PPIs: Good News on Safety

When someone gets bitten by a shark, it often makes the news.  Yet, the frequency of shark attacks is rare and it is probably much more dangerous driving to the beach than getting into the water.

For proton pump inhibitors, it seems that they get similar press coverage as shark bites.  Many times potential adverse effects are covered heavily by the media even though many of these effects are unproven or very infrequent.

A recent study (“Safety of Proton Pump Inhibitors Based on a Large, Multi-year, Randomized Trial of Patients Receiving Rivaroxaban or Aspirin” Moayyedi, Paul et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2019.05.056) shows that 3 years of pantoprazole had an excellent safety profile.

Here is the abstract:

Background & Aims

Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.

Methods

We performed a 3×2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n=8791) or placebo (n=8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient years of follow up.

Results

There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% CI, 1.01–1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.

Which Proton Pump Inhibitor is the Most Potent?

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

Briefly Noted: Pantoprazole dosing for obese children

V Shakhnovich et al. J Pediatr 2018; 193: 102-8. Using pharmocokinetic data from 41 obese children (6-17 years), the authors conclude that lean body weight dosing of pantoprazole led to pantoprazole pharmocokinetics similar to nonobese peers.  They also note that variability in age-related changes in CYP2C19 activity affected pantoprazole values in children <12 years of age.

Related blog post: #NASPGHAN17 EoE Session -James Franciosis presented data on how CYP2C19*17 allele was important in whether patients responded to PPIs for Eosinophilic Esophagitis.

 

Bright Angel Trail, Grand Canyon