Is aprotinin safe to use in a cohort at increased risk for thrombotic events: results from a randomized, prospective trial in off-pump coronary artery bypass.
BACKGROUND
Multiple randomized trials have established a favorable safety profile for aprotinin use during cardiac surgery, but recent database analyses suggest an increased risk of adverse thrombotic events. Our group previously demonstrated that off-pump coronary artery bypass (OPCAB) is linked to a postoperative hypercoagulable state. In this study, we tested whether aprotinin influences thrombotic events after OPCAB.


METHODS
Patients randomly received saline (n = 61) or aprotinin (2 x 10(6) kallikrein inhibiting units (KIU) loading dose, 0.5 x 10(6) KIU/hour [n = 59]) during OPCAB. Aprotinin levels (KIU/mL) were analyzed before, and 30 minutes (peak) and 4 hours after the loading dose. Estimated glomerular filtration rate (eGFR) was calculated daily based on Cockcroft equation with acute kidney injury (AKI) defined as eGFR less than 75% of baseline. Major adverse cardiac and cerebrovascular events (MACCE) were monitored during the first year, including acute graft failure by predischarge computed tomographic angiography.


RESULTS
Compared with placebo, the aprotinin group developed a significantly lower eGFR on day 3 (p < 0.006), but this difference resolved by day 5. Peak aprotinin level correlated with the degree of eGFR decline noted on day 3 (r = 0.56, p < 0.03) and independently predicted postoperative AKI (odds ratio 8.8, p < 0.008). The receiver operating characteristic analysis demonstrated that peak aprotinin level strongly predicts AKI (area under the curve = 0.86, 95% confidence interval 0.69 to 1.00). The percentage of patients reaching the composite MACCE endpoint was significantly reduced in the aprotinin versus placebo group (12 vs 34%, p = 0.01).


CONCLUSIONS
Compared with placebo, aprotinin use was associated with less MACCE but more AKI after OPCAB. The strong relationship between the peak aprotinin level and subsequent AKI suggests weight-based protocols for dosing aprotinin may reduce this risk.
Grant
Michael C
MC
Division of Cardiac Surgery, Department of Surgery, University of Maryland Medical System, Baltimore, Maryland, USA.
Kon
Zachary
Z
Joshi
Ashish
A
Christenson
Eric
E
Kallam
Seeta
S
Burris
Nicholas
N
Gu
Junyan
J
Poston
Robert S
RS
D007611:Aprotinin / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D001780:Blood Coagulation Tests; D047549:Coronary Artery Bypass, Off-Pump; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006490:Hemostatics / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D006801:Humans; D010979:Platelet Function Tests; D011183:Postoperative Complications; D011446:Prospective Studies; D013927:Thrombosis / Q000209:etiology*
D006490:Hemostatics; D007611:Aprotinin