Antiplatelet therapy is a cornerstone of treatment in individuals who have undergone intracoronary stent implantation. Current guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and P2Y12-receptor antagonist for 1 year after coronary stent implantation in patients with acute coronary syndrome.1–4 Patients with recent stent placement are at high risk for stent thrombosis, an event that is associated with significant morbidity and mortality. For those receiving bare metal stents (BMSs), this risk is highest within 6 weeks of placement. For those receiving drug eluting stents (DESs), the risk of stent thrombosis is highest within 6 months of placement.5
Surgery is the most common cause for early interruption of antiplatelet therapy. One study evaluating 39,362 patients found that 14% of individuals who receive percutaneous coronary intervention (PCI) required surgery within 1 year of stent placement. The majority of procedures, 79.8%, were noncardiac surgeries and roughly one third of patients required an urgent surgical procedure.6 This incidence is higher than the previously estimated rate of 4%–8% of patients who will be requiring surgery within 1 year of PCI.7 If surgery cannot be delayed until 1 year after PCI, the optimal strategy to balance the risks of stent thrombosis and intraoperative bleeding remains unclear. Observational studies have found that premature discontinuation of DAPT increases the incidence of stent thrombosis from 1% to between 8% and 29% of patients.8 In patients with stents who undergo subsequent surgical procedures who require discontinuation of P2Y12-receptor antagonists, guidelines recommend that aspirin therapy be continued throughout the procedure and P2Y12-receptor antagonists be restarted as soon as possible in the postprocedure period. If patients are deemed at high risk for stent thrombosis, bridging therapy with a glycoprotein IIb/IIIa inhibitor may be considered.3
Huang et al9 proposed a bridging strategy to help guide clinicians in the management of patients at high risk for stent thrombosis. In this bridging strategy, aspirin is to be continued throughout the procedure period while oral P2Y12 inhibitors are discontinued according to manufacturer recommendations (7 days before surgery for prasugrel and 5 days before surgery for clopidogrel or ticagrelor). Three days before surgery, bridging with eptifibatide should be initiated and continued until 6 hours before the procedure. Postprocedure, an oral P2Y12 inhibitor should be reinitiated utilizing a proper loading dose. If oral therapy is not possible, glycoprotein IIb/IIIa inhibitors may be restarted until the patient is able to tolerate oral therapy (Fig. 1).9
The aim of this descriptive report was to evaluate the management of antiplatelet therapy and outcomes of patients at our institution who were bridged with eptifibatide in the perioperative period.
We performed a retrospective analysis of consecutive patients who required surgery within 1 year of receiving one or more intracoronary stents and were bridged with intravenous eptifibatide. There were no cases involving bridging with tirofiban. The hospital’s computer medical record system was used to identify patients from January 1, 2011 to December 31, 2014. We included patients who received either planned or emergent surgeries within 1 year of stent implantation and were managed with eptifibatide preoperatively. Patients were excluded if they had received eptifibatide for purposes other than bridging for surgery or had undergone stent implantation within the same admission period. The primary outcome measure was the incidence of stent thrombosis or systemic thrombosis. Secondary outcome measures were the incidence of bleeding events within 30 days of surgery and death within 90 days. Stent thrombosis was adjudicated according to Academic Research Consortium recommendations.10 Systemic thrombosis included venous thromboembolism, pulmonary embolism, and strokes. Bleeding events were classified as major, minor, or minimal as defined by the thrombolysis in myocardial infarction (TIMI) bleeding scale.11,12 We completed a 90-day follow-up on study patients by identifying endpoints after hospitalization through our health systems’ computerized longitudinal medical record. Within our integrated health-care system, any patient encounter across 6 hospitals, 17 ambulatory clinics, and numerous private practices is recorded in the longitudinal medical record. We reviewed all subsequent hospitalizations, office visits, including discharge summaries and clinicians’ notes, laboratory tests, medical treatments, and diagnostic procedures, regardless of the facility or office location. Due to the descriptive nature of this report, no statistical analyses were performed.
We identified 18 patients who were bridged from an oral P2Y12 inhibitor with eptifibatide (Table 1). The mean patient age was 61.9 ± 12.9 years and 61.1% were male. Of the 18 patients, 100% were on DAPT and 5.6% were on triple antithrombotic therapy with aspirin, a P2Y12 inhibitor, and warfarin before surgery. Of the patients, 100% were receiving aspirin, 83.3% were receiving clopidogrel, and 16.7% were receiving prasugrel. The mean time between stent placement and discontinuation of antiplatelet agent before surgery was 106.1 days (range 12 to 258 days). DESs were used in 88.9% of patients while BMSs were present in 11.1% patients. Gastrointestinal/renal procedures (55.6%) were the most common planned intervention, followed by cardiac surgery (27.8%).
Preprocedural antiplatelet management of patients is described in Tables 2 and 3. Of the 18 patients, 72.2% were on 81 mg of aspirin daily and the remaining 27.8% were on 325 mg daily. While 50% of patients continued aspirin through the procedure, 50% of patients stopped aspirin before the scheduled surgery. Only 1 patient was on preprocedural warfarin, which was discontinued 4 days before the procedure. In total, 27.8% of patients discontinued the oral P2Y12-receptor antagonist less than 5 days before surgery. Of the patients treated with clopidogrel, 26.7% stopped therapy ≤ 5 days before their procedure. Of patients treated with prasugrel, 33.3% stopped therapy ≤ 7 days before their procedure. Four patients were on therapeutic anticoagulation before surgery. All patients received eptifibatide before surgery with 72.2% receiving a 180 mcg/kg loading dose and 88.9% received an eptifibatide maintenance dose of 2 mcg/kg/minute. Eptifibatide was infused for less than 1 day in 5.6% of patients, for 1 to 2 days in 27.8% of patients, for 2 to 3 days in 27.8% of patients, and for at least 3 days in 38.8% of patients before procedure. Of the 16 patients who originally received a 2 mcg/kg/minute dose, 1 patient had a dose reduction to 1 mcg/kg/minute for unknown reasons. The remaining 2 patients were started on a renally adjusted maintenance dose of 1 mcg/kg/min.
For postprocedure antiplatelet management (Tables 4 and 5), 77.8% patients received DAPT, 16.7% received DAPT and warfarin, and 5.6% received therapy with aspirin and warfarin. Postprocedure, 55.6% of patients were restarted on 81 mg daily aspirin, 38.9% on 325 mg daily aspirin, and 5.6% on a 300 mg daily aspirin suppository. Of those 50% who had aspirin held during the procedure, 88.9% resumed within 24 hours after the procedure was completed.
Only 22.2% of patients were restarted on eptifibatide following surgery. All 4 patients resumed the 2 mcg/kg/min maintenance dose with only 2 of the 4 patients receiving a loading dose of 180 mcg/kg. Two patients did not restart an oral P2Y12-receptor antagonist after surgery. Overall only 50% of patients received a loading dose of an oral P2Y12-receptor antagonist after surgery and 88.9% of patients started on a maintenance dose of the oral P2Y12-receptor antagonist. One patient was discharged on aspirin and warfarin combination therapy, while another only on aspirin monotherapy.
There were no systemic thromboembolic or stent thrombosis events in our patient population. One patient (patient 11) had a TIMI major bleeding event. This patient had a pericardial hematoma that required 8 units of packed red blood cells to be transfused and reoperation for resolution. This adverse event occurred on postoperative day 2. In addition, there was one documented TIMI minimal gastrointestinal bleed on postoperative day 6 (patient 10) in which the patient received 2 units of packed red blood cells. Both of these patients were on concurrent therapeutic heparin infusions at the time of the bleeding event. One patient died within 90 days of surgery due to cancer.
In this descriptive report, we found that antiplatelet therapy management in patients undergoing surgery within 1 year of intracoronary stent implantation was highly variable in the perioperative period. Half of patients did not continue aspirin throughout the surgery, 27.8% of patients stopped antiplatelet therapy less than 5 days before surgery, 27.8% did not receive a glycoprotein IIb/IIIa loading dose, and 61.1% of patients did not receive eptifibatide for the recommended duration of at least 3 days before procedure. After surgery 50% of patients did not receive a loading dose of an oral P2Y12-receptor antagonist.
Stent thrombosis has been reported to occur as frequently as 2% within the first year following implantation and is associated with a morbidity and mortality risk up to 45%.13 Our study focused on 18 individuals with intracoronary stent implantation within the past year who were bridged with eptifibatide for antiplatelet therapy. Currently, there is no consensus on guidelines for perioperative management of antiplatelet therapy.14,15 In the event that surgery cannot be postponed, the American College of Chest Physicians recommends discontinuation of DAPT around the time of surgery rather than stopping 7 to 10 days prior.5 In contrast, the American College of Cardiology/American Heart Association guidelines recommend stopping clopidogrel or ticagrelor 5 days and prasugrel 7 days before surgery in patients with a high risk of bleeding and those undergoing elective coronary bypass graft surgery.14,15 Furthermore, recent expert opinions suggest that a loading dose of eptifibatide may not be required for bridging in the absence of a need for immediate effect.16 The differences in recommendations appear largely due to the lack of evidence surrounding the use of short-acting intravenous GP IIb/IIIa inhibitors, such as eptifibatide or tirofiban, in the perioperative setting.5
Despite concerns of stent thrombosis caused by early interruption of antiplatelet therapy, the available data for periprocedural antiplatelet management are limited. One study reviewed 19 patients bridged with eptifibatide. Clopidogrel was stopped a mean of 6 days before the procedure, and 2 days before initiating eptifibatide infusion. Eptifibatide was stopped a mean of 10 hours before the procedure. Major bleeding occurred in 7/13 (53.9%) of cardiac surgery patients and no bleeding events were reported in noncardiac surgery patients. They also reported no thrombotic events.13 Another study also discontinued clopidogrel 5 days before the procedure and began a tirofiban infusion 2 to 3 days before surgery. Tirofiban was stopped approximately 4 hours before the procedure. Six major bleeding events were reported, only 2 (33.3%) corresponding with coronary artery bypass surgery. This study also reported no thrombotic events.17 The largest safety study to date analyzed 71 propensity matched patients who were bridged for surgery with eptifibatide for cardiovascular surgery and found that there was no increase in bleeding or any incidence of stent thrombosis in patients who were bridged compared to those who discontinued P2Y12 inhibitor therapy greater than 5 days prior to surgery but were not initiated on bridging therapy. The authors of this study observed an increased rate of transfusion requirements in patients who were bridged with eptifibatide and received concurrent aspirin and/or heparin.18 Both patients who experienced a bleeding event in our report were on therapeutic heparin infusions and aspirin therapy at the time of the event.
A recent metaanalysis of perioperative bridging in patients with coronary stents undergoing surgery included 8 studies with 280 patients and found stent thrombosis occurred in 1.3% of patients and major bleeding events in 7.4% of patients. Notably, the occurrence of stent thrombosis in the metaanalysis is driven by a single study in which 3 patients had a stent thrombosis in the setting of antiplatelet therapy interruption. In all 3 cases, both aspirin and clopidogrel were discontinued before surgery, contrary to our recommended protocol of continuing aspirin through the procedure while holding P2Y12 inhibitors. The authors concluded that perioperative bridging with a GP IIb/IIIa inhibitor did not eliminate stent thrombosis risk and may increase the risk for bleeding.19
A recent report reviewed a Massachusetts administrative claims database of 1838 BMS and 3565 DES patients requiring surgery within 12 months of stent placement.20 Through propensity score matching analyses, investigators determined that the incidence of adverse effects was significantly lower beyond 90 days after DES placement compared to BMSs and it may not be necessary to wait until 12 months after DES placement before performing noncardiac surgical procedures. From these reports, GP IIb/IIIa inhibitors have been effective at preventing stent thrombosis but with an associated bleeding risk.
GP IIb/IIIa inhibitors are advantageous for bridging antiplatelet therapy because of their short half-lives compared to aspirin and P2Y12 receptor antagonists. Cangrelor is a new direct P2Y12 platelet-receptor inhibitor with a short half-life and rapid onset. Normal platelet function is fully restored within 1 hour after discontinuation of infusion. Cangrelor has been recently approved by the Food and Drug Administration for PCI and may be a promising agent for perioperative use, though the dose studied for bridging is lower than the approved dose used for PCI.21,22 Also under development are new coronary stents with potentially lower rates of stent thrombosis. Strategies include bioresorbable stents and stents coated with antiplatelet drugs.23
The major limitation to our report is that there were no comparator groups to identify causality of outcomes related to eptifibatide bridging. In addition, there were a small number of patients identified and not all patients were treated uniformly. Few patients had received a BMS and variations in treatment strategies were common.
Management of patients requiring surgery less than 1 year after coronary stent placement with antiplatelet, anticoagulant, and aspirin remains complex. There is variation between patients on whether aspirin is continued through the procedure, the time between discontinuation of antiplatelet agents and surgery, and whether or not a patient receives a loading dose of eptifibatide for bridging or antiplatelet agent postprocedure. Prospective randomized-controlled trials would better define the risks and benefits of perioperative bridging and such trials are needed. Until then, standardizing therapy according to patient risk for thrombosis and bleeding might help optimize outcomes.
Dr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Vice-Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. The other authors have no conflicts of interest to disclose.
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