Once again the Food and Drug Administration (FDA) has issued a Public Health Advisory in a manner that appears decidedly grudging and half-hearted. One can only imagine how well drug company management and investors must sleep at night, knowing that even if highly reputable medical journals publish adverse findings about their products, their friends at the FDA are there to protect them. Too bad for consumers though, isn't it.

This Advisory is remarkable. While acknowledging that adverse findings have been reported from two different studies in two different medical journals, the Advisory itself begins a critique of those studies in such a way as to undermine their credibility. Here is the main FDA release but some interesting things can be found in other versions released below.

FDA Public Health Advisory
Aprotinin Injection (marketed as Trasylol) 

On January 26, 2006, The New England Journal of Medicine (NEJM) published an article by Mangano et al. reporting an association of Trasylol (aprotinin injection) with serious renal toxicity and ischemic events (myocardial infarction and stroke) in patients undergoing coronary artery bypass grafting surgery (CABG). Another publication (Transfusion, on-line edition, January 20, 2006, Karkouti, et al.) suggests an association between aprotinin administration and renal toxicity among patients undergoing cardiac surgery with cardiopulmonary bypass. FDA is evaluating these studies, along with other studies in the literature and reports submitted to the FDA through the MedWatch program, to determine if labeling changes or other actions are warranted.  

While FDA is continuing its evaluation, we are providing the following recommendations to healthcare providers and patients:

• Physicians who use Trasylol should carefully monitor patients for the occurrence of toxicity, particularly to the kidneys, heart, or central nervous system and promptly report adverse event information to Bayer, the drug manufacturer, or to the FDA MedWatch program, as described at the end of this advisory.
• Physicians should consider limiting Trasylol 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.

The study reported in the NEJM was an observational study of patients undergoing CABG who received either Trasylol, one of two other drugs intended to decrease peri-operative bleeding (aminocaproic acid or tranexamic acid), or no specific drug treatment.  

A limitation of the study was that patients were not assigned at random to receive the treatments, but rather had their treatment chosen by their physician as part of their standard medical care. Consequently, patients receiving Trasylol may have been at higher risk to begin with for these serious adverse events compared to patients receiving no treatment or treatment with another drug intended to decrease bleeding. This possibility prevents a direct assessment of whether Trasylol altered the risk for serious adverse events. The study investigators used statistical procedures (multivariable logistic regression and propensity-score adjustment) to try to adjust for known differences between the treatment groups. Using these procedures, their study concluded that Trasylol was associated with more adverse outcomes. Other findings in the study suggested that patients receiving higher Trasylol dosages were at greater risk than those receiving lower dosages.

The study reported in the on-line edition of Transfusion was also an observational study that used statistical methodology to compare outcomes from patients undergoing CABG. The patients in this study received, at physician direction, either Trasylol or another drug intended to decrease the risk for perioperative bleeding. This study suggested that Trasylol administration increased the risk for renal dysfunction. This study has some of the same limitations as the NEJM publication.

In pre-marketing clinical studies conducted among approximately 3,000 patients undergoing CABG, the risks and benefits of Trasylol were determined in clinical studies that randomized patients to either a placebo or Trasylol.  In these studies, the risks for serious renal toxicity and cardiovascular events were determined to be similar between patients receiving Trasylol and those receiving placebo.  However, in one study assessing coronary graft patency, Trasylol administration was associated with an increased risk of graft closure. The FDA will work with the authors of the publications and the manufacturer of Trasylol to carefully evaluate the risks and benefits associated with use of Trasylol in CABG. The FDA anticipates the public presentation of the recently reported information and other data at an advisory committee in the near future. The FDA will notify health care providers and patients in a timely fashion as new information becomes available.

The FDA urges health care providers and patients to report adverse event information to FDA via the MedWatch program by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet at http://www.fda.gov/medwatch/index.html.

Source: http://www.fda.gov/cder/drug/advisory/aprotinin.htm

In material evidently intended for more limited circulation, namely to cardiovascular and other healthcare professionals, the FDA takes a more conservative stance and does not attack the source of its obvious irritation.

Trasylol (aprotinin)
Audience: Cardiovascular and other healthcare professionals
[Posted 02/08/2006] FDA issued a public health advisory and other advisory information to notify both healthcare professionals and consumers of recently published studies of serious renal and cardiovascular toxicity following Trasylol administration to patients undergoing coronary artery bypass grafting surgery (CABG). An observational study published in The New England Journal of Medicine reported that Trasylol may be associated with increased risk of myocardial infarction, stroke and renal dysfunction. Another publication (Transfusion, on-line edition, January 20, 2006) has reported that Trasylol administration may increase the risk for renal toxicity.

The FDA is working with the authors of the publications and the manufacturer of Trasylol to carefully evaluate the risks and benefits associated with use of Trasylol in CABG. The FDA anticipates the public presentation of the recently reported information and other data at an advisory committee in the near future. The FDA will notify health care providers and patients in a timely fashion as new information becomes available.

Source: http://www.fda.gov/medwatch/safety/2006/safety06.htm#Trasylol

In an FDA Alert we can again see, even through the measured bureaucratic language, a tone somewhere between irritation and disdain. I have highlighted the text that appears included to convey a put-down to the authors of the studies and, by association, the journals involved (editors and peer reviewers).

Aprotinin Injection (marketed as Trasylol) Information

FDA ALERT [2/2006]

FDA is issuing this alert to provide notice of recently published reports of serious renal and cardiovascular toxicity following Trasylol administration to patients undergoing coronary artery bypass grafting surgery (CABG). An observational study published on January 26, 2006 in The New England Journal of Medicine (NEJM), reported that Trasylol may be associated with increased risk of myocardial infarction, stroke and renal dysfunction. Another publication (Transfusion, on-line edition, January 20, 2006) has reported that Trasylol administration may increase the risk for renal toxicity. Neither study was randomized, and both compared Trasylol to products that are not FDA approved for use in the management of cardiac surgery patients.

FDA is evaluating these reports in the context of the pre-marketing clinical studies supporting the safety and efficacy of Trasylol and the post-marketing reports submitted to the MedWatch program.

This information reflects FDA’s preliminary analysis of data concerning this drug. FDA is considering, but has not reached a final conclusion about, this information. FDA intends to update this sheet when additional information or analyses become available.

Source: http://www.fda.gov/cder/drug/infopage/aprotinin/default.htm

Only fools believe that FDA approval means a drug or medical device is safe. The drug prescribers and device operators are in a precarious position. Manufacturers produce drugs and devices to make money, they are not humanitarian aid organizations. The FDA theoretically filters their greed by establishing the bona fides of their claims and seeks to establish the safety of products when used for the stated purpose. Provided the FDA does indeed approve them, the prescribers and operators should be able to employ the products with confidence, and by and large, they do. But what if the filter isn't good enough? Where does that leave everyone?

Both the number and nature of the problems associated with approved drugs and devices are enough to allow any intelligent observer to conclude that the current system doesn't work. It is far from safe. The FDA appears quite defensive about the present arrangement and I suppose that is simply to be expected. However, it definitely seems to be increasingly easy to obtain approvals and much harder to persuade the FDA to revise or revoke its own decisions. If concerned medical practitioners and researchers are subjected to overt or subtle pressure not to criticize FDA findings then current dangerous situation will lurch into full crisis. Perhaps we are getting perilously close to that now.