Those who underwent cardiac surgery and took aprotinin, an
anti-bleeding drug were at a significantly higher risk of death compared to
those who received the surgery, but did not take any hemorrhage-sparing
medication, according to a new study scheduled to appear in the Feb 7 2007
issue of the Journal of the American Medical Association.
The results of the study show taking aprotinin could pose a
higher risk of death to the patients who received coronary artery bypass graft
(CABG) surgery even compared to other two medications namely aminocaproic acid and tranexamic acid, which were used for the same
antibleeding effect.
The observational study was a follow-up of one study
published last year by the same researchers with Dr. Dennis Mangano lead
investigator, who represents The Multicenter Study of Perioperative Ischemia
Research Group and the Ischemia Research and Education Foundation.
The earlier study has already linked the
anti-bleeding agent aprotinin with an elevated risk of kidney and heart failure
as well as stroke.
According to the researchers, "acute safety concerns
have been raised recently regarding certain hemorrhage-sparing medications
commonly used in cardiac surgery.
However
no comprehensive data exist regarding their associations with long-term
mortality". Thus, the purpose of this current study was to "contrast
long term all-cause mortality in patients undergoing CABG surgery according to
use of 2 lysine analog antifibrinolytics (aminocaproic acid and tranexamic
acid), the serine protease inhibitor aprotinin, or no antibleeding agent.”
The study involved a total of 3,876 of patients from 62
cardiac centers from multiple countries who received CABG surgery.
The researchers reviewed the long term
survival data from the patients annually for five years.
The patients were divided into four groups
based on the antibleeding medications they took including aminocaproic acid,
tranexamic acid, aprotinin and no antibleeding agent. Then they used
statistical methods, covariate analysis and multivariable analysis to compare
the mortality rates associated with the medications they took.
The researchers found that the death rate for those who took
aprotinin was significantly higher, 20.8 percent over 5 years.
This is compared to 15.8 percent for
those on aminocaproic acid and 14.7 percent for those on tranexamic acid. Without taking any
antibleeding agent, the mortality rate was 12.7 percent over the five years.
Compared to those taking no hemorrhage-sparing medication,
taking aprotinin seemingly raised the death risk by 48 percent whereas taking aminocaproic
acid or tranexamic acid did not raise the risk significantly, 3 percent versus
7 percent.
Results from a multivariable logistic regression model
indicated that taking aprotinin was strongly predictive of death over the five
years whereas taking either of other two medications was not.
Based on what they found, the researchers concluded in their
report that "use of aprotinin among patients undergoing CABG surgery does
not appear prudent because safer and less expensive alternatives (i.e. aminocaproic
acid and tranexamic acid) are available.”
Bayer Pharmaceuticals, the maker of aprotinin, today issued
a statement saying that the company has conducted a preliminary review of the findings
and it believes that the methodological and analytical approaches used in the study
were similar to the ones used in the authors' early study and they are not
reliable and do not support their reported conclusions.
The statement suggests that those who were treated with
aprotinin were generally considered sicker and at greater risk for mortality,
meaning that the seemingly elevated death risk may be associated with their
conditions rather than the medication they took. Additionally, Bayer says that
there are differences in clinical practices among the cardiac centers
considered in the study, which may affect the reported findings.
Aprotinin, marketed under the name Trasylol, was first
approved by the Food and Drug Administration for patients undergoing CABG using
cardiopulmonary bypass to prevent bleeding. The drug inhibits certain enzymes
that increase the risk for bleeding.
The early study by Dr. Mangano and team, published on Jan 26
2006 in The New England Journal of Medicine showed that the occurrence of
serious kidney damage, heart attack or myocardial infarction and stroke were
more common among CABG patients receiving aprotinin than those receiving no
medications intended to decrease blood loss or taking other antibleeding agents.
These serious side-effects may be associated with the clot
formation promoted by aprotinin.
Another
early study, according to the FDA, showed that use of aprotinin in CABG
patients resulted in a higher risk of clot formation or bypass closure within
coronary artery bypass grafts, compared to those who received a placebo.
The FDA sees a limitation in the early study by Dr. Mangano though.
That is, patients in the study were not
randomly assigned treatments, which caused biases.
In spite of the early findings, the federal agency did not pull aprotinin out of the market because it said the study findings are not in agreement with
the results submitted by the drug manufacturer in the application for marketing
aprotinin.
Instead, the FDA issued a
statement on Sept 29, 2006 to alert physicians to monitor those who were on
aprotinin and ask them to consider prescribing aprotinin only if its benefits outweigh
its risks.
Late on Dec. 15, 2006, FDA asked Bayer Pharmaceuticals
Corporation,
Leverkusen,
Germany to change the label for
aprotinin to warn
physicians and patients of the risks associated with the medication.
The FDA has yet to respond to what Dr Mangano and colleagues
found regarding the association between aprotinin and elevated risk of
mortality in CABG patients.
For more information about the current study and aprotinin,
visit the following sites:
http://www.trasylol.com/main.htm
http://jama.ama-assn.org/cgi/content/full/297/5/471
http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm
Source
Mortality Associated With Aprotinin During 5 Years Following
Coronary Artery Bypass Graft Surgery
Dennis T. Mangano, PhD, MD; Yinghui Miao, MD, MPH; Alain
Vuylsteke, MD; Iulia C. Tudor, PhD; Rajiv Juneja, MD; Daniela Filipescu, MD;
Andreas Hoeft, MD;
Manuel L. Fontes,
MD; Zak Hillel, PhD, MD; Elisabeth Ott, MD; Tatiana Titov, MD, PhD; Cynthia
Dietzel, MD; Jack Levin, MD; for the Investigators of The Multicenter Study of
Perioperative Ischemia Research Group and the Ischemia Research and Education
Foundation
JAMA Vol. 297 No. 5, 471-479. February 7, 2007
