What evidence is available to guide the choice of proton pump inhibitors, particularly in the geriatric population? Is there evidence that one is superior to (efficacy) or safer than the others?

Comment by InpharmD Researcher

There is limited evidence to guide the choice of proton pump inhibitors in general and in geriatric patients. Overall, there appears to be little difference for gastroesophageal reflux disease symptom relief and healing rates between the 7 available PPIs despite the variation in acid suppression. However, one randomized study found pantoprazole and rabeprazole to be significantly more effective than omeprazole in healing esophagitis and significantly more effective than omeprazole or lansoprazole in improving symptoms in an elderly population (aged ≥ 65 years). Additionally, authors from one review suggest rabeprazole may be suited for use in older patients since it requires no dosing adjustment in the elderly or patients with renal insufficiency or mild-to-moderate hepatic disease.

Background

According to the 2022 American College of Gastroenterology (ACG) guidelines for the management of gastroesophageal reflux disease (GERD), patients with classic GERD symptoms of heartburn and regurgitation who have no alarm symptoms should initiate an 8-week trial of empiric proton pump inhibitors (PPIs) once daily. Treatment with PPIs is recommended over treatment with histamine-2-receptor antagonists (H2RAs) to heal and maintain healing erosive esophagitis. Additionally, maintenance PPI therapy indefinitely is recommended for patients with Los Angeles grace C or D esophagitis. On-demand or intermittent PPI therapy should be used for heartburn symptom control in patients with non-erosive reflux disease (NERD). [1]

Meta-analyses suggest there is little difference overall for GERD symptom relief and healing rates between the 7 available PPIs; therefore, recommendations to use a specific PPI are not provided. However, data show wide variations in the acid-suppression potency of the different PPI preparations. If relative acid-suppression potencies of individual PPIs are standardized to omeprazole to yield “omeprazole equivalents” (OEs, with omeprazole having an OE of 1), the relative potencies of standard-dose pantoprazole, lansoprazole, omeprazole, esomeprazole, and rabeprazole have been estimated at 0.23, 0.9, 1, 1.6, and 1.82 OEs, respectively. The varying acid-suppression potency may result in wide variation in individual intragastric pH control between PPIs. Guidance for choosing a specific PPI for elderly patients is not provided. [1], [2], [3]

A review of proton pump inhibitor use in the elderly population for treatment of acid-related disease, including gastro-oesophageal reflux disease (GORD), discusses that rabeprazole may be particularly suited for use in older patients since it requires no dosing adjustment in the elderly or patients with renal insufficiency or mild-to-moderate hepatic disease. Additionally, it is relatively free of clinically significant drug-drug interactions, unlike omeprazole. The author also suggests that the clinical and pharmacokinetic profiles for rabeprazole make it an appropriate first choice for managing older patients with GORD. [4]

A 2016 network meta-analysis aimed to investigate the efficacy and safety of different PPIs in treating patients with NERD. A total of fifteen studies (N= 6,299) with an average of 394 patients per trial were included for analysis. The positive rate of helicobacter pylori tests ranged from 13.4% to 52.7%. Compared with placebo groups, all interventions (dexlansoprazole 30 mg, dexlansoprazole 60 mg, omeprazole 10 mg, omeprazole 20 mg, lansoprazole 15 mg, lansoprazole 30 mg, esomeprazole 20 mg, esomeprazole 40 mg, rabeprazole 10 mg, and rabeprazole 20 mg) except rabeprazole 5 mg significantly increased rate of symptomatic relief. Omeprazole 20 mg resulted in a higher rate of symptomatic relief compared to rabeprazole 5 mg (odds ratio [OR] 2.51, 95% confidence interval [CI] 1.16 to 5.42, p= 0.019) or omeprazole 10 mg (OR 1.89, 95 CI 1.34 to 2.67, p= 0.0005). Additionally, dexlansoprazole 30 mg significantly improved the rate of symptomatic relief compared with rabeprazole 5 mg (OR 2.64, 95% CI 1.08 to 6.43, p= 0.03). [5]

No significant difference was found between intervention groups for rates of adverse events. Based on a cluster plot, dexlansoprazole 30 mg was found to have the highest rate of symptomatic relief. Omeprazole 20 mg had the lowest incidence rate of adverse events, while lansoprazole 30 mg was associated with the highest incidence. The cluster plot shows that omeprazole 20 mg may be the best option for NERD treatment due to the high rate of symptomatic relief and low incidence rate of adverse events. This analysis is limited by the high risk of bias of included studies, which prevents sensitivity analyses from being performed. Additionally, this meta-analysis did not specifically evaluate the use of PPIs in elderly populations; the average age of patients from included studies ranged from 41.7 to 52 years. [5]

References:

[1] Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease. Am J Gastroenterol. 2022;117(1):27-56. doi:10.14309/ajg.0000000000001538
[2] Kirchheiner J, Glatt S, Fuhr U, et al. Relative potency of proton-pump inhibitors-comparison of effects on intragastric pH. Eur J Clin Pharmacol. 2009;65(1):19-31. doi:10.1007/s00228-008-0576-5
[3] Hatlebakk JG, Katz PO, Camacho-Lobato L, Castell DO. Proton pump inhibitors: better acid suppression when taken before a meal than without a meal. Aliment Pharmacol Ther. 2000;14(10):1267-1272. doi:10.1046/j.1365-2036.2000.00829.x
[4] Whitaker M. Proton pump inhibitors in the elderly population. Eur J Gastroenterol Hepatol. 2002;14 Suppl 1:S5-S9.
[5] Chen L, Chen Y, Li B. The efficacy and safety of proton-pump inhibitors in treating patients with non-erosive reflux disease: a network meta-analysis. Sci Rep. 2016;6:32126. Published 2016 Sep 1. doi:10.1038/srep32126

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What evidence is available to guide the choice of proton pump inhibitors, particularly in the geriatric population? Is there evidence that one is superior to (efficacy) or safer than the others?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-3 for your response.


 

Comparison of four proton pump inhibitors for the short-term treatment of esophagitis in elderly patients

Design

Open, single-center, randomized study

N= 320

Objective

To compare efficacy and tolerability of four proton pump inhibitors (PPIs) commonly used in the short-term therapy of esophagitis in elderly patients

Study Groups

Omperazole (n= 80)

Lansoprazole (n= 80)

Pantoprazole (n= 80)

Rabeprazole (n= 80)

Inclusion Criteria

Age ≥ 65 years, confirmed endoscopic diagnosis of esophagitis grade I to IV according to the Savary-Miller classification

Exclusion Criteria

History of Zollinger-Ellison syndrome; pyloric stenosis; previous surgery of the esophagus and/or gastrointestinal tract (excluding appendectomy and cholecystectomy); gastrointestinal malignancy; received antacids, sucralfate, prokinetics, H2-blockers, and/or PPIs for > 7 days in the four weeks prior to the start of study

Methods

Upon study entry, patients underwent endoscopy for the diagnosis of acute esophagitis, which was repeated 2 months after treatment to assess healing. Gastric biopsies from various parts of the gastric lining were collected for histology and rapid urease test. Patients were only considered H pylori negative if both tests were negative.

Upon inclusion, patients were randomized (1:1:1:1) to receive either omeprazole 20 mg once daily, lansoprazole 30 mg once daily; pantoprazole 40 mg once daily, or rabeprazole 20 mg once daily, all taken before breakfast, for the next two months. Patients with confirmed H pylori were treated with PPI plus two antibiotics.

Duration

8 weeks

Outcome Measures

Intention-to-treat (all patients enrolled who had taken at least one dose of study drug) and per-protocol analysis of esophagitis cure rate at 8 weeks; healing rate of esophagitis after 8 weeks 

Baseline Characteristics

 

Omeprazole
(n= 80)

Lansoprazole (n= 80)

Pantoprazole (n= 80) Rabeprazole (n= 80)

Age, years

77.9 ± 6.4 77.8 ± 9.2 76.8 ± 6.1 77.0 ± 9.5

Male/Female

44/36 36/44 39/41 37/43

Esophagitis

Grade 1

Grade 2

Grade 3 to 4

 

34 (42.5%)

27 (33.8%)

19 (23.8%)

 

26 (32.5%)

33 (41.3%)

21 (26.2%)

 

20 (25.0%)

42 (52.5%)

18 (22.5%)

 

16 (20.0%)

50 (62.5%)

14 (27.6%)

Hiatus hernia

43 (53.8%)

48 (60.0%)

50 (62.5%)

53 (66.3%)

H pylori infection

52/76 (68.4%) 61/76 (80.3%) 51/77 (66.2%) 38/77 (49.3%)

NSAIDs/Aspirin use

18 (22.5%) 17 (21.3%) 26 (32.5%) 17 (21.3%)

NSAID: non-steroidal anti-inflammatory drug

Results

Endpoint

Omeprazole (n= 80)

Lansoprazole (n= 80)

Pantoprazole (n= 80)

Rabeprazole (n= 80)

Intention-to-treat analysis of cure rates (95% confidence interval [CI])

75.0% (65.0% to 84.0%) 85.0% (77.0% to 92.8%) 90.01% (83.4% to 96.5%) 88.82% (81.5% to 95.6%)

Per-protocol analysis of cure rates (95%CI)

81.0% (72.0% to 89.9%) 90.7% (84.1% to 97.2%) 93.5% (87.9% to 99.0%) 94.6% (89.4% to 99.7%)

p-value versus omeprazole

Intention-to-treat analysis

Per-protocol analysis

 

[Reference]

[Reference]

 

--

--

 

0.022

0.039

 

0.040

0.022

Healing rates of esophagitis after 8 weeks

Grade 1

Grade 2

Grade 3 to 4

Divided by H pylori infection

H pylori positive

H pylori negative

 

81.8%

81.8%

78.9%

 

77.6%

86.4%

 

100%

96.5%

71.4%

 

94.7%

78.6%

 

100%

90%

94.1%

 

93.8%

92.3%

 

100%

95.8%

84.6%

 

97.1%

92.1%

Adverse Events

Reported only by four patients (1.3%): urticaria, glossitis, nausea, and headache.

Two patients withdrew from the study due to adverse events.

Study Author Conclusions

In elderly patients, pantoprazole and rabeprazole were significantly more effective than omeprazole in healing esophagitis and than omeprazole or lansoprazole in improving symptoms. H pylori infection did not influence the healing rates of esophagitis after short-term treatment with PPI.

InpharmD Researcher Critique

There were fewer patients available for analysis in the Grade 3 and 4 esophagitis groups and the rate of H pylori infection was different between groups (although these infection rates were higher in the pantoprazole and rabeprazole group that exhibited greater healing rates). 
 
References:

Pilotto A, Franceschi M, Leandro G, et al. Comparison of four proton pump inhibitors for the short-term treatment of esophagitis in elderly patients. World J Gastroenterol. 2007;13(33):4467-4472. doi:10.3748/wjg.v13.i33.4467

 

Esomeprazole use is independently associated with significant reduction of BMD: 1-year prospective comparative safety study of four proton pump inhibitors

Design

Prospective, open-label, comparative, parallel-group study

N= 209

Objective

To determine the association of the proton pump inhibitor (PPI) treatment regimen with the 12-month change in bone mineral density (BMD) of the lumbar spine, femur neck, and total hip, with the use of longitudinal assessment of BMD

Study Groups

Omeprazole (n= 42)

Esomeprazole (n= 41)

Lansoprazole (n= 42)

Pantoprazole (n= 42)

Control (n= 42)

Inclusion Criteria

Age 18 to 65 years, regularly active, taking PPI as gastroprotective long-term maintenance therapy in association with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs)

Exclusion Criteria

Use of calcium and vitamin D supplements and contraceptives within the last 6 months; use of acid-suppressing agents, estrogen therapy, bisphosphonates, and glucocorticoids within the last year; concomitant use of diuretics, anticoagulants, or anticonvulsants; diseases that may affect bone metabolism; confirmed malabsorption diseases or neoplastic diseases during the previous 5 years; self-reported previous fractures, history of renal disease, thyroid disease, and cardiovascular diseases; pregnancy/lactation

Methods

Patients were randomized to either not receive PPIs (control group) or one of four PPIs: omeprazole 20 mg/day, esomeprazole 20 mg/day, lansoprazole 30 mg/day, and pantoprazole 40 mg/day, all taken before breakfast. BMD measurements were performed in the lumbar spine (L1 to L4), femur neck, and total hip via dual-energy X-ray absorptiometry.

T-scores of -2.5 standard deviation (SD) or lower below the mean were representative of osteoporosis. T-score between -2.5 to -1.0 SD was representative of either osteopenia or low bone mass. T-scores -1 SD or higher below the man are considered normal BMD.

Duration

One year

Outcome Measures

One-year changes in bone density measurements based on T-score

Baseline Characteristics

 

PPI users (n= 167)

PPI nonusers (n= 42)

p-value     

Age, years

50.83 ± 10.53 49.64 ± 10.98 0.440     

Female

125 (74.9%)  31 (73.8%) 0.890     

Menopause

94 (56.3%) 19 (45.2%) 0.199    

Body mass index (BMI), kg/m2

29.04 ± 5.13 29.27 ± 4.65 0.717    

Total lumbar spine

BMD, g/cm2

T-score

 

0.93 ± 0.17

-1.15 ± 1.49

 

0.94 ± 0.17

-1.11 ± 1.48

 

0.907

0.890

   

Femur neck

BMD, g/cm2

T-score

 

0.80 ± 0.14

-0.56 ± 1.17

 

0.79 ± 0.11

-0.66 ± 0.80

 

0.881

0.802

   

Total hip

BMD, g/cm2

T-score

 

0.91 ± 0.16

-0.37 ± 1.22

 

0.92 ± 0.12

-0.35 ± 0.88

 

0.629

0.786

   

There were no statistically significant differences between PPI groups and control. 

Results

Endpoint

Omeprazole (n= 42)

Esomeprazole (n= 41)

Lansoprazole (n= 42)

Pantoprazole (n= 42) Control (n= 42)

Total lumbar spine

Initial T-score

Final T-score

p-value

 

-1.17 ± 1.42

-1.24 ± 1.38

0.643

 

-1.28 ± 1.59

-1.71 ± 1.26

0.071

 

-1.19 ± 1.51

-1.16 ± 1.52

0.588

 

-0.97 ± 1.50

-1.08 ± 1.42

0.097

 

-1.11 ± 1.48

-1.11 ± 1.29

0.284

 Femur neck

Initial T-score

Final T-score

p-value

 

-0.58 ± 1.23

-0.68 ± 1.24

0.656

 

-0.68 ± 1.19

-1.03 ± 1.08

0.093

 

-0.43 ± 1.12

-0.63 ± 1.02

0.022

 

-0.56 ± 1.15

-0.68 ± 1.20

0.401

 

-0.66 ± 0.80

-0.60 ± 0.84

0.304

 Total hip

Initial T-score

Final T-score

p-value

 

-0.37 ± 1.19

-0.48 ± 1.15

0.590

 

-0.47 ± 1.26

-0.80 ± 1.07

0.012

 

-0.29 ± 1.06

-0.42 ± 0.94

0.258

 

-0.34 ± 0.17

-0.57 ± 1.08

0.047

 

-0.35 ± 0.88

-0.40 ± 0.75

0.776

Study Author Conclusions

Among the four PPIs studied, esomeprazole was independently associated with significant reduction of BMD, whereas omeprazole had no effects on BMD. Considering the widespread use of PPIs, BMD screening should be considered in the case of prolonged PPI use.

InpharmD Researcher Critique

The mean age of all patients was 50.59 years which may not reflect the actual elder population (typically > 65 years). The majority of the population consisted of women, with little over half as menopausal. The study took place in the Republic of Kosovo, which may not reflect the US population. Lastly, the study was open-label which can contribute to patient and provider bias regarding the effect of therapy.
References:

Bahtiri, E., Islami, H., Hoxha, R. et al. Esomeprazole use is independently associated with significant reduction of BMD: 1-year prospective comparative safety study of four proton pump inhibitors. J Bone Miner Metab 34, 571–579 (2016). doi.org/10.1007/s00774-015-0699-6

 

The inappropriate use of proton pump inhibitors and its associated factors among community-dwelling older adults

Design

Mult-center, descriptive, cross-sectional study

N= 215

Objective

To assess the inappropriate use of proton pump inhibitors (PPI) and their associated factors among community-dwelling older adults 

Study Groups

PPI (n= 102)

None PPI (n= 113)

Inclusion Criteria

All older adults who regularly visited the healthcare centers during January 2020 for routine checkups and prescription renewal

Exclusion Criteria

N/A

Methods

Data about PPI use was collected retrospectively from each patient's medication card for November and December 2019. Researchers used the data collection sheets to collect the data on PPI use for each patient and then reviewed each PPI prescription to ensure it aligned with the FDA guidelines. 

The comorbid burden was measured once following the consent procedure and using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G).

Duration

November 2019 to January 2020

Outcome Measures

Primary: mild cognitive impairment (MCI), the comorbid burden

Secondary: body mass index (BMI)

Baseline Characteristics

 

All patients (N= 215)

 

 

Gender 

Male

Female

 

104 (48.1%)

111 (51.4%)

   

BMI, kg/m

Overweight

Obese

Normal

 

78 (36.3%)

46 (21.4%)

91 (42.3%) 

   

Having Dementia 

No

Yes

 

79 (36.7%)

136 (63.3%)

   

PPI Use 

No

Yes

 

112 (52.6%)

103 (47.4%)

   

PPI indication (n= 103)

No indication

Eosinophilic esophagitis

Gastroesophageal Reflux Disease (GERD)

Gastric ulcer

Gastric ulcer prophylaxis

Heartburn

 

20 (19.4%)

1 (1%)

60 (53.3%)

9 (8.7%)

7 (6.8%)

6 (5.8)

   

PPI Dosage Regimen Problem (n= 103)

Too High

Too Long (>12 months)

 

3 (2.9%)

70 (68.0%)

   

PPI Duration (n= 103)

8-12 weeks

12-24 weeks

More than 24 weeks

 

10 (9.7%)

22 (21.4%)

71 (68.9%)

   

Results

 

The mean CIRS-G score was 2.6 ± 0.3, indicating a high comorbid burden.

Outcomes

Non-PPI (n= 113) PPI (n= 102) p-value

Mild cognitive impairment (MCI)

Yes

No

 

63 (56.3%)

49 (43.8%)

 

73 (70.9%)

30 (29.1%)

0.026

Body mass index (BMI) 

Normal

Overweight

Obese

 

54 (47.8%)

42 (37.2%)

17 (15.0%)

 

37 (36.3%)

36 (35.3%)

29 (28.4%)

0.045

 

About 47% of patients were reported to have taken a PPI, while 68% of them have taken a PPI longer than required by the FDA. Adults of older age who had MCI or comorbid burden showed to have been more likely to be on PPI's long term than others. 

The logistic regression revealed that MCI is a statistically significant predictor of inappropriate PPI use (p < 0.001).

Adverse Events

N/A

Study Author Conclusions

Inappropriate PPI use is common among community-dwelling older adults in Jordan, with a significantly higher prevalence of inappropriate PPI use in people with MCI than in people with normal cognitive abilities. Future intervention studies are highly recommended to encourage optimal prescribing of PPIs for community-dwelling older adults.

InpharmD Researcher Critique

This study was limited based on the small sample size and the lack of a comprehensive medication history in baseline characteristics of the patients. Additionally, since it was performed in Jordan, the results may not be generalizable to the United States patient population.

 

References:

Rababa M, Rababa'h A. The inappropriate use of proton pump inhibitors and its associated factors among community-dwelling older adults. Heliyon. 2021;7(7):e07595. Published 2021 Jul 15. doi:10.1016/j.heliyon.2021.e07595