Data Analysis for Drug Repurposing for Effective Alzheimer's Medicines (DREAM) - Salbutamol vs Long-acting Muscarinic Antagonists
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Brigham and Women's Hospital

Data Analysis for Drug Repurposing for Effective 
Alzheimer’s Medicines – Salbutamol vs Long-acting 
Muscarinic Antagonists 
 
 
 
NCT05457868 
 
 
 
August 22, 2022 
 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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1. Comparison Details 
 
a. Intended aim(s) 
 
To evaluate the comparative risk of dementia onset between patients treated with Salbutamol (albuterol) versus 
Long-acting muscarinic antagonists (LAMAs) – umeclidinium, aclidinium, tiotropium, glycopyrolate, 
glycopyrronium – for Chronic obstructive pulmonary disease (COPD). 
 
b. Primary endpoint  
Incident dementia (i.e., Alzheimer’s disease, vascular dementia, senile, presenile, or unspecified dementia, or 
dementia in other diseases classified elsewhere). 
 
2. Person responsible for implementation 
Seanna Vine 
 
3. Data Source(s) 
Medicare, 2014-2018  
 
 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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4. Study Design Diagrams 
 

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DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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5. Cohort Identification  
 
a. Cohort Summary 
This study will employ a new user, active comparator, observational cohort study design comparing Salbutamol versus 
Long-acting muscarinic antagonists (LAMAs). The patients will be required to have continuous enrollment during the 
baseline period of 365 days before initiation of study drugs (cohort entry/index date). Follow-up for the outcome 
(dementia) differs between analyses. Follow-up begins the day after drug initiation (analysis 1, 3, 4); 180 days after 
drug initiation (analysis 2). 
 
b. Key details regarding cohort creation 
 
Index date: 
• Day of initiation of new Salbutamol versus Long-acting muscarinic antagonists (LAMAs)  
 
Inclusion criteria for analyses 1, 3, 4: 
• Aged > 65 years on the index date 
• 365 days enrollment in Medicare Parts A, B, and D with no HMO coverage  
• No use of Salbutamol versus Long-acting muscarinic antagonists (LAMAs) any time prior to index date (all 
available lookback approach with a minimum of 365 days) 
• No diagnosis of dementia any time prior to and including index date 
• No history of nursing home admission recorded in any time prior to and including index date 
• At least two claims with COPD diagnosis recorded in 365 days prior to index date (ICD-9 490, 491.0, 491.1, 
491.2x, 491.8, 491.9, 492.0, 492.8, 494.0, 494.1, 496 or ICD-10 J40, J41.0, J41.1, J41.8, J42, J43.0, J43.1, 
J43.2, J43.8, J43.9, J44.0, J44.1, J44.9, J47.0, J47.1, J47.9)  
 
Inclusion criteria for analysis 2: 
• Aged > 65 years on the index date 
• 365 days enrollment in Medicare Parts A, B, and D with no HMO coverage or 365 days registration with a 
practice contributing data to CPRD prior to index date 
• No use of Salbutamol versus Long-acting muscarinic antagonists (LAMAs), any time prior to index date (all 
available lookback approach with a minimum of 365 days) 
• No diagnosis of dementia any time prior to and including index date 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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• No history of nursing home admission recorded in any time prior to and including index date 
• At least two claims with COPD diagnosis recorded in 365 days prior to index date (ICD-9 490, 491.0, 491.1, 
491.2x, 491.8, 491.9, 492.0, 492.8, 494.0, 494.1, 496 or ICD-10 J40, J41.0, J41.1, J41.8, J42, J43.0, J43.1, 
J43.2, J43.8, J43.9, J44.0, J44.1, J44.9, J47.0, J47.1, J47.9)  
• 180-day continuous use of Salbutamol versus Long-acting muscarinic antagonists (LAMAs) starting on the 
index date 
 
 
c. Flowchart of the study cohort assembly 
 
 
 
 
 
 
 
 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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6. Variables  
 
a. Exposure-related variables:  
 
Study drug:  
The study exposure of interest is initiation of Salbutamol 
Comparator: 
Long-acting muscarinic antagonists (LAMAs) – umeclidinium, aclidinium, tiotropium, glycopyrolate, glycopyrronium 
 
b. Covariates: 
 
Demographics 
Age 
Region 
Gender 
Calendar year of index date 
Race 
Low income subsidy 
 
 
Dementia risk factors 
Diabetes 
Depression 
Obesity 
Anxiety 
Hypertension 
Bipolar disorder 
Coronary artery disease 
Schizophrenia 
 
Markers for healthy behavior, frailty, healthcare use 
Smoking 
Number of hospitalizations  
Mammography 
Number of physician office visits 
Colonoscopy 
Number of serum creatinine tests ordered 
Fecal occult blood test 
Composite frailty score 
Influenza vaccination 
Number of C-reactive protein tests ordered 
Pneumococcal vaccination 
Osteoporosis 
Herpes zoster vaccination 
Fractures 
Bone mineral density test 
Falls 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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Number of distinct generic agents 
Use of supplemental oxygen 
Number of emergency room visits 
Combined comorbidity score 
Number of outpatient visits 
 
 
COPD specific and other pulmonary relevant covariates 
Respiratory failure 
Pulmonary Hypertension 
Moderate or Severe COPD exacerbation1 
Interstitial lung disease, lung fibrosis, ARDS 
Tuberculosis 
Acute Upper/ Lower Respiratory Tract infection 
Lung Cancer 
Pneumonia 
Bronchiectasis 
Alpha-1-antitrypsin deficiency 
Sarcoidosis 
Number of Pulmonologist visits 
Pulmonary function test 
 
 
COPD medication levels (a multi-category using hierarchical definition described below)2 
1. Monotherapy 
Short acting muscarinic antagonist or short acting 
beta agonist (SAMA or SABA only): One or more 
from [Salbutamol, Fenoterol, 
Levalbuterol, Terbutaline, Ipratropium,  
Oxitropium] but not any from 2-6 below 
Long acting muscarinic antagonist or long acting beta 
agonist (LAMA or LABA only): One/more LABA 
[Arformoterol, Formoterol 
Indacaterol, Olodaterol, Salmeterol] OR 
one/more LAMA [Tiotropium, Aclidinium, 
Glycopyrronium, Umeclidinium] but not both 
3. Dual therapy  
LAMA+LABA: One/more LABA [Arformoterol, 
Formoterol 
Indacaterol, Olodaterol, Salmeterol] AND 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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One/more LAMA [Tiotropium, Aclidinium, 
Glycopyrronium, Umeclidinium] but no inhaled 
corticosteroid 
ICS + LAMA: One/more inhaled corticosteroid 
[beclomethasone, budenoside, mometasone, 
fluticasone] AND 
One/more LAMA [Tiotropium, Aclidinium, 
Glycopyrronium, Umeclidinium] but no LABA 
ICS + LABA: One/more inhaled corticosteroid 
[beclomethasone, budenoside, mometasone, 
fluticasone] AND 
One/more LABA [Arformoterol, Formoterol 
Indacaterol, Olodaterol, Salmeterol] but no LAMA 
4. Triple therapy (ICS + LAMA + LABA) 
One/more inhaled corticosteroid [beclomethasone, 
budenoside, mometasone, fluticasone] AND 
One/more LAMA [Tiotropium, Aclidinium, 
Glycopyrronium, Umeclidinium] AND 
One/more LABA [Arformoterol, Formoterol 
Indacaterol, Olodaterol, Salmeterol] 
 
Comedication use 
Lithium 
Diuretics 
Anti-epileptic mood stabilizers 
Nitrates 
Anti-epileptics (other than mood stabilizers) 
Lipid lowering drugs 
Atypical antipsychotics 
Non-insulin diabetes medications 
Benzodiazepines 
Insulin 
Serotonin-norepinephrine reuptake Inhibitors 
Antidepressants 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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Selective serotonin reuptake inhibitors 
Angiotensin II receptor blockers (ARBs) 
Tricyclic antidepressants (TCAs) 
Angiotensin converting enzyme inhibitors (ACEi) 
Typical antipsychotics 
Calcium channel blockers 
Anticoagulants 
Beta blockers 
Antiplatelet agents 
Disease-modifying antirheumatic drugs 
(DMARDs) 
Corticosteroids 
Antibiotics 
 
Comorbid conditions 
Atrial fibrillation 
Asthma 
Heart failure 
Ischemic heart disease 
Stroke or transient ischemic attack 
Malignancy 
Peripheral vascular disease 
Drug or alcohol abuse or dependence 
Hyperlipidemia 
Venous thromboembolism 
Renal dysfunction 
Rheumatoid Arthritis 
Chronic liver disease  
 
 
ICD-9, ICD-10, HCPCS, and NDC codes used to define the covariates listed above are available in Appendix A. 
 
c. Outcome variables and study follow-up:  
 
• Primary outcome: incident dementia, i.e., Alzheimer’s disease, vascular dementia, senile, presenile, or 
unspecified dementia, or dementia in other diseases classified elsewhere. Outcome will be defined by 1 inpatient 
claim or 2 outpatient claims in analysis 1, 2, 3. In analysis 4, the outcome will be defined by 1 inpatient or 1 
outpatient claims and 1 prescription claim for a symptomatic treatment [donepezil, galantamine, rivastigmine, and 
memantine] within 6 months of each other with outcome date assigned to second event in the sequence.  
• Secondary outcomes: Individual component: 
Alzheimer’s disease 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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Condition 
ICD-9 and ICD-10 codes 
Alzheimer’s disease 
331.0*, F00*, G30* 
Vascular dementia 
290.4*, F01* 
Senile, presenile, or unspecified dementia 
290.0*, 290.1*. 290.3*, 797*, F03* 
Dementia in other diseases classified elsewhere 
331.1*, 331.2*, 331.7*, 294.1*, F02* 
 
For analysis 1,3, and 4 the follow-up will start the day after initiation of Salbutamol and LAMAs and will continue until 
the earliest date of the following events: 
• The first occurrence of the outcome of interest  
• The date of end of continuous registration in the database, 
• End of the study period, 
• Measured death event occurs, 
• The date of drug discontinuation, defined as the date of the last continuous treatment episode of the index drug 
(Salbutamol and LAMAs) plus a defined grace period (i.e., 90 days after the end of the last prescription’s days’ 
supply in main analyses). 
 
For analysis 2, the follow-up will start 180 days after initiation of Salbutamol and LAMAs and will continue until the 
earliest date of the following events: 
• The first occurrence of the outcome of interest, unless otherwise specified for selected outcomes,  
• The date of end of continuous registration in the database, 
• End of the study period, 
• Measured death event occurs, 
• 
Maximum allowed follow-up time (1095 days) reached 
 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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7. Propensity score analysis  
We will use a propensity-score (PS)3-based approach to account for measured confounding in this study. The PS will 
be calculated as the predicted probability of initiating the exposure of interest (i.e., the repurposing candidate) versus 
the reference drug conditional on baseline covariates using multivariable logistic regression constructed separately 
in each data source. On average, patients with similar PSs have similar distribution of potential confounders used to 
estimate the PS. Therefore, analyses conditioned on the PS provide effect estimates that are free from measured 
confounding. For all our analyses, initiators of each exposure of interest will be matched with initiators of the reference 
exposure based on their PS within each data source.4 Pair matching will be conducted using a nearest-neighbor 
algorithm, which seeks to minimize the distance between propensity scores in each pair of treated and reference 
patients,5 and a caliper of 0.025 on the natural scale of the PS will be used to ensure similarity between the matched 
patients.6 
 
We report multiple diagnostics for PS analysis in this protocol. First, the PS distributional overlap is provided between 
two groups before and after matching to ensure comparability of these groups.7 Next, balance in each individual 
covariate between two treatment groups is reported using standardized differences.8 
 
 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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8. Table for covariate balance 
 
  
Unmatched 
PS-Matched 
Variable 
Salbutamol 
LAMAs 
St. Diff 
Salbutamol 
LAMAs 
St. Diff 
(N = 76,515) 
(N = 18,974) 
(N = 18,633) 
(N = 18,633) 
Demographics 
  
  
  
  
  
  
 Age, mean (SD)  
74.4 (6.7) 
74.9 (6.6) 
-7 
74.9 (6.8) 
74.9 (6.6) 
0.2 
 Gender, n (%)  
  
  
  
  
  
  
 Male  
34179 (44.7) 
9622 (50.7) 
-12.1 
9399 (50.4) 
9443 (50.7) 
-0.5 
 Female  
42336 (55.3) 
9352 (49.3) 
12.1 
9234 (49.6) 
9190 (49.3) 
0.5 
 Race, n (%)  
  
  
  
  
  
  
 White  
68119 (89) 
17022 (89.7) 
-2.2 
16740 (89.8) 
16717 (89.7) 
0.4 
 Black  
4701 (6.1) 
999 (5.3) 
3.8 
931 (5) 
981 (5.3) 
-1.2 
 Hispanic  
895 (1.2) 
197 (1) 
1.3 
209 (1.1) 
195 (1) 
0.7 
 Other  
2800 (3.7) 
756 (4) 
-1.7 
753 (4) 
740 (4) 
0.4 
 Region, n (%)  
  
  
  
  
  
  
 Northeast; n (%)  
12925 (16.9) 
3858 (20.3) 
-8.8 
3901 (20.9) 
3803 (20.4) 
1.3 
 South; n (%)  
30882 (40.4) 
7738 (40.8) 
-0.9 
7470 (40.1) 
7559 (40.6) 
-1 
 Midwest; n (%)  
19697 (25.7) 
4337 (22.9) 
6.7 
4238 (22.7) 
4281 (23) 
-0.5 
 West; n (%)  
12949 (16.9) 
3028 (16) 
2.6 
3016 (16.2) 
2978 (16) 
0.6 
Other; n (%) 
62 (0.1) 
13 (0.1) 
0.5 
8 (0) 
12 (0.1) 
-0.9 
Calendar year of index 
date, n (%) 
  
  
  
  
  
  

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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2014 
21088 (27.6) 
5664 (29.9) 
-5.1 
5515 (29.6) 
5603 (30.1) 
-1 
2015 
16927 (22.1) 
4117 (21.7) 
1 
4098 (22) 
4080 (21.9) 
0.2 
2016 
13486 (17.6) 
3308 (17.4) 
0.5 
3372 (18.1) 
3282 (17.6) 
1.3 
2017 
13323 (17.4) 
2979 (15.7) 
4.6 
2951 (15.8) 
2958 (15.9) 
-0.1 
2018 
11691 (15.3) 
2906 (15.3) 
-0.1 
2697 (14.5) 
2710 (14.5) 
-0.2 
Low income subsidy, n (%) 
15429 (20.2) 
3492 (18.4) 
4.5 
3416 (18.3) 
3430 (18.4) 
-0.2 
Dementia risk factors, n 
(%) 
  
  
  
  
  
  
Diabetes 
25989 (34) 
6496 (34.2) 
-0.6 
6331 (34) 
6370 (34.2) 
-0.4 
Obesity 
14618 (19.1) 
3559 (18.8) 
0.9 
3442 (18.5) 
3486 (18.7) 
-0.6 
Hypertension 
62676 (81.9) 
15707 (82.8) 
-2.3 
15419 (82.8) 
15430 (82.8) 
-0.2 
Coronary artery disease 
29486 (38.5) 
8138 (42.9) 
-8.9 
7942 (42.6) 
7989 (42.9) 
-0.5 
Depression 
13049 (17.1) 
3139 (16.5) 
1.4 
3091 (16.6) 
3071 (16.5) 
0.3 
Anxiety 
13392 (17.5) 
3112 (16.4) 
2.9 
3049 (16.4) 
3041 (16.3) 
0.1 
Bipolar disorder 
1089 (1.4) 
260 (1.4) 
0.5 
277 (1.5) 
254 (1.4) 
1 
Schizophrenia 
162 (0.2) 
30 (0.2) 
1.2 
28 (0.2) 
29 (0.2) 
-0.1 
Markers for healthy 
behavior, frailty, 
healthcare use 
  
  
  
  
  
  
Smoking, n (%) 
36477 (47.7) 
10319 (54.4) 
-13.5 
10097 (54.2) 
10136 (54.4) 
-0.4 
Mammography, n (%) 
16014 (20.9) 
3333 (17.6) 
8.5 
3263 (17.5) 
3275 (17.6) 
-0.2 
Colonoscopy, n (%) 
7990 (10.4) 
1918 (10.1) 
1.1 
1819 (9.8) 
1876 (10.1) 
-1 
Fecal occult blood test, n 
(%) 
5563 (7.3) 
1488 (7.8) 
-2.2 
1440 (7.7) 
1461 (7.8) 
-0.4 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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Influenza vaccination, n 
(%) 
49288 (64.4) 
12855 (67.8) 
-7 
12688 (68.1) 
12622 (67.7) 
0.8 
Pneumococcal 
vaccination, n (%) 
31232 (40.8) 
8082 (42.6) 
-3.6 
7935 (42.6) 
7896 (42.4) 
0.4 
Herpes zoster, n (%) 
16 (0) 
5 (0) 
-0.4 
7 (0) 
4 (0) 
0.9 
Bone mineral density, n 
(%) 
7356 (9.6) 
1716 (9) 
2 
1753 (9.4) 
1682 (9) 
1.3 
Number of distinct 
prescriptions, mean (SD) 
12.1 (5.8) 
12.1 (5.8) 
0.9 
12 (5.7) 
12 (5.8) 
-0.4 
Number of emergency 
room visits, mean (SD) 
0.9 (1.6) 
0.8 (1.4) 
9 
0.8 (1.2) 
0.8 (1.4) 
-1 
Number of outpatient 
visits, mean (SD) 
11.6 (8.4) 
12.2 (8.7) 
-6.8 
12.2 (8.7) 
12.1 (8.7) 
0.8 
Number of 
hospitalizations, mean 
(SD) 
0.3 (0.7) 
0.4 (0.7) 
-4.4 
0.4 (0.7) 
0.4 (0.7) 
0 
Number of physician 
office visits, mean (SD) 
11.6 (8.4) 
12.2 (8.7) 
-6.8 
12.2 (8.7) 
12.1 (8.7) 
0.8 
Number of C-reactive 
protein tests ordered, 
mean (SD) 
0.2 (0.8) 
0.2 (0.8) 
-1 
0.2 (0.8) 
0.2 (0.8) 
0.1 
Number of serum 
creatinine tests ordered, 
mean (SD) 
1.2 (2.1) 
1.2 (2.1) 
-1.8 
1.2 (2) 
1.2 (2.1) 
0.1 
Composite frailty score, 
mean (SD) 
0.2 (0.1) 
0.2 (0.1) 
-6 
0.2 (0.1) 
0.2 (0.1) 
-0.6 
Osteoporosis, n (%) 
10519 (13.7) 
2664 (14) 
-0.8 
2695 (14.5) 
2622 (14.1) 
1.1 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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Fractures, n (%) 
5899 (7.7) 
1347 (7.1) 
2.3 
1310 (7) 
1314 (7.1) 
-0.1 
Falls, n (%) 
4903 (6.4) 
1101 (5.8) 
2.5 
1060 (5.7) 
1071 (5.7) 
-0.3 
Use of supplemental 
oxygen, n (%) 
2548 (3.3) 
1124 (5.9) 
-12.4 
1083 (5.8) 
1103 (5.9) 
-0.5 
Combined comorbidity 
score, mean (SD) 
3 (2.6) 
3.2 (2.7) 
-8.8 
3.2 (2.7) 
3.2 (2.7) 
-0.8 
Comedication use, n (%) 
  
  
  
  
  
  
Lithium 
104 (0.1) 
31 (0.2) 
-0.7 
27 (0.1) 
30 (0.2) 
-0.4 
Anti-epileptic mood 
stabilizers 
962 (1.3) 
233 (1.2) 
0.3 
230 (1.2) 
226 (1.2) 
0.2 
Anti-epileptics (other than 
mood stabilizers) 
12688 (16.6) 
3012 (15.9) 
1.9 
2891 (15.5) 
2939 (15.8) 
-0.7 
Atypical antipsychotics 
1468 (1.9) 
364 (1.9) 
0 
357 (1.9) 
353 (1.9) 
0.2 
Benzodiazepines 
15721 (20.5) 
3774 (19.9) 
1.6 
3728 (20) 
3694 (19.8) 
0.5 
Serotonin-norepinephrine 
reuptake inhibitors 
4148 (5.4) 
1090 (5.7) 
-1.4 
1056 (5.7) 
1058 (5.7) 
0 
Selective serotonin 
reuptake inhibitors 
14107 (18.4) 
3371 (17.8) 
1.7 
3322 (17.8) 
3310 (17.8) 
0.2 
Tricyclic antidepressants 
(TCAs) 
2824 (3.7) 
615 (3.2) 
2.5 
599 (3.2) 
603 (3.2) 
-0.1 
Typical antipsychotics 
280 (0.4) 
55 (0.3) 
1.3 
46 (0.2) 
55 (0.3) 
-0.9 
Anticoagulants 
10269 (13.4) 
3023 (15.9) 
-7.1 
2964 (15.9) 
2971 (15.9) 
-0.1 
Antiplatelet agents 
10147 (13.3) 
2881 (15.2) 
-5.5 
2751 (14.8) 
2827 (15.2) 
-1.1 
Nitrates 
8214 (10.7) 
2245 (11.8) 
-3.5 
2186 (11.7) 
2202 (11.8) 
-0.3 
Lipid lowering drugs 
45866 (59.9) 
11884 (62.6) 
-5.5 
11554 (62) 
11666 (62.6) 
-1.2 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
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Non-insulin diabetes 
medications 
14767 (19.3) 
3652 (19.2) 
0.1 
3513 (18.9) 
3575 (19.2) 
-0.8 
Insulin 
5629 (7.4) 
1302 (6.9) 
1.9 
1313 (7) 
1280 (6.9) 
0.7 
Antidepressants 
22974 (30) 
5581 (29.4) 
1.3 
5529 (29.7) 
5469 (29.4) 
0.7 
Angiotensin II receptor 
blockers (ARBs) 
17841 (23.3) 
4732 (24.9) 
-3.8 
4669 (25.1) 
4650 (25) 
0.2 
Angiotensin converting 
enzyme inhibitors (ACEi) 
24902 (32.5) 
6081 (32) 
1.1 
5892 (31.6) 
5973 (32.1) 
-0.9 
Calcium channel blockers 
21852 (28.6) 
5684 (30) 
-3.1 
5476 (29.4) 
5588 (30) 
-1.3 
Beta blockers 
33549 (43.8) 
8709 (45.9) 
-4.1 
8530 (45.8) 
8547 (45.9) 
-0.2 
Disease-modifying 
antirheumatic drugs 
(DMARDs) 
2824 (3.7) 
691 (3.6) 
0.3 
650 (3.5) 
674 (3.6) 
-0.7 
Diuretics 
34617 (45.2) 
8908 (46.9) 
-3.4 
8677 (46.6) 
8751 (47) 
-0.8 
Corticosteroids 
35722 (46.7) 
7769 (40.9) 
11.6 
7603 (40.8) 
7632 (41) 
-0.3 
Antibiotics 
58260 (76.1) 
12802 (67.5) 
19.4 
12572 (67.5) 
12592 (67.6) 
-0.2 
COPD specific covariates 
  
  
  
  
  
  
Respiratory failure, n (%) 
7994 (10.4) 
2922 (15.4) 
-14.8 
2834 (15.2) 
2865 (15.4) 
-0.5 
Moderate or Severe COPD 
exacerbation, n (%) 
3341 (4.4) 
1181 (6.2) 
-8.3 
1174 (6.3) 
1175 (6.3) 
0 
Tuberculosis, n (%) 
15389 (20.1) 
4033 (21.3) 
-2.8 
3940 (21.1) 
3992 (21.4) 
-0.7 
Lung Cancer, n (%) 
3415 (4.5) 
1150 (6.1) 
-7.2 
1133 (6.1) 
1130 (6.1) 
0.1 
Bronchiectasis, n (%) 
2207 (2.9) 
820 (4.3) 
-7.7 
804 (4.3) 
805 (4.3) 
0 
Sarcoidosis, n (%) 
10967 (14.3) 
3718 (19.6) 
-14.1 
3649 (19.6) 
3659 (19.6) 
-0.1 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
17 
Pulmonary Hypertension, 
n (%) 
1643 (2.1) 
627 (3.3) 
-7.1 
610 (3.3) 
607 (3.3) 
0.1 
Interstitial lung disease, 
lung fibrosis, ARDS, n (%) 
10967 (14.3) 
3718 (19.6) 
-14.1 
3649 (19.6) 
3659 (19.6) 
-0.1 
Acute Upper/ Lower 
Respiratory Tract 
infection, n (%) 
23603 (30.8) 
4249 (22.4) 
19.2 
4103 (22) 
4175 (22.4) 
-0.9 
Pneumonia, n (%) 
6481 (8.5) 
1734 (9.1) 
-2.4 
1703 (9.1) 
1718 (9.2) 
-0.3 
Alpha-1-antitrypsin 
deficiency, n (%) 
84 (0.1) 
37 (0.2) 
-2.2 
35 (0.2) 
36 (0.2) 
-0.1 
Number of Pulmonologist 
visits, mean (SD) 
0.9 (2.2) 
1.6 (2.6) 
-27.2 
1.6 (2.9) 
1.6 (2.6) 
0 
Pulmonary function test, 
n (%) 
22718 (29.7) 
9742 (51.3) 
-45.2 
9806 (52.6) 
9550 (51.3) 
2.8 
Hierarchical COPD 
Medication, n (%) 
  
  
  
  
  
  
Monotherapy 
2536 (3.3) 
1785 (9.4) 
-25.2 
1507 (8.1) 
1726 (9.3) 
-4.2 
Dual therapy 
55581 (72.6) 
10873 (57.3) 
32.6 
10988 (59) 
10873 (58.4) 
1.3 
Triple therapy 
18398 (24) 
6036 (31.8) 
-17.4 
6138 (32.9) 
6034 (32.4) 
1.2 
Comorbid conditions, n 
(%) 
  
  
  
  
  
  
Atrial fibrillation 
13416 (17.5) 
3952 (20.8) 
-8.4 
3892 (20.9) 
3892 (20.9) 
0 
Heart failure 
14269 (18.6) 
4218 (22.2) 
-8.9 
4137 (22.2) 
4141 (22.2) 
-0.1 
Stroke or transient 
ischemic attack 
7776 (10.2) 
1943 (10.2) 
-0.3 
1900 (10.2) 
1905 (10.2) 
-0.1 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
18 
Peripheral vascular 
disease 
11563 (15.1) 
3353 (17.7) 
-6.9 
3159 (17) 
3299 (17.7) 
-2 
Hyperlipidemia 
54201 (70.8) 
13690 (72.2) 
-2.9 
13397 (71.9) 
13443 (72.1) 
-0.5 
Renal dysfunction 
15207 (19.9) 
3997 (21.1) 
-3 
3849 (20.7) 
3917 (21) 
-0.9 
Chronic liver disease 
5263 (6.9) 
1316 (6.9) 
-0.2 
1274 (6.8) 
1287 (6.9) 
-0.3 
Asthma 
45614 (59.6) 
10854 (57.2) 
4.9 
10716 (57.5) 
10630 (57) 
0.9 
Ischemic heart disease 
28709 (37.5) 
7935 (41.8) 
-8.8 
7759 (41.6) 
7791 (41.8) 
-0.3 
Malignancy 
22825 (29.8) 
6008 (31.7) 
-4 
5830 (31.3) 
5896 (31.6) 
-0.8 
Drug or alcohol abuse or 
dependence 
19920 (26) 
5549 (29.2) 
-7.2 
5436 (29.2) 
5447 (29.2) 
-0.1 
Venous 
thromboembolism 
3418 (4.5) 
915 (4.8) 
-1.7 
889 (4.8) 
899 (4.8) 
-0.3 
Rheumatoid Arthritis 
3666 (4.8) 
913 (4.8) 
-0.1 
876 (4.7) 
897 (4.8) 
-0.5 
 
9. Statistical analysis plans 
Incidence rates for the outcome will be estimated for the treatment and reference groups before and after PS 
matching. The competing risk of death could be of concern for the current set of analyses if mortality is frequent 
among patients included in the cohort and if differences in the risk of mortality between treatment and reference 
groups are substantial. In the PS-matched sample, we will use cause-specific hazard models9 to provide hazard 
ratios averaged over the entire follow-up period as well as interval specific hazard ratios (1, 2, and 3 years) for the 
association between the treatment of interest and risk of ADRD after considering all-cause mortality as a competing 
event. Pre-specified subgroup analyses will be conducted based on age, sex, and baseline cardiovascular disease.  
 
 
 

DREAM study protocol - Comparison 9 Salbutamol versus Long-acting muscarinic antagonists (LAMAs) 
 
 
19 
10. References 
 
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Gothe H, Rajsic S, Vukicevic D, et al. Algorithms to identify COPD in health systems with and without access to ICD 
coding: a systematic review. BMC Health Serv Res. 2019;19(1):737. 
2.  
GLOBAL STRATEGY FOR THE DIAGNOSIS, MANAGEMENT, AND PREVENTION OF CHRONIC OBSTRUCTIVE 
PULMONARY DISEASE: Global Initiative for Chronic Obstructive Lung Disease; 2018. 
3. 
Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. 
Biometrika. 1983;70(1):41-55. 
4. 
Rassen JA, Avorn J, Schneeweiss S. Multivariate-adjusted pharmacoepidemiologic analyses of confidential 
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Rassen JA, Shelat AA, Myers J, Glynn RJ, Rothman KJ, Schneeweiss S. One-to-many propensity score matching in 
cohort studies. Pharmacoepidemiol Drug Saf. May 2012;21 Suppl 2:69-80. 
6. 
Austin PC. Some Methods of Propensity-Score Matching had Superior Performance to Others: Results of an 
Empirical Investigation and Monte Carlo simulations. Biometrical Journal. 2009;51(1):171-184. 
7. 
AM Walker AM, Patrick A, Lauer M, et al. Tool for Assessing the Feasibility of Comparative Effectiveness Research. 
Comp Effect Res 2013;3:11-20. 
8. 
Franklin JM, Rassen JA, Ackermann D, Bartels DB, Schneeweiss S. Metrics for covariate balance in cohort studies 
of causal effects. Statistics in medicine. May 10 2014;33(10):1685-1699. 
9. 
Austin PC, Lee DS, Fine JP. Introduction to the analysis of survival data in the presence of competing risks. 
Circulation. 2016;133(6):601-609.