Tianma Gouteng Yin Formula for treating primary hypertension
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and safety of TGYF for treating primary hypertension compared to placebo or no treatment.
Background
Description of the condition
Hypertension is a worldwide health problem and has become a heavy burden on the health care system. Elevated blood pressure may potentially have harmful effects on blood vessels and the heart by causing atherosclerosis, decreased blood flow and ischemia (Hollander 1976, Humes 2000, Lopez 2006). It is a major risk factor for cerebrovascular disease, coronary heart disease, as well as cardiac and renal failure. It was estimated that about 7.6 million premature deaths (about 13.5% of the global total) and 92 million DALYs (6.0% of the global total) were attributed to high blood pressure in 2001 (Lawes 2008). About 54% of stroke and 47% of ischaemic heart disease worldwide were attributable to high blood pressure (Lawes 2008). Hypertension is defined as blood pressure above 140/90 mmHg. Primary hypertension, also known as essential hypertension, consists of 90‐95% of patients with evaluated blood pressure (Kasper 2005). Genetic and environmental factors may interact to raise blood pressure.
Description of the intervention
The ultimate aim of treatment for hypertension is to reduce morbidity and mortality, with minimum adverse effects. Diuretics, beta‐blockers, calcium‐channel blockers and angiotensin‐converting enzyme (ACE) inhibitors are commonly used antihypertensive drugs (Psaty 2003, Turnbull 2003, Sheridan 2008).
Although many different antihypertensive drugs are available today, about two thirds of patients under treatment are not being controlled to BP levels less than 140/90 mm Hg (Godley 2001, Chobanian 2003). Even if blood pressure is controlled within the normal range, the patients may still have high cardiovascular morbidity and mortality rates (WHO 2007).
Chinese herbal medicine has a history of centuries to treat hypertension in China and East Asia. It usually applies a combination of several (often more than ten) herbs that make up a formula under the guidance of traditional theory. Tianma Gouteng Yin Formula (TGYF) is widely used to treat hypertension in clinical practice in East Asia. It contains 11 different herbs: Tianma (Rhizoma Gastrodiae), Gouteng (Ramulus Uncariae Cum Unicis), Shijueming (Concha Haliotidis), Zhizi (Fructus Gardeniae), Huanqin (Radix Scutellariae), Chuanniuxi (Radix Cyathulae), Duzhong (Cortex Eucommiae), Yimucao (Herba Leonuri), Sangjisheng (Herba Taxilli), Yejiaoteng (Cauls Polugoni Multiflori), and Fushen (Poria). In clinical practice, the amount of each herb in TGYF varies based on the clinician's judgment, and sometimes some other herbs may also be added to the formula specifically for treating some symptoms. Traditionally the raw medicinal herbs are mixed and boiled in water to make decoction for oral administration. Generally the decoction is taken 300‐400 ml each time, twice daily (Zhang 2008a). Nowadays other preparations are also available, such as capsules or granules, which are made from traditional decoction with modern pharmaceutical technology (Zhan 2004, Song 2008). The Tianma Gouteng Yin Granule is generally taken after mixing 10 g with boiled water, three times daily. Some active ingredients in the herbs have been identified, such as gastrodin in Tianma, rhynchophylline in Gouteng, leonurine, stachydrine, graveoline in Yimucao, baicalin in Huangqin, geniposide in Zhizi, quercetin in Sangjisheng, emodin in Yejiaoteng, cyasterone in Chuanniuxi and chlorogenic acid in Duzhong, which are used to detect and control the quality of the herbal formula (Zhan 2004, Pharmacopoeia Commission 2005).
How the intervention might work
In clinical trials, TGYF has been shown to have a blood pressure lowering effect, reducing total cholesterol, improving clinical symptoms and quality of life, and preventing the occurrence of stroke in hypertension patients (Liu 2003, Zhang 2008a). Clinical studies and animal experiments revealed that TGYF could decrease the superoxide dismutase (SOD) (Zhang 2006), endothelin, angiotensin II (Liu 2000, Lin 2004), and calcium gene related peptide (CGRP) (Wu 1998), and improve insulin resistance (Zhang 2008b). When combined with candesartan, TGYF had more beneficial effect than candesartan alone on reversing carotid vascular remodeling in patients with essential hypertension (Huang 2008). It was also found that TGYF could attenuate myocardial and aorta hypertrophy induced by renovascular hypertension and suppress the rise of angiotensin II in tissue, which suggests that TGYF could affect left ventricular (LV) and aortic hypertrophy (Wang 2005).
Why it is important to do this review
Understanding the effect of Tianma Gouteng Yin Formula on blood pressure, quality of life and cardiovascular risk factors could be valuable for the management of high blood pressure. Currently there are no systematic reviews published regarding the effect of TGYF on primary hypertension. In order to establish the efficacy and safety of TGYF for treating primary hypertension, a systematic review is needed to summarize all the relevant clinical trials.
Objectives
To assess the efficacy and safety of TGYF for treating primary hypertension compared to placebo or no treatment.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials irrespective of masking, publication status, or language. The quasi‐randomised controlled trials will also be included, although its allocation method is not truly random; for example, allocation by date of birth, day of the week, medical record number, month of the year, or the order in which participants are included in the study (e.g. alternation).
Randomized cross‐over studies will also be included, however, only phase I data will be included in the analysis.
Types of participants
Patients with primary hypertension, including men and non‐pregnant women.
Types of interventions
The intervention of the treatment group will be Tianma Gouteng Yin Formula (TGYF) or the formula based on TGY regardless of preparation forms or administration route. The control will be placebo or no treatment.
TGYF must contain the following herbs: Tianma (Rhizoma Gastrodiae), Gouteng (Ramulus Uncariae Cum Unicis), Shijueming (Concha Haliotidis), Zhizi (Fructus Gardeniae), Huanqin (Radix Scutellariae), Chuanniuxi (Radix Cyathulae), Duzhong (Cortex Eucommiae), Yimucao (Herba Leonuri), Sangjisheng (Herba Taxilli), Yejiaoteng (Cauls Polugoni Multiflori), and Fushen (Poria). The amount of each herb is allowed to vary in different studies. The formula based on TGY may add several other herbs besides the above 11 herbs.
Co‐interventions will not be allowed for inclusion in either arm of the study.
Types of outcome measures
All the data for primary and secondary outcomes collected during the trial, or at the end of treatment or follow‐up, if available.
Primary outcomes
All cause mortality;
Non fatal serious adverse events;
Coronary heart disease events (fatal or non‐fatal myocardial infarction, excluding heart failure and if possible angina);
Cerebrovascular events (fatal or non‐fatal strokes, excluding transient ischaemic attacks if possible).
Secondary outcomes
Withdrawals due to adverse effects;
Symptoms, measured by a visual analogue scale or other scales;
Quality of life, measured by a validated scale;
Change in systolic blood pressure at end of follow‐up between TGYF and placebo or no treatment group;
Change in diastolic blood pressure at end of follow‐up between TGYF and placebo or no treatment group;
Change in serum cholesterol, triglycerides, HDL, LDL;
Change in serum glucose;
Adverse events, number and type of adverse events will be recorded.
Search methods for identification of studies
Electronic searches
The Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Database of Systematic Reviews (CDSR) will be searched for related reviews.
The following electronic databases will be searched for primary studies:
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The Cochrane Central Register of Controlled Trials (CENTRAL)
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English language databases, including MEDLINE (2005‐), EMBASE (2007‐), International Pharmaceutical Abstracts (IPA), Allied and Complementary Medicine Database (AMED), Cochrane Complementary Medicine Trials Register, PsycINFO, CINAHL, and CISCOM (Centralised Information Service for Complementary Medicine)
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Chinese language databases, including CBM (Chinese Biomedical Literature Database), CMCC (Chinese Medical Current Contents), TCMLARS (Traditional Chinese Medical Literature Analysis and Retrieval System), Chinese Dissertation Database, CMAC (China Medical Academic Conference), and Index to Chinese Periodical Literature.
Electronic databases will be searched using a strategy combining a variation of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision) with selected MeSH terms and free text terms relating to tianma gouteng and hypertension. No language restrictions will be used. The MEDLINE search strategy (Appendix 1) will be translated into the other databases using the appropriate controlled vocabulary as applicable.
Full strategies for other English language databases will be included in the Appendices of the review.
Searching other resources
Other sources:
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International Clinical Trials Registry Platform (WHO ICTRP)
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OpenSIGLE (System for Information on Grey Literature in Europe)
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Hand searching of those high‐yield journals and conference proceedings which have not already been hand searched on behalf of the Cochrane Collaboration.
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Reference lists of all papers and relevant reviews identified
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Authors of relevant papers will be contacted regarding any further published or unpublished work
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Authors of trials reporting incomplete information will be contacted to provide the missing information
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ISI Web of Science will be searched for papers which cite studies included in the review
Data collection and analysis
Selection of studies
Two authors (HWZ and JT) will independently assess the title or abstract of each retrieved record to select the potential eligible studies. Each record will be recorded as include, exclude, or unclear. Full articles will be retrieved for further assessment if they are recorded as include or unclear.
Two authors (HWZ and JT) will independently assess the full articles to decide which ones will be included. Every record will be labelled as include, exclude, or unclear. Any disagreement will be resolved by discussion and consensus. When the article falls into the unclear category in which there is missing data or unclear message, the trial author will be contacted for clarification. The result of communication will be recorded.
Data extraction and management
Two authors (HWZ and JT) will independently extract data from the included studies using a data extraction form. Any discrepancy will be resolved by discussion, and a third author (YJ) will decide if consensus is not possible. The data extraction form will at least include the data concerning general information, trial participants, interventions and outcomes. The details are as following:
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General information: published/unpublished, title, authors, source, country, publication language, publication year, duplicator publications or not, setting.
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Trial characteristics: comparison groups, method of randomisation, allocation concealment, blinding (participants, intervention administrators, outcome assessors), evaluation of blinding.
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Participants: inclusion and exclusion criteria, total number and number in comparison groups, baseline characteristics.
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Interventions: the composition or ingredients, preparation method, dose, route, and timing of intervention, comparison intervention, and co‐intervention, expertise of practitioner.
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Outcomes: outcomes specified above, any other outcomes assessed, adverse events.
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Follow up: length of follow up, reason and number of dropouts and withdrawals, intention‐to‐treat analysis.
If the above data are missing in the article, the first author will be contacted for further information. If they are not available, the results of correspondence will be recorded and reported.
One author (HWZ) will transfer the data into RevMan 5 and another author (JT) will verify the data entered.
Assessment of risk of bias in included studies
Two authors (HWZ and JT) will independently assess the risk of bias in the included studies. Any discrepancy will be resolved by discussion and conclusions be made by consensus. If needed, a third author (YJ) will make the final decision.
To detect potential selection bias, performance bias, attrition bias, detection and reporting bias, The Cochrane Collaboration's tool for assessing risk of bias will be used to assess the following domains: sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. Baseline comparability will be considered as one of other sources of bias. The risk of bias of included studies will be categorized as high, low or unclear.
We will also summarize the risk of bias for each outcome within and across the included studies by using the GRADE system. The empirical evidence for each individual outcome will be graded into four levels: high, moderate, low, or very low quality.
Measures of treatment effect
Dichotomous outcomes:
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All cause mortality;
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Non fatal serious adverse events;
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Coronary heart disease events;
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Cerebrovascular events;
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Withdrawals due to adverse events.
For dichotomous outcomes, the relative risk (RR) with 95% confidence intervals (CI) will be calculated. We will also calculate the risk difference and number needed to treat.
Continuous data:
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Change of systolic blood pressure at the end of follow‐up between TGYF and placebo or no treatment group;
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Change of diastolic blood pressure at the end of follow‐up between TGYF and placebo or no treatment group;
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Symptoms, measured by a visual analogue scale or other validated scales;
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Quality of life, measured by a validated scale;
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Change in serum cholesterol, triglycerides, HDL, LDL;
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Change in serum glucose.
For continuous data, weighted mean difference between comparison groups with 95% CI will be calculated when the same measurement scale is used. Otherwise, standardised mean difference will be calculated.
Unit of analysis issues
The analysis of outcomes will be based on the randomised individuals. Special attention will be given to the designs of cluster randomised trials, cross‐over trials or repeated measures on the same participants. Appropriate methods of statistical analysis will be applied, with advice from statisticians.
In case of multiple intervention groups within a trial, pair wise comparisons will be made of similar active interventions versus no treatment or placebo. The relevant intervention or control groups will be combined when related to the study objective.
Dealing with missing data
Available case analyses will be conducted. Proportion of missing data will be calculated, including both missing in follow‐up and dropout during the trial. Possible reasons for and potential influence of missing data will be explored.
Sensitivity analyses will be conducted, for dichotomous missing data, based on consideration of 'best‐case' and 'worst‐case' scenarios; and, for continuous data, based on imputation missing data by 'last observation carried forward'.
Assessment of heterogeneity
Study components (such as patients, interventions and outcomes) in the included studies will be assessed to establish if substantial heterogeneity is present. If not, heterogeneity will be further investigated by visual inspection of the forest plots. If the confidence intervals for the results of included studies have poor overlap, it may indicate the presence of heterogeneity. We will use chi‐square test to test for heterogeneity, in which the significance level is set at 0.1, in view of its low power. We will also use I‐square test to quantify inconsistency, which describes the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error. A value over 50% may indicate substantial heterogeneity.
Assessment of reporting biases
Reporting biases will be investigated by using the funnel plot or other corrective analytical methods depending on the number of trials included in the analysis.
Data synthesis
Meta‐analysis will be performed on primary and secondary outcomes, within comparisons of TGYF versus placebo or no treatment. If there are more than three studies included in the review, we will pool the data using the random‐effects model. The fixed‐effect model will be used if there are three or less studies, or there is a need for comparison with the results from random‐effects model to explore the influence of small‐study effects.
If the data are too sparse, or the risk of bias is high, or substantial heterogeneity is found, a narrative, qualitative summary will be done.
Data on adverse events will be tabulated.
Subgroup analysis and investigation of heterogeneity
If a sufficient number of randomised trials is found, subgroup analysis will be performed based on the stage of hypertension (BP below or above 160/100 mmHg) (Chobanian 2003) and formula composition (TGYF or added).
Where there is substantial heterogeneity, the possible clinical and methodological reasons for this will be explored qualitatively.
Sensitivity analysis
For dichotomous outcomes, participants with incomplete or missing data will be included in the sensitivity analysis by counting them as treatment failures to explore the possible effect of dropouts and withdrawals on the results (worst‐case scenario).
If sufficient number of randomised trials are found, sensitivity analyses will be performed to explore the risk of bias influencing factors on the effect estimates: adequacy of sequence generation, allocation concealment, and blinding.
