Previous studies on high sensitivity troponins (hs-cTnT) have yielded two risk stratification strategies for rule in / rule out of myocardial infarction (MI); using an initial hs-cTnT below the limit of quantification (LOQ) alone and using an algorithm with initial and 1-hour hs-cTNT (0/1-h algorithm), as currently recommended by the European Society of Cardiology.
These strategies are often combined with a risk score, of which in the United States (US) the HEART score is the most commonly used. However, due to the relatively late introduction of hs-cTnT in the US, multicenter US data for these risk stratification strategies using hs-cTnT are lacking.
The goal of the current study was to prospectively evaluate the diagnostic performance of a hs-cTnT assay (Roche, Basel Switzerland) for the detection of 30-day MACE using two different strategies: an initial hs-cTnT <LOQ alone and a 0/1-h algorithm, both with and without clinical variables (ECG interpretation and HEART score).
Paper: Allen et al. Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite United States Cohort. Circulation 2021. PMID 33474976
Clinical Questions:
- What is the diagnostic performance (safety and efficacy) of the Roche hs-cTnT assay for the detection of 30-day MACE (plus the composite of cardiac death or MI) at 30 days using an initial hs-cTnT below the limit of quantification (LOQ) and a 0/1-h algorithm?
- Same question as above both with and without the inclusion of ECG interpretation and HEART score?
What They Did:
- Prospective observational cohort study of ED patients with acute chest pain or other symptoms suggestive of ACS
- Eight US EDs between January 25, 2017 to September 6, 2018
Inclusion:
- Age ≥ 21
- Presenting with chest discomfort or other symptoms consistent with possible ACS (defined by the ED provider ordering serial troponins)
- Enrollment < 1 hour of site’s first clinical blood draw
- Have a 2nd standard of care cTnT measurement within the next 2-12 hours
Exclusion:
- ST-segment elevation MI at presentation
- SBP < 90 mmHg
- Life expectancy < 90 days
- Non-cardiac illness requiring admission
- Lack of capacity to provide consent
- Inability to be contacted for follow up
- Non-English speaking
- Pregnancy
- Prior enrollment in this study
Outcomes:
- Primary:
- 30-day major adverse cardiac events (cardiac death, MI, and coronary revascularization)
- Secondary:
- Index and 30-day composite of cardiac death or myocardial infarction
- Individual components of the MACE outcomes
Results:
- 1,462 patients were eligible for analysis
- 46.4% women, 53.6% men
- 37.1% African American
- Average age of 57.6 years (SD 12.9 years)
- Hs-cTnT at t = 0 in 1460 patients (99.9%), at t = 1 in 1432 patients (97.9%)
- Median time from ED arrival to baseline study blood drawn was 82 minutes (63 – 106 minutes)
- 30-day follow up completed in 1406 patients (96.2%), loss to follow up 3.8%
- MACE at 30-day occurred in 210 patients (14.4%)
- 9 patients (0.6%) with cardiac death
- 185 patients (12.7%) with MI
- 24 patients (1.6%) with coronary revascularization without MI
- MACE at index visit occurred in 181 patients (12.4%)
- 2 patients (0.1%) with cardiac death
- 169 patients (11.6%) with MI
- 11 patients (0.8%) with coronary revascularization without MI
- MACE after index visit (during 30-day follow up) occurred in 46 patients (3.1%)
- 7 patients (0.5%) with cardiac death
- 26 patients (1.8%) with MI
- 14 patients (1.0%) with coronary revascularization without MI
Critical Results:
Diagnostic Accuracy of hs-cTnT below LOQ (< 6 ng/L) Alone:
- Initial hs-cTnT <LOQ occurred in 32.8% (95% CI: 30.4-35.3%) of cohort
- NPV 98.3% for 30-day MACE (95% CI: 96.7-99.3%), 99.0% for 30-day Cardiac death and MI (95% CI: 97.6-99.7%), 99.2% for MI at presentation (95% CI: 97.9-99.8%)
- The addition of a low HEART score (0 – 3) to a hs-TnT <LOQ had an efficacy of 20.1% (95% CI: 18.1-22.3%)
- NPV at 30-day
- 99.0% for MACE (95% CI: 97.0-99.8%)
- 99.7% for MI or cardiac death (95%CI: 98.1-100.0%)
- NPV at index-visit
- 99.7% for MI (95% CI: 98.1-100.0%), sensitivity was 99.4% (95% CI: 96.7-100.0%)
- The addition of a non-ischemic ECG has no additional efficacy over the HEART score on a hs-cTnT below LOQ
- NPV at 30-day
Diagnostic Accuracy of the 0/1-h Algorithm:
- The 01/-h algorithm was completed in 1430 patients
- 826 patients (57.8%) were ruled out by the algorithm (hs-cTnT: 0 hr <12 ng/L and Δ 0-1hr <3 ng/L)
- 23 patients (1.6%) had MACE at 30-day (1 cardiac death, 13 MI, 9 index/30-day revascularization), all had non-ischemic ECG and 7 had a low-risk HEART score, 9 were early presenters
- NPV at 30-day
- 97.2% for MACE (95% CI: 95.9-98.2%), sensitivity 88.7% (95% CI: 83.5-92.7%)
- 98.4% for MI or cardiac death (95% CI: 97.3-99.2%), sensitivity was 92.9% (95%CI: 88.2-96.2%)
- Index visit MI occurred in 8 patients (1.0%)
- NPV at index-visit
- 99.0% for MI (95%CI: 98.1-99.6%), sensitivity was 95.1% (95%CI: 90.6-97.9%)
- 604 patients (42.2%) were unable to be ruled out by the algorithm
- PPV at 30-day
- 29.8% for MACE (95%CI: 26.2-33.6%), specificity was 65.4% (95%CI: 62.7-68.1%)
- 28.2% for MI or cardiac death (95%CI: 24.6-31.9%), specificity was 65.2% (95%CI: 62.5-67.8%)
- The addition of a low-risk HEART score to the rule out range of the 0/1h algorithm was effective in in 441 patients (30.8%)
- NPV at 30-day
- 98.4% for MACE (95%CI: 96.8-99.4%), sensitivity was 96.6% (95%CI: 93.0-98.6%)
- 99.3% for MI or cardiac death (95%CI: 98.0-99.9%), sensitivity was 98.4% (95%CI: 95.3-99.7%)
- NPV at index-visit
- 99.5% for MI (95%CI: 98.4-99.9%), sensitivity was 98.8% (95%CI: 95.7-99.9%)
- The addition of a non-ischemic ECG has no additional efficacy over the 0/1h algorithm in the rule out range
- NPV at 30-day
- PPV at 30-day
- 826 patients (57.8%) were ruled out by the algorithm (hs-cTnT: 0 hr <12 ng/L and Δ 0-1hr <3 ng/L)
The 0/1-h high-sensitivity troponin algorithm for 30 Day MACE, cardiac death or MI, and index-visit MI
ACS = acute coronary syndrome, CV = cardiovascular, ED = emergency department, MACE= major adverse cardiac event, MI= myocardial infarction, NPV = negative predictive value, PPV = positive predictive value
The 0/1-h high-sensitivity troponin algorithm combined with the HEART score for 30-day MACE, cardiac death or MI, and index-visit MI
ACS = acute coronary syndrome, CV = cardiovascular, ED = emergency department, MACE= major adverse cardiac event, MI= myocardial infarction, NPV = negative predictive value, PPV = positive predictive value
Early Presenters:
- 516 patients (35%) presented early (<3h) after onset of chest pain
- 79 (15.3%) patients had MACE
- Early presenters with initial hs-TnT measure <LOQ alone did only receive high NPV of 99.3% for MI at index-visits (95%CI: 96.3-100.0%)
- Early presenters with initial hs-TnT measure <LOQ and a HEART score of 0-3:
- NPV at 30-day
- 100.0% for MACE (95%CI: 97.2-100.0%)
- 100.0% for MI or cardiac death (95%CI: 97.2-100.0%)
- NPV at index-visit
- 100.0% for MI (95%CI: 97.2-100.0%), sensitivity was 100.0% (95%CI: 95.3-100.0%)
- Early presenters with hs-cTnT 0/1h algorithm in rule-out range alone did only receive high NPV of 99.4% for MI at index-visits (95%CI: 96.7-100.0%)
- Early presenters with hs-cTnT 0/1h algorithm in rule-out range and a HEART score of 0-3:
- NPV at 30-day
- 98.2% for MACE (95%CI: 94.9-99.6%), sensitivity was 95.9% (95%CI: 88.6-99.2%)
- 98.8% for MI or cardiac death (95%CI: 95.8-99.9%), sensitivity was 97.1% (95%CI: 89.9-99.6%)
- NPV at index-visit
- 99.4% for MI (95%CI: 96.7-100.0%), sensitivity was 98.3% (95%CI: 90.9-100.0%)
- NPV at 30-day
- NPV at 30-day
Strengths:
- This is the first and largest prospective multisite US cohort study to evaluate hs-cTnT strategies to date
- In this cohort the differences in time of chest pain onset were small and nonsignificant to the diagnostic performance of hs-cTn cut points
- The treating providers were blinded to the hs-cTnT and the HEART scores.
- Combination of a low-risk HEART score and an initial hs-cTnT measure < LOQ yielded high sensitivity and NPV for MACE even among early presenters
- Sensitivity analyses testing a variety of assumptions yielded similar diagnostic performance of the LOQ and the 0/1-h algorithm when used with or without clinical variables
Limitations:
- Although the study was conducted across eight US EDs, the sites were mostly urban academic medical centers and therefore results may not be generalizable to all US ED settings
- The cohort had a higher MACE rate than has been reported in many prior US studies
- The low PPV with the addition of the HEART score could lead to over-triage as well as over-testing
- Lost to follow-up rate was small, but the investigators were unable to contact <4% (56/1442) of the cohort, which may have caused misclassification and underestimation of MACE
- This study utilized only the Roche hs-cTnT assay, and results cannot be extrapolated to other hs-cTn assays
- Classification of patients as early or late presenters was susceptible to patient recall bias
- Subgroup analysis of early presenters was limited to 516 patients (35% of the total population), meaning the confidence intervals for this group are somewhat broader than the overall population
- No patient was managed according to the use of the hs-cTnT assay or the strategies evaluated, which means efficacy and safety of hs-cTnT strategies still need to be prospectively evaluated in the setting of implementation into clinical practice in a US population.
Discussion:
- This multisite, prospective study of hs-cTnT early rule out strategies in US ED patients suggests that adding a HEART score to these strategies improves safety
- When used alone, a single hs-cTnT measure <LOQ had insufficient NPV and sensitivity to rule-out 30-day MACE
- Interestingly, the addition of an ECG alone did not improve the diagnostic performance of either of the hs-cTnT strategies
- The HEART score, which includes ECG findings in its scoring along with other historical features, was able to improve the diagnostic performance of both hs-cTnT strategies in this analysis.
- The addition of a low-risk HEART score to an initial hs-cTnT value <LOQ, increases the NPV for 30-day cardiovascular death and MI to 99.7% and to 100% in early presenters, but with fewer patients to be ruled out
- The addition of a low-risk HEART score to a hs-cTnT 0/1-h algorithm in the rule-out range, increases the NPV for 30-day cardiovascular death and MI to 99.3%
- Among late presenters (those with chest pain onset > 3 hours), use of the LOQ at arrival for the cutoff used (<6 ng/l) yielded a 98.2% NPV for 30-day MACE
- This is the first large multicentre US study, which demonstrates that the hs-cTnT 0/1-h algorithm had a NPV of 99.0% for index visit MI, similar to prior (European) studies
- None of the patients with 30-day MACE who had initial hs-cTnT measures < LOQ or were in the rule-out range of the 0/1-h algorithm had an ischemic ECG as determined by their treating provider
- It’s worth mentioning that many patients had (near) normal levels of creatinine, raising the question what these results would look like in patients with decreased renal function
Author Conclusion: “In a prospective multisite US cohort, an initial hs-cTnT <LOQ combined with a low-risk HEART score was 99% NPV for 30-day MACE. The 0/1-h hs-cTnT algorithm did not achieve a NPV >99% for 30-day MACE when used alone or with a HEART score.”
Clinical Take Home Point: Addition of the HEART score to an initial hs-TnT below the limit of quantification improves sensitivity and NPV for cardiac events increasing patient safety, but this strategy does rule-out fewer patients.
Guest Post By:
Benjamin M. Gerretsen, MD
Emergency Medicine
Erasmus University Medical Center
Leiden, Netherlands
Twitter: @bmgerretsen
Barbra Backus, MD
Emergency Physician
Erasmus University Medical Center
Netherlands
Twitter: @barbrabackus
References:
- Allen et al. Diagnostic Performance of High Sensitivity Cardiac Troponin T Strategies and Clinical Variables in a Multisite United States Cohort. Circulation 2021 (ahead of print). PMID 33474976
Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)
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