Chronic%20obstructive%20pulmonary%20disease Treatment

• Goals of therapy
  • Prevention and control of symptoms
  • Reduction of the frequency and severity of exacerbations
  • Improvement of health status
  • Improvement of exercise tolerance

• Drug therapy for COPD is determined by individualized assessment of symptoms and exacerbation risk
• Based on studies, the existing pharmacotherapy for COPD do not modify the long-term decline in lung function; however, limited evidence suggests that regular treatment with long-acting beta₂-agonists, inhaled corticosteroid and its combination can decrease the rate of decline in lung function

Initial Treatment

• The following table summarizes treatment recommendations by patient category of COPD:

Patient Category	Recommended Initial Treatment*
A	Either short- or long-acting bronchodilator
B	Long-acting anticholinergic or long-acting beta2-agonist monotherapy
C	Long-acting anticholinergic monotherapy
D	Long-acting anticholinergic or Long-acting anticholinergic+ long-acting beta2-agonist1 or Inhaled corticosteroid2 + long-acting beta2-agonist

*Reference: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2022 report.
¹Combination treatment with long-acting anticholinergic and long-acting beta₂-agonist reduces exacerbations compared to monotherapy and can be used in patients with more severe dyspnea.
²Inhaled corticosteroid may be added to the regimen for patients who continue to have frequent exacerbations (≥2 exacerbations or >1 hospitalization) for the past year or who have blood eosinophilia ≥300 cells/μL; although, it may increase the risk for pneumonia.

Follow-up Treatment

• Should be based on the predominant symptom, either for dyspnea or persistent exacerbations, irrespective of the patient's GOLD grouping 
• Inhaler technique and treatment adherence should be investigated in every follow-up
• Patients may be considered for an additional long-acting bronchodilator if breathlessness or exercise limitation is still present despite inhaled bronchodilator monotherapy
• Dual combination therapy with 2 long-acting inhaled bronchodilators or long-acting beta₂-agonist plus an inhaled corticosteroid should be considered in patients previously given short-acting bronchodilators or long-acting inhaled bronchodilator monotherapy who show disease progression
• Triple combination therapy should be offered to patients with disease progression despite treatment with a bronchodilator and corticosteroid combination therapy
• Roflumilast or Azithromycin may be given to patients suffering from persistent exacerbations previously given bronchodilator combination therapy and with eosinophil count of <100 cells/μL
• Roflumilast should be considered in patients with FEV₁ <50% predicted and chronic bronchitis
• Azithromycin may be added for patients who are ex-smokers

Recommended Follow-up Regimens After Initial Therapy Based on Predominant Symptom: Dyspnea

Adjust therapy based on current maintenance therapy
Initial Therapy	Follow-up Therapy
Long-acting anticholinergic or long-acting beta2-agonist	Long-acting anticholinergic + long-acting beta2-agonist
Long-acting anticholinergic + long-acting beta2-agonist	Consider switching agents or devices Investigate and treat other etiologies
Long-acting beta2-agonist + inhaled corticosteroid	Triple therapy: Long-acting anticholinergic + long-acting beta2-agonist + inhaled corticosteroid combination or Long-acting anticholinergic + long-acting beta2-agonist1 Consider switching agents or devices Investigate and treat other etiologies

¹For patients with adverse effects (eg pneumonia) or unresponsive to inhaled corticosteroids, or if initial indication is unclear

Recommended Follow-up Regimens After Initial Therapy Based on Predominant Symptom: Exacerbations or Both Dyspnea and Exacerbations

Adjust therapy based on current maintenance therapy
Initial Therapy	Follow-up Therapy
Long-acting anticholinergic or long-acting beta2-agonist	Long-acting anticholinergic + long-acting beta2-agonist Long-acting beta2-agonist + inhaled corticosteroids1
Any dual-agent combination therapy	Switch agents Triple therapy Add Roflumilast or Azithromycin if eosinophil count <100 cells/µL
Triple therapy	Add Roflumilast Add Azithromycin Discontinue inhaled corticosteroids2

¹Consider in patients with blood eosinophil count ≥300 cells/microliter or with ≥100 cells/microliter and ≥2 moderate exacerbations per year or 1 severe exacerbation requiring hospitalization
²For patients with adverse effects (eg pneumonia) or unresponsive to inhaled corticosteroids, or if initial indication is unclear

Bronchodilators

• Classes (listed alphabetically): Anticholinergics, beta₂-agonists, methylxanthines
• All bronchodilators increase exercise capacity
• Inhaled bronchodilators are recommended for all symptomatic patients with stable COPD with FEV₁ of <60%
  • May also be used for symptomatic stable COPD patients with predicted FEV₁ of 60-80%
  • Inhaled therapy is preferred to oral, because of better efficacy, faster onset and decreased likelihood of adverse effects

• Short-acting bronchodilators are given on a “when required” basis for immediate relief of symptoms and long-acting bronchodilators are administered on a regular basis to prevent or reduce symptoms
• Regular treatment with long-acting bronchodilators is more effective and convenient but can be more expensive
  • When possible, therapy should be via the inhaled route but if cost is a barrier, then oral bronchodilators (beta₂-agonists) can be considered
  • Inhaled bronchodilators are preferred to Theophylline because of the latter’s low bronchodilating effect and high potential for toxicity

• Choice of drugs will depend on the patient’s response and preference, together with drug’s side effects and cost

Anticholinergics

• Eg Long-acting: Aclidinium, Glycopyrronium, Tiotropium, Umeclidinium; Short-acting: Ipratropium, Oxitropium
• Block the effects of acetylcholine on M2 and M3 (short-acting), and M1 and M3 (long-acting) receptors
• Long-acting inhaled anticholinergics are recommended for symptomatic patients with FEV₁ of <60% predicted
• Short-acting anticholinergics generally have a longer duration of bronchodilatation than short-acting beta₂-agonists
• Based on a large, long-term, randomized, controlled study in patients with moderate to very severe COPD, Tiotropium with concurrent respiratory medication other than another inhaled anticholinergic agent, resulted in the following benefits:
  • Positive effects on quality of life
  • Reduced risk of exacerbations and exacerbation-related hospitalizations
  • Reduced respiratory morbidity including respiratory failure and cardiac morbidity

• Have been shown to be very safe at a wide range of doses
• Based on short-term, clinical studies in patients with moderate to severe COPD, combination of short-acting anticholinergic and short-acting beta₂-agonist may provide superior bronchodilatation than either medication alone
• Aclidinium and Glycopyrronium have effects on lung function and breathlessness comparable to that of Tiotropium but further studies are needed

Beta₂-agonists

• Eg Long-acting: Arformoterol, Formoterol, Indacaterol, Olodaterol, Salmeterol, Tulobuterol, Vilanterol (given as combination therapy); Short-acting: Fenoterol, Levalbuterol, Salbutamol (Albuterol), Terbutaline
• Long-acting inhaled beta₂-agonists are recommended for symptomatic patients with FEV₁ of <60% predicted
• Relax airway smooth muscle by stimulating beta₂-adrenergic receptors
• Salmeterol and Formoterol significantly improves FEV₁, lung function, dyspnea, quality of life and exacerbation rate
• Vilanterol, in combination with Umeclidinium or Fluticasone, showed improved lung function and slower decline in FEV₁
• Based on several clinical trials, combination of long-acting beta₂-agonists (eg Salmeterol) and inhaled corticosteroids (eg Fluticasone) may reduce COPD exacerbation and may improve lung function and quality of life better than when each drug is used alone
• Inhaled beta₂-agonists have a faster onset of action and less side effects than oral preparations

Methylxanthines

• Eg Aminophylline, Theophylline
• May act as non-selective inhibitor of phosphodiesterase, but have also been observed to exert a range of non-bronchodilator actions
• Though have modest effect in COPD, inhaled bronchodilators are preferred to Theophylline, owing to the latter’s poor bronchodilating property and potential toxicity
• Combination of a beta₂-agonist, an anticholinergic and Theophylline may produce additional improvements in health status and lung function
• All studies that have shown efficacy of Theophylline in COPD made use of slow-release preparations

Combination Bronchodilator Therapy

• Available as single inhaler are Fenoterol/Ipratropium, Salbutamol/Ipratropium, Formoterol/Aclidinium, Formoterol/Glycopyrronium, Indacaterol/Glycopyrronium, Vilanterol/Umeclidinium, Olodaterol/Tiotropium
• Bronchodilator-corticosteroid combinations (eg Formoterol/Beclometasone, Formoterol/Budesonide, Formoterol/Mometasone, Salmeterol/Fluticasone propionate, Vilanterol/Fluticasone furoate, Fluticasone/Umeclidinium/Vilanterol, Beclometasone/Formoterol/Glycopyrronium, Budesonide/Formoterol/Glycopyrrolate) are also available
• Combination therapy with inhaled long-acting anticholinergics, long-acting beta₂-agonists, or corticosteroids are recommended for symptomatic patients with stable COPD and FEV₁ of <60% predicted
• Combining drugs with different mechanisms of action may increase bronchodilatation with less side effects compared to simply increasing the dose of a bronchodilator
• Compared to monotherapy combination treatment of short-acting beta₂-agonist and short-acting anticholinergics improves FEV₁ and symptoms
• Compared to monotherapy combination treatment of long-acting beta₂-agonist and long-acting anticholinergics increases FEV₁, decreases symptoms and reduces exacerbation

Corticosteroids

• Eg Inhaled: Beclomethasone, Budesonide, Fluticasone, Mometasone; Systemic: Prednisolone, Methylprednisolone
• Regular treatment with inhaled corticosteroids alone does not change the long-term decline of FEV₁
• Regular treatment with inhaled corticosteroids is appropriate in patients with FEV₁ <50% predicted or ≥2 exacerbations/year and repeated exacerbations (eg 3 exacerbations in the last 3 years)
  • May reduce airway hyper-reactivity in these patients and decrease symptoms of COPD including exacerbations

• Inhaled corticosteroid in combination with 1 or 2 long-acting bronchodilators is recommended in patients with:
  • History of hospitalizations for COPD exacerbations despite appropriate maintenance therapy with long-acting bronchodilator
  • ≥2 moderate COPD exacerbations per year despite appropriate maintenance therapy with long-acting bronchodilator
  • History of, or concomitant asthma
  • Blood eosinophil count >300 cells/microliter

• In patients with more advanced COPD and repeated exacerbation, treatment with inhaled corticosteroids can be beneficial
• Dose-response relationships and long-term safety of inhaled corticosteroids in COPD are not known
• On a 3-year period treatment in COPD patients with high prevalence of osteoporosis, therapy with high-dose Fluticasone alone or in combination with Salmeterol was not associated with decreased bone mineral density (BMD) compared with placebo
  • Previous long-term trials investigating BMD in COPD patients produced conflicting results

• The use of combination therapy with inhaled corticosteroids and long-acting beta₂-agonist is more effective in reducing exacerbations and improving pulmonary function than either medication alone
  • In patients with FEV₁ <60%, treatment with long-acting beta₂-agonist, inhaled corticosteroids and its combination have been shown to reduce the rate of decline of pulmonary function; addition of the combination to an anticholinergic (eg Tiotropium) appears to provide additional benefits

• Addition of a long-acting anticholinergic to combination therapy of inhaled corticosteroid and long-acting beta₂-agonist (triple inhaled therapy) has been shown to improve lung function, symptoms and health status, and reduce exacerbations compared to combination therapy of inhaled corticosteroid and long-acting beta₂-agonist, long-acting beta₂-agonist and long-acting anticholinergic, or monotherapy with a long-acting anticholinergic
• Long-term monotherapy with inhaled corticosteroids is not recommended 
• Long-term use of oral corticosteroids is not recommended
• Short-course trials of oral corticosteroids may not reliably predict which patients will respond to inhaled corticosteroids

Phosphodiesterase-4 Inhibitor

• Eg Roflumilast
• Reduce inflammation through inhibition of the breakdown of intracellular cyclic AMP
• Has no direct bronchodilator effects but has been shown to improve FEV₁ in patients treated with Tiotropium or Salmeterol
• Roflumilast has been shown to reduce exacerbations in patients with severe to very severe COPD (FEV₁ <50% predicted) with chronic bronchitis treated with oral corticosteroids
  • Same effect on exacerbation reduction has been noted when added to long-acting bronchodilators

• Roflumilast can not be administered with Theophylline
• Has more side effects compared to inhaled medications

Other Pharmacologic Agents

Alpha-1 Antitrypsin Augmentation Therapy

• May help halt the development and progression of pulmonary disease in patients with AATD
• Studies demonstrated a reduction in spirometric progression with alpha-1 antitrypsin augmentation therapy in patients with FEV₁ 35-49% predicted 
• Especially recommended for nonsmoking patients or those who stopped smoking with FEV₁ 35-60% predicted
• Further studies are needed to prove the efficacy versus cost of this treatment

Antibiotics

• Not recommended except for treatment of infectious bacterial exacerbations
• Treatment with macrolides (eg Azithromycin) may be considered for previous smokers with moderate to severe exacerbations despite inhaled bronchodilator therapy

Cough and Cold Preparations

• Eg Ambroxol, Carbocysteine, Erdosteine, N-acetylcysteine
• Antitussives are not recommended because cough has a protective effect in COPD
• Expectorants and mucolytics were seen to have benefits in few patients with viscous mucous, but overall benefits seem to be very small
  • May be considered in patients with chronic cough productive of sputum
  • Therapy may be continued if there is a decrease in the frequency of cough and sputum production

• Regular treatment with Carbocysteine or N-acetylcysteine may help reduce exacerbations in COPD patients without inhaled corticosteroid treatment

Vaccines

Influenza Vaccine

• May decrease morbidity and mortality rates due to influenza
• Should be given yearly, 1-2 months prior to anticipated peak influenza season, because of new antigens and waning immunity from the previous years
• Associated with reduced risk of all-cause mortality

Pneumococcal Vaccines

• Eg 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPSV23)
• Recommended in COPD patients ≥65 years old and in younger patients with significant comorbidities (eg cardiac disease, chronic pulmonary disease)
• PPSV23 reduces occurrence of community-acquired pneumonia (CAP) in patients <65 years old with FEV₁ <40% predicted or comorbidities
• Studies showed that PCV13 exhibited significant efficacy for both CAP and vaccine-type invasive pneumococcal disease in adults ≥65 years old with efficacy lasting for at least 4 years
  • Possesses comparable or even greater efficacy when compared to the immunogenicity of PPSV23
• Generally given only once, but revaccination may be considered in 5-10 years

COVID-19 Vaccines

• Highly effective against SARS-CoV-2 infection requiring hospitalization
• Patients with COPD should be vaccinated in line with national recommendations for COVID-19 vaccination

Inhalation Devices

• Effective drug delivery and training in inhaler technique should be emphasized and re-checked as necessary
• Choice of device depends on price, availability, the prescribing doctor, and the skills and ability of the patient
• Metered dose inhaler (MDI)
  • COPD patients may have poorer coordination and experience more difficulty with MDI use
  • Use of spacers with the MDI may be advised for patients who find it hard to master MDI inhaler technique

• Dry powder inhaler (DPI)
  • Breath-activated and may therefore require less hand-and-mouth coordination
  • May be more convenient and may provide improved deposition of the drug

• Nebulizer
  • Not recommended for routine use because of greater cost of treatment

• Assessment of inhaler technique should be done prior to modifying current therapy

ACUTE EXACERBATION OF COPD
Bronchodilators

• Long-acting selective beta₂-agonist bronchodilators include Arformoterol, Bambuterol, Formoterol, Indacaterol, Olodaterol, Salmeterol and Tulobuterol
• Short-acting selective beta₂-agonist bronchodilators include Clenbuterol, Fenoterol, Hexoprenaline,Levalbuterol, Orciprenaline, Procaterol, Salbutamol (Albuterol), Terbutaline and Trimetoquinol
• Long-acting anticholinergic bronchodilators: Aclidinium, Glycopyrronium, Tiotropium, Umeclidinium
• Short-acting anticholinergic bronchodilators: Ipratropium, Oxitropium

Hospital Management

• Short-acting inhaled beta₂-agonists, with or without short-acting anticholinergics are typically preferred for treating acute COPD exacerbations
• An anticholinergic may be added if the patient does not respond immediately to short-acting inhaled beta₂-agonists
• Long-acting bronchodilators can be used with or without inhaled corticosteroids during exacerbation or as a maintenance therapy that should be started as soon as possible before hospital discharge

Home Management

• The dose and/or frequency of ongoing bronchodilator treatment should be increased
• An anticholinergic, if not yet in use, may be added until improvement is noted
• High-dose nebulized therapy may be given when required for several days
  • Long-term use of nebulizer therapy after an exacerbation is not recommended

Corticosteroids

• Improves oxygenation and lung function, and reduces risk for relapse, treatment failure and length of hospital stay

Hospital Management

• Oral or IV corticosteroids are recommended as an addition to bronchodilator therapy, in the absence of significant contraindications
  • Oral route is preferred, as no significant difference in efficacy was seen when compared to parenteral administration
  • IV route may be used in patients with severe exacerbation and with contraindications for oral medications

• Shorten recovery time and help hasten restoration of lung function
• Duration of therapy with oral corticosteroid must not exceed 5-7 days, as there is no advantage to prolonged therapy and the risk of side effects is increased

Home Management

• Addition of oral corticosteroid to existing bronchodilator therapy may be considered if patient’s baseline FEV₁ is <50% predicted
• Nebulized Budesonide alone or in combination with Formoterol may be used as an alternative to oral corticosteroids; may cause significant reduction of complications (eg hyperglycemia)

Antibiotics

• Given in patients who presents with increased purulence of sputum together with increase in dyspnea and sputum volume or in patients who need mechanical ventilation
• May reduce recovery time, interval to relapse, treatment failure, and duration of hospital stay
• Local antibiotic sensitivity patterns for Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis must be taken into account when choosing an antibiotic agent
• Recommended oral antibiotic agents include:
  • 1st-line: Amoxicillin, Doxycycline and Clarithromycin
  • 2nd-line: Co-amoxiclav, Levofloxacin, Co-trimoxazole, Azithromycin, Cefuroxime axetil
    • Given if no improvement seen or with clinical deterioration after 72 hours of treatment initiation

• Recommended IV antibiotic agents include Co-amoxiclav, Clarithromycin, Piperacillin/tazobactam
• Recommended duration of antibiotic therapy is 5-7 days

Heparin (SC/Low Molecular Weight)

• Consider administration of SC/LMW Heparin to reduce the risk of pulmonary embolism in patients with polycythemia or dehydration, with or without a history of thromboembolic disease

Pulmonary Rehabilitation

• Multidisciplinary program for patients with chronic respiratory impairment that is individually designed to maximize a patient’s physical and social performance and autonomy
  • In regions with limited resources, simplified pulmonary rehabilitation programs are useful and are recommended

• Includes exercise training, nutrition counseling, education and psychological support
• Recommended for symptomatic patients with FEV₁ of <50% predicted
  • May also be considered in symptomatic patients with FEV₁ of >50% predicted with exercise limitations, patients with mMRC >1, and following acute exacerbations
  • Program should last 6-8 weeks to be effective; no additional benefit is seen in extending the program to 12 weeks

• In- or outpatient pulmonary rehabilitation is effective in improving clinically relevant outcomes; however, there are challenges encountered in the delivery (eg scarce in-person programs, COVID-19 pandemic)
  • As an alternative, tele-rehabilitation (eg video conferencing, mobile application with feedback, telephone calls) has been proposed

Site of Care

Please refer to the Symptom and Risk Evaluation of COPD table for characteristics per patient category

• Patients belonging to category A or B may be managed on an outpatient basis during exacerbations
• Patients belonging to category C or D may require hospitalization and more aggressive management during exacerbations

Indications for Hospital Treatment for Chronic Obstructive Pulmonary Disease Exacerbations

• Significant increase in signs and symptoms (eg sudden development of resting dyspnea, SaO₂ <90%, changes in chest X-ray, arterial pH <7.35, arterial PaO^₂ <7 kPa, <53 mmHg)
• Acute lung failure
• Onset of new symptoms (eg cyanosis, peripheral edema, impaired level of consciousness)
• Absence of response to initial medical treatment
• Significant comorbidities (eg heart failure or newly occurring arrhythmias)
• Frequent exacerbations
• Older age
• Lack of home support