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
FYTF-919治療腦出血隨機試驗的方法學問題：思考與建議
作者：李曉楫1, 胡幼平2, 楊觀虎3
摘要
**背景：**中藥治療神經系統疾病的療效研究層出不窮，由於方法學的差异，結果往往莫衷一是。本文就最近發表的“中藥方劑FYTF-919（中風醒腦口服方）治療急性腦出血的多中心隨機對照雙盲臨床試驗”為例，對其方法學展開思考和分析，探討其中可能存在的問題并對將來的類似研究提出改進建議。
**問題：**一項大型臨床隨機對照試驗(RCT)評估了傳統中藥方劑FYTF-919治療腦出血(ICH)的療效。盡管研究結果表明該中藥方劑對試驗對象沒有顯著效果，但我們通過分析該項試驗的方法學，包括樣本的選擇和歸類、試驗的隨機化和方法，以及療效評估指標的應用等，發現了其中可能存在的偏倚并因此得出了不當的結論。
**建議：**我們建議通過優化試驗設計，比如合理化試驗樣本分組，標準化治療手段及規範化療效評估以提高方法學的嚴謹性，以達到改善相關領域後續研究的有效性、可靠性和臨床相關性的目的。
**主題詞：**中藥方劑，方法學，腦出血，隨機對照試驗，中醫學
一項關於中藥方劑FYTF-919（中風醒腦口服液）治療急性腦出血（ICH）療效的大規模、多中心隨機對照試驗（RCT）近期發表在《柳葉刀》上[1]。FYTF-919在中醫臨床中有着悠久的應用歷史，既往的研究表明其在降低顱內壓和改善腦水腫、促進血腫吸收、緩解腦出血繼發炎癥和免疫功能障礙等方面具有確切療效[2-7]。然而,這項最近的臨床試驗結論却顯示FYTF-919對急性腦出血患者在功能恢復、生存率或生活質量等指標上沒有顯著影響。
此結果與該中藥方劑的既往證據存在矛盾。 為探究原因,我們在本文中探討了可能影響該研究結論的關鍵方法學問題。
1. 樣本分配
該臨床試驗共納入1,648例符合急性腦出血西醫診斷標準的患者,試驗對象的納入標準為發病後48小時內通過腦影像學確診,NIHSS評分≥8分,以及GCS評分位於7-14分。雖然這些條件符合西醫的急性腦血管意外診斷標準,但該試驗并未使用中醫辨證分型這一在中醫藥臨床研究中至關重要的基本原則。基於該試驗是以研究中藥方劑療效的前提,完全不采用中醫證型分類而僅以西醫診斷標準為分組方法的試驗設計,削弱了FYTF-919臨床試驗的可信度。
2. 中醫辨證
FYTF-919“中風醒腦口服液”的主要適應癥“中風”,是一個中醫學病名,指因正氣虧虛,飲食、情志、勞倦內傷等引起氣血逆亂,產生風、火、痰、瘀,導致腦脉痹阻或血溢脉外為基本病機,以突然昏僕、半身不遂、口舌歪斜、言語謇澀或不語、偏身麻木為主要臨床表現的病證。其對應的西醫病名為急性腦血管意外,指因腦血管病變造成的腦功能异常,包括由血管阻塞所造成的缺血性中風,以及由腦內出血或大腦外圍腔室、腦動脉瘤、腦動静脉畸形出血造成的出血性中風[8]。本文中提及的臨床試驗祇納入了急性腦出血患者。
中風的中醫辨證分型如表一。
表一：中風的辨證分型
| 病因病機 | 主要癥狀 | 舌脈 | 治療原則 | |
|---|---|---|---|---|
| 實證 | 肝陽暴亢, 風火內動 | 半身不遂, 口舌歪斜, 言語不利, 頭暈頭脹痛, 心煩易怒, 口苦咽 幹, 便幹尿黃。 | 舌質紅苔黃, 脈弦。 | 平肝潛陽, 熄風開竅。 |
| 痰熱腑實, 痹阻絡脉 | 半身不遂, 口舌喎斜, 語謇, 腹 脹便秘, 口黏痰多, 頭暈。 | 舌質紅苔黃膩, 脈 滑大。 | 通腑泄熱, 化痰通絡。 | |
| 虛證 | 肝腎陰虛, 風陽上擾 | 平素頭暈頭痛, 耳鳴目眩, 少寐 多夢, 突然發生口眼歪斜, 舌強 語謇, 或手足重滯, 甚則半身不 遂等癥。 | 舌質紅或苔膩, 脈弦 細數或弦滑。 | 滋陰潛陽, 熄風通絡。 |
| 氣虛血瘀, 脈絡瘀阻 | 半身不遂, 肢體乏力, 伴有患側 手足浮腫, 語言謇塞, 口眼歪斜, 面色萎黃, 或黯淡無華。 | 舌質淡紫, 或舌體不 正, 苔薄白, 脈細澀 無力。 | 補氣活血, 通經活絡。 |
如上所述，中風的病因病機及臨床表現因不同證型而存在顯著差异，因此每種證型都需要采用有針對性的治療方法，即通過“辨證”來“論治”。在本次FYTF-919試驗中，由於未考慮中醫辨證分型，對於實證（如肝陽上亢）和虛證（如氣虛）這樣兩級相背的試驗對象均采取了“一刀切”的治療方法，在選方用藥和服用方法上都未能根據患者的病理生理基礎進行個性化治療，削弱了試驗的預期效果，也可能是未觀察到FYTF-919療效的原因。
從方法學的角度來說，在最初的分組不當基礎上，治療方案與實際證型的不匹配則進一步限制了試驗結論的可信度。
3. 中藥方劑
FYTF-919“中風醒腦口服液”由人參（Panax ginseng）、大黃（Radix et Rhizoma Rhei）、三七（Radix notoginseng）和川芎（Rhizoma Ligustici chuanxiong）組成。
本方劑中各藥材的藥性、適應癥及功效詳見表二，藥理特性則列於表三。
表二：FYTF-919“中風醒腦口服液”組方中藥藥效 Table 2: Effects of medicinals in FYTF-919
| 性味 | 歸經 | 功效 | 適應癥 | 在本方中的作用 | |
|---|---|---|---|---|---|
| 人參 | 甘,微 苦,温。 | 入脾經、肺經。 | 大補元氣, 固脫生津, 養心安神。 | 勞傷虛損,食少,倦怠,反胃吐食,大便滑泄,虛咳喘促,自汗暴脫,驚悸,健忘,眩暈頭痛,陽痿,尿頻,消渴,婦女崩漏,小兒慢驚,及久虛不復,一切氣血津液不足之證。 | 人參可補益氣血,增强體質,在氣虛血瘀或氣滯證中為君藥。 |
| 三七 | 甘,微 苦,温。 | 入肝經、胃經、 大腸經。 | 止血散瘀, 消腫定痛。 | 吐血,咳血,衄血,便血,血痢,崩漏,癥瘕,產後血暈,惡露不下,跌撲瘀血,外傷出血,癰腫疼痛。 | 三七既活血化瘀,又止血而不留瘀,在本方中為臣藥,助人參補氣活血,增强效能。 |
| 大黃 | 苦,寒。 | 入胃經、大腸 經、肝經。 | 瀉下攻積,清 熱瀉火,涼血 解毒,逐瘀通 經。 | 實熱便秘,謠語,食積痞滿, 痢疾初起,裏急後重,瘀停 經閉,癥瘕積聚,時行熱疫, 暴眼赤痛,吐血,衄血,陽 黃,水腫,淋濁,癰瘍腫毒, 疔瘡,湯火傷。 | 大黃既可通腑 泄熱,又能活 血化瘀,在本 方中為佐藥, 利於氣血運行, 化解瘀滯。 |
| 川芎 | 辛, 溫。 | 歸肝經、膽經、 心包經。 | 行氣開鬱,祛 風燥濕,活血 止痛。 | 頭痛眩暈,難產,產後瘀阻塊 痛,癰疽瘡瘍,月經不調,經 閉痛經,瘕腹痛,胸脅刺痛, 跌撲腫痛,風濕痹痛。 | 川芎行氣活血 為使藥,引全 方藥性入肝經, 還可助人參補 氣行血,增三 七活血化瘀。 |
表三：FYTF-919“中風醒腦口服液”組方藥理作用
| 生物活性成分 | 藥理效應 | 治療作用 | |
|---|---|---|---|
| 人參 [9-11] | 人參皂苷(Ra1、Ra2、 Rb2、Rb3、Rc、Rd等)、 糖類、揮發油、氨基酸、 有機酸、微量元素、維生 素、生物碱、黃酮類、 甾醇和酶類及木質素類等。 | 人參皂苷可降低血液黏度及紅細 胞沉降,具有抗血小板凝集、抗 血栓形成的作用。人參皂甙Rb1 改善腦缺血再灌注後膠質細胞源 性神經營養因子(GDNF)的表達, 對中樞神經系統有保護作用。 | 支持缺血性心血管疾 病康復,具有心臟保 護作用,對心血管功 能具有顯著益處。 |
| 三七 [12-14] | 三七皂苷、黃酮類化合物、 糖類、揮發油、氨基酸、微 量元素、植物油脂、淄醇和 炔、烯、烴類化合物等。 | 抑制炎癥因子表達,抗自由基毒 性損傷,抗血小板聚集及抑制凋 亡調控基因,促進周圍神經細胞 再生,抑制鈣超載。 | *增强細胞功能,減少 缺血性損傷,同時抑 制炎癥反應,最大程 度降低組織損傷并支 持恢復。 *抗氧化特性能够減輕 氧化應激,保護細胞 免受損傷。 *抑制細胞凋亡防止程 序性細胞死亡,從而 促進細胞存活,維持 血腦屏障的完整性, 并保護中樞神經系統 功能。 *神經血管單元的修復 促進了損傷後大腦的 恢復,共同改善缺血 性病變後的臨床結局。 |
| 大黃 [15-17] | 蔥醞類化合物、黃酮類化合物、苯丙素類化合物、蔥酮類化合物、二苯乙烯類化合物、鞣質、有機酸及多糖類等。 | 可顯著降低血小板粘附與聚集的作用,使凝血酶原時間(PT)、活化部分凝血活酶時間(APTT)和凝血酶時間(TT)等顯著延長。 | * 增強血液循環,減少氧化應激反應,調節炎癥反應,對缺血性疾病具有顯著益處。 * 促進神經保護,并改善缺血事件後的恢復效果。 * 通過優化微循環、減少炎癥反應及強化抗氧化防御機制,支持缺血後的生理功能恢復。 |
| 川芎 [18-20] | 川芎嗪、阿魏酸鈉、川芎內 酯、揮發油、生物碱和酚類 物質等。 | 川芎嗪是一種四甲基吡嗪化合物, 具有擴張微血管、增强微循環、 降低血液黏度、改善血液流變學、 減少毛細血管通透性、調節血小 板功能以及發揮抗凝作用。 | 通過增强血流量和支 持整體循環健康對心 腦血管疾病,尤其是 缺血性疾病有良好療 效。 |
如表中所示, FYTF-919“中風醒腦口服液”的組方貫徹了中醫辨證論治的方針,以攻補兼施為法,用人參補氣養血,三七、川芎化瘀通絡,大黃活血通腑,因此更適宜於氣虛血瘀型中風,而非肝陽上亢、痰熱瘀阻及肝腎陰虛型中風。在中醫臨床試驗中,中藥方劑的療效在很大程度上依賴於其是否應用於恰當的中醫證型,如未按實際的辨證分型遣方造藥,則其療效將會南辕北辙。
4. 試驗方法學
因該臨床試驗未能融入中醫辨證分型或進行亞組分析,從而削弱了其對FYTF-919療效的準確評估能力。通過納入個體化治療策略并根據中醫證型對參與者進行分層分析,可以更深入地理解方劑的療效,并使試驗設計更貼合臨床實踐。
5. 神經外科手術
在本項FYTF-919臨床試驗中,神經外科手術得到了廣泛使用,甚至貫穿了試驗的始終。在基綫期,有相當比例的受試者(30.3%)接受了早期去骨瓣減壓術;更值得注意的是在整個試驗期間,有超過半數的試驗對象接受了腦外科手術,其中FYTF-919組為52.0%,安慰劑組為50.4%。這些神經外科幹預措施無疑成為了除FYTF-919之外的另一變量，因此違反了RCT有且祇能有唯一測試變量的基本原則，對試驗結果產生了不利影響。
大數據系統評估表明，神經外科手術在阻制腦出血擴散、減少血腫占位效應及緩解顱內壓升高方面功效顯著。同時，手術還能減輕血液降解產物的毒性效應和ICH後炎癥反應所導致的繼發性腦損傷[21, 22]。治療急性腦出血最常見的神經外科手術-血腫清除術，具有包括顯著降低ICH體積、促進功能恢復以及減少復發風險等多重功效[23, 24]。這些功效在本次FYTF-919臨床試驗中也被觀察到，並記錄為“在血腫體積和位置的默認亞組中，治療效果的主要結局存在顯著的異質性。”
此外，神經外科手術還可能影響試驗的療效評估，比如ICH的體積，以及因手術產生類似抗凝劑和抗血小板藥物的後續效應而對試驗結果造成困擾。鑒於神經外科手術對急性腦出血多重且廣泛的干擾，尤其是與抗凝相關的不利影響，都令這一原本旨在測試一種具有抗凝和抗血小板作用的中藥方劑的科學研究在可靠性和有效性上受到質疑和挑戰。
討論
近年來,中醫藥在心血管疾病的治療中得到 了廣泛應用,并通過大量的臨床試驗和動物研究 獲得了翔實可靠的療效證據。研究表明,與手術 幹預和西藥相比,中藥因侵入性較低且副作用較 少,在對神經系統疾病的治療,尤其是長期用藥 者中表現出了優良的安全性[25]。
以FYTF-919“中風醒腦口服液”為代表的 中藥方劑在腦出血後的康復中展現出了值得期待 的潛力。其生物醫學機制可能涉及抗氧化、抗炎 和抗凋亡作用,以及通過調控信號通路(如 MAPK、鈣信號、凋亡和TNF信號通路)降低血 壓并預防腦出血[26]。
FYTF-919組方中的三七和川芎是中醫學常 用於中風後康復的中藥，可緩解因組織型纖溶酶 原激活劑（tPA）導致的神經功能缺損、縮小腦 梗體積以及保護血腦屏障的完整性。這些藥理特 性使活血化瘀類中藥在缺血性中風的治療中獨樹 一幟，取得了值得肯定的成果[27-29]。
如前文所述,FYTF-919的組方原則旨在行 氣活血,更適用於缺血性心腦血管疾病。如果將 FYTF-919用於ICH這類需要止血的出血性腦血管 疾病,可能會產生適得其反的後果,加重出血并 危害患者生命。盡管中醫藥具有良好的安全性和 值得期待的應用前景,但其療效仍然依賴於實際 操作與中醫診斷和使用原則的精準匹配。本項臨 床試驗正是因為缺乏了這種精準匹配,而導致無 法達成試驗設計的初衷。這種證型和用藥的不匹 配也引發了對FYTF-919在對急性腦出血臨床試 驗安全性的擔憂,因此,我們再次強調中藥處方 與目標疾病的病理生理機制相匹配的重要性。
在中醫學中,中風的病因病機迥然不同的, 每個證型都需要通過辯證分析來量身定制個性化 的治療方案,充分體現中醫“同病異治”的靈活 性和準確性。遺憾的是,本次FYTF-919臨床試 驗未能使用中醫辨證為試驗對象分組,忽視了中醫學的核心價值觀，因此限制了該項研究評估 FYTF-919療效的能力，也使其結果難以與實際 臨床實踐相結合。
從RCT的研究方法學來看，本試驗錯誤地引 入了多重變量。除FYTF-919“中風醒腦口服 液”外，作為一種治療手段，神經外科手術在本 試驗中的廣泛使用直接改變了疾病的轉歸和患者 的預後，干擾了FYTF-919的療效評估。外科手 術在各亞組中的分布不均，以及其帶來的類似抗 凝藥的後續效應，也進一步加重了試驗結果的誤 差。
不恰當的納入和分組標準，以及對變量控制 的把握不嚴是該項臨床試驗設計的硬傷。通過這 種缺乏嚴格依照RCT原則而進行的研究和得出的 結論，準確度和可信度都被削弱了。未來的中醫 藥臨床RCT試驗應制定更符合中醫學原則的納入 和分組標準，并明確唯一變量的原則，以提高試 驗結果的可靠性和可推廣性。
最後，該研究的主要結果體現在幫助急性腦 出血患者恢復肢體功能和改善生活質量方面，尚 未充分反映中醫另一核心哲學思想——整體觀的優 勢。未來的中醫學臨床試驗可考慮納入更符合中 醫學價值觀的評估指標，如體質改善、長期康復 和疾病預防等。
引用文獻
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作者簡介：
- 李曉楫, [email protected], Natural Harmony Clinic, 103A Taylor Street, Auckland, New Zealand 0640
- 胡幼平, [email protected], 成都中醫藥大學針灸推拿學院, 十二橋路37號, 成都, 中國610072
- 楊觀虎, Department of Specialty Medicine, Ohio University, Athens, OH, United States
通訊作者：李曉楫 [email protected] +64-21818959
