Rationale: There is limited knowledge regarding sex differences and outcomes in patients with chronic obstructive pulmonary disease (COPD).
Objectives: Determine sex differences in survival, causes of death, and patient-centered outcomes in the 3-year Toward a Revolution in COPD Health (TORCH) study.
Methods: A total of 1,481 women and 4,631 men with COPD were enrolled in TORCH, a trial comparing salmeterol, 50 μg, plus fluticasone propionate, 500 μg, twice a day and each component individually. Causes of death were determined by an endpoint committee. Sex differences in survival were explored using a Cox proportional hazards model adjusted for other baseline factors. Exacerbation rate was compared using a negative binomial model. Dyspnea was evaluated using the Medical Research Council scale and health status using the St. George's Respiratory Questionnaire.
Measurements and Main Results: At baseline, women were younger (63 vs. 66 yr), had higher FEV1 (47% vs. 44% predicted), and worse St. George's Respiratory Questionnaire (51.3 vs. 48.7) and Medical Research Council score. During the study, 707 (15.3%) men and 168 (11.3%) women died. After adjusting for differences in baseline factors, the risk of dying was 16% higher in men than in women; however, this was not statistically significant (hazard ratio 1.16 [95% CI, 0.98–1.39]). Causes of death were similar in women and men. Exacerbation rate was 25% higher in women than in men.
Conclusions: Women enrolled in TORCH had a lower mortality rate than men but similar causes of death. The risk of dying was similar in women and men after adjusting for important baseline variables. Women reported more exacerbations, and worse dyspnea and health status scores than men.
Although the incidence of chronic obstructive pulmonary disease in women is increasing, there is limited knowledge regarding the relationship between sex and mortality in this disease.
The Toward a Revolution in COPD Health study was designed to evaluate risk of death and its causes using an adjudication committee in over 6,000 patients of both sexes followed over 3 years. This study showed that women were 16% less likely to die over the period of the study than men. However, correcting for important covariates, such as degree of airflow obstruction, body mass index, region of the world, and previous myocardial infarction, this difference was not statistically significant. The causes of death were similar in men and women.
The existence of sex differences in the expression of COPD is supported by several studies. Compared with men, women seem more susceptible to the toxic effects of tobacco (3–7). Even correcting for degree of airflow obstruction, women report more anxiety and depression (5–8), worse symptoms (8–10), lower exercise capacity (10, 11), more airway hyperresponsiveness (12), and worse health-related quality of life (13) than men. Data from pathologic studies show that women with severe emphysema have smaller airway lumen, thicker airway walls, smaller parenchymal airspace size, and less peripheral involvement (11, 14).
Much less is known about any sex differences in mortality and the factors that may affect it in patients with COPD. The few studies available included mostly men and patients with advanced disease and hypoxemic respiratory insufficiency (15–18). Three of the studies (15–17) reported a lower mortality rate in women compared with men, whereas in one, women had a higher fatality rate than men (18). In the only cohort with similar numbers of men and women with a wide range of COPD disease severity and where adjustments had been made for disease severity, body mass index (BMI), and comorbidity, De Torres and coworkers (19) reported a lower mortality rate in women than in men. However, this study only included 537 patients and causes of death were not well characterized.
The Toward a Revolution in COPD Health (TORCH) study was designed to determine the risk of dying after 3 years of therapy with salmeterol and fluticasone propionate combination therapy, each of the components alone, and placebo (20). In the original report, the effect of treatment on the mortality rate did not depend on sex (20). Therefore, the TORCH dataset offers a unique opportunity to explore the cause and actual risk of dying according to sex in a well-characterized COPD patient population. In addition, the use of an endpoint committee that reviewed all deaths and adjudicated the cause of death provides information that can be explored to identify any sex differences.
We hypothesized that at similar stages of COPD severity (defined spirometrically) women would have worse health status and a different risk of dying than men. Preliminary results of this analysis have been presented in the form of an abstract (21).
Details of the TORCH study have been published elsewhere (20) (Clinicaltrials.gov number, NCT00268216; GSK Study Code SCO30003). In brief, patients with a history of COPD, current or former smokers (at least 10 pack-years), aged 40–80 years, an FEV1/FVC ratio less than or equal to 70%, a prebronchodilator FEV1 less than 60% of the predicted value, and reversibility of FEV1 to 400 μg salbutamol of less than 10% of the predicted value were recruited. Main exclusion criteria included a diagnosis of asthma or respiratory disorder other than COPD, lung-volume reduction surgery or lung transplantation, long-term oxygen therapy (LTOT), significant comorbidity, or an exacerbation during the run-in period. All patients gave written informed consent and the study was approved by local ethical review boards.
TORCH was a multicenter, randomized, double-blind, parallel-group, placebo-controlled study performed in 42 countries (20). After a 2-week run-in period, patients were randomized to receive either salmeterol and fluticasone propionate combination therapy 50/500 μg, salmeterol 50 μg, fluticasone 500 μg, or placebo twice daily for 3 years via a Diskus/Accuhaler inhaler (GlaxoSmithKline, UK). All corticosteroids and inhaled long-acting bronchodilators were stopped before the run-in period but other COPD medications were allowed.
The primary efficacy endpoint of TORCH was all-cause mortality at 3 years. The patients' vital status was followed until 3 years after treatment began, regardless of whether they remained on study medication. The primary study endpoint was time to death from any cause by 3 years after treatment began. An independent Clinical Endpoint Committee (CEC) determined the primary cause of death and whether it was COPD-related using standard methodologies (22). The data used included information from investigators, patient records, and other data as available, and the CEC was masked to treatment allocation.
Secondary endpoints were frequency of exacerbations, defined as a symptomatic deterioration that required treatment with antibiotics or systemic corticosteroids, or hospitalization, dyspnea evaluated with the Medical Research Council (MRC) five-point dyspnea scale and health status assessed using the St. George's Respiratory Questionnaire (SGRQ) (23). The SGRQ was used in the 28 countries where a validated translation existed; it consists of a 100-point scale with lower numbers indicating better health status. Lung function was assessed by post-bronchodilator spirometry (24) and the detail of this analysis has been published (25). For patients who withdrew from the study prematurely, all available data up to the time of withdrawal were included for exacerbation, health status, and lung function analyses.
The differences between the baseline characteristics of men and women were compared using Pearson chi-squared test for categorical variables and t tests for continuous variables. The difference between the MRC dyspnea scores was tested using a proportional odds model. The time to death from any cause and the time to exacerbation between men and women were presented as Kaplan-Meier plots, with standard error bars. A Cox proportional hazards model was performed using time to death as the outcome variable, and baseline factors of sex; smoking status; age; BMI; treatment allocation; percent predicted FEV1; previous inhaled corticosteroid (i.e., whether the patient had taken an inhaled corticosteroid in the year before the study); previous long-acting β2-agonist; previous COPD exacerbations; previous myocardial infarctions; and region of the world.
The causes of death for each sex were divided into COPD-related, cancer, cardiovascular, other, and unknown. Details of this analysis for the whole population have been previously published (22). The current study extended the analysis to evaluate possible differences in the causes of death between men and women. The difference in exacerbation rate was analyzed using a negative binomial model adjusted for baseline factors.
The baseline characteristics of patients divided by sex are shown in Table 1. More men than women were recruited at all sites, but this differed by region with a larger proportion of women recruited in the United States compared with the rest of the world. A total of 1,481 women and 4,631 men with COPD were included in the study. The women were significantly (P < 0.001) younger (mean age, 63 vs. 66 for men); more likely to be current smokers (49% vs. 41%); and had a higher baseline FEV1 (47% vs. 44% predicted). More women than men were underweight (17% had BMI <20 vs. 12% of men; P < 0.001). Compared with men, at baseline women had worse MRC dyspnea scores (20% with 4 or 5 vs. 18%; P < 0.001) (Figure 1), even though the mean percent predicted FEV1 was higher in the women. Women scored worse in all domains of the SGRQ. Interestingly, the difference occurred primarily in patients with moderate COPD and not in those with severe or very severe disease in whom there were no differences between sexes (Figure 2).
Male (n = 4,631)
Female (n = 1,481)
Total (n = 6,112)
|Age, yr||65.6 ± 8.1||63.4 ± 8.5||65 ± 8.3|
|BMI – kg/m2, n (%)|
|<20||571 (12)||253 (17)||824 (13)|
|20 to <25||1,762 (38)||539 (36)||2,301 (38)|
|25 to <29||1,294 (28)||348 (23)||1,642 (27)|
|≥29||1,004 (22)||341 (23)||1,345 (22)|
|United States||832 (18)||556 (38)||1,388 (23)|
|Eastern Europe||973 (21)||181 (12)||1,154 (19)|
|Western Europe||1,489 (32)||419 (28)||1,908 (31)|
|Asia Pacific||686 (15)||72 (5)||758 (12)|
|Other||651 (14)||253 (17)||904 (15)|
|Current smoker, n (%)||1,898 (41)||732 (49)||2,630 (43)|
|Pack-years||50.9 ± 28.4||41.3 ± 22.7||48.5 ± 27.4|
|Requiring antibiotics or oral corticosteroids or hospitalization||1.2 ± 1.6||1.3 ± 1.6||1.2 ± 1.6|
|At least one exacerbation in the year before the study||2,615 (56)||871 (59)||3,486 (57)|
|Baseline post-bronchodilator FEV1, ml||1,296 ± 451||1,006 ± 335||1,226 ± 443|
|% predicted post-bronchodilator FEV1||43.6 ± 13.4||46.7 ± 13.3||44.3 ± 13.4|
|<30%||782 (17)||155 (10)||937 (15)|
|30% to <50%||2,301 (50)||718 (48)||3,019 (49)|
|≥50%||1,548 (33)||608 (41)||2,156 (35)|
|SGRQ score||(n = 3,427)||(n = 1,158)||(n = 4,585)|
|Total||48.7 ± 17.2||51.3 ± 16.6||49.3 ± 17.1|
|MRC Dyspnea score‖||(n = 4,627)||(n = 1,480)||(n = 6,107)|
|1||378 (8)||78 (5)||456 (7)|
|2||1,994 (43)||596 (40)||2,590 (42)|
|3||1,433 (31)||508 (34)||1,941 (32)|
|4||662 (14)||227 (15)||889 (15)|
| 5||160 (3)||71 (5)||231 (4)|
Vital status was known at 3 years for 6,111 of the 6,112 patients in the efficacy population. During the 3 years of the study 707 (15.3%) of the 4,631 men died compared with 168 (11.3%) of the 1,481 women. All-cause mortality was lower in women compared with men (Figure 3). The same was true for respiratory mortality. However, when adjusted by baseline factors, there was no significant difference between the rates of death for men and women (adjusted hazard ratio [HR] for men vs. women was 1.16; 95% confidence interval [CI], 0.98–1.39; P = 0.093).
The causes of death by sex were similar in men and women (Table 2). Of the 168 deaths in the women 56 (33%) were caused by pulmonary causes, compared with 250 (35%) of the 707 in the men, whereas 40 (24%) were caused by cardiovascular causes in the women, compared with 197 (28%) in men.
Cause of Death
Male (n = 4,631)
Female (n = 1,481)
|All deaths, n||707||168|
|Respiratory, n (% deaths)||250 (35)||56 (33)|
|Chronic obstructive pulmonary disease||188 (27)||46 (27)|
|Pneumonia||54 (8)||10 (6)|
|Pulmonary embolism||2 (0.3)||0|
|Cardiovascular, n (% deaths)||197 (28)||40 (24)|
|Congestive heart failure||18 (3)||5 (3)|
|Myocardial infarction||21 (3)||7 (4)|
|Stroke||27 (4)||6 (4)|
|Sudden death||121 (17)||18 (11)|
|Other||10 (1)||4 (2)|
|Cancer, n (% deaths)||150 (21)||34 (20)|
|Lung||94 (13)||26 (15)|
|Other||46 (7)||6 (4)|
|Other, n (% deaths)||67 (9)||19 (11)|
|Unknown, n (% deaths)||43 (6)||19 (11)|
The time to first exacerbation (Figure 4) was shorter and the rate of exacerbations was 25% (P < 0.001; 95% CI, 16–34%) higher in women than in men but the number of hospital admissions caused by exacerbations was similar in both sexes. The change in SGRQ during the study in women was the same as that of men.
This study extends the findings described in the original TORCH report and provides insight into the influence of sex on clinical outcomes in COPD. In TORCH, women had lower all-cause mortality than men over the 3 years of the study. However, after adjusting for important baseline variables including FEV1, BMI, region of the world, and myocardial infarction, the difference was no longer statistically significant. Importantly, the cause of death was similar between men and women in this cohort. However, at a similar severity of airflow obstruction, women did score worse on baseline health status questionnaires and MRC dyspnea scale. Consistent with this heightened perception of dyspnea, women had a shorter time to first exacerbation and experienced a higher number of exacerbations than men.
In population-based studies, women live longer than men (26). There is limited information on possible sex-related differences in survival in patients with COPD (15–19). The first three studies (15–17) were conducted in a selected population of patients on LTOT and the analyses were not adjusted for other prognostic factors important for mortality in COPD, such as exercise capacity, tobacco exposure, and FEV1. In all three of these studies, mortality was higher in men than in women. In contrast, the study by Machado and colleagues (18), although also conducted in a cohort of 435 patients with severe COPD receiving LTOT, indicated that the risk of death was higher in women than in men. In that study adjustments were made for age, smoking history, partial pressure of oxygen in arterial blood, FEV1, and BMI. More recently, De Torres and coworkers (19) analyzed mortality in a cohort of 265 women and 273 men from the BODE cohort, with a wide range of spirometrically defined COPD severity followed over 3 years. The authors observed a decreased mortality risk in women compared with men. In TORCH, a higher survival rate in women was also observed, as shown in Figure 2. However, when adjustments were made for variables known to influence outcomes, such as FEV1, BMI, exacerbations, region of the world, and prior myocardial infarction, the risk of death, although slightly lower for women, was not statistically significant from that of men. It is difficult to explain the reasons for the difference between the two studies. Although both included patients with a wide range of airflow obstruction, TORCH was 10 times larger than the study by De Torres and coworkers (19), and selected patients for a pharmacologic trial (with relatively lower number of comorbidities and more likely to be compliant). The study by De Torres and coworkers (19) recruited patients from the BODE cohort (27) attending pulmonary clinics and likely to have more comorbidities. If the number of comorbidities was influenced by the sex, with men having a larger number of comorbidities (28–31), mortality would be higher in men than in women at similar degree of airflow obstruction, thus helping to explain the lower mortality rate in women in that study.
A very interesting finding in TORCH was that the causes of death as determined by the CEC were similar in women and men. Based on the objective analysis, the most frequent cause of death was respiratory in nature, with cardiovascular and cancer causes following in importance. These similarities in cause of death suggest a similar expression of disease in both sexes and should help clinicians guide the efforts and direction to monitor patients. The large proportion of patients ultimately dying from cancer is very striking, and probably caused by the common risk factor of cigarette smoking in both sexes, and the presence of airflow obstruction, which is an independent risk factor for development of lung cancer (32).
Despite the similarities in mortality and its causes, the clinical expression of the disease differed in men and women, as has been suggested by others (7–12). Health status and dyspnea scores were worse in women than in men with similar degrees of airflow obstruction as defined by the GOLD/ATS/ERS criteria. Interestingly, the differences were not seen across all categories of airflow obstruction severity. Indeed, the SGRQ and MRC scores were similar for both sexes in the severe and very severe patients (GOLD III and IV), but the scores were worse in women compared with men in the milder patients (Stage II or moderate COPD) as seen in Figure 1 for the SGRQ. The difference of 6 units exceeds the accepted minimal clinically important difference. An explanation for this observation is not entirely clear but it is consistent with the observation by De Torres and coworkers (13), who also showed that women with milder COPD had significantly worse SGRQ scores than men and that this sex difference was not observed in patients with more severe disease. The decline of SGRQ was the same in both sexes over the duration of the study.
In line with the concept that women relate differently to the clinical expression of COPD is the observation that their time to first exacerbation was significantly shorter (Figure 3) and that women experienced more exacerbations than men. However, there were no differences in the number of hospitalizations and in the respiratory causes of death between sexes, a finding that is again consistent with that reported by De Torres and coworkers (19) in patients attending pulmonary clinics. We have already reported that in the TORCH cohort there was no difference in the rate of decline of FEV1 between women and men and the beneficial effect of pharmacotherapy on the rate of decline of lung function was similar in both sexes (25). A similar finding was reported by Vestbo and coworkers (33) who showed no difference in sex response to pharmacotherapy in the TRISTAN trial. This suggests that the actual physiologic impact of exacerbations is similar in women and men but that there are differences in the way women perceive changes in dyspnea, the dominant symptom driving exacerbations.
The sex difference in the perception of dyspnea is not well explored but may be independent from the disease itself. Indeed, Lopez Varela and coworkers (34) observed that over 50% of females from the PLATINO population survey reported dyspnea scores greater than or equal to 2 compared with 35% of males in the same survey. The same difference was also noted in female and male patients with COPD in the same study. The reasons for the differences may therefore be physiologic. A recent study comparing men and women with COPD at similar degree of airflow obstruction noted that the central drive, as measured by the mouth occlusion pressure, was the most important determinant of dyspnea in the women and not in men (35).
There were some limitations to this study and analysis. First, the patients were recruited after standard criteria for drug studies and therefore may not represent the COPD population at large. However, this study was well conducted with patients with COPD who were very well characterized. In addition, because of the diversity of our cohort, the patients included represent most patients with COPD worldwide. Second, we did not evaluate two important variables: the comorbidities of depression and anxiety, which are known to differ between sexes (36). Depression would, if anything, be more likely to impact mortality in women than in men, a finding that is not in agreement with our observation.
In summary, this study shows that all-cause mortality was lower in women than in men enrolled in the TORCH study. After adjusting for important baseline variables the difference is not statistically significant. In addition, causes of death were similar in both sexes. However, there were significant differences in the clinical expression of COPD between men and women, with women scoring lower on health status questionnaires, manifesting worse dyspnea scores, and experiencing more exacerbations than men.
The TORCH Study (SCO30003; NCT00268216) was funded by GlaxoSmithKline. All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. The authors thank Helen McDowell (GlaxoSmithKline) for providing editorial suggestions to draft versions of this paper, and helping to collate author comments and copyedit this manuscript. Editorial support in the form of assembling tables and figures, graphical services, and manuscript formatting was provided by David Cutler and Mark Wade at Gardiner-Caldwell Communications and was funded by GSK.
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