“…findings suggest that ad -min is tra tion [of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers] on the day of surgery is hazardous…”
AS of 2012, angiotensin- converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) were used by approximately 18% of adults in the United States.1 In the Veterans Affairs medical system, a population with a high proportion of patients with cardiovascular disease and strong centralized efforts at cardiovascular guideline compliance, as many as 43% of patients present for major surgery on either of these agents.2 In contrast to current guidelines3 according Class I recommendation for continuation of β-blockers on the day of surgery (and after) in patients without contraindications, considerable controversy exists regarding administration of ACEIs/ARBs. In this issue of A nesthesiology, Roshanov et al.4 present a sophisticated observational analysis of the associations of ACEI/ARB administration versus withholding of the dose within 24 h before noncardiac surgery in the large multinational, prospective observational cohort (Vascular events In noncardiac Surgery patIents cOhort evaluatioN [VISION]). Their findings suggest that administration on the day of surgery is hazardous, a finding that may perhaps finally lead to the large randomized clinical trial needed to definitively answer this chronic vexing issue.
Clinical investigation of the consequences of preoperative administration of ACEIs had first been reported in the cardiac and vascular surgical settings in the early 1990s in small randomized and observational cohort studies from two centers in France. One center focused on a higher observed incidence of hypotension on induction with their preoperative administration and the need for potent vasoconstrictors for its treatment.5,6 The other suggested that although simple volume infusion was adequate to prevent hypotension, during aortic cross-clamping (in vascular surgery) where the glomerular filtration rate was measured, a significant decrease was noted in some patients.7
Over the ensuing years to the present, ARBs were introduced; larger cohort analyses have reported conflicting results with regard to the incidence of drug-induced hypotension and its relation to adverse outcomes including mortality, myocardial infarction (MI), and of more recent interest, renal failure and atrial fibrillation (the latter in cardiac surgery only).8,9 Attempts to systematically analyze the literature have been inconclusive due to the lack of high-quality randomized trials, small sample sizes, and variable outcomes reported in observational analyses.10–12
Despite concerns over the safety of the immediate preoperative or any perioperative administration of these commonly prescribed medications, with strong guideline-based evidence of their benefits in patients with hypertension, post-MI, congestive heart failure, diabetes, and chronic renal disease in the nonoperative setting,13 many clinicians are reticent to withhold them during the stressful perioperative period. Current noncardiac and coronary artery bypass graft surgery guidelines support their continuation or transient discontinuation (with reinstitution later in the perioperative period) but make no Class I or Class III (harm) recommendations.3,14,15
Roshanov et al.4 have utilized the large multinational, prospective VISION cohort to examine risk-adjusted associations of ACEI/ARB administration (or not) within the 24 h before surgery in patients taking them within 7 days of surgery. The primary hypothesis of the VISION study was to evaluate associations of early postoperative troponin T release with 30-day mortality in patients over the age of 45 requiring at least an overnight stay in the hospital. The index publication of this study’s primary results reported significant associations for the highest peak troponin levels in relation to all-cause mortality.16 A subsequent analysis, reported in this journal,17 put forth this group’s unique (but not yet universally accepted) paradigm of myocardial injury after noncardiac surgery (MINS), whereby troponin elevation alone, irrespective of any clinical ischemic features, was statistically associated with mortality (and was considerably more common than the conventional definition of MI).
This subanalysis focuses exclusively on the 33% of VISION patients considered to be ACEI/ARB chronic preoperative users (n = 4,802) of whom 26% did not receive a dose within 24 h of surgery (n = 1,245). The primary outcome included 30-day mortality, along with stroke and MINS as a composite outcome. Prespecified secondary outcomes included the frequency of clinically important intra- and postoperative (up to day 3) hypotension, defined as any systolic blood pressure of less than or equal to 90 mmHg (for which an intervention was initiated). The primary outcome was detected in 12.0% of withheld patients versus 12.9% of treated patients for an adjusted risk ratio of 0.82 (95% CI, 0.70 to 0.96; P = 0.01). A similar risk ratio was noted for intraoperative hypotension (0.80; 95% CI, 0.72 to 0.93; P < 0.001), while a nonsignificant association was observed for postoperative hypotension. A variety of sensitivity analyses were performed, including a “tracer analysis” involving analyzing a bleeding outcome, which as expected showed no relation with the administration of ACEIs/ARBs. Of particular interest is that the primary outcome was no longer significant when MI was substituted for the MINS definition (related to its lower incidence).
The VISION study, given its large sample size and complex multinational logistics, was not designed to capture extensive physiologic data, and thus, the hypotension variables were limited to a categorical response (yes/no) although the total duration of the episodes was captured. Unfortunately, neither medication use after surgery nor renal outcomes were systematically captured.
Although ACEI/ARB use was associated with intraoperative hypotension and was correlated with progressively longer total duration, it was not associated with the primary outcome. Postoperative hypotension was associated with the primary outcome but not with ACEI/ARB use. Thus, there appear to be some inconsistencies in constructing a logical chain of events linking drug administration to hypotension to the primary outcome.
The capture of a single preoperative creatinine value upon which to risk adjust patients is standard operating procedure based on the calculation of the preoperative glomerular filtration rate or classification of the renal variable of the revised Cardiac Risk Index. However, in this study, a single measurement alone is potentially problematic since from the clinical standpoint, a widely accepted criteria used to decide whether or not an ACEI/ARB should be held (in any clinical setting) is an acute elevation of creatinine such as precipitated by hypovolemia, sepsis, hemodynamic instability due to new or worsening dysrhythmias, and so forth. Thus, it is tempting to speculate that patients with deteriorating renal function were given their ACEIs/ARBs inappropriately, leading to higher risk of adverse perioperative outcomes associated with either chronic preoperative or acute perioperative renal injury.18,19
Without this “hard stop,” based exclusively on a change in creatinine, we are left with either the preoperative blood pressure criteria (which was accounted for in the analysis) or the potential impact of “institutional protocols” to be the primary reason for dosing or not. With regard to the former, it is completely plausible that inappropriate administration to patients who are pharmacologically overmedicated with either an excessive dose or with other antihypertensives, are hypovolemic and/or anemic, have sustained a recent MI, or are being treated for heart failure, are likely at higher risk for the composite outcome. Some of these were adjusted for in the modeling process, but what is not known are the care patterns of the practitioners which may range from high-level, guideline-based practitioners to those who might practice less attentive care (as in the case of unrecognized hypovolemia before induction of anesthesia). As noted in the data supplement, there was also substantial variation in the ACEI/ARB administration by country, ranging over four-fold between the eight countries studied. Although this variation was adjusted for statistically, it is never entirely clear how statistical adjustment relates to the complexities of clinical practice and different healthcare systems.
Based on these findings, along with the existing literature, it seems that we have reached clinical equipoise for the requisite large randomized clinical trial that these investigators have appropriately called for. However, some might argue that the magnitude of the risk difference observed and the lack of statistical significance when using the more conventional definition for MI are not convincing enough to warrant a large trial at this time. Currently, there is only one registered trial on ClinicalTrials.gov dealing with ACEI/ARB withdrawal (NCT02096406; a pilot study in patients undergoing cardiac surgery). It would seem to require a perfect storm of adverse perioperative physiologic stressors (hypotension, hypovolemia, rapidly changing renal function, and so forth) to culminate in a catastrophic outcome from administering one or two doses of an ACEI/ARB immediately before surgery. Working at an institution that on the noncardiac surgery side has never had a consistent policy on this issue (with most if not all patients instructed to continue their ACEI/ARBs) but has recently seen the independent institution of a policy by our cardiac surgery service to discontinue these agents several days before surgery (with substitution with amlodipine as indicated), I believe that the current study does provide strong impetus for a randomized trial but does not warrant changes in local practice until such a trial is completed. That being said, many ships have unexpectedly sunk in the unpredictable, turbulent waters of the perioperative environment. We owe it to our patients to provide smooth sailing. The authors of this study are to be congratulated for so elegantly providing potential waypoints for us to follow, and with their documented expertise in large clinical trials, I hope they will eventually take us to the final port of call on this important issue.
The author is not supported by, nor maintains any financial interest in, any commercial activity that may be associated with the topic of this article.