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Review of the CCAS
Program at Pediatric
Anesthesiology 2008
Call for Nominations
for 2008 Board of
Directors Elections
ARTICLE REVIEW
Antifibrinolytic Therapy
in Surgery for
Congenital Heart Disease
Article Review:
Antifibrinolytic Therapy in Surgery for Congenital Heart Disease
Eaton MP
Anesth Analg 2008;106:1087-1100
Reviewer:
Denise Joffe, MD
Seattle Children’s Hospital
Background:
Bleeding after cardiac surgery in pediatric patients continues to be a major source of morbidity and mortality. For over a decade antifibrinolytic therapy has been used in an attempt to decrease bleeding in this population. Antifibrinolytic agents include the serine protease inhibitor aprotinin and the lysine analogs e-aminocaproic acid (EACA) and tranexamic acid (TA).
Following publication in the May 14, 2008 online issue of The New England Journal of Medicine, of: Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART study), Bayer Pharmaceuticals, the manufacturer of aprotinin, notified the FDA of their intent to remove all remaining supplies of aprotinin from hospital pharmacies. Despite the fact that a recent study demonstrated no effect of aprotinin on mortality or renal failure in over 1000 pediatric patients, the results of the BART study will severely limit the availability of aprotinin. Aprotinin will continue to be available only as an investigational drug under a special treatment protocol. http://www.fda.gov/CDER/DRUG/infopage/aprotinin/default.htm).
This paper reviews the efficacy, and safety data on these agents in congenital heart surgery.
Methods:
The Ovid and Pubmed databases were searched for relevant articles. 52 studies and case reports were found to meet search criteria. 22 randomized controlled trials of aprotinin, EACA or TA were found. It was not possible to perform a meta-analysis of these studies due to wide variations in outcome criteria and study design. Therefore, Eaton’s conclusions are based on data from individual studies. The scientific merit of these studies (based on the Jadad scores, which rates methodological design) had an overall rating of fair to poor.
The most common outcomes measured included the quantity of blood loss, the amount of blood transfused, the time for chest closure and the re-exploration rate.
Results:
EACA and TA Efficacy
These agents are thought to exert their antifibrinolytic effect by inhibiting the binding of plasminogen to fibrin, and inhibiting the formation of plasmin. TA may also inhibit platelet activation and both may exert a mild anti-inflammatory effect. These medications are eliminated by the kidney.
There were 11 comparative studies of these agents with a combined total of over 1000 patients; the majority of these patients coming from a single center in India. Most studies have been prospective randomized controlled trials.
A total of 6 studies were performed in exclusively cyanotic patients (2 with EACA, 3 with TA and one comparing both) and showed a decrease in bleeding and transfusion requirements. 24 hour blood loss was decreased by 11-44% with treated patients receiving 20-50% less blood than controls. Sternal closure times were decreased by 6-25 minutes and re-exploration rates were decreased by 50-100%.
The remaining five studies included both cyanotic and noncyanotic patients. EACA was shown to decrease introperative bleeding but only post operative bleeding decreased in cyanotic patients. In another study, TA had no effect overal, except in a subgroup of cyanotic patients. The investigators of the last study repeated it and found no difference in any subgroup, however they did find an increase in fibrinolysis and platelet activation in cyanotic patients.
One study demonstrated an effect of dose on efficacy with TA. All doses except for a single bolus dose of 50 mg/kg were shown to be effective and two studies that failed to demonstrate an effect of TA had used that dose.
Safety
There is an inadequate data to document the safety of these agents. Thrombosis is the most worrisome complication. One study that examined the use of these agents in patients with fenestrated Fontans demonstrated no increase in closure of fenestrations with these agents. Another study demonstrated an increase in the incidence of ECMO circuit changes, although it was not clear if this was a result of the antifibrinolytic or some factor related to institutional practice. EACA has been reported to cause a proximal skeletal myopathy and both these agents can cause hypotension with bolus administration. Current recommendations are for administration over one hour.
Aprotinin Efficacy
Aprotinin is a nonspecific serine protease inhibitor that inhibits the action of kallikrein and plasmin. It decreases hemostatic activation, inhibits fibrinolysis and preserves platelet function. It is eliminated by renal clearance.
14 randomized controlled trials examining the efficacy of aprotinin have generally demonstrated aprotinin’s tendency to decrease blood loss and transfusion requirements but many studies failed to reach statistical significance. In addition, no subgroup, such as age group, category of patient (cyanotic versus noncyanotic), bypass technique, complexity of surgical procedure, or re-operation status, has been consistently identified as more likely to benefit from aprotinin.
In addition, although the antiinflammatory effects of aprotinin have been touted as an advantage, few studies have demonstrated clinically significant effects of aprotinin. Interestingly, in one study of 60 patients less than 10 kg undergoing primary correction of congenital heart disease, mechanical ventilation time was significantly less in aprotinin treated patients than controls. This was attributed to aprotinin’s antiinflammatory effect, although there was no difference in the amount of inflammation as measured by multiple serum markers of inflammation. In that study, the aprotinin treated patients also received less blood and cryoprecipitate than controls. Other studies have shown less requirement for inotropic support in the aprotinin group; however, there were no other differences in the measures of ventricular function. One study did show a decrease in the transpulmonary pressure gradients in patients given aprotinin who were having Glenn or Fontan procedures, which was attributed to aprotinin’s anti-inflammatory effects.
Safety
The safety issues with aprotinin center around its potential to cause anaphylaxis, thrombosis and renal failure.
Some studies have shown that the risk of anaphylaxis with aprotinin appears to be decreased in pediatric patients compared with adults. This is true for patients receiving a first dose or for those re-exposed to aprotinin. In addition, reports indicate that reactions tend to be less severe in children. It has been speculated that the more immature immune response of neonates may confer an advantage in that group.
Although there are reports of patients having thrombosis after being given aprotinin, there does not appear to be a direct cause and effect relationship. One large study of 865 patients reported no increased risks of thrombosis related to aprotinin use.
Finally, although the negative effect of aprotinin on renal function in adult patients has been a major reason for its removal from the market, eight studies in pediatric patients have reported conflicting data. A small increase in serum creatinine was found in some but serum levels returned to normal. Other studies actually showed small increases in serum creatinine in the placebo group compared to the aprotinin treated patients. No studies have demonstrated that the use of aprotinin was associated with an increase in the incidence of renal failure.
Comparisons and Combinations
There are only a handful of studies in the pediatric population that compare antifibrinolytic therapy. They have almost uniformly shown efficacy of the study drug compared to placebo. In addition, no drug was found to be superior to another and despite the fact that aprotinin and the lysine analogs work in different ways, there was no clinical advantage in combining agents. This is in contrast to at least one animal study that demonstrated an increased incidence of microvascular thrombosis when the two classes of agents were combined.
Dosing
The wide variation in the doses used in these studies makes comparisons impossible. Eaton notes that of the 14 randomized controlled studies of aprotinin, all used different dosing schemes. In four studies of EACA, 2 different doses were used and in the seven TA studies, there were 6 different doses used. Although the doses of these agents in the pediatric population initially involved extrapolation from the adult literature, there is enough data about their pharmacokinetics in pediatrics patients to use dosing guidelines based on known pharmacological information.
Interestingly, even when kinetics are used to formulate a dosing scheme, in many studies, the dose used to prime the pump continues to be based on the weight of the patient without considering the volume of the pump prime. The volume of the pump prime (especially relative to the blood volume of the patient) has a significant effect on serum levels of the drug while on bypass.
Based on scant information, the recommened dose of EACA is 75 mg/kg loading, followed by 75 mg/kg in the prime and an infusion of 75 mg/kg/hr. That dose maintained therapeutic plasma concentrations in 95% of patients. The recommended doses of TA are 10 mg/kg load, 10 mg/kg in the prime and 10 mg/kg after protamine. Eaton stresses that although there is no pharmacological basis for these recommendations with TA, they have demonstrated clinical efficacy. The recommended dosing of aprotinin varies depending on the weight of the patient. Dilution from the pump prime has a significant impact in serum levels, especially in patients less than 10 kg. Several dosing schemes have been recommended and include a bolus of at least 30,000 KIU/kg, a continuous infusion and a pump prime bolus based on the volume of the prime.
Conclusions:
Based on these studies, Eaton has concluded that evidence supports the efficacy of these drugs in the pediatric population. No one drug has been demonstrated to be superior to another. These drugs may be of greater benefit in specific subgroups of patients such as cyanotic patients, reoperations or complex patients more than others.
There is not enough data to confidently provide safety information in the pediatric patient. However, with the available data from these small studies there does not appear to be an “excessive” risk in treated patients compared to placebo.
The dosage recommendations for these drugs needs more investigation and should be based on sound pharmacological principles.
Comment:
Eaton’s article was published before the May 14th announcement by Bayer that has removed Aprotinin from the market except under exceptional cicumstances. Aprotinin is being removed from the market because of poor safety data that was relevant to the adult patient undergoing cardiopulmonary bypass. A recent study (reviewed in the last CCAS issue) of over 1000 pediatric patients given aprotinin did not find an increase in renal failure or mortality in that group. However, because of its removal from the market, information concerning aprotinin is probably no longer relevant. No studies have demonstrated that aprotinin was in any way superior to the lysine analogs in terms of decreasing blood loss or transfusion rates. In addition, despite the fact that aprotinin has been shown to have anti-inflammatory properties, studies have not shown dramatic clinical benefits of these properties. It may be too late to study aprotinin even if well designed studies using appropriate doses and outcome measures could be used.
The only antifibrinolytics that will be available in the pediatric population will be EACA and TA. Eaton’s review has demonstrated several major difficulties in performing studies with antifibrinolytics in pediatric patients compared to adults.
First, the wide variability in patient age and size, diagnosis, surgical procedure, and bypass techniques makes it extraordinarily difficult to design a study with enough statistical power and to control for the multitude of differences in patient characteristics.
Second, the majority of studies that Eaton reviewed used different dosing regimens for the antifibrinolytic. The majority of studies did not base dosing guidelines on pharmacokinetic information. This is crucial in the pediatric population. There is no point in studying the effect of a subtherapeutic concentration of medication.
The overall fair to poor quality of the studies makes any conclusions questionable. Although Eaton notes that subgroups of cyanotic patients, patients having complex surgery or reoperations are most likely to benefit from therapy, studies have shown confounding results even in those subgroups.
Without a doubt, Eaton’s conclusions should be followed. Good quality studies must be conducted in our pediatric patients that use appropriate and consistent dosing guidelines, and that demonstrate efficacy and safety.
References:
- Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med. 2006 26;354:353-65.
- Fergusson DA, Hébert PC, Mazer D et al. A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery. N Engl J Med 2008 358:2319-2331
