Optimizing management of chronic obstructive pulmonary disease in the upcoming decade

Figures & data

Figure 1 Effects of smoking and smoking cessation on decline in lung function among A male and B female adults with chronic obstructive lung disease.¹³

Notes: *P < 0.05 versus healthy never-smokers; ^#P < 0.05 versus continuous smokers.

Abbreviations: NS, never smokers (solid line); CS, continuous smokers (dashed line, long); Q < 30, smokers who quit before the age of 30 years (dashed line, short); Q30–40, smokers who quit between the ages of 30 and 40 years (dotted line); Q40+, smokers who quit after the age of 40 years (dot-dash line). A prospective evaluation of lung function (FEV₁) over time (median follow-up 23 years) in the Framingham Offspring cohort with two or more spirometry measurements during follow-up (n = 4391) indicated marked differences in the rate of lung function decline according to smoking status. Panel A illustrates the decline in FEV₁ over time among men and Panel B illustrates the decline in FEV₁ over time among women.

Table

Age at smoking cessation	Gender	FEV1 decline (95% CI)
< 30 years	Male	15.5 (11.3–19.8)
	Female	10.4 (6.3–14.5)
30–40 years	Male	24.0 (20.0–28.1)
	Female	16.5 (14.0–19.0)
> 40 years	Male	28.9 (26.1–31.1)
	Female	21.0 (18.8–23.2)

Abbreviations: Fev₁, forced expiratory volume in 1 second; CI, confidence interval. Reprinted with permission of the American Thoracic Society. Copyright © American Thoracic Society. Kohansal R, Martinez-Camblor P, Agusti A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med. 2009;180:3–10. Official journal of the American Thoracic Society.¹³

Table 1 Current pharmacologic options for the management of COPD¹

Class	Agent/s	Mode of action	Clinical effect
Long-acting β2-agonist (LABA)	Salmeterol Formoterol	Stimulate B2-adrenergic receptors in airway smooth muscle Cause increased levels of cAMP Increase the rate of ciliary transport of mucus Decreased mast cell degranulation	Bronchodilation by relaxing smooth muscle and opening airways
LAMA	Tiotropium	Inhibit muscarinic receptors Block the parasympathetic nervous system Reduce viscous mucus secretions Act on cholinergic tone, the only reversible mechanism of COPD	Bronchodilation by reducing contraction of airway smooth muscle Reduce hyperinflation
Methylxanthines (phosphodiesterase inhibitors)	Theophylline	Phosphodiesterase inhibition Raised cAMP	Limited use due to safety profile
LABA-ICS combinations	Formoterol-budesonide Salmeterol-fluticasone	As above plus ICS-associated anti-inflammatory effects	Reduce risk of exacerbation in patients with severe/very severe disease who experience repeated exacerbations
Short-acting LABA-LAMA combinations	Fenoterol/ipratropium Salbutamol (albuterol)- ipratropium	As above for long-acting agents	Only indicated as rescue medication and not maintenance therapy May be associated with increased risk of cardiovascular events

Abbreviations: cAMP, cyclic adenosine monophosphate; COPD, chronic obstructive pulmonary disease; LAMA, long-acting muscarinic antagonist; LABA, long-acting β₂-agonist; ICS, inhaled corticosteroids.

Figure 2 The stepwise approach to the management of chronic obstructive lung disease.¹

Table 2 Emerging therapies for COPD

Study	Efficacy findings	Safety findings	Reference(s)
Indacaterol
INHANCE
26 weeks, indacaterol 150 μg and 300 μg versus placebo and open-label tiotropium in moderate-to-severe COPD (n = 2059; 77% completed study)	Indacaterol improved FEV1, dyspnea, and quality of life, and reduced use of rescue medications, and exacerbations versus placebo Noninferiority to tiotropium	Adverse events: Similar incidences in all treatment groups (64%–67%); most common were COPD worsening (18%–22%) and upper RTI (7%–8%). Higher incidence of cough occurring within five minutes of indacaterol administration (17%–21% versus 0.8% and 2.4% for tiotropium and placebo, respectively). This did not increase study discontinuation rates, and cough as an adverse event did not differ across treatment groups. Mortality: Three deaths (indacaterol 150 μg, n = 1; tiotropium, n = 2), none related to treatment	Donohue et al^Citation63
INVOLVE
52 weeks, indacaterol 300 μg and 600 μg versus placebo and formoterol 12 μg in moderate-to-severe COPD (n = 1732; 74% completed study)	Indacaterol improved FEV1, dyspnea, day and night symptoms, QoL, delayed time to exacerbation, and reduced use of rescue medications	Adverse events: Similar incidences among treatment groups (62%–71%); most common (occurring >10% patients) were COPD worsening (28%–35%) and nasopharyngitis (13%–19%). Higher incidence of cough occurring within five minutes of indacaterol administration (19% versus 0.8% and 1.8% for formoterol and placebo, respectively). This did not increase study discontinuation rates. Mortality: Eight deaths during treatment (indacaterol 350 μg, n = 1; formoterol, n = 3; placebo, n = 4); the indacaterol death (cardiac arrest) suspected to be related to treatment (patient discontinued due to dyspnea).	Dahl et al^Citation64
Roflumilast
M2–124 and M1–125 52 weeks, identical studies performed in 10 and 8 countries, respectively. Assessed roflumilast 500 μg once daily versus placebo in symptomatic moderate-to-severe COPD (total n = 3091)	Combined results of M2–124 and M2–125: Roflumilast improved FEV1, dyspnea, and reduced exacerbations; there were no differences in QoL	Adverse events: Higher rate with roflumilast versus placebo (67% versus 62%) Greater weight loss observed with roflumilast. Mortality: Similar rates between treatment arms (2% in both)	Calverley et al^Citation66
M2–127 24 weeks, roflumilast 500 μg or placebo plus salmeterol in moderateto- severe COPD (total n = 933)	Salmeterol + roflumilast versus salmeterol + placebo Addition of roflumilast improved FEV1 and reduced the frequency of exacerbations. There were no differences in dyspnea, QoL, or rescue medication use	Adverse events: Weight loss, diarrhea, and nausea were more frequently observed in salmeterol + roflumilast group Withdrawals: More withdrawals occurred in the salmeterol + roflumilast versus salmeterol + placebo group	Fabbri et al^Citation68
M2–128 24 weeks, roflumilast 500 μg or placebo plus tiotropium in moderate-to-severe symptomatic COPD (total n = 933)	Tiotropium + roflumilast versus tiotropium + placebo Addition of roflumilast improved FEV1, QoL, and dyspnea and reduced rescue medication use. There were no reductions in exacerbations	Adverse events: Weight loss, diarrhea, and nausea were more frequently observed in tiotropium + roflumilast group	Fabbri et al^Citation68

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in one second; RTI, respiratory tract infection; QoL, quality of life.

Table 3 UPLIFT and TORCH efficacy summary50,72,73

Study length	Primary endpoint	Arm	Efficacy outcomes
			Lung function	Exacerbationsa				Quality of life
			Rate of decline in post-BD FEV1	Risk of exacerbation (reduction versus control)	Risk of hospitalization for exacerbation (reduction versus control)	Mean rate of exacerbations (reduction versus control)	Mean rate of hospitalization for exacerbation (reduction versus control)	Mean improvement in SGRQ total score (MCID = 4 units) (versus control)
UPLIFT
4 years	Rate of decline in FEV1	Tiotropium (n = 2986)	40 mL/year (NS versus control)	14%	14%	14%	6% (NS)	2.7 units
		Control (n = 3006)	42 mL/year	–	–	–	–	–
TORCH
3 years	Mortality	Salmeterol alone (n = 1521)	42 mL/year	Not reported	Not reported	15%	18%	1.0 units (NS)
		ICS alone (n = 1534)	42 mL/year	Not reported	Not reported	18%	12% (NS)	2.0 units
		SFC (n = 1533)	39 mL/year	Not reported	Not reported	25%	17%	3.1 units
		Control (n = 1524)	55 mL/year	Not reported	Not reported	–	–	–

Notes:

a Reductions in risk are based on hazard ratios; reductions in rates are based on rate ratios. Data are significant versus control unless indicated with NS.

Abbreviations: BD, bronchodilator; FEV₁, forced expiratory volume in one second; ICS, inhaled corticosteroid; MCID, minimal clinically important difference; NS, not significant; SFC, salmeterol plus fluticasone propionate; SGRQ, St George’s Respiratory Questionnaire; TORCH, Towards a Revolution in COPD Health; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium.

Table 4 UPLIFT and TORCH safety and mortality summary^50,72,73

Arm	Mortality	Safety
	Reduction in risk of death (versus control)a	Adverse events (% patients)	Serious adverse events (% patients)	Most common adverse events (incidence rate/year)b
UPLIFT
Tiotropium (n = 2986)	11% (NS)c 13%d	92.6	51.6	COPD exacerbations (0.38)
Control (n = 3006)	–	92.3	50.2	COPD exacerbations (0.46)
TORCH
Salmeterol alone (n = 1521)	12% (NS)	90	40	COPD exacerbations (0.76) Nasopharyngitis (0.09) Upper RTI (0.08) Headache (0.06)
ICS alone (n = 1534)	−6% (NS)	90	42	COPD exacerbations (0.78) Nasopharyngitis (0.10) Upper RTI (0.09) Pneumonia (0.07)f Headache (0.06)
SFC (n = 1533)	18% (NS)e	89	43	COPD exacerbations (0.67) Upper RTI (0.11) Nasopharyngitis (0.10) Pneumonia (0.07)fg
Control (n = 1524)	–	90	43	COPD exacerbations (0.92) Nasopharyngitis (0.09) Headache (0.08)

Notes:

a Reductions in risk of death were based on hazard ratios;

b adverse events with incidence rates of >0.05 per year;

c per protocol analysis versus control. For UPLIFT, this was intent-to-treat + 30-day washout and for TORCH this was ITT (no washout); the results were not statistically significant for both studies (P = 0.09 for UPLIFT; P = 0.052 for SFC in TORCH);

d for comparison, the ITT (no washout) results for UPLIFT are shown, for which the result was statistically significant;

e adjusted for interim analyses;

f statistically significant increase versus control;

g statistically significant increase versus salmeterol.

Abbreviations: NS, not significant; COPD, chronic obstructive pulmonary disease; RTI, respiratory tract infection; ICS, inhaled corticosteroid; SFC, salmeterol plus fluticasone propionate; ITT, intent to treat; TORCH, Towards a Revolution in COPD Health; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium.

Figure 3 Impact of maintenance bronchodilation on A) the rate of decline in lung function, B) exacerbations, and C) quality of life.^50,72,73

Notes: A) *P < 0.003 versus placebo; ^†P f< 0.001 versus; B) *P < 0.001 versus control; ^†P < 0.02 versus salmeterol; ^‡P < 0.02 versus fluticasone; C) *P < 0.001 versus control.

Abbreviation: TORCH, Towards a Revolution in COPD Health; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium; Fev1, forced expiratory volume in one second; SGRQ, St George’s Respiratory Questionnaire; NS, nonsignificant versus control.

Table 5 UPLIFT and TORCH subgroup efficacy results for earlier disease^18,19,77,78

Subgroup	Arm	Efficacy outcomes
		Lung function	Exacerbationsa				Quality of life
		Rate of decline in post-BD FEV1	Risk of exacerbation (reduction versus control)	Risk of hospitalization for exacerbation (reduction versus control)	Mean rate of exacerbations (reduction versus control)	Mean rate of hospitalization for exacerbation (reduction versus control)	Mean improvement in SGRQ total score (MCID = 4 units) (versus control)
UPLIFT
GOLD II^Citation18	Tiotropium (n = 1384)	43 mL/year	18%	26%	20%	20% (NS)	2.7–4.0 units
	Control (n = 1355)	49 mL/year	–	–	–	–	–
Maintenance-naïve^Citation78	Tiotropium (n = 403)	42 mL/year	Not reported	23%	16% (NS)	Not reported	4.6 units
	Control (n = 407)	53 mL/year	–	–	–	–	–
Age ≤ 50 years^Citation77	Tiotropium (n = 184)	38 mL/year	13%	Not reported	27%	Not reported	0.9 units (NS)
	Control (n = 172)	58 mL/year	–	–	–	–	–
TORCH
GOLD II^Citation19	Salmeterol alone (n = 1521)	40 mL/year	Not reported	Not reported	Not reported	Not reported	0.2 unitsb
	ICS alone (n = 1534)	46 mL/year	Not reported	Not reported	Not reported	Not reported	0.8 unitsb
	SFC (n = 1533)	44 mL/year	Not reported	Not reported	31%b	Not reported	2.4 unitsb
	Control (n = 1524)	60 mL/year	–	–	–	–	–

Notes:

a Reductions in risk are based on hazard ratios; reductions in rates are based on rate ratios;

b statistical significance not reported. Results are significant versus control unless indicated with NS.

Abbreviations: BD, bronchodilator; FEV₁, forced expiratory volume in one second; QoL, quality of life; SGRQ, St George’s Respiratory Questionnaire; MCID, minimal clinically important difference; UPLIFT, Understanding Potential Long-term Impacts on Function with Tiotropium; GOLD, Global Initiative for Chronic Obstructive Lung Disease; TORCH, Towards a Revolution in COPD Health; ICS, inhaled corticosteroid; SFC, salmeterol plus fluticasone propionate; NS, not significant.

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