[HSF] Aprotinin

Sat Nov 18 09:15:53 EST 2006

Journal club critique      

A disheartening story: Aprotinin in cardiac surgery 

Lien M, Milbrandt E

Critical Care, 2006 10:317 ( 8 November 2006 )

Journal club critique

A disheartening story: Aprotinin in cardiac surgery

Marcus Lien1  and Eric B Milbrandt2 

1Clinical Fellow, Department of Critical Care Medicine, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

2Assistant Professor, Department of Critical Care Medicine, University of
Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Critical Care 2006, 10:317     doi:10.1186/cc5072

Evidence based medicine journal club critique edited by E B Milbrant

The electronic version of this article is the complete one and can be found
online at: http://ccforum.com/content/10/6/317

Published   8 November 2006 

C 2006 BioMed Central Ltd

Citation

Mangano DT, Tudor IC, Dietzel C: The risk associated with aprotinin in
cardiac surgery. N Engl J Med 2006, 354:353-365 [1].

Background

The majority of patients undergoing surgical treatment for ST-elevation
myocardial infarction receive antifibrinolytic therapy to limit blood loss.
This approach appears counterintuitive to the accepted medical treatment of
the same condition - namely, fibrinolysis to limit thrombosis. Despite this
concern, no independent, large-scale safety assessment has been undertaken.

Methods

Design and setting

Prospective observational cohort study in 69 institutions in North and South
America, the Middle East, Europe, and Asia.

Subjects

4374 patients undergoing coronary-artery revascularization. All patients
were >18 years old and completed a pre-surgery interview. Patients were
classified as undergoing primary surgery (no previous heart surgery and no
other surgery besides a coronary artery bypass graft), or complex surgery
(all other surgery).

Intervention

None.

Measurements

The authors prospectively assessed three agents (aprotinin [1295 patients],
aminocaproic acid [883], and tranexamic acid [822]) as compared with no
agent (1374 patients) with regard to serious cardiovascular, renal, and
cerebrovascular outcomes by propensity and multivariable methods.

Results

In propensity-adjusted, multivariable logistic regression (C-index, 0.72),
use of aprotinin was associated with a doubling in the risk of renal failure
requiring dialysis among patients undergoing complex coronary-artery surgery
(odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary
surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31).
Similarly, use of aprotinin in the latter group was associated with a 55
percent increase in the risk of myocardial infarction or heart failure (P <
0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P
= 0.001). Neither aminocaproic acid nor tranexamic acid was associated with
an increased risk of renal, cardiac, or cerebral events. Adjustment
according to propensity score for the use of any one of the three agents as
compared with no agent yielded nearly identical findings. All the agents
reduced blood loss.

Conclusion

The association between aprotinin and serious end-organ damage indicates
that continued use is not prudent. In contrast, the less expensive generic
medications aminocaproic acid and tranexamic acid are safe alternatives.

The medical and surgical approaches to acute ST-elevation myocardial
infarction present an interesting paradox. The medical approach focuses on
fibrinolytic therapy. Due to concerns over bleeding, the surgical approach
avoids fibrinolytic agents and instead uses agents that mitigate bleeding,
so called antifibrinolytic agents, which include aprotinin, aminocaproic
acid, and tranexamic acid. These agents were generally considered safe based
on a number of secondary analyses of studies that were not primarily
intended to assess safety. These relatively small studies were underpowered
to detect adverse events and did not involve head-to-head comparisons of the
commonly used antifibrinolytic agents. Animal studies suggest that these
agents have the potential to cause ischemic damage to multiple organ systems
and small, largely single-center studies have suggested increased graft
thrombosis and renal dysfunction [2-6]. Ideally, the safety of these agents
would be compared in a large, multi-center, randomized controlled trial.
However, because their use is embedded in practice and because regulatory
approval of these agents differs by country, conducting such a trial will be
difficult if not impossible.

To address the safety of these agents for cardiopulmonary bypass surgery,
Mangano and colleagues [1] conducted a large, prospective, observational
cohort assessing aprotinin, aminocaproic acid, and tranexamic acid as
compared to no agent in 4374 patients undergoing revascularization. Because
this was a prospective study, the authors were able to collect a wealth of
clinical information, including approximately 7500 data fields per patient.
This permitted consideration of variables that might influence both choice
of antifibrinolytic agent and clinical outcome. The authors used a
propensity score based on 45 treatment-selection covariates and
multivariable modeling to control for baseline differences between groups.
In doing so, they found that aprotinin, but not aminocaproic acid or
tranexamic acid, was associated with serious cardiovascular, renal, and
cerebrovascular adverse events. Furthermore, a dose-response relationship
was demonstrated, strengthening the inference of causality.

The main weakness of this study is that the authors failed to report details
of the surgery itself, such as whether the surgery was on vs. off-pump, time
on pump, and number of vessels bypassed. These variables are likely to
influence not only choice of antifibrinolytic agent but also outcome, and
are, therefore, a source of indication bias that could reflect unfavorably
on aprotinin.

Based on the results of this study and those of another observational study
suggesting renal toxicity [7], the United States Food and Drug
Administration (FDA) held an advisory committee meeting September 21, 2006
to consider the cardiovascular safety of aprotinin. Because of concerns
about the methodology of the study by Mangano and colleagues and because it
was the only study to suggest cardiovascular adverse events [8], the
advisory committee concluded that there was insufficient evidence to support
changing the cardiovascular safety labeling of the drug. However, just six
days after the committee met, it was revealed that the drug's manufacturer,
Bayer, had preliminary results from an observational study of 67,000 cardiac
bypass patients that suggested aprotinin was associated with increased risk
of death, renal dysfunction, congestive heart failure, and stroke [9]. The
FDA subsequently issued a statement indicating it was unaware of this study
when the advisory committee met and that it is evaluating the results of
this study and the potential implications for the use of aprotinin [10]. In
the mean time, the FDA suggests that physicians who use aprotinin should
carefully monitor patients for the occurrence of toxicity, particularly to
the kidneys, heart, or brain, and promptly report observed adverse events.
They go on to recommend that physicians should consider limiting aprotinin
use to those situations where the clinical benefit of reduced blood loss is
essential to medical management of the patient and outweighs the potential
risks.

    Recommendation    

The weight of evidence suggests that aprotinin increases the risk for a poor
outcome among patients undergoing cardiac operations. Not only is this drug
very expensive, it seems to be toxic. Although the risk of excessive
bleeding is certainly a cause for concern in certain patients, and treatment
with aprotinin can decrease blood loss in selected patients, data are
lacking to show that administration of this agent actually improves
survival.

Competing interests

The authors declare that they have no competing interests.

1.   Mangano DT, Tudor IC, Dietzel C: The risk associated with aprotinin in
cardiac surgery.

N Engl J Med 2006, 354:353-365. 

2.   Cosgrove DM III, 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.

3.   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

4.   Feindt PR, Walcher S, Volkmer I, Keller HE, Straub U, Huwer H, Seyfert
UT, Petzold T, Gams E: Effects of high-dose aprotinin on renal function in
aortocoronary bypass grafting.

Ann Thorac Surg 1995, 60:1076-1080 

5.   Sundt TM III, Kouchoukos NT, Saffitz JE, Murphy SF, Wareing TH, Stahl
DJ: Renal dysfunction and intravascular coagulation with aprotinin and
hypothermic circulatory arrest.

Ann Thorac Surg 1993, 55:1418-1424 

6.   Umbrain V, Christiaens F, Camu F: Intraoperative coronary thrombosis:
can aprotinin and protamine be incriminated?

J Cardiothorac Vasc Anesth 1994, 8:198-201 

7.   Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A,
Wijeysundera DN, Fedorko L, Yau TM: A propensity score case-control
comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac
surgery.

Transfusion 2006, 46:327-338 

8.   Hughes S: Aprotinin safety again in spotlight as new study suggests
increased cardiac events.

http://www.medscape.com/viewarticle/545400 

    October 2, 2006 

9.   Harris G: FDA says Bayer failed to reveal drug risk study.

[http://www.nytimes.com/2006/09/30/health/30fda.html] New York Times  

10.   US Food and Drug Administration: FDA Public Health Advisory: Aprotinin
Injection (marketed as Trasylol).

[http://www.fda.gov/cder/drug/advisory/aprotinin20060929.htm] 

September 29, 2006 