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Prognostic Marker Importance of Troponin I in Acute Decompensated Heart Failure (ADHF)

Posted in Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Chemical Biology and its relations to Metabolic Disease, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, tagged , , , , , , , on June 30, 2013| 1 Comment »

Troponin I in acute decompensated heart failure: insights from the ASCEND-HF study

 

Writer and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN 

Felker GM, Hasselblad V, Tang WH, Hernandez AF, Armstrong PW, et al.
Eur J Heart Fail. 2012 Nov;14(11):1257-64. http://dx.doi.org/10.1093/eurjhf/hfs110 Epub 2012 Jul 4.

AIMS: We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF.

METHODS: Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes.

RESULTS:

  • Baseline cTnI was undetectable in 22% and
  • elevated above the 99th percentile URL in 50% of subjects.

cTnI levels did not differ based on HF etiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as

  • length of stay (P = 0.01) and
  • worsening HF during the index hospitalization (P = 0.01), but
  • was not associated with worsened post-discharge outcomes at 30 or 180 days.

The relationship between cTnI and outcomes was generally linear and

  • there was no evidence of a threshold effect at any particular level of cTnI.

CONCLUSION:

  • cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and
  • predicts in-hospital outcome, but
  • is not an independent predictor of long-term outcomes.

This reviewer finds the results quite interesting, and the study was done with care.   The Ortho Diagnostics method of cTnI is high-sensitivity assay, so that the lowest measureable level at < 10% CV is manyfold lower than the 4th generation assay.

Prior to the hs-cTNI, the diagnostic cutoff for

  • AMI was 1.0 ng/ml vs
  • the cTnT at 0.1 ng/ml using a ROC curve.

AMI did occur below the ROC cutoff in both cases, but the reasons for elevations other than AMI were determined to be CRF, and this was more accurate (a small probability with the cTnT between 0.085 and 0.1 ng/ml.

However, the findings in this study did indeed exclude symptomatic ACS, or cTnI at the level not > 5x ULN.  [0.17 ng/ml] with the hs-TnI.  The hs-cTnI assay opened up the identification of non-ACS elevation related to cardiomyocyte damage unrelated to plaque rupture, but related to a persistent coronary ischemia, possibly related to cardiomegaly and/or vascular rigidity.

Test Limitations

Troponins are not normally present in serum, so any amount present in serum (measured at the 99th percentile of the upper limit of normal at a 10% imprecision) indicates structural damage to the heart, although not necessarily AMI.

  • Both troponin I (TnI) and troponin T (TnT) are affected by renal insufficiency, but TnT is to a greater extent
  •  100% of TnT is excreted in urine, but 70% of TnI is degraded by vascular endothelium; this means that minor elevations of troponins have to be considered in the context of comorbidities, especially renal impairment, and risk factors
  • Among heart failure patients, the objective parameter of NT-proBNP seems more useful to delineate the “cardiorenal syndrome” than the previous criteria of a clinical diagnosis of heart failure

However, the NT-proBNP is best interpreted by using the log(NT-proBNP)/eGFR with an adjustment.

These investigators used the log(cTnI), which I would not have thought of in this case, but it is important to do because the distribution of the peptide levels in the study population would be nonparametric.  The median values at the time points are not given.  Actually, there are presumably, not definitely, two populations – if you were to infer short- and long-term outcomes measured as 30-days, and 180-days.  That a baseline cTNI was undetectable in 22% of patients is actually not so different than would be found in a random selection from patients presenting to the emergency department.  It should not be a surprise that the test as a single predictor, did not meet the requirement for long-term prediction of outcome, despite agreement with the in-hospital outcome.   This is consistent with the absence of ACS.

[1] Troponins (Cardiac-specific Troponin I and Troponin T).  LH Bernstein.  http://PathologyOutlines.com/Chemistry
[2] Effect of renal function loss on NT-proBNP level variations. LH Bernstein, MY Zions, SA Haq, S Zarich, J Rucinski, B Seamonds, et al.  Clin Biochem 2009; 42(10-11):1091-1098. ICID: 937529  http://dx.doi.org/10.1016/j.clinbiochem.2009.02.027.
[3] Enhancing the diagnostic performance of troponins in the acute care setting. SA Haq, M Tavakol, S Silber, L Bernstein, J Kneifati-Hayek, M Schleffer, et al.  J Emerg Med 2008; x:x  ICID: 937619
http://www.nymethodistemergencymedicine.com/program/research.html   
[4] Comparison of test characteristics of cardiac troponin T in patients with normal renal function and chronic renal failure evaluated in the emergency department. S Silber, L Melniker, E Haines, LH Bernstein.
Academic Emergency Medicine 2006; 13(5):S1186-187.   ICID: 939943     http://www.nymethodistemergencymedicine.com/program/research.html
[5}  The ACC/ESC Recommendation for 99th Percentile of the Reference Normal Troponin I Overestimates the Risk of an Acute Myocardial Infarction: a novel enhancement in the diagnostic performance of troponins. “6th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke.” S Haq, M Tavakol, LH Bernstein, J Kneifati-Hayek, M Schlefer, S Silber, T Sacchi, J Pima. Circulation 2005; 111(20):e313-313. ICID: 939931
http://pt.wkhealth.com/pt/re/circ/toc.00003017-200505240-00000.htm
[6]  Minor elevations in troponin T values enhance risk assessment in emergency department patients with suspected myocardial ischemia: analysis of novel troponin T cut-off values. SW Zarich, K Bradley, ID Mayall, LH Bernstein.
Clin Chim Acta 2004; 343(1-2):223-229.  ICID: 825515     http://www.ncbi.nlm.nih.gov/pubmed/15115700
[7]  GOLDmineR: improving models for classifying patients with chest pain. L Bernstein, K Bradley, SW  Zarich.  Yale J Biol Med  2002; 75(4):183-198.  ICID: 825624
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588788/

Other related articles published on this Open Access Online Scientific Journal, include the following:

High-Sensitivity Cardiac Troponin Assays- Preparing the United States for High-Sensitivity Cardiac Troponin Assays

Reporter: Larry Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2013/06/13/high-sensitivity-cardiac-troponin-assays/

Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays

Larry Bernstein and Aviva Lev-Ari
http://pharmaceuticalintelligence.com/2013/05/18/dealing-with-the-use-of-the-hs-ctn-assays/

Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA
Aviva Lev-Ari
http://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

  • Redberg’s conclusions are correct for the initial screening. The issue has been whether to do further testing for low or intermediate risk patients.
  • The most intriguing finding that is not at all surprising is that the CCTA added very little in the suspect group with small or moderate risk.
  • The ultra sensitive troponin threw the ROC out the window
  • The improved assay does pick up minor elevations of troponin in the absence of MI.

Critical Care | Abstract | Cardiac ischemia in patients with septic …
Aviva Lev-Ari
http://pharmaceuticalintelligence.com/2013/06/26/critical-care-abstract-cardiac-ischemia-in-patients-with-septic/

  • refer to:  Cardiac ischemia in patients with septic shock randomized to vasopressin or norepinephrine

Mehta S, Granton J,  Gordon AC, Cook DJ, et al.
Critical Care 2013, 17:R117   http://dx.doi.org/10.1186/cc12789
Troponin and CK levels, and rates of ischemic ECG changes were similar in the VP and NE groups. In multivariable analysis

  • only APACHE II was associated with 28-day mortality (OR 1.07, 95% CI 1.01-1.14, p=0.033).

Assessing Cardiovascular Disease with Biomarkers
larryhbern
http://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

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