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Ann Thorac Surg 2005;80:1388-1393
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Does the Combination of Aprotinin and Angiotensin-Converting Enzyme Inhibitor Cause Renal Failure After Cardiac Surgery?

^a Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina
^b Department of Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
^c Department of Pharmacy, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Accepted for publication March 28, 2005.

^_* Address reprint requests to Dr Kincaid, Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157 (Email: tkincaid{at}wfubmc.edu).

Presented at the Fifty-first Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 2–4, 2004.

	Abstract

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BACKGROUND: Aprotinin use in cardiac surgery has been associated with mild elevations in serum creatinine but generally has not been associated with an increase in the risk of acute renal failure. In the presence of angiotensin-converting enzyme (ACE) inhibitors, however, aprotinin may contribute to significant reductions in glomerular perfusion pressure. The purpose of this study was to test the hypothesis that the combination of ACE inhibitors and aprotinin cause renal failure after cardiac surgery.

METHODS: The study consisted of a retrospective investigation of all adult patients undergoing coronary artery bypass graft, valve, or combined procedures during the years 2000 to 2002 at a single institution. Aprotinin was administered selectively for reoperations, combined procedures, and other operations deemed to be at higher risk for bleeding. Excluded from analysis were patients with preoperative serum creatinine greater than 1.5 mg/dL, a history of renal failure, emergent or salvage procedures, preoperative use of intraaortic balloon pump, and off-pump procedures. Perioperative renal failure was defined as creatinine greater than 2.0 mg/dL within 72 hours of surgery. Preoperative demographic and intraoperative variables were analyzed with univariate and logistic regression analysis with odds ratio (OR) and bootstrap validation.

RESULTS: A total of 1,209 patients were included. The incidence of perioperative renal failure was 3.5%, and mortality in this group was 48%. Controlling for other demographic and intraoperative variables that may affect renal function (age, sex, diabetes mellitus, hypertension, New York Heart Association class, prior cardiac surgery, valve procedures, cardiopulmonary bypass time, aortic cross-clamp time, lowest hematocrit during cardiopulmonary bypass, transfusions) the preoperative use of ACE inhibitors along with intraoperative use of aprotinin was significantly associated with acute renal failure (OR 2.9, 95% confidence interval [CI]: 1.4 to 5.8, p < 0.0001). The effect of either drug alone was not significant. Other identified risk factors included age (OR 1.2 per year, CI: 1.01 to 1.5, p = 0.035), valve procedure (OR 2.7, CI: 1.3 to 5.7, p = 0.016), lowest hematocrit on cardiopulmonary bypass (OR 2.2, CI: 1.6 to 3.2, p < 0.0001), and transfusions of red blood cells (OR 1.04 per unit, CI: 1.02 to 1.06, p < 0.0001) and platelets (OR 1.7 per unit, CI: 1.2 to 2.4, p = 0.001).

CONCLUSIONS: The combination of preoperative use of ACE inhibitors and intraoperative use of aprotinin should be avoided in cardiac surgery.

	Introduction

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Acute renal failure (ARF) after cardiac surgery is a devastating complication associated with a high mortality rate. While prevention is the most important component of therapy, pharmacologic strategies and other preemptive measures are minimally effective at achieving this goal. Many studies have determined the risk factors for development of ARF, and these include preoperative renal insufficiency, diabetes mellitus, hypertension, extended cardiopulmonary bypass (CPB) times, valve procedures, blood transfusions, advanced age, poor left ventricular function, and peripheral vascular disease [1–3]. Unfortunately, few of these factors are modifiable before surgery. While preoperative assessment of risk can be estimated with accuracy [1, 4], this likely impacts little on ultimate outcome.

The serine protease inhibitor aprotinin has potent antiinflammatory effects during CPB and has been associated with elevations in postoperative serum creatinine [5–7]. This appears to be mediated through its effects on kinin pathways and subsequent alteration of intrarenal hemodynamics [8, 9]. In a similar fashion, angiotensin-converting enzyme (ACE) inhibitors are known to decrease glomerular perfusion pressure, and approximately 10% of patients will experience renal complications after initiation of these medications [10]. Despite these known risks, neither aprotinin nor ACE inhibitors, when examined alone, have definitively been shown to contribute to ARF after cardiac surgery. When used together, however, a synergistic mechanism to further reduce glomerular perfusion pressure has been proposed (Fig 1) [11, 12]. Angiotensin-converting enzyme inhibitors can cause vasodilation of the efferent arteriole of the glomerulus, which reduces glomerular perfusion pressure. The compensatory response is vasodilation of the afferent arteriole, which serves to augment pressure and flow into the glomerulus. In a manner counter to this balancing effect, aprotinin has been shown to cause vasoconstriction of the afferent arteriole. Although in most scenarios this finding may be clinically irrelevant, the combination of these two agents in the setting of altered hemodynamics associated with CBP certainly has theoretical potential to greatly affect renal hemodynamics. With this background, the purpose of this study was to test the hypothesis that the combination of aprotinin and ACE inhibitors is associated with renal dysfunction after cardiac surgery.

View larger version (27K): [in this window] [in a new window]   Fig 1. Proposed mechanism for combined effects of angiotensin-converting enzyme (ACE) inhibitors and aprotinin on glomerular function. (A) The ACE inhibitors (ACE-I) promote vasodilation (outward arrows) of the efferent arteriole of the glomerulus. (B) Compensatory response is vasodilation of the afferent arteriole, which preserves glomerular perfusion pressure. (C) Aprotinin can mediate vasoconstriction (inward arrows) of the afferent arteriole, which reduces glomerular perfusion pressure and reduces renal excretory function.

	Material and Methods

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The patient population included all adult patients undergoing CABG, valve, or combined procedures during the years 2000 to 2002 at the single institution. Excluded from analysis were patients with preoperative renal insufficiency defined as serum creatinine greater than 1.5 mg/dL, a history of renal failure, emergent or salvage procedures, preoperative use of intraaortic balloon pump, and off-pump procedures. This cohort was designed to have low baseline risk of renal complications and no immediately identifiable cause of ARF, such as preoperative shock or preoperative renal insufficiency. ARF was defined as creatinine greater than 2.0 mg/dL within 72 hours after surgery. This level of creatinine elevation was chosen because it is easily identifiable to the bedside clinician, does represent at least a 25% increase in baseline serum creatinine, and has been used by other investigators [13, 14]. The time frame of 72 hours was chosen to eliminate patients with ARF caused by late complications such as sepsis.

During the study period, procedures were performed by four surgeons with minor variations in surgical practice. Conduct of CPB for all cases included general anesthesia, roller pumps, membrane oxygenation, blood cardioplegia, and alpha-stat pH management. The majority of procedures were performed with a single aortic clamping period and mild hypothermia (30°C to 32°C). Adjunctive renal protection strategies such as pulsatile perfusion or use of fenoldopam were used minimally in the study group. Dopamine infusions were not used. The decision to administer aprotinin was made on a case-by-case basis after discussion between surgical and anesthesia teams. In general, aprotinin was used in reoperations, combined procedures, and in patients thought to be at higher risk for bleeding because of recent anticoagulant and antiplatelet agent exposure. All aprotinin was given as a "high-dose" regimen. After a 10,000 KIU test dose, 2,000,000 KIU was loaded intravenously, and 2,000,000 KIU was placed in the pump prime. An infusion of 500,000 KIU/h was continued until the patient left the operating room. Aminocaproic acid (50 mg/kg load, 25 mg/kg/h infusion) was given to all patients not receiving aprotinin. When used, ACE inhibitors were continued up to the day of surgery.

Statistical Analysis
A statistical model was developed to determine the significance of predetermined risk factors on the development of ARF. Demographic variables included age, sex, diabetes mellitus, hypertension, preoperative ACE inhibition, New York Heart Association (NYHA) class, and prior cardiac surgery. Intraoperative variables included valve procedure, aprotinin use, CPB time, aortic cross-clamp time, lowest temperature on CPB, lowest hematocrit on CPB, and transfusions of packed red blood cells (RBC) and platelets. The combined use of aprotinin and ACE inhibitors was also examined as a separate variable. Statistical analysis was performed using SAS software (version 8.0; SAS, Cary, North Carolina). Univariate predictors of ARF were determined using t tests and ² where appropriate. In order to control for confounding potential causes of perioperative renal damage, significant univariate predictors were then entered into a multivariate logistic regression analysis with bootstrap validation. All p values less than 0.05 and bootstrap frequency greater than 50% were considered significant.

	Results

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A total of 1209 patients met study criteria and were included in the analysis. Demographics of the group are shown in Table 1. Acute renal failure within 72 hours of surgery occurred in 3.5%, and mortality in this group was 48%. The incidence of ARF increased with number of units of packed RBC transfused (Fig 2). Of patients with ARF, 57% received hemodialysis.

View larger version (15K): [in this window] [in a new window]   Fig 2. Incidence of acute renal failure with increasing transfusion of packed red blood cells (RBC's).

View larger version (21K): [in this window] [in a new window]   Fig 3. The impact of packed red blood cells (PRBC) transfusion and combined angiotensin-converting enzyme inhibitor/aprotinin (ACE+Apr) on probability of acute renal failure (ARF) for isolated coronary artery bypass graft surgery. Dashed lines represent probability 95% confidence intervals.

View larger version (23K): [in this window] [in a new window]   Fig 4. The impact of packed red blood cells (PRBC) transfusion and combined angiotensin-converting enzyme inhibitor/aprotinin (ACE+Apr) on probability of acute renal failure (ARF) for valve and combined valve and coronary artery bypass graft procedures. Dashed lines represent probability 95% confidence intervals.

	Comment

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Aprotinin metabolism is entirely renal and is linearly related to creatinine clearance [15]. It is actively reabsorbed in the proximal tubular cells, metabolized, and eliminated after 5 to 6 days. Initial concerns about aprotinin and renal function were based on the possibility of a direct toxic effect on tubular cells. Other attention has focused on alterations in renal hemodynamics caused by interference with prostaglandin and kinin pathways [8, 9]. Clinical studies on aprotinin in CABG and valve surgery have demonstrated increases in postoperative creatinine that are generally mild and transient [5–7]. Feindt and others [16] discovered increased urinary markers for tubular injury in the absence of increases in serum creatinine in patients undergoing CABG with aprotinin. These changes appear dose dependent, mostly occurring in patients treated with high-dose regimens. Many other studies have refuted the association between aprotinin and renal dysfunction. For example, Schweizer and colleagues [17] found no difference in a multitude of specific renal function parameters after cardiac surgery in patients treated with high-dose aprotinin compared with placebo. A recent meta-analysis of randomized studies on aprotinin revealed neutral effects on renal function [18].

An undisputed benefit of aprotinin therapy is the observed reduction in blood transfusions. Given the strong association between blood transfusions and postoperative renal failure observed in this study and others, one must ask, why is aprotinin not associated with a reduction in renal failure after cardiac surgery? A logical answer is that in large studies, potential improvements in renal failure rates with aprotinin are negated by patients who were also receiving ACE inhibitors and suffered renal damage. Another explanation is that the need for transfusion is simply a surrogate marker for other risk factors for perioperative renal dysfunction. These issues underscore the importance of further prospective testing.

The current study is limited by its retrospective design, but is strengthened by a plausible mechanism to support the finding that the combination of ACE inhibitors and aprotinin cause renal insult. A source of bias includes the use of aprotinin in the absence of a predetermined protocol. In general, it was given to patients already at higher risk for renal failure and other complications. Additionally, the indications for ACE inhibitors in this patient population include heart failure, diabetes mellitus, and hypertension, which also target a higher risk group of patients. The statistical model, however, was designed to control for these factors. The model is further supported by the finding that other risk factors for renal failure identified are similar to those previously reported [1–4]. Other features of the design of the current study are worthy of mention. One goal was to investigate renal failure not easily attributable to other causes. For this reason, patients with preoperative renal insufficiency were excluded, as were those with intra-aortic balloon pumps, preoperative shock or emergent status. Additionally, only creatinine rise within the first three days after surgery was considered in order to avoid including renal failure caused by sepsis and other intensive care unit complications.

Because avoiding the combination of ACE inhibitors and aprotinin is relatively easy to achieve with minimal risks, the results of this study should be clinically applicable and underscore the importance of reviewing perioperative medication use. Angiotensin-converting enzyme inhibitors are becoming increasingly prescribed as this medication class gains more indications, including the general diagnosis of coronary artery disease [19]. Indeed, some clinicians may be reluctant to hold these medications for 2 to 3 days before surgery, a time that should be sufficient to allow for recovery of ACE inhibitor–induced alterations in renal hemodynamics [10]. In these situations, the potential benefits of aprotinin must be weighed against the potential negative effects on renal function, especially in patients with other risk factors for perioperative renal failure. Unfortunately, many of these risk factors such as reoperations and combined procedures have become relative indications to use aprotinin over other antifibrinolytics.

In conclusion, this study demonstrates a potential interaction between ACE inhibitors and aprotinin with the potential for increased risk of renal failure after cardiac surgery. These findings, while requiring further testing and validation, offer a rare chance to improve the rates of a complication with few modifiable risk factors.

	Discussion

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DR CLIFFORD H. VAN METER (New Orleans, LA): Congratulations, Dr Kincaid. I can see a lot of inquisitive nature in this paper. Particularly, ACE inhibitors and, even more frequently, angiotensin receptor blockers are causing perfusion pressure problems in our patients on-pump, and I am curious whether you have any recollection of or any intention to evaluate what the mean pressures were on-pump in these patients, what agents were required to maintain those pressures, and what the requirements were for pressors postoperatively, because I think that can have as much a role as the coincidental use of the two drugs?

DR KINCAID: Thank you, Dr Van Meter. I agree with your comments. In a selective manner, I examined mean arterial pressures on-pump and compared patients that did develop renal failure with a selected cohort of other patients without renal failure, and found that the mean pressures on pump were identical, at approximately 60 mm Hg. I do not have data on what agents were used to maintain that pressure and exactly what flows were used on bypass. Your question brings up a good point, however, that prevention of renal failure in this setting may be as simple as maintaining higher pressures on pump.

DR RICHARD COOK (Greenville, NC): Very interesting study. I was just curious to know how you defined preoperative use of ACE inhibitors? Does that include anybody who is on an ACE inhibitor within a week or within 24 hours of surgery? And I was just wondering what you recommend now in terms of aprotinin use for patients coming to the operating room who are on ACE inhibitors?

DR KINCAID: We defined ACE inhibitor use as administration within 24 hours prior to surgery. It is unclear how long a patient should be off these agents to prevent this interaction, but extrapolating from patients who start ACE inhibitors who develop renal complications without surgery, it usually takes 2 to 3 days before creatinine comes back down, and so that is what we would recommend: 2 to 3 days. This time frame is also dependent on ACE inhibitor half-life, which varies greatly depending on the specific agent.

DR D. GLENN PENNINGTON (Johnson City, TN): I want to ask one other question regarding drugs, and that is, during the perioperative period was there any influence of drugs such as low-dose dopamine, continuous lasix infusions, or even fenoldopam, which I know you have studied there at Wake Forest? Do they have any influence on the development of renal failure? Could one prevent it?

DR KINCAID: In this group of patients who were thought to be at relatively low risk for renal failure, the use of adjunctive agents such as fenoldopam and low-dose dopamine were not used often. Additionally, a retrospective analysis done at our institution on the routine use of fenoldopam shows that it does not have an impact on postoperative creatinine.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Edward H. Kincaid David A. Ashburn John W. Hammon Neal D. Kon Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kincaid, E. H. Articles by Kon, N. D. Search for Related Content PubMed PubMed Citation Articles by Kincaid, E. H. Articles by Kon, N. D.