https://orcid.org/0000-0003-1828-2387
This editorial refers to ‘Atrial tachyarrhythmia prevention by Shensong Yangxin after catheter ablation for persistent atrial fibrillation: the SS-AFRF trial’, by H. Huang et al., https://doi.org/10.1093/eurheartj/ehae532.
The term, ‘traditional Chinese medicine’, refers to an extensive array of medicinal composites—derived from plant, animal, and mineral sources—that have been utilized to treat human disease since the 11th century Bce. These medicines are intended to correct an imbalance in Qi—the central vital energy of the body1—by modulating both yin and yang, representing material and immaterial aspects of Qi, respectively. This framework holds that human disease results from overactivity and underactivity of a multitude of interacting causal and compensatory mechanisms, which must be addressed simultaneously to restore physiological harmony. Ingredients from diverse sources are combined, not only to address the disease state, but to modulate the positive and negative features of other components.
The clash of holistic and reductionist medical philosophies
The central premise of traditional Chinese medicine is holistic, i.e. the efficacy of a medicine is related to the interconnectiveness of its components and can be explained only by reference to the whole. The development of these medicines is based on centuries of experience that guided the addition, subtraction, and titration of various ingredients. An ingredient is added or discarded based not on how it might act individually, but how it acts in the context of the entirety of the combination. This approach fundamentally differs from the reductionist framework of Western medicine, which seeks to identify the most basic individual constituents of complex phenomena. In Western medicine, medicines are single well-characterized molecules with a defined mechanism of action, and in general, it is assumed that the effect of each molecule remains unchanged even when combined with others, and thus, the end result can be predicted by understanding the sum of its parts. The validity of these assumptions can be debated.
As a result of their profoundly different world perspectives, practitioners of holistic and reductionist medicine do not typically communicate easily with each other, but the two traditions are not really that different. In both the East and West, new treatments have been derived largely from plant and animal sources, and the formulation of treatments has been empiric, with rigorous trial designs being only a recent phenomenon. The belief that trials of cardiovascular drugs should have a well-characterized patient population, double-blinding and a placebo control, one or two principal pre-specified hypotheses, minimization of a false positive error rate, and adequate statistical power is less than 40 years old. Of course, because of its reductionist focus, it was easy to apply these trial design requirements to Western medicine. The US Food and Drug Administration sets standards for approval, which were followed by the drug and medical device industry.
The rapid emergence of rigorous drug development in China
The development and evaluation of traditional Chinese medicines awaited the establishment of a formal Chinese regulatory body. The State Food and Drug Administration was established in 2013 and was restructured as the National Medical Products Administration in 2018. As a result of this oversight, companies seeking to commercialize traditional Chinese medicines (harvested from holistic traditions) were required to implement high levels of product standardization. All manufactured capsules of any product needed to be reasonably identical, but achievement of that goal required difficult and arbitrary decisions, since—by the very nature of holistic principles—no one actually knew the precise identity or dose–response relationships of any active ingredient or combination of ingredients. To complicate matters, most holistic formulations consisted of a dozen nature-derived ‘ingredients’, and taken together, the capsules delivered 150–200 potentially active molecules (by mass spectrometry). It could not be assumed that those present in the highest concentrations were the most important.
At the same time, investigators in China warmly embraced the methodology of randomized clinical trials. From 2013 to 2021, 965 clinical trials of traditional Chinese medicines were registered, and most were characterized as double-blind, placebo-controlled, and randomized.2 Fewer than 150 trials were related to cardiovascular disease. Unfortunately, in general, these trials were small, of short duration, plagued by difficulties with blinding and substantial missingness, and relied on surrogate endpoints. When efforts were made to summarize the results of these trials in meta-analyses, Chinese investigators believed that the quality of most trials was low.3
Advent of high-quality randomized controlled trials of traditional Chinese medicines in cardiovascular disease
Most Chinese physicians have long prescribed traditional Chinese medicines alongside established Western medicines, and thus, governmental agencies and pharmaceutical companies in China were motivated to sponsor high-quality large-scale randomized trials to determine whether traditional Chinese medicines were effective if used together with the single ingredient drugs developed in the West. Clinical trial expertise evolved rapidly, as the participation of investigative sites in China in international trials grew exponentially. In recent years, Chinese investigators initiated their own development programmes, and the design, execution, and analysis of these trials has been rigorous. Accordingly, the key finding of these trials have been presented and accepted for publication in top-tier medical meetings and prestigious publications in the West. Three examples of this success are particularly relevant to cardiovascular drug development.
Tongxinluo is a proprietary formulation of a traditional Chinese medicine made from 12 individual plant, insect, and mineral ingredients, and is approved in China for the treatment of angina and ischaemic stroke. Tongxinluo has been shown to reduce atherosclerotic plaque vulnerability, both in experimental models and in patients with carotid arterial disease,4,5 and in the double-blind, placebo-controlled CAPITAL trial,5 Tongxinluo decreased the risk of major adverse cardiovascular outcomes, although the benefit was based on a small number of events. Subsequently, in a large definitive confirmatory trial (CTS-AMI),6 Tongxinluo was compared with placebo in a double-blind trial, which randomized 3797 patients with an acute ST-elevation myocardial infarction, receiving all established background treatments. As compared with placebo, patients randomized to Tongxinluo for 1 year experienced large reductions in the risk of cardiovascular death, and especially, of myocardial infarction and stroke (74% and 56% risk reductions, respectively), based on an analysis of >250 events.
Qiliqiangxin is a proprietary formulation of a traditional Chinese medicine made from 11 plant-based sources and is approved in China for the treatment of heart failure. Through an action on nutrient deprivation and surplus signalling, Qiliqiangxin has been shown to enhance cardiomyocyte viability and improve ventricular structure and function in experimental models.1 In a small 12-week double-blind placebo-controlled pilot trial in patients with heart failure and a reduced ejection fraction,7 Qiliqiangxin reduced circulating natriuretic peptides and the risk of adverse heart failure outcomes, although the reported benefit was based on a small number of events. Subsequently, in a large definitive trial (QUEST),8 Qiliqiangxin was compared with placebo (randomized and double-blind) in 3119 patients with heart failure and a reduced ejection fraction, receiving all established background treatments, except for sodium-glucose cotransporter 2 (SGLT2) inhibitors. Patients randomized to Qiliqiangxin experienced a 22% reduction in the combined risk of cardiovascular death and hospitalization for heart failure, based on an analysis of >850 events. Of note, the proposed mechanism of action of Qiliqiangxin overlaps substantially with that of SGLT2 inhibitors.1,9
Finally, Shensong-Yangxin is a proprietary formulation of a traditional Chinese medicine made from 12 plant-based sources and is approved in China for the treatment of heart rhythm abnormalities. Shensong-Yangxin has been reported to mute atrial fibrosis and has actions on ion channels to suppress the initiation and propagation of cardiac arrhythmias.10–12 Small randomized double-blind trials have suggested its efficacy in atrial fibrillation.13 In this issue of the European Heart Journal, the investigators of the SS-AFRF trial present the effects of Shensong-Yangxin capsules (vs. placebo) in 920 patients who underwent catheter ablation for atrial fibrillation and were subsequently treated for 12 months, most of whom were already receiving Western antiarrhythmic drugs.14 Patients who received Shensong-Yangxin were less likely to report recurrent atrial tachyarrhythmias at the end of follow-up (14% vs. 22%), hazard ratio 0.6 (95% confidence interval, 0.4–0.8, P < .001), with modest effects on quality-of-life scores. The number of clinical events was too small to allow for a useful assessment, but the drug had none of the safety issues that plague Western antiarrhythmic drugs. Large-scale definitive trials focusing on the prevention of major clinical events are warranted.
Conclusions
Traditional Chinese medicines are being standardized and commercialized, and are undergoing formal evaluation in large-scale double-blind placebo-controlled trials. Most of these medicines are derived from diterpenoids and triterpenoids (see Graphical Abstract), which are synthesized by plants for their cytoprotective effects,1 and they minimize imbalances in cardiomyocyte cellular signalling, which lead to plaque rupture, cardiomyocyte loss and myocardial fibrosis, and the generation of cardiac rhythm abnormalities. Sceptics should remember that Western medicine was born in botany, and most of our established treatments are derived from plant and animal sources. Although physicians in the West might be perturbed by the holistic administration of dozens of nature-sourced medicinals that simultaneously deliver hundreds of molecules with potential cardiovascular structural and functional effects, in the final analysis, the results of rigorous randomized placebo-controlled trials will speak for themselves.
Declarations
Disclosure of Interest
M.P.ts consulting fees from Abbvie, Actavis, Alnylam, Altimmune, Ardelyx, Amgen, ARMGO, AstraZeneca, Attralus, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Eli Lilly and Company, Imara, Medtronic, Moderna, Novartis, Pharmacosmos, Regeneron, Salamandra.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
