A Prospective Observational Study on Evidence-Based and Unlicensed Indications for Proton Pump Inhibitors in Inpatients of a Tertiary Care Hospital

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1 Research Article A Prospective Observational Study on Evidence-Based and Unlicensed Indications for Proton Pump Inhibitors in Inpatients of a Tertiary Care Hospital B. Blessy Ruth Mounika 1, P. Saranya 2, Jose Prakash 3 * ABSTRACT Objective: The objective of this study is to assess the licensed and off-label indications and duration of therapy for proton pump inhibitors (PPIs) against established guidelines: British National Formulary, National Formulary of India, and National Institute for Health and Care Excellence guidelines 2014 update. Methods: An observational study was conducted in a sample of 300 patients with prescriptions for PPIs and to collect information about sociodemographic characteristics, drug indication, duration of treatment, number of drugs used for acid-related disorders, concomitant drugs, and diagnosis. The appropriateness is performed using the medication appropriateness index questionnaire. It contains 10 items to be evaluated, of which indication, dosage, duration of treatment, and absence of duplication of drugs were of much concern. The final score ranges from 10 (totally appropriate), (marginally appropriate), and >20 (inappropriate). Results: A total of 300 patients receiving PPIs were recruited in the general medicine ward, and their mean age was 47.2 years and 180 (60%) were female. The prescriptions with licensed indications were 59.70% and unlicensed indications 40.30%. The patients with PPIs at discharge were 127, of which 45 were not indicated about the duration of medication to be taken. A statistically significant difference in prescribing PPIs was observed between licensed and unlicensed indication with P = The sociodemographic and drug therapy characteristic differences between licensed and unlicensed indications were found to statistically significant. The number of patients with appropriate PPI therapy was 44.3%, marginally appropriate PPI therapy was 18%, and inappropriate PPI therapy was 37.6%. Conclusion: Inappropriate or the unlicensed use of PPI is incomparably related to mean number of concomitant drugs used, irrespective of the gastro toxic drug combinations apart from the recommendation of guidelines. KEY WORDS: Appropriateness, Inappropriate indications, Proton pump inhibitors, Rationale INTRODUCTION Proton pump inhibitors (PPIs) from the 80s constitute the larger area in one of the most commonly prescribed medicines with a high level of efficacy and low toxicity. [1] PPIs have ruled the areas of prescribing since their advent. [2] The first PPI introduced was omeprazole, which demonstrated to be safe with good efficacy. [2,7] PPIs are the potent inhibitors of gastric acid secretion by an irreversible inhibition of H + K + ATPase pump and decrease stimulated and basal gastric acid. [3] The indications for PPIs as recommended by the established National Institute Access this article online Website: jprsolutions.info ISSN: for Health and Care Excellence (NICE) guidelines (2014) update are appropriate for peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), H.pylori eradication, patients with documented NSAID or aspirin induced ulcers aged 65 and above, Zollinger-Ellison Syndrome, high risk of stress ulcers, and gastroprotection for NSAIDs, steroids, SSRI in patients with history of the peptic ulcer/ previous GI bleed/elderly. [4] Although there is a rising need for the use of PPIs, the extent to which they are prescribed is outside the licensed indications ignoring the appropriate indications established. [5,8] This inappropriate use and long-term use have led to the potential risk for community-acquired pneumonia, hip fractures, clostridium difficile diarrhea, severe hypo magnesium, and Vitamin B 12 deficiency. [6,12] The efficacy of certain drugs such as clopidogrel has 1 Department of Pharmacy, 5 th year, School of Pharmaceutical Sciences, Vels University, Chennai, Tamil Nadu, India, 2 Department of Pharmacy Practice, School of Pharmaceutical Sciences, Vels University, Chennai, Tamil Nadu, India, 3 Department of Pharmaceutics School of Pharmaceutical Sciences, Vels University, Chennai, Tamil Nadu, India *Corresponding author: Dr. D. Jose Prakash, Department of Pharmaceutics, School of Pharmaceutical Sciences, Vels University, Chennai, Tamil Nadu, India. Phone: jose88prakash@gmail.com Received on: ; Revised on: ; Accepted on:

2 been lowered due to low gastric acid secretion. [20,21] The inappropriate prescribing or misuses of PPIs are associated with the treatment of minor ailments with concomitant prescribing of PPIs in combination with drugs, for which GI protection is not indicated, failure to monitor the dose and treatment duration and ignoring repeated prescriptions. [8,13] This study was conducted to evaluate the licensed and off-label indications and rationality in prescribing when compared to the recommendations of established guidelines such as British National Formulary, National Formulary of India, and NICE guidelines 2014 update. METHODS A prospective observational study was conducted in the inpatient wards of the general medicine department of a tertiary care hospital. The study was conducted during the period of October 2016 March The sample size for the study was calculated to be 300. A specially designed case report form was validated and used for data collection. Medication appropriateness index score was adopted from A method for assessing drug therapy appropriateness study. All patients receiving PPIs in the age group of years were included in the study. Patients under 18 years, pregnant women, lactating mothers, and chronically ill patients were excluded from the study. Patients demographic details such as age, sex, direction of arrival, and direction of departure, patient s chief complaints, history of present illness, past medical and medication history, social history, diagnosis, investigations done, drug indication, concomitant drugs, duration of treatment, and PPIs given at discharge medications were the data collected. The appropriate indications for PPIs are shown in Table 1. To assess the appropriateness of Proton pump inhibitors prescribed [2], MAI questionnaire was used. This questionnaire contains 10 items for the assessment namely, Indication, effectiveness, dosage, and directions for taking drugs, if the directions given were practical, duration of treatment, significant drugdrug interaction, drug-disease interaction, least cost effective medication etc. [6,22] In MAI scoring, each question is provided with four options, namely, 1, 2, 3, and Appropriate; 2 - Intermediate; 3 - Inappropriate; 9 - Do not know. The score for MAI was assessed as follows: MAI is performed only for the use of PPI. MAI scores are categorized as appropriate (MAI=10). If MAI is 11 20, marginally appropriate. If MAI >20, inappropriate. Statistical Analysis Statistical analysis was performed using the GraphPad prism technique. Patient s demographic characteristic analysis was performed using MS Excel worksheet, and the statistical measures such as median, mean, range, standard deviation (SD), and percentage were calculated. Differences in licensed with unlicensed indications and its significance were tested using Student s t-test for continuous normally distributed variables and Chisquare test for distribution of categorical variables. P < 0.05 (two-tailed) was considered to be statistically significant. RESULTS The inpatients of the medical ward were screened for containing a PPI in their prescription, and about 300 patients were enrolled into the study based on the inclusion and exclusion criteria. The mean age of the study population was 47.2 years (SD ± 13.56), and 180 (60%) were female. Demographic data of the study population are shown in Table 2. The medication history of the study participants was <2 months (4%), for 2 3 years of duration, 39% were on PPIs, and for 6 months 1 year of duration, 31%, and 2 3 years 39% were on PPIs. PPI prescriptions with appropriate indications were gastroesophageal reflux disease (4%), esophagitis (1%), H. pylori eradication (1%), PUD (2%), acute gastritis (11%), acute gastroenteritis (19%), acid Table 1: Indications for PPIs Indications rated as appropriate Treatment of peptic ulcer and prophylaxis of recurrence Gastroesophageal reflux disease Pathologic hypersecretory conditions (e.g., Zollinger Ellison syndrome) Eradication of H. pylori Prevention of medication induced ulcers: NSAID at patients>65 years NSAID and corticosteroid NSAID and warfarin/coumadin NSAID and patient history of ulcer/gi bleeding Aspirin and corticosteroid Aspirin and warfarin/coumadin Aspirin and NSAID Indications rated as uncertain Ulcer prophylaxis with clopidogrel and low dose aspirin result outstanding at discharge Esophageal varices Dyspepsia History of gastritis, no endoscopy, no further information Barrett s esophagus Anemia, no endoscopy NSAID: Nonsteroidal anti inflammatory drugs, H. pylori: Helicobacter pylori, PPIs: Proton pump inhibitors, GI: gastrointestinal 698

3 peptic disease (12%), irritable bowel syndrome (1%), gastroprotection for concomitant drugs aspirin (26%), and NSAIDs (22%). The patients who received more than one category of GI drugs for GI-related disorders are 175 (58.3%). Prescriptions with PPIs and antacid were 12%, ranitidine (39%), and both antacid and ranitidine were 7%. The differences in the sociodemographic and drug therapy characteristics of patients with licensed and unlicensed indications for the PPIs are shown in Table 3. The comorbid conditions of the study population were hypertension (11.6%), diabetes (9%), and chronic obstructive pulmonary disease (COPD) (8.3%). In this study, 40% of PPI users are using long-term doses of PPI, while most of them would have brought to lower doses or tapering of the PPI dose could have done. Of these 40%, 15% were prescribed with antiplatelet monotherapy and 16.82% with dual therapy. Most of the patients were diagnosed with hypertension (41%), diabetes (18%), and COPD (17%). The prescriptions with licensed indications and unlicensed indications were 177 (59.70%) and 123 (40.30%), respectively. Concomitant drugs prescribed by PPIs for the study population are shown in Table 4. The average number of drugs per prescription was 5.2. The most commonly prescribed concomitant drugs were antimicrobials (36.33%), antiemetic (26.6%), and multivitamin preparations (25%). Among the concomitant drugs given, PPIs were found to Table 2: Baseline demographics Characteristics Values n (%) Sample size (N) 300 Age, years Median (range) 50 (18 65) Mean±SD 47.2±13.56 Length of stay, days Median (range) 5 (1 15) Mean±SD 5.46±2.19 Female 181 (60.40) Comorbid conditions DM 27 (9) HTN 35 (11.6) COPD 25 (8.3) Hypothyroidism 9 (3) Hepatitis 4 (1.3) Rheumatoid 3 (1) arthritis Preadmission drugs Antiplatelet Monotherapy 30 (15.02) Dual therapy 32 (16.82) PPIs 5 (2.35) Corticosteroids 15 (7.1) NSAIDs 5 (2.35) H 2 RAs 10 (5.01) SD: Standard deviation, DM: Diabetes mellitus, HTN: Hypertension, H 2 RAs: H 2 receptor antagonist, NSAID: Nonsteroidal anti inflammatory drugs, COPD: Chronic obstructive pulmonary disease, PPIs: Proton pump inhibitors interact with drugs such as clopidogrel (14%), ciprofloxacin (14%), phenytoin (5%), and oral iron preparations - ferrous sulfate tablets (5%). The coadministration of interacting drugs if ceased can minimize the drug-drug interactions. The reasons for unlicensed indications include gastroprotection for prescriptions containing many numbers of concomitant drugs - antibiotics, polypharmacy, age, and comorbidities as shown in Figure 1. The number of patients discharged with PPIs as discharge medications are shown in Figure 2. In this study, PPIs were prescribed even for primary and secondary prophylaxis majority of patients even at discharge. Distribution based on indicating PPIs duration of therapy on discharge is shown in Figure 3. About 36.40% of PPI user s duration of therapy was not indicated in patients with licensed indications and unlicensed indication. The statistically significant differences in drug therapy characteristics between licensed and unlicensed indications were statistically significant with the level of significance <0.05 as shown in Table 3. The unlicensed prescriptions, with more than one drug for GI disorders, are antacid, [9] ranitidine, [50] and both the drugs. [3] The patients with PPIs at discharge were 127, of which 45 were not indicated about the duration of medication to be taken. About 44.3% and 18% of the study participants had appropriate and marginally appropriate medication appropriateness score, respectively, as shown in Table 5. DISCUSSION This study yields on the patterns of the PPI usage in a tertiary care hospital in Chennai. In a study carried out by Ramirez et al. in the general and traumatology wards of a tertiary care hospital, 82% (271) of the patients were prescribed a PPI. [5] The mean ± SD age of this study population was 47.2 ± years in the current study, whereas in a study by Pasina et al. (2016), the mean age of patients receiving PPIs was 62.1 ± 16.6 as the inclusion criteria were 18 years and older. [1] The guidelines recommend the long-term use of PPIs for indications like GERD, with a documented NSAID-induced ulcer, anmd the requirement for longterm NSAIDs therapy. [2,4] In the current study, 40% of the study participants were using PPIs for long-term which, when compared to Muhammed et al. study, is 65% of patients using PPIs were on long term. [4] Of these 40%, 15% were prescribed with antiplatelet monotherapy and 16.82% with dual therapy, which is in contrary to the Pham et al. study where 20.66% were prescribed with monotherapy and 3.76% with dual therapy. [19] The most common appropriate indications for PPIs in current study were found to be gastroprotection for salicylates (26%), NSAIDs (22%), acute gastroenteritis (19%) which is similar to that reported by Pasina et al. almost common indications 699

4 Table 3: Sociodemographic and drug therapy characteristics of patients treated with PPIs Characteristics Licensed indication (177) Unlicensed indication (123) Age, years (mean±sd) 48.93± ± Range Median Women, n (%) 123 (69.4) 57 (46.3) Patients receiving PPIs, n=177 (123); P= Pantaprazole 9 (5.1) 15 (12.1) Omeprazole 160 (90.1) 97 (78.8) Rabeprazole 2 (1.1) 0 (0) Ilaprazole 5 (2.8) 11 (8.9) Other drugs for acid related disorders n=113 (62); P= Antacid 28 (24.7) 9 (14.5) Ranitidine 66 (58.4) 50 (80.6) Antacid+Ranitidine 19 (16.8) 3 (4.8) Duration of treatment >1 week 127 (72.1) 89 (72.3) 1 2 weeks 49 (27.8) 34 (27.6) Duration of treatment at discharge n=127 (87) P< Indicated 103 (81.1) 42 (48.27) Not Indicated 24 (18.9) 45 (51.72) P b univariate analysis Statistically significant with level of significance<0.05. PPIs: Proton pump inhibitors P b Table 4: Concomitant drugs S. No Drugs used Patients % 1 Antimicrobials NSAIDs Multivitamin preparations Calcium and vitamin D Antihypertensives Vitamin C Antidiabetics Antiemetics Antiplatelets Theophyllines Corticosteroids Diuretics 6 13 Antiepileptics 3 14 Antacids Antimalarial Oral iron therapy Hypolipidemics 18 NSAID: Nonsteroidal anti inflammatory drugs Table 5: MAI score Appropriateness Score Number of patients (%) Appropriate (44.3) Marginally appropriate (18) Inappropriate > (37.6) MAI: Medication appropriateness index for PPIs were prevention of GI toxicity induced by NSAIDs (19.2%), GERD (17.7%), and gastric ulcer (12.3%). Most commonly prescribed drug was omeprazole in both licensed and unlicensed indications as shown in Table 3 which is in contrast to Pasina et al. study. Pantoprazole was most commonly prescribed in licensed and unlicensed indications which were 37% and 32%, respectively. [1] About 42% of the study population received PPIs for an unlicensed indication which is closer to that reported by Pasina et al. as 48%, whereas reported by Walker et al., it was 67% treated for unlicensed indications. The most commonly prescribed concomitant drugs were antimicrobials (36.33%), antiemetic (26.6%), and multivitamin preparations (25%) which are in accordance to a study reported by Nousheen et al., and antimicrobials were prescribed in 58% of patients with PPIs as concomitant medications. [7] Pham CQD et al in his study found that in 38% of all inappropriate prescribing is linked with the utilization of corticosteroid (21%), 40% involved ulcer prophylaxis in low-risk patients whereas in the current study inappropriate use is associated with only 11% for corticosteroid use and 10% in polypharmacy [16]. In many of the prescriptions with PPIs, there is poor documentation for the duration of PPI therapy to be continued. A statistically significant difference in prescribing PPIs was observed between licensed and unlicensed indications with P = as shown in Table 4. It was observed that prescription for prophylaxis against GI toxicity was very common among women (60.4%) than men (39%) which is in contrast to that reported by Nousheen et al. (men 61% and women 39%). [7] Omeprazole was the drug of choice among the PPIs (90.1%) when compared to pantoprazole and 700

5 Figure 1: Inappropriate indications Figure 2: Distribution based on proton pump inhibitors as discharge medication each other and exhibit the subtherapeutic effect of clopidogrel. Avoiding this combination can improve the clinical efficacy of clopidogrel. [15,20] The most commonly prescribed concomitant drugs with PPI are ranitidine (80.6%) and antacid (16.5%) in the current study which is in contrast to that reported by Pasina et al., ranitidine (12.5%) and antacid (80.4%). These results are in contrast to a study reported by Pham et al. in which a combination of H2-RA and antacids with PPI was observed for 58.3% of their study population and only H2-RA with PPIs for 6.1%. [19] Our study results indicate that PPIs should be prescribed for appropriate indications and longterm use of these could be avoided when there are no indications. Physicians should consider withdrawal of drug when no specific diseases are indicated. The MAI score, despite potential limitations, promises sensible and reliable results in the extent of the appropriateness of PPI usage in clinical settings. [6,22] The number of patients with appropriate PPI therapy was 44.3%, and number of patients with marginally appropriate PPI therapy was 18% and inappropriate PPI therapy 37.6%. The most inappropriate therapy was without any clear indication. The most inappropriate therapy was without any clear indication and the therapy with marginal appropriateness was patients with prophylaxis of gastric ulcer in the elderly, ASA therapy where no risk of ulcer formation was documented. [2,18] These results were closer to that reported by Lodato and Poluzzi. that 40% were appropriately treated and 22% were inappropriately treated which was found using MAI score. [2] Thus, the large use of PPI has led to ignorance of appropriate indications for PPIs and relevant treatment duration. Inappropriate or the unlicensed use of PPI is incomparably related to mean number of concomitant drugs administered, irrespective of the gastrotoxic drug combinations apart from the recommendation of guidelines. CONCLUSION Figure 3: Distribution based on indicating proton pump inhibitors duration of therapy on discharge ilaprazole in the current study, which is in line with that reported by Ramirez et al. (omeprazole 82.62%). They have also stated that omeprazole therapy is cost effective. [4] Overuse of PPIs when there is no indication for the drug can lead to hypochlorhydria which in turn potentiates the risk for gastric cancer, colonization of clostridium difficile, incomplete calcium supplements, iron supplement absorption, and Vitamin B12 deficiency. [17,20,21] Around 14% of the study population received a combination of clopidogrel and PPI, which is reported to interact with We evaluated licensed and off-label indications and rationality in prescribing PPI inpatients of general medicine department of a tertiary care hospital. Unspecified gastroprotection and polypharmacy were the common unlicensed indications observed in the study. PPI prescription appropriateness should be improved in terms of reduction of overuse. The actual indication for PPI must be considered by the practitioners while prescribing. It was observed that continuation of PPI therapy for long term was due to inadequate data about drug therapy cessation in the prescription. The PPI prescriptions must be reviewed at regular intervals and withdrawal of treatment should be done in a stepwise manner as recommended by the guidelines. Thus, confined evaluation of the basal clinical conditions and prescribing patterns more intently linked to evidence-based guidelines and 701

6 national recommendations are essential for a rational and cost-effective approach. There is a arising need for proper vigilance in the increased non-indicated prescribing of PPIs. REFERENCES 1. Pasina L, Urru SA. Evidence-based and unlicensed indications for proton pump inhibitors and patients preferences for discontinuation: A pilot study in a sample of Italian community pharmacies. J Clin Pharm Ther 2016;41: Lodato F, Poluzzi E. Appropriateness of PPI prescription in patients admitted to hospital: Attitudes of general practitioners and hospital physicians in Italy. Eur J Intern Med 2016;1: Pasina L, Nobili A. Prevalence and appropriateness of drug prescriptions for peptic ulcer and gastro-oesophageal reflux disease in a cohort of hospitalized elderly. Eur J Intern Med 2011;22: Haroon M, Yasin F. Inappropriate use of proton pump inhibitors among medical inpatients: A questionnaire-based observational study. J R Soc Med Short Rep 2013;4: Ramirez E, Lei SH. Overuse of PPIs at admission, during hospitalization, and at discharge in a tertiary Spanish hospital. Curr Clin Pharmacol 2010;5: Hanlon JT, Schmader KE. A method for assessing drug therapy appropriateness. J Clinepidemiol 1992;45: Tadvi NA. Use of proton pump inhibitors in general practice: Is it rationale? Int J Med Res Health Sci 2014;3: Wermeling M, Hummel W. Why do GPS continue inappropriate hospital prescriptions of proton pump inhibitors? a qualitative study. Euro J Gen Pract 2013;20: Pali S, Hungin A, Rubin GP. Long term prescribing of proton pump inhibitors in general practice. Br J Gen Pract 1999;49: Saad MA, Collins N, Lobo MM, O Connor HJ. Proton pump inhibitors: A survey of prescribing in an Irish general hospital. Int J Clinpract 2005;59: Grime J, Pollock K, Blenkinssop A. Proton pump inhibitors: Perspectives of patients and their GPs. Br J Gen Pract 2001;51: Choudhry MN, Soran H, Ziglam HM. Overuse and inappropriate prescribing of proton pump inhibitors in patients with clostridium difficile-associated disease. Q J Med 2008;101: Nardino RJ, Vender RJ, Herbert PN. Overuse of acidsuppressive therapy in hospitalized patients. Am J Gastroenterol 2000;95: Ahrens D, Chenot JF, Behrens G, Grimmsmann T, Kochen MM. Appropriateness of treatment recommendations for PPI in hospital discharge letters. Eur J Clinpharmacol 2010;66: Bashford JN, Norwood J. Why are patients prescribed proton pump inhibitors? retrospective analysis of the link between morbidity and prescribing in the general practice research database. Br Med J 1998;317: Pappas M, Jolly S. Defining appropriate use of proton pump inhibitors among medical inpatients. J Gen Intern Med 2015;31: Batuwitage BT, Kingham JG, Morgan NE, Bartlett RL. Inappropriate prescribing of proton pump inhibitors in primary care. Postgrad Med J 2007;83: Lunar CD, Del Castillo SN, Díaz EL. Study of prescriptionindication of proton pump inhibitors. Rev Clín Jun 2006;206: Pham CQ, Regal RE, Bostwick TR, Knauf KS. Acid suppressive therapy use on an inpatient internal medicine service. Ann Pharmacother 2006;40: Dumbreck S, Flynn A, Nairn M, Wilson M, Treweek S, Mercer SW, et al. Drug-disease and drug-drug interactions: Systematic examination of recommendations in 12 UK National Clinical Guidelines. BMJ 2015;350: H Focks JJ, Brouwer MA. Concomitant use of clopidogrel and proton pump inhibitors: Impact on platelet function and clinical outcome-a systematic review. Heart BMJ 2013;99: Rakesh KB, Chowta MN. Evaluation of polypharmacy and appropriateness of prescription in geriatric patients: A cross sectional study at a tertiary care hospital. Indian J Pharmacol 2017;49: Source of support: Nil; Conflict of interest: None Declared 702