Secondary Logo

Journal Logo

Cardiovascular Anesthesia: Society of Cardiovascular Anesthesiologists

Drugs to Minimize Perioperative Blood Loss in Cardiac Surgery: Meta-Analyses Using Perioperative Blood Transfusion As the Outcome

Laupacis, Andreas MD; Fergusson, Dean MHA

Author Information

Abstract

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 [1]. 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 [2]. Desmopressin, a synthetic polypeptide structurally related to vasopressin, shortens bleeding time by inducing the release of factor VIII: von Willebrand factor [3]. Tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) both inhibit plasmin binding to fibrin and partially preserve platelet adenosine diphosphate content after cardiac bypass [4].

A previous meta-analysis demonstrated that aprotinin decreased postoperative blood loss and the volume of postoperative transfusion in cardiac surgery [5]. This and another meta-analysis [6] 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 [5]]; 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.

Methods

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 Collection

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 [9] (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 [10]. 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).

Analysis

Discrete data (proportions of patients transfused, perioperative myocardial infarction, and patients requiring reoperation) were analyzed using Meta-Analyst [11] (random effects model), and continuous data (mean units of blood transfused) were analyzed using RevMan [12]. 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.

Results

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].

Aprotinin

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.

Figure 1
Figure 1:
Summary of the overall odds ratios associated with aprotinin and the results of important secondary analyses. ASA = aspirin, Hgb = hemoglobin level (in g/L), CI = confidence interval, Pts = patients.

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.

Table 1
Table 1:
Efficacy of Drugs: Overall and Subgroup Analysesa

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 [15], and one used magnetic resonance imaging [16]. 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).

Table 2
Table 2:
Cardiac Vein Graft Thrombosis in Studies of Aprotinin That Routinely Screened Patients

Desmopressin

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.

Figure 2
Figure 2:
Summary of the overall odds ratio associated with desmopression, tranexamic acid, and epsilon-aminocaproic acid, and the results of important secondary analyses. ASA = aspirin, Hgb = hemoglobin level (in g/L), CI = confidence interval, Pts = patients.

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).

Tranexamic Acid

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.

EACA

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).

Figure 3
Figure 3:
Proportion of patients transfused with allogeneic blood in the placebo or openlabel control group versus the absolute difference in the proportion of patients transfused with allogeneic blood in trials of aprotinin in primary cardiac surgery.

Discussion

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 [73]. The likelihood of patients developing clinical disease from these exposures is even lower [72]. 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 [80]. 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 [81]. 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 [82]. Finally, a recent study of aprotinin reported a statistically significant increase in renal dysfunction in patients receiving aprotinin, especially in diabetics [43]. 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 [85].

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 [86] 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.

REFERENCES

1. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73-8.
2. Scott WJ, Kessler R, Wernly JA. Blood conservation in cardiac surgery. Ann Thorac Surg 1990;50:843-51.
3. Hashemi S, Palmer DS, Aye MT, et al. Molecular mechanisms of cellular responses to DDAVP. In: Mariani G, ed. Desmopressin in bleeding disorders. New York: Plenum, 1992:43-56.
4. Rubens F, Wells P. Tranexamic acid use during coronary artery bypass grafting. Ann Thorac Surg 1996;61:774-5.
5. Fremes SE, Wong BI, Lee E, et al. Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1995;58:1580-8.
6. Cattaneo M, Harris AS, Stroberg U, Mannucci PM. The effect of desmopressin on reducing blood loss in cardiac surgery: a meta-analysis of double-blind, placebo-controlled trials. Thromb Haemost 1995;74:1064-70.
7. Chalmers TC, Celano P, Sacks HS, Smith H. Bias in treatment assignment in controlled clinical trials. N Engl J Med 1983;309:1358-61.
8. Schultz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effect in controlled trials. JAMA 1995;273:408-12.
9. Lemmer JH, Dilling EW, Morton JR, et al. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996;62:1659-68.
10. Jadad AR, Moore A, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Contr Clin Trials 1996;17:1-12.
11. Meta-Analyst.977.Lau J, Chalmers TC. 1990.
12. RevMan (1.04b): The Cochrane Review Manager. 1994.
13. Havel M, Grabenwoger F, Schneider J, et al. Aprotinin does not decrease early graft patency after coronary artery bypass grafting despite reducing postoperative bleeding and use of donated blood. J Thorac Cardiovasc Surg 1994;107:807-10.
14. Kalangos A, Tayyareci G, Pretre R, et al. Influence of aprotinin on early graft thrombosis in patients undergoing myocardial revascularization. Eur J Cardiothorac Surg 1994;8:651-6.
15. Lemmer JH Jr, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency-a multicenter, randomized, double-blind, placebo-controlled study. J Thorac Cardiovasc Surg 1994;107:543-51.
16. Bidstrup BP, Underwood SR, Sapsford RN, Streets EM. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg 1993;105:147-52.
17. Rodrigus IE, Vermeyen KM, De Hert SG, et al. Efficacy and safety of aprotinin in aortocoronary bypass and valve replacement operations: a placebo-controlled randomized double-blind study. Perfusion 1996;11:313-8.
18. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91.
19. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg 1989;97:364-72.
20. Fraedrich G, Weber C, Bernard C, et al. Reduction of blood transfusion requirement in open heart surgery by administration of high doses of aprotinin: preliminary results. Thorac Cardiovasc Surg 1989;37:89-91.
21. Locatelli A, Bertollo D, Bianchi T, et al. Aprotinin in cardiosurgery: a randomized prospective study with different protocols for use. Miner Anestesiol 1990;56:973-5.
22. Dietrich W, Spannagl M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73:1119-26.
23. Boldt J, Zickmann B, Czeke A, et al. Blood conservation techniques and platelet function in cardiac surgery. Anesthesiology 1991;75:426-32.
24. Gherli T, Porcu A, Padua G, et al. Reducing bleeding during extracorporeal circulation interventions by high doses of aprotinin. Min Cardioangiol 1992;40:121-6.
25. Deleuze P, Loisance DY, Feliz A, et al. Reduction of pre- and postoperative blood loss with aprotinin (Trasylol) during extracorporeal circulation. Arch Malad Coeur Vaisseaux 1991;84:1797-802.
26. Vedrinne C, Girard C, Jegaden O, et al. Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin versus autologous fresh whole blood transfusion. J Cardiothorac Vasc Anesth 1992;6:319-23.
27. Dietrich W, Barankay A, Hahnel C, Richter JA. High-dose aprotinin in cardiac surgery: three years' experience in 1,784 patients. J Cardiothorac Vasc Anesth 1992;6:324-7.
28. Mohr R, Goor DA, Lusky A, Lavee J. Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction: a scanning electron microscope study. Circulation 1992;86(Suppl):II405-9.
29. Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031-6.
30. Baele PL, Ruiz-Gomez J, Londot C, et al. Systematic use of aprotinin in cardiac surgery: influence on total homologous exposure and hospital cost. Acta Anaesthesiol Belg 1992;43:103-12.
31. Bailey CR, Kelleher AA, Wielogorski AK. Randomised placebocontrolled double-blind study of three aprotinin regimens in primary cardiac surgery. Br J Surg 1994;81:969-73.
32. Carrera A, Martinez MV, Garcia-Guiral M, et al. Use of high doses of aprotinin in cardiac surgery. Rev Espan Anestesiol Reanim 1994;41:13-9.
33. Maccario M, Fumagalli C, Deangelis R, et al. Comparison between low and high doses of aprotinin in heart surgery. Miner Anestesiol 1994;60:315-20.
34. Murkin JM, Lux J, Shannon NA, et al. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994;107:554-61.
35. Swart MJ, Gordon PC, Hayse-Gregson PB, et al. High-dose aprotinin in cardiac surgery: a prospective, randomized study. Anaesth Intensive Care 1994;22:529-33.
36. Rocha E, Hidalgo F, Llorens R, et al. Randomized study of aprotinin and DDAVP to reduce postoperative bleeding after cardiopulmonary bypass surgery. Circulation 1994;90:921-7.
37. Casas JI, Zuazu-Jausoro I, Mateo J, et al. Aprotinin versus desmopressin for patients undergoing operations with cardiopulmonary bypass. J Thorac Cardiovasc Surg 1995;110:1107-17.
38. Penta de Peppo A, Danilo Pierri M, Scafuri A, et al. Intraoperative antifibrinolysis and blood-saving techniques in cardiac surgery. TX Heart Inst J 1995;22:231-6.
39. Corbeau JJ, Monrigal JP, Jacob JP, et al. Comparaison des effet de l'aprotinine et de l'acide tranexamique sur le saignement en chirurgie cardiaque. Ann Fr Anesth Reanim 1995;14:154-61.
40. Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995;92:2236-44.
41. Lab M, Welz A, Kochs M, et al. Aprotinin in elective primary bypass surgery: graft patency and clinical efficacy. Eur J Cardiothorac Surg 1995;9:206-10.
42. Dietrich W, Dilthey G, Spannagl M, et al. Influence of high-dose aprotinin on anticoagulation, heparin requirement, and celite- and kaolin-activated clotting time in heparin-pretreated patients undergoing open-heart surgery. Anesthesiology 1995;83:679-89.
43. D'Ambra MN, Akins CW, Blackstone E, et al. Aprotinin in primary valve replacement and reconstruction: a multicenter, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 1996;112:1081-9.
44. Harder MP, Eijsman L, Roozendaal KJ, et al. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg 1991;51:936-41.
45. Isetta C, Gunness TK, Samat C, et al. Antifibrinolytic treatment and homologous transfusion in cardiac surgery. Eur Heart J 1993;14:424.
46. Liu B, Belboul A, Radberg G, et al. Effect of reduced aprotinin dosage on blood loss and use of blood products in patients undergoing cardiopulmonary bypass. Scand J Thorac Cardiovasc Surg 1993;27:149-55.
47. Blauhut B, Harringer W, Bettelheim P, et al. Comparison of the effects of aprotinin and tranexamic acid on blood loss and related variables after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994;108:1083-91.
48. Hardy JF, Desroches J, Belisle S, et al. Low-dose aprotinin infusion is not clinically useful to reduce bleeding and transfusion of homologous blood products in high-risk cardiac surgical patients. Can J Anaesth 1993;40:625-31.
49. Bailey CR, Wielogorski AK. Randomised placebo-controlled double-blind study of two low-dose aprotinin regimens in cardiac surgery. Br Heart J 1994;71:349-53.
50. Tabuchi N, Huet RC, Sturk A, et al. Aprotinin preserves hemostasis in aspirin-treated patients undergoing cardiopulmonary bypass. Ann Thorac Surg 1994;58:1036-9.
51. Pugh SC, Wielogorski AK. A comparison of the effects of tranexamic acid and low-dose aprotinin on blood loss and homologous blood usage in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth 1995;9:240-4.
52. Speekenbrink RG, Vonk AB, Wildevuur CR, Eijsman L. Hemostatic efficacy of dipyridamole, tranexamic acid, and aprotinin in coronary bypass grafting. Ann Thorac Surg 1995;59:438-42.
53. Alvarez JM, Quiney NF, McMillan D, et al. The use of ultralow-dose aprotinin to reduce blood loss in cardiac surgery. J Cardiothorac Vasc Anesth 1995;9:29-33.
54. Wendel HP, Heller W, Michel J, et al. Lower cardiac troponin T levels in patients undergoing cardiopulmonary bypass and receiving high-dose aprotinin therapy indicate reduction of perioperative myocardial damage. J Thorac Cardiovasc Surg 1995;109:1164-72.
55. Bidstrup BP, Royston D, McGuinness C, Sapsford RN. Aprotinin in aspirin-pretreated patients. Perfusion 1990;5(Suppl):77-81.
56. Menichetti A, Tritapepe L, Ruvolo G, et al. Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. J Cardiovasc Surg 1996;37:401-7.
57. Salzman EW, Weinstein MJ, Weintraub RM, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery: a double-blind randomized trial. N Engl J Med 1986;314:1402-6.
58. Frankville DD, Harper GB, Lake CL, Johns RA. Hemodynamic consequences of desmopressin administration after cardiopulmonary bypass. Anesthesiology 1991;74:988-96.
59. Horrow JC, Van Riper DF, Strong MD, et al. Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery. Circulation 1991;84:2063-70.
60. Marquez J, Koehler S, Strelec SR, et al. Repeated dose administration of desmopressin acetate in uncomplicated cardiac surgery: a prospective, blinded, randomized study. J Cardiothorac Vasc Anesth 1992;6:674-6.
61. Ansell J, Klassen V, Lew R, et al. Does desmopressin acetate prophylaxis reduce blood loss after valvular heart operations? A randomized, double-blind study. J Thorac Cardiovasc Surg 1992;104:117-23.
62. Gratz I, Koehler J, Olsen D, et al. The effect of desmopressin acetate on postoperative hemorrhage in patients receiving aspirin therapy before coronary artery bypass operations. J Thorac Cardiovasc Surg 1992;104:1417-22.
63. Dilthey G, Dietrich W, Spannagl M, Richter JA. Influence of desmopressin acetate on homologous blood requirements in cardiac surgical patients pretreated with aspirin. J Cardiothorac Vasc Anesth 1993;7:425-30.
64. Sheridan DP, Card RT, Pinilla JC, et al. Use of desmopressin acetate to reduce blood transfusion requirements during cardiac surgery in patients with acetylsalicylic-acid-induced platelet dysfunction. Can J Surg 1994;37:33-6.
65. Temeck BK, Bachenheimer LC, Katz NM, et al. Desmopressin acetate in cardiac surgery: a double-blind, randomized study. South Med J 1994;87:611-5.
66. Spyt TJ, Weerasena NA, Bain WH, et al. The effects of desmopressin acetate (DDAVP) on haemostasis and blood loss in routine coronary artery bypass surgery: a randomized, double-blind trial. Perfusion 1990;5(Suppl):57-61.
67. Horrow JC, Van Riper DF, Strong MD, et al. The dose-response relationship of tranexamic acid. Anesthesiology 1995;82:383-92.
68. Coffey A, Pittmam J, Halbrook H, et al. The use of tranexamic acid to reduce postoperative bleeding following cardiac surgery: a double-blind randomized trial. Am Surg 1995;61:566-8.
69. Katsaros D, Petricevic M, Snow NJ, et al. Tranexamic acid reduces postbypass blood use: a double-blind, prospective, randomized study of 210 patients. Ann Thorac Surg 1996;61:1131-5.
70. Shore-Lesserson L, Reich DL, Vela-Cantos F, et al. Tranexamic acid reduces transfusions and mediastinal drainage in repeat cardiac surgery. Anesth Analg 1996;83:18-26.
71. Daily PO, Lamphere JA, Dembitsky WP, et al. Effect of prophylactic epsilon-aminocaproic acid on blood loss and transfusion requirements in patients undergoing first-time coronary artery bypass grafting: a randomized, prospective, double-blind study. J Thorac Cardiovasc Surg 1994;108:99-106.
72. Lackritz EM, Satten GA, Aberle-Grasse J, et al. Estimated risk of transmission of the human immunodeficiency virus by screened blood in the United States. N Engl J Med 1995;333:1721-5.
73. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ, for the Retrovirus Epidemiology Donor Study. The risk of transfusion-transmitted viral infections. N Engl J Med 1996;334:1685-90.
74. Busch ORC, Hop WCJ, Hoyneck van Papendrecht MAW. Blood transfusion and prognosis in colorectal cancer. N Engl J Med 1993;328:1372-6.
75. Heiss MM, Mempel W, Delanoff C, et al. Blood transfusion-modulated tumor recurrence: first results of a randomized study of autologous versus allogeneic blood transfusion in colorectal cancer surgery. J Clin Oncol 1994;12:1859-67.
76. Busch ORC, Marquet RL, Hop WCJ, Jeekel J. Colorectal cancer recurrence and perioperative blood transfusions: a critical reappraisal. Semin Surg Oncol 1994;10:195-9.
77. Chung M, Steinmetz OK, Gordon PH. Perioperative boood transfusion and outcome after resection for colorectal carcinoma. Br J Surg 1993;80:427-32.
78. Vamvakas E, Moore SB. Perioperative blood transfusion and colorectal cancer recurence: a qualitative statistical overview and meta-analysis. Transfusion 1993;33:754-65.
79. Duffy G, Neal KR. Differences in post-operative infection rates between patients receiving autologous and allogeneic blood transfusion: a meta-analysis of published randomized and nonrandomized studies. Transfus Med 1996;6:325-8.
80. Smith PK, Muhlbaier LH. Aprotinin: safe and effective only with the full-dose regimen. Ann Thorac Surg 1996;62:1575-7.
81. van der Meer J, Hillege HL, Ascoop CAPL, et al. Aprotinin in aortocoronary bypass surgery: increased risk of vein graft occlusion and myocardial infarction? Supportive evidence from a retrospective study. Thromb Haemostas 1996;15:1-3.
82. Jegaden O, Vedrinne C, Rossi R. Aprotinin does not compromise arterial graft patency in coronary bypass operations. J Thorac Cardiovasc Surg 1993;106:180-1.
83. Brzak S, Ridker PM. Discordance between meta-analyses and large-scale randomized, controlled trials. Ann Intern Med 1995;123:873-7.
84. Egger M, Davey Smith G. Misleading meta-analysis: lessons from "an effective, safe, simple" intervention that wasn't. BMJ 1995;310:752-4.
85. Lemmer JH Jr. Reporting the results of blood conservation studies: the need for uniform and comprehensive methods. Ann Thorac Surg 1994;58:1305-6.
86. Sirchia G, Giovanetti G, McClelland B, Fracchia GN. Safe and good use of blood in surgery (SANGUIS): use of blood products and artificial colloids in 43 European hospitals. Luxemburg: European Commission, 1994.
© 1997 International Anesthesia Research Society