PPI Trivia What year were PPIs introduced in the U.S.? First PPI - PDF document

9/29/2016 Should we heed the renal failure warnings associated with proton pump inhibitors (PPIs)? Mary Vilay, PharmD (mvilay@salud.unm.edu) NMSHP Balloon Fiesta Symposium October 3, 2016 PPI Trivia • What year were PPIs introduced in the U.S.? • First PPI marketed in the U.S.? • What year did PPIs become available OTC? 1

9/29/2016 76 year old female • HTN – treated with • Experiencing increasing amiloride and HCTZ for generalized malaise, fatigue, several years anorexia x 2 wk • Reflux esophagitis x 1 yr • Patient d/c amiloride and HCTZ x 5 days – Initially treated with famotidine 20 mg daily, but • Presents to hospital developed recurrent • BP 120/60, HR 70 (lying) esophageal ulceration with stricture • BP 84/56; HR 110 (standing) – 6 mo ago, Rx omeprazole 20 • Good skin turgor mg daily, which was increased to 40 mg daily • Moist mucous membranes – Responded well, sx ‐ free x 3 • No skin rashes mo, omeprazole dose • No flank tenderness lowered to 20 mg daily Ruffenack. Am J Med 1992;93:472. 76 year old female • Labs: • Urinalysis: – Hct 33.2% – pH 6.5 – WBC 10.3x10 3 /uL – Specific gravity 1.006 – Na 136 mmol/L – Trace protein – K 4.7 mmol/L – 35 WBCs/hpf – Cl 103 mmol/L – No renal tubular epithelial cells – CO 2 17 mmol/L – No red blood cells – BUN 84 mg/dL (19 mg/dL) – Wright’s stain – 6% – SCr 7.2 mg/dL (1.2 mg/dL) eosinophils – Ca 8.3 mg/dL • Renal Ultrasound – Phosphate 6.1 mg/dL – No hydronephrosis – Albumin 2.9 g/dL Ruffenack. Am J Med 1992;93:472. 2

9/29/2016 PPI associated with a number of adverse effects Could pills for heartburn give you kidney problems? Proton pump inhibitors (PPIs) may come with worrying health effects 3

9/29/2016 Presentation Objectives Pharmacists 1. Describe how PPIs cause acute kidney injury. 2. Evaluate recent studies demonstrating association between PPIs & renal injury. 3. Formulate recommendations about PPI given the recent evidence. Technicians 1. List renal effects associated with PPIs. 2. State limitations of recent studies investigating renal effects of PPIs. 3. Specify alternative medications for PPIs that are not associated with kidney injury. Lazarus B, et al. JAMA Intern Med 2016 Feb; 176(2): 238 ‐ 46 PROTON PUMP INHIBITOR USE AND THE RISK OF CHRONIC KIDNEY DISEASE 4

9/29/2016 Lazarus et al Study Design • Objective: quantify association between PPI use and incident kidney disease in general population • Secondary outcome: evaluate association between PPI use and AKI • Observational cohort study • Data sources – Atherosclerosis in Risk in Communities (ARIC) study – Geisinger Health System Aric Population ‐ based Cohort • 15,792 adults • Participants monitored via: – 45 to 64 years old – Annual telephone survey – Prospectively recruited – Reviewed community • Forsyth, NC hospital discharge lists • Jackson, MS • Suburban Minneapolis, MN – Until Dec. 31, 2011 • Washington County, MD • Deaths identified by: – Telephone survey of alternative contacts – Surveillance of public records: newspaper obituaries, state death lists, & death certificates from Dept of Vital Statistics 5

9/29/2016 Participants for PPI Study = ARIC Study Visit 4 Participants • Visit 4 conducted Feb. 1, 1996 to Jan 30,1999 (N=11,656) • CKD Analysis – ACR first obtained at this visit & few patients took PPI before 1996 – Exclusion: missing eGFR or UACR (n=215); eGFR <60 (CKD ‐ EPI) (n=725) • Missing data for education, health insurance status, cigarette smoking, BMI, mean resting SBP, use of antihypertensive or anticoagulant medications, prevalent hypertension, DM, cardiovascular disease (n=234) – N=10,482 • Dates of study analysis: Feb 1, 1996 to Dec 31, 2011 – Median follow up = 13.9 y Participants for PPI Study = ARIC Study Visit 4 Participants • Visit 4 conducted Feb. 1, 1996 to Jan 30,1999 • Visit 4: N=11,656 • AKI analysis: excluded persons with known ESRD or eGFR <15 – N=11,145 6

9/29/2016 How were outcomes determined? • Incident CKD defined by diagnostic codes that indicated CKD at hospital discharge (ICD ‐ 9) or death (ICD ‐ 10) or by incident ESRD (linkage with USRDS) • Incident AKI defined by hospitalization or death – ICD ‐ 9 & ICD ‐ 10 codes for acute kidney/renal failure • Participants who died before developing CKD, were lost ‐ to follow ‐ up or had disease ‐ free survival were censored Measurement of PPI in ARIC • PPIs and H2RAs measured at baseline visit (Jan 1987 to March 1990) via direct visual inspection of pill bottles for all medication used in the preceding 2 weeks • Subsequent PPI & H2RA exposure obtained during annual telephone follow ‐ up • 2006 onward, participants asked to assemble all medications and to “read names of all medications prescribed by a doctor” • Exposure to other medications similarly measured 7

9/29/2016 Replication Cohort • Geisinger Health System = large rural health care system in central & NE Pennsylvania • Receiving care Feb 13, 1997 to Oct 9, 2014 • Out ‐ patient eGFR ≥ 60 • Selection based on earliest time point with both SCr and SBP available • N=248,751 – Median follow up 6.2 years Geisinger Analysis • Incident CKD = 1 st outpatient eGFR <60 sustained at subsequent eGFR assessments or development ESRD (linkage to USRDS) • Incident AKI = ICD ‐ 9 code and death (linkage to National Death Index) • Individuals who did not develop outcomes censored at last follow ‐ up or death • Medication use determined by prescriber Rx within 90 days before baseline • PPI frequency categorized as daily or BID (assumed to be daily if not specified) • Comorbidities captured by billing codes (in ‐ pt & out ‐ pt) 8

9/29/2016 ARIC Baseline Characteristics Variable PPI Users H2RA Users Non ‐ Users P ‐ value Age 62.8±5.5 63.1±5.5 62.5±5.6 0.008 Male 42.5% 39.3% 44.4% 0.01 White 86% 84.2% 77.9% <0.001 Education ≥ 12 y 81.7% 79.4% 81.8% NS Health Insurance 92.2% 88.9% 85.6% <0.001 Mean eGFR 87.8±13.4 86.5±13.5 88.9±13.1 <0.001 UACR 4 (2 ‐ 7.5) 3.6 (1.8 ‐ 7.1) 3.7 (1.7 ‐ 7.5) NS Cigarette Smoker Current 11.5% 15.5% 15.2% Former 48.4% 44.2% 43.2% NS Never 40.1% 40.3% 41.6% ARIC Baseline Characteristics Variable PPI Users H2RA Users Non ‐ Users P ‐ value Mean BMI 29.4 (5.3) 29.4 (5.8) 28.7( (5.6) <0.001 SBP 126.5±18.3 128.2±18.6 127±18.8 NS HTN 54.3% 50% 44.8% <0.001 DM 14.9% 18% 15.6% NS CVD 13.7% 14.1% 10.9% 0.003 Medications Antihypertensive 55.3% 48.5% 39.9% <0.001 ACE ‐ I/ARB 16.8% 13.4% 12.9% NS Diuretic 16.1% 12.1% 9.6% <0.001 Aspirin 64.9% 67.6% 54.9% <0.001 NSAID 27.6% 32.8% 33.2% NS Statin 20.2% 13.6% 10.3% <0.001 Anticoagulant 1.9% 2.8% 1.7% 0.04 9

9/29/2016 Geisinger Cohort Baseline Characteristics Variable PPI Users H2RA Users Non ‐ Users P ‐ value Age 50.0±15.9 50.3±16.3 49.5±16.3 <0.001 Male 43.2% 42.6% 43.5% NS White 94.6% 96.4% 95.5% <0.001 Education ≥ 12 y NA NA NA NA Health Insurance NA NA NA NA Mean eGFR 94.9±17.7 95.2±18.2 96±18 NA UACR NA NA NA NA Cigarette Smoker Current 25.7% 26.1% 23.9% Former 26.4% 25.4% 23.9% <0.001 Never 47.9% 48.5% 52.2% Geisinger Cohort Baseline Characteristics Variable PPI Users H2RA Users Non ‐ Users P ‐ value Mean BMI 30.8±7.3 30.8±7.4 30.2±7.1 <0.001 SBP 126.4±15.8 128.2±16.7 128±17.7 <0.001 HTN 33.3% 34% 30.2% <0.001 DM 10.8% 9.7% 10.4% NS CVD 11.3% 11.8% 8.7% <0.001 Medications Antihypertensive 32% 31.3% 20.6% <0.001 ACE ‐ I/ARB 15.5% 13.4% 9.6% <0.001 Diuretic 13.8% 12.6% 8.3% <0.001 Aspirin 7.8% 5.9% 3.9% <0.001 NSAID 13.9% 14.4% 9.5% <0.001 Statin 13.9% 11.7% 6.1% <0.001 Anticoagulant 2.5% 2.9% 1.1% <0.001 10

9/29/2016 Prevalence PPI Ever Use Over Time in ARIC Study PPI Use & Risk of Incident CKD ARIC Geisinger (N=10,482) (N=248,751) HR (95% CI) HR (95% CI) Unadjusted baseline PPI use vs non ‐ users 1.45 (1.11 – 1.90) 1.20 (1.15 – 1.26) Adjusted baseline PPI use vs non ‐ users 1.50 (1.14 – 1.96) 1.17 (1.12 – 1.23) Time ‐ varying PPI ever use vs non ‐ users 1.35 (1.17 – 1.55) 1.22 (1.19 – 1.25) Baseline PPI use vs baseline H2RA use 1.39 (1.01 – 1.91) 1.29 (1.19 – 1.14) Baseline PPI use vs propensity score ‐ 1.76 (1.13 – 2.74) 1.16 (1.09 – 1.24) matched non ‐ users Time varying PPI ever use vs never PPI NA 1.24 (1.20 – 1.28) use, excluding baseline PPI users Baseline PPI use vs non ‐ users (excluding 1.45 (1.09 ‐ 1.96) 1.19 (1.113 ‐ 1.25) patients with albuminuria) Negative Control Baseline H2RA use vs non ‐ user 1.15 (0.98 – 1.36) 0.93 (0.88 – 0.99) 11