Creatine kinase during non-ST-segment elevation acute coronary syndromes is associated with major bleeding

Abstract

BackgroundIt 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 syndrome (NSTE-ACS) is associated with major bleeding.MethodsThe Thrombolysis In Myocardial Ischemia (TIMI) 3B trial compared recombinant tissue-type plasminogen activator (rt-PA) (35–80 mg) with placebo and early catheterisation 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 hospital death (secondary), with covariables including age, sex, body mass index, systolic blood pressure, creatinine and assignment to add-on rt-PA versus placebo. Discrimination was assessed with C-statistics.ResultsThe study included 1473 patients (66% men, 80% white, mean age 59 years, SE 0.3). CKmax ranged between 15 and 19 045 IU/L (mean (SE), 450 (24) IU/L; two times URL). Major bleeding occurred in 2.0% (mean age 65 (1.3) years; mean CKmax 1015 (319) IU/L; six times URL), and the combined outcome in 4.3% of the patients, adjusted OR per log CK increase, respectively, 3.1 (1.6 to 5.9) for major bleeding and 3.9 (2.5 to 6.1) for the combined outcome; C-index 0.8 for both outcomes. The association between CK and bleeding was independent of the use of thrombolytic therapy.DiscussionThe 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 treatment for NSTE-ACS. CK might increase the accuracy of prediction models for major bleeding in patients with NSTE-ACS.Trial registration numberNCT00000472.

Creatine kinase and bleeding in patients with acute coronary syndromes

“…Thus, our study strongly suggests the existence of a significant and independent association between peak CK and 30‐day incidence of bleeding in patients with ACS. In this regard, our data corroborate the prior findings on the association between peak CK and bleeding 6‐8 in contemporary patients with ACS.…”

“…Despite identification of a large number of risk factors for bleeding in patients with ACS after PCI, the risk stratification for this outcome remains suboptimal. Brewster et al 6‐8 have recently proposed that high plasma CK may be another factor that may increase the risk for bleeding by reducing ADP level and consequently ADP‐mediated platelet aggregation. A recent study from this group demonstrated a reduction in ADP‐dependent platelet aggregation by adding exogenous CK (500 to 4000 U/L plus creatine phosphate 5 mM) to human plasma.…”

“…After adjustment for potential confounders, CK remained independently associated with the risk of bleeding with an adjusted odds ratio of 2.6 for log peak CK increase. Another recent study by the same authors assessed the association between CK and bleeding in 1473 patients with non‐ST‐segment elevation ACS obtained from the TIMI 3B trial and reported more than a 3‐fold increase in the adjusted risk for bleeding for each unit increase in the peak CK values 8 . In aggregate, these data support the existence of an association between elevated CK and attenuation of ADP‐dependent platelet aggregation in experimental setting and an association between elevated CK and risk of bleeding in patients with ACS.…”

“…However, the risk stratification for bleeding remains suboptimal. Recently, Dutch researchers advanced an interesting hypothesis positing that elevated creatine kinase (CK) level in circulation increases the risk for bleeding via CK‐mediated adenosine diphosphate (ADP) depletion and attenuation of ADP‐dependent platelet aggregation 6‐8 . No other studies so far have investigated whether there is an association between CK and the risk for bleeding in patients with ACS.…”

Relationship between creatine kinase and major bleeding in patients with non-ST-segment elevation acute coronary syndrome

“…CK is significantly important in activating the pathogenesis of many diseases. Major bleeding is the most common cause of non-cardiac death during treatment of non-STsegment elevation acute coronary syndrome (NSTE-ACS) (2)(3)(4). Therefore, identifying patients who are at risk of bleeding complications during ACS treatment is significantly important.…”