Replication of the P04334 Asthma Trial in Healthcare Claims Data
Conditions: Asthma
Sponsor: Brigham and Women's Hospital

Replication of the P04334 Asthma Trial in Healthcare Claims Data  
DUPLICATE-P04334 
September 14, 2021 
NCT04892758 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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1. RCT Details 
This section provides a high-level overview of a published RCT that the described real-world evidence study is trying to replicate 
as closely as possible given the remaining limitations inherent in the healthcare databases. 
 
1.1 Title 
Effects of Mometasone Furoate/Formoterol Combination Versus Mometasone Furoate Alone Versus Formoterol alone 
in Persistent Asthmatics (Study P04334AM1; NCT00383240) 
1.2 Intended aim(s) 
To assess the effects of 26 weeks of treatment with mometasone furoate/formoterol (MF/F) compared with formoterol (F) 
alone on the incidence of time to first asthma deterioration in patients with persistent asthma previously receiving medium-
dose inhaled corticosteroids.  
1.3 Primary endpoint for replication  
Asthma exacerbation defined by hospitalization or treatment with additional excluded asthma medication (i.e., systemic   
corticosteroids)  
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
This trial is a superiority trial. For time to first asthma deterioration, assuming a 5% event rate for MF/F 200/10 ug and an 
18% event rate for F 10 ug, the trial’s sample size will provide ~90% power to detect a treatment difference in survival 
curves.  
1.5 Trial estimate 
The proportion of patients experiencing asthma deteriorations was MF/F, 30.4%, MF, 33.9%, F 54% (p <0.001).  (Nathan et 
al., 2010).  The calculated risk ratio is 0.90 (95% CI, 0.67-1.20) for MF/F vs MF and 0.56 (95% CI 0.44, 0.72) for MF/F vs 
F.  
 
2. Person responsible for implementation of replication in Aetion 
Hemin Lee, MD, MPH, implemented the study design in the Aetion Evidence Platform. She is not responsible for the validity of the 
design and analytic choices. All implementation steps are recorded, and the implementation history is archived in the platform. 
 
3. Data Source(s) 
Optum CDM, IBM® MarketScan® 
 
4. Study Design Diagram 
The study design diagram visualizes key aspects of the longitudinal study design for expedited review. 
 

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5. Cohort Identification  
 
5.1 Cohort Summary 
This study will involve a new user, parallel group, propensity score-matched, retrospective cohort design comparing mometasone-
furoate/formoterol 200/10ug with formoterol 12 ug in patients with persistent asthma previously receiving medium-dose inhaled 
corticosteroids.  The patients will be required to have continuous enrollment during a baseline period of 180 days before initiation 
of mometasone-furoate/formoterol or formoterol. (Note: the formoterol dose used in the trial was 10ug ; in the replication, we will 
use the market available dose which is 12 ug).  
 
5.2 Important steps for cohort formation 
New use of mometasone-furoate/formoterol 200/10ug (exposure) is defined as no use of the exposure drug within the 180 days 
prior to index date. New use of formoterol 12 ug (comparator) is defined as no use of the comparator drug within the 180 days 
prior to index date. New users of mometasone-furoate/formoterol 200/10ug are not allowed to receive formoterol 12 ug within the 
180 days prior to index date, and new users of formoterol 12 ug are not allowed to receive mometasone-furoate/formoterol 
200/10ug within the 180 prior to index date. 
 
5.2.1 Eligible cohort entry dates 
Mometasone-furoate/formoterol was approved by FDA on June 24, 2010 for the management of asthma.  The initial 
eligible cohort entry date was the first date after June 24, 2010 for both the databases investigated (IBM® MarketScan®, 
Optum CDM). The last date eligible as cohort entry date was the end of available data for IBM® MarketScan® and Optum 
CDM. The following eligible cohort entry dates were included: 
• Optum CDM: June 24, 2010 – June 30, 2020 (end of available data) 
• IBM® MarketScan®: June 24, 2010– December 31, 2018 (end of available data)  
 
5.2.2 Specify inclusion/exclusion criteria for cohort entry and define the index date 
Inclusion and exclusion criteria were adapted from the trial as closely as possible. Definitions for all inclusion/exclusion are 
provided in Appendix A and are summarized in the flowcharts below.  
 
 
5.3 Flowchart of the study cohort assembly 
For Mometasone-furoate/formoterol vs. formoterol 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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 Optum 
Marketscan 
Less Excluded Patients 
Remaining 
Patients 
  
Less Excluded 
Patients 
Remaining 
Patients 
All patients 
  
78,202,636 
  
200,203,908 
Did not meet cohort entry criteria 
-
78,142,188 
60,448 
-
200,050,120 
153,788 
Excluded due to insufficient enrollment 
-8,307 
52,141 
-16,744 
137,044 
Excluded due to prior use of referent 
-6,358 
45,783 
-12,623 
124,421 
Excluded due to prior use of exposure 
-20,136 
25,647 
-47,830 
76,591 
Excluded because patient qualified in >1 exposure category 
0 
25,647 
-4 
76,587 
Excluded based on Age : Exclude missing 
0 
25,647 
0 
76,587 
Excluded based on Gender: Exclude missing 
0 
25,647 
0 
76,587 
Excluded based on INCLUSION: Age >=12 
-1,268 
24,379 
-3,895 
72,692 
Excluded based on Inclusion 3 - Medium dose ICS [-90,0] 
-21,414 
2,965 
-60,543 
12,149 
Excluded based on Inclusion 4 - Asthma [-365, 0] 
-587 
2,378 
-1,947 
10,202 
Excluded based on Inclusion 8 - Pregnancy 
-7 
2,371 
-14 
10,188 
Excluded based on Exclusion 4/5 - Asthma exacerbation, respiratory 
failutre, Intubation [-90,0] 
-890 
1,481 
-1,153 
9,035 
Excluded based on Exclusion 6 - Smoking 
-63 
1,418 
-112 
8,923 
Excluded based on Exclusion 8 - Oropharyngeal candidiasis 
-4 
1,414 
-40 
8,883 
Final cohort 
  
1,414 
  
8,883 
 

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6. Variables  
 
6.1 Exposure-related variables:  
 
Study drug:  
New initiation of MF/F (200/10 ug twice daily). New initiation is defined as no use of MF/F in the prior 180 days before treatment 
initiation (washout period). New users of MF/F are not allowed to receive F within the 180 days prior to treatment initiation. 
 
Comparator agent: 
New initiation of F (12 ug weekly). F 12ug is the market available dose form of formoterol that was selected for formoterol 10 ug used 
in the trial. New initiation is defined as no use of F in the prior 180 days before treatment initiation (washout period). New users of F 
are not allowed to receive MF/F 200/10 ug within the 180 days prior to treatment initiation. 
 
6.2 Preliminary Covariates: 
• Age 
• Gender 
• Combined Comorbidity Index (CCI), measured over the baseline covariate assessment period, defined as 180 days prior to and 
including index date. 
 
Covariates listed above represent only a small subset of covariates that will ultimately be controlled for in the design and analysis. 
We use the covariates above only for initial feasibility analyses to judge whether there is likely to be sufficient overlap between 
treatment groups to proceed with the study. Remaining covariates are defined only after the study has passed the initial feasibility 
analysis and the initial power assessment and are listed in Table 1 (Appendix B).  
 
6.3 Outcome variables and study follow-up:  
 
6.3.1 Outcome variables 
 
Effectiveness outcome variables of interest (definitions provided in Appendix A): 
§ Primary outcome: Time to first asthma exacerbation (algorithm adapted from Nathan, et. al, and Fuhlbrigge A, et. al.,)  
 
6.3.2 Study follow-up 

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Both as-treated (AT) and intention-to-treat (ITT) analyses will be conducted with treatment defined as the index drug on the day of 
cohort entry. Because adherence in the real-world databases is expected to be much worse than in the trial, the AT analysis is the 
primary analysis, as it targets the relative hazard of outcomes on treatment. 
For the AT analyses, the follow-up will start the day after initiation of MF/F and F and will continue until the earliest date of the 
following events: 
 
§ The first occurrence of the outcome of interest, 
§ The date of end of continuous registration in the database, 
§ Discontinuation of the index drugs, 
§ End of the study period, 
§ Measured death event occurs, 
§ Nursing home admission 
o Nursing home admissions are considered a censoring event because the data sources utilized typically provide little to 
no data on a patient, particularly on drug utilization, after admission. We will utilize this as an exclusion reason for 
cohorts for the same reason. 
• The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index drug (MF/F and 
comparator) plus a defined grace period (i.e., 60 days after the end of the last prescription’s days’ supply in main analyses). 
• The date of augmentation or switching from exposure to comparator or vice versa  
§ A dosage change on the index treatment does not fulfill this criterion 
 
 
 
 
7. Initial Feasibility Analysis  
Aetion report name: 
For Mometasone-furoate/formoterol vs. formoterol 
Optum CDM - https://bwh-dope.aetion.com/projects/details/1659/results/67130/result/0 
IBM® MarketScan®- https://bwh-dope.aetion.com/projects/details/1658/results/66759/result/0 
 
Date conducted: 03/07/2021 (Marketscan), 3/17/2021 (Optum) 
 
Complete Aetion feasibility analysis using age and CCI as the only covariates and the primary endpoint (Section 6.3.1) as the 
outcome. No measures of association will be computed nor will incidence rates stratified by treatment group. 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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8. Initial Power Assessment 
 
Aetion report name: 
§ For Mometasone-furoate/formoterol vs. formoterol 
Optum CDM - https://bwh-dope.aetion.com/projects/details/1659/results/67142/result/0 
IBM® MarketScan®- https://bwh-dope.aetion.com/projects/details/1658/results/66760/result/0 
 
Date conducted:  03/07/2021 (Marketscan), 3/17/2021 (Optum)  
 
In order to complete the initial power analysis, the dummy outcome of a 90-day gap in database enrollment will be used. This outcome 
is used to ensure that no information on the comparative risks of the outcomes of interest are available at this stage. Complete a 1:1 
PS-matched comparative analysis using this outcome. PS should include only 3 covariates: age, gender, and combined comorbidity 
index. Power calculations are based on the formulas from Chow et al. (2008). 
 
• Stop analyses until feasibility and power are reviewed by primary investigators and FDA. Reviewers evaluate the results of the 
analyses described above in Sections 7 and 8, including numbers of patients, patient characteristics, follow-up time, and reasons 
for censoring by treatment group, as well as overall rates of outcomes and study power. These parameters are re-evaluated and 
reported in the subsequent sections, after incorporating feedback and refining the protocol. 
 
• Stop analyses until feasibility and power are reviewed by primary investigators, FDA, and assigned members of advisory board. 
Reviewed by PI: 
Shirley Wang 
Date reviewed: 
3/19/2021 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
4/2/2021 
Reasons for stopping 
analysis (if required): 
 
 
 
9. Balance Assessment 
For Mometasone-furoate/formoterol vs. formoterol 
Optum CDM: https://bwh-dope.aetion.com/projects/details/1659/rwrs/68458 
IBM® MarketScan®: https://bwh-dope.aetion.com/projects/details/1658/rwrs/68457 
 
Date conducted:  
04/14/2021 

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After review of initial feasibility and power analyses, complete creation of the remaining covariates from Section 6.2. Again, using the 
dummy outcome of a 90-day gap in database enrollment, complete a 1:1 PS-matched analysis. The PS should include the complete list 
of covariates. 
 
• Provide plot of PS distributions stratified by treatment group. 
Note- Please refer to Appendix B.  
 
• Report covariate balance after matching. 
Note- For Table 1, please refer to Appendix B.  
 
 
• Report reasons for censoring by treatment group. 
 
Overall 
Referent 
Exposure 
Dummy outcome 
0 (0.00%) 
0 (0.00%) 
0 (0.00%) 
Death 
2 (0.09%) 
2 (0.09%) 
0 (0.00%) 
Start of an additional exposure 
10 (0.46%) 
6 (0.28%) 
4 (0.18%) 
End of index exposure 
1747 (80.58%) 
882 (40.68%) 
865 (39.90%) 
Specified date reached 
4 (0.18%) 
0 (0.00%) 
4 (0.18%) 
End of patient data 
0 (0.00%) 
0 (0.00%) 
0 (0.00%) 
End of patient enrollment 
391 (18.04%) 
185 (8.53%) 
206 (9.50%) 
Nursing home admission, pharmacy disenrollment 
14 (0.65%) 
9 (0.42%) 
5 (0.23%) 
 
• Report follow-up time by treatment group. 
Median Follow-Up Time (Days) [IQR] 
Patient Group 
Optum 
Marketscan 
Overall Patient Population 
133.5 [88,193] 
141.5 [88,214] 
Referent  
123 [88,157] 
147 [88, 207] 
Exposure 
138 [88,254] 
132 [88,222] 
 
• Report overall risk of the primary outcome. 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
9 
  
Optum CDM 
IBM® MarketScan®  
Pooled  
Risk per 1,000 patients 
125.88 
144.24 
141.6 
 
 
10. Final Power Assessment 
Date conducted: 4/15/2021 
• Re-calculate power in the appropriate excel table, using the revised number of matched patients from the PS-match in Section 9. 
All other parameters in the table should be the same as in Section 8. 
o Pooled 
 
o Optum CDM 
Superiority Analysis
Number of patients matched
2,168
Reference
1,084
Exposed
1,084
Risk per 1,000 patients
141.60
Desired HR from RCT
0.28
Alpha (2-sided)
0.05
Number of events expected
306.9888
Power
1

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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o IBM® MarketScan® 
 
 
 
Superiority Analysis
Number of patients matched
330
Reference
165
Exposed
165
Risk per 1,000 patients
125.88
Desired HR from RCT
0.28
Alpha (2-sided)
0.05
Number of events expected
41.5404
Power
0.98391473
Superiority Analysis
Number of patients matched
1,838
Reference
919
Exposed
919
Risk per 1,000 patients
144.24
Desired HR from RCT
0.28
Alpha (2-sided)
0.05
Number of events expected
265.11312
Power
1

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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• Stop analyses until balance and final power assessment are reviewed by primary investigators, FDA, and assigned members of 
advisory board. 
Reviewed by PI: 
Shirley Wang 
Date reviewed: 
4/16/2021 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
4/30/2021 
Reasons for stopping 
analysis (if required): 
 
 
11. Study Confidence and Concerns 
 
Deadline for voting on study confidence and listing concerns: 
Date votes and concerns are summarized:    
 
• If final feasibility and power analyses are reviewed and approved, proceed to the remaining protocol steps. 
• All study team and advisory board members that review this protocol should at this stage provide their level of confidence for the 
success of the RWD study in the Google Form. This form also provides space for reviewers to list any concerns that they feel may 
contribute to a failure to replicate the findings of the RCT, including differences in study populations, poor measurement of study 
variables, or residual confounding. All responses will be kept confidential and individual-level results will only be shared with the 
individual respondent. 
• After the deadline for voting has passed, provide the distribution of responses and summarize all concerns here. 
 
12. Register study protocol on clinicalTrials.gov 
 
Date conducted:    
 
• Register the study on clinicalTrials.gov and upload this document. 
 
13. Comparative Analyses 
 
Aetion report name: 
Date conducted:    
 
13.1 
For primary analysis:  
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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13.2 
For sensitivity analyses: 
 
14.  Requested Results  
 
14.1 
Table 1: Baseline characteristics before and after adjustment 
 
Variable 
 
Before adjustment 
After adjustment 
Referent 
Exposure 
Std. diff. 
Referent 
Exposure 
Std. diff. 
Number of patients 
 
 
- 
 
 
- 
Age categories 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
14.2 
Table 2: Follow-up time 
 
Patient Group 
Median Follow-Up Time (Days) [IQR] 
Overall Patient Population 
 
Referent 
 
Exposure 
 
 
14.3 
Table 3: Censoring events 
 
 
Overall 
Referent 
Exposure 
Dummy outcome 
 
 
 
Death 
 
 
 
Start of an additional exposure 
 
 
 
End of index exposure 
 
 
 
Specified date reached 
 
 
 
End of patient data 
 
 
 
End of patient enrollment 
 
 
 
Nursing home admission, pharmacy disenrollment 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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14.4 
Table 4: Results from primary analyses; 
 
Analysis 
No. exposed events 
No. referent events 
Exposed rate 
Referent rate 
HR (95% CI) 
Crude 
 
 
 
 
 
Analysis 1 
 
 
 
 
 
Analysis 2 
 
 
 
 
 
... 
 
 
 
 
 
HR, Hazard Ratio; CI, Confidence Interval. 
 
14.5 
Table 5: Results from secondary analyses. 
 
 
15. References 
Fuhlbrigge A, Peden D, Apter AJ, et al. Asthma outcomes: exacerbations. J Allergy Clin Immunol. 2012;129(3 Suppl):S34-S48. 
doi:10.1016/j.jaci.2011.12.983 
Nathan RA, Nolte H, Pearlman DS; P04334 Study Investigators. Twenty-six-week efficacy and safety study of mometasone 
furoate/formoterol 200/10 microg combination treatment in patients with persistent asthma previously receiving medium-dose inhaled 
corticosteroids. Allergy Asthma Proc. 2010 Jul-Aug;31(4):269-79. doi: 10.2500/aap.2010.31.3364. Epub 2010 Jul 30. PMID: 20678306. 
 
Chow S, Shao J, Wang H. 2008.  Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & Hall/CRC Biostatistics 
Series. page 177. 
 

#
P04334AM1 trial definitions 
Implementation in routine care
Reference/Rationale 
Exposure ) Mometasone furoate/formoterol fumarate combination MDI 200/10 mcg BID
vs.
Referent) Formoterol fumarate 10 mcg
Exposure:Mometasone furoate/formoterol fumarate 200/10 mcg BID 
NDC code: 
00085720601 
00085720607
Referent: formoterol fumarate 10 mcg
NDC code: 
54569525400 - formoterol fumarate
54868497200 - formoterol fumarate
54868497201 - formoterol fumarate
00083016702 - formoterol fumarate
00083016711 - formoterol fumarate
00083016774 - formoterol fumarate
00085140101 - formoterol fumarate
00085140201 - formoterol fumarate
00085140202 - formoterol fumarate
68115065160 - formoterol fumarate
Time-to-first Asthma Exacerbation 
Measured 1 day after drug initiation
1) Asthma diagnosis code in inpatient primary diagnosis position
2) Asthma diagnosis code in inpatient any position or outpatient setting PLUS a prescription claim
for systemic steroids 14 days before and after the diagnosis code 
Asthma:
ICD-9: 493.x
ICD-10 : J45.*
1
Informed Consent: A signed and dated written informed consent prior to study participation 
N/A
2
Age ≥ 12 years, adult and adolescent subjects
Measured on the day of drug of initiation 
Age >=12  
3
A subject must have been using a medium daily dose of inhaled glucocorticosteroid (ICS) (either alone or in 
combination with a long-acting beta agonist (LABA)) for at least 12 weeks and must have been on a stable 
regimen (daily dose unchanged) for at least 2 weeks prior to Screening. Medium daily doses of ICS are defined 
as follows:
>500 to 1000 mcg beclomethasone chlorofluorocarbon (CFC)
>250 to 500 mcg beclomethasone hydrofluoroalkane (HFA)
>600 to 1000 mcg budesonide dry powder inhaler (DPI)
>1000 to 2000 mcg flunisolide
>250 to 500 mcg fluticasone
400 mcg MF
>1000 to 2000 mcg triamcinolone acetonide
Measured 90 days prior to drug initiation 
See tab [medium dose ICS] for NDC codes 
4
To document the diagnosis of asthma and assure the subject's responsiveness to bronchodilators before 
randomization one of the following methods can be used at the Screening Visit, Day -14, or thereafter, but prior 
to the Baseline Visit:
Measured 365 days prior to cohort entry in any position, any setting
Asthma:
ICD-9: 493.x
 ICD-10 : J45.*
Larsson K, Ställberg B, Lisspers K, Telg G, Johansson G, Thuresson M, 
Janson C. Prevalence and management of severe asthma in primary 
care: an observational cohort study in Sweden (PACEHR). Respir Res. 
2018 Jan 18;19(1):12. doi: 10.1186/s12931-018-0719-x. PMID: 
29347939; PMCID: PMC5774144.
The subject must demonstrate an increase in absolute FEV1 of at least 12% and at least 200 mL within 15 
minutes after administration of four inhalations of albuterol/salbutamol (total dose of 360 to 400 mcg) or of 
nebulized SABA (2.5 mg) if confirmed as standard office practice, 
OR
The subject must demonstrate a peak expiratory flow (PEF) variability of more than 20% expressed as a 
percentage of the highest and lowest morning prebronchodilator PEF over at least 1 week
OR
The subject must demonstrate a diurnal variation in PEF of more than 20% based on the difference between 
the prebronchodilator morning value and the postbronchodilator value from the evening before, expressed as a 
percentage of the mean daily PEF value.
N/A
5
At the Screening Visit, the subject's FEV1 must be ≥60% and ≤90% predicted.
N/A
6
At the Baseline Visit, the subject's FEV1 must be ≥60% and ≤85% predicted when all restricted medications 
have been withheld for the appropriate intervals.
N/A
7
Clinical laboratory tests (complete blood counts [CBC], blood chemistries, and urinalysis) conducted at the 
Screening Visit must be within normal limits or clinically acceptable to the investigator/sponsor. An 
electrocardiogram (ECG) using a centralized trans-telephonic technology at the Screening Visit must be 
clinically acceptable to the investigator. A chest x-ray performed at the Screening Visit, or within 12 months 
prior to the Screening Visit, must be clinically acceptable to the investigator.
N/A
Please see the following Google Drive for further details or any missing information: 
https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV?usp=sharing
ICD-10 codes are not listed in this document because of excel cell size limitations and excessive number of 
ICD-10 codes. Full ICD-10 code lists will be available in the above Google Drive Folder (link above). ICD-9 to 
ICD-10 code conversions were completed using a SAS macro that implements forward/ backward mapping 
based on the CMS ICD-9 to ICD-10 mapping:
 https://www.nber.org/data/icd9-icd-10-cm-and-pcs-crosswalk-general-equivalence-mapping.html
PRIMARY OUTCOME
Trial details- clinicaltrials.gov NCT00383240
EXPOSURE vs. COMPARISON
INCLUSION CRITERIA
Appendix A

8
A female subject of childbearing potential must have been using a medically acceptable, adequate form of 
birth control. This includes: 1) hormonal contraceptives as prescribed by a physician (oral combined, hormonal 
implant); 2) medically prescribed intra-uterine device (IUD); 3) condom in combination with a spermicide 
(double barrier method); 4) monogamous relationship with a male partner who has had a vasectomy. The 
subject must have started this birth control method at least 3 months prior to Screening (with the exception of 
condom in combination with spermicide), and must agree to continue its use for the duration of the study. A 
female subject of childbearing potential who is not currently sexually active must agree and consent to using a 
medically acceptable birth control method should she become sexually active during the course of this study. 
Women who have been surgically sterilized or are at least 1 year postmenopausal are not considered to be of 
childbearing potential. A female subject of childbearing potential must have a negative serum pregnancy test 
at Screening in order to be considered eligible for enrollment.
Measured 180 days prior to drug initiation in any setting and position
See tab [pregnancy] ; will be applied as an exclusion. 
1
A subject who demonstrates a change (increase or decrease) in absolute FEV1 of >20% at any time from the 
Screening Visit up to and including the Baseline Visit.
N/A
2
A subject who requires the use of greater than eight inhalations per day of SABA MDI, or two or more nebulized 
treatments per day of 2.5 mg SABA, on any 2 consecutive days from the Screening Visit up to and including the 
Baseline Visit.
N/A
3
A subject who experiences a decrease in AM or PM PEF below the Screening Period stability limit on any 2 
consecutive days prior to Randomization.
N/A
4
A subject who experiences an occurrence of any clinical deterioration of asthma that results in emergency 
treatment, hospitalization due to asthma, or treatment with additional, excluded asthma medication (other 
than SABA) as judged by the clinical investigator at any time from the Screening Visit up to and including the 
Baseline Visit.
5
Emergency room treatment for asthma deterioration requiring systemic corticosteroid therapy or 
hospitalization for managemenet of airway obstruction within the 3 months before baseline 
6
A subject who is a smoker or ex-smoker and has smoked within the previous year or has had a cumulative 
smoking history >10 pack-years
Measured 180 days prior to drug initiation in any setting, any position
ICD-9/10 codes:
V15.82, 305.1x, 649.0x, 989.84
OR
CPT code
99406, 99407, G0436, G0437, G9016, S9075, S9453, S4995, G9276, G9458, 1034F, 4004F, 
4001F
OR
use of varenicline tartrate or nicotine replacement therapy (“Nicotine”, “Nicotine 
Bitartrate”, and “Nicotine Polacrilex”)
6
Patients requiring concomitant asthma medication
N/A
7
Clinically significant abnormal vital sign
N/A
8
Visible evidence of oropharyngeal candidiasis at baseline or earlier 
Measured 180 days prior to drug initiation in any setting, any position
Oropharyngeal candidiasis: 
ICD-9: 112.0
ICD-10: B37.0, B37.83
Walkey AJ, Wiener RS. Use of noninvasive ventilation in patients with 
acute respiratory failure, 2000-2009: a population-based study. Ann 
Am Thorac Soc. 2013 Feb;10(1):10-7. doi: 
10.1513/AnnalsATS.201206-034OC. PMID: 23509327; PMCID: 
PMC3780971.
 Measured 90 days prior to drug initiation
Asthma exacerbation
1) Asthma diagnosis code in inpatient primary diagnosis position
2) Asthma diagnosis code in inpatient any position or outpatient setting PLUS a 
prescription claim for systemic steroids 14 days before and after the diagnosis code
Asthma:
ICD-9: 493.x
ICD-10 : J45.*
or 
Acute respiratory failure/insufficiency/arrest
ICD-9: “517.3”, “518.5”, “518.81”, “518.82”, “518.83”, “518.84”, “799.1”, “V46.1”, 
“V46.11”, “V46.12”, “V46.13”, “V46.14”, “V46.2”
ICD-10: “J80”, “J96.00”, “J96.01”, “J96.02”, “J96.10”, “J96.11”, “J96.12”, “J96.20”, 
“J96.21”, “J96.22”, “J96.90”, “J96.91”, “J96.92”, “R09.01”, “R09.2”, “Z99.11”, “Z99.12”, 
“Z99.81” }
Intubation/Non-invasive ventilatory support: 
ICD-9 Procedure code: “93.90”, “93.92”, “96.01”, “96.02”, “96.03”, “96.04”, “96.05”, 
“96.70”, “96.71”, “96.72” 
ICD-10 procedure codes: “09HN7BZ”, “09HN8BZ”, “0BH13EZ”, “0BH17EZ”, “0BH18EZ”, 
“0CHY7BZ”, “0CHY8BZ”, “0DH57BZ”, “0DH58BZ”, “0WHQ73Z”, “0WHQ7YZ”, “5A09357”, 
“5A09457”, “5A09557”, “5A1935Z”, “5A1945Z”, “5A1955Z” }
EXCLUSION CRITERIA
Appendix A

NDC codes for medium dose ICS 
37024523
85134107
85433401
85461001
173049500
173050400
173060100
173060102
173069604
173071700
173071722
173072000
173072020
173075300
173085914
173087414
173088710
173088714
21695019601
23490754201
35356009914
49999061412
49999081960
54569524200
54569566300
54868554700
54868563700
55045335400
58016481201
59310071106
68115092460
68258303101
85134101
85134102
Appendix A

85134103
85134104
85134106
85461005
93360982
173049900
173060202
173069600
173069602
173071720
173085910
173088810
49999061401
54569460200
54569460300
54569570200
54868439200
54868451700
54868554701
54868554702
55045291901
55045368601
58016460401
59310072206
59310082206
68115063713
68258891306
Appendix A

Pregnancy 
Diagnosis codes 
650   NORMAL DELIVERY
660   OBSTRUCTED LABOR
661   ABNORMALITY OF FORCES OF LABOR
662   LONG LABOR
663   UMBILICAL CORD COMPLICATIONS DURING LABOR AND DELIVERY
664   TRAUMA TO PERINEUM AND VULVA DURING DELIVERY
665   OTHER OBSTETRICAL TRAUMA
667   RETAINED PLACENTA OR MEMBRANES WITHOUT HEMORRHAGE
668   COMPLICATIONS OF THE ADMINISTRATION OF ANESTHETIC OR OTHER SEDATION IN LABOR AND DELIVERY
669.94   UNSPECIFIED COMPLICATION OF LABOR AND DELIVERY POSTPARTUM CONDITION OR COMPLICATION
V24   POSTPARTUM CARE AND EXAMINATION
V24.0   POSTPARTUM CARE AND EXAMINATION IMMEDIATELY AFTER DELIVERY
V24.1   POSTPARTUM CARE AND EXAMINATION OF LACTATING MOTHER
V24.2   ROUTINE POSTPARTUM FOLLOW
V27   OUTCOME OF DELIVERY
V27.0   MOTHER WITH SINGLE LIVEBORN
V27.1   MOTHER WITH SINGLE STILLBORN+A2:J81
V27.2   MOTHER WITH TWINS BOTH LIVEBORN
V27.3   MOTHER WITH TWINS ONE LIVEBORN AND ONE STILLBORN
V27.4   MOTHER WITH TWINS BOTH STILLBORN
V27.5   MOTHER WITH OTHER MULTIPLE BIRTH ALL LIVEBORN
V27.6   MOTHER WITH OTHER MULTIPLE BIRTH SOME LIVEBORN
V27.7   MOTHER WITH OTHER MULTIPLE BIRTH ALL STILLBORN
V27.9   MOTHER WITH UNSPECIFIED OUTCOME OF DELIVERY
Procedure codes 
72.0   LOW FORCEPS OPERATION
72.1   LOW FORCEPS OPERATION WITH EPISIOTOMY
72.2   MID FORCEPS OPERATION
72.21   MID FORCEPS OPERATION WITH EPISIOTOMY
72.29   OTHER MID FORCEPS OPERATION
72.3   HIGH FORCEPS OPERATION
72.31   HIGH FORCEPS OPERATION WITH EPISIOTOMY
72.39   OTHER HIGH FORCEPS OPERATION
72.4   FORCEPS ROTATION OF FETAL HEAD
72.5   BREECH EXTRACTION
72.51   PARTIAL BREECH EXTRACTION WITH FORCEPS TO AFTERCOMING HEAD
72.52   OTHER PARTIAL BREECH EXTRACTION
Appendix A

72.53   TOTAL BREECH EXTRACTION WITH FORCEPS TO AFTERCOMING HEAD
72.54   OTHER TOTAL BREECH EXTRACTION
72.6   FORCEPS APPLICATION TO AFTERCOMING HEAD
72.7   VACUUM EXTRACTION
72.71   VACUUM EXTRACTION WITH EPISIOTOMY
72.79   OTHER VACUUM EXTRACTION
72.8   OTHER SPECIFIED INSTRUMENTAL DELIVERY
72.9   UNSPECIFIED INSTRUMENTAL DELIVERY
73.0   ARTIFICIAL RUPTURE OF MEMBRANES
73.01   INDUCTION OF LABOR BY ARTIFICIAL RUPTURE OF MEMBRANES
73.09   OTHER ARTIFICIAL RUPTURE OF MEMBRANES
73.1   OTHER SURGICAL INDUCTION OF LABOR
73.2   INTERNAL AND COMBINED VERSION AND EXTRACTION
73.21   INTERNAL AND COMBINED VERSION WITHOUT EXTRACTION
73.22   INTERNAL AND COMBINED VERSION WITH EXTRACTION
73.3   FAILED FORCEPS
73.4   MEDICAL INDUCTION OF LABOR
73.5   MANUALLY ASSISTED DELIVERY
73.51   MANUAL ROTATION OF FETAL HEAD
73.59   OTHER MANUALLY ASSISTED DELIVERY
73.6   EPISIOTOMY
73.8   OPERATIONS ON FETUS TO FACILITATE DELIVERY
73.9   OTHER OPERATIONS ASSISTING DELIVERY
73.91   EXTERNAL VERSION ASSISTING DELIVERY
73.92   REPLACEMENT OF PROLAPSED UMBILICAL CORD
73.93   INCISION OF CERVIX TO ASSIST DELIVERY
73.94   PUBIOTOMY TO ASSIST DELIVERY
73.99   OTHER OPERATIONS ASSISTING DELIVERY
74.0   CLASSICAL CESAREAN SECTION
74.1   LOW CERVICAL CESAREAN SECTION
74.2   EXTRAPERITONEAL CESAREAN SECTION
74.3   REMOVAL OF EXTRATUBAL ECTOPIC PREGNANCY
74.4   CESAREAN SECTION OF OTHER SPECIFIED TYPE
74.9   CESAREAN SECTION OF UNSPECIFIED TYPE
74.91   HYSTEROTOMY TO TERMINATE PREGNANCY
74.99   OTHER CESAREAN SECTION OF UNSPECIFIED TYPE
75.4   MANUAL REMOVAL OF RETAINED PLACENTA
75.5   REPAIR OF CURRENT OBSTETRIC LACERATION OF UTERUS
75.6   REPAIR OF OTHER CURRENT OBSTETRIC LACERATION
75.7   MANUAL EXPLORATION OF UTERINE CAVITY, POSTPARTUM
75.9   OTHER OBSTETRIC OPERATIONS
Appendix A

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Appendix B

Variable
Formoterol fumarate 
10 mcg
Mometasone 
furoate/formoterol 
fumarate
St. Diff.
Formoterol fumarate
10 mcg
Mometasone 
furoate/formoterol 
fumarate
St. Diff.
Formoterol fumarate 
10 mcg
Mometasone 
furoate/formoterol 
fumarate
St. Diff.
Number of patients
363
1,051
1,325
7,549
1,688 
8,600 
Year of Cohort Entry Date
6,812 
5,344 
6,691 
13,208 
13,503 
18,552 
...2010; n (%)
78 (21.5%)
7 (0.7%)
0.062
305 (23.0%)
112 (1.5%)
0.061
383 (22.7%)
119 (1.4%)
0.692
...2011; n (%)
115 (31.7%)
121 (11.5%)
0.044
385 (29.1%)
992 (13.1%)
0.035
500 (29.6%)
1,113 (12.9%)
0.417
...2012; n (%)
67 (18.5%)
173 (16.5%)
0.005
258 (19.5%)
1,275 (16.9%)
0.006
325 (19.3%)
1,448 (16.8%)
0.065
...2013; n (%)
41 (11.3%)
174 (16.6%)
-0.014
143 (10.8%)
1,173 (15.5%)
-0.013
184 (10.9%)
1,347 (15.7%)
-0.142
...2014; n (%)
37 (10.2%)
163 (15.5%)
-0.015
142 (10.7%)
1,700 (22.5%)
-0.029
179 (10.6%)
1,863 (21.7%)
-0.305
...2015; n (%)
20 (5.5%)
142 (13.5%)
-0.026
79 (6.0%)
846 (11.2%)
-0.018
099 (5.9%)
988 (11.5%)
-0.200
...2016; n (%)
5 (1.4%)
124 (11.8%)
-0.041
13 (1.0%)
679 (9.0%)
-0.036
018 (1.1%)
803 (9.3%)
-0.376
...2017; n (%)
0 (0.0%)
59 (5.6%)
-0.033
0 (0.0%)
500 (6.6%)
-0.036
000 (0.0%)
559 (6.5%)
-0.373
...2018; n (%)
0 (0.0%)
30 (2.9%)
-0.024
0 (0.0%)
272 (3.6%)
-0.027
000 (0.0%)
302 (3.5%)
-0.269
...2019; n (%)
0 (0.0%)
34 (3.2%)
-0.025
NA
NA
NA
NA
NA
NA
...2020; n (%)
0 (0.0%)
24 (2.3%)
-0.021
NA
NA
NA
NA
NA
NA
Age
...mean (sd)
55.26 (15.34)
50.76 (17.81)
0.271
56.57 (15.86)
46.67 (18.21)
0.580
56.29 (15.75)
47.17 (18.16)
0.537
...median [IQR]
57.00 [48.00, 65.00]
53.00 [40.00, 63.00]
0.241
59.00 [48.00, 65.00]
50.00 [34.00, 60.00]
0.527
58.57 (15.75)
50.37 (18.16)
0.482
Age categories
...12-17; n (%)
11 (3.0%)
68 (6.5%)
-0.016
35 (2.6%)
800 (10.6%)
-0.031
046 (2.7%)
868 (10.1%)
-0.306
...18-39; n (%)
39 (10.7%)
182 (17.3%)
-0.018
124 (9.4%)
1,588 (21.0%)
-0.030
163 (9.7%)
1,770 (20.6%)
-0.308
...40 - 64; n (%)
221 (60.9%)
574 (54.6%)
0.008
814 (61.4%)
4,178 (55.3%)
0.008
1,035 (61.3%)
4,752 (55.3%)
0.122
...>= 65; n (%)
92 (25.3%)
227 (21.6%)
0.008
352 (26.6%)
983 (13.0%)
0.031
444 (26.3%)
1,210 (14.1%)
0.307
Geographic Region
...Northeast; n (%)
46 (12.7%)
97 (9.2%)
0.011
332 (25.1%)
1,239 (16.4%)
0.019
378 (22.4%)
1,336 (15.5%)
0.177
...South; n (%)
163 (44.9%)
392 (37.3%)
0.012
447 (33.7%)
2,643 (35.0%)
-0.002
610 (36.1%)
3,035 (35.3%)
0.017
...Midwest; n (%)
86 (23.7%)
372 (35.4%)
-0.022
307 (23.2%)
1,605 (21.3%)
0.004
393 (23.3%)
1,977 (23.0%)
0.007
...West; n (%)
68 (18.7%)
190 (18.1%)
0.001
222 (16.8%)
1,972 (26.1%)
-0.020
290 (17.2%)
2,162 (25.1%)
-0.194
...Unknown/Missing; n (%)
NA
NA
NA
17 (1.3%)
90 (1.2%)
0.001
NA
NA
NA
Metropolitan Statistical Area
...Urban; n (%)
NA
NA
NA
1,090 (82.3%)
6,106 (80.9%)
0.002
NA
NA
NA
...Rural; n (%)
NA
NA
NA
2 (0.2%)
132 (1.7%)
-0.015
NA
NA
NA
...Unknown/Missing; n (%)
NA
NA
NA
233 (17.6%)
1,311 (17.4%)
0.000
NA
NA
NA
General Health Related Measures
Alcohol/Drug abuse or dependence ; n (%)
6 (1.7%)
23 (2.2%)
-0.004
18 (1.4%)
76 (1.0%)
0.004
024 (1.4%)
099 (1.2%)
0.018
Obesity or Overweight; n (%)
39 (10.7%)
133 (12.7%)
-0.006
104 (7.8%)
694 (9.2%)
-0.005
143 (8.5%)
827 (9.6%)
-0.038
Obesity; n (%)
35 (9.6%)
109 (10.4%)
-0.003
93 (7.0%)
594 (7.9%)
-0.003
128 (7.6%)
703 (8.2%)
-0.022
Overweight; n (%)
4 (1.1%)
27 (2.6%)
-0.011
14 (1.1%)
112 (1.5%)
-0.004
018 (1.1%)
139 (1.6%)
-0.043
Cardiovascular Measures
Hypertension; n (%)
165 (45.5%)
403 (38.3%)
0.011
537 (40.5%)
2,096 (27.8%)
0.022
702 (41.6%)
2,499 (29.1%)
0.264
Hyperlipidemia; n (%)
135 (37.2%)
320 (30.4%)
0.012
419 (31.6%)
1,621 (21.5%)
0.020
554 (32.8%)
1,941 (22.6%)
0.229
MI, angina, Coronary atherosclerosis and other forms of chronic 
ischemic heart disease; n (%)
39 (10.7%)
56 (5.3%)
0.019
159 (12.0%)
300 (4.0%)
0.028
198 (11.7%)
356 (4.1%)
0.285
Old MI; n (%)
6 (1.7%)
7 (0.7%)
0.009
12 (0.9%)
20 (0.3%)
0.008
018 (1.1%)
027 (0.3%)
0.096
Acute MI; n (%)
2 (0.6%)
3 (0.3%)
0.004
8 (0.6%)
10 (0.1%)
0.008
010 (0.6%)
013 (0.2%)
0.063
Stable angina; n (%)
5 (1.4%)
5 (0.5%)
0.009
16 (1.2%)
47 (0.6%)
0.006
021 (1.2%)
052 (0.6%)
0.064
Coronary atherosclerosis and other forms of chronic ischemic 
heart disease; n (%)
36 (9.9%)
52 (4.9%)
0.018
143 (10.8%)
252 (3.3%)
0.028
179 (10.6%)
304 (3.5%)
0.280
History of CABG or PTCA; n (%)
4 (1.1%)
11 (1.0%)
0.001
14 (1.1%)
28 (0.4%)
0.008
018 (1.1%)
039 (0.5%)
0.067
Cerebrovascular disease (Stroke, TIA, Late effects); n (%)
7 (1.9%)
16 (1.5%)
0.003
21 (1.6%)
62 (0.8%)
0.007
028 (1.7%)
078 (0.9%)
0.071
Stroke (Ischemic or hemorrhagic); n (%)
7 (1.9%)
8 (0.8%)
0.009
13 (1.0%)
31 (0.4%)
0.007
020 (1.2%)
039 (0.5%)
0.076
TIA; n (%)
0 (0.0%)
8 (0.8%)
-0.013
10 (0.8%)
24 (0.3%)
0.007
010 (0.6%)
032 (0.4%)
0.028
Late effects of cerebrovascular disease; n (%)
2 (0.6%)
4 (0.4%)
0.003
7 (0.5%)
19 (0.3%)
0.003
009 (0.5%)
023 (0.3%)
0.032
Atrial fibrillation and Other cardiac dysrhythmia; n (%)
25 (6.9%)
75 (7.1%)
-0.001
108 (8.2%)
320 (4.2%)
0.016
133 (7.9%)
395 (4.6%)
0.137
Atrial fibrillation; n (%)
10 (2.8%)
40 (3.8%)
-0.006
64 (4.8%)
150 (2.0%)
0.015
074 (4.4%)
190 (2.2%)
0.123
Other cardiac dysrhythmia; n (%)
20 (5.5%)
59 (5.6%)
0.000
65 (4.9%)
231 (3.1%)
0.009
085 (5.0%)
290 (3.4%)
0.080
Diabetes Related Measures
Diabetes with or w/o complications; n (%)
52 (14.3%)
155 (14.7%)
-0.001
227 (17.1%)
706 (9.4%)
0.021
279 (16.5%)
861 (10.0%)
0.193
Marketscan
POOLED
Unmatched
Optum
Appendix B

Diabetes mellitus without mention of complications; n (%)
50 (13.8%)
149 (14.2%)
-0.001
214 (16.2%)
670 (8.9%)
0.021
264 (15.6%)
819 (9.5%)
0.185
Diabetes with specified complications; n (%)
9 (2.5%)
40 (3.8%)
-0.007
52 (3.9%)
119 (1.6%)
0.014
061 (3.6%)
159 (1.8%)
0.111
Diabetes with unspecified complications; n (%)
2 (0.6%)
4 (0.4%)
0.003
10 (0.8%)
24 (0.3%)
0.007
012 (0.7%)
028 (0.3%)
0.057
GI Conditions
GERD; n (%)
57 (15.7%)
195 (18.6%)
-0.007
171 (12.9%)
1,014 (13.4%)
-0.001
228 (13.5%)
1,209 (14.1%)
-0.017
Upper GI (Diseases of esophagus, stomach and duodenum including 
GERD) ; n (%)
68 (18.7%)
217 (20.6%)
-0.004
222 (16.8%)
1,216 (16.1%)
0.002
290 (17.2%)
1,433 (16.7%)
0.013
GI bleeding; n (%)
9 (2.5%)
14 (1.3%)
0.009
21 (1.6%)
85 (1.1%)
0.004
030 (1.8%)
099 (1.2%)
0.049
Non-infective enteritis and colitis; n (%)
13 (3.6%)
49 (4.7%)
-0.005
62 (4.7%)
257 (3.4%)
0.006
075 (4.4%)
306 (3.6%)
0.041
Intraoperative and postprocedural complications and disorders of 
digestive system; n (%)
10 (2.8%)
16 (1.5%)
0.009
26 (2.0%)
106 (1.4%)
0.005
036 (2.1%)
122 (1.4%)
0.053
Disorders of gallbladder, biliary tract and pancreas; n (%)
1 (0.3%)
18 (1.7%)
-0.014
15 (1.1%)
82 (1.1%)
0.000
016 (0.9%)
100 (1.2%)
-0.029
Rheumatic Conditions
Rheumatoid arthritis and other inflammatory polyarthropathies; n 
(%)
5 (1.4%)
29 (2.8%)
-0.010
23 (1.7%)
86 (1.1%)
0.005
028 (1.7%)
115 (1.3%)
0.033
Osteoarthrosis; n (%)
51 (14.0%)
122 (11.6%)
0.007
148 (11.2%)
571 (7.6%)
0.012
199 (11.8%)
693 (8.1%)
0.124
Other rheumatic disorders (including gout); n (%)
103 (28.4%)
278 (26.5%)
0.004
368 (27.8%)
1,529 (20.3%)
0.015
471 (27.9%)
1,807 (21.0%)
0.161
Gout and other crystal arthropathies; n (%)
9 (2.5%)
21 (2.0%)
0.003
20 (1.5%)
76 (1.0%)
0.004
029 (1.7%)
097 (1.1%)
0.051
Other rheumatic disorders; n (%)
95 (26.2%)
263 (25.0%)
0.002
353 (26.6%)
1,473 (19.5%)
0.015
448 (26.5%)
1,736 (20.2%)
0.149
Neuro Conditions
Alzheimer and other Dementia Disease ; n (%)
5 (1.4%)
12 (1.1%)
0.003
15 (1.1%)
46 (0.6%)
0.005
020 (1.2%)
058 (0.7%)
0.052
Seizure disorders (epilepsy); n (%)
1 (0.3%)
8 (0.8%)
-0.007
10 (0.8%)
29 (0.4%)
0.005
011 (0.7%)
037 (0.4%)
0.041
Delirium/Psychosis; n (%)
4 (1.1%)
14 (1.3%)
-0.002
16 (1.2%)
50 (0.7%)
0.005
020 (1.2%)
064 (0.7%)
0.052
Other Conditions
Hypothyroidism; n (%)
31 (8.5%)
128 (12.2%)
-0.012
135 (10.2%)
722 (9.6%)
0.002
166 (9.8%)
850 (9.9%)
-0.003
Chronic kidney disease stages I-III; n (%)
14 (3.9%)
39 (3.7%)
0.001
32 (2.4%)
118 (1.6%)
0.006
046 (2.7%)
157 (1.8%)
0.061
Chronic kidney disease stages IV-V, ESRD; n (%)
4 (1.1%)
11 (1.0%)
0.001
17 (1.3%)
51 (0.7%)
0.006
021 (1.2%)
062 (0.7%)
0.052
COPD; n (%)
83 (22.9%)
152 (14.5%)
0.019
294 (22.2%)
607 (8.0%)
0.037
377 (22.3%)
759 (8.8%)
0.379
Obstructive sleep apnea; n (%)
46 (12.7%)
111 (10.6%)
0.006
166 (12.5%)
600 (7.9%)
0.014
212 (12.6%)
711 (8.3%)
0.141
Syncope; n (%)
4 (1.1%)
23 (2.2%)
-0.009
23 (1.7%)
91 (1.2%)
0.004
027 (1.6%)
114 (1.3%)
0.025
Falls; n (%)
6 (1.7%)
21 (2.0%)
-0.002
6 (0.5%)
53 (0.7%)
-0.003
012 (0.7%)
074 (0.9%)
-0.022
VTE; n (%)
6 (1.7%)
14 (1.3%)
0.003
20 (1.5%)
67 (0.9%)
0.005
026 (1.5%)
081 (0.9%)
0.055
Combined comorbidity score, 365 days
...mean (sd)
1.48 (1.68)
1.55 (1.65)
-0.042
1.49 (1.58)
1.24 (1.16)
0.180
1.49 (1.60)
1.28 (1.23)
0.147
...median [IQR]
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
0.000
1.00 [1.00, 2.00]
1.00 [1.00, 1.00]
0.000
1.00 (1.60)
1.00 (1.23)
0.000
Frailty Score: Empirical Version 365 days as Categories
...< 0.1 non frail; n (%)
163 (44.9%)
622 (59.2%)
-0.020
512 (38.6%)
4,595 (60.9%)
-0.032
675 (40.0%)
5,217 (60.7%)
-0.423
...0.1 - < 0.2 prefrail; n (%)
98 (27.0%)
247 (23.5%)
0.007
371 (28.0%)
1,742 (23.1%)
0.010
469 (27.8%)
1,989 (23.1%)
0.108
… > 0.2 frail; n (%)
102 (28.1%)
182 (17.3%)
0.023
442 (33.4%)
1,212 (16.1%)
0.035
544 (32.2%)
1,394 (16.2%)
0.380
Medication Use
Use of oral corticosteroids; n (%)
181 (49.9%)
507 (48.2%)
0.002
663 (50.0%)
3,950 (52.3%)
-0.003
844 (50.0%)
4,457 (51.8%)
-0.036
Use of antidepressants; n (%)
95 (26.2%)
279 (26.5%)
-0.001
304 (22.9%)
1,802 (23.9%)
-0.002
399 (23.6%)
2,081 (24.2%)
-0.014
Use of anticonvulsants; n (%)
27 (7.4%)
123 (11.7%)
-0.014
157 (11.8%)
649 (8.6%)
0.010
184 (10.9%)
772 (9.0%)
0.064
Use of beta blocker OR calcium channel blocker; n (%)
72 (19.8%)
185 (17.6%)
0.005
285 (21.5%)
964 (12.8%)
0.021
357 (21.1%)
1,149 (13.4%)
0.205
Use of PPIs; n (%)
84 (23.1%)
221 (21.0%)
0.004
384 (29.0%)
1,884 (25.0%)
0.008
468 (27.7%)
2,105 (24.5%)
0.073
Use of opioids; n (%)
88 (24.2%)
249 (23.7%)
0.001
369 (27.8%)
1,516 (20.1%)
0.016
457 (27.1%)
1,765 (20.5%)
0.155
Use of antipsychotics; n (%)
4 (1.1%)
27 (2.6%)
-0.011
28 (2.1%)
141 (1.9%)
0.001
032 (1.9%)
168 (2.0%)
-0.007
Use of anxiolytics/hypnotics; n (%)
36 (9.9%)
93 (8.8%)
0.004
136 (10.3%)
576 (7.6%)
0.009
172 (10.2%)
669 (7.8%)
0.084
Use of dementia meds; n (%)
2 (0.6%)
2 (0.2%)
0.006
13 (1.0%)
28 (0.4%)
0.007
015 (0.9%)
030 (0.3%)
0.078
Use of antiparkinsonian meds; n (%)
4 (1.1%)
26 (2.5%)
-0.010
37 (2.8%)
107 (1.4%)
0.010
041 (2.4%)
133 (1.5%)
0.065
Use of Benzodiazepine; n (%)
36 (9.9%)
147 (14.0%)
-0.012
193 (14.6%)
909 (12.0%)
0.007
229 (13.6%)
1,056 (12.3%)
0.039
All antidiabetic medications; n (%)
39 (10.7%)
117 (11.1%)
-0.001
176 (13.3%)
626 (8.3%)
0.015
215 (12.7%)
743 (8.6%)
0.133
ACEI/ARB; n (%)
112 (30.9%)
299 (28.4%)
0.005
428 (32.3%)
1,681 (22.3%)
0.019
540 (32.0%)
1,980 (23.0%)
0.203
Use of Anticoagulants; n (%)
12 (3.3%)
37 (3.5%)
-0.001
58 (4.4%)
176 (2.3%)
0.011
070 (4.1%)
213 (2.5%)
0.090
Use of Amiodarone; n (%)
1 (0.3%)
3 (0.3%)
0.000
10 (0.8%)
15 (0.2%)
0.008
011 (0.7%)
018 (0.2%)
0.075
Digoxin; n (%)
2 (0.6%)
5 (0.5%)
0.001
20 (1.5%)
34 (0.5%)
0.010
022 (1.3%)
039 (0.5%)
0.085
Use of Diuretics; n (%)
85 (23.4%)
230 (21.9%)
0.003
365 (27.5%)
1,376 (18.2%)
0.019
450 (26.7%)
1,606 (18.7%)
0.192
Use of Aspirin; n (%)
3 (0.8%)
3 (0.3%)
0.007
10 (0.8%)
44 (0.6%)
0.002
013 (0.8%)
047 (0.5%)
0.037
NSAIDs (NOT including aspirin); n (%)
38 (10.5%)
137 (13.0%)
-0.007
177 (13.4%)
999 (13.2%)
0.001
215 (12.7%)
1,136 (13.2%)
-0.015
HRT (Use of estrogens, progestins, androgens); n (%)
31 (8.5%)
140 (13.3%)
-0.015
160 (12.1%)
1,209 (16.0%)
-0.010
191 (11.3%)
1,349 (15.7%)
-0.129
Use of Statins ; n (%)
109 (30.0%)
287 (27.3%)
0.005
428 (32.3%)
1,626 (21.5%)
0.021
537 (31.8%)
1,913 (22.2%)
0.218
Appendix B

Healthcare Utilization Measures
Use of any drugs claims
...mean (sd)
28.06 (20.25)
30.77 (23.08)
-0.125
29.03 (20.42)
27.03 (18.93)
0.102
28.82 (20.38)
27.49 (19.48)
0.067
...median [IQR]
23.00 [13.00, 41.00]
24.00 [16.00, 40.00]
-0.046
25.00 [15.00, 39.00]
22.00 [13.00, 36.00]
0.152
24.57 (20.38)
22.24 (19.48)
0.117
Number of office visits 
...mean (sd)
11.96 (10.10)
13.13 (11.32)
-0.109
12.13 (9.25)
11.25 (10.06)
0.091
12.09 (9.44)
11.48 (10.22)
0.062
...median [IQR]
9.00 [5.00, 15.00]
10.00 [6.00, 17.00]
-0.093
10.00 [5.50, 16.00]
9.00 [5.00, 15.00]
0.103
9.78 (9.44)
9.12 (10.22)
0.067
Number of ED visits
...mean (sd)
0.52 (1.06)
0.57 (1.62)
-0.037
0.58 (1.40)
0.43 (1.03)
0.122
0.57 (1.33)
0.45 (1.12)
0.098
...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.000
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.000
0.00 (1.33)
0.00 (1.12)
0.000
Number of hospitalizations
...mean (sd)
0.12 (0.63)
0.09 (0.41)
0.056
0.54 (2.44)
0.22 (1.55)
0.157
0.45 (2.18)
0.20 (1.46)
0.135
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.000
0.00 (2.18)
0.00 (1.46)
0.000
Recent hospitalization (-30 days to Index Rx date); n (%)
2 (0.6%)
16 (1.5%)
-0.009
29 (2.2%)
54 (0.7%)
0.012
031 (1.8%)
070 (0.8%)
0.088
Old hospitalizations (-365 to -31 days); n (%)
42 (11.6%)
113 (10.8%)
0.002
180 (13.6%)
523 (6.9%)
0.021
222 (13.2%)
636 (7.4%)
0.192
Number of Pulmonologist/Allergist visits
...mean (sd)
0.11 (0.59)
0.07 (0.49)
0.074
1.38 (3.13)
2.03 (4.35)
-0.172
1.11 (2.79)
1.79 (4.08)
-0.195
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.000
0.00 [0.00, 1.00]
0.00 [0.00, 2.00]
0.000
0.00 (2.79)
0.00 (4.08)
0.000
Pulmonologist /allergist on CED; n (%)
4 (1.1%)
5 (0.5%)
0.007
147 (11.1%)
1,099 (14.6%)
-0.010
151 (8.9%)
1,104 (12.8%)
-0.126
Number of hospital days
...mean (sd)
1.51 (10.26)
0.74 (4.89)
0.096
0.54 (2.44)
0.22 (1.55)
0.157
0.75 (5.22)
0.28 (2.24)
0.117
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.000
0.00 (5.22)
0.00 (2.24)
0.000
Occurrence of basic or comprehensive metabolic blood chemistry 
test; n (%)
149 (41.0%)
406 (38.6%)
0.004
434 (32.8%)
2,074 (27.5%)
0.010
583 (34.5%)
2,480 (28.8%)
0.123
Number of HbA1C test ordered
...mean (sd)
0.51 (1.00)
0.55 (1.12)
-0.038
0.45 (1.00)
0.38 (0.91)
0.073
0.46 (1.00)
0.40 (0.94)
0.062
...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.000
0.00 (1.00)
0.00 (0.94)
0.000
Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy; 
n (%)
18 (5.0%)
34 (3.2%)
0.009
70 (5.3%)
291 (3.9%)
0.007
088 (5.2%)
325 (3.8%)
0.068
Number of Mammograms (Breast cancer screening); n (%)
46 (12.7%)
151 (14.4%)
-0.005
175 (13.2%)
1,091 (14.5%)
-0.003
221 (13.1%)
1,242 (14.4%)
-0.038
Number of Pap smear (Cervical cancer screening); n (%)
29 (8.0%)
110 (10.5%)
-0.008
107 (8.1%)
814 (10.8%)
-0.009
136 (8.1%)
924 (10.7%)
-0.089
Flu vaccine; n (%)
66 (18.2%)
212 (20.2%)
-0.005
193 (14.6%)
1,316 (17.4%)
-0.007
259 (15.3%)
1,528 (17.8%)
-0.067
Pneumococcal vaccine; n (%)
10 (2.8%)
96 (9.1%)
-0.026
42 (3.2%)
622 (8.2%)
-0.021
052 (3.1%)
718 (8.3%)
-0.226
Copay for pharmacy cost (charges in U.S. $)
...mean (sd)
38.10 (33.36)
37.67 (31.88)
0.013
34.89 (33.21)
26.35 (23.40)
0.297
35.58 (33.24)
27.73 (24.59)
0.268
...median [IQR]
30.00 [18.95, 47.48]
31.94 [17.50, 50.14]
-0.059
28.41 [15.61, 43.95]
22.44 [11.87, 35.15]
0.208
28.75 (33.24)
23.60 (24.59)
0.176
Business Type
...Commercial; n (%)
312 (86.0%)
835 (79.4%)
0.007
NA
NA
NA
NA
NA
NA
...Medicare; n (%)
51 (14.0%)
216 (20.6%)
-0.016
NA
NA
NA
NA
NA
NA
Insurance Plan Type
...Comprehensive; n (%)
NA
NA
NA
188 (14.2%)
494 (6.5%)
0.024
NA
NA
NA
...HMO; n (%)
NA
NA
NA
150 (11.3%)
1,357 (18.0%)
-0.018
NA
NA
NA
...PPO; n (%)
NA
NA
NA
758 (57.2%)
4,103 (54.4%)
0.004
NA
NA
NA
...Others; n (%)
NA
NA
NA
229 (17.3%)
1,595 (21.1%)
-0.009
NA
NA
NA
SABA; n (%)
164 (45.2%)
615 (58.5%)
-0.019
773 (58.3%)
4,829 (64.0%)
-0.007
937 (55.5%)
5,444 (63.3%)
-0.159
SAMA; n (%)
16 (4.4%)
33 (3.1%)
0.007
60 (4.5%)
254 (3.4%)
0.006
076 (4.5%)
287 (3.3%)
0.062
SABA/SAMA; n (%)
25 (6.9%)
45 (4.3%)
0.011
118 (8.9%)
263 (3.5%)
0.022
143 (8.5%)
308 (3.6%)
0.207
ICS; n (%)
332 (91.5%)
442 (42.1%)
0.061
1,211 (91.4%)
4,052 (53.7%)
0.044
1,543 (91.4%)
4,494 (52.3%)
0.965
LABA without formoterol; n (%)
21 (5.8%)
3 (0.3%)
0.032
73 (5.5%)
57 (0.8%)
0.026
094 (5.6%)
060 (0.7%)
0.283
LAMA; n (%)
46 (12.7%)
70 (6.7%)
0.019
187 (14.1%)
378 (5.0%)
0.029
233 (13.8%)
448 (5.2%)
0.297
LABA/ICS without mometasone-formoterol; n (%)
91 (25.1%)
430 (40.9%)
-0.028
326 (24.6%)
3,189 (42.2%)
-0.031
417 (24.7%)
3,619 (42.1%)
-0.375
Blood eosinophilia test ; n (%)
0 (0.0%)
5 (0.5%)
-0.010
4 (0.3%)
15 (0.2%)
0.002
004 (0.2%)
020 (0.2%)
0.000
Serum immunoglobulin E (IgE) level test; n (%)
7 (1.9%)
28 (2.7%)
-0.005
29 (2.2%)
293 (3.9%)
-0.010
036 (2.1%)
321 (3.7%)
-0.095
H2 blocker; n (%)
5 (1.4%)
27 (2.6%)
-0.008
44 (3.3%)
311 (4.1%)
-0.004
049 (2.9%)
338 (3.9%)
-0.055
Oxygen codes; n (%)
11 (3.0%)
15 (1.4%)
0.011
40 (3.0%)
46 (0.6%)
0.018
051 (3.0%)
061 (0.7%)
0.171
Respiratory arrest/dependence on oxygen; n (%)
8 (2.2%)
6 (0.6%)
0.014
10 (0.8%)
25 (0.3%)
0.007
018 (1.1%)
031 (0.4%)
0.081
Aetion link to Optum results: https://bwh-dope.aetion.com/projects/details/1659/rwrs/68458
Aetion link to Marketscan results: https://bwh-dope.aetion.com/projects/details/1658/rwrs/68457
Appendix B

Variable
Formoterol fumarate 
10 mcg
Mometasone 
furoate/formoterol 
fumarate
St. Diff.
Formoterol fumarate 
10 mcg
Mometasone 
furoate/formoterol 
fumarate
St. Diff.
Formoterol fumarate
10 mcg
Mometasone 
furoate/formoterol 
fumarate
St. Diff.
Number of patients
165
165
919
919
1,084 
1,084 
Year of Cohort Entry Date
...2010; n (%)
11 (6.7%)
7 (4.2%)
0.0107
73 (7.9%)
89 (9.7%)
-0.0061
084 (7.7%)
096 (8.9%)
-0.044
...2011; n (%)
33 (20.0%)
41 (24.8%)
-0.0102
276 (30.0%)
247 (26.9%)
0.0058
309 (28.5%)
288 (26.6%)
0.043
...2012; n (%)
40 (24.2%)
43 (26.1%)
-0.0038
210 (22.9%)
223 (24.3%)
-0.0029
250 (23.1%)
266 (24.5%)
-0.033
...2013; n (%)
34 (20.6%)
25 (15.2%)
0.0128
131 (14.3%)
136 (14.8%)
-0.0013
165 (15.2%)
161 (14.9%)
0.008
...2014; n (%)
28 (17.0%)
26 (15.8%)
0.0030
140 (15.2%)
131 (14.3%)
0.0023
168 (15.5%)
157 (14.5%)
0.028
...2015; n (%)
15 (9.1%)
16 (9.7%)
-0.0020
76 (8.3%)
78 (8.5%)
-0.0007
091 (8.4%)
094 (8.7%)
-0.011
...2016; n (%)
4 (2.4%)
7 (4.2%)
-0.0099
13 (1.4%)
15 (1.6%)
-0.0016
017 (1.6%)
022 (2.0%)
-0.030
...2017; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
000 (0.0%)
000 (0.0%)
#DIV/0!
...2018; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
0 (0.0%)
0 (0.0%)
#DIV/0!
000 (0.0%)
000 (0.0%)
#DIV/0!
...2019; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
NA
NA
NA
NA
NA
NA
...2020; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
NA
NA
NA
NA
NA
NA
Age*
...mean (sd)
52.62 (15.47)
53.08 (16.38)
-0.0289
53.73 (15.97)
53.63 (17.30)
0.0060
53.56 (15.90)
53.55 (17.16)
0.001
...median [IQR]
54.00 [45.00, 63.50]
54.00 [44.00, 63.50]
0.0000
57.00 [45.00, 63.00]
56.00 [44.00, 64.00]
0.0601
56.54 (15.90)
55.70 (17.16)
0.051
Age categories
...12-17; n (%)
4 (2.4%)
7 (4.2%)
-0.0099
32 (3.5%)
52 (5.7%)
-0.0103
036 (3.3%)
059 (5.4%)
-0.103
...18-39; n (%)
27 (16.4%)
23 (13.9%)
0.0064
114 (12.4%)
120 (13.1%)
-0.0020
141 (13.0%)
143 (13.2%)
-0.006
...40 - 64; n (%)
95 (57.6%)
100 (60.6%)
-0.0039
580 (63.1%)
540 (58.8%)
0.0055
675 (62.3%)
640 (59.0%)
0.068
...>= 65; n (%)
39 (23.6%)
35 (21.2%)
0.0051
193 (21.0%)
207 (22.5%)
-0.0032
232 (21.4%)
242 (22.3%)
-0.022
Geographic Region*
...Northeast; n (%)
22 (13.3%)
19 (11.5%)
0.0051
225 (24.5%)
227 (24.7%)
-0.0004
247 (22.8%)
246 (22.7%)
0.002
...South; n (%)
68 (41.2%)
71 (43.0%)
-0.0028
293 (31.9%)
294 (32.0%)
-0.0002
361 (33.3%)
365 (33.7%)
-0.008
...Midwest; n (%)
44 (26.7%)
42 (25.5%)
0.0024
213 (23.2%)
206 (22.4%)
0.0017
257 (23.7%)
248 (22.9%)
0.019
...West; n (%)
31 (18.8%)
33 (20.0%)
-0.0027
172 (18.7%)
176 (19.2%)
-0.0011
203 (18.7%)
209 (19.3%)
-0.015
...Unknown/Missing; n (%)
NA
NA
NA
16 (1.7%)
16 (1.7%)
0.0000
NA
NA
NA
Metropolitan Statistical Area*
...Urban; n (%)
NA
NA
NA
742 (80.7%)
763 (83.0%)
-0.0026
NA
NA
NA
...Rural; n (%)
NA
NA
NA
2 (0.2%)
5 (0.5%)
-0.0051
NA
NA
NA
...Unknown/Missing; n (%)
NA
NA
NA
175 (19.0%)
151 (16.4%)
0.0062
NA
NA
NA
General Health Related Measures
Alcohol/Drug abuse or dependence ; n (%)
3 (1.8%)
2 (1.2%)
0.0049
9 (1.0%)
12 (1.3%)
-0.0028
012 (1.1%)
014 (1.3%)
-0.018
Obesity or Overweight; n (%)*
15 (9.1%)
20 (12.1%)
-0.0092
77 (8.4%)
87 (9.5%)
-0.0037
092 (8.5%)
107 (9.9%)
-0.048
Obesity; n (%)
13 (7.9%)
17 (10.3%)
-0.0080
68 (7.4%)
77 (8.4%)
-0.0036
081 (7.5%)
094 (8.7%)
-0.044
Overweight; n (%)
2 (1.2%)
3 (1.8%)
-0.0049
12 (1.3%)
10 (1.1%)
0.0018
014 (1.3%)
013 (1.2%)
0.009
Cardiovascular Measures
Hypertension; n (%)*
63 (38.2%)
60 (36.4%)
0.0030
325 (35.4%)
332 (36.1%)
-0.0012
388 (35.8%)
392 (36.2%)
-0.008
Hyperlipidemia; n (%)*
54 (32.7%)
49 (29.7%)
0.0054
254 (27.6%)
273 (29.7%)
-0.0039
308 (28.4%)
322 (29.7%)
-0.029
MI, angina, Coronary atherosclerosis and other forms of chronic 
ischemic heart disease; n (%)*
12 (7.3%)
9 (5.5%)
0.0071
75 (8.2%)
83 (9.0%)
-0.0027
087 (8.0%)
092 (8.5%)
-0.018
Old MI; n (%)
2 (1.2%)
1 (0.6%)
0.0063
5 (0.5%)
4 (0.4%)
0.0015
007 (0.6%)
005 (0.5%)
0.014
Acute MI; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
2 (0.2%)
2 (0.2%)
0.0000
002 (0.2%)
002 (0.2%)
0.000
Stable angina; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
10 (1.1%)
7 (0.8%)
0.0031
010 (0.9%)
007 (0.6%)
0.035
Coronary atherosclerosis and other forms of chronic ischemic 
heart disease; n (%)
12 (7.3%)
9 (5.5%)
0.0071
68 (7.4%)
72 (7.8%)
-0.0015
080 (7.4%)
081 (7.5%)
-0.004
History of CABG or PTCA; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
7 (0.8%)
5 (0.5%)
0.0037
007 (0.6%)
005 (0.5%)
0.014
Cerebrovascular disease (Stroke, TIA, Late effects); n (%)*
2 (1.2%)
3 (1.8%)
-0.0049
12 (1.3%)
9 (1.0%)
0.0028
014 (1.3%)
012 (1.1%)
0.018
Stroke (Ischemic or hemorrhagic); n (%)
2 (1.2%)
0 (0.0%)
0.0155
7 (0.8%)
6 (0.7%)
0.0012
009 (0.8%)
006 (0.6%)
0.024
TIA; n (%)
0 (0.0%)
2 (1.2%)
-0.0155
6 (0.7%)
3 (0.3%)
0.0057
006 (0.6%)
005 (0.5%)
0.014
Late effects of cerebrovascular disease; n (%)
0 (0.0%)
1 (0.6%)
-0.0110
5 (0.5%)
1 (0.1%)
0.0073
005 (0.5%)
002 (0.2%)
0.051
Atrial fibrillation and Other cardiac dysrhythmia; n (%)*
10 (6.1%)
12 (7.3%)
-0.0046
64 (7.0%)
62 (6.7%)
0.0011
074 (6.8%)
074 (6.8%)
0.000
Atrial fibrillation; n (%)
3 (1.8%)
6 (3.6%)
-0.0110
38 (4.1%)
32 (3.5%)
0.0031
041 (3.8%)
038 (3.5%)
0.016
Other cardiac dysrhythmia; n (%)
7 (4.2%)
8 (4.8%)
-0.0028
39 (4.2%)
39 (4.2%)
0.0000
046 (4.2%)
047 (4.3%)
-0.005
Diabetes Related Measures
Diabetes with or w/o complications; n (%)*
23 (13.9%)
25 (15.2%)
-0.0034
130 (14.1%)
126 (13.7%)
0.0011
153 (14.1%)
151 (13.9%)
0.006
PS-matched
Optum
Marketscan
POOLED
Appendix B

Diabetes mellitus without mention of complications; n (%)
23 (13.9%)
25 (15.2%)
-0.0034
124 (13.5%)
119 (12.9%)
0.0017
147 (13.6%)
144 (13.3%)
0.009
Diabetes with specified complications; n (%)
4 (2.4%)
7 (4.2%)
-0.0099
29 (3.2%)
20 (2.2%)
0.0061
033 (3.0%)
027 (2.5%)
0.031
Diabetes with unspecified complications; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
5 (0.5%)
3 (0.3%)
0.0032
005 (0.5%)
003 (0.3%)
0.032
GI Conditions
GERD; n (%)*
22 (13.3%)
28 (17.0%)
-0.0095
120 (13.1%)
123 (13.4%)
-0.0008
142 (13.1%)
151 (13.9%)
-0.023
Upper GI (Diseases of esophagus, stomach and duodenum including 
GERD) ; n (%)
25 (15.2%)
31 (18.8%)
-0.0087
152 (16.5%)
161 (17.5%)
-0.0024
177 (16.3%)
192 (17.7%)
-0.037
GI bleeding; n (%)*
3 (1.8%)
2 (1.2%)
0.0049
14 (1.5%)
12 (1.3%)
0.0017
017 (1.6%)
014 (1.3%)
0.025
Non-infective enteritis and colitis; n (%)
6 (3.6%)
10 (6.1%)
-0.0114
40 (4.4%)
37 (4.0%)
0.0020
046 (4.2%)
047 (4.3%)
-0.005
Intraoperative and postprocedural complications and disorders of 
digestive system; n (%)
2 (1.2%)
2 (1.2%)
0.0000
16 (1.7%)
17 (1.8%)
-0.0008
018 (1.7%)
019 (1.8%)
-0.008
Disorders of gallbladder, biliary tract and pancreas; n (%)*
1 (0.6%)
0 (0.0%)
0.0110
11 (1.2%)
7 (0.8%)
0.0040
012 (1.1%)
007 (0.6%)
0.054
Rheumatic Conditions
Rheumatoid arthritis and other inflammatory polyarthropathies; n 
(%)*
2 (1.2%)
3 (1.8%)
-0.0049
17 (1.8%)
14 (1.5%)
0.0023
019 (1.8%)
017 (1.6%)
0.015
Osteoarthrosis; n (%)*
21 (12.7%)
22 (13.3%)
-0.0017
90 (9.8%)
91 (9.9%)
-0.0003
111 (10.2%)
113 (10.4%)
-0.007
Other rheumatic disorders (including gout); n (%)*
40 (24.2%)
46 (27.9%)
-0.0073
234 (25.5%)
249 (27.1%)
-0.0031
274 (25.3%)
295 (27.2%)
-0.043
Gout and other crystal arthropathies; n (%)
2 (1.2%)
4 (2.4%)
-0.0089
14 (1.5%)
20 (2.2%)
-0.0051
016 (1.5%)
024 (2.2%)
-0.052
Other rheumatic disorders; n (%)
38 (23.0%)
43 (26.1%)
-0.0063
225 (24.5%)
233 (25.4%)
-0.0018
263 (24.3%)
276 (25.5%)
-0.028
Neuro Conditions*
Alzheimer and other Dementia Disease ; n (%)
1 (0.6%)
2 (1.2%)
-0.0063
7 (0.8%)
11 (1.2%)
-0.0040
008 (0.7%)
013 (1.2%)
-0.052
Seizure disorders (epilepsy); n (%)
0 (0.0%)
1 (0.6%)
-0.0110
6 (0.7%)
8 (0.9%)
-0.0022
006 (0.6%)
009 (0.8%)
-0.024
Delirium/Psychosis; n (%)
1 (0.6%)
1 (0.6%)
0.0000
8 (0.9%)
9 (1.0%)
-0.0010
009 (0.8%)
010 (0.9%)
-0.011
Other Conditions
Hypothyroidism; n (%)*
12 (7.3%)
13 (7.9%)
-0.0022
99 (10.8%)
110 (12.0%)
-0.0036
111 (10.2%)
123 (11.3%)
-0.036
Chronic kidney disease stages I-III; n (%)*
4 (2.4%)
4 (2.4%)
0.0000
15 (1.6%)
19 (2.1%)
-0.0037
019 (1.8%)
023 (2.1%)
-0.022
Chronic kidney disease stages IV-V, ESRD; n (%)
1 (0.6%)
2 (1.2%)
-0.0063
7 (0.8%)
10 (1.1%)
-0.0031
008 (0.7%)
012 (1.1%)
-0.042
COPD; n (%)*
25 (15.2%)
29 (17.6%)
-0.0059
147 (16.0%)
160 (17.4%)
-0.0034
172 (15.9%)
189 (17.4%)
-0.040
Obstructive sleep apnea; n (%)*
15 (9.1%)
17 (10.3%)
-0.0039
108 (11.8%)
117 (12.7%)
-0.0026
123 (11.3%)
134 (12.4%)
-0.034
Syncope; n (%)
3 (1.8%)
2 (1.2%)
0.0049
12 (1.3%)
16 (1.7%)
-0.0033
015 (1.4%)
018 (1.7%)
-0.024
Falls; n (%)
1 (0.6%)
4 (2.4%)
-0.0147
5 (0.5%)
3 (0.3%)
0.0032
006 (0.6%)
007 (0.6%)
0.000
VTE; n (%)*
3 (1.8%)
4 (2.4%)
-0.0041
14 (1.5%)
9 (1.0%)
0.0045
017 (1.6%)
013 (1.2%)
0.034
Combined comorbidity score, 365 days*
...mean (sd)
1.26 (1.30)
1.34 (1.15)
-0.0652
1.38 (1.39)
1.42 (1.52)
-0.0275
1.36 (1.38)
1.41 (1.47)
-0.035
...median [IQR]
1.00 [1.00, 1.00]
1.00 [1.00, 2.00]
0.0000
1.00 [1.00, 2.00]
1.00 [1.00, 2.00]
0.0000
1.00 (1.38)
1.00 (1.47)
0.000
Frailty Score: Empirical Version 365 days as Categories*
...< 0.1 non frail; n (%)
81 (49.1%)
90 (54.5%)
-0.0075
409 (44.5%)
406 (44.2%)
0.0005
490 (45.2%)
496 (45.8%)
-0.012
...0.1 - < 0.2 prefrail; n (%)
45 (27.3%)
39 (23.6%)
0.0073
261 (28.4%)
261 (28.4%)
0.0000
306 (28.2%)
300 (27.7%)
0.011
… > 0.2 frail; n (%)
39 (23.6%)
36 (21.8%)
0.0038
249 (27.1%)
252 (27.4%)
-0.0006
288 (26.6%)
288 (26.6%)
0.000
Medication Use
Use of oral corticosteroids; n (%)*
82 (49.7%)
79 (47.9%)
0.0026
458 (49.8%)
475 (51.7%)
-0.0027
540 (49.8%)
554 (51.1%)
-0.026
Use of antidepressants; n (%)*
40 (24.2%)
36 (21.8%)
0.0050
223 (24.3%)
228 (24.8%)
-0.0010
263 (24.3%)
264 (24.4%)
-0.002
Use of anticonvulsants; n (%)*
17 (10.3%)
15 (9.1%)
0.0039
101 (11.0%)
100 (10.9%)
0.0003
118 (10.9%)
115 (10.6%)
0.010
Use of beta blocker OR calcium channel blocker; n (%)*
24 (14.5%)
17 (10.3%)
0.0119
166 (18.1%)
164 (17.8%)
0.0007
190 (17.5%)
181 (16.7%)
0.021
Use of PPIs; n (%)*
37 (22.4%)
39 (23.6%)
-0.0025
267 (29.1%)
263 (28.6%)
0.0009
304 (28.0%)
302 (27.9%)
0.002
Use of opioids; n (%)*
37 (22.4%)
42 (25.5%)
-0.0063
245 (26.7%)
235 (25.6%)
0.0022
282 (26.0%)
277 (25.6%)
0.009
Use of antipsychotics; n (%)*
2 (1.2%)
1 (0.6%)
0.0063
16 (1.7%)
17 (1.8%)
-0.0008
018 (1.7%)
018 (1.7%)
0.000
Use of anxiolytics/hypnotics; n (%)*
15 (9.1%)
15 (9.1%)
0.0000
84 (9.1%)
96 (10.4%)
-0.0042
099 (9.1%)
111 (10.2%)
-0.037
Use of dementia meds; n (%)*
0 (0.0%)
1 (0.6%)
-0.0110
6 (0.7%)
9 (1.0%)
-0.0033
006 (0.6%)
010 (0.9%)
-0.035
Use of antiparkinsonian meds; n (%)*
2 (1.2%)
3 (1.8%)
-0.0049
23 (2.5%)
25 (2.7%)
-0.0012
025 (2.3%)
028 (2.6%)
-0.019
Use of Benzodiazepine; n (%)*
13 (7.9%)
15 (9.1%)
-0.0041
137 (14.9%)
139 (15.1%)
-0.0005
150 (13.8%)
154 (14.2%)
-0.012
All antidiabetic medications; n (%)*
17 (10.3%)
20 (12.1%)
-0.0054
109 (11.9%)
100 (10.9%)
0.0030
126 (11.6%)
120 (11.1%)
0.016
ACEI/ARB; n (%)*
48 (29.1%)
40 (24.2%)
0.0095
269 (29.3%)
256 (27.9%)
0.0026
317 (29.2%)
296 (27.3%)
0.042
Use of Anticoagulants; n (%)*
3 (1.8%)
5 (3.0%)
-0.0077
36 (3.9%)
33 (3.6%)
0.0015
039 (3.6%)
038 (3.5%)
0.005
Use of Amiodarone; n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
4 (0.4%)
6 (0.7%)
-0.0040
004 (0.4%)
006 (0.6%)
-0.028
Digoxin; n (%)
1 (0.6%)
1 (0.6%)
0.0000
9 (1.0%)
10 (1.1%)
-0.0010
010 (0.9%)
011 (1.0%)
-0.010
Use of Diuretics; n (%)*
38 (23.0%)
31 (18.8%)
0.0092
215 (23.4%)
215 (23.4%)
0.0000
253 (23.3%)
246 (22.7%)
0.014
Use of Aspirin; n (%)
1 (0.6%)
0 (0.0%)
0.0110
7 (0.8%)
7 (0.8%)
0.0000
008 (0.7%)
007 (0.6%)
0.012
NSAIDs (NOT including aspirin); n (%)
18 (10.9%)
24 (14.5%)
-0.0101
115 (12.5%)
145 (15.8%)
-0.0088
133 (12.3%)
169 (15.6%)
-0.095
HRT (Use of estrogens, progestins, androgens); n (%)*
19 (11.5%)
19 (11.5%)
0.0000
122 (13.3%)
128 (13.9%)
-0.0016
141 (13.0%)
147 (13.6%)
-0.018
Use of Statins ; n (%)*
45 (27.3%)
46 (27.9%)
-0.0011
262 (28.5%)
280 (30.5%)
-0.0037
307 (28.3%)
326 (30.1%)
-0.040
Appendix B

Healthcare Utilization Measures
Use of any drugs claims*
...mean (sd)
28.42 (20.68)
28.33 (20.78)
0.0043
28.80 (20.50)
29.10 (20.30)
-0.0147
28.74 (20.53)
28.98 (20.37)
-0.012
...median [IQR]
22.00 [13.00, 40.00]
21.00 [14.00, 36.00]
0.0482
24.00 [14.00, 38.00]
25.00 [15.00, 38.00]
-0.0490
23.70 (20.53)
24.39 (20.37)
-0.034
Number of office visits*
...mean (sd)
11.42 (9.14)
11.35 (9.38)
0.0076
12.04 (9.09)
12.12 (9.09)
-0.0088
11.95 (9.10)
12.00 (9.13)
-0.005
...median [IQR]
9.00 [5.00, 15.00]
8.00 [5.00, 13.50]
0.1080
10.00 [5.00, 16.00]
10.00 [6.00, 15.00]
0.0000
9.85 (9.10)
9.70 (9.13)
0.016
Number of ED visits*
...mean (sd)
0.41 (0.86)
0.38 (1.00)
0.0322
0.52 (1.28)
0.49 (1.20)
0.0242
0.50 (1.23)
0.47 (1.17)
0.025
...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.0000
0.00 (1.23)
0.00 (1.17)
0.000
Number of hospitalizations*
...mean (sd)
0.04 (0.23)
0.05 (0.27)
-0.0399
0.39 (2.13)
0.34 (1.75)
0.0257
0.34 (1.96)
0.30 (1.62)
0.022
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (1.96)
0.00 (1.62)
0.000
Recent hospitalization (-30 days to Index Rx date); n (%)
0 (0.0%)
0 (0.0%)
#DIV/0!
11 (1.2%)
12 (1.3%)
-0.0009
011 (1.0%)
012 (1.1%)
-0.010
Old hospitalizations (-365 to -31 days); n (%)
15 (9.1%)
11 (6.7%)
0.0085
97 (10.6%)
93 (10.1%)
0.0016
112 (10.3%)
104 (9.6%)
0.023
Number of Pulmonologist/Allergist visits*
...mean (sd)
0.10 (0.45)
0.08 (0.43)
0.0454
1.61 (3.53)
1.79 (3.40)
-0.0519
1.38 (3.26)
1.53 (3.14)
-0.047
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 2.00]
1.00 [0.00, 2.00]
-0.2885
0.00 (3.26)
0.85 (3.14)
-0.266
Pulmonologist /allergist on CED; n (%)*
2 (1.2%)
2 (1.2%)
0.0000
117 (12.7%)
136 (14.8%)
-0.0057
119 (11.0%)
138 (12.7%)
-0.053
Number of hospital days*
...mean (sd)
0.23 (1.38)
0.45 (3.12)
-0.0912
0.39 (2.13)
0.34 (1.75)
0.0257
0.37 (2.03)
0.36 (2.02)
0.005
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (2.03)
0.00 (2.02)
0.000
Occurrence of basic or comprehensive metabolic blood chemistry 
test; n (%)*
58 (35.2%)
60 (36.4%)
-0.0020
290 (31.6%)
286 (31.1%)
0.0009
348 (32.1%)
346 (31.9%)
0.004
Number of HbA1C test ordered*
...mean (sd)
0.42 (0.88)
0.56 (1.23)
-0.1309
0.42 (0.95)
0.39 (0.92)
0.0321
0.42 (0.94)
0.42 (0.97)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.94)
0.00 (0.97)
0.000
Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy; 
n (%)*
3 (1.8%)
6 (3.6%)
-0.0110
49 (5.3%)
57 (6.2%)
-0.0038
052 (4.8%)
063 (5.8%)
-0.045
Number of Mammograms (Breast cancer screening); n (%)*
21 (12.7%)
22 (13.3%)
-0.0017
131 (14.3%)
142 (15.5%)
-0.0031
152 (14.0%)
164 (15.1%)
-0.031
Number of Pap smear (Cervical cancer screening); n (%)*
14 (8.5%)
14 (8.5%)
0.0000
88 (9.6%)
78 (8.5%)
0.0037
102 (9.4%)
092 (8.5%)
0.032
Flu vaccine; n (%)*
29 (17.6%)
27 (16.4%)
0.0029
139 (15.1%)
144 (15.7%)
-0.0015
168 (15.5%)
171 (15.8%)
-0.008
Pneumococcal vaccine; n (%)*
7 (4.2%)
8 (4.8%)
-0.0028
37 (4.0%)
37 (4.0%)
0.0000
044 (4.1%)
045 (4.2%)
-0.005
Copay for pharmacy cost (charges in U.S. $)*
...mean (sd)
36.76 (34.33)
35.41 (28.84)
0.0426
32.44 (29.37)
32.24 (28.07)
0.0070
33.10 (30.17)
32.72 (28.19)
0.013
...median [IQR]
28.33 [18.09, 45.06]
29.38 [17.97, 48.77]
-0.0331
27.29 [14.61, 42.08]
27.00 [16.00, 41.79]
0.0101
27.45 (30.17)
27.36 (28.19)
0.003
Business Type*
...Commercial; n (%)
140 (84.8%)
136 (82.4%)
0.0026
NA
NA
NA
NA
NA
NA
...Medicare; n (%)
25 (15.2%)
29 (17.6%)
-0.0059
NA
NA
NA
NA
NA
NA
Insurance Plan Type*
...Comprehensive; n (%)
NA
NA
NA
96 (10.4%)
96 (10.4%)
0.0000
NA
NA
NA
...HMO; n (%)
NA
NA
NA
111 (12.1%)
102 (11.1%)
0.0029
NA
NA
NA
...PPO; n (%)
NA
NA
NA
543 (59.1%)
551 (60.0%)
-0.0012
NA
NA
NA
...Others; n (%)
NA
NA
NA
169 (18.4%)
170 (18.5%)
-0.0002
NA
NA
NA
SABA; n (%)*
87 (52.7%)
86 (52.1%)
0.0008
555 (60.4%)
540 (58.8%)
0.0021
642 (59.2%)
626 (57.7%)
0.030
SAMA; n (%)*
6 (3.6%)
7 (4.2%)
-0.0030
38 (4.1%)
42 (4.6%)
-0.0024
044 (4.1%)
049 (4.5%)
-0.020
SABA/SAMA; n (%)*
6 (3.6%)
8 (4.8%)
-0.0059
52 (5.7%)
50 (5.4%)
0.0013
058 (5.4%)
058 (5.4%)
0.000
ICS; n (%)*
138 (83.6%)
137 (83.0%)
0.0007
813 (88.5%)
805 (87.6%)
0.0010
951 (87.7%)
942 (86.9%)
0.024
LABA without formoterol; n (%)*
2 (1.2%)
3 (1.8%)
-0.0049
31 (3.4%)
33 (3.6%)
-0.0011
033 (3.0%)
036 (3.3%)
-0.017
LAMA; n (%)*
16 (9.7%)
15 (9.1%)
0.0020
106 (11.5%)
114 (12.4%)
-0.0026
122 (11.3%)
129 (11.9%)
-0.019
LABA/ICS without mometasone-formoterol; n (%)*
54 (32.7%)
55 (33.3%)
-0.0010
253 (27.5%)
266 (28.9%)
-0.0026
307 (28.3%)
321 (29.6%)
-0.029
Blood eosinophilia test ; n (%)*
0 (0.0%)
0 (0.0%)
#DIV/0!
3 (0.3%)
3 (0.3%)
0.0000
003 (0.3%)
003 (0.3%)
0.000
Serum immunoglobulin E (IgE) level test; n (%)*
2 (1.2%)
2 (1.2%)
0.0000
26 (2.8%)
33 (3.6%)
-0.0045
028 (2.6%)
035 (3.2%)
-0.036
H2 blocker; n (%)*
4 (2.4%)
2 (1.2%)
0.0089
33 (3.6%)
32 (3.5%)
0.0005
037 (3.4%)
034 (3.1%)
0.017
Oxygen codes; n (%)*
4 (2.4%)
5 (3.0%)
-0.0037
16 (1.7%)
14 (1.5%)
0.0016
020 (1.8%)
019 (1.8%)
0.000
Respiratory arrest/dependence on oxygen; n (%)*
0 (0.0%)
1 (0.6%)
-0.0110
6 (0.7%)
6 (0.7%)
0.0000
006 (0.6%)
007 (0.6%)
0.000
*Included in the 1:1 PS matching model
Appendix B