(Circulation. 1999;99:81-89.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Is 
-Aminocaproic Acid as Effective as Aprotinin in Reducing Bleeding With Cardiac Surgery?
A Meta-Analysis
From the Departments of Surgery (J.J.M., N.J.O.B., J.D.B., L.J.D.) and Medicine (G.T.O.), Center for the Evaluative Clinical Sciences (G.T.O., J.D.B.), Dartmouth Medical School, Hanover, NH, and the VA Outcomes Group (J.J.M., J.D.B.), Veterans Affairs Medical Center, White River Junction, Vt.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Although aprotinin is known to be effective in reducing postoperative hemorrhage after cardiac surgery,
-aminocaproic acid, an alternative
antifibrinolytic, is considerably less expensive. Because the results
of 3 small randomized clinical trials comparing these 2 agents directly
were inconclusive, we performed a meta-analysis to compare the
relative effectiveness and adverse-effect profile of these 2 agents
against placebo.
Methods and Results—Data from 52 randomized clinical trials
published between 1985 and 1998 involving the use of -aminocaproic
acid (n=9) or aprotinin (n=46) in patients undergoing cardiac surgery
were abstracted. Our primary outcomes were total blood loss, red blood
cell transfusion rates and amounts, reexploration, stroke, myocardial
infarction, and mortality. The meta-analysis revealed
substantial reductions in total blood loss with -aminocaproic acid
and low-dose aprotinin (each with a 35% reduction versus placebo,
P<0.001) and high-dose aprotinin (53% reduction,
P<0.001). There were identical reductions in total
postoperative transfusions with -aminocaproic acid (61% reduction
versus placebo, P<0.010) and high-dose aprotinin (62%
reduction, P<0.001). The proportion of patients
transfused was similarly reduced with -aminocaproic acid (OR, 0.32;
95% CI, 0.15 to 0.69) and high-dose aprotinin (OR, 0.28; 0.22 to
0.37). Although both drugs reduced rates of reexploration to similar
degrees, this effect was statistically significant only with high-dose
aprotinin (OR, 0.39; 0.24 to 0.61). -Aminocaproic acid and aprotinin
had no effect on risks of postoperative myocardial infarction or
overall mortality.
Conclusions—Because the 2 antifibrinolytic agents appear to have
similar efficacies, the considerably less-expensive -aminocaproic
acid may be preferred over aprotinin for reducing hemorrhage
with cardiac surgery.
Key Words: -aminocaproic acid • aprotinin • hemorrhage • meta-analysis • surgery
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Postoperative hemorrhage is one of the most common complications of cardiac surgery. Although transfusion rates vary significantly among institutions,1 overall
60% to
75% of patients undergoing open heart surgery receive
transfusions.2 3 Re-exploration for hemorrhage is
required in 2% to 6% of patients, with case-fatality rates ranging
from 10% to 22%.4 5 In addition to its impact on
patients' morbidity and mortality, bleeding and reexploration consume
considerable resources as a result of increased operative time, blood
product use, and prolonged intensive care unit and total hospital
stays.
Prophylactic antifibrinolytic therapy is one approach to
reducing postoperative hemorrhage. The most thoroughly
evaluated antifibrinolytic agent is aprotinin. Its effectiveness in
reducing postoperative hemorrhage has been established in >40
randomized clinical trials and 2 meta-analyses.2 6
However, aprotinin is expensive: $1000 for the conventional
high-dose regimen (6 million KIU [kallikrein inhibiting units]) and
$500 for the low-dose regimen (3 million KIU). In addition, there
are concerns about potential thrombosis-related side effects and
allergic reactions with antifibrinolytic agents. For these reasons,
prophylactic use of aprotinin is often limited to patients
at high risk for bleeding (eg, reoperations) or those for whom
transfusions are not acceptable because of religious beliefs (eg,
Jehovah's Witnesses).
An alternative to aprotinin is -aminocaproic acid, a synthetic
antifibrinolytic. Although it shares some of the potential side effects
of aprotinin, -aminocaproic acid is considerably cheaper
($40/average dose). Three randomized clinical trials have directly
compared -aminocaproic acid and aprotinin in cardiac surgery.
However, these studies were inconclusive owing to limited sample
size.7 8 9 For this reason, we performed a
meta-analysis to assess the relative effectiveness and
side-effect profiles of the 2 antifibrinolytic agents compared with
placebo.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Literature Review and Study Selection
A comprehensive literature search was performed with the computerized Web-based OVID interface to MEDLINE. Keywords used in the search included "
-aminocaproic acid," "aprotinin,"
"cardiac surgery," and "randomized." In addition to inspecting
bibliographies of published review articles, we performed a
bibliographic citation search using the SCI-EXPANDED database of the
Web-based Institute for Scientific Information Citation Database. The
search spanned the time interval between 1985 and 1998. Only
English-language published articles were evaluated.
Trials included in this meta-analysis were selected for the
following characteristics: (1) random allocation to drug treatment
(high-dose aprotinin, low-dose aprotinin, and/or -aminocaproic acid)
or placebo/control groups; (2) based exclusively on patients undergoing
routine cardiac procedures (ie, primary or repeat CABG, valve
replacement or repair, or both); and (3) explicit evaluation of 
1 of
the following outcomes: total blood loss, amounts and/or rates of
transfusion, reexploration, postoperative stroke, myocardial
infarction, renal impairment, allergic hypersensitivity reactions, and
mortality.
Outcomes Extraction
Outcomes data were extracted from each trial and entered into a
computer file for analysis. Only published data were included.
Data presented ambiguously in 4 studies were clarified by
direct discussion with the primary authors.3 9 10 11
We evaluated blood loss by assessing total (intraoperative and postoperative) amounts in milliliters. To examine transfusion requirements, we considered only homologous packed red blood cell (pRBC) transfusions. Few trials provided sufficient information to allow us to examine use of autologous blood, platelets, cryoprecipitate, and plasma. For each trial, we abstracted the total number of pRBC units transfused in treatment and control groups and the proportion of patients transfused in each group. Transfusion requirements recorded in milliliters were transformed to pRBC units by a conversion factor of 350 mL/U. All instances of reexploration in the trials were included, regardless of the specified indication for surgery (eg, cardiac tamponade versus chest tube bleeding versus other) or the operative findings (eg, surgical versus nonsurgical bleeding). Stroke, myocardial infarction, renal impairment, and allergic reaction were categorized as defined by the individual trials.
Statistical and Stratified Analyses
To calculate intervention effects on bleeding and transfusion
requirements, the mean and SDs of blood loss and pRBC units transfused
were recorded for treatment and placebo/control groups in each
trial. Using the methods described by Cochrane, we then calculated
summary measures of absolute (mL and U) and relative (%) reductions in
mean total blood loss and pRBC transfusions in patients receiving the
active drug.12 For dichotomous outcomes (transfusion,
reexploration, postoperative myocardial infarction, stroke, renal
impairment, allergic reactions, and mortality), the total number of
patient outcomes in the drug and placebo groups was recorded in
2x2 tables. We added 0.5 to every cell in any table containing 0 to
improve bias and precision properties.13 The summary
measure of effect used for the dichotomous outcomes was the Peto OR
described by Yusuf et al.14 To account for variance
between studies, random-effects models were used for continuous and
dichotomous summary estimates of effect.15
Stratified analysis was performed to assess whether treatment effects varied according to whether or not trials were restricted to primary CABG or included patients undergoing "mixed" procedures (including CABG, valve, reoperation, and other cardiac procedures). We also performed stratified analysis according to specific study-design criteria, such as whether trials were placebo controlled or double-blinded.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Study Selection
Of the 52 trials that met our inclusion criteria (Appendix
), most
involved either high-dose (37 trials) or low-dose (17 trials)
aprotinin, whereas only 9 considered -aminocaproic acid. Overall,
71% were double-blind, 71% were placebo-controlled, and 8% were
multicenter studies.
|
|
|
|
Hemorrhage-Related Outcomes
Compared with their placebo/control counterparts, patients
receiving antifibrinolytic therapy had substantially lower total blood
loss (Figure 1A). -Aminocaproic acid
and low-dose aprotinin each reduced total blood loss by 35%
(P<0.001), whereas high-dose aprotinin reduced blood loss
by 53% (P<0.001).
|
-Aminocaproic acid was as effective in reducing transfusion
requirements after cardiac surgery as aprotinin. Compared with their
placebo counterparts, patients given -aminocaproic acid received
61% fewer pRBC transfusions (mean reduction, 0.74 U; Figure 1B
). Patients receiving -aminocaproic acid were only 32% as
likely to receive any pRBC transfusions (OR, 0.32; 95% CI, 0.15 to
0.69; P=0.004). These reductions in transfusion requirements
were nearly identical to those observed with the high-dose aprotinin
groups (the Table and Figure 2).
|
|
Patients receiving prophylactic antifibrinolytic
therapy also were less likely to undergo reexploration for bleeding
after cardiac surgery. This reduction was only statistically
significant for high-dose aprotinin (OR, 0.39; 95% CI, 0.24 to
0.61; P<0.001). Because of smaller sample sizes with
-aminocaproic acid and low-dose aprotinin, effects of approximately
similar magnitude did not reach statistical significance (OR, 0.54;
95% CI, 0.22 to 1.33; P=0.179; and OR, 0.56; 95% CI, 0.29
to 1.08, P=0.085, respectively; Figure 2).
Other Outcomes
Although there were consistent trends toward reduced
stroke rates in patients receiving antifibrinolytics, these trends did
not reach statistical significance (-aminocaproic acid: OR, 0.47;
95% CI, 0.15 to 1.56; P=0.22, high-dose aprotinin: OR,
0.56; 95% CI, 0.26 to 1.21; P=0.14; and low-dose aprotinin:
OR, 0.54; 95% CI, 0.20 to 1.45; P=0.22; Figure 2).
Prophylactic use of -aminocaproic acid or high- or
low-dose aprotinin was not associated with significant differences in
the incidence of postoperative myocardial infarction or overall
mortality (the Table and Figure 2). There were
insufficient data to evaluate the effect of -aminocaproic acid on
risks of renal impairment and allergic reactions. Although information
pertaining to these outcomes was also limited in the aprotinin trials,
there was a statistically insignificant trend toward increased rates of
renal dysfunction with high-dose aprotinin (OR, 1.46; 95% CI, 0.92 to
2.33; P=0.11) but not low-dose aprotinin (OR, 1.01; 95% CI,
0.65 to 1.57; P=0.96). High-dose aprotinin was associated
with a similar, insignificant trend toward increased risk of allergic
reactions (OR, 1.58; 95% CI, 0.59 to 4.23; P=0.36).
Stratified Analysis
Stratified analysis did not reveal important
interactions between drug effectiveness and characteristics of the
trials. Estimates of the effectiveness of high- and low-dose aprotinin
and -aminocaproic acid in reducing transfusion requirements were
similar when analysis was stratified according to whether
studies were placebo-controlled or double-blind (data not shown).
Furthermore, drug effectiveness in reducing transfusions was similar
between trials restricted to primary CABG and those enrolling patients
undergoing "mixed" procedures. Stratified analysis of less
frequent outcomes, including reexploration, could not be performed
(meaningfully) because of sample-size limitations.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
There remains little doubt that prophylactic use of antifibrinolytic therapy reduces postoperative hemorrhage in patients undergoing cardiac surgery. The proprietary drug aprotinin, the subject of 43 randomized clinical trials to date, has been most extensively studied. As in 2 previous meta-analyses, our study demonstrates that aprotinin substantially reduces the need for transfusions and reexploration after cardiac surgery.2 6 However, sufficient data to evaluate the considerably less-expensive antifibrinolytic
-aminocaproic acid have only recently become
available. When we incorporated several new trials involving this drug,
our meta-analysis suggested that -aminocaproic acid had
similar effectiveness in reducing hemorrhage after cardiac
surgery.
Although our meta-analysis examined the relative
effects of -aminocaproic acid and aprotinin against placebo, 3
randomized clinical trials have compared the 2 drugs directly. Trials
conducted by Penta de Peppo et al7 and Menichetti et
al8 compared -aminocaproic acid to high-dose aprotinin
and determined the latter to be more effective in reducing
postoperative blood loss. However, differences in postoperative
transfusion requirements were not identified. In a larger, more recent
trial,9 patients receiving -aminocaproic acid or
low-dose aprotinin had lower transfusion rates than patients in the
control group. However, no statistically or clinically significant
differences were noted between the 2 drug groups.
-Aminocaproic acid and aprotinin were associated with trends
toward large reductions in risk of postoperative stroke. However,
unlike the findings of several aprotinin studies,3 16
associations between antifibrinolytic use and reduced stroke incidence
were statistically insignificant in our analysis. Although the
relationship remains unproven, some authors hypothesize that the
kallikrein-inhibiting properties of aprotinin may reduce cerebral
vasospasm.17 The biological explanation for the potential
cerebrovascular protective effects of -aminocaproic acid is still
unclear.
There remains little evidence that antifibrinolytic therapy
increases the risk of thrombosis-related complications with cardiac
surgery. In our analysis, neither -aminocaproic acid nor
aprotinin was associated with appreciable differences in risk of
myocardial infarction. Two randomized controlled trials showed slightly
higher rates of coronary bypass graft closure with aprotinin;
however, these findings were not statistically
significant.18 19 Another randomized controlled trial
conducted by Havel et al20 revealed no differences in
bypass graft patency rates among patients receiving high-dose
aprotinin, low-dose aprotinin, or placebo. To the best of our
knowledge, the association between -aminocaproic acid and bypass
graft patency has not been studied.
Limitations
Several potential limitations should be considered in
assessing the validity of our findings. First, it is impossible to rule
out publication bias. Studies showing large benefits with drug
intervention may be more likely to be published than studies showing
little or no benefit. Second, despite the large number of trials, the
meta-analysis lacked sufficient statistical power to detect
clinically important effects of treatment on relatively infrequent
outcomes. For example, large apparent reductions in reexploration risk
with -aminocaproic acid (OR, 0.54) and in stroke rates with both
antifibrinolytic agents (OR, 0.47 to 0.56) were not statistically
significant. For similar reasons, we cannot exclude clinically
meaningful effects of -aminocaproic acid or aprotinin on risks of
myocardial infarction and mortality.
Third, drug dosing and administration protocols varied across
trials. Although all but 1 of the high-dose aprotinin trials were
consistent in using the standard dose (6 million
KIU),21 the low-dose aprotinin studies used dosing
protocols ranging from 1 to 3 million KIU. Similarly, trials involving
-aminocaproic acid used doses ranging from 7 to 30 g. Whether
the effectiveness of these agents is dose related remains
unanswered.
Finally, variable outcome definitions across trials may
have limited our analysis in several ways. Renal toxicity
remains among the major concerns with antifibrinolytic therapy, despite
the inconclusive evidence supporting this
relationship.22 23 Because trials used variable
creatinine levels to define renal impairment, our ability
to examine this potential adverse effect of aprotinin and
-aminocaproic acid was severely limited. Other outcomes are also
subject to misclassification. Stroke and myocardial infarction are both
discretionary clinical diagnoses, and transfusion and reexploration
frequently reflect discretionary treatment decisions. In double-blind
trials (when surgeon is unaware of treatment allocation), random
outcomes misclassification in drug and control groups would be expected
to bias studies toward the null hypothesis (no drug effect). In
nonblinded trials, however, outcomes misclassification could bias
results toward larger drug effects. Despite these potential problems,
the main effects of aprotinin and -aminocaproic acid were
essentially unchanged in stratified analysis of blinded and
nonblinded trials.
Conclusions
Aprotinin and -aminocaproic acid substantially reduce
hemorrhage in patients undergoing cardiac surgery, without
appreciable adverse effects. For these reasons,
prophylactic antifibrinolytic therapy should be considered
for routine use. Because the 2 drugs appear to have similar efficacies,
the considerably less-expensive -aminocaproic acid may be preferred
over
aprotinin.
|
Footnotes |
|---|
The views expressed herein do not necessarily represent those of the Department of Veterans Affairs or the United States government.
Address correspondence to Dr John J. Munoz, VA Outcomes Group (111B), Department of Veterans Affairs Hospital, White River Junction, VT 05009.
Received May 28, 1998; revision received September 2, 1998; accepted September 17, 1998.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Goodnough LT, Johnston MF, Toy PT. The variability of transfusion practice in coronary artery bypass surgery. JAMA. 1991;265:86–90.
2. Fremes SE, Wong BI, Lee E, Mai R, Christakis GT, McLean RF, Goldman BS, Naylor CD. Meta-analysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg. 1994;58:1580–1588.[Abstract]
3.
Levy JH, Pifarre R, Schaff HV, Horrow JC, Albus R,
Spiess B, Rosengart TK, Murray J, Clark RE, Smith P. 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;92:2236–2244.
4.
Dacey LJ, Munoz JJ, Baribeau YR, Johnson ER, Lahey SJ,
Leavitt BJ, Quinn RD, Nugent WC, Birkmeyer JD, O'Connor GT.
Re-exploration for hemorrhage following coronary artery
bypass grafting: incidence and risk factors. Arch Surg. 1998;133:442–447.
5.
Unsworth-White MJ, Herriot A, Valencia O, Poloniecki
J, Smith EE, Murday AJ, Parker DJ, Treasure T. Resternotomy for
bleeding after cardiac operation: a marker for increased morbidity and
mortality. Ann Thorac Surg. 1995;59:664–667.
6. Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth Analg. 1997;85:1258–1267.[Abstract]
7. Penta de Peppo A, Pierri MD, Scafuri A, De Paulis R, Colantuono G, Caprara E, Tomai F, Chiariello L. Intraoperative antifibrinolysis and blood-saving techniques in cardiac surgery: prospective trial of 3 antifibrinolytic drugs. Tex Heart Inst J. 1995;22:231–236.[Medline] [Order article via Infotrieve]
8. Menichetti A, Tritapepe L, Ruvolo G, Speziale G, Cogliati A, Di Giovanni C, Pacilli M, Criniti A. Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. J Cardiovasc Surg. 1996;37:401–407.[Medline] [Order article via Infotrieve]
9. Landymore RW, Murphy JT, Lummis H, Carter C. The use of low-dose aprotinin, epsilon-aminocaproic acid or tranexamic acid for prevention of mediastinal bleeding in patients receiving aspirin before coronary artery bypass operations. Eur J Cardiothorac Surg. 1997;11:798–800.[Abstract]
10. Vander Salm TJ, Ansell JE, Okike ON, Marsicano TH, Lew R, Stephenson WP, Rooney K. The role of epsilon-aminocaproic acid in reducing bleeding after cardiac operation: a double-blind randomized study. J Thorac Cardiovasc Surg. 1988;95:538–540.[Abstract]
11.
Vander Salm TJ, Kaur S, Lancey RA, Okike ON, Pezzella
AT, Stahl RF, Leone L, Li JM, Valeri CR, Michelson AD. Reduction of
bleeding after heart operations through the prophylactic
use of epsilon-aminocaproic acid. J Thorac Cardiovasc
Surg. 1996;112:1098–1107.
12. Cochrane WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–129.
13.
Oler A, Whooley MA, Oler J, Grady D. Adding heparin to
aspirin reduces the incidence of myocardial infarction and death in
patients with unstable angina: a meta-analysis.
JAMA. 1996;276:811–815.
14. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–371.[Medline] [Order article via Infotrieve]
15. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.[Medline] [Order article via Infotrieve]
16.
Smith PK, Muhlbaier LH. Aprotinin: safe and effective
only with the full-dose regimen. Ann Thorac Surg. 1996;62:1575–1577.
17. Royston D. Blood-sparing drugs: aprotinin, tranexamic acid, and epsilon- aminocaproic acid. Int Anesthesiol Clin. 1995;33:155–179.[Medline] [Order article via Infotrieve]
18.
Lemmer JH Jr, Stanford W, Bonney SL, Breen JF, Chomka
EV, Eldredge WJ, Holt WW, Karp RB, Laub GW, Lipton MJ, Schaff HV,
Tatooles CJ, Rumberger JA. 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;107:543–551; discussion 551–553.
19.
Laub GW, Riebman JB, Chen C, Adkins MS, Anderson WA,
Fernandez J, McGrath LB. The impact of aprotinin on coronary
artery bypass graft patency. Chest. 1994;106:1370–1375.
20.
Havel M, Grabenwoger F, Schneider J, Laufer G, Wollenek
G, Owen A, Simon P, Teufelsbauer H, Wolner E. 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;107:807–810.
21. Harder MP, Eijsman L, Roozendaal KJ, van Oeveren W, Wildevuur CR. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg.. 1991;51:936–941.[Abstract]
22. Bidstrup BP, Harrison J, Royston D, Taylor KM, Treasure T. Aprotinin therapy in cardiac operations: a report on use in 41 cardiac centers in the United Kingdom. Ann Thorac Surg. 1993;55:971–976.[Abstract]
23.
Lemmer JH, Jr, Stanford W, Bonney SL, Chomka EV, Karp
RB, Laub GW, Rumberger JA, Schaff HV. Aprotinin for coronary
artery bypass grafting: effect on postoperative renal function.
Ann Thorac Surg. 1995;59:132–136.
24.
Ray MJ, Marsh NA, Just SJ, Perrin EJ, O'Brien MF,
Hawson GA. Preoperative platelet dysfunction increases the benefit
of aprotinin in cardiopulmonary bypass. Ann Thorac
Surg. 1997;63:57–63.
25.
D'Ambra MN, Akins CW, Blackstone EH, Bonney SL, Cohn
LH, Cosgrove DM, Levy JH, Lynch KE, Maddi R. Aprotinin in primary valve
replacement and reconstruction: a multicenter, double-blind,
placebo-controlled trial. J Thorac Cardiovasc Surg. 1996;112:1081–1089.
26.
Lemmer JH Jr, Dilling EW, Morton JR, Rich JB, Robicsek
F, Bricker DL, Hantler CB, Copeland JG III, Ochsner JL, Daily PO,
Whitten CW, Noon GP, Maddi R. Aprotinin for primary coronary
artery bypass grafting: a multicenter trial of three dose regimens.
Ann Thorac Surg. 1996;62:1659–1667; discussion 1667–1668.
27. Rodrigus IE, Vermeyen KM, De Hert SG, Amsel BJ, Walter PJ. Efficacy and safety of aprotinin in aortocoronary bypass and valve replacement operations: a placebo-controlled randomized double-blind study. Perfusion. 1996;11:313–318.[Medline] [Order article via Infotrieve]
28.
Speekenbrink RG, Wildevuur CR, Sturk A, Eijsman L.
Low-dose and high-dose aprotinin improve hemostasis in coronary
operations. J Thorac Cardiovasc Surg. 1996;112:523–530.
29. Casas JI, Zuazu-Jausoro I, Mateo J, Oliver A, Litvan H, Muniz-Diaz E, Aris A, Caralps JM, Fontcuberta J. Aprotinin versus desmopressin for patients undergoing operations with cardiopulmonary bypass: a double-blind placebo-controlled study. J Thorac Cardiovasc Surg. 1995;110(pt 1):1107–1117.
30. Dietrich W, Dilthey G, Spannagl M, Jochum M, Braun SL, Richter JA. Influence of high-dose aprotinin on anticoagulation, heparin requirement, and celite- and kaolin-activated clotting time in heparin-pretreated patients undergoing open-heart surgery: a double-blind, placebo-controlled study. Anesthesiology. 1995;83:679–689; discussion 29A–30A.[Medline] [Order article via Infotrieve]
31. Lass M, Welz A, Kochs M, Mayer G, Schwandt M, Hannekum A. Aprotinin in elective primary bypass surgery: graft patency and clinical efficacy. Eur J Cardiothorac Surg. 1995;9:206–210.[Abstract]
32.
Wendel HP, Heller W, Michel J, Mayer G, Ochsenfahrt C,
Graeter U, Schulze J, Hoffmeister HM, Hoffmeister HE. 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;109:1164–1172.
33. Bailey CR, Kelleher AA, Wielogorski AK. Randomized placebo-controlled double-blind study of three aprotinin regimens in primary cardiac surgery. Br J Surg. 1994;81:969–973.[Medline] [Order article via Infotrieve]
34.
Blauhut B, Harringer W, Bettelheim P, Doran JE, Spath
P, Lundsgaard-Hansen P. Comparison of the effects of aprotinin and
tranexamic acid on blood loss and related variables after
cardiopulmonary bypass. J Thorac Cardiovasc
Surg. 1994;108:1083–1091.
35. Boldt J, Schindler E, Knothe C, Hammermann H, Stertmann WA, Hempelmann G. Does aprotinin influence endothelial-associated coagulation in cardiac surgery? J Cardiothorac Vasc Anesth. 1994;8:527–531.[Medline] [Order article via Infotrieve]
36. Feindt P, Seyfert U, Volkmer I, Huwer H, Kalweit G, Gams E. Is there a phase of hypercoagulability when aprotinin is used in cardiac surgery? Eur J Cardiothorac Surg. 1994;8:308–313; discussion 308–314.[Abstract]
37. Kalangos A, Tayyareci G, Pretre R, Di Dio P, Sezerman O. Influence of aprotinin on early graft thrombosis in patients undergoing myocardial revascularization. Eur J Cardiothorac Surg. 1994;8:651–656.[Abstract]
38.
Murkin JM, Lux J, Shannon NA, Guiraudon GM, Menkis AH,
McKenzie FN, Novick RJ. Aprotinin significantly decreases bleeding and
transfusion requirements in patients receiving aspirin and undergoing
cardiac operations. J Thorac Cardiovasc Surg. 1994;107:554–561.
39.
Rocha E, Hidalgo F, Llorens R, Melero JM, Arroyo JL,
Paramo JA. Randomized study of aprotinin and DDAVP to reduce
postoperative bleeding after cardiopulmonary bypass surgery.
Circulation. 1994;90:921–927.
40. Swart MJ, Gordon PC, Hayse-Gregson PB, Dyer RA, Swanepoel AL, Buckels NJ, Schall R, Odell JA. High-dose aprotinin in cardiac surgery: a prospective, randomized study. Anaesth Intensive Care. 1994;22:529–533.[Medline] [Order article via Infotrieve]
41. Bidstrup BP, Underwood SR, Sapsford RN, Streets EM. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg. 1993;105:147–152; discussion 153.[Abstract]
42. Orchard MA, Goodchild CS, Prentice CR, Davies JA, Benoit SE, Creighton-Kemsford LJ, Gaffney PJ, Michelson AD. Aprotinin reduces cardiopulmonary bypass-induced blood loss and inhibits fibrinolysis without influencing platelets. Br J Haematol. 1993;85:533–541.[Medline] [Order article via Infotrieve]
43. Baele PL, Ruiz-Gomez J, Londot C, Sauvage M, Van Dyck MJ, Robert A. Systematic use of aprotinin in cardiac surgery: influence on total homologous exposure and hospital cost. Acta Anaesthesiol Belg. 1992;43:103–112.[Medline] [Order article via Infotrieve]
44. Cosgrove DM 3rd, Heric B, Lytle BW, Taylor PC, Novoa R, Golding LA, Stewart RW, McCarthy PM, Loop FD. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg. 1992;54:1031–1036; discussion 1036–1038.[Abstract]
45. 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;6:324–327.[Medline] [Order article via Infotrieve]
46. Mohr R, Goor DA, Lusky A, Lavee J. Aprotinin prevents cardiopulmonary bypass-induced platelet dysfunction: a scanning electron microscope study. Circulation. 1992;86(suppl II):II-405–II-409.
47. Vedrinne C, Girard C, Jegaden O, Blanc P, Bouvier H, Ffrench P, Mikaeloff P, Estanove S. 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;6:319–323.[Medline] [Order article via Infotrieve]
48. Havel M, Teufelsbauer H, Knobl P, Dalmatiner R, Jaksch P, Zwolfer W, Muller M, Vukovich T. Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation. J Thorac Cardiovasc Surg. 1991;101:968–972.[Abstract]
49. Bidstrup BP, Royston D, McGuinness C, Sapsford RN. Aprotinin in aspirin-pretreated patients. Perfusion. 1990;5(suppl):77–81.
50. Dietrich W, Spannagl M, Jochum M, Wendt P, Schramm W, Barankay A, Sebening F, Richter JA. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology. 1990;73:1119–1126.[Medline] [Order article via Infotrieve]
51. Alajmo F, Calamai G, Perna AM, Melissano G, Pretelli P, Palmarini MF, Carbonetto F, Noferi D, Boddi V, Palminiello A, Vaccari M. High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg. 1989;48:536–539.[Abstract]
52. 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;97:364–372.[Abstract]
53. Fraedrich G, Weber C, Bernard C, Hettwer A, Schlosser V. 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.[Medline] [Order article via Infotrieve]
54. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on need for blood transfusion after repeat open-heart surgery. Lancet. 1987;2:1289–1291.[Medline] [Order article via Infotrieve]
55. 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;9:240–244.[Medline] [Order article via Infotrieve]
56.
Speekenbrink RG, Vonk AB, Wildevuur CR, Eijsman L.
Hemostatic efficacy of dipyridamole, tranexamic acid,
and aprotinin in coronary bypass grafting. Ann Thorac
Surg. 1995;59:438–442.
57.
Bailey CR, Wielogorski AK. Randomised placebo
controlled double blind study of two low dose aprotinin regimens in
cardiac surgery. Br Heart J. 1994;71:349–353.
58. Tabuchi N, Huet RC, Sturk A, Eijsman L, Wildevuur CR. Aprotinin preserves hemostasis in aspirin-treated patients undergoing cardiopulmonary bypass. Ann Thorac Surg. 1994;58:1036–1039.[Abstract]
59. Hardy JF, Desroches J, Belisle S, Perrault J, Carrier M, Robitaille D. 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;40:625–631.[Medline] [Order article via Infotrieve]
60. Kawasuji M, Ueyama K, Sakakibara N, Tedoriya T, Matsunaga Y, Misaki T, Watanabe Y. Effect of low-dose aprotinin on coagulation and fibrinolysis in cardiopulmonary bypass. Ann Thorac Surg. 1993;55:1205–1209.[Abstract]
61. Lavee J, Raviv Z, Smolinsky A, Savion N, Varon D, Goor DA, Mohr R. Platelet protection by low-dose aprotinin in cardiopulmonary bypass: electron microscopic study. Ann Thorac Surg. 1993;55:114–119.[Abstract]
62. Liu B, Belboul A, Radberg G, Tengborn L, Dernevik L, Roberts D, William-Olsson G. Effect of reduced aprotinin dosage on blood loss and use of blood products in patients undergoing cardiopulmonary bypass. Scand J Thorac Cardiovasc Surg. 1993;27:149–155.[Medline] [Order article via Infotrieve]
63.
Hardy J-F, Belisle S, Dupont C, Harel F, Robitaille D,
Roy M, Gagnon L. Prophylactic tranexamic acid and
aminocaproic acid for primary myocardial
revascularization. Ann Thorac Surg. 1998;65:371–376.
64. Slaughter TF, Faghih F, Greenberg CS, Leslie JB, Sladen RN. The effects of aminocaproic acid on fibrinolysis and thrombin generation during cardiac surgery. Anesth Analg. 1997;85:1221–1226.[Abstract]
65.
Daily PO, Lamphere JA, Dembitsky WP, Adamson RM, Dans
NF. 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; discussion 106–108.
66.
DelRossi AJ, Cernaianu AC, Botros S, Lemole GM, Moore
R. Prophylactic treatment of postperfusion bleeding using
EACA. Chest. 1989;96:27–30.
This article has been cited by other articles:
 |
|
 |
|
  D. R. McIlroy, P. S. Myles, L. E. Phillips, and J. A. Smith Antifibrinolytics in cardiac surgical patients receiving aspirin: a systematic review and meta-analysis Br. J. Anaesth., February 1, 2009; 102(2): 168 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Henry MBChB, P. Carless BHSc MMedS, D. Fergusson PhD MHA, and A. Laupacis MD MSc The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis Can. Med. Assoc. J., January 20, 2009; 180(2): 183 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Martin, G. Wiesner, T. Breuer, R. Lange, and P. Tassani The Risks of Aprotinin and Tranexamic Acid in Cardiac Surgery: A One-Year Follow-Up of 1188 Consecutive Patients Anesth. Analg., December 1, 2008; 107(6): 1783 - 1790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dunning, M. Versteegh, A. Fabbri, A. Pavie, P. Kolh, U. Lockowandt, S. A.M. Nashef, and on behalf of the EACTS Audit and Guidelines Commit Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur. J. Cardiothorac. Surg., July 1, 2008; 34(1): 73 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Eaton Antifibrinolytic Therapy in Surgery for Congenital Heart Disease Anesth. Analg., April 1, 2008; 106(4): 1087 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Schneeweiss, J. D. Seeger, J. Landon, and A. M. Walker Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death N. Engl. J. Med., February 21, 2008; 358(8): 771 - 783. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. Bridges Valid Comparisons of Antifibrinolytic Agents Used in Cardiac Surgery Circulation, June 5, 2007; 115(22): 2790 - 2792. [Full Text] [PDF]
|
|
|
|
|
|
J. R. Brown, N. J.O. Birkmeyer, and G. T. O'Connor Meta-Analysis Comparing the Effectiveness and Adverse Outcomes of Antifibrinolytic Agents in Cardiac Surgery Circulation, June 5, 2007; 115(22): 2801 - 2813. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Mannucci and M. Levi Prevention and Treatment of Major Blood Loss N. Engl. J. Med., May 31, 2007; 356(22): 2301 - 2311. [Full Text] [PDF]
|
|
|
|
|
|
V. A. Ferraris, C. R. Bridges, R. P. Anderson, for the Blood Conservation Guideline, J. R. Brown, N. J.O. Birkmeyer, G. T. O'Connor, J. H. Levy, J. G. Ramsay, R. A. Guyton, et al. Aprotinin in cardiac surgery. N. Engl. J. Med., May 4, 2006; 354(18): 1953 - 1957. [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Cooper Jr, J. Abrams, O.H. Frazier, R. Radovancevic, B. Radovancevic, A. W. Bracey, M. J. Kindo, and I. D. Gregoric Fatal pulmonary microthrombi during surgical therapy for end-stage heart failure: Possible association with antifibrinolytic therapy J. Thorac. Cardiovasc. Surg., May 1, 2006; 131(5): 963 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Camarasa, G. Olle, M. Serra-Prat, A. Martin, M. Sanchez, P. Ricos, A. Perez, and L. Opisso Efficacy of aminocaproic, tranexamic acids in the control of bleeding during total knee replacement: a randomized clinical trial Br. J. Anaesth., May 1, 2006; 96(5): 576 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dial, E. Delabays, M. Albert, A. Gonzalez, J. Camarda, A. Law, and D. Menzies Hemodilution and surgical hemostasis contribute significantly to transfusion requirements in patients undergoing coronary artery bypass J. Thorac. Cardiovasc. Surg., September 1, 2005; 130(3): 654 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D Belway, F D Rubens, D Wozny, B Henley, and H J Nathan Are we doing everything we can to conserve blood during bypass? A national survey Perfusion, September 1, 2005; 20(5): 237 - 241. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Shander, D. Moskowitz, and T. S. Rijhwani The Safety and Efficacy of "Bloodless" Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2005; 9(1): 53 - 63. [Abstract] [PDF]
|
|
|
|
|
|
A. M. Mahdy and N. R. Webster Perioperative systemic haemostatic agents Br. J. Anaesth., December 1, 2004; 93(6): 842 - 858. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Moskowitz, J. J. Klein, A. Shander, K. M. Cousineau, R. S. Goldweit, C. Bodian, S. I. Perelman, H. Kang, D. A. Fink, H. C. Rothman, et al. Predictors of transfusion requirements for cardiac surgical procedures at a blood conservation center Ann. Thorac. Surg., February 1, 2004; 77(2): 626 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Smith, S. K. Datta, L. H. Muhlbaier, G. Samsa, A. Nadel, and J. Lipscomb Cost analysis of aprotinin for coronary artery bypass patients: analysis of the randomized trials Ann. Thorac. Surg., February 1, 2004; 77(2): 635 - 642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Shore-Lesserson, D. L. Reich, and D. H. Adams Invited commentary Ann. Thorac. Surg., February 1, 2004; 77(2): 642 - 643. [Full Text] [PDF]
|
|
|
|
|
|
A. Koster, S. Huebler, F. Merkle, T. Hentschel, M. Grundel, T. Krabatsch, L. Tambeur, M. Praus, H. Habazettl, W. M. Kuebler, et al. Heparin-Level-Based Anticoagulation Management During Cardiopulmonary Bypass: A Pilot Investigation on the Effects of a Half-Dose Aprotinin Protocol on Postoperative Blood Loss and Hemostatic Activation and Inflammatory Response Anesth. Analg., February 1, 2004; 98(2): 285 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Greilich, C. F. Brouse, C. W. Whitten, L. Chi, J. M. DiMaio, and M. E. Jessen Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of {epsilon}-aminocaproic acid and aprotinin J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1498 - 1503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. H. Scott, F. C. Seifert, P. S. A. Glass, and R. Grimson Blood Use in Patients Undergoing Coronary Artery Bypass Surgery: Impact Of Cardiopulmonary Bypass Pump, Hematocrit, Gender, Age, and Body Weight Anesth. Analg., October 1, 2003; 97(4): 958 - 963. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Karski and J. T. Balatbat Blood Conservation Strategies in Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2003; 7(2): 175 - 188. [Abstract] [PDF]
|
|
|
|
|
|
G. A. Nuttall, D. N. Fass, L. J. Oyen, W. C. Oliver Jr., and M. H. Ereth A Study of a Weight-Adjusted Aprotinin Dosing Schedule During Cardiac Surgery Anesth. Analg., February 1, 2002; 94(2): 283 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Thielmeier, J. R. Pank, R. D. Dowling, and L. A. Gray JR Anesthetic and Perioperative Considerations in Patients Undergoing Placement of Totally Implantable Replacement Hearts Seminars in Cardiothoracic and Vascular Anesthesia, November 1, 2001; 5(4): 335 - 344. [Abstract] [PDF]
|
|
|
|
|
|
G. J. Despotis, M. S. Avidan, and C. W. Hogue Jr Mechanisms and attenuation of hemostatic activation during extracorporeal circulation Ann. Thorac. Surg., November 1, 2001; 72(5): S1821 - 1831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Greilich, K. Okada, P. Latham, R. R. Kumar, and M. E. Jessen Aprotinin But Not {epsilon}-Aminocaproic Acid Decreases Interleukin-10 After Cardiac Surgery With Extracorporeal Circulation: Randomized, Double-Blind, Placebo-Controlled Study in Patients Receiving Aprotinin and {epsilon}-Aminocaproic Acid Circulation, September 18, 2001; 104 (2009): I-265 - I-269. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Wajon, J. Gibson, R. Calcroft, C. Hughes, and B. Thrift Intraoperative Plateletpheresis and Autologous Platelet Gel Do Not Reduce Chest Tube Drainage or Allogeneic Blood Transfusion After Reoperative Coronary Artery Bypass Graft Anesth. Analg., September 1, 2001; 93(3): 536 - 542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ray, M. M. Hales, L. Brown, M. F. O'Brien, and E. G. Stafford Postoperatively administered aprotinin or epsilon aminocaproic acid after cardiopulmonary bypass has limited benefit Ann. Thorac. Surg., August 1, 2001; 72(2): 521 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Fiechtner, G. A. Nuttall, M. E. Johnson, Y. Dong, N. Sujirattanawimol, W. C. Oliver Jr., R. S. Sarpal, L. J. Oyen, and M. H. Ereth Plasma Tranexamic Acid Concentrations During Cardiopulmonary Bypass Anesth. Analg., May 1, 2001; 92(5): 1131 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Ray and M. F. O'Brien Comparison of epsilon aminocaproic acid and low-dose aprotinin in cardiopulmonary bypass: efficiency, safety and cost Ann. Thorac. Surg., March 1, 2001; 71(3): 838 - 843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. East, F. Clements, J. Mathew, and T. F. Slaughter Antiphospholipid Syndrome and Cardiac Surgery: Management of Anticoagulation in Two Patients Anesth. Analg., May 1, 2000; 90(5): 1098 - 1101. [Full Text] [PDF]
|
|
|
|
|
|
J. E. Knutson, J. A. Deering, F. W. Hall, G. A. Nuttall, D. R. Schroeder, R. D. White, and C. J. Mullany Does Intraoperative Hetastarch Administration Increase Blood Loss and Transfusion Requirements After Cardiac Surgery? Anesth. Analg., April 1, 2000; 90(4): 801 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Munoz, N. J.O. Birkmeyer, L. J. Dacey, J. D. Birkmeyer, D. C. Charlesworth, E. R. Johnson, S. J. Lahey, M. Norotsky, R. D. Quinn, B. M. Westbrook, et al. Trends in rates of reexploration for hemorrhage after coronary artery bypass surgery Ann. Thorac. Surg., October 1, 1999; 68(4): 1321 - 1325. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||