Replication of the INSPIRE Trial in Healthcare Claims Data
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Brigham and Women's Hospital

Replication of the INSPIRE Trial in 
Healthcare Claims Data  
DUPLICATE INSPIRE 
August 30, 2021 

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1. RCT Details
This section provides a high-level overview of an 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
The Preǀention of Chronic ObstrƵctiǀe PƵlmonarǇ Disease Eǆacerbations bǇ SalmeterolͬFlƵticasone Propionate or 
TiotropiƵm Bromide ;INSPIRE trialͿ 
1.2 Intended aim(s) 
The objective of the study is to compare the effect of the anti-inflammatory/bronchodilator combination of 
salmeterol/fluticasone propionate (SFC) with the bronchodilator tiotropium bromide on the rate of moderate and/or severe 
exacerbations during a 2-year treatment period, and secondarily on outcomes that might relate to exacerbations. 
1.3 Primary endpoint for replication and RCT finding 
Health care utilization exacerbation rate. 
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
With a sample size of ϲ3ϱ patients per treatment group, the trial will have ϵ0й power to detect at least a 1ϱй (equal to 
1.ϰϰϱ exacerbations per subject per year) reduction in exacerbations in the SFC group at a two-sided significance level of
alpha с 0.0ϱ
1.5 Trial estimate 
Rate ratio с 0.ϵϲϳ (ϵϱй CI 0.ϴ3ϲ–1.11ϵ) comparing SFC to tiotropium bromide (Wedzicha et al., 200ϴ, Am J Respir Crit Care 
Med). HR of 0.ϴϱ was used for power assessment based on RCT statistical analysis. 
2. Person responsible for implementation of replication in Aetion
Helen Tesfaye, Pharm.D, ScM implemented the study design in the Aetion Evidence Platform. She is not responsible for the validity
of design and analytic choices. All implementation steps are recorded, and implementation history is archived in the platform.

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3. Data SoƵrce;sͿ
Optum Cliniformatics Data Mart, IBM MarketScan
4. StƵdǇ Design Diagram
The study design diagram visualizes key aspects of the longitudinal study design for expediated review

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5. Cohort Identification
5.1 Cohort Summary 
This study will involve a new user, parallel group, propensity score matched retrospective cohort study design comparing 
tiotropium to salmeterol. The patients will be required to have continuous enrollment during baseline period of 1ϴ0 days before 
initiation of SFC or tiotropium inhalers (cohort entry date).  
5.2 Important steps for cohort formation 
New users (defined as no use in 1ϴ0 days prior to index date) of an exposure and a comparator drug will be identified. 
ϱ.2.1   Eligible cohort entry date 
SFC inhaler was first approved by FDA for market availability on August 2ϰ, 2000, and tiotropium on January 30, 200ϰ 
Optum: January 30, 200ϰ – March 31, 2020 (end of data availability is September 30, 2020 but excluded data 
generated during COVID-1ϵ pandemic) 
Marketscan: January 30, 200ϰ – December 31, 201ϴ (end of data availability)  
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 Appendiǆ A and are summarized in the flowcharts below. 
5.3 Flowchart of the study cohort assembly 
OPTUM 
MARKETSCAN 
Less Excluded 
Patients 
Remaining 
Patients 
Less Excluded 
Patients 
Remaining 
Patients 
All patients 
79,335,559 
200,203,908 
Did not meet cohort entry criteria 
-77,381,938
1,953,621 
-196,683,354
3,520,554 
Excluded due to insufficient enrollment 
-308,951
1,644,670 
-522,438
2,998,116 
Excluded due to prior use of referent 
-274,142
1,370,528 
-362,567
2,635,549 
Excluded due to prior use of exposure 
-641,980
728,548 
-1,225,388
1,410,161 
Excluded because patient qualified in >1 exposure category 
-10,386
718,162 
-17,868
1,392,293 

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ϰ
Excluded based on Missing/Unknown Age 
-6 
718,156 
-1 
1,392,292 
Excluded based on Missing/Unknown Gender 
-125 
718,031 
0 
1,392,292 
Excluded based on Inclusion #1 - Age 40 to 80 years old 
-5 
718,026 
0 
1,392,292 
Excluded based on Inclusion #3a - Diagnosis of COPD 
-471,394 
246,632 
-1,038,792 
353,500 
Excluded based on Inclusion #3b - Clinical history of at least 1 COPD Exacerbation  
-110,352 
136,280 
-153,003 
200,497 
Excluded based on Exclusion #1 - COPD exacerbation in the 6 weeks prior 
-33,666 
102,614 
-34,019 
166,478 
Excluded based on Exclusion #2a - Current asthma   
-13,344 
89,270 
-13,539 
152,939 
Excluded based on Exclusion #2b - Current eczema, atopic dermatitis and/or allergic rhinitis 
-5,978 
83,292 
-7,929 
145,010 
Excluded based on Exclusion #3 - Has a known respiratory disorder other than COPD 
-15,367 
67,925 
-20,732 
124,278 
Excluded based on Exclusion #4 - Has narrow-angle glaucoma, prostatic hyperplasia or 
obstruction of the neck of the bladder  
-3,927 
63,998 
-5,648 
118,630 
Excluded based on Exclusion #5 - Has undergone lung transplantation and/or lung volume 
reduction 
-11 
63,987 
-41 
118,589 
Excluded based on Exclusion #7 - Requires regular (daily) long-term oxygen therapy (LTOT) 
-2,422 
61,565 
-1,401 
117,188 
Excluded based on Exclusion #8 - Is receiving beta-blockers (except eye drops) 
-7,770 
53,795 
-14,196 
102,992 
Excluded based on Exclusion #11 - Has evidence of alcohol, drug or solvent abuse 
-945 
52,850 
-793 
102,199 
Excluded based on Exclusion #14 - Exclude use of Salmeterol, tiotropium, and fluticasone 
containing inhaler use 
-591 
52,259 
-819 
101,380 
Final cohort 
  
52,259 
  
101,380 
 
 
6 
Variables  
6.1 Exposure-related variables: 
Study drug:  
The study exposure of interest is initiation of SFC (LABA/ICS combination). Initiation will be defined by no use of inhaled 
SFC during the prior 1ϴ0 days before treatment initiation (washout period).  
 
Comparator agents: 
Initiators of tiotropium inhaler defined as no use of inhaled tiotropium during the 1ϴ0 days prior to index date 
 
Patients are required to be incident users with respect to both exposure groups. 
 
 
 

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6.2 Preliminary Covariates: 
Age 
Sex 
Combined Comorbidity Index (CCI), measured over the default baseline covariate assessment period of 1ϴ0 days 
prior to and including the index prescription date 
Covariates listed above are a small subset of covariates that will ultimately be controlled in the design and analysis phase 
of the study. They are included in the preliminary assessment to determine the presence of adequate overlap between 
the two population of patients to proceed to the next phase of the study. Remaining covariates are defined only after 
the study has passed the initial feasibility analysis and initial power assessment and are listed in Table 1 (Appendiǆ B).  
6.3 Outcome variables and study follow-up: 
6.3.1 
Outcome variables 
Effectiveness outcome variables of interest (definitions provided in Appendiǆ A): 
Primary outcome: Healthcare utilization exacerbation rate per year (although the trial definition include 1) 
COPD hospitalizations or 2) exacerbations that required corticosteroids and/or antibiotics, in our 
emulation, we focused on 1) hospitalizations with COPD in the primary diagnosis position or 2) 
exacerbations that required corticosteroids. We did not include antibiotic use as part of the outcome 
definition because of our inability to determine whether the antibiotics were being used for COPD or some 
other indication) 
Secondary outcome: 
o
All-cause death
Control outcomes of interest (control outcomes only serve to assess aspects of study validity but are not further 
interpreted): Pneumonia 

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ϲ
6.3.2 
Study follow-up 
Both as-treated (AT) and intention-to-treat (ITT) analysis 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 primarǇ analysis, as it targets the relative rate of outcomes on treatment.  
 
For the AT analysis, the follow-up will start the day after the initiation of SFC or tiotropium and will continue until 
the earliest date of the following events: 
 The date of end of continued registration in the database, 
 End of the study period or ϳ30 days after cohort entry date, 
 Death, 
 Nursing home admission 
o Nursing home admissions are considered a censoring event because the data sources utilized typically 
provide little to no data on a patient, particularly on drug utilization, after admission. We will utilize this 
as an exclusion reason for cohorts for the same reason. 
 The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index 
drug (SFC or tiotropium) н a ϲ0-day grace period, 
 The date of switching from an exposure to comparator and vice versa, 
 The date of switching to or initiation of other LAMA (excluding tiotropium) and switch or initiation to other 
LABA/ICS (excluding SFC), LAMA/LABA, LABA only, LAMA/LABA/ICS combination, and ICS only inhalers. 
 
For the ITT analyses, the censoring based on the switching and treatment discontinuation will be replaced with a 
maximum allowed follow-up time of 3ϲϱ days. 
 
 
 
7 Initial FeasibilitǇ AnalǇsis  
Aetion report name: 
Optum- https://bwh-dope.aetion.com/projects/details/1ϳϰ2/rwrs/ϳ1ϲϲ0  
Marketscan- https://bwh-dope.aetion.com/projects/details/1ϳϰ1/rwrs/ϳ1ϲϱϴ  
 

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ϳ
Date conducted: ϲ/1ϳ/2021 
Complete Aetion feasibility analysis using age, sex, and CCI as the only covariates and the primary endpoint (Section ϲ.3.1) as the 
outcome. No measures of association will be computed nor will incidence rates stratified by treatment group. 
8 Initial Poǁer Assessment 
Aetion report name: 
Optum- https://bwh-dope.aetion.com/projects/details/1ϳϰ2/rwrs/ϳ1ϲϱϵ  
Marketscan- https://bwh-dope.aetion.com/projects/details/1ϳϰ1/rwrs/ϳ1ϲϱϳ 
Date conducted: ϲ/1ϳ/2021 
In order to complete the initial power analysis, the dummy outcome of a ϵ0-day gap in database enrollment will be used. Complete a 
1:1 PS-matched comparative analysis using this outcome. PS should include only 3 covariates: age, sex, and combined comorbidity 
index. 
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: 
Reviewed by FDA: 
Ken Quinto 
Date reviewed: 
Reasons for stopping 
analysis (if required): 

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ϴ
9. Balance Assessment 
Optum- https://bwh-dope.aetion.com/projects/details/1ϳϰ2/rwrs/ϳ23ϲ3  
Marketscan- https://bwh-dope.aetion.com/projects/details/1ϳϰ1/rwrs/ϳ23ϲϰ  
 
Date conducted: ϳ/1ϰ/2021 
 
After review of initial feasibility and power analyses, complete creation of the remaining covariates from Section ϲ.2. 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 Appendiǆ B.  
 
 
x Report covariate balance after matching. 
 
Note- For Table 1, please refer to Appendiǆ B.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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x Report reasons for censoring by treatment group. 
Overall 
Referent 
Exposure 
Dummy outcome 
0 (0%) 
0 (0%) 
0 (0%) 
Death 
706 (0.72%) 
368 (0.75%) 
338 (0.69%) 
Start of an additional exposure 
8,037 (8.18%) 
4,562 (9.28%) 
3,475 (7.07%) 
End of Index Exposure 
63,915 (65.03%) 
29,311 (59.65%) 
34,604 (70.42%) 
Specified date reached 
2,286 (2.33%) 
1,069 (2.18%) 
1,217 (2.48%) 
End of patient enrollment 
11,722 (11.93%) 
5,877 (11.96%) 
5,845 (11.89%) 
Switch to other LABA, LAMA + LABA/LAMA combo + 
LAMA/LABA/ICS combo + ICS only + NH admissions 
Occurred 
11,612 (11.82%) 
7,952 (16.18%) 
3,660 (7.45%) 
x Report follow-up time by treatment group. 
Patient Group 
Optum 
Median Follow-
Up Time (Days) 
[IQR] 
Marketscan 
Median Follow-
Up Time (Days) 
[IQR] 
Overall Patient Population 
88 [88, 162] 
113 [88, 180] 
Referent – Tiotropium 
88 [88, 160] 
99 [88, 175] 
Exposure – Salmeterol/Fluticasone 
88 [88, 165] 
120 [88, 188] 
x Report overall risk of the primary outcome. 
Optum 
MarketScan 
Pooled 
Risk per 1,000 patients 
152.99 
138.80 
143.63 
10. Final Poǁer Assessment
Date conducted: ϳ/1ϱ/2021 

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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. 
 
Superiority Analysis (Pooled)
Number of patients matched
Reference
49,138
Exposed
49,139
Risk per 1,000 patients
143.63
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
14115.52551
Power
1  
 

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Superiority Analysis (Optum)
Number of patients matched
Reference
18,017
Exposed
18,017
Risk per 1,000 patients
152.99
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
5512.84166
Power
0.999976837
Superiority Analysis (Marketscan)
Number of patients matched
Reference
31,122
Exposed
31,122
Risk per 1,000 patients
138.80
Desired HR from RCT
0.85
Alpha (2-sided)
0.05
Number of events expected
8639.4672
Power
0.999999989

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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: 
 
Reviewed by FDA: 
 
Date reviewed: 
 
Reasons for stopping 
analysis (if required): 
 
 
 
 

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Appendiǆ A͗ COPD Eǆacerbation ;primarǇ oƵtcomeͿ͕ AllͲcaƵse mortalitǇ ;secondarǇ oƵtcomeͿ 
COPD Exacerbation 
Measured 1 day after drug initiation in primary diagnosis position specified below and inpatient care setting - 
COPD (Inpatient, Primary) 
ICD-9 Diagnosis: 491.x, 492.x, 496 
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x 
OR 
Measured 1 day after drug initiation in any diagnosis position specified below and inpatient and outpatient care setting AND steroid use within 14 days - 
COPD (Any care setting, Any position) 
ICD-9 Diagnosis: 491.x, 492.x, 496 
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x 
AND 
Corticosteroid systemic administration and/or oral prescription of -- 
- Prednisone
- Prednisolone
- Methylprednisolone
- Dexamethasone
- Hydrocortisone
------------------------------------------------------------------------------- 
All-Cause Mortality 
Identified using the discharge status codes- 
Optum- Inpatient/Outpatient 
• 20 с EXPIRED
• 21 с EXPIRED TO BE DEFINED AT STATE LEVEL
• 22 с EXPIRED TO BE DEFINED AT STATE LEVEL
• 23 с EXPIRED TO BE DEFINED AT STATE LEVEL
• 2ϰ с EXPIRED TO BE DEFINED AT STATE LEVEL

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1ϰ
• 2ϱ с EXPIRED TO BE DEFINED AT STATE LEVEL
• 2ϲ с EXPIRED TO BE DEFINED AT STATE LEVEL
• 2ϳ с EXPIRED TO BE DEFINED AT STATE LEVEL
• 2ϴ с EXPIRED TO BE DEFINED AT STATE LEVEL
• 2ϵ с EXPIRED TO BE DEFINED AT STATE LEVEL
• ϰ0 с EXPIRED AT HOME (HOSPICE)
• ϰ1 с EXPIRED IN A MEDICAL FACILITY (HOSPICE)
• ϰ2 с EXPIRED - PLACE UNKNOWN (HOSPICE)
Marketscan- Inpatient 
• 20 - Died
• 22 - Died
• 23 - Died
• 24 - Died
• 2ϱ - Died
• 2ϲ - Died
• 2ϳ - Died
• 2ϴ - Died
• 2ϵ - Died
• ϰ0 - Other died status or Expired at home (Hospice claims only) (depends on year)
• ϰ1 - Other died status or Expired in medical facility (Hospice claims only) (depends on year)
• ϰ2 - Other died status or Expired - place unknown (Hospice claims only) (depends on year)
• 21 - Died or Disch./Transf. to court/law enforcement (depends on year)

#
INSPIRE trial definitions
Implementation in routine care
References/Rationale
Color coding
Please see the following Google 
drive for further details or any 
missing information  
https://drive.google.com/drive/fold
ers/1WD618wrywYjEaXzfLTcuK-
VCcnb6b-gV 
Criteria
Adequate mapping in claims
Tiotropium 18 mcg once daily vs. Salmeterol/fluticasone propionate (SFC) 50/500 mcg twice daily
Aim: To evaluate the effect of tiotropium compared to SFC on healthcare utilization of COPD exacerbations
SFC vs. Tiotropium
Exposure: SFC  Reference: Tiotropium
Intermediate mapping in 
claims
Poor mapping or cannot be 
measured in claims 
Primary endpoint: Healthcare utilization COPD exacerbation rate
Measured 1 day after drug initiation in primary diagnosis position and inpatient care setting
COPD (Inpatient, Primary)
ICD-9 Diagnosis: 491.x, 492.x, 496
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x
OR
Measured 1 day after drug initiation in any diagnosis position any care setting AND steriod use 
within 14 days 
COPD (Any care setting, Any position)
ICD-9 Diagnosis: 491.x, 492.x, 496
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x
AND
Corticosteriod systemic administration and/or oral prescription of:
- Prednisone
- Prednisolone
- Methylprednisolone
- Dexamethasone
- Hydrocortisone
Can't be measured in 
claims but not important 
for the analysis
1
40 to 80 years old
Age 40 to 80 years old at the time of drug initiation
2
Smoking history of ≥ 10 pack years
3a
Diagnosis of COPD
Measured from the start of all available data to and including the day of drug initiation in any 
diagnosis position and in the inpatient and outpatient care setting 
COPD 
ICD-9 Diagnosis: 491.x, 492.x, 496
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x
Trial details - Intended S with label change - 2 weeks run-in
EXPOSURE vs. COMPARISON
PRIMARY OUTCOME
Tiotropium 18 mcg once daily vs. SFC 50/500 mcg twice daily
Appendix A

3b
Clinical history of at least 1 COPD exacerbation 
Measured since all available data to 43 days prior to drug initiation in primary diagnosis 
position and inpatient care setting
COPD (Inpatient, Primary)
ICD-9 Diagnosis: 491..x, 492.x, 496.0
ICD-10 Diagnosis: J41, J42.x, J43.x, J44.x
OR
Measured since all available data to 43 days prior to drug initiation in any diagnosis position, 
inpatient and outpatient care setting AND steriod use within 30 days
COPD
ICD-9 Diagnosis: 491.x, 492.x, 496.0
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x
AND
Corticosteriod systemic administration and/or prescription 
- Prednisone
- Prednisolone
- Methylprednisolone
- Dexamethasone
- Hydrocortisone
4
Post bronchodilator FEV1 of < 50% of predicted normal
5
FEV1 / FVC ratio <70%
6
Reversibility to 400 mcg albuterol of less or equal to 10% of predicted FEV1 at Visit 1
7
A score of 2 or more on the Modified Medical Research Council dyspnea scale
8
Free from exacerbation in the 6 weeks prior to screening
Included in the exclusion criteria
1
COPD exacerbation in the 6 weeks prior to screening
Measured 42 days prior to and including the day of drug initiation in prescription claims
COPD (Inpatient, Any)
ICD-9 Diagnosis: 491.x, 492.x, 496.0
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x
OR
COPD (Any care setting, Any position)
ICD-9 Diagnosis: 491.x, 492.x, 496.0
ICD-10 Diagnosis: J41.x, J42, J43.x, J44.x
AND
Corticosteriod systemic administration and/or prescription
- Prednisone
- Prednisolone
- Methylprednisolone
- Dexamethasone
- Hydrocortisone
EXCLUSION CRITERIA
Appendix A

2
Current asthma, eczema, atopic dermatitis and/or allergic rhinitis
Measured 180 days prior to and including the day of drug initiation in any diagnosis position in 
the inpatient and outpatient care setting
Asthma (3 Diagnosis within 180 days)
ICD-9 Diagnosis: 493.x
ICD-10 Diagnosis: J45.x
Eczema
ICD-9 Diagnosis: 692.x
ICD-10 Diagnosis: L23.x, L24.x
Atopic dermatitis 
ICD-9 Diagnosis: 691.x
ICD-10 Diagnosis: L20.x 
Allergic rhinitis
ICD-9 Diagnosis: 477.x
ICD10 Diagnosis: J30.x
3
Has a known respiratory disorder other than COPD (e.g. lung cancer, sarcoidosis, tuberculosis or lung fibrosis)
Measured since all available data to and including the day of drug initiation in any diagnosis 
position in the inpatient and outpatient care setting
Pulmonary Fibrosis or Interstitial Lung Disease (ILD) 
ICD-9 Diagnosis:  515, 516.3x, 516.8, 516.9
ICD-10 Diagnosis: J84.10, J84.111, J84.112, J84.113, J84.114, J84.115, J84.116, J84.117, J84.09, 
J84.2, J84.89, J84.9
Sarcoidosis
ICD-9 diagnosis: 135
ICD-10 diagnosis: D86.0, D86.2 
Lymphangioleiomyomatosis
ICD-9 diagnosis: 516.4
ICD-10 diagnosis: J84.81
Primary/Pulmonary Tuberculosis
ICD-9 diagnosis: 010.x, 011.x
ICD-10 diagnosis:  A15.x
Cystic Fibrosis
ICD-9 Diagnosis: 277.0x
ICD-10 Diagnosis: E84.xx
Pulmonary Hypertension/Other Pulmonary Heart Disease
ICD-9 Diagnosis: 416.xx
4
Has narrow-angle glaucoma, prostatic hyperplasia or obstruction of the neck of the bladder that in the opinion of the 
investigator should prevent the subject from entering the study
Measured 180 days prior to and including the day of drug initiation in any diagnosis position in 
the inpatient and outpatient care setting
Narrow-angle Glaucoma
ICD-9 Diagnosis: 365.02, 36s.06, 365.2x
ICD-10 Diagnosis: H40.03x, H40.2xx, 
Prostatic hyperplasia or obstruction of the neck of the bladder 
ICD-9 Diagnosis: 600.x
ICD-10 Diagnosis: N40.x
OR
At least one 30-day supply presciption claims for oral:
Alfuzosin, doxazosin, tamsulosin, silodosin, finasteride 5 mg, dutasteride
Appendix A

5
Has undergone lung transplantation and/or lung volume reduction
Measured since all available data to and including the day of drug initiation in any diagnosis 
position in the inpatient and outpatient care setting
Lung transplant 
ICD-9 Diagnosis: V42.6, 996.84 
ICD-10 Diagnosis: Z94.2, T86.810, T86.811, T86.819
ICD-9 Procedure: 33.5x
ICD-10 Procedure: 0BYM0Z0, 0BYM0Z1, 0BYM0Z2, 0BYK0Z0, 0BYK0Z1, 0BYK0Z2, 0BYL0Z0, 
0BYL0Z1, 0BYL0Z2
CPT-4 Code: 32850 - 32856
Lung volume reduction surgery (LVRS)
ICD-9 Procedure: 32.22, 32.3x
ICD-10 Procedure: 0BBC0ZZ, 0BBC4ZZ, 0BBD0ZZ, 0BBD4ZZ, 0BBF0ZZ, 0BBF4ZZ, 0BBG0ZZ, 
0BBG4ZZ, 0BBH0ZZ, 0BBH4ZZ, 0BBJ0ZZ, 0BBJ4ZZ, 0BBK0ZZ, 0BBK4ZZ, 0BBL0ZZ, 0BBL4ZZ, 
0BBM0ZZ, 0BBM4ZZ
CPT/HCPCS codes: 32491, 32672, G0302, G0303, G0304, G0305
6
Female who is a nursing mother
7
Requires regular (daily) long-term oxygen therapy (LTOT)
Measured since all available data to and including the day of drug initiation in any diagnosis 
position in the inpatient and outpatient care setting
LTOT
ICD-9 Diagnosis: V46.2
ICD-10 Diagnosis: Z99.81
CPT/HCPCS code: E0424, E0441, E0443
8
Is receiving beta-blockers (except eye drops)
Measured 180 days prior to and including the day of drug initiation with prescription for oral:
Acebutolol, Atenolol, Betaxolol, Bisoprolol, Carteolol, Carvedilol, Labetalol, Metoprolol, 
Metiranolol, Nebivolol, Nadolol, Propranolol, Pindolol, Sotalol, Penbutolol, Oxprenolol
9
Has a serious, uncontrolled disease likely to interfere with the study
10
Has received any other investigational drugs within the 4 weeks prior to Visit 1
11
Has, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse
Measured 180 days prior to and including the day of drug initiation in any diagnosis position in 
the inpatient and outpatient care setting
Alcohol Abuse or Dependence
ICD-9 diagnosis: 291.xx, 303.xx, 305.0x, 571.0x, 571.1x, 571.2x, 571.3x, 357.5x, 425.5x, E860.0x, 
V11.3x
ICD-10 diagnosis: F10.x, K70.x, G62.1, I42.6, 099.31x
Drug Abuse or Dependence 
ICD-9 diagnosis: 292.xx, 304.xx, 305.2x-305.9x, 648.3x
ICD-10 diagnosis: F11.x, F12.x, F13.x, F14.x, F15.x, F16.x, F17.2x, F18.x, F19.x, F55.2, G62.0, 
099.32x
12
Has a known or suspected hypersensitivity to beta2-agonists, inhaled corticosteroids, anticholinergic agents or any components
of the formulations (e.g. lactose or milk protein)
Appendix A

13
Exclude use of Salmeterol, tiotropium, and fluticasone containing inhaler use within 180 days prior to CED
Measured 180 days prior to and including the day of drug initiation in prescription claims
Brand names -
STIOLTO RESPIMAT
SEREVENT
SEREVENT DISKUS
ARNUITY ELLIPTA
BREO ELLIPTA
TRELEGY ELLIPTA
FLOVENT HFA
FLOVENT DISKUS
ARMONAIR RESPICLICK
ARMONAIR
OR 
Generic name -
TIOTROPIUM BROMIDE/OLODATEROL HCL
SALMETEROL XINAFOATE
Appendix A

Optum
MarketScan
BEFORE PS MATCHING
The c-statistics for the propensity score model, pre-matching was 0.689. The post-matching c-statistic was 
0.523.
The c-statistics for the propensity score model, pre-matching was 0.7. The post-matching c-statistic was 
0.516.
Appendix A

Referent - Tiotropium
Exposure - Salmeterol/Fluticasone
St. Diff
Referent - Tiotropium
Exposure - Salmeterol/Fluticasone
St. Diff
Referent - Tiotropium
Exposure - Salmeterol/Fluticasone
St. Diff
Number of patients
21,689
30,570
36,727
64,653
58,416
95,223
Calendar Time - Year of Initiation (2004 - 2020)
...2004-2006; n (%)
1,330 (6.1%)
3,505 (11.5%)
-0.1915
5,640 (15.4%)
15,357 (23.8%)
-0.2128
6,970 (11.9%)
18,862 (19.8%)
-0.218
...2007-2008; n (%)
2,190 (10.1%)
3,669 (12.0%)
-0.0606
5,594 (15.2%)
11,223 (17.4%)
-0.0596
7,784 (13.3%)
14,892 (15.6%)
-0.065
...2009-2011; n (%)
4,060 (18.7%)
6,299 (20.6%)
-0.0478
9,988 (27.2%)
17,461 (27.0%)
0.0045
14,048 (24.0%)
23,760 (25.0%)
-0.023
...2012-2015; n (%)
6,704 (30.9%)
8,124 (26.6%)
0.0951
11,489 (31.3%)
15,233 (23.6%)
0.1732
18,193 (31.1%)
23,357 (24.5%)
0.148
...2016-2018; n (%)
5,091 (23.5%)
6,116 (20.0%)
0.0849
4,016 (10.9%)
5,379 (8.3%)
0.0883
9,107 (15.6%)
11,495 (12.1%)
0.101
...2019-Mar. 2020; n (%)
2,314 (10.7%)
2,857 (9.3%)
0.0467
2,314 (10.7%)
2,857 (9.3%)
0.047
DMG - Age
...mean (sd)
67.67 (10.33)
64.58 (13.34)
0.2590
65.73 (11.22)
62.49 (14.22)
0.2530
66.45 (10.90)
63.16 (13.94)
0.263
...median [IQR]
68.00 [60.00, 75.00]
66.00 [56.00, 74.00]
0.1676
64.00 [58.00, 74.00]
62.00 [54.00, 73.00]
0.1562
65.49 (10.90)
63.28 (13.94)
0.177
DMG - Gender
...Male; n (%)
7,779 (35.9%)
10,307 (33.7%)
0.0462
14,471 (39.4%)
22,933 (35.5%)
0.0806
22,250 (38.1%)
33,240 (34.9%)
0.067
...Female; n (%)
13,910 (64.1%)
20,263 (66.3%)
-0.0462
22,256 (60.6%)
41,720 (64.5%)
-0.0806
36,166 (61.9%)
61,983 (65.1%)
-0.067
DMG - Geographic region 
...Northeast; n (%)
2,144 (9.9%)
2,997 (9.8%)
0.0034
5,662 (15.4%)
10,090 (15.6%)
-0.0055
7,806 (13.4%)
13,087 (13.7%)
-0.009
...South; n (%)
9,881 (45.6%)
13,979 (45.7%)
-0.0020
13,969 (38.0%)
23,938 (37.0%)
0.0207
23,850 (40.8%)
37,917 (39.8%)
0.020
...North Central; n (%)
4,602 (21.2%)
6,546 (21.4%)
-0.0049
12,524 (34.1%)
21,068 (32.6%)
0.0318
17,126 (29.3%)
27,614 (29.0%)
0.007
...West; n (%)
5,062 (23.3%)
7,048 (23.1%)
0.0047
4,572 (12.4%)
9,557 (14.8%)
-0.0701
9,634 (16.5%)
16,605 (17.4%)
-0.024
DRS - Combined comorbidity score, 180 days 
...mean (sd)
1.43 (1.73)
1.20 (1.67)
0.1353
1.13 (1.45)
0.94 (1.39)
0.1338
1.24 (1.56)
1.02 (1.49)
0.144
...median [IQR]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
0.0000
1.00 [0.00, 2.00]
1.00 [0.00, 1.00]
0.0000
1.00 (1.56)
1.00 (1.49)
0.000
DRS - Frailty Score: Empirical Version (mean)
...mean (sd)
0.18 (0.06)
0.17 (0.06)
0.1667
0.17 (0.05)
0.16 (0.05)
0.2000
0.17 (0.05)
0.16 (0.05)
0.200
...median [IQR]
0.17 [0.14, 0.21]
0.16 [0.13, 0.20]
0.1667
0.16 [0.13, 0.19]
0.15 [0.12, 0.18]
0.2000
0.16 (0.05)
0.15 (0.05)
0.200
PLM - Smoking ; n (%)
6,731 (31.0%)
5,954 (19.5%)
0.2671
6,588 (17.9%)
6,674 (10.3%)
0.2197
13,319 (22.8%)
12,628 (13.3%)
0.249
PLM - Pneumonia ; n (%)
1,409 (6.5%)
1,750 (5.7%)
0.0334
2,786 (7.6%)
4,561 (7.1%)
0.0192
4,195 (7.2%)
6,311 (6.6%)
0.024
PLM - Oxygen usage; n (%)
1,538 (7.1%)
1,440 (4.7%)
0.1020
3,158 (8.6%)
3,635 (5.6%)
0.1170
4,696 (8.0%)
5,075 (5.3%)
0.109
PLM - Respiratory arrest/dependence on oxygen ; n (%)
699 (3.2%)
539 (1.8%)
0.0898
1,088 (3.0%)
1,177 (1.8%)
0.0785
1,787 (3.1%)
1,716 (1.8%)
0.084
PLM - CiPAP/BiPAP use; n (%)
904 (4.2%)
1,314 (4.3%)
-0.0050
1,943 (5.3%)
3,038 (4.7%)
0.0275
2,847 (4.9%)
4,352 (4.6%)
0.014
PLM - Pulmonary rehabilitation ; n (%)*
75 (0.3%)
46 (0.2%)
0.0200
150 (0.4%)
103 (0.2%)
0.0366
225 (0.4%)
149 (0.2%)
0.037
PLM - Moderate COPD exacerbation - [Count with 365 to 181 days before CED]*
...mean (sd)
1.37 (2.84)
1.13 (2.47)
0.0902
1.05 (2.25)
0.83 (1.81)
0.1077
1.17 (2.49)
0.93 (2.05)
0.105
...median [IQR]
0.28 [0.00, 1.53]
0.21 [0.00, 1.00]
0.0263
0.05 [0.00, 1.00]
0.08 [0.00, 1.00]
-0.0147
0.14 (2.49)
0.12 (2.05)
0.009
PLM - Moderate COPD exacerbation - [Count 180 to 31 days before CED]*
...mean (sd)
0.95 (2.07)
0.72 (1.68)
0.1220
0.68 (1.51)
0.52 (1.22)
0.1166
0.78 (1.74)
0.58 (1.38)
0.127
...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 0.84]
0.0000
0.00 [0.00, 0.81]
0.00 [0.00, 0.66]
0.0000
0.00 (1.74)
0.00 (1.38)
0.000
PLM - Moderate COPD exacerbation - [Count with 30 days to CED]*
...mean (sd)
0.02 (0.10)
0.01 (0.08)
0.1104
0.01 (0.08)
0.01 (0.07)
0.0000
0.01 (0.09)
0.01 (0.07)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.09)
0.00 (0.07)
0.000
PLM - Moderate exacerbations >=1 in 365 days before CED; n (%)
15,357 (70.8%)
21,008 (68.7%)
0.0457
23,550 (64.1%)
41,555 (64.3%)
-0.0042
38,907 (66.6%)
62,563 (65.7%)
0.019
PLM - Moderate exacerbations >=2 in 365 days before CED ; n (%)
9,947 (45.9%)
11,428 (37.4%)
0.1731
13,956 (38.0%)
19,175 (29.7%)
0.1761
23,903 (40.9%)
30,603 (32.1%)
0.184
PLM - Severe COPD exacerbation - [Count with 365 to 181 days before CED] *
...mean (sd)
0.03 (0.18)
0.03 (0.17)
0.0000
0.05 (0.21)
0.04 (0.19)
0.0499
0.04 (0.20)
0.04 (0.18)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.20)
0.00 (0.18)
0.000
PLM - Severe COPD exacerbation - [Count with 180 to 31 days before CED] *
...mean (sd)
0.02 (0.14)
0.02 (0.12)
0.0000
0.03 (0.16)
0.02 (0.14)
0.0665
0.03 (0.15)
0.02 (0.13)
0.071
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.15)
0.00 (0.13)
0.000
PLM - Severe COPD exacerbation - [Count with 30 days lookback]  *
...mean (sd)
0.00 (0.01)
0.00 (0.01)
0.0000
0.00 (0.01)
0.00 (0.01)
0.0000
0.00 (0.01)
0.00 (0.01)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.01)
0.00 (0.01)
0.000
PLM - Severe exacerbations >=1 in 365 days before CED; n (%)
1,333 (6.1%)
1,499 (4.9%)
0.0527
3,221 (8.8%)
4,394 (6.8%)
0.0746
4,554 (7.8%)
5,893 (6.2%)
0.063
PLM - Severe exacerbations >=2 in 365 days before CED ; n (%)
118 (0.5%)
128 (0.4%)
0.0149
265 (0.7%)
326 (0.5%)
0.0259
383 (0.7%)
454 (0.5%)
0.026
PLM - GOLD C/D Status ; n (%)
7,067 (32.6%)
7,801 (25.5%)
0.1569
12,368 (33.7%)
16,852 (26.1%)
0.1666
19,435 (33.3%)
24,653 (25.9%)
0.163
PRX - LABA only; n (%)
299 (1.4%)
100 (0.3%)
0.1200
1,170 (3.2%)
338 (0.5%)
0.2014
1,469 (2.5%)
438 (0.5%)
0.165
PRX - LAMA (except tiotropium) inhalers ; n (%)
123 (0.6%)
159 (0.5%)
0.0135
184 (0.5%)
175 (0.3%)
0.0317
307 (0.5%)
334 (0.4%)
0.015
PRX - ICS only inhalers ; n (%)
2,727 (12.6%)
4,010 (13.1%)
-0.0149
6,319 (17.2%)
11,104 (17.2%)
0.0000
9,046 (15.5%)
15,114 (15.9%)
-0.011
PRX - LABA/LAMA inhaler use ; n (%)
146 (0.7%)
96 (0.3%)
0.0567
83 (0.2%)
45 (0.1%)
0.0258
229 (0.4%)
141 (0.1%)
0.060
PRX - Other LABA/ICS combination  ; n (%)
3,473 (16.0%)
901 (2.9%)
0.4595
5,501 (15.0%)
1,484 (2.3%)
0.4638
8,974 (15.4%)
2,385 (2.5%)
0.464
PRX - COPD Maintenance therapy inhalers ; n (%)
3,942 (18.2%)
1,224 (4.0%)
0.4640
6,296 (17.1%)
1,719 (2.7%)
0.4968
10,238 (17.5%)
2,943 (3.1%)
0.488
PRX - SAMA inhaler use ; n (%)
765 (3.5%)
1,171 (3.8%)
-0.0160
1,653 (4.5%)
2,912 (4.5%)
0.0000
2,418 (4.1%)
4,083 (4.3%)
-0.010
PRX - SABA use ; n (%)
10,165 (46.9%)
14,075 (46.0%)
0.0180
16,966 (46.2%)
29,037 (44.9%)
0.0261
27,131 (46.4%)
43,112 (45.3%)
0.022
PRX - SABA/SAMA use; n (%)
2,485 (11.5%)
3,905 (12.8%)
-0.0398
4,865 (13.2%)
9,933 (15.4%)
-0.0629
7,350 (12.6%)
13,838 (14.5%)
-0.056
PRX - Antibiotics treatment  (180 days to 31 days before CED); n (%)
8,080 (37.3%)
11,493 (37.6%)
-0.0062
14,869 (40.5%)
27,269 (42.2%)
-0.0345
22,949 (39.3%)
38,762 (40.7%)
-0.029
OPTUM
MARKETSCAN
POOLED
UNMATCHED
Appendix B

PRX - Antibiotics treatment  (30 days to CED); n (%)
3,096 (14.3%)
5,872 (19.2%)
-0.1315
6,246 (17.0%)
14,851 (23.0%)
-0.1504
9,342 (16.0%)
20,723 (21.8%)
-0.149
PRX - Systemic Corticosteroids  (with CPT)  (180 days to 31 days before CED); n (%)
6,911 (31.9%)
9,913 (32.4%)
-0.0107
11,593 (31.6%)
20,935 (32.4%)
-0.0172
18,504 (31.7%)
30,848 (32.4%)
-0.015
PRX - Systemic Corticosteroids  (with CPT)  (30 days to CED); n (%)
1,106 (5.1%)
3,126 (10.2%)
-0.1928
2,576 (7.0%)
8,168 (12.6%)
-0.1892
3,682 (6.3%)
11,294 (11.9%)
-0.196
PRX - Roflumilast; n (%)
67 (0.3%)
42 (0.1%)
0.0448
162 (0.4%)
76 (0.1%)
0.0601
229 (0.4%)
118 (0.1%)
0.060
CVD - Unstable angina/MI; n (%)
593 (2.7%)
643 (2.1%)
0.0392
701 (1.9%)
1,029 (1.6%)
0.0229
1,294 (2.2%)
1,672 (1.8%)
0.029
CVD - Stable Angina  ; n (%)
403 (1.9%)
486 (1.6%)
0.0229
573 (1.6%)
834 (1.3%)
0.0251
976 (1.7%)
1,320 (1.4%)
0.024
CVD - Any Heart failure (HF) ; n (%)
1,334 (6.2%)
1,649 (5.4%)
0.0342
2,076 (5.7%)
3,132 (4.8%)
0.0404
3,410 (5.8%)
4,781 (5.0%)
0.035
CVD - Atrial fibrillation; n (%)
1,091 (5.0%)
1,261 (4.1%)
0.0432
1,764 (4.8%)
2,458 (3.8%)
0.0493
2,855 (4.9%)
3,719 (3.9%)
0.049
CVD - Other dysrythmias   ; n (%)*
1,576 (7.3%)
1,894 (6.2%)
0.0439
2,195 (6.0%)
3,210 (5.0%)
0.0439
3,771 (6.5%)
5,104 (5.4%)
0.047
CVD - Valve disorder   ; n (%)
277 (1.3%)
332 (1.1%)
0.0184
336 (0.9%)
612 (0.9%)
0.0000
613 (1.0%)
944 (1.0%)
0.000
CVD - Implantable cardioverter defibrillator  ; n (%)*
69 (0.3%)
82 (0.3%)
0.0000
111 (0.3%)
109 (0.2%)
0.0200
180 (0.3%)
191 (0.2%)
0.020
CVD - CABG/PCI; n (%)
521 (2.4%)
534 (1.7%)
0.0494
464 (1.3%)
595 (0.9%)
0.0384
985 (1.7%)
1,129 (1.2%)
0.042
CVD - Coronary atherosclerosis and other forms of chronic ischemic heart disease; n (%)
2,581 (11.9%)
2,968 (9.7%)
0.0709
4,121 (11.2%)
5,577 (8.6%)
0.0871
6,702 (11.5%)
8,545 (9.0%)
0.082
CVD - Stroke/TIA  ; n (%)
641 (3.0%)
713 (2.3%)
0.0436
943 (2.6%)
1,546 (2.4%)
0.0128
1,584 (2.7%)
2,259 (2.4%)
0.019
CVD - Peripheral Vascular Disease (PVD) or PVD Surgery; n (%)
1,693 (7.8%)
1,661 (5.4%)
0.0968
1,776 (4.8%)
2,384 (3.7%)
0.0545
3,469 (5.9%)
4,045 (4.2%)
0.078
CVD - Hyperlipidemia  ; n (%)
9,573 (44.1%)
12,176 (39.8%)
0.0872
10,218 (27.8%)
15,419 (23.8%)
0.0915
19,791 (33.9%)
27,595 (29.0%)
0.106
CVD - Hypertension; n (%)
11,323 (52.2%)
14,593 (47.7%)
0.0901
13,871 (37.8%)
21,783 (33.7%)
0.0856
25,194 (43.1%)
36,376 (38.2%)
0.100
CRX - ACEi or ARB; n (%)
8,168 (37.7%)
11,243 (36.8%)
0.0186
13,292 (36.2%)
22,744 (35.2%)
0.0209
21,460 (36.7%)
33,987 (35.7%)
0.021
CRX - Mineralocorticoid receptor antagonist  ; n (%)
325 (1.5%)
516 (1.7%)
-0.0159
778 (2.1%)
1,227 (1.9%)
0.0143
1,103 (1.9%)
1,743 (1.8%)
0.007
CRX - Loop or Thiazide diuretics; n (%)
4,670 (21.5%)
6,398 (20.9%)
0.0147
8,382 (22.8%)
14,759 (22.8%)
0.0000
13,052 (22.3%)
21,157 (22.2%)
0.002
CRX - Statins and other lipid lowering agents; n (%)
8,977 (41.4%)
11,512 (37.7%)
0.0757
14,474 (39.4%)
23,089 (35.7%)
0.0765
23,451 (40.1%)
34,601 (36.3%)
0.078
CRX - CCB and other antihypertensives; n (%)
4,813 (22.2%)
6,332 (20.7%)
0.0365
8,069 (22.0%)
13,275 (20.5%)
0.0367
12,882 (22.1%)
19,607 (20.6%)
0.037
CRX - Digoxin   ; n (%)*
314 (1.4%)
440 (1.4%)
0.0000
923 (2.5%)
1,584 (2.5%)
0.0000
1,237 (2.1%)
2,024 (2.1%)
0.000
CRX - Nitrates; n (%)*
702 (3.2%)
908 (3.0%)
0.0115
1,615 (4.4%)
2,613 (4.0%)
0.0199
2,317 (4.0%)
3,521 (3.7%)
0.016
OCM - Type 1 or 2 DM; n (%)
4,453 (20.5%)
6,394 (20.9%)
-0.0099
6,166 (16.8%)
10,874 (16.8%)
0.0000
10,619 (18.2%)
17,268 (18.1%)
0.003
OCM - Occurrence of Diabetic retinopathy/nephropathy/neuropathy; n (%)*
1,266 (5.8%)
1,801 (5.9%)
-0.0043
1,080 (2.9%)
1,727 (2.7%)
0.0121
2,346 (4.0%)
3,528 (3.7%)
0.016
OCM - Hypertensive nephropathy; n (%)*
689 (3.2%)
848 (2.8%)
0.0235
453 (1.2%)
611 (0.9%)
0.0294
1,142 (2.0%)
1,459 (1.5%)
0.038
OCM - Hypotension  ; n (%)*
383 (1.8%)
423 (1.4%)
0.0319
466 (1.3%)
621 (1.0%)
0.0281
849 (1.5%)
1,044 (1.1%)
0.035
OCM - Hyperkalemia ; n (%)*
210 (1.0%)
269 (0.9%)
0.0103
219 (0.6%)
297 (0.5%)
0.0135
429 (0.7%)
566 (0.6%)
0.012
OCM - CKD II, III, or IV; n (%)
1,196 (5.5%)
1,533 (5.0%)
0.0224
665 (1.8%)
968 (1.5%)
0.0236
1,861 (3.2%)
2,501 (2.6%)
0.036
OCM - HD/PD/ESRD; n (%)*
73 (0.3%)
96 (0.3%)
0.0000
155 (0.4%)
268 (0.4%)
0.0000
228 (0.4%)
364 (0.4%)
0.000
OCM - Osteoporosis; n (%)
2,569 (11.8%)
3,180 (10.4%)
0.0446
3,643 (9.9%)
5,889 (9.1%)
0.0273
6,212 (10.6%)
9,069 (9.5%)
0.037
OCM - Sleep apnea ; n (%)
2,011 (9.3%)
2,533 (8.3%)
0.0353
3,369 (9.2%)
4,832 (7.5%)
0.0615
5,380 (9.2%)
7,365 (7.7%)
0.054
OCM - Fractures  ; n (%)
939 (4.3%)
1,250 (4.1%)
0.0100
1,631 (4.4%)
2,887 (4.5%)
-0.0048
2,570 (4.4%)
4,137 (4.3%)
0.005
OCM - Other Arthritis, Arthropathies and Musculoskeletal Pain ; n (%)
7,847 (36.2%)
11,143 (36.5%)
-0.0062
11,173 (30.4%)
20,027 (31.0%)
-0.0130
19,020 (32.6%)
31,170 (32.7%)
-0.002
OCM - Dorsopathies; n (%)
6,114 (28.2%)
8,136 (26.6%)
0.0359
8,276 (22.5%)
13,884 (21.5%)
0.0241
14,390 (24.6%)
22,020 (23.1%)
0.035
OCM - Gout (acute/chronic) ; n (%)*
143 (0.7%)
251 (0.8%)
-0.0116
278 (0.8%)
437 (0.7%)
0.0116
421 (0.7%)
688 (0.7%)
0.000
OCM - Hyperthyroidism  ; n (%)*
136 (0.6%)
171 (0.6%)
0.0000
179 (0.5%)
286 (0.4%)
0.0149
315 (0.5%)
457 (0.5%)
0.000
OCM - Hypothyroidism ; n (%)*
2,033 (9.4%)
2,899 (9.5%)
-0.0034
2,650 (7.2%)
4,532 (7.0%)
0.0078
4,683 (8.0%)
7,431 (7.8%)
0.007
OCM - VTE ; n (%)*
400 (1.8%)
502 (1.6%)
0.0155
663 (1.8%)
1,090 (1.7%)
0.0076
1,063 (1.8%)
1,592 (1.7%)
0.008
OCM - GERD ; n (%)
3,134 (14.4%)
3,995 (13.1%)
0.0378
2,891 (7.9%)
4,522 (7.0%)
0.0343
6,025 (10.3%)
8,517 (8.9%)
0.048
OCM - Cancer   ; n (%)
2,248 (10.4%)
2,942 (9.6%)
0.0267
3,071 (8.4%)
4,758 (7.4%)
0.0371
5,319 (9.1%)
7,700 (8.1%)
0.036
OCM - Hypovolemia/volume depletion ; n (%)*
468 (2.2%)
601 (2.0%)
0.0139
622 (1.7%)
1,021 (1.6%)
0.0079
1,090 (1.9%)
1,622 (1.7%)
0.015
OCM - Anemia   ; n (%)
2,185 (10.1%)
3,009 (9.8%)
0.0100
2,840 (7.7%)
4,754 (7.4%)
0.0114
5,025 (8.6%)
7,763 (8.2%)
0.014
OCM - Dementia  ; n (%)*
777 (3.6%)
968 (3.2%)
0.0221
887 (2.4%)
1,320 (2.0%)
0.0273
1,664 (2.8%)
2,288 (2.4%)
0.025
OCM - Depression ; n (%)
3,467 (16.0%)
4,284 (14.0%)
0.0560
3,580 (9.7%)
5,735 (8.9%)
0.0275
7,047 (12.1%)
10,019 (10.5%)
0.051
ORX - Metformin; n (%)*
2,200 (10.1%)
3,182 (10.4%)
-0.0099
3,134 (8.5%)
5,875 (9.1%)
-0.0212
5,334 (9.1%)
9,057 (9.5%)
-0.014
ORX - 1st and 2nd Generation SUs   ; n (%)
1,054 (4.9%)
1,597 (5.2%)
-0.0137
1,837 (5.0%)
3,494 (5.4%)
-0.0180
2,891 (4.9%)
5,091 (5.3%)
-0.018
ORX - Insulins ; n (%)
897 (4.1%)
1,355 (4.4%)
-0.0149
1,551 (4.2%)
2,879 (4.5%)
-0.0147
2,448 (4.2%)
4,234 (4.4%)
-0.010
ORX - Other antidiabetic medications use; n (%)
826 (3.8%)
1,179 (3.9%)
-0.0052
1,704 (4.6%)
3,252 (5.0%)
-0.0187
2,530 (4.3%)
4,431 (4.7%)
-0.019
ORX - PPIs or H2RAs use; n (%)*
5,118 (23.6%)
6,819 (22.3%)
0.0309
7,835 (21.3%)
13,897 (21.5%)
-0.0049
12,953 (22.2%)
20,716 (21.8%)
0.010
ORX - NSAIDs ; n (%)*
3,492 (16.1%)
5,242 (17.1%)
-0.0269
6,115 (16.6%)
11,947 (18.5%)
-0.0500
9,607 (16.4%)
17,189 (18.1%)
-0.045
ORX - Use of opioids  ; n (%)*
7,529 (34.7%)
10,709 (35.0%)
-0.0063
13,564 (36.9%)
23,859 (36.9%)
0.0000
21,093 (36.1%)
34,568 (36.3%)
-0.004
ORX - Use of antipsychotics   ; n (%)*
992 (4.6%)
1,281 (4.2%)
0.0195
1,445 (3.9%)
2,380 (3.7%)
0.0105
2,437 (4.2%)
3,661 (3.8%)
0.020
ORX - Use of antidepressants  ; n (%)
7,865 (36.3%)
10,356 (33.9%)
0.0503
12,794 (34.8%)
21,535 (33.3%)
0.0317
20,659 (35.4%)
31,891 (33.5%)
0.040
ORX - Use of anxiolytics/hypnotics ; n (%)
2,098 (9.7%)
3,001 (9.8%)
-0.0034
3,956 (10.8%)
7,101 (11.0%)
-0.0064
6,054 (10.4%)
10,102 (10.6%)
-0.007
ORX - Use of anticonvulsants  ; n (%)*
3,680 (17.0%)
4,802 (15.7%)
0.0352
4,975 (13.5%)
8,461 (13.1%)
0.0118
8,655 (14.8%)
13,263 (13.9%)
0.026
ORX - Use of Benzodiazepines ; n (%)*
3,637 (16.8%)
5,129 (16.8%)
0.0000
8,276 (22.5%)
13,795 (21.3%)
0.0290
11,913 (20.4%)
18,924 (19.9%)
0.012
ORX - Use of dementia meds  ; n (%)*
546 (2.5%)
679 (2.2%)
0.0198
871 (2.4%)
1,357 (2.1%)
0.0202
1,417 (2.4%)
2,036 (2.1%)
0.020
ORX - Use of antiparkinsonian meds  ; n (%)*
821 (3.8%)
997 (3.3%)
0.0270
1,231 (3.4%)
2,000 (3.1%)
0.0169
2,052 (3.5%)
2,997 (3.1%)
0.022
ORX - Use of oral anticoagulants   ; n (%)*
1,035 (4.8%)
1,345 (4.4%)
0.0191
2,074 (5.6%)
3,252 (5.0%)
0.0268
3,109 (5.3%)
4,597 (4.8%)
0.023
ORX - Use of antiplatelet agents ; n (%)*
1,438 (6.6%)
1,582 (5.2%)
0.0594
3,661 (10.0%)
5,416 (8.4%)
0.0554
5,099 (8.7%)
6,998 (7.3%)
0.052
LFS - Obesity; n (%)
1,630 (7.5%)
2,388 (7.8%)
-0.0113
1,578 (4.3%)
2,791 (4.3%)
0.0000
3,208 (5.5%)
5,179 (5.4%)
0.004
PFT - Spirometry test only; n (%)
4,594 (21.2%)
3,785 (12.4%)
0.2370
9,392 (25.6%)
10,035 (15.5%)
0.2519
13,986 (23.9%)
13,820 (14.5%)
0.240
PFT - Spirometry test only (Count - 180 days to 31 days before CED) *
...mean (sd)
0.22 (0.74)
0.13 (0.55)
0.1380
0.23 (0.70)
0.15 (0.53)
0.1289
0.23 (0.72)
0.14 (0.54)
0.141
Appendix B

...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.72)
0.00 (0.54)
0.000
PFT - Spirometry test only (Count - 30 days to CED) *
...mean (sd)
0.18 (0.62)
0.08 (0.41)
0.1903
0.20 (0.60)
0.09 (0.39)
0.2174
0.19 (0.61)
0.09 (0.40)
0.194
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.61)
0.00 (0.40)
0.000
PFT - Lung volume, Diffuse capacity, pulmonary stress testing (any); n (%)
2,852 (13.1%)
2,795 (9.1%)
0.1276
4,207 (11.5%)
5,282 (8.2%)
0.1109
7,059 (12.1%)
8,077 (8.5%)
0.119
HCU - Pulmonologist visit (180 to 1 day before CED); n (%)
290 (1.3%)
246 (0.8%)
0.0491
7,544 (20.5%)
8,804 (13.6%)
0.1843
7,834 (13.4%)
9,050 (9.5%)
0.123
HCU - Pulmonologist visit on CED; n (%)
43 (0.2%)
28 (0.1%)
0.0258
1,568 (4.3%)
1,216 (1.9%)
0.1388
1,611 (2.8%)
1,244 (1.3%)
0.106
HCU - Pulmonologist visit (Number of during CAP) *
...mean (sd)
0.08 (1.11)
0.05 (0.93)
0.0293
0.89 (2.39)
0.49 (1.77)
0.1902
0.59 (2.01)
0.35 (1.55)
0.134
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (2.01)
0.00 (1.55)
0.000
HCU - Number of Internal Medicine/Family Medicine Visits  
...mean (sd)
7.62 (11.28)
6.95 (11.33)
0.0593
6.26 (10.74)
5.66 (9.03)
0.0605
6.76 (10.94)
6.07 (9.83)
0.066
...median [IQR]
4.00 [1.00, 10.00]
3.00 [0.00, 9.00]
0.0885
4.00 [1.00, 8.00]
3.00 [1.00, 7.00]
0.1008
4.00 (10.94)
3.00 (9.83)
0.096
HCU - Number of Cardiologist visits  
...mean (sd)
0.89 (3.16)
0.75 (2.76)
0.0472
0.81 (2.83)
0.67 (2.84)
0.0494
0.84 (2.96)
0.70 (2.81)
0.049
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (2.96)
0.00 (2.81)
0.000
HCU - Number of Emergency Department (ED) visits v3 
...mean (sd)
0.47 (1.31)
0.42 (1.18)
0.0401
0.17 (1.10)
0.16 (1.10)
0.0091
0.28 (1.18)
0.24 (1.13)
0.035
...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 (1.18)
0.00 (1.13)
0.000
HCU - Old hospitalization (-180 days to -31 days before CED)  ; n (%)
1,883 (8.7%)
2,196 (7.2%)
0.0555
4,861 (13.2%)
7,875 (12.2%)
0.0300
6,744 (11.5%)
10,071 (10.6%)
0.029
HCU - Recent hospitalization (-30 days to CED date)  ; n (%)
202 (0.9%)
264 (0.9%)
0.0000
595 (1.6%)
1,252 (1.9%)
-0.0229
797 (1.4%)
1,516 (1.6%)
-0.016
HCU - Number of hospitalizations during CAP  
...mean (sd)
0.11 (0.38)
0.09 (0.35)
0.0547
0.16 (0.43)
0.16 (0.43)
0.0000
0.14 (0.41)
0.14 (0.41)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.41)
0.00 (0.41)
0.000
HCU - Blood eosinophilia or Serum IgE test order; n (%)*
109 (0.5%)
161 (0.5%)
0.0000
145 (0.4%)
299 (0.5%)
-0.0149
254 (0.4%)
460 (0.5%)
-0.015
HCU - Pneumococcal vaccine; n (%)
2,791 (12.9%)
3,065 (10.0%)
0.0912
2,119 (5.8%)
2,509 (3.9%)
0.0885
4,910 (8.4%)
5,574 (5.9%)
0.097
HCU - Flu vaccine  ; n (%)
4,134 (19.1%)
5,214 (17.1%)
0.0520
4,507 (12.3%)
6,971 (10.8%)
0.0469
8,641 (14.8%)
12,185 (12.8%)
0.058
HCU - Bone mineral density  ; n (%)
988 (4.6%)
1,210 (4.0%)
0.0296
1,146 (3.1%)
1,659 (2.6%)
0.0301
2,134 (3.7%)
2,869 (3.0%)
0.039
HCU - Pap smear ; n (%)
817 (3.8%)
1,594 (5.2%)
-0.0676
1,625 (4.4%)
4,095 (6.3%)
-0.0845
2,442 (4.2%)
5,689 (6.0%)
-0.082
HCU - Mammogram  ; n (%)
2,744 (12.7%)
3,954 (12.9%)
-0.0060
3,874 (10.5%)
7,572 (11.7%)
-0.0382
6,618 (11.3%)
11,526 (12.1%)
-0.025
HCU - Prostate exam for DRE  ; n (%)
694 (3.2%)
751 (2.5%)
0.0421
666 (1.8%)
767 (1.2%)
0.0494
1,360 (2.3%)
1,518 (1.6%)
0.051
HCU - Number of Echocardiogram  *
...mean (sd)
0.20 (1.26)
0.17 (1.13)
0.0251
0.22 (0.79)
0.21 (0.80)
0.0126
0.21 (0.99)
0.20 (0.92)
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 (0.99)
0.00 (0.92)
0.000
HCU - Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy  ; n (%)
992 (4.6%)
1,258 (4.1%)
0.0245
1,950 (5.3%)
3,230 (5.0%)
0.0136
2,942 (5.0%)
4,488 (4.7%)
0.014
HCU - Number of Distinct Medication Prescriptions (not generalized to generics)  
...mean (sd)
20.64 (17.20)
20.20 (16.75)
0.0259
19.54 (14.98)
19.61 (15.46)
-0.0046
19.95 (15.84)
19.80 (15.89)
0.009
...median [IQR]
16.00 [9.00, 27.00]
16.00 [9.00, 27.00]
0.0000
16.00 [9.00, 26.00]
16.00 [9.00, 26.00]
0.0000
16.00 (15.84)
16.00 (15.89)
0.000
SES - Copay for pharmacy cost (charges in U.S. $)  
...mean (sd)
32.20 (38.19)
33.47 (36.20)
-0.0341
26.20 (26.21)
26.05 (26.49)
0.0057
28.43 (31.20)
28.43 (29.95)
0.000
...median [IQR]
23.64 [9.89, 41.20]
25.69 [12.25, 43.02]
-0.0551
20.87 [10.38, 35.00]
21.04 [10.00, 35.00]
-0.0065
21.90 (31.20)
22.53 (29.95)
-0.021
SES - Business type   
...Commercial; n (%)
6,697 (30.9%)
13,136 (43.0%)
-0.2527
6,697 (30.9%)
13,136 (43.0%)
-0.253
...Medicare; n (%)
14,992 (69.1%)
17,434 (57.0%)
0.2527
14,992 (69.1%)
17,434 (57.0%)
0.253
SES - Low income indicator  ; n (%)
4,586 (21.1%)
4,970 (16.3%)
0.1233
4,586 (21.1%)
4,970 (16.3%)
0.123
SES - Insurance Plan type   
...Comprehensive; n (%)
10,656 (29.0%)
16,804 (26.0%)
0.0672
10,656 (29.0%)
16,804 (26.0%)
0.067
...HMO; n (%)
4,376 (11.9%)
8,310 (12.9%)
-0.0303
4,376 (11.9%)
8,310 (12.9%)
-0.030
...PPO; n (%)
17,092 (46.5%)
30,849 (47.7%)
-0.0240
17,092 (46.5%)
30,849 (47.7%)
-0.024
...Others; n (%)
4,603 (12.5%)
8,690 (13.4%)
-0.0268
4,603 (12.5%)
8,690 (13.4%)
-0.027
___________
* Not included in PS model
Appendix B

Referent - Tiotropium
Exposure - Salmeterol/Fluticasone
St. Diff
Referent - Tiotropium
Exposure - Salmeterol/Fluticasone
St. Diff
Referent - Tiotropium
Exposure - Salmeterol/Fluticasone
St. Diff
Number of patients
18,017
18,017
31,122
31,122
49,139
49,139
Calendar Time - Year of Initiation (2004 - 2020)
...2004-2006; n (%)
1,289 (7.2%)
1,219 (6.8%)
0.0157
5,326 (17.1%)
5,292 (17.0%)
0.0027
6,615 (13.5%)
6,511 (13.3%)
0.006
...2007-2008; n (%)
2,030 (11.3%)
2,065 (11.5%)
-0.0063
5,203 (16.7%)
5,279 (17.0%)
-0.0080
7,233 (14.7%)
7,344 (14.9%)
-0.006
...2009-2011; n (%)
3,594 (19.9%)
3,602 (20.0%)
-0.0025
8,529 (27.4%)
8,599 (27.6%)
-0.0045
12,123 (24.7%)
12,201 (24.8%)
-0.002
...2012-2015; n (%)
5,440 (30.2%)
5,414 (30.0%)
0.0044
9,009 (28.9%)
8,912 (28.6%)
0.0066
14,449 (29.4%)
14,326 (29.2%)
0.004
...2016-2018; n (%)
3,880 (21.5%)
3,887 (21.6%)
-0.0024
3,055 (9.8%)
3,040 (9.8%)
0.0000
6,935 (14.1%)
6,927 (14.1%)
0.000
...2019-Mar. 2020; n (%)
1,784 (9.9%)
1,830 (10.2%)
-0.0100
1,784 (9.9%)
1,830 (10.2%)
-0.010
DMG - Age
...mean (sd)
67.43 (10.50)
67.84 (11.57)
-0.0371
65.64 (11.34)
66.01 (12.78)
-0.0306
66.30 (11.04)
66.68 (12.35)
-0.032
...median [IQR]
68.00 [60.00, 75.00]
69.00 [60.00, 76.00]
-0.0905
64.00 [58.00, 74.00]
65.00 [57.00, 76.00]
-0.0828
65.47 (11.04)
66.47 (12.35)
-0.085
DMG - Gender
...Male; n (%)
6,330 (35.1%)
6,304 (35.0%)
0.0021
12,025 (38.6%)
12,000 (38.6%)
0.0000
18,355 (37.4%)
18,304 (37.2%)
0.004
...Female; n (%)
11,687 (64.9%)
11,713 (65.0%)
-0.0021
19,097 (61.4%)
19,122 (61.4%)
0.0000
30,784 (62.6%)
30,835 (62.8%)
-0.004
DMG - Geographic region 
...Northeast; n (%)
1,731 (9.6%)
1,705 (9.5%)
0.0034
4,713 (15.1%)
4,752 (15.3%)
-0.0056
6,444 (13.1%)
6,457 (13.1%)
0.000
...South; n (%)
8,144 (45.2%)
8,102 (45.0%)
0.0040
11,758 (37.8%)
11,766 (37.8%)
0.0000
19,902 (40.5%)
19,868 (40.4%)
0.002
...North Central; n (%)
3,811 (21.2%)
3,855 (21.4%)
-0.0049
10,606 (34.1%)
10,593 (34.0%)
0.0021
14,417 (29.3%)
14,448 (29.4%)
-0.002
...West; n (%)
4,331 (24.0%)
4,355 (24.2%)
-0.0047
4,045 (13.0%)
4,011 (12.9%)
0.0030
8,376 (17.0%)
8,366 (17.0%)
0.000
DRS - Combined comorbidity score, 180 days 
...mean (sd)
1.37 (1.71)
1.38 (1.78)
-0.0057
1.10 (1.45)
1.10 (1.52)
0.0000
1.20 (1.55)
1.20 (1.62)
0.000
...median [IQR]
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
0.0000
1.00 [0.00, 2.00]
1.00 [0.00, 2.00]
0.0000
1.00 (1.55)
1.00 (1.62)
0.000
DRS - Frailty Score: Empirical Version (mean)
...mean (sd)
0.18 (0.06)
0.18 (0.06)
0.0000
0.17 (0.05)
0.17 (0.06)
0.0000
0.17 (0.05)
0.17 (0.06)
0.000
...median [IQR]
0.17 [0.14, 0.21]
0.17 [0.14, 0.21]
0.0000
0.16 [0.13, 0.19]
0.15 [0.13, 0.19]
0.1811
0.16 (0.05)
0.16 (0.06)
0.000
PLM - Smoking ; n (%)
4,968 (27.6%)
4,844 (26.9%)
0.0157
4,977 (16.0%)
4,803 (15.4%)
0.0165
9,945 (20.2%)
9,647 (19.6%)
0.015
PLM - Pneumonia ; n (%)
1,122 (6.2%)
1,104 (6.1%)
0.0042
2,335 (7.5%)
2,288 (7.4%)
0.0038
3,457 (7.0%)
3,392 (6.9%)
0.004
PLM - Oxygen usage; n (%)
1,135 (6.3%)
1,127 (6.3%)
0.0000
2,474 (7.9%)
2,436 (7.8%)
0.0037
3,609 (7.3%)
3,563 (7.3%)
0.000
PLM - Respiratory arrest/dependence on oxygen ; n (%)
452 (2.5%)
452 (2.5%)
0.0000
791 (2.5%)
735 (2.4%)
0.0065
1,243 (2.5%)
1,187 (2.4%)
0.006
PLM - CiPAP/BiPAP use; n (%)
706 (3.9%)
715 (4.0%)
-0.0051
1,569 (5.0%)
1,544 (5.0%)
0.0000
2,275 (4.6%)
2,259 (4.6%)
0.000
PLM - Pulmonary rehabilitation ; n (%)*
49 (0.3%)
36 (0.2%)
0.0200
99 (0.3%)
78 (0.3%)
0.0000
148 (0.3%)
114 (0.2%)
0.020
PLM - Moderate COPD exacerbation - [Count with 365 to 181 days before CED]*
...mean (sd)
1.27 (2.69)
1.30 (2.75)
-0.0110
0.98 (2.17)
0.97 (2.04)
0.0047
1.09 (2.37)
1.09 (2.33)
0.000
...median [IQR]
0.22 [0.00, 1.35]
0.27 [0.00, 1.40]
-0.0184
0.01 [0.00, 1.00]
0.05 [0.00, 1.00]
-0.0190
0.09 (2.37)
0.13 (2.33)
-0.017
PLM - Moderate COPD exacerbation - [Count 180 to 31 days before CED]*
...mean (sd)
0.86 (1.93)
0.82 (1.84)
0.0212
0.63 (1.44)
0.62 (1.42)
0.0070
0.71 (1.64)
0.69 (1.59)
0.012
...median [IQR]
0.00 [0.00, 0.95]
0.00 [0.00, 0.93]
0.0000
0.00 [0.00, 0.75]
0.00 [0.00, 0.75]
0.0000
0.00 (1.64)
0.00 (1.59)
0.000
PLM - Moderate COPD exacerbation - [Count with 30 days to CED]*
...mean (sd)
0.02 (0.10)
0.01 (0.09)
0.1051
0.01 (0.08)
0.01 (0.08)
0.0000
0.01 (0.09)
0.01 (0.08)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.09)
0.00 (0.08)
0.000
PLM - Moderate exacerbations >=1 in 365 days before CED; n (%)
12,493 (69.3%)
12,555 (69.7%)
-0.0087
19,559 (62.8%)
19,638 (63.1%)
-0.0062
32,052 (65.2%)
32,193 (65.5%)
-0.006
PLM - Moderate exacerbations >=2 in 365 days before CED ; n (%)
7,747 (43.0%)
7,755 (43.0%)
0.0000
11,085 (35.6%)
11,239 (36.1%)
-0.0104
18,832 (38.3%)
18,994 (38.7%)
-0.008
PLM - Severe COPD exacerbation - [Count with 365 to 181 days before CED] *
...mean (sd)
0.03 (0.18)
0.03 (0.18)
0.0000
0.05 (0.21)
0.05 (0.21)
0.0000
0.04 (0.20)
0.04 (0.20)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.20)
0.00 (0.20)
0.000
PLM - Severe COPD exacerbation - [Count with 180 to 31 days before CED] *
...mean (sd)
0.02 (0.14)
0.02 (0.13)
0.0000
0.03 (0.15)
0.03 (0.15)
0.0000
0.03 (0.15)
0.03 (0.14)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.15)
0.00 (0.14)
0.000
PLM - Severe COPD exacerbation - [Count with 30 days lookback]  *
...mean (sd)
0.00 (0.01)
0.00 (0.01)
0.0000
0.00 (0.01)
0.00 (0.01)
0.0000
0.00 (0.01)
0.00 (0.01)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.01)
0.00 (0.01)
0.000
PLM - Severe exacerbations >=1 in 365 days before CED; n (%)
1,038 (5.8%)
1,015 (5.6%)
0.0086
2,595 (8.3%)
2,650 (8.5%)
-0.0072
3,633 (7.4%)
3,665 (7.5%)
-0.004
PLM - Severe exacerbations >=2 in 365 days before CED ; n (%)
93 (0.5%)
86 (0.5%)
0.0000
198 (0.6%)
198 (0.6%)
0.0000
291 (0.6%)
284 (0.6%)
0.000
PLM - GOLD C/D Status ; n (%)
5,385 (29.9%)
5,395 (29.9%)
0.0000
9,771 (31.4%)
9,873 (31.7%)
-0.0065
15,156 (30.8%)
15,268 (31.1%)
-0.006
PRX - LABA only ; n (%)
93 (0.5%)
99 (0.5%)
0.0000
348 (1.1%)
332 (1.1%)
0.0000
441 (0.9%)
431 (0.9%)
0.000
PRX - LAMA (except tiotropium) inhalers; n (%)
79 (0.4%)
129 (0.7%)
-0.0406
104 (0.3%)
160 (0.5%)
-0.0317
183 (0.4%)
289 (0.6%)
-0.028
PRX - ICS only inhalers ; n (%)
2,225 (12.3%)
2,173 (12.1%)
0.0061
5,212 (16.7%)
5,163 (16.6%)
0.0027
7,437 (15.1%)
7,336 (14.9%)
0.006
PRX - LABA/LAMA inhaler use ; n (%)
114 (0.6%)
80 (0.4%)
0.0284
56 (0.2%)
42 (0.1%)
0.0258
170 (0.3%)
122 (0.2%)
0.020
PRX - Other LABA/ICS combination  ; n (%)
916 (5.1%)
892 (5.0%)
0.0046
1,495 (4.8%)
1,469 (4.7%)
0.0047
2,411 (4.9%)
2,361 (4.8%)
0.005
PRX - COPD Maintenance therapy inhalers; n (%)
1,183 (6.6%)
1,169 (6.5%)
0.0040
1,729 (5.6%)
1,698 (5.5%)
0.0044
2,912 (5.9%)
2,867 (5.8%)
0.004
PRX - SAMA inhaler use; n (%)
656 (3.6%)
654 (3.6%)
0.0000
1,405 (4.5%)
1,431 (4.6%)
-0.0048
2,061 (4.2%)
2,085 (4.2%)
0.000
PRX - SABA use; n (%)
8,121 (45.1%)
8,083 (44.9%)
0.0040
13,827 (44.4%)
13,671 (43.9%)
0.0101
21,948 (44.7%)
21,754 (44.3%)
0.008
PRX - SABA/SAMA use; n (%)
2,035 (11.3%)
2,140 (11.9%)
-0.0187
4,133 (13.3%)
4,220 (13.6%)
-0.0088
6,168 (12.6%)
6,360 (12.9%)
-0.009
PRX - Antibiotics treatment (180 days to 31 days before CED); n (%)
6,629 (36.8%)
6,636 (36.8%)
0.0000
12,467 (40.1%)
12,337 (39.6%)
0.0102
19,096 (38.9%)
18,973 (38.6%)
0.006
PRX - Antibiotics treatment (30 days to CED); n (%)
2,690 (14.9%)
2,627 (14.6%)
0.0085
5,514 (17.7%)
5,441 (17.5%)
0.0053
8,204 (16.7%)
8,068 (16.4%)
0.008
PRX - Systemic Corticosteroids (with CPT) use (180 to 31 days before CED); n (%)
5,612 (31.1%)
5,577 (31.0%)
0.0022
9,580 (30.8%)
9,597 (30.8%)
0.0000
15,192 (30.9%)
15,174 (30.9%)
0.000
OPTUM
MARKETSCAN
POOLED
PS MATCHED
Appendix B

PRX - Systemic Corticosteroids (with CPT) use (30 days to CED); n (%)
1,016 (5.6%)
940 (5.2%)
0.0177
2,352 (7.6%)
2,284 (7.3%)
0.0114
3,368 (6.9%)
3,224 (6.6%)
0.012
PRX - Roflumilast; n (%) *
40 (0.2%)
31 (0.2%)
0.0000
102 (0.3%)
53 (0.2%)
0.0200
142 (0.3%)
084 (0.2%)
0.020
CVD - Unstable angina/MI; n (%)
468 (2.6%)
464 (2.6%)
0.0000
596 (1.9%)
598 (1.9%)
0.0000
1,064 (2.2%)
1,062 (2.2%)
0.000
CVD - Stable Angina  ; n (%)
318 (1.8%)
314 (1.7%)
0.0076
482 (1.5%)
476 (1.5%)
0.0000
800 (1.6%)
790 (1.6%)
0.000
CVD - Any Heart failure (HF) ; n (%)
1,108 (6.1%)
1,131 (6.3%)
-0.0083
1,797 (5.8%)
1,807 (5.8%)
0.0000
2,905 (5.9%)
2,938 (6.0%)
-0.004
CVD - Atrial fibrillation; n (%)
911 (5.1%)
911 (5.1%)
0.0000
1,480 (4.8%)
1,488 (4.8%)
0.0000
2,391 (4.9%)
2,399 (4.9%)
0.000
CVD - Other dysrythmias   ; n (%)*
1,256 (7.0%)
1,324 (7.3%)
-0.0116
1,788 (5.7%)
1,841 (5.9%)
-0.0086
3,044 (6.2%)
3,165 (6.4%)
-0.008
CVD - Valve disorder   ; n (%)
231 (1.3%)
232 (1.3%)
0.0000
289 (0.9%)
283 (0.9%)
0.0000
520 (1.1%)
515 (1.0%)
0.010
CVD - Implantable cardioverter defibrillator  ; n (%)*
51 (0.3%)
59 (0.3%)
0.0000
94 (0.3%)
67 (0.2%)
0.0200
145 (0.3%)
126 (0.3%)
0.000
CVD - CABG/PCI; n (%)
407 (2.3%)
400 (2.2%)
0.0067
375 (1.2%)
359 (1.2%)
0.0000
782 (1.6%)
759 (1.5%)
0.008
CVD - Coronary atherosclerosis and other forms of chronic ischemic heart disease; n (%)
2,082 (11.6%)
2,082 (11.6%)
0.0000
3,397 (10.9%)
3,423 (11.0%)
-0.0032
5,479 (11.2%)
5,505 (11.2%)
0.000
CVD - Stroke/TIA  ; n (%)
512 (2.8%)
525 (2.9%)
-0.0060
808 (2.6%)
814 (2.6%)
0.0000
1,320 (2.7%)
1,339 (2.7%)
0.000
CVD - Peripheral Vascular Disease (PVD) or PVD Surgery; n (%)
1,333 (7.4%)
1,330 (7.4%)
0.0000
1,482 (4.8%)
1,478 (4.7%)
0.0047
2,815 (5.7%)
2,808 (5.7%)
0.000
CVD - Hyperlipidemia  ; n (%)
7,804 (43.3%)
7,866 (43.7%)
-0.0081
8,374 (26.9%)
8,401 (27.0%)
-0.0023
16,178 (32.9%)
16,267 (33.1%)
-0.004
CVD - Hypertension; n (%)
9,269 (51.4%)
9,370 (52.0%)
-0.0120
11,614 (37.3%)
11,709 (37.6%)
-0.0062
20,883 (42.5%)
21,079 (42.9%)
-0.008
CRX - ACEi or ARB; n (%)
6,749 (37.5%)
6,860 (38.1%)
-0.0124
11,265 (36.2%)
11,481 (36.9%)
-0.0145
18,014 (36.7%)
18,341 (37.3%)
-0.012
CRX - Mineralocorticoid receptor antagonist  ; n (%)
268 (1.5%)
300 (1.7%)
-0.0159
654 (2.1%)
655 (2.1%)
0.0000
922 (1.9%)
955 (1.9%)
0.000
CRX - Loop or Thiazide diuretics; n (%)
3,888 (21.6%)
3,980 (22.1%)
-0.0121
7,188 (23.1%)
7,276 (23.4%)
-0.0071
11,076 (22.5%)
11,256 (22.9%)
-0.010
CRX - Statins and other lipid lowering agents; n (%)
7,327 (40.7%)
7,417 (41.2%)
-0.0102
12,165 (39.1%)
12,317 (39.6%)
-0.0102
19,492 (39.7%)
19,734 (40.2%)
-0.010
CRX - CCB and other antihypertensives; n (%)
3,956 (22.0%)
4,018 (22.3%)
-0.0072
6,868 (22.1%)
6,911 (22.2%)
-0.0024
10,824 (22.0%)
10,929 (22.2%)
-0.005
CRX - Digoxin   ; n (%)*
279 (1.5%)
299 (1.7%)
-0.0159
804 (2.6%)
874 (2.8%)
-0.0123
1,083 (2.2%)
1,173 (2.4%)
-0.013
CRX - Nitrates; n (%)*
585 (3.2%)
585 (3.2%)
0.0000
1,392 (4.5%)
1,445 (4.6%)
-0.0048
1,977 (4.0%)
2,030 (4.1%)
-0.005
OCM - Type 1 or 2 DM; n (%)
3,731 (20.7%)
3,818 (21.2%)
-0.0123
5,268 (16.9%)
5,288 (17.0%)
-0.0027
8,999 (18.3%)
9,106 (18.5%)
-0.005
OCM - Occurrence of Diabetic retinopathy/nephropathy/neuropathy; n (%)*
1,023 (5.7%)
1,174 (6.5%)
-0.0334
914 (2.9%)
942 (3.0%)
-0.0059
1,937 (3.9%)
2,116 (4.3%)
-0.020
OCM - Hypertensive nephropathy; n (%)*
557 (3.1%)
600 (3.3%)
-0.0114
379 (1.2%)
377 (1.2%)
0.0000
936 (1.9%)
977 (2.0%)
-0.007
OCM - Hypotension  ; n (%)*
300 (1.7%)
292 (1.6%)
0.0079
389 (1.2%)
353 (1.1%)
0.0094
689 (1.4%)
645 (1.3%)
0.009
OCM - Hyperkalemia ; n (%)*
170 (0.9%)
191 (1.1%)
-0.0201
185 (0.6%)
170 (0.5%)
0.0135
355 (0.7%)
361 (0.7%)
0.000
OCM - CKD II, III, or IV; n (%)
994 (5.5%)
1,011 (5.6%)
-0.0044
565 (1.8%)
578 (1.9%)
-0.0074
1,559 (3.2%)
1,589 (3.2%)
0.000
OCM - HD/PD/ESRD; n (%)*
60 (0.3%)
63 (0.3%)
0.0000
129 (0.4%)
161 (0.5%)
-0.0149
189 (0.4%)
224 (0.5%)
-0.015
OCM - Osteoporosis; n (%)
2,105 (11.7%)
2,099 (11.7%)
0.0000
3,085 (9.9%)
3,127 (10.0%)
-0.0033
5,190 (10.6%)
5,226 (10.6%)
0.000
OCM - Sleep apnea ; n (%)
1,533 (8.5%)
1,510 (8.4%)
0.0036
2,639 (8.5%)
2,612 (8.4%)
0.0036
4,172 (8.5%)
4,122 (8.4%)
0.004
OCM - Fractures  ; n (%)
792 (4.4%)
795 (4.4%)
0.0000
1,410 (4.5%)
1,453 (4.7%)
-0.0095
2,202 (4.5%)
2,248 (4.6%)
-0.005
OCM - Other Arthritis, Arthropathies and Musculoskeletal Pain ; n (%)
6,547 (36.3%)
6,597 (36.6%)
-0.0062
9,534 (30.6%)
9,658 (31.0%)
-0.0087
16,081 (32.7%)
16,255 (33.1%)
-0.009
OCM - Dorsopathies; n (%)
5,053 (28.0%)
5,104 (28.3%)
-0.0067
7,003 (22.5%)
7,086 (22.8%)
-0.0072
12,056 (24.5%)
12,190 (24.8%)
-0.007
OCM - Gout (acute/chronic) ; n (%)*
121 (0.7%)
143 (0.8%)
-0.0116
238 (0.8%)
227 (0.7%)
0.0116
359 (0.7%)
370 (0.8%)
-0.012
OCM - Hyperthyroidism  ; n (%)*
121 (0.7%)
107 (0.6%)
0.0124
145 (0.5%)
142 (0.5%)
0.0000
266 (0.5%)
249 (0.5%)
0.000
OCM - Hypothyroidism ; n (%)*
1,760 (9.8%)
1,783 (9.9%)
-0.0034
2,214 (7.1%)
2,255 (7.2%)
-0.0039
3,974 (8.1%)
4,038 (8.2%)
-0.004
OCM - VTE ; n (%)*
333 (1.8%)
337 (1.9%)
-0.0074
570 (1.8%)
583 (1.9%)
-0.0074
903 (1.8%)
920 (1.9%)
-0.007
OCM - GERD ; n (%)
2,541 (14.1%)
2,518 (14.0%)
0.0029
2,368 (7.6%)
2,363 (7.6%)
0.0000
4,909 (10.0%)
4,881 (9.9%)
0.003
OCM - Cancer   ; n (%)
1,869 (10.4%)
1,909 (10.6%)
-0.0065
2,579 (8.3%)
2,626 (8.4%)
-0.0036
4,448 (9.1%)
4,535 (9.2%)
-0.003
OCM - Hypovolemia/volume depletion ; n (%)*
383 (2.1%)
404 (2.2%)
-0.0069
523 (1.7%)
558 (1.8%)
-0.0076
906 (1.8%)
962 (2.0%)
-0.015
OCM - Anemia   ; n (%)
1,830 (10.2%)
1,853 (10.3%)
-0.0033
2,414 (7.8%)
2,460 (7.9%)
-0.0037
4,244 (8.6%)
4,313 (8.8%)
-0.007
OCM - Dementia  ; n (%)*
639 (3.5%)
763 (4.2%)
-0.0364
751 (2.4%)
916 (2.9%)
-0.0311
1,390 (2.8%)
1,679 (3.4%)
-0.035
OCM - Depression ; n (%)
2,800 (15.5%)
2,815 (15.6%)
-0.0028
2,980 (9.6%)
2,938 (9.4%)
0.0068
5,780 (11.8%)
5,753 (11.7%)
0.003
ORX - Metformin; n (%)*
1,839 (10.2%)
1,854 (10.3%)
-0.0033
2,684 (8.6%)
2,719 (8.7%)
-0.0036
4,523 (9.2%)
4,573 (9.3%)
-0.003
ORX - 1st and 2nd Generation SUs   ; n (%)
896 (5.0%)
922 (5.1%)
-0.0046
1,594 (5.1%)
1,545 (5.0%)
0.0046
2,490 (5.1%)
2,467 (5.0%)
0.005
ORX - Insulins ; n (%)
755 (4.2%)
776 (4.3%)
-0.0050
1,328 (4.3%)
1,333 (4.3%)
0.0000
2,083 (4.2%)
2,109 (4.3%)
-0.005
ORX - Other antidiabetic medications use; n (%)
683 (3.8%)
662 (3.7%)
0.0053
1,486 (4.8%)
1,481 (4.8%)
0.0000
2,169 (4.4%)
2,143 (4.4%)
0.000
ORX - PPIs or H2RAs use; n (%)*
4,194 (23.3%)
4,378 (24.3%)
-0.0235
6,598 (21.2%)
6,855 (22.0%)
-0.0194
10,792 (22.0%)
11,233 (22.9%)
-0.022
ORX - NSAIDs ; n (%)*
2,930 (16.3%)
3,002 (16.7%)
-0.0108
5,255 (16.9%)
5,441 (17.5%)
-0.0159
8,185 (16.7%)
8,443 (17.2%)
-0.013
ORX - Use of opioids  ; n (%)*
6,320 (35.1%)
6,310 (35.0%)
0.0021
11,650 (37.4%)
11,206 (36.0%)
0.0290
17,970 (36.6%)
17,516 (35.6%)
0.021
ORX - Use of antipsychotics   ; n (%)*
815 (4.5%)
809 (4.5%)
0.0000
1,220 (3.9%)
1,219 (3.9%)
0.0000
2,035 (4.1%)
2,028 (4.1%)
0.000
ORX - Use of antidepressants  ; n (%)
6,448 (35.8%)
6,479 (36.0%)
-0.0042
10,791 (34.7%)
10,840 (34.8%)
-0.0021
17,239 (35.1%)
17,319 (35.2%)
-0.002
ORX - Use of anxiolytics/hypnotics ; n (%)
1,758 (9.8%)
1,771 (9.8%)
0.0000
3,350 (10.8%)
3,360 (10.8%)
0.0000
5,108 (10.4%)
5,131 (10.4%)
0.000
ORX - Use of anticonvulsants  ; n (%)*
3,002 (16.7%)
2,999 (16.6%)
0.0027
4,192 (13.5%)
4,186 (13.5%)
0.0000
7,194 (14.6%)
7,185 (14.6%)
0.000
ORX - Use of Benzodiazepines ; n (%)*
3,043 (16.9%)
2,933 (16.3%)
0.0161
7,066 (22.7%)
6,761 (21.7%)
0.0241
10,109 (20.6%)
9,694 (19.7%)
0.022
ORX - Use of dementia meds  ; n (%)*
451 (2.5%)
528 (2.9%)
-0.0247
744 (2.4%)
906 (2.9%)
-0.0311
1,195 (2.4%)
1,434 (2.9%)
-0.031
ORX - Use of antiparkinsonian meds  ; n (%)*
686 (3.8%)
657 (3.6%)
0.0106
1,028 (3.3%)
1,055 (3.4%)
-0.0056
1,714 (3.5%)
1,712 (3.5%)
0.000
ORX - Use of oral anticoagulants   ; n (%)*
879 (4.9%)
891 (4.9%)
0.0000
1,774 (5.7%)
1,819 (5.8%)
-0.0043
2,653 (5.4%)
2,710 (5.5%)
-0.004
ORX - Use of antiplatelet agents ; n (%)*
1,174 (6.5%)
1,104 (6.1%)
0.0165
3,085 (9.9%)
2,922 (9.4%)
0.0169
4,259 (8.7%)
4,026 (8.2%)
0.018
LFS - Obesity; n (%)
1,298 (7.2%)
1,310 (7.3%)
-0.0039
1,289 (4.1%)
1,290 (4.1%)
0.0000
2,587 (5.3%)
2,600 (5.3%)
0.000
PFT - Spirometry test only; n (%)
3,180 (17.6%)
3,028 (16.8%)
0.0212
7,080 (22.7%)
6,932 (22.3%)
0.0096
10,260 (20.9%)
9,960 (20.3%)
0.015
PFT - Spirometry test only (Count - 180 days to 31 days before CED) *
...mean (sd)
0.18 (0.66)
0.18 (0.65)
0.0000
0.20 (0.64)
0.22 (0.65)
-0.0310
0.19 (0.65)
0.21 (0.65)
-0.031
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.65)
0.00 (0.65)
0.000
PFT - Spirometry test only (Count - 30 days to CED) *
Appendix B

...mean (sd)
0.14 (0.56)
0.11 (0.48)
0.0575
0.17 (0.55)
0.13 (0.47)
0.0782
0.16 (0.55)
0.12 (0.47)
0.078
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.55)
0.00 (0.47)
0.000
PFT - Lung volume, Diffuse capacity, pulmonary stress testing (any); n (%)
1,987 (11.0%)
1,910 (10.6%)
0.0129
3,084 (9.9%)
2,970 (9.5%)
0.0135
5,071 (10.3%)
4,880 (9.9%)
0.013
HCU - Pulmonologist visit (180 to 1 day before CED); n (%)
189 (1.0%)
182 (1.0%)
0.0000
5,646 (18.1%)
5,482 (17.6%)
0.0131
5,835 (11.9%)
5,664 (11.5%)
0.012
HCU - Pulmonologist visit on CED; n (%)
24 (0.1%)
24 (0.1%)
0.0000
949 (3.0%)
932 (3.0%)
0.0000
973 (2.0%)
956 (1.9%)
0.007
HCU - Pulmonologist visit (Number of during CAP) *
...mean (sd)
0.06 (0.94)
0.07 (0.94)
-0.0106
0.75 (2.21)
0.70 (2.11)
0.0231
0.50 (1.85)
0.47 (1.77)
0.017
...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 (1.85)
0.00 (1.77)
0.000
HCU - Number of Internal Medicine/Family Medicine Visits  
...mean (sd)
7.48 (11.28)
7.62 (11.09)
-0.0125
6.14 (9.32)
6.16 (9.74)
-0.0021
6.63 (10.08)
6.70 (10.26)
-0.007
...median [IQR]
4.00 [1.00, 10.00]
4.00 [1.00, 10.00]
0.0000
4.00 [1.00, 8.00]
3.00 [1.00, 8.00]
0.1049
4.00 (10.08)
3.37 (10.26)
0.062
HCU - Number of Cardiologist visits  
...mean (sd)
0.86 (3.19)
0.86 (2.82)
0.0000
0.79 (2.82)
0.79 (3.36)
0.0000
0.82 (2.96)
0.82 (3.17)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (2.96)
0.00 (3.17)
0.000
HCU - Number of Emergency Department (ED) visits v3 
...mean (sd)
0.46 (1.29)
0.47 (1.25)
-0.0079
0.17 (1.12)
0.16 (0.95)
0.0096
0.28 (1.19)
0.27 (1.07)
0.009
...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 (1.19)
0.00 (1.07)
0.000
HCU - Old hospitalization (-180 days to -31 days before CED)  ; n (%)
1,508 (8.4%)
1,514 (8.4%)
0.0000
4,137 (13.3%)
4,095 (13.2%)
0.0029
5,645 (11.5%)
5,609 (11.4%)
0.003
HCU - Recent hospitalization (-30 days to CED date)  ; n (%)
166 (0.9%)
166 (0.9%)
0.0000
532 (1.7%)
523 (1.7%)
0.0000
698 (1.4%)
689 (1.4%)
0.000
HCU - Number of hospitalizations during CAP  
...mean (sd)
0.11 (0.37)
0.11 (0.37)
0.0000
0.17 (0.43)
0.16 (0.43)
0.0233
0.15 (0.41)
0.14 (0.41)
0.024
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (0.41)
0.00 (0.41)
0.000
HCU - Blood eosinophilia or Serum IgE test order; n (%)*
85 (0.5%)
93 (0.5%)
0.0000
113 (0.4%)
136 (0.4%)
0.0000
198 (0.4%)
229 (0.5%)
-0.015
HCU - Pneumococcal vaccine; n (%)
2,119 (11.8%)
2,112 (11.7%)
0.0031
1,615 (5.2%)
1,601 (5.1%)
0.0045
3,734 (7.6%)
3,713 (7.6%)
0.000
HCU - Flu vaccine  ; n (%)
3,385 (18.8%)
3,370 (18.7%)
0.0026
3,684 (11.8%)
3,659 (11.8%)
0.0000
7,069 (14.4%)
7,029 (14.3%)
0.003
HCU - Bone mineral density  ; n (%)
795 (4.4%)
788 (4.4%)
0.0000
931 (3.0%)
953 (3.1%)
-0.0058
1,726 (3.5%)
1,741 (3.5%)
0.000
HCU - Pap smear ; n (%)
711 (3.9%)
707 (3.9%)
0.0000
1,429 (4.6%)
1,419 (4.6%)
0.0000
2,140 (4.4%)
2,126 (4.3%)
0.005
HCU - Mammogram  ; n (%)
2,274 (12.6%)
2,273 (12.6%)
0.0000
3,319 (10.7%)
3,340 (10.7%)
0.0000
5,593 (11.4%)
5,613 (11.4%)
0.000
HCU - Prostate exam for DRE  ; n (%)
542 (3.0%)
545 (3.0%)
0.0000
517 (1.7%)
509 (1.6%)
0.0079
1,059 (2.2%)
1,054 (2.1%)
0.007
HCU - Number of Echocardiogram  *
...mean (sd)
0.20 (1.27)
0.19 (1.21)
0.0081
0.23 (0.80)
0.23 (0.84)
0.0000
0.22 (1.00)
0.22 (0.99)
0.000
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (1.00)
0.00 (0.99)
0.000
HCU - Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy  ; n (%)
816 (4.5%)
808 (4.5%)
0.0000
1,609 (5.2%)
1,634 (5.3%)
-0.0045
2,425 (4.9%)
2,442 (5.0%)
-0.005
HCU - Number of Distinct Medication Prescriptions (not generalized to generics)  
...mean (sd)
20.27 (17.04)
20.34 (16.67)
-0.0042
19.34 (15.01)
19.39 (15.01)
-0.0033
19.68 (15.78)
19.74 (15.64)
-0.004
...median [IQR]
16.00 [8.00, 27.00]
16.00 [9.00, 27.00]
0.0000
16.00 [9.00, 26.00]
16.00 [9.00, 26.00]
0.0000
16.00 (15.78)
16.00 (15.64)
0.000
SES - Copay for pharmacy cost (charges in U.S. $)  
...mean (sd)
32.00 (38.05)
31.87 (35.15)
0.0035
25.66 (26.01)
25.75 (26.16)
-0.0035
27.98 (30.97)
27.99 (29.77)
0.000
...median [IQR]
23.60 [10.60, 40.25]
24.23 [10.04, 41.52]
-0.0172
20.26 [10.00, 34.37]
20.61 [9.80, 34.59]
-0.0134
21.48 (30.97)
21.94 (29.77)
-0.015
SES - Business type   
...Commercial; n (%)
5,963 (33.1%)
5,735 (31.8%)
0.0278
5,963 (33.1%)
5,735 (31.8%)
0.028
...Medicare; n (%)
12,054 (66.9%)
12,282 (68.2%)
-0.0278
12,054 (66.9%)
12,282 (68.2%)
-0.028
SES - Low income indicator  ; n (%)
3,483 (19.3%)
3,604 (20.0%)
-0.0176
3,483 (19.3%)
3,604 (20.0%)
-0.018
SES - Insurance Plan type   
...Comprehensive; n (%)
9,074 (29.2%)
9,146 (29.4%)
-0.0044
9,074 (29.2%)
9,146 (29.4%)
-0.004
...HMO; n (%)
3,810 (12.2%)
3,763 (12.1%)
0.0031
3,810 (12.2%)
3,763 (12.1%)
0.003
...PPO; n (%)
14,372 (46.2%)
14,423 (46.3%)
-0.0020
14,372 (46.2%)
14,423 (46.3%)
-0.002
...Others; n (%)
3,866 (12.4%)
3,790 (12.2%)
0.0061
3,866 (12.4%)
3,790 (12.2%)
0.006
___________
* Not included in PS model
Appendix B