Patients who have undergone percutaneous coronary intervention (PCI) carry a considerable risk of morbidity and mortality while undergoing non-cardiac surgery (NCS). Following bare-metal stenting (BMS), mortality is reduced if the NCS is performed after a period of six weeks.1–3 Patients who have received drug-eluting stents (DES) pose a greater challenge. The period of dual antiplatelet therapy (i.e. aspirin and clopidogrel) following DES is long. While the recommended duration of therapy is four weeks for BMS, it is three months for a Cypher® stent and six months for a Taxus® stent.
Recently, there have been reports of late and very late stent thrombosis attributed to late healing and delayed endothelialisation of the DES.4,5 The DES came with a promise of preventing re-stenosis. This promise has been faithfully kept; however, it has come with the deadly price of delayed healing. The very antiproliferative drugs used to prevent re-stenosis to minimise neointimal growth has been found to be responsible for the lack of formation of neointima on the surface of the DES. The polymer coating used for the drug release causes an inflammatory reaction, creating a nidus for thrombus formation. Whether such a pathological process will persist forever and become a continuous hazard has yet to be proved.
Stent thrombosis is a very serious complication, with mortality rates of over 60%. Survivors are left with non-fatal myocardial infarction. In view of such reports of late thrombosis, the optimum duration of dual antiplatelet therapy may be much longer than hitherto advised. Though no uniformity exists in the interventional cardiology community on this issue, the consensus seems to be to continue aspirin and clopidogrel for a minimum period of one year. This could extend life in some patients. NCS with dual antiplatelet therapy could carry a risk of excessive bleeding during surgery. However, discontinuation of the antiplatelet agents poses a risk of stent thrombosis, particularly in those who have not completed the course of aspirin and clopidogrel therapy.3 The benefit of DES is lost due to a higher incidence of late stent thrombosis after discontinuation of clopidogrel therapy.6
Currently, we do not know the optimum duration or have tools to diagnose whether the stent has been endothelialised. The surgical procedure sets in motion a pro-coagulative state due to sympathetic stimulation that releases epinephrine, rennin and cortisol. Pro-coagulative factors increase while fibrinolysis is inhibited. It is an ideal milieu for thrombus formation.
Several million DES have been implanted in patients with coronary artery disease. Patients usually belong to an age group that is very likely to undergo NCS. This may be abdominal, vascular or thoracic surgery, dental extraction or removal of a malignancy, etc. In view of the fact that the DES have been on the horizon for only about five years, and that the menace of late thrombosis has been recognised only in the last couple of years, there is a paucity of literature and data regarding the safety of continuing or discontinuing aspirin and clopidogrel before NCS. There are no clear-cut data as to when it is safe to perform NCS on a patient with a DES.
When Is it Safe to Perform Non-cardiac Surgery?
Currently, the answer to this question is based on the pathological data and common sense derived from randomised controlled trials of DES versus BMS regarding timing and incidence of stent thrombosis. One must look at the time course of stent thrombosis. In a follow-up of patients for three years after Taxus stent implantation, Ellis et al.7 reported cumulative stent thrombosis of 1.28% in Taxus stents versus 0.76% in BMS (p=0.26) at three years. Up to six months after implantation, the hazard ratios were similar in both the DES and BMS groups. However, between six months and three years there were more cases of stent thrombosis in the Taxus group. It is interesting to note that clopidogrel treatment was recommended in these patients for up to six months after implantation. Thus, discontinuation of clopidogrel exposes them to the risk of stent thrombosis. After two years there were no cases of stent thrombosis in the Taxus group.
Applying the new Academic Research Consortium (ARC) classification, Mauri et al.5 found no significantly increased incidence of definite or probable stent thrombosis in the DES group compared with the BMS group between one and four years after stent implantation. Very late events (beyond 360 days) were observed in a higher number of patients with DES than with BMS. Similar concerns about late events due to very late thrombosis in patients with DES rather than BMS have been documented in other studies.4,6 Thus, there seems to be no difference in events up to six months, i.e. the period during which clopidogrel therapy is given. However, the difference emerges after six months and beyond when clopidogrel is discontinued, and the event rate is twice as frequent after DES compared with BMS (2.6 versus 1.3%).
Bearing in mind these data, it is apparent that patients with DES will be on dual antiplatelet therapy for quite a long time, possibly more than two years. Discontinuation may expose them to the risk of stent thrombosis in a pro-coagulative cascade. There seems to be no thrombosis-free period for at least four years.
Compton and associates8 examined the records of 38 patients with DES who underwent 41 major and 18 minor NCS. Major surgery was performed within a median of 260 days, whereas minor surgery was performed within a median of 297 days. In the major surgical group, four were performed within four days and 11 within 30–180 days. Aspirin and clopidogrel were continued in 78 and 41% of patients, respectively, during the peri-operative period. There were no major adverse cardiac events (MACEs) or deaths during or after major or minor NCS. No patients in the minor surgery group needed blood transfusion, and only two needed the procedure in the major surgery group. Although the number of patients was small, the study does indicate that if not both then at least one of the antiplatelets can be safely continued during the peri-operative period without much concern for excessive bleeding.
In another study, Schouten et al.9 analysed the records of 192 patients who underwent NCS after DES or BMS. They did not find a difference in the incidence of MACE between patients with BMS and DES. However, discontinuation of dual antiplatelet therapy was associated with serious MACE. Patients in whom antiplatelet therapy was stopped before the recommended period had a MACE incidence of 30.7 versus 0% in patients who continued antiplatelet therapy. Excessive blood loss was recorded in two patients, with one receiving antiplatelet therapy. Blood transfusion was required in 44 patients. Twenty-four per cent of these patients were on antiplatelet therapy and 20% were those who discontinued antiplatelet therapy. Premature discontinuation of antiplatelet therapy could lead to lethal complications such as late stent thrombosis.10
Patients who have a non-cardiac surgical condition need not have a prophylactic revascularisation (coronary artery bypass graft [CABG] or PCI) procedure. MACE rates in those who undergo the prophylactic revascularisation procedure compared with those who do not is not significantly different. In the DECREASE trial, 49 patients were assigned to revascularisation (CABG or PCI) and 52 to no revascularisation before a major vascular surgery. The one-year event rates were 49 and 44%, respectively.11
From the scant data available, one can derive the following conclusions. Before PCI, if a patient is found to be in need of an NCS, the patient should receive BMS. Surgery should be postponed for at least six weeks to allow the BMS to become endothelialised. Where the patient is stable from the point of view of myocardial ischaemia, it is safe to go ahead and perform NCS. Prophylactic routine revascularisation is not indicated until and unless the clinical situation demands so. Should an emergency surgery need arise before this period, it is advisable to continue dual antiplatelet therapy. Where the patient has already received a DES, any planned surgery should be postponed for at least one year (preferably two years). Continuing dual antiplatelet therapy does not seem to have an adverse effect on the outcome of NCS or the need for transfusions.If the need arises, surgery can be performed even earlier under cover of aspirin and clopidogrel. Under no circumstances should patients be left without the cover of antiplatelet therapy.
Patients with complex coronary artery disease such as bifurcation lesions, multivessel diabetes or long lesions requiring overlapping stents who need NCS may in the near future be given the option of CABG surgery, as such complex lesions are determinants of DES thrombosis. Data are lacking regarding excessive adverse events with DES in such complex lesions and NCS.
There have been some unpublished and ‘off-label’ approaches vaguely mentioned by interventional cardiology groups. One of them is to discontinue aspirin and clopidogrel five to seven days before NCS and administer low-molecular-weight heparin (LMWH) during this ‘off’ period. Another is to discontinue LMWH 12 hours before NCS and then re-start dual antiplatelet therapy after 24 hours or so. However, the risk of suffering an event has been reported to be more than two-fold despite heparin therapy if dual antiplatelet therapy is discontinued.3 Another strategy that is being discussed is to give eptifabatide or aggrastat to the patient after discontinuing aspirin and clopidogrel. However, both of these strategies need sound scientific evidence before being put into clinical practice.