Table A1.



APPENDICESTable A1. ICD-9-CM and ICD-10 Codes for COPDCodeTypeDescription490ICD-9 DxBronchitis, not specified as acute or chronic491.0ICD-9 DxSimple chronic bronchitis491.1ICD-9 DxMucopurulent chronic bronchitis491.20ICD-9 DxObstructive chronic bronchitis, without exacerbation491.21ICD-9 DxObstructive chronic bronchitis, with (acute) exacerbation491.22ICD-9 DxObstructive chronic bronchitis with acute bronchitis491.8ICD-9 DxOther chronic bronchitis491.9ICD-9 DxUnspecified chronic bronchitis492.0ICD-9 DxEmphysematous bleb492.8ICD-9 DxOther emphysema496ICD-9 DxChronic airway obstruction, not elsewhere classifiedJ40ICD-10 DxBronchitis, not specified as acute or chronicJ41.0ICD-10 DxSimple chronic bronchitisJ41.1ICD-10 DxMucopurulent chronic bronchitisJ41.8ICD-10 DxMixed simple and mucopurulent chronic bronchitisJ42ICD-10 DxUnspecified chronic bronchitisJ43.0ICD-10 DxUnilateral pulmonary emphysema (MacLeod’s syndrome)J43.1ICD-10 DxPanlobular emphysemaJ43.2ICD-10 DxCentrilobular emphysemaJ43.8ICD-10 DxOther emphysemaJ43.9ICD-10 DxEmphysema, unspecifiedJ44.0ICD-10 DxChronic obstructive pulmonary disease with acute lower respiratory infectionJ44.1ICD-10 DxChronic obstructive pulmonary disease with (acute) exacerbationJ44.9ICD-10 DxChronic obstructive pulmonary disease, unspecifiedTable A SEQ Appendix \* ARABIC 2. ICD-9 CM and ICD-10 Codes for Exclusionary ConditionsAsthmaCodeCode TypeDescription493ICD-9 DxAsthma493.00ICD-9 DxExtrinsic asthma, unspecified493.01ICD-9 DxExtrinsic asthma with status asthmaticus493.02ICD-9 DxExtrinsic asthma, with (acute) exacerbation493.10ICD-9 DxIntrinsic asthma, unspecified493.11ICD-9 DxIntrinsic asthma with status asthmaticus493.12ICD-9 DxIntrinsic asthma, with (acute) exacerbation493.20ICD-9 DxChronic obstructive asthma, unspecified 493.21ICD-9 DxChronic obstructive asthma with status asthmaticus493.22ICD-9 DxChronic obstructive asthma, with (acute) exacerbation 493.81ICD-9 DxExercise induced bronchospasm493.82ICD-9 DxCough variant asthma493.90ICD-9 DxAsthma, unspecified, unspecified status493.91ICD-9 DxAsthma, unspecified with status asthmaticus493.92ICD-9 DxAsthma, unspecified, with (acute) exacerbationJ45ICD-10 DxAsthmaJ4520ICD-10 DxMild intermittent asthma, uncomplicatedJ4521ICD-10 DxMild intermittent asthma with (acute) exacerbationJ4522ICD-10 DxMild intermittent asthma with status asthmaticusJ4530ICD-10 DxMild persistent asthma, uncomplicatedJ4531ICD-10 DxMild persistent asthma with (acute) exacerbationJ4532ICD-10 DxMild persistent asthma with status asthmaticusJ4540ICD-10 DxModerate persistent asthma, uncomplicatedJ4541ICD-10 DxModerate persistent asthma with (acute) exacerbationJ4542ICD-10 DxModerate persistent asthma with status asthmaticusJ4550ICD-10 DxSevere persistent asthma, uncomplicatedJ4551ICD-10 DxSevere persistent asthma with (acute) exacerbationJ4552ICD-10 DxSevere persistent asthma with status asthmaticusJ45901ICD-10 DxUnspecified asthma with (acute) exacerbationJ45902ICD-10 DxUnspecified asthma with status asthmaticusJ45909ICD-10 DxUnspecified asthma, uncomplicatedJ45990ICD-10 DxExercise induced bronchospasmJ45991ICD-10 DxCough variant asthmaJ45998ICD-10 DxOther asthmaCystic FibrosisCodeCode TypeDescription277.0ICD-9 DxCystic fibrosis277.00ICD-9 DxCystic fibrosis without mention of meconium ileus277.01ICD-9 DxCystic fibrosis with meconium ileus277.02ICD-9 DxCystic fibrosis with pulmonary manifestations277.03ICD-9 DxCystic fibrosis with gastrointestinal manifestations277.09ICD-9 DxCystic fibrosis with other manifestationsE84ICD-10 DxCystic fibrosisE84.0ICD-10 DxCystic fibrosis with pulmonary manifestationsE84.11ICD-10 DxMeconium ileus in cystic fibrosisE84.19ICD-10 DxCystic fibrosis with other intestinal manifestationsE84.8ICD-10 DxCystic fibrosis with other manifestationsE84.9ICD-10 DxCystic fibrosis, unspecifiedLung CancerCodeCode TypeDescription162.2ICD-9 DxMalignant neoplasm of main bronchus162.3ICD-9 DxMalignant neoplasm of upper lobe, bronchus or lung162.4ICD-9 DxMalignant neoplasm of middle lobe, bronchus or lung162.5ICD-9 DxMalignant neoplasm of lower lobe, bronchus or lung162.8ICD-9 DxMalignant neoplasm of other parts of bronchus or lung162.9ICD-9 DxMalignant neoplasm of bronchus and lung, unspecifiedC34ICD-10 DxMalignant neoplasm of bronchus and lungC340ICD-10 DxMalignant neoplasm of main bronchus C3400ICD-10 DxMalignant neoplasm of unspecified main bronchus C3401ICD-10 DxMalignant neoplasm of right main bronchus C3402ICD-10 DxMalignant neoplasm of left main bronchus C341ICD-10 DxMalignant neoplasm of upper lobe, bronchus or lung C3410ICD-10 DxMalignant neoplasm of upper lobe, unspecified bronchus or lungC3411ICD-10 DxMalignant neoplasm of upper lobe, right bronchus or lung C3412ICD-10 DxMalignant neoplasm of upper lobe, left bronchus or lungC342ICD-10 DxMalignant neoplasm of middle lobe, bronchus or lung C343ICD-10 DxMalignant neoplasm of lower lobe, bronchus or lung C3430ICD-10 DxMalignant neoplasm of lower lobe, unspecified bronchus or lung C3431ICD-10 DxMalignant neoplasm of lower lobe, right bronchus or lung C3432ICD-10 DxMalignant neoplasm of lower lobe, left bronchus or lung C348ICD-10 DxMalignant neoplasm of overlapping sites of bronchus and lung C3480ICD-10 DxMalignant neoplasm of overlapping sites of unspecified bronchus and lung C3481ICD-10 DxMalignant neoplasm of overlapping sites of right bronchus and lung C3482ICD-10 DxMalignant neoplasm of overlapping sites of left bronchus and lung C349ICD-10 DxMalignant neoplasm of unspecified part of bronchus or lung C3490ICD-10 DxMalignant neoplasm of unspecified part of unspecified bronchus or lung C3491ICD-10 DxMalignant neoplasm of unspecified part of right bronchus or lung C3492ICD-10 DxMalignant neoplasm of unspecified part of left bronchus or lung Table A3. COPD-related Respiratory Medications and ClassesDrug ClassSubclassMedicationController medicationsInhaled long-acting anti-muscarinic agents (LAMA)tiotropiumaclidiniumumeclidiniumglycopyrrolate Inhaled LAMA/LABA combinationumeclidinium/vilanteroltiotropium/olodaterolglycopyrrolate/indacaterolglycopyrrolate/formoterolInhaled corticosteroids (ICS)beclomethasonebetamethasonebudesonide (both inhaler and nebulizer)ciclensonidedexamethasone (nebulizer)flunisolidefluticasonemometasonetriamcinoloneLong-acting β-agonists (LABA)arformoterol (nebulizer)formoterol (oral, nebulizer)indacaterol (inhaler)olodaterol (inhaler)salmeterol (inhaler)Inhaled ICS/LABA combinationfluticasone/salmeterolbudesonide/formoterolfluticasone/vilanterolmometasone/formoterol Methylxanthines (all routes)aminophyllinedyphyllinetheophyllinePDE-4 inhibitorroflumilastRescuemedicationsShort-acting β-agonists (SABA)albuterol (oral, inhaler, nebulizer)levalbuterol (inhaler, nebulizer)Short-acting anti-muscarinic Agents (SAMA)ipratropiumSAMA/SABAipratropium/albuterolOral corticosteroids (OCS)betamethasonecortisonedexamethasonehydrocortisonemethylprednisoloneprednisoloneprednisonetriamcinoloneCOPD Guideline-recommended Antibiotic MedicationsDrug CategoryDrug ClassMedicationCOPD Guideline-recommended antibiotics*CephalosporinscefaclorcefdinircefepimecefotaximecefotetancefoxitincefpodoximecefprozilceftazidimeceftriaxonecefuroximeMacrolidesazithromycinclarithromycinPenicillinsamoxicillinamoxicillin/potassium clavulanatepiperacillin/tazobactamQuinolonesgemifloxacinlevofloxacinmoxifloxacinSulfonamide combinationssulfamethoxazole/trimethoprimTetracyclinesdoxycycline*Based on the 2014 VA/DoD Clinical Practice Guideline for the Management of COPD, in which medications are explicitly outlined Table A4. Variables Related to Treatment Initiation included in IPTW ModelVariable CategoryVariableDemographicsIndex month/year in three month intervals (e.g., Q3 2015)Age in yearsGenderGeographic regionClinical characteristics and comorbiditiesPneumonia diagnosisPneumonia/bronchitis diagnosisQuan-Charlson comorbidity index (continuous) Beta-blocker prescriptionPrescribing provider specialtyPrimary careInternal medicineAllied-health professionalCardiologyOther specialtyUnknownPharmacy-based respiratory medication use (excluding the index date)LABA useICS useICS/LABA useAny SABA use (i.e., SABA or SAMA/SABA)Any SAMA use (i.e., SAMA or SAMA/SABA)SABA monotherapy useSAMA monotherapy useSAMA/SABA useOCS useGuideline-recommended antibiotic use Triple therapy initiation on the index dateIndex medication from mail order pharmacyMedical claim-based respiratory medication use (excluding the index date)LABA useICS useAny SABA use (i.e., SABA or SAMA/SABA)Any SAMA use (i.e., SAMA or SAMA/SABA)SABA monotherapy useSAMA monotherapy useSAMA/SABA useOCS useGuideline-recommended antibiotic useAcute COPD-related exacerbationAny type of acute COPD-related exacerbationHealthcare costs and utilization (all utilization variables are y/n indicator variables)All-cause ambulatory visit, office visit, ER visit, inpatient admission, acute inpatient admission, long-term care inpatient admission, intensive care unit admissionAll-cause pharmacy (for any medication fill)COPD-related ambulatory visit, office visit, ER visit, inpatient visit, acute inpatient admission, long-term care inpatient admissionAll-cause total costs per patient per monthCOPD-related total costs per patient per monthTable A5. Logistic Regression of Follow-up All-Cause ReadmissionsIndependent VariablesFollow-up hospitalizations with a readmissionoddsratiolower95% CIupper95% CIp-valueIntercept–––0.031Index med (cohort) LAMA DPI (reference)ref.––– LAMA SMI0.6560.4600.9370.020Index date month/year 2014 - June 2015 (reference)ref.––– Q3 20150.7330.4271.2580.260 Q4 20151.2120.7491.9600.434 Q1 20160.7720.4751.2540.295 Q2 20160.8650.5171.4480.581 Q3 20160.5690.3191.0130.055 Q4 20160.6110.3211.1660.135 Q1 20171.2630.8361.9090.268 Q2 20170.7590.4721.2220.256 Q3 20171.0200.6381.6280.936 Q4 20171.1800.7291.9100.501 Q1 20180.8690.5231.4460.590 Q2 20181.0560.4182.6640.909Age (continuous)1.0030.9891.0170.684Gender (male)1.0600.8451.3310.612Region Northeast1.2900.9391.7720.117 Midwest1.0250.7841.3410.855 South (reference)ref.––– West1.0750.6901.6760.749Medication fills - pharmacy claimsLABA free dose1.6440.7783.4740.192ICS free dose0.7600.4751.2180.254ICS/LABA single inhaler combination1.0350.8001.3400.792Any SABA (free dose or combination)1.2970.7792.1610.317SABA free dose0.7310.4821.1080.139SAMA/SABA single inhaler combination1.1990.3713.8770.761Any SAMA (free dose or combination)0.8710.2622.8950.822SAMA free dose0.7540.2792.0390.578Systemic corticosteroids0.8120.6201.0630.130Guideline-recommend respiratory antibiotics1.3901.0681.8100.014Medication fills - medical claimsGuideline-recommend respiratory antibiotics1.0300.5311.9980.931LABA free dose1.3910.4923.9330.534ICS free dose1.1970.4323.3180.729Any SABA (free dose or combination)2.3680.49811.2610.279SABA free dose0.5520.1282.3770.425SAMA/SABA single inhaler combination0.8460.1474.8750.852Any SAMA (free dose or combination)0.4610.0862.4620.365SAMA free dose2.1720.5398.7560.275Systemic corticosteroids0.9680.7511.2480.804Baseline Charlson score (continuous)1.0300.9731.0910.310Baseline pneumonia flag1.3330.8752.0290.181Baseline Pneumonia or bronchitis flag0.7700.5051.1720.222Baseline acute COPD-related exacerbation flag1.0620.6501.7370.809Baseline ambulatory flag0.5100.1501.7370.282Baseline ER flag1.5300.9762.4000.064Baseline IP flag1.3480.3694.9190.652Baseline acute IP flag0.6090.1492.4790.488Baseline LTC IP flag0.8490.4181.7210.649Baseline COPD-related ambulatory flag1.1150.7161.7390.629Baseline COPD-related ER flag0.9340.6651.3110.694Baseline hospitalization (CMS hospitalization eligible for readmission) No baseline hospitalizations (reference)ref.––– Baseline hospitalization without a readmission1.1020.7891.5390.569 Baseline hospitalization with a readmission1.7271.0942.7260.019Baseline COPD-related RX flag0.8900.4471.7690.739Baseline COPD-related acute IP flag1.1480.5332.4740.725Baseline COPD-related LTC IP flag1.5210.7353.1490.259Baseline total costs, PPPM - Quartiles $0 ≤ baseline total costs ≤ $822.93ref.––– $822.93 < baseline total costs ≤ $1835.731.3620.8652.1430.182 $1835.73 < baseline total costs ≤ $3833.081.9361.1573.2390.012 $3833.08 < baseline total costs2.3851.3134.3300.004Baseline COPD-related total costs, PPPM - Quartiles $0 ≤ baseline COPD-related total costs ≤ $267.72ref.––– $267.72 < baseline COPD-related total costs ≤ $984.070.6840.4361.0750.100 $984.07 < baseline COPD-related total costs ≤ $2353.200.6120.3461.0840.092 $2353.20 < baseline COPD-related total costs0.5370.2761.0440.067Provider specialty Pulmonology (reference)ref.––– Primary care1.1080.7751.5830.575 Internal medicine1.3570.9781.8830.067 Allied Health Professional0.6300.0478.4530.728 Cardiology1.6060.6603.9080.297 Other/ unknown/ multiple specialty1.3350.9151.9480.133Triple therapy initiation flag1.0310.7961.3360.816Observations read = 2,155, Observations used= 2,155Likelihood ratio: chi-square=119.560, DF=65, p-value=<0.001Global Score: chi-square=120.877, DF=65, p-value=<0.001Global Wald: chi-square=135.349, DF=65, p-value=<0.001Hosmer and Lemeshow: chi-square=16.863, DF=8, p-value=0.032Generalized R-Square = 0.054, max-rescaled R-Square = 0.087Pseudo R-Square = 0.057c statistic = 0.668AIC-intercept: 2087.580, AIC-intercept and covariates: 2098.020SC-intercept: 2093.255, SC-intercept and covariates: 2472.606Specification link test: p-value=0.235Appendix Table A6. Baseline Clinical Characteristics: Medication and Comorbid ConditionsBaseline Medication Use?Pre-IPTWPost-IPTWLAMA DPI(N=22,880)LAMA SMI(N=5,360)LAMA DPIvsLAMA SMIp-value*LAMA DPIvsLAMA SMIStand Diff (%)*LAMA DPI(N=22,880)LAMA SMI(N=5,360)LAMA DPIvsLAMA SMIp-value**LAMA DPIvsLAMA SMIStand Diff (%)**n%n%n%n%Pharmacy claims?????????????Controller medications?????????????LAMA free dose00.0000.00––?00.0000.00––LABA free dose2741.20701.310.515-0.98?2781.22681.270.779-0.50ICS free dose1,1705.112444.550.0902.62?1,1505.023165.890.078-3.80LAMA/LABA single inhaler combination00.0000.00––?00.0000.00––???TIO/OLO00.0000.00––?00.0000.00––???UMEC/VI00.0000.00––?00.0000.00––ICS/LABA single inhaler combination6,77129.592,06338.49<0.001-18.86?7,17231.331,73132.310.244-2.10Methylxanthines2321.01470.880.3611.42?2451.07370.680.0154.13Phosphodiesterase-4 (PDE-4) inhibitors1490.65490.910.038-2.98?1560.68470.880.208-2.22Rescue medications?????????????Any SABA (free dose or combination)12,47054.503,24760.58<0.001-12.32?12,74055.663,06057.100.126-2.89???SABA free dose10,64746.532,83052.80<0.001-12.55?10,92547.732,61648.810.247-2.17???SAMA/SABA single inhaler combination3,74316.3698718.41<0.001-5.42?3,83516.7593317.400.361-1.73Any SAMA (free dose or combination)4,24618.561,11420.78<0.001-5.60?4,34618.991,05719.720.327-1.85???SAMA free dose6782.961713.190.381-1.31?6893.011683.140.690-0.73Systemic corticosteroids9,35540.892,52547.11<0.001-12.56?9,62842.072,24341.850.8110.44Guideline-recommend respiratory antibiotics11,83251.713,05857.05<0.001-10.73?12,07252.742,81852.580.8620.33Medical claims?????????????Controller medications?????????????LAMA free dose10.0000.000.6280.93?10.0000.00–0.94LABA free dose1600.70480.900.130-2.21?1690.74390.720.8780.24ICS free dose1610.70470.880.182-1.96?1680.73410.770.837-0.42Methylxanthines2220.97681.270.051-2.84?2220.97541.010.803-0.39Rescue medications?????????????Any SABA (free dose or combination)1,6217.084378.150.007-4.03?1,6717.304057.560.593-0.98???SABA free dose9244.042594.830.009-3.86?9574.182164.030.6570.75???SAMA/SABA single inhaler combination7913.462013.750.295-1.57?8093.542113.930.279-2.08Any SAMA (free dose or combination)1,0004.372464.590.482-1.06?1,0154.432604.860.298-2.00???SAMA free dose2431.06551.030.8170.35?2421.06591.100.816-0.44Systemic corticosteroids6,71829.361,72632.20<0.001-6.15?6,84329.901,57929.470.6020.94Guideline-recommend respiratory antibiotics3811.67941.750.650-0.68?3841.68801.500.3561.46Baseline inhaler types (excluding the index date) from pharmacy claims (pharmacy claims)?????????????DPI4,28118.711,15821.60<0.001-7.22?4,50419.681,00318.720.1722.43SMI1,2955.663736.96<0.001-5.34?1,3175.753175.920.674-0.71Baseline nebulized medication use (excluding the index date) from medical and pharmacy claims6,37327.851,69631.64<0.001-8.29?6,53428.551,61630.150.062-3.52Baseline Comorbidities ?Pre-IPTW?Post-IPTWLAMA DPI(N=22,880)LAMA SMI(N=5,360)?LAMA DPIvsLAMA SMIp-value*?LAMA DPIvsLAMA SMIStand Diff (%)*?LAMA DPI(N=22,880)LAMA SMI(N=5,360)?LAMA DPIvsLAMA SMIp-value**LAMA DPIvsLAMA SMIStand Diff (%)**n%n%?n%n%Allergic rhinitis2,2809.9767512.59<0.001-8.32?2,35910.3160511.300.077-3.18Anxiety (narrow)5,04422.051,21222.610.369-1.36?5,02721.961,23222.990.191-2.46Anxiety (broad)5,17322.611,24223.170.376-1.34?5,15522.521,25723.450.241-2.20Arrhythmia6,87130.031,42726.62<0.0017.57?6,73729.431,45927.230.0104.90Atrial fibrillation (narrow)4,58620.0497518.190.0024.71?4,49219.6397418.170.0463.71Atrial fibrillation (broad)4,67720.4499418.540.0024.79?4,58320.0299018.480.0353.90Acute sinusitis1,6557.235109.51<0.001-8.24?1,6957.414568.520.013-4.11Chronic sinusitis1,0614.642424.510.7010.59?1,0804.722174.060.0593.23Chronic rhinitis4792.091302.430.132-2.23?4922.151122.090.7960.43Congestive heart failure6,64429.041,36525.47<0.0018.03?6,48428.331,46427.320.2392.25Depression6,31227.591,36625.490.0024.76?6,24927.301,44927.030.7570.61Diabetes8,20235.851,87334.940.2141.89?8,17535.711,94636.310.507-1.25Dyspnea14,57863.723,50865.450.017-3.62?14,57563.683,45764.510.356-1.73Hypertension18,71581.804,38481.790.9930.01?18,68981.654,44682.970.053-3.44Ischemic heart disease9,13339.922,15140.130.774-0.44?9,10039.762,13939.920.865-0.32Metabolic syndrome21,03391.934,96892.690.064-2.85?21,03391.895,00493.39<0.001-5.74???Obesity3,94017.221,02019.030.002-4.70?3,97417.3699318.530.104-3.04???Hypercholesterolemia16,04970.143,95673.81<0.001-8.16?16,08770.293,93673.46<0.001-7.06???Hypertension18,71581.804,38481.790.9930.01?18,68981.654,44682.970.053-3.44???Type II diabetes, including insulin resistance9,94243.452,30543.000.5500.919,93543.402,37344.280.349-1.76Myocardial infarction2,62711.4854310.130.0054.35?2,56411.2055810.420.1822.52Osteoporosis2,71611.8763911.920.917-0.16?2,69611.7863711.890.847-0.36Pulmonary fibrosis1,2655.533416.360.018-3.52?1,2845.613065.720.789-0.47Peripheral vascular disease7,49132.741,66431.040.0173.64?7,42732.451,68831.500.2792.04Peptic ulcer/GERD6,74929.501,65330.840.053-2.92?6,76629.561,64030.610.232-2.28Renal disease8,03935.141,73332.33<0.0015.93?7,91934.601,86634.830.801-0.49Sleep apnea4,06017.741,14021.27<0.001-8.90?4,16818.211,03119.240.140-2.65Stroke1,4486.333276.100.5360.94?1,4036.134147.720.003-6.29Pneumonia or acute bronchitis/bronchiolitis8,17035.711,85034.510.1002.508,11035.431,81433.850.0743.33???Pneumonia5,50824.071,13021.08<0.0017.16?5,36723.451,17721.960.0633.55Smoking evidence12,95756.633,21860.04<0.001-6.91?13,03156.933,13458.490.096-3.16?Medication use was identified using NDC codes for prescription claims and CPT/HCPCS for medical claims during the baseline period, excluding the index date.* Pre-IPTW: Pearson chi-square test was used for binary and categorical measures. Two-sample t-test was used for continuous measures.** Post-IPTW: Z-test using robust standard errors was used for binary measures. Rao-Scott chi-square was used for categorical measures. Z-test using robust standard errors in an OLS regression was used for continuous measures ................
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