| Safety of traditional Chinese medicine(TCM)is always widely concerned by the society,especially adverse reactions caused by combined application of TCM and Western medicine have received more and more attention.In real-world clinical practice,TCM and Western medicine are often used in combination,thus how to discover adverse reactions caused by combined TCM and Western medicine and objectively evaluate safety of their combined application is a new challenge to safety evaluation of TCM.According to "Chinese Cardiovascular Disease Report 2018",coronary heart disease(CHD)is the second most prevalent cardiovascular disease in China and its prevention and treatment are top priority in managing the disease.Both Chinese Guidelines for the Prevention of Cardiovascular Diseases and the European Society of Cardiology(ESC)Cardiovascular Prevention Guidelines have long-term oral administration of aspirin as an important part of prevention and treatment of CHD.However,in real-world clinical practice,much literature has reported that as many as 90%of CHD patients take aspirin as a preventive medicine while taking TCM;meanwhile,research literature has also reported that combination of the two increases bleeding event risk.In this study,patent TCM Guanxinning Tablet for activating blood circulation and removing blood stasis was used as an example.On basis of having taken aspirin for a long time,Guanxinning Tablet was added;oral aspirin alone was used as control.Bleeding event incidence was observed and compared between two groups,safety of Guanxinning Tablet combined with aspirin was evaluated,and thinking and method of safety evaluation of combined TCM and Western medicine were explored.Technological roadmap of the study is shown in graphic-textual abstract.Objective:1.To observe incidences of bleeding events and adverse reactions in combined medication group and aspirin alone group and evaluate safety of adding Guanxinning Tablet on basis of aspirin.2.Separate network pharmacology predictions were combined with detection of platelet aggregation rate indicator to explore and look for possible gene targets and pathways of adverse reactions due to combined Guanxinning Tablet and aspirin,the possible protective mechanism for bleeding risk.Method:1.Clinical study1.1 Study methodThe study adopted a cluster randomize,multi-center and large-sample study design method.A total of 63 hospitals were included in the study.Cluster randomization was performed according to attributes of TCM and Western medicine hospitals.Cluster randomization ensured balance between Chinese and Western medicine hospitals and between subjects,while avoiding evaluation bias caused by Hawthorne effect due to two groups in one center.(1)Participants:Stable CHD patients who,after percutaneous coronary intervention,ever received>12-month dual antiplatelet therapy(aspirin+clopidogrel or ticagrelor)and had received aspirin for ≥1 month after discontinuing clopidogrel or ticagrelor and who had cardiac function of grade Ⅰ-Ⅲ and were not>80y.(2)Sample size:A total of 3600 subjects were included.Test group:treatment group=2:1.1.2 Main observation indicatorsObservation indicators were incidences of bleeding events,adverse events and adverse reactions;1.3 Trial drugsDrugs in test group:Aspirin+Guanxinning Tablet;Drug in control group:Aspirin.Regulation for combined medication:Two groups maintained treatments of existing diseases according to relevant diagnosis and treatment guidelines,allowing sublingual nitroglycerin during acute angina episode.During trial period,no other antiplatelet drug in the same kind or TCM promoting blood circulation and removing blood stasis could be taken at the same time.All drugs taken were truthfully recorded.1.4 Courses of treatment and visitsTest group:Safety of one-year medication,and observation for one year after discontinuing medicine.Laboratory indicators were tested before enrollment,1 month,3 months,6 months and 12 months after taking medicine.Control group:Laboratory indicators were tested before enrollment,and coagulation function was monitored at the third month after enrollment.Bleeding events,adverse events,adverse reactions and endpoint indicators were observed and recorded at each observation time point.1.5 Risk controlThe study also set up Data and Safety Monitoring Board and Endpoint Event Adjudication Committee for observation of long course of treatment and large sample in this study.According to risk of the study,Data and Safety Monitoring Meeting and Endpoint Event Adjudication Meeting were held in time.Bleeding event adjudication criteria specified in protocol were strictly followed and endpoint event adjudication and bleeding event adjudication during the study were standardized.2.Mechanism exploration2.1 Network pharmacology exploration and targetsAccording to clinical study data,candidate targets for 5 diseases or symptoms with the highest frequency of adverse reactions after taking combined aspirin and Guanxinning Tablet were obtained,and so did candidate targets for aspirin regulation and control.The above targets were mapped with candidate targets of Guanxinning Tablet ingredients and aspirin.Cytoscape software was used to construct candidate target network for drugs-candidate ingredients-adverse reaction diseases,and correlation between drug ingredients and disease action targets was analyzed.Through GlueGO plug-in,GO biological process and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed and disease targets and action pathways of adverse reactions due to combined aspirin and Guanxinning Tablet were explored.2.2 Detection of platelet aggregation ratePatients meeting inclusion criteria were selected.Test group used aspirin plus Guanxinning Tablet and control group used aspirin alone.Blood was sampled before and 3 months after enrollment,and then platelet aggregation rate was detected;aspirin test cards with arachidonic acid(AA)as the platelet activator were used to determine residual platelet aggregation function.Effects of combined medication and aspirin alone on platelet function were observed.Results:1.Clinical studyA total of 3595 patients(2400 patients in test group and 1195 patients in control group)in a total of 63 hospitals were included.Test group:control group was almost 2:1.Two groups of subjects had good consistency in baseline data such as age,sex,ethnicity,height,weight,cardiac function,TCM syndrome and vital signs,without statistically significant difference between groups.Two groups had good comparability in terms of combined medication and compliance,without statistically significant difference between groups.1.1 Bleeding events incidencesThere were a total of 66 case-times of bleeding events in 60 subjects in two groups,including 53 case-times in test group and 13 case-times in control group,with statistical difference.Wherein,bleeding events which had the highest number of cases included various types of examinations:29 cases(1.35%)in test group.Bleeding situations after excluding various types of examinations were:21 cases(0.98%)in test group and 10 cases(0.86%)in control group,without statistically significant difference between groups.For types 3-5 bleeding events of BRAC definition,difference between two groups was not statistically significant and was not clinically significant.1.2 Adverse reactions incidencesDuring trial,a total of 255 case-times of adverse reactions occurred in 208 subjects:Adverse reaction incidence in test group was 6.57%(141/2146)and that in control group was 5.77%(67/1161),without statistically significant difference between groups.When analysis was performed by symptoms of adverse reactions,among these adverse reactions the adverse reactions with statistically significant difference between two groups were gastrointestinal diseases and incidence in test group was higher than control group,wherein main manifestations were gastrointestinal symptoms.There was no statistical difference in any other adverse reaction between groups,indicating that risk of adverse reactions other than gastrointestinal symptoms does not significantly increase after addition of Guanxinning Tablet.1.3 Serious adverse reactions incidencesDuring trial,there were 10 case-times of SAEs in 10 subjects,without statistically significant difference in SAE incidence between two groups.1.4 Adverse events incidencesIncidences of adverse events in two groups were 39.24%(test group)and 31.35%(control group),with statistically significant difference.Symptoms of adverse events were analyzed by frequency,mainly:Infectious and infesting diseases:249 cases(11.6%)in test group and 168 cases(14.47%)in control group;Gastrointestinal diseases:187 cases(8.71%)in test group and 68 cases(5.86%)in control group;Heart disease:115 cases(5.36%)in test group and 36 cases(3.1%)in control group;Various neurological diseases:89 cases(4.15%)in test group and 40 cases(3.45%)in control group.Adverse events were analyzed by month.Difference between groups was statistically significant in two time points,i.e.,1 month of medication and 12 months of medication.Except above time points,difference between groups was not statistically significant in any other time point.A total of 458 case-times of SAEs occurred in 367 subjects during trial.SAE rates were 12.12%(test group)and 9.22%(control group),with statistical difference,and the analysis for the SAE is same as the AE analysis.2.Mechanism exploration2.1 Network pharmacology exploration resultIntersection of 276 candidate targets of Guanxinning Tablet with 337 candidate targets of adverse reactions was taken to obtain 28 targets of Guanxinning Tablet acting on 5 adverse reactions;these were used to generate network of candidate targets for Guanxinning Tablet-adverse reactions.Intersection of 352 candidate targets of aspirin with 337 candidate targets of adverse reactions was taken to obtain 54 targets of aspirin acting on 5 adverse reactions;these were used to generate network of candidate targets for aspirin-adverse reactions.Next,a network view was constructed.Intersection of 118 candidate targets of combined action of Guanxinning Tablet and aspirin with 337 candidate targets of adverse reactions was taken to obtain 20 targets of Guanxinning Tablet plus aspirin acting on 5 adverse reactions;these were used to generate network of candidate targets for Guanxinning Tablet plus aspirin-adverse reactions.These potential targets are:SLC25A13,GSTP1,IFNG,IL1B,SI,NOS2,CAT,TP53,CP1A2,IL6,NQO1,GLUL,GPT,COL3A1,SOD1,CPTW,EGFR,SCN5A,TNF and HMOX1.Concentrated biological significance of these targets mainly includes adverse reactions through inflammation mechanism,NO signaling mechanism,oxidative stress mechanism.2.2 Indicator detection in platelet aggregation ratePreliminary study and exploration has prompted that combined aspirin and Guanxinning Tablet may play a protective role in reducing bleeding risk.Conclusion1.For CHD patients with cardiac blood stasis syndrome,test group having taken Guanxinning Tablet(promoting blood circulation and removing blood stasis)for a long time on basis of oral aspirin for a long time did not increase bleeding event incidence or types 3-5 bleeding events’risk compared with control group taking aspirin alone;test group did not increase risk of other adverse reactions except gastrointestinal adverse reactions.2.A number of previous papers reported that combined aspirin and TCM promoting blood circulation and removing blood stasis increased bleeding adverse reactions.Combined with main results of this study,we consider:The possibility that increase in bleeding events in the literature is related to inaccurate choice of medication populations cannot be excluded.TCM promoting blood circulation and removing blood stasis should be used in patients with blood stasis syndrome.Among populations having adverse reactions,attention should be paid to accuracy of syndrome differentiation or further clinical study should be performed to analyze adverse reaction incidences in different TCM syndromes.It should be emphasized that clinical application of TCM needs to be performed under guidance of TCM theory.3.By using a cluster random and comparative study method with bleeding event incidence as an observation indicator,in comparative analysis of various confounding factors,adverse reactions and adverse events after taking combined TCM and Western medicine are better demonstrated.Aiming at status quo of widespread combined TCM and Western medicine,a comparative analysis method can more efficiently discover difference incidences of adverse reactions and adverse events.4.Through mechanism exploration,network pharmacology exploration is used to analyze mechanism of gastrointestinal adverse reactions due to combined aspirin and Guanxinning Tablet,prompting that the adverse reactions may occur through inflammatory factors and oxidative stress targets.Due to small sample size in the exploratory study,as for platelet aggregation rate exploration reflecting a possible protective role in reducing bleeding risk after taking combined aspirin and Guanxinning Tablet,further study with enlarged sample size is needed. |
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