Aspirin and P2Y12 inhibitors: Aspirin and Clopidogrel, Prasugrel or Ticagrelor
Issues for Surgery
Risk of major adverse cardiovascular events (MACE) if either or both antiplatelet agents is/are omitted.
Risk of bleeding and/or complications of bleeding if either or both antiplatelet agents is/are continued.
Risk of epidural or spinal haematoma if clopidogrel, prasugrel or ticagrelor continued prior to neuraxial anaesthesia.
Advice in the Perioperative period
A multidisciplinary discussion involving anaesthetists, cardiologists, haematologists and surgeons is needed to assess the patient’s risk of bleeding and thrombosis and determine the best management strategy1.
Consider delaying elective non-cardiac surgery until the full course of DAPT is complete1.
If this is not possible: -
Follow principles outlined under Elective Surgery; consider delaying to allow stopping of the P2Y12 inhibitor as detailed above. If stent insertion was in the last month consider delaying surgery for at least 1 month following stent insertion1.
If it is not possible to delay surgery to allow stopping of P2Y12 inhibitor avoid neuraxial (spinal/epidural) anaesthesia3 and take every precaution to secure haemostasis.
Neuraxial (Spinal/Epidural) Anaesthesia or Lumbar Punctures
If P2Y12 inhibitors cannot be discontinued for the time indicated in figure 1 (below) general anaesthesia is advisable2.
Figure 1: advice on timings of antiplatelet doses in relation to regional anaesthesia and removal of an indwelling catheter3
Continue aspirin post-operatively (in the rare situations where aspirin is stopped pre-operatively, restart post-operatively as soon as is clinically possible).
If stopped pre-operatively, restart P2Y12 inhibitors post-operatively as soon as possible (within 48 hours) – but a minimum of 6 hours after regional block performance or removal of indwelling catheter) see Perioperative Considerations above – given the substantial thrombotic risk associated with lack of platelet inhibition in the early post-operative period1. In the case of elective surgery, the multidisciplinary team should determine when P2Y12 inhibitors are to be restarted as part of the pre-operative discussions1.
If ‘bridged’ with an intravenous Glycoprotein IIb/IIIa inhibitor the P2Y12 inhibitor should be restarted 24-48 hours post-operatively with a loading dose (consult product literature)2. See Further Information.
Interaction(s) with Common Anaesthetic Agents
Interaction(s) with other Common Medicines used in the Perioperative Period
Non-Steroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs may have an additive effect on the risk of bleeding (including gastrointestinal bleeding) when given with antiplatelet drugs4; consider gastroprotection if other risk factors for gastrointestinal bleeding are present (but see Proton Pump Inhibitors (PPIs) below)5. A review by the European Medicines Agency identified a small increased risk of arterial thrombotic events with diclofenac, also, the European Society of Cardiology guidelines on acute coronary syndrome (ACS) recommend avoiding non-selective NSAIDs; therefore, the need for any NSAID should be carefully considered in patients taking antiplatelet drugs, particularly for ACS or coronary stent implantation5.
Low Molecular Weight Heparin (LMWH) / Unfractionated Heparin (UFH)
LMWHs and UFH are predicted to increase the risk of bleeding events when given with antiplatelet drugs; manufacturer advises use with caution4.
Proton Pump Inhibitors (PPIs)
Clopidogrel is converted to its active metabolite by CYP2C19 and CYP3A4. All PPIs inhibit these isoenzymes to different extents and therefore could affect the clinical efficacy of clopidogrel; however, this has not yet been studied in randomised clinical trials. Treatment decisions in individual patients must balance the risks of cardiovascular and gastrointestinal complications; sometimes the benefits of a PPI may outweigh the risk of reduced clopidogrel efficacy6.
The FDA, MHRA and EMA discourage use of omeprazole and esomeprazole in patients taking clopidogrel. Based on data from pharmacokinetics studies, pharmacodynamic studies and secondary analyses of clinical trials pantoprazole is the least likely to interact and lansoprazole and rabeprazole are also suitable alternatives6.
Morphine delays the absorption of P2Y12 inhibitors sometimes resulting in modest decreases in exposure and/or plasma concentrations. Delayed absorption is generally only important if a rapid onset of action is necessary or desirable e.g. when used acutely. Although some reduced pharmacodynamic effects were seen in some of the studies, these effects do not necessarily translate into clinical effects. No modification to standard practice regarding use of morphine in patients receiving P2Y12 inhibitors would seem appropriate or necessary5.
Duration of Antiplatelet Effect and Risk of Bleeding
Bleeding risk with DAPT may be 3.4 times higher than patients taking aspirin alone2.
Non-adherence or withdrawal of aspirin in non-surgical patients is associated with an 89-fold increased incidence of MACE in patients with coronary artery stents8. This increased incidence is thought to be due to rebound increases in thromboxane A2 activity leading to increased platelet aggregation. Due to this significantly increased risk of MACE, aspirin should be continued pre-operatively if at all possible, in patients with coronary artery stents.
An increased risk of haemorrhage has been noted in patients on clopidogrel undergoing Coronary Artery Bypass Grafting (CABG); it is recommended that clopidogrel is stopped 5 days before CABG unless the patient is deemed to have a high cardiac risk and has complex coronary anatomy2. Clopidogrel increases post-intervention bleeding risk, but not mortality due to haemorrhage or need for re-intervention, in abdominal surgery. No significant increase in mortality or morbidity has been noted in patients with femoral fractures2.
Urgency of Surgery
Surgery can result in inflammatory, hypercoaguable and hypoxic states which are associated with plaque instability and perioperative arterial thrombosis2. This increases the risk of coronary thrombosis both at the stent and throughout the coronary vasculature. In patients undergoing surgery after recent Acute Coronary Syndrome (ACS) or stent insertion the benefits of early surgery, for malignant tumours or vascular aneurysm repair, should be balanced against the risk of MACE1.
The type of implanted stent, the time interval between percutaneous coronary intervention (PCI) and proposed surgery and the angiographic features of the coronary lesions can be used to stratify the risk of stent thrombosis2 (see figure 2). In addition, patients having PCI following ACS or patients with previous stent thrombosis, ejection fraction <35%, diabetes mellitus or chronic renal failure are at increased thrombotic risk2.
Figure 2: Classification of thrombotic risk2
Newer DES might be associated with a lower risk of stent thrombosis risk and therefore require a shorter minimum duration of DAPT1, 2.
In very urgent cases where prolonged delays are not appropriate surgery can be performed 1 month after stent insertion, regardless of the type of stent1. However; in patients at high ischaemic risk due to ACS presentation or complex coronary revascularisation procedure it may be reasonable to delay surgery until 6 months post-event to minimise the risk of MACE1.
The multidisciplinary team may find the practical classification of the bleeding risk associated with each type of surgery and the recommended management proposed by Rossini et al. useful in facilitating their decision making2.
Glycoprotein IIb/IIIa Inhibitors