Studies of patients undergoing CABG surgery, either primary or repeat, indicate that Trasylol® (aprotinin) is generally well tolerated. The adverse events reported are frequent sequelae of cardiac surgery and are not necessarily attributable to Trasylol® (aprotinin) therapy. Adverse events reported, up to the time of hospital discharge, from patients in US placebo-controlled trials are listed in the following table. The table lists only those events that were reported in 2% or more of the Trasylol® (aprotinin) treated patients without regard to causal relationship.
|INCIDENCE RATES OF ADVERSE EVENTS (> = 2%) BY BODY SYSTEM AND TREATMENT FOR ALL PATIENTS FROM US PLACEBO-CONTROLLED CLINICAL TRIALS|
|Adverse Event||Aprotinin (n = 2002) values in %||Placebo (n = 1084) values in %|
|Body as a Whole|
|Liver Function Tests Abnormal||3||2|
|Hemic and Lymphatic|
|Metabolic & Nutritional|
|Creatine Phosphokinase Increased||2||1|
|Skin and Appendages|
|Kidney Function Abnormal||3||2|
|Urinary Tract Infection||2||2|
In comparison to the placebo group, no increase in mortality in patients treated with Trasylol® (aprotinin) was observed. Additional events of particular interest from controlled US trials with an incidence of less than 2%, are listed below:
|EVENT|| Percentage of patients treated with Trasylol® (aprotinin)
N = 2002
| Percentage of patients treated with Placebo
N = 1084
|Acute Kidney Failure||0.5||0.6|
|Kidney Tubular Necrosis||0.8||0.4|
Listed below are additional events, from controlled US trials with an incidence between 1 and 2%, and also from uncontrolled, compassionate use trials and spontaneous post-marketing reports. Estimates of frequency cannot be made for spontaneous post-marketing reports (italicized).
Body as a Whole: Sepsis, death, multi-system organ failure, immune system disorder, hemoperitoneum.
Cardiovascular: Ventricular fibrillation, heart arrest, bradycardia, congestive heart failure, hemorrhage, bundle branch block, myocardial ischemia, ventricular tachycardia, heart block, pericardial effusion, ventricular arrhythmia, shock, pulmonary hypertension.
Digestive: Dyspepsia, gastrointestinal hemorrhage, jaundice, hepatic failure.
Hematologic and Lymphatic: Although thrombosis was not reported more frequently in aprotinin versus placebo-treated patients in controlled trials, it has been reported in uncontrolled trials, compassionate use trials, and spontaneous post-marketing reporting. These reports of thrombosis encompass the following terms: thrombosis, occlusion, arterial thrombosis, pulmonary thrombosis, coronary occlusion, embolus, pulmonary embolus, thrombophlebitis, deep thrombophlebitis, cerebrovascular accident, cerebral embolism. Other hematologic events reported include leukocytosis, thrombocytopenia, coagulation disorder (which includes disseminated intravascular coagulation), decreased prothrombin.
Metabolic and Nutritional: Hyperglycemia, hypokalemia, hypervolemia, acidosis.
Nervous: Agitation, dizziness, anxiety, convulsion.
Respiratory: Pneumonia, apnea, increased cough, lung edema.
Urogenital: Oliguria, kidney failure, acute kidney failure, kidney tubular necrosis.
Myocardial Infarction: In the pooled analysis of all patients undergoing CABG surgery, there was no significant difference in the incidence of investigator-reported myocardial infarction (MI) in Trasylol® (aprotinin) treated patients as compared to placebo treated patients. However, because no uniform criteria for the diagnosis of myocardial infarction were utilized by investigators, this issue was addressed prospectively in three later studies (two studies evaluated Regimen A, Regimen B and Pump Prime Regimen; one study evaluated only Regimen A), in which data were analyzed by a blinded consultant employing an algorithm for possible, probable or definite MI. Utilizing this method, the incidence of definite myocardial infarction was 5.9% in the aprotinin-treated patients versus 4.7% in the placebo treated patients. This difference in the incidence rates was not statistically significant. Data from these three studies are summarized below.
|Incidence of Myocardial Infarctions by Treatment Group Population: All CABG Patients Valid for Safety Analysis|
|Treatment||Definite MI%||Definite or Probable MI %||Definite, Probable or Possible MI %|
|Pooled Data from Three Studies that Evaluated Regimen A|
|Trasylol® Regimen A n = 646||4.6||10.7||14.1|
|Placebo n = 661||4.7||11.3||13.4|
|Pooled Data from Two Studies that Evaluated Regimen B and Pump Prime Regimen|
|Trasylol® Regimen B n = 241||8.7||15.9||18.7|
|Trasylol® Pump Prime Regimen n = 239||6.3||15.7||18.1|
|Placebo n = 240||6.3||15.1||15.8|
Graft Patency: In a recently completed multi-center, multi-national study to determine the effects of Trasylol® (aprotinin) Regimen A vs. placebo on saphenous vein graft patency in patients undergoing primary CABG surgery, patients were subjected to routine postoperative angiography. Of the 13 study sites, 10 were in the United States and three were non-U.S. centers (Denmark (1), Israel (2)). The results of this study are summarized below.
|Incidence of Graft Closure, Myocardial Infarction and Death by Treatment Group|
|Overall Closure Rates*||Incidence of MI**||Incidence of Death***|
| All Centers
n = 703
| U.S. Centers
n = 381
| All Centers
n = 831
| All Centers
n = 870
|CI for the Difference (%) (Drug - Placebo)||(1.3, 9.6)†||(-3.8, 5.9)†||-3.3 to 1.5‡||-1.9 to 1.4‡|
* Population: all patients with assessable saphenous vein grafts
** Population: all patients assessable by blinded consultant
*** All patients
† 90%; per protocol
‡ 95%; not specified in protocol
Although there was a statistically significantly increased risk of graft closure for Trasylol® (aprotinin) treated patients compared to patients who received placebo (p=0.035), further analysis showed a significant treatment by site interaction for one of the non-U.S. sites vs. the U.S. centers. When the analysis of graft closures was repeated for U.S. centers only, there was no statistically significant difference in graft closure rates in patients who received Trasylol® (aprotinin) vs. placebo. These results are the same whether analyzed as the proportion of patients who experienced at least one graft closure postoperatively or as the proportion of grafts closed. There were no differences between treatment groups in the incidence of myocardial infarction as evaluated by the blinded consultant (2.9% Trasylol® (aprotinin) vs. 3.8% placebo) or of death (1.4% Trasylol® (aprotinin) vs. 1.6% placebo) in this study.
Hypersensitivity and Anaphylaxis: See CONTRAINDICATIONS and WARNINGS. Hypersensitivity and anaphylactic reactions during surgery were rarely reported in U.S. controlled clinical studies in patients with no prior exposure to Trasylol® (aprotinin) (1/1424 patients or <0.1% on Trasylol® (aprotinin) vs. 1/861 patients or 0.1% on placebo). In case of re-exposure the incidence of hypersensitivity/anaphylactic reactions has been reported to reach the 5% level. A review of 387 European patient records involving re-exposure to Trasylol® (aprotinin) showed that the incidence of hypersensitivity or anaphylactic reactions was 5.0% for re-exposure within 6 months and 0.9% for re-exposure greater than 6 months.
Serum Creatinine: Trasylol® (aprotinin) administration is associated with a risk for renal dysfunction (see WARNINGS: Renal Dysfunction).
Serum Transaminases: Data pooled from all patients undergoing CABG surgery in U.S. placebo-controlled trials showed no evidence of an increase in the incidence of postoperative hepatic dysfunction in patients treated with Trasylol® (aprotinin) . The incidence of treatment-emergent increases in ALT (formerly SGPT) > 1.8 times the upper limit of normal was 14% in both the Trasylol® (aprotinin) and placebo-treated patients (p=0.687), while the incidence of increases > 3 times the upper limit of normal was 5% in both groups (p=0.847).
Other Laboratory Findings: The incidence of treatment-emergent elevations in plasma glucose, AST (formerly SGOT), LDH, alkaline phosphatase, and CPK-MB was not notably different between Trasylol® (aprotinin) and placebo treated patients undergoing CABG surgery. Significant elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are expected in Trasylol® (aprotinin) treated patients in the hours after surgery due to circulating concentrations of Trasylol® (aprotinin) , which are known to inhibit activation of the intrinsic clotting system by contact with a foreign material (e.g., celite), a method used in these tests (see Laboratory Monitoring of Anticoagulation During Cardiopulmonary Bypass under PRECAUTIONS).