Baseline levels of MPO and sCD40L were available for 1524 survivors of non-ST elevation ACS. Their baseline characteristics stratified by MPO and sCD40L are presented in . These characteristics are compared with those without MPO and sCD40L data in Supplementary material online, Table S1
. Those with biomarker data available tended to be younger (61 vs. 65 years, P
< 0.001), to have higher body weight (83 vs. 81 kg, P
= 0.001), and to present less frequently with a qualifying MI (35 vs. 42%, P
Unadjusted association of baseline characteristics with myeloperoxidase and soluble CD40L
The median concentration of MPO was 884 pM with 1st, 25th, 75th, and 99th percentiles of 56, 489, 1381, and 6820 pM, respectively. The concentration of MPO was more likely to be elevated in patients presenting with a myocardial infarction compared with those with unstable angina (P < 0.001) and tended to be more frequently increased in patients with diabetes mellitus (P = 0.09, ). The median concentration of sCD40L was 989 pg/mL with 1st, 25th, 75th, and 99th percentiles of 5, 311, 2798, and 9153 pg/mL, respectively. Baseline characteristics were similar between those with and without elevated levels of sCD40L, with the exception that patients with an elevated concentration of sCD40L tended to be younger (P = 0.07, ). MPO was only weakly correlated with hsCRP (ρ = 0.08, P = 0.003), sCD40L (ρ = −0.12, P < 0.001), and cTnI (ρ = 0.18, P < 0.001), and not BNP (ρ = 0.03, P = 0.26), estimated GFR (ρ = −0.05, P = 0.07).
The median concentration of MPO was significantly higher in the 106 patients who subsequently suffered a non-fatal myocardial infarction or recurrent ACS event during the first 30 days (1158 pM; 25–75th percentile 729–1767 pM) compared with those without recurrent ischaemic events (866 pM; 25–75th percentile 473–1366 pM, P = 0.0003). In contrast, the median concentration of sCD40L did not differ significantly between those with recurrent ischaemia by 30 days (1091 pg/mL; 25–75th percentile 420–2871 pg/mL) and those without (971 pg/mL; 25–75th percentile 304–2795, P = 0.26). Analysis in a logistic regression model as continuous variables (log-transformed) revealed a significant relationship between MPO and the risk of recurrent ischaemic events (OR 1.42; 95% CI 1.14–1.78; P = 0.002) and a trend for sCD40L (OR 1.15; 95% CI 0.99–1.33; P = 0.07). When dichotomized at the median, an elevated baseline level of MPO (>884 pM) was associated with a two-fold higher risk of recurrent ischaemic events (MI or recurrent ACS) at 30 days (9.3 vs. 4.6%, P < 0.001), whereas patients with an elevated concentration of sCD40L (>989 pg/mL) showed only a modest trend towards higher risk (7.6 vs. 6.3%, P = 0.31). The relationship between each marker and the risk of recurrent ischaemic events is shown in revealing a significant association between MPO and MI (P = 0.004) and rehospitalization for ACS (P = 0.019) and no detectable difference for sCD40L (P = 0.49 and P = 0.39, respectively). The same pattern was maintained when the relationship between MPO and risk of recurrent ischaemic events was examined in those patients with a baseline cTnI below the 99th percentile (n = 629, 6.4 vs. 3.6%, P = 0.11).
Relationship between myeloperoxidase (MPO) and soluble CD40L (sCD40L) and the risk of recurrent ischaemic events at 30 days. MI, myocardial infarction; Hosp for ACS, hospitalization for acute coronary syndrome.
After adjustment for age, ST-deviation, diabetes mellitus, history of coronary artery disease, history of heart failure, baseline cTnI, hsCRP, and sCD40L, an elevated baseline concentration of MPO was associated with a nearly two-fold higher risk of non-fatal myocardial infarction or recurrent ACS at 30 days (adjusted OR 2.10; 95% CI 1.36–3.23, P
= 0.001). An increased concentration of sCD40L was associated with a non-significant trend towards more frequent ischaemic events in this model when treated either dichotomized at the median (adjusted OR 1.39; 95% CI 0.93–2.09, P
= 0.11) or as a continuous variable (P
= 0.15). These findings were both consistent handling the biomarkers as continuous variables (log-transformed) with an adjusted OR 1.41 (95% CI 1.22–1.77; P
= 0.003) for a log increase in MPO and adjusted OR 1.15 (95% CI 1.00–1.32; P
= 0.056) with sCD40L. In the subset of patients with BNP also available (n
= 1453), the risk related to MPO was not attenuated with the addition of BNP to the model (adjusted OR 2.36; 95% CI 1.50–3.73, P
< 0.001). With MPO in the model, hsCRP was not associated with recurrent ischaemic events (P
= 0.43); therefore, we updated our prior multimarker model2
for this analysis of recurrent ischaemia, with MPO replacing hsCRP. When evaluated in a multimarker approach integrating biomarkers measured and reported previously in TACTICS-TIMI 18, the combination of MPO, BNP, and cTnI identified a >3-fold gradient of risk for recurrent ischaemic events at 30 days ().
Multimarker strategy using myeloperoxidase (MPO), B-type natriuretic peptide (BNP), and cardiac troponin I (cTnI). Each elevated marker confers one point towards the multimarker score.
We also evaluated the relationship between MPO and sCD40L with outcomes through 6 months of follow-up. Notably, the association between MPO and the risk of myocardial infarction or recurrent ACS was attenuated by 6 months (16.7 vs. 13.9%, P = 0.14) with an adjusted OR 1.26 (95% CI 0.95–1.68). Examination of Kaplan–Meier cumulative incidence curves reveals an early separation with a gradual convergence in the risk by 6 months (). In addition, we detected a non-significant trend between sCD40L and outcome at 6 months (16.5 vs. 14.0%, P = 0.18, ). Analyses as continuous variables with respect to outcomes at 180 days did not differ qualitatively (MPO: adjusted OR 1.15; 95% CI 0.99–1.34; P = 0.072, and sCD40L: adjusted OR 1.05; 95% CI 0.95–1.15; P = 0.33). Finally, there was no evidence for an interaction between the efficacy of the early invasive management strategy and the risk associated with MPO with respect to outcomes at 30 days (P = 0.65) or 6 months (P = 0.14). Specifically, MPO was associated with an adjusted two-fold higher risk of recurrent ischaemia in patients managed with the invasive (OR 2.17; 95% CI 1.05–4.48) or conservative strategy (OR 2.13; 95% CI 1.24–3.66).
Figure 3 Kaplan–Meier estimated cumulative failure rates for recurrent ischaemic events (non-fatal myocardial infarction or rehospitalization for acute coronary syndrome) stratified by myeloperoxidase and soluble CD40L above and below the median concentration. (more ...)