Chronic obstructive pulmonary disease: An update for the primary physician
ABSTRACTOur understanding of how to manage chronic obstructive pulmonary disease (COPD) has advanced significantly over the past decade. Physicians should instill optimism for improved symptoms and quality of life in their patients with COPD, a previously stigmatized condition.
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.
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.
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
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.
