Stop-or-Not: It’s OK to Tailor RAS Inhibitor Use Around Noncardiac Surgery

LONDON, England—Clinicians can’t go wrong whether they continue or discontinue renin-angiotensin-system (RAS) inhibitors before noncardiac surgery, the Stop-or-Not trial suggests.

The rate of all-cause death or major postoperative complications at 28 days was 22% with either strategy (risk ratio 1.02; 95% CI 0.87-1.19), a finding that was consistent across various subgroups, Matthieu Legrand, MD, PhD (University of California San Francisco), reported here at the European Society of Cardiology Congress 2024.

Although intraoperative hypotension—a secondary outcome—was more frequent and longer-lasting among patients who continued their RAS inhibitors, that didn’t have an impact on other outcomes.

The findings, published simultaneously online in JAMA, indicate that “both strategies could be considered acceptable for providers and our patients,” Legrand said at a press conference. “As clinicians, we have greater flexibility in managing RAS [inhibitor] therapy based on individual patient factors [and] specifics of the surgery, but also patients’ preferences when discussing a strategy before surgery.”

Physicians may opt to discontinue treatment in patients deemed to have a high risk of severe hypotension heading into surgery, he said, adding, however, that “in most patients, as long as clinicians are aware of the strategy and able to respond with appropriate treatment during surgery, a continuation strategy might be acceptable for most patients.”

Discussing the results following Legrand’s presentation, P.J. Devereaux, MD (Population Health Research Institute, Hamilton, Canada), said the trial answers an important clinical question. Its results, “simplify care for the majority of patients, whereby continuing or withholding RAS [inhibitor therapy] is a safe approach,” Devereaux commented.

He advised using a tailored approach. “For patients who have hypotension or hypertension in the perioperative clinic or postoperative setting, I encourage physicians to individualize care regarding withholding or continuing perioperative RAS [inhibitors],” he said, specifying that additional research is needed to guide management of these medications in patients with heart failure with reduced ejection fraction and chronic low blood pressure.

Stop-or-Not Trial

More than half of patients who undergo major noncardiac surgery have cardiovascular conditions—diabetes, hypertension, and heart failure, for example—that require use of RAS inhibitors, including ACE inhibitors and ARBs. There has been debate around whether these drugs should be stopped prior to surgery due to the lack of definitive evidence from randomized trials. Keeping patients on the medications may lead to intraoperative hypotension and subsequent adverse outcomes, whereas interrupting treatment could result in postoperative hypertension, heart failure, or arrhythmias.

The lack of randomized data in this area has led to weak guideline recommendations. The American College of Cardiology and the American Heart Association, in their 2014 guideline on perioperative CV evaluation and management in patients undergoing noncardiac surgery, say that continuing the medications is reasonable (class IIa). More recent guidelines released by the European Society of Cardiology in 2022 say that withholding RAS inhibitors on the day of noncardiac surgery should be considered to prevent perioperative hypotension in patients without heart failure (class IIa) and that continuing treatment may be considered in patients with heart failure (class IIb).

To further explore the issue, Legrand and colleagues designed the Stop-or-Not trial, which was conducted at 40 centers in France. They randomized 2,222 patients (mean age 67 years; 65% men) who had been taking RAS inhibitors for more than 3 months and required noncardiac surgery, excluding those who needed emergency surgery, to continue taking their RAS inhibitors up to the day of surgery or to discontinue them 48 hours before the operation (resuming treatment as soon as possible afterwards).

Almost all patients (98%) had hypertension, with lower rates of chronic kidney disease (9%), diabetes (8%), and heart failure (4%). At baseline, 54% were taking ARBs and 46% ACE inhibitors.

For patients who have hypotension or hypertension in the perioperative clinic or postoperative setting, I encourage physicians to individualize care. P.J. Devereaux

The primary outcome, assessed 28 days after surgery, was a composite of all-cause death and various major postoperative complications, with no difference in the rate between trial arms. The findings were consistent across subgroups.

Hypotension during surgery, defined by a mean arterial pressure below 60 mm Hg or required use of vasopressors, was more commonly observed in the continuation group (54% vs 41%; RR 1.31; 95% CI 1.19-1.44) and lasted longer (median duration 9 vs 6 minutes; mean difference 3.7 minutes).

That was not, however, associated with any differences in trial outcomes, likely due to “the rapid correction of intraoperative hypertension and the overall short duration of low blood pressure,” Legrand and colleagues write.

They note that there’s mixed evidence from other trials looking at strategies for preventing intraoperative hypotension during noncardiac surgery. The INPRESS trial showed fewer postoperative complications with a hypotension prevention strategy, whereas another trial failed to show impact on postoperative complications when aiming for higher intraoperative blood pressures. In POISE-3, for which Devereaux served as chair of the steering committee, a strategy of avoiding hypotension that involved withholding RAS inhibitors 2 days before surgery versus a strategy of avoiding hypertension didn’t result in a difference in adverse outcomes.

Bianca Rocca, MD, PhD (Catholic University School of Medicine, Rome, Italy), who chaired a press conference at which the results were discussed, told TCTMD that the Stop-or-Not results will “raise a question” about whether RAS inhibitors should be temporarily discontinued prior to noncardiac surgery.

She highlighted the importance of continuing to perform new trials of older drugs like the RAS inhibitors due to changes in the patient population over time. “Sometimes old questions should be really tested in contemporary patients,” Rocca said. “That’s very important because of technology, because of comorbidities, because of aging, because of obesity, because of polypharmacy, for instance—[those] kinds of things that have an impact on these questions.”