PROTON PUMP INHIBITOR AND HISTAMINE 2 RECEPTOR ANTAGONIST USE AND VITAMIN B12 DEFICIENCYTamara Lallier, PharmD, MBAPGY-1 Resident PharmacistNortheast Iowa Family Practice CenterWaverly Health Center

ARTICLE INFORMATION Lam J, Schneider JL, Zhao W, Corley DA.

(December 2013) Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency. JAMA 310:22, 2435-2442.

Funding: Kaiser Permanente Community Benefit Grant

BACKGROUND Vitamin B12 deficiency

Dementia, neurologic damage, anemia Risk factors

Chronic alcoholismAtrophic gastritisPernicious anemiaH.pylori infectionLong-term use of biguanidesVegetarian/Vegan diet

.

ACID INHIBITORS Proton pump inhibitors

i.e. esomeprazole, omeprazole Histamine 2 receptor antagonists

i.e. ranitidine, famotidine Suppress gastric acid production

PURPOSE

To study the association between use of PPIs and H2RAs and vitamin B12 deficiency in a community-based setting in the United States

MEASURED OUTCOMES Risk of vitamin B12 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

INCLUSION CRITERIA Case Patients

≥ 18 years old ≥ 1 year Kaiser membership at index date Diagnosed with vitamin B12 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

MEDICATION 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

CONFOUNDING VARIABLES

Other conditions Health care utilization Other commonly used medications

Estrogen, thiazides, ACE-Is, CCB GERD diagnosis Metformin exposure

PATIENT CHARACTERISTICSCharacteristic Cases (%)

(n=25,956)Controls (%) (n=184,199)

Female 14,909 (57.4) 104,850 (56.9)Male 11,047 (42.6) 79,349 (43.1)

Age < 30 747 (2.9) 6620 (3.6)Age 30-69 12,566 (48.4) 94,829 (51.5)Age 70-89 11,674 (45.0) 77,130 (41.9)Age ≥ 90 969 (3.7) 5,530 (3.0)

≥ 2yr PPI use 3,120 (12.0) 13,210 (7.2)≥ 2yr H2RA use 1,087 (4.2) 5,897 (3.2)No acid inhibitor

use21,749 (83.8) 165,092 (89.6)

RESULTS Presence of other risk factors for vitamin B12

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)

HILL’S CRITERIATemporal relationship

StrengthDose-response relationship

ConsistencyPlausibility

Consideration of alternate explanationsExperimentSpecificityCoherence

CONCLUSION

Previous and current gastric acid inhibitor use was significantly associated with the presence of vitamin B12 deficiency.

These findings should be considered when balancing the risks and benefits of using these medications.

STRENGTHS

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

LIMITATIONS

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

CLINICAL RELEVANCE

≥ 2 years of PPIs or H2RAs was associated with vitamin B12 deficiency

Screen symptomatic patients Continue use of these medications for

patients who need them Recommend against higher doses Be aware of symptoms of B12 deficiency

REFERENCES1. Lam J, Schneider JL, Zhao W, Corley DA. (December 2013) Proton Pump

Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 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.

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.

QUESTIONS?PROTON PUMP INHIBITOR AND HISTAMINE 2 RECEPTOR ANTAGONIST USE AND VITAMIN B12 DEFICIENCY

Tamara Lallier, Pharm.D., MBAPGY-1 Resident PharmacistNortheast Iowa Family Practice CenterWaverly Health Center