SABD can be of 2 types: anti-cholinergics (SAMA, or short-acting muscarinic antagonists) such as ipratropium bromide, and short-acting beta-2 agonists (SABA) such as salbutamol or terbutaline, and are effective in the rapid control of symptoms. In patients with occasional symptoms, SABD reduce symptoms and improves exercise tolerance.23 These drugs, added to the baseline treatment, are preferred for on-demand treatment of symptoms, regardless of the level of severity of the disease. In patients with persistent symptoms or limitations in their daily activities as a result of their respiratory problem, regular baseline treatment with a LABD will be required.

LABD can be beta-2 adrenergics (salmeterol, formoterol, olodaterol, vilanterol and indacaterol – LABA, or long-acting beta-agonists) or anti-cholinergics (tiotropium, aclidinium, glycopyrronium, umeclidinium – LAMA, or long-acting muscarinic antagonists). They should be used as a first step in the treatment of all patients with persistent symptoms who require regular treatment, because they enable better control of symptoms than can be achieved with SABD, and improve both QoL and lung function.24–30 LABD, both LABA and LAMA, have also been shown to reduce the number of exacerbations.30

There are differences between the different LABDs; some have a duration of action of 12h (aclidinium, salmeterol and formoterol) and others 24h (tiotropium, umeclidinium, glycopyrronium, indacaterol, olodaterol and vilanterol). In terms of preventing exacerbations, tiotropium has been shown to be more effective than salmeterol in patients with COPD and a history of at least 1 exacerbation in the previous year.31 Tiotropium has also been shown to be superior to indacaterol in the prevention of exacerbations.32 For this reason, when choosing an LABD as monotherapy, a LAMA is recommended as first choice over a LABA.PICO Question. Which Bronchodilator Should be Recommended as Monotherapy?

Weak recommendation in favor: In patients with COPD who require a long-acting bronchodilator as monotherapy, treatment with a LAMA is recommended.

Specifications: The evidence analyzed is based on greater prevention of exacerbations in studies conducted with tiotropium (a LAMA). In patients with no exacerbations, there are no differences in the clinical efficacy between LAMA and LABA.

LABDs are generally well tolerated, and present few adverse effects. Nevertheless, the following should be considered. LABAs: fine tremor of the extremities, muscle cramps, tachycardia, high blood pressure, peripheral vasodilation, headache, hyperglycemia, hypokalemia, cough, bronchospasm, oropharyngeal irritation and dyspepsia. Treatment with LAMAs may be associated with dry mouth, urinary retention, increased ocular pressure and pharyngeal irritation. It should be noted that clinical trials exclude patients with significant heart disease, so clinicians must be vigilant when using new bronchodilators in these patients.

In symptomatic patients or those with clear exercise limitation despite bronchodilator monotherapy, dual bronchodilator therapy should be tried. In these cases, the combination of LABA and LAMA offers an added functional benefit, with less need for rescue medication and improvement in symptoms and QoL compared to monotherapy.33–35 For this reason, in a second treatment step in low-risk patients, two LABDs can be combined to optimize the bronchodilator effect. Existing combinations of LABD (LABA/LAMA) are presented in Table 4.

Initial treatment in a patient with high-risk non-exacerbator COPD is dual bronchodilation. This recommendation is based on evidence of superior bronchodilator efficacy compared to monotherapy, accompanied by a significant improvement in dyspnea and QoL, and a reduction in the use of rescue medication. Nevertheless, results obtained in the comparison of exercise capacity between dual bronchodilation and monotherapy are not as consistent.33,34 No direct comparisons have been made to date between the different LABA/LAMA combinations, and indirect comparative analyses do not permit identification of clear differences between them.35,37PICO Question. When Should Dual Bronchodilation (LABA/LAMA) be Used Instead of Single Bronchodilator Therapy?

Weak recommendation in favor: Treatment with dual bronchodilation provides superior bronchodilator efficacy, and is the treatment of choice in symptomatic patients (mMRC≥2) despite treatment with a single bronchodilator.

Specifications: In patients with severe or very severe spirometric impairment, therapy with dual bronchodilation is recommended over monotherapy to begin with, due to its greater effect on lung function.

Theophyllines, despite being weak bronchodilator drugs, present additive effects to those of common bronchodilators. These drugs have been reported to have a positive effect on diaphragm strength, increased performance of the respiratory muscles, reduction in gas trapping and improvement in mucociliary clearance.38 The usual dose is 200–300mg twice daily in sustained-release tablets. Their limited clinical efficacy and narrow therapeutic margin relegates them to third-line treatment, mainly in high risk patients who continue to be dyspneic following dual bronchodilator therapy.38

The toxicity of theophylline is dose-dependent. When administered on a long-term basis, plasma concentrations should be checked, and clinicians must take into account the risk of interactions with other drugs such as alopurinol, ciprofloxacin, erythromycin, benzodiazepines or cimetidine, among others.

A randomized clinical trial (RCT) compared dual indacaterol/glycopyrronium vs glycopyrronium with an open-label tiotropium treatment arm. The study population were patients with FEV1<50% predicted, who had had at least 1 exacerbation in the previous year. The results showed a significant 12% reduction in the rate of moderate or severe exacerbations (P=.038) compared to glycopyrronium. There was a numerical reduction compared to tiotropium, but this was not significant.45 This study showed that dual bronchodilation was superior to monotherapy in the prevention of exacerbations in COPD.

A subsequent RCT compared the same combination – indacaterol/glycopyrronium (LABA/LAMA) – vs salmeterol/fluticasone (LABA/ICS) in patients with COPD with FEV1 between 25% and 60% and at least 1 exacerbation in the previous year. The results showed a significant difference in favor of the indacaterol/glycopyrronium combination in the reduction of exacerbations of any degree of severity. Patients taking indacaterol/glycopyrronium also had a lower incidence of pneumonia.46 The results of both studies justify the choice of the combination LABA/LAMA as first-line therapy in the initial treatment of patients with COPD and exacerbator phenotype, except in patients with ACO. It should be remembered that in this latter RCT, patients with a history of asthma and those with blood eosinophilia greater than 600 cells per mm3 were excluded.46

ICS are indicated in patients who present frequent exacerbations despite optimal bronchodilator treatment, because their use combined with a LABA results in a significant decrease in the number of exacerbations and an improvement in QoL.47,48 In COPD, ICS should always be used in combination with a LABD, usually a LABA. The various combinations of LABA/ICS available are presented in Table 4.

Recent sub-analyses of RCTs of LABA/ICS combinations for the prevention of COPD exacerbations have shown that the greatest preventive effect of ICS is achieved in patients with high levels of blood eosinophils.49,50 Furthermore, the risk of pneumonia with the use of ICS in COPD seems to be higher in patients with low eosinophil levels.51 However, these results have not yet been demonstrated in prospective studies designed specifically to that end, nor is there a universally accepted cut-off point for blood eosinophilia to recommend or not the use of ICS in COPD. For this reason, and because registration studies on the LABA/ICS combination did not differentiate between patients with and without eosinophilia, the use of ICS cannot yet be advised against in exacerbator patients with low peripheral blood eosinophil counts, although low efficacy is expected in these cases.42

A balance must be sought between the beneficial effects of ICS and their possible adverse effects. Side effects such as oral thrush, dysphonia, hematomas, reduction in bone mineral density and pneumonia have been observed in large RCTs, although with no increase in mortality.52 Although the risk of pneumonia is greater in patients who take high-dose fluticasone, an increased risk of pneumonia has also been observed associated with the use of budesonide, but of a lesser magnitude.53,54PICO Question. What is the Treatment of Choice in Symptomatic Patients With Exacerbations? LABA/ICS or Dual LABA/LAMA Bronchodilation?

Weak recommendation in favor: In patients who are symptomatic despite a LABD, especially if they present exacerbations, treatment with dual bronchodilation (LABA/LAMA) is preferred over treatment with LABA/ICS.

Specifications: The superior efficacy of LABA/LAMA compared to LABA/ICS in the prevention of exacerbations has been demonstrated with indacaterol/glycopyrronium vs salmeterol/fluticasone.

In high risk patients who do not present good control of exacerbations with 2 drugs (either 2 LABDs or an LABD+ICS), triple therapy with LAMA/LABA/ICS can be used. The few existing studies with triple therapy suggest a greater effect on lung function43 and a decrease in exacerbations and hospital admissions in patients with severe COPD.43,55,56 These effects are evident when a LAMA is added to the LABA/ICS combination,57–59 although greater efficacy when an ICS is added to the LABA/LAMA combination is not clear.55,56 The most important aspect of triple therapy is to determine its efficacy compared to dual bronchodilator therapy (LABA/LAMA).

Long-term use of carbocysteine significantly reduces the number of exacerbations, delays worsening of symptoms and improves QoL in patients with COPD, compared to placebo.60 N-acetylcysteine (NAC) at doses of 600mg daily can reduce the number of exacerbations in patients not treated concomitantly with ICS.61 More recent studies with high-dose NAC (600mg twice daily) have shown a significant reduction in exacerbations, especially in high-risk patients (those with FEV1<50% or with 2 or more exacerbations in the previous year, or both).62,63

Both drugs have an excellent tolerance and safety profile. Although their main mechanism of action suggests that the use of mucolytics should be reserved for exacerbator patients with chronic bronchitis, clinical trials have not selected patients based on the presence of chronic expectoration, so we cannot rule out the possibility that their potential antioxidant action might also prevent exacerbations in patients with exacerbator phenotype with emphysema.PICO Question. When Should Mucolytics be Used to Prevent Exacerbations?

Weak recommendation in favor: In patients with COPD exacerbator phenotype despite adequate treatment, it is suggested that a high-dose mucolytic be added.

Specifications: The costs associated with treatment with mucolytic agents should be discussed with the patient (this treatment is currently not reimbursed in Spain).

Roflumilast is an oral anti-inflammatory drug that acts by selective inhibition of phosphodiesterase-4. It has been shown to prevent exacerbations in patients with severe COPD who present chronic cough and sputum production, and also suffer frequent exacerbations.65 This effect is maintained when roflumilast is added to maintenance treatment with an LABD, either LABA or LAMA. It also achieves a significant increase in trough FEV1 (between 50 and 70mL on top of that achieved with salmeterol or tiotropium).65,66 The effect of roflumilast in the prevention of exacerbations has been observed even when added to triple therapy (LABA/LAMA/ICS).67 A recent study has shown that this medication is more effective in reducing exacerbations in patients with more severe COPD who require hospital admission.68 The usual dose is 500μg orally once daily.

Adverse effects with roflumilast usually appear at the start of treatment, are rapidly detected by the patient and usually disappear within the first 4 weeks, although they may occasionally lead to discontinuation of the drug. The most common adverse effects are weight loss, gastrointestinal disturbances, nausea, headache and loss of appetite. The safety profile of roflumilast is not modified by any concomitant treatment that the patient may be taking for their COPD. The use of roflumilast with theophyllines should be avoided.PICO Question. When Should Roflumilast be Used to Prevent Exacerbations?

Weak recommendation in favor: Roflumilast has been suggested as a second-line drug to prevent exacerbations in patients with the exacerbator phenotype with chronic bronchitis and severe airflow limitation.

Specifications: Due to its safety profile, tolerance to the drug may be poor, and physicians should aware of the possible onset of adverse effects.

Long-term treatment with macrolides is indicated in high-risk patients with at least 3 exacerbations in the previous year despite adequate inhaled therapy.69,70

Macrolides administered on a long term basis have been shown to significantly reduce the number of exacerbations in stable patients with severe COPD.71 The regimens used were: erythromycin 250mg twice daily for 1 year,72 azithromycin 500mg daily for 3 days a week for 1 year,69,73 and azithromycin 250mg daily for 1 year.74 The results of all these studies have consistently shown a significant reduction in exacerbations. However, the study populations and regimens were different, so it is difficult to make a recommendation. It should be noted that in the study by Albert et al.,74 increased bacterial resistance to macrolides and an increase in hearing problems were found in patients treated with azithromycin. Due to its similarity to regimens used in patients with bronchiectasis, the recommended dose is azithromycin 250 or 500mg daily for 3 days a week for 1 year, repeated in successive winter periods (from November to May) if response is positive (absence of exacerbations). This treatment should be reserved for reference centers with clinical, auditory, liver biochemistry and microbiological monitoring, with identification of microorganisms in sputum and antibiotic susceptibility testing.70 There is no evidence of the efficacy of this treatment beyond 1 year of follow-up, so the possible risk-benefit should be evaluated annually.70PICO Question. When Should Long-Term Macrolides be Used to Prevent Exacerbations?

Weak recommendation in favor: In patients with COPD with an exacerbator phenotype, with at least 3 exacerbations in the previous year despite adequate treatment, long-term treatment with macrolides is recommended.

Specifications: The authors believe that this indication should be restricted to patients with frequent exacerbations and a severe degree of obstruction. Once selected, possible treatment-associated adverse effects such as prolongation of the QT interval, hearing loss or generation of resistances should be strictly monitored.

The use of quinolones during periods of stability has been shown to eradicate the bacteria present in the sputum in most patients with severe COPD and frequent exacerbations.75 One RCT evaluated the efficacy of cyclical administration of moxifloxacin (400mg daily for 5 days every 2 months) for 1 year in patients with stable COPD.76 The results showed that the treatment significantly reduced 45% of exacerbations in patients who presented purulent or mucopurulent sputum, i.e. those with a higher probability of suffering a chronic bacterial bronchial infection.

Since quinolones are the preferred therapy in the treatment of exacerbations in patients with severe COPD, it is important to preserve this class of antibiotics, so the long-term use of quinolones with a preventive objective is not recommended.PICO Question. When Should Long-Term Quinolones be Used to Prevent Exacerbations?

Strong recommendation against: In patients with COPD in a stable phase, administering chronic treatment with fluoroquinolones in order to prevent exacerbations is not recommended.

Specifications: The group drafting the guidelines agrees with rationalizing the use of fluoroquinolones, and that they should not be indicated as a preventive regimen for exacerbations due to the risk of development of bacterial resistance.

Patients who are candidates for long-term antibiotic treatment are those with a high likelihood of having bronchiectasis. Bronchiectases can help perpetuate a vicious circle, amplifying the underlying inflammation and inducing the presence of frequent exacerbations,18,77 and are even associated with higher mortality.78 In patients with COPD and bronchiectasis, the infectious component should be treated according to bronchiectasis treatment guidelines.79

Long-term home oxygen therapy (LTOT) is a treatment that improves survival in patients with COPD and respiratory failure.80 It has also been shown to reduce the number of exacerbations and hospitalizations, and to improve exercise capacity and QoL.81 The benefits achieved with oxygen therapy depend on the duration of treatment. LTOT should be given for at least 16h daily, in order to maintain a resting PaO2≥60mmHg or oxygen saturation ≥90% at sea level. The therapy is indicated when the disease is in a stable phase, and should be based on arterial blood gases (Table 5).

The use of LTOT in patients with intermittent hypoxemia, such as the hypoxemia that appears during sleep, or in patients with mild to moderate hypoxemia at rest or during exercise, has failed to show effects on survival or time to first hospital admission or other clinical parameters, so it is not recommended.82 In the absence of criteria for LTOT, nocturnal oxygen therapy can be considered in patients with proven nocturnal oxyhemoglobin desaturation (<90% for at least 30% of the total recording time) and sequelae related with the hypoxia (polycythemia or signs of right-sided heart failure). Continuous positive airway pressure (CPAP) or mechanical ventilation should be considered,83 which can replace or complement the oxygen therapy, but sleep apnea syndrome must be ruled out.

Portable oxygen therapy improves the ability of patients with severe COPD to exercise. It can be used in cases of limitation due to dyspnea and with desaturations of less than 88% in the walk test.84 The improvement obtained in both the dyspnea and the distance walked should be re-evaluated in the first 2 months.84 Nevertheless, further studies are required to define the benefits.

Augmentation treatment with purified alpha-1 antitrypsin (AAT) is recommended by the leading scientific societies (American Thoracic Society, European Respiratory Society and SEPAR)85,86 in patients with pulmonary emphysema with severe AAT deficiency and homozygous PiZZ phenotype or rare deficiency variants, due to their effect in slowing the loss of lung density measured by HRCT. The RAPID study is the largest RCT conducted to date to evaluate the efficacy of augmentation treatment in slowing the progress of emphysema in patients with severe AAT deficiency.87 The results showed that after 2 years of follow-up, lung density loss measured by HRCT was significantly less in patients on treatment vs patients in the placebo group. Moreover, the study had an open-label extension phase for a further 2 years, in which patients who had been on placebo received active treatment. The authors observed that active treatment significantly slowed disease progression in relation to the previous 2-year period with placebo. Nevertheless, the excess lung density loss that they suffered during the 2 years with placebo did not recover. This suggests the importance of early identification and treatment of patients at risk of rapid disease progression to prevent lung damage.88 Their inclusion and exclusion criteria are well defined in the guidelines specified.85,86

Serum alpha-1 antitrypsin levels should be measured at least once in all patients with COPD. After identifying a patient with AAT deficiency, a family study should be carried out to identify possible undiagnosed cases.85,86 Any cases detected must be reported to the Spanish Registry of Patients with Alpha-1 Antitrypsin Deficiency,89 and they should be referred to a reference center for complete diagnosis and assessment for possible augmentation therapy and a family study.