04RC1 The patient with coronary stents and antiplatelet agents: what to do?

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1 04RC1 The patient with coronary stents and antiplatelet agents: what to do? H. Metzler Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Austria Saturday, June 6, :00-13:45 Room: Orange Introduction New trends in interventional cardiology such as the increasing practice of percutaneous coronary intervention (PCI) with stent implantation and the prolonged use of dual antiplatelet therapy (usually a combination of clopidogrel and aspirin) has also increased the number of these patients presenting for non-cardiac surgery. Peri-operative care providers face the dilemma between peri-operative stent thrombosis due to pre-operative premature discontinuation of anti-platelet drugs or surgical bleeding by continuation. Perioperative management requires close collaboration between cardiologists, surgeons and anaesthesiologists. Background Percutaneous coronary intervention and coronary stents PCI with coronary stent implantation has become a leading strategy worldwide in patients with different forms of coronary artery disease (CAD). Before the use of stent, restenosis was the major limitation of balloon angioplasty with rates of 30-60% within the first few months [1]. Bare metal stents have effectively eliminated this phenomenon. However, in-stent re-stenosis limited long-term outcome with bare metal stents. There is a clinically relevant re-stenosis rate of 10-30% in patients treated with these. Many determinants of in-stent re-stenosis, both stent specifi c and lesion specific, have been identifi ed. In addition, foreign body immune response and metallic stent strut corrosion may be contributory. Drug eluting stents (DES) were developed to minimise re-stenosis and re-interventions in the coronary system (their re-stenosis rate is 5 10%). DES uniquely deliver an anti-proliferative agent locally to the site of injury, thereby reducing proliferation of endothelial as well as vascular smooth muscle cells without systemic toxicity. Today, at least three polymer-based DES are commercially available: the CYPHER sirolimus-eluting stent the TAXUS paclitaxel-eluting stent and the ENDEAVOR zotarolimus-eluting stent Drug eluting stents: concerns and controversies Recently, concerns about an increased risk of late stent thrombosis have initiated a broad debate worldwide among cardiologists. In the USA DESs have been enthusiastically used, so that approximately 80% of PCI procedures include DES implantation [2]. Originally, the US Food and Drug Administration approved indications were limited to newly diagnosed coronary lesions less than mm long in clinically stable patients without serious medical conditions. In the following years the implantation of DES in complex lesions (such as bifurcations) and in patients with signifi cant co-morbidities, such as diabetic or renal dysfunction increased. This resulted in an up to 60% off-label use and higher rates of stent thrombosis [3-5]. The underlying mechanism behind this seems to be delayed re-endothelialisation. Stent thrombosis is a serious adverse event, commonly associated with acute myocardial infarction and even sudden cardiac death. Stent thrombosis is classifi ed according to how long after placement it occurs: acute (within 24 h), sub-acute (2 to 30 days), late (30 days to 1 year) and very late (> 1 year). Numerous meta-analyses, registry reports and press reports contributed to uncertainty about future strategies [6-8]. Different investigators looked at the same data using different statistical approaches. In these trials DES were either associated with an increased risk of adverse events or no signifi cant differences were found

2 Dual antiplatelet drug therapy Stent implantation is itself a thrombogenic procedure and initiates complex interactions between the surface of the stent and blood components, including the activation of platelets, the complement system and coagulation factors. Platelets play a pivotal role in this process. Several trials have demonstrated that the combination of aspirin with a thienopyridine drug is superior to single drug therapy [9, 10]. Therefore, the combination of aspirin and clopidogrel is currently the accepted and recommended drug regime. Aspirin antagonises the production of thromboxane A2 (TXA2) by inhibition of COX-1 and clopidogrel irreversibly inhibits the binding of ADP at the P2Y12-receptor. Inhibition by aspirin and thienopyridines is irreversible.the effect can only be antagonised by the formation of a new platelet population or by platelet transfusion. Normal recovery of platelet function in healthy volunteers ranges from 3 to 7 days, with a recovery rate of 5 to 15% per day [11]. The risk of premature discontinuation of dual anti-platelet therapy in a non-surgical setting Premature discontinuation of dual anti-platelet therapy increases the risk of cardiac complications. Ferrari et al demonstrated that aspirin withdrawal in coronary patients represents a real risk for the occurrence of a new coronary event [12]. In the BASKET LATE trial patients were followed for one year after the discontinuation of clopidogrel [13]. Cardiac events occurred in 4.9% after DES vs. 1.3% after bare metal stent implantation. The PREMIER registry examined thienopyridine discontinuation 30 days after DES treatment [14]. Patients who stopped thienopyridine therapy at 30 days were more likely to die during the next 11 months (7.5% vs. 0.7%, p<0.0001). Recently, Ho et al observed, in a large retrospective cohort study of more than patients, a clustering of adverse events in the first 90 days after stopping clopidogrel among both medically treated and PCI treated patients with acute coronary syndrome, supporting the concept of clopidogrel rebound [15]. Stents and non-cardiac surgery From around the year 2000 retrospective studies and case reports began to be published warning of the high risk of complications including myocardial infarction and cardiac death in patients with recently inserted coronary stents and premature discontinuation of dual anti-platelet therapy [16, 17]. In a prospective observational study Vicenzi et al demonstrated that independent of the type of stent, patients with recent stenting (< 35 days) had the highest complication rate [18]. In a retrospective study by Schouten et al there was a signifi cant association between early non-cardiac surgery after stenting and peri-operative adverse events, but no difference between DES and bare metal stents [19]. De Souza reported a case of late thrombosis in a patient in whom a DES was placed 29 months previously and clopidogrel stopped one year after that [20]. In a case series of 15 patients with DES, Charbucinska et al suggested that continuation of aspirin and withdrawal of clopidogrel was not associated with severe postoperative complications [21]. Recently, the Mayo Clinic analysed in two large retrospective studies the risks in patients with bare metal stents and DES [22, 23]. In patients with bare metal stents the frequency of major adverse cardiac events was 10.5% when non-cardiac surgery was performed less than 30 days after PCI, and decreased to 2.8% when surgery took place more than 90 days after PCI. In DES patients no association was found between major adverse cardiac events and time of stenting, but the rate was lowest after one year. Age and emergency surgery are variables associated with increased risk. Risk of bleeding One the first large prospective randomised trials demonstrating the benefi cial effect of the anti-platelet agent clopidogrel in addition to aspirin on outcome (the CURE trial) showed that there were more patients with increased bleeding in the clopidogrel and aspirin group compared with the aspirin and placebo group (3.7% vs. 2.7%, relative risk 1.38, p < 0.001) but there were no more patients with episodes of life-threatening bleeding (2.1% vs. 1.8%, p < 0.13) or haemorrhagic strokes [9]. In subsequent years much data has been published from patients undergoing CABG surgery. Depending on the interval between discontinuation of clopidogrel and the time of cardiac surgery, relevant outcomes such as transfusion requirements, intubation time and hospital stay were signifi cantly increased [24]. Mortality was highest when clopidogrel was given in the two days before surgery [24]. Adding clopidogrel to aspirin increases the relative risk of bleeding up to 50% and the absolute risk up to 1%. In a meta-analysis Burger et al analysed cardiovascular risks after peri-operative withdrawal of aspirin vs bleeding risk with its continuation [25]. Except for intracranial surgery and prostatectomy, low dose aspirin increases neither the severity of bleeding complications nor the peri

3 operative mortality due to bleeding complications. From the available cardiac and non-cardiac surgery studies it may be concluded that depending on the time of discontinuation of clopidogrel and aspirin the bleeding risk may be increased, but in non-cardiac surgery the risk of stent thrombosis may be more pronounced and more relevant compared with bleeding. In a recent study by the Mayo Clinic the incidence of surgical bleeding complications was low despite the high rate of anti-platelet therapy use [22, 23]. Peri-operative strategies and decision trees Using an interdisciplinary approach the cardiologist, surgeon and anaesthesiologist have to plot the risk of thrombosis against the risk of bleeding. The anaesthesiologist plays a central role in this management triangle. The cardiologist is likely to underline the risk of stent thrombosis and the surgeon that of relevant surgical bleeding. Three determining factors influence the positioning of the patient in one of the risk categories (Table 1). Table 1 Variables infl uencing the bleeding vs thrombosis risk ratio Surgical procedure related factors Intracranial and spinal surgery Prostate surgery Surgery on the retina Abdominal aortic aneurysm repair Specific situations Patient related factors Low ejection fraction Diabetes mellitus Renal insuffi ciency Lesion and stent procedure- related factors Type of stent (bare metal vs DES) Time of implantation Number, location and length of stents Based on the available data, treatment of the patient can be guided at an acceptable risk level following the decision tree outlined in Figure 1. In emergency cases peri-operative care providers should be aware of the increased risk of intra- and postoperative bleeding. Elective surgery should be postponed until the end of mandated clopidogrel therapy. In semi-elective or urgent cases, management should be tailored to the thrombosis/bleeding tolerance: in high bleeding/low thrombosis risk scenarios the surgeon will insist on premature discontinuation of clopidogrel and aspirin, in high thrombosis/low bleeding risk scenarios dual anti-platelet therapy should continue until, or even throughout, surgery in most cases aspirin should be continued throughout the peri-operative period if clopidogrel is discontinued. Postoperatively, dual anti-platelet therapy should be re-started as soon as possible taking into account the risk of haemorrhage

4 Figure 1 Decision tree for determining peri-operative strategy for patients with coronary stents Management of stent thrombosis In both non-surgical and surgical patients, acute stent thrombosis presents as a severe symptomatic acute myocardial infarction. Mortality is high (up to 20%) in both settings. After haemodynamic stabilisation, the patient should be rapidly transferred to an interventional cardiology unit with the option of re-ptca and re-opening of the occluded stent. Management of surgical bleeding Neither aspirin nor clopidogrel can be antagonised pharmacologically. Platelet transfusion may be required. There are some reports on the efficacy of desmopressin and anti-fi brinolytics. Monitoring platelet function Adequate monitoring of platelet function in cardiovascular disease and particularly during anti-platelet drug therapy is of relevance both in a cardiological and surgical setting. Light transmission aggregometry is still considered to be gold standard but has some limitations. New platelet function assays like VASP, VerifyNow, Multiplate, and PFA-100 are on the horizon. Despite the need for limited interpretation of such data, the new assays seem to be promising. Recently, the first clinical studies demonstrating the potential usefulness of such assays, particularly in high risk patients and procedures, in assessing the levels of anti-platelet action in a peri-operative setting have reported [26]

5 Bridging Premature pre-operative discontinuation of clopidogrel and aspirin leaves the patient unprotected. Therefore, some protocols try to decrease the risk by bridging with short-acting anti-platelet or anti-thrombotic agents. The most frequently used drug types are GP IIb/IIIa inhibitors (such as eptifi batide) and low molecular weight heparin (such as enoxaparin). So far, there is no evidence-based data for these strategies. Guidelines and recommendations Several Task Forces and Advisory Committees of national and international societies have published important and helpful recommendations. The European Society of Cardiology Guidelines recommend that after implantation of a bare metal stent clopidogrel must be continued for 3-4 weeks (level of evidence - 1A) and aspirin life-long. After DES implantation clopidogrel should be administered in addition to aspirin for 12 months (level of evidence - 1C) [27]. The new AHA/ACC/SCAI/ACI advisory recommends 12 months of dual anti-platelet therapy after placement of a DES in patients who are not a high risk of bleeding [28]. It particularly addresses the problem of premature discontinuation with a relevant statement about the peri-operative setting: In patients who are likely to require surgical procedures within the next 12 months bare metal stents should be inserted. Healthcare providers must be aware of the potentially catastrophic risk of premature discontinuation. Elective procedures should be deferred until completion of thienopyridine therapy (12 months after DES). The French Task Force stated that in patients with a DES, maintaining aspirin during surgery is the preferred option [29]. Caution should be exercised, however, when considering surgery associated with high blood loss (such as major tissue detachment, aortic, prostate, neurosurgery and the posterior segment of the eye). The new ACC/AHA 2007 guidelines on peri-operative cardiovascular evaluation and care for non-cardiac surgery summarise all these available guidelines and recommendations and addresses in a careful review all relevant aspects of coronary stents and surgery [30]. Key learning points Anaesthesiologists have to become familiar with the characteristics and typical risks of bare metal and drug-eluting stents. Pre-operative premature discontinuation of anti-platelet drug therapy with clopidogrel and aspirin increases the risk of stent thrombosis, and continuation increases the risk of surgical bleeding. Peri-operative management depends on stent related factors, the type of the surgical procedure and patient related factors. References 1. Holmes DR Jr, Vliestra RE, Smith HC. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA Registry of the National Heart, Lung, and Blood Institute. American Journal of Cardiology 1984; 53: 77C-81C. 2. Farb A, Boam AB. Stent thrombosis redux: The FDA perspective. New England Journal of Medicine 2007; 356: Slottow TLP, Waksman R. Overview of the 2006 Food and Drug Administration Circulatory System Devices Panel meeting on drug-eluting stent thrombosis. Catheterization and Cardiovascular Interventions 2007; 69: Beohar N, Davidson CJ, Kip KE. Outcomes and complications associated with off-label and untested use of drug-eluting stents. Journal of the American Medical Association 2007; 297: Win HK, Caldera AE, Maresh K, et al. Clinical outcomes and stent thrombosis following off-label of drug-eluting stents. Journal of the American Medical Association 2007; 297: Kastrati A, Schömig A. Drug-eluting stents. Journal of the American College of Cardiology 2007; 50: Kaul S, Shah PK, Diamond GA. As time goes by. Current status and future directions in the controversy over stenting. Journal of the American College of Cardiology 2007; 40: Holmes DR, Kereiakes DJ, Laskey WK, et al. Thrombosis and drug-eluting stents. Journal of the American College of Cardiology 2007; 50:

6 9. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment in elevation. New England Journal of Medicine 2001; 345: Mehta SR, Yusuf S, Peters RJG, et al. Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE-Study. Lancet 2001; 358: Weber AA, Braun M, Hohlfeld T, et al. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. British Journal of Clinical Pharmacology 2001; 52: Ferrari E, Benhamou M, Cerboni P, et al. Coronary syndromes following aspirin withdrawal. A special risk for late stent thrombosis. Journal of the American College of Cardiology 2005; 45: Pfi sterer M, Brunner La-Rocca HP, Buser PT, et al. Late clinical events after clopidogrel discontinuation may limit the benefi t of drug-eluting stents. Journal of the American College of Cardiology 2006; 48: Spertus JA, Kettelkampf R, Vance C, et al. Prevalance, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement (Results from the PREMIER Registry). Circulation 2006; 113: Ho PM, Petersen ED, Wang L, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. Journal of the American Medical Association 2008; 299: Vicenzi MN, Ribitsch D, Luha O, et al. Coronary artery stenting before noncardiac surgery: More safety than treatment? Anesthesiology 2001; 94: Kaluza GL, Joseph J, Lee JR, et al. Catastrophic outcomes of noncardiac surgery soon after coronary stenting. Journal of the American College of Cardiology 2000; 35: Vicenzi MN, Meislitzer T, Heitinger B, et al. Coronary artery stenting and noncardiac surgery: A prospective outcome study. British Journal of Anaesthesia 2006; 96: Schouten O, Van Domburg RT, Bax JJ, et al. Noncardiac surgery after coronary stenting: Early surgery and interruption of antiplatelet therapy are associated with an increase in major adverse cardiac events. Journal of the American College of Cardiology 2007; 49: De Souza DG, Baum VC, Ballert NM. Late thrombosis of a drug-eluting stent presentation in the perioperative period. Anesthesiology 2007; 106: Charbucinska KN, Godet G, Itani O, et al. Anitcoagulation management for patients with drug-eluting stents undergoing vascular surgery. Anesthesia and Analgesia 2006; 103: Nuttal GA, Brown MJ, Stombaugh JW, et al. Time and cardiac risk of surgery after bare-metal stent percutaneous coronary intervention. Anesthesiology 2008; 109: Rabbitts JA, Nuttall GA, Brown MJ, et al. Cardiac risk of noncardiac surgery after percutaneous coronary intervention with drug-eluting stents. Anesthesiology 2008; 109: Ascione R, Ghosh A, Rogers CA, et al. In-hospital patients exposed to clopidogrel before coronary artery bypass graft surgery: A word of caution. Annals of Thoracic Surgery 2005; 79: Burger W, Chemnitius JM, Kneissl GD, et al. Low-dose aspirin for secondary cardiovascular prevention cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation review and meta-analysis. Journal of Internal Medicine 2005; 257: Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosophoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance. Journal of the American College of Cardiology 2008; 51: The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Guidelines for percutaneous coronary interventions. European Heart Journal 2005; 26: Grines CL, Bonow RO, Gasey DE, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: A science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with repre sentation from the American College of Physicians. Circulation 2007; 115: Albaladejo P, Marret E, Piriou V, et al. Perioperative management of antiplatelet agents in patients with coronary stents: Recommendations of a French Task Force. British Journal of Anaesthesia 2006; 97: Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Circulation 2007; 116: e418-e