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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Natriuretic peptides in acute pulmonary embolism: a systematic review

R Cavallazzi, A Nair, T Vasu, and PE Marik.

Review published: 2008.

CRD summary

This review concluded that elevated brain natriuretic peptide and N-terminal pro-brain natriuretic peptide biomarkers were associated with the diagnosis of right ventricular dysfunction in patients with acute pulmonary embolism, and were significant predictors of all-cause in-hospital mortality or short-term mortality in these patients. These broad conclusions reflected diagnostic odds ratios with wide confidence intervals and are probably reliable.

Authors' objectives

To evaluate the accuracy of brain natriuretic peptide and N-terminal pro-brain natriuretic peptide biomarkers for the diagnosis of right ventricular dysfunction in patients with pulmonary embolism. The review also assessed their prognostic value as predictors of mortality.

Searching

PubMed and EMBASE were searched with no language restrictions; search terms were reported but search dates were not. References of identified studies and relevant reviews were also checked. Some studies in non-English languages were identified, but could not be included in the review.

Study selection

Diagnostic or prognostic cohort studies of patients with pulmonary embolism were eligible for inclusion. Diagnostic studies had to compare the sensitivity and specificity (accuracy) of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide biomarkers on admission with a reference standard for the diagnosis of right ventricular dysfunction. Studies were required to report sufficient outcome data to permit the construction of a 2x2 table. Prognostic studies needed to report in-hospital or short-term mortality.

All except one diagnostic study used echocardiography as the reference standard; the remaining study used helical computed tomography with a diagnostic threshold for the right to left ventricular ratio of at least one. Detailed criteria used for the diagnosis of right ventricular dysfunction were reported in the paper.

The authors did not state how the papers were selected for the review.

Assessment of study quality

The following criteria were used to assess the validity of diagnostic studies: eligibility criteria, consecutive versus random participant sampling, reference standard, definition of right ventricular dysfunction, blinding, and characteristics of study participants. Prognostic studies were assessed using the criteria of statement of objectives, setting description, eligibility criteria, methods of participant selection, clear definition of outcomes, and characteristics of participants.

Two authors performed the assessment independently, with disagreements resolved through discussion amongst all reviewers.

Data extraction

Two authors independently extracted the data using a standardised form; disagreements were resolved through discussion amongst all reviewers. When different cut-off points were reported for plasma brain natriuretic peptide, that most closely approximating 100pg/ml was used. Where brain natriuretic peptide plasma concentrations were reported in pmol/L, they were converted to pg/ml. Where necessary, authors were contacted for additional data. For diagnostic studies, outcome data were extracted to permit the calculation of a diagnostic odds ratio (DOR) with 95% confidence intervals (CI). Data to permit the calculation of odds ratios (OR), with 95% confidence intervals, were extracted from prognostic studies.

Methods of synthesis

A pooled diagnostic odds ratio was calculated using a DerSimonian and Laird random-effects model. A Moses and Littenberg summary receiver operating characteristic (SROC) curve was used to summarise the true and false positive rates. Prognostic studies were combined using a Mantel-Haenszel fixed-effect model to calculate a pooled odds ratio with 95% confidence intervals for all-cause in-hospital mortality. Positive and negative likelihood ratios were also calculated. It appeared that statistical heterogeneity between studies was assessed using a Χ2 statistic. Subgroup analysis was used to explore the effect of excluding unstable patients and of varying the diagnostic threshold for elevated brain natriuretic peptide.

Results of the review

Sixteen studies were included in the review. Seven studies (n=278 patients) assessed the diagnosis of right ventricular dysfunction using brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. All of the studies enrolled consecutive patients and described the inclusion/exclusion criteria, reference standard, definition of right ventricular dysfunction and participant characteristics. Five studies reported blinding.

Diagnostic accuracy for right ventricular dysfunction:

The diagnostic odds ratio for studies evaluating brain natriuretic peptide, using a reference standard of echocardiography, ranged from 28.44 to 293.91. The pooled diagnostic odds ratio was 39.45 (95% CI 15.54 to 100.12; four studies), with no evidence of statistically significant heterogeneity. The area under the summary receiver operating characteristic curve was 0.91; a perfect diagnostic test would have a value of 1.00, whilst a test with no value would have a value of 0.50.

The diagnostic odds ratios for the two studies evaluating N-terminal pro-brain natriuretic peptide, using a reference standard of echocardiography, ranged from 8.32 and 96. The pooled diagnostic odds ratio was 24.73 (95% CI 2.02 to 302.37), with statistically significant heterogeneity (p=0.043).

The single study using computed tomography as the reference standard found a diagnostic odds ratio for brain natriuretic peptide of 6.56 (95% CI 1.92 to 22.39) and 5.67 (95% CI 1.69 to 18.91) for N-terminal pro-brain natriuretic peptide.

Prognostic value for patients with pulmonary embolism:

Fourteen studies assessed the prognostic value of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide (n=1,045 patients). The risk of death was increased in patients with an elevated brain natriuretic peptide, using a cut-off of 100pg/ml; the pooled odds ratio for all-cause in-hospital mortality was 6 (95% CI 1.31 to 27.43) compared to patients with a normal level.

The risk of death was also increased in patients with an elevated N-terminal pro-brain natriuretic peptide, using a cut-off of 1,000ng/L, the pooled odd ratio for all-cause in-hospital mortality was 7.34 (95% CI 1.85 to 29.03), compared with patients with normal levels. With a cut-off of 600ng/L, the pooled odds ratio was 16.12 (95% CI 3.1 to 83.68). There was no statistically significant heterogeneity in any analysis.

Results of subgroup analyses were also reported.

Authors' conclusions

Brain natriuretic peptide and N-terminal pro-brain natriuretic peptide were associated with the diagnosis of right ventricular dysfunction in patients with acute pulmonary embolism, and were significant predictors of all-cause in-hospital mortality or short-term mortality in these patients.

CRD commentary

The review questions and inclusion criteria were clear. Two relevant databases were searched but no systematic search for unpublished studies was conducted, which may have increased the chances that relevant studies were omitted and publication bias introduced. There was also the possibility that the need to exclude foreign language papers may have contributed to potential bias. The authors reported using methods designed to reduce reviewer bias and error in the extraction of data and assessment of validity, but not in the selection of papers for the review.

The study validity assessment used appropriate and relevant criteria. The decision to use meta-analyses was reasonable and attempts were made to assess and explore heterogeneity between studies. However, the use of the diagnostic odds ratio as the primary means of assessing diagnostic accuracy was not particularly informative; reporting of sensitivity and specificity would have provided more useful information on the reliability of the biomarkers assessed. The confidence intervals for the pooled diagnostic odds ratio were also wide, which meant that the true estimate of the test performance was uncertain.

The authors' conclusions were broad, reflecting these wide confidence intervals associated with the pooled diagnostic odds ratios and, as such, they are probably reliable.

Implications of the review for practice and research

Practice: The authors stated that tests of brain natriuretic peptide and N-terminal pro-brain natriuretic peptide should be included in the risk stratification process for patients with pulmonary embolism in conjunction with echocardiography.

Research: The authors did not state any implications for further research.

Funding

Not stated.

Bibliographic details

Cavallazzi R, Nair A, Vasu T, Marik PE. Natriuretic peptides in acute pulmonary embolism: a systematic review. Intensive Care Medicine 2008; 34(12): 2147-2156. [PubMed: 18626627]

Indexing Status

Subject indexing assigned by NLM

MeSH

Biological Markers /blood; Humans; Likelihood Functions; Natriuretic Peptide, Brain /blood; Odds Ratio; Peptide Fragments /blood; Pulmonary Embolism /blood /complications; ROC Curve; Ventricular Dysfunction, Right /blood /diagnosis /etiology

AccessionNumber

12009104529

Database entry date

30/06/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18626627

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