Cardiac biomarkers levels predict pulmonary embolism extent on chest computed tomography and prognosis in non-massive pulmonary embolism

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Article

Reference

Cardiac biomarkers levels predict pulmonary embolism extent on chest computed tomography and prognosis in non-massive

pulmonary embolism

VUILLEUMIER, Nicolas, et al .

VUILLEUMIER, Nicolas, et al . Cardiac biomarkers levels predict pulmonary embolism extent on chest computed tomography and prognosis in non-massive pulmonary embolism. Thrombosis and Haemostasis , 2009, vol. 101, no. 6, p. 1176-8

DOI : 10.1160/TH08-12-0815 PMID : 19492165

Available at:

http://archive-ouverte.unige.ch/unige:5484

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Letters to the Editor

Cardiac biomarkers levels predict pulmonary embolism extent on chest computed tomography and prognosis in non-massive pulmonary embolism

Nicolas Vuilleumier¹; Arnaud Perrier²; Jean-Charles Sanchez³; Natacha Turck³; Grégoire Le Gal⁴; Frank Verschuren⁵; Damien Gruson⁶; Noury Mensi¹; Denis Hochstrasser¹; Marc Righini⁷

1Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals and University of Geneva, Switzerland; ²Division of General internal Medicine, Department of Internal Medicine, Geneva University Hospitals and University of Geneva, Switzerland; ³Department of Structural Biology and Bioinformatics, Biomedical Proteomic Research Group, University Medical Centre of Geneva, Switzerland; ⁴Department of Medicine and Chest Diseases; EA 3878 (GETBO), Brest University Hospital, Brest, France; ⁵Emergency Department, Saint-Luc University Hospital, Bruxelles, Belgium; ⁶Department of Laboratory Medicine, Saint-Luc University Hospital, Bruxelles, Belgium; ⁷Division of Angiology and Haemostasis, Geneva University Hospitals and University of Geneva, Switzerland

Correspondence to:

Nicolas Vuilleumier

Division of Laboratory Medicine

Department of Genetics and Laboratory Medicine Geneva University Hospitals and University of Geneva Geneva, Switzerland

Tel.: +41 22 372 9150, Fax: +41 22 372 7390 E-mail: nicolas.vuilleumier@hcuge.ch Financial support:

The study was supported by a grant from the Swiss National Research Foundation (Grant no 3200B0–105988) and was registered with ClinicalTrial.gov, number NCT00117169.

Received: December 15, 2008

Accepted after major revision: March 18, 2009

Prepublished online: May 11, 2009 doi:10.1160/TH08-12-0815

Thromb Haemost 2009; 101: 1176–1178 Dear Sir,

Cardiac biomarkers, such as cardiac troponin I (cTnI), N-ter- minal proBrain Natriuretic Peptide (NT-proBNP), heart-type fatty acid binding protein (H-FABP) and myoglobin have all been described as emergent prognostic markers in pulmonary embolism (PE) (1–3), but, their potential association with anatomical PE clot localisation, a controversial prognostic feature in PE (4, 5), has not yet been reported. We also investigate whether combining the anatomical clot localisation with elevated levels of NT-proBNP and cTnI, recently reported as the most promising biomarkers for outcome prediction in non-massive PE (2), could yield incremental prognostic information in non-massive PE.

Data of the current study are derived from a subgroup analysis involving three out of five tertiary university hospitals involved in an international prospective multicentric study recently published elsewhere (6). Briefly, 166 patients had proven PE on multi-detector-row chest computed tomography (CT) or patho- logical lower limb ultrasonography. Herein, we studied only the 110 patients (48 men, 62 women, median age: 72 years, range:

21–92) with proven non-massive PE on multi-detector-row chest CT. All patients completed a three-months follow-up, and the composite outcome consisting in need for intensive care monitoring on admission, death, hospitalisation attributable either to PE-related complication (defined by PE/deep venous thrombosis [DVT] relapse or major bleeding under anticoagulation) or to dyspnoea with or without chest pain during follow-up (2), was adjudicated by three independent experts who were blinded to the patient outcome. We used a simplified version of the CT pul-

monary angiography (CTPE) index recently developed by Ghanima (7). Accordingly, PE localisation was assessed by a radiologist blinded to the patient outcome and biochemical results and further classified as central (main pulmonary artery), lobar and segmental (including subsegmental) according to the anatomical localisation of intraluminal defects on chest CT.

Blood samples were immediately centrifuged, stored at – 80°C, centralised at the Geneva University Hospital, where all biochemical analyses took place, as described elsewhere (2). We used the previously reported and predefined biomarker cut-offs (2, 8), set at 0.09 ng/ml for cTnI, 300 pg/ml for NT-proBNP, 70 ng/ml for myoglobin and 6 ng/ml for H-FABP.

For continuous variables (expressed as median and range), Kruskal-Wallis rank test was used to assess differences between the three PE anatomical groups (central, lobar and segmental).

Bilateral Fischer Exact test for proportion was performed for nominal variables. Univariate odds ratios (OR) with correspond- ing 95% confidence intervals (95%CI) were used to determine the association between three-months outcome and central PE localisation using logistic regression. Analyses were performed using Statistica™ software (StatSoft, Tulsa, OK, USA). Receiv- ing-operating curve (ROC) analyses were performed using Ana- lyse-It ™ software. A p-value <0.05 was considered as significant.

Overall, median values of cardiac biomarkers were 0.02 ng/

ml (range: 0–0.85) for cTnI, 527 pg/ml (5–18842) for NT- proBNP, 2.95 ng/ml (0.37–28.8) for H-FABP, and 27 ng/ml for myoglobin (6.3–133.3). Upon admission, 28 patients (26%) had central PE, 42 (38%) had lobar PE, and 40 (36%) had segmental PE. The composite outcome was met by 12 patients during three months follow-up (Deaths: 2, relapse TE event: 5, major haem- orrhagic complication: 1, intensive care unit [ICU] monitoring upon admission: 2, admission for dyspnoea with or without chest pain: 2). Patients with central PE had significantly higher levels of cTnI, NT-proBNP and H-FABP, than patients with lobar, or segmental PE localisation, but no such difference was obtained for myoglobin (Table 1). Among patients with central PE (n=28), 86% (24/28) had elevated NT-proBNP values and 60% (17/28) had elevated cTnI values, whereas 5% (4/82) of patients with more distal PE had elevated NT-proBNP (<300 pg/ml) and 11 % (9/82) elevated cTnI value. Those differences were significant (p<0.00001).

Spearman correlation showed a significant association between PE localisation and circulating levels of all cardiac biom-

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Table 1: Median biomarker values according to pul- monary embolism (PE) localisation on chest CT.

arkers (the more proximal the lesion, the higher the plasmatic biomarker levels), but the strength of association was higher for cTnI and NT-proBNP (r=0.44, p< 0.01; and r=0.40, p<0.01, respectively), than for myoglobin (r=0.22, p<0.05) and the association was not significant for H-FABP and r=0.18, p>0.05; respectively). ROC curve analyses showed that all cardiac biomarkers could significantly discriminate between central and non central PE, but cTnI and NT-proBNP were the most discrimina- tory tests with areas under the curve (AUC) of 0.81 (95%CI:

0.72–0.90; p<0.0001) and 0.77 (95%CI: 0.68–0.88; p<0.0001), respectively, compared to 0.69 (95%CI: 0.58–0.80; p=0.0003) for H-FABP and 0.62 (95%CI: 0.5–0.75; p=0.027) for myoglobin. The AUC were significantly different between myoglobin and cTnI (p=0.005) but not between the other biomarkers.

Logistic regression showed a trend to an increased risk in patients with central PE, although not statistically significant (Table 1). On the other hand, having elevated NT-proBNP or cTnI increased the risk of three-months complications by 10.6- and 3.9-fold, respectively (Table 1). Combined with central PE localisation, elevated NT-proBNP and cTnI conferred a three- months risk of complications of 4.4- and 5.1-fold, respectively (Table 1).

The current study results support an association between the degree of vascular obstruction, elevation of cardiac biomarkers and poor prognosis in PE. We assume that the herein reported associations reflect the various degrees of right myocardial strain varying upon the importance of pulmonary blood flow obstruction, which in our study was significantly affected by the clot

anatomical localisation. The reasons why those associations were stronger for cTnI and NT-proBNP compared with H-FABP and myoglobin are unclear. However, those results corroborate previous studies showing that mostly natriuretic peptides (and to a less extend cTnI) were correlated with right ventricular dys- function (8, 9) and predictive of poor prognosis in PE (2). Alto- gether, these observations suggest that significant prognostic differences can be expected among the various cardiac biomarkers currently under investigation as risk stratification tool in PE. These findings extend to NT-proBNP and cTnI prior observations showing that D-dimer elevation reflected the degree of vascular obstruction and prognosis in PE (10–11).

Central PE localisation was not a significant prognostic fac- tor in this study, although we did see a trend in that direction. This is most probably due to the small patient sample. Also, our results indicate that combining the anatomical clot localisation with an elevated level of NT-proBNP did not add any incremental prognostic value when compared to NT-proBNP alone. On the other hand, combining cTnI with central clot localisation provided a marginal increment of cTnI prognostic value. This may be due to the closer link between right ventricular dysfunc- tion (RVD), clot burden (higher in central PE) and NT-proBNP elevation. Since NT-proBNP appears highly sensitive for RVD, it is not unexpected that clot localisation does not increase predictive accuracy.

Besides the small size of our study sample, one limitation is that we chose to use a simplified version of the CT pulmonary angiography (CTPA) index proposed by Ghanima (7), instead of Median biomarker values according to PE localisation on chest CT *P values

Central Lobar Segmental Central vs Lobar

Central vs Segmental

Lobar vs Segmental NT-proBNP; pg/ml

IQR Range

1380 552–6969 160–18842

446 177–1436 5–9379

198 77–834 8–6682

0.004 <0.0001 0.73

cTnI; ng/ml IQR Range

0.1 0.04–0,24 0.007–0.85

0.01 0.01–0.04 0–0.26

0.01 0.004–0.03 0–0.32

<0.0001 <0.0001 0.73

H-FABP; ng/ml IQR Range

4.2 2.3–6 0.4–29

2.5 1.4–4 0.5–12

2.8 1.6–4.3 0.4–10

0.02 0.07 1

Myoglobin; ng/ml IQR

Range

36 22–57 8–126

29.8 21–36 21–133

25 17–35 8–83

0.38 0.08 1

Outcome prediction according to PE clots localisation, elevation of cTnI and NT-proBNP, alone and in combination with PE clot localisation

Odds Ratio (univariate) 95% Confidence interval

**P value

Central PE NT-proBNP + cTnI +

Central PE and NT-proBNP + Central PE and cTnI +

3.5 10.6

3.9 4.4 5.1

1–11.8 1.3–84.4 1.1–13.4 1.3–15.4 1.4–18.7

0.07 0.003

0.03 0.02 0.01

*P-value according to Kruskall-Wallis test. ** P-value according to Bilateral exact Fisher test. IQR: interquartile range. NT-proBNP +: NT-proBNP value above 300 pg/ml. cTnI +: cTnI value above 0.09 ng/ml.

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