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Chronic obstructive pulmonary disease: An update for the primary physician
Author(s)
Umur Hatipoglu, MD
Loutfi S. Aboussouan, MD

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,1 and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.2 The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.3

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV1 as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.4

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,5 GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection6 and increases the risk of death7 and the risk of a faster decline in lung function.8

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.9 Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV1 do not correlate strongly with exertional capacity and health status in patients with COPD.10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV1 in predicting the risk of death.12 The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,13 has five grades, numbered 0 through 4:

  • Grade 0—Breathless with strenuous exercise only
  • Grade 1—Breathless when hurrying on level ground or walking up a slight hill
  • Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
  • Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
  • Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

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The new GOLD guidelines (Table 1)5 define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

  • Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV1 of at least 50%
  • Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
  • Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV1 less than 50%
  • Group D—more symptoms, high risk.

Thus, a patient with an FEV1 of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV1 of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.5

 

 

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al14 compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.15 Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study16 retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).16

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.17

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

  • 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
  • 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
  • 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,18 in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,19 in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.18

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.20 In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.21 Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.22 Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al23 conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis24 and diffuse panbronchiolitis.25 Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al26 assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.25 The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

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Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.26

Phosphodiesterase inhibitors

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Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.27 Several phase 3 trials found the compound to have beneficial effects.

Calverley et al28 performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV1 of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al29 performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV1 values of 40% to 70% of predicted. The mean prebronchodilator FEV1 improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

 

 

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

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Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.30 Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)31 enrolled 5,993 patients with a mean FEV1 of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV1 values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV1—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.34

ACCORD COPD I35 and ATTAIN,36 two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV1 compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.37

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV1 area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.38

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.39

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV1,40–42 dynamic hyperinflation, exercise tolerance,43,44 and dyspnea.45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.50 In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,51 and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).52

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Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,53 the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.54 At the higher dose of 300 μg daily, the 52-week INVOLVE trial55 demonstrated early and more sustained improvement in FEV1 compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.56

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV1 trough before the subsequent dose is due, aptly named “pharmacologic stenting.”57 Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.58

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV1 at higher doses.59

 

 

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.60 Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.61,62

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Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.62 Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.63 Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.64 There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

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Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).67

In another randomized trial,68 settings that aimed to maximally reduce Paco2 (mean inspiratory positive airway pressure 29 cm H2O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H2O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco2, FEV1, vital capacity, and health-related quality of life66 without disrupting sleep quality.68

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.66

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.69

Pulmonary rehabilitation

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Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.70 Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.71

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,72 though more modest targets of about 50% can also be beneficial.73

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).74 Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.71

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,71 an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.75

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.71

Lung-volume reduction surgery

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Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial76 randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV1 lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

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  29. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet 2009; 374:695–703.
  30. Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129:856–870.
  31. Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359:1543–1554.
  32. Cazzola M. Aclidinium bromide, a novel long-acting muscarinic M3 antagonist for the treatment of COPD. Curr Opin Investig Drugs 2009; 10:482–490.
  33. Gavaldà A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther 2009; 331:740–751.
  34. Alagha K, Bourdin A, Tummino C, Chanez P. An update on the efficacy and safety of aclidinium bromide in patients with COPD. Ther Adv Respir Dis 2011; 5:19–28.
  35. Kerwin EM, D’Urzo AD, Gelb AF, Lakkis H, Garcia Gil E, Caracta CF; ACCORD I study investigators. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD 2012; 9:90–101.
  36. Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J 2012; 40:830–836.
  37. Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res 2011; 12:55.
  38. Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest 2012; 141:745–752.
  39. Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11:149.
  40. Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999; 115:957–965.
  41. Campbell M, Eliraz A, Johansson G, et al. Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med 2005; 99:1511–1520.
  42. Hanrahan JP, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K, Baumgartner RA. Effect of nebulized arformoterol on airway function in COPD: results from two randomized trials. COPD 2008; 5:25–34.
  43. Neder JA, Fuld JP, Overend T, et al. Effects of formoterol on exercise tolerance in severely disabled patients with COPD. Respir Med 2007; 101:2056–2064.
  44. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004; 24:86–94.
  45. Rennard SI, Anderson W, ZuWallack R, et al. Use of a long-acting inhaled beta 2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163:1087–1092.
  46. Schultze-Werninghaus G. Multicenter 1-year trial on formoterol, a new long-acting beta 2-agonist, in chronic obstructive airway disease. Lung 1990; 168(suppl):83–89.
  47. Rodrigo GJ, Nannini LJ, Rodríguez-Roisin R. Safety of long-acting beta-agonists in stable COPD: a systematic review. Chest 2008; 133:1079–1087.
  48. Baker WL, Baker EL, Coleman CI. Pharmacologic treatments for chronic obstructive pulmonary disease: a mixed-treatment comparison meta-analysis. Pharmacotherapy 2009; 29:891–905.
  49. Rodrigo GJ, Castro-Rodriguez JA, Plaza V. Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review. Chest 2009; 136:1029–1038.
  50. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129:15–26.
  51. Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775–789.
  52. Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008; 31:927–933.
  53. Lombardi D, Cuenoud B, Krämer SD. Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties? Eur J Pharm Sci 2009; 38:533–547.
  54. Kornmann O, Dahl R, Centanni S, et al; INLIGHT-2 (Indacaterol Efficacy Evaluation Using 150-μg Doses with COPD Patients) study investigators. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J 2011; 37:273–279.
  55. Dahl R, Chung KF, Buhl R, et al; INVOLVE (INdacaterol: Value in COPD: Longer Term Validation of Efficacy and Safety) Study Investigators. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax 2010; 65:473–479.
  56. Donohue JF, Fogarty C, Lötvall J, et al; INHANCE Study Investigators. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010; 182:155–162.
  57. Beeh KM, Beier J. The short, the long and the “ultra-long”: why duration of bronchodilator action matters in chronic obstructive pulmonary disease. Adv Ther 2010; 27:150–159.
  58. Worth H, Chung KF, Felser JM, Hu H, Rueegg P. Cardio- and cerebrovascular safety of indacaterol vs formoterol, salmeterol, tiotropium and placebo in COPD. Respir Med 2011; 105:571–579.
  59. Chowdhury BA, Seymour SM, Michele TM, Durmowicz AG, Liu D, Rosebraugh CJ. The risks and benefits of indacaterol--the FDA’s review. N Engl J Med 2011; 365:2247–2249.
  60. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: a meta-analysis. JAMA 2004; 291:1999–2006.
  61. Leech JA, Dulberg C, Kellie S, Pattee L, Gay J. Relationship of lung function to severity of osteoporosis in women. Am Rev Respir Dis 1990; 141:68–71.
  62. Persson LJ, Aanerud M, Hiemstra PS, Hardie JA, Bakke PS, Eagan TM. Chronic obstructive pulmonary disease is associated with low levels of vitamin D. PLoS One 2012; 7:e38934.
  63. Janssens W, Lehouck A, Carremans C, Bouillon R, Mathieu C, Decramer M. Vitamin D beyond bones in chronic obstructive pulmonary disease: time to act. Am J Respir Crit Care Med 2009; 179:630–636.
  64. Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2012; 156:105–114.
  65. Casanova C, Celli BR, Tost L, et al. Long-term controlled trial of nocturnal nasal positive pressure ventilation in patients with severe COPD. Chest 2000; 118:1582–1590.
  66. Dreher M, Storre JH, Schmoor C, Windisch W. High-intensity versus low-intensity non-invasive ventilation in patients with stable hypercapnic COPD: a randomised crossover trial. Thorax 2010; 65:303–308.
  67. McEvoy RD, Pierce RJ, Hillman D, et al; Australian trial of non-invasive Ventilation in Chronic Airflow Limitation (AVCAL) Study Group. Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial. Thorax 2009; 64:561–566.
  68. Dreher M, Ekkernkamp E, Walterspacher S, et al. Noninvasive ventilation in COPD: impact of inspiratory pressure levels on sleep quality. Chest 2011; 140:939–945.
  69. Duiverman ML, Wempe JB, Bladder G, et al. Two-year home-based nocturnal noninvasive ventilation added to rehabilitation in chronic obstructive pulmonary disease patients: a randomized controlled trial. Respir Res 2011; 12:112.
  70. Ringbaek TJ, Broendum E, Hemmingsen L, et al. Rehabilitation of patients with chronic obstructive pulmonary disease. Exercise twice a week is not sufficient! Respir Med 2000; 94:150–154.
  71. Ries AL, Bauldoff GS, Carlin BW, et al. Pulmonary Rehabilitation: Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines. Chest 2007; 131(suppl):4S–42S.
  72. Vallet G, Ahmaïdi S, Serres I, et al. Comparison of two training programmes in chronic airway limitation patients: standardized versus individualized protocols. Eur Respir J 1997; 10:114–122.
  73. Vogiatzis I, Williamson AF, Miles J, Taylor IK. Physiological response to moderate exercise workloads in a pulmonary rehabilitation program in patients with varying degrees of airflow obstruction. Chest 1999; 116:1200–1207.
  74. Martinez FJ, Vogel PD, Dupont DN, Stanopoulos I, Gray A, Beamis JF. Supported arm exercise vs unsupported arm exercise in the rehabilitation of patients with severe chronic airflow obstruction. Chest 1993; 103:1397–1402.
  75. Cote CG, Celli BR. Pulmonary rehabilitation and the BODE index in COPD. Eur Respir J 2005; 26:630–636.
  76. Fishman A, Martinez F, Naunheim K, et al; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348:2059–2073.
  77. Naunheim KS, Wood DE, Mohsenifar Z, et al; National Emphysema Treatment Trial Research Group. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg 2006; 82:431–443.
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Umur Hatipoglu, MD
Quality Improvement Officer, Respiratory Institute, Cleveland Clinic

Loutfi S. Aboussouan, MD
Respiratory Institute, Cleveland Clinic; Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Umur Hatipoğlu, MD, Respiratory Institute, A90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: hatipou@ccf.org

Dr. Hatipoğlu is the recipient of an investigator-initiated research protocol grant from Novartis and has received honoraria for speaking engagements from Forest Pharmaceuticals.

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Loutfi S. Aboussouan, MD
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Umur Hatipoglu, MD
Quality Improvement Officer, Respiratory Institute, Cleveland Clinic

Loutfi S. Aboussouan, MD
Respiratory Institute, Cleveland Clinic; Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Umur Hatipoğlu, MD, Respiratory Institute, A90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: hatipou@ccf.org

Dr. Hatipoğlu is the recipient of an investigator-initiated research protocol grant from Novartis and has received honoraria for speaking engagements from Forest Pharmaceuticals.

Author and Disclosure Information

Umur Hatipoglu, MD
Quality Improvement Officer, Respiratory Institute, Cleveland Clinic

Loutfi S. Aboussouan, MD
Respiratory Institute, Cleveland Clinic; Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Umur Hatipoğlu, MD, Respiratory Institute, A90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail: hatipou@ccf.org

Dr. Hatipoğlu is the recipient of an investigator-initiated research protocol grant from Novartis and has received honoraria for speaking engagements from Forest Pharmaceuticals.

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Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,1 and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.2 The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.3

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV1 as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.4

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,5 GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection6 and increases the risk of death7 and the risk of a faster decline in lung function.8

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.9 Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV1 do not correlate strongly with exertional capacity and health status in patients with COPD.10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV1 in predicting the risk of death.12 The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,13 has five grades, numbered 0 through 4:

  • Grade 0—Breathless with strenuous exercise only
  • Grade 1—Breathless when hurrying on level ground or walking up a slight hill
  • Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
  • Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
  • Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

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The new GOLD guidelines (Table 1)5 define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

  • Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV1 of at least 50%
  • Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
  • Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV1 less than 50%
  • Group D—more symptoms, high risk.

Thus, a patient with an FEV1 of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV1 of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.5

 

 

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al14 compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.15 Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study16 retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).16

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.17

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

  • 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
  • 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
  • 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,18 in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,19 in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.18

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.20 In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.21 Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.22 Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al23 conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis24 and diffuse panbronchiolitis.25 Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al26 assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.25 The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

RTEmagicC_Hatipoglu_COPDUpdate_T2.gif.gif

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.26

Phosphodiesterase inhibitors

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Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.27 Several phase 3 trials found the compound to have beneficial effects.

Calverley et al28 performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV1 of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al29 performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV1 values of 40% to 70% of predicted. The mean prebronchodilator FEV1 improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

 

 

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

RTEmagicC_Hatipoglu_COPDUpdate_T4.gif.gif

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.30 Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)31 enrolled 5,993 patients with a mean FEV1 of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV1 values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV1—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.34

ACCORD COPD I35 and ATTAIN,36 two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV1 compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.37

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV1 area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.38

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.39

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV1,40–42 dynamic hyperinflation, exercise tolerance,43,44 and dyspnea.45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.50 In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,51 and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).52

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Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,53 the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.54 At the higher dose of 300 μg daily, the 52-week INVOLVE trial55 demonstrated early and more sustained improvement in FEV1 compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.56

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV1 trough before the subsequent dose is due, aptly named “pharmacologic stenting.”57 Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.58

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV1 at higher doses.59

 

 

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.60 Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.61,62

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Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.62 Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.63 Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.64 There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

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Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).67

In another randomized trial,68 settings that aimed to maximally reduce Paco2 (mean inspiratory positive airway pressure 29 cm H2O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H2O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco2, FEV1, vital capacity, and health-related quality of life66 without disrupting sleep quality.68

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.66

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.69

Pulmonary rehabilitation

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Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.70 Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.71

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,72 though more modest targets of about 50% can also be beneficial.73

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).74 Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.71

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,71 an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.75

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.71

Lung-volume reduction surgery

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Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial76 randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV1 lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,1 and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.2 The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.3

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV1 as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.4

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,5 GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection6 and increases the risk of death7 and the risk of a faster decline in lung function.8

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.9 Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV1 do not correlate strongly with exertional capacity and health status in patients with COPD.10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV1 in predicting the risk of death.12 The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,13 has five grades, numbered 0 through 4:

  • Grade 0—Breathless with strenuous exercise only
  • Grade 1—Breathless when hurrying on level ground or walking up a slight hill
  • Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
  • Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
  • Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

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The new GOLD guidelines (Table 1)5 define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

  • Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV1 of at least 50%
  • Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
  • Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV1 less than 50%
  • Group D—more symptoms, high risk.

Thus, a patient with an FEV1 of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV1 of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.5

 

 

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al14 compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.15 Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study16 retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).16

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.17

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

  • 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
  • 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
  • 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,18 in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,19 in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.18

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.20 In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.21 Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.22 Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al23 conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis24 and diffuse panbronchiolitis.25 Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al26 assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.25 The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

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Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.26

Phosphodiesterase inhibitors

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Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.27 Several phase 3 trials found the compound to have beneficial effects.

Calverley et al28 performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV1 of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al29 performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV1 values of 40% to 70% of predicted. The mean prebronchodilator FEV1 improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

 

 

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

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Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.30 Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)31 enrolled 5,993 patients with a mean FEV1 of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV1 values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV1—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.34

ACCORD COPD I35 and ATTAIN,36 two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV1 compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.37

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV1 area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.38

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.39

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV1,40–42 dynamic hyperinflation, exercise tolerance,43,44 and dyspnea.45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.50 In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,51 and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).52

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Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,53 the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.54 At the higher dose of 300 μg daily, the 52-week INVOLVE trial55 demonstrated early and more sustained improvement in FEV1 compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.56

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV1 trough before the subsequent dose is due, aptly named “pharmacologic stenting.”57 Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.58

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV1 at higher doses.59

 

 

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.60 Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.61,62

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Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.62 Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.63 Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.64 There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

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Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).67

In another randomized trial,68 settings that aimed to maximally reduce Paco2 (mean inspiratory positive airway pressure 29 cm H2O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H2O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco2, FEV1, vital capacity, and health-related quality of life66 without disrupting sleep quality.68

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.66

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.69

Pulmonary rehabilitation

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Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.70 Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.71

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,72 though more modest targets of about 50% can also be beneficial.73

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).74 Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.71

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,71 an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.75

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.71

Lung-volume reduction surgery

RTEmagicC_Hatipoglu_COPDUpdate_T9.gif.gif

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial76 randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV1 lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

References
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  2. Murphy SL, Xu J, Kochanek KD. Deaths: preliminary data from 2010. National Vital Statistics Reports 2012; 60:1–51. http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf. Accessed April 10, 2014.
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  16. Jones PW, Adamek L, Nadeau G, Banik N. Comparisons of health status scores with MRC grades in COPD: implications for the GOLD 2011 classification. Eur Respir J 2013; 42:647–654.
  17. Divo M, Cote C, de Torres JP, et al; BODE Collaborative Group. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:155–161.
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References
  1. Miniño AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. National Vital Statistics Reports 2010; 59:1–52. http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_02.pdf. Accessed April 10, 2014.
  2. Murphy SL, Xu J, Kochanek KD. Deaths: preliminary data from 2010. National Vital Statistics Reports 2012; 60:1–51. http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_04.pdf. Accessed April 10, 2014.
  3. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3:e442.
  4. Behrendt CE. Mild and moderate-to-severe COPD in nonsmokers: distinct demographic profiles. Chest 2005; 128:1239–1244.
  5. Global Initiative for Chronic Obstructive Lung Disease (GOLD). http://www.goldcopd.org/Guidelines/guidelines-resources.html. Accessed April 10, 2014.
  6. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 2006; 173:1114–1121.
  7. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005; 60:925–931.
  8. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002; 57:847–852.
  9. Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010; 363:1128–1138.
  10. Cooper CB. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. Am J Med 2006; 119(suppl 1):21–31.
  11. Jones PW. Issues concerning health-related quality of life in COPD. Chest 1995; 107(suppl):187S–193S.
  12. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:1005–1012.
  13. Fletcher CM. The clinical diagnosis of pulmonary emphysema—an experimental study. J Royal Soc Med 1952; 45:577–584.
  14. Lange P, Marott JL, Vestbo J, et al. Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population. Am J Respir Crit Care Med 2012; 186:975–981.
  15. Hurst J. Phenotype-based care in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:935–936.
  16. Jones PW, Adamek L, Nadeau G, Banik N. Comparisons of health status scores with MRC grades in COPD: implications for the GOLD 2011 classification. Eur Respir J 2013; 42:647–654.
  17. Divo M, Cote C, de Torres JP, et al; BODE Collaborative Group. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:155–161.
  18. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106:196–204.
  19. Llor C, Moragas A, Hernández S, Bayona C, Miravitlles M. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186:716–723.
  20. Daniels JM, Snijders D, de Graaff CS, Vlaspolder F, Jansen HM, Boersma WG. Antibiotics in addition to systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 181:150–157.
  21. Rothberg MB, Pekow PS, Lahti M, Brody O, Skiest DJ, Lindenauer PK. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA 2010; 303:2035–2042.
  22. Vollenweider DJ, Jarrett H, Steurer-Stey CA, Garcia-Aymerich J, Puhan MA. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 12:CD010257.
  23. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007; 131:9–19.
  24. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002; 57:212–216.
  25. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med 1998; 157:1829–1832.
  26. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365:689–698.
  27. Gross NJ, Giembycz MA, Rennard SI. Treatment of chronic obstructive pulmonary disease with roflumilast, a new phosphodiesterase 4 inhibitor. COPD 2010; 7:141–153.
  28. Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009; 374:685–694.
  29. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long acting bronchodilators: two randomised clinical trials. Lancet 2009; 374:695–703.
  30. Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 1984; 129:856–870.
  31. Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008; 359:1543–1554.
  32. Cazzola M. Aclidinium bromide, a novel long-acting muscarinic M3 antagonist for the treatment of COPD. Curr Opin Investig Drugs 2009; 10:482–490.
  33. Gavaldà A, Miralpeix M, Ramos I, et al. Characterization of aclidinium bromide, a novel inhaled muscarinic antagonist, with long duration of action and a favorable pharmacological profile. J Pharmacol Exp Ther 2009; 331:740–751.
  34. Alagha K, Bourdin A, Tummino C, Chanez P. An update on the efficacy and safety of aclidinium bromide in patients with COPD. Ther Adv Respir Dis 2011; 5:19–28.
  35. Kerwin EM, D’Urzo AD, Gelb AF, Lakkis H, Garcia Gil E, Caracta CF; ACCORD I study investigators. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD 2012; 9:90–101.
  36. Jones PW, Singh D, Bateman ED, et al. Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J 2012; 40:830–836.
  37. Jones PW, Rennard SI, Agusti A, et al. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease. Respir Res 2011; 12:55.
  38. Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest 2012; 141:745–752.
  39. Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010; 11:149.
  40. Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999; 115:957–965.
  41. Campbell M, Eliraz A, Johansson G, et al. Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med 2005; 99:1511–1520.
  42. Hanrahan JP, Hanania NA, Calhoun WJ, Sahn SA, Sciarappa K, Baumgartner RA. Effect of nebulized arformoterol on airway function in COPD: results from two randomized trials. COPD 2008; 5:25–34.
  43. Neder JA, Fuld JP, Overend T, et al. Effects of formoterol on exercise tolerance in severely disabled patients with COPD. Respir Med 2007; 101:2056–2064.
  44. O’Donnell DE, Voduc N, Fitzpatrick M, Webb KA. Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004; 24:86–94.
  45. Rennard SI, Anderson W, ZuWallack R, et al. Use of a long-acting inhaled beta 2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163:1087–1092.
  46. Schultze-Werninghaus G. Multicenter 1-year trial on formoterol, a new long-acting beta 2-agonist, in chronic obstructive airway disease. Lung 1990; 168(suppl):83–89.
  47. Rodrigo GJ, Nannini LJ, Rodríguez-Roisin R. Safety of long-acting beta-agonists in stable COPD: a systematic review. Chest 2008; 133:1079–1087.
  48. Baker WL, Baker EL, Coleman CI. Pharmacologic treatments for chronic obstructive pulmonary disease: a mixed-treatment comparison meta-analysis. Pharmacotherapy 2009; 29:891–905.
  49. Rodrigo GJ, Castro-Rodriguez JA, Plaza V. Safety and efficacy of combined long-acting beta-agonists and inhaled corticosteroids vs long-acting beta-agonists monotherapy for stable COPD: a systematic review. Chest 2009; 136:1029–1038.
  50. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129:15–26.
  51. Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356:775–789.
  52. Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008; 31:927–933.
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Issue
Cleveland Clinic Journal of Medicine - 81(6)
Issue
Cleveland Clinic Journal of Medicine - 81(6)
Page Number
373-383
Page Number
373-383
Publications
Cleveland Clinic Journal of Medicine
Publications
Cleveland Clinic Journal of Medicine
Topics
Pulmonology
Drug Therapy
Article Type
Article
Display Headline
Chronic obstructive pulmonary disease: An update for the primary physician
Display Headline
Chronic obstructive pulmonary disease: An update for the primary physician
Sections
Reviews
Inside the Article

KEY POINTS

  • A new COPD classification scheme is based on severity, symptoms, and exacerbations.
  • Azithromycin 250 mg daily prevents exacerbations of COPD in those at high risk.
  • Long-acting muscarinic antagonists such as aclidinium and tiotropium are first-line therapy.
  • Relatively new options include roflumilast, an oral phosphodiesterase inhibitor, and indacaterol, an ultra-long-acting beta agonist that is taken once daily.
  • Nondrug interventions include pulmonary rehabilitation, vitamin D supplementation, noninvasive positive-pressure ventilation, and lung-volume reduction surgery.
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