ACE inhibitors (ACEi) and Angiotensin II Receptor Antagonists (AIIRA) / Angiotensin Receptor Blockers (ARB)


ACEi: Captopril, Enalapril, Fosinopril, Imidapril, Lisinopril, Perindopril, Quinapril, Ramipril, Trandolapril 

AIIRA: Azilsartan, Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan


  Issues for Surgery


Potential increase in major adverse cardiovascular events if omitted.

Potential intraoperative hypotension, including refractory hypotension, if continued, which may increase the risk of ischaemic cardiovascular events.


  Advice in the Perioperative period


Elective Surgery

Perioperative continuation or cessation of ACEi / AIIRA remains a contentious issue as there is a lack of high quality evidence on which to base a recommendation (for a discussion of the arguments for and against pre-operative omission of ACEi / AIIRA see Further Information). Until high quality evidence becomes available it is recommended that local consensus is reached regarding the pre-operative management of patients on ACE / AIIRA (including combination products). A practical approach is to omit the ACEi / AIIRA on the morning of surgery, although some centres may opt to omit them up to 48 hours pre-operatively.

Combination products: -

  • Combination products containing ACEi / AIIRA and hydrochlorothiazide or indapamide – also see Diuretics – Thiazides and Related Monograph
  • Combination products containing ACEi / AIIRA and calcium channel blocker – also see Calcium-Channel Blockers (CCBs) Monograph
  • Combination products containing AIIRA and calcium channel blocker and hydrochlorothiazide - also see Calcium-Channel Blockers (CCBs) and Diuretics – Thiazides and Related Monographs
  • Combination products containing AIIRA and sacubitril (Entresto®)

Consideration should be given to prescribing the components of combination products as separate medicines perioperatively. However, some components of combination products do not exist as individual medicines (e.g. hydrochlorothiazide, sacubitril). If there is any doubt about the need to continue / withhold component agents of a combination product, advice should be sought from an Anaesthetist.

Emergency Surgery

If patient has taken any dose(s) in previous 24-48 hours, inform Anaesthetist as potential for intraoperative hypotension (see Interaction(s) with Common Anaesthetic Agents).

Perioperative Considerations

If ACEi or AIIRA has been continued pre-operatively, monitor for intraoperative hypotension. If this occurs, treat according to advice below (see Interaction with Common Anaesthetic Agents).

Post-operative Advice

If stopped prior to surgery, restart post-operatively as soon as blood pressure and volume are stable1. It is important that the Surgical Team ensure that the patient is aware when to restart the ACEi / AIIRA post-operatively to avoid unintentional drug cessation2.

Monitor renal function post-operatively. Consider withholding ACEi / AIIRA post-operatively if patient develops acute kidney injury (AKI).

Monitor blood pressure (BP) – consider omitting if BP low.


  Interaction(s) with Common Anaesthetic Agents


Hypotension

Marked hypotension during anaesthetic induction has been seen in patients taking ACEi or AIIRA3. Hypotension secondary to ACEi / AIIRA usually occurs within 30 minutes of induction of anaesthesia and is more common in patients also taking diuretics4. The frequency and magnitude of intraoperative hypotension is greater in patients taking AIIRA than ACEi and also appears to be less responsive to ephedrine and phenylephrine3, 4.

Treatment of Hypotension
Patients taking ACEi / AIIRA should receive intravenous fluids before induction to ensure euvolemia3, 4. If hypotension occurs, sympathomimetics may not be fully effective because ACEi / AIIRA administration may result in a decreased adrenergic vasoconstrictive response2, 3. Terlipressin has been effective at correcting refractory hypotension during anaesthesia in patients taking ACEi / AIIRA2, 3, 4.


  Interaction(s) with other Common Medicines used in the Perioperative Period


Hyperkalaemia

ACEi/AIIRA can cause hyperkalaemia; the risk is further increased with concomitant use of the following medications3, 5: -

  • Non-Steroidal Anti-inflammatory Drugs (NSAIDs)
  • low molecular weight heparin (LMWH) or unfractionated heparin
  • co-trimoxazole

If concomitant treatment is required – monitor serum potassium, particularly if there is other risk factors for hyperkalaemia e.g. renal impairment.


  Further Information


Argument for Stopping Pre-operatively

A meta-analysis with 4206 patients who continued and 1816 patients who withheld ACEi / AIIRA before surgery showed no difference in all-cause mortality or MACE between the two groups. However, there was a marked heterogeneity between studies and the meta-analysis was underpowered for all reported outcomes. Continuation of ACEi / AIIRA was associated with a significantly increased risk of intraoperative hypotension (29.9%), but not postoperative hypotension, compared to those who stopped ACEi / AIIRA (23.4%)6.

Argument for Continuing Pre-operatively

Even if ACEi / AIIRA are stopped pre-operatively, hypotension can still occur3, 4; it is likely that the hypotensive effect may persist for some time after stopping therapy because of persistent tissue-based activity4. Failure to take into account the variable durations of action of ACEi / AIIRA may be a confounding factor when studying the effects of stopping pre-operatively7.

Meta-analysis of data from patients who continued ACEi / AIIRA on the day of cardiac and non-cardiac surgery found that hypotension was more likely with continuation (but most cases were sensitive to intravenous fluids and vasoconstrictors); however, continuation of ACEi / AIIRA did not increase the incidence of post-operative complications such as myocardial infarction, cerebrovascular accident, AKI or death2.

In cardiac surgery the perioperative administration of ACEi / AIIRA has been associated with a lower risk of AKI. In an observational study of 949 patients undergoing non-cardiac surgery no difference in incidence of AKI was observed between patients who continued or withheld ACEi / AIIRA pre-operatively, therefore withholding ACEI / AIIRA does not protect against development of post-operative AKI8.

Recommendations of Reputable Societies

European Society of Cardiology (ESC) & European Society of Anaesthesiology (ESA)
In stable patients with heart failure and left ventricular systolic dysfunction consider continuing ACEi or AIIRA with close monitoring during non-cardiac surgery. In hypertensive patients consider transient discontinuation of ACEi or AIIRA before non-cardiac surgery1.

American College of Cardiology (ACC) & American Heart Association (AHA)
Perioperative continuation of ACEi or AIIRA is reasonable; however, if they are held before surgery it is reasonable to restart as soon as clinically feasible post-operatively9.

Canadian Cardiovascular Society (CCS)
ACEi or AIIRA should be withheld 24 hours before non-cardiac surgery due to the substantial increase in risk of intraoperative hypotension and the lack of any clinical trials demonstrating benefit with perioperative continuation. Because the risk of hypotension is greatest within 24 hours of surgery, consider restarting on day 2 after surgery if patient haemodynamically stable10.

SPACE Clinical Trial 

Stopping Perioperative Angiotensin II Converting Enzyme inhibitors and/or angiotensin receptor blockers in major non-cardiac surgery (SPACE) is a phase III, randomised controlled trial (ISRCTN17251494) aiming to establish if perioperative continuation of ACEi / AIIRA reduces the risk of myocardial injury. Patients randomised to the discontinuation arm will stop their ACEi / AIIRA 24-48 hours pre-operatively, depending on its duration of action. The trial will run until January 2021 with publication of results soon after11.

 

  References


  1. The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA). 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management. European Heart Journal. 2014; 35:2383-2431 
  2. Ling Q. Gu Y. Chen J et alConsequences of continuing renin angiotensin aldosterone system antagonists in the preoperative period: a systematic review and meta-analysis. BMC Anesthesiology. 2018; 18:26
  3. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 27th June 2019]
  4. Mets B. Management of Hypotension Associated With Angiotensin-Axis Blockade and General Anesthesia Administration. Journal of Cardiothoracic and Vascular Anesthesia. 2013; 27(1):156-167
  5. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 27th June 2019]
  6. Hollmann C, Fernandes NL & Biccard BM. A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery. Anesth Analg. 2018; 127:678-687.
  7. Walker S, Abbott T, Brown K et al. Perioperative management of angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers: a survey of perioperative medicine practitioners. PeerJ. 2018; 6:e5061
  8. STARSurg Collaborative. Association between peri-operative angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers and acute kidney injury in major elective non-cardiac surgery: a multicentre, prospective cohort study. Anaesthesia. 2018; 73:1214-1222
  9. Fleisher L, Fleischmann K, Auerback A et al. 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Journal of the American College of Cardiology. 2014; 64(22): e77-e137
  10. Duceppe E, Parlow J, MacDonald P et al. Canadian Cardiovascular Society Guidelines on Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo Noncardiac Surgery. Canadian Journal of Cardiology. 2017; 33:17-32
  11. Stopping Perioperative Angiotensin II Converting Enzyme inhibitors and/or angiotensin receptor blockers in major non-cardiac surgery. Available at: http://www.isrctn.com/ISRCTN17251494 [Accessed 9th September 2019]