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

Replication of the POET-COPD 
Trial in Healthcare Claims Data 
DUPLICATE POET-COPD 
August 10, 2021 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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1. RCT Details 
This section provides a high-level overview of 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 
Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD (POET-COPD trial) 
 
1.2 Intended aim(s) 
 
The objective of the study is to assess the efficacy and safety of tiotropium, a long-acting anticholinergic (muscarinic 
antagonist) drug (LAMA) compared to salmeterol, a long-acting beta agonist (LABA) in patients with chronic obstructive 
pulmonary disease (COPD) 
 
1.3 Primary endpoint for replication and RCT finding 
Time to first COPD exacerbation 
 
1.4 Required power for primary endpoint and noninferiority margin (if applicable) 
With a sample size of approximately 6800 patients (3400 in each arm), the trial will have 80% power to detect a 10% 
reduction in the risk of first exacerbation with tiotropium as compared with salmeterol, with a two-sided test for the null 
hypothesis of a hazard ratio of 1 at a significance level of 0.05 
 
1.5 Trial estimate 
HR = 0.83 (95% CI 0.77–0.90) comparing tiotropium to salmeterol (Vogelmeier et al., 2011, NEJM) 
 
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. 
 
 
3. Data Source(s) 
Optum Cliniformatics Data Mart, IBM MarketScan 

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4. Study 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 180 days before 
initiation of tiotropium or salmeterol inhalers (cohort entry date).  
5.2 Important steps for cohort formation 
New users (defined as no use in 180 days prior to index date) of an exposure and a comparator drug will be identified. 
5.2.1   Eligible cohort entry date 
Tiotropium inhaler was first approved by FDA for market availability on January 30, 2004, and salmeterol on September 15, 1998 
§
Optum: January 30, 2004 – March 31, 2020 (end of data availability is December 31, 2020 but excluded data
generated during COVID-19 pandemic)
§
Marketscan: January 30, 2004 – December 31, 2018 (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 Appendix A and are summarized in the flowcharts below. 

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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 
-78,723,324
612,235 
-199,335,696
868,212 
Excluded due to insufficient enrollment 
-87,210
525,025 
-98,266
769,946 
Excluded due to prior use of referent 
-22,073
502,952 
-52,587
717,359 
Excluded due to prior use of exposure 
-298,940
204,012 
-406,646
310,713 
Excluded because patient qualified in >1 exposure category 
-164
203,848 
-292
310,421 
Excluded based on Missing/Unknown Age 
0 
203,848 
0 
310,421 
Excluded based on Missing/Unknown Gender 
-37
203,811 
0 
310,421 
Excluded based on Inclusion #1 - Age >=40 years old 
-9,129
194,682 
-19,097
291,324 
Excluded based on Inclusion #2 - Diagnosis of COPD 
-35,444
159,238 
-78,651
212,673 
Excluded based on Inclusion #4 - History of at least 1 COPD Exacerbation within the past 
year 
-75,207
84,031 
-105,442
107,231 
Excluded based on Exclusion #2a - Asthma 
-10,054
73,977 
-8,159
99,072 
Excluded based on Exclusion #2b - Severe cardiovascular or pulmonary disorders_V2 
-8,122
65,855 
-8,509
90,563 
Excluded based on Exclusion #3 - Patients with any respiratory infection or COPD 
exacerbation in the 4 weeks prior to visit 1 
-12,040
53,815 
-14,085
76,478 
Excluded based on Exclusion #5 - Salmeterol, Tiotropium containing inhaler use within 180 
days* 
-4,157
49,658 
-7,817
68,661 
Final cohort 
49,658 
68,661 
* Additional exclusion criteria applied for replication 

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5 
6 
Variables  
6.1 Exposure-related variables: 
Study drug:  
The study exposure of interest is initiation of tiotropium (LAMA). Initiation will be defined by no use of inhaled tiotropium 
during the prior 180 days before treatment initiation (washout period). Patients are required to be incident users with 
respect both exposure groups.  
 
Comparator agents: 
Initiators of salmeterol inhaler defined as no use of inhaled salmeterol during the 180 days prior to index date 
 
6.2 Preliminary Covariates: 
§ Age 
§ Sex 
§ Combined Comorbidity Index (CCI), measured over the default baseline covariate assessment period of 180 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 (Appendix B).  
 
6.3 Outcome variables and study follow-up: 
 
6.3.1 
Outcome variables 
Effectiveness outcome variables of interest (definitions provided in Appendix A): 
§ Primary outcome: Time to first COPD exacerbation   
§ Secondary outcome:  
o All-cause death 
 

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Control outcomes of interest (control outcomes only serve to assess aspects of study validity but are not further 
interpreted): Pneumonia 
 
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 primary analysis, as it targets the relative hazard of outcomes on treatment.  
 
For the AT analysis, the follow-up will start the day after the initiation of tiotropium or salmeterol and will continue 
until the earliest date of the following events: 
§ The first occurrence of the outcome of interest, 
§ The date of end of continue registration in the database, 
§ End of the study period, 
§ 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 (tiotropium or salmeterol) + a 60-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 other LABA (excluding 
salmeterol), LAMA/LABA, LABA/ICS, and LAMA/LABA/ICS combination 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 365 days. 
 
7 Initial Feasibility Analysis  
Aetion report name: 
Optum- https://bwh-dope.aetion.com/projects/details/1730/rwrs/71650  
Marketscan- https://bwh-dope.aetion.com/projects/details/1732/rwrs/71648   

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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Date conducted: 5/6/2021 (old version), 6/17/2021 (current) – In the current version, we removed the additional exclusion 
criteria “LABA, LAMA, or any combinations containing those (except study drugs) - 14 days washout period,” which was applied in 
defining the cohort used in the old version. 
 
Complete Aetion feasibility analysis using age, sex, and CCI as the only covariates and the primary endpoint (Section 6.3.1) as the 
outcome.  
§ Complete study flowchart from Section 5.3 
§ Report patient characteristics by treatment group 
 
BEFORE MATCHING 
  
  
  
  
  
  
  
  
Optum 
Marketscan 
Variable 
Referent - 
Salmeterol 
Exposure - 
Tiotropium 
Difference 
Referent - 
Salmeterol 
Exposure - 
Tiotropium 
Difference 
Number of patients 
1,077 
48,581 
- (-, -) 
3,397 
65,264 
- (-, -) 
Age 
  
  
  
  
  
  
...mean (sd) 
69.31 (10.79) 
69.64 (9.85) 
-0.34 (-0.99, 
0.31) 
70.81 (10.79) 
68.26 (11.06) 
2.55 (2.18, 
2.92) 
...median [IQR] 
70.00 [62.00, 
77.50] 
70.00 [63.00, 
77.00] 
- (-, -) 
72.00 [63.00, 
79.00] 
68.00 [60.00, 
77.00] 
- (-, -) 
Gender  
  
  
  
  
  
  
...Male; n (%) 
511 (47.4%) 
21,601 (44.5%) 
3.0% (-0.1%, 
6.0%) 
1,566 (46.1%) 
31,139 (47.7%) 
-1.6% (-3.3%, 
0.1%) 
...Female; n (%) 
566 (52.6%) 
26,980 (55.5%) 
-3.0% (-6.0%, 
0.1%) 
1,831 (53.9%) 
34,125 (52.3%) 
1.6% (-0.1%, 
3.3%) 
Combined comorbidity 
score, 180 days 
  
  
  
  
  
  
...mean (sd) 
2.37 (2.54) 
2.59 (2.56) 
-0.22 (-0.37, -
0.06) 
1.75 (1.88) 
2.05 (2.14) 
-0.31 (-0.37, -
0.24) 
...median [IQR] 
2.00 [1.00, 3.00] 
2.00 [1.00, 4.00] 
- (-, -) 
1.00 [1.00, 3.00] 
1.00 [1.00, 3.00] 
- (-, -) 
 

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§ Report summary parameters of study population 
FEASIBILITY FOR STUDY OUTCOME 
  
Optum 
Marketscan 
Variable 
Value 
Value 
Number of patients in full cohort 
49,658 
68,661 
Number of patients dropped as incomplete cases 
0 
0 
Number of patients that did not begin follow-up 
57 
72 
Number of patients in analytic cohort 
49,601 
68,589 
Number of events 
11,400 
15,086 
Number of person-years 
16,485.60 
27,150.40 
Number of patients in group: Referent - Salmeterol 
1,073 
3,389 
Number of patients in group: Exposure - Tiotropium 
48,528 
65,200 
Risk per 1,000 patients 
229.83 
219.95 
Rate per 1,000 person-years 
691.51 
555.65 
 
§ Report median follow-up time by treatment group 
FOLLOW-UP TIME FOR STUDY OUTCOME 
Median Follow-Up Time (Days) [IQR] 
  
Optum 
Marketscan 
Patient Group 
Median 
Follow-Up Time 
(Days) [IQR] 
Median 
Follow-Up 
Time (Days) 
[IQR] 
Overall Patient Population 
88 [45, 140] 
88 [57, 148] 
Referent - Salmeterol 
88 [56, 148] 
88 [73, 148] 
Exposure - Tiotropium 
88 [45, 140] 
88 [56, 148] 

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§ Report reasons for censoring in the overall study population 
CENSORING REASONS FOR STUDY OUTCOME 
  
Optum 
Marketscan 
Overall 
49,601 
68,589 
Death 
911 (1.8%) 
299 (0.4%) 
Start of an additional exposure 
137 (0.3%) 
325 (0.5%) 
End of index exposure 
19,798 (39.9%) 
29,908 (43.6%) 
Specified date reached 
1,539 (3.1%) 
712 (1.0%) 
End of patient data 
0 (0.0%) 
0 (0.0%) 
End of patient enrollment 
3,174 (6.4%) 
7,894 (11.5%) 
Switch to other LABA, LAMA + LABA/LAMA combo + 
LAMA/LABA/ICS combo + NH admissions Occurred 
12,687 (25.6%) 
14,442 (21.1%) 
 
 
8 Initial Power Assessment 
 
Aetion report name: 
Optum- https://bwh-dope.aetion.com/projects/details/1730/rwrs/71651  
Marketscan- https://bwh-dope.aetion.com/projects/details/1732/rwrs/71649  
 
Date conducted: 5/4/2021 (old version), 6/17/2021 (current version) – In the current version, we removed the additional 
exclusion criteria “LABA, LAMA, or any combinations containing those (except study drugs) - 14 days washout period,” which was 
applied in defining the cohort used in the old version. 
 
In order to complete the initial power analysis, the dummy outcome of a 90-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. 

Effectiveness research with Real World Data to support FDA’s regulatory decision making 
 
 
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Optum 
Marketscan 
Pooled 
Number of people matched 
  
  
  
Reference 
1073.0 
3389.0 
4462.0 
Exposure 
1073.0 
3389.0 
4462.0 
  
  
  
  
Risk per 1,000 patients 
229.8 
220.0 
 -- 
Rate per 1,000 person-years 
691.5 
555.7 
  
  
  
  
  
N of events 
11,400 
15,086 
26,486 
N of patients (both groups) at Step 1 
49,658 
68,661 
118,319 
Risk per 1,000 patients 
229.57 
219.72 
223.85 
 
 
 
Superiority Analysis (Pooled)
Number of patients matched
Reference
4,462
Exposed
4,462
Risk per 1,000 patients
223.85
Desired HR from RCT
0.83
Alpha (2-sided)
0.05
Number of events expected
1997.6374
Power
0.986238897

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Superiority Analysis (Optum)
Number of patients matched
Reference
1,073
Exposed
1,073
Risk per 1,000 patients
229.57
Desired HR from RCT
0.83
Alpha (2-sided)
0.05
Number of events expected
492.65722
Power
0.542994909
Superiority Analysis (Marketscan)
Number of patients matched
Reference
3,389
Exposed
3,389
Risk per 1,000 patients
219.72
Desired HR from RCT
0.83
Alpha (2-sided)
0.05
Number of events expected
1489.26216
Power
0.949012649

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•
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: 
Date reviewed: 
Reasons for stopping 
analysis (if required): 
9. Balance Assessment
Optum- https://bwh-dope.aetion.com/projects/details/1730/rwrs/72136
Marketscan- https://bwh-dope.aetion.com/projects/details/1732/rwrs/72137
Date conducted: 7/6/2021 
After review of initial feasibility and power analyses, complete creation of the remaining covariates from Section 6.2. Again, using the 
dummy outcome of a 90-day gap in database enrollment, complete a 1:1 PS-matched analysis. The PS should include the complete 
list of covariates. 
•
Provide plot of PS distributions stratified by treatment group.
Note- Please refer to Appendix B.
•
Report covariate balance after matching.
Note- For Table 1, please refer to Appendix B.

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• Report reasons for censoring by treatment group. 
 
 
Overall 
Referent 
Exposure 
Dummy outcome 
0 (0%) 
0 (0%) 
0 (0%) 
Death 
104 (1.19%) 
44 (1.01%) 
60 (1.38%) 
Start of an additional exposure 
347 (3.98%) 
317 (7.27%) 
30 (0.69%) 
End of Index Exposure 
5,180 (59.43%) 
2,735 (62.76%) 
2,445 (56.1%) 
Specified date reached 
111 (1.27%) 
56 (1.28%) 
55 (1.26%) 
End of patient enrollment 
1,133 (13%) 
485 (11.13%) 
648 (14.87%) 
Switch to other LABA, LAMA + LABA/LAMA combo + 
LAMA/LABA/ICS combo + NH admissions Occurred 
1,841 (21.12%) 
721 (16.54%) 
1,120 (25.7%) 
 
• 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 [83, 159] 
123 [88, 214] 
Referent - Salmeterol 
88 [85, 154] 
125 [88, 195] 
Exposure - Tiotropium 
88 [83, 169] 
122 [88, 226] 
 
 
• Report overall risk of the primary outcome. 
  
Optum  
MarketScan 
Pooled 
Risk per 1,000 patients 
229.57 
219.72 
223.85 
 
 
 
 
 

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10. Final Power Assessment 
 
Date conducted: 7/9/2021 
 
• Re-calculate power in the appropriate excel table, using the revised number of matched patients from the PS-match in Section 9. 
All other parameters in the table should be the same as in Section 8. 
 
 
 
Superiority Analysis (Pooled)
Number of patients matched
Reference
4,358
Exposed
4,358
Risk per 1,000 patients
223.85
Desired HR from RCT
0.83
Alpha (2-sided)
0.05
Number of events expected
1951.0766
Power
0.984427581

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Superiority Analysis (Optum)
Number of patients matched
Reference
1,073
Exposed
1,073
Risk per 1,000 patients
229.57
Desired HR from RCT
0.83
Alpha (2-sided)
0.05
Number of events expected
492.65722
Power
0.542994909
Superiority Analysis (Marketscan)
Number of patients matched
Reference
3,285
Exposed
3,285
Risk per 1,000 patients
219.72
Desired HR from RCT
0.83
Alpha (2-sided)
0.05
Number of events expected
1443.5604
Power
0.942918994

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• Stop analyses until balance and final power assessment are reviewed by primary investigators, FDA, and assigned members of 
advisory board. 
Reviewed by PI: 
Shirley Wang 
Date reviewed: 
 
Reviewed by FDA: 
 
Date reviewed: 
 
Reasons for stopping 
analysis (if required): 
 
 
 
 

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Appendix A: COPD Exacerbation (primary outcome), All-cause mortality (secondary outcome) 
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 = EXPIRED
• 21 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 22 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 23 = EXPIRED TO BE DEFINED AT STATE LEVEL
• 24 = EXPIRED TO BE DEFINED AT STATE LEVEL

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• 25 = EXPIRED TO BE DEFINED AT STATE LEVEL 
• 26 = EXPIRED TO BE DEFINED AT STATE LEVEL 
• 27 = EXPIRED TO BE DEFINED AT STATE LEVEL 
• 28 = EXPIRED TO BE DEFINED AT STATE LEVEL 
• 29 = EXPIRED TO BE DEFINED AT STATE LEVEL 
• 40 = EXPIRED AT HOME (HOSPICE) 
• 41 = EXPIRED IN A MEDICAL FACILITY (HOSPICE) 
• 42 = EXPIRED - PLACE UNKNOWN (HOSPICE) 
 
Marketscan- Inpatient 
• 20 - Died 
• 22 - Died 
• 23 - Died 
• 24 - Died 
• 25 - Died 
• 26 - Died 
• 27 - Died 
• 28 - Died 
• 29 - Died 
• 40 - Other died status or Expired at home (Hospice claims only) (depends on year) 
• 41 - Other died status or Expired in medical facility (Hospice claims only) (depends on year) 
• 42 - 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) 

#
POET-COPD 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/folders/1W
D618wrywYjEaXzfLTcuK-VCcnb6b-gV 
Criteria
Adequate mapping in claims
Tiotropium 18 mcg once daily vs. Salmeterol hydrofluoroalkane 50 mcg twice daily
Aim: To evaluate the effect of tiotropium compared to salmeterol on exacerbations of COPD
Tiotropium (Spiriva) vs. Salmeterol (Serevent)
Exposure: Tiotropium  Reference: Salmeterol
Intermediate mapping in claims
Poor mapping or cannot be 
measured in claims 
Primary endpoint: Time to first COPD exacerbation within 1 year
Measured 1 day after drug initiation in primary diagnosis position and inpatient care 
setting:
COPD
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 and inpatient and outpatient 
care setting AND steriod use within 14 days:
COPD
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 years of age or older
Measured on the day of drug initiation
Age >= 40
2
Diagnosis of COPD
Measured from the start of all available data to 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
3
Post-bronchodilator FEV1 ≤ 70% of predicted normal and FEV1 ≤ 70% of FVC and a smoking history of ≥ 10 pack years
4
History of at least 1 COPD exacerbation within the past year requiring treatment with antibiotics and/or systemic steriods and/or 
requiring hospitalization
Measured 365 days prior to 28 days prior to drug initiation in primary diagnosis position 
and inpatient care setting:
COPD
ICD-9 Diagnosis: 491..x, 492.x, 496.0
ICD-10 Diagnosis: J41, J42.x, J43.x, J44.x
OR
Measured 365 days prior to 28 days prior to drug initiation in any diagnosis position  and 
inpatient and outpatient care setting AND steriod use within 14 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
1
Patients with significant diseases other than COPD that would preclude participation in the trial or interpretation of the results 
are excluded
2
Patients with a current diagnosis of asthma, severe cardiovascular disorders and use of systemic corticosteroid medication at 
unstable doses
Measured 180 days prior to and including the day of drug initiation in any diagnosis
position and in the inpatient and outpatient care setting:
Asthma (3 Diagnosis within 180 days)
ICD-9 Diagnosis: 493.x
ICD-10 Diagnosis: J45.x
Measured 365 days prior to and including the day of drug initiation in any diagnosis 
position and in the inpatient and outpatient care setting:
Heart Transplantation
ICD-9 Diagnosis: V42.1, V49.83, 996.83 
ICD-10 Diagnosis: Z94.1, Z76.82, T86.20, T86.21, T86.22
ICD-9 Procedure: 33.6, 37.51
ICD-10 Procedure: 02YA0Z0, 02YA0Z1, 02YA0Z2
CPT-4 Code: 33935, 33945
LVAD/Implantable Heart
ICD-9 Diagnosis: V43.2x 
ICD-10 Diagnosis: Z95.811, Z95.812
ICD-9 Procedure: 37.60, 37.66 
ICD-10 Procedure: 02HA0RS, 02HA3RS, 02HA4RS, 5A02116, 5A02216, 02HA0QZ, 02HA3QZ, 
02HA4QZ
CPT-4 Code: 33975, 33976, 33979, 33981 - 33983, 33977, 33978, 33980
3
Patients with any respiratory infection or COPD exacerbation* in the 4 weeks prior to the screening Visit (Visit 1) or during the 
run-in period 
* - Measurement included in Inclusion # 4
Measured 28 days prior to and including the day of drug initiation in prescription claims:
Acute Resiratory Infections
ICD-9 Diagnosis: 460 - 466.x
ICD10 Diagnosis: J00 - J06.x, J20.x  - J22.x
Pneumonia and Influenza
ICD-9 Diagnosis: 480.x - 488.x
ICD-10 Diagnosis: J09.x  - J18.x
COPD (Inpatient, Primary)
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
Corticosteroid systemic administration and/or prescription
- Prednisone
- Prednisolone
4
Exclude use of Salmeterol, tiotropium 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
ADVAIR DISKUS
ADVAIR HFA
WIXELA INHUB
OR 
Generic name
TIOTROPIUM BROMIDE/OLODATEROL HCL
FLUTICASONE PROPIONATE/SALMETEROL XINAFOATE
Trial details - Intended S with label change - 2 weeks run-in
EXPOSURE vs. COMPARISON
PRIMARY OUTCOME
Tiotropium 18 mcg once daily vs. Salmeterol hydroflouroalkane 50 mcg twice daily
EXCLUSION CRITERIA
Appendix A

AFTER PS MATCHING
Optum
MarketScan
BEFORE PS MATCHING
The c-statistics for the propensity score model, pre-matching was 0.783
The postmatching c-statistic was 0.581 .
The c-statistics for the propensity score model, pre-matching was 0.833.
The postmatching c-statistic was 0.547.
Appendix B

Referent - Salmeterol
Exposure - Tiotropium
Referent - Salmeterol
Exposure - Tiotropium
Referent - Salmeterol
Exposure - Tiotropium
Number of patients
1,077
48,581
3,397
65,264
4,474
113,845
Calendar Time - Year of Initiation (2004 - 2020)
...2004-2006; n (%)
298 (27.7%)
2,777 (5.7%)
0.6173
1,955 (57.6%)
9,783 (15.0%)
0.9881
2,253 (50.4%)
12,560 (11.0%)
0.945
...2007-2008; n (%)
104 (9.7%)
3,944 (8.1%)
0.0562
404 (11.9%)
9,109 (14.0%)
-0.0626
508 (11.4%)
13,053 (11.5%)
-0.003
...2009-2011; n (%)
172 (16.0%)
8,025 (16.5%)
-0.0136
545 (16.0%)
17,106 (26.2%)
-0.2520
717 (16.0%)
25,131 (22.1%)
-0.156
...2012-2015; n (%)
157 (14.6%)
13,877 (28.6%)
-0.3452
316 (9.3%)
20,917 (32.0%)
-0.5842
473 (10.6%)
34,794 (30.6%)
-0.510
...2016-2018; n (%)
251 (23.3%)
13,687 (28.2%)
-0.1122
177 (5.2%)
8,349 (12.8%)
-0.2679
428 (9.6%)
22,036 (19.4%)
-0.281
...2019-Mar. 2020; n (%)
95 (8.8%)
6,271 (12.9%)
-0.1321
95 (8.8%)
6,271 (12.9%)
-0.132
DMG - Age
...mean (sd)
69.31 (10.79)
69.64 (9.85)
-0.0319
70.81 (10.79)
68.26 (11.06)
0.2334
70.45 (10.79)
68.85 (10.56)
0.150
...median [IQR]
70.00 [62.00, 77.50]
70.00 [63.00, 77.00]
0.0000
72.00 [63.00, 79.00]
68.00 [60.00, 77.00]
0.3661
71.52 (10.79)
68.85 (10.56)
0.250
DMG - Gender
...Male; n (%)
511 (47.4%)
21,601 (44.5%)
0.0582
1,566 (46.1%)
31,139 (47.7%)
-0.0321
2,077 (46.4%)
52,740 (46.3%)
0.002
...Female; n (%)
566 (52.6%)
26,980 (55.5%)
-0.0582
1,831 (53.9%)
34,125 (52.3%)
0.0321
2,397 (53.6%)
61,105 (53.7%)
-0.002
DMG - Geographic region 
...Northeast; n (%)
100 (9.3%)
5,118 (10.5%)
-0.0402
351 (10.3%)
10,691 (16.4%)
-0.1801
451 (10.1%)
15,809 (13.9%)
-0.117
...South; n (%)
385 (35.7%)
22,458 (46.2%)
-0.2148
845 (24.9%)
23,650 (36.2%)
-0.2472
1,230 (27.5%)
46,108 (40.5%)
-0.277
...North Central; n (%)
278 (25.8%)
10,162 (20.9%)
0.1160
1,108 (32.6%)
23,003 (35.2%)
-0.0549
1,386 (31.0%)
33,165 (29.1%)
0.041
...West; n (%)
314 (29.2%)
10,843 (22.3%)
0.1583
1,093 (32.2%)
7,920 (12.1%)
0.4989
1,407 (31.4%)
18,763 (16.5%)
0.355
DRS - Combined comorbidity score, 180 days 
...mean (sd)
2.37 (2.54)
2.59 (2.56)
-0.0863
1.75 (1.88)
2.05 (2.14)
-0.1489
1.90 (2.06)
2.28 (2.33)
-0.173
...median [IQR]
2.00 [1.00, 3.00]
2.00 [1.00, 4.00]
0.0000
1.00 [1.00, 3.00]
1.00 [1.00, 3.00]
0.0000
1.24 (2.06)
1.43 (2.33)
-0.086
DRS - Frailty Score: Empirical Version (mean)
...mean (sd)
0.21 (0.07)
0.22 (0.07)
-0.1429
0.19 (0.06)
0.20 (0.07)
-0.1534
0.19 (0.06)
0.21 (0.07)
-0.307
...median [IQR]
0.19 [0.16, 0.24]
0.20 [0.16, 0.25]
-0.1429
0.18 [0.14, 0.22]
0.19 [0.15, 0.23]
-0.1534
0.18 (0.06)
0.19 (0.07)
-0.153
PLM - Smoking ; n (%)
304 (28.2%)
20,039 (41.2%)
-0.2757
328 (9.7%)
14,153 (21.7%)
-0.3344
632 (14.1%)
34,192 (30.0%)
-0.391
PLM - Pneumonia ; n (%)
121 (11.2%)
6,244 (12.9%)
-0.0522
361 (10.6%)
8,855 (13.6%)
-0.0921
482 (10.8%)
15,099 (13.3%)
-0.077
PLM - Alpha-1 antitrypsin def/Pneumoconioses & other lung disease/Pul fibrosis; n (%)
79 (7.3%)
3,040 (6.3%)
0.0397
153 (4.5%)
3,648 (5.6%)
-0.0503
232 (5.2%)
6,688 (5.9%)
-0.031
PLM - Oxygen usage; n (%)
155 (14.4%)
7,652 (15.8%)
-0.0391
588 (17.3%)
10,345 (15.9%)
0.0376
743 (16.6%)
17,997 (15.8%)
0.022
PLM - Respiratory arrest/dependence on oxygen ; n (%)
129 (12.0%)
7,778 (16.0%)
-0.1155
227 (6.7%)
7,027 (10.8%)
-0.1455
356 (8.0%)
14,805 (13.0%)
-0.164
PLM - CiPAP/BiPAP use; n (%)
63 (5.8%)
3,294 (6.8%)
-0.0412
132 (3.9%)
5,015 (7.7%)
-0.1631
195 (4.4%)
8,309 (7.3%)
-0.124
PLM - Pulmonary rehabilitation ; n (%)*
7 (0.6%)
341 (0.7%)
-0.0124
9 (0.3%)
470 (0.7%)
-0.0567
016 (0.4%)
811 (0.7%)
-0.041
PLM - Moderate COPD exacerbation - [Count with 365 to 181 days before CED]*
...mean (sd)
1.67 (4.35)
2.72 (6.59)
-0.1881
1.53 (3.65)
1.65 (3.78)
-0.0323
1.56 (3.83)
2.11 (5.17)
-0.121
...median [IQR]
0.00 [0.00, 1.14]
0.42 [0.00, 2.57]
-0.0752
0.08 [0.00, 1.23]
0.15 [0.00, 1.62]
-0.0188
0.06 (3.83)
0.27 (5.17)
-0.046
PLM - Moderate COPD exacerbation - [Count 180 to 31 days before CED]*
...mean (sd)
1.72 (3.96)
2.27 (4.41)
-0.1312
1.29 (2.41)
1.40 (2.48)
-0.0450
1.39 (2.86)
1.77 (3.44)
-0.120
...median [IQR]
0.64 [0.01, 1.82]
0.88 [0.13, 2.45]
-0.0573
0.53 [0.00, 1.35]
0.61 [0.00, 1.66]
-0.0327
0.56 (2.86)
0.73 (3.44)
-0.054
PLM - Moderate COPD exacerbation - [Count with 30 days to CED]*
...mean (sd)
0.29 (1.12)
0.30 (1.11)
-0.0090
0.16 (0.53)
0.21 (0.65)
-0.0843
0.19 (0.72)
0.25 (0.88)
-0.075
...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 (0.88)
0.000
PLM - Moderate exacerbations >=1 in 365 days before CED; n (%)
864 (80.2%)
40,971 (84.3%)
-0.1075
2,520 (74.2%)
51,102 (78.3%)
-0.0965
3,384 (75.6%)
92,073 (80.9%)
-0.129
PLM - Moderate exacerbations >=2 in 365 days before CED ; n (%)
576 (53.5%)
31,738 (65.3%)
-0.2420
1,612 (47.5%)
35,919 (55.0%)
-0.1505
2,188 (48.9%)
67,657 (59.4%)
-0.212
PLM - Severe COPD exacerbation - [Count with 365 to 181 days before CED] *
...mean (sd)
0.04 (0.20)
0.07 (0.29)
-0.1204
0.06 (0.25)
0.07 (0.26)
-0.0392
0.06 (0.24)
0.07 (0.27)
-0.039
...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 (0.24)
0.00 (0.27)
0.000
PLM - Severe COPD exacerbation - [Count with 180 to 31 days before CED] *
...mean (sd)
0.06 (0.26)
0.06 (0.24)
0.0000
0.06 (0.22)
0.06 (0.21)
0.0000
0.06 (0.23)
0.06 (0.22)
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 (0.23)
0.00 (0.22)
0.000
PLM - Severe COPD exacerbation - [Count with 30 days lookback]  *
...mean (sd)
0.01 (0.09)
0.01 (0.10)
0.0000
0.01 (0.06)
0.01 (0.08)
0.0000
0.01 (0.07)
0.01 (0.09)
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 (0.07)
0.00 (0.09)
0.000
PLM - Severe exacerbations >=1 in 365 days before CED; n (%)
106 (9.8%)
6,395 (13.2%)
-0.1067
428 (12.6%)
9,050 (13.9%)
-0.0384
534 (11.9%)
15,445 (13.6%)
-0.051
PLM - Severe exacerbations >=2 in 365 days before CED ; n (%)
15 (1.4%)
1,226 (2.5%)
-0.0796
66 (1.9%)
1,138 (1.7%)
0.0150
081 (1.8%)
2,364 (2.1%)
-0.022
PLM - GOLD C/D Status ; n (%)
437 (40.6%)
26,005 (53.5%)
-0.2606
1,613 (47.5%)
35,581 (54.5%)
-0.1404
2,050 (45.8%)
61,586 (54.1%)
-0.167
PRX - LABA (except salmeterol) inhalers; n (%)
62 (5.8%)
847 (1.7%)
0.2171
195 (5.7%)
2,276 (3.5%)
0.1052
257 (5.7%)
3,123 (2.7%)
0.150
PRX - LAMA (except tiotropium) inhalers; n (%) *
14 (1.3%)
440 (0.9%)
0.0384
14 (0.4%)
520 (0.8%)
-0.0518
028 (0.6%)
960 (0.8%)
-0.024
PRX - ICS only inhalers; n (%)
416 (38.6%)
8,938 (18.4%)
0.4591
1,638 (48.2%)
14,424 (22.1%)
0.5683
2,054 (45.9%)
23,362 (20.5%)
0.560
PRX - LABA/LAMA inhaler use; n (%) *
17 (1.6%)
503 (1.0%)
0.0530
2 (0.1%)
206 (0.3%)
-0.0448
019 (0.4%)
709 (0.6%)
-0.028
PRX - LABA/ICS inhaler use; n (%)
45 (4.2%)
11,055 (22.8%)
-0.5657
107 (3.1%)
14,588 (22.4%)
-0.6045
152 (3.4%)
25,643 (22.5%)
-0.593
PRX - COPD Maintenance therapy inhalers; n (%)
126 (11.7%)
12,434 (25.6%)
-0.3627
236 (6.9%)
13,496 (20.7%)
-0.4084
362 (8.1%)
25,930 (22.8%)
-0.415
PRX - SAMA inhaler use; n (%)
108 (10.0%)
2,469 (5.1%)
0.1863
624 (18.4%)
3,835 (5.9%)
0.3898
732 (16.4%)
6,304 (5.5%)
0.355
PRX - SABA use; n (%)
523 (48.6%)
25,017 (51.5%)
-0.0580
1,562 (46.0%)
31,659 (48.5%)
-0.0501
2,085 (46.6%)
56,676 (49.8%)
-0.064
PRX - SABA/SAMA use; n (%)
243 (22.6%)
7,839 (16.1%)
0.1651
839 (24.7%)
10,570 (16.2%)
0.2119
1,082 (24.2%)
18,409 (16.2%)
0.200
PRX - Antibiotics treatment (180 days to 31 days before CED); n (%)
512 (47.5%)
24,200 (49.8%)
-0.0460
1,697 (50.0%)
34,160 (52.3%)
-0.0460
2,209 (49.4%)
58,360 (51.3%)
-0.038
PRX - Antibiotics treatment (30 days to CED); n (%)
152 (14.1%)
5,931 (12.2%)
0.0562
458 (13.5%)
9,458 (14.5%)
-0.0288
610 (13.6%)
15,389 (13.5%)
0.003
PRX - Systemic Corticosteroids (with CPT) use (180 to 31 days before CED); n (%)
539 (50.0%)
25,127 (51.7%)
-0.0340
1,638 (48.2%)
32,585 (49.9%)
-0.0340
2,177 (48.7%)
57,712 (50.7%)
-0.040
PRX - Systemic Corticosteroids (with CPT) use (30 days to CED); n (%)
102 (9.5%)
3,369 (6.9%)
0.0949
384 (11.3%)
5,550 (8.5%)
0.0939
486 (10.9%)
8,919 (7.8%)
0.107
PRX - Roflumilast; n (%) *
7 (0.6%)
378 (0.8%)
-0.0240
5 (0.1%)
487 (0.7%)
-0.0952
012 (0.3%)
865 (0.8%)
-0.068
CVD - Unstable angina/MI; n (%)
86 (8.0%)
4,729 (9.7%)
-0.0599
223 (6.6%)
4,791 (7.3%)
-0.0275
309 (6.9%)
9,520 (8.4%)
-0.056
CVD - Stable Angina  ; n (%)
46 (4.3%)
2,338 (4.8%)
-0.0240
95 (2.8%)
2,405 (3.7%)
-0.0508
141 (3.2%)
4,743 (4.2%)
-0.053
CVD - Any Heart failure (HF) ; n (%)
183 (17.0%)
9,631 (19.8%)
-0.0723
518 (15.2%)
11,652 (17.9%)
-0.0727
701 (15.7%)
21,283 (18.7%)
-0.080
CVD - Atrial fibrillation; n (%)
144 (13.4%)
6,877 (14.2%)
-0.0232
393 (11.6%)
8,538 (13.1%)
-0.0456
537 (12.0%)
15,415 (13.5%)
-0.045
CVD - Other dysrythmias   ; n (%)*
191 (17.7%)
8,444 (17.4%)
0.0079
352 (10.4%)
9,481 (14.5%)
-0.1244
543 (12.1%)
17,925 (15.7%)
-0.104
CVD - Valve disorder   ; n (%)
34 (3.2%)
1,741 (3.6%)
-0.0221
74 (2.2%)
1,841 (2.8%)
-0.0384
108 (2.4%)
3,582 (3.1%)
-0.043
CVD - Implantable cardioverter defibrillator  ; n (%)*
14 (1.3%)
951 (2.0%)
-0.0550
32 (0.9%)
961 (1.5%)
-0.0551
046 (1.0%)
1,912 (1.7%)
-0.061
CVD - CABG/PCI; n (%)
74 (6.9%)
4,336 (8.9%)
-0.0742
139 (4.1%)
3,428 (5.3%)
-0.0567
213 (4.8%)
7,764 (6.8%)
-0.086
CVD - Coronary atherosclerosis and other forms of chronic ischemic heart disease; n (%)
270 (25.1%)
13,906 (28.6%)
-0.0790
704 (20.7%)
17,219 (26.4%)
-0.1346
974 (21.8%)
31,125 (27.3%)
-0.128
CVD - Stroke/TIA  ; n (%)
60 (5.6%)
2,727 (5.6%)
0.0000
169 (5.0%)
3,400 (5.2%)
-0.0091
229 (5.1%)
6,127 (5.4%)
-0.013
CVD - Peripheral Vascular Disease (PVD) or PVD Surgery; n (%)
112 (10.4%)
6,337 (13.0%)
-0.0810
218 (6.4%)
5,918 (9.1%)
-0.1011
330 (7.4%)
12,255 (10.8%)
-0.118
CVD - Hyperlipidemia  ; n (%)
516 (47.9%)
26,282 (54.1%)
-0.1243
703 (20.7%)
22,385 (34.3%)
-0.3082
1,219 (27.2%)
48,667 (42.7%)
-0.329
CVD - Hypertension; n (%)
695 (64.5%)
33,432 (68.8%)
-0.0913
1,384 (40.7%)
33,730 (51.7%)
-0.2220
2,079 (46.5%)
67,162 (59.0%)
-0.252
CRX - ACEi or ARB; n (%)
457 (42.4%)
22,139 (45.6%)
-0.0645
1,444 (42.5%)
29,179 (44.7%)
-0.0444
1,901 (42.5%)
51,318 (45.1%)
-0.052
CRX - Mineralocorticoid receptor antagonist  ; n (%)
44 (4.1%)
2,041 (4.2%)
-0.0050
161 (4.7%)
3,176 (4.9%)
-0.0094
205 (4.6%)
5,217 (4.6%)
0.000
CRX - Loop or Thiazide diuretics; n (%)
374 (34.7%)
16,506 (34.0%)
0.0147
1,379 (40.6%)
23,473 (36.0%)
0.0947
1,753 (39.2%)
39,979 (35.1%)
0.085
CRX - Statins and other lipid lowering agents; n (%)
487 (45.2%)
25,485 (52.5%)
-0.1464
1,511 (44.5%)
32,717 (50.1%)
-0.1123
1,998 (44.7%)
58,202 (51.1%)
-0.128
CRX - Beta blockers ; n (%)
342 (31.8%)
17,833 (36.7%)
-0.1034
957 (28.2%)
23,987 (36.8%)
-0.1844
1,299 (29.0%)
41,820 (36.7%)
-0.164
CRX - CCB and other antihypertensives; n (%)
336 (31.2%)
14,658 (30.2%)
0.0217
1,148 (33.8%)
19,244 (29.5%)
0.0926
1,484 (33.2%)
33,902 (29.8%)
0.073
CRX - Digoxin   ; n (%)*
52 (4.8%)
1,689 (3.5%)
0.0652
307 (9.0%)
3,742 (5.7%)
0.1267
359 (8.0%)
5,431 (4.8%)
0.131
CRX - Nitrates; n (%)*
100 (9.3%)
4,486 (9.2%)
0.0035
431 (12.7%)
7,249 (11.1%)
0.0494
531 (11.9%)
11,735 (10.3%)
0.051
OCM - Type 1 or 2 DM; n (%)
290 (26.9%)
13,869 (28.5%)
-0.0358
681 (20.0%)
15,497 (23.7%)
-0.0896
971 (21.7%)
29,366 (25.8%)
-0.096
OCM - Occurrence of Diabetic retinopathy/nephropathy/neuropathy; n (%)*
91 (8.4%)
5,084 (10.5%)
-0.0718
127 (3.7%)
3,524 (5.4%)
-0.0816
218 (4.9%)
8,608 (7.6%)
-0.112
OCM - Hypertensive nephropathy; n (%)*
82 (7.6%)
4,127 (8.5%)
-0.0331
100 (2.9%)
2,758 (4.2%)
-0.0703
182 (4.1%)
6,885 (6.0%)
-0.087
OCM - Hypotension  ; n (%)*
42 (3.9%)
2,601 (5.4%)
-0.0713
77 (2.3%)
2,518 (3.9%)
-0.0924
119 (2.7%)
5,119 (4.5%)
-0.097
OCM - Hyperkalemia ; n (%)*
29 (2.7%)
1,448 (3.0%)
-0.0180
59 (1.7%)
1,128 (1.7%)
0.0000
088 (2.0%)
2,576 (2.3%)
-0.021
OCM - CKD II, III, or IV; n (%)
94 (8.7%)
5,205 (10.7%)
-0.0676
80 (2.4%)
3,244 (5.0%)
-0.1381
174 (3.9%)
8,449 (7.4%)
-0.152
OCM - HD/PD/ESRD; n (%)*
16 (1.5%)
510 (1.0%)
0.0450
35 (1.0%)
849 (1.3%)
-0.0281
051 (1.1%)
1,359 (1.2%)
-0.009
OCM - Osteoporosis; n (%)
135 (12.5%)
6,026 (12.4%)
0.0030
473 (13.9%)
6,609 (10.1%)
0.1171
608 (13.6%)
12,635 (11.1%)
0.076
OCM - Sleep apnea ; n (%)
139 (12.9%)
7,636 (15.7%)
-0.0800
236 (6.9%)
8,922 (13.7%)
-0.2251
375 (8.4%)
16,558 (14.5%)
-0.192
OCM - Fractures  ; n (%)
68 (6.3%)
3,465 (7.1%)
-0.0320
218 (6.4%)
4,379 (6.7%)
-0.0121
286 (6.4%)
7,844 (6.9%)
-0.020
OCM - Other Arthritis, Arthropathies and Musculoskeletal Pain ; n (%)
463 (43.0%)
22,638 (46.6%)
-0.0724
1,073 (31.6%)
25,228 (38.7%)
-0.1491
1,536 (34.3%)
47,866 (42.0%)
-0.159
OCM - Dorsopathies; n (%)
308 (28.6%)
16,451 (33.9%)
-0.1145
671 (19.8%)
16,991 (26.0%)
-0.1480
979 (21.9%)
33,442 (29.4%)
-0.172
OCM - Gout (acute/chronic) ; n (%)*
7 (0.6%)
562 (1.2%)
-0.0636
45 (1.3%)
799 (1.2%)
0.0090
052 (1.2%)
1,361 (1.2%)
0.000
OCM - Hyperthyroidism  ; n (%)*
3 (0.3%)
420 (0.9%)
-0.0778
18 (0.5%)
417 (0.6%)
-0.0135
021 (0.5%)
837 (0.7%)
-0.026
OCM - Hypothyroidism ; n (%)*
99 (9.2%)
4,864 (10.0%)
-0.0272
217 (6.4%)
5,362 (8.2%)
-0.0692
316 (7.1%)
10,226 (9.0%)
-0.070
OCM - VTE ; n (%)*
40 (3.7%)
1,870 (3.8%)
-0.0053
113 (3.3%)
2,558 (3.9%)
-0.0322
153 (3.4%)
4,428 (3.9%)
-0.027
OCM - GERD ; n (%)
203 (18.8%)
10,528 (21.7%)
-0.0722
244 (7.2%)
6,858 (10.5%)
-0.1164
447 (10.0%)
17,386 (15.3%)
-0.160
OCM - Cancer   ; n (%)
150 (13.9%)
6,452 (13.3%)
0.0175
369 (10.9%)
7,334 (11.2%)
-0.0096
519 (11.6%)
13,786 (12.1%)
-0.015
OCM - Hypovolemia/volume depletion ; n (%)*
59 (5.5%)
2,625 (5.4%)
0.0044
106 (3.1%)
2,580 (4.0%)
-0.0487
165 (3.7%)
5,205 (4.6%)
-0.045
OCM - Anemia   ; n (%)
190 (17.6%)
9,353 (19.3%)
-0.0438
387 (11.4%)
9,554 (14.6%)
-0.0953
577 (12.9%)
18,907 (16.6%)
-0.104
OCM - Dementia  ; n (%)*
73 (6.8%)
3,560 (7.3%)
-0.0195
133 (3.9%)
3,059 (4.7%)
-0.0394
206 (4.6%)
6,619 (5.8%)
-0.054
OCM - Depression ; n (%)
204 (18.9%)
10,201 (21.0%)
-0.0526
301 (8.9%)
8,006 (12.3%)
-0.1106
505 (11.3%)
18,207 (16.0%)
-0.137
ORX - Metformin; n (%)*
129 (12.0%)
5,947 (12.2%)
-0.0061
312 (9.2%)
6,884 (10.5%)
-0.0436
441 (9.9%)
12,831 (11.3%)
-0.045
ORX - 1st and 2nd Generation SUs   ; n (%)
96 (8.9%)
3,353 (6.9%)
0.0742
298 (8.8%)
4,753 (7.3%)
0.0552
394 (8.8%)
8,106 (7.1%)
0.063
ORX - Insulins ; n (%)
92 (8.5%)
3,588 (7.4%)
0.0407
198 (5.8%)
4,670 (7.2%)
-0.0568
290 (6.5%)
8,258 (7.3%)
-0.032
ORX - Other antidiabetic medications use; n (%)
49 (4.5%)
2,328 (4.8%)
-0.0142
169 (5.0%)
3,897 (6.0%)
-0.0439
218 (4.9%)
6,225 (5.5%)
-0.027
ORX - PPIs or H2RAs use; n (%)*
299 (27.8%)
15,836 (32.6%)
-0.1047
1,088 (32.0%)
18,374 (28.2%)
0.0829
1,387 (31.0%)
34,210 (30.0%)
0.022
ORX - NSAIDs ; n (%)*
151 (14.0%)
7,708 (15.9%)
-0.0533
640 (18.8%)
10,402 (15.9%)
0.0766
791 (17.7%)
18,110 (15.9%)
0.048
ORX - Use of opioids  ; n (%)*
418 (38.8%)
20,336 (41.9%)
-0.0632
1,337 (39.4%)
28,226 (43.2%)
-0.0772
1,755 (39.2%)
48,562 (42.7%)
-0.071
ORX - Use of antipsychotics   ; n (%)*
70 (6.5%)
2,908 (6.0%)
0.0207
139 (4.1%)
3,128 (4.8%)
-0.0340
209 (4.7%)
6,036 (5.3%)
-0.028
ORX - Use of antidepressants  ; n (%)
409 (38.0%)
19,790 (40.7%)
-0.0553
1,183 (34.8%)
24,738 (37.9%)
-0.0645
1,592 (35.6%)
44,528 (39.1%)
-0.072
ORX - Use of anxiolytics/hypnotics ; n (%)
116 (10.8%)
5,649 (11.6%)
-0.0254
388 (11.4%)
8,447 (12.9%)
-0.0459
504 (11.3%)
14,096 (12.4%)
-0.034
ORX - Use of anticonvulsants  ; n (%)*
207 (19.2%)
10,715 (22.1%)
-0.0717
474 (14.0%)
10,973 (16.8%)
-0.0776
681 (15.2%)
21,688 (19.1%)
-0.104
ORX - Use of Benzodiazepines ; n (%)*
215 (20.0%)
9,605 (19.8%)
0.0050
875 (25.8%)
16,742 (25.7%)
0.0023
1,090 (24.4%)
26,347 (23.1%)
0.031
ORX - Use of dementia meds  ; n (%)*
37 (3.4%)
1,668 (3.4%)
0.0000
100 (2.9%)
2,021 (3.1%)
-0.0117
137 (3.1%)
3,689 (3.2%)
-0.006
ORX - Use of antiparkinsonian meds  ; n (%)*
47 (4.4%)
2,335 (4.8%)
-0.0191
108 (3.2%)
2,814 (4.3%)
-0.0579
155 (3.5%)
5,149 (4.5%)
-0.051
ORX - Use of oral anticoagulants   ; n (%)*
122 (11.3%)
5,383 (11.1%)
0.0063
423 (12.5%)
8,094 (12.4%)
0.0030
545 (12.2%)
13,477 (11.8%)
0.012
ORX - Use of antiplatelet agents ; n (%)*
123 (11.4%)
6,436 (13.2%)
-0.0548
515 (15.2%)
11,431 (17.5%)
-0.0622
638 (14.3%)
17,867 (15.7%)
-0.039
LFS - Obesity; n (%)
96 (8.9%)
5,778 (11.9%)
-0.0984
130 (3.8%)
4,329 (6.6%)
-0.1264
226 (5.1%)
10,107 (8.9%)
-0.149
LFS - Alcohol/Drug Abuse or Dependence ; n (%)
71 (6.6%)
3,750 (7.7%)
-0.0427
66 (1.9%)
2,540 (3.9%)
-0.1194
137 (3.1%)
6,290 (5.5%)
-0.119
PFT - Spirometry test only; n (%)
213 (19.8%)
12,956 (26.7%)
-0.1639
676 (19.9%)
20,587 (31.5%)
-0.2678
889 (19.9%)
33,543 (29.5%)
-0.224
PFT - Spirometry test only (Count - 180 days to 31 days before CED) *
...mean (sd)
0.24 (0.71)
0.34 (0.92)
-0.1217
0.22 (0.67)
0.35 (0.87)
-0.1674
0.22 (0.68)
0.35 (0.89)
-0.164
...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 (0.68)
0.00 (0.89)
0.000
PFT - Spirometry test only (Count - 30 days to CED) *
...mean (sd)
0.15 (0.63)
0.21 (0.70)
-0.0901
0.11 (0.44)
0.23 (0.66)
-0.2139
0.12 (0.49)
0.22 (0.68)
-0.169
...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 (0.49)
0.00 (0.68)
0.000
PFT - Lung volume, Diffuse capacity, pulmonary stress testing (any); n (%)
151 (14.0%)
9,997 (20.6%)
-0.1752
249 (7.3%)
10,616 (16.3%)
-0.2817
400 (8.9%)
20,613 (18.1%)
-0.272
HCU - Pulmonologist visit (180 to 1 day before CED); n (%)
30 (2.8%)
1,080 (2.2%)
0.0384
787 (23.2%)
20,540 (31.5%)
-0.1870
817 (18.3%)
21,620 (19.0%)
-0.018
HCU - Pulmonologist visit on CED; n (%)
2 (0.2%)
150 (0.3%)
-0.0200
84 (2.5%)
3,729 (5.7%)
-0.1619
086 (1.9%)
3,879 (3.4%)
-0.093
HCU - Pulmonologist visit (Number of during CAP) *
...mean (sd)
0.25 (2.12)
0.17 (1.85)
0.0402
0.90 (2.40)
1.43 (3.17)
-0.1885
0.74 (2.34)
0.89 (2.69)
-0.059
...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, 1.00]
0.0000
0.00 (2.34)
0.00 (2.69)
0.000
HCU - Number of Internal Medicine/Family Medicine Visits  
...mean (sd)
9.76 (13.79)
12.05 (16.93)
-0.1483
7.86 (13.60)
9.00 (13.56)
-0.0839
8.32 (13.65)
10.30 (15.09)
-0.138
...median [IQR]
5.00 [1.00, 12.00]
7.00 [3.00, 15.00]
-0.1295
4.00 [0.00, 9.00]
5.00 [2.00, 11.00]
-0.0736
4.24 (13.65)
5.85 (15.09)
-0.112
HCU - Number of Cardiologist visits  
...mean (sd)
2.40 (6.18)
2.46 (5.82)
-0.0100
1.27 (3.79)
1.74 (4.57)
-0.1120
1.54 (4.48)
2.05 (5.14)
-0.106
...median [IQR]
0.00 [0.00, 2.00]
0.00 [0.00, 2.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.0000
0.00 (4.48)
0.00 (5.14)
0.000
HCU - Number of Emergency Department (ED) visits v3 
...mean (sd)
0.87 (1.95)
0.99 (2.07)
-0.0597
0.69 (3.14)
0.60 (2.44)
0.0320
0.73 (2.90)
0.77 (2.29)
-0.015
...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (2.90)
0.00 (2.29)
0.000
OPTUM
MARKETSCAN
POOLED
UNMATCHED
Appendix B

HCU - Old hospitalization (-180 days to -31 days before CED)  ; n (%)
251 (23.3%)
11,887 (24.5%)
-0.0281
1,027 (30.2%)
20,572 (31.5%)
-0.0281
1,278 (28.6%)
32,459 (28.5%)
0.002
HCU - Recent hospitalization (-30 days to CED date)  ; n (%)
28 (2.6%)
2,193 (4.5%)
-0.1028
152 (4.5%)
3,447 (5.3%)
-0.0371
180 (4.0%)
5,640 (5.0%)
-0.048
HCU - Number of hospitalizations during CAP  
...mean (sd)
0.35 (0.79)
0.38 (0.78)
-0.0382
0.42 (0.73)
0.44 (0.73)
-0.0274
0.40 (0.74)
0.41 (0.75)
-0.013
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.0000
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.0000
0.00 (0.74)
0.00 (0.75)
0.000
HCU - Blood eosinophilia or Serum IgE test order; n (%)*
10 (0.9%)
418 (0.9%)
0.0000
21 (0.6%)
461 (0.7%)
-0.0124
031 (0.7%)
879 (0.8%)
-0.012
HCU - Pneumococcal vaccine; n (%)
133 (12.3%)
7,651 (15.7%)
-0.0981
118 (3.5%)
4,286 (6.6%)
-0.1419
251 (5.6%)
11,937 (10.5%)
-0.181
HCU - Flu vaccine  ; n (%)
192 (17.8%)
10,097 (20.8%)
-0.0761
368 (10.8%)
8,600 (13.2%)
-0.0739
560 (12.5%)
18,697 (16.4%)
-0.111
HCU - Bone mineral density  ; n (%)
31 (2.9%)
2,136 (4.4%)
-0.0801
59 (1.7%)
1,728 (2.6%)
-0.0621
090 (2.0%)
3,864 (3.4%)
-0.086
HCU - Pap smear ; n (%)
40 (3.7%)
1,243 (2.6%)
0.0630
113 (3.3%)
2,079 (3.2%)
0.0056
153 (3.4%)
3,322 (2.9%)
0.029
HCU - Mammogram  ; n (%)
120 (11.1%)
4,993 (10.3%)
0.0259
350 (10.3%)
5,340 (8.2%)
0.0725
470 (10.5%)
10,333 (9.1%)
0.047
HCU - Prostate exam for DRE  ; n (%)
35 (3.2%)
1,790 (3.7%)
-0.0274
28 (0.8%)
1,170 (1.8%)
-0.0884
063 (1.4%)
2,960 (2.6%)
-0.086
HCU - Number of Echocardiogram  *
...mean (sd)
0.64 (3.49)
0.61 (2.97)
0.0093
0.43 (1.23)
0.47 (1.13)
-0.0339
0.48 (2.02)
0.53 (2.12)
-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 (2.02)
0.00 (2.12)
0.000
HCU - Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy  ; n (%)
60 (5.6%)
2,516 (5.2%)
0.0177
201 (5.9%)
4,071 (6.2%)
-0.0126
261 (5.8%)
6,587 (5.8%)
0.000
HCU - Number of Distinct Medication Prescriptions (not generalized to generics)  
...mean (sd)
29.01 (22.72)
28.46 (20.95)
0.0252
26.91 (17.53)
25.81 (17.21)
0.0633
27.42 (18.91)
26.94 (18.90)
0.025
...median [IQR]
23.00 [14.00, 37.00]
24.00 [14.00, 37.00]
-0.0458
23.00 [15.00, 34.50]
22.00 [14.00, 34.00]
0.0576
23.00 (18.91)
22.85 (18.90)
0.008
SES - Copay for pharmacy cost (charges in U.S. $)  
...mean (sd)
33.09 (30.71)
29.56 (35.50)
0.1064
26.74 (27.26)
24.27 (23.93)
0.0963
28.27 (28.13)
26.53 (29.43)
0.060
...median [IQR]
27.02 [12.96, 42.81]
21.96 [7.85, 38.52]
0.1524
21.25 [9.33, 35.86]
19.90 [9.93, 32.60]
0.0526
22.64 (28.13)
20.78 (29.43)
0.065
SES - Business type   
...Commercial; n (%)
394 (36.6%)
11,001 (22.6%)
0.3104
394 (36.6%)
11,001 (22.6%)
0.310
...Medicare; n (%)
683 (63.4%)
37,580 (77.4%)
-0.3104
683 (63.4%)
37,580 (77.4%)
-0.310
SES - Low income indicator  ; n (%)
184 (17.1%)
12,414 (25.6%)
-0.2086
184 (17.1%)
12,414 (25.6%)
-0.209
SES - Insurance Plan type   
...Comprehensive; n (%)
1,232 (36.3%)
21,355 (32.7%)
0.0758
1,232 (36.3%)
21,355 (32.7%)
0.076
...HMO; n (%)
959 (28.2%)
7,748 (11.9%)
0.4158
959 (28.2%)
7,748 (11.9%)
0.416
...PPO; n (%)
961 (28.3%)
28,886 (44.3%)
-0.3374
961 (28.3%)
28,886 (44.3%)
-0.337
...Others; n (%)
245 (7.2%)
7,275 (11.1%)
-0.1356
245 (7.2%)
7,275 (11.1%)
-0.136
___________
* Not included in PS model
Appendix B

Referent - Salmeterol
Exposure - Tiotropium
Referent - Salmeterol
Exposure - Tiotropium
Referent - Salmeterol
Exposure - Tiotropium
Number of patients
1,073
1,073
3,285
3,285
4,358
4,358
Calendar Time - Year of Initiation (2004 - 2020)
...2004-2006; n (%)
298 (27.8%)
303 (28.2%)
-0.0089
1,849 (56.3%)
1,872 (57.0%)
-0.0141
2,147 (49.3%)
2,175 (49.9%)
-0.012
...2007-2008; n (%)
103 (9.6%)
87 (8.1%)
0.0528
403 (12.3%)
376 (11.4%)
0.0278
506 (11.6%)
463 (10.6%)
0.032
...2009-2011; n (%)
171 (15.9%)
185 (17.2%)
-0.0350
543 (16.5%)
537 (16.3%)
0.0054
714 (16.4%)
722 (16.6%)
-0.005
...2012-2015; n (%)
157 (14.6%)
152 (14.2%)
0.0114
315 (9.6%)
348 (10.6%)
-0.0332
472 (10.8%)
500 (11.5%)
-0.022
...2016-2018; n (%)
250 (23.3%)
254 (23.7%)
-0.0094
175 (5.3%)
152 (4.6%)
0.0323
425 (9.8%)
406 (9.3%)
0.017
...2019-Mar. 2020; n (%)
94 (8.8%)
92 (8.6%)
0.0071
94 (8.8%)
92 (8.6%)
0.007
DMG - Age
...mean (sd)
69.32 (10.77)
69.31 (10.55)
0.0009
70.76 (10.81)
70.58 (10.61)
0.0168
70.41 (10.80)
70.27 (10.60)
0.013
...median [IQR]
70.00 [62.00, 77.00]
70.00 [62.00, 78.00]
0.0000
72.00 [63.00, 79.00]
71.00 [63.00, 79.00]
0.0934
71.51 (10.80)
70.75 (10.60)
0.071
DMG - Gender
...Male; n (%)
509 (47.4%)
496 (46.2%)
0.0241
1,517 (46.2%)
1,528 (46.5%)
-0.0060
2,026 (46.5%)
2,024 (46.4%)
0.002
...Female; n (%)
564 (52.6%)
577 (53.8%)
-0.0241
1,768 (53.8%)
1,757 (53.5%)
0.0060
2,332 (53.5%)
2,334 (53.6%)
-0.002
DMG - Geographic region 
...Northeast; n (%)
100 (9.3%)
99 (9.2%)
0.0035
348 (10.6%)
331 (10.1%)
0.0164
448 (10.3%)
430 (9.9%)
0.013
...South; n (%)
384 (35.8%)
379 (35.3%)
0.0104
845 (25.7%)
859 (26.1%)
-0.0091
1,229 (28.2%)
1,238 (28.4%)
-0.004
...North Central; n (%)
276 (25.7%)
265 (24.7%)
0.0230
1,107 (33.7%)
1,095 (33.3%)
0.0085
1,383 (31.7%)
1,360 (31.2%)
0.011
...West; n (%)
313 (29.2%)
330 (30.8%)
-0.0349
985 (30.0%)
1,000 (30.4%)
-0.0087
1,298 (29.8%)
1,330 (30.5%)
-0.015
DRS - Combined comorbidity score, 180 days 
...mean (sd)
2.37 (2.54)
2.30 (2.47)
0.0279
1.75 (1.88)
1.74 (1.84)
0.0054
1.90 (2.06)
1.88 (2.01)
0.010
...median [IQR]
2.00 [1.00, 3.00]
1.00 [1.00, 3.00]
0.3992
1.00 [1.00, 3.00]
1.00 [1.00, 2.00]
0.0000
1.25 (2.06)
1.00 (2.01)
0.123
DRS - Frailty Score: Empirical Version (mean)
...mean (sd)
0.21 (0.07)
0.21 (0.07)
0.0000
0.19 (0.06)
0.19 (0.06)
0.0000
0.19 (0.06)
0.19 (0.06)
0.000
...median [IQR]
0.19 [0.16, 0.24]
0.19 [0.16, 0.24]
0.0000
0.18 [0.14, 0.22]
0.18 [0.14, 0.22]
0.0000
0.18 (0.06)
0.18 (0.06)
0.000
PLM - Smoking ; n (%)
302 (28.1%)
287 (26.7%)
0.0314
319 (9.7%)
329 (10.0%)
-0.0101
621 (14.2%)
616 (14.1%)
0.003
PLM - Pneumonia ; n (%)
120 (11.2%)
123 (11.5%)
-0.0095
350 (10.7%)
372 (11.3%)
-0.0192
470 (10.8%)
495 (11.4%)
-0.019
PLM - Alpha-1 antitrypsin def/Pneumoconioses & other lung disease/Pul fibrosis; n (%)
78 (7.3%)
93 (8.7%)
-0.0516
152 (4.6%)
144 (4.4%)
0.0096
230 (5.3%)
237 (5.4%)
-0.004
PLM - Oxygen usage; n (%)
155 (14.4%)
161 (15.0%)
-0.0169
575 (17.5%)
623 (19.0%)
-0.0388
730 (16.8%)
784 (18.0%)
-0.032
PLM - Respiratory arrest/dependence on oxygen ; n (%)
129 (12.0%)
123 (11.5%)
0.0155
223 (6.8%)
228 (6.9%)
-0.0040
352 (8.1%)
351 (8.1%)
0.000
PLM - CiPAP/BiPAP use; n (%)
63 (5.9%)
57 (5.3%)
0.0261
129 (3.9%)
144 (4.4%)
-0.0251
192 (4.4%)
201 (4.6%)
-0.010
PLM - Pulmonary rehabilitation ; n (%)*
7 (0.7%)
2 (0.2%)
0.0748
8 (0.2%)
13 (0.4%)
-0.0366
015 (0.3%)
015 (0.3%)
0.000
PLM - Moderate COPD exacerbation - [Count with 365 to 181 days before CED]*
...mean (sd)
1.67 (4.35)
2.13 (9.04)
-0.0648
1.55 (3.69)
1.48 (3.49)
0.0195
1.58 (3.86)
1.64 (5.41)
-0.013
...median [IQR]
0.00 [0.00, 1.11]
0.06 [0.00, 1.57]
-0.0085
0.10 [0.00, 1.28]
0.05 [0.00, 1.22]
0.0139
0.08 (3.86)
0.05 (5.41)
0.006
PLM - Moderate COPD exacerbation - [Count 180 to 31 days before CED]*
...mean (sd)
1.73 (3.97)
1.77 (6.49)
-0.0074
1.29 (2.41)
1.31 (2.33)
-0.0084
1.40 (2.87)
1.42 (3.80)
-0.006
...median [IQR]
0.64 [0.01, 1.83]
0.62 [0.02, 1.60]
0.0037
0.54 [0.00, 1.36]
0.54 [0.00, 1.52]
0.0000
0.56 (2.87)
0.56 (3.80)
0.000
PLM - Moderate COPD exacerbation - [Count with 30 days to CED]*
...mean (sd)
0.29 (1.12)
0.29 (1.32)
0.0000
0.16 (0.54)
0.18 (0.55)
-0.0367
0.19 (0.73)
0.21 (0.81)
-0.026
...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 (0.73)
0.00 (0.81)
0.000
PLM - Moderate exacerbations >=1 in 365 days before CED; n (%)
861 (80.2%)
872 (81.3%)
-0.0279
2,449 (74.6%)
2,496 (76.0%)
-0.0325
3,310 (76.0%)
3,368 (77.3%)
-0.031
PLM - Moderate exacerbations >=2 in 365 days before CED ; n (%)
574 (53.5%)
565 (52.7%)
0.0160
1,570 (47.8%)
1,617 (49.2%)
-0.0280
2,144 (49.2%)
2,182 (50.1%)
-0.018
PLM - Severe COPD exacerbation - [Count with 365 to 181 days before CED] *
...mean (sd)
0.04 (0.20)
0.05 (0.25)
-0.0442
0.06 (0.25)
0.07 (0.27)
-0.0384
0.06 (0.24)
0.07 (0.27)
-0.039
...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 (0.24)
0.00 (0.27)
0.000
PLM - Severe COPD exacerbation - [Count with 180 to 31 days before CED] *
...mean (sd)
0.06 (0.26)
0.04 (0.18)
0.0894
0.06 (0.22)
0.06 (0.23)
0.0000
0.06 (0.23)
0.06 (0.22)
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 (0.23)
0.00 (0.22)
0.000
PLM - Severe COPD exacerbation - [Count with 30 days lookback]  *
...mean (sd)
0.01 (0.09)
0.01 (0.09)
0.0000
0.01 (0.06)
0.01 (0.09)
0.0000
0.01 (0.07)
0.01 (0.09)
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 (0.07)
0.00 (0.09)
0.000
PLM - Severe exacerbations >=1 in 365 days before CED; n (%)
106 (9.9%)
106 (9.9%)
0.0000
419 (12.8%)
431 (13.1%)
-0.0089
525 (12.0%)
537 (12.3%)
-0.009
PLM - Severe exacerbations >=2 in 365 days before CED ; n (%)
15 (1.4%)
14 (1.3%)
0.0087
63 (1.9%)
75 (2.3%)
-0.0279
078 (1.8%)
089 (2.0%)
-0.015
PLM - GOLD C/D Status ; n (%)
435 (40.5%)
424 (39.5%)
0.0204
1,569 (47.8%)
1,636 (49.8%)
-0.0400
2,004 (46.0%)
2,060 (47.3%)
-0.026
PRX - LABA (except salmeterol) inhalers; n (%)
62 (5.8%)
61 (5.7%)
0.0043
194 (5.9%)
221 (6.7%)
-0.0329
256 (5.9%)
282 (6.5%)
-0.025
PRX - LAMA (except tiotropium) inhalers; n (%) *
14 (1.3%)
9 (0.8%)
0.0491
14 (0.4%)
2 (0.1%)
0.0601
028 (0.6%)
011 (0.3%)
0.045
PRX - ICS only inhalers; n (%)
415 (38.7%)
401 (37.4%)
0.0268
1,534 (46.7%)
1,558 (47.4%)
-0.0140
1,949 (44.7%)
1,959 (45.0%)
-0.006
PRX - LABA/LAMA inhaler use; n (%) *
17 (1.6%)
8 (0.7%)
0.0845
2 (0.1%)
3 (0.1%)
0.0000
019 (0.4%)
011 (0.3%)
0.017
PRX - LABA/ICS inhaler use; n (%)
45 (4.2%)
51 (4.8%)
-0.0289
107 (3.3%)
110 (3.3%)
0.0000
152 (3.5%)
161 (3.7%)
-0.011
PRX - COPD Maintenance therapy inhalers; n (%)
126 (11.7%)
127 (11.8%)
-0.0031
235 (7.2%)
265 (8.1%)
-0.0339
361 (8.3%)
392 (9.0%)
-0.025
PRX - SAMA inhaler use; n (%)
108 (10.1%)
115 (10.7%)
-0.0197
565 (17.2%)
610 (18.6%)
-0.0365
673 (15.4%)
725 (16.6%)
-0.033
PRX - SABA use; n (%)
521 (48.6%)
510 (47.5%)
0.0220
1,486 (45.2%)
1,530 (46.6%)
-0.0281
2,007 (46.1%)
2,040 (46.8%)
-0.014
PRX - SABA/SAMA use; n (%)
242 (22.6%)
241 (22.5%)
0.0024
817 (24.9%)
880 (26.8%)
-0.0434
1,059 (24.3%)
1,121 (25.7%)
-0.032
PRX - Antibiotics treatment (180 days to 31 days before CED); n (%)
509 (47.4%)
517 (48.2%)
-0.0160
1,646 (50.1%)
1,659 (50.5%)
-0.0080
2,155 (49.4%)
2,176 (49.9%)
-0.010
PRX - Antibiotics treatment (30 days to CED); n (%)
150 (14.0%)
157 (14.6%)
-0.0171
450 (13.7%)
454 (13.8%)
-0.0029
600 (13.8%)
611 (14.0%)
-0.006
PRX - Systemic Corticosteroids (with CPT) use (180 to 31 days before CED); n (%)
537 (50.0%)
540 (50.3%)
-0.0060
1,582 (48.2%)
1,592 (48.5%)
-0.0060
2,119 (48.6%)
2,132 (48.9%)
-0.006
PRX - Systemic Corticosteroids (with CPT) use (30 days to CED); n (%)
100 (9.3%)
91 (8.5%)
0.0281
365 (11.1%)
352 (10.7%)
0.0128
465 (10.7%)
443 (10.2%)
0.016
PRX - Roflumilast; n (%) *
7 (0.7%)
1 (0.1%)
0.0952
5 (0.2%)
6 (0.2%)
0.0000
012 (0.3%)
007 (0.2%)
0.020
CVD - Unstable angina/MI; n (%)
86 (8.0%)
78 (7.3%)
0.0263
216 (6.6%)
205 (6.2%)
0.0163
302 (6.9%)
283 (6.5%)
0.016
CVD - Stable Angina  ; n (%)
46 (4.3%)
45 (4.2%)
0.0050
92 (2.8%)
71 (2.2%)
0.0384
138 (3.2%)
116 (2.7%)
0.030
CVD - Any Heart failure (HF) ; n (%)
182 (17.0%)
180 (16.8%)
0.0053
501 (15.3%)
489 (14.9%)
0.0112
683 (15.7%)
669 (15.4%)
0.008
CVD - Atrial fibrillation; n (%)
143 (13.3%)
140 (13.0%)
0.0089
381 (11.6%)
361 (11.0%)
0.0190
524 (12.0%)
501 (11.5%)
0.016
CVD - Other dysrythmias   ; n (%)*
189 (17.6%)
155 (14.4%)
0.0874
344 (10.5%)
368 (11.2%)
-0.0225
533 (12.2%)
523 (12.0%)
0.006
CVD - Valve disorder   ; n (%)
34 (3.2%)
30 (2.8%)
0.0235
71 (2.2%)
76 (2.3%)
-0.0067
105 (2.4%)
106 (2.4%)
0.000
CVD - Implantable cardioverter defibrillator  ; n (%)*
14 (1.3%)
22 (2.1%)
-0.0619
32 (1.0%)
36 (1.1%)
-0.0098
046 (1.1%)
058 (1.3%)
-0.018
CVD - CABG/PCI; n (%)
74 (6.9%)
59 (5.5%)
0.0581
136 (4.1%)
127 (3.9%)
0.0102
210 (4.8%)
186 (4.3%)
0.024
CVD - Coronary atherosclerosis and other forms of chronic ischemic heart disease; n (%)
268 (25.0%)
247 (23.0%)
0.0468
693 (21.1%)
657 (20.0%)
0.0272
961 (22.1%)
904 (20.7%)
0.034
CVD - Stroke/TIA  ; n (%)
60 (5.6%)
66 (6.2%)
-0.0255
163 (5.0%)
159 (4.8%)
0.0093
223 (5.1%)
225 (5.2%)
-0.005
CVD - Peripheral Vascular Disease (PVD) or PVD Surgery; n (%)
112 (10.4%)
105 (9.8%)
0.0199
209 (6.4%)
218 (6.6%)
-0.0081
321 (7.4%)
323 (7.4%)
0.000
CVD - Hyperlipidemia  ; n (%)
514 (47.9%)
511 (47.6%)
0.0060
690 (21.0%)
681 (20.7%)
0.0074
1,204 (27.6%)
1,192 (27.4%)
0.004
CVD - Hypertension; n (%)
692 (64.5%)
704 (65.6%)
-0.0231
1,347 (41.0%)
1,335 (40.6%)
0.0081
2,039 (46.8%)
2,039 (46.8%)
0.000
CRX - ACEi or ARB; n (%)
456 (42.5%)
471 (43.9%)
-0.0283
1,404 (42.7%)
1,370 (41.7%)
0.0202
1,860 (42.7%)
1,841 (42.2%)
0.010
CRX - Mineralocorticoid receptor antagonist  ; n (%)
43 (4.0%)
39 (3.6%)
0.0209
156 (4.7%)
153 (4.7%)
0.0000
199 (4.6%)
192 (4.4%)
0.010
CRX - Loop or Thiazide diuretics; n (%)
373 (34.8%)
389 (36.3%)
-0.0313
1,326 (40.4%)
1,310 (39.9%)
0.0102
1,699 (39.0%)
1,699 (39.0%)
0.000
CRX - Statins and other lipid lowering agents; n (%)
486 (45.3%)
473 (44.1%)
0.0241
1,462 (44.5%)
1,412 (43.0%)
0.0302
1,948 (44.7%)
1,885 (43.3%)
0.028
CRX - Beta blockers ; n (%)
341 (31.8%)
324 (30.2%)
0.0346
937 (28.5%)
909 (27.7%)
0.0178
1,278 (29.3%)
1,233 (28.3%)
0.022
CRX - CCB and other antihypertensives; n (%)
334 (31.1%)
338 (31.5%)
-0.0086
1,107 (33.7%)
1,123 (34.2%)
-0.0106
1,441 (33.1%)
1,461 (33.5%)
-0.008
CRX - Digoxin   ; n (%)*
52 (4.8%)
51 (4.8%)
0.0000
297 (9.0%)
283 (8.6%)
0.0141
349 (8.0%)
334 (7.7%)
0.011
CRX - Nitrates; n (%)*
100 (9.3%)
90 (8.4%)
0.0317
421 (12.8%)
386 (11.8%)
0.0305
521 (12.0%)
476 (10.9%)
0.035
OCM - Type 1 or 2 DM; n (%)
288 (26.8%)
277 (25.8%)
0.0227
660 (20.1%)
665 (20.2%)
-0.0025
948 (21.8%)
942 (21.6%)
0.005
OCM - Occurrence of Diabetic retinopathy/nephropathy/neuropathy; n (%)*
91 (8.5%)
104 (9.7%)
-0.0417
123 (3.7%)
115 (3.5%)
0.0107
214 (4.9%)
219 (5.0%)
-0.005
OCM - Hypertensive nephropathy; n (%)*
81 (7.5%)
79 (7.4%)
0.0038
100 (3.0%)
86 (2.6%)
0.0242
181 (4.2%)
165 (3.8%)
0.020
OCM - Hypotension  ; n (%)*
42 (3.9%)
39 (3.6%)
0.0158
75 (2.3%)
88 (2.7%)
-0.0256
117 (2.7%)
127 (2.9%)
-0.012
OCM - Hyperkalemia ; n (%)*
29 (2.7%)
32 (3.0%)
-0.0180
56 (1.7%)
27 (0.8%)
0.0811
085 (2.0%)
059 (1.4%)
0.046
OCM - CKD II, III, or IV; n (%)
93 (8.7%)
99 (9.2%)
-0.0175
80 (2.4%)
92 (2.8%)
-0.0251
173 (4.0%)
191 (4.4%)
-0.020
OCM - HD/PD/ESRD; n (%)*
16 (1.5%)
7 (0.7%)
0.0768
35 (1.1%)
22 (0.7%)
0.0424
051 (1.2%)
029 (0.7%)
0.052
OCM - Osteoporosis; n (%)
134 (12.5%)
142 (13.2%)
-0.0209
457 (13.9%)
458 (13.9%)
0.0000
591 (13.6%)
600 (13.8%)
-0.006
OCM - Sleep apnea ; n (%)
139 (13.0%)
132 (12.3%)
0.0211
232 (7.1%)
258 (7.9%)
-0.0304
371 (8.5%)
390 (8.9%)
-0.014
OCM - Fractures  ; n (%)
68 (6.3%)
67 (6.2%)
0.0041
212 (6.5%)
195 (5.9%)
0.0249
280 (6.4%)
262 (6.0%)
0.017
OCM - Other Arthritis, Arthropathies and Musculoskeletal Pain ; n (%)
461 (43.0%)
449 (41.8%)
0.0243
1,056 (32.1%)
1,004 (30.6%)
0.0323
1,517 (34.8%)
1,453 (33.3%)
0.032
OCM - Dorsopathies; n (%)
308 (28.7%)
300 (28.0%)
0.0155
662 (20.2%)
639 (19.5%)
0.0176
970 (22.3%)
939 (21.5%)
0.019
OCM - Gout (acute/chronic) ; n (%)*
7 (0.7%)
13 (1.2%)
-0.0516
45 (1.4%)
32 (1.0%)
0.0367
052 (1.2%)
045 (1.0%)
0.019
OCM - Hyperthyroidism  ; n (%)*
3 (0.3%)
14 (1.3%)
-0.1124
18 (0.5%)
17 (0.5%)
0.0000
021 (0.5%)
031 (0.7%)
-0.026
OCM - Hypothyroidism ; n (%)*
98 (9.1%)
104 (9.7%)
-0.0206
208 (6.3%)
205 (6.2%)
0.0041
306 (7.0%)
309 (7.1%)
-0.004
OCM - VTE ; n (%)*
39 (3.6%)
46 (4.3%)
-0.0359
111 (3.4%)
99 (3.0%)
0.0227
150 (3.4%)
145 (3.3%)
0.006
OCM - GERD ; n (%)
202 (18.8%)
186 (17.3%)
0.0390
233 (7.1%)
255 (7.8%)
-0.0267
435 (10.0%)
441 (10.1%)
-0.003
OCM - Cancer   ; n (%)
150 (14.0%)
166 (15.5%)
-0.0423
359 (10.9%)
349 (10.6%)
0.0097
509 (11.7%)
515 (11.8%)
-0.003
OCM - Hypovolemia/volume depletion ; n (%)*
59 (5.5%)
54 (5.0%)
0.0224
105 (3.2%)
115 (3.5%)
-0.0167
164 (3.8%)
169 (3.9%)
-0.005
OCM - Anemia   ; n (%)
190 (17.7%)
161 (15.0%)
0.0731
376 (11.4%)
356 (10.8%)
0.0191
566 (13.0%)
517 (11.9%)
0.033
OCM - Dementia  ; n (%)*
73 (6.8%)
93 (8.7%)
-0.0711
128 (3.9%)
148 (4.5%)
-0.0299
201 (4.6%)
241 (5.5%)
-0.041
OCM - Depression ; n (%)
204 (19.0%)
182 (17.0%)
0.0521
291 (8.9%)
280 (8.5%)
0.0142
495 (11.4%)
462 (10.6%)
0.026
ORX - Metformin; n (%)*
129 (12.0%)
117 (10.9%)
0.0346
300 (9.1%)
304 (9.3%)
-0.0069
429 (9.8%)
421 (9.7%)
0.003
ORX - 1st and 2nd Generation SUs   ; n (%)
96 (8.9%)
88 (8.2%)
0.0250
284 (8.6%)
279 (8.5%)
0.0036
380 (8.7%)
367 (8.4%)
0.011
ORX - Insulins ; n (%)
92 (8.6%)
102 (9.5%)
-0.0314
190 (5.8%)
199 (6.1%)
-0.0127
282 (6.5%)
301 (6.9%)
-0.016
ORX - Other antidiabetic medications use; n (%)
49 (4.6%)
63 (5.9%)
-0.0583
164 (5.0%)
169 (5.1%)
-0.0046
213 (4.9%)
232 (5.3%)
-0.018
ORX - PPIs or H2RAs use; n (%)*
299 (27.9%)
286 (26.7%)
0.0269
1,054 (32.1%)
976 (29.7%)
0.0520
1,353 (31.0%)
1,262 (29.0%)
0.044
ORX - NSAIDs ; n (%)*
150 (14.0%)
172 (16.0%)
-0.0560
619 (18.8%)
557 (17.0%)
0.0470
769 (17.6%)
729 (16.7%)
0.024
ORX - Use of opioids  ; n (%)*
418 (39.0%)
408 (38.0%)
0.0206
1,302 (39.6%)
1,273 (38.8%)
0.0164
1,720 (39.5%)
1,681 (38.6%)
0.018
ORX - Use of antipsychotics   ; n (%)*
69 (6.4%)
60 (5.6%)
0.0337
137 (4.2%)
143 (4.4%)
-0.0099
206 (4.7%)
203 (4.7%)
0.000
ORX - Use of antidepressants  ; n (%)
408 (38.0%)
393 (36.6%)
0.0290
1,150 (35.0%)
1,152 (35.1%)
-0.0021
1,558 (35.8%)
1,545 (35.5%)
0.006
ORX - Use of anxiolytics/hypnotics ; n (%)
116 (10.8%)
106 (9.9%)
0.0295
383 (11.7%)
380 (11.6%)
0.0031
499 (11.5%)
486 (11.2%)
0.009
ORX - Use of anticonvulsants  ; n (%)*
207 (19.3%)
215 (20.0%)
-0.0176
462 (14.1%)
422 (12.8%)
0.0381
669 (15.4%)
637 (14.6%)
0.022
ORX - Use of Benzodiazepines ; n (%)*
214 (19.9%)
184 (17.1%)
0.0722
847 (25.8%)
863 (26.3%)
-0.0114
1,061 (24.3%)
1,047 (24.0%)
0.007
ORX - Use of dementia meds  ; n (%)*
37 (3.4%)
45 (4.2%)
-0.0419
97 (3.0%)
125 (3.8%)
-0.0442
134 (3.1%)
170 (3.9%)
-0.044
ORX - Use of antiparkinsonian meds  ; n (%)*
46 (4.3%)
43 (4.0%)
0.0150
104 (3.2%)
115 (3.5%)
-0.0167
150 (3.4%)
158 (3.6%)
-0.011
ORX - Use of oral anticoagulants   ; n (%)*
121 (11.3%)
125 (11.6%)
-0.0094
416 (12.7%)
400 (12.2%)
0.0151
537 (12.3%)
525 (12.0%)
0.009
ORX - Use of antiplatelet agents ; n (%)*
123 (11.5%)
108 (10.1%)
0.0451
506 (15.4%)
482 (14.7%)
0.0196
629 (14.4%)
590 (13.5%)
0.026
LFS - Obesity; n (%)
95 (8.9%)
115 (10.7%)
-0.0606
126 (3.8%)
121 (3.7%)
0.0053
221 (5.1%)
236 (5.4%)
-0.013
LFS - Alcohol/Drug Abuse or Dependence ; n (%)
71 (6.6%)
62 (5.8%)
0.0332
64 (1.9%)
59 (1.8%)
0.0074
135 (3.1%)
121 (2.8%)
0.018
PFT - Spirometry test only; n (%)
213 (19.9%)
220 (20.5%)
-0.0149
672 (20.5%)
683 (20.8%)
-0.0074
885 (20.3%)
903 (20.7%)
-0.010
PFT - Spirometry test only (Count - 180 days to 31 days before CED) *
...mean (sd)
0.24 (0.71)
0.28 (0.85)
-0.0511
0.23 (0.68)
0.20 (0.65)
0.0451
0.23 (0.69)
0.22 (0.70)
0.014
...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 (0.69)
0.00 (0.70)
0.000
PFT - Spirometry test only (Count - 30 days to CED) *
...mean (sd)
0.15 (0.63)
0.13 (0.53)
0.0344
0.11 (0.45)
0.13 (0.47)
-0.0435
0.12 (0.50)
0.13 (0.49)
-0.020
...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 (0.50)
0.00 (0.49)
0.000
PFT - Lung volume, Diffuse capacity, pulmonary stress testing (any); n (%)
149 (13.9%)
155 (14.4%)
-0.0143
242 (7.4%)
260 (7.9%)
-0.0188
391 (9.0%)
415 (9.5%)
-0.017
HCU - Pulmonologist visit (180 to 1 day before CED); n (%)
30 (2.8%)
26 (2.4%)
0.0251
781 (23.8%)
794 (24.2%)
-0.0094
811 (18.6%)
820 (18.8%)
-0.005
HCU - Pulmonologist visit on CED; n (%)
2 (0.2%)
1 (0.1%)
0.0258
84 (2.6%)
87 (2.6%)
0.0000
086 (2.0%)
088 (2.0%)
0.000
HCU - Pulmonologist visit (Number of during CAP) *
...mean (sd)
0.26 (2.12)
0.23 (2.09)
0.0143
0.92 (2.44)
0.95 (2.51)
-0.0121
0.76 (2.37)
0.77 (2.41)
-0.004
...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, 1.00]
0.0000
0.00 (2.37)
0.00 (2.41)
0.000
HCU - Number of Internal Medicine/Family Medicine Visits  
...mean (sd)
9.78 (13.81)
10.82 (17.37)
-0.0663
7.74 (13.40)
7.87 (13.19)
-0.0098
8.24 (13.50)
8.60 (14.33)
-0.026
...median [IQR]
5.00 [1.00, 12.00]
6.00 [1.00, 13.00]
-0.0637
4.00 [0.00, 9.00]
4.00 [1.00, 9.00]
0.0000
4.25 (13.50)
4.49 (14.33)
-0.017
HCU - Number of Cardiologist visits  
...mean (sd)
2.39 (6.16)
2.06 (5.10)
0.0584
1.31 (3.84)
1.29 (4.06)
0.0051
1.58 (4.52)
1.48 (4.34)
0.023
...median [IQR]
0.00 [0.00, 2.00]
0.00 [0.00, 1.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 1.00]
0.0000
0.00 (4.52)
0.00 (4.34)
0.000
HCU - Number of Emergency Department (ED) visits v3 
...mean (sd)
0.87 (1.95)
0.82 (1.93)
0.0258
0.65 (2.71)
0.65 (3.32)
0.0000
0.70 (2.54)
0.69 (3.04)
0.004
OPTUM
MARKETSCAN
POOLED
MATCHED
Appendix B

...median [IQR]
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.0000
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 (2.54)
0.00 (3.04)
0.000
HCU - Old hospitalization (-180 days to -31 days before CED)  ; n (%)
251 (23.4%)
224 (20.9%)
0.0602
999 (30.4%)
969 (29.5%)
0.0196
1,250 (28.7%)
1,193 (27.4%)
0.029
HCU - Recent hospitalization (-30 days to CED date)  ; n (%)
28 (2.6%)
23 (2.1%)
0.0330
147 (4.5%)
131 (4.0%)
0.0248
175 (4.0%)
154 (3.5%)
0.026
HCU - Number of hospitalizations during CAP  
...mean (sd)
0.35 (0.79)
0.32 (0.76)
0.0387
0.42 (0.72)
0.41 (0.72)
0.0139
0.40 (0.74)
0.39 (0.73)
0.014
...median [IQR]
0.00 [0.00, 0.00]
0.00 [0.00, 0.00]
0.0000
0.00 [0.00, 1.00]
0.00 [0.00, 1.00]
0.0000
0.00 (0.74)
0.00 (0.73)
0.000
HCU - Blood eosinophilia or Serum IgE test order; n (%)*
10 (0.9%)
11 (1.0%)
-0.0103
20 (0.6%)
25 (0.8%)
-0.0240
030 (0.7%)
036 (0.8%)
-0.012
HCU - Pneumococcal vaccine; n (%)
133 (12.4%)
140 (13.0%)
-0.0180
115 (3.5%)
112 (3.4%)
0.0055
248 (5.7%)
252 (5.8%)
-0.004
HCU - Flu vaccine  ; n (%)
192 (17.9%)
178 (16.6%)
0.0344
351 (10.7%)
334 (10.2%)
0.0163
543 (12.5%)
512 (11.7%)
0.025
HCU - Bone mineral density  ; n (%)
31 (2.9%)
34 (3.2%)
-0.0174
58 (1.8%)
66 (2.0%)
-0.0146
089 (2.0%)
100 (2.3%)
-0.021
HCU - Pap smear ; n (%)
40 (3.7%)
49 (4.6%)
-0.0451
111 (3.4%)
124 (3.8%)
-0.0215
151 (3.5%)
173 (4.0%)
-0.026
HCU - Mammogram  ; n (%)
120 (11.2%)
137 (12.8%)
-0.0493
334 (10.2%)
338 (10.3%)
-0.0033
454 (10.4%)
475 (10.9%)
-0.016
HCU - Prostate exam for DRE  ; n (%)
35 (3.3%)
43 (4.0%)
-0.0373
27 (0.8%)
27 (0.8%)
0.0000
062 (1.4%)
070 (1.6%)
-0.016
HCU - Number of Echocardiogram  *
...mean (sd)
0.64 (3.50)
0.46 (1.79)
0.0648
0.44 (1.24)
0.44 (1.13)
0.0000
0.49 (2.04)
0.44 (1.32)
0.029
...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 (2.04)
0.00 (1.32)
0.000
HCU - Flexible Sigmoidoscopy or colonoscopy or CT virtual colonoscopy  ; n (%)
60 (5.6%)
62 (5.8%)
-0.0086
194 (5.9%)
190 (5.8%)
0.0043
254 (5.8%)
252 (5.8%)
0.000
HCU - Number of Distinct Medication Prescriptions (not generalized to generics)  
...mean (sd)
28.97 (22.63)
29.22 (22.55)
-0.0111
26.87 (17.54)
27.20 (17.32)
-0.0189
27.39 (18.92)
27.70 (18.74)
-0.016
...median [IQR]
23.00 [14.00, 37.00]
24.00 [14.00, 38.00]
-0.0443
23.00 [15.00, 35.00]
24.00 [15.00, 36.00]
-0.0574
23.00 (18.92)
24.00 (18.74)
-0.053
SES - Copay for pharmacy cost (charges in U.S. $)  
...mean (sd)
33.13 (30.75)
34.27 (37.75)
-0.0331
26.28 (26.21)
26.79 (30.17)
-0.0180
27.97 (27.40)
28.63 (32.20)
-0.022
...median [IQR]
27.07 [12.96, 42.81]
24.89 [11.22, 44.04]
0.0633
21.02 [9.00, 35.43]
21.11 [10.00, 36.00]
-0.0032
22.51 (27.40)
22.04 (32.20)
0.016
SES - Business type   
...Commercial; n (%)
392 (36.5%)
404 (37.7%)
-0.0248
392 (36.5%)
404 (37.7%)
-0.025
...Medicare; n (%)
681 (63.5%)
669 (62.3%)
0.0248
681 (63.5%)
669 (62.3%)
0.025
SES - Low income indicator  ; n (%)
183 (17.1%)
201 (18.7%)
-0.0417
183 (17.1%)
201 (18.7%)
-0.042
SES - Insurance Plan type   
...Comprehensive; n (%)
1,230 (37.4%)
1,231 (37.5%)
-0.0021
1,230 (37.4%)
1,231 (37.5%)
-0.002
...HMO; n (%)
854 (26.0%)
819 (24.9%)
0.0253
854 (26.0%)
819 (24.9%)
0.025
...PPO; n (%)
956 (29.1%)
987 (30.0%)
-0.0197
956 (29.1%)
987 (30.0%)
-0.020
...Others; n (%)
245 (7.5%)
248 (7.5%)
0.0000
245 (7.5%)
248 (7.5%)
0.000
___________
* Not included in PS model
Appendix B