Chronic obstructive pulmonary disease (COPD) is the third

Transcription

1 METHODS Clims-Bsed Risk Model for First Severe COPD Excerbtion Richrd H. Stnford, PhrmD, MS; Arpit Ng, PhD, MBA, MS; Dougls W. Mpel, MD; Todd A. Lee, PhD; Richrd Rosiello, MD; Michel Schtz, MD; Frncis Vekemn, MS; Mrjoline Guthier-Loiselle, PhD; J.F. Philip Merrign, PhD; nd Mei Sheng Duh, ScD Chronic obstructive pulmonry disese (COPD) is the third leding cuse of deth in the United Sttes, with more thn 147,000 ptients dying becuse of it in COPD poses substntil economic burden on ptients, helthcre systems, nd society. In the United Sttes, $32.1 billion in medicl costs were ssocited with COPD in 2010, with costs projected to rise to $49.0 billion by A mjor portion of COPD-relted helthcre costs re ttributble to excerbtions (sustined worsening of COPD from stble stte, beyond norml dy-to-dy vritions). 3,4 Excerbtions re cute in onset nd wrrnt dditionl tretment. 3,4 Incresed frequency of excerbtions leds to more hospitl nd emergency deprtment (ED) visits. 5 In 2009, pproximtely 740,000 hospitliztions were relted to COPD. 6 Hospitliztion costs represent 85% of direct medicl costs ssocited with COPD nd re lrgely ssocited with excerbtions. 7,8 Bsed on Helthcre Cost nd Utiliztion Project nlysis, Perer et l showed tht severe excerbtions, defined s hospitliztions for cute COPD excerbtions, were ssocited with incresed ggregte costs, rising from $2.96 billion in 2006 to $3.47 billion in Furthermore, in retrospective nlysis of the Thompson Reuters MrketScn dministrtive dtbse, Yu et l reported tht COPD-relted costs for ptients with severe excerbtions were $7014 per 90 dys compred with $658 per 90 dys for ptients with no excerbtions, with 83% of the costs ssocited with inptient expenses. 10 In nother retrospective study, Abudgg et l reported tht the costs ssocited with severe excerbtions were $18,120 nd incresed with ech dditionl prior excerbtion. 11 Given the high costs ssocited with COPD excerbtions, it is importnt to identify ptients t risk of excerbtion to trget them for erly tretment nd improved prevention. Prior history of excerbtions is mong the most importnt risk fctors for the development of subsequent excerbtions. 12 Previous clinicl studies hve identified dditionl risk fctors for COPD excerbtions, with severl groups developing excerbtion risk models However, risk ssessment models for COPD excerbtions utilizing redily ccessible clims dt tht re vilble to helth plns nd ABSTRACT OBJECTIVES: To develop nd vlidte predictive model for first severe chronic obstructive pulmonry disese (COPD) excerbtion using helth insurnce clims dt nd to vlidte the risk mesure of controller mediction to totl COPD tretment (controller nd rescue) rtio (CTR). STUDY DESIGN: A predictive model ws developed nd vlidted in 2 mnged cre dtbses: Truven Helth MrketScn dtbse nd Relint Medicl Group dtbse. This secondry nlysis ssessed risk fctors, including CTR, during the bseline period (Yer 1) to predict risk of severe excerbtion in the t-risk period (Yer 2). METHODS: Ptients with COPD who were 40 yers or older nd who hd t lest 1 COPD mediction dispensed during the yer following COPD dignosis were included. Subjects with severe excerbtions in the bseline yer were excluded. Risk fctors in the bseline period were included s potentil predictors in multivrite nlysis. Performnce ws evluted using C-sttistics. RESULTS: The nlysis included 223,824 ptients. The gretest risk fctors for first severe excerbtion were dvnced ge, chronic oxygen therpy usge, COPD dignosis type, dispensing of 4 or more cnisters of rescue mediction, nd hving 2 or more moderte excerbtions. A CTR of 0.3 or greter ws ssocited with 14% lower risk of severe excerbtion. The model performed well with C-sttistics, rnging from to CONCLUSIONS: This clims-bsed risk model cn predict the likelihood of first severe COPD excerbtion. The CTR could lso potentilly be used to trget popultions t gretest risk for severe excerbtions. This could be relevnt for providers nd pyers in pproches to prevent severe excerbtions nd reduce costs. Am J Mng Cre. 2018;24(2):e45-e53 THE AMERICAN JOURNAL OF MANAGED CARE VOL. 24, NO. 2 e45

2 METHODS nd vlidtion of risk model for first severe TAKEAWAY POINTS COPD excerbtion using ptient demogrphics, comorbid conditions, nd COPD tretment To prevent worsening of chronic obstructive pulmonry disese (COPD) nd its ssocited costs, identifying ptients t high risk of first severe excerbtion is criticl. clims dt s covrites; nd 2) vlidtion of A risk model for first severe COPD excerbtion ws developed nd vlidted using helth the CTR s mesure of severe COPD excerbtion risk. The CTR is the rtio of totl insurnce clims. Totl COPD tretment (controller nd rescue) rtio (CTR) cn predict first severe COPD excerbtion using helth insurnce clims. controller medictions (inhled corticosteroids [ICS], long cting β 2 COPD ptients with CTR of 0.3 or greter re t reduced risk of hving severe COPD -drenergic gonists excerbtion in the subsequent yer. [LABA], ICS + LABA, long cting muscrinic Moderte excerbtion history, dvnced ge, use of rescue mediction, chronic oxygen therpy, nd type of COPD were lso risk fctors for first severe COPD excerbtion. ntgonists, phosphodiesterse-4 inhibitors, nd methylxnthines) to totl controller plus rescue medictions (short-cting β-gonists helthcre groups, such s ntionl qulity-of-cre orgniztions, or short-cting muscrinic ntgonists [SAMA]). re not vilble. Identifying ptients t risk for their first severe excerbtion is criticl to trget erly nd effective tretment, potentilly slowing progression nd ssocited cost increses. The present study ws secondry nlysis from wider study in which mediction rtio using phrmcy clims nd risk model were developed nd vlidted. The primry results of this study hve been published. 23 In this secondry nlysis, we imed to construct nd vlidte predictive model of first severe COPD excerbtion event using helth insurnce clims, source of dt redily vilble to helth plns nd most qulity-ofcre orgniztions. This secondry nlysis imed to further vlidte the bility of the controller mediction to totl COPD tretment (controller nd rescue) rtio (CTR) to predict first severe COPD excerbtion. The CTR is similr to the current Helthcre Effectiveness Dt nd Informtion Set (HEDIS) mesure in sthm, the sthm mediction rtio, nd could hve the potentil to be used in similr cpcity. 24 METHODS Study Design This retrospective study (GlxoSmithKline study #HO ) used the Truven MrketScn Commercil Clims nd Encounter Dtbse nd Medicre Supplementl nd Coordintion of Benefits dtbse (MrketScn dtbse, Truven Helth Anlytics; Ann Arbor, Michign) from 2006 to 2011 to construct nd vlidte risk model of prediction of first severe COPD excerbtion nd to test the CTR mesure. The Relint Medicl Group (Relint dtbse, Relint Medicl Group; Worcester, Msschusetts) ws used for cross-vlidtion. The study strt dte (index dte) ws the second encounter with COPD dignosis (defined in study popultion section) within yer. Risk fctors were ssessed during the bseline period, which spnned 1 yer, strting t the index dte. This ws followed by 1 yer t-risk period during which the occurrence of severe COPD excerbtions, the primry endpoint, ws ssessed (Figure). Study Popultion Ptients with COPD who were 40 yers nd older were included Study Objectives The primry objectives of this study hve been reported elsewhere. 23 There were 2 objectives of the present nlysis: 1) construction in the study. The index dte of COPD sttus ws defined s the second outptient nd/or ED encounter with COPD dignosis (Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction [ICD-9-CM] codes 491.x [chronic FIGURE. Study Design bronchitis], 492.x [emphysem], or 496 [chronic irwy obstruction]) within 1 yer. Index dte: second outptient/ed Ptients were lso required to hve t lest 1 visit within yer with COPD dignosis End of study period dispensing for n inhled COPD mediction Observtion of risk fctors Observtion of COPD or orl theophylline during the yer following 2006 for COPD excerbtion excerbtion events 2011 the index dte nd to hve hd continuous First dy of insurnce eligibility (no more thn 45 dys insurnce eligibility BASELINE PERIOD (YEAR 1) AT-RISK PERIOD (YEAR 2) without coverge) for t lest 2 yers following At lest 1 dispensing for Sensitivity nlysis: n inhled COPD mediction 90 dys nd 180 dys the index dte. Ptients were excluded if they hd severe CONTINUOUS INSURANCE ELIGIBILITY COPD excerbtion, defined s COPD-relted hospitliztion during the bseline period, or COPD indictes chronic obstructive pulmonry disese; ED, emergency deprtment. t lest 1 clim with n ICD-9-CM dignosis e46 FEBRUARY

3 COPD Excerbtion Risk Model code for cncer (except cncer types tht re typiclly considered to hve little effect on lung function [eg, brest, prostte, or skin cncer except melnom]) or other non-copd lung disese during the bseline period. Dt Sources The MrketScn dtbse ws used for model development nd vlidtion. This dtbse includes helth insurnce clims dt from 2006 to 2011, representing pproximtely 18 million covered individuls, nd contins informtion on enrollment history nd clims for medicl (provider nd institutionl) nd phrmcy services. The Relint dtbse ws used for externl vlidtion. It includes longitudinl member-linked medicl clims (physicin nd fcility), phrmcy clims, enrollment records, lbortory results, nd electronic helth record informtion. Outcomes The primry endpoint of this study ws the occurrence of severe COPD excerbtion during the t-risk period (Yer 2). A severe COPD excerbtion ws defined s hospitliztion with either primry dignosis of COPD (excluding obstructive chronic bronchitis without excerbtion; ICD-9-CM code ) or secondry dignosis for COPD with primry dignosis of respirtory filure (ICD-9-CM codes , , or ). The choice of 1-yer window for the bseline nd t-risk periods for the bse cse scenrio mde it possible to ccount for the sesonlity of COPD excerbtions. Yet, given tht risk fctors were evluted in the yer prior to the t-risk period, they my not ccurtely reflect risk fctors during the totlity of the t-risk period. For exmple, the CTR my reflect more relibly the COPD medictions ptients received t the beginning of the t-risk period thn those received towrd the end of the t-risk period. As such, sensitivity nlyses were conducted tht limited the t-risk period to 90 dys or 180 dys following the bseline yer (Yer 1). Sttisticl Methods Cndidte risk fctors were ssessed during the bseline period nd used s predictors for severe excerbtion risk in the following yer. Cndidte risk fctors were gender, ge, region, insurnce pln, H1N1 flu seson (October 2009 to My 2010), pulmonologist visit, county chrcteristics (ltitude; number of pulmonologists per 100,000 inhbitnts; number of hospitls per 100,000 inhbitnts; proportion of households below the low-income mrgin; medin household income; proportion of ptients without helth insurnce; proportions of high school dropouts nd college grdutes; urbn/suburbn/rurl locliztion; nd proportion of white, blck, Hispnic, nd Asin ptients, derived from the Are Resource File 25 ), type of COPD dignosis, excerbtion history (moderte only [ie, defined s outptient treted or ED visit for COPD with dispensing for n orl corticosteroid within 7 dys]), COPD medictions (bsed on t lest 1 dispensing), concomitnt medictions, procedures (flu nd pneumococcl vccines, use of chronic oxygen therpy, nebulizer, nd spirometry; ll bsed on Current Procedurl Terminology nd Helthcre Common Procedure Coding System codes), nd comorbidities bsed on ICD-9-CM codes. 26 Bsed on univrite ssocitions mong risk fctors nd the probbility of n excerbtion in the t-risk period, risk fctors were excluded if P >.1. P vlues were clculted using χ 2 tests for discrete vribles nd Wilcoxon tests for continuous vribles. Risk fctors present in less thn 0.5% of the smple were excluded. The choice of fctors for the risk model ws bsed on bootstrp resmpling in combintion with stepwise vrible selection with logistic regression modeling, using rndom smple of the MrketScn smple (development smple). 27 A totl of 1000 bootstrp smples were drwn; ech ws rndom smpling with replcement from the originl development smple, nd ech bootstrp repliction ws done using different bootstrp smple. Within ech bootstrp repliction, ll cndidte risk fctors were included, then stepwise elimintion of risk fctors ws performed using the Akike informtion criterion to identify predictors of excerbtions in the finl model for the repliction. Risk fctors were chosen if they were selected in: 1) 100% of the 1000 bootstrp replictions for the modeling of severe excerbtion or 2) t lest 90% of the bootstrp replictions for severe excerbtion nd in 100% of the bootstrp replictions for moderte or ny type of excerbtions. CTR, which ws defined s the number of cnisters dispensed (converted to 30-dy equivlent) for controller mediction divided by the number of cnisters dispensed for controller plus number of cnisters of rescue mediction (ie, SAMA, shortcting β 2 -drenergic gonists [SABA], SAMA + SABA), ws included in the finl risk model. In order to ssess the CTR s predictive mesure of first severe excerbtion, vrious rtio thresholds from t lest 0.1 to t lest 0.9 were tested. A cutoff of 0.3 ws found to be the cutoff ssocited with the lrgest sttisticlly significnt risk reduction for severe excerbtions nd hs been shown to be the only cutoff ssocited with sttisticlly significntly reduced risk of ny, moderte, nd severe excerbtions in the previously published primry objectives of this study. 23 Therefore, this rtio ws used in the risk model of first severe COPD excerbtions. The risk model ws developed using the development smple, vlidted using the other rndom smple of the MrketScn dt (vlidtion smple), nd cross-vlidted using the Relint Medicl Group dt (cross-vlidtion smple). Performnce of the risk model ws evluted using C-sttistics. 28,29 Additionl model nlyses were performed on selected subpopultions, including those without history of sthm nd differing controller mediction usge. All sttisticl nlyses were performed using SAS version 9.2 or newer (SAS Institute, Inc; Cry, North Crolin). THE AMERICAN JOURNAL OF MANAGED CARE VOL. 24, NO. 2 e47

4 METHODS TABLE 1. Selected Risk Fctor Chrcteristics During Bseline Period Strtified by Excerbtion Severity During At-Risk Period (Yer 2) (MrketScn development smple nd Relint vlidtion smple) Risk Fctors, n (%) unless noted RESULTS Bseline Chrcteristics Ptients Without COPD Excerbtions (n = 179,370) A totl of 223,824 ptients without history of severe excerbtions were included in the study, with 111,904 used in the development smple. Of the entire MrketScn smple of ptients without history of severe excerbtions, pproximtely 80% experienced no excerbtions in the t-risk period (Tble 1). Ptients who experienced excerbtions during the t-risk period tended to use more COPD medictions nd were more likely to use chronic oxygen therpy during the bseline period thn ptients who did not experience n excerbtion during the t-risk period (P <.01). Ptients With Moderte COPD Excerbtions b (n = 29,614) Ptients With Severe COPD Excerbtions c (n = 14,840) Moderte vs None Risk Fctor Modeling for Severe Excerbtion A totl of 30 risk fctors were included in the model; ll were sttisticlly significntly ssocited with severe excerbtions. The 5 risk fctors with the lrgest impct on the probbility of developing severe excerbtion in the t-risk yer were dvnced ge, use of chronic oxygen therpy, use of 4 or more cnisters of rescue mediction, hving t lest 2 prior moderte excerbtions, nd type of COPD dignoses received during the bseline period (Tble 2). Ptients with CTR of 0.3 or greter hd lower risk of developing severe excerbtions (odds rtio [OR], 0.86; 95% CI, ) P d Severe vs None Femle 96,476 (53.8) 16,445 (55.5) 8018 (54.0) < Age (yers), men ± SD 67.0 ± ± ± <.01 Region Northest 25,445 (14.2) 3938 (13.3) 2131(14.4) < North-Centrl 65,655 (36.6) 10,972 (37.1) 6074 (40.9).14 <.01 South 60,566 (33.8) 10,198 (34.4) 4811 (32.4).02 <.01 West 26,471 (14.8) 4228 (14.3) 1709 (11.5).03 <.01 Visit to pulmonologist 60,847 (33.9) 11,980 (40.5) 6181 (41.7) <.01 <.01 County chrcteristics Urbn 142,785 (79.6) 23,226 (78.4) 11,736 (79.1) < Suburbn 32,924 (18.4) 5713 (19.3) 2758 (18.6) < Rurl 3661 (2.0) 675 (2.3) 346 (2.3) < COPD mediction Number of controller clsses, men ± SD 1.5 ± ± ± 1.2 <.01 < ,191 (25.8) 5032 (17.0) 2980 (20.1) <.01 < ,598 (22.1) 5408 (18.3) 2756 (18.6) <.01 < ,581 (52.2) 19,174 (64.7) 9104 (61.3) <.01 < dys of supply of controller mediction ICS 11,581 (6.5) 2792 (9.4) 1189 (8.0) <.01 <.01 ICS + LABA 50,933 (28.4) 11,337 (38.3) 5351 (36.1) <.01 <.01 LABA 5191 (2.9) 1462 (4.9) 668 (4.5) <.01 <.01 LAMA 41,176 (23.0) 9493 (32.1) 4581 (30.9) <.01 <.01 Orl theophylline 5734 (3.2) 1938 (6.5) 1017 (6.9) <.01 <.01 Any controller clss 85,983 (47.9) 18,175 (61.4) 8560 (57.7) <.01 <.01 Cnisters of rescue mediction, men ± SD 3.1 ± ± ± 6.5 <.01 <.01 1 cnisters 129,025 (71.9) 24,016 (81.1) 11,974 (80.7) <.01 <.01 4 cnisters 45,460 (25.3) 12,514 (42.3) 6379 (43.0) <.01 <.01 Number of fills for orl corticosteroids, men ± SD 0.8 ± ± ± 2.7 <.01 <.01 1 fill 66,423 (37.0) 19,644 (66.3) 8120 (54.7) <.01 <.01 (continued) e48 FEBRUARY

5 COPD Excerbtion Risk Model TABLE 1. (continued) Selected Risk Fctor Chrcteristics During Bseline Period Strtified by Excerbtion Severity During At-Risk Period (Yer 2) (MrketScn development smple nd Relint vlidtion smple) Risk Fctors, n (%) unless noted COPD excerbtions Ptients Without COPD Excerbtions (n = 179,370) Ptients With Moderte COPD Excerbtions b (n = 29,614) Ptients With Severe COPD Excerbtions c (n = 14,840) Moderte vs None P d Severe vs None Moderte excerbtions, men ± SD 0.2 ± ± ± 1.0 <.01 < ,766 (84.1) 16,208 (54.7) 9657 (65.1) <.01 < ,638 (13.2) 8018 (27.1) 3184 (21.5) <.01 < (2.8) 5388 (18.2) 1999 (13.5) <.01 <.01 Type of COPD dignosis Chronic bronchitis 60,018 (33.5) 13,083 (44.2) 6545 (44.1) <.01 <.01 Emphysem 24,320 (13.7) 5842 (19.7) 3292 (22.2) <.01 <.01 Chronic irwy obstruction 145,356 (81.0) 26,866 (90.7) 13,574 (91.5) <.01 <.01 Comorbidities e Asthm 44,262 (24.7) 8736 (29.5) 3707 (25.0) < Respirtory infection 68,250 (38.0) 13,655 (46.1) 7020 (47.3) <.01 <.01 Congestive hert filure 24,821 (13.8) 3874 (13.1) 3347 (22.6) <.01 <.01 Risk smoker 15,515 (8.6) 3233 (10.9) 1343 (9.0) < Concomitnt medictions Sttins 92,532 (51.6) 14,332 (48.4) 7517 (50.7) < Antidepressnts 61,149 (34.1) 10,821 (36.5) 5806 (39.1) <.01 <.01 Procedures Chronic oxygen therpy 34,701 (19.3) 10,251 (34.6) 6526 (44.0) <.01 <.01 Nebulizer 48,658 (27.1) 12,016 (40.6) 6207 (41.8) <.01 <.01 Spirometry 65,753 (36.7) 12,196 (41.2) 5527 (37.2) < COPD indictes chronic obstructive pulmonry disese; ICS, inhled corticosteroid; LABA, long cting β 2 -drenergic gonist; LAMA, long cting muscrinic ntgonist. Bseline period defined s the yer following the index dte. At-risk period defined s the yer following the bseline period. b Includes ptients with t lest 1 moderte excerbtion during the t-risk period nd without severe excerbtion during the t-risk period. Moderte excerbtion is defined s 1 outptient or emergency deprtment visit with dignosis of COPD (Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction [ICD-9-CM] codes 491.x [except ], 492.x, 496) in ny position nd t lest 1 dispensing for n orl corticosteroid within 7 dys following the encounter. c Includes ptients with t lest 1 severe excerbtion during the t-risk period, with or without moderte excerbtions. Severe excerbtion is defined s n inptient hospitl sty with dignosis of COPD (ICD-9-CM codes 491.x [except ], 492.x, 496), either s primry dignosis or s secondry dignosis with primry dignosis of respirtory filure (ICD-9-CM codes , , or ). d P vlues were clculted using χ 2 tests for discrete vribles nd Wilcoxon tests for continuous vribles. e These non-copd lung diseses were excluded in the study: bronchiectsis, extrinsic llergic lveolitis, pneumoconiosis, pneumonopthy due to resons other thn dust inhltion, respirtory conditions due to chemicl fumes nd vpors or other nd unspecified externl gents, lveolr nd prietolveolr pneumonopthy, lung involvement in conditions clssified elsewhere, pulmonry eosinophili, llergic bronchopulmonry spergillosis, nd rheumtoid lung. (Tble 2). In subpopultion nlysis, mong ptients with 4 or more fills for controller medictions, CTR of 0.3 or greter ws ssocited with n even lower risk of severe excerbtion (OR, 0.76; 95% CI, ) (Tble 3). The model performed reltively well in predicting severe excerbtion risk, with C-sttistics in the MrketScn development nd vlidtion nd Relint cross-vlidtion smples of 0.713, 0.714, nd 0.711, respectively (Tble 2). Sensitivity Anlyses Most risk fctors for severe excerbtion identified s most relevnt using the 1-yer t-risk period (eg, dvnced ge, use of chronic oxygen therpy, nd hving t lest 2 prior moderte excerbtions in the bseline yer) were lso identified in sensitivity nlyses using either 90- or 180-dy t-risk period (eappendix Tble [eappendices vilble t jmc.com]). Bsed on C-sttistics, the performnce of these models ws similr to tht of the model bsed on 1 yer t-risk period. DISCUSSION This report presents the development nd vlidtion of risk model nd the testing of the CTR for prediction of first severe COPD excerbtion using helth insurnce clims informtion. The min THE AMERICAN JOURNAL OF MANAGED CARE VOL. 24, NO. 2 e49

6 METHODS TABLE 2. Finl Risk Model of Severe COPD Excerbtion in Popultion Without History of Severe Excerbtion (MrketScn development smple) Risk Fctors During Bseline Period (Yer 1) H1N1 flu seson: October 2009-My 2010 Age group (yers) t index dte (ref: ged yers) Severe Excerbtion (Yer 2) (N = 111,904; excerbtions, n = 7345; no excerbtions, n = 104,559) OR (95% CI) 0.82 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 80 COPD mediction CTR 0.3 (ref: 0 < rtio < 0.3) No controller mediction (ref: 1 fill for controller mediction) No controller mediction nd 4 cnisters of rescue mediction (ref: no fill for controller mediction nd <4 cnisters of rescue mediction or 1 controller mediction) 4 cnisters of rescue mediction (ref: <4 cnisters of rescue mediction) 1 fill for orl corticosteroids (ref: no fill for orl corticosteroids) 4 fills of orl corticosteroids (ref: <4 fills for orl corticosteroids) 1 fill for theophylline (ref: no fill for theophylline) Excerbtions (ref: 0) 2.65 ( ) 0.86 ( ) 0.77 ( ) 1.01 ( ) 1.47 ( ) 1.26 ( ) 1.26 ( ) 1.29 ( ) 1 moderte 1.13 ( ) 2 moderte Type of COPD dignosis Chronic bronchitis (ICD-9-CM code 491.x) (ref: no encounter with chronic bronchitis dignosis during the bseline yer) Emphysem (ICD-9-CM code 492.x) (ref: no encounter with n emphysem dignosis during the bseline yer) Chronic irwy obstruction (ICD-9-CM code 496) (ref: no encounter with chronic irwy obstruction dignosis during the bseline yer) 1.43 ( ) 1.32 ( ) 1.42 ( ) 1.72 ( ) (continued) risk fctors of first severe COPD excerbtion identified included dvnced ge, prior moderte excerbtion history, use of rescue mediction, use of chronic oxygen therpy, nd type of COPD dignosis. A CTR of 0.3 or greter lso ws determined to predict first severe COPD excerbtion. The min dvntge of the risk model nd the CTR mesure is tht they do not rely on medicl records, which re often unvilble to qulity-of-cre orgniztions nd pyers. Unlike previously reported mesures, the CTR cn be used to specificlly ssess the risk of first severe excerbtion nd my help to identify which ptients should be trgeted for more intense mngement so tht hospitliztions nd costs could be reduced. This model performed well in predicting the risk of first severe excerbtion t popultion level using the MrketScn development nd vlidtion smples nd the Relint vlidtion smple. Given the differences between the ntionl MrketScn popultion nd the regionl Relint dtbse, the reltively consistent performnce of the risk model in the Relint popultion, with C-sttistic vlue of 0.711, indictes tht the model nd the CTR could be generlizble to heterogeneous popultions. Prior history of excerbtions is known to be mong the most importnt risk fctors for developing subsequent excerbtions. 12,18 In n nlysis of ptients enrolled in the Evlution of COPD e50 FEBRUARY

7 COPD Excerbtion Risk Model TABLE 2. (continued) Finl Risk Model of Severe COPD Excerbtion in Popultion Without History of Severe Excerbtion (MrketScn development smple) Severe Excerbtion (Yer 2) (N = 111,904; excerbtions, n = 7345; no excerbtions, n = 104,559) Risk Fctors During Bseline Period (Yer 1) OR (95% CI) Comorbidities Asthm (ref: no encounter with n sthm dignosis during the bseline yer) 0.86 ( ) Respirtory infection (ref: no encounter with respirtory infection during the bseline yer) 1.18 ( ) Congestive hert filure (ref: no encounter with congestive hert filure dignosis during the 1.39 ( ) bseline yer) Risk smoker (ref: no encounter during the bseline period with n ICD-9-CM code of 305.1, V15.82, 1.21 ( ) or ) Concomitnt mediction Sttins (ref: no fill for sttin mediction) 0.91 ( ) Antidepressnts (ref: no fill for ntidepressnt mediction) 1.19 ( ) Procedures Chronic oxygen therpy (ref: no chronic oxygen therpy) 1.92 ( ) Nebulizer (ref: no nebulizer) 1.21 ( ) Spirometry (ref: no spirometry) 0.89 ( ) C-sttistics Development (MrketScn) Vlidtion (MrketScn) Cross-vlidtion (Relint) COPD indictes chronic obstructive pulmonry disese; CTR, COPD tretment rtio (totl controller cnisters dispensed / [totl controller cnisters dispensed + totl SABA nd SAMA cnisters dispensed]); ICD-9-CM, Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction; OR, odds rtio; ref, reference; SABA, short cting β 2 -drenergic gonist; SAMA, short-cting muscrinic ntgonist. Sttisticlly significnt t the 95% level. Longitudinlly to Identify Predictive Surrogte Endpoints (ECLIPSE) study, history of excerbtion ws shown to be the best predictor of excerbtion, regrdless of Globl Inititive for Chronic Obstructive Lung Disese (GOLD) stge. 12 Previous incidence of excerbtions ws lso found to be n independent predictor of n excerbtion within 24 months (OR, 5.07; 95% CI, ) in study of 243 ptients in the Netherlnds. 18 Our study confirmed tht prior moderte excerbtions were risk fctor for subsequent first severe excerbtion; however, higher CTR vlue ws ssocited with reduced risk of first severe excerbtion regrdless of excerbtion history. These results suggest tht identifying ptients t risk for their first severe excerbtion would be criticl for trgeting erly nd effective tretment, preventing worsening of the disese, nd consequently reducing costs ssocited with COPD excerbtions. 7,8 There is lck of published literture on risk fctors for first severe COPD excerbtions. Müllerov et l evluted the risk fctors for subcohort of ptients with COPD from the ECLIPSE study who hd experienced excerbtions requiring hospitliztion for the first time during the 3-yer study follow-up period. 20 Significnt risk fctors identified were helth sttus, COPD severity (bsed on forced expirtory volume in 1 second [FEV 1 ]), incresing ge, existence of emphysem or sthm, use of home oxygen, nd elevted fibrinogen levels. 20 Becuse dt on COPD severity or fibrinogen levels were not vilble in the MrketScn dt set, their relevnce to excerbtion risk ws not considered in this study. Other studies hve focused on the risk of severe excerbtion in generl nd did not model the risk of first severe COPD excerbtion. 13,15,16 Grci-Aymerich et l considered vrious clinicl, mediction complince, lifestyle, nd sociodemogrphic risk fctors for COPD-ssocited hospitliztions. 16 They found tht previous COPD-ssocited hospitliztions, COPD severity (FEV 1 ), underprescription of long-term chronic oxygen therpy, nd smoking were the most relevnt risk fctors for subsequent COPD-ssocited hospitliztions. 16 In follow-up study of ptients from clinicl tril of tiotropium, Niewoehner et l identified incresing ge, COPD severity, prior unscheduled ED visits or hospitliztions for COPD, crdiovsculr comorbidities, nd use of orl corticosteroids s significnt risk fctors for COPD-ssocited hospitliztion. 13 Although previously published risk models of COPD excerbtions hve focused on excerbtion frequency nd COPD-ssocited THE AMERICAN JOURNAL OF MANAGED CARE VOL. 24, NO. 2 e51

8 METHODS hospitliztions, rther thn the risk of first severe excerbtion, their findings were consistent with those of the current study in tht fctors such s incresing ge nd excerbtion history were highly relevnt. 12,13,15,17-19 Moreover, the performnce of the clims-bsed model compres fvorbly with these models. In n excerbtion risk model developed by Bertens et l, in which excerbtion history, COPD severity, smoking, nd vsculr disese history were identified s risk fctors, C-sttistics vlue of 0.66 ws reported. 18 In model for frequent excerbtions published by Mirvitiles et l, in which chronic mucus hypersecretion, COPD severity, nd incresing ge were ssocited risk fctors, C-sttistics vlues of to were obtined. 15 Limittions Certin methodologic limittions in this study should be noted. First, the identifiction of excerbtion events ws bsed on definitionl lgorithms using helth insurnce clims dt tht hve not been vlidted. These my hve less thn 100% sensitivity nd specificity nd my hve misclssifiction errors for the outcome vribles. Second, helth insurnce clims dt re subject to inccurcies nd mistkes. In prticulr, n ICD-9-CM dignosis code on medicl clim is not n ttesttion tht the ptient hs the dignosis, becuse the code my represent rule-out dignosis or my be recorded incorrectly. This limittion pplies to both the excerbtion events nd the comorbidities used s risk fctors in the models. Additionlly, these records do not confirm tht ptients took the dispensed mediction. A third study limittion ws tht included ptients might hve experienced severe excerbtions prior to the index dte of this study. Finlly, the covrites for the risk equtions were limited to helth insurnce clims dt only, which lck disese severity informtion (eg, GOLD stge). Nevertheless, using subset of the Relint smple, the performnce of the risk model, including GOLD stge, ws ssessed nd showed only mrginl improvement in incrementl predictive ccurcy. CONCLUSIONS A clims-bsed risk model hs been developed tht cn ccurtely predict the likelihood of first severe COPD excerbtion. Previous outptient treted excerbtions, dvnced ge, use of rescue mediction nd chronic oxygen therpy, nd type of COPD were identified s the gretest risk fctors. In ddition, the CTR, which cn be clculted from phrmcy clims dt, cn predict the likelihood of first severe COPD excerbtion. The use of this risk model nd the CTR my llow policy mkers, providers, nd pyers to identify those ptients t highest risk for their first COPD-relted hospitliztion. Ultimtely, the CTR coupled with other HEDIS mesures hs the potentil to improve the mngement of ptients t risk of developing severe COPD excerbtions, thus voiding worsening of the disese nd significnt downstrem costs. n TABLE 3. Risk of COPD Excerbtions Associted With CTR 0.3 in Subpopultions (MrketScn development smple) Severe Excerbtion OR (95% CI) Without history of sthm b (n = 83,578) 0.88 ( ) Fills for controller mediction 1 (n = 84,854) 2 (n = 73,456) 3 (n = 67,429) 4 (n = 59,601) 1 fill for nticholinergic d (n = 46,968) Fills for controller mediction with 1 fill for nticholinergic d 1 (n = 44,512) 2 (n = 41,206) 3 (n = 38,547) 4 (n = 35,640) 0.86 ( ) c 0.83 ( ) c 0.83 ( ) c 0.76 ( ) c 0.78 ( ) c 0.78 ( ) c 0.76 ( ) c 0.76 ( ) c 0.71 ( ) c COPD indictes chronic obstructive pulmonry disese; CTR, COPD tretment rtio (totl controller cnisters dispensed / [totl controller cnisters dispensed + totl SABA nd SAMA cnisters dispensed]); OR, odds rtio; SABA, short cting β 2 -drenergic gonist; SAMA, short-cting muscrinic ntgonist. Controller mediction includes inhled corticosteroids, long-cting β-gonists, long-cting muscrinic gents, inhled corticosteroids + longcting β-gonists, nd theophylline. b History of sthm defined s t lest 1 clim with dignosis of sthm (Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction code 493.x) during the bseline period. c Sttisticlly significnt t the 95% level. d Anticholinergic mediction includes long-cting muscrinic gents nd short-cting muscrinic gents. Author Affilitions: GlxoSmithKline (RHS, AN), Reserch Tringle Prk, NC; Lovelce Clinic Foundtion (DWM), Albuquerque, NM; University of Illinois t Chicgo (TAL), Chicgo, IL; Relint Medicl Group (RR), Worcester, MA; Kiser Permnente Southern Cliforni (MS), Sn Diego, CA; Groupe d nlyse Ltée (FV, MG-L), Montrél, Québec, Cnd; Université du Québec à Montrél (JFPM), Montrél, Québec, Cnd; Anlysis Group, Inc (MSD), Boston, MA. Source of Funding: Support for this study ws provided by GlxoSmithKline (GSK) (HO ). Author Disclosures: Dr Stnford is employed by GSK, the study sponsor, nd owns GSK stock. Dr Ng is employed by Shire Phrmceuticls, ws employed by Humn, nd owns GSK stock. Dr Lee received consulting money from GSK for his prticiption in this project. Dr Schtz is member of GSK severe sthm dvisory bord, hs received grnt from GSK for severe sthm dtbse study, nd received pyment for his involvement in the development of the study concept nd methods. Mr Vekemn ws nd Dr Duh is employed by Anlysis Group, which hs received reserch funds from GSK to conduct this nd other reserch. The remining uthors report no reltionship or finncil interest with ny entity tht would pose conflict of interest with the subject mtter of this rticle. Authorship Informtion: Concept nd design (RHS, AN, DWM, TAL, RR, MS, FV, MG-L, JFPM, MSD); cquisition of dt (AN, RR, FV, MSD); nlysis nd interprettion of dt (RHS, AN, DWM, TAL, MS, FV, MG-L, JFPM, MSD); drfting of the mnuscript (RHS, DWM); criticl revision of the mnuscript for importnt intellectul content (RHS, AN, DWM, TAL, RR, MS, FV, MG-L, MSD); sttisticl nlysis (DWM, FV, MG-L, JFPM); obtining funding (RHS, AN, MSD); dministrtive, technicl, or logistic support (RHS, FV); nd supervision (RHS, AN, FV, MSD). Address Correspondence to: Richrd H. Stnford, PhrmD, MS, GlxoSmithKline, 5 Moore Dr, Reserch Tringle Prk, NC Emil: richrd.h.stnford@gsk.com. e52 FEBRUARY

9 COPD Excerbtion Risk Model REFERENCES 1. Kochnek KD, Murphy SL, Xu J, Tejd-Ver B. Deths: finl dt for Ntl Vitl Stt Rep. 2016;65(4): Ford ES, Murphy LB, Khvjou O, Giles WH, Holt JB, Croft JB. Totl nd stte-specific medicl nd bsenteeism costs of COPD mong dults ged 18 yers in the United Sttes for 2010 nd projections through Chest. 2015;147(1): doi: /chest Globl strtegy for the dignosis, mngement, nd prevention of chronic obstructive pulmonry disese. Globl Inititive for Chronic Obstructive Lung Disese website. goldcopd.org/globl-strtegy-dignosismngement-prevention-copd Updted December Accessed Jnury 15, Burge S, Wedzich JA. COPD excerbtions: definitions nd clssifictions. Eur Respir J Suppl. 2003;41(suppl):46s-53s. 5. Psqule MK, Sun SX, Song F, Hrtnett HJ, Stemkowski SA. Impct of excerbtions on helth cre cost nd resource utiliztion in chronic obstructive pulmonry disese ptients with chronic bronchitis from predominntly Medicre popultion. Int J Chron Obstruct Pulmon Dis. 2012;7: doi: /COPD.S Morbidity & mortlity: 2012 chrtbook on crdiovsculr, lung, nd blood diseses. Ntionl Hert, Lung, nd Blood Institute website. nhlbi.nih.gov/files/docs/reserch/2012_chrtbook.pdf. Published Februry Accessed Jnury 15, Blnchette CM, Dll AA, Mpel D. Chnges in COPD demogrphics nd costs over 20 yers. J Med Econ. 2012;15(6): doi: / Blnchette CM, Gross NJ, Altmn P. Rising costs of COPD nd the potentil for mintennce therpy to slow the trend. Am Helth Drug Benefits. 2014;7(2): Perer PN, Armstrong EP, Sherrill DL, Skrepnek GH. Acute excerbtions of COPD in the United Sttes: inptient burden nd predictors of costs nd mortlity. COPD. 2012;9(2): doi: / Yu AP, Yng H, Wu EQ, Setywn J, Mocrski M, Blum S. Incrementl third-prty costs ssocited with COPD excerbtions: retrospective clims nlysis. J Med Econ. 2011;14(3): doi: / Abudgg A, Sun SX, Tn H, Solem CT. Excerbtions mong chronic bronchitis ptients treted with mintennce medictions from US mnged cre popultion: n dministrtive clims dt nlysis. Int J Chron Obstruct Pulmon Dis. 2013;8: doi: /COPD.S Hurst JR, Vestbo J, Anzueto A, et l; Evlution of COPD Longitudinlly to Identify Predictive Surrogte Endpoints (ECLIPSE) Investigtors. Susceptibility to excerbtion in chronic obstructive pulmonry disese. N Engl J Med. 2010;363(12): doi: /NEJMo Niewoehner DE, Lokhnygin Y, Rice K, et l. Risk indexes for excerbtions nd hospitliztions due to COPD. Chest. 2007;131(1): doi: /chest Aron SD, Donldson GC, Whitmore GA, Hurst JR, Rmsy T, Wedzich JA. Time course nd pttern of COPD excerbtion onset. Thorx. 2012;67(3): doi: /thorxjnl Mirvitlles M, Guerrero T, Myordomo C, Sánchez-Agudo L, Nicolu F, Segú JL. Fctors ssocited with incresed risk of excerbtion nd hospitl dmission in cohort of mbultory COPD ptients: multiple logistic regression nlysis. the EOLO Study Group. Respirtion. 2000;67(5): doi: / Grci-Aymerich J, Monsó E, Mrrdes RM, et l; EFRAM Investigtors. Risk fctors for hospitliztion for chronic obstructive pulmonry disese excerbtion. EFRAM study. Am J Respir Crit Cre Med. 2001;164(6): doi: /jrccm Lee SD, Hung MS, Kng J, et l; Investigtors of the Predictive Ability of CAT in Acute Excerbtions of COPD (PACE) Study. The COPD ssessment test (CAT) ssists prediction of COPD excerbtions in high-risk ptients. Respir Med. 2014;108(4): doi: /j.rmed Bertens LC, Reitsm JB, Moons KG, et l. Development nd vlidtion of model to predict the risk of excerbtions in chronic obstructive pulmonry disese. Int J Chron Obstruct Pulmon Dis. 2013;8: doi: /COPD.S Mrin JM, Crrizo SJ, Csnov C, et l. Prediction of risk of COPD excerbtions by the BODE index. Respir Med. 2009;103(3): doi: /j.rmed Müllerov H, Mselli DJ, Locntore N, et l. Hospitlized excerbtions of COPD: risk fctors nd outcomes in the ECLIPSE cohort. Chest. 2015;147(4): doi: /chest Mpel DW, Schum M, Lydick E, Mrton JP. A new method for exmining the cost svings of reducing COPD excerbtions. Phrmcoeconomics. 2010;28(9): doi: / Montserrt-Cpdevil J, Godoy P, Mrsl JR, Brbé F, Glván L. Risk fctors for excerbtion in chronic obstructive pulmonry disese: prospective study. Int J Tuberc Lung Dis. 2016;20(3): doi: /ijtld Stnford RH, Ng A, Mpel DW, et l. Vlidtion of new risk mesure for chronic obstructive pulmonry disese excerbtion using helth insurnce clims dt. Ann Am Thorc Soc. 2016;13(7): doi: /AnnlsATS OC. 24. Summry tble of mesures, product lines nd chnges. Ntionl Committee for Qulity Assurnce website. ncq.org/portls/0/hedisqm/hedis2016/hedis%202016%20list%20of%20mesures.pdf. Published June 16, Accessed Jnury 9, Are Helth Resources Files (ARF) Helth Resources & Services Administrtion website. dtwrehouse.hrs.gov/topics/ahrf.spx. Published September 30, Accessed Jnury 9, Elixhuser A, Steiner C, Hrris DR, Coffey RM. Comorbidity mesures for use with dministrtive dt. Med Cre. 1998;36(1): Austin PC, Tu JV. Bootstrp methods for developing predictive models. Am Stt. 2004;58(2): Hnley JA, McNeil BJ. The mening nd use of the re under receiver operting chrcteristic (ROC) curve. Rdiology. 1982;143(1): doi: /rdiology Pencin MJ, D Agostino RB Sr, D Agostino RB Jr, Vsn RS. Evluting the dded predictive bility of new mrker: from re under the ROC curve to reclssifiction nd beyond. Stt Med. 2008;27(2): ; discussion doi: /sim Full text nd PDF t THE AMERICAN JOURNAL OF MANAGED CARE VOL. 24, NO. 2 e53

10 eappendix Tble. Sensitivity Anlysis of Finl Risk Model of Severe COPD Excerbtion in Popultion Without History of Severe Excerbtion (MrketScn development smple) Risk Fctors During Bseline Period (Yer 1) 90-Dy At-Risk Period Severe excerbtion (N = 111,904; excerbtions, n = 1898; no excerbtions, n = 110,006) OR (95% CI) 180-Dy At-Risk Period Severe Excerbtion (N = 111,904; excerbtions, n = 3573; no excerbtions, n = 108,331) OR (95% CI) H1N1 flu seson: October 2009-My ( ) 0.85 ( ) Age group (yers) t index dte (ref: ged yers) ( ) 1.20 ( ) ( ) 1.27 ( ) ( ) 1.50 ( ) ( ) 1.57 ( ) ( ) 1.72 ( ) ( ) 1.83 ( ) ( ) 2.12 ( ) ( ) 2.25 ( ) CTR 0.3 (ref: 0 < rtio < 0.3) 0.81 ( ) 0.86 ( ) COPD mediction No controller mediction (ref: 1 fill for 0.78 ( ) 0.82 ( ) controller mediction) No controller mediction nd 4 cnisters 0.97 ( ) 0.93 ( ) of rescue mediction (ref: no fill for controller mediction nd <4 cnisters of rescue mediction or 1 controller mediction) 4 cnisters of rescue mediction (ref: <4 cnisters of rescue mediction) 1.31 ( ) 1.40 ( ) 1 fill for orl corticosteroids (ref: no fill for orl corticosteroids) 1.10 ( ) 1.21 ( ) 4 fills of orl corticosteroids (ref: < ( ) 1.30 ( ) fills for orl corticosteroids) 1 fill for theophylline (ref: no fill for 1.40 ( ) 1.37 ( ) theophylline) Excerbtions (ref: 0) 1 moderte 1.29 ( ) 1.16 ( ) 2 moderte 1.59 ( ) 1.52 ( ) Type of COPD dignosis

11 Chronic bronchitis (ICD-9-CM code 491.x) (ref: no encounter with chronic bronchitis dignosis during the bseline yer) Emphysem (ICD-9-CM code 492.x) (ref: no encounter with n emphysem dignosis during the bseline yer) Chronic irwy obstruction (ICD-9-CM code 496) (ref: no encounter with chronic irwy obstruction dignosis during the bseline yer) Comorbidities Asthm (ref: no encounter with n sthm dignosis during the bseline yer) Respirtory infection (ref: no encounter with respirtory infection during the bseline yer) Congestive hert filure (ref: no encounter with congestive hert filure dignosis during the bseline yer) 1.28 ( ) 1.33 ( ) 1.56 ( ) 1.41 ( ) 1.72 ( ) 1.84 ( ) 1.02 ( ) 0.90 ( ) 1.14 ( ) 1.19 ( ) 1.31 ( ) 1.38 ( ) Risk smoker (ref: no encounter during the 1.10 ( ) 1.13 ( ) bseline period with n ICD-9-CM code of 305.1, V15.82, or ) Concomitnt mediction Sttins (ref: no fill for sttin mediction) 0.96 ( ) 0.92 ( ) Antidepressnts (ref: no fill for 1.21 ( ) 1.25 ( ) ntidepressnt mediction) Procedures Chronic oxygen therpy (ref: no chronic 1.89 ( ) 1.83 ( ) oxygen therpy) Nebulizer (ref: no nebulizer) 1.22 ( ) 1.24 ( ) Spirometry (ref: no spirometry) 0.83 ( ) 0.87 ( ) C-sttistics Development (MrketScn) Vlidtion (MrketScn) Cross-vlidtion (Relint) COPD indictes chronic obstructive pulmonry disese; ICD-9-CM, Interntionl Clssifiction of Diseses, Ninth Revision, Clinicl Modifiction; CTR, COPD tretment rtio (totl controller cnisters dispensed / (totl controller cnisters dispensed + totl SABA nd SAMA cnisters dispensed)); OR, odds rtio; ref, reference; SABA, short-cting β2-drenergic gonists; SAMA, short-cting muscrinic ntgonists. Sttisticlly significnt t the 95% level.