Traditional Chinese Medicine for Cardiovascular Disease - Evidence and Potential Mechanisms

Literature - Hao P, Jiang F, Cheng J, et al., - J Am Coll Cardiol. Vol 69(24), June 2017 DOI: 10.1016/j.jacc.2017.04.041

Traditional Chinese Medicine (TCM) is receiving increasing attention of clinicians for a possible role in the prevention and treatment of CV disease. In Western countries, it is mostly considered complementary or alternative medicine, because of the lack of objective and quantitative evaluation criteria. In China, however, over 71.2% of patients who have experienced Western Medicine, TCM and a combination of the two, preferred the integrative approach, and 18.7% chose TCM as their favorite [1]. TCM is also increasingly welcomed in many developed countries. It has been described that patients who use more types of TCM tend to use less guideline-recommended Western medicine [2].

TCM is often criticized or even rejected because of several reasons:

• It often contains multiple ingredients with many chemical molecules, making it impossible to elucidate therapeutic mechanisms
• Efficacy and safety cannot be guaranteed, because TCM medication does not undergo rigorous approval procedures, like Western drugs do.
• Most TCM clinical studies were conducted in China, and are of poor quality. The conclusions drawn are not accepted by Western society.

High-quality clinical trials were lacking, but recently some randomized clinical trials have advanced modernization of TCM [3]. Still, the methodology is not always optimal, for a variety of reasons. This study aimed to critically evaluate the beneficial and detrimental effects of TCM in patients with CVD, as well as the underlying mechanisms. Studies of RCTs using pre-defined, strict inclusion and exclusion criteria published in the past 10 year were considered. 56 Randomised, double-blind clinical studies with at least 50 cases were included, with follow up duration of at least 4 weeks, evaluating quantitative measurements of surrogate endpoints and/or adverse CV events and/or adverse drug effects. Methodological quality was evaluated with a Jadad score between 0 (weakest) and 5 (strongest)[4]. Only studies with Jadad score >3 were included.

Here, we briefly summarize the findings for specific CVD risk factors

TCM effect on hypertension | Based on 8 RCTs with generally high methodological quality (7 times Jadad score of 5), the authors write that some TCM medications have certain antihypertensive effects. They have a good safety profile, and may serve as an alternative approach for those who cannot tolerate or afford Western medicine. Long-term effects remain unclear.

Tiankuijiangya tablet, Zhongfujiangya capsule and Qiqilian capsule have been shown to lower both systolic and diastolic blood pressure (BP), and the effect of Zhongfujiangya was similar to that of benazepril. Jiangya capsule lowered systolic, but not diastolic BP, although no substantial difference was seen between Jiangya and nimodipine treatment. Jiangyabao lowered systolic and diastolic BP at night, but not during the day.

A rigorous study randomizing 192 hypertensives to active or sham acupuncture twice daily for 6 weeks, did not see differences in change in systolic and diastolic BP from baseline to 10 weeks after randomization between the two groups. Nor was a treatment effect evident after 12 months.

TCM effect on dyslipidemia | Some TCM herbs, among which red sage root, maybush, ginkgo and curcuma root, have been described to be effective in lowering serum lipid levels. Based on 6 eligible RCTs with low methodology quality (1 Jadad score 5, 5 times 3 or 4), the authors conclude that some TCM medications have potent lipid-lowering effect.

The only high quality RCT evaluated treatment with Jiangzhitongluo capsule in addition to atorvastatin, for 8 weeks, in 138 patients with triglycerides (TGs) >1.7 mmol/l and LDL-c >3.37 mmol/L. The treatment significantly lowered TGs, but did not affect LDL-c, total cholesterol (TC) and HDL-c as compared with placebo. A study (Jadad: 3) evaluating 6 months of treatment with Salvia miltiorrhiza and Pueraria lobate capsule in 165 post-menopausal women, found a significantly lower change in carotid intima-media thickness (cIMT) from baseline in those receiving the capsule, as compared to placebo (-0.57% vs. 0.03%), along with greater decreases in serum levels of LDL-c and TC. In another RCT (Jadad: 4), Zhibitai treatment for 8 weeks showed similar levels of TGs, TC, LDL-c and HDL-c as atorvastatin treatment. Other studies showed significantly lower levels of TG and TC upon treatment with Xiaoyujiangzhi capsule, Propolis and ginkgo extract, or glossy ganoderma and sea cucumber extract as compared with placebo. These studies did not measure cIMT.

TCM effect on diabetes | 6 out of 10 RCTs studying TCM in type 2 diabetes (T2DM) had a Jadad score of 5. Based on all studies, the authors conclude that TCM medications like Xiaoke, Tangminling, Jinlida, and Jianyutangkang haven potent beneficial effects on glycemic control and/or beta-cell function in patients with T2DM. Some other medications, such as Tangzhiping and Tianqi seem to prevent progression from pre-diabetes to diabetes. It is unknown whether they affect long-term outcomes.

A large non-inferiority study compared Xiaoke pill with glibenclamide treatment in T2DM patients. Glycemic control was improved to similar extents in both groups, but Xiaoke treatment reduced the risk of hypoglycemia. Another large RCT compared Tangminling pill with placebo in overweight individuals with early stage T2DM. After 12 weeks of treatment HbA1c was more strongly decreased with Tangminling, and fasting plasma glucose (FPG) was decreased while it showed a mild increase in the placebo group. Tangminling also improved beta-cell function, especially in those with higher HbA1c at baseline. Body weight, BMI and waist circumference and diabetes symptoms were also improved with Tangminling. Another RCT showed similar effects of Tangminling.

An RCT comparing 12 weeks of Jinlida granule with placebo in addition to metformin, and another RCT that compared 8 weeks of Jinlida directly with metformin, showed improvements in glucose metabolism (HbA1c, FPG, 2-hour plasma glucose [PG]) with Jinlida treatment. 26 weeks of treatment with Jianyutangkang tablet has also been demonstrated to improve glucose measures as compared with placebo. None of these treatment lead to serious adverse events. No beneficial differences from placebo on glucose metabolism have been observed with 6-ingredient rehmannia pill and Folium ginkgo tablet. In lower quality RCTs, Jintangning capsule also positively affected glucose measures, and improved glycemic control similar to acarbose treatment, while Tangke capsule had less clear effects.

Five studies (2 with Jadad score 5, 3 with score 4) looked into prediabetes. Persons with impaired glucose tolerance receiving Tangzhiping for 2 years showed less annual morbidity from diabetes than those on placebo. In a similar patient group, 12 months of treatment with Tianqi reduced the risk of diabetes by a third compared with placebo. Lower-quality studies showed a lower risk of developing diabetes after 12 months of Tianqijiangtang capsule or Jinqijiangtang tablet in individual with pre-diabetes, while Yitangkang granule decreased 2-h PG in overweight individuals, but not HbA1c or FPG levels.

TCM for ASCVD | 13 included RCTs focused on TCM and CAD (3 times Jadad score 5, 3 with 4, and 7 with score 3). The evidence suggests that some TCM medications might be effective in alleviating angina symptoms, myocardial perfusion abnormalities or neurological deficit in patients with CAD or ischemic stroke, and Xuezhikang might even reduce recurrent CV events after MI. More high-quality, large-scale RCTs are, however, required to draw more definite conclusions.

A high-quality study evaluated the effect of Xuezhikang, a partially purified extract of red yeast rice, on serum lipid levels and CV endpoints in almost 5000 patients with previous myocardial infarction (MI). After a mean of 4.5 years after randomization to Xuezhikang or placebo, the Xuezhikang group showed significantly fewer primary CV events (5.7% vs. 10.4%) and better lipid profiles. In another large RCT on secondary prevention of MI, the Qishenyiqi dripping pill had similar effects to aspirin in preventing recurrence of vascular events, and Qishenyiqi treatment yielded fewer adverse effects than aspirin.

RCTs with lower methodological quality have demonstrated that Xiongshao, Salvia miltiorrhiza and Pueraria lobata, Tongxinluo, compound red sage root and Xinyue were compellingly efficacious in improving hard and/or surrogate endpoints. For instance, 6 months of Xiongshao treatment ameliorated restenosis as compared with placebo (24.1% vs. 48.5%), and combined therapy with Salvia miltiorrhiza and Pueraria lobata improved flow-mediated dilation and cIMT. Tongxinluo capsule reduced myocardial no-reflow and infarction area, and improved myocardial perfusion after primary PCI for acute MI. Another combination therapy of compound red sage root tablet and Xinyue capsule significantly improved myocardial perfusion as compared with placebo in patients undergoing primary PCI for MI. No serious adverse events were noted with these medications.

Five studies compared TCM with placebo with regard to ischemic stroke (2 trials with Jadad score 5, 3 with 4). In an RCT in which 140 patients with ischemic stroke were assigned to receive Sanchitongshu capsule (Radix/Rhizoma notoginseng extract) (n = 71) or placebo capsule (n = 69) treatment, Sanchitongshu capsule significantly ameliorated neurological deficit and daily activity compared with placebo. In another study of TCM in 880 patients who had ischemic stroke, the probability of achieving functional independence (modified Rankin scale) was significantly higher with Danqipiantan treatment at 6 months, which persisted up to 18 months after stroke. After 24 months, however, the difference was no longer significant. Total mortality and vascular event rates were similar between Danqipiantan and placebo groups. Again, the TCM medications were generally well tolerated.

Lower quality studies showed improvement of neurological dysfunction as compared with placebo, upon treatment with Naoxinduotai capsule, Ginkgo tablet, and Dihuangyinzi tablet. CV events were not analyzed, and cerebral perfusion was not measured in these studies.

TCM for chronic heart failure | 9 RCTs could be included, 4 of which had Jadad score of 5, 2 had score 4 and 3 score 3. 6 RCTs evaluated effective response of treatment as measured by an increase of at least 1 in NYHA functional class. The authors conclude that the data suggest that some TCM medications, like Qiliqiangxin, Nuanxin, Shencaotongmai, and Yangxinkang may improve cardiac remodeling and function in patients with chronic HF, with a good safety profile. Long-term outcomes of patients using these TCM medications remain unknown.

High-quality RCTs demonstrated that Qiliqiangxin capsule, Nuanxin capsule, Shencaotongmai granule, and Yangxinkang tablet were efficacious in improving hard and/or surrogate endpoints. For instance, after 12 weeks of treatment Qiliqiangxin capsule significantly lowered the level of Nt-proBNP (-24.7% vs. 0.0% with placebo, 512 patients with chronic HF enrolled), and it was superior with regard to altering NYHA functional class, left ventricular ejection fraction (LVEF), 6-min walking distance (6MWD), quality of life and composite cardiac events. It is speculated that the beneficial effects of Qiliqiangxin on cardiac remodeling may involve an effect on the balance between proinflammatory and anti-inflammatory cytokines in cardiomyocytes, and down-regulation of the cardiac chymase signaling pathway and angiotensin II production. In another Jadad score 5 RCT, patients with chronic HF randomized to Nuanxin capsule showed a lower rehospitalization rate (23.9% vs. 53.4%) and incidence of acute HF (22.5% vs. 42.5%) and a higher effective response rate (78.9% vs. 64.4%) as compared with those randomized to placebo.

A lower quality RCTs also showed a better effective response rate with 12 months of Nuanxin treatment as compared with placebo (89.6% vs. 72.3%). Shencaotongmai granule was also associated with a better effective response rate and higher LVEF than placebo, after 12 weeks of treatment. Effective response and improvement of physical signs was also better with Yangxinkang tablet than with placebo. In all these studies, adverse reactions were similar for the TCM and placebo.

With regard to surrogate endpoints in patients with chronic HF, Yiqihuayu, Qiangxintongmai, and Yangxin were shown to be efficacious in improving them.

Potential limitations of available RCTs.

Most RCTs had small sample sizes and often only assessed surrogate endpoints. Hence, the therapeutic effect of TCM on hard endpoints remains unknown. Some studies did not give information on the quality of the placebo used. Publication bias may have occurred, for instance by publication of only positive results, and beneficial effects being achieved by experienced TCM practitioners, or results being published only in TCM journals, and lack of data provided about potential drug interactions.

Pharmacological effects of TCM ingredients on CVD and potential mechanisms.

A range of compounds have been isolated from TCMs and shown to have beneficial effects on the CV system, among which various polyphenols,, terpenoids, saponins and alkaloids. Some are ascribed antioxidant or anti-inflammatory characteristics, while others may interfere with endoplasmic reticulum stress-induced apoptosis.

Many TCM medications are prescribed as a complex formula of multiple compounds, often further manipulated by the practitioner for an individual patient. Moreover, active ingredients in TCM may affect multiple molecules or pathways. Thus, it is immensely challenging to interpret the observed therapeutic benefits of TCMs using contemporary pharmacological analytical methods, in the context of the single-compound-single target paradigm.

Conclusion.

RCT evidence suggests that some TCM medications might be effective in control of CV risk factors, such as hypertension, dyslipidemia and diabetes/pre-diabetes and some may exert beneficial effects on ASCVD and chronic HF. Some TCM medications, of which the pharmacological effects and the underlying mechanism of active ingredients have been unraveled, may be used as complementary and alternative approach for primary and secondary prevention of CVD. Further rigorously designed RCTs remain warranted, especially focusing on total mortality and major adverse CV events in patients with existing CV disease.

References

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