Cordyceps sinensis for hypertension in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness and adverse effects of Cordyceps Sinensis (CDS) on blood pressure compared to placebo or no treatment in hypertensive patients.
Background
Description of the condition
The Guide to management of hypertension (NBPVDAC 2008) and the World Health Organization (WHO) (Whitworth 2003) defined hypertension as having a systolic blood pressure (SBP) of 140 mm Hg or greater and/or a diastolic blood pressure (DBP) of 90 mm Hg or greater. A hypertensive patient can be classified into one of five different categories (NBPVDAC 2008, Whitworth 2003):
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Grade 1 (mild) hypertension: SBP 140‐159 mm Hg and DBP 90‐99 mm Hg
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Grade 2 (moderate) hypertension: SBP 160‐179 mm Hg and DBP 100‐109 mm Hg
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Grade 3 (severe) hypertension: SBP ≥ 180 mm Hg and DBP ≥110 mm Hg
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Isolated systolic hypertension: SBP ≥140 mm Hg and DBP < 90 mm Hg
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Isolated systolic hypertension with widened pulse pressure: SBP ≥160 mmHg and DBP ≤ 70 mm Hg
There are two types of high blood pressure: essential or primary hypertension and secondary hypertension. Essential hypertension, the most common form, refers to high blood pressure in which secondary causes are absent (Carretero 2000). Secondary hypertension is hypertension that is caused by conditions or known etiologies such as alcohol or drug abuse, pregnancy, kidney disorders, or taking certain medicines. It is much less common than essential hypertension (Oparil 2005).
Hypertension is often called the "silent killer" since it generally does not cause symptoms until there is serious physical damage (Stevens 2008). It is also considered as the leading global risk factor for mortality and disability‐adjusted life years (DALYs) (Ezzati 2002;WHO 2009), and is ranked as the third leading risk factor for burden of disease worldwide (Ezzati 2002). In addition, WHO reported that hypertension is responsible for raising the risk of stroke (cerebrovascular disease), ischaemic heart disease and kidney failure (WHO 2009). In 2001 hypertension was implicated in about 7.6 million (13.5%) of all deaths in the world and 92 million (6%) of all DALYs of the global total (Carlene 2008). By 2025, it is estimated that the number of adults with hypertension will increase by 29% (to 1.56 billion) (Kearney 2005).
Description of the intervention
To control and/or lower blood pressure in hypertensive patients, physicians will consider both pharmacologic and non‐pharmacologic treatment.
Lifestyle modifications (regular physical activity, dietary modification, weight reduction, smoking cessation, limited alcohol intake) are recommended for all hypertensive patients in order to decrease blood pressure (NBPVDAC 2008Chobanian 2003).
Low‐dose thiazide diuretics are the first choice drug in most patients with elevated blood pressure (Wright 2009). Angiotensin‐converting enzyme (ACE) inhibitors, beta‐blockers, calcium channel blockers, alpha‐blockers, angiotensin II receptor blockers (ARB) are also used as anti‐hypertensive monotherapies for patients with uncomplicated hypertension. If target blood pressure (SBP and DBP less than 140 and 90 mm Hg, respectively) cannot be reached or if there is no significant reduction with initial monotherapy, combination drug therapy is recommended rather than increasing the dose of the first agent.
Natural remedies have also been used for treating hypertension, for example, garlic, fish oil, and hawthorn berries. Cordyceps Sinensis (CDS) has been known and used in China for traditional Chinese medicine. CDS is an alternative medicine that might be used for treating hypertension. It can be called Cordyceps mushroom, Caterpillar fungus, or Dong Chong Xia Cao in Chinese (Illana 2007;Paterson 2008). People outside China were first attracted to CDS after Chinese runners broke nine world records in 1993. Many people tend to believe that the success of those Chinese athletes was partly attributed to consumption of CDS. Since then the wide range of biological functions of CDS has been studied as a treatment for many diseases (Buenz 2005). Some reports also indicated that CDS has beneficial effects on renal and hepatic function and immunomodulation‐related anti‐tumour activities (Paterson 2008).
How the intervention might work
Based on findings from animal and human studies, it has been shown that environmental and psychosocial stress have an obvious effect on blood pressure (Oparil 2005). There is a known association between stress and blood pressure. In addition, there is some evidence that stress management can reduce blood pressure in hypertensive patients (Spence 1999; Schneider 2005). Similarly, the Guide to Management of Hypertension 2010 (Hackam 2010) recommends management of stress as a lifestyle modification for preventing and treating hypertension. As it has been found that the consumption of CDS has a significant anti‐stress effect in mice (Koh 2003), we wish to determine whether or not such a benefit would also occur in human clinical trials of CDS.
Why it is important to do this review
Evidence from clinical trials has shown the potential benefit of anti‐hypertensive drugs (Williams 2003). Anti‐hypertensive drugs have also been found to contribute to a reduction of stroke and major cardiovascular events (SHEP 1991). However, some hypertensive patients using conventional antihypertensives experience adverse effects such as constipation, cough, angioedema, dyspnoea, gout, headache, flushing, and postural hypotension (NBPVDAC 2008).
Given that high‐quality evidence for the use of CDS for the treatment of hypertension is currently lacking, it is important to perform a systematic review of randomised controlled trials to determine the efficacy of CDS.
Objectives
To assess the effectiveness and adverse effects of Cordyceps Sinensis (CDS) on blood pressure compared to placebo or no treatment in hypertensive patients.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) that apply any form of Cordyceps Sinensis compared to placebo or no treatment.
Types of participants
Adults (at least 18 years old) that can be categorized by their baseline blood pressure into any one of five different categories of hypertensive patients as described in the Background section of this protocol.
Hypertensive patients taking anti‐hypertensive medications will be included if:
(a) they are adults age 18 or above, and
(b) the baseline blood pressure was reported, and
(c) both intervention and comparison group are taking the same anti‐hypertensive agents.
Hypertensive patients with any known underlying disease and pregnant women will be excluded.
Types of interventions
Cordyceps Sinensis (CDS) compared to placebo or no treatment. There will be no restrictions on form, dose or frequency of CDS administration. The duration of CDS treatment must be minimum 1 week and maximum 8 weeks. We defined the minimum and maximum duration of using CDS based on the time to follow‐up of blood pressure levels in adults in the Guide to Management of Hypertension 2008 (NBPVDAC 2008).
Types of outcome measures
Primary outcomes
Change of systolic and diastolic blood pressure (mm Hg) from baseline.
Secondary outcomes
Change of pulse pressure (mm Hg).
Change of heart rate (beats/min).
Change of HDL and LDL cholesterol (mg/dl).
Number of patients with any adverse effects.
Number of patient withdrawals due to adverse effects.
Search methods for identification of studies
There will be no restriction for any languages or publication restrictions.
Electronic searches
The following electronic databases will be searched for primary studies:
a) The Cochrane Central Register of Controlled Trials (CENTRAL)
b) English language databases, including MEDLINE (1950‐) and EMBASE (1980‐), Allied and Complementary Medicine Database, and International Pharmaceutical Abstracts
c) Chinese and Thai language databases
Electronic databases will be searched using a strategy combining 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 Cordyceps Sinensis 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.
The Chinese language databases will be searched with the assistance of the Hong Kong Branch of the Chinese Cochrane Centre.
We also plan to search databases of Current Controlled Trials (www.controlled‐trials.com) as well as System for Information on Grey Literature in Europe (OpenSIGLE; www.opensigle.inist.fr) for identifying ongoing and grey literature.
We will search for other related reviews from The Database of Abstracts of Reviews of Effectiveness (DARE).
All the search strategies will be documented in the Appendices of the review.
Searching other resources
In order to find other potentially eligible studies we will handsearch the reference lists of relevant studies and reviews identified. We will contact authors of relevant identified studies and other experts in the field to obtain missing information, additional references, unpublished studies and ongoing studies. Appropriate journals will be handsearched. The ISI Web of Science will be searched for papers which cite studies included in the review.
Data collection and analysis
Selection of studies
After removing the duplicate studies retrieved from the search strategies, Porjai Pattanittum (PP) and Chetta Ngamjarus (CN) will independently examine the title and abstract of each study to determine if it meets the inclusion criteria. If the information in the abstract clearly states that it does not meet our inclusion criteria the study will be excluded. If the title or abstract do not provide sufficient information for making this decision we will retrieve and consider the full text. The decisions of PP and CN will be compared. Charoonsak Somboonporn (CS) will be consulted to solve any differences.
In the second phase of screening, PP and CN will independently assess the full text of all potentially relevant studies from the initial phase, to determine for each study if it should be included or excluded. We also plan to contact the authors for clarification if necessary. The reasons for excluding a study will be documented. Any disagreement will be resolved through discussion with CS.
The numbers of identified records screened, assessed for eligibility, included and excluded studies with reasons for exclusions at each stage will be presented by using a flow chart from the PRISMA Statement (Liberati 2009) (see Figure 1).
Data extraction and management
Using a standardized data extraction form, PP and CN will independently extract the data from all studies that fulfilled the inclusion criteria. A cross‐checking of the results between PP and CN will be done. If there is a need for additional information and/or clarification we will contact the authors of the original articles. Any disagreements will be resolved through discussion with CS.
PP will be responsible for inputting the data from the standardized data extraction form into Review Manager Software (RevMan 2008), and then CN will cross‐check to prevent any errors.
Assessment of risk of bias in included studies
Two review authors (PP and CN) will independently assess the risk of bias of each included study using the six domains of the Cochrane Collaboration’s tool for assessing risk of bias detailed in Chapter 8 of The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008):
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sequence generation
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allocation concealment
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blinding of participants, personnel and outcome assessors
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incomplete outcome data
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selective outcome reporting
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other sources of bias
We will record the risk of bias information in the standardized data extraction form. Any contradictions between PP and CN will be resolved by consensus of all review authors. The authors of original articles will be contacted for clarification if necessary.
PP will enter the risk of bias information into the risk of bias tables. The risk of bias graph and risk of bias summary will be presented as well.
Measures of treatment effect
Continuous outcomes (e.g. change of SBP, DBP) will be presented by using mean difference with corresponding 95% confidence intervals (95% CI).
The number of patients with any adverse effect and the number of patient withdrawals due to adverse effects will be analysed by calculating risk ratio (RR) with corresponding 95% CI.
Unit of analysis issues
For multi‐arm studies
To prevent unit‐of‐analysis errors, we will incorporate all intervention and control arms into a single pair‐wise comparison that is relevant to the systematic review. The authors of original articles will be contacted to provide additional information, if necessary.
For several periods of follow‐up
We plan to analyse the data by selecting a single time point taking into account the duration of using CDS; 1 week, 1 month and 2 months (short‐, medium‐ and long‐term follow‐up, respectively) as mentioned in the subgroup analysis section.
For any study that reports different periods of follow‐up from this review, the data will be presented in additional tables.
Dealing with missing data
We will attempt to contact the original authors for clarification and provision of missing data. If no further data is provided, we will apply the appropriate imputation method suggested in Chapter 16 of The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). If there is insufficient information to perform the imputation method we will present the data in additional tables.
The intention‐to‐treat (ITT) principle will be applied if necessary.
Assessment of heterogeneity
We will consider the results from Chi‐squared test (at 10% significance level) and the magnitude of I2 statistic for assessing heterogeneity among the studies. If substantial heterogeneity is present, we will explore the possible causes of heterogeneity among results of studies by carrying out subgroup analyses.
Assessment of reporting biases
A funnel plot will be created to investigate possible publication bias only if there are at least 10 studies included in the meta‐analysis of the primary outcome. An approach proposed by Egger will be used to test for funnel plot asymmetry. We plan to do so by using the STATA program (STATA 2007).
Data synthesis
The fixed‐effect model will be used to combine data when there is no considerable heterogeneity (I2 less than 50%). On the other hand, a random‐effects model will be performed to find the pooled effect estimate for the meaningful heterogeneity and to calculate an estimate of the between‐study variance (tau‐squared).
If the possible causes of heterogeneity cannot be explained and there is limited variation in the results of studies, the random‐effects model will be used to calculate the overall treatment effect and tau‐squared.
We will not carry out any meta‐analysis if there is inconsistency in the direction of effect.
The statistical analyses will be done by using Review Manager (RevMan 2008). We will use the STATA program (STATA 2007) to analyse data if necessary.
We will use GRADE software (GRADEpro 2008) to summarize the key findings of the review and present them in the Summary of findings table.
Subgroup analysis and investigation of heterogeneity
We plan to carry out subgroup analysis in order to investigate the source of heterogeneity if substantial statistical heterogeneity is found. Subgroup analysis will be done according to the following categories:
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the five different categories of hypertensive patients (mild, moderate, severe, isolated systolic hypertension and isolated systolic hypertension with widened pulse pressure)
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duration of using CDS (1 week, 1 month and 2 months)
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taking or not taking medication or complementary medications that may increase blood pressure (e.g. caffeine product, sage, licorices)
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type of anti‐hypertensive medication
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measurement of blood pressure (in a clinic, outside a clinic (24‐hour ambulatory blood pressure or self‐measurement of blood pressure)
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form, dose and frequency of CDS administration
We planed these categories based on the information in the Guide to Management of Hypertension 2008 (NBPVDAC 2008).
We will present the overall treatment effects for each subgroup unless there is a substantial number of studies in each subgroup.
Sensitivity analysis
To explore the robustness of our conclusions we will perform sensitivity analyses if the number of included studies is sufficient for the primary outcome in the following categories:
(a) study quality (low versus high risk of bias for allocation concealment)
(b) meta‐analysis model (fixed‐effect versus random‐effects model)
(c) publication language (English versus others)
(d) imputation method for missing data
Flow of information through the different phases of a systematic review (Liberati 2009)
