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The 2020 view of proton pump inhibitors in clinical care

Learning objectivesYou will learn:

• Understanding of the essential role of proton pump inhibitors (PPIs) in the treatment of gastro-oesophageal reflux disease (GORD) and other acid-related disorders

• Revisiting PPIs’ mechanism of action and appropriate use in gastroenterological conditions

• The importance of differences in pharmacokinetic profiles when selecting a specific PPI for an individual patient

• Awareness of increased PPI use as clinicians increasingly focus on coagulopathies in COVID-19 hospitalised patients

• Examination of the latest data on the long-term safe use of PPIs

• Consideration of drug interactions with newer medications as described in recent clinical research.

IntroductionPPIs were introduced some 30 years ago, the first one being omeprazole in 1989. They have become the mainstay of therapy and first choice for treatment of erosive oesophagitis, non-erosive and erosive reflux disease, peptic ulcer disease, Helicobacter pylori eradication, the prevention of non-steroidal anti-inflammatory drug (NSAID) complications and prevention of gastrointestinal (GI) bleeding in at-risk patients on anticoagulant/antiplatelet therapy (Table 1).1

Dr Melvyn LetierGastroenterologistCape Town

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Table 1. Appropriate use of PPIs1

• GORD symptoms• Erosive oesophagitis • Non-erosive reflux disease• Barrett’s oesophagus• Peptic strictures• Eosinophilic oesophagitis • Peptic ulcer disease

• H. pylori eradication• Prevention of GI bleeding in anticoagulant/

antiplatelet therapy • Prevention of NSAID complications• Hypersecretory states• Stress ulcer bleeding (short-term therapy)

Choice of PPIs in South Africa There is comprehensive availability of US Food and Drug Administration

(FDA)-approved and South African-approved PPIs for clinical use (Table 2).

Table 2. PPI availability in South Africa

Standard dose (Healing once-daily)

Low dose (Maintenance once-daily)

Omeprazole 20/40mg 10/20mg

Esomeprazole 20/40mg 20mg

Lansoprazole 30mg 15mg

Pantoprazole 40mg 20mg

Rabeprazole 20mg 10mg

Pantoprazole IV* 40mg

Esomeprazole IV* 40mg

*For in-hospital use

When used for their appropriate clinical indication and at the lowest effective dose to achieve and maintain symptom relief, these agents have shown clear benefit. Their safety profile is generally excellent, with approxi-mately only 1-2% of patients experiencing the side effects of headaches, nausea, abdominal

pain and diarrhoea; they seldom require discontinuation.

It is perhaps precisely because of this overall tolerance and efficacy that patients, particularly those with an empirical diagnosis of GORD, are kept on these medications long term.

Mechanism of PPI action on acid controlPPIs work at the last step in acid production, blocking 70-80% of the active potassium pumps of gastric parietal cells. This blockage inhibits hydrogen secretion into the gastric lumen. Important principles of this acid con-trol are illustrated in Figure 1.2 PPIs should

be taken just before a meal (30-60 minutes) as these medications only bind to actively secreting pumps. There are some differences in the pharmacokinetic attributes of individ-ual PPIs, which although subtle do influence their effectiveness (Table 3).2

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Table 3. Pharmacokinetic properties of PPIs

Omeprazole Esomeprazole Lansoprazole Pantoprazole Rabeprazole

Bioavailability (%) 30-40 64-90 80-85 77 52

Time to peak plasma (hr) 0.5-3.5 1.5 1.7 2-3 3.5

Protein binding (%) >90 >90 >90 >90 >90

Half-life (hr) 0.5-1 1-1.5 1.6 1-1.9 1.0

Primary excretion Hepatic Hepatic Hepatic Hepatic Renal

Liver metabolism CYP2C19 CYP2C19 CYP2C19 CYP2C19 CYP2C19

CYP3A4 CYP3A4

PPIs are highly protein bound and are metab-olised primarily by hepatic P450 cytochromes. While the CYP2C19 pathway is dominant, there are differences; pantoprazole has the

lowest potential for drug interactions with other agents such as clopidogrel, which is also metabolised by the P450 system.

Figure 1. Mechanism of PPI action and acid control

Acid control depends on:• Different binding abilities of PPIs• When taken (food activates pumps)• Genetic polymorphism of cytochrome P450 system• Dosing (once or twice a day)• Some hydrogen ion activity always remains • Cannot block all pumps as there is continual new pump creation.

Acetylcholine

Into blood

H20 + CO2

H2CO3

HCO3– + H+

HCO3–

Cl–

K+

H+

H+H+H+

H+

H+

Proton pump

Histamine

Gastrin

Carbonic anhydrase

Lumen of gastric pit

ADP + Pi

ATP

K+

Cl–

Cl–

Cl–Cl–

Cl–

Parietal cell

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The advantage of this systematic comparison of PPIs is that erosive oesophagitis provides an exact diagnosis and a healing measure (complete re-epithelialisation of all ulcers/erosion) determined accurately on endoscopy

Efficacy of PPIs as appropriate therapy for erosive oesophagitis In order to evaluate the efficacy of PPIs in the treatment of GORD, a recent study focused on healing results in erosive oesophagitis, which is a severe manifestation of GORD; this provides measurable evidence of the effectiveness of different PPIs.4

The advantage of this systematic comparison of PPIs is that erosive oesophagitis provides an exact diagnosis and a healing measure (complete re-epithelialisation of all ulcers/erosion) determined accurately on endoscopy.

In this comparative review of PPIs used as monotherapy, only randomised clinical tri-als with endoscopically diagnosed erosive

oesophagitis, healing assessed at four or eight weeks and investigator-assessed symptoms of heartburn at four weeks were included. A total of 25 trials involving more than 25 000 patients showed that esomeprazole 40mg, pantoprazole 40mg, esomeprazole 20mg and lansoprazole 30mg provided greater benefits in respect of acceptability and effectiveness over other PPIs and dosage regimens.

Esomeprazole 40mg was ranked best for endoscopic healing rates at four weeks (Figure 2).4 A similar distribution of healing rate was seen at week eight, while panto-prazole 40mg had the best compliance data (Table 4).4

Figure 2. Network meta-analysis results: healing rates at four weeks

Treatment effect Healing rates at 4 weeks Mean with 95%CI

Placebo vs Omeprazole 20mg 0.10 (0.07, 0.14)

Pantoprazole 40mg 1.11 (0.89, 1.37)

Lansoprazole 30mg 1.12 (0.93, 1.35)

Rabeprazole 20mg 0.89 (0.62, 1.28)

Esomeprazole 20mg 1.20 (0.88, 1.64)


Pantoprazole 40mg vs Placebo 11.12 (7.63, 16.22)

Lansoprazole 30mg 11.26 (7.86, 16.13)

Rabeprazole 20mg 8.92 (5.36, 14.83)

Esomeprazole 20mg 12.06 (7.61, 19.12)

Esomeprazole 40mg 14.62 (10.17, 21.02)

Lansoprazole 30mg vs Pantoprazole 40mg 1.01 (0.81, 1.27)

Rabeprazole 20mg 0.80 (0.53, 1.22)



Rabeprazole 20mg vs Lansoprazole 30mg 0.79 9.053, 1.19)



Esomeprazole 20mg vs Rabeprazole 20mg 1.35 (0.84, 2.18)


Esomeprazole 40mg vs Esomeprazole 20mg 1.21 (0.89, 1.65)

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Table 4. Ranking of the PPI interventions

Treatment

Healing rates at 4 wk Healing rates at 8 wk Heartburn relief Acceptability

SUCRA Pr. bestMean Rank




Omeprazole 20mg 35.9 0 4.8 30.1 0 5.9 30.3 0.1 4.5 74.3 11.4 2.8

Placebo 0 0 7 0 0 8 NA NA NA 34 8.7 5.6

Pantoprazole 40mg 58 0.4 3.5 69.4 4.4 3.1 44.1 10.3 3.8 85.2 50.6 2

Lansoprazole 30mg 61.1 0 3.3 49.3 0 4.5 31.1 0.3 4.4 51.6 3.7 4.4

Rabeprazole 20mg 27.4 0.2 5.4 18.3 0.3 6.7 57.1 35.3 3.1 51.2 19.8 4.4

Esomeprazole 20mg 69.6 11.3 2.8 62.6 7.6 3.6 50.4 5.6 3.5 36.4 3.5 5.5

Exomeprazole 40mg 98 88.1 1.1 94.7 68 1.4 86.9 48.4 1.7 57.6 2.2 4

Dexlansoprazole 60mg NA NA NA 75.6 19.7 2.7 NA NA NA 9.7 0.1 7.3

Pr. Best = probability of being the best; SUCRA = the surface under the cumulative ranking curve

PPIS and beyond – in the time of COVID-19Patients taking PPIs are not at increased sus-ceptibility to SARS CoV-2 infection.5

The increased focus on the coagulopathy that occurs in patients with severe clinical mani-festations of COVID-19 infection and the increased treatment of a selected subset of patients (those with raised D-dimer >1 000ng/ml) with anticoagulants is likely to increase the frequency of GI bleeding in hospitalised COVID-19 patients.

A useful evidence-based clinical algorithm has been developed with regard to when to use PPIs to reduce avoidable hospital re-admissions for GI bleeding and improve patient outcomes (Figure 3).6 The key factor is to risk-stratify COVID-19 patients receiving intermediate-dosed or therapeutic anticoagu-lation by considering (i) past medical history and (ii) review of current medication such as high-dose NSAIDs, single antiplatelet therapy and dual antiplatelet therapy.

Figure 3. Proposed algorithm to assess risk of gastrointestinal bleeding in COVID-19 patients undergoing intermediate-dosed or therapeutic-dosed anticoagulation6

Need for intermediate-dosed or therapeutic-dosed anticoagulation in COVID-19 patients

Assess for GI risk factorsDoes the patient have a history of:• Previous upper GIB• History of peptic ulcer• History of H. pylori

Considered high-risk for GIB1. Ensure indication for

anticoagulation is appropriate2. Test for H. pylori infection

Treat if positive3. Recommend prophylactic PPI

for gastroprotection

Perform medication reconciliationIs the patient receiving:• Antiplatelet medications (single or DAPT)?• High dosed NSAIDs?

Patient is considered low risk for GIB

Can NSAIDs or antiplatelet therapy be discontinued while patient is

placed on anticoagluation?

Yes

Yes

No

No Yes

Yes No


6 I OCTOBER 2020


The COMPASS study points out that PPIs are not associated with any long-term harm and that the benefits outweigh the risks of these medications, provided they are used appropriately – The COMPASS trialists

Safety of use with rivaroxaban or aspirin

A recent prospective randomised study of more than 17 000 participants with sta-ble coronary artery disease and peripheral artery disease treated with rivaroxaban and/or aspirin showed that pantoprazole (40mg daily) was not associated with any adverse event, except for a possible non-significant increased risk of enteric infection. This study

was undertaken over an extended period of three years, as part of the Cardiovascular Outcomes of People using Anticoagulation Strategies (COMPASS) trial.7 The COMPASS study points out that PPIs are not associated with any long-term harm and that the bene-fits outweigh the risks, provided they are used appropriately.

Safety of PPIsObservational studies have raised concerns that PPIs may be associated with increased risk of pneumonia, fracture, Clostridium difficile-associated diarrhoea, cardiovascular disease and chronic kidney disease (CKD).

A recent evaluation of these risks provides guidance on best practice management and alertness to these possible risks of PPI treat-ment (Table 5).

Table 5. Associated risk of PPI use and best practice approach

Associated risk of PPI use Best practice approach

Conflicting data exist on cardiovascular risk (for clopidogrel see the ‘Drug interactions’ section below)

Benefits of PPIs outweigh risks.1

If there is concern regarding clopidogrel, select pantoprazole. No change in practice relative to myocardial infarction

Renal disease – association of PPIs with acute interstitial nephritis

Association is of insufficient strength to support regular monitoring on a large scale. In patients with known CKD, PPIs should be prescribed with caution

Concern about absorption of iron, calcium and vitamin B12 – lacks clinical dataDecrease in bone mineral density – only clearly associated with patients with other risk factors, e.g. smoking

It is prudent to discuss the issue with those patients at risk, particularly those who smoke. Not prescribing PPIs for the sole purpose of avoiding fractures is not recommended. In a patient needing a high chronic PPI dose, discuss alternatives, surgery or endoscopic anti-reflux therapy

Possible increased risk of bacterial enteric infection by altering gut flora responsive to pH changes. Potential risk of C. difficile infection (odds ratio: <2) (FDA class warning exists)

Caution is suggested when prescribing PPIs to patients at risk for C. difficile infection. Treatment must be individualised in these patients

Drug interactions – known and new

ClopidogrelPPIs competitively inhibit the activity of the CYP2C19 enzyme, the enzyme required for the conversion of the prodrug, clopidogrel, to its active form. Therefore, PPIs may reduce drug activation and, potentially, the desired antiplatelet effect. The clinical importance of this is unclear, and when only randomised clinical trials are assessed, no statistically

significant difference exists, suggesting that any potential interaction is not likely to be clinically significant.8,9

In this regard, it must be noted that clopi-dogrel monotherapy elevates the risk of GI bleeding, and pantoprazole is recommended for high-risk patients.3

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Dabigatran

PPIs administered with dabigatran etex-ilate reduce the risk of GI bleeding during long-term therapy. PPI use (omeprazole or pantoprazole) reduces the trough and peak of dabigatran levels, probably due to the

increase in gastric pH and reduced absorption of dabigatran. The clinical importance of this reduction in dabigatran levels with regard to clinical outcome and the risk of ischaemic adverse events has not yet been investigated.10

New cancer medications

Myeloid malignancy (fedratinib)

Pantoprazole has been shown not to have a clinically meaningful effect on the

pharmacokinetics of fedratinib, an oral selec-tive Janus Kinase 2 inhbitor.11

Tyrosine kinase inhibitors (TKIs)

This class of medications is used to treat a wide variety of solid and haematological malignancies. PPIs increase the intragastric pH, which may subsequently decrease TKI levels. Clear advice on how to manage PPI use during TKI therapy is not currently avail-able in the literature. A practical solution, so

as not to deprive cancer patients of the value of PPI treatment, is to co-ordinate the phar-macokinetic profiles of the medications with different dose-timings for the two classes of drug, as advocated in a recent publication.12

Protease inhibitorsAll PPIs interact with protease inhibitors due to modulation of gastric pH as well as inhibi-tion of CYP3A4.13 The frequency of PPI use in HIV-positive persons was examined in a UK study. It showed that approximately 10% of HIV-positive persons were co-treated

with PPIs during their antiretroviral therapy. Again, clinical management was based on separating the timed administration of the gastric acid-reducing agent from that of the antiretroviral therapy.14

Key clinical recommendations

1 We as physicians, should be aware of:• The potential risks of PPIs• The clear indications for long-term use• The fact that PPIs tend to be overused• The quality of the evidence for PPI use.

2 For each individual patient, we should:• Weigh benefits vs risks• Assess whether we should proactively inform the patient about the risk/benefit balance• Be prepared to discuss in detail and suggest online resources if asked• Periodically reassess: a) if the patient still needs long-term therapy; b) if the dose can be lowered;

c) alternative treatments.

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DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

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© 2020 deNovo MedicaReg: 2012/216456/07

This report was written for deNovo Medica by Julia Aalbers, BSc (Hons) Pharmacology; and reviewed by Dr Melvyn Letier, Gastroenterologist, Cape Town

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