Hypertension, defined as systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP)≥90 mmHg, is a prevalent chronic condition and a leading modifiable risk factor for cardiovascular disease (CVD) and mortality worldwide. The 2012–2015 China Hypertension Survey revealed that nearly a quarter of Chinese adults (approximately 244.5 million) had hypertension, and over two-fifths (around 435.3 million) had prehypertension. Alarmingly, less than a third of individuals with prehypertension are receiving treatment, and fewer than one in twelve have achieved adequate blood pressure (BP) control (Lu et al., 2017; Wang et al., 2018). Furthermore, every 10 mmHg increase in SBP raises the risk of ischemic heart disease by approximately 30%, About half of all vascular deaths in China are attributable to elevated BP (SBP >120 mmHg), resulting in nearly one million deaths annually in people under 80 years of age (Lacey et al., 2018). Despite many beneficial changes in people’s lifestyles, the incidence and prevalence of hypertension continue to rise in China due to population growth and aging, as well as adverse lifestyles such as unhealthy diets and insufficient physical activity (Zhao et al., 2019). Therefore, achieving tight BP control in hypertensive patients is imperative to prevent cardiovascular morbidity and mortality.

Pharmacological management of hypertension has advanced over the years, yet several limitations remain. One of the primary issues is poor adherence, encompassing failure to initiate medication, adhere to treatment long-term, and take medication as prescribed, which has been identified as a key contributor to suboptimal BP control among hypertensive individuals (Burnier and Egan, 2019; Jiang et al., 2020). Furthermore, antihypertensive drugs may lead to electrolyte imbalances, orthostatic hypotension, angioedema, cough, and other unfavorable reactions, which can compromise patient adherence and hinder treatment success (Shira et al., 2015; Hripcsak et al., 2020; Albasri et al., 2021).

Traditional Chinese medicine (TCM) has been used for over two millennia in China to treat a wide range of illnesses and has yielded notable outcomes. Substantial evidence supports the superior efficacy and safety of combining TCM classic formulas with conventional treatment compared to conventional treatment alone in the management of hypertension (Xiong et al., 2015; Zhang et al., 2020; Lai et al., 2022). The formulation of TCM, Qiangli Dingxuan tablet (QDT) is derived from the ancient formula “Xiong Ma Yin” in “Su Shen Liang Fang."QDT is composed of 5 herbs, including the tuber of Gastrodia elata Blume (Tianma), the bark of Eucommia ulmoides Oliv. (Duzhong), leaf of Eucommia ulmoides Oliv. (Duzhongye), rhizome of Conioselinum anthriscoides ‘Chuanxiong’ (Chuanxiong), and Chrysanthemum indicum L. (Yejuhua). Tianma is the monarch herb that can relieve wind and spasm, suppress liver yang. Yejuhua acts as a minister herb that clears heat and remove toxins, calms the liver Yang. Chuanxiong is a minister herb that invigorates blood circulation, disperses wind, and relieves pain. Duzhong and Duzhongye are the assistant herbs that nourish the liver and kidney, and strengthen the tendons and bones. The combination of these herbs has the potential to soothe the liver, regulate qi, relieve pain, and promote blood circulation. Experiments have shown that these herbs have the effects of regulating the circulatory system, regulating metabolism, regulating intestinal flora, anti-hypertension, anti-ischemia, anti-inflammation, and anti-oxidation (Matias et al., 2016; Bai et al., 2018; Chen et al., 2018; Hu et al., 2020; Sun et al., 2022). Clinical studies have shown that compared with conventional treatment, QDT combined with conventional treatment has a better antihypertensive effect and can reduce the symptoms of vertigo. Currently, QDT is a formally approved Chinese patent medicine by China Food and Drug Administration (approval number: Z61020139), which has been widely used as a complementary treatment for hypertension, hyperlipidemia, and vertigo in China (Zhao, 2018; Li et al., 2019a; Zhang et al., 2021). However, the low quality of existing studies restricts their ability to offer high-quality clinical evidence-based findings (Li et al., 2019b; Xu et al., 2021; Yin and Yan, 2021; Xu, 2022). Therefore, to validate the efficacy and safety of QDT for hypertension treatment, we conducted a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial.

To the best of our knowledge, this is the first randomized, double-blind, placebo-controlled, multicenter trial of QDT for the treatment of essential hypertension. After 12 weeks of treatment, office SBP and DBP were significantly lower in the QDT group than in the placebo group. The mean difference in office SBP reduction between the two groups was 6.86 mmHg (95%CI, 4.84–8.88), and the mean difference in office DBP reduction was 4.64 mmHg (95%CI, 3.10–6.18). In addition, QDT can significantly improve TCM symptoms, especially dizziness, impetuosity, insomnia, and tinnitus. The treatment with QDT for 12 weeks did not result in serious AE in patients with essential hypertension. Our study indicates that QDT is a relatively safe medication that can be used as an adjunctive treatment for hypertension under the guidance of a TCM practitioner.

QDT is a formally approved Chinese patent medicine, which has been widely used as an alternative approach for hypertension and vertigo in China. Previous meta-analysis (Ji et al., 2022) showed that QDT combined with conventional treatment was superior to conventional treatment alone in reducing BP and improving clinical efficacy. Similarly, a meta-analysis of 27 studies involving 2,766 patients with vertigo showed that QDT combined with Western medicine could significantly increase cerebral blood flow, reduce BP, improve vertigo and headache symptoms, and had few adverse reactions (Zhang et al., 2022). However, due to the low level of evidence of the included studies, such as low methodological quality (no description of the generation of randomized sequence, blinding, selective outcome reporting, other biases, etc.), small sample size, and incomplete safety reporting. Therefore, although QDT is a formally approved TCM and is commonly used to treat symptoms related to hypertension, its efficacy and safety in reducing BP remain uncertain. As the first placebo-controlled trial of QDT, our study shows that QDT has a significant BP lowering effect in patients with essential hypertension and has good safety.

The goal of hypertension treatment is not only to reduce BP itself, but also to improve the quality of life of patients and reduce the morbidity and mortality of cardiovascular and cerebrovascular diseases. TCM has the advantage of holistic treatment, which can improve symptoms and treat diseases by correcting the imbalance of the human body’s environment (Huang et al., 2021). In this study, we found that QDT could significantly improve the TCM symptoms of hypertensive patients, including dizziness, impetuosity, insomnia, tinnitus, etc., which is particularly important for improving the quality of life of patients. In addition, this study found that QDT had the potential ability to improve blood lipids, although no statistical difference was shown. Therefore, it is hoped that future clinical studies will further verify it.

Hypertension is categorized as “vertigo” and “headache” in TCM, and its main pathogenesis involves the imbalance of Yin and Yang in the liver and kidney (Wang et al., 2014). TCM offers comprehensive and multi-target regulation for hypertension treatment, utilizing its all-round, multi-component, and multi-pathway approach. (Xiong et al., 2013; Li et al., 2021). QDT is composed of 5 herbs, including Tianma, Yejuhua, Duzhong, Duzhongye, and Chuanxiong. We previously found through bioinformatics that the mechanism of QDT in the treatment of hypertension may be related to the PI3K-Akt signaling pathway, Ras signaling pathway, calcium signaling pathway, and cAMP signaling pathway. At the same time, quercetin, kaempferol, acacetin, and syringetin may be the effective components of QDT (Lin et al., 2021). Gastrodin is the main active ingredient obtained from Tianma. Liu et al. (Liu et al., 2015) found that gastrodin (100 mg/kg) injected intraperitoneally for 4 weeks can reduce SBP in spontaneously hypertensive rats (SHR), and the mechanism was related to the inhibition of aldosterone (ALD) and angiotensin II (Ang II) expression by activation of PPARγ. Chen et al. (Chen et al., 2021) demonstrated that gastrodin had a positive effect on the cell viability of homocysteine-induced human umbilical vein endothelial cells through PI3K/Akt/eNOS and Nrf2/ARE pathways, resulting in a significant decrease in malondialdehyde (MDA), lactate dehydrogenase (LDH) and reactive oxygen species (ROS) levels and an increase in nitric oxide (NO) content. In addition, gastrodin can cause vasodilation in the thoracic aorta. Neochlorogenic acid is one of the effective components of QDT. Neochlorogenic acid inhibited migration and proliferation of vascular smooth muscle cells by inhibiting FAK/small GTPase protein, PI3K/Akt and ras related signals, thus playing an anti atherosclerosis role (Yang et al., 2022). Lignans were the effective fraction of Duzhong for antihypertension. Ouyang et al. (Luo et al., 2010; Li et al., 2014) confirmed that the antihypertensive effect of lignans may be related to the regulation of renin-angiotensin system, direct arterial diastole, and regulation of NO through in vitro and in vivo experiments. Tetramethylpyrazine is an alkaloid and one of the active components of Chuanxiong, which exerts a wide range of cardiovascular protective effects (Lin et al., 2022). For example, tetramethylpyrazine inhibits isoproterenol-induced cardiomyocyte hypertrophy in neonatal mice by decreasing the expression of CaN (Ji et al., 2014). In a study of ApoE^−/− mice fed a high-fat diet, Zhang et al. showed that tetramethylpyrazine (45.05 mg/kgi. g.) to improve dyslipidemia by down-regulating progesterone and ADIPOQ receptor 3 and inhibiting the SCAP/SREBP-1c signaling pathway (Zhang et al., 2017). Linarin is one of the active components of Yejuhua. Studies have shown that linarin can regulate gut microbiota, and reduce the production of LPS, thereby inhibiting the expression of TLR4/Myd88 pathway in blood vessels, improving vascular endothelial function, and ultimately reducing BP in hypertensive rats (Wang et al., 2021). In brief, QDT concentrates on the advantages of these herbs and allows these herbs to play a synergistic role in the treatment of hypertension.

In this study, some limitations need to be acknowledged. First, the duration of treatment was only 12 weeks, which limits our ability to assess the medium to long-term effects and safety of QDT in treating essential hypertension. Second, the secondary outcome of 24-h ambulatory BP measures was not analyzed due to poor patient compliance and excessive missing data. Third, this study was conducted exclusively in the Chinese population, and it remains unclear whether the effects of QDT are consistent in other ethnic groups. Lastly, the COVID-19 pandemic resulted in the dropout of many cases. It is hoped that future QDT studies will refine these limitations.

The efficacy of the combination of QDT and amlodipine besylate is superior to monotherapy with amlodipine besylate in the treatment of essential hypertension. The use of QDT under the premise of syndrome differentiation and treatment holds promise as a potential adjunctive treatment for essential hypertension. However, the above conclusions still require further investigation through rigorous clinical research.