- Email: [email protected]
Corticosteroids and Chronic Obstructive Pulmonary Disease in the Nursing Home
CONTROVERSIES IN LONG-TERM CARE
Corticosteroids and Chronic Obstructive Pulmonary Disease in the Nursing Home Allegra Rich, MD WHEN SHOULD STEROIDS BE USED IN THE MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN THE NURSING HOME? Problem The use of corticosteroids, particularly inhaled preparations, in the management of chronic obstructive pulmonary disease (COPD) is controversial. There are currently no inhaled corticosteroids approved by the U.S. Food and Drug Administration for use in COPD management. However, many elderly patients with COPD are treated with long-term inhaled and oral steroids. In many cases, steroids are empirically used in patients with COPD without clear indication. These patients could be needlessly exposed to the side effects of long-term steroid use without benefit. When, therefore, should steroids be used in the management of COPD in the nursing home? I outline the evidence supporting steroid use in COPD and when it is clearly beneficial. Significance of the Problem Chronic obstructive pulmonary disease is the fourth leading cause of death in the United States after coronary artery disease, cancer, and stroke.1 COPD currently affects more than 16 million Americans.2 Each year, it accounts for 500,000 hospitalizations and $18 billion in direct healthcare costs.3,4 Symptoms of COPD usually start in the fifth to sixth decade of life. As the population ages, the prevalence of COPD is expected to rise, making it an even more important disease process for nursing home clinicians to understand.5 Definition Chronic obstructive pulmonary disease is defined as airflow limitation that is not completely reversible. This incomplete reversibility is what distinguishes COPD from asthma. COPD University of California, Los Angeles, Los Angeles, CA. Address correspondence to Allegra Rich, MD, Geriatric Medicine Fellow, University of California, Los Angeles, 11926 Goshen Ave. #8, Los Angeles, CA 90049. E-mail: [email protected]
Copyright ©2004 American Medical Directors Association DOI: 10.1097/01.JAM.0000102958.15719.97 CONTROVERSIES IN LONG-TERM CARE
is also characterized by an inflammatory response of the lungs to noxious stimuli. COPD should be suspected in patients with chronic cough, sputum production, or shortness of breath who have had significant exposure to tobacco smoke, occupational dusts, chemicals, or intense indoor home heating or cooking fuels.1 In the case of tobacco smoking, an exposure in excess of 20 pack-years is considered a significant risk factor for developing COPD. Suspected COPD should be confirmed with spirometry. Patients with COPD have a postbronchodilator forced expiratory volume in 1 second (FEV1) ⬍80% of predicted normal and an FEV1/forced vital capacity (FVC) ⬍70% of predicted normal.6 Despite this definition, a patient’s level of disability correlates poorly with their FEV1.7 Also, patients with airflow limitation could have partial but incomplete reversibility with bronchodilators, not clearly meeting the definition of COPD or asthma. The course of COPD is marked by progressive deterioration in lung function punctuated by periods of acute worsening of respiratory symptoms most often attributed to respiratory infection.6 The pathology of COPD is believed to be active inflammation within the lung as a result of inhalation of noxious particles and gases. Activated inflammatory cells such as macrophages, T-lymphocytes, and neutrophils are increased in the airways, lung parenchyma, and vasculature. To distinguish the inflammation of COPD from that of asthma, CD8 lymphocytes predominate in COPD, whereas CD4 lymphocytes predominate in asthma. These inflammatory cells and their mediators cause further inflammatory cell recruitment and lung destruction in both diseases.6 Standard Treatment of Chronic Obstructive Pulmonary Disease Smoking cessation is the only known treatment to slow the progressive decline in lung function associated with COPD. All other treatments for the chronic management of COPD are aimed at symptom control and maintenance of functional status. Such treatment routinely includes inhaled anticholinergics, inhaled B-agonists, methylxanthines, oxygen, and sometimes inhaled corticosteroids. During periods of acute decompensation, these therapies are augmented with systemic corticosteroids, antibiotics, and intensification of inhaled bronchodilator and oxygen use. Rich 31
DISCUSSION The Controversy of Inhaled Corticosteroids and Chronic Obstructive Pulmonary Disease The use of inhaled steroids in chronic COPD management is an area of considerable controversy. The widespread use of inhaled steroids in COPD stems from their substantial benefit in the treatment of asthma.8 Based on this data, inhaled steroids were often incorporated into COPD management before there was evidence of a parallel disease-modifying effect in COPD. Specifically, inhaled steroids are used to target chronic lung inflammation in patients with COPD. Despite the similarities between asthma and COPD, the body of evidence does not suggest that inhaled steroids have the same effect in COPD that they do in asthma. Several randomized, controlled trials have investigated the benefits of using inhaled corticosteroids in the management of COPD. The results of trials investigating this intervention are discussed here. These studies are presented in order of increasing severity of COPD in the study populations. The EUROSCOP Study The EUROSCOP study was a double-blind, placebo-controlled trial in which 1277 current smokers (mean age, 52 years) with mild COPD (mean FEV1 ⫽ 77% predicted) were randomized to treatment with inhaled 400 g budesonide twice daily or placebo.9 During the first 6 months of the study, subjects in the budesonide group showed a small increase in FEV1.9 This was similar to findings in others trials of inhaled steroids in COPD.10,11 After the first 9 months of the study, the rate of decline in FEV1 in these patients with mild disease was not significantly different between the placebo and the budesonide groups, 69 mL per year versus 57 mL per year. However, budesonide seemed to have a more beneficial effect on FEV1 in patients who had smoked less than 36 pack-years. Patients were followed up for 3 years.9 The Copenhagen Study The Copenhagen Study was a double-blind, placebo-controlled trial involving the randomization of 290 patients (mean age, 59 years) with mild to moderate COPD (mean postbronchodilator FEV1 ⫽ 86% predicted) to placebo or 1200 g inhaled budesonide total daily for 6 months followed by 800 g total daily thereafter.12 After 3 years follow up of the patients with mild COPD, there was no significant difference in the rate of FEV1 decline between placebo and budesonide groups, 41.8 mL per year versus 45.1 mL per year. There were no differences in the number of exacerbations of symptoms between the groups.12 The Lung Health Study The Lung Health Study was a double-blind, placebo-controlled trial that randomized 1116 people (aged 40 – 69 years; mean age, 56 years) with moderate COPD (mean FEV1 ⫽ 64% predicted) to treatment with 600 g inhaled triamcinolone acetonide twice daily or placebo.13 After 3 years, there was no significant difference in the rate 32 Rich
of decline in lung function in the placebo and triamcinolone groups, 44.2 mL per year versus 47.0 mL per year. However, the members of the triamcinolone group had fewer respiratory symptoms when assessed by the American Thoracic Society– NHLBI Division of Lung Diseases questionnaire and fewer physician visits for respiratory illness. Methacholine challenge showed lower airway reactivity in the triamcinolone group.13 A substudy of 412 patients also assessed the impact of inhaled corticosteroids use on bone density, which is discussed further subsequently.13 The ISOLDE Trial The ISOLDE trial was a double-blind, placebo-controlled trial that randomized 751 men and women (aged 40 –75 years; mean age, 64 years) with relatively severe COPD (mean FEV1 ⬍50% of predicted) to 500 g fluticasone propionate twice daily by metered dose inhaler or identical placebo.10 At 3 years follow up, the difference in rate of decline in FEV1 between the fluticasone and placebo groups was not significant, 59 mL per year versus 50 mL per year. However, fluticasone-treated patients initially saw a small rise in FEV1 and this gain was sustained throughout the study.10 The end points of health status deterioration, COPD exacerbations, and patient withdrawal for acceptance of respiratory drugs all showed statistically significant improved outcome with fluticasone versus placebo.10 The median exacerbation rate was reduced by 25% from 1.32 to 0.99 exacerbations per year. Health status measured by the St. George’s Respiratory Questionnaire showed a decline of 3.2 units per year in the placebo group versus 2.0 units per year in the fluticasone group.10 A change in score of 4 or more is significant for a change in a patient’s condition.14 Discontinuations from the trial as a result of respiratory disease, not related to malignancy, was 25% in the placebo group versus 19% in the fluticasone group.10 This study also investigated the ability to predict long-term response to inhaled corticosteroids by response to a trial of oral corticosteroids. At randomization, all patients were given 0.6 mg/kg oral prednisolone per day for 14 days and spirometry was repeated. Response of FEV1 to oral prednisolone did not reliably predict response to inhaled fluticasone over the course of the study.10 The TRISTAN Study The TRISTAN Study was a double-blind, placebo-controlled study that randomized 1465 patients (mean age, 63 years) with severe COPD (mean FEV1 ⫽ 45% predicted) to 50 g salmeterol twice daily, 500 g fluticasone twice daily, placebo, or both. Patients were followed up for 12 months.15 In this study, all active treatment groups showed an improvement in FEV1 and fewer COPD exacerbations compared with placebo. At 52-weeks follow up, FEV1 increased by 10% in the combination group, by 2% in both monotherapy groups, and decreased by 3% in the placebo group. Exacerbations fell by 25% for combination therapy, 19% for fluticasone, and 20% for salmeterol compared with placebo. This effect was most evident in those with the worst COPD, FEV1 JAMDA – January/February 2004
⬍50% predicted, who had a 30% reduction in exacerbations.15 The combination group was the only group showing significant improvement in health status questionnaire scores. The combination group also had significantly more days in which no rescue medication was needed.15 Inhaled Corticosteroids and the Risk of Mortality and Readmission in the Elderly With Chronic Obstructive Pulmonary Disease A population-based cohort study (n ⫽ 22,620) compared the combined risk of all-cause mortality and hospital readmission for elderly patients (mean age, 75 years) admitted to the hospital with a COPD exacerbation. Patients who received inhaled steroids within 90 days of hospital discharge had 24% fewer repeat hospitalizations for COPD and 29% less mortality at 1 year of follow up after adjusting for sex, severity of COPD, and comorbid illness.16 This observational study is unique in that it shows a mortality benefit from using inhaled steroids in COPD. It also likely included many patients excluded from other COPD studies as a result of age, disease severity, and reversibility by spirometry. Unfortunately, as an observational study, it could be biased. Oral Steroids in Chronic Obstructive Pulmonary Disease The value of chronic oral steroids in the management of stable COPD has been debated in the past and has largely fallen out of favor in clinical practice. The GOLD Workshop recommends against the routine use of oral steroids as a result of lack of evidence for a disease-modifying effect and the burden of side effects associated with their use.6 Of particular concern is respiratory muscle myopathy and associated decline in lung function.6,17 Despite the GOLD recommendation, many patients with COPD are on long-term steroids that are not being actively weaned. This problem has been addressed in clinical trials. Withdrawal of Chronic Systemic Steroids in Patients With Chronic Obstructive Pulmonary Disease Rice and colleagues conducted a small double-blind, placebo-controlled trial of patients (average age, 70 years) with “steroid-dependent” COPD (mean FEV1 ⫽ 0.94L). Thirtyeight patients were assigned to their usual maintenance dose of oral prednisone or were to be withdrawn from prednisone at 5 mg per week and followed for 6 months. Discontinuation of steroid treatment did not result in an increase in exacerbations, but did reduce patients’ total steroid use and body weight.18 Effects of Long-Term Treatment With Inhaled Versus Oral Corticosteroids in Chronic Obstructive Pulmonary Disease Renkema and colleagues performed a double-blind, placebo-controlled study that randomized 58 nonallergic patients (mean age, 56 years) with COPD (mean FEV1 ⫽ 63% preCONTROVERSIES IN LONG-TERM CARE
dicted) to placebo, 1600 g inhaled budesonide per day, or 1600 g inhaled budesonide per day plus 5 mg oral prednisolone per day. These patients were followed up for 2 years.19 There was no significant difference in FEV1 decline, duration or frequency of COPD exacerbations, or COPD symptoms between the inhaled steroid group and the combined group. Patients in the placebo group were more likely to withdraw from the trial as a result of respiratory complications.19 ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Systemic Steroids in Acute Exacerbations of Chronic Obstructive Pulmonary Disease Systemic steroids are commonly prescribed for acute exacerbations of COPD. There is solid randomized, controlled trial evidence for this indication for steroid use. The Veterans Affairs Cooperative Study The Veterans Affairs Cooperative Study Group performed a double-blind, placebo-controlled study in which 271 veterans (average age, 68 years; median FEV1 ⫽ 0.73 L) admitted for COPD exacerbation were randomized to placebo or systemic steroids for 2 or 8 weeks in addition to usual care. Steroids were given as 125 mg methylprednisolone intravenously every 6 hours for 72 hours followed by 60 mg oral prednisone per day initially and tapered over 2 or 8 weeks, depending on the study group. Patients were followed up for 6 months.20 Use of systemic steroids, for either 2 or 8 weeks, was associated with shorter initial hospital stays (8.5 vs. 9.7 days) and a reduction in treatment failures by approximately 10% at 30 and 90 days follow up. FEV1 was approximately 0.1 L higher on hospital day 1 for the steroid groups compared with placebo. By 6 months follow up, there were no differences between the placebo and steroid-treated groups. The outcomes with the 2-week and 8-week regimens were not significantly different.20 Oral Steroids for Inpatients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease Davies and colleagues investigated the use of oral steroids in acute exacerbations of COPD requiring hospital admission in a double-blind, placebo-controlled trial. Fifty-six patients (mean age, 67 years) admitted for nonacidotic COPD exacerbations (mean FEV1 ⫽ 0.59 L) were randomized to 30 mg prednisolone per day for 14 days or placebo, in addition to usual care with bronchodilators, antibiotics, and oxygen. Patients were followed up for 6 weeks.21 FEV1 increased more rapidly and to a larger degree in the prednisolone group. FEV1 after bronchodilators increased from 25.7% to 32.2% predicted in the placebo group and from 28.2% to 41.5% predicted in the prednisolone group by hospital discharge. Hospital stay was shorter in the prednisolone group, 7 days versus 9 days for placebo. There were no signifRich 33
icant differences in changes in symptoms between the groups and no significant differences in FEV1 at 6 weeks follow up.21 Oral Steroids for Outpatients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease Despite the common use of oral steroids in the outpatient management of COPD exacerbations, few studies have investigated this regimen. Thompson and colleagues randomized 27 outpatients (mean age, 68 years; mean FEV1 ⫽ 1.30 L) with acute COPD exacerbation in a double-blind, placebo-controlled trial of 60 mg, 40 mg, and 20 mg prednisone each for 3 days or placebo. The prednisone groups showed faster improvement in FEV1 and fewer treatment failures as well as a trend toward improvement in dyspnea scale scores.22 Aaron and colleagues performed a double-blind, placebocontrolled trial in which 147 patients seen in the emergency room for COPD exacerbation were randomized to 40 mg oral prednisone per day for 10 days or placebo. Participants also received oral antibiotics and bronchodilators.23 At 30 days follow up, the overall rate of relapse was lower in the prednisone group than in the placebo, 27% versus 43%. Prednisone-treated patients had greater improvement in FEV1 and dyspnea scores on the 10th day of follow up but no difference in health-related quality of life.23 Inhaled Steroids in Acute Exacerbations of Chronic Obstructive Pulmonary Disease Nebulized steroids are rarely used for the treatment of acute COPD; however, there is some evidence to support their use. A double-blind, placebo-controlled trial randomized 199 patients (mean age, 70 years; mean FEV1 approximately 0.8 L) requiring inpatient treatment for nonacidotic COPD exacerbation to nebulized budesonide, oral prednisolone, or placebo. Budesonide was given as 2 mg nebulized every 6 hours for 72 hours followed by 2 mg per day for 10 days. Oral prednisolone was given as 30 mg every 12 hours for 72 hours followed by 40 mg per day for 7 days.24 Both steroid groups showed improvement in postbronchodilator FEV1 at 72 hours over placebo, 0.1 L for budesonide versus placebo and 0.16 L for prednisolone versus placebo. This difference in FEV1 improvement between budesonide and prednisolone was not significant. However, in the prednisolone group, there was a tendency toward more patients showing larger increases in FEV1 and decreases in PCO2. There was no difference in length of hospital stay between the groups.24 SIDE EFFECTS OF CORTICOSTEROIDS Systemic Corticosteroids The long-term side effects of systemic corticosteroids are well established. These include adrenal suppression, diabetes mellitus, osteoporosis, cataracts, secondary infections, skin changes, mood changes, fat redistribution, hypertension, myopathy, and avascular necrosis. Of the many complications of systemic corticosteroids, osteoporosis is of particular interest to practitioners caring for 34 Rich
the frail elderly. The concern for steroid-induced osteoporosis in patients with COPD is grave given the additional risk factors of smoking, immobility, lower body mass index, and hypogonadism associated with chronic disease.25 Vertebral fractures are important for their consequences of pain, reduced physical function, and ventilatory compromise. Hip fractures are even more significant given their association with loss of ambulation and increased mortality. Patients with COPD could have an advantage over patients with other steroid-treated chronic diseases in that patients with COPD are usually older and require only intermittent bursts of steroid treatment.26 Although studies have looked at markers of bone turnover and bone mineral density, few have evaluated fracture prevalence in patients with COPD using corticosteroids. Corticosteroid Use and Vertebral Fractures in Older Men With Chronic Obstructive Pulmonary Disease In this cross-sectional study, 312 men with COPD (mean age, 69 years) were evaluated to investigate the relationship between steroid use and vertebral fracture. Subjects were divided into never-used steroids, inhaled steroid users, and systemic steroid users. Systemic steroid users included intermittent and continuous users.27 The prevalence of vertebral fractures was 48.7% in the never-used steroids group, 57.1% in the inhaled steroids group, and 63.3% in the systemic steroids group (average dose, 18 mg daily). The odds ratio for vertebral fractures in systemic versus nonsteroid users was 1.8 adjusted for age. The odds ratio for continuous systemic versus nonsteroid users was 2.56. Systemic steroid users also tended to have more multiple or severe vertebral fractures.27 Inhaled Corticosteroids Although the side effects of systemic steroids are well recognized, the side effects of inhaled corticosteroids are less clearly defined and still under investigation. Several randomized, controlled trials of inhaled corticosteroids have used known steroid side effects as secondary end points. These include skin changes, incidence of diabetes, fractures, bone density, and adrenal suppression. Population-based studies have looked at the association between inhaled steroid use and effects beyond the lung. The data available about the systemic effects of inhaled steroids are discussed here. Osteoporosis Hubbard and colleagues performed a population-based, case-control study of 16,341 cases of hip fracture from a primary care database (mean age, 79 years; 79% female) and 29,889 age and sex-matched control subjects. The odds ratio for hip fracture with exposure to inhaled steroids was 1.26. This was reduced to 1.19 after controlling for exposure to intermittent oral steroids. There was a positive dose-response relationship between inhaled steroid use and hip fracture.28 Van Staa and colleagues performed a similar retrospective cohort study and obtained relative risks of 1.15, 1.22, and 1.51 for nonvertebral, hip, and vertebral fractures, respectively, JAMDA – January/February 2004
compared with control subjects. However, there was no difference in the relative risk of fracture between the inhaled steroid group and the bronchodilator control group. This raised the possibility of underlying disease rather than inhaled steroid use as a cause for the increased fracture risk associated with inhaled steroid treatment.29 The substudy of the Lung Health Study to evaluate bone density revealed a significantly lower bone density in the lumbar spine and in the femur for the triamcinolone group. However, this difference was not seen until 3 years of follow up.13 There were no fracture rates reported. In the EUROSCOP trial, bone density of a subset of patients was assessed, and there was no significant difference between groups except for a small but significant positive effect in favor of budesonide at the femoral trochanter. There was no increase in new vertebral fractures with budesonide.9 Adrenal Suppression Most randomized, controlled trials of inhaled steroids in COPD have evaluated adrenal suppression in terms of morning cortisol levels and clinical symptoms. The TRISTAN Study found that serum cortisol concentrations fell by 1% and 3% for fluticasone and combination therapy, respectively, compared with a rise of 4% and 6% in the placebo and salmeterol groups, respectively, after 52 weeks of treatment. These changes were not associated with any clinical signs or symptoms.15 The ISOLDE trial also showed a small but significant reduction in morning cortisol levels with inhaled corticosteroid treatment. Morning cortisol levels were below the normal range at any time during the study in less than 5% of the subjects with no clinical signs or symptoms of adrenal insufficiency over the 36 months of the study.10 Skin and Oral Effects Oral candidiasis was increased in the ISOLDE, EUROSCOP, and TRISTAN trials with inhaled steroid use.9,10,15 Skin bruising was more prevalent in the inhaled steroid groups of the ISOLDE and EUROSCOP trials.9,10 Diabetes, Cataracts, and Myopathy The Lung Health Study was the only randomized, controlled trial of inhaled steroids in COPD that followed the incidence of diabetes, cataracts, and myopathy during the 3-year follow up.13 There was no significant increase in the incidence of these diagnoses in the inhaled steroid-treated group.13 Applicability of Results of Clinical Trials to Frail Elderly Nursing Home Patients Nursing Home Residents versus Study Participants The application of results of clinical trials to patient care in the frail elderly is frequently complicated by the exclusion of this patient population from clinical trials. The inclusion criteria of age limits, ability to follow up reliably, ability to give consent, and lack of severe chronic medical illness exclude most nursing home residents from participation. Physicians practicing in this arena are largely left to make judgCONTROVERSIES IN LONG-TERM CARE
ments about the suitability of a treatment based on their knowledge of an individual and the medical evidence. Inclusion criteria to participate in clinical trials of COPD frequently limit the allowed degree of reversibility in FEV1 with bronchodilators. This limit is usually set at less that 15% of predicted FEV1. In clinical practice, some nursing home patients with a diagnosis of COPD could have more reversibility of FEV1. With regard to age and frailty, most patients with clinically significant COPD, and thus study participants, are at least in the sixth decade of life. Many studies included patients in whom the mean FEV1 was less than 50% predicted.10,15,20 The inclusion of these older participants with more severe disease represents a relatively frail population to be included in clinical trials and lends credibility to extending the study conclusions to nursing home patients. The use of inhaled steroids in the nursing home population is often limited by a patient’s ability to use the delivery device. Nursing staff can help patients use a metered dose inhaler and spacer system to deliver medication correctly. However, many frail elderly have arthritis, residual deficits from strokes, dementia, and vision and hearing impairments that interfere with the correct use of metered dose inhaler medication. Poor technique can result in a large deposition of the medication in the patient’s mouth and increased risk of oral candidiasis. Currently, bronchodilators are often given by a nebulizer in the nursing home setting for ease of administration. Nebulized steroids are not widely available for use to overcome the incompatibility between nursing home patients and the metered dose delivery system. Nursing home patients have difficulty traveling to outside appointments as a result of mobility restrictions. The same physical and mental impairments that limit metered dose inhaler use can also affect the collection of accurate spirometric measurements. If accurate spirometry cannot be obtained, a clinical assessment of the patient’s COPD could suffice. However, the clinician must realize that the presence or absence of symptoms often does not correlate with the severity of the patient’s COPD. Significance of the Side Effects of Steroids in the Frail Elderly Frailty predisposes individuals to the negative side effects of medications. Thus, any treatment used in frail people should be implemented with the knowledge that such patients are highly likely to develop whatever complications were identified in a more robust study population. Many frail elderly already suffer from conditions that are known side effects of steroid use. These include diabetes, osteoporosis, hypertension, cataracts, mood disorders, muscle weakness, and fragile skin. The prevalence of these conditions makes the practitioner hesitate before using steroid medications in the nursing home. Each frail elderly patient needs to be considered as an individual. Quality of life and life expectancy need to be taken into consideration. For patients near the end of their lives, problems of osteoporosis, glucose intolerance, fat redistribution, myopathy, and others might not be significant. A patient with severe airflow obstruction and limited life exRich 35
pectancy can forgo tight blood sugar control in exchange for the ability to breath more comfortably. However, for an ambulatory patient with osteoporosis and mild COPD, the side effects of steroid use might outweigh the benefits. Increased use of bronchodilators might be a better choice for disease management. CONCLUSION When to Use Steroids in the Management of Chronic Obstructive Pulmonary Disease in the Nursing Home Systemic Steroids and Chronic Obstructive Pulmonary Disease The use of systemic steroids in the management of COPD is indicated for the treatment of COPD exacerbations in the inpatient, nursing home, and outpatient settings. Under these circumstances, systemic steroids have been shown to improve pulmonary function faster and to reduce the incidence of treatment failure.6 COPD exacerbations involving severe shortness of breath and concern for respiratory failure should be managed in the inpatient environment with parenteral or oral steroids, depending on what the patient can tolerate. This should be followed by a tapered oral regimen for 10 to 14 days total treatment.6,20 Given the numerous side effects of systemic steroids, and the lack of disease-modifying effect, the goal of treatment for most patients should be to taper off all oral steroids as quickly as possible. Oral steroids should not be part of the long-term management of chronic stable COPD.6 However, there could be patients with COPD who are at the end of life for whom the urgency to taper is not as great. Inhaled Steroids and Chronic Obstructive Pulmonary Disease The role for inhaled steroids in the nursing home population is less clear. Several well-designed studies have shown that inhaled steroids do not alter the rate of progressive decline in lung function in COPD.9,10,12,13 Given the risks and the absence of disease-modifying benefits of inhaled steroids, their use should be restricted to those patients for whom there is proven benefit or good clinical evidence of significant improvement in COPD control. The Updated 2003 GOLD Guidelines for COPD Management recommend limiting the use of inhaled steroids to symptomatic patients with COPD with FEV1 ⬍50% and frequent exacerbations after bronchodilation has been maximized.30 In these patients with severe COPD, the evidence suggests that inhaled steroids could reduce the number of COPD exacerbations and could improve dyspnea and quality of life. The U.S. Food and Drug Administration is currently considering the approval of highdose inhaled steroids for use in COPD, but only for those with severe disease and frequent exacerbations despite maximal bronchodilation. For patients with a mixed presentation of COPD and asthma, with significant reversibility, inhaled steroids could be of substantial benefit, although this has not been systematically studied. 36 Rich
The down side of inhaled steroid use appears to be systemic side effects similar to oral steroids, although to a much lesser degree. The increased risks of osteoporosis and adrenal suppression, as well as skin changes with candidiasis and bruising, limit the acceptance of inhaled steroids. The ISOLDE trial showed that a positive response in FEV1 to a trial of oral steroids did not predict improvement with inhaled steroids.10 Instead, patients should be given a 6-week to 3-month trial of inhaled corticosteroid therapy followed by repeated postbronchodilator spirometric testing to assess response. A 200-mL or 12% improvement in FEV1 compared with baseline is considered a positive response to inhaled steroids.30 In nursing home patients, it might not be feasible to assess spirometric response to inhaled steroids as a result of limited access to the necessary resources. In this instance, a trial of therapy with inhaled steroids and observation for clinical improvement or stabilization could suffice as justification for continued therapy. Without obvious benefit, inhaled steroids should be discontinued to limit adverse effects and to avoid unnecessary overtreatment in this frail population. Areas of Future Study There are still many uncertainties surrounding the use of steroids in the treatment of COPD. An area of particular interest to the nursing home practitioner is the clinical outcomes for patients with COPD treated with inhaled steroids, in which participants are not strictly limited in terms of FEV1 irreversibility and concomitant chronic disease. Also, the effects of prolonged inhaled steroid use need to be studied because patients could use these medications for decades if they are effective. It will be a major benefit to patients if long-term inhaled steroids prove to be a safer yet effective alternative to systemic steroids for the management of severe COPD symptoms. This will help to further strictly limit the use of systemic steroids in COPD management and the associated side effects. REFERENCES 1. National Heart, Lung, and Blood Institute. Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Diseases. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health; 1998. 2. McCrory D, Brown C, Gelfand S, et al. Management of acute exacerbations of COPD. Chest 2001;119:1190 –1209. 3. Statistical Abstract of the United States. Springfield, VA: US Department of Commerce, Bureau of Census; 1997. 4. Agency for Health Care Research and Policy. Healthcare Cost and Utilization Project: Nationwide Inpatient Sample for 1997. National Technical Information Service, 1997. 5. The National Lung Health Education Program. Strategies in preserving lung health prevention COPD and associated diseases. Chest 1998;113: 123S–163S. 6. Pauwels R, Buist S, Calverly P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001;163: 1257–1276. 7. MacNee W, Calverly P. Chronic obstructive pulmonary disease 7: Management of COPD. Thorax 2003;58:261–265. JAMDA – January/February 2004
8. National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma, NAEPP Expert Panel Report 2002. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health; 2002. 9. Pauwels R, Lofdahl C, Laitinen L, et al. Long term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;320:1948 –1953. 10. Burge P, Calverley P, Jones P, et al. Randomized, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: The ISOLDE trial. BMJ 2000;320:1297–1303. 11. Paggiaro P, Dahle R, Bakran I, et al. Multi-center randomized placebocontrolled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998;351:773–780. 12. Vestbo J, Sorensen T, Lange P, et al. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: A randomized controlled trial. Lancet 1999;353:1819 –1823. 13. The Lung Health Research Group. Effect of inhaler triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902–1909. 14. Jones P, Quirk F, Baveystock G. The St. George’s respiratory questionnaire. Respir Med 1991;85(suppl B):25–31. 15. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: A randomized controlled trial. Lancet 2003;361:449 – 456. 16. Sin D, Tu J. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Crit Care Med 2001;164:580 –584. 17. Decramer M, Lacquet L, Fagard R, et al. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994;150:11–16. 18. Rice K, Rubins J, Lebahn R, et al. Withdrawal of chronic systemic corticosteroids in patients with COPD. Am J Respir Crit Care Med 2000;162:174 –178. 19. Renkema T, Schouten J, Koeter GE, et al. Effects of long-term treatment with corticosteroids in COPD. Chest 1996;109:1156 –1162.
CONTROVERSIES IN LONG-TERM CARE
20. Niewoehner D, Erbland M, Deupree R, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999;340:1941–1947. 21. Davies L, Angus R, Calverley P. Oral corticosteroids for patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomized controlled trial. Lancet 1999;354:456 – 460. 22. Thompson W, Nielson C, Carvalho P, et al. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Crit Care Med 1996;154:407– 412. 23. Aaron S, Vandemheen K, Hebert P, et al. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003;348:2618 –2625. 24. Maltais F, Ostinelli J, Boureau J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;165:698 –703. 25. Biskobing D. COPD and osteoporosis. Chest 2002;121:609 – 620. 26. Singh J, Palda V, Stanbrook M, et al. Corticosteroid therapy for patients with acute exacerbations of chronic obstructive pulmonary disease. Arch Intern Med 2002;162:2527–2536. 27. McEvoy C, Ensrud K, Bender E, et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:704 – 709. 28. Hubbard R, Smith C, Smeeth L, et al. Inhaled corticosteroids and hip fracture. Am J Respir Crit Care Med 2002;166:1563–1566. 29. Van Staa T, Leufkens H, Cooper C. Use of inhaled corticosteroids and risk of fractures. Bone Miner Res 2001;16:581–588. 30. Global Initiative for Chronic Obstructive Pulmonary Disease. Global Strategy for Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. NHLBI/WHO Workshop Report. Bethesda, MD: National Heart Lung and Blood Institute, April 2001. Update of the Management Sections, GOLD web site (www.goldcopd.com) Updated July 1, 2003.
Rich 37
Corticosteroids and Chronic Obstructive Pulmonary Disease in the Nursing Home Allegra Rich, MD WHEN SHOULD STEROIDS BE USED IN THE MANAGEMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN THE NURSING HOME? Problem The use of corticosteroids, particularly inhaled preparations, in the management of chronic obstructive pulmonary disease (COPD) is controversial. There are currently no inhaled corticosteroids approved by the U.S. Food and Drug Administration for use in COPD management. However, many elderly patients with COPD are treated with long-term inhaled and oral steroids. In many cases, steroids are empirically used in patients with COPD without clear indication. These patients could be needlessly exposed to the side effects of long-term steroid use without benefit. When, therefore, should steroids be used in the management of COPD in the nursing home? I outline the evidence supporting steroid use in COPD and when it is clearly beneficial. Significance of the Problem Chronic obstructive pulmonary disease is the fourth leading cause of death in the United States after coronary artery disease, cancer, and stroke.1 COPD currently affects more than 16 million Americans.2 Each year, it accounts for 500,000 hospitalizations and $18 billion in direct healthcare costs.3,4 Symptoms of COPD usually start in the fifth to sixth decade of life. As the population ages, the prevalence of COPD is expected to rise, making it an even more important disease process for nursing home clinicians to understand.5 Definition Chronic obstructive pulmonary disease is defined as airflow limitation that is not completely reversible. This incomplete reversibility is what distinguishes COPD from asthma. COPD University of California, Los Angeles, Los Angeles, CA. Address correspondence to Allegra Rich, MD, Geriatric Medicine Fellow, University of California, Los Angeles, 11926 Goshen Ave. #8, Los Angeles, CA 90049. E-mail: [email protected]
Copyright ©2004 American Medical Directors Association DOI: 10.1097/01.JAM.0000102958.15719.97 CONTROVERSIES IN LONG-TERM CARE
is also characterized by an inflammatory response of the lungs to noxious stimuli. COPD should be suspected in patients with chronic cough, sputum production, or shortness of breath who have had significant exposure to tobacco smoke, occupational dusts, chemicals, or intense indoor home heating or cooking fuels.1 In the case of tobacco smoking, an exposure in excess of 20 pack-years is considered a significant risk factor for developing COPD. Suspected COPD should be confirmed with spirometry. Patients with COPD have a postbronchodilator forced expiratory volume in 1 second (FEV1) ⬍80% of predicted normal and an FEV1/forced vital capacity (FVC) ⬍70% of predicted normal.6 Despite this definition, a patient’s level of disability correlates poorly with their FEV1.7 Also, patients with airflow limitation could have partial but incomplete reversibility with bronchodilators, not clearly meeting the definition of COPD or asthma. The course of COPD is marked by progressive deterioration in lung function punctuated by periods of acute worsening of respiratory symptoms most often attributed to respiratory infection.6 The pathology of COPD is believed to be active inflammation within the lung as a result of inhalation of noxious particles and gases. Activated inflammatory cells such as macrophages, T-lymphocytes, and neutrophils are increased in the airways, lung parenchyma, and vasculature. To distinguish the inflammation of COPD from that of asthma, CD8 lymphocytes predominate in COPD, whereas CD4 lymphocytes predominate in asthma. These inflammatory cells and their mediators cause further inflammatory cell recruitment and lung destruction in both diseases.6 Standard Treatment of Chronic Obstructive Pulmonary Disease Smoking cessation is the only known treatment to slow the progressive decline in lung function associated with COPD. All other treatments for the chronic management of COPD are aimed at symptom control and maintenance of functional status. Such treatment routinely includes inhaled anticholinergics, inhaled B-agonists, methylxanthines, oxygen, and sometimes inhaled corticosteroids. During periods of acute decompensation, these therapies are augmented with systemic corticosteroids, antibiotics, and intensification of inhaled bronchodilator and oxygen use. Rich 31
DISCUSSION The Controversy of Inhaled Corticosteroids and Chronic Obstructive Pulmonary Disease The use of inhaled steroids in chronic COPD management is an area of considerable controversy. The widespread use of inhaled steroids in COPD stems from their substantial benefit in the treatment of asthma.8 Based on this data, inhaled steroids were often incorporated into COPD management before there was evidence of a parallel disease-modifying effect in COPD. Specifically, inhaled steroids are used to target chronic lung inflammation in patients with COPD. Despite the similarities between asthma and COPD, the body of evidence does not suggest that inhaled steroids have the same effect in COPD that they do in asthma. Several randomized, controlled trials have investigated the benefits of using inhaled corticosteroids in the management of COPD. The results of trials investigating this intervention are discussed here. These studies are presented in order of increasing severity of COPD in the study populations. The EUROSCOP Study The EUROSCOP study was a double-blind, placebo-controlled trial in which 1277 current smokers (mean age, 52 years) with mild COPD (mean FEV1 ⫽ 77% predicted) were randomized to treatment with inhaled 400 g budesonide twice daily or placebo.9 During the first 6 months of the study, subjects in the budesonide group showed a small increase in FEV1.9 This was similar to findings in others trials of inhaled steroids in COPD.10,11 After the first 9 months of the study, the rate of decline in FEV1 in these patients with mild disease was not significantly different between the placebo and the budesonide groups, 69 mL per year versus 57 mL per year. However, budesonide seemed to have a more beneficial effect on FEV1 in patients who had smoked less than 36 pack-years. Patients were followed up for 3 years.9 The Copenhagen Study The Copenhagen Study was a double-blind, placebo-controlled trial involving the randomization of 290 patients (mean age, 59 years) with mild to moderate COPD (mean postbronchodilator FEV1 ⫽ 86% predicted) to placebo or 1200 g inhaled budesonide total daily for 6 months followed by 800 g total daily thereafter.12 After 3 years follow up of the patients with mild COPD, there was no significant difference in the rate of FEV1 decline between placebo and budesonide groups, 41.8 mL per year versus 45.1 mL per year. There were no differences in the number of exacerbations of symptoms between the groups.12 The Lung Health Study The Lung Health Study was a double-blind, placebo-controlled trial that randomized 1116 people (aged 40 – 69 years; mean age, 56 years) with moderate COPD (mean FEV1 ⫽ 64% predicted) to treatment with 600 g inhaled triamcinolone acetonide twice daily or placebo.13 After 3 years, there was no significant difference in the rate 32 Rich
of decline in lung function in the placebo and triamcinolone groups, 44.2 mL per year versus 47.0 mL per year. However, the members of the triamcinolone group had fewer respiratory symptoms when assessed by the American Thoracic Society– NHLBI Division of Lung Diseases questionnaire and fewer physician visits for respiratory illness. Methacholine challenge showed lower airway reactivity in the triamcinolone group.13 A substudy of 412 patients also assessed the impact of inhaled corticosteroids use on bone density, which is discussed further subsequently.13 The ISOLDE Trial The ISOLDE trial was a double-blind, placebo-controlled trial that randomized 751 men and women (aged 40 –75 years; mean age, 64 years) with relatively severe COPD (mean FEV1 ⬍50% of predicted) to 500 g fluticasone propionate twice daily by metered dose inhaler or identical placebo.10 At 3 years follow up, the difference in rate of decline in FEV1 between the fluticasone and placebo groups was not significant, 59 mL per year versus 50 mL per year. However, fluticasone-treated patients initially saw a small rise in FEV1 and this gain was sustained throughout the study.10 The end points of health status deterioration, COPD exacerbations, and patient withdrawal for acceptance of respiratory drugs all showed statistically significant improved outcome with fluticasone versus placebo.10 The median exacerbation rate was reduced by 25% from 1.32 to 0.99 exacerbations per year. Health status measured by the St. George’s Respiratory Questionnaire showed a decline of 3.2 units per year in the placebo group versus 2.0 units per year in the fluticasone group.10 A change in score of 4 or more is significant for a change in a patient’s condition.14 Discontinuations from the trial as a result of respiratory disease, not related to malignancy, was 25% in the placebo group versus 19% in the fluticasone group.10 This study also investigated the ability to predict long-term response to inhaled corticosteroids by response to a trial of oral corticosteroids. At randomization, all patients were given 0.6 mg/kg oral prednisolone per day for 14 days and spirometry was repeated. Response of FEV1 to oral prednisolone did not reliably predict response to inhaled fluticasone over the course of the study.10 The TRISTAN Study The TRISTAN Study was a double-blind, placebo-controlled study that randomized 1465 patients (mean age, 63 years) with severe COPD (mean FEV1 ⫽ 45% predicted) to 50 g salmeterol twice daily, 500 g fluticasone twice daily, placebo, or both. Patients were followed up for 12 months.15 In this study, all active treatment groups showed an improvement in FEV1 and fewer COPD exacerbations compared with placebo. At 52-weeks follow up, FEV1 increased by 10% in the combination group, by 2% in both monotherapy groups, and decreased by 3% in the placebo group. Exacerbations fell by 25% for combination therapy, 19% for fluticasone, and 20% for salmeterol compared with placebo. This effect was most evident in those with the worst COPD, FEV1 JAMDA – January/February 2004
⬍50% predicted, who had a 30% reduction in exacerbations.15 The combination group was the only group showing significant improvement in health status questionnaire scores. The combination group also had significantly more days in which no rescue medication was needed.15 Inhaled Corticosteroids and the Risk of Mortality and Readmission in the Elderly With Chronic Obstructive Pulmonary Disease A population-based cohort study (n ⫽ 22,620) compared the combined risk of all-cause mortality and hospital readmission for elderly patients (mean age, 75 years) admitted to the hospital with a COPD exacerbation. Patients who received inhaled steroids within 90 days of hospital discharge had 24% fewer repeat hospitalizations for COPD and 29% less mortality at 1 year of follow up after adjusting for sex, severity of COPD, and comorbid illness.16 This observational study is unique in that it shows a mortality benefit from using inhaled steroids in COPD. It also likely included many patients excluded from other COPD studies as a result of age, disease severity, and reversibility by spirometry. Unfortunately, as an observational study, it could be biased. Oral Steroids in Chronic Obstructive Pulmonary Disease The value of chronic oral steroids in the management of stable COPD has been debated in the past and has largely fallen out of favor in clinical practice. The GOLD Workshop recommends against the routine use of oral steroids as a result of lack of evidence for a disease-modifying effect and the burden of side effects associated with their use.6 Of particular concern is respiratory muscle myopathy and associated decline in lung function.6,17 Despite the GOLD recommendation, many patients with COPD are on long-term steroids that are not being actively weaned. This problem has been addressed in clinical trials. Withdrawal of Chronic Systemic Steroids in Patients With Chronic Obstructive Pulmonary Disease Rice and colleagues conducted a small double-blind, placebo-controlled trial of patients (average age, 70 years) with “steroid-dependent” COPD (mean FEV1 ⫽ 0.94L). Thirtyeight patients were assigned to their usual maintenance dose of oral prednisone or were to be withdrawn from prednisone at 5 mg per week and followed for 6 months. Discontinuation of steroid treatment did not result in an increase in exacerbations, but did reduce patients’ total steroid use and body weight.18 Effects of Long-Term Treatment With Inhaled Versus Oral Corticosteroids in Chronic Obstructive Pulmonary Disease Renkema and colleagues performed a double-blind, placebo-controlled study that randomized 58 nonallergic patients (mean age, 56 years) with COPD (mean FEV1 ⫽ 63% preCONTROVERSIES IN LONG-TERM CARE
dicted) to placebo, 1600 g inhaled budesonide per day, or 1600 g inhaled budesonide per day plus 5 mg oral prednisolone per day. These patients were followed up for 2 years.19 There was no significant difference in FEV1 decline, duration or frequency of COPD exacerbations, or COPD symptoms between the inhaled steroid group and the combined group. Patients in the placebo group were more likely to withdraw from the trial as a result of respiratory complications.19 ACUTE EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Systemic Steroids in Acute Exacerbations of Chronic Obstructive Pulmonary Disease Systemic steroids are commonly prescribed for acute exacerbations of COPD. There is solid randomized, controlled trial evidence for this indication for steroid use. The Veterans Affairs Cooperative Study The Veterans Affairs Cooperative Study Group performed a double-blind, placebo-controlled study in which 271 veterans (average age, 68 years; median FEV1 ⫽ 0.73 L) admitted for COPD exacerbation were randomized to placebo or systemic steroids for 2 or 8 weeks in addition to usual care. Steroids were given as 125 mg methylprednisolone intravenously every 6 hours for 72 hours followed by 60 mg oral prednisone per day initially and tapered over 2 or 8 weeks, depending on the study group. Patients were followed up for 6 months.20 Use of systemic steroids, for either 2 or 8 weeks, was associated with shorter initial hospital stays (8.5 vs. 9.7 days) and a reduction in treatment failures by approximately 10% at 30 and 90 days follow up. FEV1 was approximately 0.1 L higher on hospital day 1 for the steroid groups compared with placebo. By 6 months follow up, there were no differences between the placebo and steroid-treated groups. The outcomes with the 2-week and 8-week regimens were not significantly different.20 Oral Steroids for Inpatients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease Davies and colleagues investigated the use of oral steroids in acute exacerbations of COPD requiring hospital admission in a double-blind, placebo-controlled trial. Fifty-six patients (mean age, 67 years) admitted for nonacidotic COPD exacerbations (mean FEV1 ⫽ 0.59 L) were randomized to 30 mg prednisolone per day for 14 days or placebo, in addition to usual care with bronchodilators, antibiotics, and oxygen. Patients were followed up for 6 weeks.21 FEV1 increased more rapidly and to a larger degree in the prednisolone group. FEV1 after bronchodilators increased from 25.7% to 32.2% predicted in the placebo group and from 28.2% to 41.5% predicted in the prednisolone group by hospital discharge. Hospital stay was shorter in the prednisolone group, 7 days versus 9 days for placebo. There were no signifRich 33
icant differences in changes in symptoms between the groups and no significant differences in FEV1 at 6 weeks follow up.21 Oral Steroids for Outpatients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease Despite the common use of oral steroids in the outpatient management of COPD exacerbations, few studies have investigated this regimen. Thompson and colleagues randomized 27 outpatients (mean age, 68 years; mean FEV1 ⫽ 1.30 L) with acute COPD exacerbation in a double-blind, placebo-controlled trial of 60 mg, 40 mg, and 20 mg prednisone each for 3 days or placebo. The prednisone groups showed faster improvement in FEV1 and fewer treatment failures as well as a trend toward improvement in dyspnea scale scores.22 Aaron and colleagues performed a double-blind, placebocontrolled trial in which 147 patients seen in the emergency room for COPD exacerbation were randomized to 40 mg oral prednisone per day for 10 days or placebo. Participants also received oral antibiotics and bronchodilators.23 At 30 days follow up, the overall rate of relapse was lower in the prednisone group than in the placebo, 27% versus 43%. Prednisone-treated patients had greater improvement in FEV1 and dyspnea scores on the 10th day of follow up but no difference in health-related quality of life.23 Inhaled Steroids in Acute Exacerbations of Chronic Obstructive Pulmonary Disease Nebulized steroids are rarely used for the treatment of acute COPD; however, there is some evidence to support their use. A double-blind, placebo-controlled trial randomized 199 patients (mean age, 70 years; mean FEV1 approximately 0.8 L) requiring inpatient treatment for nonacidotic COPD exacerbation to nebulized budesonide, oral prednisolone, or placebo. Budesonide was given as 2 mg nebulized every 6 hours for 72 hours followed by 2 mg per day for 10 days. Oral prednisolone was given as 30 mg every 12 hours for 72 hours followed by 40 mg per day for 7 days.24 Both steroid groups showed improvement in postbronchodilator FEV1 at 72 hours over placebo, 0.1 L for budesonide versus placebo and 0.16 L for prednisolone versus placebo. This difference in FEV1 improvement between budesonide and prednisolone was not significant. However, in the prednisolone group, there was a tendency toward more patients showing larger increases in FEV1 and decreases in PCO2. There was no difference in length of hospital stay between the groups.24 SIDE EFFECTS OF CORTICOSTEROIDS Systemic Corticosteroids The long-term side effects of systemic corticosteroids are well established. These include adrenal suppression, diabetes mellitus, osteoporosis, cataracts, secondary infections, skin changes, mood changes, fat redistribution, hypertension, myopathy, and avascular necrosis. Of the many complications of systemic corticosteroids, osteoporosis is of particular interest to practitioners caring for 34 Rich
the frail elderly. The concern for steroid-induced osteoporosis in patients with COPD is grave given the additional risk factors of smoking, immobility, lower body mass index, and hypogonadism associated with chronic disease.25 Vertebral fractures are important for their consequences of pain, reduced physical function, and ventilatory compromise. Hip fractures are even more significant given their association with loss of ambulation and increased mortality. Patients with COPD could have an advantage over patients with other steroid-treated chronic diseases in that patients with COPD are usually older and require only intermittent bursts of steroid treatment.26 Although studies have looked at markers of bone turnover and bone mineral density, few have evaluated fracture prevalence in patients with COPD using corticosteroids. Corticosteroid Use and Vertebral Fractures in Older Men With Chronic Obstructive Pulmonary Disease In this cross-sectional study, 312 men with COPD (mean age, 69 years) were evaluated to investigate the relationship between steroid use and vertebral fracture. Subjects were divided into never-used steroids, inhaled steroid users, and systemic steroid users. Systemic steroid users included intermittent and continuous users.27 The prevalence of vertebral fractures was 48.7% in the never-used steroids group, 57.1% in the inhaled steroids group, and 63.3% in the systemic steroids group (average dose, 18 mg daily). The odds ratio for vertebral fractures in systemic versus nonsteroid users was 1.8 adjusted for age. The odds ratio for continuous systemic versus nonsteroid users was 2.56. Systemic steroid users also tended to have more multiple or severe vertebral fractures.27 Inhaled Corticosteroids Although the side effects of systemic steroids are well recognized, the side effects of inhaled corticosteroids are less clearly defined and still under investigation. Several randomized, controlled trials of inhaled corticosteroids have used known steroid side effects as secondary end points. These include skin changes, incidence of diabetes, fractures, bone density, and adrenal suppression. Population-based studies have looked at the association between inhaled steroid use and effects beyond the lung. The data available about the systemic effects of inhaled steroids are discussed here. Osteoporosis Hubbard and colleagues performed a population-based, case-control study of 16,341 cases of hip fracture from a primary care database (mean age, 79 years; 79% female) and 29,889 age and sex-matched control subjects. The odds ratio for hip fracture with exposure to inhaled steroids was 1.26. This was reduced to 1.19 after controlling for exposure to intermittent oral steroids. There was a positive dose-response relationship between inhaled steroid use and hip fracture.28 Van Staa and colleagues performed a similar retrospective cohort study and obtained relative risks of 1.15, 1.22, and 1.51 for nonvertebral, hip, and vertebral fractures, respectively, JAMDA – January/February 2004
compared with control subjects. However, there was no difference in the relative risk of fracture between the inhaled steroid group and the bronchodilator control group. This raised the possibility of underlying disease rather than inhaled steroid use as a cause for the increased fracture risk associated with inhaled steroid treatment.29 The substudy of the Lung Health Study to evaluate bone density revealed a significantly lower bone density in the lumbar spine and in the femur for the triamcinolone group. However, this difference was not seen until 3 years of follow up.13 There were no fracture rates reported. In the EUROSCOP trial, bone density of a subset of patients was assessed, and there was no significant difference between groups except for a small but significant positive effect in favor of budesonide at the femoral trochanter. There was no increase in new vertebral fractures with budesonide.9 Adrenal Suppression Most randomized, controlled trials of inhaled steroids in COPD have evaluated adrenal suppression in terms of morning cortisol levels and clinical symptoms. The TRISTAN Study found that serum cortisol concentrations fell by 1% and 3% for fluticasone and combination therapy, respectively, compared with a rise of 4% and 6% in the placebo and salmeterol groups, respectively, after 52 weeks of treatment. These changes were not associated with any clinical signs or symptoms.15 The ISOLDE trial also showed a small but significant reduction in morning cortisol levels with inhaled corticosteroid treatment. Morning cortisol levels were below the normal range at any time during the study in less than 5% of the subjects with no clinical signs or symptoms of adrenal insufficiency over the 36 months of the study.10 Skin and Oral Effects Oral candidiasis was increased in the ISOLDE, EUROSCOP, and TRISTAN trials with inhaled steroid use.9,10,15 Skin bruising was more prevalent in the inhaled steroid groups of the ISOLDE and EUROSCOP trials.9,10 Diabetes, Cataracts, and Myopathy The Lung Health Study was the only randomized, controlled trial of inhaled steroids in COPD that followed the incidence of diabetes, cataracts, and myopathy during the 3-year follow up.13 There was no significant increase in the incidence of these diagnoses in the inhaled steroid-treated group.13 Applicability of Results of Clinical Trials to Frail Elderly Nursing Home Patients Nursing Home Residents versus Study Participants The application of results of clinical trials to patient care in the frail elderly is frequently complicated by the exclusion of this patient population from clinical trials. The inclusion criteria of age limits, ability to follow up reliably, ability to give consent, and lack of severe chronic medical illness exclude most nursing home residents from participation. Physicians practicing in this arena are largely left to make judgCONTROVERSIES IN LONG-TERM CARE
ments about the suitability of a treatment based on their knowledge of an individual and the medical evidence. Inclusion criteria to participate in clinical trials of COPD frequently limit the allowed degree of reversibility in FEV1 with bronchodilators. This limit is usually set at less that 15% of predicted FEV1. In clinical practice, some nursing home patients with a diagnosis of COPD could have more reversibility of FEV1. With regard to age and frailty, most patients with clinically significant COPD, and thus study participants, are at least in the sixth decade of life. Many studies included patients in whom the mean FEV1 was less than 50% predicted.10,15,20 The inclusion of these older participants with more severe disease represents a relatively frail population to be included in clinical trials and lends credibility to extending the study conclusions to nursing home patients. The use of inhaled steroids in the nursing home population is often limited by a patient’s ability to use the delivery device. Nursing staff can help patients use a metered dose inhaler and spacer system to deliver medication correctly. However, many frail elderly have arthritis, residual deficits from strokes, dementia, and vision and hearing impairments that interfere with the correct use of metered dose inhaler medication. Poor technique can result in a large deposition of the medication in the patient’s mouth and increased risk of oral candidiasis. Currently, bronchodilators are often given by a nebulizer in the nursing home setting for ease of administration. Nebulized steroids are not widely available for use to overcome the incompatibility between nursing home patients and the metered dose delivery system. Nursing home patients have difficulty traveling to outside appointments as a result of mobility restrictions. The same physical and mental impairments that limit metered dose inhaler use can also affect the collection of accurate spirometric measurements. If accurate spirometry cannot be obtained, a clinical assessment of the patient’s COPD could suffice. However, the clinician must realize that the presence or absence of symptoms often does not correlate with the severity of the patient’s COPD. Significance of the Side Effects of Steroids in the Frail Elderly Frailty predisposes individuals to the negative side effects of medications. Thus, any treatment used in frail people should be implemented with the knowledge that such patients are highly likely to develop whatever complications were identified in a more robust study population. Many frail elderly already suffer from conditions that are known side effects of steroid use. These include diabetes, osteoporosis, hypertension, cataracts, mood disorders, muscle weakness, and fragile skin. The prevalence of these conditions makes the practitioner hesitate before using steroid medications in the nursing home. Each frail elderly patient needs to be considered as an individual. Quality of life and life expectancy need to be taken into consideration. For patients near the end of their lives, problems of osteoporosis, glucose intolerance, fat redistribution, myopathy, and others might not be significant. A patient with severe airflow obstruction and limited life exRich 35
pectancy can forgo tight blood sugar control in exchange for the ability to breath more comfortably. However, for an ambulatory patient with osteoporosis and mild COPD, the side effects of steroid use might outweigh the benefits. Increased use of bronchodilators might be a better choice for disease management. CONCLUSION When to Use Steroids in the Management of Chronic Obstructive Pulmonary Disease in the Nursing Home Systemic Steroids and Chronic Obstructive Pulmonary Disease The use of systemic steroids in the management of COPD is indicated for the treatment of COPD exacerbations in the inpatient, nursing home, and outpatient settings. Under these circumstances, systemic steroids have been shown to improve pulmonary function faster and to reduce the incidence of treatment failure.6 COPD exacerbations involving severe shortness of breath and concern for respiratory failure should be managed in the inpatient environment with parenteral or oral steroids, depending on what the patient can tolerate. This should be followed by a tapered oral regimen for 10 to 14 days total treatment.6,20 Given the numerous side effects of systemic steroids, and the lack of disease-modifying effect, the goal of treatment for most patients should be to taper off all oral steroids as quickly as possible. Oral steroids should not be part of the long-term management of chronic stable COPD.6 However, there could be patients with COPD who are at the end of life for whom the urgency to taper is not as great. Inhaled Steroids and Chronic Obstructive Pulmonary Disease The role for inhaled steroids in the nursing home population is less clear. Several well-designed studies have shown that inhaled steroids do not alter the rate of progressive decline in lung function in COPD.9,10,12,13 Given the risks and the absence of disease-modifying benefits of inhaled steroids, their use should be restricted to those patients for whom there is proven benefit or good clinical evidence of significant improvement in COPD control. The Updated 2003 GOLD Guidelines for COPD Management recommend limiting the use of inhaled steroids to symptomatic patients with COPD with FEV1 ⬍50% and frequent exacerbations after bronchodilation has been maximized.30 In these patients with severe COPD, the evidence suggests that inhaled steroids could reduce the number of COPD exacerbations and could improve dyspnea and quality of life. The U.S. Food and Drug Administration is currently considering the approval of highdose inhaled steroids for use in COPD, but only for those with severe disease and frequent exacerbations despite maximal bronchodilation. For patients with a mixed presentation of COPD and asthma, with significant reversibility, inhaled steroids could be of substantial benefit, although this has not been systematically studied. 36 Rich
The down side of inhaled steroid use appears to be systemic side effects similar to oral steroids, although to a much lesser degree. The increased risks of osteoporosis and adrenal suppression, as well as skin changes with candidiasis and bruising, limit the acceptance of inhaled steroids. The ISOLDE trial showed that a positive response in FEV1 to a trial of oral steroids did not predict improvement with inhaled steroids.10 Instead, patients should be given a 6-week to 3-month trial of inhaled corticosteroid therapy followed by repeated postbronchodilator spirometric testing to assess response. A 200-mL or 12% improvement in FEV1 compared with baseline is considered a positive response to inhaled steroids.30 In nursing home patients, it might not be feasible to assess spirometric response to inhaled steroids as a result of limited access to the necessary resources. In this instance, a trial of therapy with inhaled steroids and observation for clinical improvement or stabilization could suffice as justification for continued therapy. Without obvious benefit, inhaled steroids should be discontinued to limit adverse effects and to avoid unnecessary overtreatment in this frail population. Areas of Future Study There are still many uncertainties surrounding the use of steroids in the treatment of COPD. An area of particular interest to the nursing home practitioner is the clinical outcomes for patients with COPD treated with inhaled steroids, in which participants are not strictly limited in terms of FEV1 irreversibility and concomitant chronic disease. Also, the effects of prolonged inhaled steroid use need to be studied because patients could use these medications for decades if they are effective. It will be a major benefit to patients if long-term inhaled steroids prove to be a safer yet effective alternative to systemic steroids for the management of severe COPD symptoms. This will help to further strictly limit the use of systemic steroids in COPD management and the associated side effects. REFERENCES 1. National Heart, Lung, and Blood Institute. Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Diseases. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health; 1998. 2. McCrory D, Brown C, Gelfand S, et al. Management of acute exacerbations of COPD. Chest 2001;119:1190 –1209. 3. Statistical Abstract of the United States. Springfield, VA: US Department of Commerce, Bureau of Census; 1997. 4. Agency for Health Care Research and Policy. Healthcare Cost and Utilization Project: Nationwide Inpatient Sample for 1997. National Technical Information Service, 1997. 5. The National Lung Health Education Program. Strategies in preserving lung health prevention COPD and associated diseases. Chest 1998;113: 123S–163S. 6. Pauwels R, Buist S, Calverly P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary. Am J Respir Crit Care Med 2001;163: 1257–1276. 7. MacNee W, Calverly P. Chronic obstructive pulmonary disease 7: Management of COPD. Thorax 2003;58:261–265. JAMDA – January/February 2004
8. National Heart, Lung, and Blood Institute. Guidelines for the Diagnosis and Management of Asthma, NAEPP Expert Panel Report 2002. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health; 2002. 9. Pauwels R, Lofdahl C, Laitinen L, et al. Long term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;320:1948 –1953. 10. Burge P, Calverley P, Jones P, et al. Randomized, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: The ISOLDE trial. BMJ 2000;320:1297–1303. 11. Paggiaro P, Dahle R, Bakran I, et al. Multi-center randomized placebocontrolled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998;351:773–780. 12. Vestbo J, Sorensen T, Lange P, et al. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: A randomized controlled trial. Lancet 1999;353:1819 –1823. 13. The Lung Health Research Group. Effect of inhaler triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902–1909. 14. Jones P, Quirk F, Baveystock G. The St. George’s respiratory questionnaire. Respir Med 1991;85(suppl B):25–31. 15. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: A randomized controlled trial. Lancet 2003;361:449 – 456. 16. Sin D, Tu J. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Crit Care Med 2001;164:580 –584. 17. Decramer M, Lacquet L, Fagard R, et al. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med 1994;150:11–16. 18. Rice K, Rubins J, Lebahn R, et al. Withdrawal of chronic systemic corticosteroids in patients with COPD. Am J Respir Crit Care Med 2000;162:174 –178. 19. Renkema T, Schouten J, Koeter GE, et al. Effects of long-term treatment with corticosteroids in COPD. Chest 1996;109:1156 –1162.
CONTROVERSIES IN LONG-TERM CARE
20. Niewoehner D, Erbland M, Deupree R, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999;340:1941–1947. 21. Davies L, Angus R, Calverley P. Oral corticosteroids for patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomized controlled trial. Lancet 1999;354:456 – 460. 22. Thompson W, Nielson C, Carvalho P, et al. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Crit Care Med 1996;154:407– 412. 23. Aaron S, Vandemheen K, Hebert P, et al. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003;348:2618 –2625. 24. Maltais F, Ostinelli J, Boureau J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;165:698 –703. 25. Biskobing D. COPD and osteoporosis. Chest 2002;121:609 – 620. 26. Singh J, Palda V, Stanbrook M, et al. Corticosteroid therapy for patients with acute exacerbations of chronic obstructive pulmonary disease. Arch Intern Med 2002;162:2527–2536. 27. McEvoy C, Ensrud K, Bender E, et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:704 – 709. 28. Hubbard R, Smith C, Smeeth L, et al. Inhaled corticosteroids and hip fracture. Am J Respir Crit Care Med 2002;166:1563–1566. 29. Van Staa T, Leufkens H, Cooper C. Use of inhaled corticosteroids and risk of fractures. Bone Miner Res 2001;16:581–588. 30. Global Initiative for Chronic Obstructive Pulmonary Disease. Global Strategy for Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. NHLBI/WHO Workshop Report. Bethesda, MD: National Heart Lung and Blood Institute, April 2001. Update of the Management Sections, GOLD web site (www.goldcopd.com) Updated July 1, 2003.
Rich 37