We identified 3434 patients who met the inclusion criteria, of whom 1342 had one or more of the prespecified exclusion criteria, resulting in a final study population of 2092 patients with suspected acute coronary syndrome. Within this population, troponin concentrations were <0.012 µg/L in 988 (47%), 0.012-0.049 µg/L in 352 (17%), and ≥0.050 µg/L in 752 (36%) patients.
Adoption of the 99th centile as the diagnostic threshold would increase the number of patients with a diagnosis of myocardial infarction from 36% (752/2092) to 53% (1104/2092), a relative increase of 47%.
Patients with troponin concentrations 0.012-0.049 µg/L were older and more likely to have a history of ischaemic heart disease, previous revascularisation, stroke, hypertension, and hyperlipidaemia than those who had concentrations <0.012 µg/L (table 1). They were also more likely to have an abnormal result on 12 lead electrocardiography (ST segment depression, T wave inversion, or bundle branch block) and renal impairment and to already be established on cardiac drugs than patients with troponin concentrations <0.012 µg/L.
Table 1 Baseline characteristics of all patients with suspected acute coronary syndrome stratified by peak troponin concentration. Figures are numbers (percentage) of patients unless stated otherwise
Patients with troponin concentrations 0.012-0.049 µg/L were a similar age to the patients with troponin concentrations ≥0.050 µg/L, although they were more likely to have a history of ischaemic heart disease and coronary revascularisation and to be established on cardiac drugs before admission (P<0.05 for all). There were no differences in renal function between these groups of patients, but those with concentrations 0.012-0.049 µg/L were more likely to present with T wave inversion or bundle branch block on the 12 lead electrocardiogram and less likely to have ST segment depression or elevation.
Management during index admission
Rates of referral to cardiology and for coronary revascularisation did not differ between patients with troponin concentrations <0.012 µg/L and 0.012-0.049 µg/L. Compared with those with troponin concentrations ≥0.050 µg/L, patients with troponin concentrations of 0.012-0.049 µg/L were less likely to be diagnosed with unstable angina or an acute coronary syndrome (98/352 (28%) v 692/752 (92%)), referred to a cardiologist (129/352 (37%) v 642/752 (85%)), receive dual antiplatelet treatment (46/352 (13%) v 550/752 (73%)), or undergo coronary revascularisation (16/352 (5%) v 394/752 (52%)) (P<0.001 for all) (table 2).
Table 2 Inpatient management of patients with suspected acute coronary syndrome stratified by peak troponin concentration. Figures are numbers (percentages)
Patients were followed up for a median of 446 (range 366-572) days. At 12 months, patients with troponin concentrations of 0.012-0.049 µg/L were four times more likely to have died or been readmitted with recurrent myocardial infarction than those with troponin concentrations <0.012 µg/L (47/352 (13%) v 31/988 (3%), P<0.001, odds ratio 4.7, 95% confidence interval 2.9 to 7.9; table 3 and fig 1). Differences in outcome were already apparent at three months, with 19/352 (5%) patients with troponin concentration 0.012-0.049 µg/L dead or readmitted with a myocardial infarction compared with 13/988 (1%) of patients with troponin concentration <0.012 µg/L (P<0.001, odds ratio 4.6, 2.5 to 8.5).
Table 3 Clinical outcomes in patients with suspected acute coronary syndrome stratified by peak troponin concentration below diagnostic threshold. Figures are numbers (percentages) of patients*
Fig 1 Survival free from death or recurrent myocardial infarction in patients with suspected acute coronary syndrome stratified by plasma troponin concentration
After adjustment for age, sex, history of vascular disease, diabetes mellitus, hypertension, and hyperlipidaemia, troponin concentration 0.012-0.049 µg/L predicted death or recurrent myocardial infarction at 12 months with an adjusted odds ratio of 2.5 (1.5 to 4.3) compared with those with troponin concentrations <0.012 µg/L (P<0.001). Similar estimates were obtained in sensitivity analyses with additional adjustment for smoking status, estimated glomerular filtration rate, and abnormal results on echocardiography (2.3, 1.3 to 4.1). Hazard ratios for time to first event obtained in Cox proportional hazards models were similar to the odds ratios for death or recurrent myocardial infarction at one year.
The association between troponin and risk of death or recurrent myocardial infarction was non-linear (P=0.005, fig 2), but there was no evidence of a threshold at the 10% coefficient of variation (0.050 µg/L) or the 99th centile (0.012 µg/L). Instead, risk increased from an undetectable level to concentrations of about 0.020 µg/L, at which point a threshold was observed above which risk of death or recurrent myocardial infarction did not increase further. An increase in the proportion of patients dead or readmitted with myocardial infarction at one year was observed with each quarter between 0.012 µg/L and 0.050 µg/L (fig 3). Clinical outcomes in the lowest quarter (0.012-0.014 µg/L) were similar to those in patients with troponin concentrations <0.012 µg/L, and outcomes in the highest quarter (0.026-0.049 µg/L) were similar to those patients with troponin concentrations ≥0.050 µg/L. The coefficient of variation for troponin measured within each quarter increased from 7.2% at the diagnostic threshold of 0.050 µg/L, to 20.8% at the 99th centile of 0.012 µg/L, to 28.9% at concentrations below the 99th centile (fig 3).
Fig 2 Association between plasma troponin concentration and odds of death or recurrent myocardial infarction. Estimates obtained from generalised additive model with cubic smoothing spline (df=3, P=0.005 for non-linearity). Rug plot shows density of data (more ...)
Fig 3 Odds of death or recurrent myocardial infarction in patients stratified by plasma troponin concentration
Despite reductions in the precision of the assay at low concentrations, plasma troponin concentration remained a good discriminator for death and recurrent myocardial infarction with a C statistic (area under the curve) of 0.75 for patients with troponin concentrations <0.050 µg/L. Lowering the diagnostic threshold from 0.050 µg/L to 0.012 µg/L increased the negative predictive value of troponin from 94% to 97%, while the positive predictive value decreased from 25% to 22% (see appendix table on bmj.com).