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A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery

Hollmann, Caryl, MBChB, DA(SA); Fernandes, Nicole L., MBChB, DA(SA); Biccard, Bruce M., MBChB, FCA, PhD

doi: 10.1213/ANE.0000000000002837
Patient Safety: Meta-Analysis

BACKGROUND: The global rate of major noncardiac surgical procedures is increasing annually, and of those patients presenting for surgery, increasing numbers are taking either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The current recommendations of whether to continue or withhold ACE-I and ARB in the perioperative period are conflicting. Previous meta-analyses have linked preoperative ACE-I/ARB therapy to the increased incidence of postinduction hypotension; however, they have failed to correlate this with adverse patient outcomes. The aim of this meta-analysis was to determine whether continuation or withholding ACE-I or ARB therapy in the perioperative period is associated with mortality and major morbidity.

METHODS: This meta-analysis was prospectively registered on PROSPERO (CRD42017055291). A comprehensive search of MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science was conducted on December 6, 2016. We included adult patients >18 years of age on chronic ACE-I or ARB therapy who underwent noncardiac surgery in which ACE-I or ARB was either withheld or continued on the morning of surgery. Primary outcomes included all-cause mortality and major cardiac events (MACE). Secondary outcomes included the risk of congestive heart failure, acute kidney injury, stroke, intraoperative/postoperative hypotension, and the length of hospital stay.

RESULTS: After abstract review, the full text of 25 studies was retrieved, of which 9 fulfilled the inclusion criteria: 5 were randomized control trials, and 4 were cohort studies. These studies included a total of 6022 patients on chronic ACE-I/ARB therapy before noncardiac surgery. A total of 1816 patients withheld treatment the morning of surgery and 4206 continued their ACE-I/ARB. Preoperative demographics were similar between the 2 groups. Withholding ACE-I/ARB therapy was not associated with a difference in mortality (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.62–1.52; I 2 = 0%) or MACE (OR, 1.12; 95% CI, 0.82–1.52; I 2 = 0%). However, withholding therapy was associated with significantly less intraoperative hypotension (OR, 0.63; 95% CI, 0.47–0.85; I 2 = 71%). No effect estimate could be pooled concerning length of hospital stay and congestive heart failure.

CONCLUSIONS: This meta-analysis did not demonstrate an association between perioperative administration of ACE-I/ARB and mortality or MACE. It did, however, confirm the current observation that perioperative continuation of ACE-I/ARBs is associated with an increased incidence of intraoperative hypotension. A large randomized control trial is necessary to determine the appropriate perioperative management of ACE-I and ARBs.

From the Department of Anaesthesia and Perioperative Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa.

Published ahead of print January 29, 2018.

Accepted for publication December 19, 2017.

Funding: No outside funding was utilized in the search and retrieval of all articles. All funding was from departmental resources.

Conflicts of Interest: See Disclosures at the end of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

PROSPERO registry: CRD42017055291.

Reprints will not be available from the authors.

Address correspondence to Caryl Hollmann, MBChB, DA(SA), Department of Anaesthesia and Perioperative Medicine, D23, Groote Schuur Hospital, University of Cape Town, Observatory, Cape Town 7925, South Africa. Address e-mail to carylhollmann@gmail.com.

KEY POINTS

  • Question: Is the withholding or continuation of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) before noncardiac surgery associated with perioperative mortality or major morbidity?
  • Findings: The continuation of ACE-Is/ARBs on the morning of noncardiac surgery is associated with increased intraoperative hypotension; however, an association with mortality and major adverse cardiac events remains unclear.
  • Meaning: Large randomized trials are needed to adequately assess for an association between perioperative ACE-I/ARB use and major morbidity in noncardiac surgery.

More than 280 million surgeries are performed globally each year1; of these patients, approximately one-third are ≥45 years and are on either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB) before surgery.2 Controversy exists as to whether ACE-Is/ARBs should be continued in the perioperative period because continuation has been associated with both harm and benefit. Intraoperative hypotension secondary to continuation of ACE-I and ARB therapy in the perioperative period3 , 4 may be associated with major perioperative morbidity2 and has led some clinicians to withhold therapy. Conversely, continuation of ACE-Is/ARBs in the perioperative period may also be associated with improved outcomes, in which preoperative ACE-I has been associated with improved outcomes in vascular surgical patients who have sustained a perioperative myocardial infarction (MI).5 This is potentially important considering a 30-day mortality rate after a perioperative MI after noncardiac surgery of approximately 10%.6 However, these cardiovascular benefits have not consistently been demonstrated in the literature.7 It is for these reasons that the potential harms or benefits associated with continuing or withholding ACE-I and ARBs in the perioperative period remain unclear.

It is not surprising that the current perioperative guidelines vary in the recommendations made regarding perioperative continuation or withholding of ACE-Is/ARBs. The 2014 American College of Cardiology/American Heart Association guidelines8 state that it is reasonable to continue therapy preoperatively, and if withheld, therapy may be reinstituted as soon as clinically feasible, while the most recent guidelines by the Canadian Cardiovascular Society9 suggest omitting therapy 24 hours before surgery (strong recommendation, low quality of evidence). In contrast, the European Society of Cardiology/European Society of Anaesthesiology10 bases its recommendations on the indication for treatment with an ACE-I/ARB, recommending discontinuation for 24 hours before surgery if prescribed for hypertension, and continuation if prescribed for heart failure and left ventricular systolic dysfunction.10 Furthermore, should these patients not be on ACE-I/ARB therapy before surgery, guidelines recommend instituting ≥1 week before surgery.10 Unfortunately, the evidence for the American, European, and Canadian guidelines is limited.

Two previous meta-analyses11 , 12 have provided information concerning perioperative ACE-I/ARB therapy and the impact on mortality and major morbidity. Unfortunately, both cardiac and noncardiac data were used in both, with main results revealing no significant difference in MI or mortality12 and a 50% increase in the incidence of postinduction hypotension11 associated with treatment continuation. These meta-analyses and numerous previous studies are therefore underpowered to address potential associations between perioperative ACE-I/ARBs and major morbidity,3 , 4 , 13–15 despite a clear demonstration of increased incidence of intraoperative hypotension. Associations with MI, acute kidney injury (AKI), death, or stroke remain unknown. Considering the uncertainty in the current literature concerning the clinical consequences associated with continuing or withholding of ACE-I/ARBs in the perioperative period, and the absence of a recent meta-analysis addressing this problem, an updated review of the literature is needed to accurately inform the decision on whether to withhold or continue perioperative ACE-I/ARB therapy.

The objectives of this meta-analysis were therefore to estimate and assess the mortality and major morbidity associated with withholding or continuation of ACE-I/ARBs before noncardiac surgery.

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METHODS

Protocol and Registration

This systematic review and meta-analysis was registered with PROSPERO (international prospective register for systematic reviews CRD42017055291). The review was approved by the ethics board at the University of Cape Town, and the need for consent waived as all data extracted was in the public domain. We adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analysis16 guidelines.

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Eligibility Criteria

The aim of this systematic review was to report on important patient outcomes associated with withholding or continuing ACE-Is/ARBs on the morning of noncardiac surgery. Study eligibility was determined by the participants or population, interventions, comparisons, outcomes, and study design criteria. Eligible populations included all adult patients (>18 years of age) who were chronically receiving either ACE-I/ARB and undergoing noncardiac surgery. The intervention included withholding of ACE-I/ARB therapy either on the day of surgery or the day before surgery, with the comparator group continuing treatment through the perioperative period. Primary outcomes included all-cause mortality and major cardiac events (MACE). We used the included study definitions of MACE in the analyses. Secondary outcomes included the incidence of AKI, congestive heart failure (CHF), cerebrovascular accident (CVA), intraoperative and postoperative hypotension, and length of hospital stay (LOS). We included the following study designs: randomized controlled trials (RCTs) or observational studies in which patients in both treatment arms were on chronic ACE-I/ARB therapy before surgery. Case reports and case–control studies were excluded. We evaluated ACE-Is/ARBs as a treatment group and did not attempt to evaluate the effects of specific classes of ACE-I or ARB drugs. We included all human studies regardless of language, sample size, publication status, or date of publication.

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Information Sources and Search

We searched 6 electronic databases through December 6, 2016: MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science. The search terms included the following: Angiotensin Type II Receptor Antagonists (MESH term) or Angiotensin-Converting Enzyme Inhibitors (MESH term) and Withholding Treatment (MESH term) and Surgical Procedures, Operative (MESH term) not Cardiac Surgical Procedures (MESH term). Limits included human studies only. The search strategy is shown in Supplemental Digital Content 1, Appendix 1, http://links.lww.com/AA/C251.

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Study Selection Process

The title and abstract of each citation were independently screened by 2 authors (C.H. and N.L.F.) to identify potentially eligible studies. Study patients were excluded if: (1) the study patients were undergoing cardiac surgery; (2) ACE-Is/ARBs were not withheld before surgery; (3) patients were not on chronic ACE-I/ARB therapy before surgery; and (4) nonhuman studies. We excluded reviews, case reports, and duplicate publications. Potentially relevant studies were retrieved for full-text evaluation.

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Data Collection Process

Full texts of all potentially relevant studies were independently evaluated by 2 reviewers (C.H. and N.L.F.) to determine eligibility. Disagreements were resolved by consensus. If no consensus could be reached, a third reviewer (B.M.B.) made the final decision. A manual search of the reference lists of all included papers was also conducted. We attempted to contact the authors of included studies if further data were required.

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Data Items

A standardized data extraction sheet was used to extract population demographics, surgery, and outcome data from the included studies by C.H. and N.L.F. We extracted the definition of each outcome and time to outcome, the duration of withholding ACE-Is/ARBs, and type of ACE-I/ARB therapy. No further data were obtained from authors, and, hence, all the data presented were extracted from the publications only.

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Risk of Bias in Individual Studies

The quality of each randomized trial was assessed using the Cochrane Collaboration risk of bias tool,17 assessing selection bias, concealment bias, performance bias, detection bias, attrition bias, and other biases. Observational studies were assessed using the Newcastle Ottawa Quality Assessment Scale.18 All assessments of bias of individual studies were conducted by 2 authors (C.H. and N.L.F.) independently, and disagreements were resolved with the third reviewer (B.M.B.).

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Summary Measures and Statistical Analysis

A meta-analysis was conducted using Review Manager Version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark, 2014). Pooled dichotomous outcomes were reported as odds ratios (ORs) and 95% confidence intervals (CIs). Heterogeneity between studies was assessed using the I 2 statistic, which describes the percentage of variation across studies that is due to heterogeneity and not chance. We considered an I 2 test of >25% to represent significant heterogeneity. Because a high degree of clinical heterogeneity and between-study variance was expected, we used a random-effects model to assess all relevant outcomes. The results are presented as forest plots where applicable. Because standard RevMan (version 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) software ignores 0 events, studies with 0 outcome events were excluded from the MACE and mortality analyses.

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Additional Analyses

We planned 2 sensitivity analyses: a sensitivity analysis of RCTs only for the outcomes of mortality, MACE, and intraoperative and postoperative hypotension; and a second sensitivity analysis of studies assessing major noncardiac surgery alone.

We also conducted a trial sequential analysis (TSA) to determine the total required sample size using Trial Sequential Analysis software19 version 0.9.5.9 Beta (Copenhagen Trial Unit; Rigshospitalet, Dept 7812, The Copenhagen University Hospital, Copenhagen, Denmark). An O’Brien-Fleming α-spending analysis with a 2-sided 5% boundary was used, and a futility analysis was included. We used a 25% relative risk reduction in the analyses and included a model-based variance heterogeneity correction when calculating the required information size calculation. A continuity correction factor of 0.5 was applied to the TSA for MACE and mortality to confirm findings from the RevMan software and the exclusion of 0 events.

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RESULTS

A total of 900 citations were retrieved from the initial search, of which 12 abstracts were selected and full articles retrieved. The reference lists of retrieved articles were further screened, and 13 additional articles were added for full-text review. Of the excluded studies, 7 had no comparator group,13 , 20–25 4 were case reports,26–29 1 included cardiac data (from which we could not extract the noncardiac data or contact the authors),30 1 was a multicenter-based questionnaire,31 1 only considered preoperative blood pressure (BP),32 and 2 only considered postoperative nonresumption of ACE-I/ARB.33 , 34 Nine studies fulfilled the eligibility criteria and were selected for inclusion in the meta-analysis.2–4 , 14 , 35–39 One of the included studies was a German publication, which required translation for data extraction.37

Figure 1

Figure 1

We were unsuccessful in obtaining further data from the authors of 3 of the studies.30 , 32 , 36 As a result, 2 of these studies were excluded. Vijay et al30 conducted an observational study on 323 patients undergoing noncardiac and cardiac surgery; however, noncardiac data only could not be extracted from the pooled results. Griffin et al32 reported on preoperative BP only, with no documentation on intraoperative or postoperative outcomes. A detailed flow diagram of the excluded and included trials is shown in Figure 1.

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Study Characteristics

Of the 9 included studies, 5 were RCTs3 , 4 , 36 , 37 , 39 and 4 were cohort studies,2 , 14 , 35 , 38 with a total of 6022 patients on chronic ACE-I/ARB therapy. A total of 1816 withheld treatment on the morning of surgery, and 4206 continued their ACE-I/ARB therapy. The patient demographics and comorbid diseases are presented in Table 1, and the type of ACE-I/ARB, duration of withholding therapy, and the outcomes measured and time to outcomes are presented in Table 2. The individual study outcome definitions used for the primary and secondary outcomes in the meta-analysis are shown in Supplemental Digital Content 2 and 3, Table 1, http://links.lww.com/AA/C252, Table 2, http://links.lww.com/AA/C253, respectively.

Table 1

Table 1

Table 2

Table 2

Six studies omitted ACE-Is/ARBs on the day before surgery,2 , 4 , 35–37 , 39 and 2 studies omitted therapy ≥10 hours before surgery.14 , 38 In 1 study, captopril was omitted 12 hours before surgery and enalapril 24 hours before surgery,3 based on the difference in the half-lives of the respective agents. There was no published information on when ACE-I/ARB therapies were resumed. There was large variability in the duration of follow-up between studies, ranging from the day of hospital discharge to 30 days after surgery.2

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Risk of Bias Within Studies

The risk of bias of the 5 RCTs is shown in Supplemental Digital Content 4, Figure 1, http://links.lww.com/AA/C254. Three4 , 36 , 39 trials had low selection bias, with unclear randomization in 2 RCTs.3 , 37 Concealment was unclear in all trials, and most experienced performance bias due to unblinded participants3 , 4 , 39 or anesthesiologists.39 Two trials were assessed as having had selective reporting, in which 1 did not report all the patients for their secondary outcome of postoperative hypertension,39 and the other study did not report on outcomes of patients treated intraoperatively with ephedrine.36 Overall, the observational studies performed well in terms of selection, comparability, and outcomes (Supplemental Digital Content 5, Table 3, http://links.lww.com/AA/C255). The funnel plots representing the possibility of publication bias associated with MACE and intraoperative hypotension are shown in Supplemental Digital Content 6 and 7, Figure 2, http://links.lww.com/AA/C256, Figure 3, http://links.lww.com/AA/C257, respectively. Results suggest minimal bias, although the analysis includes few studies.

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Results of Individual Studies and Meta-analysis

Mortality.

Figure 2

Figure 2

Five studies assessed mortality as an outcome, of which 1671 patients were in the ACE-I/ARB withholding group and 4021 in the continuation group (Figure 2). There was no difference in the mortality between patients who withheld or continued ACE-I/ARB (OR, 0.97; 95% CI, 0.62–1.52). No evidence of heterogeneity was observed with this outcome (I 2 = 0%). Of these studies, only 2 were RCTs, totaling 563 patients, with no reported mortality.

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Major Cardiac Events.

Figure 3

Figure 3

Five studies reported MACE with no significant difference between the groups (OR, 1.12; 95% CI, 0.82–1.52; P = .78) (Figure 3). One study assessed both MI and myocardial injury after noncardiac surgery (MINS)2; however, only data of those patients fulfilling the MI definition were included in the meta-analysis. No evidence of heterogeneity was observed (I 2 = 0%).

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Congestive Heart Failure.

Only 1 study4 reported on the development of CHF during hospital admission, although no events were reported in the study. It was therefore not possible to determine a pooled effect for ACE-I/ARBs on CHF.

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Cerebrovascular Complications.

Four studies2 , 14 , 35 , 39 assessed the incidence of CVAs with 1653 in the withdrawal group and 4002 in the continuation group (Supplemental Digital Content 8, Figure 4, http://links.lww.com/AA/C258). Outcome events were reported only in 2 studies, with no difference between the groups (OR, 0.95; 95% CI, 0.44–2.06), and no evidence of heterogeneity between the studies observed (I 2 = 0%).

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Acute Kidney Injury.

Two studies reported on the incidence of AKI,14 , 35 with a small sample of 146 patients in the withholding group and 181 in the continuation group (Supplemental Digital Content 9, Figure 5, http://links.lww.com/AA/C259). Only 3 events were reported in the withholding group (OR, 8.39; 95% CI, 0.43–164.12).

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Intraoperative Hypotension.

Figure 4

Figure 4

Eight studies evaluated the effect of ACE-Is/ARBs on intraoperative hypotension. One study36 reported only mean and standard deviation in the assessment of postinduction hypotension compared to preoperative BPs, and because we were unable to contact these authors to establish the absolute number of patients who experienced intraoperative hypotension, these data are not included in the meta-analysis. They did, however, show that intraoperative hypotension was significantly increased for up to 60 minutes after induction in the patients who continued ACE-Is/ARBs. Seven studies totaling 5414 patients examined the effect of withholding or continuing ACE-I/ARB therapy on intraoperative hypotension and are included in the meta-analysis. The incidence of intraoperative hypotension was 30% (Figure 4). Withholding of ACE-I/ARB was associated with significantly less hypotension (OR, 0.63; 95% CI, 0.47–0.85), although there was marked heterogeneity between studies (I 2 = 71%).

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Postoperative Hypotension.

Three studies2 , 14 , 35 reported on postoperative hypotension (Supplemental Digital Content 10, Figure 6, http://links.lww.com/AA/C260), of which 1 was up to 3 days postoperatively2 and 2 were in the postanesthesia high-care unit.14 , 35 There was no difference in treatment effect (OR, 0.95; 95% CI, 0.81–1.12; P = .52), and no evidence of heterogeneity was observed between the groups.

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Length of Hospital Stay.

Only 2 studies reported on postoperative LOS.14 , 35 One study reported a median length of 3 days in the withholding group and 2 days in the continuation group,14 and the other study only reported LOS data for the entire cohort, and not individual groups.36 Neither study reported a significant difference in the length of postoperative stay between withholding and continuing ACE-Is/ARBs. It was therefore not possible to determine a pooled effect for ACE-I/ARBs on LOS.

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Additional Analyses

Randomized Trials.

A sensitivity analysis of MACE and intraoperative hypotension was conducted (Supplemental Digital Content 11, Table 4, http://links.lww.com/AA/C261) for RCTs only. For the outcome of MACE, no significant difference was identified between groups withholding or continuing therapy (OR, 1.06; 95% CI, 0.06–18.30; P = .97), and a significant increased risk of intraoperative hypotension was observed with treatment continuation (OR, 0.09; 95% CI, 0.04–0.22; P≤ .00001). We could not conduct a sensitivity analysis of RCTs for mortality (because no outcome events were reported) or postoperative hypotension (because no RCTs reported this outcome).

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Major Surgery.

Two studies3 , 4 included major surgery only, and both assessed outcomes in vascular surgical patients. For the outcomes of mortality, CHF, AKI, and LOS, it was not possible to determine pooled effects because the outcomes were either not assessed or no events were reported. For the outcome of MACE, 1 trial could be included,4 with no difference between the groups. For intraoperative hypotension, pooled data revealed a significantly increased risk of intraoperative hypotension associated with treatment continuation (OR, 0.07; 95% CI, 0.02–0.25; I 2 = 0%; P < .0001).

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Trial Sequential Analysis.

The results of the required information size and crossing of 5% significance or futility boundaries are shown in Supplemental Digital Content 12, Table 5, http://links.lww.com/AA/C262. The TSA for intraoperative hypotension crosses the boundary line and thus favors significantly less hypotension associated with withholding ACE-I/ARB therapy (Supplemental Digital Content 13, Figure 7, http://links.lww.com/AA/C263). The analysis for intraoperative hypotension is adequately powered when the larger analysis of randomized and nonrandomized trials is included. However, all the analyses are underpowered when considering only randomized trials.

The sensitivity analysis for both arm 0 events revealed unchanged ORs and CIs for MACE and mortality when a continuity correction factor of 0.5 was applied to both arm 0 events.

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DISCUSSION

The main findings in this meta-analysis are that there is no difference in mortality, MACE, CHF, AKI, or CVA between patients withholding or continuing chronic ACE-I/ARB therapy before surgery in the published literature. However, the total sample size remains small and is underpowered for all these outcomes. Concerning intraoperative hypotension, this meta-analysis demonstrated that continuing ACE-I/ARBs on the morning of surgery is associated with approximately 30% relative risk increase in hypotension (and an absolute risk increase of 6.5%, from 23.4% to 29.9%), but not postoperative hypotension. No difference in LOS was demonstrated between the groups.

This is the most comprehensive meta-analysis of outcomes associated with noncardiac surgery after withholding or continuing ACE-Is/ARBs therapy to date. Further, the population included is >10 times larger than that of the previous meta-analysis conducted in 2008,11 in which a 50% relative increase in intraoperative hypotension was demonstrated. Because only noncardiac studies were assessed in the current analysis, it clarifies the impact of continuing ACE-Is/ARBs on intraoperative hypotension in this patient group alone.

Considering the variation in hypotensive response to ACE-I/ARB therapy among individuals, it may be important to assess the impact of treatment discontinuation on the incidence of intraoperative hypotension between differing racial or ethnic groups. Previous data have confirmed that hypertensive African American patients have decreased plasma renin activity,40 , 41 increased β-adrenergic receptors,42 increased adrenergic responses to catecholamines,43 and reduced efficacy of BP reduction by ACE-I therapy.41 , 44 , 45 Twersky et al39 were the only authors to present race in their published data; however, there were no differences in the effect of withholding or continuing ACE-Is/ARBs on the preoperative BP between African Americans and non--African Americans. Unfortunately, no assessment of intraoperative hemodynamics was made, and the impact of therapy withdrawal on mortality was not assessed. Because personalized medicine may provide better outcomes for an individual than a 1-size-fits-all approach, future studies may therefore need to assess the impact of ethnicity and perioperative ACE-I/ARB therapy on patient-relevant outcomes.

Several limitations have been identified in the current meta-analysis. These include a lack of uniform definitions for morbidity outcomes, such as MACE and hypotension across the studies. Thresholds for hypotension varied as some reported a systolic BP <80 mm Hg4 and others a mean arterial pressure <60 mm Hg37 as hypotension. All hypotensive episodes were treated according to the study hypotensive thresholds, with some studies aiming to keep BP within 20% of baseline,35 and the actual duration of hypotension was not reported in any of the studies. This is a major limitation because an intraoperative mean BP <55 mm Hg exceeding 20 minutes in duration46 has been associated with increased mortality and adverse renal and cardiac outcomes. It is possible that the earlier treatment of hypotension in our included studies may have mitigated against hypotensive-associated MACE and AKI in the included RCTs. Standardized anesthetic protocols were used in only 4 studies,3 , 4 , 36 , 37 and, hence, intraoperative BPs in the remaining 5 studies may have been affected by differing anesthetic practices and anesthetic agents.

For the assessment of MACE, our meta-analysis included only data for MI and not for MINS. Diagnostic criteria for MI were based on either electrophysiological findings or biochemical investigations2 , 4 , 14 , 35 in all studies except for one,39 in which MI was not defined and no events were reported. Active surveillance was performed in only 2 of these studies.2 , 4 In one study, MACE was detected using twice-daily 12-lead electrocardiography and daily cardiac troponin I surveillance until day 3 postoperatively;4 in the other, daily troponin I surveillance was taken until day 3.2 Because >65% of perioperative MIs are asymptomatic,6 it is possible that some episodes of MACE may have been missed in the studies that did not include postoperative troponin surveillance. Importantly, postoperative troponin elevation is independently associated with 30-day mortality, independent of a diagnosis of MI.47 , 48 Of the individual studies, the largest prospective cohort2 of 4802 patients showed a 16% reduction in the relative risk of MINS (adjusted relative risk, 0.84; 95% CI, 0.7–0.998) associated with withholding therapy; however, the meta-analysis showed no difference in the outcome for MACE, although it is underpowered. This remains an important finding considering the adverse prognosis associated with MINS,48 and it needs further investigation.

Concerning study methodology, considerable variation was identified between the studies in terms of study design, bias, and definition of outcomes. Significant bias was identified in terms of performance, and in 2 studies, it included selective outcome reporting.36 , 39 Although the funnel plots suggest little potential for publication bias associated with MACE and intraoperative hypotension, there are few studies, hence, we cannot adequately assess for publication bias. All outcomes were underpowered when considering randomized trials alone with the exception of intraoperative hypotension. The inclusion of nonrandomized studies in the meta-analysis to increase the power of the pooled analysis introduces bias and may have limited the reliability of results. The lack of uniformity in the definition of specific outcomes (stroke, MACE, and intraoperative hypotension) is also undesirable and may have contributed to the heterogeneity associated with the incidence of intraoperative hypotension when continuing ACE-Is or ARBs. We were unable to contact 3 authors30 , 32 , 36 of articles that contained data that may have been included in the meta-analysis for intraoperative hypotension32 , 36 and possibly for other outcomes in which it was not possible to separate cardiac and noncardiac surgeries.30

Although we present noncardiac surgical outcomes, it is possible that the severity of the noncardiac surgery may be an important factor associated with outcomes after withholding or continuing ACE-Is/ARBs. Previous propensity score-matched studies22 , 49 , 50 and retrospective reviews51 , 52 have ranged from either minimally invasive to major vascular surgery,50 in which ACE-Is/ARBs have been associated with an increased incidence of hypotension22 and AKI in low-risk surgeries,51 , 52 but not mortality,49 and a 5-fold risk increase in mortality in major vascular surgery.50 In the current meta-analysis, a sensitivity analysis for vascular surgery demonstrated an increased incidence of intraoperative hypotension associated with treatment continuation. However, pooled data included only 2 RCTs,3 , 4 of which population sizes remained small and studies were underpowered for other outcomes.

Finally, evidence exists for adverse renal and cardiac outcomes associated with intraoperative hypotension,46 yet it remains unclear whether the hypotension associated with continuation of ACE-Is/ARBs is associated with these adverse outcomes. Furthermore, preoperative hypotension itself has recently been linked to the increased incidence of postoperative mortality,53 and thus, the impact of continuing regular ACE-I/ARB therapy in the light of preoperative hypotension is unknown. The current data would suggest that it is both ethical and necessary to proceed with a large randomized control trial of withholding or continuing ACE-I/ARB to determine which approach is safer for patient outcomes. It would need a standardized definition of intraoperative hypotension54 and intraoperative treatment thresholds.

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CONCLUSIONS

This comprehensive meta-analysis of 5 RCTs and 4 cohort studies provides the current evidence for withholding or continuing chronic ACE-I/ARB therapy in the perioperative period in noncardiac surgery. It confirms previous observations that continuation of ACE-I/ARBs is associated with intraoperative hypotension; however, it was unable to demonstrate an association between perioperative ACE-I/ARB administration and mortality or MACE. Furthermore, it remains unclear whether this intraoperative hypotension is associated with major postoperative patient morbidity and whether perioperative ACE-I/ARB therapy is associated with major morbidity, independent of any associated hypotension. Finally, the influence of pharmacogenomics on outcomes associated with perioperative ACE-I/ARB remains unanswered. A large randomized trial is needed to address these questions.

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ACKNOWLEDGMENTS

The authors thank Lawrence Bertrand from Germany who translated our German article for us. The University of Cape Town Library was utilized for accessibility to the 6 databases used for the initial search and was pivotal in retrieving full journal articles needed.

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DISCLOSURES

Name: Caryl Hollmann, MBChB, DA(SA).

Contribution: This author helped with data search and extraction, bias extraction, and first draft manuscript preparation.

Conflicts of Interest: C. Hollmann is the primary author.

Name: Nicole L. Fernandes, MBChB, DA(SA).

Contribution: This author helped with data search and extraction, bias extraction, and critical review of the manuscript.

Conflicts of Interest: None.

Name: Bruce M. Biccard, MBChB, FCA, PhD.

Contribution: This author helped with original hypothesis, data analysis, and critical review of the manuscript.

Conflicts of Interest: None.

This manuscript was handled by: Richard C. Prielipp, MD.

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