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
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.
Results of Individual Studies and Meta-analysis
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 (I2 = 0%). Of these studies, only 2 were RCTs, totaling 563 patients, with no reported mortality.
Major Cardiac Events.
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 (I2 = 0%).
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.
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 (I2 = 0%).
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).
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 (I2 = 71%).
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.
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.
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).
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; I2 = 0%; P < .0001).
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.
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.
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.
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.
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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