Abstract
Introduction
Patients undergoing surgical procedures while being treated with antiplatelet agents are at increased risk of bleeding. This has implications for both the anaesthetist, affecting their choice of anaesthesia, and the surgeon. The increased risk of bleeding is well recognized but consideration must also be given to the potential adverse effects of antiplatelet cessation in patients at high risk of arterial occlusion especially in the cerebral and cardiac vasculature. A number of factors need to be considered when balancing the risk of increased bleeding against the risk of thrombosis following cessation of antiplatelet drugs.
Indications for clopidogrel
Antiplatelet agents are vital for both primary and secondary prevention of cardiovascular disease. There exists significant evidence to support their use in the reduction of vascular events in the peripheral, cerebral and cardiac vascular systems. Aspirin remains a first line agent but there exists evidence to support combination therapy with other agents such as clopidogrel and dipyridamole. Clopidogrel (Plavix) is a platelet ADP receptor antagonist licensed for use in patients with symptomatic ischaemic heart disease (IHD). It is used in combination with aspirin for acute coronary syndrome (ACS) without ST segment elevation as well as acute myocardial infarction with ST segment elevation. In addition, NICE Guidelines recommend clopidogrel monotherapy as an alternative to low dose aspirin in patients intolerant of aspirin with symptomatic peripheral arterial disease or having had an occlusive arterial event.
Percutaneous coronary intervention (PCI) is frequently associated with the insertion of a coronary stent. The use of coronary artery stents is seen in up to 90% of PCIs and these stents may reduce re-infarctions in ACS. However, the benefits in patients with stable coronary artery may not be as great as initially perceived. The success of these stents is dependent on the use of dual antiplatelet therapy. Ironically, stent implantation is thrombogenic via activation of platelets and the clotting cascade. Long-term durability is threatened by neointimal hyperplasia resulting in restenosis. 1 Stents can be classified as bare-metal stents (BMS) or drug-eluting stents (DES). The latter were developed to reduce the incidence of restenosis and have been show to reduce this phenomenon from as high as 30% with BMS to between 5–10% with DES (although this has not translated into a reduction in mortality). 2 Stent thrombosis may be classified as early (within 30 days) or late. While re-stenosis as a result of neointimal hyperplasia has been reduced by the increasing use of DES, late stent thrombosis is more commonly seen with DES while the incidence with BMS remains low. It is for this reason that dual antiplatelet therapy is recommended following insertion of coronary stents.
The benefits of dual therapy (aspirin and clopidogrel) in the context of IHD have been investigated by numerous trials. In the context of ACS benefits were shown with combination therapy by the CURE study. 3 In addition, clopidogrel has been shown to be beneficial post MI by the CLARITY-TIMI28 trial and the COMMIT study. 4,5 The CAPRIE trial compared the effects clopidogrel to aspirin on secondary prevention. The risk of myocardial infarction stroke and vascular death were significantly reduced by clopidogrel (relative risk reduction of 8.7% and absolute risk reduction of 0.5 %). 6 The CREDO trial, PCI-CLARITY study and PCI-CURE study all support the use clopidogrel in patients undergoing PCI. 7–9 Although The CHARISMA study did not show any difference in patients treated with combinaton clopidogrel and aspirin compared to placebo and aspirin, on subsequent analysis a symptomatic subgroup of the 15,603 patients did appear to derive benefit. 10 This group included patients with a prior history of MI, ischaemic stroke or symptomatic PAD. 11
Guidelines from the American college of Cardiology and American Heart Association recommend treatment with aspirin and clopidogrel for at least one month after implantation of BMS. The duration of dual therapy for DES has now been extended to 12 months with the increasing use of DES in more complex and high-risk lesions. 12 Similar guidelines have been released by the European Society of Cardiology with the recommendation of lifelong aspirin for BMS. 13
When should antiplatelet agents be stopped?
Although there is a lack of large randomized controlled trials to accurately assess the risk of perioperative cardiac complications following the cessation of antiplatelet therapy, the benefits of aspirin, clopidogel and dual antiplatelet therapy have been well documented. 14–16
The traditional practice of stopping antiplatelet agents 9–10 days prior to surgery predisposes the patient to perioperative cardiac complications. In the context of secondary prevention, i.e. post ACS, MI coronary artery stents, CVA and PAD, aspirin should be continued for most surgical procedures with the exemption of neurosurgical procedures in closed spaces such as intracranial surgery. 17 Similarly ophthalmic procedures, especially in the posterior chamber of the eye, should be considered as for ‘closed space’ neurosurgical procedures. In the latter aspirin has been associated with increased bleeding and even increased mortality. 18 Hence common sense would dictate that clopidogrel should also be stopped. If a patient has undergone prior coronary artery stenting then elective procedures should be delayed until it is safe to discontinue clopidogrel which may be a period of 4–6 weeks following PCI with or without BMS. In the case of DES a delay of up to 12 months may be needed. 19 In certain circumstances such a delay is not possible, for example emergency surgery and cancer surgery. In these situations the risk of bleeding needs to be balanced against the risk of cardiac complications. In the context of emergency surgery the risk of bleeding needs to be accepted and surgery performed. Cessation of clopidogrel or aspirin 24 hours prior to surgery is unlikely to provide any benefit. Both of these agents irreversibly inhibit platelet aggregation. The half-life of clopidogrel is about 4 hours. Like aspirin, the effect of clopidogrel is only reversed by the generation of new platelets and hence it is recommended that clopidogrel be stopped at least 3 days prior to surgery. For a more complete recovery of platelet activity and normalization of bleeding time, a longer period of up to 7 days may be required and should be considered in surgical procedures requiring spinal or epidural anaesthesia. Hence surgery that cannot be delayed for a prolonged period of time may have the bleeding risk reduced by a short delay.
In situations where both surgery and PCI are planned the use of BMS may be preferred over DES with a shorter period of dual antiplatelet therapy required. Following ACS a delay of 4–6 weeks is also required during which time the antiplatelet therapy should be continued.
Strategies to reduce thrombosis when surgery cannot be delayed for a prolonged period include discontinuing clopidogrel before surgery and re-starting the agent postoperatively. Consideration may be given to using an anticoagulant or short acting antiplatelet agent. Even in this situation heparin would be stopped prior to surgery during which the patient is at the greatest risk of developing a thrombosis in a pre-existing stent or unstable plaque. During neurosurgical procedures, stopping and re-starting clopidogrel may be the only option excepting the risk of stent thrombosis. 19
Such decisions should only be made in consultation with cardiologists and the surgery performed in centres with facilities to perform interventional cardiology, PCI being required as a rescue procedure to treat stent thrombosis.
The risk of stopping antiplatelet agents
Surgery on patients taking clopidogrel is associated with an increased bleeding risk. 20 This is known to increase the blood transfusion requirement and need for operative re-intervention but with the exception of neurosurgery has not been shown to increase operative mortality. 21–23 This risk has to be balanced against that of stopping the antiplatelet agents and hence exposing the patient to an increased risk of arterial occlusion. The risk will vary dependent on the type of surgery, underlying pathology and clinical indication for antiplatelet therapy.
The cessation of antiplatelet agents may be associated with a rebound effect. Excess thromboxane A2 production has been documented with aspirin cessation resulting in increased platelet aggregation. 24 In addition, surgical trauma stimulates a systemic inflammatory response resulting in increased platelet aggregation. The magnitude of this effect will vary according to the surgical procedure. Increased platelet sensitivity is recognized with various pathologies including diabetes, carcinoma, sepsis and inflammation. Any such co-morbidity has to be considered when deciding to withdraw antiplatelet therapy in patients with a history of IHD.
The risk of infarction and death is doubled following cessation of antiplatelet therapy in ACS. 25 Early surgery following the insertion of a coronary stent significantly increases the risk if perioperative MI. 26 This is the result of a fresh thrombogenic surface which may take several weeks to endothelialize. In the case of certain DES the duration may be even longer and hence the recommendation for twelve months of continous antiplatelet therapy. Major surgery carries a significant risk of mortality, upto 86%, if performed within three weeks of PCI or stenting and clopidogrel is withheld. 27 The effect of antiplatelet cessation on stent complications is exemplified by the BASKET trial where the death and MI rate was doubled in patients with DES compared to BMS. 28
Even in the context of secondary prevention a meta-analysis involving in excess of 50,000 patients by Biodi-Zoccal et al. has shown that cessation of aspirin is associated with a three-fold increase of cardiac risk. 29
The CURE trial demonstrated a significantly increased risk of major bleeding with clopidogrel compared to placebo with a relative risk of 1.38, 3 However as previously mentioned consideration must be given to the thrombosis risk. In unstable angina clopidogrel reduces the risk of MI by 18%.
Summary
The decision to stop antiplatelet drugs should be made only when the clinical indication for the drug is fully known. If this is for coronary stents then a knowledge of the type of stent and time of insertion is essential. With the exception of certain neurological and ophthalmological procedures aspirin can usually be continued with strict attention applied to haemostatic techniques. The same applies when clopidogrel is continued. When the risk of bleeding is greater than that of thrombosis then clopidgrel may need to be stopped but in high-risk patients this should be done following consultation with a cardiologist and the surgery performed in a centre with facilities for interventional cardiology so that rescue PCI can be performed in the event of life-threatening thrombosis. There is a lack of trials to assess the risk of antiplatelet cessation in patients undergoing surgery but the benefits of continued antiplatelet therapy are more likely to outweigh the risk of increased bleeding for many surgical procedures.