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Impact of the U.S. FDA regulatory approach not to report high-sensitivity cardiac troponin T concentrations below 6 ng/l on the ESC 0/1-hour algorithm for rule-out/in of acute myocardial infarction

Session Poster session 5

Speaker Raphael Twerenbold

Event : ESC Congress 2017

  • Topic : coronary artery disease, acute coronary syndromes, acute cardiac care
  • Sub-topic : Non-ST-Elevation Myocardial Infarction (NSTEMI)
  • Session type : Poster Session

Authors : R Twerenbold (Basel,CH), P Badertscher (Basel,CH), E Giannitsis (Heidelberg,DE), B Lindahl (Uppsala,SE), M Rubini Gimenez (Basel,CH), J Boeddinghaus (Basel,CH), T Nestelberger (Basel,CH), C Puelacher (Basel,CH), O Miro (Barcelona,ES), FJ Martin-Sanchez (Madrid,ES), B Morawiec (Katowice,PL), S Osswald (Basel,CH), T Reichlin (Basel,CH), C Mueller (Basel,CH)

R. Twerenbold1 , P. Badertscher1 , E. Giannitsis2 , B. Lindahl3 , M. Rubini Gimenez1 , J. Boeddinghaus1 , T. Nestelberger1 , C. Puelacher1 , O. Miro4 , F.J. Martin-Sanchez5 , B. Morawiec6 , S. Osswald1 , T. Reichlin1 , C. Mueller1 , 1University Hospital Basel - Basel - Switzerland , 2University Hospital of Heidelberg - Heidelberg - Germany , 3Uppsala Clinical Research Center - Uppsala - Sweden , 4Hospital Clinic de Barcelona - Barcelona - Spain , 5Hospital Clinic San Carlos - Madrid - Spain , 6Medical University of Silesia - Katowice - Poland ,

European Heart Journal ( 2017 ) 38 ( Supplement ), 1000

Background: High-sensitivity cardiac troponin T (hs-cTnT) has been approved by the Food and Drug Administration (FDA) as the first clinically available hs-cTn assay in the United States of America (U.S.). Due to regulatory differences regarding analytical aspects of the assay in the U.S. and Europe, hs-cTnT concentrations below 6 ng/l (limit of quantification) are not reported in the U.S. while concentrations down to 3 ng/l are reported in Europe. This regulatory limitation might weaken the efficacy and safety of rapid rule-out and rule-in protocols derived in Europe as they include hs-cTnT concentrations below 6 ng/l for rapid rule-out of acute myocardial infarction (AMI).

Purpose: We aimed to assess the clinical impact of reporting hs-cTnT concentrations only down to 6 ng/l on the safety and efficacy of the adapted European Society of Cardiology (ESC) 0/1h-hs-cTnT-algorithm.

Methods: In a prospective international multicentre diagnostic study (APACE) enrolling patients presenting with suspected NSTEMI to the ED, hs-cTnT was determined at baseline and after one hour using Elecsys hs-cTnT reporting concentrations down to 3 ng/l. Patients presenting with STEMI were excluded. The final diagnosis was centrally adjudicated by two independent cardiologists based on hs-cTnT. Safety of the 0/1h-algorithm was quantified as the negative predictive value (NPV) and sensitivity for AMI in the rule-out group, efficacy as the percentage of all patients assigned to either the rule-out or rule-in group within one hour. The 0/1h-algorithm was applied twice: A) using the original ESC rule-out pathway with hs-cTnT concentrations reported down to 3ng/l and B) using a minimally adapted rule-out pathway (direct rule-out-criteria of hs-cTnT <5 ng/l replaced by <6ng/l) with hs-cTnT concentrations trimmed below 6ng/l (simulating the U.S. scenario). Findings were externally validated in a second diagnostic multicenter study (TRAPID-AMI).

Results: Among 3267 recruited patients, prevalence of NSTEMI was 16% (n=517). Safety, quantified as the NPV (99.8% (95% CI, 99.5–100) for both approaches, p=0.994) and sensitivity (99.4% (95% CI, 98.3–99.9) for both approaches, p=1.0) was very high for the original European approach as well as the modified U.S. approach (Figure 1). Both approaches allowed rapid rule-out or rule-in of AMI within one hour in three patients out of four (76.7% versus 77.0%, p=0.774). Using the modified U.S. approach, 13 patients (0.4%) were downgraded (three from rule-in to observe/rule-out and ten from observe to rule-out) with no additional incorrectly ruled-out NSTEMI-patient. Highly comparable findings could be observed in the external validation cohort.

Conclusion: The regulatory approach of the FDA to report hs-cTnT concentrations only down to 6ng/l (instead of 3ng/l as in Europe) seems to have no relevant impact on the high safety and efficacy of the 0/1h-algorithm originally derived in Europe after minor adaptions to the U.S.

Figure 1

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