Traditional Chinese medicines in the management of cardiovascular diseases: a comprehensive systematic review

Abstract

Aims

The aim was to perform a systematic review of the efficacy of traditional Chinese medicines (TCM) in cardiovascular disease.

Methods

Electronic databases were searched up to 11 November 2015 for all randomized‐controlled trials evaluating the effect of TCM in hypertension, ischaemic stroke, heart failure, coronary heart disease and type 2 diabetes mellitus. Pooled odds ratios (ORs) were calculated using a fixed‐effects model.

Results

Four hypertension studies were eligible for statistical analysis and included 133 patients receiving TCM and 130 control patients. There were significant reductions in systolic blood pressure in patients receiving TCM, comparable to results achieved with pharmaceutical medicines. An OR of 3.781 (95% confidence interval 2.392, 5.977; P = 0.000) was observed for the anti‐hypertensive effect of TCM. Significant heterogeneity was present (P = 0.011), with a tendency towards publication bias that did not reach significance (P = 0.05275). Outcome measures for other cardiovascular diseases were inconsistent.

Conclusions

Certain TCM compounds appear to have significant anti‐hypertensive effects, and although some are associated in some studies with improved outcomes in coronary heart disease, heart failure and type 2 diabetes mellitus, the data are inconsistent and will require large‐scale randomized‐controlled trials to allow full evaluation of any potential therapeutic benefit in these areas.

Introduction

Cardiovascular diseases account for over 17.5 million deaths per year, predominantly due to myocardial infarction and stroke 1, making them the leading causes of mortality worldwide. As a result of both growth and aging of populations, the prevalence of cardiovascular morbidity and mortality continues to rise 2. New therapies are therefore constantly being sought to both prevent and treat cardiovascular diseases.

Traditional Chinese medicine (TCM) encompasses a broad range of holistic therapies, originally developed in ancient China, which are used globally to treat a multitude of pathologies, including cardiovascular diseases. The key principle underlying TCM is ‘qi’, a vital life force that is said to circulate within the body and to lead to the development of illnesses when its flow is obstructed. TCM is used in various forms, including herbology, acupuncture, and physical exercises, such as t'ai chi, in an attempt to improve the circulation of qi and thus relieve symptoms of disease. Other aspects may include the manipulation of ‘yin’ and ‘yang’, two complementary yet contrary forces that are said to lead to health and well‐being when in harmony, and to illness when they are unbalanced. These concepts are not recognized in pharmaceutical medicine (PM), where there is a greater focus on achieving physiological and symptomatic targets with the use of pharmacological agents that have regulatory quality controls.

Up to 75% of the world's population rely on traditional or herbal medications as part of their basic healthcare, and safety control measures are variable 3. Indeed, there are numerous reports of hepatotoxicity 4, renal failure 5 and cardiotoxicity 6 resulting from herbal medicine use, as well as potential drug interactions. To date, relatively few studies have been performed to evaluate the efficacy of TCM in the treatment of cardiovascular diseases. Here, we systematically review the available data on TCM in the management of some of the most important cardiovascular diseases: hypertension, acute ischaemic stroke, heart failure, coronary heart disease and type 2 diabetes

Methods

Search strategy and inclusion criteria

Electronic databases (PUBMED, MEDLINE and EMBASE) were searched up to 11 November 2015 for all studies evaluating the effect of TCM on hypertension, ischaemic stroke, heart failure and coronary heart disease. All languages were searched, but only those where the results sections were in English were included. The Medical Subject Headings text words or key words used in the search were ‘traditional Chinese’, or ‘Chinese herbal’, or ‘acupuncture’ in combination with each of the following terms: ‘coronary artery’, ‘coronary heart’, ‘angina’, ‘myocardial infarction’, ‘acute coronary’, ‘hypertension’, ‘hypertensive’, ‘antihypertensive’, ‘blood pressure’, ‘heart failure’, ‘BNP’, ‘systolic function’, ‘diastolic function’, ‘left ventricular’, ‘stroke’, ‘cerebrovascular’, ‘ischaemia’, ‘ischaemic’ and ‘diabetes’. Studies were required to be randomized‐controlled trials with adult human subjects, comparing the effect of TCM with placebo therapy or PM on clinical parameters for at least 2 weeks. Hard end‐points, such as systolic blood pressure data, and inclusion of the standard deviation or standard error of mean for data points were required. Figure 1 shows a breakdown of the search.

Figure 1.

Search strategy. Summary of the search strategy used to identify eligible studies for the systematic review

Statistical analysis

Data were analysed using Comprehensive Meta‐analysis version 3 software (Biostat, USA). A meta‐analysis was conducted for hypertension only, as this was the only condition with the use of consistent outcomes and measures of efficacy. A pooled odds ratio (OR) was calculated using a fixed‐effects model, and 95% confidence intervals (CIs) were calculated to assess the strength of the association. Heterogeneity testing was performed and publication bias was assessed using a funnel plot and Egger's regression asymmetry test.

Results

Hypertension

Patients enrolled in the studies were required to meet at least one of the current or past guidelines for definitions of hypertension according to the National Institute of Health and Care Excellence 7. Studies that either compared TCM to PM or compared TCM to placebo or no treatment were included. A total of 2254 results were accessed, of which 312 were trials. Of these, 304 trials were excluded for failing to meet the inclusion criteria. As the most data was available for systolic blood pressure (SBP) recordings, this was the parameter used to assess efficacy of treatment (Table 1).

Table 1.

Summary of the hypertension studies included in this review

Study name	Patient group	Intervention	Control	Duration	Control group (n)	Control pre‐treatment SBP (mmHg)	Control post‐treatment SBP (mmHg)	TCM group (n)	TCM pre‐treatment SBP (mmHg)	TCM post‐treatment SBP (mmHg)
Wu et al. 2014 (part A) 8	Essential hypertension commenced on 5mg amlodipine OD	Bushen Qinggan granules	Placebo	8 weeks	45	135.06 ± 13.25	130.37 ± 14.16	45	136.93 ±12.49	129.22 ± 9.71
Wu et al. 2014 (part B) 8	As above	Bushen Qinggan decoction	Placebo	8 weeks	45	135.06 ± 13.25	130.37 ± 14.16	45	138.55 ± 11.02	127.58 ± 12.15
Chen et al. 2013 9	Essential hypertension with metabolic syndrome, long‐term use of CCB or ARB therapy	Yiqi Huaju formula (huangqi, huanglian, puhuang, zexie and yinchen).	Placebo	12 weeks	21	138.43 ± 15.86	141.57 ±13.80	22	141.27 ± 14.28	129.95 ± 11.86
Fu et al. 2009 10	Essential hypertension commenced on 2.5mg levoamlodipine and 40mg telmisartan OD	Songling Xuemaikang capsule	Nil	2 weeks	35	138.0 ± 12.6	119.0 ± 8.5	35	145.0 ± 12.3	118.0 ± 13.2
Wang et al. 2006 11	Obesity hypertension commenced on benzapril 10mg OD	Pinggan Tishen Ditan Yin decoction	Nil	8 weeks	29	149.90 ± 9.43	134.72 ± 6.54	31	151.45 ± 7.51	127.65 ± 6.37
Zhong et al. 2011 12	Essential hypertension	CGSHY decoction	Enalapril 10‐20mg OD	12 weeks	32	148.3 ± 9.8	122.6 ± 8.9	32	148.9 ± 10.5	119.4 ± 10.2
Li et al. 2010 13	Elderly, isolated systolic hypertension	Jiangya capsule	Nimodipine 20mg TDS	4 weeks	24	143.21 ± 13.92	131.92 ± 11.34	24	142.21 ± 12.15	131.82 ± 10.56
Flachskampf et al. 2007 14	Uncomplicated essential hypertension	Acupuncture	Sham acupuncture	6 weeks	77	129 ± 9	130 ± 11	83	131 ± 13	125 ± 12

SBP: systolic blood pressure

Seven randomized controlled trials were identified, four of which compared TCM to placebo or no treatment 8, 9, 10, 11 and were subsequently included in the meta‐analysis (Figure 2). One of the larger studies compared two formulations of the same TCM therapy, with both producing statistically similar results 8; therefore, to avoid introducing bias, only one of the formulations (Bushen Qinggan granules) was included within the meta‐analysis. Three of the four studies showed a significant reduction in SBP in patients treated with TCM compared with placebo or no treatment, as measured by 24‐hour ambulatory blood pressure monitoring (ABPM). An odds ratio of 3.781 (95% CI 2.392, 5.977; P = 0.000) was observed for the anti‐hypertensive effect of TCM. Significant heterogeneity was present (P = 0.011), with a tendency towards publication bias that did not reach significance (P = 0.05275).

Figure 2.

Meta‐analysis of hypertension studies. Forest plot of four hypertension studies in which the anti‐hypertensive effect of TCM was compared with control groups. OR: odds ratio; CI: confidence interval

Among the remaining studies, two compared TCM to standard PM. The first, a study by Zhong et al., assessed the efficacy of a TCM decoction for calming Gan and suppressing hyperactive yang (GSHY) compared with enalapril. There were no significant differences in ABPM parameters between the two groups, the TCM decoction demonstrating a similar antihypertensive effect to enalapril in this setting 12. The second study comprised three groups of elderly patients with isolated systolic hypertension: one taking both TCM (Jiangya capsule) and PM (nimodipine tablet), one taking TCM and a simulated PM tablet, and one taking PM and a simulated TCM capsule 13. The TCM therapy was once again found to be of similar efficacy to PM, and the reduction in SBP was amplified when both TCM and PM were used in combination. Lastly, Flachskampf et al. assessed TCM acupuncture as a potential treatment for essential hypertension 14. They found that this significantly lowered SBP immediately following the procedure when compared with sham acupuncture, but blood pressure returned to baseline post‐intervention. The components of commonly used TCMs for the treatment of hypertension and other cardiovascular diseases are summarized in Table 2 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29.

Table 2.

Components of commonly used TCM for the treatment of cardiovascular disease. The table contrasts the TCM and WM teachings and identifies potential mechanisms of action for these treatments

Selected TCMs used in cardiovascular studies	Mode of action based on TCM teaching	PM diagnosis	Potential mode of action in treatment of cardiovascular disease	Components
Bushen Qinggan	Treats liver fire syndrome by suppressing liver yang hyperactivity. Relieves dizziness, sensations of swelling of the eyes and vexation	Hypertension	Several components may reverse myocardial remodelling 15	Rhizome gastrodiae (orchid), Uncaria rhynchophylla (cat's claw herb), Eucommia bark (rubber tree), Scutellariae (mint ‘skullcaps’) and bitter butyl tea
Yiqi Huaju formula (huangqi, huanglian, puhuang, zexie and yinchen)		Hypertension	In a murine model, Yiqi Huaju reduces arterial pressure in salt‐sensitive hypertension by inhibiting renin–angiotensin system activation 16	Radix astrsgali (milk vetch root), Rhizoma coptidis (Chinese gold thread), Pollen typhae (cattail pollen), Rhizoma alismatis (water plantain tuber), and Artemisia capillaris (oriental wormwood)
Songling Xuemaikang capsule	Prescribed for patients with dizziness or vertigo. Acts by cooling the liver and suppressing liver yang	Hypertension	Powdered Pinctada maxima has been shown to reduce visceral fat deposits and serum triglyceride levels in rodents 17	Radix puerariae lobatae (kudzuvine root), pinus densiflora (pine needles) and powdered Pinctada maxima (pearl oyster shell)
Pinggan Tishen Ditan Yin decoction		Hypertension	Possible modulation of diuresis vai sodium‐chloride co‐transporter in the distal tubule in a murine model 29. Several components may reverse myocardial remodelling 15	Rhizome gastrodiae (orchid), Uncaria rhynchophylla (gambir plant), Alisma plantago‐aquatica (mad‐dog weed/common water‐plantain), Radix achyranthis (achyranthes root), Rhizoma atractylodis macrocephalae (bai zhu), Thallus sargassum pallidum (seaweed), Cassia torae (sickle senna), Taxillus chinensis (loranthus), Pheretima aspergillum (earthworm extract), Prunella vulgaris (common self‐heal), and Pinellia ternata (crow‐dipper)
Calming Gan and suppressing hyperactive yang (CGSHY) decoction	Treats liver fire syndrome by suppressing liver yang hyperactivity	Hypertension	Modulates L‐type calcium channels and calcium‐ATPase in hypertensive murine model 28. Several components may reverse myocardial remodelling 15	Rhizome gastrodiae (orchid), Uncaria rhynchophylla (gambir plant), Concha haliotidis (abalone shell), Concha ostrae (oyster shell) and Radix achyranthis (achyranthes root)
Jiangya capsule	Treats liver fire syndrome by suppressing liver yang hyperactivity	Hypertension	Downregulates growth factor‐β1 in hypertensive murine model 27	Radix achyranthis (achyranthes root; 2 formulations used), Pheretima aspergillum (earthworm extract), Thallus sargassum pallidum (seaweed), Rhizome gastrodiae (orchid) and Szechwan lovage rhizome (lovage root)
Danqi Piantang Jiaonang (DPJ), formulation MLC601		Stroke	Stimulates neurogenesis and improves cognitive outcomes in murine models of cerebral ischaemia 18	Herbal components: Radix astragali (milk vetch root), Radix salvia miltiorrhizae (Danshen root), Radix paeoniae rubra (red peony root), Rhizoma chuanxiong (Sichuan lovage rhizome), Radix angelicae sinensis (female ginseng), Carthamus tinctorius (safflower), Prunus persica (peach), Radix polygalae (polygala root) and Rhizoma acori tatarinowii (sweetflag)
				Animal components: Hirudo (leech), Eupolyphaga seu steleophaga (ground beetle), Calculus bovis artifactus (cattle gall stones), Buthus martensii (Chinese scorpion), and Cornu saigae tataricae (antelope horn)
Danqi Piantang Jiaonang (DPJ), formulation MLC901		Stroke	Stimulates neurogenesis and improves cognitive outcomes in murine models of cerebral ischaemia 18	Herbal components, as per MLC601
Danhong injection	Syndromes of blood stasis, acts to promote blood circulation	Coronary heart disease	Studies in ApoE‐/‐ and LDLR ‐/‐ mice show reduced HMG‐CoA reductase messenger RNA expression, reduced LDL levels and macrophage accumulation 19	Radix salviae miltiorrhizae (Danshen) and Carthamus tinctorius (safflower)
Compound chuanxiong capsule with xinyue capsule	Chuanxiong is used in the treatment of headache. Xinyue is thought to provide beneficial effects on qi and yin to promote blood circulation	Coronary heart disease and stroke	Compound chuanxiong attenuates inflammatory responses in ApoE(‐/‐) mice, reducing plaque size and serum lipid levels 20	Compound chuanxiong: Rhizoma chuanxiong (Sichuan lovage rhizome) and Radix angelicae sinensis (female ginseng).
				Xinyue capsule: saponin of ginseng leaves and stem
Tongxinluo	Compound formulated based on TCM meridian theory	Coronary heart disease	Improves endothelial function after chronic hypoxia and promotes hypoxia‐induced angiogenesis 21. Lowers serum lipid levels and stabilizes vulnerable plaques in a rabbit model 22	Radix ginseng (ginseng root), Buthus martensi scorpion, Hirudo (leech), Eupolyphaga seu steleophaga (ground beetle), Scolopendra subspinipes (centipede), Periostracum cicadae (cicada shell), Radix paeoniae rubra (red peony root), Semen ziziphi spinosae (spine date seed), Lignum dalbergiae odoriferae (Dalbergia wood), Lignum santali albi (sandalwood), and Borneolum syntheticum (Bing Pian)
Xuezhikang	Strengthens the spleen and promotes digestion. Increases blood circulation	Coronary heart disease	Modulates cholesterol homeostasis 23 and reduces hypertensive vascular remodelling in murine models 24	Red yeast rice extract
Qili qiangxin capsule	Xin‐Shen Yang deficiency (fluid retention syndrome)	Heart failure	Reduces reactive oxygen species and thus inhibits cardiomyocyte apoptosis in rats following myocardial infarction 18	Radix astragali (milk vetch root), ginseng radix et rhizome (ginseng root), Radix aconiti lateralis (aconite), Radix salviae miltiorrhizae (Danshen root), Semen lepidii (pepperweed seed), Rhizoma alismatis (water plantain tuber), Rhizoma polygonati odorati (yu zhu), ramulus cinnamomi (cassia twig), Carthamus tinctorius (safflower), cortex periploca (Chinese silkvine root‐bark), and Pericarpium citri reticulatae viride (green tangerine peel)
Kanlijian	Xin‐Shen Yang deficiency (fluid retention syndrome)	Heart failure	Extracts of Astragalus membranaceus attenuate oxidative injury in murine myocardial ischaemia by modulating free radical and intracellular calcium levels 19	Astragalus membranaceus (milk vetch), Radix aconiti lateralis (aconite), Semen lepidii (pepperweed seed), Rhizoma atractylodis macrocephalae (bai zhu) and Radix paeoniae (peony root)

Overall, it appears that targeted TCM can cause significant reductions in SBP and may be comparable with PM in certain cases, based on the results from these small‐to‐medium studies. Larger multi‐centre trials are required, however, to allow firm conclusions to be drawn regarding the anti‐hypertensive effects of TCM.

Stroke

TCM has been extensively studied in the treatment of ischaemic stroke (apoplexy syndromes in TCM) and of post‐stroke morbidities. However, studies have tended to recruit small numbers of participants over variable time courses, for example, any time up to 12 weeks post‐stroke, and have included heterogeneous groups of patients with strokes of varying severity. Randomization techniques were rarely described; and where they were, often the methods used, such as randomizing to treatment or control groups based on gender, rendered the trial data inappropriate for further assessment. Due to the multiple modalities of assessing neurological function with no consistency in the use of functional scoring systems, such as the Barthel Index, Fugl‐Meyer Assessment (FMA) scores and National Institutes of Health Stroke Scale (NIHSS), meta‐analysis was not possible. Studies assessing motor function post‐stroke were included in this review.

Danqi Piantang Jiaonang/NeuroAid therapy

Danqi Piantang Jiaonang (DPJ), marketed across the world as ‘NeuroAid’, is the most commonly used TCM for the treatment of ischaemic stroke (Table 2). When applied to murine models of cerebral ischaemia, DPJ has been shown to stimulate neurogenesis and improve cognitive and motor outcomes 18. The results of re‐analysed data obtained from two unpublished randomized‐controlled trials from 2000, involving a total of 605 participants, demonstrated improved neurological function post‐stroke in those taking DPJ compared with another TCM approved for stroke therapy 30. A multitude of small placebo‐controlled trials followed this, showing variable degrees of mild motor function recovery with DPJ 31, 32, potentially due to increased cerebral arterial blood flow in those taking DPJ 33.

In 2013, the initial results from the multicentre ‘CHInese Medicine neuroaid Efficacy on Stroke recovery (CHIMES)’ trial were published, following recruitment of 1100 participants who had suffered an ischaemic stroke within the preceding 72 hours. Patients were treated for 12 weeks and the primary outcome was a change in the modified Rankin Scale (mRS), indicating functional improvement. The data showed that DPJ was no better than placebo at improving neurological outcomes in patients with acute or subacute ischaemic stroke 34. Subsequent post‐hoc analyses have postulated that certain patient groups, such as those with more severe strokes, may respond better to DPJ than others, but no convincing statistics are available to support this postulate robustly 35, 36, 37, 38.

Acupuncture

Stroke is the condition that is most commonly treated by acupuncture in the Chinese inpatient setting 39. Chinese traditional acupuncture utilizes a series of around 400 acupoints to manipulate the flow of qi through 12 principal meridian channels, which are divided into yin and yang groups and correspond to hollow or solid organs within the body. Electroacupuncture, laser acupuncture and dry needling, which are relatively modern techniques, have not been reviewed. While acupuncture has repeatedly proven to be safe and well‐tolerated, there is limited evidence of efficacy in improving neurological function post‐stroke. Trials to date have tended to involve low patient numbers, and the use of blinding of placebo or control therapies is understandably challenging.

When acupuncture is compared with physiotherapy and conventional rehabilitation, results from larger‐scale multicentre studies have generally found either that it provides no significant improvements in terms of motor function or that it is less effective than physiotherapy in improving functional assessment scores, without any additive/synergistic effects when used in combination with standard rehabilitation 40, 41, 42, 43, 44.

Studies that demonstrate potential benefits of acupuncture include one small trial where acupuncture paired with massage showed significant improvement in functional scores in FMA and NIHSS, but not mRS, compared with those undergoing conventional rehabilitation 45. An additional, larger study identified improved outcomes in patients receiving acupuncture compared with a control group, with six cases of stroke recurrence in the acupuncture group (n = 144) compared with 34 in the control group (n = 143) 46. This study, however, lacked detailed patient characteristics to allow further interpretation of this finding.

To summarize, despite a large number of randomized‐controlled trials investigating potential benefits in neurological recovery in those taking TCM, no effective TCM treatments for ischaemic stroke have been identified to date.

Heart failure

Although there are a variety of TCM drugs used to treat symptoms of heart failure, there is very little consistency in the use of end‐point markers, such as N‐terminal fragment brain natriuretic peptide (BNP) levels or left ventricular ejection fraction (LVEF). Meta‐analysis was therefore not performed. Despite several trials having low numbers of participants, the overall quality of the data was high, with randomization techniques described, and a relatively homogeneous pool of patients, of similar age (50–65 years) who all had chronic heart failure graded as mild to moderate according to the scales used. The results of the selected heart failure studies are included in Table 3. All patients were on optimal PM, including an ACE‐inhibitor (ACE‐I), β‐blocker, diuretic and digitalis preparation if appropriate.

Table 3.

Design and outcomes of the heart failure studies included in this review

Study name	Patient group	Concurrent medications	Intervention	Control	Duration	Control group (n)	TCM group (n)	Outcome
Jiang et al. 2006 47	Heart failure patients suffering from Xin‐Shen Yang deficiency	All patients were on an ACE‐I, β‐blocker, diuretic and digoxin if indicated	Kanlijian	Nil	24 weeks	21	39	TCM syndrome scores improved in the TCM group compared with placebo
								LVEF% significantly improved in the TCM group and remained unchanged in the placebo group
								Frequency of hospital admission over 1 year was reduced in the TCM group
Ma et al. 2010 48	Chronic heart failure patients	All patients on optimal WM as above	Shemnai injection (Radix ginseng and Radix ophiopogonis)	Nil	2 weeks	31	33	Average movement velocity of the mitral ring (a marker of haemodynamic function) was statistically improved in the TCM group compared to baseline but there was no overall statistical significance between the TCM and control groups
Kristen et al. 2010 49	Chronic heart failure patients with LVEF <40%	All patients on optimal WM as above	Genuine acupuncture	Sham acupuncture	5 weeks	8	9	Significantly improved 6 minute walking distance in the TCM group
Li et al. 2013 52	Patients with chronic heart failure	All patients on a combination of ACE‐I and β‐blocker	Qili qiangxin	Placebo	12 weeks	247	244	BNP levels were reduced in both TCM and placebo group but the reduction was significantly greater in the TCM group
Liu et al. 2014 51	Chronic heart failure patients	All patients on optimal WM as above	Xinmailong (American cockroach extract)	Nil	12 weeks	51	51	Gated myocardial perfusion imaging demonstrated a significant increase in LVEF% in the TCM group
								There was a significant reduction in BNP levels in the TCM group
Gong et al. 2010 50	Hypertensive patients with left ventricular hypertrophy	All patients on optimal WM plus introduction of valsartan	Xuezhikang	Nil	24 months	30	32	Improved left ventricular mass index scores in the treatment group receiving TCM in addition to valsartan, compared with those taking only valsartan

The signs of heart failure, such as peripheral oedema and shortness of breath, may be considered to represent Xin‐Shen Yang deficiency or fluid retention syndromes in TCM. Jiang et al. treated a group of patients with dual TCM and PM diagnoses of fluid overload with Kanlijian TCM and compared this to a control group 47. They identified that, in addition to improving TCM symptoms, there was a significant increase in LVEF in patients taking Kanlijian. Closer inspection reveals that the baseline LVEF was markedly lower in this cohort compared with the control group (43% vs. 52%), which may account for the difference observed.

Other small studies have identified that, in those taking TCM, measures including average movement velocity of the mitral ring (a marker of haemodynamic function) 48, 6‐minute walking distance 49, and left ventricular mass index scores 50 were improved compared with the control groups. A study of 102 patients randomized to TCM or control found that LVEF increased whilst BNP levels fell in patients allocated to receive TCM 51. The largest study included in this review recruited around 500 patients with heart failure to receive a TCM mixture or placebo, and identified a significant reduction in BNP levels in the treatment group, indicating improved cardiac function 52.

Whilst there are some promising results for the treatment of heart failure with TCM, the majority of the studies recruited small numbers or participants, making it challenging to extrapolate results reliably. Further large‐scale and well‐designed studies to evaluate fixed outcomes, such as BNP levels and LVEF, would be useful to better evaluate the place of TCM in heart failure.

Coronary heart disease

Coronary heart disease encompasses a spectrum of clinical presentations, with patients ranging from having no symptoms to those presenting with stable angina or acute coronary syndromes. Of the 310 clinical studies accessed, 12 were included in this review. Outcome measures were diverse and thus not suitable for meta‐analysis.

Acupuncture was evaluated as a possible treatment for stable ischaemic heart disease in several small studies, with variable results. One trial compared genuine and sham acupuncture and found no difference in improvement of angina frequency or severity of attacks between the two groups, although there was a median reduction of 50% in anginal attack rate in both groups, implying a potentially beneficial effect from both genuine and sham acupuncture treatments 53. A similar study conducted in patients with stable ischaemic heart disease found a significant increase in heart rate variability, which has positive prognostic value, in patients receiving genuine acupuncture compared with sham treatment 54. T'ai chi has also been evaluated as a potential therapy and, whilst it does not modify measures such as heart rate variability, it has been demonstrated to improve baroreflex sensitivity 55. Herbal therapy with Shenshao tablets 56 and Quyu Xiaoban capsules 57 have been shown to reduce the frequency of angina attacks compared with control treatments.

In patients with a history of previous myocardial infarction (MI), a multicentre study involving 2704 patients with ongoing hypertension compared Xuezhikang TCM with a control group, and found that those receiving treatment had a 43% reduction in coronary events 58.

A study evaluating Tongxunluo herbal therapy in patients undergoing percutaneous coronary intervention (PCI) for ST‐elevation MI identified a significant reduction in ST‐elevation compared with the control group at multiple time points, alongside increased myocardial perfusion scores, indicating a potential therapeutic role for TCM alongside PM 59. A subsequent study evaluated the use of Compound Chuanxiong capsule with Xinyue capsule in the PCI setting and found a significant reduction in the incidence of major cardiac events compared with the placebo group. These data, however, appear to have been obtained by pooling the sums of all adverse events, including the development of heart failure, angina and recurrent MI, and therefore likely overestimate the effect of a small number of unwell patients with multiple clinical problems 60.

With such a wide range of possible clinical presentations and a lack of consistent outcomes, it is difficult to arrive at definitive conclusions when evaluating the effect of TCM in this group of patients. Individual trials suggest potential benefits, but reproducible data in larger studies are required before definitive conclusions can be reached.

Type 2 diabetes mellitus (T2DM)

A multitude of clinical studies have been carried out looking at the relationship between TCM and glycaemic control; however, there have been relatively few randomized‐controlled trials in patients with T2DM. Whilst a meta‐analysis was not possible, primarily due to both the variety of biomarkers of glycaemic control that have been assessed, including glycated haemoglobin (HbA1c), plasma glucose, fasting plasma glucose and C‐peptide levels, and the heterogeneity of patients recruited for studies, there was ample literature available for review.

Tong et al. conducted one of the larger randomized‐controlled trials, using TM81 (Tang‐Min‐Ling‐Wan), a formula based on a classic combination of TCM herbs, including Rhizoma coptidis and Radix paeoniae alba. They found a significant reduction in HbA1c and fasting plasma glucose levels in those who received TM81, compared with those who received placebo 61. Similarly, positive results were found in a multicentre randomized‐controlled trial administering either Tianqi (a mixture of 10 herbal medicines, including Astragali radix and Ginseng radix) or placebo to patients with impaired glucose tolerance. They found that those taking the Tianqi capsule were more likely to develop normal glucose tolerance over the 12‐month treatment period, and fewer subjects in this group progressed to developing T2DM compared with the placebo group. Overall, there was a 32% reduction in risk of progressing to T2DM in those taking Tianqi compared with placebo 62.

Interestingly, a number of studies evaluate both the symptom‐based and physiology‐based approaches of TCM and PM respectively, and explore the value of combining the two. Zhang et al. assessed parameters of glycaemic control in 109 patients with pharmacologically treated T2DM who fell into one of three TCM syndromes: intrinsic damp syndrome, internal heat with yin deficiency, and dual qi and yin deficiency. They found that the latter group had comparatively more stable blood glucose profiles, whilst those with internal heat with yin deficiency had significantly higher HbA1c percentage values and higher fasting blood glucose levels 63. Luo et al. divided T2DM into six TCM syndrome groups and found that those with qi deficiency syndrome had higher levels of triglycerides and leptin, and additionally had higher body mass index values. The authors postulate that, according to TCM practice, qi deficiency syndrome leads to chronic fatigue and a general lack of energy, meaning that patients become less active and are prone to weight gain 64. Dual qi and yin deficiency syndrome has also been associated with late‐stage diabetes, where the heat from fire pathogens consumes yin and reduces qi, leading to symptoms of a dry mouth and intense thirst (polydipsia) and treatment aims to restore the balance of qi and yin 65.

Several studies have gone on to assess the benefit of adding TCM to PM treatment. Lian et al. recruited a group of patients with T2DM (based on World Health Organization criteria), who had achieved poor glycaemic control with metformin alone. They treated half of the patients by adding in Jinlinda therapy (a compound of 17 Chinese medicinal herbs) in addition to their regular metformin dose, whilst the other half received a placebo in addition to metformin. The Jinlinda group had a significant reduction in HbA1c percentage values compared to the placebo group 66, indicating that the compound may have hypoglycaemic properties, or possibly improves sensitivity to endogenous insulin.

Rather than adding TCM separately to standard PM diabetic treatment, one group recently published data from a placebo‐controlled randomized trial, where Xiaoke, a compound preparation of glibenclamide (0.25 μg per pill) and TCM herbs, including Radix astralgi and Rhizoma disease (Chinese yam), was produced using modern pharmaceutical techniques to ensure that precise doses of the components were present. Two groups of T2DM patients were recruited – those who were drug‐naïve and those on metformin monotherapy. Patients were randomized to receive either Xiaoke tablets or standard glibenclamide for 48 weeks, with doses of both treatments adjusted every 4 weeks to optimize markers of glycaemic control or to improve tolerability of the drug. Treatment with Xiaoke was reported to produce similar improvements in glycaemic control with a lower risk of hypoglycaemia compared to standard glibenclamide therapy 67. Although the results of this trial are somewhat challenging to interpret, as patients were on varying doses of the drugs, which were up‐ or down‐titrated on a monthly basis at the discretion of the investigators, it appears that in this case, a combination of PM and TCM is efficacious in terms of achieving target physiological control of T2DM whilst addressing TCM syndrome symptoms.

The heterogeneity of patients recruited, without uniform criteria for a diagnosis of T2DM, and the range of outcomes measured, makes it challenging to draw firm conclusions on the efficacy of current TCM compounds in the treatment of this metabolic disorder. There are ongoing clinical trials assessing the combination of PM and TCM for the treatment of T2DM, which may further elucidate the role of TCM compounds in achieving glycaemic control. Indeed, additional ventures, such as the Xiaoke trial, may allow for modernization and standardization of TCM, whilst utilizing a more holistic, symptom‐based approach in PM.

Discussion

The enduring popularity of TCM is likely due in part to the high value society places on continuing tradition and routine practices; but evidence also shows that, in some areas of Asia, younger and more affluent groups of people favour TCM compared with older people who work in so‐called blue‐collar occupations 68. One of the perceived advantages of TCM compared with PM is that it focuses on relieving symptoms rather than improving clinical signs of disease, and typically involves a holistic approach that considers the most appropriate therapy for multiple co‐morbidities.

There were many limitations to this review, which have generated challenges when evaluating and summarizing data. Firstly, only studies with at least their abstract and results section published in English were considered for inclusion, which diminishes the pool of available studies. Secondly, although the selected studies were randomized‐controlled trials, the overall methodological quality was poor, with essential information regarding randomization methods, patient demographics and reasons for participant withdrawal frequently missing from the reports.

Many studies were unable to be blinded, due to the fact that TCM is frequently administered as a highly‐scented liquid decoction several times per day, in contrast to the standard tablet or capsule containing PM. Acupuncture also represented a challenge in terms of blinding, and whilst some studies did utilize sham acupuncture procedures as a control measure, patients are generally able to discern the difference and report feeling less pressure compared with genuine acupuncture needles 43, with the distinct sensation of pressure (De Qi) from a genuine acupuncture needle inducing greater cutaneous and muscular blood flow 44. Additionally, using genuine needles with sham acupoints as a control measure may induce similar cutaneous afferent nerve responses to those of acupuncture 44, thus masking potential benefits, or perhaps identifying that the overall process of acupuncture is efficacious in improving particular disease symptoms, regardless of whether the traditional acupoints are used.

Data from studies assessing potential anti‐hypertensive effects were promising, but basic experimental studies, utilizing animal models to identify pharmacological pathways and mechanisms of drug action, followed by pharmacokinetic/pharmacodynamics and drug safety studies, in addition to large, high‐quality randomized‐controlled trials are required to confirm these preliminary findings. Indeed, for the other cardiovascular diseases assessed, there has been very little convincing data to support the recommendation of TCM for treatment of ischaemic stroke, coronary heart disease and heart failure. TCM was generally very well tolerated in the majority of studies, and its use in the context of cardiovascular disease – notwithstanding the lack of robust evidence of efficacy – may be appropriate alongside PM.

There is currently a pressing demand for studies using animal models to investigate the observed physiological responses with human TCM use (see Table 2), and it is hoped that such studies will help to elucidate pharmacological mechanisms of action and thus also facilitate the development of future therapies based on such mechanisms.

Conclusion

Certain TCM compounds appear to have significant anti‐hypertensive effects, and some may possibly improve outcomes in coronary heart disease and heart failure, but in all cardiovascular disease states discussed in this review, there is a clear need for well‐designed large‐scale randomized‐controlled trials to allow proper evaluation of any potential therapeutic benefit of such therapies.

Competing Interests

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

Layne, K. , and Ferro, A. (2017) Traditional Chinese medicines in the management of cardiovascular diseases: a comprehensive systematic review. Br J Clin Pharmacol, 83: 20–32. doi: 10.1111/bcp.13013.