Anemia, costs and mortality in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a major cause of both morbidity and mortality. In the United States, more than 10 million adults suffer from COPD and it is the fourth most common cause of death [1]. Because of the continued high rate of smoking coupled with the aging of the population, analysts predict that COPD will account for an increased proportion of deaths in the near future [2]. With respect to morbidity, COPD impairs both functional status and quality of life [1]. Economically, the costs of COPD associated with medical care and lost productivity are staggering, exceeding $37 billion annually in the United States [3].

Anemia is commonly present among individuals with chronic illnesses. In a broad range of medical conditions, concomitant anemia is increasingly being recognized as a risk factor associated with increased mortality [4, 5]. There is also growing evidence of increased health care utilization and costs associated with anemia in disease states such as chronic kidney disease, HIV, rheumatoid arthritis, inflammatory bowel disease, congestive heart failure, and cancer [6‐8]. However, less is known regarding the impact of anemia on mortality, morbidity, and costs of care for patients with COPD. Cote and colleagues observed that anemia was associated not only with increased mortality but also with worsened dyspnea scores and functional capacity as measured by the 6-minute walking distance in a COPD cohort [9, 10]. The effect of anemia was independent of age, forced expiratory volume in one second, and functional status. Similarly, a review of a French national database indicated that subjects with severe oxygen-dependent COPD and anemia experienced an increased risk of hospitalization and short-term mortality compared to those without anemia [11].

Despite the growing awareness of an association between worse clinical and functional outcomes and anemia in COPD patients, the financial implications of anemia in COPD have not been examined previously. To determine what incremental costs, if any, were associated with anemia in COPD patients, and to confirm the association of anemia with clinical and functional outcomes in a larger population, data from Medicare beneficiaries in the United States were analyzed.

The cohort included 132,424 patients with COPD. Approximately 21% (n = 27,932) were identified as having concomitant anemia that was not associated with nutritional or hereditary anemias, acute blood loss, end-stage renal disease, or malignancy. As shown in Table 1, anemic patients tended to be older and were more likely to be female. In the quarter prior to the index date, anemic patients were 1.71 times (95% CI: 1.63–1.79) more likely to have needed mechanical ventilation than non-anemic patients. With respect to comorbid conditions (Table 1), neurologic, respiratory, and musculoskeletal diagnoses were more frequent in those without anemia. Skin and GI conditions were similar between the two groups, and all other conditions occurred more often in the anemic population.

Specific rates of health care utilization during the six months prior to the index date (i.e., prior to identification of these patients having anemia) were greater for patients with co-morbid anemia (Table 2). During the six-month baseline period, anemic persons had significantly more claims for hospitalizations, ICU care, and episodes of acute exacerbations of COPD (AECB) and pneumonia. For example, being classified with co-morbid anemia was associated with a greater need for ICU care (15.5 claims per 100 patients with anemia during the baseline period vs. 7.3 claims per 100 patients without anemia, p < 0.001). These differences indicate greater baseline severity of illness among patients with COPD and anemia.

Table 3 presents the unadjusted total claims (charges) and reimbursements (payments) after the index date (in 2004 dollars). Average annual payments from Medicare were substantially higher among those with anemia. Medicare spent $1,466 per patient per year among COPD patients with anemia vs. $649 per patient per year in non-anemic COPD patients (p < 0.001). Resource utilization rates among patients with anemia (Table 4.), as well as payments for COPD patients with anemia were higher in every resource utilization category (Figure 2). Rates of mechanical ventilation, ICU care, emergency department visits, and other resource use were also higher among COPD patients diagnosed with anemia (Table 4).

Costs for Medicare enrollees in both groups, with and without anemia, rose after the index date. The increase in claims was 78.1% for COPD patients with anemia and 50.9% for patients without anemia (p < 0.001); the increase in payments was 71.5% for patients with anemia and 48.5% among patients without anemia (p < 0.001). Using linear regression to control for baseline differences in severity of illness (e.g., number of co-morbid illnesses, need for ventilation support, and episodes of pneumonia and acute exacerbations of chronic bronchitis in the six months prior to the index date) and preceding health care use (e.g., frequency of hospital admissions and emergency room care for COPD) the incremental independent annual per patient charges and reimbursements associated with anemia among COPD patients were calculated to be $8,811 (p < 0.001, 95% CI: $8,136 to $9,487) for charges and $3,582 (p < 0.001, 95% CI: $3,299 to $3,865) for payments. The independent contribution of anemia to costs in COPD was present in all categories of resource utilization (Figure 3). Of note, anemia care (defined as medical claims with an anemia diagnosis) did not appear to account directly for these incremental differences in cost. Less than 1% of the over 890,000 claims for the co-morbid anemia population filed in the 12 months after the index date had a diagnosis code specific for anemia.

Persons with anemia complicating their COPD had a nearly two-fold increase in death rates (262 per 1,000 person-years of follow-up) compared to the non-anemic individuals (133 deaths per 1,000 person-years of follow-up, p < 0.001). The association of anemia and mortality was stronger among younger Medicare patients; among those 65–69 years of age, anemia was associated with an odds ratio for death of 2.07 (95% CI: 1.94 to 2.22). In contrast, among the 80–84 year old cohort the odds ratio for mortality in those with anemia and COPD was 1.42 (95% CI: 1.36 to 1.49).

This analysis of the Medicare population indicates that anemia is frequent in COPD, occurring in 21% of the current study patients. More importantly, the presence of anemia is associated with substantial economic burden and increased resource utilization among these beneficiaries. Although persons with COPD and anemia are more severely ill than their non-anemic counterparts, the association of anemia and costs is independent of multiple important potential confounders. Moreover, the majority of incremental costs among anemic COPD patients is not coded as direct care for anemia. In addition, co-morbid anemia is associated with increased mortality for COPD patients.

Prior research into anemia in COPD is limited. John and colleagues examined a population of 101 COPD patients and estimated the prevalence of anemia at 13% [12]. They noted that neither age nor spirometric measures differed between anemic and non-anemic persons. Those with lower hemoglobins, however, had more extensive systemic inflammation as measured by both IL-6 and C-reactive protein levels [12]. The variability in the prevalence of anemia between theirs and the current study likely reflects differences in definitions. John et al. relied on actual hemoglobin measurements while the current administrative data are limited to ICD-9 codes. Additionally, the mean age in their analysis was approximately 61 years; the present study's cohort was older since it derived from a Medicare sample, and the prevalence of anemia is known to increase with increasing age [13]. Somewhat contrary to the findings by John, a recent study by Chambellan and coworkers in a cohort of COPD patients with severe oxygen-dependent COPD demonstrated that anemia (defined by laboratory values according to the WHO criteria [14]), present in 8.2–12.6%, was in fact correlated with age and disease severity in this population, and, consistent with the current findings, hematocrit was an independent predictor of survival, hospital admission rate and duration of hospitalization [11]. Cote and co-workers, focusing on a population from a US Veterans Affairs pulmonary clinic, estimated the prevalence of anemia at 30% [9]. As in the John et al. study, these investigators had patient level hemoglobin data available. Similar to the present findings, Cote et al. reported that anemic COPD patients had more co-morbid illnesses [9, 10]. They also concluded that the presence of anemia independently correlated with mortality [9, 10].

While it is likely that CKD, advanced age or certain medication exposure may play a role in the development of anemia in this population, at least one study points to the possible role of inflammation and resistance to elevated levels of erythropoietin [12]. Etiology notwithstanding, our study suggests anemia is highly prevalent in the COPD population and associated with worse clinical and economic outcomes.

The present study builds on prior data and suggests that anemia is common in COPD. As it was necessary in the present study to use ICD-9 codes rather than hemoglobin values, these findings likely underestimate the frequency of anemia. Examining a very large sample, however, adds to the robustness of the conclusions. Furthermore, this study was able to control for many confounders that the earlier reports could not assess. Specifically, the current analysis accounted for prior health care utilization and factors associated with COPD severity, such as the frequency of episodes of AECB and pneumonia. This study is also unique in that it measures the economic impact of anemia in COPD and describes the increased utilization of various healthcare resources among patients with anemia. Finally, this study was also able to corroborate previous work indicating that COPD patients with anemia are at higher risk for death.

The association between anemia and increased risk of mortality seen here among COPD patients parallels previous reports of links between anemia and decreased survival in other disease states. For example, in subjects with left ventricular dysfunction, anemia independently adversely affects survival [15, 16]. Similarly, in chronic kidney disease, anemia not only affects quality of life but also worsens survival [17]. This study's finding of relatively high costs of medical care for individuals with COPD (even those who do not have anemia) is not surprising, given that both increased age and decreased health status are associate with increased costs in several different components of healthcare [18]. Specifically, in COPD, direct healthcare costs in the United States were estimated to exceed $18 billion in 2002 and COPD led to nearly 750,000 hospital admissions [19]. These hospitalizations, along with treatment of AECB, are major drivers of costs. Results of this study, indicating that inpatient care was the single largest category of Medicare claims for this population, support findings from previous studies.

This study has several important limitations. First, as a retrospective study, it is exposed to various forms of bias. Second, since the data source was administrative claims data, findings may have been affected by coding bias; that is, only those COPD patients and the subset with anemia who had Medicare claims with appropriate ICD-9 diagnosis codes could be identified, though the presence of such codes could not guarantee the appropriateness of these diagnoses. The large sample size, however, balances these concerns, and for some endpoints, such as mortality and hospitalizations, the results are in accordance with other studies. Further, prior large chart audits indicate that ICD-9 codes for COPD are actually both specific and sensitive for this condition [20]. Third, as mentioned earlier, anemia was defined based on ICD-9 coding. As a majority of US pulmonologists participating in a recent survey did not classify anemia as being present among COPD patients using a threshold hemoglobin value of 12 g/dL, it is unlikely that this study overestimated the true prevalence of anemia in this population and may well have underestimated it [21]. If clinicians do not believe anemia is present, they are unlikely to use an anemia diagnosis code for the provided services. Additionally, there is no reason to believe, a priori, that bias in recording anemia would lead to the more "expensive" patients consistently being labeled as anemic. Finally, no specific measures of disease severity were available. Hence surrogate markers of severity of illness, which correlate with outcomes and have been validated in previous health services research in COPD, were utilized. Moreover, other than the recently proposed BODE index, no global, validated severity score in COPD exists [22]. Despite these best efforts at adjusting for identifiable confounders, residual confounding cannot be excluded as a potential source of the independent relationship between anemia and worsened outcomes shown in this study.

In conclusion, anemia is a comorbidity commonly associated with COPD. Although the nature of this retrospective observational study precludes any inference of causality, it is clear that anemia in this patient population is associated with increased healthcare costs and resource utilization, as well as worsened survival. Future research is warranted to define more accurately the epidemiology and the etiology of anemia in COPD, to evaluate the impact of anemia on quality of life among persons with COPD, and to explore options for and effects of treating anemia in COPD.

Codes used to identify study population

Exclude ESRD (Medicare Status Code = 10 aged w/o ESRD or ICD9 996.68, 996.73, V45.1, V56), malignancies (ICD9 140–239), HIV (ICD9 042, 079.53), GI bleeding (ICD9 456.0, 456.20, 530.21, 530.7)