Severe exacerbation and pneumonia in COPD patients treated with fixed combinations of inhaled corticosteroid and long-acting beta2 agonist

Figures & data

Figure 1 Flow chart of study cohort selection.

Table 1 Baseline characteristics of COPD patients prescribed fluticasone/salmeterol and budesonide/formoterol before and after matching by propensity score matching

Variables	Before propensity score matching					After propensity score matching
	Fluticasone/salmeterol		Budesonide/formoterol		P-value	Fluticasone/salmeterol		Budesonide/formoterol		P-value
Patient (n)	11,519		7,437			7,295		7,295
Age (year)	65.95±10.26		63.28±10.40		<0.0001	63.66±10.33		63.53±10.30		0.4334
Male gender	8,801	76.40%	5,434	76.14%	<0.0001	5,386	73.83%	5,360	73.47%	0.6251
Index year
2004	1,963	17.04%	1,430	20.04%	<0.0001	1,439	19.73%	1,408	19.30%	0.9301
2005	1,261	10.95%	1,231	17.25%		1,102	15.11%	1,146	15.71%
2006	1,326	11.51%	990	13.87%		987	13.53%	972	13.32%
2007	1,486	12.90%	973	13.63%		991	13.58%	967	13.26%
2008	1,375	11.94%	843	11.81%		841	11.53%	833	11.42%
2009	1,543	13.40%	762	10.68%		746	10.23%	762	10.45%
2010	1,571	13.64%	815	11.42%		818	11.21%	814	11.16%
2011	994	8.63%	393	5.51%		371	5.09%	393	5.39%
Monthly income, n (%)
<19,100	4,040	35.07%	2,481	34.76%	0.0006	2,429	33.30%	2,455	33.65%	0.8927
19,100–41,999	6,012	52.19%	3,874	54.28%		3,831	52.52%	3,805	52.16%
≥42,000	1,467	12.74%	1,082	15.16%		1,035	14.19%	1,035	14.19%
Hospital level, n (%)
Level 1	4,651	40.38%	3,077	43.11%	<0.0001	2,944	40.36%	3,004	41.18%	0.7384
Level 2	4,887	42.43%	2,907	40.73%		2,920	40.03%	2,880	39.48%
Level 3	1,477	12.82%	1,016	14.24%		1,016	13.93%	990	13.57%
Level 4 (rural area)	504	4.38%	437	6.12%		415	5.69%	421	5.77%
COPD severe AE
0	6,340	55.04%	4,580	64.17%	<0.0001	4,443	60.90%	4,457	61.10%	0.7490
1	1,915	16.62%	1,102	15.44%		1,122	15.38%	1,090	14.94%
≥2	3,264	28.34%	1,755	24.59%		1,730	23.71%	1,748	23.96%
Medication for COPD
LABA	412	3.58%	366	5.13%	<0.0001	338	4.63%	347	4.76%	0.7247
SABA	3,400	29.52%	2,514	35.22%	<0.0001	2,396	32.84%	2,426	33.26%	0.5975
LAMA	1,488	12.92%	711	9.96%	<0.0001	694	9.51%	708	9.71%	0.6941
ICS	3,155	27.39%	2,591	36.30%	<0.0001	2,459	33.71%	2,478	33.97%	0.7396
Medication for hypertension
Alpha-blocker	1,258	10.92%	782	10.96%	0.3784	802	10.99%	774	10.61%	0.4552
Beta-blocker	3,159	27.42%	1,910	26.76%	0.0082	1,902	26.07%	1,889	25.89%	0.8061
Calcium-channel Blocker	5,579	48.43%	3,358	47.05%	<0.0001	3,306	45.32%	3,315	45.44%	0.8810
Diuretic	4,359	37.84%	2,450	34.33%	<0.0001	2,413	33.08%	2,432	33.34%	0.7384
ACEI or ARB	4,139	35.93%	2,492	34.92%	0.0006	2,494	34.19%	2,456	33.67%	0.5064
Other medication
Aspirin	1,542	13.39%	813	11.39%	<0.0001	782	10.72%	807	11.06%	0.5064
Clopidogrel	633	5.50%	335	4.69%	0.0025	321	4.40%	331	4.54%	0.6887
Ticlopidine	221	1.92%	117	1.64%	0.0794	120	1.64%	116	1.59%	0.7929
Dipyridamole	1,558	13.53%	886	12.41%	0.0012	889	12.19%	881	12.08%	0.8392
Nitrate	153	1.33%	77	1.08%	0.0721	74	1.01%	76	1.04%	0.8696
Statin	1,429	12.41%	896	12.55%	0.4635	867	11.88%	883	12.10%	0.6835
NSAID	8,791	76.32%	5,748	80.54%	0.1222	5,676	77.81%	5,636	77.26%	0.4275
Anti-hyperglycemic drugs	1,857	16.12%	1,019	14.28%	<0.0001	1,015	13.91%	1,011	13.86%	0.9237
Proton-pump inhibitor	1,371	11.90%	804	11.27%	0.0213	781	10.71%	793	10.87%	0.7488
Baseline comorbidities
Charlson score (mean ± SD)	1.64±1.00		1.55±0.90		<0.0001	1.55±0.90		1.55±0.90		0.5337
Myocardial infarction	190	1.65%	95	1.33%	0.0398	86	1.18%	94	1.29%	0.5485
Congestive heart failure	1,030	8.94%	584	8.18%	0.0087	567	7.77%	584	8.01%	0.6016
Peripheral vascular disease	92	0.80%	52	0.73%	0.4412	53	0.73%	52	0.71%	0.9220
Cerebrovascular disease	578	5.02%	279	3.91%	<0.0001	255	3.50%	276	3.78%	0.3532
Dementia	194	1.68%	67	0.94%	<0.0001	65	0.89%	67	0.92%	0.8612
Rheumatologic disease	114	0.99%	74	1.04%	0.9710	71	0.97%	70	0.96%	0.9326
Peptic ulcer disease	1,703	14.78%	1,052	14.74%	0.2231	1,018	13.95%	1,032	14.15%	0.7387
Hemiplegia or paraplegia	7	0.06%	2	0.03%	0.2958	2	0.03%	2	0.03%	1.0000
Renal disease	271	2.35%	153	2.14%	0.1794	148	2.03%	152	2.08%	0.8155
Moderate/severe liver disease	1,255	10.90%	706	9.89%	0.0020	675	9.25%	701	9.61%	0.4614
Cancer	375	3.26%	239	3.35%	0.8738	241	3.30%	234	3.21%	0.7440
Diabetes mellitus	372	3.23%	202	2.83%	0.0440	205	2.81%	199	2.73%	0.7621

Abbreviations: ACEI, angiotensin-converting-enzyme inhibitor; AE, acute exacerbation; ARB, angiotensin II receptor blocker; ICS, inhaled corticosteroid; LABA, long acting beta agonists; LAMA, long acting antimuscarinics; NSAID, nonsteroidal anti-inflammatory drugs; SABA, short acting beta agonists.

Table 2 Yearly rates and rate ratios of severe exacerbation, hospitalization for COPD, and emergency department visits for COPD exacerbation in a matched cohort of COPD patients prescribed fluticasone/salmeterol and budesonide/formoterol

	Fluticasone/salmeterol cohort	Budesonide/formoterol cohort	Crude RR	(95% CI)	Adjusted RR*	(95% CI)
	Yearly rate	Yearly rate
Before propensity score matching
Severe exacerbation	1.3368	1.1096	1.05	(1.04–1.07)	1.06	(1.04–1.07)
Hospitalization for COPD	0.6271	0.4827	1.14	(1.11–1.16)	1.10	(1.07–1.12)
Emergency department visits for COPD	1.0380	0.8601	1.06	(1.04–1.07)	1.07	(1.05–1.08)
After propensity score matching
Severe exacerbation	1.2219	1.1237	1.08	(1.07–1.10)	1.08	(1.07–1.10)
Hospitalization for COPD	0.5455	0.4915	1.11	(1.08–1.13)	1.11	(1.08–1.13)
Emergency department visits for COPD	0.9528	0.8688	1.09	(1.07–1.11)	1.09	(1.07–1.11)

Note:

* Adjusted for propensity score.

Abbreviation: RR, rate ratio.

Table 3 Event rates and risks of pneumonia, pneumonia requiring MV in a matched cohort of COPD patients prescribed fluticasone/salmeterol and budesonide/formoterol

	Fluticasone/salmeterol cohort			Budesonide/formoterol cohort			Crude HR (95% CI)	Adjusted HR* (95% CI)
	Event	Person-year	Incidence rate (per 100 person-years)	Event	Person-year	Incidence rate (per 100 person-years)
Before propensity score matching
Mortality	2,438	41,741.61	5.84	1,359	30,807.16	4.41	1.32 (1.24–1.41)	1.09 (1.01–1.17)
Pneumonia	4,610	32,150.0	14.34	2,610	24,829.2	10.51	1.31 (1.25–1.38)	1.13 (1.08–1.20)
Pneumonia requiring MV	1,895	39,367.10	4.81	1,004	29,496.66	3.40	1.39 (1.28–1.50)	1.13 (1.04–1.24)
After propensity score matching
Mortality	1,461	29,857.98	4.89	1,349	29,955.79	4.50	1.09 (1.02–1.17)	1.09 (1.01–1.17)
Pneumonia	2,839	23,448.09	12.11	2,569	24,124.61	10.65	1.12 (1.06–1.17)	1.13 (1.08–1.20)
Pneumonia requiring MV	1,118	28,373.96	3.94	996	28,671.31	3.47	1.16 (1.07–1.25)	1.14 (1.05–1.24)

Note:

* Adjusted for propensity score.

Abbreviations: HR, hazard ratio; MV, mechanical ventilation.

Table 4 Sensitivity analyses for risk of pneumonia and pneumonia requiring MV among COPD patients using fluticasone/salmeterol and budesonide/formoterol

	Before propensity score matching		After propensity score matching
	Crude	Adjusted*	Crude	Adjusted*
	HR (95% CI)	HR (95% CI)	HR (95% CI)	HR (95% CI)
Primary analysis
Mortality	1.32 (1.24–1.41)	1.09 (1.01–1.17)	1.09 (1.02–1.17)	1.09 (1.01–1.17)
Pneumonia	1.31 (1.25–1.38)	1.13 (1.08–1.20)	1.12 (1.06–1.17)	1.13 (1.08–1.20)
Pneumonia requiring MV	1.39 (1.28–1.50)	1.13 (1.04–1.24)	1.16 (1.07–1.25)	1.14 (1.05–1.24)
ITT analysis + competing risk
Mortality	–	–	–	–
Pneumonia	1.24 (1.17–1.30)	1.08 (1.03–1.14)	1.11 (1.05–1.18)	1.11 (1.05–1.18)
Pneumonia requiring MV	1.27 (1.17–1.38)	1.09 (1.01–1.18)	1.09 (1.00–1.19)	1.09 (1.00–1.19)
As-treated analysis
Mortality	1.54 (1.39–1.70)	1.23 (1.09–1.37)	1.25 (1.12–1.38)	1.21 (1.08–1.35)
Pneumonia	1.44 (1.34–1.54)	1.17 (1.08–1.26)	1.17 (1.09–1.25)	1.17 (1.08–1.26)
Pneumonia requiring MV	1.70 (1.51–1.91)	1.32 (1.16–1.51)	1.34 (1.19–1.52)	1.32 (1.15–1.51)
As-treated analysis + competing risk
Mortality	–	–	–	–
Pneumonia	1.32 (1.22–1.42)	1.11 (1.03–1.20)	1.12 (1.03–1.22)	1.12 (1.03–1.22)
Pneumonia requiring MV	1.48 (1.30–1.68)	1.20 (1.06–1.37)	1.21 (1.05–1.40)	1.21 (1.05–1.39)

Note:

* Adjusted for propensity score.

Abbreviations: HR, hazard ratio; MV, mechanical ventilation; ITT, intention-to-treat.