Inhibitors of the H+, K+ -ATPase proton pumps in the parietal cells of the glands of the gastric mucosa are imidazole derivatives formed by pyridine and benzimidazole rings bound by a methylsulfinyl group. The first of these medications approved for clinical use in 1989 was omeprazole (OME); later, substitutions were made in the pyridine and/or benzimidazole rings to create pharmacologic alternatives, in an attempt to improve the speed and efficacy of these drugs, as well as prevent possible side effects.

PPIs are acid-labile weak bases that need to be protected by an enteric coating or as coated granules, sometimes combined with bicarbonate, to achieve a temporal neutralization of the intragastric pH that guarantees their integrity and passage into the duodenum for their absorption and better effect; hence the importance of not opening the capsules or breaking the tablets when they are ingested. Once absorbed, they arrive at the parietal cells of the gastric glands through the systemic circulation. The parietal cells require the active canalicular expression of the H+, K+ -ATPase pumps for binding to occur in response to a meal.3 Not all the pumps are active at the time of a meal, so only two-thirds of the pumps can be inhibited; between 3 to 5 days are needed for PPIs to achieve their maximum effect.

PPIs are metabolized in the P450 cytochrome system (CYP450) in the liver; their main pathways are the 2C19 cytochrome (CYP2C19) and 3A4 cytochrome (CYP3A4) routes.4 These pathways are shared with other medications, and so there can potentially be a lesser or greater degree of interactions with PPIs.5

Despite being safe medications for the patient, the use of PPIs for prolonged periods is not exempt from adverse events. The majority of adverse effects have been described in association studies and causality has only been demonstrated in some of them.

The advent of PPIs established a paradigm in the treatment of all diseases related to hydrochloric acid. Their superiority to other medications in the prevention and control of symptoms and the healing of erosions and ulcers, their role in the management of complications, and their benefit in eradicating Helicobacter pylori (H. pylori) are well-established.6

Table 1 lists the PPIs that are available in Mexico, including their doses, administration route, half-life, and the main pathway of liver metabolism.

Deprescribing is a carefully planned and supervised clinical process that involves reducing or suspending medications that are not useful, necessary, can cause damage, or do not provide additional benefits in the long term. The primary aim of deprescribing is to reduce the quantity of medications, minimize possible damage, and improve patient quality of life. However, this process can be difficult, especially if the medication is causing no apparent damage and the patient is accustomed to its use. In the specific case of PPIs, there is little solid evidence on how to effectively deprescribe them.7,8

All patients that take PPIs should undergo a periodic check at 4 or 8 weeks of the indications for the use of these medications, and if there is no indication, they should be considered for a deprescribing strategy.8,9

Some operational definitions follow below:8–11

• –

  Deprescribing: the process of reducing and/or suspending a medication after considering its therapeutic indication, risks, and benefits.

• –

  Abrupt/rapid deprescribing: immediate complete suspension of the customary dose of a medication.

• –

  On-demand treatment: administration of a medication decided by the patient based on the presence of symptoms. The patient takes the medication when symptoms are present and suspends it when they disappear.

• –

  Intermittent treatment: daily administration of the antisecretory agent for predetermined periods, usually 2-8 weeks, followed by the same time of suspension.

• –

  Long-term or continuous treatment: any form of uninterrupted treatment, whether a double dose or a standard dose.

• –

  Gradual deprescribing: a gradual reduction of the total daily dose of the antisecretory agent, within a determined period of time, until reaching a minimum maintenance dose that controls symptoms. It can be divided into an intermittent or lower dose, which can be a double dose reduced to a standard dose, a standard dose every other day, or a standard dose divided into 2-3 times a week.

The deprescribing process of a medication consists of 5 steps:11

• 1

  Review indications and effectiveness.

• 2

  Evaluate the balance between the risk and benefit of chronic use.

• 3

  Evaluate patient preferences.

• 4

  Decide upon whether to continue, taper, or suspend the medication.

• 5

  Deprescribe and monitor the patient.

Recommendation 1: In nonerosive reflux disease (NERD), we recommend standard dose PPI use for 4 weeks.

The short-term treatment goal with PPIs in NERD is to achieve adequate symptom control. This is achieved in 50-60% of patients with a standard dose, and the symptom response rates are similar between all PPIs. The low response rate can be explained due to the great heterogeneity in the studies, given that the majority of clinical trials only consider patients with typical symptoms of gastroesophageal reflux disease (GERD) and endoscopy with no erosions as having NERD, without carrying out the objective measuring of reflux through pH monitoring.12,13 In a meta-analysis, the short-term response with a standard dose of PPI for 4 weeks in patients with erosive reflux disease (ERD) was 72%. It was 50% in patients with NERD and no pH monitoring, and 73% in patients with NERD and positive pH monitoring. It was concluded that in patients with well-defined NERD, the response rate at 4 weeks with a PPI was comparable to the response rate in patients with ERD.14

Recommendation 2: Cicatrization treatment for GERD with a standard dose for mild esophagitis (Los Angeles A and B) for 8 weeks and a double dose in severe esophagitis (Los Angeles C and D) for 8 weeks is recommended. Patients with grade B, C, or D esophagitis should later be given a maintenance dose.

PPIs are the first-choice drugs in erosive GERD.12 The treatment goal is symptom control and mucosal healing, which is achieved with standard dose PPI use in almost 80% of cases of erosive esophagitis.15 A double dose is recommended in patients that do not respond to treatment with the standard dose, as well as in cases of severe esophagitis (Los Angeles C and D), to achieve greater acid suppression.16

In the cases of Los Angeles grade B, C, and D erosive esophagitis, the recommendation is to continue with a maintenance dose, once the first 8 weeks of treatment have passed, to maintain mucosal healing. In those cases, there can be recurrence in just one to 2 weeks after PPI suspension,17 and recurrence in almost 100% of the cases of grade C esophagitis, after 6 months.

Grade A esophagitis is not considered a complication of erosive GERD and less than 60% of those patients have reflux symptoms,18 and so maintenance therapy is not recommended.

Recommendation 3: In functional dyspepsia (FD) for both subtypes (postprandial discomfort syndrome and epigastric pain syndrome), PPIs at the standard dose for 4 weeks are recommended.

Different guidelines recommend standard PPI therapy once a day for 4 weeks as first-line treatment for patients with FD.19,20 A Cochrane meta-analysis that included 6,172 patients from 18 randomized clinical trials (RCTs) confirmed that PPIs are more effective than placebo in reducing overall symptoms in FD (RR 0.88, 95% CI 0.82-0.94, NNT 11). There was no difference between low and high PPI doses, the type of PPI, or the presence of H. pylori.21 Recently, a network meta-analysis of 16 RCTs on 6,017 patients with FD, analyzed symptom improvement with a PPI at a low dose < 20 mg, a standard dose ≥ 20 to ≤ 30 mg, and a high dose > 30 mg. The conclusion was that PPIs were more effective than placebo, in the standard-dose PPI group (RR 0.86, 95% CI 0.78-0.95), as well as at low doses (RR 0.89, 95% CI 0.81-0.97), with no benefit at high PPI doses (RR 0.86, 95% CI 0.74-1.01).22

Even though PPIs are antisecretory drugs, some studies have shown that patients with FD have an increase in duodenal permeability and inflammation, with eosinophil and mast cell infiltration near the submucosal plexus neurons.23 In a recent prospective study, pantoprazole at a dose of 40 mg/day for 4 weeks, not only produced symptom improvement in patients with FD, but also a decrease in duodenal permeability and eosinophilia, as well as in the mast cell count, which could explain the effect of PPIs in FD.24

Recommendation 4: In Helicobacter pylori eradication, we recommend a double-dose PPI for 14 days.

Inadequate acid suppression can reduce the efficacy of H. pylori infection eradication treatment through several mechanisms. Optimum PPI dosing is often overlooked, and their adequate prescription can improve H. pylori eradication rates. In cases of H. pylori infection, utilizing a double-dose PPI and adequate antibiotic regimens for 14 days can increase the probability of success in H. pylori eradication.25

Recommendation 5: In acute nonvariceal upper gastrointestinal bleeding, we recommend an initial PPI 80 mg intravenous (IV) bolus, followed by IV infusion or high-dose PPI every 12 h.

The medical treatment goal is to maintain intragastric pH > 6 for promoting platelet aggregation, stabilizing the clot, and healing.26 Clinical trials have shown that the IV infusion of high-dose PPIs was superior to placebo for reducing the risk of peptic ulcer rebleed.

In patients with active bleeding or nonvariceal upper gastrointestinal bleeding, a recent meta-analysis by Laine et al. found significant benefit in IV high-dose PPI use after endoscopic therapy, given that it reduced the risk of recurrent bleeding.27 However, in a more recent meta-analysis of 6 RCTs, only a decrease in the need for endoscopic treatment in the index endoscopy was shown and it had no impact on mortality or the need for surgery.28 Two consensuses suggest a regimen with high-dose PPI (80 mg bolus at a single dose, followed by 8 mg/h continuous infusion for 72 h),29,30 but intermittent dosing, compared with the infused bolus regimen, has shown similar effectiveness rates.31

Recommendation 6: In the treatment of gastric ulcer, a standard-dose PPI for 4-8 weeks is recommended.

Since the advent of PPIs in the 1990s, numerous clinical trials have shown that these drugs were more efficacious than the histamine-2 receptor antagonists (H2RAs) in treating gastroduodenal ulcers,32 due to their greater potency in and duration of inhibiting acid production. The standard dose is recommended (e.g., OME 20 mg, esomeprazole 20 mg, pantoprazole 40 mg, etc.), once a day. Symptom resolution is fast, and healing is produced at 4 weeks of treatment in most patients. For patients that do not have complete healing after initial treatment, cicatrization generally occurs during the next four weeks of treatment.33,34 If the ulcer was associated with H. pylori, eradication treatment is necessary to prevent recurrence.

The patients with idiopathic ulcers (negative for H. pylori and with no nonsteroidal anti-inflammatory drug [NSAID]/aspirin use) can have a high recurrence rate, and most likely require long-term treatment (>8 weeks)35.

Recommendation 7: In the treatment of duodenal ulcer, a standard-dose PPI for 4 weeks is recommended.

Standard dose PPIs for 4 weeks provide healing rates above 90% for duodenal ulcers.32 The recommended dose in patients with active duodenal ulcer is the standard dose, once a day. Symptom resolution is rapid, and healing is produced in 2 weeks in the majority of patients.26,32 For patients that do not heal after initial treatment, cicatrization generally occurs during the following 2 weeks of treatment. In a meta-analysis of 24 controlled clinical trials that included 6,188 patients, pantoprazole 40 mg/day and lansoprazole 30 mg/day for 4 weeks significantly increased the healing rate (RR 2.96, 95% CI 1.78-5.14 and RR 2.04, 95% CI 1.13-3.53, respectively), compared with H2RAs.36 In addition, a network meta-analysis showed no significant differences in the 4-week healing rate of duodenal ulcer treated with different PPIs.

As in cases of gastric ulcer, if there is H. pylori infection, it should be treated with the appropriate eradication regimen.

Recommendation 8: PPI use as a prophylactic measure is recommended in patients admitted to the intensive care unit with risk factors for stress ulcers.

Stress ulcers (part of stress-related mucosal disease) are often present in patients admitted to the intensive care unit (ICU), and are one of the significant causes of prolonged stay, as well as of increased mortality.37 Approximately 75 to 100% of patients that undergo endoscopy within the first 72 h following the appearance of critical entities are estimated to have lesions in the mucosa and clinically present with manifestations, such as blood in stools, melena, coffee-ground emesis through a nasogastric tube, and hematochezia that conditions hemodynamic instability.38

Calculations in meta-analyses suggest that significant clinical bleeding is around 1%, but despite its low frequency, it is a cause of significant mortality in that group of patients.37 The main risk factors include mechanical ventilation for more than 48 h (RR 15.6) and the presence of coagulopathy (RR 4.3).39 In different meta-analyses, the use of prophylaxis in that group of patients reduces risk by 60%. There is no difference between the frequency of PPI use (one or two times a day), dose, or administration route (enteral vs IV), for reducing the bleeding risk. Therefore, the standard dose is recommended, and the treatment should be given until the patient no longer presents with risk factors.37,40,41

Recommendation 9: We recommend on-demand PPI use in the maintenance treatment of NERD and mild esophagitis.

On-demand treatment with PPIs consists of the patient deciding on the PPI dose to take when they experience GERD symptoms and suspending treatment when the discomfort disappears. This regimen is different from intermittent treatment, in which the physician prescribes a daily PPI dose for a short period (1-2 weeks), regardless of the presence of symptoms. The standard dose of PPIs is utilized, and the minimum dose necessary for controlling symptoms is recommended.12,42,43

There are two indications for treatment with on-demand PPIs: NERD and Los Angeles grade A mild esophagitis.12,42,43 The efficacy of this treatment in NERD and mild esophagitis has been evaluated in 2 recent meta-analyses.44,45 In the first, 10 RCTs with 4,574 patients were evaluated, comparing on-demand treatment with daily treatment or placebo. The results showed that on-demand treatment with PPIs was superior to daily treatment (RM 0.50, 95% CI 0.35-0.72) in the two patient groups. Compared with placebo, on-demand treatment was effective in patients with NERD or mild esophagitis (OR 0.22, 95% CI 0.13-0.36 and OR 0.18, 95% CI 0.11-0.31, respectively). The second meta-analysis included 11 RCTs on patients with NERD and mild esophagitis, and the results showed that on-demand treatment with PPIs had similar outcomes to continuous treatment, in terms of therapeutic failure (OR 1.26, 95% CI 0.76-2.07). Both meta-analyses concluded that on-demand therapy is effective in the management of NERD and mild esophagitis. It should be clarified that the definition of mild esophagitis in those two studies was based on Savary Miller classification grade I, which is equivalent to Los Angeles classification grade A. Even though expert opinion is that on-demand maintenance treatment can be recommended in patients with Los Angeles grade B esophagitis, controlled clinical trials that support said recommendation are needed.12,42,43

In addition, on-demand PPI use has been shown to be the most cost-effective strategy in the maintenance treatment of NERD.46

Recommendation 10: Standard dose maintenance treatment is recommended in patients that have the B, C, and D erosive variants of GERD.

The chronic and recurrent nature of reflux disease affects quality of life and causes complications; thus, it requires optimum control for preventing said situations. This is especially true in the case of the erosive phenotype of reflux disease because it has the potential to induce complications (bleeding, stricture). There is greater scientific evidence on the use of PPIs in reflux disease, especially in the erosive phenotype.

The erosive phenotype spectrum of reflux disease is currently based on the Los Angeles classification, which has been extensively validated.47 Subsequent research has determined that interobserver variability is high for the Los Angeles grade A classification and that a conclusive diagnosis of GERD cannot be made in that subgroup of patients.48 On the other hand, patients with Los Angeles grade B classification have a conclusive reflux diagnosis by demonstrating the presence of elevated acid exposure and a similar treatment response to the Los Angeles C variant.49

Given the above, the treatment for inducing healing is required in these erosive variants (B, C, and D), as well as maintenance treatment. The evidence suggests that the erosive variant relapse rate, 6 months after having suspended the treatment of single-dose PPIs, is from 6 to 42%. Studies suggest that 6 months after suspending treatment with PPIs, only 10% of the patients with erosive esophagitis are still in remission.50 Therefore, PPIs are indicated as maintenance therapy for preventing the recurrence of both symptoms and mucosal lesions, and the long-term use of PPIs has been approved by the US Food and Drug Administration (FDA).51–56

A RCT showed that OME 20 mg, once a day (QID), was capable of maintaining 80% of patients with erosive esophagitis free from mucosal lesions after 12 months of continuous treatment. It also reported that OME was significantly superior to both ranitidine and cisapride.50 Similar results were later obtained with lansoprazole (15 and 30 mg, QID), which was shown to be capable of maintaining around 80% of patients with erosive esophagitis in remission at one year.57 Thus, PPIs are useful as maintenance therapy for preventing recurrences of symptoms, as well as mucosal lesions, in patients with the erosive variant, especially those with more severe lesions (Los Angeles B to D). With few exceptions, such as severe erosion grades, half the healing dose of a PPI tends to be adequate for maintenance.58 As a result, the maintenance of the lowest PPI dose necessary for controlling symptoms and esophageal mucosa healing, as a long-term treatment goal, is recommended.

Recommendation 11: Maintenance PPI use at the dose that achieves symptom control is recommended in patients with Barrett’s esophagus, as well as the standard dose for chemoprotection.

Barrett’s esophagus is the replacement of normal squamous epithelium of the distal part of the esophagus with specialized metaplasia (with goblet cells). It is the most important complication of GERD because it is considered a premalignant lesion. It is associated with maximum acid exposure, compared with other forms of the disease, strongly justifying the use of potent antisecretory therapy with PPIs.59 Some studies have shown that PPIs can reduce its progression to adenocarcinoma.60

A meta-analysis based on observational studies concluded that PPI administration led to a reduced risk for progression to low and high-grade dysplasia and to adenocarcinoma (OR 0.29, 95% CI 0.12- 0.79). The same meta-analysis also found that risk reduction was greater with PPI use above 2-3 years (OR 0.45, 95% CI 0.19-1.06 vs OR 1.09, 95% CI 0.47-2.56, respectively).61

Therefore, a standard PPI dose once a day is recommended for preventing the transformation of metaplasia into dysplasia and neoplasia, and this treatment should be continued for life.34,62,63 Based on these results, the recommendation is for asymptomatic patients with Barrett’s esophagus to maintain long-term treatment with PPIs, even if there is no solid evidence in this regard.

Recommendation 12: In peptic stricture, long-term, continuous treatment with a standard-dose PPI is recommended.

The incidence of esophageal stricture has drastically decreased over the past 2 decades, in parallel with a marked increase in PPI use. Consequently, the number of studies and their quality have decreased, and evidence is scarce. One study compared lansoprazole 30 mg, QID, versus ranitidine 300 mg twice a day (BID). The lansoprazole study arm required fewer dilatations and had a higher number of patients with no dysphagia than the ranitidine arm.64

Another study compared OME 20 mg, QID, and ranitidine 150 mg, BID, in patients with the erosive variant and concomitant peptic stricture. OME administration improved dysphagia and lowered the frequency of stricture dilatation.65

In patients with peptic stricture, the intervention by experts in therapeutic endoscopy is required for performing dilatation and rehabilitating the esophagus. Uninterrupted concomitant PPI use is necessary in this population for preventing progression and recurrence.

Recommendation 13: In patients with acid hypersecretion syndromes, continuous treatment with PPIs at a dose that is sufficient for long-term symptom control is recommended.

Acid hypersecretion syndromes, e.g., Zollinger-Ellison syndrome (ZES), are characterized by extreme acid secretion due to a neuroendocrine tumor that ectopically secretes gastrin, resulting in diseases, such as peptic ulcer and severe, continuous, recurrent GERD that is dependent on antacid treatments.66 The exact prevalence and incidence of ZES are unknown but it is a rare disease. In the US, its frequency is estimated at one per every million inhabitants and presentation age is 7 to 90 years.67

Diagnosis is made with a plasma gastrin level > 1,000 pg/mL and a baseline acid secretion of >15 mEq/h or even >5 mEq/h in patients with gastrectomy or hypergastrinemia associated with a pH < 2. If it is not possible to obtain baseline acid secretion, hypersecretion syndrome can be ruled out with a gastric pH > 2, in the absence of antisecretory medications. If the pH is >2 and the plasma gastrin level is between 100-1,000 ng/mL, a secretin stimulation test should be carried out.67

The most common symptoms are abdominal pain, diarrhea, and heartburn, followed by nausea and vomiting in some patients. The endoscopic presence of prominent gastric folds is a sign of acid hypersecretion and 25% can present with upper gastrointestinal bleeding.67

In the 1980s, with the generalized use of gastric H+, K+ -ATPase inhibitors, the medical control of gastric acid hypersecretion was made possible in almost all patients. Due to the greater potency and action duration of PPIs, enabling their doses to be given once or twice a day, they have become the drugs of choice for the treatment of this disease. Numerous acid secretion control studies on patients with hypersecretory states support the use of PPIs at varying doses, and they should be titrated individually, utilizing the established criteria for acid suppression in those patients. In patients with intact stomachs, with no GERD or moderate-to-severe multiple endocrine neoplasia type 1 (MEN1), the generally accepted criterion is the use of antisecretory drugs that induce acid suppression at <10 mEq/h for the hour before the next dose of the drug. In complicated patients (moderate-severe GERD, previous Billroth 2 surgery, or MEN1), greater acid inhibition at < 1 mEq/h may be necessary, depending on the upper gastrointestinal endoscopy findings.66 Lansoprazole showed safety and efficacy in secretion control for 10 years, in treating hypersecretors.68 The largest cohort series, with 303 patients, reported a median 14 years of treatment with PPIs and/or H2ARs and treatment of up to 48 years.66

Patients with acid hypersecretion syndrome have 2 problems: the control of acid hypersecretion and the treatment of gastrinomas, which are malignant in 60 to 90% of patients. Surgery continues to be the only possibility for the cure and treatment of the two problems.66

Recommendation 14: In eosinophilic esophagitis, we recommend long-term, continuous, standard-dose PPI use.

Eosinophilic esophagitis (EoE) is a disease that causes symptoms of esophageal dysfunction. At least 15 eosinophils per high power field (60 eos/mm2) are seen in biopsies, and other causes of esophageal eosinophilia must be ruled out in this group of patients.69

The first evidence on the potential usefulness of PPIs for achieving histologic and clinical remission of EoE was published in the pediatric literature.70 Treatment with high doses of PPIs used to be a diagnostic strategy for differentiating EoE from peptic esophagitis; at present it is used as treatment for EoE.71 The recommended PPI doses in adults are 20 to 40 mg of OME, BID, or its equivalent, and in children, 1-2 mg/kg of OME daily or its equivalent. The long-term strategy is to use the minimum efficacious dose for maintaining remission. PPIs at half the initial dose maintain histologic and clinical remission in a minimum of 75% of patients after at least one year of follow-up. The majority of patients that relapse recover remission after increasing the dose. There are no published data on safety problems of PPIs in patients with EoE.70

The benefits of treatment with PPIs in EoE are probably multifactorial, and include esophageal epithelial barrier repair and possible direct anti-inflammatory effects on certain cytokines.72–74 in vitro, PPIs inhibit Th2-cytokine-induced eotaxin-3 expression, by interfering with the binding of the signal transducer promoter and the transcription activator.75 A recent meta-analysis demonstrated that treatment with PPIs induced clinical response and histologic remission in 60.8 and 50.5% of patients, respectively.71,74

Recommendation 15: In patients with chronic NSAID/ASA use and high risk for upper gastrointestinal bleeding, we recommend continuous PPI use at the standard dose.

Both NSAIDs and ASA are often chronically indicated, especially in older adults. This is particularly true with ASA, for the prevention of cerebrovascular events and ischemic heart disease. However, there is a risk for developing complications in the upper gastrointestinal tract, such as peptic ulcer disease and gastrointestinal bleeding. In said context, numerous studies have been conducted, with results favoring the use of PPIs in combination with NSAIDs or ASA for reducing that risk. Table 2 identifies the risk factors for gastrointestinal bleeding and prophylaxis. In a systematic review of 41 RCTs, PPIs reduced the endoscopic risk for duodenal (RR 0.44, 95% CI 0.26-0.74) and gastric (RR 0.40, 95% CI; 0.32-0.51) ulcers associated with chronic NSAID use.76

In a meta-analysis, the effect of co-administering PPIs in patients with no history of peptic ulcer disease, chronically taking low-dose ASA (30-325 mg) was evaluated. Concomitant PPI use was associated with a 73% reduction in the risk for developing peptic ulcer, compared with not using a PPI (RR 0.27, 95% CI 0.17-0.42, p < 0.001), and 50% reduction in the risk for gastrointestinal bleeding (RR 0.50, 95% CI 0.32-0.80).77

On the other hand, in a case-control study conducted on 1,382 NSAID/COX-2 inhibitor users with gastrointestinal complications, the combination of a COX-2 inhibitor with a PPI resulted in a greater reduction in the risk for upper gastrointestinal complications associated with NSAIDs (OR 0.36; 95% CI 0.28-0.47); celecoxib was superior to the combination of a nonselective NSAID with a PPI.78

Recommendation 16: In patients treated with steroids, we do not recommend chronic PPI use, unless the steroids are prescribed in combination with an NSAID/ASA.

The routine use of PPIs is not indicated in patients taking steroids alone for a medical condition, unless the steroids are associated with NSAIDs. In a study conducted on 138 patients with autoimmune disease treated with corticosteroids, 20% presented with peptic ulcer disease. In the multivariate analysis, risk factors were identified: age ≥ 60 years (OR 6.80, p = 0.001), smoking (OR 7.94, p = 0.004), and NSAID use different from COX-2 inhibitors (OR 4.71, p = 0.030), whereas the protective factor was H. pylori infection (OR 0.20, p = 0.022).79 Likewise, in a meta-analysis that included 6,602 patients, the frequency of gastrointestinal complications was compared with a placebo group (n = 3,267) and a steroid group (n = 3,335). In the placebo group, 0.3% developed peptic ulcer versus 0.4% in the steroid group (p > 0.05), concluding that peptic ulcer disease is a rare complication of steroid therapy.80 In a more recent meta-analysis, there was also a low prevalence of peptic ulcer disease in patients with systemic corticosteroids, occurring in 0.4-1.8% of patients. Therefore, routine prophylaxis with PPIs is not recommended.75

Recommendation 17: In patients with upper gastrointestinal bleeding risk factors that are taking antiplatelet drugs or anticoagulants, we recommend prophylaxis with PPIs.

Gastrointestinal bleeding is the most frequent bleeding complication in patients with chronic antiplatelet drug use. In a systematic review, 71,277 participants were included. The results showed that PPI use in patients with dual antiplatelet therapy (ASA and clopidogrel) was associated with a significant reduction in adverse gastrointestinal events (OR 0.38, 95% CI 0.21-0.68, p = 0.001); specifically, upper gastrointestinal bleeds with clopidogrel plus PPI exposure (OR 0.31, 95% CI 0.19-0.51, p < 0.001).81

In the randomized, double blind, placebo-controlled phase 3 Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT), the efficacy and safety of the combination of clopidogrel (75 mg) plus OME (20 mg) versus clopidogrel alone, was evaluated. For financial reasons, the study was stopped at 3,761 patients. Upper gastrointestinal events were reported at 1.1% in the OME group and 2.9% in the placebo group, 180 days after the randomization (OR 0.34, 95% CI 0.18-0.63, p < 0.001). More importantly, there was no significant increase in the risk of cardiovascular events with the concomitant use of OME and clopidogrel (p = 0.98).82 The risk for gastrointestinal bleeding was found to be higher in patients with dual antiplatelet therapy in the form of ticagrelor or prasugrel, compared with clopidogrel. In their 2017 guidelines on dual antiplatelet therapy in coronary artery disease, the European Society of Cardiology recommends PPI use in that context (class I, level of evidence B).83

Recommendation 18: In patients taking two or more antiplatelet drugs or an antiplatelet drug plus oral anticoagulation, we recommend prophylaxis with a PPI.

In their 2020 expert review on antiplatelet therapy and anticoagulation in patients with atrial fibrillation or atherosclerotic cardiovascular disease, the American College of Cardiology (ACC) recommends starting or continuing a PPI in patients with ≥ 2 antithrombotic agents, as well as avoiding concomitant NSAID use, to reduce the risk for gastrointestinal bleeding. Once the patient is only taking oral anticoagulation, deprescribing the PPI is recommended, unless there is some other indication for its continuation.84

Recommendation 19: In chronic pancreatitis with exocrine pancreatic insufficiency, we do not recommend the addition of a PPI, given that only enteric-coated pancreatic enzymes are available in Mexico.

The aim of pancreatic enzyme supplementation, in the context of chronic pancreatitis, is suppression of the steatorrhea caused by the condition. All the factors involved in the adequate response to therapy must be kept in mind, even if there has not been therapeutic failure. The most important of these is corroborating that the dose of the supplemented pancreatic enzymes is the correct one. Physiologic studies conducted on the correct absorption of pancreatic enzymes focused on the effects of the gastrointestinal tract on the formulation. Postprandial gastric pH decreased to < 4 after 40 minutes and postprandial duodenal pH after 100 minutes.85 Said pH value is the point at which lipase is irreversibly inactivated and considerably reduces its activity at more advanced sites of the gastrointestinal tract. This is the rationale behind the theory that inhibiting acid, thus maintaining the gastric and duodenal pH above 4, is a factor involved in pancreatic enzyme supplementation to consider. That evidence was established in publications in the 1970s and led to the evolution of enteric coating of the formulations. This advance meant the drug would not have a pH-dependent degradation, preserving its lipolytic activity. The recommendation to inhibit acid through a PPI remains absolute for the non-enteric-coated enzyme formulations.86 However, there is a subgroup of patients that have normal-to-high acid secretion, together with insufficient pancreatic bicarbonate secretion for neutralizing the pH of chyme. PPI administration is suggested in those patients, even when using enteric-coated enzyme supplementation formulations.87 Thus, the recommendation to inhibit acid with a PPI is still valid, simply as a factor that can aid in the correct absorption, together with the factors of adequate dose and enteric coating.88

Recommendation 20: In all patients undergoing long-term treatment with PPIs, we recommend that the physician monitor the possible presentation of adverse effects and indicate deprescribing the PPI when the patient no longer needs it or there is no indication for its use.

The present expert panel analyzed the evidence, and these are the adverse effects in which there is cause and effect (causality) (Table 3).

Recommendation 22: We recommend the sudden, gradual, or intermittent deprescribing of PPIs in patients for whom PPI use is not indicated.

Deprescribing PPIs is justified under conditions in which there is no indication for their continuous use, or once the symptoms for which the PPI therapy was started are now resolved (Table 4). Deprescribing PPIs can be recommended after 4 to 8 treatment weeks. At present there are no studies that identify the best manner for deprescribing: abrupt, gradual, or intermittent (on-demand). Abrupt deprescribing can lead to acid secretion rebound due to a state of hyperacidity, which has been reported with therapies of 4 weeks and longer, even at low PPI doses.131

Gradual deprescribing is carried out in a reduction period of 2 to 4 weeks, decreasing the double-dose to standard dose for 2 weeks and then suspending the PPI. Another approach is reducing the standard dose to a dose every 48 h and then suspending the PPI. Other authors have used the standard dose, switched to an H2RA, and then suspended the PPI.132

In their study, Inadomi et al. studied 73 patients with GERD that had adequate symptom relief in treatment with PPIs. Deprescribing was started as follows: The double-dose was reduced to the standard dose and then the drug was suspended. If the symptoms of heartburn and regurgitation recurred 2 weeks before the follow-up appointment, the lowest PPI dose was restarted. If the symptoms recurred after the 2 weeks, treatment with an H2RA and/or a prokinetic was started. In the case of symptom persistence, those 2 drugs were used and if the symptoms still persisted the PPI therapy was restarted. The results showed that of the 73 subjects, 58% were asymptomatic at one year, with no treatment. Of those patients, 34% required an H2RA, 7% a prokinetic, 1% required the two drugs, and 15% required no medication after one year of follow-up. In the multivariate analysis, heartburn and younger age were found to possibly predict the need for PPIs.133

At present, gradual reduction is the most widely recommended deprescribing method, given that it reduces the risk of recurrence and deprescribing-associated symptoms, but evidence is still lacking on this modality (Fig. 1).

Figure 1.

Algorithm for deprescribing a PPI.

In patients taking PPIs, their indication should be reviewed and if there are none, they should be suspended. If there is an indication, the appropriate dose and duration should be prescribed; if the dose or duration is not appropriate, they should be suspended. The most adequate deprescribing strategy should be personalized for each patient, as well as the maneuvers to be employed, in case of symptom relapse.

Source: Adapted from Helgadottir H, Bjornsson ES.11

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On the other hand, deprescribing through intermittent treatment is useful in patients with adequate control, but with symptom recurrence at 2-4 weeks.

The clinical evidence on these strategies is summarized below (Table 5):