proton pump inhibitor and histamine 2 receptor antagonist use and vitamin b 12 deficiency

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Proton Pump Inhibitor 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. Article information. - PowerPoint PPT Presentation

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N-3 Fatty Acids and Cardiovascular Outcomes in Patients with Dysglycemia

Proton Pump Inhibitor and histamine 2 receptor antagonist use and vitamin b12 deficiencyTamara Lallier, PharmD, MBAPGY-1 Resident PharmacistNortheast Iowa Family Practice CenterWaverly Health CenterIntroduce myself

This is a topic that touches all of us. I challenge any health care professional to go an entire day without seeing a patient who is on either a PPI or a H2RA. It just wont happen because these medications have a very widespread use In 2012 14.9 million patients received prescriptions for PPIs. That is 5 times the population of the entire state of Iowa and that number does not include H2RAs OR products purchased over the counter. Most of us have friends and family who take these medications, or maybe even we do. Because most have OTC status, we deem them to be safe.

Medications that suppress gastric acid could lead to malabsorption of Vitamin B12 but little data exists regarding the associations between long-ter exposure to these meds and vitamin B12 deficiency in large population based studies.

This study examines whether these medications can cause Vitamin B12 Deficiency.1Article informationLam 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 GrantPrevious studiesSmall groups of elderly patients that have shown inconsistent resultsSome studies have suggested that acid suppressive meds are associated with lower vitamin B12 others found no associationNo large, population-based studies exist examining this topic

Kaiser had no role in the design and conduct of the study or the preparation, review, or approval of the manuscript. 2BackgroundVitamin B12 deficiencyDementia, neurologic damage, anemiaRisk factorsChronic alcoholismAtrophic gastritisPernicious anemiaH.pylori infectionLong-term use of biguanidesVegetarian/Vegan diet

.Vitamin B12 deficiency is relatively common, especially among older adults (because they are at risk for both malabsorption and malnutrition). The National health and Nutrition Examination Survey in 2012 showed that 1 in 31 adults in the U.S. have Vitamin B12 Deficiency. Other studies have indicated this number to be even higher. If not detected, it can lead to potentially serious medical problemsThose include dementia, neurologic damage, anemia, and others.It is important to identify causes especially the modifiable ones where we can make a difference one that should always raise suspicion is a strict, long term vegetarian or vegan diet. Unless it is carefully planned to include vitamin b12 enriched grains, these people rarely get enough vitamin B12 and should be encouraged to take a supplement.

3Acid inhibitorsProton pump inhibitorsi.e. esomeprazole, omeprazoleHistamine 2 receptor antagonistsi.e. ranitidine, famotidineSuppress gastric acid production

Acid inhibitors are among the most commonly used medications in the US.

Gastric acid is required for vitamin b12 absorption. Proton Pump Inhibitors and H2RAs suppress gastric acid productionThis could lead to malabsorption of Vitamin B12

(Gastric acid is required to cleave vitamin B12 from ingested dietary proteins for essential vitamins to be absorbed. It is produced by the same cells that produce intrinsic factor, a compound required for Vitamin B12 absorption. )4PurposeTo study the association between use of PPIs and H2RAs and vitamin B12 deficiency in a community-based setting in the United States5Measured OutcomesRisk of vitamin B12 deficiency after >2 years of PPI or H2RA useOther exposures evaluated:Number of pills/dayDiscontinuation of useDuration of useAgeGenderKnown conditions associated with vitamin B12 deficiency

6Inclusion CriteriaCase Patients 18 years old 1 year Kaiser membership at index dateDiagnosed with vitamin B12 deficiency between 1/97-6/11 Diagnosis: Presence of 1 of the following:Pernicious anemiaOther Vitamin B12 deficiency anemiaVitamin B12 deficiencyVitamin B12 deficiency (listed in the Problem List)Abnormally low value of serum vitamin B12New AND 6 month supply of injectable vitamin B12Control PatientsMax 10 per 1 Case patientThis was a retrospective case-control study within the Kaiser Permanente Northern Caifornia integrated health care system. (They provide comprehensive inpatient and outpatient services for approximately 3.3 million members) (good representation of the Northern California region)

Case PatientsIndex date was first date of diagnosis for vitamin B12 deficiency or the first date of vitamin B12 supplement treatmentUsed ICD-9 diagnosis codes to search for specific diagnoses (1-3)

Control PatientsFor each case patient, up to 10 matched control patients (as available by matched criteria) were randomly selected from the KPNC membership using incidence density sampling (controls are chosen at the time of the case diagnosis) all eligible adult members that lacked a diagnosis of vitamin B12 deficiency at time of case diagnosis(controls were matched by sex, region of home facility, race/ethnicity, age, and Kaiser membership duration)

(IRB status was waived??)7Medication exposureExposure: Days supplied variableExposure duration: time between first and last prescription (+ days supplied for last rx)AdherenceDose intensity< 0.75 pills/day0.75-1.49 pills/day 1.5 pills/dayExposed patient 2-year supply of medication prior to index date

In order to determine if these meds can cause Vitamin B12 deficiency, the exposure status or days of medication over a period of time need to be determined.Used a days supplied variable(Combined pills dispensed with instructions for use)Adherence and dose intensity was evaluated using a mean daily dose with 3 dose categories. Therefore, the dose intensity was not necessarily the dose prescribed. It was the amt of pills/day that ppl actually consumed taking into account dose prescribed and adherence rates.

Exposed H2RA patients could not have a current or prior rx for PPIs. (Index date is date of diagnosis or start of injectable vitamin B12)PPI patients could have prior rx of H2RA bc they are more potent, a lot of pts probably had had prior rxs for H2RA8Confounding variablesOther conditionsHealth care utilizationOther commonly used medicationsEstrogen, thiazides, ACE-Is, CCBGERD diagnosisMetformin exposure

Evaluated by considering other conditions associated with vitamin b12 deficiencyThat is dementia, diabetes,thryoid disease, H pylori infection, alcohol abuse, smoking, atrophic gastritis (used ICD 9 codes)Confounding by health service utilization those who use services more have greater chance of being diagnosed with vitamin b12 deficiency or to receive a prescription for acid inhibitorsOther commonly used medications (if had received 1 or more prescriptions prior to the index date)Compared whether a GERD diagnosis with or without acid inhibitors made a differenceExposed to metformin if had more than 180 day supply in the 500 days prior to the index date

9Patient characteristicsCharacteristicCases (%)(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)There were originally 43,152 cases of vitamin b12 deficiency in the data duration identified but due to exclusions it was narrowed to 25,956.

Cases have Vitamin B12 DeficiencyControls do not have vitamin B12 deficiency

Case patients were predominantly females, 60 years or older (67.2%), and I didnt list it, but of almost 70% non hispanic/ white ethnicity

* Read outloud the numbers for PPI and H2RA use

Again those who used H2RAs could not have any PPI use PPI use could also use H2RAs

Analysis was performed on the cases using conditional logistic regression and standard analytical techniques. The odds ratio was used as an estimate of relative risk. Data was pulled from the electronic health record.10

This table shows the associations between 2 or more years supply of PPIs and Vitamin B12 Deficiency by increasing mean daily dose as well as cumulative duration of use. Across the top you will see the mean daily PPI dosage in pills/day. Keep in mind the daily dose was a measure of both dose and adherence not just prescribed dose. Looking down the table on the left side you will the labels for the various categories for years of usage of PPIs. I drew red circles to kind of show your eyes where to go to find the Odds Ratios in the different rows and columns. Another thing to remember is that patients in the PPI group could have had a previous history of H2RA use. (unclear to me if this was included in the duration of use I dont think it was)-Overall, the Odds Ratio for people with > or equal to 2 years of PPI use across all categories was 1.65, which was significant (does not include 1). This value is not on this table.

Overall, there was a statistically significant increase in the association of vitamin b12 deficiency with use > or equal to 2 years among all PPI users (P 2 years of use across the various categories with a P value 0.38. That is, as we go down the table looking at just the < 0.75 pills/day group it doesnt trend upwards with each increasing duration. This is similar as we look at the other 2 groups of mean daily PPI dosage and look down the column at the years of use. Therefore, all we can say in regards to duration of use is that the risk is increased for PPI use at greater than 2 years of use when comparing users and nonusers.

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