A US study raises fresh concerns about the anti-bleeding drug aprotinin which is presecribed to patients following cardiac surgery. Compared with two other anti-bleeding drugs, this study shows that aprotinin significantly raises the risk of death following surgery. The study is published in this week’s issue of the Journal of the American Medical Association.
Concerns have been raised before about the safety of antibleeding (also called hemorrhage-sparing) medication taken by patients following cardiac surgery. The observational study followed a total of 3,876 patients who attended 62 cardiac units all over the world for coronary artery bypass graft (CABG) surgery. The researchers prospectively assessed the patients’ long term survival at 6 weeks and 6 months after surgery and then every year after that for 5 years. They also took into account the number of deaths in the cohort due to any cause over the 5 year period of the study.Dr Dennis Mangano led the team of researchers, who represent The Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation. He also led a study last year that suggested the anti-bleeding agent aprotinin was associated with increased risk of kidney and heart failure as well as strokes.The scientists compared the long term mortality of the patients with respect to their post-surgery anti-bleeding medication. Two of the groups were on lysine analog antifibrinolytics (one took aminocaproic acid and the other tranexamic acid), another was on the serine protease inhibitor aprotinin, and the fourth group had no anti-bleeding medication.The scientists first conducted a covariate analysis that compared the mortality and hazard ratio for death for each of the three medication groups against the group that did not take anti-bleeding medication (the control group).These results showed that the death rate for patients who were on aprotinin was 20.8 per cent over 5 years, with a 48 per cent increase in risk of death compared to the control group. This compared with 15.8 per cent mortality and 3 per cent increased risk for aminocaproic acid, and 14.7 per cent mortality and 7 per cent increased risk of death for tranexamic acid. The mortality rate for the control group (no anti-bleeding agent) was 12.7 per cent over the 5 years.The scientists adjusted the figures to take into account other risk factors (hence a control group with no anti-bleeding medication, this does not mean that stopping anti-bleeding medication altogether is recommended, it is just a way of providing a statistical base line for comparison).A further multivariate logistic regression analysis was conducted to see which of the medications is most closely associated with mortality, and is therefore the most likely “predictor” of death rates among the medicated groups. This showed that aprotonin was the strongest significant predictor, showing a 48 per cent likelihood of death over 5 years compared with no increased risk of death for the other two drugs, aminocaproic and tranexamic acid.Dr Mangano and his colleagues concluded that these results show that aprotonin is linked to significantly greater risk of long term mortality following CABG surgery. Together with their previous findings that showed this drug was linked to acute renal and vascular failure, they suggest that prescription of aprotinin among patients undergoing CABG surgery is not “prudent”, since safer and cheaper alternatives, such as aminocaproic acid and tranexamic acid are available.Anti-bleeding or hemorrhage-sparing drugs are used to slow down the process that breaks down blood coagulants. The drugs tested in this study are antifibrinolytics that inhibit the process of fibrinolysis – the breaking down of the mesh-like blood protein, fibrin, that coagulates at the site of a wound. Antifibrinolytics are used to reduce bleeding tendency after organ surgery, such as heart and liver surgery.Studies conducted some ten to fifteen years ago concluded that aprotinin, which is manufactured and sold by Bayer Pharmaceuticals as Trasylol, was safe for use in high risk cardiac surgery patients. The Food and Drug Administration (FDA) approved aprotinin in 1993. However, they have more recently advised surgeons to keep an eye on patients using this drug because of the work done last year by Dr Mangano and his team. Also, last year, Bayer revealed they had information that showed increased risk of death, organ damage and heart failure from use of the drug.