Andrew R. Chapman

High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study

Summary Background Suspected acute coronary syndrome is the commonest reason for emergency admission to hospital and is a large burden on health-care resources. Strategies to identify low-risk patients suitable for immediate discharge would have major benefits. Methods We did a prospective cohort study of 6304 consecutively enrolled patients with suspected acute coronary syndrome presenting to four secondary and tertiary care hospitals in Scotland. We measured plasma troponin concentrations at presentation using a high-sensitivity cardiac troponin I assay. In derivation and validation cohorts, we evaluated the negative predictive value of a range of troponin concentrations for the primary outcome of index myocardial infarction, or subsequent myocardial infarction or cardiac death at 30 days. This trial is registered with ClinicalTrials.gov (number NCT01852123). Findings 782 (16%) of 4870 patients in the derivation cohort had index myocardial infarction, with a further 32 (1%) re-presenting with myocardial infarction and 75 (2%) cardiac deaths at 30 days. In patients without myocardial infarction at presentation, troponin concentrations were less than 5 ng/L in 2311 (61%) of 3799 patients, with a negative predictive value of 99·6% (95% CI 99·3–99·8) for the primary outcome. The negative predictive value was consistent across groups stratified by age, sex, risk factors, and previous cardiovascular disease. In two independent validation cohorts, troponin concentrations were less than 5 ng/L in 594 (56%) of 1061 patients, with an overall negative predictive value of 99·4% (98·8–99·9). At 1 year, these patients had a lower risk of myocardial infarction and cardiac death than did those with a troponin concentration of 5 ng/L or more (0·6% vs 3·3%; adjusted hazard ratio 0·41, 95% CI 0·21–0·80; p<0·0001). Interpretation Low plasma troponin concentrations identify two-thirds of patients at very low risk of cardiac events who could be discharged from hospital. Implementation of this approach could substantially reduce hospital admissions and have major benefits for both patients and health-care providers. Funding British Heart Foundation and Chief Scientist Office (Scotland).

Comparison of the Efficacy and Safety of Early Rule Out Pathways for Acute Myocardial Infarction

Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the optimal approach is uncertain. We compared the European Society of Cardiology rule-out pathway with a pathway that incorporates lower cardiac troponin concentrations to risk stratify patients. Methods: Patients with suspected acute coronary syndrome (n=1218) underwent high-sensitivity cardiac troponin I measurement at presentation and 3 and 6 or 12 hours. We compared the European Society of Cardiology pathway (<99th centile at presentation or at 3 hours if symptoms <6 hours) with a pathway developed in the High-STEACS study (High-Sensitivity Troponin in the Evaluation of Patients With Acute Coronary Syndrome) population (<5 ng/L at presentation or change <3 ng/L and <99th centile at 3 hours). The primary outcome was a comparison of the negative predictive value of both pathways for index type 1 myocardial infarction or type 1 myocardial infarction or cardiac death at 30 days. We evaluated the primary outcome in prespecified subgroups stratified by age, sex, time of symptom onset, and known ischemic heart disease. Results: The primary outcome occurred in 15.7% (191 of 1218) patients. In those less than the 99th centile at presentation, the European Society of Cardiology pathway ruled out myocardial infarction in 28.1% (342 of 1218) and 78.9% (961 of 1218) at presentation and 3 hours, respectively, missing 18 index and two 30-day events (negative predictive value, 97.9%; 95% confidence interval, 96.9–98.7). The High-STEACS pathway ruled out 40.7% (496 of 1218) and 74.2% (904 of 1218) at presentation and 3 hours, missing 2 index and two 30-day events (negative predictive value, 99.5%; 95% confidence interval, 99.0–99.9; P<0.001 for comparison). The negative predictive value of the High-STEACS pathway was greater than the European Society of Cardiology pathway overall (P<0.001) and in all subgroups, including those presenting early or known to have ischemic heart disease. Conclusions: Use of the High-STEACS pathway incorporating low high-sensitivity cardiac troponin concentrations rules out myocardial infarction in more patients at presentation and misses 5-fold fewer index myocardial infarctions than guideline-approved pathways based exclusively on the 99th centile. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT01852123.

Assessment and classification of patients with myocardial injury and infarction in clinical practice

Myocardial injury is common in patients without acute coronary syndrome, and international guidelines recommend patients with myocardial infarction are classified by aetiology. The universal definition differentiates patients with myocardial infarction due to plaque rupture (type 1) from those due to myocardial oxygen supply-demand imbalance (type 2) secondary to other acute illnesses. Patients with myocardial necrosis, but no symptoms or signs of myocardial ischaemia, are classified as acute or chronic myocardial injury. This classification has not been widely adopted in practice, because the diagnostic criteria for type 2 myocardial infarction encompass a wide range of presentations, and the implications of the diagnosis are uncertain. However, both myocardial injury and type 2 myocardial infarction are common, occurring in more than one-third of all hospitalised patients. These patients have poor short-term and long-term outcomes with two-thirds dead in 5 years. The classification of patients with myocardial infarction continues to evolve, and future guidelines are likely to recognise the importance of identifying coronary artery disease in type 2 myocardial infarction. Clinicians should consider whether coronary artery disease has contributed to myocardial injury, as selected patients are likely to benefit from further investigation and in these patients targeted secondary prevention has the potential to improve outcomes.

Long-Term Outcomes in Patients With Type 2 Myocardial Infarction and Myocardial Injury

Background: Type 2 myocardial infarction and myocardial injury are common in clinical practice, but long-term consequences are uncertain. We aimed to define long-term outcomes and explore risk stratification in patients with type 2 myocardial infarction and myocardial injury. Methods: We identified consecutive patients (n=2122) with elevated cardiac troponin I concentrations (≥0.05 µg/L) at a tertiary cardiac center. All diagnoses were adjudicated as per the universal definition of myocardial infarction. The primary outcome was all-cause death. Secondary outcomes included major adverse cardiovascular events (eg, nonfatal myocardial infarction or cardiovascular death) and noncardiovascular death. To explore competing risks, cause-specific hazard ratios were obtained using Cox regression models. Results: The adjudicated index diagnosis was type 1 or 2 myocardial infarction or myocardial injury in 1171 (55.2%), 429 (20.2%), and 522 (24.6%) patients, respectively. At 5 years, all-cause death rates were higher in those with type 2 myocardial infarction (62.5%) or myocardial injury (72.4%) compared with type 1 myocardial infarction (36.7%). The majority of excess deaths in those with type 2 myocardial infarction or myocardial injury were because of noncardiovascular causes (hazard ratio, 2.32; 95% confidence interval, 1.92–2.81 versus type 1 myocardial infarction). Despite this finding, the observed crude major adverse cardiovascular event rates were similar between groups (30.6% versus 32.6%), with differences apparent after adjustment for covariates (hazard ratio, 0.82; 95% confidence interval, 0.69–0.96). Coronary heart disease was an independent predictor of major adverse cardiovascular events in those with type 2 myocardial infarction or myocardial injury (hazard ratio, 1.71; 95% confidence interval, 1.31–2.24). Conclusions: Despite an excess in noncardiovascular death, patients with type 2 myocardial infarction or myocardial injury have a similar crude rate of major adverse cardiovascular events as those with type 1 myocardial infarction. Identifying underlying coronary heart disease in this vulnerable population may help target therapies that could modify future risk.

Association of high-sensitivity cardiac troponin I concentration with cardiac outcomes in patients with suspected acute coronary syndrome

Importance High-sensitivity cardiac troponin I testing is widely used to evaluate patients with suspected acute coronary syndrome. A cardiac troponin concentration of less than 5 ng/L identifies patients at presentation as low risk, but the optimal threshold is uncertain. Objective To evaluate the performance of a cardiac troponin I threshold of 5 ng/L at presentation as a risk stratification tool in patients with suspected acute coronary syndrome. Data Sources Systematic search of MEDLINE, EMBASE, Cochrane, and Web of Science databases from January 1, 2006, to March 18, 2017. Study Selection Prospective studies measuring high-sensitivity cardiac troponin I concentrations in patients with suspected acute coronary syndrome in which the diagnosis was adjudicated according to the universal definition of myocardial infarction. Data Extraction and Synthesis The systematic review identified 19 cohorts. Individual patient-level data were obtained from the corresponding authors of 17 cohorts, with aggregate data from 2 cohorts. Meta-estimates for primary and secondary outcomes were derived using a binomial-normal random-effects model. Main Outcomes and Measures The primary outcome was myocardial infarction or cardiac death at 30 days. Performance was evaluated in subgroups and across a range of troponin concentrations (2-16 ng/L) using individual patient data. Results Of 11 845 articles identified, 104 underwent full-text review, and 19 cohorts from 9 countries were included. Among 22 457 patients included in the meta-analysis (mean age, 62 [SD, 15.5] years; n = 9329 women [41.5%]), the primary outcome occurred in 2786 (12.4%). Cardiac troponin I concentrations were less than 5 ng/L at presentation in 11 012 patients (49%), in whom there were 60 missed index or 30-day events (59 index myocardial infarctions, 1 myocardial infarction at 30 days, and no cardiac deaths at 30 days). This resulted in a negative predictive value of 99.5% (95% CI, 99.3%-99.6%) for the primary outcome. There were no cardiac deaths at 30 days and 7 (0.1%) at 1 year, with a negative predictive value of 99.9% (95% CI, 99.7%-99.9%) for cardiac death. Conclusions and Relevance Among patients with suspected acute coronary syndrome, a high-sensitivity cardiac troponin I concentration of less than 5 ng/L identified those at low risk of myocardial infarction or cardiac death within 30 days. Further research is needed to understand the clinical utility and cost-effectiveness of this approach to risk stratification.

Patient selection for high sensitivity cardiac troponin testing and diagnosis of myocardial infarction: prospective cohort study

Abstract Objective To evaluate how selection of patients for high sensitivity cardiac troponin testing affects the diagnosis of myocardial infarction across different healthcare settings. Design Prospective study of three independent consecutive patient populations presenting to emergency departments. Setting Secondary and tertiary care hospitals in the United Kingdom and United States. Participants High sensitivity cardiac troponin I concentrations were measured in 8500 consecutive patients presenting to emergency departments: unselected patients in the UK (n=1054) and two selected populations of patients in whom troponin testing was requested by the attending clinician in the UK (n=5815) and the US (n=1631). The final diagnosis of type 1 or type 2 myocardial infarction or myocardial injury was independently adjudicated. Main outcome measures Positive predictive value of an elevated cardiac troponin concentration for a diagnosis of type 1 myocardial infarction. Results Cardiac troponin concentrations were elevated in 13.7% (144/1054) of unselected patients, with a prevalence of 1.6% (17/1054) for type 1 myocardial infarction and a positive predictive value of 11.8% (95% confidence interval 7.0% to 18.2%). In selected patients, in whom troponin testing was guided by the attending clinician, the prevalence and positive predictive value were 14.5% (843/5815) and 59.7% (57.0% to 62.2%) in the UK and 4.2% (68/1631) and 16.4% (13.0% to 20.3%) in the US. Across both selected patient populations, the positive predictive value was highest in patients with chest pain, with ischaemia on the electrocardiogram, and with a history of ischaemic heart disease. Conclusions When high sensitivity cardiac troponin testing is performed widely or without previous clinical assessment, elevated troponin concentrations are common and predominantly reflect myocardial injury rather than myocardial infarction. These observations highlight how selection of patients for cardiac troponin testing varies across healthcare settings and markedly influences the positive predictive value for a diagnosis of myocardial infarction.

High-Sensitivity Cardiac Troponin and the Risk Stratification of Patients With Renal Impairment Presenting With Suspected Acute Coronary Syndrome

Background: High-sensitivity cardiac troponin testing may improve the risk stratification and diagnosis of myocardial infarction, but concentrations can be challenging to interpret in patients with renal impairment, and the effectiveness of testing in this group is uncertain. Methods: In a prospective multicenter study of consecutive patients with suspected acute coronary syndrome, we evaluated the performance of high-sensitivity cardiac troponin I in those with and without renal impairment (estimated glomerular filtration rate <60mL/min/1.73m2). The negative predictive value and sensitivity of troponin concentrations below the risk stratification threshold (5 ng/L) at presentation were reported for a primary outcome of index type 1 myocardial infarction, or type 1 myocardial infarction or cardiac death at 30 days. The positive predictive value and specificity at the 99th centile diagnostic threshold (16 ng/L in women, 34 ng/L in men) was determined for index type 1 myocardial infarction. Subsequent type 1 myocardial infarction and cardiac death were reported at 1 year. Results: Of 4726 patients identified, 904 (19%) had renal impairment. Troponin concentrations <5 ng/L at presentation identified 17% of patients with renal impairment as low risk for the primary outcome (negative predictive value, 98.4%; 95% confidence interval [CI], 96.0%–99.7%; sensitivity 98.9%; 95%CI, 97.5%–99.9%), in comparison with 56% without renal impairment (P<0.001) with similar performance (negative predictive value, 99.7%; 95% CI, 99.4%–99.9%; sensitivity 98.4%; 95% CI, 97.2%–99.4%). The positive predictive value and specificity at the 99th centile were lower in patients with renal impairment at 50.0% (95% CI, 45.2%–54.8%) and 70.9% (95% CI, 67.5%–74.2%), respectively, in comparison with 62.4% (95% CI, 58.8%–65.9%) and 92.1% (95% CI, 91.2%–93.0%) in those without. At 1 year, patients with troponin concentrations >99th centile and renal impairment were at greater risk of subsequent myocardial infarction or cardiac death than those with normal renal function (24% versus 10%; adjusted hazard ratio, 2.19; 95% CI, 1.54–3.11). Conclusions: In suspected acute coronary syndrome, high-sensitivity cardiac troponin identified fewer patients with renal impairment as low risk and more as high risk, but with lower specificity for type 1 myocardial infarction. Irrespective of diagnosis, patients with renal impairment and elevated cardiac troponin concentrations had a 2-fold greater risk of a major cardiac event than those with normal renal function, and should be considered for further investigation and treatment. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01852123.

A novel troponin I rule-out value below the upper reference limit for acute myocardial infarction

Objective To determine cut-off values for a recently introduced high sensitive cardiac troponin assay (hs-cTnI) which provide similar sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) for acute myocardial infarction (AMI) as known cut-off values for an hs-cTnT assay. Methods A prospective observational study was performed. Hs-cTnT (Roche) and hs-cTnI (Abbott) were measured in consecutive patients with symptoms suggestive of AMI. Representative measurements (obtained at least 3 h after chest pain has started) and serial measurements with a time delay between 2.5 h and 4.5 h were used to determine cut-off levels. Two independent clinicians adjudicated the final diagnosis. Results 1490 patients were included in the study of whom 114 (8%) received a final diagnosis of AMI. Receiver operating characteristics analysis showed no statistically significant differences in the areas under the curve between the two assays. Cut-off values for representative hs-TnI were found to be as follows: rule-out: 10 ng/L (sensitivity: 98.2%; 95% CI 95.7% to 100.0% and NPV: 99.8%; 99.5% to 100.0%); rule-in: 70 ng/L (specificity: 90.8%; 89.3% to 92.4% and PPV: 39.7%; 36.1% to 43.3%). For serial measurements we found a Δ rule-out cut-off value of 20 ng/L (sensitivity: 94.9%; 88.0% to 100.0% and NPV: 98.7%; 96.9% to 100.0%) and Δ rule-in cut-off values of 100 ng/L (specificity: 92.7%; 87.9% to 95.8% and PPV: 57.6%; 39.4% to 74.0%) and 300% (specificity: 93.8%; 90.4% to 97.2% and PPV: 61.3%; 51.1% to 71.5%). Conclusions Cut-off values for hs-cTnI measurements are determined which allow a similar diagnostic classification as compared with hs-cTnT. Importantly, for a rule-out paradigm this cut-off value is unmistakably lower than the upper reference limit.

Appropriate Use of High-Sensitivity Cardiac Troponin Levels in Patients With Suspected Acute Myocardial Infarction

Appropriate Use of High-Sensitivity Cardiac Troponin Levels in Patients With Suspected Acute Myocardial Infarction To the Editor We previously defined a novel approach to the risk stratification of patients with suspected acute coronary syndrome.1 In 4870 consecutive patients, a high-sensitivity cardiactroponinIconcentrationlessthan5ng/Latpresentationidentified 61% of patients as low risk with a negative predictive value (NPV) of 99.6% for myocardial infarction or cardiac death at 30 days. Carlton et al2 validated our findings, demonstrating an NPV of99.2%in3155patientsacross5separatecohorts.However,they argued against the use of this threshold in clinical practice, as the sensitivity for a diagnosis of myocardial infarction was 94.5%. We disagree with both their approach and their conclusions. Here, a threshold of 5 ng/L is not used to diagnose myocardial infarction but to risk stratify patients in whom the diagnosis is uncertain.3 Negative predictive value is the appropriate and accepted method of evaluating tests of exclusion, analogous to D-dimer testing, and is determined in those without a diagnosis of myocardial infarction at presentation. Sensitivity is determined only in those patients with a diagnosis of myocardial infarction and does not include the target population in whom the risk stratification threshold is being applied. As such, defining the optimal threshold for risk stratification based on diagnostic sensitivity is inappropriate and misleading. Carlton et al2 state that we did not openly report diagnostic sensitivity. We report the NPV, as this is the most appropriate measure. However, in the interest of transparency, a cardiac troponin concentration less than 5 ng/L at presentation had a sensitivity of 98.6% (95% CI, 97.7-99.4) for myocardial infarction or cardiac death at 30 days. Furthermore, this threshold is specific for the high-sensitivity cardiac troponin I assay; evaluating performance in cohorts in which the diagnosis was determined using an array of less precise cardiac troponin I and T assays is potentially misleading. How many of the events missed by the risk stratification threshold of 5 ng/L had high-sensitivity cardiac troponin I concentrations above the 99th percentile on serial testing? Negative predictive value is influenced by disease prevalence, and it is therefore important to determine whether this approach is consistent across different populations. While this ought to be the major strength of their study, Carlton et al2 did not report the prevalence of the primary outcome in patients without myocardial infarction at presentation or the NPV of cardiac troponin concentrations less than 5 ng/L for each cohort separately. In our cohort, the primary outcome occurred in 3.8% of patients without myocardial infarction at presentation.1 We have modeled how variation in prevalence affects the NPV. Reassuringly, if a threshold of 5 ng/L is applied to a population with double the prevalence (8%), the NPV remains 99% or greater. Given the highest reported prevalence of myocardial infarction is 7%,4 we believe our findings are generalizable and could be widely applied across different health care settings.

113 Long Term Outcomes of Patients with Type 2 Myocardial Infarction or Myocardial Injury

Background Type 2 myocardial infarction is defined as myocardial necrosis due to an imbalance in oxygen supply or demand, and is differentiated from myocardial injury by the presence of symptoms or signs of myocardial ischaemia. Both may occur in a wide range of cardiac and non-cardiac conditions and the long term consequences are uncertain. Methods We identified all consecutive patients (n = 2,122) presenting to a tertiary cardiac centre with cardiac troponin I concentrations above the diagnostic threshold of 50 ng/L irrespective of presenting complaint. Two cardiologists independently adjudicated the diagnosis of type 1 myocardial infarction, type 2 myocardial infarction or myocardial injury. The primary outcome was all-cause mortality. Secondary outcomes included subsequent hospitalisation for type 1 myocardial infarction, and cardiovascular or non-cardiovascular mortality. Incidence rates for primary and secondary outcomes were derived for patients stratified by the index diagnosis and cox proportional hazard models constructed to estimate risk of death or hospitalisation, adjusting for age and sex. Results The adjudicated diagnosis was type 1 myocardial infarction in 1,171 patients (55.2%), type 2 myocardial infarction in 429 patients (20.2%) and myocardial injury in 522 patients (24.6%; Table 1). During 8,809 patient years follow up there were 1,231 deaths (552 cardiovascular, 623 non-cardiovascular; Figure 1) and 307 patients were hospitalised for type 1 myocardial infarction. Patients with type 2 myocardial infarction were at higher risk of all-cause mortality compared to those with type 1 myocardial infarction (20.9 vs 8.7 events per 100 person years; hazard ratio [HR] 1.58, 95% CI 1.37–1.82), but were at lower risk of subsequent hospitalisation for type 1 myocardial infarction (3.2 vs 4.3 events per 100 person years; HR 0.53, 95% CI 0.38–0.73). Survival in patients with myocardial injury was worse, even compared to those with type 2 myocardial infarction (27.6 vs 20.9 events per 100 person years; HR 1.17, 95% CI 1.01–1.36). Conclusions Patients with type 2 myocardial infarction and myocardial injury have a very poor prognosis compared to those with type 1 myocardial infarction. Whether worse outcomes are due to the presence of treatable cardiovascular disease or as a consequence of other co-morbid conditions requires further investigation.Abstract 113 Table 1 Baseline characteristics of the study population stratified by index diagnosis Type 1 Myocardial Infarction (n = =1171) Type 2 Myocardial Infarction (n = =429) Myocardial Injury (n = =522) Age (mean (SD)) 68 (14.2) 75 (14.1) 76 (12.7) Male (%) 709 (60.5) 222 (51.7) 260 (49.8) Smoker (%) 380 (34) 62 (14.5) 73 (14) Diabetes Mellitus (%) 185 (16.7) 93 (21.7) 96 (18.7) Hypertension (%) 533 (48.2) 254 (59.3) 303 (58.9) Hyperlipidaemia (%) 539 (48.6) 177 (41.5) 202 (39.5) Family History (%) 193 (18.1) 14 (3.3) 10 (2.0) Previous MI (%) 231 (23.9) 109 (26) 107 (20.9) Previous PCI (%) 153 (14.7) 17 (4) 23 (4.5) Previous CABG (%) 62 (6.3) 30 (7.1) 32 (6.2)Abstract 113 Figure 1 Kaplan Meier curve displaying time to death stratified by classification of myocardial infarction or myocardial injury. Log-rank test for comparison. ** denotes p < 0.01