Impact and prevention of severe exacerbations of COPD: a review of the evidence

Figures & data

Figure 1 Hazard function of successive hospitalized COPD exacerbations (per 10,000 per day) for a cohort of 73,106 patients from the time of their first ever hospitalization for a COPD exacerbation over the follow-up period, with the time between successive exacerbations estimated using the median inter-exacerbation times as time to the next exacerbation or death, whichever occurs first.

Note: Adapted from Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality, Suissa S, Dell’Aniello S, Ernst P, Volume 67, pages 957–963, copyright 2012 with permission from BMJ Publishing Group Ltd.⁴

Figure 2 Emergency room visits and hospitalizations due to COPD exacerbations: Continuing to Confront COPD International Patient Survey.

Notes: Adapted with permission of Dove Medical Press Ltd, from Continuing to Confront COPD International Patient Survey: methods, COPD prevalence, and disease burden in 2012–2013, Landis SH, Muellerova H, Mannino DM, et al, Volume 9, Copyright 2006; permission conveyed through Copyright Clearance Center, Inc.⁴¹ Calculated from response to the questions “In the past 12 months, did any of these episodes (worsening of your breathing problems) require an ER visit?” and “In the past 12 months, did any of these episodes (worsening of your breathing problems) require hospitalization?”

Table 1 Risk factors for severe exacerbations in COPD

Proposed risk factors for severe exacerbations by category
Lung function	• Lower lung-function levels lead to higher rates of severe exacerbations and hospitalizations.^Citation50–Citation53,Citation65,Citation66,Citation70,Citation74
Dyspnea	• Severe dyspnea and recurring exacerbations are related to high health-care resource utilization, including frequent emergency visits and hospital admissions.^Citation6,Citation54 • More than half (53%) of patients with MRC breathlessness scale scores 3–5 in the Global Hidden Depths of COPD survey had experienced an exacerbation requiring hospitalization in the previous year.^Citation57
BODE index	• Worsening (higher) BODE index score is associated with increased risk of exacerbation^Citation61 and hospital admission for an exacerbation.^Citation54,Citation55
Health status	• Poor health status predicts increased hospitalizations.^Citation6,Citation26,Citation62,Citation64,Citation66 • Impairment in health status and quality of life in COPD is a marker of risk for both frequent exacerbations and hospital admissions.^Citation77
Prior exacerbations, hospital visits, and hospital admissions	• Frequency and proximity of previous exacerbations predicts subsequent exacerbations and hospitalizations.^Citation4–Citation6,Citation52,Citation53,Citation66,Citation70,Citation74,Citation78 • History of hospitalized exacerbations in the past 12 months is the strongest risk factor for future hospitalized exacerbation in ECLIPSE.^Citation6 • Severe exacerbation risk increases threefold after the second exacerbation requiring hospitalization and 24-fold after the tenth exacerbation.^Citation4 • Prior ER visits are a significant risk factor for exacerbation-related hospitalization.^Citation55
Age	• Older age is a significant risk factor for hospitalization.^Citation62,Citation70 • Older age is associated with shorter time to first readmission.^Citation69
Duration of COPD	• Patients with a longer history of COPD (>5 years) are approximately twice as likely to have frequent readmissions for COPD exacerbations.^Citation59
Comorbidities	• Presence of significant comorbidities (eg, diabetes mellitus, cardiac insufficiency, ischemic heart disease) is associated with increase in risk, specifically for severe exacerbations requiring hospitalization.^Citation50 • Comorbidities associated with increased risk of hospitalization include cardiovascular disease, diabetes, asthma, psychiatric disorders (anxiety, depression), gastroesophageal reflux disease, and pulmonary hypertension.^Citation19,Citation50,Citation58,Citation64,Citation68,Citation75
Blood-gas levels	• Hypercapnia and poor arterial blood-oxygen saturation have been reported as being associated with hospitalization for a COPD exacerbation.^Citation55,Citation67
BMI	• Low BMI is associated with hospitalization and readmission for COPD exacerbation.^Citation67,Citation72
Smoking status	• Evidence regarding impact of smoking status on risk of hospitalization is mixed,^Citation56 with some studies suggesting current smoking was associated with lower risk of hospitalization,^Citation52,Citation70 others finding no association,^Citation50,Citation67 and others indicating that smoking cessation reduces risk.^Citation63
Use of LTOT	• Patients on LTOT are at increased risk of hospitalization for exacerbation.^Citation67 • Underprescription of LTOT increases the risk of hospitalization, due to severe exacerbations.^Citation52
Socioeconomic status	• Poorer health literacy increases the likelihood of COPD-related hospitalizations and emergency department visits.^Citation71 • Lowest education category and lowest income class are associated with a greater risk of hospitalization for exacerbations.^Citation60 • Unmarried patients are at greater risk of hospital readmission than those with spousal support; patients requiring social work intervention are likely to have an increased length of stay for hospitalized COPD exacerbations.^Citation76

Abbreviations: BMI, body-mass index; BODE, BMI, airway obstruction, dyspnea, and exercise capacity; ER, emergency room; LTOT, long-term oxygen therapy; MRC, Medical Research Council.

Table 2 Randomized, controlled clinical trials assessing the effectiveness of inhaled long-acting bronchodilators, ICS, or combination therapy for reducing the risk of severe (hospitalized) exacerbations of COPD

Treatment comparison	Trial	Patients, N; study length	Outcomes
			Measures	Results	Description	P-value
Monotherapy versus placebo or monotherapy
Tiotropium Respimat^® versus placebo	Bateman et al^Citation114	3,991; 48 weeks	Time to first severe exacerbation	Placebo < tiotropium	HR 0.73, 95% CI 0.59–0.9	<0.005
			Risk of severe exacerbation	Tiotropium ↓ placebo	RR 0.81, 95% CI 0.7–0.93	<0.005
	Bateman et al^Citation115 (two duplicate studies)	1,990; 1 year	Annual incidence of severe exacerbations	Tiotropium (Respimat^® 5 μg) ↓ placebo	0.12 and 0.2 hospitalizations per patient-year	Not reported
			Patients with ≥1 hospitalization	Tiotropium (Respimat^® 5 μg) = placeboa	5.8% versus 6.7% for placebo	NS
Tiotropium HandiHaler^® versus placebo	Casaburi et al^Citation116 (two duplicate studies)	921; 1 year	Rate of severe exacerbations	Tiotropium ↓ placebo, by 47%	0.086 versus 0.161 events/patient-year	0.019
			Patients with ≥1 hospitalization	Tiotropium ↓ placebo, by 41%	5.5% versus 9.4%	<0.05
			Days in hospital for exacerbation	Tiotropium ↓ placebo, by 50%	0.6 days per patient-year versus 1.2 days/patient-year	0.023
	Chan et al^Citation117	913; 48 weeks	Number of severe exacerbations	Tiotropium = placebo	0.13 versus 0.15 events/patient-year	0.557
			Number of days in hospital	Tiotropium = placebo	1.14 versus 1.16 days/patient-year	0.775
	Niewoehner et al^Citation118	1,829; 6 months	Time to first severe exacerbation	Placebo = tiotropiuma	HR 0.73, 95% CI 0.53–1.01	0.055
			Patients with ≥1 hospitalization	Tiotropium = placeboa	7% versus 9.5%, OR 0.72, 95% CI 0.51–1.01	0.056
	UPLIFT^Citation119	5,993; 4 years	Time to first hospitalized exacerbation	Placebo < tiotropium	HR 0.86, 95% CI 0.78–0.95	0.002
Glycopyrronium versus placebo	GLOW1^Citation120	822; 26 weeks	Risk of severe exacerbation	Glycopyrronium < placebo	HR 0.35, 95% CI 0.141–0.857	0.022
Tiotropium HandiHaler^® versus glycopyrronium study also included an indacaterol–glycopyrronium arm	SPARK (Wedzicha et al)^Citation130	2,224; 64 weeks	Annual rate of severe exacerbations	Tiotropium ↓ glycopyrronium	0.08 versus 0.12, RR 1.43, 95% CI 1.05–1.97	0.025
Tiotropium HandiHaler^® versus salmeterol and placebo	Brusasco et al^Citation121 (two duplicate studies)	1,207; 6 months	Time to first hospitalized exacerbation	Not reported	Not applicable	Not reported
			Hospital admissions	Tiotropium = salmeterol or placeboa	0.1 versus 0.17 or 0.15 events/patient-year	NS
Tiotropium HandiHaler^® versus indacaterol	INVIGORATE^Citation122	3,444; 52 weeks	Annual rate of severe (hospitalized) exacerbations	Tiotropium ↓ indacaterol	0.07 versus 0.1, RR 1.36, 95% CI 1.03–1.79	0.03
Tiotropium HandiHaler^® versus salmeterol	POET-COPD^Citation123	7,376; 1 year	Risk of severe exacerbations	Tiotropium < salmeterol, by 28%	HR 0.72, 95% CI 0.61–0.85	<0.001
Tiotropium Respimat^® versus tiotropium HandiHaler^®	TIOSPIR^Citation124	17,135; 2.3 years	Risk of severe exacerbation	Tiotropium (Respimat^®) = tiotropium (HandiHaler^®)	HR 1.02, 95% CI 0.93–1.13	0.64
Combination therapy versus monotherapy or placebo
Mometasone–formoterol versus mometasone, formoterol, and placebo	Doherty et al^Citation125	1,201; 1 year (26-week treatment, 26-week safety extension)	Incidence of severe exacerbations	Mometasone + formoterol 400+10 μg BID, mometasone + formoterol 200+10 μg BID, mometasone and formoterol monotherapies BID ↓ placebo BID	4.4%, 1.7%, 2.4%, 2.1%, and 5.1%, respectively	Not reported
			Incidence of moderate or severe first exacerbations	Mometasone + formoterol 400+10 μg BID, mometasone + formoterol 200+10 μg BID ↓ placebo	15.4% and 12.8%, respectively, versus 24.6%	≤0.006
Umeclidinium–vilanterol versus umeclidinium and placebo	Donohue et al^Citation126	563; 1 year	Patients with >1 hospitalization	Umeclidinium–vilanterol and umeclidinium ↓ placebo	6% and 7% versus 12%	Not reported
Tiotropium HandiHaler^® versus fluticasone–salmeterol	INSPIRE^Citation127	1,323; 2 years	Incidence of exacerbations requiring hospitalizations	Tiotropium = fluticasone–salmeterol	13% versus 16%	0.085
Fluticasone–vilanterol versus vilanterol	NCT1009463/NCT1017952^Citation128	3,255; 1 year	Annual rate of severe exacerbations (pooled analysis of study 1 and study 2)	Fluticasone + vilanterol 50+25 μg = vilanterol 25 μg	0.08 versus 0.1, RR 0.8, 95% CI 0.6–1.2	0.3133
				Fluticasone + vilanterol 100+25 μg = vilanterol 25 μg	0.09 versus 0.1, RR 0.9, 95% CI 0.6–1.4	0.6948
				Fluticasone + vilanterol 200+25 μg = vilanterol 25 μg	0.08 versus 0.1, RR 0.8, 95% CI 0.5–1.2	0.2802
Budesonide–formoterol versus formoterol	Sharafkhaneh et al^Citation129	1,219; 1 year	Number of severe exacerbations per patient-treatment year	Budesonide + formoterol 320+9 μg BID = formoterola	0.106 versus 0.144, treatment ratio 0.732, 95% CI 0.52–1.03	0.07
				Budesonide + formoterol 160+9 μg BID = formoterola	0.127 versus 0.144, treatment ratio 0.878, 95% CI 0.64–1.22	0.433
Tiotropium HandiHaler^® versus indacaterol–glycopyrronium study also included a glycopyrronium arm	SPARK (Wedzicha et al)^Citation130	2,224; 64 weeks	Annual rate of severe exacerbations	Tiotropium = indacaterol–glycopyrronium	0.08 versus 0.09, RR 1.16, 95% CI 0.84–1.61	0.36
Mometasone–formoterol versus mometasone, formoterol, and placebo	Tashkin et al^Citation131	2,251; 26 weeks	Incidence of severe exacerbations	Mometasone + formoterol 200+10 μg BID, mometasone + formoterol 400+10 μg BID, mometasone and formoterol monotherapies BID, all ↓ placebo	1.6%, 3.4%, 2.4%, and 2.4% versus 4.2%, respectively	Not reported
Salmeterol–fluticasone versus placebo, salmeterol alone, and fluticasone alone	TORCH^Citation132	6,112; 3 years	Annual rate of severe exacerbation	Salmeterol–fluticasone ↓ placebo	0.16 versus 0.19, RR 0.83, 95% CI 0.71–0.98	0.03
				Salmeterol–fluticasone = salmeterol	0.16 versus 0.16, RR 1.02, 95% CI 0.87–1.2	0.79
				Salmeterol–fluticasone = fluticasone	0.16 versus 0.17, RR 0.95, 95% CI 0.82–1.12	0.56
Combination therapy versus other combination therapy
Indacaterol–glycopyrronium versus salmeterol–fluticasone	FLAME (Wedzicha et al)^Citation133	3,362; 1 year	Annual rate of severe exacerbations	Indacaterol–glycopyrronium = salmeterol–fluticasone	0.15 versus 0.17, RR 0.87, 95% CI 0.69–1.09	0.23
			Time to first severe exacerbation	Indacaterol–glycopyrronium > salmeterol–fluticasone	HR 0.81, 95% CI 0.66–1	0.046
Indacaterol–glycopyrronium versus free combination of tiotropium HandiHaler® plus formoterol	QUANTIFY (Buhl et al)^Citation134	934; 26 weeks	Rate of severe exacerbations	Indacaterol–glycopyrronium = tiotropium–formoterol	2.1% versus 2.4%, RR 0.88, 95% CI 0.38–2.01	0.759

Notes:

a Large numerical differences noted between comparators. Table includes randomized studies examining the outcome of severe (hospitalized) exacerbations in >500 patients with COPD; for HRs showing time to first severe exacerbation, < and > indicate shorter and longer time to event, or lower and higher risk of severe event versus comparator, respectively. Note: For POET-COPD¹²³ < is used to indicate a lower risk with tiotropium versus comparator; P-values <0.05 are deemed statistically significant; ↓ indicates a lower or RR, rate or incidence of severe exacerbations versus comparator; = indicates no statistically significant difference between comparators; NS indicates no statistically significant difference between comparators, as stated in the publication text (ie, no P-values provided).

Abbreviations: BID, bis in die (twice daily); HR, hazard ratio; ICS, inhaled corticosteroid; OR, odds ratio; RR, rate ratio.

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