Download Current Antifibrinolytic Therapy for Coronary Artery Revascularization

Current Antifibrinolytic Therapy for Coronary
Artery Revascularization
Jason Trudell, CRNA, MSN
Nicholas McMurdy, CRNA, MSN
The use of antifibrinolytic therapy is commonplace in
coronary artery revascularization procedures. Cardiac
surgery accounts for more than 700,000 surgeries per
year, with approximately 70% of these cases requiring
antifibrinolytic therapy for coronary artery bypass graft
(CABG) procedures. Two main classes of antifibrinolytics are used in CABG procedures: synthetic lysine analogues and serine protease inhibitors. Both classes of
antifibrinolytics have been shown to decrease the inci-
dence of blood transfusions. However, new data have
emerged regarding an increase in adverse outcomes
associated with serine protease inhibitors.The purpose
of this review article is to describe the clinical significance of antifibrinolytic therapy and the current implications associated with its use.
ardiovascular disease is one of the greatest
health concerns facing the nation’s healthcare
system. More than 17 million US citizens have
some degree of cardiac disease. The majority of
patients, upwards of 11 million, have coronary
artery disease, 5 million have valvular heart disease, and 1
million have congenital heart disease.1 The most common
cause of death in adults is related to coronary heart disease.2
Healthcare expenditures for cardiovascular disease are second to none in the United States. In 1995, healthcare
expenditures related to cardiovascular disorders totaled
$127.8 billion, or roughly 18% of all individual health
expenditures.3 Of the roughly 72 million surgical procedures performed each year, 700,000 are primary cardiac
procedures, and the vast majority of the cardiac surgeries,
roughly 500,000, are coronary artery bypass graft (CABG)
revascularization.2 In 2003, an estimated 1,244,000 inpatient angioplasty procedures, 467,000 inpatient bypass procedures, 1,414,000 inpatient diagnostic cardiac catheterizations, 64,000 inpatient implantable defibrillators, and
197,000 inpatient pacemaker procedures were performed
in the United States.4 The use of interventional cardiology
and, more specifically, percutaneous coronary intervention
(formally referred to as percutaneous transluminal coronary angioplasty, or PTCA) demonstrated a dramatic
increase of 326% from 1987 to 2003.4
Platelet dysfunction is the most prevalent cause of hemostatic abnormalities after cardiopulmonary bypass
(CPB), with the duration of on-pump bypass time having
the most detrimental effect on platelet function.3,5,6
Hemodilution, consumption of coagulation factors, and
degradation of coagulation factors by microvascular coagulation cause the deficiencies in blood coagulation
seen after CPB. The initiation of extracorporeal circulation elicits a microvascular activation of the factor XII in-
trinsic pathway of coagulation despite heparin therapy.5
The body’s own fibrinolysis further exacerbates
platelet dysfunction during CPB.5 Fibrinolysis is primarily or secondarily mediated during coronary artery revascularization. Primary fibrinolysis occurs via the release of
endothelial plasminogen activators.6,7 Secondary fibrinolysis occurs as a result of the intrinsic homeostasis
feedback loop in response to fibrin formation. The resultant circulating plasmin degradation products negatively affect platelet function.8
The initiation of bleeding prophylaxis in CPB should
be discussed with the cardiovascular surgeon before heparinization and initiation of extracorporeal circulation in
patients undergoing coronary artery revascularization and
valvular replacement. Antifibrinolytic agents such as
epsilon-aminocaproic acid (EACA), tranexamic acid
(TXA), and aprotinin are benchmark standards in onpump coronary artery revascularization.8 Antifibrinolytics
have demonstrated benefits in regard to blood conservation, platelet preservation, and thrombi formation.5,6,8-11
The different mechanisms of action, side effects, and
overall concerns for anesthesia providers when administering antifibrinolytics will be reviewed.
C
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Keywords: Antifibrinolytics, aprotinin, cardiac bypass,
hemostasis, transfusion.
Review of the Literature
A literature review was conducted using MEDLINE and
the Cumulative Index to Nursing and Allied health
Literature, or CINAHL. Search criteria included articles
and texts published from 1990 to the present. Potential
information sources were identified, and references were
located and screened for significance to antifibrinolytic
therapy and anesthesia caregivers. The articles and texts
were included if they met the following specific inclusion
criteria: (1) contained current information about antifibrinolytic therapy, (2) were published in a professional
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121
medical or nursing journal and/or text, and (3) discussed
coronary artery revascularization procedures or explained the action of antifibrinolytic agents.
Lysine Analogues
EACA and TXA are synthetic lysine analogues. EACA is
a synthetic chemical analog of the amino acid lysine.5,6 It
acts by binding to the lysine-binding sites of plasminogen
and plasmin. Once bound, EACA displaces plasminogen
from fibrin, resulting in inhibition of the natural tendency of plasminogen to split fibrinogen.8 A secondary proposed action of EACA is the ability to bind to fibrin and
protect it from plasmin degradation. The mechanism of
action of TXA is identical to that of EACA; however, it is
roughly 10 times more potent per unit dose than EACA.5
In addition, EACA and TXA inhibit the transformation of
plasminogen to plasmin by clot-bound tissue plasminogen activator (tPA) vs circulating tPA. Consequently, TXA
and EACA may not be as effective as a serine protease inhibitor in preventing systemic fibrinolysis when elevated
levels of tPA elicit a systemic increase in circulating
plasmin and, eventually, increased bleeding times associated with elevated fibrinogen degradation products.5,8
Several studies have evaluated the clinical implications associated with EACA and TXA in reducing blood
loss during and after cardiac surgery. These studies
showed that TXA and EACA can reduce blood loss after
cardiac surgery.6-8,10,12-14 EACA and TXA have been extensively studied and shown to have an excellent safety
margin in cardiac procedures with fewer than 1% of cases
demonstrating potential complications.5,6,8 Severe complications associated with synthetic lysine analogues administration include seizures, renal failure, and rhabdomyolysis.8,9,12
Serine Protease Inhibitor
The mechanism of action of aprotinin differs from the
previously discussed lysine analogues. As a nonspecific
serine protease enzyme inhibitor, aprotinin helps modulate the systemic inflammatory response associated with
CPB through its effects on kallikrein and plasmin inhibition. Inhibiting plasmin preserves the insoluble clot.
Kallikrein serves an important role in accelerating the
systemic inflammatory response. Kallikrein accelerates
factor XII formation, initiates complement systems, and
promotes fibrinolysis and renin formation.15 It also promotes bradykinin release, which increases vascular permeability and tPA formation.15
Aprotinin is associated with preventing fibrin degradation by inhibiting plasmin and kallikrein formation.
Fibrin degradation products (FDP) have a high affinity
for platelets, making them nonfunctional.16 The FDPs
also increase the release and synthesis of monocytemacrophage–derived interleukins 1 and 6, which induce
further endothelial and end-organ damage.16 Finally,
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FDPs weaken the ability of factor XIII to form a strong
fibrin clot.16 By preventing kallikrein and plasmin activation and decreasing FDPs, aprotinin assists with blood
preservation during CPB. In a thorough meta-analysis of
aprotinin, large and small doses decreased the proportion
of patients undergoing cardiac surgery patients who required blood products.7
In addition to blood conservation, aprotinin preserves
platelet function. Although the direct mechanism of
action of platelet preservation is unknown, a potential
explanation is that aprotinin selectively protects platelets
from desensitization that occurs throughout extracorporeal circulation time.17 This desensitization would decrease the degranulation and consumption of platelets
that occurs with thrombin formation. van Oeveren et al18
reported that the preservation of glycoprotein 1b occurred with aprotinin use. Glycoprotein 1b assists with
platelet adhesion to vascular endothelium. Proponents of
aprotinin also cite neutrophil activation and reduction of
atrial fibrillation as additional benefits.17,19
An increase in anaphylactic and anaphylactoid reactions has been reported with aprotinin.20 Despite decreasing blood product use, institutions may choose
other options owing to immunogenicity, the higher cost,
and other possible side effects associated with its use.
Comparison of Lysine Analogues and Serine
Protease Inhibitors
Meta-analyses comparing EACA, TXA, and aprotinin concluded that all 3 agents, when used in conjunction with
extracorporeal circulation, reduced blood loss and additional use of allogeneic blood products.19-21 Aprotinin is
an expensive drug, and its immunogenicity, which can potentially cause an allergic response with reexposure, has
led to the comparison, in multiple studies, of the cheaper
lysine-analog antifibrinolytic drugs for efficacy.22-29 It is
important to note that these studies had limited size, were
often not blinded clinical trials, and did not incorporate
redo surgical procedures. The mean ± SD costs for pharmacological and transfusional treatments were significantly lower for TXA ($58.10 ± $105.10) vs EACA ($100.70 ±
$158.60) vs aprotinin ($432.60 ± $118.70).13 An additional prospective randomized, partially blinded study
compared the costs of lysine analogues and serine protease inhibitors with the cost of allogeneic blood requirements.30 The study concluded that TXA was less costly
than aprotinin and achieved a comparable benefit. These
results are similar to those previously published comparing aprotinin with EACA and TXA.29 The cost-effective
advantage of the lysine analogues with similar end results
has led to their use at many institutions.
Perhaps the most conclusive literature that promotes
use of lysine analogues over aprotinin is a recent article
that reported an association of aprotinin with renal toxic
effects and ischemic events in patients undergoing CABG
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surgery.23 Among patients undergoing complex coronaryartery surgery, the use of aprotinin was associated with a
2-fold increase in renal failure requiring dialysis a 55%
increase in myocardial infarction or heart failure, and a
181% increase in stroke or encephalopathy.23 The study,
which included 4,373 patients undergoing coronary
revascularization, at more than 69 hospitals, concluded
that neither EACA nor TXA was associated with an increase risk in renal, cerebral, or cardiac events.
The study used statistical procedures to adjust for the
known differences between the treatment groups. The descriptive observational study does not demonstrate cause
and effect and did not randomly assign patients to aprotinin, TXA, EACA, or no medical intervention groups.
The patients had imbalances in baseline characteristics,
and patients treated with aprotinin had a higher propensity for multiple morbidities than did patients receiving
different antifibrinolytic therapy.23 To adjust for these imbalances, complex statistical methods involving propensity scores was used. Despite the complexity adjustment,
aprotinin, in low and high doses, showed an increase in
morbidity and mortality.23 Although all 3 agents decreased blood loss, the propensity of end-organ damage,
specifically the kidney, heart, and brain, was associated
only with aprotinin.
Aprotinin was associated with adverse outcomes in
another observational study of 898 patients, half of
whom were treated with aprotinin and the other half with
TXA, undergoing CABG with CPB. Baseline characteristics among participants were similar.30 Although the rates
of adverse events were similar between groups, there was
a noticeable rate of renal dysfunction in the aprotinin
group, especially in patients with preexisting renal dysfunction.30 Allogeneic blood transfusion requirements
were similar for both groups.30
The US Food and Drug Administration (FDA) issued an
alert in relation to the recently published reports of serious
renal and cardiovascular toxic effects following aprotinin
administration to patients undergoing CABG surgery.30 On
September 27, 2006, Bayer Pharmaceuticals told the Food
and Drug Administration that it had conducted an additional safety study of aprotinin. The preliminary findings
from this new observational study of patients from a hospital database showed that use of aprotinin may increase
the chance of death, serious kidney damage, congestive
heart failure, and stroke. The worldwide study funded by
Bayer, the maker of aprotinin, supported the data from the
2 previous observational studies.31 When using aprotinin,
providers should carefully monitor the occurrence of toxic
effects, in particular focusing on the kidneys, heart, and
brain.30 Aprotinin should be used only when blood conservation clearly outweighs the potential side effects.30
There are ongoing studies evaluating the risks and benefits
of aprotinin, and additional research is needed to determine its future use in antifibrinolytic therapy.
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Conclusion
There are 2 main pharmacologic options for antifibrinolytic therapy for patients undergoing CPB. Lysine analogues and serine protease inhibitors have been shown to
decrease the allogeneic blood transfusion requirements
that are customary with extracorporeal circulation.
Anesthetists need to understand the pharmacokinetics
and pharmacodynamics of each class of drug. Despite the
blood-salvaging benefit of these drugs, they come with
known risks. As new information is revealed about these
classes of drugs, anesthesia providers should be aware of
the risks associated with lysine analogues and serine protease inhibitors.
As of November 5, 2007, Bayer Pharmaceuticals has
suspended the marketing of aprotinin due to patient
safety concerns. Initial results from a Canadian study
suggest that patients administered aprotinin have a
greater risk of death than patients taking other antifibrinolytic drugs. Sales of aprotinin have been suspended
until the FDA can conduct further studies into the risks
and benefits of the drug. The FDA and Bayer are working
together to phase aprotinin out of the workplace and
prevent potential shortages of other antifibrinolytics.33,34
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AUTHORS*
Jason Trudell, CRNA, MSN, is a nurse anesthetist for Anesthesia Group of
Onodaga, PC, Syracuse, New York. Email: [email protected].
Nicholas McMurdy, CRNA, MSN, is a nurse anesthetist at Fairfax
Anesthesia Associates, Inc, Fairfax, Virginia.
* The authors were students at the University of Pittsburgh School of
Nursing Nurse Anesthesia Program, Pittsburgh, Pennsylvania, when this
article was written.
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