Concern about the side effects of allogeneic blood transfusion, especially the transmission of viral infections, has led to the development of a variety of methods intended to minimize perioperative transfusion. These include preoperative autologous donation, intra- and postoperative cell salvage, normovolemic hemodilution, and the use of drugs, which can be divided into two broad categories: those intended to decrease blood loss, and erythropoietin, which increases the production of red blood cells . In these meta-analyses, we evaluated the efficacy of the intraoperative use of four drugs used to decrease perioperative blood loss. Aprotinin is a protease inhibitor . Desmopressin, a synthetic polypeptide structurally related to vasopressin, shortens bleeding time by inducing the release of factor VIII: von Willebrand factor . Tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) both inhibit plasmin binding to fibrin and partially preserve platelet adenosine diphosphate content after cardiac bypass .
A previous meta-analysis demonstrated that aprotinin decreased postoperative blood loss and the volume of postoperative transfusion in cardiac surgery . This and another meta-analysis  found that desmopressin decreased postoperative blood loss but did not decrease the frequency of perioperative allogeneic transfusion in patients undergoing cardiac surgery. We have extended the work of these previous meta-analyses by (a) incorporating 41 articles published since the previous meta-analyses were performed; (b) focusing on transfusion of red blood cells rather than on blood loss; (c) considering TXA and EACA separately [trials of the two were combined in a previous meta-analysis ]; and (d) evaluating the efficacy of these medications in clinically important subgroups depending on perioperative aspirin use, type of cardiac operation (primary versus reoperation), presence of a transfusion threshold, and frequency of transfusion in the control group.
The primary objective of these meta-analyses was to determine whether the four drugs decreased the proportion of patients receiving any perioperative allogeneic transfusion. Secondary analyses included the number of units transfused per patient, the frequency of reoperation because of bleeding after cardiac surgery, and the frequency of perioperative myocardial infarction or coronary vein graft thrombosis.
Literature Search and Study Selection
A MEDLINE search was performed with no restrictions for the dates January 1966 to March 1997, to identify all articles containing any of the following terms: aprotinin, ddAVP, desmopressin acetate, I-desamino-8-D-arginine vasopressin, tranexamic acid, epsilon-aminocaproic acid, or 6-aminocaproic acid. An extensive EMBASE search was performed as well. All the titles and abstracts were examined for studies evaluating the efficacy of drugs for minimizing perioperative blood use. The manufacturers of the drugs were asked to identify any articles or reports on this subject. The references of all relevant randomized trials, reports, review articles, and the two previous meta-analyses were searched for other potentially useful trials.
Only randomized trials that described the proportion of patients receiving at least 1 U of allogeneic red blood cells were included. Studies were included regardless of whether they were full publications, abstracts, or letters to the editor; used placebo or openlabel controls; or were published in English or non-English journals. Articles comparing any of the pharmaceutical drugs with each other (e.g., aprotinin versus TXA) were also included. Because they have been shown to lead to biased estimates of treatment effect [7,8], we excluded articles that were described as randomized but in which clinicians could have been aware of which treatment the patient received (e.g., allocation by chart number, birth date, etc.). Duplicate publications, studies of children, nonelective surgery, and trials in which patients were randomized postoperatively were excluded.
Data from the studies were independently abstracted onto study data forms by two individuals. Disagreements were resolved by consensus. We did not attempt to conceal the identity of the author or the medium of publication. When necessary, authors were contacted for clarification (e.g., to ensure that the same patients were not included in more than one report from the same author), and the author of one large study of aprotinin was contacted to determine the proportion of patients transfused with allogeneic red blood cells  (the article reported the proportion transfused with any allogeneic blood product).
The primary outcome measure was the proportion of patients receiving at least 1 U of allogeneic packed red blood cells. Other data abstracted from the studies were the mean units of packed red cells transfused per patient, the dose of medication used, type of surgery (primary or reoperation), the intra- and postoperative transfusion thresholds reported (hemoglobin >100 g/L, 80-100 g/L, or <80 g/L; hematocrit was converted to hemoglobin by dividing by 3.3), reoperation because of bleeding, perioperative myocardial infarction, preoperative use of aspirin, and methodological quality of the study report using the Jadad scale . The Jadad scale contains questions about three items: the process of randomization, double-blinding, and description of withdrawals. Possible scores vary from 0 (worst score) to 5 (best score). If blood transfusion was only reported in milliliters, this value was divided by 300 mL to determine the mean number of units transfused. If patients took aspirin within 7 days of the operation, they were considered to be using the drug. A total dose of aprotinin was calculated, assuming that an intravenous (IV) transfusion lasted 4 h (e.g., if 2 million U was given IV and added to the prime and 0.5 million U was infused IV each hour, the total dose was 6 million U).
Discrete data (proportions of patients transfused, perioperative myocardial infarction, and patients requiring reoperation) were analyzed using Meta-Analyst  (random effects model), and continuous data (mean units of blood transfused) were analyzed using RevMan . If no measure of variability (standard deviation or standard error) was provided for the mean units of blood transfused, the study was not used for that part of the meta-analysis. Most results are presented as odds ratios (OR) (with 95% confidence intervals [CI] and P values), but results are occasionally presented as absolute differences. An OR of 1 suggests that there was no difference between treatment and control, an OR less than 1 suggests that fewer patients in the treatment group received at least one allogeneic transfusion, and an OR greater than 1 suggests that more patients in the treatment group received at least one allogeneic transfusion. A P value <0.05 was considered statistically significant. Tests for heterogeneity were performed with each meta-analysis, and if positive, the studies that seemed to be the major contributors to the heterogeneity were evaluated in an attempt to discover the reasons.
Four studies of aprotinin in cardiac surgery evaluated all patients for coronary vein graft thrombosis [13-16]. The results of these studies are presented descriptively. A statistical meta-analysis of these thrombotic episodes was not performed because of the different outcome measures used in the various studies.
The number of eligible randomized trials with a control or placebo group were: aprotinin 45 [9,14-56], desmopressin 12 [36,37,57-66], TXA 12 [38,39,45,47,51,52,56,59,67-70], and EACA 3 [38,56,71]. Seven studies compared aprotinin with TXA directly [38,39,45,47,51,52,56], and two compared aprotinin and desmopressin [36,37].
The 45 trials of aprotinin included a total of 5808 patients. The largest trial randomized 1784 patients, and the median size of the trials was 63 patients. Before performing a meta-analysis of all the trials, the effect of aprotinin dose on efficacy was evaluated. This was done in two ways: (a) a meta-analysis of studies that randomized patients to receive either large-dose aprotinin (2 mU in the prime, 2 mU IV bolus, and 0.5 mU/h IV infusion-a total of 6 mU) or a smaller dose, and (b) determining the pooled OR for different doses of aprotinin from randomized studies that compared aprotinin with control.
Eleven studies randomized patients to receive either large-dose aprotinin (6 mU) or a smaller dose (1-4 mU). The pooled OR was 0.93 (95% CI 0.69-1.24; P = 0.61), which suggests that the efficacy of the two doses was similar (an OR less than 1 favored the smaller dose regimens). On the other hand, the OR for the studies comparing aprotinin with control were 0.28 (95% CI 0.21-0.36; P < 0.0001) for large dose; 0.35 (95% CI 0.22-0.58; P < 0.0001) for total doses between 2.0 and 6.0 mU; and 0.49 (95% CI 0.33-0.73; P = 0.0006) for total doses <2 mU (Figure 1), thus suggesting a trend toward larger doses of aprotinin being more effective. When all doses were combined the overall OR was 0.31 (95% CI 0.25-0.39; P < 0.0001). The test for heterogeneity was statistically significant among the large-dose aprotinin trials (P = 0.001), but we were unable to identify any clinical or methodological reason for this.
To determine whether aprotinin was more effective in some patients than others, we evaluated its efficacy in a number of subgroups, including the type of surgery, aspirin use, the transfusion threshold, the type of control used, and the Jadad score (Table 1, Figure 1). The efficacy of aprotinin was similar in all subgroups of patients, except for a statistically nonsignificant trend toward a greater effect of aprotinin in studies in which the transfusion threshold was >100 g/L of hemoglobin, compared with those in which the transfusion threshold was <80 g/L.
The mean number of allogeneic units transfused was 1.43 (95% CI 1.25-1.61; P < 0.0001) units lower in the aprotinin group than in the control group. Patients receiving aprotinin required fewer reoperations because of bleeding after surgery than patients in the control group (mean 1.8% vs 5.2%; OR 0.46, 95% CI 0.29-0.73; P = 0.001). There was no statistically significant difference in the frequency of perioperative myocardial infarction (8.0% in aprotinin-treated patients and 5.6% in patients in the control groups) (OR 1.12, 95% CI 0.82-1.53; P = 0.48).
Four studies evaluated all patients for the presence of vein graft thrombosis in cardiac surgery. Two used coronary angiography [13,14], one used ultrafast computerized tomography , and one used magnetic resonance imaging . Three of the studies specifically indicated that the determination of thrombosis was made without knowledge of treatment assignment [13,15,16], and the fourth study was placebocontrolled. Three studies evaluated patients within the first 2 wk of the operation [13,14,16], whereas the fourth evaluated patients 6-8 wk after surgery. There was considerable variability among the studies in both the overall frequency of graft thrombosis and the relative frequency of thrombosis in the aprotinin and placebo groups (Table 2).
There were 12 studies involving a total of 793 patients, all but 1 of which was placebo-controlled. The largest study enrolled a total of 99 patients, and the median sample size was 65 patients. Most studies used a dose of 0.3 micro g/kg IV at the end of cardiopulmonary bypass. Desmopressin had no statistically significant effect on the proportion of patients receiving transfusion (OR 0.98, 95% CI 0.64-1.50; P = 0.92) (Figure 2). However, on subgroup analyses, the efficacy of desmopressin seemed to vary depending on the use of aspirin (Table 1, Figure 2). In studies in which no patients received aspirin, the OR was 0.75 (95% CI 0.29-1.97; P = 0.56)), compared with an OR of 1.26 (95% CI 0.81-1.94; P = 0.30) if some patients received aspirin, and an OR of 0.21 (95% CI 0.07-0.62; P = 0.005) if all patients were taking aspirin.
In the six trials that reported reoperations for bleeding 2.0% of patients receiving desmopressin required surgical exploration, compared with 2.8% in the control groups (OR 0.87, 95% CI 0.23-3.27; P = 0.83). The frequency of perioperative myocardial infarction was 4.4% in patients treated with desmopressin and 1.6% in patients in the control group (OR 1.85, 95% CI 0.74-4.62; P = 0.19). The mean number of units of allogeneic blood transfused was 0.37 U less in desmopressin-treated patients (95% CI -0.95 to 0.22; P = 0.24).
There were 12 eligible studies of TXA with a total of 882 patients (median sample size 47). The majority of studies used a 10-mg/kg bolus followed by a 1-mg/kg infusion for 10-12 h. TXA decreased the proportion of patients receiving at least 1 U of allogeneic blood (OR 0.50, 95% CI 0.34-0.76; P = 0.0009) (Figure 2). The efficacy of TXA seemed similar in all subgroups studied (Table 1, Figure 2).
There was no statistically significant effect of TXA on perioperative myocardial infarction (0.4% in the TXA groups versus 1.8% in the control group) (OR 0.50, 95% CI 0.13-1.87; P = 0.30) or reoperations because of bleeding (2.4% in patients receiving TXA and 2.9% in patients in the control group) (OR 0.91, 95% CI 0.37-2.23; P = 0.84). A mean of 0.78 (95% CI 0.18-1.39; P = 0.01) fewer units of allogeneic blood were given to TXA-treated patients in the three studies that reported this outcome.
There were only three eligible studies of EACA, with a total of 118 patients. Each study used somewhat different doses of EACA. There was no statistically significant effect of EACA on the proportion of patients transfused with allogeneic blood, although the OR was considerably less than 1.0 (OR 0.20, 95% CI 0.04-1.12; P = 0.07) (Figure 2). There were not enough studies of EACA to perform any subgroup analyses.
Direct Comparisons of Aprotinin, Desmopressin, and TXA
Seven studies randomized a total of 474 patients to receive either aprotinin or TXA. There was no statistically significant difference between the two drugs (OR 0.59, 95% CI 0.29-1.23; P = 0.16)), although there was a trend toward aprotinin being more efficacious. Two studies, with a total of 148 patients, randomized patients to receive either desmopressin or aprotinin. Aprotinin was considerably more efficacious (OR 0.16, 95% CI 0.07-0.37; P < 0.0001).
Association Between Transfusion Rate and Clinical Benefit of Aprotinin
The rate of transfusion in the control group varied from 0% to 100% in patients undergoing primary cardiac surgery. When the proportion of patients receiving an allogeneic transfusion in the control group was 75% or less, there was a positive correlation between the transfusion rate in the control group and the absolute benefit of aprotinin (Figure 3).
The main findings of these meta-analyses were that (a) aprotinin, both in large and small doses, decreased the proportion of cardiac surgery patients who received allogeneic transfusion; (b) aprotinin decreased the proportion of patients requiring reoperation because of bleeding; (c) desmopressin was not effective in most patients, although there was a possibility that it was effective in patients who were taking aspirin (this needs to be confirmed in subsequent studies); (d) TXA was effective, although the number of patients studied was much smaller than that for aprotinin; (e) EACA did not have a statistically significant effect on the proportion of patients transfused with allogeneic blood, although only three randomized trials met the inclusion criteria for this meta-analysis; and (f) there were too few patients enrolled in these studies to reliably evaluate the possibility of a small but clinically important increase in thrombotic side effects, such as myocardial infarction or graft thrombosis.
The need to ensure that these medications do not increase the incidence of thrombosis is especially important now that the risk of transmitting viral infections with allogeneic transfusion is reduced. In the United States, the risk of human immunodeficiency virus transmission during the period 1991-1993 was between 1:450,000 and 1:660,000 per unit of allogeneic blood [72,73]. The risk of exposure to hepatitis C was approximately 1:100,000 . The likelihood of patients developing clinical disease from these exposures is even lower . There is no convincing evidence that allogeneic transfusion increases postoperative bacterial infection or cancer recurrence [74-79], although sufficiently large and methodologically sound studies have not been performed to establish or refute this possibility. Ensuring that the risk of adverse events due to the drugs considered in this meta-analysis is as low as the risks of allogeneic transfusion would require randomized trials with huge sample sizes. Unfortunately, registries of the frequency of myocardial infarctions after cardiac surgery in patients receiving and not receiving these drugs are unlikely to be helpful, because it would be difficult to determine whether a myocardial infarction was caused by the drug or was simply an adverse event associated with the surgery.
Some studies have raised concerns about the side effects of these drugs. Our meta-analysis found a small, statistically nonsignificant increase in perioperative myocardial infarction in aprotinin-treated patients. A pooled analysis using individual patient data from four published and two unpublished trials found a similar trend, but at the same time found a trend toward a lower risk of stroke in aprotinin-treated patients . In a retrospective, nonrandomized evaluation of patients who underwent postoperative angiography one year after bypass surgery, one center used aprotinin in all patients, and the other nine centers did not . Occlusion rates of distal anastomoses were 20.5% in patients who received aprotinin and 12.7% in those who did not (P = 0.09). Perioperative myocardial infarction occurred in 14.3% and 7.0% of patients, respectively (P = 0.12). Results from a retrospective, nonrandomized study must be interpreted with caution, and there are other reports of very low rates of graft occlusions in aprotinin-treated patients . Finally, a recent study of aprotinin reported a statistically significant increase in renal dysfunction in patients receiving aprotinin, especially in diabetics . The results of our meta-analysis and these other reports do raise concerns about the safety of aprotinin, which must be balanced against the benefits associated with a decrease in allogeneic transfusion and reoperation for bleeding. Currently available evidence does not convincingly establish that the risk of side effects from aprotinin, or from any of the other drugs considered in this analysis, is lower than the side effects of allogeneic blood.
It is worth considering the limitations of these meta-analyses. First, the sample sizes of most of the studies included in these meta-analyses were small. Except for the meta-analysis of aprotinin in cardiac patients, which included 5808 patients, all of the other meta-analyses included less than 1000 patients. Previous meta-analyses of other interventions, such as magnesium and nitrates for patients with myocardial infarction, contained more patients than were included in most of the meta-analyses in this study, yet they still reached false-positive conclusions about efficacy when their results were compared with a subsequent "definitive" large trial [83,84]. Thus, the results of this meta-analysis must be interpreted with caution, especially the subgroup analyses, such as the efficacy of desmopressin in patients receiving aspirin. Second, there was unexplained heterogeneity in the meta-analysis of large-dose aprotinin. However, most of the studies were positive, so the uncertainty rests more with the degree of benefit associated with the drug than whether it is effective at all. Third, many studies did not report the mean number of units transfused and a measure of variability (e.g., standard deviation), so only a subset of the randomized trials could be included in this part of the analysis. Similarly, the frequency of postoperative myocardial infarction or the need for reoperation because of bleeding was not reported in all studies. This supports the belief of others that uniform and comprehensive standards are needed when reporting the results of blood conservation studies .
Which patients undergoing surgery should receive these medications? The answer to this question is influenced considerably by the usual blood transfusion requirement of the surgical team without use of the medication (the baseline risk), which varied from 0% to 100% in the studies of aprotinin in primary cardiac surgery included in this meta-analysis. This degree of variability has been documented by others  and depends on some factors that are not amenable to change (e.g., the type of surgery), and others that can be altered. The latter include the skill and commitment of the operative team in preventing blood loss and the threshold for transfusion in clinically stable patients. These factors often receive relatively little attention-simple changes in operative technique and transfusion policy may decrease the use of allogeneic blood as much as any of the drugs considered in these meta-analyses.
The results of these meta-analyses suggest that further large randomized trials using well defined transfusion guidelines need to be performed to establish the best use of these medications. These studies should carefully collect and report data on the frequency of myocardial infarction, reoperation because of bleeding, and the mean, as well as median, units of blood transfused. Questions of particular interest include further comparison of large and small doses of aprotinin, determining whether desmopressin truly is effective in patients taking aspirin, and comparison of both TXA and EACA with aprotinin and with each other. Also, these medications need to be directly compared with other methods of minimizing allogeneic transfusion, such as autologous predonation, erythropoietin, cell salvage, and acute normovolemic hemodilution. Economic evaluations should be incorporated into the design of these studies to determine the cost-effectiveness of the various options.
We thank Drs. Barbara Schmidt, Oscar Benavente, and Joe Pagliarello for translating some of the articles; Ms. Jesse McGowan, Ms. Shin, and Ms. June MacLeod for assistance with the literature searches; and Mrs. Karen Weeks for her secretarial assistance.
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