Introduction:
Primum non nocere, which means, “first, do no harm”.[1] This may be conveyed - by not prescribing an unwanted drug or discontinuing a drug that is considered unwanted.[2] Though evidence shows that the risk and benefits of medications change with time, very few attempts have been made to design procedures for regular monitoring and cessation of medications to ensure the safety of patients.[3] Deprescribing is a planned, safe and effective assessment process which involves discontinuation of medications with undefined or no efficacy, unfavorable risk/benefits ratio, drug interactions, already cured disease conditions and those that the patient desires to avoid with adequate follow up. This can be done by complete cessation, dosage adjustment, substitution or discontinuation followed by incorporation of other appropriate drugs.[4-7]
PPIs are the acid-suppressing medications that act directly by inhibiting the hydrogen pump in the parietal cells.[8,9] PPI therapy is mandatory in patients with typical Gastroesophageal Reflux Disease (GERD) and Helicobacter pylori-negative or Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) related recurrent peptic ulcer disease.[10] Though evidence shows that after 4-8 weeks of PPI use, there is no significant increase in their efficacy, they are frequently overused for dyspepsia.[9-12] Though there is no evidence to show an increase in prevalence of Gastrointestinal (GI) diseases or an increased morbidity due to GI diseases or a decrease in Histamine 2 Receptor Antagonist (H2RA) use especially after prevalent eradication of Helicobacter pylori, there has been a large increase in number of PPI prescriptions.[9,10] A prospective study conducted in Andhra Pradesh, India, revealed that PPI were prescribed irrationally in 58% of hospitalized patients without any legitimate indication.[13] This shows that PPI are being used for minor complaints and patients demand for PPI rather than change in lifestyle.[14]
A survey revealed that in Indian population, people tend to take medications for longer duration than required due to medical illiteracy.[15] Further there are no studies conducted in India regarding the use of PPI, their abuse, their effects on health status of the patient. As PPI are most consumed in a Gastroenterology unit, this study was done by using a deprescribing algorithm and Patient Information Leaflets (PIL) for the purpose of preventing the overutilization of PPI to avoid drug related problems, promoting life style modifications and quality of life.[11,16]
Methods
This is a prospective, interventional study carried out in the Department of Gastroenterology of M.S. Ramaiah Memorial Hospital for a period of 11 months from October 2017 to August 2018. The demographic profile and Global Overall Symptom (GOS) scale were recorded in a uniform structured proforma. The GOS scale is a validated 7-point scale, which was used to grade the overall severity of symptoms of gastric discomfort.[17] All patients aged 18 years and above who have been using PPI for more than 4 weeks, were included in the study. Patients with dementia, pregnancy and those in palliative care were excluded. The study was approved by the Institutional Ethics Committee.
The demographic details, medication history and lifestyle practices were collected through patient interview and medical records. After endoscopic procedure, the patients were classified into three categories based on appropriateness of PPI consumption based on the endoscopic findings (LA classification).[18] The categories include clearly appropriate, likely appropriate and potentially inappropriate indication. The patients with barrette’s esophagitis, Zollinger Ellison’s Syndrome (ZES), peptic ulcer, chronic NSAID users, GERD grade C and D were considered as clearly appropriate category to consume PPI. The patients with GERD grade A and B, gastroduodenal erosions were considered as likely appropriate category to consume PPI. The patients with normal endoscopy were considered as potentially inappropriate category to consume PPI therefore, potentially suitable for withdrawal of PPI therapy.
The patients were educated about the harms of inappropriate PPI consumption, lifestyle changes such as, dietary modifications, stress management and cessation of alcohol/smoking. Then, deprescribing was initiated by tapering the dose or by decreasing the frequency or by complete cessation of PPI. For patients on high dose and long-term use of PPI, slow tapering was applied to preclude Rebound Acid Hyper Secretion (RAHS).[19] The patients were followed up every month for a period of 4 months, through telephonic communication or in person during next visit. During follow up the patients were queried about GOS scale along with a set of 9 questions related to deprescribing. The patients experienced RAHS after deprescribing were suggested to consume lower doses of PPI or alternate Acid Suppressive Drugs (ASD).
Data were coded and analyzed using SPSS Statistics for windows. Means obtained from the GOS scale and the follow up questions were analysed using paired t-test. Patient demographics were analysed using chi-square test, odds ratio and confidence interval which was represented in the form of a Forest plot. The results were presented descriptively with the help of a consort diagram.
Results
Out of 745 patients who came for endoscopy, 454(60.93%) were not on PPI therapy. In the 291 (39.06%) subjects, 58(19.72%) were clearly appropriate prescriptions which included peptic ulcer disease 2(39.65%), H. pylori infection 23(39.65%), grade D esophagitis 5(8.62%), grade C esophagitis 7(12.06%) and barrettes esophagitis 1(1.72%). The remaining 104(35.73%) prescriptions had likely appropriate indications, which encompassed gastric erosions 67 (50.96%), grade B esophagitis 22(21.15%), grade A esophagitis 11(10.57%) and 4(3.84%) subjects were on antiplatelet therapy.
Amongst the 129(44.32%) potentially inappropriate patients, 113 consented for the intervention of deprescribing by the health care team. The Figure-1 indicates the details of deprescribing patients among the participants. In the 113 subjects, young male adults [Mean age = 42.40(21-79)] were predominant. On endoscopic evaluation Acid Peptic Disease was the most common diagnosis. Though pantoprazole was most commonly used PPI esomeprazole, omeprazole and rabeprazole were equally distributed. Among them, 54 (47.79%) did not find any improvement in GI symptoms with PPI therapy which may be attributed to their unhealthy lifestyle, which includes oily and spicy food; sedentary lifestyle and social history. The details of demographic data, PPI Utilization and general lifestyle among the subjects are shown in Table-1.
| Table 1: Demographic data, PPI Utilization and general lifestyle among the subjects |
Characteristic (n) |
Category |
n (%) |
Age (113) |
Young Adults (18-45 years) |
58 (51.33%) |
Middle aged adults (45-60 years) |
25 (22.12%) |
Geriatrics (>60 years) |
30 (26.55%) |
Gender (113) |
Male |
67 (59.29%) |
Female |
46 (40.71%) |
BMI Distribution (113) |
Underweight |
6 (5.31%) |
Normal |
69 (61.06%) |
Overweight |
26 (23.01%) |
Class-I Obese |
11 (9.73%) |
Class-II Obese |
1 (0.88%) |
Symptom (402) |
Dysphagia |
12 (2.99%) |
Weight loss |
24 (5.97%) |
Nausea/Vomiting |
36 (8.96%) |
Belching |
59 (14.68%) |
Abdominal pain |
77 (19.15%) |
Gas |
94 (23.38%) |
Dyspepsia |
100 (24.88%) |
Past Medical History (113) |
IHD |
1 (1.56%) |
Migraine |
1 (1.56%) |
Fatty liver disease |
2 (3.13%) |
Asthma |
2 (3.13%) |
Hepatitis-B |
2 (3.13%) |
Hypercholesterolemia |
5 (7.81%) |
Hypothyroidism |
6 (9.38%) |
Type-II Diabetes Mellitus |
20 (31.25%) |
Hypertension |
25 (39.06%) |
Social History (113) |
Alcohol |
21 (18.58%) |
Smoking |
15 (13.27%) |
Others |
2 (1.76%) |
Current PPI (113) |
Dexlansoprazole |
1 (0.88%) |
Lansoprazole |
1 (0.88%) |
Rabeprazole |
14 (12.39%) |
Omeprazole |
17 (15.04%) |
Esomeprazole |
19 (16.81%) |
Pantoprazole |
61 (53.98%) |
Endoscopic Finding (113) |
GERD |
15 (13.27%) |
Normal |
98 (86.73%) |
Duration of use (113) |
<2 years |
53 (46.90%) |
2-5 years |
40 (35.40%) |
>5 years |
20 (17.70%) |
Diet pattern (113) |
Vegetarian diet |
36 (31.86%) |
Mixed diet
Regular |
77 (68.14%)
36 (31.86%) |
Irregular (>10 times/week) |
77(68.14%) |
Healthy |
29 (25.66%) |
Unhealthy (Oily and spicy) |
84 (74.34%) |
Caffeine consumption (Yes) |
53 (46.90%) |
Caffeine consumption (No) |
60 (53.10%) |
Sleep Pattern (113)
(Position of sleep and time gap between food consumption to sleep) |
Appropriate |
58 (51.33%) |
Inappropriate |
55 (48.67%) |
Exercise (113) |
Active |
47 (41.59%) |
Sedentary |
66 (58.41%) |
Stress (113) |
Yes |
92 (81.42%) |
No |
21(18.58%) |
 |
Figure 1: Consort diagram representing the deprescribing process |
Table 2 provides the details of patients followed up for 4 months, were in they were queried about nine questions pertaining to deprescribing. Comparison between the first and the last follow up for 110 patients (3 lost in follow up) was performed using paired t-test revealing significant results (t-value= 4.6180 and P-value <0.01).
| Table 2: Responses from the study population after follow up |
| Question |
Followup-1
(n=110) |
Followup-4
(n=110) |
Any improvement in the condition after deprescribing |
101(90.99%) |
107 (97.27%) |
Is the patient satisfied with deprescribing |
97 (87.38%) |
101 (91.81%) |
Any new symptoms related to deprescribing developed |
0 (0.00%) |
0 (0.00%) |
Does the patient experience any intolerable side effects |
2 (1.80%) |
1 (0.90%) |
Does the patient want to continue with the previous dose |
21 (18.91%) |
15 (13.63%) |
Any non-drug approaches found to be beneficial |
95 (85.58%) |
101 (91.81%) |
Any symptom relapses after using non-drug approach |
4 (3.60%) |
2 (1.81%) |
Any alternative drug used to manage the condition |
3 (2.70%) |
2 (1.81%) |
Is the alternative drug found to be safe and efficacious |
3 (2.70%) |
2 (1.81%) |
Did the patient develop any side effects with the use of alternative drug |
0 (0.00%) |
0 (0.00%) |
Table 3 provides the details of GOS scale utilized to assess and compare the level of gastric discomfort before deprescribing and after deprescribing, where in significant results were demonstrated using paired t-test (t-value: -18.61; p value <0.01). This emphasizes that necessary lifestyle modification, (which was achieved by patient counselling) can decrease the incidence of symptoms of gastric discomfort. [Table-3]
| Table 3: Pre and Post responses for Global Overall Symptom scale |
| Global Overall Symptom scale |
Pre-Response |
Post-response |
No Problem |
0 (0.00%) |
64 (57.66%) |
Minimal Problem |
12 (10.62%) |
31 (27.93%) |
Mild Problem |
25 (22.12%) |
11 (9.91%) |
Moderate Problem |
33 (29.20%) |
5 (4.50%) |
Moderately Severe Problem |
16 (14.16%) |
0 (0.00%) |
Severe Problem |
14 (12.39%) |
0 (0.00%) |
Very Severe Problem |
13 (11.50%) |
0 (0.00%) |
Total |
113 (100%) |
111 (100%) |
The patient characteristics for on-demand PPI therapy category were predominantly lifestyle modification non-adherent, adult male population, who were on esomeprazole or pantoprazole for duration of 2-5 years were shown in Table 4. The patients who had reinitiated PPI therapy were also lifestyle non-adherent adult male population on pantoprazole for duration of up to 5 years. Though social history was observed among the subjects, it was not prevalent among the majority of study population. An odds ratio of 0.2646 (0.0870-0.8043) and p value of 0.019 was observed among omeprazole users, which revealed that the re-initiation of PPIs was more among this class of drug users. Similar statistical analysis done for the demographic data, PPI usage pattern, comorbidities and patients’ attitude towards lifestyle modifications did not reveal significant results. The odds ratios and confidence interval of the same is represented in the form of a Forest plot represented as Figure 2.
| Table 4: Possible predisposing factors for delinquency of deprescription |
| Category (n) |
Parameter |
Characteristic (n) |
Percentage (%) |
On-demand (17) |
Gender |
Male |
(13) 76.47% |
Female |
(4) 23.52% |
Age |
Adults |
(10) 58.82% |
Geriatrics |
(7) 41.17% |
PPI usage
|
Pantoprazole |
(4) 23.52% |
Esomeprazole |
(6) 35.29% |
Omeprazole |
(6) 35.29%) |
Rabeprazole |
(1) 5.88% |
Duration of PPI use
|
<2 years |
(7) 35.29% |
2-5 years |
(8) 5.88% |
>5 years |
(2) 41.17% |
Co-morbidities
|
Type-II Diabetes Mellitus |
(5) 29.41% |
Hypertension |
(6) 35.29% |
Hypothyroidism |
(1) 5.88% |
Social habits |
Yes |
(4) 23.52% |
No |
(13) 76.47% |
Dietary modifications |
Yes |
(3) 17.64% |
No |
(14) 82.35% |
Sleep modifications |
Yes |
(9) 52.94% |
No |
(8) 47.05% |
Stress management |
Yes |
(3) 17.64% |
No |
(14) 82.35% |
Re-initiated (5)
|
Gender |
Male |
(5) 100% |
Age |
Adults |
(3) 60% |
Geriatrics |
(2) 20% |
PPI usage |
Pantoprazole |
(4) 80% |
Omeprazole |
(1) 20% |
Duration of PPI use
|
<2 years |
(2) 40% |
2-5 years |
(2) 40% |
>5 years |
(1) 20% |
Co-morbidities |
Type-II Diabetes Mellitus |
(2) 40% |
Hypothyroidism |
(1) 20% |
Social habits |
Yes |
(2) 40% |
No |
(3) 60% |
Dietary modifications |
Yes |
(2) 40% |
No |
(3) 60% |
Sleep modifications |
Yes |
(1) 20% |
No |
(4) 80% |
Stress management |
Yes |
(2) 40% |
No |
(3) 60% |
 |
Figure 2: Forest plot representing odds ratio and confidence intervals of various patient characteristics [*OR= Odds Ratio, **95% CI= 95% Confidence Interval, ***P-Value=Probability value] |
Discussion
Deprescribing and shared decision-making is a method where, the physician, pharmacist and the patients are involved in, for the initiation of withdrawal of an inappropriate medication thus, improving the quality of life of the patient. When subjects with PPI-specific indications were divided on the basis of appropriateness of PPI prescription, the distribution was similar to the study conducted by Reeve et al. where 19% were clearly appropriate, 36% were likely appropriate and 45% were potentially inappropriate. Studies conducted by Reeve et al. and Krol et al. illustrate that only 16% and 18% of patients had undergone PPI cessation whereas, in this study which was conducted with help of PILs, 77% stopped PPI usage.[10]
Dyspepsia and abdominal pain were the major symptoms reported by subjects, which resembles to the study conducted by Spikjer-Huiges et al. were in the same symptoms were predominant.[3] Social habits play an important role in the incidence of gastrointestinal diseases which was incident in 16% (alcohol), 12% (smoking) and 2% (other substance abuse). Likewise, 13% smokers, 57% alcohol consumers were noted in the study conducted by Spikjer-Huiges et al. indicating that inappropriate social habits act as major risk factors. Therefore, they were advised for cessation and 80% were willing for the same.[3] The efficacy, cost burden and the incidence of ADR varies with different PPIs. A study conducted by Pullock et al., showed that 37% were on omeprazole and 29% were on lansoprazole.[20] Unlike the above study, in our study it was observed that pantoprazole (53.98%) was the most commonly used PPI, which can be correlated to a study conducted in Indian setting by Nousheen et al., which revealed similar results for pantoprazole (82%), which may be due to the fact that pantoprazole is comparatively inexpensive.[13]
Even though the subjects were on chronic PPI therapy, 48% had not experienced relief from gastric symptoms. Similarly, a study by Ryder et al., showed that 26% of subjects had disclosed to having no relief which may be associated with unhealthy lifestyle in various subjects.[20] Amelia et al. observed that amount of fat intake was directly linked with occurrence of gastric symptoms.[21] Thus, the patients were counselled to take less fat diet in smaller quantities in order to identify and avoid triggers of gastric symptoms. Brian et al., conducted a study demonstrating that patients with functional GI disorders had lesser sleep quality when compared with the patients without functional gastrointestinal disorders.[22] Inappropriate sleeping habits were reported in 49% of patients showing that there might be an association between sleeping pattern and the occurrence of GI diseases which needs further research with the help of appropriate questionnaire. Klaus et al., mentioned exercise as one of the treatments for functional dyspepsia.[23]
In addition to this, obesity is a predisposing factor for certain GI disorders. Therefore, exercise was recommended as a necessary lifestyle modification in 58% of the subjects who reported to have sedentary lifestyle. The results of cold stress test conducted by Fermin et al., revealed that stress can induce gastric symptoms.[24] In our study population, 81% of subjects agreed that they are stressed though, it was not measured using a questionnaire. On follow up, 86% of patients had found relief from non-drug approaches. At the end of follow up, 87 (77%) of the patients were asymptomatic which is contradictory to the study conducted by Inadomi et al., where only 27% of the subjects were asymptomatic after follow up.[25]
The risk factors for dereliction of deprescription were analyzed using odds ratio and confidence interval, p-value did not reveal significance which may be attributed to lesser sample size. The same study if conducted in similar setting with a larger sample size it may give significant results with comparable odds ratio. The barriers for deprescribing in our study were its tedious process, limited patient data, recall bias and loss in follow up. The major strength of the study is that, it is the first study to represent the scenario of deprescribing in a developing country. Other strengths include, good rapport between health care professionals, endoscopy reports which acted as a proof for deprescribing and cooperation from patients which is similar to the studies by Elizabeth et al. and Reeve et al.[5,26] Further studies need to be conducted on inappropriate use of all the ASDs, rather in a community setting to help assess their OTC use. Alongside, further evaluation of QOL has to be done using appropriate questionnaires.
Conclusion
The study focused on reducing the inappropriate usage of PPI, which are easily available as OTC drugs. The self-medication practice of the same was observed among 23% of subjects. Lifestyle modifications were recommended for them resulting in relief from symptoms and PPI cessation in majority of the subjects. It was observed that young male adults with PPI consumption, typically omeprazole, for more than two years with inappropriate lifestyle modifications were more prone to re-initiation of PPI. This indicates that lifestyle modifications are paramount in reducing the incidence of gastric symptoms. Thus, deprescribing of PPI conducted with the help of PILs and active contribution from health care professionals can aid in reduction of inappropriate use of PPI.
Acknowledgement
Our sincere gratitude to the Department of Gastroenterology, Ramaiah Memorial Hospital for giving us the space, time and guidance for conducting our study in a successful manner. We would like to thank, Dr. V. Madhavan - Dean of M.S. Ramaiah College of Pharmacy and Department of Pharmacy Practice for providing us the opportunity, continuous support and their valuable inputs.
Conflicts of Interest: None declared.
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