Telemonitoring in Chronic Obstructive Pulmonary Disease (CHROMED). A Randomized Clinical Trial

TLDR: In older patients with COPD and comorbidities, remote monitoring of lung function by forced oscillation technique and cardiac parameters did not change TTFH and EQ‐5D and an exploratory analysis found telemedicine was associated with fewer repeat hospitalizations.

Abstract: Rationale: Early detection of COPD exacerbations using tele-monitoring of physiological variables might reduce the frequency of hospitalisation. Objectives: To evaluate the efficacy of home monitoring of lung mechanics by the forced oscillation technique (FOT) and cardiac parameters in older COPD patients with co-morbidities. Methods: This multicentre, randomized clinical trial recruited 312 GOLD grade II-IV COPD patients (median age 71 years [IQR:66-76], 49.6% grade II, 50.4% grade III-IV), with a history of exacerbation in the previous year and at least one non-pulmonary co-morbidity. Patients were randomised to usual care (n=158) or tele-monitoring (n=154) and followed for 9 months. All tele-monitoring patients self-assessed lung mechanics daily and in a subgroup with congestive heart failure (n=37) cardiac parameters were also monitored. An algorithm identified deterioration, triggering a telephone contact to determine appropriate interventions. Measurements and Main results: Primary outcomes were time to first hospitalisation (TTFH) and change in EQ-5D utility index score. Secondary outcomes included: rate of antibiotic/corticosteroid prescriptions, hospitalisation, CAT, PHQ-9 and MLHF questionnaire scores, quality-adjusted life years and healthcare costs. Tele-monitoring did not affect TTFH, EQ-5D utility index score, antibiotic prescriptions, hospitalization rate and questionnaire scores. In an exploratory analysis, tele-medicine was associated with fewer repeat hospitalizations (-54%, p=0.017). Conclusions: In older COPD patients with co-morbidities remote monitoring of lung function by FOT and cardiac parameters did not change TTFH and EQ-5D. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01960907.

Figures

Table 2 – Corticosteroids/antibiotics prescription rates, hospitalization and re–hospitalisation rates, cost per patient and health status and depression questionnaire results

Figure 2 – Time to first hospital admission in control (continuous line) and intervention group (dashed, dark grey line). No significant difference was seen comparing the two groups.

Figure 1 – CONSORT diagram showing the flow of patients throughout the study and reason for drop out

Table 1 - Baseline characteristics of study patients.

Figure 3 – Incidence rate ratio (IRR) of hospitalizations (panel A) and systemic corticosteroids/antibiotics prescriptions (panel B) in all patients and exploratory subgroups.

Full text

1
Telemonitoring of lung function in COPD: the CHROMED study,
a randomized clinical trial
Paul P. Walker
*1
,PhD, Pasquale P. Pompilio
*2
,PhD, Paolo Zanaboni
3
,PhD, Trine S
Bergmo
3
,PhD, Kaiu Prikk
4
,MD PhD, Andrei Malinovschi
5
,PhD, Josep M. Montserrat
6
,MD,
Jo Middlemass
7
,PhD, Silvana Šonc
8
, MSc, Giulia Munaro
9
, MSc, Dorjan Marušič
8
, MSc, Ruth
Sepper
4
, PhD, Roberto Rosso
9
, MSc, A. Niroshan Siriwardena
7
, PhD, Christer Janson
10
, PhD,
Ramon Farre’
11
, PhD, Peter M.A. Calverley
#12
,PhD and Raffaele L. Dellaca’
#2,13
, PhD.
*, # : These authors contributed equally to the study
1
University Hospital Aintree, Liverpool, UK
2
Restech s.r.l., Milano, Italy
3
Norwegian Center for E-health Research, University Hospital of North Norway, Tromsø,
Norway
4
Technomedicum, Tallinn University of Technology, Tallinn, Estonia
5
Department of Medical Sciences: Clinical Physiology, Uppsala University, Sweden
6
Hospital Clinic-Universitat de Barcelona- IDIBAPS, Barcelona, Spain and CIBER de
Enfermedades Respiratorias, Madrid, Spain
7
Community and Health Research Unit, School of Health and Social Care, University of
Lincoln, England.
8
Hospital of Sežana, Sežana , Slovenia
9
Elettronica Bio Medicale S.p.a., Foligno, Italy
10
Department of Medical Sciences: Respiratory, Sleep and Allergy Research, Uppsala
University, Uppsala, Sweden
11
Unitat de Biofísica i Bioenginyeria, Facultat de Medicina i Ciències de la Salut, Universitat
de Barcelona-IDIBAPS, Barcelona, Spain and CIBER de Enfermedades Respiratorias, Madrid,
Spain
12
University of Liverpool, Liverpool, UK
13
Dipartimento di Elettronica, Informazione e Bioingegneria - DEIB, Politecnico di Milano
University, Milano, Italy
Corresponding Author: Raffaele L. Dellaca’ c/o: Dipartimento di Elettronica, Informatica e
Bioingegneria- DEIB, Politecnico di Milano University, Piazza Leonardo da Vinci 32, 20133
Milano, Italy.
E-Mail: raffaele.dellaca@polimi.it / Tel: +39 02 2399 9005 / Fax: +39 02 2399 9000
Text word count: 2969
Authors’ contributions: RLD, PMAC, RF and PPP designed the study and drafted the protocol.
RLD, PMAC, PPW, PZ and PPP wrote the manuscript with input from all authors. PZ and TB
designed and performed the cost effectiveness analysis, contributed to the drafting of the
manuscript and on its final review. PPW, KP, AM, JMM, JM, SS, DM, RS, ANS, CJ and RF
contributed to refining the study protocol, recruited and monitored the patients during the study

2
and reviewed the manuscript. GM and RR contributed to the study design, supervised the
execution of the study and reviewed the manuscript.
Funding source: This was an investigator initiated trial, funded by the European Commission
with a grant (grant no: 306093) within the call FP7-HEALTH-2012-INNOVATION-1. The
funder had no role in study design, data collection, data analysis, data interpretation, or writing
of the report. The corresponding author had full access to all the data in the study and had final
responsibility for the decision to submit for publication.
Running head: Telemonitoring of lung function in COPD: the CHROMED study
Subject category: 9.7 COPD: Exacerbations
At a Glance Commentary
Scientific Knowledge on the Subject: Despite observational studies suggesting that COPD
exacerbation can be detected using a combination of symptoms and physiological measures,
such as pulse and oxygen saturation, larger randomized controlled trials have not shown any
effect of telemonitoring on time to first hospital admission (TTFH), hospitalization and quality
of life. Tested tele-monitoring programs had a negligible impact on healthcare costs, and, in
some cases, resulted in an increased healthcare utilisation.
What This Study Adds to the Field: This randomized controlled trial of 312 COPD patients is
the first using only objective lung function data measured daily by the forced oscillation
technique to prompt early intervention. Despite being feasible and well accepted by patients,
this approach did not affect TTFH and quality of life. However, it significantly reduced
healthcare costs, mostly due to a reduction in duration and frequency of subsequent
hospitalisations, which was greatest in patients hospitalised the year before recruitment.
This article has an online data supplement, which is accessible from this issue's table of content
online at www.atsjournals.org

3
Abstract
Rationale Early detection of COPD exacerbations using tele-monitoring of physiological variables
might reduce the frequency of hospitalisation.
Objectives To evaluate the efficacy of home monitoring of lung mechanics by the forced oscillation
technique (FOT) and cardiac parameters in older COPD patients with co-morbidities.
Methods This multicentre, randomized clinical trial recruited 312 GOLD grade II-IV COPD patients
(median age 71 years [IQR:66-76], 49.6% grade II, 50.4% grade III-IV), with a history of
exacerbation in the previous year and at least one non-pulmonary co-morbidity. Patients were
randomised to usual care (n=158) or tele-monitoring (n=154) and followed for 9 months. All tele-
monitoring patients self-assessed lung mechanics daily and in a subgroup with congestive heart
failure (n=37) cardiac parameters were monitored. An algorithm identified deterioration, triggering a
telephone contact to determine appropriate interventions.
Measurements and Main results Primary outcomes were time to first hospitalisation (TTFH) and
change in EQ-5D utility index score. Secondary outcomes included: rate of antibiotic/corticosteroid
prescriptions, hospitalisation, CAT, PHQ-9 and MLHF questionnaire scores, quality-adjusted life
years and healthcare costs. Tele-monitoring did not affect TTFH, EQ-5D utility index score, antibiotic
prescriptions, hospitalization rate and questionnaire scores. Tele-medicine was associated with fewer
repeat hospitalizations (-54%, p=0.017). Previously hospitalised patients showed the greatest
reduction in hospitalization rate (-53%, p=0.017) with large potential for cost savings (-
3736€/patient/year, p=0.010).
Conclusions In older COPD patients with co-morbidities remote monitoring of lung function by FOT
and cardiac parameters did not change TTFH and EQ-5D. However patients at risk of hospitalisation
may benefit from this approach.
Keywords: Forced Oscillation technique, FOT, COPD exacerbation, Chronic Obstructive Pulmonary
disease, Home monitoring, Chronic Obstructive Pulmonary Disease

4
Introduction
Chronic obstructive pulmonary disease (COPD) is common, impairs quality of life and is a
leading cause of death worldwide
1
. Co-morbid conditions, such as cardiovascular disease often co-
exist with COPD, leading to worse outcomes
2
. Both co-morbidity and increasing age are associated
with less effective COPD self-management
3
, more frequent hospitalisation
4
and higher mortality
5–7
.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines use frequency
of exacerbation and hospitalization to stratify risk and direct treatment for COPD patients and
consider exacerbation reduction as a core management goal
1
. Pharmacological therapy
1
, pulmonary
rehabilitation
8
and influenza vaccination
9
all reduce the exacerbation rate but their impact is modest.
The use of remote tele-monitoring to detect exacerbations early is attractive as it might reduce
exacerbation duration, severity and the need for hospitalization, a major driver of healthcare costs
10
.
To date, most tele-monitoring studies in COPD have monitored symptoms and simple physiological
measures, such as heart rate and oxygen saturation, alongside enhanced clinical support
11–15
and only
a few included physiological measurements such as peak expiratory flow rate
16
. The outcomes of
these studies have been disappointing, with limited evidence of health or economic benefit
12,17
.
Moreover, none included objective, effort-independent measurements of pulmonary function.
The Forced Oscillation Technique (FOT) measures the mechanical properties of the lung
during tidal breathing in a way that is simple to perform without supervision or effort, is operator
independent and can be undertaken at home by COPD patients
18,19
. FOT can also detect changes in
lung mechanics acutely after a bronchodilator
20
and during recovery from an exacerbation
21–23
,
making it a potentially attractive way to objectively define exacerbation events in a telemonitoring
programme.
We hypothesised that, in older patients with both COPD and co-morbidities, remote
respiratory monitoring using daily FOT measurements, with or without enhanced cardiac monitoring,
would reduce the time to first hospitalization (TTFH), increase quality of life and reduce healthcare

5
costs. To test this hypothesis we conducted the CHROMED (Clinical tRials fOr elderly patients with
MultiplE Disease) study, an international randomised controlled trial funded by the European
Commission (CHROMED, project ID: 306093).
Methods
CHROMED was a multicentre, randomized unblinded parallel group clinical trial. Patients
were recruited at six sites in five countries: Spain, UK, Slovenia, Estonia and Sweden (see ONLINE
DATA SUPPLEMENT for details). The study was registered on ClinicalTrials.gov: NCT01960907.
Patients
We recruited patients aged 60 years or older, with a diagnosis of COPD GOLD grade II or
higher
24
, a history of acute exacerbation with or without hospitalization in the previous 12 months, a
smoking history of ≥10 pack/years, and one or more documented non-pulmonary chronic conditions
(see ONLINE DATA SUPPLEMENT). These included congestive heart failure (CHF), ischemic
heart disease (IHD), hypertension, hyperlipidemia and clinically significant sleep disordered
breathing. Patients with significant visual disturbance or mental health disorders that would make
them unable to use the monitoring platform, a planned prolonged absence from home, living in areas
not covered by a mobile data network or those unable to use the study equipment were excluded.
Patients were clinically stable with at least 4 weeks elapsed since their last exacerbation.
All patients provided written informed consent and the protocol was approved by the ethical
review boards of participating institutions.
Protocol
At recruitment, we recorded demographic data, measured spirometry before and 15 minutes
after inhaling 200 µg salbutamol, and administered the St George’s Respiratory Questionnaire

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Telemonitoring of lung function in copd: the chromed study, a randomized clinical trial" ?

In this paper, Walker et al. used forced oscillation technique ( FOT ) to measure the mechanical properties of the lung during tidal breathing in a way that is simple to perform without supervision or effort, and can be undertaken at home by COPD patients. 

Q2. What are the future works mentioned in the paper "Telemonitoring of lung function in copd: the chromed study, a randomized clinical trial" ?

Exacerbation duration is an important determinant of the risk for future exacerbation and disease progression35 and this may explain why patients who were hospitalised during the trial were significantly less likely to have a further hospitalisation when they were monitored. Previously hospitalised patients showed the largest cost savings exclusive of equipment costs ( 3736 €/patient/year ) suggesting that future studies should target this population. Nonetheless, applying their pre-specified health economic analysis suggested that there was a reduction in the healthcare costs in the intervention arm, with an average saving of €1712 ( 27 % lower ) per patient per year, largely driven by a reduction in hospital costs. 

Q3. What is the main driver of healthcare costs for COPD?

The use of remote tele-monitoring to detect exacerbations early is attractive as it might reduce exacerbation duration, severity and the need for hospitalization, a major driver of healthcare costs 10. 

Q4. What is the way to measure the mechanical properties of the lung during tidal?

The Forced Oscillation Technique (FOT) measures the mechanical properties of the lungduring tidal breathing in a way that is simple to perform without supervision or effort, is operator independent and can be undertaken at home by COPD patients18,19. 

Q5. What were the conditions that would make them unable to use the monitoring platform?

Patients with significant visual disturbance or mental health disorders that would make them unable to use the monitoring platform, a planned prolonged absence from home, living in areas not covered by a mobile data network or those unable to use the study equipment were excluded. 

Q6. How many alerts/patient/month were generated based on FOT parameters?

On average, 0.5 (IQR: 0.3–0.9) alerts/patient /month were generated based on FOT parameters, 1.1 (IQR: 0.8–1.4) alerts/patient/month by change in the cardiac parameters. 

Q7. What did the telemonitoring effect on the lung mechanics of older COPD patients?

In older COPD patients with co-morbidities remote monitoring of lung function by FOT and cardiac parameters did not change TTFH and EQ-5D. 

Q8. How many patients declined to participate in the study?

Of 326 patients screened, 14 declinedto participate due to concerns about the equipment or inability to perform the measurements. 

Q9. How many additional cardiac measurements were completed?

88% (IQR: 77%-95%) of the expected daily FOT measurements and 93% (IQR: 63%-98%) of the additional cardiac measurements for patients with cardiac co-morbidities were completed. 

Q10. How many physiological measures have been included in studies in COPD?

To date, most tele-monitoring studies in COPD have monitored symptoms and simple physiological measures, such as heart rate and oxygen saturation, alongside enhanced clinical support11–15 and only a few included physiological measurements such as peak expiratory flow rate16. 

Q11. What is the main reason why the study was negative?

Although ours was a negative clinical trial, it strongly suggests that using objectively defined criteria for clinical deterioration may be of value in COPD patients at risk of hospitalisation and this group should be the focus of future investigations. 

Q12. What effect did the CHROMED telemonitoring system have on re-hospital?

This effect on re-hospitalization may relate to the need for a run-in period to maximise the benefit of tele-monitoring or to a reduction in exacerbation severity during the first or subsequenthospitalisations. 

Q13. How many patients were needed to evaluate the EQ-5D utility score?

using 0.73±0.22 as an estimate of the expected EQ-5D utility score in the study population26 and anticipating a 10% drop out rate and 5% mortality rate, a sample size of at least 148 patients was needed to evaluate a minimum detectable difference of 15% of the EQ-5D utility score, with the same level of type The authorerror and power used for TTFH. 

Q14. How many additional cardiac assessments were performed?

All the patients in the intervention group performed daily FOT measurements and 37 (24%)performed additional daily cardiac assessments. 

Q15. How many patients were hospitalised in the year before enrolment?

When the authors restricted their analysis to patients hospitalised in the year before enrolment, a group at higher risk of subsequent hospitalisation, there was a 53% reduction in hospitalisation rate in monitored patients.