Evaluation of Exacerbation and Symptom-Free Time in Patients with COPD

Figures & data

Table 1. Definition of a COPD exacerbation and comorbid flare-up.^a

	Definition
COPD exacerbation	Onset was defined as “a significant negative change in two major symptoms (breathlessness, sputum production, sputum colour) or one major and one minor symptom (cough, wheeze, running nose, sore throat, fever (>38.5°)) from baseline, for at least two consecutive days.” Recovery was defined as the first day of: 1) three successive days that the patient has returned to his usual health state; or 2) seven consecutive days on which the patient continuously reports no or only a slight increase in symptoms compared to baseline, with no fever or change in sputum colour [32–34].
Chronic Heart Failure flare-up	Onset was defined as a “clear negative change in at least one symptom (fluid retention: weight, swelling of ankles or abdomen, wake up at night short of breath) from baseline, for at least two consecutive days.” The last day was defined as the first day of: 1) three consecutive successive days that the patient has returned to his usual baseline cardiac health state; 2) seven consecutive days on which patients continuously reported no or only a slightly increase of CHF symptoms compared to baseline [33,34].
Anxiety flare-up	Onset was defined as a “clear negative change in anxiety symptoms from baseline, for at least five consecutive days.” The last day of the flare-up was defined as the first day of: 1) five consecutive successive days that the patient has returned to his usual baseline anxiety health state; 2) seven consecutive days on which patients continuously reported no or only a slightly increase of anxiety symptoms compared to baseline [33,34].
Depression flare-up	Onset was defined as a “clear negative change in depression symptoms from baseline, for at least five consecutive days.” The last day of the flare-up was defined as the first day of: 1) five consecutive successive days that the patient has returned to his usual baseline depression health state; 2) seven consecutive days on which patients continuously reported no or only a slightly increase of depression symptoms compared to baseline [33,34].

Abbreviations: COPD = Chronic Obstructive Pulmonary Disease; CHF = Chronic Heart Failure.

^a To be eligible for inclusion, COPE-III patients had to have at least one comorbidity (Ischemic Heart Disease (IHD), Chronic Heart Failure, Diabetes Mellitus (DM), anxiety, depression) [33,34]. The COPE-III study data [33] did however not provide insight in flare-ups of IHD and DM  because: 1) changes in IHD-related symptoms required immediate action (because of safety) and were therefore seen as a once-off event and not as a flare-up; 2) actions for DM were only directed during medication treatment of a COPD exacerbation and no further DM diary data were collected, so no information regarding DM flare-ups could be extracted.

Table 2. Patient characteristics measured at baseline.

	Combined group (n = 313)	COPE-II (n = 142)	COPE-III (n = 171)	p-value
Age (years)	66.0 (±8.6)	63.4 (±7.9)	68.2 (±8.5)	<0.01*
Men	199 (63.6%)	84 (59.2%)	115 (67.3%)	0.14
Smoker	79 (25.2%)	47 (33.1%)	32 (18.7%)	<0.01*
Body mass index^a	28.1 (±5.9)	26.6 (±4.7)	29.4 (±6.4)	<0.01*
COPD classification^a				<0.01*
GOLD I	6 (1.9%)	6 (4.3%)	0 (0%)
GOLD II	156 (50.0%)	60 (42.6%)	96 (56.1%)
GOLD III	124 (39.7%)	59 (41.8%)	65 (38.0%)
GOLD IV	26 (8.3%)	16 (11.3%)	10 (5.9%)
FEV1 (l)^a	1.42 (±0.52)	1.42 (±0.53)	1.41 (±0.52)	0.84
FEV1 (%)	51.2 (±15.5)	50.2 (±15.7)	52.0 (±15.3)	0.30
FEV1/FVC	46.6 (±13.1)	44.2 (±12.2)	48.5 (±13.5)	<0.01*
mMRC dyspnea score^b	1.74 (±1.13)	1.32 (±1.10)	2.09 (±1.03)	<0.01*
HRQoL domains (CRQ)
Emotional functioning	4.88 (±1.14)	5.05 (±1.10)	4.74 (±1.15)	0.02*
Mastery	5.11 (±1.14)	5.35 (±1.11)	4.91 (±1.13)	<0.01*
Dyspnea	4.35 (±1.42)	4.50 (±1.42)	4.23 (±1.40)	0.08
Fatigue	4.05 (±1.27)	4.35 (±1.28)	3.80 (±1.21)	<0.01*
HADS domains^a
Anxiety	5.80 (±4.02)	4.71 (±3.70)	6.70 (±4.07)	<0.01*
Depression	5.63 (±3.94)	4.53 (±3.76)	6.53 (±3.87)	<0.01*
Comorbidities	215 (68.7%)	44 (31.0%)	171 (100%)	<0.01*
Cardiovascular disease^c	137 (43.8%)	30 (21.1%)	107 (62.6%)	<0.01*
Ischaemic heart disease	NA	ND	80 (46.8%)
Chronic heart failure	NA	ND	40 (23.4%)
Anxiety^d	51 (16.3%)	15 (10.6%)	36 (21.1%)	0.01*
Based on HADS	45 (14.4%)	15 (10.6%)	30 (17.5%)
Active treatment	NA	ND	6 (3.5%)
Depression^d	60 (19.2%)	13 (9.2%)	47 (27.5%)	<0.01*
Based on HADS	42 (13.4%)	13 (9.2%)	29 (17.0%)
Active treatment	NA	ND	18 (10.5%)
Diabetes mellitus	NA	ND	63 (36.8%)	NA
Type 1	NA	ND	2 (1.2%)
Type 2	NA	ND	60 (35.1%)
Glucocorticoid-induced	NA	ND	1 (0.6%)

Data are presented as mean (±standard deviation (SD)) or number (%). Abbreviations: COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease [1]; FEV₁=forced expiratory volume in 1 s; FVC = forced vital capacity; mMRC = modified Medical Research Council [35]; HRQoL = Health-related quality of life; CRQ = Chronic Respiratory Questionnaire [36]; HADS = Hospital Anxiety and Depression Scale [37]; NA = not applicable; ND = not documented.

^* Significantly different (p < 0.05) between the COPE-II and COPE-III populations.

a Body mass index, COPD GOLD classification score, FEV₁ (%), and HADS score were missing for one patient (0.32%).

b MRC dyspnea scores (range 1 to 5) as used in COPE-II [32] were converted to mMRC scores (range 0 to 4).

c Patients with a cardiovascular disease could be diagnosed with IHD, CHF, anomalies in cardiac action potentials, myocardial infarction, and/or arrhythmia.

d All patients were diagnosed with anxiety and/or depression based on HADS scores (≥11) [32–34]. COPE-III patients could also have a clinical diagnosis if actively treated for anxiety and/or depression at the time of inclusion [33,34].

Table 3. Changes in health outcomes after 12 months of follow-up compared to baseline.

	Combined group (n = 313)	COPE-II (n = 142)	COPE-III (n = 171)	p-value
COPD exacerbations
Frequency (patient/year)	2 (1–4)	3 (1–5)	1 (0–4)	<0.01*
Days (patient/year)	22 (4–51)	32 (11–67.5)	13 (0–39)	<0.01*
Duration in days (exacerbation/patient/year)	8 (3–13.5)	10.7 (6–14.5)	6.5 (0–11)	<0.01*
All-cause hospitalizations	86 (27.5%)	26 (18.3%)	60 (35.1%)	<0.01*
Frequency (patient/year)	0 (0–1)	0 (0–0)	0 (0–1)	<0.01*
Days (patient/year)	0 (0–3.5)	0 (0–0)	0 (0–6)	<0.01*
Duration in days (hospitalization/patient/year)	0 (0–3)	0 (0–0)	0 (0–4.7)	<0.01*
Medication
Self-reported courses of Prednisolone	1 (0–3)	2 (1–4)	1 (0–3)	<0.01*
Self-reported courses of antibiotics	1 (0–3)	1 (0–3)	0 (0–2)	<0.01*
mMRC dyspnea score^a,^b	0.07 (±1.6)	−0.05 (±1.24)	0.17 (±0.87)	0.10
HRQoL domains (CRQ)^b
Emotional functioning	0.13 (±0.98)	0.15 (±0.97)	0.11 (±0.99)	0.79
Mastery	0.25 (±0.94)	0.27 (±0.94)	0.25 (±0.95)	0.73
Dyspnea	0 (±1.07)	0.16 (±1.04)	−0.14 (±1.08)	0.02*
Fatigue	0.07 (±1.14)	0.12 (±1.33)	0.03 (±0.94)	0.54
HADS domains^b
Anxiety	−0.84 (±3.08)	−0.66 (±2.84)	−0.99 (±3.27)	0.36
Depression	−0.49 (±2.65)	−0.55 (±2.63)	−0.44 (±2.68)	0.73

Data are presented in median (interquartile range (IQR)), mean (±SD) or number (%). Abbreviations: COPD = Chronic Obstructive Pulmonary Disease; ND = not documented; mMRC = modified Medical Research Council [35]; HRQoL = Health-related quality of life; CRQ = Chronic Respiratory Questionnaire [36]; HADS = Hospital Anxiety and Depression Scale [37]. ^*Significantly different (p < 0.05) between the COPE-II and COPE-III populations.

a MRC dyspnea scores (range 1 to 5) as used in COPE-II [32] were converted to mMRC dyspnea scores (range 0 to 4).

^b Presented mMRC, CRQ, and HADS data are the 12-month follow-up scores minus the baseline scores. Positive scores indicate worsening of mMRC and HADS, and improvement of CRQ. mMRC, CRQ, and HADS scores were missing for 32 (10.2%), 28 (9.0%), and 30 (9.6%) patients, respectively.

Table 4. Primary and secondary outcomes.

	Combined group (n = 313)	COPE-II (n = 142)	COPE-III (n = 171)	p-value
Primary outcomes
COPD exacerbation-free days (patient/year)	342 (307–361)	330 (290–352)	351 (320–365)	<0.01*
Days with no more symptoms than usual (patient/year)	285 (212–330)	274 (183–324)	293 (227–337)	0.06
Secondary outcome
Combined COPD exacerbation and comorbid flare-up-free days (patient/year)	NA	ND	350 (309–365)	NA

Data are presented in median (IQR). Abbreviations: COPD = Chronic Obstructive Pulmonary Disease; NA = not applicable; ND = not documented. ^*Significantly different (p < 0.05) between the COPE-II and COPE-III populations.

Table 5. Associations of the number of COPD exacerbation-free days, days with no more symptoms than usual, and combined free days of COPD exacerbations and comorbid flare-ups with patient characteristics (negative binomial regression analyzes).

Dependent variable	Independent variables	IRR (95% CI)	p-value
Number of COPD exacerbation-free days (patient/year) (n = 313)	Self-treatment intervention^a	1.04 (0.99–1.10)	0.12
	Having no comorbidity^b	0.94 (0.88–0.99)	0.03*
	CRQ fatigue domain	1.03 (1.01–1.05)	0.02*
	CRQ mastery domain	1.03 (1.00–1.06)	0.04*
Number of days with no more symptoms than usual (patient/year) (n = 313)	Self-treatment intervention^a	1.04 (0.94–1.16)	0.44
	CRQ fatigue domain	1.05 (1.00–1.10)	0.04*
	CRQ mastery domain	1.06 (1.00–1.12)	0.04*
Number of combined COPD exacerbation and comorbid flare-up-free days^c (patient/year) (n = 171)	Self-treatment intervention^a	1.01 (0.95–1.08)	0.76
	mMRC	0.95 (0.92–0.98)	<0.01*
Sensitivity analyzes (including data of only those patients who completed the entire 12-month follow-up of symptoms diary data)
Number of COPD exacerbation-free days (patient/year) (n = 173)	Self-treatment intervention^a	1.04 (0.98–1.11)	0.24
	Having no comorbidity^b	0.94 (0.87–1.00)	0.05
	CRQ fatigue domain	1.02 (0.99–1.06)	0.12
	CRQ mastery domain	1.04 (1.00–1.07)	0.03*
Number of days with no more symptoms than usual (patient/year) (n = 173)	Self-treatment intervention^a	1.02 (0.88–1.18)	0.83
	CRQ fatigue domain	1.07 (1.00–1.15)	0.07
	CRQ mastery domain	1.10 (1.02–1.19)	0.02*
Number of combined COPD exacerbation and comorbid flare-up-free days^c (patient/year) (n = 75)	Self-treatment intervention^a	1.00 (0.91–1.10)	0.99
	mMRC	0.95 (0.91–0.99)	0.03*

Abbreviations: IRR = incidence rate ratio; CI = confidence interval; COPD = Chronic Obstructive Pulmonary Disease; CRQ = Chronic Respiratory Questionnaire; mMRC = modified Medical Research Council. ^*p < 0.05.

a Control group was set as reference.

b Having a comorbidity was set as reference.

c Data obtained with the included subsample of patients from the COPE-III study population [33].

Table 6. Associations of the number of COPD exacerbation-free days, days with no more symptoms than usual, and combined free days of COPD exacerbations and comorbid flare-ups with health outcomes (negative binomial regression analyzes).

Dependent variable	Independent variables	IRR (95% CI)	p-value
Number of COPD exacerbation-free days (patient/year) (n = 313)	Self-treatment intervention^a	1.06 (1.01–1.11)	0.01*
	Number of courses antibiotics	0.95 (0.94–0.96)	<0.01*
Number of days with no more symptoms than usual (patient/year) (n = 285)	Self-treatment intervention^a	1.09 (0.98–1.21)	0.13
	CRQ dyspnea domain^b	1.07 (1.01–1.12)	0.02*
	Number of courses antibiotics	0.94 (0.91–0.96)	<0.01*
Number of combined COPD exacerbation and comorbid flare-up-free days^c (patient/year) (n = 171)	Self-treatment intervention^a	1.00 (0.95–1.06)	0.91
	Number of courses antibiotics	0.94 (0.93–0.95)	<0.01*
Sensitivity analyzes (including data of patients who completed the 12-month follow-up symptoms diary data)
Number of COPD exacerbation-free days (patient/year) (n = 173)	Self-treatment intervention^a	1.07 (1.01–1.13)	0.02*
	Number of courses antibiotics	0.95 (0.94–0.97)	<0.01*
Number of days with no more symptoms than usual (patient/year) (n = 168)	Self-treatment intervention^a	1.07 (0.92–1.24)	0.41
	CRQ dyspnea domain^b	1.09 (1.01–1.17)	0.02*
	Number of courses antibiotics	0.94 (0.91–0.97)	<0.01*
Number of combined COPD exacerbation and comorbid flare-up-free days^c (patient/year) (n = 75)	Self-treatment intervention^a	0.98 (0.91–1.06)	0.68
	Number of courses antibiotics	0.94 (0.93–0.96)	<0.01*

Abbreviations: IRR = incidence rate ratio; CI = confidence interval; COPD = Chronic Obstructive Pulmonary Disease; CRQ = Chronic Respiratory Questionnaire. ^*p < 0.05.

a Control group was set as reference.

b The score measured after 12-month follow-up minus the baseline score.

c Data obtained with the included subsample of patients from the COPE-III study population [33].

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Data availability statement

Data that support the findings of this study are available upon reasonable request (corresponding author, A. Lenferink).