Ways to reduce the frequency of exacerbations of COPD: anti-inflammatory therapy, immunoregulators, pulmo-rehabilitation
Chronic obstructive pulmonary disease (COPD) is a progressive disease with occasional exacerbations. Exacerbations adversely affect the patient’s quality of life, worsen the symptoms and lung function, and a return to the initial level may take several weeks, accelerate the rate of decline in lung function, and are associated with significant mortality.
In 2013, the COB classification was updated. Now it takes into account not only the severity of bronchial obstruction, determined using spirometry (light – forced expiratory volume in 1 second (FEV1)> 80% of due, moderate – 50–79% of due, heavy – <50% and> 30% of due, extremely severe – <30% of due), but also takes into account the severity of symptoms (“less” or “more”), assessed by the mMRC scale (modified scale of dyspnea by the Medical Research Council), CCQ questionnaires (Clinical COPD Questionnaire) and CAT (COPD Assessment Test), as well as the risk of exacerbations, more rapid progression of the disease and death. The risk level is assessed either by spirometry (severe / very severe airway obstruction determines increased risk), or exacerbation history (> 2 exacerbations per year determine increased risk). Based on these criteria, each patient can be assigned to one of four groups: A (with a low risk of exacerbations, fewer symptoms); B (low risk, more symptoms); C (high risk, fewer symptoms) and D (high risk, more symptoms). Frequent exacerbations (> 2 per year) have been described as a separate COPD phenotype associated with a worse prognosis.
Due to the above reasons, prevention of exacerbations is a key task in managing patients with COPD.
Therapeutic measures that reduce the number of exacerbations and hospitalizations include: stopping smoking, informing the patient about the therapy being conducted, including the technique of inhalation, treatment with prolonged action inhaled bronchodilators (long-acting beta2-agonists, DBA, long-acting anticholinergic drugs, DDAHP) in combination with inhaled glucocorticosteroids (iGX) or without them, as well as treatment with a phosphodiesterase-4 inhibitor (iFDE-4), vaccination against influenza and pneumococcal infection ktsii and early connection of pulmonary rehabilitation.
Anti-inflammatory therapy – roflumilast
The frequency of exacerbations in patients with COPD is associated with the severity of inflammation. Despite the fact that long-acting bronchodilators and inhaled corticosteroids can reduce the number of exacerbations, in some patients this therapy does not allow for adequate control of the disease. The main effect of IFDE-4 is to suppress inflammation by blocking the breakdown of intracellular cyclic adenosine monophosphate, a nucleotide that regulates the function of proinflammatory, immune and structural cells (neutrophils, endothelial and epithelial cells of the respiratory tract, smooth muscle cells of the respiratory tract and vessels, fibroblasts). Roflumilast is the first in its class selective iFDE-4 with a pronounced anti-inflammatory effect, demonstrated both in vitro and in vivo. Under the name Daxas, the drug was registered in 2010 in the European Union and in 2011 in Russia, in the USA as Daloresp in 2011.
Roflumilast is a tableted oral medication, for administration 1 time per day in a dosage of 500 mg, it is well combined with all known inhalation drugs used in long-term maintenance treatment of COPD, and does not interact with oral administration (montelukast, digoxin, warfarin, sildenafil and midazolam, antacid drugs). The use of powerful cytochrome P450 inducers (rifampicin, phenobarbital, carbamazepine, phenytoin) can lead to a decrease in the therapeutic effect of roflumilast. Combined use of roflumilast with cytochrome CYP1A2 inhibitor fluvoxamine and CYP3A4 and CYP31A2 inhibitors enoxacin and cimetidine is not recommended (may lead to increased action and development of intolerance) . Do not prescribe roflumilast in combination with theophylline. The most frequent side effects are gastrointestinal disorders, weight loss, psycho-emotional disorders (headache, insomnia, depression).
The effectiveness of roflumilast enhancing the effect of both prolonged bronchodilators and inhaled corticosteroids in improving lung function and reducing the frequency and risk of exacerbations in patients with moderate to severe COPD has been proven in a large number of clinical randomized, placebo-controlled studies, as well as meta-analyzes of research results in recent years. Moreover, anti-inflammatory therapy with roflumilast can transform the phenotype of patients with COPD with frequent exacerbations into a more stable category with infrequent exacerbations, as shown by a cumulative analysis of data from two annual placebo-controlled studies.
Based on the history of exacerbations for the previous year, the patients were divided into two groups: with frequent exacerbations (? 2 during the previous year) and infrequent exacerbations (<2). In the group of frequent exacerbations, only in 32.0% of patients who received roflumilast during the year was it observed? 2 exacerbations, whereas when taking a placebo, the figure was 40.8% (relative risk (RR) 0.799; p = 0.0148); that is, 68% of patients after 12 months of treatment with roflumilast moved from the group of frequent exacerbations to the group of infrequent exacerbations. The risk of remaining in the group of frequent exacerbations was lower by 20% when treated with roflumilast. A significantly smaller number of patients with COPD with infrequent exacerbations from the roflumilast group a year later moved into the category of patients with frequent exacerbations, compared with the placebo group (RR = 0.768, p = 0.0018). Reducing the risk of severe exacerbations (i.e., associated with hospitalization or death) in the treatment with roflumilast did not depend on the combined therapy of DLA or previous IGX treatment.
A retrospective analysis of the combined results of four annual studies with a total of 5595 participants showed that in patients with severe and extremely severe COPD, roflumilast, compared with placebo, increased FEV1 after bronchodilator (p <0.05) and reliably reduced the severity of dyspnea on the TDI scale (transient dyspnea index, 95% CI 0.327 (0.166–0.488), regardless of the history of exacerbations, prior inhaled iXX therapy, concurrent administration of DBA, iXX or KDASP.
In a meta-analysis of 11 RCTs with a total of 9675 patients, the efficacy and safety of roflumilast in patients with COPD was evaluated. It has been established that long-term use of roflumilast (24–54 weeks) compared with placebo:
1) was accompanied by a significant decrease in the likelihood of developing COPD exacerbations by an average of 23% (p <0.00001);
2) improved FEV1 before bronchodilation (weighted average difference of 53.52 ml; 95% CI 42.49 to 64.55; p <0.00001) to a greater extent in patients with moderate and severe COPD than in the subgroup of severe and extremely severe, and also provided an increase in other indicators of respiratory function after bronchodilator (forced vital capacity – FVC, FEV1, forced expiratory volume in 6 seconds (FEV6), average volumetric expiratory flow rate 25–75, p <0.00003);
3) did not affect the overall mortality rate, but was associated with a significant increase in some of the frequently observed adverse events (diarrhea, nausea, weight loss), as well as symptoms such as headache, insomnia. Most of the undesirable drug reactions took place with continued treatment.
According to this meta-analysis, as well as the previous one, roflumilast did not improve the health-related quality of life assessed according to the St. George’s respiratory questionnaire (SGRQ) Respiratory Questionnaire. It was concluded that roflumilast is an effective complement to the treatment of patients with COPD with frequent exacerbations and a pronounced decrease in lung function, despite the relatively high risk of adverse events.
A recently completed annual REACT study (Roflumilast in COPD Exacerbations while taking appropriate Combination Treatment) to see if roflumilast is able to reduce the incidence of exacerbations (especially severe ones leading to hospitalization) and improve pulmonary function in patients with COPD with severe chronic bronchitis and risk frequent exacerbations, whose disease is poorly controlled by a combination of inhaled drugs (fixed iXc / ddba or ixc / ddba + ddakhp).
REACT is a one-year double-blind, placebo-controlled, multicenter study with parallel groups (the group receiving roflumilast 500 mg / day, 968 patients, placebo – 967). The study included patients aged 40 years and older with a history of smoking of at least 20 pack-years and a diagnosis of COPD with severe bronchial obstruction (post-bronchodilation ratio FEV1 / FVC <0.70 and FEV1 ≤ 50% due), symptoms of chronic bronchitis and history at least two exacerbations in the previous year, despite the recommended therapy. All patients (1935 people) used a fixed combination of inhaled corticosteroids / DBA during the 4-week baseline observation period and during the study period, and 70% of them also used tiotropium bromide. In the event of an exacerbation during the study period, if necessary, additional treatment with systemic GCS (prednisone 40 mg for 7-14 days), as well as antibiotics (in the presence of purulent sputum or a suspected bacterial infection) was carried out. The use of tableted beta2-agonists and any short-range inhaled bronchodilators other than salbutamol was not allowed.
The study showed that in the roflumilast group, the frequency of exacerbations was 13.2% lower than in placebo; this effect was noted independently of the concomitant therapy of DDAC. Compared with placebo, treatment with roflumilast led to a 23.9% reduction in exacerbations requiring hospitalization (RR 0.761 (95% CI 0.604–0.960), p = 0.02). This difference also remained significant in patients additionally receiving DDAC. In addition, statistical analysis confirmed that roflumilast reduced the total number of exacerbations (p = 0.0047), both moderate, requiring treatment with systemic corticosteroids in combination with or without antibiotics, and severe, leading to hospitalization and / or death.
Compared with placebo, therapy with roflumilast was associated with a significant increase in post-bronchodilation FEV1 (56 ml) and FVC. A significant increase in FEV1 indices was observed regardless of the type of therapy — a fixed combination of IGCC / DDBA plus DDACP (59 ml, 95% CI 39–79) or without DDACP (49 ml, 95% CI 15-83). Reducing the frequency of exacerbations and improving the performance of external respiration during treatment with roflumilast in this and other studies can be attributed directly to its anti-inflammatory properties, since roflumilast does not have a direct bronchodilator effect and the anti-inflammatory effect of roflumilast and iGX is different.
Roflumilast had a high cardiovascular safety. The study showed that the drug did not affect the frequency of serious adverse events from the cardiovascular system, nor the mortality rate. There was no increase in the incidence of pneumonia associated with taking roflumilast.
Side effects were reported in 67% of patients in the roflumilast group and 59% in the placebo group. The most frequent were exacerbation of COPD, diarrhea, weight loss. The number of patients excluded from the study due to adverse events was 2 times higher in the roflumilast group than in the placebo group (104, or 11%, versus 52, or 5%, respectively), which is consistent with results in other studies. However, adding roflumilast to combination inhalation therapy did not increase the frequency of the expected side effects. No effect of roflumilast on the overall assessment of the CAT questionnaire was noted.
The results of meta-analysis and REACT-research we have presented are of significant clinical significance. Roflumilast is the first drug targeted at a specific group of patients with severe COPD associated with chronic bronchitis and history of frequent exacerbations. Its ability to reduce the frequency of exacerbations (both moderate and severe), reduce the number of hospitalizations, and improve pulmonary function provides additional advantages in the management of patients who have exacerbations, despite adequate combined double / triple inhalation therapy. Unlike most drugs for the treatment of COPD, which are supplied in an inhalation form and create technical difficulties for a significant number of patients, roflumilast is available as an oral pill once a day, which increases patient adherence to this type of treatment (adherence to the drug during the study period). ranged from 97% to 99%).
On the other hand, roflumilast causes a large number of side effects, of which the most frequent are gastrointestinal disorders; is associated with weight loss, in connection with which the drug is not recommended for patients with weight deficit; With great caution, roflumilast should be prescribed to patients with anxiety disorders, depression and suicidal tendencies. Despite the fact that in most cases, diarrhea, dyspepsia, and headache disappear with continued treatment, a relatively large percentage of cases of premature discontinuation of roflumilast due to adverse events compared with placebo were noted in studies (15% versus 9%, respectively). In addition, as shown by a quantitative assessment of the ratio of benefit / harm (where benefit is a reduction in the risk of exacerbations, harm is side effects), in patients with COPD of male age <65 years with a 30% risk of moderate and severe exacerbations in one year The benefits of this treatment are close to 0% (the index was negative). Further research is needed in this direction. However, the use of roflumilast in everyday practice expands the range of possibilities in the treatment of patients with COPD. The decision on the appointment of roflumilast, as, indeed, any other therapy, requires an individual approach in each case in accordance with existing recommendations.
The emergence of new iFDE-4 in an inhalation form can minimize gastrointestinal adverse effects and potentially improve the tolerability of high doses, and the development of drugs based on iFDE-4 hybrid molecules and various bronchodilators can increase the effectiveness of therapy. Such developments are underway; Recently, a synthesis of a new series of hybrids combining salmeterol and PDE-4 inhibitors, roflumilast or phthalazinone (another potent PDE-4 inhibitor), has been reported, which is expected to provide both beta2-agonist and PDE-4 inhibitor activity.