Use of Tirofiban as a bridge to cardiac surgery in patients
under treatment with P2Y12 inhibitors.
JOAQUÍN J. JARMA, FLORENCIA MANDÓ, SANTIAGO ORDOÑEZ,
ÁLVARO ETCHEPARE, INÉS M. BAECK, MARCELO TRIVI, JUAN P. COSTABEL
Instituto Cardiovascular de Buenos Aires (ICBA).
Buenos Aires, Argentina. E-mail
Recibido 21-MAR-18 – ACEPTADO despues de revisión 28-ABRIL-2018.
There are no conflicts of interest to disclose.
Introduction: tirofiban is a glycoprotein IIb/IIIa inhibitor with a proven use in certain acute coronary syndrome scenarios. Its safety and efficacy as a bridge to cardiac surgery, in view of the suspension of inhibitors P2Y12 in patients with recent angioplasty, is uncertain. Objective: to study the incidence of ischemic and hemorrhagic complications in patients requiring a tirofiban bridge prior to major cardiac surgery. Methods: we conducted an observational, prospective, single-center study, including inpatients with recent angioplasty who used tirofiban as a treatment prior to myocardial revascularization surgery, with and without associated valve replacement. We used an institution protocol for the infusion of tirofiban. We measured the incidence of myocardial infarction and bleeding (BARC) in the pre-treatment and in the postoperative period of cardiac surgery. Results: Our study included 50 middle-age (69.5 +/- 62.7-74.5 yrs old) males (90%) patients. The incidence of bleeding during the bridge with tirofiban was 8%, half of them were significant according to BARC classification (2% grade 3A and 2% grade 3B). The rate of acute myocardial infarction was 2% and no intrastent thrombosis was registered. None of the patients required emergency coronary angiography. Conclusion: in our experience, the use of tirofiban as a bridge to surgery was associated with a moderate rate of ischemic and hemorrhagic events. Our results show that the events did not differ significantly from those reported in patients who did not require this strategy. The events in the bridge and in the postoperative period do not seem to be associated with the use of tirofiban or P2Y12 suspension.
The requirement of heart surgery in patients being treated with dual antiplatelet therapy, by recent implant of coronary stents, is fortunately an infrequent situation, but highly challenging for cardiologists. The suspension of dual antiplatelet therapy exposes patients to the risk of stent thrombosis, and on the other hand, surgery with aspirin or P2Y12 receptor inhibitors increases the risk of hemorrhagic events.
The aim of this study was to evaluate efficacy and safety, in terms of ischemic and bleeding complications, use of tirofiban in patients that have to suspend conventional antiplatelet treatment to undergo heart surgery, with and without extracorporeal circulation pump.
MATERIAL AND METHODS
This is an observational, retrospective, single-center study. Individuals were included consecutively, who underwent heart surgery within the first 6 months after coronary stent implant, and who had indication of continuing with dual antiplatelet therapy according to the recommendations by international guidelines.
Tirofiban hydrochloride (Aggrastat®, Techsphere) was used as a bridge to surgery following a protocol for all patients. After suspending a half-life of the P2Y12 receptor inhibitor (according to surgical times indicated by guidelines), IV infusion of the medication was started with no load dose. This was maintained at 0.1 µg/kg/min during admission, and was suspended 5 hours before the surgical intervention. The administration of aspirin was only suspended in the case of surgery with extracorporeal circulation pump. In the absence of bleeding complications in the postoperative period, all patients continued with clopidogrel, that was started in the first 24 hours.
Acute myocardial infarction (AMI):
Spontaneous AMI: increase or decrease in high-sensitivity troponin T (hsTT) values, with at least one value above the normal limit of reference for 99% of the population in two samples, associated to precordial pain, new alteration of cardiac motility in imaging studies, ECG alterations compatible with ischemia (new ST-segment or T-wave shift, new Q wave or new left bundle branch block [CLBBB]*) or image of intracoronary thrombus in coronary angiography [2,3].
Periprocedural AMI related to myocardial revascularization surgery: increase within the first 48 hours of hsTT greater than 10 times the normal upper limit if the patient presented normal values previously or increase in hsTT greater than 20% if the patient presented high but stable values, or in decrease. Moreover, chest pain for more than 20 minutes, or ECG changes (new Q wave or new CLBBB*) or occlusion image of bridge or native artery in coronary angiography or parietal motility alterations in imaging studies [2,3].
CLBBB diagnosis: QRS >120 ms, dominant S wave in V1, wide and monophasic R wave in DI, aVL, V5-V6; absence of Q wave in D1. V5-V6 and time to R wave peak in V5-V6 >60 ms.
Ischemic changes in ECG in absence of CLBBB:
New ST-segment upslope: >0.1 mv in 2 or more contiguous leads, except V2-V3 where the following cutoff points are applied: >0.2 mv if male patient older than 40 years; >0.25 mv if male patient younger than 40 years, and >0.15 in females .
New ST-segment downslope: plane in a downsloping ramp >0.05 mv in 2 or more contiguous leads .
T-wave inversion >0.1 mv in two or more contiguous leads .
Stent thrombosis (STH) by time presentation:
Acute 0-24 hours after the implant.
Subacute >24 hours-30 days after the implant.
Late >30 days-1 year after the implant.
Very late >1 year after the implant.
Stent thrombosis (STH) by diagnosis:
Definitive: acute coronary syndrome with angiographic or anatomopathological recording o stent thrombosis.
Probable: unexplained death within the first 30 days after the implant. Infarction in the stent territory with no angiographic recording and no other obvious case.
Possible: unexplained death 30 days or more after the stent implant .
Bleeding according to the Bleeding Academic Research Consortium (BARC):
Type 0: no bleeding.
Type 1: bleeding that does not require additional tests, as well as hospitalization or being managed by a health care professional. Examples: ecchymosis, small hemorrhoidal bleeding.
Type 2: any proven bleeding that does not meet criteria for types 3, 4 or 5, and meeting at least one of the following criteria:
Requiring nonsurgical intervention by the health care professional
Requiring quick assessment.
Type 3A: bleeding that leads to a 3 to 5 g/dL decrease in hemoglobin.
Type 3B: bleeding that leads to >5 g/dL decrease in hemoglobin, bleeding that leads to cardiac tamponade, bleeding requiring surgical intervention to control it (except dental/hemorrhoidal/dermal). Bleeding requiring IV vasoactive agents.
Type 3C: intracranial bleeding (not including microhemorrhages or hemorrhagic transformation). Intraocular hemorrhage affecting vision.
Type 4: bleeding related to surgery. Perioperative intracranial bleeding (within 48 hours after surgery). Reoperation with the purpose of controlling bleeding. Transfusion ≥5 blood packs in a 48 h term. Bleeding by chest drain of more than 2 L in a 24 h term.
Type 5A: suspicion of (not evident) fatal bleeding. Unconfirmed by autopsy or imaging, but suspected clinically.
Type 5B: definitive fatal bleeding. Evident bleeding or confirmed by imaging study or by autopsy .
The protocol was evaluated and approved by the Committee on Institutional Ethics. All patients signed an informed consent to participate in the study. According to Argentine Law N° 25.326 of personal data protection, all information will remain confidential.
There were 50 patients included consecutively, that received tirofiban as a bridge to heart surgery between April 2011 and August 2016. The mean age of the population was 69.5 years (62.7-74.5) and 90% (45 patients) were males (Table 1). 50% of patients had history of infarction, 40% were diabetic and 31% smoked or smoked until recently. 71.7% received angioplasty with drug-eluting stent (DES) using clopidogrel in 76% of cases, and in the rest presugrel and ticagrelor in equal percentages. The time median since angioplasty to the onset of tirofiban infusion was 29 days [7-66].
The angiographic characteristics are shown in Table 2. Urgent angioplasty was made in 74% of patients, with 64% being because of acute myocardial infarction. Anterior descending artery was affected in 42% of cases, and angioplasty to venous bypass was done in the same percentage. The median of the number of vessels with angioplasty was 2 (2-3) and the number of stents used was 2 (1-2).
Table 2. Information on the procedure
Urgent angioplasty - %
Complications - %
Number of stents
Number of vessels
TCA to ADA - %
TCA to venous bypass - %
DES - %
TCA-Tirofiban time (days)
In relation to the surgical procedures that caused the interruption, revascularization surgery without extracorporeal circulation was conducted in 39 patients (78%); while in the remaining ones, valve surgeries were made, with a time median of extracorporeal circulation of 141 minutes (81-174).
The median of hospitalization during the surgical event was 11 days (10-13). During tirofiban infusion only 1 patient presented acute myocardial infarction, of the NSTEMI type, opting for pharmacological treatment adjustment until the surgical solution. There were no events of intrastent thrombosis recorded, and none of the patients required urgent coronary angiography. About the bleeding events, the incidence of bleeding was 8% (4 patients). According to the BARC classification, in 2 of them it was grade 2, 1 of grade 3A (digestive hemorrhage with erosive gastritis and pharmacological treatment), and another of grade 3B (digestive hemorrhage with ulcer Forrest IIb and sclerotherapy). Both required red cells transfusion (Table 3).
During the postoperative period AMI - %
Bleeding - %
BARC 4 - %
BARC 5 - %
Reoperation by bleeding - %
Reoperation by infarction
Mortality - %
In relation to the events of the postoperative events, an incidence of infarction of 14% (7 patients) occurred in all cases meeting only the criteria of troponin elevation, not requiring coronary angiography, reoperation and with no ST-segment elevation. About bleedings, 14% met criteria according to the BARC classification. 10% (5 patients) presented BARC 4 bleeding, requiring transfusion in all cases, surgery in 2 patients and in the rest only transfusion. Two patients presented BARC 5, requiring surgery in all cases, one of them required reoperation by cardiac tamponade, and in the other case surgical bleeding in the immediate postoperative. Both cases evolved with multiorgan failure and refractory shock until death. 32% of all patients required transfusions with hemoderivatives and mortality in the immediate postoperative period was 8% (4 patients). Figure 1.
In this study, the evolution of a consecutive group of coronary patients is described. They underwent a bridging protocol with tirofiban prior to heart surgery, with a low rate of ischemic events, and a moderate rate of hemorrhagic events.
Faced with an increase in solving the coronary disease by angioplasty with placement of coronary stents, there has been an increase in the number of patients that are exposed to the need to undergo cardiac or noncardiac surgery, with the risk entailed by suspending antithrombotic treatment . Such interruption increases ischemic risk; particularly when taking into account the clinical scenario in which angioplasty is made. In a recent meta-analysis evaluating the optimal duration of antiplatelet therapy in different clinical scenarios, it was observed that suspension within 6 months of dual antiplatelet therapy in patients who had acute coronary syndrome is associated to a 48% increase in the risk of myocardial infarction and intrastent thrombosis .
Another systematic review evaluated the effects of interruption of antiplatelet therapy and clinical impact. In the first trials that reported on the topic, it was observed that although the incidence of intrastent thrombosis was 1.1%, 57% of patients that had suffered the event had interrupted the antiplatelet treatment within the first months . Airoldi et al, in an analysis of 3021 patients that had received angioplasty with DES, observed that suspending clopidogrel was independently associated to intrastent thrombosis (HR 13.7; Ci 95% 4 – 46.7; p<0.001) . Werkum et al, in a cohort of 437 patients with intrastent thrombosis matched with 866 controls free from events, observed that although the association is more marked during the first 30 days (HR 36.5, CI 95% 8-167.8; p<0.0001), it stays the same during the whole follow-up year . Thus, a practice capable of decreasing ischemic risk in premature suspension of antiplatelet therapy is necessary; not generating an inordinate increase in bleeding events [10,11].
Different strategies have been proposed, showing that heparins are not beneficial, as they generate an increase in bleeding risk and not exerting a protective antiplatelet effect . Using IV P2Y12 receptor inhibitors as cangrelor is safe in hemorrhagic terms, and it is efficient when maintaining optimal levels of platelet inactivation . As a drawback, these studies did not evaluate ischemic events, and up to now, this is a drug not available in our country. Tirofiban is an antiplatelet agent that produces aggregation inhibition by its selective binding to the IIb/IIIa glycoprotein receptor. Its greatest advantage is its fast inactivation, as it has a mean half-life of 2 h, and 50% of platelet activity recovers after 4 h from suspending the infusion . Its usefulness has been proven in acute coronary syndromes, mainly in the age when strong and safe oral antiplatelet drugs were not available, having an impact on the reduction of ischemic events [15,16]. In relation to safety, Bizarri et al, showed that suspending tirofiban 2 hours before myocardial revascularization surgery in patients that had used it because of acute coronary syndrome, did not present more bleeding events than the standard with heparin .
Given its favorable pathophysiological characteristics, some authors have advocated the usefulness of tirofiban as a bridging therapy in different surgeries. Marcos et al, described a cohort of 36 patients that received a bridge with tirofiban, after having implanted DES in the 6 months before surgery (15 patients with cardiac surgery). No thrombotic events or death occurred, although 17% (6 patients) presented events of bleeding with requirement for transfusions within the first 30 days after the procedure. Only one of these patients had underwent myocardial revascularization surgery and needed reoperation a few hours after it . Savonitto et al, presented 30 patients (9 with cardiac surgery, 1 of them with valve surgery) who had received DES. In this series no thrombotic or bleeding event was reported. Only one patient required red cells transfusions due to anemia previous to the surgery . Both experiences show a low rate of intrastent thrombosis, as well as what happened in our series. On the contrary, our study showed a high rate of bleeding events, which is probably related to the fact that all surgeries were cardiac, and 22% with extracorporeal circulation. When evaluating other studies where oral antiplatelet therapy was suspended, we found in the PLATO trial, a higher bleeding rate related to myocardial revascularization surgery in the ticagrelor group, of 7.4%; while in the TRITON trial, 13.4% of major bleeding was observed in patients with prasugrel, even after suspension for 7 days [20,21]. In the CURE trial, the rate of major bleeding of patients who underwent coronary surgery was 9.6% . In relation to the postoperative events, we observed a 14% rate of perioperative infarction, defined only by the criterion of troponin. It is known that valve surgery presents a higher troponin release by the greater injury on the myocardial tissue that is generated during the procedure. In our study, one of every five surgeries had valve exchange associated, a number greater than the one occurring in other series, which could have been associated with the number of events. We considered that more studies would be necessary, performed in a prospective manner and with a more prolonged follow-up to observe the clinical implications of this finding.
The study we presented here is the largest study published to this date, evaluating the efficacy and safety of using tirofiban as a bridge to heart surgery in patients that suspended dual antiplatelet therapy.
Those proper of a retrospective study in relation to data gathering, with the possible bias that this entails. On the other hand, it was a single-center study, in a monovalent institution, with a high flow of patients with acute coronary syndrome and a high number of heart surgeries, which may have repercussions on the rate of events found.
The use of tirofiban as a bridge to heart surgery was associated with a moderate rate of bleeding events and low rate of ischemic events, directly attributable to the suspension of oral dual antiplatelet therapy.
Morici N, Moja L, Rosato V, et al. Bridge with intravenous antiplatelet therapy during temporary withdrawal of oral agents for surgical procedures : a systematic review. Intern Emerg Med 2014; 9 (2): 225-35.
Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J 2012; 33 (20): 2551-67.
Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. A case for standardized definitions. Circulation 2007; 115 (17): 2344-51.
Mehran R, Rao S V, Bhatt DL, et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials A Consensus Report From the Bleeding Academic Research Consortium. Circulation 2011; 123 (23): 2736-47.
Egholm G, Kristensen SD, Thim T, et al. Risk associated with surgery within 12 months after coronary drug-eluting stent implantation. J Am Coll Cardiol 2016; 68 (24): 2622-32.
Palmerini T, Della Riva D, Benedetto U, et al. Three, six, or twelve months of dual antiplatelet therapy after DES implantation in patients with or without acute coronary syndromes: an individual patient data pairwise and network meta-analysis of six randomized trials and 11 473 patients. Eur Heart J 2017; 38 (14): 1034-43.
Gaglia MA Jr, Waksman R. Systematic review of thienopyridine discontinuation and its impact upon clinical outcomes. Eur Heart J 2011; 32 (19): 2358-64.
Gerckens U, Godino C, Melzi G, et al. Incidence and Predictors of Drug-Eluting Stent Thrombosis. Circulation 2007; 116 (7): 745-54.
Hautvast RW, Verheugt FW, Berg JM. Predictors of Coronary Stent Thrombosis The Dutch Stent Thrombosis Registry. J Am Coll Cardiol 2009; 53 (16): 1399-409.
Biancari F, Airaksinen KEJ, Lip GYH. Benefits and risks of using clopidogrel before coronary artery bypass surgery : Systematic review and meta-analysis of randomized trials and observational studies. J Thorac Cardiovasc Surg 2012; 143 (3): 665-75.
Nijjer SS, Watson G, Athanasiou T, Malik IS. Safety of clopidogrel being continued until the time of coronary artery bypass grafting in patients with acute coronary syndrome : a meta-analysis of 34 studies. Eur Heart J 2011; 32 (23): 2970-88.
McDonald SB, Renna M, Spitznagel EL, et al. Preoperative Use of Enoxaparin Increases the Risk of Postoperative Bleeding and Re-exploration in Cardiac Surgery Patients. J Cardiothorac Vasc Anesth 2005; 19 (1): 4-10.
Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery. Surv Anesthesiol 2012; 56 (5): 207-8.
Patrono C, Coller B, Fitzgerald GA, et al. Platelet-Active Drugs : The relationships among dose , effectiveness , and side effects. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3 Suppl): 234S-264S.
Van't Hof AW1, Ten Berg J, Heestermans T, et al. Prehospital initiation of tirofi ban in patients with ST-elevation myocardial infarction undergoing primary angioplasty ( On-TIME 2 ): a multicentre , double-blind , randomised controlled trial. Lancet 2008; 372 (9638): 537-46.
Valgimigli M, Biondi-Zoccai G, Tebaldi M, et al. Coronary heart disease Tirofiban as adjunctive therapy for acute coronary syndromes and percutaneous coronary intervention : a meta-analysis of randomized trials. Eur Heart J 2010; 31 (1): 35-49.
Bizzarri F, Scolletta S, Tucci E, et al. Perioperative use of tirofiban hydrochloride (Aggrastat) does not increase surgical bleeding after emergency or urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2011; 122 (6): 1181-85.
Marcos EG, Fonseca AC Da, Hofma SH. Bridging therapy for early surgery in patients on dual antiplatelet therapy after drug-eluting stent implantation. Neth Heart J 2011; 19 (10): 412-7.
Savonitto S, Urbano MD, Caracciolo M, et al. Urgent surgery in patients with a recently implanted coronary drug-eluting stent : a phase II study of “ bridging ” antiplatelet therapy with tirofiban during temporary withdrawal of clopidogrel. Br J Anaesth 2010; 104 (3): 285-91.
Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361 (11): 1045-57.
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20): 2001-15.
Yusuf S, Fox KAA, Tognoni G, et al. Efects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345 (7): 494-502.