Comparative effectiveness of budesonide/formoterol combination and tiotropium bromide among COPD patients new to these controller treatments

Figures & data

Table 1 Propensity score matching results

Matching variables	Prior to matching					After matching
	BFC (N=1,381)		Tiotropium (N=2,670)		P-value	BFC (N=1,198)		Tiotropium (N=1,198)		P-value
Required matching variables
Demographics
Age (mean, SD)	61.9	11.9	64.3	11.6	<0.001	62.7	11.9	62.9	11.6	0.699
Female (n, %)	783	56.7%	1,504	56.3%	0.823	669	55.8%	675	56.3%	0.805
Prior asthma diagnosis (n, %)	630	45.6%	795	29.8%	<0.001	492	41.1%	497	41.5%	0.836
COPD severity
Prior COPD inpatient visits (mean, SD)	0.22	0.50	0.31	0.54	<0.001	0.22	0.50	0.24	0.52	0.466
Prior COPD ED visits (mean, SD)	0.30	0.61	0.42	0.92	<0.001	0.32	0.63	0.32	0.65	0.921
Prior OCS fills (mean, SD)	2.31	2.40	1.90	2.16	<0.001	2.23	2.34	2.22	2.37	0.912
Prior antibiotic fills (mean, SD)	3.36	2.79	2.99	2.74	<0.001	3.34	2.75	3.29	2.76	0.675
COPD medications
Prior SABA or SABA/SAMA fills (mean, SD)	3.17	4.69	2.65	4.02	<0.001	3.07	4.47	3.06	4.52	0.935
Prior LABA fills (mean, SD)	0.15	1.06	0.16	1.04	0.863	0.15	1.08	0.16	1.13	0.873
Pre-index exacerbations
Pre-index exacerbations (mean, SD)	1.87	1.55	1.89	1.63	0.781	1.90	1.58	1.89	1.52	0.866
Due to COPD-related inpatient visit (mean, SD)	0.22	0.50	0.31	0.54	<0.001	0.22	0.50	0.24	0.52	0.466
Due to COPD-related ED visit (mean, SD)	0.30	0.61	0.42	0.92	<0.001	0.32	0.63	0.32	0.65	0.921
Due to COPD outpatient/office visit + OCS and/or antibiotics (mean, SD)	1.36	1.50	1.15	1.49	<0.001	1.35	1.54	1.33	1.46	0.689
Pre-index exacerbations, 0 vs 1+ (n, %)	1,381	100%	2,670	100%	NA	1,198	100%	1,198	100%	NA
Due to COPD-related inpatient visit (n, %)	262	19.0%	758	28.4%	<0.001	235	19.6%	242	20.2%	0.720
Due to COPD-related ED visit (n, %)	342	24.8%	852	31.9%	<0.001	317	26.5%	308	25.7%	0.675
Due to COPD outpatient/office visit + OCS and/or antibiotics (n, %)	1,021	73.9%	1,638	61.3%	<0.001	868	72.5%	868	72.5%	1.000

Notes: Additional balance was achieved on: index month; prescribing physician a pulmonologist; hospitalizations due to cardiovascular disease, pneumonia, or asthma; long-term oxygen use; number of inpatient stays >5 days; comorbid conditions (pneumonia, pulmonary hypertension, chronic respiratory failure, anxiety, depression or psychotropic drug use, coronary artery disease, left ventricle failure, diabetes, congestive heart failure, hypertension, and stroke); prior medication use categorized as 0, 1, or 2+ fills (OCS, antibiotics, ICS, LABA, roflumilast, theophylline, SABA, SAMA, SABA/SAMA combination, LTRA, any cardiovascular related, statins); influenza vaccination; pneumococcal vaccination; and continuity of care.

Abbreviations: BFC, budesonide/formoterol combination; COPD, chronic obstructive pulmonary disease; ED, emergency department; OCS, oral corticosteroid; SABA, short-acting β₂-agonist; SAMA, short-acting muscarinic antagonist; LABA, long-acting β₂-agonist; ICS, inhaled corticosteroid; LTRA, leukotriene receptor antagonist; SD, standard deviation; NA, not applicable.

Figure 1 Patient selection.

Notes: Patient selection (left column) and attrition (right column) after applying each inclusion and exclusion criteria in a step-wise manner, starting with over 18 million individuals identified in the HIRE during the intake period and ending with 1,198 individuals matched within each treatment group.
Abbreviations: HIRE, HealthCore Integrated Research Environment; BFC, budesonide/formoterol combination; COPD, chronic obstructive pulmonary disease; ICD-9, International Classification of Diseases, 9th Revision; ICS/LABA, inhaled corticosteroid/long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; OCS, oral corticosteroid.

Table 2 Primary outcome, sensitivity, and subgroup analyses

	BFC (N=1,198)			Tiotropium (N=1,198)			Hazard ratio	95% CI		P-value
	n	%	Median time to exacerbationa	n	%	Median time to exacerbation		Lower	Upper
Primary outcome: time to first COPD exacerbation	607	50.7	351.5	710	59.3	243.0	0.78	0.70	0.87	<0.001
Sensitivity analysis 1: Censor for treatment modificationb	559	46.7	ND	577	48.2	245.0	0.79	0.71	0.89	<0.001
Sensitivity analysis 2: Starting follow-up on day 31c	573	47.8	ND	673	56.2	248.5	0.78	0.70	0.87	<0.001
Subgroup analysis 1a: Patients with treatment modificationd	138	65.7	183.0	309	69.9	158.0	0.88	0.72	1.08	0.229
Subgroup analysis 1b: Patients without treatment modificatione	469	47.5	ND	401	53.0	314.0	0.85	0.74	0.97	0.017
Subgroup analysis 2: Patients 65 years of age and olderf	276	58.8	263.0	311	65.2	198.0	0.84	0.71	0.98	0.031
Model including interaction between index medication and prior asthma diagnosisg
Within group with prior asthma diagnosis	247	50.2	357.5	312	62.8	208.0	0.72	0.61	0.86	<0.001
Within group with no prior asthma diagnosis	360	51.0	343.0	398	56.8	273.0	0.83	0.72	0.96	0.011

Notes:

a Median time to exacerbation from Kaplan–Meier analysis. A value of “ND” indicates the median time to exacerbation could not be determined from the Kaplan–Meier analysis due to an insufficient proportion of patients having an exacerbation during the 12-month follow-up period.

b Censoring for treatment modification: patients were censored if they switched or added-on an ICS/LABA or LAMA different from the index medication (ie, tiotropium patients who fill any ICS/LABA or other LAMA therapies; BFC patients filling other ICS/LABA or any LAMA therapies) during the 12-month post-index period.

c Follow-up for COPD exacerbations started 31 days after the index date to ensure patients are allowed adequate exposure to the study medication before attributable outcomes are assessed. All persons contribute 335 days (1 year minus 30 days excluded from start of post-index period).

d Including only those who had a treatment modification (ie, tiotropium patients who fill any ICS/LABA or other LAMA therapies; BFC patients filling other ICS/LABA or any LAMA therapies) (analytic sample size: n=210 BFC, 442 tiotropium).

e Including only those who did not have a treatment modification (analytic sample size: n=988 BFC, 756 tiotropium).

f Including only those 65 years and older on index date (analytic sample size: n=469 BFC, 477 tiotropium).

g Interaction model is identical to the primary outcome with the addition of the main effect of a prior asthma diagnosis and an interaction term for the index drug with prior asthma diagnosis. Stratified estimates by asthma group were obtained from this interaction model. The median times to exacerbation come from a Kaplan–Meier analysis stratified by index medication and asthma diagnosis. The numbers in each group with asthma were BFC n=492, tiotropium n=497; and without asthma were BFC n=706, tiotropium n=701. The interaction term for index medication × prior asthma diagnosis was not statistically significant (P=0.2195).

Abbreviations: BFC, budesonide/formoterol combination; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; ND, not determined.

Figure 2 Primary outcome - time to first exacerbation.

Notes: Time to first COPD exacerbation by index treatment cohort during the 1-year follow-up period.
Abbreviations: BFC, budesonide/formoterol combination; HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease.

Figure 3 Exacerbation rates, counting all exacerbations during the post-index period.

Notes: Exacerbation rates allowing for multiple exacerbations during the 1-year follow-up period, overall and by exacerbation type.
Abbreviations: COPD, chronic obstructive pulmonary disease; ED, emergency department; OCS, oral corticosteroid; BFC, budesonide/formoterol combination; CI, confidence interval.

Table 3 COPD medication use – proportion of patients with at least one fill during the post-index period

	BFC (N=1,198)		Tiotropium (N=1,198)		Odds ratioa	95% CI		P-value
	n	%	N	%		Lower	Upper
COPD respiratory medications
ICS monotherapy use	79	6.6	145	12.1	0.45	0.33	0.62	<0.001
LABA monotherapy use	25	2.1	54	4.5	0.37	0.21	0.64	<0.001
SABA	609	50.8	651	54.3	0.84	0.71	1.00	0.043
SAMA	75	6.3	58	4.8	1.25	0.85	1.83	0.263
SABA/SAMA combination use	248	20.7	219	18.3	1.26	1.00	1.60	0.050
LTRA monotherapy use	183	15.3	172	14.4	1.13	0.83	1.55	0.448
Roflumilast	4	0.3	13	1.1	0.31	0.10	0.94	0.039
Theophylline use	46	3.8	48	4.0	0.95	0.53	1.69	0.857
OCS monotherapy use	636	53.1	645	53.8	0.95	0.81	1.12	0.553
Antibiotic use	937	78.2	912	76.1	1.09	0.90	1.33	0.378
Treatment modification
Non-index ICS/LABA useb	70	5.8	441	36.8	NA
Non-index LAMA useb	162	13.5	1	0.1	NA
Any non-index ICS/LABA or LAMA useb	210	17.5	442	36.9	0.36	0.30	0.44	<0.001

Notes:

a Prior use of the medication of interest (0 vs 1+ prescription fill) was included as a covariate in the post-index logistic regression model.

b Non-index ICS/LABA use includes the fill of any ICS/LABA for the tiotropium cohort and any ICS/LABA other than BFC for the BFC cohort. Non-index LAMA use includes the fill of any LAMA for the BFC cohort and any LAMA other than tiotropium for the tiotropium cohort.

Abbreviations: BFC, budesonide/formoterol combination; CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting β₂-agonist; SAMA, short-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid; NA, not applicable.

Table 4 Health care resource utilization during the 12-month post-index period

	BFC (N =1,198)			Tiotropium (N=1,198)			Estimatea	95% CI		P-value
								Lower	Upper
All-cause health care resource utilization
Inpatient hospitalizations
Number of patients with ≥1 event (n, %)	385	32.1%		413	34.5%		0.91	0.76	1.08	0.282
LOS (nights) (mean, SD, median)b	9.5	14.2	5.0	10.1	16.7	5.0	−0.88	−2.04	0.44	0.180
ICU stays
Number of patients with ≥1 event (n, %)	75	6.3%		83	6.9%		0.92	0.66	1.28	0.612
LOS (nights) (mean, SD, median)b	2.4	8.4	1.0	2.7	13.6	1.0	−0.45	−1.22	0.70	0.386
ED visits
Number of patients with ≥1 event (n, %)	360	30.1%		387	32.3%		0.88	0.74	1.05	0.158
Outpatient/office visits
Number of patients with ≥1 event (n, %)	1,188	99.2%		1,187	99.1%		1.10	0.47	2.60	0.827
Number of events (mean, SD, median)	33.0	30.0	25.0	34.1	28.6	27.0	−2.66	−4.25	−0.97	0.002
COPD-related health care resource utilization
Inpatient hospitalizations
Number of patients with ≥1 event (n, %)	90	7.5%		113	9.4%		0.78	0.58	1.05	0.010
LOS (nights) (mean, SD, median)b	6.9	9.7	4.0	6.1	6.8	4.0	0.91	−0.56	2.77	0.248
ICU stays
Number of patients with ≥1 event (n, %)	7	0.6%		14	1.2%		0.50	0.20	1.25	0.137
LOS (nights) (mean, SD, median)b	2.0	2.2	1.0	1.3	0.6	1.0	0.73	−0.29	2.79	0.209
ED visits
Number of patients with ≥1 event (n, %)	164	13.7%		202	16.9%		0.77	0.61	0.96	0.023
Outpatient/office visits
Number of patients with ≥1 event (n, %)	889	74.2%		1,040	86.8%		0.44	0.35	0.55	<0.001
Number of events (mean, SD, median)	7.7	11.8	3.0	9.8	14.5	4.0	−1.68	−2.26	−1.05	<0.001

Notes:

a Odds ratio from chi-square test is used for categorical variables, and mean difference from negative binomial models for count variables. All models are adjusted for the analogous pre-index variable (ie, when analyzing the number of all-cause hospitalizations in the post-index, the model controls for the number of pre-index all-cause hospitalizations).

b Length of stay analyses includes only patients with at least one event.

Abbreviations: BFC, budesonide/formoterol combination; CI, confidence interval; LOS, length of stay; SD, standard deviation; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit, ED, emergency department.

Table 5 Health care costs during the 12-month post-index period

	BFC (N=1,198)			Tiotropium (N=1,198)			Mean differencea	95% CI		P-value
	Mean	SD	Median	Mean	SD	Median		Lower	Upper
All-cause costs	$21,681	$60,517	$9,929	$24,374	$46,428	$11,564	−$2,702	−$4,160	−$1,119	0.001
All-cause medical costs	$17,434	$59,130	$5,924	$19,606	$44,429	$6,767	−$2,234	−$3,645	−$672	0.006
Inpatient hospitalization	$9,274	$53,857	$0	$10,181	$37,253	$0	−$1,080	−$2,504	$690	0.213
Emergency department	$743	$1,969	$0	$772	$2,732	$0	−$1	−$103	$122	0.986
Outpatient/office visit	$6,967	$12,036	$3,808	$8,082	$17,254	$4,056	−$1,404	−$1,916	−$845	<0.001
Skilled nursing facility	$450	$2,909	$0	$571	$3,177	$0	−$66	−$129	$12	0.091
All-cause pharmacy costs	$4,247	$5,864	$2,834	$4,768	$5,175	$3,482	−$374	−$601	−$131	0.003
COPD-related costs	$4,084	$7,308	$1,908	$5,656	$10,056	$3,067	−$1,360	−$1,715	−$967	<0.001
COPD-related medical costs	$2,773	$6,820	$394	$3,906	$9,673	$923	−$968	−$1,291	−$596	<0.001
Inpatient hospitalization	$982	$5,089	$0	$1,433	$7,840	$0	−$417	−$563	−$235	<0.001
Emergency department	$291	$1,060	$0	$380	$1,500	$0	−$38	−$86	$20	0.184
Outpatient/office visit	$1,287	$2,743	$304	$1,745	$3,523	$557	−$373	−$520	−$204	<0.001
Skilled nursing facility	$213	$1,545	$0	$348	$2,280	$0	−$149	−$74	−$117	<0.001
COPD-related pharmacy costs	$1,310	$2,094	$745	$1,750	$1,816	$1,247	−$387	−$500	−$261	<0.001

Notes:

All post-index cost models adjusted for analogous pre-index costs; all-cause pharmacy costs include costs of index medication.

a Mean differences are from gamma regression models (link = log). Statistical comparisons are comparing BFC to tiotropium (reference group). All models are adjusted for the analogous pre-index variable.

Abbreviations: BFC, budesonide/formoterol combination; CI, confidence interval; SD, standard deviation; COPD, chronic obstructive pulmonary disease.