Once-Daily Single-Inhaler Triple Versus Dual Therapy in Patients With COPD (IMPACT Trial)
Conditions: COPD
Sponsor: Brigham and Women's Hospital

 
 
 
Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD 
(IMPACT Trial) 
 
DUPLICATE IMPACT  
 
May 14, 2021  
 
NCT02164513 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1
1. RCT DeƚailƐ 
This section provides a high-level overview of a ƉƵbliƐhed 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 
Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD (IMPACT Trial) 
1.2 Intended aim(s) 
To assess the effect of once-daily combination of fluticasone furoate at a dose of 100 ug, umeclidinium at a dose of ϲ2.ϱug, and 
vilanterol at a dose of 2ϱ ug (“triple therapy”) versus fluticasone furoate-vilanterol—at doses of 100ug and 2ϱug, respectively—on the 
annual rate of moderate or severe COPD exacerbations. (Note: RCT compares additional arm of umeclidinium-vilanterol).  
1.3 Primary endpoint for replication  
The primary endpoint is the rate of moderate or severe COPD exacerbations defined as an exacerbation leading to treatment with 
antibiotics or systemic glucocorticoids or one resulting in hospitalization or death.  
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
This trial is a superiority trial. Assuming that the annual rate of moderate or severe exacerbation would be 0.ϴ0 among patients treated 
with triple therapy and 0.ϵ1 among those treated with fluticasone furoate-vilanterol, it was determined that approximately 4000 
patients would be needed in the triple-therapy group and 4000 in the fluticasone furoate-vilanterol group to achieve ϵ0й power to 
conclude superiority of  triple therapy over fluticasone furoate- vilanterol at two sided alpha of 0.01.  
1.5 Secondary endpoint for replication (assay sensitivity) and RCT finding 
Pneumonia (Hazard ratio, HRс1.02; ϵϱй CI, 0.ϴϳ-1.1ϵ) comparing fluticasone furoate-umeclidinium-vilanterol vs. fluticasone furoate-
vilanterol.  
1.6 Trial estimate 
Rate ratio, RRс0.ϴϱ (ϵϱй CI, 0.ϴ0-0.ϵ0) comparing fluticasone furoate-umeclidinium-vilanterol vs. fluticasone furoate-vilanterol during    
ϱ2 weeks (Lipson et al., 201ϴ).  
 
2. PeƌƐon ƌeƐƉonƐible foƌ imƉlemenƚaƚion of ƌeƉlicaƚion in Aeƚion 
 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. Daƚa SoƵƌce;ƐͿ 
Optum CDM, IBM® MarketScan® 
4. SƚƵdǇ DeƐign Diagƌam 
The study design diagram visualizes key aspects of the longitudinal study design for expedited review. 
 

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Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϯ
5. Cohoƌƚ Idenƚificaƚion  
 
5.1 Cohort Summary 
This study will involve a new user, parallel group, propensity score-matched, retrospective cohort study design comparing triple 
therapy to fluticasone furoate-vilanterol users. The patients will be required to have continuous enrollment during a baseline 
period of 1ϴ0 days before initiation of triple therapy or fluticasone furoate-vilanterol (index date). We will restrict the analyses to 
patients with a diagnosis of COPD who have been receiving daily maintenance therapy for at least 3 months prior to index date.  
 
5.2 Important steps for cohort formation 
New use of fluticasone furoate-umeclidinium-vilanterol (exposure), and fluticasone furoate-vilanterol (comparator) is defined as no 
use of either therapy in 1ϴ0 days prior to index date 
 
5.2.1 Eligible cohort entry dates 
Market availability of fluticasone furoate-umeclidinium-vilanterol in the U.S. for management of COPD was approved by FDA 
on September 1ϴ, 201ϳ 
 
IBM® MarketScan®: September 1ϴ, 201ϳ – December 31, 201ϴ (end of available data)  
 
Optum CDM: September 1ϴ, 201ϳ – June 30, 2020 (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 fluticasone furoate -umeclidinium-vilanterol (triple therapy) vs. fluticasone furoate-vilanterol 
 
FLOWCHART 
  
Optum 
Marketscan 
Less Excluded Patients 
Remaining 
Patients 
  
Less 
Excluded 
Patients 
Remaining 
Patients 
All patients 
  
78,202,636 
  
200,203,908 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϰ
Did not meet cohort entry criteria 
-
77,961,768 
240,868 
-
200,099,629 
104,279 
Excluded due to insufficient enrollment 
-36,776 
204,092 
-9,826 
94,453 
Excluded due to prior use of referent 
-91,082 
113,010 
-57,156 
37,297 
Excluded due to prior use of exposure 
-25,673 
87,337 
-3,129 
34,168 
Excluded because patient qualified in >1 exposure category 
-10 
87,327 
-2 
34,166 
Excluded based on Age : Exclude missing 
-1 
87,326 
0 
34,166 
Excluded based on Gender: Exclude missing 
-3 
87,323 
0 
34,166 
Excluded based on INCLUSION: Age >=40 
-5,749 
81,574 
-6,431 
27,735 
Excluded based on INCLUSION: Established clinical history of COPD 
-19,242 
62,332 
-12,995 
14,740 
Excluded based on INCLUSION: COPD Maintenance Rx previous 90 days 
0 
62,332 
0 
14,740 
Excluded based on Exclusion 1 Pregnancy 
-12 
62,320 
-6 
14,734 
Excluded based on Exclusion 3 - Alpha-1-antitrypsin deficiency 
-80 
62,240 
-35 
14,699 
Excluded based on Exclusion 4 lung disease including Tb, lung ca, 
bronchiectasis, sarcoidosis, ILD 
-5,546 
56,694 
-1,166 
13,533 
Excluded based on Exclusion 5 - Lung volume reduction surgery 
0 
56,694 
0 
13,533 
Excluded based on Exclusion 6 - HIV/Lupus, Parkinson, MG 
-473 
56,221 
-104 
13,429 
Excluded based on Exclusion 7 - Pneumonia or COPD exacerbation [-14,0] 
-2,191 
54,030 
-1,321 
12,108 
Excluded based on Exclusion 8 - Acute upper or lower respiratory infections [-
7,0] 
-1,335 
52,695 
-415 
11,693 
Excluded based on Exclusion 11 - Liver disease 
-1,625 
51,070 
-256 
11,437 
Excluded based on Excl. 12a - Life threatening cardiac disease 
-850 
50,220 
-97 
11,340 
Excluded based on Excl 12b Unstable or life threatening cardiac arrhythmia 
requiring intervention in the last 3 months 
-73 
50,147 
-37 
11,303 
Excluded based on Excl. 12c - NYHA Class IV Heart failure 
-639 
49,508 
-148 
11,155 
Excluded based on Excl. 16 - Oxygen therapy 
-1,252 
48,256 
-47 
11,108 
Excluded based on Excl. 18 - Pulmonary rehabilitation 
-77 
48,179 
-18 
11,090 
Excluded based on Excl. 19 - Drug or alcohol abuse 
-402 
47,777 
-103 
10,987 
Excluded based on Excl. 24a - Use of long term antibiotics >90 days 
-280 
47,497 
-57 
10,930 
Excluded based on Excl. 24b - Use of corticosteroids [-30,-0]] 
-3,211 
44,286 
-684 
10,246 
Final cohort 
  
44,286 
  
10,246 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϱ
 
 
6. VaƌiableƐ  
 
6.1 Exposure-related variables:  
 
Study drug:  
The study exposure of interest is new initiation of fluticasone furoate-umeclidinium-vilanterol. New initiation will be defined by no use of 
fluticasone furoate-umeclidinium-vilanterol in the prior 180 days before treatment initiation (washout period). 
 
Comparator agent: 
New initiators of fluticasone furoate-vilanterol. New initiation will be defined by no use of fluticasone furoate-vilanterol in the prior 180 days  
before treatment initiation 
 
6.2 Preliminary Covariates: 
x Age 
x Gender 
x Combined Comorbidity Index (CCI), measured over the baseline covariate assessment period, defined as 1ϴ0 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: Annual rate of moderate or severe COPD exacerbations during treatment 
 
Control outcome of interest: Pneumonia  

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϲ
 
6.3.2 Study follow-up 
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. 
The follow-up will start the day after drug initiation (i.e., cohort entry date), as described in the IMPACT, and will continue until the earliest date of 
the following events: 
x 
The first occurrence of the outcome of interest, 
x 
The date of end of continuous registration in the database, 
x 
End of the study period, 
x 
Measured death event occurs, 
x 
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.   
x The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index drug plus a defined 
grace period (i.e., ϲ0 days after the end of the last prescription’s days’ supply in main analyses). 
 
For the intention-to-treat (ITT) analyses, the censoring based on the augmentation/switching and treatment discontinuation 
will be replaced with a maximum allowed follow-up time of 365 days.  
 
7. Iniƚial FeaƐibiliƚǇ AnalǇƐiƐ  
Aetion report name: 
For fluticasone furoate-umeclidinium-vilanterol vs. fluticasone furoate-vilanterol  
Optum CDM -https://bwh-dope.aetion.com/projects/details/1ϲ1ϰ/results/ϲϳ1Ϯϳ/result/0 
IBM® MarketScan®- https://bwh-dope.aetion.com/projects/details/1ϲ1ϱ/results/ϲϳ1Ϯϲ/result/0 
 
Date conducted: 0ϯ/1ϳ/Ϯ0Ϯ1 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϳ
Complete Aetion feasibility analysis using age and CCI as the only covariates and the primary endpoint (Section ϲ.ϯ.1) as the 
outcome. No measures of association will be computed nor will incidence rates stratified by treatment group. 
 
8. Iniƚial Poǁeƌ AƐƐeƐƐmenƚ 
 
Aetion report name: 
For fluticasone furoate-umeclidinium-vilanterol vs. fluticasone furoate-vilanterol 
Optum CDM - https://bwh-dope.aetion.com/projects/details/1ϲ1ϰ/results/ϲϳ1Ϯϵ/result/0 
IBM® MarketScan®- https://bwh-dope.aetion.com/projects/details/1ϲ1ϱ/results/ϲϳ1Ϯϴ/result/0 
 
Date conducted:  0ϯ/1ϳ/Ϯ0Ϯ1 
 
In order to complete the initial power analysis, the dummy outcome of a ϵ0-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 ϯ covariates: age , gender, and 
combined comorbidity index. Power calculations are based on the formulas from Chow et al. (Ϯ00ϴ). 
 
x Stop analyses until feasibility and power are reviewed by primary investigators and FDA. Reviewers evaluate the results of the 
analyses described above in Sections ϳ and ϴ, 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. 
 
x 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: 
ϯ/1ϵ/Ϯ0Ϯ1 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
 
Reasons for stopping 
analysis (if required): 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϴ
9. Balance AƐƐeƐƐmenƚ 
For fluticasone furoate-umeclidinium-vilanterol vs. fluticasone furoate-vilanterol 
Optum CDM: https://bwh-dope.aetion.com/projects/details/1ϲ1ϰ/rwrs/ϲϳϴ10 
IBM® MarketScan®: https://bwh-dope.aetion.com/projects/details/1ϲ1ϱ/rwrs/ϲϳϴ11 
Date conducted: 0ϯ/ϯ1/Ϯ0Ϯ1 
 
ϭϬͲA͘ Second Poǁeƌ AƐƐeƐƐmenƚ 
Date conducted: ϰ/1ϰ/Ϯ0Ϯ1 
x Re-calculate power in the appropriate excel table, using the revised number of matched patients from the PS-match in Section ϵ. 
All other parameters in the table should be the same as in Section ϴ. 
o Pooled  
Superiority Analysis
Number of patients matched
27,512
Reference
13,756
Exposed
13,756
Risk per 1,000 patients
169.90
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
4674.2888
Power
0.999838206  
o Optum CDM 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
ϵ
Superiority Analysis
Number of patients matched
24,142
Reference
12,071
Exposed
12,071
Risk per 1,000 patients
185.24
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
4472.06408
Power
0.999743753  
 
o IBM® MarketScan® 
 
Superiority Analysis
Number of patients matched
3,370
Reference
1,685
Exposed
1,685
Risk per 1,000 patients
106.86
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
360.1182
Power
0.338233339  
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
10
x Stop analyses until balance and power assessment are reviewed by primary investigators, FDA, and assigned members of 
advisory board. 
Reviewed by PI: 
Shirley Wang 
Date reviewed: 
ϰ/1ϲ/Ϯ0Ϯ1 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
ϰ/ϯ0/Ϯ0Ϯ1 
Reasons for stopping 
analysis (if required): 
 
 
ϭϬͲB͘ Final Poǁeƌ AƐƐeƐƐmenƚ afƚeƌ ReeǀalƵaƚion of SƚƵdǇ ImƉlemenƚaƚion  
During a protocol review that occurred after the submission of Ϯnd feasibility and power analysis, the study team members agree that 
one inclusion criteria that was marked as “not replicable in claims” could be defined using proxy definitions. A revised cohort was 
created and with the updated cohort, final feasibility and power analysis was conducted. The study team members confirm that this 
review was performed prior to the final analysis.  
 
Flowchart of the Revised Study Cohort Assembly  
x Revised cohort inclusion highlighted in yellow 
 
  
Optum 
Marketscan 
Less Excluded Patients 
Remaining 
Patients 
  
Less 
Excluded 
Patients 
Remaining 
Patients 
All patients 
  
78,779,380   
200,203,908 
Did not meet cohort entry criteria 
-
78,538,483 
240,897 
-
200,099,629 
104,279 
Excluded due to insufficient enrollment 
-36,893 
204,004 
-9,849 
94,430 
Excluded due to prior use of referent 
-102,649 
101,355 
-60,845 
33,585 
Excluded due to prior use of exposure 
-33,482 
67,873 
-4,000 
29,585 
Excluded because patient qualified in >1 exposure category 
-10 
67,863 
-2 
29,583 
Excluded based on Age : exclude missing 
-1 
67,862 
0 
29,583 
Excluded based on Gender : exclude missing 
-3 
67,859 
0 
29,583 
Excluded based on INCLUSION: Age >=40 
-5,751 
62,108 
-6,431 
23,152 
Excluded based on INCLUSION: Established clinical history of COPD 
-19,257 
42,851 
-12,995 
10,157 
Excluded based on INCLUSION: COPD Maintenance Rx previous 90 days 
0 
42,851 
0 
10,157 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
11
Excluded based on Inclusion: COPD exacerbation 1 year prior 
-17,279 
25,572 
-5,381 
4,776 
Excluded based on Exclusion 1 Pregnancy 
-5 
25,567 
-1 
4,775 
Excluded based on Exclusion 3 - Alpha-1-antitrypsin deficiency 
-39 
25,528 
-20 
4,755 
Excluded based on Exclusion 4 lung disease including Tb, lung ca, 
bronchiectasis, sarcoidosis, ILD 
-3,141 
22,387 
-561 
4,194 
Excluded based on Exclusion 5 - Lung volume reduction surgery 
0 
22,387 
0 
4,194 
Excluded based on Exclusion 6 - HIV/Lupus, Parkinson, MG 
-250 
22,137 
-37 
4,157 
Excluded based on Exclusion 7 - Pneumonia or COPD exacerbation [-14,-
0] 
-4,339 
17,798 
-924 
3,233 
Excluded based on Exclusion 8 - Acute upper or lower respiratory 
infections [-7,-0] 
-233 
17,565 
-87 
3,146 
Excluded based on Exclusion 11 - Liver disease 
-541 
17,024 
-72 
3,074 
Excluded based on Excl. 12a - Life threatening cardiac disease 
-311 
16,713 
-37 
3,037 
Excluded based on Unstable or life threatening cardiac arrhythmia 
requiring intervention in the last 3 months 
-19 
16,694 
-13 
3,024 
Excluded based on Excl. 12c - NYHA Class IV Heart failure 
-216 
16,478 
-53 
2,971 
Excluded based on Excl. 16 - Oxygen therapy 
-626 
15,852 
-27 
2,944 
Excluded based on Excl. 18 - Pulmonary rehabilitation 
-36 
15,816 
-6 
2,938 
Excluded based on Excl. 19 - Drug or alcohol abuse 
-115 
15,701 
-33 
2,905 
Excluded based on Excl. 24a - Use of long term antibiotics >90 days 
-111 
15,590 
-21 
2,884 
Excluded based on Excl. 24b - Use of corticosteroids [-30,0]] 
-882 
14,708 
-271 
2,613 
Final cohort 
  
14,708   
2,613 
 
Balance Assessment of Revised Cohort  
 
After review of previous feasibility and power analyses, complete creation of the remaining covariates from Section ϲ.Ϯ. Again, using 
the dummy outcome of a ϵ0-day gap in database enrollment, complete a 1:1 PS-matched analysis. The PS should include the 
complete list of covariates. 
 
x Provide plot of PS distributions stratified by treatment group. 
Note- Please refer to AƉƉendiǆ B.  
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1Ϯ
x Report covariate balance after matching. 
Note- For Table 1, please refer to AƉƉendiǆ B.  
 
x Report reasons for censoring by treatment group. 
 
 
Overall 
Referent 
Exposure 
Dummy outcome 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Death 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
Start of an additional exposure 
220 (2.29%) 
186 (1.94%) 
34 (0.35%) 
End of index exposure 
4,220 (44.01%) 
2,357 (24.58%) 
1,863 (19.43%) 
Specified date reached 
3,636 (37.92%) 
1,525 (15.91%) 
2,111 (22.02%) 
End of patient data 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
End of patient enrollment 
828 (8.64%) 
409 (4.27%) 
419 (4.37%) 
Nursing home admission, pharmacy disenrollment 
684 (7.13%) 
317 (3.31%) 
367 (3.83%) 
 
 
x Report follow-up time by treatment group. 
Median Follow-Up Time (Days) [IQR] 
Patient Group 
Optum 
Marketscan 
Overall Patient Population 
131 [88, 240] 
107.5 [72.5, 177] 
Referent  
119 [88, 211.5] 
108 [86, 170] 
Exposure 
146 [88,271] 
107 [61, 188] 
 
x Report overall risk of the primary outcome. 
  
Optum CDM 
IBM® MarketScan® 
Pooled 
Risk per 1,000 patients 
ϮϵϮ.ϴϮ 
Ϯ0Ϯ.ϴϰ 
Ϯϳϴ.ϲ 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1ϯ
Final Power Assessment  
Optum: https://bwh-dope.aetion.com/projects/details/1ϲ1ϰ/rwrs/ϲϵϲϱϮ 
Marketscan: https://bwh-dope.aetion.com/projects/details/1ϲ1ϱ/rwrs/ϲϵϲϱϯ 
Date conducted: ϱ/ϲ/Ϯ0Ϯ1 
 
x Re-calculate power in the appropriate excel table, using the revised number of matched patients from the PS-match in above 
section. All other parameters in the table should be the same as in Section ϴ. 
o Pooled  
Superiority Analysis
Number of patients matched
9,588
Reference
4,794
Exposed
4,794
Risk per 1,000 patients
278.60
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
2671.2168
Power
0.987449189  
 
 
 
 
 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1ϰ
o Optum CDM 
Superiority Analysis
Number of patients matched
8,496
Reference
4,248
Exposed
4,248
Risk per 1,000 patients
292.82
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
2487.79872
Power
0.981829103  
 
o IBM® MarketScan® 
 
Superiority Analysis
Number of patients matched
1,092
Reference
546
Exposed
546
Risk per 1,000 patients
202.84
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
221.50128
Power
0.227214863  

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1ϱ
 
x 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: 
ϱ/1Ϯ/Ϯ0Ϯ1 
Reasons for stopping 
analysis (if required): 
 
 
11. SƚƵdǇ Confidence and ConceƌnƐ 
 
Deadline for voting on study confidence and listing concerns: 
Date votes and concerns are summarized:    
 
x If final feasibility and power analyses are reviewed and approved, proceed to the remaining protocol steps. 
x 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. 
x After the deadline for voting has passed, provide the distribution of responses and summarize all concerns here. 
 
12. RegiƐƚeƌ ƐƚƵdǇ Ɖƌoƚocol on clinicalTƌialƐ͘goǀ 
 
Date conducted:    
 
x Register the study on clinicalTrials.gov and upload this document. 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1ϲ
13. ComƉaƌaƚiǀe AnalǇƐeƐ 
 
Aetion report name: 
Date conducted:    
 
a. For primary analysis:  
 
b. For sensitivity analyses: 
 
 
14.  ReƋƵeƐƚed ReƐƵlƚƐ  
 
a. Table 1: Baseline characteristics before and after adjustment 
 
Vaƌiable 
 
Befoƌe adjƵƐƚmenƚ 
Afƚeƌ adjƵƐƚmenƚ 
Refeƌenƚ 
EǆƉoƐƵƌe 
Sƚd͘ diff͘ 
Refeƌenƚ 
EǆƉoƐƵƌe 
Sƚd͘ diff͘ 
Number of patients 
 
 
- 
 
 
- 
Age categories 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
b. Table Ϯ: Follow-up time 
 
Patient Group 
Median Follow-Up Time (Days) [IQR] 
Overall Patient Population 
 
Referent 
 
Exposure 
 
 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1ϳ
 
 
 
 
c. Table ϯ: Censoring events 
 
 
Overall 
Referent 
Exposure 
Outcome 
 
 
 
Death 
 
 
 
Start of an additional exposure 
 
 
 
End of index exposure 
 
 
 
Specified date reached 
 
 
 
End of patient data 
 
 
 
End of patient enrollment 
 
 
 
… 
 
 
 
 
d. Table ϰ: Results from primary analyses; 
 
AnalǇƐiƐ 
No͘ eǆƉoƐed eǀenƚƐ 
No͘ ƌefeƌenƚ eǀenƚƐ 
EǆƉoƐed ƌaƚe 
Refeƌenƚ ƌaƚe 
HR ;ϵϱй CIͿ 
Crude 
 
 
 
 
 
Analysis 1 
 
 
 
 
 
Analysis Ϯ 
 
 
 
 
 
... 
 
 
 
 
 
HR, Hazard Ratio; CI, Confidence Interval. 
 
e. Table ϱ: Results from secondary analyses. 
 
 
 
 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
1ϴ
 
 
 
 
15. RefeƌenceƐ 
 
Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, Dransfield MT, Halpin DMG, Han MK, Jones CE, Kilbride S, Lange P, 
Lomas DA, Martinez FJ, Singh D, Tabberer M, Wise RA, Pascoe SJ; IMPACT Investigators. Once-Daily Single-Inhaler Triple versus Dual 
Therapy in Patients with COPD. N Engl J Med. Ϯ01ϴ May ϯ;ϯϳϴ(1ϴ):1ϲϳ1-1ϲϴ0. doi: 10.10ϱϲ/NEJMoa1ϳ1ϯϵ01. Epub Ϯ01ϴ Apr 1ϴ. 
PMID: ϮϵϲϲϴϯϱϮ. 
 
Chow S, Shao J, Wang H. Ϯ00ϴ.  Sample Siǌe CalcƵlaƚions in Clinical Research. Ϯnd Ed. Chapman & Hall/CRC Biostatistics Series. page 
1ϳϳ. 
 
 

#
IMPACT  trial definitions 
Implementation in routine care
References
Color Coding
Please see the following Google Drive for further details or any missing 
information: 
https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-
VCcnb6b-gV?usp=sharing
Criteria
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
Adequate mapping in claims
Triple Therapy (100 μg fluticasone furoate, 62.5 μg umeclidinium [LAMA],  25 μg vilanterol [LABA]) vs. Dual Therapy 
(100 μg fluticasone furoate, 25  μg vilanterol [LABA]  OR 62.5 μg umeclidinium [LAMA],  25  μg vilanterol [LABA])
Exposure
100 μg fluticasone furoate, 62.5 μg umeclidinium,  25 μg vilanterol (Trelegy ellipta)
Referent
100 μg fluticasone furoate, 25  μg vilanterol 6 (Breo ellipta) 
Intermediate mapping in claims
Poor mapping or can't be measured in claims 
Annual rate of moderate or severe COPD exacerbations during treatment
Measured 1 day after drug initiation in primary diagnosis position and inpatient care 
setting:
Moderate exacerbation
COPD diagnosis code occuring in inpatient any position or outpatient setting accompanied 
by a prescription claim for systemic steroid occuring 14 days before or after the COPD 
diagnosis code. 
Severe exacerbation 
COPD diagnosis code occuring in inpatient primary position 
COPD
ICD-9: 491.*, 492.*,  496.0
ICD-10: J41.*, J42. * J43.*, J44.* 
Annavarapu S, Goldfarb S, Gelb M, Moretz C, Renda A, Kaila S. 
Development and validation of a predictive model to identify patients at 
risk of severe COPD exacerbations using administrative claims data. Int J 
Chron Obstruct Pulmon Dis. 2018;13:2121-2130. Published 2018 Jul 11. 
doi:10.2147/COPD.S155773
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805625/
Can't be measured in claims but not important for the analysis
1
Informed Consent: A signed and dated written informed consent prior to study participation 
N/A
2
Age ≥ 40 
Measured on the day of drug initiation:
Age >=40 
3
An established clinical history of COPD in accordance with the definition by the ATS/ERS
Measure any time prior to and including day of drug initiation  in any diagnosis position 
and inpatient or outpatient care setting:
COPD
ICD-9: 491.*, 492.*,  496.0
ICD-10: J41.*, J42. * J43.*, J44.* 
Annavarapu S, Goldfarb S, Gelb M, Moretz C, Renda A, Kaila S. 
Development and validation of a predictive model to identify patients at 
risk of severe COPD exacerbations using administrative claims data. Int J 
Chron Obstruct Pulmon Dis. 2018;13:2121-2130. Published 2018 Jul 11. 
doi:10.2147/COPD.S155773
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805625/
4
Current or former cigarette smokers with a history of cigarette smoking of 10 pack-years at screening (visit 1) 
[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 
10 years, or 10 cigarettes per day for 20 years)]. Previous smokers are defined as those who have stopped smoking for 
at least 6 months prior to Visit 1 
N/A
5
A score of ≥10 on the COPD Assessment Test (CAT) at screening. 
N/A
6
A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 at screening.
N/A
INCLUSION CRITERIA
PRIMARY OUTCOME
Trial details- clinicaltrials.gov NCT02164513
EXPOSURE vs. COMPARISON
Appendix A

7
Receiving daily maintenance treatment for their COPD for at least 3 months prior to Screening. 
Measured 90 days prior to and including day of drug initiation with at least 1 dispensing 
of following COPD maintenance medications:
LABA  
indacaterol maleate, olodaterol hcl, salmeterol xinafoate, arformoterol tartrate, 
formoterol fumarate, terbutaline sulfate 
LAMA 
aclidinium bromide, umeclidinium bromide, tiotropium bromide, glycopyrrolate
LABA/LAMA
tiotropium bromide/olodaterol hcl, indacaterol maleate/glycopyrrolate, 
glycopyrrolate/formoterol fumarate, umeclidinium bromide/vilanterol trifenatate
LABA/ICS
mometasone furoate/formoterol fumarate, budesonide/formoterol fumarate, fluticasone 
furoate/vilanterol trifenatate, fluticasone propionate/salmeterol xinafoat
LAMA/LABA/ICS
fluticasone furoate/umeclidinium bromide/vilanterol trifenat
8
A post-bronchodilator FEV1 < 50% predicted normal and a documented history
of ≥ 1 moderate or severe COPD exacerbation in the previous 12 months
OR
a post-bronchodilator 50% ≤FEV1 < 80% predicted normal and a documented history of ≥ 2 moderate exacerbations or 
a documented history of ≥1 severe COPD exacerbation (hospitalized) in the previous 12 months.
Measured 365 days prior to drug initiation (excluding cohort entry date) , occurring at 
least once:
Moderate exacerbation
COPD diagnosis code occuring in inpatient any position or outpatient setting accompanied 
by a prescription claim for systemic steroid occuring 14 days before or after the COPD 
diagnosis code. 
Severe exacerbation 
COPD diagnosis code occuring in inpatient primary position 
COPD
ICD-9: 491.*, 492.*,  496.0
ICD-10: J41.*, J42. * J43.*, J44.* 
Annavarapu S, Goldfarb S, Gelb M, Moretz C, Renda A, Kaila S. 
Development and validation of a predictive model to identify patients at 
risk of severe COPD exacerbations using administrative claims data. Int J 
Chron Obstruct Pulmon Dis. 2018;13:2121-2130. Published 2018 Jul 11. 
doi:10.2147/COPD.S155773
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805625/
 alanine aminotransferase (ALT) <2x upper limit of normal (ULN);
 alkaline phosphatase ≤1.5xULN;
 bilirubin ≤1.5xULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Applied in exclusion criteria (see severe liver disease) 
1
Pregnacy or child bearing potential without acceptable contraceptive method
Measured 180 days prior to and including day of drug initiation in any position or any care 
setting:
See codes in 'Pregnancy' tab
2
Asthma - subjects with prior history of asthma are eligible if they have a current diagnosis of COPD
N/A
3
Subjects with α1-antitrypsin deficiency as the underlying cause of COPD 
Measured 180 days prior to and including day of drug initiation in any position or any care 
setting:
Alpha-1-antitrypsin deficiency
ICD-9: 273.4
ICD-10: E88.01
EXCLUSION CRITERIA
Appendix A

4
Subjects with active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary 
hypertension, interstitial lung diseases or other active pulmonary diseases 
Measured 90 days prior to and including day of drug initiation in any position or any care 
setting:
Tuberculosis
ICD-9:  010.x - 018.x 
ICD-10:  A15.x - A19.x
Lung cancer
ICD-9: 162.2x, 162.3x, 162.4x, 162.5x, 162.8x, 162.9x 
ICD-10:  C34.0x, C34.1x, C34.2x, C34.3x, C34.8x, C34.9x
Bronchiectasis
ICD-9: 494.x
ICD-10: J47.x 
Sarcoidosis
ICD-9 135.x   ICD-10: D86.x
ICD-9: 515.x, 516.3, 516.8, 516.9, 517.1, 517.8, 518.89
Pulmonary hypertension
ICD-10: I27.0, I27.20
ICD-9: 416.0
Interstitial lung disease, lung fibrosis, ARDS
ICD-9: 515.x 516.x, 517.x, 518.8x
ICD-10: J84.x, J80.x
Other pulmonary disease
ICD-9: 416.x
ICD-10: I27.x
5
Subjects with lung volume reduction surgery within the 12 months prior to screening
Measured 365 days prior to and including day of drug initiation in any position or any care 
setting:
CPT code: 32491 32672
HCPCS code: G0305
Decker MR, Leverson GE, Jaoude WA, Maloney JD. Lung volume reduction 
surgery since the National Emphysema Treatment Trial: study of Society 
of Thoracic Surgeons Database. J Thorac Cardiovasc Surg. 
2014;148(6):2651-8.e1. doi:10.1016/j.jtcvs.2014.02.005
6
Immune suppression (e.g. HIV, Lupus) or other risk factors for pneumonia (e.g. neurological disorders affecting control 
of the upper airway, such as Parkinson’s Disease, Myasthenia Gravis)
Measured 180 days prior to and including ay of drug initiation in any position or any care 
setting:
HIV
ICD-9:
042.x Human immunodeficiency virus [HIV] disease
079.53 Human immunodeficiency virus, type 2 [HIV-2]
V08 Asymptomatic human immunodeficiency virus [HIV] infection status 
ICD-10:
B20.x Human immunodeficiency virus [HIV] disease
B97.35 Human immunodeficiency virus, type 2 [HIV-2]
Z21.x Asymptomatic human immunodeficiency virus [HIV] infection status
SLE
ICD-9: 710.0 
ICD-10: M32.x
Parkinson's disease
ICD-9-CM: 332.x 
ICD-10-CM: G20, G21.xx
Myasthenia gravis
ICD-9: 358.0x
ICD-10: G70.0x
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with 
canagliflozin versus other non-gliflozin antidiabetic drugs: population 
based cohort study." BMJ 2018;360:k119 
http://dx.doi.org/10.1136/bmj.k119
Appendix A

7
Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least 14 days prior to Screening 
and at least 30 days following the last dose of oral/systemic corticosteroids (if applicable). 
In addition, any subject that experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in 
period will be excluded 
Measured 14 days prior to and inlcuding day of drug initiation in any position or any care 
setting:
Pneumonia and or COPD exacerbation
Pnuemonia
ICD9: 480.x, 481.x, 482.x, 483.x, 484.x, 485.x, 486.x
ICD-10: J12.x, J13.x, J14.x, J15.x, J16.x, J17.x, J18.x 
COPD exacerbation
Moderate exacerbation
COPD diagnosis code occuring in inpatient or outpatient setting, any position. 
For outpatient COPD diagnosis, it is accompanied by a prescription claim for systemic 
steroid occuring 14 days before or after the COPD diagnosis code. 
Severe exacerbation 
COPD diagnosis code occuring in inpatient primary position 
COPD
“491.0”, “491.1”, “491.2”, “491.21”, “491.22”, “491.8”, “491.9”, “492.0”, “J41.8”, “J43.1”, 
“J43.8”, “J47.0”, “491.20”, “492.8”, “494.0”, “494.1”, “506.4”, “J41.0”, “J41.1”, “J43.0”, 
“J43.2”, “J43.9”, “J44.0”, “J44.1”, “J47.1”, “J47.9” 
8
Other Respiratory tract infections that have not resolved at least 7 days prior to screening
Measured 7 days prior to and including day of drug initiation in any position or any care 
setting:
Acute upper /lower respiratory infections 
ICD-9: 460.x, 461.x, 462.x, 463.x, 464.x, 461
ICD-10: J00.x, J01.x, J02.x, J03.x, J04.x, J05.x, J06.x, J20.x, J21.x, J22.x
Patorno, Elisabetta et al. "Empagliflozin and the Risk of Heart Failure 
Hospitalization in Routine Clinical Care: A First Analysis from the 
Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study."  
Circulation. 2019 Apr 8. doi: 10.1161/CIRCULATIONAHA.118.039177
9
Chest x-ray (posteroanterior and lateral) reveals evidence of pneumonia or a clinically significant abnormality not 
believed to be due to the presence of COPD, or another condition that would hinder the ability to detect an infiltrate on 
CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have a chest x-ray at Screening Visit 1 
(or historical radiograph or CT scan obtained within 3 months prior to screening) that will be over-read by a central 
vendor. 
N/A
10
Subjects with historical or current evidence of clinically significant cardiovascular, neurological, psychiatric, renal, 
hepatic, immunological, gastrointestinal, urogenital, nervous system, musculoskeletal, skin, sensory, endocrine 
(including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled 
N/A
11
Unstable liver disease as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, 
esophageal or gastric varices or persistent jaundice, cirrhosis, known biliary abnormalities (with the exception of 
Gilbert’s syndrome or asymptomatic gallstones). 
Note: Chronic stable hepatitis B and C are acceptable if the subject otherwise meets entry criteria
Measured 180 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
See codes in 'Liver disease' tab
12a
Unstable or life threatening cardiac disease: subjects with any of the following at
Screening (Visit 1) would be excluded:
Myocardial infarction or unstable angina in the last 6 months
Measured 180 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
ACS/unstable angina
ICD-9: 411.xx 
Acute MI 
ICD-9: 410.X (acute myocardial infarction) excluding 410.x2 (subsequent episode of care)
12b
 Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months
Measured 90 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
Electrical cardioversion
CPT: 92960, 92961
Catheter ablation
CPT: 93650, 93653, 93654 93655,, 93656, 93657, 93462
Permanent pacemaker
CPT: 33202-33249
Implantable cardioverter-defibrillator (ICD)
ICD-9: 00.51, 00.54, 37.94 - 37.98
ICD-10: 02HK0KZ, 02HK3KZ, 02HK4KZ, 02HL0KZ, 02HL3KZ, 02HL4KZ, 0JH609Z, 0JH639Z, 
0JH809Z, 0JH839Z
CPT-4:  33220, 33223, 33230, 33231, 33240 - 33249, 33270, 93640 - 93642, 
American Medical Association, Current Procedural Terminology (CPT). 
Professional Edition. Chicago, IL. https://www.amaassn.org/practice-
management/cpt-current-procedural-terminology * 
https://www.cms.gov/Outreach-and-Education/MedicareLearning-
Network-MLN/MLNProducts/AMA-Disclaimer.html
Appendix A

12c
NYHA Class IV Heart failure
Measured 180 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
Systolic HF 
ICD-9: 428.2x
ICD-10: I50.2x
Combined Systolic/Diastolic HF 
ICD-9: 428.4x 
ICD-10: I50.4x
13
Abnormal and clinically significant 12-Lead ECG finding: 
- AF with rapid ventricular rate >120 BPM
- sustained or nonsustained VT
- Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been 
inserted)
- QTcF ≥500 msec in patients with QRS <120 msec and QTcF ≥530 msec in patients with QRS ≥ 120 msec
N/A
14
Contraindications: A history of allergy or hypersensitivity to any corticosteroid, anticholinergic/muscarinic receptor 
antagonist, beta2-agonist, lactose/milk protein or magnesium stearate or a medical condition such as narrow-angle 
glaucoma, prostatic hypertrophy or bladder neck obstruction 
N/A
15
Cancer: Subjects with carcinoma that has not been in complete remission for at least 5 years. Subjects who have had 
carcinoma in situ of the cervix, squamous cell carcinoma and basal cell carcinoma of the skin would not be excluded 
based on the 5 year waiting period if the subject has been considered cured by treatment 
N/A
16
Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3L/min (Oxygen use 
less than or equal to 3L/min flow is not exclusionary.) 
Measured 180 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
Home oxygen use 
HCPCS: E0424, E0441, E0443, 
ICD-10: Z99.81
ICD-9: V46. 2
17
Medication prior to spirometry: Subjects who are medically unable to withhold their albuterol/salbutamol for the 4-
hour period required prior to spirometry testing at each study visit 
N/A
18
Pulmonary rehabilitation: Subjects who have participated in the acute phase of a Pulmonary Rehabilitation Program 
within 4 weeks prior to Screening or subjects who plan to enter the acute phase of a Pulmonary Rehabilitation 
Program during the study. Subjects who are in the maintenance phase of a Pulmonary Rehabilitation Program are not 
excluded
Measured 180 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
Pulmonary rehabilitation
CPT/HCPCS: G0237, G0238, G0239, G0424,S9473, 94669
https://www.modahealth.com/pdfs/med_criteria/PulmonaryRehab.pdf
19
Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse
Measured 180 days prior to and including day of drug initiation in any diagnosis position 
and inpatient or outpatient care setting:
Alcohol abuse or dependence
291.xx, 303.xx, 305.0x, 571.0x, 571.1x, 571.2x, 571.3x, 357.5x, 425.5x, E860.0x, V11.3x
Drug abuse or dependence
292.xx, 304.xx, 305.2x-305.9x, 648.3x
Patorno, Elisabetta et al. "Cardiovascular outcomes associated with 
canagliflozin versus other non-gliflozin antidiabetic drugs: population 
based cohort study." BMJ 2018;360:k119 
http://dx.doi.org/10.1136/bmj.k119
20
Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures - any infirmity, 
disability, or geographic location that would limit compliance for scheduled visit. 
N/A
21
Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation 
or other conditions that will limit the validity of informed consent to participate in the study 
N/A
22
Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a 
participating investigator or study site, or immediate family members of the aforementioned that is involved with this 
study 
N/A
23
Inability to read: Any subject who is unable to read and/or would not be able to complete study related materials
N/A
24a
The use of any of the following medications under the given conditions:
- Long term antibiotic use (short term antibiotics are allowed if treating short-term acute infection or short-term 
exacerbation
Measured 180 days prior to and including day of drug initiation,  with days supply 
exceeding >90 days:
See codes in 'Antibiotics' tab
24b Use of a systemic, oral, or parenteral corticosteroid in the last 30 days (except unless treating COPD 
exacerbations/pneumonia)
Measured 30 days prior to and including day of drug initiation:
Cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, 
dexamethasone, betamethasone 
24c Use of any other investigational drug within the last 30 days or 5 half-lives (whichever is longer)
N/A
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
Appendix A

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
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
Appendix A

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
Appendix A

Liver Disease
070.0 - VIRAL HEPATITIS A WITH HEPATIC COMA
070.2 - VIRAL HEPATITIS B WITH HEPATIC COMA
070.22 - CHRONIC VIRAL HEPATITIS B WITH HEPATIC COMA WITHOUT HEPATITIS DELTA
070.23 - CHRONIC VIRAL HEPATITIS B WITH HEPATIC COMA WITH HEPATITIS DELTA
070.3 - VIRAL HEPATITIS B WITHOUT MENTION OF HEPATIC COMA
070.30 - VIRAL HEPATITIS B WITHOUT HEPATIC COMA ACUTE OR UNSPECIFIED WITHOUT HEPATITIS DELTA
070.31 - VIRAL HEPATITIS B WITHOUT HEPATIC COMA ACUTE OR UNSPECIFIED WITH HEPATITIS DELTA
070.32 - CHRONIC VIRAL HEPATITIS B WITHOUT HEPATIC COMA WITHOUT HEPATITIS DELTA
070.41 - ACUTE HEPATITIS C WITH HEPATIC COMA
070.43 - HEPATITIS E WITH HEPATIC COMA
070.44 - CHRONIC HEPATITIS C WITH HEPATIC COMA
070.49 - OTHER SPECIFIED VIRAL HEPATITIS WITH HEPATIC COMA
070.51 - ACUTE HEPATITIS C WITHOUT MENTION OF HEPATIC COMA
070.54 - CHRONIC HEPATITIS C WITHOUT HEPATIC COMA
070.6 - UNSPECIFIED VIRAL HEPATITIS WITH HEPATIC COMA
070.7 - UNSPECIFIED VIRAL HEPATITIS C
070.70 - UNSPECIFIED VIRAL HEPATITIS C WITHOUT HEPATIC COMA
070.71 - UNSPECIFIED VIRAL HEPATITIS C WITH HEPATIC COMA
456.1 - ESOPHAGEAL VARICES WITHOUT BLEEDING
456.2 - ESOPHAGEAL VARICES IN DISEASES CLASSIFIED ELSEWHERE
570 - ACUTE AND SUBACUTE NECROSIS OF LIVER
571.0 - ALCOHOLIC FATTY LIVER
571.1 - ACUTE ALCOHOLIC HEPATITIS
571.3 - ALCOHOLIC LIVER DAMAGE UNSPECIFIED
571.40 - CHRONIC HEPATITIS UNSPECIFIED
571.41 - CHRONIC PERSISTENT HEPATITIS
571.49 - OTHER CHRONIC HEPATITIS
571.5 - CIRRHOSIS OF LIVER WITHOUT ALCOHOL
571.6 - BILIARY CIRRHOSIS
571.9 - UNSPECIFIED CHRONIC LIVER DISEASE WITHOUT ALCOHOL
572.0 - ABSCESS OF LIVER
Appendix A

572.2 - HEPATIC ENCEPHALOPATHY
572.3 - PORTAL HYPERTENSION
572.8 - OTHER SEQUELAE OF CHRONIC LIVER DISEASE
573.1 - HEPATITIS IN VIRAL DISEASES CLASSIFIED ELSEWHERE
573.8 - OTHER SPECIFIED DISORDERS OF LIVER
573.9 - UNSPECIFIED DISORDER OF LIVER
789.51 - MALIGNANT ASCITES
B15.0
B16.0
B17.10
B17.11
B17.9
B18.2
B18.9
B19.11
B19.20
B25.1
I85.00
I85.10
K70.11
K70.2
K70.30
K70.31
K70.40
K70.9
K71.0
K71.10
K71.11
K71.3
K71.50
K71.8
K71.9
Appendix A

K72.01
K72.11
K73.1
K73.9
K74.3
K74.4
K74.5
K74.60
K74.69
K75.0
K75.89
K76.2
K76.4
K76.81
K76.89
K76.9
K77
K83.5
R17
R18.8
070.1 - VIRAL HEPATITIS A WITHOUT HEPATIC COMA
070.20 - VIRAL HEPATITIS B WITH HEPATIC COMA ACUTE OR UNSPECIFIED WITHOUT HEPATITIS DELTA
070.21 - VIRAL HEPATITIS B WITH HEPATIC COMA ACUTE OR UNSPECIFIED WITH HEPATITIS DELTA
070.33 - CHRONIC VIRAL HEPATITIS B WITHOUT HEPATIC COMA WITH HEPATITIS DELTA
070.4 - OTHER SPECIFIED VIRAL HEPATITIS WITH HEPATIC COMA
070.42 - HEPATITIS DELTA WITHOUT ACTIVE HEPATITIS B DISEASE WITH HEPATIC COMA HEPATITIS DELTA WITH HEPATITIS B CARRIER STATE
070.5 - OTHER SPECIFIED VIRAL HEPATITIS WITHOUT MENTION OF HEPATIC COMA
070.52 - HEPATITIS DELTA WITHOUT ACTIVE HEPATITIS B DISEASE OR HEPATIC COMA
070.53 - HEPATITIS E WITHOUT HEPATIC COMA
070.59 - OTHER SPECIFIED VIRAL HEPATITIS WITHOUT HEPATIC COMA
070.9 - UNSPECIFIED VIRAL HEPATITIS WITHOUT HEPATIC COMA
456.0 - ESOPHAGEAL VARICES WITH BLEEDING
Appendix A

456.20 - ESOPHAGEAL VARICES IN DISEASES CLASSIFIED ELSEWHERE WITH BLEEDING
456.21 - ESOPHAGEAL VARICES IN DISEASES CLASSIFIED ELSEWHERE WITHOUT BLEEDING
571.2 - ALCOHOLIC CIRRHOSIS OF LIVER
571.4 - CHRONIC HEPATITIS
571.42 - AUTOIMMUNE HEPATITIS
571.8 - OTHER CHRONIC NONALCOHOLIC LIVER DISEASE
572.1 - PORTAL PYEMIA
572.4 - HEPATORENAL SYNDROME
573.0 - CHRONIC PASSIVE CONGESTION OF LIVER
573.2 - HEPATITIS IN OTHER INFECTIOUS DISEASES CLASSIFIED ELSEWHERE
573.3 - HEPATITIS UNSPECIFIED
573.4 - HEPATIC INFARCTION
573.5 - HEPATOPULMONARY SYNDROME
576.8 - OTHER SPECIFIED DISORDERS OF BILIARY TRACT
782.4 - JAUNDICE UNSPECIFIED NOT OF NEWBORN
789.5 - ASCITES
789.59 - OTHER ASCITES
B15.9
B16.1
B16.2
B16.9
B17.0
B17.2
B17.8
B18.0
B18.1
B18.8
B19.0
B19.10
B19.21
B19.9
I85.01
Appendix A

I85.11
K70.0
K70.10
K70.41
K71.2
K71.4
K71.51
K71.6
K71.7
K72.00
K72.10
K72.90
K72.91
K73.0
K73.2
K73.8
K74.0
K74.1
K74.2
K75.1
K75.2
K75.3
K75.4
K75.81
K75.9
K76.0
K76.1
K76.3
K76.5
K76.6
K76.7
K83.8
Appendix A

K87
R18.0
Appendix A

Antibiotics
ALATROFLOXACIN MESYLATE
AMIKACIN
AMIKACIN SULFATE
AMIKACIN SULFATE IN 0.9 % SODIUM CHLORIDE
AMIKACIN SULFATE/PF
AMOXICILLIN
AMOXICILLIN/POTASSIUM CLAVULANATE
AMPICILLIN ANHYDROUS
AMPICILLIN SODIUM
AMPICILLIN SODIUM/SULBACTAM SODIUM
AMPICILLIN TRIHYDRATE
AZITHROMYCIN
AZITHROMYCIN HYDROGEN CITRATE
AZTREONAM
AZTREONAM LYSINE
AZTREONAM/DEXTROSE-WATER
BACAMPICILLIN HCL
BACITRACIN
BACITRACIN ZINC
BACITRACIN ZINC MICRONIZED
BACITRACIN ZINC/POLYMYXIN B SULFATE
BACITRACIN ZINC/POLYMYXIN B SULFATE/PRAMOXINE
BACITRACIN, MICRONIZED
BACITRACIN/DIMETHICONE/ZINC OXIDE
BACITRACIN/LIDOCAINE
BACITRACIN/POLYMYXIN B SULFATE
BACITRACIN/POLYMYXIN B SULFATE/LIDOCAINE
BACITRACIN/PRAMOXINE HCL/ALOE VERA
BISMUTH SUBSALICYLATE/METRONIDAZOLE/TETRACYCLINE HCL
CARBENICILLIN INDANYL SODIUM
CEFACLOR
Appendix A

CEFADROXIL
CEFAMANDOLE NAFATE
CEFAMANDOLE NAFATE/DEXTROSE 5 % IN WATER
CEFAZOLIN SODIUM
CEFAZOLIN SODIUM IN 0.9 % SODIUM CHLORIDE
CEFAZOLIN SODIUM/DEXTROSE 5 % IN WATER
CEFAZOLIN SODIUM/DEXTROSE, ISO-OSMOTIC
CEFAZOLIN SODIUM/WATER FOR INJECTION,STERILE
CEFDINIR
CEFDITOREN PIVOXIL
CEFEPIME HCL
CEFEPIME HCL IN DEXTROSE 5 % IN WATER
CEFEPIME HCL IN ISO-OSMOTIC DEXTROSE
CEFIXIME
CEFONICID SODIUM
CEFOPERAZONE SODIUM
CEFOPERAZONE SODIUM/DEXTROSE 2.4 %-WATER
CEFOTAXIME SODIUM
CEFOTAXIME SODIUM/DEXTROSE 5 % IN WATER
CEFOTAXIME SODIUM/DEXTROSE, ISO-OSMOTIC
CEFOTETAN DISODIUM
CEFOTETAN DISODIUM IN ISO-OSMOTIC DEXTROSE
CEFOTETAN IN DEXTROSE
CEFOXITIN SODIUM
CEFOXITIN SODIUM/DEXTROSE 5 % IN WATER
CEFOXITIN SODIUM/DEXTROSE, ISO-OSMOTIC
CEFPODOXIME PROXETIL
CEFPROZIL
CEFTAROLINE FOSAMIL ACETATE
CEFTAZIDIME
CEFTAZIDIME IN DEXTROSE 5% AND WATER
CEFTAZIDIME IN DEXTROSE, ISO-OSMOTIC
Appendix A

CEFTAZIDIME SODIUM
CEFTAZIDIME SODIUM IN 0.9 % SODIUM CHLORIDE
CEFTAZIDIME SODIUM IN ISO-OSMOTIC DEXTROSE
CEFTAZIDIME/ARGININE
CEFTAZIDIME/AVIBACTAM SODIUM
CEFTIBUTEN
CEFTIZOXIME SODIUM
CEFTIZOXIME SODIUM/DEXTROSE, ISO-OSMOTIC
CEFTOLOZANE SULFATE/TAZOBACTAM SODIUM
CEFTRIAXONE SODIUM
CEFTRIAXONE SODIUM IN ISO-OSMOTIC DEXTROSE
CEFTRIAXONE SODIUM/LIDOCAINE HCL
CEFUROXIME AXETIL
CEFUROXIME SODIUM
CEFUROXIME SODIUM IN 0.9 % SODIUM CHLORIDE/PF
CEFUROXIME SODIUM/DEXTROSE 5 % IN WATER
CEFUROXIME SODIUM/DEXTROSE, ISO-OSMOTIC
CEFUROXIME SODIUM/WATER FOR INJECTION,STERILE
CHLORAMPHENICOL
CHLORAMPHENICOL PALMITATE
CHLORAMPHENICOL SOD SUCCINATE
CHLORAMPHENICOL/FIBRINOLYSIN/DESOXYRIBONUCLEASE
CHLOROALLYL METHENAMINE CHLORIDE
CHLORTETRACYCLINE HCL
CINOXACIN
CIPROFLOXACIN
CIPROFLOXACIN HCL
CIPROFLOXACIN HCL/DEXAMETHASONE
CIPROFLOXACIN HCL/FLUOCINOLONE ACETONIDE
CIPROFLOXACIN HCL/HYDROCORTISONE
CIPROFLOXACIN LACTATE
CIPROFLOXACIN LACTATE/DEXTROSE 5 % IN WATER
Appendix A

CIPROFLOXACIN/CIPROFLOXACIN HCL
CLARITHROMYCIN
CLINDAMYCIN HCL
CLINDAMYCIN PALMITATE HCL
CLINDAMYCIN PHOSPHATE
CLINDAMYCIN PHOSPHATE IN 0.9 % SODIUM CHLORIDE
CLINDAMYCIN PHOSPHATE/BENZOYL PEROXIDE
CLINDAMYCIN PHOSPHATE/BENZOYL PEROXIDE/EMOLLIENT COMB NO.94
CLINDAMYCIN PHOSPHATE/BENZOYL PEROXIDE/HYALURONATE SODIUM
CLINDAMYCIN PHOSPHATE/BENZOYL PEROXIDE/SKIN CLEANSER NO.5
CLINDAMYCIN PHOSPHATE/DEXTROSE 5 % IN WATER
CLINDAMYCIN PHOSPHATE/SKIN CLEANSER COMB NO.19
CLINDAMYCIN PHOSPHATE/TRETINOIN
CLOXACILLIN SODIUM
COLISTIN (AS COLISTIMETHATE SODIUM)
COLISTIN SULFATE
COLLOIDAL BISMUTH SUBCITRATE/METRONIDAZOLE/TETRACYCLINE HCL
DALBAVANCIN HCL
DAPTOMYCIN
DEMECLOCYCLINE HCL
DICLOXACILLIN SODIUM
DIRITHROMYCIN
DORIPENEM
DOXYCYCLINE CALCIUM
DOXYCYCLINE HYCLATE
DOXYCYCLINE HYCLATE/EYELID CLEANSER 3/EYELID EMOLLIENT NO.1
DOXYCYCLINE HYCLATE/EYELID CLEANSER NO2/EYELID CLEANSER NO3
DOXYCYCLINE HYCLATE/SKIN CLEANSER COMBINATION NO.19
DOXYCYCLINE MONOHYDRATE
DOXYCYCLINE MONOHYDRATE/BENZOYL PEROXIDE
DOXYCYCLINE MONOHYDRATE/OMEGA-3 COMBINATION NO.1/EYE MASK
DOXYCYCLINE MONOHYDRATE/SALICYLIC ACID/OCTINOXATE/ZINC OXIDE
Appendix A

DOXYCYCLINE MONOHYDRATE/SKIN CLEANSER COMBINATION NO.9
ENOXACIN
ERTAPENEM SODIUM
ERYTHROMYCIN BASE
ERYTHROMYCIN BASE IN ETHANOL
ERYTHROMYCIN BASE/BENZOYL PEROXIDE
ERYTHROMYCIN ESTOLATE
ERYTHROMYCIN ETHYLSUCCINATE
ERYTHROMYCIN ETHYLSUCCINATE/SULFISOXAZOLE ACETYL
ERYTHROMYCIN GLUCEPTATE
ERYTHROMYCIN LACTOBIONATE
ERYTHROMYCIN STEARATE
FOSFOMYCIN TROMETHAMINE
GATIFLOXACIN
GATIFLOXACIN/DEXTROSE 5 % IN WATER
GATIFLOXACIN/PREDNISOLONE ACETATE
GATIFLOXACIN/PREDNISOLONE ACETATE/BROMFENAC SODIUM
GATIFLOXACIN/PREDNISOLONE ACETATE/NEPAFENAC
GEMIFLOXACIN MESYLATE
GENTAMICIN SULFATE
GENTAMICIN SULFATE IN SODIUM CHLORIDE, ISO-OSMOTIC
GENTAMICIN SULFATE/PF
GENTAMICIN SULFATE/PREDNISOLONE ACETATE
GENTAMICIN SULFATE/SODIUM CHLORIDE
GENTAMICIN SULFATE/SODIUM CITRATE
GREPAFLOXACIN HCL
IMIPENEM/CILASTATIN SODIUM
KANAMYCIN SULFATE
LANSOPRAZOLE/AMOXICILLIN TRIHYDRATE/CLARITHROMYCIN
LEVOFLOXACIN
LEVOFLOXACIN/DEXTROSE 5 % IN WATER
LINCOMYCIN HCL
Appendix A

LINEZOLID
LINEZOLID IN 0.9 % SODIUM CHLORIDE
LINEZOLID IN DEXTROSE 5 % IN WATER
LOMEFLOXACIN HCL
LORACARBEF
MEROPENEM
MEROPENEM IN 0.9 % SODIUM CHLORIDE
MEROPENEM/VABORBACTAM
METHENAMINE
METHENAMINE HIPPURATE
METHENAMINE MANDELATE
METHENAMINE MANDELATE/SODIUM PHOSPHATE,MONOBASIC
METHENAMINE SULFOSALICYLATE/COAL TAR/MERCURY,AMMONIATED
METHENAMINE/BENZOIC ACID/SALICYLATE/SALICYLAMIDE
METHENAMINE/METHYLENE BLUE/BENZ AC/SALICYLATE/ATROP/HYOSCY
METHENAMINE/METHYLENE BLUE/BENZOIC ACID/SALICYLAT/HYOSCYAMIN
METHENAMINE/METHYLENE BLUE/BENZOIC/PHENYL SAL/ATROPIN/HYOSCY
METHENAMINE/METHYLENE BLUE/SALICYLATE/SODIUM PHOS/HYOSCYAMIN
METHENAMINE/METHYLENE BLUE/SALICYLATE/SODIUM/HYOSCYAMINE
METHENAMINE/METHYLENE BLUE/SOD PHOS/P.SALICYLATE/HYOSCYAMINE
METHENAMINE/SOD PHOSPH,MONOBASIC/METHYLENE BLUE/HYOSCYAMINE
METHENAMINE/SODIUM PHOSPHATE,MONOBASIC
METHENAMINE/SODIUM SALICYLATE
METRONIDAZOLE
METRONIDAZOLE BENZOATE
METRONIDAZOLE HCL
METRONIDAZOLE IN SODIUM CHLORIDE
METRONIDAZOLE/SKIN CLEANSER
METRONIDAZOLE/SKIN CLEANSER COMBINATION NO.23
MEZLOCILLIN SODIUM
MINOCYCLINE HCL
MINOCYCLINE HCL MICROSPHERES
Appendix A

MINOCYCLINE HCL/EMOL COMB NO.16/SKIN CLNSR L4/TOP AGENT NO.3
MINOCYCLINE HCL/EYELID CLEANSER COMBINATION NO. 1
MINOCYCLINE HCL/WIPES WITH SKIN CLEANSER NO.4
MOXIFLOXACIN HCL
MOXIFLOXACIN HCL IN BALANCE SALT IRRIGATION SOLUTION NO.2/PF
MOXIFLOXACIN HCL IN SODIUM ACETATE AND SULFATE,WATER,ISO-OSM
MOXIFLOXACIN HCL IN SODIUM CHLORIDE,ISO-OSMOTIC/PF
MOXIFLOXACIN HCL/DEXAMETHASONE SOD PH IN NACL,ISO-OSMOTIC/PF
MOXIFLOXACIN HCL/DEXAMETHASONE SOD PH/KETOROLAC/SOD CHL/PF
MOXIFLOXACIN HCL/SODIUM CHLORIDE, ISO-OSMOTIC
NAFCILLIN IN DEXTROSE, ISO-OSMOTIC
NAFCILLIN SODIUM
NAFCILLIN SODIUM/DEXTROSE 5 % IN WATER
NEOMYCIN SULF/BACITRACIN ZINC/POLYMYXIN B SULF/PRAMOXINE HCL
NEOMYCIN SULF/COLISTIN SUL/HYDROCORTISONE AC/THONZONIUM BROM
NEOMYCIN SULFATE
NEOMYCIN SULFATE/BACITRACIN ZINC/POLYMYXIN B
NEOMYCIN SULFATE/BACITRACIN ZINC/POLYMYXIN B SULFATE
NEOMYCIN SULFATE/BACITRACIN ZINC/POLYMYXIN B/HYDROCORTISONE
NEOMYCIN SULFATE/BACITRACIN ZINC/POLYMYXIN B/LIDOCAINE HCL
NEOMYCIN SULFATE/BACITRACIN/COLISTIMETHATE SODIUM
NEOMYCIN SULFATE/BACITRACIN/POLYMYXIN B
NEOMYCIN SULFATE/BACITRACIN/POLYMYXIN B/DIPERODON
NEOMYCIN SULFATE/BACITRACIN/POLYMYXIN B/LIDOCAINE
NEOMYCIN SULFATE/BACITRACIN/POLYMYXIN B/PRAMOXINE
NEOMYCIN SULFATE/COLISTIN SULFATE/HYDROCORTISONE
NEOMYCIN SULFATE/DEXAMETHASONE SODIUM PHOSPHATE
NEOMYCIN SULFATE/FLUOCINOLONE ACETONIDE
NEOMYCIN SULFATE/FLUOCINOLONE ACETONIDE/EMOLLIENT COMB NO.65
NEOMYCIN SULFATE/HYDROCORTISONE
NEOMYCIN SULFATE/HYDROCORTISONE ACETATE
NEOMYCIN SULFATE/POLYMYXIN B SULFATE
Appendix A

NEOMYCIN SULFATE/POLYMYXIN B SULFATE/BUFFERS/HYDROCORTISONE
NEOMYCIN SULFATE/POLYMYXIN B SULFATE/GRAMICIDIN D
NEOMYCIN SULFATE/POLYMYXIN B SULFATE/HYDROCORTISONE
NEOMYCIN SULFATE/POLYMYXIN B SULFATE/LIDOCAINE
NEOMYCIN SULFATE/POLYMYXIN B SULFATE/PRAMOXINE
NEOMYCIN SULFATE/POLYMYXIN B SULFATE/PREDNISOLONE
NEOMYCIN/BACITRACIN/POLYMYXIN B/HYDROCORTISONE
NEOMYCIN/POLYMYXIN B SULFATE/DEXAMETHASONE
NETILMICIN SULFATE
NITROFURANTOIN
NITROFURANTOIN MACROCRYSTAL
NITROFURANTOIN MONOHYDRATE/MACROCRYSTALS
NORFLOXACIN
OFLOXACIN
OFLOXACIN/DEXTROSE 5 % IN WATER
OMEPRAZOLE/CLARITHROMYCIN/AMOXICILLIN TRIHYDRATE
ORITAVANCIN DIPHOSPHATE
OXACILLIN SODIUM
OXACILLIN SODIUM IN ISO-OSMOTIC DEXTROSE
OXYTETRACYCLINE
OXYTETRACYCLINE HCL
OXYTETRACYCLINE HCL/HYDROCORTISONE ACETATE
OXYTETRACYCLINE HCL/POLYMYXIN B SULFATE
OXYTETRACYCLINE HCL/SULFAMETHIZOLE/PHENAZOPYRIDINE
OXYTETRACYCLINE/LIDOCAINE
PIPERACILLIN AND TAZOBACTAM IN DEXTROSE, ISO-OSMOTIC
PIPERACILLIN SODIUM
PIPERACILLIN SODIUM/DEXTROSE 5 % IN WATER
PIPERACILLIN SODIUM/TAZOBACTAM SODIUM
POLYMYXIN B SULFATE/TRIMETHOPRIM
QUINUPRISTIN/DALFOPRISTIN
SILVER SULFADIAZINE
Appendix A

SILVER SULFADIAZINE/FOAM BANDAGE
SPARFLOXACIN
SPECTINOMYCIN HCL
STREPTOMYCIN SULFATE
SUCCINYLSULFATHIAZOLE
SULFADIAZINE
SULFADIAZINE SODIUM
SULFAMERAZINE
SULFAMETHOXAZOLE
SULFAMETHOXAZOLE/PHENAZOPYRIDINE HCL
SULFAMETHOXAZOLE/TRIMETHOPRIM
SULFANILAMIDE
SULFAPYRIDINE
SULFATHIAZOLE
SULFATHIAZOLE SODIUM
SULFATHIAZOLE/SULFACETAMIDE/SULFABENZAMIDE
SULFATHIAZOLE/SULFACETAMIDE/SULFABENZAMIDE/UREA
TEDIZOLID PHOSPHATE
TELAVANCIN HCL
TELITHROMYCIN
TETRACYCLINE
TETRACYCLINE HCL
TICARCILLIN DISODIUM
TICARCILLIN DISODIUM/DEXTROSE 5 % IN WATER
TICARCILLIN DISODIUM/POTASSIUM CLAVULANATE
TINIDAZOLE
TOBRAMYCIN
TOBRAMYCIN IN 0.225 % SODIUM CHLORIDE
TOBRAMYCIN SULFATE
TOBRAMYCIN SULFATE/DEXTROSE 5 % IN WATER
TOBRAMYCIN SULFATE/SODIUM CHLORIDE
TOBRAMYCIN/DEXAMETHASONE
Appendix A

TOBRAMYCIN/LOTEPREDNOL ETABONATE
TOBRAMYCIN/NEBULIZER
TRIAMCINOLONE ACETONIDE/MOXIFLOXACIN HCL/WATER/PF
TRIMETHOPRIM
TRIMETHOPRIM, MICRONIZED
TROLEANDOMYCIN
TROVAFLOXACIN MESYLATE
VANCOMYCIN HCL
VANCOMYCIN HCL/BALANCED SALT SOLUTION NO.2/PF
VANCOMYCIN IN 0.9 % SODIUM CHLORIDE
VANCOMYCIN IN 5 % DEXTROSE IN WATER
Appendix A


	


	
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
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
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Appendix B

Variable
Breo ellipta (dual therapy) Trelegy ellipta (triple 
therapy) 
St. Diff.
Breo ellipta (dual therapy) Trelegy ellipta (triple 
therapy) 
St. Diff.
Breo ellipta (dual therapy) 
Trelegy ellipta 
(triple therapy) 
St. Diff.
Number of patients
7882
6796
1873
730
                                                 9,755                         7,526 
Year of Cohort Entry Date
                                                           -                                     -   
...2017; n (%)
968 (12.3%)
3 (0.0%)
0.050
489 (26.1%)
12 (1.6%)
0.066
1,457 (14.9%)
015 (0.2%)
0.579
...2018; n (%)
3,123 (39.6%)
1,451 (21.4%)
0.033
1,384 (73.9%)
718 (98.4%)
-0.027
4,507 (46.2%)
2,169 (28.8%)
0.365
...2019; n (%)
2,594 (32.9%)
3,507 (51.6%)
-0.029
NA
NA
NA
NA
NA
NA
...2020; n (%)
1,197 (15.2%)
1,835 (27.0%)
-0.026
NA
NA
NA
NA
NA
NA
Age
...mean (sd)
69.65 (10.15)
70.22 (8.91)
-0.060
62.95 (11.21)
64.09 (9.74)
-0.109
68.36 (10.36)
69.63 (8.99)
-0.131
...median [IQR]
70.00 [63.00, 77.00]
71.00 [64.00, 77.00]
-0.105
61.00 [56.00, 70.00]
62.00 [58.00, 70.00]
-0.095
68.27 (10.36)
70.13 (8.99)
-0.192
Age categories 
...40-64; n (%)
2,264 (28.7%)
1,703 (25.1%)
0.007
1,245 (66.5%)
480 (65.8%)
0.001
3,509 (36.0%)
2,183 (29.0%)
0.150
...65 - 74; n (%)
3,005 (38.1%)
2,840 (41.8%)
-0.006
281 (15.0%)
121 (16.6%)
-0.004
3,286 (33.7%)
2,961 (39.3%)
-0.117
...>= 75; n (%)
2,613 (33.2%)
2,253 (33.2%)
0.000
347 (18.5%)
129 (17.7%)
0.002
2,960 (30.3%)
2,382 (31.7%)
-0.030
Geographic Region
...Northeast; n (%)
828 (10.5%)
611 (9.0%)
0.005
383 (20.4%)
152 (20.8%)
-0.001
1,211 (12.4%)
763 (10.1%)
0.073
...North Central; n (%)
NA
NA
NA
457 (24.4%)
155 (21.2%)
0.007
NA
NA
NA
...South; n (%)
4,434 (56.3%)
3,910 (57.5%)
-0.002
874 (46.7%)
368 (50.4%)
-0.005
5,308 (54.4%)
4,278 (56.8%)
-0.048
...Midwest; n (%)
1,480 (18.8%)
1,260 (18.5%)
0.001
NA
NA
NA
NA
NA
NA
...West; n (%)
1,140 (14.5%)
1,015 (14.9%)
-0.001
158 (8.4%)
55 (7.5%)
0.003
1,298 (13.3%)
1,070 (14.2%)
-0.026
...Unknown/Missing; n (%)
NA
NA
NA
1 (0.1%)
0 (0.0%)
0.004
NA
NA
NA
General Health Related Measures
Smoking; n (%)
3,293 (41.8%)
3,589 (52.8%)
-0.016
604 (32.2%)
353 (48.4%)
-0.026
3,897 (39.9%)
3,942 (52.4%)
-0.253
Alcohol/Drug abuse or dependence ; n (%)
474 (6.0%)
435 (6.4%)
-0.002
67 (3.6%)
28 (3.8%)
-0.001
541 (5.5%)
463 (6.2%)
-0.030
Obesity or Overweight; n (%)
2,608 (33.1%)
1,958 (28.8%)
0.008
480 (25.6%)
188 (25.8%)
0.000
3,088 (31.7%)
2,146 (28.5%)
0.070
Obesity; n (%)
1,952 (24.8%)
1,386 (20.4%)
0.009
384 (20.5%)
146 (20.0%)
0.001
2,336 (23.9%)
1,532 (20.4%)
0.084
Overweight; n (%)
806 (10.2%)
691 (10.2%)
0.000
115 (6.1%)
50 (6.8%)
-0.003
921 (9.4%)
741 (9.8%)
-0.014
Cardiovascular Measures
Hypertension; n (%)
6,143 (77.9%)
5,080 (74.7%)
0.004
1,171 (62.5%)
467 (64.0%)
-0.002
7,314 (75.0%)
5,547 (73.7%)
0.030
Hyperlipidemia; n (%)
4,034 (51.2%)
3,358 (49.4%)
0.003
753 (40.2%)
281 (38.5%)
0.003
4,787 (49.1%)
3,639 (48.4%)
0.014
MI, angina, Coronary atherosclerosis and other forms of chronic 
ischemic heart disease; n (%)
1,926 (24.4%)
1,758 (25.9%)
-0.003
306 (16.3%)
151 (20.7%)
-0.010
2,232 (22.9%)
1,909 (25.4%)
-0.058
Old MI; n (%)
320 (4.1%)
244 (3.6%)
0.003
25 (1.3%)
9 (1.2%)
0.001
345 (3.5%)
253 (3.4%)
0.005
Acute MI; n (%)
0 (0.0%)
0 (0.0%)
-
10 (0.5%)
0 (0.0%)
0.010
010 (0.1%)
000 (0.0%)
0.045
Stable angina; n (%)
349 (4.4%)
310 (4.6%)
-0.001
58 (3.1%)
28 (3.8%)
-0.004
407 (4.2%)
338 (4.5%)
-0.015
Coronary atherosclerosis and other forms of chronic ischemic heart 
disease; n (%)
1,773 (22.5%)
1,620 (23.8%)
-0.003
276 (14.7%)
139 (19.0%)
-0.010
2,049 (21.0%)
1,759 (23.4%)
-0.058
History of CABG or PTCA; n (%)
498 (6.3%)
424 (6.2%)
0.000
39 (2.1%)
19 (2.6%)
-0.003
537 (5.5%)
443 (5.9%)
-0.017
Cerebrovascular disease (Stroke, TIA, Late effects); n (%)
379 (4.8%)
246 (3.6%)
0.006
75 (4.0%)
17 (2.3%)
0.010
454 (4.7%)
263 (3.5%)
0.061
Stroke (Ischemic or hemorrhagic); n (%)
222 (2.8%)
144 (2.1%)
0.004
44 (2.3%)
10 (1.4%)
0.007
266 (2.7%)
154 (2.0%)
0.046
TIA; n (%)
118 (1.5%)
85 (1.3%)
0.002
36 (1.9%)
6 (0.8%)
0.009
154 (1.6%)
091 (1.2%)
0.034
Late effects of cerebrovascular disease; n (%)
161 (2.0%)
76 (1.1%)
0.007
19 (1.0%)
3 (0.4%)
0.007
180 (1.8%)
079 (1.0%)
0.068
Atrial fibrillation and Other cardiac dysrhythmia; n (%)
1,380 (17.5%)
1,095 (16.1%)
0.003
223 (11.9%)
100 (13.7%)
-0.005
1,603 (16.4%)
1,195 (15.9%)
0.014
Atrial fibrillation; n (%)
930 (11.8%)
748 (11.0%)
0.002
140 (7.5%)
64 (8.8%)
-0.005
1,070 (11.0%)
812 (10.8%)
0.006
Other cardiac dysrhythmia; n (%)
1,380 (17.5%)
1,095 (16.1%)
0.003
223 (11.9%)
100 (13.7%)
-0.005
1,603 (16.4%)
1,195 (15.9%)
0.014
Diabetes Related Measures
Diabetes with or w/o complications; n (%)
2,383 (30.2%)
1,688 (24.8%)
0.010
393 (21.0%)
146 (20.0%)
0.002
2,776 (28.5%)
1,834 (24.4%)
0.093
Diabetes mellitus without mention of complications; n (%)
2,071 (26.3%)
1,462 (21.5%)
0.010
336 (17.9%)
131 (17.9%)
0.000
2,407 (24.7%)
1,593 (21.2%)
0.083
Diabetes with specified complications; n (%)
979 (12.4%)
617 (9.1%)
0.010
129 (6.9%)
41 (5.6%)
0.005
1,108 (11.4%)
658 (8.7%)
0.090
Diabetes with unspecified complications; n (%)
181 (2.3%)
144 (2.1%)
0.001
47 (2.5%)
11 (1.5%)
0.007
228 (2.3%)
155 (2.1%)
0.014
GI Conditions
GERD; n (%)
2,251 (28.6%)
1,592 (23.4%)
0.010
396 (21.1%)
144 (19.7%)
0.003
2,647 (27.1%)
1,736 (23.1%)
0.092
Upper GI (Diseases of esophagus, stomach and duodenum including 
GERD) ; n (%)
2,432 (30.9%)
1,730 (25.5%)
0.010
451 (24.1%)
157 (21.5%)
0.005
2,883 (29.6%)
1,887 (25.1%)
0.101
GI bleeding; n (%)
236 (3.0%)
152 (2.2%)
0.005
40 (2.1%)
17 (2.3%)
-0.001
276 (2.8%)
169 (2.2%)
0.038
Non-infective enteritis and colitis; n (%)
221 (2.8%)
157 (2.3%)
0.003
46 (2.5%)
19 (2.6%)
-0.001
267 (2.7%)
176 (2.3%)
0.026
Marketscan
POOLED
Unmatched
Optum
Appendix B

Intraoperative and postprocedural complications and disorders of 
digestive system; n (%)
183 (2.3%)
116 (1.7%)
0.004
30 (1.6%)
11 (1.5%)
0.001
213 (2.2%)
127 (1.7%)
0.036
Disorders of gallbladder, biliary tract and pancreas; n (%)
172 (2.2%)
145 (2.1%)
0.001
32 (1.7%)
14 (1.9%)
-0.001
204 (2.1%)
159 (2.1%)
0.000
Rheumatic Conditions
Rheumatoid arthritis and other inflammatory polyarthropathies; n 
(%)
303 (3.8%)
213 (3.1%)
0.004
55 (2.9%)
21 (2.9%)
0.000
358 (3.7%)
234 (3.1%)
0.033
Osteoarthrosis; n (%)
2,153 (27.3%)
1,467 (21.6%)
0.012
319 (17.0%)
112 (15.3%)
0.004
2,472 (25.3%)
1,579 (21.0%)
0.102
Other rheumatic disorders (including gout); n (%)
3,412 (43.3%)
2,656 (39.1%)
0.007
600 (32.0%)
200 (27.4%)
0.008
4,012 (41.1%)
2,856 (37.9%)
0.065
Gout and other crystal arthropathies; n (%)
302 (3.8%)
211 (3.1%)
0.004
24 (1.3%)
6 (0.8%)
0.005
326 (3.3%)
217 (2.9%)
0.023
Other rheumatic disorders; n (%)
3,264 (41.4%)
2,539 (37.4%)
0.006
584 (31.2%)
198 (27.1%)
0.008
3,848 (39.4%)
2,737 (36.4%)
0.062
Neuro Conditions
Alzheimer and other Dementia Disease ; n (%)
514 (6.5%)
245 (3.6%)
0.013
65 (3.5%)
8 (1.1%)
0.016
579 (5.9%)
253 (3.4%)
0.119
Seizure disorders (epilepsy); n (%)
183 (2.3%)
80 (1.2%)
0.008
16 (0.9%)
3 (0.4%)
0.006
199 (2.0%)
083 (1.1%)
0.073
Delirium/Psychosis; n (%)
340 (4.3%)
169 (2.5%)
0.010
48 (2.6%)
10 (1.4%)
0.008
388 (4.0%)
179 (2.4%)
0.091
Other Conditions
Hypothyroidism; n (%)
1,566 (19.9%)
1,099 (16.2%)
0.009
267 (14.3%)
99 (13.6%)
0.002
1,833 (18.8%)
1,198 (15.9%)
0.077
Chronic kidney disease stages I-III; n (%)
1,352 (17.2%)
1,005 (14.8%)
0.006
118 (6.3%)
46 (6.3%)
0.000
1,470 (15.1%)
1,051 (14.0%)
0.031
Chronic kidney disease stages IV-V, ESRD; n (%)
195 (2.5%)
131 (1.9%)
0.004
24 (1.3%)
5 (0.7%)
0.006
219 (2.2%)
136 (1.8%)
0.029
COPD; n (%)
7,071 (89.7%)
6,609 (97.2%)
-0.008
1,603 (85.6%)
709 (97.1%)
-0.012
8,674 (88.9%)
7,318 (97.2%)
-0.331
Asthma; n (%)
2,558 (32.5%)
1,198 (17.6%)
0.030
710 (37.9%)
165 (22.6%)
0.028
3,268 (33.5%)
1,363 (18.1%)
0.358
Obstructive sleep apnea; n (%)
1,667 (21.1%)
1,427 (21.0%)
0.000
351 (18.7%)
164 (22.5%)
-0.008
2,018 (20.7%)
1,591 (21.1%)
-0.010
Syncope; n (%)
308 (3.9%)
172 (2.5%)
0.008
49 (2.6%)
16 (2.2%)
0.003
357 (3.7%)
188 (2.5%)
0.069
Falls; n (%)
571 (7.2%)
353 (5.2%)
0.008
55 (2.9%)
14 (1.9%)
0.006
626 (6.4%)
367 (4.9%)
0.065
VTE; n (%)
259 (3.3%)
184 (2.7%)
0.003
60 (3.2%)
9 (1.2%)
0.013
319 (3.3%)
193 (2.6%)
0.041
Combined comorbidity score, 365 days
...mean (sd)
3.34 (2.76)
3.04 (2.53)
0.113
2.17 (2.14)
2.27 (2.07)
-0.047
3.12 (2.65)
2.97 (2.49)
0.058
...median [IQR]
3.00 [1.00, 5.00]
2.00 [1.00, 4.00]
0.378
1.00 [1.00, 3.00]
2.00 [1.00, 3.00]
-0.475
2.62 (2.65)
2.00 (2.49)
0.241
INDEX 2 - Frailty Score: Empirical Version 365 days as Categories, 
v3
...< 0.1 non frail; n (%)
6,185 (78.5%)
4,989 (73.4%)
0.006
1,546 (82.5%)
534 (73.2%)
0.011
7,731 (79.3%)
5,523 (73.4%)
0.139
...0.1 - < 0.2 prefrail; n (%)
1,316 (16.7%)
1,598 (23.5%)
-0.015
246 (13.1%)
173 (23.7%)
-0.025
1,562 (16.0%)
1,771 (23.5%)
-0.189
… > 0.2 frail; n (%)
381 (4.8%)
209 (3.1%)
0.009
81 (4.3%)
23 (3.2%)
0.006
462 (4.7%)
232 (3.1%)
0.083
Medication Use
Use of oral corticosteroids; n (%)
7,177 (91.1%)
6,374 (93.8%)
-0.003
1,774 (94.7%)
700 (95.9%)
-0.001
8,951 (91.8%)
7,074 (94.0%)
-0.086
Use of antidepressants; n (%)
3,422 (43.4%)
2,840 (41.8%)
0.002
755 (40.3%)
293 (40.1%)
0.000
4,177 (42.8%)
3,133 (41.6%)
0.024
Use of anticonvulsants; n (%)
2,188 (27.8%)
1,560 (23.0%)
0.010
383 (20.4%)
131 (17.9%)
0.006
2,571 (26.4%)
1,691 (22.5%)
0.091
Use of beta blocker OR calcium channel blocker; n (%)
3,181 (40.4%)
2,654 (39.1%)
0.002
583 (31.1%)
244 (33.4%)
-0.004
3,764 (38.6%)
2,898 (38.5%)
0.002
Use of PPIs; n (%)
2,956 (37.5%)
2,205 (32.4%)
0.009
611 (32.6%)
232 (31.8%)
0.001
3,567 (36.6%)
2,437 (32.4%)
0.088
Use of opioids; n (%)
2,762 (35.0%)
2,042 (30.0%)
0.009
587 (31.3%)
200 (27.4%)
0.007
3,349 (34.3%)
2,242 (29.8%)
0.097
Use of antipsychotics; n (%)
491 (6.2%)
339 (5.0%)
0.005
75 (4.0%)
35 (4.8%)
-0.004
566 (5.8%)
374 (5.0%)
0.035
Use of anxiolytics/hypnotics; n (%)
794 (10.1%)
651 (9.6%)
0.002
189 (10.1%)
78 (10.7%)
-0.002
983 (10.1%)
729 (9.7%)
0.013
Use of dementia meds; n (%)
290 (3.7%)
167 (2.5%)
0.007
37 (2.0%)
4 (0.5%)
0.013
327 (3.4%)
171 (2.3%)
0.066
Use of antiparkinsonian meds; n (%)
401 (5.1%)
306 (4.5%)
0.003
69 (3.7%)
26 (3.6%)
0.001
470 (4.8%)
332 (4.4%)
0.019
Use of Benzodiazepine; n (%)
1,723 (21.9%)
1,350 (19.9%)
0.004
346 (18.5%)
149 (20.4%)
-0.004
2,069 (21.2%)
1,499 (19.9%)
0.032
All antidiabetic medications; n (%)
1,859 (23.6%)
1,338 (19.7%)
0.008
336 (17.9%)
140 (19.2%)
-0.003
2,195 (22.5%)
1,478 (19.6%)
0.071
ACEI/ARB; n (%)
3,720 (47.2%)
3,158 (46.5%)
0.001
785 (41.9%)
309 (42.3%)
-0.001
4,505 (46.2%)
3,467 (46.1%)
0.002
Use of Anticoagulants; n (%)
879 (11.2%)
684 (10.1%)
0.003
150 (8.0%)
57 (7.8%)
0.001
1,029 (10.5%)
741 (9.8%)
0.023
Use of Amiodarone; n (%)
88 (1.1%)
76 (1.1%)
0.000
13 (0.7%)
9 (1.2%)
-0.005
101 (1.0%)
085 (1.1%)
-0.010
Digoxin; n (%)
97 (1.2%)
75 (1.1%)
0.001
16 (0.9%)
8 (1.1%)
-0.002
113 (1.2%)
083 (1.1%)
0.009
Use of Diuretics; n (%)
3,206 (40.7%)
2,565 (37.7%)
0.005
630 (33.6%)
268 (36.7%)
-0.005
3,836 (39.3%)
2,833 (37.6%)
0.035
Use of Aspirin; n (%)
39 (0.5%)
38 (0.6%)
-0.001
45 (2.4%)
15 (2.1%)
0.002
084 (0.9%)
053 (0.7%)
0.022
NSAIDs (NOT including aspirin); n (%)
1,489 (18.9%)
1,151 (16.9%)
0.005
379 (20.2%)
130 (17.8%)
0.006
1,868 (19.1%)
1,281 (17.0%)
0.055
HRT (Use of estrogens, progestins, androgens); n (%)
283 (3.6%)
216 (3.2%)
0.002
113 (6.0%)
42 (5.8%)
0.001
396 (4.1%)
258 (3.4%)
0.037
Use of Statins ; n (%)
4,228 (53.6%)
3,761 (55.3%)
-0.002
828 (44.2%)
317 (43.4%)
0.001
5,056 (51.8%)
4,078 (54.2%)
-0.048
Healthcare Utilization Measures
Use of any drugs claims
...mean (sd)
39.76 (25.49)
38.20 (22.20)
0.065
36.10 (22.86)
39.78 (22.55)
-0.162
39.06 (25.01)
38.35 (22.23)
0.030
...median [IQR]
35.00 [22.00, 52.00]
34.00 [22.00, 50.00]
0.042
32.00 [20.00, 48.00]
36.00 [23.00, 52.00]
-0.176
34.42 (25.01)
34.19 (22.23)
0.010
Number of office visits 
...mean (sd)
19.74 (13.91)
18.54 (12.12)
0.092
14.40 (10.08)
14.76 (9.75)
-0.036
18.71 (13.26)
18.17 (11.91)
0.043
Appendix B

...median [IQR]
17.00 [10.00, 26.00]
16.00 [10.00, 24.00]
0.077
12.00 [7.00, 19.00]
12.50 [8.00, 19.00]
-0.050
16.04 (13.26)
15.66 (11.91)
0.030
Number of ED visits
...mean (sd)
1.41 (2.24)
1.08 (1.78)
0.163
1.23 (2.39)
0.99 (1.73)
0.115
1.38 (2.27)
1.07 (1.78)
0.152
...median [IQR]
1.00 [0.00, 2.00]
1.00 [0.00, 1.00]
0.000
1.00 [0.00, 2.00]
0.00 [0.00, 1.00]
0.479
1.00 (2.27)
0.90 (1.78)
0.049
Number of hospitalizations
...mean (sd)
0.27 (0.79)
0.16 (0.51)
0.165
1.12 (3.93)
0.81 (2.20)
0.097
0.43 (1.86)
0.22 (0.84)
0.146
...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 (1.86)
0.00 (0.84)
0.000
Recent hospitalization (-30 days to Index Rx date); n (%)
253 (3.2%)
77 (1.1%)
0.014
51 (2.7%)
7 (1.0%)
0.013
304 (3.1%)
084 (1.1%)
0.140
Old hospitalizations (-365 to -31 days); n (%)
2,160 (27.4%)
1,723 (25.4%)
0.004
474 (25.3%)
196 (26.8%)
-0.003
2,634 (27.0%)
1,919 (25.5%)
0.034
Number of Pulmonologist visits 
...mean (sd)
0.09 (0.64)
0.10 (0.65)
-0.016
0.80 (1.38)
1.23 (1.60)
-0.288
0.23 (0.83)
0.21 (0.79)
0.025
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.000
0.00 [0.00, 1.00]
1.00 [0.00, 2.00]
-0.669
0.00 (0.83)
0.10 (0.79)
-0.123
Pulmonologist on CED ; n (%)
44 (0.6%)
50 (0.7%)
-0.001
207 (11.1%)
75 (10.3%)
0.002
251 (2.6%)
125 (1.7%)
0.062
Number of hospital days
...mean (sd)
2.75 (10.57)
1.06 (5.13)
0.203
1.12 (3.93)
0.81 (2.20)
0.097
2.44 (9.66)
1.04 (4.92)
0.183
...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 (9.66)
0.00 (4.92)
0.000
Occurrence of basic or comprehensive metabolic blood chemistry 
test; n (%)
5,479 (69.5%)
4,639 (68.3%)
0.001
811 (43.3%)
344 (47.1%)
-0.006
6,290 (64.5%)
4,983 (66.2%)
-0.036
Number of HbA1C test ordered
...mean (sd)
1.17 (1.46)
1.05 (1.42)
0.083
0.66 (1.15)
0.59 (1.15)
0.061
1.07 (1.41)
1.01 (1.40)
0.043
...median [IQR]
1.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.694
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.000
0.81 (1.41)
0.00 (1.40)
0.577
Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy; 
n (%)
353 (4.5%)
266 (3.9%)
0.003
88 (4.7%)
42 (5.8%)
-0.005
441 (4.5%)
308 (4.1%)
0.020
Number of Mammograms (Breast cancer screening); n (%)
1,076 (13.7%)
786 (11.6%)
0.006
220 (11.7%)
82 (11.2%)
0.001
1,296 (13.3%)
868 (11.5%)
0.055
Number of Pap smear (Cervical cancer screening); n (%)
216 (2.7%)
126 (1.9%)
0.005
85 (4.5%)
24 (3.3%)
0.006
301 (3.1%)
150 (2.0%)
0.070
Flu vaccine; n (%)
1,701 (21.6%)
1,389 (20.4%)
0.003
329 (17.6%)
114 (15.6%)
0.005
2,030 (20.8%)
1,503 (20.0%)
0.020
Pneumococcal vaccine; n (%)
2,199 (27.9%)
1,919 (28.2%)
-0.001
388 (20.7%)
143 (19.6%)
0.002
2,587 (26.5%)
2,062 (27.4%)
-0.020
Copay for pharmacy cost (charges in U.S. $)
...mean (sd)
25.22 (31.21)
30.08 (33.34)
-0.150
19.06 (19.53)
22.29 (23.21)
-0.151
24.04 (29.33)
29.32 (32.50)
-0.171
...median [IQR]
17.78 [5.47, 34.48]
22.50 [7.34, 41.01]
-0.146
14.94 [6.77, 25.21]
18.31 [9.46, 28.28]
-0.157
17.23 (29.33)
22.09 (32.50)
-0.157
SES 9 Proxy - Business Type
...Commercial; n (%)
1,247 (15.8%)
894 (13.2%)
0.007
NA
NA
NA
NA
NA
NA
...Medicare; n (%)
6,635 (84.2%)
5,902 (86.8%)
-0.003
NA
NA
NA
NA
NA
NA
SABA Copy; n (%)
4,493 (57.0%)
4,227 (62.2%)
-0.007
1,176 (62.8%)
514 (70.4%)
-0.009
5,669 (58.1%)
4,741 (63.0%)
-0.100
SAMA; n (%)
337 (4.3%)
309 (4.5%)
-0.001
72 (3.8%)
41 (5.6%)
-0.008
409 (4.2%)
350 (4.7%)
-0.024
SABA/SAMA Copy; n (%)
1,282 (16.3%)
1,384 (20.4%)
-0.010
276 (14.7%)
143 (19.6%)
-0.012
1,558 (16.0%)
1,527 (20.3%)
-0.112
ICS Copy; n (%)
1,736 (22.0%)
1,356 (20.0%)
0.004
443 (23.7%)
206 (28.2%)
-0.009
2,179 (22.3%)
1,562 (20.8%)
0.036
LABA Copy; n (%)
61 (0.8%)
73 (1.1%)
-0.003
17 (0.9%)
12 (1.6%)
-0.006
078 (0.8%)
085 (1.1%)
-0.031
LAMA Copy; n (%)
1,635 (20.7%)
1,458 (21.5%)
-0.002
513 (27.4%)
228 (31.2%)
-0.007
2,148 (22.0%)
1,686 (22.4%)
-0.010
LABA/ICS Combination Copy; n (%)
7,882 (100.0%)
2,193 (32.3%)
0.084
1,873 (100.0%)
319 (43.7%)
0.067
9,755 (100.0%)
2,512 (33.4%)
1.997
LAMA/LABA Combination Copy; n (%)
368 (4.7%)
1,228 (18.1%)
-0.040
88 (4.7%)
179 (24.5%)
-0.052
456 (4.7%)
1,407 (18.7%)
-0.446
LABA LAMA ICS Copy; n (%)
0 (0.0%)
6,796 (100.0%)
-0.142
0 (0.0%)
730 (100.0%)
-0.142
000 (0.0%)
7,526 (100.0%)
-
GOLD C/D status; n (%)
5,110 (64.8%)
5,219 (76.8%)
-0.014
1,067 (57.0%)
537 (73.6%)
-0.021
6,177 (63.3%)
5,756 (76.5%)
-0.291
blood eosinophilia test; n (%)
27 (0.3%)
23 (0.3%)
0.000
9 (0.5%)
3 (0.4%)
0.001
036 (0.4%)
026 (0.3%)
0.017
Serum immunoglobulin E (IgE) level test Copy; n (%)
204 (2.6%)
125 (1.8%)
0.005
60 (3.2%)
19 (2.6%)
0.004
264 (2.7%)
144 (1.9%)
0.053
H2 blocker; n (%)
686 (8.7%)
529 (7.8%)
0.003
130 (6.9%)
43 (5.9%)
0.004
816 (8.4%)
572 (7.6%)
0.029
Oxygen codes; n (%)
604 (7.7%)
945 (13.9%)
-0.019
115 (6.1%)
86 (11.8%)
-0.019
719 (7.4%)
1,031 (13.7%)
-0.206
Respiratory arrest/dependence on oxygen; n (%)
841 (10.7%)
1,085 (16.0%)
-0.015
166 (8.9%)
108 (14.8%)
-0.017
1,007 (10.3%)
1,193 (15.9%)
-0.167
Insurance Plan Type
...Comprehensive; n (%)
NA
NA
NA
190 (10.1%)
98 (13.4%)
-0.010
NA
NA
NA
...HMO; n (%)
NA
NA
NA
195 (10.4%)
76 (10.4%)
0.000
NA
NA
NA
...PPO; n (%)
NA
NA
NA
1,021 (54.5%)
380 (52.1%)
0.003
NA
NA
NA
...Others; n (%)
NA
NA
NA
467 (24.9%)
176 (24.1%)
0.002
NA
NA
NA
Metropolitan Statistical Area
...Urban; n (%)
NA
NA
NA
914 (48.8%)
372 (51.0%)
-0.003
NA
NA
NA
...Rural; n (%)
NA
NA
NA
343 (18.3%)
141 (19.3%)
-0.002
NA
NA
NA
...Unknown/Missing; n (%)
NA
NA
NA
616 (32.9%)
217 (29.7%)
0.006
NA
NA
NA
Aetion link to Optum results: https://bwh-dope.aetion.com/projects/details/1614/rwrs/69652
Aetion link to Marketscan results: https://bwh-dope.aetion.com/projects/details/1615/rwrs/69653
Appendix B

Variable
Breo ellipta (dual therapy) Trelegy ellipta (triple 
therapy) 
St. Diff.
Breo ellipta (dual therapy) Trelegy ellipta (triple 
therapy) 
St. Diff.
Breo ellipta 
(dual therapy) 
Trelegy ellipta 
(triple therapy) 
St. Diff.
Number of patients
4248
4248
546
546
                     4,794                           4,794 
Year of Cohort Entry Date
...2017; n (%)
3 (0.1%)
3 (0.1%)
0.0000
9 (1.6%)
12 (2.2%)
-0.0044
012 (0.3%)
015 (0.3%)
0.000
...2018; n (%)
1,216 (28.6%)
1,236 (29.1%)
-0.0009
537 (98.4%)
534 (97.8%)
0.0006
1138.67 (0.43)
1156.05 (0.43)
0.000
...2019; n (%)
2,039 (48.0%)
1,996 (47.0%)
0.0015
NA
NA
NA
NA
NA
NA
...2020; n (%)
990 (23.3%)
1,013 (23.8%)
-0.0010
NA
NA
NA
NA
NA
NA
Age*
...mean (sd)
69.91 (9.75)
69.94 (9.22)
-0.0032
63.70 (10.74)
63.68 (9.77)
0.0019
69.20 (9.87)
69.23 (9.28)
-0.003
...median [IQR]
71.00 [64.00, 77.00]
71.00 [64.00, 76.00] 0.0000
62.00 [57.00, 70.00]
62.00 [57.00, 70.00]
0.0000
69.97 (9.87)
69.97 (9.28)
0.000
Age categories 
...40-64; n (%)
1,154 (27.2%)
1,129 (26.6%)
0.0012
357 (65.4%)
364 (66.7%)
-0.0016
1,511 (31.5%)
1,493 (31.1%)
0.009
...65 - 74; n (%)
1,682 (39.6%)
1,714 (40.3%)
-0.0011
87 (15.9%)
87 (15.9%)
0.0000
1,769 (36.9%)
1,801 (37.6%)
-0.014
...>= 75; n (%)
1,412 (33.2%)
1,405 (33.1%)
0.0002
102 (18.7%)
95 (17.4%)
0.0031
1,514 (31.6%)
1,500 (31.3%)
0.006
Geographic Region*
...Northeast; n (%)
413 (9.7%)
404 (9.5%)
0.0006
114 (20.9%)
112 (20.5%)
0.0009
527 (11.0%)
516 (10.8%)
0.006
...North Central; n (%)
NA
NA
NA
122 (22.3%)
121 (22.2%)
0.0002
NA
NA
NA
...South; n (%)
2,444 (57.5%)
2,443 (57.5%)
0.0000
278 (50.9%)
273 (50.0%)
0.0013
2,722 (56.8%)
2,716 (56.7%)
0.002
...Midwest; n (%)
776 (18.3%)
792 (18.6%)
-0.0007
NA
NA
NA
NA
NA
NA
...West; n (%)
615 (14.5%)
609 (14.3%)
0.0005
32 (5.9%)
40 (7.3%)
-0.0055
647 (13.5%)
649 (13.5%)
0.000
...Unknown/Missing; n (%)
NA
NA
NA
0 (0.0%)
0 (0.0%)
-
NA
NA
NA
General Health Related Measures
Smoking; n (%)*
1,987 (46.8%)
2,011 (47.3%)
-0.0007
254 (46.5%)
245 (44.9%)
0.0024
2,241 (46.7%)
2,256 (47.1%)
-0.008
Alcohol/Drug abuse or dependence ; n (%)
264 (6.2%)
261 (6.1%)
0.0004
21 (3.8%)
21 (3.8%)
0.0000
285 (5.9%)
282 (5.9%)
0.000
Obesity or Overweight; n (%)*
1,287 (30.3%)
1,323 (31.1%)
-0.0014
132 (24.2%)
146 (26.7%)
-0.0050
1,419 (29.6%)
1,469 (30.6%)
-0.022
Obesity; n (%)
947 (22.3%)
945 (22.2%)
0.0002
105 (19.2%)
117 (21.4%)
-0.0049
1,052 (21.9%)
1,062 (22.2%)
-0.007
Overweight; n (%)
411 (9.7%)
456 (10.7%)
-0.0031
35 (6.4%)
36 (6.6%)
-0.0008
446 (9.3%)
492 (10.3%)
-0.034
Cardiovascular Measures
Hypertension; n (%)*
3,229 (76.0%)
3,262 (76.8%)
-0.0009
336 (61.5%)
342 (62.6%)
-0.0014
3,565 (74.4%)
3,604 (75.2%)
-0.018
Hyperlipidemia; n (%)*
2,122 (50.0%)
2,114 (49.8%)
0.0003
203 (37.2%)
208 (38.1%)
-0.0015
2,325 (48.5%)
2,322 (48.4%)
0.002
MI, angina, Coronary atherosclerosis and other forms of chronic 
ischemic heart disease; n (%)*
1,047 (24.6%)
1,043 (24.6%)
0.0000
97 (17.8%)
106 (19.4%)
-0.0037
1,144 (23.9%)
1,149 (24.0%)
-0.002
Old MI; n (%)
166 (3.9%)
155 (3.6%)
0.0015
9 (1.6%)
5 (0.9%)
0.0063
175 (3.7%)
160 (3.3%)
0.022
Acute MI; n (%)
0 (0.0%)
0 (0.0%)
-
3 (0.5%)
0 (0.0%)
0.0100
003 (0.1%)
000 (0.0%)
0.045
Stable angina; n (%)
193 (4.5%)
187 (4.4%)
0.0005
21 (3.8%)
23 (4.2%)
-0.0020
214 (4.5%)
210 (4.4%)
0.005
Coronary atherosclerosis and other forms of chronic ischemic heart 
disease; n (%)
971 (22.9%)
958 (22.6%)
0.0006
89 (16.3%)
96 (17.6%)
-0.0032
1,060 (22.1%)
1,054 (22.0%)
0.002
History of CABG or PTCA; n (%)
268 (6.3%)
260 (6.1%)
0.0008
12 (2.2%)
14 (2.6%)
-0.0026
280 (5.8%)
274 (5.7%)
0.004
Cerebrovascular disease (Stroke, TIA, Late effects); n (%)*
166 (3.9%)
169 (4.0%)
-0.0005
11 (2.0%)
15 (2.7%)
-0.0046
177 (3.7%)
184 (3.8%)
-0.005
Stroke (Ischemic or hemorrhagic); n (%)
88 (2.1%)
101 (2.4%)
-0.0020
7 (1.3%)
9 (1.6%)
-0.0025
095 (2.0%)
110 (2.3%)
-0.021
TIA; n (%)
61 (1.4%)
58 (1.4%)
0.0000
6 (1.1%)
6 (1.1%)
0.0000
067 (1.4%)
064 (1.3%)
0.009
Late effects of cerebrovascular disease; n (%)
60 (1.4%)
59 (1.4%)
0.0000
0 (0.0%)
2 (0.4%)
-0.0089
060 (1.3%)
061 (1.3%)
0.000
Atrial fibrillation and Other cardiac dysrhythmia; n (%)*
707 (16.6%)
688 (16.2%)
0.0010
67 (12.3%)
72 (13.2%)
-0.0025
774 (16.1%)
760 (15.9%)
0.005
Atrial fibrillation; n (%)
467 (11.0%)
474 (11.2%)
-0.0006
47 (8.6%)
43 (7.9%)
0.0024
514 (10.7%)
517 (10.8%)
-0.003
Other cardiac dysrhythmia; n (%)
707 (16.6%)
688 (16.2%)
0.0010
67 (12.3%)
72 (13.2%)
-0.0025
774 (16.1%)
760 (15.9%)
0.005
Diabetes Related Measures
Diabetes with or w/o complications; n (%)*
1,151 (27.1%)
1,149 (27.0%)
0.0002
106 (19.4%)
110 (20.1%)
-0.0016
1,257 (26.2%)
1,259 (26.3%)
-0.002
Diabetes mellitus without mention of complications; n (%)
969 (22.8%)
989 (23.3%)
-0.0010
94 (17.2%)
96 (17.6%)
-0.0010
1,063 (22.2%)
1,085 (22.6%)
-0.010
Diabetes with specified complications; n (%)
471 (11.1%)
441 (10.4%)
0.0021
38 (7.0%)
33 (6.0%)
0.0039
509 (10.6%)
474 (9.9%)
0.023
Diabetes with unspecified complications; n (%)
84 (2.0%)
102 (2.4%)
-0.0027
17 (3.1%)
7 (1.3%)
0.0121
101 (2.1%)
109 (2.3%)
-0.014
GI Conditions
GERD; n (%)*
1,067 (25.1%)
1,068 (25.1%)
0.0000
98 (17.9%)
108 (19.8%)
-0.0044
1,165 (24.3%)
1,176 (24.5%)
-0.005
Upper GI (Diseases of esophagus, stomach and duodenum including 
GERD) ; n (%)
1,149 (27.0%)
1,166 (27.4%)
-0.0008
118 (21.6%)
117 (21.4%)
0.0004
1,267 (26.4%)
1,283 (26.8%)
-0.009
GI bleeding; n (%)*
100 (2.4%)
104 (2.4%)
0.0000
14 (2.6%)
14 (2.6%)
0.0000
114 (2.4%)
118 (2.5%)
-0.006
Non-infective enteritis and colitis; n (%)
110 (2.6%)
103 (2.4%)
0.0013
12 (2.2%)
13 (2.4%)
-0.0013
122 (2.5%)
116 (2.4%)
0.006
PS-matched
Optum
Marketscan
POOLED
Appendix B

Intraoperative and postprocedural complications and disorders of 
digestive system; n (%)
82 (1.9%)
73 (1.7%)
0.0015
9 (1.6%)
9 (1.6%)
0.0000
091 (1.9%)
082 (1.7%)
0.015
Disorders of gallbladder, biliary tract and pancreas; n (%)*
92 (2.2%)
89 (2.1%)
0.0007
11 (2.0%)
12 (2.2%)
-0.0014
103 (2.1%)
101 (2.1%)
0.000
Rheumatic Conditions
Rheumatoid arthritis and other inflammatory polyarthropathies; n 
(%)*
142 (3.3%)
148 (3.5%)
-0.0011
16 (2.9%)
14 (2.6%)
0.0018
158 (3.3%)
162 (3.4%)
-0.006
Osteoarthrosis; n (%)*
1,006 (23.7%)
1,014 (23.9%)
-0.0004
85 (15.6%)
82 (15.0%)
0.0015
1,091 (22.8%)
1,096 (22.9%)
-0.002
Other rheumatic disorders (including gout); n (%)*
1,738 (40.9%)
1,755 (41.3%)
-0.0006
155 (28.4%)
161 (29.5%)
-0.0020
1,893 (39.5%)
1,916 (40.0%)
-0.010
Gout and other crystal arthropathies; n (%)
147 (3.5%)
142 (3.3%)
0.0011
7 (1.3%)
6 (1.1%)
0.0018
154 (3.2%)
148 (3.1%)
0.006
Other rheumatic disorders; n (%)
1,666 (39.2%)
1,676 (39.5%)
-0.0005
150 (27.5%)
159 (29.1%)
-0.0030
1,816 (37.9%)
1,835 (38.3%)
-0.008
Neuro Conditions
Alzheimer and other Dementia Disease ; n (%)*
191 (4.5%)
185 (4.4%)
0.0005
8 (1.5%)
7 (1.3%)
0.0017
199 (4.2%)
192 (4.0%)
0.010
Seizure disorders (epilepsy); n (%)*
69 (1.6%)
64 (1.5%)
0.0008
0 (0.0%)
2 (0.4%)
-0.0089
069 (1.4%)
066 (1.4%)
0.000
Delirium/Psychosis; n (%)*
118 (2.8%)
116 (2.7%)
0.0006
9 (1.6%)
5 (0.9%)
0.0063
127 (2.6%)
121 (2.5%)
0.006
Other Conditions
Hypothyroidism; n (%)*
748 (17.6%)
744 (17.5%)
0.0002
84 (15.4%)
76 (13.9%)
0.0039
832 (17.4%)
820 (17.1%)
0.008
Chronic kidney disease stages I-III; n (%)*
646 (15.2%)
663 (15.6%)
-0.0010
31 (5.7%)
33 (6.0%)
-0.0012
677 (14.1%)
696 (14.5%)
-0.011
Chronic kidney disease stages IV-V, ESRD; n (%)
87 (2.0%)
86 (2.0%)
0.0000
7 (1.3%)
4 (0.7%)
0.0060
094 (2.0%)
090 (1.9%)
0.007
COPD; n (%)
3,860 (90.9%)
4,087 (96.2%)
-0.0055
503 (92.1%)
527 (96.5%)
-0.0046
4,363 (91.0%)
4,614 (96.2%)
-0.214
Asthma; n (%)*
988 (23.3%)
1,018 (24.0%)
-0.0014
149 (27.3%)
140 (25.6%)
0.0033
1,137 (23.7%)
1,158 (24.2%)
-0.012
Obstructive sleep apnea; n (%)*
870 (20.5%)
890 (21.0%)
-0.0011
104 (19.0%)
118 (21.6%)
-0.0058
974 (20.3%)
1,008 (21.0%)
-0.017
Syncope; n (%)
134 (3.2%)
120 (2.8%)
0.0023
14 (2.6%)
9 (1.6%)
0.0069
148 (3.1%)
129 (2.7%)
0.024
Falls; n (%)
227 (5.3%)
237 (5.6%)
-0.0013
10 (1.8%)
12 (2.2%)
-0.0028
237 (4.9%)
249 (5.2%)
-0.014
VTE; n (%)*
119 (2.8%)
121 (2.8%)
0.0000
9 (1.6%)
8 (1.5%)
0.0008
128 (2.7%)
129 (2.7%)
0.000
Combined comorbidity score, 365 days*
...mean (sd)
3.14 (2.58)
3.14 (2.63)
0.0000
2.22 (2.09)
2.27 (2.07)
-0.0240
3.04 (2.53)
3.04 (2.57)
0.000
...median [IQR]
3.00 [1.00, 5.00]
2.00 [1.00, 5.00]
0.3839
2.00 [1.00, 3.00]
2.00 [1.00, 3.00]
0.0000
2.89 (2.53)
2.00 (2.57)
0.349
INDEX 2 - Frailty Score: Empirical Version 365 days as Categories, 
v3*
...< 0.1 non frail; n (%)
3,304 (77.8%)
3,296 (77.6%)
0.0002
417 (76.4%)
418 (76.6%)
-0.0002
3,721 (77.6%)
3,714 (77.5%)
0.002
...0.1 - < 0.2 prefrail; n (%)
786 (18.5%)
801 (18.9%)
-0.0009
111 (20.3%)
108 (19.8%)
0.0011
897 (18.7%)
909 (19.0%)
-0.008
… > 0.2 frail; n (%)
158 (3.7%)
151 (3.6%)
0.0005
18 (3.3%)
20 (3.7%)
-0.0021
176 (3.7%)
171 (3.6%)
0.005
Medication Use
Use of oral corticosteroids; n (%)*
3,931 (92.5%)
3,936 (92.7%)
-0.0002
528 (96.7%)
522 (95.6%)
0.0011
4,459 (93.0%)
4,458 (93.0%)
0.000
Use of antidepressants; n (%)*
1,804 (42.5%)
1,817 (42.8%)
-0.0005
226 (41.4%)
221 (40.5%)
0.0014
2,030 (42.3%)
2,038 (42.5%)
-0.004
Use of anticonvulsants; n (%)*
1,070 (25.2%)
1,083 (25.5%)
-0.0006
97 (17.8%)
97 (17.8%)
0.0000
1,167 (24.3%)
1,180 (24.6%)
-0.007
Use of beta blocker OR calcium channel blocker; n (%)*
1,672 (39.4%)
1,679 (39.5%)
-0.0002
177 (32.4%)
174 (31.9%)
0.0009
1,849 (38.6%)
1,853 (38.7%)
-0.002
Use of PPIs; n (%)*
1,461 (34.4%)
1,498 (35.3%)
-0.0015
174 (31.9%)
178 (32.6%)
-0.0012
1,635 (34.1%)
1,676 (35.0%)
-0.019
Use of opioids; n (%)*
1,358 (32.0%)
1,360 (32.0%)
0.0000
149 (27.3%)
150 (27.5%)
-0.0004
1,507 (31.4%)
1,510 (31.5%)
-0.002
Use of antipsychotics; n (%)*
221 (5.2%)
222 (5.2%)
0.0000
25 (4.6%)
25 (4.6%)
0.0000
246 (5.1%)
247 (5.2%)
-0.005
Use of anxiolytics/hypnotics; n (%)*
416 (9.8%)
420 (9.9%)
-0.0003
55 (10.1%)
56 (10.3%)
-0.0006
471 (9.8%)
476 (9.9%)
-0.003
Use of dementia meds; n (%)*
122 (2.9%)
134 (3.2%)
-0.0017
5 (0.9%)
4 (0.7%)
0.0022
127 (2.6%)
138 (2.9%)
-0.018
Use of antiparkinsonian meds; n (%)*
204 (4.8%)
194 (4.6%)
0.0009
22 (4.0%)
18 (3.3%)
0.0037
226 (4.7%)
212 (4.4%)
0.014
Use of Benzodiazepine; n (%)*
850 (20.0%)
854 (20.1%)
-0.0002
111 (20.3%)
110 (20.1%)
0.0004
961 (20.0%)
964 (20.1%)
-0.002
All antidiabetic medications; n (%)*
901 (21.2%)
907 (21.4%)
-0.0004
99 (18.1%)
107 (19.6%)
-0.0035
1,000 (20.9%)
1,014 (21.2%)
-0.007
ACEI/ARB; n (%)*
2,013 (47.4%)
2,018 (47.5%)
-0.0001
225 (41.2%)
231 (42.3%)
-0.0017
2,238 (46.7%)
2,249 (46.9%)
-0.004
Use of Anticoagulants; n (%)*
446 (10.5%)
449 (10.6%)
-0.0003
48 (8.8%)
50 (9.2%)
-0.0013
494 (10.3%)
499 (10.4%)
-0.003
Use of Amiodarone; n (%)
46 (1.1%)
54 (1.3%)
-0.0018
4 (0.7%)
6 (1.1%)
-0.0042
050 (1.0%)
060 (1.3%)
-0.028
Digoxin; n (%)
51 (1.2%)
51 (1.2%)
0.0000
3 (0.5%)
6 (1.1%)
-0.0067
054 (1.1%)
057 (1.2%)
-0.009
Use of Diuretics; n (%)*
1,653 (38.9%)
1,668 (39.3%)
-0.0006
193 (35.3%)
192 (35.2%)
0.0002
1,846 (38.5%)
1,860 (38.8%)
-0.006
Use of Aspirin; n (%)
19 (0.4%)
30 (0.7%)
-0.0040
12 (2.2%)
12 (2.2%)
0.0000
031 (0.6%)
042 (0.9%)
-0.035
NSAIDs (NOT including aspirin); n (%)
742 (17.5%)
741 (17.4%)
0.0002
112 (20.5%)
95 (17.4%)
0.0071
854 (17.8%)
836 (17.4%)
0.011
HRT (Use of estrogens, progestins, androgens); n (%)*
142 (3.3%)
142 (3.3%)
0.0000
28 (5.1%)
36 (6.6%)
-0.0062
170 (3.5%)
178 (3.7%)
-0.011
Use of Statins ; n (%)*
2,335 (55.0%)
2,355 (55.4%)
-0.0005
244 (44.7%)
234 (42.9%)
0.0027
2,579 (53.8%)
2,589 (54.0%)
-0.004
Healthcare Utilization Measures
Use of any drugs claims*
...mean (sd)
38.70 (25.02)
38.49 (22.66)
0.0088
38.41 (24.47)
38.81 (22.54)
-0.0170
38.67 (24.96)
38.53 (22.65)
0.006
...median [IQR]
34.00 [21.00, 51.00]
34.00 [22.00, 50.00] 0.0000
34.50 [21.00, 50.25]
35.00 [23.00, 50.00]
-0.0213
34.06 (24.96)
34.11 (22.65)
-0.002
Number of office visits*
...mean (sd)
18.87 (12.67)
18.79 (12.49)
0.0064
14.24 (9.91)
14.60 (9.82)
-0.0365
18.34 (12.39)
18.31 (12.22)
0.002
Appendix B

...median [IQR]
16.00 [10.00, 24.75]
16.00 [10.00, 24.00] 0.0000
12.00 [7.00, 18.00]
12.00 [8.00, 19.00]
0.0000
15.54 (12.39)
15.54 (12.22)
0.000
Number of ED visits*
...mean (sd)
1.19 (1.76)
1.19 (1.95)
0.0000
0.99 (1.47)
1.02 (1.70)
-0.0189
1.17 (1.73)
1.17 (1.92)
0.000
...median [IQR]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
0.0000
0.00 [0.00, 1.00]
0.00 [0.00, 2.00]
0.0000
0.89 (1.73)
0.89 (1.92)
0.000
Number of hospitalizations*
...mean (sd)
0.17 (0.52)
0.18 (0.57)
-0.0183
0.89 (2.85)
0.86 (2.33)
0.0115
0.25 (1.08)
0.26 (0.95)
-0.010
...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 (1.08)
0.00 (0.95)
0.000
Recent hospitalization (-30 days to Index Rx date); n (%)*
71 (1.7%)
66 (1.6%)
0.0008
8 (1.5%)
6 (1.1%)
0.0035
079 (1.6%)
072 (1.5%)
0.008
Old hospitalizations (-365 to -31 days); n (%)*
1,070 (25.2%)
1,098 (25.8%)
-0.0012
144 (26.4%)
146 (26.7%)
-0.0006
1,214 (25.3%)
1,244 (25.9%)
-0.014
Number of Pulmonologist visits*
...mean (sd)
0.09 (0.67)
0.09 (0.61)
0.0000
1.08 (1.76)
1.15 (1.49)
-0.0429
0.20 (0.87)
0.21 (0.76)
-0.012
...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]
-0.6133
0.00 (0.87)
0.11 (0.76)
-0.135
Pulmonologist on CED ; n (%)*
24 (0.6%)
23 (0.5%)
0.0013
55 (10.1%)
61 (11.2%)
-0.0034
079 (1.6%)
084 (1.8%)
-0.015
Number of hospital days*
...mean (sd)
1.25 (5.14)
1.29 (6.09)
-0.0071
0.89 (2.85)
0.86 (2.33)
0.0115
1.21 (4.93)
1.24 (5.79)
-0.006
...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 (4.93)
0.00 (5.79)
0.000
Occurrence of basic or comprehensive metabolic blood chemistry 
test; n (%)*
2,888 (68.0%)
2,903 (68.3%)
-0.0004
256 (46.9%)
252 (46.2%)
0.0010
3,144 (65.6%)
3,155 (65.8%)
-0.004
Number of HbA1C test ordered*
...mean (sd)
1.11 (1.45)
1.11 (1.46)
0.0000
0.58 (1.08)
0.61 (1.18)
-0.0265
1.05 (1.41)
1.05 (1.43)
0.000
...median [IQR]
1.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.6873
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.0000
0.89 (1.41)
0.00 (1.43)
0.627
Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy; 
n (%)*
171 (4.0%)
169 (4.0%)
0.0000
27 (4.9%)
32 (5.9%)
-0.0043
198 (4.1%)
201 (4.2%)
-0.005
Number of Mammograms (Breast cancer screening); n (%)*
534 (12.6%)
529 (12.5%)
0.0003
62 (11.4%)
64 (11.7%)
-0.0009
596 (12.4%)
593 (12.4%)
0.000
Number of Pap smear (Cervical cancer screening); n (%)*
86 (2.0%)
97 (2.3%)
-0.0020
18 (3.3%)
20 (3.7%)
-0.0021
104 (2.2%)
117 (2.4%)
-0.013
Flu vaccine; n (%)*
865 (20.4%)
852 (20.1%)
0.0007
85 (15.6%)
90 (16.5%)
-0.0022
950 (19.8%)
942 (19.6%)
0.005
Pneumococcal vaccine; n (%)*
1,184 (27.9%)
1,149 (27.0%)
0.0017
107 (19.6%)
114 (20.9%)
-0.0029
1,291 (26.9%)
1,263 (26.3%)
0.014
Copay for pharmacy cost (charges in U.S. $)*
...mean (sd)
27.30 (35.49)
27.85 (31.85)
-0.0163
21.53 (22.71)
20.69 (20.10)
0.0392
26.64 (34.28)
27.03 (30.74)
-0.012
...median [IQR]
19.37 [6.01, 36.26]
20.58 [6.59, 38.83]
-0.0359
16.99 [7.47, 28.40]
17.25 [9.01, 26.47]
-0.0121
19.10 (34.28)
20.20 (30.74)
-0.034
SES 9 Proxy - Business Type*
...Commercial; n (%)
605 (14.2%)
586 (13.8%)
0.0011
NA
NA
NA
NA
NA
NA
...Medicare; n (%)
3,643 (85.8%)
3,662 (86.2%)
-0.0004
NA
NA
NA
NA
NA
NA
SABA Copy; n (%)*
2,502 (58.9%)
2,495 (58.7%)
0.0003
387 (70.9%)
377 (69.0%)
0.0023
2,889 (60.3%)
2,872 (59.9%)
0.008
SAMA; n (%)*
176 (4.1%)
189 (4.4%)
-0.0015
32 (5.9%)
28 (5.1%)
0.0034
208 (4.3%)
217 (4.5%)
-0.010
SABA/SAMA Copy; n (%)*
757 (17.8%)
763 (18.0%)
-0.0005
113 (20.7%)
105 (19.2%)
0.0034
870 (18.1%)
868 (18.1%)
0.000
ICS Copy; n (%)*
856 (20.2%)
870 (20.5%)
-0.0007
142 (26.0%)
150 (27.5%)
-0.0029
998 (20.8%)
1,020 (21.3%)
-0.012
LABA Copy; n (%)*
37 (0.9%)
40 (0.9%)
0.0000
5 (0.9%)
8 (1.5%)
-0.0055
042 (0.9%)
048 (1.0%)
-0.010
LAMA Copy; n (%)*
918 (21.6%)
926 (21.8%)
-0.0004
189 (34.6%)
177 (32.4%)
0.0038
1,107 (23.1%)
1,103 (23.0%)
0.002
LABA/ICS Combination Copy; n (%)
4,248 (100.0%)
1,462 (34.4%)
0.0804
546 (100.0%)
254 (46.5%)
0.0628
4,794 (100.0%)
1,716 (35.8%)
1.894
LAMA/LABA Combination Copy; n (%)*
301 (7.1%)
312 (7.3%)
-0.0007
65 (11.9%)
73 (13.4%)
-0.0042
366 (7.6%)
385 (8.0%)
-0.015
LABA LAMA ICS Copy; n (%)
0 (0.0%)
4,248 (100.0%)
-0.1421
0 (0.0%)
546 (100.0%)
-0.1421
000 (0.0%)
4,794 (100.0%)
-
GOLD C/D status; n (%)*
3,022 (71.1%)
3,021 (71.1%)
0.0000
387 (70.9%)
378 (69.2%)
0.0020
3,409 (71.1%)
3,399 (70.9%)
0.004
blood eosinophilia test; n (%)*
14 (0.3%)
15 (0.4%)
-0.0017
3 (0.5%)
3 (0.5%)
0.0000
017 (0.4%)
018 (0.4%)
0.000
Serum immunoglobulin E (IgE) level test Copy; n (%)*
100 (2.4%)
94 (2.2%)
0.0013
13 (2.4%)
15 (2.7%)
-0.0019
113 (2.4%)
109 (2.3%)
0.007
H2 blocker; n (%)*
340 (8.0%)
336 (7.9%)
0.0004
30 (5.5%)
31 (5.7%)
-0.0008
370 (7.7%)
367 (7.7%)
0.000
Oxygen codes; n (%)*
396 (9.3%)
413 (9.7%)
-0.0013
61 (11.2%)
61 (11.2%)
0.0000
457 (9.5%)
474 (9.9%)
-0.014
Respiratory arrest/dependence on oxygen; n (%)*
501 (11.8%)
516 (12.1%)
-0.0009
70 (12.8%)
69 (12.6%)
0.0006
571 (11.9%)
585 (12.2%)
-0.009
Insurance Plan Type*
...Comprehensive; n (%)
NA
NA
NA
63 (11.5%)
68 (12.5%)
-0.0029
NA
NA
NA
...HMO; n (%)
NA
NA
NA
54 (9.9%)
55 (10.1%)
-0.0006
NA
NA
NA
...PPO; n (%)
NA
NA
NA
287 (52.6%)
289 (52.9%)
-0.0004
NA
NA
NA
...Others; n (%)
NA
NA
NA
142 (26.0%)
134 (24.5%)
0.0030
NA
NA
NA
Metropolitan Statistical Area*
...Urban; n (%)
NA
NA
NA
286 (52.4%)
278 (50.9%)
0.0021
NA
NA
NA
...Rural; n (%)
NA
NA
NA
108 (19.8%)
101 (18.5%)
0.0030
NA
NA
NA
...Unknown/Missing; n (%)
NA
NA
NA
152 (27.8%)
167 (30.6%)
-0.0052
NA
NA
NA
*Included in the 1:1 PS matching model
Appendix B