1.
Serum creatine kinase and creatinine in adult spinal muscular atrophy under nusinersen treatment.
Freigang, M, Wurster, CD, Hagenacker, T, Stolte, B, Weiler, M, Kamm, C, Schreiber-Katz, O, Osmanovic, A, Petri, S, Kowski, A, et al
Annals of clinical and translational neurology. 2021;(5):1049-1063
Abstract
OBJECTIVE To determine whether serum creatine kinase activity (CK) and serum creatinine concentration (Crn) are prognostic and predictive biomarkers for disease severity, disease progression, and nusinersen treatment effects in adult patients with 5q-associated spinal muscular atrophy (SMA). METHODS Within this retrospective, multicenter observational study in 206 adult patients with SMA, we determined clinical subtypes (SMA types, ambulatory ability) and repeatedly measured CK and Crn and examined disease severity scores (Hammersmith Functional Motor Scale Expanded, Revised Upper Limb Module, and revised Amyotrophic Lateral Sclerosis Functional Rating Scale). Patients were followed under nusinersen treatment for 18 months. RESULTS CK and Crn differed between clinical subtypes and correlated strongly with disease severity scores (e.g., for Hammersmith Functional Motor Scale Expanded: (CK) ρ = 0.786/ (Crn) ρ = 0.558). During the 18 months of nusinersen treatment, CK decreased (∆CK = -17.56%, p < 0.0001), whereas Crn slightly increased (∆Crn = +4.75%, p < 0.05). INTERPRETATION Serum creatine kinase activity and serum creatinine concentration reflect disease severity of spinal muscular atrophy and are promising biomarkers to assess patients with spinal muscular atrophy during disease course and to predict treatment response. The decrease of creatine kinase activity, combined with the tendency of creatinine concentration to increase during nusinersen treatment, suggests reduced muscle mass wasting with improved muscle energy metabolism.
2.
Creatine kinase is associated with bleeding after myocardial infarction.
Brewster, LM, Fernand, J
Open heart. 2020;(2)
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.
3.
Creatine kinase during non-ST-segment elevation acute coronary syndromes is associated with major bleeding.
Brewster, LM, Fernand, J
Open heart. 2020;(2)
Abstract
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 syndrome (NSTE-ACS) is associated with major bleeding. METHODS The 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. RESULTS The 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. 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 treatment for NSTE-ACS. CK might increase the accuracy of prediction models for major bleeding in patients with NSTE-ACS. TRIAL REGISTRATION NUMBER NCT00000472.