Brain Natriuretic Peptide, Troponin and D-Dimer Levels in Relation to Long-Term Functional Outcome after a First Episode of Pulmonary Embolism: Results from the E.L.O.P.E. Study
Authors: Kahn Susan R , Hirsch Andrew , Beddaoui Margaret , Akaberi Arash , Anderson David , Wells Philip S , Rodger Marc , Solymoss Susan , Kovacs Michael J. , Rudski Lawrence , Shimony Avi , Dennie Carole , Rush Chris , Geerts William H. , Hernandez Paul , Aaron Shawn , Granton John T 
Published: October 2019

Abstract
Background: Biomarkers such as brain natriuretic peptide (BNP), high-sensitivity cardiac troponin (hsTnT) and d-dimer (DD) are useful for acute or short-term risk stratification after pulmonary embolism (PE) to predict right ventricular dysfunction, recurrent PE or death. However, whether acute or convalescent levels of these biomarkers predict longterm functional limitation after PE has not been evaluated. To address this knowledge gap, we performed the ELOPE (Evaluation of Longterm Outcomes after PE) Study, a prospective, observational, multicenter cohort study of long-term outcomes after acute PE (www.clinicaltrials.gov NCT01174628).
Objectives: To describe levels of NT-proBNP, hsTnT and d-dimer at baseline and 6 months in patients with acute PE, and to assess the relationship between biomarker levels and functional status at 1 year.
Methods: Patients ³ 18 years old with a 1st episode of acute PE diagnosed within the previous 10 days screened at 5 Canadian recruiting centers were potentially eligible to participate. Exclusion criteria were subsegmental-only PE, preexisting severe cardiopulmonary comorbidity, previous proximal DVT, contraindication to CT pulmonary angiography (CTPA), life expectancy <1 year, unable to read questionnaire in English and French or to attend follow-up visits, and unable or unwilling to consent.
Patients attended study visits at baseline, 1, 3, 6 and 12 months. Blood samples to assay NT-proBNP (serum), hsTnT (serum) and DD (plasma) were obtained at baseline and 6 months. NT-proBNP and hsTnT were measured using the cobas® 8000 modular analyzer (Roche Diagnostics, Laval, Quebec); cut-off for normal is <300pg/mL and <15ng/mL, respectively. DD was measured with the immune-turbidimetric STA®-Liatest® assay run on a STA® analyser (DiagnosticaStago, Asnieres, France); cut off for normal is <500ug FEU/L.
The primary outcome for the ELOPE Study was maximal aerobic capacity as defined by peak oxygen uptake (VO2) as a percent of predicted maximal VO2 (VO2max) on a cardiopulmonary exercise test (CPET) performed at the 1-year visit, with <80% predicted VO2max considered abnormal, as per American Thoracic Society guidelines.
For each biomarker at baseline and 6 months, we calculated median (IQR) values, % of values above the cutoff, and univariate relative risk (RR) for VO2max <80% predicted on 1-year CPET (see Table). Multivariate logistic regression analysis (multiple log-binomial regression) was done, adjusted for age and sex, to assess the relationship between NT-proBNP, hsTnT, DD and 1-year CPET result.
Results: 984 patients were screened for participation; of these, 150 were eligible and 100 (67%) consented to participate. Mean (SD) age was 50 (15) years, 57% were male, 80% were outpatients, and 33% had concomitant DVT. PE was provoked in 21% and unprovoked in 79%; none were cancer-related.
Table. Median biomarker values, % of values above cutoff, and univariate RR for VO2max <80% predicted on 1-year CPET Variable NT-proBNP (pg/mL) hsTroponin T (ng/L) D-Dimer (ug FEU/L) Visit Date Baseline 6 months Baseline 6 months Baseline 6 months Median (IQR) 46 (21, 98) 37 (21, 81) 6 (3, 11) 5 (3, 8) 1230 (550, 2050) 200 (110, 370) N (%) > cut-off* 8 (10.1%) 4 (5.8%) 8 (10.1%) 5 (7.2%) 62 (78.5%) 8 (11.6%) Univariate RR for VO2 max <80% predicted at 1 year 1.74(0.99, 3.04) 1.15(0.41, 3.18) 1.34(0.66, 2.71) 0.44(0.07, 2.57) 1.42(0.66, 3.06) 0.84(0.33, 2.14) *Cut-offs: see Methods
In a multiple model adjusted for age and sex, baseline NT-proBNP >300 pg/mL was associated with a relative risk (RR) of 2.31 (95% CI 1.10, 4.86; p=0.027) for VO2max <80% predicted on 1-year CPET, whereas DD and hsTnT did not influence this risk.
Conclusion: In a prospective cohort of patients with a first episode of PE without preexisting severe cardiopulmonary comorbidity, baseline NT-proBNP >300 pg/mL predicted a greater than 2-fold increased risk of abnormal CPET at 1 year after PE. This finding may allow early identification of PE patients at increased risk of poor longterm outcome after PE. Further analyses are in progress to assess the relationship between changes in biomarker levels from baseline to 6 months and 1-year CPET result.
Funding: Canadian Institutes of Health Research (MOP-93627)

Disclosures
Wells: BMS/Pfizer: Research Funding; Bayer: Honoraria.