Proton pump inhibitor

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In medicine, specifically gastroenterology, proton pump inhibitors (PPI) are medications that "inhibit H(+)-K(+)-exchanging atpase. They are used as anti-ulcer agents and sometimes in place of histamine H2 antagonists for gastroesophageal reflux disease."[1] They are also used to eradicate Helicobacter pylori, in combination with antibiotics.

Examples:

  • Esomeprazole. Available as generic.
  • Lansoprazole. Available as generic.
  • Omeprazole. Available as non-prescription in the United States.
  • Pantoprazole. Available as generic.
  • Rabeprazole

Metabolism

Proton pump inhibitors are metabolized by the CYP2C19 isoenzyme of cytochrome P-450. Lanzoprazole is the strongest inhibitor of CYP2C19,[2] This may be less true for pantoprazole and esomeprazole.[3] Pantoprazole is the strongest inhibitor of the CYP2C9 isoenzyme[2]

Effectiveness

Proton pump inhibitors may improve:

PPIs may reduce the risk of gastrointestinal hemorrhage among patients enduring anticoagulation.[9]

Adverse effects

Proton pump inhibitors may be associated with spontaneous bacterial peritonitis.[10] Recent starting of these drugs may also be associated with pneumonia acquired in the community[11]or hospital[12]. These drugs may be associated with Clostridium difficile diarrhea[13], and fractures other than hip fractures[14].

Starting proton pump inhibitors in healthy volunteers may induce acid-related symptoms when PPIs are stopped[15] This is problematic considering how often PPIs are incorrectly prescribed.[16]

Proton pump inhibitors may induce acid-related symptoms in healthy volunteers after withdrawal, presumably due to rebound acid hypersecretion.[15]

Drug interactions

In the United States, the Food and Drug Administration has issued warnings regarding combining PPIs with clopidogrel.[17][18] Proton pump inhibitors (especially inhibitors other than pantoprazole[19]), which are metabolized by the CYP2C19 isoenzyme of cytochrome P-450, may or may not increase adverse cardiac events when given to patients taking clopidogrel for coronary heart disease (see evidence table). A consensus statement address this drug interaction.[20]

Studies of drug interactions between PPIs and clopidogrel[21][22][23][19][24][25][26][27][28]
Trial Patients Intervention Comparison Outcome Results
PPI Control
COGENT Randomized controlled trial[21]
2010
3,873 patients with an indication for dual antiplatelet
• 94% were anglo
1,033 concurrent users of clopidogrel and PPIs
• all used omeprazole
Placebo Serious cardiovascular disease
Odds ratio = 0.99; 95% CI, 0.68 - 1.44; P=0.96);
"There was no apparent cardiovascular interaction between clopidogrel"
Stockl et al Retrospective cohort study[22]
2010
2,066 patients hospitalized for myocardial infarction or stent 1,033 concurrent users of clopidogrel and PPIs
• 64% used pantoprazole
1,033 patients not taking PPIs Serious cardiovascular disease
Odds ratio = 1.64 (95% CI 1.16-2.32)
"Patients who received clopidogrel plus a PPI had a significantly higher risk of rehospitalization for MI or coronary stent placement than did patients receiving clopidogrel alone"
Tennessee Medicaid cohort study[23] 20,596 patients hospitalized for myocardial infarction, myocardial revascularization, or unstable angina pectoris 7593 concurrent users of clopidogrel and PPIs
• 62% used pantoprazole
13003 patients not taking PPIs Serious cardiovascular disease
"Serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk"
Ontario nested case-control study[19] 13,636 subjects taking clopidogrel after myocardial infarction 782 subjects readmitted for myocardial infarction 2057 subjects not readmitted Rate of PPI usage other than pantoprazole Odds ratio = 1.40 (95% CI 1.10–1.77)
Cohort study from the VA Cardiac Care Follow-up Clinical Study[24] 8205 subjects with acute coronary syndrome 64% were taking PPIs:
• 0.2% used pantoprazole
• 50% received stents
• Probably < 50% used drug eluting stents[29]
Subjects not taking PPIs Major vascular events 29.8% 20.8%
Odds ratio = 1.25 (95% CI: 1.11-1.41)
• "each 10% increase in the proportion of time taking clopidogrel plus PPI during follow-up was associated with a higher risk"
Cohort study taken from TRITON-TIMI 38 randomized controlled trials[25][30][31]
2 of 14 authors disclosed payments from AstraZenca, the maker of omeprazole and esomeprazole
6795 subjects with acute coronary syndrome who were randomized to the clopidogrel arm of the trial 33% (4529) were taking PPIs at randomization:
• 2814 took PPIs for duration of study
• 41% used pantoprazole
• 94% received stents
• 47% received at least one drug eluting stent
Subjects not taking PPIs Major vascular events 11.8% 12.2%
• Patients taking any PPI HR = 0.94, (95% CI 0.80–1.11)
• Patients taking any PPI for duration of study HR = 1.05 (95% CI 0.85–1.30)
• Results similar for each individual PPI
• Results also insignificant when restricted to analysis of patients with a reduced function allele
Medco cohort study[26] 16,718 subjects who took clopidogrel for 12 months after coronary stent 41% were taking PPIs:
• 24% used pantoprazole
• 100% received stents
• Unknown use of drug eluting stents
Subjects not taking PPIs Major vascular events 24% to 29% 17.9%
• Pantoprazole HR=1.61 (pantoprazole had most GI bleeding)
• Esoprazole HR=1.57
• Lansoprazole HR=1.39
• Omeprazole HR=1.39
Histamine H2 antagonists HR=1.14 (insignicant)
Danish cohort study[27] 56,406 subjects discharged after first-time myocardial infarction • 44% received clopidogrel
• 41% were taking PPIs:
• 30% of PPIs were pantoprazole
Subjects not taking PPIs Cardiovascular deaths and rehospitalization for myocardial infarction or strokes 26.3% 18.6%
• Any PPI HR=1.29
• Clopidogrel was associated with more adverse outcomes among patients taking PPIs and patient not taking PPIs. The increase due to clopidogrel was the same in both groups.
FAST-MI Registry cohort study[28] 3670 subjects  %  %
"PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles."

References

  1. Anonymous (2015), Proton pump inhibitor (English). Medical Subject Headings. U.S. National Library of Medicine.
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  3. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B (January 2009). "Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel". Am. Heart J. 157 (1): 148.e1–5. DOI:10.1016/j.ahj.2008.09.017. PMID 19081411. Research Blogging.
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  18. Anonymous (11/17/2009) Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC)
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