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Angiotensin Converting Enzyme Inhibitors Are Not Associated with Respiratory Complications or Mortality After Noncardiac Surgery

Turan, Alparslan MD*; You, Jing MS*,†; Shiba, Ayako MD*; Kurz, Andrea MD*; Saager, Leif MD*; Sessler, Daniel I. MD*

doi: 10.1213/ANE.0b013e318241f6af
Anesthetic Pharmacology
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BACKGROUND: General use of angiotensin-converting enzyme inhibitors (ACEIs) is associated with upper-airway complications such as cough, angioedema, and bronchospasm; furthermore, preoperative use is associated with increased morbidity or mortality. Our primary goal in this study was thus to evaluate the association of ACEI therapy with perioperative respiratory morbidity in adult noncardiac surgical patients. Our secondary goals were to evaluate the association between preoperative use of ACEI and 30-day mortality, as well as to a composite outcome of in-hospital morbidity and mortality in adult noncardiac surgical patients having general anesthesia.

METHODS: We evaluated 79,228 patients (9905 ACEI users [13] and 66,620 [87%] non-ACEI users) who had noncardiac surgery at the Cleveland Clinic between 2005 and 2009. Propensity matching successfully paired 9028 ACEI users (91% of 9905 patients) with 9028 controls. Matched intraoperative ACEI users and non-ACEI users were compared on intraoperative and postoperative respiratory morbidity composites as well as individual complications, 30-day mortality, and a composite of in-hospital morbidity and mortality.

RESULTS: The association between ACEI use and respiratory morbidity composites was not statistically significant intraoperatively (OR: 1.09 [97.5% CI: 0.91, 1.31], ACEI versus non-ACEI; P = 0.28) or postoperatively (OR: 0.97 [97.5% CI: 0.81, 1.16], ACEI versus non-ACEI; P = 0.69). Within the propensity-matched subset, ACEI usage was not associated with either 30-day mortality (OR: 0.93 [95% CI: 0.73, 1.19], ACEI versus non-ACEI; P = 0.56) or the composite of in-hospital morbidity and mortality (OR: 1.06 [95% CI: 0.97, 1.15], ACEI versus non-ACEI; P = 0.22). We also observed that the ACEI and the non-ACEI groups were descriptively similar (standardized differences <0.03) on multiple time periods of intraoperative hemodynamic characteristics, vasopressor use, and colloid and crystalloid infusions.

CONCLUSIONS: We did not find any association between use of ACEIs and intraoperative or postoperative upper-airway complications. Furthermore, ACEI use was not associated with in-hospital complications or increased 30-day mortality.

Published ahead of print January 17, 2012 Supplemental Digital Content is available in the text.

From the *Department of Outcomes Research and Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.

Ayako Shiba is currently affiliated with Anesthesiology Institute, Jikei University School of Medicine, Tokyo, Japan.

Funding: Institutional and/or departmental sources.

The authors declare no conflict of interest.

Reprints will not be available from the authors.

Address correspondence to Alparslan Turan, MD, Department of Outcomes Research, Cleveland Clinic, 9500 Euclid Avenue/P77, Cleveland, OH 44195. Address e-mail to turana@ccf.org. On the world wide web: www.OR.org.

Accepted October 24, 2011

Published ahead of print January 17, 2012

Angiotensin-converting enzyme inhibitors (ACEIs) are widely used to treat hypertension and heart failure. They are among the most prescribed drugs in the United States, with 163 million prescriptions (4.2% of the total) being written for ACEIs in 2009.a ACEIs reduce mortality and have cardioprotective effects in patients recovering from acute myocardial infarction.1,2 They exert antiatherosclerotic, antithrombotic, and anti-inflammatory effects, anti-ischemic actions that apparently prevent acute coronary events and related outcomes.3,4 For example, Feringa et al. demonstrated that use of perioperative ACEIs reduced mortality in patients with left ventricular dysfunction undergoing vascular surgery.5

ACEIs prevent conversion of angiotensin I to angiotensin II, which is a powerful arterial vasoconstrictor; they also reduce aldosterone secretion that in turn decreases sodium retention.6 Angiotensin-converting enzyme is identical to kininase II, an enzyme involved in the degradation of bradykinin. Thus, ACEIs increase local tissue concentration of bradykinin and enhances its effects.7 Bradykinin sensitizes airways, thereby potentially inducing cough, angioedema, and bronchospasm; these complications are the most commonly reported adverse effects of ACEIs.810 These adverse effects do not necessarily occur at initiation of the therapy, and they are also common perioperative complications. Perioperative use of ACEIs is also controversial because there have been a number of reports of refractory perioperative hypotension in patients taking the drugs.11,12 Furthermore, preoperative ACEI administration is associated with increased mortality in patients undergoing coronary artery bypass grafting13 and elective vascular surgery.14

There are thus compelling reasons to believe that preoperative use of ACEIs may trigger upper airway complications, provoke hypotension, and worsen mortality. However, available literature does not address perioperative airway complications; furthermore, substantial evidence that preoperative ACEI use is associated with increased morbidity or mortality is lacking. Our primary goal was thus to evaluate the association of ACEI therapy with perioperative respiratory morbidity in adult noncardiac surgical patients. Our secondary goals were to evaluate the association between preoperative use of ACEI and 30-day mortality, as well as to a composite outcome of in-hospital morbidity and mortality in adult noncardiac surgical patients having general anesthesia.

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METHODS

With approval (Cleveland Clinic, Cleveland, OH), this retrospective study was based on data from 79,228 adult general surgical patients treated at the Cleveland Clinic main campus hospital between 2005 and 2009. Preoperative medications and outcome variables were obtained from the Cleveland Clinic Perioperative Health Documentation System, which includes details from our electronic anesthesia record keeping system. Patients who received only general anesthesia were included. The requirement for written informed consent was waived by the IRB.

Available records include all medication use, including ACEIs. However, they do not specify if medications were taken the morning of surgery. It is our routine, though, to instruct patients who normally take ACEIs to continue until the day before surgery, but not to take them the morning of surgery.

The primary outcomes were a collapsed composite (any versus none) of intraoperative respiratory morbidity (including bronchospasm and use of albuterol), and a collapsed composite of postoperative respiratory morbidity (including pneumonia, acute pulmonary edema, and acute respiratory distress syndrome). The secondary outcomes were 30-day mortality and a collapsed composite of in-hospital mortality and 8 in-hospital morbidities: neurological complications, cardiac complications and acute lung edema, pulmonary/respiratory complications, infectious complications, urinary/renal complications, hemorrhagic complication, wound disruption, and peripheral vascular complications (Table 1).

Table 1

Table 1

Propensity score matching was used to obtain ACEI therapy and non-ACEI patients who were balanced on potentially confounding baseline variables as follows. We first estimated the propensity score (probability of taking ACEI therapy) for each patient using a logistic regression model based on all baseline characteristics listed in Table 1. We grouped each CPT code into 1 of 244 mutually exclusive clinically appropriate categories using the agency for healthcare research and quality's clinical classification software for services and procedures (AHRQ-CCS). Next, each ACEI user was matched to one nonuser by a greedy matching algorithm15 (SAS macro: gmatchb). Successful ACEI user/nonuser matches were then restricted to patients with the same AHRQ-CCS category, as well as the logit of the estimated propensity scores (i.e., log(p/(1 − p)), where p is the estimated propensity scores) within 0.2 of the SD of the logit of the propensity score of one another.16 A single imputation for missing body mass index values (10% of patients) based on all available baseline variables was used.

Balance between ACEI users and nonusers on the matched variables before and after the matching was assessed using the absolute standardized difference (ASD), i.e., the absolute difference in means or proportions divided by the pooled SD. To account for even minimal potential confounding, we used a conservative criterion of >0.03 (i.e.,

) ASD difference as indication of imbalance16). Any imbalanced variables after the propensity matching were included in the multivariable models when comparing the matched ACEI users and nonusers on outcomes.

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Primary Outcomes

The matched ACEI users and nonusers were compared on the 2 primary outcomes (intraoperative and postoperative respiratory morbidity composites) and their individual outcome components with multivariable logistic regression models. A Bonferroni correction was used to adjust for multiple testing to control the overall significance level at 0.05. Thus, 97.5% confidence intervals (CI) are reported; and the significance criterion for the 2 primary outcomes was P < 0.025 (i.e., 0.05/2). In addition, since the incidences among the individual components were quite distinct (e.g., acute respiratory distress syndrome: >3%; and pneumonia: 0.1%), the generalized estimating equation average relative effect (i.e., average log odds ratio [OR]) of ACEI therapy across the individual components of each of the 2 primary outcomes was assessed.17 This method summarizes the individual component treatment effects independent of their baseline incidences.

We also performed 2 sensitivity analyses. The matched ACEI users and nonusers were compared on primary outcomes using logistic regression, without adjusting for the residual imbalanced variables. Second, we compared the matched patients using a more conservative approach, adjusting for all of the variables used for the propensity score matching.18

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Secondary Outcomes

Within the matched subset, we also assessed the associations between use of ACEIs and 30-day mortality as well as the composite of in-hospital mortality and morbidity by multivariable logistic regression models, adjusting for imbalanced covariables after the propensity score matching.

Finally, we summarized the intraoperative hemodynamic characteristics of the propensity-matched patients, including amount of ephedrine, phenylephrine, and epinephrine given, estimated blood loss, transfusion of crystalloid and colloid, arterial blood pressure, heart rate, and incidence of intraoperative hypotension. Standard summary statistics were reported; differences between the ACEI and non-ACEI patients were estimated using the standardized difference. We assessed the association between use of ACEI and incidence of intraoperative hypotension by multivariable logistic regression, adjusting for preoperative use of β blockers, angiotensin receptor blockers, and calcium channel blockers. Intraoperative hemodynamic monitoring data were acquired from an electronic anesthesia record-keeping system, which records data from the anesthesia monitor. Arterial blood pressure in patients with invasive arterial catheters was recorded each minute and in patients without an arterial line at every 1- to 5-minute intervals. We used 2 different definitions for intraoperative hypotension. Intraoperative hypotension was defined by systolic blood pressure <90 mm Hg for at least 5 continuous minutes or a reduction in mean arterial blood pressure of ≥35% (based on the first reading before anesthetic induction).19

With 18,056 patients (9028 per group), we had 13%, 48%, 83%, and 97% power at the 0.025 significance level to detect ORs of 1.1, 1.2, 1.3, and 1.4, respectively, with a 2-tailed test using a reference incidence of 3%. SAS software version 9.2 for UNIX (SAS Institute, Cary, NC) and the base and the stats packages in R software version 2.12.0 for Windows (the R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses.

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RESULTS

Data from 79,228 surgical patients were available, of these 2703 patients with missing values of preoperative ACEI therapy usage information or any of the 2 primary outcomes were excluded. Thus, 76,525 patients (9905 ACEI users [13%] and 66,620 [87%] non-ACEI users) were analyzed. Among these, the observed incidence of experiencing at least 1 intraoperative respiratory morbidity was 3.6% (n = 360) for patients who took ACEIs and 2.7% (n = 1814) for patients who did not. The observed incidence of the collapsed postoperative respiratory morbidity was 4.2% (n = 412) and 3.1% (n = 2053) in patients who did and did not take ACEIs.

Propensity matching successfully paired 9028 ACEI users (91% of 9905 patients) with 9028 controls. As seen in Table 2, the ACEI and non-ACEI users were much better balanced on covariables as a result of propensity matching. However, a slight imbalance (0.03 ≤ ASD < 0.10) remained for ASA status, history of hypertension, coronary artery disease, use of β blockers, angiotensin II receptor blockers and statins, and year of surgery (ASD: 0.15). To be conservative, we included all the above factors in the multivariable models when comparing the 2 groups on the outcomes.

Table 2

Table 2

Within the propensity-matched subset (18,056 patients), the observed incidence of having at least 1 intraoperative respiratory morbidity was 3.6% for the ACEI group and 3.4% for the non-ACEI group, corresponding to an OR (97.5% CI) of 1.09 (0.91, 1.31) P = 0.28. Likewise, the observed postoperative respiratory morbidity incidences were 3.8% for the ACEI and 4.0% for the non-ACEI group, corresponding to an estimated OR of 0.97 (97.5% CI: 0.81, 1.16; ACEI versus non-ACEI), P = 0.69 (Table 3). The sensitivity analyses gave very similar results (Table 4). In addition, the average relative effect (i.e., giving equal weight to the effect on each morbidity in the composite) of ACEI therapy across the individual intraoperative respiratory morbidities was estimated as an OR (97.5% CI) of 0.99 (0.37, 2.64; ACEI versus non-ACEI), P = 0.99, and as an OR (97.5% CI) of 0.84 (0.65, 1.09; ACEI versus non-ACEI), P = 0.19, across the individual postoperative respiratory morbidities.

Table 3

Table 3

Table 4

Table 4

No significant association was found between ACEI use and any of the secondary outcomes, including 30-day mortality (OR [95% CI]: 0.93 [0.73, 1.19], ACEI versus non-ACEI; P = 0.56) and the composite of in-hospital morbidity and mortality (OR [95% CI]: 1.06 [0.97, 1.15], ACEI versus non-ACEI; P = 0.22, Table 5). Seven hundred sixty-four patients with missing 30-day mortality were excluded when assessing the association with 30-day mortality.

Table 5

Table 5

We also observed that the ACEI and the non-ACEI groups were descriptively similar (ASD <0.03) on use of vasopressor, amount of ephedrine, epinephrine, crystalloid, and colloid, estimated blood loss, and systolic and diastolic blood pressures during surgery (Table 6 and Figs. 1 and 2). Although patients in the ACEI group, on average, were more likely to receive more phenylephrine, and more likely to have higher systolic and diastolic blood pressures at baseline, and to have a faster heart rate during surgery (ASD ≥0.03), none of the differences was clinically relevant (Table 6).

Table 6

Table 6

Figure 1

Figure 1

Figure 2

Figure 2

The incidence of hypotension was observed to be very similar between the ACEI and non-ACEI users (ASD <0.03; Table 7). After adjusting for use of β blockers, angiotensin receptor blockers, and calcium channel blockers, use of ACEIs was not associated with the incidence of intraoperative hypotension: systolic blood pressure <90 mm Hg for at least 5 continuous minutes (OR [95% CI]: 0.98 [0.92, 1.04], ACEI versus non-ACEI; P = 0.54), and occurrence of a decrease ≥35% reduction in mean arterial blood pressure (OR [95% CI]: 1.03 [0.96, 1.09], ACEI versus non-ACEI; P = 0.43) (Table 8).

Table 7

Table 7

Table 8

Table 8

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DISCUSSION

The most common respiratory side effects associated with ACEI use are cough, angioedema, and bronchospasm.10 The incidence of these respiratory problems is variously reported, and their impact on patients with compromised airways remains controversial.20,21 Endotracheal intubation is also a potent airway stimulant, even in patients with normal airways. Because patients receiving ACEI tend to have increased bronchial reactivity, they might be expected to experience perioperative respiratory complications. Surprisingly, though, we did not find significant associations between preoperative ACEI usage and either intraoperative or postoperative respiratory complications. Our study suggests that patients taking ACEIs preoperatively are between 10% less likely to 24% more likely to experience intraoperative respiratory complications and 17% less likely to 13% more likely to experience postoperative respiratory complications. Our results are supported by studies in which ACEIs were used in patients with asthma and chronic obstructive pulmonary disease and demonstrated no change in respiratory functions in long-term use.22 We were unable to find any other study in the literature investigating the effects of ACEIs on respiratory complications in anesthetized patients.

The renin–angiotensin–aldosterone system plays an important role in endothelial dysfunction, which is an important first step in atherosclerosis, leading to numerous clinical consequences including hypertension, myocardial ischemia, and stroke.23 ACEIs have revolutionized the treatment of hypertension by preventing or even reversing endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardio- and cerebrovascular events.24 The benefit of ACEIs is supported by clinical studies demonstrating clear improvements in mortality and morbidity in patients with congestive heart failure.25,26 However, perioperative use of ACEIs remains controversial. For example, small studies report refractory intraoperative hypotension in patients using ACEIs.2729 Subsequently, intraoperative hypotension was associated with increased risk of cardiac adverse events and mortality.13,14

Again surprisingly, we were unable to demonstrate any association between ACEI use and arterial blood pressure despite considering several definitions of hypotension and various phases of anesthesia. There was also no difference in vasopressor use, or in crystalloid or colloid consumption. Our hemodynamic results are consistent with Keterpal et al.,30 who also did not identify an independent association of ACEIs with hypotension, although concomitant use of diuretics increased intraoperative hypotension. In another study, patients taking ACEIs 10 hours before surgery had an increased risk of moderate hypotension in the first 30 minutes after anesthetic induction, although there was no difference at any other time point, and no difference in vasopressor use.31 Available information thus suggests that ACEIs either do not provoke intraoperative hypotension, or that the effect is modest.

Similar controversy surrounds the relationship between ACEI and perioperative mortality and morbidity. For example, ACEI use in patients with left ventricular dysfunction was independently associated with reduced in-hospital mortality in patients having major vascular surgery.5 In contrast, ACEI therapy was associated with increased mortality in patients having coronary artery bypass grafting surgery.13 And in a recent cohort study, mortality was increased in patients undergoing elective open abdominal aortic aneurysm repair.14 Our results are consistent with those of the IMAGINE (Ischemia Management with Accupril Post Bypass Graft via Inhibition of Angiotensin Converting Enzyme) multicenter randomized trial, which included 2553 patients and found that ACEI use did not promote cardiovascular events or worsen postoperative mortality.32

Considering the variable and sparse available literature, it is perhaps unsurprising that there is no consensus among clinicians as to whether to continue or withhold ACEIs before surgery: some suggest stopping ACEIs before surgery to reduce the risk of intraoperative hypotension, others suggest continuing ACEIs to avoid rebound hypertension, and yet others suggest stopping ACEIs only in patients taking multiple antihypertensive medications to avoid “double hits.” Our practice at the Cleveland Clinic is to ask patients not to take ACEIs the morning of surgery and also to resume the day of the surgery or after surgery. This abstinence period from last dose is more than the half-life of most ACEIs. It remains possible that significant and clinically important differences in arterial blood pressure and mortality might have been observed had ACEIs been continued through the morning of surgery.

Our study and that of Keterpal et al.30 included a broad range of surgical patients, whereas most others were restricted to various high-risk populations, which limited their generalizability. In contrast, we included both serious and minor procedures; it is also likely that our patients had fewer baseline comorbidities than those in previous studies. An advantage of a registry analyses is that the sample sizes are large, and the results thus presumably generalizable. Furthermore, inclusion criteria are uniform, and reliability is enhanced by consistent data collection. There are nonetheless distinct limitations to retrospective analyses. Most importantly, retrospective analysis reduces the protections against selection bias and confounding that are normally provided by randomization. However, our use of sophisticated statistical techniques, especially propensity matching, presumably improves validity of the analysis.

An additional limitation is that our outcomes, aside from 30-day mortality, are based on in-hospital ICD-9 billing codes rather than being specifically and prospectively evaluated. It is thus likely that some clinically important in-hospital events, such as silent myocardial infarctions, were not recorded. Another important limitation is related to preoperative compliance of the patients with the use ACEI and the reinitiation of ACEI after surgery. Furthermore, no postdischarge events were included. To the extent that outcomes occurred postoperatively or were missed through incomplete coding, reported frequencies will underestimate the true incidence. But unless outcome identification in our registry is biased, reported ORs will remain accurate.

Perhaps the most serious limitation of our analysis is that while we routinely ask patients not to take ACEIs the morning of surgery, we do not actually know whether they did or did not. We note, though, that taking ACEIs the morning of surgery would presumably worsen results rather than the reverse. Our conclusion that pulmonary and hemodynamic complications and mortality are not worsened by chronic ACEI use (stopped the morning of surgery) is thus probably valid.

In summary, we did not observe an association between use of ACEIs and intraoperative or postoperative upper-airway complications. Furthermore, ACEI use was not associated with worsened hypotension, more complications, or increased 30-day mortality. Considering all available data, we conclude that insufficient evidence supports the theory that ACEI use, discontinued on the morning of surgery, augments the risk of upper-airway complications, or of serious complications or mortality.

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DISCLOSURES

Name: Alparslan Turan, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Alparslan Turan has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Jing You, MS.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Jing You has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ayako Shiba, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Ayako Shiba has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Andrea Kurz, MD.

Contribution: This author helped design the study and write the manuscript.

Attestation: Andrea Kurz has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Leif Saager, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Leif Saager has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Daniel I. Sessler, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

Attestation: Daniel I. Sessler reviewed the analysis of the data and approved the final manuscript.

This manuscript was handled by: Tony Gin, MD, FRCA, FANZCA.

a IMS Health. Top therapeutic classes by U.S. dispensed prescriptions. April 6, 2010. Available at: http://www.imshealth.com/deployedfiles/imshealth/Global/Content/StaticFile/Top_Line_Data/Top%20Therapy%20Classes%20by%20U.S.RXs.pdf. Accessed February 21, 2011.
Cited Here...

b Bergstralh E, Kosanke J. Gmatch SAS program, Mayo Clinic Division of Biomedical Statistics and Informatics. Rochester, Mayo Clinic (HSR CodeXchange), 2003. Computerized matching of cases to controls using the greedy matching algorithm with a fixed number of controls per case, 2003. Available at: http://mayoresearch.mayo.edu/mayo/research/biostat/sasmacros.cfm. Last accessed September 22, 2010.
Cited Here...

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