Neuroendocrine hormones as prognostic biomarkers in the setting of acute stroke: overcoming the major hurdles

Abstract

Stroke represents one of the major causes of disability and mortality worldwide and prediction of outcome represents a challenge for both clinicians and researchers. In the past years, many blood markers have been associated with stroke outcome but despite this evidence, no biomarker is routinely used in stroke management. In this review, we focus on markers of the neuroendocrine system, which represent potential candidates to be implemented in clinical practice. Moreover, we present a systematic review and literature-based meta-analysis for copeptin, a new biomarker of the hypothalamo–pituitary–adrenal axis that has shown additional predictive value over clinical information in a large prospective study. The meta-analysis of the included 7 studies, with more than 2000 patients, reinforced its association with poor outcome (pooled odds ratio: 2.474 [1.678–3.268]) and mortality (pooled OR: 2.569 [1.642–3.495]). We further review the current situation of the topic and next steps to implement these tools by clinicians.

Keywords::

• biomarker
• copeptin
• meta-analysis
• neuroendocrine marker
• outcome
• prognosis
• stroke
• systematic review

Financial & competing interests disclosure

Neurovascular Research Laboratory takes part in the Spanish stroke research network INVICTUS (RD12/0014/0005) and is supported on stroke biomarkers research by FIS 11/0176. A Bustamante is supported by a Rio Hortega contract CM/00265 from the Instituto de Salud Carlos III and V Llombart is supported by a pre-doctoral fellowship from Vall d’Hebron Institut de Recerca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Biomarkers of the neuroendocrine system represent surrogate tools in stroke clinical practice for outcome assessment. Although most of them have disclosed independent association with outcome, their added predictive value over clinical information should be addressed for both classical and new candidates.

• However, most of the literature in this topic is exploratory. Studies with large sample sizes are needed. While the preferable model is a large, multicenter study, meta-analyses or individual participant data approaches may be also useful in generating evidence.

• While the most studied marker of these system, B-type natriuretic peptides, seems not to be useful for outcome prediction in stroke patients, at least by itself, mid-regional fragment of proANP and copeptin have shown promising results in this field.

• A literature-based meta-analysis of copeptin in outcome prediction reinforces its association with stroke outcome, besides the existence of publication bias. Publication of negative results in the biomarker field should be considered and recommended for both researchers and editors.

• For the surrogate markers, it would be useful to clarify if the association with outcome is mediated with a specific worsening cause, which could facilitate translation into use in clinical practice. Evaluation in semi-interventional clinical studies about the impact of the biomarker use in clinical practice, in terms of outcome modification, should be the last step before clinical implementation.

Notes