Prognostic Value in Acute Coronary Syndrome

In addition to significant diagnostic value in ACS, H-FABP has been consistently and robustly shown to offer huge value in the long term prognosis of such patients – even when compared to a high sensitivity Troponin assay.

“Heart-type fatty acid-binding protein predicts long-term mortality after acute coronary syndrome and identifies high-risk patients across the range of troponin values” 8

Kilcullen N, Viswanathan K, Das R, Morrell C, Farrin A, Barth JH, Hall AS; EMMACE-2 Investigators. J. Am. Coll. Cardiol. 2007;50(21):2061-7.

“H-FABP provides direct evidence not only of acute myocyte necrosis, but also of myocardial ischemia.”

Kilcullen (JACC 2007) published the details of a prospective observational study in the Journal of American College of Cardiology 2007 detailing a cohort of 1448 patients admitted with confirmed ACS across 11 hospitals in the UK. The patients had both troponin I (Beckman Accu TnI) and H-FABP measured from a single blood sample taken 12-24 hours after ACS symptom onset. Upon follow-up of patients for 1 year, it was demonstrated that raised concentrations of H-FABP are strongly predictive of mortality after ACS and H-FABP was able to identify patients at high risk across the full range of TnI concentrations. Patients who were negative for both H-FABP and troponin I at 6 months exhibited 0% mortality and so could be deemed as very low risk. However, patients that were positive for H-FABP and negative for troponin had a significantly higher risk of death after 1 year, compared to patients who were H-FABP negative (fig. 5).

H-FABP predicts 1-year mortality after ACS: even in TnI- patients at 12-24h

Fig 5: Kaplan-Meier mortality curves for patients with either TnI≤0.06 μg/l (unstable angina) or TnI>0.06 μg/l (MI inclusive of STEMI/BBBMI) according to the H-FABP cut-off value of 5.8μg/l.

These individuals were followed up for 6 years and the pattern remains very similar except that the troponin negative, H-FABP positive group of patients exhibit the highest mortality after 6 years (fig 6) (Pearson et al., 20109). Not only is H-FABP an independent prognostic marker but it identifies high-risk patients who are considered to be troponin negative.

H-FABP predicts 6-year mortality after ACS: even in TnI- patients at 12-24h

Fig 6: Kaplan-Meier mortality curves for patients with either TnI≤0.06 μg/l (unstable angina) or TnI>0.06 μg/l (MI inclusive of STEMI/BBBMI) according to the H-FABP cut-off value of 5.8μg/l.

“Heart-type fatty acid-binding protein predicts long-term mortality and re-infarction in consecutive patients with suspected acute coronary syndrome who are troponin-negative” 10

Viswanathan K, Kilcullen N, Morrell C, Thistlethwaite SJ, Sivananthan MU, Hassan TB, Barth JH, Hall AS. J. Am. Coll. Cardiol. 2010;55(23): 2590-8.

“H-FABP is a marker of myocardial ischemia even in the absence of frank necrosis.”

In an extension of this study, Viswanathan et al., (JACC 2010) again showed that H-FABP concentration was an independent predictor of death or MI after multivariate adjustment in consecutively admitted patients with suspected ACS (n= 1,080). STEMI patients were excluded and in troponin-negative patient results were divided into quartiles depending on H-FABP concentration. Table 1 shows increasing risk in quartiles 2, 3 and 4 compared with quartile 1, with a very significantly increased event rate in patients with H-FABP concentrations above 6.48μg/l. This long-term prognostic value of H-FABP in troponin-negative patients was found to be independent of age and serum creatinine.

Hazard Ratios for Death or MI Stratified by H-FABP results among Troponin-Negative patients

Quartile Unadjusted HR(95% CI) pValue
1 H-FABP 0.15-3.26 μg/l 1.00 <0.001
2 H-FABP 3.27-6.48 μg/l 3.46 (1.69-7.10) <0.001
3 H-FABP 6.49-12.77μg/l 11.20 (4.95-25.36) <0.001
4 H-FABP 12.78-151.0 μg/l 16.64 (2.21-125.51) 0.006
Adjusted for Age and Serum Creatinine Adjusted HR (95% CI) pValue
1 H-FABP 0.15-3.26 μg/l 1.00 0.01
2 H-FABP 3.27-6.48 μg/l 1.55 (0.72-3.36) 0.26
3 H-FABP 6.49-12.77μg/l 3.12 (1.11-8.76) 0.03
4 H-FABP 12.78-151.0 μg/l 16.67 (2.19-127.06) 0.007
Table 1: Hazard Ratios for Death or MI stratified by H-FABP results among troponin-negative patients

Figure 7 also highlights that increased H-FABP concentration confers increased risk. Specifically, patients with H-FABP concentrations >6.48μg/l had significantly increased risk of adverse events. Among troponin-negative patients, the cut-off of 6.48μg/l identified patients at very high risk of adverse outcomes independent of patient age and serum creatinine levels.

Increased H-FABP concentrations confers increased risk after ACS

Fig 7: Kaplan-Meier event-free survival curves for death or MI in the 4 groups of patients on the basis of H-FABP concentrations

In addition this research group measured TnI-Ultra (high sensitivity) in the cohort and demonstrated that the prognostic value of elevated H-FABP is additive to troponin in low- and intermediate-risk patients with suspected ACS. They also reported that H-FABP is a marker of ischemia even in the absence of necrosis.

Kilcullen et al. (2007) described the mortality and the adjusted multivariable prognostic value of the H-FABP clinical cut-off across a range of ACS subtypes defined by ECG in conjunction with troponin. This demonstrated the additive value of H-FABP, particularly for ACS subtypes such as unstable angina, traditionally considered to be associated with a low long-term risk. Thus H-FABP can identify not only STEMI and NSTEMI but also unstable angina patients and represents a true global ACS biomarker (table 2).

H-FABP – Value in Unstable Angina

Unstable Angina NSTEMI STEMI
All Cause Mortality
H-FABP negative (5.8μg/l) 2.1% (2) 4.8% (9) 0% (0)
H-FABP positive (5.8μg/l) 22.9% (19) 26.1% (189) 23.0% (77)
p Value 0.006 0.004 *
ECG No No Yes
Troponin No Yes Yes
H-FABP Yes Yes Yes
Table 2: All-Cause mortality (No. of deaths in brackets) according to H-FABP diagnostic “cut-off” with hazard ratio adjusted using GRACE risk factors plus hs-CRP with TnI as an additional continuous variable

“Prognostic utility of Heart-type fatty acid-binding protein in patients with acute coronary syndromes” 12

O’Donoghue M, de Lemos JA, Morrow DA, Murphy SA, Buros JL, Cannon CP, Sabatine MS. Circulation. 2006;114(6):550-7.

“Elevation of H-FABP is associated with an increased risk of death and major cardiac events in patients presenting across the spectrum of ACS and is independent of other established clinical risk predictors and biomarkers.”

These studies confirm results from an earlier study by O’Donoghue et al. (2006) that included 2287 patients from the OPUS-TIMI 16 trial who were followed up for 10 months for major cardiac events including all-cause mortality, nonfatal MI, new or worsening congestive heart failure (CHF) and the composite of these end points. In addition recurrent ischemia requiring either rehospitalisation or urgent revascularisation was included. Blood was collected from patients at enrolment and the mean time from onset of chest pain to randomisation was 41±20hours.

Patients with an elevated level of H-FABP at baseline (mean 41±20 hours after chest pain) had a significantly higher clinical event rate over 10 months of follow up than those with an undetectable H-FABP level (figure 8).

H-FABP predicts Death, AMI & CHF through 10-month follow-up

Fig 8: Cumulative incidence curves for the composite end point of death, MI or CHF through 10-month follow up stratified by H-FABP levels of >8 or ≤8ng/ml

Furthermore, elevated levels of H-FABP were associated with an increased risk of MI or recurrent ischemia by 30days, especially in unstable angina patients, either as their index diagnosis of with a negative troponin I (Biosite).

Again it was noted that elevated levels of H-FABP were associated with the composite of death, MI or CHF through 10 months follow-up in patients who were troponin I negative ( ≤1.5ng/ml) and also in those who were troponin I positive (>1.5ng/ml). Even when a lower threshold of troponin I was used (≤0.1ng/ml), H-FABP remained significantly associated with the risk of death, MI or CHF.

BNP was also measured in the collected samples and it was found that patients with an elevated levels of H-FABP but low plasma BNP, had a >6-fold-higher risk of death and a 5-fold-higher risk of developing CHF. Even in patients with elevated plasma BNP (≥80pg/ml, an elevated H-FABP level was associated with a >2-fold-higher risk of the composite end point including death or CHF.

Importantly, when H-FABP, troponin I and BNP were evaluated simultaneously, H-FABP provided incremental information for risk stratification regardless of baseline troponin or BNP status (Fig 9).

H-FABP is predictive of 10-month adverse outcome, independent of Troponin & BNP

Fig 9: Rates of death, MI or CHF observed through 10 months of follow-up stratified by baseline concentration of BNP, troponin I or H-FABP. BNP+ indicates BNP≥80pg/ml; and Tn+, Biosite troponin I>1.5ng/ml
Value in Pulmonary Embolism

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