Published ahead of print on June 12, 2008, doi:10.1164/rccm.200803-459OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200803-459OC
Brain-Type Natriuretic Peptide Levels in the Prediction of Adverse Outcome in Patients with Pulmonary EmbolismA Systematic Review and Meta-analysis1 Section of Vascular Medicine, Department of General Internal Medicine–Endocrinology, Leiden University Medical Center, Leiden, The Netherlands Correspondence and requests for reprints should be addressed to M.V. Huisman, M.D., LUMC (C4-70), Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands. E-mail: m.v.huisman{at}lumc.nl
Rationale: The potential role of elevated brain-type natriuretic peptides (BNP) in the differentiation of patients suffering from acute pulmonary embolism at risk for adverse clinical outcome has not been fully established. Objectives: We evaluated the relation between elevated BNP or N-terminal–pro-BNP (NT–pro-BNP) levels and clinical outcome in patients with pulmonary embolism. Methods: Articles reporting on studies that evaluated the risk of adverse outcome in patients with pulmonary embolism and elevated BNP or NT–pro-BNP levels were abstracted from Medline and EMBASE. Information on study design, patient and assay characteristics, and clinical outcome was extracted. Primary endpoints were overall mortality and predefined composite outcome of adverse clinical events. Measurements and Main Results: Data from 13 studies were included. In 51% (576/1,132) of the patients, BNP or NT–pro-BNP levels were increased. The different analyses were performed in subpopulations. Elevated levels of BNP or NT–pro-BNP were significantly associated with right ventricular dysfunction (P < 0.001). Patients with high BNP or NT–pro-BNP concentration were at higher risk of complicated in-hospital course (odds ratio [OR], 6.8; 95% confidence interval [CI], 4.4–10) and 30-day mortality (OR, 7.6; 95% CI, 3.4–17). Patients with a high NT–pro-BNP had a 10% risk of dying (68/671; 95% CI, 8.0–13%), whereas 23% (209/909; 95% CI, 20–26%) had an adverse clinical outcome. Conclusions: High concentrations of BNP distinguish patients with pulmonary embolism at higher risk of complicated in-hospital course and death from those with low BNP levels. Increased BNP or NT–pro-BNP concentrations alone, however, do not justify more invasive treatment regimens.
Key Words: venous thromboembolism • brain-type natriuretic peptide • right ventricular dysfunction • mortality • complicated clinical course
Right ventricular dysfunction on echocardiography is a common clinical finding in patients with acute pulmonary embolism (PE) (1–3) and predicts poor outcome in these patients. Prognostic stratification in patients with acute PE may have consequences on management decisions. Patients identified with a low risk of complicated outcome may be eligible for outpatient management and high-risk patients may benefit from more aggressive treatment (1, 2). Several cardiac biomarkers have emerged as indicator of right ventricular dysfunction and predictor of clinical outcome in patients with acute PE. A recent meta-analysis demonstrated that elevated troponin levels identify patients with PE at high risk of short-term death and adverse outcome (4). Also, brain-type natriuretic peptide (BNP) is a marker of ventricular dysfunction. This hormone is released in response to myocyte stretch. It is synthesized as an inactive prohormone (pro-BNP) that is split into the active hormone BNP and the inactive N-terminal fragment (NT–pro-BNP) (5). Several prospective studies have been performed to identify to potential role of either BNP or NT–pro-BNP in the risk stratification of patients with PE (6–18). However, reported studies have limited patient numbers, used different cutoff points, and involved different clinical endpoints. Therefore, we performed a meta-analysis of studies in patients with acute PE to evaluate the relation between elevated levels of BNP or NT–pro-BNP and clinical outcome.
Data Sources A literature search was performed to identify all published prospective studies on BNP or NT–pro-BNP levels and clinical outcome in patients with PE. Medline and EMBASE were searched using predefined search terms between January 1980 and October 2007. Search criteria included "pulmonary embolism" and "pro–brain natriuretic peptide" or "brain natriuretic peptide" or "natriuretic peptide." Also, by searching the reference lists of all established studies, the researchers aimed to identify additional relevant articles. Articles were not limited to the English language. Only complete articles were applicable for this analysis.
Study Outcome
Study Selection and Data Extraction
Statistical Analysis
Study Selection As a result of the literature search, 124 studies were found. Articles were excluded by review of title and abstract in case of review articles (n = 48), animal studies (n = 2), case reports (n = 5), editorials, letters or author replies (n = 13), studies not including the clinical course of PE (n = 6), and if the article concerned studies on other diseases than PE (n = 17; Figure 1). After full review, an additional 20 studies were excluded because our predefined endpoints were not reported (17) or no cutoff points were mentioned (3). We identified 13 studies that met our criteria (6–18).
Characteristics of Included Studies Demographic characteristics of the patients were comparable between all included studies (Tables 1 and 2). Mean age of the patients varied between 53 and 75 years; the proportion of females ranged from 36 to 74%. In most patients, the diagnosis of PE was confirmed by CT scan, high-probability  / scan, or pulmonary angiography. In three studies, hemodynamically unstable patients were excluded (7, 11, 17). Noticeably, in two of these latter studies, some patients received thrombolytic therapy during their hospital stay (7, 11). Two included studies reported on partially overlapping patient cohorts (16, 18). Because one of these studies used BNP (16) and the other NT–pro-BNP (18) levels as an outcome parameter, both studies could be incorporated into subgroup analyses based on type of BNP testing.
Assays and Cutoff Points As shown in Table 1, all studies reporting NT–pro-BNP levels used a Roche analyzer (two types: Elecsys 2010 analyzer, Meylan France; electrochemiluminescence method-ECLIA, Roche Diagnostics GmbH, Mannheim, Germany), with three different cutoff levels, varying from 500 to 1,000 pg/ml. In the BNP studies, two assays with four different cutoff levels varying between 75 and 100 pg/ml were used. In all included studies, the timing of sampling is comparable. Cutoff levels were not predefined in most studies. In these 10 articles, receiver operating characteristic (ROC) analyses were performed to retrospectively determine optimal cutoff values with regard to complicated PE. Normal levels are defined as levels beneath or equal to the cutoff point.
Clinical Outcome
Numbers on PE-related mortality were only available in three studies (11, 13, 17). Because follow-up time was dissimilar between these studies and not all mortality cases were adjudicated by an independent, blinded committee to determine the cause of death, we could not use PE-related mortality as an outcome of this analysis. Ten studies provided data on adverse clinical outcome (6, 8–13, 15, 16, 18) of which six had NT–pro-BNP levels as an outcome parameter (6, 8, 12, 13, 15, 18). Overall, criteria for adverse clinical outcome were comparable throughout all studies. In the BNP study group, 47 of 128 (37%; 95% CI, 28–46%) patients with elevated BNP levels had adverse advents during follow-up in comparison with 28 of 208 (13%; 95% CI, 9.1–19%) patients with normal plasma concentrations. High BNP levels were associated with a higher risk of occurrence of adverse clinical events (OR, 6.3; 95% CI, 3.6–11; Figure 3). This OR was even higher (9.5; 95% CI, 3.5–25) after exclusion of one study with 6 months of follow-up (9), thereby limiting the outcome to in-hospital clinical course. Of the 318 patients with elevated NT–pro-BNP levels, 102 experienced short-term adverse events (32%; 95% CI, 27–38%) as compared with 12 of 225 (5.3%; 95% CI, 2.8–9.1%) patients with normal NT–pro-BNP levels. Patients with high NT–pro-BNP serum concentration were at higher risk of complicated in-hospital course compared with patients with normal levels (OR, 7.5; 95% CI, 3.8–15; Figure 3). Pooled data of all assays showed elevated BNP or NT–pro-BNP levels in 52% of the patients with a risk of 23% (209/909; 95% CI, 20–26%) and an OR of 6.8 (95% CI, 4.4–10) toward complicated clinical course.
Right Ventricular Dysfunction Data on right ventricular dysfunction were reported in six studies (Figure 4). Four studies were evaluating BNP (243 patients) (7, 11, 14, 16) and two studies evaluated NT–pro-BNP levels (197 patients) (12, 18). The incidence of right ventricular dysfunction was 85% (116 of 137 patients; 95% CI, 78–90%) and 12% (13 of 106 patients; 95% CI, 6.7–20%) in patients with and without elevated BNP levels, respectively (P < 0.0001). A positive association was found between increased concentration of BNP and the presence of right ventricular dysfunction (OR, 81; 95% CI, 27–238). In NT–pro-BNP studies, the incidence of right ventricular dysfunction was 45% (49 of 109 patients; 95% CI, 35–55%) in patients with elevated NT–pro-BNP levels compared with 4.5% (4 of 88 patients; 95% CI, 1.3–11%) in patients with normal NT–pro-BNP levels. Elevated NT–pro-BNP levels were associated with the presence of right ventricular dysfunction (OR, 16.81; 95% CI, 5.73–49.37). Pooled data of all assays revealed a combined OR of 39 (95% CI, 17–89).
This meta-analysis demonstrates a significant relation between high levels of BNP or NT–pro-BNP and deterioration of clinical condition in patients with acute PE. This is physiologically plausible because BNP is released as a reaction to right ventricular stress, which has been shown to predict a nonbenign course in patients with PE (1–3). This relation is also demonstrated in this analysis: we found a very strong correlation between increased levels of BNP or NT–pro-BNP and right ventricular dysfunction on echocardiography (Figure 4). There are some points for discussion if BNP or NT–pro-BNP levels would be incorporated in clinical treatment strategies for patients with acute PE. First, timing of blood sampling has consequences for the established BNP concentration. The BNP prohormone (pro-BNP) in normal ventricular myocytes is not stored to a significant amount. As a consequence, it takes several hours for the plasma natriuretic peptide levels to increase significantly after the onset of acute myocardial stretch (20). A very recent onset of complaints could therefore result in false-negative BNP or NT–pro-BNP test results. Second, many different cutoff levels for BNP or NT–pro-BNP are proposed in the literature (21, 22). The variation may be related to patient selection, sex, and age (22). Despite the different cutoff levels and different assays, the prognostic value of both NT–pro-BNP and BNP was consistent in all included studies. What are the potential implications of our findings? First, normal levels of BNP have a high negative predictive value for unfavorable outcome. Patients with normal levels of BNP or NT–pro-BNP have low risks for death as well as for hemodynamic deterioration resulting in any adverse events. Conversely, elevated concentrations of B-type natriuretic peptides are a nonspecific finding. An explanation for this phenomenon is the elevation of natriuretic peptides in a multitude of other conditions, including preexisting left ventricular dysfunction, older age, renal impairment, and chronic lung disease (23). The combination of BNP with other clinical risk factors for adverse outcome may improve sensitivity and positive predictive value for clinical deterioration. Such algorithms for risk stratification would be clinically useful if they were able to identify patients eligible for outpatient management or for standard or intensive in-hospital treatment. Proposals for such algorithms including markers or biomarkers of right ventricular function (e.g., BNP or NT–pro-BNP, troponin [4], or heart-type fatty acid–binding protein [8, 24]) have been made but not yet validated prospectively in clinical outcome studies (12, 13, 25). Future studies are required to determine the clinical benefits of more aggressive treatments in patients with adverse prognosis as identified by these risk stratifications and less intensive treatment, including out of hospital treatment, in patients with normal values of BNP. This meta-analysis has limitations. First, included studies used different assays with different retrospectively calculated cutoff points. Second, duration of follow-up and definitions of endpoints varied among the studies. In addition, most studies did not mention completeness of follow-up. Nonetheless, we have included a large cohort of prospectively followed patients (n = 1,128) and our analysis showed no evidence of heterogeneity between the outcomes of the incorporated studies. Third, the relative risk for mortality is not adjusted for confounding factors, thus part of the effect ascribed to high BNP values may be related to clinical conditions associated with PE. Fourth, we could not determine the ideal cutoff for the two BNP tests because we did not have the raw data to do ROC curves and other analyses. Finally, in the included studies, it is not stated whether thrombolytic therapy or intensive care unit admission was the result of the clinical condition or a high BNP or NT–pro-BNP value. In summary, an elevated level of BNP or NT–pro-BNP is a risk factor for short-term mortality and overall short-term complicated clinical outcome, and an indicator of right ventricular dysfunction in patients with acute PE. It remains to be demonstrated whether it could play a role in risk stratification algorithms identifying patients who could benefit from differentiated forms of therapy, of which thrombolytic therapy and home treatment are two poles of the spectrum.
* These authors contributed equally to this article.  Originally Published in Press as DOI: 10.1164/rccm.200803-459OC on June 12, 2008 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has a interest in the subject of this manuscript. Received in original form March 25, 2008; accepted in final form June 5, 2008
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AT A GLANCE COMMENTARY
2 test and the I2 test for heterogeneity were used to assess interstudy heterogeneity. The 
