Comparative effectiveness of six Chinese herb formulas for acute exacerbation of chronic obstructive pulmonary disease: a systematic review and network meta-analysis

We included randomized controlled trials of patients with acute exacerbation of COPD that investigated the efficacies of six Chinese herb formulas combined with routine pharmacotherapy. Patients with AECOPD were confirmed to have the disorder via global standard diagnostic criteria and clinical symptoms [18]. Intervention regimens consisted of pharmacotherapy combined with the following formulas: WJ, MXSG, YBBX, QQHT, DC and SBP. Studies were included in the analysis if they reported one or more of the following pre-defined outcomes. The primary outcomes were FEV1, PaO2, PaCO2 and length of hospital stay. The secondary outcomes included (1) dyspnoea; (2) health-related quality of life; (3) hospital readmission for acute exacerbation; (4) effective rate [19]; and (5) adverse events. Studies were excluded if (1) a study included participants with complications of COPD, such as cor pulmonale or pulmonary hypertension or (2) data were unavailable.

We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, AMED, the Chinese Biomedical Database (CBM), the Chinese National Knowledge Infrastructure (CNKI), the Chongqing VIP information (CQVIP) and the Wanfang database from the starting dates of these databases to December 2016. Furthermore, the reference lists of the retrieved systematic reviews and the included studies were also screened. Language restrictions were not applied. The search terms are presented in Additional file 2.

Two independent reviewers (JL and JZ) screened the titles and abstracts of the citations and evaluated the full texts according to the selection criteria. Any disagreement was resolved by discussion with a third reviewer (JC).

Data extraction was performed by using the Epidata software 3.1 with a pre-designed database sheet. The following variables were included for the analysis: first author, publication year, diagnosis information, disease duration, stage, sample size, age, details of the interventions, control, outcomes, treatment duration, follow-up period and adverse events.

Two researchers (JL and JZ) independently evaluated the biases of the eligible studies by using the Cochrane collaboration of risk of bias tool. Six items (including randomization methods, allocation concealment, the blinding of participants and personnel, the blinding of the outcome assessors, incomplete outcome data, selective reporting and other sources of bias) were assessed, and any discrepancies were resolved by consensus.

We conducted a traditional, pair-wise meta-analysis using a random-effects model. For the continuous data, such as FEV1, mean differences were estimated, along with 95% confidence intervals (CIs), for the individual studies. Effective rates, as the dichotomous data, were reported with odds ratios (ORs) and 95%CIs. The chi-squared test and I² test were used to assess the heterogeneity.

We conducted the NMA by using the Markov Chain Monte Carlo methods to compare the treatment effects of the six Chinese herb formulas. The posterior distribution was calculated by using 100,000 iterations, with a first burn-in of 20,000 iterations. The consistency between the direct and indirect comparisons was not determined because direct evidence was unavailable. The adjusted indirect comparisons were estimated with a 95% credible interval (95%CrI) for the dichotomous and continuous outcomes. To investigate the best interventions for the various treatments, a surface under the cumulative ranking curve (SUCRA) and mean ranks were performed for the main outcomes. We also generated a comparison-adjusted funnel plot to investigate the potential publication bias. The network meta-analysis was conducted by using the WinBUGS 1.4.3 software, and the main relative graphs were created by using Stata 13.1 software.

The literature search identified a total of 1232 citations, and 55 studies involving 4560 participants met the eligible criteria and were included in the analyses (Fig. 1) [20‐74]. All of the included studies diagnosed the participants according to the Chinese COPD guidelines. Twenty-six of the included studies reported the severity of the condition at baseline, ranging from mild to very severe. The mean age of the patients with AECOPD was 63.76 years. The mean duration of the condition ranged from 173.47 days [64] to 22.65 years [67].

For the intervention of the Chinese herb formulas, MXSG was the most frequently reported treatment (15 trials), followed by WJ (12 trials), SBP (10 trials), QQHT (9 trials), DC (6 trials) and YBBX (3 trials). The formula ingredients and scientific names of herbs are listed in Additional file 3. In clinical practice, a formula is usually modified based on the original/classical formula according to the theory of Chinese medicine and a patient’s clinical symptoms. The herb details of included studies are presented in Additional file 4. The treatment duration ranged from 5 days [70] to 30 days [20]. Only one study reported the follow-up period and investigated the recurrence after 1 month of treatment [41].

FEV1 as the primary outcome was reported in 18 studies. The most frequently investigated outcome was the effective rate, which was evaluated in 52 studies. Other outcomes, such as hospital admissions and lengths of hospital stay, were not reported in any of the included studies. The additional characteristics of the included studies are summarized in Table 1.

Nineteen studies (35%) reported an appropriate method for randomization, and allocation concealment was only reported in one study. None of the studies made efforts to blind the personnel or the participants. In terms of selective outcome reporting, four studies were assessed as being high risk because several of the pre-specified outcomes were not reported in their results. The risk of bias summary is listed in Fig. 2.

This study is the first comprehensive, systematic review to compare Chinese herb formulas for the treatment of AECOPD. The ranking of the commonly used formulas might be beneficial for clinical practice. Additionally, our study had some limitations. First, there were no head-to-head comparisons performed among these formulas. Second, some of the formulas were estimated by using small sample sizes and wide credible intervals, conclusions based on these studies are more likely to be changed by further research. Third, the formula ingredients of some studies varied substantially comparing with the fixed classical formulas, which may be difficult to replicate the results for other researchers. In addition, little information was reported for the use of routine pharmacotherapy among the included studies. In fact, the treatments also varied among the studies, in terms of antibiotic types, bronchodilators, doses and administration frequencies of these drugs. Several previous systematic reviews have compared the effectiveness of different treatment scenarios and have indicated different therapeutic advantages [79‐81]. These differences might have introduced heterogeneity into our network meta-analysis. Therefore, the results should be interpreted with caution. Fourth, FEV1 as the primary outcome was only reported in eighteen studies and was evaluated in the five formulas. The results were still unreliable due to the small sample size. When considering that this outcome could provide objective measurements on the severity of the condition, future studies are suggested to include this outcome in order to reflect the clinically important outcomes. At last, methodology limitations existed in the included studies, such as inappropriate sequence generations, a lack of allocation concealment and a lack of blinding. Although we conducted a sensitivity analysis that focused on studies with low risks of bias on randomization, in order to explore the robustness of the results, the potential biases may affect the real therapeutic effects of these formulas due to the lack of blinding.

Inadequate reporting in the current Chinese herb formula studies has affected the judgements about the efficacy and safety of Chinese Medicine (CM). For Chinese medicinal herbs, some may be referring to the multiple species [82, 83]. The absence of the herbal scientific names will introduce the difficulties to researchers in determining which kinds of species were observed. Moreover, this incompleteness may impede dissemination of information from clinical trials of CHM formulas and discourage the clinical practice [84]. Future studies of Chinese herb formulas should comply with the recommendations of the CONSORT Extension for Chinese herbal medicine formulas [84, 85]. Efforts on the standardized reporting of clinical trials will promote data quality, research transparency, repeatability, generalization and readiness for synthesis, and these efforts may also help the authors in minimizing biases in research design from the start of a study. Moreover, in terms of comparing the safety of a Chinese herb formula, observational studies are also encouraged, especially real-world studies that use electrical medical records with long-term durations of follow-up.

In addition to the heterogeneity of the Chinese herb formulas, another major challenge in evaluating the clinical effects is the variety of the uses of pharmacotherapy in different clinical and research settings. Hence, future treatment scenarios should strictly follow the clinical guidelines, which will be beneficial in identifying the optimal treatments for guiding clinical practice.

Further research should be designed with the use of rigorous methodology, and the key outcome measures need to be reported, especially for FEV1, lengths of hospital stay and mortality. The effective rate, as a composite outcome, is defined as the improvement of clinical symptoms, including cough, phlegm and dyspnoea. However, inconsistent results are always produced, due to a lack of objective criteria; thus, clinical treatment effectiveness should be evaluated with the use of better validated outcome measures.