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

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, Funding: Kaiser Permanente Community Benefit Grant

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.

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

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

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

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

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 pills/day ≥ 1.5 pills/day “Exposed” patient ≥ 2-year supply of medication prior to index date

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

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 < (2.9)6620 (3.6) Age ,566 (48.4)94,829 (51.5) Age ,674 (45.0)77,130 (41.9) Age ≥ (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)

R ESULTS Presence of other risk factors for vitamin B 12 deficiency None: OR 1.65 (95% CI ) ≥ 1 risk factor: OR 1.50 (95% CI ) Age <30 years: OR 8.12 (95% CI ) > 80 years: OR 1.04 (95% CI ) Gender Female: OR 1.84 (95% CI ) Male: OR 1.43 (95% CI ) Race/Ethnicity No significant interaction (P=0.18)

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

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.

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

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

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

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, 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. Accessed February 18, 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):

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