Effects of Cardiovascular Drugs on Mortality in SevereChronic Obstructive Pulmonary DiseaseA Time-Dependent Analysis

Magnus P. Ekstrom1,2, Anna Bornefalk Hermansson3, and Kerstin E. Strom1,2

1Department of Respiratory Medicine and Allergology, Institution for Clinical Sciences, Lund University, Lund, Sweden; 2Department of Medicine,

Blekinge Hospital, Karlskrona, Sweden; and 3Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden

Rationale: Cardiovascular drugsmay improve survival in chronic ob-structive pulmonary disease (COPD). However, previous studies didnot account formajor sources ofbias, anddrugeffectshavenotbeenevaluated in severe COPD.Objectives: To estimate the time-dependent effects of cardiovascu-lar drugs on survival in oxygen-dependent COPD, accounting forimmortal and immeasurable time bias.Methods: Prospective national study of patients starting long-termoxygentherapy forCOPD inSwedenbetween1October2005and30June 2009. Effects on mortality were estimated using extended Coxregression adjusted for age, sex, PaO2

, PaCO2, World Health Organi-

zation performance status, body mass index, comorbidity, and con-comitant medications. Immortal and immeasurable time bias wasaddressed by analyzing allmedications as time-dependent variablesand accounting for hospitalized time, respectively.MeasurementsandMainResults:Time-dependenteffectsofangiotensin-converting enzyme inhibitors or angiotensin receptorblockers, anti-platelet drugs, b-blockers, and statins on all-cause mortality weremeasured. Of the 2,249 included patients, 1,129 (50%) died underobservation. No patient was lost to follow-up. The adjusted time-dependent model was compatible with reduced mortality for anti-platelet drugs (hazard ratio [HR], 0.86; 95%CI, 0.75–0.99; P¼0.030)and trends for angiotensin-converting enzyme inhibitors or angio-tensin receptorblockers (HR, 0.90; 95%CI, 0.79–1.04; P¼0.166) andstatins (HR, 0.86; 95% CI, 0.72–1.03; P¼ 0.105), whereas b-blockersincreased mortality (HR, 1.19; 95% CI, 1.04–1.37; P ¼ 0.010).Conclusions: This study supports that antiplatelet drugs improvesurvival and b-blockers decrease survival in oxygen-dependentCOPD.

Keywords: chronic obstructive pulmonary disease; long-term oxygentherapy; survival; comorbidity

As chronic obstructive pulmonary disease (COPD) is a leadingcause of mortality worldwide, treatments that improve survivalare needed (1).

Comorbidity is known to be highly prevalent in COPD (2)and is an important predictor of mortality (3, 4). A number ofnonrandomized studies have suggested a beneficial effect onmortality for cardiovascular drugs: angiotensin-converting en-zyme inhibitors (ACEI) (5–7), angiotensin receptor blockers(ARB) (5), antiplatelet drugs (7), b-blockers (7–12), and statins(5–7, 13–15).

However, the surprisingly large effect sizes in previous studieshave raised the concern that the findings might have been biased.According to a recent analysis (16), the apparent drug effects inseveral of the studies (5, 13) were explained by immortal timebias and immeasurable time bias (17, 18). These biases might infact have affected most previous cardiovascular drug studies inCOPD (5–7, 9, 11, 13).

Immortal time bias may arise when exposure is assessed af-ter the start of follow-up. All patients who become exposedduring follow-up must, by definition, have lived until the dateof exposure, whereas nonexposed patients must not; this cre-ates a spurious association between drug exposure and im-proved survival (16). Immeasurable time bias can arise whendrug exposure cannot be measured during hospitalizations.Therefore, hospitalized patients with shorter survival are morelikely to be misclassified as unexposed, which also createsa spurious association between drug exposure and improvedsurvival (16). Methods to account for both types of bias havebeen described (16).

In addition, previous studies evaluated the effects of drug ex-posure defined at baseline only, which might be inappropriate asdrug exposure is likely to vary over time. The effects of cardio-vascular drugs have not been previously studied in patients withsevere COPD, who have high mortality, including from cardio-vascular disease (19).

We therefore conducted a national prospective study of thetime-dependent effects of cardiovascular drugs on mortality insevere COPD, accounting for immortal and immeasurable time

(Received in original form August 30, 2012; accepted in final form December 12, 2012)

Funded by the Research Council of Blekinge, the Swedish Heart-Lung Founda-

tion, and the Swedish National Board of Health and Welfare.

Author Contributions: M.P.E. had full access to all the data in the study and takes

full responsibility for the integrity of the data and the accuracy of the data anal-

ysis. Conception and design: M.P.E., A.B.H., K.E.S. Acquisition of data: M.P.E.,

K.E.S. Analysis and interpretation of data: M.P.E., A.B.H. Drafting the article: M.P.E.,

A.B.H. Revising it for important intellectual content and approval of the version to

be published: M.P.E., A.B.H., K.E.S.

Correspondence and requests for reprints should be addressed to Magnus Ekstrom,

M.D., Ph.D., Department of Medicine, Blekinge Hospital, SE-37185, Karlskrona,

Sweden. E-mail: pmekstrom@gmail.com.

This article has an online supplement, which is accessible from this issue’s table of

contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 187, Iss. 7, pp 715–720, Apr 1, 2013

Copyright ª 2013 by the American Thoracic Society

Originally Published in Press as DOI: 10.1164/rccm.201208-1565OC on January 17, 2013

Internet address: www.atsjournals.org

AT A GLANCE COMMENTARY

Scientific Knowledge on the Subject

Cardiovascular drugs may improve survival in chronic ob-structive pulmonary disease (COPD), but previous studiesdid not account for major sources of bias, and drug effectshave not been evaluated in very severe COPD.

What This Study Adds to the Field

This prospective study supports a beneficial effect ofantiplatelet drugs on survival and beneficial trends forangiotensin-converting enzyme inhibitors, angiotensinreceptor blockers, and statins. However, b-blockers maydecrease survival in oxygen-dependent COPD.

bias. Some of the results of this study were previously presentedin the form of an abstract (20).

METHODS

This was a national prospective multicenter study of patients aged45 years or older registered in the national Swedevox Register, whostarted long-term oxygen therapy (LTOT) for physician-diagnosed COPDbetween 1 October 2005 and 30 June 2009. The Swedevox Register is ad-ministered by the Swedish Society of Respiratory Medicine and prospec-tively includes patients starting LTOT for COPD in Sweden since 1987,with a population-based coverage of some 85% (21).

Only the latest treatment episode was included for patients who hadstarted LTOT more than once (n ¼ 62). Exclusion criterion was a diag-nosis of lung cancer before the date of starting LTOT (baseline). Datawere collected at baseline on resting PaO2

and PaCO2breathing air and

during oxygen therapy, FEV1, FVC, body mass index (BMI), smokinghistory, and World Health Organization performance status (22).

Comorbidity and in-hospital time within 4 years before baselinewere obtained from the National Patient Register for in- and out-patient care, which covers more than 99% of all hospitalizations since1987 and about 80% of all hospital-based outpatient care in Swedensince 2001 (23). The 4-year assessment period assured that all patientshad the same assessment time for comorbidity, as data on outpatientcare were available after 2001. Comorbidities were coded according tothe tenth revision of the International Classification of Disease (ICD)(24). Definitions of all diagnosis entities are found in Table E1 in theonline supplement.

Data on medications were obtained from the Swedish PrescribedDrug Register, which includes all dispensed prescriptions in outpatientcare in Sweden after 1 July 2005 (25). Medications were categorizedaccording to the Anatomical Therapeutic Chemical Classification Sys-tem codes (26), as shown in Table E2. Patients were followed untilwithdrawal of LTOT, death, or 31 December 2009, whichever camefirst. Vital status was obtained from the Swedish Causes of DeathRegister. The underlying cause of death was available between 2005and 2008 (n ¼ 758; 67% of total deaths).

All patients gave their informed consent to participate. The studywas approved by all the relevant ethics committees in Sweden, the Swed-ish National Board of Health and Welfare, and the Data InspectionBoard.

Statistical Analysis

Data were tabulated using frequencies and percentages for categor-ical variables, mean with SD, and median with range or interquartilerange for continuous variables with normal and skewed distribution,respectively.Drug exposure. Dispensed prescribed drugs (prescriptions) were

assessed during each full 91-day period (quarter) from the quarter be-fore baseline until end of follow-up for each individual patient, as shownin Figure 1. A 91-day period was chosen, because the drugs in this studyare usually prescribed for 3 months at a time. The probability of drugexposure for each quarter was set to 1 if there was at least one pre-scription during the quarter and set to 0 if there was no prescriptionduring either this or the next quarter. To account for medications givenin the hospital, the probability of exposure was set to the proportion ofthe current quarter spent in the hospital for quarters with no prescrip-tion but with a prescription during the next quarter. Exposure at base-line was defined as an exposure probability greater than 0 for thequarter before baseline. A more detailed description of the exposureassessment is provided in Section E1 in the online supplement.Time-dependent model. The exposures of primary interest were treat-

ment with ACEIs or ARBs (merged into the category ACEI/ARB ow-ing to few cases of exposed to ARB and presumed similar effects),antiplatelet drugs, b-blockers, and statins. Secondary hypotheses werethose of treatment effects of the combination of a long-acting b2 ago-nist and an inhaled corticosteroid (LABA 1 ICS), oral glucocorticoids,and tiotropium.

Time-dependent drug effects on all-cause mortality were estimatedusing an extension of the Cox model (27). The time-varying covariatewas set to the exposure probability for the 91-day period before thequarter of the event for each drug (Figure 1). This lag-time effect

allowed for the time it takes for the cardiovascular medications toachieve their therapeutic effects, and the model assumed that the ther-apeutic effects remained for no more than 3 months after the lastprescription.

Missing elements were imputed for PaO2air (n ¼ 289), PaCO2

air(n ¼ 301), and BMI (n ¼ 701), as detailed in Section E2 in the onlinedata supplement. The model estimates were robust to the imputations.FEV1, smoking history, the number of previous hospitalizations, andthe presence of diabetes mellitus were not included in the final analysis,as they had no significant independent effects and did not affect any ofthe multiple regression estimates.

In the final model, the drug effects were adjusted for baseline differ-ences in age, sex, PaO2

air, PaCO2air, BMI, World Health Organization

performance status (22), and comorbidities: anemia, renal failure, andcardiovascular diseases (cerebrovascular disease, heart failure, hyper-tension, ischemic heart disease, peripheral artery disease, pulmonaryembolism, or other circulatory disease).

Time-dependent drug effects, expressed as hazard ratios (HRs) with95% confidence intervals (CIs), are interpreted as, at any given time, thehazard for a patient who was exposed during the previous quarter ascompared with the hazard for a patient who was not exposed, adjustedfor all other covariates.

Data management of dispensed prescriptions was performed usingMimer SQL version 10.1 (Mimer Information TechnologyAB,Uppsala,Sweden), and analyses were conducted with Stata version 11.1 (Stata-Corp LP; College Station, TX) and SAS version 9.2 (SAS Institute,Inc., Cary, NC).

RESULTS

In total, 2,249 patients, 1,328 (59%) women and 921 men, wereincluded after excluding 2 (0.09%) patients due to data irregu-larities and 39 (2%) patients with a lung cancer diagnosis at base-line. No patient was lost to follow-up. The cohort generated3,118.1 person-years at risk and was followed for a median1.1 years (first quartile–third quartile, 0.6–2.0 yr). During thistime, 1,129 (50%) patients died. The main causes of death wererespiratory disease (68%), cardiovascular disease (20%), andcancer (6%).

Drug Exposure and Compliance

At baseline, ACEI/ARBs were used by 763 (34%) patients, anti-platelet drugs by 887 (39%), b-blockers by 829 (37%), andstatins by 431 (19%). The number of patients treated with com-binations of drugs and patient characteristics according to drugexposure at baseline are shown in Table 1. Patients treated withACEI/ARB, antiplatelet drugs, b-blockers, or statins had higherBMI and more cardiovascular disease, diabetes mellitus, andrenal failure than patients on none of these drugs (Table 1).

Figure 1. Assessment of drug exposure over time. Dispensed prescrip-

tions (arrows) and hospitalizations (boxes) were assessed during each

91-day period (quarter) from 91 days before study start until the endof follow-up for each patient. The probability of exposure (E) was set to

the proportion of the present quarter spent in the hospital (50% of the

second quarter, thus E2 ¼ 0.5) if there was no drug prescription in the

present but at least one prescription in the next quarter. The time-varyingcovariate in the survival analysis was set to the exposure probability for

the quarter before the event period, in this example E6.

716 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 187 2013

The most commonly used ACEI/ARBs were enalapril andlosartan, 98% of all b-blockers were cardioselective, and theantiplatelet and statin categories were dominated by aspirinand simvastatin, respectively. Dispensed drugs within each drugcategory are listed in Table E3. Of patients taking LABA orICS, the majority (85%) used both drugs concomitantly; onlyfew had monotherapy with LABA (5%) or ICS (10%). Table 2shows changes in exposure status and drug adherence; of pa-tients categorized as exposed to cardiovascular drugs at base-line, 10 to 14% changed status to unexposed during follow-up,and 5 to 10% of those unexposed at baseline were later ex-posed. During follow-up, patients were hospitalized for a me-dian 7% (minimum, 0; maximum, 89%) of the time.

Effects on Mortality

The adjusted estimates were compatible with decreased mortalityfor antiplatelet drugs (HR, 0.86; 95% CI, 0.75–0.99; P ¼ 0.030)and beneficial trends for ACEI/ARB (HR, 0.90; 95% CI,0.79–1.04; P ¼ 0.166) and statins (HR, 0.86; 95% CI, 0.72–1.03;P ¼ 0.105), as shown in Table 3. In contrast, b-blockers wereassociated with increased mortality (HR, 1.19; 95% CI, 1.04–1.37;P ¼ 0.010). In addition, oral glucocorticoids were significantlyassociated with higher mortality, and tiotropium tended to de-crease mortality. The drug effects are depicted in Figure 2.

There was no additional explanatory power in the model forinteractions between ACEI/ARB and statins (P ¼ 0.298),

cardiovascular comorbidities and ACEI/ARB (P ¼ 0.642), car-diovascular comorbidities and b-blockers (P ¼ 0.909) or statins(P ¼ 0.325), or between b-blockers and LABA 1 ICS or sex(P . 0.15 for both).

To explore the b-blocker effect, we estimated the time-dependent effects of b-blockers for subgroups of patients basedon (1) the presence of cardiovascular disease, defined as at leastone cardiovascular diagnosis at baseline; (2) exposure to LABA1ICS at baseline; and (3) sex. The negative impact of b-blockerstended to be stronger in patients without LABA 1 ICS,patients with cardiovascular disease, and in men (Figure E1).The increased mortality for b-blockers (HRs > 1.20) was con-sistent across all subgroups except in women with LABA 1ICS. However, there was no signs of interaction betweenb-blockers, sex, and LABA 1 ICS in the fully adjusted model(P ¼ 0.782). Adjusting for ischemic heart disease in addition tothe cardiovascular score did not change the b-blocker effect.

DISCUSSION

This study supports that antiplatelet drugs, and possibly ACEI/ARBs and statins, improve survival, whereas b-blockers decreasesurvival in patients with severe oxygen-dependent COPD.

This is the first study, to the authors’ knowledge, to evaluatethe effects of cardiovascular drugs on mortality in very severeCOPD and to account for immortal and immeasurable time biasas well as changes in drug exposure over time.

TABLE 1. PATIENT CHARACTERISTICS ACCORDING TO STUDY DRUG EXPOSURE AT BASELINE

Characteristic All Patients ACEI/ARB b-Blockers Statins Nontreated

N (%) 2,249 (100) 763 (34) 829 (37) 431 (19) 965 (43)

Age, yr 74.7 6 8.2 75.3 6 7.7 75.6 6 7.8 73.5 6 7.1 74.1 6 8.6

Women, n (%) 1,328 (59) 423 (55) 461 (56) 216 (50) 611 (63)

PaO2air, kPa 6.5 6 0.9 6.5 6 0.9 6.5 6 0.8 6.6 6 0.8 6.6 6 0.9

PaCO2air, kPa 6.3 6 1.3 6.3 6 1.3 6.3 6 1.3 6.1 6 1.3 6.2 6 1.2

FEV1 % predicted 37.7 6 19.1 39.8 6 18.9 40.5 6 19.9 40.2 6 20.7 35.9 6 18.0

Known ever smoking, n (%) 2,106 (93) 726 (95) 781 (94) 408 (95) 893 (93)

Body mass index, n (%)

,18.5 279 (12) 60 (8) 81 (10) 42 (10) 152 (16)

18.5–24.9 693 (31) 203 (27) 230 (28) 115 (27) 339 (35)

25–29.9 338 (15) 125 (16) 132 (16) 78 (18) 120 (12)

>30 235 (10) 112 (15) 113 (14) 58 (13) 64 (7)

WHO performance status, n (%)

0 132 (6) 40 (5) 37 (4) 30 (7) 63 (7)

1 881 (39) 292 (38) 321 (39) 169 (39) 392 (41)

2 714 (32) 240 (31) 268 (32) 140 (32) 302 (31)

3 292 (13) 101 (13) 116 (14) 48 (11) 113 (12)

4 31 (1) 10 (1) 11 (1) 3 (1) 16 (2)

Hospitalizations* 5 (2–8) 5 (3–9) 6 (3–9) 5 (3–9) 4 (2–8)

Anemia, n (%) 196 (9) 79 (10) 95 (11) 36 (8) 70 (7)

Cardiovascular diagnoses, n (%)

0 755 (34) 134 (18) 116 (14) 56 (13) 510 (53)

1 823 (37) 266 (35) 330 (40) 160 (37) 318 (33)

2 449 (20) 229 (30) 245 (30) 135 (31) 98 (10)

.2 222 (10) 134 (18) 138 (17) 80 (19) 39 (4)

Diabetes mellitus, n (%) 291 (13) 159 (21) 158 (19) 120 (28) 53 (5)

Renal failure, n (%) 97 (4) 55 (7) 62 (7) 34 (8) 13 (1)

ACEI/ARB, n (%) 763 (34) 763 (100) 415 (50) 229 (53) 0

Antiplatelet drugs, n (%) 887 (39) 402 (53) 453 (55) 321 (74) 210 (22)

b-Blockers, n (%) 829 (37) 415 (54) 829 (100) 256 (59) 0

LABA 1 ICS, n (%) 1,562 (69) 536 (70) 570 (69) 315 (73) 657 (68)

Oral glucocorticoids, n (%) 1,375 (61) 437 (57) 498 (60) 282 (65) 598 (62)

Statins, n (%) 431 (19) 229 (30) 256 (31) 431 (100) 0

Tiotropium, n (%) 1,165 (52) 412 (54) 427 (52) 233 (54) 482 (50)

Definition of abbreviations: ACEI ¼ angiotensin-converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; ICS ¼ inhaled corticosteroids; LABA ¼ long-acting

b2 agonists; WHO ¼ World Health Organization.

Data presented as mean 6 SD unless otherwise specified. Percentages may not add up to 100 owing to rounding. Elements were missing for PaO2air (n ¼ 289), PaCO2

air (n ¼ 301), FEV1 (n ¼ 849), FVC (n ¼ 863), body mass index (n ¼ 701), and WHO performance status (n ¼ 199). Hospitalizations and diagnoses were assessed within

4 years before baseline.

*Median (first quartile–third quartile).

Ekstrom, Bornefalk Hermansson, and Strom: Cardiovascular Drugs and Mortality in Severe COPD 717

The improved survival for antiplatelet drugs and the beneficialtrends for ACEI/ARBs and statins are consistent with studies ofpatients with less severe COPD (5–7, 11, 13–15). van Gestel andcolleagues reported that statins reduced mortality (HR, 0.67;95% CI, 0.52–0.86) (10, 14). The study by van Gestel and col-leagues is interesting because it was likely free from immortaland immeasurable time bias (14) but was a single-center study ofa selected population of patients with COPD undergoing vascularsurgery. Improved survival for statins was also found by Ruttenand colleagues (HR, 0.83; 95% CI, 0.65–1.08), but no effect wasfound for ACEI/ARB (HR, 1.01; 95% CI, 0.84–1.21) (11). Shortand colleagues recently reported a reduced mortality for ACEI/ARB (HR, 0.79; 95% CI, 0.72–0.88), antiplatelet drugs (HR, 0.80;95% CI, 0.73–0.88), and statins (HR, 0.89; 95% CI, 0.81–0.97) (7).Compared with previous findings, the effect sizes in the presentstudy were smaller, which might be because we accounted forimmortal and immeasurable time bias.

Despite initial concerns, cardioselective b-blockers have inrecent years been considered safe and effective to use in COPDbased on studies of patients with mostly mild to moderate air-flow limitation (7–12, 28, 29). A recent meta-analysis reportedthat b-blockers were associated with a lower relative risk ofmortality of 0.69 (95% CI, 0.62–0.78) but also indicated thepresence of publication bias; studies reporting nonbeneficialeffects of b-blockers were less likely to be published (12). Ourfinding of increased mortality in oxygen-dependent COPD is inline with a previous report that the positive effect of b-blockersin milder forms of COPD is lost in patients with more severerespiratory impairment (29).

Strengths of the present study are that it included a large rep-resentative national sample of patients with severe oxygen-dependent COPD with complete follow-up. The study could bespecifically designed to address immortal and immeasurable timebias, as complete nationwide data was available on hospitaliza-tions and dispensed outpatient drugs. The validity of our findingsis supported by the fact that we found effects of LABA1 ICS andtiotropium that were compatible with those of the randomizedTORCH and UPLIFT trials (30, 31), in contrast to the dramaticeffect shown in previous nonrandomized studies (7, 11, 13).

There were two main limitations to our study design, the firstbeing that dispensed prescriptions do not necessarily imply con-sumption. Adherence to the cardiovascular drugs was, however,generally high among users, and most exposed patients receivedregular prescriptions, implying that they actually took their drugs.The second limitation, common to all observational designs, ispossible confounding by indication owing to the lack of random-ization (32). Previous studies have tried to compensate for thisby using propensity score methods, which model with or match onthe conditional probability of receiving the treatment using a

high-dimensional set of pretreatment characteristics (6, 7, 9–11,33). However, the patient characteristics in this study, as in allprevious studies in this field, were collected at study start andnot at the start of each drug treatment, implying that the use ofpropensity score methods might be inappropriate. We addressedconfounding by indication by restricting the analysis to patients

TABLE 2. CHANGES IN EXPOSURE STATUS FROM BASELINE DURING FOLLOW-UP IN 2,249 PATIENTS WITH OXYGEN-DEPENDENTCHRONIC OBSTRUCTIVE PULMONARY DISEASE

Drug

From Exposed to

Unexposed, n (% of Exposed)

From Unexposed to

Exposed, n (% of Unexposed)

Continuously Exposed,

n (% of Total)

Median Adherence for

Continuously Exposed (Min–Max), %

ACEI/ARB 100 (14) 102 (7) 637 (28) 89 (25–100)

Antiplatelet drugs 93 (10) 140 (10) 759 (34) 88 (18–100)

b-Blockers 83 (10) 128 (9) 714 (32) 92 (41–100)

LABA 1 ICS 182 (12) 173 (24) 1,345 (60) 87 (13–100)

Oral glucocorticoids 354 (27) 288 (31) 980 (44) 84 (15–100)

Statins 55 (13) 99 (5) 365 (16) 88 (38–100)

Tiotropium 211 (18) 160 (14) 934 (42) 89 (18–100)

Treatment status was measured per quarter (91-d period) during follow-up and adjusted for immeasurable (hospitalized) time. Baseline status denotes the exposure

status of the quarter before inclusion. During follow-up, unexposed changed status at the first exposure, and exposed changed status when they were unexposed for all

(and at least two) subsequent quarters. Compliance was calculated as the sum of the exposure probabilities for each full quarter observed, divided by the number of full

quarters observed.

TABLE 3. TIME-DEPENDENT DRUG EFFECTS ON ADJUSTED ALL-CAUSE MORTALITY IN 2,249 PATIENTS WITH OXYGEN-DEPENDENTCHRONIC OBSTRUCTIVE PULMONARY DISEASE

Parameter Hazard Ratio 95% CI P Value

Age, per yr 1.04 1.03–1.05 ,0.001

Woman 0.77 0.67–0.87 ,0.001

BMI ,0.001*

,18.5 1.36 1.14–1.61 ,0.001

18.5–24.9 Ref — —

25–29.9 0.72 0.60–0.87 ,0.001

>30 0.79 0.64–0.99 0.044

WHO performance status ,0.001*

0 Ref — —

1 1.01 0.74–1.39 0.930

2 1.47 1.07–2.00 0.017

3 2.42 1.74–3.36 ,0.001

4 3.28 1.98–5.42 ,0.001

Missing 1.37 0.96–1.96 0.082

PaO2air, per 1 kPa 0.91 0.85–0.98 0.009

PaCO2air† — — ,0.001

Anemia 1.24 1.02–1.50 0.034

Cardiovascular diagnoses ,0.001*

0 Ref — —

1 1.25 1.08–1.46 0.003

2 1.41 1.18–1.69 ,0.001

.2 1.39 1.11–1.75 0.005

Renal failure 1.34 1.03–1.74 0.027

ACEI/ARB 0.90 0.79–1.04 0.166

Antiplatelet drugs 0.86 0.75–0.99 0.030

b-Blockers 1.19 1.04–1.37 0.010

LABA 1 ICS 0.98 0.86–1.12 0.790

Oral glucocorticoids 1.53 1.35–1.73 ,0.001

Statins 0.86 0.72–1.03 0.105

Tiotropium 0.90 0.79–1.03 0.126

Definition of abbreviations: ACEI ¼ angiotensin-converting enzyme inhibitors;

ARB ¼ angiotensin receptor blockers; CI ¼ confidence interval; ICS ¼ inhaled

corticosteroids; LABA ¼ long-acting b2 agonists; Ref ¼ reference category;

WHO ¼ World Health Organization.

The hazard ratios for medications are interpreted as, at any given time, the

hazard for a patient who was exposed during the 91-day period before the

period of the event, as compared with the hazard for a patient who was unex-

posed, adjusted for all other covariates.

*Wald test of total significance for class variables with more than two

categories.yVariable included as a second-degree polynomial, wherefore estimates are

not reported.

718 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 187 2013

with very severe COPD and adjusting for markers of diseaseseverity, concomitant medication, and the presence of underlyingindicatory diseases. These approaches have been found to be aseffective as propensity score methods in terms of reducing con-founding by indication, but the absence of residual bias needs to beconfirmed by further observational studies and, ultimately, by ran-domized trials (34).

The mechanism betweenACEI/ARB and statins, respectively,and reduced mortality could be their well-documented effects oncardiovascular mortality (35, 36). Our trend of reduced mortalityindependent of documented cardiovascular disease may beexplained either by an effect on undiagnosed disease, becausecardiac disease is difficult to identify in severe COPD (37), orby an effect on the excess risk of cardiovascular morbidity and mor-tality that seems to be a systemic consequence of COPD (38). ACEI/ARBs and statins may also have direct effects on the respiratory

system. Animal models recently found effects of ARB on em-physema, exercise capacity, and lung function (39), and effectsof simvastatin on smoke-induced pulmonary artery remodelingand emphysema (40). Treatment with an ARB was also shownto decrease the lung hyperinflation in patients with COPD ina placebo-controlled randomized trial (41).

A link between antiplatelet drugs and improved survivalcould be the systemic antithrombotic effect, because COPD isassociated with increased platelet activation (42).

The association between oral glucocorticoids and increasedmortality is in linewith previous reports andmight reflect a causalrelation or an association between taking oral steroids and moresevere underlying disease and exacerbations (43–45).

Data are limited on adverse effect of b-blockers in severeCOPD. A recent Cochrane review found that b-blockers hadno negative effects on respiratory symptoms or FEV1 (46). How-ever, this conclusion was based on a small number of relativelyold studies with short follow-up, and these studies generally ex-cluded patients with heart failure and other significant comorbid-ities (46, 47). In contrast, cardioselective b-blockers worsened theairway obstruction in patients with COPD in a randomized double-blind crossover trial (47, 48).

To further explore possible mechanisms behind the increasedmortality, we studied the b-blocker effects in different patientsubgroups. The adverse effect on survival was generally consistentacross groups but tended to be lower for patients using LABA 1ICS. This could indicate that long-acting bronchodilation counter-acts some of the adverse respiratory effects of b-blockers (47), butsubanalyses, including analyses of interaction, have low power andshould be interpreted with caution. It cannot be precluded thatb-blockers have adverse effects on lung function, airway respon-siveness, or other parameters that could increase mortality in frailpatients with very severe COPD.

In conclusion, the possible detrimental effect of b-blockers inpatients with severe COPD is a novel and important finding thatneeds to be further validated. In addition, this study supportsthat antiplatelet drugs, and possibly ACEI/ARB and statins,have beneficial effects on survival in oxygen-dependent COPD.

Author disclosures are available with the text of this article at www.atsjournals.org.

Acknowledgment: The authors thank all physicians and nurses who included andcared for the patients.

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