By Michael H. Crawford, MD, Editor
A randomized study of stopping vs. continuing renin-angiotensin system inhibitors prior to elective non-cardiac surgery in older patients did not decrease the incidence of myocardial injury and may have increased the incidence of hypertensive adverse events.
Acktand GL, Patel A, Abbott TEF, et al. Discontinuation vs. continuation of renin-angiotensin system inhibition before non-cardiac surgery: The SPACE trial. Eur Heart J 2024;45:1146-1155.
Based on the results of observational studies, some guidelines recommend stopping renin-angiotensin system inhibitors (RASI) prior to elective non-cardiac surgery because of concern that these agents will potentiate intraoperative hypotension, leading to myocardial, kidney, or brain injury. However, this practice also could result in acute postoperative hypertension, which also could be injurious. Thus, these investigators from six centers in the United Kingdom conducted a randomized, open-label trial of discontinuing RASI preoperatively vs. continuing them to assess whether either strategy would prevent postoperative myocardial injury, other morbidity, and mortality.
From 2017 to 2021, patients ≥ 60 years of age on RASI, who were American Society of Anesthesiology grade ≥ 3 and were undergoing major elective surgery of > 120 minutes duration, were recruited. Of the 262 patients randomized, eight patients later withdrew consent or had their surgery cancelled and 13 patients had incomplete data, leaving 120 patients in the continued RASI group and 121 patients in the stopped group. Their median age was 71 years, 48% were women, 21% had diabetes, and 70% were taking statins or other blood pressure-lowering medications. In the discontinue group, the time pre-surgery to stop RASI was based on the pharmacokinetics of each drug. Those with a long half-life were stopped 48 hours before surgery and those with shorter half-lives were stopped 24-32 hours before surgery.
In both groups, drugs were restarted on day 2 postoperatively without a dose change unless systolic blood pressure (SBP) was < 90 mmHg in the preceding 12 hours or acute kidney injury (AKI) was detected. Laboratory studies were performed pre-op and at 24, 48, and 72 hours post-op. The primary endpoint was myocardial injury as defined by a troponin T (TnT) of ≥ 15 ng/L if the pre-op value was < 15 ng/L or an increase ≥ 5 ng/L if the pre-op value was > 15 ng/L.
Secondary endpoints included the highest TnT value in the 48 hours post-op and the occurrence of a myocardial infarction (MI), heart failure, stroke, or death. Safety endpoints included hypotension requiring vasopressors, SBP > 180 mmHg, diastolic BP > 100 mmHg, or AKI within 30 days post-op. Statistical analysis was on an intention-to-treat basis. The pre-study SBP was 138 mmHg ± 20 mmHg in the continue group and 140 mmHg ± 21 mmHg in the stop group. In the stop group, SBP rose by 16 mmHg on average immediately pre-op (95% confidence interval, 0.04-1.31; P = 0.33). Peak TnT levels were similar (mean difference, 0.16 ng/L; P = 0.92). Hypertensive events were more frequent in the stop group (16) vs. the continue group (seven). Hypotensive events and AKI were similar. Six patients experienced MI, stroke, or heart failure, but all were in the stop group. There were were three deaths: two in the continue group and one in the stop group. The authors concluded that discontinuing RASI prior to elective non-cardiac surgery in patients > 60 years of age did not reduce the incidence of myocardial injury and may increase the number of hypertensive adverse events.
COMMENTARY
This study from the United Kingdom is a much-needed randomized controlled trial of the common practice promulgated by some guidelines to hold RASI drugs prior to non-cardiac surgery, because previous studies have shown inconsistent results. Most have been retrospective observational studies; few are randomized, and the mean number of patients in these studies is about 50.
One consistent result of the prior studies is that failure to reinstitute RASI therapy after surgery did result in increased adverse events. Although not a large trial, the Ackland study is large enough to assess the myocardial injury concern because of presumed intraoperative hypotension. There clearly was no increase in myocardial injury as assessed by serum troponin levels. Also, SBP predictably increased after cessation of RASI, since most of the patients were taking these drugs for hypertension and not heart failure or other reasons. Less than 10% of the patients had nonfatal clinical events, so firm conclusions cannot be drawn here, but it is noteworthy that none of those with such events were in the continue group. Only three patients died in the perioperative period (≤ 30 days), attesting to the overall safety of major surgery in older patients today. Thus, the authors opined that perhaps those guidelines that recommend holding RASI for non-cardiac surgery should be reconsidered.
One major strength of the Ackland study is that the protocol for when to stop RASI pre-op was drug-specific based on the pharmacokinetics. Stopping all RASI 24 hours before surgery means that some of the longer-acting ones still will be having an effect during surgery. Also, the researchers focused on patients 60 years of age and older, those most likely to be at risk for cardiovascular adverse events. In addition, the primary endpoint was a discrete measure of myocardial injury (troponin) rather than just assessing clinical events. Finally, the protocol did not prevent anesthesiologists from monitoring SBP and immediately responding to low blood pressure with fluids or pressors as they normally would do.
There were weaknesses to the Ackland study as well. The study lacked power to evaluate clinical endpoints. Almost all the patients were white. Most of the patients were taking RASI for hypertension, with less than 10% for heart failure or other reasons. The diagnosis of MI was by troponin only; no electrocardiogram or other clinical data were used. It was open-label, but the oversight committee was unaware of patient assignment and events were adjudicated by someone blinded. At this point, it is fair to say that there is no strategy beyond excellent anesthesia care that results in better outcomes for those taking RASI.
