Xiaoji Li, PhD 1, Prof. Youping Hu 2, and Guanhu Yang3
Abstract
Background: The efficacy of Chinese herbal medicine on neurological outcomes has been extensively studied in numerous clinical trials. However, methodological heterogeneity often leads to varied and inconsistent results. In this critique, we analyze the recently published study, “Traditional Chinese Medicine FYTF-919 (Zhongfeng Xingnao Oral Prescription) for the Treatment of Acute Intracerebral Hemorrhage: A Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial” as a representative example, to evaluate its methodology and identify areas for improvement.
Challenge: A large randomized controlled trial (RCT) assessed the efficacy of FYTF-919, a Chinese herbal treatment, for intracerebral hemorrhage (ICH). While the study concluded no significant effects of the treatment on measured outcomes, our critique identifies specific methodological concerns, including the selection of outcome measures, adequacy of the sample size, and potential biases in randomization and blinding. These factors may have contributed to the reported lack of efficacy.
Recommendations: We propose actionable recommendations to enhance the validity, reliability, and clinical relevance of future studies in this field, such as optimizing trial designs, standardizing outcome measures, and improving methodological rigor.
Keywords: Chinese Herbal Medicine, Methodological Critique, Intracerebral Hemorrhage, Randomized Controlled Trial, Traditional Chinese Medicine.
A large-scale, multicenter randomized controlled trial (RCT) investigating the efficacy of the herbal formula FYTF-919 (Zhongfeng Xingnao Oral Prescription) for acute spontaneous intracerebral hemorrhage (ICH) was recently published in The Lancet [1]. While FYTF-919 has a long history of clinical use in Traditional Chinese Medicine (TCM) and previous studies suggest benefits for ICH in reducing intracranial pressure and brain edema, promoting hematoma absorption, and mitigating inflammation and immune dysfunction secondary to intracerebral hemorrhage [2-7], the RCT concluded that the formula had no significant effect on functional recovery, survival, or quality of life.
This result challenges prior evidence and raises important questions about the trial’s methodology. In this critique, we examine key methodological issues that may have influenced the study’s conclusions.
1. Sample allocation
The trial enrolled 1,648 participants diagnosed with ICH based on Western medical criteria, including brain imaging within 48 hours, NIHSS scores (≥8), and GCS scores (7-14). These criteria, while standard in Western medicine for the diagnosis of acute spontaneous ICH, excluded TCM pattern identification, which is essential for tailoring treatment. By applying a generalized treatment approach without accounting for TCM pattern types, the trial may have diluted the clinical efficacy of FYTF-919.
2. TCM Pattern Identification
The main indication for FYTF-919 is categorized as “wind-stroke” (zhongfeng) in TCM. This refers to a fundamental pathomechanism caused by right qi depletion in which factors such as diet, affect-mind, taxation-fatigue and internal damage trigger chaotic counterflow of qi and blood. This in turn produces wind, fire, phlegm, and stasis, which cause obstruction of the brain vessel or blood hemorrhaging outside the vessels. The main clinical manifestations are sudden fainting, hemiplegia, deviated mouth and tongue, sluggish speech or inability to speak, and numbness throughout the body. The corresponding Western medical disease is acute spontaneous ICH, which refers to abnormal brain function due to cerebrovascular disease, including ischemic stroke due to vascular obstruction, as well as hemorrhagic stroke due to intracerebral hemorrhage or bleeding in the cavities surrounding the brain, from a cerebral aneurysm, or due to a cerebrovascular malformation [8]. The clinical trial mentioned in this critique only included patients with acute ICH.
The TCM pattern types of wind-stroke are presented in Table 1.
Table 1: Wind-Stroke Pattern Types
Pathogenesis | Primary Symptoms | Tongue and Pulse | Treatment Principle | |
|---|---|---|---|---|
Repletion patterns | Liver Yang Rising Sudden hyperactivity of liver yang accompanied by the disturbance of wind-fire stirring internally. | Hemiplegia, deviation of the mouth and tongue, impaired speech, dizziness accompanied by a sensation of head distention and pain, heart vexation, irascibility, bitter mouth, dry pharynx, dry stools, and yellow urine. | The tongue body is red with yellow fur and the pulse is stringlike. | Calming the liver, subduing yang, extinguishing wind, and opening the orifices. |
Phlegm-Heat Phlegm-heat and bowel repletion, resulting in obstruction of the network vessels. | Hemiplegia, deviation of the mouth and tongue, slurred speech, abdominal distention, constipation, slimy sensation in the mouth with copious phlegm, and dizziness. | The tongue body is red with slimy yellow fur and the pulse is slippery and large. | Freeing the bowels, discharging heat, transforming phlegm, and freeing the network vessels. | |
Vacuity patterns | Yin Vacuity Liver and kidney yin vacuity with wind yang harassing the upper body. | Constitutional dizziness and headaches, tinnitus, blurred vision, and reduced sleep with profuse dreaming. Sudden onset of facial paralysis, evidenced by deviation of the mouth and eyes, may also occur, along with tongue stiffness and impeded speech. Additional manifestations could involve heaviness in the limbs, and, in severe cases, hemiplegia. | The tongue body is red or has slimy fur, and the pulse is stringlike, fine, and rapid, or stringlike and slippery. | Enriching yin and subduing yang, extinguishing wind, and freeing the network vessels. |
Qi Vacuity Qi vacuity with blood stasis leads to obstruction of the vessels and networks. | Hemiplegia and lack of strength in the limbs, accompanied by puffy swelling in the affected hand and foot, sluggish speech, facial paralysis with deviation of the mouth and eyes, and a withered- yellow or pale, dull complexion lacking luster. | The tongue body is pale purple and may deviate; the tongue fur is thin and white, and the pulse is fine, rough, and forceless. | Supplementing qi, quickening blood, and freeing the channels and network vessels. |
As noted, the etiology, pathogenesis, and clinical manifestations of wind-stroke differ significantly among its pattern types. Accordingly, each pattern type requires specific therapeutic approaches; that is, treatment is determined on the basis of pattern identification. Because this trial of FYTF-919 did not consider TCM pattern identification, taking a one-size-fits-all approach to subjects with repletion patterns (such as ascendant hyperactivity of liver yang) and vacuity patterns (such as qi vacuity), it failed to provide individualized treatments based on patients’ underlying pathophysiology. This weakened the expected effects of the experiment and may be a reason why the benefits of FYTF-919 were not observed.
From a methodological standpoint, building on an inappropriate initial grouping of subjects, the lack of alignment between the treatment strategies and actual pattern types further limited the reliability of the trial’s conclusions.
3. Herbal formula
FYTF-919 is composed of ren shen (Panax ginseng), da huang (Radix et Rhizoma Rhei), san qi (Radix notoginseng), and chuan xiong (Rhizoma Ligustici chuanxiong). The nature, indications, and effects of each medicinal in this formulation are analyzed in Table 2, while their pharmacological properties are presented in Table 3.
Table 2: Effects of medicinals in FYTF-919
Properties | Channel Entry | Effects | Indications | Role in the Formula | |
|---|---|---|---|---|---|
Ren shen – Panax ginseng | Sweet, slightly bitter, warm. | 。 The lung and spleen channels. | Greatly supplements original qi, stems desertion, engenders liquids, nourishes the heart, and quiets the spirit. | All symptoms of insufficient qi, blood, and fluids, including taxation damage, vacuity detriment, low food intake, fatigue, stomach reflux vomiting, efflux diarrhea, vacuity cough, panting, hasty breathing, spontaneous sweating, fulminant desertion, fright palpitations, forgetfulness, dizziness, headache, impotence, urinary frequency, dispersion-thirst, gynecological flooding and spotting, chronic fright in children, and enduring vacuity that does not improve. | Supplements qi and blood, and strengthens the constitution. It serves as a sovereign medicinal to treat qi deficiency accompanied by blood stasis or qi stagnation. |
San qi – Radix notoginseng | Sweet, slightly bitter, warm. | The liver, stomach, and large intestine channels. | Staunches bleeding, dissipates stasis, disperses swelling, and settles pain. | Blood ejection, coughing of blood, nosebleed, bloody stool, blood dysentery, flooding and spotting, concretions and conglomerations, postpartum blood dizziness, retention of lochia, blood stasis due to knocks and falls, bleeding due to external injury, and painful swollen welling-abscess. | Quickens blood and transforms stasis while staunching bleeding without causing additional stasis. It serves as a minister medicinal in this formula, assisting ren shen in supplementing qi and quickening blood, and enhancing the formula’s effectiveness. |
Da huang – Radix et Rhizoma Rhei | Bitter, cold. | The stomach, large intestine, and liver channels. | Drains downward, attacks accumulation, clears heat and drains fire, cools the blood and resolves toxin, expels stasis, and frees the channels. | Repletion heat constipation, delirious speech, food accumulation with glomus and fullness, initial stages of dysentery, abdominal urgency with tenesmus, menstrual block due to stasis, seasonal heat diseases, acute eye redness and pain, blood ejection, nosebleed, yang jaundice, water swelling, strangury-turbidity, welling- abscess, sores, swelling, and toxin, clove sores, burns, and scalds. | Acts as a purgative to free the bowels and discharge heat, while also quickening blood and transforming stasis. As an assistant medicinal in this formula, it improves the movement of qi and blood while transforming stasis and resolving stagnation. |
Chuan xiong – Rhizoma Ligustici chuanxiong | Acrid, warm. | The liver, gall bladder, and pericardium channels. | Moves qi and opens depression, dispels wind and dries dampness, quickens blood, and relieves pain. | Headache and dizziness, difficult delivery, postpartum pain due to blood stasis impediment and clotting, welling- and flat- abscesses, sores, menstrual irregularities, menstrual block, menstrual pain, abdominal pain due to conglomeration, stabbing pain in the chest and rib-side, swelling and pain due to knocks and falls, and pain due to wind- damp impediment. | Moves qi and quickens blood; acting as an envoy medicinal, it guides all medicinals in the formula to enter the liver channel. It also assists ren shen in supplementing qi and moving blood, and enhances san qi’s properties of quickening blood and transforming stasis. |
Table 3: Pharmacological Effects of FYTF-919
Bioactive components | Biomedical Compounds | Therapeutic Effects | |
|---|---|---|---|
Ren shen – Panax ginseng [8-10] | Ginsenosides (Ra1, Ra2, Rb2, Rb3, Rc, and Rd), saccharides, volatile oils, amino acids, organic acids, trace elements, vitamins, alkaloids, flavonoids, sterols, enzymes, and lignins. | Ginsenosides can reduce blood viscosity and erythrocyte sedimentation rate; they exhibit anti- platelet aggregation effects, and possess anticoagulant and anti- thrombotic properties. Ginsenoside Rb1 enhances the expression of glial cell line-derived neurotrophic factor (GDNF) after cerebral ischemia- reperfusion, with a protective effect on the central nervous system. | Supports recovery from ischemic cardiovascular conditions and acts as a cardioprotective agent with significant benefits for cardiovascular functioning. |
San qi – Radix notoginseng [14-16] | Notoginsenosides, flavonoids, saccharides, volatile oils, amino acids, trace elements, plant oils and lipids, terpenes and hydrocarbons. | Inhibits the expression of inflammatory factors, prevents toxicity from free radicals, inhibits platelet aggregation, exhibits anti- apoptotic effects, promotes peripheral nerve regeneration, and prevents calcium overload. | * Enhances cellular function and reduces ischemic damage while suppressing inflammation to minimize tissue injury and support recovery. * The antioxidant properties mitigate oxidative stress, protecting cells from damage. * The inhibition of apoptosis prevents programmed cell death, thereby promoting cell survival, maintaining the integrity of the blood-brain barrier, and protecting central nervous system function. * The restoration of the neurovascular units facilitates brain recovery following injury, collectively contributing to improved outcomes after ischemic conditions. |
Da huang – Radix et Rhizoma Rhei [11-13] | Anthraquinone derivatives, flavonoids, phenylpropanoids, anthrone compounds, stilbene compounds, tannins, organic acids, and polysaccharides. | Significantly reduces platelet adhesion and aggregation, and prolongs prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT). | * Enhances blood circulation, reduces oxidative stress, modulates inflammation, and provides significant benefits for ischemic conditions. * Promotes neuroprotection and improves recovery outcomes following ischemic events. * Supports the restoration of normal physiological functions after ischemia by optimizing microcirculation, reducing inflammatory responses, and strengthening antioxidant defense mechanisms. |
Chuanxiong – Rhizoma Ligustici chuanxiong [17-19] | Ligustrazine, ferulic acid sodium, chuanxiong lactone, volatile oils, alkaloids, and phenolic substances. | Ligustrazine is a tetramethylpyrazine compound with a wide range of beneficial effects including dilating microvessels, enhancing microcirculation, reducing blood viscosity, improving blood rheology, decreasing capillary permeability, regulating platelet function, and exerting anticoagulant effects. | Effectively targets vascular conditions, particularly those involving ischemia, by enhancing blood flow and supporting overall circulatory health. |
As outlined above, these ingredients embody TCM principles of balancing attacking with supplementation. Ren shen is used to supplement qi and nourish blood, while san qi and chuan xiong transform stasis and free the network vessels, and da huang quickens blood and frees the bowels. Thus, this formula is more appropriate for the qi vacuity and blood stasis pattern type of wind-stroke, rather than pattern types with ascendant hyperactivity of liver yang, phlegm-heat with obstruction by stasis, or liver and kidney yin vacuity. In the clinical practice of TCM, a formula’s efficacy depends heavily on its application to appropriate TCM pattern types. When used without considering pattern identification, the therapeutic potential of a formula may be diminished.
4. Methodological Implications
The trial’s failure to incorporate TCM pattern identification or allow for subgroup analyses undermines its ability to accurately evaluate the efficacy of FYTF-919. Incorporating individualized treatment strategies and stratifying participants based on TCM pattern types could provide a more nuanced understanding of the formula’s efficacy and better align the trial design with clinical practice.
5. Neurosurgical Interventions
Neurological interventions were widely utilized in this herbal formula trial, which warrants careful consideration. A notable proportion of participants (30.3%) underwent early decompressive surgery at baseline. More significantly, over half of the participants received neurosurgical interventions during the study period, with 52.0% in the FYTF-919 group and 50.4% in the placebo group undergoing such procedures. These neurosurgical interventions, performed from baseline through the study period, represent an additional variable beyond the herbal formula, which was intended to be the sole intervention in this RCT. As such, these interventions likely had a considerable impact on the trial’s outcomes.
Comprehensive reviews of large databases [20, 21] highlight the fact that neurosurgical interventions for ICH can significantly improve patient outcomes. These interventions are effective in limiting ICH expansion, reducing mass effects, and alleviating elevated intracranial pressure. Additionally, they can mitigate secondary brain injuries induced by the toxic effects of blood degradation products and the inflammatory response following ICH. The most common neurosurgical intervention, hematoma evacuation, offers several critical benefits, including significant reduction in ICH volume, high functional independence, and a decreased risk of recurrence [22, 23]. These outcomes have also been supported by findings from this trial. Researchers identified “significant heterogeneity in the treatment effect on the primary outcome for the prespecified subgroups of the volume and location of the hematoma.”
Furthermore, neurosurgical interventions also interact with additional factors, including initial ICH volume, anticoagulant use, and antiplatelet use. Given these extensive and multifactorial influences – particularly those related to anticoagulant and antiplatelet effects – the reliability and validity of this RCT, which seeks to evaluate a formula originally intended to exert anticoagulant and antiplatelet effects, are significantly compromised.
Discussion
In recent years, Chinese medicine has been employed to treat a wide range of cardiovascular conditions, with substantial evidence supporting its efficacy from both clinical trials and animal studies. In the context of various neurological diseases, herbal medicine has demonstrated a favorable safety profile over extended periods compared to surgical interventions and western pharmaceutical treatments. This is primarily because herbal medicines are less invasive and associated with fewer side effects [24].
Chinese medicinal formulas, represented by FYTF- 919, have shown significant promise in aiding recovery following intracerebral hemorrhage. The potential mechanisms underlying these effects may involve antioxidative, anti-inflammatory, and antiapoptotic processes, as well as the reduction of blood pressure through the modulation of signaling pathways (such as MAPK, calcium, apoptosis, and TNF signaling pathways) [25].
Furthermore, the unique properties of san qi and chuan xiong, medicinals in FYTF-919 that are commonly employed in traditional Chinese medicine for post-stroke conditions, render them particularly effective for ischemic stroke. These medicinals demonstrate efficacy by mitigating tissue-type plasminogen activator (tPA)- induced neurological deficits, reducing infarction, and protecting the integrity of the blood-brain barrier [26-28].
As mentioned above, the FYTF-919 formula is designed to move qi and quicken blood, so it is well-suited for ischemic cerebrovascular conditions. Its use in hemorrhagic conditions like ICH, where stabilizing hemostasis is critical, may lead to unintended consequences, such as exacerbating bleeding. Although Chinese medicine has a favorable safety profile and promising potential uses, its efficacy relies on how it is actually applied, and accurate matching between the TCM diagnosis and the principles of its use. The lack of accurate matching in this trial made it impossible to achieve the goals for which it was designed. This mismatch between pattern types and the formula used raises significant concerns about the appropriateness of FYTF-919 in this trial and highlights the importance of aligning herbal prescriptions with the specific pathophysiological mechanisms of the target condition.
Wind-stroke in TCM is understood through distinct pathophysiological frameworks, and each pattern type requires tailored treatment protocols developed through pattern identification and analysis, exemplifying the flexibility and accuracy of the TCM principle of “unlike treatment of like diseases”. The failure to apply TCM diagnostic pattern identification in this trial disregards the individualized treatment principles central to TCM practice. This methodological oversight limits the trial’s ability to evaluate the formula’s efficacy accurately and align findings with real-world clinical practice.
From the research methodology point of view, the widespread use of neurosurgical interventions in this trial introduces significant confounding variables. Hematoma evacuation and other procedures independently improve outcomes, making it difficult to attribute observed benefits to FYTF-919. The unequal distribution of these interventions across subgroups and their interaction with anticoagulant and antiplatelet use further complicates the interpretation of the trial’s findings.
Consequently, in addition to inappropriate inclusion criteria and subgrouping, the trial design fails to adequately control for key variables, such as anticoagulant use and ICH heterogeneity. This lack of stratification undermines the study’s internal validity and limits its ability to draw definitive conclusions about FYTF-919’s efficacy, as it does not strictly follow RCT principles. Future trials should incorporate subgroup analyses and stricter inclusion criteria that fit TCM principles, and clearly identify a single intervention, to enhance reliability and generalizability.
Lastly, the study’s primary outcomes focused on functional recovery and quality of life for patients who experienced ICH, which may not fully reflect another core philosophical tenet of TCM—the holistic view. Future trials should consider incorporating outcomes more aligned with TCM principles, such as constitutional improvement, long-term recovery, and prevention of further disease.
About the author:
- Xiaoji Li: [email protected] +64-21818959, Natural Harmony Clinic Ltd., 103A Taylor Street, Auckland, New Zealand 0640
- Youping Hu: [email protected] +86-13683413730, Acupuncture & Moxibustion Institute, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China 610072
- Guanhu Yang, Department of Specialty Medicine, Ohio University, Athens, OH, United States
Correspondence should be addressed to:
Xiaoji Li: [email protected] +64-21818959
