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Predictors of short-term LAMA ineffectiveness in treatment naïve patients with moderate to severe COPD

Summary

Background

No specific (only subgroup) recommendations for the use of long-acting muscarinic antagonists in chronic obstructive pulmonary disease (COPD) exist. The aim of this exploratory hypothesis generating study was to assess whether different phenotypic/endotypic characteristics could be determinants of the short-term ineffectiveness of the initial tiotropium bromide monotherapy in treatment naïve moderate to severe COPD patients.

Methods

A total of 51 consecutively recruited COPD patients were followed for 3 months after the initial evaluation and prescribed initial treatment (tiotropium). Short-term treatment ineffectiveness was assessed as a composite measure comprising COPD exacerbations, need for additional treatment, and no improvement in functional parameters, e.g. 6‑min walking test (6MWT), body-mass index, airflow obstruction, dyspnea, and exercise (BODE) index and forced expiratory volume in 1 s (FEV1), and as single components.

Results

Treatment ineffectiveness was significantly associated with baseline hemoglobin level, COPD assessment test (CAT) score, modified Medical Research Council (mMRC) scale and BODE index (p = 0.002). Incident exacerbation during the follow-up was associated with baseline bronchoalveolar lavage fluid (BALF) alpha-amylase level and CAT score (p < 0.001), and change in treatment with leukocyte count, 6MWT desaturation and fatigue (p < 0.001). No improvement in 6MWT was associated with baseline CAT score, body mass index, mMRC, fatigue, 6MWT and BODE index (p = 0.002). No improvement in BODE index was associated with leukocyte count, serum interleukin 8 (IL-8) and BALF albumin levels (p < 0.001); and no improvement in FEV1 with CAT score, baseline vital capacity and BALF tumor necrosis factor alpha (TNF-alpha) level (p < 0.001).

Conclusion

Our results suggest that there is a possibility to identify predictors of short-term tiotropium ineffectiveness in patients with moderate to severe COPD.

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Abbreviations

ACE:

Angiotensin-converting enzyme

ALP:

Alkaline phosphatase

AT1T:

Alpha1-antitrypsin

ATS:

American Thoracic Society

AUC:

Area under the curve

BALF:

Bronchoalveolar lavage fluid

BMI:

Body mass index

BODE:

Body-mass index, airflow obstruction, dyspnea, and exercise

CAT:

COPD assessment test

CBC:

Complete blood cell

CD:

Cluster of differentiation

CI:

Confidence interval

COPD:

Chronic obstructive pulmonary disease

CRP:

C-reactive protein

DLCO :

Diffusing capacity of the lungs for carbon monoxide

ERS:

European Respiratory Society

FAS:

Tilburg fatigue assessment scale

FeNO:

Fraction of exhaled nitric oxide

FEV1 :

Forced expiratory volume in 1 s

FVC:

Forced vital capacity

GCP:

Good clinical practice

GOLD:

Global Initiative for Chronic Obstructive Lung Disease

HRQoL:

Health related quality of life

ICS:

Inhaled corticosteroids

IL:

Interleukin

LAMA:

Long-acting muscarinic antagonists

LDH:

Lactate dehydrogenase

mMRC:

Modified Medical Research Council

NPV:

Negative predictive value

OR:

Odds ratio

PEF:

Peak expiratory flow

pCO2:

Partial pressure of carbon dioxide

pO2:

Partial pressure of oxygen

PPV:

Positive predictive value

RV:

Residual volume

SD:

Standard deviation

SpO2:

Arterial oxygen saturation

6MWT:

6 min walking test

TGF-beta:

Transforming growth factor beta

TLC:

Total lung capacity

TNF-alpha:

Tumor necrosis factor alpha

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Funding

No grant, equipment or drugs were received for this study.

Author contributions

V. Fijačko conceived the idea for the study, together with M. Labor, S. Škrinjarić-Cincar, S. Labor, T. Bačun, A. Včev and M. Fijačko collected data. D. Plavec and S. Popović-Grle were responsible together with V. Fijačko for the design of the research and for data analysis. I. Dumbović Dubravčić contributed by literature research, writing and editing the data. All authors contributed by editing and approving the final version of the manuscript. All authors have read and approved the final version of the manuscript.

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Correspondence to Davor Plavec MD, PhD.

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Conflict of interest

V. Fijačko has received honoraria for lectures from Novartis, Sandoz, AstraZeneca, Berlin Chemie, Pliva, and Boehringer Ingelheim. S. Škrinjarić-Cincar has received honoraria for lectures from Novartis, Sandoz, AstraZeneca, Berlin Chemie, Pliva, and Boehringer Ingelheim. S. Labor has received honoraria for lectures from Novartis, and Boehringer Ingelheim. T. Bačun has received honoraria for lectures from Novo Nordisk, Eli Lilly, Novartis, Sandoz, AstraZeneca, Berlin Chemie, Pliva, and Boehringer Ingelheim. S. Popović-Grle has received honoraria for advisory boards and/or lectures from Boehringer Ingelheim, Novartis, AstraZeneca, Pliva-Teva, Takeda, GlaxoSmithKline, Meda Pharma, Sanofi Aventis, Krka farma, Berlin Chemie Menarini Hrvatska, and Sandoz Hrvatska. D. Plavec has received research grants from GlaxoSmithKline, honoraria for advisory boards and/or lectures and/or clinical trials from GlaxoSmithKline, Menarini, Pliva, Boehringer Ingelheim, Belupo, AbbVie, MSD, and Chiesi. M. Labor, I. Dumbović Dubravčić, M. Fijačko and A. Včev declare that they have no competing interests.

Ethical standards

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee (Institutional Review Board and Medical Faculty Ethics Committee) and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in the study.

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Fijačko, V., Labor, M., Fijačko, M. et al. Predictors of short-term LAMA ineffectiveness in treatment naïve patients with moderate to severe COPD. Wien Klin Wochenschr 130, 247–258 (2018). https://doi.org/10.1007/s00508-017-1307-7

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Keywords

  • Cholinergic antagonists
  • Chronic obstructive pulmonary disease
  • Endophenotypes
  • Treatment failure
  • Outcome assessments