Creatine Kinase during Non-ST-Segment Elevation Acute Coronary Syndromes is Associated with Major Bleeding

Background It was recently reported that highly elevated plasma activity of the ADP-scavenging enzyme creatine kinase (CK), to >10 times the upper reference limit (URL), is independently associated with fatal or non-fatal bleeding during treatment for ST-segment elevation myocardial infarction (OR 2.6 [95% CI, 1.8 to 2.7]/log CK increase). Evidence indicates that CK attenuates ADP-dependent platelet aggregation. This study investigates whether moderately elevated CK in non-ST-segment elevation acute coronary syndromes (NSTE-ACS) is associated with major bleeding. Methods The Thrombolysis In Myocardial Ischemia (TIMI) 3B trial compared rt-PA (35 to 80 mg) with placebo, and early catheterization with conservative management in patients with NSTE-ACS. Main outcomes of the current study are the independent association of peak plasma CK (CKmax) with adjudicated fatal or non-fatal major bleeding (primary), and with combined major bleeding, stroke, and all-cause mortality (secondary) in multivariable binomial logistic regression analysis, with co-variables including age, sex, BMI, SBP, creatinine, and treatment assignment. Discrimination was assessed with C-statistics. Results The study included 1473 patients (66% men, 80% white, mean age 59 y, SE 0.3). CKmax ranged between 15 and 19045 IU/L (mean (SE), 450(24) IU/L; i.e. 2 times URL). Major bleeding occurred in 2.0% (mean age 65(1.3) y; mean CKmax 1015(318) IU/L; 6 times URL), and the combined outcome in 4.3% of the patients, adjusted OR per log CK increase respectively 3.1 [1.6 to 5.8] for major bleeding, and 3.9 [2.5 to 6.1] for the combined outcome; C-index 0.8 for both outcomes. Discussion The presented data add to the existing evidence that proportionate to its plasma activity, the ADP-binding enzyme CK is strongly and independently associated with non-fatal and fatal major bleeding during ACS treatment. CK might increase the accuracy of prediction models for major bleeding in patients treated with antithrombotic or thrombolytic drugs for ACS. ClinicalTrials.gov identifier NCT00000472