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Three Part Question

In [patients with definite pulmonary embolus] can a [low/negative BNP/NT-proBNP result] predict [low risk of death / adverse outcome?]

Clinical Scenario

A patient presents with a few days history of pleuritic chest pain. All clinical findings and investigations are normal except for a raised d-dimer. A high probability V/Q scan confirms the diagnosis of pulmonary embolism. The patient is very keen to be discharged. You are aware that right ventricular strain is associated with a poor outcome in pulmonary embolism and you also know that B natriuretic peptides are raised in the presence of ventricular strain. You wonder if a low B natriuretic peptide level could be used to confirm the absence of ventricular stain and low risk of death or serious complications, therefore suggesting suitability for outpatient management.

Search Strategy

Cochrane Database of Systematic Reviews, EMBASE and Ovid Medline through Ovid interface, January 2015.

[bnp.mp. OR brain natriuretic peptide.mp. OR natriuretic peptide.mp. OR NT-proBNP.mp. OR proBNP.mp.] AND [pulmonary embolism.mp. OR pe.mp. OR thromboembolic disease.mp. OR lung embolism.mp.] LIMIT to english language and human (Limit not valid in CDSR)

Search Outcome

277 articles were found. 4 systematic reviews were found ranging from 2008 to 2011. Two of these are reported, the most recent and the met high quality. In addition 3 further prospective cohort studies were found which are reported individually.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Coutance et al 2008 France	Systematic review with meta analysis which took data from 12 articles with a total of 868 patients. All of the research involved patients who had a diagnosis of pulmonary embolism confirmed by CT, V/Q scan or angiogram	All patients had BNP or NT-proBNP measured at some point following admission and were followed up for up to 3 months to monitor adverse events.	Short term mortality (12 studies, 868 patients)	OR 6.57 (95% CI 3.11-13.91), Sens 0.93, Spec 0.48, PPV 0.14, NPV 0.99	Metaanalysis done from published data so limited information and analysis on patients observations, characteristics and demographics. Different cut-offs used in different studies.
			Serious adverse events (9 studies, 688 patients)	OR 7.47 (95% CI 4.2-13.15), Sens 0.89, Spec 0.48, PPV 0.33, NPV 0.94
Klok et al 2008 The Netherlands	13 studies included in systematic review and metaanalysis involving a total of 1,132 patients. All patients had a confirmed diagnosis of pulmonary embolism.	All patients had a BNP or NT-proBNP level measured at some point following admission and were then followed up for adverse events.	Overall mortality (8 studies)	OR 7.56 (95%CI 3.35-17.09) Sens 0.85, Spec 0.56, PPV 0.14, NPV 0.98	Variable cut-off levels. Variable follow up time.
			Adverse events(10 studies)	OR 6.77 (95% CI 4.36-10.49), Sens 0.80, Spec 0.56, PPV 0.36, NPV 0.91
Lankeit et al 2014 Germany	688 normotensive patients with confirmed acute pulmonary embolism from 12 European centres. Haemodynamic instability, incidental finding and declined consent were only exclusions	Prospective cohort looking to validate use of NTProBNP at serial cutoffs to predict adverse outcome (a composite of PE related death, need for vasopressor/ionotropic support, need for intubation and need for CPR.	AUC for NTProBNP >600pg/ml	0.70 (95% CI 0.6 to 0.8)	Unclear if patients were managed as in or outpatients within studies. No UK centres. Primary outcome does not include ICU admission and contains some subjective endpoints.
			Odds ratio for NTProBNP >600pg/ml to predict primary outcome	6.04 (95% CI 2.07 to 17.59)
Jiminez et al 2014 Spain	Prospectively enrolled patients with acute pulmonary embolism (848 in derivation cohort and 529 in the validation cohort). Patients with haemodynamic instability, life expectancy <3 months, pregnancy, geographical inaccessibility, age <18 and use of thrombolytics were excluded.	Derivation and validation of a multi marker clinical decision rule to predict outcome in acute pulmonary embolism. Composite primary outcome included all cause mortality, adjudicated recurrent PE and haemodynamic collapse.	OR for BNP >100pg/ml	2.12 (95% CI 1.13 - 3.99), p=0.02	Unclear who was managed as outpatients within study. Derived and validated within 2 cohorts prospectively recruited for other studies. All cause mortality as part of the outcome raises the issue that patients may have died due to malignancy - this is not necessarily a barrier to outpatient treatment if palliation is being considered.
			Negative predictive value for simplified PESI + negative BNP to predict adverse outcome	97% (95% CI 88-99)
Vuilleumier et al 2008 Switzerland	146 prospectively recruited consecutive adult patients with non-massive PE.	biomarker assessment at inclusion, followed by 3 months follow up to assess adverse outcome rate. Primary composite included ICU admission, all cause mortality, hospitalisation attributable to PE complication or representation with dyspnoea +/- chest pain.	AUC for NTProBNP >300pg/ml	0.87 (95% CI 0.81 to 0.94)	Small study, exclusion criteria unclear, low cutoff therefore although sensitive there would be a high likelihood of false positive results with this range, rendering the test unlikely to provide clinical benefit. No likelihood ratios reported. ICU admission subjective and unclear reasoning - may lead to overestimate of adverse outcomes when compared to UK practice.
			NPV	100% (95% CI 92 to 100)
			OR for NTProBNP >300pg/ml to predict adverse events	15.8 (95% CI 2.1 to 122) p=0.001
Wang et al 2012 China	224 patients with confirmed PE were included (276 patients screened, 52 excluded)	Prospective observational cohort study. Primary outcome was recurrent fatal or non-fatal VTE	Recurrence rate in patients with NT-proBNP >1000 pg/mL	20 patients of 158 patients	Small, single centre study. Significant numbers of excluded patients. Variation in duration of treatment with anticoagulants and period of follow-up
			Recurrence rate in patients with NT-proBNP <1000 pg/mL	One patient of 66 patients
Ozsu et al 2010 Turkey	108 patients with PE confirmed by CTPA. (138 patients screened, 30 excluded)	Prospective observational cohort study. Primary outcome of all-cause mortality at 30 days	Overall mortality	14 deaths from 108 patients.	Small study with significant number of patients excluded including 10 patients who did not have echocardiography
			Mortality in patients with NT-proBNP level ≤90 ng/mL	One death from 55 patients
			Predictive value of NT-proBNP ≤90 ng/mL for PE-related deaths	Sens 11, Spec 90, NPV 54, PPV 100
Agertof et al 2010 The Netherlands	152 patients with normotensive PE and NT ProBNP values <500 pg/mL	Prospective observational cohort study. Primary outcome of all cause mortality	Mortality at 10 days	0%	No use of clinical risk score prior to NTProBNP testing. Limited follow up and outcome reporting. Single centre, therefore generalisability limited. No control arm
			Readmission due to PE or a complication of treatment within first 10 days	2%

Comment(s)

Brain natriuretic peptide is released from cardiac ventricles in response to stretch, synthesised initially as pro-BNP which is then split into the active component (BNP) and the inactive N terminal portion (NT-proBNP). The main diagnostic role for this peptide so far has been in assessment of heart failure. However, levels have also been noted to rise in patients with clinically significant PE, as a potential marked of right ventricular strain/dysfunction. It follows that a rise in levels of BNP/NT-proBNP in the context of acute PE may also warn of an increased risk of adverse events and mortality. Conversely, a low BNP, even in the presence of a definite diagnosis of PE, may confer a low risk of adverse events.

The available evidence suggests that BNP/NTProBNP at diagnosis correlates with morbidity. Furthermore, it also demonstrates an impressive negative likelihood ratio and predictive value, suggesting that patients who do not have a raised BNP at presentation are at low risk of adverse events. This is further supported by adequately powered prospective data such as that from Agertof et al.

Following the 2008 meta-analysis, several authors have conducted large observational cohorts looking at specific cut points for natriuretic peptides and the additional prognostic influence alongside validated clinical decision rules. The evidence suggests BNP/NTProBNP to have cumulative prognostic power in addition to decision rules. Jiminez et al have produced perhaps the most convincing data recently, suggesting that even in patients with a low simplified PE Severity Index score, use of BNP can further stratify patients into a lower risk category, with reasonable specificity. These patients have a risk for adverse events of <1% and so would be suitable for outpatient therapy.

Although the cohort data are increasingly robust and thus provide a high level of evidence, there are currently no randomised controlled trials comparing biomarker-led discharge strategies against routine clinical care.

Editor Comment

AUC, area under the curve; BNP, brain natriuretic peptide; CTPA, computed tomography pulmonary angiogram; NPV, negative predictive value; NT-proBNP, n terminal pro brain natriuretic peptide; PE, pulmonary embolism; PESI, PE Severity Index; PIOPED, prospective investigation of pulmonary embolism diagnosis; PPV, positive predictive value; VTE, venous thromboembolism.

Clinical Bottom Line

Patients with confirmed pulmonary embolism who have a BNP/NTProBNP within a validated normal range are at low risk for adverse events over 30-day follow-up. When combined with a simplified PE Severity Index score <1, the risk falls further, to <1%. These patients should be considered for ambulatory management/early discharge.

Level of Evidence

Level 1 - Recent well-done systematic review was considered or a study of high quality is available.

References

1. Coutance G, Le Page O, Lo T, et al Prognostic value of brain natriuretic peptide in acute pulmonary embolism Crit Care 2008;12:R109.
2. Klok F, Mos I, Hulsman M. Brain-Type Natriuretic Peptide Levels in Prediction of Adverse Outcome in Patients with Pulmonary Embolism Am J Respir Crit Care Med 2008;178:425–30.
3. Lankeit M, Jiménez D, Kostrubiec M, et al. Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism Eur Respir J 2014;43:1669-1677.
4. Jiménez D, Kopecna D, Tapson V et al. Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism Am J Respir Crit Care Med. 2014; 189:718–26.
5. Vuilleumier N, Le Gal G, Verschuren F, et al. Cardiac biomarkers for risk stratification in non-massive pulmonary embolism: a multicenter prospective study. J Thromb Haemost 2009;7:391–8.
6. Wang Y, Liu ZH, Zhang HL, et al. Association of elevated NTproBNP with recurrent thromboembolic events after acute pulmonary embolism. Thromb Res 2012; 129:688–92.
7. Ozsu S, Karaman K, Mentese A, et al. Combined risk stratification with computerized tomography/echocardiography and biomarkers in patients with normotensive pulmonary embolism. Thromb Res 2010; 126:486–92.
8. Agertof MJ, Schutgens REG, Snidjer RJ, et al. Out of hospital treatment of acute pulmonary embolism in patients with a low NT-ProBNP level. J Thromb Haemost 2010; 8:1235–41.