Information for Healthcare - Professionals Aprotinin (marketed as Trasylol) 9/2006
|This information is not current. The FDA has issued new information about this safety issue, please see Aprotinin Injection (marketed as Trasylol) Information|
FDA ALERT [9/2006]:
We are updating this Alert to note that the Cardiovascular and Renal Drugs Advisory Committee met on September 21, 2006 and discussed Trasylol safety information. At that meeting, the Committee reviewed the two observational epidemiological studies described below, the Bayer worldwide safety review and the FDA review of its own post-marketing database, which included a summary of post-marketing reports to FDA about potential life threatening anaphylactic allergic reactions following administration of aprotinin injection (summarized below).
On September 27, 2006 Bayer Pharmaceuticals told FDA that it had conducted an additional safety study of Trasylol. The preliminary findings from this new observational study of patients from a hospital database reported that use of Trasylol may increase the chance for death, serious kidney damage, congestive heart failure and strokes. FDA was not aware of these new data when it held the September 21, 2006, Advisory Committee meeting on the safety of Trasylol. FDA is actively evaluating these new data along with other published reports and the pre-marketing clinical studies and will update this alert when we have completed our review. Meanwhile, our recommended considerations remain as below.
In the Bayer study, existing hospital data from 67,000 records of patients undergoing coronary artery bypass graft surgery were examined. 30,000 of the patients were treated with aprotinin (Trasylol) and 37,000 were treated with alternative products. This study used complex epidemiological and statistical methods to examine the relationship of aprotinin to a variety of health outcomes.
FDA ALERT [2/2006]:
FDA is issuing this alert to provide notice of two recently published studies reporting 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 cardiovascular events (myocardial infarction or heart failure), cerebrovascular events such as stroke, encephalopathy or coma and renal dysfunction or failure. Another publication (Transfusion, on-line edition, January 20, 2006) has reported that Trasylol administration may increase the risk for renal toxicity (dysfunction or failure). 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 observational studies 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.
Adverse reactions or quality problems experienced with the use of this Product may be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax, using the contact information at the bottom of this sheet.
Physicians should consider the following:
- Consistent with clinical practice guidelines for patients undergoing CABG, physicians who use Trasylol should carefully monitor for the occurrence of toxicity, particularly to the kidneys, heart, or central nervous system.
- 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 the benefit outweighs the potential risks.
- Physicians should promptly report serious and unexpected adverse events associated with Trasylol to the drug manufacturer (Bayer), or to the FDA MedWatch program, as described at the end of this alert advisory.
- Physicians should monitor patients closely for anaphylactic reactions, even when administering a test dose of Trayslol. Anaphylactic reactions occur more frequently in patients who have been exposed previously to aprotinin-containing products (for example, Trasylol, and fibrin glues such as Tissucol or Tisseel). The most frequently reported sign of hypersensitivity is hypotension.
Trasylol is indicated "for prophylactic use to reduce peri-operative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery."
New Study Results from the NEJM
A January 26, 2006 NEJM publication described the findings from an observational study of 4,374 patients (1,295 treated with Trasylol) scheduled for CABG at multiple centers in multiple countries. Baseline and outcome data were prospectively collected from patients who were prescribed either no preventive drug therapy for blood loss or one of three drugs intended to prevent blood loss (Trasylol, aminocaproic acid or tranexamic acid). Patients were not randomized to these treatments. Instead, the choice of study drug (or no treatment) was at physician discretion. Aminocaproic acid and tranexamic acid are anti-fibrinolytic drugs approved by the FDA for indications other than prevention of blood loss in the CABG setting. The following information provides the major findings from the NEJM publication.
- Certain imbalances in baseline characteristics suggest that Trasylol-treated patients may have been sicker at baseline than patients receiving other treatments. To adjust for imbalances in baseline characteristics, the study authors used complex statistical methodology involving propensity scores. The study classified patients as primary (the surgery was elective and involved only coronary artery revascularization or angioplasty, with no history of cardiac or vascular surgery) or complex (all other patients).
- After propensity adjustment, primary patients receiving Trasylol had increased risk for the following outcomes when compared to patients who received no preventive drug therapy:
- a renal event (dialysis or increase in creatinine), p = 0.006
- either myocardial infarction or heart failure, p = 0.01
- stroke, encephalopathy, or coma, p = 0.02
- After propensity adjustment, complex patients receiving Trasylol had an increased risk for a renal event (dialysis or increase in creatinine, p = 0.004) compared to patients who received no preventive drug therapy. Myocardial infarction, heart failure and stroke risk were not increased among these patients.
- Risks for adverse renal events increased with the administered Trasylol dose.
- All three drug therapies (Trasylol, aminocaproic acid or tranexamic acid) were reported to reduce blood loss to similar extents.
New Study Results from Transfusion
A January 20, 2006 Transfusion (on-line edition) publication described the findings from an observational study of 898 patients (449 treated with Trasylol) undergoing CABG with cardiopulmonary bypass at a single center. Baseline and outcome data were obtained from a prospectively developed database for these patients. Patients received either Trasylol or tranexamic acid. Patients were not randomized to these treatments. Instead, the choice of study drug was at physician discretion. The 898 patients studied were a subset of a larger group of 10,870 patients selected on the basis of propensity scores to adjust for imbalances in measured baseline characteristics. Major findings from the Transfusion publication were:
- In general, the measured baseline characteristics were similar between the two patient groups in the study.
- The rate of renal dysfunction was higher among patients receiving Trasylol than among patients receiving tranexamic acid. The association between Trasylol and renal dysfunction was especially evident in patients with existing renal dysfunction.
- The rates of other adverse events were similar between the two study groups.
- The rate of red blood cell transfusion was similar for the two patient groups.
The premarketing clinical studies supporting Trasylol safety and efficacy enrolled a total of approximately 3,000 patients (2,002 treated with Trasylol). The studies, including six placebo-controlled trails, consistently showed that Trasylol decreased peri-operative blood loss and the need for blood transfusion. The risks for serious renal and cardiovascular adverse events and deaths were similar between patients receiving Trasylol and those receiving placebo. One study of approximately 800 subjects showed that patients receiving Trasylol had higher rates of coronary graft occlusion than patients receiving a placebo; however, this altered coronary patency was not associated with differences in myocardial infarction and mortality risk between the two study groups. The major pre-market safety signal was a risk for anaphylaxis, especially among subjects re-exposed to Trasylol. The Trasylol label carries a black box warning relating to anaphylaxis.
Post-marketing Spontaneous Reports
Two hundred ninety-one cases of hypersensitivity possibly associated with Trasylol, including 52 cases with fatal outcomes, have been reported to Bayer. A test dose was administered in 139 of the 291 cases. A hypersensitivity reaction occurred with the test dose alone in 81 cases, including 19 fatal cases. Additionally, the test dose did not illicit a reaction among 38 cases (9 fatal) of anaphylaxis that occurred with a therapeutic dose.
The FDA will work with the authors of the reports and the manufacturer of Trasylol to evaluate the risks and benefits associated with use of Trasylol among patients undergoing cardiopulmonary bypass for CABG surgery. The FDA will notify health care providers and patients in a timely fashion as new information becomes available. Physicians should carefully monitor patients for the occurrence of toxicity and promptly report toxicity to Bayer, the Trasylol manufacturer, or to the FDA MedWatch program.