Prospective prescription review system correlated with more rational PPI medication use, better clinical outcomes and reduced PPI costs: experience from a retrospective cohort study

Critically ill patients are at high risk for experiencing stress ulcers (SUs). When using a positive faecal occult blood test or unexplained haemoglobin decline as the diagnostic criteria, the incidence of SUs in critically ill patients ranges from 15 to 50% [1]. To prevent the occurrence of SUs, proton pump inhibitors (PPIs) are considered effective and rank as the most commonly prescribed drugs worldwide [2]. However, with the surge in PPI expenditures, the irrational use of PPIs without evidence has increased rapidly [3], resulting in unreasonable financial expenditures. Forgacs I et al. [4] indicated that almost £2 billion are being spent on PPIs with unnecessary medication purposes each year worldwide. In addition to the economic waste of PPIs, adverse effects of long-term use and potential disadvantages in health issues have been identified and attracted the attention of researchers. The adverse effects of long-term use included increased risks of infections (lungs and gastrointestinal tract), bone fractures, liver and kidney damage, as well as a decrease in absorption of vitamins and minerals from the intestine [5‐9]. In terms of potential harms, drug-drug interactions (DDIs) may occur when PPIs are added to polytherapy, which could result in unpredictable outcomes and threaten patients’ health [10].

In recent years, various measures have been taken to improve the abuse of PPIs globally. Clinical pharmacists, as the initiators of rational drug use, have been actively involved in this work and have achieved satisfactory results. Khalili H et al. [11] reported that clinical pharmacists introduced a treatment guideline for stress ulcer prophylaxis (SUP) based on a warranted evidenced protocol and assisted physicians in prescribing acid-suppressive therapy (AST) for SUP, which obtained reductions in the overall use of AST and the use of AST for patients without reasonable indications. Masood U et al. [12] showed that their clinical pharmacist team reviewed SUP patients during medical rounds, made appropriate changes according to the guidelines and educated residents and fellows on the implemented initiative of SUP, which caused a substantial reduction in the costs related to inappropriate SUP use. Moreover, Mitchell S et al. [13] described that their team owned prescriptive authority on decreasing inappropriate stress ulcer prophylaxis rates instead of recommendations, which could be more time-efficient and cost-saving. As in China, the “Consensus Review for SUP and Treatment” and “Prevention and Treatment of Stress Related Mucosal Disease” were released in 2015 and to some extent promoted the rational drug use of PPIs and the prevention of SUs [14]. Under the guidance, Chinese clinical pharmacists have been taking interventions to control PPI overuse on the premise of reducing the incidence of SUs in hospitals. The majority of the interventions are focused on daily rounds with physicians and educative group activities about the rational use of PPIs [15, 16]. Some pharmacists have explored classic management methods for improving rational PPI use. Yun H et al. [17] studied the application of the plan-do-check-act (PDCA) method in promoting rational prophylactic injectable proton pump inhibitor use (PIPU), while clinical pharmacists led a guidance team in providing pharmaceutical care.

In China, the prospective prescription review system is a real-time prescription monitoring system that requires clinical pharmacists to set rules for intercepting prescriptions with drug-related problems (DRPs) according to clinical guidelines, medical insurance policy, drug descriptions, etc. Since the National Health Commission issued a prescription review of medical institutions in July 2018, approximately 42.7% of hospitals have successively carried out a prospective prescription review system and achieved remarkable results [18]. Xie H et al. [19] reported that the introduction of the prescription review system was associated with safer prescribing of analgesics. However, to date, few studies have examined prospective prescription review systems regarding the promotion of rational PPI use.

Therefore, the clinical pharmacists in our hospital developed a prospective prescription review system correlating PPI prescriptions to the fasting state and all the related diagnoses of stressors. This system attempts to improve clinical outcomes associated with gastrointestinal bleeding while controlling unreasonable PPI use and reducing unnecessary PPI expenses.

A flow chart of the prospective prescription review is shown in Fig. 1. This figure shows how the intervention was performed on the rational use check of PPIs.

Table 1 presents the comparisons of PPI use and PPI costs. The number of PPIs used and PPI costs were significantly lower in the postintervention group than in the preintervention group (P < 0.001).

According to the data shown in Fig. 2, the number of unreasonable medical orders was 2736 and 4847 in the pre- and postintervention groups, respectively. The rationality evaluation results were categorized as follows: frequency of PPIs, PPIs course, drug interactions, PPIs for special populations, contraindications, administration route, dosage and incompatibility. The most common problem was the dosage, with 1060 (38.74%) and 1848 (38.13%) patients in the pre- and postintervention groups, respectively. The composition ratios of the frequency of PPIs and drug interactions were significantly higher in the preintervention group than in the postintervention group (P < 0.01). The PPI course in the preintervention group had a higher composition ratio than that in the postintervention group (P < 0.05). Of note, the composition ratio of PPIs for the special populations in the preintervention group was significantly lower than that in the postintervention group (P < 0.01).

As shown in Fig. 3, the number of medication orders in the pre- and postintervention groups was 30,888 and 30,379, respectively. The proportion of oral PPIs increased significantly after intervention (29.30% vs. 34.56%, p < 0.01), and there was a significant difference in unreasonable medical orders (8.86% vs. 15.96%, p < 0.01) between the two groups.

The review points of intravenous PPIs were presented as follows: upper gastrointestinal bleeding, vomiting blood (+), fasting, coma, faecal occult blood (+) and indwelling gastric tube. When doctors prescribed intravenous PPIs, the most common review point they chose was fasting (3633, 40.15%), followed by upper gastrointestinal bleeding (1550, 17.19%) and coma (1443, 15.95%) (Fig. 4).

The characteristics of the patients included in the analysis are shown in Table 2. Since the characteristics of age, sex, department, and CCI score were not comparable between the two groups, PSM was applied to make them comparable. After the adjustment for the demographic variables by PSM analysis, there were no significant differences in age, sex, department, CCI or purpose of PPI use between the two groups.

The purpose of PPI use was divided into prevention and treatment. For the utilization of PPIs for prevention, the total DDDs (231,765 vs. 202,541) and the DDDs/100 patient-days (110.71 ± 70.02 vs. 100.71 ± 69.68) were substantially decreased in the postintervention group (P < 0.001). Moreover, the DUIs between the two groups were 1.52 and 1.4, respectively. The number of days stayed in the hospital was significantly different between the two groups. For the utilization of PPIs for treatment, DUI and DDDs/100 patient-days were significantly different between the pre- and postintervention groups. The incidence of SUs in the postintervention group was 44.95%, and that in the preintervention group was 51.93% (P < 0.05). The improvement rate and cure rate of gastrointestinal haemorrhage in the two groups were not significantly different (Table 3).

Previous studies have shown that clinical pharmacists have achieved satisfactory results in ICUs, surgical wards and medical wards regarding the interventions of reviewing indications for SUP, educating residents, and making ward rounds [12, 23−24]. The uniqueness of this study is that unlike some studies requiring that clinical pharmacists review prescriptions [25, 26], the tasks for clinical pharmacists were to set reasonable interception rules and wait for feedback from doctors when alerts occurred, which is a more efficient and cost-effective method. The findings in this study show that in the postintervention group, the total PPI utilization rate (PPIs used) and PPI costs decreased significantly compared to those in the preintervention group. The total PPI utilization rate in this study was lower than some of the previous studies domestically and worldwide [16, 27]. This means that reminding doctors of the utilization rules with this system has achieved the initial goal. In addition, the clinical pharmacists in our hospital have given PPI recommendations in clinical pharmacists’ consultations, which to some extent promoted the rational use of PPIs [28]. The findings demonstrated a significant reduction in PPI costs, which is consistent with what Chen QY et al. reported [29]. In October 2019, the government officially implemented the “4 + 7” centralized procurement policy and the price of drugs was greatly adjusted; Shanghai was among the 11 pilot cities. Chinese researchers found that the “4 + 7” policy had positive effects in promoting the substitution of generic drugs for original drugs, reducing drug prices and promoting rational drug use [30, 31]. For the change in PPI costs shown in Table 1, although PPI prices decreased several times during the study period, based on the consumption of drugs, we observed that there was a significant difference in the DDDs between the preintervention group and postintervention group (241,579 vs. 212,346, p < 0.001). The significant decrease in consumption suggested that even though the PPI prices remained stable during the study period, the PPI costs could be significantly reduced after the intervention. This indirectly indicated the significance of the system in reducing PPI costs. Furthermore, we do not need to take cost measurement into consideration in this study. Because clinical pharmacists do not have to spend much time reviewing prescriptions, salaries related to costs were partly saved, unlike the method presented in Bao ZW et al. [25].

We achieved the increased utilization of oral PPIs, instead of intravenous PPIs in this study. As indicated in a previous study [32] and expert consensus [33], for SUP, intravenous PPIs can be selected only when patients are unable to eat, which emphasizes the recommended use of oral PPIs. To improve the current status that includes a high utilization rate of intravenous PPIs and physicians’ lack of realization of indications for intravenous PPIs, we used this system to double check the appropriateness of intravenous PPIs (Fig. 1). Before an intravenous PPI medical order is prescribed, the reasons why intravenous PPIs rather than oral PPIs should be used must be selected (Fig. 4). All the interventions led to a significant reduction in utilization. For the intervention on the various types of irrational drugs, the setting of the rules was more detailed, which means that a prescription could be issued only after the rules were met. For example, one of the rules is that the routine treatment course of intravenously administered PPIs should be less than 7 days. If the treatment course exceeds this duration, the doctor should make sure that the patient is still fasting in the system. Due to the strict restrictions of the rules, the irrational prescriptions of medication frequency and treatment course and those with DRPs were significantly reduced. It is worth noting that the irrational utilization rate of special drug users, including pregnant women, children and people with liver and kidney dysfunction, significantly increased, demonstrating the advantage of this intervention method in intercepting unreasonable prescriptions for these groups over a previous study [13]. We set the rules for this group according to the drug instructions so that more clinical pharmacists’ efforts could influence them.

SUs have the characteristics of a low incidence rate and high mortality. According to the latest finding [34], the bleeding risk of ICU patients receiving SUP can be reduced by approximately 60%. Therefore, prevention is important to reduce the occurrence of SUs, and early application of acid suppressants has been shown to be an effective method. Among the recommended acid suppressants, oral PPIs ranked as the first choice by the guidelines [20, 35]. In this study, the incidence of SUs decreased after the intervention. In addition, the ratio of oral administration was significantly increased, while the ratio of intravenous administration was significantly reduced. The findings of this study showed a much better improvement than the reported research over 20 tertiary hospitals domestically, and this research demonstrated that the use rate of PPIs in hospitalized patients was 57.4% (of which intravenous administration accounted for 82.9%) [36]. Hohl CM et al. [37] reported that a reduced hospital stay could be achieved by pharmacist prescription review. In line with this finding, this study showed a significantly shorter hospital stay in the group that had PPIs for prevention. Furthermore, it is worth noting that the DUI and DDDs/100 patient-days*100 in the postintervention group were significantly lower than those in the preintervention group both for prevention and treatment, demonstrating that the frequency of clinical use and rational drug use was significantly improved. This improvement could be attributed to the implementation of a prospective review system on rational PPI use, with which physicians’ prescriptions could be prospectively reviewed by clinical pharmacists. However, for DUI, the results after the intervention were much higher than the previous findings reported by Zhang Y et al. [16] and Ying J et al. [38], which means multidimensional measures should be implemented to further reduce the DUI. An important issue identified in this study was that the DDDs/100 patient-days after the intervention were 100.71 ± 69.68 and 172.89 ± 100.81 for prevention and treatment, respectively, which were still much higher than the findings of previously reported studies [12, 16]. The reason was that our result covered all the indications of PPIs over the entire inpatient setting, including rational and irrational indications, instead of irrational indications or those limited to only one department.

To the best of our knowledge, this is the first retrospective study to evaluate the improvement of PPI use, patients’ clinical outcomes and medical expenses after implementing a prospective prescription review system in the entire inpatient setting. To reduce bias, a propensity score method was used to match the patients’ conditions. While this study has many methodological strengths, several limitations still exist. First, although this prospective prescription review system reflected the whole picture of how PPIs were used in the real-world inpatient setting, it was a single-centre study. To further study the advancement and advantages of this model, multicentre studies are needed. Second, based on the physicians’ relatively low recognition of the clinical pharmacists’ work, the current acceptance rate of prospective prescription review is only approximately 80%, which means that 20% of physicians choose to sign a guarantee to circumvent the obstruction of the system. Improving the physicians’ recognition is a goal that requires time to complete. A considerable number of physicians believe that clinical pharmacists should improve their professional level [39, 40]. Therefore, continuous improvement of clinical pharmacists’ abilities may be able to reduce these research limitations to some extent. Third, due to some inherent deficiencies in the design of the system, patients who need PPIs but are not prescribed PPIs cannot be included in the unreasonable medication use statistics. To address these issues, more reasonable review rules should be made. Finally, as pointed out in many Chinese studies [41, 42], National Centralized Drug Procurement has been implemented by the Chinese government since 2019. During procurement, the average bid-winning drug price was reduced by 52%. Therefore, the positive effect of the system on total drug costs cannot be accurately evaluated. To counteract this issue, evaluation could be performed after drug prices remain stable.

In this study, the implementation of the prospective prescription review system on rational PPI use correlated with reduced PPI costs, more rational PPI medications and better clinical outcomes, including a lower incidence rate of SUs and shorter in-hospital days for patients using PPIs for SUP. It is essential that clinical pharmacists and their methods to improve clinical medication use help physicians achieve better medical care quality. To obtain the best effect of this system, clinical pharmacists should develop more rational medication rules to cover more drugs. Furthermore, improving the expertise of pharmacists for higher recognition by physicians is meaningful not only for the system but also for pharmaceutical care.