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Impact of renin-angiotensin system inhibitors continuation versus discontinuation on outcome after major surgery: protocol of a multicenter randomized, controlled trial (STOP-or-NOT trial).

ABSTRACT: BACKGROUND:Chronic treatment of hypertension or heart failure very often includes an angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) as renin-angiotensin system inhibitors (RASi) treatments. To stop or not to stop these medications before major surgery remains an unresolved issue. The lack of evidence leads to conflicting guidelines with respect to RASi management before major surgery. The purpose of this study is to evaluate the impact of a strategy of RASi continuation or discontinuation on perioperative complications in patients undergoing major non-cardiac surgery. METHODS:This is a multicenter, open-labeled randomized controlled trial in > 30?French centers. In the experimental group, RASi will be continued while the treatment will be stopped 48?h before the surgery in the control arm. The primary endpoint is a composite endpoint of major complications after surgery. An endpoint adjudication committee will review clinical data and adjudicate efficacy endpoints while blinded to the assigned study drug group. Main analysis will be by intention-to-treat comparing the composite outcome measure at 28?days in the two groups. A total of 2222 patients are planned to detect an absolute complications difference of 5%. DISCUSSION:The results of the trial should provide robust evidence to anesthesiologists and surgeons regarding management of RASi before major non-cardiac surgery. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03374449 . Registered on 11 December 2017.

SUBMITTER: Legrand M

PROVIDER: S-EPMC6402139 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Impact of renin-angiotensin system inhibitors continuation versus discontinuation on outcome after major surgery: protocol of a multicenter randomized, controlled trial (STOP-or-NOT trial).

Legrand Matthieu M Futier Emmanuel E Leone Marc M Deniau Benjamin B Mebazaa Alexandre A Plaud Benoît B Coriat Pierre P Rossignol Patrick P Vicaut Eric E Gayat Etienne E

Trials 20190305 1

<h4>Background</h4>Chronic treatment of hypertension or heart failure very often includes an angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) as renin-angiotensin system inhibitors (RASi) treatments. To stop or not to stop these medications before major surgery remains an unresolved issue. The lack of evidence leads to conflicting guidelines with respect to RASi management before major surgery. The purpose of this study is to evaluate the impact of a stra ...[more]

PMID: 30836981

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Project description:Background and aimsHaemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear.MethodsFrom 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin-angiotensin system inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy.ResultsTwo hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45-1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16-1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)].ConclusionsDiscontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies.

Project description:BackgroundSARS-CoV-2 entry in human cells depends on angiotensin-converting enzyme 2, which can be upregulated by inhibitors of the renin-angiotensin system (RAS). We aimed to test our hypothesis that discontinuation of chronic treatment with ACE-inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) mitigates the course o\f recent-onset COVID-19.MethodsACEI-COVID was a parallel group, randomised, controlled, open-label trial done at 35 centres in Austria and Germany. Patients aged 18 years and older were enrolled if they presented with recent symptomatic SARS-CoV-2 infection and were chronically treated with ACEIs or ARBs. Patients were randomly assigned 1:1 to discontinuation or continuation of RAS inhibition for 30 days. Primary outcome was the maximum sequential organ failure assessment (SOFA) score within 30 days, where death was scored with the maximum achievable SOFA score. Secondary endpoints were area under the death-adjusted SOFA score (AUCSOFA), mean SOFA score, admission to the intensive care unit, mechanical ventilation, and death. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT04353596.FindingsBetween April 20, 2020, and Jan 20, 2021, 204 patients (median age 75 years [IQR 66-80], 37% females) were randomly assigned to discontinue (n=104) or continue (n=100) RAS inhibition. Within 30 days, eight (8%) of 104 died in the discontinuation group and 12 (12%) of 100 patients died in the continuation group (p=0·42). There was no significant difference in the primary endpoint between the discontinuation and continuation group (median [IQR] maximum SOFA score 0·00 (0·00-2·00) vs 1·00 (0·00-3·00); p=0·12). Discontinuation was associated with a significantly lower AUCSOFA (0·00 [0·00-9·25] vs 3·50 [0·00-23·50]; p=0·040), mean SOFA score (0·00 [0·00-0·31] vs 0·12 [0·00-0·78]; p=0·040), and 30-day SOFA score (0·00 [10-90th percentile, 0·00-1·20] vs 0·00 [0·00-24·00]; p=0·023). At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥1) or were dead (p=0·017). There were no significant differences for mechanical ventilation (10 (10%) vs 8 (8%), p=0·87) and admission to intensive care unit (20 [19%] vs 18 [18%], p=0·96) between the discontinuation and continuation group.InterpretationDiscontinuation of RAS-inhibition in COVID-19 had no significant effect on the maximum severity of COVID-19 but may lead to a faster and better recovery. The decision to continue or discontinue should be made on an individual basis, considering the risk profile, the indication for RAS inhibition, and the availability of alternative therapies and outpatient monitoring options.FundingAustrian Science Fund and German Center for Cardiovascular Research.

Project description:BackgroundBiological considerations suggest that renin-angiotensin system inhibitors might influence the severity of COVID-19. We aimed to evaluate whether continuing versus discontinuing renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) affects outcomes in patients admitted to hospital with COVID-19.MethodsThe REPLACE COVID trial was a prospective, randomised, open-label trial done at 20 large referral hospitals in seven countries worldwide. Eligible participants were aged 18 years and older who were admitted to hospital with COVID-19 and were receiving a renin-angiotensin system inhibitor before admission. Individuals with contraindications to continuation or discontinuation of renin-angiotensin system inhibitor therapy were excluded. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin-angiotensin system inhibitor using permuted block randomisation, with allocation concealed using a secure web-based randomisation system. The primary outcome was a global rank score in which participants were ranked across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction during the hospitalisation. Primary analyses were done in the intention-to-treat population. The REPLACE COVID trial is registered with ClinicalTrials.gov, NCT04338009.FindingsBetween March 31 and Aug 20, 2020, 152 participants were enrolled and randomly assigned to either continue or discontinue renin-angiotensin system inhibitor therapy (continuation group n=75; discontinuation group n=77). Mean age of participants was 62 years (SD 12), 68 (45%) were female, mean body-mass index was 33 kg/m2 (SD 8), and 79 (52%) had diabetes. Compared with discontinuation of renin-angiotensin system inhibitors, continuation had no effect on the global rank score (median rank 73 [IQR 40-110] for continuation vs 81 [38-117] for discontinuation; β-coefficient 8 [95% CI -13 to 29]). There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group died. 29 (39%) participants in the continuation group and 28 (36%) participants in the discontinuation group had at least one adverse event (χ2 test of adverse events between treatment groups p=0·77). There was no difference in blood pressure, serum potassium, or creatinine during follow-up across the two groups.InterpretationConsistent with international society recommendations, renin-angiotensin system inhibitors can be safely continued in patients admitted to hospital with COVID-19.FundingREPLACE COVID Investigators, REPLACE COVID Trial Social Fundraising Campaign, and FastGrants.

Project description:Importance:Few large-scale long-term prospective cohort studies have assessed changes in antidiabetes treatment after bariatric surgery. Objective:To describe the association between bariatric surgery and rates of continuation, discontinuation, or initiation of antidiabetes treatment 6 years after bariatric surgery compared with a matched control obese group. Design, Setting, and Participants:This nationwide observational population-based cohort study extracted health care reimbursement data from the French national health insurance database from January 1, 2008, to December 31, 2015. All patients undergoing primary bariatric surgery in France between January 1 and December 31, 2009, were matched on age, sex, body mass index category, and antidiabetes treatment with control patients hospitalized for obesity in 2009 with no bariatric surgery between 2005 and 2015. Exposures:Bariatric surgery, including adjustable gastric banding (AGB), gastric bypass (GBP), and sleeve gastrectomy (SG). Main Outcome and Measure:Reimbursement for antidiabetes drugs. Mixed-effects logistic regression models estimated factors of discontinuation or initiation of antidiabetes treatment over a period of 6 years. Results:In 2009, a total of 15 650 patients (mean [SD] age, 38.9 [11.2] years; 84.6% female; 1633 receiving antidiabetes treatment) underwent primary bariatric surgery, with 48.5% undergoing AGB, 27.7% undergoing GBP, and 22.0% undergoing SG. Among patients receiving antidiabetes treatment at baseline, the antidiabetes treatment discontinuation rate was higher 6 years after bariatric surgery than in controls (-49.9% vs -9.0%, P < .001). In multivariable analysis, the main predictive factors for discontinuation were the following: GBP (odds ratio [OR], 16.7; 95% CI, 13.0-21.4), SG (OR, 7.30; 95% CI, 5.50-9.50), and AGB (OR, 4.30; 95% CI, 3.30-5.60) compared with no bariatric surgery, as well as insulin use (OR, 0.17; 95% CI, 0.13-0.22), dual therapy without insulin (OR, 0.38; 95% CI, 0.32-0.45) vs monotherapy, lipid-lowering treatment (OR, 0.76; 95% CI, 0.63-0.91), antidepressant treatment (OR, 0.67; 95% CI, 0.55-0.81), and age (OR, 0.96; 95% CI, 0.95-0.97) per year. For patients without antidiabetes treatment at baseline, the 6-year antidiabetes treatment initiation rate was much lower after bariatric surgery than in controls (1.4% vs 12.0%, P < .001). In multivariable analysis, protective factors were GBP (OR, 0.06; 95% CI, 0.04-0.09), SG (OR, 0.08; 95% CI, 0.06-0.11), and AGB (OR, 0.16; 95% CI, 0.14-0.20) vs controls, and risk factors were as follows: body mass index category (OR, 2.04; 95% CI, 1.68-2.47 for ≥50.0 vs 30.0-39.9 and OR, 1.68; 95% CI, 1.49-1.90 for 40.0-49.9 vs 30.0-39.9), antihypertensive treatment (OR, 1.49; 95% CI, 1.33-1.67), low income (OR, 1.43; 95 % CI, 1.26-1.62), and age (OR, 1.04; 95 % CI, 1.03-1.05) per year. Conclusions and Relevance:Bariatric surgery was associated with a significantly higher 6-year postoperative antidiabetes treatment discontinuation rate compared with baseline and with an obese control group without bariatric surgery.

Project description:Background Renin-angiotensin system blockers (RASBs) have well-validated benefit in patients with hypertension, coronary artery disease, and left ventricular systolic dysfunction. Their use in the perioperative period, however, has been controversial, including in patients undergoing cardiac surgery, who often have a strong indication for their use. In the current study, we explore the impact of RASB use with 30-day and 1-year mortality after cardiac surgery. Methods and Results The Veterans Affairs Surgical Quality Improvement Program and Corporate Data Warehouse were data sources for this retrospective cohort study. A total of 37 197 veterans undergoing elective coronary artery bypass grafting and or valve repair or replacement over a 10-year period met inclusion criteria and were stratified into 4 groups by preoperative exposure (preoperative exposure versus no preoperative exposure) and postoperative continuing exposure (current exposure versus no current exposure) to RASBs. After adjusting for all baseline covariates, the preoperative exposure/current exposure group had lower 30-day and 1-year mortality than the preoperative exposure/no current exposure (30-day hazard ratio [HR], 0.25; 95% CI, 0.19-0.33 [P<0.001] and 1-year HR, 0.40; 95% CI, 0.33-0.48 [P<0.001] or no preoperative exposure/no current exposure (30-day HR, 0.44; 95% CI, 0.32-0.60 [P<0.001] and 1-year HR, 0.72; 95% CI, 0.62-0.84 [P<0.001] groups. The no preoperative exposure/current exposure group had significantly lower 30-day (HR, 0.31; 95% CI, 0.14-0.71 [P=0.006]) and 1-year (HR, 0.64; 95% CI, 0.53-0.77 [P<0.001]) mortality than the no preoperative exposure/no current exposure group. Conclusions Continuation of preoperative RASBs and initiation before discharge is associated with decreased mortality in veterans undergoing cardiac surgery. Given these findings, continuation of preoperative RASBs or initiation in the early postoperative period should be considered in patients undergoing cardiac surgery.

Project description:ImportanceIt is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR).ObjectiveTo investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD).Design, setting, and participantsThis retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019.ExposuresIndividuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2.Main outcomes and measuresThe association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD.ResultsOf the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65).Conclusions and relevanceThe findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Dataset Information

Impact of renin-angiotensin system inhibitors continuation versus discontinuation on outcome after major surgery: protocol of a multicenter randomized, controlled trial (STOP-or-NOT trial).

Publications

Impact of renin-angiotensin system inhibitors continuation versus discontinuation on outcome after major surgery: protocol of a multicenter randomized, controlled trial (STOP-or-NOT trial).

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