Background

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the world1. Native coronary disease develops over many years. Different types of plaques are identified, of which the most vulnerable is thin-cap fibroatheroma with the highest potential for rupture, leading to luminal thrombosis. This is the most fearful complication of native coronary disease, leading to acute myocardial infarction. After myocardial revascularization, disease progression is accelerated, causing saphenous vein graft stenosis or stent restenosis within months to years. Similar to native disease plaque rupture is leading mechanism of vein graft or stent thrombosis1. Inhibition of platelets with antiplatelet agents is therefore a cornerstone of disease management in all stages. Main indication for antiplatelet therapy is primary or secondary prevention of ischemic complications in coronary artery disease or cerebrovascular disease. It is also indicated in peripheral arterial disease and in selected patients with atrial fibrillation. Intensity of platelet inhibition, duration of therapy and risks of its discontinuation depend on clinical setting and time from initiating event – acute coronary syndrome (ACS), stable coronary artery disease (SCD), after implantation of drug eluting stents (DES) or bare metal stents (BMS), after coronary artery bypass grafting (CABG), after carotid angioplasty etc. After implantation of coronary stents, the risk of thrombosis is increased until endothelization and strut coverage is complete. 5% to 15% of patients after coronary stent implantation are estimated to undergo a surgical procedure within 2 years2. Perioperatively, inhibition of platelet function could lead to increased bleeding risk. Patients on dual antiplatelet therapy (DAPT), especially those after coronary stent implantation, are particularly challenging for perioperative management. Determination of individual’s bleeding and ischemic risk is crucial to guide handling of drugs in this vulnerable period.

Mechanism of Action of Antiplatelet Drugs

Antiplateled drugs inhibit some of the processes of platelet activation. Aspirin is irreversible inhibitor of COX-1, inhibiting synthesis of TXA2, a potent inducer of platelet aggregation. Some other mechanisms of platelet inhibition, which are dose dependent, are also seen with aspirin3. Aspirin has been the mainstay of antithrombotic therapy for many years and is still the drug of choice for antiplatelet monotherapy. If more intense platelet inhibition is needed, a combination of aspirin with ADP receptor antagonist is prescribed – DAPT. Thienopyridine clopidogrel is a prodrug, which is metabolized into an active substance via liver cytochrome P-450 pathway. It is irreversible P2Y12 receptor antagonist. There is considerable interpatient variability in response to a drug due to genetic variability in CYP450 activity and variability in resorption of the drug3. Prasugrel is another thienopyridine, also a prodrug, which is converted to active drug in a two-step process, involving CYP450. Prasugrel was found to be 10-fold more potent than clopidogrel in inhibiting thrombus formation and increasing bleeding time. This superiority is most likely a consequence of the more extensive and rapid formation of the equipotent active metabolite3. Ireversible inhibitors exert their antiplatelet effect for the lifespan of platelet, which is 7-10 days. Ticagrelor is non- thienopyridine direct and reversible inhibitor of P2Y12 receptor. Ticagrelor acts in a dose-dependent manner with a rapid onset and offset of its antiplatelet effect. There is minimal residual antiplatelet effect 48 h after last dose3. Newer ADP receptor antagonists (prasugrel and ticagrelor) have been shown to have better protecting effects against recurrent ischemic events after ACS than clopidogrel with similar or greater bleeding risk. Cangrelor is intravenous direct acting reversible ADP antagonist with fast onset of action and short half-life. Platelet function recovers within 5 min of infusion discontinuation. Glycoprotein IIb/IIIa inhibitors (tirofiban, abciximab, eptifibatide) inhibit fibrinogen mediated platelet agreggation. Compared to oral drugs, they result in prompt, uniform, and very potent platelet inhibition3. They are mostly used periprocedural at the time of stenting or as a bridging therapy before major surgery in high risk patients after discontinuation of oral drugs.

Perioperative Management of Antiplatelet Drugs

Intense inhibition of platelet activity as is the case with DAPT is not desired in the perioperative period due to impaired haemostasis. On the other hand, indication for DAPT means increased risk of thrombosis, which lasts until endothelization is complete. The risk is even higher in perioperative period due to hypercoagulability and frequent use of prohemostatic blood products in this setting. When dealing with such a patient several questions have to be clarified before surgery:

  • what is risk of thrombosis or ischemia (indication for DAPT, type of stent, time from stent implantation/myocardial infarction, previous recurrent ischemic episodes)
  • what is risk ob bleeding (type of surgery, localization of surgery, other drugs and diseases which increase the risk)
  • what is recommended duration of DAPT
  • what is the risk of discontinuation of DAPT (time from stent implantation, procedural/anatomic factors of stenting, unfavourable clinical conditions – comorbidities etc)
  • what is the risk of delaying the surgery

DAPT is indicated in CAD patients who have undergone stent implantation and those with an acute coronary syndrome (ACS) who are medically treated. Duration of recommended DAPT depends on the type of stent and clinical indication for stent placement. Endothelization is faster after BMS than DES implantation. Early thrombosis is rarely seen 4 weeks after BMS, whereas it is possible more than a year after DES implantation. New generations of DES have substantially reduced rate of thrombosis. Studies comparing shorter (3-6 months) versus longer (12 months) of DAPT after DES in stable CAD have not found any increased risk of stent thrombosis with shorter duration DAPT, but less bleeding complications. In stable CAD, DAPT with clopidogrel and low-dose aspirin should be given for the minimum of 1 month after BMS and 6 months after new generations of DES implantation4,5. Longer duration (18 to 36 months after DES) decrease incidence of late stent thrombosis and ischemic complications of 1% to 2% at the expense of 1% increased bleeding. Prolongation after recommended period may be reasonable in stable patients who have tolerated DAPT without bleeding and who have low bleeding risk. In those with high bleeding risk (including those who undergo major surgery) shortening of DAPT to 3 months after DES may be reasonable. If stenting is performed in ACS setting, duration of DAPT should be at least 1 year, regardless of stent type4,5. Ticagrelor or prasugrel are preferred P2Y12 inhibitors over clopidogrel after ACS, if there are no contraindications. Again, in low risk for bleeding, DAPT can be prolonged after 12 months, in high risk of bleeding, it can be shortened to 6 months. If ACS is managed with medical therapy alone (without stenting), duration of DAPT, preferably with ticagrelor, is also at least 12 months. DAPT with clopidogrel is recommended for at least 1 months after carotid angioplasty with stenting and for 3 months after ischemic stroke with high risk for recurrence10. For primary prevention in CAD, in selected patients with AF and peripheral arterial disease, monotherapy usually with aspirin is sufficient.

Importance of DAPT after recent stent implantation cannot be over-emphasized. Discontinuation of DAPT soon after stent implantation is one of the strongest risk factors for stent thrombosis, with the magnitude of risk and mortality inversely proportional to the timing of occurrence after the procedure4. Importantly, stent thrombosis is a serious complication often presenting with death (mortality varying from 30% to 86%8) or a large nonfatal ST- elevation myocardial infarction2. If discontinuation is temporary and controlled by a physician (for example during noncardiac surgery), the incidence of ischemic complications is not increased6. Non-cardiac surgery (NCS) is frequent indication for DAPT withdrawal. The risk NCS related stent thrombosis decreases significantly with time and is greatest in the first 6 months, irrespective of stent type (BMS/DES)4. Surgery is proinflammatory and prothrombotic state that may increase the risk of coronary thrombosis not only in the stent but also in other parts of the coronary tree. The risk of ischemic complications in patients with stents undergoing surgery is greatest in the first 6 months, and more than a stent type the emergency of operation and severity of underlying cardiac disease are the risk factors for complications7. Therefore, postponing elective surgery after stent placement until the risk of thrombosis declines is reasonable to avoid thrombotic complications. After BMS implantation, noncardiac surgery should be delayed for 1 month and after DES implantation optimally 6 months4. Delaying of emergent surgery after DES can be shortened to 3 months if needed. If the course of DAPT is not completed at the time of surgery, discontinuation of antiplatelet drugs has to be considered. The decision should be guided by the bleeding risk of surgery. Preoperative discontinuation of DAPT is needed only in surgery with high bleeding risk. Preferably only P2Y12 inhibitor is omitted and aspirin is continued, except for the highest risk surgery, such as intracranial and medullary canal neurosurgery, posterior chamber eye surgery and transurethral prostate surgery4,8. Another option is to consider if surgery can be performed in less invasive manner with less tendency for bleeding. To recover full platelet activity, aspirin should be discontinued 7-10 days before surgery, clopidogrel 5 days, prasugrel 7 days and ticagrelor 3-5 days before surgery8,9. In patients at very high risk for thrombosis, bridging with short-acting intravenous drugs (cangrelor, GP IIb/IIIa inhibitors) while off P2Y12 drug is possible, as no increase in thrombotic or haemorrhagic events with this strategy has been reported8. After the operation, the P2Y12 inhibitor should be restarted as soon as possible to complete recommended period of DAPT. Optimal timing of surgery after discontinuation of DAPT can be guided by the platelet function tests which monitor recovery of platelet function and have been shown to reduce the waiting time for cardiac surgery and bleeding after clopidogrel discontinuation2,9. If patient is on antiplatelet monotherapy for primary prevention or AF, it can usually be safely withdrawn.

The main issues in patients on antiplatelet therapy before major surgery are therefore:

  1. to continue DAPT or not
  2. to discontinue only P2Y12 inhibitor or aspirin as well
  3. to postpone surgery until the course of DAPT is completed or not

Because perioperative management of patients with coronary stents is so complex, some issues have to be considered in advance when preparing patient with CAD for surgery. First, unnecessary (prophylactic) preoperative coronary interventions have to be avoided. Also, type of intervention (PCI, stenting, type of stent) has to be adjusted if necessary. For a long period of time, BMS have been considered safer than DES and recommendations were to avoid DES placement in favour of BMS in patients anticipated to require NCS11. The new generations of DES are safer with very low risk of thrombosis. Non-cardiac surgery within the first year after implanatation of these stents has been shown to has lower risk of cardiovascular events opposed to a BMS. The risk of DES fell remarkably after 90 days, while the higher risk ascribed to the BMS persisted throughout the time of analysis 11, 12.

Conclusion

Patient on antiplatelet therapy is challenging for perioperative management due to very fine balance between risk of ischemia and risk of bleeding. Careful evaluation of individual patient-related and surgery-related factors to guide handling of antiplateled agents has to be performed before surgery. There are no uniform guidelines to fit all patients. Decision should be made interdisciplinary with involvement of cardiologist, anesthesiologist and surgeon. New generations of DES stents appear to be safe even in perioperative period, the recommended duration of DAPT is shorter than previously stated. In selected patients and with proper management surgery can be performed as short as 3-6 months after implantation.

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