Effects of Traditional Chinese Patent Medicine on Essential Hypertension

Traditional Chinese patent medicine (TCPM) is widely used for essential hypertension (EH) in China. However, there is no critically appraised evidence, such as systematic reviews or meta-analyses, regarding the potential benefits and disadvantages of TCPM to justify their clinical use and recommendation. The aim of this review was to systematically evaluate and meta-analyze the effects of TCPM for EH. Seven databases, the Cochrane Library, PubMed, EMBASE, the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Chinese Biomedical Literature Database, and the Wanfang Database, were searched from their inception to August 2014 for relevant studies that compared one TCPM plus antihypertensive drugs versus antihypertensive drugs alone. The methodological quality of the included trials was assessed using the Cochrane risk-of-bias tool. The primary outcome measures were mortality or progression to severe complications and adverse events. The secondary outcome measures were blood pressure (BP) and quality of life (QOL). Seventy-three trials, which included 8138 patients, on 17 TCPMs were included. In general, the methodological quality was low. Two trials evaluated the effects of TCPMs on mortality and the progression to severe complications after treatment, and no significant difference was identified compared with antihypertensive drugs alone. No severe adverse events were reported. Thirteen TCPMs used in complementary therapy significantly decreased systolic BP by 3.94 to 13.50 mmHg and diastolic BP by 2.28 to 11.25 mmHg. QOL was significantly improved by TCPM plus , Yuqing Zhang, MD, and Xiaoke Li, MD EH was supported by evidence of class level III. As a result of the methodological drawbacks of the included studies, more rigorously designed randomized controlled trials that focus on mortality and cardiovascular events during long-term follow-up are warranted before TCPM can be recommended for hypertensive patients. Two TCPMs, Song ling xue mai kang capsules and Yang xue qing nao granules, should be prioritized for further research. (Medicine 94(5):e442) Abbreviations: AEs = adverse events, BP = blood pressure, CAM = complementary and alternative medicine, CCT = controlled clinical trials, CFDA = China Food and Drug Administration, CI = confidence interval, CNED = Chinese National Essential Drug, CVDs = cardiovascular diseases, DBP = diastolic blood pressure, EH = essential hypertension, PPRC = Pharmacopoeia of the People’s Republic of China, QOL = quality of life, RCT = randomized controlled trial, RR = risk ratio, SBP = systolic blood pressure, TCM = traditional Chinese medicine, TCPM = traditional Chinese patent medicine, TPAD = traditional Chinese patent medicine plus antihypertensive drugs, WMD = weighted mean difference. INTRODUCTION H ypertension is one of the most important worldwide publichealth challenges because of its high frequency and concomitant risks of cardiovascular and kidney disease. Across all World Health Organization regions, approximately 62% of strokes and 49% of myocardial infarctions are caused by high blood pressure (BP). Hypertension has been identified as the fourth leading cause of the global burden of disease. The prevention and effective treatment of essential hypertension (EH) is of utmost importance both in China and the West. However, the effective control of hypertension is far from satisfactory and is limited by the availability, cost, and adverse effects of antihypertensive medications. Therefore, a certain proportion of patients have turned to complementary and alternative medicine (CAM), including traditional Chinese medicine (TCM), in the search for a treatment modality with potential efficacy and few adverse effects. In Western countries, interest in TCM stems from the hope that it might complement Western medicine. This situation is also partially supported by recent studies. The most significant distinction between China and the West in EH treatment is the application of acupuncture and traditional Chinese patent medicines (TCPMs), which have been considered complementary or adjunctive therapies for symptom management and quality of life (QOL) enhancement care. Although no TCPMs have been nal new drug by the US Food and Drug PMs have resulted in great economic and www.md-journal.com | 1 clinical benefits in China. For example, yang xue qing nao granules are composed of Rehmannia (Dihuang, Radix Rehmanniae Glutinosae), Chinese Angelica Root (Danggui, Radix Angelicae Sinensis), Gambir Vine Stems and Thorns (Gouteng, Ramulus Uncariae Cum Uncis), Mother of Pearl (Zhenzhumu, Concha Margaratiferae), Foetid Cassia Seeds (Juemingzi, Semen Cassiae Torae), Prunella (Xiakucao, Spica Prunellae Vulgaris), White Peony Root (Baishao, Radix Albus Paeoniae Lactiflorae), Szechuan Lovage Root (Chuanxiong, Rhizoma Ligustici Chuanxiong), Spatholobus (Jixueteng, Caulis Milletiae Seu Spatholobi), Corydalis Rhizome (Yanhusuo, Corydalis Rhizome), and Chinese Wild Ginger (Xixin, Herba Asari Cum Radice). Yang xue qing nao granules have been extensively tested in various types of clinical trials. In 2012, the global market of yang xue qing nao granules was approximately 0.5 billion RMB (equivalent to 81.7 million USD). Several randomized controlled trials (RCTs) and systematic reviews regarding the efficacy of acupuncture for EH have been published in English. However, there is insufficient clinical evidence to support or discourage the use of many commonly used TCPMs in hypertensive patients, especially in conjunction with conventional therapy, despite wide acceptance and authoritative recommendations by the China Food and Drug Administration (CFDA) (available at http://www.sda.gov.cn) and the Pharmacopoeia of the People’s Republic of China (2010 edition) for EH in China. Therefore, confirmation of the effectiveness of TCPMs as complementary therapies could have a substantial impact on EH management worldwide. These TCPMs are composed of >100 herbs, most of which have specific antihypertensive effects both in vitro and in vivo when tested alone. Pharmacological studies have indicated that most studied TCPMs can be used to lower BP, and the potential mechanisms may be related to improvements in the plasma levels of endothelin, calcitonin gene-related peptide, and nitric oxide; the inhibition of sympathetic activity; and the regulation of the rennin-angiotensin system. The most commonly used formulations of TCPM for EH include tablets, capsules, pills, granules, and oral liquid. It remains unknown whether there is robust evidence on the clinical effects of TCPM or whether TCPM can be recommended for routine treatment. However, some relevant trials have been reported in China. Thus, the objective of this study was to provide a comprehensive systematic review to summarize and evaluate the evidence regarding the efficacy of TCPM combined with antihypertensive drugs as a complementary therapy for hypertension. To our knowledge, this is the first systematic English-language review of the clinical trials of all TCPMs for the treatment of EH. METHODS A methodological evaluation and meta-analysis were conducted in accordance with the recommendations of the Cochrane Collaboration. Eligibility Criteria Type of Studies Only RCTs were eligible for this review, with no restriction on language or publication status. According to the methodological quality of the included RCTs, they were categorized into 3 levels: trials with a clear method of randomization were Xiong et al defined as definite RCTs; trials with an unknown methodology, in which the claimed ‘‘RCTs’’ may not be real ‘‘RCTs,’’ were defined as potential RCTs; and trials that included treatment and 2 | www.md-journal.com control groups, and in which treatment allocation was not necessarily randomized, were defined as controlled clinical trials (CCTs). Types of Participants Participants enrolled in the studies of this review had to meet at least one of the current or past guidelines or definitions of EH, which are described as follows: systolic BP (SBP) 140 mmHg and/or diastolic BP (DBP) 90 mmHg on at least 2 occasions with off-antihypertensive treatment (after a 4-week washout period) and/or treatment with antihypertensive medication, while excluding secondary hypertension. Trials without a description of the detailed diagnostic criteria but that included patients with definite EH were also included. Because there are many TCM syndromes (also known as zheng or patterns) of EH, no restriction regarding the diagnostic criteria of TCM was utilized. Trials that included patients of any age, sex, or ethnic origin with EH were eligible. There were no restrictions on population characteristics. Types of Interventions TCPMs that had been subjected to a relatively strict drug evaluation process, including active constituent identification, a compatibility mechanism study, efficiency and safety evaluation, and RCTs were included. Substantial systemic preclinical or clinical data (regardless of whether they were provided in publications) were available for these selected TCPMs. In our review, only TCPMs listed in the Chinese National Essential Drug (CNED) of 2012 (available at http://www.sda.gov.cn), the Pharmacopoeia of the People’s Republic of China (PPRC) (2010 edition), and commonly used TCPMs in current clinical practice for EH were included in the analysis. Drugs in CNED and PPRC represent the most important therapies listed by the Chinese government, which have been studied extensively and proven to be safe and effective in treatment. More clinical studies reported the use of commonly used TCPMs. In total, 82 TCPMs were identified for further evaluation. All parallel RCTs of the 82 TCPMs that compared 1 TCPM plus antihypertensive drugs (TPAD) versus antihypertensive drugs alone for EH were eligible. Co-interventions were matched in both the treatment and control groups. Trials were excluded for the following reasons: a multimodal intervention, including TCPM and other complementary and alternative approaches, was used in either the treatment or control groups; a combination of >2 TCPMs was included in the treatment group; head-to-head comparisons of different types of TCPMs were utilized without a standard Western medicine control group; the types and dosages of antihypertensive drugs used in the treatment or control groups were not the same; only biochemical markers, rather than BP, were reported; no data on BP outcome could be extracted; and duplicated publications reported the same results. Trials that evaluated any TCPM formulation (tablets, capsules, or pills) were included regardless of the treatment period length and the treatment dosage. Types of Outcome Measures For inclusion, RCTs had to have evaluated at least one of the following outcomes. The primary outcome measures included mortality, progression to severe complications, and adverse events (AEs). Severe complications were defined as Medicine Volume 94, Number 5, February 2015 coronary heart disease, myocardial infarction, heart failure, cerebral infarction, cerebral hemorrhage, transient ischemic attack, renal failure, and retinopathy. The secondary outcome Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. measures included SBP, DBP, and QOL after treatment. Trials were excluded if missing information about the outcome measure were found. Search Strategy Studies on 82 TCPMs were identified through searches of the following 7 electronic databases from their inception until August 17, 2014: the Cochrane Library (searched in August 2014), PubMed (1959–2014), EMBASE (1980–2014), the China National Knowledge Infrastructure (1979–2014), the Chinese Scientific Journal Database (1989–2014), the Chinese Biomedical Literature Database (1978–2014), and the Wanfang Database (1985–2014). Because TCPMs were invented and are primarily used in China, we conducted a literature search in the 4 main Chinese electronic databases to include the maximum possible number of clinical trials. To include unpublished studies, we also searched the website of the Chinese clinical trial registry (available at http://www.chictr.org/) and the international clinical trial registry maintained by the US National Institutes of Health (available at http://clinicaltrials.gov/). For the database searches, the following keywords were used in combination: (‘‘clinical trial’’ OR ‘‘randomized trial’’ OR ‘‘randomized controlled trial’’ OR ‘‘randomised controlled trial’’) AND (‘‘essential hypertension’’ OR ‘‘primary hypertension’’ OR ‘‘hypertension’’ OR ‘‘high blood pressure’’ OR ‘‘blood pressure’’) AND (‘‘traditional Chinese patent medicine’’ OR ‘‘Chinese patent medicine’’ OR ‘‘song ling xue mai kang capsule’’ OR ‘‘Pinus armandi Franch benefiting blood vessel capsule’’ OR ‘‘yang xue qing nao granule’’ OR ‘‘nourishing the blood and clearing brain granule’’ OR ‘‘liu wei dihuang pill’’ OR ‘‘liu wei dihuang wan’’ OR ‘‘rehmannia six formula’’ OR ‘‘quan tianma capsule’’ OR ‘‘total gastrodia capsule’’ OR ‘‘xin ke shu’’ OR ‘‘smoothing heart capsule’’ OR ‘‘qing nao jiang ya tablet’’ OR ‘‘clearing brain and antihypertensive tablet’’ OR ‘‘tianma gouteng granule’’ OR ‘‘granule of gastrodia and uncaria’’ OR ‘‘qiang li tianma duzhong capsule’’ OR ‘‘powerful gastrodia and eucommia capsule’’ OR ‘‘qi ju dihuang pill’’ OR ‘‘lycii, chrysanthemi and rehmanniae pill’’ OR ‘‘niuhuang jiang ya pill’’ OR ‘‘calculus bovis antihypertensive pill’’ OR ‘‘zhen ju jiang ya tablet’’ OR ‘‘pearl and lycii antihypertensive pill’’ OR ‘‘qiang li ding xuan tablet’’ OR ‘‘powerful fixing vertigo tablet’’ OR ‘‘tianma shouwu tablet’’ OR ‘‘gastrodia and polygonum multiflorum tablet’’ OR ‘‘qing gan jiang ya capsule’’ OR ‘‘clearing liver and antihypertensive capsule’’ OR ‘‘qing xuan jiang ya tablet’’ OR ‘‘clearing vertigo and antihypertensive tablet’’ OR ‘‘tian shu capsule’’ OR ‘‘capsule of chuanxiong rhizome and gastrodia tuber for headache’’ OR ‘‘lingyangjiao capsule’’ OR ‘‘cornu saigae tataricae capsule’’ OR ‘‘duzhong shuang jiang pao dai ji’’ OR ‘‘eucommia ulmoides bubble bag agent’’ OR ‘‘an gong jiang ya pill’’OR ‘‘an gong antihypertensive pill’’ OR ‘‘yun tong ding tablet’’ OR ‘‘vertigo and headache fixing tablet’’ OR ‘‘fu fang luobuma granule’’ OR ‘‘compound apocynum granule’’ OR ‘‘xin nao jing tablet’’ OR ‘‘clearing heart and brain tablet’’ OR ‘‘zhen nao ning capsule’’ OR ‘‘calming brain capsule’’ OR ‘‘jiang ya ping tablet’’ OR ‘‘antihypertensive tablet’’ OR ‘‘shanzha jiang ya tablet’’ OR ‘‘hawthorn antihypertensive tablet’’ OR ‘‘xing nao jiang ya pill’’ OR ‘‘clearing brain and antihypertensive pill’’ OR ‘‘xuan yun ning granule’’ OR ‘‘fixing vertigo granule’’ OR ‘‘yu feng ning xin tablet’’ OR ‘‘calming wind and relieving heart Medicine Volume 94, Number 5, February 2015 tablet’’ OR ‘‘yi nao ning tablet’’ OR ‘‘reinforcing brain tablet’’ OR ‘‘yi ling jing mixture’’ OR ‘‘supplementing vital essence mixture’’ OR ‘‘yang yin jiang ya capsule’’ OR ‘‘nourishing yin Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. and antihypertensive capsule’’ OR ‘‘huan jing jian oral liquid’’ OR ‘‘sperm-return oral liquor’’ OR ‘‘tian mu jiang ya tablet’’ OR ‘‘gastrodia and pearl antihypertensive tablet’’ OR ‘‘xia sang ju granule’’ OR ‘‘prunella, folium mori and chrysanthemum granule’’ OR ‘‘jiang ya bi feng tablet’’ OR ‘‘antihypertensive and avoiding wind tablet’’ OR ‘‘jiang ya granule’’ OR ‘‘antihypertensive granule’’ OR ‘‘jiang ya tablet’’ OR ‘‘antihypertensive tablet’’ OR ‘‘jiang ya pill’’ OR ‘‘antihypertensive pill’’ OR ‘‘fu fang duzhong tablet’’ OR ‘‘compound eucommia tablet’’ OR ‘‘duzhong ping ya capsule’’ OR ‘‘eucommia antihypertensive capsule’’ OR ‘‘shan lv cha jiang ya tablet’’ OR ‘‘hainan holly leaf antihypertensive tablet’’ OR ‘‘luobuma jiang ya tablet’’ OR ‘‘apocynum antihypertensive tablet’’ OR ‘‘shan zhuang jiang zhi tablet’’ OR ‘‘hawthorn lipid-lowering tablet’’ OR ‘‘luo huang jiang ya tablet’’ OR ‘‘apocynum and rhubarb antihypertensive tablet’’ OR ‘‘luo ji jiang ya tablet’’ OR ‘‘apocynum and stephaniae tetrandrae antihypertensive tablet’’ OR ‘‘zhen xin jiang ya tablet’’ OR ‘‘calming heart antihypertensive tablet’’ OR ‘‘ju ming jiang ya tablet’’ OR ‘‘chrysanthemum and cassia seed antihypertensive tablet’’ OR ‘‘fu fang lingyangjiao capsule’’ OR ‘‘compound cornu saigae tataricae capsule’’ OR ‘‘fu fang xiakucao jiang ya syrupus’’ OR ‘‘compound prunella antihypertensive syrupus’’ OR ‘‘gao xue ya su jiang pill’’ OR ‘‘quickly lowering blood pressure pill’’ OR ‘‘xue ya an ba bu gao’’ OR ‘‘antihypertensive babu plaster’’ OR ‘‘jiu qiang nao li qing’’ OR ‘‘enduring and powerful clearing brain pill’’ OR ‘‘luobuma tea’’ OR ‘‘apocynum tea’’ OR ‘‘luobumaye granule’’ OR ‘‘apocynum venetum leaves granule’’ OR ‘‘sanqihua granule’’ OR ‘‘notoginseng flower granule’’ OR ‘‘xin ling pill’’ OR ‘‘calming heart pill’’ OR ‘‘dong qing bu zhi’’ OR ‘‘holly fill juice’’ OR ‘‘duzhong granule’’ OR ‘‘eucommia granule’’ OR ‘‘feng shi xi tong tablet’’ OR ‘‘siegesbeckiae and clerodendroa trichotomum tablet’’ OR ‘‘shanzha jing jiang zhi tablet’’OR ‘‘hawthorn lipid-lowering tablet’’ OR ‘‘guan tong tablet’’ OR ‘‘dredging coronary artery tablet’’ OR ‘‘xing nao niu huang qing xin tablet’’ OR ‘‘calculus bovis calming brain and heart tablet’’ OR ‘‘kang mai xin oral liquid’’ OR ‘‘benefiting blood vessel and heart oral liquid’’ OR ‘‘mai jun an tablet’’ OR ‘‘calming pulse tablet’’ OR ‘‘mai luo tong tablet’’ OR ‘‘promoting blood circulation tablet’’ OR ‘‘quan duzhong capsule’’ OR ‘‘total eucommia capsule’’ OR ‘‘yan you cha’’ OR ‘‘yan you tea’’ OR ‘‘su xiao niuhuang pill’’ OR ‘‘quick-actng calculus bovis pill’’ OR ‘‘qing re xing nao ling tablet’’ OR ‘‘clearing heat and calming brain tablet’’ OR ‘‘qing re ming mu tea’’ OR ‘‘clearing heat and improving eyesight tea’’ OR ‘‘rong shuan capsule’’ OR ‘‘thrombolysis capsule’’ OR ‘‘shan hua jing granule’’ OR ‘‘hawthorn and chrysanthemi granule’’ OR ‘‘fu fang tianma granule’’ OR ‘‘compound gastrodia granule’’ OR ‘‘shu luo tablet’’ OR ‘‘dredging collaterals tablet’’ OR ‘‘shu xin ning tablet’’ OR ‘‘regulating heart tablet’’ OR ‘‘xin shu bao tablet’’ OR ‘‘relieving heart tablet’’ OR ‘‘xin xue ning tablet’’ OR ‘‘calming heart and blood tablet’’ OR ‘‘xiatianwu injection’’ OR ‘‘corydalis injection’’ OR ‘‘xianlingpi granule’’ OR ‘‘epimedium granule’’ OR ‘‘xin an capsule’’ OR ‘‘calming heart capsule’’ OR ‘‘xin an ning tablet’’ OR ‘‘calming heart and tranquilizing mind tablet’’ OR ‘‘xin mai tong tablet’’ OR ‘‘promoting heart and blood circulation tablet’’). Furthermore, the reference lists of the identified original articles were manually searched for additional eligible studies. The pharmaceutical companies that manufacture TCPMs were contacted to identify further published and unpublished studies. Effects of TCPM on EH: A Systematic Review The literature search was independently conducted by 2 reviewers, and disagreements were settled by discussion between the reviewers or a consultation with a third party. www.md-journal.com | 3 Data Extraction and Management Two reviewers independently screened the trials based on the titles and abstracts. The following information was extracted from the eligible trials that met the inclusion criteria: basic characteristics (age, gender, race of participants, and sample size) of the included subjects and basic characteristics (authors, title of study, year of publication, randomization, allocation concealment, blinding, intention to treat analysis, drop-out or withdrawal, diagnosis standard, TCPM name, interventions in the treatment and control groups, outcome measures, treatment duration, and safety reporting) of the included trials:. Missing data were obtained from the original authors via email, fax, or telephone when possible. Disagreements were resolved by discussion with a third reviewer. Risk of Bias in Individual Studies Two reviewers independently assessed the risk of bias in the included studies using tools from the Cochrane Handbook for Systematic Review of Interventions Version 5.1.0 (updated March 2011). The factors assessed included the following 7 items: random sequence generation (selection bias); allocation concealment (selection bias); blinding of participants and personnel (performance bias); blinding of outcome assessment (detection bias); incomplete outcome data (attrition bias); selective reporting (reporting bias); and other sources of bias Xiong et al (from Chapter 8: assessing risk of bias in included studies). For each item, the risk of bias was classified as ‘‘low,’’ ‘‘unclear,’’ or ‘‘high’’ according to the previously discussed criteria. Records identified through database searching (n = 11991) Records after duplic (n = 11 Records scr (n = 118 Full-text articles for eligib (n = 15 Studies inclu this revie (n = 73 Id en tif ic at io n