Impaired Fibrinolysis Predicts Adverse Outcome in Acute Coronary Syndrome Patients with Diabetes: A PLATO Sub-Study

Abstract

Hypofibrinolysis is a key abnormality in diabetes but the role of impaired clot lysis in predicting vascular events and mortality in this population is yet to be determined. We aimed to investigate the relationship between fibrin clot properties and clinical outcomes in patients with diabetes and recent acute coronary syndrome (ACS). Plasma samples were collected at hospital discharge from 974 ACS patients with diabetes randomised to clopidogrel or ticagrelor in the PLATO trial. A validated turbidimetric assay was employed to study fibrin clot lysis and maximum turbidity. One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were determined using Cox proportional analysis. After adjusting for CV risk factors, each 50% increase in lysis time was associated with increased risk of CV death/MI (HR 1.21; 95% confidence interval [CI] 1.02-1.44; p = 0.026) and CV death alone (HR 1.38; 1.08-1.76; p = 0.01). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death/MI (HR 1.25; 1.02-1.53; p = 0.031) and CV death alone (HR 1.49; 1.08-2.04; p = 0.014). The relationship between lysis time and the combined outcome of CV death and MI remained significant after adjusting for multiple prognostic vascular biomarkers (p = 0.034). Neither lysis time nor maximum turbidity was associated with major bleeding events. Impaired fibrin clot lysis predicts 1-year CV death and MI in diabetes patients following ACS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier NCT00391872.

Conflict of interest statement

W.S.: Speaker fee from Bayer. L.W.: Institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics, Merck & Co; consulting fees from Abbott; holds two patents involving GDF-15 licensed to Roche Diagnostics. S.K.J.: Institutional research grant, honoraria and consultant/advisory board fee from AstraZeneca; institutional research grant and consultant/advisory board fee from Medtronic; institutional research grants and honoraria from The Medicines Company; consultant/advisory board fees from Janssen, Bayer. A.S.: Institutional research grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Roche Diagnostics; consultancy fees from Olink Proteomics. K.G.: Institutional research grants from AstraZeneca. A.H.: Employed by AstraZeneca. R.A.A.: Research/educational support and consultancy fees from Abbott Diabetes Care, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, NovoNordisk, Roche and Takeda. R.F.S.: Institutional research grants, consultancy fees, and honoraria from AstraZeneca; consultancy fees and honoraria from Bayer and Bristol Myers Squibb/Pfizer; consultancy fees from Amgen, GlyCardial Diagnostics, Haemonetics, Novartis, Thromboserin and Idorsia.

Georg Thieme Verlag KG Stuttgart · New York.

Figures

Fig. 1

Relationship between fibrin clot lysis time and 1-year clinical outcomes in patients with diabetes mellitus, 1-year rates of cardiovascular (CV) death and spontaneous myocardial infarction (MI) (A) and CV death alone (B) in relation to lysis time transformed using restricted cubic splines. Shaded areas represent 95% confidence intervals. Vertical lines indicate quartiles.

Fig. 2

Relationship between fibrin clot maximum turbidity and 1-year clinical outcomes in patients with diabetes mellitus, 1-year rates of cardiovascular (CV) death and spontaneous myocardial infarction (MI) (A) and CV death alone (B) in relation to maximum turbidity (AU, arbitrary units) transformed using restricted cubic splines. Shaded areas represent 95% confidence intervals. Vertical lines indicate quartiles.

Fig. 3

Forest plot for the associations between fibrin clot lysis time and clinical outcomes following acute coronary syndrome (ACS) in patients with diabetes. Squares represent hazard ratio (HR) estimates. Horizontal lines represent 95% confidence intervals. Number of patients, 971 for model 1 and 853 for subsequent models. Model 1: Clinical characteristics including randomised treatment, age, gender, body mass index (BMI), smoking history, hypertension, dyslipidaemia, chronic kidney disease (CKD), ST-elevation ACS and previous MI, congestive heart failure, revascularisation, ischaemic stroke or peripheral artery disease; Model 2: Clinical characteristics as per model 1 + C-reactive protein (CRP) + white cell count (WCC); Model 3: All characteristics and biomarkers as per model 2 (except CKD) + cystatin C; Model 4: All characteristics and biomarkers as per model 3 + troponin + N-terminal pro B-type natriuretic peptide (NT-proBNP); Model 5: All characteristics and biomarkers as per model 4 + growth differentiation factor 15 (GDF-15).

Fig. 4

Relationship between fibrin clot lysis time and cardiovascular death according to randomised treatment (A), low-molecular-weight heparin treatment (B), presentation (C) and treatment strategy (D). One-year rates of cardiovascular death in relation to lysis time, transformed using restricted cubic splines. Shaded areas represent 95% confidence intervals, vertical lines indicate quartiles. LMWH, low-molecular-weight heparin; NSTE-ACS, non-ST-elevation acute coronary syndrome; STEMI, ST-elevation myocardial infarction.

Fig. 5

Relationship between fibrin clot lysis time and clinical outcomes according to diabetes status. One-year rates of cardiovascular (CV) death or spontaneous myocardial infarction (MI) (A) and CV death alone (B) in relation to lysis time, transformed using restricted cubic splines, according to diabetes status.