The Application Of Using Survival Analysis And Disease And Syndrome Combination To Evaluate The Effectiveness Of Chinese Medicine Which Can Promote Blood Circulation For Acute Ischemic Stroke

Among those acute cerebral vascular diseases which are important threatens to human health, Acute Ischemic Stroke(AIS) is the worst one not only for its high incidence and mortality, but also for the bad influence to the survivor’s daily life. Both the individual’s ability for daily life and his role in family and the society or the life quality will change to some difficulties, which may result in serious economic and social burden to the individual, family or society.Among the treatments for AIS, thrombolytic therapy is the recognized one, while other drugs are still used to aim at prevention, or being in the stage of effect confirmation from laboratory to clinic. But the clinical application of thrombolysis is limited by the therapeutic timing, complications and medical conditions of the hospitals. Well-designed and high quality Randomized Controlled Trials (RCT) can speak for new drugs, which also can provide the best evidence for its clinical validation.Differating syndrome and prescribing drugs correctly are important for Chinese medicine to treat disease. In the pathological theory of Chinese Medicine, Blood Stasis Syndrome(BSS) is the key point for the happening of AIS. Ischemia and hypoxia of the brain cells will lead to microcirculation disturbance, which also can aggravate the ischemia and hypoxia, or even cause series of cascade reactions, which eventually may lead to bad cell events such as necrosis, apoptosis or autophagy. The curing of BSS with Chinese medicine is helpful for AIS both clinically or laboratorily. Evidence showed that Chinese herbs with the effect of Promoting Blood Circulation(PBC) may have good influence to AIS both in animals or in human. In animals with AIS, PBC may help to narrowering the infarction area, improving the defect functional scores. The mechanism may be related to healing damages caused by free radicals, excitatory toxicity, inflammation, etc, which eventually may lead Cell apoptosis or autophagy. On the another hand, Chinese medicines of PBC have been widely use for patients with cardiovascular or cerebrovascular diseases. But the effect elucidation of PBC in Chinese medicine is hard to tell clearly and sicientifically for the bad quality of clinical research of Chinese Medicine.At present, Disease and Syndrome Combination(DSC)is the main idea to diagnose, cure, or even evaluate the effect for Chinese medicine. When doing effect evaluation, some new methods are needed to meet not only the standards of Western Medicine, but also the characteristics of Syndrome Differentiation and Treatment(SDT) in Chinese Medicine. Appropriate methods for effect evaluation of Chinese Medicine will be meaningful for not only patients with AIS, but also the progress of researches in Chinese Medicine. ObjectiveHere we did the study through carrying out of a phase II clinical trial-Effectiveness and Safety of Hydroxysafflor Yellow A(HSYA) on AIS. After having strictly controlled the quality of the RCT, We aimed to evaluate the effect of HSYA on AIS and elucidate the idea of DSC by using different statistical methods and testing some serum biochemical markers of patients with AIS, whose results may be good evidences for the treatment of AIS with Chinese medicine of PBC.1. According to analysis plan, use the chi square test or covariance analysis to compare the statistics before and after treatment, from which the effectiveness and safety of HSYA for AIS may be shown.2. According the characteristics of syndrome evaluation, use different statistical methods to manipulate the data of different points. Use Repeated Measurement Variance (RMVA) and the Survival Analysis(SA) to meet different kinds of syndrome informations, such as the changing tendancy or classic symptoms of AIS over different time point.3. To observe the changes of some serum biomarkers of the patients with AIS and discuss the possible mechanisms that PBC have on AIS.MethodsThis study was carried out simultaneously with the a randomized controlled multi center phase II clinical trial of HSYA for AIS, which is also a dose groping trial.1. After treatment, compared the score differences of mRS, NIHSS, BI, BSS of Chinese medicine, adverse events, et al by using general clinical statistical methods (such as chi square for the cure rate data and covariance for measurement data) between the 4 groups. Then the effectiveness and safety of them were discussed.2. According to the repeated time points of the study plan, RMVA were used to analyse the data of those different points, and the the influence of time effect intra and inter the groups were discussed from those data analysis.3. Combinating the concepts of disease, syndrome and symptoms of Chinese medicine together, statistical analysis of SA were done to compare the "end point events" and "time to survival" which the major symptoms of AIS and scores of BSS had existed from the beginning of addmission.4. The serum biomarkers of Beclin-1、Glu、GABA、SOD、GSH-Px、MDA were tested on different time points such as before drugs、7 days after drugs、14days after drugs, then the changes caused by the 4 diffenent treatments and the possible mechanisms of them were discussed, which may also help to provide helpful evidence on HSYA for patients with BSS of AIS.Result1. The scores of all the clinical outcome items such as mRS、NIHSS、BI、SS-QOL between the first and the last time point among the 4 groups all tended to be better, among which the group of HSYA in middle dose had the trend to the best, but there were no statistical significance among them. The group of HSYA in the middle dose also seemed to improve the scores of BSS of Chinese medicine significantly than other groups clinically and statistically.2. Data about the safety of the drugs included the changes in laboratory examinations and the Adverse Events(AE) in record, which showed that the main AEs most possibly caused by HSYA injection were occult blood in shit and urine. Other changes could be explained by related professional knowledge and the status of the disease itself.3. Results from the RMVA showed that as time passed, the scores of the mRS and NIHSS tended to decrease, while that of BI tended to increase after the treatments of 4 groups, among which the group of HSYA in middle dose had a trend to be the best one, but the difference were of no statistical significance. As time went on, the scores of BSS also have difference in all groups, among which the scores of the 3 groups treated with HSYA tended to decrease, while that of the control group tended to change nothing. And the results showed statistical significance in the interaction between the groups and the observing time points. Totally, the difference among the 4 groups showed no statistical significance.4. The results from SA showed the eliminating time of the major symptoms of AIS or BSS score of the 4 groups, among which the group of HSYA in middle dose tended to do best in eliminating the symptom of hemiplegia and BSS scores, the group of HSYA in high dose tended to be the best in eliminating the symptom of aphasia, the group of HSYA in low dose tended to be the best in eliminating the symptom of facial paralysis, the control group tended to be the best in eliminating the symptom of feeling numbness, but the difference among the groups did not showed statistical significance.5. The changes of the serum biomarkers among different group were analysed with the statistical method of RMVA, and the results showed that as time went on, the level of Glu had a clear tendancy to decrease gradually, which showed statistical significance within each group but not among the groups. As for the changes in level of Beclin-1, some slight increase could be seen in groups of HSYA in low dose、high dose and the control group, but that the group of HSYA in high dose tended to decrease first and then being stable to the last time point, also without significant changes among groups. However, the changes of other serum biomarkers showed no regularity in their line charts.Conclusion1. BSS is the important type of AIS. Our study showed that after treating with HSYA injection, good changes had taken place in patients of all groups in the main symptoms of AIS, levels of body disability, activities, social participation and quality of life after stroke. Good changes also could be found in the scores of BSS, and the changes among the 3 groups of HSYA in different dose and Erigeron Injection were little(without statistical significance).2. In our study, we evaluate the effectiveness of HSYA injection for AIS from different clinical out items by using different statistical methods in addition to the original plan, such as chi square test, covariance analysis, RMVA, SA. The results got from RMVA and general statistical methods for clinical data were similar to each other, which could tell little difference between HSYA injection and Erigeron Injection for AIS in effectiveness. The results got from the SA seemed not consistence with those from general methods and RMVA, such variation may be caused by the small sample size, short observation period or the reduced testing efficacy of SA. But for the clinical consideration, we still could tell there seemed to be little difference among the HSYA groups and the Erigeron group.3. After treating with HSYA or Erigeron, the level of Glu in the patients’ serum tended to decrease gradually, which indicates that the method of PBC could be helpful to decrease the level of excitatory transmitter and eventually improve the damage of ischemia and anoxia in the brain, but for the exact mechanism of it, there will still have a lot of deep research to do.