Diagnosis of pulmonary embolism (PE) is a challenge, being based on clinical suspicion or probability. It has an estimated annual incidence of 1 out of 1000 patients, which increases with age (mean age 62 years) in both sexes.1

PE has high morbidity and mortality, both early and late. Overall mortality is 7–11%, 10% of deaths occurring within an hour of hospital admission; it is 15% at three months and reaches around 50% in patients who present in shock at admission.1–4 Factors contributing to these alarming figures include inadequate primary and secondary prevention, the wide spectrum of clinical presentation and the high rate of recurrence of thromboembolic events.

Early diagnosis and risk stratification are thus essential in adjusting therapy to individual patient risk. The European Society of Cardiology (ESC) recommends classifying PE patients into three risk categories (low, intermediate or high), based on clinical criteria (presence or absence of shock and hypotension), biomarkers of myocardial injury (troponins) and echocardiographic evidence of right ventricular (RV) dysfunction (Figure 1).

Figure 1.

Risk stratification for early (30-day) mortality in patients with pulmonary embolism.

(0.18MB).

Adapted from the ESC guidelines.5

Patients with high-risk PE present mortality of >15% at 30 days, and are indicated for thrombolysis based on available evidence.5 Those at intermediate risk (hemodynamically stable, with elevated troponin and/or RV dysfunction) include a wide variety of patients with differing forms of clinical presentation and prognosis, for whom early mortality ranges between 3 and 15%.5 In this gray area, thrombolysis has shown no benefit in terms of mortality, although it does appear to improve morbidity and length of hospital stay, and so therapeutic options vary.5 There is an obvious need for more accurate risk stratification, based on clinical and/or laboratory factors that have greater discriminatory power and are thus better predictors of prognosis.

Various biomarkers have been studied in recent years for both diagnosis and stratification of risk and prognosis in PE patients, including natriuretic peptides such as N-terminal brain natriuretic peptide (NT-proBNP) that play an important role in cardiovascular, endocrine and renal homeostasis.6

Initially linked to left ventricular overload and wall stress, particularly in patients with heart failure and left ventricular dysfunction, release of NT-proBNP has since been demonstrated in RV dysfunction,7 and levels of this biomarker in PE correlate with the severity of RV dysfunction, hemodynamic compromise and prognosis.5,8–10 However, the role of NT-proBNP in the management of PE patients is poorly defined and remains the subject of debate.

The aims of this study were to characterize a sample of patients with acute PE according to NT-proBNP level at hospital admission and to assess the impact of this biomarker on short-term evolution.

We performed a retrospective analysis of consecutive patients admitted to the coronary care unit between July 2005 and December 2008 with a diagnosis of acute PE (established according to the diagnostic algorithms proposed by the ESC).5 We assessed demographic characteristics, personal history, cardiovascular risk factors, etiological and predisposing factors for PE, form of clinical presentation, serum levels of NT-proBNP, troponin I and creatinine at admission, electrocardiographic alterations (complete or partial right bundle branch block, T-wave inversion in V1-V4 and S1Q3T3 pattern) and transthoracic echocardiographic data (left ventricular ejection fraction [LVEF], right chamber dilatation, pulmonary artery systolic pressure [PASP] and presence of right chamber thrombi), Geneva and Wells scores, and therapy.

Based on the median NT-proBNP (pg/ml) at admission, patients were divided into two groups: Group 1

Ninety-one patients, mean age 69±16.4 years (51.6% aged ≥75 years), 53.8% male, were analyzed. Of the total sample, 41.8% had no etiological or predisposing factors for PE, 38.5% had transient factors, and 19.8% had cancer. On admission, most patients had intermediate probability of PE according to both the revised Geneva score and the Wells score (65.9% and 72.5%, respectively). Most patients (84.6%) also had intermediate-risk PE according to the ESC guidelines.5 Only 9.9% presented high risk (shock or hypotension) and 5.5% had low risk.

Mean serum troponin I was 0.3μg/l (0.02–1.73), with a median of 0.06μg/l; mean creatininemia was 1.3mg/dl (0.5–5.2), with a median of 1.1mg/dl; and mean NT-proBNP was 7429.9pg/ml (23–57893), with a median of 2440pg/ml.

Those in Group 2 (61 patients), based on median NT-proBNP assessed at admission and before institution of therapy, were significantly older and more had a history of heart failure and chronic kidney disease (Table 1). On initial clinical evaluation, Group 2 patients had more tachypnea, less chest pain and higher creatininemia. On echocardiographic assessment, Group 2 patients also more frequently had right chamber dilatation, lower LVEF, and a tendency for PASP ≥60mmHg (Table 2).

Treatment did not differ significantly between the two groups.

Regarding the studied endpoints, Group 2 patients needed more catecholamine support, more frequently had the combined endpoint and had higher in-hospital and 30-day mortality (Table 3).

By ROC curve analysis, NT-proBNP had excellent discriminatory power for 30-day all-cause mortality, with an area under the curve (AUC) of 0.848, p=0.003 (Figure 2). The best NT-proBNP cut-off value was 4740pg/ml.

Figure 2.

ROC curve showing relation between NT-proBNP and 30-day all-cause mortality.

(0.08MB).

In this study, elevated NT-proBNP levels at admission in patients with PE correlated significantly with worse in-hospital evolution and worse prognosis at three months.

These results corroborate those of other published studies that have demonstrated a lower rate of in-hospital complications and better short-term prognosis in PE patients with low NT-proBNP levels.10–12

Most of the study population presented intermediate-risk PE, the gray area in which there is uncertainty regarding therapeutic approach and aggressiveness of therapy. It is probably in this large patient group that biomarkers such as NT-proBNP will prove most useful by enabling more accurate risk stratification and guiding therapeutic decisions.

The short-term prognosis of patients with PE depends mainly on their hemodynamic status at admission and underlying conditions. Many factors besides natriuretic peptides have been shown to have prognostic value in the short term, including echocardiographic criteria of overload and RV dysfunction, as well as clinical parameters.13

In our study, Group 2 patients, with NT-proBNP ≥ median, also had significantly more heart failure and chronic kidney disease and were older, variables that have been shown to be associated with elevated NT-proBNP. This group also showed a greater incidence of tachypnea and had higher creatininemia on initial assessment.

There is debate regarding the biomarkers that should be measured. In a study comparing various biomarkers (NT-proBNP, troponin I, myoglobin, D-dimers and heart-type fatty acid-binding protein) in patients classified with non-massive PE, NT-proBNP was the best predictor of adverse events at three months.14

A recent meta-analysis of 32 studies, including 1127 patients with PE, again demonstrated the ability of NT-proBNP to predict adverse events, and also concluded that in patients with higher NT-proBNP, concomitant elevation of troponins added prognostic value.15

The inclusion of NT-proBNP with other recommended clinical, laboratory and echocardiographic parameters when evaluating patients with PE may provide valuable additional information for risk stratification and follow-up, with improved sensitivity and positive predictive value for assessment of clinical deterioration and short-term and long-term prognosis.16 Agterof et al. have gone so far as to suggest that PE patients who are hemodynamically stable and with low NT-proBNP levels (<500pg/ml) can be treated as outpatients, with no increase in complications or adverse events, which if confirmed would bring considerable benefits in both clinical and economic terms.17

Besides the importance of the absolute value of NT-proBNP level at admission, Kostrubiec et al. have shown that persistent NT-proBNP elevation 24hours after diagnosis (reduction of <50% from initial values) predicts higher mortality at 30 days.12 Serial measurement of NT-proBNP may thus provide additional prognostic information compared to a single measurement at admission, as well as being an indicator of therapeutic efficacy. In the same study, the clinical efficacy of thrombolysis was associated with a significant reduction in serum levels of this biomarker.12 It should be noted that since the mean half-life of NT-proBNP is 48–72hours, daily measurement of NT-proBNP is not indicated.

However, the results of previous studies are conflicting, probably due to small sample sizes, use of varying NT-proBNP cut-offs, measurement at different stages of presentation and clinical evolution and analysis of different endpoints.

Despite its proven relevance for prognostic assessment, routine NT-proBNP measurement is not a generally accepted strategy for patients with PE.

This work corroborates data from previous studies and meta-analyses that point to a potentially important role for NT-proBNP as an indicator of short-term prognosis in patients with PE. Prospective multicenter studies are essential to determine conclusively this biomarker's prognostic impact.

To summarize, it can be concluded that measurement of NT-proBNP at hospital admission of patients with suspected PE could be a useful parameter to monitor in-hospital evolution and to assess short-term prognosis.

The authors have no conflicts of interest to declare.