SPACE
Research type
Research Study
Full title
Stopping Perioperative Angiotensin II Converting Enzyme inhibitors and/or receptor blockers in major non-cardiac surgery (SPACE): a phase II, explanatory, randomised controlled trial.
IRAS ID
207629
Contact name
Gareth Ackland
Contact email
Sponsor organisation
Queen Mary University of London
Eudract number
2016-004141-90
Duration of Study in the UK
4 years, 0 months, 30 days
Research summary
Research Summary
Prolonged activation of neurohormones such as angiotensin-II occurs after major surgery. Around 40% of surgical patients most at risk of postoperative complications are prescribed angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin-II receptor blockers (ARB). These drugs improve outcomes from several chronic diseases, including hypertension, chronic kidney disease and cardiac failure.
ACE-I and/or ARB are frequently stopped before surgery in the widely-held belief that this prevents intraoperative hypotension, although robust evidence for this is lacking. UK practice and international guidelines reflect clinical uncertainty regarding ACE-I and/or ARB withdrawal. However, a strong association exists between stopping ACE-I and/or ARB and an increased risk of mortality. These data suggest that acute withdrawal of ACE-I and/or ARB, coupled with substantial elevations in angiotensin-2 after surgery, could lead to excess postoperative morbidity and mortality. This hypothesis is highly plausible since the use of ACE-I and/or ARB reduces cardiovascular morbidity and inflammation, particularly in patients with established cardiovascular and chronic kidney disease. We do not currently know whether ACE-I and/or ARB should be stopped or continued in major surgery.
Summary of Results
We randomly assigned patients ≥60 years undergoing elective non-cardiac surgery to either to discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. RAS inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians and patients, was myocardial injury (plasma high-sensitivity troponin-T (hsTnT) ≥15 ng/L within 48 hours after surgery (or ≥5ng/L increase when pre-operative hsTnT≥15ng/L). Prespecified adverse haemodynamic events occurring within 48h of surgery included acute hypertension (>180mmHg) and hypotension requiring vasoactive therapy. 262 participants were randomised to continue (n=132) or stop (n=130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomised to continue, compared with 50 (41.3%) patients who discontinued, RAS inhibitors (OR:0.77; 95% confidence interval [CI], 0.45-1.31). Hypertensive adverse events were more frequent when RAS inhibitors were stopped (16 (12.4%), compared with 7 (5.3%) who continued RAS inhibitors/ARBs; OR:0.40; 95%CI0.16-1.00). Hypotension rates were similar when RAS inhibitors were stopped (12 (9.3%)) or continued (11 (8.4%)).
Conclusion: Discontinuing RAS inhibitors before non-cardiac surgery does not reduce myocardial injury, but increases the risk of clinically significant acute hypertension. Clinical effectiveness trials are now required to confirm the optimal approach to managing RAS inhibitors during non-cardiac surgery.REC name
London - City & East Research Ethics Committee
REC reference
16/LO/1495
Date of REC Opinion
16 Sep 2016
REC opinion
Favourable Opinion