Dual Antiplatelet Therapy


 

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


Elective Surgery

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.

Assess1: -

  • the risk of stent thrombosis (especially if DAPT needs to be interrupted)
  • the consequences of delaying the surgical procedure
  • the increased intra- and peri- procedural bleeding risk, and possible consequences of this bleeding if DAPT is continued (see Further Information)

Consider delaying elective non-cardiac surgery until the full course of DAPT is complete1.

If this is not possible: -

  • For low bleeding risk surgery consider continuing DAPT2
  • For moderate bleeding risk surgery where it is not possible to perform the operation on DAPT consider stopping the P2Y12 inhibitor as detailed below:
    • Clopidogrel – at least 5 days1 (7 days if neuraxial anaesthesia planned3)
    • Prasugrel – 7 days1
    • Ticagrelor – at least 3 days1 (5 days if neuraxial anaesthesia planned3)
  • Continue aspirin (unless multidisciplinary team determine surgery is associated with an extremely high bleeding risk, e.g. intracranial procedures) as benefit of continuing outweighs bleeding risk in most clinical situations1, 2
  • In situations where the multidisciplinary team determine both aspirin and the P2Y12 inhibitor must be stopped pre-operatively consider bridging with intravenous glycoprotein IIb/IIIa inhibitor1, 2(see Further Information).

Emergency Surgery

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.

Perioperative Considerations

Neuraxial (Spinal/Epidural) Anaesthesia or Lumbar Punctures
Neuraxial anaesthesia can safely be performed in a patient taking aspirin as monotherapy; however, DAPT is a contraindication to neuraxial anaesthesia3.

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

Post-operative Advice

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


None4, 5.


  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.

Antimicrobials

Clopidogrel
Erythromycin might reduce the antiplatelet effect of clopidogrel although the clinical relevance of the reduction is uncertain and an interaction is not yet established5.

Ticagrelor
Clarithromycin (an inhibitor of CYP3A4) is predicted to markedly increase ticagrelor exposure4, 5; manufacturer advises the combination is contraindicated4.

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

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.


  Further Information


Duration of Antiplatelet Effect and Risk of Bleeding

Bleeding risk with DAPT may be 3.4 times higher than patients taking aspirin alone2.

Aspirin
Aspirin exerts its antiplatelet effect by inhibiting cyclooxygenase (COX) thus preventing prostaglandin-mediated production of thromboxane A2 that is responsible for platelet activation and aggregation. The irreversible inhibition of COX means the pharmacological effects persist until platelets are regenerated7.

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.

Clopidogrel
Clopidogrel is a prodrug, which when metabolised produces an active metabolite that inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor, thus inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed to clopidogrel are affected for the remainder of their 7-10 day lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover7, 9. After 3 days 40% of platelet function will be restored. If its antiplatelet action is not desired the manufacturers advise clopidogrel should be stopped 7 days pre-operatively2, 4, 9, although it may be sufficient to stop 5 days before surgery1.

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.

Ticagrelor
Ticagrelor inhibits P2Y12 through a reversible binding action. If its antiplatelet action is not desired the manufacturers advise ticagrelor should be stopped 5 days pre-operatively2, 4, 10, although it may be sufficient to stop 3 days1. After 24 hours 57% of platelet function should be restored7.

Prasugrel
Prasugrel has a higher antiplatelet effect and has been associated with an increased risk of bleeding compared to clopidogrel2. If its antiplatelet action is not desired the manufacturers advise prasugrel should be stopped 7 days pre-operatively2, 4, 11.

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.

Thrombotic Risk

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.


Bleeding Risk

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.

‘Bridging’ 

UFH/LMWH
Use of UFH or LMWH to ‘bridge’ discontinuation of antiplatelets is NOT recommended, as it might be associated with increased bleeding risk, without conferring an anti-ischaemic protective effect2.

Glycoprotein IIb/IIIa Inhibitors
For patients who have a high risk of stent thrombosis and perioperative discontinuation of DAPT is required because of an unacceptably high bleeding risk, use of ‘bridge’ therapy with off-label use of tirofiban (or eptifibatide) should be considered1, 2. Clopidogrel / ticagrelor should be stopped 5 days before surgery, 7 days if prasugrel, and tirofiban (or eptifibatide) – consult product literature for dose (reduce by 50% if renal impairment or increased pre- or post-surgery bleeding risk) – should be commenced 3 days before surgery and continued until 4 hours before surgery (8 hours if renal impairment). This should be prescribed by a cardiologist and administered on a cardiology ward. P2Y12 inhibitors should be restarted 24-48 hours post-operatively with a loading dose (consult product literature). In abdominal surgery, if gastrointestinal function has not recovered the tirofiban (or eptifibatide) infusion can be restarted (with a loading dose) a few hours post-operatively and continued until oral treatment can be resumed2.

 

  References


  1. The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Sirgery (EACTS). 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. European Heart Journal. 2018; 39:213-254
  2. Rossini R, Musumeci G, Visconti LO et al. Perioperative management of antiplatelet therapy in patients with coronary stents undergoing cardiac and non-cardiac surgery: a consensus document from the Italian cardiological, surgical and anaesthesiological societies. EuroIntervention. 2014; 10:38-46
  3. Gogarten W, Vandermeulen R, Van Aken H et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010; 27:999–1015
  4. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 18th August 2019]
  5. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 18th March 2019]
  6. UKMI Medicines Q&A. Do proton pump inhibitors reduce the clinical efficacy of clopidogrel? Accessed via www.sps.nhs.uk 13/09/2019. Date prepared 22nd July 2019.
  7. Hall R & Mazer CD. Antiplatelet Drugs: A Review of Their Pharmacology and Management in the Perioperative Period. Anesth Analg. 2011; 112:292-318
  8. Biondi-Zoccai G, Lotrionte M, Agostoni P et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. European Heart Journal. 2006: 27(22):2667–2674 
  9. Summary of Product Characteristics – Plavix® (clopidogrel). SANOFI. Accessed via www.medicines.org.uk 18/08/2019 [date of revision of the text October 2018]
  10. Summary of Product Characteristics – Brilique® (ticagrelor) 90mg film coated tablets. AstraZeneca UK Limited. Accessed via www.medicines.org.uk 18/08/2019 [date of revision of the text June 2019]
  11. Summary of Product Characteristics – Efient® (prasugrel) 10mg film-coated tablets. Daiichi Sanyko UK Limited. Accessed via www.medicines.org.uk 18/08/2019 [date of revision of the text January 2019]