Do optimal prognostic thresholds in continuous physiological variables really exist? Analysis of origin of apparent thresholds, with systematic review for peak oxygen consumption, ejection fraction and BNP.
BACKGROUND
Clinicians are sometimes advised to make decisions using thresholds in measured variables, derived from prognostic studies.


OBJECTIVE
We studied why there are conflicting apparently-optimal prognostic thresholds, for example in exercise peak oxygen uptake (pVO2), ejection fraction (EF), and Brain Natriuretic Peptide (BNP) in heart failure (HF).


METHODS
Studies testing pVO2, EF or BNP prognostic thresholds in heart failure, published between 1990 and 2010, listed on Pubmed.


METHODS
First, we examined studies testing pVO2, EF or BNP prognostic thresholds. Second, we created repeated simulations of 1500 patients to identify whether an apparently-optimal prognostic threshold indicates step change in risk.


RESULTS
33 studies (8946 patients) tested a pVO2 threshold. 18 found it prognostically significant: the actual reported threshold ranged widely (10-18 ml/kg/min) but was overwhelmingly controlled by the individual study population's mean pVO2 (r = 0.86, p<0.00001). In contrast, the 15 negative publications were testing thresholds 199% further from their means (p = 0.0001). Likewise, of 35 EF studies (10220 patients), the thresholds in the 22 positive reports were strongly determined by study means (r = 0.90, p<0.0001). Similarly, in the 19 positives of 20 BNP studies (9725 patients): r = 0.86 (p<0.0001). Second, survival simulations always discovered a "most significant" threshold, even when there was definitely no step change in mortality. With linear increase in risk, the apparently-optimal threshold was always near the sample mean (r = 0.99, p<0.001).


CONCLUSIONS
This study cannot report the best threshold for any of these variables; instead it explains how common clinical research procedures routinely produce false thresholds.


RESULTS
First, shifting (and/or disappearance) of an apparently-optimal prognostic threshold is strongly determined by studies' average pVO2, EF or BNP. Second, apparently-optimal thresholds always appear, even with no step in prognosis.


CONCLUSIONS
Emphatic therapeutic guidance based on thresholds from observational studies may be ill-founded. We should not assume that optimal thresholds, or any thresholds, exist.
International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College, London, United Kingdom ; Department of Cardiovascular Medicine, Fondazione Toscana G. Monasterio, Pisa, Italy.
Alberto
A
Giannoni
International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Resham
R
Baruah
International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Tora
T
Leong
Cardiology Department, Poitiers University Hospital, Poitiers, France.
Michaela B
MB
Rehman
Department of Cardiovascular Medicine, Fondazione Toscana G. Monasterio, Pisa, Italy.
Luigi Emilio
LE
Pastormerlo
Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
Frank E
FE
Harrell
International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College, London, United Kingdom ; Norfolk and Norwich Hospital, University of East Anglia, Norwich, United Kingdom.
Andrew J S
AJ
Coats
International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Darrel P
DP
Francis
D006801:Humans; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology*; D011379:Prognosis; D012016:Reference Values; D013318:Stroke Volume / Q000502:physiology*
D020097:Natriuretic Peptide, Brain