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Aprotinin Use in Europe: A personal view

 

 

 

Aprotinin Use in Europe: A personal view

By Philip Arnold, MD
Alder Hey Children’s Hospital
Liverpool, UK

Aprotinin has a long history both as a medicinal substance and as a subject for study and curiosity for organic chemists(1).  The earliest recorded use, as a means to reduce blood loss during heart surgery, dates to 1964(2) and since then it has been the subject of numerous studies. Unfortunately its investigation has been adversely effected by underpowered and poorly designed studies, by commercial interests and even by outright research fraud(3). It is remarkable that 50 years after the first use of this drug for this indication there remains profound controversy. The current controversy dates to 2006 with the publication of a large observational study in adults (4) (5) which appeared to show increased renal dysfunction, myocardial infarction, stroke and mortality with use of this drug. These findings were supported by two further observational studies and data released by the pharmaceutical company Bayer. This led to a temporary suspension of marketing in November 2007 by Bayer at the request of the FDA.  An interim analysis of a large randomized controlled trial (the BART study) concluded that mortality was increased in those receiving aprotinin rather than a synthetic antifibrinolytic drug. The trial was stopped early and this led to the effective withdrawal of aprotinin in the United States with Bayer (again at the request of the FDA) removing all stocks from hospitals.

The response in Europe, whilst outwardly similar, has had different implications for the availability of aprotinin (at least within the UK). In November 2007 marketing of aprotinin was suspended in several European Union (EU) countries (including the UK and Germany). This led to a review by the European Medicines Agency (EMA) and withdrawal of marketing of the drug across the EU(6). In the UK aprotinin was not, however, removed from hospital stocks. In addition an alternative supplier (Nordic Pharma) maintained supplies of Aprotinin via a ‘compassionate limited access program’.  This meant that Aprotinin has remained available for use within the UK throughout this period. Despite this, most local hospital drug committees decided to suspend use of aprotinin. A number of standalone children’s hospitals continued to use aprotinin (during heart surgery) arguing that the safety data on which the decisions had been based was entirely from studies in adult patients and likely to have a low applicability to children. In a survey of practice of UK paediatric cardiac anesthetists conducted in 2009,  89% stated that these restrictions had altered their practice, though over half continued to use aprotinin on selected patients(7).

The situation changed when in September 2011, Health Canada reversed an earlier decision to suspend marketing of aprotinin(8). This was largely based on a re-analysis of the results of the BART study. Criticisms of the BART study have included(9):

A similar decision was reached in Europe in 2012 leading to re-instatement of marketing of aprotinin throughout the EU(10). The indications for use are, however, highly restrictive(8):

The first stipulation appears counter intuitive: patients undergoing more complex surgery are at greater risk of major bleeding and therefore more likely to benefit from treatments aimed at reduction in bleeding. Regarding the second point, it is unclear how doctors are to make judgments as the risk benefits in an individual patient. A recent Cochrane analysis of anti-fibrinolysis, in adult patients, made 107 different analysis of the data and examined a number of beneficial and adverse effects(11). It is difficult to be certain how risks or benefits are modified in an individual patient. It is also unclear as to the relative importance of these effects. The statement that ‘alternative treatments are available’ is important. Aprotinin almost certainly reduces bleeding by inhibition of fibrinolysis. Alternative anti-fibrinolytics (tranexamic acid and epsilon aminocaproic acid) are available and any assessment of efficacy or risks of aprotinin should be against these and not against placebo.

Application of these findings to children is less clear still. Decisions regarding this drug have been made almost entirely with reference to adult practice and this has impacted on paediatric practice without proper considerations of risks and benefits in this subgroup. The first stipulation appears to preclude any use during surgery for congenital heart disease. We frequently, however, use drugs outside of their licensed indications and this ruling will certainly lead to greater availability of aprotinin.

To state the evidence as it stands:

 
Given the above it is clear that there is considerable uncertainty about the risk benefits of aprotinin versus synthetic antifibrinolytics. It is likely that any greater efficacy of aprotinin over synthetic anti-fibrinolytics is only marginal. Any evidence of increased risks associated with use of aprotinin in adult patients should be applied only cautiously to children. It is the author’s belief that there is not a good case for wider use of aprotinin in children. There is also insufficient evidence to allow a considered view as to the risk benefit of aprotinin in any particular pediatric population.

Major bleeding following heart surgery in infants and children is a distressingly common situation and doctors looking after these patients desperately require more effective strategies for preventing and treating hemorrhage. The question of choice of anti-fibrinolytic drug could potentially be answered by large randomized control trials to compare synthetic antifibrinolytic drugs to aprotinin. In reality many of the adverse events are uncommon and only very large trials are likely to be conclusive. There are other therapies more likely to impact significantly on severe bleeding than the choice of antifibrinolytic: fibrinogen concentrates, pro-thrombin concentrates, recombinant factor VIIa, and miniaturization of bypass circuits. Smaller well designed trial to establish dosing of synthetic anti-fibrinolytic drugs and collection of high quality observational data (such as the STS/ CCAN database) to quantify adverse effects of these drugs are justified and of greater priority.

 

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