Increased Relative Mortality in Women With Severe Oxygen-Dependent COPD

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1 CHEST Originl Reserch Incresed Reltive Mortlity in Women With Severe Oxygen-Dependent COPD Mgnus Ekström, MD ; Krl A. Frnklin, MD, PhD ; nd Kerstin E. Ström, MD, PhD COPD Bckground: Although the incidence of COPD is rpidly incresing in women, knowledge is lcking concerning differences in reltive mortlity nd cuses of deth in women compred with men. We imed to nlyze differences in reltive mortlity nd cuse-specific mortlity between men nd women on long-term oxygen therpy (LTOT) for COPD. Methods: Ptients strting LTOT for COPD in Sweden between Jnury 1, 1987, nd December 31, 2004, were prospectively followed until termintion of LTOT or through December 31, Cuses of deth ccording to the Swedish Ntionl Cuses of Deth Register were compred between the study group nd the generl Swedish popultion mtched for ge nd sex, with the reltive mortlity expressed s stndrdized mortlity rtes (SMRs ). Results: A totl of 7,646 ptients, 4,033 women nd 3,613 men, were followed for medin of 1.7 yers (rnge ). No ptient ws lost to follow-up. A totl of 5,448 ptients, 2,745 women nd 2,703 men, died. Women hd higher SMR thn men: overll mortlity, SMR 12.0 (95%, ) vs 7.4 (95% CI, ); for respirtory disese, SMR (95% CI, ) vs 66.0 (95% CI, ); cncer, SMR 3.5 (95% CI, ) vs 2.2 (95% CI, ); nd crdiovsculr disese, SMR 3.7 (95% CI, ) vs 2.5 (95% CI, ), respectively. Conclusions: In severe COPD treted with long-term oxygen, women hve higher reltive mortlity thn men both overll nd for respirtory disese, s well s for crdiovsculr disese nd cncer. CHEST 2010; 137(1):31 36 Abbrevitions: ICD 5 Interntionl Clssifiction of Disese; LTOT 5 long-term oxygen therpy; SMR 5 stndrdized mortlity rte COPD is one of the leding cuses of deth worldwide.1 Smoking is the mjor pthogenic fctor, ccounting for some 80% of the cses in high-income countries.2 Long-term oxygen therpy (LTOT) doubles the survivl time in ptients with COPD nd chronic hypoxi (P o 2, 7.3 kp). 3,4 Despite the impct of Mnuscript received Mrch 13, 2009; revision ccepted July 7, Affilitions: From the Deprtment of Respirtory Medicine (Drs Ekström nd Ström), Blekinge Hospitl Krlskron, University of Lund, Krlskron, Sweden; nd the Deprtment of Surgery (Dr Frnklin), Umeå University, Umeå, Sweden. Funding/Support: The study ws supported by grnts from the Swedish Hert nd Lung Foundtion, the Swedish Ntionl Bord of Helth nd Welfre, nd the Reserch Council of Blekinge. Correspondence to: Mgnus Ekström, MD, Deprtment of Respirtory Medicine, Blekinge Hospitl, SE Krlskron, Sweden; e-mil: mgnus_ekstrom@hotmil.com 2010 Americn College of Chest Physicins. Reproduction of this rticle is prohibited without written permission from the Americn College of Chest Physicins ( / site /misc /reprints.xhtml ). DOI: /chest LTOT, mortlity is high in ptients with COPD nd LTOT Ptients with COPD hve incresed comorbidity, such s cncer nd crdiovsculr disese. 11 Reporting cuse-specific mortlity is essentil becuse it hs been shown tht up to two-thirds of ptients with severe COPD who re treted with LTOT die of cuses other thn respirtory disese. 12 Previous studies of prognosis in men nd women with severe, oxygen-dependent COPD hve shown contrdictory results. Five previous studies report tht men hve shorter survivl time thn women fter strting LTOT. 5-7,9,13 In contrst, Mchdo et l 8 report tht women hve shorter survivl time, nd Crnston et l 13 reported tht women lost more yers of life thn men s compred with the generl popultion. Sex-relted differences in cuse-specific mortlity hve not previously been studied in ptients with LTOT for COPD. Knowledge bout sex differences in reltion to mortlity is urgently needed becuse women hve rpidly rising rtes of smoking, CHEST / 137 / 1 / JANUARY,

2 prticulrly in low- nd middle-income countries, nd COPD is incresingly becoming women s disese. 14 The mjority of ctive smokers nd ptients strting LTOT for COPD in Sweden tody re women, 9,15 nd the rte of women strting LTOT is predicted to increse further. 9 Women hve longer life expectncies thn men in the generl popultion, which might result in sex-relted differences in mortlity nd cuses of deth in LTOT for COPD. 16 Most ptients strting LTOT re lso elderly nd cn be expected to hve reltively high bckground mortlity. 9,10 We therefore conducted ntionl prospective study of ptients strting LTOT for COPD with the im of studying cuse-specific stndrdized mortlity rtes (SMRs) with respect to sex. Mterils nd Methods Ptients strting LTOT for chronic hypoxi due to COPD in Sweden between Jnury 1, 1987, nd December 31, 2004, were included in Ntionl Oxygen Register dministered by the Swedish Society of Respirtory Medicine Every center prescribing LTOT in Sweden greed on the ntionl guidelines from the Swedish Society of Respirtory Medicine, s described elsewhere. 9 Ptients who strted LTOT more thn once were excluded. All other ptients were followed prospectively, with cuse of deth s the primry outcome, until LTOT ws withdrwn or through December 31, 2004, whichever cme first. Bseline dt were collected t the strt of LTOT on rteril blood gs tensions when brething ir nd during oxygen therpy, FVC, FEV 1, smoking history, the prescribed oxygen dose, the prescribed durtion of oxygen tretment per dy, nd tretment with orl steroids. Cuses of deth were obtined from the Cuses of Deth Register t the Swedish Ntionl Bord of Helth nd Welfre nd coded ccording to the ninth (before 1996) nd the 10th revisions of the Interntionl Clssifiction of Disese (ICD). 20,21 ICD codes were grouped (ICD-9, ICD-10) s respirtory diseses (276C, 277, 279, , 786; E84, E87.2, E88.0, J00-J99, R04-R06), circultory diseses ( , 785; I00-I99, R00, R01), cncer ( ; C00-D48), digestive orgn diseses ( , 787; K00-K93), endocrine ( , 274, 275, 278; E00-E83, E85, E86), hemtologic (273, ; D50-D89), infectious diseses ( W; A00-B99), urogenitl diseses ( , 788; N00-N99), musculoskeletl diseses ( ; M00-M99), COPD ( , 496; J40-J44, J96), ischemic hert disese ( ; I20-I25), lung cncer (162; C34), hert filure (425, 428; I42, I50, I51.7), stroke ( ; I60-I69), ortic neurysm (441; I71), venous thromboembolism (415.1, 451; I26, I80), tuberculosis ( , 137; A15-A19, B90), pneumoni ( ; J13-J18), nd colon cncer (153; C18). All ptients gve their informed consent to prticipte. The study ws pproved by ll ethics committees in Sweden, the Swedish Ntionl Bord of Helth nd Welfre, nd the Dt Inspection Bord. Sttisticl Anlysis Bseline ptient chrcteristics were expressed s men 6 SD. Age-, sex-, nd clendr yer-specific person time t risk for deth during LTOT were clculted for ech ptient from the strt of LTOT to the time of deth, until LTOT ws withdrwn, or until the end of the observtion period (December 31, 2004), whichever cme first. Survivl fter strting LTOT ws compred between men nd women using Cox proportionl hzrds regression djusted for ge nd period of strting LTOT. Mortlity ws studied in the form of SMRs, defined s the rtio of the observed deths in the study popultion to the expected number of deths. The expected number of deths ws clculted using ntionl ge-, sex-, nd clendr yer-specific mortlity rtes from the Cuses of Deth Register, presented by the Swedish Ntionl Bord of Helth nd Welfre. The underlying cuse of deth ws used in ll nlyses becuse this is the bsis for the ntionl mortlity rtes. SMRs were clculted with 95% CIs. Sttisticl nlyses were performed with SPSS 14.0 (SPSS; Chicgo, IL), nd Stt 10.0 (SttCorp LP; College Sttion, TX). Results A totl of 7,646 ptients, 4,033 women nd 3,613 men, were included in the study fter exclusion of 71 ptients who hd strted LTOT more thn once. No ptient ws lost to follow-up. LTOT ws withdrwn in 436 (5.7%) ptients s result of improvement in oxygention (n 5 195), poor complince (n 5 36), or for other resons (n 5 205). Ptient chrcteristics t bseline re shown in Tble 1. Women hd slightly lower men ge t the strt of LTOT nd slightly higher P co 2 both when brething ir nd oxygen. The prescribed durtion of oxygen tretment per dy nd the men P o 2 brething oxygen were similr between the groups. Slightly more women thn men were never-smokers. Overll Reltive Mortlity The cohort ws followed for medin of 1.79 yers (rnge ) for women nd 1.55 yers (rnge ) for men nd generted totl of 16,175.5 person-yers with risk of mortlity. A totl of 5,448 ptients, 2,745 women nd 2,703 men, died during follow-up in the study group, compred with the expected 596, resulting in incresed reltive mortlity, SMR 9.1 (95% CI, ). Both women nd men hd incresed reltive mortlity for cncer nd respirtory, circultory, infectious, digestive, nd urogenitl diseses, s shown in Tble 2. Sex-Relted Differences in Mortlity Women hd lower bsolute risk of dying compred with men, with hzrd rtio of 0.86 (95% CI, , P,.001), using Cox proportionl hzrd regression djusted for ge nd the period of strting LTOT. Cuse-specific SMRs for women nd men re shown seprtely in Tble 2. Women hd significntly higher overll reltive mortlity thn men, SMR 12.0 (95% CI, ) vs SMR 7.4 (95% CI, ), respectively. Women lso hd significntly incresed reltive mortlity for cncer, respirtory, nd circultory disese compred with men. 32 Originl Reserch

3 Tble 1 Ptient Chrcteristics t Study Strt All Ptients, n 5 7,646 Women, n 5 4,033 Men, n 5 3,613 Age, y P o 2 ir, kp P co 2 ir, kp P o 2 oxygen, kp P co 2 oxygen, kp FEV 1, L FVC, L Smoking history, % Never Pst Current Oxygen dose, L/min Oxygen durtion, h/24 h Orl steroids, % All vlues re presented s mens 6 SD or percentge. Most ptients died of COPD (66%), ischemic hert disese (8.6%), lung cncer (4.4%), or hert filure (2.3%) (Tble 3 ). Women hd significntly higher reltive mortlity thn men for ll four of these min cuses of deth. Women lso hd incresed reltive mortlity from stroke, which ws not observed in men. Mortlity from ortic neurysm, venous thromboembolism, tuberculosis, nd pneumoni ws incresed in both men nd women, but with no significnt sexrelted differences. Discussion A new finding in the present study is tht women hve significntly higher reltive mortlity thn men, not only concerning ll-cuse mortlity nd mortlity from respirtory disese, but lso from crdiovsculr disese nd cncer. Studies of differences in observed survivl rtes between men nd women fter initition of LTOT for COPD hve shown contrdictory results. Most studies showed higher survivl rtes for women, 5-7,9,13 wheres the study by Mchdo et l 8 found survivl dvntge for men. Longer ge-djusted survivl for women ws lso shown in previously published study of some of the ptients included in this study. 9 The present findings illustrte tht lthough women hve better observed survivl fter strting LTOT, their reltive mortlity compred with the generl popultion mtched for ge is mrkedly higher. Women hve higher reltive mortlity from cncer nd respirtory nd crdiovsculr diseses nd lose more yers of life thn men. The higher reltive ll-cuse mortlity for women in the present study supports the findings of the study by Crnston et l 13 of reltive mortlity in 505 ptients with LTOT for COPD, in which women lost Tble 2 SMRs for Entity of Dignosis of Deth Women Men Disese Types Observed/Expected SMR (95% CI) Observed/Expected SMR (95% CI) Cncer 213/ ( ) 201/ ( ) Circultory 388/ ( ) 459/ ( ) Digestive 33/ ( ) 29/ ( ) Endocrine 11/ ( ) 11/ ( ) Hemtologic 2/ ( ) 3/ ( ) Infections 28/ ( ) 20/ ( ) Mentl 6/ ( ) 1/ (0-0.7) Musculoskeletl 11/ ( ) 3/ ( ) Nervous system 6/ ( ) 4/ ( ) Respirtory 1,983/ ( ) 1,902/ ( ) Urogenitl 9/ ( ) 14/ ( ) Other 55/ ( ) 56/ ( ) All cuses 2,745/ ( ) 2,703/ ( ) Expected 5 number of expected deths in the generl popultion mtched for ge nd sex; Observed 5 observed number of deths; SMR 5 stndrdized mortlity rte. Cuses of deth with significnt sex-relted differences in SMR. CHEST / 137 / 1 / JANUARY,

4 Tble 3 SMRs for the 10 Most Common Dignoses of Deth Women Men Observed/Expected SMR (95% CI) Observed/Expected SMR (95% CI) COPD 1,860/ ( ) 1762/ ( ) Ischemic hert disese 191/ ( ) 280/ ( ) Lung cncer 116/ ( ) 123/ ( ) Hert filure 70/ ( ) 50/ ( ) Stroke 45/ ( ) 34/ ( ) Aortic neurysm 15/ ( ) 22/ ( ) Venous thromboembolism 13/ ( ) 20/ ( ) Tuberculosis 17/ ( ) 7/ ( ) Pneumoni 8/ ( ) 13/ ( ) Colon cncer 13/ ( ) 8/ ( ) See Tble 2 for expnsion of bbrevitions. Cuses of deth with significnt sex-relted differences in SMR. more yers of life thn men, compred with the generl popultion (16.3 yers for women vs 13 yers for men). The mjority of studies compring the sex-relted differences of the impct of smoking in ptients with COPD hve studied the rte of decline in FEV 1. They come to contrdictory conclusions, but most studies hve found tht women seem more disposed to developing COPD t n erlier ge thn men nd with less tobcco exposure In one study, women with COPD were found to be younger, hd fewer pckyers, nd fewer comorbidities, 28 nd in nother study, women were found to be less susceptible to irwy obstruction. 29 When women hve been found to be more susceptible, the explntions hve often been differences in irwy dimeter nd irwy responsiveness. 27,30 But mortlity, even in COPD so severe tht the ptient qulifies for LTOT, is not cused only by the respirtory disese. The 215 ptients included in the study by Zielinski et l 12 of cuse-specific mortlity in ptients with COPD receiving LTOT died of respirtory filure (38%), crdiovsculr disese (27%), pulmonry infection (11%), pulmonry embolism (10%), lung cncer (7%), or other cuses (7%). However, the mortlity ws not relted to the expected mortlity bsed on ge nd sex in the popultion, only few women were included, nd the study did not report ny sex-relted differences in mortlity. The present study shows tht ptients who receive LTOT for severe COPD hve mrkedly incresed reltive mortlity from number of different diseses nd tht there is sex-relted difference: women hve significntly higher reltive mortlity thn men for cncer, respirtory nd crdiovsculr diseses in cses of severe COPD. However, becuse gedjusted mortlity from crdiovsculr disese in the generl popultion is considerbly lower in women thn in men, deth from crdiovsculr disese ws still more common in men who received LTOT for COPD thn in women. The strengths of the present study re its ntionl prospective design nd tht it includes lrger ptient group, especilly more women, thn other studies in the field. 5-9,13 No ptient ws lost to follow-up, thnks to the fct tht Sweden hs complete popultion register of vitl sttus nd cuses of deth. This is, to our knowledge, the first study of sex-relted differences in cuse-specific mortlity in ptients who received LTOT for COPD. Using reltive mortlity model mde it possible to describe the excess cusespecific mortlity mong the ptients compred with the mtched generl popultion, nd hs been shown to be superior to using Cox regression models in djusting for the effects of ge nd differences in life expectncy in reltion to mortlity. 10 Severl studies hve questioned the vlidity of cuse of deth registers in reltion to COPD, nd most hve found COPD to be underestimted s n underlying cuse of deth The rte of underestimtion of COPD s the cuse of deth hs been shown to decrese with incresing severity of COPD, especilly for women. 34 Therefore, underestimtion of COPD s the cuse of deth is probbly only minor problem in the present study of ptients with known severe COPD treted with long-term oxygen. The incresed reltive mortlity in women s compred with men in our study could to some extent be cused by the lower ge-djusted mortlity in women thn in men in the generl popultion. 16 The mechnism for this is lrgely unknown, but it might prtly be ttributble to lower prevlence of risk fctors mong women, most notbly smoking. Although smoking rtes hve incresed in Sweden for women, the rtes of ever-smokers nd the men number of cigrettes smoked per dy re still higher in men. 15 Studies hve shown tht women my be more sensitive to the dverse helth effects of smoking nd 34 Originl Reserch

5 my more esily develop severe COPD with respirtory filure thn men on the bsis of the sme smoking burden A recent Swedish study showed tht the incresing incidence of women strting LTOT for severe COPD could not be explined solely by differences in smoking rtes. Women lso seem more susceptible to developing severe disese thn men. 9 We thus find it likely tht the observed higher reltive mortlity in women who received LTOT for COPD is cused by combintion of the lower ge-djusted mortlity rte for women compred with men in the generl popultion nd the fct tht women strting LTOT often hve more severe diseses nd comorbidities tht eliminte their norml survivl dvntge. The present findings stress the importnce of promoting smoking cesstion, especilly for women, who hve incresing smoking rtes in mny prts of the world. Becuse mortlity in severe COPD is incresed in severl nonrespirtory diseses, such s crdiovsculr disese, erlier dignosis nd tretment of comorbidity re importnt in women, s they hve even more incresed reltive mortlity thn men in reltion to crdiovsculr disese nd cncer. In conclusion, in cses of severe COPD treted with long-term oxygen, women lose more yers of life nd hve significntly higher reltive mortlity thn men, not only overll nd for respirtory disese, but lso for crdiovsculr disese nd cncer. Acknowledgments Author contributions: Dr Ekström: contributed to the design of the study nd the nlysis, interprettion, nd presenttion of dt, drfted the submitted rticle, nd provided finl pprovl of the version to be published. Dr Frnklin: contributed to the nlysis nd interprettion of dt, revised it criticlly for importnt scientific content, nd provided finl pprovl of the version to be published. Dr Ström: ws responsible for the Swedish Oxygen Register during the collection of the dt, initited the study, prticipted in the design, nlysis, nd interprettion of the dt, gve dvice on the drfting of the mnuscript, revised the mnuscript, nd provided finl pprovl of the version to be published. Finncil /nonfinncil disclosures: The uthors hve reported to CHEST the following conflicts of interest: Dr Ekström received reimbursement from Union Chimique Belge for ttending the Europen Respirtory Society nnul conference in Dr Frnklin hs no potentil conflict with ny compnies/ orgniztions whose products or services my be discussed in this rticle. Dr Ström received reimbursement from Pifizer for ttending the Americn Thorcic Society conference in 2006 nd from Union Chimique Belge for ttending the Europen Respirtory Society nnul conference in Dr Ström lso received $1,000 for lecturing t conferences orgnized by Boehringer-Ingelheim in 2006 nd Other contributions: The work ws performed t the Deprtment of Respirtory Medicine, Blekinge Hospitl Krlskron, University of Lund, Sweden. We thnk ll the physicins nd nurses who collected the dt. The dt nlysis ws performed by Philippe Wgner nd Jons Rnstm (t the Swedish Musculoskeletl Competence Centre in Lund, Sweden), who lso ssisted with development of the study design nd prticipted in the preprtion of the mnuscript. References 1. Lopez AD, Mthers CD, Ezzti M, et l. Globl Burden of Disese nd Risk Fctors. Wshington : The World Bnk ; Puwels RA, Buist AS, Clverley PM, Jenkins CR, Hurd SS ; GOLD Scientific Committee. 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