Creatine kinase is associated with bleeding after myocardial infarction

Abstract

Background: The ADP-scavenging enzyme creatine kinase (CK) is reported to reduce ADP-dependent platelet activation. Therefore, we studied whether highly elevated CK after ST-elevation myocardial infarction (STEMI) is associated with bleeding.

Methods: Data of the Thrombolysis in Myocardial Infarction Study Group phase II trial on the efficacy of angioplasty, following intravenous recombinant tissue-type plasminogen activator (rt-PA), are used to assess whether peak plasma CK (CKmax) is independently associated with adjudicated fatal or non-fatal bleeding (primary) and combined bleeding/all-cause mortality (secondary) in multivariable binomial logistic regression analysis, adjusting for baseline and treatment allocation covariates.

Results: The included patients (n=3339, 82% men, 88% white, mean age 57 years, SE 0.2) had a history of angina pectoris (55%), hypertension (38%) and/or diabetes mellitus (13%). CKmax ranged from 16 to 55 890 IU/L (mean 2389 IU/L, SE 41), reached within 8 hours in 51% of the patients (93% within 24 hours). Adjudicated fatal/non-fatal bleeding occurred in 30% of the patients (respectively 26% in the low vs 34% in the high CK tertile), and bleeding/all-cause mortality in 35% (29% in the low vs 40% in the high CK tertile). In multivariable regression analysis, the adjusted OR for fatal/non-fatal bleeding (vs not bleeding and survival) was 2.6 (95% CI 1.8 to 3.7)/log CKmax increase, and 3.1 (2.2 to 4.4) for bleeding/all-cause mortality.

Conclusion: Highly elevated plasma CK after myocardial infarction might be an independent predictor of bleeding and haemorrhagic death. This biologically plausible association warrants further prospective study of the potential role of extracellular CK in ADP-dependent platelet activation and bleeding.

Keywords: coronary artery disease; emergency medicine; platelets.

Figure 1

Highly schematic representation of thrombus formation and the proposed inhibitory action of the ADP-scavenging enzyme CK herein. The intrinsic and extrinsic pathways leading to thrombus formation are elaborately described elsewhere. After spontaneous plaque rupture during acute coronary syndromes and percutaneous coronary intervention, platelets adhere to the injured vessel wall, undergo shape change, cytosolic Ca²⁺ mobilisation and activation (through collagen and vWF). Platelet activation leads to release of ADP and TXA2 synthesised from AA through PG catalysed by COX1 (inhibited by aspirin). These secondary agonists amplify the response to injury and produce sustained platelet aggregation. In addition, thrombin generated by tissue damage activates platelets’ PAR. Platelet activation leads to the generation of more thrombin on the platelets’ surface, which further activates platelets, converts fibrinogen to fibrin and activates coagulation factors including factor XIII to further stabilise the platelet–fibrin clot. Plasminogen and (r)T-PA bind to the surface of the clot and plasmin degrades fibrin. ADP is considered to be central to platelet activation. ADP-stimulation of the P2Y1 receptor activates phospholipase C resulting in weak, transient platelet aggregation. Activation of P2Y12 receptor results in the activation of glycoprotein receptors IIb/IIIa (integrin (I)-αIIbβ3) and firm platelet aggregation. CK has a high binding capacity for ADP, which can be converted to ATP. Highly elevated extracellular CK released during major tissue damage might function to reduce ADP and dampen platelet activation, but might also lead to increased bleeding risk,⁶ in particular when multiple antithrombotic drugs (rt-PA, heparin, and aspirin in this study) are used. AA, arachidonic acid; COX1, cyclooxygenase 1; CK, creatine kinase; PARs, protease activated receptors; PG, prostaglandin; (r)T-PA, (recombinant) tissue-type plasminogen activator; TXA2, thromboxane A2; vWF, von Willebrand factor.

Figure 2

Diagram of the thrombolysis in MI phase II (TIMI 2) studies. TIMI 2 patients were treated with intravenous recombinant tissue plasminogen activator (rt-PA) within 4 hours of the onset of chest pain thought to be caused by MI, before randomisation to an invasive strategy (cardiac catheterisation, and when anatomically appropriate, PTCA or CABG within 24 to 48 hours after infarction) or conservative strategy (with invasive procedures only in response to the occurrence of spontaneous or provoked ischaemia). The trial included 3534 patients in three subsets: (1) TIMI 2 main study (large square, n=3339) in which patients were randomised between a delayed invasive strategy (n=1681) and a conservative strategy groups (n=1658); (2) TIMI 2A substudy n=586), overlapping with the main study but also including an immediate invasive strategy treatment group; and (3) the beta-blocker substudy (n=1434), a component of main study in which eligible patients were further randomised between immediate and delayed 3-blocker therapy; *excluding n=195 immediate invasive treatment; †including participants with PTCA on day 7 (n=197). CABG, coronary artery bypass grafting; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; TIMI 2, Thrombolysis in Myocardial Infarction phase II.

Figure 3

Panel A to H concern the association of peak plasma creatine kinase (CKmax) with bleeding. Panel A (CK, IU/L) and B (CK normalized for the URL), show highly elevated CK activity after myocardial infarction, to more than 90 times the URL, which is thought to inhibit ADP-dependent platelet activation. Panel C and D depict the time to peak CK value (at 8 hours) and time to the first adjudicated bleeding (peak at Day 1). Panel E considers the distribution of primary adjudicated bleeding sites by severity. Panel F (n, respectively, no bleeding=1389; IR=965; Minor=361; Major=387; LNS=237) and G indicate bleeding severity by CK tertile (n=1109 per tertile, with 12 missing CK). Panel H shows the adjusted OR with (95% CI) for bleeding vs non- bleeding per log CKmax increase. I. All bleeding; II. Excluding puncture bleeding. *Primary outcome; †adjudicated bleeding events. Complete cases without imputation (n = 911 to 1428). Missing cases analysis for the multivariable binary logistic regression analyses, handling of missing data, and outcomes for other variables are reported in the online supplementary data. Adj. bleeding. First adjudicated bleeding event (fatal or non-fatalbleeding); ACM, adjudicated all-cause mortality. CI, confidence interval; CK, creatine kinase; GI, gastrointestinal; GU, genitourinary; IC, intracranial; Inter., intermediate; IR, investigator reported; LNS, loss-no-site/other; OR, odds ratio PS, puncture sites, URL, upper reference limit.