Perioperative management of antiplatelet agents in noncardiac surgery Juan V. Llau, Cristina López-Forte, Luisa Sapena and Raquel Ferrandis

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1 Review 181 Perioperative management of antiplatelet agents in noncardiac surgery Juan V. Llau, Cristina López-Forte, Luisa Sapena and Raquel Ferrandis It is common that patients who are scheduled for surgery are treated with antiplatelet agents (APAs) due to their wide indications. The management of these APAs in the perioperative period (acetylsalicylic acid alone, a thienopyridine alone or, in most cases, a combination of them) has a dual perspective: the risk of bleeding when the patient is operated under the effect of the APA against the risk of thrombosis if it has been withdrawn. The main challenges for the anaesthesiologist and the surgeon include patients with a coronary stent (mainly, new drug-eluting coronary stents), those undergoing urgent surgery and those undergoing high bleeding risk surgery. We review current protocols and discuss the most recent proposals for the management of APAs in patients undergoing noncardiac surgery. Current recommendations include the maintenance of aspirin if possible throughout the perioperative period, in order to limit the risks of cardiological, vascular or neurological postoperative events, although this makes it necessary to assume a small risk for haemorrhagic complications in some patients. Nevertheless, there are many circumstances that are not clear yet and, in this situation, it is crucial that patients are treated with a multidisciplinary approach (anaesthesiologists, surgeons, cardiologists and haematologists). Eur J Anaesthesiol 26: Q 2009 European Society of Anaesthesiology. European Journal of Anaesthesiology 2009, 26: Keywords: antiplatelet agents, arterial thrombosis, aspirin, clopidogrel, coronary stent, noncardiac surgery Department of Anaesthesiology and Critical Care Medicine, University Clinic Hospital, Valencia, Spain Correspondence to Juan V. Llau, Department of Anaesthesiology, Critical Care and Pain Therapy, Hospital Clínico Universitario, Avda, Blasco Ibáñez 17, Valencia, Spain Tel: ; fax: ; juanvllau@gmail.com Accepted 2 October 2008 Introduction It is becoming more and more frequent that patients who are scheduled for surgery are treated with a large variety of drugs capable of modifying haemostasis. These drugs include antiplatelet agents (APAs) and anticoagulants, both of which are used in arterial or venous thromboprophylaxis or both. The aim of this article is to review the recent findings and purposes of the management of APAs in patients scheduled for noncardiac surgery. Antiplatelet agents APAs are drugs of diverse origin, whose prophylactic and therapeutic effects are especially important in the prevention and treatment of arterial thrombosis, in which platelets are clearly involved in the formation of the thrombus. The current indications of APAs are as follows [1 4]: (1) Indications in cardiology (a) Acute myocardial infarction (b) Acute coronary syndrome (i) Stable angina (ii) Unstable angina/acute myocardial infarction without Q wave (c) Percutaneous coronary angioplasty with coronary stent (d) Atrial fibrillation (in patients of less than 65 years without any other associated risk factor) (e) Patients undergoing cardiac surgery (f) Some patients with valvulopathies (2) Indications in neurology (a) Acute phase of stroke (b) Secondary prevention of strokes in patients without embolic heart disease (3) Other indications (a) Patients with a valve prosthesis (b) Embolic carotid stenosis (c) Carotid endarterectomy (d) Patients with antiphospholipid antibodies (e) Peripheral arteriopathy with or without intermittent claudication (f) Primary prevention in patients with cardiovascular risk APAs are able to inhibit platelet function, particularly activation and subsequent aggregation, although they produce this effect in different ways [2,5] (Table 1). APAs can be classified into four groups, depending on their mechanisms of action, as described below. The first group includes APAs that antagonize the adenosine diphosphate (ADP) receptor, such as the thienopyridine compounds ticlopidine and clopidogrel. They reach their peak of activity after 3 5 days and produce a prolonged antiplatelet effect (7 10 days) as a result of their a long half-life. New ADP receptor antagonists include ß 2009 Copyright European Society of Anaesthesiology DOI: /EJA.0b013e328324b79f

2 182 European Journal of Anaesthesiology 2009, Vol 26 No 3 Table 1 Antiaggregant effect of some of the antiplatelet agents Agent Complete reversal time (days) Antiaggregant effect Blocking receptor ADP and GP IIB/IIIA Ticlopidine High Clopidogrel 7 10 High Abciximab 2 High NSAIDs ASA 7 High Piroxicam 7 High Indometacin 3 High Ketorolac 2 High Flurbiprofen 1 High Ibuprofen 1 Moderate Naproxen 2 Moderate Ketoprofen 1 Moderate Diclofenac 1 Moderate Salsalate <1 Weak Diflunisal <1 Weak Paracetamol <1 Weak Proparacetamol <1 Weak Metamizol <1 Weak Rofecoxib 0 No Celecoxib 0 No Others Trifusal 7 High Dipyridamole 1 Moderate ADP, adenosine diphosphate; ASA, acetylsalicylic acid; GP, glycoprotein. prasugrel (a thienopyridine) and cangrelor, which are administered orally and parenterally, respectively. As with clopidogrel, prasugrel is a prodrug that requires hepatic conversion and a loading dose to shorten the onset of platelet inhibition. Moreover, cangrelor produces almost immediate and dose-proportional inhibition of ADPinduced platelet aggregation after intravenous administration: its half-life is 3 5 min and the recovery of platelet function appears within 60 min after the end of therapy [6]. The second group consists of agents that antagonize the glycoprotein IIb/IIIa (GP IIb/IIIa) receptors, that are exclusively for intravenous use and that are more effective, although with a shorter lasting action (24 h): eptifibatide, abciximab and tirofiban. The third group comprises agents that increase the intraplatelet levels of camp (cyclic adenosine monophosphate). The best known agent is dipyridamole (moderate antiplatelet effect lasting about 24 h). Other agents are the I-2 prostaglandin epoprostenol and its analogue iloprost, both used intravenously with a brief antiplatelet effect (<3 h). The fourth group consists of inhibitors of cyclooxygenase 1 enzyme (COX-1). The best known are acetylsalicylic acid (ASA) and NSAIDs. Among them, ASA is the most studied and its antiplatelet effect takes place via an irreversible blockade of COX-1, so its action lasts throughout the life of the platelet (7 10 days). Nevertheless, there are enough platelets to guarantee suitable haemostasis from the third to fourth day. The NSAIDs also produce inhibition of platelet aggregation by a similar mechanism to ASA, although there are two important aspects to bear in mind: first, the blocking effect of the COX-1 is reversible, thus once the drug has been eliminated, platelet function is restored; and second, the differing capacities of all the NSAIDs to inhibit COX-1 and, consequently, their differing antiplatelet action. At this point, it is important to highlight that inhibitors of COX-2 have been shown to inhibit the production of vascular prostacyclin (which has vasodilatatory effects and inhibits platelet aggregation) but not the production of thromboxane (which promotes platelet aggregation); so, COX-2 inhibitors have no antiplatelet action and they could potentially contribute to a prothrombotic state, which, at present, remains under discussion [7]. Recently, it has been hypothesized that ultralow doses of ASA (not used in clinical practice, but present after ASA withdrawal) could have a similar prothrombotic action to COX-2 inhibitors by a modification in the mechanism of action of ASA via the COX-1 and COX-2 pathways [8]. Nowadays, the indications for use of APAs are being continuously updated. In that respect, the following questions should be considered. The role of aspirin in primary prevention has extended its prescription based on factors related to cardiovascular or neurological risk or both. Moreover, the combination of two APAs (mainly ASA and clopidogrel) in high-risk patients is a more common practice [5]. Dual antiplatelet therapy must be maintained for at least 12 months after drug-eluting stent (DES) placement and elective surgery must be postponed. If surgery cannot be postponed, ASA at least should be continued if at all possible throughout the perioperative period so that patients undergo their operation under its antiplatelet effect [9]. A thienopyridine should be restarted as soon as possible after the procedure [10]. Probably, a specific protocol for antiaggregation in terms of the type, combination and duration of APA needs to be applied to these patients [11,12]. The interindividual response to the APA is evident, and it can be modified by several factors such as the dose and the patient s compliance and whether the patient smokes, takes exercise, is taking concomitant medications or has heart failure, hyperlipidaemia or hyperglycaemia, and so on. A valid universal pattern of antiplatelet management for all patients does not seem to exist [13]. In most ambulatory surgery with low bleeding risk, the current attitude is to maintain APA therapy throughout the perioperative period. Patients with high risk of bleeding should not be accepted for day surgery [9]. Some NSAIDs could be an alternative to the classic APA during the perioperative period because of their

3 Perioperative management of APAs in noncardiac surgery Llau et al. 183 antiplatelet effect and shorter duration [14]. NSAIDs such as flurbiprofen or indobufen have been used in daily practice because of their antiplatelet effects. Although some studies have recommended flurbiprofen as an acceptable substitute for current APAs in the close perioperative period, when the withdrawal of ASA and clopidogrel is necessary [11], it seems that there is not enough evidence to recommend this practice for the majority of patients [15]. APA cessation has proved to be an independent factor per se of death and major cardiac events [16]. This finding could be related to the rebound effect after APA interruption, which may be a consequence of the progressive recovery of the activity of the platelet COX. Monitoring of antiplatelet effect It would be helpful in the perioperative period to have a haemostatic test to identify those patients at risk of bleeding because of platelet dysfunction related to the administration of any APA. Several tests could be used to assess platelet function. Optical platelet aggregometry is presently considered to be the reference assay to diagnose platelet disorders [17], although it is not completely standardized, the laboratory procedure is complex and it is not possible for it to be performed immediately before surgery. The platelet function analyser (PFA-100) explores the platelet adhesive capacity, measuring the closure time taken for a platelet plug to occlude an aperture in a membrane impregnated with collagen and epinephrine or ADP [18]. ASA and clopidogrel have been shown to prolong this closure time, but without any evident correlation with increased perioperative bleeding. The Plateletworks analyser measures the percentage of aggregation of whole blood before and after exposure to ADP. Its results are contradictory when compared with optical aggregometry: there is good correlation for clopidogrel [19] but limited usage for ASA [20]. Thromboelastography is a whole blood coagulation monitor that can demonstrate the alteration of platelet aggregation. However, it is unable to detect the defects that occur with ASA or to demonstrate the ADP blockade caused by clopidogrel. The Ultegra rapid platelet function assay (RPFA) system is a whole blood, point-of-care assay that incorporates a single-use cartridge with some biochemical reagents that can detect platelet dysfunction [21]. It has been proposed to monitor efficacy of aspirin and to detect the aspirin-resistant population. Finally, multiple electrode aggregometry measures whole blood platelet aggregation, being a method that could be of some interest to evaluate platelet activity in patients with platelet dysfunction who are under treatment with APAs [22]. Unfortunately, none of these tests has good correlation with perioperative bleeding and further clinical investigations are necessary in this field. Bleeding and thrombotic risks in antiplatelet agent management during the perioperative period When a patient is scheduled for surgery under the effects of an APA, there is a risk of surgical bleeding. The relevance of this haemorrhage will depend on the kind of surgery and on the type and dose of the previously administered agent. A large meta-analysis on the risk of increased surgical bleeding in patients on low-dose aspirin therapy has demonstrated that aspirin increases the rate of bleeding complications by a factor 1.5 [23]. Nevertheless, it is not so evident that this result could be extended to all surgical procedures [2]. Unfortunately, there is a lack of data regarding the risk of surgical bleeding in patients under the effect of thienopyridines in noncardiac surgery. Because of their more potent effect on platelet activity than ASA, most experts agree that the withdrawal of these agents and their substitution by ASA at least 7 10 days before surgery could minimize the risk of bleeding without increasing the thrombotic risk, excluding patients with a drug-eluting coronary stent, as discussed below. Moreover, the increased bleeding risk with ASA, if any, does not mean an increase in mortality or morbidity, an increase in transfusion requirements [1], or a worse result in most surgical procedures, with the evident exception of intracranial surgery and possibly transurethral prostatectomy. Acute withdrawal of an APA is associated with an increased risk of development of thrombotic events. The scope of the cardiovascular or neurological risk related to the preoperative withdrawal of ASA has been quantified as follows [23]: the average time between the withdrawal of ASA and the appearance of coronary complications is about 8.5 days, around 14 days in the case of neurological alterations, and around 26 days for peripheral arterial vascular complications. In another review [24], aspirin nonadherence or its withdrawal was associated with three-fold higher risk of major adverse cardiac events, and this risk was magnified in patients with intracoronary stents, as discontinuation of APA treatment was associated with an even higher risk of adverse events. The need for an optimal balance between the induced APA s bleeding risk and the potential thrombotic risk after APA withdrawal requires accurate recommendations of the management of these agents throughout the perioperative period. There are four major situations in this field in which the dilemma of bleeding versus thrombosis could be treated in different ways as follows: (1) management of an APA in patients scheduled for elective surgery;

4 184 European Journal of Anaesthesiology 2009, Vol 26 No 3 (2) management of an APA in patients with a coronary stent; (3) implications of an APA in the performance of neuraxial techniques of anaesthesia; (4) management of an APA in cases of urgent surgery. Management of antiplatelet agent in patients scheduled for elective surgery The practical guidelines for the management of an APA in patients scheduled for elective surgery are controversial, and there is a need for specific protocols depending on local agreement between anaesthesiologists, surgeons, haematologists, cardiologists and neurologists. The following general recommendations can be used as a background for discussions [2,9,23 25] (Table 2). Elective surgery of high haemorrhagic risk Elective high-risk haemorrhagic surgery has to be delayed if thrombotic risk is high, or if the risk is intermediate and surgery is not absolutely necessary. When surgery is mandatory and it is associated with a moderateto-high thrombotic risk, the recommendation is to maintain ASA and to withdraw clopidogrel. If the neurological and cardiovascular risk is low or the prescription of the APA is for primary prevention, the APA should be withdrawn (7 days for ASA, 10 days for clopidogrel and 14 days for ticlopidine). Elective surgery of moderate haemorrhagic risk In these patients, if thrombotic risk is high, surgery should be postponed, but, if not, the maintenance of ASA is mandatory and clopidogrel can be maintained or stopped 3 5 days prior to surgery. When the thrombotic risk is intermediate, the recommendation is similar: maintenance of ASA until the day before surgery (if the APA is another one, it has to be substituted by ASA between 10 and 14 days before) and administration of the first dose after surgery not more than 24 h after surgery has finished. It is also possible to stop the APA close to the intervention between 2 (trifusal) and 5 days (ticlopidine, clopidogrel) prior to surgery without substituting the APA if the patient is stable and has a moderate thrombotic risk [26]. Elective surgery of low haemorrhagic risk Although it is also recommended that surgery is delayed if the thrombotic risk is high, in general ASA can be maintained until surgery. If the patient is under treatment with a thienopyridine, we can replace it with ASA and maintain it. If a dual therapy is necessary, the recommendation is to maintain ASA and to stop clopidogrel 5 days before surgery. Management of the antiplatelet agent in patients with a coronary stent Noncardiac surgery after coronary stent placement, bare metal stents (BMS) or DES, is associated with a moderate-to-high risk of major adverse cardiac events, mostly due to in-stent thrombosis and probably related to APA interruption during the perioperative period [27]. A surgical intervention promotes a prothrombotic and proinflammatory state, which leads to hypercoagulability. Moreover, a sudden withdrawal of clopidogrel or ASA or both has a rebound effect with an increase in the hypercoagulation and prothrombotic state [28]. So, dual antiplatelet therapy should be maintained for at least 4 6 weeks after placement of a BMS and at least 6 12 months after placement of a DES. During this period of time (at least 6 weeks for BMS and 12 months for DES), elective surgery should be postponed and only life-saving operations should be performed [11,12,28,29]. Some protocols have been proposed to bridge the perioperative period for mandatory surgery in patients with a BMS placed less than 6 weeks or with a DES placed less than a year before. They include the maintenance of ASA and the introduction of continuous intravenous perfusion of heparin or argatroban. Nevertheless, cardiac events are the most important complication in these patients scheduled for noncardiac surgery, in whom the occlusion rate is higher than that in patients without surgery, usually less than 1% per year [30]. The recommendations about the perioperative management of the APA in these patients are not fully agreed, but they can be summarized as follows [9 12,18,25, 28 32]. Table 2 Stratification of the haemorrhagic and thrombotic risk Minor Moderate Major Haemorrhagic risk Thrombotic risk Transfusion usually not needed. Minor plastic/general/ortho surgery; biopsies, tooth extraction, surgery of the anterior segment of the eye >6 months after AMI, CABG, percutaneous coronariography, BMS, coronary surgery, CVS (>12 months if complications) Transfusion usually needed. Cardiac, major ortho/visceral/ent/urology or reconstructive surgery 6 24 weeks after AMI, CABG, BMS, CVS (6 12 months if complications or high risk or diabetic or low LVEF) >12 months after DES Possible bleeding in an enclosed space. Neurosurgery, spinal surgery, surgery of the posterior segment of eye <6 weeks after AMI, CABG, BMS, CVS (<6 months if complications) <12 months after DES AMI, acute myocardial infarction; BMS, bare metal stent; CABG, coronary artery bypass grafting; CVS, cerebrovascular stroke; DES, drug-eluting stent; ENT, ear nose throat surgery; LVEF, left ventricular ejection fraction; ortho, orthopaedic surgery.

5 Perioperative management of APAs in noncardiac surgery Llau et al. 185 In the case of elective surgery after BMS or DES placement, ASA should be maintained throughout the perioperative period, except in high-risk bleeding patients undergoing neurosurgery, retinal surgery and probably prostatic surgery. Clopidogrel could be withdrawn for a 5-day period, except in the high-risk bleeding patients in whom the window of time will be 10 days. There is not enough evidence to support the efficacy of bridge therapy with low-molecular-weight heparins (LMWH) or a short-acting APA such as flurbiprofen or ibuprofen. If surgery must be performed before the safety period (6 weeks for BMS and 12 months for DES), a multidisciplinary evaluation with the anaesthesiologist, cardiologist, neurologist and surgeon must be considered. The following issues have been proposed: (1) Low bleeding risk of surgery: the recommendation is to maintain dual therapy until the day before surgery. (2) Moderate bleeding risk: ASA should be maintained and clopidogrel could be stopped 3 5 days before surgery. Some authors have proposed a bridging therapy: an infusion of tirofiban and unfractionated heparin started 3 days before surgery and maintained until 6 h before surgery, mainly if the patient has additional risk factors and very high thrombotic risk of DES [32]. (3) High bleeding risk: stop ASA and clopidogrel 5 days before surgery (considered to be the best option) or stop ASA and clopidogrel for 10 days and start bridging therapy as explained above. Another question to solve is the reintroduction of treatment. The best decision is to restart ASA or thienopyridine therapy or both as soon as possible [10]. Also the optimal timing to avoid bleeding complications needs to be discussed together with the surgeon [30]. In patients at low-to-moderate haemorrhagic risk, the first dose could be administered in the first 24 h, with or without a loading dose of clopidogrel (300 mg, the common loading dose). If the patient has higher bleeding risk, the first dose of clopidogrel could be delayed until it decreases, usually after a maximum of 3 4 days, and in this case, only if the risk of stent thrombosis is high, a loading dose is recommended. Implications of the antiplatelet agent in the performance of neuraxial techniques of anaesthesia At this point, it is necessary to mention the relationship between the anaesthetic technique and the previous administration of APA. Current recommendations have been published in some articles [33 38], which could be summarized as follows. First of all, the scarce data available in the literature suggest that ASA and NSAIDs at regular doses and without the interaction of other anticlotting drugs do not increase the risk of spinal haematoma in patients undergoing a regional anaesthetic analgesic technique, and it could, therefore, be safely performed. But, if a patient is under the effects of ASA, and another anticoagulant drug such as LMWH or unfractionated heparin should be administered in the perioperative period, some guidelines recommend a window in thromboprophylaxis or ASA treatment [35,36] but others disagree [34,37,38]. It is not recommended that regional anaesthetic techniques should be performed in patients under the effects of thienopyridines. These need a window of at least 7 days for clopidogrel and days for ticlopidine. Owing to the limited evidence with these drugs in this setting, perhaps the best recommendation could be to consider them case-by-case. With regard to the GP IIb/IIIa inhibitors, the usual recommendation is to avoid the performance of regional anaesthetic techniques, if a patient is under the effect of any of these drugs. If the performance of a regional anaesthetic technique is highly advisable and the patient is under the effect of an APA, probably the worst option would be to delay surgery. In these circumstances, the anaesthesiologist should evaluate the small risk of developing spinal bleeding and, if necessary, perform the regional technique with the minimum associated bleeding risk: peripheral block is better than spinal puncture and spinal puncture is better than peridural puncture with an indwelling catheter. Management of the antiplatelet agent in cases of urgent surgery In urgent surgery, it is not possible to consider the complete management of APA: maintenance, retirement or substitution. Thus, the key question in this case is the decision on the need to prevent or treat bleeding, and whether the haemorrhagic risk may endanger the vital or functional prognosis of the intervention. The following strategies to decrease the consequences of the haemorrhage could be considered. Pharmacological treatment The administration of desmopressin, in a dose of 0.3 mgkg 1 intravenously over min, has been used to reduce excessive bleeding in patients scheduled for cardiac surgery and having surgery under the effects of ASA. However, consistent beneficial effects of this practice cannot be shown in large studies, and the drug cannot be recommended as an effective haemostatic agent in patients treated with aspirin [39]. The use of recombinant factor VII is controversial and has been included off label in some strategies or protocols to control a lifethreatening haemorrhage. There is not enough evidence

6 186 European Journal of Anaesthesiology 2009, Vol 26 No 3 to support the inclusion of rfviia as a standard recommendation in urgent surgery for patients under the effect of an APA. Platelet transfusion The cause of bleeding in patients on antiplatelet therapy is usually platelet dysfunction, and the logical treatment of choice, therefore, would be platelet transfusion. Urgent transfusion of platelets at a dose of 1 unit per each 5 10 kg of weight can be the only valid alternative for some patients, those who have received inhibitors of GP IIb/IIIa or adjuvant in the remaining cases. Yet, regular prophylactic transfusion of platelets should be discouraged and evaluated carefully on a case-by-case basis, considering the expected benefit gained from it and the possible risks of platelet transfusion. In patients who have received clopidogrel, despite the low immediate haemostatic effect, the preoperative transfusion of platelets could be a good alternative to facilitate postoperative haemostasis, only in those patients undergoing high bleeding risk surgery [18,40]. The dilemma of whether to transfuse platelets prophylactically, that is, before the beginning of clinical bleeding, or only with the aim of treating a clinically significant haemostatic alteration (thus, only when the haemorrhage is not easy to control with surgical measures) depends in most cases on the kind of surgery and the inherent bleeding risk. In any case, the implications of platelet transfusion (or any other haemoderivate) should always be kept in mind. Conclusion Nowadays, there are many drugs that are commonly used that alter haemostasis. Among these drugs, the APAs are the most challenging in the perioperative period. For patients who receive an APA, it is usually advisable to withdraw treatment with these agents between 1 week and 10 days before surgery to decrease perioperative bleeding. The decision to stop the antiplatelet treatment before surgery to avoid bleeding opposes the maintenance of an APA perioperatively to minimize the risk of arterial thrombosis. However, the current recommendation is to maintain ASA if possible throughout the perioperative period, thus risking haemorrhagic complications but limiting the risks of cardiological, vascular or neurological postoperative events. If the thrombotic risk is due to a DES, the challenge is greater and the impact of APA withdrawal is more important. The current trend is to delay all surgery that is not life-threatening, and, if not possible, to give optimal protection to the DES with the maintenance of an APA or running an alternative protocol with anticoagulants and ASA. 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