Research On The Prophylactic Treatment Of Proton Pump Inhibitors In Glucocorticoid Therapy Based On Medical Big Data

Background:Proton pump inhibitors(PPIs)were a class of drugs commonly used to treat diseases related to gastric acid secretion.It inhibits gastric acid secretion by irreversibly binding to the H~+-k~+-ATPase pump of parietal cells.Major clinical indications of PPIs include peptic ulcer,gastroesophageal reflux disease,Zollinger-Ellison syndrome,non-steroidal anti-inflammatory drug-associated ulcer,eradication of helicobacter pylori,prevention of stress ulcer in critically ill patients,and treatment of functional dyspepsia.PPIs has the advantages of long acting time,good effect of inhibiting gastric acid secretion after meal,and not easy to appear drug tolerance,etc.In recent years,its use has increased sharply,which brings with it a series of problems such as overtreatment,increased adverse drug reactions and increased burden of patients.The preventive treatment of gastrointestinal adverse reactions caused by Glucocorticoids(GCs)is an important source of overuse of PPIs,but the clinical benefits of the combination of the two drugs have not been clear,and the two drugs may have some adverse reactions of synergistic effect,increasing the risk of use.To standardize the use of PPIs in such patients,new evidence-based medical evidence needs to be produced,especially the specific reasons for the unreasonable use of PPIs,the efficacy of PPIs prevention and the adverse reactions caused by PPIs treatment.At present,the research on the above problems is mainly limited by the lack of large medical databases,which cannot provide sufficient case samples to support the testing effectiveness of relevant studies.Objective:To clarify the benefits and risks of the use of PPIs,further standardize the use of PPIs and promote appropriately drug use,as well as provide new evidence for clinical drug use decisions,we study the influencing factors of PPIs overuse,the efficacy of PPIs prevention and the risks caused by PPIs treatment in inpatients receiving GCs treatment through medical big data.Methods:1.Analysis of characteristic attributes of patients receiving PPIs treatment.Through the data management center of the clinical application of antibacterial drugs in Shanghai Changhai hospital,the diagnosis and treatment data of adult inpatients with GCs usage records were collected from 20 general hospitals in China from January 1,2015 to March 31,2018.Then,a random forest model was established to explore the characteristics of patients using PPIs,which can better distinguish the users and non-users of PPIs,and has an important connection with the prescription of PPIs.According to the calculation results of the random forest model,the importance of each feature was ranked,and the most relevant feature attributes were obtained to distinguish patients using PPIs from those not using PPIs.In addition,different types of PPIs were modeled separately to analyze the characteristic properties of corresponding drugs.Finally,the influencing factors for inappropriate use of PPIs can be inferred from these characteristics.2.Efficacy of proton pump inhibitors in preventing risk of glucocorticoid therapy.We designed a case-control study to explore the preventive use of PPIs can reduce GCs related clinical significance of gastrointestinal bleeding(CSGB)risk.The case group in this study was patients with CSGB after the use of GCs.Patients with the same admission date and no gastrointestinal bleeding were randomly matched as the control group.The matching ratio between case group and control group was 1:10.Univariate analysis was used to select the risk factors that might affect the occurrence of CSGB as covariables,and the adjusted odds ratio of PPIs exposure in the case group and control group was calculated by using the nonconditional logistic regression model.3.Risk assessment of proton pump inhibitors combined with glucocorticoids.We designed a cohort study to explore whether patients receiving PPIs increased the risk of Hospital acquired pneumonia(HAP)in hospitalized patients treated with GCs.The exposure in this study was the use of PPIs,while the control group was the GCs patients who had not received PPIs treatment.The odds ratio of HAP in the exposed group and the control group was calculated by two methods:covariate adjustment and propensity score matching.Results:1.Analysis of characteristic attributes of patients receiving PPIs treatment.From Jan.1,2015 to Mar.31,2018,701,673 GCs patients from 20 hospitals were included in the study,among which 510,100 patients received PPIs treatment,and the utilization rate of PPIs was 72.7%.Poor basic conditions(old age,high comorbidity index),malignant tumors, digestive tract diseases,bleeding related drugs(non-steroidal anti-inflammatory drugs, heparin,high dose GCs)were important factors leading to the use of PPIs in combination with GCs,while PPIs combined with treatment is rarely used in eye diseases.In different varieties of PPIs,the characteristic attributes highly associated with increased use of omeprazole were spinal disease and high dose GCs;The use of pantoprazole was mainly associated with glomerular disease and urogenital malignancy.The characteristics of lansoprazole,rabeprazole and esomeprazole were relatively concentrated in malignant tumor, cardiovascular disease or drug and digestive tract disease,respectively.2.Efficacy of proton pump inhibitors in preventing risk of glucocorticoid therapy.Of the 701,673 patients treated with GCs,1,465(0.21%)were discharged with upper gastrointestinal bleeding.After selecting,a total of 178 case group and 1 780 control group were included in the study.After adjusting for covariates,the odds ratio of PPIs exposure between the case group and the control group was 0.9(95%CI:0.6-1.4,p=0.5989).Risk factors associated with increased risk of CSGB included males(OR:1.6;95%CI:1.1-2.4),peripheral vascular disease(OR:3.6;95%CI:1.4-9.1),cerebrovascular disease(OR: 2.8;95%CI:1.6-4.9),diabetes(OR:2.3;95%CI:1.3-4.0),antithrombotic drugs(OR:2.8;95%CI:1.5-5.3)and risk factors for gastrointestinal bleeding(mechanical ventilation>48h OR coagulation disorder)(OR:28.1;95%CI:18.0 43.9).Among them,there was an interaction effect between PPIs and high risk factors of gastrointestinal hemorrhage(p=0.0241).After analyzing the interaction effects,it was found that the adjusted odds ratio was 82.0(95%CI:27.2-246.8)for patients with high risk of gastrointestinal bleeding without PPIs 22.8(95%CI:13.1-39.4)for patients with high risk of gastrointestinal bleeding without PPIs when compared to the reference(without PPIs and without high risk of gastrointestinal bleeding).3.Risk assessment of proton pump inhibitors combined with glucocorticoids.Among the 307,622 GCs patients eligible for the study,217,460 and 90,162 patients were exposed to PPIs and unexposed,and the incidence of HAP was 5 626 and 1,292,respectively.The incidence of HAP in the PPIs exposed group was higher than that in the control group (2.6%vs 1.4%,OR:1.8,95%CI:1.7-1.9).After adjusting for covariates,the adjusted odds ratio of HAP in the exposed group and control group was 1.7(95%CI:1.5-1.8).After propensity score matching,both the exposed PPIs group and the control group included83,786 patients,while the exposed group and the control group included 1,795(2.1%)and 1,286(1.5%)HAP patients,respectively.The odds ratio associated with HAP was 1.4(95%CI:1.3-1.5),and the population attributable risk percentage of PPIs was 17.2%.Then,patients were divided into four dose groups of 0,0-2,2-7 and>7 in Defined drug dose(DDD)units,of which adjusted odds ratios were 1(reference group),1.0(95%CI:0.9-1.1),1.3(95%CI:1.2-1.4)and 1.9(95%CI:1.8-2.1),respectively.Conclusions:1.Analysis of characteristic attributes of patients receiving PPIs treatment.In patients treated with GCs,the characteristic attributes associated with combined use of PPIs were poor basic condition in admission,malignant tumor and anti-tumor drugs,drugs related to gastrointestinal bleeding risk and gastrointestinal diseases.Excessive use of PPIs to prevent chemotherapy-related vomiting may be the main influencing factor for overuse of PPIs.The characteristic attributes associated with the use of omeprazole,rabeprazole and esomeprazole were stress ulcer prevention,cardiovascular disease and digestive tract disease,respectively.Prescription of lansoprazole and pantoprazole may not be appropriate,and their characteristic attributes were mainly malignant tumors and anti-tumor drugs.2.Efficacy of proton pump inhibitors in preventing risk of glucocorticoid therapy.The incidence of CSGB was lower in hospitalized patients treated with GCs.PPIs prophylaxis was not considered to reduce the risk of CSGB in patients treated with GCs;However,PPIs prophylaxis might reduce the risk of CSGB when patients treated with GCs were in the condition of respiratory failure or coagulopathy.3.Risk assessment of proton pump inhibitors combined with glucocorticoids. Combined use of PPIs increased the risk of HAP in hospitalized patients receiving GCs.The percentage of population attributable risk of PPIs was high,which was an important cause of HAP.The risk of HAP increased with the cumulative dose of PPIs,while the use of a short course of PPIs was relatively safe.Controlling the course of PPIs may be an effective method to reduce the risk of HAP.