1. P ROTON P UMP I NHIBITOR AND HISTAMINE 2 RECEPTOR ANTAGONIST USE AND VITAMIN B 12 DEFICIENCY Tamara Lallier, PharmD, MBA PGY-1 Resident Pharmacist Northeast Iowa Family Practice Center Waverly Health Center

2. A RTICLE INFORMATION Lam J, Schneider JL, Zhao W, Corley DA. (December 2013) Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B 12 Deficiency. JAMA 310 :22, 2435- 2442. Funding: Kaiser Permanente Community Benefit Grant

3. B ACKGROUND Vitamin B 12 deficiency Dementia, neurologic damage, anemia Risk factors Chronic alcoholism Atrophic gastritis Pernicious anemia H.pylori infection Long-term use of biguanides Vegetarian/Vegan diet.

4. A CID INHIBITORS Proton pump inhibitors i.e. esomeprazole, omeprazole Histamine 2 receptor antagonists i.e. ranitidine, famotidine Suppress gastric acid production

5. P URPOSE To study the association between use of PPIs and H 2 RAs and vitamin B 12 deficiency in a community-based setting in the United States

6. M EASURED O UTCOMES Risk of vitamin B 12 deficiency after >2 years of PPI or H2RA use Other exposures evaluated: Number of pills/day Discontinuation of use Duration of use Age Gender Known conditions associated with vitamin B12 deficiency

7. I NCLUSION C RITERIA Case Patients ≥ 18 years old ≥ 1 year Kaiser membership at index date Diagnosed with vitamin B 12 deficiency between 1/97- 6/11 Diagnosis: Presence of 1 of the following: Pernicious anemia Other Vitamin B12 deficiency anemia Vitamin B12 deficiency Vitamin B12 deficiency (listed in the Problem List) Abnormally low value of serum vitamin B12 New AND ≥ 6 month supply of injectable vitamin B12 Control Patients Max 10 per 1 Case patient

8. M EDICATION EXPOSURE Exposure: “Days supplied” variable Exposure duration: time between first and last prescription (+ days supplied for last rx) Adherence Dose intensity < 0.75 pills/day 0.75-1.49 pills/day ≥ 1.5 pills/day “Exposed” patient ≥ 2-year supply of medication prior to index date

9. C ONFOUNDING VARIABLES Other conditions Health care utilization Other commonly used medications Estrogen, thiazides, ACE-Is, CCB GERD diagnosis Metformin exposure

10. P ATIENT CHARACTERISTICS CharacteristicCases (%) (n=25,956) Controls (%) (n=184,199) Female14,909 (57.4)104,850 (56.9) Male11,047 (42.6)79,349 (43.1) Age < 30747 (2.9)6620 (3.6) Age 30-6912,566 (48.4)94,829 (51.5) Age 70-8911,674 (45.0)77,130 (41.9) Age ≥ 90969 (3.7)5,530 (3.0) ≥ 2yr PPI use3,120 (12.0)13,210 (7.2) ≥ 2yr H2RA use1,087 (4.2)5,897 (3.2) No acid inhibitor use21,749 (83.8)165,092 (89.6)

14. R ESULTS Presence of other risk factors for vitamin B 12 deficiency None: OR 1.65 (95% CI 1.43-1.91) ≥ 1 risk factor: OR 1.50 (95% CI 1.42-1.58) Age <30 years: OR 8.12 (95% CI 3.36-19.59) > 80 years: OR 1.04 (95% CI 0.96-1.13) Gender Female: OR 1.84 (95% CI 1.74-1.95) Male: OR 1.43 (95% CI 1.33-1.53) Race/Ethnicity No significant interaction (P=0.18)

16. H ILL ’ S CRITERIA Temporal relationship Strength Dose-response relationship Consistency Plausibility Consideration of alternate explanations Experiment Specificity Coherence

17. C ONCLUSION Previous and current gastric acid inhibitor use was significantly associated with the presence of vitamin B 12 deficiency. These findings should be considered when balancing the risks and benefits of using these medications.

18. S TRENGTHS Large size 15 years of data Retrieval of all recorded diagnoses Data for dispensed medication Generalizable control group Ability to evaluate several confounders

19. L IMITATIONS Case-control study Asymptomatic screening for patients No information on short-term or intermittent use Mean daily dose OTC product use Study location not generalizable

20. C LINICAL R ELEVANCE ≥ 2 years of PPIs or H2RAs was associated with vitamin B 12 deficiency Screen symptomatic patients Continue use of these medications for patients who need them Recommend against higher doses Be aware of symptoms of B 12 deficiency

21. R EFERENCES 1. Lam J, Schneider JL, Zhao W, Corley DA. (December 2013) Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B 12 Deficiency. JAMA 310 :22, 2435-2442. 2. Evatt MLMP, Bobo JK, Kimmons J, Williams J. Why Vitamin B12 Deficiency Should be on Your Radar Screen. Centers for Disease Control and Prevention website. http://www.cdc.gov/ncbddd/b12/index.html. Accessed February 18, 2014. http://www.cdc.gov/ncbddd/b12/index.html 3. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risks of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004;57(4):422-428.

22. QUESTIONS? P ROTON P UMP I NHIBITOR AND HISTAMINE 2 RECEPTOR ANTAGONIST USE AND VITAMIN B 12 DEFICIENCY Tamara Lallier, Pharm.D., MBA PGY-1 Resident Pharmacist Northeast Iowa Family Practice Center Waverly Health Center