Should renin–angiotensin system inhibitors be stopped or not before non-cardiac surgery?

The global annual volume of major surgical procedures is estimated to exceed 300 million, representing ∼5% of the world's population, with numbers likely increasing due to an ageing population. 1 Approximately 85% of these are non-cardiac surgeries (NCSs). Perioperative mortality for patients over 45 years of age following NCS is around 2%, 2 with other complications, such as perioperative myocardial injury or infarction (PMIs), occurring much more frequently. 3 Significant efforts have been made to reduce perioperative complications, with optimal drug management being crucial. 4 Continuation of renin-angiotensin system inhibitor (RASI; angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) during the perioperative period is linked to an increased risk of perioperative hypo-tension, leading to higher use of vasopressors and inotropes. Prolonged intraoperative hypotension may increase the risk of end-organ damage, including kidney injury, myocardial damage, and stroke. 5-7 However, a systematic review of nine studies (five randomized controlled trials and four cohort studies) found that withholding RASI therapy on the morning of NCS did not reduce mortality or major adverse cardiovas-cular events. 8 The POISE-3 trial further evaluated 7490 patients undergoing NCS on blood pressure medications and reported no significant difference in major cardiovascular events within 30 days post-surgery between a hypotension-avoidance strategy (withholding RASI before and for 2 days after surgery) and a hypertension-avoidance strategy (13.9 vs. 14%, P = 0.92). 9,10 Anaesthesiologists maintained a mean arterial pressure (MAP) of ≥80 mm Hg in the hypotension-avoidance group and ≥60 mm Hg in the hypertension-avoidance group. The minimal difference in blood pressure and heart rate between the groups likely accounts for the similar outcomes. Study design The STOP-or-NOT trial (NCT03374449) 11,12 is an investigator-initiated, multicentre, open-label, randomized controlled trial conducted at 40 French hospitals, designed to compare the effect of a strategy of preoperative discontinuation of RASI therapy vs. a strategy of preopera-tive continuation of RASI therapy on all-cause mortality and post-operative complications after major NCS. The target enrolment for the trial was 2222 patients. The study included patients requiring major NCS, defined as a procedure with an expected duration of more than 2 h from incision and an anticipated post-operative hospital stay of at least 3 days. The enrolled patients were required to have been on RASI therapy for a minimum of 3 months prior to surgery. Study endpoint The primary endpoint was a composite of all-cause mortality and major post-operative complications, which included (i) post-operative major cardiovascular events (such as acute myocardial infarction, arterial or venous thrombosis, stroke, acute pulmonary oedema, cardiogenic shock, hypertensive crisis, and cardiac arrhythmias requiring intervention), (ii) sepsis or septic shock, (iii) respiratory failure requiring re-intubation or non-invasive ventilation, (iv) unplanned admission to intensive care, (v) acute kidney injury, (vi) hyperkalaemia, and (vii) surgical complications necessitating reintervention. 11 Prespecified secondary endpoints included intraoperative hypoten-sion (MAP <60 mm Hg or requiring treatment with vasopressors), all-cause mortality, acute kidney injury, post-operative organ failure assessed by the maximum Sequential Organ Failure Assessment score, length of hospital and intensive care stay, and hospital-free days. Study patients At baseline, the mean age of the 2222 patients was 67 years (SD, 10 years); 65% were male, 98% were being treated for hypertension, 9% had chronic kidney disease, 8% had diabetes, and 6% had heart failure. The baseline characteristics of the 2222 patients randomized to a RASI discontinuation strategy (n = 1115 patients) or a RASI continuation strategy (n = 1107 patients) were comparable between the groups. In both groups, it was recommended that RASI therapy was resumed as soon as possible after surgery. Follow-up was for a median of 28 days [interquartile range (IQR) 28-31 days].