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Original Articles: Adult Cardiac

Aprotinin is Not Associated With Postoperative Renal Impairment After Primary Coronary Surgery

^a Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden
^b Department of Clinical Sciences, Intervention and Technology and Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden

Accepted for publication March 18, 2008.

^_* Address correspondence to Dr Lindvall, Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, SE-17176, Sweden (Email: gabriella.lindvall{at}karolinska.se).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background: Studies on the safety of aprotinin in coronary artery surgery have given conflicting results. Therefore, we studied the possible link between perioperative aprotinin treatment and renal dysfunction in patients undergoing first-time coronary surgery with a high risk of bleeding.

Methods: We performed a matched cohort study, comparing 200 patients receiving high-dose aprotinin with 200 patients receiving tranexamic acid during primary isolated coronary surgery. Patients were matched according to age, sex, and presence of acute coronary syndrome. Primary outcome was fractional change in creatinine clearance. Secondary outcomes were other evaluations of postoperative renal function, mortality, stroke, reoperation for bleeding, and transfusion requirements.

Results: The groups were similar in baseline characteristics except that triple-vessel disease and history of myocardial infarction were more prevalent in the aprotinin group. No significant differences were found in fractional change in creatinine clearance (-11% versus –12%, medians, p = 0.75) or any other assessments of postoperative renal function between the tranexamic acid and the aprotinin group. Adverse event rates were similar: early mortality (3.5% versus 4.5%, p = 0.80), stroke (1.5% versus 2%, p = 1.0), reoperation for bleeding (3.5% versus 2.5%, p = 0.77), and 5-year survival (87% versus 84%, p = 0.17). Patients in the aprotinin group received fewer transfusions (48% versus 60.5%, p = 0.02), fewer units of packed red blood cells (2.0 versus 1.4, p = 0.02) and plasma (1.3 versus 0.5, p < 0.001), but more units of platelets (0.1 versus 0.2, p = 0.02).

Conclusions: Aprotinin treatment during primary coronary surgery was not associated with impaired postoperative renal function in comparison with patients treated with tranexamic acid.

	Introduction

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During the last decade, clopidogrel given together with aspirin has become standard therapy for patients with acute coronary syndrome [1]. However, when clopidogrel had been discontinued less than 5 days before surgery, the drawbacks of this treatment were increased perioperative bleeding and higher transfusion and reoperation rates in patients with acute coronary syndrome [2, 3]. Several therapeutic strategies have been devised to neutralize clopidogrel's effect on perioperative bleeding, namely, treatment with aprotinin and lysine analogs (tranexamic acid [TA], aminocaproic acid). So far, only aprotinin has been proved effective [4–6]. That may be partly because, unlike other fibrinolytics, aprotinin has an additional inhibitory effect on the inflammatory cascade [7]. Moreover, aprotinin's platelet-protective properties may help to preserve platelet function after cardiopulmonary bypass (CPB) [8].

Contradicting earlier randomized studies, including three meta-analyses [9–11], two recent large observational studies by Mangano and colleagues [12, 13] indicated that, when compared with lysine analogs or a control group, perioperative treatment with aprotinin significantly increased the risk of renal, cardiac, and cerebral events as well as mortality. The authors concluded that "continued use of aprotinin is not prudent" and that "lysine analogs are safe alternatives." However, the results could not be corroborated in a similar observational study from Canada except for the finding that the use of aprotinin in CABG may be associated with renal dysfunction [14].

The present concern about the safety profile of aprotinin, and in particular its claimed impact on renal function, prompted us to conduct a matched cohort study of patients who underwent primary isolated CABG with a high risk of bleeding, while being treated with aprotinin or with TA. Our chief objective was to confirm or refute the possible link between perioperative aprotinin treatment and renal dysfunction in patients undergoing first-time CABG. The primary outcome measure was the fractional change in calculated creatinine clearance. Secondary outcome measures were early and late all-cause mortality, postoperative stroke, reoperation for bleeding, new onset of atrial fibrillation, and transfusion requirements.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Patient Selection
At one of the two Stockholm hospitals that provide cardiac surgery, we identified 209 patients treated with high-dose aprotinin during isolated primary CABG performed because of acute coronary syndrome during 2001 through 2003. In all cases, aprotinin had been administered to reduce perioperative blood loss in patients for whom clopidogrel treatment had been stopped less than 5 days before surgery. This cohort was matched according to age, sex, and presence of acute coronary syndrome, to patients having isolated primary CABG at the second hospital where not aprotinin but TA was used during this period. The pool of patients available for matching at the second hospital consisted of 1,809 patients. Three elderly female patients with acute coronary syndrome in the aprotinin group had to be excluded as it was not possible to find a suitable match. Two patients with incomplete personal identification numbers and 4 with dialysis-dependent renal failure were also excluded, leaving 200 patients in each group. The study was approved by the regional Human Research Ethics Committee, Stockholm, Sweden (2006/272-31/2). Individual consent was waived.

Data Collection and Follow-Up
Data were collected by reviewing patients' records, hospital databases, and the national Swedish Cardiac Surgery register. Patient data were prospectively entered into the databases at the time of hospital discharge. Follow-up of mortality was performed by linking each subject's unique Swedish personal identification number to data from the Total Register of the Swedish Population, Statistics Sweden. Thus, all patients could either be assigned to a date of death or identified as being alive on July 18, 2007.

Definitions
Patients were defined as having diabetes mellitus if treated with insulin or oral hypoglycemic agents, and as having hypertension if treated with antihypertensive medication. Left ventricular ejection fraction was assessed by preoperative contrast ventriculography or echocardiography and was categorized as normal (>0.49), reduced (0.30–0.49), or severely reduced (<0.30). Peripheral vascular disease was defined as a history of exertional claudication, prior revascularization, or both, to the legs. Prior stroke was defined as history of stroke regardless of residual neurologic deficit. The patients were classified as having acute coronary syndrome if chest pain at rest on admittance to the hospital or new onset or accelerated angina within 4 weeks of the operation. Creatinine clearance (CrCl) was calculated from serum creatinine applying the equation of Cockroft and Gault [16]. Creatinine was routinely measured preoperatively, day 1, 2, and 4 or 5 postoperatively, and more frequent if creatinine was abnormal. The postoperative calculation of CrCl was based on the highest postoperative creatinine level.

Outcome Measures
Primary outcome measure was CrCl% calculated as follows: ([peak postoperative_CrCl – preoperative_CrCl]/preoperative_CrCl) x 100. Secondary outcome measures of postoperative renal function were defined and calculated as follows: absolute change in CrCl (CrCl) as CrCl__{postoperative} – CrCl__preoperative; absolute change in Cr (Cr) as Cr__{postoperative} – Cr__preoperative; fractional change in Cr (Cr%) as ([Cr__{postoperative} – Cr__preoperative]/Cr__preoperative) x 100; and renal dysfunction as a 50% increase in creatinine. Additional outcome measures included early mortality within 30 days of the operation; postoperative stroke, defined as focal neurologic deficit persisting more than 72 hours; and postoperative atrial fibrillation, defined as new onset of atrial fibrillation or flutter in a patient without history of chronic or intermittent atrial fibrillation.

Anesthetic Management, Surgery, and CPB
Aspirin and low molecular weight heparin treatment was never stopped before surgery. Angiotensin-converting enzyme inhibitors were omitted at the day of surgery. Surgery was performed through a standard sternotomy. Anesthetic and CPB management was similar for all patients. Cardiopulmonary bypass was performed with a flow rate of 2.4 L/m² or more at 34°C, through a hollow fiber membrane oxygenator (Dideco Simplex D708; Dideco, Mirandola, Italy). The CPB circuit was primed with Ringer's acetate and 300 mL of mannitol 10%. Antegrade or retrograde cold blood cardioplegia, or both, was applied. Anticoagulation was achieved with sodium heparin (400 IU/kg) intravenously and 7,500 IU in the CPB prime, and monitored with a kaolin-activated device (Hemotec; Medtronic, Englewood, Colorado). The activated clotting time was maintained above 400 seconds. At completion of CPB, heparin was reversed with protamine sulfate at a 1:1–1:3 ratio. In addition, if activated clotting time remained greater than 140 s, 100 mg protamine was administered. All patients in the aprotinin group received the full Hammersmith aprotinin regimen [4–6], and CPB was conducted with a roller pump perfusion system. In the TA group, all patients received a bolus of 4 g TA intravenously before start of surgery, and CPB was accomplished with a centrifugal pump.

Transfusions and Reoperation Due to Bleeding
During the postoperative period, patients received transfusions of packed red blood cells (PRBC), platelets, and plasma at the discretion of the surgeon or the intensivist. The PRBC transfusion was given at an arterial hemoglobin of less than 70 g/L during CPB and less than 85 g/L after CPB, except in patients with major ongoing hemorrhage; plasma was given if more than 2 U PRBC was given; and platelets were given if bleeding was excessive and clots were missing after the reversal of heparin with protamine. The policy aimed at a hemoglobin value of 85 g/L or more.

Statistical Analysis
Continuous variables are reported as mean, standard deviation, or median. Comparisons between groups were performed with Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. Quantile regression was used to estimate and compare the median in the continuous outcomes of renal function (absolute and fractional change in Cr and CrCl) because the distributions were not symmetrical. Quantile regression is a robust statistical method that makes no assumptions about the distribution of the outcome variable. Standard errors and confidence intervals (CI) for the regression coefficients were obtained by generating 500 bootstrap samples. Multivariable analysis was performed to adjust for the difference in cardiac morbidity (prior myocardial infarction and ejection fraction) between groups by assessing outcomes of renal function by logistic or quantile regression. A two-way analysis of variance (ANOVA) was used to study the effect of number of transfusions on CrCl% by treatment group (aprotinin or TA). A separate analysis was made for PRBC, plasma, and platelets. Number of transfusions was categorized as follows: 0, 1, 2, 3, 4, 5, and 6 units or more of PRBC; 0, 1, 2, 3, 4, and 5 or more units of plasma, and 0, 1, and 2 or more units of platelets. Cumulative survival rates are presented as Kaplan-Meier estimates. Differences between survival curves were analyzed by using the log-rank test. Differences were considered significant at p less than 0.05. Statistical analyses were performed using SPSS 15.0 (SPSS, Chicago, Illinois) and STATA 10 (Stata Corp, College Station, Texas).

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Patient Characteristics
Preoperative patient characteristics are shown in Table 1. The groups were matched for age, sex, and presence of acute coronary syndrome. Other baseline characteristics were well balanced between the groups with the exception of number of diseased coronary vessels and history of myocardial infarction. Patients in the aprotinin group more often had triple-vessel disease and a history of myocardial infarction. In the aprotinin group, 40.5% of the patients had a reduced or severely reduced left ventricular ejections fraction, compared with 34% in the TA group, but the difference did not reach statistical significance. Thus, the only observed dissimilarity between the groups was a higher preoperative cardiac morbidity in the aprotinin group.

View larger version (6K): [in this window] [in a new window]   Fig 1. Boxplot of fractional change in creatinine clearance (CrCl%) in 200 aprotinin-treated patients compared with 200 matched patients receiving tranexamic acid undergoing primary coronary artery bypass graft surgery.

Multivariable Analysis
After adjustment for previous myocardial infarction and baseline ejection fraction by logistic regression and quantile regression, as appropriate, the different renal outcomes remained unchanged.

Long-Term findings
The cumulative follow-up was 1,829 patient-years, and median follow-up was 4.7 years. Overall 5-year survival was 87% in the TA group and 84% in the aprotinin group (p = 0.17). There was no loss to follow-up.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The main finding of this study was that aprotinin was not associated with postoperative renal impairment when compared with TA in patients undergoing isolated primary CABG with a high risk of bleeding. The patients in the aprotinin group received fewer transfusions, and no significant differences appeared between the two groups regarding postoperative reexploration due to bleeding, the incidence of new atrial fibrillation postoperatively, the postoperative stroke rate, or early or late mortality.

Patients in this study had an increased risk of perioperative bleeding. They had been diagnosed as having acute coronary syndrome and were preoperatively on a regimen of standard antihemostatic drugs, namely, aspirin, clopidogrel, and low molecular weight heparin. In a group so prone to excessive bleeding, the transfusion rate is bound to be high, and this may also affect renal function. Kincaid and coworkers [16] have shown that transfusions of PRBC, platelets, and low intraoperative hematocrit will increase the risk of perioperative renal failure, defined as "creatinine greater than >2.0 mg/dL [150 µmol/L] within 72 hours of surgery." Other recent observational studies used different definitions of renal dysfunction. Mangano and colleagues [12] defined it as "a postoperative Cr level of 177 µmol/L with an increase over the preoperative baseline levels of 62 µmol/L." The definition of Karkouti and colleagues [14] was "a >50% increase in Cr during the first postoperative week to >100 µmol/L in women and >110 µmol/L in men, or a new requirement for dialysis support."

We chose to present several different measurements to evaluate postoperative renal function, with CrCl% as the primary method. Calculated CrCl is considered to be a convenient, and reproducible surrogate measure for estimation of glomerular filtration rate [17], which is advantageous to measured CrCl and Cr [15, 18, 19]. Notably, the accuracy and precision of measured CrCl has generally been low [17, 20]. Furthermore, urine sampling is inconvenient, and short collection times may magnify inaccuracies [21]. The comprehensive study by Wijeysundera and colleagues [17] evaluated different measurements of renal function regarding clinical outcomes after cardiac surgery. They found that calculated CrCl is a valid substitute measure of perioperative renal function, which correlated well with patient-relevant clinical outcomes (mortality, dialysis, and prolonged hospitalization). Consequently, we based the calculation of CrCl% on the difference between preoperative creatinine and the highest creatinine value registered on any postoperative day.

A further drawback of the recent nonrandomized trials [12–14] is that the individual surgeon usually decides who should receive aprotinin treatment and who not. So far, only one placebo-controlled randomized trial with more than 100 patients undergoing CABG has been published regarding the effect of aprotinin on postoperative renal function as the primary outcome. That study demonstrated no significant difference between aprotinin-treated patients and placebo controls with respect to creatinine, electrolytes, blood urea, nitrogen, urinalysis, or abnormal CrCl rates, except on postoperative day 7, when there was a transient increase in creatinine levels in the aprotinin group [22]. This finding is consistent with our study, which showed a slight decrease in CrCl% (–12% and –11%) after aprotinin and TA treatment, respectively, in patients undergoing CABG.

In their observational studies, Mangano and colleagues [13] and Karkouti and colleagues [14] found significant increases in renal dysfunction in aprotinin-treated patients when compared with controls. A recent retrospective report of more than 11,000 patients undergoing cardiac surgery suggested that the increase in renal failure seen in patients on aprotinin was related to increased transfusion rates, and that aprotinin does not independently increase the risk of renal failure after cardiac surgery [23]. Unfortunately, the number of transfusions was not reported in the former studies. Their results could thus be explained as being due to a greater propensity to prescribe aprotinin to patients at high risk for bleeding who consequently have to carry a higher transfusion burden. Finally, it is worthy of note that a more recent publication from the Mangano group [24] concerning perioperative risk factors for renal failure after cardiac surgery did not mention aprotinin as a risk factor, although this study used the exact definition of renal dysfunction/failure and the same patient data set as were used in the original Mangano publication on aprotinin [13]. A comprehensive analysis of the latter study including further incompatibilities has recently been published [25].

Experimental studies have shown that aprotinin with its high affinity for the kidneys is deposited in the proximal tubular cells, and is not significantly secreted until 5 to 7 days after its administration [26, 27]. These findings may explain why a reversible increase in creatinine has been noted during the first postoperative week in patients receiving aprotinin treatment during cardiac surgery [22]. Because we measured creatinine on multiple occasions during the first postoperative week, it may be assumed that a possible difference between the two cohorts in this respect would have been detected. It is also possible that the slight decrease in postoperative fractional CrCl observed after aprotinin is restricted by its coincidental ability to lower the transfusion rate more efficaciously that TA. Thus, the observed decrease in postoperative fractional CrCl in the TA group may be explained by its higher transfusion rate.

The two cohorts were comparable except for a higher prevalence of earlier acute myocardial infarction, a higher rate of three-vessel disease, and a slightly reduced ejection fraction in the aprotinin group. The resulting higher number of anastomoses ought to have conduced to a higher risk of perioperative bleeding and a higher transfusion rate in the aprotinin group. In spite of this drawback, the aprotinin group had a reduced overall transfusion requirement, although they were on clopidogrel less than 5 days preoperatively. The latter may explain the significantly higher platelet transfusion rate in the aprotinin group compared with the TA group if we assume a lower rate of patients receiving clopidogrel in the TA group. Hypothetically, even if the fraction of patients in the TA group on clopidogrel varies, it cannot be higher than that of the aprotinin group. Thus, an increased fraction of patients on clopidogrel could only have augmented the transfusion requirements of the TA group and not vice versa.

Recent observational studies regarding the overall safety of aprotinin in patients undergoing cardiac surgery have included different cardiac procedures [12–14, 28, 29]. In our study, aprotinin was given according to the policy at the department namely, when clopdiogrel had been discontinued less than 5 days before surgery. Furthermore, the selection was based on patients undergoing isolated primary CABG surgery, who were matched for age, sex, and presence of acute coronary syndrome. The authors are not aware of any similar study regarding primary isolated CABG in patients on clopidogrel with a high risk of bleeding.

When trying to evaluate cohort studies like the present one, the crucial question always is: are the analyzed groups really comparable or has some form of selection taken place? Therefore, it should be realized that the health care system in Sweden, financed by the notoriously high Swedish taxes, provides equal medical treatment, unrelated to socioeconomic factors, to any patient in need of acute medical care. Neither do patients in need of surgery select individual surgeons or hospitals. Before being merged in 2004, the two cardiothoracic departments compared here had a continuous interchange of surgeons, anesthetists, nurses, and perfusionists. Medical practice at the two departments was thus very similar. However, only one department started to use aprotinin in patients undergoing cardiac surgery when there was a high risk of perioperative bleeding, namely, clopidogrel treatment [5, 6], reoperations, and endocarditis. The other department did not.

Admittedly, different pump systems were used at the two centers. Roller pumps were used in the aprotinin group and centrifugal pumps in the TA group. However, a recent evidence-based meta-analysis of randomized clinical trials comparing roller and centrifugal pumps concluded that there is no evidence in favor of a centrifugal pump over a roller pump in elective CABG with respect to blood loss or clinical outcomes [30]. Even more important, if the claim that centrifugal pumps cause less blood trauma were true, this would have unduly favored the TA group and not the aprotinin group.

Thus, we feel free to conclude that the results of this study support the use of aprotinin in patients on clopidogrel undergoing primary CABG. The alternative treatment with TA resulted in a similar slight decrease in postoperative CrCl, but the overall transfusion rate was higher. We agree with the conclusion of Furnary and colleagues [23] that all effort to minimize transfusion of packed red blood cells should be undertaken to prevent renal complication. The risks of death, perioperative infection, respiratory and renal failure, length of intensive care unit and hospital stay all worsen with more transfusion [31]. Finally, the long-term effects of transfusions of PRBC have been linked to increased long-term mortality after CABG [32, 33].

In summary, perioperative aprotinin treatment during primary CABG for patients given clopidogrel was not associated with impaired postoperative renal function in comparison with patients given TA. Furthermore, aprotinin reduced the overall transfusions rate to a greater extent than did TA.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Financial support was provided by Karolinska Institute, and through regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institute, Stockholm, Sweden. One of the authors (J.v.d.L.) has received an unconditional research grant from Bayer Sweden, which is supervised by Karolinska University Hospital. Further, we wish to thank registered nurse Kristina Kilsand for her help in compiling data for the study. None of the sponsors was involved in the design of the study, in the collection, analysis, or interpretation of the data, or in the preparation of the manuscript.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments 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): Ulrik Sartipy Torbjörn Ivert Jan van der Linden Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lindvall, G. Articles by van der Linden, J. Search for Related Content PubMed PubMed Citation Articles by Lindvall, G. Articles by van der Linden, J. Related Collections Cardiac - pharmacology