Overuse of proton pump inhibitors for stress ulcer

International Journal of Clinical Pharmacology and Therapeutics, Vol. ■■ – No. ■■/2016 (1-6)

Overuse of proton pump inhibitors for stress ulcer prophylaxis in Jordan Original ©2016 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP202533 e-pub: ■■month ■■day, ■■year

Key words stress ulcer – proton pump inhibitors – overuse – inpatients

Abbreviations PPIs = proton pump inhibitors; ASHP = American Society of Health-System Pharmacists; NSAIDs = nonsteroidal anti-inflammatory drugs; GI = gastrointestinal; NPO = not allowed to feed by mouth; KAUH = King Abdullah University Hospital; INR = international normalized ratio; PTT = prothrombin time; ICU = intensive care unit; ISS = injury severity score; IV = intravenous Received October 13, 2015; accepted March 16, 2016 Correspondence to Mohammad A.Y. Alqudah, PharmD, PhD Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology Irbid, 22110, Jordan [email protected]

Mohammad A.Y. Alqudah, Sayer Al-azzam, Karem Alzoubi, Mohammad Alkhatatbeh, and Neda’ Rawashdeh Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

Abstract. Objective: To determine the frequency of inappropriate proton pump inhibitor (PPI) prescriptions during hospitalization for stress ulcer prophylaxis on the general medical ward in a tertiary Jordanian hospital. Materials and methods: A retrospective chart review was executed on 236 patient admissions prescribed any PPI in a tertiary Jordanian hospital. For each patient, a detailed range of demographic and clinical variables was recorded. Patient’s clinical variables were clustered into major vs. minor criteria for using PPIs in stress ulcer prophylaxis according to the American society of health-system pharmacists’ (ASHP) therapeutic guidelines on stress ulcer prophylaxis. Results: The 236 patients (51% females) had a mean age of 52 ± 18.1 years. Around 56% of the patients were using PPIs before admission. All our patients started PPI use for stress ulcer prophylaxis. Of these, 86% were unnecessary and should be avoided since they do not have at least 1 major or 2 minor indications. Previous PPI use before admission or the presence of one risk factor for stress ulcer motivated initiation of therapy predominately. Recent gastrointestinal (GI) ulcer/bleeding (23%) and coagulopathy (8%) were the main major indications. High-dose corticosteroid (24%) was the most frequent minor indication. Conclusions: The high frequency of inappropriate PPI prescriptions in stress ulcer prophylaxis for inpatients is a major issue in Jordan. Following the current recommended therapeutic guidelines of stress ulcer prophylaxis could minimize the overuse of PPIs in inpatient settings and thus decrease both the possible safety issues of PPIs and the economic burden on the healthcare system.

Introduction Proton pump inhibitors (PPIs), the most effective acid suppression therapy, have been approved for treatment of several hy•

persecretory conditions including dyspepsia, gastroesophageal reflux disease, peptic ulcer disease, Helicobacter pylori eradication therapy, nonsteroidal anti-inflammatory drugs (NSAIDs)-induced ulcers, among others [1]. There is increasing evidence supporting the overuse of PPIs in clinical practice. For instance, the use of PPIs have increased by more than 450% only 10 years after the first PPI (omeprazole) was introduced in the late 1980s [2]. In addition, according to the National Prescription Audit, PPIs have become the 8th therapeutic class on the prescription list in 2013. Moreover, several studies have shown a marked overuse of PPIs in ambulatory and clinical care settings in all age groups, which is associated with high cost [3, 4, 5, 6]. Several postulated factors are responsible for PPI overuse including: high prevalence of medical conditions related to acid hypersecretion, consumer-oriented advertising, high response rate, reasonable costs, availability as over-thecounter-drugs, and a relatively safe side-effect profile, which make PPIs among the top 10 highest-selling pharmaceutical products for several years [7]. PPIs have recently been introduced into clinical practice as a modality of choice in stress ulcer prophylaxis among patients with coagulopathy, recent gastrointestinal (GI) bleeding, or those requiring prolonged mechanical ventilation [8]. Interestingly, PPIs are frequently prescribed for patients who are NPO (Not allowed to feed by mouth) to prevent stress ulcer [8]. In addition, several studies have shown that PPIs are not absolutely safe medications, and their overuse could be associated with serious healthrelated problems such as pneumonia and clostridium difficile infection [9, 10]. As a result, these additional complications could

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Alqudah, Al-azzam, Alzoubi, et al.

Table 1. Distribution of comorbid conditions among hospitalized patients using PPIs divided into major vs. minor criteria. Major criteria Recent GI ulcers/bleeding within 12 months of admission Coagulopathy Traumatic brain injury, traumatic spinal cord injury, or thermal injury Mechanical ventilation longer than 24 hours

At least one major

N (%) Minor criteria 23 (10) High dose corticosteroids 8 (3) 0 (0)

Hepatic failure Renal failure

0 (0)

Current NSAID use Sepsis Occult bleeding within 6 days Organ transplantation ICU > 1 week Injury severity score > 15 Shock 31 (13) At least two minors

N (%) 57 (24) 14 (6) 13 (5.5) 6 (2.5) 4 (2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 4 (2)

PPI = proton pump inhibitors; GI = gastrointestinal; NSAIDs = non-steroidal anti-inflammatory drugs; ICU = intensive care unit.

increase the economic burden on the health care system. However, few data are available regarding frequency of hospitalized patients on unnecessary stress ulcer prophylaxis in Jordan. Therefore, the aim of our study is to determine the frequency of inappropriate PPI use during hospitalization for stress ulcer prophylaxis on the general medical ward of a tertiary university hospital to further clarify the picture of unnecessary PPI prescriptions during hospitalization.

Methods Study population The Jordan University of Science and Technology Institutional Review Board approved this study (Approval # 37/89/2015). During 7 months of study, a total of 236 patients admitted to King Abdullah University Hospital (KAUH) who received at least 1 dose of PPIs during hospitalization were included in this study. Patients who were using PPIs before hospitalization were also allowed to participate in this study. Exclusion criteria were severely ill patients (terminal illness and malignancy) and patients with incomplete medical records (a total of 30 patients excluded). Retrospective chart review was executed on patient admissions to collect demographics (age and gender) and clinical variables (indication for stress ulcer prophylaxis and •

type of PPIs used). PPIs are licensed in Jordan as prescription-only medications for the indications mentioned previously [1]. The American Society of Health-System Pharmacists (ASHP) therapeutic guidelines on stress ulcer prophylaxis was used as an accepted reference to specify PPI indication as having at least 1 major or 2 minor criteria [11]. Major criteria include: coagulopathy (platelet count of < 50 × 103 mm3, international normalized ratio (INR) value (> 1.5), prothrombin time (PTT) of > 2 times the control), mechanical ventilation longer than 24 hours, recent GI ulcers/bleeding within 12 months of admission, traumatic brain injury, traumatic spinal cord injury, or thermal injury (> 35% of the body surface area). Minor criteria include: current sepsis, shock, intensive care unit (ICU) admission > 1 week, occult bleeding within 6 days, high dose corticosteroids (equivalent to 250 mg hydrocortisone), hepatic failure, renal failure, organ transplantation, administration of NSAIDs, or injury severity score (ISS) > 15.

Statistical analysis Statistical significance was detected using the descriptive analysis (%) among categorical variables. Statistical data analyses were performed using Statistical Package for the Social Sciences version 17.0 (SPSS Inc., Chicago, IL, USA) and Excel software version 2010 were used. A p-value of 0.05 or less was considered to be statistically significant.

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Overuse of proton pump inhibitors for stress ulcer prophylaxis in Jordan

Table 2. Dosage regimen of prescribed PPIs given to hospitalized patients. Prescribed PPI

Recommended dosage regimen –

Prescribed dosage regimen –

N (%)

Comments

41 (17)

Omeprazole

40 mg IV QD

Oral PPIs Lansoprazole

– 30 mg PO QD

Esomeprazole

20 mg PO QD

40 mg IV QD 40 mg IV b.i.d. – 30 mg PO QD 30 mg PO b.i.d. 40 mg PO QD 40 mg PO b.i.d.

30 (13) 11 (5) 195 (83) 183 (77) 7 (3) 3 (1) 2 (1)

Totally unneeded since patients were not NPO Recommended dose Overdose – Recommended dose Overdose Overdose Overdose

IV PPIs

PPI = proton pump inhibitors; IV = intravenous; QD = once daily; b.i.d. = twice daily; NPO = not allowed to feed by mouth.

Results A total of 236 patients admitted to KAUH and administered at least 1 dose of PPIs during hospitalization were selected. The mean age of patients was 52, with almost equal distribution of gender and prior PPI use at admission. More than half of the patients (56%) prescribed PPIs during hospitalization for stress ulcer prophylaxis were originally using PPIs before admission. There is a clear trend that physicians prescribe PPIs during hospitalization for patients who are admitted using PPIs, without following the recommended criteria which suggests that prior PPI use is one of the factors contributing to PPI overuse in stress ulcer prophylaxis. To shed light on possible indications of PPI use in stress ulcer prophylaxis during hospitalization that could justify the attending physician rationale, we clustered patient comorbid conditions (and concomitant medications) into major or minor criteria according to the ASHP therapeutic guidelines (Table 1). Surprisingly, after extensive chart review, the bulk of our sample patients had no determined indication for PPI use. Only a small subset of the patients were classified as having major or minor criteria, which suggests an absence of the proper indication to use PPIs in stress ulcer prophylaxis. In the major criteria, 10% of patients had recent GI ulcers and/or bleeding during the previous year, while only 3% had coagulopathy represented by high INR value (> 1.5), PTT more than 2 times of the normal value, or low platelet count less than 50,000 (not shown in the Table). No other major indications related to mechanical ventilation or •

traumatic injury were reported. On the other hand, minor criteria include some concomitant medications such as patients administered high dose corticosteroids (24%) and those who currently use NSAIDs (2.5%). In addition, minor criteria include liver failure (6%), renal failure (5.5%), and sepsis (2%). No other indications related to shock, occult bleeding, ICU admission, or high ISS value were reported. Interestingly, only 13% of patients had at least 1 major criterion, and only 2% of patients had at least 2 minor criteria. Together, these findings illustrate how most of the sample patients ordered PPIs during hospitalization are not real candidates for stress ulcer prophylaxis. To complete the picture of PPI overuse, we merged patients with at least 1 major criterion with those having at least 2 minor criteria in one group called “correct indication” vs. those with no justified use in another group called “no correct indication”. As expected, there was a significant statistical difference between the two groups (14.4% vs. 85.6%). Finally, we extended our analysis onto the prescribed dose of each PPI medication given to the patients during hospitalization. As shown in Table 2, although there is no difference in the efficacy of oral vs. intravenous (IV) PPIs, 83% of the patients were given oral PPIs, while 17% were given IV PPIs. In addition, all our study patients were admitted to the general medical ward, which indicates the unneeded IV therapy. Moreover, the recommended IV omeprazole dose, if needed, is 40 mg once daily (given to 13%) instead of twice daily dosing (given to 5%). Further, although most patients were not candidates for

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PPI acid suppression therapy, most of them were prescribed the correct dosing regimen represented by 30 mg oral lansoprazole once daily (77%), but there were still some deviations from the recommended oral dosing represented by 30 mg oral lansoprazole twice daily (3%). Regarding esomeprazole, the recommended dose is 20 mg once daily, while the actual prescribed doses were 40 mg once (1%) and twice (1%) daily.

Discussion Medication overuse is a well-known ubiquitous problem of improper drug utilization [12]. In the present study, the frequency of hospitalized patients on unnecessary stress ulcer prophylaxis was estimated for the first time in Jordan. At our institution, of all hospitalized patients in the general medical ward, about 86% were prescribed PPIs for stress ulcer prophylaxis in an unnecessary fashion. Specifically, 56% of all hospitalized patients were using PPIs before admission. Of more concern, the prescribed doses were not completely as recommended by the current guidelines. Although limited by a relatively small sample size, this study underscores the need for a better approach to PPI prescription to avoid possible drug-related health problems and decrease additional costs that burden the health-care system. Several recent studies have implicated PPIs in the list of medication overuse at both ambulatory and clinical-care settings worldwide [12-15]. For instance, PPI use rose significantly from 2002 to 2009 in the U.S. outpatient settings [13]. In addition, IV PPIs have been reported to be prescribed for patients with unexplained abdominal pain with no appropriate justification, suggesting the absence of evidence-based indication [14]. Moreover, Moran et al. have reported that most of the PPI prescriptions were inappropriate in the emergency department and continued even upon discharge [15]. Furthermore, it has been reported that this increase in inappropriate use could result in significant economic burden on the health-care system as shown by significant cost expenditure represented as incorrect stress ulcer prophylaxis in non-ICU settings as well as unnecessary PPI discharges [12]. •

The ASHP guidelines for stress ulcer prophylaxis in non-ICU settings do not recommend acid-suppression therapy for general medical patients with no major or at least 2 minor criteria [11]. In this study, we selected all of our patients as current PPI users during hospitalization. Almost 86% of our study patients had no correct indication according to the ASHP guidelines. This trend has been previously reported in several studies. For instance, Ntaios et al. [16] reported that 81.2% of hospitalized patients in an internal medicine department had no indications for administration of PPIs, according to national guidelines. In addition, Akram et al. [17] showed that 81.2% of patients prescribed PPIs did not comply with the local guidelines. Moreover, in another study by Lai et al. [14], 52.8% of patients with empirical IV administration of PPIs for unexplained abdominal pain had incorrect prescriptions. Furthermore, in a Spanish drug-utilization study, 28.65% were using PPIs on admission and 82.62%, during hospitalization. Interestingly, in 74.47% and 61.25% of cases, PPIs were prescribed with incorrect indications, respectively. In our study, alarmingly, we found that 56% of our patients were using PPIs before admission, which is considered as one of the contributing factors for nonevidence-based PPI prescribing for stress ulcer prophylaxis during hospitalization. We considered this as an alarm since in previous studies it has been reported that between 1/3 to 1/2 of patients started on inappropriate acid suppression therapy are usually discharged on these medications [18, 19]. A putative reason for such practice is transcribing the admission medications into inpatients, or even outpatient prescriptions upon discharge without applying the current therapeutic guidelines for the real need of such medications. However, there were not enough data in our study to further identify the frequency of patients with incorrect indication upon discharge to be added to the 86% incorrect use during hospitalization. Together, these findings illustrate that our results are consistent with previous studies. Our results demonstrated that PPIs were prescribed in accordance with the current therapeutic guidelines in only 1/8 of the cases studied, which is much less compared to what was reported by Akram et al. [17], who found

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Overuse of proton pump inhibitors for stress ulcer prophylaxis in Jordan

that only 1/5 met such guidelines. Only ~ 15% of the patients in this study had correct indications with 13% having at least 1 major criterion. Recent GI ulcer/bleeding and coagulopathy were the only major indications for stress ulcer prophylaxis. A small number of patients (2%) had at least 2 minor criteria that justify the need for PPI prescriptions. Concomitant corticosteroid therapy (24%), as 1 minor criterion, was the main indication. A recent study in Greece also found that glucocorticosteroids was one of the main reasons for PPI prescriptions in 22.3% of patients who originally had no correct indication for stress ulcer prophylaxis upon hospitalization in an internal medicine department of a tertiary hospital [16]. The greatest concern from this study was the overuse of IV omeprazole in patients who are not NPO and admitted to the general medical ward with the less severe forms of GI conditions. Approximately 17% of the patients were using IV omeprazole for stress ulcer prophylaxis, which is absolutely not recommended if patients are able to administer by mouth. In addition, omeprazole and other PPIs have been used in doses higher than recommended. In addition, previous studies have linked PPI overuse to significant health problems such as community acquired pneumonia, Clostridium difficile infection, and colonization with methicillin resistant Staphylococcus aureus and vancomycin-resistant enterococcus [9, 10, 19, 20]. Moreover, PPI overuse has been linked to bone fracture [21], vitamin B12 deficiency [22], and interaction with antiplatelet agents [23]. Together, these findings and health-related problems, alarmingly, suggest the need for an alternative practical tool for how physicians or pharmacists should recall indications and improve appropriate use of PPIs. As one of the novel tools for improving the appropriate prescription of PPIs for the right indication and choosing the right dose at both outpatient and inpatient settings, recent studies have implicated the use of computerized decision-support prompt in community pharmacies as well as the use of electronic alerts for dosing of IV PPIs in hospital pharmacies [24, 25]. In both systems, the quality use of PPIs has been encouraged via utilizing a decision support software that allowed the pharmacist to perform patient-focused interventions, positively influenced PPI prescrib•

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ing practice, and significantly resulted in cost savings in the health-care system [24, 25]. This study is limited by a few factors. First, since it was conducted for a short duration of follow-up at one site at KAUH, the exact frequency of PPI overuse (although high) might be underestimated in Jordan. Second, absence of discharge medication records could result in lack of estimating the misuse of PPIs upon discharge. Finally, we do not have any reports as to whether our patients had any of the PPI-overuse healthrelated issues during the period of follow-up. Despite such limitations, our findings not only show the problem in following the current practice guidelines in overprescribing PPIs for stress ulcer prophylaxis but also a major problem in choosing the route of administration and recommended dosage regimen, which could eventually lead to major health-related problems.

Conclusions In summary, our findings elucidate, for the first time, the frequency of PPI overprescreption for stress ulcer prophylaxis among hospitalized Jordanian patients. This inappropriate use of PPIs can be predominantly attributed to transcription of patient medication list before admission into inpatient medication lists as well as the missing role of the current therapeutic guidelines in patient pharmaceutical plans related to stress ulcer prophylaxis. In addition, frequent, unnecessary PPI prescriptions can be one of the main factors of high cost expenditure and potential risk of adverse effects, which could increase the economic burden on the healthcare system. Enforcement of educational interventions to improve physician awareness, collaboration between hospitals and clinical pharmacists, and following evidence-based guidelines could have a real impact on minimizing PPI abuse in hospitalized patients.

Acknowledgment This work was supported by the Deanship of Research at JUST. The contents of this publication are solely the responsibility of the authors, and the funders had no role

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in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest The authors have declared that no competing interests exist.

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