Background: Essential hypertension (EH) with anxiety or depression belongs to the category of psycho-cardiology. Hypertension is closely related to anxiety and depression. The adverse reactions of Western medicine are apparent and the compliance is poor. Supplementary and replacement therapies have accumulated rich experience in clinical practices, which can reduce side effects and improve clinical efficacy. This study intends to use the Bayesian network meta-analysis (NMA) analysis method for the first time to gather randomized controlled trials (RCTs) related to complementary and alternative therapies in the treatment of hypertension with anxiety or depression disorder and rank efficacy and safety, to provide a reference basis for the treatment of hypertension with anxiety or depression disorder. Methods: All randomized controlled trials (RCTs) and registered and ongoing trials of Chinese and English databases, related to supplementation and replacement therapies of EH with anxiety or depression disorder, published from initial state to February 2021, will be collected in the form of computer retrieval. Two researchers will independently screen the literature, extracting data, assessing bias risk and assessing heterogeneity. We will use software WinBUGS 1.4.3 and Stata 16.0 for pairwise meta-analysis and NMA to comprehensively evaluate various interventions. The quality of evidence will be evaluated through the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: This NMA will comprehensively compare and rank the efficacy and safety of a series of complementary and alternative therapies in treating EH with anxiety or depression disorder. Conclusion: Supplementary and replacement therapies have accumulated rich experience of clinical practices in improving EH with anxiety or depression disorder. We expect that this NMA will guide practice and research by providing reliable evidence of evidence-based medicine for the treatment of EH with anxiety or depression disorder. Protocol registration number: INPLASY202120068.
Psycho-cardiology, which was put forward by James W. Jefferson for the first time [[
In recent years, the prevalence of essential hypertension (EH) in China has increased. Hypertension is a primary risk factor for high morbidity and mortality of cardiovascular and cerebrovascular diseases worldwide. The World Health Organization has reported that 54% of stroke and 47% of ischemic heart disease are direct consequences of hypertension [[
Hypertension is closely related to anxiety and depression [[
The mechanism of anxiety and depression leading to the increase of BP is roughly in 3 aspects. First, anxiety can affect the vascular endothelial function by activating the sympathetic nerve, causing the vascular endothelium to release vasoactive substances out of balance and affect the regulation of BP [[
EH with anxiety or depression belongs to the category of psycho-cardiology. In terms of treatment, we should not only treat hypertension but also pay more attention to psychological diseases in order to achieve an excellent antihypertensive effect. Western medicine is often combined with anti-anxiety drugs or antidepressants. Although the anxiety and depression of patients are alleviated to some extent, many adverse reactions such as respiratory inhibition, mental fatigue, addiction, gastrointestinal reactions and so on are bad for the quality of life of patients. Another significant problem in treating anti-anxiety drugs or antidepressants is poor compliance, with about 50% of patients discontinuing prescription drugs in the first month of medication [[
The network meta-analysis (NMA) can be used to compare three or more interventions simultaneously, and can provide the probability of choosing the best intervention. This study intends to use the Bayesian network meta-analysis (NMA) analysis method for the first time to gather randomized controlled trials (RCTs) related to complementary and alternative therapies in the treatment of hypertension with anxiety or depression disorder and rank efficacy and safety, to provide a reference basis for the treatment of hypertension with anxiety or depression disorder.
This NMA will be implemented according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) details [[
This study is based on published data, and so it does not require ethical approval. The results of this NMA will be presented at scientific conferences and published in a peer-review journal.
The type of study is RCTs related to complementary and alternative therapies for EH complicated with anxiety or depression disorder, and the languages are Chinese and English.
- Patients who have diagnosed EH (SBP≥140 mmHg or DBP≥90mmHg, according to the diagnostic criteria of the Guidelines for Prevention and Control of Hypertension in 2010), with anxiety or depression disorder (according to the score of any validated scales).
- It is not affected by the age, sex and region of the included patients.
The control group was treated with or without conventional hypotensive drugs, at the same time, with or without anti-anxiety drugs or antidepressants. The treatment group was treated with complementary replacement therapies on the basis of the control group. The complementary replacement therapies include biological-based therapies, traditional Chinese medicine (TCM), acupuncture, massage, qigong, moxibustion, yoga, Chinese herbal medicines, music therapy, five-animal exercises, cognitive-behavioral therapy, relaxation training, tai chi, mindfulness meditation, and so on. They can also be used without conventional hypotensive drugs.
Primary outcomes include the change of SBP and DBP, the change in score of any validated scales, such as HAMA, HAMD, or SAS, SDS, which can assess the severity of anxiety or depression. The total efficacy rate, stationarity of hypotension, adverse effects, and TCM symptoms score are secondary outcomes.
- The type of study is non-RCTs;
- The subjects included were diagnosed patients with secondary hypertension;
- Patients without anxiety or depression;
- Studies of unknown specific inclusion, exclusion criteria, and intervention measures;
- There are obvious errors or the research data are unknown and cannot be extracted.
Chinese and English databases such as MEDLINE, PubMed, Embase, ClinicalTrials.gov, PsycINFO, Web of Science, Cochrane Library, Biosis, CNKI, Wanfang Database, Weipu Database and China Biology Medicine disc (CBMdisc) and so on will be searched by two independent researchers. RCTs, related to supplementation and replacement therapies of EH with anxiety or depression disorder, which were published from initial state to February 2021, will be collected in the form of computer retrieval. For the researches on incomplete information or some problems in the data, the corresponding author will be contacted to supplement the missing data as much as possible. At the same time, references of systematic review/meta-analysis as well as registered and ongoing trials will be traced. Take PubMed as an example, and the retrieval strategy is shown in Table 1.
Graph
Table 1 Search strategy for PubMed.
NO. Search item #1 Essential Hypertension [MeSH] #2 Essential Hypertension[Title/Abstract] OR High Blood Pressure[Title/Abstract] OR Hypertension[Title/Abstract] OR Blood Pressure[Title/Abstract] OR Psycho-cardiology[Title/Abstract] OR Psychocardiology[Title/Abstract] #3 #1 OR #2 #4 Depression[MeSH] #5 Depressions[Title/Abstract] OR Emotional Depressions[Title/Abstract] OR Depression, Emotional [Title/Abstract] OR Depressive Symptom[Title/Abstract] OR Symptom, Depressive[Title/Abstract] OR Depressions, Emotional [Title/Abstract] OR Emotional Depression[Title/Abstract] OR Depressive Symptoms [Title/Abstract] OR Symptoms, Depressive [Title/Abstract] OR Depression Disorder [Title/Abstract] #6 #4 OR #5 #7 Anxiety[MeSH] #8 Anxiety[Title/Abstract] OR Anxiety Disorder[Title/Abstract] OR Emotional Anxieties[Title/Abstract] OR Anxiety, Emotional[Title/Abstract] OR Symptom, Anxious[Title/Abstract] OR Anxieties, Emotional[Title/Abstract] OR Emotional Anxiety[Title/Abstract] OR Anxious Symptom[Title/Abstract] OR Symptoms, Anxious [Title/Abstract] OR Anxious Symptoms [Title/Abstract] #9 #7 OR #8 #10 #3 AND #6 #11 #3 AND #9 #12 #10 OR #11 #13 Complementary Therapies[MeSH] #14 Therapy, Alternative[Title/Abstract] OR Complementary and Alternative Therapies[Title/Abstract] OR Complementary Medicine[Title/Abstract] OR Alternative Therapies[Title/Abstract] OR Medicine, Complementary[Title/Abstract] OR Alternative Medicine[Title/Abstract] OR Complementary Therapies[Title/Abstract] OR Medicine, Alternative[Title/Abstract] OR Therapy, Complementary[Title/Abstract] #15 #13 OR #14 #16 Chinese Herbal Medicines[Title/Abstract] OR Yoga[Title/Abstract] OR Exercise[Title/Abstract] OR Music Therapy[Title/Abstract] OR Chinese Medicine[Title/Abstract]OR Biological-based Therapies[Title/Abstract] OR Five-Animal Frolics Exercise[Title/Abstract] OR Acupuncture[Title/Abstract] OR Massage[Title/Abstract] OR Cognitive-behavioral Therapy[Title/Abstract] OR Relaxation Training[Title/Abstract] OR Traditional Chinese Medicine[Title/Abstract] OR Tai chi[Title/Abstract] OR Qigong[Title/Abstract] OR Moxibustion[Title/Abstract] OR Massage[Title/Abstract] OR Mindfulness Meditation[Title/Abstract] #17 #15 OR #16 #18 Randomized Controlled Trial[Publication Type] OR Controlled Clinical Trial[Publication Type] OR Randomized[Title/Abstract] OR Randomly[Title/Abstract] #19 #12 AND #17 AND #18
Literature screening: according to the retrieval strategy, the two researchers will check all the databases independently, and obtain all the studies related to this research. Then, by reading the title and abstract of studies, the studies which have nothing to do with the research will be excluded. Finally, we will read through the full text and screen the literature according to the inclusion and exclusion criteria mentioned above. The data will be imported into Endnote X9 software (Clarivate Analytics, Philadelphia, PA USA).
Data extraction: the chart of literature information will be drawn, and the two researchers will independently extract the information from the included researches. The level of agreement between the two researchers will be analysed by using the Kappa value [[
The quality of literature will be scored according to the Jadad scale [[
Stata 16.0 software will be used for statistical analysis. The ratio (OR) will be used as the index for the counting data, and the mean difference (MD) will be used for the measurement data. The 95% confidence interval (95% CI) of each effect size will be given. A p-value <0.05 will be considered significant. We will combine with I
In this paper, the NMA is mainly based on the Bayesian theory to compare all the intervention measures and make a comprehensive evaluation at the same time. We will use I
We will divided data into smaller units according to different design scheme, quality of literature, publishing year, etc., to make a further comparison.
After excluding the studies with abnormal results, the NMA will be carried out again, and the results are compared with the results of NMA, which does not exclude the studies with abnormal results, so as to probe the influence of the studies on the merger effect. The methods of sensitivity analysis include including or excluding those controversial studies on whether they meet the inclusion criteria, excluding studies with low quality, using different statistical methods to re-analyze data, and so on.
IF and 95% CI will be calculated. The consistency of closed loops will be evaluated by 95% CI. We can also use the node splitting method to analyze each node of NMA and compare the difference of direct and indirect comparison. If P > 0.05, it means that there is no inconsistency.
The included data will be tested by Begg´s and Egger´s funnel plot to evaluate whether there are publication bias and the effect of small sample size. If the included studies are concentrated near the midline and symmetrically distributed, it shows that the publication bias has little influence on this research. On the contrary, there will be publication bias.
The quality of evidence is divided into five levels—risk of bias, indirectness, inconsistency, imprecision, and publication bias—in NMA according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) [[
There is often a causal relationship between hypertension and psychological disorders. The prevalence rate of hypertension in patients with anxiety or depression is significantly higher than that in patients without anxiety or depression. On the contrary, the risk of anxiety and depression in patients with hypertension is significantly higher than that in patients without hypertension [[
At present, It is difficult to achieve a satisfactory antihypertensive response by conventional hypotensive drugs for EH with anxiety or depression disorder and the side effects are obvious. Complementary and replacement therapies of EH with anxiety or depression disorder play an increasingly vital role. However, there are many kinds of complementary and replacement therapies and the efficacy is uneven, so it is difficult to choose the best scheme in the clinic. This will be the first NMA to systematically evaluate the efficacy and safety of different complementary and alternative therapies for EH with anxiety or depression disorder, and then we will rank them in order to get the best regimen, which can guide the clinical treatment.
We expect that this NMA will guide practice and research by providing reliable evidences of evidence-based medicine for treatment of EH with anxiety or depression disorder. Nevertheless, this study also has some limitations. For example, the use of different anxiety and depression scales in different studies may lead to publication bias.
S1 Checklist. PRISMA-P checklist.
(DOC)
By Xueyan Han; Xinxin Liu; Fengxing Zhong; Yiguo Wang and Qiming Zhang
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