Effects of comprehensive therapy based on traditional Chinese medicine patterns on older patients with chronic obstructive pulmonary disease: a subgroup analysis from a four-center, randomized, controlled study

Abstract

This study aimed to evaluate the efficacy of comprehensive therapy based on traditional Chinese medicine (TCM) patterns on older patients with chronic obstructive pulmonary disease (COPD) through a four-center, open-label, randomized controlled trial. Patients were divided into the trial group treated using conventional western medicine and Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules, and Yi-Qi Zi-Shen granules based on TCM patterns respectively; and the control group treated using conventional western medicine. A total of 136 patients≥65 years completed the study, with 63 patients comprising the trial group and 73 comprising the control group. After the six-month treatment and the 12-month follow-up period, significant differences were observed between the trial and control groups in the following aspects: frequency of acute exacerbation (P≤0.040), duration of acute exacerbation (P = 0.034), symptoms (P≤0.034), 6-min walking distance (6MWD) (P≤0.039), dyspnea scale (P≤0.036); physical domain (P≤0.019), psychological domain (P≤0.033), social domain (P≤0.020), and environmental domain (P≤0.044) of the WHOQOL-BREF questionnaire; and daily living ability domain (P≤0.007), social activity domain (P≤0.018), depression symptoms domain (P≤0.025), and anxiety symptoms domain (P≤0.037) of the COPD-QOL. No differences were observed between the trial and control groups with regard to FVC, FEV1, and FEV1%.

Keywords

chronic obstructive pulmonary disease / older adult / clinical trial / Bu-Fei Jian-Pi granules / Bu-Fei Yi-Shen granules / Yi-Qi Zi-Shen granules

1 Introduction

Chronic obstructive pulmonary disease (COPD) is one of the main causes of the increasing morbidity and mortality rates as well as the rising health costs worldwide, especially in elderly patients with high prevalence of the disease and great economic burden [1]. COPD is projected to become the third leading cause of death worldwide by 2030 [2]. The prevalence of COPD among individuals 65 years of age and older was recently estimated to be 14.2%, which is higher than the estimation for those aged 40 years and above (9.9%) [3]. In Canada, COPD has a much higher prevalence among men and women aged above 75 years, given the prevalence rates of 11.8% and 7.5%, respectively; these values are nearly triple and double the national average (4.4%) [4]. In the US, 6.3% adults have been diagnosed with COPD by a healthcare provider, and the prevalence has increased from 3.2% among those aged 18 to 44  years to > 11.6% among those aged≥65 years [5]. In China, 185 million people above the age of 60, or 13.7% of the population, have COPD according to the China Report of the Development on Aging Cause (2013) [6]. The overall prevalence of the disease is 8.2% among individuals aged 40 years and above and 11.7% among those aged over 60 years [7]. Hospitalization rate, length of hospital stay, and mortality are high for elderly COPD patients.

The management of elderly COPD patients requires a multidisciplinary approach and appropriate treatment plans [8]. Non-pharmacological therapy methods include patient education, smoking cessation, oxygen therapy, influenza vaccination, and pulmonary rehabilitation. On the contrary, pharmacological drugs mainly contain short-acting bronchodilators, long-acting bronchodilators, inhaled glucocorticosteroids, and low-dose, slow-release theophylline [9]. However, the adverse effects of medications among elderly patients require further attention [10].

The remarkable longevity and current popularity of traditional Chinese medicine (TCM) for COPD treatment implies its potential advantages. Our previous study reported three common TCM patterns of stable COPD and one specific herbal intervention corresponding to each pattern [11]. The comprehensive TCM interventions based on TCM patterns have shown definite effects on ameliorating symptoms, reducing the frequency of acute exacerbation, and improving the quality of life (QOL) of COPD patients [12,13]. However, limited evidence has been found concerning elderly COPD patients. Therefore, we perform a subgroup analysis from a multi-center randomized controlled trial (RCT) to evaluate the efficacy of comprehensive therapy based on TCM patterns for older COPD patients.

2 Materials and methods

2.1 Participants

In the four-center RCT, patients aged 40 to 80 years and diagnosed with mild to severe COPD (Global Initiative for Chronic Obstructive Lung Disease, GOLD 1, 2, 3 and TCM pattern criteria of COPD) [11,14] were enrolled from out-patient departments or through open recruitment. These patients received treatment voluntarily and signed the necessary informed consent forms. Patients who suffered from confusion, dementia, or any type of mental illness; serious diseases such as tumor, heart failure, and liver and kidney diseases; or allergies to treatment drugs were excluded. For the subgroup analysis of the four-center RCT, patients≥65 years old were calculated.

2.2 Sample size and randomization

Sample size was calculated by {\displaystyle \frac{\mathrm{2}{({\mu }_a+{\mu }_{\beta })}^{\mathrm{2}}{\sigma }^{\mathrm{2}}}{{\delta }^{\mathrm{2}}}}, which is based on a comparison between the equal numbers of a two-sample mean. The two-sided α level was 0.05, and the β level was 0.10. After the calculation, the final sample size was 352, with each group comprising 176 patients. The subgroup analysis included all patients aged≥65 years from four research centers. A stratified and block randomization design was adopted. The patients were divided into two groups, with a distribution ratio of one-to-one and a block length of four. Treatment allocation was conducted when the participant met the inclusion criteria and signed the informed consent form. The design was provided by the DME Department of Guangzhou University of TCM.

2.3 Interventions

COPD patients in the control group were given conventional western medicine according to the GOLD and Chinese Treatment Guidelines [14,15]; these guidelines included the following: GOLD 1: albuterol sulfate (Ventolin, Glaxo- SmithKline), 100 μg/dose, 100 μg each time; GOLD 2: formoterol fumarate dehydrate (Oxis Turbuhaler, AstraZeneca), 4.5 μg/dose, 4.5 μg each time, twice daily; and GOLD 3: salmeterol/fluticasone propionate (Seretide, GlaxoSmith- Kline), 50/250 μg each time, twice daily.

The patients in the trial group treated with conventional western medicine were also given Bu-Fei Jian-Pi granules for lung-spleen qi deficiency (batch number: 080103), 3.83 g per bag; Bu-Fei Yi-Shen granules for lung-kidney qi deficiency (batch number: 080102), 4.25 g per bag; and Yi-Qi Zi-Shen granules for lung-kidney qi and yin deficiency (batch number: 080104), 5.16 g per bag. The granules were compound preparations of TCM produced by Jiang Yin Tian Jiang Pharmaceutical Co. Ltd. The quality of the granules met the required quality standards. Each type of granule was given orally, three bags each time, twice daily for six months. During the follow-up period, the patients in the trial group were no longer given any TCM granules, and the patients in both groups continued the conventional western medication treatment.

3 Outcomes

The frequency and duration of the acute exacerbation of COPD (AECOPD) each time during treatment were recorded for six months and at a follow-up survey after 12 months. AECOPD is characterized by a change in patients’ original conditions of dyspnea, cough, and/or expectoration in the development of the disease; such change is beyond the variation in daily routine and requires a change in regular medication [16]. If the interval between two onsets of acute exacerbation was within one week, it was considered as one count of acute exacerbation [17]. The indicators of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1 percentage of the predicted value (FEV1%) were tested. Symptoms such as coughing, sputum, shortness of breath, dyspnea, gasping, and cyanosis were recorded. The dyspnea scale questionnaire (MMRC) [18] and the 6-min walking distance (6MWD) results were evaluated. The WHOQOL-BREF questionnaire [19] and the adult COPD quality of life questionnaire (COPD-QOL) [20] were adopted to measure the quality of life of the patients. The data on lung function, symptoms, 6MWD, the dyspnea scale questionnaire, and quality of life were observed before treatment (month 0), in the third month (month 3) of the treatment period, in the sixth month (month 6) of the treatment period, and in the 12th month (month 18) of the follow-up period. The AECOPD data were observed and calculated in months 0, 6, and 18, whereas the data on safety were recorded in months 0 and 6.

3.1 Statistical analysis

All P values were two-tailed, and the α level of significance was set at 0.05. Measurement data were analyzed through independent samples t-tests or Mann-Whitney U-tests based on data distribution to compare the differences between the two groups. Repeated measures were used to compare the differences in the time-continuous observations. Analysis of covariance was performed to compare the value differences of the center effect. Numerical data were described using absolute frequency. All statistical analyses were performed using SAS9.2 (KEY: FQ37-WSB8-7G5C).

4 Results

4.1 Comparison of general information

A total of 352 patients underwent randomization. Based on the withdrawal and rejection criteria, 306 patients were deemed to have fully completed the study. For the subgroup analysis, 136 patients≥65 years old were analyzed; 63 patients belonged to the trial group while 73 patients belonged to the control group. The enrollment of patients and the completion of the study are depicted in Fig. 1. No significant difference was observed in the two groups in terms of gender, age, course of disease, body mass index (BMI), exacerbations, lung function, and GOLD classification of lung function. The comparison of the general information of the two groups is shown in Table 1.

4.2 Comparison of the frequency and duration of AECOPD

Before treatment, no significant difference was recorded in the AECOPD of the two groups (P = 0.908). However, for months 6 and 18, a significant difference was observed in the frequency of the AECOPD of the two groups (P = 0.040, P = 0.000). The average frequencies and the constituent ratios of the two groups were also significantly different (P = 0.000, P = 0.003). Furthermore, the average durations of the AECOPD of the two groups were significantly different (P = 0.034). The results are shown in Table 2.

4.3 Comparison of lung function

During months 3, 6, and 18, a downward trend was observed among FVC, FEV1, and FEV1%. However, no significant difference was noted in the FVC, FEV1, and FEV1% of the two groups (P = 0.654, P = 0.475, P = 0.908). The results are shown in Fig. 2A, 2B, and 2C.

4.4 Comparison of symptoms and the dyspnea scale

No significant difference was noted in the mean scores of symptoms and the dyspnea scale of the two groups before treatment (P = 0.388, P = 0.883). However, the mean scores of symptoms and the dyspnea scale of the trial group were significantly lower over time compared with those of the control group (P = 0.000, P = 0.005). During months 3, 6, and 18, a significant difference emerged in the mean scores of symptoms and the dyspnea scale in the trial group compared with those in the control group (P = 0.034, P = 0.000; P = 0.036, P = 0.010). The results are shown in Fig. 2D and 2E.

4.5 Comparison of 6MWD

No significant difference was observed in the mean values of 6MWD of the two groups before treatment and during month 3 (P = 0.862, P = 0.415). The mean value of 6MWD was significantly higher over time in the trial group than in the control group (P = 0.040). During months 6 and 18, the mean value of 6MWD was significantly higher in the trial group than in the control group (P = 0.039, P = 0.035). The results are shown in Fig. 2F.

4.6 Comparison of WHOQOL-BREF questionnaire

Before treatment, no significant difference was recorded in each domain score and in the total scores of the two groups (P>0.05). QOL scores of the trial group continued to increase over time and were significantly higher than those of the control group (P<0.05). During months 3, 6, and 18, QOL scores were higher in the trial group than in the control group, specifically in terms of the physical (Fig. 3A, P≤0.019), psychological (Fig. 3B, P≤0.033), environmental (Fig. 3C, P≤0.044), social (Fig. 3D, P≤0.020), and total scores (Fig. 3E, P≤0.043).

4.7 Comparison of COPD-QOL questionnaire

Before treatment, no significant difference was noted in each domain score and in the total scores of the two groups (P>0.05). The QOL scores of the trial group continued to decrease over time and were significantly lower than those of the control group (P<0.05). During months 3, 6, and 18, QOL scores were lower in the trial group than in the control group, specifically in terms of daily living ability (Fig. 3F, P≤0.007), social activity (Fig. 3G, P≤0.018), depression symptoms (Fig. 3H, P≤0.025), anxiety symptoms (Fig. 3I, P≤0.037), and total score (Fig. 3J, P≤0.001).

5 Discussion

COPD is a major public health problem that affects a significant proportion of the elderly population. The diagnosis of elderly individuals is complicated by the fact that many COPD patients ignore or are relatively tolerant of the disease’s symptoms and therefore do not seek medical attention [21]. In addition, the course of COPD in elderly patients is often complicated by multiple comorbidities that need to be addressed to optimize treatment outcomes [22]. Although bronchodilators and corticosteroids remain the cornerstone of the pharmaceutical management of COPD, the efficacy of such methods relies on correct medication administration. The inhaler technique should be frequently assessed, and the choice of inhaler device should be tailored to the patients’ needs, situation, and preferences. Careful attention to the mental health of elderly patients is also vital. Furthermore, elderly patients with severe COPD receive inadequate palliative care despite the elevated mortality risk associated with this illness. Therefore, management techniques that are specific to the elderly should be considered [23].

Acute exacerbations present a risk for acute respiratory failure, and elderly patients with advanced COPD tend to experience an average of two to three exacerbations each year, with each exacerbation lasting 12 days. Bacterial and viral infections are the most frequent causes of exacerbations, and other triggers include air pollution and environmental temperature changes [24]. The AECOPD is associated with poor QOL, accelerated lung function decline, increased utilization of healthcare resources, and increased mortality. The clinical presentation and outcome of COPD exacerbations among the elderly differ from those among middle-aged patients because of age-associated changes in respiratory structure and functional decline; these conditions in turn limit the respiratory facilities for such acute illnesses [25]. Therefore, the reductions in the frequency and duration of exacerbations are important indicators for treatment evaluation. In the present work, the frequency and duration of the AECOPD in the trial group were 0.62 times and 4.08 days, respectively. On the contrary, the frequency and duration of the AECOPD in the control group were 1.18 times and 6.62 days, respectively. TCM granules reduce the frequency and duration of acute exacerbation. This result may be attributed to the combined effects of conventional western medicine and TCM.

An accelerated decline in lung function is the main hallmark of COPD. A considerable limitation of spirometry for the elderly is the impossibility of performing it correctly because of fatigue, lack of coordination, and cognitive impairment. In fact, about 40% of COPD patients over 65 years old are not able to perform spirometry properly [26]. Although FEV1 does not fully explain the complex clinical pathophysiological consequences of COPD, it is a simple and reproducible spirometric measurement that provides a reasonable marker in predicting morbidity and mortality in COPD. The rate of decline in FVE1 in COPD patients has been found to decrease from 47 ml to 69 ml per year [27]. Based on the results from the well-known UPLIFT Trial and TORCH Trial, the rates of decline in FVE1 in the salmeterol/fluticasone group and in the tiotropium group have been found to be 39 and 41 ml per year, respectively [28]. In our work, the rate of decline in FVE1 in the trial group decreased by approximately 40.02 ml per year, and that in the control group decreased by approximately 100.04 ml per year. These rates are consistent with the results of other large trials. Therefore, TCM granules can maintain the rate of decline in FEV1.

Symptoms, exercise tolerance, and health status were also observed in the current study. Although COPD is defined by airflow limitation, the decision to seek medical help in practice is usually determined by the effect of a symptom on a patient’s daily life. Evaluating the degree of breathing difficulty is important to understand the severity of COPD, the health status, and the clinical intervention effects. Therefore, observations of symptoms and the dyspnea scale questionnaire were employed in the current study [29]. The 6MWD is widely used in the area of respiratory diseases for the comprehensive evaluation of the functional status of the human body with a moderate or severe disease [30]. The main objective of the 6MWD is to determine exercise tolerance and oxygen saturation during sub-maximal exercise. In our work, the cut-off point for the 6MWD was approximately 350 m, and the minimal significant difference in COPD patients was 25 m [31]. QOL is an indispensable indicator and assessment tool. As a result of the long course of COPD and the progressive decline in lung function associated with it, the daily activities of COPD patients are limited, they are forced to rely heavily on family members, they carry great financial burden, and they experience decreased family status. Therefore, COPD patients usually have low self-esteem and suffer from depression, anxiety, and other adverse effects on psychological emotion and social adaptation ability; e.g., the incidence of depression and that of anxiety among the AECOPD patients in our work were 22.8% to 45.9% and 9.6% to 24.3%, respectively [32,33]. Many types of effective and reliable health-related QOL questionnaires on chronic respiratory diseases are widely available [34]. Given the reliability and validity of the WHOQOL-BREF and COPD-QOL questionnaires, they were adopted in the current study to evaluate the QOL of COPD patients. The improvement in the 6MWD of the trial group was 34.21 m, which is better than that of the control group at 13.23 m. The improvement in QOL was 16.04% and 16.22% in the trial group and 6.61% and 6.03% in the control group. The symptoms were also reduced, given the lower dyspnea scale scores in the trial group than in the control group. Therefore, TCM granules reduced the symptoms and improved the exercise tolerance and health status of the COPD patients.

As indicated in the results of the subgroup analysis from the four-center RCT study, Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules, and Yi-Qi Zi-Shen granules based on TCM patterns have beneficial effects on measured outcomes in elderly COPD patients. However, further studies on this age group should be performed to evaluate TCM treatment. The influencing factors for elderly patients should also be analyzed.

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