Cardiovascular and bronchoobstructive diseases, namely bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD), are among the main public health problems in people aged 40 and older [1]. The reasons behind the high prevalence of comorbidity of cardiovascular and bronchoobstructive pathologies are the common risk factors, pathophysiological processes that jointly aggravate the course of the diseases [2, 3]. From the epidemiological point of view, cardiovascular diseases (CVD) are among the top reasons of death of patients with COPD and BA [4]. The drugs used to treat a cardiorespiratory pathology are β₁-blockers and β₂-agonists, which block or activate the adrenergic system. These drugs are not 100% selective, and the receptors are located close to each other; these factors translate into a possibility of cross-receptor interaction, which often leads to side effects and to suboptimal effect of the drugs on both conditions: underprescription or rejection of pathognomonic therapy [5].

β₁-Blockers are widely used in the treatment of CVD, the particular conditions being coronary heart disease, cardiac arrhythmia and heart failure [6]. There are two types of β-blockers: non-selective, which block both β₁- and β₂-adrenergic receptors, and selective (cardioselective) β₁-adrenoblockers, which act mainly on β₁-adrenergic receptors. Traditionally, there are concerns about prescribing β-blockers to patients with concomitant COPD and BA, since they can cause reduction of the vital lung capacity, bronchospasm, erosion of the efficacy of short-acting β₂-agonists taken to arrest an attack, same as erosion of the efficacy of long-acting β₂-agonists, which is the result of direct blockade of β₂-adrenergic receptors of bronchi's smooth muscles. Therefore, the preferred drugs should be cardioselective β₁-adrenoblockers [7, 8]. At that, it should be remembered that selectivity of β₁-blockers deteriorates as their dose grows up [9]. Even nebivolol, the selectivity of which is 1:22–46, does not eliminate the risks of bronchospasm because of uneven distribution of β-adrenergic receptors through organs and tissues.

In turn, β₂-agonists are the main symptomatic drugs for patients with a bronchoobstructive pathology. However, since there are β₂-adrenoreceptors in the heart, such drugs, especially their short-acting varieties, can indirectly (through activation of the sympathoadrenal system) provoke growth of blood pressure and heart rate in patients with comorbid CVDs, and, according to some authors, decrease of the concentration of potassium in the blood triggered by higher doses of β₂-agonists may be the cause of development of life-threatening arrhythmias [10].

At the same time, combined intake of selective β₁-adrenoblockers and β₂-agonists, through suppression of tachycardia and hypertension associated with high doses of β₂-agonists taken to arrest COPD and BA exacerbations, has shown capability to decrease the frequency of cardiovascular events. Some randomized trials, as well as a number of metaanalyses, have revealed a decreased CVD-associated mortality among COPD and BA patients taking β₁-adrenoblockers [11, 12]. There is also evidence suggesting that β₂-agonists can mitigate the risk of cardiovascular complications through reduction of the residual volume of air in the lungs, which translates into lighter inspiratory dyspnea [13]. Moreover, the right ventricular compliance indicators improve [13], and the pulmonary artery pressure goes down [14], which means fewer COPD and BA exacerbations raising the risk of cardiovascular diseases and mortality.

Thus, treatment of patients with a combined cardiorespiratory pathology often requires simultaneous administration of a selective β₁-adrenoblocker and a β₂-agonist. Today, medical professionals seek practical recommendations covering the order of prescription of these drugs if they need to be used together. It should be noted that currently, there are no evidence-based data on the comparative safety and efficacy of prescribing β-agonists first and β-adrenoblockers second in a regimen, nor is there evidence describing the approach involving initial prescription of β-adrenoblockers. This study aimed to determine the preferred sequence of administration of selective β₁-adrenoblockers (bisoprolol) and long-acting β₂-agonists (formoterol) in patients with cardiovascular and bronchoobstructive diseases based on the assessment of functional parameters.

METHODS

This work was a was pilot, single-center prospective study that involved 30 patients (66.97 ± 9.84 years, 18 male, 12 female). The inclusion criteria were: cardiovascular diseases — arterial hypertension, coronary heart disease, cardiac arrhythmia, — concomitant with bronchoobstructive diseases (BOD) — bronchial asthma, chronic obstructive pulmonary disease. All the patients were prescribed a selective β₁-adrenoblocker (bisoprolol) and a β₂-agonist (formoterol).

Using the envelopes method, we divided the patients into two groups comparable in age, gender, and therapy at the time of inclusion in the study. Tables tab. 1 and tab. 2 present clinical characteristics of the patients [15].

Patients of group 1 started therapy with a β₁-adrenoblocker, bisoprolol 2.5 mg, and for group 2, the initial drug was a longacting β₂-agonist, formoterol 12 µg twice a day. A week later, group 1 began taking formoterol, group 2 — bisoprolol. Selection of the initial doses of the drugs was based on the preceding computer spirometry, specialized tests and questionnaires (fig. 1). SuperSpiro spirometer enabled spirometry (MICRO MEDICAL; UK), and the acquired values were compared to the spirometry reference values developed by the European Coal and Steel Community (ECSC) in 1993.

In order to prevent the development of bronchospasm, all patients underwent a 4-hour spirometry before being prescribed the first dose of the β₁-adrenoblocker. This test allows evaluating the initial external respiration parameters (FVC — forced vital capacity, FEV1 — forced exhale volume in 1 s, FEV1/FVC) before taking the drug and 30 minutes, 90 minutes, 150 minutes and 240 minutes after taking bisoprolol 2.5 mg.

Participants of the study

A total of 30 patients (66.97 ± 9.84 years old, 18 male and 12 female) participated in the study. They were divided into two comparable groups of 15 people.

The inclusion criteria were: CVD and BOD, compensation stage, lack of any acute process at the time of screening for the study; confirmed BA diagnosed in accordance with the generally accepted clinical, laboratory and functional criteria (GINA 2017 [16]); COPD diagnosed in accordance with the GOLD 2017 criteria [17]; signature under the informed consent form confirming voluntary participation in the study.

The exclusion criteria were: severe CVD (acute cerebrovascular accident, myocardial infarction less than 6 months before inclusion in the study, unstable angina pectoris); exacerbation of COPD, BA less than 1 month before

inclusion in the study; contraindications to intake of selective β₁-adrenoblockers and β₂-agonists; oncological diseases; pregnancy, breastfeeding; clinical conditions that, according to the doctor, prevent participation in the study.

The study was conducted at the National Medical Research Centre of Cardiology named after Academician E.I. Chazov, in the department of hypertension. The length of the study was 2 weeks, its key outcome — evaluation of functional parameters of patients with comorbidities in the context of different sequences of administration of selective β₁-adrenoblockers and long-acting β₂-agonists.

Statistical analysis

This was a pilot study, therefore, we did estimate power of the sample. PSPP 1.2.0 (GNY project; USA) enabled statistical processing of the data, and Kolmogorov–Smirnov test — verification of the distribution hypotheses. For quantitative variables in the context of normal distribution, we used the mean ± standard deviation, and for nonparametric indicators — median and percentiles [25; 75]. The differences were considered significant at p < 0.05.

RESULTS

Four-hour spirometry revealed no significant (over 20% from the baseline) drop of the level of FVC and FEV1; overall, the participants in both groups reported no deterioration of condition, which was subjectively assessed with the help of ACT, CAT, mMRC questionnaires (tab. 3). However, analysis of data of all patients has shown that in 29 patient out of 30, bisoprolol 2.5 mg/day triggered a reversible decrease of FEV1, maximum to 300 ml, which is down 17% from the baseline, the recovery to which occurred after a bronchodilation test with salbutamol 400 mg (fig. 2). In most cases, FEV1 drops (in absolute values and in % from the baseline) were registered 30 minutes and 240 minutes after initial administration of bisoprolol 2.5 mg. We included the drop values starting from 2% (fig. 2) into the calculations, thus eliminating the possibility of measurement error.

Statistical processing of the patient data by groups revealed a greater percentage of FEV1 reduction cases in group 1 (33.3% of the participants), where the therapy began with a selective β₁-adrenoblocker (bisoprolol 2.5 mg). At the same time, in group 2, which received a long-acting β₂-agonist (formoterol 24 µg) as the initial drug and started taking bisoprolol 2.5 mg only after 7 days of bronchodilation therapy, the share of those whose FEV1 decreased was 7% (fig. 3).

DISCUSSION

The problems of drug therapy aimed at combined cardiovascular and bronchopulmonary pathologies, COPD and BA in particular, remain relevant. The need for β₁-adrenoblockers in treatment of patients with bronchoobstructive diseases remains a debatable subject. A meta-analysis of observational studies that included 15 cohort studies with a follow-up period of up to 7.2 years, all of which investigated the use of β₁-adrenblockers in patients with CVD and BOD, has shown that these drugs significantly reduce mortality and exacerbations of BOD [18]. The results of this analysis is confirmed in two other major studies. One of them demonstrated that cardioselective β₁-adrenoblockers boost the response to β₂-agonists and cause no clinically significant side effects on the part of the respiratory system [7]; another reported that administration of β₁-adrenoblockers decreases overall mortality and sudden cardiac death by reducing heart rate and prolonging the diastolic period of the cardiac cycle, which improves myocardial perfusion [19]. Still, there are registered cases of decreasing vital lung capacity in the context of regimens that start the therapy with β₁-adrenoblockers. Our study confirms that: against the background of complete clinical well-being and lack of any deterioration of condition, as reported by the patients with CVD and BOD comorbidities, FEV1 reversibly dropped, in the extreme case — to 300 ml and 7% of the baseline. In an earlier paper, 4-hour spirometry has also revealed decreasing FEV1 in patients with cardiorespiratory pathology, and the share of those in whom the drop exceeded 20% from the baseline was 6.4%. However, authors of that work emphasized that longterm use of selective β₁-adrenoblockers (bisoprolol) did not translate into a significant FEV1 and FVC decrease that could be detected by spirometry [20]. 

Taking into account the results of our study, patients at high risk of bronchospasm who require prescription of a β₁-adrenoblocker can be recommended a 4-hour spirometry in a hospital setting. The test will help practitioners initiate administration of β-adrenoblockers, starting with small doses and continuing with their gradual titration. 

Our study lacked statistical power to allow an unambiguous conclusion, yet, we demonstrated that it is advantageous to start therapy with a long-acting β₂-agonist, thus reducing the risk of a bronchospastic component in patients with CVD and BOD comorbidities that need constant and longterm administration of β₁-adrenoblockers. Of course, this suggestion should be backed with more extensive clinical studies, which would seek to ultimately determine the variability of FEV1 against the background of different tactics of simultaneous administration of selective β₁-adrenoblockers and β₂-agonists.

Study limitations

The limitation of this study is the small sample of patients. However, the results are significant, which raises the need for continued research of this subject matter with sufficient statistical power.

CONCLUSIONS

Despite the close pathogenetic relationships between CVD and BOD and availability of clinical recommendations covering these comorbidities, in everyday practice, medical professionals still face difficulties in selecting therapy for such patients. Our study has shown the importance of sequence in regimens involving both β₂ -agonists and β₁ -adrenoblockers. Starting the therapy with long-acting β₂ -agonists, in particular formoterol, reduces the risk of bronchospastic effect of selective β₁-adrenoblocker, bisoprolol, in patients with a cardiorespiratory pathology. This phenomenon deserves attention and requires further studies on a larger sample of patients.