Tag Archives: esomeprazole

Which Proton Pump Inhibitor is the Most Potent?

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A recent study (DY Graham, A Tansel. Clin Gastroenterol Hepatol 2018; 16: 800-808) analyzed 56 randomized trials to determine relative potency of proton pump inhibitors (PPIs) based on time in which intragastric pH was 4 or less (pH4time).

Key findings:

  • Pantoprazole 20 mg was equivalent to 4.5 mg of omeprazole
  • Lansoprazole 15 mg was equivalent to 13.5 mg of omeprazole
  • Esomeprazole 20 mg was equivalent to 32 mg of omeprazole
  • Rabeprazole 20 mg was equivalent to 36 mg of omeprazole

The authors note that peak effectiveness for PPIs was at ‘approximately 70 mg of omeprazole equivalents’.  In addition, they state that twice a day dosing was more effective than increasing once a day dosing; however, three times a day dosing was not more effective than twice a day. “Dexlansoprazole, a quasi-twice-a-day formulation produced similar acid suppression to the lowest twice-daily PPI regimen and 20 mg vonoprazan once daily provided similar efficacy aas high-dose twice-daily PPI.” The authors also compare costs; generics of pantoprazole, omeprazole, and esomeprazole cost as little as $0.02-0.04 per omeprazole equivalent.  Thus, 20 mg of omeprazole would be as little as 40 cents.

My take: Using the lowest effective dose of a PPI is recommended.  In patients needing higher dosing or with suboptimal response to acid suppression, this data can be very helpful.

 

Proctor Creek Trail

‘Little’ Knowledge Exists Regarding Medicines for Neonates

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Despite federal legislation encouraging the study of products used in the pediatric population, very little of these studies has translated into meaningful information regarding neonates (JAMA Pediatr 2014; 168: 130-36, thanks to Ben Gold for this reference).

This publication reviewed studies submitted to the FDA between 1997-2010.  The authors identified all drugs with pediatric studies that included neonates.  Subsequently, the use of these drugs was examined in a oohort of neonates admitted to 290 neonatal intensive care units (NICU) (Pediatrix Data Warehouse) in the U.S. form 2005-2010.

Key findings:

  • 28 drugs (in 41 studies) were examined in neonates. This led to 24 labeling changes.
  • 11 of 24 neonatal labeling changes included an approval for use in neonates, including 4 for HIV and 3 for anesthesia.
  • 13 of 24 labeling changes were the following: “safety and effectiveness have not been established.”  These drugs included several reflux medications: esomeprazole, lansoprazole, pantoprazole, and ranitidine.
  • In the Pediatrix database involving 446,335 hospitalized neonates, there were 399 different drugs identified that had been administered.  Of the 28 studied drugs, the gastroesophageal reflux medicines were used most frequently.  13 of the 28 studied drugs were not used at all in the NICUs.
  • Of the 11 drugs with a neonatal indication, 7 were never used in the Pediatrix neonatal population and the other 4 drugs were used infrequently.

Conclusions:

  • Neonates are a vulnerable and an understudied population
  • Most of the exposure to drugs was off-label for neonates.
  • Most often, off-label drugs were prescribed “despite studies indicating they were not effective…For example, ranitidine, lansoprazole, and inhaled nitric oxide (for the prevention of bronchpulmonary dysplasia) were the top 3 drugs used in neonates…none have FDA labelling for the indication studied because of lack of efficacy.”
  • Furthermore, drugs like ranitidine and lansoprazole” are associated with serious adverse effects in neonates.” (Clin Perinatol 2012; 39: 99-109)

Related blog entries:

Nexium versus Fluticasone for EoE

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As noted in previous blog posts (EoE: Drugs, Diets, Dilatation and PPI-REE | gutsandgrowth, EoE –Journal Club (Part 1) | gutsandgrowth, and EoE –Journal Club (Part 2) | gutsandgrowth), proton pump inhibitors are recommended as 1st line therapy in suspected eosinophilic esophagitis (EoE) for several reasons.  Besides the potential for gastroesophageal reflux to cause esophageal eosinophilia, there has been recognition of PPI-responsive eosinophilic esophagitis (PPI-REE).  In adults, the response to proton pump inhibitors, both clinically and histologically, is likely higher than in children; nevertheless, in children it is anticipated that 20-40% of patients with suspected EoE will have a histological remission with PPI therapy.

A recent study in adults suggests that PPIs may in fact outperform topical steroids (Am J Gastroenterol 2013; 108: 366-72).  Thanks to Ben Gold and Seth Marcus for identifying this reference.  This study enrolled 42 patients: 90% male, 81% white, mean age 38 years. It was a prospective single-blinded, randomized controlled trial with newly suspected EoE; half of the patients received esomeprazole 40 mg daily and half fluticasone swallowed aerosol 440 mcg twice a day.  After 8 weeks, all patients had repeat endoscopy; a total of eight biopsies were obtained –four at two locations: 15 cm above LES and 3 cm above LES.  In addition, at the start of the study, patients also underwent 24-h pH/impedance monitoring.  4 of the 21 patients in each group had abnormal degrees of gastroesophageal reflux/gastroesophageal reflux disease (GERD).

Study characteristics note that 62% of patients had coexisting atopic disorders.

Results:

  • There was no significant difference in esophageal eosinophilia response with 19% of the fluticasone and 33% of the esomeprazole achieving an eosinophil count < 5/hpf (P=0.484)
  • In patients with coexisting GERD, all 4 esomeprazole patients achieved histologic remission  compared with none of the fluticasone-treated patients.
  • When the GERD patients were excluded, the histological remission was quite similar: 24% with fluticasone and 18% for esomeprazole.

Overall, this study population had a lower rate of response to topical steroids than in multiple previous studies.  More typically, response rates of ~50% have been reported; however, studies have shown lower responses in some adult studies.  Variability in response could be related to multiple factors included dosage, duration, delivery, and definition of response.  In addition, population characteristics included disease duration and frequency of underlying atopic disease and GERD play a role.

Take-home points: Although this is a small study, it reinforces the fact that PPIs induce a histological response and clinical response in some patients suspected of having EoE regardless of whether GERD is present.  PPIs are considered 1st line therapy.  Topical fluticasone had a lower response rate in this study.  However, in clinical pediatric practice, topical steroids are effective in about 50% of patients.

Additional related blog entries:

Do medicines work for GERD infants?

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“Absence of evidence is not evidence of absence.” Carl Sagan

If medicines work for infantile GERD, it is difficult to prove (Winter H, et al. JPGN 2012; 55: 14-20).  The cited study is the latest having difficulty proving that proton pump inhibitors are effective in infants.  In this randomized, double-blind, placebo-controlled multinational study from 33 centers, 98 infants (1-11 months) were enrolled.  My colleague, Dr. Benjamin Gold, was one of the researchers.  Initially, a 2-week open-label treatment was given which was followed by a 4-week randomized phase.   Study participants had to have a clinical diagnosis of GERD with at least one GERD symptom  –at least twice per week in a 4-week period:

  • vomiting/regurgitation
  • irritability
  • supraesophageal manifestations (cough, wheeze, stridor)
  • respiratory symptoms triggered by feedings
  • feeding difficulties

The treatment administered was weight-based dosing of esomeprazole:

  • 3-5 kg:     2.5mg
  • 5-7.5kg    5mg
  • 7.5-12kg  10mg

Daily symptoms were captured with an interactive voice response system.  Among the initial 98 patients enrolled, 80 reached the randomization phase.  During the initial 2-week period, 81 (82.7%) had symptom improvement based on physician global assessment.  During the double-blind phase, 48.8% of placebo-treated patients and 38.5% of esomeprazole-treated patients discontinued therapy due to symptom worsening.  While the time for discontinuing esomeprazole was longer in a posthoc analysis, the primary outcome, discontinuation rate, was not significantly different.

So what is the reason that this was a negative study?  While the reasons are unclear, all of the following are possible:

  • Patient selection/lack of accurate diagnosis.  Mixed-population was recruited for the study –though this type of population is similar to clinical practice.
  • Dose of esomeprazole.
  • Inadequately powered study.  If the effectiveness of PPIs is small, a much larger population is needed.
  • Maybe these agents don’t work in infants.  Infants secrete less acid than children and adults; thus, acid blockers may not work as well. (The Medical Pendulum and Gastroesophageal Reflux)

Why not give PPIs even if they don’t work?  The previous link discusses many of the potential adverse problems that are possible with medical treatment of GERD. However, even if a medicine does not harm does not mean you should do something because it ‘might’ do some good.  An example of this is the apocryphal tale of the famous pianist who died one day in the middle of a recital. (I saw this in a journal article but cannot remember the reference.)  The manager came out to announce his death.  A man in the audience shouts, ‘Give him an enema.’ Initially, the manager tries to ignore him. After the man yells this three times, the manager responds, ‘the poor man is dead…what good will an enema do?’ The voice replies, ‘What harm will it do?

Additional references:

  • -JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placebo in withdrawal rates due to lack of efficacy. n=128.
  • -NASPGHAN 2009, Abstract#21. Meds/Rx of NICU pts did not shorten hospital stay or promote wt gain, n=1149. Abstract#26. prevacid more effective than ranitidine in infants.
  • -J Pediatr 2009; 155: 601 (letter). Should not be used to treat symptoms unless proven to be reflux.
  • -JPGN 2009; 49: 498. GERD guidelines.  “In infants and toddlers, there is no symptom or symptom complex that is diagnostic of GERD or predicts a response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatr 2009; 154: 514-20.)  Reflux is “not a common cause of unexplained crying. irritability..in otherwise healthy infants.” “There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants.”