Post-marketing Studies Of Safety Of Shenmai Injection Based On The Combination Of Real World And Evidence-based Review

Objective: To study the influence factors of suspected allergic reactions in the clinical application of the Shenmai injection;Evaluating conditions on adverse reaction incidence of Shenmai injection systematically in order to provide evidence of evidence-based medicine of safety use of Shenmai injection in clinic,also it can provide new ideas and new methods to post-marketing safety evaluation of traditional Chinese medicine injections.Methods: The first part: Using prospective,multicenter,large sample,nested case-control studies,and combining the method of prescription design and sequence analysis,collecting medical records of patients who had used Shenmai injection,patients used anti-allergic medicines such as dexamethasone within 24 h were defined as suspected allergic reactions,then compare with people may not produce allergic reaction,make a contrastive analysis,to explore correlation between suspicious allergic reactions and state of illness when patient go hospital,allergies,single dosage,drug combination.The second part: Retrieving randomized controlled studies and observational studies of Shenmai injection in Pubmed,EMbase(OVID),the Cochrane Library,China National Knowledge Infrastructure(CNKI),China Scientific Journal Database(CSJD)and Wan Fang data by computer,each retrieval time were when databases were built until October 31,2016.Two independent researchers filtrated literatures and extracted information according to include and exclude standard,and evaluated methodological quality of research,then made a Meta analysis by using software R3.2.3.Results: The first part: Case-control study results showed that differences between the solvent types(P = 0.000)and single dosage(P = 0.042)have statistical significance;There was no statistical significant of difference between state of illness(P = 0.287)and allergies(P = 0.249).There were lower risk of allergic reactions occur when using Shenmai injection combined with vitamin B6(OR = 0.352,95% CI(0.287,0.932),P =0.0233),vitamin C(OR = 0.278,95% CI(0.183,0.421),P = 0.0401),granisetron injection(OR = 0.028,95% CI(0.014,0.073),P = 0.0038),levofloxacin injection(OR= 0.741,95% CI(0.474,0.958),P = 0.0155),oleum fructus bruceae(OR = 0.015,95%CI(0.007,0.056),P = 0.0001),Ai Di injection(OR = 0.238,95% CI(0.133,0.641),P =0.0013)and Paclitaxel Injection(OR = 0.334,95% CI(0.149,0.798),P = 0.0006];However,it would increase risk of allergic reactions when using Shenmai injection combined with pantoprazole [OR = 3.112,95% CI(1.805,7.536),P = 0.0169),cimetidine(OR = 2.226,95% CI(1.923,3.629),P = 0.0024),sophora element sodium chloride injection(OR = 2.548,95% CI(1.925,3.373),P = 0.0018)and ondansetron injection(OR = 5.224,95% CI(4.928,10.616),P = 0.0235].The second part: We chose 175 articles finally according to the standards,all studies were conducted in mainland China,the research objects were Chinese.Total sample sizes were 25132 cases,which included Shenmai injection users 18184 cases,721 cases had adverse reaction totally.Meta analysis results showed that the total incidence of adverse reactions was 5.72% [95% CI(0.0485,0.0665)].Subgroup analysis showed that the incidence of children and adults were 6.04% [95% CI(0.0329,0.0941)] and 6.07% [95% CI(0.0491,0.0732)] respectively.The incidence of 5%,10%glucose injection and 0.9% sodium chloride injection was 6.00% [95% CI(0.0373,0.0868)],5.31% [95% CI(0.0309,0.0799)] and 6.18% [95% CI(0.0505,0.0719)]respectively.Dose of 10 ~ 30 ml,40 ~ 60 ml,> 60 ml were 6.23% [95% CI(0.0443,0.0827)],5.69% [95% CI(0.0466,0.0681)] and 7.01% [95% CI(0.0444,0.1003)]respectively.The rate of adverse reactions when treatment time of ? 7d and >7d was5.80% [95% CI(0.0397,0.0789)] and 5.60% [95% CI(0.0470,0.0656)] respectively.Single drug and drug combination was 5.60% [95% CI(0.0357,0.0798)] and 5.85%[95% CI(0.0503,0.0672)].Incidence of light adverse reaction and adverse symptoms,in turn,were dry and thermal feeling(6.36%),dry mouth(4.42%),digestive system damage(3.89%),nervous system damage(3.70%),sharp pain of blood vessels at the injected area(3.42%),skin and its accessories damage(2.62%),cardiovascular system damage(1.70%),respiratory system damage(0.8%).Severe adverse reaction is main allergic shock(2.00%).Sensitivity analysis results were stable;Egger's inspection results suggested that the study may not exist publication bias(total rate P = 2.216).Conclusion: 1.The existing research methods and evidence-based medical evidence suggest that suspicious influencing factors of adverse reactions of Shenmai injection may have correlations with types of solvent,dosage,age,time of treatment and drug combination,and there are big differences between different damage types of adverse reactions incidence.2.Adverse reactions occur is mainly in short time after patient use Shenmai injection,at the same time,the risk of adverse reactions is larger with dose of 60 ~ 100 ml.3.Using Shenmai injection combine with pantoprazole cimetidine,sophora element sodium chloride injection and the ondansetron injection is a risk factor of suspected allergic reaction.4.There are no clear relationships between suspected allergic reaction and state of illness when patient go hospital or allergies.