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 undering 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 (2024), Proton pump inhibitor (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. ↑ 2.0 2.1 Li XQ, Andersson TB, Ahlström M, Weidolf L (2004). "Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities.". Drug Metab Dispos 32 (8): 821-7. PMID 15258107.
  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.
  4. ↑ Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D (2006). "Pharmacological interventions for non-ulcer dyspepsia.". Cochrane Database Syst Rev (4): CD001960. DOI:10.1002/14651858.CD001960.pub3. PMID 17054151. Research Blogging. Review in: Evid Based Med. 2007 Jun;12(3):79
  5. ↑ van Pinxteren B, Numans ME, Bonis PA, Lau J (2006). "Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease.". Cochrane Database Syst Rev 3: CD002095. DOI:10.1002/14651858.CD002095.pub3. PMID 16855986. Research Blogging.
  6. ↑ Pace F, Tonini M, Pallotta S, Molteni P, Porro GB (2007). "Systematic review: maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken 'on-demand'.". Aliment Pharmacol Ther 26 (2): 195-204. DOI:10.1111/j.1365-2036.2007.03381.x. PMID 17593065. Research Blogging. Review in: Evid Based Med. 2007 Dec;12(6):177 Review in: ACP J Club. 2007 Nov-Dec;147(3):69
  7. ↑ Bardhan KD, Müller-Lissner S, Bigard MA, Bianchi Porro G, Ponce J, Hosie J et al. (1999). "Symptomatic gastro-oesophageal reflux disease: double blind controlled study of intermittent treatment with omeprazole or ranitidine. The European Study Group.". BMJ 318 (7182): 502-7. PMID 10024259. PMC PMC27748.
  8. ↑ Khan M, Santana J, Donnellan C, Preston C, Moayyedi P (2007). "Medical treatments in the short term management of reflux oesophagitis.". Cochrane Database Syst Rev (2): CD003244. DOI:10.1002/14651858.CD003244.pub2. PMID 17443524. Research Blogging.
  9. ↑ Massó González EL, García Rodríguez LA (2008). "Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study.". Aliment Pharmacol Ther 28 (5): 629-37. DOI:10.1111/j.1365-2036.2008.03780.x. PMID 18616644. Research Blogging.
  10. ↑ Bajaj JS, Zadvornova Y, Heuman DM, et al. (May 2009). "Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites". Am. J. Gastroenterol. 104 (5): 1130–4. DOI:10.1038/ajg.2009.80. PMID 19337238. Research Blogging.
  11. ↑ Sarkar M, Hennessy S, Yang YX (2008). "Proton-pump inhibitor use and the risk for community-acquired pneumonia.". Ann Intern Med 149 (6): 391-8. PMID 18794558.
  12. ↑ Herzig SJ, Howell MD, Ngo LH, Marcantonio ER (2009). "Acid-suppressive medication use and the risk for hospital-acquired pneumonia.". JAMA 301 (20): 2120-8. DOI:10.1001/jama.2009.722. PMID 19470989. Research Blogging.
  13. ↑ Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA (2010). "Proton pump inhibitors and risk for recurrent Clostridium difficile infection.". Arch Intern Med 170 (9): 772-8. DOI:10.1001/archinternmed.2010.73. PMID 20458084. Research Blogging.
  14. ↑ Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE et al. (2010). "Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative.". Arch Intern Med 170 (9): 765-71. DOI:10.1001/archinternmed.2010.94. PMID 20458083. Research Blogging.
  15. ↑ 15.0 15.1 Reimer C, Søndergaard B, Hilsted L, Bytzer P (2009). "Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy.". Gastroenterology 137 (1): 80-7, 87.e1. DOI:10.1053/j.gastro.2009.03.058. PMID 19362552. Research Blogging. Cite error: Invalid <ref> tag; name "pmid19362552" defined multiple times with different content
  16. ↑ Wohlt PD, Hansen LA, Fish JT (2007). "Inappropriate continuation of stress ulcer prophylactic therapy after discharge.". Ann Pharmacother 41 (10): 1611-6. DOI:10.1345/aph.1K227. PMID 17848420. Research Blogging.
  17. ↑ Anonymous. (2009) Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix)
  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)
  19. ↑ 19.0 19.1 19.2 Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV et al. (2009). "A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.". CMAJ 180 (7): 713-8. DOI:10.1503/cmaj.082001. PMID 19176635. PMC PMC2659819. Research Blogging. Review in: Ann Intern Med. 2009 Aug 18;151(4):JC2-13 Review in: Evid Based Med. 2009 Oct;14(5):154
  20. ↑ American College of Cardiology Foundation Task Force on Expert Consensus Documents. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ et al. (2010). "ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use.". J Am Coll Cardiol 56 (24): 2051-66. DOI:10.1016/j.jacc.2010.09.010. PMID 21126648. Research Blogging.
  21. ↑ 21.0 21.1 Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ et al. (2010). "Clopidogrel with or without omeprazole in coronary artery disease.". N Engl J Med 363 (20): 1909-17. DOI:10.1056/NEJMoa1007964. PMID 20925534. Research Blogging.
  22. ↑ 22.0 22.1 Stockl, Karen M.; Lisa Le, Armen Zakharyan, Ann S. M. Harada, Brian K. Solow, Joseph E. Addiego, Scott Ramsey (2010-04-26). "Risk of Rehospitalization for Patients Using Clopidogrel With a Proton Pump Inhibitor". Arch Intern Med 170 (8): 704-710. DOI:10.1001/archinternmed.2010.34. Retrieved on 2010-04-27. Research Blogging.
  23. ↑ 23.0 23.1 Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K et al. (2010). "Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study.". Ann Intern Med 152 (6): 337-45. DOI:10.1059/0003-4819-152-6-201003160-00003. PMID 20231564. Research Blogging.
  24. ↑ 24.0 24.1 Ho PM, Maddox TM, Wang L, et al. (March 2009). "Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome". JAMA 301 (9): 937–44. DOI:10.1001/jama.2009.261. PMID 19258584. Research Blogging.
  25. ↑ 25.0 25.1 O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y et al. (2009). "Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials.". Lancet 374 (9694): 989-97. DOI:10.1016/S0140-6736(09)61525-7. PMID 19726078. Research Blogging.
  26. ↑ 26.0 26.1 Stanek EJ et al. (2009) A National Study of the Effect of Individual Proton Pump Inhibitors on Cardiovascular Outcomes in Patients Treated with Clopidogrel Following Coronary Stenting: The Clopidogrel Medco Outcomes Study Society for Cardiovascular Angiography and Interventions 2009 Annual Meeting
  27. ↑ 27.0 27.1 Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ et al. (2010). "Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study.". Ann Intern Med 153 (6): 378-86. DOI:10.1059/0003-4819-153-6-201009210-00005. PMID 20855802. Research Blogging.
  28. ↑ 28.0 28.1 Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen M et al. (2011). "Clinical Events as a Function of Proton Pump Inhibitor Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide Cohort of Acute Myocardial Infarction: Results From the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Registry.". Circulation 123 (5): 474-82. DOI:10.1161/CIRCULATIONAHA.110.965640. PMID 21262992. Research Blogging.
  29. ↑ Ho PM, Fihn SD, Wang L, Bryson CL, Lowy E, Maynard C et al. (2007). "Clopidogrel and long-term outcomes after stent implantation for acute coronary syndrome.". Am Heart J 154 (5): 846-51. DOI:10.1016/j.ahj.2007.08.028. PMID 17967588. Research Blogging.
  30. ↑ Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. (2009). "Cytochrome p-450 polymorphisms and response to clopidogrel.". N Engl J Med 360 (4): 354-62. DOI:10.1056/NEJMoa0809171. PMID 19106084. Research Blogging.
  31. ↑ Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S et al. (2007). "Prasugrel versus clopidogrel in patients with acute coronary syndromes.". N Engl J Med 357 (20): 2001-15. DOI:10.1056/NEJMoa0706482. PMID 17982182. Research Blogging.
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