Abstract
Rationale: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. The prevalence of COPD is rising among women and is approaching that of men, but it is not known if sex affects survival.
Objectives: To measure the survival differences between men and women with oxygen-dependent COPD.
Methods: We conducted a 7-yr prospective cohort study of 435 outpatients with COPD (184 women, 251 men) referred for long-term oxygen therapy (LTOT) at two respiratory clinics in Sao Paulo, Brazil. Baseline data were collected on enrollment into oxygen therapy, when patients were clinically stable.
Measurements: We examined the effect of sex on survival using Kaplan-Meier survival curves, and then used Cox proportional hazards models to control for potential confounders.
Main Results: In unadjusted analyses, we observed a nonsignificant trend toward increased mortality for women (hazard ratio, 1.28; 95% confidence interval, 0.98–1.68; p = 0.07). After accounting for potential confounders (age, pack-years smoked, PaO2, FEV1, body mass index), females were at a significantly higher risk of death (hazard ratio, 1.54; 95% confidence interval, 1.15–2.07; p = 0.004). Other independent predictors of death were lower PaO2 (p < 0.001) and lower body mass index (p < 0.05).
Conclusions: Among patients with COPD on LTOT, women were more likely to die than men.
Chronic obstructive pulmonary disease (COPD) is one of the most important causes of morbidity and mortality worldwide, being the fourth leading cause of death in the United States and the fifth in Brazil (1–3). Mortality is especially high in patients with severe disease. Although COPD has been historically more common in men, there are data to suggest that women may be at increased risk of developing COPD (4). Other studies suggest that women may have more severe COPD and greater COPD-associated mortality (5–8).
In light of this hypothesized increased susceptibility for women, the recent data suggesting that the sex gap in COPD prevalence is decreasing is of particular concern (5–8). We report results of a 7-yr follow-up of outpatients with COPD referred for long-term oxygen therapy (LTOT). We hypothesized that, in patients with oxygen-dependent COPD, women have a higher mortality rate than men. Some of the results of this study have been previously reported in the form of an abstract (9).
We conducted a prospective cohort study of 435 outpatients with COPD (184 women, 251 men) enrolled in the LTOT program at two respiratory clinics affiliated with two hospitals in Sao Paulo, Brazil, between January 1996 and January 2003. Criteria recommended by the Global Initiative for Chronic Obstructive Lung Diseases (GOLD) (1) and the Brazilian Thoracic Society (BTS) (2) were used to define COPD. Patients were eligible for this study if they had a post-bronchodilator ratio of FEV1 to FVC less than 0.70 and were enrolled in the LTOT program for a minimum of 6 mo. Current smokers (based on patient self-report and physician judgment) were not eligible for the LTOT offered in the respiratory clinics, and hence are not included in the study cohort. In addition, patients with a diagnosis of lung cancer before initiating LTOT were excluded from this study.
Participants were managed according to the GOLD/BTS recommendations, including LTOT therapy. Due to their disease severity, none of the study participants was enrolled in a pulmonary rehabilitation program. Baseline data were collected when patients were clinically stable (i.e., no exacerbation in the past 30 d). All study participants were followed until January 2003 or death. The average observation time was 27 mo (range, 6–80 mo). No patients were lost to follow-up. The study was reviewed and approved by the institutional review boards of both hospitals.
On enrollment, the following data were collected: sex, age, lung function, PaO2 and PaCO2 in mm Hg measured on room air by the pH and blood gas analyzer (instrument used: ABL330; Radiometer, Copenhagen, Denmark), body mass index (BMI) in kg/m2, the number of pack-years of cigarette smoking, the number of hospitalizations due to respiratory causes in the previous 12 mo, and the Charlson comorbidity index (10). Post-bronchodilator spirometry was performed according to American Thoracic Society criteria (11) and used to measure FEV1 and FVC, and their ratio. American Thoracic Society recommendations were followed to calculate the post-bronchodilator percent of predicted FEV1 (FEV1, % predicted). The Charlson comorbidity index was calculated using information on comorbid conditions, as assessed by a review of clinical records (hospital data and clinic charts); as it includes COPD, the minimum index score for everyone was 1.
We used Student's t test and the Pearson χ2 statistic to compare differences in baseline characteristics between men and women. In these analyses, BMI (< 18.5, 18.5–24.9, 25–29.9, ⩾ 30 kg/m2), the number of hospitalizations (0, 1, 2, ⩾ 3), and the number of comorbid conditions weighted by the Charlson comorbidity index (1, 2, ⩾ 3) were analyzed as ordinal, categorical variables to facilitate interpretation. Kaplan-Meier survival curves were compared using the log rank test. We developed a multivariable Cox proportional hazards model to compare survival between men and women after adjusting for potential confounders. Those variables significant at the p level less than 0.20 in univariate analyses were included in the multivariate model. We also evaluated the possibility of interactions between sex and other independent predictors of mortality in the multivariable model. All p values are two-sided. The term significant refers to a p value less than 0.05. Computations were performed using STATA, version 8.2 (Stata Corporation, College Station, TX [12]).
At the baseline visit, the study cohort ranged in age from 35 to 85 yr (mean = 66.6 yr), the average FEV1 was 31.4% predicted, and the average PaO2 was 51.7 mm Hg (Table 1). Women were significantly younger and had less lifetime exposure to cigarette smoking than men, despite having similar levels of FEV1, PaO2, and PaCO2. Over 75% of both men and women reported one or more hospitalizations in the 12 mo before enrollment.
Characteristics | Total (n = 435) | Male (n = 251) | Female (n = 184) | p Value |
|---|---|---|---|---|
| Age, yr | 66.6 ± 7.6 | 69.3 ± 7.2 | 62.9 ± 6.5 | < 0.0001 |
| Pack-years smoked | 69.6 ± 30.1 | 72.5 ± 30.1 | 65.7 ± 29.8 | < 0.01 |
| PaO2, mm Hg | 51.7 ± 5.5 | 51.7 ± 5.3 | 51.8 ± 5.8 | 0.90 |
| PaCO2, mm Hg | 47.0 ± 5.7 | 47.0 ± 5.9 | 46.9 ± 5.4 | 0.80 |
| FEV1% predicted | 31.4 ± 8.0 | 31.4 ± 8.4 | 31.4 ± 7.5 | 0.96 |
| BMI, kg/m2 | ||||
| < 18.5 | 36 (8.3) | 19 (7.6) | 17 (9.2) | |
| 18.5–24.9 | 222 (51.0) | 135 (53.8) | 87 (47.3) | 0.36 |
| 25–29.9 | 125 (28.7) | 65 (25.9) | 60 (32.6) | |
| ⩾ 30.0 | 52 (12.0) | 32 (12.8) | 20 (10.9) | |
| No. of hospitalizations | ||||
| 0 | 73 (16.8) | 41 (16.3) | 32 (17.4) | |
| 1 | 130 (29.9) | 72 (28.7) | 58 (31.5) | 0.87 |
| 2 | 129 (29.7) | 76 (30.3) | 53 (28.8) | |
| ⩾3 | 103 (23.7) | 62 (24.7) | 41 (22.3) | |
| Charlson comorbidity index | ||||
| 1 | 139 (32.0%) | 87 (34.7) | 52 (28.3) | |
| 2 | 183 (42.1%) | 94 (37.4) | 89 (48.4) | 0.07 |
| ⩾ 3 | 113 (26.0%) | 70 (27.9) | 43 (23.4) |
Over two-thirds of participants (68.1%) had at least one clinically significant comorbid condition other than COPD (i.e., Charlson comorbidity index ⩾ 2). Men had a higher Charlson comorbidity index than women, although differences were not significant.
Results of the Kaplan-Meier analysis showed a nonsignificant trend toward increased mortality among women compared with men (Figure 1). By 48 mo, there were relatively few patients in the cohort, so the survival curve estimates begin to grow unstable past this point. In the univariate Cox proportional hazards models (Table 2), a lower PaO2, lower FEV1, greater number of pack-years smoked, and lower BMI were all significantly associated with higher mortality. In the multivariable (i.e., adjusted) analysis, women had a significantly higher risk of death compared with men (hazard ratio, 1.54; 95% confidence interval, 1.15–2.07) after adjusting for age, pack-years smoked, PaO2, FEV1, and BMI. In this model, lower PaO2 and lower BMI were also significant independent predictors of mortality (Table 2). None of the baseline patient characteristics significantly modified the association between sex and survival in the multivariable model (tests for interaction with age [p = 0.28], pack-years smoked [p = 0.25], PaO2 [p = 0.74], FEV1 [p = 0.22], BMI categories [p = 0.64], and Charlson comorbidity index [p = 0.29]).
Figure 1. Differences in survival, men versus women (p = 0.07 [log-rank]). The number of males and females in the follow-up period at Months 0 (baseline), 24, 48, and 72 are shown below graph. Kaplan-Meier survival curves for males and females after initiating long-term oxygen therapy (LTOT).
[More] [Minimize]Univariate | Multivariate† | |||||
|---|---|---|---|---|---|---|
| Characteristics | HR (95% CI) | p Value | HR (95% CI) | p Value | ||
| Female (vs. male) | 1.28 (0.98–1.68) | 0.07 | 1.54 (1.15–2.07) | 0.004 | ||
| Age, per 10 yr | 1.13 (0.94–1.37) | 0.19 | 1.17 (0.95–1.45) | 0.14 | ||
| Smoking, per 10 pack-years | 1.06 (1.02–1.10) | 0.005 | 1.04 (0.99–1.08) | 0.09 | ||
| PaO2, per 10 mm Hg | 0.51 (0.41–0.64) | < 0.001 | 0.57 (0.45–0.72) | < 0.001 | ||
| PaCO2, per 10 mm Hg | 1.03 (0.81–1.30) | 0.81 | — | — | ||
| FEV1, per 10% predicted | 0.82 (0.69–0.97) | 0.02 | 0.91 (0.75–1.09) | 0.33 | ||
| BMI, kg/m2 | ||||||
| < 18.5 | 3.06 (1.63–5.73) | < 0.001 | 2.22 (1.15–4.28) | 0.01 | ||
| 18.5–24.9 | 2.34 (1.36–3.99) | 0.002 | 1.75 (1.01–3.06) | 0.04 | ||
| 25.0–29.9 | 1.39 (0.78–2.49) | 0.26 | 1.23 (0.68–2.23) | 0.49 | ||
| ⩾ 30.0 | 1.00 (—) | — | ||||
| No. of hospitalizations | ||||||
| 0 | 1.00 (—) | — | ||||
| 1 | 1.04 (0.68–1.59) | 0.86 | ||||
| 2 | 1.21 (0.80–1.83) | 0.37 | ||||
| ⩾ 3 or more | 1.22 (0.79–1.88) | 0.36 | ||||
| Charlson comorbidity index* | ||||||
| 1 | 1.00 (—) | — | ||||
| 2 | 1.09 (0.79–1.50) | 0.61 | ||||
| ⩾ 3 | 1.60 (0.70–1.44) | 0.99 | ||||
In this 7-yr prospective cohort study of patients with COPD referred for LTOT, women were younger and reported fewer pack-years of cigarette smoking then men, yet had similar impairment in lung function and oxygenation. We found that women had a 54% increase in the risk of death after initiating LTOT compared with men.
We know that the life expectancy is poor in patients with advanced COPD, particularly when FEV1 is less than 1 L, PaO2 is less than 55 mm Hg, and hypercapnia or pulmonary hypertension is present (13–18). The only therapeutic regimen that has been shown to improve the life expectancy in these patients is oxygen therapy. Two well-known studies, Medical Research Council (MRC) (19) and Nocturnal Oxygen Therapy Trial (NOTT) (20), found that oxygen therapy improved survival in patients with COPD who were markedly hypoxemic.
Although the differences in survival between men and women in our unadjusted analysis failed to reach statistical significance (p = 0.07), after adjusting for potentially confounding factors (age, severity of lung disease, FEV1, PaO2, lifetime history of pack-years smoked, and BMI), women on LTOT were more likely to die than men. Interestingly, we found that men and women exhibited similar survival rates during the initial follow-up period; differences in survival became more apparent only after approximately 3 yr of follow-up. The clinical management for COPD was similar for both groups, and was based on GOLD/BTS guidelines. We do not know why survival differences occurred largely during the second half of the follow-up period; further research is needed to confirm our findings and identify potential explanations.
Our findings that women with COPD on LTOT fare worse than men are consistent with the results of some previous studies (26, 27), but not with those of others (19–25, 28–31). We speculate that differences in patient populations and analytic approaches may help explain the discrepancy between our results and those of previous studies. For example, we used GOLD/BTS criteria to define COPD (including the requirement for airflow obstruction based on spirometry) and to identify patients with indications for LTOT. By contrast, the definition of COPD was based on clinical criteria alone in one study (21), two other studies did not require evidence of airflow obstruction (22, 23), and a fourth study (25) included patients with respiratory conditions other than COPD (e.g., tuberculosis, pulmonary fibrosis) who were eligible for LTOT. We excluded current smokers and patients with preexisting lung cancer; it is unclear if these patients were systematically excluded in previous studies as well. The MRC clinical trial (19) excluded patients who were older than 70 yr, presented with another respiratory disorder, or had systemic hypertension and/or coronary arterial disease. The NOTT (20) study excluded patients if they were considered to be “too sick,” lived far from the hospital, or (as in the study by Cooper and colleagues [24]) were considered high risk for nonadherence to LTOT. Finally, in contrast to previous analyses, we accounted for several potential confounders, including pack-years of cigarettes smoked and BMI.
Studies have documented the prognostic value of low body weight in patients with COPD and in the general population (32–34). Celli and coworkers (35) studied a multidimensional grading system, BODE (B = body mass index, O = airway obstruction, D = dyspnea, E = exercise capacity) that can predict risk of death in patients with COPD. The BODE index, based on four variables that can mark the degree of disease severity, is better than FEV1 alone at predicting the risk of death from any cause and from a respiratory cause among patients with COPD. Gray-Donald and coworkers (36) studied the role of BMI in the prognosis of patients with severe COPD in a cohort of Canadian patients, including those with hypoxemia, recruited for a clinical trial of negative-pressure ventilation. In the total cohort, lower BMI and use of home oxygen were independently associated with reduced survival. These reports are in agreement with our results, which found that the worse hypoxemia and lower BMI (< 24.9 kg/m2) were independently associated with higher mortality. Schools and coworkers (37) showed that, despite a BMI greater than 25 kg/m2 being an independent predictor of mortality in COPD, the negative effect of low body weight can be reversed by appropriate therapy in some patients with COPD. We recommend additional cohort studies using standardized approaches to diagnose and manage patients with oxygen-dependent COPD to confirm our findings.
Results of previous studies suggest than women who smoke have a greater decrease in FEV1 compared with men who smoke, suggesting a possible increased susceptibility to development of COPD in women (38, 39). There may also be an increased propensity for women to develop bronchial hyperresponsiveness compared with men (40–43), although data from the U.S. Lung Health Study (43) would suggest that the increased bronchial hyperresponsiveness in women smokers, compared with men who smoke, may be largely due to smaller airways. These observations are consistent with findings in the current study, where women had similar levels of impaired lung function (measured by FEV1, PaO2, and PaCO2) despite fewer pack-years of cigarette smoking.
COPD affects many organ systems in addition to the lungs (44, 45). For example, individuals who smoke and develop COPD further increase their risk of cardiovascular disease (46). The concurrence of COPD with cardiovascular disease represents more than the simultaneous presence of relatively common conditions (47). Individuals with reduced FEV1 are at increased risk for atherosclerosis. Zureik and coworkers (48) studied 194 healthy men free of coronary heart disease to determine the relationship between FEV1 and pulse wave velocity, a surrogate measurement for central arterial stiffness, endothelial dysfunction, and atherosclerosis. They showed that reduced FEV1 was associated with increased pulse wave velocity, suggesting that airways disease was an independent risk factor for central arterial stiffness. Several groups have reported on the relationship between FEV1 and cardiovascular mortality (49–51). All of these studies showed that reduced FEV1 among female and male adults, independent of established risk factors, such as cigarette smoking or hypertension, is an important risk factor for cardiovascular mortality and a reasonable marker for COPD in population-based studies.
There is substantial evidence linking oxidative stress (52–57) and airway inflammation (58–62) with COPD disease progression and severity (63–65). For example, hydrogen peroxide, 8-isoprostane, and lipid peroxides are elevated in the breath or serum of individuals with COPD (64). Similarly, an increased number of neutrophils, macrophages, and natural killer lymphocytes in the airway wall are associated with more symptomatic COPD and lower FEV1 (66). There is now considerable evidence of both local and systemic oxidative stress in patients with COPD. However, we found no studies comparing oxidative stress and airway inflammation in women and men with COPD and evaluating whether such differences help to explain the increased susceptibility and severity of COPD among women. We speculate that the sex differences in mortality found in our study will be better understood after further studies of systemic inflammation and oxidative stress in patients with severe COPD, with attention to possible sex differences.
This study has limitations that should be considered when interpreting our findings. Whereas our analyses accounted for a number of clinical factors on enrollment, we did not collect data on adherence to LTOT during the follow-up period. Also, although current smokers were ineligible for enrolling in our LTOT program, we did not collect objective data on smoking status (e.g., serum cotinine) on initiating LTOT therapy or during the follow-up period. It is therefore possible that confounding due to these factors (e.g., sex differences in adherence to LTOT or smoking status after initiating LTOT) may have contributed to our results. Another limitation is that our study had a limited number of participants with follow-up times greater than 48 mo (n = 67 patients—15% of the initial study cohort). If the follow-up is censored at 48 mo, then the adjusted hazard ratio for death in women compared with men is 1.35 (95% CI, 1.00–1.83; p = 0.050). These observations suggest that larger studies, in which additional patients are followed for more than 4 yr, are needed to obtain more precise comparisons of the risk of death between men and women with COPD treated with LTOT.
Our results suggest that, when properly adjusted for potential confounding factors, women with severe COPD using LTOT have a greater risk of death than do men. It is not clear why this is the case; we recommend additional studies that address the role of inflammation, bronchial hyperresponsiveness, oxidative stress, and other variables that may influence women's lower survival rate.
The lead author acknowledges the contribution of the American Thoracic Society's Methods in Epidemiologic, Clinical, and Operations Research course in the development of this article.
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