• 
• 

Three Part Question

In [an adult over 18 years of age presenting with low risk cardiac pain] is a [high sensitivity Troponin T (hs-cTnT) taken at 0-hour and 1-hour after presentation] sensitive enough to [rule out Acute Coronary Syndrome (ACS).]

Clinical Scenario

A 45-year-old man attended the Emergency Department (ED) with one-hour history of chest pain that could be of cardiac origin. His ECG did not reveal acute ischemic changes. It is important to substantiate or rule-out ACS in this situation. This analysis is aimed at finding whether a hs-cTnT measurement taken at 0-hour and 1-hour after presentation is sensitive enough for this purpose.

Search Strategy

MEDLINE, PubMed, EMBASE, CINAHL, Cochrane, Google Scholar, NICE, ESC guidelines and bibliographies.
(Low risk chest pain and Emergency Department and high sensitivity troponin T and (1 or one hour). LIMIT to Human and English

558 papers were found of which 549 were considered irrelevant, duplicates or of insufficient quality. The remaining 9 papers were included in the analysis.

Search Outcome

Analysis of the 9 papers are shown in the table.

MACE: Major adverse cardiac events, CAG: Coronary angiography, AMI: Acute myocardial infarction, NPV: Negative predictive value, CI: Confidence Interval, PPV: Positive predictive value, TIMI: Thrombolysis in Myocardial Infarction, LR: Likelihood ratio, hs-cTnI: High sensitivity cardiac troponin I

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
M Shiozaki et al. 7 september 2017 (accepted Japan and Taiwan	413 Emergency Department (ED) patients with chest pain in three hospitals	Prospective cohort, international, multicentre, diagnostic	Primary endpoint: MACE, ACS, death and urgent admission for CAG in 30 days follow up from initial attendance	Ruled out AMI with NPV 100% (CI 95%, 96.8% - 100%) and sensitivity 100% (CI 95%, 88.0% - 100%) PPV for AMI 33.1%(95%CI, 25.1% - 41.9%) and specificity 66.3% (95%CI, 60.2% - 72.0%)	Small numbers recruited - possible selection bias Unclear if convenience sample or consecutive patients Treating physicians not blinded Sample included patients with Takotsubo cardiomyopathy and patients receiving haemodialysis
2. Mueller C et al. July 2016 USA, Europe and Australia	1282 ED patients with chest pain in twelve institutes across three continents	Prospective observational diagnostic study to validate hs-cTnT 0-hour/1-hour algorithm for rapid rule-out and rule-in AMI	Primary: The NPV and sensitivity for AMI of the hs-cTnT 0-hr/1-hr rule-out rule Secondary: PPV and specificity of the hs-cTnT 0-hr/1-hr rule-in rule	NPV for AMI 99.1% (95%CI 98.2 - 99.7%) and sensitivity 96.7% (95% CI 93.4 - 98.7%) PPV for AMI 77.2% (95%CI 70.4 - 83.0%) and specificity 96.1% (95% CI 94.7 - 97.2%)	Observational diagnostic study – does not evaluate use of hs-cTnT in clinical decision making Convenience sample Large exclusion criteria - extrapolation to wider population difficult
E Carlton et al December 2015 UK	963 ED patients with chest pain	Prospective diagnostic cohort study	Primary outcome: Fatal or nonfatal AMI within 30 days of hospital attendance (including the index visit)	A TIMI and modified Goldman score 1 or less with hs-cTnT had the potential to achieve a NPV greater than or equal to 99.5% while identifying >30% patients as suitable for immediate discharge	Risk of incorporation bias - outcome measures based on the hs-cTnT results under evaluation Primary endpoints were fatal and non-fatal AMI - patients with unstable angina possibly missed Excluded patients over the age of 80 years Conflict of interests
Mokhtari A et al January, 2016 Sweden	1038 ED patients with chest pain	Prospective observational study	Primary outcome: MACE within 30 days including the index visit	The combination algorithm ruled out MACE 60% of all patients and had a higher sensitivity than the troponin only algorithm (97.5% vs. 87.6%; p<0.0001) The NPV was 99.5% and the LR was 0.04 with the combination algorithm versus 97.8% and 0.17 respectively, with the troponin only algorithm. The combination algorithm ruled-in with higher sensitivity (75.2% vs. 56.2%; p<0.001) but a slightly lower specificity (94.0% vs. 96.4%; p<0.001) than the troponin algorithm	Single centre study Convenience sample Not all patients had two hs-cTnT samples taken
A Mokhtari et al. February 27, 2017(accepted) Sweden	1020 ED patients with chest pain	Secondary analysis of prospective observational study	Primary outcome: MACE within 30 days including the index visit	The combination of an adapted TIMI score 1 or less, a non-ischemic ECG, and either a 0-hour hs-cTnT<5ng/L or a 0-hour hs-cTnT <12ng/L combined with a 1-hour increase <3ng/L identified 42.4% patients as very low risk with a NPV of 99.5% (95%CI = 98.3% - 99.9%) and a negative LR of 0.04 (95%CI = 0.01 – 0.14) for 30-day MACE	Single centre study Convenience sample Excluded patients with missing data Unstable angina not included in final diagnosis, which altered results Few patients had hs-cTnT taken within 2 hours of onset – patient safety in this cohort is unclear
Reichlin et al 2012 Switzerland	872 ED patients with chest pain	Prospective multicentre study	Primary prognostic end point: 30 days’ all-cause of mortality	Sensitivity and NPV of 100% for rule-out, a specificity and PPV of 97% and 84%, respectively for rule-in of AMI	Proportion of patients with end diagnosis of AMI was higher than other studies - possible lack of external generalizability Death was the primary endpoint Observational data - not validated for clinical use Same assay used for derivation and validation of hs-cTnT
J Pickering et al. November, 2016 Australia, New Zealand and Canada	2222 ED patients with chest pain. Combined data from 5 studies in 3 countries	Secondary analysis of ADAPT-ADP RCT, EDACS-ADP RCT, Canada RING study	Primary outcome: The sensitivity of rule-out strategy as a measure of safety and the proportion categorized as rule-out (low-risk) as a measure of efficacy. Secondary outcome: PPV and proportion categorized as rule-in (high-risk) as measure of efficacy	hs-cTnT algorithm ruled out 1425 (64.1%) with a sensitivity 97.1% (95%CI, 94.0% - 98.8%) and ruled-in 292 (13.1%) with a PPV of 63.4% (95%CI, 57.5%-68.9%)	Samples used collected at 90 minutes and 2 hours. Adjudication of final diagnosis not standardised - In 3 countries hs-cTnI was used, not hs-cTnT Conflicts of interests
E Rottger, et al. December 2017 2017, Netherlands	374 ED patients with chest pain	Prospective study	Primary endpoint: 6-week occurrence of MACE following index visit to ED	No patients had AMI or died during 6 weeks follow up 16 patients (4.3%) suffered MACE and 3 diagnosed non-cardiac chest-pain patients (0.8%) returned with unstable angina	Possible incorporation bias as hs-cTnT was part of diagnosis standard One quarter of patients excluded due to missing values at one hour
T Reichlin et al. May, 2015 Switzerland, Spain and Italy	1320 ED patients with chest pain in three countries	Prospective cohort study	Primary endpoint: AMI	Ruled-out AMI in 59.5% of patients with a sensitivity of 99.6% (95%CI 97.6 to 99.9%) and NPV 99.9% (95%CI 99.3-100%) Ruled-in AMI 16.4% of patients with specificity 95.7% (95%CI 94.3-98.6%), although PPV was 78.2% (95%CI 72.1-83.6%)	Possible incorporation bias as hs-cTnT was part of diagnosis standard One quarter of patients excluded due to missing values at one hour

Comment(s)

The primary end-point of most studies were MACE within 30 days including the index visit. The NPV and the sensitivity for AMI of the hs-cTnT 0-hr/1-hr rule-out rule was the primary outcome measure. The secondary outcome measures included mortality at 30 days and 1 year. This included the PPV and specificity of the hs-cTnT 0-hr/1-hr rule-in rule. All studies tested hs-cTnT and most of them produced NPV of 99.1% or above (100%), lowest being 99.1% in one study11 for rule out AMI. However, PPV for rule-in AMI varied between 63.4% to 84% except one study showing PPV 33.1%1.

Clinical Bottom Line

Based on the findings of the studies reviewed, it would seem very appropriate to consider the 0-hour/1-hour hs-cTnT algorithm in combination with a current established risk scoring to rule-out ACS in adult patients with low risk chest pain.

References

1. 1. Shiozaki M et al. Utility of the 0-hour/1-hour high-sensitivity cardiac troponin T algorithm in Asian patients with suspected non-ST elevation myocardial infarction. International Journal of Cardiology 2017; 249: 32-35
2. Mueller C et al. Multicenter Evaluation of a 0-Hour/1-Hour Algorithm in the Diagnosis of Myocardial Infarction With High-Sensitivity Cardiac Troponin T Annals of Emergency Medicine 2016; 68(1):76-87
3. E Carlton et al Identifying Patients Suitable for Discharge After a Single-Presentation High-Sensitivity Troponin Result: A Comparison of Five Established Risk Scores and Two High-Sensitivity Assays Annals of Emergency Medicine 2015; 66(6):635-645
4. Mokhtari A et al A 1-h Combination Algorithm Allows Fast Rule-Out and Rule-In of Major Adverse Cardiac Events Journal of the American College of Cardiology 2016; 67(13):1531-40
5. A Mokhtari et al. A 0-Hour/1-Hour Protocol for Safe, Early Discharge of Chest Pain Patients Academic Emergency Medicine 2017; 24(8):983-992.
6. Reichlin et al. One-hour rule-out and rule-in of Acute Myocardial Infarction using high-sensitivity cardiac Troponin T. Arch Intern Med 2012;172(16): 1211-18
7. J Pickering et al. Assessment of European society of Cardiology 0-hour/1-hour algorithm to rule-out and rule-in Acute Myocardial Infarction Circulation 2016; 134:1532-41
8. E Rottger, et al. Safety of a 1-hour rule-out high sensitive Troponin T protocol in patients with chest pain at the Emergency Department Critical pathways in cardiology 2017; 16(4): 129-34
9. T Reichlin et al. Prospective validation of a 1-hour algorithm to rule-out and rule-in Acute Myocardial Infarction using a high-sensitivity cardiac troponin T assay CMAJ 2015; 187(8):243-52