This study is a multicenter, randomized, double-blind, placebo-controlled trial conducted at six tertiary hospitals in China. The leading site is The First Affiliated Hospital of Soochow University, and the participating sites are Zhongshan Hospital Fudan University, Fudan University Shanghai Cancer Center, Shanghai General Hospital, The First Affiliated Hospital of Zhengzhou University, and The First Affiliated Hospital of Anhui Medical University.

The study protocol is approved by the Medical Ethics Committee of The First Affiliated Hospital of Soochow University (Approval No. 2020-077-1) and by the institutional ethics review board of each participating center. This study is registered at the Chinese Clinical Trials Registry on October 25, 2020 (http://www.chictr.org.cn, identifier: ChiCTR2000039376), before the enrollment of the first subject. This study follows the Declaration of Helsinki and the International Conference on Harmonization guidelines for Good Clinical Practice. This report follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement (20).

At each study center, an independent preoperative investigator who is not involved in patient care or data management will screen patients' admission records to identify potentially qualified participants. Patients who meet the eligibility criteria and provide their written informed consent will be included in this study. According to the sample size estimation, a total of 2,036 eligible patients who plan to undergo non-cardiac surgical procedures will be randomly assigned, in a 1:1 ratio, to an ACEIs/ARBs continued group or an ACEIs/ARBs withheld group. Patients can withdraw their consent at any time during this study. The patient recruitment started on November 1, 2020. The expected date for completion of recruitment is December 2023. The flow chart of participants is shown in Figure 1.

Patients are eligible for this trial if they are 60–80 years old with ASA physical status II or III, receiving regular ACEIs or ARBs therapy for hypertension for more than 2 weeks, who are scheduled for non-cardiac surgery under general anesthesia.

The exclusion criteria are as follows: (1) unplanned or emergent surgery, (2) spinal and/or epidural anesthesia, (3) ACEIs/ARBs use only in the evening, intermittent ACEIs/ARBs use, or concomitant use of ACEIs and ARBs, (4) uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 180 mmHg or diastolic blood pressure (DBP) ≥ 110 mmHg, (5) baseline mean blood pressure (MBP) ≤ 65 mmHg, (6) intravenous use of vasoactive agents, (7) severe cardiopulmonary or cerebrovascular disease, (8) liver or kidney dysfunction (Child-Pugh grade ≥ B, creatinine ≥ 200 μmol/L), or (9) rejection of participation.

An independent biostatistician who is not involved in the following study or data management generated a randomization sequence with a 1:1 ratio, permuted block sizes of 2 and 4, and stratification according to study center. Randomization is implemented by using a web-based central randomization system, and allocation concealment is ensured by password protection.

According to the random codes, an independent research nurse will prepare the study medications (either ACEIs/ARBs or inactive placebos) in identical capsules, which were kept in bags labeled with the study numbers and “Antihypertensive agent.” Subjects who meet the eligibility criteria will be randomly assigned to either an ACEIs/ARBs continued group or an ACEIs/ARBs withheld group. The participants, anesthesiologists, surgeons, investigators responsible for data collection, and other healthcare providers will remain masked to treatment allocation until the completion of final analysis.

In case of a severe adverse event considered to be related to study interventions, the attending anesthesiologists or physicians should notify the principal investigator to decide whether unmasking of treatment allocation is needed, and such an event will be documented by an independent data monitoring committee (DMC).

The schedule of enrollment, interventions, and assessments in accordance with the SPIRIT 2013 statement is shown in Table 1. The baseline blood pressure is obtained by independent nursing personnel when patients are comfortably seated in surgical wards before the day of surgery. According to the web-based centralized randomization list, patients will take the study medications (either the ACEIs/ARBs or placebo pills) orally on the morning of surgery. The time of study medication will be documented.

In the operating room, patients will receive a standard monitoring including heart rate (HR), non-invasive blood pressure, and pulse oximetry. Induction of general anesthesia will be performed with sufentanil 0.2–0.4 μg/kg and etomidate 0.2–0.3 mg/kg. Tracheal intubation will be facilitated with rocuronium 0.6 mg/kg or cisatracurium 0.2 mg/kg. Mechanical ventilation will be performed with a tidal volume of 8–10 ml/kg, frequency of 12–18 breaths/min, adjusted to maintain end-tidal CO₂ values within 30–40 mmHg. General anesthesia will be maintained with propofol infusion titrated to bispectral index (BIS) values within 40–60, or with sevoflurane inhalation titrated to end-tidal minimal alveolar concentration within 0.8–1.3. To provide adequate intraoperative analgesia and neuromuscular blockade, additional doses of sufentanil and rocuronium (or cisatracurium) can be administered. Body temperature will be maintained at 36–37°C with a nasopharyngeal probe by using a warming blanket and/or an infusion heating device. Other perioperative management will be left to the discretion of the attending anesthesiologists according to the routine practice of each study center. After tracheal extubation, patients will be transferred to the PACU. When a modified Aldrete score ≥ 9 is achieved, patients will be discharged from the PACU to the surgical wards.

For both groups, the use of ACEIs/ARBs will be continued in the morning of the first post-operative day. If a perioperative hypertensive event occurs during the study period, patients will receive antihypertensive treatments based on the institutional clinical practice.

The primary outcome measure of this trial is the incidence of perioperative hypotensive events, defined as MBP <65 mmHg or ≥30% reduction in MBP from baseline for which an intervention is needed (including intravenous fluids infusion and/or use of vasopressors), which occur during surgery and in the PACU.

The secondary outcome measures are: (1) duration of perioperative hypotension, (2) intraoperative use of fluids and vasopressors, (3) postoperative hypotensive events in the surgical wards within 3 days after surgery, and (4) perioperative neurocognitive disorders (PND), major adverse cardiocerebral events (MACEs, a composite outcome of permanent or transient stroke, coma, myocardial infarction, heart block, and cardiac arrest), and mortality within 30 days after surgery. MACE will be assessed as a composite outcome, and each complication will also be assessed individually, according to the definitions in Table 2.

The exploratory outcomes are as follows: (1) the incidence of hypertensive events (MBP > 110 mmHg or ≥ 30% increase in MBP from baseline) during surgery, in the PACU, and within 3 postoperative days, (2) tachycardia or bradycardia events defined as HR > 100 beats/min or HR <50 beats/min, (3) intraoperative adverse events (arrythmia, hypoxia, allergic reaction, major bleeding, hyperthermia, hypothermia, oliguria, acid-base disturbances, electrolyte disorders, lactic acidosis, and cardiac arrest), (4) Ramsay sedation scores in the PACU, (5) numerical rating scale scores for pain, analgesic consumption, and postoperative nausea and vomiting (PONV) in the PACU and in the wards within three post-operative days, (6) time to extubation, (7) intensive care unit (ICU) admission, and (8) length of postoperative hospital stay.

Patients' demographics, baseline characteristics, and intraoperative data will be collected in the Case Report Forms by independent investigators. Trained postoperative assessors who are unaware of group allocation will collect postoperative in-hospital data by ward visits and 30-day follow-up data via telephone. The lead investigator of each study center is responsible for the accuracy and completeness of data. Site visits will be carried out by two investigators for source data verification during the implementation of this study. After de-identification, all data will be stored electronically in a web-based database (https://www.91trial.com/) and monitored by the independent data monitoring committee.

The sample size calculation was performed using the PASS software (version 11.0.7, NCSS, LCC, Kaysville, UT, USA). Based on an international prospective cohort study of 4802 patients undergoing non-cardiac surgery, the incidence of intraoperative hypotensive events was 28.6% in the ACEIs/ARBs continued group (15). We hypothesize that the suspension of ACEIs/ARBs before surgery would reduce the incidence of hypotension by 20%, that is, to a hypotension rate of 22.88%. To detect such a difference with α = 0.05 and power = 80%, 916 patients per group are needed. We estimate a drop-out rate of 10%, and thus 1,018 patients will be enrolled in each group.

Data distribution and normality will be assessed with Shapiro-Wilk test. Continuous variables will be presented as mean ± standard deviation or median (interquartile ranges), depending on their distribution. Categorical variables will be presented as number (percentages). All analyses will follow the intention-to-treat principle, which includes all participants after randomization and excludes the patients who drop out of the study due to withdrawal of informed consent or cancellation of surgery. The per-protocol analysis will be carried out as a sensitivity analysis, which includes all participants with planned interventions and minimal protocol violation. As we expect that the missing data will be uncommon in our dataset, there will be no plan for imputation of missing data.

The primary outcome of perioperative hypotension occurrence will be assessed using multivariate logistic regression adjusting for the following baseline covariates: age, body mass index, ASA status, hypertension grade, previous myocardial infarction, atrial fibrillation, diabetes mellitus, hemoglobin value, use of diuretics, and trial site. The odds ratio with 95% confidence intervals will be reported.

In addition, subgroup analyses for the primary outcome will be conducted to explore whether the effects of study interventions will vary, according to six variables: age, hypertension grade, diabetes mellitus, type of surgery, duration of surgery, and trial site. The interaction analysis of effects across the subgroups will be performed using a test of treatment-by-covariate interaction on a logistic regression model.

For the secondary outcomes, analysis will be conducted using generalized linear model for continuous variables or using multivariate logistic regression for binary variables, adjusting for the above-mentioned baseline covariates. The Benjamini-Hochberg procedure will be used to control the false-discovery rate for multiple comparisons. The P-values before and after correction will be presented. For the exploratory outcomes, only descriptive statistics will be applied, without multiple testing or statistical inference.

It is expected that the risk of the study interventions will not be significantly higher compared to the standard medical practice, and there is no ethically risk associated with the primary outcome assessment. Hence, interim analysis will not be performed. All analyses will be done using the SAS software (version 9.4, SAS Institute Inc., Cary, NC, USA) and R statistical software (version 3.6.0, R Foundation for Statistical Computing, Vienna, Austria), with a two-sided P-value < 0.05 indicating a statistically significant difference.