Clopidogrel

[This monograph covers clopidogrel as a single antiplatelet, for patients taking Aspirin and Clopidogrel - see Dual Antiplatelet Therapy (DAPT) monograph]

  Issues for Surgery

Risk of major adverse cardiovascular events (MACE) if omitted.

Risk of bleeding and/or complications of bleeding if continued.

Risk of epidural or spinal haematoma if continued prior to neuraxial anaesthesia.

  Advice in the Perioperative period

Elective Surgery

Cardiac Surgery

Multi-disciplinary Team to evaluate if benefit outweighs risk of bleeding and decide if aspirin should be continued or stopped pre-operatively.

Non-cardiac Surgery
For minor surgery with low bleeding risk: consider continuing clopidogrel pre-operatively.

For other procedures: -

• stop clopidogrel 7 days preoperatively¹
• for those patients who have high risk of thrombosis but clopidogrel cannot be continued pre-operatively:
  • consider shortening stopping time to 5 days
  • consider switching to aspirin 75mg daily for 7 days pre-operatively

Emergency Surgery

If patient has taken any doses of clopidogrel in previous 7 days avoid neuraxial (spinal/epidural) anaesthesia and take every precaution to secure haemostasis.

Patient Undergoing Surgery Associated with Unacceptably High Risk of Bleeding

• consider withholding clopidogrel and delaying surgery for 3 days to allow partial restoration of platelet function (see Further Information).
• if this is not possible consider platelet transfusion to indirectly reverse the effects of clopidogrel by increasing the total circulating pool of platelets

Perioperative Considerations

Neuraxial (Spinal/Epidural) Anaesthesia or Lumbar Punctures
There have been reports of spinal epidural haematoma following neuraxial blockade in patients receiving clopidogrel; it is recommended that neuraxial anaesthesia is not performed until at least 7 days after the last dose of clopidogrel² – see figure 1.

Figure 1: advice on timings of clopidogrel in relation to regional anaesthesia and removal of an indwelling catheter²

  Interaction(s) with Common Anaesthetic Agents

None^{3, 4}.

  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 clopidogrel³; consider gastroprotection if other risk factors for gastrointestinal bleeding are present (but see Proton Pump Inhibitors (PPIs) below)⁴. 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 clopidogrel, particularly for ACS or coronary stent implantation⁴.

Low Molecular Weight Heparin (LMWH) / Unfractionated Heparin (UFH)

LMWHs and UFH are predicted to increase the risk of bleeding events when given with clopidogrel; manufacturer advises use with caution³.

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 efficacy⁵.

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 alternatives⁵.

Antimicrobials

Erythromycin might reduce the antiplatelet effect of clopidogrel although the clinical relevance of the reduction is uncertain and an interaction is not yet established⁴.

Morphine

Morphine delays the absorption of clopidogrel 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 clopidogrel would seem appropriate or necessary⁴.

  Further Information

Mode of Action

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 turnover¹. After 3 days 40% of platelet function will be restored⁶.

Risk of Major Adverse Cardiovascular Events (MACE)

A retrospective review found an increased incidence of death and acute myocardial infarction in the 90 days after discontinuation of clopidogrel; this raises the possibility of a rebound increase in platelet activity after discontinuation of clopidogrel⁶. It is possible that the risk of discontinuation is further increased in the perioperative period as surgery promotes an inflammatory state that increases platelet reactivity⁷.

Risk of Bleeding

Perioperative continuation of clopidogrel has been associated with an increased need for surgical re-exploration for bleeding and use of blood products after cardiac surgery⁶. In abdominal surgery clopidogrel significantly increases post-intervention bleeding risk but this doesn’t seem to be associated with an increased mortality due to haemorrhage or need for re-intervention⁸. Furthermore, perioperative clopidogrel does not seem to be associated with a significant increase in mortality or morbidity in patients with femoral fractures⁸.

  References

1. Summary of Product Characteristics – Plavix^® (clopidogrel). SANOFI. Accessed via www.medicines.org.uk 18/08/2019 [date of revision of the text October 2018]
2. 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
3. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 18^th August 2019]
4. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 18^th August 2019]
5. 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 22^nd July 2019.
6. Hall R & Mazer CD. Antiplatelet Drugs: A Review of Their Pharmacology and Management in the Perioperative Period. Anesth Analg. 2011; 112: 292-318
7. Gerstein N, Schulman P, Gerstein W et al. Should more patients continue aspirin therapy perioperatively? Clinical impact of aspirin withdrawal syndrome. Annals of Surgery. 2012: 255(5):811–819.
8. 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