Eur J Cardiothorac Surg 2008;33:849-855. doi:10.1016/j.ejcts.2008.01.059
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Does perioperative use of aprotinin reduce the rejection rate in heart transplant recipients?
Jeffrey H. Shuhaiber*,
Kimberley Goldsmith,
Stephen R. Large,
Steven Tsui
Transplant Unit, Papworth Hospital, Papworth Everard, Cambridge, United Kingdom
Received 4 September 2007;
received in revised form 22 January 2008;
accepted 24 January 2008.
* Corresponding author. Address: 6 Grassmount, Taymount Rise, London SE 23 3UW, United Kingdom. Tel.: +44 0208 291 0909. (Email: jeffrey01{at}mac.com).
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Abstract
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Objective: Allograft rejection continues to be one of the most common causes of mortality after heart transplantation. We investigated if perioperative use of antifibrinolytics such as aprotinin and tranexamic acid can decrease the rate of rejection after heart transplant and their effect on transfusion. Methods: A retrospective analysis was conducted on the data from patients who received a first heart transplant at Papworth Hospital between 2000 and 2005. Transplant registry and audit data were used for the study. Rejection biopsy results and treatment were used to designate rejection episodes as mild (grades 1A, 1B or 2 untreated) or severe (grades 2 treated, grades 3 and 4). The relationship between antifibrinolytics and rejection episodes was assessed using univariate and multiple Poisson regression. Kaplan–Meier methods and Kruskal–Wallis tests, respectively, were used to analyse survival/time to first rejection and transfusion. Results: There were 225 patients who underwent a first heart transplant between January 2000 and December 2005. Of these, 101 patients (44.9%) had received aprotinin, 63 (28.0%) tranexamic acid, 2 (0.9%) both (aprotinin and tranexamic acid) and 59 (26.2%) no antifibrinolytics. There was no difference in time to first rejection by antifibrinolytic treatment (p
= 0.20). There was no difference in the rate of treated rejection per 100 patient-days between aprotinin and tranexamic acid groups between 0 and 3 months post-transplant, (0.6 in both), but aprotinin had a small clinical effect when compared to no treatment (0.6 vs 0.8, p
= 0.54). Between 4 and 6 months, the treated and severe rejection rates were lower in the patients receiving aprotinin as compared to those receiving tranexamic acid, but these differences again did not reach statistical significance (0.1 vs 0.3, p
= 0.14, 0.2 vs 0.4, p
= 0.18). Aprotinin was associated with higher postoperative blood loss and transfusion requirements in the subgroup of patients that had a ventricular assist device, prior sternotomy or anticoagulant therapy. Conclusions: The use of aprotinin in heart transplant surgery may be associated with a small decrease in the incidence of treated/severe rejection within 6 months of transplantation. The perioperative use of antifibrinolytics did not influence time to first rejection or reduce blood transfusion.
Key Words: Heart transplantation • Aprotinin • Rejection
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1. Background
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Heart transplantation is the standard of care for patients with end-stage heart disease. More than 2500 successful heart transplantation surgeries are carried out each year around the world [1]. Despite the success of surgery, primary graft dysfunction due to rejection remains the most common cause of morbidity and mortality in these transplantation recipients [2]. Thus, optimisation of heart allograft function by reducing the rejection rate remains one of the most important management issues in heart transplant surgery. Aprotinin is a serine-protease inhibitor that has been shown to have antifibrinolytic, anti-inflammatory and immunosuppressive effects, and currently is being used in cardiovascular and lung transplantation surgery [3]. Aprotinin is clinically proven to reduce bleeding and transfusion requirements in cardiothoracic surgery [4]. Evidence for this also extends to heart transplantation in paediatric as well as in the adult population [5]. Recent studies have indicated that the use of aprotinin in perioperative patient management in lung transplantation has strong beneficial effects on patient outcomes by decreasing reperfusion injury and allograft dysfunction [6,7]. Aprotinin inhibits activator of DNA replication (ADR) protein, an important mediator for lymphocyte DNA synthesis and cell division [8]. Given the reported benefits of aprotinin in high-risk cardiac surgery requiring transfusion and in lung transplantation surgery, we were interested to review our experience with the effect of aprotinin on rejection, and as a haemostatic agent, after heart transplantation surgery utilising the Papworth Heart Transplant Registry and cardiac surgery audit data from 2000 onwards.
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2. Methods
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From January 2000 through December 2005, 225 adult orthotopic heart transplants were performed by the transplant service at Papworth Hospital. A retrospective analysis of these patients was performed. Recipient and donor demographic data including rejection episodes and mortality are recorded in the prospectively maintained transplant registry. Transfusion data, use of anticoagulants or antiplatelet agents and cumulative blood loss were obtained prospectively by a specialised nurse. Although we recommend leukocyte-depleted blood, this was not always possible given the urgent nature of transplant and immediate need of blood products when haemorrhage occurs. The result is that the majority of blood transfused is often not leukocyte depleted.
2.1 Immunosuppression and prophylaxis
The standard immunosuppression was a combination of prednisolone, cyclosporine, and azathioprine until April 2002. Since then, mycophenolate has been substituted for azathioprine. Anti-thymocyte globulin is routinely used as an induction immunosuppression regimen with the same levels of target immunosuppression.
Post-transplant prophylaxis for cytomegalovirus (CMV) consisted of intravenous ganciclovir followed by oral ganciclovir for 3 months if CMV mismatch was present. Anti-fungal prophylaxis consisted of nebulised amphotericinB for the first 3 weeks. For pneumocystis prophylaxis patients were put on lifelong co-trimoxazole or nebulised pentamidine if allergic to co-trimoxazole.
2.2 Rejection diagnosis
Both treated and biopsy-proven rejections were studied. Treated rejection was defined as any episode where a heart transplant recipient received intravenous pulsed corticosteroids for 3 days. In many cases, the diagnosis of acute rejection was made on the basis of histology obtained from endomyocardial biopsy samples, so treated and biopsy-proven rejection necessarily overlap, but are recorded separately in our registry. The majority of treated patients had high-grade rejection on histology, whilst others underwent therapy based on left ventricular function and clinical judgment. Biopsies were performed on the basis of a suspicion of acute rejection, as assessed by clinical parameters. Additionally, surveillance endomyocardial biopsies were performed weekly during the first month post-transplantation, then monthly for the next 6 months, and after that every 3 months until the end of first post-transplantation year. Endomyocardial biopsies were then performed every 3–6 months thereafter, depending on clinical circumstances. Cellular rejection was graded histologically on the basis of classification proposed by the International Society of Heart and Lung Transplantation [9].
Rejection biopsy results in combination with evidence of treatment were used to separate biopsy-proven rejection episodes into mild and severe. Biopsies graded as 1A, 1B or 2 without treatment were coded as mild rejection episodes. Biopsies of Grade 2 with treatment through Grade 4 were coded as severe rejection episodes. In all cases, the rate of rejection was calculated as the number of rejection episodes in a given time period post-transplant divided by the time at risk in days during the time period, multiplied by 100 to give the rate of rejection per 100 patient days.
2.3 Blood loss and transfusion
Postoperative blood loss, blood product transfusion and type of antifibrinolytic as well as antiplatelet/anticoagulant agents used during surgery were registered prospectively by a transfusion nurse. The parameters measured included total blood loss (total loss starting from the end of the operation to before any re-exploration for bleeding) and total units of blood products such as red blood cells, platelets and fresh frozen plasma, transfused during the patients hospital stay. Twenty-four hour blood loss is recorded in the transplant database and is loss starting from the end of the operation to 24 h after the operation. There was one patient who was recorded as losing more than 10 l of blood who was excluded from the transfusion analyses as an outlier.
2.4 Statistical analysis
Analyses were done using the Statistical Package for the Social Sciences, version 14. Patient characteristics were summarised as mean and standard deviation, median and interquartile range or frequencies and proportions. The relationship between antifibrinolytic use and patient pre-, peri- and postoperative characteristics was assessed by Pearson chi-square, Fisher–Freeman–Halton, ANOVA or Kruskal–Wallis/Bonferroni-adjusted Mann–Whitney U tests as appropriate. Kaplan–Meier methods and the log rank test were used to study patient survival and time to rejection. Patient survival was calculated using the time from first transplant to death. Time to rejection was calculated using the time from first transplant to first rejection episode or death from rejection-related causes, whichever came first. Patients who were alive/rejection-free at the study or who died from other causes were censored. Poisson regression with Bonferroni adjustment for multiple tests was used to compare rejection rates between antifibrinolytic treatment groups. Follow-up for survival, rejection episodes and time at risk for rejection was until December 31, 2006.
Multiple variable Poisson regression was used to determine if any of the following: recipient or donor age, recipient or donor gender, donor organ ischaemic time, having a VAD/previous cardiac surgery, or number of units of blood products transfused, affected the relationship between antifibrinolytic treatment and rate of rejection. A three-level (none, aprotinin, tranexamic acid) antifibrinolytic treatment group variable was forced in the model and other variables were added in a forward stepwise manner. Variables were assessed for addition to the model using the likelihood ratio test. The variable with the lowest p value from the test was added at each iteration until all variables significant at p
< 0.1 had been added. The aim was not to create predictive models, but to see if adjusting for other important variables changed the magnitude of the effect of antifibrinolytic treatment.
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3. Results
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There was little difference in preoperative characteristics in patients in different antifibrinolytic treatment groups, except that patients that had ventricular assist devices and/or other previous cardiac surgery were more likely to have been given aprotinin (p
= 0.003, Table 1
). Patients taking aprotinin were also more likely to be taking anticoagulants than those not on antifibrinolytic therapy and less likely to be taking inotropes than the other patients, although this was not statistically significant.
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Table 1 Preoperative characteristics of heart transplant patients between 2000 and 2005 by antifibrinolytic treatment
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Antifibrinolytic treatment group was related to cardiopulmonary bypass time, length of stay in ICU and total blood loss (p
0.03, Table 2
), although there was no significant difference in 24 h blood loss. Patients treated with aprotinin (or both drugs) had longer CPB times, longer stay in the ICU and more total blood loss postoperatively. Patients taking aprotinin did not differ in their requirement for red blood cells or platelets, but they were given more units of fresh frozen plasma than patients in the other two groups (median [IQR] none 2 [4], aprotinin 4 [5], tranexamic acid 2.5 [5], p
= 0.01). There was no significant difference in hospital stay or mortality (Table 2) between the non-treated and antifibrinolytic-treated groups.
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Table 2 Peri- and postoperative characteristics of heart transplant patients between 2000 and 2005 by antifibrinolytic treatment
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Patient survival in the no antifibrinolytic, aprotinin and tranexamic acid groups respectively at 1 year was 81.4%, 79.6% and 90.5%, and at 5 years was 74.4%, 66.0% and 77.6%. People taking tranexamic acid had better survival early after transplant, but differences between the groups did not reach significance (p
= 0.41). Time to first rejection or death in years was longer in people taking tranexamic acid, although this did not reach significance (Fig. 1
, p
= 0.14).
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Fig. 1. Kaplan–Meier plot of time to first rejection or death after heart transplantation by antifibrinolytic treatment group.
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There were no statistically significant differences in treated rejection rates between antifibrinolytic receiving groups in any time period post-transplantation (Fig. 2
). Adjustment for recipient age, donor age, recipient gender, donor gender, donor ischaemic time, having a VAD/previous cardiac surgery, or number of units of blood products transfused did not have an appreciable effect upon these results (data not shown).
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Fig. 2. Treated rejection episode rates after heart transplantation by antifibrinolytic treatment group. *
p
 0.54 except for aprotinin versus tranexamic acid comparison in 4–6 month time period where p
= 0.14. **Tranexamic acid.
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There were, however, some small differences that could be clinically significant. Patients that had not been treated had a relative risk of rejection of 1.3 as compared to those that had taken aprotinin (rejection rate per 100 patient-days of 0.80 vs 0.60, p
= 0.54). Patients taking tranexamic acid had a higher rejection rate between 4 and 6 months post-transplant than patients on aprotinin (0.3 vs 0.1, p
= 0.14). During the same time interval, there was no difference in rates between the group that received aprotinin and the group that had not had antifibrinolytics (0.14 vs 0.17). Severe rejection episodes as classified at our institution were very similar to treated rejection episodes by definition. The results for severe rejection were therefore similar to those for treated rejection; patients that received tranexamic acid had a higher rejection rate than patients who had aprotinin between 4 and 6 months post-transplantation that did not reach statistical significance (0.4 vs 0.2, p
= 0.18, Fig. 3
). Patients taking aprotinin had a higher rate of mild rejection between 0 and 3 months post-transplant than those taking nothing (2.5 vs 1.8, p
= 0.05) and those taking tranexamic acid, although the latter difference was not significant (2.5 vs 1.9, p
= 0.12). This was also true 4–6 months post-transplant, although this did not reach significance (1.2 in the aprotinin group vs 0.8 for no treatment and 0.9 for tranexamic acid, p
> 0.17, Fig. 4
).
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Fig. 3. Severe rejection episode rates after heart transplantation by antifibrinolytic treatment group. *
p
0.36 except for aprotinin versus tranexamic acid comparison in 4–6 month time period where p
= 0.18 and 7–12 month p
= 0.21. **Tranexamic acid.
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Fig. 4. Mild rejection episode rates after heart transplantation by antifibrinolytic treatment group. *Aprotinin versus none comparison, 0–3 months p
= 0.05, 4–6 months p
= 0.18 and aprotinin versus tranexamic acid comparison, 0–3 months p
= 0.12, 4–6 months p
= 0.21, otherwise p
0.99. **Tranexamic acid.
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When transfusion requirements were studied within the subgroups of patients that had not had a ventricular assist device (VAD), previous cardiac surgery or anticoagulant treatment versus patients that had one or more of these, blood loss and quantity of products transfused differed by antifibrinolytic treatment. Patients that had a VAD, previous surgery or anticoagulants that were also treated with aprotinin had significantly greater total blood loss, and greater 24 hour blood loss and products transfused than patients taking no antifibrinolytics, although the latter two measures did not reach the traditional level of statistical significance (Table 3
). Blood loss did not differ between groups for those with no VAD/previous surgery or anticoagulant treatment.
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Table 3 Transfusion requirements by antifibrinolytic group within previous surgery subgroups/VAD or anticoagulant/antiplatelet therapy
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4. Discussion
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Rejection of the cardiac allograft is a major cause of morbidity and mortality in the first year after heart transplantation [2]. Acute rejection can occur along a spectrum of mild to severe depending on multitude of factors that are related on the surveillance regimen and recipient response to immunosuppression and allosensitisation. Recurring and frequent episodes of acute rejection long-term have been shown to correlate with development of chronic rejection. This cumulative acute rejection burden results in cardiac dysfunction and early demise of the graft [10]. Induction and maintenance of immunosuppression are the current mainstay therapeutic modalities but remain suboptimal [11]. To find a medication that could reduce rejection rate any further would be highly sought after.
The rejection of cardiac allograft is a T-cell-mediated response with infiltration of lymphocytes, neutrophils and macrophages, and resultant myocytolysis [2]. However, there is ongoing research showing that inflammation associated with ischaemia–reperfusion injury (IRI) is one of the primary culprits leading to the initial endothelial injury and setting the scene for acute rejection to occur [12]. The initial ischaemic insult leads to production of cytokines and increased expression of adhesion molecules by endothelial cells, which all lead to recruitment of immune cells to the site of ischaemia [12]. Studies with lung transplant models have indicated that the neutrophils are the first immune cells that get recruited to initiate the organ injury [12]. Neutrophils get activated by adhering to activated endothelial cells and start secreting reactive oxygen species and proteolytic enzymes which injure the reperfused tissues and lead to their destruction [10]. Clinicians and researchers have tried to find agents that can prevent IRI from occurring and recently several promising studies have been published which demonstrate that the use of aprotinin may significantly decrease the incidence of severe post transplant IRI [7,12,14].
Aprotinin is a serine-protease inhibitor that is widely used in cardiovascular surgery for its antifibrinolytic haemostatic properties in an attempt to minimise blood loss, and transfusion requirements. Aprotinin preserves platelet function and minimises associated hazards and burden of blood transfusion [3]. In addition, both in vivo and in vitro studies have demonstrated that aprotinin can act as an anti-inflammatory agent by inhibiting neutrophil extravasation and activation [4]. Other studies have revealed that addition of aprotinin to standard crystalloid preservation solutions improved lung transplant function. Recently, results published by Bittner and colleagues suggest that perioperative management with aprotinin in lung transplant surgery has strong beneficial effects on patient outcome by significantly reducing severe post transplant IRI [7,13].
Besides the antifibrinolytic and anti-inflammatory properties, aprotinin also has the ability to inhibit the cell cycle [8]. Aprotinin is able to suppress cell division in cell lines at concentrations that are given perioperatively [3]. One of the main targets of aprotinin is a protein called activator of DNA receptor (ADR) [8]. ADR is a ubiquitous heat-labile protein that is mainly expressed in proliferating immune cells, and is undetectable in resting cells [8]. ADR is capable of inducing DNA synthesis, thus leading to cell division [3]. Presumably if aprotinin can inhibit the division of responding host immune cells after the transplant then it can partly lessen the anti-graft immune pathways rendering the graft more likely to sustain function in the host.
In our study we investigated the role of aprotinin and tranexamic acid in modulating the rejection rate in heart transplantation patients. The results of our study demonstrated that perioperative use of aprotinin showed a small but clinically significant reduction in the overall rate of acute rejection within 6 months of heart transplantation that did not reach statistical significance. This was true after assessing the need for adjustment for recipient and donor characteristics. One explanation for these results is that aprotinin has no appreciable effect, or a small effect, upon the rate of rejection. A second possibility is that aprotinin has an effect upon rejection that is not sustained in comparison to maintenance immunosuppression; therefore the anti-rejection effect of aprotinin would only be short-term at best, perhaps giving the small differences seen here.
The second major purpose of this study was to study aprotinin as a haemostatic agent in heart transplantation. The results of our study indicate that aprotinin did not reduce blood loss and transfusion requirement in patients undergoing heart transplantation surgery. These results do not agree with meta-analysis findings regarding the clinical haemostatic properties of aprotinin. The statistical summary of 35 coronary artery bypass grafting trials (n
= 3879) confirm that aprotinin reduces transfusion requirements (relative risk 0.61, 95% confidence interval 0.58–0.66) relative to placebo, with a 39% risk reduction [4]. However, more recent evidence has documented the lack of added haemostatic benefit of aprotinin in adult cardiothoracic surgery. Two very recent studies demonstrated after appropriate risk-adjustment that aprotinin did not reduce blood transfusion in cardiac surgery [15,16]. Although very few studies have been published in the field of heart transplantation, a group at the University of Chicago analysed the haemostatic properties of aprotinin in 70 patients who underwent primary heart transplantation between 1993 and 1994 [14]. Thirty-eight heart recipients who underwent primary sternotomy for heart transplantation were randomised to an aprotinin or no aprotinin group. No significant differences were found in blood loss or blood transfusion between patients receiving and not receiving aprotinin. In this same study, 32 additional patients undergoing reoperative heart transplantation were randomised to aprotinin (n
= 16) or no aprotinin (n
= 16). Aprotinin decreased bleeding after reoperative heart transplantation (894 vs 526 mls) and total blood product requirement (5.9 vs 3.6 units) but did not minimise the need for transfusion. These results suggest that aprotinin may be more beneficial for reoperative patients, therefore we also separately analysed the reoperative group of patients in our study. Ninety-four patients had a previous VAD or other cardiac surgery or were on coumadin/antiplatelet; blood loss and quantity of products transfused differed by antifibrinolytic treatment. Patients that had a VAD, previous surgery or anticoagulants that were also treated with aprotinin had greater blood loss and products transfused.
Rejection of allografts has been associated with units of blood transfusion. Recently, Fernandez et al. [17] studied 67 patients who underwent heart transplantation, and found that the incidence of acute cardiac rejection was inversely correlated with the number of blood transfusions to the recipient. Given that our data revealed a decrease in severe rejection in the aprotinin receiving patients while adjusting for differences in units of blood transfused further supports an immunomodulatory role of aprotinin during transplantation.
4.1 Study limitations
First, there were a limited number of patients with chronic allograft vasculopathy and so we could not address the effect of antifibrinolytics on this outcome. Furthermore, the immunosuppression protocol evolved over time. Although the changes were implemented uniformly it is possible that there was an unquantified impact on the incidence of acute rejection. It is possible that even the diagnosis of rejection using biopsy has the potential for bias because biopsies were often obtained when clinical judgment suggested that it was necessary. This in turn could have influenced the pathologists grading as well. Furthermore, it is possible that transfusions are also related to adverse events that can compromise renal function. Renal function generally leads to a reduction in the use of calcineurin inhibitors that can increase the risk of rejection. Our database held data on use of immunosuppression but not those who received calcineurin versus cyclosporine. Also we did not have any data on compliance of the medication or immunosuppression levels. Finally, we may have had limited power to detect differences between the antifibrinolytic groups. Larger studies in future could help clarify the effect of aprotinin on rejection after heart transplantation.
In conclusion, aprotinin use may be associated with a small clinically important decrease in the incidence of treated/severe rejection within 6 months of heart transplantation as compared to tranexamic acid, which did not reach statistical significance. There did not appear to be any particular haemostatic advantage to the use of aprotinin in patients undergoing primary or repeat sternotomy at the time of cardiac transplantation.
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Appendix A
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Conference discussion
Dr C. Aigner (Vienna, Austria): Do you really think your conclusion is supported by your data? Because, obviously, you didn’t find any statistically significant differences, not even major trends. So based on what do you draw your conclusion?
Dr Shuhaiber: I think at the period of time between 0 and 6 months we saw a decrease in both treated and severe rejection among the aprotinin group compared to tranexamic acid. However, this did not translate into statistical significance. Nonetheless, it's a clinical observation based on a small cohort of patients, and I think this should be delegated prospectively, especially when aprotinin is given nowadays routinely among patients undergoing heart transplantation.
Dr A. Poncelet (Brussels, Belgium): You had a significant increased proportion of patients who were reoperated in the aprotinin group. And I guess that all those redo surgeries were tested for PRAs (panel reactive antibodies), Class I and Class II, and I haven’t seen on your slide that you analysed this data, though we know that increased Class II antibodies will increase the rate of acute rejection both in the acute and the chronic setting.
Dr Shuhaiber: We looked at the subgroup – I didn’t mention it in this presentation due to lack of time – but we looked at the VAD subgroup of patients. There is no statistically significant difference in rejection when compared to the rest of the cohort.
Now, this does not say that there isn’t any literature out there saying as what you just stated. I think that should be looked on in a more objective way. The purpose of this study is to introduce aprotinin as a possible mediator for being an anti-inflammatory drug. It's FDA approved. It can be used. And now at Papworth more surgeons use this routinely at the time of heart transplantation.
During this time period, we were fortunate to have a mixed bag of patients, those who received tranexamic acid, those who received no antifibrinolytics, and those who received aprotinin. And the idea was to find out if there was any benefit in one group versus the other. But I think a larger population sample used prospectively may give us more information about it, especially knowing that there are immunomodulator effects of aprotinin per se.
Dr G. Laufer (Innsbruck, Austria): I want to come back to the question from Dr Aigner. Do you think that the outcome of this data are really so significant that you justify a prospective randomised trial? Because this is not a randomised trial. It's a retrospective analysis and you have a lot of confounding factors in your analysis. And even having these confounding factors, you do not find something which is really, let's say, remarkable, that would justify the randomised trial, the investigation in a randomised trial.
Dr Shuhaiber: I think the reason I suggest that is we did that just for both donor and recipient characteristics. The number of confounders in heart transplantation is quite long and everyone has their set in their mind. But for adjusting the main ones, the age, the ischaemic time, gender, it showed that there was actually a decrease in severe rejection among the aprotinin group.
Now, why do I say prospective randomised trial? The reason I say that is because these drugs are available to us. And if we can reduce even the slightest amount of rejection just by giving this drug that's already available and safe, we can actually reduce the number of incidents of acute rejection, which determine the long-term function of the graft. We may not know the results now because of this retrospective study, but I think looking at it more objectively and controlling for the confounders that we would pick, may help us to use aprotinin more often than not. So I think there is room for this, but that still remains to be seen.
Dr Laufer: Did you look at the incidence of renal failure? Because we know from the CABG population there have been some data that suggests that the use of aprotinin might be associated with more renal failure after surgery, might be associated with more stroke and more bypass graft occlusion, which certainly is only one significant paper. Did you look on the renal function?
Dr Shuhaiber: There are lots of papers on that. I think the debate on aprotinin is ongoing. There are people that agree that it may be a friend, it may be a foe. However, I think it's here to stay. The FDA has not removed the drug. It's used routinely among many surgeons that I know of for redo surgery. It does have an effect on creatinine. I’m not sure about the renal failure in the paper that you state. But it does increase the level of creatinine. Whether that translates to worse outcomes, I don’t know.
I’m aware of several studies that have shown the detrimental side effects of aprotinin, both from the States, especially the Mangano papers; but again, reading through the literature, that hasn’t been confirmed with randomised prospective trials.
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Acknowledgments
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We are grateful for Caroline Gerrard's efforts in prospectively collecting and auditing transfusion and blood loss data.
This study received no grants or funding and was supported by Papworth Hospital NHS Trust.
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Footnotes
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Presented at the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16–19, 2007.
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Abstract
1. Background
