Abstract
Background: Proton pump inhibitors (PPIs) are the most potent antacids used in clinical practice with greater safety and efficacy. Limited data are available on the usage of PPIs in Indian health-care settings. Our aim was to understand the usage pattern and potential drug interactions with concurrently administered medications employing a single-day cross-sectional study design. Methods: A prospective observational cross-sectional study conducted on a single day, at two tertiary care teaching hospitals in South India. Inpatients of above 18 years of age were included. Case profiles were reviewed and data were collected in predesigned forms and analyzed. Drug interactions were identified using Micromedex and Medscape drug-interaction databases. Results: A total of 797 case profiles screened from both the centers; 714 were prescribed with PPIs. In intensive care units (ICUs), the use of PPIs was highest with 95% of cases getting these drugs. A PPI was seen in about 93% of patients, who had more than or equal to 4 drugs in their prescriptions. Pantoprazole was the mostly prescribed PPI in around 90% of the cases. Around 33% of the PPIs usage was through IV (intravenous) route, and 75% of that use was seen in wards. Around 134 drug interactions were identified, of which 10 were of major severity. Conclusions: Around 90% of inpatients were prescribed with PPIs. Pantoprazole is the most commonly prescribed PPI (90%). The IV administration was seen more in wards than ICUs, and 10 major drug interactions were observed in this single-day study. Careful monitoring is needed to avoid serious drug interactions involving PPIs, and training programs should sensitize the clinicians on the evidence-based use of PPIs.
Keywords: proton pump inhibitors, drug usage, cross-sectional study, drug interactions
Introduction
Proton pump inhibitors (PPIs), introduced in the late 1980s are considered as effective inhibitors of gastric acid secretion with very a good safety profile.1-3 PPIs are indicated in the treatment of esophagitis, gastric ulcers, gastroesophageal reflux disease (GERD), dyspepsia, bleeding peptic ulcers, eradication of Helicobacter pylori, Zollinger–Ellison syndrome, and prevention of gastrointestinal toxicity induced by nonsteroidal anti-inflammatory drugs (NSAIDs).4
Owing to their superiority to other agents, usage of PPIs is on the rise, with annual sales worldwide have surpassed $25 billion. The reasons for this raise being unclear and difficult to be explained solely by new indications or a decrease in alternative medication or increased morbidity.5 A staggering 113-million4 prescriptions are filled for PPIs each year, making these drugs the third highest seller in the world.6 Along with the good safety profile and efficacy, PPIs can be conveniently administered as oral dosage form once daily (OD) making them highly preferred.7
Despite an acceptable safety profile, recent reports have highlighted the concerns in connection with inappropriate and long-term usage of PPIs.8 Potential consequences of prolonged PPI therapy include parietal cell hypertrophy, leading to rebound acid hypersecretion, hypergastrinemia, and enterochromaffin-like cell hyperplasia. In addition, PPIs have also been linked to increased risk of infections like community-acquired pneumonia, Clostridium difficile–associated diarrhea, bone fracture, interference with the metabolism of antiplatelet agents, and nutritional deficiencies.9
There are reports of PPIs being associated with the development of acute interstitial nephritis.2 It has been documented that risk of moderate hyponatremia is increased by chronic use of PPI in the elderly population,10 likely a result of drug-induced SIADH (Syndrome of inappropriate antidiuretic hormone secretion).2
Drug interaction of the greatest clinical importance is a reduction in the clearance of benzodiazepines by omeprazole.10 The other serious interactions observed are with carbamazepine, diazepam, phenytoin, and theophylline, due to alterations in CYP2C19 enzyme metabolism.11 Interference in the metabolism of clopidogrel is also associated with competitive effects of PPIs on CYP2C19 enzyme systems. Potentially higher risk of adverse clinical outcomes is known to exist in such patients.12
In elderly patients, overprescribing of PPIs is a concern because this can lead to increased morbidity, adverse drug events, hospitalization and mortality, owing to multi-morbidities, and use of numerous drugs.12 Although, PPIs are widely prescribed in both hospital and general practice settings, the data available on appropriateness remain inadequate due to the unavailability of complete details about the patients.12 Prescription of PPIs without clear indications have been frequently observed in many hospitals13,14 and primary care centers.15
The aim of our study is to understand the usage patterns of PPI and to identify the occurrence of any drug interaction that exists between PPI and concurrently prescribed drugs.
Materials and Methods
Our study was a prospective observational cross-sectional study conducted at two tertiary care teaching hospitals in South India. The study was conducted over a day, between 8 am and 8 pm at both the centers. All records of inpatients admitted across the hospitals were screened, and only patients of above 18 years of age were included. Data were collected in predesigned forms and included details on demographics, the location of patient, insurance status, and drugs prescribed. The study bearing IEC no. 728/2016 was conducted only after receiving approval from the Institutional Ethics Committee. The presence of PPI-drug interaction (PPI-DI) was identified using the drug interaction databases like Micromedex Drug Interaction and Medscape Drug Interaction Checker.
Data were entered into SPSS (version 20.0), and the analysis was performed using the same. Descriptive statistics were used. Continuous variables were represented as mean (SD), and the categorical variables were represented as frequencies and percentage.
Results
A total of 797 prescriptions were screened in both the centers, of which 714 patients were found to have PPI in their prescription. From the first center, 621 prescriptions were available for screening and in the second center 176 prescriptions were screened. Data from both these centers were combined for analysis.
Among the patients admitted in wards, 613 out of 691 (89%) were on PPIs. In the intensive care units (ICUs), 101 out of 106 (95%) cases were prescribed with PPIs. The mean (SD) age of the male patients on PPI was 49 (16.23) years, whereas in female patients it was 46.10 (17.42) years. Most of the patients were in the age group of 51 to 60 years. It was observed that PPI was prescribed in 92% of non-insured patients and 86% of patients with insurance. Among the patients on polypharmacy, a PPI was seen in about 92% of them, who had four or more drugs in their prescriptions. The demographic data and prescription details of PPIs are presented in Table 1.
Table 1.
Basic Demographics, Insurance Status, and Drug Interaction (PPI-DI) of Inpatients.
| Total patients N = 797 |
Patients on PPI n = 714 (90%) |
Patients “not” on PPI n = 83 (10%) |
|
|---|---|---|---|
| Location | |||
| ICU | 106 (13) | 101 (95) | 5 (5) |
| Ward | 691(87) | 613 (89) | 78 (11) |
| Gender | |||
| Male | 454 (57) | 412 (91) | 42 (9) |
| Female | 343 (43) | 302 (88) | 41 (12) |
| Insurance status | |||
| Insured | 293 (37) | 251 (86) | 42 (14) |
| Non-insured | 504 (63) | 463 (92) | 41 (8) |
| Age group, y | |||
| Mean (SD) age | 47.16 (16.95) | 49.93 (17.81) | |
| 12-20 | 38 (5) | 30 (4) | 8 (10) |
| 21-30 | 118 (15) | 114 (16) | 4 (5) |
| 31-40 | 122 (15) | 111 (16) | 11 (13) |
| 41-50 | 155 (19) | 138 (19) | 17 (20) |
| 51-60 | 174 (22) | 156 (22) | 18 (22) |
| 61-70 | 118 (15) | 106 (15) | 12 (14) |
| 71-80 | 49 (6) | 39 (5) | 10 (12) |
| 81-90 | 21 (3) | 18 (3) | 3 (4) |
| 91-100 | 2 (0.25) | 0 (0) | 2 (2) |
| No. of drugs | |||
| ≤3 | 82 (10) | 52 (7) | 30 (36) |
| 4-7 | 382 (48) | 352 (49) | 30 (36) |
| 8-10 | 209 (26) | 194 (27) | 15 (18) |
| 11-15 | 98 (12) | 93 (13) | 5 (6) |
| 15-20 | 25 (31) | 22 (3) | 3 (4) |
| ≥21 | 1 (0.1) | 1 (0.1) | 0 (0) |
| PPI-drug interaction | |||
| Major | 10 (1) | 10 (1) | |
| Moderate | 99 (12) | 99 (14) | |
| Minor | 25 (3) | 25 (4) | |
Note. Numbers in bracket represent percentages. In shaded rows, the row percentage is mentioned. PPI-DI = PPI-drug interaction; PPI = proton pump inhibitors; ICU = intensive care unit.
Regarding the pattern of PPI use at the study hospitals, it was observed that in ICU, 96% of patients had OD regimen and 60% of the patients received it as IV (intravenous) dosage form, whereas in wards, 88% were on OD regimen and 29% received it as IV dosage form. It was also observed that the use of twice-daily PPI was predominant in wards. Further details on usage pattern of different dosing frequencies and dosage forms are shown in Table 2. Out of 714 patients who were on PPIs, 238 received them via IV route, while the remaining (476) received it through oral route. About 178 out of 238 patients (75%) of IV PPIs were used in wards.
Table 2.
Details on the Usage Pattern of Different Dosage Forms and Dosing Frequencies.
| Total patients (N = 714) |
ICU (n = 101) |
Ward (n = 613) |
|
|---|---|---|---|
| Dosing frequency | |||
| OD | 638 (89) | 97 (96) | 541 (88) |
| BD | 76 (11) | 4 (4) | 72 (12) |
| Dosage form | |||
| IV | 238 (33) | 60 (60) | 178 (29) |
| Oral | 476 (67) | 41 (40) | 435 (71) |
| PPI-drug interaction | |||
| Major | 10 | 2 (20) | 8 (80) |
| Moderate | 99 | 31 (31) | 68 (69) |
| Minor | 25 | 2 (8) | 23 (92) |
| PPIs | |||
| IV | |||
| Pantoprazole | 219 (31) | 56 (55) | 163 (27) |
| Rabeprazole | 14 (2) | 4 (4) | 10 (2) |
| Esomeprazole | 4 (<1) | 0 | 4 (<1) |
| Omeprazole | 1 (<1) | 0 | 1 (<1) |
| Oral | |||
| Pantoprazole | 423 (59) | 39 (39) | 384 (63) |
| Rabeprazole | 30 (4) | 2 (2) | 28 (4) |
| Esomeprazole | 17 (2) | 0 | 17 (3) |
| Omeprazole | 6 (<1) | 0 | 6 (<1) |
Note. Numbers in bracket represent column percentages. ICU = intensive care unit; OD = once daily; BD = twice daily; IV = intravenous; PPI = proton pump inhibitors.
Among the patients on PPI, pantoprazole was predominantly prescribed in 90% of them followed by rabeprazole in 6%. The lowest incidence of PPI use was observed in the gastroenterology department (0.75), whereas the highest was observed in the emergency medicine department. Table 3 depicts in detail about the department wise use of PPIs.
Table 3.
Department Wise Distribution of PPI Usage and the Incidence of PPI-DI.
| Departments | PPI |
Frequency |
PPI-drug interaction |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | PPI | Eso | Ome | Pan | Rabe | OD | BD | Maj | Mod | Min | |
| Emergency medicine | 6 | 6 | 5 | 1 | 2 | 4 | |||||
| Cardiology | 58 | 55 | 55 | 50 | 5 | 3 | 22 | 2 | |||
| Gastroenterology | 20 | 15 | 1 | 13 | 1 | 6 | 9 | 2 | 2 | 1 | |
| Gynecology | 40 | 38 | 38 | 16 | 22 | 1 | 5 | ||||
| General medicine | 189 | 165 | 1 | 6 | 152 | 6 | 155 | 10 | 2 | 25 | 9 |
| Oncology | 20 | 18 | 16 | 2 | 18 | ||||||
| Nephrology | 34 | 31 | 29 | 2 | 28 | 3 | 4 | 1 | |||
| Neurosurgery | 43 | 37 | 37 | 37 | 12 | 3 | |||||
| Obstetrics | 35 | 28 | 24 | 4 | 28 | 1 | |||||
| Orthopedics | 154 | 136 | 1 | 1 | 124 | 10 | 125 | 11 | 6 | ||
| Pulmonary | 54 | 53 | 13 | 34 | 6 | 47 | 6 | 2 | 17 | 1 | |
| General surgery | 144 | 132 | 5 | 115 | 12 | 126 | 6 | 1 | 9 | 3 | |
| Grand total | 797 | 714 | 21 | 7 | 642 | 44 | 638 | 76 | 10 | 99 | 25 |
Note. PPI = proton pump inhibitors; PPI-DI = PPI-drug interaction; Eso = esomeprazole; Ome = omeprazole; Pan = pantoprazole; Rabe = rabeprazole; OD = once daily; BD = twice daily; Maj = major; Mod = moderate; Min = minor.
In total, around 134 drug interactions were identified between PPI and any other drug (PPI-DI) in the prescription. Based on the severity, interactions were classified as major, moderate, and minor. Ten patients were found to have major severity PPI-DI in their prescriptions. Majority (99) of the interactions were of moderate severity, and 25 prescriptions were found to have PPI-DI of minor severity. The highest number of interactions was noted among the patients admitted under the cardiology department (49%). About 2% of patients admitted either in ward or ICU were found to have a major interaction in their prescription. Moderately severe PPI-DI was the most common type of interaction, in which 31% were from ICU prescriptions and 11% were from wards. Digoxin and methotrexate had a major PPI-DI, which was observed in 9 and 1 prescriptions, respectively. Among PPI-DI with moderate severity, clopidogrel was the most common drug involved, as observed in 33 prescriptions. The drugs which had a minor severity PPI-DI were dexamethasone, phenytoin, and vitamin B12. The incidence and severity of various PPI-DI were shown in Table 4.
Table 4.
Details About Drugs Identified to Have PPI-DI and Their Incidence in Various Departments.
| CAR | GEC | GYN | MED | NPH | NUS | OBS | ORT | PUL | SUR | Grand total | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Major | 3 | 2 | 2 | 2 | 1 | 10 | |||||
| Digoxin | 3(2) | 2 | 1 | 2 | 1 | 9 | |||||
| Methotrexate | 1 | 1 | |||||||||
| Moderate | 22 | 2 | 1 | 25 | 4 | 12 | 1 | 6 | 17 | 9 | 99 |
| Carbamazepine | 1 | 1 | |||||||||
| Clopidogrel | 19(12) | 2 | 3(1) | 1(1) | 1(1) | 4(2) | 3 | 33 | |||
| Clopidogrel, fluconazole, theophylline | 1(1) | 1 | |||||||||
| Clopidogrel, levothyroxine | 1 | 1 | |||||||||
| Clopidogrel, theophylline | 1 | 1 | |||||||||
| Clopidogrel, warfarin | 1 | 1 | |||||||||
| Clopidogrel, ferrous Fumerate, rifaximin |
1(1) | 1 | |||||||||
| Duloxetine | 1 | 1 | 2 | ||||||||
| Duloxetine, ferrous fumarate | 1 | 1 | |||||||||
| Ferrous fumarate | 1 | 1 | 2 | ||||||||
| Fluconazole | 1 | ||||||||||
| Levothyroxine | 1 | 3(1) | 1 | 1 | 1 | 1 | 1 | 3(1) | 12 | ||
| Levothyroxine, warfarin | 1(1) | 1 | |||||||||
| Phenytoin | 1 | 9(3) | 1 | 11 | |||||||
| Rifampicin | 1 | 1(1) | 2 | 4 | 7 | ||||||
| Rifampicin, warfarin | 1 | 1 | |||||||||
| Rifaximin | 2(2) | 2 | |||||||||
| Theophylline | 1 | 3(1) | 6(2) | 11 | |||||||
| Voriconazole | 1 | 1 | |||||||||
| Warfarin | 3 | 1 | 1 | 1 | 6 | ||||||
| Warfarin, levothyroxine | 1 | 1 | |||||||||
| Minor | 2 | 1 | 5 | 9 | 1 | 3 | 1 | 3 | 25 | ||
| Dexamethasone | 3(1) | 1 | 6 | ||||||||
| Phenytoin | 1 | 1 | |||||||||
| Vitamin B12 | 2(1) | 1 | 5 | 7(1) | 1 | 2 | 18 |
Note. Bracket represents prescriptions with PPI-drug interaction in ICUs. PPI-DI = PPI-drug interaction; PPI = proton pump inhibitors; CAR = cardiology; GEC = gastroenterology; GYN = gynecology; MED = general medicine; NPH = nephrology; NUS = neurosurgery; OBS = obstetrics; ORT = orthopedics; SUR = general surgery; ICU = intensive care unit.
Discussion
On the day of survey, PPI was prescribed in 90% of patients admitted in the study hospitals, which raises a concern, regarding the rationality for such a practice and a question, whether PPI is really indicated in those patients. In the present study, we aimed to assess the usage of PPIs in two different settings and assessing the appropriateness of PPIs was out of our purview as it is difficult to assess with cross-sectional study design.
Cross-sectional study design was chosen to perform this study as it requires less human resources, relatively faster and cheaper when compared to cohort study design, thus making it ideal for centers with limited resources. It comes with certain bias and difficulties in interpreting the associations. But it provides extensive baseline data across the entire setting at a snapshot of time, which can be used to measure the prevalence of a condition.16
The mean (SD) age of the patients in our study was 47.16 (16.95) years, which was similar to the study performed by Churi and Jogani17 where the mean age was 45.38 years, but it was lower than in a multicenter (9 Colombian cities) study conducted by Machado-Alba et al,18 where the mean (SD) age was 54.4 (18.7) years. Older mean age in the multicenter study suggests that high use of PPI was observed among the older patients compared to the observations in our study. Voukelatou et al19 in their study on PPIs’ use in elderly patients has identified Charlson Comorbidity Index, Katz index score, use of blood thinners, number of diseases, and number of medications as the factors associated for use of PPI, but when run a multivariate logistic regression, only the number of medications received was found to be an independent predictor. Thus it can be interpreted as polypharmacy as a risk factor.
Most of the patients in our study were in the middle age group of 41-60 years (41%), followed by 20-40 years (35.7%) and above 61 years (22.82%) of age, and our observations were similar to the study performed by Patil et al20 where 41% of the patients were in the middle age group of 41-60 years, 32% were in 20-40 years, and 27% belong to above 61 years of age group, showing a uniformity in the prescription pattern of PPI among patients of particular age group and demonstrates that overall highest use is among the patients in age group of 41 to 60 years.
There was not much difference in the mean (SD) ages of male and female patients on PPI, which was also observed in the study done by Machado-Alba et al18 where average age of male and female patients was 54.5 years and 54.3 years, respectively. Suggesting that, in patients of similar age, the practice of PPI use does not differ on the basis of gender.
Irrespective of whether the patient is covered by insurance or not, a similar proportion of patients were prescribed with PPI, signifying that the insurance status of the patient is not biasing the PPI prescribing practices. Among the prescriptions having 4 or more drugs, a PPI was seen in about 92% of them, which was much higher than the findings from a study done by Shahsavani et al21 in which only 68.41% of prescriptions had a PPI. There lies a huge difference in the practice of PPI use, which suggests the need for awareness among physicians for Continuing Medical Education programs and a policy for limiting the use and duration of PPI to medically relevant conditions.9 Regarding the use of different PPIs, the most commonly used PPI in our study was pantoprazole and omeprazole was the least used one, and this pattern was almost similar to a reported study.20 Kelly et al22 in their study conducted in a teaching hospital has reported a different usage pattern with lansoprazole (45%) being the choice of PPI followed by omeprazole (32%), esomeprazole (17%), and pantoprazole (6%). However, the National Institute for Health and Care Excellence (NICE) guidelines on PPI use does not recommend a particular PPI over other ones, except on the basis of cost or for some specific indications thereby leaving it to the clinicians’ discretion to make a choice based on their experience and patients’ condition.23 Rabeprazole and esomeprazole were found to have superior acid suppression activity and faster cure.24
There was no location-based differences in prescriptions of PPIs between ICUs and wards showing similar pattern of use across the hospital, irrespective of the critical status of the patients. Majority of the PPIs (67%) were used in oral dosage form and predominantly seen in wards (71%) followed by ICUs, whereas the use of IV dosage form (33%) is more in ICUs and about one-third of ward patients also on IV PPIs. A study conducted by Nasser et al25 have found a high prevalence of IV PPI use at a university teaching hospital, and only about 50% of their use was having a rational indication. Raising a concern about the added cost associated with IV formulation and the inconvenience caused to the patient due to either presence of peripheral line or repeated injections.
OD dosing was observed across the hospital, but a few departments like emergency medicine, gastroenterology, and gynecology used twice daily (BD) regimen more than OD regimen. Savarino et al24 reported that about 30% to 50% of pregnant women tend to have suffering due to heartburn and elevated serum levels of progesterone, thus might be requiring more aggressive management of the symptoms. Although all PPIs are safe during pregnancy with no major teratogenicity,26 omeprazole has proven safety data from multicenter randomized clinical trials.27 As pantoprazole was the commonly used PPI, it was also the drug which was prescribed at double the daily dose. But, as per NICE guidelines, the use of twice-daily dose of pantoprazole is an off-labeled indication used only for GERD.23
Out of all the PPI-DI observed in the prescriptions, the highest number of PPI-DI were observed in prescriptions of patients admitted under the cardiology department; the primary determinant for this attribution is more use of digoxin and clopidogrel in patients with cardiovascular conditions. In a study done by Ho et al28 in patients suffering from myocardial infarction (MI), it was reported that prescribing a PPI (irrespective of the variant) along with clopidogrel increases the readmission of the patient. Concomitant use of methotrexate and PPIs may cause delayed elimination of methotrexate and its metabolite and subsequent methotrexate toxicity. Usage of methotrexate along with PPIs should be avoided and H2 blocker should be substituted instead of PPI inhibitors.29
The predominant mechanism of drug interactions in our study is due to the binding of drugs inside the gastrointestinal tract. Thus, spacing the drugs appropriately can be an efficient intervention for the management of such interactions. Ansari30 in his article further discusses about the various strategies that can be employed for managing the drug interactions.
The resources we used to categorize the PPI-DI were Micromedex and Medscape; during the study we have also observed that the category of interaction (Minor, Moderate, Major) between a particular PPI and a drug sometimes differs among these sources. In such cases, reports of Micromedex was considered final. When there are conflicting data on interactions, it is ideal to compare the available evidences on mechanisms of interactions, confounding factors, reported incidence and patient risk factors to make a clinical decision.31
Conclusion
About 90% of inpatients were found to have PPI in their prescriptions, and a similar proportion were prescribed with OD dose. IV administration was seen more in ICU than in wards with around 30% of ward patients receiving IV PPI. Pantoprazole is the most commonly prescribed PPI (90%). Ten patients were found to have a PPI-DI of major severity in their prescriptions and 99 had of moderate severity. Careful monitoring is needed to avoid serious drug interactions involving PPIs, and training programs should sensitize the clinicians on the evidence-based use of PPIs.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Zabiuddin Ahad M 
https://orcid.org/0000-0003-2856-3000
Alekhya Lavu
https://orcid.org/0000-0003-3198-6020
Maria Ansari
https://orcid.org/0000-0003-2955-6734
Rajesh Vilakkathala
https://orcid.org/0000-0003-1261-4977
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