Download Aprotinin

Aprotinin
Brian Minarcik, DO January 24, 2014
Goals
Aprotinin
Pharmacology
Mangano study
Costs and profits
Lysine analogs
Future of Aprotinin
Pharmacologic approaches to reduce bleeding and transfusion in
cardiac surgical patients are based on either preventing the defects
associated with the CPB induced coagulopathy
Different pharmacologic agents have been reported, however the
currently accepted pharmacologic interventions are based on using
a protease inhibitor, aprotinin, or lysine analogs to inhibit fibrinolysis
History
Initially named "kallikrein inactivator", aprotinin was first isolated from
cow parotid glands in 1930 and purified from bovine lung in 1964
As it inhibits pancreatic enzymes, it was initially used in the treatment
for acute pancreatitis in which destruction of the gland by its own
enzymes is thought to be part of the pathogenesis
Named BPTI - Bovine Pancreas Trypsin
BPTI was the cover image on a protein
Inhibitor
folding compendium volume by Thomas
Because it is a small, stable protein whose
structure had been determined at high
resolution by 1975, it was the first
macromolecule of scientific interest to be
simulated using molecular dynamics
computation, in 1977
Creighton in 1992
History
This serine protease inhibitor has a long history of use in clinical
medicine including its use in cardiac surgery as far back as in the
1960s
Aprotinin (Trasylol) is a serine protease inhibitor derived from bovine
lung that inhibits trypsin, chymotrypsin, plasmin, tissue plasminogen
activator, and kallikrein
Although aprotinin was studied in the 1960's, low doses were
evaluated in an effort to treat bleeding after cardiac surgery rather
than to prevent it
However, it was not until the late 1980's that prophylactic use was
reported
Aprotinin
There was a resurgence of interest
in aprotinin in the 1980s following
the reports from the United
Kingdom by Royston who
demonstrated its blood-sparing
effects during cardiac surgery
In 1987 Van Oeveren reported a
47% reduction in blood loss in
patients receiving aprotinin during
CABG surgery
In 22 patients having reoperations
with bubble oxygenators, Royston
developed a pharmacologic approach
to inhibit inflammatory responses
during CPB administering a loading
dose of 2 million units of aprotinin
following intubation, and a continuous
infusion of 500,00 units/hour with a
CPB pump prime dose of 2 million
units
Studying Aprotinin’s Efficacy
Dietrich found decreased blood loss in patients receiving aprotinin as
compared to those receiving placebo (738 ml vs. 1431 ml) for primary
CABG
He also reported less formation of thrombin, fibrin, split products, and Ddimers in patients receiving aprotinin
Separate studies by Blauhut, Havel, Lemmer, and Marx have all confirmed
decreased blood loss in patients receiving aprotinin at high doses
Aprotinin also reduced blood loss 49-75% and transfusion requirements from
49-77% in three studies in patients receiving aspirin
Studying Aprotinin’s Efficacy
In redo CABG patients, Cosgrove reported 171 patients who received either high dose
aprotinin, low dose aprotinin, or placebo
They found that low dose aprotinin was as effective as high dose aprotinin in decreasing blood
loss and blood transfusion requirements
Levy found that transfusion of allogenic packed RBC's was significantly less in the aprotinintreated patients compared to the placebo (high dose: 1.6 units, low dose: 1.6 units, pump prime
only: 2.5 units, placebo: 3.4 units), with even greater reductions in total blood product exposure
in high dose and half dose groups compared to placebo or pump prime cohorts
There were no differences in treatment groups for the incidence of perioperative MI, and the
incidence of stroke was lower in the aprotinin treated patients.
Antifibrinolytic Agents Studied
Most of the early studies using
antifibrinolytic agents showed decreased
mediastinal drainage in patients treated
with Amicar
However, many of these studies lacked
controls, were retrospective, and not
blinded
In 350 patients undergoing CABG, Del
Rossi reported using a low dose of amicar
a significant decrease in mediastinal
drainage and RBC transfusion with no
difference in MI or stroke
Vander Salm reported a reduction in chest
tube drainage in 51 patients who received
Amcar, no differences in platelet function
between Amicar and the placebo group,
and no differences in blood transfusion
Horrow studied TA given in a prophylactic
manner prior to skin incision for primary
CABG showing 12 hour postop blood loss
was 496 ml in the TA group compared to
750 ml in the placebo group. However,
transfusions were not different
Studying Aprotinin’s Efficacy
Favorable results from randomized, double-blind and placebo-controlled trials
in the United States led to the approval of aprotinin by the FDA in 1993 for
patients undergoing re-op CABG surgery or for those at high-risk for excessive
bleeding
This approval was later extended to all CABG patients in 1998.
Pharmacology
Aprotinin is a broad spectrum protease inhibitor which modulates the
systemic inflammatory response associated with CPB
Aprotinin, through its inhibition of multiple mediators [e.g., kallikrein, plasmin]
results in the attenuation of inflammatory responses, fibrinolysis, and
thrombin generation
Aprotinin inhibits pro-inflammatory cytokine release and maintains
glycoprotein homeostasis
In platelets, aprotinin reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa), while
in granulocytes it prevents the expression of pro-inflammatory adhesive
glycoproteins (e.g., CD11b)
Pharmacology
The effects of aprotinin use in CPB involves a reduction in inflammatory
response which translates into a decreased need for allogeneic blood
transfusions, reduced bleeding, and decreased mediastinal re-exploration for
bleeding
Aprotinin inhibits several serine proteases, specifically trypsin, chymotrypsin
and plasmin at a concentration of about 125,000 IU/ml, and kallikrein at
300,000 IU/ml
Its action on kallikrein leads to the inhibition of the formation of factor XIIa
As a result, both the intrinsic pathway of coagulation and fibrinolysis are
inhibited
Pharmacology
Its action on plasmin independently slows fibrinolysis.
Aprotinin is slowly degraded by lysosomal enzymes.
Following a single IV dose of radiolabelled aprotinin, approximately 2540% of the radioactivity is excreted in the urine over 48 hours. After a
30 minute infusion of 1 million KIU, about 2% is excreted as unchanged
drug. After a larger dose of 2 million KIU infused over 30 minutes,
urinary excretion of unchanged aprotinin accounts for approximately
9% of the dose
The Risk Associated with Aprotinin
in Cardiac Surgery
Mangano NEJM 2006
Antifibrinolytic therapy to limit blood loss
Observational study of 4374 patients undergoing
revascularization with 3 agents
Aprotinin (1295)
Aminocaproic acid (883)
Tranexamic Acid (882)
No agent (1374)
MANGANO
69 institutions in North and
South America, Europe, the
Middle East, and Asia
Each outcome event was
prespecified, defined by the
protocol, and classified as
cardiovascular (MI or heart
failure), cerebrovascular
(stroke, encephalopathy, or
coma), or renal (dysfunction
or failure)
MANGANO
Overall, the use of aprotinin was associated with an increased risk of renal and
nonrenal events when compared with aminocaproic acid, tranexamic acid, or no
antifibrinolytic therapy a finding confirmed by multivariable logistic regression
Interaction by drug group and complexity of surgery was not significant
The three medications reduced blood loss to similar extents
EBL
827±573 ml in the control group
753±660 ml in the aprotinin group (P<0.001)
719±578 ml in the aminocaproic acid group (P<0.001)
676±741 ml in the tranexamic acid group (P<0.001)
Unlike lysine analogues, aprotinin has high affinity for the kidneys
After free glomerular passage, aprotinin binds selectively to the brush border of the
proximal tubule membrane, and then, by pinocytosis, it enters into and accumulates
within the cytoplasm, inhibiting tubule protease secretion, prostaglandin and renin
synthesis, prostasin secretion, and bradykinin release.
A dose-dependent renal afferent vasoconstriction; deep cortical and medullary perfusion
and its autoregulation are thereby impaired, and focal tubular necrosis ensues
Because of Aprotinin’s interference with the synthesis and release of endothelial nitric
acid, aprotinin also may instigate macrovascular or microvascular thrombosis
The Financial life of Aprotinin
FDA approval 1993
Withdrawn from market November
2007
Sales:
$300 Million in 2005
$225 Million in 2006
$135 Million in 2007
That research concluded that halting
the drug’s use would prevent 10,000
to 11,000 cases of kidney failure a
year and save more than $1 billion a
year in dialysis costs.
Lysine Analogs
Amicar and tranexamic acid are
derivatives of the amino acid
lysine
Plasmin cleaves fibrinogen and a
series of other proteins involved in
coagulation
Both of these drugs inhibit the
proteolytic activity of plasmin
and the conversion of
plasminogen to plasmin by
plasminogen activators
Tranexamic acid is 6 to 10 times
more potent than e-aminocaproic
acid
Lysine Analogs
After the withdrawal of aprotinin from the market, tranexamic acid and ɛaminocaproic acid are the agents of choice for this indication and are used
routinely in most centers worldwide
Both agents are effective in reducing blood loss after cardiac surgery when
used prophylactically, which has been demonstrated in recent meta-
analyses
Lysine Analogs
The blood sparing effect of the lysine analogues was also shown in the
Mangano study and in the BART trial, even though there was a trend towards
aprotinin being more efficacious to prevent massive bleeding compared with
both lysine analogues combined (RR 0.79; 95% CI 0.61–1.01)
However, the BART trial was ultimately not adequately powered to determine
the superiority of aprotinin because of early termination.
Lysine Analogs
Comparing the two lysine analogues directly, tranexamic acid seems to reduce
blood loss more effectively than ɛ-aminocaproic acid, but only retrospective
data are available to support this
Therefore, a recommendation to use one of the lysine analogues in preference
to the other cannot be made based on the existing literature
European Medicines Agency recommends lifting suspension of aprotinin
Review finds that benefits of all antifibrinolytic medicines outweigh risks in restricted range of
indications
This follows a full review of the benefits and risks of all antifibrinolytic medicines, which found that the
results of the BART study on which the suspension was based are unreliable.
The Committee found that there were a number of problems with the way the BART study was
conducted, which cast doubt on the previous conclusions
These included the imbalances in the way blood-thinning medicines such as heparin were used,
inappropriate monitoring of the use of these medicines and how problems with the way that data from
some patients were excluded from the initial analysis
The Committee found that the BART study’s results were not replicated in other studies and that the
overall data available showed that aprotinin’s benefits are greater than its risks in the restricted
indication
References
Mangano DT, Tudor IC, Dietzel C (2006). "The risk associated with aprotinin in cardiac surgery". N. Engl. J. Med. 354 (4): 353–65.
doi:10.1056/NEJMoa051379.PMID 16436767
Mahdy AM, Webster NR (2004). "Perioperative systemic haemostatic agents". British journal of anaesthesia 93 (6): 842–58.
doi:10.1093/bja/aeh227.PMID 15277296.
Anesthesia & Analgesia:
November 2006 - Volume 103 - Issue 5 - pp 1067-1070
Aprotinin Use During Cardiac Surgery: A New or Continuing Controversy?