that after clopidogrel discontinuation, patients with DES have higher rates of cardiac death and MI than those receiving BMS. In BASKET-LATE [14], investigators followed 746 patients from BASKET [47] (in which participants were randomized to DES or BMS to determine cost-effectiveness) for one year after discontinuation of clopidogrel to determine incidence and timing of thrombosis in BMS versus DES. Although 18-month rates of cardiac death/MI were not different between DES and BMS patients, these events occurred in 4.9% DES versus 1.3% BMS patients. Late stent thrombosis and target vessel MI were twice as common in the DES than the BMS group (2.6% vs 1.3%). The timing of events was evenly distributed over the 12-month period. Target vessel revascularization was lower for DES. However, the authors found that in nonselected patients, for every 5 cases of restenosis prevented at 6 months (per 100 patients receiving DES), three might experience cardiac death or MI in month 7 to 18. The cohort of patients followed was a high- risk group, and the study was underpowered to detect large differences in rare events, such as stent thrombosis. To help assess the effectiveness of antiplatelet therapy in preventing late stent thrombosis after DES, Eisenstein et al [15] completed an observational study in 4,666 patients receiving intracoronary stents in a standard clinical practice. Consecutive patients receiving BMS (n = 3,165) and DES (n = 1,501) were evaluated at 6, 12, and 24 months. Patients who were event-free at 6 and 12 months (ie, alive with no history of target vessel revascularization or MI) were divided into 4 groups according to stent type and self-reported use of clopidogrel. The primary outcome measures were death, nonfatal MI, and composite death/MI at 24 months. Clopidogrel use was found to be a significant predictor of lower adjusted death rates (2.0% with vs 5.3% without; P = 0.03) and death/MI (3.1% vs 7.2%; P = 0.02) in patients with DES who were eventfree at 6 months (637 with vs 579 without clopidogrel). In contrast, there were no differences in death (3.7% vs 4.5%; P = 0.50) or death/MI (5.5% vs 6.0%; P = 0.70) in BMS patients (417 with and 1976 without clopidogrel) at 6 months. Clopidogrel use continued to be a predictor of lower rates of

Drug-eluting stents in the perioperative period death (0% vs 3.5%; P = 0.004) and death/MI (0% vs 4.5%; P b 0.001) in the 12-month event-free DES group. Again, clopidogrel use was not a predictor of death or death/MI in the BMS group. The authors concluded that extended use of clopidogrel might be associated with reduced risk of death and death/MI in patients with DES. However, they conceded that the appropriate duration of clopidogrel treatment could be determined only in a large, randomized, clinical trial. Data recently published from a large Swedish registry found that DES were associated with an increased risk of death versus BMS [48]. In an analysis of 6,033 DES patients and 13,738 BMS patients over three years, Lagerqvist et al [48] evaluated rates of death, MI, and composite death/MI between the two groups. Attempts were made to adjust for differences in baseline patient characteristics. They found no significant difference in the composite death/MI rate between groups during three years of follow-up and an early trend (b6 mo) toward lower unadjusted events rates in DES patients was identified. After 6 months however, DES patients had a significantly higher event rate, and three-year mortality was significantly higher, with an 18% increase in the relative risk of death, an absolute increase in the risk of death per year of 0.5%. The restenosis rate was lower with DES, but the absolute difference versus BMS was not greater than 3% and was lower than for published clinical trials. Although the analysis involved a large number of patients, it was obtained retrospectively from a sample of nonrandomized subjects, making it subject to bias from differences in patient characteristics and stent selection criteria. Furthermore, data on the duration of aspirin and clopidogrel treatment were not available for individual patients. As a result of increased concern about late stent thrombosis, many cardiologists and professional societies, including the American Heart Association (AHA) and the American College of Cardiology (ACC), are recommending an increased duration of dual antiplatelet therapy, up to 12 months or longer [44,49,50]. There also appears to be an increased focus on indication and patient selection for DES placement [45,49]. Patients who are anticipating noncardiac surgery may be better served with BMS implantation. At the same time, patients who are not likely to adhere to long-term, dual antiplatelet therapy either for compliance, economic, or other reasons, may not be good candidates for DES implantation. Patient compliance with antiplatelet therapy is an important consideration. A recent report from Spertus et al [51] found that 30 days after DES placement, nearly one in 7 patients had discontinued dual antiplatelet therapy. They followed 500 patients with DES placement in the setting of AMI for one year and evaluated compliance with therapy and outcome. Not only was patient compliance with therapy found to be low, but also those who stopped thienopyridine treatment early had a significantly higher risk of death than those who continued therapy (7.5% vs 0.7%, respectively; P b 0.0001). The authors suggested that improved identification of appropriate DES candidates and increased patient education be areas of focus.

391 Because of the increasing body of evidence suggesting increased risk of late stent thrombosis, an FDA Circulatory Systems Advisory Panel Meeting was convened in December 2006 to discuss DES safety [49]. In this meeting, a panel of experts and FDA representatives reviewed recent evidence and discussed future recommendations for DES use and antiplatelet therapy. Panelists suggested that physicians and patients be educated and given strong warnings about the risks associated with DES. However, because of a significant lack of clinical data, especially regarding “off-label” indications for DES, it was difficult to reach a consensus in many areas. In patients receiving DES for on-label indications (discrete lesions ≤28 to 30 mm in length in coronary vessels ≥2.5 to ≤3.75 mm in diameter), they concluded that DES are associated with a small yet significant increase in stent thrombosis, which emerges about one year after implantation. Available data do not support an increased risk of death or MI in this population. In contrast, for off-label indications (estimated to account for more than 60% of DES placed) the Panel acknowledged that there is an increased risk of stent thrombosis and cardiac death/MI compared with on-label use. The Panel recommended that DES labeling include references to current AHA/ACC guidelines, which suggest aspirin therapy indefinitely and extension of clopidogrel therapy for 12 months after DES implantation in patients at low risk for bleeding. As a result of recent findings, the AHA and ACC, along with the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons, and the American Dental Association, recently published an advisory on the hazards of premature discontinuation of dual antiplatelet therapy in patients with DES [52]. The publication concisely reviews recent data, emphasizes risks associated with antiplatelet therapy discontinuation, and offers recommendations to reduce its occurrence. With this background, the common practice of stopping antiplatelet therapy before elective surgery may have devastating consequences in patients with DES. Stent thrombosis, STEMI, and even death can result. Alternatively, continuation of potent antiplatelet medications perioperatively often leads to serious bleeding complications. For patients with bare metal coronary stents in place, it is established that undergoing noncardiac surgery shortly after coronary stenting increases perioperative cardiac morbidity and mortality. Kaluza et al [53] reported that patients having PCI with BMS placement less than 6 weeks before noncardiac surgery had a subsequent perioperative mortality of 20% (8 of 40 patients). All deaths occurred in those who underwent surgery less than 14 days after stent placement and were secondary to acute myocardial infarction (AMI) (6 patients) or bleeding complications (two patients). Stent thrombosis accounted for most fatal events and occurred in patients whose antiplatelet therapy was interrupted. A subsequent retrospective review by Wilson et al [54] found an increased risk of major adverse cardiac events (cardiac death, AMI, and stent thrombosis) among 207 patients

392 having non-cardiac surgery within two months of coronary stenting. All 8 patients who experienced complications underwent non-cardiac surgery less than 6 weeks after stent placement; 6 of the 8 patients died. No adverse events occurred in patients who had surgery more than 7 weeks after BMS placement. In this report, no significant bleeding complications were noted, even among patients receiving dual antiplatelet therapy. As a result of these findings, current ACC/AHA guidelines call for “a delay of at least two weeks and ideally 4 to 6 weeks” after BMS placement before undergoing noncardiac surgery [55]. This delay allows for a 4-week course of antiplatelet therapy and BMS endothelialization. However, because the necessary duration of antiplatelet therapy with DES is unknown and likely prolonged, perioperative management of these patients is more complex. Two options include complete discontinuation of antiplatelet medications before surgery or, alternatively, continuing antiplatelet treatment throughout the perioperative period. Other considerations include perioperative monotherapy with aspirin alone or supplemental anticoagulation with either unfractionated or low-molecular-weight heparin. Unfortunately, each strategy may be associated with problems, either thrombotic or hemorrhagic in nature. Furthermore, current established guidelines for antiplatelet therapy after DES implantation do not account for the hemostatic challenges and alterations associated with major surgery. Clearly, complete cessation of antiplatelet therapy is a risk factor for stent thrombosis. Multiple reports have established that discontinuation of aspirin and clopidogrel frequently precedes a thrombotic episode. Considering this finding, and the fact that the mortality rate for stent thrombosis is in the range of 28% to 45% [10-13], routine perioperative discontinuation of these medications may be hazardous. A case report describes postoperative DES thrombosis after only one dose of aspirin and clopidogrel was withheld [56]. The risk of stent thrombosis must be carefully balanced against the danger of excessive perioperative blood loss. The situation is further complicated by the often prothrombotic state induced by the surgical procedure. Continuing dual antiplatelet therapy may increase bleeding complications. The best available data on noncardiac surgical patients continued perioperatively on aspirin and clopidogrel suggest an increased risk of bleeding, although no randomized, controlled clinical trials have been completed [53,57-59]. Patients who present for coronary artery bypass grafting on dual antiplatelet therapy are known to experience more clinical bleeding and have a higher rate of blood transfusion than those patients who are not receiving such therapy [60,61]. However, the need for long-term, dual antiplatelet therapy after PCI is compelling. For instance, Steinhubl et al [62] found that one year after PCI (pre-DES era), dual therapy with aspirin and clopidogrel was associated with a 27% relative reduction in the combined risk of death, AMI, and stroke (P = 0.02). Another option for the perioperative management of patients with DES is to elect monotherapy with aspirin alone.

D.E. Head et al. It is known that an aspirin-thienopyridine combination is superior to aspirin alone in the prevention of BMS stent thrombosis [24,26,63]. Patients taking aspirin monotherapy are 5 times more likely to experience stent thrombosis. However, aspirin alone is likely superior to placebo. Recent aspirin withdrawal is a risk factor for acute coronary syndrome and is associated with higher 30-day rates of AMI and death [64,65]. A meta-analysis estimated that low-dose aspirin reduces the risk of AMI and stroke by approximately one third and the risk of death from a cardiovascular cause by one sixth [59]. Thus, perioperative discontinuation of aspirin may increase the cardiovascular risk for these patients. Based on these considerations, aspirin therapy should be continued in the perioperative period unless the planned operation is one in which even minor bleeding could be catastrophic (ie, neurosurgical or ophthalmologic surgery) [58]. Anticoagulant therapy with unfractionated or low-molecular-weight heparin in the perioperative period could be considered. To date, there are no clinical studies investigating the perioperative use of heparin with DES for prevention of stent thrombosis. However, heparin therapy alone was inadequate to prevent acute and subacute stent thrombosis with BMS [9]. In fact, aggressive anticoagulation with heparin and warfarin early in the BMS era did not prevent high incidences of acute and subacute stent thrombosis [20,21]. As a result of this finding, dual antiplatelet therapy was shown to be superior to various anticoagulation regimens after PCI [24,26,63]. It is likely, therefore, that anticoagulation alone would not be efficacious. Recently, Vicenzi et al [66] published a prospective, observational study in 103 patients undergoing noncardiac surgery within one year of coronary stent placement (BMS and DES). Antiplatelet therapy was not, or else only briefly, discontinued, and all patients received concomitant heparin. They found that despite the heparin treatment, 44.7% (46 patients) of the study group experienced an adverse event. With the exception of two patients with significant bleeding, all events were of cardiac origin, they occurred early in the postoperative period, and were more likely to occur when surgery was performed within 35 days of stent placement. This finding emphasizes that patients who have undergone prior coronary stenting continue to be at risk of cardiac morbidity postoperatively. It also suggests that life-threatening, postoperative bleeding occurs infrequently, even when anti-coagulant and antiplatelet therapy is continued through the perioperative period. Patients with DES require thoughtful, multidisciplinary perioperative management that considers 4 factors: (1) the surgical procedure, (2) its urgency, (3) the type of DES, and (4) the period since stent implantation (Fig. 4). Consultation with the patient's cardiologist and surgeon should focus on continuation or discontinuation of aspirin and clopidogrel in the perioperative period. For elective cases in which the surgical procedure is appropriate, continuing dual antiplatelet therapy may be the safest course, recognizing the

Drug-eluting stents in the perioperative period

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Fig. 4

Flow diagram for perioperative management of patients with drug-eluting stents (DES).

increased risk of blood loss. In this circumstance, additional IV access is appropriate, along with consideration of arterial and central venous catheter hemodynamic monitoring. Serial Hct determinations and patient type-specific blood should be readily available. For elective surgeries not appropriate for continued aspirin and clopidogrel treatment, the patient should complete the recommended duration of antiplatelet therapy for the type of DES in place. After this action, and in consultation with the patient's cardiologist, therapy can be discontinued and the procedure performed. However, increased vigilance for myocardial ischemia is required in the perioperative period because the patient is

at risk for stent thrombosis. Careful intraoperative and postoperative monitoring is necessary to allow for early identification and treatment of myocardial ischemia. Intensive or intermediate care unit admission, continuous ECG monitoring, serial 12-lead ECG assessment, and serial troponin measurements may be warranted. Preoperative cardiac medications, especially β-blockers, angiotensin-converting enzyme inhibitors, and statins, should be continued. Maintenance of stable hemodynamics and myocardial oxygen supply/demand relationships is important. Rapid intervention is imperative when ischemia is detected because of the high mortality associated with stent thrombosis. A readily available

394 heart catheterization laboratory is ideal. Resuming antiplatelet medications as soon as possible postoperatively should be a priority. For emergency procedures amenable to dual antiplatelet therapy, the procedure may proceed with recognition of the increased risk of operative blood loss. Urgent and emergent procedures that require discontinuation of aspirin and clopidogrel must proceed with the understanding that the patient is at risk of DES thrombosis. Patients with recently placed DES who have not completed the recommended regimen of antiplatelet therapy are likely to be at higher risk than those patients whose stents were placed much earlier and who have completed the currently recommended course of antiplatelet therapy. Regardless of the clinical circumstances, patients with DES in place are likely at greater risk for perioperative morbidity and mortality. Clinical trials of DES have reported restenosis rates as low as 0% to 10% and no increased risk of early stent thrombosis. However, substantial evidence suggests an increased risk of late thrombosis with DES due to delayed endothelialization of DES. Indeed, most late thrombotic events occur soon after discontinuation of antiplatelet therapy (aspirin and clopidogrel). Thus, the optimal duration of antiplatelet therapy after DES implantation is unknown but continues to be extended for longer periods. Nonetheless, antiplatelet therapy is frequently withdrawn before elective surgery due to the risk of increased perioperative bleeding and its associated complications, placing patients with DES stents at substantial risk for intraoperative or postoperative stent thrombosis. Additional monitoring for cardiac ischemia in the perioperative period is appropriate, especially if antiplatelet therapy has been discontinued. Strong consideration should be given to continuing aspirin and clopidogrel through the operative period, if feasible (Fig. 4). Although continued antiplatelet therapy may increase perioperative bleeding, DES thrombosis often represents an even greater risk with a high mortality. The approach to optimal use of DES stents and post- stent antithrombotic management continues to be refined, and clinicians should expect further changes in the recommendations for long-term and perioperative management of these challenging patients.

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