Prospective Randomized Evaluation of Preoperative Angiotensin-Converting Enzyme Inhibition (PREOP-ACEI)

Duration of Intraoperative Hypotension

The median cumulative duration of intraoperative SBP < 80 was two minutes (range 0-41) in patients allocated to the ACEI omission group compared with seven minutes (range 0-214) in those allocated to the continuation group (P < .01). The median cumulative duration of mean arterial pressure < 55 mm Hg was also shorter in the omission group (median 0 min [range 0-39] vs 3 min [range 0-122], P < .01) than in the continuation group. The duration of surgery did not differ between groups (median 141 min [range 77-554] vs 142 min [range 57-665], P = .97).

Postoperative Outcomes

RAAS inhibitor therapy was resumed within 48 h after surgery in 122 of 137 (89%) patients allocated to the omission group and in 128 of 138 (93%) patients allocated to the continuation group (RR: 0.96, 95% CI: 0.89-1.03, P = .30).

Patients allocated to the omission group were significantly less likely to experience postoperative hypotension (15 of 137 [11%] vs 31 of 138 [22%], RR: 0.49, 95% CI: 0.28 to 0.86, P = .02) and significantly more likely to experience severe postoperative hypertension (33 of 137 [24%] vs 17 of 138 [12%], RR: 1.95, 95% CI: 1.14 to 3.34, P = .01) than those allocated to the continuation group. The occurrences of postoperative AKI (RR: 0.60, 95% CI: 0.23 to 1.60, P = .44) or MACE (RR: 4.03, 95% CI: 0.46 to 35.59, P = .21) in the omission group did not differ from the continuation group. The two groups exhibited similar PACU recovery time (mean 97.2 min) and overall hospital length of stay (mean 3.0 days) (P = .49 and P = .56 ). No episodes of inpatient mortality in either group were observed.

The omission of the final preoperative ACEI dose was associated with a significant reduction in the risk of intraoperative hypotension in patients undergoing NCNV surgery. This result confirmed our hypothesis. Coupled with the knowledge that intraoperative hypotension is associated with an increased risk of complications and mortality,^7-9,16 this study favors the omission of the final preoperative ACEI dose prior to NCNV surgeries.

Our findings are in agreement with those of previous randomized studies that explored this question^4,5 and help extend results from cardiac and vascular surgeries to NCNV surgeries. Previous studies on the use of RAAS inhibitors in NCNV surgeries did not employ randomization and yielded mixed results.^3,10-12,17 A large single-institution study (n = 18,056) noted no difference in intraoperative blood pressure between patients taking ACEIs and a matched group of non-ACEI users.³ More recently, a subgroup analysis of the international VISION study showed that omitting RAAS inhibitors on the day of surgery reduced the risk of intraoperative hypotension.¹¹ In that analysis, however, only a small amount of the variability in preoperative RAAS inhibitor management was explainable by modeling known factors, thus allowing for the possibility of unmeasured confounding. Our study, which minimized confounding through randomization, is the first to prospectively compare protocols for patients undergoing NCNV surgery. In contrast to previous studies, the present study was able to report the lack of difference in postoperative RAAS inhibitor administration between study groups. Postoperative RAAS inhibitor management affects complications and mortality.^18,19

Our present finding that preoperative ACEI management affects postoperative hypotensive and hypertensive events conflicts with some previous findings.^11,20 However, recent evidence has revealed that postoperative hypotensive episodes are associated with vascular events and mortality.^11,21 In the context of that evidence, our study lends further support to the omission of the final preoperative ACEI dose. However, we did not detect any decrease in AKI, MACE, or mortality in the ACEI omission group.

This study should be considered in light of its limitations. The pragmatic nature of the study allowed for certain potential biases. Although adherence to allocation was high, the specific ACEI agent taken and the exact timing of the final dose in relation to surgery were not controlled. Anesthetic and postoperative management decisions were made by the treatment team and may have systematically varied given that the treatment team was not blinded to allocation. Furthermore, all outcome data were collected as part of routine care and may not have captured events with great fidelity. Generalizability is limited by the execution of the study at a single academic institution, the preponderance of orthopedic and spine surgeries, and by the negligible representation of ethnicities other than Caucasian. Additionally, recruitment from the preoperative evaluation clinic likely resulted in a patient group with greater comorbidity than the overall population of patients undergoing NCNV surgery. This study was powered for intraoperative hypotension and not postoperative outcomes. Our primary outcome, intraoperative hypotension, is an intermediate measure but one that has well-established associations with adverse outcomes, including mortality. One study showed that sustaining an intraoperative SBP below 70 mm Hg for longer than 5 min increased the risk of mortality from less than 1% to nearly 6%.¹⁶ A large study detected an increase in mortality associated with SBP sustained below 80 mm Hg for 10 min or longer.⁷ Intraoperative hypotension has also been associated with postoperative AKI and myocardial injury.^8,9,12

Many of the limitations of the current study could be addressed by a large randomized controlled trial of ACEI management prior to NCNV surgeries that examines clinically important endpoints beyond intraoperative hypotension. Several specific aspects of perioperative RAAS inhibitor management also deserve further investigation. Our findings may not be generalizable to patients taking ARBs or to patients with congestive heart failure. The preoperative management of ARBs and the preoperative management of RAAS inhibitors in those with congestive heart failure are important areas of focus for future research. Lastly, our finding that preoperative ACEI management decisions can affect postoperative hypotensive and hypertensive events should be substantiated by future research, and any negative consequences of those events should be further explored.

Nonetheless, our study is the largest randomized study of preoperative RAAS inhibition published to date. More than twice as many patients were randomized in this study than in all previous randomized studies combined.^4-6 To the best of our knowledge, this is also the first randomized study evaluating NCNV surgeries. Finally, our use of a practical ACEI omission protocol based on known pharmacokinetics allows for direct application to clinical practice.