See Article, page 763

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) lower blood pressure through inhibition of the renin-angiotensin system. Both groups of drugs are recommended as first-line medications in the treatment of hypertension carrying the strongest (class I) recommendation based on the highest level of evidence.1,2 In addition to their blood pressure-lowering effects, there is good evidence that these drug classes provide renal protection and improve cardiovascular outcomes, the latter via their additional cardioprotective benefits in patients who have experienced a myocardial infarction or those with heart failure.3 Therefore, it is likely that a substantial proportion of patients presenting for surgery will be on one of these medications.

Several studies have reported an association between preoperative continuation of ACEIs or ARBs and intraoperative hypotension, which can be refractory to usual treatment (eg, phenylephrine and ephedrine). However, this evidence is plagued by numerous limitations such as high risk of selection bias, variability in the type of surgical procedures, lack of standardization of perioperative care, and evaluation of outcomes focused on physiological end points such as hypotension rather than clinical end points (Table).4–9 Not surprisingly, even the meta-analyses are limited due to significant heterogeneity in the included studies (Table).10,11 Thus, the available data are not the best-level evidence to guide clinical practice. Nevertheless, it is common practice to withhold ACEIs and ARBs preoperatively.

Table. - Studies Evaluating the Effects of ACEI/ARB on Intraoperative Blood Pressure in Hospitalized Patients Undergoing Noncardiac Surgery Authors Study design Conclusions Comfere et al4 Retrospective Discontinuation of ACEI/ARB therapy at least 10 h before anesthesia was associated with a reduced risk of immediate postinduction hypotension Kheterpal et al5 Retrospective ACEI/ARB therapy combined with diuretic therapy was associated with increased episodes of hypotension Shiffermiller et al6 Randomized Omitting preoperative ACEI dose was associated with less frequent intraoperative hypotension and lower use of vasopressor, but more frequent postoperative hypertension episodes Roshanov et al7 Retrospective observational cohort Patients who withheld ACEIs/ARBs within 24 h before surgery were less likely to suffer the primary composite outcome of all-cause death, stroke, or myocardial injury at 30 d, and less likely to have intraoperative hypotension with no influence on postoperative hypotension Lee et al8 Retrospective cohort Preoperative withholding of ARB therapy was associated with increased 30-day mortality, especially in younger patients, most likely due to delay in resuming ARB therapy after surgery STARSurg Collaborative9 Prospective cohort There was no association between withholding ACEI/ARB therapy and the incidence of postoperative acute kidney injury and requirement for renal replacement therapy as well as 30-day mortality. The lack of association remained even after propensity score matching for use of medications with known nephrotoxicity (eg, diuretics and aminoglycoside antibiotics) Hollmann et al10 Meta-analysis Continuation of ACEIs/ARBs was associated with intraoperative hypotension, but with no demonstrable association between ACEI/ARB administration and mortality, major adverse cardiac events, stroke, or acute kidney injury Ling et al11 Meta-analysis There is insufficient evidence to recommend discontinuing ACEIs/ARBs on the day of surgery

Abbreviations: ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

It is critical to recognize that the recommendations to withhold ACEIs and ARBs before surgery are primarily based on evidence from inpatient populations and thus may not be applicable to the ambulatory setting—involving minimally invasive surgical procedures with negligible fluid shift and hemodynamic derangements as well as the use of short-acting anesthetics and analgesics to allow rapid emergence from general anesthesia. Unfortunately, studies evaluating the influence of ACEIs and ARBs on outcomes after ambulatory surgery are sparse. A prospective, randomized, single-blind study of patients presenting for ambulatory surgery observed a similar incidence of preoperative and postoperative hypertension with continuation or discontinuation of ACEIs and ARBs.12 However, the incidence of intraoperative hypotension was not reported. Nevertheless, despite several limitations, the authors concluded it was safe to discontinue these drugs on the day of surgery without increasing adverse hemodynamic outcomes.12

Given the scant evidence regarding the continuation or withholding of ACEIs and ARBs before ambulatory surgery, it is no wonder that the debate rages on. Thus, the prospective cohort study in this issue of Anesthesia & Analgesia by Gurunathan et al13 is particularly timely. This study is unique in that it examines patients undergoing ambulatory surgery, compares groups with respect to early hypotension (within 15 minutes after induction of general anesthesia) as the primary outcome and clinically significant hypotension during surgery (“any hypotension”), the overall variability in blood pressure, length of stay in recovery room and quality of recovery-15 scores at 24 hours post surgery as secondary outcomes. Importantly, this study by Gurunathan and colleagues also examines perioperative hemodynamics in patients on other antihypertensives. Thus, the study included 4 groups: no hypertensive therapy, ACEI or ARB therapy discontinuation (<10 hours vs >10 hours before surgery), and other antihypertensive therapy. The authors concluded that intraoperative hypotension (early or otherwise) occurred more frequently in those on any antihypertensive medication than those not on any antihypertensives. Intraoperative hypotension and blood pressure variability were strongly associated with baseline hypertension status more so than type of antihypertensives or timing of last intake of ACEIs or ARBs before ambulatory surgery.

This study raises 2 important points: (1) hypotension after induction is an anticipated consequence of anesthetic drugs; and (2) hypotension occurs in most patients, but is more likely and exaggerated in patients taking any antihypertensive medication. Also, patients on antihypertensive therapy experience more intraoperative blood pressure variability. Although the study by Gurunathan et al13 provides important new insight, it has some limitations, which could be addressed in future studies. In addition to the innate limitations of any observational trial design, there was variability in surgical population, variability in general anesthetic technique, and variability in timing and approach to hypotension therapy. The study is also underpowered for secondary outcomes including length of stay in the recovery room and the quality of recovery at 24 hours after surgery. Other outcomes that could have been measured include delayed discharge home and unplanned hospital admission.

Overall, even after decades of debating the pros and cons of preoperatively withholding or continuing ACEI or ARB therapy, there remains a lack of consensus. The 2014 American College of Cardiology/American Heart Association guidelines state that it is reasonable to continue ACEIs and ARBs,14 but if they are withheld, they should be restarted as soon as possible. In contrast, the 2017 Canadian Cardiovascular Society guidelines recommend withholding these group of drugs for 24 hours before surgery.15 Moreover, the 2022 European Society of Cardiology/European Society of Anaesthesiology states that it is reasonable (a) to continue these drugs in patients who are taking them for the management of hypertension and (b) to withhold them in patients who are taking them for heart failure in whom the baseline blood pressure is low.16

Considering the available evidence or lack thereof, a pragmatic approach is necessary with a primary aim of maintaining patient safety. We could make the argument, especially in the ambulatory setting, that stopping ACEIs and ARBs preoperatively may not be necessary. In fact, we could standardize the recommendation that all antihypertensives should be continued. This would avoid any confusion in patient education and preoperative instructions, and avoid delay in resuming ACEIs and ARBs postoperatively. Importantly, with perioperative care, it is optimal to customize care to specific patient populations based on their comorbidities, intended surgery, and concurrent therapies, rather than a one-size-fits-all approach. Ultimately, we need to anticipate, prevent, monitor, and treat perioperative hemodynamic changes. In the ambulatory surgery population, it is imperative that the general anesthetic technique should avoid of postinduction hypotension.17 For patients receiving ACEIs or ARBs, it is also necessary to manage hypotension promptly and appropriately with drugs that have been shown to be effective (eg, vasopressin analogs and/or norepinephrine).

In summary, the evidence for preoperative discontinuation of ACEIs and ARBs remains inconclusive. Failure to recognize the limitations of available evidence may incorrectly influence clinical practice and result in acceptance of an intervention subsequently shown to be inappropriate or harmful. This emphasizes the need for high-quality evidence to support and to improve clinical practice. Future research is needed to further define preoperative management of ACEIs and ARBs in the ambulatory setting. Multicenter randomized trials with adequate sample size, in addition to rigorously defined perioperative care with fewer variables between the control and the intervention groups and well-defined primary and secondary outcomes, are necessary. The data generated from such well-designed randomized trials could be combined with multicenter, multinational, highly standardized prospective cohort studies that minimize bias and confounding factors.

DISCLOSURES

Name: Niraja Rajan, MD, FASA, SAMBA-F.

Contribution: This author helped write and revise the manuscript, and approved the final version of the article.

Name: Girish P. Joshi, MBBS, MD, FFARCSI, FASA, SAMBA-F.

Contribution: This author helped write and revise the manuscript, and approved the final version of the article.

This manuscript was handled by: Thomas R. Vetter, MD, MPH, MFA.

REFERENCES 1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/ AGS/APhA/ ASH/ASPC/ NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71:1269–1324. 2. Williams B, Mancia G. Ten commandments of the 2018 ESC/ESH HTN guidelines on hypertension in adults. Eur Heart J. 2018;39:3007–3008. 3. Reboussin DM, Allen NB, Griswold ME, et al. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71:e116–e135. 4. Comfere T, Sprung J, Kumar MM, et al. Angiotensin system inhibitors in a general surgical population. Anesth Analg. 2005;100:636–644. 5. Kheterpal S, Khodaparast O, Shanks A, O’Reilly M, Tremper KK. Chronic angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy combined with diuretic therapy is associated with increased episodes of hypotension in noncardiac surgery. J Cardiothorac Vasc Anesth. 2008;22:180–186. 6. Shiffermiller JF, Monson BJ, Vokoun CW, et al. Prospective randomized evaluation of preoperative angiotensin-converting enzyme inhibition (PREOP-ACEI). J Hosp Med. 2018;13:661–667. 7. Roshanov PS, Rochwerg B, Patel A, et al. Withholding versus continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers before noncardiac surgery: an analysis of the vascular events in noncardiac surgery patIents cOhort evaluatioN Prospective Cohort. Anesthesiology. 2017;126:16–27. 8. Lee SM, Takemoto S, Wallace AW. Association between withholding angiotensin receptor blockers in the early postoperative period and 30-day mortality: a cohort study of the veterans affairs healthcare system. Anesthesiology. 2015;123:288–306. 9. 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. 10. 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. 11. Ling Q, Gu Y, Chen J, et al. Consequences of continuing renin angiotensin aldosterone system antagonists in the preoperative period: a systematic review and meta-analysis. BMC Anesthesiol. 2018;18:26. 12. Twersky RS, Goel V, Narayan P, Weedon J. The risk of hypertension after preoperative discontinuation of angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists in ambulatory and same-day admission patients. Anesth Analg. 2014;118:938–944. 13. Gurunathan U, Roe A, Milligan C, Hay K, Ravichandran G, Chawala G. Preoperative renin-angiotensin systems antagonists intake and blood pressure responses during ambulatory surgical procedures: a prospective cohort study. Anesth Analg. 2024;138:763–774. 14. Fleisher LA, Fleischmann KE, Auerbach AD, et al. ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:2215–2245. 15. 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. Can J Cardiol. 2017;33:17–32. 16. Halvorsen S, Mehilli J, Cassese S, et al.; ESC Scientific Document Group. ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery. Eur Heart J. 2022;43:3826–3924. 17. Joshi GP. General anesthetic techniques for enhanced recovery after surgery: Current controversies. Best Pract Res Clin Anaesthesiol. 2021;35:531–541.